An Electrochemical Approach to Designer Peptide alpha-Amides Inspired by alpha-Amidating Monooxygenase Enzymes

Abstract

Designer C-terminal peptide amides are accessed in an efficient and epimerization- free approach by pairing an electrochemical oxidative decarboxylation with a tandem hydrolysis/reduction pathway. Resembling Nature's dual enzymatic approach to bioactive primary a-amides, this method delivers secondary and tertiary amides bearing high-value functional motifs, including isotope labels and handles for bioconjugation. The protocol leverages the inherent reactivity of C-terminal carboxylates, is compatible with the vast majority of proteinogenic functional groups, and proceeds in the absence of epimerization, thus addressing major limitations associated with conventional coupling-based approaches. The utility of the method is exemplified through the synthesis of natural product acidiphilamide A via a key diastereoselective reduction, as well as bioactive peptides and associated analogues, including an anti-HIV lead peptide and blockbuster cancer therapeutic leuprolide.