Total Synthesis of (-)-Peniphenone A

The asymmetric total synthesis of the polyketide benzannulated spiroketal natural product, (-)-peniphenone A, is reported. The key reaction in the synthesis involved sp³-sp² Negishi cross-coupling between a chiral organozinc species and an aryl bromide to construct the challenging α-chiral β-aryl carbonyl motif present in the natural product. Access to the spiroketal possessing the correct stereochemistry was facilitated by an unusual thermodynamic resolution at C10. The synthesis was achieved in 14 steps (longest linear sequence) from commercially available 2,4-dihydroxybenzaldehyde in 6% overall yield. Investigations into a parallel approach required extension of Krische's enantioselective hydrogen-mediated C-C coupling to α-substituted alcohols and oxetane ring-opening with an aryllithium for assembly of the polyketide domain. These studies provide a useful foundation for further work toward the natural product family, members of which demonstrate significant activity against M. tuberculosis and offer continuing inspiration for the development of efficient new chemical methods.