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

适用于立体选择性和位点选择性糖基化反应的广泛适用的小分子催化剂

基本信息

批准号：
9900832
负责人：
ERIC N JACOBSEN
金额：
$ 33.78万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-02-28
项目状态：
已结题

项目摘要

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.

该项目旨在开发稳健、实用和通用的糖基化方法尽管付出了巨大的努力和进步，但亲核试剂仍具有可预测的立体选择性和区域选择性。在过去的一个世纪里，聚糖合成仍然是一项极具挑战性的工作，主要由专家完成。鉴于碳水化合物在生物化学的几乎所有方面中无可争议的重要性，方法我们需要可预测且广泛地应用来实现感兴趣分子的糖基化。实验室帮助开创了使用小分子手性氢键供体作为对映选择性催化剂在这些研究的成果中，我们发现了影响这两种反应的新原理。精确定制的双硫脲催化剂促进立体选择性和位点选择性糖基化反应。醇亲核试剂与糖基氯和糖基磷酸酯的立体特异性、反转反应亲核试剂和亲电子试剂的协同激活，因为供体非常稳定且稳定。主要且通常仅以 α 构型存在，并且催化剂与广泛的相容由于具有多种功能，这种催化模式代表了一种广泛适用的 β- 生成方法我们将寻求在以下背景下发展催化原理的范围和局限性。模型二糖偶联和生物学重要化合物的糖苷合成。寻求广泛的通用协议，我们将集中精力研究特别具有挑战性的 cis-1,2- 糖苷我们还将探索吡喃糖苷和呋喃糖苷的协同激活方式。该机制可应用于未受保护的糖和其他糖的位点选择性激活和糖基化如果开发成功，这种方法将极大地促进多官能亲核试剂的发展。生物医学相关聚糖、糖肽、糖蛋白、糖脂和微生物的合成由非专业人员进行的多糖和复合糖。