Synthesis of Complex Carbohydrates.

描述（由申请人提供）：在合成碳水化合物化学领域内，糖苷键的立体选择性形成是至关重要的。在异头中心的键连接的有效操纵开辟了新的方法，用于合成复杂的碳水化合物，包括1，2-顺-2-氨基糖苷。这些氨基糖组成了天然存在的寡糖和糖缀合物的最重要类别之一，其作为凝集素、抗体和酶的细胞表面受体配体起着至关重要的作用。然而，由于从天然来源获得足够的定义明确的糖苷的巨大挑战，对1，2-顺式-2-氨基糖的特定功能的理解进展受到阻碍。在许多情况下，高纯度的1，2-顺式-2-氨基糖只能通过化学合成获得，这也提供了获得结构变体的途径。虽然在1，2-顺式-2-氨基糖苷的合成中已经有显著的进展，但是当前方法的缺点包括使用过量的活化剂和不可预测/差的异头选择性。 在这份拨款申请中，我们的目标是 是开发一种新的和创新的策略，用于通过过渡金属催化的α-选择性糖基化有效合成1，2-顺式-2-氨基糖苷（具体目标1）。本课题组目前正在开发的方法将具有广泛的适用性，并能以高产率和优异的α-选择性提供产品。所提出的方法的成功完成将在碳水化合物领域产生广泛的影响，其中仍然缺乏立体选择性糖基化的催化方法。这种过渡金属催化的1，2-顺式-2-氨基糖基化方法将被应用于生物活性碳水化合物靶标的合成，包括空肠弯曲杆菌N-连接聚糖（特异性目标2），其可用于阻断空肠弯曲杆菌粘附于人胃上皮细胞并与哺乳动物凝集素结合，以及肝素寡糖，其具有强效抗凝活性和最小副作用（特异性目标3）。1

DESCRIPTION (provided by applicant): Within the realm of synthetic carbohydrate chemistry, the stereoselective formation of glycosidic bonds is of paramount importance. Efficient manipulation of bond connectivity at the anomeric center opens up new approaches for the synthesis of complex carbohydrates, including the 1,2-cis-2-amino glycosides. These aminosugars make up one of the most important classes of naturally occurring oligosaccharides and glyco-conjugates, which play a crucial role as cell-surface receptor ligands for lectins, antibodies, and enzymes. However, progress toward understanding the specific functions of 1,2-cis-2-aminosugars has been hampered, due to the formidable challenge of obtaining an adequate supply of well-defined glycosides from natural sources. In many cases, high purity 1,2-cis-2-aminosugars can only be obtained by chemical synthesis, which also provides access to structural variants. Although there have been remarkable advances in the synthesis of 1,2-cis-2-amino glycosides, the disadvantages of current methodologies include the use of excess activating agents and unpredictable/poor anomeric selectivity. In this grant application, our goal is to develop a new and innovative strategy for the effective synthesis of 1,2-cis-2-amino glycosides via transition metal-catalyzed a-selective glycosylation (Specific Aim 1). The method that is currently being developed in our group will be broadly applicable and provide products in high yield and with excellent a-selectivity. The successful completion of the proposed method would have broad impact in the carbohydrate field, where catalytic methods for stereoselective glycosylation are still lacking. This transition-metal catalyzed 1,2-cis-2-amino glycosylation methodology will be applied to the synthesis of bioactive carbohydrate targets, including Campylobacter jejuni N-linked glycan (Specific Aim 2) which can be used to block Campylobacter jejuni adherence to human gastric epithelial cells and biding to mammalian lectins, and heparin oligosaccharides which have potent anticoagulant activity and minimal side effect (Specific Aim 3). 1