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|All Authors / Contributors:||
Matthieu Willot; Jieping Zhu; Université de Paris-Sud. Faculté des Sciences d'Orsay (Essonne).
|Description:||1 vol. (270 p.) : ill. en noir et en coul. ; 30 cm.|
|Responsibility:||Matthieu Willot ; [sous la direction de] Jieping Zhu.|
Ecteinascidins are a family of marine tetrahydroisoquinolines with very promising anticancer properties. The most powerful natural molecule, ecteinascidin 743, is commercialized since 2007 in Europe as Yondelis® for treatment of advanced soft tissues sarcomas. The interest of these compounds is also that they constitute a new class of antitumoral agents thanks to an original mechanism of action. The discovery of simplified analogues of ecteinascidin 743, in particular phthalascidin and Zalypsis®, confirms the numerous perspectives given by these molecules. The main aim of this thesis was the development of new routes for the synthesis of unpublished analogues of ecteinascidin 743, taking support on the total syntheses of ecteinascidins 743 and 597 realized in the laboratory. These works enabled us to study in detail a key-step which consists in a diastereoselective N-alkylation between an enantiomerically pure amine and a racemic 2-aryl-2-bromoacetate. Then we developed a new route to the pentacyclic core of ecteinascidin 743, via an original Swern oxidation / Pomeranz-Fritsch type cyclization / thiol insertion sequence. Nevertheless, we used another synthetic way to obtain an advanced scaffold, precursor of the designed analogues of ecteinascidin 743. Finally, we also studied the generalization to other aromatic compounds of the mild conditions of the Friedel-Crafts type reaction used in the total synthesis of ecteinascidin 743.