NO824256L - PROCEDURE FOR THE PREPARATION OF AN INSECT PHARMACY - Google Patents

Description

The present invention relates to a method for producing 3,3,7-trimethyl-2,9-dioxatricyclo[3,3,1,0 4 ' 7] nonane (commonly used name: lineatin) which is a gathering pheromone for an ambrosia beetle , and the optically active compounds thereof, as well as the intermediate products for this compound and a method for producing these.

Insect pheromones, due to their strong attraction effect on insects, have recently been used to control insect diseases. However, it is very difficult to isolate large amounts of pheromone from nature, the development of an economic, synthetic method for pheromone is therefore in great demand.

Lineatin is an assembly pheromone isolated from the excreta of female beetles of the species Tr ypodendron lineatum, and it is known to exhibit an attractive effect on the beetles and is believed to be useful as a control agent for insect diseases (Journal of the Chemical Ecology,

Vol. 3, 549 (1977)). Later it was reported by Borden et al. that the attraction effect of lineatin is written from

the (+)-isomer and that the (-)-isomer hardly exhibits one

such effect [The Canadian Entomologist, Vol. 112, 107

(1980)]. Furthermore, lineatin was synthesized and its chem

structure was determined by Mori et al. [Tetrahedron, Vol. 36, 2197 (1980)] and Slessor et al. ]Journal of the Organic Chemistry, Vol. 45, 2290 (1980)].

The present inventors managed to produce lineatin

based on dichloroketene and isoprene, since both are cheap raw materials, by the following formula:

Dichloroketene Isoprene

The form reproduced above shall be explained. The compound (I) is first prepared by adding dichloroketene to isoprene and then it is converted to the compound (II) by reductive dechlorination. The compound (II) is condensed with acetone using lithium diisopropylamide to give the compound (III) which is then reduced to the compound (IV) with lithium tri-sec-butylborohydride. The secondary alcohol group in the compound (IV) is protected by the reaction with tert-butyldimethylsilyl chloride in dimethylformamide in the presence of imidazole, whereby the vinyl hydroxy ether (V) is obtained which is then converted to the diol ether (VI) by hydroboration. The diol ether (VI) is oxidized to the endosyloxy lactone (VII). The endosyloxylactone (VII) is desilylated to the endohydroxylactone (VIII) which is then reduced and treated with an acid to form lineatine.

Linatin is also produced by reducing the endosyloxylactone (VII), one of the intermediates in the scheme shown above,

with diisobutylaluminum hydride and treatment with an acid after desilylation.

Furthermore, lineatin is produced by the reaction of a diether (VI), (XI) or (XII), the intermediates in the scheme shown above, with an oxidizing agent, followed by acid treatment. The diether (XI) or (XII) can be prepared by reacting the previously mentioned compound (IV) with dihydropyran or ethyl vinyl ether in the presence of a p-toluenesulfonic acid catalyst and converting the obtained compound, vinyl hydroxy ether (IX) or (X), by hydroboration.

Here, isoprene, which is one of the starting materials, is a commodity and dichloroketene, another starting material, is a well-known compound (Tetrahedron, Vol. 27, 615 - 638, 1971).

In the following, the present invention will be illustrated

in detail.

(1) Preparation of 3-methyl-3-vinylcyclobutanone

[Compound (II)]

Compound (II) can be prepared by reducing 2,2-dichloro-3-methyl-3-vinylcyclobutanone [Compound (I), see Example 1] with zinc at a temperature between room temperature and the boiling point of a solvent for 3 to 30 hours in presence of preferably not less than two equivalents of an acid.

As a solvent, lower alcohols, such as ethanol, water and lower fatty acids, such as acetic acid, can be used alone or in mixtures of them or with other inert solvents. As the acid, hydrochloric acid, acetic acid, etc. are used. After completion of the reaction, post-treatment is carried out in the usual way followed by purification by chromatography or distillation if necessary.

(2) Preparation of 1,5,5-trimethyl-7-endo-tert-butyl-dimethylsilyloxy-4-oxabicyclo[4,2,0]octan-3-one

[Endosyloxylactone (VII)]

Endosilyloxylactone (VII) can be prepared by oxidizing 2-dimethylhydroxymethyl-3-methyl-3-(2-hydroxyethyl)-1-tert-butyldimethylsilyloxycyclobutane [diol ether (VI, see Examples 3 to 6)] with not less than one equivalent of an oxidizing agent under reaction conditions suitable for the oxidizing agent, whereby the hydroxyethyl group in the diol ether (VI) is oxidized. When the reaction conditions are not alkaline, the intended endosyloxy lactone (VII) is obtained which has formed a ring. When the condition is alkaline, however, the endosyloxylactone (VII) is obtained by acidification after the oxidation.

Various oxidizing agents can be used: Chromic acid-type agents such as chromic acid, chromic anhydride and modifications thereof (e.g. "John's reagent", "Cornforth reagent", pyridine chlorochromate) (Fieser et al.: Reagents in Organic Synthesis, Vol. 1, 142 - 147, 1967), and dichromic acid type agents such as pyridine dichromate, etc. Furthermore, potassium permanganate, silver carbonate/celite and the like can also be used. The turnover is preferably carried out close to neutrality,

and pyridine dichromate is particularly a preferred oxidizing agent. When pyridine dichromate is used, commonly used solvents that are inert to oxidizing agents can be used, e.g. chlorinated hydrocarbons (eg methylene chloride, dichloroethane), ketones (eg acetone), ethers (eg diethyl ether, tetrahydrofuran) and the like. In this case, the reaction temperature is 0° to 50°C, preferably 20° to 30°C, and the reaction time is 5 to 50 hours. After completion of the reaction, post-treatment is carried out in the usual way, followed by purification by chromatography or recrystallization if necessary.

(3) Preparation of 1,5,5-trimethyl-7-endo-hydroxy-4-oxabicyclo[4,2,0]octan-3-one

[Endohydroxylactone (VIII)]

Endohydroxylactone (VIII) can be prepared by desilylation

of 1,5,5-trimethyl-7-endo-tert.-butyldimethylsilyloxy-4-oxabicyclo[4,2,0]octan-3-one [Endosyloxylactone (VII)] usually at ca. 0 to 50°C for 1 to 10 hours in an inert organic solvent in the presence of not less than the equimolar amount of an acid or base. The inert organic solvent comprises e.g. ethers (eg diethyl ether, tetrahydrofuran), hydrocarbons (eg n-hexane, toluene), halogenated hydrocarbons (eg chloroform) and the like. As an acid, protonic acids such as acetic acid, hydrofluoric acid, etc. and Lewis acids, such as boron trifluoride, iron chloride, etc. are used. As a base, special bases such as tetraalkylammonium fluoride,

especially tetra-n-butylammonium fluoride. After completion of the turnover, post-processing is carried out in the usual way, onr-emergency-

followed by purification by chromatography or recrystallization.

1,5,5-trimethyl-7-exo-hydroxy-4-oxabicyclo-[4,2,0]octan-3-one with the same planar structure as that of the endohydroxylactone (VIII), was synthesized by Mori et al [Tetrahedron , Vol. 36, 2197 (1980)]. But this compound differs from the endohydroxylactone (VIII) in that the hydroxyl group in the 7-position assumes an exo-configuration.

(4) Preparation (a) of lineatine

Lineatin can be prepared by reducing 1,5,5-trimethyl-7-endo-hydroxy-4-ixabicyclo[4,2,0]ocatn-3-one IEndohydroxy-lactone (VIII) with diisobutylaluminum hydride in 2 to 3

times larger molar amounts at a temperature of -78°C to room temperature (20°C) for 10 minutes to 1 hour in an inert solvent; after acidification, acid treatment at a temperature from -78°C to the boiling point of the solvent for 10 minutes to 5 hours and extracting with a low-boiling solvent, such as n-pentane, followed by drying and distillation.

The inert solvent comprises e.g. ethers (eg diethyl ether), aromatic hydrocarbons (eg toluene), hydrocarbons (eg n-hexane) and the like. The acid includes e.g. for example protonic acids such as hydrochloric acid. Lineatine obtained in this way is purified if necessary

by column chromatography or distillation.

(5) Preparation (b) of lineatine

Lineatin can also be prepared by reducing 1,5,5-trimethyl-7-endo-tert-butyldimethylsilyloxy-4-oxabicyclo[4,2,0]octan-3-one [Endosyloxylactone (VII)] with diisobutylaluminum hydride in 1 to 1.5 times molar amounts thereof at -78°C to room temperature (20°C) for 10 minutes to 1 hour in an inert solvent, add an acid or base to the reaction solution, and desilylate usually at 0° to 50°C for 1 to 10 hours.

In this desilylation, the use of an acid results in ring closure, so that the intended lineatin is obtained directly. When a base is used, ring closure is easily achieved by acidifying the reaction mixture by adding an acid such as hydrochloric or hydrofluoric acid, and keeping the reaction solution near room temperature for several hours, thereby obtaining the intended lineatin.

The inert solvent comprises e.g. ethers (eg diethyl ether, tetrahydrofuran), aromatic hydrocarbons (eg toluene), hydrocarbons (eg n-hexane) and the like. Protic acids (e.g. hydrochloric acid, hydrofluoric acid) and Lewis acids (e.g. boron trifluoride, ferric chloride) are used as the acid. As the base, special bases, such as tetraalkylammonium fluoride, especially tetra-n-butylammonium fluoride, are preferred. After completion of the turnover, post-treatment is carried out in the usual way, if necessary followed by purification by means of distillation or column chromatography.

(6) Preparation (c) of lineatine

Furthermore, lineatin can also be prepared by reacting the diol ether with the formula (VI, XI, XII),

wherein R is a tert-butyldimethylsilyl, tetrahydropyranyl, or 1-ethoxyethyl group, with an approximately equimolar amount of an oxidizing agent at 0 to 10°C for one minute to 30 minutes in an inert solvent, treating the reaction mixture at 0 to 10°C in 5 to 48 hours after acidification, preferably by addition of inorganic acid, and separate the organic layer, if necessary followed by distillation or column chromatography. The inert solvent comprises e.g. halogenated hydrocarbons (eg dichloromethane, chloroform), ketones (eg acetone), ethers (eg diethyl ether), aromatic hydrocarbons (eg toluene) and the like. The oxidizing agent includes e.g. pyridine chlorochromate, pyridine dichromate and the like. The acid includes e.g. protonic acids, preferably inorganic acids such as 15 to 30% hydrochloric acid. The diol ether (XI, XII), a starting material for this reaction, where R is a tetrahydropyranyl or 1-ethoxyethyl group, can be obtained by reacting the above-mentioned compound (IV) with dihydropyran or ethyl vinyl ether in the presence of a p-toluenesulfonic acid catalyst, and converting the obtained compound by hydroboration. After completion of the turnover, post-treatment is carried out in the usual way, if necessary followed by purification by distillation or column chromatography. (+)-lineatin, one of the optically active forms of lineatin, can be prepared from racemic endohydroxylactone (VIII), which is an important intermediate in the previously mentioned scheme, with the following scheme:

The (+)-endohydroxylactone can be easily obtained by the hydrolysis or alcoholysis of an optically active lactone ether (XIII)

(see example 15) which can be obtained by reacting the (-)-endohydroxylactone and (-)-4-hydroxy-6,6-dimethyl-3-oxabi-cyclo[3,1,0]hexan-2-one, and to separate the diastereomers.

This hydrolysis is preferably carried out under acidic conditions. As the acid, 0.01 to 1 mol of various acids can be used, such as inorganic acids (e.g. hydrochloric acid, sulfuric acid) and organic acids (e.g. p-toluenesulfonic acid, methanesulfonic acid, formic acid). As the solvent to be used, only water can be used, but preferably alcohols (e.g. methanol, ethanol), ethers (e.g. diethyl ether, dioxane, tetrahydrofuran) and ketones (e.g. acetone) are used, or mixtures with other common organic solvents. The reaction takes place completely at room temperature, but heating may be used depending on the solvent. The reaction time is usually 0.5 to 5 hours.

Hereby (-)-4-hydroxy-6,6-dimethyl-3-oxabicyclo[3,1,0] hexan-2-one can be easily synthesized from (+)-cis-chrysanthemic acid (U.S. Patent No. 1,270,270) .

The present invention will now be specifically illustrated by means of the following examples.

Example 1

Preparation of 2,2-dichloro-3-methyl-3-vinylcyclobutanone

[Compound .(I)]

A four-necked flask was dried by heating while flowing with nitrogen gas. After cooling, 68.1 g (1.0 mol) of isoprene, 74.2 g (1.1 mol) of active zinc and 1.5 liters of ether were added, and with stirring a mixture of 208.8 g (1 .1 mol) trichloroacetyl chloride and 159.5 g (1.04 mol) phosphorus oxychloride added dropwise at 10 to 25°C over 2.5 hours.

After completion of the dropwise addition, the reaction mixture was stirred at 20°C for 1 hour and then refluxed for 1 hour. After cooling, the reaction mixture was filtered through celite and the filtrate was poured into 300 ml of ice water, washed with water, three 500 ml portions of a saturated aqueous sodium bicarbonate solution and then with 500 ml of a saturated aqueous sodium chloride solution. The ether layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, whereby 154.8 g of an oily product was obtained (yield 86.5%).

IR (unmixed, cm"1): 1815, 1640, 990, 930, 765.

By means of gas chromatographic analysis, it was found that the product was a mixture of 72% of compound (I) and 22% of 2,2-dichloro-3-isoprenylcyclobutanone.

Example 2

Preparation of 3-methyl-3-vinylcyclobutanone

[Compound (II)]

1 liter of acetic acid was added to a four-necked flask

and 282.6 g (4.32 mol) of zinc powder, and while stirring, 154.8 g (0.81 mol, mixture) of the above-mentioned crude mixture containing compound (I) was added dropwise at 20 to 25°C . After stirring at room temperature for 24 hours and then at 70°C for a further 2 hours, the reaction mixture was cooled and 1 liter of ether was added. The reaction mixture was filtered through celite and 500 ml of water was added to the filtrate which was then neutralized by the addition of sodium carbonate while stirring. The ether layer was washed with 500 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

After filtration, ether was removed by evaporation from the filtrate which was then distilled, whereby 68.9 g of a liquid was obtained. This liquid was fractionated by distillation, whereby 44.1 g of the intended compound (II) was obtained

(yield 38.9%).

Boiling point: 84° - 85°C (114 mmHg)

n^<4>1.4408

Elemental analysis:

Example 3

Preparation of 2-dimethylhydroxymethyl-3-methyl-3-vinylcyclobutanone

[Compound III)]

To a solution of 0.97 g (0.0096 mol) diisopropylamine i

To 5 ml of tetrahydrofuran was added dropwise 6.9 ml (1.43 mol solution, 0.0099 mol) of n-butyllithium at -78°C under an argon atmosphere. Then, 1.0 g (0.0091 mol) of the above-mentioned compound (II) was added at the same temperature, and after stirring for 1 hour, 1.4 ml (0.0182 mol) of acetone was added dropwise at no more than -60°C, followed by standing overnight at -78°C. The reaction solution was poured into a cooled, saturated aqueous ammonium chloride solution and extracted with three 60 ml portions of ether. The ether layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Ether was then removed by evaporation to give 1.24 g of the intended crude oily product. The result of gas chromatographic analysis showed that the product was a mixture of 36% of the cis form and 41% of the trans form. This crude, oily product was used as such for the subsequent turnover.

IR (unmixed, cm"<1>): 3460, 1775.

Example 4

Preparation of 2-dimethylhydroxymethyl-3-methyl-3-vinylcyclobutanol

[Compound (IV)]

A solution of 1.24 g of the above-mentioned compound (III) (purity 77%, 0.0057 mol) in 10 ml of tetrahydrofuran was added dropwise to 14.8 ml of lithium-tri-sec-butylborohydride (a tetrahydrofuran solution with concentration 1 mol, 0.015 mol) at -60 to -70°C under argon atmosphere. After stirring at -74°C for one hour, the temperature of the reaction solution was gradually increased. After 2 hours, an aqueous sodium acetate solution was added under ice-cooling, and then 4.7 ml of 30% aqueous hydrogen peroxide was added dropwise at 20° to 30°C. Tetrahydrofuran was removed by evaporation, the residue was extracted with three 60 mL portions of ether, and the ether layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, ether was removed by evaporation, yielding 1.76 g of the intended crude oily product. IR (unmixed, cm"<1>): 3360, 1635.

Example 5

Preparation of 2-dimethylhydroxymethyl-3-methyl-3-vinyl-1-tert.-butyldimethylsilyloxycyclobutane

[Connection (V)]

A solution of 1.76 g of the above-mentioned compound (IV) and 1.51 g (0.022 mol) of imidazole in 4.5 ml of dimethylformamide was added to a solution of 1.11 g (0.0074 mol) of tert.- butyl dimethylsilyl chloride in 15 ml of dimethylformamide at room temperature, followed by stirring for 24 hours. The reaction mixture was poured into ice water and extracted with three 60 ml portions of ether. The ether layer was washed with water and then with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, ether was removed by evaporation, yielding 2.19 g of a crude, oily product. The product was then purified by silica gel column chromatography using benzene/methylene dichloride mixed solvent as a developing solvent to give 0.66 g of the intended product.

IR (unmixed, cm<-1>): 3540, 1638.

Example 6

Preparation of 2-dimethylhydroxymethyl-3-methyl-3-(2-hydroxyethyl)-1-tert-butyldimethyl-silyloxycyclobutane

[Dioleth (VI)]

To 0.66 g (0.0024 mol) of the above-mentioned vinyl hydroxy ether (V) was added dropwise 3.6 ml (0.0036 mol) of a tetrahydrofuran solution (1 M concentration) of borane at room temperature under an argon atmosphere, followed by of stirring for 14 hours. Then, 3.5 ml of a tetrahydrofuran:water (2:1) mixed solution was added at 0°C, followed by stirring for 1 hour. Furthermore, 3 ml of 3N aqueous sodium hydroxide solution and then 3 ml of a 30% aqueous hydrogen peroxide were added dropwise, followed by stirring at room temperature for 3 hours. Tetrahydrofuran was then removed by evaporation and the residue was extracted with three 60 ml portions of ether. The ether layer was dried over anhydrous magnesium sulfate and after filtration, the ether was removed by evaporation to give 0.9 g of crude, oily product. This product was purified by column chromatography with silica gel and chloroform as a generating solvent to give 0.44 g of the oily intended product.

IR (untreated, cm<-1>): 3450.

Example 7

Preparation of 1,5,5-trimethyl-7-endo-tert-butyldimethylsilyl-oxy-4-oxabicyclo[4,2,0]octan-3-one

[Endosyloxylacetone (VII)]

To 3.6 ml of methylene dichloride was added 1.44 g (0.00383 mol) of pyridine dichromate and to the resulting mixture was added dropwise 0.4 4 g (0.00146 mol) of the above-mentioned diether (VI), followed by stirring at room temperature for 36 hours. Then 50 ml of ether was added to the reaction mixture which was then filtered through celite. The filtrate was concentrated, 50 ml of n-hexane was added and the mixture was filtered again through celite. The filtrate was concentrated to give 0.35 g of a crude, oily product. This product was purified by multi-step development on

a silica gel thin-layer chromatography plate using a hexane : acetone (5:1) mixed solvent to give 0.183 g of the intended endosyloxylactone (VII)

(yield 53%). Melting point 54 - 56°C. This crystal was recrystallized from petroleum ether whereby a crystal with a melting point of 60.5 to 61°C was obtained.

Elemental analysis:

Example 8

Preparation of 1,5,5-trimethyl-7-endo-hydroxy-4-oxabicyclo[4,2,0]octan-3-one

[Endohydroxylactone (VIII)]

To a solution of 0.109 g (0.366 mmol) of the endosyloxy lactone (VII) in 0.5 ml of tetrahydrofuran was added dropwise a solution of 0.37 ml (0.366 mmol) of tetra-n-butylammonium fluoride in 0.2 ml of tetrahydrofuran at 0°C under argon atmosphere, followed by stirring for 3 hours. Then 5 ml of a saturated aqueous ammonium chloride solution was added at 0°C, and tetrahydrofuran was removed by evaporation. The residual liquid was extracted with two 50 ml portions of ether,

and the ether layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, ether was removed by evaporation and the crude oily product obtained was purified by thin-layer chromatography in the same manner as above to give 45.6 mg of the intended oily endohydroxylactone (VIII) (yield 67.7% ). This product was recrystallized from ether to obtain a crystal with a melting point on it

64 to 65°C.

Elemental analysis:

Example 9

Preparation (a) of 3,3,7-trimethyl-2,9-dioxatricyclo

4 7

[3,3,1,0'] nonane (lineatin)

To a solution of 39.7 mg (0.216 mmol) of the endohydroxylactone (VIII) in 0.3 ml of ether, 0.27 ml of diisobutylaluminum hydride (25% hexane solution) was added dropwise with stirring at -74°C under an argon atmosphere. The temperature of the mixture was increased from -74 to -50°C within 1 hour,

and 0.63 ml of 1N hydrochloric acid was added at -50°C. The temperature was further raised to room temperature over one hour, and 0.08 ml of 6N hydrochloric acid was added, followed by stirring for another hour. The reaction solution was extracted with three 10 ml<1>s portions of n-pentane and the pentane layer was dried over anhydrous magnesium sulfate and filtered, n-pentane was removed by evaporation, whereby 9 mg of a crude, oily product was obtained (yield 25%). It was confirmed by gas chromatography/mass spectrometry that this oily product was identical to lineatin synthesized by Mori et al. according to the method described in the above-mentioned literature.

Example 10

Preparation (b) of lineatin

To a solution of 69 mg (0.2 3 mmol) of the endosylyloxy lactone (VII) in 0.5 ml of ether, 0.17 ml of diisobutylaluminum hydride (25% hexane solution) was added dropwise with stirring at -7 4°C under an argon atmosphere honor. The temperature of the mixture was increased to -50°C within 1 hour,

and after adding a drop of water, 0.7 ml of 10% hydrofluoric acid was added, followed by stirring at room temperature for another 3 hours. The reaction mixture was extracted with three 10 mL<1>s portions of n-pentane, and the pentane layer was dried over anhydrous magnesium sulfate and filtered. The n-pentane was then removed by evaporation, whereby a crude, oily product was obtained. This product was cleaned using

by column chromatography with alumina and n-pentane as a developing solvent which gave 7 mg of an oily product, lineatin (yield 18%).

Example 11

Preparation (c) of lineatin

226 mg (0.75 mmol) of the diol ether (VI) was dissolved in 2 mL of methylene chloride and 165 mg (0.75 mmol) of pyridine chlorochromate was added to the resulting solution at no more than 5°C, followed by stirring for 30 minutes at the same temperature. Then 6 ml of 15% aqueous hydrochloric acid was added, followed by stirring for 48 hours. After separation, the organic layer was washed with water, aqueous sodium bicarbonate solution and then with water, and dried over anhydrous magnesium sulfate. After filtration, methylene chloride was removed by evaporation under normal pressure and the residue was purified by column chromatography on alumina, whereby 33 mg of lineatin was obtained (yield 26.2%).

Example 12

Preparation (c) of lineatin

The procedure was carried out in the same way as in Example 11 with the exception that 202 mg (0.75 mmol) of pyridine dichromate was used as oxidizing agent instead of pyridine chlorochromate. 26 mg of lineatin was obtained (yield 11.6%).

Example 13

Preparation (c) of lineatin

204 mg (0.75 mmol) of 2-dimethylhydroxymethyl-3-methyl-3-(2-hydroxyethyl)-1-tetrahydropyranyloxy-cyclobutane, the diol ether (XI) was dissolved in 2 ml of chloroform and 165 mg

(0.75 mmol) of pyridine chlorochromate was added to the resulting solution at 10°C, followed by stirring for 10 minutes. Then 3 ml of 30% aqueous hydrochloric acid was added

set, followed by stirring for 16 hours. After separation, the procedure was carried out in the same way as in Example 11, whereby 36 mg of lineatin was obtained (yield 28.6%).

Example 14

Preparation (c) of lineatin

258 mg (1.0 mmol) 2-dimethylhydroxymethyl-3-methyl-3-(2-hydroxyethyl)-1-(1-ethoxyethyl)oxycyclobutane, the diol ether (XII)

was dissolved in 2 ml of methylene chloride and 270 mg (1.0 mmol) of pyridine dichromate was added to the resulting solution

solution at 10°C followed by stirring for 30 minutes.

Then 3 ml of 20% aqueous hydrochloric acid was added, followed by stirring for 5 hours. After separation, the organic layer was washed with water, aqueous sodium bicarbonate and then with water, and dried over anhydrous magnesium sulfate. After filtration, methylene chloride was removed by evaporation

under normal pressure and the residue was distilled under reduced pressure, whereby 24 mg of lineatin was obtained (yield 14.2%). Boiling point: 120° - 130°C (bath temperature)/60 mmHg.

Example 15

Preparation of optically active lactone ether (XIII)

1.5 grams (8.14 mmol) of the (-)-endohydroxylactone (VIII),

1.16 g (8.14 mmol) of (-)-4-hydroxy-6,6-dimethyl-3-oxa-bicyclo[3,1,0]hexan-2-one [[a]^<3> -97.3° (c = 1.0, ethanol), mp 113°-114°C] and 12 mg of p-toluenesulfonic acid were dissolved in 50 ml of benzene, followed by reflux by heating.

The water formed was removed azeotropically during 30 min.

and then the solvent was removed by evaporation to give 2.82 g of a crude oily product.

This oily product was separated by means of column chromatography on silica gel (dichloromethane : acetone = 50 : 1) and recrystallized from ethanol, whereby two diastereomers with the following formulas were obtained:

The first eluted diastereomer (A):

Yield 1.1 g (88%)

Melting point 143 - 144°C

[a] ^<3>-108.0° (c = 1.06, ethanol)

Elemental analysis:

Later eluted diastereomer (B):

Yield 1.1 g (88%)

Melting point 12 4 - 12 5°C

[a]^<3>-65.1° (c = 1.02, ethanol)

Elemental analysis:

The absolute configuration for the diastereomer (A) obtained here was determined using the X-ray crystal diffraction method. The diastereomer (A) was finally converted to (+)-lineatin. When comparing the diastereomers (A) and

(B), (A) is less soluble in hydrocarbon solvents such as n-hexane than (B), suggesting a

possibility that both diastereomers can be separated from each other by means of recrystallization.

Example 16

Preparation of the (+)-endohydroxylactone (XIV)

4.27 g (13.8 mmol) of the above-mentioned diastereomer (A) was dissolved in 15 ml of methanol and a drop of concentrated salt-

acid was added at room temperature, followed by stirring for 2 hours. After adding 1 ml of a saturated aqueous sodium bicarbonate solution, methanol was removed by evaporation, and the residue was dissolved in chloroform and dried over anhydrous magnesium sulfate. After filtration, chloroform was removed by evaporation, whereby a crude, oily product was obtained. This product was purified by chromatography on silica gel (chloroform : acetone = 33 : 1), and then recrystallized from ether to give 2.2 g of the intended (+)-endohydroxylactone (XIV) (yield 86%).

Melting point 90 - 91°C.

[a]<21>'<2>+48.2° (c = 1.0, carbon tetrachloride)

Elemental analysis:

Example 17

Preparation of (+)-lineatin

1.7 g (9.2 3 mmol) of the above-mentioned (+)-endohydroxylactone (XIV) was dissolved in 13.4 ml of dry ether, and after cooling to -74°C, 11.9 ml of diisobutylaluminum hydride (25 % hexane solution) slowly added dropwise to the resulting solution under an argon atmosphere.

The temperature of the reaction solution was increased to -50°C within 1 hour and after adding 2 7.8 ml of 1N hydrochloric acid, the temperature was increased to room temperature within a further 1 hour. Then 3.4 ml of 6N hydrochloric acid was added followed by stirring for one hour. The reaction mixture was extracted with four 30 mL portions of n-pentane, and the extracts were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation to give 2.0 g of the oily product. This product was distilled, whereby 874 mg of the intended (+)-lineatin was obtained (Yield 56.3%).

Boiling point: 110°C/53 mmHg

The NMR and IR spectra of this compound were completely identical to those of (-)-lineatin previously prepared (Mori et al.: Tetrahedron, Vol. 36, 2197 - 2208, 1979).

Claims (17)

1. Process for the production of 3,3,7-trimethyl-2,9-dioxatricyclo[3,3,1,0 4 ' 7]nonane with the formula: characterized by reducing 1,5,5-trimethyl-7-endo-tert-butyldimethylsilyloxy-4-oxabicyclo[4,2,0]octan-3-one with diisobutylaluminum hydride and treating with an acid after desilylation. 2. Process according to claim 1, characterized in that 1,5,5-trimethyl-7-endo-tert-butyldimethylsilyl-oxy-4-oxabicyclo[4,2,0]octan-3-one is prepared by oxidizing 2- dimethylhydroxymethyl-3-methyl-3-(2-hydroxyethyl)-1-tert.-butyldimethylsilyloxycyclobutane with the formula: 3. Method for preparing 3,3,7-trimethyl-2,9-dioxatricyclo[3,3,1,0 4 ' 7]nonane with the formula: characterized by reacting a diether with the formula: where R is a tert-butyldimethylsilyl group, a tetrahydro-pyranyl group or a 1-ethoxyethyl group, with an oxidizing agent and then treated with an acid. 4. Process according to claim 3, characterized in that the diol ether is prepared by, as a series of successively following steps, to (1) condense 3-methyl-3-vinylcyclobutanone with the formula: with acetone in the presence of lithium diisopropylamide, whereby 2-dimethylhydroxymethyl-3-methyl-3-vinylcyclobutanone is obtained with the formula: (2) reduce the obtained 2-dimethylhydroxymethyl-3- methyl-3-vinylcyclobutanone with lithium tri-sec.-butylborohydride, whereby 2-dimethylhydroxy-methyl-3-methyl-3-vinylcyclobutanol is obtained with the formula: (3) protecting the secondary alcohol group in the obtained 2-dimethylhydroxymethyl-3-methyl-3-vinylcyclobutanol by reaction with tert-butyldimethylsilyl chloride in the presence of imidazole in dimethylformamide, or with dihydropyran or ethyl vinyl ether in the presence of p-toluenesulfonic acid, whereby a vinyl hydroxy ether with the formula is obtained: where R is as defined in claim 3, (4) converting the vinyl hydroxy ether obtained by hydroboration, whereby the diol ether is obtained. 5. Method according to claim 4, characterized in that 3-methyl-3-vinylcyclobutanone is produced by reductive dechlorination of 2,2-dichloro-3-methyl-3-vinylcyclobutanone with the formula: 6. Process according to claim 5, characterized in that 2,2-dichloro-3-methyl-3-vinylcyclobutanone is produced by reacting dichloroketene with isoprene. 7. Process for preparing 3,3,7-trimethyl-2,9-dioxatricyclo[3,3,1,0 4 ' 7]nonane with the formula characterized by reducing 1,5,5-trimethyl-7-endo-hydroxy-4-oxabicyclo]4,2,0]octan-3-one with diisobutylaluminum hydride, and then treating with an acid. 8. Method according to claim 7, characterized in that 1,5,5-trimethyl-7-endo-hydroxy-4-oxabicyclo[4,2,0]-octan-3-one is produced by desilylation of 1,5,5- trimethyl-7-endo-tert-butyldimethylsilyloxy-4-oxabicyclo[4,2,0]-octan-3-one with an acid or a base. 9. Process for the production of (+)-3,3,7-trimethyl-2,9-dioxatricyclo[3,3,1,0 4 ' 7]nonane with the formula: characterized by reacting a (+)-endohydroxylactone with the formula with diisobutylaluminum hydride and then treat with an acid. 10. Method according to claim 9, characterized in that the ( + ).-endohydroxylactone with the formula: is produced by the hydrolysis of an optically active lactone ether with the formula: 11. Method according to claim 10, characterized in that the optically active lactone ether is prepared by reacting 1,5,5-trimethyl-7-endo-hydroxy-4-oxabicyclo-[4,2,0]octan-3-one with ( -)-4-hydroxy-6,6-dimethyl-3-oxabicyclo[3,3,0]hexan-2-one and to separate the diastereomers. 12. Compound, characterized in that it has the formula: where R is a tert-butyldimethylsilyl group, a tetrahydro-pyranyl group or a 1-ethoxyethyl group. 13. Compound according to claim 12, characterized in that it is 1,5,5-trimethyl-7-endo-tert-butyldimethyl-1-silyloxy-4-oxabicyclo[4,2,0]octan-3-one. 14. Compound according to claim 12, characterized in that it is 1,5,5-trimethyl-7-endo-hydroxy-4-oxa-bicyclo[4,2,0]octan-3-one. 15. Compound according to claim 12, characterized in that it is (+)-1,5,5-trimethyl-7-endo-hydroxy-4-oxa-bicyclo[4,2,0]octan-3-one. 16. Compound, characterized in that it has the formula: 17. Compound, characterized in that it has the formula: