Chiral Organocatalysis For(3+2) Cyclo Additions And Mannich Additions Of Unsaturated Carbonyl Compounds With Cyclic Imines

Chiral organic catalysis is widely used in asymmetric synthesis.It is the third kind of chiral catalyst after biocatalysis(such as enzyme catalysis)and metal-organic complex chiral catalyst.Benzo[e][1,2,3]oxathiazine 2,2-dioxides can be considered as N-sulfonyl cyclic imines.The trifluoromethyl group represent lipophilicity and strong electron absorption,so it can improve the polarity,electrostatic potential,dipole moment,binding selectivity,bioavailability and other properties of the parents molecules.It shows great significance in the molecular design of pharmaceutical chemistry.In this paper,we studied the asymmetric reactions of cyclic trifluoromethyl ketoimines and unsaturated carbonyl compounds under the two kinds of chiral organic catalysis: Asymmetric(3+2)cycloaddition reaction catalyzed by N-heterocyclic carbene(NHC)and asymmetric Mannich reaction catalyzed by chiral primary amine and acid.Part ?: Asymmetric(3+2)cycloaddition reaction catalyzed by Chiral NHC.The enantioselective(3+2)cycloadditions of enals and cyclic N-sulfonyl trifluoromethylated ketimines via N-heterocyclic carbene-catalyzed homoenolate addition were developed.Using substituted trifluoromethyl ketonimines and different ?,?-unsaturated aldehydes as substrates,various reaction conditions were optimized and finally fused N-heterocyclic ?-lactam with two adjacent chiral centers were effectively constructed with high stereoselectivity > 20:1 dr,94-99% ee,with one chiral center as a trifluoromethylated a-tetrasubstituted carbon stereocenter.The absolute configuration of one of the compounds was determined by single crystal diffraction,and the other compounds were determined by the chemical analogy method of similar mechanism.Finally,the functional groups of cycloaddition products were derivatized without loss of stereoselectivity.Patt ?: Asymmetric Mannich reaction catalyzed by chiral primary amine and acid.The chiral primary amines and acids co-catalyze to activate ?,?-unsaturated ketones to form enamine intermediates increased the energy of the highest occupied orbital(HOMO)and promoted the nucleophilic addition with cyclic N-sulfonyl trifluoromethyl ketoimines.The cascade Mannich-Michael reaction will occur in theory.The experimental results show that only the Mannich reaction is carried out to obtain the unclosed ring product.Using substituted cyclic N-sulfonyl trifluoromethylated ketimines and different acyclic ketenes as substrates,After optimizing the experimental conditions such as primary amine catalyst,co-catalytic acid,solvent and temperature,the chiral benzo-fused trifluoromethylated ?-aminocarbonyl compound was constructed with a good yield and up to 97% ee.The absolute configuration of one of the compounds was determined by single crystal diffraction,and the other compounds were determined by the chemical analogy method of similar mechanism.