Internal Activation of Peptidyl Prolyl Thioesters in Native Chemical Ligation

• DOI: 10.1021/jacs.6b01202
• Publication Date: 2016-03-16T20:24:27Z
• Authors: Yue Gui; Lingqi Qiu; Yaohao Li; Hongxing Li; Suwei Dong
• Keywords: Thioester; Native chemical ligation; Aminolysis; Chemical Ligation; Chemoselectivity; Thiolactone; Thiol; Peptide bond

Prolyl thioesters have shown significantly lower reactivities in native chemical ligation (NCL) comparison to that of the alanyl thioester. This report describes a mild and efficient internal activation protocol peptidyl prolyl NCL without using any thiol-based additives, where introduction 4-mercaptan substituent on C-terminal proline improves reactivity via formation bicyclic thiolactone intermediate. The kinetic data indicate reaction rate is comparable reported thioesters, mechanistic studies suggest two peptide segments proceeds through an NCL-like pathway instead direct aminolysis, which ensures chemoselectivity compatibility various amino acid side chains. 4-mercaptoprolyl thioester-based also allows one-pot ligation-desulfurization procedure. utility this method has been further demonstrated synthesis proline-rich region Wilms tumor protein 1.