Pyridines Involved Asymmetric Hydrogenation And Synthesis Of Chiral NHC-P Ligands

In the last decades,transition metal catalyzed asymmetric hydrogenation,which was a simple,high atom economy and environmentally friendly method to synthesize natural products,chiral drugs and food additives,has attracted much attention in organic synthesis and industrial application.Asymmetric hydrogenation of prochiral substrates,such as ketones,imines,alkenes,and aromatic compounds,has been fully developed.Although asymmetric hydrogenation has made big progress,there are still some unsolved problems.For example,the asymmetric hydrogenation of pyridine derivatives is still limited to some special substrates.So,the diacovery of new chiral catalysts and new reactions is always a challenging work.In this work,we paid attention on the asymmetric hydrogenation of ketones and alkenes that containing pyridine groups,and preparation of chiral 3,4-disubstituted piperidines through asymmetric hydrogenation of pyridine derivatives.At the same time,new NHC-P ligands were prepared and used in asymmetric reactions.The research details are as follows:1.The catalytic asymmetric hydrogenation of 2-pyridine ketones.With the help of coordination effects of pyridines in the rhodium catalyzed asymmetric hydrogenation,2-pyridine ketones were hydrogenated with high enantioselectivities with Rh-BinaPine as the catalysts.Key intermediates for bepotastine besilate were synthesized efficiently using this new method.The recognizaton of chirality depended on the weak oordination effects of pyridines and rhodium,and this new method have overcame the substrates limitations and improved the efficiency of preparing chiral 2-pyridine aryl/alkyl alcohols.2.After achieving the asymmetric hydrogenation of 2-pyridine ketones,we found that he pyridine groups could also acted as directing groups in the asymmetric hydrogenation of 2-pyridine alkenes.Using Rh-DuanPhos as the catalysts,asymmetric hydrogenation of 2-pyridine alkenes were achieved with high enantioselectivities.This method was suitable for the synthesis of 1,1-disubstituted ethanes that owning pyridine groups.3.Asymmetric synthesis of chiral piperidines with new strategy.The Methyl nicotinate could be easily converted to 3,4-dihydropyridines through Comins’ method.And the asymmetric hydrogenation of 3,4-dihydropyridines with Rh-JosiPhos gave excellent enantioselectivity and reactivity(>99%ee and>99%conv.).Trans-3,4-disubstituted piperidines were obtained after simple tranformations,which were important antidepress drugs-paroxetine.This work had developed a high efficient method to construct chiral multi-substituted piperdines.4.New NHC-P ligands were designed and synthized.Although they performed high reactivity,low enantioselectivities were achieved in the asymmetric hydrogenation and other asymmetric Suzuki coupling reactions.Although the experiments indicated this new type ligands had high reactivity,they gave low enantioselectivities,and further modifications were needed.