Enantioselective Total Synthesis of (+)-Obtusenyne

Abstract

A total synthesis of the laurencia metabolite (+)-obtusenyne has been completed. The key steps include a Sharpless kinetic resolution and an asymmetric glycolate alkylation to establish the stereogenic centers adjacent to the ether linkage and a ring-closing metathesis reaction to construct the nine-membered ether without the aid of a cyclic conformational constraint. The synthesis was completed in 20 linear steps from commercially available 1,5-hexadiene-3-ol.

Asymmetrische Totalsynthese und Festkörperstruktur des marinen cytotoxischen Diterpens (+)‐Vigulariol

“…= 83:17). [26] Die BF 3 -vermittelte Cyclokondensation [13] [27] Zwar hatten Crimmins et al [28] demonstriert, dass Oxacyclononene durch Ringschlussmetathese zugänglich sind, allerdings schien die Cyclisierung von 18 problematisch zu sein. Die Versuche von Overman und Joe [29] sowie Jung und Pontillo [30] zum Aufbau ähnlicher Di-und Tricyclen durch Metathese scheiterten.…”

Diene, Enyne, and Diyne Metathesis in Natural Product Synthesis

“…The structure of 183 spans more than 3 nm and is characterized by 12 six-to nine-membered trans-fused cyclic ethers and a spiroannulated terminal tetra-Scheme 33 RCM-based total synthesis of the marine cyclic ethers obtusenyne (177) [88] and rogioloxepane (180) [89] by Crimmins and coworkers hydrofuran ring. Causative toxins such as 183 are produced by the marine dinoflagellate Gambierdiscus toxicus and accumulate in fish of many species through the food chain.…”

Synthesis of (+)‐Obtusenyne

“…In 2003, the second enantioselective synthesis of (+)-obtusenyne was reported by Crimmins and coworkers. [13] In their synthesis, the core nine-membered ether was directly synthesised from an acyclic precursor by means of a highly efficient ring-closing metathesis. Herein, we report a full account [8] of our synthetic efforts towards this marine natural product which has culminated in the total synthesis of (+)-obtusenyne.…”

“…Subsequently Crimmins [13] demonstrated the successful introduction of both halogen atoms at a very late stage in the synthetic route and hence "early-stage" halogenation is not a prerequisite for synthesis of the natural product. However, our synthetic endeavours pre-dated the Crimmins publication, and our own and Murais results indicated that "early-stage" halogenation may be required.…”

“…Completion of the synthesis of (+)-obtusenyne and formal synthesis of (À)-obtusenyne: While we were exploring alternative strategies for the installation of the ethyl substituent in the non-natural series towards (À)-obtusenyne ent-1, Crimmins and co-workers [13] reported their elegant total synthesis of (+)-obtusenyne (+)-1, featuring two late-stage halogenations of a fully substituted D…”