Diastereoselective, large scale synthesis of beta-amino acids via asymmetric enamide hydrogenation as alpha 2 delta ligands for the treatment of generalized anxiety disorder and insomnia

作者：Magano Javier^*; Conway Brian; Bowles Daniel; Nelson Jade; Nanninga Thomas N; Winkle Derick D; Wu Haifeng; Chen Michael H

来源：Tetrahedron Letters, 2009, 50(46): 6329-6331.

DOI：10.1016/j.tetlet.2009.08.111

• beta-Amino acid
• alpha 2 delta Ligand
• Asymmetric enamide reduction
• Rh catalyst
• Generalized anxiety disorder
• Insomnia

The syntheses of beta-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 alpha 2 delta 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 beta-carbon via asymmetric hydrogenation of an enamide precursor. Two Rh-based catalysts. (R)-mTCFP-Rh(COD)BF(4) and (R)-binapine-Rh(COD)BF(4), were found to be superior in this transformation and gave very high diastereoselectivities. The process development for catalyst selection is described.

• 出版日期2009-11-18