Total Syntheses of All Six Chiral Natural Pyrethrins: Accurate Determination of the Physical Properties, Their Insecticidal Activities, and Evaluation of Synthetic Methods.

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 [()-cinerolone, ()-jasmololone, and ()-pyrethrolone] were synthesized: (i) straightforward Sonogashira-type cross-couplings using available ()-4-hydroxy-3-methyl-2-(2-propynyl)cyclopent-2-en-1-ones (the prallethrin alcohol) for ()-cinerolone (overall 52% yield, 98% ee) and ()-pyrethrolone (overall 54% yield, 98% ee) and (ii) traditional decarboxylative-aldol condensation and lipase-catalyzed optical resolution for ()-jasmololone (overall 16% yield, 96% ee). Two counter acid segments [(1,3)-chrysanthemic acid () and (1,3)-second chrysanthemic acid precursor ()] were prepared: (i) C(1) epimerization of ethyl ()-chrysanthemates and optical resolution using ()-naphthylethylamine to afford (96% ee) and (ii) concise derivatization of to (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/-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 (KD and IC) against the common mosquito () 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).