Visible Light-Mediated, Highly Diastereoselective Epimerization of Lactams from the Most Accessible to the More Stable Stereoisomer
Most known methods to access delta-lactams with stereogenic centers at the alpha- and beta-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 approach for the epimerization of delta-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 degrees, 2 degrees, and 3 degrees 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.
Kazerouni, Amaan M., Daniel S. Brandes, Cassondra C. Davies, et al. 2022. "Visible Light-Mediated, Highly Diastereoselective Epimerization of Lactams from the Most Accessible to the More Stable Stereoisomer." ACS Catalysis 12(13): 7798-7803.
American Chemical Society
Chemistry and Biochemistry
Photoredox, Epimerization, Lactam, Stereoselective, Hydrogen atom transfer, Deracemization, Piperidine