30 カルシウムチャネル活性化物質ピンナトキシンAの全合成(口頭発表の部)
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概要
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Pinnatoxins were isolated from the shellfish Pinna muricata and characterized by Uemura and co-workers in 1995. Owing to its unprecedented molecular architecture coupled with its biological profile as a Ca^<2+> channel activator, pinnatoxin A (1) has emerged as a highly attractive and important target for synthetic investigations. In 1998, Kishi and co-workers accomplished the first total synthesis of (-)-1, which also established the absolute stereochemistry of natural pinnatoxin A. In 2004, Hirama and co-workers reported a formal total synthesis, and very recently, Zakarian and Stivala have completed a total synthesis of 1. Herein we wish to report a total synthesis of pinnatoxin A (1). We have already reported a highly stereoselective construction of the 6,5,6-dispiro-ketal (BCD ring) system by exploiting the tandem hemiketal formation/hetero-Michael reaction sequence through the agency of LiOMe as a base. The assembly of the EF ring was effected upon exposure of the dispiroketal 8 to TsOH, completing the synthesis of the C10-C31 (BCDEF ring) portion of pinnatoxin A. With regard to the crucial Diels-Alder reaction to construct the G ring, the stereochemical arrangement requires an exo mode of cycloaddition. We found that the reaction of diene 5 with α-methylene lactone 6 exhibited complete regioselectivity and modest exo and diastereoface selectivity to give desired exo cycloadduct 4 as the major product, which was uneventfully transformed to enyne 3 in 8 steps. Upon employing a procedure reported by the Trost group, Ru-catalyzed cycloisomerization of enyne 3 proceeded with complete regioselectivity to provide 27-membered carbocycle 17 in 79% yield. The 1,2-disubstituted olefin thus formed was reduced with the Stryker reagent after oxidation of the allylic alcohol at C6. Functional group manipulations, oxidation state adjustment, self-catalyzed dehydration of the ketoamino acid to form cyclic imine (A ring) and global deprotection completed the total synthesis of pinnatoxin A.
- 2008-09-01
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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