N-Terminal-selective Cu-catalyzed [3+2] cycloaddition for irreversible assembly of two modules with a peptide

Site-selective introduction of multiple components into peptides is greatly needed for the preparation of densely functionalized peptides with uniform quality. In particular, N-terminal-selective peptide modification has attracted considerable attention in recent years for the purpose of single-site modification. In this work, an N-terminal selective [3+2] cycloaddition of peptide-based azomethine ylides with maleimides was developed. This reaction was catalyzed by Cu/Xantphos complex under mild conditions to afford the cycloadduct in excellent yield and with complete exo-diastereoselectivity, leaving the alkyl amine of a lysine residue untouched. Furthermore, the reaction forms an irreversible C–C bond, preventing the elimination of the introduced modules, which has been a major concern in previous methods. The reaction was applied to a convenient three-component assembly by a one-pot procedure using a peptide with aldehyde and maleimide. Furthermore, this method was efficiently applied to a single-site modification of oligopeptides. These results showcase the utility of this method for the single-site bi-functionalization of complex peptides.