Development Of New Reaction Modes Involving Fluorinated Building Blocks And Their Application For The Construction Of Drug Skeletons

BackgroundBiologically active molecules are widespread in natural products,and the heterocyclic skeletons in them are of wide interest among scientists.In response to the concept of "green chemistry",due to the limitations of "green chemistry",scientists have begun to explore and develop simple and efficient new reaction modes.The C-H functionalization-oriented synthesis strategy,which can be green and efficient and maximize the atomic economy,has undoubtedly become one of the synthesis strategies favored by researchers.With the rapid development of organic fluorine chemistry,more and more fluorine-containing compounds are synthesized,and the unique properties of fluorine atoms in the structure of the compound have gradually attracted the attention of chemists,and also created greater opportunities for enhancing the biological activity of heterocyclic drug skeleton molecules.Chemists use C-H activation strategy,with the participation of directing groups and various fluorinated building blocks to obtain the corresponding fluorinated products,or to afford non-fluorinated drug skeletons via defluorination,so as to find the new reaction modes.At present,based on the fluorinated block method has obvious advantages compared with the direct fluorination method,the synthesis of fluorinated block has been developed,which also provides a greater development prospect for the development of the new reaction modes and the synthesis of drug molecular skeletons.PurposeBased on the current research hotspots of C-H activation reactions involving fluorine containing blocks and the previous work of the research group,this study utilizes a simple and easily available directing group to couple with fluorine containing blocks such as gem-difluoroalkene,in order to provide a more simple and efficient synthesis method for synthesizing heterocyclic drug skeleton molecules,and further elucidate the reaction characteristics of gem-difluoroalkene substrates.In addition,by designing new fluorinated blocks and utilizing processes such as C-F bond cleavage,fluorinated or non fluorinated drug molecular frameworks are synthesized.At the same time,due to the special nature of fluorine atoms,unexpected transformation and special regioselectivity often occur.In addition,preliminary biological activities such as antitumor activity were explored for a series of highly functionalized drug skeleton molecules expected to be synthesized.Methods1.Using the simply and easily available substrates and fluorinated building blocks to design and develop new reaction modes;2.Optimize the reaction catalyst,additive,temperature,solvent,etc.,investigate the universality of the substrate and the diversity of the reaction,further explore the synthesis potential of the reaction,and provide an ideal and feasible synthesis path for the efficient construction of drug skeleton molecules;3.Explore the late-stage modification of the products,and preliminarily evaluate the biological activity of the products,so as to provide application potential for the research and development of new drugs in medicinal chemistry;4.Based on relevant literature research,kinetic isotope effects,control experiments and combined DFT calculations were used to explore possible reaction paths and clarify the origins for regulating regio/chemo selectivity.Results(1)Starting from a simple and easily available N-phenoxy-amide substrate,the [3,3]-σ rearrangement occurs with a difluoroalkene under the mediation of cesium carbonate,and the rapid construction of 2-aminobenzofuran skeleton molecules is realized in one step.The reaction involves the process of C-H,O-N and double C-F bond breaking.The substrate has good universality and can be successfully applied to the on-DNA synthesis without transition metal catalysis,which is helpful to promote the application in the DNA coding compound library.Furthermore,the application of the obtained products as potential anticancer agents further demonstrates the versatility of this transformation.(2)Through the design and development of novel gem-difluoromethylene allenes as a multifunction coupling partner,efficient and regio-controlled Rh(Ⅲ)catalyzed C-H bond activation,C-C bond coupling and C-N bond cyclization cascades were achieved,and selective Z-configuration monofluoroenyl isoquinolones and pyridinones were successfully constructed.Density functional theory calculation and experimental mechanism study show that there is a non-covalent weak interaction between the gemdifluoromethylene moiety and OPiv,which is used for unconventional and regionspecific selective control.ConclusionsIn conclusion,based on the C-H functionalization synthesis strategy,we use fluorinated building blocks such as gem-difluoroalkene,gem-difluoromethylene allene as multifunctional coupling partners for efficient construction of fluorinated drug skeleton molecules or non-fluorinated drug skeleton molecules,so as to develop new reaction mode.In addition,we evaluated the bioactivity of benzofuran derivatives and proved them to have preliminary anti-tumor cytotoxicity;explored the kinetic isotope effect,the control experiment and the density functional theory calculation,studied the role of fluorinated group in the reaction process,and provided new ideas for the development of new reaction mode.Therefore,the research in this paper creates more possibilities for the efficient construction of heterocyclic drug backbone molecules and the development of new fluorinated building blocks.