Synthesis and Stereostructure-Activity Relationship of Novel Pyrethroids Possessing two Asymmetric Centers on a Cyclopropane Ring

Abstract

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 >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.