The Squaramide-catalyzed Michael/cyclization Tandem Reaction For The Synthesis Oftetrahydrobenzofuranones

Asymmetric tandem reaction,which means the reagents taking place in multistage continuous steps in the presence of chiral catalysts,could achieve transformation from simple compounds to the complex.It is an efficient,economical and green method to build multiple chemical bonds and stereocenters.Recently,this bio-inspired synthesis has been widely explored as a promising approach for drugs and a variety of natural products.Trifluoromethylated hydroxyimino tetrahydrobenzofuranones represent privileged biological activities and chemical applications compared with other natural compounds due to their unique structural features.For the construction of such target chiral molecules with versatile functional groups,asymmetric tandem reaction has fully demonstrated its superiority to the general synthetic methods: simple and easy operation,no group protection and deprotection,no need to isolate the reaction intermediates in the process.Asymmetric tandem reaction catalyzed by small organic molecules has been extensively developed in asymmetric reaction.Structures with multiple stereocenters could be efficiently prepared by asymmetric tandem reaction catalyzed by organocatalyst,which is of great significance and practical value for the synthesis of diversity physiological molecules.This paper focused on the enantioselective Michael/cyclization tandem reactionof 1,3-cyclohexanediones with ?-CF3-?-disubstituted nitroalkenescatalyzed by squaramide bifunctional organocatalyst.Based on the bifunctional organocatalysts evaluation,1,2-cyclohexanediamine derivative Cat.II showed good catalytic activity.Through detailed screenings of other reaction conditions,a combination of 10 mol% Cat.II,dichloromethane as solvent and-10 ? was chosen as the optimized condition.Under the optimized condition,the scope of the reaction was tested.Nearly all the chosen substrates,including 2 kinds of 1,3-cyclohexanediones and 10 kinds of ?-CF3-?-disubstituted nitroalkenes,could reacted smoothly to obtain corresponding chiral trifluoromethylated hydroxyimino tetrahydrobenzofuranones with good yields(up to 81% yield)and enantioselectivities(up to 89% ee).The absolute configuration of the product was unambiguously assigned as R-configuration by single crystal X-ray analysis.According to the reported literatures and the X-ray analysis of the product,a possible model for the asymmetric induction was proposed.In this work,a methodology was successfully developed to prepare hydroxyimino tetrahydrobenzofuranones featuring a trifluoromethyl group at C3-position of all-carbon quaternary stereocenter.Currently this is the first use of ?,?-disubstituted nitroalkenes in asymmetric Michael addition/cyclization tandem reaction.Biological evaluations of the optical pure trifluoromethylated hydroxyimino tetrahydrobenzofuranones are underway.