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

Abstract

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.

Keywords: Sharpless dihydroxylation; asymmetric synthesis; malaria; mefloquine; total synthesis.