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.

Asymmetric Synthesis of (+)-anti- and (−)-syn-Mefloquine Hydrochloride

“…The resulting ester was then subjected to a DIBAL-mediated reduction to afford allylic alcohol 17. As hoped, Sharpless asymmetric epoxidation of 17 furnished the desired epoxy alcohol (18) in good yield (77%) and with excellent enantioselectivity (er = 98:2). The enantiomeric purity of 18 was established by comparing it with a corresponding racemic sample 21 by HPLC analysis on a chiral, nonracemic stationary phase.…”

“…After some effort, we were able to develop a new, concise, highly enantioselective (er > 99:1) synthesis of (−)-anti-mefloquine hydrochloride that maintained the annulative epoxide ring opening strategy. 18 The key asymmetric transformation in this case was a Sharpless asymmetric dihydroxylation of a structurally advanced olefin. As part of this work, we were also able to gain access to (−)-syn-mefloquine hydrochloride in an equally concise manner from the same Sharpless-derived diol.…”

The antimalarial drug mefloquine enhances TP53 premature termination codon readthrough by aminoglycoside G418

“…G418 was purchased from MicroCombiChem. Mefloquine stereoisomers (+)- anti -mefloquine hydrochloride [(+)- 1 ] and (-)- syn -mefloquine hydrochloride [(-)- 2 ] were synthesized and purified as described [16,17]. Mefloquine stereoisomers (-)- anti -mefloquine hydrochloride [(-)- 1 ] and (+)- syn -mefloquine hydrochloride [(+)- 2 ] were synthesized in an analogous manner (Fig 1).…”

A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine

“…The first enantioselective synthesis of (−)- erythro -mefloquine via the asymmetric rhodium-catalyzed hydrogenation was reported in 1993 [ 22 , 23 ]. Other enantioselective methods include: asymmetric aldol reaction and the Beckmann rearrangement [ 24 ], asymmetric Darzens reaction [ 25 ], Pd-catalyzed asymmetric borylative isomerization [ 26 ], domino Sonogashira-6π-electrocyclization [ 27 ], synthesis from chiral pipecolic acid, enantioselective transfer hydrogenation with ruthenium catalysts [ 28 , 29 ], and the Sharpless asymmetric dihydroxylation [ 30 , 31 ].…”