Synthesis of conformationally restricted analogs of baclofen, a potent GABA(B) receptor agonist, by the introduction of a cyclopropane ring

Conformationally restricted analogs of baclofen (2), i.e., 5, 6, and their enantiomers ent-5, and ent-6, the conformations of which were restricted by introducing a cyclopropane ring, were designed as potential GABA(B) receptor ligands. Reaction of (R)-epichlorohydrin [(R)-7] and (4- chlorophenyl)acetonitrile in the presence of NaNH₂ in benzene/tetrahydrofuran gave chiral cyclopropane derivatives 11 and 12, which were then converted into the target compounds 5 and 6, respectively. Their corresponding enantiomers, ent-5 and ent-6, were also synthesized starting from (S)-epichlorohydrin [(S)-7].