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

This thesis deals with the assignment of the absolute configuration of organic molecules by a non empirical analysis of their chiroptical properties, i.e. Electronic Circular Dichroism (ECD), optical rotatory power and optical rotation dispersion (ORD). This thesis is organized in two different parts (Part I and Part II). In Part I.1 we discuss the fundamentals of the phenomena of optical activity, in particular optical rotation and circular dichroism in the VIS-UV region (ECD). In the section I.2 we focus about the methods of interpretation of ECD data: we present mainly the coupled oscillator method, in particular the DeVoe approach. Furthermore, a particular place is left to the modern methods for the ab initio calculation of the ECD spectrum. In the section I.3 the ab initio calculation of the optical rotation at different wavelengths is treated. In Part II we mainly discuss some applications of the above methods. In Chapter 1, we treat the scope and limitations of the ab initio calculation of the optical rotatory power using a small basis set scheme: we show that this approach can be very useful, at least in particular instances, to assign in a simple and reliable way the absolute configuration of natural molecules having even a medium-large size. Afterwards, we analyse the case of the optical rotation calculation of the (S)-propylene oxide showing that this apparently small and simple molecule is one of the most difficult cases to be treated, to date. In Chapter 2 we assign the absolute configuration to two natural products ((-)-naringenin and (+)-diplopyrone) using both the DeVoe calculations of the ECD spectra and the ab initio prediction of the [α]D. We show that both these completely different methods lead to the same result; therefore, the absolute configuration of these natural products has been safely assigned. Particular attention is addressed to the coupled oscillator analysis of the ECD spectrum of the Troeger’s base, so we can find the reason of the failure of its treatment. By contrast, chiroptical properties of this molecule can be quite simply analysed by the ab initio methods. In Chapter 3 we study the ab initio prediction of the optical rotation dispersion curve showing that this one is the simplest and reliable way to assign the absolute configuration. This new approach is used to determine the AC of two new bioactive, interesting molecules, cis and trans isocytoxazone. In the Final Conclusion Section we propose a practical protocol in order to select, taking into account the nature and the experimental chiroptical properties of the molecule under study, the best approach to be followed to carry out a simple and reliable assignment of the absolute configuration.

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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

Tesi di Dottorato

Dipartimento: Chimica

Autore: Egidio Giorgio Contatta »

Composta da 197 pagine.


Questa tesi ha raggiunto 372 click dal 19/10/2005.

Disponibile in PDF, la consultazione è esclusivamente in formato digitale.