Development of novel approaches for stereoselective construction of glycosidic linkages

提案摘要 众所周知，复杂的寡糖和复合糖在许多生物领域发挥着关键作用。 流程。然而，由于糖生物学方面的障碍，对糖生物学的广泛研究受到了严重阻碍。 获得均匀的碳水化合物结构。近年来，化学合成已被证明是 一种有价值且可行的工具，用于制备大量均质、结构明确的材料 碳水化合物，因为异质糖型通常是从天然来源中分离出来的。尽管引人注目 尽管已取得成功，但缺乏温和、催化、易于操作且稳健的糖基化方法 即使对于合成来说，复杂的α-和β-低聚糖的立体选择性合成仍然是一个挑战 碳水化合物化学家，更不用说非专家了。 为了应对糖科学中这一至关重要的挑战，该提案提出了七个目标，分别是 分为三个主题。在主题 1 中，a) 建议利用金催化来利用软酸性 阳离子 Au(I) 配合物通过金卡宾开发温和催化供体活化 中间体或硫化物环化过程，b) Au(I) 配合物的稳健且相当独特的线性结构 将用于开发模拟酶的协同酸碱催化，以实现 SN2 糖基化，以及c）Yu的金基材料将开发一种更实惠且可扩展的银催化 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 存在于微生物荚膜寡糖和细菌细胞壁中的连接，例如 6-脱氧-β-D-甘露糖- 吡喃庚糖苷、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方法获得 我们最近开发了β-甘露糖基化。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乳醇供体的异头SN2 O-烷基化来实现 三氟甲磺酸糖。随着这些糖基化方法的开发，主题#3将以权宜之计的方式展示它们 从炭疽芽孢杆菌细胞壁合成六糖重复单元。 这些目标将通过团队努力并利用朱氏集团和 张实验室。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。 经密歇根州立大学黄雪飞教授实验室验证。 最终，该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.