Enantiodivergent Difluoroalkylation of Alkenes via Photoenzymatic Catalysis

Abstract

Fluorinated compounds are extensively utilized in pesticides, pharmaceuticals, and materials. Despite significant advances in syn-thetic methodology, the stereocontrolled installation of chiral fluorinated motifs remains a formidable challenge. Here, we report the photoenzymatic enantiodivergent synthesis of difluoroalkyl compounds using a simple, commercially accessible difluoromethyl-sulfonyl reagent. Through a highly controlled asymmetric hydrogen atom transfer process catalyzed by two different photoenzymes, both enantiomers of the products are obtained with enantiomeric excesses of 99%. The broad substrate scope and functional -group tolerance highlight the generality and robustness of our photoenzymes. Radical clock experiments and deuterium labeling studies demonstrate the generation of radical species during this reaction process, and the asymmetric hydrogen atom transfer step is shown to be cofactor-mediated. Furthermore, computer simulations elucidated the selectivity of different olefin reductases toward products with distinct conformations. Our work has successfully introduced difluoromethylsulfonyl groups into organic small molecules, advancing the development of enzyme-catalyzed fluorinated alkylation strategies and revealing a novel route for the radical-mediated asymmetric synthesis of chiral difluoroalkyl compounds that are otherwise difficult to access through conventional chemical approaches.