Synthesis Of Chiral P,N,N-Ligands And Application In Ir-catalyzed Asymmetric Hydrogenation Of β-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 ofβ-ketoesters yields chiralβ-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 ofβ-ketoesters have been reported.However,iridium catalyzed asymmetric hydrogenation ofβ-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 ofβ-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 chiralβ-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 ofα-alkyl-substitutedβ-aryl-β-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-β-hydroxyesters can be obtained in good yields and high enantioselectivities（up to 97%ee）and excellent anti-diastereoselectivity.