The impact of fluorine in medicinal chemistry is reviewed in the first chapter ofthis work and the fluorine gauche effect, which has not been fully exploited inmedicinal chemistry, is also discussed. GABAA and GABAB receptors are thenpresented and the synthesis of neurosteroid antagonists acting at GABAA receptors isreported. The synthesis of such compounds was motivated to explore the mode of actionof neurosteroids at GABA receptors.The observation that the C-F bond has a strong preference to align gauche to theC-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 stepsand in an overall yield of 31%. The preferred conformations of 3-fluoro-GABA insolution are then explored by NMR analysis and ab initio calculations. The biologicalevaluation 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 acidsare 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 adiamine of potential interest for catalysis is also observed in this synthesis.
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Synthesis and evaluation of β-fluoro-γ-aminobutyric acid enantiomers
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