Synthesis of carbohydrate-based glycosyltransferase inhibitors

This thesis describes the synthesis of three proposed carbohydrate-based glycosyltransferase inhibitors. They were beta N-acetyl C-mannosamine and C-glucosamine 1-phosphonates, alpha N-acetyl D-glucosamine 2-hydroxy and 2-keto phosphonates, and alpha-L-Rha-(1 → 3)-alpha-D-GlcNAc disaccharide analogues.; N-acetyl D-mannosamine and N -acetyl D-glucosamine 1-phosphates are two glycosyl donors used by glycosyltransferases to synthesize a variety of important biological components such as the bacterial cell wall. However, beta C-glycosyl analogues of these glycosyl donors have not been explored as potential inhibitors yet. In order to prepare these analogues, several synthetic routes have been proposed and evaluated in this thesis. It has been found that the Homer-Emmons/Michael reaction approach to the C-glycosyl analogue of mannosaminyl 1-phosphate and the gluconolactone approach to the analogue of glucosaminyl 1-phosphate were the most efficient synthetic routes.; One of the key features in the glycosyltransferase-catalyzed glycosylation is the binding of the donor diphosphate and the divalent metal ion at the enzyme active site, in which the divalent metal ion activates the diphosphate moiety as a leaving group. However, the currently reported analogues of glycosyl pyrophosphate haven't taken full account of this binding nature. Therefore, both glycosyl 2-hydroxy and 2-keto phosphonates were proposed as close mimics to the glycosyl pyrophosphate in this research. Both glycosyl 2-hydroxy and 2-keto phosphonates were prepared through an epoxide approach. Nucleophilic addition of a phosphonate nucleophile to the glycosyl epoxide gave a glycosyl 2-hydroxyl phosphonate in good yield. This glycosyl 2-hydroxy phosphonate was then converted to a glycosyl 2-keto phosphonate with a good yield by oxidation with acetic anhydride/DMSO.; The synthesis of mycobacterial glycosyltransferase inhibitors was based on the structure of a specific mycobacterial cell wall Rha-(1 → 3)-GlcNAc disaccharide linker. This linker is a key component in the biosynthesis of the mycobacterial cell wall, but has not been targeted for drug design so far. It provides a novel structure for modifications as potential inhibitors of mycobacterial glycosyltransferases. These disaccharide analogues were prepared using a thioglycoside approach. For this purpose, a series of glycosyl donors and acceptors was synthesized. (Abstract shortened by UMI.)...