Photoenzymatic stereodivergent hydrophosphinylation to access diverse P-chirogenic and P-/C-bichirogenic phosphorus compounds

Phosphorus-radical chemistry faces a major challenge in achieving stereochemical control over radical intermediates, a key requirement for accessing diverse P-chirogenic phosphorus compounds that are widely applied in pharmaceuticals, agrochemicals, and materials1–4. Enzymes capable of catalyzing chiral carbon-phosphorus (C-P) bond formation remain scarce5, limiting the biosynthetic development of chiral organophosphorus compounds. Recent advances in non-natural photoenzymatic catalysis expanded the radical reactivity repertoire of biocatalysis, yet P-centered radical transformations remain unexplored6,7. Consequently, the asymmetric synthesis of diverse P- chirogenic or P-/C-bichirogenic phosphorus compounds through highly stereocontrolled phosphorus-radical transformations remains an unmet challenge in both chemical and enzymatic catalysis. In this study, a nicotinamide-dependent imine reductase was repurposed into an asymmetric hydrophosphinylation enzyme (AHP), enabling single-electron oxidation of secondary phosphine oxides to generate P-centered radicals and facilitate subsequent C-P coupling in a redox-neutral, stereoselective fashion. Several series of tertiary phosphine oxide products bearing C-, P-, or P-/C-bistereocenters were prepared using stereodivergent mutants obtained through a focused site-directed evolution strategy. Mechanistic studies reveal a previously unobserved pathway involving single-electron oxidation of the substrate, initiated by photoexcited NADP+. This study advanced enzymatic strategies for chiral P-C coupling and addressed longstanding challenges in achieving stereocontrol over P- and P-/C-bistereocentered radical intermediates in radical chemistry.