Chiral bronsted acid catalyzed enantioselective alfa-amidoalkylation reactions in the synthesis of tetrahydroisoquinoline systems

Résumé

The research work described in this thesis has focused on the study of enantioselective intra and intermolecular ¿-amidoalkylation reactions catalyzed by chiral Brønsted acids for the synthesis of tetrahydroisoquinoline systems. The intermolecular ¿-amidoalkylation reactions of hydroxylactams, generated by Parham cyclization of the corresponding imides, with nucleophiles, such as indoles and enamides that have an H bond donor group, catalyzed by sterically demanding BINOL-derived N-triflylphosphoramides and phosphoric acids, afforded moderate to good enantioselectivities. The reaction is proposed to take place via a bicyclic N-acyliminium /chiral conjugate base ion pair, in which the chiral Brønsted acid catalyst may act as a bifunctional catalyst, interacting also with the nucleophile.In a similar way, the enantioselective intramolecular ¿-amidoalkylation reaction requires phenolic activation on the benzene ring acting as internal ¿-nucleophile to achieve reasonable levels of enantioselection. In this case, different substituents can be introduced at C-1 position of the isoquinoline moiety by changing the organometallic reagent at the first step of the organometallic addition/intramolecular ¿-amidoalkylation sequence, giving rise to useful precursors for the construction of more complex alkaloids.