Catalytic Stereoselective Synthesis of Glycosides

The power of carbohydrate synthesis has been highlighted by the development of vaccines and anticoagulants for human use and the recent chemical synthesis of glycoproteins. Thus, expedient chemical methods to streamline the synthesis of these complex molecules will be an important development not only in synthetic chemistry but also in glycobiology research, with long term impact in the area of glycomedicine.
The stereoselective synthesis of glycosides is one of the biggest challenges in oligosaccharide synthesis. The chemical synthesis of complex carbohydrates generally involves the coupling of a fully protected glycosyl donor bearing a leaving group at its anomeric centre with a suitably protected glycosyl acceptor containing a nucleophile (R-OH). In most instances, these reactions lead to a mixture of two stereoisomers. The most reliable method for stereoselective glycosylations is based on neighbouring group participation (NGP), which requires the introduction of specific groups at the C-2 position to direct nucleophilic attack. However, the incorporation of NGP groups is often troublesome, impractical and not applicable to every type of monosaccharide i.e. N-2, 2-deoxy glycosides, etc.
Our team have recently reported a mild organocatalytic method for the synthesis of 2-deoxygalactosides, with excellent yields and alpha-selectivity. (Angew. Chem. Int. Ed. (2012), 51, 36, 9152-9155). The proposed project aims to develop general and catalytic methods for the stereoselective synthesis of glycosides.

Carbohydrates have emerged as important factors in molecular recognition. Targeted oligosaccharide synthesis is vital to provide tools for the study of the biological roles of these combinatorially diverse molecules and their implications in health and disease.

Academic impact
O-glycosylation, though one of the most common forms of glycosylation in eukaryotic cells, is currently understudied due the lack of tools. Developing catalytic methods that can make the synthesis of oligosaccharide mainstream will have a tremendous impact, as high purity glycans will be available to help provide basic understanding of the biological role of O-glycans. In a general sense, it will help provide insights into the structural parameters that control the combinatorial diversity of O-glycosylation in Nature and the implications of such diversity in terms of biological function. Having expedient access to any glycan library ("Dial-a-Sugar") will provide colleagues in the glycobiology community, e.g. UK Glycoarray Consortium and other collaborators with pure and defined glycan molecules, which were not easily accessible before, to complement and expand their range of research tools available. Availability of these compounds to glyco-biologists would be major asset for drug discovery and early development of novel therapeutics. Moreover, the diastereoselective acetal formation methods that will be developed within this proposal are not only applicable to oligosaccharide synthesis but will be of great interest to the synthesis of other important natural products that also contain cyclic acetals. Thus, the methods proposed here will provide a valuable addition to the toolbox of synthetic chemistry with applications in, and beyond, the field of carbohydrates.

Economic impact
Benefits will not only be expected from expedient access to glycan targets, but the new organocatalytic methods proposed here, should make the stereoselective synthesis of acetals a more efficient and greener methodology that will impact the pharmaceutical, agrochemical and fine chemicals sectors. The methods and tools developed within this programme can be exploited for glycan screening arrays in pathology, vaccine and glyco-therapeutics development by pharma.

Societal impact
Industrial use and further development of the catalytic methods developed here has the potential to provide access to molecules that can improve early disease detection and stage-appropriate therapy in diseases like bowel cancer, where changes in glycosylation are gradual. A benefit to quality of life can be envisaged if glycans and understanding of glycobiology can be integrated in the development of diagnostic tools, novel therapeutics and vaccines.
Involvement with ChemLabS and the outreach programme of the School of Chemistry in Bristol will contribute to the understanding of the Chemistry of Carbohydrates and its relevance to Health and Disease. We have plans to deliver lectures for the RSC Chemistry week (Nov. 2013) and participate in the outreach programmes for scientific education in schools and other public events.

Thus, the research programme has the potential to deliver important insights into chemistry, biology and in the longer term will impact the chemical industry sector and in due course the areas of health science and diagnostic medicine. Additionally, the project will have significant impact in glycoarray screening, diagnostic tests, vaccine development and glycan therapeutics.