Synthesis of Olefinic Pheromones

PaUadiiun-catalyzed coupling of the borane derived from A with 1-bromo-1-pentyne to give B as well as the coupling of iodoalkene C with alkyne D were the two key-steps. 

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Recent trend in the synthesis of olefinic pheromones is the use of transition metal-catalyzed cross coupling reaction for carbon-carbon bond formation. Scheme 8 summarizes a synthesis of the termite trail marker pheromone, (3Z,6Z)-3,6-dodecadien- l-ol (2) by Oehlschlager [19]. The key-step is the palladium-catalyzed cross-coupling of allylic chloride A and alkenylalane B. 

By this method (Z)-monounsaturated fatty acids and esters could be obtained with an ( )-isomer content of less than 10% this stereoselectivity being however inferior to that of the commonly used acetylenic approach 55,56). However, the salt-free techniques used today in Wittig reactions allow (Z)-alkenoic acids to be synthesized with less than 2% of the ( )-isomers. Thus, Bestmann et al. prepared methyl and ethyl esters of (Z)-4,5,6,7,8,9,ll- and 13-alkenoic acids of different chain lengths 35,57 62), which served as intermediates in the synthesis of insect pheromones, both by reaction of co-alkoxycarbonyl-substituted alkyl-triphenyl-phosphonium salts with simple alkanals and of co-formylalkanoic esters with alkylidenephosphoranes. As the starting material for the synthesis of -substituted alkyl-phosphonium salts co-chloro- and -bromocarboxylic esters were used. The corresponding -substituted aldehydes can usually be obtained by ozone cleavage of suitable olefin derivatives or by oxidation of alkohols 57,58). 

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]. 

A new thiophen synthesis is based on deprotonation and cyclization of the resultant carbanion (65) of a keten dimethylthioacetal. Other applications of cr-(phenylthio)- or cr-(alkylthio)-alkyl-lithiums include preparations of disparlure (the sex pheromone of the gypsy moth) and other chiral epoxides,of an anti-peptic-ulcer diterpene from Croton sublyratus, of carbene-thiometal chelates through reaction with fCr(CO)gl or fW(CO)jl, of olefins via )ff-hydroxy-sulphides, and of Michael adducts of enones. In other work, the chiral solvent l,4-dimethylamino-2,3-dimethoxybutane is employed in enantioselective addition reactions of cr-thio-carbanions with ketones and Michael acceptors. a,P -Elimination of cr-thio-carbanions such as (66) provides a useful synthesis of olefins, and a 2-(lithiomethylthio)-A -oxazoline (67) has been used to prepare a C-labelled thiiran for a microwave study of the valence tautomerism of allene episulphide. ... 

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). 

The use of microwaves for synthesis of olefins via elimination has become increasingly interesting in recent years because olefins are the basic moiety of many ole-finic natural products, for example, the insect hormones, pheromone, etc. It is also used in nonenzymic biogenetic-like cyclizations to form polycyclic compounds. 

Stereoselective syntheses of cii-olefins have been widely explored by Bestmann. An example of a pheromone synthesis is given below (H.J. Bestmann, 1976). 

For trisubstituted olefins, the nucleophile attacks predominantly at the less substituted end of the allyl moiety, e.g. to afford a 78 22 mixture of 13 and 14 (equation 7). Both the oxidative addition of palladium(O) and the subsequent nucleophilic attack occur with inversion of configuration to give the product of net retention7. The synthesis of the sex pheromone 15 of the Monarch butterfly has been accomplished by using bis[bis(l,2-diphenylphosphinoethane)]palladium as a catalyst as outlined in equation 87. A substitution of an allyl sulfone 16 by a stabilized carbon nucleophile, such as an alkynyl or vinyl system, proceeds regioselectively in the presence of a Lewis acid (equation 9)8. The... 

Scheme 41 summarizes Couladouros s synthesis of the oviposition attractant pheromone of the Southern house mosquito (Culexpipiensfatigans)y (5R,6S)-6-acetoxy-5-hexadecanolide (28) [66]. The key-steps are (i) -selective Schlosser olefination (A B), asymmetric dihydroxylation (B C), and lactonization of carbonate C to the desired 6-lactone with inversion at C-5. 

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... 

A three-step synthesis of a mixture of stereoisomers of 5,9 -dimethylpentadecane, the sex pheromone of the coffee leaf miner, Leucoptera coffeella, has been described. The key step being the unsymmetrical Wittig olefination to build the carbon skeleton of the molecule. 

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. ... 

In the reactions with mono- and 1,2-disubstituted olefins, however, no ene product was obtained. This limitation has been overcome by the use of vinylic sulfides and selenides instead of mono- and 1,2-disubstituted olefins. With these substrates, the ene products are obtained with comparably high enantioselectivity and high diastereoselectivity [15]. The synthetic utility of the vinylic sulfide and selenide is shown in the synthesis of enantiopure (R)-(-)-ipsdienol, an insect-aggregation pheromone (Scheme 8C.4) [16]. 

The CM of fatty acids and derived compounds also has been used for the production of fine chemicals that are difficult to obtain by other synthetic approaches. Some examples include the synthesis of a plant growth stimulant, an insect pheromone precursor, the sex pheromone of the peach twig borer moth, and others [28]. Furthermore, the conjugation of fatty acid derivatives, sugars, and amino acids via CM was shown by Vemall and Abell [41]. C4 with a catalyst loading of 20 mol% was used to perform the CM of either Ai-Boc-L-ly sine or N-Boc-L-cysteine bearing a 10-undecenoic chain with methyl 10-undecenoate or a sugar olefin. 

Acetals result from oxidative coupling of alcohols with electron-poor terminal olefins followed by a second, redox-neutral addition of alcohol [11-13]. Acrylonitrile (41) is converted to 3,3-dimethoxypropionitrile (42), an intermediate in the industrial synthesis of thiamin (vitamin Bl), by use of an alkyl nitrite oxidant [57]. A stereoselective acetalization was performed with methacrylates 43 to yield 44 with variable de [58]. Rare examples of intermolecular acetalization with nonactivated olefins are observed with chelating allyl and homoallyl amines and thioethers (45, give acetals 46) [46]. As opposed to intermolecular acetalizations, the intramolecular variety do not require activated olefins, but a suitable spatial relationship of hydroxy groups and the alkene[13]. Thus, Wacker oxidation of enediol 47 gave bicyclic acetal 48 as a precursor of a fluorinated analogue of the pheromone fron-talin[59]. 

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). 

Zarbin, P.H.G., Princival, J.L., de Lima, E.R., dos Santos, A.A., Ambrogio, B.G. and de Oliveira, A.R.M. (2004). Unsymmetrical double Wittig olefination in the syntheses of insect pheromones. Part 1 synthesis of 5,9-dimethylpentadecane, the sexual pheromone of Leucoptera coffeella. Tetrahedron Lett., 45, 239-241. 

The special potential for constructing double bonds stereoselectively, often necessary in natural material syntheses, makes the Wittig reaction a valuable alternative compared to partial hydrogenation of acetylenes. It is used in the synthesis of carotenoids, fragrance and aroma compounds, terpenes, steroides, hormones, prostaglandins, pheromones, fatty acid derivatives, plant substances, and a variety of other olefinic naturally occurring compounds. Because of the considerable volume of this topic we would like to consider only selected paths of the synthesis of natural compounds in the following sections and to restrict it to reactions of phosphoranes (ylides) only. 

For the synthesis of 313 Hammond and Descoins also used a Wittig reaction 205). Thus, starting from l-hepten-3-ol 319 the phosphonium salt 320 is formed via several steps. The ylide of this salt is olefinated with atdehyde 305 to 311. Reduction of 311 and subsequent acetylation afford the pheromone 313 (Scheme 58) 205). 

For the preparation of the second component 421 of the cockroach pheromone Burgsthaler et al. 228) also used a Wittig reaction. Lithium acetylide is alkylated with the two halides 414 and 416 and the resulting alkynyl bromide 417 converted into the phosphonium salt. Olefination of the corresponding ylide with 9-bromo-2-nonanone 418 gives a (Z)/( )-mixture of olefin 419 which is converted into the pheromone 3,ll-dimethyl-29-hydroxynonacosan-2-one 421 by aeetoaeetate synthesis, hydrogenation, hydrolysis, and decarboxylation 228) (Scheme 73). 

The specificity of blends of compounds used for pheromone communication by Lepidoptera species is the result of essentially two distinct sets of biosynthetic enzymes which regulate the production of specific olefinic bonds and synthesis of the oxygenated functional moiety, respectively. In Heliothis moths the regulatory systems that are responsible for production of the functional group during the final stages of pheromone biosynthesis consist of cellular acetate esterases and extracellular alcohol oxidases. Evidence indicates that the relative activities of these enzymes differ for each species of Heliothis. Thus, pheromone mediated reproductive isolation between closely related species of Heliothis is probably the result, in large measure, of the fact that some species require only aldehydes for communication while others use acetates, alcohols and aldehydes. 

Although the trisubstituted olefinic linkage of the pheromone could be fashioned readily in a less selective manner followed by HPLC purification, we sought a stereoselective route in addition. Still and Mitra completed a synthesis of the... 

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