INTO FORAYS THE SYNTHESIS OF ZOANTHENOL: INTRIGUING PATTERNS IN REACTIVITY AND SELECTIVITY
Thesis by Jennifer L. Stockdill
In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy
California Institute of Technology Pasadena, CA 2009 (Defended 5 December 2008)
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2009 Jennifer L. Stockdill All Rights Reserved
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DEDICATION
To my parents, Dave and Lucy Stockdill, who have sacrificed so much for me. To my sister and brother, Teresa Barth and Jon Stockdill, who have been role models to me all of my life. To my eighth grade science teacher, Mary Alice Robinson, who sparked a passion that has not died. Finally, to my nieces and nephews, Hudson Barth, Deirdre Stockdill, Landen Barth, Jonah Stockdill, and Zoe Barth, who have provided the extra motivation to finish my Ph.D.
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ACKNOWLEDGEMENTS
...It is impossible to start....
It cannot be argued with that the most influential person in my graduate career has been my advisor, Brian M. Stoltz. Brian's passion, guidance, and discipline have been indispensable to my growth as a scientist and as a person over these past five and a half years. I am especially grateful to Brian for his devotion to his students' education and success. I have not heard of another professor who goes so far out of his/her way to make sure students are prepared for whatever the next step in their journeys may be. Also, Brian introduced me to my best friend EVER, TLC. After all, it is the fastest, cheapest, easiest way to obtain meaningful information about what's going on in your reaction flask! I am especially indebted to my thesis committee members, who have been simply unreal. Dennis Dougherty, my committee chair, has done a surprising job of keeping Harry in line, not to mention the insights he has provided in discussing my ideas and the depth to which he forces me to think. Harry Gray has been a constant source of support that has proven to be truly invaluable over the past two years when life has seemed so overwhelming. Bob Grubbs, the most recent addition to my committee has been asking me regularly how my research is going for years (I always regret not having a more cheerful reply, but the inquiries have meant a lot to me), and he always remembers to tell me when he's going climbing and I have to stay in lab! In all seriousness, all of my committee members have been very gracious and generous with their time, ideas, and recommendation letters. Thank you so much to all of them. I have had the great pleasure of working on my project with Dr. Doug Behenna and Dr. Andy McClory. Doug was the single most influential person on my development as a
v bench chemist. He taught me everything from what a TBS group is, to how to run a column, to the true meaning of scale-up. His hard work and friendship over the past years have been critical. I am grateful to Andy for helping me to learn that there is more than one way to approach a problem. He is a brilliant scientist, and I am sure he will be an amazing professor. The various members of the Stoltz group have provided a diverse, if occasionally tumultuous, environment that has not only shaped me as a chemist, but also as a person. Through all of the ups and downs of the 72+ hours/week that we spend together, I wouldn't replace any of the people I have had the opportunity to work with in the lab. The early lab members were instrumental to me in learning techniques and in how to think about chemistry. I am especially grateful to Eric Ashley, Eric Ferreira, Doug Behenna, and Raissa Trend for their advice in my early years. Toward the middle and through the end of my graduate career, I had the great fortune of becoming close friends with Dave Ebner and Ryan McFadden, who were both willing to talk endlessly with me about my chemistry and who always tried the ideas that I suggested for their work. They, of course, have both ditched me, and I miss them dearly. (Congratulations to RMAC on the birth of his son, Nathan!! And Dave...you can't escape! I'll be in NYC soon.) I am more and more grateful to Dan Daspi every day as I write my thesis. Dan is so
thoughtful in always trying to make the annoying parts of lab life run more smoothly. He has created a macro for everything you might need to do with a spectrum, and I think I'd still be trying to figure out how to get the things into my thesis right now if it weren't for him. My classmates are an awesome crew. I'm grateful to JT, who is a fountain of info from what's the deal with my NMR or the pKa of chemical X to what's the last step of the Rubik's cube algorithm. (Congratulations to JT on the birth of his daughter, Marie!!) Mike Krout always has what I'm looking for, whether it be a reagent or a procedure, and his generosity with both is appreciated. Also, I've always been grateful to
vi him for being so nice during group sports...I suck at most of them, and he is always patient. Mike Meyer has been a great friend over the years, and he will always hold a special place in my heart. Which brings me to Jenny Roizen...Jenny, I'll put your part at the end. The fou...fifth years are an eclectic bunch, that I have loved having around for the past four years. Nat Sherden has always been good to me, from bringing my mail in that ended up at his house to walking out of his way to walk me home when it's late at night, to apologizing when I have done something wrong, his kindness is overwhelming. Also, the emails...I love the emails. I hope I don't get taken off the group list right away because I will miss the misspelled sarcasm-rich frustrations. John Enquist is one of the most dedicated people I've known. It has been fun trying to break through his wall of seriousness (the trick is mint-chip ice cream!), and his dry sense of humor really gets me laughing sometimes. I have really enjoyed Kevin Allan's company as a baymate (briefly) and on years of coffee runs. I will always cherish the memory of late night flash columns listening to Ok Go, and I really admire his enthusiasm in the lab. Also, thanks for the cookie. Sandy Ma is one of the more unusual (in a good way) characters I've met. (DOGGIE!) She always makes me laugh and has the most quotable quotes. Brinton Anna Seashore-Ludlow was a fun baymate and is a great friend. I have missed her often since she moved to Sweeden. I've enjoyed getting to know Pam Tadross better over the past 9 months or so, and I'm sad that it took so long. She is a really thoughtful person and devoted friend. Chris Gilmore has always cracked me up. He's a great person to talk about life with, and lately I've enjoyed talking Obama with him as well. It's been
awesome to have Hosea in the lab. He has such a different perspective from the statusquo, it's always fun to see what he thinks. I've really enjoyed Narae's company over the past few years. She is a genuine and sweet person, and I've grown to expect her in lab on Saturday over the past 6 months. I always thought she was joking when she said he hobby was sleeping, but she seems to be in lab the rest of the time! :P I've grown to
vii really enjoy having Allen Hong in 264, and it will be really sad to say goodbye. I'm thankful for all the candy and especially for his concern...he always wants to know how you're doing when he asks. Of course, I'll miss my secret admirer, aka Hahvard, aka Matt Winston. Matt has been a great cheerleader in my thesis effort and his support is really appreciated. Also, he cheers Jenny up, which cheers me up! The first years in the group are a hilarious bunch, and I regret that I won't have the opportunity to get to know them better. Nathan Bennett, my newest baymate, always has something nice to say, and he is very encouraging, even to himself... "Alright, self..." Jonny Gordon is just too cool for school (but he comes anyway). I dig the purple sweatband and the blue glasses. Alex Goldberg is our newest member, and he seems to share my sarcastic sense of humor. Finally, there are the postdocs. There have been many...I'm especially grateful to Amanda Jones, who has been a really good friend, and is always a pleasure to have in lab, but most importantly, hosts the poker night (no boss allowed!). Jan Streuff has been a fun companion over the past year, and I will miss him when he goes back to Deutschland. Also, Corinne Baumgartner has been a fun exercise buddy, and Christian Defieber always tried to speak German with me. If it weren't for Nolan McDougal, I would not be able to say that I've walked from campus to Roscoe's, or worse, I might not know how to properly eat bread at a nice dinner! I'm grateful to him for the fun
memories and for introducing me to scallops. I mentioned Andy McClory briefly, but I need to mention here that he is one of the more loyal friends a person could ask for, and I really enjoyed his friendship. A recent addition to the lab, Chris Henry, has fast become one of my closest friends, and I am very thankful to have met him. Thanks also to Xiaoquing Han (X-Dog), Andy Harned, Haiming Zhang, and Kousuke Tani for their kindness and advice. I need to make a separate paragraph here for my baymates. Eric Ashley was my first baymate, and I am ever grateful to him for all that he taught me those first few years.
viii Also, I wouldn't know important things like "what ever happened to a good old fashioned passionate *%&-whuppin', getting your shoes, coat and your hat tooken." Brinton
Seashore-Ludlow is one of those people that you just love right away. We had lots of fun hiking and going to yoga, and of course running collumm-collummns!! Enough cannot be said about Thomas Jensen, who among other things was the first baymate I had who liked all the same music as me. We had a blast jammin' in the lab and talking chemistry. Not to mention playing 10:1 with Dave! I would like to thank Thomas Jensen, Dave Ebner, Chris Henry, and Brian Stoltz for proofreading all of my thesis. Amanda Jones, Doug Behenna, Kevin Allan, Jenny Roizen also edited chapters. Jenny, thanks for doing it at the last minute with no notice. I am especially grateful to Chris Henry for his help with numbering compounds and to Dave Ebner for making my table of contents and list of figures. Dave is also the only person who proofread my whole thesis twice (or was it three times?). He must be really bored over in New Jersey waiting to start his postdoc! ;) Thank you all so much. This document would be a mess without you. In addition to the outstanding members of the Stoltz group, I have been warmly welcomed by the Grubbs, Bercaw, Gray, Dougherty, and Reisman labs. To thank each of the people in these groups would be overwhelming, but they are all truly appreciated, and I look forward to seeing them in the future. Amazingly, I managed to meet some people outside of the department, and it turns out that many of them have been among my most critical and constant supporters. I would not be the same person without the friendships of Justin Bois, Raviv Perahia, Hernan Garcia, Tristan Smith, Anna Folinsky, Erin Koos, Nhat Vu, Nate Bode, Vikram Deshpande, Eric Peterson, Lucia Cordiero, Heidi Privett, Crystal Shih, Jeff Byers, Steve Baldwin, Dan Grin and Harmony Gates. You guys have all been truly amazing friends, and I am so thankful for all the times you've scraped me off the ground and reassembled
ix me into a human again. My move to the West Coast would not have been conceived of without Joe Polidan, and my last year of college would have definitely not been as fabulous without Sheila (a.k.a. Pony 2) Gradwell. Boo Shan Tseng and Hari Shroff were indispensable companions in Argentina/Chile. Likewise, Mike Olsen was a blast to have along in Costa Rica. It was a pleasure spending two weeks with each of them in paradise. Those memories bring me to Tristan Ursell, who was my companion for three of the most challenging, yet adventure-packed years of grad school. Tristan remains one of my closest friends, and I cannot thank him enough for everything that we shared. I will always treasure our many memories in some of the most beautiful places in the world. Tristan also helped me to learn a lot about myself and ultimately led me in the direction of actually paying attention to what's happening in the world. He taught me to look deeper into myself and to become the person I wanted to be instead of wishing things were different. I've put this off for awhile now, but it comes time to try to thank Jenny Roizen. There aren't words to express my gratitude to Jenny. For the first three years of grad school, Jenny was my roommate, labmate, and friend. We did everything together. I could not possibly have gotten through some of the rougher times of the past five and a half years without Jenny's constant love and support. I have grown to really appreciate her direct candor with me about everything. To put it briefly, Jenny rocks. I'm so sad to be leaving her in the lab without me. I know that she will get through everything fine, but I wish I could be here to support her, as she has so devotedly supported me over this thesis journey. Most people are lucky to have one friend as constant and close to their heart as Jenny is to mine. I have had the great fortune during my graduate career of having developed two such friends. Professor Dr. Jen Dionne has become a critical appendage over the years. To lose her would be like losing an arm. I am left frustrated again with the
x English language for not having the appropriate words to match the quality and magnitude of Jen's friendship. She has become like a twin sister to me, which is exciting because I never had a twin sister! I will just say to both Jen and Jenny, I love you. You are irreplaceable. Finally, to thank the people who shaped me into who I am. Becky (Doyal) Orrock and Aimee (Dudash) Ketner have been my best friends since I can remember, and it has been awesome watching each other grow from little girls ogling at cute boys at the beach to grown women, ogling at cute boys at the beach. Sally, I am glad you moved to Virginia. It's been nice having some extended family nearby, and I always enjoy our phone calls, surprisingly also often relating to ogling at boys at the beach! Grandma Stockdill, it has been fabulous visiting with you more often over the past ten years. I'm glad you were persistent about calling. Your support has been treasured. Grandma Vorlicek, I wish I could see you more, but I wanted to take this chance to thank you for working so hard to keep the family together over the years. I know it was challenging raising 8 kids as a single mom, and I'm amazed that you managed to do it so successfully. Teresa and Jon, thanks for all that you have done for me over the years. I have always looked up to you, and I continue to be awed by your talents as you raise your families. You have the 5 coolest kids in the world. I can't wait to be back with you and with them. Mom and Dad, I love you both and I wish you all the happiness and adventure that you have ensured that I had the opportunity to experience. You have all contributed
irreversibly to the person I have become. I cannot thank you enough.
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ABSTRACT
The zoanthamine family of alkaloids has attracted the attention of synthetic chemists for over two decades, beginning with the first report of their isolation in 1984. Not only are these stereochemically dense polycyclic compounds structurally fascinating, but they also display interesting and important biological activities. Foremost among these is the potent anti-osteoporotic effect of norzoanthamine. To date, norzoanthamine remains the only member to have succumbed to total synthesis, by Miyashita and coworkers in 2004. Our studies began by targeting zoanthenol, a structurally similar natural product that possesses the key stereochemical challenges of norzoanthamine, while offering unique opportunities for strategic development as compared to the other family members. The synthetic work described herein focuses on approaches to the tricyclic core of zoanthenol, specifically employing an approach by which the stereochemical complexity of the C ring, marked by the challenging vicinal all-carbon quaternary centers, is addressed early in the synthesis. These functionalized C ring synthons are then tethered to an aromatic A ring synthon, and methods to form the final bond of the B ring are explored. Special attention is given to the acid-mediated Friedel-Crafts cyclization
approach. In addition to the acid-mediated cyclization approach, an alternative cyclization method is discussed wherein the A ring is substituted with a halogen in order to enable generation of a radical. This radical then undergoes a 1,4-addition into a fully substituted enone to close the B ring and provide the desired stereochemistry both of the two new stereocenters that are generated in the cyclization. In these efforts, we have learned a great deal about the factors governing selectivity and reactivity in these systems. For each case, stereochemical models are discussed and key structural requirements for future investigations are outlined.
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PROLOGUE
The Importance of Natural Products Synthesis
This prologue is primarily for the benefit of readers outside of the field of chemistry, who may not be familiar with the nuances of the field of total synthesis, and thus, the impact of the research described in this thesis. Natural products are complex molecules that have been isolated from a natural source, such as a tree bark, a fungus, a bacterial species, or even a marine creature. The study of natural products synthesis is essential to the advancement of organic chemistry, as well as to society as a whole. A natural product synthesis involves looking at a structure that has been isolated from nature, and then finding a way to make it from much smaller starting materials. As such, it is an ideal platform for the discovery of new reactions because every natural product presents a unique array of bonds that have likely not been made before. In order to make some of these bonds, new chemistry must be invented. These new reactions are typically applied to related molecules of varying levels of complexity, leading to the development of a new reaction methodology. Thus, total synthesis fuels the discovery of new methodology, while new methodology
simultaneously allows for the completion of total syntheses. The broader impact of these studies is realized largely through the pharmaceutical industry. Although pharmaceutical companies invest a great deal of time and money into their own research programs, they are generally very focused on a specific goal such as finding a drug for breast cancer. This is a large enough problem on its own that the company cannot invest their own man-hours into synthesizing natural products from scratch. Thus, they turn to academic groups for key information about what bonds were the most challenging to make and what disconnections lead to the shortest and most modular synthesis of a compound. Short syntheses are important to pharmaceutical
xiii companies because even if every step of a 30-step synthesis of a compound proceeds with 90% yield (this is not typical), the overall yield for the process is (.9)30 or 4%. If the company is going to conduct testing on the compound, they cannot afford to waste 96% of their original materials. Thus, it is important for academic groups to discover as many different types of reactions and ways to disconnect natural products as possible. It is also important to have a modular synthesis, so that analog compounds can be made and tested. In many cases, the best pharmaceutical agents are modified versions of natural products. Natural products offer the great advantage of having already been compatible with at least one living system, the one from which they were isolated. If that creature was able to survive with this compound inside it, it is more likely that a human will be able to tolerate the compound than for a molecule that has been 100% designed. Some important drugs that are natural products or derivatives include the antibiotics penicillin and vancomycin, contraceptives (+)-norgestrel and 17-ethynylestradiol, the antiinflammatory agent indomethacin, and the ovarian, breast, and small lung cancer drug paclitaxel (taxol). The research presented herein centers around the synthesis of a marine alkaloid, zoanthenol, isolated off the coast of the Canary Islands from polyps of the genus Zoanthus. A number of very similar compounds were also isolated from the zoanthids, and they comprise a family of natural products called the zoanthamines. As a family, the zoanthamines offer a range of biological activities including inhibition of inflammation in mouse ears, cytotoxicity against murine leukemia cells, broad-spectrum antibacterial activity, and activity against human platelet aggregation. Perhaps the most exciting biological activity is the excellent anti-osteoporotic activity demonstrated by
norzoanthamine.
In ovarioectomized mice, a good model for post-menopausal
osteoporosis, treatment with norzoanthamine hydrochloride prevented the loss of bone mass and strength. Additionally, bone strength can be restored in ovarioectomized mice
xiv by treatment with norzoanthamine hydrochloride without any observed uterine atrophy, a side effect of treatment with 17-estradiol, the current standard in this type of therapy. This difference points to the possibility of a different mechanism of action than estrogen therapy, making the zoanthamines an important family of natural products to target for synthesis.
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TABLE OF CONTENTS
Dedication................................................................................................................................iii Acknowledgements .................................................................................................................ix Abstract ....................................................................................................................................xi Prologue ..................................................................................................................................xii Table of Contents.................................................................................................................... xv List of Figures .........................................................................................................................xx List of Schemes..................................................................................................................xxxiii List of Tables............................................................................................................................xl List of Abbreviations ............................................................................................................xliii
CHAPTER 1: THE BIOLOGY AND CHEMISTRY OF THE ZOANTHAMINE ALKALOIDS .................... 1 1.1.1 1.2 1.2.1 Introduction ................................................................................................................. 1 The Zoanthamine Natural Products ...........................................................................3 Isolation and Structural Characterization of the Zoanthamine Natural Products........................................................................................................................3 1.2.2 1.2.3 1.3 1.3.1 1.3.2 1.4 1.4.1 1.4.2 1.4.3 Biosynthesis of the Zoanthamine Natural Products..................................................6 Reactivity Studies of Norzoanthamine......................................................................11 Biological Activities of Zoanthamine Alkaloids ....................................................... 13 Anti-Osteoporotic Activity ........................................................................................ 13 Miscellaneous Biological Activities........................................................................... 15 Synthetic Approaches Toward the Zoanthamine Natural Products....................... 17 General Remarks ....................................................................................................... 17 Miyashita's Synthesis of Norzoanthamine...............................................................18 Tanner's Diels-Alder Approach to the Zoanthamine ABC Ring System ................22
xvi 1.4.4 1.4.5 1.4.6 Uemura's Approach to the Norzoanthamine ABC Ring System ............................28 Williams's Approach to the Norzoanthamine AB and EFG Ring Systems............ 28 Theodorakis's Annulation Approach to the Norzoanthamine ABC Ring System .........................................................................................................................31 1.4.7 Kobayashi's Synthesis of the Heterocyclic CDEFG Zoanthamine Ring System ........................................................................................................................ 33 1.4.8 1.5.1 Hirama's Strategy for the Zoanthenol ABC Ring System ....................................... 34 Summary and Outlook ..............................................................................................38
References ..............................................................................................................................40
CHAPTER 2: EARLY EFFORTS TOWARD THE SYNTHESIS OF ZOANTHENOL ............................ 43 2.1.1 2.2.1 2.2.2 2.2.3 2.3.1 2.4.1 2.5.1 2.5.2 Introduction and Retrosynthetic Analysis............................................................... 43 Synthesis of the A Ring Synthon .............................................................................. 45 Synthesis of the C Ring Synthon .............................................................................. 45 Synthesis of the Tricyclic Core of Zoanthenol ......................................................... 47 Enantioselective Synthesis of the DEFG Synthon................................................... 53 Summary of Early Synthetic Work........................................................................... 55 Materials and Methods ............................................................................................. 56 Preparation of Compounds....................................................................................... 58
References .............................................................................................................................. 85 Synthetic Summary................................................................................................................ 89
APPENDIX A: SPECTRA AND X-RAY CRYSTALLOGRAPHIC DATA: EARLY EFFORTS TOWARD THE SYNTHESIS OF ZOANTHENOL ....................................................... 92
CHAPTER 3: ACID-MEDIATED CYCLIZATION APPROACHES TO THE DENSELY SUBSTITUTED CARBOCYCLIC CORE OF ZOANTHENOL .......................................181
xvii 3.1.1 3.2 3.2.1 3.2.2 3.3.1 3.3.2 3.4.1 3.5.1 3.5.2 3.6.1 3.6.2 3.7.1 3.7.2 3.8.1 3.8.2 3.9.1 Revised Retrosynthetic Analysis.............................................................................182 Toward a Vicinal Quaternary Center-Containing C Ring Synthon ......................182 Synthesis and Desymmetrization of a meso-Anhydride .......................................182 Elaboration of the Half-Ester..................................................................................186 Toward a Lactone-Derived C Ring Synthon .......................................................... 187 Acid-Mediated Cyclizations of Lactone-Derived AC Ring Systems ...................188 Functionalization of Allylic Alcohol 248 ...............................................................190 Toward a 7-Membered Acetal-Derived C Ring .......................................................191 Acid-Mediated Cyclization of the 7-Membered Acetal Substrate.........................193 Synthesis of a Homologated C Ring Synthon ........................................................194 Acid-Mediated Cyclizations of the Homologated AC Ring System.................... 195 Modification of the Homologated AC Ring System ............................................196 Acid-Mediated Cyclizations of Carboxylic Acid-Derived AC Ring Systems ...... 196 Mechanistic Hypotheses.......................................................................................... 197 Mechanistic Summary and Substrate Requirements............................................201 Summary of Brnsted Acid Cyclization Efforts .................................................... 202
3.10.1 Materials and Methods........................................................................................... 203 3.10.2 Preparation of Compounds .................................................................................... 205 References ........................................................................................................................... 240 Summary Schemes .............................................................................................................. 243
APPENDIX B: SPECTRA AND X-RAY CRYSTALLOGRAPHIC DATA: ACID-MEDIATED CYCLIZATION APPROACHES TO THE DENSELY SUBSTITUTED CARBOCYCLIC CORE OF ZOANTHENOL ................................................................................... 248
xviii CHAPTER 4: RADICAL CYCLIZATION APPROACHES TOWARD THE TRICYCLIC CORE OF ZOANTHENOL .................................................................................... 366 4.1.1 4.2.1 4.3.1 Introduction............................................................................................................. 366 Synthesis and Cyclization of a Lactone-Derived Precursor..................................368 Synthesis and Cyclization of a Homologated Nitrile-Derived Cyclization Precursor.................................................................................................................. 370 4.4.1 Synthesis and Cyclization of a Homologated Ester-Derived Cyclization Precursor...................................................................................................................371 4.5.1 Synthesis and Cyclization of a 7-Membered Acetal-Derived Cyclization Precursor.................................................................................................................. 372 4.6.1 4.7.1 4.8.1 4.8.2 Substrate Requirements and Limits of System ..................................................... 373 Summary.................................................................................................................. 376 Materials and Methods ........................................................................................... 377 Preparation of Compounds..................................................................................... 378
References ............................................................................................................................389 Summary Schemes...............................................................................................................390
APPENDIX C: SPECTRA AND X-RAY CRYSTALLOGRAPHIC DATA: RADICAL CYCLIZATION APPROACHES TOWARD THE TRICYCLIC CORE OF ZOANTHENOL ...................... 392
APPENDIX D: CURRENT AND FUTURE I NVESTIGATIONS TOWARD ZOANTHENOL ...................417 D.1 D.2 D.3.1 Introduction..............................................................................................................417 Proposed Methods for the Utilization of Tricycle 192...........................................417 Development and Cyclization of a 6-Membered Acetal-Derived AC Ring System with Inverted C(10) Stereochemistry........................................................ 419 D.3.2 Advancement of Cyclopentylidene-Derived C Ring Synthon for
xix Acid-Mediated Cyclization ...................................................................................... 421 D.3.3 Advancement of Cyclopentylidene-Derived C Ring for Radical Cyclization .......422 D.4.1 Alternative Approaches to the Tricyclic Core of Zoanthenol................................423
D.4.2 Allylation/Diels-Alder Approach ............................................................................424 D.4.3 -Arylation Approach..............................................................................................427 D.5.1 Precedence for Planned Late-Stage Side Chain Couplings ...................................429
D.5.2 Alkyne Addition into Enantiopure Lactam Synthon ............................................ 430 D.5.3 Synthesis of a Horner-Wadsworth-Emmons Reagent for Side Chain Synthesis................................................................................................................... 431 D.6.1 D.7.1 Summary .................................................................................................................. 431 Materials and Methods............................................................................................432
D.7.2 Preparation of Compounds .....................................................................................433 References ............................................................................................................................454
APPENDIX E: SPECTRA AND X-RAY CRYSTALLOGRAPHIC DATA: CURRENT AND FUTURE INVESTIGATIONS TOWARD ZOANTHENOL ........................................................456
Comprehensive Bibliography ............................................................................................. 509 Notebook Cross-references.................................................................................................. 518 About the Author..................................................................................................................527
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LIST OF FIGURES
CHAPTER 1 Figure 1.1.1 Figure 1.1.2 Figure 1.2.1 Figure 1.2.2 Representative zoanthids ...................................................................1 Natural products isolated from zoanthids........................................ 3 Zoanthamine natural products isolated by Rao............................... 4 Zoanthamine natural products isolated by Uemura and Clardy .................................................................................................. 5 Figure 1.2.3 Figure 1.3.1 Zoanthamine natural products isolated by Norte............................ 6 IC50 values for the inhibition of IL-6 production in Uemura's SAR study ..........................................................................................15 Figure 1.3.2 Figure 1.4.1 Figure 1.4.2 Figure 1.4.3 Figure 1.4.4 Figure 1.4.5 Figure 1.4.6 APPENDIX A Figure A.1 Figure A.2 Figure A.3 Figure A.4 Figure A.5 Figure A.6
1H
IC50 values for the inhibition of IL-6 dependent cell growth .........15 Miyashita's retrosynthetic analysis of norzoanthamine.................18 Tanner's retrosynthetic analysis of zoanthamine .......................... 22 Uemura's retrosynthetic analysis of norzoanthamine................... 28 Williams's retrosynthetic analysis of norzoanthamine ................. 29 Theodorakis's retrosynthetic analysis of norzoanthamine ............31 Hirama's retrosynthetic analysis of zoanthenol............................. 34
NMR (300 MHz, CDCl3) of compound 172 .............................. 93
Infrared spectrum (thin film/NaCl) of compound 172 ................. 94
13C 1H
NMR (75 MHz, CDCl3) of compound 172 ................................ 94 NMR (300 MHz, CDCl3) of compound 174 .............................. 95
Infrared spectrum (thin film/NaCl) of compound 174 ................. 96
13C
NMR (75 MHz, CDCl3) of compound 174 ................................ 96
xxi Figure A.7 Figure A.8 Figure A.9 Figure A.10 Figure A.11 Figure A.12 Figure A.13 Figure A.14 Figure A.15 Figure A.16 Figure A.17 Figure A.18 Figure A.19 Figure A.20 Figure A.21 Figure A.22 Figure A.23 Figure A.24 Figure A.25 Figure A.26 Figure A.27 Figure A.28 Figure A.29 Figure A.30 Figure A.31 Figure A.32
1H
NMR (300 MHz, CDCl3) of compound 173...............................97
Infrared spectrum (thin film/NaCl) of compound 173..................98
13C 1H
NMR (75 MHz, CDCl3) of compound 173 .................................98 NMR (300 MHz, CDCl3) of compound 175 ...............................99
Infrared spectrum (thin film/NaCl) of compound 175................100
13C 1H
NMR (75 MHz, CDCl3) of compound 175 ...............................100 NMR (300 MHz, CDCl3) of compound 168 ............................ 101
Infrared spectrum (thin film/NaCl) of compound 168 ...............102
13C 1H
NMR (75 MHz, CDCl3) of compound 168 ..............................102 NMR (300 MHz, CDCl3) of compound (+)-177 ......................103
Infrared spectrum (thin film/NaCl) of compound (+)-177 .........104
13C 1H
NMR (75 MHz, CDCl3) of compound (+)-177 ........................104 NMR (300 MHz, CDCl3) of compound ()-177 ......................105
Infrared spectrum (thin film/NaCl) of compound ()-177 .........106
13C 1H
NMR (75 MHz, CDCl3) of compound ()-177 ........................106 NMR (300 MHz, CDCl3) of compound 178.............................107
Infrared spectrum (thin film/NaCl) of compound 178 ...............108
13C 1H
NMR (75 MHz, CDCl3) of compound 178...............................108 NMR (300 MHz, CDCl3) of compound 169 ............................109
Infrared spectrum (thin film/NaCl) of compound 169 ............... 110
13C 1H
NMR (75 MHz, CDCl3) of compound 169 .............................. 110 NMR (300 MHz, CDCl3) of compound ()-170....................... 111
Infrared spectrum (thin film/NaCl) of compound ()-170 .........112
13C 1H
NMR (75 MHz, CDCl3) of compound ()-170 .........................112 NMR (300 MHz, CDCl3) of compound (+)-180 ......................113
Infrared spectrum (thin film/NaCl) of compound (+)-180 .........114
xxii Figure A.33 Figure A.34 Figure A.35 Figure A.36 Figure A.37 Figure A.38 Figure A.39 Figure A.40 Figure A.41 Figure A.42 Figure A.43 Figure A.44 Figure A.45 Figure A.46 Figure A.47 Figure A.48 Figure A.49 Figure A.50 Figure A.51 Figure A.52 Figure A.53 Figure A.54 Figure A.55 Figure A.56 Figure A.57 Figure A.58
13C 1H
NMR (75 MHz, CDCl3) of compound (+)-180 ........................114 NMR (300 MHz, CDCl3) of compound 183............................. 115
Infrared spectrum (thin film/NaCl) of compound 183................ 116
13C 1H
NMR (75 MHz, CDCl3) of compound 183 ...............................116 NMR (300 MHz, CDCl3) of compound 184............................. 117
Infrared spectrum (thin film/NaCl) of compound 184 ...............118
13C 1H
NMR (75 MHz, CDCl3) of compound 184 ...............................118 NMR (300 MHz, CDCl3) of compound 187 .............................119
Infrared spectrum (thin film/NaCl) of compound 187............... 120
13C 1H
NMR (75 MHz, CD2Cl2) of compound 187 ............................. 120 NMR (500 MHz, CDCl3) of compound 188.............................121
Infrared spectrum (thin film/NaCl) of compound 188 ...............122
13C 1H
NMR (125 MHz, CDCl3) of compound 188 .............................122 NMR (300 MHz, CDCl3) of compound 189.............................123
Infrared spectrum (thin film/NaCl) of compound 189 ...............124
13C 1H
NMR (75 MHz, CDCl3) of compound 189 ...............................124 NMR (300 MHz, CDCl3) of compound 191 .............................125
Infrared spectrum (thin film/NaCl) of compound 191 ................126
13C 1H
NMR (75 MHz, CDCl3) of compound 191................................126 NMR (300 MHz, CDCl3) of compound 192 .............................127
Infrared spectrum (thin film/NaCl) of compound 192............... 128
13C 1H
NMR (75 MHz, CDCl3) of compound 192 .............................. 128 NMR (500 MHz, C6D6) of compound 193 ...............................129
Infrared spectrum (thin film/NaCl) of compound 193............... 130
13C 1H
NMR (125 MHz, C6D6) of compound 193 .............................. 130 NMR (500 MHz, CDCl3) of compound 194 .............................131
xxiii Figure A.59 Figure A.60 Figure A.61 Figure A.62 Figure A.63 Figure A.64 Figure A.65 Figure A.66 Figure A.67 Figure A.68 Figure A.69 Figure A.70 Figure A.71 Figure A.72 Figure A.73 Figure A.74 Figure A.75 Figure A.76 Figure A.77 Figure A.78 Figure A.79 Figure A.80 Figure A.81 Figure A.82 Figure A.83 Figure A.84 Infrared spectrum (thin film/NaCl) of compound 194 ............... 132
13C 1H
NMR (125 MHz, CDCl3) of compound 194.............................132 NMR (500 MHz, CDCl3) of compound 195............................. 133
Infrared spectrum (thin film/NaCl) of compound 195 ............... 134
13C 1H
NMR (125 MHz, CDCl3) of compound 195.............................134 NMR (500 MHz, CDCl3) of compound 196 ............................ 135
Infrared spectrum (thin film/NaCl) of compound 196 ............... 136
13C 1H
NMR (125 MHz, CDCl3) of compound 196.............................136 NMR (300 MHz, CDCl3) of compound ()-210 ..................... 137
Infrared spectrum (thin film/NaCl) of compound ()-210 ........138
13C 1H
NMR (75 MHz, CDCl3) of compound ()-210........................138 NMR (300 MHz, CDCl3) of compound ()-211 ...................... 139
Infrared spectrum (thin film/NaCl) of compound ()-211 .........140
13C 1H
NMR (75 MHz, CDCl3) of compound ()-211 ........................140 NMR (300 MHz, CDCl3) of compound ()-212.......................141
Infrared spectrum (thin film/NaCl) of compound ()-212 ........ 142
13C 1H
NMR (75 MHz, CDCl3) of compound ()-212 ........................142 NMR (300 MHz, CDCl3) of compound 213 ............................143
Infrared spectrum (thin film/NaCl) of compound ()-213 ........ 144
13C 1H
NMR (75 MHz, CDCl3) of compound ()-213 ........................144 NMR (300 MHz, CDCl3) of compound 214 ............................ 145
Infrared spectrum (thin film/NaCl) of compound 214 ...............146
13C 1H
NMR (75 MHz, CDCl3) of compound 214...............................146 NMR (300 MHz, CDCl3) of compound 215............................. 147
Infrared spectrum (thin film/NaCl) of compound 215 ...............148
13C
NMR (75 MHz, CDCl3) of compound 215...............................148
xxiv Figure A.85 Figure A.86 Figure A.87 Figure A.88 Figure A.89 Figure A.90 Figure A.91 Figure A.92 Figure A.93 Figure A.94 Figure A.95 Figure CHAPTER A.96 3 Figure 3.2.1 Figure 3.8.1 APPENDIX B Figure B.1 Figure B.2 Figure B.3 Figure B.4 Figure B.5 Figure B.6 Figure B.7 Figure B.8 Figure B.9
1H 1H
NMR (300 MHz, CDCl3) of compound 215a.......................... 149
Infrared spectrum (thin film/NaCl) of compound 215a............. 150
13C 1H
NMR (75 MHz, CDCl3) of compound 215a ............................ 150 NMR (300 MHz, CDCl3) of compound 203 ............................ 151
Infrared spectrum (thin film/NaCl) of compound 203 ...............152
13C 1H
NMR (75 MHz, CDCl3) of compound 203 ..............................152 NMR (500 MHz, CDCl3) of compound 168.............................153
Infrared spectrum (thin film/NaCl) of compound 168 ...............154
13C
NMR (125 MHz, CDCl3) of compound 168 .............................154
Representation of Lactone 184......................................................155 Representation of Acid 187CHCl3 ............................................. 164 Representation of Diketone 196 ....................................................173
Known meso-anhydride desymmetrization substrates............... 184 Requirements for future acid cyclization substrates ...................202
NMR (500 MHz, CDCl3) of compound 225.............................241
Infrared spectrum (thin film/NaCl) of compound 225 .............. 242
13C 1H
NMR (125 MHz, CDCl3) of compound 225 ............................242 NMR (500 MHz, CDCl3) of compound 226 ...........................243
Infrared spectrum (thin film/NaCl) of compound 226 .............. 244
13C 1H
NMR (125 MHz, CDCl3) of compound 226............................244 NMR (500 MHz, CDCl3) of compound 242 ........................... 245
Infrared spectrum (thin film/NaCl) of compound 242 .............. 246
13C
NMR (125 MHz, CDCl3) of compound 242............................246
xxv Figure B.10 Figure B.11 Figure B.12 Figure B.13 Figure B.14 Figure B.15 Figure B.16 Figure B.17 Figure B.18 Figure B.19 Figure B.20 Figure B.21 Figure B.22 Figure B.23 Figure B.24 Figure B.25 Figure B.26 Figure B.27 Figure B.28 Figure B.29 Figure B.30 Figure B.31 Figure B.32 Figure B.33 Figure B.34 Figure B.35
1H
NMR (300 MHz, C6D6) of compound 247 ..............................247
Infrared spectrum (thin film/NaCl) of compound 247 .............. 248
13C 1H
NMR (75 MHz, C6D6) of compound 247 ............................... 248 NMR (500 MHz, CDCl3) of compound 247a ..........................249
Infrared spectrum (thin film/NaCl) of compound 247a............ 250
13C 1H
NMR (125 MHz, CDCl3) of compound 247a ......................... 250 NMR (500 MHz, CDCl3) of compound 248............................ 251
Infrared spectrum (thin film/NaCl) of compound 248 ..............252
13C 1H
NMR (125 MHz, CDCl3) of compound 248 ............................252 NMR (300 MHz, CDCl3) of compound 250............................253
Infrared spectrum (thin film/NaCl) of compound 250...............254
13C 1H
NMR (75 MHz, CDCl3) of compound 250 ..............................254 NMR (300 MHz, CDCl3) of compound 251.............................255
Infrared spectrum (thin film/NaCl) of compound 251 ...............256
13C 1H
NMR (75 MHz, CDCl3) of compound 251...............................256 NMR (300 MHz, CDCl3) of compound 251a ..........................257
Infrared spectrum (thin film/NaCl) of compound 252...............258
13C 1H
NMR (75 MHz, CDCl3) of compound 252 ..............................258 NMR (300 MHz, CDCl3) of compound 252 ............................259
Infrared spectrum (thin film/NaCl) of compound 252.............. 260
13C 1H
NMR (75 MHz, CDCl3) of compound 252 ............................. 260 NMR (300 MHz, CDCl3) of compound 253 ............................261
Infrared spectrum (thin film/NaCl) of compound 253...............262
13C 1H
NMR (75 MHz, CDCl3) of compound 253 ..............................262 NMR (300 MHz, CDCl3) of compound 255 ............................263
Infrared spectrum (thin film/NaCl) of compound 255 ...............264
xxvi Figure B.36 Figure B.37 Figure B.38 Figure B.39 Figure B.40 Figure B.41 Figure B.42 Figure B.43 Figure B.44 Figure B.45 Figure B.46 Figure B.47 Figure B.48 Figure B.49 Figure B.50 Figure B.51 Figure B.52 Figure B.53 Figure B.54 Figure B.55 Figure B.56 Figure B.57 Figure B.58 Figure B.59 Figure B.60 Figure B.61
13C 1H
NMR (75 MHz, 255) of compound 255 .................................. 264 NMR (500 MHz, CDCl3) of compound 256............................ 265
Infrared spectrum (thin film/NaCl) of compound 256 .............. 266
13C 1H
NMR (75 MHz, CDCl3) of compound 256..............................266 NMR (500 MHz, CDCl3) of compound 257 ............................ 267
Infrared spectrum (thin film/NaCl) of compound 257...............268
13C 1H
NMR (125 MHz, CDCl3) of compound 257 ............................268 NMR (300 MHz, CDCl3) of compound 258 ...........................269
Infrared spectrum (thin film/NaCl) of compound 258 .............. 270
13C 1H
NMR (125 MHz, CDCl3) of compound 258............................270 NMR (300 MHz, CDCl3) of compound 259 ............................271
Infrared spectrum (thin film/NaCl) of compound 259 .............. 272
13C 1H
NMR (75 MHz, CDCl3) of compound 259.............................. 272 NMR (300 MHz, CDCl3) of compound 260 ........................... 273
Infrared spectrum (thin film/NaCl) of compound 260.............. 274
13C 1H
NMR (75 MHz, CDCl3) of compound 260 ............................. 274 NMR (300 MHz, CDCl3) of compound 261 ............................ 275
Infrared spectrum (thin film/NaCl) of compound 261............... 276
13C 1H
NMR (75 MHz, CDCl3) of compound 261 .............................. 276 NMR (300 MHz, CDCl3) of compound 262a ......................... 277
Infrared spectrum (thin film/NaCl) of compound 262a ............ 278
13C 1H
NMR (75 MHz, CDCl3) of compound 262a ........................... 278 NMR (300 MHz, CDCl3) of compound 262b ......................... 279
Infrared spectrum (thin film/NaCl) of compound 262b............280
13C 1H
NMR (75 MHz, CDCl3) of compound 262b ...........................280 NMR (300 MHz, C6D6) of compound 263.............................. 281
xxvii Figure B.62 Figure B.63 Figure B.64 Figure B.65 Figure B.66 Figure B.67 Figure B.68 Figure B.69 Figure B.70 Figure B.71 Figure B.72 Figure B.73 Figure B.74 Figure B.75 Figure B.76 Figure B.77 Figure B.78 Figure B.79 Figure B.80 Figure B.81 Figure B.82 Figure B.83 Figure B.84 Figure B.85 Figure B.86 Figure B.87 Infrared spectrum (thin film/NaCl) of compound 263.............. 282
13C 1H
NMR (300 MHz, C6D6) of compound 263 ............................ 282 NMR (300 MHz, CDCl3) of compound 264........................... 283
Infrared spectrum (thin film/NaCl) of compound 264.............. 284
13C 1H
NMR (75 MHz, CDCl3) of compound 264 ............................. 284 NMR (300 MHz, CDCl3) of compound 265 ............................285
Infrared spectrum (thin film/NaCl) of compound 265.............. 286
13C 1H
NMR (75 MHz, CDCl3) of compound 265 ............................. 286 NMR (300 MHz, CDCl3) of compound 266............................287
Infrared spectrum (thin film/NaCl) of compound 266.............. 288
13C 1H
NMR (75 MHz, CDCl3) of compound 266 ............................. 288 NMR (500 MHz, CDCl3) of compound 270 ........................... 289
Infrared spectrum (thin film/NaCl) of compound 270.............. 290
13C 1H
NMR (125 MHz, CDCl3) of compound 270 ........................... 290 NMR (500 MHz, CDCl3) of compound 272 ............................291
Infrared spectrum (thin film/NaCl) of compound 272 ...............292
13C 1H
NMR (125 MHz, CDCl3) of compound 272.............................292 NMR (300 MHz, CDCl3) of compound 273 ............................293
Infrared spectrum (thin film/NaCl) of compound 273 ...............294
13C 1H
NMR (75 MHz, CDCl3) of compound 273 ..............................294 NMR (300 MHz, CDCl3) of compound 274 ............................295
Infrared spectrum (thin film/NaCl) of compound 274 ...............296
13C 1H
NMR (75 MHz, CDCl3) of compound 274 ..............................296 NMR (300 MHz, C6D6) of compound 276 ..............................297
Infrared spectrum (thin film/NaCl) of compound 276 .............. 298
13C
NMR (75 MHz, C6D6) of compound 276 ............................... 298
xxviii Figure B.88 Figure B.89 Figure B.90 Figure B.91 Figure B.92 Figure B.93 Figure B.94 Figure B.95 Figure B.96 Figure B.97 Figure B.98 Figure B.99 Figure B.100 Figure B.101 Figure B.102 Figure B.103 Figure B.104 Figure B.105 Figure B.106 Figure B.107 Figure B.108 Figure B.109 Figure B.110 Figure B.111 Figure B.112 Figure B.113
1H
NMR (300 MHz, CDCl3) of compound 278............................299
Infrared spectrum (thin film/NaCl) of compound 278 ..............300
13C 1H
NMR (75 MHz, CDCl3) of compound 278..............................300 NMR (300 MHz, CDCl3) of compound 279............................ 301
Infrared spectrum (thin film/NaCl) of compound 279 ..............302
13C 1H
NMR (75 MHz, CDCl3) of compound 279..............................302 NMR (500 MHz, CDCl3) of compound 280 ...........................303
Infrared spectrum (thin film/NaCl) of compound 280..............304
13C 1H
NMR (125 MHz, CDCl3) of compound 280 ...........................304 NMR (500 MHz, CDCl3) of compound 281a..........................305
Infrared spectrum (thin film/NaCl) of compound 281a ............306
13C 1H
NMR (125 MHz, CDCl3) of compound 281a..........................306 NMR (500 MHz, CDCl3) of compound 281b .........................307
Infrared spectrum (thin film/NaCl) of compound 281b ............308
13C 1H
NMR (125 MHz, CDCl3) of compound 281b..........................308 NMR (300 MHz, CDCl3) of compound 282 ...........................309
Infrared spectrum (thin film/NaCl) of compound 282 .............. 310
13C 1H
NMR (75 MHz, CDCl3) of compound 282 ............................. 310 NMR (300 MHz, CDCl3) of compound 269 ............................311
Infrared spectrum (thin film/NaCl) of compound 269 ...............312
13C 1H
NMR (75 MHz, CDCl3) of compound 269 ..............................312 NMR (300 MHz, CDCl3) of compound 283 ............................313
Infrared spectrum (thin film/NaCl) of compound 283 ...............314
13C
NMR (75 MHz, CDCl3) of compound 283 ..............................314
Representation of Allylic Alcohol 248 ..........................................315 Representation of Allylic Alcohol 253.......................................... 323
xxix Figure B.114 Figure B.115 APPENDIX C Figure C.1 Figure C.2 Figure C.3 Figure C.4 Figure C.5 Figure C.6 Figure C.7 Figure C.8 Figure C.9 Figure C.10 Figure C.11 Figure C.12 Figure C.13 Figure C.14 Figure C.15 Figure C.16 Figure C.17 Figure C.18 Figure C.19 Figure C.20 Figure C.21 Figure C.22
1H
Representation of Bisacetoxyacetal 256...................................... 338 Representation of Tetracycle 269 .................................................347
NMR (500 MHz, CDCl3) of compound 255a ..........................393
Infrared spectrum (thin film/NaCl) of compound 255a.............394
13C 1H
NMR (125 MHz, CDCl3) of compound 255a ..........................394 NMR (500 MHz, CDCl3) of compound 255b..........................395
Infrared spectrum (thin film/NaCl) of compound 255b ............396
13C 1H
NMR (125 MHz, CDCl3) of compound 255b ..........................396 NMR (500 MHz, CDCl3) of compound 315.............................397
Infrared spectrum (thin film/NaCl) of compound 315 .............. 398
13C 1H
NMR (125 MHz, CDCl3) of compound 315 ............................ 398 NMR (500 MHz, CDCl3) of compound 317 .............................399
Infrared spectrum (thin film/NaCl) of compound 317............... 400
13C 1H
NMR (125 MHz, CDCl3) of compound 317 ............................ 400 NMR (300 MHz, CDCl3) of compound 320............................401
Infrared spectrum (thin film/NaCl) of compound 320 ............. 402
13C 1H
NMR (75 MHz, CDCl3) of compound 320 ............................. 402 NMR (300 MHz, CDCl3) of compound 322 ........................... 403
Infrared spectrum (thin film/NaCl) of compound 322.............. 404
13C 1H
NMR (75 MHz, CDCl3) of compound 322 ............................. 404 NMR (500 MHz, CDCl3) of compound 323 ........................... 405
Infrared spectrum (thin film/NaCl) of compound 323.............. 406
13C 1H
NMR (125 MHz, CDCl3) of compound 323 ........................... 406 NMR (500 MHz, CDCl3) of compound 324 ............................407
xxx Figure C.23 Figure C.24 Figure C.25 APPENDIX E Figure E.1 Figure E.2 Figure E.3 Figure E.4 Figure E.5 Figure E.6 Figure E.7 Figure E.8 Figure E.9 Figure E.10 Figure E.11 Figure E.12 Figure E.13 Figure E.14 Figure E.15 Figure E.16 Figure E.17 Figure E.18 Figure E.19 Figure E.20 Figure E.21
1H
Infrared spectrum (thin film/NaCl) of compound 324 ..............408
13C
NMR (125 MHz, CDCl3) of compound 324............................408
Representation of Alcohol 324 .....................................................409
NMR (500 MHz, CDCl3) of compound 341 ............................ 457
Infrared spectrum (thin film/NaCl) of compound 341............... 458
13C 1H
NMR (125 MHz, CDCl3) of compound 341 ............................458 NMR (300 MHz, CDCl3) of compound 342 ........................... 459
Infrared spectrum (thin film/NaCl) of compound 342 ..............460
13C 1H
NMR (125 MHz, CDCl3) of compound 342............................460 NMR (500 MHz, CDCl3) of compound 343 ........................... 461
Infrared spectrum (thin film/NaCl) of compound 343 .............. 462
13C 1H
NMR (75 MHz, CDCl3) of compound 343..............................462 NMR (500 MHz, CDCl3) of compound 344 ...........................463
Infrared spectrum (thin film/NaCl) of compound 344 ..............464
13C 1H
NMR (125 MHz, CDCl3) of compound 344............................464 NMR (500 MHz, CDCl3) of compound 346 ........................... 465
Infrared spectrum (thin film/NaCl) of compound 346 ..............466
13C 1H
NMR (125 MHz, CDCl3) of compound 346............................466 NMR (500 MHz, CDCl3) of compound 347............................ 467
Infrared spectrum (thin film/NaCl) of compound 347 ..............468
13C 1H
NMR (125 MHz, CDCl3) of compound 347 ............................468 NMR (300 MHz, CDCl3) of compound 348a .........................469
Infrared spectrum (thin film/NaCl) of compound 348a............ 470
13C
NMR (125 MHz, CDCl3) of compound 348a .........................470
xxxi Figure E.22 Figure E.23 Figure E.24 Figure E.25 Figure E.26 Figure E.27 Figure E.28 Figure E.29 Figure E.30 Figure E.31 Figure E.32 Figure E.33 Figure E.34 Figure E.35 Figure E.36 Figure E.37 Figure E.38 Figure E.39 Figure E.40 Figure E.41 Figure E.42 Figure E.43 Figure E.44 Figure E.45 Figure E.46 Figure E.47
1H
NMR (500 MHz, CDCl3) of compound 348b ......................... 471
Infrared spectrum (thin film/NaCl) of compound 348b ............472
13C 1H
NMR (125 MHz, CDCl3) of compound 348b..........................472 NMR (300 MHz, CDCl3) of compound 348c..........................473
Infrared spectrum (thin film/NaCl) of compound 348c ............474
13C 1H
NMR (125 MHz, CDCl3) of compound 348c ..........................474 NMR (500 MHz, CDCl3) of compound 364 ............................475
Infrared spectrum (thin film/NaCl) of compound 364...............476
13C 1H
NMR (500 MHz, CDCl3) of compound 364 ...........................476 NMR (500 MHz, CDCl3) of compound 365 ............................477
Infrared spectrum (thin film/NaCl) of compound 365...............478
13C 1H
NMR (125 MHz, CDCl3) of compound 365 ............................478 NMR (500 MHz, CDCl3) of compound 366 ............................479
Infrared spectrum (thin film/NaCl) of compound 366.............. 480
13C 1H
NMR (125 MHz, CDCl3) of compound 366 ........................... 480 NMR (500 MHz, CDCl3) of compound 368............................481
Infrared spectrum (thin film/NaCl) of compound 368 ............. 482
13C 1H
NMR (125 MHz, CDCl3) of compound 368 ........................... 482 NMR (500 MHz, CDCl3) of compound 379 ........................... 483
Infrared spectrum (thin film/NaCl) of compound 370.............. 484
13C 1H
NMR (XXX MHz, XX) of compound 379 .............................. 484 NMR (300 MHz, CDCl3) of compound 380 ...........................485
Infrared spectrum (thin film/NaCl) of compound 380 ............. 486
13C 1H
NMR (75 MHz, CDCl3) of compound 380............................. 486 NMR (300 MHz, CDCl3) of compound 387 ............................487
Infrared spectrum (thin film/NaCl) of compound 387.............. 488
xxxii Figure E.48 Figure E.49 Figure E.50 Figure E.51 Figure E.52 Figure E.53 Figure E.54 Figure E.55 Figure E.56 Figure E.57 Figure E.58 Figure E.59 Figure E.60 Figure E.61 Figure E.62 Figure E.63 Figure E.64 Figure E.65 Figure E.66 Figure E.67
13C 1H
NMR (75 MHz, CDCl3) of compound 387..............................488 NMR (300 MHz, CDCl3) of compound 388 ...........................489
Infrared spectrum (thin film/NaCl) of compound 388..............490
13C 1H
NMR (75 MHz, CDCl3) of compound 380 .............................490 NMR (300 MHz, CDCl3) of compound 389 ........................... 491
Infrared spectrum (thin film/NaCl) of compound 389 .............. 492
13C 1H
NMR (75 MHz, CDCl3) of compound 389 .............................492 NMR (300 MHz, CDCl3) of compound 391 ............................493
Infrared spectrum (thin film/NaCl) of compound 391...............494
13C 1H
NMR (75 MHz, CDCl3) of compound 391 ..............................494 NMR (500 MHz, CDCl3) of compound 392 ........................... 495
Infrared spectrum (thin film/NaCl) of compound 392 ..............496
13C 1H
NMR (125 MHz, CDCl3) of compound 392............................496 NMR (500 MHz, CDCl3) of compound 393 ........................... 497
Infrared spectrum (thin film/NaCl) of compound 393 ..............498
13C 1H
NMR (125 MHz, CDCl3) of compound 393............................498 NMR (300 MHz, CDCl3) of compound 396 ...........................499
Infrared spectrum (thin film/NaCl) of compound 396 ..............500
13C
NMR (75 MHz, 75) of compound 396....................................500
Representation of Allyl ketone 366.............................................. 501
xxxiii
LIST OF SCHEMES
CHAPTER 1 Scheme 1.2.1 Scheme 1.2.2 Scheme 1.2.3 Scheme 1.2.4 Scheme 1.2.5 Hypothetical polyketide precursor....................................................7 Potential mechanism for cyclization of polyketide precursor 22 ...8 Proposed biosynthesis of norzoanthamine.......................................9 Structure of zooxanthellamine ........................................................10 Equilibria between lactone and enamine isomers of norzoanthamine................................................................................ 12 Scheme 1.2.6 Scheme 1.4.1 Scheme 1.4.2 Scheme 1.4.3 Scheme 1.4.4 Scheme 1.4.5 Scheme 1.4.6 Scheme 1.4.7 Scheme 1.4.8 Scheme 1.4.9 Scheme 1.4.10 Scheme 1.4.11 Scheme 1.4.12 Anomalous reduction of norzoanthamine ...................................... 12 Miyashita's Diels-Alder construction of the ABC core................... 19 Functionalization of the ABC core.................................................. 20 Attaching the southern sidechain.................................................... 21 The completion of norzoanthamine ................................................22 Tanner's approach to a model ABC ring system.............................23 Model cyclizations of compounds derived from ()-carvone........24 Mechanism for formation of undesired products ..........................25 Tanner's approach to the functionalized ABC ring system............26 Mechanism for formation of by-product 95...................................26 Diels-Alder cyclization and cycloadducts advancement ................27 Uemura's approach to norzoanthamine .........................................28 Williams's early efforts toward the norzoanthamine AB rings ...................................................................................................29 Scheme 1.4.13 Williams's recent efforts toward the norzoanthamine AB rings .................................................................................................. 30 Scheme 1.4.14 Williams's synthesis of a model EFG ring system .......................... 31
xxxiv Scheme 1.4.15 Scheme 1.4.16 Scheme 1.4.17 Scheme 1.4.18 Scheme 1.4.19 Scheme 1.4.20 Scheme 1.4.21 Scheme 1.4.22 Theodorakis's approach to the ABC ring system ........................... 32 Theodorakis's installation of the C(9) quaternary center ............. 33 Kobayashi's sulfone approach to the CDEFG ring system ............ 34 Hirama's Heck strategy for the zoanthenol ABC ring system....... 35 Hirama's alternative assembly of the B ring .................................. 36 Hirama's installation of the C(9) methyl group ............................. 36 An alternate approach by Hirama................................................... 37 Hirama's synthesis of the fully functionalized ABC core of zoanthenol ........................................................................................38 CHAPTER 2 Scheme 2.1.1 Scheme 2.2.1 Scheme 2.2.2 Scheme 2.2.3 Retrosynthetic analysis of zoanthenol ............................................ 44 Synthesis of the A ring synthon ...................................................... 45 Racemic synthesis of the C ring synthon........................................ 46 Decarboxylative alkylation enables enantioselective synthesis ........................................................................................... 47 Scheme 2.2.4 Scheme 2.2.5 Scheme 2.2.6 Scheme 2.2.7 Scheme 2.2.8 Scheme 2.2.9 Scheme 2.2.10 Scheme 2.2.11 Scheme 2.3.1 Scheme 2.3.2 Diastereoselective Grignard addition ............................................. 47 Discovery of an unusual acid-mediated cyclization....................... 48 Other substrates for cyclization ...................................................... 49 A proposed mechanism for the SN' cyclization...............................50 Deoxygenation of the A ring ............................................................50 Refunctionalization of the C(20)-C(21) olefin ................................51 Plan for the elaboration of the tricyclic core .................................. 52 Attempts to enolize at C(9).............................................................. 53 Retrosynthetic analysis of the DEFG synthon ............................... 53 Jacobsen hetero-Diels-Alder cycloaddition ................................... 54
xxxv Scheme 2.3.3 Conjugate addition and Mitsunobu reaction provide key intermediate......................................................................................54 Scheme 2.3.4 Scheme 2.3.5 SUMMARY SCHEMES Scheme S2.1 Scheme S2.2 Scheme S2.3 Scheme S2.4 Scheme S2.5 Retrosynthetic Analysis of Zoanthenol ...........................................89 Synthesis of the A Ring Synthon .....................................................89 Racemic Synthesis of the C Ring Synthon ..................................... 90 Enantioselective Synthesis of C Ring Methyl Ketone 177 ............ 90 Fragment Coupling and Acid-Mediated Cyclization of the A and C Rings ...................................................................................... 90 Scheme S2.6 Scheme S2.7 CHAPTER 3 Scheme 3.1.1 Scheme 3.2.1 Scheme 3.2.2 Revised retrosynthesis of zoanthenol ...........................................182 Synthesis of vicinal all-carbon quaternary centers ......................183 Mechanism of meso-anhydride desymmetrization by cinchona alkaloids ..........................................................................183 Scheme 3.2.3 C ring functionalization: iodolactonization and displacement ................................................................................... 187 Scheme 3.3.1 Scheme 3.3.2 Scheme 3.3.3 Scheme 3.4.1 Scheme 3.5.1 Synthesis of a lactone-derived C ring synthon .............................188 Grignard addition to synthon 252 ................................................188 Lactone-derived AC ring system cyclizations.............................189 Lactone reduction and triol differentiation ..................................190 Synthesis of a 7-membered acetal-derived C ring .........................191 Deoxygenation of the A Ring and Refunctionalization of C(20) ... 91 Enantioselective Synthesis of DEFG Synthon ................................ 91 Conversion of the -lactone to the -lactam synthon.....................55 Vinylation of the -lactam to access the enone synthon ................55
xxxvi Scheme 3.5.2 Grignard addition and oxidation to access cyclization substrates.........................................................................................192 Scheme 3.5.3 Scheme 3.5.4 Scheme 3.6.1 Scheme 3.6.2 Cyclization of allylic alcohol 265 ...................................................192 Cyclization of 7-membered acetal-derived enone substrate ........193 Synthesis of a homologated C ring synthon ..................................195 Fragment coupling an...