Lactam Framework Editing via Formal Methylene Deletion

High Resolution Image Download MS PowerPoint Slide 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, we 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.