Poster Presentation International Peptide Symposium 2023

N-methylation is a simple backbone modification technique that can significantly enhance the bioavailability of peptide-based drugs.^1-3 Recent work by Fairlie and coworkers has demonstrated that N-methylation can connect or expand hydrophobic regions within peptides, thereby improving permeability through Caco-2 model cells.⁴ Despite the importance of backbone methylation, much of the available literature on such modifications relies on a building block approach.⁵ In contrast, late-stage peptide backbone modifications are underexplored, specifically those involving electrochemical methods Electrochemistry provides a tunable, sustainable and mild approach to accomplishing redox transformations on peptide substrates, and therefore has significant untapped potential for the advancement of peptide-based therapeutics.⁸

Building on the venerable Shono oxidation,⁹ Chiba and coworkers introduced a 2,4,6-trimethoxyphenyl electroauxiliary group onto C-terminal proline residues to facilitate the generation of N-acyl iminium ions, which can be captured by nucleophiles to introduce diverse functionalities at the C-terminal position. In addition, earlier work by our group exploited the utility of N,O-acetals in late-stage modifications by leveraging their unique reactivity.¹¹ Upon treatment with a Lewis/Brønsted acid, C-terminal N,O-acetals were re-converted into the N-acyl iminium intermediates, which could be trapped with diverse nucleophiles to form modified peptides.

Herein, we aim to expand the scope of electrochemical peptide backbone modifications by synthesizing peptides with 2,4-dimethoxybenzyl and 2,4,6-trimethoxybenzyl motifs as amide-derived electroauxiliaries integrated into the peptide backbone (Figure 1). Inspired by Chiba's work, these electroauxiliaries are designed to operate through the generation of an iminium intermediate, N-substituted peptide products.