Asymmetric Anti-Hydrogenation of Tetrasubstituted Alkenes
Abstract
Asymmetric alkene hydrogenation is a foundational method for constructing chiral molecules, with broad applications in pharmaceutical synthesis, natural-product synthesis and materials science. However, the stereochemical outcomes accessible through conventional asymmetric hydrogenation are constrained by its underlying mechanism. Established catalysts, including complexes of iridium, rhodium, ruthenium and platinum, typically deliver both hydrogen atoms to the same face of an alkene to give syn-hydrogenation products. The complementary process, in which hydrogen atoms are stereoselectively delivered from opposite alkene faces, would provide direct access to complementary stereochemical products, but remains poorly developed. Here we show that engineered heme proteins catalyze asymmetric anti-hydrogenation of unactivated cyclic tetrasubstituted alkenes. These genetically encoded catalysts operate through a cooperative radical mechanism in which an active-site iron hydride delivers a hydrogen atom to one face of the alkene to generate a transient carbon-centered radical, which is subsequently quenched from the opposite face by a distal cysteine residue. The spatially separated hydrogen-atom donors thereby enable sequential stereodetermining events, furnishing anti-hydrogenated products with high diastereo-
Related
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BibTeX
@misc{manoff2026asymmetric,
title = {{Asymmetric Anti-Hydrogenation of Tetrasubstituted Alkenes}},
author = {Justin Manoff and Kyle Schultz and Julian Morales and Aris V. Rubio and Cesar Torres and Sattwik Chakraborty and Max Lyons and Yu-Shen Sun and K. N. Houk and Soumitra V. Athavale},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009529/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009529/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Asymmetric Anti-Hydrogenation of Tetrasubstituted Alkenes
AU - Justin Manoff
AU - Kyle Schultz
AU - Julian Morales
AU - Aris V. Rubio
AU - Cesar Torres
AU - Sattwik Chakraborty
AU - Max Lyons
AU - Yu-Shen Sun
AU - K. N. Houk
AU - Soumitra V. Athavale
PY - 2026
DA - 2026/09/28
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009529/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009529/v1
AB - Asymmetric alkene hydrogenation is a foundational method for constructing chiral molecules, with broad applications in pharmaceutical synthesis, natural-product synthesis and materials science. However, the stereochemical outcomes accessible through conventional asymmetric hydrogenation are constrained by its underlying mechanism. Established catalysts, including complexes of iridium, rhodium, ruthenium and platinum, typically deliver both hydrogen atoms to the same face of an alkene to give syn-hydrogenation products. The complementary process, in which hydrogen atoms are stereoselectively delivered from opposite alkene faces, would provide direct access to complementary stereochemical products, but remains poorly developed. Here we show that engineered heme proteins catalyze asymmetric anti-hydrogenation of unactivated cyclic tetrasubstituted alkenes. These genetically encoded catalysts operate through a cooperative radical mechanism in which an active-site iron hydride delivers a hydrogen atom to one face of the alkene to generate a transient carbon-centered radical, which is subsequently quenched from the opposite face by a distal cysteine residue. The spatially separated hydrogen-atom donors thereby enable sequential stereodetermining events, furnishing anti-hydrogenated products with high diastereo-
ER -