Chrysanthemic acid synthesis

Bicyclic ketone (33) was needed for a chrysanthemic acid synthesis. tarbene disconnection next to the ketone group (Chapter T30) reveals y. (5-unsaturated acid (35) as an intermediate, available by a Claisen-Cope rearrangement. 

Lowenthal and Masamune (44) investigated the cyclopropanation of trisubsti-tuted alkenes leading to a chrysanthemic acid synthesis. They found that ligand 50c provided poor selectivities in this case (24% de for the trans isomer). Substitution in the 5 position of the oxazolines leads to increased selectivities, with excellent results provided by the BHT ester (94 6, 94% ee), Eq. 32. This ligand proved to be applicable to other trisubstituted and several cis-disubstituted alkenes, providing the corresponding cyclopropanes in ee values of 82-95%. These authors note that catalysts generated from CuOTf, CuOf-Bu, and Cu(II) precursors (with activation) provided similar yields and enantioselectivities. 

In 1971, Sumitomo started to apply this reaction to the chrysanthemic acid synthesis (Scheme 2). The first problem was how to choose a suitable catalyst which would achieve the highest ee of the product. Here we describe our approach to this problem [10,11,12,13,14,15,16,17,18]. Other effective catalysts... 

In the chrysanthemic acid synthesis (Scheme 2), the ee of the product increased with the bulkiness of the R group [11]. The highest ee achieved was 70%, when R was methyl (the amino acid was alanine) and R was 2-octyloxy-5-tert-butylphe-nyl. The catalyst with the R-configuration (from D-amino acid) favored the formation of d-trans and d-cis isomers to that of l-trans and l-cis isomers, respectively. 

The foregoing prospectus for the chrysanthemic acid synthesis represents enantioselective transformations of the first kind (Scheme 39, equation i). The second kind (equation ii) is represented by studies directed toward the (+) and (—) grandisol enantiomers (183). 

In all, only six steps are involved, making this a most economical synthesis. Chrysanthemic acid is important enough to have been made in many other ways too (e.g. Tetralredron Letters, 1976, 2441 Bull. Soc. Chim. France, 1966, 3499). 

For the synthesis of permethric acid esters 16 from l,l-dichloro-4-methyl-l,3-pentadiene and of chrysanthemic acid esters from 2,5-dimethyl-2,4-hexadienes, it seems that the yields are less sensitive to the choice of the catalyst 72 77). It is evident, however, that Rh2(OOCCF3)4 is again less efficient than other rhodium acetates. The influence of the alkyl group of the diazoacetate on the yields is only marginal for the chrysanthemic acid esters, but the yield of permethric acid esters 16 varies in a catalyst-dependent non-predictable way when methyl, ethyl, n-butyl or f-butyl diazoacetate are used77). 

The grem-dibromocyclopropanes 152 bearing a hydroxyalkyl group, prepared by the addition of dibromocarbene to allylic or homoallylic alcohols, undergo an intramolecular reductive carbonylation to the bicyclic lactones 153. bicyclic lactone derived from prenyl alcohol is an important precursor for the synthesis of ris-chrysanthemic acid. (Scheme 54)... 

Recently novel methods were reported to make (lR)-trans-chrysanthemic acid including optical resolutions with the (+)-3-caranediol or l,l -binaphthol monoethylether, enzymatic resolution with Arthrobacter globiformis and the asymmetric synthesis with a new Cu catalyst. These methods are reviewed in this section. 

Recent Advance of Asymmetric Synthesis of (1R)-tr sms-Chrysanthemic Acid with a New Chiral Copper Complex... 

Scheme 4 Synthesis of (lR)-trans-chrysanthemic acid with the bacterium...

However, further studies were discontinued at that time because they could not find any advantage in developing these norchrysanthemic acid esters due to the increased difficulty in the synthesis of norchrysanthemic acid compared to chrysanthemic acid. 

Syntheses of (l )-frans-isomers were reported by Crombie [24] and Elliott [25] starting from (1 /t Wran.v-chrysanthemic acid by means of the Wittig reaction. Their method were convenient to obtain (Z)-isomer (Scheme 10, step a) but not appropriate for the synthesis of ( )-isomer because of the (Z)-selective nature of the Wittig reaction in the case of nonstabilized ylides. It was very difficult to separate the pure ( )-isomer out of the (E)- and (Z)-mixture. This problem was overcome by use of the Takai s method (Scheme 10, step b) [26]. The ( )-selectivity of the double bond was fairly high (E Z = 89 11) (Scheme 10). 

The reaction appears to be general and the additions are regiospecific and stereoselective. The product from the reaction with 2-propanol has been used for the synthesis of cis-chrysanthemic acid,8 and the product with methanol has been used for the construction of novel 2, 3 -dideoxy-3 -hydroxymethylnucleosides.9 In addition, ethane-1,2-diol provides the expected photoadduct as a 1 1 mixture of the two possible diastereoisomers, and these can be easily separated as their acetonides, to provide compounds with three contiguous chiral centers emanating from furan-ones with only one chiral center.9 More recently, we have shown that photoinduced-... 

The synthesis of compounds 39, 41, and 43 by the ODPM rearrangement opens a novel photochemical route to chrysanthemic acid and other cyclopropane carboxylic acids present in pyrethrins and pyrethroids [52]. In fact, aldehyde 43 can be transformed to tran -chrysanthemic acid by simple oxidation. This new synthetic route to ecologically benign insecticides competes with the one previously described by us using the 1-ADPM rearrangement of p,y-unsaturated oxime acetates [30,53]. 

Much effort this year has been expended on chrysanthemic acid syntheses. Aratani et al. have extended earlier work on asymmetric synthesis (Vol. 6, p. 21) by decomposing various alkyl diazoacetates in 2,5-dimethylhexa-2,4-diene in the presence of chiral copper complexes to yield up to 92% of rrans-chrysanthemic acid in 88% dextrorotatory enantiomeric excess. Mitra has used ozonolysis of (+)-a-pinene to obtain, stereospecifically, the bromo-ketone (104) which undergoes Favorskii rearrangement to yield the anticipated ester (105) from which (+)-trans-chrysanthemic acid is readily obtained a second paper reports another route from (+)-car-3-ene initially to methyl (—)-c/s-chrysanthemate or to (—)-dihydro-chrysanthemolactone (106), both of which are convertible into (+)-rra s-chrysan-... 

The asymmetric synthesis of (lR,3S)-d.v-chrysanthemic acid was reported by Mukaiyama et al. 268) (R)-phenylglycinol was used as chiral auxiliary. 

Intramolecular cyclopropanation using diazoesters is a powerful synthetic tool. Diazoesters are readily prepared from the corresponding alcohol via House s methods56-57. Numerous examples using the application of this transformation in synthesis have been reported. These include the potent synthetic pyrethroid NRDC 182 (22)58, (1 R)-( )-cis-chrysanthemic acid (23)59, the highly strained bicyclic system 2460, antheridic acid 2561,62 and cycloheptadiene 26 (equations 33-37). 

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. 

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... 

A more dramatic example is the synthesis of cA-chrysanthemic acid 11, the basis of most modern insecticides, from dimedone 8, whose synthesis we discussed in chapter 21. Methylation between the two carbonyl groups gives 9, with the complete skeleton of 11—a little reorganisation of the atoms is needed. Treatment with bromine and base gives the inevitably cis-fused bicyclic dione 10 and a further three simple steps produce chrysanthemic acid.3... 

Insecticides of the pyrethroid class, such as trans-chrysanthemic acid (190), have significant commercial value (see Chapter 31).241 An asymmetric synthesis of 190 has been achieved through the use of a chiral copper carbenoid reaction (Scheme 12.77).242 243 With ethyl diazoacetate, equal amounts of the cis- and trans-cyclopropanes were formed. However, when the size of the alkyl... 

---