Pd-Catalyzed Site-Selective Dehydrogenative Alkenyl Etherification of Tyrosine Residues in Peptides and Proteins

Abstract

We report a palladium-catalyzed selective cross-coupling alkenyl etherification of the C(sp²)-O bond in tyrosine side chains, enabling the synthesis of diverse tyrosine-derived alkenyl ethers in moderate to good yields. This transformation provides a convenient strategy for introducing functional groups into peptides and proteins.Peptides possess several attractive features, including high biological activity and excellent target specificity, making them promising therapeutic agents.¹ However, their clinical application is often limited by unfavorable pharmacokinetic properties such as poor membrane permeability and rapid degradation in vivo.² Late-stage chemical modification has therefore emerged as an effective strategy to improve peptide pharmacological properties and introduce new functionalities. Various approaches-including cyclization, conjugation, backbone or side-chain modification, and incorporation of noncanonical amino acids-have been developed to modulate peptide structure, stability, and biological activity.³