Research On Construction Of Cyclic Molecular Skeleton Of Natural Products By Palladium Catalyzed Allyl Substitution Reaction

As a kind of important organic substances,cyclic compounds widely existed in nature and were closely related to the fields of material chemistry,pharmaceutical chemistry.The diversity of cyclic compounds led to the difference of biological activities and the difficulties of synthesis.Allylic substitution reactions were widely used in cyclization reactions because the ability of constructing C-C,C-N,C-O bonds and other carbon hetero bonds quickly.Decarboxylation cycloaddition generated highly active intermediates in situ,which were widely reported.This thesis focused on the construction of natural product ring molecular skeleton,basing on the palladium catalyzed allyl substitution reaction,the following three aspects have been done:1.Pyrrole were widely used in natural products,drugs and functional materials because of their special physical and chemical activities.Although researchers have reported a lot on the synthesis and application of pyrrole since Paar Knorr reported the first synthesis method,there was still a gap in this field: the flexible construction of multi substituted pyrrole.In this thesis,the palladium/copper double-site catalyzed [4 + 1] cycloaddition reaction of alkynol and aromatic amine successfully solved this historical problem.This method has good universality,could pass through gram scale synthesis in laboratory,and also carry out various forms of transformation,especially can modify bioactive molecules,such as pyrrolation of Ve molecules.Through mechanism experiments,the reactive intermediate-(z)-enynylamine was successfully separated,which showed that the reaction also had an excellent stereoselective effect.2.As the core skeleton of many natural products,aza nine membered ring has great significance in organic synthesis.However,due to the inherent ring tension and the easy occurrence of cross cyclization between / within molecules,it was difficult to synthesize azonane.In this part,palladium catalyzed decarboxylation of vinyl methylene cyclic carbonate to produce 1,5-dipolar active intermediate,through [5 + 4] cycloaddition reaction with azabutadiene to efficiently obtain aza nine membered ring was reported.This method have good regioselectivity,strong group tolerance,mild reaction conditions,and can easily achieve amplification reaction in laboratory with a yield of 81%.It has great potential in transformation research.3.The synthesis of nine-membered carbocycle mainly focus on intramolecular cyclization,a few reports obtained by cocyclization or bridging,while there is only one report on cycloaddition of mono-nine membered carbocycles with non-fused/bridged structure.The challenge comes from the strong rigidity and huge ring tension of the structure itself,as well as the most critical technical barrier: the synthesis of all carbon dipoles with strong nucleophilic activity.In order to overcome this barrier,we designed and synthesized a new carbonate substrate,which was decarboxylated under the catalysis of palladium to form an allyl palladium active intermediate.This intermediate can form stable carbon anions through enol tautomerism,to realize the preparation of all carbon five dipoles,and reacted with butadiene to realize [5 +4] cycloaddition reaction to synthesize mono-nine membered carboncycles for the first time.By adjusting the reaction conditions,the high-efficiency synthesis of the kinetic dominant product nine membered ring,and the thermodynamic dominant product seven membered carbon ring,could synthesized respectively.This reaction has high regioselectivity and strong substrate tolerance.It can also realize the laboratory scale-up synthesis,which is of great significance in organic synthesis and drug application.