Enantioselective [4+1] Annulation Reactions Of α-substituted Ammonium Ylides To Construct Spirocyclic Oxindoles

Since Aggarwal firstly reported accessing enantioselective epoxides with chiral sulful ylide using aldehydes in 1996, Ylide chemistry has received extensive attention from the synthetic community. A variety of chiral ylides, such as sulfur, phosphorus, nitrogen, and tellurium, etc, have been widely used in many asymmetric reactions. However, the ammonium ylides mediated asymmetric reactions are comparatively less developed, and a few examples are limited to asymmetric [2+1] cyclopropanations and aziridinations by treatment of simple ?-halogenated ketones or esters with electrophiles under the participation of chiral tertiary amine. Meanwhile, ?-substituted ?-halogenated precursors, which construct products bearing quaternary center or spirocyclic skeleton, are still to be developed. In this paper, asymmetric [4+1] annulation reaction of 3-bromooxindoles and electron- deficient 1-azadienes has been developed the first time through ammonium ylide catalysis of a newly designed 2-methyl ?-isocupreine(?-MeIC), efficiently delivering spirocyclic oxindole compounds incorporating a dihydropyrrole motif in desirable enantioselectivity(up to 99% ee). To our knowledge, this work represents the first example of asymmetric catalysis of ammonium ylides bearing ?-substitutions and the [4+1] annulation pathway of ammonium ylides. Moreover, the mass spectroscopy and computational calculation studies were applied, through which the catalytic cycle and enantioselective mechanism were demonstrated.This work provided a variety of efficient synthetic protocols for the construction of chiral products bearing quaternary center or spirocyclic skeleton, which is a common structure in a number of biologically important compounds. Applying this novel synthesis strategy, a library of complex chiral compounds can be developed and provides substances for further biological activity studies.The reaction condition for high chemo- and enantioselectivity was optimized by screening the type of catalyst, solvents, concentrations, temperatures and so on based on the common protocols of asymmetric synthesis. The scope of subtracts and reaction activity were also examined. The characteristic methods include NMR, LC-MS,HPLCand HRMS.