Total Chemical Synthesis of a Glycoprotein by Native Chemical Ligation
Fmoc-Based Synthesis of Peptide-αThioesters: Application to the Total Chemical Synthesis of a Glycoprotein by Native Chemical Ligation.
J. Am. Chem. Soc. 1999;
19 March 2019 (online)
Key wordsnative chemical ligation - thioesters - Fmoc chemistry - glycoproteins - alkanesulfonamides
The authors have developed a new approach for the synthesis of unprotected αthioesters by using Fmoc-based solid-phase peptide synthesis and have demonstrated its utility in the total synthesis of a glycosylated protein, the antimicrobial O-linked glycoprotein diptericin, by the native chemical ligation method. This method utilizes an alkanesulfonamide ‘safety-catch’ linker, which circumvented the problems associated with the incompatibility of glycosidic linkages with Boc chemistry and of thioesters with Fmoc chemistry.
The C-terminal residue of the peptide is attached to the resin through an acid- and base-stable N-acyl sulfonamide linkage. After peptide synthesis, the sulfonamide is activated by cyanomethylation and then cleaved with a thiol nucleophile. This general synthetic approach permits access to unprecedented quantities of homogeneous glycoproteins.