P-74 ピンナトキシンAの全合成研究(ポスター発表の部)
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概要
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The pinnatoxins and pteriatoxins are structurally related marine toxins isolated and characterized by Uemura and co-workers. These natural products have been considered as culprits in shellfish poisoning, and majority of them have also been found to be Ca^<2+> channel activators. Their unprecedented molecular architecture, combined with the associated biological activity and scarcity of natural supply, has promoted a major effort toward the synthesis of pinnatoxins. In 1998, Kishi and co-workers accomplished the first total synthesis of (-)-1, establishing the absolute stereochemistry of natural pinnatoxin A. Herein we wish to report our studies on the synthesis of pinnatoxin A (1). We have already developed a route to access the C10-C31 fragment 7. After selective liberation of the C12 hydroxyl group in 9 with 1N aqueous HCl, treatment with LiOMe effected a tandem double hemiketal formation/intramolecular hetero-Michael addition to provide desired dispiroketal 8 in 77% yield. Exposure of ketone 8 to TsOH in benzene furnished bicycloketal 7 in 73% yield. After a protection group exchange, selective desilylation of the C31 TBS ether of 10, followed by Dess-Martin oxidation, Horner-Emmons reaction with β-ketophosphonate 12 and Wittig reaction afforded the diene 5. Diels-Alder reaction of 5 with a-methylene lactone 6 in p-xylene at 160℃ in a sealed tube proceeded with complete regioselectivity to provide a mixture of four stereoisomers out of the eight possible isomers, from which the desired isomer 4 could be separated in 35% yield. Cycloadduct 4 was converted to alkyne 15 by the removal of the benzyl group, oxidation and treatment with Ohira-Bestmann reagent. After reduction of lactone moiety with LiAlH_4, the C1 hydroxyl group was selectively silylated to provide alcohol 16. Dess-Martin oxidation was followed by addition of allylmagnesium bromide and silylation to give enyne 3. Macro-cycloisomerization of 3 proceeded in the presence of 10mol % of [CpRu(CH_3CN)_3]PF_6 in acetone at 50℃ to afford 2 in 79% yield. Exposure of 2 to PPTS in EtOH resulted in the selective removal of the silyl protecting groups at C1 and C6, affording diol, which, upon tosylation of primary alcohol, gave 18. Dess-Martin oxidation was followed by conjugate reduction with the Stryker reagent and displacement of the tosylate with NaN_3 to provide azideketone 19. Further efforts toward a total synthesis are currently in progress.
- 天然有機化合物討論会の論文
- 2007-08-24
著者
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橋本 俊一
北大院薬
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菊地 史朗
北大院薬
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中村 精一
北大院薬
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橋本 俊一
Fac. Of Pharmaceutical Sciences Hokkaido Univ. Sapporo 060-0812 Jpn
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中村 精一
Faculty Of Pharmaceutical Sciences Hokkaido University
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