The Absolute Configuration of (+)‐ and (−)‐erythro‐Mefloquine

Abstract

The controversy over the absolute configuration of (+)-erythro-mefloquine, the less psychosis-causing enantiomer of the anti-malarial drug Lariam, has been resolved by Mosher ester crystallization. The configuration determined previously by physical methods is correct, whereas the configuration determined by three enantioselective syntheses is wrong.

A Stereospecific Synthesis and Unambiguous Assignment of the Absolute Configuration of (−)‐erythro‐Mefloquine Hydrochloride

“…Herein, we describe a new asymmetric synthesis and unambiguous assignment of the absolute configuration of (−)‐ erythro ‐ 1 . Our results show that the absolute configuration of (−)‐ erythro ‐ 1 is definitely (11 R ,12 S ) and that of (+)‐ erythro ‐ 1 is (11 S ,12 R ) (Figure 2), confirming the correctness of the determination of the absolute configuration by three physical chemistry methods,8,14–15 and, unbelievably, the erroneous assignment by all previous five asymmetric syntheses 9–13…”

“…Five asymmetric syntheses of (+)‐ erythro ‐ 1 have been reported9–13 and all these syntheses supported the CD assignment of Carrol,7 determining the absolute configuration of (+)‐ erythro ‐ 1 as (11 R, 12 S ). Recently, Griesinger and co‐workers14,15 determined the absolute configuration of (−)‐ erythro ‐ 1 to be (11 R ,12 S ) using residual dipolar coupling (RDC)‐enhanced NMR spectroscopy in combination with optical rotatory dispersion (ORD) and circular dichroism (CD) spectroscopy, as well as on the basis of crystal‐structure determinations of the Mosher amides of both enantiomers of mefloquine.…”

Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the Four Stereoisomers of Mefloquine

“…Furthermore, an X-ray crystal structure analysis of the Mosher amides of (+)-erythro-and (À)-erythro-mefloquine led to an absolute configuration of (+)-erythro-mefloquine as (11S,12R). [14] Importantly, all past published syntheses [15] determined the stereochemistry of (+)-erythro-mefloquine as (11R,12S), which is opposite to the mentioned Abstract: Here we report the synthesis of all four stereoisomers of mefloquine. Mefloquine (Lariam) is an important anti-malaria drug that is applied as a racemate of the erythro form.…”

“…Also, residual dipolar coupling (RDC)‐enhanced NMR spectroscopy in combination with optical rotatory dispersion (ORD) and electronic circular dichroism (ECD) spectroscopy13 confirmed the result of the crystal structure in 2012. Furthermore, an X‐ray crystal structure analysis of the Mosher amides of (+)‐ erythro ‐ and (−)‐ erythro ‐mefloquine led to an absolute configuration of (+)‐ erythro ‐mefloquine as (11 S ,12 R ) 14. Importantly, all past published syntheses15 determined the stereochemistry of (+)‐ erythro ‐mefloquine as (11 R ,12 S ), which is opposite to the mentioned physical chemistry techniques.…”

3,3-Dibromo-2-trifluoromethyl acrylic acid ethyl ester: a versatile platform for the stereoselective preparation of functionalized-α-trifluoromethyl α,β-unsaturated lactones and trifluoromethyl pyrazolinones

“…1 Nowadays, numerous CF3 substituted heterocycle-containing pharmaceuticals on the market can be witnessed, 2 with examples such as trifluridine, 3 efavirenz, 4 celecoxib 5 and mefloquin. 6 Over the past decades, there has been an increasing interest in the development of method for the efficient synthesis of such fluorinated heterocyclic molecules as potential biological targets. 7 Nevertheless, synthetic method accessing an array of CF3-containing heterocycles remains underdeveloped, in particular for nonaromatic heterocycles.…”