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.

Pnictogen‐Bonding Catalysts, Compared to Tetrel‐Bonding Catalysts: More Than Just Weak Lewis Acids

“…Violations of the Baldwin rules were realized with epoxide‐opening polyether cascade cyclizations ( Scheme 2). [54,62,63] Charismatic in chemistry and biology, classics in total synthesis, they respond to as many mechanistic variables as possible [8,64–77] . With regard to chemoselectivity, the Baldwin rules, [78] or maybe the Eschenmoser–Dunitz–Baldwin guidelines, [79,80] are central.…”

“…The found endo selectivity for Sb(III) 1 and particularly Sb(V) 3 compared very well with the literature on the topic. The only system approaching similar selectivity, that is 1‐ethyl‐3‐methylimidazolium tetrafluoroborate ([EMIM]BF 4 ) in perfluoro‐ tert ‐butanol (PFTB), has been found recently by Jin Qu and coworkers [66] . While hydrogen‐bonding contributions from the strongly ionizing PFTB solvent to the epoxide are trivial, multiple charge‐dipole interactions from C−F and B−F dipoles from catalyst and solvent to the carbocation‐like intermediate have been proposed to account for high endo selectivity [88] .…”

“…While hydrogen‐bonding contributions from the strongly ionizing PFTB solvent to the epoxide are trivial, multiple charge‐dipole interactions from C−F and B−F dipoles from catalyst and solvent to the carbocation‐like intermediate have been proposed to account for high endo selectivity [88] . With the [EMIM]BF 4 in PFTB catalyst, the cyclization of trans ‐ 10 gave 55 % trans‐ (AA)‐ 14 and 11 % trans‐ (BB)‐ 11 [66] . This result was slightly better than Sb(III) 1 but clearly inferior to Sb(V) 3 ( Scheme 3).…”

“…[54,62,63] Charismatic in chemistry and biology, classics in total synthesis, they respond to as many mechanistic variables as possible. [8,[64][65][66][67][68][69][70][71][72][73][74][75][76][77] With regard to chemoselectivity, the Baldwin rules, [78] or maybe the Eschenmoser -Dunitz -Baldwin guidelines, [79,80] are central. In biology, anti-Baldwin (A) cascade cyclizations that violate the Baldwin rules are best known from the putative epoxide 6 that, according to the Nakanishi hypothesis, cyclizes into brevetoxin B.…”

“…The only system approaching similar selectivity, that is 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM]BF 4 ) in perfluoro-tert-butanol (PFTB), has been found recently by Jin Qu and coworkers. [66] While hydrogen-bonding contributions from the strongly ionizing PFTB solvent to the epoxide are trivial, multiple charge-dipole interactions from CÀ F and BÀ F dipoles from catalyst and solvent to the carbocation-like intermediate have been proposed to account for high endo selectivity. [88] With the [EMIM]BF 4 in PFTB catalyst, the cyclization of trans-10 gave 55 % trans-(AA)-14 and 11 % trans-(BB)-11.…”