Total syntheses of zaragozic acids A and C by a carbonyl ylide cycloaddition strategy |
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Authors: | Hirata Yuuki Nakamura Seiichi Watanabe Nobuhide Kataoka Osamu Kurosaki Takahiro Anada Masahiro Kitagaki Shinji Shiro Motoo Hashimoto Shunichi |
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Institution: | Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. |
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Abstract: | A carbonyl ylide cycloaddition approach to the squalene synthase inhibitors zaragozic acids A and C is described. The carbonyl ylide precursor 8 was synthesized starting from di-tert-butyl D-tartrate (47) via an eleven-step sequence involving the regioselective reduction of the mono-MPM (MPM=4-methoxybenzyl) ether 48 with LiBH4 and the diastereoselective addition of sodium tert-butyl diazoacetate to alpha-keto ester 10. The reaction of alpha-diazo ester 8 with 3-butyn-2-one (40) in the presence of a catalytic amount of Rh2(OAc)4] gave the desired cycloadduct 59 as a single diastereomer. The dihydroxylation of enone 59 followed by sequential transformations permitted the construction of the fully functionalized 2,8-dioxabicyclo3.2.1]octane core 5. Alkene 79 derived from 5 serves as a common precursor to zaragozic acids A (1) and C (2), since the elongation of the C1 alkyl side chain can be attained by olefin cross-metathesis, especially under the influence of Blechert's catalyst (85). |
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Keywords: | carbonyl ylides cycloaddition diazo compounds metathesis total synthesis |
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