A facile synthesis of racemic aggregation pheromones of palm pests, Rhinoceros beetle and Rhynchophorus weevil

Pheromones of palm pests were successfully synthesized using a Grignard coupling as the key step. The synthesis of ethyl 4-methyloctanoate ( 1 ), the Oryctes rhinoceros L. aggregation pheromone, was achieved from 2-bromohexane via two pathways with overall yields over 40%. 4-Methyl-5-nonanol ( 2 ), and 4-methyl-5-nonanone ( 3 ), Rhynchophorus ferrugineus Oliv. aggregation pheromones, were synthesized by nucleophilic addition of a Grignard reagent to an aldehyde to afford a diastereoisomeric mixture of alcohols with varying ratios of threo and erythro isomera


Introduction
2][3] Their aggregation pheromones include the methyl-branched ethyl ester (1), secondary alcohol (2) and ketone (3) (Figure 1).The aggregation pheromone of O. rhinoceros was identified by Hallett et al. 4 as ethyl 4-methyloctanoate.Field trials showed that the attraction of racemic 1 to be substantially more effective than attraction of both (4S)-1 and (4R)-1 enantiomers.It was also found that a combination of 2 and 3 was an aggregation pheromone of R. ferrugineus.6][7][8] Therefore, effective and cost-efficient control of the insect populations is possible with pheromones and enhanced synthetic routes to these pheromones became an important goal.Thus the (R)-and (S)-isomers of 1 were prepared from the respective optical isomers of citronellol. 4The racemic mixture was obtained by conjugate addition of an organocuprate to ethyl acrylate 9 or coupling between an alkyl iodide and ethyl acrylate in the presence of a Ni catalyst 10 or Grignard reagent coupling with ethyl 4-bromobutanoate. 11ecently, Ragoussis et al. 12 have described an efficient route from hexanal to synthesize R. ferrugineus pheromone 2 in four steps (greater than 50% overall yield) while many different approaches for its synthesis have recently been reported.The most commonly useful way for the preparation of chiral compound 2 was from a chiral species such as an epoxy alcohol, 13 a methyl-branched alcohol, 7 a methyl-branched epoxide 14 or an organolithium. 15Recently, isomer (4S, 5S)-2 was synthesized by asymmetric aldol condensation between the boron enolate derived from (4R,5S)-4-methyl-5-phenyl-3-propionyl-2-oxazolidinone and pentanal, followed by Grignard coupling with the corresponding alkyl. 16However, the methods reported above involve starting materials that are not readily available and/or use of complicated routes that are unsuitable for large scale preparations.A low-cost synthesis is essential for the practical use of these pheromones.8][19] Taking into account the drawbacks, it was decided to design an effective path to the racemic aggregation pheromones of Rhinoceros beetle and Rhynchophorus weevil to control the population of the insects.Herein, we describe an efficient procedure for the synthesis of pheromones from simply commercial starting materials.

Synthesis of O. rhinoceros pheromone
In our initial synthetic work to the O. rhinoceros pheromone, 20 2,6-dimethyl-2-decene was prepared from natural citronellol then converted by a one-step oxidation using KMnO4-FeCl3 into 4-methyloctanoic acid, which was then esterified with microwave-assistance, giving 1 in an overall yield of over 60% (Figure 2).However, this reaction generated a small content of minor products that complicated the purification process.In the present work, the synthetic strategy to make 1 used the retrosynthetic analysis shown in Figure 3.The important key intermediate, 4-methyloctanoic acid, would be obtained by oxidation of the respective aldehyde or alcohol, which would be synthesized from two fragments, 2-bromohexane (fragment A) and a bromoaldehyde or bromo-alcohol unit (fragment B).Efficient syntheses of the fragment B have been reported from acrolein 17 and diols. 18erformed as a crucial step.Our first route led to the aldehyde 6a and involved a Grignard coupling at 0 o C in the presence of dilithium tetrachlorocuprate (Li2CuCl4) followed by protective group cleavage with 50% aqueous acetic acid in a yield over 65% for two steps.In the second route, we prepared the alcohol 6b, the intermediate 5b bearing tetrahydropyran group was mildly deprotected using PTSA in metanol, with a yield of 78% for the two steps.Oxidation of 6a or 6b with KMnO4 afforded the acid 7 in 76% and 73% yields, respectively.Finally, the acid 7 was mildly esterified with ethanol and PTSA to afford the pheromone 1 in 81% yield by microwave heating in five minutes.The latter pathway, which not only led to the products in higher overall yields, but also in which economical and nontoxic starting materials were used, is preferred for the preparation of the pheromone.

Synthesis of R. ferrugineus pheromones
For the synthesis of R. ferrugineus pheromone 2, approach A utilized pentanal (8a) as the aldehyde component in reaction with the Grignard reagent generated from 2-bromopentane (9a).Because the nucleophilic Grignard reagent addition to an aldehyde commonly results in a racemic mixture of secondary alcohols, the present reaction generated a mixture of two diastereoisomers (threo: erythro) 2a in a 1:1 ratio as revealed by analysis of the 1 H NMR spectrum (Figure 6A).In approach B, 2-methylpentanal (8b) as the aldehyde component was reacted with the Grignard reagent generated from 1-bromobutane (9b) to afford the pheromone 2b in 94% yield (Figure 5).According to Cram's rule, the Grignard reagent has the choice of approach from the two faces of the carbonyl group and is much more likely to opt for the less hindered face.As illustrated in Figure 7, the threo isomer should be a major product.The peak corresponding to the proton at C-5 for the threo isomer is a multiplet at δ 3.50 (CDCl3) while the one corresponding to the erythro isomer appears at δ 3.44 (CDCl3). 7,15The ratio of the two diastereoisomeric isomers (threo:erythro) clearly observed from the NMR spectrum (Figure 6B) is 5:3.Finally, the alcohol 2 was treated with the Jones reagent to afford racemic ketone 3 in 85% yield.

Conclusions
This work demonstrates a short, simple and efficient synthetic route to a racemic mixture of aggregation pheromones.Compound 1, O. rhinoceros was synthesized via two routes in overall yields of 40% (via aldehyde) and 46% (via alcohol).The R. ferrugineus pheromone 2 was synthesized by two different approaches which generated a diastereoisomeric mixture with different ratios of threo and erythro isomers.Pheromone 3 was produced by oxidation with the Jones reagent in overall yields of over 75%.These ratios contribute to multiform options in the practical use of pheromones as environmentally benign tools for pest control.

Experimental Section
General.All manipulations were performed under a dry nitrogen atmosphere using Schlenk techniques.All of the materials were purchased from Merck (Germany) or Aldrich.THF was dried with Na/benzophenone and freshly distilled prior to use.The other solvents were purchased from Fluka and used without further purification.Column chromatography was performed with Merck Kieselgel 60.Esterification was carried out under microwave-assistance in a SANYO EM-D9553N reactor.IR spectra were recorded on a Bruker Equinox 55 IR spectrophotometer. 1 H (500 MHz) and 13 C (125 MHz) NMR spectra were determined on a Bruker AVANCE 500 NMR spectrometer using CDCl3 as solvent and tetramethylsilane (TMS) as an internal standard.Chemical shifts are reported in δ relative to TMS.GC-MS analyses were carried out using an Agilent Technologies 6890N (USA).Refractive indices (nD) were measured with an Abbe refractometer Way-2S.

Figure 3 . 1
Figure 3. Synthetic strategy to the O. rhinoceros pheromone