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

Abstract 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.