JP2786900B2 - Cyclopentene derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a cyclopentene derivative.

The cyclopentene derivatives provided by the present invention are novel and have antimicrobial activity themselves or are easily converted to compounds having antimicrobial activity. Therefore, the cyclopentene derivative provided by the present invention is useful as an active ingredient of an antibacterial agent or a synthetic intermediate thereof. The cyclopentane derivative provided by the present invention is also useful as a constituent of the chromophore skeleton of neocarzinostatin.

[Prior Art] Neocarzinostatin containing a cyclopentene derivative having a diyne structure in a side chain as a chromophore has been clinically used as an anticancer agent and is also known to have antibacterial activity [Tetrahedron Letters] (Tetr
ahedron Letters), Vol. 29, p. 909 (1988)].

[Problems to be Solved by the Invention] Although the above neocarzinostatin is produced by fermentation, separation and purification are complicated, and it is difficult to obtain high purity and uniform quality while securing it. In addition, since the chromophore portion, which is the active body of neocarzinostatin, is extremely unstable in the absence of the inclusion protein, it is not easy to remove the chromophore portion while maintaining the activity.

Accordingly, an object of the present invention is to provide a novel cyclopentene derivative having a diyne structure in a side chain, which is a synthetic intermediate of the above-mentioned cyclopentene derivative constituting the chromophore skeleton of neocarzinostatin. Another object of the present invention is to provide a novel cyclopentene which can be easily obtained in high purity by a chemical method, has antibacterial activity, and has a diyne structure in a side chain having relatively high stability. It is to provide a derivative and a compound useful as a synthetic intermediate thereof.

[Means for Solving the Problems] According to the present invention, the above object is achieved by the general formula (I) (Wherein, R represents a hydrogen atom or a lower alkyl group;
And Y each represent a hydroxyl group which may be protected) [Hereinafter, this is referred to as cyclopentene derivative (I)], a general formula (II) (Wherein R and X are as defined above) [hereinafter referred to as cyclopentene derivative (II)], a general formula (III) (Wherein, R is as defined above, Z ¹ represents a hydroxyl group or a halogen atom, and Z ² represents a hydroxyl group which may be protected.) [Hereinafter, this is referred to as a cyclopentene derivative. (III)], general formula (IV) (Wherein R and Y are as defined above) [hereinafter referred to as cyclopentene derivative (IV)] and a general formula (V) (Wherein X is as defined above), which is achieved by providing a cyclopentene derivative (hereinafter referred to as cyclopentene derivative (V)).

The cyclopentene derivative (IV) constitutes the chromophore skeleton of neocarzinostatin. The cyclopentene derivative (I), the cyclopentene derivative (IV) and the cyclopentene derivative (V) have antibacterial activity. The cyclopentene derivative (II) is a synthetic intermediate of the cyclopentene derivative (I), and the cyclopentene derivative (III) is a synthetic intermediate of the cyclopentene derivative (II).

R, X, Y, Z ¹ and Z ² in each of the above general formulas will be described in detail below.

As the lower alkyl group represented by R in the general formulas (I), (II), (III) and (IV),
Examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.

The protected hydroxyl group represented by X in the general formulas (I), (II) and (V) and Y in the general formulas (I) and (IV) achieves the purpose of protecting the hydroxyl group. As long as it is a hydroxyl group protected by any commonly used protecting group, it may be used. Examples of the protected hydroxyl group include a trisubstituted silyloxy group, an optionally substituted alkoxymethoxy group, an acyloxy group, and an alkoxycarbonyloxy group. Here, as the trisubstituted silyloxy group, for example, trimethylsilyloxy group, triethylsilyloxy group, triisopropylsilyloxy group, trialkylsilyloxy group such as tert-butyldimethylsilyloxy group; tert-butyldiphenylsilyloxy group and the like Examples of the alkoxymethoxy group which may have a substituent include a diarylalkylsilyloxy group and the like, for example, a methoxymethoxy group, a methoxyethoxymethoxy group, a 1-ethoxyethoxy group, a 1-methoxy-1-methylethoxy group 1-
Alkoxyalkoxy groups; 2-oxacycloalkyloxy groups such as tetrahydropyran-2-yloxy group and tetrahydrofuran-2-yloxy group; and the acyloxy groups include, for example, acetoxy group, propionyloxy group, butyryloxy, isobutyryl Oxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group, benzoyloxy group, monochloroacetoxy group, trifluoroacetoxy group, and the like.Examples of the alkoxycarbonyloxy group include, for example, methoxycarbonyloxy group, ethoxycarbonyloxy group, Lower alkoxycarbonyloxy groups such as isopropyloxycarbonyloxy group; allenoxycals such as phenoxycarbonyloxy group and p-methoxyphenoxycarbonyloxy group Niruokishi group; benzyloxycarbonyl group, etc. aralkyloxycarbonyl group such as a p- nitrobenzyloxycarbonyl group and the like.

The halogen atom represented by Z ¹ in formula (III), chlorine atom, bromine atom, and an iodine atom. Preferable examples of the protected hydroxyl group represented by Z ² in the general formula (III) include the above-mentioned groups exemplified as the protected hydroxyl group represented by Y.

The cyclopentene derivative (I), the cyclopentene derivative (II), the cyclopentene derivative (III), the cyclopentene derivative (IV) and the cyclopentene derivative (V) can be produced, for example, by the following method.

The cyclopentene derivative represented by the following general formula (I-1), the cyclopentene derivative represented by the general formula (I-2), and the cyclopentene derivative represented by the general formula (I-3) are included in the cyclopentene derivative (I). The cyclopentene derivative represented by the general formula (II-1) and the cyclopentene derivative represented by the general formula (II-2) are included in the cyclopentene derivative (II), and are represented by the general formula (III-
A cyclopentene derivative represented by the general formula (III-
A cyclopentene derivative represented by the general formula (III):
The cyclopentene derivative represented by -3) is included in the cyclopentene derivative (III), and the cyclopentene derivative represented by the general formula (IV-1) and the cyclopentene derivative represented by the general formula (IV-2) are the cyclopentene derivative (IV) The cyclopentene derivative represented by the general formula (V-1) and the cyclopentene derivative represented by the formula (V-2) are encompassed by the cyclopentene derivative (V).

(Wherein R is as defined above, X ¹ , Y ¹ and
Z ²¹ represents a hydroxyl-protecting group, and Z ¹¹ represents a halogen atom. That is, 2-bromo-1- (4-hydroxy-2-
(Butynyl) -2-cyclopenten-1-ol and a 2-penten-4-yn-1-ol derivative represented by the general formula (VI) were converted into a palladium catalyst comprising a palladium compound and a tertiary phosphine, and 2-bromo- 1- (4-
(Hydroxy-2-butynyl) -2-cyclopentene-1
An amine such as tert-butylamine, diethylamine, diisopropylamine or the like in an amount of 1 equivalent or more to all; sodium ethoxide, sodium tert-butoxide, tert-
The cyclopentene derivative represented by the general formula (III-1) can be obtained by reacting in the presence of a base such as an alkali metal alkoxide such as potassium butoxide at a temperature in the range of about 0 to 50 ° C. In this reaction, it is desirable to allow 0.5 to 10 equivalents of cuprous iodide to coexist with the palladium catalyst. Examples of palladium compounds include palladium acetate, palladium chloride, bis (triphenylphosphine) palladium, bis (acetylacetonato) palladium, and tris (dibenzylideneacetone) 2.
Palladium (chloroform), tetrakis (triphenylphosphine) palladium and the like are used, and the used amount thereof is 2-bromo-1- (4-hydroxy-2-butynyl).
About 1 mol of 2-cyclopenten-1-ol
It is 0.01 to 0.2 mol. As the tertiary phosphine, triphenylphosphine, tolylphosphine, 1,2-
Bis (triphenylphosphino) ethane, 1,3-bis (triphenylphosphino) propane, tributylphosphine and the like are used, and the amount of use is usually about 1 to 20 mol per 1 mol of the palladium compound. .

To the cyclopentene derivative represented by the general formula (III-1) thus obtained, 1 to 2 equivalents of triphenylphosphine and carbon tetrabromide, carbon tetrachloride or iodine with respect to the cyclopentene derivative are added to triethylamine,
By reacting in the presence or absence of an amine such as diisopropylamine or imidazole at a temperature in the range of about −30 ° C. to about 70 ° C., a cyclopentene derivative represented by the general formula (III-2) is obtained. Can be.

The cyclopentene derivative represented by the general formula (III-2) is derived from the cyclopentene derivative represented by the general formula (III-3) by removing a hydroxyl-protecting group according to a conventional method.

The cyclopentene derivative represented by the general formula (III-3) is prepared by converting the cyclopentene derivative into an inert solvent such as tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, N, N-dimethylformamide, and hexamethylphosphoric triamide. By reacting the derivative with about 1 to 2 equivalents of a strong base such as sodium hydride, potassium hydride, potassium tert-butoxy, butyllithium, phenyllithium at about 0 to 80 ° C, the compound represented by the general formula (II-
It is converted to the cyclopentene derivative shown in 1).

The cyclopentene derivative represented by the general formula (II-1) is converted into a cyclopentene derivative represented by the general formula (II-2) by introducing a protecting group into its hydroxyl group according to a conventional method.

In an inert solvent such as tetrahydrofuran, 1,2-dimethoxyethane, or hexamethylphosphoric triamide, about 1 to 2 equivalents of butyllithium to the cyclopentene derivative is added to the cyclopentene derivative represented by the general formula (II-2), Bases such as tert-butyllithium, methyllithium and lithium diisopropylamide are treated at about -100 ° C to about 0 ° C.
By operating at a temperature within the range of the general formula (I-
The cyclopentene derivative represented by 1) can be obtained.

Among the cyclopentene derivatives represented by the general formula (I-1), the cyclopentene derivative in which R is a hydrogen atom can be dehydrated according to a conventional method to obtain a compound represented by the general formula (V-
It is converted to the cyclopentene derivative shown in 1). This dehydration reaction includes, for example, pyridine, triethylamine,
In the presence of an amine such as N, N-dimethylaminopyridine, diisopropylethylamine, 2,6-lutidine, or collidine, 1 to 50 equivalents of methanesulfonyl chloride relative to the cyclopentene derivative represented by the general formula (I-1), Chloride p
-Toluenesulfonyl, phosphorus oxychloride, phosphorus trichloride,
It is carried out by reacting a dehydrating agent such as phosphorus tribromide or thionyl chloride. The cyclopentene derivative represented by the general formula (V-1) is converted into a cyclopentene derivative represented by the formula (V-2) by removing a hydroxyl-protecting group according to a conventional method.

The cyclopentene derivative represented by the general formula (I-1) is converted into a cyclopentene derivative represented by the general formula (I-2) by introducing a protecting group into a hydroxyl group thereof according to a conventional method. The cyclopentene derivative represented by the general formula (I-2) is converted to the cyclopentene derivative represented by the general formula (I-3) by removing the protecting group (X ¹ ) of the hydroxyl group. The cyclopentene derivative represented by the general formula (I-3) is converted into a cyclopentene derivative represented by the general formula (IV-1) by dehydration according to a conventional method. The cyclopentene derivative represented by the general formula (IV-1) is converted to a cyclopentene derivative represented by the general formula (IV-2) by removing a hydroxyl-protecting group according to a conventional method.

The cyclopentene derivative (I), the cyclopentene derivative (II), the cyclopentene derivative (III), the cyclopentene derivative (IV) or the cyclopentene derivative (V) thus obtained can be obtained by converting an organic compound from a reaction mixture obtained in a usual organic reaction. Can be separated and purified from the reaction mixture by a method similar to that employed when separating and purifying. For example, the reaction mixture is poured into an aqueous solution of ammonium chloride, extracted with an organic solvent such as diethyl ether, ethyl acetate, methylene chloride, and the like, and then separated by silica gel column chromatography, alumina column chromatography, or the like, to convert the above cyclopentene derivative into a single unit. It can be purified.

[Examples] Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited by these Examples.

Example 1 30 ml of benzene, 73 mg (3 mol%) of palladium acetate, 393 mg (12 mol%) of triphenylphosphine, 150 mg (6 mol%) of copper (I) iodide and 2.6 ml of tert-butylamine
(25 mmol) was added to 1- (4-hydroxy-
2-butynyl) -2-bromo-2-cyclopentene-1
-A solution of 2.77 g (12.5 mmol) of benzene in benzene (15 m
l) and 5- (2-tetrahydropyranyloxy) -3-
A solution of pentene-1-yne (2.5 g, 15 mmol) in benzene (15 ml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, washed successively with a mixed aqueous solution of ammonium chloride and ammonia, 1 N hydrochloric acid, aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. After the low-boiling substances were distilled off under reduced pressure, the residue was purified by silica gel column chromatography to give 1-
(4-hydroxy-2-butynyl) -2- [5- (2-
3.2 g of tetrahydropyranyloxy) -3-penten-1-ynyl] -2-cyclopenten-1-ol was obtained (yield 90%). ¹ H-NMR spectrum δ (ppm): 6.17 (br s, 1H), 5.68 to 6.24 (m, 2H), 4.6 to 4.8 (br, 1
H), 4.1 ~ 4.6 (m, 2H), 4.2 (br, 2H), 3.4 ~ 4.0 (m, 2
H), 1.9-2.9 (m, 6H), 1.3-1.8 (m, 6H) ¹³ C-NMR spectrum δ (ppm): 139.785, 139.001, 138.398, 130.118, 112.651, 111.958, 97.786, 96.960, 89.117, 89.030, 88.11,88.725,84.956,81.835,80.663,63.932.61.987,61.723,59.973,36.756,36.539,30.557,30.384,25.443,19.158,18.941 IR spectrum (neat; cm ^-1 ): 3370,2925,2850,2170,1440 , 1380, 1320, 1260, 1200, 1140, 1120, 1060, 1020, 960, 900, 860, 780, 760 Example 2 100 ml of anhydrous acetonitrile, 1- (4-hydroxy-2-butynyl) -2- [5-
(2-tetrahydropyranyloxy) -3-pentene-
1-ynyl] -2-cyclopenten-1-ol 3.28
(11.3 mmol) and triethylamine (1.74 ml, 11.3 mmol) in a mixed solution at -30 ° C at 6.2 g (18.7 mmol) of tetrabromomethane and 4.73 mmol of triphenylphosphine.
9 g (14.4 mmol) was added and stirred for 15 minutes. The reaction solution was poured into ice-cooled aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic layer was washed with saturated saline. After drying over magnesium sulfate and evaporating low-boiling substances under reduced pressure, the residue was purified by silica gel column chromatography to give 1- (4-bromo-2-butynyl) -2- [5- (2-tetrahydro Pyranyloxy) -3-penten-1-ynyl] -2-
800 mg of cyclopenten-1-ol was obtained (yield 16
%).

Example 3 15 ml of methanol and 1- (4
-Bromo-2-butynyl) -2- [5- (2-tetrahydropyranyloxy-3-penten-1-ynyl] -2
A catalytic amount of pyridinium p-toluenesulfonate was added to a mixed solution of 800 mg (1.8 mmol) of -cyclopenten-1-ol, and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into ice-cooled aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over magnesium sulfate. After the low-boiling substances are distilled off under reduced pressure, the residue is purified by silica gel chromatography to give 1- (4
-Bromo-2-butynyl) -2- (5-hydroxy-3
-Pentene-1-ynyl) -2-cyclopentene-1-
600 mg of all was obtained (94% yield). ¹ H-NMR spectrum δ (ppm): 6.23 (t , J = 1.8Hz, 1H), 6.19 (dt, J = 11.0,6.2Hz, 1H),
6.07 (br d, J = 11.0Hz, 1H), 4.43 (br d, J = 6.2Hz, 2
H), 3.92 (t, J = 2.4 Hz, 2H), 2.72 (dt, J = 16, 2.4 Hz, 1
H), 2.68 (dt, J = 16, 2.4 Hz, 1H), 1.8-2.6 (m, 4H) ¹³ C-NMR spectrum δ (ppm): 141.692, 140.042, 129.556, 110.397, 89.117,88.683,85.129,83.915 , 77.108,60.550,36.886,30.601,30.427,15.300 IR spectrum (neat; cm ^-1 ): 3300,2900,2850,2230,2180,1210,1010,1160,1060,960,920,840,780,760,600 Example 4 Sodium hydride ( Suspension in 60% mineral oil) 150m
g (3.75 mmol) was washed with anhydrous hexane, and then 20 ml of anhydrous tetrahydrofuran and 4 ml of hexamethylphosphoric amide were added thereto.
(4-bromo-2-butynyl) -2- (5-hydroxy-3-penten-1-ynyl) -2-cyclopentene-
A solution of 48 mg (0.18 mmol) of 1-ol in anhydrous tetrahydrofuran (20 ml) was added dropwise over 3.5 hours, followed by stirring at room temperature for 4 hours. The reaction solution was poured into an ice-cooled aqueous solution of ammonium chloride and extracted with diethyl ether. The organic layer was washed with saturated saline and dried over magnesium sulfate. After the low-boiling substances are distilled off under reduced pressure, the residue is purified by silica gel column chromatography to give bicyclo [10.3.0] -7-oxapentadeca-1 having the following physical properties.
(15) 17 mg of 4-dien-2.9-diyn-12-ol was obtained (44% yield). ¹ H-NMR spectrum δ (ppm): 5.99 to 6.25 (m, 3H), 4.5 to 4.44 (m, 4H), 1.85 to 2.90
(M, 6H), 1.58 (br s, 1H) Example 5 0.2 ml of anhydrous methylene chloride, bicyclo [10.3.0] -7-oxapentadeca-1 (1
5) To a mixed solution of 17 mg (0.08 mmol) of 1,4-diene-2,9-diyn-12-ol and 1 ml of diisopropylethylamine, 0.08 ml of chloromethyl methyl ether was added under ice-cooling, followed by stirring at room temperature for 12 hours. The reaction solution was diluted with diethyl ether, washed sequentially with ice water, 1N hydrochloric acid, aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. After the low-boiling substances were distilled off under reduced pressure, the residue was purified by silica gel column chromatography to obtain bicyclo [10.3.0] -12-methoxymethoxy-7-oxapentadeca-1 (15) having the following physical properties. 11 mg of 4-diene-2,9-diyne was obtained (54% yield). ¹ H-NMR spectrum δ (ppm): 6.33 (m, 1H), 5.86 to 6.09 (m, 2H), 4.44 to 4.91 (m, 6)
H), 3.44 (s, 3H), 2.10 to 3.08 (m, 6H) Example 6 2 ml of anhydrous tetrahydrofuran and the bicyclo [10.3.0] -12-methoxymethoxy-7- obtained in Example 5
Oxapentadeca-1 (15), 4-diene-2,9-diyne 1
1.9N tert. At -78 ° C in 0mg (0.04mmol) mixed solution
0.03 ml (0.057 mmol) of -butyllithium hexane solution was added, and the mixture was stirred for 5 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution at -78 ° C, the mixture was returned to room temperature, and extracted with diethyl ether. The organic layer was washed with saturated saline and dried over sodium sulfate, and then the low-boiling substances were distilled off under reduced pressure. The residue is purified by silica gel column chromatography to give bicyclo [7.3.0]-having the following physical properties.
9-methoxymethoxy-4-vinyldodeca-1 (12)-
4 mg of ene-2,6-diyn-5-ol was obtained (yield 36
%). ¹ H-NMR spectrum δ (ppm): 5.35 to 6.28 (m, 4H), 4.76 (d, J = 1.08 Hz, 2H), 4.40 (b
r, 2H), 3.41 (s, 3H), 1.85-2.96 (m, 6H), 1.61 (s, 1
H) Example 7 10 ml of tetrahydrofuran and the bicyclo [7.3.0] -9-methoxymethoxy-4-vinyldodeca-1 (12) -en-2,6-diyn-5-ol4 obtained in Example 6
A catalytic amount of p-toluenesulfonic acid was added to a mixed solution of the resulting mixture with mg (0.02 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into water, extracted with diethyl ether, and the organic layer was washed with brine and dried over magnesium sulfate. Low-boiling substances are distilled off under reduced pressure, and the residue is purified by silica gel column chromatography to give bicyclo [7.3.0] -4-vinyldodeca-1 (12) -ene- having the following physical properties.
3 mg of 2,6-diyne-5,9-diol was obtained (yield 90%).

Mass spectrum (FD; m / z): M ⁺ 214 Example 8 222 mg (3 mol%) of palladium acetate, 1.2 g (12 mol%) of triphenylphosphine, 435 mg (6) of copper (I) iodide
Mol%) and 8.0 ml (76 mmol) of tert-butylamine
Was mixed in 80 ml of benzene, and 8.80 g (38.1 mmol) of 1- (4-hydroxy-2-butynyl) -2-bromo-2-cyclopenten-1-ol was added to the mixture.
0-ml, and 7.59 g of 1- (2-tetrahydropyranyloxy) -2-penten-4-yne (4.
5.7 mmol) in 40 ml of benzene was added at room temperature. After stirring at room temperature for 10 hours, the reaction mixture was diluted with ethyl acetate and filtered using cotton wool. The filtrate was washed successively with a mixed aqueous solution of ammonium chloride and ammonia, 1 N hydrochloric acid, aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography, and 1- (4-hydroxy-2-butynyl) -2- [5- (2-tetrahydropyranyl) having the same physical properties as those obtained in Example 1. Oxy)
-3-penten-1-ynyl] -2-cyclopentene-
11.0 g of all were obtained (91% yield).

Example 9 1- (4-hydroxy-2-butynyl) -2- [5-
(2-tetrahydropyranyloxy) -3-pentene-
1-ynyl] -2-cyclopenten-1-ol 4.66 g
(14.7 mmol) and pyridine 1.19 ml (14.7 mmol)
Was dissolved in 90 ml of anhydrous acetonitrile, and 4.91 g of carbon tetrabromide and 3.89 g of triphenylphosphine were added in three portions at -40 ° C. After stirring at -20 ° C for 1 hour, the reaction mixture was poured into ice-cooled aqueous sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent, pentane 40 ml was added to the residue,
40 ml of diethyl ether, 4 ml of ethyl acetate and 4 ml of water were added, and the mixture was stirred for 1 hour. After decantation, the mixture was sequentially washed with an aqueous solution of sodium bicarbonate and a saturated saline solution, and dried over magnesium sulfate. After evaporation of the solvent, the residue was diluted with 50 ml of methanol. A catalytic amount of pyridinium p-toluenesulfonate was added to the diluted solution, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into ice-cooled aqueous sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography, and 1- (4-bromo-2-butynyl) -2 having the same physical properties as obtained in Example 3.
-(5-hydroxy-3-penten-1-ynyl) -2
-Cyclopenten-1-ol (1.36 g, yield 31)
%).

Example 10 After washing 150 mg of 60% sodium hydride three times with anhydrous hexane, 20 ml of anhydrous tetrahydrofuran and 0.02 ml of ethanol were added thereto and suspended.
(4-bromo-2-butynyl) -2- (5-hydroxy-3-penten-1-ynyl) -2-cyclopentene-
A solution obtained by dissolving 57 mg (0.19 mmol) of 1-ol in 20 ml of anhydrous tetrahydrofuran was added dropwise at 20 ° C. over 5 hours. After stirring at 20 ° C. for 1 hour, the reaction mixture was poured into an ice-cooled aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain bicyclo [10.3.0] -7-oxapentadeca-1 having the following physical properties.
(15) 33 mg of 4-diene-2,9-diyn-12-ol was obtained (80% yield). ¹ H-NMR spectrum δ (ppm): 6.185 (t , 1H, J = 2.79Hz), 6.078 (ddd, 1H, J = 10.5,7.7
6,7.22Hz), 5.988 (d, 1H, J = 10.5Hz), 4.431 (dd, 1H, 1
0.7,7.76Hz), 4.383 (dd, 1H, 10.7,7.22Hz), 4.19 (dt, 1
H, J = 16.1,2.2Hz), 4.18 (dt, 1H, J = 16.1,2.0Hz), 2.74
4 (dt, 1H, J = 16.8,2.2Hz), 2.619 (dt, 1H, J = 16.8,2.0H
z), 2.553 (dddd, 1H, J = 18.2,8.7,3.8,2.8Hz), 2.374
(Dddd, 1H, J = 18.2,7.8,6.4,2.8Hz), 2.149 (ddd, 1H, J
= 13.5,8.7,6.4Hz), 1.948 (ddd, 1H, J = 13.5,7.8,3Hz) ^13C -NMR spectrum δ (ppm): 139.13,136.45,130.42,117.07,90.63,89.51,83.70,82.88,80.01 , 63.85, 56.30, 38.36, 31.90, 29.78 IR spectrum (neat; cm ^-1 ): 3430,3030,3940,2850,2280,2200, 1450,1360,1320,1140,1060,1020,960,920,900,880,840,790,760 Example 11 Bicyclo [10.3.0] -7-oxapentadeca-1-
(15) 121 mg of 4-diene-2,9-diyn-12-ol (0.
56 mmol) and 2 ml of diisopropyldiethylamine were dissolved in 1 ml of anhydrous methylene chloride, and 0.26 ml of chloromethyl methyl ether was added dropwise to the resulting solution at 0 ° C. At room temperature
After stirring for 18 hours, the reaction mixture was diluted with diethyl ether. The extract was washed successively with an aqueous solution of copper sulfate, an aqueous solution of sodium bicarbonate and saturated saline, and dried over sodium sulfate. After distilling off the solvent,
The residue was purified by silica gel column chromatography, and bicyclo [10.3.
0] -12-methoxymethoxy-7-oxapentadeca
126 mg of 1- (15), 4-diene-2,9-diyne was obtained (yield
87%).

Example 12 Bicyclo [10.3.0] -7-oxapentadeca-1 (1
5) 117 mg of 4,4-diene-2,9-diyn-12-ol (0.55
Mmol) and 0.37 ml (2.75 mmol) of anhydrous triethylamine were dissolved in 5 ml of anhydrous methylene chloride, and the resulting solution was added at 0 ° C with 0.25 ml of tert-butyldimethylsilyl triflate.
After dropwise addition of ml (1.1 mmol), the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with diethyl ether, washed sequentially with aqueous sodium bicarbonate and saturated saline, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain bicyclo [10.3.0] -12-tert-
Butyldimethylsilyloxy-7-oxapentadeca-
160 mg of 1 (15), 4-diene-2,9-diyne was obtained (yield 90
%).

Example 13 Bicyclo [10.3.0] -7-oxapentadeca-1 (1
5) 31 mg of 4,4-diene-2,9-diyn-12-ol (0.145
Mmol) and 0.24 ml (1.45 mmol) of anhydrous triethylamine were dissolved in 2 ml of anhydrous methylene chloride, and 0.1 ml (0.435 mmol) of trimethylsilyl triflate was added dropwise to the obtained solvent at 0 ° C., followed by stirring at room temperature for 6 hours. The reaction mixture was diluted with diethyl ether, washed sequentially with aqueous sodium bicarbonate and saturated saline, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain bicyclo [10.3.0] -12-trimethylsilyloxy-7-oxapentadeca-1 (15), 4-diene-.
29 mg of 2,9-diyne was obtained (70% yield).

Example 14 Bicyclo [10.3.0] -12-methoxymethoxy-7-oxapentadeca-1 (15), 4-diene-2,9-diyne 86m
g (0.33 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and a 1.93 N tert-butyllithium solution (0.21 ml) was added dropwise to the resulting solution at -100 ° C. After 30 minutes, 3 ml of an aqueous ammonium chloride solution was added at -100 ° C. And stirred at room temperature for 10 minutes. The reaction mixture was diluted with diethyl ether and washed with an aqueous ammonium chloride solution. The aqueous layer was extracted with diethyl ether, and the organic layers were combined and washed with saturated saline. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain bicyclo [7.3.
0] -9-methoxymethoxy-4-vinyldodeca-1 (1
2) 56 mg of -ene-2,6-diyn-5-ol was obtained (yield)
65%). ¹ H-NMR spectrum δ (ppm): 6.199 (br s, 1H), 5.851 (ddd, 1H, J = 16.95,10.08,6.42
Hz), 5.429 (dd, 1H, J = 16.95, 1.37Hz), 5.286 (dd, 1H, J
= 10.08, 1.37Hz), 4.786 (d, 1H, J = 7.34Hz), 4.742 (d,
1H, J = 7.342Hz), 4.447 (br, 1H), 3.753 (br dd, 1H, J =
6,42,3.9Hz), 3.414 (s, 3H), 2.565 (m, 1H), 2.558 (d,
1H, J = 17.2Hz), 2.382 (m, 1H), 2.279 (m, 1H), 1.846
(M, 1H) ¹³ C-NMR spectrum δ (ppm): 138.36, 132.57, 126.78, 118.94, 97.81, 95.45, 93.95, 92.31, 87.10, 86.73, 67.85, 55.74, 48.87, 36.67, 31.78, 30.40 Example 15 In Example 14, instead of 86 mg of bicyclo [10.3.0] -12-methoxymethoxy-7-oxapentadeca-1 (15), 4-diene-2,9-diyne, bicyclo [10.3.0] -12 was used.
By performing the same reaction and operation except that 108 mg of -tert-butyldimethylsilyloxy-7-oxapentadeca-1 (15), 4-diene-2,9-diyne was used, bicyclo [ 7.3.0] -9-tert-Butyldimethylsilyloxy-4-vinyldodeca-1 (12)-
71 mg of ene-2,6-diyn-5-ol was obtained (yield 66
%). ¹ H-NMR spectrum δ (ppm): 5.959 (t , 1H, J = 2.56Hz), 5.847 (ddd, 1H, J = 17.1,9.8
3,5.99Hz), 5.424 (ddd, 1H, J = 17.1,2.99,1.28Hz), 5.2
72 (ddd, 1H, J = 9.83, 2.99, 1.28 Hz), 4.451 (br dd, 1H, J
= 10.26, 4.70Hz), 3.790 (br dd, 1H, J = 5.99, 4.70Hz),
2.569 (m, 1H), 2.494 (dd, 1H, J = 16.7, 1.29 Hz), 2.415
(M, 1H), 2.094 (ddd, 1H, J = 14.10, 8.98, 3.42 Hz), 1.93
4 (ddd, 1H, J = 14.10, 8.98, 5.56 Hz), 0.898 (s, 9H), 0.1
35 (s, 3H), 0.109 (s, 3H) ¹³ C-NMR spectrum δ (ppm): 134.40, 132.53, 130.77, 118.80, 96.46, 96.36, 90.56, 87.90, 86.16, 67.77, 49.06, 38.30, 34.31, 30.16 , 25.79, 18.26, −3.00, −3.16 IR spectrum (neat; cm ⁻¹ ): 3000, 2920, 2859, 2180, 1460, 1385, 1250, 1215, 1080, 1010, 985,920, 830, 750, 660 Example 16 In Example 14, Bicyclo [10.3.0] -12 instead of 86 mg of bicyclo [10.3.0] -12-methoxymethoxy-7-oxapentadeca-1 (15), 4-diene-2,9-diyne
-Trimethylsilyloxy-7-oxapentadeca-1
(15) Bicyclo [7.3.0] -9-trimethylsilyloxy-4-vinyldodeca-1 having the following physical properties was obtained by conducting the same reaction and operation except that 96 mg of 4,4-diene-2,9-diyne was used. (12) -ene-2,6-diyne-
58 mg of 5-ol were obtained (60% yield). ¹ H-NMR spectrum δ (ppm): 5.95 (m, 1H), 5.89 (ddd, 1H, J = 15, 9.5, 5.6 Hz), 5.44
(Ddd, 1H, J = 15Hz), 5.26 (ddd, 1H, J = 9.5Hz), 4.24
(M, 1H), 3.72 (br dd, 1H, J = 5.6, 4.6Hz), 1.64 (d, 1H,
J = 16.4Hz), 2.53 (dd, 1H, J = 16.4,1.0Hz), 1.8 ~ 2.5
(M, 1H), 0.17 (s, 9H) Example 17 Bicyclo [7.3.0] -9-tert-butyldimethylsilyloxy-4-vinyldodeca-1 (12) -ene-2,6-
20 mg (0.06 mmol) of diyn-5-ol and 100 mg (0.82 mmol) of 4-dimethylaminopyridine were dissolved in 2 ml of methylene chloride, and 0.02 ml (0.25 mmol) of methanesulfonyl chloride distilled in the resulting solution was added at -20 ° C. Dripping,
Then it was stirred at 0 ° C. for 30 minutes. Pour the reaction mixture into water,
The aqueous layer was extracted with pentane. The organic layers were combined, washed with saturated saline, and dried over sodium sulfate. About 1 ml of solution
Then, the mixture was concentrated with silica gel, filtered with pentane, and the filtrate was concentrated to give bicyclo [7.3.0] -9-t-butyldimethylsilyloxy-4-vinyldodeca-1 (12) having the following physical properties. , 4-Diene-2,6-diyne was obtained quantitatively. ¹ H-NMR spectrum δ (ppm): 6.38 (dd, 1H, J = 16.3, 9.9 Hz), 6.06 (t, 1H, J = 2.6 Hz),
5.98 (br, 1H), 5.71 (d, 1H, J = 9.9Hz), 5.69 (d, 1H, J =
16.3Hz), 2.88 (d, 1H, J = 18Hz), 2.85 (d, 1H, J = 18H)
z), 1.8-2.7 (m, 4H), 0.89 (s, 9H), 0.06 (s, 6H) Example 18 88 mg (3 mol%) of palladium acetate, 476 mg (12 mol%) of triphenylphosphine, copper iodide (I) 173 mg (6 mol%) and 3.2 ml (30 mmol) of tert-butylamine were mixed in 32 ml of benzene, and 1- (4-hydroxy-2-butynyl) -2-bromo-2-cyclopentene was added to the mixture. 3.5 g (15.2 mmol) of -1-ol in 16 ml of benzene
And 3-methyl-1- (2-tetrahydropyranyloxy) -2-penten-4-yne
A solution obtained by dissolving 3.27 g (18.1 mmol) in 16 ml of benzene was added at room temperature. After stirring at room temperature for 3.5 hours,
The reaction mixture was diluted with ethyl acetate and filtered using cotton wool. The filtrate was washed sequentially with an aqueous solution of ammonium chloride and ammonia mixed with 1N hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with aqueous sodium bicarbonate and saturated saline, and dried over magnesium sulfate. After distilling off the solvent,
The residue was purified by silica gel column chromatography to give 1- (4-hydroxy-2-butynyl) -2- [3-methyl-5- (2-tetrahydropyranyloxy) -3-pentene-1- having the following physical properties. 4.38 g of [inyl] -2-cyclopenten-1-ol were obtained (87% yield). ¹ H-NMR spectrum δ (ppm): 6.20 (br, 1H), 5.95 (brt, 1H), 4.73 (br, 1H), 3.5 to
4.4 (m, 6H), 2.0 ~ 2.7 (m, 6h), 1.93 (br s, 3H), 1.4 ~
1.8 (m, 6H) Example 19 1- (4-hydroxy-2-butynyl) -2- [3-
Methyl-5- (2-tetrahydropyranyloxy) -3
-Pentene-1-ynyl] -2-cyclopentene-1-
All 3.8 g (11.5 mmol) and pyridine 0.94 ml (11.6
Mmol) were dissolved in 80 ml of anhydrous acetonitrile, 3.84 m of carbon tetrabromide and 3.04 g of triphenylphosphine were added to the resulting solution at −40 ° C. in several portions, and the mixture was stirred at −20 ° C. for 2 hours. 1 ml was added. The reaction mixture was poured into ice-cooled aqueous sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over sodium sulfate. After the solvent was distilled off, 40 ml of pentane, 20 ml of diethyl ether, 2 ml of ethyl acetate and 1 ml of water were added to the residue, followed by vigorous stirring. After decantation, 20 ml of pentane, 10 ml of diethyl ether and 0.5 ml of water were added to the residue, and after vigorous stirring, decantation was repeated 5 times. The washings were combined, washed sequentially with an aqueous solution of copper sulfate, an aqueous solution of sodium bicarbonate and saturated saline, and dried over sodium sulfate. After evaporation of the solvent, the residue was diluted with 50 ml of methanol. A catalytic amount of pyridinium p-toluenesulfonate was added to the diluted solution, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated to about 10 to 20 ml, poured into ice-cooled aqueous sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give 1- (4-bromo-2-butynyl) -2 having the following physical properties.
-(5-hydroxy-3-methyl-3-pentene-1-
2.50 g of (inyl) -2-cyclopenten-1-ol were obtained (yield 70%). ¹ H-NMR spectrum δ (ppm): 6.20 (t, 1H, J = 2.8 Hz), 5.89 (tq, 1H, J = 6.8, 1.6 Hz),
4.28 (dd, 2H, J = 6.8,0.9Hz), 3.91 (t, 2H, J = 2.5Hz),
2.70 (dt, 1H, J = 16.6,2.5Hz), 2.65 (dt, 1H, J = 16.6,2.
5 Hz), 1.9 to 2.6 (m, 4H), 1.93 (dt, 3H, 1.6, 0.9 Hz) ¹³ C-NMR spectrum δ (ppm): 139.96, 135.97, 129.60, 120.93, 91.20, 88.21, 85.13, 83.87, 77.20 , 66.01, 61.16, 36.93, 30.51, 23.06, 15.21 Example 20 After washing 280 mg of 55% sodium hydride three times with 5 ml of anhydrous hexane, 65 ml of anhydrous tetrahydrofuran, 0.5 ml of anhydrous hexamethylphosphoric triamide and 0.03 ml of ethanol were added. , Suspended. To the obtained suspension, 207 mg of 1- (4-bromo-2-butynyl) -2- (5-hydroxy-3-methyl-3-penten-1-ynyl) -2-cyclopenten-1-ol (0.67 (Mmol) in anhydrous tetrahydrofuran (65 ml), and the resulting solution was added dropwise at 20 ° C over 32 hours using a microfeeder. After stirring at 20 ° C. for 1 hour, the reaction mixture was poured into an ice-cooled aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain bicyclo [10.3.0] -7 having the following physical properties.
134 mg of -oxa-4-methylpentadeca-1 (15), 4-diene-2,9-diyn-12-ol was obtained (88% yield). ¹ H-NMR spectrum δ (ppm): 6.18 (t, 1H, J = 2.9 Hz), 5.85 (tq, 1H, J = 7.9, 1.6 Hz),
4.30 (br d, 2H, J = 7.9Hz), 4.15 (t, 2H, J = 2.1Hz), 2.6
9 (dt, 1H, J = 17,2.1Hz), 2.64 (dt, 1H, J = 17,2.1Hz),
1.8-2.6 (m, 4H), 1.97 (d, 3H, J = 1.6 Hz) ¹³ C-NMR spectrum δ (ppm): 139.27,131.12,130.55,127.21,91.85, 89.33,83.48,82.96,80.36,65.06, 56.35,38.45,31.94,29.78,22.67 IR spectrum (neat; cm ^-1 ): 3350,2925,2850,1440,1350,1260,1040,890,790 Example 21 Bicyclo [10.3.0] -7-oxa-4- Methylpentadeca-1 (15), 4-diene-2,9-diyn-12-ol 1
34 mg (0.59 mmol) and 0.35 ml of anhydrous triethylamine
(3 mmol) was dissolved in 3 ml of anhydrous methylene chloride, and 0.19 ml of trimethylsilyl triflate was added to the resulting solution at 0 ° C.
(0.83 mmol) was added dropwise, and the mixture was stirred at 20 ° C. for 18 hours. The reaction mixture was diluted with diethyl ether, washed sequentially with aqueous sodium bicarbonate and saturated saline, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain bicyclo [10.3.0]-having the following physical properties.
123 mg of 7-oxa-4-methyl-12-trimethylsilyloxypentadeca-1 (15), 4-diene-2,9-diyne was obtained (yield 70%). ¹ H-NMR spectrum δ (ppm): 6.10 (t, 1H, J = 2.8 Hz), 5.78 (m, 1H), 3.8 to 4.3 (m, 4
H), 2.56 (dt, 1H, J = 13,2.6 Hz), 1.8 to 2.54 (m, 5H), 1.
95 (br s, 3H), 0.20 (s, 9H) ¹³ C-NMR spectrum δ (ppm): 137.77,132.17,131.53,126.90,91.80,90.58,85.90,85.02,78.62,61.62,55.93,40.02,33.09, 29.77,22.60,2.05 IR spectrum (neat; cm ^-1 ): 2950,2896,2848,2284,2198,1624,1450,1352,1320,1250,1181,1123,1090,1059,988,927,894,842,756 Example 22 Example 14 In place of 86 mg of bicyclo [10.3.0] -12-methoxymethoxy-7-oxapentadeca-1 (15), 4-diene-2,9-diyne, bicyclo [10.3.0] -7-
By performing the same reaction and operation except that 99 mg of oxa-4-methyl-12-trimethylsilyloxypentadeca-1 (15), 4-diene-2,9-diyne was used, bicyclo [7.3 having the following physical properties was obtained. .0] -9-Trimethylsilyloxy-4-methyl-4-vinyldodeca-1 (12)
-Ene-2,6-diyn-5-ol (66 mg, yield 67)
%). ¹ H-NMR spectrum δ (ppm): 5.945 (t , 1H, J = 2.75Hz), 5.839 (dd, 1H, J = 16.95,10.0
8Hz), 5.502 (dd, 1H, J = 16.95, 1.38Hz), 5.230 (dd, 1H,
J = 10.08, 1.38Hz), 4.037 (d, 1H, J = 9.16Hz), 2.670
(D, 1H, J = 16.96 Hz), 2.564 (dddd, 1H, J = 18.3, 8.71, 5.
50, 2.75 Hz), 2.482 (d, 1H, J = 16.96 Hz), 2.403 (dddd, 1
H, J = 18.3, 9.16, 4.13, 2.75 Hz), 2.218 (ddd, 1H, J = 13.
6,8.71,4.13Hz), 1.941 (ddd, 1H, J = 13.6,9.16,5.50H
z), 1.359 (s, 3H), 0.161 (s, 9H) Example 23 Bicyclo [7.3.0] -9-trimethylsilyloxy-
4-methyl-4-vinyldodeca-1 (12) -ene-2,6
-34 mg (0.11 mmol) of diin-5-ol and 0.18 ml (2.2 mmol) of pyridine are dissolved in 2 ml of methylene chloride,
To the resulting solution, 0.08 ml (1.1 mmol) of acetyl chloride was added dropwise at 0 ° C, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water, the organic layer was washed with an aqueous solution of copper sulfate, and the aqueous layer was extracted with diethyl ether. The organic layer was collected, washed sequentially with aqueous sodium bicarbonate and saturated saline, and dried over sodium sulfate. The solvent was distilled off to obtain bicyclo [7.3.0] -5-acetoxy-9.
A crude product of -trimethylsilyloxy-4-methyl-4-vinyldodeca-1 (12) -ene-2,6-diyne was obtained.
This was used for the next reaction without purification.

Example 24 Bicyclo [7.3.0] -5 obtained in Example 23
Acetoxy-9-trimethylsilyloxy-4-methyl-4-vinyldodeca-1 (12) -ene-2,6-diyne was added to a crude product of acetic acid-tetrahydrofuran-water in a volume ratio of 4: 1.
2 ml of the mixed solution of 1 was added at 20 ° C., and stirred at the same temperature for 1 hour. The reaction mixture was diluted with diethyl ether, washed sequentially with aqueous sodium bicarbonate and saturated saline, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain bicyclo [7.
3.0] -5-Acetoxy-4-methyl-4-vinyldodeca-1 (12) -en-2,6-diyn-9-ol 16 ml was obtained (55% in two steps). ¹ H-NMR spectrum δ (ppm): 5.979 (t , 1H, J = 2.75Hz), 5.61 (dd, 1H, J = 17.0,10.1H
z), 5.524 (dd, 1H, J = 17.0, 1.37 Hz), 5.295 (brs, 1
H), 5.165 (dd, 1H, J = 10.1, 1.37 Hz), 2.679 (d, 1H, J = 1
7.0Hz), 2.640 (dd, 1H, J = 17.0, 1.37Hz), 2.616 (dddd,
1H, J = 18.3, 8.7, 4.13, 2.75Hz), 2.422 (dddd, 1H, J = 18.
3,9.17,5.50,2.75Hz), 2.180 (ddd, 1H, J = 13.7,9.17,4.
13Hz), 1.924 (ddd, 1H, J = 13.7, 8.7, 5.50Hz), 2.041
(S, 3H), 1.427 (s, 3H) ¹³ C-NMR spectrum δ (ppm): 169.97,136.80,134.55,129.77,116.86,100.09,93.16,87.40,86.97,87.50,72.92,51.58,36.50,32.83, 30.17, 26.18, 20.92 IR spectrum (neat; cm ^-1 ): 3440,2930,2850,2352,2210,1742,1453,1370,1228,1149,1063,1023,927,850,759 Example 25 Bicyclo [7.3.0 ] -5-acetoxy-4-methyl-
4-vinyldodeca-1 (12) -ene-2,6-diyne-9
-Ol (15 mg, 0.056 mmol) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) were dissolved in methylene chloride (2 ml).
02 ml (0.25 mmol) was added dropwise, and the mixture was stirred at 20 ° C. for 20 minutes. The reaction mixture was poured into water, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with saturated saline, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain bicyclo [7.3.0] -5-acetoxy-4- having the following physical properties.
Methyl-4-vinyldodeca-1 (12), 8-diene-2,6
-12 mg of diyne were obtained (86% yield). ¹ H-NMR spectrum δ (ppm): 6.347 (m , 1H), 5.684 (dd, 1H, J = 16.95,10.08Hz), 5.50
0 (dd, 1H, J = 16.95, 1.37Hz), 5.384 (dd, 1H, J = 1.38H
z), 5.282 (br, 1H), 5.161 (dd, 1H, J = 10.08,1.37Hz),
2.718 (m, 2H), 2.587 (m, 2H), 2.039 (s, 3H), 1.452
(S, 3H) Test Example 1 1. Test method 2 mg of a test compound was dissolved in 1 ml of ethanol, and this solution was diluted twice with ethanol to prepare each dilution. 0.5 ml of each diluted solution was poured into a petri dish having a diameter of 9 cm, and a potato dextrol agar medium (pH 6.5, manufactured by Nissui Pharmaceutical Co., Ltd.) heated at 45 ° C. was added to each petri dish at 10 ml each. In this method, a plate having seven concentrations from 100 ppm to 1.6 ppm was prepared, and a plate of 0 ppm was prepared as a control, followed by Salmonella typhimurium.
typhimurium ) (IFO12529) was inoculated with one platinum loop.
In addition, the bacterial solution was 1 bacteria grown overnight in bouillon slant.
A platinum loop was prepared by suspending it in 0.5 ml of sterile saline. Inoculate each plate at 30 ° C
After culturing for 48 hours, the bacterial growth state was observed, and the minimum growth inhibitory concentration was measured.

2. Test results Test compound: Bicyclo [7.3.0] -9-methoxymethoxy-4-vinyldodeca-1 (12) -ene-2,6-diyn-5-ol Minimum growth inhibitory concentration: 1.6 ppm Test Example 2 Test Using the same method as in Example 1, the minimum growth inhibitory concentration was measured. The results are shown in Table 1. The bacteria used are as shown below.

(1) Escherichia coli (Escherichia coli) (IFO
3301) (2) Salmonella typhlum
imurium ) (IFO12529) (3) Serratia marcescen
s ) (IFO12648) (4) Sarcina lutea (IFO323
2) (5) Aspergillus niger
(M-63) (6) Candida albican
s ) (IFO1060) Test compound: bicyclo [7.3.0] -5-acetoxy-4
-Methyl-4-vinyldodeca-1 (12) -ene-2,6-
Diin-9-ol Test Example 3 Using the same method as in Test Example 1, the minimum growth inhibitory concentration was measured.

Test compound: bicyclo [7.3.0] -5-acetoxy-4
-Methyl-4-vinyldodeca-1 (12), 8-diene-2,
6-Diyne bacterium: Serratia marcescens Minimum growth inhibitory concentration: 100 ppm Test Example 4 Using the same method as in Test Example 1, the minimum growth inhibitory concentration was measured.

Test compound: bicyclo [7.3.0] -9-tert-butyldimethylsilyloxy-4-vinyl-dodeca-1 (12)-
En-2,6-diyn-5-ol Bacteria: Salmonella typhimurium Minimum inhibitory concentration: 12.5 ppm: Serratia marcesens Minimum inhibitory concentration: 6.25 ppm: Candida albicans Minimum inhibitory concentration: 12.5 ppm Test Example 5 Test Using the same method as in Example 1, the minimum growth inhibitory concentration was measured.

Test compound: bicyclo [7.3.0] -9-tert-butyldimethylsilyloxy-4-vinyl-dodeca-1 (12), 4
-Diene-2,6-diyne bacterium: Salmonella typhimurium Minimum growth inhibitory concentration: 50 ppm Bacteria: Serratia marcesens Minimum growth inhibitory concentration: 50 ppm According to the present invention, according to the present invention, it is clear from the above Examples. ,
The cyclopentene derivative (I), the cyclopentene derivative (IV) or the cyclopentene derivative (V) is easily synthesized by sequentially passing through the cyclopentene derivative (III) and the cyclopentene derivative (II). Further, as is clear from the above test examples, the cyclopentene derivative (I), the cyclopentene derivative (IV) and the cyclopentene derivative (V) are useful as antibacterial agents because they have antibacterial activity. The cyclopentene derivative (IV) is useful as a compound having a chromophore skeleton of neocarzinostatin.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07F 7/18 C07F 7/18 A // A01N 31/06 A01N 31/06 55/00 55/00 C A61K 31/045 ADZ A61K 31/045 ADZ 31/075 31/075 31/695 31/695 C07C 29/56 C07C 29/56 Z

Claims (5)

(57) [Claims] (1) General formula (Wherein, R represents a hydrogen atom or a lower alkyl group;
And Y each represents a hydroxyl group which may be protected.) 2. The general formula (Wherein, R and X are each as defined in claim 1). 3. The general formula (Wherein, R is as defined in claim 1, Z ¹ represents a hydroxyl group or a halogen atom, and Z ² represents an optionally protected hydroxyl group). 4. General formula (Wherein, R and Y are each as defined in claim 1). 5. The general formula (Wherein X is as defined in claim 1).