Cobalt-catalyzed Asymmetric Hydrogenation Of Unsaturated Carboxylic Acids

Asymmetric hydrogenation is a type of efficient catalytic reduction of prochiral unsaturated compounds catalyzed by a chiral catalyst under hydrogen atmosphere,which has been widely applied in an asymmetric construction of carbon-carbon and carbonheteroatom bonds.Asymmetric hydrogenation plays an important role in the asymmetric synthesis of organic and pharmaceutical intermediates.The chiral carboxylic acids,obtained through asymmetric hydrogenation of ?,?-unsaturated carboxylic acids,are widely used in the synthesis of refine chemicals including drugs,pesticides,spices,perfumes.Therefore,the efficient and economical asymmetric reduction of unsaturated carboxylic acids has received broad attention.In recent years,research on the asymmetric hydrogenation of unsaturated carboxylic acids has mainly focused on noble-metal-based catalysts such as Ru,Rh and Ir complexs,and there are no reports of asymmetric hydrogenation of unsaturated carboxylic acids catalyzed by inexpensive metals such as Fe,Co and Ni.Using inexpensive base-metal catalysts in combination with chiral phosphine ligands,only efficient asymmetric hydrogenation of ketones has been reported.Considering the current status of these studies,this dissertation was focused on the study of base-metal-catalyzed asymmetric hydrogenation of ?,?-unsaturated carboxylic acids.Zhang's group has long-standing interest on the design and synthesis of chiral ligands as well as their applications in asymmetric hydrogenation to synthesize key organic and pharmaceutical intermediates.This dissertation has also evaluated several types of chiral bisphosphine ligands developed by our group on the asymmetric hydrogenation reaction of ?,?-unsaturated carboxylic acids.In this thesis,cobalt-catalyzed asymmetric hydrogenation of different ?,?-unsaturated carboxylic acids has been studied,and two efficient catalytic systems were finally identified after extensive investigation of various commercially available chiral phosphine ligands and those developed by our group.Using Co?acac?₂/?S,S?-Ph-BPE catalyst,asymmetric hydrogenation of ?-substituted cinnamic acid could be achieved under mild conditions with up to 97% ee.For ?-phenylcinnamic acid,TON up to 1860 was obtained.Using CoCl₂/?S,S?-Ph-BPE catalytic system,the asymmetric hydrogenation of ?-substituted butenoic acid was accomplished under more harsh conditions.Notably,>99% ee was obtained for the eantioselective hydrogenation of ?-substituted acrylic acid.Futhermore,we applied the highly efficient asymmetric hydrogenation transformation for the asymmetric construction of chiral intermediates of six drug or biologically active molecules,thus showing the potential application value of this method.