705-16-8

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).

An operationally simple method to affect an atom-transfer radical addition of commercially available ICH2Bpin to terminal alkenes has been developed. The intermediate iodide can be transformed in a one-pot process into the corresponding cyclopropane upon treatment with a fluoride source. This method is highly selective for the cyclopropanation of unactivated terminal alkenes over non-terminal alkenes and electron-deficient alkenes. Due to the mildness of the procedure, a wide range of functional groups such as esters, amides, alcohols, ketones, and vinylic cyclopropanes are well tolerated.

2,2,5,5-Tetramethylcyclohexane-1,3-dione is a valuable starting-material precursor of cis-chrysanthemic acid. The (1S)-stereoisomer is a precursor of pyrethrin I, the most active natural insecticide from Chrysanthemum cinerariifolium, whereas the (1R)-stereoisomer is efficiently transformed to deltamethrin, the most active commercially available pyrethroid insecticide. Several intermediates have been identified and used with variable success for that purpose.

We report an unprecedented type of reactivity of 'anhydrous potassium hydroxide' ('APH') in which it plays, over a large variety of related educts, sequentially the role of base and nucleophile. Some insight into the structure of reactive species as well as comparative reactivity of related reagents prepared by fusion of commercially available potassium hydroxide or by adding stoichiometric amount of water to potassium hydride is provided.

O-Acylation of 4- and 4,5-substituted N-hydroxythiazole-2(3H)-thiones occurred in solutions of acetone upon treatment with solid K2CO3 and a variety of neat acyl chlorides (primary, secondary, and tertiary alkyl, aryl; 60-87% yield; ～10 g scale).

The electron transfer photochemistry of optically pure (1R,3S)-(+)-cis-chrysanthemol (cis-2) results in the formation of (R)-5-(1-(p-cyanophenyl)-1-methylethyl)-2,2-dimethyl oxacyclohex-3-ene (4) with significant retention of optical activity. The product is rationalized via nucleophilic attack of the alcoholic function of the radical cation on the terminal carbon of the vinyl group with simultaneous replacement of an isopropyl radical as an intramolecular leaving group in an apparent S(N)2' reaction. This mode of attack is unprecedented in vinylcyclopropane radical cations and is interpreted as evidence for the significant role that relief of ring strain and its avoidance play in determining the course of nucleophilic capture in radical cationic systems.

Optically active (1R)(-) and (1S)(+)-trans-Chrysanthemic acid and its esters were prepared from corresponding racemic methyl ester by lipase mediated enantioselective hydrolysis, is described.

The Cu(I) complexes of new bis-oxazolines (3-7) prepared from the corresponding amino alcohols and malono-bis-imidate exhibit high enantioselectivity of up to 94 percent ee in the catalytic cyclopropanation of trisubstituted and unsymmetrical cis-1,2-disubstituted olefins.New diazoacetate reagents have also been developed giving high trans/cis ratios of up to 99:1 trans.

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Metalation of chrysanthemic nitrile 1 with lithium diisopropylamide followed by sulfenylation with diphenyl disulfide or oxygenation with a molybdenum peroxide complex gave chrysanthemic nitrile derivatives bearing phenylthio (3 and 4) or hydroxyl (6) substituents at C-1.These compounds provided access to the following series of 1-substituted chrysanthemylamines: 1-(phenylthio)chrysanthemylamine (5), 1-methoxychrysanthemylamine (8), 1-methoxydihydrochrysanthemylamine (10), and the N-nitrosooxazolidinone (13) derived from 1-hydroxychrysanthemylamine (11).Nitrous acid deamination of 5 and 8 and hydrolytic deamination of 13 gave acyclic alcohols (14, 17, and 18) related in structure to yomogi alcohol as major products by cleavage of the 1-3 cyclopropane ring bond.Products formed by cleavage of the 1-2 cyclopropane ring bond (15 and 24) and related in structure to santolinatriene were obtained in lesser amounts from the deamination of 5 and 13.Pinacol-type ring expansion to the isomeric cyclobutanones 19 and 20 was observed as a minor reaction pathway in the deaminations of 8 and 13.In contrast, deamination of 10 gave dihydrocyclobutanones 21 and 22 as the major isolated products.

A novel approach to (+/-) trans chrysanthemic acid, from commercially avaiable 2,5-dimethyl-3-hexyne-2,5-diol /30 percent overall yield) is described.