Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Significance Cyclic peptides and peptidomimetics are valuable tools in biomedical research. This paper describes chemistry to convert linear, unmodified peptides directly into stable, templated macrocycles. The ring-closing reaction is an allylic substitution catalyzed by palladium(0). It requires no tailored amino acid residues or protecting groups. It proceeds rapidly at room temperature and largely independent of product-ring size and composition. The catalysis shows broad scope and predictable chemoselectivity while engaging functional groups native to peptides. These methods could be applied broadly and have special utility for those attempting to perturb biological systems with unique small molecules. Peptide–protein interactions are important mediators of cellular-signaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification.