Total Synthesis of Sporolide B and 9-<i>epi</i>-Sporolide B

The total synthesis of the structurally unique secondary metabolite sporolide B (<b>1b</b>) is described. The total synthesis of <b>1b</b> was developed on the basis of preliminary studies that revealed the reactivity of an appropriate <i>o</i>-quinone as a diene system toward a number of indene derivatives as dienophiles, first in intermolecular and thence intramolecular settings. Thus, substrates were devised (<b>37</b> and <b>75</b>) that underwent exquisite intramolecular [4+2] cycloaddition reactions under thermal conditions to provide primitive sporolide-type structures that were subsequently elaborated to a sporolide model system, 9-<i>epi</i>-sporolide B, and <b>1b</b>. The requisite indene <i>o</i>-quinone precursor <b>75</b> was synthesized through a ruthenium-catalyzed [2+2+2] cycloaddition reaction between a propargylic alcohol and a chloroacetylenic cyclopentenyne, followed by elaboration and silver-promoted oxidation of the resulting chloroindene derivative. In addition to the total synthesis of <b>1b</b>, this work demonstrated, for the first time, the power of the intramolecular hetero [4+2] cycloaddition reaction in the total synthesis of complex molecules and the application of the ruthenium-catalyzed [2+2+2] cycloaddition reaction to highly substituted indene systems possessing a chlorine residue on the aromatic nucleus.