Concise Synthesis and Antimalarial Activity of All Four Mefloquine Stereoisomers Using a Highly Enantioselective Catalytic Borylative Alkene Isomerization

Abstract

The pluses and minuses of mefloquine: A highly enantioselective catalytic borylative isomerization/aldehyde allylboration method for the stereoselective synthesis of the antimalarial drug mefloquine was optimized, thus leading to an efficient synthesis of all four mefloquine stereoisomers and analogues (see scheme). The absolute configuration of these potent compounds was determined for the first time by using chemical synthesis.

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

“…[24] Thee.r. [14] Theenantiomeric purity of our synthetic material was established in the same manner as we described previously, [17] and was found to be > 99:1 e.r. Compound 19 was next treated with hydrazine followed by acidification with HCl, which, as anticipated, provided (+ +)-anti-mefloquine hydrochloride [(+ +)-1]i ne xcellent yield.…”

“…[11] In another approach to enantiomerically enriched (+ +)-anti-mefloquine hydrochloride,a no rganocatalytic aldol addition was used (71 % ee). [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. ( + +)-anti-Mefloquine hydrochloride was also prepared in unspecified enantioselectivity starting from (S)-(À)-1-N-Boc-2-piperidinecarboxylic acid.…”

Preparation of (−)-(R)-2-(2,3,4,5,6-pentafluorophenoxy)-2-(phenyl-d5)acetic acid: an efficient 1H NMR chiral solvating agent for direct enantiomeric purity evaluation of quinoline-containing antimalarial drugs

“…Unfortunately, partial efficacy, 5 drug resistance, and side-effects [1][2][3][4] have seriously flawed these attempts. Several traditional, quinoline-containing antimalarial agents such as chloroquine 1, hydroxychloroquine 2, and mefloquine 3 are dispensed as racemates, while evidence indicates that the corresponding isolated enantiomers may have different pharmacodynamic, 6,7,11 toxicological, 8,10,13 and pharmacokinetic properties. 9,10,12,14 Thus, the chiral switch 15 approach (the use of single enantiomers in lieu of the corresponding racemate) might offer a straightforward way to safer and more efficacious drugs.…”

A Robust, Recyclable Resin for Decagram Scale Resolution of (±)‐Mefloquine and Other Chiral N‐Heterocycles

“…[7] It is currently sold as aracemate and epitomizes the potential pitfalls of marketing and administering racemic drugs,assome neurological side effects are suspected to be caused by one of the enantiomers. [8] Our selection was further encouraged by its molecular structure. Mefloquine is agood representation of the functional groups commonly found in pharmaceutical candidates;a long with the piperidine ring, (AE)-mefloquine includes af ree alcohol and ab asic nitrogen in the quinoline core.…”