Catalyst-Controlled Stereo- and Regioselective Glycosidation Reactions

催化剂控制的立体和区域选择性糖苷化反应

• 批准号: 9237117
• 负责人: Alison Wendlandt
• 金额: $ 5.67万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237117
• 关键词: Amino Acids; Area; Biological Process; Biological Response Modifier Therapy; Carbohydrates; Chemicals; Complex; Development; Diagnosis; Evaluation; Family; Glycobiology; Glycoconjugates; Glycosides; Goals; Hydrogen Bonding; Inflammation; Libraries; Methods; Modeling; Modification; Monosaccharides; Nature; Nucleotides; Oligosaccharides; Play; Polymers; Positioning Attribute; Protein-Carbohydrate Interaction; Reaction; Research; Resources; Role; Route; Site; Structure; Testing; Thiourea; Time; Virus Diseases; Work; biological systems; cancer therapy; catalyst; chemical synthesis; computerized tools; design; human disease; hydroxyl group; improved; molecular recognition; public health relevance; small molecule; stereochemistry; therapeutic target; tool

 DESCRIPTION (provided by applicant): Carbohydrates play an important role in many fundamental biological processes, as well as in the diagnosis and treatment of human disease. Efficient chemical methods for accessing oligosaccharides and glycoconjugates are crucial for continued progress in the field of glycobiology. Unlike amino acids and nucleotides, which form linear polymers, monosaccharides polymerize into a variety of different stereo- and regioisomeric structures. Control over the stereo- and regioselectivity of chemical glycosidation reactions is, therefore, paramount. However, the selective functionalization of one hydroxyl group in the presence of numerous others poses a significant chemical challenge, and most oligosaccharide syntheses must rely upon elaborate and lengthy protecting group strategies to promote reaction at only the desired site. The research described in this proposal focuses on the development of small-molecule catalysts capable of controlling both the stereochemistry and the regiochemistry of glycosidation reactions. The research approach involves the rational design of hydrogen-bond donor catalysts guided, in part, by protein-carbohydrate interactions found in nature. State-of-the-art synthetic, mechanistic and theoretical tools will facilitate the systematic evaluation and optimization of these catalysts towards the goal of controlling the relative reactivity of different carbohydrate hydroxyl groups. The successful development of this proposed research is anticipated to transform oligosaccharide synthesis, dramatically reducing the time and resources necessary to chemically synthesize complex carbohydrates. Further, fundamental mechanistic findings revealed en route to this goal are anticipated to contribute significantly to our understanding of carbohydrate molecular recognition and to lay the groundwork for catalytic approaches to more diverse site-selective functionalization reactions.

 描述（由申请人提供）：碳水化合物在许多基本生物过程以及人类疾病的诊断和治疗中发挥着重要作用。获取寡糖和糖复合物的有效化学方法对于糖生物学领域的持续进步至关重要。与形成线性聚合物的氨基酸和核苷酸不同，单糖聚合成各种不同的立体异构体和区域异构体结构。因此，控制化学糖苷化反应的立体选择性和区域选择性至关重要。然而，在存在许多其他羟基的情况下，一个羟基的选择性官能化提出了重大的化学挑战，并且大多数寡糖合成必须依赖于复杂且冗长的保护基策略来仅在所需位点促进反应。该提案中描述的研究重点是开发能够控制糖苷化反应的立体化学和区域化学的小分子催化剂。该研究方法涉及氢键供体催化剂的合理设计，部分是由自然界中发现的蛋白质-碳水化合物相互作用指导。最先进的合成、机械和理论工具将有助于对这些催化剂进行系统评估和优化，以达到控制不同碳水化合物羟基的相对反应性的目标。这项研究的成功发展预计将改变寡糖合成，大大减少化学合成复杂碳水化合物所需的时间和资源。此外，在实现这一目标的过程中揭示的基本机制研究结果预计将极大地促进我们对碳水化合物分子识别的理解，并为更多样化的位点选择性功能化反应的催化方法奠定基础。