Three-component Isatin-derived Ketimine Trapping Aromatic C-H Bond Functionalized Zwitterion Intermedaite:An Efficient Access To 3-amino-3'-arylbioxindole

The oxindole structure is widely distributed in natural products,pharmaceuticals and pharmaceutically active compounds,and its absolute configuration and substituents at the stereocenter of the oxindole's C3 position have a significant effect on biological activity.Functionalized oxindole is also widely used in the synthesis of starting materials for a variety of heterocyclic compounds.Therefore,previous studies on the enantioselective synthesis of this prominent structural skeleton have been extensively studied.The dioxindole skeleton is an important derivative of oxindole,and is often used in pharmaceutical reagents and natural products because of its good biological activity.However,there are relatively few methods for constructing such compounds due to limitations of chemical synthesis.In particular,there is a lack of efficient synthesis methods.Therefore,the development of an efficient,convenient,and mildly prepared methods for the preparation of dioxindole derivatives has received continued attention from chemists.The quaternary carbon center plays an important role in natural products and pharmaceutically active molecules,and these molecules exhibit better physical and chemical properties and biological activities due to the presence of quaternary carbon centers.Therefore,the construction of quaternary carbon and continuous quaternary carbon has become a research hotspot in synthetic chemistry and medicinal chemistry.Dioxindole and continuous quaternary carbon are extremely challenging in terms of synthesis due to their large steric hindrance effect.Therefore,the synthesis of antimony bismuth containing continuous quaternary carbon is especially rare in these literatures.In a few reported cases,the synthesis method is usually inefficient or requires strong reaction conditions such as strong base to overcome the large steric hindrance effect.In response to these key scientific issues,this paper intends to develop a mild,convenient and efficient method for synthesizing dioxindole derivatives containing continuous quaternary carbon.The first chapter of the paper introduces the important role of dioxindole in the natural product in medicine and the construction method of dioxindole.Among them,the dioxindole structural compound is a precursor of many alkaloids,but less related literature reports.At the same time,the construction methods of building dioxindole containing quaternary carbon are introduced,including single quaternary carbon dioxindole and continuous quaternary carbon dioxindole.However,dioxindole containing continuous double quarternary carbons is blocked by its ortho-doublequaternary carbons,which makes it difficult to construct,so there are few reports in related literature.Based on the existing research of Hu Wenhao's research group,we have constructed a double-quaternary carbon dioxindole structure compound in one step by means of electrophilic reagents to capture the zwitterion-intermediates.In the second chapter,we used a Ruthenium(II)-catalyzed eosinimine to capture the three-component reaction of an active intermediate formed by N,N-disubstituted aniline with a diazonium compound at room temperature.Under the conditions,a continuous quaternary carbon dioxindole structure compound was constructed from a simple compound in one step.The reaction has a broad substrate range,the yield is up to 99%,and the diastereoselectivity is as high as 20:1.The reaction mechanism was explored through a series of controlled experiments,and the possible reaction pathways were proposed.The asymmetric catalytic reaction of the reaction was also explored,providing guidance for the development of such asymmetric catalytic reactions.The developed reaction not only provides a high-recovery,one-pot condition mild and high diastereoselective synthesis method for the convenient construction of 3-amino-3-aryl continuous quaternary carbon dioxindole compound.It enriches the research strategy of multi-component new reactions based on active intermediates.In the third chapter,we conducted a preliminary study on the bioactivity of the synthesized quaternary dioxindole derivatives,indicating that at least four of these compounds showed good inhibitory activity against breast cancer metastasis and at least nine of these compounds showed good inhibitory activity against osteosarcoma cells.The fourth chapter is the experimental part.