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Chemistry. 2013 Dec 16;19(51):17584-8. doi: 10.1002/chem.201303403. Epub 2013 Nov 13.

Trapped in misbelief for almost 40 years: selective synthesis of the four stereoisomers of mefloquine.

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  • 1Max-Planck-Institute of Biophysical Chemistry, Department of NMR-Based Structural Biology, Am Fassberg 11, 37077 Göttingen (Germany), Fax: (+49) 551 201-2202.

Abstract

Here we report the synthesis of all four stereoisomers of mefloquine. Mefloquine (Lariam) is an important anti-malaria drug that is applied as a racemate of the erythro form. However, the (-)-isomer induces psychosis, while the (+)-enantiomer does not have this undesired side effect. There are six syntheses of which five lead to the wrong enantiomer without the authors of these syntheses noting that they had synthesized the wrong compound. At the same time physical chemistry investigations had assigned the absolute configuration correctly and the last enantioselective synthesis that took these results into account delivered the correct absolute configuration. Since various synthetic approaches failed to provide the correct stereoisomers in previous syntheses, we submit here a synthetic approach with a domino Sonogashira-6π-electrocyclisation as key step that confirmed synthetically the correct absolute configuration of all four isomers.

Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

KEYWORDS:

domino reactions; drug design; mefloquine; structure elucidation; total synthesis

PMID:
24226934
[PubMed - indexed for MEDLINE]
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