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

该项目致力于开发健壮、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 在过去的一个世纪里，多糖合成仍然是一项极具挑战性的工作，主要是留给专家进行的。 鉴于碳水化合物在生物化学几乎所有方面的重要性是毋庸置疑的，方法 可以预测和广泛地应用于影响感兴趣分子的糖基化。我们的 实验室率先使用小分子手性氢键供体作为对映体选择性的催化剂 反应。在这些研究的结果中，我们发现了影响两者的新原则 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 醇亲核试剂与糖基氯化物和糖基磷酸盐的立体特异的可逆反应 亲核性和亲核性的协同激活。因为捐赠者很稳定， 以α构型为主且通常是唯一存在的，催化剂与广泛的 一系列功能，这种催化模式代表了创建β的一种广泛适用的方法 糖苷键。我们将寻求在以下背景下发展催化原则的范围和局限性 二糖偶联模型和生物重要化合物糖苷的合成。而当 广泛寻求一般方案，我们将集中我们的努力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联系。我们还将探索合作激活的方式 该机制可应用于未保护的糖和其他物质的位置选择性激活和糖基化 多官能团亲核剂。如果完全和成功地开发，这种方法将极大地使 生物医学相关的多糖、糖肽、糖蛋白、糖脂和微生物的合成 非专业人士提供的多糖类和糖结合物。

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.