Enantioselective Synthesis of ( 2 R , 3 R , 7 S )-3 , 7-Dimethylpentadecan-2-ol , Sex Pheromone Component of Pine Sawflies

A mosca Neodiprion sertifer (Geoffrey) (Hymenoptera: Diprionidae) é uma importante praga em florestas de pinheiro no norte da Europa, Ásia e América do Norte. Os componentes majoritários do feromônio sexual desta espécie são acetatos ou propionatos do 3,7-dimetilpentadecan-2-ol (diprionol). Neste trabalho relatamos a síntese enantiosseletiva do (2 R,3R,7S)-diprionol em 12 etapas (7.5% de rendimento total), partindo-se do (-)-isopulegol comercial.


Introduction
Insect pest management, monitoring and control programs utilizing sex pheromones as behavior modifying chemicals have become important for several insect groups, particularly moths.Such programs frequently include masstrapping and mating disruption techniques.This development has been accompanied by the search for simple, efficient and less aggressive synthetic methodologies for the preparation of pheromones.
The pine sawfly, Neodiprion sertifer (Geoffrey) (Hymenoptera: Diprionidae), is a widespread and economically important forest insect in North America, Japan and Europe.Field tests and electrophysiological experiments demonstrated that males of several Neodiprion species are strongly attracted by diprionyl acetate, while some species of this genus, and of the genus Diprion, prefer the corresponding propionate.It has been suggested that species specificity in diprionid sawflies is based on different combinations of the isomers of diprionyl acetate and/or propionate 1 .
Anderbrant et al. have investigated the geographic pattern of male sawfly response at eight field sites ranging from Japan in the east to Canada in the west 2 .They found an increased inhibitory effect of the (2S,3R,7R)-isomer from Japan and Siberia to Europe.At the eastern sites, increasing amounts of the (2S,3R,7R)-isomer up to and equal to the amount of the (2S,3S,7S)-isomer, did not influence the trap catch, whereas at sites in Europe, as little as 1% of the (2S,3R,7R)-isomer almost completely inhibited the attraction.The response of the North American population was intermediate.The only site in which the (2S,3R,7R)isomer was essential for the attraction of males was in Siberia.A similar pattern was found for the (2S,3R,7S)-isomer.Both the acetate and the propionate form of the (2S,3S,7S)-isomer were attractive by themselves in Japan, Europe and North America, and neither the (2S,3R,7S)-isomer nor the (2S,3R,7R)-isomer alone were attractive, in the acetate or propionate form.
It is evident from the facts discussed above that diprionyl esters with high degree of enantiomeric purity and well-known composition are necessary to accomplish reliable biological tests or ultimately for field application.Several research groups have synthesized racemic 3 or optically enriched stereoisomers of diprionol and its esters 4,5 .Högberg et al. have prepared all eight diprionol isomers using a convergent approach in 22 steps.The synthetic intermediates were prepared from tartaric acid and by asymmetric synthesis using either an oxazoline or a prolinol derivative as chiral auxiliary 6 .
In this paper we present the enantioselective synthesis of (2R,3R,7S)-diprionol from commercially available (-)isopulegol in 12 steps.Our synthetic strategy was based on a methodology developed by Ferreira and Zarbin 7 and applied for the synthesis of two isomers of methyl 2,6,10trimethyldodecanoate, male-produced pheromone of stink bugs Euschistus spp.

Experimental
Unless otherwise noted, all commercially available reagents were purchased from Aldrich Chemical Co.Reagents and solvents were purified when necessary according to the usual procedures described in the literature.The IR spectra refer to films and were measured on a Bomem M102 spectrometer. 1 H and 13 C NMR spectra were recorded on a Bruker ARX-200 (200 and 50 MHz respectively) and DRX-400 (400 and 100 MHz respectively) spectrometers.Optical rotations were measured on a Perkin-Elmer 241 polarimeter.Mass spectra were recorded on a Shimadzu GCMS-QP5000.Analytical thin-layer chromatography was performed on a 0.25 µm film of silica gel containing fluorescent indicator UV 254 supported on an aluminum sheet (Sigma-Aldrich).Flash column chromatography was performed using silica gel (Kieselgel 60, 230-400 mesh, E. Merck).Gas chromatography was performed in a Shimadzu GC-17A with H 2 as carrier and using a DB-5 column.Chiral GC was performed in a HP 5890 with H 2 as carrier (14 psi) and using an heptakis (2,6-di-O-methyl-3-O-phenyl)-βcyclodextrin column (20% in OV 1701, w/w, 25 m, 0,25mm i.d.) column.Elemental analyses were performed on a Fisons EA 1108 CHNS-O.

(-)-(1R,3R,4S,8R)-9-Benzyloxy-p-menthan-3-ol (4)
Diol 3 (1.60 g, 9.3 mmol) was added dropwise to a stirred suspension of NaH (60% dispersion in mineral oil, 0.41 g, 10.2 mmol) in dry DMF (32 cm 3 ) under N 2 at 0 o C. The resulting solution was cooled at -10 o C and stirred for 1.5 h.The mixture was cooled at -60 o C and a solution of benzyl bromide (1.10 cm 3 , 9.3 mmol) in DMF (6.0 cm 3 ) was slowly added.The mixture was stirred at -60 o C for 2 h, then the reaction temperature was raised to room temperature, and stirred for an additional 12 h.Saturated aqueous NH 4 Cl (30 cm 3 ) was added, and the resulting mixture was extracted with ethyl acetate (3 x 40 cm 3 ).The organic layer was washed with brine (30 cm 3 ) and dried over Na 2 SO 4 , concentrated and the oil obtained was purified by column chromatography (hexane: ethyl acetate, 5:1v/v) to afford compound 4 (2.01 g, 83% yield) as a colorless oil.

Results and Discussion
The synthetic route used for the synthesis of (2R,3R,7S)diprionol is shown in Scheme 1.The stereogenic center at C-3 of diprionol was established through a stereoselective hydroboration of (-)-isopulegol (2), with a diastereoisomeric Scheme 1. Synthetic route for the preparation of (2R,3R,7S)-diprionol (1). in 67% yield.In this step, we initially obtained a 4:1 mixture of the desired product 9 and an olefin resulting from the elimination of the tosyl group.To overcome this problem, the reaction mixture was diluted two times.Alcohol 9 was converted into its corresponding tosylate 10 (93% yield) and then coupled with n-hexyl magnesium bromide, using Li 2 CuCl 4 as a catalyst 8 , affording 11 in 90% yield.Catalytic hydrogenation of the benzyl group furnished alcohol 12 in 73% yield.Oxidation of this alcohol with PCC supplied aldehyde 13 (81% yield), which showed high optical purity by chiral GC.The stability of this aldehyde under basic conditions was also investigated by chiral GC.In dichloromethane solution, in the presence of DMAP at r.t.only after one week we started to detect some epimerization product (<5%).However, in the presence of an ethanolic solution of NaOH at r.t., we observed complete epimerization after 48 h.
The last step of our synthetic route generated the stereogenic center at C-3 of diprionol.According to either Cram's rule or Felkin-Ahn model, the methyl group should add to the Re face of the aldehyde furnishing the (2R,3R,7S)-1 isomer.However, it is well known from the literature that variations in the reaction conditions may drastically influence the stereoselectivity of the addition.
Based on these results, we decided to employ methyl magnesium bromide in THF in the nucleophilic addition to aldehyde 13.When the reaction was carried out at -78 o C, the diastereoisomeric ratio was 66:34 by chiral GC, but at -100 o C we obtained a 4:1 ratio and 69% isolated yield, having (2R,3R,7S)-1 as the major product.The absolute configuration at C-2 was assigned based on 1 H NMR data.According to the literature, the peak corresponding to the methyl group at C-3 for (2R,3R,7S)-1 is a doublet at δ 1.15 whereas the one corresponding to (2S,3R,7S)-1 appears at δ 1.12 (Figure 1  Separation of the stereoisomers obtained was quite difficult.After carefull purification by column chromatography, we still observed by chiral GC the presence of the (2S,3R,7S)-isomer (<2.8%) and a third compound (<0.6%),probably the (2S,3S,7S)-isomer, which could come from partial epimerization of aldehyde 13 under the reaction conditions.Thus, the (2R,3R,7S)diprionol (1) was obtained in >96.6% purity by chiral GC.