Development of novel approaches for stereoselective construction of glycosidic linkages

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Proposal abstract Complex oligosaccharides and glycoconjugates have been known to play critical roles innumerous biological processes. However, extensive studies on glycobiology have been substantially hindered due to obstacles in obtaining homogeneous carbohydrate structures. Over past years, chemical synthesis has demonstrated to be a valuable and viable tool for preparation of significant quantities of homogenous structurally well-defined carbohydrates, as heterogeneous glycoforms are usually isolated from natural sources. Despite remarkable success has been achieved, the lack of mild, catalytic, easy-to-operate, and robust glycosylation methods for stereoselective synthesis of complex α- and β-oligosaccharides still remains a challenge even for synthetic carbohydrate chemists, let alone non-specialists. To address this challenge of critical importance in glycoscience, the proposal entails seven aims, which are grouped into three themes. In Theme #1, a) gold catalysis are proposed to harness the soft acidic nature of cationic Au(I) complexes in the development of mild and catalytic donor activation via either gold carbene intermediates or a sulfide cyclization process, b) the robust and rather unique linear structure of Au(I) complexes is to be exploited to develop an enzyme-mimicking synergistic acid and base catalysis en route to SN2 glycosylation, and c) a much more affordable and scalable silver catalysis is to be developed by Yu’s gold-based versatile glycosylation chemistry. In Theme #2, stereoselective synthesis of β-mannoside type of glycosidic linkages existing in microbial capsular oligosaccahrides and bacterial cell walls, such as 6-deoxy-β-D-manno- heptopyranosides, 2-deoxy-2-amino-β-D-mannuronic acids, and β-D-mannosamines, will be achieved via a new β-mannosylation we recently developed. In this approach, construction of these challenging glycosidic linkages will be achieved via cesium carbonate-mediated anomeric SN2 O-alkylation of corresponding lactol donors with sugar triflates. With those glycosylation methods developed, Theme # 3 will feature them in an expedient synthesis of a hexasaccharide repeat units from Bacillus anthracis cell walls. These aims will be implemented via team effort and by harnessing the expertise of both the Zhu group and the Zhang lab. The new methods developed will be first validated internally and then in the fourth year cross- validated by Prof. Xuefei Huang’s lab at MSU. Ultimately, the glycosylation strategies developed in this proposal would be adopted by non-specialists for the synthesis of oligosaccharides or carbohydrate libraries for biological studies or medical purpose.