Chrysanthemic acid derivatives, pyrethroid

In the 1960s and 1970s, from ingredients of chrysanthemums, an important group of insecticides, the pyrethroids, was developed these are derived from chrysanthemic acid. The pyrethroids and the phosphate esters replaced the previously intensively applied chlorinated hydrocarbons such as, for example, DDT. 

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. 

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],... 

Synthesis and practical applications of furan carboxylic acids 85MI8. Synthetic pyrethroids—furan derivatives of chrysanthemic acid ... 

Punja et al. (1973) prepared several new esters of chrysanthemic acid, combining structural features of the pyrethroids with those of juvenile hormones. Of these, the JH effect of the most potent derivatives, 57,58 and 59, was nearly the same as that of the natural juvenile hormones. 

From 1967, the efforts of Michael EUiott at Rothamsted (England) produced pyrethroids of ever increasing potency, suited for bulk production, and useful in agriculture. The first of these, bioresmethrin (Elliott et aL, 1967), in which chrysanthemic acid is esterified with a furan-derived alcohol 6.53), proved to be the first synthetic substance with the full potency of pyrethrum I against a wide range of insects. It is non-toxic to mammals, and is still much used in market gardens, particularly on carrots, cabbage, and lettuce. 

Cyclopropanes are occasionally found in Nature, and one class of naturally occurring cyclopropanes, the pyrethroids, are useful insecticides. These compounds are highly toxic to insects but not to mammals, and because they are rapidly biodegraded, cyclopropanes do not persist in the environment. The naturally occurring pyrethroids are found in members of the chrysanthemum family and are formally derived from chrysanthemic acid. Many modified pyrethrins not found in Nature have been made in the laboratory and several are widely used as pesticides. The molecule known as pyrethrin I has the systematic name 2,2-dimethyl-3-(2-methyl-l-propenyl)cyclopropanecarboxylic acid 2-methyl-4-oxo-3-(Z-2,4-dipentadienyl)-2-cyclopenten-1-yl ester. See why the shorthand is used ... 

Hydrolysis of the pyrethroids may occur prior to hydroxylation. For dichloro groups (i.e., cyfluthrin, cypermethrin and permethrin) on the isobutenyl group, hydrolysis of the trans-isomers is the major route, and is followed by hydroxylation of one of the gem-dimethyls, the aromatic rings, and hydrolysis of the hydroxylated esters. The cis-isomers are not as readily hydrolyzed as the tran -isomers and are metabolized mainly by hydroxylation. Metabolism of the dibromo derivative of cypermethrin, deltamethrin, is similar to other pyrethroids (i.e., cyfluthrin, cypermethrin, and permethrin) that possess the dichloro group. Type 11 pyrethroid compounds containing cyano groups (i.e., cyfluthrin, cypermethrin, deltamethrin, fenvalerate, fenpropathrin, and fluvalinate) yield cyanohydrins (benzeneacetonitrile, a-hydroxy-3-phenoxy-) upon hydrolysis, which decompose to an aldehyde, SCN ion, and 2-iminothia-zolidine-4-carboxylic acid (TTCA). Chrysanthemic acid or derivatives were not used in the synthesis of fenvalerate and fluvalinate. The acids (i.e., benzeneacetic acid, 4-chloro-a-(l-methylethyl) and DL-valine, Af-[2-chloro-4-(trifluoromethyl) phenyl]-) were liberated from their esters and further oxidized/conjugated prior to elimination. Fenpropathrin is the oifly pyrethroid that contains 2,2,3,3-tetramethyl cyclopropane-carboxylic acid. The gem-dimethyl is hydroxylated prior to or after hydrolysis of the ester and is oxidized further to a carboxylic acid prior to elimination. 

The potentials of this and other similar chiral Schiff base complexes of copper were originally explored for the manufacture of synthetic pyre-throids, a class of highly active pesticides. Cyclopropane rings with asymmetric centers are an integral part of the molecular structures of synthetic pyrethroids. Synthetic pyrethroids were made because the natural product chrysanthemic acid, 7.69, and its derivatives have insecticidal properties. 

Pyrethroids are synthetic analogs of derivatives of chrysanthemic acid, 25.6, naturally occurring in plants of the Chrysanthemum genus. The naturally extracted materials, pyrethrin I and II (25.7, 25.8), have been modified for better activity in compounds such as permethrin, 25.9, and deltamethrin, 25.10. They are toxic to cats and to aquatic life but have otherwise generally low toxicity to mammals and are broken down rapidly in the environment. They are widely used as domestic insecticides. You should note that although a single stereoisomer... 

Miyamoto J, Nishida T, Ueda K (1971) Metabolic fate of resmethrin, 5-benzyl-3-furylmethyl A -trans chrysanthemate in the rat. Pestic Biochem Physiol 1 293-306 Miyamoto J, Suzuki T, Nakae C (1974) Metabolism of phenothrin (3-phenoxybenzyl A-trans-chrysanthemumate) in mammals. Pestic Biochem Physiol 4 438-450 Moss GP, Derden JC, Patel H, Cronin MT (2002) Quantitative structure-permeability relationships (QSPRs) for percutaneous absorption. Toxicol In Vitro 16 299-317 Mugeng J, Soderlund DM (1982) Liquid chromatographic determination and resolution of the enantiomers of the acid moieties of pyrethroid insecticides as their (-)-l-(l-phenyl)ethylamide derivatives. J Chromatogr A 248(1) 143-149... 

---