Studies related to heteroatom analogues of D-Galactofuranose and its Alditol

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(Thesis) Ph.D.
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This thesis describes the heteroatom analogues of the monosaccharide Dgalactofuranose and its alditol, a mild Pummerer-like reaction of seleno-and thio-ethers, and the synthesis of the first seleno sugar derivative. D-Galactofuranose (Galj) is present in the cell walls of mycobacteria and other microorganisms such as protozoa and fungi. These microorganisms are responsible for a variety of life-threatening diseases, and Galf is known to be crucial for their survival, pathogenicity, or infectivity. The syntheses of potential inhibitors of the enzymes UDPgalactopyranose mutase and UDP-galactofuranosyltransferase that are responsible for the formation and incorporation of Galf, respectively, in cell walls of microorganisms are described. The compounds were intended to mimic the oxacarbenium ion transition state in the enzyme-catalyzed reactions. Two ammonium salts of 1,4-dideoxy- 1 ,4-imino-Dgalactitol, a known inhibitor of the enzyme UDP-galactopyranose mutase, as well as their selenonium analogues, derived from 1,4-dideoxy- 1 ,4-seleno-D-galactitol were synthesized. Both series of compounds contained a pendant polyhydroxylated alkyl chain with a sulfate counterion. Progress towards the synthesis of the 4-thio-analogue of UDPgalactofuranose, a potential inhibitor or substrate for the enzyme UDP-Galp mutase, is also described. The Pummerer rearrangements of carbohydrate-based heterocycles containing sulfur and selenium were investigated. Ozonization of 1,4 anhydro-D- galactitol or 1,5 anhydroxylitol derivatives containing sulfur or selenium as the ring heteroatom gave unstable intermediates, that were attributed to ozonides. These intermediates decomposed upon warming to give selenoxides or sulfoxides. Addition of acetic anhydride at low temperature to the ozonization reaction mixtures gave Pummerer-rearrangement-products after warming to ambient temperature, in contrast to the much higher reaction temperatures required for rearrangement of the isolated selenoxides or sulfoxides. The mechanism of the rearrangement, probed by trapping experiments with rubrene, and electron paramagnetic resonance (EPR) studies with the radical trap 5,5-dimethy-1- pyrroline N-oxide (DMPO), is consistent with the intermediacy of radical species in the rearrangement. Finally, the synthesis of the hitherto unknown 4-seleno-D-galactofuranose is described. The synthesis represents the first of a selenosugar. A preliminary study of 4- seleno-D-galactofuranosyl derivatives as glycosyl donors is also described.
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