Biocatalytic, asymmetric radical hydrogenation of unactivated alkenes.

Alkene hydrogenation is a cornerstone of chemical synthesis, yet enzymatic strategies remain limited to electron-deficient substrates by means of hydride transfer. Using heme enzymes, we unlock a hydrogenation pathway 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 and oxygen tolerant, use Earth-abundant iron, and can operate on the gram scale under ambient conditions. Orthogonal hydrogen atom sources enable site-divergent asymmetric isotope labeling. Mechanistic and computational studies support a stepwise radical process. Our work introduces a biochemical approach for stereoselective olefin reduction and provides a platform for next-generation biocatalytic hydrogenation. Editor's summary: In organic chemistry, hydrogenation of alkenes is typically catalyzed by transition metals, whereas biology uses hydride transfer, which is limited to electrophilic alkenes. Vallapurackal et al. hypothesized that an alternative mechanism for hydrogenation of unactivated alkenes would be possible with the right combination of functional groups and cofactors. Starting by screening for activity for a simpler intramolecular olefin-coupling probe reaction, the authors identified heme enzymes capable of generating iron-hydride species. They then expanded this activity by screening cysteine residues on the opposite face of the active site that can participate in hydrogen atom transfer, enabling radical hydrogenation. Directed evolution enhanced this activity through eight mutations throughout the enzyme, and the authors conducted scaled-up experiments and mechanistic investigations that confirm the proposed biochemical logic for this reaction. —Michael A. Funk [ABSTRACT FROM AUTHOR]