Palladium-catalysed methylene C(sp 3)-H lactamization and cycloamination enabled by chlorinated pyridine-pyridone
Hau Sun Sam Chan1, Yilin Lu1, Jin-Quan Yu1
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Abstract:
Recent developments of bifunctional ligands have rapidly advanced palladium-catalyzed C(sp 3)-H activation reactions directed by native carboxylic acids. However, using this approach in inter or intramolecular C(sp 3)-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(sp 3)-H activation and C(sp 3)-N bond formation in this reaction is distinct from existing C(sp 3)-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.
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