Asymmetric Hydrogenation Of ?-imino Ketones

Asymmetric catalytic hydrogenation is a simple,economic and efficient method for the synthesis of chiral compounds,such as drugs and natural products.Chiral amino alcohol is an important part of many natural products and drugs.At the same time,as a chiral assistant and ligand,chiral amino alcohol is also widely used in the field of asymmetric synthesis.In recent decades,the synthesis of chiral amino alcohols has been widely concerned.Up to now,there have been reports about the reduction of carbonyl or imine in ?-imino ketones,but the study of asymmetric hydrogenation reduction of them by one-step method has not been published,and the synthesis of ?-imino ketones is rarely reported.In this paper,we have developed a kind of asymmetric hydrogenation of ?-imino ketones with high catalytic activity and high stereoselectivity by using(SP,RC)-Duanphos developed by our research group.The details are as follows: a systematic method for the synthesis of ?-imino ketones compounds has been developed.The results show that the electron withdrawing ?-imino ketones can be prepared by heating and refluxing the electron withdrawing substituted benzoyl and pmethoxyaniline in anhydrous ethanol;the electron donating ?-imino ketones can be prepared by heating the electron substituted benzoyl and p-methoxyaniline in toluene with p-toluenesulfonic acid and triethylamine as additives.The asymmetric hydrogenation of ?-imino ketones was carried out by using the catalytic system of diphosphonic ligand(SP,RC)-Duanphos and metal Rh.Through the selective conditions,the carbon nitrogen double bond and carbon oxygen double bond in the substrate can be reduced simultaneously by asymmetric hydrogenation catalysis,and the excellent reaction results(up to 96% yield,>20 : 1 dr,>99% ee)are obtained,and the reaction has good substrate universality.In this paper,a kind of efficient synthesis methodology of chiral amino alcohols has been developed.This method can be applied to the synthesis of drug molecules or bioactive molecules containing the structure of chiral amino alcohols(eliglustat,clorprenaline,mirabegron).It has great significance in academic research and industrial production.