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

Abstract

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-benzyloxyhexanal ( 11a) provided the tetracyclic intermediates methyl (3 aSR,4 RS,11b RS)-3-benzyl-2,3,3a,4,5,7-hexahydro-4-[2- ζ-(1,3-dioxalan-2-yl)-4-benzyloxy)-1-butyl]-1 H -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.