Develop Catalytic Methods to Streamline the Assembly of Oligosaccharides

开发简化低聚糖组装的催化方法

• 批准号: 9391272
• 负责人: Weiping Tang
• 金额: $ 57.71万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9391272
• 关键词: Acylation; Address; Biological; Carbohydrates; Carbon; Catalysis; Cations; Chemicals; Communities; Coupling; Development; Ensure; Event; Glycols; Glycosides; Human; Ions; Knowledge; Literature; Mannosides; Methods; Modeling; Modernization; Modification; Monosaccharides; Oligonucleotides; Oligopeptides; Oligosaccharides; One-Step dentin bonding system; Oxygen; Peptide Synthesis; Physiological; Play; Polysaccharides; Preparation; Publishing; Reaction; Research; Research Personnel; Role; Site; Theoretical model; Training; Transition Elements; analog; base; carbohydrate analog; carbohydrate structure; catalyst; computational chemistry; density; design; experience; glycosylation; human disease; hydroxyl group; improved; innovation; novel; nucleotide metabolism; polyol; public health relevance; stereochemistry; success; theories; therapeutic development; tool

ABSTRACT The carbohydrate synthesis is lagging far behind the current status of peptide and nucleotide synthesis. This is not due to the lack of importance. In fact, carbohydrates are ubiquitous and play a vital role in many important biological events. The development of efficient and selective chemical methods for the synthesis of carbohydrates and their analogues is necessary for the understanding of the specific roles of carbohydrates and for therapeutic development. Current carbohydrate synthesis requires extensive training and knowledge. One has to think outside the box for transformative solutions that can enable non-experts in the biomedical community to study carbohydrate structure and function. The two most essential issues in carbohydrate synthesis are stereoselective glycosidic bond formation and differentiation of hydroxyl groups. In this proposal, we will develop catalytic methods to address both issues and streamline the assembly of oligosaccharides. In Aim 1, we propose to site-selectively functionalize hydroxyl groups in various monosaccharides in a predictable, general, and systematic manner. These transformations will be used for streamlining the synthesis of carbohydrate building blocks. Working models that can predict the site-selectivity in diverse carbohydrates will be established with the help from computational chemists. In Aim 2, we propose to develop novel transition metal-catalyzed cross-coupling glycosylation (CCG) to construct the glycosyl carbon-oxygen bond guided by density functional theory calculations and published literature on cross-coupling reactions. The CCG will allow us to assemble the stereochemically defined benchtop stable glycosyl donors and novel glycosyl acceptors stereospecifically without any manipulation after glycosylation. Our proposed glycosylation methods are innovative because they don’t involve the formation of the oxocarbenium ion, which often makes the current glycosylation methods not completely stereoselective. The glycosyl donors and acceptors for CCG will be derived from naturally occurring monosaccharides. Similar to all chemical methods, the CCG can also be used for the synthesis of carbohydrate analogues. In Aim 3, we will demonstrate the efficiency of the proposed methods in several iterative syntheses of bioactive bacterial and human glycans. The iterative synthesis only involves one step of activation of glycosyl donors or acceptors and one step of CCG for the addition of any monosaccharide unit. Glycosyl donors and acceptors without protecting the nonparticipating hydroxyl groups can also be employed because of the unique feature of the CCG. The above proposed aims are significant because they will yield readily available tools for anyone in the biomedical community including non-experts to study carbohydrate structures and functions. The successful development of the proposed methods will place the oligosaccharide synthesis close to the modern status of oligopeptide and oligonucleotide synthesis.

摘要 碳水化合物的合成远远落后于肽和核苷酸合成的现状。这是 不是因为缺乏重要性。事实上，碳水化合物是无处不在的，并在许多重要的 生物事件。发展高效和选择性的化学方法来合成 了解碳水化合物及其类似物对于理解碳水化合物的特殊作用是必要的 和治疗发展。目前的碳水化合物合成需要广泛的培训和知识。 人们必须跳出框框思考变革性的解决方案，使生物医学领域的非专家能够 研究碳水化合物的结构和功能。碳水化合物中最重要的两个问题 合成是立体选择性糖苷键形成和羟基的分化。在这项提案中， 我们将开发催化方法来解决这两个问题，并简化寡糖的组装。在 目的1，我们提出了一个在不同的单糖中位点选择性地官能化羟基的方法， 可预测的、一般的和系统的方式。这些转换将用于简化综合 碳水化合物构建块。可以预测不同碳水化合物的位点选择性的工作模型 将在计算化学家的帮助下建立。在目标2中，我们建议开发新的过渡 金属催化的交叉偶联糖基化（CCG），以构建糖基碳-氧键， 密度泛函理论计算和交叉偶联反应的出版文献。CCG将允许 我们组装立体化学定义的台式稳定的糖基供体和新的糖基受体 糖基化后没有任何操作。我们提出的糖基化方法是 创新，因为它们不涉及氧碳正离子的形成，这往往使电流 糖基化方法不是完全立体选择性的。CCG的糖基供体和受体将是 来源于天然单糖。与所有化学方法类似，CCG也可用于 用于合成碳水化合物类似物。在目标3中，我们将证明所提出的 方法在几个迭代合成生物活性的细菌和人类聚糖。迭代合成只 包括一个活化糖基供体或受体的步骤和一个CCG步骤，用于添加任何 单糖单位不保护非参与羟基的糖基供体和受体 由于CCG的独特功能，也可以使用。上述拟议目标意义重大 因为它们将为生物医学界的任何人（包括非专家）提供现成的工具， 研究碳水化合物的结构和功能。所提出的方法的成功开发将使 寡糖合成接近于现代寡肽和寡核苷酸合成的现状。