An Alternative Mechanistic Paradigm for the Electrochemical C-Terminal Decarboxylation of Peptides

Abstract

The C-terminal decarboxylation of peptides provides an important opportunity to synthesize modern peptide pharmaceuticals that contain C-terminal amides. This transformation can be achieved by electrochemical oxidation; however, the standard implementation depends on oxidation potential for selectivity which may represent a challenge when amino acid residues containing electroactive side chains are present. To address this limitation, an alternative mechanistic paradigm has been introduced for selective decarboxylation of a C-terminal carboxylate, one that relies on a chelation event. In a proof-of-principle experiment used to probe and define the viability of this mechanism, it is demonstrated that the combination of an iron mediator and a C-terminal glutamate residue can be used to conduct the reaction in the presence of the more electron-rich tyrosine residue frequently found in medicinally active peptides. Investigations into the reaction specifics and the scope/limitations provide key insights into the reaction mechanism and how such processes can be optimized. The success of the method highlighted here points to a more general binding-based approach to drive C-terminal decarboxylation that utilizes a functional group motif not possible at any other position in a peptide.