Sterodynamics of chiral and conformationally flexible molecules studied by chromatography and chiro-optical methods

PART A Conformational chirality arises from the presence of stereogenic elements different than the stereogenic centre, as axis, plane and helix. Compounds that exhibit such elements have peculiar characteristics profitably exploited in material chemistry, supramolecular chemistry and asymmetric catalysis. In this work is reported the study of the stereodynamics of helicenes, in the first part, and axially chiral compounds, in the second part, that allowed to determine the energetic barriers of the stereomutation events. Enantioselective HPLC coupled to electronic circular dichroism and optical rotation dispersion has been employed to separate and characterize the enantiomers of the studied compounds gathering valuable information about their outstanding chiroptical properties and interconversion rates. PART B Compounds with a non-planar seven-membered ring in their molecular backbone are known to be chiral. The absence of planarity allows the existence of two enantiomeric species that can interconvert due to a ring-flip mechanism. Many bioactive compounds like benzodiazepines or dibenzoazepinones, widely prescribed for different therapeutic applications, present this structural feature. In this study, is reported the investigation of the stereodynamic behaviour of three different bioactive compounds: the anti-HIV drug Nevirapine and the anti-epileptic Oxcarbazepine, both showing a seven membered ring fused in a tricyclic system, and Estazolam, a triazole-benzodiazepine without a stereogenic centre. Low temperature dynamic-HPLC with chiral stationary phase coupled to computer simulations and NMR studies were employed to demonstrate the presence of two enantiomers in rapid interconversion and to measure the kinetic parameters of the process for all the three investigated compounds. PART C In the first section are reported the results from the period of my academic program at the Ludwig-Maximilians University (LMU) of Munich (GE) under the supervision of Prof. Dr. Oliver Trapp, during the second year of my PhD course. Xaa-Pro bond is a common structural element that can give rise to trans and cis isomers thanks to rotation around the amidic bond. Trans/cis isomerization influences the structure of peptides and proteins resulting as an important feature in controlling signal transduction, aggregation, enzymatic catalysis. This pattern is common in catalytically active small peptides and the trans/cis isomerization can influence the performance of catalysis and the outcome of the reaction. Here is reported the optimization of an analytical method to chromatographically resolve mixtures of conformers trans and cis of proline rich small molecules. The kinetic parameters of the isomerization processes have been measured by variable temperature HPLC experiments coupled to stochastic model-based computations. In the second part it will be discussed the assignment of a chemical correlation and the absolute configuration of four stereoisomers of a conformationally flexible indole derivative featuring a -ketoester fragment and two stereogenic centres. The two diastereoisomeric pairs have syn- and anti-periplanar conformations and can be easily converted into each other by treatment with a base. In this study a combination of different techniques is employed: HPLC, X-ray, ECD, NMR and computational methods. HPLC with ECD detection allowed to chemically correlate the four stereoisomers and the AC is assigned for two of the stereoisomers (one in anti-periplanar conformation and one in syn-periplanar) by X-ray.