Two methods are presented that were designed to circumvent the persistent problem of benzofuran formation and instead yield a spiroketal of the rubromycin family type. First, using an alternative disconnection, a hemiketal conjugate addition to a naphthaquinone electrophile was investigated. Synthesis of the requisite electrophile provided insight into the selective oxidation and functionalization of the naphthalene portion. Second, the electronic features of the isocoumarin ring system were adjusted, and the corresponding reactivity further supports the hypothesis that electron-rich isocoumarins are capable of spiroketalization. Robust, flexible syntheses from simple precursors were developed that allowed multiple reduced isocoumarins to be generated. Combined, the data presented herein give insight into the sensitivities of this family and illuminate other potential methods of spiroketalization. In addition, the convergent assembly of substrates containing different naphthaquinone and isocoumarin subunits highlights the utility of our 1,3-dipolar cycloaddition approach to generate analogs of these structures for SAR, as well as chemical reactivity studies.