An Endo‐Selective Epoxide‐Opening Cascade for the Fast Assembly of the Polycyclic Core Structure of Marine Ladder Polyethers

Abstract The rapid synthesis of marine ladder polyethers from polyepoxide precursors (in analogy with the biosynthetic pathway hypothesized by Nakanishi) is hampered by the fact that the exo ‐selective epoxide‐opening cyclization cascade that gives THF‐type polyethers is preferred over the endo ‐selective cascade that gives the desired products. We found that perfluoro‐ tert ‐butanol (PFTB) cooperating with 1‐ethyl‐3‐methylimidazolium tetrafluoroborate ([EMIM]BF 4 ) can promote endo ‐selective epoxide‐opening cyclization reactions of trisubstituted epoxy alcohols. Starting from readily accessible homochiral polyepoxy alcohols with a methyl group at all the endo ‐cyclization sites, we were able to construct polyethers up to five consecutive fused 6‐, 7‐, and/or 8‐membered rings in one step. Notably, molecules with the 7/7/6/6 and 7/7/6/7/6 polyether frameworks of hemibrevetoxin B and brevenal, respectively, could be synthesized in 40 % and 17 % chemical yields.