Synthesis of Racemic Fomannosin and Illudol Using a Biosynthetically Patterned Common Intermediate

The synthesis of fomannosin, a toxic fungal metabolite with a unique methylenecyclobutene structure, is approached in two different ways, making use of rigid tricyclic intermediates to control the configuration at two crucial chiral centers. The first approach was carried through the formation of the cyclobutane ring, using cycloaddition of ethoxyacetylene to a ketene. The stereoselectivity was disappointing, and that strategy was abandoned in favor of an approach which derived from the biosynthesis pathway for fomannosin. In this route, the Diels-Alder reaction of a cyclobutenecarboxylate with the appropriate diene generates the tricyclic protoilludane skeleton stereospecifically. The Diels-Alder adduct is converted through a series of eight steps to racemic illudol, a natural protoilludane sesquiterpene, and through 11 steps to result in the first total synthesis of fomannosin.