Development of New Carbohydrate Synthesis Methodologies

描述（由申请人提供）：提出了一项致力于开发碳水化合物合成新方法并研究其生物活性的研究计划。碳水化合物和复合糖是许多医学上重要的生理过程的介质，例如癌症转移、炎症、抗凝和细菌感染。寡糖的化学合成对于为糖生物学研究提供纯样品至关重要。由于繁琐的保护基操作和中间纯化，传统的碳水化合物合成是一个耗时的过程。提出了两种新颖的一锅法，其中可以在单个反应烧瓶中进行多个糖基化反应，而无需分离合成中间体。第一个提出的方法利用具有异头活性的糖基结构单元，通过具有各种吸电子能力的苷元进行调整，并且具有多种反应性水平的结构单元可以从共同的中间体衍生。这将大大扩展反应窗口并减少构建块制备的时间和精力。提出的第二个策略是基于在没有受体的情况下预激活糖基供体，该策略可以独立于供体异头反应性迭代进行。迭代一锅法代表了一种通用且强大的方法，有可能成为一种全自动的基于溶液相的碳水化合物合成方法。将研究两种拟议方法的机制，并将吸取的经验教训用于进一步的发展。为了证明所提出的策略的广泛适用性，将合成复杂型双触角十二糖和一系列硫酸化壳寡糖。将确定硫酸化壳寡糖的抗凝血特性，以便更好地了解其结构-活性关系并开发更有效的抗凝血剂。

DESCRIPTION (provided by applicant): A research program devoted to the development of new methods for carbohydrate synthesis and studies of their biological activities is proposed. Carbohydrates and glycoconjugates are mediators of many medicinally important physiological processes, such as cancer metastasis, inflammation, anticoagulation and bacterial infection. Chemical syntheses of oligosaccharides are crucial for providing pure samples for glycobiological studies. Traditional carbohydrate synthesis is a time-consuming process due to tedious protective group manipulation and intermediate purification. Two novel one-pot approaches where multiple glycosylation reactions can be carried out in a single reaction flask without separation of synthetic intermediates are proposed. The first proposed method utilizes glycosyl building blocks with anomeric activities tuned through aglycons with various electron withdrawing power and building blocks with multiple levels of reactivity can be derived from a common intermediate. This will greatly expand the reactivity window and reduce the time and efforts for building block preparation. The second proposed strategy is based on pre-activation of glycosyl donors in the absence of acceptors, which can be carried out iteratively independent of donor anomeric reactivities. The iterative one-pot method represents a general and powerful approach, which can potentially become a fully automated solution-phase based carbohydrate synthesis method. Mechanisms of the two proposed methods will be investigated and the lessons learned will be applied for further development. To demonstrate the broad applicability of proposed strategies, a complex type bi-antennary dodecasaccharide and a series of sulfated chitosanoligosaccharides will be synthesized. The anticoagulant properties of the sulfated chitosanoligosaccharides will be determined for better understanding of their structure-activity relationship and development of more potent anticoagulants.