- Ynamide-Mediated Thiopeptide Synthesis
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Exploration of the full potential of thioamide substitution as a tool in the chemical biology of peptides and proteins has been hampered by insufficient synthetic strategies for the site-specific introduction of a thioamide bond into a peptide backbone. A novel ynamide-mediated two-step strategy for thiopeptide bond formation with readily available monothiocarboxylic acids as thioacyl donors is described. The α-thioacyloxyenamide intermediates formed from the ynamides and monothiocarboxylic acids can be purified, characterized, and stored. The balance between their activity and stability enables them to act as effective thioacylating reagents to afford thiopeptide bonds under mild reaction conditions. Amino acid functional groups such as OH, CONH2, and indole NH groups need not be protected during thiopeptide synthesis. The modular nature of this strategy enables the site-specific incorporation of a thioamide bond into peptide backbones in both solution and the solid phase.
- Yang, Jinhua,Wang, Changliu,Xu, Silin,Zhao, Junfeng
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supporting information
p. 1382 - 1386
(2019/01/08)
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- 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
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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).
- Fotouhi, Nader,Galakatos, Nicholas George,Kemp, D. S.
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p. 2803 - 2817
(2007/10/02)
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