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 of 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-mediated ester 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 could be isolated chromatographically. In the second, an easily synthesized alpha-keto-beta-lactam was reduced by yeast cells to afford the desired cis isomer as well as the undesired trans diastereomer. Substituting a yeast strain deficient in fatty acid synthase in this reduction suppressed formation of the trans diastereomer. These results suggest that a single enzyme is responsible for both the D- and L-cis-alcohols resulting from reduction of the alpha-keto-beta-lactam. All of the yeast strains used in this project are available commercially, and these biocatalytic reductions require only common laboratory equipment.
Kayser
Margaret M.
MM
Department of Chemistry, University of New Brunswick, P.O. Box 5050, Saint John, New Brunswick E2L 4L5, Canada, and Department of Chemistry, University of Florida, Gainesville, Florida 32611.
Mihovilovic
Marko D.
MD
Kearns
Jeff
J
Feicht
Anton
A
Stewart
Jon D.
JD