Methods and Mechanisms in Carbohydrate Chemistry

碳水化合物化学的方法和机制

• 批准号: 6656869
• 负责人: David Crich
• 金额: $ 22.42万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2004-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6656869
• 关键词: N acetylglucosamine; N acetylneuraminate; biomedical automation; chemical synthesis; glycosylation; hydrogen bond; nuclear magnetic resonance spectroscopy; oligosaccharides; sialate; structural biology

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.

现代寡糖合成的目标是有效生产能够建设性地干扰疾病状态的天然和非天然寡糖及其模拟物。 这种干扰可能是通过阻断寡糖加工酶、破坏细菌细胞壁生物合成、调节细胞间识别、增强药物与 DNA 的结合和选择性以及在合成疫苗中提供抗原性寡糖而引起的。 所有这些非常理想的过程都需要低聚糖的高效合成。最终，希望寡糖合成能够发展到可编程、自动化固相合成成为真正可能的程度。尽管寡糖合成在过去十年左右的时间里取得了突飞猛进的发展，但这一目标仍然任重而道远。 其原因是多方面的，并且在于糖苷形成化学的复杂性。 然而，实现这一目标的方法数量绝对是压倒性的，其中绝大多数都是凭经验开发的，因此它们的基础是对机制的详细理解很少。 该提案的主要论点是，自动化寡糖合成的最终目标需要简化该领域，并且这种简化最好通过对一些更成功的糖基化反应的机制进行详细研究来实现。 希望这种仔细的研究能够为糖基化物质的真实性质提供新的线索，从而有助于标准化方法和条件。为此，对三类重要的糖基化反应的机理进行了一系列研究，即亚砜法、硫代糖苷法和三氯乙酰亚胺法。 这些研究将涉及活化后实际中间体的表征，以及通过确定次级α-氘动力学同位素效应以及尽可能的动力学来确定实际偶联过程的分子性。 邻近基团的参与对于控制许多类型的糖基化中的立体化学至关重要，但其理解远远落后于其应用水平。 为此，还将对邻近群体的参与机制进行类似的研究。更具方法论性质的问题，同时牢记相同的总体目标，包括对糖基化反应中 N-乙酰氨基葡萄糖和 N-乙酰神经氨酸反应性差的原因的研究。 希望加强对这些物种的低反应性的了解将有助于开发保护组和条件来规避它。