Title

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

Abstract

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.

Publisher

American Chemical Society

Publication Date

7-1-2022

Publication Title

ACS Catalysis

Department

Chemistry and Biochemistry

Document Type

Article

DOI

10.1021/acscatal.2c02232

Keywords

Photoredox, Epimerization, Lactam, Stereoselective, Hydrogen atom transfer, Deracemization, Piperidine

Language

English

Format

text

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