Traceless β-mercaptan-assisted activation of valinyl benzimidazolinones in peptide ligations.

Yinglu Wang,Ning Yuan,Suwei Dong,Qiang Zhang,Hanxuan Wang,Hongxing Li,Huan Chen,Lin Han,Jinrong Liu

doi:10.1039/c7sc04148a

Abstract

Peptidyl thioesters or their surrogates with C-terminal β-branched hydrophobic amino acid residues usually exhibit poor reactivities in ligation reactions. Thus, activation using exogenous additives is required to ensure an acceptable reaction efficiency. Herein, we report a traceless ligation at Val-Xaa sites under mild thiol additive-free reaction conditions, whereby the introduction of β-mercaptan on the C-terminal valine residue effectively activates the otherwise unreactive N-acyl-benzimidazolinone (Nbz), and enables the use of a one-pot ligation-desulfurization strategy to generate the desired peptide products. The orthogonality between β-thiovaline-Nbz and a conventional alkyl thioester, as well as the convenient access to the former from readily available penicillamine, also allowed expedited assembly of the peptidic hormone β-LPH and hPTH analogues, based on a kinetically controlled one-pot three-segment ligation and desulfurization strategy.

Highlights

Native chemical ligation (NCL) is one of the most powerful and frequently used methods employed in the elds of chemistry and chemical biology[1] for the construction of polypeptides and proteins.[2]
The addition of MPAA accelerated the ligation of peptidyl Val-Nbz (Fig. 2b and c), which is in accordance with a previous report,[5] but required a longer time than that of the bthio Val-Nbz derived peptide to achieve over 90% conversion (i.e. 8 h)
These results indicate that the b-mercaptan group on the terminal valine residue drastically increases the reaction rate

Summary

Introduction

Native chemical ligation (NCL) is one of the most powerful and frequently used methods employed in the elds of chemistry and chemical biology[1] for the construction of polypeptides and proteins.[2]. We report a traceless ligation at Val-Xaa sites under mild thiol additive-free reaction conditions, whereby the introduction of b-mercaptan on the C-terminal valine residue effectively activates the otherwise unreactive N-acyl-benzimidazolinone (Nbz), and enables the use of a one-pot ligation–desulfurization strategy to generate the desired peptide products.

Results

Conclusion