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- Title
A One-Step Biocatalytic Process for ( S)-4-Chloro-3-hydroxybutyronitrile using Halohydrin Dehalogenase: A Chiral Building Block for Atorvastatin.
- Authors
Wan, Nan‐Wei; Liu, Zhi‐Qiang; Xue, Feng; Shen, Zhen‐Yang; Zheng, Yu‐Guo
- Abstract
( 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.
- Subjects
BIOCATALYSIS; HALOHYDRINS; DEHALOGENASES; ENANTIOSELECTIVE catalysis; ATORVASTATIN; CHIRALITY
- Publication
ChemCatChem, 2015, Vol 7, Issue 16, p2446
- ISSN
1867-3880
- Publication type
Article
- DOI
10.1002/cctc.201500453