New Ru-Catalyzed Dynamic Kinetic Resolution-Asymmetric Transfer Hydrogenation Reaction And Its Application In Pharmaceutical Synthesis

Chirality is extremely important because today a great amount of marketed drugs are chiral.The stereoisomeric composition of drug substances has become a critical issue in the development,approval,and clinical use of drugs.Follow the reasons above,over the past decades,stereoselectivity in drug synthesis has become a well-recognized consideration and hot research area.Beside classic kinetic resolution,various asymmetric catalysts are developed which greatly expand the source of chirality.Among these work the asymmetric hydrogenation become the center of attention due to its high atomic economy and broad applicability of substrates.In the thesis,we have developed three new series of substrates and explored new diamine Ru-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenations(DKR-ATH)method to synthesize chiral inidoleanoate,β-substituted-α-ketamide and 2-substituted 3-quinolones:1.Stereogenic cis-2-substituted-N-acetyl-3-hydroxy-indolines via ruthenium(Ⅱ)-catalyzed DKR-ATHThis work firstly describes about using DKR-ATH to prepare enantiomerically pure indolines through asymmetric transfer hydrogenation(DKR-ATH).Ruthenium(Ⅱ)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation of racemic 2-substituted-N-acetyl-3-oxoindolines to cis-2-substituted-N-acetyl-3-hydroxyindolines is reported.Using homochiral {Ru[TfDPEN](p-cymene)} catalyst with S/C=400 in HCO2H/Et3N mixture,the product with up to>99.9%ee and>99:1 dr are obtained in high yields(79-98%).2.Ru(Ⅱ)-catalyzed asymmetric hydrogenation of β-substituted-a-ketoamide.(R,R)-1 has excellent selective hydrogenation activity for β-substituted-a-ketoamide,and it can be used for various substrates.The substituents on the substrate can not only be alkyl,benzyl,but also be suitable for aliphatic groups.In addition,it has excellent stereoselectivity(ee value is more than 99%,dr value is 98:2)for five membered cyclolactam,ee value is more than 99%for six membered and seven membered cyclolactam,dr value is more than 88:12.After the subsequent derivatization reaction,the ee and dr values of the product can be well transmitted,and the stereoselectivity is basically not lost.3.Ruthenium-catalyzed highly enantioselective synthesis of cis-3-quinuclidinols via DKR-ATHA method for the enantioselective synthesis of cis-3-quinuclidinols by Ru-catalyzed DKR-ATH is described.The reaction proceeds under mild conditions using ammonium formate as the hydrogen donor,affording the products in high yields(up to 99%)with excellent diastereoselectivity(up to 99:1 dr)and enantioselectivity(95-99%ee).This protocol is applicable to gram-scale preparation with perfect enantioselectivity through simple recrystallization.we also got one of the single crystal structure to confirm the exact stereostructure of the productIn this thesis,two chiral centers have been constructed simultaneously by using chiral diamine Ru catalysts and DKR-ATH reaction system.The system involved HCOONH4 or HCOOH/Et3N as hydrogen source,common solvents,and moderate reaction temperature,avoids the risk caused by hydrogen gas,leads to less pollutions,and is crucial to the development of key intermediate reaction and green technology for an important medicament,which provides an important technical choice in high efficient and green manufacturing for the key APIs in the future.