Baker's yeast-mediated reductions of alpha-keto esters and an alpha-keto-beta-lactam. Two routes to the paclitaxel side chain

Baker's yeast (Saccharomyces cerevisiae) has been used to reduce a series o f alkyl esters derived from pyruvate and benzoylformate. Both the yield and enantioselectivities of these reductions were maximized when methyl esters were used, and the (R)-alcohols were isolated in all instances. Yeast-medi ated eater hydrolysis was a significant side reaction for products derived from long-chain alcohols. In the case of ethyl benzoylformate, the addition of methyl vinyl ketone increased the enantioselectivity of the reduction. These reductions were applied to two syntheses of the paclitaxel C-13 Side chain [(2R,3S)-N-benzoyl-3-phenylisoserine]. In the first, a racemic alpha- keto-beta-azido ester was reduced by whole cells of Baker's yeast to afford a diastereomeric mixture in which the desired product predominated and cou ld be isolated chromatographically. In the second, an easily synthesized al pha-keto-beta-lactam was reduced by yeast cells to afford the desired cis i somer as well as the undesired trans diastereomer. Substituting a yeast str ain deficient in fatty acid synthase in this reduction suppressed formation of the trans diastereomer. These results suggest that a single enzyme is r esponsible for both the D- and L-cis-alcohols resulting from reduction of t he alpha-keto-beta-lactam. All of the yeast strains used in this project ar e available commercially, and these biocatalytic reductions require only co mmon laboratory equipment.