Biocatalytic, asymmetric radical hydrogenation of unactivated alkenes
- Jaicy Vallapurackal
- Rajib Mandal
- Justin Bossenbroek
- Aris V. Rubio
- Ethan Poladian
- James D. Collings
- Cesar Torres
- Matthew Hendrickson
- Julian Morales
- Max B. Lyons
- Kyle Schultz
- Hannah S. Shafaat
- K. N. Houk
- Soumitra V. Athavale
2025-10-16
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.