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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10341140
• 关键词: Alcohols; Biochemistry; Carbohydrates; Catalysis; Chlorides; Complex; Coupling; Development; Disaccharides; Glycoconjugates; Glycolipids; Glycopeptides; Glycoproteins; Glycosides; Hydrogen Bonding; Laboratories; Libraries; Link; Lipids; Methodology; Methods; Modeling; Molecular Conformation; Oligosaccharides; Phenols; Polysaccharides; Preparation; Production; Property; Proteins; Protocols documentation; Reaction; Research; Site; Specialist; Technology; analog; anomer; base; catalyst; chiral molecule; cost effective; glycosylation; inorganic phosphate; interest; microbial; polyol; pyranose; small molecule; sugar; virtual

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.

这个项目的目的是发展强大的、实用的、通用的糖基化方法