Synthesis and evaluation of β-fluoro-γ-aminobutyric acid enantiomers
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The impact of fluorine in medicinal chemistry is reviewed in the first chapter of this work and the fluorine gauche effect, which has not been fully exploited in medicinal chemistry, is also discussed. GABAA and GABAB receptors are then presented and the synthesis of neurosteroid antagonists acting at GABAA receptors is reported. The synthesis of such compounds was motivated to explore the mode of action of neurosteroids at GABA receptors. The observation that the C-F bond has a strong preference to align gauche to the C-N+ bond in protonated β-fluoroamines stimulated the enantioselective synthesis of 3-fluoro-GABA enantiomers. This was achieved from L- and D- phenylalanine in six steps and in an overall yield of 31%. The preferred conformations of 3-fluoro-GABA in solution are then explored by NMR analysis and ab initio calculations. The biological evaluation of 3-fluoro-GABA enantiomers on GABA aminotransferase was then investigated and showed that the (R)-enantiomer undergoes HF elimination ten times more rapidly than the (S)-enantiomer, suggesting a preferred binding conformation of GABA on GABA aminotransferase. This study demonstrates that the C-F bond can be used as a chemical probe to reveal the binding conformation of a bioactive amine and this offers exciting prospects for future research. The synthesis of 3-fluoro-GABA from phenylalanine indicated that amino acids are practical starting materials for the preparation of β-fluoroamines. This methodology is applied to L-lysine to generate (2R)-fluorohexane-1,6-diamine. The formation of a diamine of potential interest for catalysis is also observed in this synthesis.
Thesis, PhD Doctor of Philosophy
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