Determining the absolute configuration of (+)-mefloquine HCl, the side-effect-reducing enantiomer of the antimalaria drug Lariam.
Determining the absolute configuration of (+)-mefloquine HCl, the side-effect-reducing enantiomer of the antimalaria drug Lariam.
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DOI：
10.1021/ja209050k
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发表时间：
2012-02
影响因子：
15
通讯作者：
Manuel Schmidt;Han Sun;P. Rogne;G. Scriba;C. Griesinger;L. T. Kuhn;U. Reinscheid
中科院分区：
文献类型：
--
作者：
Manuel Schmidt;Han Sun;P. Rogne;G. Scriba;C. Griesinger;L. T. Kuhn;U. Reinscheid
尽管重要的抗疟药盐酸消旋-阿克罗-甲氟喹已作为Lariam上市数十年，但其对映异构体的绝对构型尚未最终确定。这是需要的，因为（-）对映异构体被认为在疟疾治疗中由于与人脑中的腺苷受体结合而引起不利的副作用。由于有冲突的分配的基础上对映选择性合成和异常的X-射线衍射，我们确定了绝对配置使用的组合NMR，旋光色散（ORD），圆二色性（CD）光谱与密度泛函理论计算。首先，构建了与NMR衍生的（3）J（HH）标量耦合、（15）N化学位移、旋转Overhauser效应和残余偶极耦合相容的盐酸赤甲氟喹的结构模型。其次，我们计算了结构模型的ORD和CD谱，并与实验值进行了比较。对（-）-赤型甲氟喹盐酸盐的实验结果与我们计算的11 R，12 S模型的手性光学数据相匹配。因此，我们得出结论，11 R，12 S的归属（-）-赤型盐酸甲氟喹是正确的。
Even though the important antimalaria drug rac-erythro-mefloquine HCl has been on the market as Lariam for decades, the absolute configurations of its enantiomers have not been determined conclusively. This is needed, since the (-) enantiomer is believed to cause adverse side effects in malaria treatment resulting from binding to the adenosine receptor in the human brain. Since there are conflicting assignments based on enantioselective synthesis and anomalous X-ray diffraction, we determined the absolute configuration using a combination of NMR, optical rotatory dispersion (ORD), and circular dichroism (CD) spectroscopy together with density functional theory calculations. First, structural models of erythro-mefloquine HCl compatible with NMR-derived (3)J(HH) scalar couplings, (15)N chemical shifts, rotational Overhauser effects, and residual dipolar couplings were constructed. Second, we calculated ORD and CD spectra of the structural models and compared the calculated data with the experimental values. The experimental results for (-)-erythro-mefloquine HCl matched our calculated chiroptical data for the 11R,12S model. Accordingly, we conclude that the assignment of 11R,12S to (-)-erythro-mefloquine HCl is correct.