Total Synthesis of nor-1,6-Germacradion-5-ols

M. Nevalainen, A.M.P. Koskinen

    Research output: Contribution to journalArticleScientificpeer-review

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    Abstract

    The first total synthesis of (()-nor-1,6-germacradien-5-ols is described. The synthetic route involves the RCM methodology for the ring formation and a selective 1,2 addition of MeLi to cyclodecenone. By altering the order of the last synthetic steps, TBSO-protected (()-(1Z,6E)-nor-1,6-germacradien-5-ols (()-(5S*,8R*)-16 and -(()-(5S*,8S*)-16 were obtained. The synthetic strategy via cyclodecenone offers the possibility of preparing different analogues of the title compounds through addition of other nucleophiles. Moreover, nor-germacrene D could be accessed from the target molecule by methylenation of its carbonyl moiety. (()-nor-1,6-Germacradien-5-ol [(()-(1E,5S*,6E,8S*)-2] was synthesized in eight steps from isovaleric acid. The 10-membered ring was formed by RCM, and the tertiary alcohol moiety was introduced in the last step via a highly diastereoselective addition of MeLi to (()-(1E,6E)-1,6-cyclodecen-5-one (()-E,E-5. Addition of MeLi to cyclodecenone (()-Z,E-5 also occurred with complete selectivity to provide (()-(1Z,5S*,6E,8S*)-2. A slightly different synthetic pathway was also explored, in which the order of the final synthetic steps was switched: the enone formation and the addition of MeLi were conducted prior to the cyclization. When the hydroxy group was protected as a TBS ether, the newly formed olefin had exclusively Z configuration. Thus, TBSO-protected (()-(1Z,6E)-nor-1,6-germacradien-5-ols (()-16 were obtained as a 1:1 (5S*,8S*)/(5R*,8S*) mixture. The NMR spectra of these two diastereomers confirmed the relative stereochemistry of natural (-)-1,6-germacradien-5-ol (1) at C5 and C8.
    Original languageEnglish
    Pages (from-to)1554-1560
    JournalJournal of organic chemistry
    Volume67
    Publication statusPublished - 2002
    MoE publication typeA1 Journal article-refereed

    Keywords

    • asymmetric synthesis
    • natural products
    • organic chemistry

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