Development of a Synthetic Platform for Ent-Pimaranes Reveals their Potential as Novel Non-Redox Active Ferroptosis Inhibitors.

We present a comprehensive account on the evolution of a synthetic platform for a subfamily of ent-pimaranes. For the most complex member, norflickinflimiod C, five distinct strategies relying on either cationic or radical polyene cyclizations to construct the requisite tricyclic carbon scaffold were explored. Insights from early and late stage oxidative and reductive dearomatization studies ultimately led to a mild, rhodium-catalyzed arene hydrogenation for the final synthetic route. A Sharpless asymmetric dihydroxylation was found to be suitable to render the platform enantioselective and diversification of a late-stage key intermediate culminated in the total synthesis of eight ent-pimaranes in 11-16 steps. These compounds were found to inhibit the formation of pro-inflammatory leukotrienes and other 5-lipoxygenase products. Notably, three ent-pimaranes exhibited low micromolar, non-redox active ferroptosis inhibition with remarkable structural specificity.