Lin, YutongMalins, Lara2021-11-11J. Am. Chem. Soc. 2021, 143, 30, 11811–118190002-7863http://hdl.handle.net/1885/251751Designer 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 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 bioactive peptides and associated analogues, including an anti-HIV lead peptide and blockbuster cancer therapeutic leuprolide.This work was supported by the Australian Research Council (DE180100092; fellowship to L.R.M.).application/pdfen-AU© 2021 American Chemical Society2021-08-0410.1021/jacs.1c05718