Methods and Mechanisms in Carbohydrate Chemistry

描述（由申请人提供）：尽管糖化学在过去十年左右有了突飞猛进的发展，但合成复杂的低聚糖或糖缀合物仍然是一项非常具有挑战性的任务，尽管它非常重要。与寡核苷酸和肽的合成相比，这种合成的内在困难是由许多原因引起的，这些原因主要集中在化学的复杂性上。在任何低聚糖合成中最重要的反应是糖苷键的形成，并且存在绝对压倒性数量的方法来达到这一目的。不幸的是，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，而且很少具有普遍性。本提案的基本主题是，通过对糖苷键形成机制的更好理解，再加上开发更有效、更直接和更通用的基于机制的方法，可以最好地解决复杂低聚糖合成的简化挑战。实现这一目标的必要步骤是对糖基化机制的详细研究，因此本提案解决了几个被认为对解决这一问题至关重要的问题。需要解决的问题包括发展糖基氧羰基离子的光谱鉴定和研究方法，发展基于核磁共振的动力学同位素效应方法来研究糖基化动力学，发展基于质谱的方法来研究保护基团对氧羰基离子稳定性的影响，以及基于这些机制研究的改进糖基化体系的发展。

DESCRIPTION (provided by applicant): Although glycochemistry has developed in leaps and bounds in the last decade or so, 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 an absolutely overwhelming number of methods toward this end. Unfortunately the vast majority of these methods have been developed empirically, are therefore underpinned by very little detailed understanding of mechanism, and have very little generality. The underlying theme of this proposal is that the challenge of the simplification of complex oligosaccharide synthesis is best met by an improved understanding of the mechanisms of glycosidic bond formation, coupled with the development of more efficient, straightforward and general mechanism-based methods. A necessary step toward this goal is the detailed investigation of the mechanisms of glycosylation mechanisms, and accordingly this proposal addresses several issues considered critical to the resolution of this problem. The issues to be addressed include the development of methods for the spectroscopic identification and study of glycosyl oxocarbenium ions, the development of NMR-based kinetic isotope effect methods for the study of glycosylation kinetics, the development of mass spectrometry-based methods for the study of the influence of protecting groups on oxocarbenium ion stability, and the development of improved glycosylation systems based these studies of mechanism.