An Engineered Imine Reductase for Highly Diastereo‐ and Enantioselective Synthesis of β‐Branched Amines with Contiguous Stereocenters

• Published in: Angewandte Chemie International Edition Vol. 63; no. 47; pp. e202408686 - n/a
• Main Authors: Zhu, Zhen‐Yu, Shi, Min, Li, Chen‐Lin, Gao, Yun‐Fei, Shen, Xin‐Yuan, Ding, Xu‐Wei, Chen, Fei‐Fei, Xu, Jian‐He, Chen, Qi, Zheng, Gao‐Wei
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 18.11.2024; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Amination; Amines; Amines - chemistry; Amines - metabolism; Asymmetric synthesis; Asymmetry; Biocatalysis; Biological activity; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; dynamic kinetic resolution; Enantiomers; imine reductase; Imines - chemistry; Imines - metabolism; Ketones; Kinetics; Molecular Structure; Oxidoreductases - chemistry; Oxidoreductases - metabolism; Physical Sciences; Protein Engineering; Reductase; Reductases; Science & Technology; Stereoisomerism; Stereoselectivity; tofacitinib; ALCOHOLS; imine reductase; protein engineering; AMINATION; ASYMMETRIC-SYNTHESIS; HYDROGENATION; TRANSAMINASES; BIOCATALYST; DIRECTED EVOLUTION; biocatalysis; dynamic kinetic resolution; tofacitinib
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202408686

β‐Branched chiral amines with contiguous stereocenters are valuable building blocks for preparing various biologically active molecules. However, their asymmetric synthesis remains challenging. Herein, we report a highly diastereo‐ and enantioselective biocatalytic approach for preparing a broad range of β‐branched chiral amines starting from their corresponding racemic ketones. This involves a dynamic kinetic resolution‐asymmetric reductive amination process catalyzed using only an imine reductase. Four rounds of protein engineering endowed wild‐type PocIRED with higher reactivity, better stereoselectivity, and a broader substrate scope. Using the engineered enzyme, various chiral amine products were synthesized with up to >99.9 % ee, >99 : 1 dr, and >99 % conversion. The practicability of the developed biocatalytic method was confirmed by producing a key intermediate of tofacitinib in 74 % yield, >99.9 % ee, and 98 : 2 dr at a challenging substrate loading of 110 g L−1. Our study provides a highly capable imine reductase and a protocol for developing an efficient biocatalytic dynamic kinetic resolution‐asymmetric reductive amination reaction system. β‐Branched chiral amines are valuable blocks in various biologically active molecules. An efficient biocatalytic dynamic kinetic resolution‐asymmetric reductive amination system was developed for preparing the chiral moieties with high diastereo‐, enantioselectivity and a large substrate scope. The practicability was confirmed by producing a key intermediate of tofacitinib in 74 % yield, >99.9 % ee, and 98 : 2 dr at a substrate loading of 110 g L−1.