Stereoselective, Biocatalytic Reductions of α-chloro-β-keto Esters

Document Type

Article

Publication Date

1-1-2005

Publication Title

Journal of Organic Chemistry

DOI

10.1021/jo0484981

ISSN

1520-6904

Abstract

Homochiral glycidic esters are versatile intermediates that can be converted into a variety of high-value products. Optically active glycidates can be prepared by a number of routes including asymmetric Darzens reactions, chiral alkene oxidation methodologies, and ring closure of homochiral α-halo-β-hydroxy esters (see ref 1 and references cited therein). We were particularly interested in the last strategy because asymmetric reductions of α-chloro-β-keto esters might afford each of the four possible glycidate precursors via dynamic kinetic resolution processes from single, inexpensive starting materials (Scheme 1). Here, we explore the potential of individual reductase enzymes from baker's yeast (Saccharomyces cerevisiae) as solutions to the problem of obtaining homochiral glycidate precursors. Reductions of α-chloro-β-keto esters by whole cells of commercial baker's yeast generally produce disappointing mixtures of alcohol diastereomers.2-5 Recent work has revealed that the yeast genome encodes a large number of reductases,6 and it seemed likely that their simultaneous participation was mainly responsible for the modest stereoselectivities commonly observed in yeast-mediated ketone reductions.7-9 In response, we have adapted a fusion protein strategy10 that allows the properties of yeast reductases to be assessed individually, so that enzymes yielding homochiral products can be uncovered.11,12 Moreover, after a reductase with the desired properties has been identified, whole Escherichia coli cells expressing the same protein can be employed for bioconversions on preparative scales using glucose fed-batch conditions.13 Cellular metabolic pathways supply NADPH and the whole cells display very high stereoselectivities because they express only a single yeast reductase.

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