Estudi teòric i experimental de la reacció de fotocicloaddició [2+2] de 2(5H)-furanones a olefines. Modelització i síntesi de compostos ciclohexànics amb activitat uberculostàtica

Abstract

A new family of 2(5H)-furanones has been prepared with a two hydroxyl side chain; said hydroxyl groups have been independently protected. The [2+2] fotocycloaddition reaction of said 2(5H)-furanones with ethylene and 1,1-diethoxyethylene has been studied. It has been found that the presence of a second group in the side chain is important to improve the facial selectivity of the reaction, but its nature is not an important factor. In the fotocycloaddiciton with 1,1-diethoxyethylene a HT:HH total regioselectivity towards the HT regioisòmer has been found when R1 is benzyl. When R1 is pivaloyl the regioselectivity is not total and depends on the solvent: the less polar solvent, the higher the selectivity. The facial selectivity is not affected by the solvent and has been determined around 60%, just bellow the facial selectivity using ethylene (80%). The [2+2] fotocycloaddition reaction of said 2(5H)-furanones with ethylene has also been theoretically studied. It has been found that the lowest triplet of the ethylene is of lower energy that that of the 2(5H)-furanone. Hence, the ethylene has been considered to be the excited species in the fotosensibilized reaction. Other olefins have also been studied and also show a lower triplet than that of the 2(5H)-furanone. In order to determine if there is any possible path to reach the triplet of the olefin, the decays of a number of sensitizers in the presence of olefins and 2(5H)-furanone using flash photolysis have been studied. It has been determined that acetone can sensitize ethylene and 1,1-diethoxyethylene. It has also been found that the use of the DFT functional MPWB1K, although is mono-configurational, is able to describe the full reaction surface, including the singlet state. This is the methodology used in all the examples studied. The [2+2] fotocycloaddition reaction of the (5S)−hydroxymethyl−2(5H)−furanone has been studied with computational methodologies, and has been determined that the DFT functional MPWB1K correctly describes the facial diastereoselectivity determined experimentally. Using the same methodology the reaction of the 2(5H)−furanone with 1,1-dimethoxyethylene has been studied and the experimental regioselectivity has been correctly described. It has been found that the regioselectivity is determined in the first step of the reaction. Using a set of enantiopure ciclohexànic compounds previously prepared in our research group and which have shown to have tubersulostatic activity a pharmacophore model has been obtained which has been used to search in databases in order to guess the mechanism of action of said compounds. The retrieved compounds do not have a common mechanism of action and show a diverse chemical structure. It has been observed that some of the retrieved show a nitrogen where our compounds show a carbonyl group. Attempts to introduce a nitrogen in our best compound did not succeed, but the introduction of a nitrogen in a related compound, with lower activity, did succeed and the tuberculostatic activity has been improved in this compound.

Date of Award	19 Jun 2009
Original language	Undefined/Unknown
Supervisor	Ramon Alibes Arques (Director) & Josep Font Cierco (Director)