SYNTHESIS OF STABLE GALACTO DISACCHARIDE MIMETICS

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There is considerable interest in molecules which mimic carbohydrates involved in mechanisms associated with health disorders. Carbohydratees analogs in which the exocyclic or endocyclic acetal oxygen is replaced by a methylene, C-glycoside or carbasugar respectively have attracted interest. These molecules are expected to have similar conformational and steric properties, and therefore similar ligating characteristics as the natural O-saccharide. Importantly, they are not glycosides and therefore will be stable to glycosyl processing enzymes and to chemical hydrolysis. They are potentially useful as therapeutic agents or tools for biochemical research. This project deals with new methodology for the synthesis of three groups of glycomimetics: C-glycosides and carbasugars of Galbeta glycosides, and C-glycosides of glycophospatidyl (GPI) subunits. The specific aims are: (I) C-glycosides which are potential Iselectin ligands and could provide the basis for the design of novel, hydrolytically, stable anti-inflammatory agents. (II) C-Glycosides and carbasugars of Gal-beta-disaccharides, which are substrates for preparation of stable complexes with glycosyl processing enzymes and may have inhibitory properties. (III) C-glycoside analogs of GPI components, which are relevant to the investigation of GPI related processes, such as survival mechanisms in parasitic protozoa and signal transduction related to insulin action. The synthetic strategy centers on novel chemistry of thio- isopropylidinated acetals (TIA's). The method is well suited for making disaccharide mimetics, although it may be just as easily applied to monosaccharide structures. The concept for making disaccharide analogs involves the initial linking of a cyclic sugar derivative to a TIA synthon. Subsequently, the second ring is formed by an oxocarbenium ion-alkene cyclization to give a dihydropyran or cyclohexene derivative, depending on the choice of the TIA fragment used. Stereoselective functionalization of the alkene leads to the targeted glycomimetics. This strategy provides solutions to the problems of coupling efficiency and stereoselectivity which limit the direct connection of two intact cyclic sugar derivatives.