Synthesis of model compounds derived from natural clerodane insect antifeedants

Abstract

Insect antifeedants are compounds with the ability to reduce or inhibit insect feeding without directly killing the insect. Such compounds offer a number of properties that are highly desirable in environmentally friendly crop protection agents. Although the principle of insect control using antifeedants has been shown to work under field conditions, practical application of these compounds has until now been limited to a few examples, mainly consisting of extracts of the Neem tree containing the highly potent tetranortriterpene azadirachtin.One of the factors hampering the introduction of insect antifeedants in crop protection is the limited availability of many of these compounds, which prevents their widespread application at low cost. In efforts to solve these availability problems, synthetic approaches might provide an alternative to the isolation of antifeedants from natural sources. Since the total synthesis of natural insect antifeedants usually is too long and complex for this purpose, a more practical approach would be to develop simplified analogues, which have retained as much of the desired biological properties as possible. Apart from being potential crop protection agents themselves, such analogues may also serve as model compounds to investigate structure-activity relationships and thus to provide a basis for the design of more potent synthetic insect antifeedants.The class of neo -clerodane diterpenes has attracted considerable attention as a source of natural insect antifeedants. In the present thesis, neo -clerodane diterpenes as clerodin, ajugarin I and teucjaponin B were chosen as starting points in a search for potentially active model compounds. From the literature it is known that both halves of these molecules ( i.e. the decalin-fragment and the C-9 sidechain) are involved in the bioactivity of these diterpenes. Both parts separately also display antifeedant activity, but these fragments are much less potent than their parent compounds and are therefore unsuitable candidates for practical application. However, model compounds that consist of structural features from both halves soon become complicated themselves and were therefore considered to be an unpractical approach towards simplified bioactive analogues. Instead, we decided to focus our attention upon the C-9 sidechains of these molecules and to investigate the possibility to optimize the activity of such fragments.In the search for modifications that could enhance the activity of clerodane fragments, we were struck by the structural resemblance between the furo[2,3b]furan sidechain of clerodin and the furo[2,3b]pyran substructure present in azadirachtin. In view of this similarity, it was hypothesized that the introduction of structural features from azadirachtins furo[2,3b]pyran substructure into clerodane C-9 sidechain fragments might increase the antifeedant activity of these model compounds. Especially the C-20 hydroxy group present in the furo[2,3b]pyran substructure was seen as an interesting candidate for such a strategy.To examine this hypothesis, we synthesized several series of model compounds (furo[2,3b]pyrans, furo[2,3b]furans, 3-alkyl-but-2-enolides and -butanolides, 4-furano-2-spirolactones) with and without an extra hydroxy group at the corresponding position. These model compounds were tested in insect antifeedancy bioassays, using various insect species. Against larvae of the large cabbage white butterfly ( Pieris brassicae ) several of the test compounds displayed statistically significant antifeedant activity, though none of the compounds was found to be highly active. For the test series of furo[2,3b]furan analogues, the presence of a C-3a hydroxy group did not generally increase the activity of the test compounds, although this feature was present in the most potent compound within this series. Similarly, in the 3-alkyl-butyrolactone series the 3-hydroxy-butanolides were about equally active as the corresponding butenolides. For larvae of the Colorado potato beetle ( Leptinotarsa decemlineata ) and for nymphs of the green peach-potato aphid ( Myzus persicae ), none of the compounds tested showed statistically significant antifeedant activity.</p