71(P52) ザラゴジン酸類の合成研究(ポスター発表の部)
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概要
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Zaragozic acids (squalestatins), fungal metabolites isolated and characterized independently by research groups at Merck and Glaxo in 1992, have been shown to be picomolar competitive inhibitors of the enzyme squalene synthase. Herein we wish to report our studies directed toward a convergent synthesis of zaragozic acids. The key feature of our first synthesis is a simultaneous creation of the consecutive quaternary carbon centers at C4 and C5 by Sn(OTf)_2-promoted aldol coupling reaction between α-keto ester and silyl ketene thioacetal derived from L- and D-tartaric acids, respectively. While the desired configuration at C4 was secured by this coupling, the stereoselectivity at C5 of the aldol products was found to be highly dependent on the nature of the protective groups on each reaction partner as well as the geometry of the silyl ketene thioacetal (Table 1 and 2). The best result was attained when (Z)-silyl ketene thioacetal 8 with isopropylidene acetal protection was coupled with α-keto ester 15 protected by pentylidene acetal and MEM groups. Conversion of the desired adduct 24 to the cyclization precursor 32 was achieved by the twelve-step sequence including protective groups manipulations, oxidations and installation of the C1 side chain by addition of the lithium acetylide of 31 (Scheme 2). Exposure of 32 to 90%aq. TFA underwent deprotection of the acetal and silyl protective groups and subsequent ketalization to provide the desired bicyclic core 33 in 68% yield, which was uneventfully transformed to zaragozic acid C via Carreira's intermediate 37. Toward a second-generation synthesis of zaragozic acids, it occurred to us that 1,3-dipolar cycloaddition of cyclic carbonyl ylide 43 generated by Rh(II)-catalyzed decomposition of the α-diazo compound 44 with suitable dipolarophiles might lead to a highly efficient construction of the common 2,8-dioxabicyclo[3.2.1]octane core structure of these natural products. In the presence of 5mol% of Rh_2(OAc)_4, 1,3-dipolar cycloaddition reaction of α-diazo ester 49 with 3-hexene-2,5-dione was found to lead to the formation of the desired cycloadduct 52 as the single isomer in 47% yield, whereas a complex mixture of products was obtained with 4-epi-49.
- 1997-07-20
著者
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佐藤 浩樹
北大薬:ゼリア新薬工業(株)中央研究所
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橋本 俊一
北大院薬
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中村 精一
北大薬
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片岡 治
北大薬
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北垣 伸治
北大薬
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渡邉 信英
北大薬
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橋本 俊一
北大薬
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橋本 俊一
Fac. Of Pharmaceutical Sciences Hokkaido Univ. Sapporo 060-0812 Jpn
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Kitagaki Shinji
Faculty Of Pharmaceutical Sciences Osaka University
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中村 精一
Faculty Of Pharmaceutical Sciences Hokkaido University
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