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：
10341140
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.

该项目致力于开发糖基化的鲁棒，实用和一般方法具有可预测的立体选择性和调节选择性的亲核试剂。尽管付出了非凡的努力和进步在过去的一个世纪中，聚糖合成仍然是一项高度挑战，主要保留给专家。鉴于几乎所有生物化学方面的碳含物的重要性，需要可预测的广泛应用于影响感兴趣分子的糖基化。我们的实验室帮助开拓了小分子手性H键供体作为对映选择性的催化剂反应。在这些研究的产物中，我们发现了一个新的原则来实现两者立体选择性和位点选择性糖基化反应。精确量身定制的Bisthiourea催化剂促进酒精核亲核与糖基氯化物和糖基磷酸盐的立体特异性，反转反应通过核phobile和亲电的合作激活。因为捐助者很稳定，并且主要存在于α-配置中，并且催化剂与宽阔的功能范围，这种催化模式代表了一种广泛适用于创建β-的方法糖苷连接。我们将寻求在背景下发展催化原则的范围和局限性模型二糖耦合和生物学上重要化合物的糖苷的合成。尽管广泛的一般协议被感觉到，我们将重点放在特别挑战的CIS-1,2-糖苷上金直肌剂和呋喃糖苷的连锁。我们还将探索合作激活的方式机制可以应用于未受保护的糖和其他的位点选择性激活和糖基化多功能核粒子。如果完全成功地发展，此方法将极大地使生物医学相关的聚糖，糖磷酸酯，糖蛋白，糖脂和微生物的合成非专家的多糖和糖缀合物。