Total syntheses of racemic albifloranine and its anti-addictive congeners, including 18-methoxycoronaridine

Condensation of methyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (12) with 4-(1,3-dioxolan-2-yl)-6-benzylaxyhexanal (11a) provided the tetracyclic intermediates methyl (3aSR,4RS,11bRS)-3-benzyl-2,3,3a,4,5,7-hexahydro-4-[2-zeta-(1,3-dioxalan-2-yl)-4-benzyloxy)-1-butyl]-1H-pyrrolo[2,3-d]carbazole-6-carboxylates (14a,15a), which were further elaborated to afford racemic albifloranine (3). The first total synthesis of albifloranine was completed in 13 steps, with an overall 7% yield. Ester and ether derivatives of albifloranine were synthesized for evaluation as anti-addictive agents. Among these, 18-methoxycoronaridine (20b) stands out as a nontoxic agent that significantly reduces demand for morphine, cocaine, nicotine and alcohol in rats. (C) 1999 Elsevier Science Ltd. All rights reserved.