Synthesis of Complex Carbohydrates.

描述(申请人提供)：在合成碳水化合物化学领域，糖苷键的立体选择性形成是至关重要的。异构体中心键连接性的有效操纵为合成包括1，2-顺-2-氨基糖苷在内的复杂碳水化合物开辟了新的途径。这些氨基糖组成了一类最重要的天然低聚糖和糖结合物，它们作为凝集素、抗体和酶的细胞表面受体配体发挥着至关重要的作用。然而，理解1，2-顺-2-氨基糖的具体功能的进展一直受到阻碍，因为从自然来源获得足够的明确糖苷供应是一项艰巨的挑战。在许多情况下，高纯度的1，2-顺-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1，2-顺式-2-氨基糖苷的合成已经取得了显著的进展，但现有方法的缺点包括使用过多的活化剂和不可预测的/较差的异构体选择性。在这项拨款申请中，我们的目标是 目的是开发一种新的创新策略，通过过渡金属催化的α-选择性糖基化有效地合成1，2-顺式-2-氨基糖苷(特定目标1)。我们小组目前正在开发的方法将具有广泛的适用性，并提供高产率和良好的a-选择性的产品。该方法的成功完成将在碳水化合物领域产生广泛的影响，目前尚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-2-氨基糖基化方法将被应用于合成生物活性碳水化合物靶标，包括空肠弯曲菌N-连接多糖(特异性目标2)，可用于阻断空肠弯曲菌与人胃上皮细胞的黏附和与哺乳动物凝集素的结合，以及具有强大的抗凝血活性和最小副作用的肝素低聚糖(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