Derivados de piperazina-2,5-diona como sintones para la preparación de compuestos de aplicación en la terapia antitumoral

Abstract

Piperazine-2,5-diones are not only privileged scaffolds which are used as effective and powerful tools in the discovery of novel biological active molecules because of their attractive properties as small, rigid and stable heterocycles that can mimic the main conformations of peptides without having their deficiencies, they are also very useful tools in the synthesis of alkaloids, as well as in asymmetric synthesis. In this scope the purpose of this thesis is to study mainly new routes towards the pentacyclic system of the saframycin family, and on the other hand, to obtain simplified derivatives of ardeemin, an alkaloid with reversal effects on MDR cancer cell lines. In the scope concerning simplified ardeemin analogs, the alkylation studies realized with halogenated derivatives over the azaenolates of (4S)-2-phenyl-4-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione showed that there is a great stereoselectivity toward the 1,4-cis isomers. This is in contrast with the observed 1,4-trans diastereoisomer formation, when the same tricyclic system wears a hydrogen, a methyl, or a benzyl group at position 2. This atypical behavior can be attributed to the major acidic character of the C-1 protons in the 2-phenylderivatives that propitiates the thermodynamic balance from the originally formed 1,4-trans-diastereoisomer toward the more stable 1,4-cis-isomer...