Development of New Carbohydrate Synthesis Methodologies

描述(由申请人提供)：提出了一个致力于开发碳水化合物合成的新方法及其生物活性研究的研究计划。碳水化合物和糖结合物是许多医学上重要的生理过程的媒介，如癌症转移、炎症、抗凝和细菌感染。低聚糖的化学合成对于为糖生物学研究提供纯样品至关重要。传统的碳水化合物合成是一个耗时的过程，因为繁琐的保护基团操作和中间体纯化。提出了两种新的一锅法，可以在一个反应瓶中进行多个糖基化反应，而不需要分离合成中间体。第一种方法利用糖基构建块，该构建块具有通过具有不同吸电子能力的苷元调节的异常活性，并且具有多水平反应活性的构建块可以从共同的中间体中获得。这将极大地扩大反应性窗口，并减少构建块准备的时间和精力。第二种策略是基于在没有受体的情况下糖基供体的预激活，这可以迭代地进行，而不受供体异常反应的影响。迭代一锅法代表了一种通用而强大的方法，它有可能成为一种完全自动化的基于溶液相的碳水化合物合成方法。将调查两种拟议方法的机制，并将吸取的经验教训用于进一步发展。为了证明所提出的策略的广泛适用性，我们将合成一种复合型双触角十二糖和一系列硫酸化的壳寡糖。为了更好地了解它们的构效关系和开发更有效的抗凝血剂，将对硫酸化壳低聚糖的抗凝性能进行测定。

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.