Anionic polycyclization : towards the total synthesis of indole alkaloids and morphine derivatives

Aspidosperma alkaloids receive special attention of synthetic chemists due to their enticing structures and a wide range of remarkable biological activities. A Key feature of these molecules lies in its tetracyclic scaffold, the 6-5-6-5 ABCE ring system called Büchi’s ketone, from which many aspidosperma alkaloids could be elaborated. As part of our ongoing efforts to rapidly access to indole alkaloids, A new sequential polycyclization to the 6-5-6-5 ABCE tetracyclic framework of aspidosperma alkaloids has been developed. Specifically Lewis-acid mediated spirocyclization of a sulfonamide-activated enone, synthesized from tryptamine derivatives, afforded spiroindolenine intermediate; subsequent ring closing imino-aldol reaction afforded a tetracyclic product. We next turned our attention to the total synthesis of a different family of alkaloids, morphine derivatives. Another novel anionic polycyclization to afford the 6-5-6-6 ACNO teteracyclic core of morphine has been developed. Finally, the synthetic utility of this methodology was demonstrated by the application to the short and efficient synthesis of ACNO analogue of morphine, which is expected to be a potent novel analgesic.