Enantioselective Synthesis of Medium-Sized Lactams via Chiral α,β-Unsaturated Acylammonium Salts

Medium-sized lactams are important structural motifs found in a variety of bioactive compounds and natural products but are challenging to prepare, especially in optically active form. A Michael addition/proton transfer/lactamization organocascade process is described that delivers medium-sized lactams, including azepanones, benzazepinones, azocanones, and benzazocinones, in high enantiopurity through the intermediacy of chiral alpha,beta-unsaturated acylammonium salts. An unexpected indoline synthesis was also uncovered, and the benzazocinone skeleton was transformed into other complex heterocyclic derivatives, including spiroglutarimides, isoquinolinones, and delta-lactones.