Transition Metal/Bisphosphine-Thioureacatalyzed Asymmetric Hydrogenation

Prochiral compounds such as olefins,ketones,or imines,can be converted into corresponding chiral hydrogenation products through catalytic asymmetric hydrogenation.Compared to other methods,the homogeneous asymmetric hydrogenation is one of the most efficient and atomic economical methods for the construction of chiral molecules using the clean,eco-friendly hydrogen gas as a reducing agent.Since the first report about the homogeneous asymmetric hydrogenation half century ago,the asymmetric hydrogenation has developed rapidly and has been widely used in the field of industry in these decades.The growing demand for chiral drugs,spices,biologically active molecules,and other chiral chemicals in human daily life has further promoted the development of asymmetric hydrogenation.Because of the important role of asymmetric hydrogenation in human life,Knowles and Noyori have been awarded the 2001 Nobel Prize in Chemistry for their outstanding work in the field of asymmetric hydrogenation.In this thesis,the development of chiral phosphine ligands accompanied by asymmetric hydrogenation and the problem solving ideas of experts in this field are briefly introduced.The structural characteristics of the new dual-function bisphosphine-thiourea ligand ZhaoPhos and its unique application in catalytic hydrogenation were introduced.We successfully applied the Rh/ZhaoPhos system to the asymmetric hydrogenation of a series 3-substituted maleimides with or without N-protecting group to access optically active 3-substituted succinimide with >99 % conversion and the ee value can also reach >99 %.Besides we provide a feasible route for the synthesis of a series of pyrroline compounds with the chiral succinimides.Then we applied this catalytic system in the asymmetric hydrogenation of the 3-substituted maleic anhydrides.In the optimal reaction condition,conversion and enantioselectivity are provided at high level.In the high TON experiment,the hydrogenation can be finished with full conversion with S/C = 3 000.The optically active succinic acid anhydride was went through ring-open reaction with the corresponding amine to obtain the hypoglycaemic agent-Mitiglinide.Afterwards,we successfully developed a highly efficient Ir/N-Me ZhaoPhos catalytic system,which can proceed the hydrogenation of a series of prochiral benzoxazinones and derivatives with strong Br?nsted acid as a co-catalyst.Compared with the previous catalytic system,the reaction conditions are mild and the reaction efficiency is greatly improved.At the same time,the imine substrate does not need to be pre-preparation of corresponding imine hydrochloride.Most hydrogenation products were provided with have full conversion and >99% ee values.The Ir/N-Me ZhaoPhos catalytic system still successfully proceed asymmetric hydrogenation in the presence of only 0.00002 mol%(S/C = 50 000)catalyst,and the chiral product can be obtained with 80% conversion(40 000 TON),75% yield and 99% ee value,the product can be purified without alkaline hydrolysis.We also have applied a Ir/ZhaoPhos catalytic system into the asymmetric reduction of challenging tetra-substituted substrates ?-fluorodihydroamino acid esters.The system showed high catalytic activity and enantioselectivity in the hydrogenation of a series of tetrasubstituted ?-fluoro-?-dehydrogenated carboxylic acid esters,the corresponding chiral ?-fluoro-?-amino carboxylic acid esters can be obtained with up to 99% ee value,>25: 1 dr value and 3 000 TON.