30 (-)-Zampanolideの全合成(口頭発表の部)

抄録

(-)-Zampanolide (-)-1 was isolated from Okinawa sponge (Faciospongia rimosa) by Higa and Tanaka in 1996. Five years later, Riccio and co-workers isolated (+)-dactylolide (+)-2 possessing antipodal macrolactone ring of (-)-1 from Dactylospongia sp. collected in Vanuatsu island. The enantiomeric relationship vis-a-vis the common macrecyclic domains of (-)-1 and (+)-2, is a rare occurrence in marine natural products. This observaton aptly suggests that if dactylolides were either a direct biosynthetic precursor to zampanolide, or perhaps a degradaton product thereof, one should expect to either find both (-)-1 and (-)-2 in Fasciospongia rimosa or (+)-1 together with (+)-2 in Dactylospongia sp.; however, neither was the case. (-)-Zampanolide (-)-1 is a potent cytotoxic agent and possesses a unique molecular architecture comprised of a highly unsaturated macrolactone ring, a bridged 2,6-cis-tetrahydropyran unit and an exocyclic N-acylhemiaminal group with the pendant N-(2Z,4E)-hexadienoylamide (23). In this pater, we report a concise total synthesis of (-)-1 and (-)-2. The key synthetic transformations involve i) the Kita-Trost macrolactonization, ii) a short seco-acid formation by a mind HWE reaction, iii) consecutive Sonogashira/Kumada-Tamao-Corriu couplings, iv) stereo selective cis-THP ring formation. A biological evaluation of (-)-1 and its diastereomer 24 revealed an importance of the stereochemistry of the hemiaminal moiety. The analysis of the extract obtained from the Okinawa sponge by LC-MS turned up no evidence of (-)-dactlolide as a distinct entity in the sponge extract. Therefore, we conclude that (+)-dactylolide is indeed a naturally occurring entity, and currently, we hypothesized that the macrolactone ring may from after formation of N-acylhamiaminal in the sponge.