Tropoloisoquinoline alkaloids have been attractive synthetic targets due to their unique architecture and potent cytotoxicity. Pareitropone, the most effective tropoloisoquinoline against the leukemia P388 cell line (IC50 = 2.7 nM), was first chemically synthesized via alkynyliodonium chemisty by Feldman and coworkers in 2002. We have completed the second total synthesis of pareitropone via intramolecular radical coupling of phenolic nitronate. Starting from vanillins, properly substituted biaryl aldehydes were prepared by Suzuki coupling and introduction of nitroalkyl(or nitroalkenyl) group afforded the cyclization precursors.
To investigate how the methoxy substituents affect the biological activities, several analogs of pareitropone have been prepared and all the compounds were synthesized by the intramolecular radical coupling as a key reaction.