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.

Keywords

• chemoselectivity
• mediated electrolysis
• oxidative decarboxylation
• peptides