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A One‐Step Biocatalytic Process for ( S )‐4‐Chloro‐3‐hydroxybutyronitrile using Halohydrin Dehalogenase: A Chiral Building Block for Atorvastatin
Author(s) -
Wan NanWei,
Liu ZhiQiang,
Xue Feng,
Shen ZhenYang,
Zheng YuGuo
Publication year - 2015
Publication title -
chemcatchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.497
H-Index - 106
eISSN - 1867-3899
pISSN - 1867-3880
DOI - 10.1002/cctc.201500453
Subject(s) - yield (engineering) , epichlorohydrin , chemistry , enantiomeric excess , biocatalysis , substrate (aquarium) , enantiomer , dehalogenase , block (permutation group theory) , stereochemistry , enantioselective synthesis , catalysis , enzyme , organic chemistry , mathematics , reaction mechanism , materials science , oceanography , geometry , geology , metallurgy
( S )‐4‐Chloro‐3‐hydroxybutyronitrile [( S )‐CHBN] was used as a chiral building block for the preparation of atorvastatin. In this study, ( R , S )‐epichlorohydrin [( R , S )‐ECH] and 1,3‐dichloro‐2‐propanol (1,3‐DCP) were investigated to prepare ( S )‐CHBN by using the halohydrin dehalogenase HheC from Agrobacterium radiobacter AD1. Preparing ( S )‐CHBN from ( R , S )‐ECH gave a modest enantiomeric excess ( ee ), whereas by using 1,3‐DCP as the substrate, ( S )‐CHBN was obtained with 97.3 % ee after pH optimization. However, a low ee value and low yield of ( S )‐CHBN were obtained if the substrate concentration was increased to 10 g L −1 . To obtain a higher ee value and yield, 16 mutants were constructed and screened. The variant W249F with improvements in activity and enantioselectivity was identified and applied at a 1,3‐DCP loading of 10 g L −1 , which gave ( S )‐CHBN in 86 % yield with 97.5 % ee in 1 h. This is the first report of a one‐step biocatalytic process for the preparation of ( S )‐CHBN from prochiral 1,3‐DCP.