Carboxylate-Directed Pd-Catalyzed -C(sp³)-H Arylation of N-Methyl Alanine Derivatives for Diversification of Bioactive Peptides

This study presents a Pd(II)-catalyzed method for the beta-C(sp(3))-H arylation of N-Cbz- or N-Fmoc-protected N-methyl alanines, providing ready access to building blocks for N-methylated peptide synthesis. For this transformation, the native carboxylate was exploited as the directing group, attributing its success to the use of a monoprotected amino-pyridine ligand. Its synthetic utility was demonstrated by facile generation of nine analogues of the naturally occurring N-methylated cyclic peptide cycloaspeptide A.