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SummaryPreviously 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(l-13) segment 19 of human insulin, previously employed in the total synthesis of this hormone.Some years ago, we reported that S-trityl-cysteine peptides and S-acetamidomethyl-cysteine peptides [2] could be directly converted into cystine peptides by oxidation with iodine [3] [4]. In the meantime, this method has been applied by us and by others to the synthesis of a variety of structurally different cystine peptides PI ~61. I)Abbreviations are according to the IUPAC-IUB Commission on Biochemical Nomenclature [I]. In addition, the following abbreviations have been adopted in the text: Acm = acetamidomethyl; HFIP= hexafluoroisopropyl alcohol; TFE= trifluoroethanol; DMF = dimethylformamide.

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( 2 2 111 71) Suvnvnavy. The conversion of S-acetamidornethyl cysteine peptitics to cystine peptides by it reaction with iodine is described. The method is applied in the synthesis of the hitherto unknown cyclo-L-cystine. The structure of this compound was confirmed by molecular weight determination, NMK. a n d mass spectroscopy.Die Verwendung der Acetamidomethylgruppe (CH,-CO-NH-CH,- Zur Uberfiihrung von IV in das Diketopiperazin VI wurde das von Nitecki et al. [7] beschriebene Verfahren angewendet. Die hbspaltung der t-Butyloxycarbonylgruppe mit 98-proz. Ameisensaure fiilirte zum Formiat des Dipeptid-methylesters V. Die Cyclisierung desselben zu VI gelang unter bemerkenswert milden Bedingungen. Walirend fur die Kildung von Dioxopiperazinen nach diescr Metliode ublicherweise Iangeres Koclien in einem sec-Butanol-Toluol-Gemiscli erforderlich ist, kristallisierte VI schon aus einer metlianolischen 120sung von V bei 45" nach kurzer Zeit aus.Die Umkristallisation aus Eisessig odcr Methanol lieferte cyclo-L-Cystin (VI) als selir feine Nadeln, die sic11 zwisclien 250" und 310" zersetzen. Sie sind in Diniethylsulfoxid gut, in den anderen iiblichen Losungsniitteln nur sparlich loslich. I)Die Uinsetzung van S-Tritylcystein-Derivaten niit Jot1 Linter direkter Dildung von Cystinpeptiden wurdc schoii fruher beschrifben 131.

Total synthesis of human insulin. IV. Description of the final steps. SummaryRecently a preliminary account was given of a new synthetic pathway leading to human insulin. In the present report the last steps of this synthesis -i.e. as from the unsymmetrical cystine derivative I -are described in detail. I contains the sequences A(14-21) and B(17-30), linked by the disulfide bridge A20-B19. These last steps are : 1) selective removal by pH-controlled acidolysis in trifluoroethanol of N(K)-Trt from leucine B17, 2) completion of the B-chain by coupling with the fragment B(l-l6), 3) selective removal by trifluoroethanol of N(cr)-Bpoc at tyrosine A14, 4) completion of the A-chain by coupling with the cyclic fragment A (1-1 3), 5) removal of the acid labile protecting groups, and 6) formation of the disulfide bond A7-B7 from the two S-acetamido-protected cysteine residues by treatment with iodine.As judged by the composition of the reaction mixture the closure of the 85-membered ring proceeds with a cyclization yield of over 70%. From the last step in the synthesis two products were obtained after extensive purification by counter-current distribution: pure human insulin in a yield of 50% and its [D-tyrosine B16]Isomer in a yield of 25%. Although the partial racemization of tyrosine B16 occurred during coupling with sequence B( 1-16), the [D-tyrosine B 161-stereoisomer could only be separated at the endproduct stage.The available evidence indicates that the ease of formation of the disulfide bond A7-B7 does not depend on the precursor molecule already having an insulin-like conformation.Vorlaufige Mitteilung siehe [l].