Transition-Metal-Catalyzed Inverse-Electron-Demand Cycloadditions

Heterocyclic units are widely present in many natural products,drug molecules and functional materials.Therefore,it’s an important research content of synthetic chemistry to develop efficient method to synthesize functional heterocyclic products.The transition metal catalyzed dipolar cycloaddition reaction is an effective way to realize the construction of heterocycles.The synthesis of five to twelve membered rings havs been successfully constructed,through the unremitting efforts of chemists.Most of these reactions are initiated by the electrophilic addition of metal-stable zwitterionic intermediates to electron-deficient substrates(such as aldehydes,imines,isocyanates,electron-deficient olefins or ketenes,etc.),and then through intramolecular ring-closing reactions to achieve the construction of heterocycles.We believe that theoretically metal-stable zwitterionic intermediates can first react with nucleophiles(such as sulfur ylides,enamines,amines or enols,etc.),and then close the ring within the molecule,thereby realizing the "inverse-electron-demand" dipolar cycloaddition reaction.This dissertation focuses on the "inverse-electron-demand" dipolar cycloaddition reaction,and conducts related research on the metal-stable dipolar cycloaddition reaction in the field of chiral heterocycles and the construction of the medium-sized ring.Brsides,it provides a new method for further enriching the transition metal-catalyzed dipolar cycloaddition chemistry and the efficient method for the construction of heterocyclic compounds.In the first part,we designed and synthesized vinyl aminoalcohol as a more atom economic 1,4-dipolar precursor.Under the synergistic catalysis of iridium complex and amine catalyst,we successfully developed[4+2]cycloaddition reaction with high yield and enantioselectivity to form quinoline hemiaminals architecture.Then using hemiaminals as common intermediate,it is efficiently converted into a variety of chiral tetrahydroquinoline or quinolinone products in a one pot-two step transformation.Unlike the previous cycloaddition,which was mainly palladium catalysis,this is a dipolar cycloaddition that uses an iridium catalyst to realize the "inverse-electron-demand" dipolar cycloaddition reaction.At the same time,the[4+2]cycloaddition reaction of the transition metal Iridium and amine was achieved by using vinyl aminoalcohol as 1,4-dipolar precursor and β,γ unsaturated ketone.Furthermore,by adjusting the configuration of the Iridium catalyst ligand and the configuration of the primary amine catalyst,we prepared all the stereoisomers of chiral tetrahydroquinoline with moderate to good yield and high enantioselectivity and distereoselectivity,and realized the stereodiversity control of non-adjacent chiral centers.Subsequently,chiral morpholine framework was synthesized by[3+3]cycloaddition reaction of acetylene ethylene carbonate and 3-oxetanamine though asymmetric propargyl amination/desymmetrization ring-opening with copper catalysis and acid promotion.By using the Pybox chiral ligand modified by the C5 diphenyl group,the high enantioselectivity synthesis of chiral tertiary amines is realized and converts into chiral morpholine compounds in situ.The efficient construction of the medium-sized ring skeleton is another important challenge in the field of heterocyclic synthesis.We use vinyl aminoalcohol and 2-carbonylcyclobutanone as starting materials,through asymmetric allyl alkylation catalyzed by transition metal iridium and Lewis acid,combined with a base-promoted ring expansion reaction,to achieve formal asymmetric[4+4]cycloaddition reaction.We screened a variety of organic and inorganic bases,and finally obtain chiral hexahydrobenzodiacine derivatives with high yield and high enantioselectivity and diastereostereoselectivity.Finally,we used 2-ethynyl epoxyhexyl ring and in situ generated ketene from α-diazo ketone via visible light promoted Wolff rearrangement as starting materials,and the[3,3]ketene-Claisen rearrangement reaction occurred in the presence of Lewis acid to successfully construct a ten-membered allene lactone.