Pyrethroids, synthetic compounds

Many pesticides are not as novel as they may seem. Some, such as the pyre-throid and neonicotinoid insecticides, are modeled on natural insecticides. Synthetic pyrethroids are related to the natural pyrethrins (see Chapter 12), whereas the neo-nicotinoids share structural features with nicotine. In both cases, the synthetic compounds have the same mode of action as the natural products they resemble. Also, the synthetic pyrethroids are subject to similar mechanisms of metabolic detoxication as natural pyrethrins (Chapter 12). More widely, many detoxication mechanisms are relatively nonspecific, operating against a wide range of compounds that... 

Pyrethroids for agricultural use were developed in the 1970s in Japan, USA, and Europe after research on photostable synthetic pyrethroids. Those compounds were composed of an acid moiety obtained by various modifications and a chemically stable alcohol component, such as benzyl group and m-phenoxybenzylalcohol. According to recent statistics, pyrethroids accounted for approximately 20% in value of agricultural insecticides used annually all over the world in 2009. 

Application of natural products to pest control is subject to similar considerations to those that affect synthetic compounds. Elucidation of structure may be a relatively routine matter, but synthesis may present difficulties, particularly where there are several stereochemical possibilities. There are often great differences in biological activity among different stereoisomers and the presence of Inactive Isomers in a product may be undesirable. However, such technical problems can be overcome as in the case of the synthetic pyrethroids where specific stereoisomers of high purity are now produced on a commercial scale. 

With regard to ectoparasiticides, public health and environmental concerns have led to the withdrawal of the organochlorines and organophos-phates in many countries. Since Elliot (1973) reported the first photostable synthetic pyrethroid, these compounds have both replaced the naturaUy occurring pyrethrins (extracted from chrysanthemum flowers) and progressively become the mainstay of external parasite control programs. 

Prior to the advent of DDT and the organophosphates, the natural pyrethrins (32.33) found considerable use but were limited by their instability. The discovery of permethrin by Michael Elliot (3 4) proved a turning point for the new synthetic pyrethroids. Here were very active compounds that did not suffer from the stability problems of the natural compounds. And even now pyrethroid-like compounds continue to interest synthetic chemists due to their high insecticidal activity and relatively low mammalian toxicity. You would think that by now most of the very active compounds would have been found. but it seems that persistence and originality pay off. Workers at du Pont and FMC detail the structure-activity relationships for two groups of new pyrethroid-like compounds. Chemists at Dow reveal some of the intricacies in the synthesis of the cyclopropane carboxylate end of the molecule. 

Pyrethroids are neurotoxic synthetic compounds used as insecticides. Cypermethrin and fenvalerate have been reported as causing positive allergic patch tests, but only fenvalerate was relevant in an agricultural worker. 

The system was applied to series of synthetic pyrethroids. Some compounds belonging to a candidate structural class selected from structures "generated" from fenvalerate as the input structure were synthesized and bioassayed. Certain compounds possessing the isobutyranilidoxime O-phenoxybenzyl ether structure were shown to be highly active as house-dust miticides and patented. 

These chemorational techniques have generated great interest in, and high expectations for, the acceleration of development of innovative pesticides. However, many purportedly successful appHcations of QSAR procedures have reHed on the quaHtative insights traditionally associated with art-based pesticide development programs. Retrospective QSAR analyses have, however, been helpful in identifying the best compounds for specific uses (17). Chemorational techniques have also found some appHcations in the development of pesticides from natural product lead compounds, the best known examples being the synthetic pyrethroid insecticides (19) modeled on the plant natural product, pyrethmm. 

Some of the newer compounds may contain both saturated and unsaturated rings, heteroatoms such as oxygen, nitrogen, or sulfur, and halogen substituents. Others, such as synthetic pyrethroids, may have one or more chiral centers, often needing stereospecific methods of synthesis or resolution of isomers (42). Table 4 Hsts examples of some more complex compounds. Stmctures are shown ia Eigure 1 (25). 

The compounds featured in Table 1.1 are considered briefly here. Pyrethrins are lipophilic esters that occur in Chrysanthemum spp. Extracts of flower heads of Chrysanthemum spp. contain six different pyrethrins and have been used for insect control (Chapter 12). Pyrethrins act upon sodium channels in a manner similar to p,p -DDT. The highly successful synthetic pyrethroid insecticides were modeled on natural pyrethrins. 

There is the perception that suitable alternative pesticidal chemicals are available, including some carbamates, organophosphorus compounds, and synthetic pyrethroids. 

As described in the section on Cross-resistance in this chapter, it was found that some insect species showed extremely low cross-resistance to three ingredients, pyrethrins as well as d-allethrin and prallethrin, although they developed resistance to photostable synthetic pyrethroids. The latter two compounds of d-allethrin and prallethrin have quite similar chemical structures and the same configuration as cinerin I (an ingredient of pyrethrins). It is considered preferable to develop pyrethroids retaining the characteristics of natural pyrethrins and household insecticides containing them in the perspectives of safety and low cross-resistance. 

Figure 7 shows the course of development of various synthetic pyrethroids developed by retaining chrysanthemic acid as the acid moiety and modifying the alcohol moiety. Numerous useful compounds with favorable characteristics have been derived from the structural modification of natural cinerin I (7). These underlined compounds have been put into practical use as active ingredients, mainly for household insecticides. 

Resistance to insecticides has drawn global attention since the Korean War in 1950 when the mass use of organic synthetic insecticides, such as DDT and BHC, against agricultural pests and sanitary pests became common. Organophosphorus compounds and carbamates were used thereafter, but invited problems of safety concerns and insect resistance. Synthetic pyrethroids were watched with keen interest as alternatives and have become used widely not only for sanitary pests but also agricultural pests. The development of resistance to synthetic pyrethroids is also not a rare phenomenon and has spread all over the world. 

Allethrin, the first synthetic pyrethroid, is a compound which is the closest in structure to cinerin I. Pyrethroids developed subsequently are mostly esters of chrysanthemic acid, and cinerin II analogs, i.e., esters of chrysanthemum acid have not been industrialized. 

However, we are concerned about the behavior, safety, and environmental problems of photostable synthetic pyrethroids remaining in and around houses, considering the present situation of their increased indoor use. In particular, compounds with strong insecticidal potency need long-term safety and residue studies for the health of infants and pets. 

The synthesis of compounds 39, 41, and 43 by the ODPM rearrangement opens a novel photochemical route to chrysanthemic acid and other cyclopropane carboxylic acids present in pyrethrins and pyrethroids [52]. In fact, aldehyde 43 can be transformed to tran -chrysanthemic acid by simple oxidation. This new synthetic route to ecologically benign insecticides competes with the one previously described by us using the 1-ADPM rearrangement of p,y-unsaturated oxime acetates [30,53]. 

Insect resistance and environmental pollution due to the repeated application of persistent synthetic chemical insecticides have led to an Increased interest in the discovery of new chemicals with which to control Insect pests. Synthetic insecticides, including chlorinated hydrocarbons, organophosphorus esters, carbamates, and synthetic pyrethroids, will continue to contribute greatly to the increases in the world food production realized over the past few decades. The dollar benefit of these chemicals has been estimated at about 4 per 1 cost (JJ. Nevertheless, the repeated and continuous annual use in the United States of almost 400 million pounds of these chemicals, predominantly in the mass agricultural insecticide market (2), has become problematic. Many key species of insect pests have become resistant to these chemicals, while a number of secondary species now thrive due to the decimation of their natural enemies by these nonspecific neurotoxic insecticides. Additionally, these compounds sometimes persist in the environment as toxic residues, well beyond the time of their Intended use. New chemicals are therefore needed which are not only effective pest... 

---