A One‐Step Biocatalytic Process for (S)‐4‐Chloro‐3‐hydroxybutyronitrile using Halohydrin Dehalogenase: A Chiral Building Block for Atorvastatin. Issue 16 (17th July 2015)

• Record Type: Journal Article
• Authors: Wan, Nan‐Wei; Liu, Zhi‐Qiang; Xue, Feng; Shen, Zhen‐Yang; Zheng, Yu‐Guo
• Is Part Of: ChemCatChem. Volume 7:Issue 16(2015:Aug.)
• Page Start: 2446
• Page End: 2450
• Publication Date: 2015-07-17
• Subjects: Catalysis -- Periodicals; 541.39505
• DOI: 10.1002/cctc.201500453
• Languages: English
• ISSNs: 1867-3880

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>(<italic>S</italic>)‐4‐Chloro‐3‐hydroxybutyronitrile [(<italic>S</italic>)‐CHBN] was used as a chiral building block for the preparation of atorvastatin. In this study, (<italic>R</italic>, <italic>S</italic>)‐epichlorohydrin [(<italic>R</italic>, <italic>S</italic>)‐ECH] and 1, 3‐dichloro‐2‐propanol (1, 3‐DCP) were investigated to prepare (<italic>S</italic>)‐CHBN by using the halohydrin dehalogenase HheC from <italic>Agrobacterium radiobacter</italic> AD1. Preparing (<italic>S</italic>)‐CHBN from (<italic>R</italic>, <italic>S</italic>)‐ECH gave a modest enantiomeric excess (<italic>ee</italic>), whereas by using 1, 3‐DCP as the substrate, (<italic>S</italic>)‐CHBN was obtained with 97.3 % <italic>ee</italic> after pH optimization. However, a low <italic>ee</italic> value and low yield of (<italic>S</italic>)‐CHBN were obtained if the substrate concentration was increased to 10 g <sc>L</sc>⁻¹. To obtain a higher <italic>ee</italic> 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 <sc>L</sc>⁻¹, which gave (<italic>S</italic>)‐CHBN in 86 % yield with 97.5 % <italic>ee</italic> in 1 h. This is the first report of a one‐step biocatalytic process for the preparation of (<italic>S</italic>)‐CHBN from prochiral 1, 3‐DCP.</p> </abstract>