First synthesis of the antimalarial naphthylisoquinoline alkaloid dioncophylline C, and its unnatural anti-HIV dimer, jozimine C

Abstract

The first total synthesis of dioncophylline C, a new antimalarial lead structure, is described. For the directed construction of the stereogenic biaryl axis, the ‘lactone methodology’ is applied, despite the lack of a ‘bridgehead oxygen’ function in the target molecule. Furthermore, the novel dimer of dioncophylline C, ‘jozimine C’, is prepared, by oxidative phenolic coupling of the protected natural monomer. Jozimine C displays good antimalarial activity ( Plasmodium falciparum; IC 50 = 0.445 μg/ml), and, in particular, represents the first unnatural dimer of a naphthylisoquinoline alkaloid with a high anti-HIV activity (HIV-1; EC 50 = 27 μg/ml).