Small-Molecule Catalysts for the Stereoselective Synthesis of Oligosaccharides

用于立体选择性合成低聚糖的小分子催化剂

• 批准号: 8985298
• 负责人: ERIC N JACOBSEN
• 金额: $ 32.97万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985298
• 关键词: Address; Affect; Alcohols; Amines; Binding; Biomimetics; Carbohydrates; Catalysis; Chemicals; Chloride Ion; Chlorides; Complex; Coupling; Development; Disaccharides; Generations; Glean; Glycoconjugates; Glycolipids; Glycopeptides; Glycoproteins; Glycosides; Goals; Health; Human; Hydrogen Bonding; Kinetics; Laboratories; Libraries; Link; Lipids; Methodology; Methods; Modeling; Nature; Nucleotides; Oligosaccharides; Peptides; Phase; Phenols; Polynucleotides; Polysaccharides; Positioning Attribute; Preparation; Production; Property; Proteins; Protocols documentation; Reaction; Role; Science; Series; Site; Solid; Solutions; Staging; Structure; System; Technology; Thiourea; Work; alkalinity; analog; base; carbonyl group; catalyst; computer studies; cost effective; design; glycosylation; glycosyltransferase; improved; interest; microbial; milligram; polypeptide; public health relevance; small molecule; sugar

 DESCRIPTION (provided by applicant): This project has as its aim the development of robust, practical, and general methods for glycosylating nucleophiles with predictable stereoselectivity. Our laboratory has helped pioneer the use of small-molecule chiral H-bond donors as catalysts for enantioselective reactions. As an extension of these studies, we have uncovered a new principle for effecting selective glycosylation reactions. Precisely designed macrocyclic bis-thiourea catalysts promote stereospecific, invertive reactions of alcohol nucleophiles with glycosyl chlorides. Because glycosyl chlorides are quite stable and exist predominantly and often exclusively in the a-configuration, this mode of catalysis represents a widely applicable solution to the creation of ß-glycosidic linkages. We will seek to explore the scope and limitations of the macrocylic catalysts devised thus far in the context of model disaccharide couplings and the synthesis representative biologically important oligosaccharides. The rate of glycosylation is correlated to the Lewis basicity of the carbonyl group on the catalyst, and our current mechanistic hypothesis invokes a functional role for this moiety as a general base to activate the acceptor nucleophile in a manner that mimics invertive glycosyltransferases. We will carry out a systematic mechanistic study of the catalytic reaction in order to ascertain whether a biomimetic general-base mechanism is indeed operative, and to identify the optimal nature and position of the Lewis base component for maximum reactivity and scope. We will also explore whether this cooperative activation mechanism might be extended to the design of catalysts that promote a-selective glycosylations via doubly invertive substitutions. If developed fully and successfully, this methodology would enable the synthesis of complex oligosaccharides in a programmable manner that could be applied by non-specialists, and also allow the production of biomedically relevant glycans, glycopeptides, glycoproteins, glycolipids, and microbial polysaccharides and glycoconjugates on a practical scale.

 描述（由适用提供）：该项目的目标是发展具有可预测的立体选择性的糖基化核ph虫的稳健，实用和一般方法。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反应的催化剂。作为这些研究的扩展，我们发现了一种新的原理来实现选择性糖基化反应。精确设计的大环双胞胎催化剂可促进酒精核亲核与糖基氯化物的立体特异性，反转反应。由于糖基氯化物非常稳定，并且主要存在于A-Configuration中，因此这种催化模式代表了一种广泛适用于β-糖苷链接的解决方案。我们将寻求探索迄今为止在模型二糖耦合的背景下设计的大环催化剂的范围和局限性，以及代表生物学上重要的寡糖的合成。糖基化的速率与催化剂上羰基的刘易斯碱性相关，而我们当前的机械假设则使该部分的功能作用作为一般基础，以一种以一种模拟异内性糖基质酶的方式激活受体核phole。我们将对催化反应进行系统的机械研究，以确定仿生的通用基准机制是否确实在运行，并确定刘易斯基碱基成分的最佳性质和位置，以实现最大的反应性和范围。我们还将探讨这种合作激活机制是否可能扩展到通过双重反转替代来促进A-选择性糖基化的催化剂的设计。如果完全成功地开发，这种方法将以可编程的方式促进复杂的寡糖合成，该方式可以由非特殊主义者应用，也允许生产生物医学相关的聚糖，糖磷酸酯，糖蛋白，糖蛋白，糖蛋白，糖果，糖果含量，以及微生物多糖含量和小糖含量。