Methods and Mechanisms in Carbohydrate Chemistry

描述（由申请人提供）：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，并且存在于糖苷键形成的化学复杂性中。为此目的设计了绝对压倒性的方法，然而，这些方法中的绝大多数都是经验性的，因此，它们的基础是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，提出了一系列的调查的几个重要类别的糖基化反应的机制，即与形成中间体糖基三氟甲磺酸盐的硫代糖苷方法，活化的硫代糖苷通过N-碘代琥珀酰亚胺，和三氯乙酰亚胺方法。这些研究将涉及活化后实际中间体的表征，以及通过测量次级α-氘动力学同位素效应来确定实际偶联过程的分子度。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。特别地，我们将关注3-位酯的相邻基团参与，既在α-葡糖基化等中使用这种效应，又在防止这种参与但保留3-位酯的强大解除能力方面。我们还将进行N-乙酰神经氨酸化学的研究，其双重目的是开发用于形成α-唾液酸糖苷的改进的立体选择性糖基化方案，以及提高唾液酸衍生物作为糖基受体的反应性。

DESCRIPTION (provided by applicant): 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 bonds. An absolutely overwhelming number of methods toward this end have been devised, however, the vast majority of these 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 several important classes of glycosylation reaction, namely the thioglycoside method with the formation of intermediate glycosyl triflates, the activation of thioglycosides by means of N-iodosuccinimide, 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 measurement of secondary alpha-deuterium kinetic isotope effects. 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. In particular we will focus on neighboring group participation by esters at the 3-position, both in terms of the use of this effect in alpha-glucosylation and the like, and in terms of preventing this participation yet retaining the powerful disarming ability of an ester at the 3-position. We will also undertake a study of N-acetylneuraminic acid chemistry with the two fold intention of developing improved stereoselective glycosylation protocols for the formation of alpha-sialyl glycosides, and of improving the reactivity of sialic acid derivatives as glycosyl acceptors.