Develop Catalytic Methods to Streamline the Assembly of Oligosaccharides

摘要 糖类的合成远远落后于肽和核苷酸的合成现状。这是 不是因为不重要。事实上，碳水化合物无处不在，并在许多重要的 生物事件。高效、选择性的化学合成方法的研究进展 碳水化合物及其类似物对于理解碳水化合物的具体作用是必要的。 并用于治疗发展。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，寻找变革性的解决方案，使生物医学领域的非专家 社区研究碳水化合物的结构和功能。碳水化合物的两个最基本的问题 合成是立体选择性糖苷键的形成和羟基的分化。在这份提案中， 我们将开发催化方法来解决这两个问题，并简化低聚糖的组装。在……里面 目的1，我们建议在不同的单糖中选择性地将羟基官能化。 可预测的、一般的和系统的方式。这些变换将用于简化合成 碳水化合物的积木。可预测不同碳水化合物的位置选择性的工作模型 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)构筑糖基碳氧键 关于交叉偶联反应的密度泛函理论计算和已发表的文献。CCG将允许 美国将组装立体化学定义的台式稳定糖基供体和新型糖基受体 糖基化后无需任何操作即可立体定向。我们建议的糖基化方法是 创新是因为它们不涉及氧碳正离子的形成，而氧碳正离子通常使电流 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 从天然产生的单糖中提取。与所有化学方法类似，CCG也可以使用 用于合成碳水化合物类似物。在目标3中，我们将展示建议的 方法在生物活性细菌和人多聚糖的多次迭代合成中。仅限迭代综合 涉及糖基供体或受体的一步活化和CCG的一步加成 单糖单位。不保护非参与羟基的糖基供体和受体 也可以使用，因为CCG的独特功能。上述建议的目标意义重大 因为它们将为生物医学社区中的任何人提供现成的工具，包括非专家 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在 寡糖的合成接近于寡肽和寡核苷酸合成的现代状态。

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.