Asymmetric Recation Of Benzoisothiazole Derivatives With Azomethine Ylides By Silver/(S,S)-IP-FOXap

Benzosultams are an important privileged class of structures in drug discovery,and are attractive synthetic targets due to their biological activities and intermediates for constructing molecular complexity and diversity.The catalytic asymmetric 1,3-dipolar cycloaddition reaction plays a crucial role in the enantioselective preparation of five-membered heterocycles.More specically,the asymmetric 1,3-dipolar cycloaddition of azomethine ylides with activated olefins has become one of the most powerful methods for the construction of chiral spirocyclic pyrrolidines containing spiro quaternary stereogenic centers,which represent the key structural moiety widely present in a myriad of natural products and biologically active compounds.The main work that we have accomplished is as follows: 1-methyl-1,3-dihydro-benzoisothiazole-2,2-oxides was obtained with 2-bromoaniline as raw material.Benzoisothiazole-2,2-dioxide-3-ylidene derivatives were obtained by Knoevenagel condensation of aliphatic aldehydes and aromatic aldehydes with 1-methyl-1,3-dihydro-benzoisothiazole-2,2-oxides.Glycine methyl ester hydrochloride or glycine tert-butyl ester was used as the substrate,different kinds of imines were prepared by condensation reaction with aromatic aldehydes containing different substituents and aldehydes with heterocyclic structures.The effects of different substituents on the yield of the reaction were explored and analyzed.The preparation of 3-substituted methylene-2,1-benzosultams as pro dipolarbody,1,3-cycloaddition and methylenimine ylides,discusses the influence of different types of methylenimine ylides with different functional groups of benzosultams derivatives of 1,3-cycloaddition reaction.On this basis,study on the asymmetric 1,3-dipole substituted methylene benzosultams and methylenimine ylide cycloaddition reaction.To explore the types of silver,two phosphine ligands,the yield of dioxadiazoline ligands and two ferrocene type ligand catalyst reaction to asymmetric catalysis and influence on the enantioselectivity,found silver acetate product two ferrocene catalyst in toluene solvent yield and enantioselectivity.By screening the optimal reaction temperature and the best reaction conditions such as alkali,synthesis of a new spiro pyrrole benzosultams compounds.With benzoisothiazole-2,2-dioxide-3-ylidene derivatives as the dipolarophiles and azomethine ylides as dipoles,novel spiro benzoisothiazole dioxide derivatives were synthesized under a chiral condition,in which silver acetate /(S,S)-ip-FOXAP catalyzed system was used as the chiral catalyst.Reaction has a good regioselectivity and enantioselectivity,enantioselectivity of the highest ee value 98%,non the enantioselectivity is greater than 99:1.Found the benzene ring methylenimine ylides with the substituents,the reaction yield and enantioselectivity was significantly higher than that of ortho and meta substituent,showed that the steric and electronic effect on the reaction of benzene with different substituents have a certain influence.Study of different prodipolarbody found the benzene ring double bond substituent groups on the non reaction has no effect on the enantioselectivity,while prodipolarbody with alkyl and furan group involved in the reaction,the reaction yield and decreased enantioselectivity of The new compounds were characterized by 1H NMR,13 C NMR and HRMS.The absolute spatial configuration of target compounds was determined by single crystal X-ray diffraction of compound 13 m,and the reaction mechanism of silver acetate/S,S-ip-FOXA reaction was proposed.This study is of great significance for the asymmetric catalytic 1,3-dipolar cycloaddition reaction and the synthesis of benzenesulfonamide compounds,and further explore the biological activity of these compounds.