Total Synthesis of ent-Dioxepandehydrothyrsiferol via a Bromonium-Initiated Epoxide-Opening Cascade

Abstract

In the first total synthesis of ent-dioxepandehydrothyrsiferol, the signature trans-anti-trans 7,7,6-fused tricyclic polyether framework was constructed in a single bromonium-initiated epoxide-opening cascade that incorporates both endo- and exo-selective epoxide openings, each directed by the substitution pattern of the epoxide (methyl groups). This study thus demonstrates the feasibility of a possible biogenesis.

Total (Bio)Synthesis: Strategies of Nature and of Chemists

“…Other impressive examples can be found in the preparation of large natural polyethers [236] from their corresponding poly-epoxide precursors [237]. Using such a strategy, the Jamison lab recently used polyepoxide 229 in a bromine-induced polycyclization cascade via 230 to obtain polyether 231 , an advanced building block in their synthesis of ent -dioxepandehydrothyrsiferol ( 232 ) [238]. Further research in these fields will undoubtedly result in highly effective routes to other diverse natural products.…”

Biomimetic Synthesis of Polyether Natural Products via Polyepoxide Opening

“…Computational studies by Houk [40,42] that suggest that alkyl group-directed 6-endo cyclization normally requires a loose, S N 1-like transition state prompted Holton to carry out the cascade in a strongly polar solvent. In a fashion similar to the work of the Murai [164], Jamison [80,195], and Floreancig [196], the alkene in 294 was activated with N-(phenylseleno)phthalimide, and the cascade leading to formation of the 7,6-fused BC ring system of hemibrevetoxin B proceeded in high yield (Scheme 15.23).…”

“…Formation of a bromonium species by the action of an electrophile could initiate the epoxide-opening cascade reaction, producing the complete tricycle of 39 in a single step (electrophilic initiation, Figure 15.5) [80]. However, isolation of dehydrovenustatriol and predehydrovenustatriol acetate (35 and 37, Figure 15.4) from the same producing organism suggests that at least two discrete steps are involved in the cyclization of the polyepoxy precursor.…”

“…The Jamison group recently reported an epoxide-opening cascade-based approach to the synthesis of the enantiomer of the oxasqualenoid natural product dioxepandehydrothyrsiferol (Scheme 15.13) [80]. The presence of bromine in dioxepandehydrothyrsiferol presented the opportunity to initiate the epoxide-opening cascade with electrophilic bromine reagents.…”

“…Scheme 15.13 (a) Bromonium-initiated epoxide-opening cascades; (b) synthesis of ent-dioxepandehydrothyrsiferol reported byJamison[80]. NBS = N-bromosuccinimide.…”