Application Of Chiral Tridentate PNN Ligands F-amphox In Iridium-catalyzed Asymmetric Hydrogenation Of Functionalized Ketones

Chiral alcohols are important building blocks in the fields of pharmaceutical,agrochemical industries,due to their distinct biological activities.In principle,preparation of chiral alcohols through catalytic asymmetric hydrogenation(AH)of readily available pre-chiral ketones is one of the most straightforward and operationally simple approaches.Although the homogeneous asymmetric hydrogenation of ketones has already achieved a great success,since the Noyori's novel catalytic systems were reported,there are still many urgent problems in this field.For example,highly efficient catalytic system for the asymmetric hydrogenation of aliphatic ketone has not been found until now.Therefore,the asymmetric hydrogenation of ketones is still a research field that needs to be explored.In this dissertation,we performed the following work:1)Tridentate f-amphox ligands were successfully applied to the iridium-catalyzed asymmetric hydrogenation of various a-amino ketones to afford a series of chiral 1,2-amino alcohols with excellent results(all products up to>99%conversion and>99%ee,TON up to 500 000).The products chiral 1,2-amino alcohols are important motifs in many pharmaceuticals,chiral auxiliaries and ligands.Our catalytic system provided an efficient synthetic route to prepare important chiral intermediate of(S)-phenylephrine with practical industrial potential(up to 200 000 TON and>99%ee),which is the enantiomer of a famous a-adrenergic receptor agonist.2)Asymmetric synthesis of chiral hydroxy amides has been successfully accomplished by enantioselective catalytic hydrogenation of various prochiral ?-,?-,?,-8-keto amides in the presence of Ir/f-amphox catalyst with excellent results(almost all products with>99%conversion and>99%ee).Furthermore,a gram-scale asymmetric hydrogenation of 5-(4-fluorophenyl)-5-oxo-N-phenylpentanamide proceeded smoothly with only 0.001 mol%(S/C = 50 000)catalyst.The hydrogenation product was obtained with 98%yield and>99%ee,which is the important structural framework of an anti-hyperlipidemic drug Ezetimibe.3)A new chiral tridentate PNN ligand,[(RC,SC)-SC,RFC]-indan-f-amphox(a sister ligand of(SC,SC,RFC)-f-amphox),was synthesized and has formed an iridium catalyst for the direct hydrogenation of ?-aryl ?-ketoesters.A wide range of ?-aryl ?-ketoesters are reduced by Ir(III)-f-amphox catalyst with excellent enantioselectivities and reactivities(up to 99%ee,10 000 TON).