Ketenimine Multicomponent Strategy for Multifaceted Amidine Functionalization of Peptides on the Solid Phase

The amidine group and its derivatives serve as proteolytically stable bioisosteres of the peptide bond, and their selective incorporation into peptides attributes significant chemical and biological features. This study introduces an efficient synthesis of amidine‐containing peptides by a copper‐catalyzed, solid‐phase‐compatible multicomponent reaction (MCR), leveraging ketenimine intermediates that are generated in situ. Through the reaction of sulfonyl azides with terminal alkynes and a wide variety of amines, we establish the robust on‐resin synthesis of δ/ε‐amidine amino acids, arginine isologues, fluorescently labeled peptides, drug‐peptide hybrids, and PEGylated derivatives. This strategy notably supports a wide range of peptide modifications, including side chain alteration, amine functionalization, and peptide macrocyclization through both backbone and side chain groups, as well as incorporating aromatic scaffolds into the peptide backbone. The methodology demonstrates broad substrate tolerance, compatibility with peptide chemistry protocols, and access to complex motifs, including pharmacophores and imaging tags, all within a single reaction platform. Our results underscore the synthetic versatility and functional applicability of ketenimine‐based MCRs for advanced peptide modification, expanding the chemical space of peptide medicinal chemistry and therapeutics.