Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation

Abstract

The introduction of fluoroalkyl groups into pharmaceutical compounds has the potential to enhance their therapeutic properties. Nevertheless, the synthesis of enantiomerically pure C(sp³)–CF₃ compounds poses a significant challenge. Biocatalysis offers precise stereochemical control, however, the scarcity of fluorine-containing natural products makes it difficult to find enzymes capable of incorporating fluoroalkyl groups. Herein, we develop a ground-state flavin-dependent enzyme-catalyzed strategy for the radical-mediated enantioselective trifluoromethylation. Two engineered flavin-dependent enzymes are successfully developed to catalyze stereoselective hydrotrifluoromethylation and trifluoromethyl-alkyl cross-electrophile coupling reactions using trifluoromethyl thianthrenium triflate as a radical donor. Experimental investigations and computational simulations demonstrate that the reaction is initiated through single-electron transfer from the ground state flavin hydroquinone (FMN_hq) and quenched through hydrogen atom transfer by flavin semiquinone (FMN_sq). This strategy provides an opportunity to bridge the gap between biocatalysis and organic fluorides but also introduces an alternative approach to address challenging stereoselective fluoroalkylation reactions in organic synthesis.