Metathesis pheromone synthesis

Interesting results have been obtained in the synthesis of biologically active compounds such as insect pheromones. Conventional synthetic routes to these pheromones are often multistep sequences, which make many pheromones too expensive for widespread use [23]. Metathesis offers a shorter, alternative route to pheromone synthesis, generating these compounds in a few steps only. The use of insect sex pheromones is an environmentally friendly, effective, and selective method of pest control. Kiipper and Streck [24] synthesized insect sex pheromones by cross-metathesis reactions between linear olefins. In the presence of the catalyst Re207/Al203, 9-tricosene was synthesized by cross-metathesis of the readily available aUcenes 2-hexadecene and 9-octadecene (Eq. 8). 

Product stereochemistry is a critical factor determining the applicability of metathesis pheromones to insect control [23]. The steric course of the metathesis reaction normally results in a (thermodynamic) cis/trans mixture, whereas the physiologically active pheromones are either isomerically pure compounds or specific cis/trans mixtures. When it is necessary to obtain a single stereoisomer, the separation step required is tedious and expensive. The synthesis of pure cis isomers via the metathesis reaction, therefore, forms a challenge for catalyst development. 

Jones, G., M. A. Acquadro, and M. A. Carmody Long chain enals via carbonyl-olefin metathesis. An application in pheromone synthesis. J. Chem. Soc. Chem. Commun. 1975,206—2Q1. 

The aggregation pheromone of the broad-horned flour beetle (Gnatocerus cornutus) was reported to be (lJR,4i, 5S)-(+)-acoradiene (33) by Tebayashi et al. [72]. Scheme 47 shows Mori s synthesis of (lRy4Ry5S)-33 [73]. The key-step was the ring-closing olefin metathesis of A to give B. An X-ray analysis of C confirmed the structure shown. The product (lJR,4JR,5S)-33, however, was different... 

The use of menthol in the synthesis of important synthons for optically active methyl branched insect pheromones is discussed briefly. Applications of olefin cross metathesis in production of commercial products, including insect pheromones has been discussed. ... 

Ring-closing metathesis, which has proved to be a popular route to the marine toxins, has found a further application as the key step in the synthesis of the pheromone (-)- and ( )-frontalin <99TL1425>. The precursor in this reaction is a mixture of the syn- and anri-isomers 39. Ring closure in the presence of a ruthenium benzylidene catalyst occurs within minutes at room temperature when only the syn-isomer cyclises to 40. The unreacted anri-isomer can be re-equilibrated for a further cyclisation. 

Olefin metathesis can be very useful in the CM mode, as shown in the synthesis of insect phere-mones.46 In the first example for the synthesis of the peach twig borer pheromone 23, an excess of 1-hexene was used to increase the yield of the desired product. However, both of the other products could be recycled (Scheme 28.17). In the second example, CM was used to change the ester groups of meadowfoam oil (24) through cleavage of the alkenes rather than ester bonds. The sequence resulted in the synthesis of the mosquito pheromone (25) (Scheme 28.18). 

Since a number of insect pheromones are nonfiinctionalized alkenes, they are potential target molecules for synthesis from petrochemicals by the metathesis reaction. Cross metathesis between unsymme-trical internal alkenes can lead to a complex mixture of products however, in some cases, this reaction provides the easiest method for production of such alkenes. For example, the pheromone for Musca do-mestica, tricosene, has been prepared from 2-hexadecene and 9-octadecene (equation 6). Both of these alkenes are readily available. 

Via stereoselective ethenolysis of 1,5-cyclooctadiene (COD), Bykov et al. [25] prepared l,d5-5,9-decatriene, a precursor for the synthesis of many ds-isomeric insect sex pheromone compounds. In the presence of the MoCl5/Si02/Me4Sn catalyst system, at 20 °C and an ethene pressure of 25 bar, a 80 % conversion of COD was obtained with a selectivity of 68.4% for l,ds-5,9-decatriene. From this triene, many long-chain (CiQ-Cig) unsaturated acetates, alcohols and aldehydes can be obtained with the required biologically active cis conformation. Cross-metathesis of cyclooctene with a-olefins in the presence of the same catalyst gave... 

Synthesis of Pheromones and other Products via Cross-metathesis... 

Derivatives of oleic acid that imdergo cross-metathesis with simple olefins are listed in Table 9.4, while Table 9.5 gives some examples of cross-metathesis reactions of simple olefins with other functional olefins. Such cross-metathesis reactions may provide useful routes to speciality chemicals such as synthetic perfumes, insect pheromones (Crisp 1988), prostaglandin intermediates (Dalcanale 1985), etc. (see Mol 1982, 1991). Of special interest are ethenolysis reactions, which allow the synthesis of compoimds with terminal double bonds. Ethenolysis (and cross-metathesis with lower olefins) has been investigated extensively for... 

The fact that the unsymmetrical product dominates in the cross-metathesis of a cyclic olefin and a terminal olefin is an advantage for the efficient synthesis of the brown algae pheromones multifidene (yield 31%) and viridiene (yield 30%) via the cross-metathesis between bicyclo[3.2.0]hepta-2,6-diene and but-l-ene or butadiene, respectively (molar ratio 1/2), in the presence of lmol% of Ru(=CHCH=CPh2)(Cl)2(PCy3)2 Scheme 15.1 (Randall 1995). 

Perhaps the most basic form of the olefin metathesis reaction is the cross metathesis (CM) of acyclic olefins to yield new acyclic olefins (Fig. 4.11). The ratio of CM products may be controlled by steric and electronic factors to provide one product preferentially, rather than a statistical mixture, which is key to the synthetic utility of this reaction. For example, various functionalized olefins, dimers with bioactive substituents, and trisubstituted olefins have all been made by CM [33], and one of the industrial applications is the synthesis of insect pheromones [34]. 

Another example of organic synthesis via cross-metathesis is the synthesis of biologically active compounds such as insect pheromones. Use of such pheromones offers an effective and selective pest control method. Thus, cross-metathesis of ethyl oleate with 5-decene results in a cis-trans mixture of ethyl 9-tetradecenoate, an insect pheromone precursor [15]. Cross-metathesis of methyl d.y-5-eicosenoate (obtained from meadowfoam oil) with excess 5-decene gives methyl tm 5-decenoate, which can be transformed into a 83 17 mixture of trani -5-decenylacetate and tran.y-5-decenol (in total 90% trans), the sex pheromone of the Peach Twig Borer moth, a major pest in Northern Hemisphere fruit orchards. The isomeric mixture was active in mating disruption [16]. Other examples of organic synthesis via cross-metathesis are summarised elsewhere [17 18]. 

Saicie and eo-workers used olefin metathesis as one of the final steps in their synthesis of ( )-periplahone C, a C-macrolide pheromone. a-Hydroxy ketoester 156, when treated with 3 mol% of 3 in dichloromethane at room temperature over the course of 23 h, gave the desired carbocyle 157 in 81% yield. The authors applied this methodology to access a number of other intermediates in the periplanone family. 

Dicarboxylic esters are used to prepare polyesters and polyamides. The residual double bonds permit cross-linking of the polymer chains. Cross metathesis of methyl oleate with excess ethene affords methyl 9-decenoate, a key intermediate in the synthesis of queen bee substance , a honey bee pheromone. 

A mixed di-f-butylsilylene has been prepared from (5)-5-hexen-2-ol and prochiral l,4-pentadiene-3-ol for synthesis of (25, 7S)-dibutyroxynonane, the sex pheromone of Sitodiplosis mosellana. The intermediate 43 was then subjected to ring closing metathesis to provide the diene 44 in 70% yield over two steps (eq 16). Deprotection of the nine-membered silylene was achieved using TBAF under refluxing condition in the presence of molecular sieves. Reduction with H2/Pt02 and diacetylation yielded the desired (25, 7S)-dibutyroxynonane in 22% overall yield. ... 

The commercial synthesis of the housefly pheromone 12.4 illustrates the technique of driving the metathesis reaction by removing the more volatile alkene product, in this case, ethylene undesired noncross products can easily be separated by distillation. Unfortunately, the presence of the alkylaluminum co-catalyst severely limits the range of functional groups tolerated by this system. 

Rossi, R. Simple synthesis of sex pheromones of the housefly and tiger moths by transition metal-catalyzed olefin cross-metathesis reactions. Chim. Ind. Milan 57, 242—243 (1975). 

---