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by Copyright Brandon Lee Ashfeld 2004 The Dissertation Committee for Brandon Lee Ashfeld Certifies that this is the approved version of the following dissertation: An Enantioselective Total Synthesis of Tremulenediol A and Tremulenolide A and Development of the [Rh(CO)2Cl]2-Catalyzed Direct, Stereoselective Allylic Alkylation of Unsymmetrical Substrates Committee: Stephen F. Martin, Supervisor Philip D. Magnus Nathan L. Bauld Dean R. Appling Christian P. Whitmann An Enantioselective Total Synthesis of Tremulenediol A and Tremulenolide A and Development of the [Rh(CO)2Cl]2-Catalyzed Direct, Stereoselective Allylic Alkylation of Unsymmetrical Substrates by Brandon Lee Ashfeld, B.S. Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin December, 2004 Dedication This dissertation is dedicated to the one person who stood by me with undying support throughout the course of this work. Helping in more ways than I could have imagined. All the while constantly reminding me to breathe. To my loving wife, Leea Acknowledgements Special thanks goes first and foremost to my Mom and Dad who, without their constant encouragement, I may not have been able to achieve nearly as much as I have. I would also like to thank Professor Stephen F. Martin for the guidance and support that he has given me throughout this journey. For introducing me to the science of synthetic chemistry and mentoring me through my early years as a scientist I thank Dr. Andrew S. Judd and Professor Thomas R. Hoye. Finally I would like to thank my fellow Martin Group members, both past and present, with which I have had the distinct honor to call my coworkers. Without the guidance, support and overall friendship of my colleagues at the University of Texas at Austin I would not be the chemist or the person I am today. v An Enantioselective Total Synthesis of Tremulenediol A and Tremulenolide A and Development of the [Rh(CO)2Cl]2-Catalyzed Direct, Stereoselective Allylic Alkylation of Unsymmetrical Substrates Publication No._____________ Brandon Lee Ashfeld, Ph. D. The University of Texas at Austin, 2004 Supervisor: Stephen F. Martin A method for the enantioselective construction of the [5.3.0] bicyclic carbon skeleton present in the tremulane sesquiterpenes is described. The route incorporates an enantioselective rhodium(II)-catalyzed intramolecular cyclopropanation that sets the stage for a diastereoselective rhodium(I)-catalyzed [5+2] cycloaddition as an efficient approach to the tremulane natural products tremulenediol A and tremulenolide A. The use of rhodium(I)-catalyzed carbocyclization and allylic alkylation transformations was likewise explored. To that end, a novel regio- and stereoselective [Rh(CO)2Cl]2- catalyzed allylic alkylation of unsymmetrical allylic carbonates was discovered. The regioselectivity favors product ratios in which the major product arises from substitution vi at the carbon that previously bore the allylic leaving group by the malonate nucleophile. When an enantiomerically enriched carbonate ( 99% ee) was examined, the Rh(I)catalyzed allylic alkylation proceeded stereoselectively to provide the alkylation product with retention of absolute stereochemistry (98% ee). To establish the scope of the [Rh(CO)2Cl]2-catalyzed allylic alkylation, a variety of carbon and heteroatom nucleophiles were examined and the results described. A series of unsymmetrical allylic carbonates were treated with the sodium salts of various substituted malonates, b-ketoesters and sulfones in the presence of [Rh(CO)2Cl]2 to provide the corresponding direct substitution products in good yield and with excellent regioselectivity. Preliminary studies were conducted to include allylic etherifications utilizing sterically hindered phenols and aminations of unsymmetrical carbonates with Nalkylated sulfonamides. As an application of the rhodium(I)-catalyzed allylic alkylation, a series of novel domino reactions have been invented that involve the regioselective and stereoselective [Rh(CO)2Cl]2-catalyzed alkylation of allylic trifluoroacetates with the a-substituted sodiomalonates followed by either an intramolecular Pauson-Khand annulation, a cycloisomerization, or a [5+2] cycloaddition. A unique aspect of the method described is the use of a single catalyst to effect sequential transformations in which the catalytic activity is moderated simply by controlling the reaction temperature. This strategy thus provides a rapid and efficient entry into a variety of bicyclic carbon skeletons. vii Table of Contents List of Tables....................................................................................................xiii List of Figures...................................................................................................xvi List of Schemes................................................................................................xvii Chapter 1. Transition Metals in Organic Synthesis ........................................1 1.A Introduction........................................................................................1 1.B Transition Metal-Catalyzed Allylic Alkylations ..................................4 1.B.1 Introduction ...............................................................................4 1.B.2 Overview ...................................................................................7 1.B.2.1 Breadth of Nucleophiles Employed in the Transition Metal-Catalyzed Allylic Alkylation ...................................9 1.B.2.2 Diastereoselectivity...................................................12 1.B.2.3 Regioselectivity ........................................................13 1.B.3 Palladium-Catalyzed Allylic Alkylations..................................15 1.B.3.1 Regiochemistry .........................................................16 1.B.3.2 Stereoselectivity........................................................20 1.B.3.3 Olefin Geometry .......................................................22 1.B.3.4 Summary ..................................................................24 1.B.4 Molybdenum-Catalyzed Allylic Alkylations ............................24 1.B.4.1 Regioselectivity .......................................................25 1.B.4.2 Stereoselectivity........................................................30 1.B.4.3 Geometric Selectivity................................................35 1.B.4.4 Summary ..................................................................38 1.B.5 Iridium-Catalyzed Allylic Alkylations......................................38 1.B.5.1 Regioselectivity ........................................................39 1.B.5.2 Olefin Geometry .......................................................43 1.B.5.3 Summary ..................................................................45 1.B.6 Ruthenium- and Tungsten-Catalyzed Allylic Alkylations.........45 viii 1.B.6.1 Tungsten-Catalyzed Substitution Reactions...............46 1.B.6.2 Ruthenium-Catalyzed Allylic Substitutions...............48 1.B.7 Rhodium-Catalyzed Allylic Alkylation ....................................50 1.B.7.1 Regioselectivity ........................................................51 1.B.7.2 Stereoselectivity........................................................57 1.B.7.3 Summary ..................................................................59 1.B.8 The Transition Metal-Catalyzed Enantioselective Allylic Alkylation................................................................................60 1.B.9 Overall Summary of Section 1.B..............................................62 1.C Transition Metal-Catalyzed Carbocyclization Reactions ...................64 1.C.1 Introduction .............................................................................64 1.C.2 Transition Metal-Mediated Asymmetric Cyclopropanation Reactions .................................................................................65 1.C.2.1 Intermolecular Cyclopropanations.............................69 1.C.2 Intramolecular Cyclopropanations............................................78 1.C.2.3 The Origin of Diastereo- and Enantioselection in the Intramolecular Asymmetric Cyclopropanation of a-Diazoesters with Chiral Rhodium(II) Catalysts...................................83 1.C.3 The Transition Metal-Catalyzed [5+2] Cycloaddition of Alkynes and Vinyl Cyclopropanes................................................................89 1.C.3.1 The First Transition Metal-Catalyzed Intramolecular [5+2] Cycloadditions ................................................................93 1.C.3.2 Regio- and Stereoselectivity in the Rhodium(I)-Catalyzed Intramolecular [5+2] Cycloaddition of Cyclopropyl Enynes ............................................................................96 1.C.3.3 Ruthenium-Catalyzed Intramolecular [5+2] Cycloadditions .............................................................. 106 1.C.3.4 The Transition Metal-Catalyzed Intermolecular [5+2] Cycloaddition................................................................ 109 1.C.3.5 Summary ................................................................ 112 1.C.4 The Transition Metal-Catalyzed Pauson-Khand Annulation ... 112 1.C.4.1 Titanium-Catalyzed Pauson-Khand Annulations ..... 115 ix 1.C.4.2 Ruthenium- and Rhodium-Catalyzed Pauson-Khand Reactions....................................................................... 116 1.C.4.3 The Enantioselective Pauson-Khand Reaction......... 117 1.C.4.4 Alternative [2+2+1] Cycloaddition Substrates: The Allenic and Dienyl Pauson-Khand Type Reactions........ 121 1.C.5 Transition Metal-Catalyzed Cycloisomerizations ................... 123 1.C.5.1 Palladium-Catalyzed Cycloisomerizations .............. 124 1.C.5.2 Ruthenium-Catalyzed Cycloisomerizations ............. 126 1.C.5.3 Rhodium- and Iridium-Catalyzed Cycloisomerizations ...................................................... 127 1.C.5.4 Mechanistic Discussion of the Transition Metal-Catalyzed Cycloisomerization of 1,6-Enynes ................................. 128 1.C.6 Transition Metal-Catalyzed Domino Reactions Which Incorporate a Carbocyclization Event .......................................................... 131 1.C.7 Overall Summary of Section 1.C............................................ 136 1.D Chapter 1 Conclusions .................................................................... 136 Chapter 2. Enantioselective Total Synthesis of Tremulenediol A and Tremulenolide A.................................................................................... 139 2.1 Introduction.................................................................................... 139 2.2 Davies Total Synthesis of Tremulenolide A and Tremulenediol A............................................................................. 141 2.3 1st Generation Strategy Toward The Total Synthesis of Tremulenolide A and Tremulenediol A ...................................................................... 149 2.4 2nd Generation Approach Involving a Transition Metal-Catalyzed Allylic Alkylation....................................................................................... 161 2.5 Conclusions .................................................................................... 180 Chapter 3. [Rh(CO)2Cl]2-Catalyzed Allylic Alkylations ............................. 182 3.1 Introduction.................................................................................... 182 3.2 [Rh(CO)2Cl]2-Catalyzed Direct Substitution of Simple Unsymmetrical Carbonates with Dimethyl Malonate............................................... 187 3.2.1 Optimizing Condition for the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation.............................................................................. 187 x 3.2.2 [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation of Unsymmetrical Primary Carbonates with Dimethyl Malonate......................... 195 3.2.3 [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation of Unsymmetrical Secondary and Tertiary Carbonates with Dimethyl Malonate................................................................................ 200 3.2.4 Summary of the Regiochemical Trends Observed in the Alkylation of Simple Allylic Carbonates with Dimethyl Malonate Catalyzed by [Rh(CO)2Cl]2 ......................................................................... 205 3.2.5 Conservation of Absolute Stereochemistry in the [Rh(CO)2Cl]2Catalyzed Allylic Alkylation of Enantioenriched Secondary Allylic Carbonates ............................................................................. 209 3.2.6 The Scope with which the Z-Geometry is Maintained in the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation of Z-Allyl Carbonates ............................................................................. 214 3.2.7 Attempts at Developing an Asymmetric [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation .................................................................. 218 3.3 [Rh(CO)2Cl]2-Catalyzed Allylic Alkylations with a-Substituted Malonates and b-Ketoesters............................................................................. 221 3.3.1 Utilizing a-Substituted Malonates as Pronucleophiles in the [Rh(CO)2Cl]2-Catalyzed Allylic Substitution Reaction ........... 222 3.3.2 Utilizing b-Ketoesters as Pronucleophiles in the [Rh(CO)2Cl]2catalyzed Allylic Substitution Reaction.................................. 229 3.4 Heteroatom Nucleophiles................................................................ 231 3.3.1 [Rh(CO)2Cl]2-Catalyzed Allylic Etherifications...................... 232 3.3.2 [Rh(CO)2Cl]2-Catalyzed Allylic Aminations .......................... 234 3.5 Utilizing Hard Nucleophiles in [Rh(CO)2Cl]2-Catalyzed Allylic Alkylations ..................................................................................... 237 3.6 Intramolecular [Rh(CO)2Cl]2-Catalyzed Allylic Alkylations for the Synthesis of Medium-Sized Rings .................................................. 240 3.7 Applications to Domino Processes .................................................. 242 3.7.1 Development of the Domino [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation/Pauson-Khand Annulation.................................... 244 3.7.2 Development of the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation/Cycloisomerization Reaction ................................ 247 xi 3.7.3 A Novel [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation/Intramolecular [5+2] Cycloaddition............................................................... 248 3.8 Conclusions .................................................................................... 253 Chapter 4. Experimental Procedures........................................................... 256 4.1 General........................................................................................... 256 4.2 Compounds .................................................................................... 257 References ...................................................................................................... 398 Vita ................................................................................................................ 433 xii List of Tables Table 1b.1. Regioselectivity in the palladium-catalyzed allylic alkylation. .......17 Table 1b.2. Regioselectivity in the molybedenum-catalyzed allylic alkylation..27 Table 1b.3. Selectivity in the iridium-catalyzed allylic alkylation of 1b.103. ....41 Table 1b.4. Selectivity in the iridium-catalyzed allylic alkylation of 1b.106 and 1b.107. ..........................................................................................42 Table 1b.5. Z-Selectivity in the iridium-catalyze allylic alkylation of 1b.116. ..........................................................................................44 Table 1b.6. Regioselectivity in the ruthenium-catalyzed allylic alkylation of 1b.126. ..........................................................................................49 Table 1b.7. Regioselectivity in the RhCl(PPh3)3/(POMe)3-catalyzed allylic alkylation.......................................................................................54 Table 1c.1. Enantioselective rhodium(II)-catalyzed intermolecular cyclopropanation. ..........................................................................77 Table 1c.2. Enantioselective intramolecular cyclopropanation of diazoacetamide 1c.118............................................................................................87 Table 1c.3. Asymmetric intramolecular cyclopropanation of vinyl diazoacetate 1c.120............................................................................................88 Table 1c.4. Asymmetric intramolecular cyclopropanation of aryl diazoacetate 1c.122............................................................................................89 Table 1c.5. The [5+2] cycloaddition of trans-2-substituted-1vinylcyclopropanes. ..................................................................... 102 Table 1c.6. The [5+2] cycloaddition of cis-2-substituted-1vinylcyclopropanes. ..................................................................... 103 xiii Table 1c.7. PKR catalyzed under CO-free conditions..................................... 116 Table 1c.8. Ruthenium- and rhodium-catalyzed Pauson-Khand reaction ........ 117 Table 1c.9. Asymmetric Rh(I)-catalyzed Pauson-Khand reaction ................... 120 Table 2.1. Table 2.2. Protecting Groups Analyzed for Propargyl Alcohol (2.41) ........... 157 Bromination Attempts from the Corresponding Tertiary Bromide....................................................................................... 159 Table 2.3. Palladium-catalyzed allylic alkylation of cyclopropyl lactone 2.8a .................................................................................. 168 Table 2.3. Table 2.4. Table 2.5. Principle NMR spectral data for cycloadduct 2.61........................ 171 Attempted carboxylic acid reduction of compound 2.61............... 173 Conditions explored in the attempted [5+2] cycloaddition of enyne 2.56.a ................................................................................. 176 Table 3.1. Solvent effects on the [Rh(CO)2Cl]2-Catalyzed Allylic Substitution Reaction of Carbonate 3.14a with Sodiodimethyl Malonatea ........ 189 Table 3.2. Effect of Catalyst Loading on the [Rh(CO)2Cl]2-Catalyzed Allylic Substitution Reaction of Carbonate 3.14a with Sodiodimethyl Malonatea..................................................................................... 190 Table 3.3. Effect of Varying the Reaction Concentration on the [Rh(CO)2Cl]2Catalyzed Allylic Substitution Reaction of Carbonate 3.14a with Sodiodimethyl Malonate.............................................................. 191 Table 3.4. Regioselectivity in the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation of Unsymmetrical Primary Carbonatesa ............................................ 198 Table 3.5. [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation of 2 and 3 Carbonatesa .................................................................................. 202 xiv Table 3.6. Regioselectivity in the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation Reaction Utilizing a-Substituted Malonate 3.86a.......................... 225 Table 3.7. Regioselectivity in the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation Reaction Utilizing a-Substituted Malonate 3.87a.......................... 227 Table 3.8. Regioselectivity in the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation Reaction Utilizing a-Substituted Malonate 3.88a.......................... 228 Table 3.9. Regioselectivity in the [Rh(CO)2Cl]2-Catalyzed Allylic Amination of Carbonate 3.14aa.......................................................................... 236 xv List of Figures Figure 1b.1. Nomenclature for substituents on -allyl intermediates. .................21 Figure 1b.2. Proposed transition states for the observed diastereoselectivity in Eq. 1b.25 .............................................................................................58 Figure 1b.3. Chiral ligands employed in asymmetric allylic alkylations. ............61 Figure 1c.1. Typical a-diazo reagents used in intermolecular cyclopropanations. .........................................................................69 Figure 1c.2. Chiral Catalysts Used for the Asymmetric Cyclopropanation of Styrene ..........................................................................................72 Figure 1c.3. Carbene-bound transition metal geometries....................................73 Figure 1c.4. Chiral dirhodium(II) carboxylate ligands for asymmetric cyclopropanations. .........................................................................75 Figure 1c.5. Chiral dirhodium(II) carboxamidate ligands...................................76 Figure 1c.6. Model for stereocontrol observed in the dirhodium(II)-catalyzed cyclopropanations. .........................................................................78 Figure 1c.7. Structures and proposed substrate approach in the Rh2[5(S)-MEPY]4Rh2[5(R)-MEPY]4-catalyzed cyclopropanations .............................84 Figure 2.1. Tremulane Sesquiterpenes and Related Natural Products ............. 140 Figure 3.1. Relative influence of allylic and homoallylic substitution on regioselectivity. ........................................................................... 207 Figure 3.2. Substrate types for enantioselective allylic alkylations ................. 219 Figure 3.3. Alcohols examined in the [Rh(CO)2Cl]2-catalyzed allylic etherification reaction........................................................................................ 233 xvi List of Schemes Scheme 1b.1 Scheme 1b.2 Scheme 1b.3 Scheme 1b.4 Scheme 1b.5 Scheme 1b.6 Scheme 1b.7 Scheme 1b.8 Scheme 1b.9 Scheme 1b.10 Scheme 1b.11 Scheme 1b.12 Scheme 1b.13 Scheme 1b.14 Scheme 1b.15 Scheme 1c.1 Scheme 1c.2 Scheme 1c.3 Scheme 1c.4 Scheme 1c.5 Scheme 1c.6 Scheme 1c.7 Scheme 1c.8 ..................................................................................................5 ..................................................................................................6 ..................................................................................................7 ................................................................................................10 ................................................................................................13 ................................................................................................15 ................................................................................................22 ................................................................................................23 ................................................................................................29 ................................................................................................30 ................................................................................................33 ................................................................................................35 ................................................................................................37 ................................................................................................56 ................................................................................................61 ................................................................................................65 ................................................................................................66 ................................................................................................67 ................................................................................................68 ................................................................................................70 ................................................................................................86 ................................................................................................95 ................................................................................................99 xvii Scheme 1c.9 Scheme 1c.10 Scheme 1c.11 Scheme 1c.12 Scheme 1c.13 Scheme 1c.14 Scheme 1c.15 Scheme 1c.16 Scheme 1c.17 Scheme 1c.18 Scheme 1c.19 Scheme 1c.20 Scheme 1c.21 Scheme 1c.22 Scheme 2.1 Scheme 2.2 Scheme 2.3 Scheme 2.4 Scheme 2.5 Scheme 2.6 Scheme 2.7 Scheme 2.8 Scheme 2.9 Scheme 2.10 Scheme 2.11 .............................................................................................. 100 .............................................................................................. 105 .............................................................................................. 107 .............................................................................................. 109 .............................................................................................. 110 .............................................................................................. 111 .............................................................................................. 118 .............................................................................................. 121 .............................................................................................. 122 .............................................................................................. 124 .............................................................................................. 127 .............................................................................................. 130 .............................................................................................. 131 .............................................................................................. 134 .............................................................................................. 141 .............................................................................................. 142 .............................................................................................. 143 .............................................................................................. 144 .............................................................................................. 145 .............................................................................................. 146 .............................................................................................. 146 .............................................................................................. 148 .............................................................................................. 151 .............................................................................................. 152 .............................................................................................. 155 xviii Scheme 2.11 Scheme 2.12 Scheme 2.13 Scheme 2.14 Scheme 2.15 Scheme 2.16 Scheme 2.17 Scheme 3.1 Scheme 3.1 Scheme 3.2 Scheme 3.3 Scheme 3.4 Scheme 3.5 Scheme 3.6 Scheme 3.7 Scheme 3.8 Scheme 3.9 Scheme 3.10 Scheme 3.11 Scheme 3.12 Scheme 3.13 Scheme 3.14 Scheme 3.15 Scheme 3.16 Scheme 3.17 .............................................................................................. 160 .............................................................................................. 162 .............................................................................................. 164 .............................................................................................. 175 .............................................................................................. 177 .............................................................................................. 179 .............................................................................................. 180 .............................................................................................. 183 .............................................................................................. 184 .............................................................................................. 186 .............................................................................................. 194 .............................................................................................. 196 .............................................................................................. 196 .............................................................................................. 201 .............................................................................................. 201 .............................................................................................. 206 .............................................................................................. 209 .............................................................................................. 210 .............................................................................................. 211 .............................................................................................. 212 .............................................................................................. 214 .............................................................................................. 216 .............................................................................................. 217 .............................................................................................. 220 .............................................................................................. 220 xix Scheme 3.18 Scheme 3.19 Scheme 3.20 Scheme 3.21 Scheme 3.22 Scheme 3.23 Scheme 3.24 Scheme 3.25 .............................................................................................. 223 .............................................................................................. 223 .............................................................................................. 237 .............................................................................................. 241 .............................................................................................. 242 .............................................................................................. 244 .............................................................................................. 252 .............................................................................................. 252 xx Chapter 1. Transition Metals in Organic Synthesis 1.A INTRODUCTION Over the past century, organic synthesis has evolved into one of the key scientific disciplines responsible for technological advances ranging in scope from materials to biological sciences. Although the development of synthetic methods continues to modernize the science which thereby contributes significantly to the standard of living enjoyed by much of the world today, organic synthesis is far from being fully developed. Issues receiving increased attention as of late to further advance the organic chemistry include atom economic transformations and optimizing synthetic efficiency. These efforts have focused primarily on utilizing transition metal catalysts to facilitate usually indiscriminate or unconventional reaction processes to proceed in a selective facile manner. Through the use of transition metals to mediate organic reactions, one can stabilize otherwise highly reactive intermediates thereby rendering them efficient synthetic reagents, alter normal reactivity patterns of functional groups by making nucleophilic species electrophilic and vice versa, and allow for unprecedented selectivity to obviate the need for wasteful chiral auxiliaries or inefficient protection-deprotection sequences. A number of transition metal-catalyzed processes have been extensively developed over past few decades to the point at which one would be hard pressed to devise a concise synthesis of a complex target without employing at least one if not more of these reactions. Just a representative few are illustrated below in Eqs. 1a.1 and 1a.2. In 2003, Martin and coworkers illustrated the use of the ruthenium-catalyzed ring closing metathesis reaction to arrive at a formal synthesis of the indole alkaloid ( )-peduncularine (Eq. 1a.1).1 Treatment of lactam 1a.1 with Grubb s second generation olefin metathesis 1 catalyst provided the bridged bicycle 1a.2 in 96% yield that was an intermediate in Speckamp s synthesis of the target indole (Eq. 1a.1). Transition metal-catalyzed allylic alkylations represent one of the most prevalent transformations mediated by a metal catalyst. In 2002, Trost and coworkers illustrated the use of a molybdenum-catalyzed asymmetric allylic alkylation of carbonate 1a.3 with the enolate of azalactone 1a.4 to provide quaternary amino acid precursor 1a.5 (Eq. 1a.2).2 In fact, if one peruses the literature, few total synthesis reports do not include at least a few reactions in which a transition metal species is used. Ring Closing Metathesis Mes N Cl N O N Mes Ph Ru H Cl PCy3 HO N O 1a.2 (1a.1) HO 1a.1 CH2Cl2, reflux 96% Asymmetric Allylic Alkylation O NH HN O OCO2Me + Me N Ph 1a.3 1a.4 O N O O Me N O N Ph (1a.2) C7H8Mo(CO)3, THF LiHMDS, 65 C 92% Ph 1a.5 dr = 97:3; ee = 99% The use of palladium has revolutionized the field of transition metal catalysis. The Heck reaction has become a staple in synthetic chemistry with Overman s group pioneering the development and utilization of the asymmetric Heck reaction in total 2 synthesis. As illustrated in Eq. 1a.3, treatment of aryl triflate 1a.6 with Pd(OAc)2 in the presence of (R)-BINAP provided silyl enol ether 1a.7 in 93% ee.3 Palladium catalysis has also found increased use in cross-coupling reactions such as the Stille and Suzuki couplings. For example, treatment of vinyl iodide 1a.8 with Pd(dppf)2 and alkyl boronate 1a.9 yielded the cross-coupling product 1a.10 in 77% yield.4 These examples illustrate a very limited sampling of the recent advances in transition metal catalysis in recent decades. Asymmetric Heck Reaction Pd(OAc)2, (R)-BINAP OTf OTBDPS 1a.6 K2CO3, THF, 60 C, 48 h (1a.3) Me OTBDPS 1a.7 87%, 93% ee Suzuki Cross-Coupling OMe MeO N OAc + TIPSO TBSO Pd(dppf)2/AsPh3 Cs2CO3/H2O/DMF 77% S N OAc MeO OTIPS I R2B 1a.9 1a.10 OTBS OMe S (1a.4) 1a.8 With the multitude of advances made on transition metal chemistry, so much is still not well understood. Due to the myriad of potential mechanisms for many processes, understanding reaction pathways to accurately predict product formation and/or selectivities associated with their formation can at times be an impossible task. The involvement of reaction intermediates and pathways of similar energies further 3 complicates the analysis. However, these observations can be viewed as an Transition metals can provide unprecedented opportunity in organic synthesis. alternative reaction pathways through small modifications of the catalytic species, and even allow for entirely new reaction mechanisms untenable through traditional synthetic methods. In proceeding sections, this discussion will focus on the realm of allylic alkylations and ring forming reactions as a backdrop to future chapters. No matter the role of the chemist in synthesis, the use of transition metal catalyst will, of the foreseeable future, play a critical part in complex molecule synthesis. 1.B TRANSITION METAL-CATALYZED ALLYLIC ALKYLATIONS 1.B.1 Introduction Few transition metal-catalyzed transformations in recent years, have gained as much attention or been so frequently employed in the synthesis of complex molecules of biological significance as the allylic alkylation reaction.5 Such reactions have arguably changed the face of organic synthesis. Beginning in the mid-1970 s, the allylic alkylation6-13 has been studied for its synthetic utility, and its mechanism has been elucidated through a variety of studies and experimental observations. The general process involves oxidative addition of the metal catalyst to an allyl substrate 1b.1 to yield an intermediate -allyl metal intermediate 1b.2 that undergoes nucleophilic addition to provide the alkylated product 1b.3. Gradual trends, such as the ever-increasing focus on asymmetric processes, in organic synthesis have also played a role in the evolution of transition metal-catalyzed allylic alkylations. More recently the main thrust of work in the area has been toward enabling enantioselective capabilities. As the nature of organic synthesis has changed from the construction of complex molecules to their asymmetric 4 assembly, so too has the transition metal-catalyzed allylic substitution reaction been rendered enantioselective through the use of chiral ligands on the metal center. Although a number of reactions have seen their utility explode by the development of asymmetric variants, few can say that they have achieved the hierarchal position that the asymmetric transition metal-catalyzed allylic alkylation enjoys. Scheme 1b.1 OLG 1b.1 Palladium, Molybdenum Tungsten, Iridium Rhodium or Ruthenium M 1b.2 1b.3 NucNuc What has really established the metal-mediated allylic alkylation as a cornerstone reaction in the organic chemists synthetic toolbox is its versatility. The scope has expanded through the plethora of allylic substrates and nucleophiles and the discovery that a number of different transition metals are capable of mediating the transformation. The differences in catalytic activity that each metal exhibits range from subtle to dramatic. The factors that influence one catalytic species to direct the regio- and stereochemical outcome of the substitution reaction may yield an entirely different result when a different metal complex is employed. The exploitation of these various selectivity trends in the synthesis of complex molecules has been one of the primary factors in establishing the transition metal-catalyzed allylic alkylation as a force in the synthesis of biologically significant natural products. The asymmetric synthesis of C-2-epi-hydromycin A (1b.9) (Scheme 1b.2) provides a glimpse at the nucleophilic diversity of the palladium-catalyzed allylic alkylation. Asymmetric allylic alkylation of meso-bisbenzoate 1b.4 in the presence of ligand 1b.5 provided the syn substitution product 1b.6 in 91% yield and 93% ee.14 5 Immediately following this substitution reaction, allylic etherification with phenol 1b.7 provided ether 1b.8 in 75%.15 Although this reaction was performed in the presence of a chiral ligand, the inherent diastereoselectivity in the palladium-catalyzed allylic substitution reaction, which will be discussed later, would have still provided the desired adduct stereoselectively. However, at times the palladium species generated in situ by the presence of chiral ligands exhibits enhanced reactivity, thereby making it the catalyst of choice for the desired substitution reaction. Scheme 1b.2 PMBO NO2 BzO O OBz PhO2S 1b.5 (4 mol%) (h3-C3H5PdCl)2 (1 mol%) THAB, CH2Cl2 91% 93% ee O2N PhO2S 1b.6 O OBz HO 1b.7 1b.5 (4 mol%) (h3-C3H5PdCl)2 (1 mol%) THAB, CH2Cl2 75% HO O PMBO O2N PhO2S 1b.8 O O CHO HO O O OH O HO HN O HO C-2-epi-Hygromycin A (1b.9) OH O CHO 1b.4 O NH HN PPh3 Ph3P 1b.5 O Heteroatom nucleophiles were used to further illustrate the scope and utility of the transition metal-catalyzed allylic alkylation reaction. As depicted in Scheme 1b.3, the 6 intramolecular asymmetric allylic amination of racemic sulfonamide 1b.10 with the sterically less demanding chiral ligand 1b.11 provided the bicycle 1b.12 in 90% yield and 86% ee. This intermediate was then advanced to the highly toxic bicyclic natural product (-)-anatoxin A (1b.13) in four steps.16 The synthesis of natural products 1b.9 and 1b.13 illustrate how the transition metal-catalyzed allylic alkylation, in this case the asymmetric variant, can be used to construct structurally complex products in an inter- or intramolecular fashion through the use of various nucleophilic components. Scheme 1b.3 O NH HN CO2Me TsHN 1b.10 OCO2t-Bu PPh3 1b.11 N O Ts N Pd2dba3 CHCl3 (2.5 mol%) CH2Cl2, 0 C 90% 86% ee CO2Me 1b.12 H N 4 steps 60% yield O (-)-anatoxin A 1b.13 1.B.2 Overview One of the key features that helps to distinguish the transition metal-catalyzed allylic alkylation from most other metal-mediated carbon-carbon bond forming reactions is the number of mechanistic possibilities there exist to yield the varied substitution products observed. Additionally, once the reaction is rendered enantioselective, the 7 different ways in which enantio-discrimination can be manifested invariably leads to thought provoking mechanistic analyses. The mechanistic process, in a general sense, of an allylic alkylation catalyzed by a metal species involves two components, a metalstabilized allyl moiety and the nucleophile. However, a number of reports, particularly in the realm of nickel catalysis, have illustrated how the allylmetal intermediate can in fact act as the nucleophile in some cases. For the sake of brevity, this discussion will focus simply on those transformations in which the p-allyl intermediate acts as the electrophilic partner. An allylic substrate of type 1b.14, where X is typically a leaving group that undergoes facile ionization in the presence of a catalyst, is often resistant to substitution under strictly anionic conditions. When treated with a nucleophile in the presence of a transition metal catalyst, the alkylation product 1b.15 is obtained. Transition Metal + Nuc- X 1b.14 Nuc 1b.15 + Catalyst X- (1b.1) The origin of group X has undergone rapid expansion in recent years to include a wide variety of leaving groups. In most cases a suitable X group can be either a halogen,17 epoxide,18 ester,17 carbonate,17,19 alcohol,17 amine,20 ammonium salt21 or phosphate.22 In general, alcohols are particularly poor leaving groups although their use has been demonstrated in limited cases. Studies performed on the allylic alkylation reaction have primarily focused on derivatives of allylic alcohols. The majority of experimental data obtained on transition metal-catalyzed processes involves the use of allylic esters, particularly acetates and carbonates. 8 1.B.2.1 Breadth of Nucleophiles Employed in the Transition Metal-Catalyzed Allylic Alkylation Within the confines of the process depicted in Eq. 1b.1, the nucleophile can be considered as either hard , characterized by a pKa > 25 of the conjugate acid, or soft , derived from a conjugate acid with a pKa < 15.23,24 Interestingly enough, whether a hard or soft nucleophile is employed dictates the mechanism through which the alkylation occurs.13 As illustrated below in Scheme 1b.4, Cycle A shows the mechanistic pathway for the allylic alkylation of substrate 1b.14 with a soft nucleophile, whereas Cycle B depicts the utilization of a hard nucleophile. Initial complexation of the transition metal catalyst to 1b.14 provides intermediate 1b.16, which then undergoes oxidative ionization to yield the allylmetal intermediates 1b.17 and 1b.19. If a stabilized nucleophile is used, addition occurs in a bimolecular sense from outside the coordination sphere of the metal and ligands on the face of the allyl moiety as depicted by structure 1b.17 to provide the metal-complexed substitution product 1b.18. Release of the catalyst completes the cycle and delivers the allylic alkylation product 1b.15. However, if an unstabilized nucleophile is used, transmetallation occurs prior to the carbon-carbon bondforming event. Nucleophilic attack on the metal, as depicted by structure 1b.19 provides intermediate 1b.21a. Reductive elimination ensues yielding the metal-complexed alkylation product 1b.21, which upon decomplexation provides the desired substitution product 1b.15. 9 Scheme 1b.4 MLn Nuc-Soft 1b.17 Nuc-Soft Nucleophilic Attack Nuc-Soft MLn 1b.18 Oxidative Addition X MLn 1b.16 Cycle A: "Soft" Nucleophilic Substitution Metal Decomplexation Nuc MLn 1b.15 Metal Complexation X 1b.14 Metal Decomplexation Nuc-Hard MLn 1b.21 Metal Complexation Reductive Elimination Cycle B: "Hard" Nucleophilic Substitution X MLn 1b.16 LnM Nuc-Hard 1b.20 Transmetallation Nuc-Hard MLn Oxidative Addition Nuc-Hard 1b.19 The range of nucleophiles that can be used in the transition metal-catalyzed allylic alkylation has expanded greatly over the past 20 years. Essentially, the type of anion can be divided into two classes of nucleophiles, carbon- or heteroatom-based compounds. 10 The carbon nucleophiles can further be dissected into the previously addressed hard and soft subclasses. Compounds that are considered to be soft nucleophiles are those of the generic formula RCXY, where R is either alkyl or H and X and Y are both functional groups that stabilize adjacent carbanions. The functional groups most often utilized include esters, ketones, nitriles, nitro groups, sulfones and sulfoxides.7-9,17,25 Additionally, the cyclopentadienyl anion26 and nitroalkanes27 have also been shown to react as soft nucleophiles in metal-catalyzed allylic alkylations. The range of hard nucleophiles, although slightly more diverse, is less developed in the allylic alkylation reaction. Enolate derivatives such as tin enolates,28-30 silyl enol ethers,31 silyl ketene acetals32 and copper enolates33 are all viable coupling partners. Organometal reagents including tin,34-36 aluminum,37 zinc,37,38 zirconium37 and thallium39 species lead to the formation of alkylation products. Grignard reagents have also been used, but they are limited in their utility due to the propensity for b-hydride elimination following transmetallation to palladium.40 Therefore their use has been primarily restricted to methyl and phenyl Grignard, as well as others devoid of b hydrogens. The class of heteroatom nucleophiles is much smaller than what has been observed through the use of carbon-based species. phenols,43,44 alcohols,45 and carboxylates.46 Oxygen nucleophiles41,42 include The latter typically find utility in rearrangement process in which the leaving group then acts as the nucleophile to provide an epimeric or regioisomeric allylic alcohol derivative.47 Nitrogen nucleophiles48-50 include simple secondary amines,51 sulfonamides52,53 and azides,54 although primary amines often times suffer from the formation of diallylation byproducts. Sulfinic acids and sulfinate salts have also been shown to be useful, however sulfides have rather limited utility due to their propensity for tight coordination and subsequent poisoning of most transition metal species.55 Reports of organometallics derived from transition 11 metals such as iron, nickel and cobalt56 have appeared, and the utilization of phosphites57 and silyl surrogate58 nucleophiles have been examined. 1.B.2.2 Diastereoselectivity The allylic substitution reaction can be dissected into two major steps, the first being oxidative addition of the metal complex to the allylic substrate and secondly, nucleophilic addition to the resulting allylmetal species. In determining the diastereoselectivity of transition metal-catalyzed allylic alkylation reactions, the outcome of both of these stereochemical determining processes must be understood. Starting from an enantioenriched allylic substrate 1b.22, the transition metal [M] can oxidatively add to the allylic system in either a syn or anti fashion to yield the diastereomeric p-allylmetal intermediates 1b.23 and 1b.24 (Scheme 1b.5). The nucleophile may then attack the allylmetal intermediate either on the same face (syn addition) as the transition metal or the opposite face (anti addition). Syn addition to complex 1b.23 provides the allylic alkylation product 1b.25, thereby resulting in an overall retention of stereochemistry through a syn-syn pathway. However, anti addition to 1b.23 provides the epimeric substitution product 1b.26 via a syn-anti mechanism. Nucleophilic addition to A subsequent anti intermediate 1b.24 provides the opposite product distribution. addition yields product 1b.25 whereas the syn route provides 1b.26. The factors that dictate the stereochemical outcome of these two processes have provided the impetus for many mechanistic studies over the last few decades. The stereochemistry of the metal oxidative addition step is often dependent on the nature of the transition metal species, in conjunction with the type of leaving group and steric environment attributed to the allylic substrate. The result of nucleophilic addition is most often dictated by the basicity of the nucleophile itself. Soft nucleophiles attack in an anti 12 orientation as a result of minimizing unfavorable steric interactions between the ligands and coordination sphere of the metal and the approaching nucleophile. However, hard nucleophiles typically provide products resulting from a syn addition to the allylmetal intermediate via a reductive elimination process from the metal (except for in the case of metal enolates). The propensity for hard nucleophiles to undergo transmetallation prior to attack on the allyl ligand obviates the steric influences that dictate the path followed by stabilized anions. Scheme 1b.5 A [M] R1 M NucR NucR R 1b.25 Nuc syn Path A: syn B 1b.23 R R 1b.22 OLG Nuc- Path B: anti B [M] R R M 1b.24 NucNucR R 1b.26 Nuc anti Path A: syn A 1.B.2.3 Regioselectivity The issue of regioselectivity in transition metal-catalyzed allylic alkylations is particularly complex and will only be mentioned briefly here. The regiochemical outcome generally depends on the nature of the transition metal used, and more in-depth analysis will be reserved for the discussion sections dealing with each metal separately. 13 However, there are a few generalizations that may be made with regards to the anticipated regioselectivity. Under the catalysis of most transition metals, allylically transposed carbonates 1b.27 and 1b.28 will undergo ionization to yield the same allylmetal species 1b.29 through an h1-h3-h1 isomerization process (Scheme 1b.6). Nucleophilic addition to intermediate 1b.29 then provides the regioisomeric substitution products 1b.30 and 1b.31b. Which product is formed preferentially depends on a delicate balance of steric and electronic factors influencing the structure of 1b.29. These dynamics can have a profound influence in inducing asymmetry on the conformation of the -allylmetal species via a distribution of electron deficiency throughout the allyl moiety. Additionally, these factors effect the ratio of regioisomers formed by distorting the position of the metal relative to the allyl moiety. The orientation of the metal is often a direct result of unfavorable steric interactions between the metal, its ligands and the substituents on the substrate. This balancing act between steric and electronic factors appears to vary with which metal complex employed and therefore will be discussed in more detail in subsequent sections of this chapter. 14 Scheme 1b.6 OLG R1 1b.27 [M] NucR2 R1 1b.30 Nuc R2 M R1 1.29 R2 [M] OLG R1 1b.28 R2 NucNuc R1 1b.31 R2 1.B.3 Palladium-Catalyzed Allylic Alkylations The first transition metal found to exhibit catalytic activity to enable the alkylation of allylic substrates under relatively mild conditions in a regio- and stereoselective manner was palladium.7,8,25 The use of palladium has revolutionized the area of -allylmetal chemistry to the point in which not only has the process been established as chemo-, regio- and diastereoselective, but also significant strides have been made over the past decade to render the process asymmetric through the use of chiral palladium complexes.13 Much of what is known about transition metal-catalyzed allylic alkylations today was elucidated from palladium-catalyzed processes. Due to the breadth of palladium-catalyzed allylic alkylations, this section will primarily focus on the substitution reaction of allylic alcohol derivatives with stabilized or soft nucleophiles. 15 1.B.3.1 Regiochemistry The first reports of allylic alkylations being performed in the presence of catalytic quantities of palladium species began to surface in the early 1970 s. Along with the advent of -allylpalladium species and their role in allylic alkylations, the issue of regiochemistry in the nucleophilic addition step was one of the first addressed.8,59 In general, palladium-catalyzed processes are quite regioselective, generally providing the substitution product that arises from alkylation at the less sterically encumbered allylic terminus preferentially.7,19,60 However, it has been reported that at lower temperatures and shorter reaction times, the reaction may proceed under kinetic control, thereby providing the product resulting from substitution at the more substituted allylic terminus.61 Interestingly, steric factors seem to over-ride electronic influences in the distortion of -allylpalladium intermediates. In 1984, Keinan and Sahai published a concise look at how the steric effects from the substituents on the allylic substrate can determine the regiochemical outcome in palladium-catalyzed processes.60 In general, when either allylic acetate 1b.32 or 1b.33 was treated with sodium dimethyl malonate in the presence of 5 mol% Pd(PPh3)4, the alkylation product 1b.34, resulting from alkylation away from the bulky R group, was obtained preferentially (Table 1b.1). As the R group became more sterically cumbersome, the regioselectivity improved indicating that the steric environment influenced the geometric nature of the -allylpalladium intermediate (compare entries 1 and 2). As indicated by entries 3 and 4, when the allylically transposed acetates 1b.32 and 1b.33 were subjected to the same conditions, malonate 1b.34 was obtained with >99:1 selectivity in each case indicating that both reactions proceeded through a common -allylpalladium intermediate. Probably the most compelling result is illustrated in entry 5 wherein R was a deuterated methyl group to provide a 1:1 mixture of 1b.34 and 1b.35. 16 This result indicates that in the absence of overriding steric or electronic influences, the regioisomers would be formed in equal amounts. Table 1b.1. Regioselectivity in the palladium-catalyzed allylic alkylation. OAc R 1b.32 or OAc R 1b.33 Pd(PPh3)4 (5 mol%) NaCH(CO2Me)2, THF, rt MeO2C R 1b.34 1b.35 CO2Me + R MeO2C CO2Me Entry 1 2 3 4 5 Allylic Acetate 1b.32 1b.32 1b.32 1b.33 1b.32 R n-Bu i-Bu i-Pr i-Pr CD3 Yield (%) 92 90 67 64 84 1b.34/1b.35 78:22 93:7 >99:1 >99:1 50:50 An interesting example of regiocontrol was illustrated by the discovery that when palladium was used to catalyze the allylic alkylation to synthesize medium-sized rings, the cyclized product resulting from alkylation at the least sterically congested allylic terminus was preferred over the kinetic product.62,63 Thus intramolecular allylic alkylation of sulfonyl ester 1b.36 yielded the eight-membered ring lactone 1b.37 resulting from alkylation at the less hindered primary allylic terminus (Eq. 1b.2).64 The fact that none of the corresponding six-membered ring regioisomer was observed is 17 particularly noteworthy. Although formation of the larger ring sized product corresponds to attack at the most sterically accessible allylic site, other factors including nature of the nucleophile and the ligands on palladium have been reported to contribute to the observed regioselectivity. The use of a phenyl sulfonyl ester as the nucleophile is crucial to product distribution. If the corresponding acetoacetate was employed, the six- membered lactone was formed preferentially. Additionally, if the sterically demanding ligand dppe was withheld from the reaction, mixtures of regioisomers were obtained. O O SO2Ph OAc 1b.36 Pd(PPh3)4, dppe NaH, THF 73% O PhO2S 1b.37 O (1b.2) Electronic factors can also play a significant role in palladium-catalyzed allylic alkylations, although the effect is not as dramatic as that observed due to steric influences. The presence of electron-withdrawing groups on the allyl moiety have been shown to direct substitution to the proximal allylic carbon.59 When allylic acetate 1b.38 was alkylated with sodium dimethyl malonate in the presence of Pd(PPh3)4 at room temperature, malonate 1b.39 (88%) was obtained exclusively (Eq. 1b.3). This regioselective outcome is best rationalized by extrapolating the electrophilicity of the allylpalladium complex to that of an allyl cation. The authors conclude from this analysis that the benzylic carbon in 1b.38 is more electron deficient thereby leading to exclusive alkylation at that site. OAc Ph 1b.38 CN Pd(PPh3)4 (5 mol%) NaCH(CO2Me)2, THF, rt 88% MeO2C Ph 1b.39 CO2Me (1b.3) CN 18 Ligand effects have also been shown to shape the regiochemical outcome of palladium-catalyzed alkylations by influencing the electronics of the -allylpalladium species. kermark et. al. reported in 1987 a study in which they analyzed the regiocontrol in the allylic alkylation of the -allyl complex derived from 3-methylbutene as different acceptor and donor ligands were associated with palladium.65 The utilization of acceptor ligands on palladium had the effect of developing increased electrophilic character on the more substituted allylic terminus, thereby resulting in more of the branched regioisomer formed. Conversely, donor ligands on palladium produced a less reactive -allylpalladium complex resulting in alkylation at the less substituted allylic terminus preferentially. A remarkable report by Williams and coworkers in 2000 showed that the regiochemical outcome could also be affected by the steric environment the ligand imparts on the -allyl intermediate.66 The authors found that in going from PPh3 to the bulkier PCy3 ligand, alkylation of 1b.40 could be influenced to favor the branched alkylation product 1b.43 nearly exclusively (Eq. 1b.4). However, if allyl acetate 1b.41 was subjected to the reaction conditions, only 10% conversion was observed providing a 1:1 ratio of substitution products in low yield with PCy3 and only limited preference for 1b.42 with PPh3. The lack of reactivity observed with acetate 1b.41 when PCy3 was used may be due to the inability of bulky palladium reagent to oxidatively add to an internal olefin. Likewise, the origin of regioselectivity presumably arises from the preference for the bulky catalyst, upon ionization to orient itself away from the more substituted -allyl terminus, thus allowing for alkylation to occur at the more substituted allylic center. 19 Me OAc 1b.40 or Me 1b.41 OAc [Pd(allyl)Cl]2, Ligand NaCH(CO2Me)2, THF, rt 75-80% Me CO2Me CO2Me 1b.42 + MeO2C CO2Me Me (1b.4) 1b.43 Ligand = PPh3 = PCy3 From 1b.40: 1b.42/1b.43 = 1:1; From 1b.41: 1b.42/1b.43 = 1.3:1 From 1b.40: 1b.42/1b.43 = 1:120; From 1b.41: 1b.42/1b.43 = 1:1* 1.B.3.2 Stereoselectivity In general, palladium-catalyzed allylic alkylations proceed with overall net retention of stereochemistry as a result of an anti-anti mechanistic pathway. For example, alkylation of allylic acetate 1b.44 proceeded in 96% to yield the substitution product 1b.45 as a mixture (92:8) of regioisomers in 30% ee (Eq. 1b.5).67 Convincing evidence for the initial anti addition of the palladium species to the allylic acetate was reported in 1983 by Hayashi and coworkers. They were able to isolate the - allylpalladium species obtained from the enantioenriched allylic acetate 1b.44. The absolute configuration of the intermediate resulted from addition of the palladium catalyst anti to the leaving group with minimal loss of optical purity (58% ee to 47% ee).68 Me OAc 1b.44 38% ee Ph Pd(PPh3)4, dppe 96% Me MeO2C Ph (1b.5) CO2Me 1b.45 30% ee Regioselectivity = 92:8 To understand many of the concepts associated with -allyl species, it is important to understand the nomenclature assigned to substituents on the allylmetal 20 intermediates. Traditionally, the reference point on the allyl species is the hydrogen on the 2-carbon. Substituents are designated syn if they are aligned syn to the twohydrogen, whereas those anti are likewise termed anti. Generally, an allyl isomer is regarded as either syn or anti in conjunction with the substituent of interest to the reaction in question. Figure 1b.1. Nomenclature for substituents on -allyl intermediates. H Rsyn 1 2 3 H Rsyn H 1 2 3 H H H Ranti Ranti 1b.46 "syn" substituents 1b.47 "anti" substituents A particularly interesting observation is illustrated in Scheme 1b.7. When the enantioenriched Z-allylic acetate 1b.48 was alkylated with sodium dimethyl malonate in the presence of Pd(PPh3)4/dppe, E-olefinic 1b.51 was obtained with complete inversion of stereochemistry.69 The formation of 1b.51 can be rationalized by the h1-h3-h1 isomerization of the less stable anti -allylpalladium intermediate 1b.49, formed by oxidative addition to 1b.48, to provide the thermodynamically more stable syn intermediate 1b.51. Alkylation then occurs via nucleophilic attack on the face of the allyl moiety opposite the catalyst to provide the E-substitution product with inverted stereochemistry. 21 Scheme 1b.7 Me OAc Ph 1b.48 73% ee Pd(PPh3)4, dppe Me Pd Ph Me Pd Ph anti-1b.49 syn-1b.50 Regioselectivity = 90:10 Me MeO2C Ph CO2Me 1b.51 73% ee 1.B.3.3 Olefin Geometry As exemplified by the results illustrated in Scheme 1b.6, retaining the carbon- carbon double bond configuration in Z-allylic substrates is a substantial problem in palladium-catalyzed allylic alkylations. It has long been observed that the intermediate -allylpalladium species isomerize to their more stable syn isomers at a faster rate than nucleophilic addition occurs.70,71 However, two reports which have surfaced recently illustrate how this complication may be overcome. The first came from Kazmaier and Zumpe in 2000 as they illustrated how a more reactive nucleophile could be used to enable nucleophilic addition to occur at a faster rate than isomerization.72 Thus, when enantioenriched allylic carbonate 1b.54 was treated with the zinc enolate 1b.53, derived from deprotonation of 1b.52 followed by transmetallation with ZnCl2, the Z-substitution product 1b.55 was obtained with complete chirality transfer and with excellent diastereoselectivity (98%) (Scheme 1b.8). Not only is the nature of the nucleophile key to obtaining a good Z/E ratio of the product, but also the use of a methyl carbonate leaving group was found to be critical. For example, the corresponding allylic acetate 22 furnished a mixture of products favoring the E-isomer (E/Z = 77:23) with reduced optical purity (68% ee) in low yield (<10%). Scheme 1b.8 OtBu O 1b.52 LiHMDS, ZnCl2 THF, -78 C OtBu Zn O 1b.53 TfaHN TfaN 1b.48, [Pd(allyl)Cl]2 Ph OCO2Me 1b.54 97% ee PPh3, THF, -78 C rt 68% Ph NHTfa CO2tBu 1b.55 97% ee d.s. = 98% In 2002, Hayashi and coworkers reported the utility of bidentate phosphine ligands in palladium-catalyzed allylic alkylations in reducing the amount of syn-anti isomerization.73 They observed that the rate of isomerization was significantly faster when bisphosphine ligands with small bite angles, the P-Pd-P angle arising from bidentate bisphosphine ligands, were employed (i.e. dppe = 85.8 vs. dppb = 94.5 ). Additionally, the electronics of the ligands significantly affected the observed outcome. Phosphine ligands that are electron-withdrawing, such as CF3-dppf, accelerate the synanti isomerization as much as 3-4 times in comparison to neutral phosphine ligands like dppf. Phosphine ligands that are electron-donating (MeO-dppf) reduce the rate of isomerization by 4-5 fold. Therefore, syn-anti isomerization and hence the ratio of Z- and E-substitution products formed in palladium-catalyzed allylic substitution reactions, may be controlled through a judicial selection of bisphosphine ligands. 23 1.B.3.4 Summary The use of palladium to catalyze the allylic alkylation of unsymmetrical substrates has advanced significantly over the past few decades. Most of what is understood about this important transformation has been determined by studies performed on palladiumcatalyzed processes. The important aspects of the palladium-catalyzed allylic alkylation can be summarized in the following three main points. The first lesson is that the regioselectivity of the process generally provides the alkylation product arising from nucleophilic attack at the less hindered allyl terminus. Secondly, the substitution reaction proceeds with overall retention of stereochemical configuration via an anti-anti mechanism. Finally, the olefin geometry throughout the process undergoes facile isomerization to provide the energetically more stable E-isomer. The scope of substrate and nucleophile combinations, and the shear volume of different chemical transformations that can be enabled through the palladium-catalyzed allylic alkylation has solidified its role as a premier synthetic process. 1.B.4 Molybdenum-Catalyzed Allylic Alkylations Reports of utilizing molybdenum complexes as catalysts for allylic alkylations first began to surface in the early 1980 s as a result of the pioneering work performed by Trost and coworkers.74,75 Given the success that the Trost group experienced with palladium-catalyzed allylic substitutions, a natural extension was their experimentation with other late transition metals as allylic alkylation catalysts. The focus of much of the early work was to examine how regio-, chemo- and diastereoselectivities would differ from the use of these other catalyst systems. The establishment of a molybdenum species as a viable catalyst in this class of reactions opened the door to a unique realm of possibilities untenable through traditional p-allylpalladium chemistry. 24 1.B.4.1 Regioselectivity The first indication that molybdenum behaved differently as an allylic alkylation catalyst was the unusual regiochemical trend for forming the substitution products.75,76 The regioselectivities observed in palladium-catalyzed allylic substitutions are most often attributed to steric influences that may be tuned by altering the ligand field of the metal. However, initial observations in molybdenum-catalyzed alkylations indicated that steric and electronic factors could at times be working in opposing directions.77-81 If a suitable balance was not attained, the ratio of regioisomers could be fairly poor. However, if the right set of reaction conditions were found, either regioisomer could be prepared selectively. Limited success was encountered in discriminating primary and tertiary allylic termini by altering the nature of the nucleophile under palladium-catalyzed conditions.82 Attempts to direct alkylation by changing the nature of the catalyst enhanced substitution at the primary center, but typically failed in directing alkylation at the tertiary carbon. In initial studies, the more electropositive octahedral molybdenum complexes were thought to be ideal candidates to enhance electronic influences in the intermediate p-allylmetal species such that they would override steric preferences to provide alkylation at the more substituted allylic termini more.83 77 Catalysts derived from Mo(CO)6 were examined first.74 Initial studies indicated that the molybdenum-bipyridyl complex, Mo(CO)4bipy proved advantageous. However, upon further analysis this catalyst was determined not to be sufficiently reactive with a wide range of substrates, and at times gave inconsistent regioselectivities. Mo(CO)6 itself was found to be reactive enough to alkylate allyl acetate 1b.56 with the anion of dimethyl malonate to give 1b.57 in 76% yield as one regioisomer (Eq. 1b.6).77 To examine the effect of b-ketoester substitution on regioselectivity, treatment of 1b.56 with the sodium 25 anion of methyl 5-methyl-3-oxohexanoate also provided the analogous regioisomer in 91% yield.77 CO2Me CO2Me (1b.6) OAc + MeO2C Mo(CO)6 CO2Me PhMe, reflux 76% 1b.56 1b.57 The sodium anion of dimethyl malonate was able to discriminate between primary and secondary allylic termini with good selectivity, but would the regiochemical trends hold when the nucleophile was asked to differentiate between a tertiary and primary allylic carbon? To answer this question, acetates 1b.58 and 1b.59 acetate were treated with sodium dimethyl malonate in the presence of Mo(CO)6 to yield mixtures of the branched substitution product 1b.60 and both E- and Z-isomers of the corresponding linear product 1b.61 in good yield (Table 1b.2).83 In each case, the major product obtained was 1b.60 resulting from alkylation at the tertiary allylic carbon. Although alkylation of either 1b.58 or 1b.59 provided the same major product, the rate at which substitution occurred was markedly different. Allylic acetate 1b.58 containing a trisubstituted olefin underwent alkylation at a significantly slower rate than did the corresponding monosubstituted terminal alkene. This result suggests that oxidative addition of the molybdenum catalyst may be sensitive to the steric environment of the allylic system such that more congested substrates result in slower formation of the allyl species (entries 1 and 2 versus entry 4). Alternatively, the reason could be that the ionization of 1b.54 occurs at a faster rate due to the ability of low valent metals to coordinate monosubstituted olefins easier than the corresponding disubstituted carboncarbon double bonds. Intramolecular displacement through the aid of a non-bonding pair 26 of electrons allows for steric hindrance at the tertiary site to be minimized, and the weaker C-O bond of the more substituted acetate to undergo ionization at a faster rate. The nature of the base also had an effect on the rate and regioselectivity of the alkylation.83 When a coordinating base such as N,O-bis(trimethylsilyl)acetamide was used, the regioselectivity improved dramatically (entry 3). However, if the base was too strongly coordinating, the reaction was shutdown presumably due to poisoning of the catalyst (entry 5). Table 1b.2. Regioselectivity in the molybedenum-catalyzed allylic alkylation. OAc or 1b.58 MeO2C CO2Me MeO2C 1b.60 + CO2Me 1b.61 CO2Me CO2Me Mo(CO)6 OAc 1b.59 Entry 1 2 3 4 5 Substrate 1b.59 1b.59 1b.59 1b.58 1b.59 Base NaH KH BSA NaH DBU Time (h) 3 2 1.5 48 48 Yield (%) 80 82 82 65 N.R. 1b.60/E-1b.61/Z-1b.61 85:12:3 80:17:3 97:1.5:1.5 85:12:3 - In analyzing the regiochemical outcome of the molybdenum-catalyzed allylic alkylation, a number of different factors must be considered. 27 Inherently, the regiochemistry of the reaction relies more on electronic than steric factors. Often times this leads to substitution at the more substituted allylic site where there exists the lowest electron density within the allylic system. However, when bulky nucleophiles are used, this trend can be reversed to provide the corresponding linear substitution products. One of the more attractive aspects in the molybdenum-catalyzed allylic alkylation is the inherent ability of the metal species to seemingly override existing factors within the substrate to consistently yield products resulting from primarily electronic control. The use of protecting groups to mask functionality within a substrate such that other entities present can be manipulated has become a mainstay in the synthesis of natural products. Unfortunately, the employment of protecting groups often adds unwanted synthetic operations to a route, and typically suffers from poor atom economy by generating waste. Therefore, if chemical transformations could be performed chemoselectively in the presence of other reactive functionality, without resorting to the use of protecting groups, there could be a significant advantage in synthetic efficiency provided the route itself was optimal. In 1987, Trost and coworkers examined whether molybdenum-catalyzed allylic alkylations could be performed on substrates containing other leaving groups that were subject to nucleophilic displacement.75 Under standard, non-transition metal-catalyzed displacement conditions, nucleophiles, such as malonate anions, will react with primary alkyl halides to provide the corresponding substitution products. The question was thus: would molybdenum-catalyzed allylic alkylations proceed faster than simple alkylations. As illustrated in Scheme 1b.9, the chemoselectivity of the Mo(CO)6-catalyzed allylic alkylation was analyzed by utilizing acetate 1b.62 containing competing functionality.75 Treatment of alkyl bromide 1b.62 with sodium dimethyl malonate in the absence of a molybdenum catalyst provided solely malonate 1b.63 in 61% yield (Scheme 28 1b.8). However, when the same reaction was run in the presence of Mo(CO)6, a mixture (5.5:1) of regioisomers 1b.64/1b.65 was obtained in excellent yield. Of particular note is the fact that the alkyl bromide functionality remained intact to allow for further manipulation at a later stage. Scheme 1b.9 MeO2C CO2Me MeO2C 5 DMF, rt, 61% CO2Me 1b.63 OAc Br 5 OAc 1b.62 MeO2C CO2Me Br 5 MeO2C 1b.64 + CO2Me Mo(CO)6, PhMe, reflux 82% 1b.64/1b.65 = 5.5:1 CO2Me Br 5 CO2Me 1b.65 It has been well established that allylsilanes undergo protodesilylation in palladium catalyzed processes.84,85 Given the reactivity and synthetic utility of allylsilanes, it would be desirable to enable the metal-catalyzed allylic alkylation of an allyl acetate with a stabilized nucleophile while not affecting a pendant allylsilane functionality. It is therefore noteworthy that treatment of allyl acetate 1b.66 with Mo(CO)6 and the sodium enolate 1b.67 provided the allylic alkylation product 1b.68 in 58% yield without evidence of protodesilylation (Scheme 1b.9).75 One may attribute the lack of C-Si bond cleavage in the molybdenum-catalyzed case to the fact that pallylpalladium intermediates are more electrophilic than the corresponding pallylmolybdenum species. The synthetic utility of intermediates such as 1b.68 was 29 further illustrated by the intramolecular alkylation/ring expansion to yield cyclooctenone 1b.69 en route to muscone.86 Scheme 1b.10 TMS + OAc 1b.66 1b.67 O ONa E Mo(CO)6 PhMe 58% E E 1b.68 1b.69 O TMS 1.B.4.2 Stereoselectivity The issue of diastereoselectivity in molybdenum-catalyzed allylic alkylations was first investigated using the allyl acetate 1b.70 (Eq. 1b.7).75 The diastereoselectivity of the reaction showed a remarkable dependence on the base used, and, not as surprisingly, the nature of the nucleophile. Treatment of 1b.70 with sodium dimethyl malonate in the presence of Mo(CO)6 produced syn and anti diastereomers 1b.71 and 1b.72 in equal amounts. When BSA was used as the base however, only 1b.66 was formed (75%). Thus, the reaction proceeded cleanly with overall retention of configuration as observed in palladium-catalyzed reactions. CO2Me MeO2C CO2Me CO2Me CO2Me 1b.71 + CO2Me (1b.7) CO2Me OAc 1b.70 Base, Mo(CO)6 PhMe CO2Me CO2Me 1b.72 50 0 NaH: BSA: 90% 75% 50 100 30 Although the alkylation of allyl acetate 1b.70 with sodiodimethyl malonate was not stereoselective, the reaction of sodiodimethyl methylmalonate with 1b.70 provided a mixture (8:1) of syn and anti diastereomers 1b.71 and 1b.72 respectively.75 In this case the diastereoselectivity improved when a more sterically hindered nucleophile was used, illustrating that the allylic alkylation could still be diastereoselective in the presence of Mo(CO)6 with sodium hydride as the base. In 1990 Trost and Merlic reported the use of the tert-butylisonitrile molybdenum complex, Mo(CO)2(CNC4H9-t)4, and showed that the stereorandom reaction of 1b.70 with sodiodimethyl malonate as illustrated in Eq. 1b.7 proceeded with excellent stereocontrol in the presence of the isonitrile complex (dr > 99:1, 70% yield).79 This report showed that the reaction could proceed diastereoselectively with simple sodium salts of malonate nucleophiles with the right ligands on molybdenum. Acyclic allylic acetates have also been used as substrates. Equatorial allylic acetate 1b.73 and its axial stereoisomer 1b.74 were both treated with dimethyl malonate and BSA in the presence of Mo(CO)6 to determine how the diastereoselectivity of the reaction would be affected when proceeding through a sterically biased acyclic pallylmolybdenum intermediate (Eq. 1b.8).75,77 Thus, treatment of either 1b.73 or 1b.74 yielded a mixture (5.5:1) of diastereomers 1b.75 and 1b.76 favoring equatorial attack. t-Bu 1b.73 or OAc MeO2C CO2Me CO2Me MeO2C + CO2Me (1b.8) BSA, Mo(CO)6 PhMe OAc t-Bu 1b.75 CO2Me t-Bu 1b.76 1b.75/1b.76 = 5.5:1 t-Bu From 1b.73: 89% 1b.74 From 1b.74: 69% 31 The stereochemical outcome in molybdenum catalyzed allylic alkylations has been a subject of debate since 1995 when the first suggestions of the involvement of an unprecedented syn-syn mechanism began to surface. Given the net retention of stereochemistry observed in the absence of factors inherent to the substrate, the molybdenum-catalyzed reaction was originally believed to proceed through an anti-anti mechanism similar to the palladium catalyzed reaction.74,77,83 However, encouraged by the observations of Faller87 and Liebeskind88 that showed stoichiometric reactions produced molybdenum h3-complexes through a syn pathway, Kocovsky examined the Mo(CO)6-catalyzed alkylation of bicycle 1b.77 (Scheme 1b.11).89 Allyl acetate 1b.77 is inert to Pd(0)-catalyzed substitutions, but its epimer 1b.78 undergoes alkylation with PhZnCl in the presence of a palladium(0) species, presumably through an anti-syn pathway. On the other hand, allylic acetate 1b.78 was unreactive to the lithium salt of dimethyl malonate under palladium-catalyzed conditions, which should proceed via an anti-anti process. These observations are rationalized by the hypothesis in that for allyl acetate 1b.77, the endo face of the bicyclic ring system is too sterically congested to allow for metal complexation followed by ionization with palladium. However, the epimer 1b.78 can react to form the p-allylpalladium intermediate 1b.79 from the exo face. The resulting p-allylmetal complex can only react with unstabilized nucleophiles that add in a syn fashion via transmetallation followed by reductive elimination, and not stabilized malonates which attack from the opposite face that the metal rests on, in the case of 1b.79 the more sterically congested endo approach. 32 Scheme 1b.11 H OAc MoLn 1b.77 MoLn AcO H 1b.78 MoLn Mo(CO)6 Mo(CO)6 syn anti MoLn 1b.79 Nuc- CH2(CO2Me)2, BSA syn H MeO2C CO2Me 1b.80 When Kocovsky and coworkers treated allyl acetate 1b.77 with Mo(CO)6, dimethyl malonate and BSA, the alkylation product 1b.80 was produced in >90% conversion. Under identical conditions, the epimeric acetate 1b.78 was inert, providing none of the desired product. These results seem to suggest that a syn-syn mechanism is in effect under molybdenum-catalyzed allylic alkylation conditions. Additionally, the authors speculated that the rate of the reaction was enhanced by coordination of the molybdenum center to the carbonyl oxygen of the acetate to facilitate delivery of the catalyst and act as a Lewis acid in the ionization step. This hypothesis was examined by alkylation of the corresponding allylic trifluoroacetates, because their electronwithdrawing capability would presumably favor the anti mechanism. The corresponding carbamates were also examined due to their electron-donating influence that would 33 presumably facilitate precoordination of the metal, thereby causing a rate enhancement in the syn mechanism. In accordance with the hypothesis, the trifluoroacetate derived from 1b.77 reacted approximately three times slower than the corresponding allyl acetate, and the carbamate benefited from a substantial rate increase.89 Conversely, the trifluoroacetate derived from 1b.78 reacted much faster than the acetate whereas the corresponding carbamate was essentially inert to the reaction conditions. These additional observations lent support to the hypothesis that molybdenum-catalyzed allylic alkylations operate under a syn-syn mechanistic pathway. Finally in 2003 there appeared conclusive evidence for molybdenum-catalyzed allylic alkylations operating under a syn-syn mechanism. Lloyd-Jones and coworkers reported that they were able to crystallize the intermediate p-allylmolybdenum complexes from the enantiomeric allylic carbonates 1b.81 and 1b.82 in the presence of chiral ligand 1b.89. When this complex was treated with a malonate nucleophile the substitution products resulting from an overall syn-syn addition were obtained (Scheme 1b.12).90 Thus, treatment of allylic carbonate 1b.81 with the chiral molybdenum catalyst 1b.89 cleanly provided the p-allyl complex 1b.83 whose 1H NMR data corresponded with the corresponding protio complex. Addition of malonate nucleophile to intermediate 1b.83 provided malonate 1b.87 with net retention and no deuteron transposition, presumably via a syn addition pathway. When carbonate 1b.82 was treated with 1b.89, the 1H NMR data obtained corresponded to deuteroisomer 1b.86, which was formed by an h3-h1-h3 isomerization of the unobserved metal-stabilized intermediate 1b.84. Subsequent treatment with sodiodimethyl malonate provided the retention product 1b.88 with no deuteron transposition. These results seem to provide conclusive evidence for a syn-syn mechanistic pathway in the molybdenum-catalyzed allylic alkylation. 34 Scheme 1b.12 MeO2CO Ph 1b.81 D H MeO2CO Ph 1b.82 D H Inversion Retention Inversion Retention H Mo D Ph 1b.83 H Ph H Mo D H 1b.84 Retention MeO2C Ph H Mo H Ph 1b.85 D 1b.87 CO2Me D H Inversion H Mo H Ph 1b.86 D Inversion MeO2C Ph 1b.88 CO2Me H D Retention O NH HN O Mo(CO)4 N 1b.89 1.B.4.3 Geometric Selectivity The issue of olefin geometry in molybdenum-catalyzed allylic substitution was addressed in two ways. The first, as illustrated in Eq. 1b.9, involves the alkylation of a secondary allyl acetate with a terminal olefin as 1b.90 to yield one of two geometric 35 isomers 1b.91 and 1b.92 by alkylation at the primary allylic terminus. The most common manifestation of this type is observed by the substitution of a tertiary allylic acetate at the terminal olefin to yield the corresponding Z- and E-isomers of a trisubstituted carbon-carbon double bond. The second involves the retention or isomerization of olefin geometry during the course of the reaction, as explored in the context of palladium-catalyzed alkylations. The most common example involves starting from a Z-allyl acetate 1b.93 that can lead to either the Z- or E-alkylation products 1b.94 and 1b.95 respectively (Eq. 1b.10). R OAc 1b.90 NucMo-catalyst 1b.91 R Nuc + R 1b.92 Nuc (1b.9) R2 R1 1b.93 OAc NucMo-catalyst R1 R2 Nuc 1b.94 + R1 R2 Nuc 1b.95 (1b.10) The first analysis of olefin geometry in the molybdenum-catalyzed allylic alkylation was performed by examining the reaction of the exocyclic allylic acetate 1b.96 with sodium dimethyl methylmalonate in the presence of Mo(CO)6 in PhMe to provide a mixture (10:1) of 1b.97 and 1b.98 respectively, favoring the E-substitution product (Eq. 1b.11).75 In comparison, palladium-catalyzed allylic alkylation of 1b.96 provided a similar mixture with the E-alkylation product 1b.97 being formed with somewhat higher selectivity. 36 MeO2C OAc + MeO2C CO2Me CO2Me + MeO2C CO2Me (1b.11) Allylic Alkylation Catalyst 1b.96 Mo(CO)6, PhMe: Pd(PPh3)4, THF: 1b.97/1b.98 = 10:1 1b.97 1b.97/1b.98 = 17:1 1b.98 In order to examine the extent to which olefin geometry is retained, the E- and Zexocyclic allyl acetates 1b.99 and 1b.100 were alkylated with dimethyl malonate and BSA in the presence of Mo(CO)6 (Scheme 1b.13).75 The alkylation of both substrates proceeded in good yield to provide the same mixture (5:1) of products 1b.101 and 1b.101c. Whether acetate 1b.99 or 1b.100 was used, the E-olefin was the only carboncarbon double bond isomer observed. The authors provide this result as evidence that there existed an equilibrium of the molybdenum-stabilized p-allyl intermediates and that alkylation occurred at a slower rate than equilibration. Scheme 1b.13 C5H11 CO2Me CO2Me OAc C5H11 1b.99 MeO2C 1b.102 Mo(CO)6 CH2(CO2Me)2, BSA 1b.101 + C5H11 CO2Me Mo(CO)6 CH2(CO2Me)2, BSA 1b.100 OAc C5H11 1b.101/1b.102 = 5:1 37 1.B.4.4 Summary In general, the molybdenum-catalyzed allylic alkylations proceed with comparable or better selectivity than what is observed with most transition metals capable of catalyzing the allylic substitution reaction. The chemoselectivity of the transformation is often superior and the E-olefin selectivity observed is nearly as good as the analogous palladium-catalyzed processes. The stereoselectivity for diastereomerically pure substrates is on par with the trends associated with other transition metal catalysts. When enantiomerically enriched allylic substrates are alkylated under molybdenum-catalyzed conditions, enantiopurity is maintained, and the reaction has been found to proceed through a supposedly unique syn-syn. Additionally, the regiochemical trends are In general, alkylation at the more There are, however, some reversed from those observed with palladium. substituted allylic terminus proceeded preferentially. drawbacks to its use. These include the poisoning of the molybdenum catalyst by strongly Lewis basic reaction conditions (i.e. the use of DBU as a base shut down the reaction completely)83 and the relatively low catalytic turnover numbers in comparison to palladium. However, the increased air-stability and low cost of molybdenum negates some of the drawbacks associated with its use. One primary advantage in choosing a molybdenum catalyst to perform an allylic alkylation is that the regiochemical trends provide an opportunity to construct tertiary and quaternary centers, thereby lending itself applicable toward asymmetric catalysis through the use of chiral ligands as depicted in section 1b.0 and will be discussed further. 1.B.5 Iridium-Catalyzed Allylic Alkylations Over the past six years Takeuchi and coworkers have pioneered the use of iridium-based catalysts to achieve allylic alkylations.91 When initial reports on the use of 38 iridium catalysts began to surface, a number of different transition metals had already been found to catalyze this reaction. The majority of work done on the development of iridium catalysis has centered around their utility as exquisite hydrogenation92-94 and hydrosilylation95 catalysts, and there had been a lack of key carbon-carbon bond forming operations. The use of iridium species to form carbon-carbon bonds stereoselectively for the construction of complex intermediates was a relatively unexplored area until the late 1990 s.96,97 However, Takeuchi has shown that iridium catalysis contributed to the expanding the field of allylic alkylation catalysts. 1.B.5.1 Regioselectivity The control of regiochemistry in transition metal-catalyzed allylic alkylations is arguably the most important factor in determining the utility of a particular catalyst. As already mentioned, palladium typically results in alkylation at the least substituted allylic terminus, whereas molybdenum species selectively provide the branched regioisomers. However, prior to 1997, the catalysts that preferentially provided branched products did so using only a limited variety of substrates. Molybdenum83-, tungsten98- and ruthenium99-catalyzed processes provided the products arising from substitution at the more substituted terminus, but only on aryl or simple substituted substrates. However, Takeuchi and coworkers discovered and developed iridium complexes that not only catalyzed the allylic alkylation reaction, but did so regioselectively to yield the branched regioisomer.91 Preliminary studies illustrated that as little as 4 mol% of the iridium complex, [Ir(COD)Cl]2 was capable of catalyzing the allylic alkylation of 1b.103 with sodium diethyl malonate in a modest 66% yield after 19 h of heating under reflux (Table 1b.3, entry 1).100-102 Interestingly, the regioselectivity favored the linear substitution product 39 1b.105.101 The use of phosphine ligands allowed the reaction to be run under more mild conditions while having a significant effect on the yield of the reaction, and also the regioselectivity.100,101 For example, one equivalent of triphenylphosphite to iridium catalyst increased the yield to 90% and reversed the regioselectivity to favor the branched isomer 1b.104 (regioselectivity = 96:4) (entry 2). Use of either P(O-p-MeC6H4)3 or P(Op-FC6H4)3 as ligands slowed the reactions but did not increase the yield or show a dramatic effect on the regioselectivity (entries 3 and 4). The addition of triethylphosphite provided the products 1b.104 and 1b.105 in good yield, but poor regioselectivity, requiring reflux temperatures to see any conversion to product (entry 5). A reaction run in the presence of triphenylphosphine and dppe proceeded in poor yields resulting in a reversal of regioselectivity to favor 1b.105 (entries 6 and 7). In general, P(OPh)3 was found to provide superior results and was used as the additive in subsequent studies. 40 Table 1b.3. Selectivity in the iridium-catalyzed allylic alkylation of 1b.103. n-Pr OAc [Ir(COD)Cl]2 (0.02 mol%), Ligand NaCH(CO2Me)2, THF 1b.103 n-Pr + EtO2C CO2Et CO2Et n-Pr 1b.105 CO2Et 1b.104 Entry 1 2 3 4 5 6 7 Ligand P(OPh)3 P(O-p-MeC6H4)3 P(O-p-FC6H4)3 P(OEt)3 PPh3 dppe Temperature reflux rt rt rt reflux reflux reflux Time (h) Yield (%) 1b.104/1b.105 19 3 8 23 3 16 16 66 90 81 55 81 6 18 12:88 96:4 95:5 94:6 59:41 24:76 39:61 E/Z 97:3 78:22 73:27 94:6 90:10 63:37 94:6 The scope of the reaction was next examined by analyzing the behavior of allylically transposed acetates 1b.106 and 1b.107 under the optimized combination of ligand and iridium complex for the desired transformation (Table 1b.4). As in other experiments, alkylation of the linear allylic acetate 1b.106 provided the branched product 1b.108 in excellent yields ( 77%) and regioselectivities ( 95:5) regardless of whether the R group was phenyl (entry 3), methyl (entry 1) or a long alkyl chain (entry 5).100 Likewise, the secondary allylic acetate 1b.102 proceeded regioselectively ( 95:5) to provide the branched substitution product in excellent yields ( 86%) regardless of the nature of the R group (entries 2, 4 and 6). 41 Table 1b.4. Selectivity in the iridium-catalyzed allylic alkylation of 1b.106 and 1b.107. R 1b.106 or R OAc 1b.107 OAc [Ir(COD)Cl]2, P(OPh)3 NaCH(CO2Et)2, THF rt R + EtO2C CO2Et 1b.109 R CO2Et CO2Et 1b.108 Entry 1 2 3 4 5 6 Substrate 1b.106 1b.107 1b.106 1b.107 1b.106 1b.107 R Me n-Pr Ph Ph Oct Oct Yield (%) 77 86 98 91 95 95 1b.108/1b.109 97:3 95:5 99:1 99:1 95:5 95:5 E/Z 78:22 100:0 79:21 69:31 78:22 To examine the scope of the substitution pattern tolerated in iridium-catalyzed allylic alkylation reactions, the tertiary allylic acetate 1b.110 and the primary allylic acetate 1b.1113 were examined under optimized conditions.100 The reaction illustrated in Eq. 1b.12 proceeded in good yield and with complete regioselectivity to yield the substitution product 1b.111 (R = Me, n-Bu) bearing a quaternary carbon center. Conversely, attempted alkylation of the primary allylic acetate 1b.113 failed, yielding neither of the regioisomeric substitution products 1b.114 or 1b.115 (Eq. 1b.13). This result is not altogether surprising because most other transition metal catalysts failed to 42 promote the alkylation of substrates similar in substitution to acetate 1b.113. It is thought that the lack of reactivity is due to the inability of the metal catalyst to efficiently oxidatively ionize the allylic substrate in an SN2 fashion due to the increased steric interference caused by the trisubstituted olefin. R + EtO2C CO2Et R CO2Et CO2Et 1b.112 (1b.12) R OAc 1b.110 R = Me, n-Bu [Ir(COD)Cl]2, P(OPh)3 NaCH(CO2Et)2, THF 80% 1b.106/1b.107 = 100:0 1b.111 [Ir(COD)Cl]2, P(OPh)3 OAc 1b.113 NaCH(CO2Et)2, THF X EtO2C CO2Et 1b.114 + CO2Et CO2Et 1b.115 (1b.13) 1.B.5.2 Olefin Geometry Although the regioselective trends observed make iridium a synthetically attractive catalyst, one of its more intriguing properties is that in a few cases the olefin geometry was retained regardless of the structure of the starting allylic substrate.100,101 The unique nature of the iridium catalytic system is evident by comparison with other catalysts. For example, the use of both palladium7 and molybdenum75 catalysts, lead to rapid isomerization of Z-allylic substrates to the corresponding E-substitution products. It has been postulated that in the allylic alkylations catalyzed by these transition metals, nucleophilic addition was believed to proceed at a slower rate than h3-h1-h3 isomerization.73 Upon isomerization, the more stable anti allylmetal species should predominate, and alkylation would then occur to provide the corresponding transsubstitution product. Apparently in the iridium-catalyzed process, as illustrated by the 43 results obtained from the alkylation of Z-allylic acetate 1b.116, the rate of nucleophilic attack is faster than isomerization.101 For example the iridium-catalyzed allylic alkylation of the Z-allylic acetate 1b.116 with a series of ligands was examined (Table 1b.5).100 Use of P(OPh)3 as the phosphine additive provided the alkylation product 1b.117 in a 93:7 Z/E ratio, but with poor regioselectivity (1b.117/1b.118 = 75:25) (entry 1). However, when the bulkier phosphite ligand, P(O-2-t-Bu-4-MeC6H3)3 was used, the reaction proceeded in good yields to give synthetically useful Z/E ratios of substitution products. The reaction also provided the malonate 1b.117 in impressive linear/branched regioselectivities ( 97:3) regardless of the substituent R (entries 2-4). The only potential drawback to these conditions is the need to achieve refluxing temperatures to enable the alkylation to proceed in a synthetically useful time frame. Table 1b.5. Z-Selectivity in the iridium-catalyze allylic alkylation of 1b.116. [Ir(COD)Cl]2, Ligand R OAc 1b.116 NaCH(CO2Et)2, THF R CO2Et + CO2Et 1b.117 EtO2C CO2Et 1b.118 R Entry 1 2 3 4 a R n-Pra n-Prb n-Hexb n-Octb Ligand P(OPh)3 P(O-2-t-Bu-4-MeC6H3)3 P(O-2-t-Bu-4-MeC6H3)3 P(O-2-t-Bu-4-MeC6H3)3 Yield (%) 81 85 86 84 1b.117/1b.118 75:25 97:3 98:2 98:2 Z/E 93:7 92:8 90:10 88:12 Reaction reached completion in 2 h at room temperature. bReaction reached completion in 3-5 h at reflux. 44 1.B.5.3 Summary In conclusion, the iridium-catalyzed allylic alkylation, although not fully developed, is a regioselective reaction that provides the substitution products arising from alkylation at the more substituted allyl terminus, irrespective of the nature of the substituents on the carbon-carbon double bond. Other transition metal catalysts have exhibited this regiochemical trend, but the scope of those is limited to substrates that are phenyl-substituted so the alkylation occurs at the more electrophilic benzylic position. Moreover, iridium-catalyzed allylic alkylations also proceed to yield the Z-substitution products from Z-allyl acetates in a limited number of examples. These results are in stark contrast to palladium and molybdenum processes in which Z-substrates are isomerized to produce the corresponding E-substitution products. The stereoselectivity, although not addressed specifically in this section, follows the same trends observed with palladium and molybdenum. The ability of iridium complexes to catalyze allylic alkylations to regioselectively produce the more substituted alkylation products opens the door to asymmetric catalysis through the use of chiral ligands. 1.B.6 Ruthenium- and Tungsten-Catalyzed Allylic Alkylations The first reports of the use of tungsten to catalyze allylic alkylations surfaced as early as 1983, in a seminal publication by Trost and coworkers.98 A subsequent publication by Lloyd-Jones et. al. in 1995 elaborated on the use of a tungsten-bipyridine complex to mediate the desired transformation.103 It was not established that ruthenium was capable of catalyzing the allylic substitution reaction until the early 1990 s when Watanabe illustrated the use of Ru(h4-1,5-cyclooctadiene)(h6-1,3,5-cyclooctatriene), Ru(COD)(COT), as a regioselective allylic alkylation ruthenium catalyst.99 Trost and coworkers then reported in 2002 that the cationic ruthenium species, [(h545 C5Me5)Ru(NCMe)3]PF6, regioselectivity.104 catalyzed the allylic alkylation in excellent yields 1.B.6.1 Tungsten-Catalyzed Substitution Reactions Initial reports on tungsten-mediated allylic alkylations in the early 1980 s showed that allylic carbonates underwent alkylation when treated with 15 mol% The W(CO)3(MeCN)3, 15 mol% 2,2 -bipyridine (bpy) and a stabilized nucleophile. reaction was found to regioselectively provide the more substituted alkylation product.98 Findings illustrated that W(CO)6 was catalytically inactive, whereas W(CO)3(MeCN)3 showed modest reactivity (31% yield in 16 h). Efforts to enhance catalytic activity by the addition of phosphine ligands merely poisoned the catalyst. However, use of the bpy ligand led to a significant improvement in yield (65% in 18 h) presumably due to the strong s-donor capability of the bpy ligand to facilitate the opening of a coordination site on the metal. For example, treatment of either the conjugated allylic carbonate 1b.119 or the secondary allylic acetate 1b.120 with sodium dimethyl malonate in the presence of the tungsten-bypyridyl complex yielded the alkylation product 1b.121 resulting from alkylation at the more substituted allylic position (Eq. 1b.14). The aryl group was found to be critical in obtaining good regioselectivity in these cases, as alkyl substituted substrates often times gave mixtures of regioisomers, typically in a 75:25 ratio favoring the branched product. 46 Ar OCO2Me 1b.119 or Ar OAc 1b.120 Ar W(CO)3(MeCN)3, bpy NaCH(CO2Me)2, THF reflux 1b.121/1b.122 = 100:0 MeO2C CO2Me + Ar 1b.122 CO2Me CO2Me (1b.14) 1b.121 Ar = Ph Ar = Furyl 91% from 1b.119 81% from 1b.120 The diastereoselectivity of the process was shown to proceed with syn selectivity to provide the product of net retention of stereochemistry.98 This result runs parallel to that observed with palladium and molybdenum catalysts However, whether the reaction proceeded through a double inversion sequence as is observed with palladium, or a double retention as with molybdenum to result in a net retention was not explored. The chemoselectivity was likewise examined with the tungsten-bipyridyl catalyst, and it was observed that allylic carbonates underwent substitution exclusively in the presence of a primary alkyl bromide.98 Lloyd-Jones and coworkers in 1995 found that the more air-stable and THF soluble tungsten complex, W(CO)3(h6-C7H5)3, was a useful alternative to achieve identical regio- and stereoselective results in the allylic alkylation.103 They also established that the reaction proceeded with net retention of stereochemistry. Thus, alkylation of enantioenriched carbonate 1b.123 preferentially yielded the branched substitution product 1b.124 (1b.124/1b.125 = 96:4) in 84% yield without loss of optical purity (Eq. 1b.15). Catalyst reactivity led the authors to speculate that tungsten-catalyzed allylic alkylations did not proceed via the mechanism established for palladium and molybdenum. Nonetheless, conclusive mechanistic studies were not performed, and therefore remain purely speculative. 47 OCO2Me MeO2C W(CO)3(MeCN)3, bpy NaCH(CO2Me)2, THF 60 C, 11 h, 84% 1b.124/1b.125 = 96:4 CO2Me + MeO2C CO2Me (1b.15) 1b.123 1b.124 1b.125 88% ee 88% ee 1.B.6.2 Ruthenium-Catalyzed Allylic Substitutions Reports from Watanabe and coworkers on ruthenium-catalyzed allylic alkylations showcased the differences in product selectivity from other metal-stabilized allyl intermediates.99 Additionally, the intermediate p-ally ruthenium complexes exhibited a propensity to react as allyl nucleophiles under some conditions. Notably, by attenuating the reaction conditions in the ruthenium-catalyzed process, diallylation products were attainable, a transformation often times difficult under palladium catalysis. A series of allylic carbonates 1b.126 were alkylated with either a dialkyl malonate or b-ketoester nucleophile to yield mixtures of three different isomers (Table 1b.6).99 The product arising from alkylation at the more substituted allylic terminus was most often the dominant reaction product. However, presence of the isomerized product 1b.128 was observed in a few cases in which b-ketoesters were used as the nucleophile (entry 1). Although the alkylation of carbonate 1b.126 with b-ketoesters proved regioselective (entries 1 and 3), the use of dialkyl malonate gave equal amounts of branched 1b.127 and linear 1b.129 substitution products (entries 2 and 4). An additional finding was that diallylation of b-ketoesters could be accomplished by performing the reaction with as much as a three-fold excess of allylic carbonate. Treatment of allylic carbonate 1b.130 with methyl acetoacetate in the presence of Ru(COD)(COT) provided a mixture (10:90) 48 of the mono- and dilacerated products 1b.131 and 1b.132 respectively in good yield (Eq. 1b.16).99 Table 1b.6. Regioselectivity in the ruthenium-catalyzed allylic alkylation of 1b.126. Ru(COD)(COT) (4 mol%) R OCO2Me 1b.126 Nuc-, N-methylpiperidine 80 C, 10 h R 1b.127 Nuc + R 1b.128 Nuc + R 1b.129 Nuc Entry 1 R Ph Much O O OEt O O OEt O OEt O O OEt Yield (%) 69 1b.127/1b.128/1b.129 93:7:0 2 Ph EtO O 52 50:0:50 3 4 Me Me 73 46 90:0:10 50:0:50 EtO O OCO2Me + 1b.130 O O OMe Ru(COD)(COT) (4 mol%) O OMe + O O OMe (1b.16) N-methylpiperidine 50 C, 20 h 79% 1b.131/1b.132 = 10:90 1b.131 1b.132 Later Trost found that when the cationic ruthenium complex [(h5- C5Me5)Ru(NCMe)3]PF6 was used, the allylic alkylation of unsymmetrical carbonates proceeded in improved yield and with regioselectivities superior to those reported by Watanabe.104 In general, alkylations proceeded at the more substituted benzylic terminus with regioselectivities as high as 100:1. When either the linear or branched allylic 49 carbonate 1b.133 or 1b.134 was allowed to react with sodiodimethyl malonate in the presence of [(h5-C5Me5)Ru(NCMe)3]PF6 (1 mol%), the branched alkylation product 1b.135 was obtained in excellent yield (99%) and high regioselectivity (93:7) (Eq. 1b.17).104 The catalyst also provided substitution products with complete chirality transfer, as illustrated by alkylation of the chiral carbonate 1b.137 (94% ee) to provide the corresponding substitution product 1b.138 (94% ee) (Eq. 1b.18). Nitrogen and oxygen nucleophiles were also shown to be viable components in the rutheniumcatalyzed process as illustrated by the total synthesis of (-)-fluoxetine.104 Ph OCOt-Bu 1b.133 or OCOt-Bu Ph 1b.134 [Cp*Ru(MeCN)3] (1 mol%) NaCH(CO2Me)2, DMF rt, 2 h 99% 1b.135/1b.136 = 93:7 MeO2C Ph 1b.135 CO2Me CO2Me CO2Me 1b.136 + Ph (1b.17) OCOt-Bu MeO2C [Cp*Ru(MeCN)3] (1 mol%) NaCH(CO2Me)2, DMF CO2Me (1b.18) 1b.137 1b.138 94% ee 94% ee 1.B.7 Rhodium-Catalyzed Allylic Alkylation The first use of a rhodium species catalyst to promote the allylic alkylation of an allylic carbonate was reported in 1984 by Tsuji and coworkers.105 They found that the rhodium-catalyzed process showed a weak preference in some cases, to yield the products resulting from substitution at the allylic site that originally bore the leaving 50 group. This regioselectivity was heretofore unseen in studies involving other metals.105 Only two regiochemical trends had been previously observed in transition metalcatalyzed allylic alkylations. There were those in which the substitution occurred at the less sterically congested allyl terminus (as observed with palladium) or the more substituted site (preferred by molybdenum, iridium, ruthenium and tungsten catalysts). Evans and coworkers subsequently discovered a rhodium(I) complex capable of catalyzing the allylic alkylation to selectively provide substitution products resulting from alkylation at the more substituted terminus.106 These results are in accord with those observed for molybdenum, tungsten, iridium and ruthenium. 1.B.7.1 Regioselectivity Tsuji first examined the alkylation of methyl allylcarbonate 1b.139 with b- ketoester 1b.140 in the presence of Wilkinson s catalyst, RhCl(PPh3)3. Unfortunately, this rhodium(I) complex showed little catalytic activity in effecting this transformation. The addition of phosphines (95% with PnBu3) and phosphates (90% with P(OEt)3) enhanced the reactivity; however, yields were rather poor in some instances (15% with PPh3, and 90% with dppe). The real improvement was observed when the rhodium(I) source was changed from Wilkinson s catalyst to RhH(PPh3)4, and the alkylation was performed in the presence of PnBu3 to provide the substitution product in 93% yield.105 With a suitable catalyst system in hand, the regioselectivity of the allylic alkylations was analyzed by screening a number of allylic carbonates. Although the products arising from substitution at the more substituted terminus were formed exclusively from the corresponding branched carbonates, two substrates provided unusual results when alkylated with b-ketoester 1b.140. The primary allylic carbonate 1b.139 provided a mixture (72:28) of regioisomers 1b.141 and 1b.142 respectively in 97% yield 51 (Eq. 1b.19).105 However, when the secondary allylic carbonate 1b.143 was treated with 1b.140 in the presence of RhH(PPh3)4 and PnBu3, the regioselectivity of the reaction was reversed to favor 1b.142 (regioselectivity = 86:14) (Eq. 1b.20). Hence this observed substitution at the carbon bearing the leaving group laid the groundwork for additional studies of the rhodium-catalyzed allylic alkylations. O OCO2Me + 1b.139 1b.140 O OMe CO2Me + PnBu3, dioxane, 100 C 97% O 1b.141 O 1b.142 CO2Me (1b.19) RhH(PPh3)3 (5 mol%) 1b.141/1b.142 = 72:28 O OCO2Me 1b.143 + O OMe 1b.140 RhH(PPh3)3 (5 mol%) 1b.141 PnBu3, dioxane, 100 C 81% + 1b.142 (1b.20) 1b.141/1b.142 = 14:86 In 1998, Takeuchi described the use of [Rh(COD)Cl]2 in the presence of P(OPh)3 to catalyze the allylic substitution reaction.107 Although secondary allylic carbonates underwent alkylation in good yields and regioselectivities, primary carbonates were not very selective in providing one regioisomer over another. At about the same time, Evans and coworkers reported the use of a phosphite-modified Wilkinson s catalyst complex to catalyze the allylic alkylation of a series of unsymmetrical secondary and tertiary allylic carbonates.106 Evans found that the triorganophosphite-modified Wilkinson s catalyst, RhCl(PPh3)3/P(OMe)3, provided substitution products arising from alkylation at the more substituted allylic terminus (Table 1b.7).106 Secondary allylic carbonates of the type 1b.143 provided the branched substitution product 1b.144 in excellent yield and 52 regioselectivity in each case (entries 1-3). Reactions involving tertiary allylic carbonates were substantially more sluggish. In order to achieve useful selectivities for tertiary allylic carbonates, it was necessary to increase the catalyst load to 10 mol% from the 5 mol% catalyst load required for the secondary carbonates. Less trimethylphosphite was necessary for the secondary substrates than with the tertiary analogs (entries 4 and 5). Although the yields were erratic, the regioselectivity observed in these reactions was superb, providing the branched product 1b.144 almost exclusively. Interestingly, the chexyl methyl tertiary carbonate was unreactive under the reaction conditions (entry 6). Additionally, when the primary carbonate 1b.146 was subjected to the reaction conditions, no substitution product was obtained and 95% of the starting carbonate was recovered. The authors speculate that this result indicates the reaction does not proceed via a direct insertion mechanism. Rather, they proposed oxidative ionization in an SN2 fashion, which would be difficult given the increased steric congestion of carbonate 1b.146. The increased yield and excellent regioselectivities observed in the RhCl(PPh3)3/P(OMe)3 complex is presumably a consequence of the increased p-accepting of the phosphite ligand that upon coordination to the rhodium center increases the rate of catalytic turnover. 53 Table 1b.7. Regioselectivity in the RhCl(PPh3)3/(POMe)3-catalyzed allylic alkylation. R1 R2 OCO2Me 1b.143 Rh(PPh3)3Cl (5-10 mol%) NaCH(CO2Me)2 P(OMe)3, 30 C, THF R1 R2 CO2Me CO2Me 1b.144 + R1 R2 CO2Me CO2Me 1b.145 Entry 1 2 3 4 5 6 R1 H H H Me Me Me R2 Me Ph c-Hex Me Ph c-Hex Yield (%) 91 95 84 89 32 trace 1b.144/1b.145 99:1 98:2 93:7 99:1 99:1 - Rh(PPh3)3Cl, P(OMe)3 Ph OCO2Me 1b.146 NaCH(CO2Me)2 Ph X CO2Me + Ph CO2Me 1b.147 CO2Me CO2Me 1b.148 (1b.21) Two observations made by the Evans research group in 1998 led them to propose an alternative mechanistic hypothesis for the rhodium(I)-catalyzed allylic alkylation.106 The first observation was that the deuterated allylic carbonate 1b.149 underwent reaction with sodium dimethyl malonate in the presence of RhCl(PPh3)3/P(OPh)3 to produce a mixture ( 19:1) of substitution products 1b.150 and 1b.151 in 92% yield favoring 54 alkylation at the carbon that bore the leaving group (Eq. 1b.22). Similarly, alkylation of unsymmetrical carbonates 1b.152a/b provided the formal direct substitution products 1b.153 and 1b.154 in a 97:3 ratio.106 The authors suggested that these results illustrate the rhodium(I) species generated in situ was capable of exhibiting a memory effect with regards to leaving group departure and the site of alkylation (Eq. 1b.23). However, this level of selectivity was only observed when RhCl(PPh3)3 was modified with P(OPh)3 and not P(OMe)3. The experiments with carbonates 1b.149 and 1b.152 seem to indicate that, unlike the other transition metal-stabilized intermediates, the allylrhodium species does not equilibrate prior to alkylation, and therefore a common intermediate is not encountered when allylically transposed carbonates are alkylated. Therefore, it appears that the presence of P(OPh)3 slows the rate of equilibration between allylmetal intermediates. OCO2Me Me D 1b.149 Me Rh(PPh3)3Cl, P(OPh)3 NaCH(CO2Me)2 30 C, THF, 92% MeO2C Me CO2Me + D Me MeO2C D Me CO2Me (1b.22) Me 1b.151 1b.150/1b.151 19:1 1b.150 OCO2Me R1 1b.152 R2 Rh(PPh3)3Cl, P(OPh)3 NaCH(CO2Me)2 30 C, THF MeO2C Me CO2Me + MeO2C Me CO2Me (1b.23) i-Pr i-Pr 1b.154 1b.153 a: R1 = Me, R2 = iPr 83% 1b.153/1b.154 = 97:3 b: R1 = iPr, R2 = Me 87% 1b.153/1b.154 = 3:97 In order to account for the unusual regioselectivity Evans and Tsuji observed in these experiments, Evans proposed that the rhodium-catalyzed allylic alkylation reaction proceeded through an enyl (s+ ) intermediate rather than the -allyl complex thought to 55 be involved in other transition metal-catalyzed allylic alkylations (Scheme 1b.14).106 Upon rhodium(I) complexation and subsequent oxidative ionization to a secondary allylic substrate 1b.155, an enyl intermediate 1b.156 was presumably formed. This could undergo alkylation by the nucleophile in an SN2 -like fashion to yield the product of direct substitution 1b.157. Alternatively, 1b.157 may undergo s-p-s isomerization to yield enyl intermediate 1b.159, which when treated with the nucleophile provides the linear substitution product 1b.161a. Likewise, the primary allylic substrate 1b.158 would react via intermediate 1b.159, which can either undergo substitution to provide 1b.160 or isomerize to enyl 1b.156. Nucleophilic attack (k2) to 1b.156 is in all probability faster than isomerization (k-1) due to the relative stability of intermediate 1b.156 in comparison to 1b.159. The equilibrium position of the two intermediates is based on the influence of substituents on the ally moiety and their influence on the position of the transition metal (k1 >> k-1). However, in the absence of any overriding steric or electronic substituent effects, the allylic alkylation should proceed to give the direct substitution product without isomerization of the enyl intermediates. Scheme 1b.14 OLG R 1b.155 Rh(I) Rh(III) R 1b.156 NucNuc R 1b.157 Path A k2 k-1 k1 Rh(I) R OLG 1b.158 Rh(III) R 1b.159 Nuc- Path B k3 R 1b.160 Nuc 56 1.B.7.2 Stereoselectivity Evans then expanded the scope of the rhodium(I)-catalyzed allylic alkylation to include acyclic unsubstituted33 and a-alkoxy-substituted108 copper(I) enolates as nucleophiles. The use of unstabilized enolates in the allylic substitution reaction dramatically enhances the synthetic utility of the method by enabling the use of more structurally diverse nucleophiles. The use of hard nucleophiles in transition metal- catalyzed allylic alkylations has suffered from a number of limitations associated with regiochemical inconsistency.109 To overcome the inherent drawbacks to this class of nucleophiles, Evans attenuated the hardness of the alkali metal enolate salt by transmetallation with a copper(I) salt, thereby rendering the anion softer.33 When ketone 1b.161 was treated with LiHMDS, transmetallated with CuI, then treated with allylic carbonate 1b.162 in the presence of RhCl(PPh3)3/P(OMe)3, the secondary substitution product was obtained in a regioisomeric ratio 19:1 (Eq. 1b.24). Subsequent ring closing metathesis with Grubbs ruthenium catalyst yielded a mixture (10:1) of the anti and syn cyclohexene products 1b.163 and 1b.164.33 O Ph OCO2Me + BnO 1. LiHMDS, CuI, 0 C; RhCl(PPh3)3, P(OMe)3 2. Grubbs' catalyst CH2Cl2, rt, 75% 1b.158 Ph BnO 1b.159 O + Ph BnO 1b.160 O (1b.24) 1b.157 ds = 10:1 2 /1 19:1 In a subsequent report, Evans illustrated how acyclic a-alkoxy-substituted copper(I) enolates could be used as nucleophiles in the allylic substitution reaction catalyzed by RhCl(PPh3)3/P(OMe)3.108 One of the key features of this method is the high diastereoselectivity observed in the alkylation of unsymmetrical allylic carbonates. 57 Alkylation of carbonate 1b.165 with the copper enolate of a-benzyloxyketone 1b.166 in the presence of RhCl(PPh3)3/P(OMe)3, followed by Baeyer-Villiger oxidation110,111 provided ketone 1b.167 in excellent yield and regio- and diastereoselectivity (Eq. 1b.25).108 The authors proposed that the acyclic diastereocontrol was obtained via a Zchelated enolate 1b.168 that avoids an unfavorable eclipsing interaction between the copper metal the substituent R2 present in 1b.169 (Figure 1b.1). This constitutes a regioand diastereoselective method to alkylate unsymmetrical allylic alcohol derivatives with acyclic a-alkoxy-substituted enolates. O + Ar OBn 1b.161 1b.162 NHTs 1. LiHMDS, THF, CuI RhCl(PPh3)3, P(OMe)3 2. SnCl4, (TMSO)2, K2CO3 NHTs 89% ArO OBn 1b.163 O (1b.25) OCO2Me ds 19:1 2 /1 99:1 Figure 1b.2. Proposed transition states for the observed diastereoselectivity in Eq. 1b.25 Cu H O Ph X RhLn H R2 O X = OR1 Ph H H X R2 Cu RhLn 1b.168 Favored TS 1b.169 Disfavored TS The scope of the rhodium(I)-catalyzed allylic alkylation was further expanded in 2003 by Evans when he reported the use of organozinc halides to alkylate unsymmetrical allylic alcohol derivatives regioselectively.112 When the enantioenriched allylic fluorocarbonate 1b.170 was treated with the arylzinc bromide in the presence of 58 TpRh(C2H4)2 (Tp = hydrotris(pyrazolyl)borate), LiBr and dibenzylideneacetone (dba) at 0 C, a mixture (10:1) of the arylated products 1b.171 and 1b.172 was obtained in 90% yield (Eq. 1b.26). Interestingly the reaction proceeded without loss of optical purity to provide 1b.171 in 95% ee, but an inversion of absolute configuration was observed. The stereochemical outcome of this process is most likely a result of an anti-syn mechanism in which the rhodium catalyst ionizes the allylic carbonate in an anti fashion, the aryl group is transferred to the rhodium(III) species by transmetallation followed by reductive elimination in a syn manner to provide an overall inversion of absolute configuration. OCO2CH(CF3)2 Me 1b.170 TpRh(C2H4)2, Et2O LiBr, dba, ArZnBr 90% Me 1b.171 1b.172 Ar + Ar (1b.26) 95% ee 1b.171/1b.172 = 10:1 Ar = 95% ee t-Bu 1.B.7.3 Summary The Evans research group pioneered the use of -allylrhodium chemistry by developing a high yielding, regioselective method enabling the allylic alkylation of unsymmetrical allylic carbonates. The development of this class of allylic alkylations raises serious questions as to the nature of the allylmetal intermediates due to the observation that limited examples involving P(OPh)3 a memory effect was observed resulting in substitution products in which the nucleophile becomes bonded to the carbon bearing the leaving group. The authors propose that this indicates a slow isomerization of allylrhodium intermediates in the absence of overriding substituent effects that often dictated the regiochemical outcome in molybdenum-, tungsten- and iridium- catalyzed processes. The scope of the procedure was expanded by using heteroatom (phenols45 and 59 sulfonamides53), unstabilized copper(I) enolates and organozinc halide nucleophiles as viable components in the overall carbon-carbon bond forming event. The reaction proceeded with net retention of absolute configuration in the allylic alkylation of enantioenriched allylic carbonates with stabilized nucleophiles, net inversion of configuration when treated with unstabilized aryl zinc reagents, and unique diastereocontrol in sequential allylic substitutions to allow for control of 1,3stereochemistry.113 1.B.8 The Transition Metal-Catalyzed Enantioselective Allylic Alkylation More recent advances in the realm of allylic alkylations have led to the development of enantioselective variants. When chiral ligands are present on the catalyst, the metal species then becomes an asymmetric manifold by which the overall process can be rendered enantioselective. The majority of the work by far has been focused on palladium-based chiral templates,5,13 although significant advances have been made using molybdenum,114-118 and reports have also surfaced using tungsten119, iridium101 and rhodium.120 Some of the most common ligands used for these asymmetric transformations are depicted in Figure 1b.3. Ligand 1b.173 is most commonly referred to as the Trost ligand named for its discoverer. The BINAP121,122 (1b.174) and DIOP123 (1b.176) ligands, although extremely useful for enantioselective hydrogenations, have shown limited utility in asymmetric allylic substitutions. Likewise, the bisoxazoline 1b.175 ligands have also exhibited limited asymmetric induction in allylic alkylations. 60 Figure 1b.3. Chiral ligands employed in asymmetric allylic alkylations. O NH HN PPh2 Ph2P 1b.173 1b.174 O O PPh2 R 1b.175 N N R Ph2P 1b.176 PPh2 O Ph2P O O An notable example of the use of an asymmetric allylic alkylation in the total synthesis of a complex natural product is illustrated by synthesis of the macrolide amphidinolide 1b.180 (Scheme 1b.15).124 The approach featured assembly of the chiral side chain employing the asymmetric allylic alkylation of meso-allylic carbonate 1b.178 with sulfone ester 1b.177 in the presence of ligand ent-1b.173 to provide the alkylation product 1b.179 in 90% ee and as a mixture (1:1) of diastereomers. This disconnection led to an efficient, atom economical approach to this complex natural product. Scheme 1b.15 CO2Me N N N + S N O O Ph 1b.177 OCO2Et Pd2dba3 (1.5 mol%), ent-1b.167 (6 mol%) CsCO3, CH2Cl2 1b.178 CO2Me N N N S N O O Ph 1b.179 84%, 90% ee O HO HO HO OH amphidinolide A (1b.180) O O 61 This discussion on the enantioselective variant of transition metal catalyzed allylic substitutions is brief, and the reader is encouraged to consult any number the reviews cited on the subject for further information. Although the asymmetric allylic alkylation has been around for quite some time, relatively little has been accomplished using the vast array of allylic alkylation catalysts capable of mediating the carbon-carbon bond forming event. The future of this transformation may lie in the development of new chiral ligands for different metal templates to combine asymmetry with the catalyst s unique regio-, chemo- and stereoselectivity to achieve the synthesis of previously problematic target structures. Due to its broad applicability the synthetic community should witness greater application of the asymmetric variant of the allylic alkylation with each coming year. 1.B.9 Overall Summary of Section 1.B Although particularly succinct in covering the enormous volume of work that has been presented over the past 30-35 years on transition metal-catalyzed allylic alkylations, this discussion should afford the reader with a broad sense of what can be accomplished with the different transition metals capable of forming -allyl intermediates from ionizable allylic substrates. The issue of regioselectivity in the allylic alkylation is quite possibly the defining factor that separates one catalyst system from another. Also, the mechanistic rationales and hypotheses set forth by the prominent researchers in the field have provided a wealth of intellectual discussion on the origin of the three different types of regioselectivity observed. There are three general regiochemical trends observed in the transition metalcatalyzed allylic alkylation. The first arises as a result of primarily steric effects to yield substitution products arising from alkylation at the less hindered allyl terminus, as 62 exemplified by palladium catalysis. Second, electronic factors play the dominant role in product distribution yielding alkylation at the more substituted allylic carbon, as observed with molybdenum, tungsten, iridium, ruthenium and with most rhodium catalysts. Finally, there have been limited reports in rhodium-catalyzed allylic alkylations of substitution occurring at the site of leaving group departure resulting in a formal direct substitution reaction. Transition metal catalysts have been sufficiently developed to address the first two of these regiochemical trends with broad scope and utility with regards to the allylic substrate and nucleophile. However, a catalyst which showed a general propensity for formal direct substitution of the leaving group had yet to be discovered. The stereoselectivity exhibited in the allylic alkylation proved quite general regardless of the metal complex used. In each case, alkylations with stabilized anions provided overall net retention of configuration. Most catalysts are thought to proceed via an anti-anti mechanism, except in the case of molybdenum which was shown to go through a syn-syn pathway. To stay competitive with the catalysts known to mediate this process, any new transition metal complexes should at least allow for the reaction to proceed without loss of enantiopurity. In the future, studies on the allylic substitution reaction may be classified not only by the substrates involved, but by the transition metal used to catalyze it, the overall stereoselectivity throughout the reaction and the synthetic utility of the alkylation products. There is still the potential to explore the origin of, optimize to a useful synthetic level, and determine the scope of various combinations of the selectivities enjoyed by each transition metal catalysts in the development of novel processes. Additionally, given the number of different reactions some allylic alkylation catalysts mediate, the potential for developing cascade reaction sequences should be a major area 63 of emphasis in future studies. These opportunities should maintain the transition metalcatalyzed allylic alkylation as one of the most vigorously studies and useful reactions in modern synthetic organic chemistry. 1.C TRANSITION METAL-CATALYZED CARBOCYCLIZATION REACTIONS 1.C.1 Introduction The term carbocyclization has been used extensively in recent years to describe those cyclizations that involve a carbon-carbon bond forming event to close a ring, which is often mediated by a transition metal catalyst.125 These types of reactions are typically distinguished by the formation a metallocycle intermediate. The presence of this metalstabilized species separates these annulations from those which proceed through radical intermediates and those initiated by thermal or photochemical means. Given such a broad definition, it comes as no surprise that a wide variety of transformations fit this loose criteria. Cyclopropanations,126 annulations including the Pauson-Khand reaction,127,128 the Heck reaction,129-132 and numerous [m+n+o] cycloadditions fall into this category of transformations.125 A number of different metal species exist that are capable of catalyzing these reactions. Palladium-mediated transformations129,133,134 have been one of the more widely studied classes, although ruthenium, rhodium, titanium, and molybdenum have seen applicability as well.125 The overall process typically involves a specific carbometallation event. The transition metal catalyst transfers one carbon atom-containing fragment across either a carbon-carbon double bond or triple bond to form the metallocycle intermediate. Often times the fragment 1c.2 transferred by the catalyst 1c.1 to the original p-system 1c.3 via intermediate 1c.4 is a carbon-carbon double or triple bond (Scheme 1c.1). Formation of 64 the five-membered metallocycle 1c.5 occurs upon carbometallation. If the alkene and alkyne depicted in Scheme 1c.1 are tethered, the reaction then becomes intramolecular, and a carbocyclization event ensues. Given the enormous volume of published work on transition metal-catalyzed carbocyclization reactions125 the discussion herein will be limited to asymmetric cyclopropanations,126,135-137 [5+2] cycloadditions,138 Pauson-Khand annulations127,128,139 and cycloisomerizations.133,134,140 In the context of these transformations, only the most widely used catalysts which provide superior results will be addressed. Scheme 1c.1 Complexation MLn 1c.1 + 1c.2 + 1c.3 1c.4 MLn Carbometallation MLn 1c.5 1.C.2 Transition Metal-Mediated Asymmetric Cyclopropanation Reactions The cyclopropanation of olefins via transition metal-catalyzed decomposition of diazoalkanes has long been recognized as a critical tool in the synthesis of complex natural products.126,141,142 The study of the cyclopropane subunit has been the focus of many research groups for a number of years due to the synthetic potential incorporated into the small, strained carbocycle. Attempts to synthesize this highly-strained cycloalkane subunit has led to many approaches. A main thrust in recent decades has been the development of highly diastereo- and enantioselective process for the synthesis of cyclopropanes.143-146 The ligation of chiral entities on the surface of transition metal catalysts generate a chiral template through which the desired cyclopropanation reaction is rendered asymmetric.126 Diazoalkanes are typically substrates of choice in this 65 process due to their ease in preparation and reactivity.136,147 In general, diazoalkanes of type 1c.8-1c.11, which differ only in their various electronic properties, are treated with a transition metal catalyst in the presence of an alkene 1c.6 to form the desired cyclopropane 1c.7. The relative stereochemistry of the cyclopropanation is often determined by the geometry of the carbon-carbon double bond and the substituents occupying the allyl or homoallyl positions along the chain (Scheme 1c.2). The absolute stereochemistry is thereby dictated by the chiral ligands on the metal catalyst. Scheme 1c.2 R1 1c.6 N2CHR3 R2 MLn R1 1c.7 R2 R3 (TMS) H N2 H (Ar) EWG N2 H EWG N2 R EWG1 N2 EWG2 1c.8 1c.9 1c.10 1c.11 Substrates of the type 1c.10 in which the R group is vinyl provide vinylcyclopropanes that may serve as intermediates in the synthesis of more functionalized cyclic148-151 and acyclic152,153 alkanes. Vinylcyclopropanes 1c.14 are obtained by diazodecomposition of 1c.13 to yield a vinylcarbenoid species that upon subsequent reaction with alkene 1c.12 provides the desired product (Scheme 1c.3).154,155 In much of the early work on cyclopropanations utilizing diazoesters, carbenoids derived from 1c.13 had shown limited utility, suffering from low yields and poor stereoselectivity.156 Additionally, the vinyldiazomethane precursors are notoriously difficult to handle, often times rearranging to 3H-pyrazoles.157 However, subsequent 66 work reported by Davies showed that rhodium(II) acetate facilitated the cyclopropanation of vinyldiazoesters 1c.13 to yield vinylcyclopropanes 1c.14.158 The synthetic utility of the reaction was expanded by placing a diene moiety in place of the simple alkene in 1c.11c. The intermediate vinylcyclopropane would then undergo a Cope rearrangement to access bicyclic compounds 1c.15-1c.19.158,159 Products arising from ring opening of cyclopropane 1c.20 as well as simple, enantioenriched cyclopropanes are also obtained from this process.160 Scheme 1c.3 + EWG N2 1c.13 H 1c.15 R O O R' R1 1c.12 H2N CO2H 1c.21 R1 R2 R' CO2Me R EWG 1c.14 NR1 O R2 1c.20 1c.16 R1 R2 R3 CO2Me R7 R6 O 5 R4 R CO2Me R3 R2 R1 O 1c.19 R1 1c.17 R2 1c.18 The generally accepted catalytic cycle for the cyclopropanation of olefins via diazodecomposition is illustrated in Scheme 1c.4.135 67 Electrophilic addition of a coordinatively unsaturated transition metal catalyst to the diazo compound 1c.22 produces a transient electrophilic metal carbene 1c.23 as first proposed by Yates in 1952.161 Subsequent loss of dinitrogen provides the metal-stabilized carbene 1c.24, which undergoes cyclopropanation with an electron rich substrate 1c.25. Transfer of the carbene center from the metal to the substrate completes the catalytic cycle. Scheme 1c.4 S: 1c.25 SCR2 1c.26 R2C MLn 1c.24 MLn N2 LnM CR2 N2 1c.23 N2 CR2 1c.22 The focus of this section will rest heavily on asymmetric cyclopropanations catalyzed by either chiral copper or rhodium complexes. Additionally, different variants will be addressed to provide the reader with a succinct overview of the multitude of study that has been incorporated into this area of synthetic chemistry. Although a number different catalysts and ligand combinations have been reported for various substrates, the 68 goal of this discussion is to provide the reader with a broad overview, providing a reference from which more in-depth analysis can be undertaken if so desired. 1.C.2.1 Intermolecular Cyclopropanations The most common substrates for intermolecular cyclopropanations are adiazoesters of the type 1c.27 (Y = OR).136,147,162 However, a number of similar compounds 1c.28-1c.31 have been shown to be viable substrates in the asymmetric cyclopropanation reaction (Figure 1c.1).163-167 Diazosubstrates containing just one electron withdrawing group, such as a-diazoester 1c.27, proved to be excellent substrates in intramolecular and intermolecular reactions with a wide array of catalysts. The reaction of diazoesters with achiral alkenes is one of the most studied asymmetric reactions in past decades. Issues of diastereo- and enantioselectivity have been critically examined and comprise the forefront of studies to date.147 Figure 1c.1. Typical a-diazo reagents used in intermolecular cyclopropanations. O H N2 1c.27 Y H N2 1c.28 CN H N2 O P(OR)2 H N2 1c.30 SO2R H N2 1c.31 NO2 1c.29 In general, alkene 1c.32 will react with the diazodecomposition product of a diazoester and transition metal catalyst such that the cyclopropanation event can potentially provide one of four possible cyclopropanes 1c.33-1c.36 (Scheme 1c.5). Typically, the field of products can be halved if one chooses the appropriate alkene and diazoester combination to maximize the trans/cis ratio of diastereomers. In many cases, an appropriate R1 substituent on the alkene substrate or the use of a bulky ester group R2 69 on the diazoester in conjunction with the catalyst can heavily influence the diastereomeric ratio of the cyclopropanation through a number of steric and electronic factors.168 The addition of chiral ligands to the reaction mixture can further simplify the situation by rendering the overall transformation enantioselective. Scheme 1c.5 R1 N2CHCO2R2 R1 1c.32 CO2R2 1c.33 R1 CO2R2 1c.34 Chiral Catalyst R1 CO2R2 1c.35 R1 CO2R2 1c.36 A number of catalysts have been shown to provide the resulting cyclopropanes in good yields and selectivity in the intermolecular reaction. The catalysts that have been shown to be the most effective are copper-, rhodium-, ruthenium- and cobalt based species.168 Overall, copper(I) salts provide the best combination of trans/cis ratio of products with good to excellent enantiomeric excesses.169,170 Additionally, copper seems to enjoy a broader substrate scope than do other metal catalysts. Rhodium has also been shown to be an extraordinary cyclopropanation catalyst. However, in intermolecular reactions, the rhodium catalysts examined have yielded moderate trans/cis ratios and low ee s.171 On the other hand, cobalt has been shown to be quite cis selective, but the catalysts are not easy to prepare due to the complexity of the ligands required.172 A vast array of ligands have been developed for the copper-catalyzed asymmetric cyclopropanation. Evans reported the use of bis(oxazoline) ligand 1c.38 as an extremely efficient chiral ligand.173 Due to the success enjoyed by 1c.38, this ligand has been used as the benchmark standard from which subsequent bis(oxazoline) ligands are measured 70 against to compare efficiency and selectivity.170 The scope of substrates in the copper(I)catalyzed transformation is quite broad. It has been demonstrated that highly substituted alkenes,170 cyclic silyl enol ethers174 and vinyl halides175 are well tolerated. For example, cyclopropanation of allyl ether 1c.37 with ethyl diazoacetate in the presence of CuOTf and ligand 1c.38 provided cyclopropane 1c.39 in 74% yield, good trans/cis ratio (88:12) and excellent enantiomeric excess (93% ee) (Eq. 1c.1).176 O N OBn tBu O N tBu 1c.38 OBn (1c.1) CO2Et 1c.39 CuOTf, N2CHCO2Et 74% 1c.37 trans/cis = 88:12 trans = 93% ee In recent years, a number of ligands have been developed that are capable of inducing asymmetry in copper-catalyzed cyclopropanation reactions. Nozaki was the first to report the use of an N-benzylethylamine-based chiral salicylaldimino complex to cyclopropanate styrene with ethyldiazoacetate albeit in a mere 6% ee.177 Over the next 40 years, a plethora of ligands, some with small and others with significant structural variations on Nozaki s ligand, have been reported to catalyze this reaction. Just a few examples of such ligands are illustrated in Figure 1c.2. Pfaltz reported in the mid-1980 s that semicorrin-type ligand 1c.40 provided good dr s and excellent ee s of each diastereomer in the cyclopropanation of styrene with menthyl diazoacetate.178,179 Unfortunately this class of ligands suffers from low yields with unactivated alkenes due to the poor Lewis acidity of the ligands. Ligands 1c.41,180 1c.42181 and 1c.43182 represent just two of the many bis(oxazoline) ligands and other bidentate ligands capable of 71 catalyzing cyclopropanations with excellent results. Bipyridine-type ligands such as 1c.44 have also been shown to be effective in providing good trans/cis ratios and enantioselectivities.183,184 Figure 1c.2. Chiral Catalysts Used for the Asymmetric Cyclopropanation of Styrene N N N HOMe2C Cu 1c.40 N CMe2OH TMSOMe2C CuOTf 1c.41 N CMe2OTMS O N tBu O N Cu 1c.42 tBu dr = 82:12 (N2CHCO2d-menthyl) trans = 97% ee, cis = 95% ee dr = 84:16 (N2CHCO2d-menthyl) trans = 98% ee, cis = 99% ee dr = 86:14 (N2CHCO2l-menthyl) trans = 98% ee, cis = 96% ee O N N O CuOTf (PhH)0.5 1c.43 tBu tBu N TMS N TMS CuOTf (PhH)0.5 1c.44 dr = 68:32 (N2CHCO2l-menthyl) trans = 95% ee, cis = 97% ee dr = 86:14 (N2CHCO2t-Bu) trans = 92% ee, cis = 98% ee Rhodium-catalyzed cyclopropanations have also found great applicability, but intramolecular variants often suffer from poor diastereoselectivity. As shown in Eq. 1c.2, the cyclopropanation of styrene with menthyl diazoacetate in the presence of the chiral dirhodium catalyst 1c.46 provided a mixture (37:63) of cyclopropanes 1c.47 and 1c.48 in 45% ee and 99% ee respectively.185 In a few cases, the cis diastereomers can be produced selectively in good ee to provide an option for the asymmetric synthesis of cis cyclopropanes.186 The rhodium-bound carbene is one of the more reactive carbenoid species when compared to other metals. 72 However, in general the level of diastereocontrol is quite low in comparison.171 This lack of selectivity has led to the limited employment of rhodium catalysis in intermolecular cyclopropanations. MeO CO2Me O MeO O 4 Rh Rh 1c.46 Ph 1c.45 N2CHCO2d-menthyl 100% Ph CO2R Ph + CO2R (1c.2) 1c.47 1c.48 trans/cis = 37:63 45% ee 99% ee Although the utility of chiral rhodium catalysis in enantioselective intermolecular cyclopropanation reactions has been limited, a number of catalysts developed provide useful levels of enantioselective induction in intramolecular cyclopropanations and C-H insertions. The early transition state for such processes indicate that the chiral environment, as dictated by the ligands on the metal, must extend out to if not beyond the electrophilic carbene carbon. Therefore the spatial arrangement of the ligands should play a key role in the asymmetric induction. Figure 1c.3 illustrates three different metal geometries 1c.49-1c.51 in which the chiral ligands may orient themselves. As can be seen, the octahedral arrangement of structure 1c.51 places the ligands on the metal nearest to the reacting carbene center.155 Figure 1c.3. Carbene-bound transition metal geometries. L L L 1c.49 M C H L L 1c.50 R L L M C H L R L L R H M C L 1c.51 73 The ligands having found broad applicability in rhodium-catalyzed processes can be divided into two classes, dirhodium(II) carboxylates 1c.52-1c.57 (Figure 1c.4)187-189 and carboxamides 1c.58-1c.88 (Figure 1c.5).171,190-192 Prolinate derived carboxylate catalysts 1c.52-1c.54 encompass the vast majority of successful ligands in this category. One general observation is that the N-arylsulfonyl group seems to be a critical structural requirement for useful enantioselectivities.160 Although the phthalamide derivatives of phenylalanine 1c.57 gave improved results over other dirhodium catalysts in asymmetric cyclopropanations, it has been shown to be a more effective chiral ligand in C-H insertion reactions.193 The catalysts shown are dimeric, and are presumed to maintain this dimeric structure throughout the course of the reaction. Each catalyst contains four bridging carboxylate ligands allowing for coordination of the substrate to the axial sites on the metal center that is where metal carbene formation is thought to occur. 74 Figure 1c.4. Chiral dirhodium(II) carboxylate ligands for asymmetric cyclopropanations. Dirhodium(II) Carboxylates: O N O S O O 4 Rh Rh O O NPhth 4 Rh Rh R 1c.52 R = H Rh2[2S-BSP]4 1c.53 R = tBu Rh2[2S-TBSP]4 1c.54 R = C12H26 Rh2[2S-DOSP]4 1c.55 O O 4 Rh Rh O Ph N O O O 4 Rh Rh 1c.56 1c.57 Chiral dirhodium(II) carboxamidates have enjoyed widespread utility in enantioselective cyclopropanations. Complexes developed by Doyle and coworkers over the past couple of decades have been shown to be applicable in the synthesis of biologically active natural products.137,155,171,191,194-196 Each catalyst is dimeric in nature, as seen in the carboxylate series 1c.52-1c.57. However, the catalysts all contain four bridging carboxamides with a nitrogen and oxygen from each ligand bound to the metal (Figure 1c.5). Additionally, the spatial arrangement around the metal center is such that two nitrogens are adjacent to each other. The arrangement that places the stereogenic center within the ligand moiety a to the metal-bound nitrogen atom allows for the R group to extend out from the catalyst center toward the electrophilic carbene. As in the dirhodium(II) carboxylate catalysts, the axial coordination sites are free, and it is there 75 that carbene formation is thought to occur. The four types of carboxamide ligands depicted in Figure 1c.5 are most effective in asymmetric catalysis involving metal carbene formation.126,136 What separates these catalysts from conventional ligand design is that the focus does not involve incorporating steric interactions to control enantioselectivity, but to includes dipolar influences and electrostatic effects to obtain an optimal ligand design. Figure 1c.5. Chiral dirhodium(II) carboxamidate ligands. Dirhodium(II) Carboxamides: R X N O 4 R Rh Rh Rh2[5S-MEPY]4 Rh2[5S-NEPY]4 Rh2[5S-ODPY]4 Rh2[5S-DMAP]4 1c.62 1c.63 1c.64 1c.65 1c.66 N O 4 O Rh Rh Rh2[4S-MEOX]4 Rh2[4S-THREOX]4 Rh2[4S-BNOX]4 Rh2[4S-IPOX]4 Rh2[4S-PHOX]4 1c.58 1c.59 1c.60 1c.61 R = CO2Me R = CO2Et R = CO2(CH2)17Me R = CONMe2 R = CO2Me, X = H R = CO2Me, X = Me R = Bn, X = H R = i-Pr, X = H R = Ph, X = H R N O 4 RO2C Rh Rh N O 4 O X 1c.77 1c.78 1c.79 1c.80 1c.81 1c.82 N Rh Rh R = CO2Me, X = Me R = CO2Me, X = Ph R = CO2Me, X = 4-t-BuC6H4 R = CO2Me, X = Bn R = CO2Me, X = PhCH2CH2 R = CO2Me, X = c-C6H11CH2 Rh2[4S-MACIM]4 Rh2[4S-MBOIM]4 Rh2[4S-TBOIM]4 Rh2[4S-MPAIM]4 Rh2[4S-MPPIM]4 Rh2[4S-MCHIM]4 1c.83 1c.84 1c.85 1c.86 1c.87 1c.88 R = i-Bu R = Bn R = Me R = CH2CMe3 R = c-C6H11 R = l-menthyl Rh2[4S-IBAZ]4 Rh2[4S-BNAZ]4 Rh2[4S-MEAZ]4 Rh2[4S-IBAZ]4 Rh2[4S-CHAZ]4 Rh2[4S-, R-menthAZ]4 Diazoesters substituted by an aryl or vinyl group were also explored as substrates in the enantioselective cyclopropanation reaction. These types of reagents are attractive in that they incorporate a second functional group to serve as a handle for future 76 manipulations. Early results indicated that rhodium(II) catalysts provided the best ratios of trans/cis isomers than most other transition metal catalysts.197 Davies was the first to explore the use of auxiliaries on the diazoester substrate198,199 and chiral dirhodium(II) catalyst for the asymmetric cyclopropanation of this class of compounds.187 In 1996, Davies showed that the cyclopropanation of alkene 1c.90 with vinyldiazoester 1c.89 in the presence of either dirhodium(II) carboxylate catalysts 1c.53 or 1c.54 proceeded with an excellent level of enantiocontrol (Table 1c.1).160 The yields were moderate at best, with the simple vinylacetate 1c.90 (R = OAc) substrate suffering from a particularly poor 26% yield (entry 2). Although complete diastereocontrol was observed in each case, trans-disubstituted alkenes were unreactive under the optimized conditions. Alternatively, chiral auxiliaries could be implemented in the transformation in lieu of a chiral dirhodium(II) catalyst. Excellent diastereoselectivity was observed in these The method was also quite reactions to provide a single diastereomeric product. efficient, producing the cyclopropanation products in good yields.199 Table 1c.1. Enantioselective rhodium(II)-catalyzed intermolecular cyclopropanation. Ph N2 1c.89 CO2Me + Rh2(TBSP)4, (1c.53) R 1c.90 or Rh2(DOSP)4, (1c.54) Ph R 1c.91 CO2Me Entry 1 2 3 4 R Ph AcO EtO i-Pr Catalyst 1c.54 1c.54 1c.54 1c.53 77 Yield (%) 68 26 65 58 ee (%) 98 95 93 95 To rationalize the level of diastereocontrol asymmetric induction observed in these chiral dirhodium(II)-catalyzed intermolecular cyclopropanations, the authors proposed a model as exemplified by Figure 1c.6.160 Upon decomposition of the vinyldiazoester with the chiral rhodium catalyst, the resulting metallocarbene intermediate formed is depicted by structure 1c.92. Approach of the alkene to the stabilized carbene center from the side of the electron-withdrawing group leads to structure 1c.93. Clockwise rotation of the alkene during the cyclopropanation event yields the cyclopropane product 1c.94. The unusually high level of diastereocontrol arises from the approach of the alkene in the metallocarbene intermediate from the side occupied by the ester functionality. The presence of both an electron-donating group, such as a vinyl moiety, and an electron-withdrawing group (i.e. methyl ester) is critical to controlling the approach of the alkene in this fashion. Substrates which lack this dual push-pull relationship of electron flow suffer from particularly low diastereocontrol with these dirhodium(II) catalysts as was observed with unsubstituted a-diazoesters. Figure 1c.6. Model for stereocontrol observed in the dirhodium(II)-catalyzed cyclopropanations. Ph R MeO2C Rh Bulky Ligand 1c.92 R O Rh 1c.93 OMe Ph H R Ph Rh 1c.94 MeO2C Clockwise Rotation 1.C.2 Intramolecular Cyclopropanations Intramolecular cyclopropanations in which the diazoester functionality and the alkene to be cyclopropanated are tethered within the same molecule provide an opportunity to form various bicyclic ring systems.200,201 The issue of diastereocontrol is 78 crucial, but in the formation of larger ring structures where the absence of steric strain allows for the formation of diastereomeric products stereocontrol can become more problematic. Typically, the most successful substrates have involved g,d-unsaturated or d,e-unsaturated diazocarbonyl systems to form [3.1.0] and [4.1.0] bicyclic products. In these cases, diastereocontrol is not an issue because only one diastereomer can be formed due to the inherent ring strain of the bicycle. Although a number of different transition metals are capable of catalyzing these transformations, copper and rhodium catalysts have been found to be particularly successful at inducing exceptional enantioselectivity. Additionally, the types of substrates that can be used for this reaction class can be categorized into three classes, diazoketones, diazoesters and diazoacetamides. Each type of substrate has been shown to be suitable in asymmetric intramolecular cyclopropanations. The use of chiral catalysts for mediating the intramolecular cyclopropanation of diazoketones has been thoroughly examined, and until recently, Pfaltz obtained the best results with the copper(I) catalyst 1c.40.202 Although good to excellent enantioselectivities were observed, the reactions typically suffered from low yields (<60%). Since then a number of dirhodium(II) catalysts derived from ortho-metallated aryl phosphine ligands exhibited excellent yields and comparable enantioselectivities.203 However, the copper(I) derived species seem to be the preferred transition metal complexes for catalyzing this class of transformations. In his phorbol CD-ring skeleton synthesis, Shibasaki showed that the asymmetric copper(I)-catalyzed cyclopropanation could be performed on a silyl enol ether. When silyl enol ether 1c.95 was treated with the bis(oxazoline) catalyst 1c.96, the desired [4.1b.0] bicycle 1c.97 was produced in good yield (70%) and 92% ee (Eq. 1c.3).204,205 79 O N TMSO O N2 1c.96 N O OTMS (15 mol%) CuOTf (5 mol%) CH2Cl2, 0 C rt 70%, 92% ee O H (1c.3) TESO 1c.95 OTES 1c.97 The intramolecular cyclopropanation of diazoacetates constitutes an important class of substrates. This reaction has found a number of useful applications in target oriented synthesis as a method for the formation of [n.1.0] bicycles. Depending upon the nature of the diazoacetate substrate employed, the products obtained from this transformation can be divided into two categories. The most common cyclopropane products, the Class A cyclopropyl lactone 1c.99, is derived from a substrate in which the pendant olefin is incorporated into the ester 1c.98 (Eq. 1c.4). The second category, Class B, is not quite as common due to the fewer synthetic opportunities their products present. The substrates typified by this category incorporate the alkene into part of the alkyl side chain of the molecule, as depicted by 1c.100 (Eq. 1c.5). The products arising from these cyclopropanations are cyclopropanecarboxylates 1c.101. This reaction is far less common, and suffers from the lack of a chiral catalyst which can render this reaction asymmetric with synthetically useful selectivities.206 80 Class A: Cyclopropyllactone Formation N2 n rhodium or copper n (1c.4) O 1c.99 O O 1c.98 O Class B: Cyclopropanecarboxylate Formation O n CO2R rhodium or copper n CO2R (1c.5) 1c.100 1c.101 Small (five and six membered) and medium/large rings are accessible from the Class A cyclopropanations. The dirhodium(II) carboxamidate catalysts are optimal in the asymmetric synthesis of small ring bicyclic lactones, whereas medium/large ring products are formed with superior enantiocontrol by using the bis(oxazoline) ligated copper(I) species.207 A number of other catalysts have also shown utility in the intramolecular asymmetric cyclopropanation of diazoesters including cobalt208 and ruthenium.209 These metals have been shown to be particularly useful in the synthesis of trisubstituted cyclopropanes in the formation of small ring bicycles The synthesis of 1,2,3-trisubstituted cyclopropanes has also been a compelling area of study in intramolecular cyclopropanations. If the diazoacetate is secondary or tertiary the issue of endo versus exo diastereomers arises, thereby complicating issues of diastereoselectivity. The chiral dirhodium(II) carboxamide catalyst Rh2[(5S)-MEPY]4 has been shown to impart exemplary enantiocontrol, and in some cases diastereocontrol, in the cyclopropanation of these substrates. In 1994, Martin and coworkers illustrated that divinyl diazoesters 1c.102 underwent cyclopropanation in the presence of Rh2[(5S)MEPY]4 to yield cyclopropyl lactones 1c.103 and 1c.104 in good yields and 81 enantioselectivities (Eq. 1c.6).210 In the case of monosubstituted (R = H) divinyl substrates, the diastereoselectivity observed was excellent (1c.103/1c.104 > 95:5). However, when the olefins were symmetrically 1,2-disubstited (R = Me), the two diastereomers were formed in nearly equal amounts. Homoallylic diazoacetates 1c.105 were also viable cyclopropanation substrates with Rh2[(5S)-MEPY]4 to form the corresponding [4.3.0] bicycles 1c.106 in moderate yields and with slightly lower enantioselectivities overall (Eq. 1c.7).194,211 One observation made by the authors was that the olefin substitution was not critical in dictating the stereochemical outcome of the cyclopropanation of diazoacetate 1c.105 as it was for the corresponding allylic diazoacetates 1c.102. O O R R N2 Rh2(5S-MEPY)4 R O 1c.103 R=H 75% >95 ( 94% ee) 45 (92% ee) O R H + R R H O (1c.6) O 1c.104 <95 1c.102 R = Me 73% 55 (91% ee) R1 R2 R3 O O 1c.105 71-90% ee N2 Rh2(5S-MEPY)4 CH2Cl2, reflux 55-80% R2 R3 R1 H O O (1c.7) 1c.106 In addition to analyzing the diastereoselectivity of 1,1-disubstituted divinyl diazoesters such as 1c.102, the Martin group also examined how the corresponding 1,2disubstituted substrates, such as vinyl iodide 1c.107, would react under standard 82 cyclopropanation conditions. It was discovered that upon diazodecomposition of 1c.107 with Rh2[(5S)-MEPY]4, regioisomers 1c.108 and 1c.109 were formed in excellent diastereomeric ratios and enantioselectivities.210 In this way, racemic divinyl diazoacetates could be kinetically resolved by formation of the corresponding cyclopropyl lactones selectively. Intriguingly, the chiral catalyst was capable of selectively cyclopropanating one enantiomer of diazoacetate 1c.107 onto both pendant olefins thereby forming the two regioisomers, enantioselectively. represents one of the early examples of parallel kinetic resolution. O O N2 Rh2[(5S)-MEPY]4 CH2Cl2, reflux I 1c.107 41% 90% de 87% ee 42% 88% de 91% ee I 1c.108 1c.109 H O H O + O H H I H (1c.8) O This reaction 1.C.2.3 The Origin of Diastereo- and Enantioselection in the Intramolecular Asymmetric Cyclopropanation of a -Diazoesters with Chiral Rhodium(II) Catalysts Although a number of chiral dirhodium(II) carboxamidate catalysts have found utility in the intramolecular asymmetric cyclopropanation reaction, a great majority of the work in exploring the chemo-, diastereo-, and enantioselectivities associated with this class of chiral catalysts have been performed utilizing the 5-MEPY 1c.58a/b dirhodium(II) series (Figure 1c.7).126 The carboxamide ligands orient themselves around the metal center as illustrated by structures 1c.58a and 1c.58b, a trend followed by the majority of carboxamide ligands associated with the dirhodium(II) cyclopropanation 83 catalysts.171 As alluded to earlier, this leaves the axial coordination sites on the metal open for carbene formation. When viewed along the Rh-C bond of the metal-stabilized carbene, the face of the catalyst can be divided into four quadrants in which the substrate approach can occur. Two of these quadrants are occupied by the methyl carboxylate group on the ligands themselves leaving only one open for the carboxylate group of the substrate and the other for approach of the alkene. Calculations have shown that the preferred spatial arrangement is that dictated by structure 1c.111 in which the olefin approaches the electrophilic carbene center from the less hindered si face. Structure 1c.110 where the olefin approaches the carbene center by bisecting the N-Rh-N bond angle has a higher calculated energy minima, and it is therefore postulated that it contributes less to the overall product distribution. Figure 1c.7. Structures and proposed substrate approach in the Rh2[5(S)-MEPY]4Rh2[5(R)-MEPY]4-catalyzed cyclopropanations H O O Rh N N O Rh O N N N CO2Me O O Rh N O Rh O N N CO2Me H Rh2(5S-MEPY)4 (1c.58a) Rh2(5R-MEPY)4 (1c.58b) N A N H N H A O2C O O O2C N O A O 1c.110 A 1c.111 84 A simple model to explain the observed enantioselectivities obtained by using Rh2[(5R)-MEPY]4 is illustrated below in Scheme 1c.6.191 Considering the approach angle of the olefin, which was calculated to have the lowest possible energy minima in structure 1c.111, the steric limitations on the metal stabilized carbene dictate that the orientation, when Ri = H, is represented by 1c.112. Upon cyclopropanation, structure 1c.112 produces the observed cyclopropane product 1c.114, whereas the rotameric 1c.113 provides the minor enantiomeric adduct 1c.115. Alternatively, if angle of approach in the higher energy structure 1c.116 is considered, the reaction proceeds to form the enantiomeric cyclopropanes 1b.114 and 1c.115 via the rotameric structures 1c.116 and 1c.117. Analysis of structure 1c.112, which leads to the observed major product, shows that a trans substituent (Rt) would interact unfavorably with the ester functionality on the carboxamidate ligands thereby leading to a decrease in the energy difference between 1c.112 and 1c.113. This decrease in energy would cause a decrease in the enantioselectivities, which is in fact what is observed. However, the presence of a cis substituent (Rc) should not adversely effect the outcome of the reaction due to the remote position of Rc to the reacting center. Their hypothesis is likewise supported by the experimental data. 85 Scheme 1c.6 E O Rh O N N Rt E Ri Rc O O O Rh O N 1c.113 H E N ER c Rt H Ri O O 1c.112 Rc Ri O Rt H O O Rt H O Rc Ri 1c.114 1c.115 E N E O Rh O N Rc Rt H Ri O O 1c.116 E O N E N Rh O Ri Rt Rc H O O 1c.117 Diazoacetamides were also analyzed for their efficacy in the intramolecular cyclopropanation reaction.212 As illustrated in Table 1c.2, Rh2[(5S)-MEPY]4 provided superior results for diazoacetamide 1c.118 (compare entries 1 and 2) in which the olefin was monosubstituted.213 However, the presence of a methyl group at the terminus of the olefin required the use of Rh2[(4S)-MPPIM]4 to provide a good yield and enantioselectivity. It is noteworthy that the use of N-methyl acetamides as 86 cyclopropanation substrates resulted in minimal dipolar addition side-products, and provided the s-trans conformers preferentially. Table 1c.2. Enantioselective intramolecular cyclopropanation of diazoacetamide 1c.118. N2 O R2 R1 1c.118 NMe N Me 1c.119 Chiral Dirhodium(II) Catalyst R1 H R2 H O Entry 1 2 3 R1 H H Me R2 H H Me Catalyst Rh2[(5S)-MEPY]4 Rh2[(4S)-MPPIM]4 Rh2[(4S)-MPPIM]4 Yield (%) 62 20 88 ee (%) 93 75 94 The use of aryl and vinyl diazoacetates in the enantioselective intramolecular cyclopropanation proved to be a more challenging endeavor than their corresponding alkyl counterparts. For these substrates, a more reactive catalyst was required. Consequently, a delicate balancing act ensued to establish conditions that provided the best yield and optimal enantioselectivity. Davies has shown that the chiral dirhodium(II) catalyst, Rh2[(S)-DOSP]4 (1c.54), is quite useful in catalyzing these stubborn cyclopropanations in an asymmetric fashion.159 When vinyl diazoester 1c.120, containing either a 1,1- or trisubstituted, was treated with 1c.54, the corresponding cyclopropane 1c.121 was obtained in moderate yield and good enantioselectivity (entries 2 and 3, Table 1c.3). However, when a monosubstituted olefin was employed, the yield of the 87 transformation was good (81%) although the enantioselectivity suffered (28% ee) (entry 1). Table 1c.3. Asymmetric intramolecular cyclopropanation of vinyl diazoacetate 1c.120. O Ph N2 1c.120 O R1 R3 R2 O 1c.121 O Rh2(S-DOSP)4 Ph R3 R2 R1 Entry 1 2 3 R1 H Me Me R2 H H Me R3 H H Me Yield (%) 81 53 46 ee (%) 28 87 60 Doyle has recently shown that the use of aryl diazoacetates provides the corresponding cyclopropyl lactones in excellent yield and enantioselectivity when the dirhodium(II) species Rh2[(4S)-IBAZ]4 (1c.83) and Rh2[(4S)-MEAZ]4 (1c.85) are employed (Table 1c.4).196,214,215 Treatment of aryl diazoester 1c.122 with 1c.54 resulted in an excellent yield (92%), but poor enantiomeric excess (28% ee) (entry 1). However, utilizing Doyle s chiral dirhodium(II) carboxamidate catalysts 1c.83 and 1c.85, the desired products were obtained in good yield ( 80%) and moderate enantiomeric excess ( 68% ee). 88 Table 1c.4. Asymmetric intramolecular cyclopropanation of aryl diazoacetate 1c.122. O Ph N2 1c.122 O O 1c.123 O Chiral Dirhodium(II) Catalyst R3 R1 R2 Ph Entry 1 2 3 Catalyst Rh2[(S)-DOSP]4 Rh2[(4S)-IBAZ]4 Rh2[(4S)-MEAZ]4 Yield (%) 92 83 80 ee (%) 28 64 68 1.C.3 The Transition Metal-Catalyzed [5+2] Cycloaddition of Alkynes and Vinyl Cyclopropanes Although a long standing goal in the synthetic community has been to develop efficient, atom economical methods to assemble complex molecules, in recent years, greater emphasis has been placed on synthetic routes which exemplify these aspects. One focus of many synthetic methods is to create a way in which intermediates can be obtained in an environmentally friendly, practical and efficient manner. Cycloadditions constitute one of the most powerful ways in which the target compound can be efficiently synthesized, as these reactions often allow for the formation of multiple bonds and the creation of a number of stereocenters in a one-pot sequence. Another requirement, which most cycloadditions adeptly fulfill, is the use of readily available starting materials.216 Possibly the most often utilized cycloaddition reaction is the Diels-Alder cycloaddition.217 The desire to form six membered rings in a concise, stereocontrolled manner has kept the Diels-Alder reaction at the forefront of modern organic synthesis. 89 The simple requirement of a diene and dienophile, formally a 4p electron system in conjunction with a 2p electron system, make the Diels-Alder reaction that much more attractive (Eq. 1c.9). The available methods for seven-membered ring synthesis are much less general than the Diels-Alder reaction in that they are often severely limited in scope. The number of ways in which one can construct a seven-membered ring are few in comparison to the wide range of methods for the synthesis of their six-membered analogs. The two basic methods of assembling seven-membered rings are essentially isoelectronic variations of each other. The first involves exchanging the dienophile 2p electron component in the Diels-Alder reaction for a 3 carbon, 2p electron allyl cation fragment 1c.128, as illustrated in Eq. 1c.11a. Such [4+3] cycloadditions yield the cationic 7-membered ring 1c.129.218-220 The second variant employs a pentadienyl cation 1c.130 which can then undergo a charged [5+2] cycloaddition to yield the allyl cationic seven-membered ring 1c.132 as illustrated in Eq. 1c.11b.221-223 Unfortunately, both methods described require the use, or formation of ionic intermediates to achieve the desired carbon-carbon bond forming events. A unique solution to the issue of ionic intermediate involvement was first posed by Sarel and Breuer in 1959.224 The authors proposed that the reactivity pattern shared by vinylcyclopropanes and dienes could be harnessed to yield seven-membered rings via a cycloaddition pathway. Their hypothesis was such that the reaction of an electronically neutral vinylcyclopropane (5 carbon, 4 electron component), in place of the diene component in the Diels-Alder reaction, with a dienophile (2 carbon, 2 electron component) would yield the corresponding seven-membered ring by a concerted cycloaddition/cyclopropyl ring opening pathway (Eq. 1c.12). They reported that a phenyl substituted vinylcyclopropane reacted with maleic anhydride to yield a seven-membered ring product through a [5+2] cycloaddition pathway. Unfortunately, repeated attempts by 90 independent research groups to reproduce this result proved fruitless.225 In some isolated examples, vinylcyclopropanes were shown to react with activated olefins, but only to yield products arising from the [2+2] cycloaddition pathway.226 [4+2] Cycloaddition + 1c.124 4C 4 e1c.125 2C 2 e- (1c.9) 1c.126 6-membered ring + 1c.127 4C 4 e1c.128 3C 2 e- [4+3] Cycloaddition (1c.10) 1c.129 7-membered ring + 1c.130 5C 4 e1c.131 2C 2 e- [5+2] Cycloaddition (1c.11) 1c.132 7-membered ring + 1c.133 5C 4 e1c.134 2C 2 e- [5+2] Cycloaddition (1c.12) 1c.135 7-membered ring Although numerous attempts were made, a useful [5+2] cycloaddition strategy had proved elusive. A few reports had surfaced in which the authors were able to obtain products containing seven-membered rings, but the methods were extremely limited in scope, and the vinylcyclopropanes involved required activation by enhanced ring strain associated with incorporation into a heteroatom-containing bicyclic array.227-229 91 Fortunately, the 1980 s saw this problem of medium ring synthesis addressed in a bold new way, namely through the use of transition metal catalysis.145 A number of research groups began by examining the use of transition metals to catalyze those reactions which proved difficult or impossible through the use of conventional synthetic methods. Notably, Wender and coworkers reported in 1986 the first example of a transition metalcatalyzed intramolecular [4+4] cycloaddition of bis-dienes to yield eight-membered rings.230 The overall reaction process is thermally forbidden and even under photochemical conditions is inefficient, often leading to the more entropically favored [2+2] cycloadduct. However, as illustrated in Eq. 1c.14, treatment of diene 1c.136 with the metal complex Ni(COD)2 and PPh3 provided the [4+4] cycloadduct 1c.137 in 84% yield and with excellent stereoselectivity (>99:1). The process proved to be quite broad in scope as a wide array of substrates were tolerated, thereby allowing access to the core carbon frameworks of a variety of natural products. H Ni(COD)2 (5 mol%), PPh3 (10 mol%) (1c.13) PhMe, 60 C, 84% CO2Me >99:1 Stereoselectivity 1c.136 CO2Me 1c.137 In addition to catalyzing [4+4] cycloadditions, otherwise difficult [4+2] cycloadditions have also been reported as proceeding smoothly in the presence of transition metal complexes. For example, diene 1c.138 suffers from decomposition under standard Diels-Alder conditions. However, in the presence of a nickel(0) catalyst, the dienyne readily undergoes the metal-catalyzed [4+2] cycloaddition to provide 1,4-diene 1c.139 (Eq. 1c.14).231 Given the success at constructing six- and eight-membered rings 92 through the use of transition metal catalysts, efforts were turned toward the assembly of seven-membered ring products. OAc Ni(COD)2 (5 mol%) P(O-o-BiPh)3 (30 mol%) THF, 55 C, 85% H (1c.14) OAc 1c.138 1c.139 1.C.3.1 The First Transition Metal-Catalyzed Intramolecular [5+2] Cycloadditions In 1995, Wender an coworkers reported the use of a transition metal catalyst to construct seven-membered rings through a formal intramolecular [5+2] cycloaddition strategy.232 When vinylcyclopropylenynes 1c.140 were treated with a rhodium(I) catalyst, the [5.3.0] bicycles 1c.141 were be obtained (Eq. 1c.15). The process proved to be exceptionally efficient and broad in scope, thereby providing a long awaited solution to the problem of medium-sized ring construction. The process has been shown to be suitable for a variety of substituted E- and Z-alkenes.233 Additionally, electron rich, electron poor and conjugated internal and terminal alkynes were fitting substrates.234 Systems with additional substitution on the alkene moiety proved efficient [5+2] cycloaddition precursors, providing the desired cycloadducts under the optimized conditions. For some sterically congested substrates with multiple substituents along the 1,6-enyne backbone (R1, R2 H), longer reaction times were required to achieve complete consumption of the starting enyne. Yields for the transformation were found to be quite insensitive to reaction concentration, but concentrations of 0.05 to 0.1 were found to be optimal. Reactions run at concentrations above 1a.1 become heterogeneous and were slower, although they still proceeded in good yield.235 93 R1 Rh(PPh3)3Cl/AgOTf or [Rh(CO)2Cl]2 R2 MeO2C MeO2C 1c.140 1c.141 R3 MeO2C MeO2C R2 R3 (1c.15) R1 Intramolecular [5+2] Cycloaddition When vinylcyclopropane 1c.142 was treated with 10 mol% RhCl(PPh3)3 in PhMe, cycloadduct 1c.143 was obtained in 84% yield after 48 h.232 However, increasing the solvent polarity by using trifluoroethanol in place of PhMe, allowed the reaction to reach completion in only 19 h. The authors propose that this dramatic decrease in reaction time is due to facilitated ligand dissociation commonly experienced with solvents of increased polarity. Remarkably, when 0.5 mol% of RhCl(PPh3)3 was used in conjunction with 0.5 mol% AgOTf in PhMe at 110 C, the desired cycloadduct 1c.143 was obtained in 83% yield after 20 min (Eq. 1c.16). The addition of AgOTf to the reaction mixture is thought to facilitate the irreversible formation of a vacant coordination site on the rhodium(I) species by precipitating AgCl from the solution. This seminal work by Wender s group proved to be the beginning of an elaborate study toward illustrating the impact the rhodium(I)-catalyzed [5+2] cycloaddition would be to modern synthetic chemistry. RhCl(PPh3)3 (0.5 mol%), AgOTf (0.5 mol%) MeO2C MeO2C 1c.142 PhMe, 110 C, 20 min, 83% MeO2C MeO2C (1c.16) 1c.143 94 Scheme 1c.7 X 1c.149 MLn X 1c.144 Reductive Elimination Complexation MLn X X 1c.148 MLn 1c.145 Strain Driven Ring Expansion X MLn Cyclometallation 1c.146 or LnM X 1c.147 The mechanistic design behind the development of this transition metal-catalyzed [5+2] cycloaddition is illustrated in Scheme 1c.7.236 Initial complexation of the metal species to cyclopropyl enyne 1c.144 provides intermediate 1c.145. Subsequent oxidative addition to the enyne moiety via a well established cyclometallation pathway yields either the five- or six-membered metallocycles 1c.146 or 1c.147 respectively. Assisted strain driven ring expansion of the cyclopropane by the proximal metal-carbon bond occurs to yield metallocyclooctadiene 1c.148. Reductive elimination of the transition metal 95 catalyst regenerates the active complex and provides the [5+2] cycloadduct 1c.149. Overall, the ingenuity and foresight exhibited by the Wender group resulted in the first catalytic [5+2] cycloaddition reaction of a vinylcyclopropane and alkyne. The method was further extended to include the intramolecular [5+2] cycloaddition of cyclopropyl dienes of the type 1c.150 (Eq. 1c.17).233 The use of 1,6dienes in this metal-catalyzed reaction provided the first insight into the relative stereochemistry at the bridgehead carbon atoms. Additionally, utilizing alkenes in the place of alkynes allowed access into previously difficult seven-membered ring analogs which can be utilized as intermediates in target directed synthesis. Therefore, treatment of ene-vinylcyclopropane 1c.150 with 1 mol% RhCl(PPh3)3 and 1 mol% AgOTf provided cycloadducts 1c.151 in 93% yield as a single diastereomer. MeO2C MeO2C H MeO2C MeO2C H 1c.151 (1c.17) RhCl(PPh3)3 (1 mol%), AgOTf (1 mol%) PhMe (0.05 M), 110 C, 5 h 93% 1c.150 1.C.3.2 Regio- and Stereoselectivity in the Rhodium(I)-Catalyzed Intramolecular [5+2] Cycloaddition of Cyclopropyl Enynes In 1998, Wender and coworkers reported the use of a new rhodium(I) species capable of catalyzing the [5+2] cycloaddition in a uniquely selective fashion.234 They found that [Rh(CO)2Cl]2 catalyzed the intramolecular [5+2] cycloaddition of various cyclopropylenynes to typically provide the [5.3.0] bicyclic cycloadducts in a more efficient fashion than the analogous RhCl(PPh3)3/AgOTf catalyzed reactions. This observation led to a detailed analysis of the scope and utility of this novel [5+2] 96 cycloaddition catalyst. In multiple instances the RhCl(PPh3)3/AgOTf catalyst system either failed to provide the desired cycloadduct, proceeded in low yield after extended reaction times at elevated temperatures, or gave mixtures of double bond isomers in the products with a number of different substrates. Wender thus discovered a new catalyst that would prove more efficient at catalyzing the cycloaddition of problematic substrates. When [Rh(CO)2Cl]2 was used as the rhodium(I) source to catalyze the [5+2] cycloaddition of cyclopropylenynes 1c.152 and 1c.155, cycloadducts 1c.153 and 1c.156 were obtained in excellent yields without formation of the double bond isomerized byproducts 1c.154 and 1c.157 (Eqs. 1c.18 and 1c.19). However, when RhCl(PPh3)3 was used to catalyze the reaction of enyne 1c.152, cycloadduct 1c.153 was obtained in a diminished 69% yield after 2 d along with 20% of the double bond isomers 1c.154. Likewise, when enyne 1c.155 was treated with RhCl(PPh3)3/AgOTf at 100 C for 17 h, a mixture (5:1) of cycloadducts 1c.156 and 1c.157 was produced. The authors propose that the lower ligand count of the anticipated active catalyst species, Rh(CO)2Cl, may aid in cyclopropane ring expansion by facilitating coordination to the metal. Unfortunately, when the dimeric rhodium(I) catalyst, [Rh(CO)2Cl]2, was used to facilitate the cycloaddition of enynes containing terminal alkynes and alkenes, no cycloadducts were obtained. However, the RhCl(PPh3)3/AgOTf combination gave moderate to high yields of the desired products. As for those cases in which a terminal alkyne was involved, the authors proposed that the electron deficient nature of the catalyst led to primarily alkyne C-H insertion over the [5+2] cycloaddition pathway. With regards to the presence of a terminal alkene, no reaction occurred even after prolonged reaction times at elevated temperatures. 97 Rh(I) MeO2C MeO2C 1c.152 MeO2C MeO2C + MeO2C MeO2C (1c.18) E/Z = 3.3:1 5 mol% [Rh(CO)2Cl]2 2 M, 110 C, 3 h 10 mol% RhCl(PPh3)3 110 C, 2 d 1c.153 84% 69% 1c.154 0% 20% Rh(I) O O 1c.155 + O (1c.19) E/Z = 3.3:1 5 mol% [Rh(CO)2Cl]2 110 C, 20 min 10 mol% RhCl(PPh3)3/AgOTf 100 C, 17 h, THF 1c.156 78% 65% 1c.157 0% 13% A systematic study was performed by Wender and coworkers in 1999 to analyze the regio- and stereochemical trends observed in the [Rh(CO)2Cl]2-catalyzed [5+2] cycloaddition.237 The results seemed to indicate that the stereoselectivity in the reaction is independent of the rhodium(I) catalyst. However, the regioselectivity observed when disubstituted cyclopropanes were employed as substrates varied markedly on the source of rhodium(I) and the nature of the functional group substituent on the three-membered ring. Then, the [5+2] cycloaddition of a cyclopropyl enyne 1c.158 could potentially yield any one of the four possible regio- and diastereoisomers 1c.159-1c.162 (Scheme 1c.8). The diastereoselectivity in the cycloaddition was determined to depend solely on the stereochemistry around the cyclopropane ring. Enynes with trans substitution as in 1c.158 provide [5.3.0] bicycles with the proton at the bridgehead position and the substituent R in a trans alignment across the ring system as in cycloadducts 1c.159 and 1c.160. However, enynes containing cis-cyclopropanes yield cycloadducts with the 98 corresponding relative stereochemistry in a cis configuration as depicted by structures 1c.161 and 1c.162. Scheme 1c.8 R R MeO2C H 1c.159 MeO2C H 1c.161 Path A MeO2C MeO2C Path A H H R H H 1c.158 Rh(I) Path B Path B MeO2C MeO2C H 1c.160 R MeO2C MeO2C H 1c.162 R The regioselectivity in the intramolecular [5+2] cycloaddition reaction was not such a clear-cut issue. A number of factors seem to dictate whether the cycloaddition would proceed via Path A or Path B to yield either regioisomers 1c.159/1c.161 or 1c.160/1c.162. The experimental results led the authors to propose that the regiochemical outcome of the reaction is determined by which bond of the cyclopropane is cleaved in the ring expansion step in the proposed mechanism outlined in Scheme 1c.8. If the more substituted cyclopropane bond is severed (Scheme 1c.8, path A) cycloadducts 1c.159 and 1c.161 are produced. However, if the less substituted bond is cleaved, the cycloaddition yields 1c.160 and 1c.162 following reductive elimination of the metal complex. It was determined that there existed a delicate balance of three separate factors dictating which regioisomer would be formed preferentially. First, the nature of the catalyst played a significant role in the regioselectivity, most notably in the trans series of cyclopropyl enynes. When methyl ester-substituted cyclopropanes such as 1c.163 were treated with [Rh(CO)2Cl]2, only one regioisomer 1c.165 was produced, whereas the 99 combination RhCl(PPh3)3/AgOTf provided the regioisomeric cycloadduct 1c.164 (Scheme 1c.9). Secondly, the functional group nature of the cyclopropane substituent strongly influenced the regioselectivity of the reaction. Functional groups varying from silyl-protected methyl carbinols to aldehydes and methyl esters often times gave very different results. Lastly, the stereochemistry about the cyclopropane ring also had an effect on the regiocontrol of the [5+2] cycloaddition, although not nearly as pronounced as the influence this factor had on the diastereoselectivity. Scheme 1c.9 Rh(PPh3)3OTf PhMe, 110 C, 1 h 81% H CO2Me H MeO2C MeO2C 1c.163 [Rh(CO)2Cl]2 PhMe, 110 C, 1 h 93% CO2Me MeO2C MeO2C H 1c.165 MeO2C MeO2C H 1c.164 CO2Me The trans-cyclopropylenyne 1c.166 was analyzed first to see how dramatic an effect the first two factors would play on the outcome of the cycloaddition (Table 1c.5). The substrates 1c.166, in which the R group was either a silyl-protected carbinol or a methyl ester, gave good yields and exhibited excellent regiocontrol with RhCl(PPh3)3/AgOTf as the rhodium(I) source (entries 1 and 5). However, when an aldehyde functionality was present on the cyclopropane ring, this cationic rhodium 100 complex failed completely, giving only decomposition products. When [Rh(CO)2Cl]2 was employed as the cycloaddition catalyst, a different set of results was obtained for each enyne substrate. Excellent yields were obtained as was observed with RhCl(PPh3)3/AgOTf. However, the formyl substituted substrate proceeded in 98% yield, a result which contrasted sharply with the decomposition observed when RhCl(PPh3)3/AgOTf was employed. Additionally, the formyl substituted enyne proceeded with complete regioselectivity to provide exclusively cycloadduct 1c.168. For R = CO2Me, the regioselectivity was reversed, yielding a mixture (11:1) of cycloadducts favoring cleavage of the more substituted cyclopropane bond. When enyne 1c.166 (R = CH2OTBS) was subjected to the optimized reaction conditions, the major cycloadduct was still 1c.167 regardless of the rhodium catalyst, but the level of regiocontrol was greatly diminished when [Rh(CO)2Cl]2 was used, decreasing from 100% to 77% of the product mixture. 101 Table 1c.5. The [5+2] cycloaddition of trans-2-substituted-1-vinylcyclopropanes. H R R H MeO2C MeO2C 1c.166 Rh(I) (10 mol%) PhMe, 110 C MeO2C MeO2C H 1c.167 R + MeO2C MeO2C H 1c.168 Entry 1 2 3 4 5 6 R CH2OTBS CH2OTBS CHO CHO CO2Me CO2Me Catalyst Rh(PPh3)3OTf [Rh(CO)2Cl]2 Rh(PPh3)3OTf [Rh(CO)2Cl]2 Rh(PPh3)3OTf [Rh(CO)2Cl]2 Yield (%) 95 86 decomposition 98 81 93 1c.167:1c.168 1:0 3.5:1 0:1 20:1 1:11 The cis-cyclopropylenyne series produced noticeably different results than those observed for the corresponding trans-substrates. When cyclopropyl enyne 1c.169 was treated with RhCl(PPh3)3/AgOTf for each of the same functional groups that 1c.166 was tested with, similar regiochemical results were obtained regardless of the R group (Table 1c.6, entries 1, 3 and 5). For R = CO2Me and CH2OTBS, cycloadduct 1c.170 was favored in excellent overall yields, whereas the formyl substituted cyclopropane resulted in decomposition as with 1c.166. However, in general the cis-substituted 1c.169 did not benefit for the most part by switching catalysts to [Rh(CO)2Cl]1c. Enyne 1c.169 still 102 provided cycloadduct 1c.170 exclusively in excellent yield and regioselectivity, except when R = CO2Me (entry 6). In this case a nearly equal mixture of 1c.170 and 1c.171 was produced. Interestingly, the formyl substituted cyclopropyl enyne 1c.169 gave an excellent yield of exclusively cycloadduct 1c.171 resulting from cleavage of the more substituted cyclopropane bond, a result congruent with that which was observed in the trans series (entry 4). The experimental results depicted in Tables 1c.5 and 1c.6 seem to indicate that cyclopropyl enynes in which the ring is substituted by a formyl group constitute a unique class of substrates in which the more substituted cyclopropane bond is preferentially cleaved in the [5+2] cycloaddition regardless of the rhodium catalyst. Table 1c.6. The [5+2] cycloaddition of cis-2-substituted-1-vinylcyclopropanes. R H R H MeO2C MeO2C 1c.169 Rh(I) (10 mol%) PhMe, 110 C MeO2C MeO2C H 1c.170 R + MeO2C MeO2C H 1c.171 Entry 1 2 3 4 5 6 R CH2OTBS CH2OTBS CHO CHO CO2Me CO2Me Catalyst Rh(PPh3)3OTf [Rh(CO)2Cl]2 Rh(PPh3)3OTf [Rh(CO)2Cl]2 Rh(PPh3)3OTf [Rh(CO)2Cl]2 103 Yield (%) 81 96 decomposition 92 85 98 1c.170:1c.171 1:0 1:0 0:1 6.4:1 1b.5:1 A mechanistic rational for the formation of regio- and diastereomers in the [5+2] cycloaddition has been proposed (Scheme 1c.10).235,237 As is illustrated, the formation of the specific cycloadduct corresponds to the nature of the initial metal-p system coordination event to enyne 1c.172 at the onset to provide either 1c.173a or 1c.173b. Subsequent cyclometallation produces the initial metallocycles 1c.174a and 1c.174b. Bond rotation about carbon-carbon bond a aligns one of two cyclopropyl carbon-carbon bonds syn to the carbon-metal bond, thereby allowing for concerted ring expansion. A critical factor in determining whether metallocycles 1c.175 or 1c.176 will undergo migratory insertion relies on the geometrical syn requirement of the two protons necessary for formation of the resulting cis carbon-carbon double bond in the products. This factor requires that only one of the two possible cyclopropyl carbon-carbon bonds can be aligned properly with the carbon-metal bond to yield a [5.3.0] bicycle. Subsequent ring expansion of 1c.176a/b followed by reductive elimination of the metal catalyst provides cycloadducts 1c.178a/b. This mechanistic rationale suggests that the regioselectivity observed is a result of the initial p-facial selectivity in the formation of diastereomeric intermediates. Due to the remote nature of the R group in the formation of intermediates 1c.174-1c.176, the regioselectivity is thus believed to be a direct result of the reversible nature of the preliminary mechanistic steps. This equilibrium then allows for either a favorable or unfavorable interaction between the R group and the rest of the molecule at a later stage. If this interaction results in a high-energy intermediate, the reaction can funnel back upstream in the proposed mechanistic sequence. Subsequent decomplexation/recomplexation of the metal to form either intermediate 1c.173a or 1c.173b and reaction down the opposite, presumably more energetically favorable pathway would provide the level of selectivity observed in these reactions. 104 Scheme 1c.10 H HM H 1c.173a R H H H R H H HM H 1c.173b R H H 1c.172 H M H H a H R M H H a R 1c.174a H M H H H M H H 1c.176a R 1c.175a R H H M H 1c.175b H R 1c.174b H H M H H 1c.176b R H H M H H 1c.177a 1c.178a R H R H H H R H H M R H H 1c.177b 1c.178b The diastereoselectivity in the [5+2] cycloaddition arises from a combination of two events in the mechanistic outline depicted in Scheme 1c.10. First, the alkene facial selectivity of the initial coordination event to provide 1c.173a/b dictates the bridgehead substituent s orientation. Then, alignment of one cyclopropane bond to allow for metal105 mediated ring expansion sets the relative stereochemistry. The studies Wender has performed on the regioselectivity of the reaction can by summarized in a few general trends. The Rh(PPh3)3OTf catalyst system generally yields cycloadducts resulting from cleavage of the less-substituted cyclopropane bond regardless of cyclopropane stereochemistry and for most R-groups. On the other hand, [Rh(CO)2Cl]2 exhibited a reversal in regiochemistry in the trans-series of cyclopropyl enynes, and proved capable of catalyzing the reaction of formyl-substituted substrates. However, the cis-series yielded similar results to what RhCl(PPh3)3/AgOTf produced with the exception that the formyl-substituted cyclopropyl enyne gave the product resulting from cleavage of the more substituted cyclopropane bond. Therefore, it appears that [Rh(CO)2Cl]2 is a more versatile catalyst, and the desired diastereo- and regioselectivity can be obtained by constructing a substrate with the right combination of cyclopropane stereochemistry and functional group substituent on the ring. 1.C.3.3 Ruthenium-Catalyzed Intramolecular [5+2] Cycloadditions In 2000, Trost and coworkers described how a ruthenium complex was capable of mediating the same intramolecular [5+2] cycloaddition which Wender had developed utilizing rhodium(I) catalysis.238 Although the overall transformation remained the same with only the nature of the catalyst changing, a different set of results was obtained regarding the regio- and diastereoselectivity in the product distribution for some substrates. A sample of the most intriguing results is illustrated in Scheme 1c.11. When the formyl-substituted cis cyclopropylenyne 1c.179 was treated with the cationic ruthenium species, cycloadduct 1c.180 was obtained with complete regiocontrol as a mixture (10:1) of diastereomers. However, if the silyl protected methyl carbinolThe substituted substrate 1c.179 was used, syn-cycloadduct 1c.181 was obtained. 106 formation of 1c.181 follows the same regio- and diastereomeric trends that Wender observed in the rhodium-catalyzed [5+2] cycloaddition. Even though the regiochemistry observed in the formyl substituted case is also in line with Wender s results, the diastereoselectivity is quite different. In general however, the diastereoselectivity of the reaction is quite high, and the authors report that the incomplete reversal of diastereocontrol in the cycloaddition of formyl-substituted 1c.179 is a result of the enolizability of the aldehyde functionality. Scheme 1c.11 R R E E H 1c.180 CpRu(MeCN)3PF6 acetone, rt, 80% E E 1c.179 H CpRu(MeCN)3PF6 acetone, rt, 85% E R E H 1c.181 H R = CHO Regioselectivity = 10:1 R = CH2OTIPS Regioselectivity = 1:0 When ether 1c.182 was treated with the cationic ruthenium species, a mixture (1.7:1) of cycloadducts 1c.183 and 1c.184 was obtained (Eq. 1c.20). However, when the same substrate was treated with the cationic Wilkinson s catalyst system reported by Wender, a complex mixture containing none of the desired cycloadduct or cycloisomerized product was obtained. When [Rh(CO)2Cl]2 was used to catalyze the cycloaddition, an 80% yield of only cycloadduct 1c.183 was obtained. These strikingly different results seem to indicate that there exists at least subtle differences in the mechanistic pathway of the rhodium-catalyzed [5+2] cycloaddition and the cationic ruthenium variant. 107 Ph CpRu(MeCN)3PF6 (10 mol%) Ph O 1c.182 acetone, rt 80% 1c.189/1c.190 = 1.7:1 O + O Ph (1c.20) 1c.183 1c.184 E/Z = 2.5:1 RhCl(PPh3)3/AgOTf [Rh(CO)2Cl]2 0% 80% 0% 0% In general, Trost reported that the cationic ruthenium-catalyzed [5+2] cycloaddition provided regio- and diastereomeric results similar to those Wender observed in the rhodium-catalyzed reaction.239 The trans-substituted cyclopropyl enynes produced cycloadducts containing an anti relative stereochemical configuration across the ring, whereas the corresponding cis-substrates produced the syn-cycloadducts. In most cases, the cationic ruthenium catalyst produced mixtures (3:1 to 1:2.5) of cycloadducts 1c.186 and 1c.187 for the trans-substituted cyclopropane substrates (Scheme 1c.12). Once again though, the case in which R = CHO proved anomalous, providing cycloadduct 1c.187 as a mixture (15:1) of regioisomers in excellent yield. Additionally, treatment of 1c.188 (R = CHO) with the cationic ruthenium species produced cycloadduct 1c.189 with complete regio- and diastereoselectivity. The aldehyde substrates present a unique situation in which the exact balance of steric and electronic effects provide results that differ markedly from others. The cis-substituted cyclopropyl enynes also gave similar results with ruthenium as was found with rhodium by providing primarily cycloadduct 1c.189 in excellent yield and regioselectivity. The advantages of ruthenium catalysis over the rhodium variant of this reaction seem to be limited simply to the milder conditions required for ruthenium. Namely, the reactions are run under a 100 C in toluene for rhodium vs. room temperature in acetone for ruthenium. 108 Scheme 1c.12 H R R H MeO2C MeO2C 1c.185 R H H MeO2C MeO2C 1c.188 CpRu(MeCN)3PF6 (10 mol%) rt MeO2C MeO2C H 1c.189 CpRu(MeCN)3PF6 (10 mol%) rt MeO2C MeO2C H 1c.186 R + MeO2C MeO2C H 1c.187 R 1.C.3.4 The Transition Metal-Catalyzed Intermolecular [5+2] Cycloaddition To follow the studies Wender and coworkers reported in 1995 on the intramolecular [5+2] cycloadditions, the first intermolecular [5+2] cycloaddition of vinyl cyclopropanes and alkynes was described in 1998 as a homologous Diels-Alder reaction.240 In these initial studies, the authors report the need for an activated siloxycyclopropane 1c.190 to facilitate the reaction with various alkynes 1c.191, thereby providing the corresponding seven-membered ring ketones 1c.193 upon subsequent hydrolysis of the resulting silyl enol ether 1c.192 (Scheme 1c.13). Vinyl cyclopropanes lacking an oxygen substituent were unreactive under the reaction conditions. However, the scope of the alkyne was quite general in that the reaction proceeded whether electron poor or rich, internal or terminal alkynes were employed. 109 Scheme 1c.13 OTBS + R2 1c.190 1c.191 CH2Cl2, 40 C R2 R1 R2 R1 R1 [Rh(CO)2Cl]2 (5 mol%) OTBS HCl, EtOH O 1c.192 1c.193 R1 = H, Me, Et R2 = CO2Me, C(O)Me, CH2OMe CH2OH, TMS, Ph, iPr, Et, H However, Wender and coworkers reported in 2001 that unactivated vinylcyclopropanes were in fact useful substrates in the intermolecular [5+2] cycloaddition reaction.241 Vinyl cyclopropanes 1c.194 containing an additional alkyl substituents at the 1-position were shown to react smoothly with alkyne 1c.195 in the presence of [Rh(CO)2Cl]2 to provide the corresponding cycloadducts 1c.196 in excellent yield and with complete regioselectivity (Eq. 1c.21). The excellent regioselectivity observed is believed to be a result of the unfavorable steric interaction between the vinyl substituent and methyl ester. If a terminal alkene is present in the vinyl cyclopropane, the reaction produces an equal amount of both regioisomers. A number of different alkyne substituents proved viable substrates in the cycloadditions of siloxy substituted vinyl cyclopropanes. + OTBS 1c.194 [Rh(CO)2Cl]2 (5 mol%) CO2Me 5% TFE in DCE, 80 C 95% MeO2C 1c.196 OTBS (1c.21) 1c.195 110 These studies suggest that the presence of an oxygen substituent at the 1-position of vinylcyclopropanes is not critical. Rather a quaternary allylic carbon on the cyclopropane is all that is required to force the vinylcyclopropane into a favorable geometrical configuration. The presence of any R group has been shown to reduce the energy differences between the s-cis 1c.197a and s-trans 1c.197b conformers (Scheme 1c.14). Naturally, as R increases in size the energy effect is likewise increased thereby diminishing the difference. This effect on the conformers could increase the likelihood of forming Z-allyl intermediate 1c.198a over the E-allyl 1c.198b. The requirement of a cisalkene in the product then requires that 1c.198a undergoes cyclization to provide 1c.199a whereas 1c.198b can only proceed to the improbable trans cycloadduct 1c.199b.242 Scheme 1c.14 H + H R H 1c.197a f = 0 C R M f = 0 C H R 1c.198a 1c.199a cis-alkene H H R H 1c.197b f = 180 C + H R f = 180 C R X M H 1c.199b trans-alkene 1c.198b 111 1.C.3.5 Summary In summary, a vast amount of work has been accomplished on the transition metal-mediated [5+2] cycloaddition reaction. The reaction has been shown to be widely applicable to a variety of substrates tolerating various substitution patterns on the cyclopropane and both p-systems involved in the carbocyclization event. Additionally, high regio- and diastereoselectivity has been observed in the formation of cycloadducts from their corresponding cyclopropyl enynes. A unique level of regiocontrol has been illustrated by either designing the substrate with a particular functional group as the substituent on the cyclopropane, or choosing the proper rhodium(I) catalyst. The diastereoselectivity has been shown to arise from the relative configuration about the cyclopropane ring. One drawback to this transformation is that the stereochemical consequence of the reaction is relative, namely the optical purity of the cycloadduct is a direct consequence of how enantioenriched the starting enyne is. This issue may be addressed in one of two ways, by the future development of an enantioselective variant through the use of chiral ligands or synthesizing the cyclopropylenyne in enantiopure form. The latter is most efficiently accomplished through the coupling of the [5+2] cycloaddition with an asymmetric cyclopropanation to establish the absolute stereochemistry of the starting enyne. It should come as no surprise that this transition metal-catalyzed carbocyclization reaction has found applicability, and will continue to be valuable in the synthesis of complex natural products.243,244 1.C.4 The Transition Metal-Catalyzed Pauson-Khand Annulation The Pauson-Khand reaction has quickly become of the most useful transition metal-catalyzed carbocyclization reactions available to the synthetic chemist in recent years.127,128,139 Formally a [2+2+1] cycloaddition, the Pauson-Khand annulation involves 112 the three-component coupling of an alkene, alkyne and formally carbon monoxide to yield a cyclopentenone. The reaction was first discovered in the early 1970 s and has since undergone incredible expansion with regards to efficiency and applicability.245,246 Early work showed that this transformation suffered in scope and utility by requiring elevated temperatures and extended reaction times, the combination of which frequently led to decomposition of starting materials. Additionally, the Pauson-Khand reaction was limited to symmetrical, strained alkenes to mask the poor efficiency of the overall reaction, and eliminate the unavoidable mixtures of cyclopentenone regioisomers. The reaction was also found to be quite sensitive to the steric and electronic environment on both the alkene and alkyne. It was originally shown that stoichiometric dicobaltoctacarbonyl was able to effect this transformation, and this catalyst continues to be the primary transition metal complex for the Pauson-Khand reaction. Since the seminal publication and subsequent work immediately following, a number of advances have been made toward making the PKR more efficient and broader in scope. In 1981, Schore discovered that the issue of alkene regiochemistry could be overcome by tethering the alkene and alkyne rendering the process intramolecular.247 It has since been shown that the reaction can be performed catalytically and enantioselectively through the use of chiral ligands. Another important advance has been the discovery of a number of different transition metals capable of catalyzing the [2+2+1] cycloaddition, thereby further broadening the scope of this reaction. One of the most significant advances made in the PKR was reported by Rautenstrauch and coworkers when they showed that the cycloaddition of a non-strained alkene could be effected with 1a.22 mol% of Co2(CO)8 under a relatively high CO pressure (100 bar) in 47% yield.248 The authors proposed that the cobalt catalyst had the tendency to aggregate into an inactive species under the previously reported reaction 113 conditions, and thus lead to a decrease in yield. Jeong was the first to show that through the use of phosphite ligands, the active cobalt species could be stabilized, thus providing the corresponding cyclopentenone in good yield. Thus, when enyne 1c.200 was treated with 3 mol % Co2(CO)8 in the presence of 10 mol% P(OPh)3 under one atmosphere of carbon monoxide, the corresponding PKR product 1c.201 was obtained in 82% yield (Eq. 1c.22). 249 Co2(CO)8 (3 mol%) P(OPh)3 (10 mol%) CO (1 atm), DME 120 C, 82% EtO2C EtO2C 1c.200 EtO2C EtO2C 1c.201 O (1c.22) A number of important contributions to the cobalt-catalyzed PKR have since been made, further increasing the efficiency and scope of the reaction. First, Livinghouse noted that the use of high purity Co2(CO)8 was critical in achieving a good conversion for both the thermal and photochemical PKR.250 Additionally, Sugihara reported that hard Lewis bases, which are known to labialize the ligands on low-valent metal complexes, can be employed to promote otherwise difficult cycloadditions.251 Notably, the use of 1,2-dimethoxyethane (DME) as solvent was the most efficient promoter of the PKR catalyzed by Co2(CO)8. In recent years, the focus has shifted toward the use of other transition metal catalysts to promote the Pauson-Khand reaction. The discovery of other PKR catalysts have enabled a number of previously problematic substrates to undergo the desired carbocyclization to yield the corresponding cyclopentenones, thereby leading to a resurgence of this [2+2+1] cycloaddition in the synthesis of natural products. Zirconium,252 nickel253 and molybdenum254 carbonylated species were found to be viable 114 catalysts providing the corresponding bicyclic enones in good yields. Iron,255 titanium256 and tungsten257 complexes have also found their way into the realm of PKR catalysts. More recently, ruthenium258,259 and rhodium260,261 carbonyl catalysts have shown wide applicability in providing the desired [2+2+1] cycloadducts. 1.C.4.1 Titanium-Catalyzed Pauson-Khand Annulations Buchwald and coworkers showed in the early 1990 s that a number of titanocene complexes were capable of catalyzing the Pauson-Khand reaction in good to excellent yields.262,263 The use of chiral ligands on the titanium metal center has since led to an enantioselective variant of the cycloaddition, providing enantioenriched cyclopentenones in good yield and enantioselectivity.264 In 1993, Buchwald showed that the use of a (trialkylsilyl)cyanide could serve as a CO surrogate in the presence of a titanocene complex to catalyze the PKR of enyne 1c.202. The cycloaddition yields an intermediate imine 1c.203, which upon acid hydrolysis affords the desired bicyclic enone 1c.204 (Table 1c.7). 115 Table 1c.7. PKR catalyzed under CO-free conditions Ph O 1c.202 "Titanocene" TMSCN, PhH, 45 C TMS O Ph 1c.203 N H3O+ O Ph 1c.204 O Entry 1 2 3 Catalyst Cp2Ti(PMe3)2 Cp2TiCl2/n-BuLi Ni(COD)2/Ligand Mol% 10 10 5 Yield (%) 80 82 60 1.C.4.2 Ruthenium- and Rhodium-Catalyzed Pauson-Khand Reactions Although the catalysts mentioned a priori have demonstrated their utility in catalyzing the PKR with good to excellent results, much of the work reported recently has been utilizing ruthenium and rhodium species to facilitate the cycloaddition. Ruthenium was the first of these metals to show applicability in catalyzing the PKR of enyne substrates. Murai259 and Mitsudo258 reported independently the ruthenium- catalyzed PKR of enyne 1c.205 in the presence of 2 mol% Ru2(CO)12 to yield bicyclic enone 1c.206 in 86% yield (Table 1c.8, entry 1). To achieve satisfactory yields with this ruthenium species, elevated CO pressures were necessary, and the choice of solvent was critical. The use of rhodium complexes to catalyze the PKR has been the focus of a number of endeavors among different research groups recently.260,261,265-267 The use of various rhodium(I) catalysts have been shown to catalyze the PKR of previously troublesome substrates, as well as some novel [2+2+1] cycloadditions. Narasaka was one 116 of the first to illustrate that as little as 1 mol% of [Rh(CO)2Cl]2 was capable of catalyzing the intramolecular Pauson-Khand reaction of enynes 1c.205 to yield the corresponding enones 1c.206 in good to excellent yields (Table 1c.8, entry 2). In the same year, Jeong reported the use of [Rh(CO)(dppp)Cl]2 as an effective PKR catalyst under 1 atm of CO to yield the desired product in excellent yield (entry 3). Table 1c.8. Ruthenium- and rhodium-catalyzed Pauson-Khand reaction R EtO2C EtO2C 1c.205 catalyst, CO solvent, temperature EtO2C EtO2C R 1c.206 O Entry 1 2 3 R Me Ph Ph Catalyst Ru2(CO)12 [Rh(CO)2Cl]2 [Rh(CO)(dppp)Cl]2 Mol% 2 1 1c.5 CO Pressure (atm) 10-15 1 1 Yield (%) 86 94 99 Solvent dioxane Bu2O PhMe 1.C.4.3 The Enantioselective Pauson-Khand Reaction In the past decade focus has been geared toward rendering the Pauson-Khand reaction enantioselective. The methods which have proven to be the most successful either incorporate a chiral auxiliary in the substrate to render the process diastereoselective by starting with enantioenriched substrates or enable asymmetry through the use of chiral ligands on the metal complex. Chiral promoters have also seen applicability although their use has been rather limited and have not seen the attention which other methods have been afforded. 117 Pericas and Riera have pioneered the use of chiral auxiliaries in the asymmetric PKR.268 The method developed incorporates a sulfur moiety appropriately positioned to coordinate to the cobalt-alkyne complex thereby rendering the process diastereoselective. For example, when the chiral camphor-derived enyne 1c.207 was treated with dicobaltoctacarbonyl, the tricyclic intermediate 1c.208 was produced as a mixture (9:1) of diastereomers (Scheme 1c.15). This intermediate was then advanced to the tricyclic natural product (+)-15-nor-pentalenene (1c.209).269 Scheme 1c.15 1. Co2(CO)8 2. NMO, rt, 44 h SMe 1c.207 H H O O dr = 9:1 OXA 1c.208 H (+)-15-nor-pentalenene (1c.209) Attempts to render the transition metal-catalyzed Pauson-Khand reaction enantioselective through the use of chiral catalysts have not, until recently, produced fruitful results. Early work suggested that stoichiometric chiral catalyst in conjunction with high CO pressures and elevated temperatures were necessary to impart asymmetric induction, but more recently a chiral catalyst has been reported that eliminate the need to use such rigorous conditions. One of the main difficulties in this reaction is that most late transition metals require that CO ligands be present for the catalyst to exhibit useful levels of catalytic activity. Unfortunately, carbon monoxide is a non-tunable, extremely strong p-acceptor ligand for the late transition metals that have a high electron density 118 around their center. Therefore, the introduction of chiral ligands displace CO, thereby rendering the catalyst less efficient, and subsequently leading to a rather difficult catalytic processes.270 Buchwald showed in 1996 that the chiral titanium catalyst, (S,S)- (EBTHI)Ti(CO)2, was capable of inducing asymmetry.264 The use of cobalt species in the presence of BINAP ligands has also shown promise, but with limited success.271 In 2000, Jeong reported the use of [Rh(CO)2Cl]2 in the presence of BINAP ligands as an effective enantioselective catalyst system for the PKR.270 When enynes of type 1c.210 were treated with bisphosphine ligand and the rhodium(I) catalyst in the presence of AgOTf under an atmosphere of CO, the desired bicyclic enones 1c.211 could be obtained in good yield and excellent enantioselectivities ( 96% ee) (Table 1c.9). The use of a silver salt was found to be crucial in the initiation of the reaction. Additionally, finding the optimal pressure of CO was necessary to obtain the right balance of high yield and enantioselectivity. Although a low pressure of CO was most favorable for enantiocontrol, significant amounts of the 1,4-diene byproduct 1c.212, resulting from cycloisomerization of the enyne, effectively lowered the chemical yield of the process. 119 Table 1c.9. Asymmetric Rh(I)-catalyzed Pauson-Khand reaction [Rh(CO)2Cl]2 (3 mol%) (S)-BINAP (9 mol%) X AgOTf (12 mol%) CO (pressure) THF, reflux H 1c.211 1c.212 Me O + X Me Me X 1c.210 Entry 1 2 3 X C(CO2i-Pr)2 O O CO Pressure (atm) 1 2 1 Yield of 1c.211 (%) 40 85 40 ee (%) 90 86 96 Alternatively, diastereoselective Pauson-Khand cycloadditions of enantioenriched starting materials have also found applicability, particularly in the total synthesis of natural products. In 1997, Hoveyda showed how a stereoselective alkylation of enantioenriched allyl ether 1c.213 (>96% ee) with homopropargyl Grignard reagent 1c.214 could be used to assemble the 1,6-enyne 1c.215 (Scheme 1c.16).272 Treatment of 1c.215 with dicobaltoctacarbonyl provided the corresponding PKR product 1c.216 in excellent yield and with complete diastereoselectivity. 120 Scheme 1c.16 MgBr OBn O H 1c.213 1c.215 OBn 1c.214 HO H >96% ee 1. Co2(CO)8 2. NMO H2O 78% over 2 steps 1c.216 HO H O OBn >96% ee 1.C.4.4 Alternative [2+2+1] Cycloaddition Substrates: The Allenic and Dienyl Pauson-Khand Type Reactions Recently attention in the synthetic community has shifted toward developing not only better methods of realizing the [2+2+1] cycloaddition, but also discovering new starting materials that could be employed for the assembly of more structurally complex intermediates. One class of substrates that has received a great deal of study has been the cycloaddition of allenynes to establish a useful allenic Pauson-Khand-type of transformation.265,266,273 Starting from allenyne 1c.217, the absence of an R2 alkyl substituent routinely yields cycloadducts 1c.219 (Scheme 1c.17). However, if the allene is 1,1-disubstituted, bicyclic enones 1c.218 are obtained. Whether one cycloadduct or the other is formed preferentially is dependent upon which allenic olefin participates in the carbocyclization event, which in turn is dependent upon the substitution pattern within the substrate. 121 Scheme 1c.17 R2 R2 R3 R4 O R1 1c.218 D: R1, R3, R4 = H, R2 = alkyl 1c.217 R1 1c.219 A: R1 = TMS, R2, R3, R4 = H B: R1, R2, R3 = H, R4 = alkyl or silyl C: R1, R2 = H, R3, R4 = alkyl R4 R3 R3 R2 R4 O R1 A number of research groups have recently focused on developing the dienyl Pauson-Khand annulation. intramolecular dienyl Wender and coworkers demonstrated in 2003 the first sequence catalyzed by the rhodium(I) species, PKR [RhCl(CO)(PPh3)2].274,275 When dieneyne 1c.220 was treated with the rhodium(I) catalyst in the presence of AgSbF6 under 1 atm of CO, the corresponding bicyclic enone 1c.221 was obtained in excellent yield (Eq. 1c.23). The following year, Wender reported the first intermolecular variant of the dienyl Pauson-Khand reaction thereby expanding the scope of this reaction.276 He showed that when disubstituted alkynes 1c.222 in the presence of 1,4-dienes 1c.223 were treated with the rhodium(I) species, [Rh(CO)2Cl]2, cyclopentenone 1c.224 was obtained regioselectively in 95% yield. 122 [RhCl(CO)(PPh3)2] (2.5 mol%) AgSbF6 (2.5 mol%), DCE MeO2C MeO2C 1c.220 CO (1 atm), 40 C, 1 h 96% MeO2C MeO2C O (1c.23) 1c.221 TMS + CO2Et 1c.222 1c.223 [Rh(CO)2Cl]2 (5 mol%) CO (1 atm), DCE/TCE (1:1) 60 C, 24 h 95% O TMS EtO2C 1c.224 (1c.24) 1.C.5 Transition Metal-Catalyzed Cycloisomerizations With synthetic organic chemistry evolving as it has toward the rapid construction of complex intermediates through one step sequences starting from relatively simple starting materials, the use of transition metal-catalyzed methods have taken a lead role in this endeavor. The transition metal-catalyzed cycloisomerization of 1,n-enynes, 1,ndienes and 1,n-diynes has been established as a critical method in which such transformations are possible.140 Although the development of cycloisomerization methodology to include diene and diyne substrates has greatly expanded the scope of this reaction, in this discussion we will primarily focus on the use of enynes as substrates. There exists three different mechanistic pathways whereby a transition metal catalyst can interact with a 1,n-enyne as illustrated in Scheme 1c.18. Most transition metals react with enyne 1c.225 by first complexation to both p-systems, followed by oxidative addition to yield the metallocyclopentene 1c.226 depicted by Path a. Alternatively, if the substrate were to incorporate a leaving group in the allylic position, the p-allyl complex 1c.227 could be formed that can then undergo reaction with the pendant alkyne (Path b). 123 Finally, hydrometallation of the alkyne to yield the vinyl metal species 1c.228 encompasses the final possibility for a transition metal catalyst (Path C). Subsequent reaction of 1c.226-1c.228 forms the carbocyclic product 1c.229. The discussion here will be limited to those reactions which are thought to undergo metallocyclopentene 1c.226 formation via path a. Scheme 1c.18 Path a X LG X 1c.226 M Path b X 1c.225 X = LG M 1c.227 1c.229 Path c X LG X M X 1c.228 1.C.5.1 Palladium-Catalyzed Cycloisomerizations A number of different metals have been shown to catalyze the cycloisomerization of enynes to the corresponding carbocyclic products.133,140 However, the vast majority of work in this field has focused primarily on palladium-catalyzed processes.134 Preliminary findings showed that when a substrate such as enyne 1c.230 was treated with Pd(OAc)2 in the presence of the bisimine ligand BBEDA, the 1,3-diene 1c.231 was obtained exclusively.277 The reaction is selective for the conjugated dienes when the starting enyne 124 lacks allylic hydrogens. Additionally, the effects of substituents on the tether between the alkene and alkyne did not produce a dramatic effect on the efficiency of the reaction. The presence of the gem diester moiety and a protected propargylic alcohol both seemed to increase the rate of the reaction relative to the presence of simple alkyl or the complete lack of substitutents.278 TMS TMS MeO2C MeO2C 1c.231 (1c.25) MeO2C MeO2C Pd(OAc)2, BBEDA PhH, 60 C 85% 1c.230 In palladium catalyzed cycloisomerizations, the nature of the diene formed in the cyclized products is partially dependent on the steric influences present in the starting material.277,279 For enynes containing an allylic methylene as represented by 1c.232, 1,4diene 1c.233, a net Alder-ene type product, was obtained regioselectively in 71% yield (Eq. 1c.26). However, if there is branching at the allylic position as in 1c.234, product distribution was completely reversed, providing the conjugated 1,3-diene 1c.235 in good yield (Eq. 1c.27). Additionally, the presence of a protected allylic alcohol produced the 1,3-diene products, where if the protected hydroxyl was in the homoallylic position, the 1,4-diene was produced. It has been proposed that the regiocontrol observed by an allylic or homoallylic oxygen substituent was a product of electronic influences.280 In addition to these electronic factors, whether the allylic methylene contains branching or not directs the regiochemistry of b-elimination due to the presence of unfavorable steric interactions. These results seem indicate that in palladium-catalyzed cycloisomerizations a discrete balance of steric and electronic factors influence the regiochemistry. 125 MeO2C MeO2C 1c.232 8 OMe OMe (PPh3)2Pd(OAc)2, PhH 60 C, 71% MeO2C MeO2C 1c.233 OMe 8 (1c.26) OMe MeO2C MeO2C 1c.234 MeO2C (PPh3)2Pd(OAc)2, THF 66 C, 64% MeO2C (1c.27) 1c.235 1.C.5.2 Ruthenium-Catalyzed Cycloisomerizations The scope of the transition metal-catalyzed cycloisomerization reaction has been expanded to include the use of ruthenium complexes. Initial work utilizing the CpRu(cod)Cl species to catalyze the cycloisomerization reaction proved efficient on unactivated enynes, unfortunately only monosubstituted alkenes were viable substrates.281 The authors proposed that the alkene substituent must be attached to the ruthenium complex to allow for b-elimination as illustrated in structure 1c.235 and 1c.236 (Scheme 1c.19). This would then lead to 1,3-bridging that cannot occur if a shorter tether is employed. However, recently Trost illustrated the use of the ruthenium complex, CpRu(MeCN)3+PF6-, in the cycloisomerization of 1,2-disubstituted alkene 1c.237 to provide the 1,4-diene 1c.238 regioselectively in 82% yield.282 With this ruthenium species, trisubstituted olefins are well tolerated in the carbocyclization, producing results similar to those obtained under palladium catalysis. Although the mechanism is thought to proceed through a ruthenacyclopentene, the possibility exists that a p-allyl intermediate may actually be involved.283 126 Scheme 1c.19 + Ru H 1c.236 H 1c.237 + Ru MeO2C MeO2C 1c.238 MeO2C CpRu(MeCN)3+PF6DMF, rt 82% MeO2C 1c.239 1.C.5.3 Rhodium- and Iridium-Catalyzed Cycloisomerizations Much of the synthetic efforts in the context of transition metal-catalyzed cycloisomerizations in recent years has focused on the development of rhodium-catalyzed processes.284 In most cases, it was found that rhodium(I) complexes in the presence of silver salts provided superior results in catalyzing the desired transformation as compared to those reactions run in the absence of any additives. The best results were obtained when the cycloisomerization of cis-enyne 1c.240 was catalyzed by a rhodium(I) species in the presence of either dppb or BICPO ligands and AgSbF6 to yield 1,4-diene 1c.241 in moderate to excellent yields (Eq. 1c.28). By tuning the bisphosphine ligand the reaction conditions could be easily optimized for each substrate. Recently, the first asymmetric cycloisomerization of 1,6-enynes was reported by employing the chiral Me-DuPhos ligands to achieve enantioselectivities as high as 95% ee.285 127 R1 X [Rh(ligand)Cl]2, AgSbF6 DCE, rt 50-100% X R1 (1c.28) R2 1c.241 R2 1c.240 Ligand = dppb, BICPO X = O, Ar-N, (EtO2C)2C Finally, Murai reported that the iridium complex [IrCl(CO)3]n effectively catalyzed the cycloisomerization of 1,6-enynes.286 For example, when enyne 1c.242 was treated with 4 mol% of [IrCl(CO)3]n, 1,3-diene 1c.243 was obtained in a moderate 47% yield as the sole product (Eq. 1c.30). The reaction of 1c.242 is unusual in that even though the enyne contains a vinyl cyclopropane moiety, no [5+2] cycloaddition product was obtained from the reaction. For a variety of other substrates, yields were reported to be as high as 99%. MeO2C MeO2C [IrCl(CO)3]n (4 mol%) PhMe, 80 C, 12 h 47% 1c.242 MeO2C MeO2C 1c.243 (1c.29) 1.C.5.4 Mechanistic Discussion of the Transition Metal-Catalyzed Cycloisomerization of 1,6-Enynes The formation of metallocyclopentenes from enyne substrates is a mechanistic pathway common in a wide array of transition metal-catalyzed reactions. The cycloisomerization begins when the metal species initially complexes simultaneously to the alkene and alkyne in enyne 1c.244 to form intermediate 1c.245 (Scheme 1c.20). Oxidative addition of the metal to the substrate occurs to yield metallocycle 1c.246. At 128 this stage one of three different reaction events can take place depending upon the nature of the metal catalyst and substrate structure. If an electrophile is present, electrophilic cleavage of the metallocyclopentene can occur to yield the functionalized product 1c.247. If the metal species, or the substitution in the substrate cannot undergo b-elimination, reductive elimination of the catalyst yields bicycle 1c.248. The most likely pathway in these transformations involves b-hydride elimination to yield the vinyl metal species 1c.249, which then undergoes reductive elimination to yield the cycloisomerization product 1c.250 and regenerate the active catalyst species. 129 Scheme 1c.20 MLn 1c.244 1c.250 Reductive Elimination M H M 1c.249 1c.245 b-Elimination Oxidative Coupling Reductive Elimination 1c.248 M Electrophilic Cleavage E1 1c.246 E2 1c.247 The regioselectivity in the b-hydride elimination step has been the subject of much scrutiny in this mechanistic hypothesis.280,287 Depending upon which hydrogen the catalyst chooses to extract, either a 1,3- or 1,4-diene product is obtained. Two critical criteria must be met to allow for b-hydride elimination to occur. The first of these is that there must be an open coordination site on the metal to accommodate the resulting hydride species. The second criteria is that there must be a cis alignment of the carbon130 hydrogen and carbon-metal bonds to allow for maximum orbital overlap. As illustrated in Scheme 1c.21, a metallocyclopentene 1c.251 has two hydrogens, Ha and Hb from which abstraction could occur to yield one of two possible regioisomers 1c.252 and 1c.253. Upon subsequent reductive elimination cycloisomerization products 1c.254 and 1c.255 are formed. Although the C-Hb bond energy is less than C-Ha due to its allylic nature, the geometry for elimination of Ha is more favorable. Therefore, finding the right combination of steric and electronic factors present in the starting 1,6-enyne in conjunction with the nature of the transition metal catalyst, either regioisomer can usually be had selectively. Scheme 1c.21 Ha M Ha 1c.252 M Hb 1c.251 Ha 1c.254 Hb M Hb 1c.253 1c.255 1.C.6 Transition Metal-Catalyzed Domino Reactions Which Incorporate a Carbocyclization Event As the field of transition metal-catalyzed reactions expands, the prospect of being able to rapidly assemble structurally complex intermediates from relatively simple 131 starting materials becomes ever easier. One of the major thrusts in research endeavors by a number of groups recently has been the development of tandem/domino processes in which a number of transformations occur in a single reaction vessel. The variety of reactions amenable to domino processes greatly expands when transition metal-mediated transformations are considered. An increasing amount of attention has been paid recently to developing methods that involve the manifestation of multiple transformations occurring in a single pot mediated by a single catalyst. The advent of such processes dramatically increases the efficiency by providing the desired products in a low-cost manner, while keeping the waste generated to a minimum. With the development certain transition metal species capable of catalyzing a number of different reactions, it has become even easier to establish conditions in which combining these transformations to yield a single-pot method resulting in more and more reports surfacing with ever increasing frequency.288 These types of processes can be divided into two categories: sequential and concurrent catalysis. The first type, sequential catalysis, is distinguished by those transformations in which the product of the first reaction serves as the starting material for the second in which the catalytic activity of the metal is moderated by some change in the reaction conditions (i.e. temperature change). Alternatively, concurrent reactions are those that occur simultaneously in the same reaction vessel by the same catalyst. This discussion will be limited to addressing the first of these classes, namely the recent advances in sequential catalysis.288 Possibly the largest subclass of sequential reactions to provide numerous successful examples in recent years feature the utilization of ruthenium olefin metathesis catalysts, namely those developed by Grubbs and coworkers.289 These domino processes include at least one of the sequential reactions, usually the first, to be either a ring-closing 132 metathesis (RCM), cross metathesis, ring-opening metathesis polymerization (ROMP) or an acyclic diene metathesis (ADMET). Oxidation of ketones and the reduction of carbon-carbon double bonds have been shown to be viable reactions in domino processes in which the metathesis event occurs first. For example, a cross metathesis of styrene derivative 1c.256 with 1c.257 was followed by hydrogenation under 100 psi of H2 to yield methyl ester 1c.259 in 69% yield (Eq. 1c.30).290 Likewise, initial RCM of diene 1c.260 using Grubbs second generation catalyst 1c.258 followed by oxidation with 3pentanone and subsequent hydrogenation yielded (R)-(-)-muscone (1c.261) in an attractive three-step one-pot sequence (Eq. 1c.31). MesN Cl Cl Ru NMes Ph PCy3 CO2Me (1c.30) Cl 1c.259 + Cl 1c.256 1c.258 CO2Me 1c.257 then H2 (100 psi), 70 C 69% OH O 2.258, then Et2CO, NaOH then H2 56% (1c.31) (R)-(-)-muscone (1c.261) 1c.260 Evans and coworkers have established a unique regioselective rhodium(I)catalyzed allylic alkylation reaction to yield products resulting from substitution at the more substituted allylic terminus vida supra. The unique regioselectivity of this method was then utilized in conjunction with the ability of the rhodium(I) source to establish 133 sequential reaction sequences. In 2001 Evans showed that the alkylation of allylic carbonate 1c.262 with alkyne 1c.263 proceeded in the presence of [RhCl(CO)dppp]2 under 1 atm of CO to yield enyne 1c.264 which underwent subsequent Pauson-Khand annulation when the reaction temperature was elevated (room temperature to 82 C) to provide bicyclic enone 1c.265 in 87% yield and a diastereomeric ratio of 88:12 (Scheme 1c.22).291 Scheme 1c.22 [RhCl(CO)dppp]2 MeO2C 1c.262 CO2Me CO (1 atm), 30 C MeO2C MeO2C 1c.264 OCO2Me + 1c.263 82 C 87% MeO2C MeO2C H 1c.265 O dr = 88:12 In 2002, Evans expanded the scope of the rhodium(I)-catalyzed domino allylic alkylation/carbocyclization methodology to include the tandem three-component rhodium(I)-catalyzed allylic alkylation/[4+2+2] cycloaddition reaction. In this carbocyclization event, a diene in solution coordinates to the metallocarbocycle intermediate, undergoes migratory insertion and, following reductive elimination of the rhodium(III) species, provides a [6.3.0] bicyclic diene.292 As illustrated by Eq. 1c.32, when allylic carbonate 1c.266 was treated the lithium sulfonamide 1c.267 in the presence of RhCl(PPh3)3/AgOTf and 1,3-butadiene, an excellent yield of cycloadduct 1c.268 was obtained with little homocycloaddition product 1c.269 observed. 134 Ts(Li)HN OCO2Me 1c.266 1c.267 TsN RhCl(PPh3)3, AgOTf PhMe, 1,3-butadiene, D 87% 1c.268/1c.269 19:1 + TsN H 1c.268 H NTs (1c.32) 1c.269 The use of zinc catalysts, although less frequent in the processes discussed thus far, have also shown utility in the development of transition metal-catalyzed sequential reactions. In 2003, Du and Ding showed how the chiral zinc catalyst 1c.272 catalyzed the hetero-Diels-Alder cycloaddition of Danishefsky s diene 1c.271 to dialdehyde 1c.275 which upon treatment with diethyl zinc in situ provided benzyl alcohol 1c.273 in 92% yield (Eq. 1c.33).293 Analysis showed that the [4+2] cycloaddition proceeded in 97% ee and the subsequent addition of diethyl zinc to the remaining aldehyde went with near complete diastereoselectivity (> 97:3). The chemoselectivity of the process is noteworthy in that the initial cycloadduct was less prone to undergo another hetero-Diels-Alder reaction, thereby allowing for diethyl zinc addition. OMe + 1c.272 TBSO CHO OHC 1c.270 1c.271 then Et2Zn 92% O O (1c.33) OH 1c.273 Mes O Zn O Mes 1c.272 N Ph N Ph 135 1.C.7 Overall Summary of Section 1.C The use of transition metals to catalyze carbocyclization reactions has become an intriguing topic in recent years, leading to a rapid expansion of methods and scope. Utilizing the methods described herein, a number of ring sizes can be formed in very unique ways. Most of these cyclizations are simply not possible without the assistance of a transition metal catalyst in some way or another. The potential to render such reactions enantioselective is one of the more intriguing aspects of this budding area of research. Through the use of chiral ligands and low quantities of reagents necessary (catalytic loadings < 5 mol% in most cases) decreases the amount of waste generated, as well as enhancing the atom economy of such processes. Unfortunately, with the exception of intramolecular cyclopropanations, enantioselective variants of the reactions detailed is this section have not been fully developed to include a wide range of substrates and alternative catalyst systems. With the progress being made to develop tandem/domino sequences, the assembly of complex intermediates becomes ever more rapid, increasing efficiency and throughput. As a result, transition metal-catalyzed processes of these types represent the vanguard of synthetic methodology. 1.D CHAPTER 1 CONCLUSIONS Transition metal-catalyzed reactions constitute a useful method to rapidly assemble complex molecules, often times by enabling reactions untenable without the assistance of a metal catalyst. Although the metal-catalyzed allylic alkylation of unsymmetric allylic substrates constitutes one of the most widely used transformations in modern synthetic chemistry, it is as of yet not fully developed. Many of the transition metals examined have exhibited limited utility in the allylic alkylations of unsymmetrical substrates with hard nucleophiles. Additionally, the formal direct regiochemical trend 136 observed in rhodium-catalyzed reactions has not been explored fully, and a reliable method developed. The second major section of this chapter dealt with those cyclizations that are unlikely or inefficient without the use of a transition metal catalyst. Although there are numerous benefits to their use, particularly in the area of natural product synthesis, there still exists many opportunities to improve upon what has been reported. As mentioned earlier, many of these reactions have not been developed into a reliable enantioselective transformation, glaringly absent considering the present focus on asymmetric transformations. The intramolecular [5+2] cycloaddition, although extremely diastereoselective, relies on the enantiopurity of the starting enynes for asymmetry. Therefore, it would be advantageous if a method were developed that allowed a rapid assembly of chiral starting materials for the [5+2] cycloaddition. Possibly synthesizing the starting cyclopropylenynes utilizing a short sequence starting with an asymmetric cyclopropanation? A method such as this would use one efficient transition metalcatalyzed carbocyclization to lead into another for the rapid assembly of complex intermediates. The other transformations introduced, the Pauson-Khand annulation and enyne cycloisomerization, have been used in natural product synthesis, but recent endeavors have focused on incorporating these reactions into domino sequences. These aspects, in conjunction with the unique functionality of the compounds assembled in this manner allow for the potential development of domino reactions to optimize reaction efficiency and process throughput. Although a vast amount of work has been accomplished with regards to studying transition metal-catalyzed reactions, there still exists the potential to improve upon what has been reported. As one might expect, with each new development in the field, presumably answering a crucial scientific question, another dilemma is uncovered. 137 Future endeavors will most certainly focus on further development of asymmetric variants and designing novel and more efficient domino sequences. Hopefully, this chapter has laid the framework for understanding the concepts of a sampling of transition metal catalysis while causing the reader to ask how improvements can be made on existing methodology. 138 Chapter 2. Enantioselective Total Synthesis of Tremulenediol A and Tremulenolide A 2.1 INTRODUCTION The tremulanes constitute a novel class of sesquiterpene natural metabolites containing a unique carboskeletal array.294 The carbon skeleton of the tremulanes 2.1 is isomeric to the lactarane skeleton (2.2) and similar in structure to some particularly intriguing terpenes such as guanecastapene (Figure 2.1).295 Tremulenolide A (2.3) and tremulenediol A (2.4) are two representative tremulanes that were isolated in 1993 from the fungal pathogen Phellinus tremulae as part of a project to develop methods for controlling fungal decay and staining in trembling or quaking aspen (Populus tremuloides).294 Aspen represents 11% of the entire Canadian timber resource and 54% of the net merchantable hardwood timber. P. tremulae, the most serious wood rotting pathogen of aspen in Canada, greatly reduces the potential economic value of this timber reserve. Although the commercial advantages associated with the potential biological activity that these two natural products may possess is intriguing in itself, the interesting structural aspects of their skeletal core was the primary reason for choosing 2.3 and 2.4 as synthetic targets. Most notably, the 2,3,6,9-substitution pattern around the [5.3.0] bicyclic carbon skeleton and the relative configurations of the three stereogenic centers around the 7-membered ring caught our attention as being well suited for the application of synthetic methodology recently developed in our research group. The goal was to establish an atom economical, convergent enantioselective approach to the tremulanes by assembling them in manner that showcased the synthetic methodology developed in the Martin research group. 139 Figure 2.1. Tremulane Sesquiterpenes and Related Natural Products 11 15 10 9 14 8 1 7 6 5 13 14 3 4 12 15 10 9 8 1 7 6 11 3 2 4 5 12 2 13 Tremulane Carbon Skeleton (2.1) Lactarane Carbon Skeleton (2.2) O O OH OH H H Tremulenolide A (2.3) Tremulenediol A (2.4) Tremulenolide A and tremulenediol A were chosen as synthetic targets to illustrate how the intramolecular rhodium(II)-catalyzed enantioselective cyclopropanation strategy,191 which was developed in our research group over the last decade, can be used to set the stage for a diastereoselective intramolecular rhodium(I)-catalyzed [5+2] cycloaddition235 as an efficient entry into the tremulane carbon skeleton. As illustrated in Scheme 2.1, this approach establishes the absolute configuration of the C-3 stereocenter in cycloadduct 2.5 from the asymmetric cyclopropanation of diazoester 2.9 to provide cyclopropyl lactone 2.8. Construction of the C-7 stereogenic center in 2.5 arises as a consequence of the diastereoselectivity inherent to the intramolecular [5+2] cycloaddition. Subsequent diastereoselective reactions allow for the formation of the C-6 stereocenter in the tremulane natural products. The proposed route is highly convergent as each carbon in the [5.3.0] bicycle, as well as all five substituents, are introduced by the 140 union of alkyne 2.7 and lactone 2.8 to provide enyne 2.6. To date, an enantioselective synthesis of 2.3 or 2.4 has not been reported although Davies revealed a synthesis of the racemic compounds in 1998 utilizing a tandem intramolecular cyclopropanation/Cope rearrangement strategy; this is the only reported approach to these two natural products.296 Scheme 2.1 2 5 1 4 R R Intramolecular [5+2] Cycloaddition 5 1 3 H H 2 H 3 4 2.5 2.6 2 5 O 1 O H H Asymmetric Cyclopropanation 3 E E 4 + 3 O O N2 1 2.7 2.8 2.9 2.2 DAVIES TOTAL SYNTHESIS OF TREMULENOLIDE A AND TREMULENEDIOL A Davies was the first to report in 1998 a synthetic approach toward members of the tremulane sesquiterpene metabolites.296 The focal point of their synthetic approach was the use of a cyclopropanation/rearrangement strategy involving a vinylcarbenoid and diene to prepare stereoselectively seven-membered ring analogs.297 This method was introduced in 1994 as a unique [3+4] annulation strategy that could be rendered enantioselective with the use of chiral ligands in the initial cyclopropanation reaction.298 As illustrated in Scheme 2.2, diazodecomposition of 2.10 by the chiral prolinate dirhodium(II) catalyst 2.14 leads to an asymmetric cyclopropanation of the cis double 141 bond nearest the tether to provide trans-divinylcyclopropane 2.11. Lactone 2.11 underwent smooth Cope rearrangement upon heating in refluxing xylenes to yield the tremulane skeleton 2.12. Subsequent catalytic hydrogenation of 2.12 with Wilkinson s catalyst provided the tremulane carbon skeleton 2.13 in 76% yield. Scheme 2.2 O O cat. 2.14, hexane N2 -78 C, 79% 93% ee H H O O H xylene 140 C, 85% 2.10 2.11 O O H2, RhCl(PPh3)3 76% O O (p-(C12H25)C6H4)O2S N O H O 4 H 2.12 H 2.13 2.14 Rh Rh The authors speculated that 2.12 was formed by equilibration first to the corresponding cis-divinylcyclopropane to satisfy the geometrical requirements for the Cope rearrangement. As illustrated in Scheme 2.3, this thermally induced isomerization process is thought to proceed through the diradical intermediate 2.15.299 Initial cleavage yields intermediate 2.15a that, following bond rotation as indicated, proceeds through intermediate 2.15b to reform the cyclopropane ring and give the cis-divinyl isomer 2.16. The overall transformation was amended to a tandem process by heating the reaction mixture following the initial rhodium(II) prolinate-catalyzed cyclopropanation of diazoester 2.10. Davies proposed that this sequence would provide a rapid, enantioselective entry into the skeletal cores of tremulenolide A and tremulenediol A. 142 Scheme 2.3 O O H H H HH 2.15a H 2.15b 2.16 O O H O O H H H O O H H 2.11 The retrosynthetic outline Davies used to assemble these two natural products is illustrated in Scheme 2.4. Both tremulenolide A and tremulenediol A would be obtained from a common intermediate 2.17 that contains the complete tremulane carbon skeletal framework with all three stereocenters in the correct relative configuration. Intermediate 2.17 arises from an intermolecular tandem cyclopropanation/Cope rearrangement of diazoester 2.19 and diene 2.20 through the unisolated intermediate divinyl cyclopropane 2.18. This approach does an excellent job of highlighting the regio- and stereoselectivity associated with intermolecular vinylcarbenoid cyclopropanations of diazoesters with dienes to form cis-divinylcyclopropanes.300 However, the success of this approach relies on being able to control the relative stereochemistry of the three stereogenic centers. Fortunately, the stereoselectivity arises as a result of the boat transition state required in the subsequent Cope rearrangement of intermediate 2.18.301 143 Scheme 2.4 O O H 2.3 OH OH MeO2C AcO OAc CO2Me H 2.17 H 2.4 2.18 CO2Me N2 + OAc 2.19 2.20 Davies synthesis of 2.3 and 2.4 began with the synthesis diazoester 2.19 in a four-step sequence from known cyclopentanone 2.23 (Scheme 2.5). Ketone 2.23 was obtained in three steps from allylic alcohol 2.21 as reported independently by Boeckman302 and Bosnich.303 Mercury-catalyzed vinylation296 of 2.12 followed by Claisen rearrangement304 of the resulting allyl vinyl ether provided aldehyde 2.22 in 82% overall yield. Rhodium-catalyzed hydroacylation of aldehyde 2.22 yielded cyclopentanone 2.23 in excellent yield.303 Subsequent Horner-Emmons olefination of ketone 2.23 followed by deconjugation of the resulting a,b-unsaturated ester 2.24 with LiTMP and TFA regioselectively provided b,g-unsaturated ester 2.25 in 60% overall yield (contaminated with ~5% of the other possible olefinic regioisomer). Diazo transfer utilizing p-acetamidobenzenesulfonyl azide (p-ABSA) in the presence of DBU provided 144 ester 2.19 in 55% yield from 2.23. The authors reported that p-ABSA was chosen as the diazo transfer reagent due to better yields, greater ease of handling and the amide byproduct is easily removed in the work up as compared to typical reagents such as ptoluenesulfonyl azide. Scheme 2.5 1. Hg(OAc)2, CH2=CHOEt, 82% OH 2.21 2. PhH, reflux, 24 h, 100% 2.22 CO2Me CO2Me 1. LiTMP, HMPA 2. TFA, THF 86% over 2 steps 2.23 CO2Me 2.24 N2 CO2Me CHO [Rh(dppe)]2(ClO4)2 CD2Cl2, 6 min, rt 100% O O (MeO)2P nBuLi, THF, 70% p-ABSA, DBU MeCN, 55% 2.25 2.19 The diene component 2.20 was obtained in a three-step sequence from pyrylium perchlorate, which was synthesized in two steps from commercially available pyridine and sulfuryl chloride.305 Treatment of 2.26 with methyllithium resulted in regioselective addition to C-2, and subsequent heating of the reaction mixture initiated a rearrangement that provided aldehyde 2.27 in >95% stereochemical purity and 89% yield. Borohydride reduction of 2.27 and acylation of the resulting primary alcohol yielded allylic acetate 2.20.306 145 Scheme 2.6 MeLi, THF O ClO42.26 89% 2.27 OHC 1. NaBH4, THF 2. Ac2O, DMAP 2.20 OAc Rhodium(II)-catalyzed diazodecomposition of 2.19 in refluxing hexanes and in the presence of a 12-fold excess of diene 2.20 initially provided a mixture of the desired product 2.17 and cis-divinylcyclopropane 2.18 (Scheme 2.7). In order to induce the Cope rearrangement, forcing conditions were necessary to overcome the high energy of activation associated with the crowded boat transition state. Thus, when excess diene 2.20 was removed from the crude mixture of 2.17 and 2.18 by Kugelrohr distillation under vacuum at 60 C and subsequent heating of the distillation apparatus to 140 C, cisdivinylcyclopropane 2.18 underwent Cope rearrangement to provide the desired cycloadduct 2.17 as the sole regioisomer in 49% yield. Scheme 2.7 AcO CO2Me N2 + OAc Rh2(OOct)4 hexanes 49% 2.20 2.18 140 C H 2.17 MeO2C CO2Me OAc 2.19 Davies next examined an asymmetric approach to bicycle 2.17 in which the tandem cyclopropanation/Cope rearrangement sequence would be rendered enantioselective through the use of the chiral prolinate catalyst, Rh2[(S)-DOSP]4. This catalyst was chosen based on Davies previous report illustrating the use of Rh2[(S)146 DOSP]4 as an effective catalyst for the enantioselective cyclopropanation of olefins with vinylcarbenoids.160 Unfortunately, when the intermolecular cyclopropanation of 2.20 with 2.19 was conducted in the presence of Rh2[(S)-DOSP]4, subsequent heating to initiate the Cope rearrangement provided cycloheptadiene 2.17 in a disappointing 4% ee. To determine whether the poor facial selectivity was due to the vinylcarbenoid or the diene, the test reactions depicted in Eqs. 2.1 and 2.2 were performed. The good enantioselectivity observed in the cyclopropanation of diazoester 2.17 with styrene (2.28) in the presence of Rh2[(S)-DOSP]4 suggests that the cyclopropanation reaction proceeds with good facial selectivity (Eq. 2.1). However, when diazoester 2.30 was treated with diene 2.20 and Rh2[(S)-DOSP]4, the resulting cycloheptadiene 2.31 was obtained in only 48% ee (Eq. 2.2). Given that cyclopropanations of 2.30 with a number of other dienes,307 including styrene,160 proceeded with excellent enantioselectivities (98% ee as reported with styrene at -78 C), the authors surmised that the low enantioselectivity was most likely the result of poor facial selectivity associated with the diene 2.20 and not the carbenoid resulting from 2.19. CO2Me N2 + Ph Rh2(S-DOSP)4 76% ee 2.29 CO2Me (2.1) 2.19 2.28 MeO2C N2 + OAc MeO2C Rh2(S-DOSP)4 48% ee Ph OAc (2.2) Ph 2.30 2.20 2.31 147 Given the lack of success at rendering the key cyclopropanation/Cope rearrangement step enantioselective, Davies pursued the synthesis of racemic tremulenediol A and tremulenolide A (Scheme 2.8). Catalytic hydrogenation of 2.17 with Wilkinson s catalyst under an atmosphere of 40 psi of H2, reduced the disubstituted olefin leaving the tetrasubstituted double bond intact to yield intermediate 2.32 in 90% yield. One salient feature of this route is that intermediate 2.32 represents a branching point where one can pursue either tremulenolide A or tremulenediol A. To that end, saponification of both esters in 2.32 with potassium carbonate in MeOH followed by in situ lactonization provided 2.3 in 75% yield. Alternatively, reduction of diester 2.32 with excess DIBALH in CH2Cl2 at -78 C gave tremulenediol A in 87% yield. Scheme 2.8 O K2CO3 MeOH 75% MeO2C OAc MeO2C RhCl(PPh3)3 H2 (40 psi), EtOH 90% 2.17 H 2.32 DIBALH CH2Cl2 87% OH OH OAc O H 2.3 H H 2.4 Thus, Davies showed how the tandem cyclopropanation/Cope rearrangement strategy developed in his laboratories provided an efficient, stereoselective entry into the tremulane carbon skeleton, as illustrated by the syntheses of racemic tremulenolide A and tremulenediol A. The synthetic route required 16 total steps from commercially available 148 starting materials, and was completed in an overall yield of 0.8% for 3.3 and 0.9% for 3.4. The approach highlights the exceptional level of stereoselectivity in the tandem process to assemble three stereogenic centers in a single transformation. Unfortunately, due to problems associated with alkene facial selectivity in the intermolecular cyclopropanation of diene 2.20 with diazoester 2.19, the use of a chiral dirhodium(II) catalyst failed to provide the desired [5.3.0] bicycle enantioselectively. 2.3 1ST GENERATION STRATEGY TOWARD THE TOTAL SYNTHESIS OF TREMULENOLIDE A AND TREMULENEDIOL A The tremulanes provide a unique opportunity to explore new techniques for the synthesis of carbocyclic natural products. The substitution pattern coupled with the relative configuration of each stereogenic center make this class of metabolites attractive synthetic targets. Upon analysis of tremulenolide A and tremulenediol A, we were immediately drawn to the construction of the [5.3.0] bicyclic core, which we envisioned to arise as a result of a transition metal catalyzed [5+2] cycloaddition reaction of an appropriately functionalized, enantioenriched cyclopropyl enyne. With this disconnection in mind, the opportunity presented itself to utilize the rhodium(II)catalyzed asymmetric cyclopropanation methodology developed in our group to establish the first asymmetric synthesis of 2.3 and 2.4. The chiral carboxamide dirhodium(II)-catalyzed enantioselective cyclopropanation methodology described in Chapter 1 has been used for the synthesis of enantioenriched, conformationally constrained peptide analogs to study protein-ligand interactions.308 The recent total synthesis of ambruticin by Martin and coworkers establishes a benchmark in utilizing this method for the construction of complex natural products.309 The focus of the present project was to illustrate the synthetic utility of the 149 enantioselective cyclopropanation as the entry point for a diastereoselective intramolecular [5+2] cycloaddition leading to the synthesis of tremulane natural products. Thus, we engaged in studies directed toward the first enantioselective total synthesis of tremulenolide A (2.3) and tremulenediol A (2.4). Our first generation approach toward these tremulane sesquiterpenes is illustrated in Scheme 2.9. We envisioned that tremulenolide A would arise from the allylic oxidation of the diol moiety present in tremulenolide A that in turn would be synthesized through a series of standard functional group manipulations from intermediate 2.33. The substituted [5.3.0] bicyclic carbon skeleton in 2.33 would be formed from a diastereoselective rhodium(I)-catalyzed intramolecular [5+2] cycloaddition of the cyclopropyl enyne 2.34. Utilizing an organocuprate reagent derived from alkyl halide 2.35 to facilitate an SN2 ring opening of lactone 2.8 followed by reduction of the resulting carboxylic acid moiety yields enyne 2.34. The aldehyde 2.34 contains all the carbon atoms present in 2.3 and 2.4, thereby illustrating the convergency and efficient aspects of the proposed route. Cyclopropyl lactone 2.8 was envisioned to arise from the enantioselective, intramolecular rhodium(II)-catalyzed cyclopropanation of diazoester 2.9. 150 Scheme 2.9 O O OH OH H Tremulenolide A (2.3) H Tremulenediol A (2.4) OBn CHO [5+2] Cycloaddition H 2.33 OHC H H OBn 2.34 MetallocuprateMediated SN2 Ring Opening O X BnO H + Me 2.35 2.8 O H Cyclopropanation Asymmetric O O N2 2.9 Based on this strategy, we commenced our efforts with the enantioselective construction of cyclopropyl lactone 2.8 in a straightforward four-step approach from commercially available 2-methyl-2-vinyl oxirane 2.36 (Scheme 2.10). Thus, treatment of oxirane 2.36 with the sulfur ylide of trimethylsulfonium iodide followed by an in situ belimination of dimethylsulfide provided divinyl carbinol 2.37 in 84% yield.310 In order to circumvent the use of expensive reagents at this early stage, we briefly explored an alternative method in which alcohol 2.36 could be obtained by the addition of excess vinyl magnesium bromide to ethyl acetate. Unfortunately, this process was extremely unreliable, often providing the desired carbinol in less than 20% yield. Subsequent 151 acylation of 2.37 with diketene in the presence of 4-dimethylaminopyridine (DMAP) and sodium acetate provided acetoacetate 2.38 in 93% yield. A one-pot diazo transfer reaction of 2.38 with p-toluenesulfonyl azide (p-TsN3) and Et3N, followed by hydrolytic cleavage of the ketone functionality with LiOH H2O provided diazoester 2.9 in an optimized 97% overall yield. This process proved extremely difficult to optimize, as the facility with which diazoester 2.9 decomposed was quite astounding. Under even the most mildly acidic conditions led to extensive decomposition of 2.9 from which no amount of desired product could be extracted. Application of the Corey-Myers diazoesterification procedure311 to carbinol 2.37 was also problematic. The sterically hindered tertiary alcohol was extremely resistant to acylation with anything but a highly activated carbonyl moiety. Scheme 2.10 O O O O O O n-BuLi, Me2SI THF, -10 C to rt 2.5 h, 84% OH DMAP, NaOAc, THF 93% 2.37 2.38 2.36 p-tosyl Azide, Et3N CH3CN, rt, 2 h; then LiOH H2O 4 h, 97% O O N2 Rh2[5(R)-MEPY]4 CH2Cl2, reflux, 23 h 99% 2.9 H Me O 2.8 H O endo/exo = 1:1 When the diazoester 2.9 was exposed to 0.1 mol% of Rh2[5(R)-MEPY]4 intramolecular cyclopropanation proceeded smoothly to yield the desired cyclopropyl lactone 2.8 as a disatereomer.191,312 mixture (1:1) of C4 epimers in 99% yield and 94% ee for each The enantioselectivity of the cyclopropanation reaction was determined by treating the diastereomeric mixture of cyclopropyl lactones 2.8 with 152 phenyllithium in THF to yield diols 2.39a and 2.39b (Eq. 2.3). Subsequent analytical chiral HPLC analysis of each diastereomeric ketone provided the enantiomeric excess from the cyclopropanation of diazoester 2.9 with Rh2[5(R)-MEPY]4. That a mixture of cyclopropyl lactones was obtained in the cyclopropanation is inconsequential due to the destruction of the epimeric center in the next step of the synthesis. Gratifyingly, this optimized sequence provided the desired cyclopropyl lactone 2.8 in 71% overall yield over four steps. Ph PhLi, THF O 2.8 O 92% yield, 94% ee Ph HO Me 2.39a OH H + H Ph Ph HO Me 2.39b OH H (2.3) H H Me H In an effort to examine the feasibility of the proposed organocuprate mediated SN2 ring opening reaction, cyclopropyl lactone 2.8 was treated with the tertiary cuprate reagent derived from t-BuLi and CuCN (Eq. 2.4).313 To our delight, the desired vinyl cyclopropane 2.40 was obtained in 80% yield as a mixture (2.3:1) of olefinic isomers. Confident that the organocuprate reagent derived from alkyne 2.35 would add in a regioselective fashion to cyclopropyl lactone 2.8 to provide the desired cyclopropyl enyne, we turned our attention toward the difficult task of synthesizing the homopropargylic tertiary halide 2.35. HO2C H Me O 2.8 2.40 H H H t-BuLi, CuCN, THF O -78 C to rt, 3 h 80% 2.3:1 olefin isomers (2.4) 153 We originally envisioned that halide 2.35 could be synthesized directly from the corresponding tertiary alcohol. Toward this end, homopropargylic tertiary alcohol 2.43 was synthesized in a high yielding, two step sequence as illustrated in Scheme 2.11. First, propargyl alcohol (2.41) was treated with BnBr and NaH in the presence of TBAI to yield benzyl ether 2.42 in 98% yield.314 The benzyl protecting group was chosen at this stage to allow for its concomitant removal along with catalytic hydrogenation of the trisubstituted olefin present in the advanced bicyclic intermediate 2.33 en route to tremulenediol A. With alkyne 2.42 in hand, the lithium acetylide was generated by addition of nBuLi and treated with isobutylene oxide in the presence of BF3 OEt2 to provide the tertiary alcohol 2.43 in 95% yield.315 Unfortunately, conversion of alcohol 2.43 to the corresponding bromide 2.44 proved to be anything but straightforward. After considerable experimentation, the conversion was effected with TMSBr in CH2Cl2; however, this reaction proceeded in a paltry 23% yield.316 A plethora of bromination conditions were screened, including, but not limited to, PBr3, PBr3 and pyridine, and TMSCl and LiBr. Unfortunately, none of these conditions improved upon the results obtained with TMSBr. The lack of success experienced in this transformation may be due to the apparent instability of the resulting homopropargylic, tertiary bromide, the formation of elimination side products or the migratory aptitude of the intermediate tertiary carbocation. 154 Scheme 2.11 O BnBr, NaH, TBAI OH 2.41 DMF, 0 C rt 98% OBn 2.42 n-BuLi, BF3 OEt2 THF, -78 C rt 95% OH BnO 2.43 TMSBr, CH2Cl2 rt 50 C, 6 h 23% BnO 2.44 Br With limited quantities of tertiary alkyl bromide 2.44 in hand, we turned our attention toward coupling the derived organocuprate with cyclopropyl lactone 2.8. Unfortunately, metallation of 2.44 proved difficult as might be expected of a tertiary homopropargylic halide. Attempts to effect metal-halogen exchange using either lithium wire or lithium powder, followed by transmetallation with CuCN and subsequent treatment with lactone 2.8 led to none of the desired cyclopropyl enyne 2.45 (Eq. 2.5). In each case, lactone 2.8 was recovered from the reaction mixture intact. Additionally, when lithium wire was used in excess, the reduced, deprotected propargylic alcohol 2.46 was obtained. Formation of the lithium alkoxide upon benzyl group deprotection may be playing an inhibitory role in obtaining a quantitative metallation, or interfere with the resulting nucleophilic addition to lactone 2.8. However, the exact nature of any potential interference arising from the formation of 2.46 is purely speculative at this juncture. Therefore, we turned our attention toward reexamining our protecting group strategy to prepare a substrate that would be stable to the metallation conditions. 155 HO2C H Me O 2.8 H O + Br BnO Li(0), CuCN THF 2.44 H H OBn X (2.5) Li(0) = lithium wire or lithium powder 2.45 H HO 2.46 A number of propargylic alcohols of type 2.47 with different hydroxyl protecting groups were considered as potential substrates. The caveat in choosing the protecting group was finding one that was not only stable to the metal-halogen exchange conditions, but also the acidic conditions required for forming the tertiary bromide. Additionally, the optimal protecting group would provide the necessary tertiary alkyl halide in better yield than what was obtained for bromide 3.37 and resist deprotection under the metallation conditions. Based upon these considerations, the series of propargyl alcohol protected substrates chosen were prepared as illustrated in Table 2.1. For our purposes, methyl propargyl ether 2.47a would be a particularly robust substrate (entry 1). However, the difficulty associated with removal of the methyl ether as a late-stage synthetic operation would make this protecting group undesirable, and it was therefore chosen simply as a model to investigate metallation conditions. The TIPS-protected317 alcohol 2.47b and the TBDPS-protected318,319 substrate 2.47c were chosen for their anticipated stability to the metal-halogen exchange conditions and ease of removal at a later stage. Both silyl protecting groups were installed by treating alcohol 2.41 with the corresponding silyl chloride in excellent yields (entries 2 and 3). 156 Finally, methoxy methyl (MOM) etherification was performed using CH2(OMe)2 and TfOH to provide 2.47d in 97% yield (entry 4).320,321 Treatment of protected alcohol 2.47 with nBuLi followed by isobutylene oxide and BF3 OEt2 provided the homopropargylic alcohols 2.48a-d in excellent yields. Table 2.1. Protecting Groups Analyzed for Propargyl Alcohol (2.41) O Alcohol HO 2.41 Protection PGO 2.47 OH PGO 2.48 n-BuLi, BF3 OEt2 THF, -78 C to rt Entry 1 Protected Alcohol 2.47 2.47a Protecting Group Me Protection Conditions TIPSCl, imid., Yield (%) of 2.47 Yield (%) of 2.48 96 2 2.47b TIPS DMF TBDPSCl, imid. 94 99 3 2.47c TBDPS DMF CH2(OMe)2, TfOH CH2Cl2 97 100 4 2.47d MOM 89 97 With tertiary alcohols 2.48a-d in hand, a variety of bromination conditions were analyzed.316,322 To our disappointment, each substrate gave results similar to those which were observed with benzyl ether 2.44. Bromination reagents PBr3, TMSBr, and TMSCl/LiBr provided the most promising results with TBDPS-protected substrate 2.48c (Eq. 2.6). However, yields of 2.49c under these conditions did not exceed 25%. Bromination of the TIPS- and MOM-protected ethers 2.48b and 2.48d gave either 157 deprotected alcohol or products that were not characterized. Equally disappointing was the observation that attempts to brominate the methyl-protected substrate 2.48a led in either to decomposition or recovered starting material. OH TBDPSO 2.48c TMSBr, CH2Cl2 < 25% TBDPSO 2.49c Br (2.6) Unsatisfactory results obtained with: PBr3, Et2O; PPh3, Br2, pyr., CH2Cl2; TMSCl, LiBr, CH3CN; BBr3, CH2Cl2; BF3 OEt2, NaBr, CH3CN; PPh3, CBr4, Et2O Mioskowski323 and Vankar324 reported independently that tertiary THP ethers could be converted to the corresponding alkyl bromides by treatment with either BF3 OEt2 or PPh3 and CBr4 followed by LiBr. Under these conditions tertiary THP ethers are readily ionized under relatively mild bromination conditions to form their respective carbocations, which are then trapped by the bromide source. Thus, THP ethers 2.50a-c were synthesized in excellent yields from the corresponding tertiary alcohols 2.43 and 2.48a-b by treatment with dihydropyran in the presence of pyridinium p-toluenesulfonate (PPTS) (Table 3.2).325 However, when these THP ethers were treated with either a combination of LiBr and BF3 OEt2324 or PPh3, CBr4 and LiBr323 the tertiary bromides 2.44 and 2.49a-b were not obtained. It is conceivable that the difficulties encountered may have been due to the potential for b-elimination of the THP ether moiety facilitated by the homopropargylic nature of the substrates analyzed. However, this hypothesis cannot be corroborated at this time due to our inability to isolate the conjugated elimination product. 158 Table 2.2. Bromination Attempts from the Corresponding Tertiary Bromide O OH PPTS CH2Cl2, rt PGO 2.50a-c OTHP LiBr, BF3 OEt2 CH3CN; or PPh3, CBr4 LiBr, CH3CN Br PGO 2.43 or 2.48a-b X PGO 2.44 or 2.49a-b Entry 1 2 3 Substrate 3.36 3.41a 3.41b Protecting Group Bn Me TIPS Yield (%) of 2.50 99 76 96 Not entirely discouraged by the difficulties encountered in synthesizing the tertiary organocuprate reagent derived from 2.44, we surveyed the literature and discovered a few other methods for generating tertiary anions. Knochel showed in 1992 that organozinc compounds could be obtained by treating the corresponding organophosphate with zinc dust.326 Subsequent transmetallation of the organozinc reagent with CuCN LiCl served as an efficient way in which highly functionalized organocuprate reagents could be synthesized and used as nucleophiles in conjugate additions. Encouraged by Knochel s work, both diethyl and diphenyl phosphates 2.51a and 2.51b were synthesized by treating the tertiary alcohol 2.43 with the dialkyl chlorophosphate and n-BuLi in 68% and 53% yield, respectively (Scheme 2.11).327 Unfortunately, treatment of either tertiary phosphate 2.51a or 2.51b with LiI, LiBr and zinc dust in DMA as described by Knochel and coworkers failed to provide the organozinc compound 2.52. Extended reaction times and elevated temperatures resulted primarily in thermal b-elimination of the organophosphate functionality to yield a side 159 product whose 1H NMR was consistent with the conjugated alkyne 2.54. We speculated that the inability to perform the desired metallation with zinc dust in these experiments may have been due to difficulties associated with Zn(0) activation. A variety of techniques were employed to activate the zinc dust, including treatment with TMSCl and dibromoethane and purification by washing the metal with a solution of inorganic acid. Unfortunately, all efforts to form an organozinc were ineffective. Given the lack of success with zinc dust as a source of Zn(0), we turned our attention toward examining the more reactive Rieke zinc reagent as the source of Zn(0). Once again, tertiary phosphates 2.51a and 2.51b proved resistant to metallation, undergoing elimination or decomposition preferentially. Scheme 2.11 O OH BnO 2.43 ClP(O)(OR)2, n-BuLi THF, -78 C to rt BnO 2.51a 2.51b R = Et: 68% (86% borsm) R = Ph: 53% OP(OR)2 Zn(0), LiI LiBr, DMA X ZnX BnO 2.52 CuCN, LiCl BnO 2.53 Cu(CN)ZnX BnO 2.54 At this point it was rapidly becoming apparent that introducing the gem-dimethyl moiety directly at this early stage in the synthesis of cyclopropyl enyne 2.34 was not going to work. The lack of success encountered at generating homopropargylic tertiary organocopper species for the coupling reaction was not entirely surprising. There is little 160 literature support for the metallation of tertiary sp3 centers, likely owing to the instability of the resulting carbanions. Therefore, an approach that utilized a stabilized carbanion in assembling the [5+2] cycloaddition substrate, we envisioned to simplify the route toward the two tremulanes. 2.4 2ND GENERATION APPROACH CATALYZED ALLYLIC ALKYLATION INVOLVING A TRANSITION METAL- Although a number of difficulties had been encountered thus far in assembling the carbon framework present in 2.3 and 2.4, we felt that the proposed rhodium(II)-catalyzed asymmetric cyclopropanation could still be used to set the stage for a diastereoselective intramolecular [5+2] cycloaddition as an efficient entry into the tremulane natural carbon skeleton. However, an alternate strategy for synthesizing the intermediate cyclopropyl enyne was necessary. Inspection of cyclopropyl lactone 2.8 revealed an allyl carboxylate moiety that could be exploited to access the desired 1,6-enyne via a transition metalcatalyzed allylic alkylation. The successful incorporation of this allylic substitution reaction in the synthetic approach would represent a third transition metal-catalyzed step in the synthesis. Although the precedent established in the field allylic alkylations indicated that a palladium complex should be the most effective catalyst to provide the regioselectivity desired,328 Evan s report of a modified Wilkinson s catalyst-mediated allylic alkylation captured our attention.329 We reasoned that if RhCl(PPh3)3/P(OMe)3 were capable of catalyzing the allylic alkylation of cyclopropyl lactone 2.8 with an appropriately functionalized alkyne regioselectively, the possibility of inducing the subsequent intramolecular [5+2] cycloaddition in situ was too attractive to ignore. If successful, a 161 novel rhodium(I)-catalyzed allylic alkylation/[5+2] cycloaddition sequence would represent a rapid entry into the [5.3.0] bicyclic core of tremulenediol A and tremulenolide A. Although a tandem allylic alkylation/[5+2] cycloaddition sequence would provide an efficient and concise approach to the tremulanes, one unattractive aspect of this method would be the need to utilize the stabilized sodiodimethyl malonate derivative 2.57 in the rhodium(I)-catalyzed allylic alkylation. This requirement would then necessitate reduction of the gem-diester moiety in 2.55 to the gem-dimethyl functionality present in 2.3 and 2.4. While this series of reduction steps would add to the number of synthetic operations, we felt that the rapid assembly of advanced intermediates utilizing a unique transition metal-mediated operation made this pathway worth exploring (Scheme 2.12). Scheme 2.12 OH OH MeO2C H Tremulenediol A (2.4) 2.55 MeO2C H OBn CO2H [5+2] Cycloaddition HO2C H H Transition MetalOBn Catalyzed Allylic Alkylation MeO2C CO2Me 2.57 OBn + Me O H O H 2.8 MeO2C MeO2C 2.56 162 With our focus set squarely upon the exciting possibility of developing a novel rhodium(I)-catalyzed allylic alkylation/[5+2] cycloaddition process, our initial task was to synthesize the dimethyl malonate derivative 2.57 from commercially available 2butyn-1,4-diol (2.58) in a straightforward three-step sequence (Scheme 2.13). Our first efforts to prepare alcohol 2.59 relied upon reports in which symmetrical diols such as 2.58 were selectively monobenzylated with Ag2O and benzyl bromide.330 Indeed, when diol 2.58 was treated with Ag2O and BnBr, the monobenzylated product 2.59 was obtained, albeit in only 51% yield. Given the low yield and high cost of the silvermediated monoalkylation reaction, we examined more conventional benzylation methods as less expensive alternatives. When diol 2.58 was treated with BnBr and NaH in THF, alcohol 2.59 was obtained in a mere 17% yield. By changing the solvent from THF to DMF only a slight increase in the yield (24%) was observed. Finally, during the course of optimizing this transformation, it was found that treatment of diol 2.58 with benzyl bromide, NaH, and tetrabutylammonium iodide (TBAI) in DMF, the desired monobenzylated product 2.59 could be obtained in 53% yield.314 Although the yield was not significantly higher, this method represents a marked improvement over the use of costly silver oxide. Subsequent treatment of propargyl alcohol 2.59 with methanesulfonyl chloride (MsCl) and Et3N in CH2Cl2 provided mesylate 2.60 in 92% yield.331 It is noteworthy that extended reaction times for this transformation led to the formation of significant amounts of alkyl chloride via displacement of the labile propargylic mesylate. Treatment of mesylate 2.60 with sodiodimethyl malonate in THF gave 2.57 in 97% yield. With this optimized three-step sequence, multigram quantities of 2.57 could be obtained with an overall yield of 48% at relatively low cost. 163 Scheme 2.13 BnBr, TBAI, NaH HO 2.58 OH DMF, rt, 2 h 53% HO 2.59 OBn MsCl, Et3N, CH2Cl2 0 C to rt 92% CH2(CO2Me)2, NaH, THF MsO 2.60 OBn 0 C to rt, 5 h 97% MeO2C CO2Me 2.61 OBn With cyclopropyl lactone 2.8 and malonate 2.57 in hand, we turned our attention toward investigating the RhCl(PPh3)3/P(OMe)3-catalyzed allylic alkylation. The main question that needed to be answered was whether the alkylation of cyclopropyl lactone 2.8 would provide the desired substitution product regioselectively. Would it follow the trend of palladium(0) catalysis and provide the desired product arising from alkylation at the less hindered allylic terminus, or would the regioselectivity mirror the results reported by Evan s to yield substitution products resulting from alkylation at the more substituted carbon? Although we were not optimistic that the regioselectivity would be in our favor, the potential development of a tandem [5+2] cycloaddition warranted examination. When cyclopropyl lactone 2.8 was treated with the sodium enolate of malonate 2.57 in the presence of RhCl(PPh3)3/P(OMe)3, allylic alkylation failed to proceed even after extended reaction times and elevated temperatures (Eq. 2.7). Repeated attempts with this catalyst system resulted in recovered starting material each time. We quickly learned that generating the active catalytic species in this reaction was not only experimentally sensitive but also difficult to reproduce. Even when simple, unsymmetrical allylic carbonates were used as test substrates, the reaction would often fail to provide the substitution product. However, if lactone 2.8 was treated with the anion of 2.57 in the presence of the dimeric rhodium(I) catalyst, [Rh(CO)2Cl]2, likewise 164 known for its ability to catalyze the desired intramolecular [5+2] cycloaddition, cyclopropyl enyne 2.56 was formed with complete regiocontrol as a mixture (1:1) of E/Z isomers. This regiochemical trend was quite surprising considering that Evans results suggested that the opposite regioisomer should have been attained. Although the desired reaction took place, the transformation proceeded in a disappointing 20% yield. Attempts at optimizing the [Rh(CO)2Cl]2-catalyzed allylic alkylation of 2.8 involved performing the reaction at lower temperatures ( 0 C) for extended reaction times (2 to 48 h). However, these experiments failed to provide 2.56 in an improved yield. HO2C O H O Me 2.8 H + H H (2.7) MeO2C MeO2C 2.56 OBn Rh(I)-Catalyzed MeO2C CO2Me 2.57 OBn Allylic Alkylation Conditions: RhCl(PPh3)3, P(OMe)3, NaH THF, 0 C 40 C, 24 h [Rh(CO)2Cl]2, NaH THF, reflux, 2 h NR 20% yield E/Z = 1:1 Encouraged by the formation of cyclopropyl enyne 2.56 when lactone 2.8 was treated with malonate 2.57 in the presence of [Rh(CO)2Cl]2, focus shifted toward developing the tandem reaction sequence with the hope of isolating cycloadduct 2.55. However, initial attempts to perform the one-pot, domino reaction under conditions similar to the [Rh(CO)2Cl]2-catalyzed allylic alkylation failed to yield cycloadduct 2.55 (Eq. 2.8). Changing the solvent to PhMe led to problems associated with the solubility of the malonate anion, thereby leading to inefficient formation of enyne 2.56. Attempts to circumvent this problem employing a mixed solvent system of toluene/THF (1:1) were also unsuccessful. 165 A number of factors may have contributed to the failure of the desired reaction. Some of these may include the ability of the rhodium catalyst to catalyze the [5+2] cycloaddition following the allylic alkylation, excess malonate present in the reaction mixture, or the coordinative aspects of the sodium carboxylate functionality. The absence of a carboxylic acid-substituted cis-cyclopropyl enyne undergoing the intramolecular [5+2] cycloaddition in Wender s studies may indicate that this functional group is not a viable substrate for this carbocyclization.235 Subsequent studies on the cycloaddition of enyne 3.54, which will be discussed shortly, suggest that this may be the case. OBn H O Me 2.8 + MeO2C H CO2Me 2.57 2.55 OBn [Rh(CO)2Cl]2, NaH THF; then D CO2H O X MeO2C MeO2C H (2.8) Given the poor efficiency with which [Rh(CO)2Cl]2 catalyzed the allylic alkylation of cyclopropyl lactone 2.8 with malonate 2.57, we decided to examine other transition metals as alternative catalysts. We first focused on traditional palladium(0) catalysts that were known to provide substitution products with the regiochemistry we required (Eq. 2.9) (see Section 1.B.3.1). A summary of the conditions examined can be found in Table 2.3. We first examined the reaction of 2.8 with sodiomalonate 2.57 in the presence of Pd(PPh3)4.312 This reaction afforded cyclopropyl enyne 2.56 in 49% yield after 4 hours at reflux (entry 1).332 We speculated that diligent stoichiometric control of the base used to generate the enolate was required to ensure that formation of metal hydride complexes would not compete with generation of the (h3-allyl)PdLn complex. 166 Given the difficulties in controlling stoichiometry with NaH, a series of bases were screened that would allow for greater stoichiometric control. Thus, lithium diisopropylamine (LDA), lithium hexamethyldisilazide (LiHMDS), and potassium tbutoxide (t-BuOK) (entry 2) were all examined, but each failed to provide 2.56 in better yield. HO2C O H O Me 2.8 + H MeO2C CO2Me 2.57 OBn H H (2.9) MeO2C MeO2C 2.56 OBn Palladium Catalysis See Table 2.3 The notorious instability of Pd(PPh3)4 may also have been to blame for incomplete conversion of cyclopropyl lactone 2.8 to enyne 2.56.332 Thus, other sources of palladium(0) were examined. Under phosphine free reaction conditions, Pd2(dba)3 and its recrystallized chloroform complex, Pd2(dba)3 CHCl3, gave only 17% of the desired product (entries 3 and 4). The best single result that we observed was by generating the active allylic alkylation catalyst in situ from Pd(OAc)2 and P(OiPr)3 while employing n-BuLi as the base (entry 5).332 Under these conditions, cyclopropyl enyne 2.56 was obtained in 84% yield. Unfortunately, this result was not reproducible, and enyne 2.56 was often obtained in extremely low yields (<5%). It is conceivable that some of the difficulties were associated with generating the active catalytic species. In early reports on palladium-catalyzed allylic alkylations, it was found that additional phosphine would sometimes improve the yield of otherwise troublesome reactions.25 Therefore, use of Pd2(dba)3 CHCl3 in the presence of an additional 70 mol% PPh3 gave a substantially better yield of 2.56 (compare entries 4 and 167 6). However, when Pd(dba)2 was employed under identical conditions cyclopropyl enyne 2.56 was obtained in a disappointing 15% yield (entry 7). On the other hand, treatment of cyclopropyl lactone 2.8 with the sodium enolate of 2.57 in the presence of 10 mol% Pd(PPh3)4 and 70 mol% PPh3 gave enyne 2.56 in 74% yield (entry 8). This set of conditions proved very reliable even when the reaction was run on multigram scale. With an optimized set of conditions for the desired transformation in hand, our attention turned toward synthesizing the [5.3.0] bicycle via an intramolecular [5+2] cycloaddition. Table 2.3. Entry 1 2 3 4 5 6 7 8 a b Palladium-catalyzed allylic alkylation of cyclopropyl lactone 2.8a Catalyst Pd(PPh3)4 Pd(PPh3)4 Pd2(dba)3 Pd2(dba)3 CHCl3 Pd(OAc)2, P(OiPr)3 Pd2(dba)3 CHCl3, PPh3 Pd(dba)2, PPh3 Pd(PPh3)4, PPh3 t Base NaH BuOK NaH NaH n Yield(%)b 59 RSM 17 17 84 c 50 15 74 BuLi NaH NaH NaH Conditions: 10 mol% Pd(0), 1.1 equiv of base, 1.2 equiv of 2.57, 0.1M in THF with respect to 2.8. Isolated yields. cResult was irreproducible. The absence of a cis-carboxylate substituted vinylcyclopropane, similar in structure to 2.56, in Wender s 1999 study of regioselectivity in the [5+2] cycloaddition 168 may be because it was either not examined or failed to produce the [5+2] cycloadduct.235 Hoping that the former and not the latter was the case, we went ahead and analyzed the intramolecular [5+2] cycloaddition of carboxylate 2.56 to assemble the tremulane carbon skeleton (Eq. 2.10). In an effort to induce the rhodium(I)-catalyzed [5+2] cycloaddition of cyclopropyl enyne 2.56 to furnish 2.55, various combinations of catalyst, additive, solvent and temperature were examined (Table 2.4). The first rhodium(I) catalyst used was the dimeric complex [Rh(CO)2Cl]2 because of its greater propensity to yield cycloadducts resulting from cleavage of the more substituted cyclopropane bond. Thus, when a solution of 2.56 containing [Rh(CO)2Cl]2 in toluene was heated to 55 C, an unknown byproduct was obtained in 37% yield after 12 h. After careful examination of the 1H and 13 C NMR spectra, additional 1H-1H NMR correlation (COSY) and 1H-13C NMR correlation (HMQC) experiments, and mass spectral analysis the allylically transposed benzyl ether 2.61 was most consistent with the spectral data. CO2H BnO MeO2C HO2C H H MeO2C MeO2C 2.56 OBn MeO2C [Rh(CO)2Cl]2, PhMe 55 C, 12 h 37% H 2.61 Proposed Structure OBn CO2H MeO2C MeO2C H (2.10) 2.55 Not Observed 169 Mass spectral analysis of 2.61 provided an M+1 peak of 429 consistent with both the proposed structure and cycloadduct 2.55. However, the NMR data was more conclusive, and the resonances that led us to the proposed structure 2.61 are listed in Table 2.3. The multiplet at 5.30-5.27 coincides with the olefinic proton on C5 that had a 13 C shift of 120.6 ppm. The HMQC experiment indicated that the protons whose chemical shifts corresponded to 5.18 and 5.12 resided on the same carbon with a resonance of 108.7 ppm. This data suggests that these signals derive from a terminal olefinic methylene consistent with C11 on 2.61. The benzyl protons on C16 gave a rather unusual signal. Instead of the expected two signals integrating to one proton each with a large geminal coupling constant, we observed one singlet that integrated to two protons. This was not the first time we witnessed this phenomena and it will be discussed later in the synthesis of other cycloadducts. The rest of the resonances associated with the carbocyclic ring protons listed in Table 2.3 are consistent with the proposed structure of 2.61. The regioselectivity of the [5+2] cycloaddition was determined by examination of the long range 1H-13C NMR correlation (HMBC) experiment. These results showed a strong correlation between the 1H NMR olefinic signals on C11 and the 13 C NMR resonances of C3 and C1 as well as the C3 proton and the carboxylate carbonyl carbon. 170 Table 2.3. Principle NMR spectral data for cycloadduct 2.61. 17 Ph 16 11 12 MeO2C MeO2C 15 14 10 9 8 O 2 3 1 7 6 CO2H 4 5 13 H 2.61 Assignmenta C5-1H C11-1Hd C11-1Hd C16-2H C3-H C10-1Hd C7-1H C10-1Hd C8-1Hd C4-1Hd C4-1Hd C8-1Hd a c 1 H NMR d b 5.30-5.27 5.18 5.12 4.71 3.27-3.25 3.04 2.95-2.91 2.92 2.78 2.76-2.71 2.55-2.49 1.89 Multiplicity m app t app t s m d m d ddd m m dd Coupling Constant Jc 1.0 1.0 15.5 15.5 14.0, 6.0, 1.0 14.0, 13.0 13 C NMR d b 120.6 108.7 108.7 65.4 45.7 40.9 54.1 40.9 35.9 34.5 34.5 40.9 Indicates the carbon and number of hydrogens associated with the resonance. bMeasured in ppm. Measured in Hz. dGeminal coupling indicated by HMQC experiment. 171 At this point, we felt that by synthesizing a crystalline derivative of 2.61 suitable for X-ray analysis we could determine whether or not the proposed structure was correct. To achieve this, we envisioned that reduction of the corresponding carboxylic acid moiety to the primary alcohol and subsequent acylation with either a p-bromo- or pnitrobenzoyl chloride should yield suitable a solid suitable for X-ray crystallography. Surprisingly, the carboxylic acid moiety in 2.61 proved resistant to reduction to the corresponding alcohol (Table 2.4). Attempted reduction under standard conditions with borane reagents333,334 only returned starting material from the mixture, even after prolonged reactions times (>48 h) (entries 1 and 2). Lewis acid mediated reduction of 2.61 with BF3 OEt2 and NaBH4 gave a complex mixture of products (entry 3). Attempts at reducing 2.61 through the in situ generation of the mixed anhydride again failed (entries 4 and 5). Compound 2.61 was also treated with LiAlH4 and LiBHEt3, but a complex mixture of products was obtained from which the desired triol could not be isolated. 172 Table 2.4. Entry 1 2 3 Attempted carboxylic acid reduction of compound 2.61. Conditions BH3 THF BH3 DMS BF3 OEt2, NaBH4 ClCO2Me, Et3N, then NaBH4, MeOH ClCO2iBu, NMM, DME, then NaBH4, MeOH Result Recovered Starting Material Recovered Starting Material Complex Mixture of Products 4 Recovered Starting Material 5 Recovered Starting Material 6 7 LiAlH4 LiBHEt3 Complex Mixture of Products Complex Mixture of Products In order to gain some insight into the structural nature of compound 2.61, a series of analogous cyclopropyl enynes were synthesized in which the nature of the cis functional group on the cyclopropane was varied. It was thought that [5+2] cycloaddition of these substrates should yield spectroscopic data that may lead to useful insights into the structure of 2.61. A survey of the literature prompted us to prepare the two cyclopropyl enynes 2.62 and 2.63 whose corresponding [5+2] cycloadducts could be easily compared to published spectral data (Scheme 2.14). Cyclopropyl enyne 2.62 was obtained by treatment of carboxylic acid 2.56 with oxalyl chloride and DMF to give an intermediate acid chloride that was then reduced with NaBH4 to provided 2.62 in 71% yield over the two steps.335 Interestingly, when the NaBH4 reduction of 2.66 was 173 performed under anhydrous conditions, the alcohol 2.67, resulting from 1,6-hydride addition into the vinyl cyclopropane moiety could be isolated in 37% yield (Eq. 2.11). In an attempt to circumvent the formation of 2.67, Luche reduction conditions were explored.336 Unfortunately, this reaction proved problematic due to the insolubility of CeCl3 7H2O in THF. It was eventually discovered that when the reduction was conducted in the presence of water (~10 vol%) at 0 C, the alcohol 2.62 could be obtained in good yield. Treatment of cyclopropyl enyne 2.56 with thionyl chloride in methanol gave the triester 2.63 in 85% yield. Subsequent [5+2] cycloaddition of 2.62 and 2.63 with [Rh(CO)2Cl]2 at 110 C provided cycloadducts 2.64 and 2.65 in 80% and 50% yield, respectively. Both alcohol 2.62 and ester 2.63 provided cycloadducts resulting from cleavage of the less substituted cyclopropane bond. The regiochemistry in the [5+2] cycloaddition of 2.62 and 2.63 was determined by HMQC and HMBC NMR experiments as well as comparison of spectral data to Wender s results. When comparing the 1H NMR spectra of cycloadducts 2.64 and 2.65 to the spectral data associated with compound 2.61 a number of significant differences were apparent. Alcohol 2.64 displayed doublets (J = 11.5 Hz) at 4.06 and 4.03 ppm for the geminal C15 protons. However, the benzyl methylene C18 protons produced a singlet at 4.45 ppm that integrated to two protons similar to what was observed with compound 2.61. Interestingly, the 1H NMR of ester 2.65 showed a complex signal at 4.45 ppm for the two benzylic C18 protons, and a broad singlet at 4.04 ppm assigned to the allylic C15 protons. These results seem to suggest that the signal which corresponds to the benzylic protons on cycloadduct 2.61 can at times appear as a singlet around 4.50 ppm that integrates to two protons on [5.3.0] bicyclic compounds. 174 Scheme 2.14 18 Ph O OH HO 1. (COCl)2 DMF, CH2Cl2 2. NaBH4 THF/H2O HO2C H H MeO2C MeO2C 2.56 SOCl2 MeOH, 85% MeO2C MeO2C 2.63 MeO2C OBn 71% over two steps MeO2C MeO2C 2.62 H 15 H OBn [Rh(CO)2Cl]2 PhMe, 110 C 80% MeO2C MeO2C H 2.64 Regioselectivity > 95:5 18 Ph O H 15 H [Rh(CO)2Cl]2 PhMe, 110 C OBn 50% MeO2C MeO2C H 2.65 CO2Me Regioselectivity = 5.3:1 ClOC H OH H NaBH4, THF OBn 2.62 48% + MeO2C MeO2C 2.67 37% (2.11) OBn MeO2C MeO2C 2.66 Our first thought was to determine whether the formation of 2.61 could be suppressed by changing the reaction conditions used for the [5+2] cycloaddition. If the reaction was performed at 110 C for 2 h, compound 2.61 was obtained in 57% yield (entry 1). Switching catalytic systems to the modified Wilkinson's catalyst (RhCl(PPh3)3/AgOTf) as reported by Wender led to no improvement, and provided 2.61 in 25% yield (entry 2). A series of solvents were examined for their compatibility in the [5+2] cycloaddition. It has been reported that the use 1,2-dichloroethane (DCE) effects 175 clean conversion of cyclopropyl enynes to their corresponding [5+2] cycloadducts.337 Unfortunately, performing the cycloaddition in DCE at 90 C and 110 C only gave 2.61 in 57% and 49% yield, respectively (entries 3 and 4). THF was also examined, but either the starting enyne 2.56 was recovered or, after extended reaction times at elevated temperatures, baseline material was observed by TLC (entry 5). Table 2.5. Entry 1 2 3 4 5d a c Conditions explored in the attempted [5+2] cycloaddition of enyne 2.56.a Catalyst [Rh(CO)2Cl]2 Solvent PhMe PhMe DCE DCE THF Temperature ( C)b 110 110 90 110 110 Yield(%) of 2.61c 57% 25% 57% 49% NR RhCl(PPh3)3/AgOTf [Rh(CO)2Cl]2 [Rh(CO)2Cl]2 [Rh(CO)2Cl]2 Conditions: 10 mol% of Rh(I), 0.01M in dry, degassed solvent relative to 2.56. bBath temperatures. Isolated yields. dReaction run in a sealed screw-cap vial. At this juncture, we reexamined Wender s results and observed that the regioselective cleavage of the more substituted cyclopropane bond of cis-cyclopropyl enynes occurred when a formyl-substituted cis-cyclopropyl enyne was heated in the presence of [Rh(CO)2Cl]2 in PhMe. Therefore, acid 2.56 was converted to the corresponding aldehyde 2.68 in a straightforward sequence of transformations (Scheme 2.15). Thus, treatment of carboxylic acid 2.56 with oxalyl chloride and DMF followed by reduction of the crude acid chloride with LiAlH(OiBu)3 provided aldehyde 2.68 in 84% yield.338 The alcohol 2.62 was also obtained as a side product in 12% yield, but it 176 was oxidized quantitatively with Dess-Martin periodinane to bring the overall yield of this sequence to 96%.339 Heating of 2.68 in the presence of [Rh(CO)2Cl]2 provided the desired cycloadduct 2.69 in 85% yield with complete regioselectivity. The regiochemistry in the cycloaddition of 2.68 was apparent by analysis of the HMQC and HMBC NMR data in addition to comparisons made to Wender s reported spectral data. Subsequent reduction of aldehyde 2.69 with NaBH4 gave the primary alcohol 2.70 in 83% yield. Scheme 2.15 HO2C H H MeO2C MeO2C 2.56 OBn CHO MeO2C MeO2C H 2.69 NaBH4, THF 0 C, 2 h 99% MeO2C MeO2C H 2.70 OBn 1. (COCl)2, DMF, CH2Cl2 2. LiAlH(OtBu)3, THF -78 C, 84% MeO2C MeO2C 2.68 OBn OH OHC H H OBn [Rh(CO)2Cl]2, PhMe 110 C, 30 min 85% With alcohol 2.70 in hand, efforts were focused on obtaining a crystal of a suitable derivative that would provide further structural verification. Acylation of 2.70 with p-bromobenzoyl chloride in the presence of DMAP yielded benzoate 2.71 in 78% yield as an amorphous solid (Eq. 2.12).340 Unfortunately, all attempts to recrystallize 2.71 to provide a crystalline solid suitable for X-ray analysis failed. A number of other derivatives were also synthesized, but the tremulane core proved resistant to all crystallization efforts. Therefore, the most straightforward method to confirm the 177 structural assignments would be to complete the synthesis and compare synthetic and natural spectroscopic data for tremulenediol A. OBn OH MeO2C MeO2C H 2.70 O O MeO2C MeO2C H Ar (2.12) OBn p-BrC6H4COCl, DMAP, pyr. CH2Cl2, 0 C rt 78 % 2.71: Ar = p-BrC6H4 To this end, our efforts focused on the task of completely reducing the diester moiety to install the requisite gem-dimethyl substitution present in tremulanes 2.3 and 2.4. Our initial protecting group strategy was to treat alcohol 2.70 with benzyl bromide and NaH in the presence of TBAI to allow for concomitant removal of both alcohol protecting groups in one operation. Unfortunately, attempts at incorporating an additional benzyl ether moiety under the conditions described failed to yield the dibenzylated product. Acid-catalyzed benzylation utilizing the trichlorobenzyl imidate in the presence of TMSOTf also proved futile. Thus, alcohol 2.70 was protected as its TBSether by treatment with TBSCl and imidazole to provide 2.72 in 81% yield (Scheme 2.16).341 Surprisingly, when diester 2.72 was treated with DIBALH in PhMe, not only did reduction of the methyl esters occur to provide the 1,3-diol moiety, but silyl deprotection also took place. Removal of TBS-ethers using DIBALH has been reported in the literature, but in all those cases, CH2Cl2 was used as the solvent.342 Gratifyingly, reduction of 2.72 with LiAlH4 gave 1,3-diol 2.73 in 91% yield.343 Subsequent treatment of diol 2.73 with methansulfonyl chloride (MsCl) and Et3N provided bismesylate 2.74 in 79% yield.344 178 Scheme 2.16 OBn OH MeO2C MeO2C H 2.70 OBn OTBS HO OH H 2.73 MsCl, Et3N, CH2Cl2 79% MsO OMs H 2.74 TBSCl, imid., DMF 81% MeO2C MeO2C H 2.72 OBn OTBS OBn OTBS LiAlH4, THF 91% Initial attempts to reduce the bismesylate functionality in 2.74 to provide the gemdimethyl moiety were performed utilizing LiAlH4. However, the reaction never proceeded to completion, and a monomesylate intermediate was recovered, even after extended reaction times (>24 h). Ultimately, the reduction of 2.74 was accomplished using LiBHEt3 as the reductant to provide the gem-dimethyl intermediate. Subsequent treatment with TBAF in THF induced removal of the TBS protecting group to give 2.75 in 70% yield over the two steps (Scheme 2.17). With the gem-dimethyl intermediate 2.75 in hand, heterogeneous catalytic hydrogenation with base-washed palladium on carbon under an atmosphere of H2 chemoselectively reduced the trisubstituted olefin with concomitant removal of the benzyl protecting group to provide tremulenediol A in 82% yield. This reduction occurred diastereoselectively to establish the third and final stereocenter on the tremulane carbon skeleton by delivering hydrogen from the less sterically hindered convex face of the [5.3.0] bicyclic core. The spectral data for 2.4 was identical in all respects to that reported in the literature. The absolute configuration of 2.4 was determined by comparison of the optical rotation ([a]D24 = 40.0 (c 0.24 MeOH)) 179 to that for the isolated natural product ([a]D24 = 41.3 (c 0.24 MeOH)) Subsequent treatment of 2.4 with MnO2 provided lactone 2.3. Scheme 2.17 OBn OTBS MsO OMs H 2.74 OH OH MnO2, CH2Cl2 86% H 2.4 H 2.3 1. LiBHEt3, THF 2. TBAF, THF 70% over 2 steps OBn OH H2, Pd/C 82% H 2.75 O O 2.5 CONCLUSIONS In summary, a concise synthesis of two representative sesquiterpene metabolites of the class tremulane has been achieved. The synthetic route is highlighted by a chiral rhodium(II)-catalyzed enantioselective cyclopropanation to establish the absolute stereochemistry necessary in the two target tremulanes, tremulenediol A and tremulenolide A. A transition metal-catalyzed allylic alkylation is then utilized to assemble the complete carbon ensemble present in the natural products, as well as set up a diastereoselective rhodium(I)-catalyzed [5+2] intramolecular cycloaddition. These studies led to the discovery and development of a novel [Rh(CO)2Cl]2-catalyzed allylic alkylation reaction with unusual regioselectivity. Additionally, this method has since been expanded to include domino [Rh(CO)2Cl]2-catalyzed allylic alkylation/carbocylization reactions as ways in which to gain access to complex cyclic 180 carboskeletal frameworks. The trio of transition metal-catalyzed operations described herein represents a convergent and highly efficient enantioselective entry into the tremulane carbon skeleton. A series of relatively straightforward synthetic manipulations completes the total synthesis of 2.3 and 2.4. Tremulenediol A was obtained in 16 steps and in an 8% overall yield. Although the total number of steps is comparable to Davies synthesis, the overall yield of our approach is better by 10-fold. 181 Chapter 3. [Rh(CO)2Cl]2-Catalyzed Allylic Alkylations 3.1 INTRODUCTION Transition metal-catalyzed allylic alkylations constitute one of the more widely utilized classes of reactions in modern synthetic organic chemistry.2,5,12,25,33,345-348 Recent efforts in this area have focused on the development of catalysts that enable high regioand stereochemical control in substitution reactions involving symmetrical and unsymmetrical allylic substrates. Palladium-catalyzed processes typically favor nucleophilic substitution at the sterically less hindered allylic terminus, irrespective of the structure of the starting materials (e.g., 3.1 or 3.2), to yield substitution products 3.3.8 However, Ru,104,349,350 Mo,116 Rh,105,107,120,329 Ir91 and W98 preferentially deliver products 3.4 that arise from substitution at the more substituted allylic terminus (Scheme 3.1).2,25,33,101,106,345-348 The reader is referred to section 1 of chapter 1 in which the regioand stereochemical trends associated with each metal catalyst is discussed. These reactions are generally believed to proceed via transition metal-stabilized allyl intermediates that may range in structure from an unsymmetrical h1-complex to a symmetrical h3-allyl complex. The regioselectivity of the ensuing nucleophilic attack is dictated by a combination of steric and electronic factors that vary with the intermediate complex and the nucleophile.19 182 Scheme 3.1 R2 R1 3.1 Ru, Mo, Rh Ir, W Ru, Mo, Rh Ir, W 3.2 R1 Nuc 3.4 R2 Z Pd R1 3.3 R2 Nuc Pd R2 R1 Z During our investigations into a domino rhodium(I)-catalyzed allylic alkylation/[5+2] cycloaddition to assemble rapidly the [5.3.0] bicyclic core of tremulenediol A and tremulenolide A, we initially examined how RhCl(PPh3)3/P(OMe)3 would catalyze the allylic alkylation of cyclopropyl lactone 3.7 with sodiomalonate 3.8 (Scheme 3.2). We hoped that given the literature precedent for the Wilkinson s catalyst mediated [5+2] cycloaddition, the allylic alkylation catalyzed via Evan s protocol would lend itself to an efficient domino process. Lactone 3.7 was synthesized in two steps from commercially available divinyl carbinol 3.5. Diazoesterification of alcohol 3.5 following the Corey-Myers procedure311 provided diazoester 3.6 in moderate yield. Asymmetric cyclopropanation of diazoester 3.6 with the dirhodium(II) catalyst Rh2[5(S)-MEPY]4 provided the known cyclopropyl lactone 3.7 as one diastereomers in good yield (86%).191 When cyclopropyl lactone 3.7 was treated with the sodium salt of malonate 3.8 in the presence of RhCl(PPh3)3/P(OMe)3, the expected substitution product resulting from alkylation at the more substituted site was not observed. However, the ring-opened product 3.9, resulting from nucleophilic attack at the terminal olefinic site, was obtained in 49% yield as the sole regioisomer. In addition to the low yield obtained from this transformation, we encountered significant difficulties associated with generating the 183 active catalyst species in situ through the described incubation procedure. All too often the reaction was not initiated, leading to recovered starting material. Scheme 3.1 O OH p-TsNHN=CHCOCl, N,N-DMA CH2Cl2; then Et3N, 61% O N2 Rh2[5(S)-MEPY]4, CH2Cl2 86% 3.5 3.6 HO2C H H MeO2C MeO2C 3.9 H H O 3.7 H + O Rh(PPh3)3Cl, P(OMe)3, NaH MeO2C 3.8 CO2Me THF, 0 C 40 C, 49% Regioselectivity = 100:0 Given the difficulties associated with generating the active catalyst species and low yield in going from cyclopropyl lactone 3.7 to enyne 3.9, we pondered whether [Rh(CO)2Cl]2 dimeric rhodium(I) catalyst, also known for its ability to catalyst the [5+2] cycloaddition, would promote the allylic alkylation of 3.7. Thus, when cyclopropyl lactone 3.7 was treated with sodiodimethyl malonate in the presence of [Rh(CO)2Cl]2, carboxylic acid 3.10 was obtained in 93% yield and with complete regiocontrol (Eq. 3.1). The mode of regioselection observed in these [Rh(CO)2Cl]2-catalyzed allylic alkylations of 3.7 to give 3.9 is that which would be expected by palladium. According to Evans, rhodium(I)-catalyzed allylic alkylations should yield the opposite regioisomer. Therefore, we examined whether [Rh(CO)2Cl]2 was indeed an efficient allylic alkylation catalyst with regiochemical trends similar to palladium catalysts, or if cyclopropyl lactone was merely an anomalous case. 184 HO2C H H O 3.7 O H + [Rh(CO)2Cl]2, THF MeO2C CO2Me 93% H H (3.1) Regioselectivity = 100:0 MeO2C CO2Me 3.10 The regioselectivity of these rhodium-catalyzed alkylations of cyclopropyl lactone 3.7 was intriguing, and we were curious as to its origin. One reason for the reversal of regioselectivity maybe be attributed to detrimental steric interactions that would result from nucleophilic addition at the more substituted allylic carbon. Although sterics may play a part in directing the alkylation, the substitution of tertiary allylic carbonates at the more substituted carbon with the modified Wilkinson s catalyst as reported by Evan s makes this unlikely to be the determining factor. Because 3.7 is a vinyl lactone, the allylic leaving group cannot disassociate itself from the incipient p-allyl metal complex upon oxidative addition of the transition metal catalyst, the carboxylate is then allowed to interact with the cationic metal complex. The position of the carboxylate moiety within the rhodium(III)-bound intermediate may influence the regiochemical outcome of the reaction through the formation of a chelated intermediate as depicted in Scheme 3.2. Initial oxidative addition of the rhodium(I) complex to the vinyl cyclopropyl lactone 3.7 provides an allylmetal intermediate to which the carboxylate moiety could then coordinate. Thus, an equilibrium mixture of a six (3.11) and an eight (3.12)-membered chelate results. Upon alkylation of the presumably more stable six-membered chelate 3.11 would provide the formal direct substitution product 3.10, whereas alkylation of the eight-membered chelate 3.12 would result in the unobserved malonate 3.13. 185 Scheme 3.2 H H O 3.7 O H [Rh(CO)2Cl]2 O LnRh O H H MeO2C 3.11 CO2Me NaCH(CO2Me)2 HO2C H H 3.10 O O LnRh H H 3.12 NaCH(CO2Me)2 HO2C H H MeO2C CO2Me 3.13 Given the unusual regioselectivity observed in the [Rh(CO)2Cl]2-catalyzed alkylation of lactone 3.7 with malonate nucleophiles, we decided to explore further this reaction to determine whether the regioselectivity was more general. We thus discovered a transition metal-catalyzed allylic alkylation that proceeded with unprecedented regiocontrol. It is generally possible to prepare either 3.3 or 3.4 through a judicious selection of catalyst and allylic substrate 3.1 or 3.2, given the various catalysts capable of promoting allylic alkylations. However, a direct correlation between the structure of 3.1 or 3.2 and the major product may not exist, a situation that might be a disadvantage in certain instances. Indeed, in all the reports of allylic alkylations, no single catalyst has yet been identified that allows for direct, stereoselective allylic substitution at the carbon atom bearing the leaving group. Moreover, if such a catalyst were discovered that was also capable of promoting subsequent transformations, the potential to develop a variety 186 of cascade sequences exists. When the efficacy of [Rh(CO)2Cl]2 was examined in more detail as an allylic alkylation catalyst, and a series of carbocyclization reactions, we realized that this dimeric rhodium(I) species provided an opportunity to address these issues. 3.2 [Rh(CO)2Cl]2-CATALYZED DIRECT SUBSTITUTION OF SIMPLE UNSYMMETRICAL CARBONATES WITH DIMETHYL MALONATE The observation that [Rh(CO)2Cl]2 catalyzed the rapid and highly regioselective allylic alkylation of carbonate 3.14a (R = Et, R R = H) with sodiodimethyl malonate to provide 3.15a (R = Et, R R = H) immediately captured our attention because the regiochemical outcome was opposite to that observed by Evans for allylic alkylations catalyzed by RhCl(PPh3)3/P(OMe)3 (Eq. 3.2).106 We therefore explored the scope of this novel [Rh(CO)2Cl]2-catalyzed allylic alkylation, and some of our preliminary findings are summarized in this section. R2 R3 R1 3.15 R4 CO2Me CO2Me + MeO2C CO2Me 3.16 R1 3 R2 R 1 2 4 1 2 4 R2 R3 R1 R4 OCO2Me [Rh(CO)2Cl]2 NaCH(CO2Me)2 THF or DMF R4 (3.2) 3.14 Major Minor 3.2.1 Optimizing Condition for the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation In an effort to determine the optimal conditions for this novel allylic alkylation, we examined a few core reaction parameters. Our focus was initially limited to varying the nature of the solvent, the concentration of reactants and the catalyst loading to evaluate changes in efficiency. We quickly determined that the reaction temperature, and 187 to a lesser extent the solvent, exhibited a marked effect on the regiochemistry of the reaction. Allylic carbonate 3.14a was chosen as the first test substrate due to its reactivity in the alkylation reaction (Eq. 3.3). [Rh(CO)2Cl]2 (X mol%), NaCH(CO2Me)2 OCO2Me 3.14a solvent, [M] MeO2C CO2Me 3.15a (3.3) We first examined solvent effects using five common solvents, as the medium for the reaction of 3.14a with the sodium anion of dimethyl malonate to provide 3.15a (Table 3.1). The reaction proceeded efficiently in most solvents (entries 1-4), although the reaction was particularly sluggish when run in toluene (entry 5), providing a mere 51% yield of the desired substitution product. These problems may have arisen from the low solubility of sodiodimethyl malonate in toluene. Albeit excellent yields of 3.15a were obtained with MeCN and Et2O respectively, the reactions were sluggish in these solvents, taking upwards of 10-12 hours to reach completion. Again, the malonate anion was only partially soluble in these solvents. 188 Table 3.1. Solvent effects on the [Rh(CO)2Cl]2-Catalyzed Allylic Substitution Reaction of Carbonate 3.14a with Sodiodimethyl Malonatea Solvent DMF THF MeCN Et2O PhMe Yield (%) 91 84 95 90 51 Entry 1 2 3 4b 5b a Conditions: 5 mol% of [Rh(CO)2Cl]2, 2.5 equiv. of CH2(CO 2Me)2, 2.0 equiv. of NaH, 0.1M in carbonate 3.14, room temperature, 2-4 h. 3.15a/3.16a = 97:3. bReaction run for 24 h. We next examined how the rate of the reaction varied by altering the catalyst load. A low catalyst loading would be ideal to reduce the amount of catalyst and the overall cost of performing the transformation. The results of these studies are summarized in Table 3.2. Essentially, 5 mol% of [Rh(CO)2Cl]2 can be used to catalyze the alkylation efficiently (entry 2), but the reaction rate decreased to 4 h in comparison to 1 h with 10 mol% of catalyst. When 1 mol% of the catalyst was employed, the rate of the reaction plummeted, providing only 16% of malonate 3.15a, even after allowing the reaction to proceed for over 24 h. 189 Table 3.2. Effect of Catalyst Loading on the [Rh(CO)2Cl]2-Catalyzed Allylic Substitution Reaction of Carbonate 3.14a with Sodiodimethyl Malonatea Entry 1b 2 3 Catalyst Load 1 mol% 5 mol% 10 mol% Yield (%) 16 85 84 a Conditions: 2.5 equiv. of CH2(CO2Me)2, 2.0 equiv. of NaH, 0.1M in THF, room temperature, 2-4 h. 3.15a/3.16a = 97:3. bReaction run for 24 h. The concentration of reactants in transition metal-catalyzed transformations plays an important role in determining the efficiency and rate of the reaction, particularly when utilizing a low catalyst load. If the concentration is too low, the rate of catalyst turnover proves to be too slow to effect the desired reaction in a reasonable amount of time. However, if the concentration is too high, issues of insolubility or competing reaction pathways (i.e. readdition of the leaving group to the -ally intermediate thereby producing mixtures of allylic carbonates) become detrimental factors. To establish the optimal concentration in which the [Rh(CO)2Cl]2-catalyzed allylic substitution could be run, a series of reactions were run in which the concentration with respect to carbonate 3.14a was varied, and the results are tabulated below in Table 3.3. The best yields of alkylation product 3.15a were obtained when the reaction was run at a concentration of 0.1 M (entry 2). However, when the concentration of 3.14a was increased to 0.5 M, the yield of the reaction plummeted to <10% as insolubility issues complicated the transfer of reagents, in particular the sodium salt of dimethyl malonate (Entry 3). Under high dilution conditions (0.01 M with respect to 3.14a) the reaction proved less efficient, providing malonate 3.15a in only 68% yield after an inordinate reaction time (>24 h) 190 (entry 1). Therefore, the standard concentration of 0.1 M was utilized for subsequent studies. Table 3.3. Effect of Varying the Reaction Concentration on the [Rh(CO)2Cl]2Catalyzed Allylic Substitution Reaction of Carbonate 3.14a with Sodiodimethyl Malonate Entry 1b 2 3b a Concentration [M] of 3.14a 0.01 0.1 0.5 Yield (%) 68 85 <10 Conditions: 2.5 equiv. of CH2(CO2Me)2, 2.0 equiv. of NaH, THF, room temperature, 2-4 h. 3.15a/3.16a = 97:3. b Reaction run for 24 h. A serendipitous discovery was made when we analyzed the [Rh(CO)2Cl]2catalyzed allylic alkylation of the allylic carbonate 3.14b (Eq. 3.4). Namely, when substrate 3.14b was allowed to react with sodiodimethyl malonate in the presence of [Rh(CO)2Cl]2 at room temperature, a mixture (ca. 1:1) of regioisomeric products was obtained under the same conditions that had been used for carbonate 3.14a. However, when the solvent was switched from THF to DMF and the temperature of the reaction was lowered to -20 C, the ratio of 3.15b/3.16b improved from 59:41 to 80:20 favoring the branched regioisomer 3.15b. These results suggest that changing the solvent from THF to DMF increased the rate of nucleophilic attack by the malonate anion, so the reaction could be conducted at a lower temperature where the rate of enyl isomerization is suppressed. Oxidative addition of the metal catalyst followed by rapid nucleophilic attack prior to isomerization of the allylmetal intermediate results in the formal direct substitution product. By modifying the solvent and temperature of the reaction to 191 increase the rate of nucleophilic attack and slow the isomerization of metal-stabilized intermediates, the extent of regioisomeric leakage can be minimized. OCO2Me MeO2C CO2Me MeO2C CO2Me + CO2Me CO2Me (3.4) [Rh(CO)2Cl]2, 75% 3.14b Regioselectivity (a/b): THF, rt = 59:41 DMF, -20 C = 80:20 3.15b 3.16b Although the ratio of regioisomers could be improved in the substitution of carbonate 3.14b, we were perplexed that such poor regiocontrol was observed in comparison to the alkylation of 3.14a. Additionally, the complete reversal of regioselectivity in the alkylation of cyclopropyl lactone 3.7 further piqued our curiosity. The allylic moiety in substrates 3.7 and 3.14b both contained a terminal olefin, whereas the carbonate in 3.14a was allylic to an internal 1,2-disbustituted carbon-carbon double bond. This observation led us to analyze the effect temperature and solvent would have on the regioselectivity in a series of other terminally substituted allyl substrates. Toward this end, we studied the reaction of carbonate 3.14c, which is commonly used in reactions promoted by numerous allylic alkylation catalysts (see Chapter 1). Allylic carbonate 3.14c was synthesized in two steps from acrolein (3.17) by sequential addition of phenyl magnesium bromide (3.18) and acylation of the resulting carbinol (Scheme 3.3). When the allylic alkylation was performed at room temperature in THF, the formation of the linear regioisomer 3.16c, resulting from substitution at the allylic carbon not bearing the leaving group, was observed. However, when the temperature of the reaction was lowered to 20 C and the reaction was performed in DMF instead of THF, the ratio of 3.15c/3.16c decreased to a 50:50 ratio. 192 The main structural difference between 3.14b and 3.14c is the benzylic nature of the carbonate moiety in compound 3.14c. It is conceivable that the additional steric bulk of the phenyl group in 3.14c, as compared to methyl, was a dominant factor in controlling the regioselectivity of the substitution reaction. However, conjugative stabilization of the phenyl ring, present only in the formation of 3.16c, may also be a significant driving force. To test this hypothesis, we synthesized carbonate 3.14d by reaction of cyclohexyl magnesium bromide (3.19) with acrolein followed by acylation of the resulting secondary carbinol. Treatment of allylic carbonate 3.14d under the standard [Rh(CO)2Cl]2- catalyzed allylic alkylation conditions in THF at room temperature provided the linear product 3.16d preferentially (regioselectivity = 79:21). However, carbonate 3.14d failed to react with sodiodimethyl malonate in the presence of [Rh(CO)2Cl]2 when the alkylation reaction was performed in DMF at either 0 C or 20 C for extended time (>24 h). This result seems to suggest that the conjugative stabilization is not a significant determinant in the regiochemistry of the alkylation of 3.14c and that steric factors might be more important. 193 Scheme 3.3 MeO2C 1. MgBr 3.18 THF, 70% 2. ClCO2Me, pyr. CH2Cl2 69% OCO2Me [Rh(CO)2Cl]2 3.15c NaCH(CO2Me)2 93% 3.14c + CO2Me CO2Me 3.16c CO2Me Regioselectivity (3.15/3.16): THF, rt, 2 h = 20:80 DMF, -20 C, 24 h = 50:50 CHO 3.17 MeO2C 1. MgBr 3.19 THF, 72% 2. ClCO2Me, pyr. CH2Cl2 50% OCO2Me [Rh(CO)2Cl]2 NaCH(CO2Me)2 THF, rt, 2 h, 97% 3.14d CO2Me 3.15d + CO2Me CO2Me 3.16d Regioselectivity (3.15/3.16): THF, rt, 2 h = 21:79 DMF, -20 C, 24 h = NR With the preliminary optimization of the [Rh(CO)2Cl]2-catalyzed allylic alkylation complete, we were able to see that the reaction could proceed efficiently with 5 mol% catalyst loading at a concentration of 0.1M with respect to the starting carbonate. The solvent and temperature had a dramatic effect on the results obtained from the reaction. Although the reaction proceeded with good regioselectivity and with relatively short reaction times at room temperature in THF, the reaction was qualitatively much faster in DMF, which allowed the use of lower temperatures. Extending reaction times and lowering the temperature to 20 C was found to improve the regioselectivity in the 194 substitution of allylic carbonates performed in DMF. However, THF was the solvent of choice because it was operationally easier to handle. Namely, those reactions run in DMF required an aqueous workup to remove the solvent, whereas those performed in THF could be filtered through a short plug of silica gel and the products isolated after flash column chromatography. 3.2.2 [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation of Unsymmetrical Primary Carbonates with Dimethyl Malonate Having established a set of reaction conditions as a starting point, the scope of the [Rh(CO)2Cl]2-catalyzed allylic alkylation using a number of allylic carbonates was examined. Preliminary results utilizing primary allylic carbonates in the substitution reaction are listed in Table 3.3. The synthesis of the requisite allylic substrates was straightforward. The methyl carbonates were obtained in one step from the corresponding allylic alcohols by reaction with methyl chloroformate and pyridine in CH2Cl2.351 Yields for the acylation reactions were generally excellent. The corresponding allylic alcohol precursors to carbonates 3.14e-f and 3.14i-k were commercially available. The synthesis of carbonates 3.14g and 3.14h was Thus, cyclopropyl aldehyde 3.20 was straightforward as illustrated in Scheme 3.4. treated with the anion of trimethyl phosphonoacetate to provide the a,b-unsaturated ester 3.21 in 98% yield.286 Subsequent reduction with DIBALH gave the desired allylic alcohol 3.22, which gave the carbonate 3.14g in 71% yield upon treatment with methyl chloroformate and pyridine. 195 Scheme 3.4 O (MeO)2P CHO 3.20 NaH, THF 98% CO2Me CO2Me 3.21 DIBALH, CH2Cl2 81% ClCO2Me, pyr. OH 3.22 CH2Cl2 71% OCO2Me 3.14g Carbonate 3.14h was obtained in four steps from commercially available cis-2butene-1,4-diol (3.23) (Scheme 3.5). Bisacylation of diol 3.23 with methyl chloroformate provided dicarbonate 3.24 in good yield. Ozonolytic cleavage of 3.24 followed by sequential treatment with PPh3 and 1-triphenylphosphoranylidene-2propanone gave the a,b-unsaturated ketone 3.25 in modest yield.352 Silyl enol ether formation with TIPSOTf and Et3N provided enol ether 3.14h. Scheme 3.5 ClCO2Me, pyr., CH2Cl2 HO 3.23 OH 71% MeO2CO 3.24 OCO2Me 1. O3, CH2Cl2; then PPh3 2. Ph3PCHC(O)CH3 CH2Cl2 37% over 2 steps O OCO2Me 3.25 TIPSOTf, Et3N, CH2Cl2 71% OTIPS OCO2Me 3.14h Examination of the entries in Table 3.4 reveals that [Rh(CO)2Cl]2 catalyzed the facile and regioselective alkylations of various primary carbonates 3.14a-k to provide the 196 corresponding substitution products 3.6a-k selectively in each case.353 The reactions typically proceeded with excellent regiocontrol that favored substitution at the carbon atom bearing the leaving group. A number of general trends and notable features merit additional discussion. 197 Table 3.4. Regioselectivity in the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation of Unsymmetrical Primary Carbonatesa Allylic Carbonate OCO2Me 3.14a Entry Major Product Yieldb (%) Ratio 3.15:3.16c 97:3 1d MeO2C CO2Me 3.15a 84 CO2Me 2e OCO2Me 3.14e 3.15e OCO2Me CO2Me 86 99:1 (97:3)i CO2Me CO2Me 3e 3.14f 93 90:10 3.15f 4e OCO2Me 3.14g CO2Me MeO2C 3.15g OTIPS CO2Me CO2Me 3.15h CO2Me 84 89:11 OTIPS 5 f OCO2Me 3.14h 94 97:3 6 f OCO2Me 3.14i CO2Me 3.15i 71 - CO2Me 7 g OCO2Me 3.14j CO2Me 3.15j CO2Me MeO2C 3.15k 75 92:8 8e a OCO2Me 3.14k 52 99:1 Conditions: 5 mol% of [Rh(CO)2Cl]2, 2.5 equiv of CH2(CO2Me)2, 2.0 equiv of NaH (2.0 eq.). bIsolated yields. cRatios determined by GLC. dTHF, rt. eTHF, 0 C. fDMF, rt. gDMF, -20 C. hDMF, 0 C. iRatio of cis/trans isomers. 198 Primary allylic carbonates having internal disubstituted carbon-carbon double bonds provided primarily linear alkylation products (Entries 1 5). As discussed in Section 1.1.3.1 palladium catalysts exhibited this mode of regioselectivity. This is noteworthy as results outlined in Sections 1.B.4-1.B.7 illustrate that the opposite is typically observed for ruthenium, molybdenum, iridium and most rhodium catalysts.5,12,19,354 The Z-carbonate 3.14e (entry 2) underwent alkylation to provide the less stable Z-product with little carbon-carbon double bond isomerization. This is noteworthy because extensive Z E isomerization of Z-allylic substrates is generally observed using other transition metal catalysts, although there are reports of Z-selective allylic substitutions of Z-substrates that are catalyzed by iridium,91,100,101 palladium,72,355,356 and tungsten.357 The temperature and solvent were critical to maintaining the Z-double bond. For example, if the reaction was performed at room temperature, the mixture of Z/E isomers dropped to 86:13. However, if the reaction was run in DMF at temperatures ranging from room temperature to 20 C, the E-isomer was obtained as the major product. This solvent effect was rather surprising because we believed that increasing the rate of nucleophilic attack, a phenomena that we observed by running the reaction in DMF, would lead to less isomerization of the double bond. Unfortunately, this had the opposite effect on Z E isomerization. The reader is referred to Sections 1.1.3.3 and 1.1.5.2 for a discussion of double bond geometry in the transition metal-catalyzed allylic alkylation reaction. Allylic alkylation of carbonate 3.14f provided the linear product 3.15f with good regiocontrol. This result is significant because using molybdenum,77 iridium101 and ruthenium104 catalysts, nucleophilic attack generally occurs at the more electrophilic benzylic site. The presence of sensitive enol ethers in conjugation with the allylic subunit did not adversely affect the regiochemistry or efficiency of the reaction as illustrated by 199 the alkylation of carbonate 3.14h (entry 5). It is thus evident that additional functional handles can be present for manipulations consequent to the [Rh(CO)2Cl]2-catalyzed allylic alkylation. As illustrated by the alkylation of carbonate 3.14i, internal substitution does not affect the efficiency of the alkylation, as malonate 3.15i was isolated in 71% yield (entry 6). That 3.14j (entry 7) underwent any alkylation is noteworthy because 2,3,3-trisubstituted allylic carbonates are inert to the modified Wilkinson s catalyst reported by Evans and typically require forcing conditions with other transition metal catalysts.106,277,358 Finally, [Rh(CO)2Cl]2 may be used effectively to catalyze the alkylation of propargylic carbonates to give substituted alkynes with none of the allenic product commonly observed in palladium catalysis (Entry 10).359 3.2.3 [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation of Unsymmetrical Secondary and Tertiary Carbonates with Dimethyl Malonate The reaction scope was further extended to include secondary and tertiary allylic carbonates, as illustrated by the results in Table 3.5. The allylic carbonates were readily synthesized from their corresponding allylic alcohols by reaction with methyl chloroformate in the presence of pyridine. The allylic alcohol precursors for carbonates 3.14l-n and 3.14p and allylic acetate 3.14o were commercially available. However, allyl carbonate 3.14q was synthesized by the addition of methylmagnesium bromide to 2pentenal followed by acylation with methyl chloroformate.360 Also, carbonate 3.14r was synthesized in a three-step sequence as illustrated in Scheme 3.6.361 Horner-WadsworthEmmons olefination of cyclohexane carboxaldehyde (3.26) provided a,b-unsaturated ketone 3.27 in 94% yield. Reduction of 3.27 with LiAlH4 gave allylic alcohol 3.28, which was subsequently acylated under standard conditions to form allylic carbonate 3.14r in 86% yield. 200 Scheme 3.6 CHO O (EtO)2P O O LiAlH4, Et2O 94% 3.27 OH OCO2Me NaH, THF, 94% 3.26 ClCO2Me, pyr., CH2Cl2 86% 3.28 3.14r Allylic carbonate 3.14s was synthesized in two steps from commercially available cyclohexyl bromide (3.29) by generation of the corresponding Grignard reagent followed by nucleophilic addition to crotonaldehyde (3.30) (Scheme 3.7). The resulting allylic alcohol 3.31 was then acylated under standard conditions to provide allyl carbonate 3.14s. Scheme 3.7 CHO Br OH 3.30 Mg(0), THF, 76% 3.29 3.31 ClCO2Me, pyr. CH2Cl2, quant. 3.14s OCO2Me 201 Table 3.5. Entry [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation of 2 and 3 Carbonatesa Allylic Carbonate OCO2Me Major Product CO2Me CO2Me Yield (%) 80 Ratio 3.16:3.17 94:6 1e 3.14l 3.15l 2e OCO2Me 3.14m MeO2C CO2Me 89 91:9 3.15m 3d OCO2Me 3.14n MeO2C CO2Me 80 60:40 3.15n 4e,j OAc 3.14o OCO2Me MeO2C CO2Me 74 96:4 3.15o MeO2C CO2Me 5d 3.14p 89 3.15p OCO2Me MeO2C CO2Me 6h 3.14q 88 3.15q MeO2C CO2Me 96:4 OCO2Me 7e 3.14r 3.15r MeO2C CO2Me 94 93:7 OCO2Me 8h 4.14s a 94 4.16s 93:7 Conditions: 5 mol% of [Rh(CO)2Cl]2, 2.5 equiv of CH2(CO2Me)2, 2.0 equiv of NaH (2.0 eq.). bIsolated yields. cRatios determined by GLC. dTHF, rt. eTHF, 0 C. fDMF, rt. gDMF, -20 C. hDMF, 0 C. iRatio of cis/trans isomers. jThe corresponding carbonate was unstable. 202 Although a quaternary center was generated in the process, the isomeric tertiary allylic carbonate 3.14i underwent facile substitution to provide the product 3.15i (Table 3.5, entry 1) with excellent regioselectivity. The differences in reactivity of [Rh(CO)2Cl]2 and other catalysts capable of promoting allylic substitutions is underscored by the preliminary results obtained with secondary allylic carbonates and acetates 3.14m-s (Entries 2 8). In each case, formal direct displacement of the leaving group is the dominant reaction pathway. When the substrate contained additional unsaturation, which in the case of carbonate 3.14m renders the leaving group homoallylic as well as allylic, the substitution product 3.15m was obtained in good yield (89%) and regioselectivity (91:9) (Entry 2). However, when the terminal double bond is absent as in 3.14n, the regiocontrol in the reaction suffers, providing only a 60:40 ratio of substitution products 3.15n and 3.16n in THF at room temperature (entry 3). When the alkylation of 3.14n was performed in DMF at lower temperature (i.e. 20 C to room temperature) no improvement in the regiocontrol was observed. It has been observed that pendant olefins can direct the regiochemistry of the transition metal-catalyzed allylic alkylation reactions, presumably via a weak coordination of carbon-carbon double bond to the metal.362 This additional directing effect may be one reason for the enhanced regiocontrol observed in the reaction of 3.14m (entry 2) in an otherwise problematic substrate. This general trend of formal direct substitution holds even when conjugation would favor substitution at the opposite allylic terminus as illustrated by the reaction of carbonate 3.14o to provide the branched substitution product 3.15o (entry 4). Entries 6 and 7 illustrate the efficiency of the [Rh(CO)2Cl]2-catalyzed allylic substitution reaction in which electronic factors are not present to aid in directing the regioselectivity of the alkylation. 203 When substrate 3.14s was treated with the sodium enolate of dimethyl malonate in the presence of [Rh(CO)2Cl]2, the substitution product 3.16s, which resulted from SN2 like alkylation was obtained as the major product in a 93:7 ratio of regioisomers. This result stands in stark contrast with what was observed when carbonate 3.14r was alkylated under the same conditions. Apparently the observed memory effect was not strong enough to overcome what could be the increased steric demand by the branching on the cyclohexyl group. Given the drastically different the regiochemical outcomes associated with the alkylation of carbonates 3.14r and 3.14s, it appears that branching on the carbon one atom removed from the allyl moiety imparts a particularly strong influence on the outcome of the [Rh(CO)2Cl]2-catalyzed allylic alkylation. This effect is apparently more pronounced than even that observed when the substitution on the three allylic carbons themselves is increased. Although understanding the steric interactions between the catalyst, allylic substrate and the nucleophile is critical to gaining insight into regiochemical trends, electronic factors are also known to influence the regiochemistry, and much be considered. If one compares the results obtained when carbonate 3.14d and 3.14s are treated with sodiodimethyl malonate in the presence of [Rh(CO)2Cl]2, steric effects do not adequately explain the regioselectivities observed. Based upon steric effects alone, one would expect that malonate 3.16d should be formed with higher selectivity (79:21) than 3.16s (97:3). These results seem to suggest a contributing electronic influence in the regiochemistry as has been observed with molybdenum, tungsten, iridium and Evan s modified Wilkinson s catalyst system (see Chapter 1.B). Regiochemical leakage in the formation of 3.16d results from electronic preference for alkylation to occur at the secondary allylic carbon, a factor not present in the allylmetal intermediate formed by ionization of carbonate 3.14s. 204 3.2.4 Summary of the Regiochemical Trends Observed in the Alkylation of Simple Allylic Carbonates with Dimethyl Malonate Catalyzed by [Rh(CO)2Cl]2 That [Rh(CO)2Cl]2 catalyzes the allylic alkylations of unsymmetrical substrates to give products in which substitution occurs at the carbon atom bearing the leaving group may be regarded as a memory effect . Such phenomena have been examined in palladium-catalyzed allylic alkylations of enantioenriched and racemic secondary allylic substrates having the same number of substituents on the allyl moiety.363 The nature of the memory effect observed in [Rh(CO)2Cl]2-catalyzed allylic alkylations thus differs significantly from those previously studied because the termini of the allylic moieties are unequally substituted. Mechanistic studies must be conducted to understand the origin of the regiochemistry in [Rh(CO)2Cl]2-catalyzed allylic alkylations and why it differs from analogous reactions promoted by other transition metal catalysts. Of particular interest in this regard is whether the rhodium-stabilized allyl intermediate resembles one of two sbonded metal species 3.33 or 3.39, the (s+p) enyl complexes 3.34 or 3.38, as suggested by Evans in the modified Wilkinson s catalyst mediated allylic alkylations, or one of the other possible distorted p-allyl variant 3.35-3.37 (Scheme 3.8).106 The regioselectivity of the allylic alkylation is dependent on the relative concentration of each intermediate and the rate of equilibration. If equilibration is rapid, the product distribution should arise from the most stable allylmetal intermediate. However, if equilibration is slow, the regiochemical ratios should mirror the structure of the starting material providing products resulting from a formal direct substitution. Unfortunately, determining where this equilibrium lies is not necessarily a simple endeavor. Qualitative analysis of the data obtained from the alkylation of a number of allylic substrates can provide an indication in most cases which of these allylmetal intermediates is dominant. However, if the metal-bound allyl species can be 205 recrystallized, and its structure determined by X-ray analysis, a more accurate picture of the reaction intermediate can be attained. Scheme 3.8 R1 R2 3.32 Z MLn R1 3.33 MLn R2 R1 M Ln 3.34 R2 R1 R2 R MLn 3.36 R1 R2 3.39 2 R1 LnM 3.35 R1 MLn R2 3.37 R1 M R2 Ln 3.38 MLn +Nuc -MLn R1 Nuc R2 3.40 To the best of our knowledge, this level of regioselective dependence on homoallylic substitution with respect to the starting allylic carbonate, while seemingly independent of the steric environment associated with the allylic moiety itself, has not been extensively explored. To clarify, if one considers the four possible allylic carbonates 3.41a-d as depicted in Figure 3.1 there exists the allylic two sphere and 206 homoallylic sphere of steric influence represented by the allylic substituent R1 and the homoallylic substituents R2-R4 respectively (Figure 3.1). In cases we examined (Scheme 3.3, Table 3.2, entry 8) It appears as though if the homoallylic sphere is large (R2, R3 or R4 H) alkylation is directed to the opposite allylic terminus. However, if R2-R4 = H substitution occurs at the carbon where the leaving group Z resided, regardless of the steric bulk of R1. Typically, if the regiochemistry of a transition metal-catalyzed allylic alkylation is influenced by the steric environment around the homoallylic centers of the starting carbonate, than a similar effect is observed as the steric congestion on the allylic carbons is likewise altered.7,83,104 However, for the regiochemical outcome to be seemingly independent of the allylic sphere while the homoallylic sphere has a profound steric effect on the outcome is particularly unique. Figure 3.1. Relative influence of allylic and homoallylic substitution on regioselectivity. Z R1 R3 3.41a Z R2 R4 R3 3.41b R1 R2 R4 R1 Z R2 R3 3.41c R4 R1 Z R2 R3 3.41d R4 To summarize the observations we have made up to this point, Scheme 3.9 provides a graphical representation of how initial oxidative addition of the rhodium(I) complex provides allylmetal variants 3.43a and 3.43b from the corresponding starting allylic carbonates 3.42a and 3.42b. Nucleophilic attack at the less hindered allyl 207 terminus of intermediate 3.43a yields the alkylation product 3.44a, which corresponds to the product of substitution at the carbon bearing the leaving group. Nucleophilic attack in a similar fashion on 3.43b would be expected to be relatively slow due to the steric interactions between the large substituents attached to the allylic substrate and the attacking nucleophile. When nucleophilic attack is slowed, s-p-s isomerization can produce the intermediate 3.43a. This isomerization could then lead to preferential formation of 3.44a as observed for carbonate 3.14s (Table 3.5, entry 8). The steric effect from substituents in these examples is strikingly absent from entries 1-4 in Table 3.5 where differing substitution is present directly on the allyl moiety. The lack of influence these substituents seem to impart on the product distribution may arise as a function of their proximity to the angle of nucleophilic attack. Although we are unfamiliar with studies addressing this issue, the steric environment around the homoallylic carbon of the starting carbonate may be more in line with the path of anion addition depending upon the nature of the metal stabilized complex. This discussion is purely speculative at this point as studies have not been conducted to determine the validity of this hypothesis. The absence of reports describing a similar phenomena of such steric influence on the regioselectivity with other transition metals known to catalyze allylic alkylations warrants further exploration in the reaction catalyzed by [Rh(CO)2Cl]2. 208 Scheme 3.9 OCO2Me Rh(I) Ln Rh NucFavored MeO2C CO2Me 3.42a 3.43a 3.44a NucOCO2Me Rh(I) Ln Rh MeO2C Disfavored CO2Me 3.42b 3.43b 3.44b 3.2.5 Conservation of Absolute Stereochemistry in the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation of Enantioenriched Secondary Allylic Carbonates In order to determine the stereochemical outcome of [Rh(CO)2Cl]2-catalyzed allylic substitutions, enantioenriched allylic carbonate (+)-3.47 was synthesized in three steps from cinnamaldehyde (3.45) to determine if the reaction proceed with net inversion, net retention or racemize the starting carbonate (Scheme 3.10). Addition of methyl magnesium bromide to aldehyde 3.45 provided the corresponding racemic alcohol 3.46 in 69% yield. Subjecting alcohol 3.46 to Sharpless kinetic resolution364 followed by acylation of the enantioenriched alcohol under standard conditions, afforded the allylic alkylation precursor (+)-3.47 in 99% ee (Scheme 3.8). The enantiomeric excess of carbonate (+)-3.47 was determined by chiral HPLC and the absolute configuration ascertained by comparison of the optical rotation to literature values. When allylic carbonate (+)-3.47 was treated with the sodium salt of dimethyl malonate in the presence 209 of [Rh(CO)2Cl]2, malonate (+)-3.48 was obtained in 93% yield and 98% ee (regioselectivity = 93:7). The enantioselectivity of the allylic alkylation was determined by chiral HPLC analysis of malonate (+)-3.48 whose optical rotation was compared to literature values to obtain the absolute configuration. Based upon these experiments, [Rh(CO)2Cl]2 appears to catalyze substitutions of secondary allylic carbonates with net retention of configuration as has been observed with Pd,5,12,13 Ru,104 Mo,75 Rh106 and Ir101 catalysts. However, whether the reaction proceeds via an anti-anti or syn-syn mechanistic pathway has not yet been determined. Scheme 3.10 CHO MeMgBr, Et2O 69% 3.45 OCO2Me 3.46 MeO2C [Rh(CO)2Cl]2, NaCH(CO2Me)2 DMF, 93% CO2Me OH 1. (+)-DIPT, Ti(OiPr)4, TBHP 4 MS, CH2Cl2, 49% conv. 2. ClCO2Me, pyr. CH2Cl2, 87% Regioselectivity = 93:7 (+)-3.47 (+)-3.48 99% ee 98% ee At this point we became interested in determining the stereochemical outcome of the [Rh(CO)2Cl]2-catalyzed substitution reaction in the rare case where the formal indirect substitution product was obtained preferentially. To that end, known enantioenriched carbonate (+)-3.14s was obtained in 86% ee, which was determined by chiral HPLC analysis, via Sharpless kinetic resolution of the corresponding allylic alcohol 3.31 followed by acylation with methyl chloroformate (Scheme 3.11). The absolute configuration of (+)-3.14s was confirmed by comparison of the optical ration to 210 known literature values.364 Alkylation of (+)-3.14s under the same conditions established for 3.14s yielded the substitution product (+)-3.16s with complete conservation of optical purity, as determined by chiral HPLC. In order to determine the absolute stereochemistry of (+)-3.16s, we first attempted to obtain an X-ray crystal structure of a chiral amine salt derived from the corresponding monocarboxylic acid that was formed by ester hydrolysis and subsequent decarboxylation. Unfortunately, crystals suitable for X-ray analysis proved elusive, and we therefore resorted to transforming (+)-3.16s into diester 3.50, whose enantiomer 3.55 was synthesized independently from propanoic acid (3.51)365 (Scheme 3.12). By comparing the optical rotations of esters 3.50 and 3.55 the absolute configuration of (+)3.16s could be elucidated. monoester 3.49. Thus, Krapcho decarboxylation366 of (+)-3.16s provided Subsequent oxidative cleavage followed by esterification utilizing trimethylsilyl diazomethane should provide diester 3.50. Scheme 3.11 1. (+)-DIPT, Ti(OiPr)4 TBHP, 4 MS CH2Cl2, 29% conv. 2. ClCO2Me, pyr. CH2Cl2, 87% 3.31 (+)-3.14s MeO2C [Rh(CO)2Cl]2 NaCH(CO2Me)2, THF 80% CO2Me OH OCO2Me Regioselectivity = 93:7 (+)-3.16s 86% ee 86% ee CO2Me NaCl, DMSO H2O, 92% 3.49 1. NaIO4, RuCl3, CCl4 CH3CN, H2O 2. TMSCH2N2, PhH MeOH CO2Me MeO O 3.50 211 The diester 3.55 was synthesized starting from propanoic acid (3.51). Installation of chiral oxazolidinone 3.52 under standard conditions provided imide 3.53 in 65% yield (Scheme 3.12). Diastereoselective alkylation with methyl bromoacetate provided ester 3.54 in 71% yield. Subsequent cleavage of the chiral auxiliary with sodium methoxide in methanol provided the diester 3.55.366 By comparing the optical rotations for diesters 3.50 and 3.55, we should be able to confirm that although the regiochemistry of the alkylation reversed itself, the overall stereochemical outcome remained the same. Scheme 3.12 O OH + O Bn 3.51 3.52 MeO2C O N O 3.54 Bn O HN O THF, 65% O 3.53 MeO2C OMe O 3.55 LiCl, tBuCOCl, Et3N O N Bn O BrCH2CO2Me, NaHMDS THF, 71% NaOMe, MeOH, CH2Cl2 74% Thus, the [Rh(CO)2Cl]2-catalyzed allylic alkylation proceeded with retention of stereochemistry irrespective of the regiochemical consequence of the alkylation. This result is in accord with the facial selectivity previously observed with transition metalcatalyzed allylic alkylations. It is important to note that although the allylic alkylation reaction catalyzed by [Rh(CO)2Cl]2 proceeds stereoselectively, one can draw either an anti-anti or syn-syn mechanistic possibility to explain this result. For brevity, the antianti pathway will be discussed at this time. As illustrated in Scheme 3.13, treatment of allylic substrate 3.56 with the transition metal catalyst, initial complexation yields 3.57, which then undergoes oxidative addition from the opposite face of the allyl system than 212 the leaving group Z. Formation of allylmetal intermediate 3.58 can then undergo racemization, presumably via an h3-h1-h3 isomerization pathway to yield intermediate 3.59. The fact that we do not see an appreciable loss of enantiopurity and that absolute stereochemistry is conserved throughout the course of the reaction, suggests that this racemization is slow or does not occur at all. Subsequent addition of the nucleophile in this case provides the metal-complexed regioisomeric substitution products 3.60 and 3.61, which upon decomplexation, yield products 3.62 and 3.63 without loss of enantiopurity. The overall result of this metal-catalyzed allylic alkylation is retention of stereochemistry via an anti-anti mechanistic pathway. Although most transition metal catalysts are believed to proceed by the mechanism illustrated in Scheme 3.13,68 the molybdenum-catalyzed process transfers stereochemical identity via a double retention pathway.89,90 Whether or not [Rh(CO)2Cl]2-catalyzed substitutions proceed by an antianti or syn-syn mechanism, the p-allyl intermediates would likewise be of the same relative structure in order to yield the observed products without loss of enantiomeric purity. Therefore, isomerization from 3.58 to 3.59, or vice versa, would presumably be slow relative to nucleophilic addition. 213 Scheme 3.13 R1 R2 3.63 or R1 Nuc 3.62 LnRh R1 R2 3.60 RhLn Nuc or R1 Nuc 3.61 3.57 R2 LnRh R1 R2 R2 RhLn Nuc R1 R2 3.56 Z Decomplexation Complexation Z Nucleophilic Addition NucR1 RhLn R2 3.58 Ionization -X- RhLn R1 R2 3.59 3.2.6 The Scope with which the Z-Geometry is Maintained in the [Rh(CO)2Cl]2Catalyzed Allylic Alkylation of Z-Allyl Carbonates It has been well established that olefin geometry in transition metal-catalyzed allylic alkylations is not easy to control for systems in which both isomers are on an equal energetic footing, or the desired configuration is actually the less stable of the two (see Chapter 1.B). This is lack of command is prevalent in the allylic alkylations of substrates 214 with cis carbon-carbon double bonds. Most transition metals will isomerize the Z-olefin to provide the more stable E-isomeric substitution product, as was discussed in Chapter 1. The plausible mechanistic pathway by which this may occur is illustrated in Scheme 3.13.10 Complexation of the catalyst to the Z-olefin in substrate 3.64 is followed by the subsequent ionization step, and the syn-3.65 -allyl complex is formed. There exists an unfavorable interaction in syn-3.65 between R and the metal center with its ligands. Isomerization of syn-3.65 can presumably occur via an h3-h1-h3 isomerization pathway to yield the thermodynamically more stable anti-3.65. Nucleophilic attack onto syn-3.65 provides the corresponding Z-substitution product cis-3.68, whereas addition of the nucleophile to anti-3.65 yields the isomeric alkylation product trans-3.66. Therefore, the relative ratio of cis to trans products can be correlated to the relative rates of nucleophilic attack on the metal-stabilized p-allyl complexes syn-3.65 and anti-3.65 (k2 and k3) and the rate of syn/anti isomerization (k1/k-1). Therefore, if nucleophilic attack on syn-3.65 is faster than isomerization to anti-3.65 (k2>k1) the olefin geometry will be conserved; otherwise loss of double bond character will be observed. Given that Z E isomerization occurs readily with the majority of allylic alkylation catalysts, it would be advantageous for a new catalyst that mediates this transformation to be capable of maintaining olefin geometry. 215 Scheme 3.14 [Rh(CO)2Cl]2 R OCO2Me 3.64 R MLn Nuck2 R Nuc syn-3.65 cis-3.66 k1 k-1 MLn R Nuck-2 R Nuc anti-3.65 trans-3.66 R MLn h3 h1 LnM R R MLn h1 h3 R MLn syn-3.65 syn-3.67 anti-3.67 anti-3.65 Given the excellent Z-selectivity observed with allylic carbonate 3.14e (Table 3.4, entry 2), we examined the scope of this olefin selectivity. To this end, secondary Zallylic carbonates and more sterically congested nucleophiles (i.e. sulfones) were scrutinized for their propensity to provide Z-selective allylic alkylations. In an attempt to answer the first of these two queries, Z-allylic carbonate 3.70 was synthesized in two steps from propargyl alcohol 3.68 as illustrated in Scheme 3.15. Partial reduction of the alkyne 3.68 utilizing Lindlar s catalyst in EtOAc under an atmosphere of H2 provided cisallyl alcohol 3.69. Subsequent acylation of 3.69 under the standard conditions gave the desired allyl carbonate 3.70 in 57% yield over the two steps. Treatment of substrate 3.70 with the sodium salt of dimethyl malonate in either THF or DMF at reaction temperatures ranging from room temperature to -20 C was either too sluggish, resulting in 80% recovered starting material, or yielded malonate 3.71 with excellent regioselectivity ( 95:5), but extensive cis trans isomerization (in THF at 20 C). The loss of olefin 216 integrity observed with carbonate 3.70 may be due to the decreased rate of nucleophilic addition as a result of the increased steric environment around the electrophilic site of alkylation in comparison to the primary Z-allyl carbonate 3.14e. Scheme 3.15 OH H2, Lindlar's cat. EtOAc 3.68 HO 3.69 ClCO2Me, pyr. CH2Cl2 57% over 2 steps [Rh(CO)2Cl]2, NaCH(CO2Me)2 MeO2CO 3.70 THF, 0 C, 87% MeO2C CO2Me 3.71 Regioselectivity 95:5 cis/trans = 75:25 If steric factors are in fact the reason why alkylation of carbonate 3.70 proceeded with only moderate cis/trans selectivity, then increasing the steric bulk associated with the nucleophile would, likewise slow the rate of nucleophilic attack to the allylic center, resulting even in greater loss of olefin integrity. To answer this question we analyzed the affect a more sterically demanding such as methyl phenyl sulfonylacetate (3.72). In order to establish first whether sulfones were even viable nucleophiles in [Rh(CO)2Cl]2-catalyzed allylic alkylations, carbonate 3.14a was treated with the sodium salt 3.72 in the presence of [Rh(CO)2Cl]2 and the alkylation product 3.73 was obtained in 75% yield and with excellent regioselectivity (99:1) (Eq. 3.5). Satisfied with this result, Z-allyl carbonate 3.14e was treated with the sodium anion of phenylsulfone 3.71 in the presence of [Rh(CO)2Cl]2 to provide a mixture of carbon-carbon double bond isomers 3.73 and 3.74 with excellent regioselectivity and good yield (Eq. 3.6). Unfortunately, there was extensive loss of olefin integrity as is reflected by the ratio (1.5:1) of 3.73 to 3.73. These results, in conjunction with those illustrated in Scheme 3.16, seem to 217 indicate that in the [Rh(CO)2Cl]2-catalyzed allylic alkylation reaction, maintaining olefin geometry during the reaction depends not only on the relative size of the nucleophile, but also on the substitution of the allylic carbon at which substitution will occur. Therefore, the results suggest that as the rate of nucleophilic attack (k2 or k3) slows, syn-anti isomerization (k1/k-1) becomes more important, and erosion in the stereoselectivity of the process occurs (Scheme 3.14). [Rh(CO)2Cl]2, THF OCO2Me 3.14a + PhO2S CO2Me 3.72 75% PhO2S CO2Me 3.73 (3.5) Regioselectivity = 99:1 OCO2Me 3.14e [Rh(CO)2Cl]2, 3.72, NaH THF, -20 C, 76% CO2Me + SO2Ph PhO2S 3.74 (3.6) CO2Me 3.73 Regioselectivity > 95:5 cis/trans = 1:1.5 3.2.7 Attempts at Developing an Asymmetric [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation Based on previous work involving [Rh(CO)2Cl]2-catalyzed asymmetric transformations,270 we were interested in determining whether asymmetric induction could be obtained by the presence of chiral ligands during the allylic alkylations of racemic carbonates. The goal of this effort would be to start with a substrate whose electrophilic site is sp3 hybridized and yield a substitution product where there is minimal loss of chemical yield and good enantioselectivity. In order for this to occur, either the initial ionization of the allylic substrate by the metal catalyst or the nucleophilic attack must be enantiodiscriminating. To avoid losing material in a kinetic resolution, meso218 substrates 3.75-3.77 are typically employed to provide a synthetically useful method in which the enantiodetermining step involves facial discrimination of the olefin in metal complexed intermediates 3.78 and 3.79 and the maximum yield is 100 % (Figure 3.1).13 Figure 3.2. Substrate types for enantioselective allylic alkylations Z Z 3.75 3.76 Z R Z 3.77 Z Z MLn* vs. Z 3.78 MLn* Z 3.79 Unsymmetrical allylic substrates such as 3.80 can also be used for such asymmetric allylic alkylations, but the enantiofacial exchange of h3-allyl transition metalbound intermediates 3.81 and 3.83 must be possible (Scheme 3.16). This exchange is usually believed to occur through the h3-h1-h3 isomerization sequence 3.82a 3.82b. Alternatively, diastereofacial exchange may occur via a pathway in which a -allylmetal species as 3.84 is transferred from one palladium complex to another to form 3.85 (Scheme 3.17). The exact mechanism for this process is uncertain, but it has been observed that isomerization can be inhibited by the presence of halide ions, low palladium(0) concentration, or through the use of bidentate ligands.367 By one of the two mechanisms illustrated in Schemes 3.16 and 3.17, cyclic or unsymmetrical allyl systems can yield substitution products in good yields and with synthetically useful enantioselectivity.13 219 Scheme 3.16 H R1 Z 3.80 R1 R2 MLn* H R2 MLn* h3 h1 H R2 3.82a H MLn* R1 3.81 H Ln*M R1 3.83 R2 h1 h3 H H Ln*M R1 R1 3.82b H Scheme 3.17 L L L 3.84 L L L L L 3.85 To determine whether the [Rh(CO)2Cl]2-catalyzed allylic alkylation conditions could be modified so that the process could be rendered enantioselective, the reaction was conducted with racemic carbonate ( )-3.47 in the presence of an added chiral ligand (Eq. 3.7). Two ligands, (R)-BINAP (3.86) and Trost s diamide 3.87, were chosen for initial examination. Unfortunately, best result was obtained with 3.87 to provide malonate 3.48 with low enantioselectivity (15% ee), as determined by chiral HPLC, in a mere 48% yield. To determine whether this method could be modified to achieve a kinetic 220 resolution of racemic carbonates, the recovered starting carbonate 3.47 was hydrolyzed with KOH in MeOH, and the optical purity of the resulting alcohol 3.46 was analyzed by chiral HPLC (Eq. 3.8). To our dismay, minimal enantiomeric excess was observed (< 15% ee). However, the realm of asymmetric allylic alkylations using [Rh(CO)2Cl]2 remains attractive, and therefore a screening of ligands, reaction conditions and analyzing meso allylic carbonates are avenues that offer future potential. OCO2Me MeO2C [Rh(CO)2Cl]2, NaCH(CO2Me)2 L*, DMF, 48% CO2Me (3.7) ( )-3.47 Regioselectivity = 93:7 < 15% ee 3.48 O L* = (R)-BINAP (3.88), N 3.89 NH HN O N OH Recovered 3.47 KOH, MeOH (3.8) 3.46 > 15% ee 3.3 [Rh(CO)2Cl]2-CATALYZED ALLYLIC ALKYLATIONS WITH a-SUBSTITUTED MALONATES AND b-KETOESTERS With our discovery that [Rh(CO)2Cl]2 catalyzed the direct substitution of unsymmetrical allylic carbonates with the sodium salt of dimethyl malonate in good yield and excellent regioselectivity, our focus shifted toward analyzing the scope and limitation 221 of the process in the context of utilizing other nucleophiles. Herein, we report an extension of this method to include alkylations involving substituted malonate derivatives and other carbon-based nucleophiles. 3.3.1 Utilizing a-Substituted Malonates as Pronucleophiles in the [Rh(CO)2Cl]2Catalyzed Allylic Substitution Reaction Nucleophile compatibility plays a crucial role in the expanding scope and utility of transition metal-catalyzed allylic alkylations. Previously reported catalyst systems have shown a substantial tolerance toward dialkyl malonates substituted at the aposition.1-9 In fact, these are often the preferred nucleophiles in these types of transformations due to their nucleophilic softer character. Whereas palladium-catalyzed allylic alkylations have received the most attention in this field, analyzing the efficiency of reactions catalyzed by a rhodium(I) species has yet to be performed. To that end, the series of malonate derivatives 3.86-3.88 (Scheme 3.18) were used as nucleophiles in reaction with various unsymmetrical carbonates 3.14 in the presence of [Rh(CO)2Cl]2 to provide the substitution products 3.89 and 3.90. The malonates 3.86-3.88 were selected because the products thus obtained could be used in subsequent reactions such as transition metal-catalyzed carbocyclizations. R5 R2 R3 R1 R4 OCO2Me 3.14 R5 = 3.86 3.87 3.88 MeO2C CO2Me R1 R2 R3 R5 R4 R1 3 R2 R [Rh(CO)2Cl]2 NucH, base CO2Me + MeO2C R5 CO2Me CO2Me 3.90 R4 (3.9) 3.89 Major Minor 222 The three a-substituted malonate nucleophiles 3.86-3.88 were synthesized in a relatively straightforward manner as illustrated in Schemes 3.18 and 3.19 and Eq. 3.10. Mesylation of propargyl alcohols 3.91 and 3.93 provided the corresponding propargyl mesylates 3.92 and 3.94 in good yields. Subsequent nucleophilic displacement with sodium dimethyl malonate yielded the desired propargyl and 2-butyne substituted malonate nucleophiles 3.86 and 3.87, respectively. The n-butyl substituted malonate 3.88 was prepared without incident from n-butyl bromide (3.95) and sodiodimethyl malonate. Scheme 3.18 MsCl,Et3N OH 3.91 CH2Cl2, 1.5 h, rt 93% 3.92 OMs CH2(CO2Me)2, NaH THF, rt, 83% MeO2C 3.86 CO2Me Scheme 3.19 MsCl, NaH, THF OH 3.93 1.5 h, rt 100% OMs 3.92 CH2(CO2Me)2, NaH THF, rt, 55% MeO2C 3.87 CO2Me CH2(CO2Me)2, Na(0) Br 3.95 MeOH, reflux, 4 h 65% CO2Me CO2Me 3.88 (3.10) With the desired malonate nucleophiles 3.86-3.88 in hand, their utility in the [Rh(CO)2Cl]2-catalyzed allylic alkylation was examined with a series of carbonates. In general, good to excellent yields were obtained in all cases (Tables 3.6-3.8). It is important to note that the [Rh(CO)2Cl]2-catalyzed allylic alkylations were complete in a matter of hours (1-2 h was typical) at ambient temperatures. Product distribution favored formal direct substitution as was seen in the [Rh(CO)2Cl]2-catalyzed alkylations of 223 unsymmetrical carbonates with sodiodimethyl malonate itself.353 The tolerance of additional unsaturation present in the nucleophile was analyzed by examining the reactions of dimethyl 2-(but-2-ynyl)malonate (3.86). As illustrated by entries 1-3 in Table 3.6, the formal direct substitution products were formed preferentially from primary carbonates 3.14a, 3.14e, and 3.14j in good yields. Notably, the Z-carbonate 3.14e (entry 2) underwent alkylation to yield enyne 3.89b regiospecifically and with minimal olefin isomerization under conditions analogous to those used previously (Table 3.4, entry 2). Secondary and tertiary allylic carbonates 3.14l and 3.14m also proved to be viable substrates in reactions with the sodium salt of malonate 3.86 to provide the corresponding products 3.89d and 3.89e (entries 4 and 5). Allylically transposed carbonates 3.14j and 3.14l furnished the corresponding substitution products 3.89c and 3.89d in good yields (entries 3 and 4). However, unlike the excellent regioselectivity observed when carbonate 3.14l (99:1) was alkylated with dimethyl malonate, reaction of 3.14l with sodiomalonate 3.86 provided 3.89d in a diminished ratio of regioisomers (57:43) in either THF at room temperature or DMF at 20 C. The reaction of carbonate 3.14m with sodiomalonate 3.86 under identical conditions to 3.14l also proceeded with less regiocontrol to provide 3.89e in a 67:33 ratio. Performing the reaction in DMF at low temperatures (0 C to 20 C) showed no improvement in the regioselectivity. Silyl enol ether 3.14h underwent alkylation with sodiomalonate 3.86 to provide 3.89f with excellent regioselectivity, but in a disappointing 35% yield. Even after prolonged reaction times (>48 h), whether the alkylation was performed in THF or DMF, starting carbonate 3.14h was still recovered from the reaction mixture. 224 Table 3.6. Regioselectivity in the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation Reaction Utilizing a-Substituted Malonate 3.86a Allylic Carbonate Major Product MeO2C MeO2C 3.89a Entry Yield (%)b Ratio 3.89:3.90c 1d OCO2Me 3.14a 95 94:6 2e OCO2Me 3.14e CO2Me CO2Me 3.89b 98 100:0 (88:12)f 3g OCO2Me 3.14j MeO2C 3.89c CO2Me 85 99:1 OCO2Me 4 g CO2Me 3.14l CO2Me 3.89d 82 57:43 5d OCO2Me 3.14m MeO2C MeO2C 3.89e 74 67:33 OTIPS OTIPS OCO2Me 6 d CO2Me CO2Me 3.89f 35 >95:5 3.14h a c Conditions: 10 mol% [Rh(CO)2Cl]2, 1.5 equiv of malonate 3.86, 1.4 equiv of NaH. bIsolated Yields. Ratios determined by GLC or 1H NMR (400 MHz). dTHF, rt. eTHF, 20 C. fRatio of cis/trans isomers. g DMF, 20 C. 225 In some cases it has been reported that the presence of acetylenic protons has shut down carbocyclization reactions catalyzed by [Rh(CO)2Cl]2.234 Therefore, it would be beneficial if the allylic alkylation methodology was immune to this phenomena, thereby providing the desired substitution products containing terminal carbon-carbon triple bonds. Hence, we next examined reactions of malonate 3.87 to demonstrate the feasibility of the alkylation procedure in the presence of a terminal alkyne (Table 3.7). Indeed, the reactions of carbonates 3.14a and 3.14j with sodiomalonate 3.87 provided the corresponding enynes 3.89g and 3.89h in excellent yield and regioselectivity (entries 1 and 2). Interestingly, substrate 3.14l gave the desired enyne 3.89i with better regiocontrol than previously observed with malonate 3.86 (entry 3). It is unclear at present why the use of malonate 3.87 should lead to a significant increase in regioselectivity for the alkylation of carbonate 3.14l. When carbonate 3.14m was treated with malonate 3.87, the reaction proceeded with poor regiocontrol (entry 4) even in DMF at 20 C. In summary, the presence of a terminal acetylene seemed to exhibit no adverse effect when most allylic carbonates were subjected to the [Rh(CO)2Cl]2-catalyzed allylic alkylation conditions. In at least one case, improved regiocontrol was observed than what was experienced while examining the corresponding internal alkyne. However, another yielded little to no regiocontrol. At this stage we cannot venture an explanation for these particular results. 226 Table 3.7. Regioselectivity in the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation Reaction Utilizing a-Substituted Malonate 3.87a Allylic Carbonate OCO2Me 3.14a Entry 1d Major Product MeO2C MeO2C 3.89g Yield (%)b Ratio 3.89/3.90c 75 98:2 2e OCO2Me 3.14j MeO2C CO2Me 70 99:1 3.89h 3 e OCO2Me 3.14l CO2Me CO2Me 3.89i 98 88:12 4d OCO2Me 3.14m MeO2C MeO2C 3.89j 71 50:50 a c Conditions: 10 mol% [Rh(CO)2Cl]2, 1.5 equiv of malonate 3.87, 1.4 equiv of NaH. bIsolated Yields. Ratios determined by GLC or 1H NMR (400 MHz). dTHF, rt. eDMF, 20 C. The n-butyl substituted malonate 3.88 was examined to probe the effect an alkyl substitution in the nucleophile would have on the regiochemical outcome of reactions with carbonates 3.14a, 3.14j, 3.14l, and 3.14m. In each case, substitution products 3.89k-n were formed in good to excellent yields (Table 3.8, entries 1-4). The substitution product 3.89k was formed with excellent regioselectivity (entry 1). Interestingly enough, allylically transposed carbonates 3.14j and 3.14l provided the corresponding substitution products 3.89l and 3.89m with excellent regioselectivity (entries 2 and 3). The formation of alkylation product 3.89m in a ratio of 93:7 shows another marked 227 improvement in selectivity involving substituted malonates. Finally, the reaction of allylic carbonate 3.14m with 3.88 proceeded to yield the corresponding substitution products 3.89n and 3.90n as a mixture (1:1) of regioisomers in good yield (entry 4). Running the reaction in DMF at low temperatures (0 C to 20 C) failed to improve the regioselectivity. In general, these results seem to indicate that the absence of a coordinative functional group within the framework of substituted malonate nucleophiles does not adversely effect the direct regiochemical trends in the [Rh(CO)2Cl]2-catalyzed allylic alkylation reactions. Table 3.8. Regioselectivity in the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation Reaction Utilizing a-Substituted Malonate 3.88a Allylic Carbonate Major Product MeO2C MeO2C 3.89k Entry Yield (%)b Ratio 3.89/3.90c 1 d OCO2Me 3.14a 91 91:9 2e OCO2Me 3.14j MeO2C CO2Me 88 99:1 3.89l OCO2Me CO2Me CO2Me 3.89m 3 e 62 93:7 3.14l 4d a c OCO2Me 3.14m MeO2C MeO2C 3.89n 71 50:50 Conditions: 10 mol% [Rh(CO)2Cl]2, 1.5 equiv of malonate 3.88, 1.4 equiv of NaH. bIsolated Yields. Ratios determined by GLC or 1H NMR (400 MHz). dTHF, rt. eDMF, 20 C. 228 Examination of Tables 3.6-3.8 yields a noteworthy trend. As carbonate 3.14l was treated with an internal alkyne, as in malonate 3.86, the terminal acetylene 3.87, and finally the simple butyl-substituted malonate 3.88, formation of vicinal quaternary carbon centers did not seem to affect the chemical yield (good to excellent in each case), but the regioselectivity improved from nearly 1:1 to 13:1 in favor of the formal direct substitution product 3.89. The fact that carbonate 3.14j underwent any alkylation is noteworthy because 2,3,3-trisubstituted allylic carbonates are inert to modified Wilkinson s catalyst and typically require forcing conditions with most other transition metal catalysts.106,277,358 In conclusion, the ability to perform the [Rh(CO)2Cl]2-catalyzed allylic alkylation reaction with unsaturated, a-substituted malonates such as 3.86 and 3.87 should prove critical as the substitution products 3.89a-i are 1,6-enynes, which can be further used in transition metal-catalyzed carbocyclization reactions to construct complex natural products. 3.3.2 Utilizing b-Ketoesters as Pronucleophiles in the [Rh(CO)2Cl]2-catalyzed Allylic Substitution Reaction b-Ketoesters were also examined as pronucleophiles in the [Rh(CO)2Cl]2catalyzed allylic alkylation in order to define the scope of this new methodology. Utilizing b-ketoesters in allylic alkylations adds another functional moiety to the chemists toolbox of available nucleophiles that can be employed in this class of transformations. Ester hydrolysis followed by decarboxylation of the b-ketoester product then yields a simple ketone that can provide an entry into various synthetically useful compounds. Ethyl 2-cyclohexanone carboxylate (3.96) was chosen as a representative bketoester. 229 When allylic carbonate 3.14a was treated with the sodium enolate of 3.96 in the presence of [Rh(CO)2Cl]2, 3.97a was obtained in 98% yield and with 95:5 regioselectivity (Eq. 3.11). This result is consistent with the excellent yields and regiocontrol observed with this class of allylic carbonates regardless of the nucleophile employed. Likewise, when allylically transposed carbonates 3.14j and 3.14l were alkylated with the sodium enolate of 3.96 under identical conditions, the corresponding substitution products 3.97b and 3.97c respectively were obtained. Compound 3.97b was isolated in 86% yield and 99:1 regioselectivity (Eq. 3.12), whereas ester 3.97c was formed in good yield (74%) as a mixture (90:10) of regioisomers (Eq. 3.13). Of particular note is that this allylic alkylation reaction provided 3.97c, which contains two contiguous quaternary carbon centers. The regioselectivity observed in this case is consistent with that observed for the alkylations of 3.14l with a-substituted malonates (entry 2, Tables 3.6-3.8). The reactions exemplified by Eqs. 3.11-3.13 illustrate how bketoesters are useful as nucleophiles in the [Rh(CO)2Cl]2-catalyzed allylic substitution reaction, thereby increasing the scope and utility of this transformation. O OCO2Me + CO2Et [Rh(CO)2Cl]2, THF 98% EtO2C O (3.11) Regioselectivity = 95:5 3.14a O OCO2Me 3.14j O OCO2Me + CO2Et + CO2Et 3.96 [Rh(CO)2Cl]2, THF 86% O 3.96 3.97a CO2Et (3.12) Regioselectivity = 99:1 3.97b EtO2C O [Rh(CO)2Cl]2, THF 74% (3.13) 3.14l 3.96 Regioselectivity = 90:10 3.97c 230 The results thus far described illustrate an efficient and reliable method in which sodium salts of substituted malonates and b-ketoesters can be used as nucleophiles in the regioselective [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical carbonates. It is noteworthy that two contiguous carbon centers can be formed. The use of substituted malonates has already been applied in the development of domino applications in which the resulting 1,6-enynes undergo an additional [Rh(CO)2Cl]2-catalyzed carbocyclization vida infra. Future studies may include expanding the types of carbocyclizations that can be involved, as well as their applications toward total synthesis. 3.4 HETEROATOM NUCLEOPHILES Heteroatom nucleophiles have played an important role in expanding the utility of transition metal-catalyzed allylic alkylations in recent decades. By employing a nucleophile that incorporates either a nitrogen, oxygen or sulfur atom as the reacting center, the breadth of the reaction is increased so that the products now incorporate a heteroatom thereby making them attractive synthetic intermediates in the synthesis of complex natural products. A number of different transition metals such as palladium, molybdenum and rhodium have been used to catalyze allylic etherifications368 and aminations48,50,53,369,370 en route to polyoxygenated and alkaloid natural products. Recent reports have illustrated that sulfides can react as nucleophiles in transition metalcatalyzed alkylations. We thus decided to take a preliminary look at utilizing oxygenand nitrogen-containing nucleophiles in the [Rh(CO)2Cl]2-catalyzed allylic alkylation reaction. 231 3.3.1 [Rh(CO)2Cl]2-Catalyzed Allylic Etherifications The transition metal-catalyzed allylic etherification reaction has received less attention than the corresponding amination. A survey of the literature uncovered relatively few examples where a transition metal catalyst was used to mediate the desired allylic etherification.368 Allylic etherifications have typically been investigated utilizing symmetrically substituted allylic systems or allylic systems with internal nucleophiles.41,93,371-374 Examples of aliphatic alcohols being used as nucleophiles in the literature are few, presumably due to their poor nucleophilicity, whereas phenols and carboxylates have been found to be suitable coupling partners in transition metalcatalyzed carbon-oxygen bond formations.46 Our goal was to determine if [Rh(CO)2Cl]2 could be used to prepare allylic ethers with good regioselectivity using alcohols and phenols. Studies were first performed to establish how the unsymmetrical carbonate 3.14a would react under a variety of conditions with phenol 3.98 (Eq. 3.14). Preliminary studies on effecting the [Rh(CO)2Cl]2-catalyzed etherification of carbonate 3.14a by in situ generation of phenoxide with LiHMDS failed to provide the allyl ether products. OH OCO2Me 3.14a + Ph [Rh(CO)2Cl]2, CuI LiHMDS, THF, rt 84% O Ph 3.99 + O Ph 3.100 (3.14) 3.98 4.99/4.100 = 92:8 In 2002, Lee and coworkers reported the effectiveness of zinc(II) alkoxides as nucleophiles for the Pd(PPh3)4-catalyzed etherification of allylic acetates, to provide allyl ethers.375 Unfortunately, treatment of carbonate 3.14a the zinc(II) phenoxide of 3.98 generated with Et2Zn proceeded in low yield. Evans and coworkers reported in 2002 that treatment of unsymmetrical carbonates with copper(I) alkoxides in the presence of 232 RhCl(PPh3)3/P(OMe)3 provided the products of allylic etherification.45 The in situ formation of the copper(I) phenoxide obtained by sequential treatment of 2-phenyl phenol (3.98) with LiHMDS and CuI provided allyl ether 3.99 as a mixture (92:8) of regioisomers in 84% yield. Although phenol 3.98 provided the best results, various other secondary alcohols were examined but failed to provide the corresponding etherification products. The secondary, rather hindered aliphatic alcohol 3.101 did not react with 3.14a (Figure 3.2). Rather a considerable amount of the corresponding allylic alcohol was formed, presumably resulting from transesterification of the carbonate moiety. This result is not all that unusual considering that aliphatic alcohols are typically poor nucleophiles for these transformations. Additionally, when (+)-menthol (3.102) was chosen as an oxygen nucleophile the etherification products were not formed. Deprotonation of 3.102, transmetallation with CuI and subsequent treatment with carbonate 3.14a likewise failed to provide the etherification products. Instead, a complex mixture of products was obtained, none of which could be isolated cleanly from the crude reaction mixture. Cyclopropyl phenyl carbinol 3.103 also failed to provide the desired ether. Figure 3.3. Alcohols examined in the [Rh(CO)2Cl]2-catalyzed allylic etherification reaction. OH OH OH 3.101 3.102 3.103 Given the probability that transesterification was the dominant pathway when 3.101 and 3.102 were employed, we postulated that the reaction could be performed if a sterically crowded leaving group was used in its stead. Therefore, the methyl carbonate 233 was exchanged for the sterically more crowded pivolate ester. However, treating the allylic pivolate 3.104 with the copper(I) alkoxides of 3.101 and 3.102 in the presence of [Rh(CO)2Cl]2, failed to yield the corresponding allylic etherification products 3.103c and 3.03d (Eq. 3.15). Future studies in examining this etherification reaction should focus on utilizing phenols with various substitution patterns, including electron withdrawing and donating substituents, and determine whether these changes affect the regioselectivities. ROH = 4.101 or 4.102, [Rh(CO)2Cl]2 OPiv 3.104 LiHMDS, CuI, THF X + OR 3.106 OR 3.107 (3.15) 3.3.2 [Rh(CO)2Cl]2-Catalyzed Allylic Aminations The [Rh(CO)2Cl]2-catalyzed allylic amination of unsymmetrical carbonates was also investigated. The use of transition metal-catalyzed allylic aminations for the construction of allyl amines has received increased attention from the synthetic community in recent years. The utility of these cross-coupling reactions in target- oriented synthesis is well documented.49,51,52,376 However, the early work on transition metal-catalyzed allylic aminations primarily involved substrates that produce symmetrical h3-metal-bound intermediates to eliminate regioselectivity issues.48 These observations led us to examine whether [Rh(CO)2Cl]2 would catalyze the regioselective allylic amination of unsymmetrical carbonates with nitrogen nucleophiles. Thus, unsymmetrical carbonate 3.14a was treated with various secondary nitrogen containing nucleophiles of the type 3.108 in the presence of [Rh(CO)2Cl]2 to determine the regioselectivity, and the efficiency of the transformation (Eq. 3.16). 234 R1R2NH (4.108), [Rh(CO)2Cl]2 OCO2Me 3.14a Base, THF NR1R2 3.109 + NR1R2 3.110 (3.16) We first examined the allylic amination of 3.14a with a simple secondary amine. To that end, benzylmethyl amine (3.108a) was added to a mixture of carbonate 3.14a and [Rh(CO)2Cl]2 in THF at room temperature (Table 3.9, entry 1). Unfortunately, we were unable to isolate either of the aminated regioisomers 3.109a or 3.110a. We then explored the use of deprotonated sulfonamides in these reactions. Sulfonamides make particularly attractive nucleophiles due to their ability to incorporate a protected nitrogen functionality into the products. When carbonate 3.14a was treated with the lithium amide of propargyl p-toluenesulfonamide 3.108b in the presence of [Rh(CO)2Cl]2, sulfonamide 3.109b was obtained as a mixture of regioisomers (90:10) in good yield (78%) (entry 2). It should be noted that the utilization of LiHMDS to generate the desired anion routinely provided superior yields and regioselectivity than other bases such as LDA and NaHMDS. When carbonate 3.14a was treated with the lithium anion of p- toluenesulfonamide 3.108c in the presence of [Rh(CO)2Cl]2, allyl amine 3.109c was obtained in moderate yield (42%) and good regioselectivity (88:12) (entry 3). 235 Table 3.9. Regioselectivity in the [Rh(CO)2Cl]2-Catalyzed Allylic Amination of Carbonate 3.14aa Entry R1R2NH (3.108) Major Product Yield (%)b Ratio 3.109:3.110c 1d MeNHBn 3.108a Me N Bn NR 3.109a 2e TsNHBn 3.108b Ts N Bn 78 90:10 3.109b 3f a TsHN 3.108c TsN 3.109c 42 88:12 Conditions: 10 mol% [Rh(CO)2 Cl]2, 2.0 equiv of 3.108, 1.9 equiv of a 1.0 M solution of LiHMDS in THF, 0.1 M in THF, room temperature. bIsolated Yields. cRatios determined by GLC. In conclusion, we have described preliminary results that establish limited feasibility in which phenoxides and sulfonamides can be used as nucleophiles in the regioselective [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical carbonates to give allyl ethers and allyl amines. The method described herein potentially expands the field of transition metal-catalyzed allylic substitution reactions by providing a catalyst that efficiently provides substitution products regioselectively. Future studies in this area should focus on examining various other primary and secondary unsymmetrical allylic carbonates to analyze the scope of the etherification and amination reactions. Extensions of the present methodology with regards to applications toward the synthesis of biologically active natural products, as well as the development of tandem transition metal-catalyzed processes are presently underway. 236 3.5 UTILIZING HARD NUCLEOPHILES IN [Rh(CO)2Cl]2-CATALYZED ALLYLIC ALKYLATIONS It has been well established that transition metal catalysts can promote allylic alkylations in good yields with stabilized or soft nucleophiles, although unstabilized or hard nucleophiles have shown utility in the process.28,33,72,108,115,377,378 As is illustrated in Scheme 3.20, the mechanism for this class of reactions is thought to be slightly different than that for stabilized anions. Namely, when hard nucleophiles (HNuc) are used, transmetallation is believed to occur to place the anion on the transition metal-stabilized p-allyl complex 3.112 to form complex 3.113. Migratory insertion of HNuc to the p-allyl moiety forms the carbon-carbon bond present in 3.114, and decomplexation of the transition metal yields the substitution product 3.115. Alternatively, soft nucleophiles (SNuc) react intermolecularly to form the carbon-carbon bond as illustrated by complex 3.116. Subsequent decomplexation of the catalyst provides the product 3.118. Scheme 3.20 R1 Z 3.111 R1 HNuc R2 R2 MLn MLn R1 SNuc R2 3.115 MLn R1 HNuc 3.118 R2 R1 R2 MLn 3.112 HNucSNuc- MLn Unstabilized "Hard" Nucleophiles Stabilized "Soft" Nucleophiles R1 SNuc R2 3.114 3.117 R1 HNuc R2 MLn R1 MLn 3.116 R2 3.113 SNuc- 237 In an effort to expand the array of nucleophiles that can be used, we examined the reaction of carbonate 3.14a with various hard nucleophiles. However, treatment of carbonate 3.14a with the lithium enolate of cyclohexanone (3.119) in the presence of [Rh(CO)2Cl]2 failed to provide either of the two regioisomeric substitution products (Eq. 3.14). Likewise, when carbonate 3.5a was treated with either diethyl zinc or isopropenyl tributyltin, the expected coupling product 3.118 was not observed. These preliminary results seem to indicate that hard anions are not compatible with [Rh(CO)2Cl]2 as allylic alkylation substrates. However, the potential for enabling this reaction still exists in that future experiments may include the use of more easily ionizable allylic substrates, different metal cations (i.e. copper(I) enolates) for enolate alkylations, and organometal reagents derived from sp2 or sp3 organic starting materials. O OCO2Me 3.14a + [Rh(CO)2Cl]2, LDA THF O X 3.120 (3.17) 3.119 Et2Zn or OCO2Me 3.14a SnBu3 [Rh(CO)2Cl]2 X (3.18) Nuc 3.121 Nuc = Et, isopropenyl As described in Chapter 1, Evans illustrated the use of arylzinc halides, generated in situ from ZnBr2 and an aryl lithium reagent, to arylate allylic fluorinated carbonates in the presence of TpRh(C2H4)2, LiBr and dibenzylidene acetone (dba) regioselectively with overall net inversion of configuration. However, this process suffers from the need to use 238 an extremely labile leaving group, a rhodium source that is not commercially available, and a mixture of reagents that renders the overall process very inefficient from an atom economical standpoint. With this as precedent, we wondered whether this reaction could be simplified by using a standard allylic methyl carbonate substrate, and an arylzinc halide in the presence of [Rh(CO)2Cl]2 without the need to supplement the reaction mixture with LiBr or additional ligands. Gratifyingly, when enantioenriched carbonate (+)-3.47 was treated with phenylzinc bromide in the presence of [Rh(CO)2Cl]2 at room temperature, the arylated product ( )-3.122 was obtained in less than 15 minutes in excellent yield and regioselectivity with net inversion of absolute configuration (Eq. 3.19). Chiral HPLC analysis of ( )-3.122 showed that the reaction proceeded with minimal loss of enantiopurity, and comparison of the optical rotation to literature values confirmed the absolute stereochemical configuration in the product. Future studies should focus on examining the scope of this process, whether the arylation proceeds stereoselectively and if the product is obtained with net inversion or retention of configuration. OCO2Me Ph [Rh(CO)2Cl]2, PhLi ZnBr2, THF, rt, 99% (+)-3.47 (3.19) Regioselectivity > 95:5 ( )-3.122 99% ee 92% ee 239 3.6 INTRAMOLECULAR [Rh(CO)2Cl]2-CATALYZED ALLYLIC ALKYLATIONS FOR THE SYNTHESIS OF MEDIUM-SIZED RINGS We have thus demonstrated that [Rh(CO)2Cl]2 has the propensity to catalyze allylic substitutions of unsymmetrical substrates at the carbon atom bearing the leaving group. The obvious question that now arises is: How can this unusual reactivity be exploited in synthesis? The allylic substitutions of Z-alkenes proceeding with retention of double bond geometry suggest that this methodology could be used in an intramolecular sense to form medium and large rings containing Z-olefins. Transition metal-catalyzed cyclizations to synthesize rings has received considerable attention since the early 1980 s.62-64 Inasmuch as the synthesis of seven-membered rings is particularly demanding, we first examined whether seven-membered lactones might be formed by [Rh(CO)2Cl]2 -catalyzed cyclizations. Toward this end, we first targeted 3.124, which was synthesized in two steps from commercially available cis-2-buten-1,4-diol (3.23) (Scheme 3.21). Monoacylation of diol 3.23 with methyl chloroformate and pyridine provided monocarbonate 3.123 in 57% yield. Subsequent acylation of alcohol 3.123 with diketene in the presence of DMAP yielded acetoacetate 3.124 in 73% yield. Unfortunately, treatment of carbonate 3.124 with NaH and then [Rh(CO)2Cl]2 failed to yield either the desired 7-membered lactone 3.125 or the 5-membered analogue 3.126. A potential complication with the desired cyclization may arise in part because of the allylic nature of the b-ketoester functionality. This may lead to competitive h3-allyl intermediates, which would fail to produce the desired alkylation products. However, as no identifiable products were obtained from the reaction mixture, this hypothesis is purely conjecture at this point. 240 Scheme 3.21 O ClCO2Me, pyr., CH2Cl2 HO 3.23 OH 57% HO 3.123 OCO2Me O DMAP, THF 73% O O [Rh(CO)2Cl]2, NaH DMF O O O or O O O O MeO2CO 3.124 X 3.125 3.126 To avoid any potential complications with a bisallylic substrate, we turned toward synthesizing the cyclic ketone 3.132, the carbocyclic analog of lactone 3.125 (Scheme 3.22). Toward that end, 3.130 was prepared in five steps from diol 3.23. Monosilylation of diol 3.23 with TBSCl in the presence of imidazole provided alcohol 3.127 in 47% yield. Mesylation of the remaining primary alcohol provided mesylate 3.128, which was immediately alkylated with the dianion of methyl acetoacetate to provide acetoacetate 3.129 in 55% yield over two steps. The silyl group was removed with TBAF, and the resulting alcohol was converted under standard conditions to give carbonate 3.130. Sequential treatment of b-ketoester 3.130 with NaH then [Rh(CO)2Cl]2 in DMF at room temperature provided the O-alkylation product 3.131 with none of the corresponding seven-membered carbocycle 3.132 was observed. 241 Scheme 3.22 TBSCl, imid., DMF HO 3.23 O O OMe MsCl, Et3N, CH2Cl2 HO 3.127 OTBS OH 47% O MeO O 1. TBAF, THF TBSO 3.129 CO2Me 2. ClCO2Me, pyr. CH2Cl2 57% over 2 steps MsO OTBS NaH, LDA, THF 55% over 2 steps 3.128 O MeO O [Rh(CO)2Cl]2, NaH DMF, 71% O O MeO O MeO2CO 3.130 3.131 3.132 Not Observed 3.7 APPLICATIONS TO DOMINO PROCESSES Recently there has been a major push toward developing synthetic methods to transform relatively simple starting materials into structurally complex intermediates with high efficiency and atom economy. One way in which this can be accomplished is to execute sequential reactions wherein the product of the first serves as the starting material for the second and where each transformation is catalyzed by the same transition metal. Such processes enable the preparation of desired targets with minimal expenditure of raw materials, energy, and waste. One goal of modern-day organometallic exploration has been the development of multifunctional catalysts that can be utilized to promote mechanistically discrete domino reactions.288 Although, the transition metal-catalyzed allylic alkylation has been widely studied,5,12,13 the utility of this reaction has been significantly expanded by the development of domino reaction processes in which the 242 allylic substitution serves as the initial construction.291,379 We now report several novel domino reactions that are catalyzed by [Rh(CO)2Cl]2. Our attention on domino reactions began shortly after our initial discovery that [Rh(CO)2Cl]2 catalyzed highly regio- and stereoselective allylic alkylations to provide products arising from substitution at the carbon atom bearing the leaving group, irrespective of the structure of the starting carbonate.353 The significance of this discovery became ever more apparent as we realized to what extent [Rh(CO)2Cl]2 and other rhodium(I) catalysts catalyzed a number of carbocyclization reactions, including intramolecular variants of the Pauson-Khand reaction (PKR),127,267,380 [5+2] cycloadditions,236,239,337 and cycloisomerizations of 1,6-enynes.134,267,284 In order to expand the utility of our rhodium(I)-catalyzed allylic alkylation method, we set to the task of developing [Rh(CO)2Cl]2 as a multifunctional catalyst to promote various domino reactions. These reactions could then be exploited to assemble complex molecular architectures of the general types 3.140-3.142 from simple starting materials 3.137-3.139 according to the general strategy set forth in Scheme 3.23. 243 Scheme 3.23 R Rh(I) OLG R Pauson-Khand E E 3.137 E E 3.140 O Annulation 3.134 R Rh(I) E E E 3.133 3.135 OLG R R [5+2] E Cycloaddition E 3.138 E 3.141 R R Rh(I) OLG CycloE E E E isomerization 3.136 3.139 3.142 3.7.1 Development of the Domino [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation/Pauson-Khand Annulation As noted in Chapter 1, Evans reported in 2001 that [RhCl(CO)dppp]2 was capable of catalyzing a regio- and diastereoselective tandem allylic alkylation/PausonKhand annulation of simple carbonates with appropriately functionalized carbon and nitrogen nucleophiles.291 We were thus encouraged to determine whether [Rh(CO)2Cl]2 was capable of catalyzing a similar transformation. That such a process should be feasible was suggested by the fact that [Rh(CO)2Cl]2 was known to catalyze efficiently the Pauson-Khand reaction for a variety of enynes (see Chapter 1). In order to ascertain whether this catalyst would promote a PKR of a substrate that might be produced by the [Rh(CO)2Cl]2-catalyzed allylic alkylation, the enyne 3.89a was treated with [Rh(CO)2Cl]2 244 under an atmosphere of CO in Bu2O at 130 C for 12 h to provide the desired [3.3.0] bicycle 3.143 in 99% yield (Eq. 3.20).260 However, when allylic carbonate 3.14a was alkylated with 1.2 equivalents of sodiomalonate 3.86 in the presence of [Rh(CO)2Cl]2 under a blanket of CO (1 atm) in a variety of solvents, good conversion to enyne 3.89a was observed by TLC, but no PKR product was obtained (Eq. 3.21). Allylic amination of carbonate 3.14a with 1.2 equivalents of sulfonamide 3.108c and subsequent heating of enyne 3.109c under an atmosphere of CO also failed to provide the desired [3.3.0] bicycle 3.144 (3.22). MeO2C MeO2C 3.89c [Rh(CO)2Cl]2, CO (1 atm) Bu2O, 130 C, 12 h 99% MeO2C MeO2C 3.143 O (3.20) [Rh(CO)2Cl]2, CO (1 atm) OCO2Me 3.14a + MeO2C 3.86 CO2Me NaH, solvent rt to reflux, 24 h X 3.143 (3.21) [Rh(CO)2Cl]2, CO (1 atm) OCO2Me 3.14a + NHTs 3.108c LiHMDS, CH3CN rt to reflux, 24 h X TsN 3.144 O (3.22) Not completely disheartened by the lack of positive results, there still existed a variety of reaction parameters that needed to be analyzed before achieving the desired domino allylic alkylation/Pauson-Khand reaction would be abandoned. Having thus established that [Rh(CO)2Cl]2 catalyzed alkylations of a-substituted malonates with allylic carbonates, we turned our attention toward developing the desired domino allylic alkylation/carbocyclization reactions by first determining whether it was the allylic 245 alkylation or the PKR that inhibited the domino process. Although allylic carbonates and acetates may be used as substrates in the [Rh(CO)2Cl]2-catalyzed allylic alkylations, poor yields were seen when these traditional substrates were employed for the domino reaction sequence. However, after considerable experimentation, a graduate student in our group, Kenneth A. Miller discovered that when allylic trifluoroacetates were used as substrates the domino process proceeded in good yield. Thus, Miller showed that allyl trifluoroacetate 3.145 reacted smoothly with the anion of malonates 3.87 and 3.146 in the presence of [Rh(CO)2Cl]2 (10 mol%) under an atmosphere of CO to yield bicyclic enones 3.147 and 3.148 in good overall yields (Eq. 3.23). After optimization, Miller showed that the allylic substitution reaction proceeded rapidly at room temperature, whereas the subsequent PKR required heating under reflux to push the reaction to completion (12 24 h). To date this scope of this reaction seems limited by the requirement that the allylic substrate be 3.145. Unsymmetrically substituted allylic trifluoroacetates have thus far failed to yield the desired bicyclic enones under identical conditions. Further studies to apply this reaction to form the heterobicyclic enone 3.144 and related intermediates are in progress. R OCOCF3 3.145 + MeO2C CO2Me CO (1 atm) THF,rt reflux R MeO2C MeO2C 3.147: R = H (73%) 3.148: R = Ph (68%) O (3.23) [Rh(CO)2Cl]2, NaH 3.87: R = H 3.146: R = Ph 246 3.7.2 Development of the [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation/Cycloisomerization Reaction During the course of our studies we discovered somewhat surprisingly that [Rh(CO)2Cl]2 catalyzed the facile isomerization of enynes to yield vinyl alkylidene cyclopentanes. The cyclization of 1,6-enynes leading to the formation of 1,4-dienes is an excellent example of a synthetic strategy that is challenging or nearly impossible to perform without the use of a transition metal catalyst. Although cationic rhodium(I) catalysts are well known to promote such reactions,134,284 neutral rhodium(I) catalysts have not been reported to catalyze this class of carbocyclizations. Initial efforts involving the reaction of carbonate 3.14a with malonate 3.86 failed to produce the desired 1,4-diene 3.149 (Eq. 3.24). Heating the reaction for extended reaction times at reflux following initial formation of the intermediate enyne 3.89a resulted in unidentifiable side products. Fortunately, a graduate student in our group, Anna J. Smith, discovered that when allylic trifluoroacetate 3.150 was treated with the anion of malonate 3.86 at room temperature in the presence of [Rh(CO)2Cl]2, the intermediate enyne arising from the regioselective allylic alkylation underwent cycloisomerization upon heating to provide 3.149 (Eq. 3.25). [Rh(CO)2Cl]2 OCO2Me 3.14a + NaH, solvent MeO2C CO2Me 3.86 MeO2C X MeO2C 3.149 (3.24) OCOCF3 [Rh(CO)2Cl]2, NaH + MeO2C CO2Me MeCN,rt 110 C 87% MeO2C MeO2C 3.149 (3.25) 3.150 3.86 247 3.7.3 A Novel [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation/Intramolecular [5+2] Cycloaddition We next investigated the tandem [Rh(CO)2Cl]2-catalyzed allylic alkylation/[5+2] cycloaddition that initially led us to the discovery that [Rh(CO)2Cl]2 catalyzed the allylic alkylation reaction to begin with. Before we examined the tandem process, it was necessary to establish the feasibility of the [Rh(CO)2Cl]2-catalyzed allylic alkylation of an allylic carbonate containing a vinyl cyclopropane moiety. To that end, carbonate 3.14g was treated with the anion of malonate 3.86 to provide cyclopropyl enyne 3.151 in excellent yield (98%) and regioselectivity (>95:5) (Eq. 3.26). Although the allylic substitution reaction proceeded at room temperature, standard conditions for rhodium(I)catalyzed [5+2] cycloadditions require elevated temperatures (typically 110 C in PhMe). Therefore, initial attempts at effecting the domino process focused on using higher boiling solvents. However, when the domino sequence was attempted with carbonate 3.14g and malonate 3.86 in MeCN, none of the desired cycloadduct 3.152 was formed; only enyne 3.151 was observed (3.27). + OCO2Me 3.14g MeO2C CO2Me [Rh(CO)2Cl]2, THF rt, 4 h, 98% MeO2C MeO2C 3.151 (3.26) Regioselectivity > 95:5 3.86 + OCO2Me 3.14g MeO2C CO2Me [Rh(CO)2Cl]2 MeCN, D X MeO2C MeO2C 3.152 (3.27) 3.86 248 Suspecting that the methyl carbonate leaving group, which has been proposed to decarboxylate upon ionization in allylic alkylations to form CO2 and MeO , was hindering the subsequent [5+2] cycloaddition, we examined the cycloaddition of enyne 3.151 in the presence of the sodium salts which would be produced from allylic substrates. In model studies performed by a talented undergraduate student, Kristy Tran, enyne 3.151 was heated in the presence of [Rh(CO)2Cl]2 to give cycloadduct 3.152 in an unoptimized 52% (Eq. 3.28). When the cycloaddition was performed in the presence of NaOMe, only the starting enyne 3.151 was obtained from the reaction mixture. However, when NaOAc was added to a solution of enyne 3.151 and [Rh(CO)2Cl]2, the cycloadduct 3.152 was formed as indicated by TLC. This result led us to examine allylic acetates as substrates in the domino sequence. [Rh(CO)2Cl]2, additive MeO2C MeO2C 3.151 MeCN, D MeO2C MeO2C 3.152 (3.28) Additive: None NaOMe NaOAc 52%* NR Cycloaddition Indicated by TLC Analysis Allylic acetate 3.153 was treated with the sodiomalonate 3.86 in the presence of [Rh(CO)2Cl]2 under a variety of conditions in attempts to obtain cycloadduct 3.152. Kristy Trans screened a number of solvents and temperatures including THF at 110 C (bath temperature in a sealed vial), PhMe from 90-110 C, DMF from 110-150 C and MeCN from 90-110 C (bath temperature in a sealed vial) in attempts to optimize the domino sequence. She found that the best results were obtained when the reaction was 249 allowed to run over the course of six days thereby providing cycloadduct 3.152 in 69% yield (Eq. 3.29). In these experiments, we found that there existed a delicate balance between time and temperature. Elevated temperatures for extended periods of time often resulted in low yield, presumably due to decomposition of either enyne 3.151 or cycloadduct 3.152 as indicated an increase in material remaining at the baseline in the TLC. However, if the reaction was stopped too early, insufficient conversion to product was observed, yielding primarily enyne 3.151 and recovered allylic acetate 3.153. Optimal conditions would allow for the allylic alkylation to proceed rapidly at room temperature, whereupon the reaction would be heated to promote the [5+2] cycloaddition before decomposition can occur. Because the substitution reaction was often not going to completion, a more reactive acetate derivative was examined. In the end, allylic trifluoroacetate 3.154 was treated with sodiomalonate 3.86 in the presence of [Rh(CO)2Cl]2 at room temperature, and then the mixture was warmed to 80 C (bath temperature) to provide cycloadduct 3.152 in 89% yield after 8 h (Eq. 3.30). [Rh(CO)2Cl]2 + OAc 3.153 MeO2C CO2Me MeCN, rt 90 C, 6 d 69% MeO2C MeO2C 3.152 (3.29) 3.86 [Rh(CO)2Cl]2 + OCOCF3 3.154 MeO2C CO2Me MeCN, rt 80 C, 8 h 89% MeO2C MeO2C 3.152 (3.30) 3.86 Having established optimized conditions, our next goal was to determine whether the domino allylic alkylation/[5+2] cycloaddition would proceed with the same regio250 and diastereoselectivity Wender observed in the [5+2] cycloaddition of various cyclopropyl enynes. Thus, cis- and trans- substituted cyclopropane allylic trifluoroacetates 3.159 and 3.161 respectively were targeted as substrates for a domino [Rh(CO)2Cl]2-catalyzed allylic alkylation/[5+2] cycloaddition reaction. Trifluoroacetate 3.159 was obtained as illustrated in Scheme 3.24 from alcohol 3.23. Simmons-Smith cyclopropanation of alcohol 3.23 provided cis-cyclopropane 3.155 in very good yield (79%). Notably, if diiodomethane was not added to a solution of substrate and diethylzinc at 78 C, the yield of the transformation was significantly lower (<60%). Oxidation of alcohol 3.155 proceeded uneventfully to yield aldehyde 3.156 in 88% yield. Subsequent HWE-olefination yielded the trans-a,b-unsaturated ester 3.157 with excellent control of olefin geometry (>95:5) in 99% yield. Reduction of 3.157 with DIBALH provided allylic alcohol 3.158, which upon treatment with trifluoroacetic anhydride in Et2O at room temperature yielded the desired trifluoroacetate 3.159. The corresponding trans-cyclopropane 3.161 was obtained in a similar sequence of synthetic steps. Namely, treatment of 2-butyn-1,4-diol (3.51) with LiAlH4 in THF provided the trans-2-buten-1,4-diol, which was immediately monosilylated with TBSCl in the presence of imidazole to yield alcohol 3.160 (Scheme 3.25). Following the same route used to synthesize 3.159, we were able to obtain trifluoroacetate 3.161 in good overall yield. 251 Scheme 3.24 CH2I2, Et2Zn, CH2Cl2 HO 3.23 OTBS -78 C rt, 3 h 79 % HO 3.155 H H OTBS TPAP, NMO CH2Cl2, 88% H OHC H OTBS 3.156 O (MeO)2P CO2Me MeO2C H H OTBS DIBALH, THF -78 C rt, 89% NaH, THF -10 C rt, 2 h, 99% E/Z > 95:5 3.157 H H OTBS TFAA, Et2O 96% F3COCO H H OTBS HO 3.158 3.159 Scheme 3.25 H 1. LiAlH4, THF, 65% HO 3.51 OH 2. TBSCl, imid., DMF 38% HO 3.160 H OTBS OTBS OCOCF3 3.161 Thus, subjecting allylic trifluoroacetates 3.159 and 3.161 were subjected to the optimized conditions to provide cycloadducts 3.162 and 3.163, respectively, in excellent overall yields (Eqs. 3.31 and 3.32). The regiochemistry and diastereoselectivity in the in situ [5+2] cycloaddition proceeded in accord with precedent established by Wender. The 1 H NMR spectra of cycloadducts 3.162 and 3.163 were similar in all aspects to the published spectral data.237 252 TBSO H H + MeO2C CO2Me [Rh(CO)2Cl]2 MeCN, rt 80 C 83% MeO2C MeO2C H 3.162 OTBS (3.31) OCOCF3 3.159 3.86 H H OTBS [Rh(CO)2Cl]2 + MeO2C CO2Me MeCN, rt 80 C 92% MeO2C MeO2C H 3.163 OTBS (3.32) OCOCF3 3.161 3.86 In summary, we have discovered that the commercially available complex [Rh(CO)2Cl]2 catalyzes facile and efficient domino processes that feature an initial allylic alkylation followed by one of three different carbocyclizations, including the PausonKhand reaction, cycloisomerization, and [5+2] cycloaddition. The ability to exploit multifunctional catalysts to promote two or more sequential reactions in a single operation has significant potential for the preparation of structurally complex targets from simple starting materials. These results suggest that [Rh(CO)2Cl]2 serves as a highly effective, multifunctional catalyst that can promote a variety of mechanistically different reactions in a single operation. Studies to explore these and other [Rh(CO)2Cl]2-catalyzed cascade reactions are in progress. 3.8 CONCLUSIONS Although there is no disputing the wealth of knowledge that exists on the subject of transition metal-catalyzed allylic alkylations, there remains a great deal yet to be learned about this often-utilized transformation. 253 The issue of regiocontrol in these reactions is typically of primary importance. Different catalyst systems have subsequently been developed to control all possible regiochemical outcomes one might expect from nucleophilic addition to a metal stabilized allyl complex. The seminal work by a number of research groups has focused on controlling such regioselectivity through the use of steric or electronic constraints put in place by the construction of a suitable substrate. However, in recent years the focus has shifted from controlling the regioselectivity by utilizing an appropriately substituted allylic substrate, toward directing the outcome by varying the electronic nature of the catalyst. Throughout the years chemists have been capable of manipulating the regioselectivity in transition metal-catalyzed allylic alkylations to provide allylic substitution products derived from alkylation at the less hindered allylic termini, as well as those that would result from nucleophilic attack at the more substituted carbon of the allylic system. However, until now, a reliable and efficient method had yet to be identified that would allow for a direct correlation between the position of the allylic leaving group and the site of nucleophilic substitution in transition metal-catalyzed allylic alkylations. With the discovery that [Rh(CO)2Cl]2 is capable of catalyzing allylic alkylations to provide product distributions regio- and stereoselectively, we feel as though a critical hole in the field of transition metal catalysis has been filled. The use of [Rh(CO)2Cl]2 as an allylic alkylation catalyst incorporates a number of advantages that separate it from most other metals used for this transformation. First, the formal direct substitution pattern and excellent regiocontrol exhibited is unlike any observed with other catalysts. Secondly, the mild conditions with which the reaction can be performed make it useful for thermally sensitive substrates. Third, the catalyst The employed is quite unusual among transition metals used for these reactions. ligandless nature and the commercial availability of the catalyst is a salient feature of the 254 methodology. Additionally, the unnecessary use of stringent procedures designed for the exclusion of oxygen, and incubation times to derive the active catalyst species typically associated with a variety of allylic alkylation catalysts, add to the appeal of [Rh(CO)2Cl]2. Finally, the wide array of other transformations which [Rh(CO)2Cl]2 is capable of catalyzing makes it a prime candidate for the development of domino processes. The highly convergent and atom economical nature of the domino processes allow for the rapid assembly of complex carbocyclic intermediates from relatively simple substrates.. In summary, we have discovered that the commercially available catalyst [Rh(CO)2Cl]2 may be used to catalyze the facile allylic alkylation of unsymmetrical substrates. Because [Rh(CO)2Cl]2 is known to catalyze other transformations, a number of synthetic applications may be envisaged in which allylic alkylations are combined with other transformations, resulting in cascade processes to rapidly assemble complex structures. This concept was illustrated by development of the first domino allylic alkylation/cycloisomerization and allylic alkylation/[5+2] cycloaddition. The method was also expanded to include the domino allylic alkylation/Pauson-Khand annulation. Future experiments to elucidate the mechanistic details, scope and utility of [Rh(CO)2Cl]2-catalyzed allylic substitutions and whether chiral ligands may be employed as additives for enantioselective applications are in progress and will be reported in due course. In conclusion, this [Rh(CO)2Cl]2-catalyzed allylic alkylation method should find great utility in the field of synthetic organic chemistry as both a tool for further developing new classes of reactions as well the synthesis of complex natural, or unnatural, products. 255 Chapter 4. Experimental Procedures 4.1 GENERAL Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Tetrahydrofuran (THF) and diethyl ether (Et2O) were filtered through two columns of neutral alumina prior to use. Acetonitrile (CH3CN) and methanol (MeOH) were filtered through two columns of molecular sieves prior to use. N,N-dimethyl formamide (DMF) was filtered through two columns of molecular sieves prior to use. Dichloromethane (CH2Cl2), triethylamine (Et3N), and N,Ndimethylaniline were distilled from calcium hydride prior to use. Toluene was filtered through one column of neutral alumina and one column of Q5 reactant prior to use. Air- and moisture-sensitive reactions were performed in oven-dried glassware with rubber septa under a positive pressure of dry nitrogen or argon from a manifold or balloon. Similarly air-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. Reaction mixtures were stirred using Teflon-coated stir bars. Elevated temperatures were maintained using Thermowatch-controlled sand or silicon oil baths. Organic solutions were concentrated using a B chi rotary evaporator with a B chi digitally controlled diaphragm pump. Flash column chromatography was performed following the Still protocol381 using EM silica gel 60 (230~400 mesh). Analytical TLC was performed using Merck-60 TLC plates. The plates were visualized either by an ultraviolet light source, or immersion in a p-anisaldehyde, ceric ammonium molybdate, potassium permangenate, or phosphomolybdic acid solution followed by gentle heating. 1 H and 13 C NMR spectra were measured on a Bruker AC-250, Varian INOVA 500, or Varian Gem-300 magnetic resonance spectrometer. Chemical shifts for 1H and 13 C NMR spectra are expressed in parts per million (d) relative to tetramethylsilane with 256 either TMS or residual solvent as an internal reference for 1H, and residual solvent for 13C unless otherwise noted. The following format was used to assign chemical shift peaks: chemical shift (d ppm), (multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, dt = doublet of triplets, m = multiplet, comp = multiple lines of magnetically different hydrogen atoms, app = apparent), coupling constant(s) (Hz), integration). 4.2 COMPOUNDS O 4 2 1 3 O 7 6 8 O 5 2.38 3-Methylpenta-1,4-dien-3-yl acetoacetate (2.38) (BLA-II-220). A solution of freshly distilled diketene (1.048 g, 12.5 mmol) in THF (2 mL) was added dropwise to a stirred mixture of N,N-dimethylaminopyridine (DMAP) (152 mg, 1.25 mmol), sodium acetate (102 mg, 1.25 mmol), and 2.37 (610 mg, 6.23 mmol) (synthesized from 2-methyl2-vinyloxirane 2.36 and trimethylsulfonium iodide)310 in THF (18 mL) at 10 C. The reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for 5.5 h. Saturated aqueous NaCl (20 mL) and Et2O (20 mL) were added, and the layers were separated. The aqueous phase was extracted with Et2O (2 x 20 mL), and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by Kugelrohr distillation (55-57 C, 0.1 mmHg) to yield 1.052 g (93%) of 2.38 as a colorless oil: 257 1 H NMR (300 MHz) d 6.08 (dd, J = 17.4, 10.8 Hz, 2 H), 5.20 (m, 4 H), 3.38 (s, 2 H), 2.23 (s, 3 H), 1.61 (s, 3 H); 13C NMR (65 MHz) d 200.7, 165.6, 139.7, 114.7, 83.3, 51.0, 30.1, 23.9; IR (CHCl3) 2987, 1744, 1720, 1642, 1410, 1361, 1318, 1269, 1149, 997, 932 cm-1; mass spectrum (CI) m/z 183.1028 [C10H15O3 (M+1) requires 183.1021] 165, 161, 159, 139, 135, 121, 103 (base). NMR Assignments: 1H NMR (300 MHz) d 6.08 (dd, J = 17.4, 10.8 Hz, 2 H, C2H), 5.20 (m, 4 H, C1-H), 3.38 (s, 2 H, C6-H), 2.23 (s, 3 H, C8-H), 1.61 (s, 3 H, C4-H); 13 C NMR (65 MHz) d 200.7 (C5), 165.6 (C7), 139.7 (C2), 114.7 (C1), 83.3 (C3), 51.0 (C6), 30.1 (C8), 23.9 (C4). O 4 2 1 3 O 5 6 N2 2.9 3-Methylpenta-1,4-dien-3-yl diazoacetate (2.9) (BLA-II-103). A solution of ptoluenesulfonyl azide (826 mg, 4.28 mmol) (synthesized from p-toluenesulfonyl chloride and sodium azide)382 in CH3CN (6 mL) was added to a stirred solution of 2.38 (648 mg, 3.57 mmol) and Et3N (0.75 mL, 5.35 mmol) in CH3CN (30 mL) at room temperature. The reaction was stirred for 4 h, whereupon a solution of LiOH H2O (449 mg, 10.7 mmol) in H2O (3.5 mL) was added, and the reaction was stirred for an additional 4 h. The mixture was diluted with water (30 mL) and extracted with Et2O (3 x 30 mL). The combined organic fractions were washed with saturated aqueous NaCl (100 mL), dried (MgSO4), and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (10:1) to give 573 mg (97%) of 2.9 as a yellow oil: 1H NMR (300 MHz) d 6.08 (dd, J = 17.5, 10.7 Hz, 2 H), 5.23 (d, J = 17.5 Hz, 258 2 H), 5.18 (d, J = 10.7 Hz, 2 H), 4.69 (br s, 1 H), 1.65 (s, 3 H); 13 C NMR (65 MHz) d 171.0, 140.2, 131.8, 114.1, 82.6, 20.8; IR (CHCl3) 3033, 2985, 2109, 1694, 1371, 1248, 1186, 1092, 992, 924, 740 cm-1; mass spectrum (CI) m/z 167.0821 [C8H11N2O2 (M+1) requires 167.0821] 166 (base), 143, 142. NMR Assignments: 1H NMR (300 MHz) d 6.08 (dd, J = 17.5, 10.7 Hz, 2 H, C2H), 5.23 (d, J = 17.5 Hz, 2 H, C1-H), 5.18 (d, J = 10.7 Hz, 2 H, C1-H), 4.69 (br s, 1 H, C6-H), 1.65 (s, 3 H, C4-H); 13 C NMR (65 MHz) d 171.0 (C5), 140.2 (C1), 131.9 (C6), 114.1 (C2), 82.6 (C3), 20.8 (C4). H 8 1 H 3 4 Me 6 7 2 5 O 2.8 O [1S-(1b,5a)]-4-Methyl-4-vinyl-3-oxabicyclo[3.1.0]hexan-2-one (2.8) (BLA-I189). A solution of 2.9 (23 mg, 0.137 mmol) in CH2Cl2 (7 mL) was added to a refluxing solution of Rh2(5R-MEPY)4 (13 mg, 13.7 mmol) in CH2Cl2 (114 mL) over 17 h using a syringe pump. The resulting mixture was heated under reflux for 4 h and then allowed to cool to room temperature. The mixture was concentrated under reduced pressure and a crude 1H NMR spectra indicated a mixture (1:1) of endo and exo isomers. The crude residue was purified by flash chromatography eluting with pentane/Et2O (1:1) to give 19 mg (99%) of 2.8 as a clear, colorless oil (combined mass of both isomers isolated). Isomer A: 1H NMR (300 MHz) d 5.98 (dd, J = 17.2, 10.7 Hz, 1 H), 5.37 (d, J = 17.2 Hz, 1 H), 5.18 (d, J = 10.7 Hz, 1 H), 2.16-2.04 (m, 2 H), 1.44 (s, 3 H), 1.17 (ddd, J = 8.8, 7.6, 5.0 Hz, 1 H), 1.00 (dt, J = 5.0, 3.2 Hz, 1 H); 13 C NMR (65 MHz) d 174.3, 133.0, 119.0, 259 66.7, 31.6, 29.8, 28.3, 21.5; IR (CHCl3) 2987, 1769, 1453, 1413, 1313, 1248, 1196, 1044, 959, 838 cm-1 mass spectrum (CI) m/z 139.0764 [C8H11O2 (M+1) requires 139.0759] 139 (base). Isomer B: 1H NMR (300 MHz) d 5.85 (dd, J = 17.3, 10.9 Hz, 1 H), 5.27 (dd, J = 17.3, 1.0 Hz, 1 H), 5.15 (dd, J = 10.9, 1.0 Hz, 1 H), 2.21-2.04 (m, 2 H), 1.55 (s, 3 H), 1.14 (ddd, J = 8.8, 7.6, 4.9 Hz, 1 H), 0.88 (dt, J = 4.9, 3.4 Hz, 1 H). NMR Assignments. Isomer A: 1H NMR (300 MHz) d 5.98 (dd, J = 17.2, 10.7 Hz, 1 H, C6-H), 5.37 (d, J = 17.2 Hz, 1 H, C7-H), 5.18 (d, J = 10.7 Hz, 1 H, C7-H), 2.162.04 (m, 2 H, C2-C3-H), 1.44 (s, 3 H, C8-H), 1.17 (ddd, J = 8.8, 7.6, 5.0 Hz, 1 H, C1-H), 1.00 (dt, J = 5.0, 3.2 Hz, 1 H, C1-H); 13 C NMR (65 MHz) d 174.3 (C4), 133.0 (C6), 119.0 (C7), 66.7 (C5), 31.6 (C1), 29.8 (C3), 28.3 (C2), 21.5 (C8). Isomer B: 1H NMR (300 MHz) d 5.85 (dd, J = 17.3, 10.9 Hz, 1 H, C6-H), 5.27 (dd, J = 17.3, 1.0 Hz, 1 H, C7H), 5.15 (dd, J = 10.9, 1.0 Hz, 1 H, C7-H), 2.21-2.04 (m, 2 H, C2-C3-H), 1.55 (s, 3 H, C8-H), 1.14 (ddd, J = 8.8, 7.6, 4.9 Hz, 1 H, C1-H), 0.88 (dt, J = 4.9, 3.4 Hz, 1 H, C1-H). 12 11 10 9 OH 1 Ph 8 H 2 4 5 6 3 HO 7 H 2.39 2-((1R,2S)-2-(hydroxydiphenylmethyl)cyclopropyl)but-3-en-2-ol (2.39) (BLAVIII-152). A 1.0 M solution of PhLi in THF (0.58 mL, 0.58 mmol) was added to a stirred solution of 2.38 (20 mg, 0.14 mmol) in THF (1.5 mL) at 0 C, the cooling bath was removed, and the mixture was stirred for 1.5 h. It was then cooled to 0 C, and saturated aqueous NaHCO3 (2 mL) was added. The layers were separated, and the 260 aqueous phase was extracted with Et2O (3 x 2 mL). The organic fractions were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 38 mg (92%) of 2.39 as a mixture (1:1) of diastereomers as a clear, colorless oil: 1H NMR (500 MHz) d 7.69-7.66 (comp, 2 H), 7.42-7.39 (comp, 2 H), 7.38-7.31 (comp, 2 H), 7.28-7.23 (comp, 3 H), 7.17 (app tt, J = 7.5, 1.5 Hz, 1 H), 6.02 (dd, J = 17.5, 11.0 Hz, 1 H), 5.19 (dd, J = 17.5, 1.0 Hz, 1 H), 5.02 (dd, J = 11.0, 1.0 Hz, 1 H), 1.98 (ddd, J = 16.5, 9.0, 7.0 Hz, 1 H), 1.23 (ddd, J = 12.5, 7.5, 5.0 Hz, 1 H), 1.11 (ddd, J = 16.5, 9.0, 7.5 Hz, 1 H), 0.95 (s, 3 H), 0.80 (ddd, J = 14.0, 9.0, 5.0 Hz, 1 H); 13 C NMR (125 MHz) d 149.3, 149.0, 145.5, 127.8, 127.8, 126.8, 126.7, 126.6, 126.2, 111.3, 75.2, 72.0, 30.8, 28.7, 28.4, 3.11; IR (CH2Cl2) 3585, 3366, 3003, 1598, 1491, 1448, 1185, 1062, 924 cm-1; mass spectrum (CI) m/z 239.1499 [C20H21O2 (M+1) requires 239.1541] 277 (base), 259, 199, 193; HPLC (Chiracel AD column, hexanes/isopropanol = 98:2, flow = 0.5 mL/min, tR = 60.8, 62.7, 73.1, 78.1 min). NMR Assignments: 1H NMR (500 MHz) d 7.69-7.66 (comp, 2 H, CAR-H), 7.427.39 (comp, 2 H, CAR-H), 7.38-7.31 (comp, 2 H, CAR-H), 7.28-7.23 (comp, 3 H, CAR-H), 7.17 (app tt, J = 7.5, 1.5 Hz, 1 H, CAR-H), 6.02 (dd, J = 17.5, 11.0 Hz, 1 H, C6-H), 5.19 (dd, J = 17.5, 1.0 Hz, 1 H, C7-H), 5.02 (dd, J = 11.0, 1.0 Hz, 1 H, C7-H), 1.98 (ddd, J = 16.5, 9.0, 7.0 Hz, 1 H, C2-H), 1.23 (ddd, J = 12.5, 7.5, 5.0 Hz, 1 H, C4-H), 1.11 (ddd, J = 16.5, 9.0, 7.5 Hz, 1 H, C3-H), 0.95 (s, 3 H, C8-H), 0.80 (ddd, J = 14.0, 9.0, 5.0 Hz, 1 H, C3-H); 13C NMR (125 MHz) d 149.3 (C9), 149.0 (C9), 145.5 (C6), 127.8, 127.8, 126.8, 126.7, 126.6, 126.2, 111.3 (C7), 75.2 (C1), 72.0 (C5), 30.8, 28.7, 28.4, 3.11 (C3). 261 1 HO2C 10 5 2 4 H 3 H 7 8 6 9 2.40 (2S,3S)-(2-(1,4,4-Trimethylpent-1-enyl)cyclopropanecarboxylic acid (2.40). (BLA-IV-49). A 1.40 M solution of t-BuLi in pentane (0.31 mL, 0.43 mmol) was added to a solution of CuCN (20 mg, 0.22 mmol) in degassed THF (1 mL) at 78 C, and the resulting slurry was allowed to warm slowly to 0 C with stirring (approx. 10 min). This yellow solution was then transferred via cannula to a solution of 2.8 (20 mg, 0.14 mmol) in degassed THF (0.5 mL) at 0 C, the solution was allowed to warm to room temperature by removal of the cooling bath and stirred for 4 h. The mixture was then cooled to 0 C and saturated aqueous NH4Cl/NH4OH (9:1, 2 mL) was added. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 2 mL), the combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 22 mg (80%) of 2.40 as a mixture (2.3:1) of trans and cis isomers as a clear, colorless oil: trans isomer: 1H NMR (400 MHz) d 5.43-5.40 (m, 1 H), 2.06-1.79 (m, 4 H), 1.62 (d, J = 0.7 Hz, 3 H), 1.43 (app dt, J = 7.8, 5.2 Hz, 1 H), 1.11 (ddd, J = 12.4, 7.6, 4.8 Hz, 1 H), 0.86 (s, 9 H); 13C NMR (100 MHz) d 177.9, 130.1, 126.0, 41.8, 31.7, 30.7, 29.2, 19.6, 17.1, 12.0; IR (CHCl3) 3689, 3022, 1602, 1226 cm-1; mass spectrum (CI) m/z 197.1543 [C12H21O2 (M+1) requires 197.1542] 393, 197 (base), 179, 151, 141, 125. NMR Assignments: : trans isomer: 1H NMR (400 MHz) d 5.43-5.40 (m, 1 H, C6-H), 2.06-1.79 (m, 4 H, C2-C4-C7-H), 1.62 (d, J = 0.7 Hz, 3 H, C10-H), 1.43 (app dt, J = 7.8, 5.2 Hz, 1 H, C3-H), 1.11 (ddd, J = 12.4, 7.6, 4.8 Hz, 1 H, C3-H), 0.86 (s, 9 H, 262 C8-H); 13C NMR (100 MHz) d 177.9 (C1), 130.1 (C5), 126.0 (C6), 41.8 (C7), 31.7 (C8), 30.7 (C2), 29.2 (C9), 19.6 (C4), 17.1 (C10), 12.0 (C3). 3 1 2 4 O 2.42 6 5 7 8 Prop-2-ynyloxymethyl-benzene (2.42) (BLA-III-170). NaH (1.094 g of a 60% mineral oil suspension, 27.3 mmol) was added to a stirred solution of propargyl alcohol 2.41 (1.534 g, 27.3 mmol) in dry DMF (50 mL) at 10 C, and stirring was continued for 30 min. TBAI (505 mg, 1.37 mmol) and benzyl bromide (1.63 mL, 13.6 mmol) were added sequentially, and the reaction was allowed to warm to room temperature. The resulting dark brown solution was stirred for an additional 2 h. H2O (20 mL) and 10 % HCl (20 mL) were then added, the layers were separated, and the aqueous phase was extracted with Et2O (3 x 100 mL). The combined organic fractions were washed sequentially with saturated aqueous NaCl (100 mL) and saturated aqueous NH4Cl (100 mL), dried (MgSO4), and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes to give 1.934 g (97%) of 2.42 as a clear, yellow oil: 1H NMR (400 MHz) d 7.34-7.26 (m, 5 H), 4.58 (s, 2 H), 4.14 (d, J = 2.4 Hz, 2 H), 2.45-2.44 (m, 1 H); 13C NMR (100 MHz) d 137.0, 128.2, 127.8, 127.6, 79.5, 74.6, 71.4, 56.9; IR (neat) 3291, 3031, 2856, 2116, 1496, 1454, 1355, 1074 cm-1; mass spectrum (CI) m/z 147.0804 [C10H11O1 (M+1) requires 147.0810] 161, 147, 123, 107, 105, 91 (base). 263 NMR Assignments: 1 H NMR (400 MHz) d 7.34-7.26 (m, 5 H, C6-C7-C8-H), 4.58 (s, 2 H, C4-H), 4.14 (d, J = 2.4 Hz, 2 H, C3-H), 2.45-2.44 (m, 1 H, C1-H); 13C NMR (100 MHz) d 137.0 (C4), 128.2 (C7), 127.8 (C6), 127.6 (C5), 79.5 (C8), 74.6 (C3), 71.4 (C1), 56.9 (C2). General procedure for the lithium acetylide addition to isobutylene oxide. A solution of n-BuLi in hexanes at the indicated molarity (2 mmol) was added to a stirred solution of protected propargyl alcohol (2 mmol) in THF (2.5 mL) at 78 C, and the resulting yellow solution was stirred for 1 h. A solution of isobutylene oxide (72.1 mg, 0.089 mL, 1 mmol) in THF (2.5 mL) freshly distilled BF3 OEt2 (283 mg, 0.25 mL, 2 mmol) were added and the reaction was stirred for 7 h at 78 C. The solution was allowed to warm to room temperature by removal of the cooling bath and stirred for an additional 40 min. Saturated aqueous NaHCO3 (5 mL) was added, and the layers were separated. The aqueous phase was extracted with Et2O (3 x 5 mL), and the combined organic fractions were washed with saturated aqueous NaCl (5 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to yield the desired homopropargylic alcohol. 264 1 7 9 10 11 8 4 2 3 6 OH 5 O 2.43 6-Benzyloxy-2-methyl-4-hexyn-2-ol (2.43) (BLA-III-286). A 1.9M solution of n-BuLi in hexanes was used to provide alcohol 2.43 in 100% yield (4.48 mmol scale) as a clear, yellow oil: 1H NMR (400 MHz) d 7.34-7.25 (m, 5 H), 4.58 (s, 2 H), 4.18 (t, J = 2.0 Hz, 2 H), 2.42 (t, J = 2.0 Hz, 2 H), 2.29 (br s, 1H), 1.31 (s, 6 H); 13C NMR (100 MHz) d 137.2, 128.2, 127.8, 127.6, 83.5, 78.7, 71.4, 69.9, 57.5, 34.4, 28.7; IR (neat) 3416, 3031, 2973, 2930, 2858, 2282, 2220, 1496, 1454, 1359 cm-1; mass spectrum (CI) m/z 219.1374 [C14H19O2 (M+1) requires 219.1385] 237, 219, 183, 171 (base), 161, 143. NMR Assignments: 1 H NMR (400 MHz) d 7.34-7.25 (m, 5 H, C10-C11-C12- H), 4.58 (s, 2 H, C8-H), 4.18 (t, J = 2.0 Hz, 2 H, C7-H), 2.42 (t, J = 2.0 Hz, 2 H, C3-H), 2.29 (br s, 1H, O-H), 1.31 (s, 6 H, C1-C7-H); 13C NMR (100 MHz) d 137.2 (C9), 128.2 (C12), 127.8 (C11), 127.6 (C10), 83.5 (C6), 78.7 (C5), 71.4 (C7), 69.9 (C8), 57.5 (C2), 34.4 (C3), 28.7 (C1). 1 4 2 3 OH 5 6 H3CO 7 2.47a 6-Methoxy-2-methylhex-4-yn-2-ol (2.47a) (BLA-IV-106). A 2.0 M solution of n-BuLi in hexanes was used to provide alcohol 2.47a in 96% yield (5.50 mmol scale) as a clear, colorless oil: 1H NMR (400 MHz) d 4.11 (t, J = 2.0 Hz, 2 H), 3.38 (s, 3 H), 2.43 (t, J = 2.0 Hz, 2 H), 1.32 (s, 6 H); 13C NMR (100 MHz) d 83.5, 78.3, 69.8, 60.0, 57.3, 34.3, 265 28.6; IR (CHCl3) 3600, 3016, 2978, 1464, 1375, 1091 cm-1; mass spectrum (CI) m/z 143.1071 [C8H15O2 (M+1) requires 143.1072] 143, 125 (base), 95. NMR Assignments: 1H NMR (400 MHz) d 4.11 (t, J = 2.0 Hz, 2 H, C1-H), 3.38 (s, 3 H, C7-H), 2.43 (t, J = 2.0 Hz, 2 H, C4-H), 1.32 (s, 6 H, C6-H); 13C NMR (100 MHz) d 83.5 (C3), 78.3 (C2), 69.8 (C5), 60.0 (C1), 57.3 (C7), 34.3 (C4), 28.6 (C6). 8 7 1 4 2 3 OH 5 6 Si O 2.47b 6-Benzyloxy-2-methyl-4-hexyn-2-ol (2.47b) (BLA-III-286). A 1.9M solution of n-BuLi in hexanes was used to provide alcohol 2.47b in 100% yield (4.48 mmol scale) as a clear, yellow oil: 1H NMR (400 MHz) d 7.34-7.25 (comp, 5 H), 4.58 (s, 2 H), 4.18 (t, J = 2.0 Hz, 2 H), 2.42 (t, J = 2.0 Hz, 2 H), 2.29 (br s, 1H), 1.31 (s, 6 H); 13C NMR (100 MHz) d 137.2, 128.2, 127.8, 127.6, 83.5, 78.7, 71.4, 57.5, 34.4, 28.7; IR (neat) 3416, 3031, 2973, 2930, 2858, 2282, 2220, 1496, 1454, 1359 cm-1; mass spectrum (CI) m/z 219.1374 [C14H19O2 (M+1) requires 219.1385] 237, 219, 183, 171 (base), 161, 143. NMR Assignments: 1H NMR (400 MHz) d 7.34-7.25 (comp, 5 H, C9-C10-C11H), 4.58 (s, 2 H, C7-H), 4.18 (t, J = 2.0 Hz, 2 H, C1-H), 2.42 (t, J = 2.0 Hz, 2 H, C4-H), 2.29 (br s, 1H, O-H), 1.31 (s, 6 H, C6-H); 13C NMR (100 MHz) d 137.2 (C8), 128.2 (C11), 127.8 (C10), 127.6 (C9), 83.5 (C1), 78.7 (C3), 71.4 (C2), 57.5 (C5), 34.4 (C4), 28.7 (C6). 266 1 8 7 4 2 3 OH 5 6 Si O 9 10 2.47c 11 12 6-(tert-Butyldiphenylsilanyloxy)-2-methylhex-4-yn-2-ol (2.47c) (BLA-IV-169). A 2.2 M solution of n-BuLi in hexanes was used to provide alcohol 2.47c in 100% yield (2.09 mmol scale) as a clear, colorless oil: 1H NMR (400 MHz) d 7.70 (ddd, J = 6.2, 1.4, 1.4 Hz, 4 H), 7.45-7.36 (comp, 6 H), 4.35 (t, J = 2.1 Hz, 2 H), 2.34 (t, J = 2.1 Hz, 2 H), 1.72 (s, 1H), 1.25 (s, 6 H), 1.05 (s, 9 H); 13C NMR (100 MHz) d 135.4, 133.0, 129.6, 127.5, 81.9, 81.4, 69.8, 52.8, 34.5, 28.6, 26.7, 19.2; IR (CHCl3) 3568, 3054, 2964, 2860, 1472, 1427, 1374, 1264, 1214, 1112, 1073 cm-1; mass spectrum (CI) m/z 365.1934 [C23H29O2Si (M+1) requires 365.1936] 365, 349 (base), 309, 289. NMR Assignments: 1H NMR (400 MHz) d 7.70 (ddd, J = 6.2, 1.4, 1.4 Hz, 4 H, C10-H), 7.45-7.36 (comp, 6 H, C11-C12-H), 4.35 (t, J = 2.1 Hz, 2 H, C1-H), 2.34 (t, J = 2.1 Hz, 2 H, C4-H), 1.72 (s, 1H, O-H), 1.25 (s, 6 H, C6-H), 1.05 (s, 9 H, C8-H); 13C NMR (100 MHz) d 135.4 (C10), 133.0 (C9), 129.6 (C12), 127.5 (C11), 81.9 (C3), 81.4 (C2), 69.8 (C5), 52.8 (C1), 34.5 (C4), 28.6 (C6), 26.7 (C8), 19.2 (C7). 1 7 8 4 2 3 OH 5 6 O O 2.47d 6-Methoxymethoxy-2-methylhex-4-yn-2-ol (2.47d) (BLA-IV-91). A 2.16 M solution of n-BuLi in hexanes was used to provide alcohol 2.47d in 97% yield (2.77 267 mmol scale) as a clear, colorless oil: 1H NMR (400 MHz) d 4.72 (s, 2 H), 4.24 (t, J = 2.0 Hz, 2 H), 3.39 (s, 3 H), 2.42 (t, J = 2.0 Hz, 2 H), 1.31 (s, 6 H); 13C NMR (100 MHz) d 94.4, 83.3, 78.0, 69.8, 55.4, 54.6, 34.3, 28.6; IR (CHCl3) 3583, 2977, 1464, 1375, 1149, 1045 cm-1; mass spectrum (CI) m/z 173.1176 [C9H17O3 (M+1) requires 173.1178] 173, 141, 125 (base). NMR Assignments: 1H NMR (400 MHz) d 4.72 (s, 2 H, C7-H), 4.24 (t, J = 2.0 Hz, 2 H, C1-H), 3.39 (s, 3 H, C8-H), 2.42 (t, J = 2.0 Hz, 2 H, C4-H), 1.31 (s, 6 H, C6-H); 13 C NMR (100 MHz) d 94.4 (C7), 83.3 (C3), 78.0 (C2), 69.8 (C5), 55.4 (C1), 54.6 (C8), 34.3 (C4), 28.6 (C6). 1 7 9 10 11 8 4 2 3 Br 6 5 O 2.44 6-Benzyloxy-2-bromo-2-methyl-4-hexyne (2.44) (BLA-III-291). Trimethylsilyl bromide (0.12 mL, 0.916 mmol) was added to a solution of 2.43 (50 mg, 0.229 mmol) in CH2Cl2 (3 mL) at room temperature, and the reaction was stirred for 4 h. The mixture was warmed to 50 C (bath temperature), stirred for an additional 2 h and allowed to cool to room temperature by removal of the cooling bath. The reaction was diluted with saturated aqueous NaHCO3 (3 mL), and the layers were separated. The aqueous phase was extracted with Et2O (3 x 12 mL). The combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (20:1) to give 15 mg (23%) of 2.44 as a clear, colorless oil: 1H NMR (400 MHz) d 7.38-7.26 (m, 5 H), 4.61 (s, 2 H), 4.19 (t, J = 268 2.0 Hz, 2 H), 2.86 (t, J = 2.0 Hz, 2 H), 1.85 (s, 6 H); 13C NMR (100 MHz) d 137.2, 128.3, 128.0, 127.7, 83.1, 78.9, 71.3, 62.4, 57.4, 38.3, 33.6; IR (CDCl3) 2969, 2926, 2859, 2259, 1721, 1453, 1371, 1264, 1107, 1070, 707 cm-1; mass spectrum (CI) m/z 279.0378 [C14H16O1Br (M-1) requires 279.0384] 281, 279, 265, 263, 201, 183, 171 (base). NMR Assignments: 1 H NMR (400 MHz) d 7.38-7.26 (m, 5 H, C10-C11-C12- H), 4.61 (s, 2 H, C7-H), 4.19 (t, J = 2.0 Hz, 2 H, C1-H), 2.86 (t, J = 2.0 Hz, 2 H, C4-H), 1.85 (s, 6 H, C1-C6-H); 13C NMR (100 MHz) d 137.3 (C8), 128.3 (C11), 128.0 (C10), 127.7 (C9), 83.1 (C3), 78.9 (C2), 71.3 (C7), 62.4 (C5), 57.4 (C1), 38.4 (C4), 33.6 (C6). General procedure for the protection of tertiary alcohols as their tetrahydropyranyl ethers. Pyridinum p-toluenesulfonate (25 mg, 0.1 mmol) was added to a solution of dihydropyran (168 mg, 0.18 mL, 2 mmol) and homopropargylic alcohol (1 mmol) in CH2Cl2 (10 mL) at room temperature, and the resulting solution was stirred for 8 h. Et2O (10 mL) was added, and the solution was washed with saturated aqueous NaCl (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (5:1) to yield the desired tetrahydropyranyl ether. 16 1 7 9 8 10 11 6 4 2 3 O O 12 13 14 15 O 5 2.50a 2-(5-Benzyloxy-1,1-dimethylpent-3-ynyloxy)tetrahydropyran (2.50a) (BLAIV-177). Ether 2.50a was obtained in 99% yield (0.46 mmol scale) as a clear, colorless 269 oil: 1H NMR (400 MHz) d 7.37-7.28 (comp, 5 H), 4.82 (dd, J = 5.6, 3.2 Hz, 1 H), 4.60 (s, 2 H), 4.18 (t, J = 2.4 Hz, 2 H), 3.97 (ddd, J = 11.2, 4.8, 2.8 Hz, 1 H), 3.45 (app dt, J = 11.2, 4.8 Hz, 1 H), 2.54 (dt, J = 16.8, 2.4 Hz, 1 H), 2.47 (dt, J = 16.8, 2.4 Hz, 1 H), 1.841.47 (comp, 6 H), 1.36 (s, 3 H), 1.34 (s, 3 H); 13C NMR (100 MHz) d 137.5, 128.3, 128.0, 127.7, 94.5, 84.3, 75.6, 71.2, 63.1, 62.8, 57.6, 32.4, 30.6, 26.2, 26.0, 25.3, 19.6; IR (CDCl3) 2946, 2854, 2247, 1722, 1454, 1385, 1354, 1129, 1073, 1030 cm-1; spectrum (CI) m/z 303.1946 [C19H27O3 (M+1) requires 303.1960] 303 (base). NMR Assignments: 1H NMR (400 MHz) d 7.37-7.28 (comp, 5 H, C9-C10-C11H), 4.82 (dd, J = 5.6, 3.2 Hz, 1 H, C12-H), 4.60 (s, 2 H, C7-H), 4.18 (t, J = 2.4 Hz, 2 H, C2-H), 3.97 (ddd, J = 11.2, 4.8, 2.8 Hz, 1 H, C13-H), 3.45 (app dt, J = 11.2, 4.8 Hz, 1 H, C13-H), 2.54 (dt, J = 16.8, 2.4 Hz, 1 H, C4-H), 2.47 (dt, J = 16.8, 2.4 Hz, 1 H, C4-H), 1.84-1.47 (comp, 6 H, C14-C15-C16-H), 1.36 (s, 3 H, C6-H), 1.34 (s, 3 H, C6-H); 13C NMR (100 MHz) d 137.5 (C8), 128.3, 128.0, 127.7, 94.5 (C12), 84.3 (C3), 75.6 (C2), 71.2 (C7), 63.1 (C13), 62.8 (C5), 57.6 (C1), 32.4 (C16), 30.6 (C4), 26.2 (C6), 26.0 (C6), 25.3 (C14), 19.6 (C15). mass 12 1 4 2 3 O O 8 9 10 11 H3CO 7 5 6 2.50a 2-(5-Methoxy-1,1-dimethylpent-3-ynyloxy)tetrahydropyran (2.50a) (BLA-IV114). Ether 2.50a was obtained in 76% yield (0.70 mmol scale) as a clear, colorless oil: 1 H NMR (400 MHz) d 4.80 (dd, J = 5.2, 2.8 Hz, 1 H), 4.09 (t, J = 2.4 Hz, 2 H), 3.96 (ddd, J = 11.6, 5.1, 3.4 Hz, 1 H), 3.45 (app dt, J = 11.6, 5.5 Hz, 1 H), 3.37 (s, 3 H), 2.52 (app 270 dt, J = 16.4, 2.0 Hz, 1 H), 2.44 (app dt, J = 16.4, 2.0 Hz, 1 H), 1.89-1.79 (m, 1 H), 1.701.62 (m, 1 H), 1.57-1.46 (m, 4 H), 1.34 (s, 3 H), 1.33 (s, 3 H); 13C NMR (100 MHz) d 93.9, 84.1, 77.4, 75.6, 63.1, 60.1, 57.3, 32.4, 32.2, 26.3, 26.1, 25.4, 20.6; IR (CDCl3) 3690, 3607, 2939, 2247, 1717, 1601, 1441, 1375, 1276, 1129, 1075, 1031 cm-1; mass spectrum (CI) m/z 227.1651 [C13H23O3 (M+1) requires 227.1647] 242, 227 (base), 211, 167. NMR Assignments: 1H NMR (400 MHz) d 4.80 (dd, J = 5.2, 2.8 Hz, 1 H, C8-H), 4.09 (t, J = 2.4 Hz, 2 H, C1-H), 3.96 (ddd, J = 11.6, 5.1, 3.4 Hz, 1 H, C12-H), 3.45 (app dt, J = 11.6, 5.5 Hz, 1 H, C12-H), 3.37 (s, 3 H, C7-H), 2.52 (app dt, J = 16.4, 2.0 Hz, C4H), 2.44 (app dt, J = 16.4, 2.0 Hz, 1 H, C4-H), 1.89-1.79 (m, 1 H, C9-H), 1.70-1.62 (m, 1 H, C9-H), 1.57-1.46 (m, 4 H, C10-C11-H), 1.34 (s, 3 H, C6-H), 1.33 (s, 3 H, C6-H); 13C NMR (100 MHz) d 93.9 (C8), 84.1 (C3), 77.4 (C2), 75.6 (C12), 63.1 (C5), 60.1 (C1), 57.3 (C7), 32.4 (C9), 32.2 (C4), 26.3 (C6), 26.1 (C6), 25.4 (C11), 20.6 (C10). 13 8 7 1 4 2 3 O O 9 10 11 12 Si O 5 6 2.50c Triisopropyl[5-methyl-5-(tetrahydropyran-2-yloxy)hex-2-ynyloxy]silane (2.50c) (BLA-IV-95). Ether 2.50c was obtained in 96% yield (0.18 mmol scale) as a clear, colorless oil: 1H NMR (400 MHz) d 4.79 (ddd, J = 5.5, 3.1, 3.1 Hz, 1 H), 4.37 (t, J = 2.4 Hz, 2 H), 3.95 (ddd, J = 11.3, 5.1, 3.1 Hz, 1 H), 3.44 (app dt, J = 11.2, 5.5 Hz, 1 H), 2.50 (app dt, J = 16.4, 2.0 Hz, 1 H), 2.42 (app dt, J = 16.4, 2.0 Hz, 1 H), 1.84 (app ddt, J = 11.6, 9.6, 2.0 Hz, 1 H), 1.66 (app ddt, J = 11.6, 9.6, 2.0 Hz, 1 H), 1.55-1.46 (m, 4 H), 271 1.33 (s, 1 H), 1.31 (s, 1 H), 1.15-1.06 (comp, 21 H); 13C NMR (100 MHz) d 94.1, 82.1, 80.4, 75.8, 63.2, 52.1, 32.5, 32.3, 26.3, 26.1, 25.5, 20.7, 18.0, 12.1; IR (CHCl3) 2945, 2866, 1464, 1370, 1260, 1224, 1141, 1074, 1030 cm-1; mass spectrum (CI) m/z 369.2811 [C21H41O3Si (M+1) requires 369.2824] 369 (base), 325. NMR Assignments: 1H NMR (400 MHz) d 4.79 (ddd, J = 5.5, 3.1, 3.1 Hz, 1 H, C9-H), 4.37 (t, J = 2.4 Hz, 2 H, C1-H), 3.95 (ddd, J = 11.3, 5.1, 3.1 Hz, 1 H, C13-H), 3.44 (app dt, J = 11.2, 5.5 Hz, 1 H, C13-H), 2.50 (app dt, J = 16.4, 2.0 Hz, 1 H, C4-H), 2.42 (app dt, J = 16.4, 2.0 Hz, 1 H, C4-H), 1.84 (app ddt, J = 11.6, 9.6, 2.0 Hz, 1 H, C10H), 1.66 (app ddt, J = 11.6, 9.6, 2.0 Hz, 1 H, C10-H), 1.55-1.46 (m, 4 H, C11-C12-H), 1.33 (s, 1 H, C6-H), 1.31 (s, 1 H, C6-H), 1.15-1.06 (comp, 21 H, C7-C8-H); 13C NMR (100 MHz) d 94.1 (C9), 82.1 (C3), 80.4 (C2), 75.8 (C13), 63.2 (C5), 52.1 (C1), 32.5 (C10), 32.3 (C4), 26.3 (C6), 26.1 (C6), 25.5 (C12), 20.7 (C11), 18.0 (C8), 12.1 (C7). General procedure for the synthesis of homopropargylic diethyl phosphates from tertiary alcohols. A solution of n-BuLi in hexanes at the indicated molarity (0.92 mmol) was added to a solution of homopropargylic alcohol (0.92 mmol) in THF (9 mL) at 78 C, and the resulting yellow solution was stirred for 1 h. Diethyl chlorophosphate (0.20 mL, 1.37 mmol) was added via syringe and the reaction was allowed to warm slowly to room temperature by removal of the cooling bath and stirred for the indicated time. Saturated aqueous NaHCO3 (9 mL) was added, and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL), and the combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to yield the desired phosphate. 272 12 1 7 9 8 10 11 6 4 2 3 5 13 O O O OP O 14 15 2.51a Phosphoric acid 5-benzyloxy-1,1-dimethylpent-3-ynyl ester diethyl ester (2.51a) (BLA-IV-206). A 2.23 M solution of n-BuLi in hexanes was used to provide 2.51a in 68% yield (0.92 mmol scale) after 24 h as a clear, colorless oil: 1H NMR (400 MHz) d 7.36-7.30 (comp, 5 H), 4.59 (s, 2 H), 4.17 (t, J = 2.0 Hz, 2 H), 4.09 (app ddt, J = 14.8, 14.4, 7.2 Hz, 2 H), 2.72 (t, J = 2.0 Hz, 2 H), 1.60 (s, 6 H), 1.31 (ddd, J = 8.0, 6.8, 0.8 Hz, 3 H); 13C NMR (100 MHz) d 137.4, 128.4, 127.9, 127.8, 82.7, 82.5, 78.3, 71.3, 63.5, 63.4, 57.5, 33.3, 27.1, 16.1, 16.0; IR (CDCl3) 2984, 2937, 2360, 2243, 1633, 1398, 1259, 1028 cm-1; 355.1674] 355 (base). NMR Assignments: 1H NMR (400 MHz) d 7.36-7.30 (comp, 5 H, C9-C10-C11H), 4.59 (s, 2 H, C7-H), 4.17 (t, J = 2.0 Hz, 2 H, C1-H), 4.09 (app ddt, J = 14.8, 14.4, 7.2 Hz, 2 H, C12-H), 2.72 (t, J = 2.0 Hz, 2 H, C4-H), 1.60 (s, 6 H, C6-H), 1.31 (ddd, J = 8.0, 6.8, 0.8 Hz, 3 H, C13-H); 13C NMR (100 MHz) d 137.4 (C8), 128.4, 127.9, 127.8, 82.7 (C3), 82.5 (C2), 78.3 (C7), 71.3 (C5), 63.5 (C12), 63.4 (C14), 57.5 (C1), 33.3 (C4), 27.1 (C6), 16.1 (C13), 16.0 (C15). mass spectrum (CI) m/z 355.1664 [C18H28O5P (M+1) requires 273 16 4 2 3 5 6 15 O OP 1 8 7 O O 14 13 Si O 9 10 11 12 2.51ab Phosphoric acid 5-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-pent-3-ynyl ester diethyl ester (2.51ab) (BLA-IV-202). A 2.29 M solution of n-BuLi in hexanes was used to provide 2.51ab in 69% yield (0.18 mmol scale) after 8 h as a clear, colorless oil: 1H NMR (400 MHz) d 7.72 (dd, J = 14.4, 6.8 Hz, 4 H), 7.39 (app dt, J = 14.4, 6.8 Hz, 6 H), 4.32 (t, J = 2.0 Hz, 2 H), 4.10-4.03 (m, 2 H), 2.64 (t, J = 2.0 Hz, 2 H), 1.54 (s, 6 H), 1.33-1.27 (m, 6 H), 1.05 (s, 9 H); 13C NMR (100 MHz) d 135.5, 133.1, 129.7, 127.6, 82.0, 80.8, 63.4, 63.4, 52.8, 33.2, 26.9, 26.9, 19.1, 16.0; IR (CDCl3) 2984, 2932, 2860, 2245, 1728, 1472, 1428, 1391, 1257, 1147, 1112, 1029, 1006 cm-1; mass spectrum (CI) m/z 503.2373 [C27H40O5SiP (M+1) requires 503.2383] 503 (base), 280, 263, 255, 239. NMR Assignments: 1H NMR (400 MHz) d 7.72 (dd, J = 14.4, 6.8 Hz, 4 H, C10H), 7.39 (app dt, J = 14.4, 6.8 Hz, 6 H, C11-C12-H), 4.32 (t, J = 2.0 Hz, 2 H, C1-H), 4.10-4.03 (m, 2 H, C13-H), 2.64 (t, J = 2.0 Hz, 2 H, C4-H), 1.54 (s, 6 H, C6-H), 1.331.27 (m, 6 H, C14-C16-H), 1.05 (s, 9 H, C8-H); 13C NMR (100 MHz) d 135.5, 133.1, 129.7, 127.6, 82.0 (C3), 80.8 (C2), 63.4 (C5), 63.4 (C13), 52.8 (C1), 33.2 (C4), 26.9 (C6), 26.9 (C6), 26.6 (C8), 19.1 (C14), 16.0 (C7). General procedure for the synthesis of homopropargylic diphenyl phosphates from tertiary alcohols. A solution of n-BuLi in hexanes at the indicated molarity (0.23 mmol) was added to a solution of homopropargylic alcohol (0.23 mmol) in THF (2.3 mL) at 78 C, and the resulting yellow solution was stirred for 1 h. Diphenyl 274 chlorophosphate (0.07 mL, 0.34 mmol) was added via syringe, and the reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for the indicated time. DMAP (5.0 mg, 0.041 mmol) was then added in one portion, and the reaction was stirred for additional 12 h. Saturated aqueous NaHCO3 (3 mL) was added, and the layers were separated. The aqueous phase was extracted with Et2O (3 x 4 mL), and the combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (ratios given) to yield the desired phosphate. 1 15 17 16 18 19 4 2 3 5 6 O 9 O O OP O 7 11 12 13 14 8 9 2.51b 10 Phosphoric acid 5-benzyloxy-1,1-dimethylpent-3-ynyl ester diphenyl ester (2.51b) (BLA-IV-213). A 2.23 M solution of n-BuLi in hexanes was used to provide phosphonate 2.51b in 55% yield (0.23 mmol scale) after 12 h, followed by flash chromatography (hexanes/EtOAc = 2:1) as a clear, pale yellow oil: 1H NMR (400 MHz) d 7.35-7.14 (comp, 15 H), 4.56 (s, 2 H), 4.12 (t, J = 2.0 Hz, 2 H), 2.75 (br s, 2 H), 1.65 (s, 6 H); 13C NMR (100 MHz) d 150.6, 137.4, 129.6, 128.3, 128.0, 127.7, 125.0, 120.0, 85.4, 82.1, 78.8, 71.3, 57.4, 33.3, 27.1; IR (CDCl3) 2985, 2248, 1594, 1490, 1284, 1192, 1025 cm-1; mass spectrum (CI) m/z 451.1667 [C26H28O5P (M+1) requires 451.1674] 451 (base), 343. NMR Assignments: 1H NMR (400 MHz) d 7.35-7.14 (comp, 15 H, C8-C9-C10C12-C13-C14-C17-C18-C19-H), 4.56 (s, 2 H, C7-H), 4.12 (t, J = 2.0 Hz, 2 H, C1-H), 275 2.75 (br s, 2 H, C4-H), 1.65 (s, 6 H, C6-H); 13C NMR (100 MHz) d 150.6 (C12), 137.4 (C8), 129.6, 128.3, 128.0, 127.7, 125.0, 120.0, 85.4 (C3), 82.1 (C2), 78.8 (C7), 71.3 (C5), 57.4 (C1), 33.3 (C4), 27.1 (C6). 20 19 18 1 12 11 4 2 3 5 6 O OP 17 O O 7 8 9 10 Si O 13 14 15 16 2.51bb Phosphoric acid 5-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-pent-3-ynyl ester diphenyl ester (2.51bb) (BLA-V-63). A 2.20 M solution of n-BuLi in hexanes was used to provide phosphonate 2.51bb in 66% yield (0.27 mmol scale) after 24 h, followed by flash chromatography (hexanes/EtOAc = 5:1) as a clear, pale yellow oil: 1H NMR (400 MHz) d 7.70 (app dt, J = 6.5, 1.4 Hz, 4 H), 7.38 (app dt, J = 13.6, 6.5, 1.4 Hz, 6 H), 7.29 (t, J = 8.0 Hz, 4 H), 7.21 (app dt, J = 7.2, 1.4 Hz, 4 H), 7.13 (ddd, J = 8.0, 7.2, 0.8 Hz, 2 H), 4.27 (t, J = 2.0 Hz, 2 H), 2.66 (t, J = 2.0 Hz, 2 H), 1.58 (s, 6 H), 1.04 (s, 9 H); 13C NMR (100 MHz) d 150.7, 150.6, 135.5, 133.1, 129.7, 129.6, 127.6, 125.0, 120.1, 120.0, 85.6, 81.2, 80.7, 52.7, 33.3, 27.0, 26.6, 19.1; IR (CDCl3) 3073, 2961, 2932, 2859, 2247, 1592, 1490, 1282, 1132, 1112, 1025, 957 cm-1; mass spectrum (CI) m/z 599.2384 [C35H40O5SiP (M+1) requires 599.2383] 599, 410, 349 (base), 327, 309. NMR Assignments: 1H NMR (400 MHz) d 7.70 (app dt, J = 6.5, 1.4 Hz, 4 H, C14-H), 7.38 (app dt, J = 13.6, 6.5, 1.4 Hz, 6 H, C15-C16-H), 7.29 (t, J = 8.0 Hz, 4 H, C9-H), 7.21 (app dt, J = 7.2, 1.4 Hz, 4 H, C8-H), 7.13 (ddd, J = 8.0, 7.2, 0.8 Hz, 2 H, 276 C10-H), 4.27 (t, J = 2.0 Hz, 2 H, C1-H), 2.66 (t, J = 2.0 Hz, 2 H, C4-H), 1.58 (s, 6 H, C6H), 1.04 (s, 9 H, C12-H); 13C NMR (100 MHz) d 150.7 (C7), 150.6 (C17), 135.5, 133.1, 129.7, 129.6, 127.6, 125.0, 120.1, 120.0, 85.6 (C3), 81.2 (C2), 80.7 (C5), 52.7 (C1), 33.3 (C4), 27.0 (C6), 26.6 (C12), 19.1 (C11). 15 14 1 4 2 3 6 H3CO 7 5 O 12 O P O O 13 8 9 10 11 2.51bc Phosphoric acid 5-methoxy-1,1-dimethylpent-3-ynyl ester diphenyl ester (2.51bc) (BLA-VI-41). DMAP was not used in the synthesis of this substrate. A 2.30 M solution of n-BuLi in hexanes was used to provide phosphonate 2.51bc in 48% yield (1.11 mmol scale) after 24 h, followed by flash chromatography (hexanes/EtOAc = 2:1) as a clear, colorless oil: 1H NMR (400 MHz) d 7.33 (dd, J = 8.2, 8.0 Hz, 4 H), 7.24-7.22 (comp, 4 H), 7.17 (ddd, J = 8.2, 7.5, 1.0 Hz, 2 H), 4.04 (t, J = 2.0 Hz, 2 H), 3.33 (s, 3 H), 2.73 (br s, 2 H), 1.64 (s, 6 H); 13C NMR (100 MHz) d 150.6, 129.6, 125.0, 120.0, 85.4, 82.0, 78.6, 59.9, 57.3, 33.2, 27.0; IR (CHCl3) 3016, 2361, 1592, 1490, 1284, 1192, 1162, 1093, 1025, 957, 908 cm-1; mass spectrum (CI) m/z 375.1360 [C20H24O5P (M+1) requires 375.1361] 375 (base), 343. NMR Assignments: 1H NMR (400 MHz) d 7.33 (dd, J = 8.2, 8.0 Hz, 4 H, CARH), 7.24-7.22 (comp, 4 H, CAR-H), 7.17 (ddd, J = 8.2, 7.5, 1.0 Hz, 2 H, C11-C15-H), 4.04 (t, J = 2.0 Hz, 2 H, C1-H), 3.33 (s, 3 H, C7-H), 2.73 (br s, 2 H, C4-H), 1.64 (s, 6 H, C6- 277 H); 13C NMR (100 MHz) d 150.6 (C8), 129.6, 125.0, 120.0, 85.4 (C3), 82.0 (C2), 78.6 (C5), 59.9 (C1), 57.3 (C7), 33.2 (C4), 27.0 (C6). 1 4 2 3 5 HO O 7 6 2.59 8 9 4-Benzyloxy-2-butyn-1-ol (2.59) (BLA-III-142). NaH (2.326 g of a 60% mineral oil suspension, 58.0 mmol) was added portionwise to a solution of 2-butyn-1,4diol 2.58 (10.0 g, 116.3 mmol) in DMF (250 mL) at 0 C. The resulting mixture was stirred for 30 min, whereupon TBAI (2.148 g, 5.8 mmol) and benzyl bromide (6.9 mL, 58.0 mmol) were added and the reaction allowed to warm to room temperature by removal of the cooling bath and stirred for an additional 2 h. H2O (200 mL) and 10% HCl (200 mL) were added, and the layers separated. The aqueous phase was extracted with Et2O (3 x 200 mL), and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 5.460 g (53%) of 2.59 as a clear, yellow oil whose spectral data was consistent with that reported in the literature:383 1 H NMR (500 MHz) d 7.35-7.27 (comp, 5 H), 4.57 (s, 2 H), 4.30 (t, J = 1.8 Hz, 2 H), 4.19 (t, J = 1.8 Hz, 2 H), 1.82 (br s, 1 H); 13C NMR (65 MHz) d 137.1, 128.4, 128.0, 127.8, 84.7, 81.6, 71.7, 57.3, 51.0; mass spectrum (CI) m/z 176 (base), 154, 146. NMR Assignments: 1H NMR (500 MHz) d 7.35-7.27 (m, 5 H, C7-C8-C9-H ), 4.57 (s, 2 H, C5-H), 4.30 (t, J = 1.8 Hz, 2 H, C1-H), 4.19 (t, J = 1.8 Hz, 2 H, C4-H), 1.82 278 (bs, 1 H, O-H); 13 C NMR (65 MHz) d 137.1 (C6) 128.4 (C9), 128.0 (C8), 127.8 (C7), 84.7 (C2), 81.6 (C3), 71.7 (C5), 57.3 (C4), 51.0 (C1). 10 O 1 2 3 4 5 S O O O 7 6 2.60 8 9 Methylsulfonic acid 4-benzyloxy-2-butynyl ester (2.60) (BLA-III-144). Methanesulfonyl chloride (2.13 mL, 27.6 mmol) was added to a solution of 2.59 (4.410 g, 25.0 mmol) and Et3N (5.24 mL, 37.6 mmol) in CH2Cl2 (100 mL) at 0 C, and the solution was stirred for 20 min. The reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for an additional 5 min. H2O (100 mL) was added and the layers were separated. The aqueous phase extracted with Et2O (3 x 100 mL). The combined organic fractions were washed with saturated aqueous NaCl (50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (4:1) to give 5.834 g (92%) of 2.60 as a clear, red oil: 1H NMR (300 MHz) d 7.34 (comp, 5 H), 4.92 (t, J = 1.5 Hz, 2 H), 4.59 (s, 2 H), 4.24 (t, J = 1.5 Hz, 2 H), 3.12 (s, 3 H). 13C NMR (65 MHz) d 136.8, 128.2, 127.7, 127.6, 85.6, 78.4, 71.6, 57.4, 56.8, 38.5; IR (neat) 3030, 2938, 2860, 1723, 1700, 1454, 1360 cm-1; mass spectrum (CI) m/z 255.0686 [C12H15O4S1 (M+1) requires 255.0691] 255, 181, 159, 131, 129 (base). NMR Assignments: 1H NMR (500 MHz) d 7.34 (comp, 5 H, C7-C8-C9-H), 4.92 (t, J = 1.5 Hz, 2 H, C1-H), 4.59 (s, 2 H, C5-H), 4.24 (t, J = 1.5 Hz, 2 H, C4-H), 3.12 (s, 3 279 H, C10-H). 13C NMR (65 MHz) d 136.8 (C6), 128.2 (C9), 127.7 (C8), 127.6 (C7), 85.6 (C2), 78.4 (C3), 71.6 (C5), 57.4 (C4), 56.8 (C1), 38.5 (C10). 4 12 11 5 1 3 2 H3CO2C O 8 6 7 CO2CH3 2.57 9 10 2-(4-Benzyloxy-2-butynyl)-malonic acid dimethyl ester (2.57) (BLA-II-226). Dimethyl malonate (2.58 mL, 22.6 mmol) was added to a suspension of NaH (542 mg of a 60% mineral oil suspension, 13.5 mmol) in THF (15 mL) at 0 C, and the mixture was stirred for 25 min. A solution of 2.60 (1.147 g, 4.51 mmol) in THF (5 mL) was then added via syringe, and the reaction was allowed to warm to room temperature and stirred for an additional 2.5 h. The mixture was cooled to 0 C, H2O (20 mL) was added, and the layers were separated. The aqueous phase was extracted with Et2O (3 x 20 mL), and the combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with 1 hexanes/EtOAc (2:1) to give 1.269 g (97%) of 3.50 as a clear, colorless oil: H NMR (500 MHz) d 7.33-7.25 (comp, 5 H), 4.53 (s, 2 H), 4.10 (t, J = 2.1 Hz, 2 H), 3.74 (s, 6 H), 3.60 (t, J = 7.6 Hz, 1 H), 2.84 (dt, J = 7.5, 2.1 Hz, 2 H); 13C NMR (65 MHz) d 168.3, 137.3, 128.3, 128.0, 127.7, 82.4, 79.4, 71.1, 57.2, 52.7, 23.9; IR (neat) 3031, 2954, 2853, 1738, 1454, 1345, 1071 cm-1; mass spectrum (CI) m/z 291.1232 [C16H19O5 (M+1) requires 291.1230] 261, 183. NMR Assignments: 1H NMR (500 MHz) d 7.33-7.25 (comp, 5 H, C8-C9-C10H), 4.53 (s, 2 H, C6-H), 4.10 (t, J = 2.1 Hz, 2 H, C1-H), 3.74 (s, 6 H, C12-H), 3.60 (t, J = 280 7.6 Hz, 1 H, C5-H), 2.84 (dt, J = 7.5, 2.1 Hz, 2 H, C4-H); 13C NMR (65 MHz) d 168.3 (C11), 137.3 (C8), 128.3 (C9), 128.0 (C10), 127.7 (C7), 82.4 (C3), 79.4 (C2), 71.1 (C5), 57.2 (C4), 52.7 (C6), 50.9 (C1). 1 HO2C 13 5 2 4 H 3 H 15 14 7 8 10 9 6 12 11 16 H3CO2C O 17 20 19 H3CO2C 18 2.56 2-(4-Benzyloxy-but-2-ynyl)-2-[3-(2S,3S)-(2-carboxycyclopropyl)-but-2-enyl]malonic acid dimethyl ester (2.56) (BLA-III-29). Pd(PPh3)4 (81 mg, 73 mmol) and PPh3 (190 mg, 0.725 mmol) were added sequentially to a solution of 2.8 (100 mg, 0.725 mmol) in degassed THF (4 mL) at room temperature, and the resulting solution was stirred for 20 min. In a separate flask, 2.57 (462 mg, 1.59 mmol) was added to a slurry of NaH (58 mg of a 60% mineral oil suspension, 1.45 mmol) in degassed THF (4 mL) at room temperature. After stirring for 20 min at room temperature, the resulting homogeneous solution was transferred via cannula to the flask containing the catalyst and substrate. The mixture was heated under reflux for 4 h. The resulting dark brown solution was allowed to cool to room temperature by removal of the oil bath and then cooled to 0 C. Aqueous 1M NaHSO4 (8 mL) was added, and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic fractions were washed with saturated aqueous NaCl (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1 to 1:1) to give 220 mg (71%) of 2.56 281 as a clear, yellow oil: 1H NMR (500 MHz) d 7.35-7.27 (comp, 5 H), 5.13 (t, J = 7.4, 1.5 Hz, 1 H), 4.57 (s 2 H), 4.07 (t, J = 1.0 Hz, 6 H), 3.68 (s, 3 H), 3.66 (s, 3 H), 2.83 (br s, 2 H, C9-H), 2.81 (br s, 2 H, C7-H), 1.95 (br q, J = 16.2, 8.1 Hz, 1 H), 1.81 (m, 1 H), 1.70 (s, 3H), 1.36 (m, 1 H), 1.10 (m, 1 H); 13C NMR (125 MHz) d 175.9, 170.5, 137.5, 128.4, 128.2, 127.8, 127.8, 121.1, 82.0, 78.8, 71.2, 57.1, 52.7, 30.7, 29.7, 22.8, 19.6, 17.3, 17.3; IR (CDCl3) 2952, 2259, 1735, 1698, 1436, 1291, 1211, 1070 cm-1; mass spectrum (CI) m/z 429.1907 [C16H19O5 (M+1) requires 429.1913] 399, 321, 279. NMR Assignments: 1H NMR (500 MHz) d 7.35-7.27 (comp, 5 H, C18-C19-C20H), 5.13 (t, J = 7.4, 1.5 Hz, 1 H, C6-H), 4.57 (s 2 H, C16-H), 4.07 (t, J = 1.0 Hz, 6 H, C12-H), 3.68 (s, 3 H, C15-H), 3.66 (s, 3 H, C15-H), 2.83 (br s, 2 H, C9-H), 2.81 (br s, 2 H, C7-H), 1.95 (br q, J = 16.2, 8.1 Hz, 1 H, C2-H), 1.81 (m, 1 H, C4-H), 1.70 (s, 3H, C13-H), 1.36 (m, 1 H, C3-H), 1.10 (m, 1 H, C3-H); 13C NMR (65 MHz) d 175.9 (C1), 170.5 (C14), 137.5 (C17), 128.4 (CAR), 128.2 (CAR), 127.8 (C5,CAR), 121.1 (C6), 82.0 (C11), 78.8 (C10), 71.2 (C16), 57.1 (C12), 52.7 (C15), 30.7 (C7), 29.7 (C4), 22.8 (C9), 19.6 (C2), 17.3 (C3,13). 1 H 2 4 3 HO 13 5 H 15 14 7 8 10 9 6 11 12 16 H3CO2C O 17 20 19 H3CO2C 18 2.62 2-(4-Benzyloxybut-2-ynyl)-2-[3-(2S,3S)-2-hydroxymethylcyclopropyl)but-2enyl]-malonic acid dimethyl ester (2.62) (BLA-III-179). Oxalyl chloride (15 mL, 0.128 282 mmol) was added dropwise to a solution of 2.56 (25 mg, 0.058 mmol) in dry benzene (0.5 mL) at 0 C. The reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for 1 h. The solution was concentrated under reduced pressure, and the crude acid chloride was dissolved in dry THF (1 mL). NaBH4 (5 mg, 0.12 mmol) was added in one portion with stirring at room temperature. The reaction was cooled to 0 C, H2O (0.5 mL) was added dropwise, and stirring continued for 3 h. The reaction was quenched with 1 M HCl (1 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 1 mL), and the combined organic fractions were washed with saturated aqueous NaCl (2 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 17 mg (71%) of 2.62 as a clear, colorless oil: 1H NMR (500 MHz) d 7.35-7.27 (comp, 5 H), 4.99 (app ddt, J = 7.2, 7.0, 1.4 Hz, 1 H), 4.55 (s, 2 H), 4.13 (t, J = 2.2 Hz, 2 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.50 (dd, J = 11.2, 6.2 Hz, 1 H), 3.35 (dd, J = 11.2, 8.4 Hz, 1 H), 2.89 (dd, J = 14.7, 8.4 Hz, 1 H), 2.84 (t, J = 2.0 Hz, 2H), 2.81 (dd, J = 14.8, 7.0 Hz, 1H), 1.78 (d, J = 0.6 Hz, 3 H), 1.28 (app ddt, J = 11.0, 6.0, 2.2 Hz, 2 H), 0.72 (ddd, J = 13.2, 8.2, 5.2 Hz, 1 H), 0.47 (app dt, J = 11.4, 5.4 Hz, 1 H); 13C NMR (125 MHz) d 170.6, 170.6, 137.5, 137.2, 128.4, 128.1, 127.9, 81.6, 79.2, 71.3, 62.3, 57.4, 52.8, 30.9, 24.5, 23.2, 19.7, 18.4, 6.8; IR (CDCl3) 2954, 2260, 1733, 1436, 1264, 1208, 1070 cm-1; mass spectrum (CI) m/z 415.2115 [C24H31O6 (M+1) requires 413.2121] 415 (base), 307, 229. NMR Assignments: 1 H NMR (500 MHz) d 7.35-7.27 (comp, 5 H, C18-C19- C20-H), 4.99 (app ddt, J = 7.2, 7.0, 1.4 Hz, 1 H, C6-H), 4.55 (s, 2 H, C16-H), 4.13 (t, J = 2.2 Hz, 2 H, C12-H), 3.74 (s, 3 H, C15-H), 3.73 (s, 3 H, C15-H), 3.50 (dd, J = 11.2, 6.2 Hz, 1 H, C1-H), 3.35 (dd, J = 11.2, 8.4 Hz, 1 H, C1-H), 2.89 (dd, J = 14.7, 8.4 Hz, 1 H, C7-H), 2.84 (t, J = 2.0 Hz, 2H, C9-H), 2.81 (dd, J = 14.8, 7.0 Hz, 1H, C7-H), 1.78 (d, J = 283 0.6 Hz, 3 H, C13-H), 1.28 (app ddt, J = 11.0, 6.0, 2.2 Hz, 2 H, C2-C4-H), 0.72 (ddd, J = 13.2, 8.2, 5.2 Hz, 1 H, C3-H), 0.47 (app dt, J = 11.4, 5.4 Hz, 1 H, C3-H); 13C NMR (125 MHz) d 170.6 (C14), 170.6 (C14), 137.5 (C17), 137.2 (C5), 128.4 (C20), 128.1 (C19), 127.9 (C18), 118.4 (C6), 81.6 (C11), 79.2 (C10), 71.3 (C16), 62.3 (C1), 57.4 (C12), 52.8 (C15), 30.9 (C7), 24.5 (C2), 23.2 (C9), 19.7 (C4), 18.4 (C13), 6.8 (C3). 1 14 H3CO2C 13 5 2 4 H 3 H 16 15 7 8 10 9 6 13 12 17 H3CO2C O 18 21 20 H3CO2C 19 2.63 (1S,2R,E)-methyl 2-(9-(benzyloxy)-5,5-bis(methoxycarbonyl)non-2-en-7-yn-2yl)cyclopropanecarboxylate (2.63) (BLA-III-173). Thionyl chloride (16 mL, 0.217 mmol) was added to a solution of 2.56 (31 mg, 0.072 mmol) in MeOH (0.5 mL) at room temperature and stirred for 7 h. Saturated aqueous Na2CO3 (1 mL) was added, the MeOH removed under reduced pressure, and CH2Cl2 (2 mL) was added to the crude residue. The layers were separated and the aqueous phase was washed with saturated aqueous NaCl (2 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 25 mg (85%) of 2.63 as a clear, colorless oil: 1 H NMR (500 MHz) d 7.35-7.29 (comp, 5 H), 5.10 (t, J = 7.8 Hz, 1 H), 4.55 (s, 2 H), 4.13 (t, J = 1.8 Hz, 2 H), 3.74 (s, 3 H), 3.74 (s, 3 H), 3.62 (s, 3 H), 2.88 (app dt, J = 4.5, 2.1 Hz, 2 H), 2.84 (br d, J = 7.8 Hz, 2H), 1.91-1.79 (m, 2 H), 1.66 (s, 3H), 1.35 (app dt, J = 7.2, 5.4 Hz, 1 H), 1.05 (ddd, J = 284 8.4, 8.1, 4.8 Hz, 1 H); 13C NMR (125 MHz) d 171.8, 170.5, 170.4, 137.6, 134.9, 128.4, 128.1, 127.8, 120.9, 82.0, 78.9, 71.2, 57.4, 57.1, 52.8, 51.6, 30.8, 29.3, 22.8, 19.7, 17.3, 11.5; IR (CDCl3) 3690, 2954, 2254, 1734, 1602, 1438, 1292, 1201, 1070 cm-1; mass spectrum (CI) m/z 443.2074 [C25H31O7 (M+1) requires 443.2070] 443 (base), 411, 335, 153. NMR Assignments: 1 H NMR (500 MHz) d 7.35-7.29 (comp, 5 H, C19-C20- C21-H), 5.10 (t, J = 7.8 Hz, 1 H, C6-H), 4.55 (s, 2 H, C17-H), 4.13 (t, J = 1.8 Hz, 2 H, C12-H), 3.74 (s, 3 H, C16-H), 3.74 (s, 3 H, C16-H), 3.62 (s, 3 H, C14-H), 2.88 (app dt, J = 4.5, 2.1 Hz, 2 H, C9-H), 2.84 (br d, J = 7.8 Hz, 2H, C7-H), 1.91-1.79 (m, 2 H, C2-C4H), 1.66 (s, 3H, C13-H), 1.35 (app dt, J = 7.2, 5.4 Hz, 1 H, C3-H), 1.05 (ddd, J = 8.4, 8.1, 4.8 Hz, 1 H, C3-H); 13C NMR (125 MHz) d 171.8 (C1), 170.5 (C14), 170.4 (C14), 137.6 (C18), 134.9 (C5), 128.4 (C20), 128.1 (C21), 127.8 (C19), 120.9 (C6), 82.0 (C11), 78.9 (C10), 71.2 (C17), 57.4 (C8), 57.1 (C12), 52.8 (C16), 51.6 (C16), 30.8 (C7), 29.3 (C2), 22.8 (C9), 19.7 (C4), 17.3 (C13), 11.5 (C3). 22 19 18 15 16 11 10 9 8 1 7 20 21 O 3 2 4 6 5 14 H3CO2C H3CO2C 17 12 H 13 OH 2.64 (3aS,4Z,6R,8E)-dimethyl 8-(benzyloxymethyl)-6-(hydroxymethyl)-4-methyl(2.64) (BLA-III-177). 3,3a,6,7-tetrahydroazulene-2,2(1H)-dicarboxylate 285 [Rh(CO)2Cl]2 (1 mg, 1.2 mmol) was dissolved in degassed toluene (0.5 mL), stirred at room temperature for 5-10 min, and then a solution of 2.62 (5 mg, 0.012 mmol) in degassed toluene (1 mL) was added at room temperature over 10 sec. The resulting solution was heated 110 C (bath temperature), with stirring for an additional 5 h. The reaction was then allowed to cool to room temperature, and filtered through a short column of neutral alumina. The filtrate was concentrated under reduced pressure, and the crude residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 4 mg (80%) of 2.64 as a clear, colorless oil: 1 H NMR (500 MHz) d 7.35-7.27 (comp, 5 H), 5.34 (br s, 1 H), 4.45 (s, 2 H), 4.06 (d, J = 11.6 Hz, 1 H), 4.03 (d, J = 11.4 Hz, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.64-3.57 (m, 1 H), 3.51-3.46 (m, 1 H), 3.18 (dd, J = 17.1, 1.8 Hz, 1 H), 2.84 (br d, J = 15.3 Hz, 1 H), 2.78 (ddd, J = 12.7, 7.8, 2.2 Hz, 1 H), 2.31-2.26 (m, 1 H), 2.07 (t, J = 12.4 Hz, 1 H), 1.76 (s, 3 H). NMR Assignments: 1 H NMR (500 MHz) d 7.35-7.27 (comp, 5 H, C20-C21- C22-H), 5.34 (br s, 1 H, C5-H), 4.45 (s, 2 H, C18-H), 4.06 (d, J = 11.6 Hz, 1 H, C15-H), 4.03 (d, J = 11.4 Hz, 1 H, C15-H), 3.74 (s, 3 H, C16-H), 3.73 (s, 3 H, C17-H), 3.64-3.57 (m, 1 H, C7-H), 3.51-3.46 (m, 1 H, C14-H), 3.18 (dd, J = 17.1, 1.8 Hz, 1 H, C10-H), 2.84 (br d, J = 15.3 Hz, 1 H, C10-H), 2.78 (ddd, J = 12.7, 7.8, 2.2 Hz, 1 H, C8-H), 2.31-2.26 (m, 1 H, C3-C4-H), 2.07 (t, J = 12.4 Hz, 1 H, C8-H), 1.76 (s, 3 H, C13-H). 286 22 19 18 15 16 11 10 9 8 1 7 20 21 O 3 2 4 6 5 14 23 H3CO2C H3CO2C 17 12 CO2Me H 13 2.65 (3aS,4Z,6R,8E)-trimethyl 8-(benzyloxymethyl)-4-methyl-3,3a,6,7- tetrahydroazulene-2,2,6(1H)-tricarboxylate (2.65) BLA-III-177. [Rh(CO)2Cl]2 (1 mg, 2.3 mmol) was added in one portion to a solution of 2.63 (10 mg, 0.022 mmol) in degassed toluene (0.5 mL). The solution was stirred at room temperature for 15 min and then at 110 C (bath temperature) for 5 h. The reaction was then allowed to cool to room temperature and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 5 mg (50%) of 2.65 as a clear, colorless oil: 1H NMR (500 MHz) d 7.35-7.32 (comp, 5 H), 5.54 (app ddt, J = 2.6, 2.4, 1.2 Hz 1 H), 4.46-4.44 (comp, 2 H), 4.04 (br s, 2 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.70 (s, 3 H), 3.62-3.60 (m, 1 H), 3.16 (br d, J = 16.7 Hz, 1 H), 3.17-3.13 (m, 1 H), 2.82 (br d, J = 16.5 Hz, 1 H), 2.78 (ddd, J = 12.6, 7.8, 2.2 Hz 1 H), 2.62-2.53 (m, 2 H), 2.07 (t, J = 12.2 Hz, 1 H), 1.77 (dd, J = 2.4, 1.4 Hz, 3 H); 13C NMR (125 MHz) d 174.8, 171.7, 171.5, 140.8, 138.5, 135.6, 129.8, 128.4, 127.7, 127.6, 123.6, 71.8, 71.1, 57.6, 52.8, 51.9, 51.9, 44.2, 39.3, 38.4, 30.9, 24.9; mass spectrum (CI) m/z 441.1913 [C25H29O7 (M+1) requires 441.1913] 443, 411, 335 (base), 303, 275. NMR Assignments: 1 H NMR (500 MHz) d 7.35-7.32 (comp, 5 H, C20-C21- C22-H), 5.54 (app ddt, J = 2.6, 2.4, 1.2 Hz 1 H, C5-H), 4.46-4.44 (comp, 2 H, C15-H), 4.04 (br s, 2 H, C18-H), 3.74 (s, 3 H, C16-H), 3.73 (s, 3 H, C17-H), 3.70 (s, 3 H, C23-H), 287 3.62-3.60 (m, 1 H, C7-H), 3.16 (br d, J = 16.7 Hz, 1 H, C10-H), 3.17-3.13 (m, 1 H, C4H), 2.82 (br d, J = 16.5 Hz, 1 H, C10-H), 2.78 (ddd, J = 12.6, 7.8, 2.2 Hz 1 H, C8-H), 2.62-2.53 (m, 2 H, C3-H), 2.07 (t, J = 12.2 Hz, 1 H, C8-H), 1.77 (dd, J = 2.4, 1.4 Hz, 3 H, C13-H); 13C NMR (125 MHz) d 174.8 (C14), 171.7 (C11), 171.5 (C12), 140.8 (C1), 138.5 (C19), 135.6 (C6), 129.8 (C2), 128.4 (C22), 127.7 (C21), 127.6 (C20), 123.6 (C5), 71.8 (C18), 71.1 (C15), 57.6 (C9), 52.8 (C23), 51.9 (C16), 51.9 (C17), 44.2 (C7), 39.3 (C4), 38.4 (C8), 30.9 (C4), 24.9 (C13). 1 OHC 13 5 2 4 H 3 H 15 14 7 8 10 9 6 11 12 16 H3CO2C H3CO2C O 17 20 19 18 2.68 2-(4-Benzyloxybut-2-ynyl)-2-[3-(2S,4S)-(2-formylcyclopropyl)but-2-enyl]malonic acid dimethyl ester (2.68) (BLA-III-274). Oxalyl chloride (50 mL, 0.485 mmol) was added dropwise to a solution of 2.56 (104 mg, 0.242 mmol) and DMF (5 drops) in CH2Cl2 (2.5 mL) at 0 C. The reaction was allowed to warm to room temperature by removal of the cooling bath and then stirred for 3 h. The mixture was concentrated under reduced pressure, and the crude acid chloride was dissolved in THF (2 mL). The solution was cooled to 78 C, and a slurry of LiAlH(OtBu)3 (124 mg, 0.485 mmol) in THF (0.5 mL) was added. The reaction was stirred at 78 C for 1 h. Aqueous 1M HCl (2 mL) was added, and the mixture allowed to warm to room temperature by removal of the cooling bath, and then the layers were separated. The aqueous phase was extracted with EtOAc (3 x 2 mL), and the combined organic fractions were then dried 288 (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 84 mg (84%) of 2.68 as a clear, colorless oil. Oxidation of alcohol 2.62 (BLA-III-243). Dess-Martin periodinane (58 mg, 0.137 mmol) was added in one portion to a solution of 2.62 (104 mg, 0.242 mmol) in CH2Cl2 (1 mL) at room temperature, and the mixture was stirred for 1.5 h. Saturated aqueous NaHCO3/Na2S2O3 (1 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 1 mL), and the combined organic fractions were then dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 19 mg (100%) of 2.68 as a clear, colorless oil: 1H NMR (300 MHz) d 8.74 (d, J = 6.9 Hz, 1 H), 7.36-7.28 (comp, 5 H), 5.31 (t, J = 7.8 Hz, 1 H), 4.55 (s, 2 H), 4.13 (t, J = 2.1 Hz, 2 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 2.91-2.83 (comp, 4 H), 2.11 (app dt, J = 15.9, 8.1 Hz, 1 H), 1.86 (app ddt, J = 12.0, 7.8, 4.8 Hz, 1 H), 1.72 (s, 3H), 1.59 (app dt, J = 7.2, 5.1 Hz, 1 H), 1.33 (app dt, J = 7.8, 5.4 Hz, 1 H); 13C NMR (75 MHz) d 201.7, 170.3, 137.5, 134.9, 128.1, 127.8, 121.1, 81.3, 79.3, 71.2, 57.3, 56.9, 52.8, 30.6, 30.2, 28.3, 23.2, 17.8, 11.8; IR (CDCl3) 2953, 2853, 2256, 1736, 1697, 1437, 1292, 1208, 1069 cm-1; mass spectrum (CI) m/z 413.1959 [C24H29O6 (M+1) requires 413.1964] 413 (base), 305, 245. NMR Assignments: 1H NMR (300 MHz) d 8.74 (d, J = 6.9 Hz, 1 H, C1-H), 7.367.28 (comp, 5 H, C18-C19-C20-H), 5.31 (t, J = 7.8 Hz, 1 H, C6-H), 4.55 (s, 2 H, C16-H), 4.13 (t, J = 2.1 Hz, 2 H, C12-H), 3.74 (s, 3 H, C15-H), 3.73 (s, 3 H, C15-H), 2.91-2.83 (comp, 4 H, C7-C9-H), 2.11 (app dt, J = 15.9, 8.1 Hz, 1 H, C2-H), 1.86 (app ddt, J = 12.0, 7.8, 4.8 Hz, 1 H, C4-H), 1.72 (s, 3H, C13-H), 1.59 (app dt, J = 7.2, 5.1 Hz, 1 H, C3H), 1.33 (app dt, J = 7.8, 5.4 Hz, 1 H, C3-H); 13C NMR (75 MHz) d 201.7 (C1), 170.3 (C14), 137.5 (C5), 134.9 (C17), 128.1 (CAR), 127.8 (CAR), 121.1 (C6), 81.3 (C10), 79.3 289 (C11), 71.2 (C16), 57.3 (C12), 56.9 (C15), 52.8 (C8), 30.6 (C7), 30.2 (C2), 28.3 (C4), 23.2 (C9), 17.8 (C13), 11.8 (C3). 22 19 18 15 16 11 10 9 8 1 7 20 21 O 2 3 6 5 CHO 4 14 H3CO2C H3CO2C 17 12 H 13 2.69 (3aS,7S)-8-Benzyloxymethyl-7-formyl-4-methyl-3,3a,6,7-tetrahydro-1Hazulene-2,2-dicarboxylic acid dimethyl ester (2.69) (BLA-III-245). [Rh(CO)2Cl]2 (2 mg, 4.8 mmol) was dissolved in degassed toluene (2 mL), and a solution of 2.68 (20 mg, 0.048 mmol) in degassed toluene (5 mL) was added. The resulting mixture was heated for 30 min at 110 C (bath temperature). The mixture was allowed to cool to room temperature by removal of the oil bath, and then filtered through a short plug of neutral alumina. The filtrate was concentrated under reduced pressure, and the crude residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 17 mg (85%) of 2.69 as a clear, colorless oil: 1H NMR (500 MHz) d 9.59 (s, 1 H), 7.36-7.27 (comp, 5 H), 5.51-5.49 (m, 1 H), 4.51 (d, J = 11.6 Hz, 1 H), 4.46 (d, J = 11.8 Hz, 1 H), 4.01 (app dt, J = 12.1, 1.2 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s, 3 H), 3.37 (br s, 1 H), 3.23 (dd, J = 17.3, 2.0 Hz, 1 H), 3.20 (t, J = 6.0 Hz, 1 H), 2.89 (dd, J = 16.7, 1.4 Hz, 1 H), 2.73 (ddd, J = 12.4, 7.4, 2.0 Hz, 1 H), 2.68-2.59 (m, 1 H), 2.35-2.29 (m, 1 H), 2.07 (t, J = 12.7 Hz, 1 H), 1.68 (d, J = 0.6 Hz, 1 H); 13C NMR (125 MHz) d 200.4, 171.7, 171.4, 142.5, 138.2, 134.3, 290 128.4, 127.7, 127.6, 122.8, 71.9, 71.2, 57.3, 52.9, 52.8, 51.7, 44.5, 39.3, 39.3, 26.4, 24.2; IR (CDCl3) 3022, 2954, 1732, 1698, 1436, 1374, 1291, 1211, 1071 cm-1; mass spectrum (CI) m/z 413.1956 [C24H29O6 (M+1)] 413, 305 (base), 273, 245. NMR Assignments: 1H NMR (500 MHz) d 9.59 (br s, 1 H, C14-H), 7.36-7.27 (comp, 5 H, C18-C19-C20-H), 5.51-5.49 (m, 1 H, C5-H), 4.51 (d, J = 11.6 Hz, 1 H, C18H), 4.46 (d, J = 11.8 Hz, 1 H, C18-H), 4.01 (app dt, J = 12.1, 1.2 Hz, 1 H, C15-H), 3.76 (s, 3 H, C16-H), 3.74 (s, 3 H, C17-H), 3.37 (br s, 1 H, C7-H), 3.23 (dd, J = 17.3, 2.0 Hz, 1 H, C10-H), 3.20 (t, J = 6.0 Hz, 1 H, C3-H), 2.89 (dd, J = 16.7, 1.4 Hz, 1 H, C10-H), 2.73 (ddd, J = 12.4, 7.4, 2.0 Hz, 1 H, C8-H), 2.68-2.59 (m, 1 H, C4-H), 2.35-2.29 (m, 1 H, C4-H), 2.07 (t, J = 12.7 Hz, 1 H, C8-H), 1.68 (d, J = 0.6 Hz, 1 H, C13-H); 13C NMR (125 MHz) d 200.4 (C14), 171.7 (C11), 171.4 (C12), 142.5 (C1), 138.2 (C19), 134.3 (C6), 128.4 (C22), 127.7 (C21), 127.6 (C20), 122.8 (C5), 71.9 (C18), 71.2 (C15), 57.3 (C9), 52.9 (C16), 52.8 (C17), 51.7 (C3), 44.5 (C7), 39.3 (10), 39.3 (C8), 26.4 (C4), 24.2 (C13). 22 19 18 15 16 11 10 9 8 1 7 20 21 O 14 2 3 6 OH 4 H3CO2C H3CO2C 17 12 H 13 5 2.70 [2S,3S]-8-Benzyloxymethyl-7-hydroxymethyl-4-methyl-3,3a,6,7-tetrahydro1H-azulene-2,2-dicarboxylic acid dimethyl ester (2.70) (BLA-III-244). NaBH4 (2 mg, 0.029 mmol) was added in one portion to a solution of 2.69 (6 mg, 0.014 mmol) in THF 291 (1 mL) at 0 C, and the mixture was stirred for 1 h 15 min. Saturated aqueous NH4Cl (1 mL) was added and the layers separated. The aqueous phase was extracted with EtOAc (3 x 1 mL), and the combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 5 mg (83%) of 2.70 as a clear, colorless oil: 1H NMR (500 MHz) d 7.35-7.27 (comp, 5 H), 5.50-5.48 (m, 1 H), 4.53 (s, 2 H), 4.03 (d, J = 10.0 Hz, 1 H), 3.79 (d, J = 10.0 Hz, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.69 (dd, J = 13.9, 5.2 Hz, 1 H), 3.64 (dd, J = 10.6, 6.0 Hz, 1 H), 3.60-3.55 (m, 1 H), 3.17 (br d, J = 16.7 Hz, 1 H), 2.95-2.92 (m, 1 H), 2.75 (ddd, J = 12.4, 7.4, 2.0 Hz, 1 H), 2.42-2.35 (m, 2 H), 2.282.20 (comp, 2 H), 2.04 (t, J = 12.6 Hz, 1 H), 1.71 (s, 3 H); 13C NMR (125 MHz) d 171.9, 171.7, 141.8, 137.9, 135.2, 130.7, 128.4, 127.8, 127.7, 123.2, 72.7, 72.2, 64.1, 57.0, 52.9, 52.8, 45.2, 42.9, 39.4, 39.2, 29.0, 23.8; IR (CHCl3) 3468, 3015, 2954, 1731, 1436, 1273, 1201, 1060 cm-1; mass spectrum (CI) m/z 415.2124 [C25H31O6 (M+1) requires 415.2121] 415, 307 (base), 207, 247. NMR Assignments: 1 H NMR (500 MHz) d 7.35-7.27 (comp, 5 H, C20-C21- C22-H), 5.50-5.48 (m, 1 H, C5-H), 4.53 (s, 2 H, C18-H), 4.03 (d, J = 10.0 Hz, 1 H, C15H), 3.79 (d, J = 10.0 Hz, 1 H, C15-H), 3.74 (s, 3 H, C16-H), 3.73 (s, 3 H, C17-H), 3.69 (dd, J = 13.9, 5.2 Hz, 1 H, C14-H), 3.64 (dd, J = 10.6, 6.0 Hz, 1 H, C14-H), 3.60-3.55 (m, 1 H, C7-H), 3.17 (br d, J = 16.7 Hz, 1 H, C10-H), 2.95-2.92 (m, 1 H, C10-H), 2.75 (ddd, J = 12.4, 7.4, 2.0 Hz, 1 H, C8-H), 2.42-2.35 (m, 2 H, C3-C4-H), 2.28-2.20 (comp, 2 H, C4-H), 2.04 (t, J = 12.6 Hz, 1 H, C8-H), 1.71 (s, 3 H, C13-H); 13C NMR (125 MHz) d 171.9 (C11), 171.7 (C12), 141.8 (C1), 137.9 (C19), 135.2 (C6), 130.7 (C2), 128.4 (C22), 127.8 (C21), 127.7 (C20), 123.2 (C5), 72.7 (C18), 72.2 (C15), 64.1 (C14), 57.0 (C9), 52.9 (C16), 52.8 (C17), 45.2 (C7), 42.9 (C3), 39.4 (C10), 39.2 (C8), 29.0 (C4), 23.8 (C13). 292 15 12 11 14 25 24 13 14 O 17 O 19 H3CO2C H3CO2C 8 7 6 O 2 18 20 21 22 Br 10 1 9 5 4 H 23 3 2.71 [2S,3S]-8-Benzyloxymethyl-7-(4-bromobenzoyloxymethyl)-4-methyl-3,3a,6,7tetrahydro-1H-azulene-2,2-dicarboxylic acid dimethyl ester (2.71) (BLA-IV-287). 4Bromobenzoyl chloride (16 mL, 0.073 mmol) was added in one portion to a stirred solution of 2.70 (15 mg, 0.036 mmol), DMAP (1 mg, 7.3 mmol), and pyridine (6.0 mL, 0.073 mmol) in CH2Cl2 (1 mL) at room temperature, and the reaction was stirred for 4 h. The mixture was then diluted with saturated aqueous NaCl (1 mL) and Et2O (2 mL), and the layers were separated. The aqueous layer was extracted with Et2O (3 x 2 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (2 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (5:1) to give 17 mg (78%) of 3.64 as an clear, colorless oil: 1H NMR (400 MHz) d 7.84 (dt, J = 8.8, 2.4 Hz, 2 H), 7.54 (dt, J = 8.8, 2.4 Hz, 2 H), 7.33-7.26 (comp m, 5 H), 5.45 (br t, J = 5.6 Hz, 1 H), 4.49 (d, J = 12.0 Hz, 1 H), 4.44 (d, J = 12.0 Hz, 1 H), 4.40 (d, J = 7.2 Hz, 2 H), 4.01 (s, 2 H), 3.73 (s, 3 H), 3.72 (s, 3 H), 3.55-3.49 (m, 1 H), 3.15 (d, J = 16.8 Hz, 1 H), 2.93 (dd, J = 16.8, 2.0 Hz, 1 H), 2.88 (app dq, J = 12.0, 7.2, 7.2, 7.2 Hz, 1 H), 2.78 (ddd, J = 12.4, 7.2, 2.0 Hz, 1 H), 2.39 (br s, 2 H), 2.05 (t, J = 12.4 Hz, 1 H), 1.74 (s, 3 H); IR (CDCl3) 3691, 2954, 2360, 2254, 1792, 1731, 1591, 1436, 1272, 1211, 1172, 1103, 1070, 1043, 1012 cm-1; mass 293 spectrum (CI) m/z 599.1483 [C31H34O7Br (M+2) requires 599.1467] 627, 599, 597, 595, 505, 491, 489 (base), 384, 379, 365. NMR Assignments: 1H NMR (400 MHz) d 7.84 (dt, J = 8.8, 2.4 Hz, 2 H, C20H), 7.54 (dt, J = 8.8, 2.4 Hz, 2 H, C21-H), 7.33-7.26 (comp m, 5 H, C14-C15-C16-H), 5.45 (br t, J = 5.6 Hz, 1 H, C3-H), 4.49 (d, J = 12.0 Hz, 1 H, C12-H), 4.44 (d, J = 12.0 Hz, 1 H, C12-H), 4.40 (d, J = 7.2 Hz, 2 H, C17-H), 4.01 (s, 2 H, C11-H), 3.73 (s, 3 H, C25-H), 3.72 (s, 3 H, C25-H), 3.55-3.49 (m, 1 H, C1-H), 3.15 (d, J = 16.8 Hz, 1 H, C8H), 2.93 (dd, J = 16.8, 2.0 Hz, 1 H, C8-H), 2.88 (app dq, J = 12.0, 7.2, 7.2, 7.2 Hz, 1 H, C5-H), 2.78 (ddd, J = 12.4, 7.2, 2.0 Hz, 1 H, C6-H), 2.39 (br s, 2 H, C2-H), 2.05 (t, J = 12.4 Hz, 1 H, C6-H), 1.74 (s, 3 H, C23-H). 21 20 19 18 11 17 14 22 23 O 13 10 9 6 7 24 26 25 Si O 8 MeO2C MeO2C 16 15 5 4 3 1 2 H 12 2.72 (3aS,4Z,7S,8E)-dimethyl 8-((benzyloxy)methyl)-3,3a,6,7-tetrahydro-7-((t- butyl dimethylsiloxy)methyl)-4-methylazulene-2,2(1H)-dicarboxylate (2.72) (BLAVI-268). TBSCl (24 mg, 0.16 mmol) was added in one portion to a solution of imidazole (11 mg, 0.16 mmol) and 2.70 (32 mg, 78.0 mmol) in DMF (2 mL) at room temperature, and the reaction was stirred for 4 h. Saturated aqueous NaCl (1 mL) was added, and the 294 layers were separated. The aqueous phase was extracted with Et2O (3 x 1 mL), and the combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexane/EtOAc (2:1) to provide 33 mg (81%) of 2.72 as a clear, colorless oil: 1H NMR (500 MHz) d 7.32-7.31 (comp, 5 H), 5.42-5.41 (m, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.42 (d, J = 12.0 Hz, 1 H), 3.96 (d, J = Hz, 1 H), 3.95 (d, J = Hz, 1 H), 3.72 (s, 3 H), 3.71 (s, 3 H), 3.64 (app t, J = 9.5 Hz, 1 H), 3.59 (dd, J = 9.5, 5.5 Hz, 1 H), 3.37-3.36 (m, 1 H), 3.10 (d, J = 17.0 Hz, 1 H), 2.96 (dd, J = 17.5, 2.5 Hz, 1 H), 2.54 (m, 1 H), 2.35-2.31 (m, 1 H), 2.27-2.23 (m, 1 H), 1.96 (app t, J = 13.0 Hz, 1 H), 1.70 (d, J = 1.0 Hz, 3 H), 0.84 (s, 9 H), 0.03 (s, 6 H); 13C NMR (125 MHz) d 171.9, 171.9, 138.8, 138.4, 133.2, 131.9, 128.3, 127.6, 127.4, 123.4, 72.4, 71.8, 62.6, 57.4, 56.7, 52.7, 46.5, 41.7, 39.1, 25.8, 25.6, 17.9, 3.7; mass spectrum (CI) m/z 529.2957 [C30H45O6Si (M+1) requires 529.2985] 529, 421, 289 (base), 275. NMR Assignments: 1 H NMR (400 MHz) d 7.32-7.31 (comp, 5 H, C20-C21- C22 -H), 5.42-5.41 (m, 1 H, C7-H), 4.47 (d, J = 12.0 Hz, 1 H, C18-H), 4.42 (d, J = 12.0 Hz, 1 H, C18-H), 3.96 (d, J = Hz, 1 H, C11-H), 3.95 (d, J = Hz, 1 H, C11-H), 3.72 (s, 3 H, C16-H), 3.71 (s, 3 H, C17-H), 3.64 (app t, J = 9.5 Hz, 1 H, C13-H), 3.59 (dd, J = 9.5, 5.5 Hz, 1 H, C13-H), 3.37-3.36 (m, 1 H, C9-H), 3.10 (d, J = 17.0 Hz, 1 H, C5-H), 2.96 (dd, J = 17.5, 2.5 Hz, 1 H, C5-H), 2.54 (m, 1 H, C5-H), 2.35-2.31 (m, 1 H, C2-H), 2.272.23 (m, 1 H, C3-H), 1.96 (app t, J = 13.0 Hz, 1 H, C3-H), 1.70 (d, J = 1.0 Hz, 3 H, C12H), 0.84 (s, 9 H, C30-C31-C32-H), 0.03 (s, 6 H, C28-C29-H); 13C NMR (125 MHz) d 171.9 (C14), 171.9 (C15), 138.8 (C6), 138.4 (C19), 133.2, 131.9, 128.3, 127.6, 127.4, 123.4 (C7), 72.4 (C18), 71.8 (C11), 62.6 (C13), 57.4, 56.7, 52.7 (C16,C17), 46.5, 41.7, 39.1, 25.8 (C12), 25.6 (C26), 17.9 (C25), 3.7 (C23,C24). 295 19 18 17 16 11 14 5 20 O 13 10 9 6 21 23 Si 22 O 8 HO 15 4 1 2 OH 3 H 12 7 2.73 (3aS,4Z,7S,8E)-Dimethyl 8-((benzyloxy)methyl)-3,3a,6,7-tetrahydro-7-((t- butyl dimethylsiloxy)methyl)-4-methylazulene-2,2(1H)-diol (2.73) (BLA-VII-272). LiAlH4 (21 mg, 0.55 mmol) was added to a stirred solution of diester 2.72 (145 mg, 0.27 mmol) in THF (3 mL) at 0 C. The reaction was allowed to warm slowly to room temperature and stirred for 4 h. The mixture was then cooled to 0 C, and saturated potassium sodium tartrate (3 mL) was added, and the mixture was stirred for 30 min at room temperature. The layers were separated, and the aqueous phase was extracted with EtOAc (5 x 5 mL). The combined organic fractions were washed with saturated aqueous NaCl (5 mL), dried (Na2SO4) and concentrated under reduced pressure to yield 120 mg (91%) of 2.73 as an opaque, colorless oil: 1H NMR (500 MHz) d 7.34-7.28 (comp, 5 H), 5.42-5.40 (m, 1 H), 4.49 (d, J = 11.6 Hz, 1 H), 4.44 (d, J = 11.6 Hz, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.95 (d, J = 10.4 Hz, 1 H), 3.71 (d, J = 9.2 Hz, 1 H), 3.65 (d, J = 9.2 Hz, 1 H), 3.74-3.57 (comp, 4 H), 3.43-3.38 (m, 1 H), 2.55-2.52 (m, 1 H), 2.41-2.16 (comp, 6 H), 1.71 (s, 3 H), 0.88 (s, 9 H), 0.01 (s, 6 H); 13C NMR (125 MHz) d 141.8, 138.5, 134.8, 131.5, 128.3, 127.8, 127.6, 122.7, 72.8, 72.1, 71.1, 67.4, 62.9, 45.7, 45.3, 44.5, 42.4, 42.2, 37.6, 37.5, 35.9, 18.3, 5.4, 5.4; mass spectrum (CI) m/z 473.3063 [C28H45O4Si (M+1) requires 473.3087] 473, 365, 233, 215 (base). 296 NMR Assignments: 1 H NMR (500 MHz) d 7.34-7.28 (comp, 5 H, C18-C19- C20-H), 5.42-5.40 (m, 1 H, C7-H), 4.49 (d, J = 11.6 Hz, 1 H, C16-H), 4.44 (d, J = 11.6 Hz, 1 H, C16-H), 3.97 (d, J = 10.4 Hz, 1 H, C11-H), 3.95 (d, J = 10.4 Hz, 1 H, C11-H), 3.71 (d, J = 9.2 Hz, 1 H, C13-H), 3.65 (d, J = 9.2 Hz, 1 H, C13-H), 3.74-3.57 (comp, 4 H, C14-C15-H), 3.43-3.38 (m, 1 H, C2-H), 2.55-2.52 (m, 1 H, C9-H), 2.41-2.16 (comp, 6 H, C3-C5-C8-H), 1.71 (s, 3 H, C12-H), 0.88 (s, 9 H, C23-H), 0.01 (s, 6 H, C21-H); 13 C NMR (125 MHz) d 141.8 (C6), 138.5 (C17), 134.8, 131.5, 128.3, 127.8, 127.6, 122.7 (C6), 72.8 (C16), 72.1 (C11), 71.1 (C14), 67.4 (C15), 62.9 (C13), 45.7 (C2), 45.3 (C4), 44.5 (C5), 42.4 (C9), 42.2 (C3), 37.6 (C8), 37.5 (C12), 35.9 (C23), 18.3 (C22), 5.4 (C21), 5.4 (C21). 22 19 18 11 14 5 21 20 23 24 26 25 O 13 10 9 6 7 Si O 8 MeO2SO 16 15 4 3 1 2 MeO2SO 17 H 12 2.74 ((3aS,4Z,7S,8E)-8-(benzyloxymethyl)-7-((tert-butyldimethylsilyloxy)methyl)4-methyl-2-((methylperoxy)thio)oxy))methyl)-1,2,3,3a,6,7-hexahydroazulen-2yl)methyl methanesulfonate (2.74) (BLA-VII-277). Methanesulfonyl chloride (291 mg, 0.20 mL, 2.50 mmol) was added dropwise to a stirred solution of 2.73 (120 mg, 0.25 mmol) and Et3N (257 mg, 0.35 mL, 2.50 mmol) in CH2Cl2 (5 mL) at 0 C, and the resultant mixture was stirred for 3 h. Saturated aqueous NaHCO3 (5 mL) was added, and 297 the layers were separated. The aqueous phase was extracted with Et2O (3x mL), and the combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to provide 137 mg (79%) of 3.67 as a clear, colorless oil: 1H NMR (500 MHz) d 7.37-7.28 (comp, 5 H), 5.48-5.44 (m, 1 H), 4.49 (d, J = 11.6 Hz, 1 H), 4.44 (d, J = 11.6 Hz, 1 H), 4.21-4.06 (comp, 2 H), 4.16 (d, J = 9.6 Hz, 1 H), 4.08 (d, J = 9.6 Hz, 1 H), 3.92 (br s, 1 H), 3.70-3.62 (comp, 2 H), 3.51-3.44 (m, 1 H), 3.03 (s, 3 H), 3.03 (s, 3 H), 2.54-2.53 (m, 1 H), 2.42-2.25 (comp, 3 H), 2.17 (dd, J = 13.2, 8.0 Hz, 1 H), 1.70 (s, 3 H), 0.88 (s, 9 H), 0.01 (s, 6 H); 13C NMR (125 MHz) d 138.8, 138.2, 133.9, 133.1, 128.2, 127.6, 127.5, 123.4, 72.5, 72.3, 72.3, 72.1, 69.1, 62.7, 42.8, 37.2, 37.1, 36.6, 36.6, 31.4, 25.8, 24.3, 18.1, 5.1, 5.2; IR (CDCl3) 3100, 3031, 2929, 2856, 2260, 1730, 1469, 1362, 1255, 1178, 1094, 978, 850, 778, 527; mass spectrum (CI) m/z 629.2627 [C30H49O8SiS2 (M+1) requires 629.2638] 629, 557, 555 (base). NMR Assignments: 1 H NMR (500 MHz) d 7.37-7.28 (comp, 5 H, C20-C21- C22-H), 5.48-5.44 (m, 1 H C7-H), 4.49 (d, J = 11.6 Hz, 1 H, C18-H), 4.44 (d, J = 11.6 Hz, 1 H, C18-H), 4.21-4.06 (comp, 2 H), 4.16 (d, J = 9.6 Hz, 1 H, C11-H), 4.08 (d, J = 9.6 Hz, 1 H, C11-H), 3.92 (br s, 1 H, C14-H), 3.70-3.62 (comp, 2 H), 3.51-3.44 (m, 1 H, C13-H), 3.03 (s, 3 H, C16-H), 3.03 (s, 3 H, C17-H), 2.54-2.53 (m, 1 H, C2-H), 2.42-2.25 (comp, 3 H), 2.17 (dd, J = 13.2, 8.0 Hz, 1 H), 1.70 (s, 3 H, C12-H), 0.88 (s, 9 H, C25-H), 0.01 (s, 6 H, C23-H); 13 C NMR (125 MHz) d 138.8 (C6), 138.2 (C19), 133.9, 133.1, 128.2, 127.6, 127.5, 123.4 (C7), 72.5 (C18), 72.3 (C14), 72.3 (C15), 72.1 (C11), 69.1 (C13), 62.7 (C2), 42.8 (C4), 37.2, 37.1, 36.6, 36.6, 31.4 (C16,C17), 25.8 (C25), 24.3 (C12), 18.1 (C24), 5.1 (C23), 5.2 (C23). 298 20 17 16 11 14 5 4 15 3 1 2 18 19 O 13 10 9 6 7 OH 8 H 12 2.75 ((3aE,5S,7Z,8aS)-4-(benzyloxymethyl)-2,2,8-trimethyl-1,2,3,5,6,8ahexahydroazulen-5-yl)methanol (2.75) (BLA-VIII-22, BLA-VIII-25). A 1.0 M solution of LiBHEt3 (0.71 mL, 0.71 mmol) in THF was added to a solution of 2.74 (56 mg, 0.08 mmol) in THF (2 mL) at room temperature, and the mixture was stirred for 8 h. The reaction was then cooled to 0 C, 1 M HCl (2 mL) was added, and the mixture allowed to warm to room temperature. The layers were separated, and the aqueous phase was extracted with EtOAc (5 x mL). The combined organic fractions were washed with saturated aqueous NaCl (mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was then dissolved in THF (1.7 mL), and a solution of TBAF (85 mg, 0.27 mmol) in THF (0.3 mL) was added at room temperature. The reaction was stirred for 3 h and then saturated aqueous NaCl (mL) was added, and the layers were separated. The aqueous phase was extracted with EtOAc (5 x mL), the combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to provide 20 mg (70%) of 2.75 as a clear, colorless oil: 1H NMR (500 MHz) d 7.38-7.27 (comp, 5 H), 5.49-5.44 (m, 1 H), 4.52 (s, 1 H), 4.01 (d, J = 9.6 Hz, 1 H), 3.75-3.68 (comp, 3 H), 2.51 (app t, J = 6.0 Hz, 1 H), 2.47-2.78 (comp, 2 H), 2.25 (dd, J = 16.0, 2.0 Hz, 1 H), 2.20299 2.18 (m, 1 H), 2.13 (d, J = 16.0 Hz, 1 H), 1.76 (ddd, J = 11.6, 7.6, 2.0 Hz, 1 H), 1.68 (s, 3 H), 1.51 (app t, J = 12.0 Hz, 1 H), 1.07 (s 3 H), 0.96 (s, 3 H); 13C NMR (125 MHz) d 147.2, 138.1, 137.2, 129.2, 128.4, 127.8, 127.7, 122.5, 72.7, 72.5, 64.3, 47.0, 46.0, 44.8, 43.3, 35.4, 29.4, 29.3, 26.8, 23.9; IR (CDCl3) 2955, 2247, 1602, 1454, 1365, 1307, 1058; mass spectrum (CI) m/z 325.2171 [C22H29O2 (M+1) requires 325.2168] 327, 323, 295, 247, 219 (base). NMR Assignments: 1 H NMR (500 MHz) d 7.38-7.27 (comp, 5 H, C18-C19- C20-H), 5.49-5.44 (m, 1 H, C7-H), 4.52 (s, 1 H, C16-H), 4.01 (d, J = 9.6 Hz, 1 H, C11H), 3.75-3.68 (comp, 3 H, C11-C13-H), 2.51 (app t, J = 6.0 Hz, 1 H, C2-H), 2.47-2.78 (comp, 2 H, C9-C8-H), 2.25 (dd, J = 16.0, 2.0 Hz, 1 H, C5-H), 2.20-2.18 (m, 1 H, C3-H), 2.13 (d, J = 16.0 Hz, 1 H, C5-H), 1.76 (ddd, J = 11.6, 7.6, 2.0 Hz, 1 H, C8-H), 1.68 (s, 3 H, C12-H), 1.51 (app t, J = 12.0 Hz, 1 H, C3-H), 1.07 (s 3 H, C14-H), 0.96 (s, 3 H, C15H); 13C NMR (125 MHz) d 147.2 (C6), 138.1 (C17), 137.2, 129.2, 128.4, 127.8, 127.7, 122.5 (C7), 72.7 (C16), 72.5 (C11), 64.3 (C13), 47.0, 46.0, 44.8, 43.3, 35.4 (C9), 29.4 (C14), 29.3 (C15), 26.8 (C8), 23.9 (C12). 11 14 5 4 15 3 OH 13 OH 8 10 9 1 2 6 H 12 7 2.4 Tremulenediol A (2.4) (BLA-VIII-95). Palladium on carbon (10 wt%, 1 mg) was added to a solution of 2.75 (5 mg, 15.3 mol) in MeOH (0.1 mL) at room temperature. The atmosphere in the flask was then replaced with H2 (1 atm) and the 300 mixture was stirred under and atmosphere of H2 (balloon) for 3 d. The reaction was then filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to provide 3 mg (82%) of 2.4 as a clear, colorless oil. Spectra results were consistent with literature data:294 1H NMR (500 MHz) d 4.25 (d, J = 11.0 Hz, 1 H), 4.02 (app t, J = 9.5 Hz, 1 H), 3.84 (dt, J = 11.0, 1.5 Hz, 1 H), 3.62 (dd, J = 9.5, 5.0 Hz, 1 H), 3.10 (br t, J = 8.5 Hz, 1 H), 2.57-2.54 (m, 1 H), 2.29 (dd, J = 15.5, 2.5 Hz, 1 H), 1.93 (br d, J = 15.0 Hz, 1 H), 1.84-1.81 (m, 1 H), 1.80 (br d, J = 11.5 Hz, 1 H), 1.79-1.74 (m, 1 H), 1.61 (dd, J = 12.5, 3.0 Hz, 1 H), 1.59-1.58 (m, 1 H), 1.54-1.51 (m, 1 H), 1.38 (br d, J = 12.0 Hz, 1 H), 1.07 (s, 3 H), 0.87 (s, 3 H), 0.82 (d, J = 7.0 Hz, 3 H); 13C NMR (125 MHz) d 145.8, 132.4, 65.8, 63.3, 48.0, 46.0, 45.5, 45.4, 37.0, 32.6, 31.6, 28.5, 26.9, 22.5, 11.6; IR (CHCl3) 3415, 2929, 2861, 2337, 1601, 1465, 1265, 1016; mass spectrum (CI) m/z 238.1910 [C15H26O2 (M+1) requires 238.1932] 237, 221 (base), 203; [a]D25 = +40.0 (c 0.24, MeOH). NMR Assignments: 1H NMR (500 MHz) d 4.25 (d, J = 11.0 Hz, 1 H, C11-H), 4.02 (app t, J = 9.5 Hz, 1 H, C12-H), 3.84 (dt, J = 11.0, 1.5 Hz, 1 H, C11-H), 3.62 (dd, J = 9.5, 5.0 Hz, 1 H, C12-H), 3.10 (br t, J = 8.5 Hz, 1 H, C7-H), 2.57-2.54 (m, 1 H, C3-H), 2.29 (dd, J = 15.5, 2.5 Hz, 1 H, C10-H), 1.93 (br d, J = 15.0 Hz, 1 H, C10-H), 1.84-1.81 (m, 1 H, C5-H), 1.80 (br d, J = 11.5 Hz, 1 H, C4-H), 1.79-1.74 (m, 1 H, C6-H), 1.61 (dd, J = 12.5, 3.0 Hz, 1 H, C5-H), 1.59-1.58 (m, 1 H, C4-H), 1.54-1.51 (m, 1 H, C8-H), 1.38 (br d, J = 12.0 Hz, 1 H, C8-H), 1.07 (s, 3 H, C14-H), 0.87 (s, 3 H, C15-H), 0.82 (d, J = 7.0 Hz, 3 H, C13-H); 13C NMR (125 MHz) d 145.8 (C1), 132.4, (C2), 65.8 (C11), 63.3 (C12), 48.0 (C10), 46.0 (C7), 45.5 (C8), 45.4 (C3), 37.0 (C9), 32.6 (C5), 31.6 (C6), 28.5 (C14), 26.9 (C15), 22.5 (C4), 11.6 (C13). 301 O 14 5 4 15 3 11 O 13 1 2 10 9 6 8 7 H 12 2.3 Tremulenolide A (2.3) (BLA-VIII-168). MnO2 (3.0 mg, 33.0 mmol) was added to a solution of 2.4 (4.0 mg, 16.0 mmol) in CH2Cl2 (1 mL) at room temperature. The resulting mixture was stirred for 24 h, filtered through a short plug of silica gel and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (5:1) to provide 3.4 mg (86%) of 2.3 as a clear, colorless oil. Spectra results were consistent with literature data.294 O O 3 2 1 4 N2 5 3.6 1,4-Pentadien-3-yl diazoacetate (3.6) (BLA-II-243). p- Toluenesulfonylhydrazone of glyoxylic acid chloride (1.4 g, 5.63 mmol) and N,Ndimethylamine (0.6 mL, 4.88 mmol) were added to a solution 3.5 (316 mg, 3.76 mmol) in CH2Cl2 (19 mL) at 0 C, and the mixture was stirred for 30 min. Et3N (2.62 mL, 18.78 mmol) was added, the cooling bath was removed, and the reaction was then stirred for 4 h at room temperature. H2O (20 mL) was added, the aqueous phase was extracted with Et2O (3 x 20 mL), and the combined organic fractions were washed with saturated aqueous NaCl (100 mL). The combined organic fractions were dried (MgSO4) and 302 concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with Et2O/pentane (1:10) to give 396 mg (70%) of 3.6 as a bright, yellow oil. Spectral data was consistent with literature data:384 1H NMR (300 MHz) d 5.84 (comp, 3 H), 5.29 (comp, 4 H), 4.79 (br s, 1 H); mass spectrum (CI) m/z 153.0656 [C7H9N2O2 (M+1) requires 153.0664] 149, 125 (base), 110. NMR Assignments: 1 H NMR (300 MHz) d 5.84 (comp, 3 H, C2,3-H), 5.29 (comp, 4 H, C1-H), 4.79 (br s, 1 H, C5-H). H H 6 7 2 1 H 3 4 5 O 3.7 O [1S-(1b,5a)]-4-Methyl-4-vinyl-3-oxabicyclo[3.1.0]hexan-2-one (3.7) (BLA-II251). A solution of 3.6 (379 mg, 2.49 mmol) in CH2Cl2 (25 mL) was added to a refluxing solution of Rh2[5(R)-MEPY]4 (46 mg, 50 mmol) in CH2Cl2 (100 mL) over 20 h via syringe pump. The resulting mixture was then maintained at reflux for an additional 2 hr, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with pentane/Et2O (1:1) to give 251 mg (81%) of 3.7 as a clear, colorless oil. Spectral data was consistent with literature data:384 1 H NMR (300 MHz) d 5.85 (ddd, J = 17.1, 10.5, 5.4 Hz, 1 H), 5.39 (dt, J = 17.1, 1.2 Hz, 2 H), 5.30 (dt, J = 10.8, 1.2 Hz, 2 H), 5.06 (t, J = 5.1 Hz, 1 H), 2.29 (dddd, J = 9.3, 5.4, 4.5 Hz, 1 H), 2.13 (ddd, J = 9.0, 5.7, 3.3 Hz, 1 H), 1.15 (ddd, J = 8.7, 7.5, 5.4 Hz, 1 H), 0.95 (m, 1 H); 13C NMR (65 MHz) d 175.6, 132.8, 118.2, 79.1, 20.9, 18.3, 9.2; mass spectrum (CI) m/z 125.0602 [C7H9O2 (M+1) requires 125.0602] 172, 149. 303 NMR Assignments: 1H NMR (300 MHz) d 5.85 (ddd, J = 17.1, 10.5, 5.4 Hz, 1 H, C6-H), 5.39 (dt, J = 17.1, 1.2 Hz, 1 H, C7-H), 5.30 (dt, J = 10.8, 1.2 Hz, 1 H, C7-H), 5.06 (t, J = 5.1 Hz, 1 H, C3-H), 2.29 (dddd, J = 9.3, 5.4, 4.5 Hz, 1 H, C1-H), 2.13 (ddd, J = 9.0, 5.7, 3.3 Hz, 1 H, C4-H), 1.15 (ddd, J = 8.7, 7.5, 5.4 Hz, 1 H, C5-H), 0.95 (m, 1 H, C5-H); 13C NMR (65 MHz) d 175.6 (C1), 132.8 (C6), 118.2 (C7), 79.1 (C5), 20.9 (C2), 18.3 (C4), 9.2 (C3). 1 HO2C 5 7 8 10 9 2 4 H 3 H 6 11 13 12 H3CO2C H3CO2C 3.9 (1S,2S,E)-2-(4,4-bis(methoxycarbonyl)hept-1-en-6ynyl)cyclopropanecarboxylic acid (3.9). Pd(PPh3)4-Catalyzed Allylic Alkylation (BLA-II-297). Pd(PPh3)4 (23 mg, 20.2 mmol) was added in one portion to a solution of 3.7 (50 mg, 0.403 mmol) in degassed THF (1 mL) at room temperature. In a separate flask, 3.8 (234 mg, 0.806 mmol) was added to a slurry of sodium hydride (31 mg of a 60% mineral oil suspension, 0.766 mmol) in degassed THF (1 mL) at room temperature, and the resultant mixture was stirred for 20 min. The solution containing the malonate anion was then added via cannula to the flask containing 3.7 and Pd(PPh3)4, and the resulting mixture was warmed to 70 C (bath temperature) for 20 h. The resulting dark brown solution was allowed to cool to room temperature and aqueous 1 M HCl (2 mL) added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 304 2 mL), and the combined organic fractions were washed with saturated aqueous NaCl (2 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 78 mg (84%) of 3.9 as a light brown solid: 1H NMR (500 MHz) d 5.59 (dd, J = 15.0, 9.0 Hz, 1 H), 5.51 (dd, J = 15.0, 7.5 Hz, 1 H), 3.74 (s, 3 H), 3.72 (s, 3 H), 2.78 (comp, 4 H), 2.01 (t, J = 2.5 Hz, 1 H), 1.96 (m, 1 H), 1.88 (m, 1 H), 1.25 (m, 2 H); 13C NMR (125 MHz) d 177.7, 170.2, 132.1, 125.5, 78.7, 71.5, 57.1, 52.7, 35.3, 24.6, 22.7, 20.7, 14.9; IR (CHCl3) 3308, 3026, 1733, 1439, 1386, 1294, 1202, 1178, 1076, 974 cm-1; mass spectrum (CI) m/z 295.1191 [C16H19O5 (M+1) requires 295.1182] 277, 179. NMR Assignments: 1H NMR (500 MHz) d 5.59 (dd, J = 15.0, 9.0 Hz, 1 H, C5H), 5.51 (dd, J = 15.0, 7.5 Hz, 1 H, C6-H), 3.74 (s, 3 H, C13-H), 3.72 (s, 3 H, C13-H), 2.78 (comp, 4 H, C7-C9-H), 2.01 (t, J = 2.5 Hz, 1 H, C11-H), 1.96 (m, 1 H, C2-H), 1.88 (m, 1 H, C4-H), 1.25 (m, 2 H, C3-H); 13C NMR (125 MHz) d 177.7 (C1), 170.2 (C12), 132.1 (C5), 125.5 (C6), 78.7 (C10), 71.5 (C11), 57.1 (C8), 52.7 (C13), 35.3 (C7), 24.6 (C3), 22.7 (C9), 20.7 (C2), 14.9 (C4). RhCl(PPh3)3/P(OMe)3-Catalyzed Allylic Alkylation (BLA-II-263). P(OCH3)3 (45 mg, 0.363 mmol) was added to a mixture of RhCl(PPh3)3 (112 mg, 0.121 mmol) in degassed THF (1 mL), and the mixture was stirred for 10-15 min. The solution was then sonicated for 2 min, and then stirred for an additional 10 min at which time 3.7 (30 mg, 0.242 mmol) was added. The resultant solution was stirred at room temperature for 15 min. In a separate flask, 3.8 (82 mg, 0.484 mmol) was added to a slurry of sodium hydride (19 mg of a 60% mineral oil suspension, 0.460 mmol) in degassed THF (1.5 mL) at room temperature, and the resultant mixture was stirred for 20 min. The solution containing malonate anion was then added via cannula to the flask containing 3.7 and RhCl(PPh3)3/P(OCH3)3, and the resulting mixture was heated at 40 C (bath temperature) 305 for 5 h. The resulting dark brown solution was allowed to cool to room temperature, aqueous 1 M HCl (2 mL) was added, and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 2 mL), and the combined organic fractions were washed with saturated aqueous NaCl (2 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 36 mg (49%) of 3.9 as a light brown solid. [Rh(CO)2Cl]2-Catalyzed Allylic Alkylation (BLA-III-153). [Rh(CO)2Cl]2 (6 mg, 0.015 mmol) was dissolved in degassed THF (1 mL) at room temperature and 3.7 (36 mg, 0.29 mmol) added. In a separate flask, 3.8 (99 mg, 0.58 mmol) was added to a slurry of NaH (22 mg of a 60% mineral oil suspension, 0.55 mmol) in degassed THF (1 mL) at room temperature, and the resultant mixture was stirred for 20 min. The solution containing malonate anion was added via cannula to the flask containing [Rh(CO)2Cl]2 and 3.7, and stirred for 2 h. The resulting dark brown solution was diluted with aqueous 1 M NaHSO4 (2 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 2 mL). The combined organic fractions were washed with saturated aqueous NaCl (2 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with CHCl3/MeOH (95:5) to give 45 mg (52%) of 3.9 as a light brown, waxy solid. 306 1 14 H3CO2C 2 4 5 7 8 10 9 6 H 3 H 11 13 12 H3CO2C H3CO2C 3.9a 2-[3-(2R,3R)-(2-Methoxycarbonylcyclopropyl)-allyl]-2-prop-2-ynylmalonic acid dimethyl ester (3.9a). (BLA-III-168). Rh(PPh3)3Cl (112 mg, 0.121 mmol) was dissolved in degassed THF (1.5 mL) and placed under an atmosphere of CO (1 atm). The solution turned from a brick red to yellow after stirring for 5 min at room temperature. Then 3.7 (30 mg, 0.242 mmol) was added. In a separate flask, 3.8 (82 mg, 0.484 mmol) was added to a slurry of NaH (18 mg of a 60% mineral oil suspension, 0.459 mmol) in degassed THF (1.5 mL) at room temperature, and the resultant mixture was stirred for 20 min. The solution containing malonate anion was added via cannula to the flask containing Rh(PPh3)3Cl and 3.7, and the resulting mixture was heated at 40 C (bath temperature) for 24 h. The resulting dark red solution was allowed to cool to room temperature, aqueous 1 M NaHSO4 (3 mL) was added, and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 3 mL), and the combined organic fractions were washed with brine (3 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was partially purified by flash chromatography eluting with CHCl3/MeOH (95:5). The mixture obtained was dissolved in Et2O/EtOAc (1:1) (5 mL) and a 1 M solution of CH2N2 in Et2O was added with vigorous stirring until the yellow color persisted (approx. 4 mL). Acetic acid (approx. 4 mL) was added until the yellow color disappeared, and the resulting solution was concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc 307 (2:1) to give 32 mg (43%) of 3.9a as a clear, colorless oil: 1H NMR (500 MHz) d 5.54 (ddd, J = 15.3, 6.1, 3.1 Hz, 1 H), 5.47 (dd, J = 14.7, 7.2 Hz, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.68 (s, 3 H), 2.78-2.76 (comp, 4 H), 2.01 (t, J = 2.8 Hz, 1 H), 1.89 (dd, J = 8.2, 6.6 Hz, 1 H), 1.88 (ddd, J = 10.0, 4.8, 3.8 Hz, 1 H), 1.20 (dd, J = 13.5, 4.8 Hz, 1 H) 1.20 (ddd, J = 15.3, 11.4, 4.8 Hz, 1 H); 13C NMR (125 MHz) d 172.2, 170.2, 170.2, 132.6, 125.0, 78.8, 71.4, 57.2, 52.7, 51.7, 35.3, 23.7, 22.6, 20.8, 14.2; IR (CDCl3) 3287, 3007, 2955, 2848, 1765, 1738, 1714, 1462, 1385, 1293, 1199, 1073 cm-1; mass spectrum (CI) m/z 309.1343 [C16H21O6 (M+1) requires 309.1338] 309 (base), 277. NMR Assignments: 1H NMR (500 MHz) d 5.54 (ddd, J = 15.3, 6.1, 3.1 Hz, 1 H, C5-H), 5.47 (dd, J = 14.7, 7.2 Hz, 1 H, C6-H), 3.74 (s, 3 H, C13-H), 3.73 (s, 3 H, C13H), 3.68 (s, 3 H, C14-H), 2.78-2.76 (comp, 4 H, C7-C9-H), 2.01 (t, J = 2.8 Hz, 1 H, C11H), 1.89 (dd, J = 8.2, 6.6 Hz, 1 H, C2-H), 1.88 (ddd, J = 10.0, 4.8, 3.8 Hz, 1 H, C4-H), 1.20 (dd, J = 13.5, 4.8 Hz, 1 H, C3-H) 1.20 (ddd, J = 15.3, 11.4, 4.8 Hz, 1 H, C3-H); 13C NMR (125 MHz) d 172.2 (C1), 170.2 (C12), 170.2 (C12), 132.6 (C5), 125.0 (C6), 78.8 (C10), 71.4 (C11), 57.2 (C8), 52.7 (C13), 51.7 (C14), 35.3 (C9), 23.7 (C2), 22.6 (C7), 20.8 (C4), 14.2 (C3). O 4 1 2 3 5 OCO2Me 6 7 3.25 (E)-methyl 4-oxopent-2-enyl carbonate (3.25) (BLA-VIII-90). A steady stream of ozone was bubbled through a solution of 3.24 (1.0 g, 4.9 mmol) in CH2Cl2 (50 mL) at 78 C until the blue color of ozone persisted. O2 was then bubbled through the solution until the blue color dissipated, and PPh3 (1.9 g, 7.3 mmol) was then added in one portion. 308 The cooling bath was removed, and the resulting mixture was stirred for 12 h at room temperature. 1-Triphenylphosphranylidene-2-propanone (3.74 mg, 11.7 mmol) was added in one portion, and the reaction was stirred at room temperature for 12 h. The solution was concentrated under reduced pressure, and the crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to provide 570 mg (37%) of 3.25 as a clear, colorless oil: 1H NMR (400 MHz) d 6.76 (dt, J = 16.0, 4.8 Hz, 1 H), 6.30 (dt, J = 16.0, 2.0 Hz, 1 H), 4.83 (dd, J = 4.8, 2.0 Hz, 1 H), 3.83 (s, 3 H), 2.29 (s, 3 H); 13C NMR (100 MHz) d 197.2, 154.9, 138.8, 130.6, 65.6, 54.8, 27.1; IR (CDCl3) 3690, 2959, 2256, 1752, 1681, 1445, 1276, 1251, 973 cm-1; mass spectrum (CI) m/z 159.0658 [C7H11O4 (M+1) requires 159.0657] 241, 187, 159 (base), 139, 111. NMR Assignments: 1H NMR (400 MHz) d 6.76 (dt, J = 16.0, 4.8 Hz, 1 H, C4H), 6.30 (dt, J = 16.0, 2.0 Hz, 1 H, C3-H), 4.83 (dd, J = 4.8, 2.0 Hz, 1 H, C5-H), 3.83 (s, 3 H, C7-H), 2.29 (s, 3 H, C1-H); 13C NMR (100 MHz) d 197.2 (C2), 154.9 (C6), 138.8 (C4), 130.6 (C3), 65.6 (C5), 54.8 (C7), 27.1 (C1). 9 8 Si 2 1 3 4 5 6 7 OCO2Me 3.14h (E)-methyl 4-(triisopropylsilyl)penta-2,4-dienyl carbonate (3.14h) (BLA-VIII93). TIPSOTf (1.36 g, 1.20 mL, 4.40 mmol) was added dropwise to a solution of 3.25 (539 mg, 3.40 mmol) and Et3N (0.95 mL, 6.80 mmol) in CH2Cl2 (12 mL) at 0 C, and the resulting mixture was stirred for 2 h. The solution was diluted with saturated aqueous NaHCO3 (12 mL), and the layers were separated. The aqueous phase was extracted with 309 CH2Cl2 (3 x 12 mL), and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (8:1) to provide 930 mg (87%) of 3.14h as a clear, colorless oil: 1H NMR (400 MHz) d 6.17-6.07 (comp, 2 H), 4.71 (d, J = 4.8 Hz, 2 H), 4.36 (s, 1 H), 4.31 (s, 1 H), 3.79 (s, 3 H), 1.23 (app q, J = 6.8 Hz, 3 H), 1.10 (d, J = 6.8 Hz, 18 H); 13C NMR (100 MHz) d 155.4, 154.1, 131.9, 122.9, 95.8, 67.4, 54.5, 17.8, 12.6; IR (CHCl3) 2946, 2867, 1748, 1595, 1443, 1325, 1276, 1028 cm-1; mass spectrum (CI) m/z 314.1912 [C16H30O4Si (M+1) requires 314.1913] 315 (base), 239, 183. NMR Assignments: 1 H NMR (400 MHz) d 6.17-6.07 (comp, 2 H, C3-C4-H), 4.71 (d, J = 4.8 Hz, 2 H, C5-H), 4.36 (s, 1 H, C1-H), 4.31 (s, 1 H, C1-H), 3.79 (s, 3 H, C7-H), 1.23 (app q, J = 6.8 Hz, 3 H, C8-H), 1.10 (d, J = 6.8 Hz, 18 H, C9-H); 13C NMR (100 MHz) d 155.4 (C6), 154.1 (C2), 131.9 (C4), 122.9 (C3), 95.8 (C1), 67.4 (C5), 54.5 (C7), 17.8 (C9), 12.6 (C8). General procedure for the synthesis of allylic methyl carbonates. Methyl chloroformate (284 mg, 0.23 mL, 3.0 mmol) was added to a solution of allylic alcohol (1.0 mmol) and pyridine (237 mg, 0.24 mL, 3.0 mmol) in CH2Cl2 (5 mL) at 0 C. The cooling bath was removed, and the mixture was stirred for the indicated time at room temperature. The solution was then diluted with saturated aqueous NaCl (5 mL), and the layers were separated. The aqueous layer was extracted with Et2O (3 x 5 mL), and the combined organic fractions were washed with saturated aqueous NaHCO3 (5 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (ratios given) to provide the desired allylic carbonate. 310 7 6 1 H3CO2CO 2 3 4 5 3.14a trans-Carbonic acid methyl ester pent-2-enyl ester (3.14a) (BLA-III-283). Carbonate 3.14a was obtained in 100% yield (11.6 mmol scale) after 3 h at room temperature as a clear, colorless oil: 1H NMR (400 MHz) d 5.86 (dddt, J = 15.2, 6.0, 5.2, 1.2 Hz, 1 H), 5.57 (dtt, J = 15.2, 6.4, 1.6 Hz, 1 H), 4.57 (dd, J = 6.8, 0.8 Hz, 2 H), 3.78 (s, 3 H), 2.12-2.04 (comp, 2 H), 1.00 (t, J = 7.6 Hz, 3 H); 13C NMR (100 MHz) d 155.2, 138.4, 121.9, 68.4, 54.4, 25.1, 12.9; IR (CDCl3) 3052, 2985, 2304, 1749, 1442, 1421, 1273 cm-1; mass spectrum (CI) m/z 145.0868 [C7H13O3 (M+1) requires 145.0865] 145, 117 (base). NMR Assignments: 1H NMR (400 MHz) d 5.86 (dddt, J = 15.2, 6.0, 5.2, 1.2 Hz, 1 H, C2-H), 5.57 (dtt, J = 15.2, 6.4, 1.6 Hz, 1 H, C3-H), 4.57 (dd, J = 6.8, 0.8 Hz, 2 H, C1-H), 3.78 (s, 3 H, C7-H), 2.12-2.04 (comp, 2 H, C4-H), 1.00 (t, J = 7.6 Hz, 3 H, C5H); 13C NMR (100 MHz) d 155.2 (C6), 138.4 (C2), 121.9 (C3), 68.4 (C7), 54.4 (C1), 25.1 (C4), 12.9 (C5). 10 5 6 7 8 4 9 3 2 11 1 OCO2Me 3.14d Carbonic acid 1-cyclohexylallyl ester methyl ester (3.14d). (BLA-VI-62). Carbonate 3.14d was obtained in 50% yield (3.56 mmol scale) after 30 min at room 311 temperature as a clear, colorless oil after chromatography (pentane/Et2O = 5:1): 1H NMR (400 MHz) d 5.77 (dddd, J = 17.2, 10.4, 7.2, 1.2 Hz, 1 H), 5.27 (dd, J = 17.2, 0.8 Hz, 1 H), 5.23 (dd, J = 10.4, 0.8 Hz, 1 H), 4.85 (app t, J = 2.8 Hz, 1 H), 3.76 (d, J = 1.2 Hz, 3 H), 1.81-1.54 (comp, 6 H), 1.28-0.96 (comp, 5 H); 13C NMR (100 MHz) d 155.3, 134.5, 118.1, 83.2, 54.4, 41.3, 28.3, 28.2, 26.2, 25.8, 25.7; IR (CHCl3) 3022, 2932, 2855, 1744, 1443, 1274, 958, 909 cm-1; mass spectrum (CI) m/z 199.1334 [C11H19O3 (M+1) requires 199.1334] 199, 123 (base). NMR Assignments: 1H NMR (400 MHz) d 5.77 (dddd, J = 17.2, 10.4, 7.2, 1.2 Hz, 1 H, C2-H), 5.27 (dd, J = 17.2, 0.8 Hz, 1 H, C1-H), 5.23 (dd, J = 10.4, 0.8 Hz, 1 H, C1-H), 4.85 (app t, J = 2.8 Hz, 1 H, C3-H), 3.76 (d, J = 1.2 Hz, 3 H, C11-H), 1.81-1.54 (comp, 6 H), 1.28-0.96 (comp, 5 H); 13C NMR (100 MHz) d 155.3 (C10), 134.5 (C2), 118.1 (C1), 83.2 (C3), 54.4 (C11), 41.3 (C4), 28.3, 28.2, 26.2, 25.8, 25.7. 1 2 3 4 6 5 OCO2Me 7 8 3.14g Carbonic acid 3-cyclopropylallyl ester methyl ester (3.14g). (BLA-V-96). Carbonate 3.14g was obtained in 87% yield (3.84 mmol scale) after 3 h at room temperature as a clear, colorless oil after chromatography (pentane/Et2O = 10:1): 1 H NMR (400 MHz) d 5.67 (dt, J = 15.4, 6.8 Hz, 1 H), 5.33 (dd, J = 15.4, 8.9 Hz, 1 H), 4.55 (dd, J = 6.8, 1.0 Hz, 1 H), 3.77 (s, 3 H), 1.46-1.38 (m, 1 H), 0.75 (app ddt, J = 8.0, 6.4, 4.4, 4.4 Hz, 1 H), 0.41 (app ddt, J = 9.2, 6.4, 4.4, 4.4 Hz, 1 H); 13C NMR (100 MHz) d 155.6, 141.4, 120.5, 68.5, 54.5, 13.4, 6.8; IR (CDCl3) 3009, 2958, 2258, 1745, 1444, 312 1266 cm-1; mass spectrum (CI) m/z 156.0788 [C8H12O3 (M) requires 156.0786] 157, 81 (base). NMR Assignments: 1H NMR (400 MHz) d 5.67 (dt, J = 15.4, 6.8 Hz, 1 H, C5H), 5.33 (dd, J = 15.4, 8.9 Hz, 1 H, C4-H), 4.55 (dd, J = 6.8, 1.0 Hz, 1 H, C6-H), 3.77 (s, 3 H, C8-H), 1.46-1.38 (m, 1 H, C3-H), 0.75 (app ddt, J = 8.0, 6.4, 4.4, 4.4 Hz, 1 H, C1H), 0.41 (app ddt, J = 9.2, 6.4, 4.4, 4.4 Hz, 1 H, C2-H); 13C NMR (100 MHz) d 155.6 (C7), 141.4 (C4), 120.5 (C5), 68.5 (C6), 54.5 (C8), 13.4 (C3), 6.8 (C1,2). 7 6 2 1 3 4 5 H3CO2CO 3.14e cis-Carbonic acid methyl ester pent-2-enyl ester (3.14e) BLA-III-284. Carbonate 3.14e was obtained in 100% yield (5.8 mmol scale) after 3 h at room temperature as a clear, yellow oil: 1H NMR (400 MHz) d 5.67 (dddd, J = 10.4, 7.2, 6.0, 1.6 Hz, 1 H), 5.52 (dddd, J = 10.8, 7.2, 5.2, 1.6 Hz, 1 H), 4.68 (dd, J = 6.8, 0.8 Hz, 2 H), 3.78 (s, 3 H), 2.17-2.09 (m, 2 H), 1.00 (t, J = 7.6 Hz, 3 H); 13C NMR (100 MHz) d 155.4, 137.2, 121.8, 63.4, 54.5, 20.8, 13.9; IR (CDCl3) 3051, 2982, 2304, 1753, 1441, 1360, 1262 cm-1; mass spectrum (CI) m/z 145.0862 [C7H13O3 (M+1) requires 145.0865] 145, 117, 105, 80, 77 (base). NMR Assignments: 1 H NMR (400 MHz) d 5.67 (dddd, J = 10.4, 7.2, 6.0, 1.6 Hz, 1 H, C2-H), 5.52 (dddd, J = 10.8, 7.2, 5.2, 1.6 Hz, 1 H, C3-H), 4.68 (dd, J = 6.8, 0.8 Hz, 2 H, C1-H), 3.78 (s, 3 H, C7-H), 2.17-2.09 (m, 2 H, C4-H), 1.00 (t, J = 7.6 Hz, 3 H, C5-H); 13C NMR (100 MHz) d 155.4 (C6), 137.2 (C2), 121.8 (C3), 63.4 (C7), 54.5 (C1), 20.8 (C4), 13.9 (C5). 313 5 6 7 4 3 2 1 8 9 OCO2CH3 3.14f trans-Carbonic acid methyl ester 3-phenylallyl ester (3.14f) BLA-III-297. Carbonate 3.14f was obtained in 100% yield (3.73 mmol scale) after 3 h at room temperature as a clear, colorless oil: 1H NMR (400 MHz) d 7.36-7.20 (m, 5 H), 6.64 (br d, J = 16.0 Hz, 1 H), 6.26 (dt, J = 16.0, 6.0 Hz, 1 H), 4.75 (d, J = 6.4 Hz, 2 H), 3.76 (s, 3 H); 13C NMR (100 MHz) d 155.2, 135.7, 134.3, 128.3, 127.8, 126.3, 122.1, 68.2, 54.6; IR (CDCl3) 3051, 2984, 2304, 1746, 1442, 1421, 1272 cm-1; mass spectrum (CI) m/z 192.0778 [C11H12O3 (M+1) requires 192.0786] 192, 145, 117 (base). NMR Assignments: 1 H NMR (400 MHz) d 7.36-7.20 (m, 5 H, C5-C6-C7-H), 6.64 (br d, J = 16.0 Hz, 1 H, C3-H), 6.26 (dt, J = 16.0, 6.0 Hz, 1 H, C2-H), 4.75 (d, J = 6.4 Hz, 2 H, C1-H), 3.76 (s, 3 H, C9-H); 13C NMR (100 MHz) d 155.2 (C8), 135.7 (C4), 134.3 (C3), 128.3 (C6), 127.8 (C7), 126.3 (C5), 122.1 (C2), 68.2 (C9), 54.6 (C1). 5 3 4 2 1 6 7 OCO2CH3 3.14j Carbonic acid methyl ester 3-methyl-2-butenyl ester (3.14j) (BLA-II-176). Carbonate 3.14j was obtained in 95% yield (5.8 mmol scale) after 1.5 h at room temperature as a clear, colorless oil: 1H NMR (300 MHz) d 5.38 (dddt, J = 8.7, 6.0, 2.7, 1.2 Hz, 1 H), 4.63 (d, J = 7.5 Hz, 2 H), 3.78 (s, 3 H), 1.76 (s, 3 H), 1.73 (s, 3 H); 13C 314 NMR (62.5 MHz) d 155.6, 139.5, 117.9, 64.3, 54.2, 25.4, 17.6; mass spectrum (CI) m/z 144.0780 [C7H12O3 (M) requires 144.0786] 145, 137, 69 (base). NMR Assignments: 1H NMR (300 MHz) d 5.38 (dddt, J = 8.7, 6.0, 2.7, 1.2 Hz, 1 H, C2-H), 4.63 (d, J = 7.5 Hz, 2 H, C1-H), 3.78 (s, 3 H, C7-H), 1.76 (s, 3 H, C4-H), 1.73 (s, 3 H, C5-H); 13C NMR (62.5 MHz) d 155.6 (C6), 139.5 (C3), 117.9 (C2), 64.3 (C7), 54.2 (C1), 25.4 (C4), 17.6 (C5). 4 1 3 2 OCO2CH3 5 6 3.14k Carbonic acid but-2-ynyl ester methyl ester (3.14k) (BLA-IV-146). Carbonate 3.14k was obtained in 88% yield (14.3 mmol scale) after 6 h at room temperature as a clear, red oil: 1H NMR (400 MHz) d 4.69 (q, J = 2.4 Hz, 2 H), 3.79 (s, 3 H), 1.85 (t, J = 2.4 Hz, 3 H); 13C NMR (100 MHz) d 154.9, 83.5, 72.3, 55.7, 54.5, 3.1; IR (CDCl3) 2957, 2258, 1746, 1446, 1375, 1281, 1156, 947 cm-1; mass spectrum (CI) m/z 129.0553 [C6H9O3 (M+1) requires 129.0552] 129, 113, 105 (base). NMR Assignments: 1H NMR (400 MHz) d 4.69 (q, J = 2.4 Hz, 2 H, C1-H), 3.79 (s, 3 H, C6-H), 1.85 (t, J = 2.4 Hz, 3 H, C4-H); 13C NMR (100 MHz) d 154.9 (C5), 83.5 (C2), 72.3 (C3), 55.7 (C4), 54.5 (C6), 3.1 (C1). 315 7 1 2 3 4 8 5 OCO2CH3 6 3.14m Carbonic acid methyl ester 1-vinyl-3-butenyl ester (3.14m) (BLA-III-298). Carbonate 3.14m was obtained in 100% yield (5.1 mmol scale) after 3 h at room temperature as a clear, colorless oil: 1H NMR (400 MHz) d 5.81 (ddd, J = 17.6, 10.4, 6.8 Hz, 1 H), 5.75 (ddt, J = 17.2, 10.4, 6.8 Hz, 1 H), 5.31 (dt, J = 17.2, 1.2 Hz, 1 H), 5.22 (dt, J = 10.8, 1.2 Hz, 1 H), 5.15-5.09 (comp, 3H), 3.77 (s, 3 H), 2.44 (dddt, J = 13.6, 7.6, 7.2, 6.8 Hz, 2 H); 13C NMR (100 MHz) d 154.9, 135.1, 132.5, 118.1, 117.5, 77.9, 54.6, 38.8; IR (CDCl3) 3083, 2984, 2957, 2258, 1740, 1443, 1338, 1271, 1045 cm-1; mass spectrum (CI) m/z 157.0859 [C8H13O3 (M+1) requires 157.0865] 157, 115, 81 (base). NMR Assignments: 1H NMR (400 MHz) d 5.81 (ddd, J = 17.6, 10.4, 6.8 Hz, 1 H, C2-H), 5.75 (ddt, J = 17.2, 10.4, 6.8 Hz, 1 H, C5-H), 5.31 (dt, J = 17.2, 1.2 Hz, 1 H, C1-H), 5.22 (dt, J = 10.8, 1.2 Hz, 1 H, C1-H), 5.15-5.09 (comp, 3H, C6-C3-H), 3.77 (s, 3 H, C8-H), 2.44 (dddt, J = 13.6, 7.6, 7.2, 6.8 Hz, 2 H, C4-H); 13C NMR (100 MHz) d 154.9 (C7), 135.1 (C2), 132.5 (C5), 118.1 (C1), 117.5 (C6), 77.9 (C3), 54.6 (C8), 38.8 (C4). 2 1 3 4 5 6 7 OCO2CH3 8 9 3.14n Carbonic acid 1-butylallyl ester methyl ester (3.14n) (BLA-IV-59). Carbonate 3.14n was obtained in 69% yield (4.38 mmol scale) after 3 h at room temperature as a 316 clear, colorless oil after chromatography (pentane/Et2O = 5:1): 1 H NMR (400 MHz) d 5.79 (ddd, J = 17.2, 10.4, 6.8 Hz, 1 H), 5.28 (app dt, J = 17.6, 0.8 Hz, 1 H), 5.19 (app dt, J = 10.4, 1.2 Hz, 1 H), 5.04 (app dt, J = 13.2, 6.8 Hz, 1 H), 3.76 (s, 3 H), 1.75-1.66 (m, 1 H), 1.65-1.56 (m, 1 H), 1.38-1.29 (m, 4 H), 0.90 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz) d 154.9, 135.8, 116.9, 78.3, 54.3, 33.8, 27.0, 22.3, 13.8; IR (CDCl3) 2958, 2862, 2260, 1743, 1443, 1270 cm-1; mass spectrum (CI) m/z 173.1177 [C7H13O3 (M+1) requires 173.1178] 173, 97 (base). NMR Assignments: 1H NMR (400 MHz) d 5.79 (ddd, J = 17.2, 10.4, 6.8 Hz, 1 H, C2-H), 5.28 (app dt, J = 17.6, 0.8 Hz, 1 H, C1-H), 5.19 (app dt, J = 10.4, 1.2 Hz, 1 H, C1-H), 5.04 (app dt, J = 13.2, 6.8 Hz, 1 H, C3-H), 3.76 (s, 3 H, C9-H), 1.75-1.66 (m, 1 H, C4-H), 1.65-1.56 (m, 1 H, C4-H), 1.38-1.29 (m, 4 H, C5-C6-H), 0.90 (t, J = 7.2 Hz, 3 H, C7-H); 13C NMR (100 MHz) d 154.9 (C8), 135.8 (C2), 116.9 (C1), 78.3 (C3), 54.3 (C9), 33.8 (C4), 27.0 (C5), 22.3 (C6), 13.8 (C7). 6 4 5 3 2 1 7 OCO2CH3 3.14p trans-Carbonic acid methyl ester 1-methylbut-2-enyl ester (3.14p) (BLA-IV286). Carbonate 3.14p was obtained in 98% yield (34.6 mmol scale) after 3 h at room temperature as a clear, colorless oil after chromatography (pentane/Et2O = 5:1): 1H NMR (400 MHz) d 5.77 (ddd, J = 15.4, 6.8, 1.0 Hz, 1 H), 5.49 (ddq, J = 15.4, 7.2, 1.4 Hz, 1 H), 5.14 (app pent, J = 6.5 Hz, 1 H), 3.76 (s, 3 H), 1.70 (dd, J = 6.2, 1.4 Hz, 3 H), 1.34 (d, J = 6.5 Hz, 3 H); 13 C NMR (100 MHz) d 154.8, 129.9, 128.7, 75.2, 54.2, 20.3, 17.6; IR 317 (CHCl3) 3034, 2986, 1741, 1443, 1276 cm-1; mass spectrum (CI) m/z 145.0862 [C7H13O3 (M+1) requires 145.0865] 145, 137 (base). NMR Assignments: 1H NMR (400 MHz) d 5.77 (ddd, J = 15.4, 6.8, 1.0 Hz, 1 H, C4-H), 5.49 (ddq, J = 15.4, 7.2, 1.4 Hz, 1 H, C3-H), 5.14 (app pent, J = 6.5 Hz, 1 H, C2H), 3.76 (s, 3 H, C7-H), 1.70 (dd, J = 6.8, 1.4 Hz, 3 H, C5-H), 1.34 (d, J = 6.5 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 154.8 (C6), 129.9 (C3), 128.7 (C4), 75.2 (C2), 54.2 (C7), 20.3 (C1), 17.6 (C5). 11 2 3 4 5 7 1 8 6 9 12 OCO2Me 10 3.14r Carbonic acid 3-cyclohexyl-1-methylallyl ester methyl ester (3.14r). (BLAVI-100). Carbonate 3.14r was obtained in 86% yield (0.58 mmol scale) after 30 min at room temperature as a clear, colorless oil after chromatography (pentane/Et2O = 5:1): 1H NMR (400 MHz) d 5.69 (dd, J = 15.6, 6.4 Hz, 1 H), 5.42 (ddd, J = 15.6, 7.2, 1.2 Hz, 1 H), 5.15 (dq, J = 6.8, 6.4 Hz, 1 H), 3.76 (s, 3 H), 1.98-1.91 (m, 1 H), 1.73-1.62 (comp, 5 H), 1.34 (d, J = 6.8 Hz, 3 H), 1.31-1.01 (comp, 5 H); 13 C NMR (100 MHz) d 155.0, 139.7, 126.2, 75.6, 54.3, 40.1, 32.4, 32.4, 26.0, 25.9, 20.3; IR (CHCl3) 3018, 2928, 2853, 1742, 1444, 1275 cm-1; mass spectrum (CI) m/z 212.1412 [C12H20O3 (M) requires 212.1402] 213, 137 (base). NMR Assignments: 1H NMR (400 MHz) d 5.69 (dd, J = 15.6, 6.4 Hz, 1 H, C8H), 5.42 (ddd, J = 15.6, 7.2, 1.2 Hz, 1 H, C7-H), 5.15 (dq, J = 6.8, 6.4 Hz, 1 H, C9-H), 3.76 (s, 3 H, C12-H), 1.98-1.91 (m, 1 H, C1-H), 1.73-1.62 (comp, 5 H), 1.34 (d, J = 6.8 318 Hz, 3 H, C10-H), 1.31-1.01 (comp, 5 H); 13 C NMR (100 MHz) d 155.0 (C11), 139.7 (C7), 126.2 (C8), 75.6 (C9), 54.3 (C12), 40.1, 32.4, 32.4, 26.0, 25.9, 20.3 (C10). 11 2 3 4 5 1 6 7 8 12 9 OCO2CH3 10 3.14s (E)-1-cyclohexylbut-2-enyl methyl carbonate (3.14s) (BLA-IV-262). Carbonate 3.14s was obtained in 97% yield (0.65 mmol scale) after 6 h at room temperature as a clear, colorless oil after chromatography (pentane/Et2O = 5:1): 1 H NMR (400 MHz) d 5.75 (dq, J = 14.8, 6.4 Hz, 1 H), 5.41 (ddq, J = 14.8, 6.4, 1.6 Hz, 1 H), 4.78 (app t, J = 7.6 Hz, 1 H), 3.76 (s, 3 H), 1.81-1.63 (m, 5 H), 1.71 (dd, J = 6.4, 1.6 Hz, 3 H), 1.59-1.50 (m, 1 H), 1.27-1.11 (m, 3 H), 1.03-0.91 (m, 2 H); 13C NMR (100 MHz) d 155.3, 130.7, 127.6, 83.5, 54.3, 41.5, 28.5, 28.4, 26.2, 25.8, 25.7, 17.7; IR (CHCl3) 2931, 2360, 1741, 1442, 1275, 969 cm-1; mass spectrum (CI) m/z 213.1482 [C12H21O3 (M+1) requires 213.1491] 273 (base), 213. NMR Assignments: 1H NMR (400 MHz) d 5.75 (dq, J = 14.8, 6.4 Hz, 1 H, C9H), 5.41 (ddq, J = 14.8, 6.4, 1.6 Hz, 1 H, C8-H), 4.78 (app t, J = 7.6 Hz, 1 H, C7-H), 3.76 (s, 3 H, C12-H), 1.81-1.63 (m, 5 H), 1.71 (dd, J = 6.4, 1.6 Hz, 3 H, C10-H), 1.59-1.50 (m, 1 H, C1-H), 1.27-1.11 (m, 3 H), 1.03-0.91 (m, 2 H); 13C NMR (100 MHz) d 155.3 (C11), 130.7 (C13), 127.6 (C2), 83.5 (C4), 54.3 (C12), 41.5 (C5), 28.5 (CHex), 28.4 (CHex), 26.2 (CHex), 25.8 (CHex), 25.7 (CHex), 17.7 (C1). 319 9 6 7 8 5 4 3 10 OCO2Me 2 1 (+)-3.47 Carbonic acid methyl ester 1-methyl-3-phenylallyl ester ((+)-3.47) (BLA-VI79). Carbonate (+)-3.47 was obtained in 87% yield (1.34 mmol scale) after 30 min at room temperature as a clear, colorless oil after chromatography (pentane/Et2O = 5:1): 1H NMR (400 MHz) d 7.39-7.36 (m, 2 H), 7.32-7.27 (m, 2 H), 7.26-7.21 (m, 1 H), 6.64 (d, J = 16.0 Hz, 1 H), 6.19 (dd, J = 16.0, 7.2 Hz, 1 H), 5.37 (ddq, J = 7.2, 6.4, 1.2 Hz, 1 H), 3.76 (s, 3 H), 1.46 (d, J = 6.5 Hz, 3 H); 13C NMR (100 MHz) d 155.0, 136.0, 132.1, 128.4, 127.9, 127.8, 126.5, 75.1, 54.4, 20.3; IR (CHCl3) 3025, 2958, 1743, 1443, 1274, 1036, 967, 942 cm-1; mass spectrum (CI) m/z 206.0945 [C12H14O3 (M) requires 206.0943] 207, 131 (base). NMR Assignments: 1H NMR (400 MHz) d 7.39-7.36 (m, 2 H, CAR-H), 7.32-7.27 (m, 2 H, CAR-H), 7.26-7.21 (m, 1 H, C4-H), 6.64 (d, J = 16.0 Hz, 1 H, C4-H), 6.19 (dd, J = 16.0, 7.2 Hz, 1 H, C3-H), 5.37 (ddq, J = 7.2, 6.4, 1.2 Hz, 1 H, C2-H), 3.76 (s, 3 H, C10H), 1.46 (d, J = 6.5 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 155.0 (C9), 136.0 (C5), 132.1, 128.4, 127.9, 127.8, 126.5, 75.1 (C2), 54.4 (C10), 20.3 (C1). 320 10 3 7 8 9 6 5 4 2 11 1 OCO2Me 3.14t Carbonic acid methyl ester 1-phenylethynyl-allyl ester (3.14t) (BLA-VI-68). n-BuLi (9.1 mL, 2.34 M in hexanes) was added to a solution of phenylacetylene (2.19 g, 2.35 mL, 21.4 mmol) in THF (36 mL) at 78 C, and the resultant solution was stirred for 1 h. Acrolein (3.17) (1.00 g, 0.84 mL, 17.8 mmol) was added at 78 C, and stirred for 1 h. Methyl chloroformate (2.53 g, 2.1 mL, 26.7 mmol) was then added, the cooling bath was removed, and the resulting mixture was stirred at room temperature for 2 h. Et2O (10 mL) was added and the solution was washed sequentially with H2O (2 x 20 mL) and saturated aqueous NaCl (20 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. A 250 mg aliquot of the crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to provide 3.14t as a clear colorless oil: 1 H NMR (400 MHz) d 7.59-7.57 (m, 1 H), 7.48-7.42 (m, 2 H), 7.39-7.28 (m, 2 H), 6.06- 5.96 (comp, 2 H), 5.65 (dd, J = 16.4, 1.6 Hz, 1 H), 5.39 (dd, J = 9.6, 1.6 Hz, 1 H), 3.82 (s, 3 H); 13C NMR (100 MHz) d 154.7, 132.9, 131.8, 128.8, 128.5, 128.2, 119.5, 87.6, 83.5, 68.7, 54.9; IR (CHCl3) 3022, 2957, 2227, 1749, 1443, 1286, 941 cm-1; mass spectrum (CI) m/z 216.0781 [C13H12O3 (M) requires 216.0786] 217, 173, 161, 141 (base). NMR Assignments: 1 H NMR (400 MHz) d 7.59-7.57 (m, 1 H, C4-H, CAR-H), 7.48-7.42 (m, 2 H, CAR-H), 7.39-7.28 (m, 2 H, CAR-H), 6.06-5.96 (comp, 2 H, C9-C10-H), 5.65 (dd, J = 16.4, 1.6 Hz, 1 H, C11-H), 5.39 (dd, J = 9.6, 1.6 Hz, 1 H, C11-H), 3.82 (s, 3 H, C13-H); 13C NMR (100 MHz) d 154.7 (C12), 132.9 (C10), 131.8, 128.8, 128.5, 128.2, 119.5 (C11), 87.6 (C8), 83.5 (C7), 68.7 (C9), 54.9 (C13). 321 6 2 1 3 7 8 OCO2Me 4 5 3.14u Carbonic acid 1-ethynyl-1-methyl-allyl ester methyl ester (3.14u) (BLA-VI66). Ethynyl magnesium bromide (34 mL, 0.5 M in THF) was added to a solution of methyl vinyl ketone (1.00 g, 0.84 mL, 14.3 mmol) in THF (30 mL) at 78 C and stirred for 20 min. Methyl chloroformate (2.02 g, 1.65 mL, 21.4 mmol) was added to the dark brown solution at 78 C, the cooling bath was removed, and the mixture was stirred at room temperature for 4 h. Et2O (10 mL) was added, and the solution washed sequentially with H2O (2 x 20 mL) and saturated aqueous NaCl (20 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. A 250 mg aliquot of the crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to provide 3.14u as a clear colorless oil: 1H NMR (400 MHz) d 5.99 (dd, J = 17.1, 10.3 Hz, 1 H), 5.65 (d, J = 17.1 Hz, 1 H), 5.30 (d, J = 10.3 Hz, 1 H), 3.77 (s, 3 H), 2.73 (s, 1 H), 1.74 (s, 3 H); 13C NMR (100 MHz) d 153.3, 137.5, 116.8, 81.3, 76.1, 75.5, 54.4, 28.4; IR (CHCl3) 3306, 3027, 2958, 1755, 1442, 1275, 1059, 941, 886 cm-1; mass spectrum (CI) m/z 155.0703 [C8H11O3 (M+1) requires 155.0708] 187 (base), 155, 141, 111. NMR Assignments: 1H NMR (400 MHz) d 5.99 (dd, J = 17.1, 10.3 Hz, 1 H, C2H), 5.65 (d, J = 17.1 Hz, 1 H, C1-H), 5.30 (d, J = 10.3 Hz, 1 H, C1-H), 3.77 (s, 3 H, C8H), 2.73 (s, 1 H, C5-H), 1.74 (s, 3 H, C6-H); 13C NMR (100 MHz) d 153.3 (C7), 137.5 (C2), 116.8 (C1), 81.3 (C4), 76.1, 75.5, 54.4 (C8), 28.4 (C6). 322 General procedure for the [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical allylic carbonates with dimethyl malonate. [Rh(CO)2Cl]2 (19.0 mg, 5 mol %) was dissolved in the indicated degassed solvent (5 mL) and stirred for 5-10 min at room temperature. The allylic carbonate 3.14 (1.0 mmol) was added and the solution stirred for 30 min. In a separate flask, dimethyl malonate (330 mg, 0.29 mL, 2.5 mmol) was added to a slurry of NaH (40 mg of a 60% mineral oil suspension, 2.0 mmol) in the indicated degassed solvent (5 mL) and stirred for 20 min at room temperature. The resulting malonate anion was added via syringe to the solution of allylic substrate and [Rh(CO)2Cl]2 at room temperature. The mixture was then stirred for the indicated time at the indicated temperature. General Workup A: Saturated aqueous NaHCO3 (10 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL), and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. General Workup B: The reaction was filtered through a short plug of silica gel eluting with Et2O (50 mL), and the combined filtrate was concentrated under reduced pressure. General Workup C: Saturated aqueous NH4Cl (10 mL) was added, and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL), and the combined organic fractions were washed with saturated aqueous NaCl (10 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O to provide the alkylation products 3.15/3.16 in the specified ratio. 323 1 HO2C 5 7 8 H 2 4 3 H 6 H3CO2C CO2CH3 9 10 3.10 2-[3-[2R,3R]-(2-Carboxycyclopropyl)-allyl]-malonic acid dimethyl ester (3.10). (BLA-IV-61). Malonate 3.10 was obtained in 93% yield (0.40 mmol scale) after 1 h in THF at room temperature. Aqueous 1 M NaHSO4 (2.5 mL) was added to the reaction and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 3 mL) and the combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 96 mg (93%) of 3.10 as a clear, pale yellow oil: 1H NMR (400 MHz) d 5.64 (app dt, J = 15.2, 6.8 Hz, 1 H), 5.53 (dd, J = 15.6, 8.8 Hz, 1 H), 3.72 (s, 3 H), 3.71 (s, 3 H), 3.42 (t, J = 7.2 Hz, 1 H), 2.61 (app t, J = 7.2 Hz, 2 H), 1.96 (app dt, J = 8.8, 8.4 Hz, 1 H), 1.88 (ddd, J = 14.0, 8.0, 6.0 Hz, 1 H), 1.29-1.21 (m, 2 H); 13C NMR (100 MHz) d 177.9, 169.0, 129.7, 127.6, 52.5, 52.4, 51.8, 31.8, 24.7, 20.7, 15.0; IR (CDCl3) 3010, 2955, 2258, 1733, 1698, 1437, 1234, 1161 cm-1; mass spectrum (CI) m/z 257.1031 [C12H17O6 (M+1) requires 257.1025] 257, 239 (base), 207, 179. NMR Assignments: 1H NMR (400 MHz) d 5.64 (app dt, J = 15.2, 6.8 Hz, 1 H, C6-H), 5.53 (dd, J = 15.6, 8.8 Hz, 1 H, C5-H), 3.72 (s, 3 H, C11-H), 3.71 (s, 3 H, C12H), 3.42 (t, J = 7.2 Hz, 1 H, C8-H), 2.61 (app t, J = 7.2 Hz, 2 H, C7-H), 1.96 (app dt, J = 8.8, 8.4 Hz, 1 H, C2-H), 1.88 (ddd, J = 14.0, 8.0, 6.0 Hz, 1 H, C4-H), 1.29-1.21 (m, 2 H, C3-H); 13 C NMR (100 MHz) d 177.9 (C1), 169.0 (C9), 129.7 (C5), 127.6 (C6), 52.5 (C11), 52.4 (C12), 51.8 (C8), 31.8 (C7), 24.7 (C2), 20.7 (C4), 15.0 (C3). 324 4 5 6 3 2 1 H3CO2C 8 7 CO2CH3 3.15a trans-2-Pent-2-enylmalonic acid dimethyl ester (3.15a). (BLA-IV-120). Malonate 3.15a was obtained in 84% yield (0.34 mmol scale) after 2 h in THF at room temperature (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 98:2 regioisomeric ratio: 1H NMR (400 MHz) d 5.56 (dddt, J = 15.2, 6.8, 5.2, 1.6 Hz, 1 H), 5.34 (dddt, J = 15.2, 7.2, 5.2, 1.6 Hz, 1 H), 3.73 (s, 3 H), 3.41 (t, J = 7.6 Hz, 1 H), 2.58 (app dt, J = 8.0, 1.2 Hz, 2 H), 2.02-1.95 (m, 2 H), 0.94 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz) d 169.2, 135.5, 123.9, 52.4, 52.0, 31.9, 25.6, 13.8; IR (CDCl3) 2955, 1731, 1436, 1272, 1232, 1158 cm-1; mass spectrum (CI) m/z 201.1117 [C10H17O4 (M+1) requires 201.1127] 201 (base), 169. NMR Assignments: 1H NMR (400 MHz) d 5.56 (dddt, J = 15.2, 6.8, 5.2, 1.6 Hz, 1 H, C4-H), 5.34 (dddt, J = 15.2, 7.2, 5.2, 1.6 Hz, 1 H, C3-H), 3.73 (s, 3 H, C8-H), 3.41 (t, J = 7.6 Hz, 1 H, C6-H), 2.58 (app dt, J = 8.0, 1.2 Hz, 2 H, C5-H), 2.02-1.95 (m, 2 H, C2-H), 0.94 (t, J = 7.2 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 169.2 (C1), 135.5 (C4), 123.9 (C5), 52.4 (C8), 52.0 (C2), 31.9 (C3), 25.6 (C6), 13.8 (C7). 6 7 MeO2C 1 5 2 CO2Me 4 3 3.15b 2-(1-Methylallyl)-malonic acid dimethyl ester (3.15b) (BLA-V-203). Malonate 3.15b was obtained in 93% yield (0.38 mmol scale) after 3 h in DMF at 20 C (General 325 Workup C) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 80:20 regioisomeric ratio: 1H NMR is consistent with the assigned structure.385 11 12 6 7 8 9 5 10 4 3 2 1 MeO2C 5 6 7 8 4 9 10 3 CO2Me 1 2 11 12 CO2Me CO2Me 3.15d 3.16d 2-(1-Cyclohexylallyl)-malonic acid dimethyl ester (3.15d) (BLA-VI-64). Malonate 3.15d was obtained in 97% yield (0.25 mmol scale) after 24 h in THF at rt (General Workup B) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 79:21 regioisomeric ratio: Regioisomer 3.16d: 1H NMR (400 MHz) d 5.43 (dt, J = 15.6, 6.8 Hz, 1 H), 5.34-5.27 (m, 1 H), 3.73 (s, 6 H), 3.40 (t, J = 7.2 Hz, 1 H), 2.57 (ddd, J = 8.4, 7.2, 1.2 Hz, 2 H), 1.92-1.85 (m, 1 H), 1.71-1.62 (m, 4 H), 1.29-0.96 (m, 6 H); 13C NMR (100 MHz) d 169.4, 137.6, 122.6, 52.4, 52.0, 31.8, 13.4, 6.5; Regioisomer 3.15d: 1 H NMR (400 MHz) d 5.82 (ddd, J = 18.0, 10.0, 7.6 Hz, 1 H), 5.10-5.04 (comp, 2 H), 3.74 (s, 6 H), 3.54 (d, J = 8.8 Hz, 1 H), 2.12 (ddd, J = 17.6, 8.8, 8.8 Hz, 1 H), 0.87-0.84 (m, 1 H), 0.49 (ddd, J = 8.0, 2.8, 1.6 Hz, 2 H), 0.25-0.22 (m, 1 H), 0.15-0.11 (m, 1 H); IR (CHCl3) 2927, 2853, 2362, 1732, 1437, 1265, 1159 cm-1; mass spectrum (CI) m/z 213.1118 [C11H17O4 (M+1) requires 213.1127] 213 (base). NMR Assignments: Regioisomer 3.16d: 1 H NMR (400 MHz) d 5.43 (dt, J = 15.6, 6.8 Hz, 1 H, C4-H), 5.34-5.27 (m, 1 H, C3-H), 3.73 (s, 6 H, C12-H), 3.40 (t, J = 7.2 Hz, 1 H, C1-H), 2.57 (ddd, J = 8.4, 7.2, 1.2 Hz, 2 H, C2-H), 1.92-1.85 (m, 1 H, C5-H), 1.71-1.62 (m, 4 H, CHEX-H), 1.29-0.96 (m, 6 H, CHEX-H); 13C NMR (100 MHz) d 169.4 (C11), 140.1 (C4), 122.6 (C3), 52.4 (C12), 52.0 (C1), 40.5 (C5), 31.8 (C2), 31.9, 26.3, 326 26.0, 25.9; Regioisomer 3.15d: 1H NMR (400 MHz) d 5.82 (ddd, J = 18.0, 10.0, 7.6 Hz, 1 H, C2-H), 5.10-5.04 (comp, 2 H, C1-H), 3.74 (s, 6 H, C12-H), 3.54 (d, J = 8.8 Hz, 1 H, C10-H), 2.12 (ddd, J = 17.6, 8.8, 8.8 Hz, 1 H, C3-H). 8 7 6 4 H3CO2C H3CO2C 3 2 1 5 3.15e cis-2-Pent-2-enylmalonic acid dimethyl ester (3.15e). (BLA-IV-121). Malonate 3.15e was obtained in 86% yield (0.34 mmol scale) after 12 h in THF at 0 C (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 99:1 regioisomeric ratio and 97:3 cis/trans ratio: 1H NMR (400 MHz) d 5.58 (dddt, J = 10.4, 8.8, 7.2, 1.2 Hz, 1 H), 5.25 (dddt, J = 10.8, 9.2, 7.6, 2.0 Hz, 1 H), 3.73 (s, 6 H), 3.39 (t, J = 7.2 Hz, 1 H), 2.67-2.63 (m, 2 H), 2.11-2.03 (m, 2 H), 0.96 (t, J = 7.6 Hz, 3 H); 13C NMR (100 MHz) d 169.2, 134.8, 123.6, 52.5, 51.8, 26.7, 20.6, 14.2; IR (CDCl3) 2956, 2258, 1732, 1437, 1240, 1158 cm-1; mass spectrum (CI) m/z 201.1124 [C10H17O4 (M+1) requires 201.1127] 201 (base), 169. NMR Assignments: 1H NMR (400 MHz) d 5.58 (dddt, J = 10.4, 8.8, 7.2, 1.2 Hz, 1 H, C4-H), 5.25 (dddt, J = 10.8, 9.2, 7.6, 2.0 Hz, 1 H, C3-H), 3.73 (s, 6 H, C8-H), 3.39 (t, J = 7.2 Hz, 1 H, C6-H), 2.67-2.63 (m, 2 H, C5-H), 2.11-2.03 (m, 2 H, C2-H), 0.96 (t, J = 7.6 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 169.2 (C7), 134.8 (C4), 123.6 (C3), 52.5 (C8), 51.8 (C6), 26.7 (C5), 20.6 (C2), 14.2 (C1). 327 6 7 8 5 4 3 2 9 1 CO2CH3 10 CO2CH3 3.15f 2-(3-Phenylallyl)-malonic acid dimethyl ester (3.15f). (BLA-IV-212). Malonate 3.15f was obtained in 93% yield (0.26 mmol scale) after 2 h in THF at 0 C (General Workup A) as a clear, pale yellow oil after chromatography (pentane/Et2O = 5:1) in a 90:10 regioisomeric ratio: 1H NMR (400 MHz) d 7.35-7.19 (comp, 5 H), 6.48 (d, J = 15.6 Hz, 1 H), 6.14 (dt, J = 15.6, 7.2 Hz, 1 H), 3.75 (s, 6 H), 3.53 (t, J = 7.2 Hz, 1 H), 2.81 (ddd, J = 9.2, 7.6, 2.0 Hz, 2 H); 13C NMR (100 MHz) d 169.2, 132.9, 128.4, 127.4, 126.1, 52.5, 51.7, 32.3; IR (CDCl3) 3029, 2954, 2259, 1732, 1437, 1265, 1234, 1201, 1157 cm-1; mass spectrum (CI) m/z 249.1127 [C14H17O4 (M+1) requires 249.1127] 249 (base). NMR Assignments: 1 H NMR (400 MHz) d 7.35-7.19 (comp, 5 H, C6-C7-C8- H), 6.48 (d, J = 15.6 Hz, 1 H, C4-H), 6.14 (dt, J = 15.6, 7.2 Hz, 1 H, C3-H), 3.75 (s, 6 H, C10-H), 3.53 (t, J = 7.2 Hz, 1 H, C1-H), 2.81 (ddd, J = 9.2, 7.6, 2.0 Hz, 2 H, C2-H); 13C NMR (100 MHz) d 169.2 (C9), 132.9 (C5), 128.4, 127.4, 126.1, 52.5 (C10), 51.7 (C1), 32.3 (C2). 328 1 2 3 4 6 5 7 8 9 1 9 8 7 MeO2C CO2Me 2 3 CO2Me 4 5 6 MeO2C 3.15g 3.16g 2-(3-Cyclopropylallyl)-malonic acid dimethyl ester (3.15g) (BLA-V-131). Malonate 3.15g was obtained in 84% yield (0.32 mmol scale) after 20 h in THF at 0 C (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 89:11 regioisomeric ratio: Regioisomer 3.15g: 1H NMR (400 MHz) d 5.43 (dt, J = 15.6, 6.8 Hz, 1 H), 5.13-5.04 (comp, 1 H), 3.73 (s, 6 H), 3.40 (t, J = 7.2 Hz, 1 H), 2.57 (ddd, J = 8.4, 7.2, 1.2 Hz, 2 H), 1.37-1.28 (m, 1 H), 0.68-0.64 (m, 2 H), 0.33-0.29 (m, 2 H); 13C NMR (100 MHz) d 169.4, 137.6, 122.6, 52.4, 52.0, 31.8, 13.4, 6.5; Regioisomer 3.16g: 1H NMR (400 MHz) d 5.82 (ddd, J = 18.0, 10.0, 7.6 Hz, 1 H), 5.10-5.04 (comp, 2 H), 3.74 (s, 6 H), 3.54 (d, J = 8.8 Hz, 1 H), 2.12 (dt, J = 17.6, 8.8 Hz, 1 H), 0.87-0.84 (m, 1 H), 0.49 (ddd, J = 8.0, 2.8, 1.6 Hz, 2 H), 0.25-0.22 (m, 1 H), 0.15-0.11 (m, 1 H); IR (CHCl3) 3033, 2955, 1733, 1437, 1265, 1232, 1156, 909 cm-1; mass spectrum (CI) m/z 213.1118 [C11H17O4 (M+1) requires 213.1127] 213 (base). NMR Assignments: Regioisomer 3.15g: 1H NMR (400 MHz) d 5.43 (dt, J = 15.6, 6.8 Hz, 1 H, C5-H), 5.13-5.04 (comp, 1 H, C4-H), 3.73 (s, 6 H, C9-H), 3.40 (t, J = 7.2 Hz, 1 H, C7-H), 2.57 (ddd, J = 8.4, 7.2, 1.2 Hz, 2 H, C6-H), 1.37-1.28 (m, 1 H, C3H), 0.68-0.64 (m, 2 H, C1-H), 0.33-0.29 (m, 2 H, C2-H); 13C NMR (100 MHz) d 169.4 (C8), 137.6 (C4), 122.6 (C5), 52.4 (C9), 52.0 (C7), 31.8 (C6), 13.4 (C3), 6.5 (C1,2); Regioisomer 3.16g: 1H NMR (400 MHz) d 5.82 (ddd, J = 18.0, 10.0, 7.6 Hz, 1 H, C5H), 5.10-5.04 (comp, 2 H, C6-H), 3.74 (s, 6 H, C9-H), 3.54 (d, J = 8.8 Hz, 1 H, C7-H), 2.12 (dt, J = 17.6, 8.8 Hz, 1 H, C4-H), 0.87-0.84 (m, 1 H, C3-H), 0.49 (ddd, J = 8.0, 2.8, 1.6 Hz, 2 H, C1-H), 0.25-0.22 (m, 1 H, C2-H), 0.15-0.11 (m, 1 H, C2-H). 329 10 9 Si O 2 1 3 4 5 7 6 8 CO2CH3 CO2CH3 3.15h 2-[4-(Triisopropylsilanyloxy)-penta-2,4-dienyl]malonic acid dimethyl ester (3.15h). (BLA-VI-132). Malonate 3.15h was obtained in 94% yield (0.32 mmol scale) after 12 h in DMF at room temperature (General Workup B) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 97:3 regioisomeric ratio: 1H NMR (400 MHz) d 5.97-5.95 (comp, 2 H), 4.26 (s, 1 H), 4.21 (s, 1 H), 3.73 (s, 6 H), 3.46 (t, J = 7.6 Hz, 1 H), 2.70 (ddd, J = 7.6, 6.0, 3.2 Hz, 2 H), 1.21 (app q, J = 6.8 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 18 H); 13C NMR (100 MHz) d 169.2, 154.6, 130.9, 125.9, 94.4, 52.5, 51.6, 31.4, 18.0, 12.7; IR (CHCl3) 2948, 2868, 1734, 1592, 1437, 1320, 1286, 1158, 1026 cm-1; mass spectrum (CI) m/z 371.1904 [C18H31O6Si (M+1) requires 371.1890] 371, 215, 176, 159, 135 (base). NMR Assignments: 1H NMR (400 MHz) d 5.97-5.95 (comp, 2 H, C3-C4-H), 4.26 (s, 1 H, C1-H), 4.21 (s, 1 H, C1-H), 3.73 (s, 6 H, C8-H), 3.46 (t, J = 7.6 Hz, 1 H, C6-H), 2.70 (ddd, J = 7.6, 6.0, 3.2 Hz, 2 H, C5-H), 1.21 (app q, J = 6.8 Hz, 3 H, C9-H), 1.08 (d, J = 6.8 Hz, 18 H, C10-H); 13C NMR (100 MHz) d 169.2 (C7), 154.6 (C2), 130.9 (C4), 125.9 (C3), 94.4 (C1), 52.5 (C6), 51.6 (C8), 31.4 (C5), 18.0 (C10), 12.7 (C9). 330 5 2 1 3 6 4 7 CO2CH3 CO2CH3 3.15i 2-(2-Methylallyl)-malonic acid dimethyl ester (3.15i). (BLA-IV-52). Malonate 3.15i was obtained in 71% yield (0.38 mmol scale) after 1 h in THF at room temperature (General Workup A) as a clear, colorless oil: 1H NMR (400 MHz) d 4.75 (d, J = 0.8 Hz, 1 H), 4.72 (d, J = 0.8 Hz, 1 H), 3.73 (s, 6 H), 3.62 (t, J = 8.0 Hz, 1 H), 2.62 (d, J = 7.6 Hz, 2 H), 1.74 (s, 3 H); 13C NMR (100 MHz) d 169.2, 141.3, 112.2, 52.5, 50.3, 36.6, 22.3; IR (CDCl3) 2955, 2258, 1732, 1437, 1248, 1157 cm-1; mass spectrum (CI) m/z 187.0976 [C10H17O4 (M+1) requires 187.0970] 187, 155, 127 (base). NMR Assignments: 1H NMR (400 MHz) d 4.75 (d, J = 0.8 Hz, 1 H, C1-H), 4.72 (d, J = 0.8 Hz, 1 H, C1-H), 3.73 (s, 6 H, C7-H), 3.62 (t, J = 8.0 Hz, 1 H, C4-H), 2.62 (d, J = 7.6 Hz, 2 H, C3-H), 1.74 (s, 3 H, C5-H); 13C NMR (100 MHz) d 169.2 (C6), 141.3 (C2), 112.2 (C1), 52.5 (C7), 50.3 (C3), 36.6 (C5), 22.3 (C4). 1 3 2 4 5 7 6 8 CO2CH3 CO2CH3 3.15j 2-(3-Methylbut-2-enyl)-malonic acid dimethyl ester (3.15j). (BLA-IV-78). Malonate 3.15j was obtained in 75% yield (0.34 mmol scale) after 12 h in DMF at -20 C (General Workup C) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 92:8 regioisomeric ratio: 1H NMR (400 MHz) d 5.04 (app tt, J = 7.6, 1.2 Hz, 1 H), 3.73 (s, 6 H), 3.37 (t, J = 7.6 Hz, 1 H), 2.59 (app t, J = 7.6 Hz, 2 H), 1.68 (d, J = 1.2 Hz, 3 331 H), 1.63 (br s, 3 H); 13C NMR (100 MHz) d 169.3, 134.9, 119.3, 52.4, 51.9, 25.8, 17.8, 14.3; IR (CDCl3) 2977, 2874, 2258, 1732, 1436, 1337, 1247, 1152, 1111, 1043 cm-1; mass spectrum (CI) m/z 201.1125 [C10H17O4 (M+1) requires 201.1127] 201 (base), 169. NMR Assignments: 1H NMR (400 MHz) d 5.04 (app tt, J = 7.6, 1.2 Hz, 1 H, C4-H), 3.73 (s, 6 H, C8-H), 3.37 (t, J = 7.6 Hz, 1 H, C6-H), 2.59 (app t, J = 7.6 Hz, 2 H, C5-H), 1.68 (d, J = 1.2 Hz, 3 H, C1-H), 1.63 (br s, 3 H, C2-H); 13C NMR (100 MHz) d 169.3 (C7), 134.9 (C3), 119.3 (C4), 52.4 (C8), 51.9 (C6), 25.8 (C1), 17.8 (C5), 14.3 (C2). 2 1 5 CO2CH3 3 4 7 8 CO2CH3 6 3.15l 2-(1,1-Dimethylallyl)-malonic acid dimethyl ester (3.15l). (BLA-IV-92). Malonate 3.15l was obtained in 80% yield (0.34 mmol scale) after 4 h in THF at 0 C (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 94:6 regioisomeric ratio: 1H NMR (400 MHz) d 6.03 (dd, J = 17.2, 0.8 Hz, 1 H), 5.03 (dd, J = 17.2, 0.8 Hz, 1 H), 5.01 (dd, J = 11.2, 0.8 Hz, 1 H), 3.70 (s, 6 H), 3.37 (s, 1 H), 1.23 (s, 6 H); 13C NMR (100 MHz) d 168.0, 144.4, 112.2, 60.6, 52.0, 38.9, 25.2; IR (CDCl3) 2954, 2873, 2258, 1733, 1436, 1329, 1247, 1144, 1031 cm-1; mass spectrum (CI) m/z 201.1121 [C10H17O4 (M+1) requires 201.1127] 201 (base), 169, 141. NMR Assignments: 1H NMR (400 MHz) d 6.03 (dd, J = 17.2, 0.8 Hz, 1 H, C2H), 5.03 (dd, J = 17.2, 0.8 Hz, 1 H, C1-H), 5.01 (dd, J = 11.2, 0.8 Hz, 1 H, C1-H), 3.70 (s, 6 H, C8-H), 3.37 (s, 1 H, C4-H), 1.23 (s, 6 H, C5-C6-H); 13C NMR (100 MHz) d 168.0 (C7), 144.4 (C2), 112.2 (C1), 60.6 (C4), 52.0 (C8), 38.9 (C3), 25.2 (C5,C6). 332 2 1 3 7 4 5 6 H3CO2C 9 8 CO2CH3 3.15m 2-(1-Vinylbut-3-enyl)-malonic acid dimethyl ester (3.15m). (BLA-IV-68). Malonate 3.15m was obtained in 89% yield (0.32 mmol scale) after 1 h in THF at room temperature (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 91:9 regioisomeric ratio: 1H NMR (400 MHz) d 5.76-5.66 (m, 2 H), 5.10-4.99 (m, 4 H), 3.73 (s, 3 H), 3.69 (s, 3 H), 3.45 (d, J = 8.4 Hz, 1 H), 2.89 (app ddt, J = 14.0, 8.4, 4.8 Hz, 1 H), 2.27 (app dddt, J = 14.0, 8.4, 4.8, 0.8 Hz, 1 H), 2.16 (app dddt, J = 12.8, 8.0, 6.8, 0.8 Hz, 1 H); 13C NMR (100 MHz) d 168.4, 168.2, 137.3, 134.9, 117.2, 117.0, 55.7, 52.4, 52.3, 43.6, 36.9; IR (CDCl3) 3081, 2954, 2845, 2258, 1732, 1436, 1251, 1195, 1151 cm-1; mass spectrum (CI) m/z 213.1132 [C11H17O4 (M+1) requires 213.1127] 213 (base), 181. NMR Assignments: 1H NMR (400 MHz) d 5.76-5.66 (m, 2 H, C2-C5-H), 5.104.99 (m, 4 H, C1-C6-H), 3.73 (s, 3 H, C9-H), 3.69 (s, 3 H, C9-H), 3.45 (d, J = 8.4 Hz, 1 H, C7-H), 2.89 (app ddt, J = 14.0, 8.4, 4.8 Hz, 1 H, C4-H), 2.27 (app dddt, J = 14.0, 8.4, 4.8, 0.8 Hz, 1 H, C4-H), 2.16 (app dddt, J = 12.8, 8.0, 6.8, 0.8 Hz, 1 H, C3-H); 13C NMR (100 MHz) d 168.4 (C8), 168.2 (C8), 137.3 (C2), 134.9 (C5), 117.2 (C6), 117.0 (C1), 55.7 (C7), 52.4 (C9), 52.3 (C9), 43.6 (C4), 36.9 (C3). 333 2 3 1 8 4 5 6 7 H3CO2C 10 9 CO2CH3 3.15n 2-(1-Butylallyl)-malonic acid dimethyl ester (3.15n). (BLA-IV-216). Malonate 3.15n was obtained in 80% yield (0.20 mmol scale) after 4 h in THF at room temperature (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 57:43 regioisomeric ratio: 1H NMR (400 MHz) d 5.62 (ddd, J = 16.8, 10.0, 9.6 Hz, 1 H), 5.10-5.05 (comp, 2 H, C1-H), 3.73 (s, 3 H), 3.72 (s, 3 H), 3.38 (d, J = 8.4 Hz, 1 H), 2.75 (app ddt, J = 13.2, 9.2, 3.6 Hz, 1 H), 1.48-1.39 (m, 1 H), 1.33-1.16 (m, 5 H), 0.87 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz) d 168.5, 168.3, 137.9, 117.3, 56.9, 52.2, 52.0, 32.0, 31.5, 22.5, 14.0; IR (CDCl3) 2956, 2930, 2258, 1732, 1436, 1268, 1245, 1155 cm-1; mass spectrum (CI) m/z 229.1446 [C12H21O4 (M+1) requires 229.1440] 229 (base), 197, 169. NMR Assignments: 1H NMR (400 MHz) d 5.62 (ddd, J = 16.8, 10.0, 9.6 Hz, 1 H, C2-H), 5.10-5.05 (comp, 2 H, C1-H), 3.73 (s, 3 H, C10-H), 3.72 (s, 3 H, C10-H), 3.38 (d, J = 8.4 Hz, 1 H, C8-H), 2.75 (app ddt, J = 13.2, 9.2, 3.6 Hz, 1 H, C3-H), 1.48-1.39 (m, 1 H, C4-H), 1.33-1.16 (m, 5 H, C4-C5-C6-H), 0.87 (t, J = 7.2 Hz, 3 H, C7-H); 13C NMR (100 MHz) d 168.5 (C9), 168.3 (C9), 137.9 (C2), 117.3 (C1), 56.9 (C8), 52.2 (C10), 52.0 (C10), 32.0 (C3), 32.0 (C4), 31.5 (C5), 22.5 (C6), 14.0 (C7). 334 5 6 MeO2C 2 1 4 3 CO2Me 3.15o 2-(1-Vinylallyl)-malonic acid dimethyl ester (3.15o) (BLA-V-116). Malonate 3.15o was obtained in 74% yield (0.39 mmol scale) after 12 h in THF at 0 C (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 96:4 regioisomeric ratio: 1H NMR (400 MHz) d 5.84-5.75 (m, 2 H), 5.15-5.09 (m, 4 H), 3.71 (s, 6 H), 3.53-3.49 (comp, 2 H); 13C NMR (100 MHz) d 168.0, 136.4, 117.1, 56.2, 52.4, 47.5; IR (CHCl3) 3031, 2955, 1734, 1436, 1263, 1150, 1024, 928 cm-1; mass spectrum (CI) m/z 199.0962 [C10H15O4 (M+1) requires 199.0970] 199 (base), 65. NMR Assignments: 1H NMR (400 MHz) d 5.84-5.75 (m, 2 H, C2-H), 5.15-5.09 (m, 4 H, C1-H), 3.71 (s, 6 H, C6-H), 3.53-3.49 (comp, 2 H, C3-C4-H); 13 C NMR (100 MHz) d 168.0 (C5), 136.4 (C2), 117.1 (C1), 56.2 (C4), 52.4 (C6), 47.5 (C3). 7 H3CO2C 4 5 3 6 2 CO2CH3 1 8 3.15p 2-(1-Methylbut-2-enyl)-malonic acid dimethyl ester (3.15p). (BLA-IV-85). Malonate 3.15p was obtained in 89% yield (0.34 mmol scale) after 1 h in THF at room temperature and an additional 1 h at reflux (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1): 1H NMR (400 MHz) d 5.51 (ddd, J = 15.6, 6.5, 1.7 Hz, 1 H), 5.33 (ddq, J = 15.6, 8.4, 1.2 Hz, 1 H), 3.72 (s, 3 H), 3.69 (s, 3 H), 3.26 335 (d, J = 9.2 Hz, 1 H), 2.94-2.84 (m, 1 H), 1.63 (dd, J = 6.5, 1.7 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz) d 168.6, 168.5, 132.0, 126.1, 57.9, 52.3, 52.2, 37.4, 18.6, 17.9; IR (CHCl3) 3026, 2954, 1732, 1436, 1250, 1149 cm-1; mass spectrum (CI) m/z 201.1123 [C10H17O4 (M+1) requires 201.1127] 201 (base), 169. NMR Assignments: 1H NMR (400 MHz) d 5.51 (ddd, J = 15.6, 6.5, 1.7 Hz, 1 H, C3-H), 5.33 (ddq, J = 15.6, 8.4, 1.2 Hz, 1 H, C4-H), 3.72 (s, 3 H, C8-H), 3.69 (s, 3 H, C8-H), 3.26 (d, J = 9.2 Hz, 1 H, C6-H), 2.94-2.84 (m, 1 H, C2-H), 1.63 (dd, J = 6.5, 1.7 Hz, 3 H, C5-H), 1.06 (d, J = 6.8 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 168.6 (C7), 168.5 (C7), 132.0 (C3), 126.1 (C4), 57.9 (C6), 52.3 (C8), 52.2 (C8), 37.4 (C2), 18.6 (C5), 17.9 (C1). 13 6 7 8 9 5 4 12 11 2 3 1 MeO2C CO2Me 10 3.15r/3.16s 2-(3-Cyclohexyl-1-methylallyl)-malonic acid dimethyl ester (3.15r) (BLA-VI104). Malonate 3.15r was obtained in 94% yield (0.23 mmol scale) after 24 h in THF at 0 C (General Workup B) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 93:7 regioisomeric ratio: 1H NMR (400 MHz) d 5.43 (dd, J = 15.6, 6.8 Hz, 1 H), 5.26 (ddd, J = 15.6, 8.4, 0.8 Hz, 1 H), 3.73 (s, 3 H), 3.68 (s, 3 H), 3.26 (d, J = 9.6 Hz, 1 H), 2.87 (ddq, J = 10.0, 9.6, 6.8 Hz, 1 H), 1.19-1.84 (m, 1 H), 1.71-1.61 (comp, 5 H), 1.28-0.99 (comp, 5 H), 1.05 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz) d 168.8, 168.7, 137.8, 128.5, 58.2, 52.2, 52.1, 40.5, 37.6, 33.0, 32.9, 26.1, 25.9, 22.3, 18.7; IR (CDCl3) 336 3692, 2927, 2852, 2257, 1732, 1602, 1436, 1250, 1196, 1153, 1022, 971 cm-1; mass spectrum (CI) m/z 269.1765 [C15H25O4 (M+1) requires 269.1753] 269 (base). NMR Assignments: 1H NMR (400 MHz) d 5.43 (dd, J = 15.6, 6.8 Hz, 1 H, C3H), 5.26 (ddd, J = 15.6, 8.4, 0.8 Hz, 1 H, C4-H), 3.73 (s, 3 H, C13-H), 3.68 (s, 3 H, C13H), 3.26 (d, J = 9.6 Hz, 1 H, C11-H), 2.87 (ddq, J = 10.0, 9.6, 6.8 Hz, 1 H, C2-H), 1.191.84 (m, 1 H, C5-H), 1.71-1.61 (comp, 5 H, C6-C7-C8-C9-Heq), 1.28-0.99 (comp, 5 H, C6-C7-C8-C9-Hax), 1.05 (d, J = 6.8 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 168.8 (C12), 168.7 (C12), 137.8 (C3), 128.5 (C4), 58.2 (C11), 52.2 (C13), 52.1 (C13), 40.5 (C5), 37.6, 33.0, 32.9, 26.1, 25.9, 22.3, 18.7, (C1). 2 1 5 3 6 4 5 6 4 3 7 2 1 MeO2C CO2Me 7 8 MeO2C CO2Me 8 3.15 3.16 Dimethyl 2-(pent-1-en-4-yn-3-yl)malonate (3.15/3.16) (BLA-V-130). Malonates 3.15/3.16 were obtained in 91% yield (0.35 mmol scale) after 20 h in DMF at room temperature (General Workup B) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 53:47 regioisomeric ratio: 3.15 1 H NMR (500 MHz) d 5.83 (ddd, J = 18.0, 10.5, 6.5 Hz, 1 H), 5.44 (dt, J = 18.0, 1.0 Hz, 1 H), 5.22 (dt, J = 10.5, 1.0 Hz, 1 H), 3.89-3.85 (m, 1 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.57 (d, J = 9.0 Hz, 1 H), 2.29 (d, J = 2.5 Hz, 1 H); 13C NMR (125 MHz) d 167.4, 167.2, 133.2, 118.5, 80.9, 73.0, 56.6, 50.9, 32.0; 3.16: 1H NMR (500 MHz) d 6.16 (dt, J = 16.0, 7.5 Hz, 1 H), 5.57 (ddt, J = 16.0, 2.0, 1.5 Hz, 1 H), 3.75 (s, 6 H), 3.45 (t, J = 7.5 Hz, 1 H), 2.83 (dd, J = 2.0, 0.5 Hz, 1 337 H), 2.70 (ddd, J = 9.0, 8.0, 0.5 Hz, 2 H); 13C NMR (125 MHz) d 168.8, 140.9, 111.9, 81.6, 77.1, 52.7, 52.7, 35.2; IR (CDCl3) 3307, 1737, 1436, 1264, 1196, 1166, 1029, 988 cm-1; mass spectrum (CI) m/z 197.0813 [C10H13O4 (M+1) requires 197.0814] 197 (base). NMR Assignments: 3.15: 1H NMR (500 MHz) d 5.83 (ddd, J = 18.0, 10.5, 6.5 Hz, 1 H, C2-H), 5.44 (dt, J = 18.0, 1.0 Hz, 1 H, C1-H), 5.22 (dt, J = 10.5, 1.0 Hz, 1 H, C1-H), 3.89-3.85 (m, 1 H, C3-H), 3.77 (s, 3 H, C8-H), 3.74 (s, 3 H, C8-H), 3.57 (d, J = 9.0 Hz, 1 H, C6-H), 2.29 (d, J = 2.5 Hz, 1 H, C5-H); 13C NMR (125 MHz) d 167.4 (C7), 167.2 (C7), 133.2 (C2), 118.5 (C1), 80.9 (C4), 73.0 (C5), 56.6 (C8), 50.9 (C8), 32.0 (C6); 3.16: 1H NMR (500 MHz) d 6.16 (dt, J = 16.0, 7.5 Hz, 1 H, C2-H), 5.57 (ddt, J = 16.0, 2.0, 1.5 Hz, 1 H, C3-H), 3.75 (s, 6 H, C8-H), 3.45 (t, J = 7.5 Hz, 1 H, C6-H), 2.83 (dd, J = 2.0, 0.5 Hz, 1 H, C1-H), 2.70 (ddd, J = 9.0, 8.0, 0.5 Hz, 2 H, C5-H); 13C NMR (125 MHz) d 168.8 (C7), 140.9 (C3), 111.9 (C4), 81.6 (C2), 77.1 (C1), 52.7 (C8), 52.7 (C6), 35.2 (C5). 10 MeO2C 6 7 8 5 4 3 9 CO2Me 11 1 2 (+)-3.48 2-(1-Methyl-3-phenylallyl)-malonic acid dimethyl ester ((+)-4.48) (BLA-VI116). Malonate (+)-4.48 was obtained in 93% yield (0.24 mmol scale) after 24 h in DMF at room temperature (General Workup C) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 93:7 regioisomeric ratio: 1 H NMR (400 MHz) d 7.34-7.26 (comp, 4 H), 7.21 (tt, J = 6.4, 1.2 Hz, 1 H), 6.45 (d, J = 15.7 Hz, 1 H), 6.12 (dd, J = 15.7, 8.5 Hz, 1 H), 3.75 (s, 3 H), 3.67 (s, 3 H), 3.40 (d, J = 8.9 Hz, 1 H), 3.17-3.08 (m, 1 H), 338 1.19 (d, J = 6.8 Hz, 3 H); 13 C NMR (100 MHz) d 168.6, 168.5, 137.0, 131.1, 130.8, 128.4, 127.3, 126.2, 57.7, 52.4, 52.3, 37.7, 18.4; IR (CDCl3) 3692, 2955, 2257, 1733, 1601, 1436, 1249, 1195, 1165 cm-1; mass spectrum (CI) m/z 263.1284 [C15H19O4 (M+1) requires 263.1283] 263 (base), 131; HPLC (Chiracel AD column, hexanes/isopropanol = 98:2, flow = 0.5 mL/min) 24[a]D = +38.1 (c = 1.0, CHCl3). NMR Assignments: 1 H NMR (400 MHz) d 7.34-7.26 (comp, 4 H, C6-C7-H), 7.21 (tt, J = 6.4, 1.2 Hz, 1 H, C8-H), 6.45 (d, J = 15.7 Hz, 1 H, C4-H), 6.12 (dd, J = 15.7, 8.5 Hz, 1 H, C3-H), 3.75 (s, 3 H, C11-H), 3.67 (s, 3 H, C11-H), 3.40 (d, J = 8.9 Hz, 1 H, C9-H), 3.17-3.08 (m, 1 H, C2-H), 1.19 (d, J = 6.8 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 168.6 (C10), 168.5 (C10), 137.0 (C5), 131.1, 130.8, 128.4, 127.3, 126.2, 57.7 (C9), 52.4 (C11), 52.3 (C11), 37.7 (C2), 18.4 (C1). 3 1 8 2 4 5 6 MeO2CO 7 3.70 (Z)-hex-3-en-2-yl methyl carbonate (3.70) (BLA-VI-187). Hex-3-yn-2-ol (3.68) (500 mg, 5.09 mmol) was added to a slurry of Lindlar s catalyst (25 mg) and quinoline (24 mL, 0.20 mmol) in EtOAc (2.5 mL) at room temperature. The reaction flask was then flushed with H2, and the slurry was stirred vigorously under an atmosphere of H2 (balloon) for 3 h. The mixture was filtered through celite, the filter cake was washed with EtOAc (50 mL), and the combined filtrate and washings were concentrated under reduced pressure. The crude residue was dissolved in CH2Cl2 (20 mL) and cooled to 0 C, whereupon pyridine (1.21 g, 1.24 mL, 15.3 mmol) and methyl chloroformate (1.44 g, 339 1.20 mL, 15.3 mmol) were added sequentially. The cooling bath was removed, and the resulting solution was stirred for 2 h at room temperature. Saturated aqueous NaCl (20 mL) was added, and the layers separated. The aqueous layer was extracted with Et2O (3 x 20 mL), and the combined organic fractions were washed with saturated aqueous NaHCO3 (20 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to provide 459 mg (57%) of 3.70 as a clear, colorless oil: 1H NMR (400 MHz) d 5.56-5.47 (comp, 2 H), 5.36 (ddt, J = 10.8, 8.8, 1.6 Hz, 1 H), 3.76 (s, 3 H), 2.23-2.09 (m, 1 H), 1.34 (d, J = 6.8 Hz, 3 H), 1.00 (t, J = 7.6 Hz, 3 H); 13C NMR (100 MHz) d 155.0, 135.0, 128.0, 70.9, 54.3, 20.9, 20.7, 14.0; IR (CHCl3) 3024, 2983, 1746, 1443, 1345, 1319, 1272, 1170, 1051, 943, 867 cm-1. NMR Assignments: 1 H NMR (400 MHz) d 5.56-5.47 (comp, 2 H, C4-C5-H), 5.36 (ddt, J = 10.8, 8.8, 1.6 Hz, 1 H, C3-H), 3.76 (s, 3 H, C8-H), 2.23-2.09 (m, 1 H, C2H), 1.34 (d, J = 6.8 Hz, 3 H, C6-H), 1.00 (t, J = 7.6 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 155.0 (C7), 135.0 (C4), 128.0 (C3), 70.9 (C5), 54.3 (C8), 20.9 (C2), 20.7 (C6), 14.0 (C1). 3 1 2 7 MeO2C 8 4 5 6 9 CO2Me 3.71 (Z)-dimethyl 2-(hex-3-en-2-yl)malonate (3.71) (BLA-VI-265). Malonate 3.71 was obtained after 24 h in THF at room temperature (General Workup B) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a >95:5 regioisomeric ratio 340 and cis/trans ratio of 75:25: cis-isomer: 1H NMR (400 MHz) d 5.38 (dt, J = 11.2, 7.2 Hz, 1 H), 5.19-5.13 (m, 1 H), 3.74 (s, 3 H), 3.68 (s, 3 H), 3.26-3.24 (m, 1 H), 2.16-2.03 (m, 2 H), 1.04 (d, J = 6.4 Hz, 3 H), 0.96 (d, J = 7.6 Hz, 3 H). trans-isomer: 1H NMR (400 MHz) d 5.54 (dt, J = 15.6, 5.6 Hz, 1 H), 5.31 (ddt, J = 15.6, 8.8, 1.2 Hz, 1 H), 3.73 (s, 3 H), 3.67 (s, 3 H); 13C NMR (100 MHz) d 168.8, 132.9, 130.2, 57.9, 53.4, 32.5, 25.1, 19.2, 14.3; IR (CDCl3) 2955, 2258, 1754, 1732, 1436, 1265, 1196, 1144 cm-1; mass spectrum (CI) m/z 215.1290 [C11H19O4 (M+1) requires 215.1283] 215 (base), 201. NMR Assignments: cis-isomer: 1H NMR (400 MHz) d 5.38 (dt, J = 11.2, 7.2 Hz, 1 H, C4-H), 5.19-5.13 (m, 1 H, C3-H), 3.74 (s, 3 H, C9-H), 3.68 (s, 3 H, C11-H), 3.26-3.24 (m, 1 H, C5-C7-H), 2.16-2.03 (m, 2 H, C2-H), 1.04 (d, J = 6.4 Hz, 3 H, C6-H), 0.96 (d, J = 7.6 Hz, 3 H, C1-H). trans-isomer: 1H NMR (400 MHz) d 5.54 (dt, J = 15.6, 5.6 Hz, 1 H, C4-H), 5.31 (ddt, J = 15.6, 8.8, 1.2 Hz, 1 H, C3-H), 3.73 (s, 3 H, C9-H), 3.67 (s, 3 H, C11-H). O 6 7 8 9 5 10 4 3 2 1 3.27 4-Cyclohexyl but-3-en-2-one (3.27). (BLA-VI-95). Diethyl (2-oxopropyl)- phosphonate (495 mg, 0.5 mL, 2.54 mmol) was added to a slurry of NaH (97 mg of a 60% mineral oil suspension, 2.4 mmol) in THF (6.4 mL) at 0 C, and stirred for 1 h. Cyclohexyl carboxaldehyde (3.26) (143 mg, 0.15 mL, 1.29 mmol) was then added dropwise, the cooling bath was removed, and the resulting solution stirred for an additional 1.5 h at room temperature. H2O (5 mL) was added and the layers were 341 separated. The aqueous phase was extracted with Et2O (3 x 5 mL), and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to give 182 mg (94%) of 3.27 as a clear, colorless oil: 1H NMR (400 MHz) d 6.73 (dd, J = 16.0, 6.8 Hz, 1 H), 6.02 (dd, J = 16.0, 1.2 Hz, 1 H), 2.25 (s, 3 H), 2.17-2.11 (m, 1 H), 1.79-1.67 (comp, 5 H), 1.36-1.11 (comp, 5 H); 13 C NMR (100 MHz) d 198.9, 153.2, 128.6, 40.4, 31.6, 26.7, 25.7, 25.5; IR (CHCl3) 3016, 2930, 2854, 1669, 1621, 1450, 1359, 1265, 980 cm-1; mass spectrum (CI) m/z 153.1270 [C10H17O1 (M+1) requires 153.1279] 305, 185, 153 (base), 65. NMR Assignments: 1H NMR (400 MHz) d 6.73 (dd, J = 16.0, 6.8 Hz, 1 H, C4H), 6.02 (dd, J = 16.0, 1.2 Hz, 1 H, C3-H), 2.25 (s, 3 H, C1-H), 2.17-2.11 (m, 1 H, C5H), 1.79-1.67 (comp, 5 H, C6-C7-C8-C9-Heq), 1.36-1.11 (comp, 5 H, C6-C7-C8-C9-Hax); 13 C NMR (100 MHz) d 198.9 (C2), 153.2 (C4), 128.6 (C3), 40.4 (C5), 31.6 (C6,C10), 26.7 (C8), 25.7 (C7,C9), 25.5 (C1). OH 6 7 8 9 5 10 4 3 2 1 3.28 4-Cyclohexyl but-3-en-2-ol (3.28). (BLA-VI-98). Enone 3.27 (100 mg, 0.65 mmol) was added to a slurry of LiAlH4 (25 mg, 0.65 mmol) in Et2O (6 mL) at 0 C and the resulting mixture was stirred for 1 h. Saturated aqueous NH4Cl (5 mL) was added and the reaction allowed to warm to room temperature by removal of the cooling bath. The layers were separated and the aqueous phase was extracted with Et2O (3 x 5 mL). 342 The combined organic fractions were dried (MgSO4) and concentrated under reduced pressure to afford 93 mg (94%) of 3.28 as a clear, colorless oil: 1H NMR (400 MHz) d 5.58 (ddd, J = 15.2, 6.4, 0.8 Hz, 1 H), 5.46 (ddd, J = 15.2, 6.4, 1.2 Hz, 1 H), 4.24 (app dq, J = 6.8, 6.0 Hz, 1 H), 1.97-1.89 (m, 1 H), 1.75-1.62 (comp, 5 H), 1.38 (s, 1 H), 1.32-1.01 (comp, 5 H), 1.25 (d, J = 6.0 Hz, 3 H); 13C NMR (100 MHz) d 136.7, 131.5, 68.9, 40.1, 32.8, 32.7, 26.0, 25.9, 23.4; IR (CDCl3) 3692, 3606, 2927, 2853, 2250, 1602, 1449, 1374, 1250, 1044, 972 cm-1; mass spectrum (CI) m/z 155.1431 [C10H19O (M+1) requires 155.1436] 155, 153, 137 (base). NMR Assignments: 1H NMR (400 MHz) d 5.58 (ddd, J = 15.2, 6.4, 0.8 Hz, 1 H, C3-H) 5.46 (ddd, J = 15.2, 6.4, 1.2 Hz, 1 H, C4-H), 4.24 (app dq, J = 6.8, 6.0 Hz, 1 H, C2-H), 1.97-1.89 (m, 1 H, C5-H), 1.75-1.62 (comp, 5 H, C6-C7-C8-C9-C10-Heq), 1.38 (s, 1 H, O-H), 1.32-1.01 (comp, 5 H, C6-C7-C8-C9-C10-Hax), 1.25 (d, J = 6.0 Hz, 3 H, C1H); 13C NMR (100 MHz) d 136.7 (C4), 131.5 (C3), 68.9 (C2), 40.1 (C5), 32.8, 32.7, 26.0, 25.9, 23.4 (C1). 12 11 6 7 8 9 5 10 4 3 2 1 13 CO2Me 3.49 5-Cyclohexyl-3-methyl pent-4-enoic acid methyl ester (3.49) (BLA-V-244). H2O (1 drop) was added to a solution of malonate (+)-3.16s (47 mg, 0.18 mmol) and NaCl (21 mg, 0.35 mmol) in DMSO (2 mL) at room temperature. The reaction was immersed in an oil bath preheated to 140 C (bath temperature), and the mixture stirred for 24 h. The reaction was allowed to cool to room temperature, H2O (50 mL) was 343 added, and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 25 mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to give 3.49 as a clear, colorless oil: 1H NMR (400 MHz) d 5.37 (dd, J = 15.4, 6.2 Hz, 1 H), 5.27 (ddd, J = 15.4, 7.2, 1.0 Hz, 1 H), 3.64 (s, 3 H), 2.64-2.57 (m, 1 H), 2.29 (dd, J = 14.5, 7.2 Hz, 1 H), 2.24 (dd, J = 14.5, 7.4 Hz, 1 H), 1.91-1.84 (m, 1 H), 1.71-1.59 (comp, 5 H), 1.29-0.98 (comp, 5 H), 1.01 (d, J = 6.8, 3 H); 13C NMR (100 MHz) d 173.2, 135.6, 131.4, 51.3, 42.0, 40.6, 33.8, 33.2, 26.2, 26.1, 20.5; IR (CHCl3) 2926, 2852, 1731, 1436, 1350, 1287, 1208, 1171, 970 cm-1; mass spectrum (CI) m/z 211.1692[C13H23O2 (M+1) requires 211.1698] 211 (base). NMR Assignments: 1H NMR (400 MHz) d 5.37 (dd, J = 15.4, 6.2 Hz, 1 H, C4H), 5.27 (ddd, J = 15.4, 7.2, 1.0 Hz, 1 H, C3-H), 3.64 (s, 3 H, C13-H), 2.64-2.57 (m, 1 H, C2-H), 2.29 (dd, J = 14.5, 7.2 Hz, 1 H, C11-H), 2.24 (dd, J = 14.5, 7.4 Hz, 1 H, C11-H), 1.91-1.84 (m, 1 H, C5-H), 1.71-1.59 (comp, 5 H, C6-C7-C8-C9-C10-Heq), 1.29-0.98 (comp, 5 H, C6-C7-C8-C9-C10-Hax), 1.01 (d, J = 6.8 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 173.2 (C12), 135.6 (C3), 131.4 (C4), 51.3 (C13), 42.0 (C11), 40.6 (C5), 33.8, 33.2, 26.2, 26.1, 20.5 (C1). 344 6 5 4 2 MeO2C 1 O 3 7 O 8 9 10 11 12 13 14 N O 3.54 (3R)-4-[(4R)-4-Benzyl-2-oxo-oxazolidin-3-yl]-3-methyl-4-oxobutyric acid methyl ester (3.54). (BLA-VI-93). NaHMDS (1.29 mL, 1.0 M in THF) was added to a solution of imide 3.53 (200 mg, 0.85 mmol) in THF (9 mL) at 78 C, and the resulting solution was stirred for 1.5 h. Methyl bromoacetate (262 mg, 0.16 mL, 1.7 mmol) was then added dropwise at 78 C, the cooling bath was removed, and the reaction stirred at room temperature for 24 h. Saturated aqueous NH4Cl (10 mL) was added, and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL), and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexane/EtOAc (2:1) to give 182 mg (71%) of 3.54 as a clear, colorless oil: 1H NMR (400 MHz) d 7.367.32 (comp, 2 H), 7.29-7.25 (comp, 3 H), 4.68 (app ddt, J = 9.6, 7.2, 3.6 Hz, 1 H), 4.224.15 (comp, 3 H), 3.67 (s, 3 H), 3.33 (dd, J = 13.2, 3.6 Hz, 1 H), 2.95 (dd, J = 16.8, 10.4 Hz, 1 H), 2.76 (dd, J = 13.2, 10.4 Hz, 1 H), 2.47 (dd, J = 16.8, 4.4 Hz, 1 H), 1.23 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz) d 175.9, 172.2, 152.9, 135.4, 129.4, 128.8, 127.2, 65.9, 55.3, 51.7, 37.5, 37.4, 34.4, 17.2; IR (CHCl3) 3022, 1781, 1734, 1698, 1455, 1439, 1390, 1353, 1264, 1108, 1075, 1053, 1016, 974, 909 cm-1; mass spectrum (CI) m/z 306.1350 [C16H20NO5 (M+1) requires 306.1341] 306 (base), 129. NMR Assignments: 1H NMR (400 MHz) d 7.36-7.32 (comp, 2 H, CAR-H), 7.297.25 (comp, 3 H, CAR-H), 4.68 (app ddt, J = 9.6, 7.2, 3.6 Hz, 1 H, C8-H), 4.22-4.15 (comp, 3 H, C9-C2-H), 3.67 (s, 3 H, C6-H), 3.33 (dd, J = 13.2, 3.6 Hz, 1 H, C10-H), 2.95 345 (dd, J = 16.8, 10.4 Hz, 1 H, C4-H), 2.76 (dd, J = 13.2, 10.4 Hz, 1 H, C10-H), 2.47 (dd, J = 16.8, 4.4 Hz, 1 H, C4-H), 1.23 (d, J = 6.8 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 175.9 (C3), 172.2 (C5), 152.9 (C7), 135.4 (C11), 129.4, 128.8, 127.2, 65.9 (C9), 55.3 (C6), 51.7 (C8), 37.5, 37.4, 34.4 (C2), 17.2 (C1). 11 10 9 7 6 5 MeO2C 2 3 4 1 O 8 12 O 13 14 17 16 18 19 N 15 O 3.54a (3R)-4-[(4R)-4-Benzyl-2-oxo-oxazolidin-3-yl]-3-cyclohexyl-4-oxo-butyric acid methyl ester (3.54a) (BLA-V-244). NaHMDS (2.49 mL, 1.0 M in THF) was added to a solution of imide 3.53a (500 mg, 1.65 mmol) in THF (8 mL) at 78 C, and the resulting solution was stirred for 1 h. Methyl bromoacetate (761 mg, 0.47 mL, 4.98 mmol) was then added dropwise at 78 C, the cooling bath was removed, and the reaction was stirred at room temperature for 18 h. Saturated aqueous NH4Cl (10 mL) was added, and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL), and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with 1 hexane/EtOAc (5:1) to give 534 mg (87%) of 3.54a as a clear, colorless oil: H NMR (400 MHz) d 7.35-7.32 (comp, 2 H), 7.28-7.20 (comp, 3 H), 4.70-4.65 (m, 1 H), 4.224.12 (comp, 3 H), 3.65 (s, 3 H), 3.36 (dd, J = 13.2, 3.2 Hz, 1 H), 2.92 (dd, J = 17.2, 12.0 Hz, 1 H), 2.73 (dd, J = 13.6, 10.4 Hz, 1 H), 2.58 (dd, J = 17.2, 3.6 Hz, 1 H), 1.93-1.88 346 (m, 1 H), 1.76-1.58 (comp, 5 H), 1.33-0.96 (comp, 5 H); 13C NMR (100 MHz) d 175.2, 172.9, 153.0, 135.7, 129.4, 128.7, 127.0, 65.6, 55.6, 51.7, 43.8, 39.8, 37.2, 32.8, 30.7, 28.9, 26.3, 26.2, 26.0; IR (CHCl3) 3025, 2931, 2856, 1780, 1733, 1693, 1450, 1386, 1350, 1236, 1196, 1103, 1017, 909 cm-1; mass spectrum (CI) m/z 374.1957[C21H28NO5 (M+1) requires 374.1967] 374 (base). NMR Assignments: 1 H NMR (400 MHz) d 7.35-7.32 (comp, 2 H), 7.28-7.20 (comp, 3 H), 4.70-4.65 (m, 1 H, C13-H), 4.22-4.12 (comp, 3 H, C14-C7-H), 3.65 (s, 3 H, C11-H), 3.36 (dd, J = 13.2, 3.2 Hz, 1 H, C15-H), 2.92 (dd, J = 17.2, 12.0 Hz, 1 H, C9-H), 2.73 (dd, J = 13.6, 10.4 Hz, 1 H, C15-H), 2.58 (dd, J = 17.2, 3.6 Hz, 1 H, C9-H), 1.931.88 (m, 1 H, C1-H), 1.76-1.58 (comp, 5 H, C2-C3-C4-C5-C6-Heq), 1.33-0.96 (comp, 5 H, C2-C3-C4-C5-C6-Hax); 13C NMR (100 MHz) d 175.2 (C8), 172.9 (C10), 153.0 (C12), 135.7 (16), 129.4, 128.7, 127.0, 65.6 (C14), 55.6 (C11), 51.7 (C13), 43.8 (C15), 39.8 (C7), 37.2 (C9), 32.8 (C1), 30.7, 28.9, 26.3, 26.2, 26.0. 2 1 7 8 6 3 4 5 MeO2C SO2Ph 3.73 2-Benzenesulfonyl hept-4-enoic acid methyl ester (3.73). (BLA-VI-23). [Rh(CO)2Cl]2 (7 mg, 17.0 mmol) was dissolved in degassed THF (1.5 mL), 3.14a (50 mg, 0.34 mmol) was added, and the solution stirred for 30 min at room temperature. In a separate flask, methyl phenylsulfonylacetate 3.72 (0.15 mL, 0.87 mmol) was added to a slurry of NaH (28 mg of a 60% mineral oil suspension, 0.69 mmol) in degassed THF (2.0 mL) at room temperature and stirred for 20 min. The resulting anion was added via syringe to the solution of 3.14a and [Rh(CO)2Cl]2 at room temperature and stirred for 4 h. 347 The resulting dark brown solution was then filtered through a short plug of silica gel eluting with Et2O (50 mL) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to give 72 mg (75%) of 3.73 in a 95:5 regioisomeric ratio as a clear, colorless oil: 1 H NMR (400 MHz) d 7.91-7.87 (m, 2 H), 7.72-7.67 (m, 1 H), 7.61-7.56 (m, 2 H), 5.56 (app dt, J = 15.4, 6.1 Hz, 1 H), 5.22 (app dddt, J = 15.4, 8.8, 7.6, 1.2 Hz, 1 H), 3.97 (dd, J = 11.3, 3.8 Hz, 1 H), 3.66 (s, 3 H), 2.77-2.69 (m, 1 H), 2.60 (dddd, J = 19.2, 11.6, 7.6, 0.8 Hz, 1 H), 1.95 (dq, J = 14.0, 6.4 Hz, 2 H), 0.91 (app t, J = 7.6 Hz, 3 H); 13 C NMR (100 MHz) d 165.9, 137.2, 136.9, 134.3, 129.2, 129.0, 121.6, 70.6, 52.7, 29.9, 25.4, 13.4; IR (CHCl3) 3021, 2965, 1742, 1448, 1327, 1265, 1150, 1084, 969, 909 cm-1; mass spectrum (CI) m/z 283.1009 [C14H19O4S (M+1) requires 283.1004] 315, 283 (base). NMR Assignments: 1H NMR (400 MHz) d 7.91-7.87 (m, 2 H, CAr-H), 7.72-7.67 (m, 1 H, C12-H, CAr-H), 7.61-7.56 (m, 1 H, CAr-H), 5.56 (app dt, J = 15.4, 6.1 Hz, 1 H, C2-H), 5.22 (app dddt, J = 15.4, 8.8, 7.6, 1.2 Hz, 1 H, C3-H), 3.97 (dd, J = 11.3, 3.8 Hz, 1 H, C6-H), 3.66 (s, 3 H, C8-H), 2.77-2.69 (m, 1 H, C1-H), 2.60 (dddd, J = 19.2, 11.6, 7.6, 0.8 Hz, 1 H, C1-H), 1.95 (dq, J = 14.0, 6.4 Hz, 2 H, C4-H), 0.91 (app t, J = 7.6 Hz, 3 H, C5-H); 13C NMR (100 MHz) d 165.9 (C7), 137.2, 136.9, 134.3, 129.2, 129.0, 121.6, 70.6 (C6), 52.7 (C8), 29.9 (C4), 25.4 (C1), 13.4 (C5). From 3.14e. (BLA-VI-222). [Rh(CO)2Cl]2 (13 mg, 34 mmol) was dissolved in degassed THF (2 mL), 3.14e (mmol) was added, and the solution stirred for 30 min. In a separate flask, methyl phenylsulfonylacetate (186 mg, 0.87 mmol) was added to a slurry of NaH (28 mg of a 60% mineral oil suspension, 0.69 mmol) in degassed THF (1.5 mL) at room temperature, and stirred for 20 min. The resulting enolate was added via syringe to the solution of 3.14e and [Rh(CO)2Cl]2 at room temperature and stirred for 4 h. The resulting dark brown solution was then filtered through a short plug of silica gel eluting 348 with Et2O (50 mL) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to give 73 mg (76%) of 3.73 in >95:5 regioselectivity and Z/E = 1:1.5 as a clear, colorless oil whose spectral characterization was equal in all respects to that reported previously. General procedure for the [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical allylic carbonates with dimethyl 2-(but-2-ynyl)malonate. [Rh(CO)2Cl]2 (19.0 mg, 10 mol %) was dissolved in the indicated degassed solvent (5 mL), 3.14 (1.0 mmol) was added, and the solution stirred for 10-15 min. In a separate flask, dimethyl 2-(but-2-ynyl)malonate (276 mg, 1.5 mmol) was added to a slurry of NaH (56 mg of a 60% mineral oil suspension, 1.4 mmol) in the indicated degassed solvent (5 mL) and stirred for 20 min at room temperature. The resulting malonate anion was added via syringe to the solution of allylic substrate and [Rh(CO)2Cl]2 at room temperature. The mixture was then stirred for the indicated time at the indicated temperature. General Workup A: Saturated aqueous NaHCO3 (10 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. General Workup B: The reaction was filtered through a short plug of silica gel eluting with Et2O (50 mL) and was concentrated under reduced pressure. General Workup C: Saturated aqueous NH4Cl (10 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL) and the combined organic fractions were washed with saturated aqueous NaCl (10 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography to provide the alkylation products 3.89/3.90 in the specified ratio. 349 4 12 11 5 6 7 3 8 2 1 9 10 H3CO2C H3CO2C 3.89a 2-But-2-ynyl-2-pent-2-enylmalonic acid dimethyl ester (3.89a). (BLA-V-25). Malonate 3.89a was obtained in 95% yield (0.13 mmol scale) after 2 h in THF at room temperature (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 94:6 regioisomeric ratio: 1H NMR (500 MHz) d 5.59 (dddt, J = 15.2, 7.6, 6.5, 1.1 Hz, 1 H), 5.22 (dddt, J = 15.2, 9.0, 7.5, 1.6 Hz, 1 H), 3.72 (s, 6 H), 2.74-2.70 (m, 4 H), 1.99 (ddq, J = 9.0, 7.5, 1.1 Hz, 2 H), 1.76 (t, J = 2.5 Hz, 3 H), 0.94 (t, J = 7.5 Hz, 3 H); 13C NMR (125 MHz) d 170.7, 137.5, 122.0, 78.7, 73.4, 57.6, 52.5, 35.3, 25.6, 22.9, 13.7, 3.5; IR (CHCl3) 3027, 2956, 1732, 1438, 1283, 1228, 1202, 1068, 971 cm-1; mass spectrum (CI) m/z 253.1434 [C14H21O4 (M+1) requires 253.1440] 253 (base), 221, 194, 133. NMR Assignments: 1H NMR (400 MHz) d 5.59 (dddt, J = 15.2, 7.6, 6.5, 1.1 Hz, 1 H, C4-H), 5.22 (dddt, J = 15.2, 9.0, 7.5, 1.6 Hz, 1 H, C3-H), 3.72 (s, 6 H, C12-H), 2.742.70 (m, 4 H, C5-C7-H), 1.99 (ddq, J = 9.0, 7.5, 1.1 Hz, 2 H, C2-H), 1.76 (t, J = 2.5 Hz, 3 H, C10-H), 0.94 (t, J = 7.5 Hz, 3 H, C1-H); 13C NMR (125 MHz) d 170.7 (C11), 137.5 (C3), 122.0 (C4), 78.7 (C9), 73.4 (C8), 57.6 (C6), 52.5 (C12), 35.3 (C5), 25.6 (C2), 22.9 (C7), 13.7 (C1), 3.5 (C10). 350 3 1 2 4 7 6 8 11 10 9 5 CO2Me 12 MeO2C 3.89b (Z)-dimethyl 2-(but-2-ynyl)-2-(pent-2-enyl)malonate (3.89b). (BLA-VII-179). Malonate 3.89b was obtained in 94% yield (0.34 mmol scale) after 12 h in THF at 20 C (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a >95:5 regioisomeric ratio and a mixture (88:12) of Z/E-isomers: 1 H NMR (400 MHz) d 5.54 (dtt, J = 10.8, 8.8, 2.0 Hz, 1 H), 5.11 (dtt, J = 10.8, 9.2, 2.0 Hz, 1 H), 3.76 (s, 6 H), 2.81 (dd, J = 8.0, 1.6 Hz, 2 H), 2.73 (q, J = 2.4 Hz, 2 H), 2.09 (ddq, J = 9.2, 7.2, 1.6 Hz, 2 H), 1.75 (t, J = 2.8 Hz, 3 H), 0.96 (t, J = 7.6 Hz, 3 H); 13C NMR (100 MHz) d 170.6, 136.3, 121.4, 78.6, 73.4, 57.1, 52.6, 29.7, 22.8, 20.5, 14.1, 3.4; IR (CDCl3) 3690, 2956, 2359, 1733, 1601, 1437, 1294, 1247, 1215, 1054 cm-1; mass spectrum (CI) m/z 253.1446 [C14H21O4 (M+1) requires 253.1440] 253 (base), 221, 193. NMR Assignments: 1H NMR (400 MHz) d 5.54 (dtt, J = 10.8, 8.8, 2.0 Hz, 1 H, C3-H), 5.11 (dtt, J = 10.8, 9.2, 2.0 Hz, 1 H, C4-H), 3.76 (s, 6 H, C12-H), 2.81 (dd, J = 8.0, 1.6 Hz, 2 H, C5-H), 2.73 (q, J = 2.4 Hz, 2 H, C7-H), 2.09 (ddq, J = 9.2, 7.2, 1.6 Hz, 2 H, C2-H), 1.75 (t, J = 2.8 Hz, 3 H, C10-H), 0.96 (t, J = 7.6 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 170.6 (C11), 136.3 (C4), 121.4 (C3), 78.6 (C8), 73.4 (C9), 57.1 (C12), 52.6 (C6), 29.7 (C5), 22.8 (C7), 20.5 (C2), 14.1 (C1), 3.4 (C10). 351 10 1 3 2 4 9 8 7 11 5 6 CO2CH3 CO2CH3 12 3.89c 2-But-2-ynyl-2-(3-methylbut-2-enyl)malonic acid dimethyl ester (3.89c). (BLA-V-26). Malonate 3.89c was obtained in 85% yield (0.14 mmol scale) after 20 h in DMF at 20 C (General Workup B) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 99:1 regioisomeric ratio: 1H NMR (400 MHz) d 4.91 (dt, J = 7.6, 1.6 Hz, 1 H), 3.72 (s, 6 H), 2.75 (d, J = 7.6 Hz, 2 H), 2.71 (q, J = 2.4 Hz, 2 H), 1.75 (t, J = 2.4 Hz, 3 H), 1.69 (d, J = 1.6 Hz, 3 H), 1.65 (d, J = 1.6 Hz, 3 H); 13C NMR (100 MHz) d 170.8, 136.5, 117.2, 77.8, 73.7, 57.4, 52.6, 30.7, 26.0, 22.8, 17.8, 3.5; IR (CDCl3) 2954, 2922, 2359, 2258, 1732, 1437, 1264, 1227, 1207, 1058 cm-1; mass spectrum (CI) m/z 253.1436 [C14H21O4 (M+1) requires 253.1440] 253, 221, 193 (base), 185, 151. NMR Assignments: 1H NMR (400 MHz) d 4.91 (dt, J = 7.6, 1.6 Hz, 1 H, C4-H), 3.72 (s, 6 H, C12-H), 2.75 (d, J = 7.6 Hz, 2 H, C5-H), 2.71 (q, J = 2.4 Hz, 2 H, C7-H), 1.75 (t, J = 2.4 Hz, 3 H, C10-H), 1.69 (d, J = 1.6 Hz, 3 H, C2-H), 1.65 (d, J = 1.6 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 170.8 (C11), 136.5 (C3), 117.2 (C4), 77.8 (C8), 73.7 (C9), 57.4 (C6), 52.6 (C12), 30.7 (C2), 26.0 (C5), 22.8 (C1), 17.8 (C7), 3.5 (C10). 352 8 7 6 2 1 4 6 3 5 9 CO2CH3 CO2CH3 10 11 3.89d 2-But-2-ynyl-2-(1,1-dimethyl-allyl)-malonic acid dimethyl ester (3.89d). (BLA-IV-183). Malonate 3.89d was obtained in 82% yield (0.34 mmol scale) after 20 h in DMF at 20 C (General Workup B) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 57:43 regioisomeric ratio: 1H NMR (400 MHz) d 6.16 (dd, J = 17.6, 11.2 Hz, 1 H), 5.03 (dd, J = 11.2, 1.2 Hz, 1 H), 5.01 (dd, J = 17.6, 1.2 Hz, 1 H), 3.74 (s, 6 H), 2.72 (q, J = 2.4 Hz, 2 H), 1.73 (t, J = 2.4 Hz, 3 H), 1.25 (s, 6 H); 13C NMR (100 MHz) d 170.2, 144.1, 112.9, 77.8, 73.7, 64.1, 52.0, 41.9, 23.9, 17.8, 3.5; IR (CDCl3) 2953, 2922, 2259, 1731, 1436, 1294, 1227, 1207, 1070 cm-1; mass spectrum (CI) m/z 253.1433 [C14H21O4 (M+1) requires 253.1440] 253, 193 (base), 185. NMR Assignments: 1H NMR (400 MHz) d 6.16 (dd, J = 17.6, 11.2 Hz, 1 H, C2H), 5.03 (dd, J = 11.2, 1.2 Hz, 1 H, C1-H), 5.01 (dd, J = 17.6, 1.2 Hz, 1 H, C1-H), 3.74 (s, 6 H, C11-H), 2.72 (q, J = 2.4 Hz, 2 H, C6-H), 1.73 (t, J = 2.4 Hz, 3 H, C9-H), 1.25 (s, 6 H, C4-H); 13C NMR (100 MHz) d 170.2 (C10), 144.1 (C2), 112.9 (C1), 77.8 (C7), 73.7 (C8), 64.1 (C3), 52.0 (C11), 41.9 (C5), 23.9 (C4), 17.8 (C6), 3.5 (C9). 353 2 3 1 7 4 5 9 6 10 H3CO2C 13 12 8 CO2CH3 3.89e 11 2-But-2-ynyl-2-(1-vinylbut-3-enyl)-malonic acid dimethyl ester (3.89e). (BLAV-27). Malonate 3.89e was obtained in 74% yield (0.13 mmol scale) after 2 h in THF at room temperature (General Workup A) as a clear, colorless oil after chromatography (hexanes/EtOAc = 5:1) in a 93:7 regioisomeric ratio: 1H NMR (500 MHz) d 5.83-5.67 (m, 1 H), 5.51 (app dt, J = 16.8, 10.0 Hz, 1 H), 5.17-4.97 (comp, 4 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 2.90 (app dt, J = 11.2, 2.8 Hz, 1 H), 2.73 (q, J = 2.8 Hz, 2 H), 2.59 (ddddd, J = 14.0, 5.2, 2.8, 1.2, 1.2 Hz, 1 H), 1.99-1.91 (m, 1 H), 1.76 (t, J = 2.8 Hz, 3 H); 13C NMR (125 MHz) d 170.6, 170.1, 136.9, 135.9, 118.9, 115.9, 78.8, 73.7, 60.2, 52.4, 52.3, 47.3, 35.1, 24.4, 3.5; IR (CDCl3) 2954, 2922, 2844, 2359, 2259, 1731, 1437, 1219, 1051 cm-1 mass spectrum (CI) m/z 265.1443 [C15H21O4 (M+1) requires 265.1440] 265 (base), 233, 205, 145. NMR Assignments: 1H NMR (500 MHz) d 5.83-5.67 (m, 1 H, C5-H), 5.51 (app dt, J = 16.8, 10.0 Hz, 1 H, C2-H), 5.17-4.97 (comp, 4 H, C1-C6-H), 3.75 (s, 3 H, C13-H), 3.74 (s, 3 H, C13-H), 2.90 (app dt, J = 11.2, 2.8 Hz, 1 H, C3-H), 2.73 (q, J = 2.8 Hz, 2 H, C8-H), 2.59 (ddddd, J = 14.0, 5.2, 2.8, 1.2, 1.2 Hz, 1 H, C4-H), 1.99-1.91 (m, 1 H, C4H), 1.76 (t, J = 2.8 Hz, 3 H, C11-H); 13C NMR (125 MHz) d 170.6 (C12), 170.1 (C12), 136.9 (C2), 135.9 (C5), 118.9 (C6), 115.9 (C1), 78.8 (C9), 73.7 (C10), 60.2 (C7), 52.4 (C13), 52.3 (C13), 47.3 (C3), 35.1 (C4), 24.4 (C8), 3.5 (C11). 354 14 13 10 8 7 4 3 5 6 9 Si O 2 1 CO2CH3 CO2CH3 11 12 3.89f 2-But-2-ynyl-2-[4-(triisopropylsilanyloxy)-penta-2,4-dienyl]malonic acid dimethyl ester (3.89f). (BLA-IV-188). Malonate 3.89f was obtained in 35% yield (0.06 mmol scale) after 24 h in THF at room temperature (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a >95:5 regioisomeric ratio: 1 H NMR (500 MHz) d 5.98 (d, J = 15.1 Hz, 1 H), 5.85 (dt, J = 15.1, 7.6 Hz, 1 H), 4.26 (s, 1 H), 4.21 (s, 1 H), 3.72 (s, 6 H), 2.84 (dd, J = 7.6, 0.6 Hz, 2 H), 2.72 (q, J = 2.4 Hz, 2 H), 1.76 (t, J = 2.4 Hz, 3 H), 1.21 (sept, J = 7.8 Hz, 3 H), 1.09 (d, J = 7.8 Hz, 18 H); 13C NMR (125 MHz) d 170.4, 154.7, 132.3, 124.2, 94.3, 78.9, 73.3, 57.4, 52.6, 34.9, 23.1, 18.0, 12.7, 3.5; IR (CHCl3) 2956, 2867, 1736, 1438, 1258, 1206, 1094, 1069, 1024, 982 cm-1; mass spectrum (CI) m/z 423.2557 [C23H39O5Si (M+1) requires 423.2567] 423 (base). NMR Assignments: 1H NMR (400 MHz) d 5.98 (d, J = 15.1 Hz, 1 H, C3-H), 5.85 (dt, J = 15.1, 7.6 Hz, 1 H, C4-H), 4.26 (s, 1 H, C1-H), 4.21 (s, 1 H, C1-H), 3.72 (s, 6 H, C12-H), 2.84 (dd, J = 7.6, 0.6 Hz, 2 H, C5-H), 2.72 (q, J = 2.4 Hz, 2 H, C7-H), 1.76 (t, J = 2.4 Hz, 3 H, C10-H), 1.21 (sept, J = 7.8 Hz, 3 H, C13-H), 1.09 (d, J = 7.8 Hz, 18 H, C14-H); 13C NMR (100 MHz) d 170.4 (C11), 154.7 (C2), 132.3 (C3), 124.2 (C4), 94.3 (C1), 78.9 (C9), 73.3 (C8), 57.4 (C6), 52.6 (C12), 34.9 (C5), 23.1 (C7), 18.0 (C14), 12.7 (C13), 3.5 (C10). 355 11 1 2 13 3 4 6 5 7 12 10 9 8 MeO2C CO2Me 3.151 2-But-2-ynyl-2-(3-cyclopropyl-allyl)-malonic acid dimethyl ester (3.151). (BLA-V-110). Malonate 3.151 was obtained in 63% yield (0.13 mmol scale) after 1.5 h in THF at room temperature (General Workup B) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a >95:5 regioisomeric ratio: 1H NMR (500 MHz) d 5.29 (app dt, J = 15.1, 7.5 Hz, 1 H), 5.10 (dd, J = 15.1, 9.0 Hz, 1 H), 3.72 (s, 6 H), 2.73 (app q, J = 5.0, 2.5 Hz, 2 H), 1.75 (app t, J = 2.5 Hz, 3 H), 1.33 (app ddt, J = 13.1, 8.5, 4.8 Hz, 1 H), 0.66 (dddd, J = 8.0, 6.0, 4.5, 4.5 Hz, 2 H), 0.31 (app dt, J = 6.5, 4.5 Hz, 2 H); 13C NMR (125 MHz) d 170.7, 139.3, 120.5, 78.7, 73.5, 57.6, 52.5, 35.3, 22.9, 13.6, 6.6, 3.5; mass spectrum (CI) m/z 265.1451 [C15H21O4 (M+1) requires 265.1440] 265, 205 (base). NMR Assignments: 1H NMR (500 MHz) d 5.29 (app dt, J = 15.1, 7.5 Hz, 1 H, C5-H), 5.10 (dd, J = 15.1, 9.0 Hz, 1 H, C4-H), 3.72 (s, 6 H, C13-H), 2.73 (app q, J = 5.0, 2.5 Hz, 2 H, C8-H), 2.70 (dd, J = 7.5, 1.0 Hz, 2 H, C6-H), 1.75 (app t, J = 2.5 Hz, 3 H, C11-H), 1.33 (app ddt, J = 13.1, 8.5, 4.8 Hz, 1 H, C3-H), 0.66 (dddd, J = 8.0, 6.0, 4.5, 4.5 Hz, 2 H, C1-C2-H), 0.31 (app dt, J = 6.5, 4.5 Hz, 2 H, C1-C2-H); 13C NMR (125 MHz) d 170.7 (C12), 139.3 (C4), 120.5 (C5), 78.7 (C9), 73.5 (C10), 57.6 (C7), 52.5 (C13), 35.3 (C6), 22.9 (C8), 13.6 (C3), 6.6 (C1,C2), 3.5 (C11). General procedure for the [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical allylic carbonates with 356 dimethyl 2-(prop-2-ynyl)malonate. [Rh(CO)2Cl]2 (19.0 mg, 10 mol%) was dissolved in the indicated degassed solvent (5 mL), 3.14 (1.0 mmol) was added and the solution stirred for 10-15 min. In a separate flask, dimethyl 2-(prop-2-ynyl)malonate (255 mg, 1.5 mmol) was added to a slurry of NaH (56 mg of a 60% mineral oil suspension, 1.4 mmol) in the indicated degassed solvent (5 mL) and was stirred for 20 min at room temperature. The resulting malonate anion was added via syringe to the solution of allylic substrate and [Rh(CO)2Cl]2 at room temperature. The mixture was then stirred for the indicated time at the indicated temperature. General Workup A: Saturated aqueous NaHCO3 (10 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. General Workup B: The reaction was filtered through a short plug of silica gel eluting with Et2O (50 mL) and the combined filtrates were concentrated under reduced pressure. General Workup C: Saturated aqueous NH4Cl (10 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL) and the combined organic fractions were washed with saturated aqueous NaCl (10 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography to provide the alkylation products 3.89/3.90 in the specified ratio. 357 10 11 8 9 H3CO2C 3 2 1 4 CO2CH3 5 6 7 3.89g trans-2-Pent-2-enylmalonic acid dimethyl ester (3.89g). (BLA-III-292). Malonate 3.89g was obtained in 75% yield (0.34 mmol scale) after 6 h in THF at room temperature (General Workup A) as a clear, colorless oil after chromatography (hexanes/EtOAc = 5:1) in a 98:2 regioisomeric ratio: 1H NMR (400 MHz) d 5.62 (dtt, J = 14.8, 7.6, 0.8 Hz, 1 H), 5.19 (dtt, J = 15.2, 7.6, 1.2 Hz, 1 H), 3.73 (s, 3 H), 2.78 (d, J = 2.8 Hz, 2 H), 2.73 (dd, J = 7.6, 1.2 Hz, 2 H), 2.04-1.96 (m, 3 H), 0.95 (t, J = 2.8 Hz, 3 H); 13C NMR (100 MHz) d 170.0, 137.7, 121.5, 78.9, 71.3, 57.2, 52.7, 35.3, 25.8, 22.7, 13.8; IR (CDCl3) 3308, 2956, 2259, 1734, 1438, 1283, 1213 cm-1; mass spectrum (CI) m/z 239.1280 [C13H19O4 (M+1) requires 239.1283] 239 (base), 207, 179. NMR Assignments: 1H NMR (400 MHz) d 5.62 (dtt, J = 14.8, 7.6, 0.8 Hz, 1 H, C6-H), 5.19 (dtt, J = 15.2, 7.6, 1.2 Hz, 1 H, C7-H), 3.73 (s, 3 H, C11-H), 2.78 (d, J = 2.8 Hz, 2 H, C3-H), 2.73 (dd, J = 7.6, 1.2 Hz, 2 H, C5-H), 2.04-1.96 (m, 3 H, C1-C8-H), 0.95 (t, J = 2.8 Hz, 3 H, C9-H); 13C NMR (100 MHz) d 170.0 (C10), 137.7 (C6), 121.5 (C7), 78.9 (C2), 71.3 (C1), 57.2 (C4), 52.7 (C11), 35.3 (C3), 25.8 (C5), 22.7 (C8), 13.8 (C9). 358 9 2 3 1 4 8 5 7 10 6 11 CO2CH3 CO2CH3 3.89h 2-(3-Methylbut-2-enyl)-2-prop-2-ynylmalonic acid dimethyl ester (3.89h). (BLA-V-42). Malonate 3.89h was obtained in 70% yield (0.34 mmol scale) after 12 h in DMF at 20 C (General Workup B) as a clear, colorless oil after chromatography (hexanes/EtOAc = 5:1) in a 99:1 regioisomeric ratio: 1H NMR (400 MHz) d 4.90 (tt, J = 7.9, 1.4 Hz, 1 H), 3.73 (s, 6 H), 2.79-2.78 (m, 4 H), 2.00 (t, J = 2.4 Hz, 1 H), 1.70 (d, J = 1.0 Hz, 3 H), 1.65 (s, 3 H); 13C NMR (100 MHz) d 170.5, 136.9, 116.9, 79.2, 71.2, 57.1, 52.7, 30.7, 26.0, 22.5, 17.9; IR (CDCl3) 3308, 2955, 2259, 1733, 1437 cm-1; mass spectrum (CI) m/z 239.1283 [C13H19O4 (M+1) requires 239.1283] 239 (base), 207. NMR Assignments: 1H NMR (400 MHz) d 4.90 (tt, J = 7.9, 1.4 Hz, 1 H, C4-H), 3.73 (s, 6 H, C11-H), 2.79-2.78 (m, 4 H, C5-C7-H), 2.00 (t, J = 2.4 Hz, 1 H, C9-H), 1.70 (d, J = 1.0 Hz, 3 H, C2-H), 1.65 (s, 3 H, C1-H); 13C NMR (100 MHz) d 170.5 (C10), 136.9 (C7), 116.9 (C6), 79.2 (C2), 71.2 (C1), 57.1 (C4), 52.7 (C11), 30.7 (C9), 26.0 (C5), 22.5 (C8), 17.9 (C3). 7 6 2 1 4 3 5 8 CO2CH3 CO2CH3 9 10 3.89i 2-(1,1-Dimethylallyl)-2-prop-2-ynylmalonic acid dimethyl ester (3.89i). (BLAIV-159). Malonate 3.89i was obtained in 98% yield (0.34 mmol scale) after 24 h in DMF 359 at 20 C (General Workup B) as a clear, colorless oil after chromatography (hexanes/EtOAc = 5:1) in a 88:12 regioisomeric ratio: 1H NMR (400 MHz) d 6.15 (dd, J = 17.2, 10.8 Hz, 1 H), 5.04 (dd, J = 10.8, 1.2 Hz, 1 H), 5.03 (dd, J = 17.2, 1.2 Hz, 1 H), 3.75 (s, 6 H), 2.80 (d, J = 2.8 Hz, 2 H), 1.98 (t, J = 2.8 Hz, 1 H), 1.25 (s, 6 H); 13C NMR (100 MHz) d 169.9, 143.7, 113.3, 81.0, 70.4, 63.9, 52.1, 42.0, 23.9, 23.1; IR (CDCl3) 3308, 2953, 2258, 1730, 1435, 1264, 1206, 1068 cm-1; mass spectrum (CI) m/z 239.1285 [C13H19O4 (M+1) requires 239.1283] 239, 179, 171 (base), 147, 139. NMR Assignments: 1H NMR (400 MHz) d 6.15 (dd, J = 17.2, 10.8 Hz, 1 H, C2H), 5.04 (dd, J = 10.8, 1.2 Hz, 1 H, C1-H), 5.03 (dd, J = 17.2, 1.2 Hz, 1 H, C1-H), 3.75 (s, 6 H, C10-H), 2.80 (d, J = 2.8 Hz, 2 H, C6-H), 1.98 (t, J = 2.8 Hz, 1 H, C8-H), 1.25 (s, 6 H, C4-H); 13C NMR (100 MHz) d 169.9 (C9), 143.7 (C2), 113.3 (C1), 81.0 (C7), 70.4 (C8), 63.9 (C5), 52.1 (C10), 42.0 (C3), 23.9 (C4), 23.1 (C6). 2 1 3 7 4 5 9 6 H3CO2C 12 11 8 CO2CH3 3.89j 10 2-Prop-2-ynyl-2-(1-vinylbut-3-enyl)-malonic acid dimethyl ester (3.89j). (BLA-V-48). Malonate 3.89j was obtained in 71% yield (0.32 mmol scale) after 1.5 h in THF at room temperature (General Workup B) as a clear, colorless oil after chromatography (hexanes/EtOAc = 5:1) in a 93:7 regioisomeric ratio: 1 H NMR (400 MHz) d 5.65-5.58 (m, 1 H), 5.30-5.23 (m, 1 H), 5.05-4.98 (comp, 4 H), 3.76 (s, 3 H), 3.76 (s, 3 H), 2.83-2.73 (comp, 5 H), 2.02 (t, J = 2.4 Hz, 2 H); 13C NMR (100 MHz) d 170.2, 136.5, 133.4, 124.1, 115.3, 78.8, 71.4, 57.0, 52.3, 36.6, 35.3, 22.6; IR (CDCl3) 360 3308, 2954, 2844, 2259, 1733, 1639, 1437, 1289, 1208, 1072 cm-1; mass spectrum (CI) m/z 251.1281 [C14H19O4 (M+1) requires 251.1283] 251 (base), 219, 191. NMR Assignments: 5.65-5.58 (m, 1 H), 5.30-5.23 (m, 1 H), 5.05-4.98 (comp, 4 H, C1-C6-H), 3.76 (s, 3 H, C12-H), 3.76 (s, 3 H, C12-H), 2.83-2.73 (comp, 5 H, C4-C3C8-H), 2.02 (t, J = 2.4 Hz, 2 H, C10-H); 13C NMR (100 MHz) d 170.2 (C11), 136.5, 133.4, 124.1, 115.3, 78.8 (C10), 71.4 (C9), 57.0 (C7), 52.3 (C12), 36.6, 35.3, 22.6. General procedure for the [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical allylic carbonates with dimethyl 2-butylmalonate. [Rh(CO)2Cl]2 (19.0 mg, 10 mol%) was dissolved in the indicated degassed solvent (5 mL), 3.14 (1.0 mmol) was added and the solution stirred for 10-15 min. In a separate flask, dimethyl 2butylmalonate (282 mg, 1.5 mmol) was added to a slurry of NaH (56 mg of a 60% mineral oil suspension, 1.4 mmol) in the indicated degassed solvent (5 mL) at room temperature, and the mixture was stirred for 20 min at room temperature. The resulting malonate anion was added via syringe to the solution of allylic substrate and [Rh(CO)2Cl]2 at room temperature. The mixture was then stirred for the indicated time at the indicated temperature. General Workup A: Saturated aqueous NaHCO3 (10 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. General Workup B: The reaction was filtered through a short plug of silica gel eluting with Et2O (50 mL) and the combined filtrates were concentrated under reduced pressure. General Workup C: Saturated aqueous NH4Cl (10 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL) and the combined organic fractions were washed with saturated aqueous NaCl (10 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was 361 purified by flash chromatography to provide the alkylation products 3.89/3.90 in the specified ratio. 4 12 11 5 6 7 3 8 2 1 10 9 H3CO2C H3CO2C 3.89k 2-Butyl-2-pent-2-enylmalonic acid dimethyl ester (3.89k). (BLA-IV-304). Malonate 3.89k was obtained in 91% yield (0.34 mmol scale) after 3 h in THF at room temperature and an additional 4 h at 70 C (bath temperature) (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 91:9 regioisomeric ratio: 1H NMR (400 MHz) d 5.52 (dtt, J = 15.2, 6.4, 1.2 Hz, 1 H), 5.22 (dtt, J = 15.2, 7.2, 1.2 Hz, 1 H), 3.70 (s, 3 H), 2.57 (dd, J = 7.2, 1.2 Hz, 2 H), 2.01-1.83 (m, 4 H), 1.35-1.27 (m, 2 H), 1.17-1.09 (m, 2 H), 0.94 (t, J = 7.2 Hz, 3 H), 0.89 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz) d 171.9, 136.7, 122.5, 57.8, 52.1, 35.7, 31.9, 26.0, 25.6, 22.8, 13.8, 13.7; IR (CDCl3) 2958, 2873, 2258, 1727, 1456, 1435, 1270, 1210, 1145, 1044, 970 cm-1; mass spectrum (CI) m/z 257.1751 [C14H25O4 (M+1) requires 257.1753] 257 (base), 196, 168. NMR Assignments: 1H NMR (400 MHz) d 5.52 (dtt, J = 15.2, 6.4, 1.2 Hz, 1 H, C3-H), 5.22 (dtt, J = 15.2, 7.2, 1.2 Hz, 1 H, C4-H), 3.70 (s, 3 H, C12-H), 2.57 (dd, J = 7.2, 1.2 Hz, 2 H, C5-H), 2.01-1.83 (m, 4 H, C2-C7-H), 1.35-1.27 (m, 2 H, C9-H), 1.171.09 (m, 2 H, C8-H), 0.94 (t, J = 7.2 Hz, 3 H, C1-H), 0.89 (t, J = 7.2 Hz, 3 H, C10-H); 13 C NMR (100 MHz) d 171.9 (C11), 136.7 (C4), 122.5 (C3), 57.8 (C6), 52.1 (C12), 35.7 (C5), 31.9 (C7), 26.0 (C2), 25.6 (C8), 22.8 (C9), 13.8 (C1), 13.7 (C10). 362 2 3 1 4 5 6 7 8 9 10 H3CO2C CO2CH3 11 12 3.89l 2-Butyl-2-(3-methylbut-2-enyl)malonic acid dimethyl ester (3.89l). (BLA-IV183). Malonate 3.89l was obtained in 88% yield (0.34 mmol scale) after 12 h in DMF at -20 C (General Workup B) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 99:1 regioisomeric ratio: 1H NMR (400 MHz) d 4.93 (app ddt, J = 8.8, 7.2, 1.2 Hz, 1 H), 3.70 (s, 3 H), 2.60 (d, J = 7.2 Hz, 2 H), 1.85 (dd, J = 9.2, 7.2 Hz, 2 H), 1.69 (d, J = 0.8 Hz, 3 H), 1.61 (br s, 3 H), 1.34-1.26 (m, 2 H), 1.16-1.08 (m, 2 H), 0.89 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz) d 172.1, 135.4, 117.7, 57.6, 52.2, 31.9, 31.0, 26.2, 25.9, 22.9, 17.8, 13.8; IR (CDCl3) 2956, 2874, 2259, 1728, 1435, 1209, 1128, 1052 cm-1; mass spectrum (CI) m/z 257.1758 [C14H25O4 (M+1) requires 257.1753] 257 (base), 196. NMR Assignments: 1H NMR (400 MHz) d 4.93 (app ddt, J = 8.8, 7.2, 1.2 Hz, 1 H, C4-H), 3.70 (s, 3 H, C12-H), 2.60 (d, J = 7.2 Hz, 2 H, C5-H), 1.85 (dd, J = 9.2, 7.2 Hz, 2 H, C7-H), 1.69 (d, J = 0.8 Hz, 3 H, C1-H), 1.61 (br s, 3 H, C2-H), 1.34-1.26 (m, 2 H, C9-H), 1.16-1.08 (m, 2 H, C8-H), 0.89 (t, J = 7.2 Hz, 3 H, C10-H); 13C NMR (100 MHz) d 172.1 (C11), 135.4 (C3), 117.7 (C4), 57.6 (C6), 52.2 (C12), 31.9 (C7), 31.0 (C8), 26.2 (C2), 25.9 (C5), 22.9 (C9), 17.8 (C1), 13.8 (C10). 363 9 8 2 7 6 10 3 5 11 1 4 CO2CH3 CO2CH3 3.89m 2-Butyl-2-(1,1-dimethylallyl)-malonic acid dimethyl ester (3.89m). (BLA-V45). Malonate 3.89m was obtained in 62% yield (0.34 mmol scale) after 12 h in DMF at 20 C (General Workup B) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1) in a 93:7 regioisomeric ratio: 1H NMR (400 MHz) d 6.17 (dd, J = 17.6, 11.2 Hz, 1 H), 5.01 (dd, J = 11.2, 1.2 Hz, 1 H), 4.98 (dd, J = 17.6, 1.2 Hz, 1 H), 3.74 (s, 6 H), 1.85 (t, J = 8.4 Hz, 2 H), 1.30 (tq, J = 14.0, 7.2 Hz, 2 H), 1.19 (s, 6 H), 1.16-1.10 (m, 2 H), 0.88 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz) d 171.3, 144.5, 112.4, 64.7, 52.4, 32.2, 28.5, 25.9, 24.0, 22.9, 13.8; IR (CDCl3) 2956, 2873, 2259, 1728, 1456, 1435, 1278, 1209, 1127, 1054, 1018 cm-1; mass spectrum (CI) m/z 257.1749 [C14H25O4 (M+1) requires 257.1753] 257 (base), 225, 196, 157. NMR Assignments: 1H NMR (400 MHz) d 6.17 (dd, J = 17.6, 11.2 Hz, 1 H, C2H), 5.01 (dd, J = 11.2, 1.2 Hz, 1 H, C1-H), 4.98 (dd, J = 17.6, 1.2 Hz, 1 H, C1-H), 3.74 (s, 6 H, C11-H), 1.85 (t, J = 8.4 Hz, 2 H, C6-H), 1.30 (tq, J = 14.0, 7.2 Hz, 2 H, C8-H), 1.19 (s, 6 H, C4-H), 1.16-1.10 (m, 2 H, C7-H), 0.88 (t, J = 7.2 Hz, 3 H, C9-H); 13C NMR (100 MHz) d 171.3 (C10), 144.5 (C2), 112.4 (C1), 64.7 (C5), 52.4 (C11), 32.2 (C3), 28.5 (C7), 25.9 (C6), 24.0 (C8), 22.9 (C4), 13.8 (C9). 364 2 3 1 4 7 8 5 9 6 11 10 H3CO2C 13 12 CO2CH3 3.89n 2-Butyl-2-(1-vinylbut-3-enyl)-malonic acid dimethyl ester (3.89n). (BLA-V23). Malonate 3.89n was obtained in 71% yield (0.32 mmol scale) after 3 h in THF at room temperature and an additional 4 h at 70 C (General Workup A) as a clear, colorless oil after chromatography (pentane/Et2O = 5:1): 1H NMR (400 MHz) d 5.69 (app ddt, J = 16.8, 10.0, 7.2 Hz, 1 H), 5.54 (dt, J = 16.4, 9.6 Hz, 1 H), 5.13 (dd, J = 10.0, 1.6 Hz, 1 H), 5.04-4.96 (comp, 3 H), 3.74 (s, 3 H), 3.72 (s, 3 H), 2.71-2.63 (comp, 2 H), 2.45 (dddd, J = 14.0, 6.8, 1.2, 1.2 Hz, 1 H), 1.89-1.83 (comp, 2 H), 1.34-1.24 (comp, 4 H), 0.87 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz) d 171.9, 171.5, 136.4, 134.2, 118.3, 115.9, 60.9, 52.0, 51.9, 35.3, 34.1, 26.4, 26.1, 22.9, 13.8; IR (CDCl3) 2956, 2863, 2359, 1726, 1601, 1435, 1267, 1210, 1127, 992 cm-1; mass spectrum (CI) m/z 269.1762 [C15H25O4 (M+1) requires 269.1753] 269 (base), 238, 209. NMR Assignments: 1H NMR (400 MHz) d 5.69 (app ddt, J = 16.8, 10.0, 7.2 Hz, 1 H, C12-H), 5.54 (dt, J = 16.4, 9.6 Hz, 1 H, C12-H), 5.13 (dd, J = 10.0, 1.6 Hz, 1 H), 5.04-4.96 (comp, 3 H), 3.74 (s, 3 H, C13-H), 3.72 (s, 3 H, C13-H), 2.71-2.63 (comp, 2 H, C3-C4-H), 2.45 (dddd, J = 14.0, 6.8, 1.2, 1.2 Hz, 1 H, C4-H), 1.89-1.83 (comp, 2 H), 1.34-1.24 (comp, 4 H), 0.87 (t, J = 7.2 Hz, 3 H, C11-H); 13C NMR (100 MHz) d 171.9 (C12), 171.5 (C12), 136.4 (C2), 134.2 (C5), 118.3 (C1), 115.9 (C6), 60.9 (C7), 52.0 (C13), 51.9 (C13), 35.3 (C3), 34.1 (C4), 26.4 (C8), 26.1 (C9), 22.9 (C10), 13.8 (C11). General procedure for the [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical allylic carbonates with 365 ethyl 2-oxocyclohexanecarboxylate. [Rh(CO)2Cl]2 (19.0 mg, 10 mol%) was dissolved in the indicated degassed solvent (5 mL), 3.14 (1.0 mmol) was added and the solution stirred for 10-15 min. In a separate flask, ethyl 2-oxocyclohexanecarboxylate (255 mg, 1.5 mmol) was added to a slurry of NaH (56 mg of a 60% mineral oil suspension, 1.4 mmol) in the indicated degassed solvent (5 mL) and stirred for 20 min at room temperature. The resulting malonate anion was added via syringe to the solution of allylic substrate and [Rh(CO)2Cl]2 at room temperature. The mixture was then stirred for the indicated time at the indicated temperature. General Workup A: The resulting dark brown solution was diluted with saturated aqueous NaHCO3 (10 mL), the layers were separated, and the aqueous phase was extracted with Et2O (3 x 10 mL). The combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. General Workup B: The reaction was filtered through a short plug of silica gel eluting with Et2O (50 mL). The combined filtrate and washings were then concentrated under reduced pressure. General Workup C: The resulting dark brown solution was then diluted with saturated aqueous NH4Cl (10 mL), the layers were separated, and the aqueous phase was extracted with Et2O (3 x 10 mL). The combined organic fractions were washed with saturated aqueous NaCl (10 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography to provide the alkylation product 3.97 with the specified regioselectivity. 366 4 14 13 12 5 6 7 8 9 11 10 2 3 1 H3CH2CO2C O 3.97a 2-Oxo-1-pent-2-enyl-cyclohexanecarboxylic acid ethyl ester (3.97a). (BLA-V37). b-Ketoester 3.97a was obtained in 98% yield (0.34 mmol scale) in THF after 4 h at room temperature (General Workup B) as a clear, colorless oil after chromatography (hexanes/EtOAc = 5:1) in a 95:5 regioisomeric ratio: 1H NMR (400 MHz) d 5.47 (dt, J = 15.4, 6.2 Hz, 1 H), 5.33 (dt, J = 15.4, 7.9 Hz, 1 H), 4.17 (q, J = 7.5 Hz, 2 H), 2.55 (dd, J = 14.0, 6.8 Hz, 1 H), 2.45 (dd, J = 6.2, 3.1 Hz, 2 H), 2.25 (dd, J = 14.3, 7.5 Hz, 1 H), 2.031.94 (m, 1 H), 1.99 (app pent, J = 7.5 Hz, 2 H), 1.74-1.65 (m, 4 H), 1.47-1.40 (m, 1 H), 1.25 (t, J = 7.2 Hz, 3 H), 0.94 (t, J = 7.5 Hz, 3 H); 13C NMR (100 MHz) d 207.8, 171.5, 136.0, 123.4, 61.2, 61.0, 41.1, 38.0, 35.7, 27.5, 25.5, 22.4, 14.2, 13.7; IR (CDCl3) 2941, 2358, 1709, 1219, 1200 cm-1; mass spectrum (CI) m/z 239.1641 [C14H23O3 (M+1) requires 239.1647] 239 (base), 193, 171, 165. NMR Assignments: 1H NMR (400 MHz) d 5.47 (dt, J = 15.4, 6.2 Hz, 1 H, C4H), 5.33 (dt, J = 15.4, 7.9 Hz, 1 H, C3-H), 4.17 (q, J = 7.5 Hz, 2 H, C13-H), 2.55 (dd, J = 14.0, 6.8 Hz, 1 H, C8-H), 2.45 (dd, J = 6.2, 3.1 Hz, 2 H, C5-H), 2.25 (dd, J = 14.3, 7.5 Hz, 1 H, C8-H), 2.03-1.94 (m, 1 H, C11-H), 1.99 (app pent, J = 7.5 Hz, 2 H, C2-H), 1.741.65 (m, 4 H, C9-C10-H), 1.47-1.40 (m, 1 H, C11-H), 1.25 (t, J = 7.2 Hz, 3 H, C14-H), 0.94 (t, J = 7.5 Hz, 3 H, C1-H); 13C NMR (100 MHz) d 207.8 (C7), 171.5 (C12), 136.0 (C4), 123.4 (C3), 61.2 (C6), 61.0 (C13), 41.1 (C8), 38.0 (C5), 35.7 (C11), 27.5 (C10), 25.5 (C2), 22.4 (C9), 14.2 (C1), 13.7 (C14). 367 1 3 2 4 5 12 13 14 10 9 CO2CH2CH3 6 11 7 O 8 3.97b 1-(3-Methylbut-2-enyl)-2-oxocyclohexanecarboxylic acid ethyl ester (3.97b). (BLA-V-38). b-Ketoester 3.97b was obtained in 86% yield (0.34 mmol scale) in THF after 6 h at room temperature (General Workup B) as a clear, colorless oil after chromatography (hexanes/EtOAc = 5:1) in a 99:1 regioisomeric ratio. 1 H NMR was consistent with literature data:386 IR (CDCl3) 3690, 2941, 2862, 2360, 1709, 1648, 1614, 1448, 1298, 1261, 1218, 1178, 1083 cm-1; mass spectrum (CI) m/z 239.1638 [C14H23O3 (M+1) requires 239.1647] 239, 171 (base), 167, 125. 13 12 11 10 3 5 9 8 6 7 H3CH2CO2C 1 2 4 5 O 3.97c 1-(1,1-Dimethyl-allyl)-2-oxo-cyclohexanecarboxylic acid ethyl ester (3.97c). (BLA-V-43). b-Ketoester 3.97c was obtained in 74% yield (0.34 mmol scale) in THF after 20 h at room temperature (General Workup B) as a clear, colorless oil after chromatography (hexanes/EtOAc = 5:1) in a 90:10 regioisomeric ratio: 1 H NMR (400 MHz) d 6.21 (dd, J = 17.6, 10.4 Hz, 1 H), 4.98 (dd, J = 10.4, 1.2 Hz, 1 H), 4.95 (dd, J = 17.6, 1.2 Hz, 2 H), 4.21 (q, J = 7.2 Hz, 2 H), 2.52-2.46 (m, 1 H), 2.39-2.77 (m, 1 H), 2.27-2.22 (comp, 2 H), 1.71-1.49 (comp, 4 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.21 (s, 3 H), 368 1.13 (s, 3 H); 13C NMR (100 MHz) d 206.6, 171.9, 145.1, 112.2, 65.9, 60.9, 42.8, 32.2, 29.0, 26.6, 22.3, 14.1; IR (CDCl3) 2941, 2868, 2257, 2082, 2009, 1707, 1298, 1260, 1218, 1082, 1016 cm-1; mass spectrum (CI) m/z 239.1642 [C14H23O3 (M+1) requires 239.1647] 239 (base), 221, 172. NMR Assignments: 1H NMR (400 MHz) d 6.21 (dd, J = 17.6, 10.4 Hz, 1 H, C2H), 4.98 (dd, J = 10.4, 1.2 Hz, 1 H, C1-H), 4.95 (dd, J = 17.6, 1.2 Hz, 2 H, C1-H), 4.21 (q, J = 7.2 Hz, 2 H, C12-H), 2.52-2.46 (m, 1 H, C7-H), 2.39-2.77 (m, 1 H), 2.27-2.22 (comp, 2 H), 1.71-1.49 (comp, 4 H), 1.30 (t, J = 7.2 Hz, 3 H, C13-H), 1.21 (s, 3 H, C4H), 1.13 (s, 3 H, C4-H); 13C NMR (100 MHz) d 206.7 (C6), 171.9 (C11), 145.1 (C2), 112.2 (C1), 65.9 (C5), 60.9 (C12), 42.8 (C7), 32.2 (C3), 29.0 (C9), 26.6 (C8), 22.9 (C10), 22.3 (C4), 14.1 (C13). 4 5 3 12 2 1 11 10 O 14 15 16 13 7 8 9 3.99 2-Phenyl-1-((E)-pent-2-enyloxy) benzene (3.99) (BLA-V-167). A 1.0 M solution of LiHMDS (0.66 mL, 0.66 mmol) was added to a slurry of 2-phenylphenol (3.98) (118 mg, 0.69 mmol) and CuI (132 mg, 0.69 mmol) in THF (1.5 mL) at room temperature. The mixture was stirred at rt for 30 min. In a separate flask, [Rh(CO)2Cl]2 (13 mg, 0.034 mmol) was dissolved in THF (2 mL), stirred for 5 min at rt then transferred via syringe to the flask containing phenoxide. Carbonate 3.14a was then added to the mixture, and the reaction was stirred at rt for 24 h. The mixture was filtered through a 369 short plug of SiO2 eluting with Et2O (50 mL). The eluent was concentrated under reduced pressure, and the crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to provide 67 mg (84%) of 3.99 as a clear, brown oil: 1H NMR (500 MHz) d 7.57-7.54 (comp, 2 H), 7.41-7.37 (comp, 2 H), 7.34-7.28 (comp, 3 H), 7.066.96 (comp, 2 H), 5.78 (dtt, J = 15.4, 7.8, 1.4 Hz, 1 H), 5.60 (dtt, J = 15.4, 5.6, 1.6 Hz, 1 H), 4.48 (ddt, J = 5.6, 2.5, 1.6 Hz, 2 H), 2.08-2.02 (m, 2 H), 0.98 (t, J = 7.5 Hz, 3 H); 13C NMR (125 MHz) d 155.7, 138.6, 137.8, 136.1, 130.9, 129.6, 127.9, 126.8, 124.0, 121.0, 113.4, 69.4, 25.3, 13.3; IR (CHCl3) 2964, 1596, 1480, 1434, 1255, 1216, 912, 846 cm-1; mass spectrum (CI) m/z 239.1426 [C17H19O1 (M+1) requires 239.1436] 243, 239, 199, 171 (base). NMR Assignments: 1 H NMR (500 MHz) d 7.57-7.54 (comp, 2 H), 7.41-7.37 (comp, 2 H), 7.34-7.28 (comp, 3 H), 7.06-6.96 (comp, 2 H), 5.78 (dtt, J = 15.4, 7.8, 1.4 Hz, 1 H, C3-H), 5.60 (dtt, J = 15.4, 5.6, 1.6 Hz, 1 H, C4-H), 4.48 (ddt, J = 5.6, 2.5, 1.6 Hz, 2 H, C5-H), 2.08-2.02 (m, 2 H, C2-H), 0.98 (t, J = 7.5 Hz, 3 H, C1-H); 13C NMR (125 MHz) d 155.7, 138.6, 137.8, 136.1 (C3), 130.9, 129.6, 127.9, 126.8, 124.0 (C4), 121.0, 113.4, 69.4 (C5), 25.3 (C2), 13.3 (C1). General Procedure for the [Rh(CO)2Cl]2-Catalyzed Allylic Amination of Unsymmetrical Allylic Carbonates with Sulfonamides. [Rh(CO)2Cl]2 (5 mol %) was dissolved in dry, degassed THF (5 mL), the allylic substrate (1.0 mmol) was added, and the solution stirred for 30 min at room temperature. In a separate flask, a 1.0 M solution of LDA in THF was added to a solution of sulfonamide (0.29 mL, 2.5 mmol) in THF (5 mL) and stirred for 20 min at room temperature. The resulting amide was added via syringe to the solution of allylic substrate and [Rh(CO)2Cl]2 at room temperature. The mixture was then sealed in a screw cap vial under argon and stirred for 2 h at room 370 temperature. The resulting dark brown solution was then filtered through a short plug of silica gel eluting with Et2O (50 mL), and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O to provide the amination products in the specified ratios. 2 1 6 7 8 9 10 11 3 4 5 N SO2 12 13 14 15 3.109b (E)-N-benzyl-4-methyl-N-(pent-2-enyl)benzenamine (3.109b) (BLA-VI-171). The reaction was performed on a 0.34 mmol scale, and LiHMDS was used in place of LDA. After stirring at room temperature for 24 h, flash chromatographic purification eluting with pentane/Et2O (5:1) as described above (General Procedure), provided 79 mg (71%) of 3.109b in a ratio of 82:18 ratio of regioisomers as a clear colorless oil: 1H NMR (500 MHz) d 7.73 (d, J = 6.8 Hz, 2 H), 7.57-7.54 (comp, 7 H), 5.42 (dddt, J = 12.4, 6.4, 5.6, 1.6 Hz, 1 H), 5.06 (dddt, J = 12.4, 6.8, 5.6, 1.2 Hz, 1 H), 4.32 (s, 2 H), 3.69 (br d, J = 5.6 Hz, 2 H), 2.44 (s, 3 H), 1.91-1.86 (m, 2 H), 0.84 (t, J = 6.0 Hz, 3 H); 13C NMR (125 MHz) d 143.1, 137.7, 137.6, 136.3, 129.6, 128.4, 128.4, 127.2, 122.0, 50.0, 48.9, 25.1, 21.5, 13.1; mass spectrum (CI) m/z 330.1531 [C19H24NO2S (M+1) requires 330.1528] 330 (base), 274. NMR Assignments: 1 H NMR (500 MHz) d 7.73 (d, J = 6.8 Hz, 2 H, CAR-H), 7.57-7.54 (comp, 7 H, CAR-H), 5.42 (dddt, J = 12.4, 6.4, 5.6, 1.6 Hz, 1 H, C4-H), 5.06 (dddt, J = 12.4, 6.8, 5.6, 1.2 Hz, 1 H, C3-H), 4.32 (s, 2 H, C6-H), 3.69 (br d, J = 5.6 Hz, 2 371 H, C5-H), 2.44 (s, 3 H, C15-H), 1.91-1.86 (m, 2 H, C2-H), 0.84 (t, J = 6.0 Hz, 3 H, C1H); 13C NMR (125 MHz) d 143.1 (C14), 137.7 (C4), 137.6, 136.3, 129.6, 128.4, 128.4, 127.2, 122.0 (C3), 50.0 (C6), 48.9 (C5), 25.1 (C2), 21.5 (C15), 13.1 (C1). 4 5 3 2 1 7 8 O2S 10 11 9 N 6 12 13 3.109c (E)-4-methyl-N-(pent-2-enyl)-N-(prop-2-ynyl)benzenamine (3.109c) (BLA-IV275). The reaction was performed on a 0.14 mmol scale, and LiHMDS was used in place of LDA. After stirring at room temperature for 2 h, flash chromatographic purification eluting with pentane/Et2O (5:1) as described above (General Procedure), provided 16 mg (42%) of 3.109c as a clear colorless oil. literature data.387 1 H NMR and 13C NMR were consistent with 12 11 10 6 7 8 5 4 3 9 2 1 3.122 (S,E)-1,3-diphenylbut-1-ene (3.122) (BLA-VIII-111). A 2.35 M solution of nBuLi (0.22 mL, 0.51 mmol) in hexanes was added to a solution bromobenzene (80 mg, 372 0.05 mL, 0.51 mmol) in THF (1.5 mL) at 78 C and stirred for 1 h. The mixture was allowed to warm to 0 C by exchange of cooling baths and a solution of ZnBr2 (109 mg, 0.48 mmol) in THF (0.5 mL) was added. The resulting mixture was stirred for 30 min then added to a solution of (+)-3.47 in THF (1 mL) at 0 C and the reaction stirred for 15 min. The reaction was diluted with saturated sodium NaHCO3 (3 mL), allowed to warm to room temperature and the layers separated. The aqueous phase was extracted with Et2O (3 x 3 mL), the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to give 48 mg (99%) as a clear, colorless oil whose spectral properties and optical rotation were consistent with literature data.388 2 3 4 5 6 HO 1 OCO2Me 3.123 (Z)-4-Hydroxybut-2-enyl methyl carbonate (3.123) (BLA-VI-153). Methyl chloroformate (0.88 mL, 11.3 mmol) was added to a solution of cis-2-butene-1,4-diol (3.23) (0.94 mL, 11.3 mmol) and pyridine (0.92 mL, 11.3 mmol) in CH2Cl2 (25 mL) at 0 C and stirred for 30 min. The reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for 2 h. Saturated aqueous NaCl (25 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 25 mL) and the combined organic fractions were washed with saturated aqueous NaHCO3 (30 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (1:1) to provide 946 mg (57%) of 3.123 as a clear, colorless oil: 1H NMR (400 MHz) d 5.91 (dtt, J = 11.2, 6.8, 0.8 373 Hz, 1 H), 5.68 (dtt, J = 11.2, 7.2, 1.2 Hz, 1 H), 4.74 (dd, J = 6.8, 1.2 Hz, 2 H), 4.27 (app t, J = 6.0 Hz, 2 H), 3.79 (s, 3 H), 2.01 (br t, J = 6.0 Hz, 1 H); 13C NMR (100 MHz) d 155.6, 133.9, 124.4, 63.1, 57.9, 54.7; IR (CHCl3) 3610, 3502, 3024, 2959, 1746, 1444, 1277, 1019, 942, 908 cm-1; mass spectrum (CI) m/z 147.0657] 147 (base), 129. NMR Assignments: 1H NMR (400 MHz) d 5.91 (dtt, J = 11.2, 6.8, 0.8 Hz, 1 H, C2-H), 5.68 (dtt, J = 11.2, 7.2, 1.2 Hz, 1 H, C3-H), 4.74 (dd, J = 6.8, 1.2 Hz, 2 H, C1-H), 4.27 (app t, J = 6.0 Hz, 2 H, C4-H), 3.79 (s, 3 H, C5-H), 2.01 (br t, J = 6.0 Hz, 1 H, O-H); 13 147.0654 [C6H11O4 (M+1) requires C NMR (100 MHz) d 155.6 (C5), 133.9 (C3), 124.4 (C2), 63.1 (C4), 57.9 (C1), 54.7 (C6). O 1 2 O 5 4 6 7 8 O 3 MeO2CO 10 9 3.124 (Z)-4-(3-oxobutanoxy)-but-2-enyl methyl carbonate (3.124) (BLA-VI-157). Diketene (0.53 mL, 6.8 mmol) was added dropwise to a solution of alcohol 3.123 (500 mg, 3.42 mmol) and DMAP (56 mg, 0.68 mmol) in THF (17 mL) with stirring at 0 C. The reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for 1 h. Saturated aqueous NH4Cl (20 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 20 mL) and the combined organic fractions were washed with saturated aqueous NaCl (20 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (1:1) to provide 574 mg (73%) of 3.124 as a 374 clear, colorless oil: 1H NMR (400 MHz) d 5.85-5.75 (comp, 2 H), 4.76 (d, J = 8.0 Hz, 2 H), 4.75 (d, J = 8.0 Hz, 2 H), 3.79 (s, 3 H), 3.48 (s, 2 H), 2.27 (s, 3 H); 13C NMR (100 MHz) d 200.2, 166.7, 155.4, 127.9, 127.8, 63.0, 60.5, 54.7, 49.7, 30.0; IR (CHCl3) 3024, 1748, 1720, 1650, 144, 1348, 1273, 1151, 966 cm-1; mass spectrum (CI) m/z 231.0874 [C10H15O6 (M+1) requires 231.0869] 231, 155 (base), 129. NMR Assignments: 1 H NMR (400 MHz) d 5.85-5.75 (comp, 2 H, C6-C7-H), 4.76 (d, J = 8.0 Hz, 2 H, C5-H), 4.75 (d, J = 8.0 Hz, 2 H, C8-H), 3.79 (s, 3 H, C10-H), 3.48 (s, 2 H, C3-H), 2.27 (s, 3 H, C1-H); 13C NMR (100 MHz) d 200.2 (C2), 166.7 (C4), 155.4 (C9), 127.9 (C7), 127.8 (C6), 63.0 (C8), 60.5 (C5), 54.7 (C10), 49.7 (C3), 30.0 (C1). 5 O S O O 2 1 3 4 6 8 O Si 7 3.128 (Z)-4-(tert-butyldimethylsilyloxy)but-2-enyl methanesulfonate (3.128) (BLAVI-188). Methanesulfonyl chloride (0.17 mL, 1.97 mmol) was added to a solution of 3.127 (400 mg, 1.97 mmol) and Et3N (0.40 mL, 2.96 mmol) in CH2Cl2 (10 mL) and stirred for 1 h at 0 C. Saturated aqueous NaHCO3 (10 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. The 1H NMR of the crude residue was consistent with literature data for 3.128 and was therefore used without further purification.389 375 O 1 O 6 4 3 11 7 5 MeO 2 Si 10 O 9 8 12 3.129 (Z)-methyl 8-(tert-butyldimethylsilyloxy)-3-oxooct-6-enoate (3.129) (BLA-VI210). Methyl acetoacetate (0.86 mL, 7.99 mmol) was added to a slurry of NaH (320 mg of a 60% mineral oil suspension, 7.99 mmol) in THF (20 mL) and stirred for 20 min at room temperature. A 1.0 M solution in THF of LDA (0.49 mL, 0.49 mmol) was added at room temperature and the reaction stirred for 30 min. The mixture was cooled to 0 C and a solution of 3.128 (1.49 g, 5.30 mmol) in THF (7 mL) was added dropwise via syringe and stirred for 4 h. Saturated aqueous NaHCO3 (25 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 25 mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to provide 878 mg (55%) of 3.129 as a clear, colorless oil: 1H NMR (400 MHz) d 5.56 (dtt, J = 10.8, 6.4, 1.2 Hz, 1 H), 5.37 (dtt, J = 10.8, 7.6, 1.2 Hz, 1 H), 4.23 (m, 2 H), 3.74 (s, 3 H), 3.45 (s, 2 H), 2.62 (t, J = 7.2 Hz, 2 H), 2.34 (m, 2 H), 0.90 (s, 9 H), 0.07 (s, 6 H); 13C NMR (100 MHz) d 201.7, 167.4, 131.0, 128.2, 59.2, 52.2, 48.9, 42.5, 25.8, 25.6, 18.2, -5.3; IR (CHCl3) 2955, 2929, 2856, 1742, 1716, 1471, 1361, 1254, 1072, 1005, 838 cm-1; mass spectrum (CI) m/z 301.1823 [C15H29O4Si (M+1) requires 301.1835] 301, 243, 169 (base). NMR Assignments: 1H NMR (400 MHz) d 5.56 (dtt, J = 10.8, 6.4, 1.2 Hz, 1 H, C8-H), 5.37 (dtt, J = 10.8, 7.6, 1.2 Hz, 1 H, C7-H), 4.23 (m, 2 H, C9-H), 3.74 (s, 3 H, C1H), 3.45 (s, 2 H, C3-H), 2.62 (t, J = 7.2 Hz, 2 H, C5-H), 2.34 (m, 2 H, C6-H), 0.90 (s, 9 376 H, C12-H), 0.07 (s, 6 H, C10-H); 13C NMR (100 MHz) d 201.7 (C4), 167.4 (C2), 131.0 (C8), 128.2 (C7), 59.2 (C9), 52.2 (C1), 48.9 (C3), 42.5 (C5), 25.8 (C12), 25.6 (C6), 18.2 (C11), -5.3 (C10). O 1 MeO 2 3 O 6 4 7 5 8 9 10 MeO2CO 11 3.130 (Z)-Methyl 8-(methoxycarbonyloxy)-3-oxooct-6-enoate (3.130) (BLA-VI-200). A solution of TBAF (154 mg, 0.59 mmol) in THF (0.59 mL) was added to a solution of 3.129 in THF (2 mL) and stirred for 3 h at room temperature. Saturated aqueous NaCl (2 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 2 mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2 (1 mL) and cooled to 0 C. Pyridine (0.05mL, 0.58 mmol) and methyl chloroformate (0.05 mL, 0.56 mmol) were added sequentially and the reaction allowed to warm to room temperature by removal of the cooling bath and stirred for 30 min. Saturated aqueous NaCl (1 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 1 mL), and the combined organic fractions were washed with saturated aqueous NaHCO3 (30 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to provide 27 mg (57%) of 3.130 as a clear, colorless oil: 1H NMR (400 MHz) d 5.66-5.56 (m, 2 H), 4.71 (d, J = 5.6 Hz, 2 H), 3.78 (s, 3 H), 3.74 (s, 3 H), 3.47 (s, 2 H), 2.66 (t, J = 7.2 Hz, 2 H), 2.42 (app t, J = 7.2 Hz, 2 H); 13C NMR (100 MHz) d 201.3, 167.3, 155.5, 377 149.6, 133.2, 63.2, 54.5, 52.1, 48.8, 42.0, 21.3; IR (CHCl3) 3025, 2957, 1747, 1443, 1271, 948 cm-1; mass spectrum (CI) m/z 245.1029 [C11H17O6 (M+1) requires 245.1025] 245 (base), 169. NMR Assignments: 1H NMR (400 MHz) d 5.66-5.56 (m, 2 H, C7-C8-H), 4.71 (d, J = 5.6 Hz, 2 H, C9-H), 3.78 (s, 3 H, C11-H), 3.74 (s, 3 H, C1-H), 3.47 (s, 2 H, C3H), 2.66 (t, J = 7.2 Hz, 2 H, C5-H), 2.42 (app t, J = 7.2 Hz, 2 H, C6-H); 13C NMR (100 MHz) d 201.3 (C4), 167.3 (C2), 155.5 (C10), 149.6 (C8), 133.2 (C7), 63.2 (C9), 54.5 (C11), 52.1 (C1), 48.8 (C3), 42.0 (C5), 21.3 (C6). 8 7 6 9 CO2Me 5 4 O 3 2 1 3.131 (E)-methyl 2-(5-vinyl-dihydrofuran-2(3H)-ylidene)acetate (3.131) (BLA-VI216). 3.130 (50 mg, 0.20 mmol) was added to a slurry of NaH (5 mg of a 60% mineral oil suspension, 0.20 mmol) in DMF (2 mL) and stirred for 30 min at room temperature. [Rh(CO)2Cl]2 (8 mg, 0.02 mmol) was added and the reaction stirred for 2 h. Saturated aqueous NH3Cl (2 mL) and Et2O (2 mL) were added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 2 mL) and the combined organic fractions were washed with saturated aqueous NaCl (2 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to provide 24 mg (71%) of 3.131 as a clear, colorless oil: 1 H NMR (500 MHz) d 5.86 (ddd, J = 17.0, 10.5, 6.5 Hz, 1 H), 5.34 (app t, J = 2.0 Hz, 1 H), 378 5.33 (app dt, J = 17.0, 1.5 Hz, 1 H), 5.23 (app dt, J = 10.5, 1.5 Hz, 1 H), 4.85-4.80 (m, 1 H), 3.66 (s, 3 H), 3.27 (dddd, J = 18.5, 9.0, 5.0, 2.0 Hz, 1 H), 3.02 (dddd, J = 18.5, 9.0, 8.5, 2.0 Hz, 1 H), 2.30-2.23 (m, 1 H), 1.85 (dddd, J = 16.5, 8.5, 7.5, 5.0 Hz, 1 H); 13C NMR (125 MHz) d 176.2, 169.0, 135.9, 117.6, 89.4, 83.9, 50.7, 30.2, 29.8; mass spectrum (CI) m/z 169.0870 [C9H13O3 (M+1) requires 169.0865] 169 (base), 137. NMR Assignments: 1H NMR (500 MHz) d 5.86 (ddd, J = 17.0, 10.5, 6.5 Hz, 1 H, C2-H), 5.34 (app t, J = 2.0 Hz, 1 H, C7-H), 5.33 (app dt, J = 17.0, 1.5 Hz, 1 H, C1-H), 5.23 (app dt, J = 10.5, 1.5 Hz, 1 H, C1-H), 4.85-4.80 (m, 1 H, C3-H), 3.66 (s, 3 H, C9-H), 3.27 (dddd, J = 18.5, 9.0, 5.0, 2.0 Hz, 1 H, C5-H), 3.02 (dddd, J = 18.5, 9.0, 8.5, 2.0 Hz, 1 H, C5-H), 2.30-2.23 (m, 1 H, C4-H), 1.85 (dddd, J = 16.5, 8.5, 7.5, 5.0 Hz, 1 H, C4-H); 13 C NMR (125 MHz) d 176.2 (C6), 169.0 (C8), 135.9 (C2), 117.6 (C1), 89.4 (C7), 83.9 (C3), 50.7 (C9), 30.2 (C5), 29.8 (C4). 9 13 12 10 2 3 H3CO2C H3CO2C 8 7 6 1 O 5 4 11 3.143 4-Ethyl-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pentalene-2,2-dicarboxylic acid dimethyl ester (3.143). (BLA-IV-204). A solution of 3.89c (10 mg, 40.0 mmol) in Bu2O (0.4 mL) was added to a flask charged with [Rh(CO)2Cl]2 (2 mg, 3.9 mmol) under an atmosphere of CO (balloon) and heated under reflux for 24 h. The solution was allowed to cool to room temperature, filtered through a short plug of neutral alumina eluting with EtOAc (25 mL), and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 379 11 mg (99%) of 3.143 as a clear, colorless oil: 1H NMR (500 MHz) d 3.80 (s, 3 H), 3.76 (s, 3 H), 3.23 (d, J = 18.8 Hz, 1 H), 3.17 (d, J = 18.8 Hz, 1 H), 2.82 (dd, J = 12.7, 7.5 Hz, 1 H), 2.69-2.65 (m, 1 H), 2.00 (app dt, J = 9.7, 3.9 Hz, 1 H), 1.94 (ddq, J = 14.0, 7.5, 4.1 Hz, 1 H), 1.76-1.70 (m, 1 H), 1.71 (app dt, J = 3.4, 2.4 Hz, 3 H), 1.41 (ddq, J = 14.0, 9.7, 7.2 Hz, 1 H), 0.98 (t, J = 7.5 Hz, 3 H); 13C NMR (125 MHz) d 210.6, 175.2, 172.2, 171.5, 132.5, 61.3, 55.8, 53.2, 53.1, 49.3, 39.5, 34.0, 22.2, 12.1, 8.7; IR (CDCl3) 3691, 2957, 2874, 2358, 2257, 1791, 1705, 1671, 1601, 1436, 1276, 1075 cm-1; mass spectrum (CI) m/z 281 (base). NMR Assignments: 1H NMR (400 MHz) d 3.80 (s, 3 H, C13-H), 3.76 (s, 3 H, C13-H), 3.23 (d, J = 18.8 Hz, 1 H, C6-H), 3.17 (d, J = 18.8 Hz, 1 H, C6-H), 2.82 (dd, J = 12.7, 7.5 Hz, 1 H, C8-H), 2.69-2.65 (m, 1 H, C8-H), 2.00 (app dt, J = 9.7, 3.9 Hz, 1 H, C2-H), 1.94 (ddq, J = 14.0, 7.5, 4.1 Hz, 1 H, C9-H), 1.76-1.70 (m, 1 H, C1-H), 1.71 (app dt, J = 3.4, 2.4 Hz, 3 H, C11-H), 1.41 (ddq, J = 14.0, 9.7, 7.2 Hz, 1 H, C9-H), 0.98 (t, J = 7.5 Hz, 3 H, C10-H); 13C NMR (125 MHz) d 210.6 (C4), 175.2 (C2), 172.2 (C12), 171.5 (C12), 132.5 (C3), 61.3 (C7), 55.8 (C5), 53.2 (C13), 53.1 (C13), 49.3 (C1), 39.5 (C8), 34.0 (C6), 22.2 (C9), 12.1 (C10), 8.7 (C11). 1 2 3 4 6 5 O 7 8 O 3.153 Acetic acid 3-cyclopropylallyl ester (3.153). (BLA-V-150). Acetyl chloride (1.10 g, 0.51 mL, 7.14 mmol) was added to a solution of 3.22 (350 mg, 3.57 mmol) and pyridine (978 mg, 0.58 mL, 7.14 mmol) in CH2Cl2 (16 mL) at 0 C. The reaction was 380 allowed to warm to room temperature by removal of the cooling bath and stirred for 3 h. Saturated aqueous NaHCO3 (10 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 10 mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to give 3.153 as a clear, colorless oil: 1 H NMR (400 MHz) d 5.65 (dt, J = 15.2, 6.8 Hz, 1 H), 5.29 (br dd, J = 15.2, 8.9 Hz, 1 H), 4.89 (dd, J = 6.8, 1.0 Hz, 2 H), 2.06 (s, 3 H), 1.46-1.37 (m, 1 H), 0.74 (dddd, J = 10.6, 6.5, 4.4, 4.4 Hz, 2 H), 0.43-0.39 (m, 2 H); 13C NMR (100 MHz) d 170.9, 140.7, 121.1, 65.2, 21.0, 13.5, 6.8; IR (CDCl3) 3009, 2255, 1732, 1371, 1236, 1025, 956 cm-1; mass spectrum (CI) m/z 139.0760 [C8H11O2 (M-1) requires 139.0759] 139 (base). NMR Assignments: 1H NMR (400 MHz) d 5.65 (dt, J = 15.2, 6.8 Hz, 1 H, C5H), 5.29 (br dd, J = 15.2, 8.9 Hz, 1 H, C4-H), 4.89 (dd, J = 6.8, 1.0 Hz, 2 H, C6-H), 2.06 (s, 3 H, C8-H), 1.46-1.37 (m, 1 H, C3-H), 0.74 (dddd, J = 10.6, 6.5, 4.4, 4.4 Hz, 2 H, C2H), 0.43-0.39 (m, 2 H, C1-H); 13C NMR (100 MHz) d 170.9 (C7), 140.7 (C4), 121.1 (C5), 65.2 (C6), 21.0 (C8), 13.5 (C3), 6.8 (C1,C2). 5 4 6 3 1 2 O 7 O CF3 8 3.154 (E)-3-cyclopropylallyl 2,2,2-trifluoroacetate (3.154). (BLA-VIII-37). Trifluoroacetic anhydride (129 mg, 0.61 mmol, 0.09 mL) was added to a solution of 3.158a (50 mg, 0.51 mmol) in Et2O (3 mL) at 0 C. The reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for 15 min. Saturated 381 aqueous NaHCO3 (3 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 3 mL) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure to provide 66 mg (65%) of 3.161 as a clear colorless oil: 1H NMR (400 MHz) d 5.68 (dt, J = 15.2, 7.2 Hz, 1 H), 5.41 (dd, J = 15.2, 9.2 Hz, 1 H), 4.75 (d, J = 7.2 Hz, 2 H), 1.49-1.40 (m, 1 H), 0.79 (ddt, J = 12.4, 6.4, 4.4 Hz, 2 H), 0.45 (ddt, J = 11.2, 6.4, 4.8 Hz, 2 H); 13C NMR (100 MHz) d 157.1, 144.1, 118.6, 115.9, 68.7, 13.5, 7.0; IR (CDCl3) 3689, 3009, 1780, 1667, 1602, 1337, 1223, 1173, 1149 cm-1; mass spectrum (CI) m/z 194.0560 [C8H9O2F3 (M+1) requires 194.0555] 195, 183 (base), 179. NMR Assignments: 1H NMR (400 MHz) d 5.68 (dt, J = 15.2, 7.2 Hz, 1 H, C2H), 5.41 (dd, J = 15.2, 9.2 Hz, 1 H, C3-H), 4.75 (d, J = 7.2 Hz, 2 H, C1-H), 1.49-1.40 (m, 1 H, C4-H), 0.79 (ddt, J = 12.4, 6.4, 4.4 Hz, 2 H, C5-C6-H), 0.45 (ddt, J = 11.2, 6.4, 4.8 Hz, 2 H, C5,6-H); 13C NMR (100 MHz) d 157.1 (C7), 144.1 (C3), 118.6 (C2), 115.9 (C8), 68.7 (C1), 13.5 (C4), 7.0 (C5,6). 6 H 2 5 4 3 1 8 9 O Si 7 H OH 3.155 (2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)methanol (3.155). (BLAVII-49). Diiodomethane (2.91 g, 0.88 mL, 10.9 mmol) was added to a solution of Et2Zn (1.0 M in hexane, 5.9 mmol, 5.9 mL) in CH2Cl2 (20 mL) at 0 C and stirred for 15 min. The resulting white slurry was cooled to 78 C and a solution of 3.154 (500 mg, 2.47 mmol) in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm slowly 382 to 0 C by exchange of cooling baths and stirred for 1 h. The mixture was then allowed to warm to room temperature by removal of the cooling bath and stirred for an additional 2 h. The reaction was cooled to 0 C, saturated aqueous NH4Cl (12 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 12 mL) and the combined organic fractions dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (5:1) to give 421 mg (79%) of 3.155 as a clear, colorless oil: 1H NMR (400 MHz) d 4.15 (dd, J = 11.6, 5.6 Hz, 1 H), 3.97 (ddd, J = 17.6, 12.4, 5.6 Hz, 1 H), 3.293.21 (comp, 3 H), 1.42-1.32 (m, 1 H), 1.23 (dddt, J = 13.6, 11.2, 5.6, 5.2 Hz, 1 H), 0.92 (s, 9 H), 0.76 (ddd, J = 13.6, 8.4, 5.2 Hz, 1 H), 0.91 (dq, J = 10.0, 5.2 Hz, 1 H), 0.12 (s, 3 H), 0.10 (s, 3 H); 13C NMR (100 MHz) d 63.7, 62.9, 25.7, 18.1, 18.0, 17.2, 8.2, -5.4, -5.7; IR (CDCl3) 3454, 2956, 2930, 2858, 16012, 1471, 1257, 1216, 1057, 1036 cm-1; mass spectrum (CI) m/z 217.1615 [C11H25O2Si (M+1) requires 217.1624] 217, 199 (base), 133. NMR Assignments: 1H NMR (400 MHz) d 4.15 (dd, J = 11.6, 5.6 Hz, 1 H, C5H), 3.97 (ddd, J = 17.6, 12.4, 5.6 Hz, 1 H, C1-H), 3.29-3.21 (comp, 3 H, C1-C5-O-H), 1.42-1.32 (m, 1 H, C2-H), 1.23 (dddt, J = 13.6, 11.2, 5.6, 5.2 Hz, 1 H, C4-H), 0.92 (s, 9 H, C9-H), 0.76 (ddd, J = 13.6, 8.4, 5.2 Hz, 1 H, C3-H), 0.91 (dq, J = 10.0, 5.2 Hz, 1 H, C3-H), 0.12 (s, 3 H, C6-H), 0.10 (s, 3 H, C7-H); 13C NMR (100 MHz) d 63.7 (C5), 62.9 (C1), 25.7 (C9), 18.1 (C4), 18.0 (C8), 17.2 (C2), 8.2 (C3), -5.4 (C6), -5.7 (C7). 383 6 H 2 5 4 3 8 9 O Si 7 H CHO 1 3.156 2-((tert-butyldimethylsilyloxy)methyl)cyclopropanecarbaldehyde (3.156). (BLA-VII-218). 4 MS (630 mg) and NMO (256 mg, 2.1 mmol) were added sequentially to a solution of 3.155 in CH2Cl2 (7 mL) at room temperature and stirred for 10 min. TPAP (26 mg, 0.07 mmol) was then added and stirring continued for 6 h at room temperature. The crude mixture was filtered through a pad of celite and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (2:1) to give 272 mg (88%) of 3.156a as a clear, colorless oil: 1 H NMR (400 MHz) d 9.43 (d, J = 5.2 Hz, 1 H), 3.98 (dd, J = 11.2, 5.2 Hz, 1 H), 3.63 (dd, J = 11.2, 7.6 Hz, 1 H), 1.97 (m, 1 H), 1.82-1.73 (m, 1 H), 1.34 (ddd, J = 10.0, 6.8, 5.2 Hz, 1 H), 1.28-1.20 (m, 1 H), 0.88 (s, 9 H), 0.05 (s, 3 H), 0.05 (s, 3 H); 13C NMR (100 MHz) d 200.8, 62.8, 27.4, 26.2, 25.8, 18.2, 12.0, -5.4, -5.4; IR (CDCl3) 3691, 2956, 2938, 2858, 2254, 1699, 1601, 1256, 1089 cm-1; mass spectrum (CI) m/z 215.1460 [C11H23O2Si (M+1) requires 215.1467] 215 (base), 157. NMR Assignments: 1H NMR (400 MHz) d 9.43 (d, J = 5.2 Hz, 1 H, C1-H), 3.98 (dd, J = 11.2, 5.2 Hz, 1 H, C4-H), 3.63 (dd, J = 11.2, 7.6 Hz, 1 H, C4-H), 1.97 (m, 1 H, C2-H), 1.82-1.73 (m, 1 H, C3-H), 1.34 (ddd, J = 10.0, 6.8, 5.2 Hz, 1 H, C5-H), 1.28-1.20 (m, 1 H, C5-H), 0.88 (s, 9 H, C9-C10-C11-H), 0.05 (s, 3 H, C6-H), 0.05 (s, 3 H, C7-H); 13 C NMR (100 MHz) d 200.8 (C1), 62.8 (C5), 27.4 (C2), 26.2 (C4), 25.8 (C9), 18.2 (C8), 12.0 (C3), -5.4 (C6), -5.4 (C7). 384 8 H 4 7 6 5 10 11 O Si 9 H 2 3 O 1 OMe 3.157 12 (E)-methyl 3-(2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)acrylate (3.157). (BLA-VII-36). Trimethyl phosphonoacetate (639 mg, 3.5 mmol, 0.57 mL) was added to a slurry of NaH (133 mg of a 60% mineral oil suspension, 3.33 mmol) in THF (5 mL) at 0 C and stirred for 1 h. A solution of 3.156 (376 mg, 1.75 mmol) in THF (4 mL) was added, the mixture allowed to warm to room temperature by removal of the cooling bath and stirred for 2 h. H2O (10 mL) was added and the layers were separated. The aqueous layer was extracted with Et2O (3 x 10 mL), and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 468 mg (99%) of 3.157 as a clear, colorless oil: 1H NMR (400 MHz) d 6.74 (dd, J = 15.2, 10.0 Hz, 1 H), 5.93 (d, J = 15.2 Hz, 1 H), 3.82 (dd, J = 11.2, 6.0 Hz, 1 H), 3.71 (s, 3 H), 3.61 (dd, J = 11.2, 7.2 Hz, 1 H), 1.71-1.68 (m, 1 H), 1.55-1.48 (m, 1 H), 1.14 (ddd, J = 13.2, 8.4, 4.8 Hz, 1 H), 0.89 (s, 9 H), 0.72 (dd, J = 11.6, 5.2 Hz, 1 H), 0.06 (s, 3 H), 0.05 (s, 3 H); 13C NMR (100 MHz) d 166.8, 150.3, 119.8, 62.5, 51.2, 25.8, 23.3, 19.3, 18.3, 12.9, 5.4, -5.4; IR (CDCl3) 2954, 2929, 2857, 1711, 1646, 1437, 1270, 1148, 1074 cm-1; mass spectrum (CI) m/z 271.1742 [C14H27O3Si (M+1) requires 271.1730] 271, 255, 213, 139 (base). NMR Assignments: 1H NMR (400 MHz) d 6.74 (dd, J = 15.2, 10.0 Hz, 1 H, C3H), 5.93 (d, J = 15.2 Hz, 1 H, C2-H), 3.82 (dd, J = 11.2, 6.0 Hz, 1 H, C7-H), 3.71 (s, 3 H, 385 C12-H), 3.61 (dd, J = 11.2, 7.2 Hz, 1 H, C7-H), 1.71-1.68 (m, 1 H, C4-H), 1.55-1.48 (m, 1 H, C6-H), 1.14 (ddd, J = 13.2, 8.4, 4.8 Hz, 1 H, C5-H), 0.89 (s, 9 H, C11-H), 0.72 (dd, J = 11.6, 5.2 Hz, 1 H, C5-H), 0.06 (s, 3 H, C8-H), 0.05 (s, 3 H, C9-H); 13C NMR (100 MHz) d 166.8 (C1), 150.3 (C3), 119.8 (C2), 62.5 (C7), 51.2 (C12), 25.8 (C11), 23.3 (C4), 19.3 (C10), 18.3 (C6), 12.9 (C5), -5.4 (C8), -5.4 (C9). 8 H 4 7 6 5 10 11 O Si 9 H 2 3 1 OH 3.158 (E)-3-(2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)prop-2-en-1-ol (3.158). (BLA-VII-40). A 1.0M solution of DIBALH in PhMe (5.2 mmol, 5.2 mL) was added to a solution of 3.157 in THF (9 mL) at 78 C. The reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for 2 h at room temperature. The mixture was then cooled to 0 C, saturated Rochelle s salt (10 mL) was added and stirring continued for 30 min. The layers were separated and the aqueous phase extracted with EtOAc (3 x 10 mL). The combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (2:1) to yield 349 mg (89%) of 3.158 as a clear, colorless oil: 1H NMR (400 MHz) d 5.77 (app dt, J = 15.2, 5.6 Hz, 1 H), 5.51 (app ddt, J = 15.2, 8.4, 0.8 Hz, 1 H), 4.10 (br d, J = 5.6 Hz, 1 H), 3.70 (dd, J = 11.2, 6.4 Hz, 1 H), 3.56 (dd, J = 11.2, 7.2 Hz, 1 H), 1.59 (app ddt, J = 14.0, 8.4, 6.4 Hz, 1 H), 1.331.24 (m, 1 H), 0.89 (s, 9 H), 0.42 (app q, J = 5.6 Hz, 1 H), 0.06 (s, 3 H), 0.05 (s, 3 H); 13C 386 NMR (100 MHz) d 131.9, 129.3, 63.5, 63.1, 25.9, 20.6, 18.3, 18.3, 10.6, -5.2, -5.2; IR (CDCl3) 2929, 2857, 2360, 1471, 1255, 1083, 968 cm-1; mass spectrum (CI) m/z 243.1785 [C13H27O2Si (M+1) requires 243.1780] 243 (base), 241. NMR Assignments: 1H NMR (400 MHz) d 5.77 (app dt, J = 15.2, 5.6 Hz, 1 H, C2-H), 5.51 (app ddt, J = 15.2, 8.4, 0.8 Hz, 1 H, C3-H), 4.10 (br d, J = 5.6 Hz, 1 H, O-H), 3.70 (dd, J = 11.2, 6.4 Hz, 1 H, C7-H), 3.56 (dd, J = 11.2, 7.2 Hz, 1 H, C7-H), 1.59 (app ddt, J = 14.0, 8.4, 6.4 Hz, 1 H, C6-H), 1.33-1.24 (m, 1 H, C4-H), 0.89 (s, 9 H, C11-H), 0.42 (app q, J = 5.6 Hz, 1 H, C5-H), 0.06 (s, 3 H, C8-H), 0.05 (s, 3 H, C9-H); 13C NMR (100 MHz) d 131.9 (C3), 129.3 (C2), 63.5 (C7), 63.1 (C1), 25.9 (C11), 20.6 (C4), 18.3 (C6), 18.3 (C10), 10.6 (C5), -5.2 (C8), -5.2 (C9). 11 10 Si 1 O 4 5 7 6 2 H 3 H O O 8 CF3 9 3.159 (E)-3-(2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)allyl trifluoroacetate (3.159) (BLA-VII-304). 2,2,2- Trifluoroacetic anhydride (101 mg, 0.48 mmol, 0.07 mL) was added to a solution of 3.158 (100 mg, 0.44 mmol) in Et2O (2 mL) at 0 C. The reaction was allowed to warm to room temperature by removal of the ice bath and stirred for 15 min. Saturated aqueous NaHCO3 (3 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 3 mL) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure to 387 provide 143 mg (96%) of 3.159 as a clear colorless oil: 1H NMR (400 MHz) d 5.71-5.68 (comp, 2 H), 4.75-4.73 (comp, 2 H), 3.74 (dd, J = 11.2, 6.0 Hz, 1 H), 3.50 (dd, J = 11.2, 7.6 Hz, 1 H), 1.63-1.56 (m, 1 H), 1.38-1.29 (m, 1 H), 0.95 (ddd, J = 13.2, 8.4, 5.2 Hz, 1 H), 0.86 (s, 6 H), 0.47 (dd, J = 10.8, 5.2 Hz, 1 H), 0.03 (s, 9 H); 13C NMR (100 MHz) d 157.5, 139.3, 121.1, 115.9, 68.7, 62.8, 25.9, 21.2, 18.5, 18.3, 11.0, -5.3, -5.3; IR (CDCl3) 2929, 2857, 1781, 1472, 1338, 1223, 1174, 1149, 1074 cm-1; mass spectrum (CI) m/z 339.1607 [C15H26O3F3Si (M+1) requires 339.1603] 338 (base), 306. NMR Assignments: 1 H NMR (400 MHz) d 5.71-5.68 (comp, 2 H, C5-C6-H), 4.75-4.73 (comp, 2 H, C7-H), 3.74 (dd, J = 11.2, 6.0 Hz, 1 H, C1-H), 3.50 (dd, J = 11.2, 7.6 Hz, 1 H, C1-H), 1.63-1.56 (m, 1 H, C4-H), 1.38-1.29 (m, 1 H, C2-H), 0.95 (ddd, J = 13.2, 8.4, 5.2 Hz, 1 H, C3-H), 0.86 (s, 6 H, C10-H), 0.47 (dd, J = 10.8, 5.2 Hz, 1 H, C3H), 0.03 (s, 9 H, C12-H); 13C NMR (100 MHz) d 157.5 (C8), 139.3 (C5), 121.1 (C6), 115.9 (C9), 68.7 (C1), 62.8 (C7), 25.9 (C12), 21.2 (C4), 18.5 (C11), 18.3 (C2), 11.0 (C3), -5.3 (C10), -5.3 (C10). 6 H 2 1 5 4 3 8 9 O Si 7 H OH 3.155a (2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)methanol (3.155a). (BLAVII-166). Diiodomethane (629 mg, 0.19 mL, 2.34 mmol) was added to a solution of Et2Zn (1.0 M in hexane, 1.28 mmol, 1.28 mL) in CH2Cl2 (4 mL) at 0 C and stirred for 15 min. The resulting white slurry was cooled to 78 C and a solution of 3.154 (216 mg, 1.06 mmol) in CH2Cl2 (2 mL) was added. The reaction was allowed to warm to 0 C by 388 exchange of cooling baths and stirred for 1 h. The mixture was then allowed to warm to room temperature by removal of the cooling bath and stirring continued for 2 h. The reaction was cooled to 0 C, saturated aqueous NH4Cl (6 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 6 mL) and the combined organic fractions dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (2:1) to give 175 mg (81%) of 3.155a as a clear, colorless oil: 1H NMR (400 MHz) d 3.60 (dd, J = 10.8, 5.6 Hz, 1 H), 3.45 (dd, J = 10.8, 6.4 Hz, 1 H), 3.52-3.42 (comp, 2 H), 1.38 (br s, 1 H), 1.07-0.98 (m, 1 H), 0.96-0.88 (m, 1 H), 0.89 (s, 9 H), 0.50 (ddd, J = 8.0, 4.8, 4.8 Hz, 1 H), 0.45 (ddd, J = 8.0, 5.2, 5.2 Hz, 1 H), 0.05 (s, 6 H); 13C NMR (100 MHz) d 66.0, 65.9, 25.9, 19.2, 19.1, 18.3, 7.6, -5.3, -5.3; IR (CDCl3) 3612, 3417, 2955, 2883, 2858, 2247, 1471, 1256, 1077, 1006, 837 cm-1; mass spectrum (CI) m/z 215.1465 [C11H23O2Si (M-1) requires 215.1467] 217, 199 (base). NMR Assignments: 1H NMR (400 MHz) d 3.60 (dd, J = 10.8, 5.6 Hz, 1 H, C5H), 3.45 (dd, J = 10.8, 6.4 Hz, 1 H, C5-H), 3.52-3.42 (comp, 2 H, C1-H), 1.38 (br s, 1 H, O-H), 1.07-0.98 (m, 1 H), 0.96-0.88 (m, 1 H), 0.89 (s, 9 H, C5-H, C9-H), 0.50 (ddd, J = 8.0, 4.8, 4.8 Hz, 1 H, C3-H), 0.45 (ddd, J = 8.0, 5.2, 5.2 Hz, 1 H, C3-H), 0.05 (s, 6 H, C6C7-H); 13C NMR (100 MHz) d 66.0 (C5), 65.9 (C1), 25.9 (C9), 19.2 (C4), 19.1 (C2), 18.3 (C8), 7.6 (C3), -5.3 (C6), -5.3 (C7). 389 6 H 2 1 5 4 3 8 9 O Si 7 OHC H 3.156a 2-((tert-butyldimethylsilyloxy)methyl)cyclopropanecarbaldehyde (3.156a). (BLA-V-48). Dess-Martin periodinane (509 mg, 1.20 mmol) was added in one portion to a solution of 3.160 (130 mg, 0.60 mmol) in CH2Cl2 (6 mL) and stirred for 2 h at room temperature. Saturated aqueous NaHCO3/Na2S2O3 (6 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 6 mL) and the combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with pentane/Et2O (2:1) to give 130 mg (quant.) of 3.156a as a clear, colorless oil: 1H NMR (400 MHz) d 9.09 (d, J = 5.2 Hz, 1 H), 3.71 (dd, J = 10.4, 4.4 Hz, 1 H), 3.64 (dd, J = 10.4, 4.4 Hz, 1 H), 1.85 (app ddt, J = 9.6, 8.4, 4.4 Hz, 1 H), 1.73 (app ddt, J = 11.2, 9.2, 6.8, 4.8 Hz, 1 H), 1.27 (app dt, J = 8.8, 4.8, 4.8 Hz, 1 H), 1.13 (ddd, J = 11.2, 6.4, 4.4 Hz, 1 H), 0.88 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz) d 200.7, 62.5, 27.3, 25.7, 23.7, 18.2, 11.5, -5.5; IR (CDCl3) 2956, 2858, 2256, 1703, 1471, 1258, 1098, 837 cm-1; mass spectrum (CI) m/z 215.1470 [C11H23O2Si (M+1) requires 215.1467] 215 (base), 159. NMR Assignments: 1H NMR (400 MHz) d 9.09 (d, J = 5.2 Hz, 1 H, C1-H), 3.71 (dd, J = 10.4, 4.4 Hz, 1 H, C5-H), 3.64 (dd, J = 10.4, 4.4 Hz, 1 H, C5-H), 1.85 (app ddt, J = 9.6, 8.4, 4.4 Hz, 1 H, C2-H), 1.73 (app ddt, J = 11.2, 9.2, 6.8, 4.8 Hz, 1 H, C3-H), 1.27 (app dt, J = 8.8, 4.8, 4.8 Hz, 1 H, C4-H), 1.13 (ddd, J = 11.2, 6.4, 4.4 Hz, 1 H, C3-H), 0.88 (s, 9 H, C9-H), 0.05 (s, 6 H, C6-C7-H); 13C NMR (100 MHz) d 200.7 (C1), 62.5 (C5), 27.3 (C2), 25.7 (C9), 23.7 (C4), 18.2 (C8), 11.5 (C3) 5.5 (C6-C7). 390 8 H 4 3 6 7 5 10 11 O Si 9 H 2 O 1 OMe 12 3.157a (E)-Methyl 3-(2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)acrylate (3.157a). (BLA-VII-181). Trimethyl phosphonoacetate (257 mg, 1.4 mmol, 0.23 mL) was added to a slurry of NaH (54 mg of a 60% mineral oil suspension, 1.34 mmol) in THF (4 mL) at 0 C and stirred for 1 h. A solution of 3.156a (151 mg, 0.70 mmol) in THF (3 mL) was added, the reaction allowed to warm to room temperature by removal of the cooling bath and stirred for 1.5 h. H2O (7 mL) was added and the layers were separated. The aqueous phase was extracted with Et2O (3 x 7 mL), and the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 176 mg (93%) of 3.157a as a clear, colorless oil: 1H NMR (400 MHz) d 6.49 (dd, J = 15.2, 10.0 Hz, 1 H), 5.86 (d, J = 15.2 Hz, 1 H), 3.71 (s, 3 H), 3.64 (dd, J = 11.2, 5.2 Hz, 1 H), 3.58 (dd, J = 11.2, 5.6 Hz, 1 H), 1.51 (app ddt, J = 10.0, 8.4, 4.4 Hz, 1 H), 1.30 (ddd, J = 8.8, 5.6, 4.0 Hz, 1 H), 0.94 (ddd, J = 10.8, 6.0, 4.8 Hz, 1 H), 0.88 (s, 9 H), 0.82 (app dt, J = 8.4, 4.8 Hz, 1 H), 0.05 (s, 6 H); 13C NMR (100 MHz) d 166.9, 152.9, 117.7, 64.2, 51.1, 25.8, 24.5, 19.3, 18.2, 12.8, -5.4; IR (CDCl3) 3690, 2954, 2929, 2857, 2256, 1711, 1649, 1601, 1471, 1437, 1330, 1252, 1215, 1151, 1076 cm-1; mass spectrum (CI) m/z 271.1743 [C14H27O3Si (M+1) requires 271.1730] 271 (base), 139. NMR Assignments: 1H NMR (400 MHz) d 6.49 (dd, J = 15.2, 10.0 Hz, 1 H, C3H), 5.86 (d, J = 15.2 Hz, 1 H, C2-H), 3.71 (s, 3 H, C12-H), 3.64 (dd, J = 11.2, 5.2 Hz, 1 391 H, C7-H), 3.58 (dd, J = 11.2, 5.6 Hz, 1 H, C7-H), 1.51 (app ddt, J = 10.0, 8.4, 4.4 Hz, 1 H, C5-H), 1.30 (ddd, J = 8.8, 5.6, 4.0 Hz, 1 H, C4-H), 0.94 (ddd, J = 10.8, 6.0, 4.8 Hz, 1 H, C5-H), 0.88 (s, 9 H, C11-H), 0.82 (app dt, J = 8.4, 4.8 Hz, 1 H, C6-H), 0.05 (s, 6 H, C8-C9-H); 13C NMR (100 MHz) d 166.9 (C1), 152.9 (C3), 117.7 (C2), 64.2 (C7), 51.1 (C12), 25.8 (C11), 24.5 (C4), 19.3 (C6), 18.2 (C10), 12.8 (C5), -5.4 (C8,C9). 8 H 4 3 1 2 7 6 5 10 11 O Si 9 H OH 3.158a (E)-3-(2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)prop-2-en-1-ol (3.158a). (BLA-VII-170). A 1.0 M solution of DIBALH in PhMe (0.93 mmol, 0.93 mL) was added to a solution of 3.157a in THF (5 mL) at 78 C. The reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for 2 h. The mixture was then cooled to 0 C, saturated Rochelle s salt (5 mL) was added and stirred for 30 min. The layers were separated and the aqueous phase extracted with EtOAc (3 x 5 mL). The combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure to yield 110 mg (quant.) of 3.158a as a clear colorless oil: 1 H NMR (400 MHz) d 6.69 (app ddt, J = 15.2, 6.4, 0.8 Hz, 1 H), 5.29 (app ddt, J = 15.2, 8.8, 1.2 Hz, 1 H), 4.07 (dt, J = 7.2, 1.2 Hz, 1 H), 3.60 (dd, J = 10.8, 6.0 Hz, 1 H), 3.52 (dd, J = 10.8, 6.0 Hz, 1 H), 1.32 (app ddt, J = 12.8, 8.8, 4.4 Hz, 1 H), 1.21 (app t, J = 6.8 Hz, 1 H), 1.07 (app dddt, J = 12.4, 7.2, 5.6, 4.4 Hz, 1 H), 0.89 (s, 9 H), 0.69 (app dt, J = 8.4, 4.8 Hz, 1 H), 0.59 (app dt, J = 8.0, 4.8 Hz, 1 H), 0.05 (s, 6 H); 13C NMR (100 MHz) d 135.6, 392 126.7, 65.5, 63.4, 25.9, 22.7, 18.7, 18.3, 11.4, -5.2; IR (CDCl3) 4195, 3605, 3053, 2956, 2857, 2305, 1666, 1421, 1260, 1074, 837, 766 cm-1; mass spectrum (CI) m/z 243.1769 [C13H27O2Si (M+1) requires 243.1780] 243 (base), 241. NMR Assignments: 1H NMR (400 MHz) d 6.69 (app ddt, J = 15.2, 6.4, 0.8 Hz, 1 H, C2-H), 5.29 (app ddt, J = 15.2, 8.8, 1.2 Hz, 1 H, C3-H), 4.07 (dt, J = 7.2, 1.2 Hz, 1 H, C1-H), 3.60 (dd, J = 10.8, 6.0 Hz, 1 H, C7-H), 3.52 (dd, J = 10.8, 6.0 Hz, 1 H, C7-H), 1.32 (app ddt, J = 12.8, 8.8, 4.4 Hz, 1 H, C5-H), 1.21 (app t, J = 6.8 Hz, 1 H, O-H), 1.07 (app dddt, J = 12.4, 7.2, 5.6, 4.4 Hz, 1 H, C5-H), 0.89 (s, 9 H, C11-H), 0.69 (app dt, J = 8.4, 4.8 Hz, 1 H, C6-H), 0.59 (app dt, J = 8.0, 4.8 Hz, 1 H, C4-H), 0.05 (s, 6 H, C8-C9H); 13C NMR (100 MHz) d 135.6 (C3), 126.7 (C2), 65.5 (C7), 63.4 (C1), 25.9 (C11), 22.7 (C4), 18.7 (C6), 18.3 (C10), 11.4 (C5), -5.2 (C8-C9). 11 8 7 5 10 H 4 3 1 2 6 O Si 9 H O O 12 CF3 13 3.161 (E)-3-(2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)allyl trifluoroacetate (3.161). (BLA-VII-303). 2,2,2- Trifluoroacetic anhydride (101 mg, 0.48 mmol, 0.07 mL) was added to a solution of 3.158a (100 mg, 0.44 mmol) in Et2O (2 mL) at 0 C. The reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for 15 min. Saturated aqueous NaHCO3 (2 mL) was added and 393 the layers were separated. The aqueous phase was extracted with Et2O (3 x 2 mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure to provide 147 mg (99%) of 3.161 as a clear colorless oil: 1H NMR (400 MHz) d 5.65 (app dt, J = 15.6, 6.8 Hz, 1 H), 5.47 (dd, J = 15.6, 9.2 Hz, 1 H), 4.74 (d, J = 6.8 Hz, 2 H), 3.58 (d, J = 5.6 Hz, 2 H), 1.38 (app ddt, J = 13.2, 8.8, 4.4 Hz, 1 H), 1.12 (app ddt, J = 10.0, 5.6, 4.4 Hz, 1 H), 0.89 (s, 9 H), 0.78 (app dt, J = 8.4, 5.2 Hz, 1 H), 0.65 (app dt, J = 8.8, 4.4 Hz, 1 H), 0.05 (s, 6 H); 13C NMR (100 MHz) d 157.2, 142.7, 118.8, 115.9, 68.7, 65.1, 25.9, 23.2, 18.9, 18.4, 11.7, -5.2; IR (CDCl3) 3690, 2956, 2929, 2857, 1781, 1601, 1471, 1223, 1173, 1149, 1089 cm-1; mass spectrum (CI) m/z 339.1601 [C15H26O3F3Si (M+1) requires 339.1603] 351, 339, 337 (base), 323, 309. NMR Assignments: 1H NMR (400 MHz) d 5.65 (app dt, J = 15.6, 6.8 Hz, 1 H, C2-H), 5.47 (dd, J = 15.6, 9.2 Hz, 1 H, C3-H), 4.74 (d, J = 6.8 Hz, 2 H, C1-H), 3.58 (d, J = 5.6 Hz, 2 H, C7-H), 1.38 (app ddt, J = 13.2, 8.8, 4.4 Hz, 1 H), 1.12 (app ddt, J = 10.0, 5.6, 4.4 Hz, 1 H), 0.89 (s, 9 H, C11-H), 0.78 (app dt, J = 8.4, 5.2 Hz, 1 H, C5-H), 0.65 (app dt, J = 8.8, 4.4 Hz, 1 H, C5-H), 0.05 (s, 6 H, C8-C9-H); 13C NMR (100 MHz) d 157.2 (C12), 142.7 (C3), 118.8 (C2), 115.9 (C13), 68.7 (C7), 65.1 (C1), 25.9 (C11), 23.2 (C4), 18.9 (C10), 18.4 (C6), 11.7 (C5), -5.2 (C8,C9). Procedure for the [Rh(CO)2Cl]2-Catalyzed Tandem Allylic Alkylation/[5+2] Cycloaddition of Allylic Trifluoroacetates 3.154, 3.159 and 3.161. The allylic trifluoroacetate (0.1 mmol) was added to a solution of [Rh(CO)2Cl]2 (5 mol%) in degassed MeCN (0.5 mL), and the solution stirred for 10 min at room temperature. In a separate flask, malonate 3.86 (1.5 mmol) was added to a slurry of NaH (60% w/w in mineral oil, 1.4 mmol) in degassed MeCN (0.5 mL) and stirred for 20 min at room 394 temperature. The resulting enolate solution was added via syringe to the solution of trifluoroacetate and [Rh(CO)2Cl]2 at room temperature. The mixture was then sealed in a screw cap vial under an atmosphere of argon, and stirring was continued at room temperature until the starting material was consumed (as indicated by TLC). The reaction was then heated to 80 C (bath temperature) and stirring continued until intermediate enyne was consumed (as indicated by TLC). The reaction was then filtered through a short plug of silica gel eluting with Et2O (50 mL), and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography, eluting with pentane/Et2O (5:1 or 10:1) to furnish the products 3.152, 3.162 or 3.163. OHC 2 4 5 7 8 10 9 6 1 H 3 H 12 11 15 14 13 H3CO2C O 16 17 18 19 H3CO2C 2.68a Dimethyl 2-(4-(benzyloxy)but-2-ynyl)-2-((E)-3-((1R,2R)-2- formylcyclopropyl)allyl)malonate (2.68a) (BLA-III-244 and BLA-IV-233). Pd(PPh3)4 (170 mg, 0.15 mmol) and PPh3 (281 mg, 1.07 mmol) were added in one portion each to a solution of 3.7 (211 mg, 1.52 mmol) in degassed THF (8 mL) and stirred for 20 min at room temperature. In a separate flask, 2.57 (887 mg, 3.06 mmol) was added to a mixture of NaH (92 mg of a 60% mineral oil suspension, 2.29 mmol) in degassed THF (8 mL) at room temperature and the mixture was stirred for 20 min. The resulting homogeneous 395 solution of malonate anion was transferred via cannula to the solution containing 3.7 and Pd(PPh3)4. The resulting mixture was heated under reflux and stirred for 4 h. The resulting dark brown solution was allowed to cool to room temperature, a saturated aqueous solution of NaHSO4 (15 mL) was added, and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 15 mL) and the combined organic fractions were washed with saturated aqueous NaCl (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1 to 1:1) to give 440 mg (70%) of the carboxylic acid cyclopropyl enyne. Oxalyl chloride (0.18 mL, 2.06 mmol) was added to a solution of the carboxylic acid (440 mg, 1.03 mmol) and DMF (5 drops) in CH2Cl2 (10 mL) and stirred for 30 min at 0 C. The reaction was allowed to warm to room temperature by removal of the cooling bath and stirred for 5 h. The mixture was then concentrated under reduced pressure and the crude acid chloride was dissolved in THF (7 mL) and cooled to 78 C. A slurry of LiAlH(OtBu)3 (523 mg, 2.05 mmol) in THF (3 mL) was added and the reaction stirred for 4 h at 78 C. An aqueous 1 M HCl (10 mL) solution was added at 78 C and the mixture allowed to warm to room temperature by removal of the cooling bath. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 332 mg (81%) of 2.68a as a clear, colorless oil: 1H NMR (400 MHz) d 9.30 (d, J = 4.8 Hz, 1 H), 7.36-7.29 (comp, 5 H), 5.56-5.53 (comp, 2 H), 4.56 (s, 2 H), 4.14 (t, J = 2.0 Hz, 2 H), 3.73 (s, 3 H), 3.72 (s, 3 H), 2.84 (t, J = 2.0 Hz, 2 H), 2.78 (dd, J = 4.4, 2.4 Hz, 2 H), 2.13-2.06 (m, 2 H), 1.45 (app dt, J = 11.8, 5.2 Hz, 1 H), 1.37 (ddd, J = 11.8, 7.6, 5.2 Hz, 1 H); 13C NMR (100 MHz) d 200.6, 170.1, 137.4, 131.4, 128.4, 128.2, 126.1, 81.1, 79.3, 71.2, 57.3, 57.1, 52.7, 35.3, 396 29.8, 25.9, 23.1, 14.5; IR (CDCl3) 3031, 2954, 2848, 2258, 1734, 1702, 1437, 1207, 1070 cm-1; mass spectrum (CI) m/z 399.1799 [C23H27O6 (M+1) requires 399.1807] 399 (base), 369, 307, 291, 241. NMR Assignments: 1H NMR (400 MHz) d 9.30 (d, J = 4.8 Hz, 1 H, C1-H), 7.367.29 (comp, 5 H, C17-C18-C19-H), 5.56-5.53 (comp, 2 H, C5-C6-H), 4.56 (s, 2 H, C15H), 4.14 (t, J = 2.0 Hz, 2 H, C12-H), 3.73 (s, 3 H, C14-H), 3.72 (s, 3 H, C14-H), 2.84 (t, J = 2.0 Hz, 2 H, C9-H), 2.78 (dd, J = 4.4, 2.4 Hz, 2 H, C7-H), 2.13-2.06 (m, 2 H, C2-C4H), 1.45 (app dt, J = 11.8, 5.2 Hz, 1 H, C3-H), 1.37 (ddd, J = 11.8, 7.6, 5.2 Hz, 1 H, C3H); 13 C NMR (100 MHz) d 200.6 (C1), 170.1 (C13), 137.4 (C16), 131.4 (C5), 128.4, 128.2, 126.1 (C6), 81.1 (C10), 79.3 (C11), 71.2 (C15), 57.3 (C12), 57.1 (C8), 52.7 (C14), 35.3 (C7), 29.8 (C2), 25.9 (C4), 23.1 (C9), 14.5 (C3). 397 References 1. Washburn, D. G.; Heidebrecht, R. W., Jr.; Martin, S. F. "Concise Formal Synthesis of (-)-Peduncularine via Ring-Closing Metathesis." Org. Lett. 2003, 5, 3523-3525. Trost, B. M.; Andersen, N. G. 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"Synthesis of ( )-Prepinnaterpene, a Bromoditerpene from the Red Alga Laurencia Pinnata Yamada." Tetrahedron Lett. 1987, 28, 4303-4306. Martin, S. F.; Dwyer, M. P.; Hartmann, B.; Knight, K. S. "Cyclopropane-Derived Peptidomimetics. Design, Synthesis, and Evaluation of Novel Enkephalin Analogues." J. Org. Chem. 2000, 65, 1305-1318. Faller, J. W.; Sarantopoulos, N. " Retention of Configuration and Regiochemistry in Allylic Alkylations via the Memory Effect." Organometallics 2004, 23, 21792185. Cole, B. M.; Han, L.; Snider, B. B. "Mn(III)-Based Oxidative Free-Radical Cyclizations of Unsaturated Ketones." J. Org. Chem. 1996, 61, 7832-7847. Boehmer, J.; Grigg, R.; Marchbank, J. D. "Diastereoselective Cascade Synthesis of Azabicyclo[3.1.0]hexanes from Acyclic Precursors." Chem. Commun. 2002, 7, 768-769. Schwink, L.; Knochel, P. "Enantioselective Preparation of C2-Symmetrical Ferrocenyl Ligands for Asymmetric Catalysis." Chem. Eur. J. 1998, 4, 950-968. 431 378. 379. 380. 381. 382. 383. 384. 385. 386. 387. 388. 389. Leonard, M. S.; Carroll, P. J.; Joullie, M. M. "Synthesis of a Pondaplin Dimer and Trimer. Aromatic Interactions in Novel Macrocycles." J. Org. Chem. 2004, 69, 2526-2531. 432 Vita Brandon L. Ashfeld was born in Golden Valley, Minnesota on March 8, 1976, the first son of Normal Louis Ashfeld and Shirley Anne Keebler. After graduating from Robbinsdale Neil A. Armstrong High School, Plymouth, Minnesota, in 1994, he attended the University of Minnesota-Twin Cities. During the course of his undergraduate education he was fortunate to serve as an undergraduate research assistant in the laboratories of Professor Thomas R. Hoye under the direct supervision of Dr. Stephen A. Judd. In 1998, he graduated with a degree of Bachelor of Science in Chemistry. In August 1999, he entered the Graduate School of the University of Texas at Austin and joined the research laboratories of Professor Stephen F. Martin. In May of 2003 he was awarded a Welch Research Fellowship from the Department of Chemistry. In September 2004 he was awarded the American Cancer Society postdoctoral fellowship and is currently working as a National Institute of Health, Ruth L. Kirschtein postdoctoral fellow under the direction of Professor Barry M. Trost at Stanford University, Stanford, California. Permanent address: 9408 Northwood Pkwy, New Hope MN, 55427 This dissertation was typed by the author. 433

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