Aminocatalyzed ?'-selective Functionalization Of Cyclic Enones And DFT Calculation

One of the major challenges in modern asymmetric catalysis is the selective activation and functionalization of reactants having multiple activation sites.Cyclic enones are potential synthons in natural products synthesis and have multiple reactive sites under aminocatalysts,and the researches about them have attracted the attention of chemists in the past decades.The?-,?-,?-functionalization and ?',?-difunctionalizations have been described.The first example of organocatalyzed ?'-selective functionalization of cyclic enones with 3-substituted maleimides results in the stereoselective construction chiral quaternary carbon centers was presented.The reaction provided easy access to chiral 3,4-disubstituted cyclic enones with a chiral quaternary carbon center adjacent to C4 of the cyclic enones,and chiral 3-substituted cyclopentenone with a quaternary carbon center adjacent to C3 in good to excellent yields with excellent diastereo-and enantioselectivites.Secondly,organocatalytic diastereodivergent direct vinylogous Michael additions of 3-alkyl-?,?'-unsaturated cyclohexanones to nitroolefins have been discovered.We selectively realized the syn-adducts using chiral aminocatalysis that derived from(R,R)-1,2-diphenylethylenediamine and L-lecucine combined with 4-nitro-benzoic acid.On the other hand,the system combined primary amino-thiourea catalyst derived from(R,R)-1,2-diaminocyclohexane and quinine with 2,6-tBu-4-methyl-phenol gave the anti-adducts.The development of this methodology not only solved the challenging issues for ?'-functionalization of 3-alkyl-cyclohexenone,but also offered a new route to achieve ?'-functionalization of the cyclic enones in the synthesis of natural products.Finally,DFT calculation was conducted to explain the chiral quaternary carbon center and excellent stereoselectivity.DFT calculation indicated that the reaction might proceed as a[4+2]cycloaddition/retro-Mannich mechanism.The cycloaddition was a spontaneous step which exclude the direct vinylogous Michael addition mechanism.The second step retro-Mannich reaction which contains acid-assited hydrogen transformation.ReactIR and deuteriation experiments were also conducted to support the acid-assited hydrogen transformation mechanism.The confirmation of the[4+2]cycloaddition/retro-Mannich mechanism supported the application of theso methodologies that we presented.