22 抗インフルエンザAウイルス活性物質(+)-スタキフリンの全合成研究(口頭発表の部)

抄録

Stachyflin (1) was isolated from the culture broth of Stachbotrys sp. RE-7260 by Shionogi's group in 1997 and reported to exhibit potent antivairal activity against influenza A/WSN/33 (H1N1) virus in vitro with an IC_<50> value of 0.003μM with a novel mechanism of action. The structure of 1 involves a unique pentacyclic ring system with five asymmetric carbon centers, in which an etheral oxygen is joined at the cis-fused decaline juncture. This attractive biological activity and its intriguing structure prompted us to embark on a project directed towards the total synthesis of stachyflin (1). Our synthetic strategy for stachyfline (1) is shown in Scheme 1, which features the domino epoxide-opening/carbocation rearrangement/cyclization reaction (4→5) as the key step to elaborate its unique benzo[d]xanthene skeleton. The synthesis commenced with Birch reductive alkylation between the known Wieland-Miescher ketone derivative (+)-2 and the benzyl bromide 3, synthesized from 3,5-dihydroxybenzoic acid, to give a mixture of the expected coupling products 15 and 16 in moderate yield. After several steps involving stereoselective hydrogenation, the acid catalyzed isomerization of exocyclic olefin to the corresponding endocyclic olefin, and epoxidation reaction, the precursor 4 for the key reaction was obtained. Next, the key domino epoxide-opening/carbocation rearrangement/cyclization reaction of epoxide 4 was explored. After several experiments, we found that the expected domino reaction proceeded by exposure of 4 to BF_3・Et_2O and trifluoroacetic acid (TFA) in dichloromethane, which led to the formation of the desired cyclized product 5 in reasonable yield (41%). Further modification of 5 including deprotection of 3,4-dimethoxybenzyl (3,4-DMB) and methyl groups would accomplish the total synthesis of optically active stachyflin (1).