Abstract:
This account describes the total synthesis of the title compound, a polyketide metabolite with in vitro antitumor activity. A first-generation approach involving an sp3–sp2 Suzuki cross-coupling reaction of a chiral trifluoroboratoamide and a rotationally symmetric aryl bromide successfully established the carbon framework required to construct the spiroketal core of the molecule. However, removal of the phenolic protecting groups with concomitant spiroketalization could not be achieved. A revised strategy was therefore devised, employing different protecting groups and incorporating greater functionality on the aryl bromide coupling partner. Suzuki cross-coupling, extension of the carbon backbone using a diastereoselective Mukaiyama aldol reaction and deprotection/cyclization furnished the spiroketal ring system. The final transformation required was carboalkoxylation of the aromatic ring to form the phthalide subunit present in the molecule. This manipulation was difficult to achieve due to competing protodehalogenation. Finally, a reordering of synthetic events provided access to virgatolide B by exploitation of an intramolecular hydrogen-bonding interaction in order to control the regioselectivity of the spiroketalization process.