(+)-Aromadendrene as chiral starting material for the synthesis of sesquiterpenes

H.J.M. Gijsen

Research output: Thesisinternal PhD, WU


<p>One of the distillation tails of the oil of Eucalyptus globulus, which is commercially available, contains about 55-70% of (+)-aromadendrene ( <strong>2</strong> ), together with 10-15% of alloaromadendrene ( <strong>3</strong> ). In this thesis has been described how (+)-aromadendrene from <em>Eucalyptus</em> oil can be used as a chiral starting material for the synthesis of sesquiterpenes.<p>Two methods have been described to purify the crude distillation tail in order to obtain pure derivatives of <strong>2</strong> (and <strong>3</strong> ). In the first method, described in chapter 3, the crude distillation tail was ozonolyzed to give the crystallizable (+)-apoaromadendrone ( <strong>222</strong> ) (Scheme 9.1). In the second method, described in chapter 7, treatment of the crude distillation tail with potassium on aluminum oxide (K/Al <sub><font size="-1">2</font></sub> O <sub><font size="-1">3</font></sub> ) gave a quantitative conversion of <strong>2</strong> and <strong>3</strong> into isoledene ( <strong>224</strong> ). Oxidative cleavage of the central double bond in <strong>224</strong> produced bicyclogermacrane-1,8-dione ( <strong>304</strong> ).<p><img src="/wda/abstracts/i1716_1.gif" height="172" width="600"/><p>Both derivatives <strong>222</strong> and <strong>304</strong> were used as starting materials for the synthesis of compounds with carbon skeletons from several classes of sesquiterpenes. Selective, acid-catalyzed cleavage of the C3-C4 bond of the cyclopropane ring in <strong>222</strong> (and <strong>223</strong> ) gave (-)-isoapoaromadendrone ( <strong>253</strong> ) in high yield (chapter 3, scheme 9.2). Ozonolysis of <strong>253</strong> afforded the keto alcohol <strong>262</strong> which is a suitable chiral intermediate for the syntheses of guaianes. This was demonstrated in the synthesis of (-)-kessane ( <strong>264</strong> ), which proceeded in a 9 steps reaction sequence in an overall yield of 43% from <strong>262</strong> (chapter 4).<p><img src="/wda/abstracts/i1716_2.gif" height="173" width="600"/><p>The synthesis of the mono- and dihydroxy aromadendranes <strong>4-7</strong> , <strong>31</strong> , <strong>40</strong> , <strong>41</strong> , <strong>227</strong> , <strong>276</strong> , and <strong>277</strong> from <strong>222</strong> has been described in chapter 5. The <em>cis</em> -fused alloaromadendrone ( <strong>223</strong> ), the key intermediate for the synthesis of (-)-ledol ( <strong>6</strong> ) and (+)-viridiflorol ( <strong>7</strong> ), was obtained from the <em>trans</em> -fused apoaromadendrone ( <strong>222</strong> ) via a selective protonation of the thermodynamic enol trimethylsilylether <strong>278</strong> (Scheme 9.3). Hydroxylation of the tertiary C11 of <strong>222</strong> with RuO <sub><font size="-1">4</font></sub> gave <strong>226</strong> , which could be transformed into (+)-spathulenol ( <strong>31</strong> ), (-)-allospathulenol ( <strong>276</strong> ), and the aromadendrane-diols <strong>40</strong> , <strong>41</strong> , <strong>227</strong> , and <strong>277.</strong> Compounds <strong>4-7</strong> , <strong>31</strong> , <strong>40</strong> , <strong>41</strong> , <strong>227</strong> , <strong>276</strong> , and <strong>277</strong> were tested for antifungal properties, but their activity was only moderate.<p><img src="/wda/abstracts/i1716_3.gif" height="450" width="600"/><p>A stereoselective epoxidation of the thermodynamic enol trimethylsilylether <strong>278</strong> gave the hydroazulene α-ketol <strong>289</strong> (chapter 6, scheme 9.4). Starting from this α-ketol, two different routes to hydronaphthalene compounds with a maaliane skeleton were developed, both in high overall yield. The first route via α-ketol <strong>290</strong> led to <em>cis</em> -fused maaliane ketone <strong>293</strong> ; the second one offered access to the <em>trans</em> -fused maaliane compound <strong>299</strong> . From <strong>299</strong> the naturally occurring (+)-maaliol ( <strong>288</strong> ) was synthesized.<p><img src="/wda/abstracts/i1716_4.gif" height="215" width="600"/><p>Synthon <strong>304</strong> , obtained via the second purification method of the crude distillation tail <em>(vide supra</em> ), was used as starting material of compounds with a humulane or cadinane skeleton (chapter 7). The α-keto-cyclopropane compound <strong>304</strong> was found to be thermolabile. Thermal rearrangement of <strong>304</strong> gave via a homo [1,5] hydrogen shift at relatively low temperature (refluxing dioxane) the humulane compound <strong>311</strong> and at higher temperatures (Flash Vacuum Pyrolysis, 500°C and up) the products <strong>313</strong> and <strong>314</strong> , both with a cadinane skeleton (Scheme 9.5). Epimerization of <strong>311</strong> gave the naturally occurring humulenedione ( <strong>306</strong> ). Starting from <strong>313</strong> , the naturally occurring (-)-cubenol ( <strong>310</strong> ) was synthesized in a 4 steps reaction sequence.<p><img src="/wda/abstracts/i1716_5.gif" height="223" width="600"/><p>The results described in this thesis are shortly summarized in scheme 9.6. With (+)-aromadendrene ( <strong>2</strong> ) from <em>Eucalyptus</em> oil as starting material, compounds have been synthesized with sesquiterpene skeletons belonging to the classes of the guaianes, the aromadendranes, the maalianes, the bicyclogermacranes, the humulanes, and the cadinanes. (-)-Kessane ( <strong>264</strong> ) (chapter 4), several mono- and dihydroxy aromadendranes (chapter 5 and 6), (+)-maaliol ( <strong>288</strong> ) (chapter 6), humulenedione ( <strong>306</strong> ) (chapter 7), and (-)-cubenol ( <strong>310</strong> ) (chapter 7) are naturally occurring sesquiterpenes which have been synthesized from <strong>2</strong> . On the basis of these results it can be concluded that (+)-aromadendrene from <em>Eucalyptus</em> oil is a versatile chiral starting material for the synthesis of sesquiterpenes.<p><img src="/wda/abstracts/i1716_6.gif" height="491" width="600"/>
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • de Groot, Æ., Promotor, External person
  • Wijnberg, J.B.P.A., Promotor
Award date15 Dec 1993
Place of PublicationS.l.
Print ISBNs9789054852018
Publication statusPublished - 1993


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

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