Rh（Ⅲ）-catalyzed C-H Activation Strategy For Synthesis Of Anti-tumor Active Molecules

With the development of medicinal chemistry,the anti-cancer drugs is growing in our live,which significantly improved quality of life.However,due to the functional deficiencies of drugs and the drug resistance of cancer cells make the drug treatment of cancer still have great limitations.Therefore,it is particularly important to develop new,efficient and specific anti-cancer drugs.Traditional strategies for the synthesis of drug molecules usually require pre-functionalized modification of the substrate,with cumbersome synthetic steps and low atomic economy.In the past few years,transition metal-catalyzed C-H activation has been rapidly developed due to its efficient and concise synthesis method,the pioneering use of C-H activation strategy to construct novel drug molecules has effectively reduced the reaction steps and even completed the structures of drug molecules that cannot be synthesized by traditional reaction strategies,and constructed new drug molecule backbones,making a major step forward in drug synthesis.This thesis mainly completed the construction of drug molecules with anti-tumor activity through Rh（Ⅲ）catalyzed olefin C（sp~2）-H activation.The specific research content is as follows:1.The rhodium（Ⅲ）-catalyzed coupling of C-H substrates with iodonium ylides has been realized for the efficient synthesis of diverse cyclic skeletons,where the iodonium ylides have been identified as efficient and outstanding carbene precursors.The reaction systems are applicable to both sp~2 and sp~3 C-H substrates under mild and redox-neutral conditions.Representative products exhibit cytotoxicity toward human cancer cells at nanomolar levels.Through the detection of the anti-proliferative activity of MCF-7,REC-1 and Ramos cells,representative products exhibit cytotoxicity toward human cancer cells at nanomolar levels.,which has great potential for drug development.2.Divergent synthesis of useful skeletons has been realized via rhodium（Ⅲ）-catalyzed C-H activation of iminopyridinium ylides and coupling with various unsaturated coupling reagents.The structures of isocoumarin and isoquinolone were obtained with good yield,and the coupling products with fluorinated olefin could be produced with high selectivity.The anti-tumor activity test results of some isocoumarin substrates reached the nanomolar level,and the fused ring products showed good solid-state fluorescence characteristics.3.The Rh（Ⅲ）-catalyzed carboxylic acid-directed alkene C（sp~2）-H activation is realized.Through the tandem reaction of alkyne insertion/Michael addition in the alkynone structure,the ring-containing exocyclic（Z,E）The cis-hydrogenated benzofuranone structure of the butadiene structure,and the reaction conditions are simple and mild.After testing the anti-proliferative activity of A549 cells（non-small cell lung cancer cells）,some of the product molecules showed good anti-tumor activity,indicating that the core structure has the potential of being a small molecule anti-cancer drug.