Peptide Synthesis by Prior Thiol Capture. 6. Rates of the Disulfide Bond Forming Capture Reaction and Demonstration of the Overall Strategy by Synthesis of the C-Terminal 29-Peptide Sequence of BPTI

Article abstract of DOI:10.1021/jo00273a008

Peptide bond formation by prior thiol capture involves as a first step formation of a disulfide bond between two S-functionalized peptide fragments, one bearing a 4-(acyloxy)-6-mercaptodibenzofuran at its C-terminus, the other bearing an S-activated cysteine residue at its N-terminus.The Scm procedure (Scm MeO-CO-S) of Brois and others is used to generate disulfides of general structure -Cys(S-S-Ar)- by reaction of suitable arene thiols with -Cys(S-Scm)- derivatives.Mixtures of hexafluoroisopropyl alcohol (HFIP) with water and acetonitrile facilitate this reaction, which is markedly accelerated by traces of tertiary amines, by electron-withdrawing groups near the Scm function, and by an increase in the fraction of water in the mixture.A 94percent yield in 5 min was seen for reaction of the trifluoroacetate salt of H-L-Cys(S-Scm)-OMe (5*10^-4 M) with 4-mercaptodibenzofuran (5*10^-4 M) in 9:1 HFIP-MeCN.The scope of the thiol capture strategy is demonstrated by a four-fragment, three-stage assembly of the 29-peptyde sequence 30-58 of the protein basic pancreatic trypsin inhibitor (BPTI).