Una nueva síntesis de antitumorales relacionados con alcaloides del grupo de las saframicinas

Résumé

The purpose of this thesis is the study of new routes towards the pentacyclic system of alkaloids belonging to the saframycin family, based on the use of 2,5-piperazinadiones as starting materials. We describe, in the first place, that microwave irradiation of N-BOC-protected dipeptide esters is a general method for the synthesis of 2,5-piperazinadiones. This procedure has several advantages over traditional ones, including short reaction times, higher yields and a higher stereochemical integrity. We have developed a very concise method for the generation of the D ring of the saframycins using a route that involves breaking the symmetry of 3,6-bis(arylmethylene)-2,5- piperazinadione precursors by selective reduction of one of their double bonds followed by selective activation of the N-2 lactam nitrogen using a carbamoylation-reduction sequence. B ring generation was achieved by Pictet-Spengler chemistry involving N-acyliminium intermediates, starting from 1-arylmethyl derivatives of the C ring or the CDE fragment. A new variation of the Pictet-Spengle reaction has been developed, using nonisolated amidosulfones as precursors of the N-acyliminium intermediates. This method leads to pentacyclic systems containing the whole saframycin framework in a single synthetic operation. This is the first description of the use of amidosulfones as intermediates in heterocyclic synthesis. In the reactions involving B ring formation using aromatic acetals and trimethylsilyl triflate as a catalyst, the presence of the CDE fragment directs the entry of the acetal and leads to the generation of compounds with the same relative configuration as the natural products with complete diastereoselectivity. The presence of N-H bonds close to the C-7 or C-4 carbonyls (in pentacyclic or CDE tricyclic systems, respectively) prevents their reductive cyanation due to a competing intramolecular hydride transfer that leads to the complete reduction of the lactam groups to amines. Finally, the biological studies have proved that some arylmethylene derivatives of the CDE ring system show in vitro antitumour activity, although they lack a good leaving group at C-4. These compounds can be considered as cribrostatin seco analogues.