Small-Molecule Catalysts for the Stereoselective Synthesis of Oligosaccharides

 描述(由申请人提供)：该项目的目标是开发稳健、实用和通用的方法，使亲核试剂具有可预测的立体选择性。我们的实验室开创了使用小分子手性氢键供体作为不对称反应催化剂的先河。作为这些研究的延伸，我们发现了影响选择性糖基化反应的新原理。精心设计的大环双硫脲催化剂促进了醇亲核试剂与糖基氯化物的立体专一性反转反应。由于糖基氯化物非常稳定，并且主要且通常是以a-构型存在，这种催化模式代表了一种广泛适用的解决方案，以建立β-糖苷键。我们将试图探索到目前为止在双糖偶联模型和合成具有生物重要性的代表性低聚糖的背景下设计的大环催化剂的范围和局限性。糖基化的速度与催化剂上羰基的Lewis碱性有关，我们目前的机理假说调用了这一部分的功能作用作为一般碱基，以模拟逆转糖基转移酶的方式激活受体亲核试剂。我们将对催化反应进行系统的机理研究，以确定仿生通用碱基机制是否确实起作用，并确定刘易斯碱基成分的最佳性质和位置，以获得最大的反应活性和范围。我们还将探索这种协同激活机制是否可以扩展到通过双反取代促进a-选择性糖基化的催化剂的设计。如果完全和成功地开发，这一方法将能够以可编程的方式合成复杂的寡糖，可供非专业人员使用，还可以在实际规模上生产具有生物医学意义的多糖、糖肽、糖蛋白、糖脂以及微生物多糖和糖共轭化合物。

 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.