Ladder Polyether Synthesis via Epoxide-Opening Cascades Using a Disappearing Directing Group

Abstract

The combination of a trimethylsilyl group, a Brønsted base, a fluoride source, and a hydroxylic solvent enables the first construction of the tetrad of tetrahydropyran rings found in the majority of the ladder polyether natural products by way of a cascade of epoxide-opening events that emulates the final step of Nakanishi's proposed biosynthetic pathway. The trimethylsilyl group disappears during the course of the cascade, and thus these are the first epoxide ring-opening cascades that afford ladder polyether subunits containing no directing groups at the end of the cascade.

Three‐Membered Heterocycles. Structure and Reactivity

“…An illustrative example is found with the titanium-promoted cyclization of the highly oxygenated bicyclic epoxide 537 to give the spiroketal 538 with retention of configuration [593]. Similar intramolecular processes have been catalyzed by caesium [594] and p-toluenesulfonic acid [595]. In one such intramolecular epoxide ring opening -a key step in the diastereoselective synthesis of a-tocopherol -anhydrous hydrochloric acid in ether/acetonitrile was chosen to promote the disfavored 6-endo-tet ring closure mode [596].…”

Biomimetic Synthesis of Polyether Natural Products via Polyepoxide Opening

“…However, when a cascade reaction under the same Lewis acid conditions was attempted on diepoxide 256, with suitably positioned silyl groups, the only isolable product was bis-tetrahydrofuran 257 (Scheme 15.20a) [198]. Thorough evaluation of reaction conditions revealed that the outcome of this reaction was very different when a Brønsted base in alcoholic solvents was used.…”

“…Surprisingly, the trimethylsilyl directing group was absent from the ring junction in the product. Further modification to the design of polyepoxide substrates and reaction conditions resulted in the development of epoxide-opening cascades directed by ''disappearing'' silyl groups (Scheme 15.20b) [198]. These modifications included the pre-formation of one THP ring in substrates 259, 262, and 265 prior to the cascade and the addition of CsF to the reaction mixture.…”

Metalated heterocycles in organic synthesis: Recent applications

“…310 Interestingly, when this Lewis acid is used with the diepoxyde 157, the 5-exo-ditetrahydrofuran 158 is obtained in a ladder polyether fashion, whereas the more interesting natural product-containing tetrahydropyrane dyad 159 is generated after treatment of compound 157 with cesium carbonate (Scheme 49). 311 The boron-trifluoride epoxide oxacyclization has also applied to triepoxides, leading to bisoxepanes. …”