How Intramolecular Epoxide-Opening Cascades Generate Polyether Ionophores, Marine Ladder Polyethers, and Oxasqualenoids

The synthesis of polycyclic polyether natural products, including linked-THF-type polyethers (polyether ionophores), trans -fused-type polyethers (i.e., marine ladder polyethers), and oxasqualenoids, has long been of interest. Synthetic chemists have attempted to prepare polycyclic polyethers from polyepoxide precursors via intramolecular tandem epoxide-opening cyclizations, inspired by proposed biosynthetic pathways, such as the Cane–Celmer–Westley pathway and the pathway hypothesized by Nakanishi. Here, we used NMR spectroscopy to monitor intramolecular tandem epoxide-opening cyclization pathways that generate linked-THF-type and trans -fused-type polyethers. We found that the linked-THF-type polyether glabrescol forms in a stepwise manner through hydroxy-to-epoxide ring-opening cyclizations. Surprisingly, however, all the ether rings in the trans -fused-type polyether hemibrevitoxin B form either simultaneously or via rapid, contiguous epoxide-to-epoxonium ring-opening cyclizations once the polyepoxide precursor is in the cyclization conformation. Moreover, the skeletons of two oxasqualenoids could be synthesized by hydroxy-to-epoxide and epoxide-to-epoxonium ring-opening cyclizations within a single molecule. By manipulating the nucleophilicity of the hydroxy group, we could control the relative contributions of the two types of ring-opening cyclizations.