Assignment of the absolute configuration of organic molecules by a non empirical analysis of their chiroptical properties

2 Introduction The assignment of the molecular absolute configuration is a fundamental problem of the structural organic chemistry. It is well known that the absolute configuration of a given chiral substance has a remarkable role on its biological activity and, consequently, on its interaction with the living organisms and, more generally, with the ecosystem. In fact, the building blocks of the living matter (carbohydrates, amino acids, etc) and many secondary metabolites exist in nature in a single enantiomeric form, while synthetic compounds with which the human beings deal during their every day life (drugs, food additives, cosmetics, agrochemicals, flavours and fragrances) are often chiral molecules and can exist as optical antipodes. The biological activity of such products is generally a function of the molecular structure and usually only one of the two antipodes shows the right activity. There are several examples of this behaviour. 1 It clearly turns out that it is of fundamental importance to be able to distinguish the structure of the two antipodes, that is to be able to determine the molecular absolute configuration. In order to solve this problem several methods have been proposed, 2 the chemical correlation and the X-Ray diffraction analysis being the most reliable ones. The first approach requires a long and tedious process for transforming the compound under analysis into one having known absolute configuration. The diffraction technique, on the other side, introduces strong limitations: necessity of having single crystals, availability of expensive and complex equipment, participation of specialists. In this framework an organic chemist can tackle the problem by resorting to more accessible approaches like those based on the chiroptical properties (optical rotation (OR), and circular dichroism in UV-VIS (ECD)) which allow to quickly analyse molecules in solution and therefore also not crystalline compounds. The empirical usage of the circular dichroism, that is the simple comparison of the measured values with those of analogous compounds reported in the literature, has the advantage of easy and rapid execution. However it could lead to rough errors in the case of wrong choice of the reference compound, as demonstrated in many instances. 3 On the other side, nonempirical methods for interpreting ECD spectra, like the exciton chirality one, 4 still have some limitations. In order to find new solutions to the problem of the absolute configuration assignment, we started a research program (which will be presented in this thesis) aimed at setting up new theoretical and experimental methods for configurational assignment which were general, simple and reliable. Such program has the goal to develop nonempirical methods of analysis of circular dichroism spectra in the UV-VIS range, and of the optical rotation measurements. In particular, we will study the application of ECD spectroscopy using a general theoretical prediction of ECD spectra by the exciton (coupled oscillator) model in order to remove the