Methods and Mechanisms in Carbohydrate Chemistry

现代寡糖合成的目标是有效生产天然和非天然寡糖及其模拟物，能够建设性地干预疾病状态。 这种干扰可能是通过阻断低聚糖加工酶、破坏细菌细胞壁生物合成、调节细胞-细胞识别、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低聚糖而产生的。 所有这些非常理想的方法都需要高效合成寡糖。最终，希望寡糖合成能够发展到可编程的、自动化的固相合成成为真实的可能性的程度。虽然寡糖合成在过去十多年中有了长足的发展，但这一目标仍然很遥远。 其原因是多方面的，并且存在于糖苷形成的化学的复杂性中。 然而，绝大多数方法都是根据经验开发的，因此对机制的详细了解很少。 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区域，并且这种简化可以通过详细研究几个更成功的糖基化反应的机制来实现。 希望这样的仔细调查将揭示新的糖基化物种的真实性质，从而帮助标准化的方法和条件。为此，一系列的调查提出了三个重要的糖基化反应，即亚砜法，硫代糖苷法，三氯乙酰亚胺法的机制。 这些研究将涉及活化后实际中间体的表征，以及通过测定二级α-氘动力学同位素效应和（如可能）动力学来测定实际偶联过程的分子量。 邻基参与对于控制许多类型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。 为此，还将对邻近群体参与的机制进行类似的研究。更多的方法学性质的问题，同时牢记相同的总体目标，包括N-乙酰葡糖胺和N-乙酰神经氨酸在糖基化反应中反应性差的原因的研究。 人们希望，这些物种的反应性差的增强理解将使保护基团和条件的发展，以规避它。

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.