Biocatalytic, asymmetric radical hydrogenation of unactivated alkenes
Jaicy Vallapurackal, Rajib Mandal, Justin Bossenbroek, Aris V. Rubio, Ethan Poladian, James Collings, César Guerra Torres, Matthew Hendrickson, Julian Morales, Max B. Lyons, Kyle Schultz, Hannah S. Shafaat, K. N. Houk, Soumitra V. Athavale
Abstract
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.