Methods and Mechanisms in Carbohydrate Chemistry

现代低聚糖合成的目标是有效地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，并且存在于糖苷形成的化学复杂性中。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。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，对三种重要的糖基化反应，即亚砜法、硫代糖苷法和三氯乙酸酯法的机理进行了一系列的研究。这些研究将涉及活化后实际中间体的表征，并通过测定次级α -氘动力学同位素效应和可能的动力学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。基于此，本文也将对相邻群体参与机制进行类似的研究。在记住相同的总体目标的同时，更具方法学性质的问题包括对n -乙酰氨基葡萄糖和n -乙酰神经氨酸在糖基化反应中反应性差的原因的研究。希望加深对这些物种的不良反应性的了解，将使保护群体和条件的发展能够规避它。

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.