Study On The Direct C-H Functionalization With Four-membered Tension Rings And Its Application In The Synthesis Of Drug Skeletons

ObjectiveThe efficient and highly selective construction of C-C and C-X bonds can significantly improve the synthesic efficiency of the target product,which has a positive impact on the synthesis and development of modern drug molecules.Therefore,it should be of great theoretical significance and application value.The progressive development of the transition-metal-catalyzed C-H activation provides more straightforward and atom/step-economical shortcuts toward the direct construction of C-C and C-X bonds.Up to date,multifarious coupling partners(CPs)containing strained rings have been developed and employed in this field,in which they acted as viable reagents featuring high reactivity via the ring-opening processes.Enlightened by these developments and in consideration of our continuing effort in exploring TM-catalyzed selective C-H functionalization for the efficient construction of bioactive molecules,we designed and synthesized a series of four-numbered strained ring cores(e.g.cyclobutane,cyclobutanol)as the CPs in the reaction to realize the selective ring-opening of the four-membered C-C bond via Rh(Ⅲ)-catalyzed,solvent and leaving group-controlled cascade C-H activation.Combined computational and experimental mechanistic studies defined the reaction paths as well as the roles of the strained rings at the CPs in the reactions.Besides,after systematic screening of several parameters such as the catalyst,the solvent,the additive and the proportion of substrates,we also established several efficient routes for one-pot synthesis of a variety of heterocyclic compounds.Furthermore,their antitumor activities against various human cancer cells including Hep G2,A549,MCF-7 and SH-SY5 Y were evaluated and the corresponding action mechanism of the selected compound was also investigated in vitro.Methods1.Designed and synthesized new directing groups and four-numbered strained rings to develop relative C-H bond functionalization reactions based on the established transition metal catalytic system.2.Inspected the reaction,systemtically optimized the reaction conditions,and developed a series of specific C-H bond functionalization reactions to further improve the diversity and compatibility of the reactions and provide practical synthetic strategies for the one-pot construction and subsequent structural modification of bioactive molecules.3.Clarified the corresponding reaction mechanisms by designed experimental investigations and DFT calculations,thus guiding the subsequent optimization of reaction paths and synthetic applications.4.Evaluated the antitumor activities of the obtained compound and identifying the potential anti-tumor drug candidates.Results Part 1 : Rh(Ⅲ)-Catalyzed C-H Activation/Selective Lactone Ring-Opening of Methyleneoxetanones: Chemodivergent Synthesis of Quinolinones and DihydroisoquinolinonesInspired by the existence of the alkene moiety and the lactone unit of methyleneoxetanones,we had developed the Rh(Ⅲ)-catalyzed tunable C-H couplings of aromatic amides with methyleneoxetanones for the synthesis of quinolinones and dihydroisoquinolinones.Combined computational and experimental studies revealed that the substituent attached at the oxidizing directing group plays the important role in tuning the reaction outcomes.Cascade C-H activation/Lossen rearrangement sequences were engaged with N-acetoxybenzamides to furnish the quinolinone skeleton via unprecedented C-C bond cleavage of the four-membered lactone ring,while conventional C-N reductive elimination followed by transesterification led to the formation of a dihydroisoquinolinone framework when N-pivaloyloxybenzamides were used as the model substrates.Part 2 : Rhodium(Ⅲ)-catalyzed Chemoselective C-H Functionalization of N-methoxybenzamide with Methyleneoxetanones Controlled by the SolventA Rh(Ⅲ)-catalyzed and solvent-controlled double C-H functionalization via selective acyl C-O cleavage(β-H elimination)or alkyl C-O cleavage(β-O elimination)of the methyleneoxetanone substrate were described,which provides a straightforward way for the divergent synthesis of chain alkylated benzamides and seven-membered1H-benzo[c]azepine-1,3(2H)-diones in a highly chemoselective manner.Through a series of experimental investigations together with theoretical studies,the effect of the solvent has been systematically elucidated.Part 3:Rh(Ⅲ)-Catalyzed Redox-Neutral [4+2] Annulation for Direct Assembly of3-Acyl Isoquinolin-1(2H)-ones as Potent Antitumor Agents By virtue of an efficient rhodium(Ⅲ)-catalyzed redox-neutral C-H activation/[4+2]annulation cascade of N-methoxybenzamides with propargyl cycloalkanols,diverse3-acyl isoquinolin-1(2H)-ones were directly obtained.This transformation features mild conditions,broad substrate compatibility and specific regio-and chemoselectivity.Considering the biological application potentials of 3-acyl isoquinolin-1(2H)-one skeletons,we also present the in vitro studies of the obtained 3-acyl isoquinolin-1(2H)-ones as the potent anti-tumor agents against diverse human cancer cell lines,among which the selected compounds possessed the potent antitumor effects by inhibiting proliferation and inducing apoptosis of A549,H1299 and H460 cells.Conclusion By virtue of the the transition metal-catalyzed C-H activation reaction system,we have developed several types of C-H functionalization for the one-pot construction of highly valuable organic Structural motifs with controllable selectivity.As demonstrated in below,by utilizing the outstanding features of methyleneoxetanones and rationally tuning the fine structure of the substrate as well as the reaction conditions,we present herein the Rh(Ⅲ)-catalyzed tunable C-H couplings of aromatic amides with methyleneoxetanones for the chemodivergent synthesis of quinolinones,dihydroisoquinolinones,allylated benzamides and benzoazepineones.Combined computational and experimental mechanistic studies revealed the reaction paths and accounted for the selective lactone ring-opening-enabled chemodivergence.This diversity-oriented strategy complemented the synthetic potential of four-numbered strained rings substrates and achieved diverse transformations in constructing heterocyclic ring frameworks.Moreover,in combination with the Rh(Ⅲ)-catalyzed C-H functionalization and unique structure of cyclobutanol,we established the efficient route for one-pot synthesis of a variety of isoquinolinone derivatives.The synthesized compounds were then evaluated against four human cancer cells,including Hep G2(human liver cancer cell line),MCF-7(human breast cancer cell line),A549(human lung cancer cell line),SH-SY5Y(human neuroblastma cell line),and the results demonstrated that such type of compound possessed potent antitumor effect.Undoubtedly,further development of new and highly efficient C-H functionalization strategies to conduct the structural modification of these compounds should have a great chance for the potential “hit”discovery,thus providing a systematic basis for the future development by using isoquinolinones as anti-cancer candidates.