Determining the Absolute Configuration of (+)-Mefloquine HCl, the Side-Effect-Reducing Enantiomer of the Antimalaria Drug Lariam

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• 作者：Manuel Schmidt ; Han Sun ; Per Rogne ; Gerhard K. E. Scriba ; Christian Griesinger ; Lars T. Kuhn ; Uwe M. Reinscheid
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：February 15, 2012
• 年：2012
• 卷：134
• 期：6
• 页码：3080-3083
• 全文大小：265K
• 年卷期：v.134,no.6(February 15, 2012)
• ISSN：1520-5126

文摘

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 (鈭? 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 ³J_HH scalar couplings, ¹⁵N 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 (鈭?-erythro-mefloquine HCl matched our calculated chiroptical data for the 11R,12S model. Accordingly, we conclude that the assignment of 11R,12S to (鈭?-erythro-mefloquine HCl is correct.