ECHET96 Article 043: Dr R A Aitken
Synthesis of (+/-)3,3,7-trimethyl-2,9-dioxabicyclo[3.3.1.04,7]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[3.3.1.04,7]nonane (lineatin) . 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 .
A number of methods for the synthesis of lineatin have been described. 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  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  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 .
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 . 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 .
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 . 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
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 . Although DIBAH gave similar results we prefer LiAlH(ButO)3 because it is less
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.
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.
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
13C NMR d= C1 207.1; C2 45.8; C2' (2x) 21.9; C3 93.7; C4
208.7; C5 77.9.
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.
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.
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)
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.
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[3.3.1.04,7]nonane (1) -
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.
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J. Can. Entomol. 1980, 112, 107.
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Cumulenes. Elsevier, Amsterdam, 1981, p. 204-205.
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