Cyclopropene Cycloadditions with Annulated Furans: Total Synthesis of (+)- and (−)-Frondosin B and (+)-Frondosin A

The asymmetric total
syntheses of the natural products (+)- and
(−)-frondosin B and (+)-frondosin A are reported based on a
diastereoselective cycloaddition between tetrabromocyclopropene and
an annulated furan to provide a highly functionalized common building
block. The bridged bicyclic intermediate could be stereo- and chemoselectively
manipulated to produce the two structurally distinct members of the
frondosins. Both syntheses feature regioselective palladium-coupling
reactions and an unprecedented phosphine-mediated ether bridge cleavage.
Surprisingly, the planned enantioselective synthesis of frondosin
B led to the opposite epimer of the natural product, suggesting an
unusual late stage stereoinversion at C8. Frondosin A, but not frondosin
B, was shown to have selective antiproliferative activity against
several B-cell lines.