Synthesis and Applications of Biologically Active Carbohydrate Derivatives and Related Compounds

Grindley研究计划的主要目标是开发以有用的方式使用碳水化合物和其他含氧有机化合物的工具和方法。该建议包括四个部分。 第一部分涉及研究一种广泛用于区分碳水化合物中许多羟基的反应，即亚锡基反应。该反应被广泛使用，因为它提供了可预测的产物，可以由有经验的和新的研究人员可靠地获得。有机锡试剂的缺点是它们的毒性。催化版本的反应正在介绍，但没有普遍协议的反应机制和观察到的区域选择性的原因。关键问题是：溶液中最多的物质是二聚体、反应中间体还是单体？添加的亲核试剂如何影响反应机理和区域选择性？提出实验来回答这些问题，以扩大可能的催化反应的集合，并提高区域选择性。 第二部分提出研究三氯乙叉缩醛作为一种获得呋喃糖的方法。 糖与三氯乙醛和酸的反应总是产生1，2-O-三氯亚乙基-呋喃糖，这是一种潜在的呋喃糖衍生物的路线。我们建议通过使用化学计量的三氯乙醛而不是使用三氯乙醛作为溶剂来使这些衍生物的合成更环保，并研究用于去除这些酸稳定的缩醛的改进方法。 第三，我们建议调查糖脂免疫学，一个新兴的领域，通过调查的抗原糖脂，BbGL 1和2，伯氏疏螺旋体，导致莱姆病的细菌。我们将尝试通过广泛修饰BbGL 1结构和通过对CD 1-糖脂复合物和三元CD 1-糖脂-T细胞受体复合物的建模研究来寻找更多的抗原衍生物。 我们将通过结合和建模研究确定哪些CD 1亚型参与BbGL 1的识别。 多价被证明是关键的获得蛋白质-碳水化合物结合的方式，影响生物事件。 在第四部分中，我们提出研究两种获得多价性的新方法，这两种方法都旨在产生高度集中在小区域中的稀释浓度的结合配体，与实现与细菌和病毒上广泛分布的碳水化合物受体的强结合一致。建议通过合成树枝化多糖和树枝化聚合物来实现这一点，其中树枝化分子将提供高局部浓度的碳水化合物配体。 这些聚合物应具有良好的水溶性。

The broad aims of the Grindley research program are to develop tools and methods to use carbohydrates and other oxygen-containing organic compounds in useful ways. This proposal consists of four parts. The first part involves studying a reaction that is widely used to differentiate among the many hydroxyl groups of carbohydrates, the stannylene reaction. This reaction is widely used because it gives predictable products that can be obtained reliably by both experienced and beginning researchers. A disadvantage of the organotin reagents is their toxicity. Catalytic versions of the reaction are being introduced but there is no general agreement about the mechanism of the reaction and the reasons for the observed regioselectivity. Key questions are: Are the most populated species in solution, the dimers, the reaction intermediates, or are monomers?; How do added nucleophiles influence the reaction mechanism and regioselectivity? Experiments are proposed to answer these questions, to expand the set of reactions that are possible catalytically, and to improve regioselectivity. The second part proposes studying trichloroethylidene acetals as a way to access furanose sugars. Reaction of sugars with chloral and acid always yield 1,2-O-trichloroethylidene-furanoses, a potential route to furanose derivatives. We propose to make the synthesis of these derivatives greener, by using stoichiometric chloral rather than using chloral as the solvent, and to investigate improved methods for the removal of these acid-stable acetals. Thirdly, we propose to investigate glycolipid immunology, an emerging area, through investigation of the antigenic glycolipids, BbGL1 and 2, of Borrelia burgdorferi, the bacteria that cause Lyme disease. We would attempt to find more antigenic derivatives by extensive modification of the BbGL1 structure and by modelling studies of the CD1-glycolipid complexes and of the terniary CD1-glycolipid-T-cell receptor complexes. We would establish which of the CD1 subtypes are involved in recognition of BbGL1 by binding and modelling studies. Multivalency are been shown to be critical for obtaining protein-carbohydrate binding in a way that influences biological events. In the fourth section, we propose to investigate two new ways to obtain multivalency, both of which are designed to produce dilute concentrations of binding ligands that are highly concentrated in small areas, consistent with achieving strong binding to the widely spaced carbohydrate receptors on bacteria and viruses. It is proposed to do this by synthesizing dendronized polysaccharides and dendronized polymers, where the dendrons would provide the high local concentrations of carbohydrate ligands. These polymers should have good water solubility.