Photoenzymatic Aliphatic C─Br Activation for Enantioselective Synthesis of γ-Stereogenic Nitriles from Alkenes

Enzymatic strategies for direct cyano group incorporation remain underdeveloped, creating synthetic bottlenecks for accessing chiral nitrile derivatives in pharmaceuticals and functional materials. Herein, we have developed a photoenzymatic γ-hydrocyanation strategy that addresses this gap. The system demonstrates remarkable efficiency in activating the challenging aliphatic C─Br bond of bromoacetonitrile through engineered ene-reductase catalysis. Upon visible light excitation, the reduced flavin cofactor generates cyanomethyl radicals that are spatially confined and precisely oriented within the enzyme's active site for efficient coupling with α-methylstyrenes. This synergistic photoenzymatic system also demonstrates distinct stereochemical control, with the engineered active site simultaneously governing radical generation and subsequent enantioselective hydrogen atom transfer to afford a large range of γ-stereogenic nitriles in up to 93% yield, 94% ee - a transformation that poses considerable challenges for traditional transition metal catalysis. Beyond providing a robust platform for asymmetric cyanoalkylation, this work significantly advances photoenzymatic catalysis by establishing unactivated alkyl bromides as viable radical precursors for selective bond formations.