Synthesis of novel chiral dipyridylphosphine ligands and their application in catalytic asymmetric hydrogenation reactions

We have recently developed a chiral dipyridylphosphine ligand 2,2 ′,6,6′-tetramethoxy-4,4′-bis(diphenylphosphino)-3,3 ′-bipyridine (P-Phos), which was found to be very effective in the Ru-catalyzed asymmetric hydrogenation of 2-(6′-methoxy-2 ′-naphthyl)propenoic acid to give the nonsteroidal anti-inflammatory drug naproxen.; In this study, we have designed and prepared two analogs of P-Phos, 2,2 ′,6,6′-tetramethoxy-4,4′-bis[di( p-methyl-phenyl)phosphino]-3,3′-bipyridine (Tol-P-Phos) 2,2′,6,6′-tetramethoxy-4,4 ′-bis[di-(3,5-dimethylphenyl)phosphino]-3,3′-bipyridine (Xyl-P-Phos) by introducing various substituents onto the four phenyl rings in P-Phos to tune its electronic and steric properties. In addition, we also designed type of P-Phos variant, 2,2′,6,6′ -tetramethoxy-4,4′-bis(dicyclohexylphosphino)-3,3 ′-bipyridine (Cy-P-Phos), which bears four bulky, electron-donating cyclohexyl groups in the two phosphorus atoms, instead of the four arene groups of conventional P-Phos ligands.; The ruthenium complexes of these dipyridylphosphine ligands have been found to be highly active and enantioselective catalysts in the asymmetric hydrogenation of β-keto esters. The reactions proceeded smoothly at 70–90°C and under 200–500 psi of H₂ to give quantitative yield and up to 98.5% ee in 1–3 h.; The chiral trans-[RuCl₂(dipyridylphosphine)(1,2-diamine)] complex combined with (CH₃)₃COK in 2-propanol acted as a very effective catalyst system for the enantioselective hydrogenation of a diverse range of simple ketones including aromatic ketones, hetero-aromatic ketones, substituted benzophenones, alkenyl ketones as well as cyclopropyl ketones with high activities (substrate-to-catalyst ratio up to 100,000) and excellent enantioselectivities (up to >99.9%).; The good efficacy of these chiral ligands in the Ru- and Rh-catalyzed asymmetric hydrogenation of methyl esters of a variety of (Z)-2-acetamido-3-arylacrylic acids and various β-alkyl-substituted β-(acylamino)acrylates was also demonstrated (up to 99.7% ee).; We have also studied the application of the dipyridylphosphine ligands in the Ru-catalyzed asymmetric hydrogenation of 2-(6′-methoxy-2 ′-naphthyl)propenoic acid leading to the popular anti-inflammatory drug (S)-naproxen. The best ee obtained was 95.2%.; In addition, the effects of the backbones and the substituents on the phosphorous atoms of the chiral ligands were extensively investigated. The results showed that the electronic and steric properties of these ligands as well as the different transition metal ions have significant influences on the catalytic properties. Particularly noteworthy was the observation that the use of Xyl-P-Phos as the chiral diphosphine ligand often provided far superior ee's to those obtainable with the parent ligand P-Phos or Tol-P-Phos, which strongly supported our cognition for the design of efficient chiral ligands.; In this study, it is of great interest to note that the Ru-P-Phos catalyst system is highly air-stable even in solution, which makes the experimental procedure very convenient and shows good potential for industrial applications.; The combination of desirable features, such as fast reaction rate, broad substrate scope, excellent enantioselectivity, high substrate-to-catalyst ratio and high air-stability of the catalysts in solution makes the studied catalyst system of high practical interest.