Theoretical Studies On Mechanism And Stereoselectivity Of Two Catalytic [4+2] Cycloadditions

During the past decades, asymmetric synthesis has developed rapidly and has made significant achievements, especially, those organic asymmetric syntheses which are economical, environment-friendly, or those reacting under mild reaction conditions, but presenting high yield and high stereoselectivities have attracted wide attention of researchers. In this paper, the possible reaction mechanisms and stereoselectivities of two [4+2] cycloadditions have been explored with the theoretical method. We believe those studies should be helpful to deeper understanding of reaction mechanism of the asymmetric synthesis at the molecular level, and should be of very important meaning for design of new reactions or more efficient renewable catalysts.In Chapter 1, we gave a brief introduction to the research progress of asymmetric syntheses catalyzed by NHCs or imine. Chapter 2 provided part of the correlated basis knowledge about the theories and computational methods. Chapters 3 and 4presented the detailed studies towards mechanisms and stereoselectivities of the two catalytic [4+2] cycloadditions. Chapter 5 summarized the full paper. More details about the two catalytic reactions are given below:1. DFT study on mechanism and stereoselectivity of NHC-catalyzed synthesis of substituted trifluoromethyl dihydropyranones with contiguous stereocenters The substituted α,β-unsaturated ketones or aldehydes have become most efficient substrates of [4+2] cycloadditions that are catalyzed by N-heterocyclic carbenes(NHCs), and the asymmetric synthesis of compounds with contiguous stereocenters is an interesting but quite challenging topic in industry, biology,catalysis, and chemistry. Recently, Smith and co-workers reported an interesting work which provides a facile approach to access substituted trifluoromethyl dihydropyranones with two contiguous stereocenters by utilizing the α,β-substitutedα,β-unsaturated trifluoromethyl ketones as substrate of NHC-catalyzed [4+2]cycloadditions, and the most significant point of this reaction lies in the capability of introducing substituents, including methyl, benzyl, and aryl, to the C(5) position of the dihydropyranones. In the present study, we performed investigations towards the detailed catalytic mechanism of this reaction from the molecular level, and figured out the origins of diastereo- and enatioselectivities through analyses on distortion energies of two key species and on components of Gibbs free energy barriers of elementary steps in which the stereocenters generate. The theoretically predicted configuration of the main product was well consistent with the experimental results,and the relative free energy barriers(?) through the four transition states corresponding to the four diastereo- and enatioisomers were found to correlate very well with the relative enthalpy barriers(?), which indicates that the generation of stereoselectivity should originate from differences of enthalpy barriers, rather than differences of changes of the entropy item(?). The systematic study of the substituent effect affords a conclusive evidence to the catalytic mechanism we proposed, but failed to give any clue to the mechanism of how the various electronic properties of substituents act onto the experimental yields.2. DFT studies to the imine-catalyzed stereoselective [4+2] cycloaddition of allylidene malononitriles with cinnamaldehyde2. Theoretical investigations toward mechanisms and stereoselectivities of the the imine-catalyzed [4+2] cycloaddition of allylidene malononitriles with cinnamaldehyde The possible mechanisms and the stereoselectivities of the imine-catalyzed [4+2] cycloaddition of allylidene malononitriles with cinnamaldehyde have been investigated using the density functional theory(DFT) method. According to the experimental reports, we have suggested and studied two possible reaction mechanisms(denoted as Pathways A and B). The calculated results indicate that Pathway B is more energetically favorable to Patheay A, and it occurs through three stages: the [4+2] cycloaddition of R1 and R2 for the formation of intermediate M2,in which two chiral centers associated with four configurations(SS, RR, SR and RS)are consequently generated; the formation of intermediate M5 by tautomerization of intermediate M2, and finally the generation of the final product P by tautomerization and dissociation of the catalyst. The [4+2] cycloaddition step was identified to be the stereoselectivity-determining step and the product in SS configurational is the predominant product, which is in good agreement with the experimental results.