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

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 enantiocomplementa...

Full description

Saved in:
Bibliographic Details
Published in:Chemistry : a European journal 2001-11, Vol.7 (21), p.4562-4571
Main Authors: Wolberg, Michael, Hummel, Werner, Müller, Michael
Format: Article
Language:English
Subjects:
alcohols
asymmetric catalysis
Bacteria - metabolism
Caproates - chemistry
Catalysis
enzymes
Esters - chemistry
Esters - metabolism
Hydrocarbons, Chlorinated - chemistry
Hydrocarbons, Chlorinated - metabolism
ketones
Magnetic Resonance Spectroscopy
Mass Spectrometry
Oxidation-Reduction
reduction
Stereoisomerism
Yeasts - metabolism
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. A variety of enantiopure 1,3‐diol building blocks is available on an attractive scale by a stepwise reduction of a chlorinated β,δ‐diketo ester (see scheme). The fruitful combination of two highly enantioselective and two highly diastereoselective reduction methods permits free choice of the absolute configuration of the corresponding crystalline dihydroxy ester.
ISSN:0947-6539
1521-3765
DOI:10.1002/1521-3765(20011105)7:21<4562::AID-CHEM4562>3.0.CO;2-4