奎宁手性催化合成苯并噻唑氨基酸酯反应机理研究

The Study of Mechanism to Dissymmetric Mannich Reaction of Diethyl Malonate and Benzothiazol Imine Catalyzed by Applying Chiral Quinine

苯并噻唑-β-氨基酸酯不对称Mannich反应研究,对寻找具有良好生物活性的对映异构体具有重要意义。本文采用高精度量化计算和试验相结合的方法,研究了奎宁手性催化合成苯并噻唑-β-氨基酸酯的Mannich反应机理。利用密度泛函理论(DFT)M06-2X方法,溶剂采用CPCM模型,在6-311G(d,p)基组水平上,对反应的过渡态TS(S,R)进行了详细的研究。结果表明,奎宁手性催化作用位点有两个,分别形成O(12)—H(25)—N(57)和N(1)—H(90)—O(79)氢键。通过过渡态红外振动频率计算与分析进一步验证了过渡态的准确性。计算结果与试验结果能很好吻合,反应体系的温度是提高立体选择性的关键因素之一,温度越低立体选择性越好。

The dissymmetric Mannich reaction of benzothiazol-β-amino esters is of great importance for exploring effective enantioisomer with good bioactivity.The mechanism for Mannich reaction of benzothiazol-β-amino esters catalyzed by simple chiral quinine organocatalyst was investigated through a combination of experiment with theoretical approaches(DFT).With solvent effect taken into consideration,transition states TS(S or R)were confirmed with potent strategy of hybrid density functional M06-2X at the level of 6-311G(d,p)basis set.The key feature of dual activation mechanism lies in the formation of one hydrogen bond O(12)—H(25)—N(57)related to quinine hydroxyl(Cat)and benzothiazol imines(EI)N(57)and the other hydrogen bond N(1)—H(90)—O(79)formation related to tertiary amine of quinine(Cat),by which diethyl malonate is able to be activated into enolic Nu simultaneously.The result obtained through energetic calculation was identified further by IR vibrating frequency to convince of transition state attained to be accurate.As a 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 enantioisomer(S).At the same time,one of reacting factors was optimized for increasing enantio-and distereoselectivity using DFT calculations,that is reacting temperature.The lower the temperature is going on,the more the enantio-and distereoselectivity are upgraded.