Simple Amino Acids Catalyzed Asymmetric Michael Addition: A Theoretical Exploration

The dissertation is devoted to the theoretical study on asymmetric Michael addition catalyzed by simple amino acids and their derivatives. We employed the hybrid density functional, B3LYP, in combination with the standard 6-31G* basis sets (denoted B3LYP/6-31G*), as implemented in GAUSSIAN 03. To obtain more realistic energetics, single-point calculations were performed using the larger 6-31+G** basis sets in combination with the CPCM model to include solvent effects. Through the differences of conformation and energy among the enantiomers of transition states, the origins of stereoselectivities and main factor of these reactions were explained very well. It could be employed as a trend of designing new catalysts in future experimental studies. The following conclusions can be drawn:1. Michael addition of cyclohexanone andβ-nitrostyrene catalyzed by simple amino acids: reaction mechanism and selectivity(1) In the so-called proline catalyzed reaction, the classical enamine mechanism is kinetically unfavorable, therefore the proline does not affect the C-C bond forming. The major pathway is the uncatalyzed mechanism without enantioselectivity, which is kinetically more favorable, thus the poor selectivity of proline catalyzed Michael reaction can be explained.(2) In the proline derivative (tetrazole of homoproline) case, the major way is enamine mechanism, which is kinetically more favorable. In the alanine case the major ways are two different enamine mechanisms.(3) A trend was concluded that the flexibility of catalysts determines the viability of enamine pathway of proline-like catalysts.(4) A new way to enhance the enantioselectivities of amino acids and their derivatives could be developed by simply increasing the length of side chain or transforming cyclic catalysts to acyclic catalysts.2. Michael addition of cyclohexenone and nitropropane catalyzed by simple amino acids: reaction mechanism, selectivity and the usage of additives(1) The major adduct of proline catalyzed conjugate addition is R-enantiomer, the addition of piperazine-like additives can enhance the enantioselectivity.(2) The major adduct of alanine catalyzed conjugate addition is also R-enantiomer, although the original selectivity is not very good, the addition of piperazine-like additives can enhance the enantioselectivity effectively.(3) The double hydrogen bonding effect of piperazine-like additives can lower the energies of transition states of R-enantiomer, thus can enhance the enantioselectivity, and it is applicable among amino acids and their derivatives catalyzed Michael reactions which undergo through imine mechanism.3. [3+3] cycloaddition catalyzed by proline: reaction mechanism and selectivity(1) The simultaneous existences of imine and enamine intermediates formed by proline andα,β-unsaturated aldehyde can greatly lower the energy barrier of the Michael reaction of first step. The [3+3] reaction undergoes through the MBH-like mechanism.(2) In the [4+2] reaction, the indirect Mannich pathway proposed by Hong is unfavorable because of its very high energy barrier caused by the two excessively close proline rings. The aldol pathway which releases one molecule of proline by hydrolyzation is reasonable.(3) 2-methylcrotonaldehyde can not undergo [3+3] cycloaddtion because of the steric blockage of the methyl in its intermediate. The major pathway of crotonaldehyde is not [4+2] cycloaddition because of the high energy barrier of hydrolyzation of its intermediate.(4) The key steps to determine the stereoselectivity of products are the Michael reaction step and aldol reaction step.