Optically Active Chrysanthemic Acid

S. Carloni, V. Borzatta, L. Moroni, G. Tanzi, G. Sartori, R. Maggi, Catalysts Based on Metal Complexes for the Synthesis of Optically Active Chrysanthemic Acid (2005), p. 55 (Patent WO2005123254A1)... 

Hydrolysis of cinenn I gives an optically active carboxylic acid (+) chrysanthemic acid Ozonolysis of (+) chrysanthemic acid followed by oxidation gives acetone and an optically active dicarboxyhc acid (—) caronic acid (C7H10O4) What is the struc ture of (—) caronic acid" Are the two carboxyl groups cis or trans to each other What does this information tell you about the structure of (+) chrysanthemic acid" ... 

Caronaldehyde 155 prepared by ozonolysis of chrysanthemic acid 1 provided Elliott with an extremely versatile source for many interesting new racemic and optically active pyrethroid acids (Reaction scheme 99) [242] by applying the Wittig-reaction. 

Comments The diene A is symmetrical so it doesn t matter which double bond is attacked by the carbene. On the other hand, it may be difficult to stop carbene addition to the second double bond. The only control over the stereochemistry will be that the trans compound we want is more stable. Japanese chemists have recently synthesised optically active trans chrysanthemic acid by this route (Tetrahedron Letters. 1977, 2599). 

Menthol ester (20) with (l/ S)-frans-2,2-dimethyl-3-(2,2-dichloroethenyl) cyclopropanecarboxylic acid (19) has been utilized to produce ( R)-trans-2, 2-dimethyl-3-(2,2-dichloroethenyl) cyclopropanecarboxylic acid (21), an acid moiety of transfluthrin (22) [9]. Matsuo et al. surveyed various optically active secondary alcohols for their potential in the optical resolution of (lRS)-trans-chrysanthemic acid [10] (Scheme 2). 

Essentially all of the early studies were directed towards enantioselective cyclopropanation and Maas has reviewed the literature up to 198 54. The most successful of these early studies were those of Aratani and coworkers"2 174 who developed chiral copper(II) chelates of type 153 from salicylaldehyde and optically active amino alcohols with which to catalyse intermolecular cyclopropanation with diazoesters. Enantioselectivities exceeding 90% ee could be achieved in selected cases (equations 133 and 134) including the synthesis of permethrinic acid 154 and /ram-chrysanthemic acid 155. 

Because caronic acid is optically active, its carboxyl groups must be trans to each other. (The cis stereoisomer is an optically inactive meso form.) The structure of (+)-chrysanthemic acid must therefore be either the following or its mirror image. 

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... 

Synthetic pyrethroids are a group of ester compounds having excellent insecticidal activities. After the discovery of allethrin (1), a variety of useful synthetic pyrethroids have been produced mainly by structural modification of an alcohol having an asymmetric center. The insecticidal activities greatly depend upon the stereoisomers. Therefore, much effort has been expended to develop technologies for obtaining optically active isomers. However, contrary to the case of chrysanthemic acid, chemical methods of optical resolution were not very effective for these alcohols. 

It is worth recalling that the asymmetric cyclopropanation of styrene with ethyl diazoacetate, reported in 1966 by Noyori and co-workers, appears to be the first example of transition metal catalyzed enantioselective reaction in homogeneous phase. This reaction remains a landmark in asymmetric cyclopropanation. On a general standpoint, catalytic asymmetric cyclopropanation continues to attract much attention, due in part to the marked trends toward marketing more and more optically active molecules as the optically pure eutomer. This topic has been much studied in connection, inter alia, with the synthesis of valuable intermediates such as chrysanthemic acid derivatives and cilastatin. The subject has been recently reviewed [17]. 

Tricarbonyliron complexes of conjugated trienes react with diazoalkanes at the free (uncom-plexed) double bond. In the synthesis of dimethyl 2-formylcyclopropane-l, 1-dicarboxylate (48), the ceric ion served the double function of catalyzing the deazetization and removing the tricarbonyl iron protecting group. When the optically active iron carbonyl complex was used, the addition of diazomethane gave selectively one diastereomer and this was used to make optically active dimethyl 2-formylcyclopropane-l,1-dicarboxylate (>90% ee). A similar route was employed to make the optically active formyl cyclopropanes 49, precursors to optically active cis- and tran.v-chrysanthemic acids. 

The preparation of the lactone 291 (R = H) has already been described (Vol. 4, p. 486, Ref. 243), and this route to chrysanthemic acid has now been improved by making the optically active lactone, starting from commercially available optically active phenylglycinol (reduction of a-phenylglycine) and the anhydride... 

In this way, esters of chrysanthemic acid (2) [15,16,18] and permethrinic acid [17,18], which are important precursors for the synthesis of pyrethroid insecticides, can be prepared in >90% ee. Although enantioselective cyclopropanation cannot compete with conventional industrial syntheses of optically active pyrethroids, a technical process for the cyclopropanation of 2-methylpropene was successfully implemented at Sumitomo [18]. The product, ethyl (-l-)-2,2-dimeth-ylcyclopropanecarboxylate, serves as a starting material for the production of cilastatin, a dehydropeptidase inhibitor used as a drug to suppress the degradation of the P-lactam antibiotic iminipenem. 

Certain kinds of cyclopropanecarboxylic acids are important in the production of pyrethroid, an insecticide with low mammalian toxicity [1]. For example, chrysanthemic acid is an acid component of allethrin (Fig. 1). Various kinds of alcohols have been developed to produce pyrethroids for special application [2]. Chrysanthemic acid has two chiral centers and there are four optical isomers. There is a close correlation between the chirality of a molecule and its biological activity [3]. In the case of chrysanthemic acid, the most effective isomer is shown to be the d-trans isomer, which is followed by the d-cis isomer whereas... 

Miscellaneous Reactions of Methylenephosphoranes.—The synthesis of three-membered rings by means of phosphorus ylides has been reviewed and there have been several new reports of this type of reaction. Optically active a,p-un-saturated esters have been converted into cyclopropanes highly stereoselectively by reaction with isopropylidenetriphenylphosphorane as the key step in syntheses of both (li ,3 )-chrysanthemic acid methyl ester (53) and the (IR) cis-gem dibromovinyl analogue (54). The addition of reactive phosphonium ylides to functionalized 1,3-butadienylphosphonates provides a new synthesis of 2-cyclopen ten-1 -ylphosphonates (5 5). ... 

Chiroptical measurements in the chrysanthemic acid series have shown that 1,2,2,3-tetra-alkylcyclopropanes have the same chiralities as, yet Cotton effects opposite to, those previously reported for corresponding 1,3-dialkylcyclopropanes. Magnetic circular dichroism of cyclopropane and c.d. studies of optically active derivatives indicate that configuration interaction is of considerable importance in the low-energy excited states. ... 

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. 

However, treatment of this ds/trans add with sulfuric add at 160 °C yields trans racemate [107]. On the other hand the trans ester, when treated with sulfuric acid in pentane at room temperature, gives rise to a irreversible ring opening at carbon bond C —and formation of optically active lavandulyl esters 72 [108] as seco chrysanthemates. Loss of optical activity is accomphshed by moderate thermal treatment of 1-S-configurated anhydrides 73 in the presence of iodine [110] or in the presence of a Lewis acids (Reaction scheme 44). 

Even sugar can be transformed into 1-R-chrysanthemic acid [118] via a multistep procedure. Likewise, optically active pantolactone 78 [119] can be reduced, ketalized, mesylated and later on subjected to cyanide exchange to give 79. 

Substantial effort has been put into utilizing the optically active natural hydrocarbons (-h)"a-pinen and (-h)-A-3-caren for synthesis of chrysanthemic acid, permethric acid and other pyrethroid acids. These reactions are explained in Sect. I.3.6.5. 

Single isomers of permethric acid, the dihalovinylanalogues of chrysanthemic acid esters, which are sometimes easier to obtain, can also be ozonized to give optionally the optically active caronaldehyde [127, 245] or the epoxides. The epoxides of permethric acid can not be prepared by means of the most reactive peracids [246], the usual epoxidizing agents. 

Resolutions of racemic trans-permethric acid succeed analogously to chrysanthemic add with the aid of diverse optically active amines ... 

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