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

Recent developments of bifunctional ligands have rapidly advanced palladium-catalyzed C( )-H activation reactions directed by native carboxylic acids. However, using this approach in inter or intramolecular C( )-H amination reactions is often hampered by -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 -coordination and enable exclusive carboxylic-acid directed lactamization and cycloamination of -protected ω-amino acids. The compartmentalization of directed C( )-H activation and C( )-N bond formation in this reaction is distinct from existing C( )-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.