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-3methylimidazolium 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.

Synthetic and biosynthetic methods for selective cyclisations of 4,5-epoxy alcohols to tetrahydropyrans

“…More recently, Qu and co-workers demonstrated how trialkyl substituted epoxides are converted to the corresponding THP products through reaction with 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM]BF 4 ) in perfluoro-tertbutanol (PFTB). 74 In contrast, disubstituted epoxides formed solely the THF products. These contrasting results indicate the important role that an extra substituent on the epoxide can play in controlling 6-endo cyclisation.…”

Fluorinated alcohols: powerful promoters for ring-opening reactions of epoxides with carbon nucleophiles

“…To maintain focus, we have not extended this review beyond the heterocyclic epoxide and aziridine electrophiles, even though the analogous ring-opening reactions of aryl-substituted cyclopropanes with electron-rich aromatic nucleophiles in HFIP may be mechanistically related. 13 Nonafluoro-tert-butyl alcohol (NFTB) promotes epoxide ring-opening with oxygen nucleophiles, including regioselective cascade cyclizations of polyepoxides terminated by alcohols, 14…”

Biomimetic Construction of a syn-2,7-Dimethyloxepane Ring via 7-Endo Cyclization

“…Via a vinyl group-assisted 6 -endo cyclization, Nicolaou transformed 1 into 2 , thus providing a syn -2,6-dimethyltetrahydropyran ring despite the 1,3-repulsion between its methyl groups (Scheme A) . Various 7- endo cyclizations have also been studied, where oxepane rings lacking angular methyl groups or bearing only one angular methyl group were successfully constructed. , However, syn -2,7-dimethyloxepane rings have not yet been formed via the 7 -endo cyclization, despite the plausible biosynthetic importance of this strained ring system toward C-CTX-1, gymnocin-B, and brevisulcenal-F natural syntheses. For example, Yoshikawa et al failed to convert vinyl epoxide 3 into the desired oxepane 4 via acid-catalyzed cyclization because an elimination product had formed (Scheme B) .…”