55667-40-8

The based-induced contraction of enolisable 2-halocyclobutanones is often not stereoselectiv.The cis/trans-isomer ratio in the cyclopropanecarboxylic acid 9 derived from 2,4-cis-substituted cyclobutanones 7 depends on the nature of the leaving group.In addition, the choice of the base, the temperature and the solvent can profoundly affect the stereoselectivity of the Favoskii-reaction.The use of the p-bromophenylsulfonyloxy group as leaving group and an inhomogenous reaction medium leads exclusively to cis-carboxylic acid.

Chemical behaviour and thermal stability differences between the diastereoisomeric cis- and trans-permethrines are elucidated on the basis of their crystal structures.Crystals of the trans-isomer are monoclinic with space group C2/c, with 8 molecules in a unit cell of dimensions a = 38.030(5), b = 9.163(2), c = 11.715(6) Angstroem and B = 105.95(4).Previously published cis-structures are reinvestigated in order to obtain the same accoracy for both derivatives.

An efficient multi-gram synthesis of (1R,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate, a key chiral bicyclic proline fragment employed in the construction of the potent anti-HCV drug boceprevir, has been presented. The synthetic route commences with the readily available cis-cypermethric acid, a cheap source of the cyclopropane ring required in the targeted compound, and utilizes the cis-orientation of the 2,2-dichlorovinyl and carboxylic acid side arms, already present in the starting material, to effect a diastereoselective construction of the proline moiety.

The gene encoding pyrethroid-hydrolyzing esterase (EstP) from Klebsiella sp. strain ZD112 was cloned into Escherichia coli and sequenced. A sequence analysis of the DNA responsible for the esfP gene revealed an open reading frame of 1914 bp encoding for a protein of 637 amino acid residues. No similarities were found by a database homology search using the nucleotide and deduced amino acid sequences of the esterases and lipases. EstP was heterologously expressed in E. coli and purified. The molecular mass of the native enzyme was approximately 73 kDa as determined by gel filtration. The results of sodium dodecyl sulfate - polyacrylamide gel electrophoresis and the deduced amino acid sequence of EstP indicated molecular masses of 73 and 73.5 kDa, respectively, suggesting that EstP is a monomer. The purified EstP not only degraded many pyrethroid pesticides and the organophosphorus insecticide malathion, but also hydrolyzed ρ-nitrophenyl esters of various fatty acids, indicating that EstP is an esterase with broad substrates. The Km for trans- and cis-permethrin and kcat/Km values indicate that EstP hydrolyzes both these substrates with higher efficiency than the carboxylesterases from resistant insects and mammals. The catalytic activity of EstP was strongly inhibited by Hg2+, Ag+, and ρ-chloromercuribenzoate, whereas a less pronounced effect (3-8% inhibition) was observed in the presence of divalent cations, the chelating agent EDTA, and phenanthroline.

The pyrethroid pesticides residues on foods and environmental contamination are a public safety concern. Pretreatment with pyrethroid hydrolase has the potential to alleviate the conditions. For this purpose, a fungus capable of using pyrethroid pesticides as a sole carbon source was isolated from the soil and characterized as Aspergillus niger ZD11. A novel pyrethroid hydrolase from cell extract was purified 41.5-fold to apparent homogeneity with 12.6% overall recovery. It is a monomeric structure with a molecular mass of 56 kDa, a pl of 5.4, and the enzyme activity was optimal at 45°C and pH 6.5. The activities were strongly inhibited by Hg2+, Ag+, and p-chloromercuribenzoate, whereas less pronounced effects (5-10% inhibition) were observed in the presence of the remaining divalent cations, the chelating agent EDTA and phenanthroline. The purified enzyme hydrolyzed various insecticides with similar carboxylester. trans-Permethrin is the preferred substrate.

Assays to detect esterases associated with resistance to organophosphorus and pyrethroid insecticides in larvae of H. virescens were developed and evaluated. Cross-resistance to a variety of insecticides was measured in strains resulting from selection with either profenofos (OP-R) or cypermethrin (PYR-R), and resistance in both strains appeared to have a metabolic component. Esters were synthesized that coupled 3-(2,2-dichlorovinyl)-2,2- dimethylcyclopropanecarboxylate, the acid moiety of some pyrethroid insecticides, with groups (e.g., p-nitrophenyl-) that could be detected spectrophotometrically following hydrolysis of the resulting esters. Activities toward these pyrethroid esters were significantly higher in both resistant strains than those in a susceptible reference strain. In addition, all pyrethroid esters significantly increased the toxicity of cypermethrin in bioassays with larvae from both PYR-R and OP-R strains. The biological and biochemical activities of these compounds are compared with those with more conventional esterase substrates and insecticide synergists, and the utility of pyrethroid esters as components of rapid assays for detecting esterases associated with insecticide resistance is discussed.

Polymer bound olefins undergo free radical initiated 1,2-addition when reacted with a variety of haloalkanes. The strategy could be applied successfully to the solid-phase synthesis of dihaloethenylcyclopropane carboxylic acids which are the key fragments of synthetic pyrethroids.

Hydrazides are selectively oxidised to esters/acids in high yields using Oxone in the presence of an appropriate alcohol/water as a nucleophile at ambient temperature. A variety of functional groups including alkenes, alcohols, ethers, cyclopropyl groups and nitriles are unaffected.

Kinetic resolution of trans-substituted cyclopropane carboxylic acids anchored on a solid support by lipase is described.

The phenoxybenzyl moiety of conventional pyrethroids is a major site of oxidative metabolism in resistant tobacco budworms, Heliothis virescens (F.). In this study, this group was replaced with known P450 monooxygenase-inhibiting or oxidatively blocked groups. A variety of isomers (1R/1S, cis/trans) of the resulting chrysanthemates were tested as insecticides or synergists against tobacco budworms that were insecticide-susceptible (LSU) or that expressed metabolic resistance to cypermethrin (Pyr-R). A number of compounds with pentafluorophenyl, methylenedioxyphenyl, and propargyloxyphenyl groups were insecticidal, and activity was dependent on both geometric and stereochemical configuration of the acid moiety. Both trans and cis isomers of 1(R)-fenfluthrin, which contains a pentafluorophenyl group, suppressed resistance to cypermethrin in Pyr-R insects, confirming that oxidative metabolism of the phenoxybenzyl moiety is a major mechanism of resistance in this strain. Of the methylenedioxyphenyl compounds, 1R, trans, and cis isomers were toxic and partially suppressed resistance in Pyr-R larvae. Similarly, both trans and cis isomers of α(S),1(R)-propargyloxyphenyl-containing compounds were insecticidal. Finally, α(R),1(R)-cis-methylenedioxyphenyl- and -propargyloxyphenyl- containing compounds were nontoxic but significantly enhanced toxicity of cypermethrin.

Promising procedures were developed for the synthesis of permethrin and I-chloropermethrin starting from acid chloride, nitrile, and esters of 3,3-dimethyl-2,2,4,6,6-pentachloro-5-alkenoic acid and 3,3-dimethyl-2,2,6,6-tetrachloro-5-alken-4-olide, which were prepared by adding derivatives of trichloroacetic acid to 1,1-dichloro-4-methyl-1,3-pentadiene in the presence of catalytic amounts of monovalent copper ions and amine.

A synthesis of the title compounds 5 involves the reaction between 3-methyl-2-buten-1-ol and triethyl orthoacetate to produce ethyl 3,3-dimethyl-4-pentenoate, which is followed by the addition of various carbon tetrahalides to the double bond.The reaction of resulting adducts with a base affords 5 in high yields.Stereoselective preparation of the cis-isomer was achieved by the following two methods: First one involves selective transformation of ethyl 4-bromo-6,6,6-trichloro-3,3-dimethylhexanoate to ethyl 6,6,6-trichloro-2,3-dimethyl-4-hexanoate (8a) with piperidine followed by the selective conversion of 8a to cis-2,2-dichloroethenyl compound (cis-5a).Second one is based on the stereoselective cyclization of ethyl 4,6,6,6-tetrachloro-3,3-dimethyl-hexanoate (t-BuONa/solvent/HMPA) to ethyl cis-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarboxylate which is transformed into cis-5a without cis-trans isomerisation.

-