Total synthesis of insect antifeedant drimane sesquiterpenes

B.J.M. Jansen

Research output: Thesisinternal PhD, WU


<p>The investigations described in this thesis deal with the total synthesis of sesquiterpenes of the drimane family, named for their widespread occurrence in the stem bark of South American <em>Drimys</em> species. These compounds contain the bicyclofarnesol nucleus <strong>1</strong> , which is invariably oxidized at C-11 and/or C-12 and often at other sites as well (see figure 8.1).<p><img src="/wda/abstracts/i1601_1.gif" height="179" width="600"/><p>A few rearranged drimanes, <em>e.g.,</em> (+)-colorata-4(13),8-dienolide <strong>6</strong> , and (-)-muzigadial <strong>7</strong> , are also isolated from natural products. The rearranged bicyclofarnesol nucleus <strong>5</strong> presumably owes its biogenesis to a cation-induced migration of a methyl group from C-4 to C-3 followed by loss of a proton from C-13 to give the exocyclic methylene group (see figure 8.2).<p><img src="/wda/abstracts/i1601_2.gif" height="190" width="600"/><p>Interest in this class of compounds has been stimulated by the discovery of drimanes exemplified by (-)-warburganal <strong>2</strong> , (-)-polygodial <strong>3</strong> , and (-)-ugandensidial <strong>4</strong> , which exhibit remarkable physiological activities, <em>e.g.,</em> antifungal, molluscicidal, cytotoxic, and plant growth regulation. Especially the insect antifeedant activity has attracted much attention, for the application of naturally occurring antifeedants is of potential value for crop protection due to their specificity of action and their usually low mammalian toxicity. A survey of these drimanic sesquiterpenes and their physiological properties is presented in chapter 1.<p>The common structural feature in these drimanes is the presence of a Δ <sup><font size="-2">7,8</font></SUP>ene-11,12β-dialdehyde functionality which, in the more potent substances, is further completed with a 9α-hydroxyl substituent. This array of functional groups clearly provides a challenging target to synthetic organic chemists, as does the rearranged drimane muzigadial <strong>7</strong> with its additional exocyclic methylene group at C-4 and the chiral center at C-3. Chapter 2 is devoted to a literature survey of synthetic studies towards the total synthesis of drimanes and rearranged drimanes.<p>From a retrosynthetic analysis of these compounds an approach, starting from the <em>trans-</em> decalones <strong>10</strong> and <strong>11</strong> seemed to offer good perspectives, as outlined in scheme 8.1. Both <strong>10</strong> and <strong>11</strong> were synthesized in multigram quantities by approaches developed at our laboratory, as described in chapter 4.<p><img src="/wda/abstracts/i1601_3.gif" height="332" width="600"/><p>In both decalones the carbonyl function is properly located for the introduction of the necessary functionalized. carbon atoms at C-8 <em>via</em> Claisen condensation with ethyl formate and at C-9 <em>via</em> addition of suitably functionalized nucleophiles.<p>Ketones <strong>8a</strong> and <strong>9a</strong> were obtained in a straightforward manner. Addition of [ <em>(phenylthio)methyl</em> ] <em>lithium</em> to <strong>8a</strong> followed by hydrolysis and oxidation afforded sulfoxide <strong>12</strong> , which in turn gave regiospecifically (phenylthio)furan <strong>13</strong> upon heating in acetic anhydride. Hydrolysis then completed a new approach for the regiospecific annulation of butenolides from ketones of type <strong>10</strong> (see scheme 8.2).<p><img src="/wda/abstracts/i1601_4.gif" height="366" width="600"/><p>This sequence was also applied to <strong>9a</strong> thus giving rise to the first stereoselective total synthesis of the rearranged drimanic lactone (±)-colorata-4(13),8-dienolide <strong>6</strong> .<p>Thermolysis of sulfoxide <strong>12</strong> in refluxing toluene gave the unsaturated aldehyde <strong>15</strong> . Since the latter has been converted into (±)-warburganal <strong>2</strong> , this approach allows a synthetic entry to this antifeedant (see scheme 8.3).<p><img src="/wda/abstracts/i1601_5.gif" height="192" width="600"/><p>In chapter 5 the promising nueleophile <em>[methoxy(phenylthio)methyl</em> ] <em>lithium</em> was used to introduce a masked aldehyde group at C-9. The addition of this nucleophile to aldehydes, ketones, α,β-unsaturated ketones, α-oxo acetals, and (aryl- or alkylthio)methylene ketones was straightforward and the adducts were obtained in high yields. These adducts could be rearranged into α-sulfenylated aldehydes upon treatment with thionyl chloride and sometimes also with acid. This new rearrangement was developed as a new synthetic method and applied in the synthesis of several drimane sesquiterpenes (see scheme 8.4).<p><img src="/wda/abstracts/i1601_6.gif" height="635" width="600"/><p>The adducts <strong>16</strong> were subjected to hydrolysis and the lactones <strong>14</strong> and/or <strong>17</strong> were obtained dependent on the conditions used. Mixtures of lactones were separated with difficulty and the best way to proceed turned out to be their reduction into the diol <strong>18</strong> , a well-known intermediate in the synthesis of drimanes such as confertifolin <strong>17</strong> and (-)-warburganal <strong>2</strong> .<p><em>trans</em> -Decalone <strong>10</strong> was formylated and the aldehyde function was protected as its (phenylthio)methylene derivative <strong>8a</strong> or as its dioxolan <strong>8b</strong> . The adducts <strong>19</strong> , obtained by addition of [methoxy(phenylthio)methyl]lithium to <strong>8a</strong> , rearranged into rather unstable aldehydes and therefore a reduction was performed immediately. A spontaneous cyclization then afforded (±)-euryfuran <strong>20</strong> .<p>When the adducts <strong>19</strong> were subjected to a mercuric chloride assisted hydrolysis an unexpected ring expansion reaction was observed.<p>Several drimanes could be synthesized starting from 10 and 11, but a straight-forward total synthesis of the more biologically active drimanes (-)-warburganal <strong>2</strong> , polygodial <strong>3</strong> , and (-)- muzigadial <strong>7</strong> proved to be troublesome. Therefore a new concept was taken into consideration starting from the <em>trans</em> -decalones <strong>21</strong> and <strong>22</strong> , as is dealt with in chapter 6. Both were synthesized in multigram quantities <em>via</em> adaptation of known procedures.<p><img src="/wda/abstracts/i1601_7.gif" height="333" width="600"/><p>Formylation of <strong>21</strong> and subsequent dehydrogenation afforded the unsaturated keto aldehyde <strong>23</strong> . Addition of HCN then introduced the functionalized C-11 carbon atom and the remaining β-keto aldehyde was reduced to an unsaturated aldehyde to afford <strong>24</strong> . Protection of the aldehyde group and reduction of the nitrile function then gave the <em>mono</em> protected dialdehyde <strong>25</strong> . It turned out that the α-positioned aldehyde group in <strong>25</strong> had to be epimerized before introducing the 9α-hydroxyl group via oxidation of the enolate of <strong>25</strong> . This epimerization is a crucial step in this approach and it had to be performed with an excess of potassium <em>tert</em> -butoxide in refluxing <em>tert</em> -butyl alcohol for just 10 minutes. Subsequent oxidation of the enolate of <strong>26</strong> then afforded (±)-warburganal <strong>2</strong> in a wholly acceptable 3 8 % overall yield (see scheme 8. 5).<p>Since all the reaction conditions and reagents used for the conversion of <strong>21</strong> into (±)-warburganal <strong>2</strong> were compatible with the presence of an exocyclic double bond in the molecule, the transformation of <em>trans</em> -decalone <strong>22</strong> into (±)-muzigadial <strong>7</strong> was expected to be straightforward and indeed no serious problems were encountered and (±)-muzigadial <strong>7</strong> was obtained in 24% overall yield (see scheme 8.6).<p><img src="/wda/abstracts/i1601_8.gif" height="173" width="600"/><p>In principle, the natural enantiomers of polygodial <strong>3</strong> , warburganal <strong>2</strong> , and muzigadial <strong>7</strong> are to be preferred over their racemic forms, so a synthesis of the intermediate ketones <strong>21</strong> and <strong>22</strong> in the optically active form was investigated as described in chapter 7.<p>The synthesis of the chiral <em>trans</em> -decalones <strong>21</strong> and <strong>22</strong> was undertaken, using (S)-(+)-and (R)-(- )-carvone as a chiral starting compound, respectively. The isopropenyl group of carvone first served as a chiral handle and was converted afterwards into the desired carbonyl group at C- 7. (-)-Dihydrocarvone, obtained from (+)-carvone by lithium bronze reduction, was converted into (-)- <em>trans</em> -decalone <strong>21</strong> starting with a conventional Robinson annulation. The ketol <strong>28</strong> could be isolated in pure form via crystallization from hexane, leaving the enone <strong>29</strong> in solution.<p><img src="/wda/abstracts/i1601_9.gif" height="290" width="600"/><p>This ketol was transformed into <strong>30</strong> , which upon Wolff-Kishner reduction also gave an isomerization of the double bond in the isopropenyl group as an accompanying reaction. Subsequent selective ozonolysis and reduction with lithium in liquid ammonia then gave the chiral (-)- <em>trans</em> -decalone <strong>21</strong> (see scheme 8.7).<p>(+)- <em>trans</em> -Decalone <strong>22</strong> , the starting material for the synthesis of (-)-muzigadial <strong>7</strong> , had to be synthesized starting with (+)-dihydrocarvone in order to obtain the desired R configuration at C-10 (see scheme 8.8).<p><img src="/wda/abstracts/i1601_10.gif" height="287" width="600"/><p>The isopropenyl group of enone <strong>33</strong> was removed by ozonolysis followed by decomposition of the ozonide by cupric acetate and ferrous sulfate to give dienone <strong>34</strong> . Conjugate addition of dimethylcopper lithium then afforded the deconjugated enone <strong>35</strong> , with the methyl groups in a <em>trans</em> position. This enone was further elaborated into (+)- <em>trans</em> -decalone 22 via known procedures, developed at our laboratory.<p>In summary, starting from easily available ketones efficient syntheses of several drimanic sesquiterpenes were performed. Especially the biologically active compounds (±)-polygodial <strong>3</strong> , (±)-warburganal <strong>2</strong> , and (±)-muzigadial <strong>7</strong> were synthesized straightforward in good yields.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • de Groot, Æ., Promotor, External person
Award date23 Mar 1993
Place of PublicationS.l.
Print ISBNs9789054850977
Publication statusPublished - 1993


  • diterpenoids
  • sesquiterpenoids
  • terpenoids
  • essential oils
  • sesquiterpenes
  • synthesis
  • organic compounds

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