Visible-Light Catalyzed Nitrogen-Centred Radical Cascade Reaction And Its Application In Synthesis Of Indole Alkaloids

This thesis is about the visible-light catalyzed nitrogen-centred radical cascade reaction and its application in the synthesis of indole alkaloids.Nitrogen-containing heterocycles play an important role in heterocyclic compounds.Many natural products,drugs,and biologically active compounds contain at least one nitrogen heterocycle.Among numerous research results,N-radicals,as highly active reaction species,have the potential to undergo chain reactions and are suitable for the construction of complex nitrogen-containing polycyclic systems.Traditional methods for generating N-radicals are based on the reductive cleavage of relatively weak N–X（N–N,N–O,N–S,N–Cl or Br）bonds,or the oxidative cleavage of N–H bond.Those methods usually require the use of stoichiometric radical initiators,strong oxidants,high temperature pyrolysis or strong ultraviolet photolysis,thus limiting the application of nitrogen radical reactions.Over recent years,visible-light catalyzed radical reactions have received extensive attention in the field of organic synthesis.Since visible-light photocatalysis is a powerful tool to achieve multiple chemical transformations via versatile highly reactive intermediates under mild conditions,it becomes a popular method to construct carbon-carbon and carbon-heteroatom bonds.Although the field of visible-light catalysis to generate N-radicals has developed rapidly,most of the research results are about breaking the N–X bonds to generate N-radicals.Such methods require the use of unstable precusors or pre-installation of activating groups at the nitrogen atom,which have limitations in functional group compatibility or substrate scope.Therefore,the development of a mild,efficient and atom-economic method for the generation of N-radical by visible-light catalyzed cleavage of N–H bond is of great value and significance for the field of radical chemistry and synthetic chemistry.With the purposes mentioned above,this thesis developed a visible-light catalyzed N-radical cascade reaction:under the radiation of blue LEDs,Ir（dtbbpy）（ppy）₂PF₆ was used as a photocatalyst,degassed tetrahydrofuran as the solvent,KHCO₃ as a base,the readily available substrate S11was converted into N-radical through a single electron transfer（SET）process,then the resultant N-radical underwent intra-intermolecular radical chain reaction with the Michael acceptors to afford a series of tetrahydro-β-carboline products with high efficiency and selectivity.This method can generate N-radical directly by visible-light catalyzed cleavage of N–H bond under mild conditions and construct a chiral tetrahydro-β-carboline skeleton with high efficiently,which has great potential for application.One of the purposes of chemical research is application.It is an important goal for synthetic community to develop new chemical reactions which could be applied to the synthesis of materials,new drugs and bioactive natural products.The above-mentioned visible-light photocatalyzed N-radical cascade reaction has been successfully applied into the synthesis of the following indole alkaloids:1)By using visible-light photocatalytic intra-intermolecular radical cascade reaction,starting from photocatalytic product 259a,the synthesis of（+）-harmicine was efficiently performed in 6 steps and 39%total yield;2)After delicated experimental design and optimization of synthetic route,substrate 382 was prepared,and the intra-intramolecular radical cascade reaction was realized to obtain the key intermediate 383,in which the tetracyclic skeleton and the C20 quaternary center was efficiently constructed,and the stereoselectivity of C21 was controlled.The key intermediate 383 was used for the first asymmetric total synthesis of complex natural products（–）-eburnaminol,（+）-larutenine,（–）-terengganensine B,（–）-strempeliopine,and formal synthesis of（–）-terengganensine A in 6 steps,7 steps,6 steps,7steps and 8 steps respectively;3)With the substrate designed and condition screened,compound 438 containing an alkyne chain was used as a photoreaction precursor to realize the intra-inter-intramolecular radical cascade reaction with MVK.（+）-16,17,20-epi-deserpidine（451）and deserpidine derivative 457were successfully synthesized in 11 steps and 10 steps respectively.The successful development of the the above photocatalytic reaction and its application in total synthesis of indole alkalids are progressive and complementary,which demonstrate the methodology in this thesis has broad application prospects in synthetic chemistry.