7 ホスホリパーゼA_2阻害物質、マノアリド類の効率的な全合成(口頭発表の部)

抄録

Manoalide isolated from the sponge is a nonsteroidal anti-inflammatory agent. This sesterterpenoid also showes not only significant activity against Gram positive bacteria but also inactivate directly phospholipase A_2 which is a rate limiting enzyme in phospholipid metabolisms and prostaglandin synthesis. Beside manoalide, seco-manoalide, E- and Z-neomanoalide were isolated from the same sponge. We report here the first and highly efficient syntheses of manoalide, seco-manoalide, and E-neomanoalide. For the synthesis of manoalide, the construction of γ-hydroxybutenolide moiety is the main problem. As the efficient synthetic method of γ-hydroxybutenolide possessing various substituents had not been established yet, we have developed the general synthetic method by photosensityzed oxygenation of substituted α-trimethylsilylfuran, and chemo-selective oxidation of furan ring has been achieved (Table 1). 3-Substituted-5-trimethylsilylfuran derivative 11 required for the synthesis of manoalide was obtained by two methods. One is the connection of allylchloride 4 with α-alkoxystannane 10, and the other is the Pd(0) catalized coupling of 4 with CO and stannylfuran 15. The synthesis of manoalide and seco-manoalide was achieved from compound 11 by the sequences shown in scheme 4 and 6. E-neomanoalide was also synthesized by the similar method which was shown in scheme 7. These synthestic study may help for understanding the action mechanism of phospholipase A_2.