Development of novel approaches for stereoselective construction of glycosidic linkages

提案摘要 已知复杂寡糖和糖缀合物在许多生物学中起关键作用， 流程.然而，糖生物学的广泛研究已经由于以下障碍而受到实质性阻碍： 得到均匀的碳水化合物结构。在过去的几年里，化学合成已被证明是 一种有价值的和可行的工具，用于制备大量的均匀的结构明确的 碳水化合物，作为异质糖型，通常从天然来源分离。尽管引人注目 尽管已经取得了成功，但缺乏温和的、催化的、易于操作的和稳健的糖基化方法用于 复杂α-和β-寡糖立体选择性合成仍然是一个挑战， 碳水化合物化学家更别说非专业人士了 为了应对这一对糖科学至关重要的挑战，该提案提出了七个目标， 分为三个主题。在主题#1中，a）提出金催化以利用 阳离子Au（I）配合物在温和和催化供体活化的发展中通过金卡宾 中间体或硫化物环化过程，B）Au（I）络合物的稳健且相当独特的线性结构 开发一种模拟酶的协同酸和碱催化剂， 糖基化，和c）一个更负担得起的和可扩展的银催化是由Yu的金基 通用糖基化化学。在主题#2中，β-甘露糖苷型糖苷的立体选择性合成 存在于微生物荚膜寡糖和细菌细胞壁中的连接，如6-脱氧-β-D-甘露糖- 七吡喃糖苷，2-脱氧-2-氨基-β-D-甘露糖醛酸，和β-D-甘露糖胺，将通过一种新的 我们最近开发的β-甘露糖基化。在这种方法中，这些具有挑战性的糖苷键的构建 将通过碳酸铯介导的相应内半缩醛供体的异头SN 2 O-烷基化来实现， 三氟甲磺酸糖随着这些糖基化方法的发展，主题#3将以一种权宜之计来展示它们 从炭疽杆菌细胞壁合成六糖重复单元。 这些目标将通过团队努力和利用朱氏集团和 Zhang实验室开发的新方法将首先在内部验证，然后在第四年进行交叉验证。 由密歇根州立大学黄雪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， 用于生物学研究或医学目的的寡糖或碳水化合物文库的合成。

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.