Stereochemistry assignment can be a challenge

27 April 2013 - Drug development

Mefloquine (Lariam) is an antimalarial drug and commercially available as the racemate. The (-) enantiomer is believed to be responsible for some undesirable neuropsychiatric symptoms so an improved product would only involve the (+) enantiomer. In a surprising report Muller et al. (DOI) state that several previous assignments of the absolute configuration have been wrong. Notable three total synthesis efforts (from 2008, 2011 and 2012) erroneously assigned (+) to 11R,12S where it should have been 11S,12R. Total synthesis is usually a reliable tool for configuration elucidation and any attempt at producing the (+) enantiomer requires the correct absolute stereochemistry information.
The Muller group used X-ray crystallography of the Mosher's acid adducts for their assignment. As to the why of the three erroneous total syntheses: one of them could have overlooked an epimerization and another one only disclosed the absolute configuration of an intermediate.