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

As an important skeleton in asymmetric synthesis,chiral alcohols have a wide range of application,in particular in chiral drug synthesis,which attracts more and more attention to its synthesis methods.Highly efficient and stereoselective asymmetric catalytic hydrogenation(ACH)is one of the most suitable methods for industrial mass production of chiral alcohol compounds due to relatively mild conditions,high reactivity,high selectivity,high atomic economy and easy operation.Therefore,the synthesis of chiral alcohol compounds by a novel ACH process is becoming more and more important.In order to develop a powerful system for asymmetric catalytic reduction of functionalized ketones,based on a series of new dentate ligands with electronic-rich ligands and steric hindrance developed by our group in recent years,iridium-catalyzed asymmetric hydrogenation of the simple ketones and their derivatives has obtained excellent results.Herein,we develop ACH of functionalized ketones with important application,and the research contents are as follows:(1)We successfully developed a highly efficient asymmetric hydrogenation of prochiral halogenated ketones to produce various chiral halohydrins with excellent results under basic reaction condition(up to >99% conversion,99% yield and >99% ee).This asymmetric catalytic methodology can provide versatile and important intermediates,which can be used to prepare pharmaceuticals.In addition,a gram-scale experiment was proceeded smoothly with only 0.005 mol%(S/C = 20 000)Ir/f-amphox catalyst with 99% yield and >99% ee.(2)We successfully developed the Ir/f-Amphol L4-catalyzed asymmetric hydrogenation of a series of benzo-fused five to seven-membered cyclic ketones to prepare the corresponding chiral alcohols with high yields and excellent enantioselectivities(75%-99% yields and 93%->99% ee,up to 297 000 TON).In addition,our Ir/f-Amphol L4-catalyzed asymmetric hydrogenation of benzo-fused cyclic ketones can be applied to provide the key intermediate for the synthesis of the enantiomer of an anticonvulsant drug eslicarbazepine acetate(BIA 2-093)with excellent result(full conversion,99% yield and >99% ee).