A study in carbohydrate chemistry: From anomerisation to synthesis of glycoclusters based on neoglycopeptides
Di Salvo, Claudia
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1,2-cis aminoglycosides are considered difficult to prepare in a highly stereoselective manner. Some strategies have been developed to date including the preparation of 2-azido, 2-benzylidine and 2,3-oxazolidinone glycosyl donor for the stereoselective α-1,2-cis-glycosylation. However, there is a need for the development of other methods due to the constant screening of glycosylation conditions, along with preparation of different glycosyl donors and significant protecting group manipulation. This thesis work was concerned in part, with determining the potential of anomerisation reactions for the stereoselective synthesis of 1,2-cis glycosides of GlcNAc and GalNAc and other related and important glycosides. An introduction to carbohydrate chemistry is provided in the first chapter of this thesis with a summary of what is known to date about anomerisation reaction. The second and third chapters deal with the investigation of anomerisation of thiols derived from GlcNAc and GalNAc as well as some of their O/S-glycosides. Glycosyl thiols are useful building blocks for the synthesis of S-glycosides. These are of interest for the synthesis of various types of glycoconjugates, mostly glycomimetics. A relatively small number of procedures are known to produce α-glycosyl thiols, compared to the corresponding β-anomers. A series of acetylated and benzoylated β-GlcNAc and GalNAc thiols were synthesised and their anomerisation reactions investigated under different conditions. The anomerisation/epimerisation of α-glycosyl thiols to the β-anomer was also investigated. Benzoylated glycosyl thiols showed a higher propensity to undergo anomerisation reactions compared to corresponding acetylated glycosyl thiols. Equilibrium between α- and β-anomers was established for acetylated glycosyl thiols in EtOAc. The use of TiCl4 in dichloromethane led to the α-anomer, via a thiazoline. This observation was included in a paper published in Organic Letters (DOI: 10.1021/acs.orglett.7b02760), contributing to formation of a mechanistic proposal for the epimerisation of glycosyl thiols. The Lewis acid catalysed anomerisation of some O-glycosides and S-glycosides derived from GlcNAc and GalNAc is described, with limitations identified. The next part of the thesis (Chapter 4) deals with the design and synthesis of glycoclusters based on neoglycopeptides. Molecular self-assembly is considered to be a useful approach for the synthesis of novel molecular architecture. Proteins and peptides can self-organize and form well-defined structures with a role as scaffold for the presentation of biological and immunological active ligands, such as carbohydrates. Herein the coiled-coil motif was explored as a scaffold for the multivalent display of peptide and carbohydrate ligands. De novo peptides self-assemble into dimeric and trimeric coiled coils when exposed to aqueous media. A lactose disaccharide, bearing a triethylene glycol (TEG) chain, was linked to asparagine and then subjected to solid phase peptide synthesis to produce peptide sequences creating divalent and tetravalent dimeric neoglycopeptides as well as trivalent trimeric neoglycopeptides. Such glycoclusters based on lactose are of interest as galectin inhibitors. These glycoclusters have been analysed by circular dichroism (CD) spectroscopy, which showed evidence for helical formation. They are currently under study of their self-assambly characteristics by analytical ultracentrigugation (AUC) and under biological evaluation to ascertain their galectin-3 inhibitory potential.
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