关键词: 奎尼丁, 苯并噻唑-β-氨基酸酯, 密度泛函理论, 过渡态, 反应机理

Benzothiazol-β-amino esters, acted as β-amino acids derivatives, perform excellent bioactivity in antibacterial and antivirus. To gain highly and purely optical single enantioisomer of benzothiazol-β-amino esters with simple organocatalyst, recently, the development for a classic Mannich reaction of diethyl malonate (Nu) with benzothiazol imine (EI) in the presence of cinchona alkaloid derivatives as organocatalyst has been made. The study for mechanism of applying unmodified cinchona alkaloid-chiral quinidine as potent organocatalyst to asymmetric Mannich reaction of benzothiazol-β-amino esters plays a vital role in asymmetric synthesis. In this work, the mechanism for Mannich reaction of benzothiazol-β-amino esters catalyzed by simple chiral quinidine organocatalyst was investigated through a combination of experiment with theoretical approaches (DFT). All geometry structures of reactants (Nu and EI), intermediates and product were optimized completely with the moderate approach M06-2X/6-311G (d,p) basis set in the gas phase. Afterward, the effect of solvent for DCM was took into consideration, and CPCM was used as polarization continuum model. Frequency calculations were performed at the same level of 6-311G (d,p) basis set as the geometry optimizations to confirm stable transition state (TS), which was verified further by means of IR vibrating frequency calculations (zero and only one imaginary frequency respectively). As comparison of (R)TS pathway with (S)TS pathway in potential energy profile, it enables to elaborate that (S)TS pathway executes to afford unique enatioisomer (S). The calculating results indicate that (1) Active sites of quinidine have been confirmed, that are 9-hydroxyl and tertiary amine; (2) The product exhibits S enantiomer as major configuration; (3) Moreover, the results of DFT calculation indicated that the stereo selectivity of the reaction could be improved by lower reaction temperature. The lower temperature is, the more distereoselectivity is upgraded. The calculation demonstrated that all of results are able to be in agreement with experimental data that β-amino acid esters derivatives carrying S as major configuration could arrive to range of 81%～95% ee.

Key words: chiral quinidine, benzothiazol-β-amino esters, DFT, transition state, mechanism