Synthesis Of Chiral N-Sulfonyl-α-Amido Boronic Esters And 4-Substituted Tetrahydroquinolines Via Rhodium/Ruthenium-Bisphosphine Ligand-Catalyzed Asymmetric Hydrogenation

Chiral compounds play an important role in life activities.Asymmetric hydrogenation is one of the most efficient methods for synthesizing chiral compounds.Based on the problem of difficult synthesis of chiral compounds with high stereoselectivity,this dissertation aims to synthesize bioactive ingredients chiral N-sulfonyl-α-amido boronic esters and natural product skeleton 4-substituted tetrahydroquinolines via transition-metal/bisphosphine ligand-catalyzed asymmetric hydrogenation.Focusing on characteristics of substrates,structural of bisphosphine ligands and control of reaction conditions,the target molecules are constructed through a green and efficient pathway.The main research results are as follows:1.Rh/L6-catalyzed asymmetric hydrogenation for synthesizing chiral N-sulfonyl-α-amido boronic estersFocusing on the problems of low synthesis efficiency and difficult process scale-up for multi-bond construction and multi-reagent use,in the first part of research work,using the self-synthesized（Z）-N-sulfonyl-α-dehydroamido boronic esters as the novel substrates,the asymmetric hydrogenation catalyzed by rhodium/bisphosphine ligands was intensively studied,and the efficient synthesis of chiral N-sulfonyl-α-amido boronic esters was realized.After studying the repeatability of asymmetric hydrogenation in preliminary work,it was found that the reagent quality of the metal precursor Rh（cod）₂BF₄ had a significant influence on the reactivity of the reaction Through the preliminary screening of five common chiral bisphosphine ligands,it was found that the Josi Phos-type ligand with ferrocene backbone had a better catalytic effect.Further ligand screening experiments showed that the dialkyl-substituted Josi Phos-type bisphosphine ligand L6 was the optimal catalyst.After investigation of temperature and pressure,the optimal conditions of the reaction were finally established:room temperature,Rh（cod）₂BF₄/L6 as catalyst,dichloromethane as solvent and H₂（30 atm）as a reducing agent.Under optimal reaction conditions,17 chiral N-sulfonyl-α-amido boronic esters were synthesized with good yields（67-99%）and excellent enantioselectivities（91-99%ee）.The reaction was successfully carried out on a gram scale with a reduced catalyst equivalent to 1 mol%.The product of asymmetric hydrogenation was smoothly converted into chiralβ-amido boronic esters with important medical value and chiralβ-amino alcohols,which commonly used as chiral auxiliary reagents and catalysts.In addition,the PMB on the nitrogen atom could be easily removed under acidic conditions,and the deprotected product could be converted into potassium fluoroborate,a commonly used substrate of the Suzuki coupling.Compared with other synthesis methods,the synthesis of chiral N-sulfonyl-α-amido boronic esters by asymmetric hydrogenation does not require the construction of carbon-nitrogen bonds or carbon-boron bonds,avoiding the use of a large number of organic amines and organic boron reagents,which will result in easier process scale-up.2.Ru/dtbm-Seg Phos-catalyzed asymmetric hydrogenation for synthesizing chiral 4-substituted tetrahydroquinolinesFocusing on the problem that the stereoselectivity of 4-position of tetrahydroquinolines is difficult to control,in the second part of research work,using the self-synthesized N-protected 1,2-dihydroquinolines as substrates,the asymmetric hydrogenation catalyzed by ruthenium/bisphosphine ligands was intensively studied,and the efficient synthesis of chiral 4-substituted tetrahydroquinolines was realized.Through the screening of five axial chiral bisphosphine ligands,it was found that dtbm-Seg Phos,an electron-rich ligand with a small dihedral angle,had a better catalytic effect.Through the investigation of six protecting groups on nitrogen atoms,it was proved that the reaction obtained the best stereoselectivity with the acetyl group.The product obtained a better enantioselectivity with toluene as the solvent,due to its weak polarity.Through investigation of temperature and pressure,the optimal conditions of the reaction were finally established:40℃,Ru[（R）-dtbm Seg Phos]（OAc）₂ as catalyst,toluene as solvent and H₂（50 atm）as a reducing agent.Under optimal reaction conditions,18 chiral 4-substituted tetrahydroquinolines were synthesized with excellent yields（95-99%）and enantioselectivities（87-99%ee）.The reaction was successfully carried out on a gram scale with a reduced catalyst equivalent to 0.1 mol%.Through deuterated experimental,the reaction mechanism of migration insertion,β-H elimination and re-migration insertion was proposed.The product of asymmetric hydrogenation was smoothly converted into a valuable drug synthon,chiral4-hydroxytetrahydroquinoline.In addition,the acetyl on the nitrogen atom was easily removed under acidic conditions,resulting in a key intermediate of the male hormone receptor modulator LG 121071 Compared with other synthesis methods,the synthesis of chiral 4-substituted tetrahydroquinolines by asymmetric hydrogenation is more straightforward and more atomically economical,and can better achieve chiral control of 4 position of tetrahydroquinolines.In conclusion,through rational design and system optimization,17 chiral N-sulfonyl-α-amido boronic esters and 18 4-substituted tetrahydroquinolines were synthesized with excellent activity and enantioselectivity via asymmetric hydrogenation catalyzed by transition metals and chiral bisphosphine ligands.Gram-scale synthesis,derivatization and deprotection experiments proved the practical value of the methodology.Based on the nitrogenous organic building blocks,this dissertation provides useful enlightenment for asymmetric synthesis methodology and related drug development.