Efficient synthesis of an apremilast precursor and chiral β-hydroxy sulfones via ketoreductase-catalyzed asymmetric reduction. Issue 10 (18th February 2022)

• Record Type: Journal Article
• Authors: Guo, Jiyang; Gao, Xiao; Qian, Dong; Wang, Huibin; Jia, Xian; Zhang, Wenhe; Qin, Bin; You, Song
• Is Part Of: Organic & biomolecular chemistry. Volume 20:Issue 10(2022)
• Page Start: 2081
• Page End: 2085
• Publication Date: 2022-02-18
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/d1ob02485j
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : The synthesis of an apremilast precursor and chiral β-hydroxy sulfones catalyzed by ketoreductase with high efficiency and enantioselectivity is reported. Abstract : Ketoreductase (KRED)-catalyzed asymmetric reduction of prochiral ketones is an attractive method to synthesize chiral alcohols. Herein, two KREDs LfSDR1-V186A/E141I and CgKR1-F92I with complementary stereopreference were identified towards reduction of apremilast prochiral ketone intermediate 1a . LfSDR1-V186A/E141I exhibited >99% conversion and 99.2% ee yielding an apremilast chiral alcohol intermediate (( R )-2a ) at 50 g L −1 substrate loading. Furthermore, we investigated the substrate scope of β-keto sulfones by using LfSDR1-V186A/E141I and CgKR1-F92I to produce both enantiomers of the corresponding β-hydroxy sulfones, with good-to-excellent conversion (up to >99%) and enantioselectivity (up to 99.9% ee) being obtained in most cases. Finally, the gram-scale synthesis of ( R )-2a was performed by employing the crude enzyme of LfSDR1-V186A/E141I and BsGDH to afford the desired enantiomer with >99% conversion, 85.9% isolated yield and 99.2% ee. This study presents a biocatalytic strategy to synthesize chiral β-hydroxy sulfones.