串联的分子内苷元传递反应（IAD）构建beta-甘露糖苷键

Synthesis of beta-mannoside is one of the biggest challenge in carbohydrate chemistry, the anomeric effect, steric effect and neighboring group participation effect usually used to control the stereoselectivity in glycosylations largely prefer alfa-selectivity in mannosylation. Intramolecular aglycon delivery (IAD) is one of the most reliable strategies to construct the beta-mannosidic bonds. However, the tedious reaction steps required for most IAD methods limited the overall efficiency. The present proposal plan to combine the separated reaction steps in traditional IAD methods by design tandem reactions. These tandem reactions based on the concept that activation of sulfoxide could generate sulfinate intermediate which subsequently active sulfide. The strategy would shorten the conventional four-steps IAD reaction to two steps, which will largely increase the efficiency. The strategy will be further applied to synthesize other 1,2-cis-glycosides including beta-rhamnoside, beta-arabinofuranoside, alfa-glucoside and alfa-galactose, as well as bioactive oligosaccharides and glycoconjugates containing these skeletons.

Beta-甘露糖苷键的构建是糖化学领域最具挑战性的难题之一，糖化学中常用于控制糖基化选择性的异头碳效应、立体位阻效应以及邻基参与效应在甘露糖基化中都更倾向于形成alfa-糖苷键。分子内苷元传递反应（IAD）是构建Beta-甘露糖苷键的最有效方法之一，但是已报到的IAD方法大都步骤冗长、操作复杂、整体效率不高。本项目拟通过设计串联反应将IAD的各独立步骤合并，缩短反应进程。该策略借助亚砜活化产生的活性中间体活化活泼硫醚，从而实现甘露糖和苷元连接的串联或者苷元连接和糖基化的串联，将常规IAD的四步反应精简为最多两步反应，有效提高整体效率。该串联的IAD策略也将进一步应用于其他1，2-cis糖苷键如beta-鼠李糖苷键、beta-阿拉伯呋喃糖苷键、alfa-葡萄糖苷键及alfa-半乳糖苷键等的构造，以及含有这些糖苷键的生物活性寡糖和糖缀合物的合成。

糖苷键的立体选择性构建是糖化学研究领域一直以来面临最大的困难之一，本项目紧密围绕开发包括β-甘露糖苷化在内的糖苷化新方法这一核心议题开展研究工作。在本基金的支持下，基于对亚砜、硫醚、硫醇(酚)活化机理的深入研究，建立了几种高效的糖苷键构建与糖化合物修饰方法，为包括含β-甘露糖苷结构在内的糖类化合物合成提供了更有效的手段。经过四年的努力，项目取得的成果以研究论文的形式得以展现，其中包括J. Am. Chem. Soc. (2 篇), Chemical science (1 篇)，Chin. J. Chem (3 篇)等研究论文和综述论文 （Org. Chem. Front.）。在本基金的支持下项目负责人获得了药明康德生命化学研究奖（2020）、Organic Process Research & Development 奖（2020）、国家杰出青年科学基金项目（22025102）等奖项和项目，参与项目的陈薇、蔡磊等同学还获得了新和成《中国化学》创新奖(NHUCJCInnovation Award)（2022、2020）等奖项。