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.
Keywords: Alkenes; Azidation; Biocatalysis; Nonheme iron enzymes; Trifluoromethylation.
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