First Stereoselective Total Synthesis of a Dimeric Naphthoquinonopyrano-[gamma]-lactone: (+)-[gamma]-Actinorhodin

We have accomplished the first total synthesis of an isomerically pure naphthoquinonopyrano-[gamma]-lactone dimer, [gamma]-actinorhodin, in eleven steps. Two steps exploit pairs of peri-MeO groups as unusual selectivity controls. The respective MeO groups convey the steric bulk of a bromo or iodo substituent located ortho to one MeO group as steric hindrance into the vicinity of the second MeO group. This relay effect was indispensable for exerting regiocontrol in an aromatic bromination and diastereocontrol in an oxa-Pictet-Spengler cyclization. The absolute configuration of our target compound was established in an asymmetric Sharpless dihydroxylation of a [beta],[gamma]-unsaturated ester, which was synthesized in a Heck coupling of a bromoiodonaphthalene with ethyl vinylacetate. The dihydroxylation provided the [gamma]-hydroxylactone moiety of the bromonaphthalene that was used as the substrate in the oxa-Pictet-Spengler cyclization. Dimerization to the core of [gamma]-actinorhodin occurred by two Suzuki couplings.