JPH06708B1 - 4-isopropyl-7-methylene-5-cyclodecene-1-ol - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to 4-useful intermediates for synthesizing periplanone-B, a sex pheromone of the American cockroach.
Isopropyl-7-methylene-5-cyclodecene-1-
Regarding oars.

Background Art Periplanin-B is the main component of female sex pheromones of the American cockroach (Periplaneta americana), which is a pest that is distributed almost all over the world. Has been determined and has a unique germaclen type sesquiterpenoid structure (CJ Persoons et al., Tetrahedoron
Letters, 24, 2055 (1976)). Persoons et al. Report that periplanone-B has a very potent bioactivity, one picogram (1 / thousandth of a gram) of which attracts males of the American cockroach and causes sexual arousal. After that, the racemic form of periplanone-B was synthesized by Double Sea Seel and its relative configuration was determined (WCStill, J. Am. Chem. Soc., 101,2493 (197).
9)). Furthermore, Kay Nakanishi et al. Determined the absolute configuration of periplanone-B by spectroscopic methods by optical resolution of the racemate synthesized by Stil (K. Nakanishiet).
al., J. Am. Chem. Soc., 101, 2495 (1979)). Another method of synthesizing periplanone-B is also described by S. L. Shriver et al. In J. Am. Chem. Soc., 106, 4038 (1984).

As described above, periplanon-B is a sex pheromone of the American cockroach, and it can be used to attract and kill the male American cockroach at a specific place. However, since insects including the American cockroach produce only a very small amount of sex pheromone, it is not practical to obtain it by extraction. Therefore, there is a demand for development of a method capable of synthesizing periplanone-B on an industrial scale.

Both the above-mentioned stil synthesis method and Shuliver's synthesis method were used as a starting material in a racemic form ((±) -5- (hydroxymethyl) cyclohexenone ethoxyethyl ether in the former method, and the latter method in the latter method). (±) -4-isopropyl-2-cyclohexen-1-one) is used, and therefore the final target product, periplanone-B, can be obtained only as a racemate. However, the racemic starting material used in these conventional methods is very difficult to optically resolve, and requires complicated operations. In addition, these methods are not efficient because they make use of the oxiscope transfer, which is difficult to scale up, for the formation of the ten-membered ring, which is a key reaction in the synthesis of periplanone-B. Furthermore, in these methods, there are many steps in which reaction conditions such as organometallic reaction and photoreaction need to be finely adjusted.

DISCLOSURE OF THE INVENTION Accordingly, it is an object of the present invention to provide an optically active intermediate which enables the synthesis of optically active periplanone-B on an industrial scale.

According to the invention, 4-isopropyl-7-methylene-
5-Cyclodecen-1-ol is provided.

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention 4-isopropyl-7-methylene-5
-Cyclodecen-1-ol has the formula Indicated by. This compound can be produced according to the following route using optically active d-dihydrolimonene as a starting material, which is known per se and easily available.

Hereinafter, the method for producing the compound of the present invention will be described along the above route.

(i) In step 1, d-dihydrolimonene represented by the formula A is subjected to ozonolysis, and the ozonolysis product is reduced with dimethyl sulfide. Ozonolysis can be carried out by suspending d-dihydrolimonene in an alcoholic solvent and passing ozone through the suspension at a temperature of 0 ° C or lower, preferably -30 ° C or lower. As the alcohol solvent, an alcohol such as methanol, ethanol or ethylene glycol, or a mixture of alcohol and methylene chloride or chloroform can be used. The preferred solvent is a mixture of methanol and methylene chloride. Ozone is included in the enzyme or air in a concentration of 1 to 10% by volume and passes through the suspension. Ozone decomposition is usually completed in 5 to 10 hours.

The reduction is carried out by adding dimethyl sulfide to the ozonolysis reaction mixture together with an acid catalyst such as hydrochloric acid, sulfuric acid or paratoluenesulfonic acid, and adding the reaction mixture at a temperature of -60 ° C or lower.
Then, the reaction can be carried out at 0 ° C to 30 ° C. Usually, dimethyl sulfide is d-
The dihydrolimonene is used in a ratio of 2 to 3 equivalents, and the acid catalyst is used in a ratio of 0.05 to 0.1 equivalent to 1 equivalent of d-dihydrolimonene.

This ozonolysis and reduction gives formula B (3
R) -3-Isopropyl-6-oxoheptanal dialkyl acetal is obtained. The alkyl group R ° in the formula B is introduced as a result of the ozone decomposition product reacting with the alcohol used as the solvent. The compound of formula B can be purified by vacuum distillation. The yield of the compound of formula B is usually 90 to 95%.

In step (2), the compound of the formula B is treated with a dialkyl carbonate or chloroform in the presence of sodium hydride at a temperature of 50 ° to 120 ° in an ether solvent under a stream of an inert gas such as nitrogen or argon. React with alkylate (Claisen condensation). As the dialkyl carbonate or alkyl chloroformate, those in which each alkyl group has 1 to 3 carbon atoms can be usually used, and dimethyl carbonate is preferable. As the ether solvent, diethyl ether, tetrahydrofuran (THF), ethers such as dioxane and dimethoxyethane (DME), or a mixture of dioxane and methanol, a mixture of dioxane, methanol and dimethylformamide (DMF) or benzene. Mixtures with diethyl ether can be used. Sodium hydride is used in 1 to 5 equivalents, preferably 3 equivalents, relative to 1 equivalent of the compound of formula B.

This reaction results in (6R) -alkyl of formula C
6-Isopropyl-9,9-dialkoxy-3-oxooctanoate is obtained in solution in the form of its sodium salt. Alkoxycarbonyl group-COOR of compounds of formula C
¹ is derived from dialkyl carbonate or alkyl chloroformate. The sodium salt of the compound of formula C is used in the next step without isolation.

Two methods (-a) and (-b) can be used for producing the compound represented by the formula H from the compound represented by the formula C.

(-A) First, in step 3, in a solution of the sodium salt of the compound of formula C obtained in step 2, 1-2 equivalents, preferably 1: 1 equivalents of allyl halide (e.g. , Allyl chloride, allyl bromide) at 50 ° C
The reaction is performed at a temperature of ˜120 ° C. for 1 hour to 5 hours to obtain (2RS, 7R) -alkyl 7-isopropyl-9,9-dialkoxy-3-alkoxycarbonyl-4-oxononanoate represented by the formula D.

Then, in step 4, the compound of formula D is treated without purification with an alkali metal hydroxide (lithium hydroxide, sodium hydroxide or hydroxide) in a mixed solvent of water and alcohol, preferably a water-methanol mixed solvent. Saponification and deodorization are carried out by heating with potassium) at 60 ° C. to 100 ° C. for 1 to 3 hours. The alkali metal hydroxide is used in a proportion of 3 to 5 equivalents relative to 1 equivalent of the compound of formula D.
By this reaction, (8R) -8-isopropyl-10,10-dialkoxy-1-decene-5 represented by formula E is obtained.
You get on. This compound can be purified by vacuum distillation. The yield of the compound of formula E is usually 65-85%
Is.

Then, in step 5, the compound of formula E is oxidized and its oxidation product is reduced to a compound of formula H (5H, 8RS)-
6,9-Dihydroxy-3-isopropylnonanal dialkyl acetal is obtained. Oxidation of the compound of formula E is carried out as an oxidizing agent by adding 2
To 5 to 5 equivalents, preferably 3 equivalents of potassium permanganate are used, 0.01 to 1 equivalent, preferably 0.1 equivalent of potassium permanganate and 2 to 5 equivalents, preferably 3
With a mixture with an equivalent of sodium periodate or with a mixture of 0.1 to 1 equivalent, preferably 0.1 equivalent of osmium tetroxide and 2 to 5 equivalents, preferably 3 equivalents of sodium periodate. It can be carried out in a biphasic solvent of diethyl ether and water at a temperature of 0 ° C. to 30 ° C. for 3 hours to 5 hours. The obtained oxidation product is used in the next step without purification.

The reduction of the oxidation product is carried out by using 1 to 2 equivalents, preferably 1.2 equivalents of lithium aluminum hydride as a reducing agent, relative to 1 equivalent of the oxidation product, in an ether solvent at a temperature of 0 ° C. to 10 ° C. It can be done for 1 to 3 hours.

(-B) First, in step 6, to the sodium salt solution of the compound of formula C obtained in step 2, 1 to 2 equivalents, preferably 1.1 equivalents of alkyl bromoacetate, preferably bromo Methyl acetate is added and the reaction mixture is reacted at 50 ° C to 120 ° C for 1 hour to 5 hours to give a (3RS, 7R) -alkyl of formula F.
7-Isopropyl-9,9-dialkoxy-3-alkoxycarbonyl-4-oxononanoate is obtained. Formula F
The alkoxycarbonyl group —COOR ^{2 of} is derived from the alkyl bromoacetate used.

Next, in step 7, the compound of formula F is saponified decarboxylated by the procedure of step 4 without purification and then treated with diazomethane or in the presence of an acid catalyst (eg paratoluenesulfonic acid). Is treated with an alcohol (eg, methanol) to give (7R) -alkyl 6-isopropyl-9,9-dialkoxy-4-.
Oxononanoate is obtained. Diazomethane is used in a proportion of 1 to 2 equivalents per equivalent of the compound of formula F.
The alcohol and acid catalysts are used in proportions of 3 to 5 equivalents and 0.05 to 0.1 equivalents, respectively, relative to 1 equivalent of the compound of formula F. Compound G by this method
The yield is usually 70 to 80%.

Alternatively, the compound of formula G can be converted from the compound of formula F to the compound of formula G in one step. That is, in step 8, the compound of formula F was treated with dimethyl sulfoxide.
In a mixed solvent of (DMSO) and water, a dealkoxycarbonylation (at the 3-position) is performed by heating with a dealkoxycarbonyl agent (sodium chloride, sodium cyanide or sodium cyanide) at 100 ° C to 150 ° C for 3 hours to 5 hours. -COOR ¹ group is removed). The dealkoxycarbonyl agent is used in a ratio of 0.5 to 1 equivalent based on 1 equivalent of the compound of the formula F. This reaction gives the compound of formula G. The yield of compound G by this method is usually 60
To 70%.

Then, in step 9, the compound of formula G is treated with 1 to 2 equivalents of lithium aluminum hydride per equivalent of the compound of formula G at 0 ° C. to 20 ° C. for 1 hour to 2 hours.
Reduction over time gives the compound of formula H.

To prepare the compound of formula H from the compound of formula C, it is preferred to go through steps 3, 4 and 5. This procedure is more suitable for industrially producing compounds of formula H.

In step () 10, two hydroxyl groups of the compound of formula H are acylated with an acylating agent (carboxylic anhydride, preferably acetic anhydride, or acyl chloride, preferably acetyl chloride) in the presence of pyridine or triethylamine. The acylating agent is used in a ratio of 1.5 to 5 equivalents relative to 1 equivalent of the compound of the formula H. This acylation is carried out at 20 ° C to 50 ° C for 4 to 15 hours. This reaction gives the compound of formula I. In formula I, each R ³ is an acyl group. The compound of formula I is used in the next step without isolation.

In step (11), the compound of formula I is treated with a strong acid such as hydrochloric acid, sulfuric acid, perchloric acid, preferably hydrochloric acid at -10 ° C to 20 ° C for 5 minutes to 1 hour. The strong acid has formula I
The compound is used in a ratio of 2 to 4 with respect to 1 equivalent of the compound. This treatment gives the compound of formula J.

() In step 12, under an inert gas stream such as nitrogen or argon, an ether solvent such as diethyl ether,
The compound of formula J is condensed with an alkyl phenylthioacetate, preferably methyl phenylthioacetate, in the presence of a base catalyst in tetrahydrofuran, dimethoxyethane. As the base catalyst, n-butyllithium, lithium diisopropylamide or sodium hydride can be used. The preferred catalyst is lithium diisopropylamide. The base catalyst is used in a proportion of 1 to 1.5 equivalents relative to 1 equivalent of the compound of formula J. The condensation temperature is -60 ° C to -10 ° C, and the condensation time is 10 minutes to 1 hour. Thus, as shown by the equation K (5R, 8RS, 2E
Z) -Alkyl 8,11-diacyloxy-5-isopropyl-2-phenylthio-2-undecenoate is obtained. In Formula K, Ph represents a phenyl group, and the alkoxycarbonyl group —COOR ⁴ is derived from the alkyl acetate portion of the used phenylthioacetate alkyl.

In step () 13, deacylation is carried out by reacting a compound of formula K with an alkali metal alkoxide in an alcohol such as methanol at temperatures from room temperature to 50 ° C. As the alkali metal alkoxide, lithium alkoxide, sodium alkoxide or potassium alkoxide can be used, and sodium methoxide is preferable. The alkoxide is used in a ratio of 1 to 3 equivalents relative to 1 equivalent of the compound of the formula K. This deacylation leads to the formula (5R, 8RS, 2EZ)-
The alkyl 8,11-dihydroxy-5-isoprop-2-phenylphenyl-2-undecenoate is obtained.

() In step 14, the compound of formula L is treated with paratoluenesulfonyl chloride or alkanesulfonyl chloride in the presence of triethylamine or pyridine and dimethylaminopyridine in methylene chloride or chloroform at a temperature of 0 ° C or lower, preferably -15 ° C or lower. Preferably it is reacted with paratoluenesulfonyl chloride. Triethylamine or pyridine is used in a ratio of 2 to 4 equivalents to 1 equivalent of the compound of formula L, and dimethylaminopyridine is used in a ratio of 0.1 to 0.3 equivalents to 1 equivalent of the compound of formula L. Paratoluenesulfonyl chloride or alkanesulfonyl chloride is 1.5 per 1 equivalent of the compound of formula L.
Used at a ratio of 3 to 3 equivalents. By this reaction, the 11-position hydroxyl group of the compound of formula L is regioselectively alkylsulfonylated to obtain the compound of formula M. In formula M, R ⁵ is an alkyl group and is derived from a sulfonylating agent.

() In step 15, the compound of formula M is reacted with dihydropyran or ethyl vinyl ether in methylene chloride or chloroform at 0 ° C. to 20 ° C. using paratoluenesulfonic acid or pyridinium paratoluenesulfonate as a catalyst. The catalyst is compound 1 of formula M
It is used in a ratio of 0.05 to 0.1 equivalents relative to equivalents. Further, dihydropyran or ethyl vinyl ether is used in a ratio of 1.2 to 5 equivalents relative to 1 equivalent of the compound of the formula M. The reaction is completed in 1 to 4 hours. By this reaction, the 8-position hydroxyl group of the compound of formula M is protected by an acetal protecting group, and the compound represented by formula N (5R, 8R
S, 2EZ) -Alkyl 5-isopropyl-2-phenylthio-8-alkoxy-11-alkylsulfonyloxy-2-undecenoate is obtained. In formula N, R ⁶ is an alkyl group and is derived from an acetal protecting group.

In step () 16, in an ethereal solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane and diglyme, or an aromatic solvent such as benzene and toluene under an inert gas stream such as nitrogen or argon, a temperature of room temperature to 100 ° C. is preferable. Heats the compound of formula N in the presence of a base catalyst at 70 to 90 ° C. to reduce it. The solvent used is preferably dimethoethane. As the base catalyst, lithium, sodium or potassium diisopropylamide or bistrimethylsilylamide, or n-butyllithium and 1,4-diazabicyclo [2,2,2] octane can be used, preferably sodium bistrimethylsilylamide. is there. The base catalyst is used in a ratio of 1.2 to 1.5 equivalents relative to 1 equivalent of the compound of formula N. This dehydrogenation reaction can be carried out in 30 minutes to 1 hour. Thus, the formula O having a trans double bond in the ring
The ten-membered ring compound (1RS, 2E, 4S, 7RS) -alkyl 4-isopropyl-1-phenylthio-7-tetrahydropyranyloxy-2-cyclodecenecarboxylate is obtained. This cyclization reaction has excellent efficiency, and the yield of the cyclized compound is 60 to 70%.

In step (17), the alkoxycarbonyl group —COOR ⁴ of the compound of formula O is reduced and converted to a hydroxyl group. Specifically, the compound of formula O is reacted with the reducing agent lithium aluminum hydride for 0.5 hours to 2 hours in an ether solvent such as diethyl ether at a temperature of -10 ° C to 10 ° C. The reducing agent is used in a ratio of 1.2 to 2 equivalents relative to 1 equivalent of the compound of formula O. By this reduction, the compound represented by the formula P is obtained almost quantitatively.

In step () 18, the compound of formula P is first reacted with an acylating agent in the presence of pyridine or a mixture of triethylamine and dimethylaminopyridine in tetrahydrofuran. As the acylating agent, benzoyl chloride, p-methoxybenzoyl chloride or acetic anhydride can be used, and the amount is 1 to 5 per 1 equivalent of the compound of the formula P.
Used at the equivalent ratio. The acylation is carried out at a temperature of 0 ° C to 30 ° C for 5 hours to 10 hours. This acylation gives the compound of formula Q. In formula Q, R ⁷ is an acyl group.

() In step 19, the compound of formula Q
The acylation product of the acid catalyst such as acetic acid, hydrochloric acid, sulfuric acid or an acidic ion exchange resin (for example, Dow Chemical Co. Do
Wex 50W (H ⁺ type)) to remove the acetal protecting group. The acid catalyst is used in a proportion of 0.05 to 0.5 per equivalent of the compound of formula Q. The treatment with the acid catalyst can be carried out for 1 hour to 5 hours. Thus, the (1RS, 2E, 4S, 7RS) -7-hydroxy-4-isopropyl-1-phenylthio-2-cyclodecene-1-alkanolcarboxylic acid ester represented by the formula R is obtained.

In step (20), the compound of formula Q is reacted with a reducing agent under a stream of an inert gas such as nitrogen or argon. This reduction can be performed by three methods. The first method uses an alkali metal (metal lithium, sodium or potassium) and naphthalene as a reducing agent, and is carried out in an ether solvent such as diethyl ether, tetrahydrofuran or dimethoxyethane at a temperature of −70 ° C. or lower. . The alkali metal is used in a ratio of 5 to 10 equivalents to 1 equivalent of the compound of formula Q, and the naphthalene is used in a ratio of 5 to 10 equivalents to 1 equivalent of the compound of formula Q.

The second method uses an alkali metal (metal lithium, sodium, potassium) in liquid ammonium at a temperature of −30 ° C. or lower. The alkali metal is used in a ratio of 5 to 10 equivalents relative to 1 equivalent of the compound of formula Q.

The third method uses an amalgam of an alkali metal (metal lithium, sodium or potassium) and mercury as a reducing agent, and is performed in tetrahydrofuran at a temperature of −0 ° C. or lower. Amalgam is used in a proportion of 5 to 10 equivalents per equivalent of the compound of formula Q.

The preferred approach is the first approach, in which case it is most preferred to use sodium as the alkali metal.

By this reduction, the phenylthio group and the acyloxy group are removed from the compound of the formula R to give the compound (1RS, 4S, 5E) -4-isopropyl-of the present invention represented by the formula 1a.
7-Methylene-5-cyclodecen-1-ol is obtained.

When the compound of the present invention is reacted with an oxidizing agent in methylene chloride or chloroform at 0 ° C. to room temperature for 0.5 to 5 hours, it is an optically active substance which is an intermediate of the racemic synthesis of Schleiber et al. Yes (4S, 5E)-
4-isopropyl-7-methylene-5-cyclodecene-
1-on (Equation 2) is obtained. As the oxidizing agent, a mixture of chromic anhydride and pyrozine, a mixture of pyridinium chlorochromate and molecular sieves, pyridinium dichromate, or a mixture of dimethyl sulfoxide and oxalyl chloride can be used. The oxidant is
2 to 8 equivalents relative to 1 equivalent of the compound of formula 1.

From the compound of formula 2, the compound represented by the formula The optically active periplanone-B represented by can be produced.

Briefly, the compound of formula 2 is treated with lithium diisopropylamide or lithium bistrimethylsilylamide in an ether solvent in a stream of an inert gas such as nitrogen or argon to form an enol, and then dienyl disulfide or phenyl. Sulfenylated with ruthiobenzene sulfonate to give (4S, 5E) -4-isopropyl-7-
Methylene-10-phenylthio-5-cyclodecene-1
-Get on. This compound is oxidized with sodium periodate or hydrogen peroxide in a water-alcohol solvent at () room temperature, or m-chloroperbenzoic acid at a temperature of -20 ° C or lower in a () chlorine-based solvent. Oxidation with Sulfoxide Compound (4S, 5E) -4-isopropyl-7-methylene-10phenylsulfonyl-5-cyclodecen-1-one.

An aromatic solvent such as benzene is used as the sulfoxide compound.
Dissolve in toluene, xylene, preferably toluene, and heat at 50-150 ° C in the presence of calcium carbonate, pyridine or trimethylphosphite. This heating causes decomposition of the sulfoxide group, resulting in (8S, 2Z, 6
E) -8-Isopropyl-5-methylene-2,6-cyclodecadien-1-one is obtained.

This decomposition product is combined with an alkali metal t-butyl peroxide, preferably potassium t-butyl peroxide, in an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, preferably tetrahydrofuran under an inert gas stream such as nitrogen or argon. The reaction is carried out at ℃ to room temperature to stereoselectively epoxidize the enone moiety. By this reaction, epoxide (4S, 5
E, 9R, 10R) -9-Epoxy-4-isopropyl-7-methylene-5-cyclodecen-1-one is obtained.

This epoxide is reacted with lithium diisopropylamide or lithium bistrimethylsilylamide in an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, preferably tetrahydrofuran under an inert gas stream such as argon to obtain an enolate. This enolate is reacted with phenylselenyl bromide to give the selenide compound.

The selenide compound is oxidized with hydrogen peroxide in water-tetrahydrofuran to give a selenooxide compound (4S, 5E, 9
R, 10R) -9-epoxy-4-isopropyl-7-
Methylene-2-phenylselenenyl-5-cyclodecen-1-one is obtained.

Then, the selenooxide compound is treated with acetic anhydride-sodium acetate in tetrahydrofuran or tetrahydrofuran-pyrazine to cause selenapummeler transition to generate acetoxyselenide, which is hydrolyzed with water and potassium carbonate to produce α- Diketone compound (3
R, 4E, 8R, 9R) -8-Epoxy-3-isopropyl-6-methylene-10-oxo-4-cyclodecen-1-one is obtained.

Finally, the α-diketone compound is reacted with dimethylsulfonium methylide in an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, preferably in a mixture of tetrahydrofuran and dimethyl sulfoxide, under a stream of an inert gas such as nitrogen or argon. When,
Only one ketone is regioselectively epoxidized to give the compound of formula 3
Optically active periplanone-B is obtained.

Example 1 (1RS, 4S, 5E) -4-isopropyl-
Synthesis of 7-methylene-5-cyclodecen-1-ol (1) 200 grams of d-dihydrolimonene was suspended in a mixture of 800 milliliters of methanol and 200 milliliters of methylene chloride. While maintaining the temperature at −30 ° C. in a dry ice-acetone bath, oxygen gas containing 5% of ozone was blown into the suspension for about 6 hours under vigorous stirring to carry out ozonolysis. After the completion of ozonolysis, nitrogen gas was blown into the reaction mixture to drive off excess ozone.

The reaction mixture was cooled to −60 ° C. and a suspension of 300 milliliters of dimethyl sulphide and 20 grams of paratoluenesulfonic acid in 100 milliliters of methanol was added portionwise. The reaction mixture is stirred at -60
After reacting for about 2 hours at 0 ° C., the temperature was raised to about room temperature over about 2 hours and stirring was continued overnight. After that, the reaction mixture was neutralized with a saturated aqueous solution of sodium carbonate, and concentrated under reduced pressure to about 300 milliliter. 300 milliliters of water was added to the concentrate, and extraction was performed 3 times with 400 milliliters of diethyl ether each. The ether layers were collected, and water was added three times with 200 milliliters each and saturated aqueous sodium chloride solution was added 100 times.
It was washed with milliliter, dried over anhydrous magnesium sulfate and filtered. The ether was removed from the filtrate under reduced pressure to obtain 299 g of a crude product, which was distilled under reduced pressure (99 ° C. /
(3R) -3-isopropyl-6-oxoheptanal dimethyl acetal (compound of formula B in which each R ° is a methyl group) 288 grams purified by subjecting to 1.6 mmHg). Yield 92%. Analysis result : Boiling point 99 ° C./1.6 mmHg.

Infrared absorption spectrum (cm ^-1 ): 2980, 2900, 2850, 1740, 1720,
1470, 1440, 1390, 1370, 1255, 1195, 1165,
1125, 1055, 965, 910.

Nuclear magnetic resonance spectrum (δ, ppm): 4.31 (t, J = 5.5Hz, H-7), 3.20 (S, 5H, -0-methyl), 2.32 (d
d, J = 5,6Hz, 1H, H-9), 2.05 (s, 3H, H-1), 1.8-1.0 (6H), 0.85
(d, J = 6.5Hz, 6H, isopropyl-methyl).

(2-a-1) Sodium hydride 25 under argon flow
Grams are suspended in 500 millilitres of dry dioxane,
Dimethyl carbonate (143 g) and methanol (3.6 milliliter) were added, and the mixture was stirred under reflux. To this mixture was added a solution of 114 grams of the product of Step 1 in 90 millilitres of dry dioxane over 4 hours and further stirred at reflux overnight. By this reaction, (3R) -3-isopropyl-6-oxoheptanal dimethyl acetal is converted to a sodium salt of (6R) -methyl 6-isopropyl-8,8-dimethoxy-3-oxooctanoate, which is a Claisen condensation product. It has been converted.

(2-a-2) 72 g of allyl bromide was added to the reaction mixture of step 2-a-1 over 30 minutes, and the mixture was reacted under reflux for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into 100 g of ice, and concentrated under reduced pressure to remove dioxane. The concentrate was extracted twice with 200 milliliters of diethyl ether each time, and the ether was removed under reduced pressure to obtain the crude product (2RS, 7R) -methyl 7-isopropyl-9,9-dimethoxy-3-methoxycarbonyl-4-. 168 grams of oxononanoate was obtained.

This crude product is treated with 45 grams of potassium hydroxide in 800 parts of water.
The solution was added to milliliter and methanol in 550 milliliter, and the mixture was reacted under reflux for 1.5 hours. The reaction mixture is cooled to room temperature, extracted 6 times with 200 milliliters of diethyl ether each time, the ether phases are collected, washed with 100 milliliters of saturated aqueous sodium chloride solution, evaporated to dryness and distilled under reduced pressure (128-130 ° / 0.35 mm
Hg). Thus purified (8R) -8-isopropyl-10,10-dimethoxy-1-decene-5-
111 grams of on (a compound of formula E in which each R ⁰ is a methyl group) was obtained. Yield 82%.

Analysis results: Infrared spectrum (cm ^-1 ): 3100, 2975, 2900, 2850, 1715,
1645, 1465, 1440, 1415, 1390, 1370, 1250,
1195, 1125, 1075, 1050, 1000, 960, 915, 82
0.

Nuclear magnetic resonance spectrum (δ, ppm): 5.7 (m, 1H, H-2), 4.95 (m, 2H, H-1), 4.32 (t, J = 6Hz, 1H, H-1
0), 3.20 (s, 6H, -0-methyl), 2.6-2.0 (6H, H-3,4,6), 1.9-
1.0 (6H), 0.85 (d, J = 6,5Hz, 6H, isopropyl-methyl).

6.2 g of (2-a-3) osmium tetroxide and 327 g of sodium periodate were added to diethyl ether 1
The mixture was suspended in a mixture of liter and 1.5 liter of water, 111 g of the product of step 2-a-2 was added, and the mixture was stirred at room temperature for 4 hours. The ether phase was separated, the aqueous phase was extracted three times with 200 milliliters of diethyl ether each time, then all ether phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness. This gave 160 grams of oily product.

The oily product was dissolved in 300 mL of dry diethyl ether and pre-ice cooled lithium aluminum hydride 2
To 3.5 grams of a suspension in 800 milliliters of dry diethyl ether was added dropwise with stirring at a temperature below 10 ° C over 1.5 hours. 15% sodium hydroxide aqueous solution 30
After adding milliliter, the mixture was filtered through a Buchner funnel with tight Celite and the precipitate washed with tetrahydrofuran. All the filtrates were combined, concentrated under reduced pressure and the crude product (5R, 8RS) -6,9-dihydroxy-3-
154 grams of isopropylnonanal dimethyl acetal (compound of formula H in which each R ⁰ is a methyl group) was obtained.

The above crude product was dissolved in a mixture of 100 milliliters of acetic anhydride and 300 milliliters of pyridine without purification, and reacted overnight with stirring. Pyridine was distilled off from this reaction mixture under reduced pressure, the residue was poured into a mixture of 100 milliliters of concentrated hydrochloric acid and 200 grams of ice, stirred for 5 minutes, and extracted with 300 milliliters of ether. The ethereal phase is washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness to give 148 g of a compound of formula J in which each R ³ is a methyl group. It was Yield 80%. Analysis results : Infrared spectrum (cm ^-1 ): 3000, 2910, 2750, 1460, 1390,
1375, 1245, 1025, 970.

Nuclear magnetic resonance spectrum (δ, ppm): 9.79 (brs, 1H, H-1), 4.8 (m, 1H, H-6), 3.98 (m, 2H, H-9), 2.25
(m, 2H, H-2), 1.98 (s, 6H, -acetyl-methyl), 1.8-1.2
(10H), 0.85 (2d, J = 6.5Hz, 6H, isopropyl-methyl).

(2-b-1-i) Under an argon stream, 47 g of sodium hydride was suspended in 660 milliliters of dry dioxane, 150 milliliters of dimethyl carbonate was added, and the mixture was stirred under reflux. To this mixture was added a solution of 126 grams of the product of step 1 in 100 milliliters of dry dioxane over 4 hours and further stirred under reflux overnight. To this reaction mixture was added methyl bromoacetate 64 millilitres DMF60.
Add the solution in milliliter over 30 minutes and add 1.5
Stir under reflux for hours. Thereafter, the reaction mixture was cooled to room temperature, poured into 100 g of ice, and concentrated under reduced pressure to remove dioxane. The residue was extracted twice with 300 milliliters of ether each time, the ether phases were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give the crude product (3
RS, 7R) -Methyl 7-isopropyl-9,9-dimethoxycarbonyl-4-oxononanoate (compound of formula F wherein each R ⁰ , R ¹ and R ² is a methyl group)
Got 207 grams.

The above crude product was added to a solution of sodium hydroxide in 900 milliliters of water and 600 milliliters of methanol without purification, and reacted under reflux for 1.5 hours. Then, the reaction mixture was cooled to room temperature, and the pH was adjusted to 6 with 1N hydrochloric acid under ice cooling.
It was extracted 6 times with 0 milliliter. After combining all the ether phases and washing it with saturated aqueous sodium chloride solution,
After evaporating to dryness, 200 milliliters of benzene was added and evaporation to dryness was repeated twice. The residue was dissolved in 500 milliliters of dry diethyl ether, and a solution of diazomethane in diethyl ether was added under ice-cooling until the color of diazomethane disappeared. Acetic acid was added to the reaction mixture until the color of diazomethane disappeared to decompose excess diazomethane,
Wash successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give (7R) -methyl 6-isopropyl-9,9-dimethoxy-4-oxononanoate. (Compound of Formula G wherein each R ⁰ and R ² is a methyl group) 121
Got gram. Yield 72%.

Analysis result: Infrared spectrum (cm ^-1 ): 2980, 2900, 2850, 1745, 1725,
1670, 1470, 1400, 1390, 1375, 1200, 1170,
1130, 1060, 965, 910.

Nuclear magnetic resonance spectrum (δ, ppm): 4.30 (t, J = 5,5Hz, H-9), 3.58 (s, 3H, ester-0-methyl), 3.17 (s, 6H, acetal-0-methyl) , 2.6-2.1
(6H, H-2,3,5), 1.7-1.1 (6H), 0.85 (d, J = 6.5Hz, 6H, isopropyl-methyl).

Under a stream of (2-b-1-) argon, 20 grams of sodium hydride was suspended in 200 milliliters of dry dioxane, 60 milliliters of dimethyl carbonate was added, and the mixture was stirred under reflux. To this mixture was added a solution of 48 grams of the product of step 1 in 50 milliliters of dry dioxane over 4 hours and further stirred at reflux overnight. In this reaction mixture,
A solution of 30 milliliters of methyl bromoacetate in 30 milliliters of DMF was added over 30 minutes, and the mixture was further stirred under reflux for 1.5 hours. Thereafter, the reaction mixture was cooled to room temperature, poured into 100 g of ice, and concentrated under reduced pressure to remove dioxane. The residue is diethyl ether 100 each
Extracted twice with millilitre, combined the ether phases, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to dryness to obtain the crude product (3RS, 7R) -methyl 7- Isopropyl-9,9
37 grams of -dimethoxy-3-methoxycarbonyl-4-oxononanoate were obtained.

The crude product was purified without purification to 6 grams of sodium chloride, 5 milliliters of water and 6 grams of dimethyl sulfoxide.
Mix into a mixture of 0 millilitre and stir at reflux for 4 hours. Then, the reaction mixture was allowed to cool, 50 milliliters of water was added, the mixture was extracted twice with 100 milliliters of diethyl ether each time, the ether phases were combined, washed three times with water, and further washed with saturated aqueous sodium chloride solution, and anhydrous sulfuric acid was added. Dry over magnesium, evaporate to dryness (7R)-
Methyl 6-isopropyl-9,9-dimethoxy-4-
42 grams of oxononanoate was obtained. Yield 65%. This compound gave the same analytical result as the compound obtained in the step (2-b-1-i).

(2-b-2) 120 grams of (7R) -methyl 6-isopropyl-9,9-dimethoxy-4-oxononanoate obtained above was dissolved in 100 milliliters of dry diethyl ether and pre-ice cooled lithium hydride. A suspension of 18 grams of aluminum in 900 milliliters of dry diethyl ether was added dropwise with stirring at a temperature below 10 ° C over 30 minutes. After adding 10 milliliters of a 15% aqueous sodium hydroxide solution, the mixture was filtered through a Buchner funnel with tight Celite, and the precipitate was washed with tetrahydrofuran. All the filtrates were combined, concentrated under reduced pressure, and the crude product (5R, 8R
S) -6,9-Dihydroxy-3-isopropylnonanal dimethyl acetal (formula H in which each R ⁰ is a methyl group)
Compound of 3) was obtained. Yield 95% The above crude product was dissolved in a mixture of 150 milliliters of acetic anhydride and 1.2 liters of pyridine without purification, and reacted overnight with stirring. Pyridine was distilled off from this reaction mixture under reduced pressure, and the residue was put into a mixture of 100 milliliters of concentrated hydrochloric acid and 100 grams of ice, stirred for 5 minutes, and extracted twice with 200 milliliters of ether. The ether phase was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give 92 g of a compound of formula J in which each R ³ group is an acetyl group. Obtained. Yield 95%. This compound gave the same analytical results as the product of step (2-a-3).

(3) Dissolve 41 milliliters of diisopropylamine in dry tetrahydrofuran under an argon stream and -10 ° C.
After cooling to 1.70 nM, 173 milliliter of 1.66N n-butyllithium solution was added dropwise to prepare a solution of lithium diisopropylamide. The solution was cooled to below -60 ° C in a dry ice-acetone bath and a solution of 52 grams of methyl phenylthioacetate in 100 millilitres of dry tetrahydrofuran was added with stirring. After stirring this mixture for 1 hour, a solution of 69 grams of the compound of formula J in 200 millilitres of dry tetrahydrofuran was added dropwise at a temperature below -60 ° C. The reaction mixture was allowed to react for 20 minutes.

Thereafter, the reaction mixture was mixed with a saturated aqueous solution of ammonium chloride 1
00 milliliters, then saturated aqueous sodium chloride solution 5
After dropping 0 millilitre, the solution was concentrated under reduced pressure to about 150 millilitre. The concentrate was extracted twice with 200 milliliters of diethyl ether each time, the ether phase was washed with water and saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 130 g of an oily product. .

Without purification of the oily product, 600 milliliters of acetic anhydride and 18 grams of anhydrous sodium acetate were mixed and heated in an oil bath preheated to 140 ° C. with stirring for 1 hour. After the reaction mixture was allowed to cool, it was poured onto 300 g of ice and 500 milliliters of diethyl ether was added.
With stirring, sodium carbonate was added little by little to neutralize. The ether phase is separated, washed with water and saturated sodium chloride, dried over anhydrous magnesium sulfate, evaporated to dryness (5R, 8RS, 2EZ) -methyl 8,11-diacetyloxy-5-isopropyl-3-. 90 grams of phenylthio-2-undecenoate (compound of formula K in which each R ³ and R ⁴ is a methyl group) was obtained. Yield 84%.

Analysis results: Infrared spectrum (cm ^-1 ): 2970, 2950, 2880, 1740, 1720,
1615, 1585, 1480, 1460, 1370, 1240, 1040,
1025, 790, 760, 760, 740, 690.

Nuclear magnetic resonance spectrum (δ, ppm): 7.20 (m, 1H, H-3), 7.18 (s, 5H, -S-phenyl), 4.75 (m, 2H,
H-11), 3.57 (s, 3H, ester-0-methyl), 2.4 (m, 2H, H
-4), 1.98 (s, 6H, acetyl-methyl), 1.8-1.1 (10H), 0.8
7 (d, J = 6Hz, 6H, isopropyl-methyl).

(4) 90 grams of the product of step 3 was dissolved in 1 liter of a 1% sodium methylate solution in methanol and refluxed for 1 hour. The reaction mixture was allowed to cool, neutralized with 2N hydrochloric acid, and concentrated under reduced pressure to about 150 milliliter. Add 100 milliliters of water to the concentrate, and add 2 diethyl ether each.
Extraction three times with 00 millilitre, the ether phases were combined, washed with water and saturated aqueous sodium chloride solution and evaporated to dryness to give 64 g of crude product. Using hexane-ethyl acetate as the eluent, the crude product was purified by silica gel 20.
Chromatograph at 0 grams. Fractions eluted with hexane-ethyl acetate (1: 2) were collected, concentrated and purified (5R, 8RS, 2EZ) -methyl 8,11-dihydroxy-5-isopropyl-2-phenylthio-2.
- undecenoate (R ⁴ is a compound of formula L is a methyl group)) to give 49 grams. Yield 66%.

Analysis result: Infrared spectrum (cm ^-1 ): 3375, 2975, 2900, 1730, 1720,
1610, 1590, 1480, 1470, 1440, 1390, 1375,
1255, 1045, 1035, 910, 745, 695.

Nuclear magnetic resonance spectrum (δ, ppm): 7.20 (m, 1H, H-3), 7.13 (s, 5H, -S-phenyl), 4.22 (m, 1H,
H-8), 3.53 (s, 3H, ester-methyl), 3.4 (m, 2H, H-11),
2.6-2.3 (m, 2H, H-4), 1.9-1.0 (10H), 0.85 (s, J = 6.5Hz, 6H,
Isopropyl-methyl).

(5) 25 grams of the product of step 4, triethylamine 2
3 milliliters and 4.8 grams of dimethylaminopyridine were dissolved in 150 milliliters of dry methylene chloride. This solution was placed in a dry ice-carbon tetrachloride bath at -22 ° C.
Cooled to 20 ° C. and stirred under paratoluenesulfonyl chloride 20
A solution of 20 g of dry methylene chloride in 20 milliliter was added dropwise, and the mixture was reacted at a temperature of -15 ° C or lower for 2.5 hours. To this reaction mixture was added 20 grams of ice and 100N 1N hydrochloric acid.
Milliliter was added, and the mixture was extracted twice with 200 milliliters of diethyl ether each. The ether phases are collected, washed with aqueous sodium carbonate solution and saturated aqueous sodium chloride solution,
It was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness.

The residue was dissolved in a solution of 30 milliliters of dihydropyran in 120 milliliters of dry methylene chloride, and 1 g of pyridinium paratoluenesulfonate was added while stirring under ice cooling. Then, the temperature of the reaction mixture was raised to room temperature and the reaction was carried out for 2 hours. The reaction mixture was filtered using 50 grams of Florisil, the Florisil was washed with methylene chloride, the filtrate and washings were combined and evaporated to dryness to give 56 grams of crude product. Using n-hexane-ethyl acetate as an elution solvent, the crude product was purified by silica gel 6
Column chromatography using 00 grams. Fractions eluting with n-hexane-ethyl acetate (8: 2) were collected, evaporated to dryness and purified (5R, 8RS, 2).
EZ) -Methyl 5-isopropyl-2-phenylthio-8-methoxy-11-methylsulfonyloxy-2-
33 grams of undecenoate (a compound of formula N in which R ^4, R ⁵ and R ⁶ are each a methyl group) were obtained. Yield 8
1%.

(6) Under an argon stream, 4.6 g of sodium bistrimethylsilylamide was dried over 400 g of dimethytoxyethane.
It was dissolved in milliliter and refluxed. To this solution was added 12.0 grams of the product of step 5 dry dimethoxyethane 40.
The solution in 0 milliliter was added dropwise under reflux over 40 minutes. After the dropping, the reaction mixture was immediately cooled to room temperature, and saturated ammonium chloride aqueous solution (5 milliliter) was added thereto.
It concentrated under reduced pressure to a milliliter.

This concentrate was extracted twice with 150 millilitres of diethyl ether each time, the ether phases were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated to dryness and the crude cyclized product was obtained. I got 3 grams.
The crude product was subjected to column chromatography using 100 g of silica gel using n-hexane-ethyl acetate as an elution solvent. Fractions eluted with n-hexane-ethyl acetate (85:15) were collected, evaporated to dryness and purified (IRS, 2E, 4S, 7RS) -methyl 4
- isopropyl-1-phenylthio-7-tetrahydropyranyloxy-2-cyclopropyl-decene carboxylate (compound of the formula 0 ^{R 4} and ⁶ are methyl groups) 5,6
Got gram. Yield 62%. This series of operations was repeated 3 times to obtain a total of 16.8 grams of product.

Analysis result: Nuclear magnetic resonance spectrum (δ, ppm): 7.30 (s, 5H, -S-phenyl), 5.50 (m, 2H, H-2,3) 4.52 (m, 1
H, tetrahydropyran-6), 2.3-1.0 (m, 18H), 0.9 (m, 3
H, isopropyl-methyl).

(7) 2.08 g of lithium aluminum hydride was suspended in 600 milliliters of dry diethyl ether, and 16.3 g of the cyclized product of Step 6 was added dropwise over 10 minutes while stirring under ice cooling. After stirring for 1 hour, 3 ml of 15% aqueous sodium hydroxide solution was added dropwise to the reaction mixture, the mixture was filtered through a Buchner funnel, and the precipitate on the funnel was washed with tetrahydrofuran. The filtrate and washings are combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give the desired product (compound of formula P in which R ⁶ is a methyl group) 15 Got 6 grams. The yield was quantitative.

The above product was mixed with 90 milliliters of pyridine, 2.3 grams of dimethylaminopyridine and 250 milliliters of dry tetrahydrofuran, and a solution of 8.7 grams of benzoyl chloride in 30 milliliters of pyridine was added dropwise over 20 minutes while stirring under ice cooling. did. Raise the temperature to room temperature,
The reaction mixture was allowed to react overnight with stirring. Pour the reaction mixture into ice water and add 2 to 200 milliliters of ether each.
Extracted twice. The ether phases were collected, washed with saturated aqueous sodium chloride solution, and concentrated under reduced pressure to remove pyridine.
To the residue was added 100 milliliters of water, extracted with 300 milliliters of ether, the ether phase was washed 3 times with an aqueous solution of copper sulfate, further washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered, Concentrated to give about 20 grams of crude product.

Add 50 milliliters of benzene to all the crude products,
Concentration under reduced pressure was performed twice. Concentrate the methanol 200
Dissolve in Milliliter and add 20 grams of Dowex 50W (H ⁺ type) (acid ion exchange resin manufactured by Dow Chemical Co.),
The mixture was stirred at 40 ° C for 3 hours. After filtering off the ion exchange resin, the reaction mixture was evaporated to dryness to give 16.5 grams of crude product. The crude product was subjected to column chromatography using 100 g of silica gel, using n-hexane-ethyl acetate as the eluting solvent. Fractions eluting with n-hexane-ethyl acetate (8: 2) were collected and evaporated to dryness to give the desired compound (compound of formula Q where R ⁶ is methyl and R ⁷ is acetyl) 12. I got 7 grams. Yield 81
%.

(8) Under an argon stream, 14 g of naphthalene was dissolved in 400 milliliters of dry tetrahydrofuran, and 2.3 g of fine metallic sodium was added. This mixture was reacted at room temperature for 4 hours to completely dissolve sodium, thereby preparing a black-green sodium naphthalenide solution. The solution was cooled to -70 ° C in a dry ice-acetone bath. Add the product of Step 7 under stirring to the cooled solution.
A solution of 5 g of dry tetrahydrofuran in 50 milliliter was added all at once, and the reaction was carried out for 5 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture until the color disappeared.

The mixture was concentrated under reduced pressure, 10 milliliters of water was added,
It was extracted twice with 50 milliliters of diethyl ether each.
The ether phases were collected, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was subjected to column chromatography using n-hexane-ethyl acetate as an eluting solvent and 100 g of alumina (activity II). n-hexane-
After eluting naphthalene with ethyl acetate (95: 5),
Fractions eluting with n-hexane-ethyl acetate (8: 2) were pooled, evaporated to dryness and purified to give the compound of this invention, purified (1RS, 4S, 5E) -4-isopropyl-7-methylene-. 12.8 grams of 5-cyclodecen-1-ol were obtained. Yield 80%.

Analysis result: Specific rotation ▲ [α] ²² _D ▼ -253 ° (c = 1.85,
n-hexane) Infrared spectrum (cm ^-1 : 3375, 3100, 2980, 2960, 1755)
(W), 1730 (W), 1640, 1615, 1470, 1450, 1390,
1375, 1315, 1240, 1180, 1060, 1040, 995, 9
45,890.

Nuclear magnetic resonance spectrum (δ, ppm): 5.98 (d, J = 16Hz, 1H, H-6), 5.50 (dd, J = 16Hz, 10Hz, 0.5H, H-
5), 5.25 (dd, J = 16Hz, 9Hz, 0.5H, H = 5 '), 4.77 (brs, 2H, exomethylene), 3.83 (m, 0.5H, H-1), 3.55 (m, 0.5H , H-1 '),
2.26 (m, 3H, H-4,8), 2.0-1.0 (10H),-0.88 (m, 6H, isopropylmethyl).

Example 2 Synthesis of Optically Active Periplanone-B (1) Example 1 was added to a suspension of 6.3 grams of chromic anhydride, 9.5 milliliters of pyridine and 10 grams of Molecular Sieve 3A in 160 milliliters of dry methylene chloride. 2.16 grams of a compound of this invention obtained in
Stir at room temperature for about 30 minutes. Thereafter, 200 milliliters of diethyl ether was added to the reaction mixture, and filtration was performed using 20 g of florisil. Florisil was washed with diethyl ether, the filtrate and washings were combined and evaporated to dryness to give 2.8 grams of crude product. Fractions eluting with n-hexane-ethyl acetate (97: 3) as the eluting solvent were collected, evaporated to dryness and purified (4S, 5E) -4-isopropyl-7-methylene-5-cyclodecene-1. -On 2.26 grams were obtained. Yield 86%.

Analysis results: Specific rotation ▲ [α] ²² _D ▼ -362 ° (c = 1, n-hexane).

Infrared spectrum (cm ^-1 ): 3100, 2980, 2900, 1715, 1650
(W), 1615, 1465, 1430, 1390, 1
370, 1330, 1260, 1215, 1185, 1155, 1120, 1095, 1055, 1010,
985,880,600 Nuclear magnetic resonance spectrum (δ, ppm): 5.98 (d, J = 16Hz, 1H, H-6), 5.10 (dd, J = 16Hz, 10Hz, 1H, H-5),
4.76 (s, 2H, exomethylene), 2.6-1.0 (12H), 0.85 (d, J =
6.5Hz, 3H), isopropyl-methyl), 0.78 (d, J = 6.5Hz, 3
H, isopropyl-methyl).

(2) Hexamethyldisalazan (HM
D) 2.7 milliliters of dry tetrahydrofuran 50
Dissolve in milliliter and, under ice cooling, 1.72 normal n-
A lithium bistrimethylsilylamide solution was prepared by dropping 7.3 milliliter of n-hexane solution of butyllithium. The solution was cooled to -70 ° and, under stirring, 2.0 grams of the product of Step 1 dry tetrahydrofuran 5
The solution in milliliter was added dropwise, and the mixture was further stirred for 1 hour.
The reaction mixture was added all at once with stirring to a solution of 3.16 grams of pre-ice cooled phenylthiobenzene sulfonate in 40 milliliters of dry tetrahydrofuran. After stirring for 10 minutes, 5 ml of saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. To the residue, add 50 milliliters of water and add 50 parts of diethyl ether each.
It was extracted three times with milliliter. Collect the ether phase, water,
It was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness (4R, 5E) -4-isopropyl-
7-Methylene-10-phenylthio-5-cyclodecen-1-one was obtained.

The obtained product was stirred without purification in a mixed solvent of 35 milliliters of water and 170 milliliters of methanol with 3.5 g of sodium periodate at room temperature for 20 hours. The reaction mixture was filtered and the precipitate was washed with methanol. The filtrate and the washing solution were combined and concentrated under reduced pressure. 50 milliliters of water was added to this concentrate, and extraction was performed 3 times with 50 milliliters of diethyl ether each. The ether phases were collected, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous potassium carbonate and evaporated to dryness to give 3.1 g of crude product.

The crude product was subjected to column chromatography using 200 g of alumina (Activity II) using n-hexane-ethyl acetate as an elution solvent. n-hexane-
Fractions eluting with ethyl acetate (3: 2) were collected, evaporated to dryness and purified (4S, 5E) -4-isopropyl-.
2.66 grams of 7-methylene-10-phenylsulfinyl-5-cyclodecen-1-one were obtained. Yield 83
%.

(3) 2.6 g of the product of step 2 was dissolved in 200 milliliters of toluene, 2.5 g of calcium carbonate was added, and the mixture was refluxed for 5 hours under a nitrogen stream. Thereafter, the reaction mixture was filtered to remove calcium carbonate, and the filtrate was concentrated under reduced pressure to 5 milliliter. Hexane 10 millilitre was added to the concentrate. Using n-hexane-ethyl acetate as an elution solvent, this mixture was mixed with alumina (Activity II) 1
Column chromatography using 00 grams. Fractions eluting with n-hexane-ethyl acetate (95: 5) were collected, evaporated to dryness and purified (8S, 2Z,
6E) -8-Isopropyl-5-methylene-2,6-diclodecadien-1-one (760 mg) was obtained. Yield 47%.

Analysis result: Nuclear magnetic resonance spectrum (δ, ppm): 5.58 (d, J = 11Hz, 1H, H-7), 5.77 (dd, J = 15Hz, 1H, H-6), 5.45
(ddd, J = 11.4Hz, 10.7Hz, 7Hz, 1H, H-3), 5.32 (dd, J = 15Hz, 11
Hz, 1H, H-7), 4.87 (s, 1H, exomethylene), 4.80 (s, 1H,
Exomethylene), 3.69 (dd, J = 12Hz, 11Hz, 1H, H-4), 2.57
(dd, J = 12Hz, 7Hz, 1H, H-4H '), 2.16 (m, 1H, H-10), 2.12 (m, 1
H, H-8), 1.91 (dd, J = 14Hz, 5Hz, 1H, H-10 '), 1.54 (m, 2H, H-
9), 1.45 (m, 1H, isopropyl-H), 0.89 (d, J = 6.7Hz, 3H, isopropyl-methyl), 0.88 (d, J = 6.7Hz, 3H, isopropyl-methyl).

(4) Dry tetrahydrofuran 150 under argon flow
730 milligrams of potassium hydride was suspended in milliliter, and 9 milliliter of a toluene solution of 4N t-butyl hydroperoxide was added while stirring under ice cooling.
Stir for 5 minutes. To this mixture was added the product of Step 3 750
A solution of milligrams of dry tetrahydrofuran in 10 milliliters was added dropwise. The temperature was raised to room temperature and the reaction mixture was stirred for 1 hour. After completion of the reaction, 10 g of ice was added, and the mixture was extracted 4 times with 100 milliliters of diethyl ether each.
The ether phases were collected, washed with saturated aqueous sodium sulfite solution, and concentrated under reduced pressure.

50 milliliters of water was added to the concentrate, and the mixture was extracted twice with 100 milliliters of diethyl ether each. The ether phases were collected, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous potassium carbonate, and evaporated to dryness to give a crude product. The crude product was subjected to column chromatography using 100 g of alumina (Activity II) using n-hexane-ethyl oxylate as an elution solvent. Fractions eluting with n-hexane-ethyl acetate (9: 1) were collected, evaporated to dryness and purified (4S, 5E, 9R, 10R) -epoxy-4-.
Isopropyl-7-methylene-5-cyclodecene-1-
On 660 milligrams were obtained. Yield 82%.

Analysis results: melting point 39-41 ° C. Specific rotation ▲ [α] ²² _D ▼ -347 ° (c = 1.30,
n-hexane) Infrared spectrum (cm ^-1 ): 3100, 2980, 2950, 2890, 1725,
1655, 1615, 1470, 1445, 1415, 1370, 1325,
1255, 1205, 1185, 1120, 1085, 1065, 1025
980, 895, 860, 815, 800.

Nuclear magnetic resonance spectrum (δ, ppm, 500MHz, benzene _{-d 6): 5.74 (d,} J = 16Hz, 1H, H-6), 5.08 (dd, J = 10Hz, 16Hz, 1H, H-5),
4.84 (s, 1H, exomethylene), 4.82 (s, 1H, exomethylene), 3.11 (d, J = 5Hz, 1H, H-10), 2.86 (ddd, J = 4Hz, 5Hz, 1
0Hz, 1H, H-9), 2.60 (dd, J = 3Hz, 13Hz, 1H, H-8), 2.44 (dd, J = 1
0Hz, 13Hz, 1H, H-8 '), 2.16 (m, 1H, H-4), 1.93 (dd, J = 12Hz, 1
6Hz, 1H, H-2), 1.72 (dd, J = 7Hz, 1H, H-2 '), 1.45 (m, 1H, isopropyl-H), 1.37 (m, 2H, H-3), 0.83 (d , J = 6Hz, 3H, isopropyl-methyl), 0.83 (d, J = 6Hz, 3H, isopropyl-methyl).

(5) Under an argon stream, 0.38 milliliter of HMD was dissolved in 16 milliliters of dry tetrahydrofuran, and 1.02 milliliter of n-hexane solution of 1.72N n-butyllithium was added dropwise under ice cooling, and a lithium bistrimethylsilylamide solution was added. Was prepared. -7 this solution
After cooling to 0 ° and under stirring, a solution of 300 milligrams of the product of step 4 in 4 millilitres of dry tetrahydrofuran was added dropwise and stirred for a further 30 minutes. To this reaction mixture, 5.8 milliliters of a 0.33N tetrahydrofuran solution of phenylselenyl bromide was added with stirring and reacted for 10 minutes. The reaction mixture was put on ice and extracted twice with 50 milliliters of diethyl ether each. The ether phases were collected, washed with water and saturated sodium chloride, dried over anhydrous potassium carbonate and evaporated to dryness to give the crude product.

The crude product was subjected to column chromatography using 40 g of alumina (activity II) using n-hexane-ethyl acetate as an elution solvent. Fractions eluting with n-hexane-ethyl acetate (97: 3) were collected and evaporated to dryness to give 416 mg of purified selenide compound. Yield 85%.

(6) 200 milligrams of the selenide compound of step 5 was dissolved in 1 milliliter of tetrahydrofuran, 0.5 milliliter of 35% hydrogen peroxide solution was added with stirring under ice cooling, and then 2 drops of pyridine was added. The temperature was raised to room temperature and the reaction mixture was allowed to react for 1 hour with stirring.
After completion of the reaction, the reaction mixture was diluted with 10 milliliters of ethyl acetate, cooled with ice, and 5 milliliters of 10% sodium sulfite aqueous solution was added dropwise. The organic phase is separated, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous potassium carbonate, evaporated to dryness and unstable (4S, 5E, 9R,
10R) -9-epoxy-4-isopropyl-7-methylene-2-phenylselenenyl-5-cyclodecene-1
-Given 208 milligrams on. Yield 88%.

(7) 109 milligrams of sodium acetate was suspended in 2.7 milliliters of dry tetrahydrofuran and 100 milligrams of the product of step 6 was added. 0.14 milliliter of acetic anhydride was added dropwise to this mixture while stirring under ice cooling, the temperature was immediately raised to room temperature, and the mixture was stirred for 2 hours. To this reaction mixture, 2 milliliters of methanol was added and stirred for 5 minutes, then 2 milliliters of saturated potassium carbonate aqueous solution was added and further stirred for 2 hours. The reaction mixture was extracted twice with 20 milliliters each of diethyl ether. The ether phases were collected, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous potassium carbonate and evaporated to dryness to give 54 mg of crude product.

The crude product was subjected to column chromatography using 20 g of alumina (Activity II) using n-hexane-ethyl acetate as an eluting solvent. Fractions eluting with n-hexane-ethyl acetate (98: 2) were collected, evaporated to dryness and purified (3S, 4E, 8R, 9R) -8-epoxy-3-isopropyl-6-methylene-. 26 mg of 10-oxo-4-cyclodecen-1-one were obtained. Yield 60%.

Analysis result: Specific rotation ▲ [α] ²³ _D ▼ -424 ° (c = 0.44,
n-hexane).

Infrared spectrum (cm ^-1 ): 3100, 2980, 2950, 2900, 1725,
1710, 1645, 1615, 1470, 1455, 1430, 1410,
1390, 1375, 1305, 1260, 1245, 1170, 1115,
1075, 1045, 1030, 1010, 985, 960, 925, 90
5,880,850, 800,755.

Nuclear magnetic resonance spectrum (δ, ppm, 500MHz, benzene _{-d 6): 5.65 (d,} J = 16Hz, 1H, H-5), 5.14 (dd, J = 11Hz, 16Hz, 1H, H-4),
4.76 (s, 1H, Exomethylene), 4.71 (s, 1H, Exomethylene), 4.34 (d, J = 5Hz, 1H, H-9), 3.33 (dd, J = 10Hz, 11Hz, 1H,
H = 7), 2.78 (ddd, J = 3Hz, 5Hz, 10Hz, H-8), 2.52 (dd, J = 3Hz, 11
Hz, 1H, H-7 '), 2.16 (dd, J = 10Hz, 14Hz, 1H, H-2), 2.14 (dd, J
= 6Hz, 10Hz, 1H, H-2 '), 1.84 (m, 1H, H-3), 1.21 (m, 1H, isopropyl-H), 0.67 (d, J = 7Hz, 3H, isopropyl-methyl), 0.68 (d, J = 6Hz, 3H, isopropyl-methyl).

(8) Under a stream of argon, 22 mg of trimethylsulfonium iodide, 1 ml of dimethyl sulfoxy and 3 mg of sodium hydride were stirred to prepare a solution of dimethylsulfonium methylide. This solution was added dropwise to a solution of 25 milligrams of the product of step 7 in 1 milliliter of tetrahydrofuran under ice cooling and reacted for 5 minutes. 1 milliliter of water was added to the reaction mixture, and the mixture was extracted with 15 milliliters of diethyl ether. The ethereal phase was washed twice with water, saturated aqueous sodium chloride solution, dried over anhydrous potassium carbonate and evaporated to dryness to give the crude product.

The crude product was subjected to column chromatography using 1 g of alumina (activity II) using n-hexane-ethyl acetate as an elution solvent. Fractions eluting with n-hexane-ethyl acetate (98: 2) were collected, evaporated to dryness and purified optically active periplanone-B crystals 14.0.
Got milligrams. Yield 53%.

Analysis results: melting point 47-50 ° C. Specific rotation ▲ [α] ²³ _D ▼ -667 ° (c = 0.13,
n-hexane).

Infrared spectrum (cm ^-1 ): 3075, 2350, 2925, 2870, 1705
1695, 1655 (W), 1645 (W), 160
5, 1455, 1420, 1380, 1360, 132
5,1300,1270,1245,1225,116
0,1110,1100,970,935,905,890,850,835,8
15, 805, 790, 720, 710, 695.

Nuclear magnetic resonance spectrum (δ, ppm, 500 MHz, in carbon disulfide).

5.91 (brd, J = 16Hz, 1H, H-5), 5.78 (dd, J = 16Hz, 10Hz, 1H, H-
6), 5.02 (brs, 1H, H-15), 4.87 (brs, 1H, H-15 '), 3.52 (d, J =
4Hz, 1H, H-1), 2.84 (d, J-6Hz, 1H, H-14), 2.68 (ddd, J = 8Hz, 6
Hz, 4Hz, 1H, H-2), 2.63 (d, J = 6Hz, 1H, H-14 '), 2.58 (d, J = 12
Hz, 2H, H-3), 2.55 (dd, J = 11.5Hz, 10Hz, 1H, H-8), 2.08 (m, 1
H, H-7), 2.04 (dd, J = 11.5Hz, 5.5Hz, 1H, H-8 '), 1.56 (m, 1H,
H-11), 0.92 (d, J = 6.5Hz, 3H, isopropyl-methyl), 0.
87 (d, J = 6.5Hz, 3H, isopropyl-methyl).

Industrial Applicability As described above, the compound of the present invention can be produced as an optically active substance by a method suitable for industrial scale production, and the yield is excellent. Therefore, the compound of the present invention is very useful as an intermediate in the production of optically active periplanone-B on an industrial scale.

Claims (2)

[Claims] 1. A formula 4-isopropyl-7-methylene-5-cyclodecen-1-ol represented by 2. The compound according to claim 1, which is (IRS, 4S, 5E) -4-isopropyl-7-methylene-5-cyclodecen-1-ol.