Photocatalytic 3D skeletal editing of carboxylic acids via [4 + 1] cyclization for streamlined synthesis of unsaturated γ-lactams

Abstract

The three-dimensional (3D) transformation of readily accessible planar molecules is of great importance in drug synthesis. We herein report a photocatalytic strategy for the three-dimensional skeletal editing of carboxylic acids via sequential deoxygenation, precisely modulated by acid–base conditions. This approach efficiently constructs 3D lactam frameworks in a single step from a carboxylic acid center. It synergistically integrates radical decarboxylative acylation under basic conditions, acid-promoted intramolecular nucleophilic cyclization, and double bond isomerization. This strategy directly converts structurally diverse and stable carboxylic acids into biologically relevant unsaturated γ-lactams. It provides a concise route for drug synthesis, significantly shortening the synthesis of an endothelin receptor antagonist from eight steps (17% yield) to three steps (35% yield).