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

Abstract

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).

Pyrethrins elicit olfactory response and spatial repellency in Aedes albopictus

“…The previous work of our group showed that pyrethrin II and pyrethrin I exhibited similar potencies on cockroach sodium channels expressed in the Xenopus oocytes 23 . A very recent study reported that the order of potency of both knockdown and killing for the six pyrethrins against Culex pipiens pallens , ranging from high to low, was pyrethrin I > cinerin I > cinerin II > pyrethrin II > > jasmolin I > jasmolin II 39 . The discrepancies in the repellency versus insecticidal activity for each pyrethrin are interesting and likely reflect differential binding affinities of each pyrethrin to olfactory receptors versus sodium channels.…”

A modified synthesis of (Z)-pyrethrolone

“…Production of the final carbon scaffold could be readily achieved by implementing similar Sonogashira cross-coupling conditions to those used by Matsuo and co-workers. 5,7 Prior to addition of the catalytic components, a solution of vinyl bromide in THF was deaereated with argon to prevent the competitive Glaser coupling of the alkynyl substrate 7. The enyne 8 was generated by reaction with the vinyl bromide in the presence of Pd(Ph3P)4, CuI and Et3N.…”

“…More recently, a shorter reaction time and alternate solvent mixture have been described. 5 Notably, these reactions require the use of over 150 equivalents of activated zinc which may contribute to the observed over-reduction and generate significant quantities of heavy metal waste. Optimisation of this protocol allowed for a significant drop in the amount of zinc used from the aforementioned 150 to 20 equivalents.…”

“…While a number of pre-existing syntheses have been published in the literature since the elucidation of the rethrolone structure, many are lengthy or make use of undesirable, toxic reagents. The most recent of these syntheses uses prallethrin alcohol 7 as a starting material, 5 however this is difficult to obtain, expensive and unavailable in appreciable quantities. Alternatively, the most recent synthesis starting from easily accessible starting materials was reported by Matsuo and co-workers generating (Z)-pyrethrolone 9 over five synthetic operations.…”

Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination

“…Consistent with our continuing interest in chiral discrimination studies between enantiomers and diastereomers [ 18 , 19 , 20 , 21 , 22 , 23 ], a major topic in pharmaceutical and agrochemical research, we envisaged the chiral total syntheses of three sets of plymuthipyranones to evaluate the anti -MRSA activity of natural plymuthipyranone B (more active than A), synthetic analogues 4c , 4d and novel synthetic analogue 4e . This study is closely related to our total synthetic studies of a 3-acyl-5,6-dihydro-2 H -pyran-2-one series [ 7 , 10 , 15 ] and relevant 4-methoxy derivatives (all four stereoisomers of pestalotin) [ 24 ].…”