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Synthesis of (+/-)3,3,7-trimethyl-2,9-dioxabicyclo[,7]nonane (lineatin) - the aggregation pheromone of an ambrosia beetle Trypodendron lineatum

Uno Mäeorg and Ebba Loodmaa

Institute of Organic Chemistry, University of Tartu, Jakobi 2 Str., EE 2400 Tartu, Estonia


The striped ambrosia beetle Trypodendron lineatum (Oliver) is a serious pest in coniferous forests in Europe and North America. This beetle bores into the sapwood of fallen and sawn timber in forest and even during transportation. Silverstein and coworkers have isolated and identified the essential component of the aggregation pheromone of striped ambrosia beetle 3,3,7-trimethyl-2,9-dioxabicyclo[,7]nonane (lineatin) [1]. Entomologists have demonstrated that only the (+)-enantiomer (1R,4S,5R,7R) is the active natural pheromone, however the (-)-enantiomer does not possess any inhibitory effect and the racemic mixture can be used [2].

A number of methods for the synthesis of lineatin have been described[3]. These are multistep procedures and give relatively low overall yield and in addition require expensive and not readily navailable chemicals and special equipment.

Our method resembles the published scheme of Skattebol [4] but we have radically improved and simplified most steps of the synthesis to give an increased yield.

Results and discussion

In our scheme we started from 2-propyn-1-ol and 2-methylpropanal.

By introducing gaseous HCl into a mixture of these compounds at 0 °C the (1-chloro-2-methyl)propyl prop-2-ynyl ether was obtained. After neutralization and drying the product was directly converted to the 2,2-dimethyl-3.4-pentadienal (2) by heating in N,N-diethylaniline. As described earlier [5] by heating at 100 °C the elimination of HCl was taking place and isobutenyl prop-2-ynyl ether was formed. By continuing to heat at 140 °C the Claisen-Cope [3.3] sigmatropic rearrangement gave compound 2 in 70% yield. In spite of two steps our procedure was giving substantially higher yield and the separation of product was simpler compared to the published method [4].

Condensation of the aldehyde (2) with methallylmagnesium chloride in diethyl ether gave 2,2,5-trimethylocta-1,6,7-trien-4-ol (3) in excellent yield. Oxidation of the alcohol (3) obtained was performed with pyridinium chlorochromate in CH2Cl2 [6]. After stirring the mixture at room temp. for 24 h the corresponding ketone (4) was prepared in 81% yield. Oxidation with the original reagent Na2Cr2O7 in diethyl ether proceeded very slowly and was complete only after several days of stirring.

Distillation of the ketone (4) through a heated to 495 °C and filled with quartz wool afforded a mixture of 1,4,4-trimethyl-6-methylenebicyclo[3.2.0]heptan-3-one (5) and 3-ethynyl-2,2,4,4-tetramethyl cyclopentanone (6) with the same results as described in literature [4].

We detected by oxidation of the mixture of compounds (5) and (6) that using MCPBA in this amount is needed only for the conversion of (5) to (7) compound (6) remained unchanged. This finding made the process much simpler. After this selective oxidation compound (7) was separated from the mixture with (6) by column chromatography on silica. The yield was more than 10% higher compared to the original method [4]. It was nto necessary to use silver nitrate for isolation of the side products and the amount of MCPBA was reduced.

The epoxylactone (7) prepared was oxidized with HIO4 .2H2O to prepare 1,5,5-trimethyl-4-oxabicyclo[4.2.0]octane-3,7-dione (8) in quantitative yield.

The final product lineatin was synthesized from the compound (8) by reduction with LiAlH(ButO)3 and following ketalization. The overall yield was remarkably high compared to the analogous scheme [4]. Although DIBAH gave similar results we prefer LiAlH(ButO)3 because it is less hazardous.

Pheromone dispensers made with our our synthetic lineatin have shown very high biological activity against ambrosia beetles in the forest, comparable to the commercial Linoprax dispensers.

Experimental section

All experiments with air and moisture sensitive compounds were performed in an atmosphere of dry argon.

1H and 13C NMR spectra were measured with a Bruker AC200P (Spectrospin AG) spectrometer at 200 MHz and 50 MHz respectively. Chemical shifts were reported relative to SiMe4 in CDCl3.

GLC analyses were performed on Fractovap 4160 series (Carlo Erba Strumentazione) capillary gas chromatograph and Chrom 5 (Laboratorni Przistroje, Praha) equipped with FID, using fused silica capillary columns OV-101 25 m x 0.2 mm, Nordibond NB 20M 25 m x 0.32 mm and glass column 2.5 m x 3 mm packed with 5% Carbowax 20M on Chromosorb W AW-DMCS 80-100 mesh.

2,2-Dimethyl-3,4-pentadienal (2)

Gaseous HCl was introduced to the stirred mixture of 56 g prop-2-ynyl alcohol and 72 g of fresh destilled 3-methylbutanal in a 2 l round bottomed flask at 0 °C until the gas was absorbed (ca. 3 h). The organic layer was separated and the water phase was extracted with pentane (2 x 200 ml). Combined extracts and organic layer were dried on MgSO4 and the solvent was evaporated. To the crude product 240 g of diethylaniline was added and the mixture was heated at 100 °C 30 min until the gas evolution was completed. The temperature was then increased to 175 °C and the mixture was stirred for 1 h. The mixture was cooled, 150 ml of ice water was added, layers were separated and the water phase was extracted with pentane (3 x 100 ml). Combined extracts and organic layer were washed twice with water and dried on MgSO4. After evaporation of the solvent the product was destilled to give 78.3 g (2). Yield 70%.

13C NMR d= C1 207.1; C2 45.8; C2' (2x) 21.9; C3 93.7; C4 208.7; C5 77.9.

2,5,5-trimethylocta-1,6,7-trien-4-ol (3)

To a stirred solution of Grignard reagent ( prepared from 11.5 g of Mg and 43.4 g of fresh distilled 2-methyl-1-bromo-2-propene) 18 g of (2) in 200 ml diethyl ether was added at 0 °C during 4 h. Saturated NH4Cl solution was added to the mixture and usual work-up as described in the previous experiment was giving 27.5 g of crude product, pure enough (>96%) for the next step of synthesis.

13C NMR d= C1 113.4; C2 143.5; C2' 22.2; C3 40.8; C4 75.4; C5 38.7; C5' 23.96 and 24.13; C6 97.6; C7 207.8; C8 76.4.

2,5,5-trimethylocta-1,6,7-trien-4-on (4)

To a stirred suspension of 80 g pyridinium chlorochromate in 800 ml CH2Cl2 30 g of (3) was added and the mixture was left to stir at room temp. for 24 h. 80 ml of dry diethyl ether was added and the mixture was filtered through the silica layer. After evaporation of the solvent 26.9 g (91%) of very pure compound was obtained.

13C NMR d= C1 114.6; C2 139.7; C2' 22.6; C3 46.1; C4 210.1; C5 47.8; C5' (2x) 24.3; C6 98.4; C7 207.8; C8 77.8.

1,4,4-trimethyl-6-methylenebicyclo[3.2.0]heptan-3-on (5)

5 g of (4) was distilled at 0.5 mmHg using 60 x 2.5 cm quartz deflegmator packed with 10 g of quartz wool and heated to 495 °C. The product was collected in a cool trap (-80 °C). Redistillation of the crude product was giving 3 g of the mixture of (5) and (6)

5,5,9-trimethyl-2,6-dioxa-7-oxabicyclo[4.3.0]octylspiro[2.7]decane (7)

To the solution of 3 g of the crude product prepared in the previous experiment in 50 ml CH2Cl2 7.2 g MCPBA (50%) and 4.6 g NaHCO3 was added in portions with stirring at room temp. After 18 h when the reaction was complete 30 ml of 10% aqueous solution of Na2S2O3 was added dropwise. The mixture was stirred for 0.5 h, the organic layer was separated, the water phase was extracted with ch2Cl2 (3 x 15 ml), combined organic phase and extracts were washed with a sat. solution of NaHCO3, dried on MgSO4, evaporated and chromatographed on silica (50 g) using hexane-diethyl ether (1:4) as eluent. 28 g of pure (99% by GLC) (7) was obtained. Yield 56%.

13C NMR d= C1 50.91; C3 56.68; C4 54.54; C5 80.95; C5' 26.28; 26.54; C7 171.73; C8 41.28; C9 31.61; C9' 29.68; C10 50.91.

1,5,5-trimethyl-4-oxabicyclo[4.2.0]octan-3,7-dione (8)

To a stirred solution of 1.4 g (7) in 30 ml dry diethyl ether 1.6 g of HIO4x2H2O was added at room temp. and stirred overnight. Water was added, the ethereal layer was separated and water phase was extracted with diethyl ether (4 x 10 ml). Combined organic phases were washed with sat. Na2CO3 and NaCl solutions, dried on MgSO4 and the solvent was evaporated. 1.2 g of the pure (>98% by GLC) (8) was obtained.

13C NMR d= C1 29.72; C1 28.16; C2 40.14; C3 170.00; C5 80.63; C5' 26.63; 26.70; C6 67.79; C7 205.0; C8 58.0.

3,3,7-trimethyl-2,9-dioxabicyclo[,7]nonane (1) - lineatin

1.2 g of (8) was dissolved in 100 ml diethyl ether and 3.5 g of LiAlH(ButO)3 was added portionwise during 1 h by stirring at room temp. After overnight stirring when the reaction was complete 10 ml of 4 M HCl was added, the ethereal layer decanted, remained suspension was washed five times with diethyl ether, organic phases were combined, washed with a sat. solution of NaHCO3 and NaCl and dried on MgSO4. After carefully removing of solvent 1g of pure lineatin in 91% yield was obtained.

13C NMR d= C1 92.74; C3 72.44; C3' 26.29; 27.83; C4 48.16; C5 71.44; C6 42.16; C7 37.85; C7' 28.92; C8 43.48.


  1. 1. MacConnell, J. G.; Borden, J. H.; Silverstein, R. M.; Stokkink, E. J. Chem. Ecol.1977, 3, 549.
  2. Borden, J. H.; Oehlschlager, A. C.; Slessor, K. N.; Chong, L.; Pierce, H. D. J. Can. Entomol. 1980, 112, 107.

  3. Baeckström, P.; Li, L.; Polec, I.; Unelius, R.; Wimalasiri, W. R. J. Org. Chem.1991, 56, 3358 and references cited therein.

  4. Skattebol, L.; Stenström, Y. Acta Chem. Scand. 1985, B39, 291.
  5. Brandsma, L.; Vercruijsse, H. D. Synthesis of Acetylenes, Allenes and Cumulenes. Elsevier, Amsterdam, 1981, p. 204-205.
  6. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647.