Diastereoselective, large scale synthesis of β-amino acids via asymmetric enamide hydrogenation as α2δ ligands for the treatment of generalized anxiety disorder and insomnia

The syntheses of β-amino acids 1 and 2 are presented by means of an alternative route to the asymmetric Michael-addition route reported in the preceding article. These two compounds, which bind to the α2δ subunit of calcium channels and have important medical applications, have been prepared on multi-kilogram scale in our pilot plant through a new approach that introduces the chirality at the β-carbon via asymmetric hydrogenation of an enamide precursor. Two Rh-based catalysts, (R)-mTCFP-Rh(COD)BF4 and (R)-binapine-Rh(COD)BF4, were found to be superior in this transformation and gave very high diastereoselectivities. The process development for catalyst selection is described.