Synthesis Of Novel Tridentate PNN Ligands F-Amphox And Its Application In Asymmetric Hydrogenation Of Ketones

Chiral alcohols are important intermediates and building blocks in organic chemistry.These compounds have been widely used as pharmaceuticals,pesticides,natural compounds and functional materials.In terms of atom efficiency,the asymmetric hydrogenation of prochiral ketones is one of the most effective methods for the construction of chiral alcohols.Since the Noyori’s catalytic systems was reported,transition-metal-catalyzed homogeneous asymmetric hydrogenation of ketones has achieved great success in the past nearly 30 years.Many excellent catalysts and ligands have been applied to synthesize chiral drugs and organic intermediates in industry.Ru-catalyzed asymmetric hydrogenation of ketones has been dominant in a long period of time.Until recent years,some complexes of iridium and the cheap metal Fe,Co,Ni etc have been applied to the asymmetric hydrogenation of ketones and made certain progress.Especially,some excellent bidentate ligands,tridentate ligands and multidentate ligands have achieved high activity and enantioselectivity in Ir-catalyzed asymmetric hydrogenation of ketones.Many excellent catalytic systems always exist some problems.Some of ligands and catalysts are unstable and difficulty in synthesis,others need the high catalyst loading and have narrow substrate scope.In addition,some ketones,such as the asymmetric hydrogenation of simple aliphatic ketones with highly efficient and enantioselectivity remains unresolved.Therefore,it is still necessary to develop a series of low-cost and easily accessible catalyst to hydrogenate various ketones with high efficiency and stereoselectivity.In order to develop privileged catalysts to reduce ketones,we have synthesized a series of novel tridentate PNN ligands.These ligands are stable to air,easy to synthesis,rich electronic and sterically hindered.We successfully applied iridium complexes of these ligands into asymmetric transformation of various ketones.It provided a new powerful catalytic strategy to asymmetric hydrogenation of ketones,and afforded the guidance for the design of new ligands.The research contents are as follows:1)We designed and synthesized a class of novel tridentate ligand f-amphox containing chiral ferrocene and chiral oxazoline.These ligands are stable to air,easy to synthesis,rich electronic and sterically hindered.We successfully applied iridium complexes of f-amphox into asymmetric hydrogenation of simple ketones and functional α-hydroxy ketones to afford corresponding chiral alcohols with excellent results(>99%conversion and>99%ee).The catalytic system is extremely activity,for a-hydroxy ketone reach an unprecedented 1 000 000 TON.Besides,the catalyst is effective to heteroaryl ketones with strong coordinating group(>99%ee,10 000 TON).The density functional theory(DFT)calculations have explained to the efficiency of the catalyst and the source of the chirality.2)In view of the excellent performances of Ir-f-amphox catalyst in asymmetric hydrogenation of simple ketone and α-hydroxy ketone,we used the catalytic system to prepare importantly chiral β-amino alcohols via DKR process.The asymmetric hydrogenation of a series of racemic a-amino β-unfunctionalized ketones can be achieved>99%conversion,>99%ee and 99:1 dr value catalyzed by Ir-f-amphox.Experiments show that the catalyst has high catalytic activity and strong resistance to poison effect,and it can reach 100 000 TON in this asymmetric hydrogenation.In addition,the catalyst is effective to many substrates with strong coordinating group and can obtain corresponding chiral alcohols containing two adjacent stereocenters with excellent enantioselectivities and diastereoselectivities.