Synthesis and Applications of Biologically Active Carbohydrate Derivatives and Related Compounds

格林德利研究计划的主要目标是开发工具和方法，以有用的方式利用碳水化合物和其他含氧有机化合物。本建议由四个部分组成。***第一部分涉及研究一个反应，这个反应被广泛用于区分碳水化合物的许多羟基，即锡炔反应。这种反应被广泛使用，因为它可以提供可预测的产物，经验丰富的和初级的研究人员都可以可靠地获得。有机锡试剂的缺点是它们的毒性。目前正在介绍该反应的催化版本，但对反应的机理和观察到的区域选择性的原因没有普遍的共识。关键问题是：溶液中最密集的物质是二聚体、反应中间体还是单体？加入的亲核试剂如何影响反应机理和区域选择性？实验被提出来回答这些问题，以扩大可能的催化反应集，并提高区域选择性。第二部分提出研究三氯乙基缩醛作为一种获取呋喃糖的方法。糖与氯醛和酸反应总是生成1,2- o -三氯乙基呋喃糖，这是呋喃糖衍生物的潜在途径。我们建议使用化学计量氯醛代替氯醛作为溶剂，使这些衍生物的合成更加环保，并研究去除这些酸稳定缩醛的改进方法。***第三，我们建议通过研究莱姆病病原菌伯氏疏螺旋体（Borrelia burgdorferi）的抗原糖脂BbGL1和2来研究糖脂免疫学这一新兴领域。我们将通过对BbGL1结构的广泛修饰，以及对cd1 -糖脂复合物和三元cd1 -糖脂- t细胞受体复合物的建模研究，试图找到更多的抗原性衍生物。我们将通过结合和建模研究确定哪些CD1亚型参与BbGL1的识别。***多价性已被证明是影响生物事件的蛋白质-碳水化合物结合的关键。在第四部分中，我们建议研究两种获得多价性的新方法，这两种方法都旨在产生稀浓度的结合配体，这些配体高度集中在小区域，与细菌和病毒上广泛间隔的碳水化合物受体的强结合一致。有人建议通过合成树突化多糖和树突化聚合物来实现这一目标，其中树突将提供高浓度的局部碳水化合物配体。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.**