Synthesis of (R)-(-)-Baclofen

Significance

Baclofen is a GABA_B receptor ­antagonist. Racemic baclofen (Lioresal, Baclon) is marketed as an antispasmodic agent, although only the (R)-enantiomer is active. The key step in the route depicted is an asymmetric conjugate addition of nitromethane to the 4-nitro-5-styrylisoxazole A catalyzed by the phase-transfer catalyst B. The enantiomer (S)-C could also be prepared with similar efficiency by using the related cinchonidine-based catalyst E. The scope of the conjugate addition step was explored with ten catalysts, eleven 4-nitro-5-styrylisoxazoles and five nitroalkanes.