Synthesis of Chrysanthemic Acid

The synthesis of chrysanthemic acid 1 as mixture of stereoisomers, as racemate of pure stereoisomers or as single optically active isomer was important before the advent of synthetic photostable pyrethroids. Because of the approved and favourable properties of pyrethrin I as a non-toxic and fast-acting contact insecticide, not only pyrethrum, but also other esters of chrysanthemic acids with similar properties are of commercial interest. Therefore cheap methods for the synthesis of this add or even total synthesis of the natural compound deserve the attention of chemists involved in synthesis. Many interesting reactions, involving rearrangements, eliminations and additions were apphed in the synthesis of this archetypical pyrethroid cydopropane carboxyhc acid. 

Diazoacetic esters offer a simple method for introducing carbon atom No. 1. The very first synthesis of chrysanthemic add by Staudinger [1] applied this classical reaction, preparing a mixture of stereoisomers 1 (Reaction scheme 1), which was also the method of choice in the first technical process at Carbide and Carbon 

Chemical Corporation (USA) in 1950 [2] and which is still applied at Sumitomo s in Japan. 

The needed 2,5-dimethylhexadien-2,-4, 2, originally very difficult to obtaine in a pure state, was prepared from acetone and acetylene, but-may also be obtained from methallylchloride and dimerization with magnesium, followed by catalytic isomerization to the conjugated system [2, 3, 4]. 

Petrochemical approaches are the reaction of butene with methallylchloride at 500 °C [5], and the addition of isobutyraldehyde to isobutylene [6] in the presence of a niobium catalyst. 

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When the carbinol substituents (R) were the bulky 5-ler -butyl-2-(n-octyloxy)phenyl group, optimum enantioselectivities were achieved with the catalytic use of the corresponding Cu(II) complex (2) in both enantiomeric forms. Specific applications of the Aratani catalysts have included the synthesis of chrysanthemic acid esters (Eq. 5.6) and a precursor to permethrinic acid, both potent units of pyrethroid insecticides, and for the commercial preparation of ethyl (S)-2,2-dimethylcyclopropanecarboxylate (Eq. 5.2), which is used for constructing cilastatin. Several other uses of these catalysts and their derivatives for cyclopropanation reactions have been reported albeit, in most cases, with only moderate enantioselectivities [26-29],... 

Well-known is the cyclopropanation of various alkenes. As shown by 329, cyclopropanation starts by electrophilic attack to the alkene. Electron-rich alkenes have higher reactivity. Numerous applications of intramolecular cyclopropanation to syntheses of natural products have been reported. Optically active cyclopropanes are prepared by enantioselective cyclopropanation [100], As the first successful example, asymmetric synthesis of chrysanthemic acid (331) was carried out by cyclopropanation of 2,5-dimethyl-2,4-hexadiene (330) with diazoacetate, catalysed by the chiral... 

Perhaps the most sensational synthesis of chrysanthemic acid uses this strategy. You may remember that TM31 is usually made from the adduct of acetylene and acetone. Draw out... 

This is Raphael s complete synthesis of chrysanthemic acid (Chem. Comm.. 1971, 555 J.C.S. Perkin IT 1973, 133) ... 

The reaction has also featured in a synthesis of chrysanthemic acid (49), occlusive rearrangement occurring to give the secondary allylic benzoate (equation 21). ... 

A similar procedure has been used in the synthesis of chrysanthemic acid derivatives (228) starting from isopropylidenemalonate (226) and a Grignard reagent (227) containing a sulphonyl function (equation 68). S-Containing leaving groups have also... 

The ds-hydrogenation of cyclopropenes is unexceptional in itself but when preceded by the addition of diazopropane to the yne component of an enyne (Section II.B) it provides a stereospecific synthesis of chrysanthemic acid esters (natural pesticides) in high yield. Reduction of unsymmetrical cyclopropenes with lithium aluminium... 

This is a classic Claisen [3,3]-sigmatropic rearrangement sequence starting with an allylic alcohol This product was used in a ind forming a vinyl ether by acetal (or in this case, orf/ioester) exchange. The reaction is very trans- synthesis of chrysanthemic acid by... 

Additions to the double bond of cyclopropenes have recently found considerable attention from both a synthetic and a mechanistic point of view. For example, Lehmkuhl et al.57) have developed a stereoselective synthesis of chrysanthemic acid via a 1,2-Grignard addition to 3,3-dimethylcyclopropene. Nesmeyanova et al.58) have found that the bromination of 3,3-dimethylcyclopropene possibly proceeds via a concerted, electrocyclic trans-addition. 

Loss of the carbethoxy group and conversion of CN to COOH in the product leads ultimately to synthesis of chrysanthemic acid, derivatives of which serve as effective insecticides known as pyrethrins. J. P. Genet and F. Piau, J. Org. Chem., 1981, 46, 2414. 

Table 5. Synthesis of Chrysanthemic Acid Derivatives from y,i5-Unsaturated Carbonyl or Nitrile Compounds...

Alkylidene- and ethenylidenecyclopropanes are versatile compounds which have been used, for example, in the synthesis of chrysanthemic acid esters. ... 

Hirai, H.. Ueda, K.. and Matsui. M.. Studies on chrysanthemic acid. Part 25. Alternative synthesis of chrysanthemic acid via tetrahydrofuran derivatives. Agr. Biol. Chem., 40, 153, 1976. 

An example of the formation of an ester of an -4,5-alkenoic acid 164 comes in a synthesis of chrysanthemic acid by Ficini and her group.31 Reduction gives the allylic alcohol 163 and [3,3] Claisen rearrangement with triethyl ortho-acetate gives the product 164 in one step. 

The regioselectivity of the addition is affected by functionality. In another synthesis of chrysanthemic acid, Ficini43 combined the monoacetate of the cis (Z)-alkene diol 254 with malonate to give only the trans (E)-adduct 255 in 80% yield. 

Copper complex catalyzed asymmetric cyclopropanation has been extensively applied to the synthesis of chrysanthemic acid (4, R = H) and other pyrethroid compounds. Cyclopropanation of 2,5-dimethyl-2.4-hexadiene (3) with ethyl diazoacetate in the presence of a copper complex... 

The synthesis of chrysanthemic acid (15), the acid component of the esters 9,11 and 13, was first solved by Staudinger et al. (1924). Starting from 2,5-dimethylhexa-2,4-diene (16) and ethyl diazoacetate, they obtained ( )-(Z)-chrysanthemic acid (15). 

This product was used in a synthesis of chrysanthemic acid by Jacqueiine Ficini and Jean d Angeio Tetrahedron Lett., 1976,2441. 

Allylic oxidation. A recent, simple synthesis of ( )-chrysanthemic acid (5, the (+) acid is the most active constituent of the insecticide pyrethrine) is outlined in scheme 1. The overall yield is A key step involves an allylic oxidation of (1) with rearrangement to give the benzoate (2) this product can be cyclized by a 1,3-elimination to give a mixture of (3) and (4), both of which are convertible into ( )-chrysanthemic acid (5). Various homologs can be prepared in the same way. 

Laevoglucosenone provides short, stereoselective routes to chiral synthons leading to (-)-S-multistriatin and (+)-Prelog-Djerassi lactonic acid (84)(see also Vol.16, p.265). The allo-oxiran (85) (obtained from D-glucose) has been used as the chiral control in a synthesis of chrysanthemic acids (86)(Scheme 17), the cyclopropane ring being formed by Wadsworth-Emmons reaction. ... 

FinaUy, the one-pot synthesis of chrysanthemic acid developed by Roussel Uclaf belongs in this list of elegant syntheses cf. Section 8.3). Treatment of maleic aldehyde ester with two equivalents of isopropylidenetriphenyiphosphorane produces an interesting building block for the synthesis of pyrethroids. 

A new high-yield synthesis of chrysanthemic acid derivatives has employed the... 

A project directed towards the synthesis of chrysanthemic acid enantiomers illustrates some of our recent work on cyclopropano-pyranosides. The sequence (Scheme 40) that had worked so well (25) for the preparation of the simple cyclopropyl ketone (169) from the methanol adduct (168) was not adaptable for preparation of the gem-dimethyl analogue (171). The photoaddition of isopropanol to (83) gave an excellent yield of (170), but efforts to convert this into (171) were not encouraging. However, the Wittig cyclopropanation (24) of epoxide (51) gave the ester (172) whose stereochemistry was deduced by two pieces of nmr data (a) the value J12 < 1 Hz (76) (see Scheme 4), and (b) a ten percent Nuclear Overhauser Effect between H-1 and the methyl protons. 

A variety of vinylcyclopropanes have been obtained in yields of up to 38 % by the one-step reaction of olefin with 3-diazopropene, catalysed by copper salts. Cupric trifiuoromethanesulphonate and cupric hexafluoroacetonylacetonate proved to be the most effective catalysts, and the reactions proceed stereospecifically cuprous chloride was totally ineffective. The use of chiral copper complexes for asymmetric induction in a-diazo-ester addition has been applied to the synthesis of chrysanthemic acid in an optical yield of 60—70%. ... 

The direct synthesis of chrysanthemic acid was accomplished by the reaction of a tungsten carbonyl carbene complex 28 with senecio acid 77 [41] (Reaction scheme 18). 

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