Biocatalytic, Asymmetric Radical Hydrogenation of Unactivated Alkenes

Alkene hydrogenation is a cornerstone of chemical synthesis, yet enzymatic strategies remain limited to electron deficient substrates via hydride transfer. With heme enzymes, we unlock an unprecedented hydrogenation pathway – termed biocatalytic cooperative metal hydrogen atom transfer – for the asymmetric reduction of unactivated olefins. A silane promoted, heme-cysteine redox cycle in the active site catalyzes sequential hydrogen atom transfer to challenging scaffolds including 1,1-disubstituted as well as tri- and tetrasubstituted alkenes. The evolved enzymes are promiscuous, oxygen-tolerant, utilize earth-abundant iron, and can operate on gram scale under ambient conditions. Orthogonal hydrogen atom sources enable site-divergent asymmetric isotope labeling. Mechanistic and computational studies support a stepwise radical process, highlighting the potential for independent stereocontrol during the delivery of each hydrogen atom. Our work introduces a fundamentally new biochemical logic for stereoselective olefin reduction and provides a platform for next-generation biocatalytic hydrogenation.