University of Leicester
2007milesjalpdh.pdf (6.45 MB)

Total Synthesis of Conformationally-locked Difluorinated Pento- and Hexopyranose Analogues, and Pentopyranosyl Phosphate Mimetics

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posted on 2010-08-27, 08:33 authored by Jonathan Andrew Lawrence Miles
A range of pentopyranosyl phosphate mimetics including 2,2-difluoro-3R*,4R*- dihydroxy-9-oxa-1S*,5R*-bicyclo[3.3.1]nonanyl-1S*-phosphate ammonium sodium salt have been prepared concisely from trifluoroethanol. Such species once activated to full NDP sugars are intended as probes for the glycosyl transferase class of enzymes. Trifluoroethanol was elaborated, via a telescoped sequence involving a metallated difluoroenol, a difluoroallylic alcohol, [2,3]-Wittig rearrangement and ultimately a ring closing metathesis (RCM) reaction, and requiring minimal intermediate purification, to a number of cyclooctenone intermediates including 3-benzyloxy-2,2-difluoro-cyclooct-4Zen- 1-one. Studies on the RCM reaction with alternate metathesis catalysts including Neolyst resulted in the unexpected isolation and full characterisation of a number of unusual homodimeric species. From 3-benzyloxy-2,2-difluoro-cyclooct-4Z-en-1-one a divergent approach delivers novel bicyclic analogues of pentopyranoses, either via epoxidation followed by transannular ring-opening, or dihydroxylation followed by transannular hemiacetalisation. These species were further elaborated with an emphasis on minimal protecting group manipulation to analogues of glycosyl phosphates. Furthermore the library of non natural sugars has been expanded with the initial steps toward a range of hexoses based on the 6-deoxy class of sugars being elucidated. 3- benzyloxy-2,2-difluoro-5-methyl-cyclooct-4Z-enone was synthesised via a relay RCM after initial attempts with a traditional RCM precursor (3-benzoyloxy-4-4-difluoro-9- methyl-deca-1,9-diene-5-one) failed to deliver satisfactory quantities of material. In both cases RCM precursors were synthesised via chemistry analogous to that used in the construction of 3-benzyloxy-2,2-difluoro-cyclooct-4Z-en-1-one. The epoxide transanular ring opening has been further investigated with a range of neutral and anionic nucleophiles which has allowed the mechanism of initial nucleophilic attack at the ketone to be proven and a new class of nitrogen bridged azasugar analogues to be characterised.



Percy, Jonathan M.

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Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD



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