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Chiral total syntheses of all six insecticidal natural pyrethrins (three pyrethrin I and three pyrethrin II compounds) contained in the chrysanthemum (pyrethrum) flower were performed. Three common alcohol components [(S)-cinerolone, (S)-jasmololone, and (S)-pyrethrolone] were synthesized: (i) straightforward Sonogashira-type cross-couplings using available (S)-4-hydroxy-3-methyl-2-(2-propynyl)cyclopent-2-en-1-ones (the prallethrin alcohol) for (S)-cinerolone (overall 52% yield, 98% ee) and (S)-pyrethrolone (overall 54% yield, 98% ee) and (ii) traditional decarboxylative-aldol condensation and lipase-catalyzed optical resolution for (S)-jasmololone (overall 16% yield, 96% ee). Two counter acid segments [(1R,3R)-chrysanthemic acid (A) and (1R,3R)-second chrysanthemic acid precursor (B)] were prepared: (i) C(1) epimerization of ethyl (±)-chrysanthemates and optical resolution using (S)-naphthylethylamine to afford A (96% ee) and (ii) concise derivatization of A to B (96% ee). All six pyrethrin esters (cinerin I/II, jasmolin I/II, and pyrethrin I/II) were successfully synthesized utilizing an accessible esterification reagent (TsCl/N-methylimidazole). To investigate the stereostructure-activity relationship, all four chiral stereoisomers of cinerin I were synthesized. Three alternative syntheses of (±)-jasmololone were investigated (methods utilizing Piancatelli rearrangement, furan transformation, and 1-nitropropene transformation). Insecticidal activity assay (KD50 and IC50) against the common mosquito (Culex pipiens pallens) revealed that (i) pyrethrin I > pyrethrin II, (ii) pyrethrin I (II) > cinerin I (II) ≫ jasmolin I (II), and (iii) "natural" cinerin I ≫ three "unnatural" cinerin I compounds (apparent chiral discrimination).

Pyrethroid insecticides contain natural pyrethrins extracted from pyrethrum flowers, and their synthetic derivatives, pyrethroids. The present article provides an overview of the structure of natural pyrethrins, and the discovery and development of pyrethroids with an emphasis on the background of selected compounds. The stereochemical relationships among pyrethroid secondary alcohols, and toxicologic and environmental effects of pyrethroids are also discussed. Finally, the pyrethroid resistance of mosquitoes and future aspects of pyrethroids are addressed.

2-Methylcyclopropane pyrethroid insecticides bearing chiral cyanohydrin esters or chiral ethers and two asymmetric centers on the cyclopropane ring, were synthesized. These compounds were designed using a “reverse connection approach” between the isopropyl group in Fenvalerate, and between two dimethyl groups in an Etofenprox analogue (the methyl, ethyl form), respectively. These syntheses were achieved by accessible ring opening reactions of commercially available (±)-, (R)-, and (S)-propylene oxides using 4-chlorobenzyl cyanide anion as the crucial step, giving good overall yield of the product with &gt, 98% ee. The insecticidal activity against the common mosquito (Culex pipiens pallens) was assessed for pairs of achiral diastereomeric (1R*,2S*)-, (1R*,2R*)-cyanohydrin esters, and (1R*,2S*)-, (1R*,2R*)-ethers, only the (1R*,2R*)-ether was significantly effective. For the enantiomeric (1S,2S)-ether and (1R,2R)-ether, the activity was clearly centered on the (1R,2R)-ether. The present stereostructure‒activity relationship revealed that (i) cyanohydrin esters derived from fenvalerate were unexpectedly inactive, whereas ethers derived from etofenprox were active, and (ii) apparent chiral discrimination between the (1S,2S)-ether and the (1R,2R)-ether was observed. During the present synthetic study, we performed alternative convergent syntheses of Etofenprox and novel 4-EtO-type (1S,2S)- and (1R,2R)-pyrethroids from the corresponding parent 4-Cl-type pyrethroids, by utilizing a recently-developed hydroxylation cross-coupling reaction.

We have developed an efficient practical resolution method for (1 R ,3 R )- trans -chrysanthemic acid 1 and (1 R ,3 S )- trans -2,2-dimethyl-3-(2,2-dichloroethenyl)cyclopropanecarboxylic acid 2 , based on the preliminary results of the simpler analogues, (1 R )-2,2-dichlorocyclopropanecarboxylic acid 3 and (1 R )-2,2-dimethylcyclopropanecarboxylic acid 4 , using a crystalline-liquid separation procedure (without column chromatography) with chiral 1,1′-binaphthol monoethyl ethers ( R )- 5b as the key auxiliary. Direct esterifications of 1 , 2 , 3 , and 4 with ( R )- 5b gave four sets of (1 R )- and (1 S )-diastereomeric esters 8 , 9 , 6 , and 7 , respectively, with markedly different melting points. All of these diastereomers were easily obtained using a simple and one-step crystalline-liquid separation. The separated diastereomers 8 and 9 were easily hydrolyzed to the desired enantiopure acids 1 (>98%) and 2 (>99%), respectively, with recovery of ( R )- 5b (>90%).

3-Methyl-2 H -furo[2,3- c ]pyran-2-ones 1 and 2 , a unique and remarkable seed germination stimulant, and its analogue were synthesized using direct and regioselective Ti-crossed aldol addition between dihydro-2 H -pyran-3(4 H )-ones and methyl pyruvate as the key step, followed by furanone formation.

A series of [1(2H),2'-bipyridin]-2-one derivatives were synthesized and their insecticidal activity against German cockroaches and houseflies was evaluated. The strength of activity varied markedly depending upon the substituents and their positions on the pyridone and the pyridine ring. Electron-withdrawing substituents at the 3, 3', 5 and 5'-positions on both rings are required for the insecticidal activity, especially against German cockroaches. Furthermore, a couple of trifluoromethyl groups at the 5 and 5'- positions on both rings are essential for the activity. Among all compounds tested, a chlorine atom at the 3-position on the pyridone ring, and a chlorine atom, a fluorine atom or a trifluoromethyl group at the 3'-position on the pyridine ring were more preferable.

The three commercial synthetic pyrethroids containing a carbon-carbon triple bond, α-ethynyl-2-methylpent-2-enyl (1 R)-trans-chrysanthemate, (S)-2-methyl-4-oxo-3-(2-propynyl)cyclopent-2-enyl (1R)-trans,cis-chrysanthemate and [2,5-dioxo-3-(2-propynyl)-1-imidazolidinyl]methyl (1R)-trans-chrysanthemate are reviewed with emphasis on their inventive histories. Their chemistry and efficacy are described briefly. The relationship between stereochemistry and the biological activity is also discussed.

Development of pyrethroids for household use and recent advances in the syntheses of (1R)-trans-chrysanthemic acid, the acid moiety of most of the household pyrethroids, are reviewed. As another important acid moiety, we discovered norchrysanthemic acid to have a significant vapor action at room temperature when esterified with fluorobenzyl alcohols. In particular, 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R)-trans-norchrysanthemate (metofluthrin) exhibits the highest potency in mosquito coil formulations as well as the vapor action at room temperature against various mosquitoes. Structure-activity relationships of norchrysanthemic acid esters and synthetic studies of norchrysanthemic acid are discussed.

(Z)-1,4-Dibromo-1,1,2-trifluoro-2-butene (2a) reacts regioselectively with sodium benzenesulfinate and triethyl phosphite respectively to yield the (Z)-isomers of 3,4,4-trifluoro-4-bromo-2-butenyl phenyl sulfone (3) and diethyl (Z)-4-bromo-3,4,4-trifluoro-2-butenylphosphonate (6). These could easily be transformed to a variety of polyfunctional monofluoroalkene derivatives.

2,2,2-Trifluoroethyldiphenylphosphine oxide [Ph2P(O)CH2CF3] (2) is known to give no Horner reaction product with enolizable aldehydes. We found, however, that some enolizable aldehydes such as N-Boc-pyrrolidine-2-aldehyde (9) gave the expected 3,3,3-trifluoroprop-1-enyl compounds by reaction with 2. The products could be further transformed to some 2,2,2-trifluoroethyl-substituted nitrogen-containing heterocycles by using radical cyclization or Heck reaction.

The structure of an usual catechol byproduct in the aldol condensation of the salt of 3-oxo-6-heptenoate and pyruvic aldehyde, and the discovery of an additive to inhibit its formation are described.

New fluorinated pyrethroids were designed to block microsomal oxidation at the C-10 methyl group of biophenothrin and at the C-7′ methylene of bioallethrin. By using diethylaminosulfur trifluoride and/or hexafluoropropene diethylamine, 10,10-difluorobiophenothrin and 7′-fluorobioallethrin were synthesized from the oxidized derivatives of the parent insecticides, which have been recognized as microsomal metabolites. While 10-hydroxybiophenothrin was not successfully converted into the corresponding 10-fluoro derivative by either fluorination reagent, other monofluorinated compounds were formed and their structures were elucidated.

(Z)-1,4-Dibromo-1,1,2-trifluoro-2-butene (2a) reacts regioselectively with sodium benzenesulfinate and triethyl phosphite respectively to yield the (Z)-isomers of 3,4,4-trifluoro-4-bromo-2-butenyl phenyl sulfone (3) and diethyl (Z)-4-bromo-3,4,4-trifluoro-2-butenylphosphonate (6). These could easily be transformed to a variety of polyfunctional monofluoroalkene derivatives.

La methoxylation et bromation du compose du titre conduit a l'ether de bromo-4 trifluoro-1,1,2 butene-2yle et de methyle (A). (A) reagit avec des organomagnesiens pour conduire a des fluoro-2 alcene2oates de methyle. A partir de (A) obtention de piperide de fluoro-2 piperine. Synthese egalement de methoxycarbonyl-3 dimethyl-2,2 α-fluoro cyclopropaneacrylate de methyle

La methoxylation et bromation du compose du titre conduit a l'ether de bromo-4 trifluoro-1,1,2 butene-2yle et de methyle (A). (A) reagit avec des organomagnesiens pour conduire a des fluoro-2 alcene2oates de methyle. A partir de (A) obtention de piperide de fluoro-2 piperine. Synthese egalement de methoxycarbonyl-3 dimethyl-2,2 α-fluoro cyclopropaneacrylate de methyle