Enantiomers, pyrethroid

Liu W, Gan JJ (2004) Determination of enantiomers of synthetic pyrethroids in water by solid phase microextraction - enantioselective gas chromatography. J Agric Food Chem 52 736-741... 

For the production of various pyrethroid insecticides the (S)-4-hydroxy-3-methyl-2-(2-propynyl)-2-cyclopenten-l-one was required. Arthrobacter lipase hydrolysed only the P-enantiomer of the racemic acetate and, after extraction, the mixture of the alcohol and acetate were submitted to methanesulfonyl chloride and triethylamine. The thus-obtained acetate/mesylate mixture was hydrolysed/ inverted yielding 82% of (S)-4-hydroxy-3-methyl-2-(2-propynyl)-2-cyclopenten-l-one with an ee of 90% (Scheme 6.17 B). The procedure was also proved to work with other secondary alcohols and instead of the mesylate a Mitsunobu inversion could be applied [35]. 

Figure 4.5 Structures of some synthetic pyrethroid pesticides. Chiral centers are denoted by asterisks, a carbon by a. Only one enantiomer of each compound Is depicted...

In laboratory microcosms, ira 5-permethrin was selectively degraded compared to the other diastereomer, cw-permethrin, by six bacterial strains [19]. These strains also preferentially biotransformed 15-cw-bifenthrin over their antipodal l/ -cw-enantiomers, which were more toxic to daphnids [19]. Enantioselectivity was more pronounced for cw-permethrin than for cw-bifenthrin, and was strain-dependent. The (—)-enantiomer of both pyrethroids was preferentially depleted in sediments adjacent to a plant nursery, suggesting that in situ microbial biotransformation was enantioselective [20]. Although all enantiomers of permethrin were hydrolyzed quickly in C-labeled experiments in soils and sediments, the degradates of both cis- and irara-permethrin s -enantiomers were mineralized more quickly than those of the 5-enantiomer, while degradation products of cA-permethrin were more persistent than those of the trans-isomex [185]. Enantioslective degradation of fenvalerate in soil slurries has also been reported [83]. These smdies underscore how enantiomer-specific biotransformation can affect pyrethroid environmental residues, the toxicity of which is also enantiomer-dependent [18-20]. 

Stereoselective toxicokinetics of pyrethroids was observed in rodents. Rats injected with a racemic dose of 0-cypermethrin had much lower amounts of the (+)-enantiomer compared to the (—)-enantiomer in plasma, heart, liver, kidney, and fat tissues. The authors suggested rapid interconversion of (+)-a5, l/f,35 -cypermethrin to its antipode ( )-a/f,15, 3R-cyper-methrin in plasma, but no reverse conversion of the ( )-enantiomer back to the (+)-enantiomer. This hypothesis was criticized [285] as implausible, as three separate epimer-ization reactions would be necessary for conversion of (+)-a5, l/f,35 -cypermethrin to (—)-a R, 15,3R-cypermethrin. However, the results do indicate significant enantioselectivity in the in vivo processing of cypermethrin by rats, but is not clear to what extent this enantioselectivity was from biotransformation or from tissue-specific redistribution. The latter was suggested by the data [84] consistent with the highly enantioselective screening of a-HCH by the rat blood-brain barrier [259]. 

In addition, although most abiotic processes are nonenantioselective, not aU are indeed the case. Nucleophilic 5 jv2-substitution reactions at a chiral center will result in chiral inversion to the antipodal enantiomer. While such processes are often biologically mediated, as for the nonsteroidal anti-inflammatory drugs [328], they can also be abiotic. Appropriate sterile controls should be used for experiments with such compounds, as was done in the demonstration of microbial chiral inversion of ibuprofen in Swiss lake water [329]. Photolysis of a-HCH [114], /3-PCCH [114], and chlordane compounds [116] was demonstrated not to be enantioselective, as expected for an abiotic process. However, this may not be the case for some pyrethroids, known to isomerize photolytically. 

C, but was negligible at 180 °C or when on-column GC injection was used [96]. Cypermethrin [96] and cyfluthrin [96,330] also isomerized slowly (half-life ca. 160 days) at the asymmetric a-carbon atom in sterile water, as does deltametrin, which also has a cyano substituent at the asymmetric a-carbon atom in polar solvents [331, 332]. Cypermethrin isomerized rapidly in isopropanol (half-life of 3-7 days) and methanol (half-life of 2-3 days), as well as in organic solvent-water mixtures depending on water content and temperature [333]. Photolytic epimerization was observed for deltamethrin [331, 334] and for cyhalothrin, another cyano-bearing pyrethroid [335]. No isomerization by any means was observed for bifenthrin [96] and permethrin [96, 333], both of which lack cyano substituents. Thus, caution should be applied to cyano-bearing pyrethroids to avoid exposure to light and use of incompatible solvents (e.g. HPLC mobile phases), and in interpretation of enantiomer composition from environmental data to account for abiotic isomerization. 

Liu, W. Gan, J.J. Qin, S., Separation and aquatic toxicity of enantiomers of synthetic pyrethroid insecticides Chirality 2005, 17, S127-S133. 

Pyrethroids have two kinds of stereoisomerism, i.e., geometric isomerism and enantiom-erism. The cyclopropene ring shown in the general structure acts like a double bond, resulting in geometric isomers, cis/trans or Z/E forms, depending on whether the two substitutes (C-l and C-3) are on the same side (cis or Z) or on opposite sides (trans or E), as shown in the following text ... 

Pyrethroid insecticides can exist as enantiomers because they have two chiral centers, i.e., asymmetric carbons at C-l and C-3. An enantiomer exhibits optical activity and R/S configuration. Thus, a pyrethroid can show as either dextrorotatory (+) or levorotatory (-) isomer. A pyrethoid also can exist as either R or S form. However, only C-l is important to the biological activity of these compounds, and, for activity, it must be in the R position. As shown next, to be the 1R form, the -COOR group must be below the page. The IS form, which has -COOR group above the page, is nontoxic. Therefore, the active isomer of deltamethrin is expressed as (+)-ris-(lR) deltamethrin. The active isomer of permethrin is (lR)-ds-permethrin. 

We explored the potency of pyrethroid action in this system using deltamethrin, NRDC 157 (3-phenoxybenzyl [lR,cis]-3-( 2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate the non-cyano analog of deltamethrin), and their nontoxic enantiomers as test compounds ( Table II). Deltamethrin produced half-maximal enhancement of veratridine-dependent activation at 25 nM, whereas NRDC 157 was approximately tenfold less potent and the nontoxic enantiomers were inactive. These findings demonstrate that the effect of pyrethroids on mouse brain sodium channels is both potent and stereospecific for toxic isomers. The relative potencies of deltamethrin and NRDC 157 in this assay also agree well with their... 

The pyrethroid insecticide fenvalerate, (a-cyano-3-phenoxybenzyl-2-(4-chlorophenyl)isovalerate, contains two centers of chirality in its structure (designated as the 2 and a positions Fig. 19) and therefore four stereoisomers, two pairs of enantiomers are possible. Initial evaluation of the mixture, by addition to the diet of a number of species, resulted in granulomatous changes in the liver, lymph nodes, and spleen. Separation and evaluation of the individual stereoisomers indicated that the toxidty was associated with one of the four, the 2i ,a5-stereoisomer, and subsequent metabolic studies found the cause to be associated with the formation and disposition of a cholesterol ester of (i )-2-(4-chlorophenyl)isovalerate (Fig. 19). A metabolic transformation shown to be stereospedfic in mice, only the 2i ,a5-stereoisomer yielding the ester both in vitro and in vivo [159]. 

The method is particularly attractive when it is accompanied by spontaneous in situ racemisation of the enantiomer remaining in solution, allowing for a theoretical yield of 100%. This is often referred to as deracemisation. An industrially relevant example is shown in equation 7.2, whereby a synthetic pyrethroid undergoes base catalysed epimerisation at the CH group adjacent to the cyano group, precipitating the S,R,R, isomer exclusively, in a 98.6% yield [23]. 

The isomeric dihydrofurancarboxyhc 154 ester is closely related. Upon irradiation its optically active single R-enantiomer yields 1 R cis/trans caronaldehyde 155, another important key intermediate in pyrethroid chemistry (Reaction scheme 97) [240]. 

Synthesis of Individual Enantiomers of Chrysanthemic Add, Permethric Add and Other Pyrethroid Adds from Optically Active Naturally Occurring a-Pinene and Carene... 

Resolution of 262, using phenethyl amine [532], phenyl-tolyl-ethylamin [534] or cinchonidin [535] produces the S-enantiomer [529, 530, 533], essential for insecticidal activity of its pyrethroid ester esfenvalerate. Flucythrinate acid is resolved by phenethyl amine [531]. 

Permethrinic acid has two enantiomer pairs and four isomers (2" = 4) (Table B33, Appendix B). The acid leaving group for permethrin, cypermethrin, and cyfluthrin is permethrinic acid. The structure of this acid is given in Table 3. Angerer and Ritter (1997) separated the methyl esters of cis- and trans-permethrinic acid on a polysiloxane capillary column by GC (Table C18, Appendix C). The carboxylic acids of several of these pyrethroids were also listed as trans- or cw-3-(2, 2-dichlorovinyl)-2, 2-dimethyl cyclopropane carboxylic acid. The acids may be separated on a CHIREX phase 3005 column (Phenomenex, 2320 W 205th Street, Torrance, CA 90501) by HPLC. 

Synthesize analytical standards for hydroxylated pyrethroids (enantiomer pairs) and develop chromatographic methods for separating and identifying them. 

Develop in vitro metabolic rate constants (Fmax and m) for the CYP-catalyzed hydroxylation of parent pyrethroids (i.e., active pyrethroid isomers, enantiomer pairs), and the carboxylesterase-catalyzed hydrolysis of parent and hydroxylated... 

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Gao R, Zhu L, Chen Z (1998) Separation of pyrethroid enantiomers of fenpropathrin and fluvalinate by chiral high performance liquid chromatography. Nongyao (Pesticides) 37(9) 22-24 Gargas ML, Burgess RJ, Voisard DE, Cason GH, Andersen ME (1989) Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol Appl Pharmacol 98 87-99... 

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... 

Oi N, Horiba M, Kitahara H (1981) Gas chromatographic separation of optical isomers of chrysanthemic acid on an optically active stationary phase. Agric Biol Chem 45(6) 1509-1510 Oi N, Kitahara H, Kira R (1990) Enantiomer separation of pyrethroid insecticides by high-performance liquid chromatography with chiral stationary phases. J Chromatogr A 515 441 50... 

Xu C, Wang J, Liu W, Sheng GD, Tu Y, Ma Y (2007) Separation and aquatic toxicity of enantiomers of the pyrethroid insecticide Lambda-Cyhalothrin. Environ Toxicol (Them 27 174-181... 

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