Peptide Diversification through Addition Reaction of Free Carboxylic Acids to Ynamides

Peptide modification has emerged as an important topic in the academic community and pharmaceutical industry. However, they are primarily focused on the diversification of amines, thiols, and alcohols. Direct and chemoselective modification of acid residues in peptides is relatively underdeveloped. In this context, we report a novel and efficient method for the direct functionalization of acid residues in peptides. By using ynamides as reaction partners, the adducts are rapidly obtained in moderate to excellent yields at room temperature in water. This approach shows excellent chemoselectivity and a broad scope including dipeptides bearing unprotected Trp or Tyr residue and free Ser or Gln residue.