Disulfide Interchange and Its Avoidance during the Synthesis of Peptides Containing Cystine

18 DISULFIDE INTERCHANGE AND ITS AVOIDANCE DURING THE SYNTHESIS OF PEPTIDES CONTAINING CYSTINE 

The synthesis of peptides containing cystine is rarely performed starting with derivatives of cystine because of the obstacle of disulfide interchange. Disulfide interchange was discovered by F. Sanger during his attempts to determine the primary 

FIGURE 6.22 Disulfide interchange.92 (A) Discovered in synthesis when hydrazinolysis of an unsymmetrical derivative of cystine gave two symmetrical products instead of the expected monohydrazide at the urethane-protected cysteine moiety of the derivative.95 (B) Mechanism for interchange catalyzed by strong acid,94 which is suppressed by thiols. (C) Mechanism for interchange catalyzed by weak alkali, which is enhanced by thiols. 

FIGURE 6.23 The synthesis of insulin, starting with a cystine-containing peptide. [Kamber et al., 1977]. Moc = methoxycarbonyl, Bpoc = biphenylisopropoxycarbonyl, Trt = trityl, Acm = acetamidomethyl. (a) HOBt-assisted carbodiimide-mediated coupling (b) removal of Trt by HC1 in CF3CH2OH-CH2Cl2 (9 1) at pH 3.5 (c) removal of Bpoc by CF3CH2OH-CH2 Cl2 (9 1) at 60°C (d) removal of Acm and oxidation by iodine. 

AP Ryle, F Sanger. Disulfide interchange reactions. Biochem J 535, 1955. 

---