Construction Of Asymmetric Catalytic Hydrogenation System For Highly Efficient Synthesis Of Chiral Amines

Chiral amines,which are present ubiquitously in bioactive molecules and natural products,are important building block for pharmaceuticals and fine chemicals.Developing the efficient and environmentally friendly methods to construct chiral amines have attracted increasing attention of academia and pharmaceutical industry.As a typical atom economic reaction,catalytic asymmetric hydrogenation is the most efficient and low-cost methods for the preparation of chiral amines,usually exhibits excellent efficiency in a green and cleanness manner.Although success has been achieved with enantioselective hydrogenation of prochiral imines in the last few decades,only limited cases achieved industrialization.As a result of the properties of the C=N bond:（1）Electrically riched imines are usually undesirable substrates for hydrogenation with low TON and TOF value;（2）It is more difficult to prepare imines because of its instability,leading to limited types of substrates;（3）Relatively low catalytic activities were usually observed,probably due to the coordination of the N atom in imine and amine with the metal catalyst;（4）The imine-enamine tautomerization and interconversion of imine E/Z stereoisomers could also erode the enantioselectivities;（5）Enantioselective hydrogenations of the aromatic heterocyclic compounds remains a challenging task.Therefore,development of the most efficient enantioselective catalytic systems to prepare the various of chiral amines has always been a hot topic in asymmetric hydrogenation.As part of our ongoing research toward the development of the efficient asymmetric hydrogenation catalytic system.In this thesis,four asymmetric catalytic hydrogenation system have been constructed for highly efficient synthesis of chiral amines.The research contents are as follows:（1）Preparation of chiral amines by asymmetric reductive amination of aromatic ketones1-Aryl-substituted chiral amines are of great importance as synthetic building blocks,which also widely exist in the pharmaceutical drugs,agrochemicals and fine chemicals.Since the instability of imine substrate,an efficient asymmetric reductive amination of aromatic ketones catalyzed by Ir-ax-Josi Phos complex was described.22 kinds of chiral secondary amines can be readily synthesized,of which the yields and ees are higher than90%for 18 chiral amines,and 8 kinds of amines were new compounds.These chiral secondary amines can be further converted into primary amines after simple deprotection.To demonstrate the potential utility of this catalytic system,a gram scale preparation of（R）-methyl-4-trifluoromethyl benzylamine was performed,adduct was obtained in 90%isolated yield and 96%ee,which is an important building block for pharmaceutical drugs.（2）Enantioselective synthesis of 1-aryl-tetrahydroisoquinoline alkaloids via intramolecular asymmetric reductive aminationChiral C-1 substituted tetrahydroisoquinoline（THIQs）skeletons are widely presented in natural products,pharmaceuticals and bioactive compounds.To further verify the practicality of ax-Josi Phos ligands,highly efficient intramolecular asymmetric reductive amination of tert-butyl-（2-benzoylphenylethyl）-carbamate in combination with N-Boc deprotection was carried out in an one-pot process to prepare chiral 1-aryl-THIQs.32 kinds of tert-butyl-（2-benzoylphenylethyl）-carbamate substrates were synthesized from commercial 2-arylethylamine in four steps,of which 22 were new compounds.A series of chiral 1-aryl-THIQs were successfully synthesized by the intramolecular asymmetric reductive amination catalyzed by Ir-ax-Josi Phos complex in 78%-96%yield and 80%-99%ee.Among them,the enantioselectivity of 23 chiral products were more than 90%ee and 6were new compounds.（3）Preparation of Chiral 4-aryl-tetrahydroisoquinoline derivatives by catalytic asymmetric hydrogenationChiral 4-aryl-THIQs alkaloids proved to exhibit unique physiological activities in central nervous system,but the lack of effective enantioselective synthesis methods has greatly restricted its’further research and development.The ax-Josi Phos and Josi Phos ligands were applied in the enantioselective hydrogenation of aromatic 4-aryl-isoquinoline to construct chiral 4-aryl-THIQs skeletons for the first time.22 kinds of 4-aryl-isoquinoline were synthesized from isoquinoline by two-step reaction in high yield,and 8 of which were new compounds.Asymmetric catalytic hydrogenation of the above substrates was successfully carried out to afford chiral 4-aryl-THIQs with 78%-96%yield and 37%-61%ee,among which 17 are new compounds.Although only limited enantioselectivity was obtained,this is the first systematic investigation of 4-arylisoquinoline by direct asymmetric hydrogenation.Further optimization is still in progress.（4）Preparation of key intermediate for herbicide（S）-Metolachlor by asymmetric hydrogenation（S）-Metolachlor is a highly selective chiral herbicide developed by Syngenta.Due to Syngenta’s monopoly on the synthesis technology of（S）-Metolachlor,its price remains high.We have carried out exploratory research on the synthesis of the key intermediate of（S）-Metolachlor.9 novel chiral ferrocene phosphine ligands have been synthesized and applied to the asymmetric hydrogenation of MEA imine.The enantioselectivities of 86%ee,89%ee and 85%ee were obtained respectively,which is higher than（S）-Metolachlor（79%ee）.Moreover,these catalytic systems are much safer at only 20 atm H₂pressure,compared with80 atm H₂ of Syngenta.However,the catalytic activity is far from industrial production,further optimization is still in progress.