Establishment of “Ring-Size-Divergent” Synthetic Strategy and Its Application to Divergent Synthesis of Natural Products

The epoxide-opening cascade biogenesis was originally proposed for ionophoric polyether antibiotics as in the Cane-Celmer-Westley hypothesis and has been utilized as an efficient method to rapidly construct natural polyether skeletons. For example, teurilene, the marine polyether derived from red algae, was synthesized from squalene tetraepoxide, a hypothetical biogenetic precursor, via a three-step, 5-exo selective epoxide-opening cascade cyclization triggered by Brønsted-acid-catalyzed hydrolysis of the terminal epoxide. In previous work, it was shown that the epoxide-opening cascade cyclization that produces tetrahydrofuran (THF) products in acidic aqueous media instead yields tetrahydropyran (THP) in neutral water. The THP formation proceeded via an epoxonium-ion intermediate by simple heating in neutral water. In this report, we successfully established a “ring-size-divergent” synthetic method to divergently construct five-, six-, and seven-membered ether rings from identical diepoxides, achieving the synthesis of seven-membered (oxepane) ring under acidic conditions using Lewis acid. With this new synthetic strategy, we also accomplished the divergent synthesis of nerolidol-type sesquiterpenoids and feroniellins, revising the proposed stereochemistry of certain natural products and determining their absolute configurations. Additionally, we evaluated the anti-inflammatory activities of the synthetic samples.