Methods and Mechanisms in Carbohydrate Chemistry

虽然糖化学在过去的二十年里有了突飞猛进的发展， 合成复杂的寡糖或糖共轭化合物仍然是非常重要的 这是一项艰巨而又极其重要的任务。这类合成中固有的困难 产生的原因有很多，这些原因集中在化学的复杂性上， 与寡核苷酸和多肽的合成相比。最重要的 任何低聚糖合成中的反应都是糖苷键的形成和 为了达到这个目的，有很多经验方法。 这笔赠款的长期主题是使复杂的 低聚糖的合成最好是通过更好地理解 糖苷键的形成机制，加上更多 高效、直接和通用的基于机制的方法。在这些方面取得的进展 LINES在一定程度上改变了我们对糖苷键形成的看法 现在可以做出这样的预测了。这项提案的一个方面是解决剩余的问题 从阳离子时钟方法的发展看糖苷作用机制中的问题 用于测定唾液酸糖苷键形成的反应动力学。一个 这一提议的另一个方面是基于机制的反应性预测，导致 一种控制异构体立体选择性的新方法 侧链构象的控制。最后，了解侧链是如何 构象影响反应活性与糖苷稳定过渡态有关 水解酶和糖基转移酶，导致改进的抑制剂的设计 这种关键的碳水化合物加工酶。

Although glycochemistry has developed in leaps and bounds in the last two decades, the synthesis of a complex oligosaccharide or of a glycoconjugate remains a very challenging albeit critically important task. The difficulties inherent in such syntheses arise because of numerous reasons that center on the complexity of the chemistry when compared to that of oligonucleotide and peptide synthesis. The most important reactions in any oligosaccharide synthesis are the formation of the glycosidic bonds and there exists many empirical methods toward this end. The longstanding theme of this grant has been that the rationalization of complex oligosaccharide synthesis is best achieved by an improved understanding of the mechanisms of glycosidic bond formation, coupled with the development of more efficient, straightforward and general mechanism-based methods. Progress along these lines has transformed by the way we think about glycosidic bond formation to the extent that predictions can now be made. One aspect of this proposal addresses remaining issues in glycosidation mechanisms through the development of cation clock methods for the determination of reaction kinetics in sialic acid glycosidic bond formation. A further aspect of this proposal is the mechanism-based prediction of reactivity leading to the development of a novel method for the control of anomeric stereoselectivity through the control of side chain conformation. Finally, the knowledge of how side chain conformation affects reactivity is related to transition state stabilization by glycoside hydrolases and glycosyltransferases, resulting in the design of improved inhibitors for such critical carbohydrate processing enzymes.