Synthesis of ( S )-( + )-2-Methyl-4-octanol : Male-Specific Compound Released by Sugarcane Weevil Sphenophorus levis ( Coleoptera : Curculionidae )

O composto (S)-2-metil-4-octanol (1) é produzido especificamente pelos machos da broca da cana-de-açúcar Sphenophorus levis, e sua atividade biológica está aparentemente associada ao comportamento de agregação da espécie. Desenvolveu-se neste trabalho uma nova metodologia sintética para a preparação deste composto, utilizando-se o D-manitol (2) como material de partida, tendo-se o (R)-gliceraldeído acetonídeo (4) como intermediário chave. Através de análises cromatográficas de um acetil derivado do produto final, empregando-se colunas quirais, estabeleceuse um excesso enantiomérico de 99,5%. O composto (1) já foi previamente identificado como componente do feromônio de agregação de uma grande variedade de espécies de curculionídeos.


Introduction
The genus Sphenophorus is commonly found in the South America having up to fourteen species described in Brazil.Sphenophorus levis (Coleoptera: Curculionidae) was first identified as a new species in 1978 and it is an important pest against sugarcane. 1Due to its behaviour in the larval stage, synthetic insecticides have been unsuccessfully used to control this weevil.During this period, as occur with other species of this family, S. levis digs tunnels on sugarcane stalks, destroys tissues, and weakens the plant. 2Because of that, attractive semiochemicals can be employed as an extremely useful tools in integrated pest management.
We have recently identified the alcohol (S)-2-methyl-4-octanol (1) as a male-specific compound produced by S. levis. 3Preliminary indoor bioassays employing the racemic mixture suggested that this compound elicit aggregation behavior among both males and females of the species. 3,4][7] In order to establish the importance of the stereochemistry on the biological activity of this compound, we have developed an alternative synthesis of (S)-( 1), starting from D-mannitol (2).The natural isomer and the previously synthesized racemic compound 3 will be employed in field experiments, and the results will appear elsewhere.

Experimental
Gas chromatography analyses were performed on a Varian 3800 GC equipped with FID, electronic pressure control, and operated in split mode.The following capillary column was used: VA-5 (30 m x 0.25 mm x 0.25 mm), oven temperature was held at 50 °C for 3 min, programmed at 7 °C min -1 to 230 °C, and held at this temperature for 20 min.Helium was used as carrier gas (1mL min -1 ).Mass spectra were recorded on a Varian Saturn 2000 GC/MS/MS ion trap detector using the same type VA-5 capillary column under the same condition described above.The equipment was operated in the electron impact (EI) ionization mode (70 eV) and in the chemical ionization (CI) mode (CH 3 CN).Chiral separations were obtained on a cyclodextrin-based capillary column [Cyclosil-B, w/w 30 m, 0.25 mm i.d, 0.25 µm; J&W Scientific] using helium as carrier gas (275.8KPa) at 60 °C.High-Resolution-GC-Mass-Spectra (HR-GC-MS) was carried out on a HP6890(GC)/VG70-70(MS), operated in the electron impact (EI) ionization mode (70 eV).The following capillary column was used: BPX5 (30 m x 0.25 mm x 0.25 µm), oven temperature was held at 80 °C for 3 min, programmed at 5 °C min -1 to 300 °C, held at this temperature for 10 min.Helium was used as carrier gas (1mL min -1 ).The IR spectra refer to films and were measured on a Bomem M-102 spectrometer.The 1 H-NMR spectra were recorded with TMS as an internal standard at 400 and 200 MHz on a Bruker ARX-400 and ARX-200 spectrometer, respectively.The 13 C-NMR spectra were recorded with TMS as an internal standard at 100 and 50 MHz on a Bruker ARX-400 and ARX-200 spectrometer, respectively.Optical rotations were measured on a Bellinghan + Stanley Ltd Model D polarimeter.All reagents and solvents used in the syntheses were of highest commercially available standard.Chromatographic purifications were carried out on silica gel 60, Merck, 230-400 mesh.

Results and Discussion
The synthesis of (S)-2-methyl-4-octanol 1 is summarized in Scheme 1.The (R)-glyceraldehyde acetonide 4 was prepared in 33.5% yield from D-mannitol (2), by the known method, 8,9 via an oxidative cleavage of the diol 3. The freshly distilled aldehyde 4 was subjected to the Wittig reaction with (triphenylphosphonium)propanide (CH 3 CH 2 CH=PPH 3 ) 11 to give compound 5 in 88% yield [it was observed that the (Z)-isomer was preferentially obtained , as indicated by 1 H-NMR data].Hydrogenation over Pd/C furnished compound 6 (81% yield), which was hydrolyzed 12 under acidic Dowex ® resin (W50) yielding diol 7 in 79% yield.This diol 7 was converted into the mono tosylate 8 in 60% yield, by reaction with TsCl in pyridine, and then coupled with sec-propyl magnesium bromide, using CuI as catalyst, 3 affording the desired alcohol 1 in 78% yield.
The enantiomeric purity of the final synthetic product could be estimated by chiral GC analisys of its respective acetyl derivative 1a (prepared by reaction of (R/S)-3 and (S)-1 with Ac 2 O in pyridine 11 ), since no resolution was possible for the alcohol 1 employing the Cyclosil-B ® column.Racemic 1a was resolved to baseline, showing two peaks with retention times of 60.75 and 62.66 min.The (S)-1a isomer corresponded to the second peak, and the analysis indicated an e.e.> 99.5% (Figure 1).
Few examples of enantioselective synthesis of compound 1 have appeared in the literature.Mori and coworkers 13 described the first synthesis of (R)-and (S)-1 in five steps and 11% overall yield, starting from (R)-and (S)-leucine.Baraldi and co-workers 14 published a synthetic route for both isomers of 1, employing a microbiological reduction of β-ketoesters as asymmetric source.(R)-1 was prepared in five steps and 20% overall yield, while the (S)enantiomer was synthesized in 6 steps and 14% overall yield.More recently, we developed a short synthesis of (R)-and (S)-1 in 92% e.e, starting from (R)-and (S)-2,2dimethyl-1,3-dioxolane-4-methanol. 3 These synthetic compounds were successfully employed as authentic samples to establish the absolute configuration of the natural product released by males S. levis, 3 but could not be used as attractants in field experiments due to the poor enantiomeric enhancement.We have now introduced a new approach to (S)-1, starting from the easily available D-mannitol 2, a route which uses the known (R)glyceraldehyde acetonide 4 as key intermediate, over seven steps and 8.8% overall yield.The example given here shows that this natural isomer can be obtained via an operationally simple strategy.