Methods and Mechanisms in Carbohydrate Chemistry

描述（由申请人提供）：虽然低聚糖合成在过去十年左右取得了突飞猛进的发展，但这一目标仍然很遥远。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。本文的论点是，低聚糖的合理化和改进最好是双管齐下。一方面是对几种糖基化反应的机理进行详细的研究，以期为进一步的发展提供良好的基础。第二个方面（不能与第一个完全分开）是谨慎地开发改进的方法，重点放在更具挑战性的问题上。在机制方面，我们将研究在熟悉的2位以外的位置上酯可能参与邻基的潜在基础。重点将放在用化学和光谱方法检测桥接中间体。在合成方面，我们将以广泛的初步结果为基础，开发一种立体选择性合成唾液酸糖苷的方法，重点是n -乙二醇基神经氨酸和KDO的1-糖苷。我们还将开发基于不稳定的糖基酯基序连接的糖肽的合成方法。公共卫生相关性：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，能够建设性地干预疾病状态。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。该项目的目标是提供合成更具挑战性的糖苷键类的方法，并通过合成生物学相关的低聚糖和糖肽来展示这些方法。

DESCRIPTION (provided by applicant): 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 thesis of this proposal is that the rationalization and improvement of oligosaccharide is best be brought about by a two pronged approach. One prong is the detailed investigation of the mechanisms of a few of glycosylation reactions with the aim of providing a sound basis for further development. The second prong, which can not be entirely separated from the first, is the careful development of improved methodology, with a focus on the more challenging problems. In the mechanistic prong we will investigate the underlying basis for possible neighboring group participation by esters at positions other than the familiar 2-position. The emphasis will be on the detection of bridging intermediates by chemical and spectroscopic methods. In the synthetic prong we will build on our extensive preliminary results to develop a method for the stereoselective synthesis of sialic acid glycosides, with an emphasis on the 1-glycosides of N-glycolyl neuraminic acid and KDO. We will also develop methods for the synthesis of glycopeptides linked based on the labile glycosyl ester motif. PUBLIC HEALTH RELEVANCE: 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. The goal of this project is to provide methods for the synthesis of the more challenging classes of glycosidic bond and to display these methods through the synthesis of biologically relevant oligosaccharides and glycopeptides.