O

cucujolide I

4 cucujolide li

Figure 6.19

Cucujolides I and II. When farnesene was labelled with deuterium and18 O on C-l, both isotopes were incorporated into cucujolide I. Cucujolide II is synthesized from an unsaturated acid, possibly oleic. Labelled hydroxyl oxygen is retained in the lactone oxygen of the product

(Figure 6.19). Cucujolide I might not at first look like a farnesene derivative, but when farnesene was labelled with deuterium and lsO, both were incorporated into the product, indicating the biosynthetic plan shown, which requires oxidation at the terminal double bond to a carboxylic acid. However cucujolide II has no methyl branches and biosynthetic studies show that it has a fatty acid origin (see Figure 3.38). Neither lauric (dodecanoic) nor 11-hydroxydodecanoic acid were effective precursors of cucujolide II, but 3-(Z)-dodecenoic and ll-hydroxy-3-(Z)-dodecenoic acids were. It seems therefore that oleic or palmitoleic acids are the natural precursors. These are chain-shortened to a 3-dodecenoic acid (Figure 6.19).

6.4.1 Sesquiterpene Pheromones

Simple sesquiterpenes like farnesols, dihydrofarnesols and nerolidols, esters of these and farnesenes are used as pheromones. (£)-P-Farnesene is an alarm pheromone of some aphids (Figure 6.20); nomadone, slightly more modified, comes from the mandibular glands of Nomada bees. Its function is unknown. More complex are the monocyclic periplanones A and B, sex attractants from the females of the American cockroach Peri-planeta americana (Figure 6.20). Periplanone A is very unstable and twice the wrong structure was proposed for it, synthesized and found to

ancistrofuran caparrapioxide

Figure 6.20 Some examples of insect sesquiterpenes used as pheromones or defensive secretions ancistrofuran caparrapioxide

Figure 6.20 Some examples of insect sesquiterpenes used as pheromones or defensive secretions be inactive before the correct structure was found. Other species of cockroach use related periplanones. The larvae of swallowtail butterflies have a horn-like organ, called an osmeterium, on their heads, normally hidden, but everted when disturbed. They attempt to smear its secretion onto the disturber. In one species, Papilio memnon, the osmeterial secretion contains caryophylline oxide (Figure 6.20), which is also found in the oil of some tropical plants and there acts as a deterrent to leaf-cutting ants. Papilio protenor produces germacrenes A and B in its osmeterium. When the organ was treated with D4-acetic acid, both compounds incorporated the deuterium. The monoterpenes in the defensive gland of soldier termites have already been mentioned. A great variety of monocyclic and bicyclic sesquiterpenes like y-cadinene and germacrene A are also present in their secretions. While well-known in plants, little is yet known about how they are biosynthesized in insects. Ancistrodial is the principal constituent of the defensive secretion of minor soldiers of the termite Ancistrotermes cavithorax. The compound is repellent to ants, which are the chief invaders of termite mounds. Ancistrofuran is the chief repellent of the major soldiers of that species. Caparrapioxide is found in the defensive secretion of Amitermes. All these can be seen as further oxidation and cyclization products from farnesol, or possibly p-farnesene.

6.4.2 Cantharidin

Cantharidin is a defensive secretion of meloid beetles (another type of blister beetle, Plate 10). It forms about 0.25-0.5% of the body weight, and is stored in the haemolymph and male genitalia. It is present in all life stages. When disturbed, adult insects bleed as a reflex from the leg joints, early larvae regurgitate a milky secretion from the mouth. Cantharidin is highly toxic in humans and an extreme irritant to all tissues, it is known to inhibit protein phosphatases. Cantharidin is synthesized by both sexes as larvae, but only by the male adult beetles. Females acquire it from males through frequent copulation and it passes thence to eggs. Anyone attempting labelling experiments with adult female beetles would be puzzled to find no incorporation of the label. Cantharidin (C10H12O4) may look something like a monoterpene, but by use of labelled acetate, mevalonate, and multiply labelled farnesol, it has been shown to be formed through farnesol with loss of carbon atoms 1 and 5 to 7 (Figure 6.21). The whole synthesis apparently takes place on one enzyme without formation of an intermediate that can be isolated.

Figure 6.21 The biosynthesis of cantharidin. The asterisks and black dots represent two different experiments with labelled farnesol that showed these particular carbon atoms are retained in cantharidin. The two teminal methyls (asterisked) of farnesol become scrambled during the synthesis. The excision of atoms 5 to 7, ring closure between C-3 and C-ll, insertion of the oxygen bridge, oxidation to acid and anhydride formation all occur without the molecule dissociating from the enzyme. No mechanism has been proposed for this unusual reaction

Figure 6.21 The biosynthesis of cantharidin. The asterisks and black dots represent two different experiments with labelled farnesol that showed these particular carbon atoms are retained in cantharidin. The two teminal methyls (asterisked) of farnesol become scrambled during the synthesis. The excision of atoms 5 to 7, ring closure between C-3 and C-ll, insertion of the oxygen bridge, oxidation to acid and anhydride formation all occur without the molecule dissociating from the enzyme. No mechanism has been proposed for this unusual reaction

6.4.3 Lac Insects

A group of homopterous insects, chiefly Laccifera lacca, feeding on various forest trees produce an excretion on the bark of the tree which eventually covers the insects. This has been a commercial product for a long time as lac for making varnish or in a purified form as shellac. As with many insect products, it is not yet certain whether lac is made by the insects themselves or by symbiotic micro-organisms in them. Lac consists of a mixture of polyhydroxylated palmitic acids and sesquiterpenes. The palmitic acids are hydroxylated at C-10 and C-ll or C-16 or all three, as in aleuritic acid (Figure 6.22).

The principal terpenes are jalaric acid and laccijalaric acid (Figure 6.22), which have a cedrene structure. It is known from plants that

Figure 6.22 The principal substances in lac produced by Laccifera insects. The lac consists of a mixture of hydroxylated palmitic acid and tricyclic sesquiterpenes. The formation of cedrene according to the plant route is shown

cedrenes are formed there from farnesyl pyrophosphate via linalyl pyrophosphate (Figure 6.17) as shown in Figure 6.22, but there is no information on the insect route. While a-cedrene and cedrol are found in Juniperus trees, there is no cedrene in the trees that the lac insects attack, and, for insects, a different isomer of cedrene is involved.

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