STEREOCONTROLLED FORMATION OF OCTAHYDRO-1H-PYRROLO[2,3-D]CARBAZOLES BY REDUCTIVE CYCLIZATION - TOTAL SYNTHESIS OF (+-)-N-BENZYLASPIDOSPERMIDINE

The synthesis of a series of 20-substituted octahydro-1H-pyrrolo[2,3-d]carbazoles 7, intermediates in the synthesis of Aspidosperma alkaloids, is described. Nonoxidative photocyclization of aryl enaminone 12 led to hexahydrocarbazol-4-ones 15a,b. Alkylation of the anions derived from 15a,b with KH and iodoacetonitrile gave rise to an undesirable intramolecular cyclization while reaction with LDA and nitroethylene as Michael acceptor afforded the trisubstituted hexahydrocarbazolones 21a,b. Reductive cyclization (H-2, PtO2) of cyano model compounds 16a,b and 17 provided octahydro-1H-pyrrolo[2,3-d]carbazoles 25 and 27 whose stereochemistry depended on hindrance of the alpha and beta face of the molecule. In contrast, reduction (HCOONH4, Pd/C, and then Na/EtOH) of nitro model compounds 18a,b and 19 via nitrones 22a,b and 23 and imine 24 led essentially to the more stable isomers 25B, 25C, and 27B with the natural stereochemistry at C-21. Reduction (HCOONH4, Pd/C) of nitro compounds 21a,b, which possess the elements for the future construction of the D and E rings, induced a tandem cyclization and afforded the pentacyclic iminium 30 which was converted by catalytic hydrogenation into (+/-)-N-benzylaspidospermidine (4). This compound was thus synthesized in seven steps from N-benzylaniline and cyclohexane-1,3-dione.