Pd-Catalyzed Dipolar Cycloadditions:Construction Of Heterocycles Bearing Chiral Quaternary Stereocenters

Heterocyclic compounds as a kind of common structural units exist widely in pharmaceutical active molecules and natural products.Therefore,the efficient synthesis of heterocyclic compounds has been the research focus of chemists.Palladium-catalyzed dipolar cycloaddition reactions have attracted more and more attention in recent years because of their high efficiency and high selectivity in obtaining complex product from simple and easily available starting materials.In this dissertation,the latest research advances in this field were reviewed,and the Pd-catalyzed dipolar cycloadditions for asymmetric synthesis of heterocyclic compounds with quaternary stereocenters were investigated based on three aspects:the reasonable design of chiral ligands,the introduction of photoactivation process and the reasonable selection of dipole precursors.First,we used vinyl benzoxazinanones as precursor of Pd-stablized dipoles,with the chiral P,S ligand developed by our group as the best ligand,the in situ generated 1,4-dipoles would undergo[4+2]cycloaddition reaction with electron-deficient olefins having two different electron-withdrawing groups.This method provided an efficient access to a series of tetrahydroquinolines owning three contiguous stereocenters including a quaternary stereocenter.Meanwhile,the control experiments showed that chiral thioether backbone is the vital for achieving stereoselectivity induction,and phosphoramidite structure is the core of catalytic activity of the ligand.In addition,we proposed a possible transition state with the help of two-dimensional NMR and DFT calculation.Moreover,we gave a reasonable explanation for the high diastereoselectivity of the reaction.Subsequently,we successfully combined visible light-induced Wolff rearrangement with palladium-catalyzed dipole reactions.With readily accessible ?-diazo ketone as starting material,ketene as a kind of active intermediate could be generated via Wolff rearrangement under visible light irradiation.Then ketene would act as dipolarophile to react with vinyl benzoxazinanones in the presence of palladium and chiral P,S ligand,which provide efficient access to a series of quinolinones containing an all-carbon stereocenter.In order to further study the reaction,we first conducted the UV-vis absorption experiment of ?-diazo ketone to prove that the reaction is a visible light activation process,and then successfully tracked the reaction process with the light on-off experiment and NMR experiment.In addition,the decomposition and control experiments of diazo and ketene compounds were carried out to explain the key to achieve high chemoselectivity.It is worth mentioning that the visible light flow reaction device independently designed by our group were used to realize scaled up experiment of this reaction.Under the irradiation of sunlight,gram scale reaction could be successfully achieved with the yield and stereoselectivity unaffected.Finally,we applied vinyl ethylene carbonates as dipole precursor in the sequential process of visible light photoactivation and palladium catalyzed dipole cycloaddition.It is worth mentioning that the generated palladium stabilized dipole would serve as 1,5-dipole to participate in[5+2]cycloaddition reaction,synthesizing a variety of seven-membered cyclolactones containing all-carbon quaternary stereocenters with up to 99%yield and 92%enantioselectivity.Furthermore,the mechanism of the reaction was preliminarily studied by means of nonlinear effect experiment and ESI-MS analysis experiment of palladium complex.Besides,the possible transition state was proposed according to the absolute configuration of the product.