Direct Synthesis Of Chiral Nh Lactams By Asymmetric Reductive Amination-cyclization Cascade Reactions

Biaryl aza-seven-membered ring compounds with an axial chirality have a special bridging skeleton,a structure that usually exists in molecules with physiological activity,and is widely incorporated into the synthesis of potentially pharmaceutical molecules;in the same time,this structure also serves as an important subunit for small-molecule organocatalysts and chiral ligands used in asymmetric catalysis.Therefore,the asymmetric synthetic research on these molecules with such a novel structure may open a new window for the development of chiral amine drugs,and in the meanwhile help to develop novel organo-catalysts and chiral ligands,which may contribute to further development of the field of asymmetric catalysis.At present,there are very few reports on the catalytic synthesis of biaryl aza-seven-membered ring compounds with an axial chirality.Therefore,it is highly desirable to develop highly efficient and concise asymmetric synthesis of this type of compounds.In order to solve this problem,this thesis mainly studies the asymmetric reductive amination-cyclization cascade reaction of biaryl ketoneester catalyzed by ruthenium complex in the presence of ammonium salts.The detailed contents mainly include: syntheses of the substrate biaryl ketone esters through the Suzuki coupling reaction;study of the asymmetric reductive amination-cyclization cascade reaction of biaryl ketone esters with ruthenium complexes ligated with a chiral bisphosphine ligand as catalysts,ammonium acetate as the ammonia source and H2 as the reductant.The experimental results have proved that this method can achieve asymmetric transformations of biaryl ketone esters under relatively mild conditions,leading to the synthesis of biaryl sevenmembered ring lactams containing a central chirality and axial chirality.The method features simple operation,high atomic economy,good tolerance to various functional groups.Most of the tested substrates could reach up to 98% yield and >99% ee;to showcase the potential application of this methodology,further derivatization of the axially chiral biaryl seven-membered ring lactams is also investigated.