Synthesis of Cyclophane-Braced Peptide Macrocycles via Palladium-Catalyzed Intramolecular C(sp³)–H Arylation of <i>N</i>-Methyl Alanine at C-Termini

Abstract

A method for the construction of cyclophane-braced peptide macrocycles via Pd-catalyzed aminoquinoline-directed intramolecular C(sp³)-H arylation with aryl iodides is developed. Unlike our previous AQ-directed exo-type intramolecular C-H arylation of long alkyl tails, this endo-type C-H cyclization reaction takes places on the β-methyl group of <i>N</i>-methyl alanine at the C-termini of peptides. Unusual C-N cleavage side products of Ala were observed and attributed to intramolecular deprotonation-assisted α,β-elimination of the palladacycle intermediate.