Enantioselective Trifluoromethylazidation of Styrenyl Olefins Catalyzed by an Engineered Nonheme Iron Enzyme

Organofluorines, particularly those containing trifluoromethyl (CF3) groups, play a critical role in medicinal chemistry. While trifluoromethylation of alkenes provides a powerful synthetic route to construct CF3‐containing compounds with broad structural and functional diversity, achieving enantioselective control in these reactions remains a formidable challenge. In this study, we engineered a nonheme iron enzyme, quercetin 2,3‐dioxygenase from Bacillus subtilis (BsQueD), for the enantioselective trifluoromethylazidation of alkenes. Through directed evolution, the final variant BsQueD‐CF3 exhibited excellent enantioselectivity, with an enantiomeric ratio (e.r.) of up to 98:2. Preliminary mechanistic studies suggest the involvement of radical intermediates. This work expands biocatalytic organofluorine chemistry by reprogramming metalloenzymes for innovative trifluoromethylation reactions.