康 · 学术 | Reaction of the Day No. 1713

来源：市场资讯

（来源：康龙化成）

Lactam Framework Editing via Formal Methylene Deletion

Nicholas D. D’Arcy-Evans, Gabriele Rossini, Benjamin D. A. Shennan, and Darren J. Dixon*

Department of Chemistry, University of Oxford, Oxford OX1 3TA, United Kingdom.

—J. Am. Chem. Soc., 2026, 148，28293

Recommended by Yuting Gao_ MC3

KEY WORDS: dehomologation, skeletal editing, ring contraction (反应类型),lactams (原料), one carbon less lactams (产物), Csp2-N (成键类型), TEMPO+TfO-,TIPSOTf, m-CPBA,N-carboxyanhydride (NCA) intermediate (其他)

ABSTRACT: Lactams are cyclic amide building blocks of fundamental importance within synthetic chemistry and drug discovery. Despite their ubiquity, general and convenient methods to interconvert between ring sizes are scarce. Herein, the group of Pro. Darren J. Dixon disclose a new and general strategy enabling the direct dehomologation of lactams, via formal deletion of α-methylene units, streamlining access to a series of valuable medium-to-small-sized lactams from their homologues. This transformation is made possible in a one-pot, two step sequence, comprising initial amide α-oxidation using an oxoammonium salt, followed by oxidative decarboxylation using readily available m-CPBA. The utility of this approach is demonstrated in the ring size scanning of several biologically relevant, drug-like examples, and is extended to the preparation of a diverse range of β-amino acid derivatives, through a net dehomologation-transamidation process from a simple lactam starting material.

Background

This Work

Substrate Scope

Applications (selected examples)

Summary and Comments

The approach described here provides a general and operationally simple solution, permitting direct dehomologation of a range of secondary and tertiary lactams through a decarboxylative strategy. Importantly, in addition to the broad scope and application to pharmaceutically relevant compounds, the N-carboxyanhydride intermediate could be harnessed as a valuable means of generating modular molecular diversity, providing a new strategy to repurpose lactams as diverse building blocks. Beyond its immediate synthetic utility, this work establishes previously ungrounded retrosynthetic logic whereby larger lactam homologues may function as precursors to diversified, ring-contracted cyclic amines, redefining how these cyclic scaffolds can be reconfigured. By enabling facile manipulation of these privileged heterocycles, this work presents a powerful approach for expediting the synthesis and investigation of bioactive molecules and natural products, where control of ring size and scaffold geometry are of crucial importance.