The Trifluoromethyl Group as a Conformational Stabilizer and Probe: Conformational Analysis of Cinchona Alkaloid Scaffolds
The Trifluoromethyl Group as a Conformational Stabilizer and Probe: Conformational Analysis of Cinchona Alkaloid Scaffolds
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DOI：
10.1021/ja504376u
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发表时间：
2014-07-23
影响因子：
15
通讯作者：
Olah, George A.
中科院分区：
文献类型：
--
作者：
Prakash, G. K. Surya;Wang, Fang;Olah, George A.
在奎尼丁的C9原子上引入CF 3基团可以显著增加金鸡纳生物碱支架的构象互变屏障。通过这种修饰，金鸡纳生物碱在不同溶剂中的构象行为可以方便地通过F-19 NMR光谱进行研究。基于获得的可靠的构象分布信息，理论（PCM）和经验（Kamlet-Taft）溶剂化模型的准确性进行了评估，使用线性自由能关系的方法。经验溶剂化模型被发现提供准确的预测溶剂效应，而PCM表现出相对较低的可靠性在本研究中。利用类似的经验溶剂化模型沿着与Karplus型方程，奎尼丁和9-epi-quinidine的构象行为也进行了研究。提出了S（N）2反应模型，揭示了溶剂诱导的金鸡纳碱构象行为在其反应性中的重要作用。
The introduction of the CF3 group on the C9 atom in quinidine can significantly increase the conformational interconversion barrier of the cinchona alkaloid scaffold. With this modification the conformational behavior of cinchona alkaloids in various solvents can be conveniently investigated via F-19 NMR spectroscopy. Based on the reliable conformational distribution information obtained, the accuracy of both theoretical (PCM) and empirical (Kamlet-Taft) solvation models has been assessed using linear free energy relationship methods. The empirical solvation model was found to provide accurate prediction of solvent effects, while PCM demonstrated a relatively low reliability in the present study. Utilizing similar empirical solvation models along with Karplus-type equations, the conformational behavior of quinidine and 9-epi-quinidine has also been investigated. A model S(N)2 reaction has been presented to reveal the important role of solvent-induced conformational behavior of cinchona alkaloids in their reactivity.