Pyrethroid discovery

Naumann K (1998) Research into fluorinated pyrethroid alcohols-an episode in the history of pyrethroid discovery. Pestic Sci 52 3-20... 

Matsuo N, Ujihara K, Shono Y, Iwasaki T, Sugano M, Yoshiyama T, Uwagawa S (2005) Discovery and development of a novel pyrethroid insecticide metofluthrin (SumiOne , eminence ) . Sumitomo Kagaku 2 4-16... 

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... 

The high cost of developing compounds with limited markets has reversed the trend to narrower spectrum agents. The reversal began with the pyrethroids and has continued with the discovery, from fermentation sources, of the avermectins. In addition to their anthelmintic properties (see Section 1.08.2), a semisynthetic derivative, ivermectin (16), is in use in the control of lice, mites and warbleflies. Activity against Boophilus ticks, including all... 

Pyrethroid insecticides. Continued interest in and research into this important class of insecticides has resulted in a number of important discoveries, one of which involved replacement of the vinylic chlorine of traditional pyrethroids with trifluoromethyl to give X-cyhalothrin (Cyhalon , Grenade ) (ICI/Zeneca) [171], in... 

Synthetic pyrethroids are a group of ester compounds having excellent insecticidal activities. After the discovery of allethrin (1), a variety of useful synthetic pyrethroids have been produced mainly by structural modification of an alcohol having an asymmetric center. The insecticidal activities greatly depend upon the stereoisomers. Therefore, much effort has been expended to develop technologies for obtaining optically active isomers. However, contrary to the case of chrysanthemic acid, chemical methods of optical resolution were not very effective for these alcohols. 

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. 

Fore recently a comparable enhanced inhibition in resistant strains has been observed with aryloxadiazolone anticholinesterases (38). A second promising example is the discovery that some natural and synthetic isobutylamides are selectively toxic against houseflies that carry the super-kdr resistance trait (39). This gene causes an alteration in the sensitivity of the site of action for DDT and pyrethroids and is a major threat to the continued efficacy of synthetic pyrethroids in many of their applications. 

This is a target site for very few current insecticides, and resistance to compounds acting there has not been developed. This discovery gave additional momentum to the synthesis program. Eventually compounds with activity comparable to the synthetic pyrethroids were discovered (50) and investigations in this area continue. 

Recent cost analyses (Watkinson, I. A., Abbott Laboratories, personal communication, 1989) indicate that the development of pyrethroid resistance in IL.. virescens would approximately double control costs to mid-south cotton growers from an average of 32.00/acre to 61.50/acre and reduce yield by 11% (Graves, J. B., Louisiana State University, personal communication, 1989) This cost analysis assumes a 50% replacement of the pyrethroids by more expensive and less effective alternatives. Second, the discovery and development of replacement chemicals with novel modes of action does not come cheaply. Recent cost estimates are about 50 million and 8-10 years for the development of a compound. An additional 40-100 million can be added if a manufacturing plant is required. Third, yet another consequence is an increase in the amount of active ingredient put out into the environment. Pyrethroid application rates range from about 0.02 to 0.2 lb. ai/acre, whereas many alternative products have effective use rates of up to 1.5 lb./acre. 

Fenitrothion (Sumithion) was developed by Sumitomo as a potent phosphorus insecticide with low toxicity. Sumitomo developed the industrial synthesis of aiiethrin in the early 1950 s, and continued to invent effective pyrethroids such as fenvalerate and metofiuthrin. Mitsufs etofenprox is a unique pyrefhroid possessing no stereogenic carbon atom. The discovery of photo-stable synthetic pyrethroids such as fenvalerate and etofenprox enabled their widespread use in outdoor agriculture. 

A breakthrough in the use of pyrethroids as agricultural insecticides came with the discovery that esters of permethric acid are both highly potent and exhibit remarkable photostability. 

Synthesis of permethric acid (also called DV-acid) 91 became one of the central items in the years of industrial pyrethroid research in the 1970 s. Many original proposals have been made. Only a very small number have appeared in the scientific hterature. But the wealth of findings as pubhshed in patent apphcations show, in a fascinating way, that modem synthetic organic chemistry can turn many diverse and simple chemicals into permethric acid for less and less money as shown in the following chapter, in which the vast majority of the pubhshed discoveries has been taken into account. 

The change in the alcohol moiety to allethrone led to the development of the first synthetic pyrethroid, allethrin. It also led to improved chemical stability of the natural pyrethrins and to reduced cost, because the original pyrethrins had been sourced from natural products (LaForge and Soloway 1947). The stability of alle-thrin made it superior to the natural pyrethrins in both kill and knock-down effects against mosquitoes. Allethrin s successful discovery was followed by the development of other successful pyrethroids, to wit, tetramethrin (Kato et al. 1965) (1965, patent appl date) from tetrahydrophtalimide, resmethrin (Elliott et al. 1967) (1967, patent appl date) from 5-benzyl-3-furylmethyl alcohol and phenothrin (Fujimoto et al. 1973) (1968, patent appl date) by changing a-benzylfuran to phenoxyphenyl. 

The alcohol moieties used in the synthesis of the 15 pyrethroids are shown in Table 4. A discussion of the synthesis of each alcohol (i.e., stereochemistry, etc.) is beyond the scope of this review, although allethrone and 5-(phenylmethyl)-3-furanmethanol have been mentioned in the discovery section. Information oti the synthesis of ot-hydroxy-a-(3-phenoxyphenyl) acetonitrile (R, S forms) (cyanohydrin of phenoxyphenyl aldehyde) and the resolution of the desired S form that produces (IR, 3R, a-S) deltamethrin may be found in Chap. 2 of the Deltamethrin Monograph (1982). The alcohols and their metabolites are readily separated by partition chromatography on GC or HPLC columns. Ruzo and Casida (1977) and Ruzo et al. (1978, 1979) used TLC to separate and identify the alcohol metabolites. 

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