Efficient Asymmetric Synthesis of Ethyl (S)-4-Chloro-3-hydroxybutyrate Using Alcohol Dehydrogenase SmADH31 with High Tolerance of Substrate and Product in a Monophasic Aqueous System

• DOI: 10.1021/acs.oprd.0c00088
• Publication Date: 2020-04-28T18:35:30Z
• Authors: Zeyu Yang; Wenjie Ye; Youyu Xie; Qinghai Liu; Rong Chen; Hualei Wang; Dongzhi Wei
• Keywords: Biocatalysis

Bioreductions catalyzed by alcohol dehydrogenases (ADHs) play an important role in the synthesis of chiral alcohols. However, ethyl (S)-4-chloro-3-hydroxybutyrate [(S)-CHBE], drug intermediate, has significant challenges concerning high substrate or product inhibition toward ADHs, which complicates its production. Herein, we evaluated a novel ADH, SmADH31, obtained from Stenotrophomonas maltophilia genome, can tolerate extremely concentrations (6 M) both and product. The coexpression SmADH31 glucose dehydrogenase Bacillus subtilis Escherichia coli meant that as much 660 g L–1 (4.0 4-chloroacetoacetate was completely converted into (S)-CHBE monophasic aqueous system with >99.9% ee value space-time yield (2664 d–1). Molecular dynamics simulation shed light on activity stereoselectivity SmADH31. Moreover, five other optically pure alcohols were synthesized at (100–462 L–1) result broad spectrum All these compounds act intermediates, demonstrating industrial potential SmADH31-mediated bioreductions.