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

Study of Mechanism to Asymmetric Mannich Reaction of Diethyl Malonate and Benzothiazol Imine Catalyzed by Applying Chiral Quinidine

手性催化剂奎尼丁催化丙二酸乙酯与苯并噻唑亚胺的不对称Mannich反应机理研究,对β-氨基酸酯类衍生物合成具有重要的指导意义.采用密度泛函理论(DFT)的M06-2X方法,通过精确计算:(1)确定了奎尼丁催化剂催化活性位点为9位碳上的羟基和位于1位的叔氮原子;(2)S构型反应过渡态能量比R构型反应过渡态能量低,反应产物以S构型为主;(3)计算进一步表明较低温度有助于提高反应的立体选择性.计算结果与实验数据相符,反应获得S构型的β-氨基酸酯类衍生物,其ee可达到81%-95%.

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.