Peptide C-terminal α-amidation has been associated with increased peptide stability as well as enhanced affinity for specific biological targets, thus comprising an important peptide structural modification.[ref 1] In nature, α-amidating monooxygenase enzymes exclusively generate primary amides.[ref 2] Although there is considerable interest in “designer” amides bearing more complex substitution patterns, to date remarkably few chemical or biochemical strategies enabling access to a broad diversity of amidated peptides have been developed.
Building on the pioneering work of Seebach et al.[ref 3] on the anodic oxidation of peptides and our prior work on C-terminal peptide arylation,[ref 4] herein we report a biomimetic approach to designer C-terminal peptide amides by pairing an electrochemical oxidative decarboxylation with a tandem hydrolysis/reduction pathway.[ref 5] Inspired by Nature’s dual enzymatic approach to bioactive primary α-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 an anti-HIV lead peptide and blockbuster cancer therapeutic leuprolide. We therefore envisage that this approach to designer C-terminal alkylamides will have broad application in the development and advancement of peptide-based therapies.