JP3035658B2 - Cyclopentenol derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel cyclopentenol derivatives. The cyclopentenol derivative provided by the present invention is useful as an antibacterial agent or an anticancer agent.

[0002]

2. Description of the Related Art Neocarzinostatin containing a cyclopentene derivative having an enediyne structure in a side chain as a chromophore has been clinically used as an anticancer agent,
It is also known to have antibacterial activity [Tetrahedron Letters
s), Vol. 29, p. 909 (1988))).

[0003]

Since the above-mentioned neocarzinostatin is a protein complex, the clinical route of use is restricted to intravascular (venous and arterial) administration. Further, the chromophore portion, which is considered to be the active body of neocarzinostatin, is extremely unstable in the absence of the inclusion protein, so that it is not easy to remove the chromophore portion while maintaining the activity. Therefore, at present, it is desired to develop a compound that is a close compound of the chromophore portion of neocarzinostatin described above and that has few restrictions in clinical use, is stable, and has high activity. .

Accordingly, an object of the present invention is to have a [7,3,0] -dodeca-3,7-diyne skeleton, which is the basic skeleton of the chromophore portion of neocarzinostatin,
It is to provide a novel cyclopentenol derivative which is stable and has antibacterial activity and antitumor activity.

[0005]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have reached the present invention.
That is, the present invention provides:

Embedded image (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or a hydroxyl-protecting group. R ⁵ may represent an acyl group substituted with a water-soluble functional group. A cyclopentenol derivative represented by the formula (2):

Embedded image (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or a hydroxyl-protecting group. R ⁵ may represent an acyl group substituted with a water-soluble functional group. ) And a synthetic intermediate of the cyclopentenol derivative represented by the above formulas (1) and (2). (3) Formula (3)

Embedded image (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² , R ³ and R ⁴ each represent a hydrogen atom or a hydroxyl-protecting group. (4) a cyclopentenol derivative represented by the formula (4):

Embedded image (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² , R ³ and R ⁴ each represent a hydrogen atom or a protecting group for a hydroxyl group, X represents an —OR ⁶ group or a halogen atom, and Y represents a hydrogen atom, —CH ₂ OR ⁷ group or —CH ₂
Represents a Z group. Wherein R ⁶ and R ⁷ each represent a hydrogen atom, an organic sulfonyl group or a protecting group for a hydroxyl group;
Represents a halogen atom. A cyclopentenol derivative represented by the formula (5):

Embedded image (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² , R ³ and R ⁸ each represent a hydrogen atom or a protecting group for a hydroxyl group, A represents a hydrogen atom, and B represents —OR
Either ⁹ groups are represented, or A and B together represent an oxo group. Here, R ⁹ represents a hydrogen atom or a hydroxyl-protecting group. And (6) a cyclopentenol derivative represented by the formula:

Embedded image (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² and R ⁸ each represent a hydrogen atom or a hydroxyl-protecting group. )).

In the above general formulas, R ¹ , R ² ,
The groups represented by R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are described in detail below. The lower alkyl group represented by R ¹ may be linear or branched and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. And the like. R ² , R ³ ,
As the protecting group for the hydroxyl group represented by R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ , any group may be used as long as it is a group that functions to protect a commonly used hydroxyl group. For example, acyl groups such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, caproyl group, benzoyl group, trifluoroacetyl group; methoxycarbonyl group, ethoxycarbonyl group, propoxy group Alkoxycarbonyl groups such as carbonyl group, isopropoxycarbonyl group, allyloxycarbonyl group and benzyloxycarbonyl group; trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and the like Trisubstituted silyl group; methoxymethyl Groups, 1- (alkoxy) alkyl groups such as methoxyethoxymethyl group, 1- (ethoxy) ethyl group and methoxyisopropyl group; 2-oxacycloalkyl groups such as tetrahydrofuranyl group and tetrahydropyranyl group. . Also,
R ⁵ may represent an acyl group having 1 to 10 carbon atoms substituted with a water-soluble functional group. Examples of such a water-soluble functional group include a carboxyl group, a hydroxyl group, a substituted or unsubstituted amino group, and a substituted or unsubstituted ammonium group.

The organic sulfonyl groups represented by R ⁶ and R ⁷ include alkane sulfonyl groups such as methanesulfonyl group and arenesulfonyl groups such as benzenesulfonyl group and p-toluenesulfonyl group.

The halogen atom represented by X and Z includes fluorine, chlorine, bromine and iodine.

The compound of the present invention can be prepared by the following scheme 1
It can be manufactured according to

[0010]

Embedded image

The cyclopentenol derivatives represented by the formulas (1) and (2) obtained according to the above scheme 1 are novel compounds. Cyclopentenol derivatives represented by formulas (3) to (6), which are synthetic intermediates thereof, are also novel compounds.

Each step of the above scheme 1 will be described in detail below. A known compound having a protected hydroxyl group 4
-Oxo-2-cyclopentenol derivative (a) is oxidized with an oxidizing agent such as sodium hypochlorite or basic aqueous hydrogen peroxide in the presence or absence of a phase transfer catalyst such as a quaternary ammonium salt. Thus, the hydroxyl-protected 4
-Oxo-2,3-epoxycyclopentanol derivative (b) is obtained. Next, a 3-substituted-2-pentene-protected hydroxyl group is added to the cyclopentanol derivative (b).
The 4-yn-1-ol derivative is reacted with an acetylide obtained from a base such as butyllithium, methyllithium, phenyllithium, ethylmagnesium chloride, methylmagnesium bromide, etc. to give 1-substituted-2,3-epoxycyclopentane-1 , 4-diol derivative (c). Further, the cyclopentane-1,4-diol derivative (c) is reacted with trifluoromethanesulfonic anhydride, thionyl chloride, or the like in the presence of a base such as lutidine, pyridine, quinoline, diazabicyclononane, or diazabicycloundecane. By dehydration, the formula (6) of the present invention is obtained.
The cyclopentenol derivative represented by the following formula can be obtained.

The cyclopentenol derivative represented by the formula (6) is reacted with a carboxylic acid such as benzoic acid or p-methoxybenzoic acid in the presence of a palladium catalyst, and if necessary, deprotected and oxidized to give the present compound. The cyclopentenol derivative represented by the formula (5) of the invention can be obtained.

The cyclopentenol derivative represented by the formula (5) is reacted with a propargylating agent such as propargylmagnesium bromide to convert the terminal acetylene to methylol, if necessary, and further, if necessary, to protect and deprotect the hydroxyl group. The cyclopentenol derivative represented by the formula (4) of the present invention can be obtained by performing organic sulfonylation and halogenation of a hydroxyl group.

Among the cyclopentenol derivatives represented by the formula (4), a compound in which one of the terminal hydroxyl groups is substituted with a halogen atom or an organic sulfonyl compound is
In an inert solvent such as tetrahydrofuran, 1,2-dimethoxyethane, dimethylsulfoxide, N, N-dimethylformamide and hexamethylphosphoric triamide, about 1-2 equivalents of sodium hydride and hydrogen are added to the core cyclopentenol derivative. Potassium iodide, potassium t-butoxide,
About 0% with strong bases such as butyl lithium and phenyl lithium
By reacting at ~ 80 ° C, it can be converted to the cyclopentenol derivative of the present invention represented by the formula (3). Further, a compound in which one of the terminal hydroxyl groups is not substituted with a halogen atom and which is not organic sulfonylated is obtained by substituting one of the terminal hydroxyl groups with a halogen atom or performing an organic sulfonylation by a conventional method. Similarly, it is converted to the cyclopentenol derivative of the present invention represented by the formula (3).

The cyclopentenol derivative represented by the formula (3) can be prepared by reacting the cyclopentenol derivative in an inert solvent such as tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, N, N-dimethylformamide and hexamethylphosphoric triamide. About 1-2 equivalents of a base such as butyllithium, t-butyllithium, methyllithium and lithium diisopropylamide to the pentenol derivative are added to about -1
By acting at a temperature in the range of 00 ° C. to about 0 ° C., it can be converted to the cyclopentenol derivative of the present invention represented by the formulas (1) and (2).

The thus obtained formula (1) of the present invention
The isolation and purification of the cyclopentenol derivative represented by the formula (6) from the reaction mixture is performed by a method generally used in isolating and purifying an organic compound from the reaction mixture. For example, the reaction mixture is poured into ice-water, extracted with an organic solvent such as diethyl ether, extract was successively washed with cold dilute hydrochloric acid, aqueous sodium bicarbonate, brine, etc., dried, and concentrated to give the crude product, the The crude product may be purified by recrystallization, chromatography, or the like, if necessary, to obtain the cyclopentenol derivatives of the present invention represented by formulas (1) to (6).

The cyclopentenol derivatives represented by the formulas (1) and (2) of the present invention have antibacterial activity and antitumor activity, and are useful as antibacterial agents or anticancer agents.

[0019]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited by these examples.

Reference Example 1 (1) 4- (t-butyldimethylsilyloxy) -2
13.4 g of cyclopentenone (corresponding to (a) above)
1.3 g of tetrabutylammonium hydrogen sulfate was added to and mixed with 200 ml of a dichloromethane solution of, and 33 ml of a 10% aqueous solution of sodium hypochlorite was added at 0 ° C. Next, the obtained reaction solution was stirred at room temperature for 24 hours, and then poured into a saturated aqueous solution of sodium thiosulfate. The obtained aqueous layer was extracted with diethyl ether, and the organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give rel- (2S, 3S,
4R) -4- (t-butyldimethylsilyloxy)-
10.3 g of 2,3-epoxycyclopentanone (corresponding to the above (b)) was obtained (yield 71%).

NMR spectrum (90 MHz, CDCl
₃ ) δ: 4.60 (brd, 1H, J = 5.7 Hz),
3.79 (d, 1H, J = 2, 1 Hz), 3.40 (b
rd, 1H, J = 2, 1 Hz), 2.61 (dd, 1
H, J = 18.0, 5.7 Hz), 1.93 (dd, 1
H, J = 18.0 Hz), 0.89 (s, 9H), 0.
12 (s, 6H) IR spectrum (neat) cm ^-1 : 2930,28
56, 1756, 1470, 1396, 1347, 12
58, 1161, 1084, 1006, 977, 90
2,782,669,432

(2) Next, (Z) -1- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-2
To a solution of 1.04 g of -penten-4-yne in 20 ml of tetrahydrofuran was added dropwise a hexane solution of butyllithium (1.84 N, 2.9 ml) at -78 ° C. Then, after stirring for 1 hour, the rel-
10 ml of a tetrahydrofuran solution of 1.01 g of (2S, 3S, 4R) -4- (t-butyldimethylsilyloxy) -2,3-epoxycyclopentanone (corresponding to the above (b)) was added dropwise, and- The temperature was raised to 50 ° C. The resulting reaction mixture poured into a saturated ammonium chloride aqueous solution, and extracted with diethyl ether. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give rel- (2S, 3S, 4R) -4- (t-butyldimethylsilyloxy) -1-[(Z) -5- ( Tetrahydro-2H-pyran-2-yloxy) -3-methyl-3
-Penten-1-yn-1-yl] -2,3-epoxycyclopentanol (corresponding to the above (c)) 1.37 g
Was obtained (75% yield).

NMR spectrum (200 MHz, CDC
l ₃ ) δ: 5.83 (dd, 1H, J = 7.41, 6.
59 Hz), 4.69 (m, 1H), 4.45 (d, 1
H, J = 5.29 Hz), 4.28 (d, 1H, J =
7.41 Hz), 4.25 (m, 1H), 3.79-
3.93 (m, 1H), 3.56 (d, 1H, J = 2.
36 Hz), 3.44 to 3.58 (m, 1H), 3.3
8 (dd, 1H, J = 2.36 Hz), 2.06 (d,
1H, J = 13.9 Hz), 1.89 (dd, 1H, J
= 13.9, 5.29 Hz), 1.83 (s, 3H),
1.4 to 1.8 (m, 6H) 0.845 (s, 9H), 0.04 (s, 6H) IR spectrum (neat) cm ^-1 : 3422,29
46, 2242, 1632, 1384, 1253, 11
21,1020,908,838,733,429

Example 1 rel- (2S, 3S, 4R) -4- (t-butyldimethylsilyloxy) -1-[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3- Methyl-3-
Penten-1-yn-1-yl] -2,3-epoxycyclopentanol (corresponding to the above (c)) 1.53 g in 30 ml of dichloromethane solution was added with 2,6-lutidine 1.
30 ml and trifluoromethanesulfonic anhydride 0.6
3 ml was added dropwise at -78 ° C. Then, after stirring at the same temperature for 20 minutes, the obtained reaction solution was poured into water and extracted with diethyl ether. The obtained organic layer was washed successively with a saturated aqueous solution of copper sulfate, aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give rel- (3R, 4S, 5) having the following physical properties.
R) -3- (t-Butyldimethylsilyloxy) -1-
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yne-1
-Yl] -4,5-epoxy-1-cyclopentene (corresponding to the compound represented by the formula (6) of the present invention) (786 mg) was obtained (yield: 54%).

NMR spectrum (200 MHz, CDC
_{l 3) δ: 6.12 (m} , 1 H), 6.10 (m, 1H), 4.6
1 (m, 2H), 4.34 to 4.10 (m, 2H), 3.94 to 3.78
(M, 3H), 3.44 to 3.58 (m, 1H), 1.85 (m, 3
H), 0.90 (m, 9H), 0.12 (m, 6H) IR spectrum (neat) cm ^-1 : 2948, 2192, 1632, 1593, 1460,
1202, 1024, 834, 671

Example 2 50.6 mg of palladium acetate, 237 mg of triphenylphosphine and 415.3 mg of benzoic acid were stirred at room temperature for 1 hour. The rel obtained according to Example 1 was added to this mixture.
-(3R, 4S, 5R) -3- (t-butyldimethylsilyloxy) -1-[(Z) -5- (tetrahydro-2
H-pyran-2-yloxy) -3-methyl-3-penten-1-yn-1-yl] -4,5-epoxy-1-
5 ml of a tetrahydrofuran solution of 442.6 mg of cyclopentene was added dropwise at 0 ° C. Then, after stirring at room temperature for 24 hours, the obtained reaction mixture was filtered through celite, and the celite layer was washed with hexane. The obtained filtrate was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give rel- (1S, 2S, 3) having the following physical properties.
R) -2- (t-Butyldimethylsilyloxy) -5
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yne-1
-Yl] -3-hydroxy-4-cyclopentenyl benzoate (equivalent to the compound represented by the formula (5) of the present invention) (515 mg) was obtained (yield: 89%).

NMR spectrum (90 MHz, CDCl
₃ ) δ: 8.31 to 7.26 (m, 5H), 6.21
(M, 1H), 5.85 (m, 2H), 4.79 (m,
1H), 4.70-4.40 (m, 2H), 4.30-
3.20 (m, 2H), 1.70 (m, 3H), 2.0
~ 1.2 (m, 6H), 0.86 (m, 9H), 0.0
5 (m, 6H)

Example 3 rel- (1S, 2S, 3R)-obtained by Example 2
2- (t-butyldimethylsilyloxy) -5-
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yne-1
-Yl] -3-hydroxy-4-cyclopentenyl benzoate (837 mg) and dihydropyran (0.22 ml) were dissolved in dichloromethane (10 ml), and a catalytic amount of p-toluenesulfonic acid was added to the resulting solution at 0 ° C. Then, the obtained reaction solution was stirred at room temperature for 20 minutes, a large excess of triethylamine was added thereto, and the mixture was concentrated under reduced pressure to obtain rel- (1S, 2S, 3R) -2- (t-butyl) having the following physical properties. Dimethylsilyloxy) -5-[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yn-1-yl] -3- (tetrahydro-2H- 980 mg of pyran-2-yloxy) -4-cyclopentenyl benzoate (corresponding to the compound of the present invention represented by the formula (5)) was obtained. FD mass spectrum [M] ⁺ 596

Example 4 rel- (1S, 2S, 3R)-obtained by Example 3
2- (t-butyldimethylsilyloxy) -5-
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yne-1
-Yl] -3- (tetrahydro-2H-pyran-2-yloxy) -4-cyclopentenyl benzoate 98
2.0 g of potassium carbonate was added to 20 ml of a 0 mg methanol solution at room temperature. Then, after stirring at room temperature for 24 hours, the reaction solution was filtered through celite, and the celite layer was washed with hexane. The obtained filtrate was washed with brine and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain rel- (1S, 2S, 3R) -2- (t-butyldimethylsilyloxy) -3- (tetrahydro-2H-pyran-2 having the following physical properties. -Yloxy) -5-[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-
3-penten-1-yn-1-yl] -4-cyclopentenol (corresponding to the compound represented by the formula (5) of the present invention)
800 mg were obtained. FD mass spectrum [M] ⁺ 492

Example 5 rel- (1S, 2S, 3R)-obtained by Example 4
2- (t-butyldimethylsilyloxy) -3- (tetrahydro-2H-pyran-2-yloxy) -5
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yne-1
-Yl] -4-cyclopentenol in 15 ml of dichloromethane.
5 g were added at room temperature. Then, after stirring at room temperature for 8 hours, the reaction solution was diluted with dichloromethane and filtered through florisil. The obtained filtrate was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give rel- (2S, 3R) -2- (t-butyldimethylsilyloxy) -3- (tetrahydro-2H-pyran-2-yloxy having the following physical properties. ) -5-[(Z) -5- (Tetrahydro-2H-pyran-2-yloxy) -3-methyl-3
-Penten-1-yn-1-yl] -4-cyclopentenone (corresponding to the compound represented by the formula (5) of the present invention) 46
3 mg were obtained.

NMR spectrum (90 MHz, CDCl
₃ ) δ: 7.44 (d, 1H, J = 2.2 Hz);
86 (m, 1H), 3.4 to 5.0 (m, 10H),
1.91 (d, 3H, J = 1.1 Hz), 1.2-2.
0 (m, 6H), 0.91 (m, 9H), 0.17
(M, 6H) IR spectrum (neat) cm ^-1 : 3456,29
32,2202,1738,1463,1256,11
20,1033,839,782,783

Example 6 rel- (2S, 3R) -2- obtained by Example 5
(T-butyldimethylsilyloxy) -3- (tetrahydro-2H-pyran-2-yloxy) -5-[(Z)
-5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yn-1-yl] -4-cyclopentenone in 2 ml of a diethyl ether solution was mixed with propargyl bromide. Ethyl ether solution of magnesium (1,2N, 0.20ml) at 0 ° C
Was dropped. Then, after stirring at 0 ° C. for 1 hour, the reaction solution was added to an ice-cooled saturated aqueous ammonium chloride solution with vigorous stirring. The aqueous layer was extracted with diethyl ether, and the obtained extract and the organic layer were combined, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. By purifying the obtained residue by silica gel column chromatography, rel- having the following physical properties is obtained.
(2S, 3R) -2- (t-butyldimethylsilyloxy) -1- (2-propyn-1-yl) -3- (tetrahydro-2H-pyran-2-yloxy) -5-
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yne-1
-Yl] -4-cyclopentenol (formula (4) of the present invention)
39.0 mg were obtained (yield: 8).
0%).

NMR spectrum (90 MHz, CDCl
₃ ) δ: 6.17 (m, 1H), 6.02 (m, 1)
H), 4.0-4.8 (m, 6H), 3.4-4.0.
(M, 4H), 2.5 (m, 2H), 2.0 (m, 1
H), 1.85 (m, 3H), 1.4 to 2.0 (m, 1
2H), 0.93 (m, 9H), 0.17 (m, 6H)

Example 7 rel- (2S, 3R) -2- obtained by Example 6
(T-butyldimethylsilyloxy) -1- (2-propyn-1-yl) -3- (tetrahydro-2H-pyran-2-yloxy) -5-[(Z) -5- (tetrahydro-2H-pyran -2-yloxy) -3-methyl-3
-Penten-1-yn-1-yl] -4-cyclopentenol (880 mg), dried diethyl ether (20 ml)
And butyllithium (1.61N, 2.05 ml) was added dropwise to the resulting solution at -78 ° C. After stirring at -40 ° C for 1 hour, the mixture was cooled to -78 ° C. Formaldehyde gas generated by thermally decomposing 5.0 g of paraformaldehyde was blown into the reaction solution at -78 ° C for 30 minutes. The obtained reaction solution was poured into water and extracted with diethyl ether. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. By purifying the obtained residue by silica gel column chromatography, rel- (2S, 3R) having the following physical properties is obtained.
-2- (t-butyldimethylsilyloxy) -1- (4
-Hydroxy-2-butyn-1-yl) -3- (tetrahydro-2H-pyran-2-yloxy) -5
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yne-1
-Yl] -4-cyclopentenol (formula (4) of the present invention)
323 mg (corresponding to the compound represented by) were obtained (yield: 37).
%).

NMR spectrum (90 MHz, CDCl
₃ ) δ: 5.8 to 6.2 (m, 2H), 3.3 to 4.9.
(M, 10H), 4.16 (brs, 2H), 2.2-
2.8 (m, 2H), 1.84 (brs, 3H), 1.
3-1.8 (m, 12H), 0.90 (s, 9H),
0.15 (s, 3H), 0.12 (s, 3H)

Example 8 rel- (2S, 3R) -2- obtained by Example 7
(T-butyldimethylsilyloxy) -1- (4-hydroxy-2-butyn-1-yl) -3- (tetrahydro-2H-pyran-2-yloxy) -5-[(Z) -5
-(Tetrahydro-2H-pyran-2-yloxy)-
3-methyl-3-penten-1-yn-1-yl] -4
To a solution consisting of 305 mg of cyclopentenol, 0.12 ml of triethylamine and 5 ml of tetrahydrofuran was added 0.020 ml of methanesulfonyl chloride at -20 ° C.
was added and stirred for 1 hour. Lithium bromide 14
2 mg was added, and the mixture was stirred at room temperature for 3 hours. The obtained reaction solution was poured into water and extracted with diethyl ether. The extract was washed sequentially with a saturated aqueous solution of copper sulfate, aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 10 ml of methanol, and a catalytic amount of pyridinium p-toluenesulfonate was added to the obtained solution, followed by stirring at room temperature for 16 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give rel- (2S, 3R) -2- (t-butyldimethylsilyloxy) -1- (4-bromo-2-butyne-1 having the following physical properties. −
Yl) -5-[(Z) -5-hydroxy-3-methyl-
74 mg of 3-penten-1-yn-1-yl] -4-cyclopentene-1,3-diol (corresponding to the compound represented by the formula (4) of the present invention) was obtained (yield: 30%).

NMR spectrum (90 MHz, CDCl
₃ ) δ: 5.8 to 6.1 (m, 2H), 3.4 to 4.8
(M, 4H), 3.84 (brs, 2H), 2.52
(Dt, 1H, J = 10.2, 2.3 Hz), 2.48
(Dt, 1H, J = 10.2, 2.0 Hz), 1.87
(Brs, 3H), 0.94 (s, 9H), 0.16
(S, 6H)

Example 9 58 mg of sodium hydride was washed with hexane, suspended in 20 ml of tetrahydrofuran, added with 0.2 ml of hexamethylphosphoric triamide and 0.02 ml of ethanol, and stirred at room temperature for 30 minutes. The obtained mixture was treated with rel- (2S, 3R) -2- (t-butyldimethylsilyloxy) -1- (4-bromo-2-) obtained in Example 8.
(Butyn-1-yl) -5-[(Z) -5-hydroxy-
3-methyl-3-penten-1-yn-1-yl] -4
-A solution of 20 mg of cyclopentene-1,3-diol in tetrahydrofuran (20 ml) was added at 25-30 ° C for 10 minutes.
It was dropped slowly over time. After the dropwise addition, the mixture was stirred at the same temperature for 1 hour, the obtained reaction solution was poured into a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue has the following physical properties by being purified by silica gel column chromatography.
rel- (14R, 15S) -15- (t-butyldimethylsilyloxy) -9-methyl-6-oxabicyclo-
[10,3,0] -pentadeca-8,12-diene-
7 mg of 3,10-diyne-1,14-diol (corresponding to the compound represented by the formula (3) of the present invention) was obtained.

NMR spectrum (300 MHz, CDC
l ₃ ) δ: 6.02 (d, 1H, J = 2.0 Hz),
5.94 (brt, 1H, J = 7.0 Hz), 4.3-
4.42 (m, 2H), 4.18 to 4.23 (m, 1
H), 4.17 (dt, 1H, J = 16.2, 2.0H
z) 4.13 (dt, 1H, J = 16.2, 2.4 Hz) 4.03 (d, 1H, J = 5.7 Hz), 2.87 (d
t, 1H, J = 17.2, 2.0 Hz) 2.25 (dt, 1H, J = 17.2, 2.4 Hz) 1.96 (d, 3H, J = 0.4 Hz), 0.93
(S, 9H), 0.15 (s, 6H)

Example 10 rel- (1S, 2S, 3R)-obtained by Example 2
2- (t-butyldimethylsilyloxy) -5-
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yne-1
-Yl] -3-hydroxy-4-cyclopentenyl benzoate (6.3 g) was dissolved in 30 ml of dimethylformamide, and 3.0 g of imidazole and t were added to the resulting solution.
3.3 g of -butyldimethylsilyl chloride were added at 0 ° C. Then, after stirring the obtained reaction solution at room temperature for 5 hours,
The reaction mixture was poured into 1N hydrochloric acid and extracted with ether.
The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain rel- (1S, 2S, 3R)-having the following physical properties.
2,3-di (t-butyldimethylsilyloxy) -5
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yne-1
-Yl] -4-cyclopentenyl benzoate (corresponding to the compound of the present invention represented by the formula (5)) 11.2 g was obtained. FD mass spectrum [M] ⁺ 626

Example 11 rel- (1S, 2S, 3R) obtained according to Example 10
-2,3-di (t-butyldimethylsilyloxy) -5
-[(Z) -5- (tetrahydro-2H-pyran-2-
Yloxy) -3-methyl-3-penten-1-yne-
1-yl] -4-cyclopentenyl benzoate in 200 ml of methanol solution was added potassium carbonate at room temperature.
7 g were added. Then, after stirring at room temperature for 15 hours, the reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give rel- (1S, 2
(S, 3R) -2,3-di (t-butyldimethylsilyloxy) -5-[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-pentene-
5.4 g of 1-yn-1-yl] -4-cyclopentenol (corresponding to the compound represented by the formula (5) of the present invention) was obtained. FD mass spectrum [M] ⁺ 522

Example 12 rel- (1S, 2S, 3R) obtained in Example 11
-2,3-di (t-butyldimethylsilyloxy) -5
-[(Z) -5- (tetrahydro-2H-pyran-2-
Yloxy) -3-methyl-3-penten-1-yne-
To a solution of 5.4 g of 1-yl] -4-cyclopentenol in 60 ml of dichloromethane, 4.2 g of sodium acetate and 6.6 g of pyridinium chlorochromate were added at room temperature. Then, after stirring at room temperature for 15 hours, 1 g of magnesium sulfate and 60 ml of diethyl ether were added to the reaction mixture.
Was added and the mixture was further stirred for 5 minutes, and the obtained reaction solution was filtered through celite. The obtained filtrate was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue is purified by silica gel column chromatography to give rel- (2S, 3R) -2,3-di (t) having the following physical properties.
-Butyldimethylsilyloxy) -5-[(Z) -5-
(Tetrahydro-2H-pyran-2-yloxy) -3
-Methyl-3-penten-1-yn-1-yl] -4-
4.0 g of cyclopentenone (corresponding to the compound of the present invention represented by the formula (5)) was obtained (yield: 74%).

NMR spectrum (300 MHz, CDC
l ₃ ) δ: 7.21 (d, 1H, J = 2.1 Hz),
6.10 (dd, 1H, J = 6.0, 7.0 Hz),
4.68 (dd, 1H, J = 2.1, 3.0 Hz),
4.61 to 4.63 (m, 1H), 4.28 (dd, 1
H, J = 14.0, 6.0 Hz), 4.18 (d, 1
H, J = 3.0 Hz), 4.13 (dd, 1H, J = 1)
4.0, 7.0 Hz), 3.80 to 3.90 (m, 1
H), 3.45 to 3.55 (m, 1H), 1.87.
(S, 3H), 1.50 to 1.80 (m, 6H), 0.
96 (s, 18H), 0.19 (s, 3H), 0.16
(S, 3H), 0.15 (s, 3H), 0.14 (s,
3H), IR spectrum (neat) cm ^-1 : 3032, 29
26,2854,2202,1740

Example 13 rel- (2S, 3R) -2, obtained according to Example 12,
3-di (t-butyldimethylsilyloxy) -5
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yne-1
-Yl] -4-cyclopentenone 1.58 g (3.04
(mmol) of diethyl ether solution at -78 ° C.
, And a solution of propargyl magnesium bromide in ethyl ether (1.2 N, 3.8 ml) was slowly added dropwise at -78 ° C. Then, after stirring at −78 ° C. for 10 minutes,
The reaction solution was added to 100 ml of a saturated aqueous ammonium chloride solution with vigorous stirring. The aqueous layer was extracted with diethyl ether, and the obtained extract and the organic layer were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give rel- (2S, 3R) -2,3-di (t-butyldimethylsilyloxy) -1- (2-propyne-1-) having the following physical properties. Yl) -5-[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-pentene-1
3.4 g of -in-1-yl] -4-cyclopentenol (corresponding to the compound represented by the formula (4) of the present invention) was obtained (yield: 81%).

NMR spectrum (90 MHz, CDCl
₃ ) δ: 5.90 to 6.00 (m, 1H), 5.95
(D, 1H, J = 2.0 Hz), 4.51 (brs, 1
H), 4.45 (dd, 1H, J = 2.0, 5.0H)
z), 4.11 (t, 2H, J = 5.2 Hz), 4.0
0 (d, 1H, J = 5.0 Hz), 3.60 to 4.00
(M, 2H), 2.55 (d, 2H, J = 2.0H
z), 2.02 (t, 1H, J = 2.0 Hz), 2.0
5 (t, 2H, J = 2.0 Hz), 1.84 (brs,
3H), 1.00-2.00 (m, 6H), 0.92
(S, 9H), 0.88 (s, 9H), 0.14 (s,
3H), 0.11 (s, 3H), 0.07 (s, 3
H), 0.33 (s, 3H), IR spectrum (neat) cm ^-1 : 3414,29
24, 2194, 2118, 1632, 1468, 11
34,779

Example 14 rel- (2S, 3R) -2, obtained according to Example 13,
3-di (t-butyldimethylsilyloxy) -1- (2
-Propyn-1-yl) -5-[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yn-1-yl] -4-cyclopen. 1.30 g of tenol was dissolved in 35 ml of dried tetrahydrofuran under an argon atmosphere, 1.21 ml of hexamethylphosphoric triamide was added, and the mixture was cooled to -78 ° C. Butyllithium (1.73N, 3.
35 ml) was added dropwise at -78 ° C, and the mixture was stirred at the same temperature for 20 minutes. Then, a solution of 0.54 ml of dimethylformamide dissolved in 10 ml of dry tetrahydrofuran was added,
Stirred at -10 ° C for 20 minutes. The obtained reaction solution was poured into a saturated aqueous solution of ammonium chloride, and extracted with diethyl ether. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in methanol (50 ml) and cooled to -10 ° C. Cerium chloride heptahydrate 1.30 was added to the resulting solution.
g and sodium borohydride 110 mg, and -10
Stirred at 150C for 15 minutes. Next, 20 ml of 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue has the following physical properties by being purified by silica gel column chromatography.
rel- (2S, 3R) -2,3-di (t-butyldimethylsilyloxy) -1- (4-hydroxy-2-butyn-1-yl) -5-[(Z) -5- (tetrahydro- 2
H-pyran-2-yloxy) -3-methyl-3-penten-1-yn-1-yl] -4-cyclopentenol (equivalent to the compound represented by the formula (4) of the present invention) 552 m
g was obtained (40% yield).

NMR spectrum (90 MHz, CDCl
₃ ) δ: 5.8 to 6.2 (m, 2H), 3.3 to 4.9.
(M, 7H), 4.16 (brs, 2H), 2.2-
2.8 (m, 2H), 1.84 (brs, 3H), 1.
3-1.8 (m, 6H), 0.92 (s, 9H), 0.
88 (s, 9H), 0.14 (s, 3H), 0.11
(S, 3H), 0.07 (s, 3H), 0.33 (s,
3H) IR spectrum (neat) cm ^-1 : 3402,29
28, 2224, 1670, 1463, 1120, 10
22,838,757

Example 15 rel- (2S, 3R) -2, obtained according to Example 14,
3-di (t-butyldimethylsilyloxy) -1- (4
-Hydroxy-2-butyn-1-yl) -5-[(Z)
1.56 g of -5- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-3-penten-1-yn-1-yl] -4-cyclopentenol and 0.74 ml of triethylamine were placed under an argon atmosphere. It was dissolved in 50 ml of dry dichloromethane and cooled to -78 ° C. 0.31 ml of methanesulfonyl chloride was added to the obtained solution.
Was added and stirred at -78 ° C for 10 minutes. The obtained reaction mixture was poured into water and extracted with diethyl ether. The extract was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 30 ml of tetrahydrofuran, and 703 mg of lithium bromide was added to the obtained solution.
Stirred for hours. The reaction mixture was poured into 100 ml of water and extracted with diethyl ether. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue has the following physical properties by being purified by silica gel column chromatography.
rel- (2S, 3R) -2,3-di (t-butyldimethylsilyloxy) -1- (4-bromo-2-butyne-1
-Yl) -5-[(Z) -5- (tetrahydro-2H-
1.15 g of pyran-2-yloxy) -3-methyl-3-penten-1-yn-1-yl] -4-cyclopentenol (corresponding to the compound of the present invention represented by the formula (4)) were obtained. (Yield 67%). FD mass spectrum [M] ⁺ 652,654

Example 16 rel- (2S, 3R) -2, obtained according to Example 15,
3-di (t-butyldimethylsilyloxy) -1- (4
-Bromo-2-butyn-1-yl) -5-[(Z) -5
-(Tetrahydro-2H-pyran-2-yloxy)-
3-methyl-3-penten-1-yn-1-yl] -4
-Dissolve cyclopentenol in 30 ml of a mixed solvent of tetrahydrofuran: acetic acid: water (1: 4: 1) and add
Stir for 5 hours. The obtained reaction solution was poured into a saturated aqueous solution of sodium bicarbonate,
Extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue is purified by silica gel column chromatography to give rel- (2S, 3R) -2,3-di (t) having the following physical properties.
-Butyldimethylsilyloxy) -1- (4-bromo-
2-butyn-1-yl) -5-[(Z) -5-hydroxy-3-methyl-3-penten-1-yn-1-yl]
560 mg of 4-cyclopentenol (corresponding to the compound represented by the formula (4) of the present invention) was obtained (yield: 56%).

NMR spectrum (90 MHz, CDCl
₃ ) δ: 5.8 to 6.1 (m, 2H), 3.4 to 4.8
(M, 4H), 3.84 (brs, 2H), 2.56
(Dt, 1H, J = 10.2, 2.3 Hz), 2.48
(Dt, 1H, J = 10.2, 2.0 Hz), 1.87
(Brs, 3H), 0.92 (s, 9H), 0.88
(S, 9H), 0.14 (s, 3H), 0.11 (s,
3H), 0.07 (s, 3H), 0.33 (s, 3H)

Example 17 50 mg of sodium hydride was washed with hexane, suspended in 5 ml of tetrahydrofuran, added with 0.03 ml of hexamethylphosphoric triamide and 0.03 ml of ethanol, and stirred at room temperature for 30 minutes. The rel- (2S, 3R) -2,3- obtained in Example 16 was added to the obtained mixture.
Di (t-butyldimethylsilyloxy) -1- (4-bromo-2-butyn-1-yl) -5-[(Z) -5-hydroxy-3-methyl-3-penten-1-yne-1 −
A solution of 25 mg of yl] -4-cyclopentenol in tetrahydrofuran (5 ml) was gradually added dropwise at room temperature over 1 hour. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, the obtained reaction solution was poured into a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give rel- (14R,
15S) -1-Hydroxy-14,15-di (t-butyldimethylsilyloxy) -9-methyl-6-oxabicyclo- [10,3,0] -pentadeca-8,12-diene-3,10- 11 mg of diyne (corresponding to the compound represented by the formula (3) of the present invention) was obtained (yield: 52%).

NMR spectrum (300 MHz, CDC
l ₃ ) δ: 6.02 (d, 1H, J = 2.0 Hz),
5.94 (t, 1H, J = 7.0 Hz), 4.30-
4.42 (m, 2H), 4.18 to 4.23 (m, 1
H), 4.17 (dt, 1H, J = 16.2, 2.0H
z) 4.13 (dt, 1H, J = 16.2, 2.4 Hz) 4.03 (d, 1H, J = 5.7 Hz), 2.87 (d
t, 1H, J = 17.2, 2.0 Hz) 2.25 (dt, 1H, J = 17.2, 2.4 Hz) 1.96 (d, 3H, J = 0.4 Hz), 0.92
(S, 9H), 0.88 (s, 9H), 0.14 (s,
3H), 0.11 (s, 3H), 0.07 (s, 3
H), 0.33 (s, 3H)

Example 18 rel- (14R, 15S) -1 obtained in Example 17
-Hydroxy-14,15-di (t-butyldimethylsilyloxy) -9-methyl-6-oxabicyclo- [1
[0,3,0] -pentadeca-8,12-diene-3,1
0.07 ml of triethylamine was added to 10 ml of a dichloromethane solution of 46 mg of 0-diyne, and the mixture was cooled to 0 ° C.
Trimethylsilyl triflate 0.04 was added to the resulting solution.
ml was added dropwise at 0 ° C., and then stirred at the same temperature for 5 minutes. The resulting reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ether. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue is purified by silica gel column chromatography to give rel- (14R, 15S) having the following physical properties.
-1-trimethylsilyloxy-14,15-di (t-
Butyldimethylsilyloxy) -9-methyl-6-oxabicyclo- [10,3,0] -pentadeca-8,12
47 mg of -diene-3,10-diyne (corresponding to the compound of the present invention represented by the formula (3)) was obtained (89% yield). FD mass spectrum [M] ⁺ 560

Example 19 In Reference Example 1- (2), (Z) -1- (tetrahydro-2H-pyran-2-yloxy) -3-methyl-2
Performing the reaction, separation and purification in the same manner except that (Z) -1- (tetrahydro-2H-pyran-2-yloxy) -2-penten-4-yne was used instead of -penten-4-yne Rel- (2S, 3S, 4R)
-4- (t-butyldimethylsilyloxy) -1-
[(Z) -5- (tetrahydro-2H-pyran-2-yloxy) -3-penten-1-yn-1-yl]-
2,3-Epoxycyclopentanol was obtained. Example 1 was prepared using the cyclopentanol thus obtained as a raw material.
By carrying out the reaction and the separation and purification according to
el- (14R, 15S) -15- (t-butyldimethylsilyloxy) -6-oxabicyclo- [10,3
0] -pentadeca-8,12-diene-3,10-diyne-1,14-diol (corresponding to the compound represented by formula (3) of the present invention). FD mass spectrum [M] ⁺ 360

Example 20 rel- (14R, 15S) obtained in Example 18
-1-trimethylsilyloxy-14,15-di (t-
Butyldimethylsilyloxy) -9-methyl-6-oxabicyclo- [10,3,0] -pentadeca-8,12
T-butyllithium (1.62N, 1.62N,
0.1 ml) was added dropwise at -100 ° C. Next, after stirring at the same temperature for 40 minutes, 3 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was further stirred at room temperature for 10 minutes. The obtained reaction solution was diluted with ether, washed with brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give the following physical properties (11R,
12S) -1-trimethylsilyloxy-11,12-
Di (t-butyldimethylsilyloxy) -6-methyl-
6-vinylbicyclo- [7,3,0] -dodec-9-ene-3,7-diyn-5-ol (compound A) (corresponding to the compound represented by formula (1) of the present invention) and having physical properties (13R, 14S) -1- trimethylsilyloxy-13,14-di (t- butyldimethylsilyloxy) -8- methylbicyclo - [9,3,0] - tetradeca -7,11 diene - 3, to obtain a mixture 29mg of 9-diyne-5-ol (corresponding to compounds of formula (2) of the present invention) (compound B) (62% yield). Both were separated by high performance liquid chromatography.

The NMR spectrum of compound A (300 MH
z, CDCl ₃ ) δ: 5.85 (dd, 1H, J = 1)
6.0, 11.0 Hz), 5.80 (d, 1H, J =
2.0 Hz), 5.44 (d, 1H, J = 16.0H)
z), 5.22 (d, 1H, J = 11.0 Hz), 4.
34 (dd, 1H, J = 4.0, 2.0 Hz), 4.2
1 (d, 1H, J = 4.0 Hz), 4.05 (d, 1
H, J = 10.0 Hz), 2.26, 2.60 (AB
q, 2H, J = 16.0 Hz) 1.84 (d, 1H, J = 10.0 Hz), 1.34
(S, 3H), 0.89 (s, 18H), 0.05 to
0.20 (m, 21H)

The NMR spectrum of compound B (300 MH
z, CDCl ₃ ) δ: 5.88 (s, 1H), 5.82
(T, 1H), 4.1-4.3 (m, 3H), 2.72
(D, 1H), 2.50 (brs, 1H), 1.12
(D, 1H), 1.9 (s, 3H), 1.7 to 1.9.
(M, 2H), 0.9 (s, 18H), 0.05-0.
25 (m, 21H)

[0058] to give et been by Example 21 Example 20 rel- (11R, 12S)
-1-trimethylsilyloxy-11,12-di (t-
Butyldimethylsilyloxy) -6-methyl-6-vinylbicyclo- [7,3,0] -dodec-9-ene-3,
26 mg of phthalic anhydride and 1 mg of 4-dimethylaminopyridine were added to 0.2 ml of a pyridine solution of 8 mg of 7-diyn-5-ol (compound A). After the resulting solution was stirred at room temperature for 2 hours, it was diluted with 30 ml of chloroform.
After washing with N hydrochloric acid and brine and drying over anhydrous magnesium sulfate, the solvent was distilled off. The resulting residue by a child purified by silica gel column chromatography,
(11R, 12S) -1-trimethylsilyloxy-11,12-di (t-butyldimethylsilyloxy) -6-methyl-6-vinylbicyclo- having the following physical properties
[7,3,0] -Dodeca-9-ene-3,7-diyne-
10 mg of 5-yl-o-carboxybenzoate (corresponding to the compound of the present invention represented by the formula (1)) was obtained (yield: 83%).

NMR spectrum (300 MHz, CDC
l ₃ ) δ: 5.81 (d, 1H, J = 3.0 Hz),
5.80 (dd, 1H, J = 10.0, 19.0H
z), 5.47 (s, 1H), 5.46 (d, 1H, J
= 19.0 Hz), 5.15 (d, 1H, J = 10.0)
Hz), 4.32 to 4.34 (m, 1H), 4.17.
(D, 1H, J = 3.0 Hz), 2.60, 2.32
(ABq, 2H, J = 17.0 Hz), 1.47 (s,
1H), 0.89 (s, 18H), 0.07 to 0.21
(M, 21H)

Example 22 rel- (11R, 12S) -1 obtained in Example 21
-Trimethylsilyloxy-11,12-di (t-butyldimethylsilyloxy) -6-methyl-6-vinylbicyclo- [7,3,0] -dodec-9-ene-3,7-
Diin-5-yl-o-carboxybenzoate 10m
g was dissolved in a mixed solution of 1.9 ml of acetonitrile and 0.5 ml of 40% hydrofluoric acid, and stirred at room temperature for 4 hours. 10 ml of pure water was added to the obtained reaction solution, followed by lyophilization to obtain rel- (11R, 12) having the following physical properties.
S) -1,11,12-Trihydroxy-6-methyl-
6-Vinylbicyclo- [7,3,0] -dodec-9-ene-3,7-diyn-5-yl-o-carboxybenzoate was obtained. NMR spectrum (300 MHz, CDCl ₃ ) δ:
7.5-8.1 (m, 4H), 5.8-6.0 (m, 2
H), 5.2-5.4 (m, 2H), 5.0-5.2.
(M, 1H)

[0061]

According to the present invention, a compound related to the chromophore portion of neocarzinostatin, which has less restrictions in clinical use, is stable, and has antibacterial activity and antitumor activity. A cyclopentenol derivative represented by 1) and formula (2) is provided. These cyclopentenol derivatives are useful as antibacterial agents or anticancer agents. Also provided are novel intermediates (cyclopentenol derivatives represented by formulas (3) to (6)) useful for synthesizing the cyclopentenol derivatives represented by formulas (1) and (2). Is done.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07D 313/00 C07D 313/00 C07F 7/18 C07F 7/18 A // A61K 31/045 A61K 31/045 31/12 31 / 12 31/215 31/215 31/335 31/335 A61P 31/04 A61P 31/04 35/00 35/00 (58) Fields studied (Int. Cl. ⁷ , DB name) C07C 35/06 C07C 35 / 48 C07C 49/743 C07C 49/753 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] (1) Formula (1) (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or a hydroxyl-protecting group. R ⁵ may represent an acyl group substituted with a water-soluble functional group. A) a cyclopentenol derivative; (2) Formula (2) (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² , R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or a hydroxyl-protecting group. R ⁵ may represent an acyl group substituted with a water-soluble functional group. A) a cyclopentenol derivative; (3) Formula (3) (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² , R ³ and R ⁴ each represent a hydrogen atom or a hydroxyl-protecting group. A) a cyclopentenol derivative; 4. A compound of the formula (4) (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² , R ³ and R ⁴ each represent a hydrogen atom or a protecting group for a hydroxyl group, X represents an —OR ⁶ group or a halogen atom, and Y represents a hydrogen atom, —CH ₂ OR ⁷ group or —CH ₂
Represents a Z group. Wherein R ⁶ and R ⁷ each represent a hydrogen atom, an organic sulfonyl group or a protecting group for a hydroxyl group;
Represents a halogen atom. A) a cyclopentenol derivative; 5. A compound of the formula (5) (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² , R ³ and R ⁸ each represent a hydrogen atom or a protecting group for a hydroxyl group, A represents a hydrogen atom, and B represents —OR
Either ⁹ groups are represented, or A and B together represent an oxo group. Here, R ⁹ represents a hydrogen atom or a hydroxyl-protecting group. A) a cyclopentenol derivative; 6. A compound of the formula (6) (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² and R ⁸ each represent a hydrogen atom or a hydroxyl-protecting group. A) a cyclopentenol derivative;