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

A concise asymmetric (>99:1 e.r.) total synthesis of (+)‐ anti ‐ and (−)‐ syn ‐mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless‐derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)‐ anti ‐ and (−)‐ syn ‐mefloquine, respectively. The synthetic (+)‐ anti ‐ and (−)‐ syn ‐mefloquine samples were derivatized with ( S )‐(+)‐mandelic acid tert ‐butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X‐ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)‐ anti ‐ as well as (−)‐ syn ‐mefloquine.