Direct syntheses of stereoisomers of 3-fluoro GABA and β-fluoroamine analogues of the calcium receptor (CaR) agonists, cinacalcet, tecalcet, fendilines and NPS R-467

Abstract

Abstract Synthetic routes following a sequential MacMillan organocatalytic asymmetric a-fluorination protocol for aldehydes and then reductive amination, has allowed ready access to bioactive b-fluoroamines. The approach is demonstrated with a short synthesis of (S)-3-fluoro-g-aminobutyric acid (3F-GABA) and was extended to b-fluoroamine stereoisomers of cinacalcet, tecalcet, fendilines 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 b-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.