Author: Todd Markham
Markham, Todd, 2021 Synthetic modification of the natural Pyrethrins, Flinders University, College of Science and Engineering
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Pyrethrum is derived from Tanacetum cinerariifolium (Pyrethrum daisies) and has been used extensively as an insect control agent both domestically and agriculturally for many years. This natural extract is comprised of the Pyrethrins 5-7, six structurally related esters that impart the concentrate with its insecticidal properties. Whilst the Pyrethrum extract has long served as an insecticidal agent for its many beneficial characteristics like broad spectrum activity, low toxicity and low environmental impact, it suffers from a lack of long term stability due to the readiness of the Pyrethrins 5-7 to undergo degradation by a number of pathways. Although there are measures in place to limit this degradation, there remains a need to further limit or prevent these degradative processes leading to pyrethrin losses. Due to this, the work described in this thesis has pursued the direct synthetic modification of the naturally derived Pyrethrins 5-7 as a potential means of stabilising the insecticidal esters whilst retaining their advantageous qualities.
Pyrethrins I 5a and II 5b make up over 50% of the pyrethrin content in Pyrethrum however, they are the most susceptible of the six Pyrethrins 5-7 to degradation particularly about the pentadienyl side chain. Two of the minor Pyrethrins, the jasmolins 7, differ from the pyrethrins 5 by a single point of saturation and as such may be accessed through reduction of the terminal double bond. Chapter 2 details the exploration into the reduction chemistry of the pyrethrins 5 in a bid to elicit the transformation into their more stable jasmolin counterparts 7 (Figure 1). As a result, a number of reduced pyrethrin analogues were prepared by several common reductive pathways and the desired transformation to the jasmolins 7 was successful with their isolation as a mixture with the corresponding tetrahydropyrethrins 53.
With the rethrolone moiety of the pyrethrins 5 containing a pentadienyl chain, its applicability in Diels-Alder cycloadditions was explored as highlighted in Chapter 3. Whilst the cis-geometry of the natural pyrethrins 5 was found to be inactive in the normal electron demand Diels-Alder reaction, it was found there is precedent for the trans-isomer 34 to take part. Alternatively, the inverse electron demand Diels-Alder reaction could be applied with the pyrethrins 5 acting as dienophile and electron-deficient tetrazines serving as dienes (Figure 2).
In addition, the alkenes within the pyrethrin scaffold were of particular interest for application in palladium-catalysed cross coupling, specifically Heck reactions. Ultimately, a protocol was developed for the site-selective coupling of the terminal double bond in the pyrethrins 5 to aryl iodides (Figure 3), detailed in Chapter 4. The resulting products were the E-isomer and the migration isomer of the terminally arylated product with distribution of the two dependent on the electronic properties of the aromatic coupling partner.
Finally, Chapter 5 details attempts to produce racemic (Z)-pyrethrolone 21, the rethrolone moiety of the pyrethrins 5, for its potential in gaining further insight into the reactivity and degradative properties of the more prominent of the Pyrethrin esters 5-7. As a result, racemic (Z)-pyrethrolone 21 could be prepared as a mixture with its precursor 155 over a series of five synthetic steps in a yield of 11% as determined by 1H NMR analysis (Figure 4).
Keywords: pyrethrins, synthetic modification, natural products chemistry, phytochemistry
Subject: Chemistry thesis
Thesis type: Doctor of Philosophy
Completed: 2021
School: College of Science and Engineering
Supervisor: Martin Johnston