Methods and Mechanisms in Carbohydrate Chemistry

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，而且存在于糖苷形成化学的复杂性。然而，为了实现这一目标，绝大多数方法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，我们对三类重要的糖基化反应的反应机理进行了一系列的研究，这三类反应分别是亚硫醇法、硫代糖苷法和三氯乙酰亚胺酸法。这些研究将包括对活化后的实际中间体进行表征，并通过确定次级α-氘动力学同位素效应以及尽可能确定动力学来确定实际耦合过程的分子。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。为此，还将对邻近群体参与的机制进行类似的研究。在牢记同一总体目标的同时，更具方法学性质的问题包括研究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。人们希望，加强对这些物种反应能力差的了解，将有助于发展保护团体和条件，以绕过它。

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.