Biocatalytic reduction of β,δ-diketo esters: A highly stereoselective approach to all four stereoisomers of a chlorinated β,δ-dihydroxy hexanoate

Article abstract of DOI:10.1002/1521-3765(20011105)7:21<4562::AID-CHEM4562>3.0.CO;2-4

A stereoselective chemoenzymatic synthesis of all four stereoisomers of tert-bulyl 6-chloro-3,5-dihydroxyhexanoate (6a) 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 (1a) by two enantiocomplementary biocatalysts. Alcohol dehydrogenase from Lactobacillus brevis (recLBADH) afforded a 72% yield of enantiopure tert-butyl (5)-6-chloro-5-hydroxy-3-oxohexanoate [(S)-2a]. The enantiomer (R)-2a 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 2a thus obtained was reduced by synand anti-selective borohydride reductions. Permutation of the reduction methods yielded all four stereoisomers of the crystalline target compound 6a (≥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-dioxohexanoate (1b) and tert-butyl 3,5-dioxoheptanoate (1c) were reduced on a preparative scale as well to afford the corresponding δ-hydroxy-β-keto esters (R)-2b and (R)-2c with 99.4% ee and 98.1% ee, respectively. Wiley-VCH Verlag GmbH, 2001.