Synthetic Studies toward Anguidine: Assembly of the Tricyclic Ether Scaffold

Anguidine, a type A trichothecene (TCN) isolated from Fusarium graminearum, features a highly functionalized 6/6/5 tricyclic scaffold incorporating a central six-membered ether ring and a C12-C13 epoxide. Its pronounced bioactivity and structural complexity render it a challenging synthetic target. Herein, we describe our synthetic investigations toward anguidine and its tricyclic ether scaffold. An initial model study enabled efficient construction of the 6/5/6 tricyclic framework through a sequence comprising intramolecular aldol condensation, 1,2-addition, and acid-catalyzed intramolecular cyclization as the key transformations. This strategy established the fused carbocyclic system featuring a central ether linkage in a concise, convergent manner. Application of this approach to the total synthesis of anguidine commenced with the assembly of a highly functionalized cyclopentane precursor, featuring key transformations such as Wittig olefination and dihydroxylation. Subsequent 1,4-conjugate addition, intramolecular aldol condensation, 1,2-addition, and intramolecular cyclization were designed to construct the tricyclic framework that encompasses the full carbon skeleton of anguidine. Although advanced intermediates bearing the required connectivity were successfully obtained, completion of the total synthesis proved challenging due to the steric hindrance associated with the pre-functionalized cyclopentane precursor.