Targeting Peptides with an Iron-Based Oxidant: Cleavage of the Amino Acid Backbone and Oxidation of Side Chains

Abstract

The oxidation of protected amino acids using an iron-based oxidant is described. Substrates of the general formula Ac-X-NHtBu, where X = Gly (1), Ala (2), Val (3), Phe (4), Tyr (5), Trp (6), and Met (7) were constructed to model individual amino acid residues within a polypeptide chain. Oxidation of 1 by the iron catalyst [FeII(N4Py)(MeCN)](ClO4)2 (8) and KHSO5 leads to scission of the amino acid backbone and produces N-acetylformamide as the major product. Decomposition of the iron-based oxidant [FeIV(O)(N4Py)]2+, derived from 8, is slower in the presence of 2,2-d2-1 (96% D) than with 1, giving a kinetic isotope effect of 4.8, which is consistent with [FeIV(O)(N4Py)]2+ cleaving an α-CH bond of 1. Aliphatic amino acid substrates 2 and 3 do not react with [FeIV(O)(N4Py)]2+ under the same conditions used with 1. With substrates 4−7 oxidation of the amino acid side chain is observed. Decomposition of [FeIV(O)(N4Py)]2+ upon treatment with 10 equiv of 1 and 4−7 revealed that 5 is the most reactive toward the FeIVO species. Pseudo-first-order rate constants of 17.0(5) × 10-3, 3.15(8) × 10-3 and 5.8(2) × 10-5 s-1 were obtained for decomposition of [FeIV(O)(N4Py)]2+ ([Fe] = 1 mM, 1:1 H2O/MeCN) by 6, 7, and 1, respectively.