30 トポイソメラーゼ-II阻害活性を有する海綿由来ポポロフアノンEの全合成研究(口頭発表の部)

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Popolohuanone E (1) isolated from the Pohnpei marine sponge Dysidea sp. along with the known arenarol (2), is a potent inhibitor of topoisomerase-II and exhibits highly selective cytotoxicity against human non-small cell lung cancer cells. The structure of 1 was revealed to have a unique 3,7,8-trihydroxydibenzofuran-1,4-dione skeleton which possesses two identical cis-fused decalin moieties the same as in 2. It has been proposed that 1 may be produced biogenetically by oxidative dimerization of 6'-hydroxyarenarol (3). Its remarkable biological properties, unique structural feature, and plausible biogenetic pathway make 1 an exceptionally intriguing and timely target for total synthesis. To date, none of the total syntheses of 1 have been reported. Herein we report a method for the synthesis of the model compounds for the tricyclic core of 1. Moreover, by employing this method as the key steps, the synthesis of the compound 29, which possesses the full carbon framework with the requisite asymmetric carbons involved in 1, was successfully achieved. Our synthetic strategy for 1 features the biogenetic-type annulation of the phenolic segment 4 with the quinone segment 5 to regioselectively construct the tricyclic core of 1 as the key step. At first, we investigated the synthesis of the model compounds 10a-10d for the tricyclic core of 1 to explore the feasibility of our synthetic strategy. The regioselective annulation of the phenols 11a-11d with the quinones 12a-12d turned out to be effected by a two-step sequence, giving rise to the requisite dibenzofuran-1,4-dione systems 10a-10d. Having completed the synthesis of the model compounds 10a-10d, we next pursued the synthesis of the cis-fused decalin segment 6 required for the synthesis of the phenolic segment 4 and the quinone segment 5, starting from the enantiomerically pure (-)-Wieland-Miescher ketone derivative 9. The sequence involves ortho ester Claisen rearrangement of the allylic alcohol 18 to construct the C-1 quatemary carbon and Ir-catalyzed hydrogenation of the exocyclic olefin 20 to control the C-2 stereochemistry. Both the phenolic segment 4 and the quinone segment 5 were efficiently synthesized through the coupling reaction of 6 with the corresponding aryllithiums 7 and 8, respectively. The crucial annulation of the phenolic segment 4 with the quinone segment 5 was accomplished by employing the reaction sequence similar to that described for the synthesis of the model compounds 10a-10d, providing the desired dibenzofuran-1,4-dione derivative 29 through the coupling product 28. Since the compound 29 is considered as a potential advanced key intermediate in our designed synthetic strategy, conversion of 29 to the target molecule 1 is in progress. We have succeeded in developing a general and efficient synthetic pathway to the 2,6-disubstituted-3,7,8-trihydroxydibenzofuran-1,4-dione derivatives representing the central tricyclic core of Popolohuanone E (1). By employing this reaction sequence as the key steps in our synthetic strategy for 1, the synthesis of the compound 29 which possesses the full carbon framework with the requisite asymmetric carbons involved in 1, was successfully achieved. Work on the total synthesis of 1 is being pursued in our laboratories.
天然有機化合物討論会の論文
1998-08-31

30 トポイソメラーゼ-II阻害活性を有する海綿由来ポポロフアノンEの全合成研究(口頭発表の部)

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