The total synthesis of insect antifeedant (-)-dihydroclerodin starting from R-(-)-carvone

T.M. Meulemans

Research output: Thesisinternal PhD, WU


<p>The first total synthesis of the natural enantiomer of the insect-antifeedant dihydroclerodin ( <strong>1</strong> ) and lupulin C ( <strong>268</strong> ) has been achieved in 18 and 17 steps respectively starting from R-(-)-carvone ( <strong>2</strong> ). A new strategy was developed in which the hexahydrofuro[2,3- <em>b</em> ]furan fragment was introduced in the beginning of the synthesis, via a remarkably diastereoselective Mukaiyama reaction of silyl enol ether <strong>135</strong> with 2-methoxy-hexahydrofuro[2,3- <em>b</em> ]furan ( <strong>156</strong> ), which gave only two of the possible eight diastereoisomers. After separation of the two diastereoisomers, ketone <strong>142</strong> with the correct configuration at C9, C11, C13, and C16 was obtained in an easy procedure (chapter 2). For the annulation of ketone <strong>142</strong> , the Robinson annulation was investigated first, but this did not give good results due to steric hindrance (chapter 4). To reduce the steric congestion, the isopropenyl group was transformed into a double bond by ozonolysis, followed by treatment of the ozonide with Cu(OAc) <sub>2</sub> and FeSO <sub>4</sub> to give enone <strong>146</strong> . A 1,2-addition of 3-(1,3-dioxolan-2-yl)-propyllithium to this enone, followed by an oxidative rearrangement yielded enone <strong>249</strong> . Catalytic reduction of this enone with palladium took place from the b-side and thus gave the correct stereochemistry at C10. Deprotection of the aldehyde, followed by an aldol reaction led to decalone <strong>144</strong> .</p><DIV ALIGN="Center"><p><strong>scheme 7.1</strong></p><img src="/wda/abstracts/i2784_1.gif" WIDTH="582" HEIGHT="348"/><p>( <strong>a</strong> ) MeMgI, CuBroMe <sub>2</sub> S, TMSCl;<br/>( <strong>b</strong> ) TrClO <sub>4</sub> , <strong>156</strong> ;<br/>( <strong>c</strong> ) separation of diastereoisomers;<br/>( <strong>d</strong> ) i) O <sub>3</sub> , ii) Cu(OAc) <sub>2</sub> , FeSO <sub>4</sub> ;<br/>( <strong>e</strong> ) <em>t</em> -BuLi, <strong>246</strong> ;<br/>( <strong>f</strong> ) PCC;<br/>( <strong>g</strong> ) Pd/C, H <sub>2</sub> ;<br/>( <strong>h</strong> ) PPTS, H <sub>2</sub> O; ( <strong>k</strong> ) PPTS, D.</p></DIV><p>The conjugate addition of vinylmagnesium bromide to <strong>144</strong> and trapping of the enolate with a solution of monomeric formaldehyde introduced the last carbon atoms of the clerodane skeleton and established the desired stereochemistry at C5. The hydroxyl group was protected as its silyl ether ( <strong>253</strong> ) to ensure a selective reduction of the carbonyl function to give a diol with the desired configuration at C6. The obtained diol was protected as its acetonide, followed by ozonolysis of the double bond, and subsequent reduction of the ozonide gave alcohol <strong>260</strong> .</p><DIV ALIGN="Center"><p><strong>scheme 7.2</strong></p><img src="/wda/abstracts/i2784_2.gif" WIDTH="580" HEIGHT="172"/><p>( <strong>a</strong> ) i) vinylMgBr, CuBroMe <sub>2</sub> S, ii) CH <sub>2</sub> O;<br/>( <strong>b</strong> ) TBDMSiCl, imidazole;<br/>( <strong>c</strong> ) LiAlH <sub>4</sub> ;<br/>( <strong>d</strong> ) MeO <sub>2</sub> CMe <sub>2</sub> , PPTS;<br/>( <strong>e</strong> ) i) O <sub>3</sub> , ii) NaBH <sub>4</sub> .</p></DIV><p>To obtain an exocyclic double bond at C4, the hydroxyl group in compound <strong>260</strong> was transformed into its xanthate ester <strong>264</strong> . Elimination of this ester at 216øC gave the desired <strong>265</strong> (Chugaev reaction). After careful deprotection of the acetonide, an epoxidation of the double bond by <em>m</em> -CPBA was carried out. Acetylation of the hydroxyl groups then gave dihydroclerodin ( <strong>1</strong> ) and <em>epi</em> -dihydroclerodin ( <strong>268</strong> ) which could be separated by flash column chromatography. The measured [a] <sub>D</sub> fitted well with reported optical rotations of dihydroclerodin isolated from natural sources, which proved that we had synthesized the natural enantiomer of dihydroclerodin. Acetylation of diol <strong>266</strong> completed the synthesis of lupulin C (chapter 5).</p><DIV ALIGN="CENTER"><p><strong>scheme 7.3</strong></p><img src="/wda/abstracts/i2784_3.gif" WIDTH="567" HEIGHT="373"/><p>( <strong>a</strong> ) i) NaH, CS <sub>2</sub> , ii) MeI;<br/>( <strong>b</strong> ) 216øC;<br/>( <strong>c</strong> ) CF <sub>3</sub> CO <sub>2</sub> H;<br/>( <strong>d</strong> ) <em>m</em> -CPBA;<br/>( <strong>e</strong> ) Ac <sub>2</sub> O, pyridine, DMAP.<br/>overall yield of 0.35% in 18 steps</p></DIV>
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • de Groot, Æ., Promotor, External person
  • Jansen, B.J.M., Promotor, External person
Award date10 May 2000
Place of PublicationS.l.
Print ISBNs9789058081957
Publication statusPublished - 2000


  • antifeedants
  • carvone
  • insects
  • insect control
  • synthesis

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