Structural analysis of natural products focussing on the absolute configuration.

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 limonene, strychnine, and menthol-type compounds. Using limonene as test molecule, t...

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Bibliographic Details
Main Author: Reinscheid, Frauke
Contributors: Keusgen, Michael (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:English
Published: Philipps-Universität Marburg 2016
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Summary: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 limonene, strychnine, and menthol-type compounds. Using limonene as test molecule, the success and the limitations of three chiroptical methods, optical rotatory dispersion (ORD), electronic and vibrational circular dichroism (ECD and VCD respectively), could be demonstrated. At the mpw1pw91/cc-pvdz (IEFPCM for solvent modelling) level of theory, 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. 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, it was 25 kcal/mole higher in energy than the non-inverted form, which suggests 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 throughout the literature values concerning 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. A stringent proof of the AC of neoisomenthol based on literature information using the gold standard (x-ray crystallography) as starting point was shown. To the best of my 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 linear regression was performed. It was 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 < [alpha] < +10 were taken, all 12 compounds would have been correctly assigned even without low-temperature NMR data as restraints.
DOI:https://doi.org/10.17192/z2016.0805