Establishment of "Ring-Size-Divergent" Synthetic Strategy: Divergent Synthesis, Stereochemical Assignments, and Biological Activity Studies of Nerolidol-Type Sesquiterpenoids and Feroniellins.

Abstract

Biomimetic epoxide-opening cascade cyclizations of polyepoxides enable the efficient and rapid construction of polyether skeletons. In this study, we discovered a method for switching the cyclization mode from tetrahydrofuran to tetrahydropyran (THP) formation in epoxide-opening cascades of polyepoxides. The THP formation proceeded via an epoxonium-ion intermediate by simple heating in neutral water. Next, by expanding the switching reaction, we successfully established a "ring-size-divergent" synthetic strategy that enabled the synthesis of the five-, six-, and seven-membered ether rings from identical diepoxide cyclization precursors under simple acidic or neutral conditions. The "ring-size-divergent" synthetic strategy was applied to the short divergent synthesis of nerolidol-type sesquiterpenoids and feroniellins, resulting in the revision of the proposed stereochemistry of certain natural products and the determination of all of the absolute configurations. Additionally, the anti-inflammatory activities of the synthetic samples were evaluated.