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DOI: 10.1055/s-0033-1340698
Synthesis of the Four Stereoisomers of Mefloquine
Publication History
Publication Date:
17 February 2014 (online)
Significance
The antimalarial agent mefloquine hydrochloride (Lariam®) is a racemic compound that contains (+)- and (–)-erythro-mefloquine. Adverse dose-related neuropsychiatric and gastrointestinal effects have been attributed to (–)-erythro-mefloquine, which is a potent blocker of adenosine receptors in the central nervous system. The synthesis depicted delivered the (–)-erythro- and (+)-threo-mefloquine diastereoisomers and the identical sequence beginning with (R)-A gave the (+)-erythro and (–)-threo diastereoisomers.
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Comment
The key step in the synthesis is a Sonogashira coupling (D + E → F) followed by a 6π-electrocyclization cascade (G → H) leading to an inseparable diastereoisomeric mixture of quinolines I (dr = 3.6:1). After deprotection, the diastereoisomers were separable by chromatography. For another recent synthesis of all four diastereoisomers of mefloquine, see: J. Ding, D. G. Hall Angew. Chem. Int. Ed. 2013, 52, 8069.
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