Synthese chiraler Alignmentmedien zur Enantiomerenunterscheidung via anisotroper NMR-Parameter & Bestimmung der absoluten Konfiguration von (–)-erythro-Mefloquin HCl

Abstract

During this PhD project it was presented a new chiral alignment medium for the enantiodiscrimination of chiral amines. Initially (R)- or (S)-2-acrylamido-2-phenylethane sulfonic acid, respectively ((R)- / (S)-APhES), the chiral monomer of that new polymer-based alignment medium was synthesized over five steps starting from the enantiopure (R)- or (S)-configurated beta-aminoalcohol. Thus, the resulting chiral polymer gels are available in both enantiomeric forms. At the beginning of that project, the existing chiral alignment media were either compatible with aqueous solutions or apolar solvents, like chloroform. One benefit of this new alignmemt medium is the compatibility with polar solvents like DMSO, DMF, MeOH or water. In contrast to liquid crystalline based alignment media there is no critical, i.e. a minimal concentration so that the alignment strength can be tuned over a wide range according to requirements. In addition to the excellent alignment properties the new chiral polymer gel especially stands out due to its enantiodiscriminating ability. Thus, both enantiomers of erythro-mefloquine hydrochloride were successfully distinguished based on different residual dipolar couplings (RDCs). Finally, with the chiral molecules strychnine hydrochloride and menthylamine hydrochloride the enantiodiscriminating power of the APhES gels was demonstrated on two additional examples. In an independent side project the absolute configuration of erythro-mefloquine hydrochloride, the active ingredient of one important anti malaria drug, was successfully determined. Since its development and especially in the last decade were published several inconsistent structure proposals concerning the absolute configuration. Because of contrary results using the two major methods for the determination of the absolute configuration, i.e. total synthesis or X-ray crystallography, here it is presented an interdisciplinary method including the spectroscopic techniques NMR, ORD and ECD in combination with quantum mechanical calculations. Based on that approach the absolute configuration of (–)-erythro-mefloquine hydrochloride was reliably determined as 11R,12S. Subsequently, this result was validated in our department using two independent synthetic or synthetic/analytical methods, respectively.