Defense substances

The parent TMM precursor (1), now commercially available, has played a pivotal role in the execution of many synthetic plans directed at natural and unnatural targets. Reaction of (1) with 2-(methoxycarbonyl)cyclohexenone (14, R=C02Me) in the presence of palladium acetate and triethyl phosphite produced the adduct (15) in near quantitative yield. This cycloadduct is a critical intermediate in the total synthesis of a hydroxykempenone (16), a component of the defensive substances secreted by termites (Scheme 2.5) [12]. In accord with a previous observation by Trost that unactivated 2-cyclohexenone reacts poorly with TMM-Pd [13], the substrate (14, R=Me) was essentially inert in the cycloaddition. 

Until rather recently, our choice among chemicals repellant to insects was very limited (9), and some of the available remedies seem to have been almost equally repellent to their human users. The most familiar of them undoubtedly is the classical oil of citronella, a mixture of plant terpenes which consists principally of geraniol, citronellol, and citronellal. It is a remarkable coincidence that at least one insect species, an ant discussed by Dr. Happ, also makes use of some of these same terpenes as repellents against other insects. It biosynthesizes them de novo rather than simply taking them from plant sources. Many other examples of insect repellency have been observed (9), and Roth and Eisner (28) list over 30 compounds which have been identified as defense substances of anthropods. 

An excellent review by Roth and Eisner (63) summarized the chemical defense substances found in arthropods up to 1962. These authors listed 31 defense substances of known structure one anhydride, three carboxylic acids, nine aldehydes, one furan, three hydrocarbons, two ketones, one lactone, eight quinones, and three inorganic compounds. Many of these same compounds (unsaturated aldehydes and quinones) have been found in other arthropods since 1962 (38). The compounds are discharged when the animal is disturbed by predators, and there can be no doubt that the action of most of them... 

Defensive substances are often general irritants that can be used in a variety of contexts. For example, the alloxystine wasps (Cynipoidea), all hyperpara-sitoids of other hymenopteran parasitoids, produce a large number of compounds in their cephalic (mainly mandibular) glands. These compounds include m/p-xylol, 6-methylhept-5-en-2-one 16, various iridoids 21 and frans-dihydro-nepetalactone 22 [46,73]. 

Condensation of coumaric acid with malonic acid yields the basic chalcone and stilbane skeletons (see Fig. 3.6). Stilbenes are found in most vascular plants, where they exhibit fungicidal and to a lesser extent antibiotic properties. They function as both constitutive and inducible defense substances. Some stilbenes inhibit fungal spore germination and hyphal growth, whereas others are toxic to insects and parasitic nematodes (round-worms). They also possess antifeeding and nematicide properties in mammals. For example, resveratrol (a stilbene in red wine) suppresses tumor formation in mammals. 

Nishida R (2002) Sequestration of defensive substances from plants by Lepidoptera. Annu Rev Entomol 47 57-92... 

Defensive Compounds. All developmental stages of oedemerid beetles contain and produce cantharidin as a defensive substance. The total amount of the terpenoid anhydride increases in successive instars [306]. Moreover, by using deuterium-labelled cantharidin it was found that males of Oedemerafemorata transfer no or only very small amounts of cantharidin 48 to females during copulation. False blister beetles cause a severe dermatitis, i.e. blisters with burning and itching sensation a few hours after contact with oedemerid haemo-lymph [307]. 

Cardiac glycosides have high biological activity not only medically but also as defense substances in both plants and insects (8,9). A separation of two cardiac glycosides is shown in Figure 11. To reduce the peak tailing the ion source temperature and the solvent flow rate were increased. 

Aetinidine (9a) has been identified as an anal gland product of three species of dolichoderine ants in the genera Conomyrma and Iridomyrmex (Table I). The venoms of ants of the Myrmecia species are rich in histamine (136) (Table VIII), which can act as a defensive substance, together with hemolytic, smooth-muscle-stimulating, and histamine-releasing components. 

The (R)- and (S)-enantiomers of (E)-4.6-dimethyl-6-octene-3-one (147), a defense substance of spiders (known commonly as daddy longlegs Leiobunum vittatum and L. calcar) were recently synthesized by Enders and Baus 163> using the (R)-proline derivative RAMP and the (S)-proline derivative SAMP (137) as chiral auxiliary, respectively. (S)- and (R)-enantiomers of (147) have been obtained in an overall chemical yield of 70% and in very high stereoselectivities of 95% e.e., respectively. 

Some volatile iridoid monoterpenes with biological activity are also found in essential oils and in insect pheromonal and defensive substances. Eisner ( ) found that 17 species of insects were repelled by the iridoid monoterpene nepetalactone. Lacewings (Chrysopa septempunctata) are attracted by the leaves and fruits of Actinidia polyqama (Actinidiaceae) which contain a series of volatile iridoid monoterpenes (67). 

In summary, the approach to drug discovery from plants thus has both a historical justification (it has yielded many important new anti cancer agents) and a biochemical rationale (the position of plants in the ecosystem demands that they produce defense substances, and many of these have a novel phenotype). 

Numerous catechols and hydroquinones in both glycoside-masked and -unmasked forms are useful metabolites in plant chemical defense. Many such metabolites are present in concentrations that can prove detrimental due to oxygenation of the tissue accompanying wounding of the plant in the infection process or in other direct physical injury. Some agents are also synthesized subsequent to enzyme induction in association with infection to mediate chemical defense, as in the broad class of defensive substances known as phytoalexins.12 Some of these induced substances are oxidizable polyphenols, while others are not (Figure 8.1). 

The utility of this reaction is shown by a stereoselective synthesis of 4,6-dimethyl-(E)-6-nonene-3-one (1), the defense substance of L. tongipes (equation II).1... 

Quennedey, A. (1975). Morphology of exocrine glands producing pheromones and defensive substances in subsocial and social insects. In Pheromones and defensive secretions in social insects. Dijon Proceedings of the IUSSI, pp. 1-21. 

Hydroboration of limonene with disiamylborane followed by oxidation afforded the isomeric alcohols as 3 2 mixture. These starting materials are utilized in the synthesis of juvabione isomers2101 and in the synthesis of beetle defense substances, chrysomelidial 211), plagiolactone 212) and dehydroiridodial213) (Scheme 6). 

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