Broadly Applicable, Small Molecule Catalysts for Stereoselective and Site-Selective Glycosylation Reactions

该项目旨在开发稳健、实用和通用的糖基化方法， 具有可预测的立体选择性和区域选择性的亲核试剂。尽管做出了非凡的努力和进步 在过去的世纪中，聚糖合成仍然是一项高度挑战性的奋进，主要留给专家。 鉴于碳水化合物在生物化学的几乎所有方面都具有无可争议的重要性， 可预测地和广泛地应用于实现感兴趣分子的糖基化。我们 一个实验室已经帮助开创了使用小分子手性H键供体作为对映选择性催化剂的先河。 反应.在这些研究的结果中，我们发现了一种影响两者的新原理。 立体选择性和位点选择性糖基化反应。精确定制的双硫脲催化剂促进 醇类亲核试剂与糖基氯化物和糖基磷酸酯的立体专一性转化反应， 亲核试剂和亲电试剂的协同活化。因为捐赠者相当稳定， 主要且通常仅以α-构型存在，并且催化剂与广泛的 的功能范围，这种催化模式代表了一种广泛适用的方法，以创造β- 糖苷键。我们将在以下方面探讨催化原则的范围和局限性： 模型二糖偶联和生物重要化合物糖苷的合成。而 为了寻求更广泛的通用方案，我们将集中精力研究特别具有挑战性的顺式-1，2-糖苷 吡喃糖苷和呋喃糖苷中的键。我们还将探讨合作激活的方式， 该机制可应用于未保护的糖的位点选择性活化和糖基化以及其它 多功能亲核体。如果充分和成功地开发，这种方法将大大有助于 生物医学相关聚糖、糖肽、糖蛋白、糖脂和微生物的合成 多糖和糖复合物。

This project is directed toward the development of robust, practical, and general methods for glycosylating nucleophiles with predictable stereoselectivity and regioselectivity. Despite extraordinary efforts and advances over the past century, glycan synthesis remains a highly challenging endeavor largely reserved for specialists. Given the unquestioned importance of carbohydrates in virtually all facets of biological chemistry, methods that can be applied predictably and broadly for effecting glycosylations of molecules of interest are needed. Our laboratory has helped pioneer the use of small-molecule chiral H-bond donors as catalysts for enantioselective reactions. In an outgrowth of these studies, we have uncovered a new principle for effecting both stereoselective and site-selective glycosylation reactions. Precisely tailored bisthiourea catalysts promote stereospecific, invertive reactions of alcohol nucleophiles with glycosyl chlorides and glycosyl phosphates via cooperative activation of both the nucleophile and the electrophile. Because the donors are quite stable and exist predominantly and often exclusively in the α-configuration, and the catalysts are compatible with a wide range of functionalities, this mode of catalysis represents a widely applicable approach to the creation of β- glycosidic linkages. We will seek to develop the scope and limitations of the catalytic principle in the context of model disaccharide couplings and the synthesis of glycosides of biologically important compounds. While broadly general protocols are sought, we will focus our efforts on especially challenging cis-1,2-glycosidic linkages in pyranosides and furanosides. We will also explore the ways by which the cooperative activation mechanism can be applied to site-selective activation and glycosylation of unprotected sugars and other polyfunctional nucelophiles. If developed fully and successfully, this methodology would greatly enable the synthesis of biomedically relevant glycans, glycopeptides, glycoproteins, glycolipids, and microbial polysaccharides and glycoconjugates by non-specialists.