Total synthesis of lactarane and marasmane sesquiterpenes

R.P.L. Bell

Research output: Thesisinternal PhD, WU


<p>Lactarane and marasmane sesquiterpenes are mostly found in nature as metabolites from mushrooms of the genera <em>Lactarius</em> and <em>Russula</em> . Because a considerable number of these compounds possesses a variety of interesting biological activities, they are assumed to take part in the mushroom's chemical defense mechanism. The total synthesis of these natural products via extension of the base-induced rearrangement of perhydronaphthalene 1,4-diol monosulfonate esters, initially designed for the synthesis of <em>cis</em> -hydroazulenes, is the key subject of this thesis.</p><p>The first synthetic challenge was the total synthesis of the lactarane furanether B (Scheme 1). Upon exposure to Li(O <em>t</em> -Bu) <sub>3</sub> AlH in refluxing toluene mesylate <strong>2</strong> , prepared from the readily available ketone <strong>1</strong> , underwent rearrangement to the <em>cis</em> -fused cation intermediate <strong>3</strong> . Intramolecular trapping of the positive charge in <strong>3</strong> by the proximate alcoholate provided tricyclic ether <strong>4</strong> . Completion of the synthesis of the natural product was accomplished by an annulation method based on a Pummerer-induced cyclization reaction of compound <strong>6</strong> .</p><div class="scheme" align="center"><img src="/wda/abstracts/i2875_1.gif" width="540" height="340" alt="Inline image scheme 1" border="0"/><br/><strong>Scheme 1</strong></div><p>As a second objective the synthesis of the marasmane skeleton via a tandem rearrangement-cyclopropanation reaction was investigated. Initial studies on model system <strong>9</strong> lacking the methyl group at C(8) demonstrated that this tandem reaction could be applied successfully for the synthesis of the tricylic core of marasmanes as followed from the formation of ketone <strong>11</strong> (Scheme 2). However, poor results were obtained with the fully substituted system <strong>12</strong> probably due to severe steric hindrance (Pitzer strain) in the cyclopropanation step ( <strong>13</strong> →<br/><strong>14</strong> ).</p><p>In contrast the silyl enol ether <strong>16</strong> , prepared form the easily available dione <strong>15</strong> , rearranged readily to the normarasmane compound <strong>18</strong> upon treatment with the Lewis-acid MgI <sub>2</sub> . In this case, the better stabilized cyclopropylcarbinyl cation <strong>17</strong> compensated for the increased steric hindrance caused by Pitzer strain. Compound <strong>18</strong> was then further converted to the two 'simple' marasmanes <strong>19</strong> and <strong>20</strong> .</p><div class="scheme" align="center"><img src="/wda/abstracts/i2875_2.gif" width="540" height="430" alt="Inline image scheme 2" border="0"/><br/><strong>Scheme 2</strong></div><p>Optically pure (+)- <strong>21</strong> , needed for the preparation of (+)-isovelleral via the tandem rearrangement-cyclopropanation reaction, was obtained via an enzymatic resolution of racemic <strong>21</strong> with <em>Candida rugosa</em> lipase (Scheme 3). The enantiomericaly pure building block (+)- <strong>21</strong> might also be used for the synthesis of optically pure lactaranes via the sequence developed for furanether B.</p><div class="scheme" align="center"><img src="/wda/abstracts/i2875_3.gif" width="540" height="110" alt="Inline image scheme 3" border="0"/><br/><strong>Scheme 3</strong></div><p>The methodology developed for the synthesis of the marasmane skeleton was successfully applied in the synthesis of (+)-isovelleral. When mesylate <strong>23</strong> possessing an allyl group was treated with MgI <sub>2</sub> , ketone (<img src="/wda/abstracts/i2875_5.gif" width="11" height="7" alt="minus" border="0"/>)- <strong>24</strong> was obtained in high yield (Scheme 4). The best route to synthesize both aldehydes groups, present in (+)-isovelleral, proved to be the following. Isomerization of the double bond present in (<img src="/wda/abstracts/i2875_5.gif" width="11" height="7" alt="minus" border="0"/>)- <strong>24</strong> and enolization of the ketone followed by treatment with Tf <sub>2</sub> NPh gave (<img src="/wda/abstracts/i2875_5.gif" width="11" height="7" alt="minus" border="0"/>)- <strong>25</strong> . Selective ozonolysis of the allyl moiety in (<img src="/wda/abstracts/i2875_5.gif" width="11" height="7" alt="minus" border="0"/>)- <strong>25</strong> and subsequent treatment with NaBH <sub>4</sub> afforded enol triflate (<img src="/wda/abstracts/i2875_5.gif" width="11" height="7" alt="minus" border="0"/>)- <strong>26</strong> , which via palladium-catalyzed methoxycarbonylation, reduction and Swern oxidation gave (+)-isovelleral. When a different sequence was applied, the ozonolysis of the allyl group or the synthesis of the enol triflate moiety turned out to be troublesome.</p><div class="scheme" align="center"><img src="/wda/abstracts/i2875_4.gif" width="550" height="220" alt="Inline image scheme 4" border="0"/><br/><strong>Scheme 4</strong></div>
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • de Groot, Æ., Promotor, External person
  • Wijnberg, J.B.P.A., Promotor
Award date30 Oct 2000
Place of PublicationS.l.
Print ISBNs9789058083067
Publication statusPublished - 2000


  • synthesis
  • sesquiterpenes

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