The anomerisation of glycosyl thiols and synthesis of multivalent GlcNAc and GalNAc glycoclusters

Abstract

There are several published procedures available for the synthesis of b-thiopyranoses such as gluco- or galacto-pyranoses. Given the ease with which one can access such b -thiopyranoses, the development of a reproducible anomerisation of these b-thiopyranoses to give the a-thiopyranoses would greatly facilitate the synthesis of various types of a-S-glycoconjugates. This was a major aim of this thesis work. To that end, a variety of thio-glycopyranoses were prepared and their anomerisation reactions investigated using Lewis acid promoters. The anomeristion of benzoylated thiopyranoses have been shown to be achievable in moderate to very good yields. Reactions were carried out for gluco-, galacto-, xylo-, arabino-, fuco- and rhamno-pyranose derivatives. In addition some disaccharide derivatives containing a thiol functional group were anomerised. Alkylation of these glycosyl thiols was also demonstrated during the course of the thesis work. These results are reported in chapter one.

The second chapter of the thesis describes the synthesis of glycoclusters containing N-acetyl glucosamine (GlcNAc) for evaluation as bactericidal agents against Helicobacter pylori. This is a spiral shaped bacterium that lives in the stomach and duodenum and infects about half of the world's population with some of these infected individuals developing peptic ulcers, gastric cancer and mucosa-associate lymphoma. This research was based on work showing that O-glycans expressing terminal 1,4-linked a-GlcNAc residues have antimicrobial activity against Helicobacter pylori. Previous work from the Murphy laboratory has identified two bivalent GlcNAc derivatives with activity against two different strains of Helicobacter pylori. Analogues of these bivalent structures were prepared. This included S-glycoside based analogues.

The final chapter of this thesis work describes the synthesis of N-acetyl galactosamine containing glycoclusters. In this case bivalent, trivalent and tetravalent structures were prepared, which included a-thiopyranose derivatives. A tetravalent compound synthesised was shown to have very high potency for a macrophage galactose C-type lectin receptor when compared to GalNAc itself. The work on this topic has been published in Organic and Biomolecular Chemistry (Org. Biomol. Chem., 2015, 13, 4190-4203).