Methods and Mechanisms in Carbohydrate Chemistry

碳水化合物化学的方法和机制

基本信息

批准号：
6525977
负责人：
David Crich
金额：
$ 22.44万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2004-08-31
项目状态：
已结题

项目摘要

The goal of modern oligosaccharide synthesis is the efficient production of natural and unnatural oligosaccharides, and their mimetics, capable of interfering constructively in disease states. This interference may be brought about by the blocking of oligosaccharide processing enzymes, by disruption of bacterial cell wall biosynthesis, by modulating cell-cell recognition, by enhancing binding and selectivity of drugs to DNA, and by the provision of antigenic oligosaccharides in synthetic vaccines. All of these very desirable processes require the highly efficient synthesis of oligosaccharides. Ultimately it is to be hoped that oligosaccharide synthesis can be developed to a point at which programmable, automated solid phase synthesis is a real possibility. Although oligosaccharide synthesis has developed in leaps and bounds in the last decade or so, this goal is still a long way off. The reasons for this are multiple and reside in the complexity of the chemistry of formation of glycosidic. An absolutely overwhelming number of methods toward this end however, the vast majority have been developed empirically and they are therefore underpinned by very little detailed understanding of mechanism. The main thesis of this proposal is that the ultimate goal of automated oligosaccharide synthesis demands a simplification of the area and that this simplification can best be brought about by a detailed investigation of the mechanisms of a few of the more successful glycosylation reactions. It is hoped that such careful investigations will shed new light on the true nature of glycosylating species and so help standardize methods and conditions. Toward this end a series of investigations are proposed into the mechanism of three important classes of glycosylation reaction, namely the sulfoxide method, the thioglycoside method, and the trichloroacetimidate method. These studies will involve characterization of the actual intermediates following activation, and determination of the molecularity of the actual coupling processes by a determination of secondary alpha- deuterium kinetic isotope effects and, wherever possible, kinetics. Neighboring group participation is of critical importance for controlling stereochemistry in many types of glycosylation, but its understanding lags far behind its level of application. For this reason a similar study of the mechanism of neighboring group participation will also be conducted. Problems of a more methodological nature, while keeping in mind the same overall goal, include a study of the reasons underlying the poor reactivity of N-acetylglucosamine and N-acetylneuraminic acid in glycosylation reactions. It is hoped that an enhanced understanding of the poor reactivity of these species will enable the development of protecting groups and conditions to circumvent it.

现代寡糖合成的目的是有效地产生天然和不自然的寡糖及其模拟物，能够在疾病状态中建设性地干扰。可以通过通过调节细胞壁识别，通过增强药物与DNA的结合和选择性来通过调节细菌细胞壁生物合成的破坏，通过在合成疫苗中提供抗原性寡糖，通过调节细胞细胞识别，通过调节细胞细胞识别，通过调节细胞细胞识别来阻止寡糖加工酶。所有这些非常理想的过程都需要高效合成寡糖。最终，希望可以开发寡糖合成到一个可编程，自动化的固相合成是一种实际可能性。尽管在过去的十年左右的时间里，寡糖的合成发展迅速，但这个目标仍然很长一段路。其原因是多重的，并且存在于糖苷形成化学的复杂性。然而，绝对压倒性的方法是，绝大多数的方法是经验发展的，因此，对机制的详细理解几乎没有详细的理解为基础。该提案的主要论点是，自动寡糖合成的最终目标需要简化该区域，并且可以通过详细研究对一些更成功的糖基化反应的机制进行详细研究，从而最好地实现这种简化。希望这样的仔细研究能够对糖基化物种的真实本质进行新的启示，从而帮助标准化方法和条件。为此，提出了一系列研究，包括三种重要类的糖基化反应的机理，即硫氧化物法，硫代糖苷方法和三氯乙二醇化方法。这些研究将涉及激活后实际中间体的表征，以及确定实际耦合过程的分子，通过测定次级α-脱丁氏菌同位素效应以及动力学的情况。相邻的组参与对于控制许多类型的糖基化的立体化学至关重要，但其理解远远落后于其应用水平。因此，还将对邻近群体参与机制进行类似的研究。在牢记相同的整体目标的同时，还包括对N-乙酰基葡萄糖和N-乙酰基神经胺在糖基化反应中的反应性不佳的原因的研究。希望对这些物种的反应性不佳的不良反应性的增强理解能够开发保护群体和条件以规避其。