Development of alpha-selective 2-azido-2-deoxy glucose and 2- azido-2-deoxy galactose donors for stereoselective synthesis of biologically important oligosaccharides.

摘要

In forms of glycoconjugates, carbohydrates play significant roles in a diverse set of biological events, including viral and bacterial infections, cell growth and proliferation, cell-cell communication, as well as immunoresponse. Thus carbohydrates are crucial in both life sustaining and life threatening processes.;Carbohydrate research currently faces two main hurdles. Firstly, the low binding affinity of carbohydrates to their receptors making it difficult to identify, isolate and characterize carbohydrate binding partners. Secondly, access of carbohydrate molecules in their homogeneous forms in sufficient amounts for biological studies is very challenging. Carbohydrates have higher structural diversity compared to the other biopolymers and are often present as heterogeneous mixtures in nature making their isolation from natural sources very difficult. Molecular biology as a method of accessing carbohydrates molecules also faces a much bigger challenge due to the fact that carbohydrates structures are not encoded directly in the DNA sequences. Chemical synthesis remains the most powerful means to access sufficient and structurally diverse natural and non-natural oligosaccharides in their homogeneous forms for biological studies.;Over the years, chemical synthesis of oligosaccharides has been hampered by difficulties associated with stereoselectivity and regioselectivity. Whereas protecting groups can be summoned to help resolve the regioselectivity problem, stereoselectivity still remains a considerable challenge especially in the synthesis of 1,2-cis glycosidic linkages. There is a need to develop a more reliable way to construct 1,2-cis glycosidic linkages because such linkages are commonly found in biologically important oligosaccharides.;This thesis reports design and synthesis of excellent alpha-selective GalN3 and GlcN3 donors that can be very handy in installation of alpha-GlcNH2, alpha-GalNH2, alpha-GlcNAc and alpha-GalNAc linkages. This discovery came out of a systematic study on how protecting groups especially acetyl esters at remote positions other than C-2 can possibly influence stereochemical outcome of glycosylation reactions. Progress towards total synthesis of hexasaccharide active against H. pylori and dual tagged carbohydrate ligands for identification of potential drug targets on H. pylori is also described. The last part of this dissertation elaborates our combinatorial synthesis of a library of glycosylated flavonols, members of the flavonoid family with very interesting biological activities.