Asymmetric Synthesis of Chiral Benzoins Enabled by Engineered Ketoreductase-Catalyzed Stereoselective Reduction of Benzils

立体选择性 化学 组合化学 催化作用 还原(数学) 生物催化 立体化学 有机化学 反应机理 几何学 数学
作者
Yangtian Ye,Yuan Tao,Pan Hu,Yajiao Zhang,Li Zhang,Xiaofan Wu,Zedu Huang,Fen‐Er Chen
出处
期刊:ACS Sustainable Chemistry & Engineering [American Chemical Society]
标识
DOI:10.1021/acssuschemeng.4c02575
摘要

Chiral benzoins are versatile precursors to various valuable synthons such as chiral hydrobenzoins and chiral vicinal amino alcohols. In principle, ketoreductase (KRED)-catalyzed asymmetric reduction of benzils could be one of the most straightforward, green, and stereoselective methods for the synthesis of chiral benzoins. Nevertheless, the practical application potential of this appealing approach has been hampered by the low substrate loadings (usually <10 g/L) and unsatisfactory catalytic efficiency reported to date. In the present work, through enzyme screening, wild-type (WT) ketoreductase SSCR was revealed to possess a decent specific activity of 69.8 U/mg against the unsubstituted benzil molecule 1a. Aided by structure-guided semirational protein engineering including alanine-scanning and site-saturation mutagenesis, SSCRQ245G, a variant of SSCR, was evolved with 5.0-fold improvement in specific activity (350.5 U/mg) and 7.0-fold enhancement in catalytic efficiency (1131 s–1·mM–1), compared with the WT. By using SSCRQ245G as the reductase and employing glucose dehydrogenase (GDH) for the regeneration of nicotinamide adenine dinucleotide phosphate (NADPH), gratifyingly, as high as 100 g/L of 1a was completely reduced in a 5-gram-scale reaction, with the desired benzoin (S)-2a obtained in 96% isolated yield with 99% ee. Our developed biocatalytic synthesis also features a good space-time yield of 233 g·L–1·day–1 and a decent E-factor of 44 (including water). Moreover, a three-step transformation of such biosynthesized benzoin (S)-2a into a synthetically useful chiral vicinal amino alcohol ligand 5 was realized in 64% overall yield. Finally, the synthetic potential of SSCRQ245G was further underscored by the smooth reduction of 16 other symmetrical and unsymmetrical benzils, delivering the corresponding chiral benzoins in 57–93% isolated yields with mostly good-to-excellent stereoselectivities (up to >99% ee). The current study not only provides efficient and sustainable access to chiral benzoins but also highlights the synthetic versatility of engineered ketoreductase-catalyzed stereoselective reduction of prochiral ketones.
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