Síntesis de hidroxiaminoácidos conformacionalmente restringidos, análogos de aminoácidos naturales

Zusammenfassung

The a-amino acids are a very important class of molecules in the metabolism, since they are constituent parts of peptides and proteins. Over the last few years, the synthesis of new non-proteinogenic a-amino acids has received an increasing interest, specially the synthesis of conformationally restricted analogues of natural amino acids. These amino acids are very different from their natural equivalents, due to the conformational rigidity which the quaternary a-carbon can give to the peptidic bond. Such amino acids could be incorporated into the structure of bioactive peptides, giving the corresponding analogues, known as peptidomimetics and pseudopeptides which have alteredl properties and biological activity. Furthermore, the incorporation of a hydroxyl group in a predetermined position of the amino acid opens the way to new families of products with interesting perspectives in the field of Glycobiology, a topic of growing interest. The work of the Doctoral Thesis is focused in the racemic and asymmetric synthesis of non-natural hydroxy quaternary a-amino acids, by means of the Diels-Alder reaction of 2-acylaminoacrylates and different dienes, such as 1,3-butadiene and Danishefsky¿s diene. After further stereoselective transformations, some cyclohexane and azabicycle hydroxy amino acids, analogues of the natural serine, proline and threonine have been synthesised. The first aim was the synthesis of 3-OH-cyclohexane-a-amino acids. The cycloadducts from the Diels-Alder reaction with 1,3-butadiene were functionalised by means of intramolecular reactions, giving two enantiomerically pure isomers analogues of homoserine. The next step was to synthesise hydroxylated amino acids in different positions of the cyclohexane ring. After trying alternative methodologies, incluiding the use of different oxygenated dienes, 2- (analogues of serine) and 4-hydroxycyclohexane-a-amino acids were synthesised. Once completed the synthesis of all the stereoisomers of these cyclohexane-a-amino acids, it have been synthesised some derivatives with an azabicyclic squeleton, such as proline and hydroxyproline analogues and a formal synthesis of the alkaloid epibatidine. Finally, it have been obtained some intermediate products, such us epoxycyclohexane and allylic cyclic substrates for palladium catalysed reactions, with a potential synthetic interest for being developed in further projects.