Visible Light-Mediated, Highly Diastereoselective Epimerization of Lactams from the Most Accessible to the More Stable Stereoisomer.

ABSTRACT: Most known methods to access δ-lactams with stereogenic centers at the α- and β-positions are highly selective for the contra-thermodynamic syn diastereomer, typically via hydrogenation of the corresponding pyridinones or quinolinones. We describe here the development of a photoredox-mediated hydrogen atom transfer (HAT) approach for the epimerization of δ-lactams to access the more stable anti diastereomers from the contra-thermodynamic syn isomers. The reaction displays broad functional group compatibility, including acid, ester, 1°, 2° and 3° amide, carbamate, and pyridyl groups, and was effective for a range of differently substituted monocyclic and bicyclic lactams. Experimentally observed diastereoselectivities are consistent with the calculated relative stabilities of lactam diastereomers. Convergence to the same diastereomer ratio from the syn- and anti- diastereomers establishes that reversible epimerization provides an equilibrium mixture of diastereomers. Additionally, deuterium labeling and luminescence quenching studies shed further light on the mechanism of the reaction.

SUBMITTER: Kazerouni AM 

PROVIDER: S-EPMC9273106 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature