Glycosyl ortho-(1-phenylvinyl)benzoates versatile glycosyl donors for highly efficient synthesis of both O-glycosides and nucleosides

Penghua Li,Zixi Chen,Rui Yang,Limei Bao,Yingying Huang,Guozhi Xiao,Yunqin Zhang,Haiqing He,Lili Xu

doi:10.1038/s41467-020-14295-z

Abstract

Both of O-glycosides and nucleosides are important biomolecules with crucial rules in numerous biological processes. Chemical synthesis is an efficient and scalable method to produce well-defined and pure carbohydrate-containing molecules for deciphering their functions and developing therapeutic agents. However, the development of glycosylation methods for efficient synthesis of both O-glycosides and nucleosides is one of the long-standing challenges in chemistry. Here, we report a highly efficient and versatile glycosylation method for efficient synthesis of both O-glycosides and nucleosides, which uses glycosyl ortho-(1-phenylvinyl)benzoates as donors. This glycosylation protocol enjoys the various features, including readily prepared and stable donors, cheap and readily available promoters, mild reaction conditions, good to excellent yields, and broad substrate scopes. In particular, the applications of the current glycosylation protocol are demonstrated by one-pot synthesis of several bioactive oligosaccharides and highly efficient synthesis of nucleosides drugs capecitabine, galocitabine and doxifluridine.

Highlights

Both of O-glycosides and nucleosides are important biomolecules with crucial rules in numerous biological processes
The problems inherent to nucleosides synthesis mainly include the poor solubility and nucleophilicity of nucleobases, which results in the unfavorable competition for glycosylation with other nucleophilic species derived from the leaving group and promoters in the coupling reaction
In 2019, the group of Yu37 reported another highly effective and versatile glycosylation method with 3,5-dimethyl-4-(2′-phenylethynylphenyl)phenyl (EPP) glycosides as donors, which is suitable for efficient synthesis both of O-glycosides and nucleosides (Fig. 1d)

Summary

Introduction

Both of O-glycosides and nucleosides are important biomolecules with crucial rules in numerous biological processes. Due to the stoichiometric use of strong Lewis acids, e.g. trimethylsilyl triflate and SnCl4, the limitations of this method are obvious, including: (1) the poor functional group compatibility of the strong Lewis acid; (2) the low coupling yields and moderate N9/N7 regioselectivity when purines are used; and (3) the issues of work-up and disposal, especially on preparative scale To overcome these issues, Jamison’s group[34] introduced pyridinium triflate salts as efficient bronsted acid catalysts for nucleosides and nucleosides analogs synthesis (Fig. 1b). In 2019, the group of Yu37 reported another highly effective and versatile glycosylation method with 3,5-dimethyl-4-(2′-phenylethynylphenyl)phenyl (EPP) glycosides as donors, which is suitable for efficient synthesis both of O-glycosides and nucleosides (Fig. 1d) Notwithstanding these breakthroughs, the challenges still remain in this realm. General glycosylation methods suitable for industrial appllications with lower costs for efficient synthesis of both O-glycosides and nucleosides remain extremely rare

Methods

Results

Conclusion