significant cytotoxicity against the NCI-60 cancer cell panel (mean GI50 = 72 nM), and is uniquely effective against cancer types with defects in apoptotic signaling. Detailed studies in apoptosis-resistant glioblastoma cell lines show that 1 induces paraptosis, a phenotype linked to the ability of 1 to covalently modify phosphatidylethanolamine. This potentially impactful pharmacology has inspired several efforts to prepare 1 via total synthesis. Two distinct solutions to the sesterterpene have been disclosed. The first, established by Nakada in 2011, approaches (+)-1 from completed A-ring and C-ring fragments. More recently, Maimone developed a synthetic entry point to (+)-6epi-ophiobolin A (2) that exploits a radical polycyclization strategy. These advances in the chemical synthesis of 1 complement ongoing efforts to resolve its mechanism(s) of action. Several structure-activity relationships have emerged from this work. Most importantly, the 1,4-dicarbonyl functional group in 1 has been shown to react with primary amines to afford pyrroles. As a result, the absence of either carbonyl group markedly reduces the cytotoxicity of 1 in cell culture. The configuration of substituents at C2, C3, and C6 (i.e. the A-ring stereotriad) impacts the rate and selectivity of this condensation chemistry. Computational modeling suggests that epimerization of the C6 stereocenter changes the conformation of the B-ring, thereby slowing the rate of reactions between 2 and its condensation partner(s) in vivo. This working hypothesis has been expanded to rationalize the diminished cytotoxicity of 3-anhydro-OpA (3) and 3-anhydro-6-hydroxy-OpA (4) relative to 1. Guided by this model, Taube and Romo developed (±)-5, a fragment of 1 that emerged as the minimal substructure for activity against the triple-negative MDA-MB-231 breast cancer cell line. However, this study revealed a significant difference in efficacy between (±)-5 and 1, suggesting an important ancillary role for the C and D rings. This observation inspired us to explore a different approach to the 5-8-5 carbocyclic nucleus of 1. Herein, we report our initial findings from this nontrivial endeavor.