Methods and Mechanisms in Carbohydrate Chemistry

描述(申请人提供)：现代寡糖合成的目标是高效地生产天然和非天然低聚糖，以及它们的模拟物，能够在疾病状态下建设性地干扰。这种干扰可能是通过阻断低聚糖加工酶，通过破坏细菌细胞壁的生物合成，通过调节细胞-细胞识别，通过增强药物与DNA的结合和选择性，以及通过在合成疫苗中提供抗原寡糖来实现的。所有这些非常理想的过程都需要高效地合成低聚糖。最终，人们希望低聚糖的合成能够发展到可编程的、自动化的固相合成成为可能的程度。虽然低聚糖的合成在过去十年左右得到了突飞猛进的发展，但这一目标仍有很长的路要走。造成这种情况的原因是多方面的，原因在于糖苷键形成的化学复杂性。为了达到这个目的，已经设计出了绝对压倒性的方法，然而，这些方法中的绝大多数都是通过经验开发的，因此它们的基础是对机制的很少详细了解。这一建议的主要论点是，自动化低聚糖合成的最终目标需要简化该区域，而这种简化最好通过详细研究几个较成功的糖基化反应的机理来实现。人们希望，这种仔细的调查将为糖基化物种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，我们对几类重要的糖基化反应的反应机理进行了一系列的研究，即形成中间体三氟代糖的硫代糖苷法、N-碘代丁二酰亚胺活化硫代糖苷的方法和三氯乙酰亚胺法。这些研究将涉及对活化后的实际中间体的表征，以及通过测量次级阿尔法-氚动力学同位素效应来确定实际耦合过程的分子性。邻基参与在许多类型的糖基化反应中对于控制立体化学是至关重要的，但它的理解远远落后于它的应用水平。特别是，我们将重点关注3位酯的邻基参与，这既是在α-葡萄糖化等方面使用这种效应，也是在防止这种参与的同时保留3位酯的强大的解除武装能力。我们还将进行N-乙酰神经氨酸化学的研究，以开发用于形成α-唾液酸苷的改进的立体选择性糖基化方案，并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.