Stereoselective esterification

Asymmetric esterification. me.vo-Cyclohexanedicarboxylic anhydride (1) undergoes a highly stereoselective esterification with the diphenylboric ester (2) of (R)-2-methoxy-l-phenylethanol in the presence of diphenylboryl triflate to provide,... 

In an alternative approach to prepare the chiral side chain of captopril (14) and zofenopril (18), the lipase-catalyzed stereoselective esterification of racemic 3-benzoylthio-2-methylpropionic acid (19) (Fig. 8B) in an organic solvent system was demonstrated to yield i -(+)-methyl ester (20) and unreacted acid enriched in the desired S-( )-enantiomer (19) [45], Using lipase PS-30 with toluene as solvent and methanol as nucleophile, the desired S-(-)-(19) was obtained in 37% reaction yield (theoretical max. 50%) and 97% e.e. Substrate was used at 22-g/ liter concentration. The amount of water and the concentration of methanol supplied in the reaction mixture was very critical. Water was used at 0.1 % concentration in the reaction mixture. More than 1% water led to the aggregation of enzyme in the organic solvent, with a decrease in the rate of reaction which was due to... 

Stereoselective Esterifications of Racemic Carboxylic Acids 85 IPG butyrate —IPG... 

A concise and straightforward hydrolytic kinetic resolution of ( ) 1,1-difluoro-3,4-epoxybutylphosphonate (453) using a chiral Salen-Co complex was employed as a key step to obtain enantiomeric diols in 99% ee as important intermediates. The enantiomerically homogenous l,l-difluoro-2,3-di-hydroxypropylphosphonates (454) and (455) were converted by stereoselective esterification and deprotection into the novel phosphatase resistant analogues of lysophosphatidic acid and phosphatidic acid (456) and (457), respectively (Figure 86). ° ... 

It should be evident that the maximum yield of a particular enantiomer normally available from a racemic mixture is 50%. However, in some enzymic catalysed kinetic resolutions it is possible to obtain >50% yield of one enantiomer from a racemate. For this to occur, it is necessary to have the desired chemical reaction, e.g. enzyme-catalysed stereoselective esterification, occurring at the same time as the enantiomers of the racemic starting compound are interconverting under equilibrium conditions. A successful example of this technique is provided by ben-zaldehyde cyanhydrin (2-hydroxy-2-phenylacetonitrile), whose R and S enantiomers, 49 and 50, respectively, equilibrate in the presence of a basic anion-exchange resin (Scheme 3.5). In the presence of lipase, (S)-ben-zaldehyde cyanhydrin acetate 51 was formed in 95% yield and in 84% enantiomeric excess (see Inagaki et al.u and Ward15). 

Kinetic resolution of chiral alcohols by selective esterification has also been performed in SCCO2 by several groups. A glass-immobilized lipase from Candida cylindracea was found to catalyze the stereoselective esterification of only the S isomer from racemic citronellol (Eq. (3)] in a continuous-flow reactor (78) ... 

Other methods of esterification that do not utilize a carbodi-imide coupling method have also been explored. For example, the stereoselective esterification of 20-(S)-camptothecin, a hindered 3 ° alcohol, with amino acid derivatives was accomplished with the use of scandium triflate (Sc(OTf)3) in high yields while retaining the integrity of the amino acid stereocenter (eq 9). ... 

R. Patel, 1. Howell, A. Banerjee, K. Fortney, L. Szarka, Stereoselective esterification of... 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

Analogously, for preparation of racemic carba-a-glucopyranose 49 from 52, esterification of (—)-52 furnished the ester 95, which was transformed into compound 96 by debromination with zinc dust and acetic acid. Stereoselective hydroxylation of 96 with osmium tetraoxide and hydrogen peroxide, followed by acetylation, gave compound 97. Lithium aluminum hydride reduction of 97, and acetylation of the product, gave pentaacetate 98, which was converted into 99 by hydrolysis. ... 

Preparative-scale fermentation of papaveraldine, the known benzyliso-quinoline alkaloid, with Mucor ramannianus 1839 (sih) has resulted in a stereoselective reduction of the ketone group and the isolation of S-papaverinol and S-papaverinol M-oxide [56]. The structure elucidations of both metabolites were reported to be based primarily on ID and 2D NMR analyses and chemical transformations [56]. The absolute configuration of S-papaverinol has been determined using Horeau s method of asymmetric esterification [56]. The structures of the compounds are shown in Fig. 7. 

The stereoselective total synthesis of both ( )-corynantheidine (61) (170,171) (alio stereoisomer) and ( )-dihydrocorynantheine (172) (normal stereoisomer) has been elaborated by Szdntay and co-workers. The key intermediate leading to both alkaloids was the alio cyanoacetic ester derivative 315, which was obtained from the previously prepared ketone 312 (173) by the Knoevenagel condensation accompanied by complete epimerization at C-20 and by subsequent stereoselective sodium borohydride reduction. ( )-Corynantheidine was prepared by modification of the cyanoacetate side chain esterification furnished diester 316, which underwent selective lithium aluminum hydride reduction. The resulting sodium enolate of the a-formyl ester was finally methylated to racemic corynantheidine (171). 

To a much smaller extent non-enzymic processes have also been used to catalyse the stereoselective acylation of alcohols. For example, a simple tripeptide has been used, in conjunction with acetic anhydride, to convert rram-2-acctylaminocyclohexanol into the (K),(R)-Qster and recovered (S),(S)-alcohol[17]. In another, related, example a chiral amine, in the presence of molecular sieve and the appropriate acylating agent, has been used as a catalyst in the conversion of cyclohexane-1(S), 2(/ )-diol into 2(S)-benzoyloxy-cyclohexan-1 f / j-ol1 IS]. Such alternative methods have not been extensively explored, though reports by Fu, Miller, Vedejs and co-workers on enantioselective esterifications, for example of 1-phenylethanol and other substrates using /. vo-propyl anhydride and a chiral phosphine catalyst will undoubtedly attract more attention to this area1191. 

Stereoselective cleavage and esterification of Meldrum s acid derivatives... 

The second Nicolaou synthesis is shown in Scheme 13.49. Stereoselective aldol additions are used to construct the fragments which are brought together by esterification at step D. The synthesis uses an olefin metathesis reaction to construct the 16-membered ring (step E). 

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