Methods and Mechanisms in Carbohydrate Chemistry

描述（由申请人提供）：现代低聚糖合成的目标是高效生产天然和非天然低聚糖及其模拟物，能够建设性地干扰疾病状态。这种干扰可能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低聚糖来实现。所有这些非常理想的过程都需要高效的低聚糖合成。最终，人们希望寡糖合成可以发展到一个地步，在这个地步上，可编程的、自动化的固相合成是一种真正的可能性。虽然低聚糖合成在过去十年左右有了突飞猛进的发展，但实现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，并且存在于糖苷键形成的化学复杂性中。为了达到这个目的，已经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根据经验开发的，因此对机制的详细了解很少。本提案的主要论点是，自动化低聚糖合成的最终目标需要简化该区域，而这种简化可以通过对一些更成功的糖基化反应的机制的详细研究来实现。希望这种细致的调查将揭示糖基化物种的真实性质，从而有助于标准化方法和条件。为此，对几种重要的糖基化反应的机理进行了一系列的研究，即形成中间三氟化糖基的硫糖苷法、用n -碘琥珀酰亚胺活化硫糖苷法和三氯乙酸酯法。这些研究将包括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耦合过程的分子度。邻基参与在许多类型的糖基化中对控制立体化学至关重要，但对它的理解远远落后于它的应用水平。我们将特别关注3位上酯对邻基的参与，一方面是在-糖基化过程中利用这种效应，另一方面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，目的是开发改进的立体选择性糖基化方案，以形成-唾液酸苷，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.