Silver(I)-Mediated Oxazoline Formation: A Mild Route to 2,4-Oxazoles in Peptides

Abstract

Incorporating heterocyclic frameworks into peptide molecules represents a promising and evolving strategy for advancing therapeutic peptide design; however, synthetic methodologies for precise heterocycle integration remain relatively underexplored. Herein, we report a silver-promoted intracyclization of peptide thioamides that enables site-specific insertion of oxazole and methyloxazole motifs via oxazoline intermediates. In the presence of neighboring serine and threonine residues, peptide thioamides undergo efficient cyclization to form oxazole and methyloxazole products in high yield under mild, moisture-tolerant conditions. This method is demonstrated in both dipeptide and tetrapeptide systems, providing a robust and generalizable approach that expands the synthetic toolkit for generating structurally diverse, conformationally constrained oxazole peptidomimetics.