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.

Trifluoroacetimidoyl halides: a potent synthetic origin

“…The similar synthetic method to access 2-fluoromethylated quinoline derivatives was successfully applied to the total synthesis of all four stereoisomers of mefloquine by Leonov, Griesinger and co-workers. 92 In the protocol, a domino Sonogashira-6π-electrocyclization reaction was identified as the key step.…”

Idiosyncratic quinoline central nervous system toxicity: Historical insights into the chronic neurological sequelae of mefloquine

“…Recent attempts to mitigate mefloquine neurotoxicity, including efforts sponsored by the U.S. military to develop a human “safety test” ( Walter Reed Army Institute of Research, 2006 ) to identify individuals with idiosyncratic susceptibility, have thus far failed to yield satisfactory results. Notwithstanding recent confusion over the absolute configuration of the currently marketed drug ( Ding and Hall, 2013; Schützenmeister et al, 2013 ), randomized trials of enantiomeric mefloquine ( Knight et al, 2011 ), originally thought less likely to induce CNS effects owing to slightly lower average brain accumulation ( Baudry et al, 1997; Dow et al, 2011 ), have also demonstrated a propensity similar to the currently licensed racemic mixture to induce idiosyncratic “centrally mediated” symptoms of “dizziness” and difficulties in concentration ( Tansley et al, 2010 ).…”

A Concise and Highly Enantioselective Total Synthesis of (+)‐anti‐ and (−)‐syn‐Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines

“…( + +)-anti-Mefloquine hydrochloride was also prepared in unspecified enantioselectivity starting from (S)-(À)-1-N-Boc-2-piperidinecarboxylic acid. [13] Theg roups of Hall [14] and subsequently Leonov [15] independently reported routes to both syn-a nd anti-mefloquine hydrochloride in enantiomerically enriched form. In each case,t hese routes were used to access all four stereoisomers.InHalls synthesis,anovel enantioselective (99 % ee) allyl boration reaction was used as ak ey step to provide access to a syn-vicinal amino alcohol precursor that was used to obtain syn-mefloquine hydrochloride.…”