Study of Mechanism to Asymmetric Mannich Reaction of Diethyl Malonate and Benzothiazol Imine Catalyzed by Applying Chiral Quinidine
Xie Chengwei, Bai Song, Song Baoan, Yang Song
Center for Research & Development of Fine Chemicals, State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering of Ministry of Education, Guizhou University, Guiyang 550025
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.
谢承卫, 柏松, 宋宝安, 杨松. 金鸡纳碱奎尼丁催化含苯并噻唑基团亚胺与丙二酸酯Mannich反应机理研究[J]. 化学学报, 2013, 71(09): 1301-1306.
Xie Chengwei, Bai Song, Song Baoan, Yang Song. Study of Mechanism to Asymmetric Mannich Reaction of Diethyl Malonate and Benzothiazol Imine Catalyzed by Applying Chiral Quinidine. Acta Chimica Sinica, 2013, 71(09): 1301-1306.