Tunable Electrochemical Peptide Modifications: Unlocking New Levels of Orthogonality for Side‐Chain Functionalization

Abstract Electrochemical transformations provide enticing opportunities for programmable, residue‐specific peptide modifications. Herein, we harness the potential of amidic side‐chains as underutilized handles for late‐stage modification through the development of an electroauxiliary‐assisted oxidation of glutamine residues within unprotected peptides. Glutamine building blocks bearing electroactive side‐chain N,S ‐acetals are incorporated into peptides using standard Fmoc‐SPPS. Anodic oxidation of the electroauxiliary in the presence of diverse alcohol nucleophiles enables the installation of high‐value N,O ‐acetal functionalities. Proof‐of‐principle for an electrochemical peptide stapling protocol, as well as the functionalization of dynorphin B, an endogenous opioid peptide, demonstrates the applicability of the method to intricate peptide systems. Finally, the site‐selective and tunable electrochemical modification of a peptide bearing two discretely oxidizable sites is achieved.