Resolution 3-keto ester enolates

Another enzymatic approach to obtain the desired stereochemistry in the side chain is shown in Scheme 17.13. The keto ester precursor 10 of the side chain ethyl ester can be reduced to the hydroxy (2R,3S) ester 11 using either of the yeasts Hansenula polymorpha SC 13865 or Hansemla fabianii SC 13894. Screening a variety of strains from our culture collection revealed many other strains that could carry out the reduction reaction, but the best yields and ee s using whole cells were obtained with the two strains of Hansenula. Of four possible reduction products, the desired product 11 is obtained with 95 to 99% ee and 80 to 90% yield. Because of rapid ketone/enol tautomerism, the enzymatic reduction can work as a dynamic resolution and fix the stereochemistry at both the 2- and 3-positions. 

Similarly, the two diastereoisomeric cyclic hydroxy esters can be obtained when baker s yeast or R. arrhizus is employed. The successful reduction of these racemic a-substituted (3-keto esters to a single enantiomer is based on the enolization/racemization of the keto esters, which allows a dynamic kinetic resolution. If coupled with the specificity of the enzymes from different microorganisms, this can lead to preparation of compounds of diverse chirality. Thus in the series of the 5- and 6-membered ring compounds (Scheme 18) both the lS,2R-cis- and the lS,2S-trans-hydroxy ester can be obtained by switching from baker s yeast to the biomass from R. arrhizus [97]. Such compounds are highly versatile chiral synthons that have been currently used in the asymmetrical synthesis of biologically active compounds [98]. 

Reductions of P-keto esters with yeasts have been performed quite often it seems generally accepted that the enantioselectivity of the reduction of cyclic esters seems to be higher than those of open chain (3-keto esters substituted at C-2. Recently, a neuronal network model for these reactions was developed [267,268]. The influence of organic solvents has been investigated [269]. The reduction of six-membered cyclic p-keto esters is rather widespread thus, the reduction of the simplest compound in this context 211 (Fig. 54) gave 65-85% of ethyl(+)(iR,2S)-2-hydroxycyclohexane carboxylate (212) in 86-99% e.e. [270-272] and a diastereoselectivity of 76-99% [270]. Due to an equilibrium by enolization of the starting material followed by a kinetic resolution only one of the possible diastereomers is produced in excess. 

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