Application of a catalytic palladium biaryl synthesis reaction, via C-H functionalization, to the total synthesis of Amaryllidaceae alkaloids

The total synthesis of the Amaryllidaceae alkaloids dehydroanhydrolycorine, hippadine, pratosine, anhydrolycorine, assoanine, anhydrolycorin-7-one and oxoassoanine was achieved from the appropriate N-benzylisatin precursors using an intramolecular, palladium catalyzed, dehydrohalogenation, biaryl synthesis reaction to establish the carbon skeleton of the natural products. In order to avoid the formation of regioisomers in the cyclization reactions it was found necessary to incorporate the halogen on the benzyl group. Borane reduction of the 7H-pyrrolo[3,2,1-de]phenanthridine-4,5-dione derivatives gave 7H-pyrrolo[3,2,1-de]- and 4,5-dihydro-7H-pyrrolo[3,2,1-de]-phenanthridines (dehydroanhydrolycorine, dehydroassoanine, anhydrolycorine and assoanine). The former were readily reduced to the latter with NaCNBH₃ to give anhydrolycorine and assoanine. These compounds were then oxidized to anhydrolycorin-7-one and oxoassoanine whilst the same mixtures of borane reduction products could be oxidized to give hippadine and pratosine.