Synthesis Of Enantioenriched Fluorinated Compound By Transition Metal Catalysed Asymmetric Hydrogenation

As a biological isostere of carbonyl and other polar functional groups,introducing the gem-difluoromethylene group into target molecules can change the pharmacological properties of drug molecules and improve their biological activity;Meanwhile,the trifluoromethylthio group with the highest Hansch hydrophobicity coefficient（π=1.44）displays unique physical and chemical properties（such as enhancing the penetration of cell membranes,improving the metabolic stability of drugs）,and often be introduced into various types of drugs and biologically active molecules.The chiral recognition in organisms would leads to different pharmacological activities with different configurations of drug molecules.Thus,developing some synthesis methods to synthesize compounds containing methyl difluoroma methyl or trifluoro methyl groups is of great significance.Catalytic asymmetric synthesis constitutes one of the most efficient methods of preparing such two types of chiral fluoro-containing molecules.Although considerable progresses have been made towards this direction,there still remains some limitations including narrowed substrate/product scope.Therefore,the purpose of this thesis is to construct chiral gem-difluoromethylene-and trifluoromethylthio-based compounds by using transition metal-catalyzed asymmetric catalytic hydrogenation.The detailed research works are as follows:（1）An enantioselective hydrogenation ofα,α-difluoro-β-arylbutenoates catalyzed by Pd（OAc）₂/（S）-Difluorphos/H⁺was achieved,affording a series ofα,α-difluorinated carboxylic esters in high yields with moderate to good er values.The mild conditions,wide substrate applicability and strong functional group compatibility highlight the practicability of this protocol.Control experiments have shown that the difluoromethylene group in the substrate is a key factor for chiral control in the reaction system.With the catalytic system of Ni（OAc）₂·4H₂O/（S）-Binapine,the asymmetric hydrogenation reaction ofα,α-difluoro-β-arylbutenoates is realized,providing the desired product in 83-99%yields and 19:81-8:92 er values.（2）By combining achiral and chiral ligands,the asymmetric hydrogenation reaction of（E）-β-trifluoromethylthio-α-aryl acrylic acids using the catalytic system of Rh（cod）₂BF₄/L23/PPh₃ was realized,and a class of enantioenriched trifluoromethylthio-containing compounds were afforded in 82-92%yields and 88:12-99:1 er values.The catalytic system was also been applied in the asymmetric hydrogenation of（Z）-α-trifluoromethylthio-β-aryl acrylic acids,giving the target product in 91%yield and 95:5 er value.