Biocatalytic Reduction of β,δ-Diketo Esters: A Highly Stereoselective Approach to All Four Stereoisomers of a Chlorinated β,δ-Dihydroxy Hexanoate

Abstract

A stereoselective chemoenzymatic synthesis of all four stereoisomers of tert-butyl 6-chloro-3,5-dihydroxy-hexanoate (6 a) is presented. The key step of the sequence is a highly regio- and enantioselective single-site reduction of tert-butyl 6-chloro-3,5-dioxohexanoate (1 a) by two enantiocomplementary biocatalysts. Alcohol dehydrogenase from Lactobacillus brevis (recLBADH) afforded a 72 % yield of enantiopure tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate [(S)-2 a]. The enantiomer (R)-2 a was prepared with 90–94 % ee by Baker's yeast reduction in a biphasic system (50 % yield). Both biotransformations were performed on a gram scale. The β-keto group of the enantiomeric δ-hydroxy-β-keto esters 2 a thus obtained was reduced by syn- and anti-selective borohydride reductions. Permutation of the reduction methods yielded all four stereoisomers of the crystalline target compound 6 a (≥99.3 % ee, dr≥205:1), which is a versatile 1,3-diol building block. recLBADH accepts a variety of β,δ-diketo esters as was determined in a photometric assay. tert-Butyl 3,5-dioxo-hexanoate (1 b) and tert-butyl 3,5-dioxo-heptanoate (1 c) were reduced on a preparative scale as well to afford the corresponding δ-hydroxy-β-keto esters (R)-2 b and (R)-2 c with 99.4 % ee and 98.1 % ee, respectively.