Various naphthopyranones were synthesized and tested for their cytotoxicity and apoptotic activity. The synthesis was carried out using two building blocks, which were prepared from enantiomerically pure oxiranes and methyl acetoacetate and then reacted with each other to form naphthopyranones. Monomeric and dimeric naphthopyranones were synthesized and then a structure–activity relationship study was carried out.

Abstract

Dimeric naphthopyranones are known to be biologically active, however, for the corresponding monomeric naphthopyranones this information is still elusive. Here the first enantioselective total synthesis of semi-viriditoxic acid as well as the synthesis of semi–viriditoxin and derivatives is reported. The key intermediate in the synthesis of naphthopyranones is an α,β-unsaturated δ-lactone, which we synthesized in two different ways (Ghosez–cyclization and Grubbs ring–closing metathesis), while the domino–Michael–Dieckmann reaction of the α,β-unsaturated δ-lactone with an orsellinic acid derivative is the key reaction. A structure-activity relationship study was performed measuring the cytotoxicity in Burkitt B lymphoma cells (Ramos). The dimeric structure was found to be crucial for biological activity: Only the dimeric naphthopyranones showed cytotoxic and apoptotic activity, whereas the monomers did not display any activity at all.