Bestimmung der absoluten Konfiguration von Naturstoffen in Lösung auf Basis eines integrierten experimentellen und theoretischen Ansatzes
Zusammenfassung der Projektergebnisse
The absolute configuration (AC) of a variety of natural products was determined by an integrated approach: experimental spectroscopic data together with DFT calculated data of important bioactive molecules such as mefloquine, limonene, strychnine, and menthol-type compounds. As a milestone of the Research Group, a joint publication concerning the possibility to predict the absolute configuration by RDCs has been presented. Using limonene as test molecule, the success and the limitations of three chiroptical methods (optical rotation dispersion (ORD), electronic and vibrational circular dichroism, ECD and VCD) could be demonstrated. At quite low levels of theory (pw1pw91/cc-pvdz, IEFPCM for solvent modelling) the experimental ORD values differ by less than 10 units from the calculated values. Application of this level of theory allowed the correct prediction of the AC of strychnine base and hydrochloride based on the comparison between experimental and calculated ORD and ECD data. Importantly, a typical level of theory for geometry optimization (B3LYP/6-31G(d)) delivered a structural model with which the calculated 13C resonances did not match very well to experiment, in contrast to the structural model obtained at the mpw1pw91/cc-pvdz level of theory. Therefore, this level of theory was further used for the limonene and menthol work. Structural aspects such as chemical exchange, dimerization, solvent association, nitrogen inversion and protonation status of strychnine were investigated using experimental and calculated data. The information was mainly interpreted in view of a successful AC determination with strychnine (base and salt) as test molecule due to its importance in chemistry and biology. By geometry optimization a stable isomer of protonated strychnine was found with an inverted nitrogen, however, 25 kcal/mole higher in energy, which means that its concentration will be very low under ambient conditions. The complete series of menthol isomers and its corresponding amino derivatives, the latter as base and protonated/HCl forms, were investigated using experimental and theoretical data. Large discrepancies were found among the literature values about the calculated conformer population of even the best studied member of the series, i.e. menthol. It is shown that the correct determination of the population mix is a must for the correct prediction of the AC of neoisomenthol. The neoiso forms are of special interest since a number of structural speculations can be found in the literature. We show a stringent prove of the AC of neoisomenthol based on literature information using the gold standard (x-ray crystallography) as starting point. To the best of our knowledge, the AC of neoisomenthylamine is for the first time proven by comparison between experimental and calculated optical rotation data. A correction of a series of publications containing an important error in the assignment of (+)- menthylamine (correct: (+)-neomenthylamine) is presented. With 26 data pairs (experimental versus calculated) of optical rotation a regression is performed. We have shown that the AC of all 12 compounds could be predicted correctly when experimental low-temperature NMR data were used for the most difficult neoiso forms. If only experimental data with an optical rotation outside the range of −10 < [α] > +10 were taken, all 12 compounds would have been correctly assigned even without low temperature NMR data as restraints.
Projektbezogene Publikationen (Auswahl)
- 2011, Bijvoet in solution reveals unexpected stereoselectivity in a Michael addition, Chem. Eur. J., 17, 1811-1817
H Sun, EJ d`Auverge, UM Reinscheid, LC Dias, CKZ Andrade, RO Rocha, C Griesinger
(Siehe online unter https://doi.org/10.1002/chem.201002520) - 2011, Challenge of large-scale motion for residual dipolar coupling based analysis of configuration: The case of fibrosterol sulphate A, J. Am. Chem. Soc., 133, 14629-14636
H Sun, UM Reinscheid, EL Whitson, EJ d`Auvergne, CM Ireland, A Navarro-Vazquez, C Griesinger
(Siehe online unter https://doi.org/10.1021/ja205295q) - 2011, Residual chemical shift anisotropy (RCSA): A tool for the analysis of the configuration of small molecules, Angew. Chem. Int. Ed., 50, 9487-9490
F Hallwass, M Schmidt, H Sun, A Mazur, G Kummerlöwe, B Luy, A Navarro-Vazquez, C Griesinger, UM Reinscheid
(Siehe online unter https://doi.org/10.1002/anie.201101784) - 2011, The structure elucidation of isomalyngamide K from the marine cyanobacterium Lyngbia majuscula by experimental and DFT computational methods, J. Mol. Struct., 989, 109-113
B Han, UM Reinscheid, WH Gerwick, H Gross
(Siehe online unter https://doi.org/10.1016/j.molstruc.2011.01.012) - 2012, Chiral discrimination of amines by anisotropic NMR parameters using chiral polyacrylamide-based gels, Magn. Reson. Chem., 50, S38-S44
M Schmidt, H Sun, A Leonov, C Griesinger, UM Reinscheid
(Siehe online unter https://doi.org/10.1002/mrc.3886) - 2012, Determining the absolute configuration of (+)-mefloquine HCl, the side-effect-reducing enantiomer of the antimalaria drug Lariam, J. Am. Chem. Soc., 134, 3080-3083
M Schmidt, H Sun, P Rogne, GKE Scriba, C Griesinger, L Kuhn, UM Reinscheid
(Siehe online unter https://doi.org/10.1021/ja209050k) - 2012, Is Enantiomer assignment possible by NMR spectroscopy using residual dipolar couplings from chiral nonracemic alignment media ? A critical assessment, Angew. Chem. Int. Ed., 51, 8388-8391
R Berger, J Courtieu, RR Gil, C Griesinger, M Köck, P Lesot, B Luy, D Merlet, A Navarro- Vazquez, M Reggelin, UM Reinscheid, CM Thiele, M Zweckstetter
(Siehe online unter https://doi.org/10.1002/anie.201107626) - 2013, The absolute configuration of (+)- and (−)-mefloquine, Angew. Chem. Int. Ed., 52, 6047-6049
M Müller, CM Orben, N Schützenmeister, M Schmidt, A Leonov, UM Reinscheid, B Dittrich, C Griesinger
(Siehe online unter https://doi.org/10.1002/anie.201300258) - 2013, Trapped in misbelief for almost 40 years: Selective synthesis of the four stereoisomers of mefloquine, Chem. Eur. J., 19, 17584-17588
N Schützenmeister, M Müller, UM Reinscheid, C Griesinger, A Leonov
(Siehe online unter https://doi.org/10.1002/chem.201303403)
