Highly Efficient SN2 Glycosylation for Stereoselective 1,2-cis Glycosidic Bond Synthesis

Background

Carbohydrates serve essential biological functions, including energy storage and primary metabolites; they also play key roles in a broad range of biological processes such as signal transduction, fertilization, metathesis, cell-cell adhesion, and immune responses. Oligosaccharides are short-chain carbohydrates that have exceptional structural complexity, which poses significant challenges to their synthesis and hinders the study of their biological functions. Advances in stereoselective glycosylation reactions have been achieved, especially in the context of the formation of 1,2-trans glycosidic bonds via neighboring group assistance. However, the formation of 1,2-cis glycosidic bonds remains challenging, and a strategy that is applicable to every sugar type has yet to be discovered. Current strategies to overcome this challenge suffer from limitations that could be addressed by improved methods of glycosylation.

Description

Researchers at the University of California, Santa Barbara have addressed the long-standing challenge of stereoselective 1,2-cis glycosidic bond formation by employing a basic directing group attached to the anomeric leaving group, activated by an electrophilic reagent such as a cationic gold catalyst. The directing group promotes nucleophilic attack via an SN2 pathway, resulting in stereo-inversion and traceless removal of the directing group in the product. This method is broadly applicable to all glycosyl donors, including pyranosides and furanosides, achieving excellent yields with high selectivity. Additionally, this approach enables iterative oligosaccharide synthesis, facilitates differentiation of alcohol acceptors by steric hindrance, and supports development of automated carbohydrate synthesis platforms, thus greatly advancing glycoscience research and applications.

Publication: https://pubs.acs.org/doi/pdf/10.1021/jacs.3c02792 

Advantages

• Broad applicability to any glycosyl donor sugar type
• Highly stereoselective construction of challenging 1,2-cis glycosidic bonds
• Traceless directing group avoids complications in downstream modifications
• Compatible with both pyranoside and furanoside synthesis
• Enables iterative oligosaccharide assembly and selective acceptor differentiation
• Potentially adaptable for automated carbohydrate synthesis platforms
• Improves step economy by eliminating need for special protecting groups

Applications

• Automated oligosaccharide synthesis services and platforms
• Pharmaceutical and biotechnology research targeting glycoscience and glycobiology
• Development of complex glycosylated natural products, glycoproteins, and glycolipids
• Production of oligosaccharides for vaccines, diagnostics, and therapeutics
• Companies engaged in carbohydrate synthesis and glycoconjugate manufacturing
• Academic and industrial research accelerating understanding of carbohydrate functions

Patent Status