Carbohydrates in the synthesis of macrocycles and glycoclusters
Fox, Karen A.
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This thesis deals with efforts to generate new bioactive organic compounds. The main focus has been on the use of carbohydrate building blocks for synthesis of both macrocyclic compounds and glycoclusters for biological study. The thesis begins with a short review on the importance of natural products, macrocyclic compounds and carbohydrates in the search for new drug candidates. Many drug molecules are based on scaffolds, which are proposed to have been naturally selected to optimally interact with proteins and some of these are macrocycles. Those macrocycles which have compelling biological properties contain features found in natural products, such as chiral centres, glycosidic linkages, alkenes, aromatic groups, methyl groups and hydroxyl groups, for example. The first two results chapters of this thesis work are concerned with synthesis of new macrocycles containing some of the features of natural products as well as triazoles. In Chapter 2 the synthesis of a new natural product-like macrocyclic compound is described. Here the use of a chiral building block, used previously in the synthesis of migrastatin and analogues, is combined with a glucuronic acid derivative to produce a new macrocyclic compound. In the third chapter new macrocyclic frameworks that combine two galactose residues are prepared. In the latter case it was demonstrated that alkylation could be carried out at C-2 of the galactopyranose residue, which enabled different alkyl groups to be incorporated into the macrocycle. The chemistry used in the construction of the macrocycles in these two chapters included C- and O-glycosylation, ring closing metathesis, copper and ruthenium catalysed azide-alkyne cycloaddition. Carbohydrates are known to be versatile orchestraters of numerous cellular effects. Glycoclusters are multivalent ligands that present a variable number of ligating carbohydrate headgroups on a molecular template or scaffold. Multisite carbohydrate binding proteins or lectins found on the cell surface are vital for the regulation of biological systems within that cell and these can interact with glycoclusters. Assessing and examining exchanges between membrane bound lectins and multiple carbohydrate ligands i.e. glycoclusters, are vital to understanding, controlling, interfering and/or blocking carbohydrate/lectin interactions. Thus, in Chapter 4 the synthesis of new bi- and trivalent glycoclusters based on GlcNAc derivatives is described. This work focused on varying the GlcNAc headgroup, varying the nature of the substituent at C-2. A synthetic route to the glycoclusters involved the use of an alpha-glycosyl thiol intermediate and its subsequent S-glycosylation; epimerisation of the thiol was found to occur in some cases. This enabled the synthesis of the glycocluster from dihydroxy and trihydroxybenzene derivatives and again copper catalysed azide-alkyne cycloaddition was used.
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