Chemical Synthesis of Beta-Manno and Rehamnopyranosides

描述（由申请人提供）：当代碳水化合物化学不断受到糖生物学领域不断扩大的挑战，更具体地说，受到所发现的生物学和医学上重要的寡糖的复杂性和多样性的挑战，这些寡糖的合成是通过从天然来源中以微量进行极其繁琐的分离和纯化来完成的。已经取得了巨大的进步，使得一些更简单的寡糖的自动化合成现在成为现实，并且已经通过溶液相合成以使得能够进行临床试验的规模生产了潜在的基于碳水化合物的抗肿瘤疫苗。完全合成的五糖现在是欧洲的一种商业抗血栓药物。较小的寡糖链对许多药物的生物学具有深远的影响，通常以尚未完全理解的方式。尽管这些和其他显着的进展，其中许多不能被认为是几年前，仍然有许多重要的问题，在碳水化合物化学解决之前，糖生物学的全部潜力，甚至可以开始实现。该项目的目的是为生物学中发现的一些更复杂类型的糖苷键的直接，立体控制合成提供化学支持，并通过生物学意义的特定结构的全合成来说明这些方法。我们在这个项目中的努力集中在1，2-顺式赤道键吡喃糖苷。这种连接类型的最常见形式是β-D-吡喃甘露糖苷连接，尽管各种脱氧形式也很普遍，包括β-吡喃鼠李糖苷。在大环内酯类抗生素中，这种类型的糖苷键使其以与真菌胺的β-糖苷键的形式出现，即3，6-二脱氧-3-氨基-β-甘露糖苷。最近，发现来自邻单胞菌Shigelloides O 54的核心O-特异性IPS含有两种不寻常的β-连接七吡喃糖苷，具有D-甘油-D-甘露糖和6-脱氧甘油-D-甘露糖构型。 本提案中描述的化学具有使1，2-顺式-赤道糖苷键的合成实用且有效的具体目的，使其与寡核苷酸和肽的合成具有相似的基础，并且通过合成适当复杂的生物活性寡糖来证明这一点。

DESCRIPTION (provided by applicant): Contemporary carbohydrate chemistry is being continually challenged by the ever expanding field of glycobiology and, more specifically, by the complexity and diversity of biologically and medically important oligosaccharides uncovered whose synthesis is mandated by their extremely tedious isolation and purification from natural sources in minute quantities. Great strides forward have been made such that the automated synthesis of some of the more straightforward oligosaccharides is now a reality and potential carbohydrate-based antitumor vaccines have been produced by solution phase synthesis on such a scale as to enable clinical trials. A fully synthetic pentasaccharide is now a commercial antithrombotic drug in Europe. Smaller oligosaccharide chains have a profound effect on the biology of many drugs, often in ways not yet fully understood. In spite of these and other remarkable advances, many of which could not have been contemplated a few years ago, there still remain many important problems in carbohydrate chemistry to be addressed before the full potential of glycobiology can even begin to be realized. The aims of this project are to provide enabling chemistry for the direct, stereo-controlled synthesis of some of the more complex types of glycosidic bond found in biology and to illustrate these methods through the total synthesis of specific structures of biological significance. We focus our efforts in this project on the 1,2-cis-equatorial bonds to pyranosides. The most common form of this linkage type is the beta-D-mannopyranoside linkage, although various deoxy forms are also widespread, including the beta-rhamnopyranosides. In macrolide antibiotics this type of glycosidic bond makes it appearance in the form of beta-glycosidic bonds to mycosamine, that is of 3,6-dideoxy-3-amino-beta-mannosides. More recently, the core O-specific IPS from Plesimonas Shigelloides O54 has been found to contain two unusual beta-linked heptopyranosides having the D-glycero-D- manno and 6-deoxyglycero-D-manno configuration. The chemistry described in this proposal has the specific aim of making the synthesis of the 1,2-cis- equatorial glycosidic bonds practical, and efficient, putting it on a similar footing to that of oligonucleotides and peptides, and of demonstrating this through the synthesis of suitably complex, biologically-active oligosaccharides.