Pheromones enantiomers

Plettner E., Lazar J., Prestwich E. G. and Prestwich G. D. (2000) Discrimination of pheromone enantiomers by two pheromone binding proteins from the gypsy moth Lymantria dispar. Biochemistry 39, 8953-8962. 

The relationships between stereochemistry and bioactivity among pheromones are diverse and far from straightforward. Organisms utilize chirality to enrich and diversify their communication systems.8,9 It must be emphasized that such diversity could be found only through experiments by using pure pheromone enantiomers of synthetic origin. In this section, several examples will be given to illustrate the diverse stereochemistry-bioactivity relationships. 

Miller JR, Mori K, Roelofs WL (1977) Gypsy Moth Field Trapping and Electroantennogram Studies with Pheromone Enantiomers. J Insect Physiol 23 1447... 

Male I. paraconfusus have a greater overall antennal sensitivity to ( - )ipsdie-nol produced by I. pini than to their pheromonal component (+)ipsdienol (Light and Birch, 1982). Females, however, show a greater and more typical response to their pheromonal enantiomer. 

Miller, J. R., and W. L. Roelofs Gypsy moth responses to pheromone enantiomers as evaluated in a sustained-flight tunnel. Environ. Entomol. 7, 42—44 (1978). 

Gas chromatography (GC) has also been used for preparative purposes, but is restricted to relatively volatile racemates such as anesthetics, pheromones or monoterpenes and, therefore, very few applications are reported. Nevertheless, in the cases to which GC may be applied, it could be considered as an economical alternative to HPLC. Most of the resolutions of enantiomers were performed on cyclodex-trin-derived CSPs [109, 144-153], and only on very few occasions were other chiral selectors used [153]. 

Lipases also catalyze the intramolecular transesterification (lactonization) of hydroxy esters. Macrolactonization of a racemic hydroxy ester in the presence of PSL provided the corresponding (R)-lactone (Figure 6.22). This compound is the naturally occurring enantiomer of the pheromone produced by the merchant grain beetle [70]. Chemical macrolactonizations require high dilution to minimize... 

An enantio-selective enzymatic hydrolysis of meso( )-2,5-diacetoxy-3-hexene gives (+)-( )-(25 ,5/ )-5-acetoxy-3-hexen-2-ol in 77% yield (92% ee).97 The monoacetate with its two allylic groups offers possibilities for stereo-controlled introduction of nucleophiles via Pd(0) catalysis. Synthesis of both enantiomers of the Carpenter bee pheromone based on this strategy is presented in Scheme 5.14.98... 

Four different syntheses were reported for the enantiomers of l-methyl-2-cyclohexen-1 -ol, a component of the aggregation pheromone of Dendrocton us pseudotsugae [47-50]. 

A myxobacterium Stigmatella aurantiaca uses stigmolone (22) as its fruiting body inducing pheromone. Both the enantiomers of 22 were synthesized by Mori [56] and also byEnders [57], and found to be equally bioactive. Scheme 33 shows Mori s synthesis, and Scheme 34 summarizes that of Enders. Since both (R)- and (S)-22 were bioactive, ( )-22 was synthesized in a very efficient manner by Kulinkovich (Scheme 35) [58]. 

JR,9Z)-9-Octadecen-4-olide (30) is the female pheromone of the currant stem girdler (currant sawfly, Janus integer). Both the enantiomers of 30 were synthesized as summarized in Scheme 44 [69]. Lipase-catalyzed asymmetric acetylation of ( )-A was the key-step to give unreacted CR)-A and acetylated (S)-B. 

Isopropyl-4,6-dimethyltricyclo[4.4.05 9]dec-3-en-2-one (40) with unknown absolute configuration was isolated as a putative male pheromone of a Brazilian predatory stink bug (Tynacantha marginata), and its enantiomers were synthesized by Kuwahara as shown in Scheme 58 [88]. The triene A gave B and C by an intramolecular Diels-Alder reaction, and they could be converted to the enantiomers of 40. 

By synthesizing pure enantiomers of pheromones, various stereochemistry-pheromone activity relationships could be clarified. For example, in the case of sulcatol (6-methyl-5-hepten-2-ol),both the enantiomers are necessary for bioactivity. For other relationships, please refer to [4-9]. 

A chiral GC column is able to separate enantiomers of epoxy pheromones in the Type II class, but the applications are very limited as follows a custom-made column packed with a p-cyclodextrin derivative as a liquid phase for the stereochemical identification of natural 3,4- and 6,7-epoxydienes [73, 74] and a commercialized column of an a-cyclodextrin type (Chiraldex A-PH) for the 3,4-epoxydiene [71] (See Table 3). The resolution abilities of chiral HPLC columns have been examined in detail, as shown in Table 7 and Fig. 14 [75,76, 179]. The Chiralpak AD column operated under a normal-phase condition separates well two enantiomers of 9,10-epoxydienes, 6,7-epoxymonoenes and 9,10-epoxymonoenes. Another normal-phase column, the Chiralpak AS column, is suitable for the resolution of the 3,4-epoxydienes. The Chiralcel OJ-R column operated under a reversed-phase condition sufficiently accomplishes enantiomeric separation of the 6,7-epoxydienes and 6,7-epoxymonoenes. 

The importance of the three stereogenic centers became evident as two of the stereoisomers [(2S,3S,7S) and (2S,3R,7R)] were recognized early as sex pheromones and that other enantiomers and diastereoisomers were often found to be inhibitory to the attractive response. Recently, the sawfly pheromone field has undergone a major advance with the recognition that several sawfly species synthesize and utilize sex pheromones of different structural types than the 3,7-dimethylpentadecan-2-ols. Shorter and longer chain lengths (undecan-2-ols 2 and tridecan-2-ols 3) and an additional methyl group in position 9 or 11 (4 and 5) characterize these new pheromone discoveries (Fig. 1). With an ad-... 

Sometimes the inactive isomer may interfere with the active isomer and significantly lower its activity. For example, when the ( /-derivative of the sex pheromone of a Japanese beetle is contaminated with only 2% of its enantiomer, the mixture is three times less active than the optically pure pheromone. The pheromone with as little as 0.5% of the (.S )-enantiomer already shows a significant decrease of activity.3... 

Recent advances in gas chromatographic separations of enantiomers allow precise determination of the enantiomeric purity of the algal pheromones. The czs-disubstituted cyclopentenes, such as multifidene, viridiene, and caudoxirene, are of high optical purity [ 95% enantiomeric excess (e.e.)] whenever they have been found (32,33). The situation is different with the cyclopropanes and the cycloheptadienes, as shown in Table 2 and Figure 1. Hormosirene from female gametes or thalli of... 

FIGURE 2 Pheromone structures of the American cockroach (periplanone B), the brownbanded cockroach (supellapyrone), bark beetles (ipsdienol enantiomers), and the cabbage looper moth (six acetates). 

Scheme 23 Chemoenzymatic synthesis of the (3S,4R)-enantiomer of the lactol pheromone of Biprorulus bibax [112]...

The authors then used a modification of their Lipase-AK route to produce the natural enantiomer, as described in detail in the chapter by Kenji Mori in this volume. Instead of using the enzyme to execute a stereoselective monohydrolysis of meso diacetate 140, the enzyme was used to esterify selectively one of the hydroxy groups of meso diol 128, resulting in the antipodal hydroxyester. After oxidation of the free hydroxyl to the acid, and recrystallization of its salt with (JR)-l-naphthylethylamine, the purified acid was then carried through the remaining steps to furnish the chiral pheromone compound (see the chapter by Kenji Mori in this volume). 

In one final improvement to the synthesis of the racemate, after it had been shown that even the unnatural enantiomer of the pheromone attracted bugs, the Z-isomer of diene ester 139 was used in the ester-enolate Claisen rearrangement, resulting in a slightly higher yield, and avoiding the use of HMPA as a solvent in that step [113]. 

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