Late-stage peptide backbone modifications have the potential to confer increased therapeutic or industrial value to peptides by enhancing permeability, stability or kinetic properties of the molecule.1, 2 One such example is cyclosporin, which is sold as an oral immunosuppressive drug. This peptide natural product contains seven N-methylated amino acids that are critical to stability and bioavailability.3 However, despite the importance of backbone modifications, there are limited synthetic approaches for incorporating them into peptides. In this work, we examine a new synthetic strategy for late-stage peptide backbone modifications.
In recent years, electrochemistry has re-emerged as a powerful technique for organic synthesis. However, electrochemical reactions in peptide chemistry remain underexplored. Such methods have the inherent advantage of using mild conditions while avoiding toxic or expensive catalysts, making the technique highly suitable for industrial scale-up.4 This poster will highlight our work on site-specific, late-stage backbone modifications of peptide-based substrates via anodic oxidation. We start with the synthesis of an amino acid building block bearing an electron-rich benzyl electroauxiliary that can be coupled to any peptide using Fmoc-SPPS (Figure 1). The auxiliary-mounted peptide can then undergo anodic oxidation in protic solvent to produce the corresponding N,O-acetals via an N-acyl iminium intermediate. Once synthesized, these N,O-acetals can be transformed into various backbone N-substituted peptide products (Figure 1). This poster will also showcase the versatile use of electrochemical backbone modifications for modifying both linear pentapeptides and macrocyclic scaffolds, as well as for applications in peptide stapling using click reactions.
References
(1) Gare, C. L. et al., Trends Biochem. Sci. 2025, 50 (8), 467-480 .
(2) Boto, A. et al., Org. Chem. Front. 2021, 8 (23), 6720-6759.
(3) Ovadia, O. et al., Mol. Pharm. 2011, 8 (2), 479-487.
(4) Yoshida, J. I. et al., Chem. Rev. 2008, 108 (7), 2265-2299.