Photobiocatalytic Radical Hydroalkylation with C(sp³)–H Bonds Enabled by Engineered Imine Reductase and Redox Buffering

Photobiocatalytic systems that leverage nicotinamide- or flavin-dependent oxidoreductases have enabled diverse hydro-functionalization of alkenes. However, these typically rely on preactivated radical precursors and native reducing equivalents (e.g., reduced nicotinamide adenine dinucleotide phosphate (NADPH)). Direct hydroalkylation using abundant C–H substrates remains attractive yet highly challenging. Here, we report a photobiocatalytic "redox buffering" strategy that repurposes imine reductase (IRED) to catalyze the hydroalkylation of enamides with commercial alkanes. Cooperative external peroxide and synthetic photocatalyst activate C(sp3)–H bonds via hydrogen atom transfer (HAT), while engineered IRED with its native NADPH precisely orchestrates subsequent C-radical addition to enamides and stereodetermining HAT steps. This synergistic integration of an external oxidant with the native reductant, coupled with the merging of photoredox and biocatalysis, unlocks unnatural enzyme functionalities, producing enantioenriched amines (with up to >99% ee, low to 0.02 mol % of IRED).