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.
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.
Arylthioether functional groups serve as effective electroauxiliaries
for tunable oxidations. Herein, we disclose the synthesis of second-generation
glutamine building blocks bearing 2,4-dimethoxythiophenyl and 2,4-dichlorothiophenyl-derived
electroauxiliaries. These building blocks improve SPPS efficiency
and enable fine-tuning of the electrochemical window for selective
anodic oxidation reactions in comparison to first-generation 4-methoxythiophenyl-
and 4-nitrothiophenyl-substituted variants. Installation onto a segment
of involucrin, a protein component of human skin, emphasizes the practical
application of the new building blocks for iterative functionalizations.
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