Facile access to C-glycosyl amino acids and peptides via Ni-catalyzed reductive hydroglycosylation of alkynes

Yan-Hua Liu,Haotian Li,Dapeng Zhu,Biao Yu,Zhifei Hu,Yu-Nong Xia,Tayyab Gulzar,Peng Xu,Bingcheng Wei

doi:10.1038/s41467-021-25127-z

Abstract

C-Glycosyl peptides/proteins are metabolically stable mimics of the native glycopeptides/proteins bearing O/N-glycosidic linkages, and are thus of great therapeutical potential. Herein, we disclose a protocol for the syntheses of vinyl C-glycosyl amino acids and peptides, employing a nickel-catalyzed reductive hydroglycosylation reaction of alkyne derivatives of amino acids and peptides with common glycosyl bromides. It accommodates a wide scope of the coupling partners, including complex oligosaccharide and peptide substrates. The resultant vinyl C-glycosyl amino acids and peptides, which bear common O/N-protecting groups, are amenable to further transformations, including elongation of the peptide and saccharide chains.

Highlights

C-Glycosyl peptides/proteins are metabolically stable mimics of the native glycopeptides/ proteins bearing O/N-glycosidic linkages, and are of great therapeutical potential
More than 13 monosaccharides can join with eight amino acid residues to provide at least 41 distinct types of glycosidic linkages connecting the saccharides with the proteins[6]
These linkages are mostly O/N-glycosidic bonds with the hydroxyl and amido groups pending on serine, threonine, or asparagine residues[7,8,9], with Man-Trp being the only C-glycosidic motif known to date[10, 11] (Fig. 1a)

Summary

Introduction

C-Glycosyl peptides/proteins are metabolically stable mimics of the native glycopeptides/ proteins bearing O/N-glycosidic linkages, and are of great therapeutical potential. We disclose a protocol for the syntheses of vinyl C-glycosyl amino acids and peptides, employing a nickel-catalyzed reductive hydroglycosylation reaction of alkyne derivatives of amino acids and peptides with common glycosyl bromides. It accommodates a wide scope of the coupling partners, including complex oligosaccharide and peptide substrates. More than 13 monosaccharides can join with eight amino acid residues to provide at least 41 distinct types of glycosidic linkages connecting the saccharides with the proteins[6]. Synthesis of complex C-glycosyl peptides, especially a convergent synthesis using oligosaccharides as donors still poses a formidable challenge, due to the following methodological limits: (i) scarcity of methods for construction of alkyl/alkenyl C-glycosidic bonds, in contrast to the well-studied aryl C-glycosylation; (ii) harsh reaction conditions, including high temperature, strong bases, stoichiometric amount of

Methods

Results

Conclusion