Palladium-catalysed methylene C(sp³)–H lactamization and cycloamination enabled by chlorinated pyridine–pyridone ligands

Recent developments of bifunctional ligands have rapidly advanced palladium-catalysed C(sp³)–H activation reactions directed by native carboxylic acids. However, using this approach in inter- or intramolecular C(sp³)–H amination reactions is often hampered by N-coordination overriding the directing effect of the native carboxyl group. Here we report the design and development of chlorinated pyridine–pyridone ligands, which can overcome N-coordination and enable exclusive carboxylic-acid-directed lactamization and cycloamination of N-protected ω-amino acids. The compartmentalization of directed C(sp³)–H activation and C(sp³)–N bond formation in this reaction is distinct from existing C(sp³)–H amination approaches, in which both processes are directed by nitrogen. The protocols described in this report transform linear ω-amino acids into valuable cyclic β-amino acids possessing γ- and δ-lactam, pyrrolidine and tetrahydroquinoline scaffolds pertinent to drug discovery. The utility of this process was demonstrated by the formal synthesis of stemoamide.