Copper-mediated oxidative C-terminal N-dealkylation of peptide-derived ligands. A possible model for enzymatic generation of desglycine peptide amides

Article abstract of DOI:10.1021/ja00162a038

A number of Cu(II) complexes of peptide derivatives that coordinate via N-deprotonation at the C-terminal amino acid residue have been characterized by tirimetry and the Cu(III)-Cu(II) electrochemical potentials. Reaction of these complexes with persulfate induces oxidative decarboxylation and hydrolysis of the resulting N-acylimines to carboxamide and either HCHO, CH₃CHO, or acetone depending on the identity of the C-terminal residue (Gly, Ala, or Aib, respectively). For complexes with Cu(III)-Cu(II) potentials of +1.4 V vs NHE or lower, reaction with IrCl₆^2- results in C-N dehydrogenation at the C-terminus, giving (after hydrolysis) carboxamide and either glyoxylic or pyruvic acid for C-terminal Gly or Ala. In the case of C-terminal Aib, Ir(IV) oxidation results in a very slow production of acetone. Complexes with E(p) above + 1.5 V do not react with IrCl₆^2-₆, and sarcosine-termianl complexes, as well as those containing phenolate ligation, are inert to both persulfate and Ir(IV). The optimal complex studied here for investigating the mechanism of C-N dehydrogenation was picolinyl-Aib-Ala (E(p) = +0.882 vs NHE), in which case the Ir(IV)-mediated cleavage to pyruvic acid and picolinyl-Aib-NH₂ proceeds via a Cu(III) intermediate. The same transformation could be effected electrochemically. The C-terminal oxidative N-dealkylation reaction, induced by Cu(III), has not been previously observed and may be a relevant model for the copper enzyme peptidyl α-amidating monooxygenase, which is responsible for conversion of glycine-extended peptide prohormones to the biologically active peptide carboxamides.