Biomimetic Total Synthesis of Mbandakamine A and Further Antiplasmodial Naphthylisoquinoline Dimers

The first total synthesis of mbandakamine A, an unsymmetrically coupled dimeric naphthylisoquinoline alkaloid with a high steric hindrance, is described. Key step was the phenol-oxidative cross-coupling of its two 5,8'-linked monomeric units, 5-epi-korupensamine E and 8-O-methylkorupensamine A. These two naphthylisoquinolines were synthesized atroposelectively by applying the lactone method. As an alternative to the largely separate synthesis of the two monomers, both of them were provided simultaneously, by the - intentionally non-selective - O-demethylation of a late joint precursor, thus shortening the synthesis substantially. Oxidative coupling of a 1:1 mixture of the two monomers provided mbandakamine A as a single atropisomer, along with four further naphthylisoquinoline dimers, nearly all of them based on new coupling types. Some of these new quateraryls showed excellent antiplasmodial activities, in particular the 6 '-6'''-coupled main product.