Development of novel approaches for stereoselective construction of glycosidic linkages

建议书摘要 已知复杂的寡糖和糖偶联物在许多生物中起着关键作用。 流程。然而，糖生物学的广泛研究由于以下方面的障碍而受到很大阻碍 获得均一的碳水化合物结构。在过去的几年里，化学合成已经证明是 一种有价值和可行的工具，用于制备大量结构明确的同质 碳水化合物，作为异质糖类，通常从天然来源中分离出来。尽管不同寻常 已经取得了成功，但缺乏温和、催化、易于操作和健壮的糖基化方法 立体选择性合成复杂的α-和β-寡糖仍然是一个挑战，即使对合成的 碳水化合物化学家，更不用说非专家了。 为了应对这一在糖科学中至关重要的挑战，该提案需要七个目标，它们是 分为三个主题。在主题#1中，a)提出了金催化剂，以利用 阳离子Au(I)配合物通过任一种金卡宾发展温和的和催化的给体活化 中间体或硫化物环化过程，b)Au(I)络合物强健且相当独特的线性结构 将被开发用于开发一种模拟酶的协同酸碱催化合成SN2 糖基化，以及c)一种更实惠和可扩展的银催化剂将由Yu的金基 多功能糖基化化学。主题#2，β-甘露糖苷型糖苷的立体选择性合成 存在于微生物囊膜低聚糖和细菌细胞壁中的联系，如6-脱氧-β-D-甘露- 七氢吡喃糖苷、2-脱氧-2-氨基-β-D-甘露糖酸和β-D-甘露糖胺将通过一种新的 β-我们最近开发的甘露糖化作用。在这种方法中，构建这些具有挑战性的糖苷键 将通过碳酸铯介导的相应的乳糖醇供体与 糖分不多。随着这些糖基化方法的发展，主题#3将把它们作为权宜之计。 炭疽芽孢杆菌细胞壁六糖重复单元的合成。 这些目标将通过团队努力和利用朱集团和 张的实验室。开发的新方法将首先在内部进行验证，然后在第四年进行交叉验证。 由密歇根州立大学黄学飞教授的实验室验证。 最终，本提案中开发的糖基化策略将被非专家采用 用于生物研究或医学目的的低聚糖或碳水化合物库的合成。

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.