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（由申请人提供）：该项目的目标是开发稳健、实用且通用的方法，用于具有可预测的立体选择性的糖基化亲核试剂。我们的实验室率先使用小分子手性氢键供体作为对映选择性反应的催化剂。作为这些研究的延伸，我们发现了实现选择性糖基化反应的新原理。精确设计的大环双硫脲催化剂可促进醇亲核试剂与糖基氯的立体定向、反转反应。由于糖基氯非常稳定，并且主要且通常仅以 a-构型存在，因此这种催化模式代表了一种广泛适用的创建 ß-糖苷键的解决方案。我们将寻求在二糖偶联模型和合成具有代表性的生物学上重要的寡糖的背景下探索迄今为止设计的大环催化剂的范围和局限性。糖基化的速率与催化剂上羰基的路易斯碱性相关，我们目前的机制假设调用了该部分作为通用碱的功能作用，以模拟反向糖基转移酶的方式激活受体亲核试剂。我们将对催化反应进行系统的机理研究，以确定仿生通用碱机制是否确实有效，并确定路易斯碱组分的最佳性质和位置，以获得最大的反应活性和范围。我们还将探讨这种协同激活机制是否可以扩展到通过双重反向取代促进α-选择性糖基化的催化剂设计。如果开发充分且成功，这种方法将能够以可编程的方式合成复杂的寡糖，可供非专业人员应用，并且还允许以实际规模生产生物医学相关的聚糖、糖肽、糖蛋白、糖脂、微生物多糖和糖复合物。