Rhodium-or Nickel-Catalyzed Asymmetric Hydrogenation Of Multi Substituted Enamides

With the development of science and technology in the 21st century,green chemistry attracts more and more attention.Using a chiral catalyst as a chiral source,asymmetric catalytic reaction affords maximum chiral increments to synthesize chiral molecules.Asymmetric catalytic hydrogenation with high atom economy is popular with academia and industry.In 2001,the Nobel Prize in chemistry was awarded to Knowles and Noyori for their outstanding contributions,which fully demonstrates the importance of asymmetric catalytic hydrogenation.Despite significant achievements,undesolved problems remain,such as a limited substrate scope of tetrasubstituted multifunctional olefins,poor asymmetric hydrogenation results of tetrasubstituted fluorolefin,control of enantioselectivity and diastereoselectivity.Therefore,it’s so important and necessary to develop new metal/chiral phosphine ligand catalytic systems and expand more novel and challenging substrates.Herein,we designed trisubstitutedγ-keto-α-enamido esters and efficiently synthesized homophenylalanine.Moreover,asymmetric hydrogenation of two kinds of challenging tetrasubstituted olefins was catalyzed by chiral metal catalysts.One was rhodium-catalyzed asymmetric hydrogenation of a series ofβ-acetoxy-α-enamido esters,which broke through low reactivity of phenyl substituted substrates.And the other was nickel-catalyzed asymmetric hydrogenation of tetrasubstituted fluorinated enamides,which overcome defluorination and efficiently obtained chiralβ-fluoroamines.The detailed research contents are as follows:（1）Asymmetric hydrogenation of trisubstituted（Z）-γ-keto-α-enamido esters was studied.Highly efficient and stereoselective asymmetric hydrogenation of（Z）-γ-keto-α-enamido esters（up to 99%ee）were realized using Rh/（S,S）-Ph-BPE,featuring with a broad substrate scope.Meanwhile,homophenylalanine derivative was afforded in high yield with excellent enantioselectivity through reduction of C=O bond by Pd/C.This protocol that is highly chemoselective toward the reduction of the C=C bonds provides efficient access to homophenylalanine derivatives.（2）A series of challenging tetrasubstituted（E）-β-acetoxy-α-enamido esters prepared were used for Rh/（R_C,S_P）-Duan Phos catalyzed asymmetric hydrogenation,givingβ-acetoxy-α-amido esters of two adjacent stereocenters in high yields and excellent enantioselectivities with TON up to 500（98%yield,>99%ee）.After deprotection,a concise route for the synthesis of droxidopa was developed.This method features a broad substrate scope,mild reaction conditions,and potential application to the construction of bioactive important molecules containing aβ-hydroxy-α-amino acid unit.（3）Nickel-catalyzed asymmetric hydrogenation of tetrasubstituted（E）-β-enamido-α-fluoro esters was developed.Using Ni（OAc）₂/（S）-Binapine as a catalyst,after optimizing reaction conditions and modulating the reaction pathway,chiralα-fluoro-β-amino esters（up to98%yield,>99:1 dr,up to>99%ee）were efficiently produced without defluorination.This catalytic system with a broad substrate scope provides efficient access to chiralβ-fluoroamines.Furthermore,the experimental results showed that the acid protons in the reaction system greatly accelerated the stereospecific protonolysis of C-Ni bond,generating the syn hydrogenation products,which layed the foundation for further research on the mechanism of nickel-catalyzed asymmetric hydrogenation.