The synthesis of glycoconjugates has facilitated a wide variety of techniques for the detailed study of carbohydrates and their interactions in biological systems. However, when only small amounts of the isolated oligosaccharide are available, multistep synthetic approaches are not possible. This thesis explores new synthetic methods for the preparation of glycoconjugates without protecting group manipulations.
A new glycosidation method was developed which introduces N-glycopyranosylsulfonohydrazides as glycosyl donors for the protecting group-free synthesis of O-glycosides, glycosyl azides and oxazolines. The glycosyl donors were synthesized in a single chemical step by condensing p-toluenesulfonylhydrazide with the corresponding mono- and disaccharides. The N-glycopyranosylsulfonohydrazides were activated with NBS and subsequently glycosylated with the desired alcohol or transformed to the oxazoline or glycosyl azide.
Recent advances in chemoselective ligation methods for the functionalization of unprotected carbohydrates have provided new routes towards complex glycoconjugates. Despite the wide use of those chemoselective methods, the properties of these linkages have not been thoroughly investigated. Characterization of a series of glycoconjugates formed by chemoselective ligation of xylose, glucose and N-acetylglucosamine with either an acyl hydrazide, a p-toluenesulfonylhydrazide or an N-methylhydroxylamine were carried out to gain further insight into the optimal conditions for the formation and the stability of these useful conjugates. Their apparent association constants (9-74 M-1) at pD 4.5, as well as rate constants for hydrolysis were determined at pH 4.0, 5.0 and 6.0. The half-lives of the conjugates varied between 1 h and 300 days. All the compounds were increasingly stable as the pH approached neutrality.
Finally, selective chemical modification of a glycosaminoglycan chondroitin sulfate was attempted at the non-reducing end by utilizing the Δ4-uronic acid functional group formed upon cleavage of the glycosaminoglycan with a bacterial lyase enzyme. The captodative double bond of the unique Δ4-uronic acid functionality was unreactive towards Michael addition, even if the carboxylate was methylated. Trials towards radical addition using thiyl radicals were unsuccessful, although a synthesized model phenyl Δ4-uronic acid monosaccharide was successfully functionalized under the same conditions.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/26457 |
| Date | 07 March 2011 |
| Creators | Gudmundsdottir, Anna V. |
| Contributors | Nitz, Mark |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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