Synthesis Of Chiral P,N,N-Ligands And Application In Ir-catalyzed Asymmetric Hydrogenation Of ?-ketoesters

Among the numerous catalytic methods,asymmetric hydrogenation is one of the most direct and convenient methods for the synthesis of enantiomerically pure chiral compounds.In this regard,the hydrogenation of?-ketoesters yields chiral?-hydroxyesters,which are important building blocks for the synthesis of chiral drugs and nature products.After decades of development,a large number of asymmetric hydrogenation reactions by ruthenium catalyzed enantioselective hydrogenation of?-ketoesters have been reported.However,iridium catalyzed asymmetric hydrogenation of?-ketoesters remains less explored.In this paper,we designed and synthesized a new kind of ferrocene P,N,N-ligand with two chiral centers and successfully applied it to the iridium catalyzed asymmetric hydrogenation of?-ketoesters.1.We disclosed that the Schiff base-imines readily obtained by the condensation of?S_c,R_p?-PPFNH₂ with various 2-acylpyridines,could be hydrogenated by 5%Pd/C to give?S_c,R_p,R_c?-P,N,N-lingands in high yields and with nearly complete diastereoselectivity.The presence of an additional chiral center at the pyridinylmethyl position of these P,N,N-ligands is crucial to achieve the satisfactory performance in the hydrogenation.2.The hydrogenation was carried out in MeOH?3 mL?under 20 bar H₂ in the presence of0.1 mol%catalyst prepared in situ from[Ir?COD?Cl]₂ and ferrocene P,N,N-ligand.A series of chiral?-hydroxyesters can be obtained in good yields and high enantioselectivities?up to 95%ee?under the optimal conditions.3.This represents the first successful example in the catalytic asymmetric hydrogenation of?-alkyl-substituted?-aryl-?-ketoesters via the dynamic kinetic resolution by using a newly developed chiral tridentate ferrocene P,N,N-ligand.The optimal reaction condition was dentified as follow:ligand?0.11 mol%?,[Ir?COD?Cl]₂?0.05 mmol%?,^tBuOK?5 mmol%?,20bar H₂,in MeOH?3 mL?at room temperature for 12 hours.A variety of optically active anti-?-hydroxyesters can be obtained in good yields and high enantioselectivities?up to 97%ee?and excellent anti-diastereoselectivity.