The total synthesis of the structurally unique secondary metabolite sporolide B (1b) is described. The total synthesis of lb was developed on the basis of preliminary studies that revealed the reactivity of an appropriate o-quinone as a diene system toward a number of indene derivatives as dienophiles, first in intermolecular and thence intramolecular settings. Thus, substrates were devised (37 and 75) that underwent exquisite intramolecular [4+2] cycloaddition reactions under thermal conditions to provide primitive sporolidetype structures that were subsequently elaborated to a sporolide model system, 9-epi-sporolide B, and 1 b. The requisite indene o-quinone precursor 75 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 1 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 rutheniumcatalyzed [2+2+2] cycloaddition reaction to highly substituted indene systems possessing a chlorine residue on the aromatic nucleus.