Biocatalytic Enantioselective β‐Hydroxylation of Unactivated C−H Bonds in Aliphatic Carboxylic Acids
Kun Zhang, Ai-Qin Yu, Xuan Chu, Fudong Li, Juan Liu, Lin Liu, Wen‐Ju Bai, Chao He, Xiqing Wang
Abstract
Abstract Catalytic selective hydroxylation of unactivated aliphatic (sp 3 ) C−H bonds without a directing group represents a formidable task for synthetic chemists. Through directed evolution of P450 BSβ hydroxylase, we realize oxyfunctionalization of unactivated C−H bonds in a broad spectrum of aliphatic carboxylic acids with varied chain lengths, functional groups and (hetero‐)aromatic moieties in a highly chemo‐, regio‐ and enantioselective fashion (>30 examples, Cβ/Cα>20 : 1, >99 % ee ). The X‐ray structure of the evolved variant, P450 BSβ ‐L78I/Q85H/G290I, in complex with palmitic acid well rationalizes the experimentally observed regio‐ and enantioselectivity, and also reveals a reduced catalytic pocket volume that accounts for the increased reactivity with smaller substrates. This work showcases the potential of employing a biocatalyst to enable a chemical transformation that is particularly challenging by chemical methods.