Chemical Synthesis of Beta-Manno and Rehamnopyranosides

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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.