JPH09176079A - Production of 3-oxodicyclopentadiene - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain the above compound useful as a synthetic intermediate for various physiologically active substances by carrying out specific reaction of a specific compound in the presence of a metal halide. SOLUTION: (A) An 4-alkoxy-2-cyclopentene-1-one of formula I (R is a 1-10C alkyl) is subjected to Diels-Alder reaction with (C) cyclopentadiene in the presence of (B) a metal halide (preferably a zinc halide or a titanium halide) to afford an isomer mixture of Diels-Alder adducts represented by formula Hand formula III, which is then passed through dealkylation process using a titanium compound (preferably titanium halide) and dehydration process under basic conditions to provide the objective compound of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing 3-oxodicyclopentadiene, which is useful as a synthetic intermediate for various physiologically active substances.

[0002]

2. Description of the Related Art Conventionally, as a method for producing 3-oxodicyclopentadiene, a method of oxidizing 3-hydroxydicyclopentadiene has been widely known, and as an oxidant, zinc bismuthate (Bull. Chem. Soc. .J
pn. , 65 , 1131 (1992)), zinc chlorochromate (Synthesis, 1992 , 999), pyridinium fluorochromate (Synthesis, 1).
982 , 588), quinolinium fluorochromate (B
ull. Chem. Soc. Jpn. , 67 , 1894
(1994)), dimethyl sulfoxide / chlorosulfonyl isocyanate (Synthesis, 1980 ,
141) and many other examples. However, it is difficult to say that all of these oxidizers are suitable for mass production because they have problems in availability, wastewater treatment, reaction temperature, etc., and development of a more practical and efficient manufacturing method is desired. It was The 3-oxodicyclopentadiene in the present invention is a useful compound that can be widely used as a synthetic intermediate for various physiologically active substances. For example, if this compound is used as a starting material,
(+)-Eilenin (J. Chem. S), which is one of the promising estrogen steroid hormones as an oral contraceptive
oc. Chem. Commun. , 1990 , 154
4) and (+)-Estrone (Tetrahedron)
Lett. , 33 , 1909 (1992)) can be easily synthesized. In addition, (-)-aphanorphine (J. Ch
em. Soc. Chem. Commun. , 199
0 , 290) and (-)-physobenin (J. Org. Chem., 56 , 5982) having a central nervous system excitatory action.
(1991)) can also be efficiently synthesized from 3-oxodicyclopentadiene.

[0003]

Based on the above points, the present inventors have conducted extensive studies to find a method for efficiently obtaining 3-oxodicyclopentadiene, and as a result, 4-alkoxy-2-cyclopentene-1- Dines-Ald in the presence of metal halides with on and cyclopentadiene
er reaction to produce 3 represented by the above formula (III)
The present invention has been accomplished by finding a method for efficiently obtaining -oxodicyclopentadiene. As is apparent from the above description, the object of the present invention is to provide a method as described above.

[0004]

The present invention includes the following (1).
To (7).

Equation (1) (I)

Embedded image (In the formula, R represents a straight-chain or branched alkyl group having 1 to 10 carbon atoms.) 4-alkoxy-2-cyclopenten-1-one is mixed with cyclopentadiene and Diels in the presence of a metal halide. -Alder reaction to give formula (II)

Embedded image And formula (II ')

Embedded image (Wherein R represents a straight-chain or branched alkyl group having 1 to 10 carbon atoms), an isomer mixture of the Diels-Alder adducts is obtained, followed by dealkylation using a titanium compound, and a base. Formula (III) via dehydration process under sexual conditions

Embedded image (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) A method for producing 3-oxodicyclopentadiene.

(2) The production method according to (1) above, wherein the metal halide is zinc halide or titanium halide, and the titanium compound is titanium halide.

(3) The production method according to (1) above, wherein the alkoxy group of 4-alkoxy-2-cyclopenten-1-one is a tert-butoxy group.

(4) In the above (1), the formula (I)

Embedded image (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) A formula (III) in which 4-alkoxy-2-cyclopenten-1-one represented by the formula is an optically active substance.

Embedded image (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) A method for producing an optically active form of 3-oxodicyclopentadiene.

(5) Formula (IV)

Embedded image (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) (±) -4-alkoxy-2-
By subjecting cyclopenten-1-ol to a transesterification reaction with fatty acid vinyl using a lipase and acylating it stereoselectively, a compound of the formula ((+)-V)

Embedded image (In the formula, R represents a straight-chain or branched alkyl group having 1 to 10 carbon atoms, and R ′ represents a straight-chain or branched alkyl group having 1 to 20 carbon atoms.) (+)- 1-acyloxy-4-alkoxy-2-cyclopentene and the formula ((-)-
IV)

Embedded image (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) (-)-4-alkoxy-2-
It is optically resolved into cyclopenten-1-ol, and each optically active compound is separated from the mixture, followed by a deesterification step and an oxidation step of a hydroxyl group to obtain a compound of the formula ((+)-
I)

Embedded image (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) (+)-4-alkoxy-2-
Cyclopenten-1-one, and formula ((-)-I)

Embedded image (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) (-)-4-alkoxy-2-
A process for producing optically active 4-alkoxy-2-cyclopenten-1-one, which comprises obtaining cyclopenten-1-one.

(6) The production method according to the above (5), wherein the alkoxy group of 4-alkoxy-2-cyclopenten-1-ol is a tert-butoxy group.

(7) The production method according to (5) above, wherein the lipase is derived from Pseudomonas.

Next, the present invention will be described in detail. The 3-oxodicyclopentadiene (III) of the present invention can be produced according to the following steps.

[0013]

Embedded image

(In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.)

The racemate of the compound represented by the formula (I) used in the present invention can be obtained by a method known in the literature (for example, Takano et al.,
Heterocycles, 16 , 605 (198)
It can be easily synthesized by 1)). That is,
Compound represented by formula (I) and cyclopentadiene (VI)
And in the presence of a metal halide, Diels-Alde
By carrying out the r reaction, an isomer mixture of the compounds represented by the formula (II) and the formula (II ′) can be obtained. Examples of metal halides include zinc compounds such as zinc chloride, zinc bromide and zinc iodide, and titanium compounds such as titanium tetrachloride. The metal halide can be used in an amount of 0.01 to 10 equivalents relative to the substrate, and particularly preferably 0.1 to 5 equivalents. The reaction is preferably carried out in a solvent, and as the reaction solvent, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, an aromatic hydrocarbon solvent such as benzene or toluene can be used. The reaction temperature is suitably -50 to 150 ° C, particularly preferably 0 to 50 ° C.

The mixture of the compounds represented by the formulas (VII) and (VII ') is obtained by dealkylating the mixture of the compounds represented by the formulas (II) and (II') with a titanium compound. Can be obtained by Titanium tetrachloride can be mentioned as an example of a titanium compound. The titanium compound can be used in an amount of 0.1 to 10 equivalents relative to the substrate, but is particularly preferably 0.5 to 5 equivalents. As the reaction solvent, a halogenated hydrocarbon solvent such as methylene chloride can be preferably used. The reaction temperature is suitably -50 to 100 ° C, particularly preferably -10 to 50 ° C.

The compound represented by the formula (III) has the formula (VII)
And a compound represented by the formula (VII ′) are dehydrated in a basic aqueous solution. Examples of the base used for the dehydration reaction include metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and barium hydroxide, and metal carbonates such as sodium carbonate and potassium carbonate. The base can be used in an amount of 0.1 to 50 equivalents relative to the substrate, and particularly preferably 1 to 10 equivalents. The reaction solvent can be widely used as long as it is an organic solvent that does not inhibit the reaction, for example, methylene chloride, a halogenated hydrocarbon solvent such as chloroform, ether,
An ether solvent such as tetrahydrofuran can be preferably used. The reaction temperature is suitably -50 to 150 ° C, particularly preferably -10 to 100 ° C.

By the above operation, (±) -3-oxodicyclopentadiene can be efficiently produced.
Each of the above-mentioned three steps may be carried out stepwise, but a cyclopentadiene-metal halide, a titanium compound, a compound represented by the formula (I) dissolved in a reaction solvent,
By sequentially dropping and reacting a basic aqueous solution,
(±) -3-Oxodicyclopentadiene can also be produced in one pot. If optically active ((+)-I) and ((-)-I) are used as the starting materials of the present invention, optically active 3-oxodicyclopentadiene can be produced through the same steps. .

The compounds represented by the formula ((+)-I) and the formula ((-)-I) can be prepared by methods known in the literature (for example, Hamb).
ley et al. Org. Chem. , 56 , 4760
(1991)) for easy synthesis. Alternatively, the method of the present invention, namely (±) -4-alkoxy-
2-Cyclopenten-1-ol (IV) is optically resolved by subjecting it to transesterification with fatty acid vinyl in the presence of lipase to obtain optically active ((-)-IV) and ((+)-V). After separating the mixture of using a method such as silica gel column chromatography, deesterification,
It can also be obtained by performing oxidation. The steps are shown below.

[0020]

Embedded image

As the lipase, commercially available lipases shown in the following table can be used.

[0022]

[Table 1]

In addition to these, any lipase can be used as long as it is a microorganism producing a lipase having a transesterification ability, regardless of its type. Examples of such microorganisms include Pseudomonus genus, Chromobacterium genus, Arthrobacter
(Arthrobacter) genus, Acromobacte
r) genus, Alcaligenes genus, Aspergilius genus, Candida genus,
Examples thereof include those belonging to the genus Mucor, the genus Rhizopus, and the like. Particularly preferable among these are those derived from the genus Pseudomonas.

The fatty acid vinyl may, for example, be vinyl acetate, vinyl propionate, vinyl caproate or vinyl laurate. Fatty acid vinyl is 0.1 to the substrate
50 equivalents can be used, but particularly preferably 0.5
10 to 10 equivalents. Typical reaction solvents include hydrocarbon solvents such as heptane and hexane, aromatic hydrocarbon solvents such as toluene and benzene, and ether solvents such as diethyl ether, t-butyl methyl ether, and tetrahydrofuran. Any organic solvent that does not inhibit the lipase activity can be widely used. Reaction temperature is 10
To 100 ° C is suitable, and particularly preferably 20 to 50 ° C.
It is. The reaction time is 1 to 300 hours, preferably 10 to 100 hours.

Further, the compound represented by the formula ((+)-V) can be easily led to the compound represented by the formula ((+)-IV) by hydrolysis or alcoholysis under basic conditions. You can As the base used for hydrolysis,
Examples thereof include hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, sodium methoxide and sodium ethoxide. The reaction may be carried out in water or a mixed solvent of water and alcohol, and the reaction temperature is preferably -20 to 150 ° C. The base used for alcoholysis is similar to hydrolysis. The reaction is preferably carried out in a lower alcohol such as methanol, ethanol or propanol. Reaction temperature is -2
A temperature of 0 to 150 ° C is suitable.

The compounds represented by the formula ((+)-IV) and the formula ((-)-IV) are obtained by oxidizing the hydroxyl group according to a known method to obtain the formula ((+)-I) and the formula ((-). ) -I) can be easily converted. Examples of the oxidation method include chromic acid oxidation using pyridinium chlorochromate and the like, activated DMSO oxidation using dimethylsulfoxide / sulfur trioxide-pyridine complex and the like. Optically active 4
-Alkoxy-2-cyclopenten-1-one can be obtained. By using this as a starting material, optically active 3-oxodicyclopentadiene can be efficiently produced.

[0027]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Synthesis of (±) -3-oxodicyclopentadiene Step 1 (±) -3-oxo-5-tert-butoxy-4,5
-Synthesis of dihydrodicyclopentadiene (±) -4-tert-butoxy-2-cyclopenten-1-one (536 mg, 3.5 mmol) was dissolved in anhydrous benzene (30 ml), and zinc chloride (570 mg,
4.2 mmol) and added at room temperature under argon flow for 30
Stirred for minutes. Then cyclopentadiene (0.84m
1, 10.4 mmol) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was made alkaline with saturated aqueous sodium hydrogen carbonate under ice cooling, and the mixture was filtered through Celite. The Celite layer was washed with ethyl acetate and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine. The extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate /
Hexane = 2/98 (v / v)) and colorless solid (±) -endo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (70
3 mg, 92%) and colorless oily (±) -exo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (48 mg, 6%) were obtained. (±) - endo -3- oxo -5-tert-butoxy-4,5-dihydro-dicyclopentadiene; mp: 42-42.5 ℃ IR (Nujol ): 1735cm -1 1 H-NMR (CDCl 3): δ 1.19 (s),
1.34 (d, J = 8.0 Hz), 1.48 (d, J =
8.0 Hz), 2.05 (dd, J = 19.0, 9.5)
Hz), 2.31 (ddd, J = 19.0, 9.0,
1.5Hz), 2.87 (dd, J = 8.5, 4.8H
z), 3.06 (m), 3.13 (brs), 3.19.
(Brs), 4.28 (q, J = 9.2 Hz), 5.9
4 (dd, J = 5.5, 2.9 Hz), 6.33 (d
d, J = 5.5Hz) (± ) - exo -3-oxo ^{-5-tert-butoxy-4,5-dihydro-dicyclopentadiene; IR (Neat): 1735cm -1} 1 H-NMR (CDCl 3): δ 1.19 (s),
1.41 (d, J = 8.0 Hz), 1.55 (d, J =
8.0 Hz), 2.24 (ddd, J = 19.0, 5.
1,1.5 Hz), 2.34 (dd, J = 19.0,
7.3 Hz), 2.95 (dt, J = 6.6, 2.9H)
z), 3.17 (m), 3.69 (m), 3.19 (b)
rs), 6.15 (brs)

Step 2 Synthesis of (±) -3-oxo-5-hydroxy-4,5-dihydrodicyclopentadiene (±) -endo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclo Pentadiene (375m
g, 1.7 mmol) was dissolved in anhydrous methylene chloride (7 ml), and titanium tetrachloride (0.23 ml, 2.0 mmo)
1) was added, and the mixture was stirred at 0 ° C. for 5 minutes under an argon stream. The reaction mixture was made alkaline with saturated aqueous sodium hydrogen carbonate, and the mixture was filtered through Celite. The Celite layer was washed with methylene chloride and the organic phase was separated. The aqueous phase was extracted with methylene chloride, the organic phases were combined and washed with saturated brine. The extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 → 1/4 (v / v)), and colorless solid (±) -3-oxodicyclopentadiene (46
mg, 19%) and (±) -endo-3-oxo-5-hydroxy-4,5-dihydrodicyclopentadiene (2
25 mg, 80%) was obtained. Similarly, (±) -exo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (150 mg, 0.68 m
mol) from colorless solids (±) -3-oxodicyclopentadiene (10 mg, 10%) and (±) -exo-
3-oxo-5-hydroxy-4,5-dihydrodicyclopentadiene (84 mg, 75%) was obtained. (±) -endo-3-oxo-5-hydroxy-4,5
- dihydrodicyclopentadiene; mp: 154-155 ℃ IR (Nujol ): 3220,1720cm -1 1 H-NMR (CDCl 3): δ 1.42 (d, J =
8.4 Hz), 1.56 (d, J = 8.4 Hz), 1.
70 (brs), 2.10 (dd, J = 18.6, 1
0.3 Hz), 2.49 (ddd, J = 18.6, 9.
2,1.1 Hz), 3.00 (m), 3.21 (m),
4.62 (m), 6.05 (dd, J = 5.5, 2.9)
Hz), 6.38 (dd, J = 5.5, 2.6 Hz) (±) -exo-3-oxo-5-hydroxy-4,5
- ^{dihydrodicyclopentadiene; IR (Neat): 3418,1731cm -1} 1 H-NMR (CDCl 3): δ 1.43 (d, J =
8.4 Hz), 1.55 (d, J = 8.4 Hz), 1.
71 (brs), 2.17 (d, J = 19.0 Hz),
2.34 (dd, J = 19.0, 6.6 Hz), 2.9
3 (dd, J = 9.2, 4.0 Hz), 3.09
(M), 3.19 (brs), 4.05 (brs),
6.11 (brs)

Step 3 Synthesis of (±) -3-oxodicyclopentadiene (±) -endo-3-oxo-5-hydroxy-4,5
-Dihydrodicyclopentadiene (39 mg, 0.23
mmol) in tetrahydrofuran (0.48 ml) and dissolved in 5% aqueous sodium hydroxide solution (0.48 ml,
0.6 mmol) was added dropwise and the mixture was stirred at room temperature for 30 minutes.
Ether (5 ml) and water (1 ml) were added to the reaction solution to separate the organic phase. The aqueous phase was extracted with ether, and the organic phases were combined and washed with saturated brine. The extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/9 (v
/ V)) to give colorless solid (±) -3-oxodicyclopentadiene (30 mg, 87%).
Similarly, (±) -exo-3-oxo-5-hydroxy-4,5-dihydrodicyclopentadiene (36 m
g, 0.22 mmol) to a colorless solid (±) -3-
Oxodicyclopentadiene (27 mg, 85%) was obtained. mp: 52-55 ℃ IR (Nujol) : 1713cm -1 1 H-NMR (CDCl 3): δ 1.62 (d, J =
8.4 Hz), 1.72, dt, J = 8.4, 1.6H
z), 2.80 (t, J = 5.1 Hz), 2.97 (b
rs), 3.22 (brs), 3.42 (m), 5.7
8 (dd, J = 5.6, 3.0 Hz), 5.94 (d
d, J = 5.6, 2.7 Hz), 5.96 (dd, J =
5.8, 1.6 Hz), 7.39 (dd, J = 5.8,
2.5 Hz) MS (m / z): 146 (M ⁺ ), 117, 66

Examples 2 to 4 (±) -3-oxo-5-tert-butoxy-4,5
-Synthesis of dihydrodicyclopentadiene In the same manner as in Example 1, step 1, (±) -4-tert-
From butoxy-2-cyclopenten-1-one (±)-
Endo-3-oxo-5-tert-butoxy-4,5
-Dihydrodicyclopentadiene and (±) -exo-
Table 2 shows the results of obtaining 3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene.

[0032]

[Table 2]

Example 5 Synthesis of (±) -3-oxodicyclopentadiene (±) -4-tert-butoxy-2-cyclopenten-1-one (185 mg, 1.2 mmol) was dissolved in anhydrous benzene (10 ml). And cyclopentadiene (0.29 ml, 3.6 mmol) at 0 ° C. under an argon stream.
, Then titanium tetrachloride (66 μl, 0.6 mmo
1) was added dropwise and the mixture was stirred at the same temperature for 1 hour. Subsequently, anhydrous methylene chloride (2.5 ml) was added, and titanium tetrachloride (0.13 ml, 1.2 mmol) was added dropwise with stirring. After stirring at the same temperature for 5 minutes, a 5% aqueous sodium hydroxide solution (1
0 ml, 12.5 mmol) dropwise at room temperature for a further 40
Stirred for minutes. The reaction mixture was filtered through Celite, the Celite layer was washed with ether, and the organic phase was separated. The aqueous phase was extracted with ether, and the organic phases were combined and washed with saturated brine. The extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 (v / v)) to obtain colorless solid (±) -3-oxodicyclopentadiene (146 mg, 83%). Each spectral data was in perfect agreement with that obtained in Example 1, step 3.

Example 6 Synthesis of (±) -3-oxodicyclopentadiene (±) -4-tert-butoxy-2-cyclopenten-1-one (185 mg, 1.2 mmol) was dissolved in anhydrous benzene (10 ml). And cyclopentadiene (0.29 ml, 3.6 mmol) at 0 ° C. under an argon stream.
And then zinc chloride (196 mg, 1.4 mmo
1) was added dropwise and the mixture was stirred at the same temperature for 12 hours. Subsequently, anhydrous methylene chloride (2.5 ml) was added, and titanium tetrachloride (0.14 ml, 1.3 mmol) was added dropwise with stirring. After stirring at the same temperature for 5 minutes, a 5% aqueous sodium hydroxide solution (10 ml, 12.5 mmol) was added dropwise, and the mixture was further stirred at room temperature for 40 minutes. Post-treatment and purification were carried out in the same manner as in Example 5 to obtain colorless solid (±) -3-oxodicyclopentadiene (141 mg, 81%). Each spectral data was in perfect agreement with that obtained in Example 1, step 3.

Example 7 Synthesis of optically active 4-tert-butoxy-2-cyclopenten-1-one Step 1 Synthesis of optically active 4-tert-butoxy-2-cyclopenten-1-ol (±) -4-tert- Butoxy-2-cyclopenten-1-ol (1.2 g, 7.6 mmol) was dissolved in benzene (35 ml) and vinyl acetate (2.1 ml, 23
mmol) and lipase PS (Amano Pharmaceutical Co., Ltd., 120 mg) were sequentially added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through Celite, and the Celite layer was washed with methylene chloride. The organic phase was concentrated under reduced pressure to give (+)-1-acetoxy-4.
-Tert-butoxy-2-cyclopentene and (+)-
A mixture of 4-tert-butoxy-2-cyclopenten-1-ol was obtained. These were subjected to silica gel column chromatography (ethyl acetate / hexane = 5/95 (v /
(v) → 1/2 (v / v)) for separation and purification, and colorless oily (+)-1-acetoxy-4-tert-butoxy-2-cyclopentene (727 mg, 48%) and (−).
-4-tert-butoxy-2-cyclopentene-1-
Obtained all (639 mg, 53%). (+)-1-acetoxy-4-tert-butoxy-2
- cyclopentene; [α] _D ²⁷ -12.2 ° _{(CHCl 3) IR (film)} : ν 1725cm -1 1 H-NMR (CDCl 3): δ = 1.21 (s, 9
H), 1.62 (dt, 1H, J = 14.0, 4.8H
z), 2.20 (s, 3H), 2.77 (dt, 1H,
J = 14.0, 6.6 Hz), 4.52 (brt, 1
H, J = 5.8 Hz), 5.46 (brt, 1H, J =
5.8 Hz), 5.89 (dt, 1H, J = 5.5,
1.8 Hz), 5.94 (dt, 1H, J = 5.5)
1.8 Hz) MS: m / z 198 (M ⁺ ), 43 (100%) HRMS: m / z Calc. forC ₁₁ H ₁₈ O ₃ : 1
98.1256 found: 198.1292 (−)-4-tert-butoxy-2-cyclopenten-1-ol; [α] _D ²⁸ −20.5 ° (CHCl ₃ ) IR (film): ν 3376 cm ^{−1 1} H-NMR (CDCl ₃ ): δ = 1.23 (s, 9
H), 1.51 (dt, 1H, J = 13.9, 7.0H
z), 4.47 (brs, 1H), 5.94 (brt,
1H, J = 5.5 Hz) MS: m / z 141 (M ⁺ -15), 57 (100
%) HRMS: m / z Calc. forC ₈ H ₁₃ O ₂ : 1
41.0916 found: 141.0898 (+)-1-acetoxy-4-tert-butoxy-2
-A mixture of cyclopentene (201 mg, 1.0 mmol) and potassium carbonate (841 mg, 6.1 mmol) was stirred in methanol (5 ml) at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2 (v / v)), and colorless oily (+)-4-tert-butoxy-2-cyclopenten-1-ol (147 mg, 87%). [Α] _D ²⁵ + 22.9 ° (CHCl ₃ ) Each spectrum data is (−)-4-tert-
Consistent with that of butoxy-2-cyclopenten-1-ol.

Step 2 Synthesis of optically active 4-tert-butoxy-2-cyclopenten-1-one (+)-4-tert-butoxy-2-cyclopenten-1-ol (357 mg, 2.3 mmol) was added to methylene chloride ( 8 ml) and pyridinium chlorochromate (741 mg, 3.4 mmol) was added little by little at room temperature. After stirring for 1.5 hours at room temperature, the reaction mixture was diluted with methylene chloride and filtered through silica gel. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 (v / v)), and colorless oily (+)-4-tert-butoxy-2-cyclopenten-1-one (289 mg, 82%). [Α] _D ²⁸ + 47.8 ° (CHCl ₃ ) HPL using an optical isomer separation column (CHIRALCEL OB, isopropanol: hexane = 1: 99)
When the optical purity was determined by C, the optical purity was 91% e.
e. Similarly, (-)-4-tert-butoxy-2-cyclopenten-1-ol (147 mg,
0.9 mmol) to (-)-4-tert-butoxy-2-cyclopenten-1-one (117 mg, 81
%). [Α] _D ²⁹ -53.1 ° (CHCl ₃ ) HPL using an optical isomer separation column (CHIRALCEL OB, isopropanol: hexane = 1: 99)
When the optical purity was determined by C, the optical purity was 97% e.
e.

Example 8 Synthesis of optically active 3-oxodicyclopentadiene Step 1 (-)-endo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene, and (+)
-Exo-3-oxo-5-tert-butoxy-4,
Synthesis of 5-dihydrodicyclopentadiene (+)-4-tert-butoxy-2-cyclopenten-1-one (64 mg, 0.4 mmol) was dissolved in anhydrous benzene (2.5 ml) and zinc chloride (67 mg, 0 ．
5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes under an argon stream. Then cyclopentadiene (0.1 ml,
1.2 mmol) was added dropwise, and the mixture was stirred at the same temperature for 2 hours.
Post-treatment was carried out in the same manner as in step 1 of Example 1 to give a colorless oily (-)-
Endo-3-oxo-5-tert-butoxy-4,5
-Dihydrodicyclopentadiene (69 mg, 76%)
And colorless oily (+)-exo-3-oxo-5-ter
t-Butoxy-4,5-dihydrodicyclopentadiene (7 mg, 8%) was obtained. (-) - endo -3-oxo -5-tert-butoxy-4,5-dihydro-dicyclopentadiene; [α] _D ²⁷ -185.5 ° (CHCl ₃₎ (+) - exo -3-oxo -5 -tert- butoxy-4,5-dihydro-dicyclopentadiene; each spectral data [α] _D ²⁷ +103.2 ° (CHCl ₃₎ were consistent with those obtained in example 1, step 1.

Step 2 Synthesis of optically active 3-oxodicyclopentadiene (-)-endo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (54 mg,
0.25 mmol) was dissolved in anhydrous methylene chloride (1 ml), titanium tetrachloride (32 μl, 0.3 mmol) was added, and the mixture was stirred at 0 ° C. for 5 minutes under an argon stream. Then 5% aqueous sodium hydroxide solution (1.4 ml, 1.7 mm
ol) was added dropwise and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was extracted with ether, and the organic phases were combined and washed with saturated saline. The extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/6 (v / v)) to obtain colorless crystalline (−)-3-oxodicyclopentadiene (28 mg, 78%). . mp: 75.5-76 ° C. [α] _D ³⁰ -161.7 ° (CHCl ₃ ) Each spectral data was in agreement with that obtained in Step 3 of Example 1. In addition, an optical isomer separation column (CHIRA
LCEL OB, isopropanol: hexane = 1: 9
When the optical purity was determined by HPLC using 9),
The optical purity was 99% ee. Similarly, (+)-
Exo-3-oxo-5-tert-butoxy-4,5
-Dihydrodicyclopentadiene (22 mg, 0.1 m
(+)-3-oxodicyclopentadiene (9 mg, 62%) was obtained from (mol). mp: 74-75 ° C. [α] _D ²⁸ + 151.1 ° (CHCl ₃ ) Each spectral data was in agreement with that obtained in Step 3 of Example 1. In addition, an optical isomer separation column (CHIRA
LCEL OB, isopropanol: hexane = 1:
When the optical purity was determined by HPLC using 9),
The optical purity was 99% ee or higher.

Example 9 Synthesis of optically active 3-oxodicyclopentadiene Step 1 (+)-endo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene, and (-)
-Exo-3-oxo-5-tert-butoxy-4,
Synthesis of 5-dihydrodicyclopentadiene (−)-4-tert-butoxy-2-cyclopenten-1-one (133 mg, 0.86 mmol) was dissolved in anhydrous benzene (7.5 ml), and zinc chloride (141 m
g, 1.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes under an argon stream. Then cyclopentadiene (0.2
ml, 2.6 mmol) was added dropwise, and the mixture was stirred at the same temperature for 4 hours. Post-treatment was conducted in the same manner as in Step 1 of Example 1, and colorless oily (+)-endo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (139 m
g, 73%) and colorless oily (-)-exo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (21 mg, 11%) were obtained. (+) - endo -3-oxo -5-tert-butoxy-4,5-dihydro-dicyclopentadiene: [α] _D ²⁵ +180.7 ° (CHCl ₃₎ (-) - exo-3-oxo-5- tert- butoxy-4,5-dihydro-dicyclopentadiene; each spectral data [α] _D ²⁸ -97.8 ° (CHCl ₃₎ were consistent with those obtained in example 1, step 1.

Step 2 Synthesis of Optically Active 3-Oxodicyclopentadiene (+)-endo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (100 m
g, 0.45 mmol) in anhydrous methylene chloride (2 ml)
Dissolved in titanium tetrachloride (60 μl, 0.55 mmo
1) was added, and the mixture was stirred at 0 ° C. for 5 minutes under an argon stream. Then 5% aqueous sodium hydroxide solution (2.6 ml,
(3.2 mmol) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. Post-treatment was conducted in the same manner as in Step 2 of Example 7 to obtain (+)-3-oxodicyclopentadiene (50 mg, 76%). mp: 75-76 ° C. [α] _D ²⁵ + 153.5 ° (CHCl ₃ ) Each spectral data was in agreement with that obtained in Example 1, step 3. In addition, an optical isomer separation column (CHIRA
LCEL OB, isopropanol: hexane = 1: 9
When the optical purity was determined by HPLC using 9),
The optical purity was 99% ee or higher. Similarly,
(−)-Exo-3-oxo-5-tert-butoxy-4,5-dihydrodicyclopentadiene (19 mg,
(−)-3-oxodicyclopentadiene (11 mg, 86%) was obtained from 0.09 mmol). mp: 75.5-76 ° C. [α] _D ²⁶ -158.5 ° (CHCl ₃ ) Each spectral data was in agreement with that obtained in Step 3 of Example 1. In addition, an optical isomer separation column (CHIRA
LCEL OB, isopropanol: hexane = 1:
When the optical purity was determined by HPLC using 9),
The optical purity was 99% ee or higher.

[0041]

INDUSTRIAL APPLICABILITY By using this production method, racemic or optically active 3-oxodicyclopentadiene can be efficiently produced. 3-oxodicyclopentadiene is
It is a compound useful as a synthetic intermediate for various physiologically active substances.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 45/29 C07C 45/29 45/65 45/65 45/69 45/69 49/753 9049- 4H 49/753 B C12P 41/00 C12P 41/00 G // C07B 37/12 7419-4H C07B 37/12 61/00 300 61/00 300 (C12P 41/00 C12R 1:38) C07M 7:00

Claims (7)

[Claims] 1. A compound of the formula (I) (In the formula, R represents a straight-chain or branched alkyl group having 1 to 10 carbon atoms.) 4-alkoxy-2-cyclopenten-1-one is mixed with cyclopentadiene and Diels in the presence of a metal halide. -Alder reaction yields formula (II): And the formula (II ′): (Wherein R represents a straight-chain or branched alkyl group having 1 to 10 carbon atoms), an isomer mixture of the Diels-Alder adducts is obtained, followed by dealkylation using a titanium compound, and a base. Formula (III) ## STR00004 ## through a dehydration process under sexual conditions (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) A method for producing 3-oxodicyclopentadiene. 2. The method according to claim 1, wherein the metal halide is zinc halide or titanium halide, and the titanium compound is titanium halide. 3. Alkoxy-2-cyclopentene-
The production method according to claim 1, wherein the alkoxy group of 1-one is a tert-butoxy group. 4. The method according to claim 1, wherein the formula (I): (In the formula, R represents a straight-chain or branched alkyl group having 1 to 10 carbon atoms.) The formula (III) in which 4-alkoxy-2-cyclopenten-1-one represented by formula (III) is an optically active compound. 6] (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) A method for producing an optically active form of 3-oxodicyclopentadiene. 5. Formula (IV): (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) (±) -4-alkoxy-2-
Cyclopenten-1-ol is subjected to a transesterification reaction with fatty acid vinyl using a lipase and stereoselectively acylated to give a compound of the formula ((+)-V) (In the formula, R represents a straight-chain or branched alkyl group having 1 to 10 carbon atoms, and R ′ represents a straight-chain or branched alkyl group having 1 to 20 carbon atoms.) (+)- 1-acyloxy-4-alkoxy-2-cyclopentene and the formula ((-)-
IV) [Chemical 9] (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) (-)-4-alkoxy-2-
It is optically resolved into cyclopenten-1-ol, and each optically active compound is separated from the mixture, followed by a deesterification step and an oxidation step of a hydroxyl group to obtain a compound of the formula ((+)-
I) (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) (+)-4-alkoxy-2-
Cyclopenten-1-one, and the formula ((-)-I) (In the formula, R represents a linear or branched alkyl group having 1 to 10 carbon atoms.) (-)-4-alkoxy-2-
A process for producing optically active 4-alkoxy-2-cyclopenten-1-one, which comprises obtaining cyclopenten-1-one. 6. 4-Alkoxy-2-cyclopentene-
The production method according to claim 5, wherein the alkoxy group of 1-ol is a tert-butoxy group. 7. The method according to claim 5, wherein the lipase is derived from Pseudomonas.