Direct Syntheses of Stereoisomers of 3-Fluoro GABA and -Fluoroamine Analogues of the Calcium Receptor (car) Agonists, Cinacalcet, Tecalcet, Fendiline and NPS R-467

Synthetic routes following a sequential MacMillan organocatalytic asymmetric a-fluorination protocol for aldehydes and then reductive amination, have allowed ready access to bioactive beta-fluoroamines. The approach is demonstrated with a short synthesis of (S)-3-fluoro-gamma-aminobutyric acid (3F-GABA) and was extended to beta-fluoroamine stereoisomers of cinacalcet, tecalcet, fendiline and NPS R-467, all allosteric modulators of the calcium receptor (CaR). Stereoisomers of the fluorinated calcimimetic analogues were then assayed in a CaR receptor assay and a comparison of beta-fluoroamine matched pair stereoisomers revealed a binding mode preference to the receptor as deduced from conformations which will be favoured as a consequence of the electrostatic gauche effect. [GRAPHICS] .