Small-Molecule Catalysts for the Stereoselective Synthesis of Oligosaccharides

 描述（由申请人提供）：本项目的目标是开发具有可预测立体选择性的亲核试剂糖基化的稳健、实用和通用方法。我们的实验室帮助开拓了使用小分子手性氢键供体作为对映选择性反应的催化剂。作为这些研究的延伸，我们发现了一个新的原则，影响选择性糖基化反应。精确设计的大环双硫脲催化剂促进醇类亲核试剂与糖基氯化物的立体定向、转化反应。因为糖基氯是相当稳定的，并且主要且通常仅以α-构型存在，所以这种催化模式代表了产生α-糖苷键的广泛适用的解决方案。我们将寻求探索的范围和限制的大环催化剂设计到目前为止的背景下，模型二糖耦合和合成代表性的生物重要的寡糖。糖基化的速率与催化剂上羰基的刘易斯碱性相关，并且我们目前的机理假设调用了该部分作为通用碱的功能作用，以模拟可逆糖基转移酶的方式激活受体亲核试剂。我们将进行一个系统的催化反应的机理研究，以确定是否一个仿生一般的基础机制确实是可操作的，并确定最佳的性质和位置的刘易斯基地的最大反应性和范围。我们还将探讨这种合作激活机制是否可以扩展到催化剂的设计，促进通过双反转取代的选择性糖基化。如果充分和成功地开发，这种方法将能够以可编程的方式合成复杂的寡糖，可以由非专业人员应用，并且还允许以实际规模生产生物医学相关的聚糖，糖肽，糖蛋白，糖脂，微生物多糖和糖缀合物。

 DESCRIPTION (provided by applicant): This project has as its aim the development of robust, practical, and general methods for glycosylating nucleophiles with predictable stereoselectivity. Our laboratory has helped pioneer the use of small-molecule chiral H-bond donors as catalysts for enantioselective reactions. As an extension of these studies, we have uncovered a new principle for effecting selective glycosylation reactions. Precisely designed macrocyclic bis-thiourea catalysts promote stereospecific, invertive reactions of alcohol nucleophiles with glycosyl chlorides. Because glycosyl chlorides are quite stable and exist predominantly and often exclusively in the a-configuration, this mode of catalysis represents a widely applicable solution to the creation of ß-glycosidic linkages. We will seek to explore the scope and limitations of the macrocylic catalysts devised thus far in the context of model disaccharide couplings and the synthesis representative biologically important oligosaccharides. The rate of glycosylation is correlated to the Lewis basicity of the carbonyl group on the catalyst, and our current mechanistic hypothesis invokes a functional role for this moiety as a general base to activate the acceptor nucleophile in a manner that mimics invertive glycosyltransferases. We will carry out a systematic mechanistic study of the catalytic reaction in order to ascertain whether a biomimetic general-base mechanism is indeed operative, and to identify the optimal nature and position of the Lewis base component for maximum reactivity and scope. We will also explore whether this cooperative activation mechanism might be extended to the design of catalysts that promote a-selective glycosylations via doubly invertive substitutions. If developed fully and successfully, this methodology would enable the synthesis of complex oligosaccharides in a programmable manner that could be applied by non-specialists, and also allow the production of biomedically relevant glycans, glycopeptides, glycoproteins, glycolipids, and microbial polysaccharides and glycoconjugates on a practical scale.