Ireland Claisen Rearrangment

Ireland Claisen Rearrangment - The Ireland-Claisen...

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Unformatted text preview: The Ireland-Claisen Rearrangement Introduction The Ireland-Claisen rearrangement. first reported in 1972.| has developed over the ensuing years to become a powerful tool in organic synthesis. The importance of this rearrangement derives from the flexibility it provides the synthetic organic chemist to control the diastereoselectivity of two newly generated stereocenters as well as the pre- dictability of product stereochemistry. This review covers the development of this reac- tion from its inception to its current role in synthetic methodology. The Ireland-Claisen rearrangement refers to the [3.3l-sigmatropic rearrangement of allylic esters (l) as ester enolates (2) to give 3.4-unsaturated acids (3)(Scheme 1).‘ The rearrangement is a suprafacial. concerted. non-synchronous. pericyclic process. When the spz-hybridized Cl and C6 positions of the allyl vinyl ether are substituted. the rear- rangement can proceed via two achiral tran- sition states to give two racemic diaste- reomers. bearing two centers of asymmetry at Cz and C3 of the product. Prior to the development of Ireland's modi- fication. other popular variants of the ali- phatic Claisen rearrangement included the vinyl ether‘. the Johnson orthoester3 and the Scheme 1 Base-cata- amideacetal rearrangements.‘ lyzed reactions of allylic esters were also reported. but employed harsh conditions and gave low yields.5 The major advantage of the Ireland modification over these base- catalyzed rearrangements is the ease of prepa- ration and subsequent facile rearrangement of allyl vinyl ethers as their lithium enolates. Generation of Ester Enolates Theoretically. alpha allyloxy enolates can undergo either [3.3]—sigmatropic or compet- ing [2.31-Wittig type rearrangements. Sur- prisingly. ester enolates. especially silyl ketene acetals. do not undergo a [2,31-Wittig Schubert Pereira and Morris Srebmk‘ Department of C hemistn' Univerriry of Toledo Toledo. OH 43606. rearrangement.° In his initial work. Ireland employed lithium ester enolates generated by the method of Rathke.7 but these proved unsatisfactory as they rearranged to give unwanted aldol condensation side products.‘ However. the lithium enolates. when silylated by TMSCl. afford trimethylsilyl ketene acetals (Scheme 2) which in turn rearrange readily to give 3,4- unsaturated acids. One problem with this approach is the formation of 2-6% C -silylated product.I This was overcome by using tert- butyldimethylchlorosilane (TBSCl) as the silylation reagent which provides predomi- nantly the O-silylated ketene acetal.‘ Scheme 3 R, R2 H ' R‘ R1 H — o- —. A/R RM [3.3] H = Tusou 2 ___. 2 —. o 32 H H “v 0 THF Ja°c O / W Ra Ra H 11450 O O'M. (E)-onolato4 1 2 H H : RI R 0 R2 R1 _ / . / 1 9’7 i = HO H 2 M . 0_ R2 mso H r51 R2 R3 0 o Erythro products 3 n, l’ H H ’ (if = °-“JI —-* Schemez r? "- °>¢< so R2 " “‘ RZC 32c mso F*2 JL /R1 Maser-tic: JL R‘ (Z)-enolat06 UO 0 .73 0c. THF Measro 0/ U R” Lithium Enolate , H H 0 H1 Silyl Ketene Acetal R2 H Aldrichimica Acta. Vol. 26. No. I. 1993 l7 Stereoselective Generation of Ester- Enolates The geometry of the products of the Ire- land-Claisen rearrangement can be predicted by the stereochemistry of the double bonds involved in the ketene acetal rearrangement. The (ID—enolate (4) gives predominantly an erythro product (5). while the (Z)~enolate (6) gives a threo compound (7) as the main product (Scheme 3)" The rearrangement is proposed to proceed through a four centered "chairlike" transition state as shown, thus allowing stereoselection of the products?” The geometry of the silyl ketene acetal can be controlled during the ester enolization process by varying the solvent system. The formation of (Z)-enolates is favored by THF as the solvent. while the use of 23% HMPA/ THF favors the formation of the (E)-enolate (lithium enolate). Regardless of the allylic bond configuration (cis or trans). the stereo chemistry is retained on silylation and the two compounds give predominantly the erythro and threo isomers. respectively. on rearrangement (Scheme 4).“ Mechanism of Ester-Enolate Control - Thermodynamic or Kinetic‘.‘ It was initially proposed that the E22 ratio of the enolate esters was kinetically deter- mined, regardless whether THF or a mixture of HMPA/THF was used.” The two possible transition states 1 and 2 are shown in Figure I. In the absence of HMPA, the lithium atom is strongly coordinated to the carbonyl oxygen leading to an unfavorable interaction between R and R1. In the pres- ence of HMPA. the lithium atom is highly solvated. In this case. favorable steric interactions between R and RI lead preferen- tially to (Z)-enolate formation. Note that these steric considerations had initially been used to explain ketone enolate selectivity and can also be used to explain ester enolate selectivity. Corey's studies on enolate selectivity led to the conclusion that the use of hindered bulky bases like lithium Ien-octyl butyl amide (LOBA) gave superior selectivity to (E)- enolates as compared to LDA (Table 1).” He argued that the stereochemical outcome in the presence of HMPA was not a kinetic effect. but was due to equilibration to the more thermodynamically stable (Z)-enolate. Corey's conclusion was based on his experi- ments using TMSCl as an internal quenching agent during the enolization with a lithium base (Table 2). The investigations of Rathke also support this conclusion (Scheme 5)." The addition of 1—4 equivalents of HMPA or TMEDA did not change the [5:2 ratio‘ but the addition of 0.2 equivalent of 3-pentanone caused rapid isomerization to an equilibrium mixture of enolates with an El ratio of 16:84. Rathke suggested the reverse aldol condensation isomerization mechanism il- lustrated in Scheme 6." It was possible to control the deprotonation of 3-pentanone in THF solution so as to produce predomi— 18 Aldrichimica Acta. Vol. 26. No. I, 1993 nantly the (E)-isomer (8) by addition of the ketone to 10% excess lithium 2.2.6.6- tetramethyl pipen'dide (LiTMP) at 0” C (Ezl ratio 87zl3). or to produce predominantly the (Z)-isomer (9) by addition of the ketone to a slight deficiency of LiTMP (5:2 ratio 16:84). He concluded that the formation of the (ED-enolate could be the result of kineti- cally controlled deprotonation. but the for- mation of the (Z)-enolate is thermodynami- cally favored. To thoroughly examine the aspects of selectivity in ketene acetal formation. Ire- land conducted a number of experiments. varying different parameters and using ethyl propionate as the ester.“ Solvent Effects The effect of solvent on the stereoselectivity of silyl ketene acetal for- mation of ethyl propionate with LDA is indicated in Table 3. 'Ihe addition of metal- chelating solvents such as HMPA. TMEDA and DMPU reversed the selectivity in favor of the (Z)-isomer. as opposed to the predomi- nant formation of the (E)-isomer in pure THF. The best selectivity was attained by increasing the amount of DMPU to 45%. However. when the amount of TMEDA is increased. the yield decreases substantially. Scheme 4 Redux OK; W o LDA THF, 778 °c, 2V fl 5 ya )=\ LiO LIO r78 ~> 23 “C, H', H20 0 77a a 23 “C. H', H20 86 % 21 °/o 4— / HOZC Erythro 23a65 "C 23a65 “C 75 % 75 % F F H020 Threo T580 T850 23 % HMF’AVTHF 778 “C 2 min, LDAt THF, —78 “C, 2 min TBSCI, *78 a 23 °C TBSCI, 778 a 23 “C Note The yields obtained from TBS-ketene acetals are olten better than for the corresponding lithium enolates Adapted lrom Ireland. R E (Willard, A , K Tetrahedron Lett 1975, 46, 3975-3978 fl °>H O Flguret Wammamrs. dudhuwum nihTHFuthnom MW 7 4 , i ” Mi '4’; LE Kw R“ ' i A: ,' a )o‘g A ” H} Tnnotflonsub 1 2 Favaedin abseneeofHMPA FavoredinpreaenceofHMPA Table 1. ENOLATE SELECTIVITY WITH DIFFERENT BASES Substrate TMS Ketene Aeetal E:Z E Z LDA LOBA o n c H g OCH H oms H502 arms 9” 95:5 ' 3 5 3 fl /—\ H502 OCH3 H 0cm3 o n H oms H30 oms 02H5C OCHZCGHS V 8020 . H36 ociizcfiu5 H oct-tzcstis - 95-5 Y2, HMPAVTHF, 778 no, 2 mln Table 2. Enolate selectivity with Corey‘s Internet quench experiments some cf”? of” (E) - (Z) - Method Solvent internal quench THF 98 2 internal quench (8 equiv. TMSCI) HMPA/T HF 37 63 internal quench (17 equivs. TMSCI) HMPA/T HF 46 54 two step procedure' HMPNTHF 18 82 'slow addition of ketone to LDA followed by silylation Scheme 5 U0 uo CH. CH3CH2COCH20H, + LDA __> + >==< H502 CH3 H562 H (E) - 87% (Z) - 13% Scheme 6 U0 H H + CH36H2600H20H3 H502 CH3 (E)- 8 DU 1 U0 CH3 (CH30H2)2CCH(CH3)COCH20H3] = H502 (Z)- 9 + CH30H2000H20H3 Scheme 7 0 8m %°V reset 0 \ °\/ . wov o ores ores (Z) ' (E) - Ester to Base Ratio Table 4 summarizes Ireland's ester to base ratio experiments. In THF. a decrease in the ester to base ratio from 1:1 to 06:1 does not change the selectivity or yield. However. an increase in that ratio from 1:1 to 1:4 drasti- cally reduces the yield from 90% to 5%. A decrease in the ester to base ratio in the mixed THF/chelating solvent system lowers the (Z)-selectivity and decreases the yield. Conversely. a slight increase in the ester to base ratio leads to an increase in (Z)-selectiv- ity. accompanied by a drop in yield. Thus. increased (Z)-silylketene acetal selectivity can be obtained by adding a slight excess of the ester solution. It is also pertinent that addition of small amounts of a polar solvent like DMSO after enolization also increases the (Aselectivityfl‘ Effect of the Base The comparison of LDA with a slightly bulkier base. i.e. lithium hexamethyl disilazide (LHMDS). showed that LHMDS is slightly more efficient for (E)-selective enolate formation than LDA in 23% HMPA/ THF solvent mixture.“ Effect nfan \lphu 0v. zen Suhstituent on the ill-Eritilutc The formation of the (Z)-enolate predomi~ nates due to chelation with an alpha Gatom as shown in Scheme 7. When the solvent is THF. the 2:5 ratio is 90:10. whereas when 23% HMPA/THF is used the ratio drops to 63:37 with the (Z)-isomer still favored. Ireland pointed out that the conclusions of Rathke and Corey were based on ketone enolates and not directly applicable to ester enolates. An aldol type equilibrium would be too slow and irreversible with acid de- rivatives such as esters and amides. To support his claim lreland set up an analogous experiment with ethyl propionate in THF andTMSCl. Afterenolization of oneequiva~ lent of the ester by one equivalent of LDA. addition of 30% DMPU led to a 2:5 silyl ketene acetal ratio of only 1:4. Furthermore. addition of 0.1 equivalents of ester to 2 equivalents of a prefomied 60:40 mixture of (E)- to (Z)-lithium ester enolates led to only a small change in ratio to 69:31 (Scheme 81. These observations suggest a kinetic reso- lution process. A preformed ratio of (2')- and (E)- ester enolates can be altered by addition of a small amount of trapping agent that reacts at different rates with the two isomers. thus making it possible to carry out the reaction with the more reactive enolate. Ireland then set up a series of experiments using competitive trapping of the more reac~ tive enolate with TBSCl (Scheme 9; Table 5). The change in ratios is due to a competi- tion for silylation between the two enolates (competition constant. K=kZJkE. of 2.6 with DMPU and 1.4 with HMPA). It was con- cluded that "...kinetically controlled enoliution in combination with a kinetic resolution process accounts for the selective Aldrichimt'ca Acta, Vol. 26. No. l, 1993 19 formation of (E)- and (Z). silyl ketene ac- etals in THF and THF/dipolar solvent sys- tems with bases such as LDA. LHMDS. and KHMDS.'" Ireland's experiments thus shift the evidence in favor of a kinetic resolution process in the case of ester enolates, but do not account for the observations made by Rathke and Corey on the mechanism of enolate formation from ketones (3— pentanone ). Chelution Control of linoluac Sclccthit} The lithium enolates’ preference for the Z- conformer is well established. Investiga- tions by Bartlett," Fujisawa’° and Burltel7 showed that in the case of a heteroatom substituent that can undergo chelation with the lithium atom. the major isomer formed is the E-conformer (Scheme 10). Although the ratio of the isomers was not measured. it could be determined from the ratio of the final products. This coordination effect has been uu'lized in stereoselective syntheses. wherein control of the prostereogenic sp2 sites is achieved by an allylic oxygen sub- stituent." Yet another method for enolate control has been developed by Corey and Kim.” A chiral boron reagent (Figure 2) has been used to promote enantioselective aldol reac- tions of achiral propionate esters to give either syn or anti aldol products with excel- lent enantioselectivity and diastereoseleco tivity. The enolate of choice can easily be con- trolled by use of the proper solventzbase combinations When the chiral boron re- agent [RZBBrl and TEA in a toluene/hexane! CH.Clz solvent is used with ten-butyl propi- onaie at -78°C, the transoid boron enolate is formed (0-8 and methyl are trans to each other: Z-isomer by priority group nomencla- l ture ). These enolates react with aldehydes ‘ to give the expected anti aldol products in 90-97% e.e. However, when the base is the sterically demanding diisopropylethylamine and the solvent the more polar CH2Clz. the cisoid enolate is formed to give the syn aldol product in 83-97% e.e. Prior investigations of [3,3]»sigmatropic rearrangements showed that unhindered 1.5- diene systems undergo rearrangement via a chair transition state.m Later evidence sug- gested the possibility of a chair. boat. twist helix or twist plane transition state for the closely related Claisen rearrangement}I Since Ireland's variant takes place at moderately low temperatures. the twist configurations are not likely. Further transition state studies of the Cope reanangement led to the conclu- sion that substituents on the 1.5-hexadiene play a major role. In fact, a boat transition state is favored due to the nature of the substituents on certain ester enolates.“ From previous studies on the Cope“ and Claisenm5 rearrangements, it was generally 1 l 1 line l’ransitmn \ttitc -1 219: or ii .1: ‘ l l l l l l l l l 20 Aldrichimica Acta, Vol. 26. No. I, 1993 Table 3. Eflect of eolvent on ester enolate eelectlvlty O OTBS a“. ores A /\ ° W / o’\ . ’ ° ENTRY SOLVENT ESTER:BASE 2:5 YIELD 1 THF 1:1 6:94 90 2 THF/25%TMEDA 1:1 60:40 so a THF/50%TMEDA 1:1 — o 4 THF/15%DMPU' 1:1 37:63 90 5 THF/30%DMPU 1:1 69:31 85 6 THF/45%DMPU 1:1 93:7 90 7 THF/23%HMPA 1:1 85:15 90 'DMPLbN,N'—di'nethyl-N,N'-propyiene urea Table 4. Effect 01 ester to base retlo on the etereoeeleetivlty In ellyl keteneeceteltonnetlonotethytproplonetewithLDA ENTRY SOLVENT ESTER:BASE ZE YIELD 1 THF 1 .411 1 :1 5 2 THF 1 2:1 20:80 35 3 THF 1 .1 :1 6:94 90 4 THF 0.621 6:94 90 5 THF/30%DMPU 1 .21 98:2 70 6 THF/30%DMPU 0.95:1 67:33 90 7 THF/30%DMPU 0.8:1 68:32 85 8 THF/30%DMPU 05:1 60:40 95 Scheme 8 CU OJ \Ao“ . 6°“ (5) ’ (z) ‘ mu: in! W was euro “5‘34 11““ 126*“ OTBS \IKOA . [’k°/\ ores cm 353'- /\ Table 5. Resutte at competitive trapping 01 the enolate with TBSCI emv sowem esreasase T380! 225 1 THF/1S%DMPU 0.821 0.9 30:70 2 THF/15%DMPU 0.8:1 0.08 14:86 a THF/23%DMPU 08:1 0.9 73:27 4 THF/23%DMPU 0.821 0.08 66:34 5 THF 1:1 1.1 94:6 6 THF 1:1 0.9 4:96 Figure 2 F30 Ph Ph 01:3 028 - N\ ,N- $02 ‘1” F3C 8! c1=3 O - L1 0 O . OR OR HO ‘ HQ ——> ’ \ ii motor product mlnor product R: MAJORzfllNOR YIELD -Me 10.221 65 -CH2Ph 96:1 77 MEM' 7.211 70 H 2.411 38 ..‘(2-memoxyethoxy)methoxy Scheme 1 1 O 0TB$ 0TBS /o O. (E) \JLO m y —. TBSCI \%o E5 Chan rearrangement —""'" HOOC ‘ HOOC = (I) (u) SOLVENT 5:2 ): n) amew FAVORED rs. THF 83:17 84:16 79 chair THF/45%DMPU 4:96 72:28 91 boat THF/23%HMPA 14:86 73:27 60 boat found that in cyclic systems a boat transition state is preferred. Another interesting ob- servation was made by Bartlett in his studies of the ester enolate rearrangement of cyclohexenal propanoate.” The (B-srlyl ketene acetal rearranged via a chair transr- tion state. while the (Z)-silyl ketene acetal rearranged via a boat transition state. Bartlett explained his observations by considering the transition states involvmg the chair and boat forms (Figure 3). In the case of the (Z)-isorner then: is an unfavorable interaction between the -OSiR‘ group and the methylene proton of the cyclohexene ring if the transition state pro- ceeds through chair form 1. Thus. the boat form is favored. However. the boat transi- tion state of the (D-isomer has greater steric interaction between the R group and the cyclohexene ring as in 2 (Figure 3). thus favoring the chair form. Ireland carried out a systematic investiga- tion of the effects of various cyclic and acyclic systems on the rearrangement to determine the underlying factors leading to stabilization of either the chair or boat tran- sition state?7 Cyclohexene and Pyranoid Derivatives Ireland's results with cyclohexenyl propi« onate were identical to those of Bartlett's. Though diastereoselectivity was observed with both the (E)- and the (Z)-silyl ketene acetals. the (E)-isomer rearranged via a chair transition state while the (Z)—silyl ketene acetals rearranged via a boat transition state (Scheme 11). The rearrangement employ- ing a pyranoid derivative involved a boat transition state for either (5- or (Z)- silyl ketene acetals (Scheme 12). These results suggest that the ring oxygen atom can con- tribute between l.0 kcal/mol (Z-silyl ketene acetal) and 2.2 kcal/mol (E-silyl ketene ac- etal) to the relative stabilization of a boat over a chair transition state. Since both the cyclohexene and the pyranoid rings are steri- cally similar. the stabilization of the boat transition state is. most likely. due to stereoelectronic rather than steric factors. Figure 3 Mg? 0 - 7 H “1 Transition State 1 (2)- Transition State 2 (E)- Aldrichimica Acta. Vol. 26. No. I. 1993 21 22 A more useful picture of the rearrange- ment can be obtained by considering the chair and boat forms of the transition states of both (E)- and (Z)- conformers of the enolate (Figure 4). Cyclopentene and l-‘uranoid Deri» ativ es In the case of a cyclopentene derivative both the (E)- and the (Z)- isomers rearrange by a chair transition state (Scheme 13). However. the furanoid derivative rearranged by a boat transition state for both the ketene acetal configurations. thereby supporting the results of the pyranoid-cyclohexene series. The O-atom leads to relative stabilization of the boat form of the transition state over the chair form on the order of L4 kcal/mol (E- conformer) and L9 kcal/mol (Z—conformer). The chair and boat forms of the transition states of the (E)- and (Z)-enolates of cyclopentene-furanoid glycal derivatives are depicted in Figure 5. Methoxy Allyl Propionate Derivative The (By and (Z)-silyl ketene acetals of methoxy allyl propionate gave a mixture of carboxylic acids with a preference for the isomer expected via the chair transition state. Thus. in the acyclic series. the effect of the O-atom is not as important as it is in the cyclic series for stabilizing the boat transi- tion state. Using alpha-secondary deuterium isotope effects. Gajewski proposed that the transi- tion state of the aliphatic Claisen rearrange- ment resembles an oxoallyl radical-allyl radi- cal pair. rather than a 2«oxocyclohexane- 1.4.diy1 (Scheme 14).:8 This results in a transition state with much more advanced 0 Scheme 12 OTBS OTBS \JLO LOA Kko . vko b (a a O O 0 Chan rearrangement ———> HOOC (E) (2) V0 To ’ HOOC - o o (I) ("l SOLVENT : SHIELD FAVORED ts. THF 29:71 77 boat THF/45%DMPU 86: 1 4 35 boat Scheme 13 View Una: Figure 4. Transition states of cyclohexene-pyrenoid glycal derlvatives (5-ny listen. eeetai Aldrichimica Acta, Vol. 26. No. I, 1993 O é E E Figure 5 (Eyeltyt intone MI “:39 ‘ , t X: —‘ I v— . I CH3 1 ’ H,c (ZHltyl ketene acetai Boat 0(3).C(4) bond breaking than in the parent unsubstituted system. Thus. one would ex- OTBS pect a rate enhancement effect from 3 C(6)- A T850 ,0.\ / donor substituent to be especially effective / T _ in glycal systems. 6000 - —’ s‘ —’ 0 Ireland concluded that there is a definite I ‘ COOTBS stereoelectronic effect which stabilizes the o boat over the chair form. The energy differ- o , ences between the chair and the boat forms in “NM M m 9‘" the transition state are small and hence tend to be influenced by substituent interactions. In the absence of steric interactions. the 92 OAc Scheme 15 R Ra pyranoid and furanoid systems will rear~ 1. KHMDS_ THF _78.c range by a boat transition state. A simple 2. t-BUMOISICI. HMPA acyclic substiruent with a C(6)— oxygen atom R‘ 3. Room Temp. R‘ 0M3 will not rearrange via the chair form. as S'CHINI R3 Variations of the lreland-Claisen Rearrangement An interesting variation of the Ireland- Claisen rearrangement developed by Ritter 60 uses an organotin ester and the chelation Bu3 62 effect of the counterion to produce primarily 54 the (Z)—enolate from the O—protected butenyl Stannane (8). This rearrangement gives a high diastereoselectivity ratio (Scheme 15).” Figure 6. Possible Transition States of the Enolate The chair transition state (10.). with R. in H R the pseudoequatorial position. is energeti- ‘ cally favored over (10b), with R. in the x R2 R2 x pseudoaxial position, resulting in the exclu- o R H o sive formation of the (ED-isomers (9a - c). ‘ \ x = osm, The (E)<tributylstannylbutenol reacted six times faster than the (Z)-isomer. reflecting 1 R3 R3 R, the energy difference between the transition 10. 10‘, states with the tributyltin moiety in a pseudo- equatorial (10:) or pseudoaxial (10b) posi- tion (Figure 6). Ritter also investigated the chelation ef- scmm. ‘6 fect of the counterion to form predominantly 3R1 )K\ the (E)—enolate from O-protected butenyl ’ ‘ glycolates. The rearrangement of (Z)- or R: mws Stu (E)-4-tributylstannyl-3-butcn~2-yl i ' (benzyloxy)acetate (11) (Scheme 16). through intermediate 12. gave (E)-2- 4‘ RI m THF-‘m benzyloxy‘3-txibutylstaruiyl-4-hexenoicacid H " , M. methyl ester in a 92% yield. Due to the chelation control of enolate 11 H geometry. the syn ester (13) is the main 12 product (synzanti ratio 39:1) from the glycolate ester (11) (E). The glycolate ester (11) (Z) rearranges to give an antizsyn ester ratio of 40: 1, thus emphasizing the utility of the rearrangement of organotin compounds 3‘55“ to afford diastereoselective products. Brown and co-workers recently reported a Me useful method for controlling enolate geom- 1. TMSCI (excess) THF. an etry through the use of dialkylboron reagents 90°C heattoRT of the type RZBX (X = Cl. OTB in the :;o.—’ 13 m presence of tertiary amines.’0 They found 3. ciiZNz that the formation of the (E)-enol borinate is favored by the following: (i) use of RIBCl instead of RzBOTF: “"35" (ii) use of Sgt: instead of i-PrIEtN; (iii) use of a dialkylboron group with a - Me larger steric requirement (i.e. dicyclohexylboron instead of 9-BBN). 1‘ mu A recent publication by Corey extends this work to the highly enantioselective and l Aldrichimica Acta, Vol. 26, No. I, 1993 23 7A diastereoselective Ireland-Claisen rearrange- ment of achiral allylic ester's.’l The rear- rangement utilizes a recyclable chiral boron reagent (Scheme 17). resulting in greater than 97% e.e. in some cases. The (E)- or (Z)-enolate is selected using the specific solvent combinations along with the chiral catalyst as shown in Tables 6 and 7. The (EHsomer rearranged to give predominantly threo products while the (Z)- isomer rearranged to form mainly the erythro carboxylic acids. The diastereoselectivity of the rearrangements is consistent with the assigned geometry of the boron enolate and the expectation of the preferred chair geom- etry of the transition state. Applicationsof the lreland-Claisen Rearrangement The rearrangement has been used in the synthesis of polyether antibiotics?“ ses- quiterpenes.” steroids," iridoids,’s tetronates.’6 marine natural products,” amino acids.” C-glycosides.” large carbocycles‘o and chiral stannanesz" and silanes.‘1 Recent applications include the synthesis of long chain or large ring molecules and demon- strate the utility of this rearrangement in controlling stereocenters. A clever strategy utilizing a boron medi- ated aldol condensation in tandem with the Ireland-Claisen rearrangement provided a synthetic route to ebelactone-A. an esterase inhibitor." Furthermore. a general method for the synthesis of unsaturated diesters with a high degree of stereocontrol at four chiral centers as well as two trisubstituted double bonds was devised (Scheme 18). Interest- ingly. the rearrangement could be canted out without protection of the keto group at C,. After the rearrangement of the diester 16A. the resulting diacid was esterified to give the desired meso all syn diester 18A (63% yield. 86% d.s.). The unsymmetrical diester 18B is obtained in 53% yield and 95% ds. from 163. An important aspect is that the electrophilic ketone carbonyl group is not attacked and there is no epimerization at the adjacent stereocenters. This is probably due to the flanking methyl groups which protect it from the sterically hindered base LDA and also blocks intramolecular aldol condensation. This synthesis demonstrates the use of a "double" lreland-Claisen rear- rangement to create two contiguous stereocenters. A new. high yield synthesis of coumarin derivatives employing the rearrangement was reported by Collado and is shown in Scheme 19!3 The rearrangement does not occur un- less the phenolic hydroxyls are protected as. for example, their benzyl ethers. Curran and co-workcrs have used the [re- land-Claisen rearrangement in a stereo- selective synthesis of chiral iridoid agly- cones (Scheme 20).“ The iridoids are a family of natural products which have an oxygenated fused cyclopentapyran ring sys- Aldrirhimirn Arm Val 76 Mn 1 100? tem possessing anti-microbial to anti~leuke~ mic properties. The best stereoselectivity was obtained by the generation of the (E)—silyl ketene acetal. This proceeded with good diastereoselectivity by a chair transition state to give 23 and its diastereomer in a 5: 1 ratio. The rearrangement of the (Z)-silyl ketene acetal also gave 23 as the major product in a 3:2 ratio. but this time via the boat transition state. a result in keeping with the Schreiber and co—workers have described the asymmetric synthesis of the cyclohexyl moiety of FK-506. a macrolide antibiotic with potent immunosuppressive propertieslScheme 21)." The rearrangement from 27 to 28 pro- ceeded in 71% overall yield via the boat tran- sition state. Wang has also used this rearrange- ment in the synthesis of the C m-Cz‘ fragment of FK-506.“ Jasperse and Curran have used the rear- findings of Bartlett and Ireland. rangement to form two contiguous quater- Scheme 17 Ph Ph 083' 7. _ ‘0 e *2" N0 if?“ 0 \ R a," 28-N\ ,u-sozA: Mafia 0 \ H 1 ea... 1 cup, K4 / HM“ 3! —’_m / R2 .7“: 0 R2 (5* o (z)- l mMoJk/m 1 O \\ R1 R1 HO HO \ I: a: \ '0 R2 erythro than n cptmlly saw. Table 6. Enantloselecttve rearrangement In C1126!a vla the (E)-boron enolate THREO: ENTRY Rt R2 %YIELD ERYTHRO e.e.% 1 Me Me 75 99:1 <97 2 Et Me 79 98:2 95 3 Me Me 75 91 :9 >97 4 Et Ph 72 91 :9 >97 5 Ph Ph 1 00 23:77 >97 6 SPh Me 52 39:61 >97 7 CHzPh H 70 82 8 CHz-l’naphthyi H 48 -- 77 Diastereomenc ratios were determined by GC analysis at benzyl or methyl esters. e.e. values were determined by HPLC anatysis of methyl esters using a Diaoel OJ cotumn. Table 7. Enantlosetectlve rearrangement in toluene-hexane via the (E)- boron enolate THREO: ENTRY Rt R2 °/.YIELD ERYTHRO e.e.% 1 Me Me 65 90: 1 0 96 2 Et Me 79 89:1 1 >97 3 Me Ph 88 96:4 >97 4 Et Ph 69 95:5 >97 5 Ph Ph 1 00 98:2 >97 6 SPh Me 56 95:5 >97 7 SPh Ph 45 91 :9 >97 8 CHzPh H 57 -- 84 9 CH2-1 ~naphthyl H 63 -- 79 Diastereornenc ratios were determined by GC analysis oi benzyl or methyi esters. e.e. values were determined by HPLC analysis of methyl esters using a Diacet OJ column. nary centers needed for the intermediate in Scheme 18 their synthesis of modhephene in 50% yield (Scheme 22)." Intermediatesto lv xinsw ' h - (“who po 0 hrc arech a turally related to nucleoside peptide antibi- EaN CH ml ones were prepared by Duthaler.“ As shown / \ '—’.. in Scheme 23 the (Z)-allyl ester rearranges 0m in a highly stereoselective manner to give / \ OH 0 OH R, 0 o DWI/\R2 predominantly the trans-substituted lactone. o 0 while the (ID—ally! ester rearranges to give mainly the cis-lactone. ‘5 A55 1‘ A‘s The rearrangement was evaluated for ap- plication to the synthesis of macrocyclic lactones. Brunner and Borschberg investi— Mafia, E ‘ mum; R2 gated the potential synthesis of (R.S)- ——-. o ‘ muscone (37) as shown in Scheme 24" On I rearrangement. 33 gave a mixture of 34. 35 O H 06"“3 and 36. The stereoselectivity of this rear- rangement is rather low compared to that of 17 acyclic systems. While of noconsequence to I R R2 the synthesis of the target molecule. this $113! ' result highlights the fact that Cesilylation I 2 “Wrap I M00 \ / 0M9 may still be a problem in the case of large molecules. These findings supplement the O o 0 model studies on the synthesis of medium and large carbocycles using the Ireland- 13 A53 Claisen rearrangement carried out by Knight, where a lack of stereospecificity was re- ported. and by Danishefsky.” Burke has used the reaction to prepare the hydropyran subunit in his synthesis of macrodiolide and macrotriolide ionophores. He was able to effect the rearrangement of 38 s°"°'“° ‘9 to 39 in 76% yield (Scheme 25)}0 In their paper titled "Stereocontrolled Syn- thesis of a Polyether Fragment”. Bartlett 0 323:. 0 . . K200 ,1 Mm /\J\ descrrbes the use of the Ireland—Claisen rear- 0 / -—> o / rangement to synthesrze a tetrahydropyran lactone with several chiral centers.“ The R OH R 031 stereoselective step using the rearrangement l 19‘ R = H 20A R = H is shown in Scheme 26. 1983.40” meazoaz Theratioof40to4l is [0:1 sincetheuse of HMPA favors the formation of the (Z)- enolateester, which in turn gives 10. Cane and co—workers have used the rear- rangement in the synthesis of chain elonga- tion intermediates of the Monensin biosyn- i thetic pathway.’2 They have been able to 21‘ R = H prepare 43 from 42 in 50-75% yield (Scheme 21B R = OH 27). ! Danishefsky has ingeniously used the [re- land-Claisen rearrangement to merge awk- 0 Scheme 20 wardly positioned chiral centers in his syn- ’u\/ thesis of the C3- C‘9 unit of Rapamycin, a o R metabolite of Streptomyces hygroscopicus. ‘ : Lama), / an antibiotic with immunosupressive prop- mscr erties (Scheme 28).” I o ""902C: 9‘ 0 After preparing alcohol 44 and acid 45 ; j separately. esterification in the presence of 3 CE! R OE? l-[3~(dimethylamino)propyll-3-ethyl- carbodiimide (EDCl) and DMAP gave 46 22 "=5", 23 which. in turn. after reanangement of the I N__° silyl enol ether furnished 47. 1 mm“ Noz/ : The rearrangement of lactones to l ammo F “NCO carbocycles has also been carried out by I —"L-. “t O —-> o Danishefslty in his synthesis of the Fusarr'um “~70 toxin equisetin.“ Keto—lactone 48 was “‘8’” n 06: R OE! convened to its bisilyl derivative 49 and 2‘ 25 subsequently rearranged to yield ester 50in 52% yield (Scheme 29). Aldrichl'mica Acta. Vol. 26, No. 1, I993 25 Scheme 21 Scheme 24 I I i rason H 0'40 Tm, m 0'“ E594 HUI 0 go ‘ ‘—'. H ——-—’ LEA/M p.31 71% ———_-. _. ! o o 'I: O cr,so,s.a, o l “ Teso «we 26 27 WI“ 3 32 33 2W —. —> -—-> 'OTBS ° 28 29 cyclohexyl moiety of “(606 34 (76%) 35 (9%) 36 (Z-lsomor) (8%) Scheme 22 ' 34 + 38 ' O —. B! W/u‘o \ T Moloc Q; 1. Imus-Chm and uh 37 ———-——D 2 CH2": / OOOCH, so 31 Scheme 25 Me I o 1 m M. o 301:. an: on. a“ -——-——-—-. Scheme 23 Max]: 0 m... at: “KL” 0 " coon OCHzPh OCHzPh 38 39 Scheme 26 LDATHF TBSCI, 73°C / = OBz —. S O O W \ I O M trans-lactom clo-lactono HOOC 082 (a): 1. hemmmyidisilazane/reflux 2. LlCNTHF/-76°C 3. “ASCII-78°C to reflux 5‘ Al;.;-l.:_.:.... A“- II-) 0‘ M- 1 1m; Scheme 28 on BnO, OH cu: . W o _ onso : rsso was ‘4 45 0 CH, cu, ‘ can 0 - ano, raso eras case 43 raso CH3 cu, = 081 o \ E ano, TBSO ores cuao Scheme 27 1 LDA‘ HMPA M9385 \ Taousa. 78°C Measi -———> CY 2H6! O 42 Scheme 29 [BAH-(Fm ~1I‘Q 30m ’0: HO EEODMAP Scheme 30 0 _Co\ Lmtzm).T}-f.dooeo20'c ——> \ N OTIPS was: I 0005: 51 H cups 3 TBSOW/KEN- coca goo, mow-Hp /‘ ———> O / . ZO‘C. 2 m. H 52 =< !— 000M. =< I— CW1 (3V onps _. (1 1;: a 00094 c005: 53 Kalnk: acid Scheme 31 mm W, are r~8u th s: 0-” 0 08a 0 54 I Bu Me, 55 mp0 m W‘x‘rsgo ———. v-BuPh sao-’ osau.2'-eu “T 2 “(L/#08“ 55 mp0 H006 can —> —. 1 Eu th s. o-’ 56 Ophlobofln C Aldrirhimirn Arm VI)! 76 No I 100,? ‘27 28 The Ireland-Claisen rearrangement has also been used in syntheses involving the ring contraction of lactones (Claisen con- traction). For example. Knight and co—work- ers have devised a strategy for the enantiospecific total synthesis of ( - )-t1-kainic acid using ring contraction of lactone (51) to pyrrolidinedicarboxylic acid (53) in 55% overall yield (Scheme 30).” The silyl ketene acetal 52 was proposed to rearrange through a boat transition state. Another excellent example of Claisen ring contraction was reported by Funk for the preparation of the in.out-bicyclo[4.4.l] undecan-7-one core of the potent tumor pro- moter ingenol 049.56 In Kishi's total synthesis of ophiobolin C the silyl ketene acetal 55 prepared from 54 rearranged to stereoisomer 56 in 72% overall yield and 6:1 diaritereoselectivity (Scheme 31)}7 Conclusion Over the years the discipline of synthetic organic chemistry has seen a trend towards the catalyzed stereoselective synthesis of natural products. These natural products often contain large carbocyclic rings and polyether fragments of well defined stereo— chemistry. The Claisen rearrangement.57 reported more than 80 years ago. has re- mained an important synthetic tool." The Ireland modification of this rearrangement enables the chemist to have better control over diastereoselectivity and to apply it to unsaturated esters. The Ireland—Claisen rearrangement has often been used to syn- thesize large carbocyclic structures with com- . plex stereochemistry and will continue to be an important synthetic strategy in this class of compounds. The discovery that the Claisen rearrangement is routinely used by nature in the synthesis of aromatic amino acids via the shikimic acid pathway empha— sizes the importance of the rearrangement in the synthetic preparation of these chiral natu- ral products and others." Recent developments involving the use of organotin and organoboron chemistry have given excellent enantioselectivities (ca. 98% e.e.). In an age where high enantiomeric excesses and stereoselectivity are the order of the day. the rearrangements with organotin and organoboron reagents will be used more frequently in the future. However. there are several areas that still have not been actively researched. Synthetic work involving the Claisen rearrangement (though not the Ireland-Claisen rearrange ment) has already been investigated using organoaluminum as the diastereoselective agent. and has shown great promise for higher diastereoselectivity.” These, as well as other organometallic agents. should be utilized in the Ireland-Claisen rearrangements and may well enhance the diastereomeric selectivity currently achieved. The effect of electron withdrawing sub- stituents on the allylic ester is also signifi- Aldrichimica Acta, Vol. 26, No. 1, I993 cant. Welch and co-workers have studied the ester enolate rearrangement of allyl a- fluoroacetates and propanoates and demon- strated these rearrangements to be fairly selective."c 'Ihe aspect of diastereoselective synthesis of large carbocycles also leaves ample room for impr0vement of the rearrangement. For example, this topic has not been systemati- cally investigated with the use of organometallic or lanthanide catalysts/ diastereoselective agents which are now known to exert a significant chelation effect. The "double" Ireland-Claisen rearrangement described earlier could well be investigated for various chain lengths and cyclic com- pounds. Another area which has received consid- erable attention is that of biochemical ca- talysis. A recent publication reports a highly stereospecific Claisen rearrangement cata- lyzed by an antibody.“ References 1) Ireland. R.E.; Mueller. RH. J. Am. Chem. Soc. 1972. 94. 5897. 2) Burghstahler. A.W.; Nordin. 1.C. ibid. I961. 83. 198 3) Johnson. W.S.; Werthemann. L; Bartlett. W.R.; Brocksom. TJ.; Li.T.; Faulkner. D.J.; Petersen. MR. ibid. 1970. 92. 741. 4) Wick. AF... Felix D.; Steen. K.; Eschenmoser. A. Helv. Chint Acta. 1964. 47. 2425. 5) Amold..R.T.;Hofmann. C. Synth. Commun. 1972. 2. 27. 6) Takahashi. 0.; Maeda. T.; Mikami. K.; Nakei. T. Chem Lett. I986. 1355. 7) (a) Rathke. M.W.; Linden. A. J. Am. Chem. Soc. 1971. 93. 2318. (b) Julia. 3.: Julia. M.; Linstrumelle. G. Bull. Soc. Chim. Fr. 1964. 2693. 8) Rathke. M.W.; Sullivan. D.F. Synth. Conunun. 1973. 3. 67. 9) Ireland. R.E.; Willard. A.K. Tetrahedron Lett. 1975. 3975. (a) Vittorelli. P.; Winkler. T.: Hansen. HJ.; Schmid. H. Helv. Chim. Acta. 1968. 51. 1457. (b) Doen'ng. W. von 13.; Roth W.R. Tetrahedron I967. 18. 67. Ireland. R.E.; Mueller. R.H.; Willard. A.K. J. Ant Chem. Soc. 1976. 98, 2868. Corey.EJ.; Gross. A.W. Tetrahedron lett. I984. 25. 495. Fataftah. Z.A.; Kopka. I.E.; Rathlte. M.W. J. Am. Chem. Soc, 1980. 102. 3959. Ireland. R.E.; Wipf. P.; Armstrong 111, ID. J. Org. Chem. 1991.56. 650, Bartlett. P.A.; Tanzella. D..l.; Barstow, .I.F. ibr'd. I982. 47. 3941. Sato. T.; Tajima. K.; Fujisawa. T. Tetra- hedron Lett. 1983. 24, 729. Burke. S.D.; Forbare. W.F.; Pacofslty. GJ. J. Org. Chem. 1983. 48. 5221. Cha. l.K.; Lewis. S.C. Tetrahedron Lett. 1984. 25. 5263. Corey. 5.1.; Kim. 8.3. J. Ant Chem Soc. I990. 112. 4976. 10) 31) 32) 33) 34) 35) 36) 37) 38) 39) 40) 41) 42) Gajewski. 1.1.. Mechanic: of Molecular Migrations ; Thyagyarajan. 3.5.. (Ext; Wiley: New York. 1971; Vol. 4. Ireland. R.E.; Anderson. R.C.; Badoud. R.; Fitzsimmons. BJ.; McGarvey. GJ.; Thaisrivongs. S.; Wilcox. C.S. J. Am. Chent Soc. 1983. 105. 1988. Gajewslti. 1.1.; Hoffman. L.K.; Shih. CN. ibid. I974. 96. 3705. Doering. W. von 15.; Troise. CA. (bid. I985. 107. 5734. Buchi. 0.; Powell. LE. Jr. that 1970. 92. 3126. (a)Chapleo. C.B.; Hallet. P.; Lythgoe. B.; Waterhouse. 1.; Wright. PW. J. Chem. Soc. Perkin Trans. 1 1977. 1211. (b) Cave. RJ.; Lythgoe. 13.; Metcalfe. D.A.; Waterhouse. I. [bid 1977. 1218. Bartlett. P.A.; Pizzo. C.F. J. Org. Chem. 1981. 46. 3896. Ireland. R.E.; Wipf. P.; Xiang. l. ibid. I991. 56. 3572. Gajewski.lJ.;Conr-ad. N.D.J. Ant Client Soc. 1979, 101. 6693. Riner. K. Tetrahedron Lett. 1990. 31. 869. Brown. H.C.; Dhar. R.K.; Bakshi. R.K.; Pandiarajan. P.K.: Singatam. B. J. Ant Chem. Soc. 1989. 111. 3441. Corey. E.J.; Lee. D.H. ibid. I991. 113. 4026. Monensin: (a) Ireland. R.E.; Norbeclt. D.W.; Mandel. 0.5.; Mandel. N.S. ibid. 1985. 107. 3285. Lasalocid: (b)lreland. R.E.; Thaisrivongs. S.; Wilcox, CS. ibt'd 1980. 102. 1155. Guanianolide: (a) Begley. MJ.; Cameron. A.G.; Knight. D.W. J. Chem Soc. ChentComnum. I984. 827. Widdrol: (b) Danishefsky. S.; Tsuzulti. K. 1. Ant Client Soc. 1980. 102. 6891. Aphidicolin: (c) Ireland.R.E.; GodfreyJ.D.; Thaisn'vongs. S. ibid. 1981. [03. 2446. Stephalic acid: (d) Piers. E.; Flemingff. J. Chem Soc. Chent Commun. 1989. 1665. Nemoto. H.; Satoh. A; Ando. M.; Fukumoto. K. ibid. I990. 1001. Abelman. M.M.; Funk. R.L.; Munger. JD. Jr. J. Ant Chem. Soc. 1982. 104. 4030. Chlorothricolide: (a) Ireland. R.E.; Vamey. MD. J. Org. Chem 1986. 51. 635. Streptolic acid: (1)) Ireland. R£.; Smith.M.G. J. Ant Chem. Soc. 1988. 110. 854. Ophiobolin C: Rowley. M.; Tsukamoto. M.; Kishi. Y. (bid. I989. 11!. 2735. (a) Bartlett. P.A.; Barstow. 1F. J. Org. Chem. 1982. 47. 3933. (b) Dell. C.P.: Khan. K.M.: Knight. D.W. J. Chem. Soc. Chem. Commun. 1989. 1812. Ireland. R.E.; Wilcox, C.S.; Thaisrivongs. S.; Vaniet. NR. Can. J. Chem. 1979.57. 1743. Brunner. R.K.; Borshberg. HJ. Helv. Chim. Acta. 1983. 66. 2608. Cameron. A.G.; Knight. D.W. J. Chem. Soc. Perkin Trans. 1 I986. 161. Paterson. 1.; Hulme. A.N.; Wallace. DJ. Tetrahedron Lett. 1991. 32. 7601. 43) 44) 45) 46) 47) 48) Collado, 1.6.; Hemandez-Galan. R.: Massanet. G.M.; Rodriguez-Luis, F.; Salva. 1. [but 1991, 32. 3209. Kim. B.H; Jacobs, PB; Elliott. R.L.; Curran. DP. Tetrahedron 1988, 44, 3079. Schreiber. S.L; Smith. DB. J. Org. Chem. 1989, 54. 9. Wang, Z. Tetrahedron Len. I989, 30, 661 l. Jasperse. C.P.; Curran. D.P. J. Am. Chem Soc. 1990,112,560l. Baumann. H.; Duthaler. R.O. Helv. Chim. Acta. 1988. 71. 1025. SJ. J. Am. Chem. Soc. 1989.11], 8239. (b) Danishefsky. 5.1.; Audia. LE. Tetrahedron Lett. 1988. 29. l37l. (3) Cooper, 1.: Knight. D.W.; Gallagher. PT. J. Chem. Soc, Chem. Commun. 1987. 1220. (b) Cooper, 1.; Knight. D.W.; Gallagher. P.T. Tetrahedron Lett. 1987. 28, 303i. Funk, R.L.; Olmstead. T.A.; Parvez, M. J. Am Chem. Soc. 1988, 110, 3298. Claisen, L. Chem Ber. I912, 45, 3157. Andrews. P.R.; Haddon, R.C. Aust. J. Chem. 1979. 32, I921. 55) 56) 57) S8) cosmetics R & D industry in India for a few years. he joined the University of Toledo's doctoral program in chemistry where he is engaged in the synthesis of siderophores for magnetic resonance imaging. Professor Morris Srebnik received his PhD from the Hebrew University in Jenisalem in l984, under the direction of Raphael Mechoulam. in 1985/86 he went to Purdue University on a Lady Davis Fellowship where he worked with Professor H.C. Brown on the asymmetric chemistry of organoboranes. Except for a sojourn during 1986/87 at the 49) Danishefsky, 8.; Funk,R.L.; Kerwin. J.F.. 59) Mamuka. K; Banno. H.; Yamamoto. H. Aldrich Chemical Company. he remained at Jr. J. Ant Chem. Soc. 1980. 102. 6889. Tetrahedron Asymm. 1991. 2. 647. Purdue until I990 when he m0ved to the 50) Burke. S. D.; Porter. W..l.; Rancourt. 1.; 60) Welch, }.T.; Plummer. J.S.; Chou. T. J. Department of Chemistry at the University Kaltenbach, R.F. Tetrahedron an. 1990, Org. Chem 1991. 56. 353. of Toledo. His research group. consisting of 37, 5285. 61) Hilvcrt. D.; Nared, K.D. J. Am Chem. MSc, PhD and undergraduate students. is 51) Bartlett. P.A.; Helm. K.H.; Morimoto, A. Soc. 1988. 110. 5593. exploring the chemistry of organozincs. J. Org. Chem. 1985. 50, 5179. organoboranes. transmetallations and asym- 52) Block, M.H.; Cane. D.E. ibid. 198. 53. About the Authors metric catalysis. 4923- Schubert Pereira was born in Bombay. 53) Fisher. MJ-l Myefi. CD; 1081311 1-1 India in I967. He received his BSc and MSc Danishefsky. SJ. ibid. 191. 56, 5826. from the Bombay University in 1987 and 54) (a) Tums, 5.: Andil “3-: DaniShefSky. 1989 respectively. After working in the Below are a few of the products discussed in the previous article i l 24,861-1 Lithium dilaopropylamido, 97% 11,001 -9 Diisopropylamine, 99% ' 259 $61 .20; 1009 $1 75.20 100ml $9.20: 500ml $1 3.20; 2L $32.10 29,896-1 Lithium dilaopropylamide, 10 wt% sspension ~n hexanes 38,646-4 Olisopropylamine, redistilled. 99.5% 100ml $19.00 759 $15.70: 5009 $66.40 18,617—1 Butyllithlum, 1.6M solution in hexanes 36,179-8 Lithium dlisopropylamide, 2.0M solution in heptane/ 100ml $14.50; 800ml $32.80; 81. $191.10; 18L $375.50 THF/ethylbenzene 100ml $20.90; 800ml $99.00 23,070—7 Butyllithium, 2.5M solution in hexanes 38,441 -0 Chlorotrlmathylaiiana, 1.0M solution in THF 100ml $1 7.90; 800ml $45.80; 8L $275.50; 18L $497.00 § 100ml $1 0.00; 800ml $59.00 23,071 -5 Butyllithlum, 10.0M solution in hexanes 38,543-3 Chlomtrlmothylallano, 1.0M solution in dichloromethane 100ml $31 .10; 800ml $183.90: 8L $789.15; 181. $1 520.80 l 100ml $10.00; 800ml $59.00 30,210-4 Butyllithium, 2.0M solution in pentano . 38,652-9 Chlorotrlmethylsilano, Iedistilled. 99+% 100ml $13.10; 800ml $63.90 I 100ml $22.00; 800ml $1 30.00 30,21 2-0 Butyllithium, 2.0M solution in cyclohexane ! 07285-4 Chlorotrlmothylsllana, 98% 100ml $13.10; 800ml $53.90 5 Sml $5.50; 100ml $10.20; 500ml $22.80 19,559-6 seo-Butyliithium, 1.3M solution in wclohexane ' 19,050-0 tert-Butyldlmtihylallyl chloride, 97% 100ml $17.00; 800111] $40.90 5 19 $5.70; 59 $14.40; 259 $46.50; 1009 $130.00 40,365-2 seo-Butyllithium, 1 .3M solution in cyclohexane/heptane ; 37,295-1 temButyldlmathylailyl chloride, 1.0M solution in THF (90:10) 100ml $21.00; 800ml $41.00 2 100ml $39.00 18,619—8 ten-Butyllithium, 1.7M solution in pentane l 38,4428 ten-Butyldimothylsllyl chloride, 1 .0M solution in 100ml $17.50; 800ml $57.80; 8L $407.70; 18L $801.40 [ dichloromethane 100ml $39.00 24,172-5 Triisopropylsilyi chloride, 98% l H1160-2 Houmothylphosphoramide,99% 19 $7.45; 109 $41.50; 509 $125.30 ; 59 $10.65; 1009 $21 .20 19,553-7 ten-Butylchlorodiphenylsilane, 98% l 72250-0 N,N,MAI-Tetramathylethylanediamine, 99% 29 $6.90; 109 $21.40; 509 $75.10 3 Sml $8.50; 100ml $1 3.75; 500111! $44.10 02800-0 Diazald, 99% l 25,1569 1,3-01mothyt-3,4,5Wydro-2(1H)—pynmidinone, 99% 259 $8.05; 1009 $25.75; 5009 $79.85; 1kg $137.50 l 259 $10.10; 1009 $1 7.70; 5009 $59.00 210,025-0 Diazald Kit $402.30 13206-3 Triathylamine, 99% 500ml $20.00; 2L $43.80 210,889-8 Mini Diazald apparatus, with 3‘ 19/22 clear-seal jomts 23,9623 Triethylamine, 99+% 509 $19.80 $179.00 25,452-5 terr-Butyl propionate, 99% 259 $31.20; 1009 $85.55 210,851-0 Macro diazald kit, with 3‘ 24/40 clear-seal joints $595.00 38,7545 N,N~Oilaopropylethylamina. redistilled, 99.5% 221,353-5 Macro diazald'kit, 3' 24/40, with a 1000ml receiver flask 100ml $23.00; 800ml $135.00 $595.00 i 01 2,580-8 N,N-Dllsopropylethylamlne, 99% 12,994-1 1-Methyl-3—nltro-1mltrosoguanldlne, 97% 5 51111 $10.55; 100ml $19.35; SOOmL $64.85 109 $23.00; 259 $41.45 1 37,921 -2 1,1,1,3,3,3-Hexamethyldlsllazane, 99.9% 210,100-1 MNNG-Diazomethane generation apparatus, millimole 25ml $11.00; 100ml $30.00 size. with 'O'-ring . $75.40 3 H1000-2 1,1,1,3,3,3—Haxamathyldiailazano, 98% 210,148-6 Rubber septum and cap, for millimole-size MNNG = 25ml $7.90; 100ml $17.05; 500ml $39.45 apparatus $14.30/12 i 10,770-0 4-Dlmothylamlnopyridin0, 99% 210,159-1 MNNG Diazomathane generation apparatus, millimole 59 $9.10; 259 $28.85; 1009 $85.15 size/clear seal joints $59.45 ' 33245-3 4—Dlmothylaminopyrldina, 99W. 59 $15.20 210,151-5 'O“-rin9, for millimole-stze MNNG apparatus $28.50/12 23,953-4 Dlisopropytamine, 99+% 509 $9.70 Aldrichimica Acta, Vol. 26. No. I, 1993 29 ...
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Ireland Claisen Rearrangment - The Ireland-Claisen...

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