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。这项建议由四个部分组成。 第一部分涉及研究一种被广泛用于区分碳水化合物的许多羟基的反应，即亚锡反应。这种反应被广泛使用，因为它提供了可预测的产品，经验丰富的和新手的研究人员都可以可靠地获得这些产品。有机锡试剂的一个缺点是它们的毒性。正在引入催化版本的反应，但对于反应的机理和观察到的区域选择性的原因没有普遍的一致意见。关键问题是：最多的物种是溶液中的二聚体、反应中间体还是单体？添加的亲核剂是如何影响反应机理和区域选择性的？我们建议用实验来回答这些问题，扩大催化可能的反应范围，并提高区域选择性。 第二部分建议研究三氯乙叉缩醛作为一种获得呋喃糖类的方法。糖与三氯乙醛和酸的反应总是生成1，2-O-三氯亚乙叉呋喃葡萄糖，这是一条合成呋喃糖衍生物的潜在途径。我们建议用化学计量比的三氯乙醛代替三氯乙醛作为溶剂，使这些衍生物的合成更环保，并研究去除这些酸性稳定缩醛的改进方法。 第三，我们建议通过对引起莱姆病的伯氏疏螺旋体抗原性糖脂BbGL1和BbGL2的研究，来研究糖脂免疫学这一新兴领域。我们将试图通过对BbGL1结构的广泛修饰和对CD1-糖脂复合体和CD1-糖脂-T细胞受体三元复合体的模拟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来确定哪些CD1亚型参与BbGL1的识别。 多价性被证明是以一种影响生物事件的方式获得蛋白质-碳水化合物结合的关键。在第四部分，我们建议研究两种获得多价态的新方法，这两种方法都是为了产生稀有浓度的结合配体，这些结合配体高度集中在小区域，与细菌和病毒上广泛分布的碳水化合物受体实现强结合是一致的。人们建议通过合成树枝状多糖和树枝状聚合物来实现这一点，其中树枝状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.