Methods and Mechanisms in Carbohydrate Chemistry

描述(申请人提供)：虽然低聚糖的合成在过去十年左右取得了突飞猛进的发展，但这一目标仍然遥遥无期。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。这项建议的论点是，低聚糖的合理化和改进最好是通过双管齐下的方法来实现。一是对几种糖基化反应的机理进行详细的研究，为进一步的研究奠定基础。第二个方面与第一个方面不能完全分开，那就是认真制定改进的方法，把重点放在更具挑战性的问题上。在机械论方面，我们将调查在熟悉的2位以外的位置上的酯可能参与相邻基团的潜在基础。重点将放在通过化学和光谱方法检测桥联中间体上。在合成方面，我们将在我们广泛的初步结果的基础上，开发一种立体选择性合成唾液酸苷的方法，重点是N-羟基神经氨酸和KDO的1-糖苷。我们还将开发基于不稳定的糖酯基序连接的糖肽的合成方法。与公共健康相关：现代低聚糖合成的目标是高效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预。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。该项目的目标是提供合成更具挑战性的糖苷键的方法，并通过合成生物相关的寡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.