Total synthesis of cis-Hydroazulene sesquiterpenes : base-induced and -directed elimination and rearrangement reactions of perhydronaphthalene-1,4-diol monosulfonate esters

L.H.D. Jenniskens

Research output: Thesisinternal PhD, WU


<p>The total synthesis of a number of cis-fused hydroazulene sesquiterpenes is described in this thesis. In this synthetic study, ample attention is paid to the mechanistic aspects of the base- induced and -directed rearrangement and elimination reactions of perhydronaphthalene-1,4-diol monosulfonate esters. These reactions form the key steps in the synthetic routes that were followed.<p>A general introduction into the chemistry of terpenes, with emphasis laid on the sesquiterpenes with a hydroazulene skeleton, is given in Chapter 1.<p>In Chapter 2, an overview of the literature on the synthesis of these hydroazulene sesquiterpenes is presented. The different synthetic strategies towards the hydroazulene skeleton and their use in natural product synthesis are mentioned in first part of this chapter. The rearrangement reaction of the hydronaphthalene skeleton to the hydroazulene framework is described in more detail. The photochemical, the pinacol, and the solvolytic Wagner-Meerwein rearrangement are discussed successively. Upon solvolytic Wagner-Meerwein rearrangement of the hydronaphthalene framework towards the hydroazulene framework, a mixture of double bond isomers is formed in a ratio reflecting the relative stability of the products. This is a serious drawback of this method for the selective synthesis of hydroazulene sesquiterpenes with an exocyclic C(10)-C(15) double bond.<p>In Chapter 3 the utility of trans-fused hydronaphthalene precursors for the synthesis of cis-fused hydroazulene sesquiterpenes with an exocyclic C(10)-C(15) double bond is examined. For this purpose the tosylates <strong>131</strong> and <strong>132</strong> were prepared, and their behaviour under basic conditions was studied. Upon treatment with sodium tert-amylate, the tosylate <strong>131</strong> , which has a tertiary axial hydroxyl group at CM, rearranged with high selectivity (90%) to the desired cis-fused exo 10-olefinic hydroazulene <strong>143</strong> . When the tosylate <strong>132</strong> with a secondary axial hydroxyl group at C(4), was treated this way, a lower selectivity (57%) in the formation of the corresponding hydroazulene <strong>148</strong> was observed. A mechanism for the rearrangement reaction is proposed. According to this mechanism the reaction starts with the deprotonation of the axial hydroxyl group at C(4). The generated alkoxide then induces the heterolysis of the tosylate ester bond, thereby leading to the formation of a secondary carbocation (ion pair). The system then rearranges to a more stable tertiary carbocation by a 1,2-shift of the central bond, thereby forming the hydroazulene skeleton. The subsequent intramolecular proton abstraction from the former angular methyl group by the axial alkoxide at CM directs the elimination reaction to the selective formation of the isomer with the exocyclic C(10)-C(15) double bond.<p><img src="/wda/abstracts/i1539_1.gif" height="423" width="600"/><p>As an application of this base-induced and -directed rearrangement the total synthesis of the guaiane sesquiterpene ( <u>+</u> )-5- <em>epi</em> -nardol <strong>26</strong> is described in Chapter 4. In Chapter 5 the selective introduction of a double bond at the C(6)-C(7) position in the hydronaphthalene system is described.<p>Compound 27 was formed selectively by treatment of both the axial mesylate <strong>173</strong> and the equatorial mesylate <strong>180</strong> with sodium <em>tert</em> -amylate in refluxing toluene. The mechanism proposed for this base-induced and -directed elimination bears strong resemblance with the one proposed for the rearrangement. The hydroxyl group at C(4). is deprotonated by the base and the thereby formed alkoxide induces the heterolysis of the mesylate ester bond. By abstraction of the C(6) proton, the alkoxide C(4). then directs the reaction to the selective formation of <strong>27</strong> . Apart from proton abstraction also homofragmentation was found to take place in the equatorial mesylate <strong>180</strong> , thereby reducing the yield of <strong>27</strong> . By increasing the sodium tert-amylate concentration this homofragmentation could be suppressed.<p>In Chapter 6 the total synthesis of the (±)-alloaromadendrane-4,10-diols <strong>28</strong> and <strong>29</strong> is described. The C(6)-C(7) double bond of <strong>27</strong> was used for the annulation of the cyclo propane ring. Selective epoxidation of the C(10)-C(15) double bond in the rearranged product <strong>186</strong> , followed by reduction gave <strong>28</strong> . Inversion of the stereochemistry at C(4). by dehydration of <strong>186</strong> . selective epoxidation and reduction resulted in the natural product <strong>29</strong> . In Chapter 7, studies towards a 6α,7β-lactone ring and (±)-alismol. and the synthesis of ( <u>+</u> )-oplodiol are described.<p><img src="/wda/abstracts/i1539_2.gif" height="151" width="600"/>
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • de Groot, Æ., Promotor, External person
  • Wijnberg, J.B.P.A., Promotor
Award date2 Oct 1992
Place of PublicationS.l.
Publication statusPublished - 1992


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


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