Oxidative Friedel-Crafts Reaction and its Application to the Total Syntheses of Amaryllidaceae Alkaloids

An oxidative Friedel-Crafts reaction involving different aromatic compounds mediated by a hypervalent iodine reagent has been performed, using polysubstituted phenols. The strategy fits within the concept of aromatic ring umpolung, which opens up novel opportunities in chemical synthesis. The reaction takes place in useful yields, and allows rapid access to highly functionalized compounds containing a dienone, a quaternary carbon center, and an aromatic ring. The product's skeleton is present in numerous natural products. As an illustration of the potential of this transformation, total syntheses of compounds belonging to the Amaryllidaceae alkaloids family such as O-methyljoubertiamine, mesembrine, and its natural derivative the dihydro-O-methylsceletenone have been achieved in eight/nine steps. The synthetic route to these molecules features a novel and efficient transformation on the basis of a Fukuyama and Michael-retro-Michael tandem process to produce the required nitrogen-containing ring system.