Development of New Carbohydrate Synthesis Methodologies

描述（由申请人提供）：拟设立一个研究项目，致力于开发碳水化合物合成的新方法及其生物活性的研究。碳水化合物和糖缀合物是许多重要的医学生理过程的介质，如癌症转移、炎症、抗凝和细菌感染。低聚糖的化学合成是为糖生物学研究提供纯样品的关键。传统的碳水化合物合成是一个耗时的过程，由于繁琐的保护基操作和中间的纯化。提出了两种新的一锅方法，其中多个糖基化反应可以在一个反应烧瓶中进行，而不需要分离合成中间体。第一种提出的方法利用糖基构建单元，通过具有不同电子吸能的糖元调整糖基活性，并且可以从一个共同的中间体衍生出具有多级反应性的构建单元。这将极大地扩展反应窗口，减少构建块制备的时间和精力。第二种提出的策略是基于在没有受体的情况下糖基供体的预激活，这可以独立于供体的端粒反应进行迭代。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液相的碳水化合物合成方法。将调查这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，将合成一种复杂类型的双天线十二糖和一系列硫酸壳寡糖。研究磺化壳寡糖的抗凝血性能，有助于更好地了解其构效关系，开发更有效的抗凝剂。

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.