The Synthesis of Cystine Peptides by Iodine Oxidation of <i>S</i>‐Trityl‐cysteine and <i>S</i>‐Acetamidomethyl‐cysteine Peptides

Abstract

Abstract Previously reported studies of the iodine oxidation of S ‐trityl‐cysteine peptides and S ‐acetamidomethyl‐cysteine peptides, leading directly to cystine peptides, have been extended. Detailed investigations have been made of the reactivities of the S ‐trityl and the S ‐acetamidomethyl group towards iodine in various solvents. In chloroform, methylene chloride, trifluoroethanol, and hexafluoroisopropyl alcohol the differences in the reaction rates of the two groups have been found to be extremely large, allowing the selective conversion of the tritylthio groups to disulfides in the presence of the S ‐acetamidomethyl derivatives. In a second group of solvents, consisting of methanol, acetic acid, dioxane, and mixtures of these solvents with water, simultaneous iodine oxidation of S ‐trityl‐ and S ‐acetamidomethyl‐cysteine peptides leads to a preferential combination of these two residues, resulting in predominantly asymmetrical cystine derivatives. ‐ The suitability of the two sulfur‐protecting groups in the synthesis of cyclic cystine peptides has been assessed. ‐ Possible reaction mechanisms are discussed. ‐ The scope and limitations of iodine oxidation in peptide synthesis have been studied. The applicability of the method has been demonstrated in the preparation of the open‐chain asymmetrical cystine peptide 5 , the protected somatostatin derivative 17 , and the A(1–13) segment 19 of human insulin, previously employed in the total synthesis of this hormone.