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

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. Five to four: A total synthesis that yields all four stereoisomers of the important antimalarial drug mefloquine (Lariam) has been developed. This five-step approach with a domino Sonogashira-6π- electrocyclisation as key step has confirmed synthetically the correct absolute configuration of all four isomers (see scheme). © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.