Synthesis of pindikamine A, a michellamine-related dimer of a non-natural, 'skew' naphtylisoquinoline

The synthesis of an unnatural dimeric naphthylisoquinoline, pindikamine A (3), as a ‘skew’ analog of antiviral michellamines, is described. Because of the unusual coupling positions, this C2-symmetric quateraryl is the first michellamine analog without axial chirality. Key steps of the total synthesis are the preparation of the molecular precursor 9 by intermolecular biaryl coupling, followed by a highly efficient oxidative ‘dimerization’ to give 8, which is transformed to 3. Pindikamine A (3) and its monomeric ‘half’ 10 show good antimalarial activity against Plasmodium falciparum in vitro.
The novel, non-natural dimeric naphthylisoquinoline 3, the first michellamine analog with non-stereogenic axes exclusively, has been prepared. It shows good antimalarial activity against Plasmodium falciparum.