Pyrethroids preparation

The insecticidal activity and structure-activity relationships of novel pyrethroids prepared by reacting methyl phenyl substituted pyrazole methanols with dichloro chrysanthemic acid chloride are reported. These pyrethroids are active on tobacco budworm, fall armyworm, southern corn rootworm, and aster leafhopper, generally in the concentration range of 1000-250 ppm. Although less active than the pyrethroid standard bifenthrin, the overall structure-activity of these pyrazole pyrethroids with regard to substitution patterns is similar to that previously observed with bifenthrin analogs. 

Ruigt, G.S.F. and J.V.D. Bercken. 1986. Action of pyrethroids on a nerve-muscle preparation of the clawed frog, Xenopus laevis. Pestic. Biochem. Physiol. 25 176-187. 

Pyrethrum became the main source of household insecticides in sprays in the USA (1919) and mosquito coils (1895) as well as oil-based preparations (1924) in Japan. Thereafter, the insecticidal ingredients shifted from pyrethrins to various synthetic pyrethroids, but mosquito coils have been used worldwide for more than 110 years without changing in shape. 

First, considering safety and resistance problems, agricultural pyrethroids used outdoors in large quantities should be discriminated from pyrethroids used as household insecticides in and around houses from the development stage of preparations. 

Mitsuda S, Umemura T, Hirohara H (1988) Preparation of an optically pure secondary alcohol of synthetic pyrethroids using microbial lipases. Appl Microbiol Biotechnol 29 310-315... 

An alternative nomenclature (Type I and Type II) has been proposed for subgroups of pyrethroids based not only on the syndromes of intoxication produced in mammals but also on their chemical structures, their signs of poisoning in insects, and their actions on insect nerve preparations [2, 14, 18]. The Type I/II nomenclature has been used in parallel with the T/CS nomenclature, so that Type I and Type II pyrethroids are generally considered to induce T- or CS syndrome, respectively [4]. However, the relationship between the two syndromes and types are neither necessarily confirmed in all pyrethroids nor absolute from the recent available data. 

Tsuji R The classification of 7 pyrethroids based on the data of comparative Functional observation battery study in rats (in preparation)... 

F. Matsumura, sponsored by the National Institute of Environmental Health Sciences (NIEHS), plans to study the toxic effects of chlorinated and pyrethroid pesticides primarily on calcium and sodium regulating processes in the nervous system. To examine the interactions of the pesticides with calcium regulating processes, researchers will use synaptosomal preparations from the brains of rats and the central nervous systems of squid. To examine the interactions of the pesticides with sodium regulating processes, they will collect antibodies directed against sodium channel proteins. 

The mechanism of insecticidal action has been attributed to blocking of the sodium channel in target cell membranes and consequent blocking of ion transport [124]. Following these observations a considerable effort was developed for the preparation of synthetic pyrethroids as commercial insecticides. 

The partially fluorinated vinylzinc reagent, reported by Shi and coworkers, has been utilized to prepare the fluoro analog of Naproxen and for the key intermediate for a novel synthetic pyrethroid (equations 67 and 68)44. 

In the presence of excess zinc and acetic anhydride, 1,1,1 -trichlorotrifluoro-ethane reacts with aldehydes to yield trifluoromethyl substituted Z-alkenes as the major isomer [64], which has been utilized to prepare artificial pyrethroids containing the CH = C1CF3 moiety [65,66] (Scheme 23). 

A variety of three-membered carbocycles including cyclopropylcarbonyl and -sulfonyl derivatives, cyclopropylcarbonitriles and -methanols, nitrocyclopropanes, cyclo-propanols and cyclopropylamines have been prepared via the 1,3-elimination of HX. Some representative cyclopropyl derivatives recently prepared by this method are shown in Scheme 116-18 and in equations 8-26. Conversion of chelated homoserine, 5,to chelated 2-amino-4-bromobutyrate and treatment with aqueous base directly affords chelated 1-aminocyclopropane-l-carboxylate (equation 8)19. The 1,3-elimination in 6 interestingly leads to the preferential formation of the cis isomer, from which 7, a key structural element of synthetic pyrethroid insecticides, is obtained (equation 9)20. A sulfur substituent can serve both as an activating group and as a leaving group in this type of reaction and, thus, 1,3-bis(phenylthio)propane affords cyclopropyl phenyl sulfide upon treatment with butyl-... 

Intramolecular cyclopropanation using diazoesters is a powerful synthetic tool. Diazoesters are readily prepared from the corresponding alcohol via House s methods56-57. Numerous examples using the application of this transformation in synthesis have been reported. These include the potent synthetic pyrethroid NRDC 182 (22)58, (1 R)-( )-cis-chrysanthemic acid (23)59, the highly strained bicyclic system 2460, antheridic acid 2561,62 and cycloheptadiene 26 (equations 33-37). 

When the carbinol substituents (R) were the bulky 5-ler -butyl-2-(n-octyloxy)phenyl group, optimum enantioselectivities were achieved with the catalytic use of the corresponding Cu(II) complex (2) in both enantiomeric forms. Specific applications of the Aratani catalysts have included the synthesis of chrysanthemic acid esters (Eq. 5.6) and a precursor to permethrinic acid, both potent units of pyrethroid insecticides, and for the commercial preparation of ethyl (S)-2,2-dimethylcyclopropanecarboxylate (Eq. 5.2), which is used for constructing cilastatin. Several other uses of these catalysts and their derivatives for cyclopropanation reactions have been reported albeit, in most cases, with only moderate enantioselectivities [26-29],... 

Blood and various organs of humans and other animals contain esterases capable of acetylsalicylic acid hydrolysis. A comparative study has shown that the liver is the most active tissue in all animal species studied except for the guinea pig, in which the kidney is more than twice as active as the liver. Human liver is least active the enzyme in guinea pig liver is the most active. The relatively low toxicity of some of the new synthetic pyrethroid insecticides appears to be related to the ability of mammals to hydrolyze their carboxyester linkages. Thus mouse liver microsomes catalyzing (+)-/runs-resin e 111ri n hydrolysis are more than 30-fold more active than insect microsomal preparations. The relative rates of hydrolysis of this substrate in enzyme preparations from various species are mouse > > milkweed bug > > cockroach > > cabbage looper > housefly. 

The search for other amino acid-based catalysts for asymmetric hydrocyanation identified the imidazolidinedione (hydantoin) 3 [49] and the e-caprolactam 4 [21]. Ten different substituents on the imide nitrogen atom of 3 were examined in the preparation, from 3-phenoxybenzaldehyde, of (S)-2-hydroxy-2-(3-phenoxy-phenyl)acetonitrile, an important building block for optically active pyrethroid insecticides. The N-benzyl imide 3 finally proved best, affording the desired cyanohydrin almost quantitatively, albeit with only 37% enantiomeric excess [49]. Interestingly, the catalyst 3 is active only when dissolved homogeneously in the reaction medium (as opposed to the heterogeneous catalyst 1) [49]. With the lysine derivative 4 the cyanohydrin of cyclohexane carbaldehyde was obtained with an enantiomeric excess of 65% by use of acetone cyanohydrin as the cyanide source [21]. 

Preparation of Optically Active Pyrethroids via Enzymatic Resolution... 

Efficient biochemical processes were developed for the preparation of the two optically active pyrethroid insecticides by a combination of enzyme-catalyzed reactions and chemical transformations. These are based on the findings that a lipase from Arthrobacter species hydrolyzes the acetates of the two important secondary alcohols of synthetic pyrethroids with high enantioselectivity and reaction rate. The two alcohols are 4-hydroxy-3-methy1-2-(2 -propynyl)-2-cyclopentenone (HMPC) and a-cyano-3-phenoxybenzyl alcohol (CPBA). The enzyme gave optically pure (R)-HMPC or (S)-CPBA and the unhydrolyzed esters of their respective antipodes. 

It is known that the (S)-forms are the essential stereoisomers for the insecticidal activities of both alcohols (4,5). Chemico-enzymatic processes are also reported in this article on the preparation of the optically active pyrethroid insecticides having the (S)-isomers of the two alcohols. Processes were developed that use enantioselective hydrolysis with a lipase. 

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