Synthesis of Conformationally Restricted Analogs of Baclofen, a Potent GABA_B Receptor Agonist, by the Introduction of a Cyclopropane Ring

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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 NaNH-2, 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)-epichlorohydring [(S)-7].