Iron-Mediated Electrolysis for Selective Oxidative Decarboxylation of C-Terminal Acids Using Metal-Binding Residue

Abstract

With the increasing concern of the environmental impact of solid-phase peptide synthesis (SPPS), semi-recombinant processes, in which recombinantly expressed peptides are selectively modified, are of growing interest. The strategies employed for these modifications must overcome the challenges associated with recombinant peptides: selectivity across many functional groups and solubility of the full-length peptide. Electrochemistry is a viable solution to these challenges as it is a mild and tunable process which can operate in both organic and aqueous systems. Herein, a model tetramer with a redox-active residue, tyrosine, is selectively decarboxylated at the C-terminus in an iron-mediated electrolysis. Chemoselectivity is achieved by exploiting the metal-binding property of a C-terminal glutamic acid residue. In the presence of the iron mediator, the tyrosine oxidation pathway is suppressed while the oxidative decarboxylation pathway is favored. Mechanistic controls demonstrate that the glutamic acid, iron, and applied current are all necessary to impart the desired chemoselectivity.