JPH0776569A - Optically active 2-phenylthio-2-cycloalkene derivative and production thereof - Google Patents

Abstract

PURPOSE:To obtain a novel compound which can be broadly utilized as a stable building block for physiologically active substances such as medicines or agrochemicals. CONSTITUTION:Optically active 2-phenylthio-1-acyloxy-2-cycloalkene of formula I (* means asymmetric carbon atom; R is H, alkylcarbonyl; n is 1 to 4). The compound of the formula I is obtained by ester interchange reaction of a racemic 2-phenylthio-2-cycloalkene-1-ol of formula II with an acylating agent such as a vinyl ester in the presence of a lipase (e.g. from Pseudomonas bacteria) or by hydrolysis of racemic 2-phenylthio-1-acyloxy-2-cycloalkene in the presence of lipase.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active 2-phenylthio-2-cycloalkene derivative useful as a starting material for medicines, agricultural chemicals and the like, and a method for producing the same.

[0002]

2. Description of the Related Art Optically active 2-phenylthio-2-cycloalkene-1-ol has two different substituents, a hydroxyl group and phenylthioether. These substituents can be stereoselectively or stereospecifically converted into various functional groups. Furthermore, various functional groups can be introduced into the 3-position stereoselectively or stereospecifically by utilizing the double bond in the molecule, which is useful as a building block for optically active substances as raw materials for medicines, agricultural chemicals, etc. It is a compound. However, the optically active substance has not been synthesized so far, and its usefulness could not be sufficiently evaluated.
A method for producing optically active 2-iodo-2-cycloalkene-1-ols, which are related compounds, is described by Johnson et al.
nlett, 813 (1992)) and a method for producing optically active 2-alkoxycarbonyl-2-cycloalkene-1-ols are reported by Takano et al. (Japanese Patent Application No. 4-190215). According to a report by Johnson et al., The result of the transesterification reaction using lipase SP-435 was as follows.
When 2-iodo-2-cyclopentene-1-ol is used as the substrate, the S-form is obtained with> 98% ee, whereas 2-cyclopentene-1-ol is 16 % Ee
I can only get it. Further, in the case of 2-bromo-2-cycloalkene-1-ol, it is 87% ee and 10% ee.
Nearly, the optical yield is lower than that of 2-iodo-2-cycloalkene-1-ol. Cycloalkeno
It can be said that in the optical resolution method of a lipe derivative with a lipase, the optical yield thereof largely varies depending on the functional group at the 2-position. Furthermore, 2-iodo-2-cycloalkene-1-o-
However, iodine has a problem of stability, because iodine, which is a substituent, has a releasability. Since the substituent is iodine, it has a drawback that it is limited to the nucleophilic substitution reaction. 2 more
-Iodo-2-cyclohexen-1-ol has a lower optical yield than 2-iodo-2-cyclopenten-1-ol and cannot be said to be a sufficiently versatile production method.

[0003]

As is clear from the above, the object of the present invention is a novel compound which is a stable compound and is useful as a building block of a versatile optically active substance in which various substituents can be easily introduced. It is to provide a compound and a method for producing the same. 2-phenylthio-2-cycloalkene-1-
With ole, there is no problem in the stability of thiophenyl, and conversion to other substituents is easy.

[Chemical 9]

[Chemical 10]

[Chemical 11] For example, as exemplified above, it is possible to easily eliminate phenylthio by using a Raney-nickel catalyst or the like. It is also possible to obtain a ketone body by using titanium tetrachloride or the like. It is also possible to introduce an ester into a double bond in the molecule and further draw thiophenyl with lithium-ammonia to induce an unsaturated terpene. Thus, the optically active 2-phenylthio-2-cycloalkene-1-ol is a very versatile compound.

[0004]

The present invention is based on the general formula (1)

[Chemical 12] (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) An optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the general formula (2)

[Chemical 13] (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
An optically active 2-phenylthio-2-cycloalkene-1-ol represented by or a general formula (3)

[Chemical 14] (In the formula, n represents 1 to 4.) Racemic 2-phenylthio-2-cycloalkene-1-ol represented by the general formula by transesterification with an acylating agent in the presence of lipase. (1)

[Chemical 15] (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) And an optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the general formula (2)

[Chemical 16] (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
And a general formula (4) for producing an optically active 2-phenylthio-2-cycloalkene derivative characterized by obtaining optically active 2-phenylthio-2-cycloalkene-1-ol represented by

[Chemical 17] (In the formula, R represents an alkyl group, and n represents 1 to 4.) Hydrolyzing a racemic 2-phenylthio-1-acyloxy-2-cycloalkene represented by the formula in the presence of lipase. By the general formula (1)

[Chemical 18] (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) And an optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the general formula (2)

[Chemical 19] (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
The invention relates to a method for producing an optically active 2-phenylthio-2-cycloalkene derivative, which comprises obtaining optically active 2-phenylthio-2-cycloalkene-1-ol represented by

The racemic 2-phenylthio-2-cycloalkene-1-ol (3) and 2-phenylthio-1-acyloxy-2-cycloalkene (4) which are the starting materials of the present invention are as follows: It can be easily synthesized according to the formula.

[0006]

[Chemical 20]

First, commercially available cycloalkanone is trimethylsilylated by heating in N, N-dimethylformamide at 130 ° C. for 7 hours, and in a tetrahydrofuran solution at −78 ° C. in the presence of tetrabutylammonium fluoride.
And react with S-phenylbenzenethiosulfate for 10 minutes to induce 2-phenylthiocycloalkan-1-one. 2-phenylthiocycloalkane-1-
The one is oxidized with m-chloroperbenzoic acid in methylene chloride at 0 ° C. and treated with methanesulfonic acid in acetic anhydride-methylene chloride at 0 ° C. for 6 hrs to give 2-phenylthiocycloalkene-1-one. Further, 2-phenylthiocycloalkene-1-one can be reduced with a reducing agent such as sodium borohydride to obtain racemic 2-phenylthio-2-cycloalkene-1-ol (3). . In addition, racemic 2-phenylthio-2-cycloalkene-1-ol (3) is esterified according to a conventional method such as using acid chloride or triethylamine, and is represented by the general formula (4). A racemic 2-phenylthio-1-acyloxy-2-cycloalkene can be obtained.

The reaction route of the production method of the present invention is represented by the following formula.

[Chemical 21]

Racemic 2-phenylthio-2-cycloalkene-1-ol (3) is enantiomerized by adding a suspension of an acylating agent and lipase and stirring at room temperature. Either one of the compounds is preferentially acylated to give an optically active 2-phenylthio-1-acyloxy-2-cycloalkene and an optically active 2-phenylthio-2-cycloalkene-1-ol. The reaction time is 1 hour to 1 month, depending on the amount of treatment. These separation methods include, for example, column chromatography, which can separate the enantiomers.

In the above production method, the acylating agent to be used is a fatty acid ester, benzoic acid ester, or the like.
Although it can be widely used as long as it can be a substrate for the transesterification reaction of zetin, vinyl esters such as vinyl acetate, vinyl propionate, vinyl caproate, and vinyl laurate are preferable. The organic solvent to be used is preferably benzene, toluene, hexane, heptane, dichloromethane, t-butyldimethyl ether, etc., but any kind of organic solvent may be used as long as it does not inhibit the lipase reaction.

The racemic 2-phenylthio-1-acyloxy-2-cycloalkene (4) is hydrolyzed by adding lipase to a phosphate buffer (buffer / acetone = 9/1 (v / v)). Upon reaction, either one of the enantiomers is preferentially hydrolyzed to give optically active 2-phenylthio-2-cycloalkene-1-ol and optically active 2-phenylthio-1-acyloxy-2- A cycloalkene is obtained. In this case, the lipase may or may not be immobilized. The phosphate buffer has a pH of 4-9,
The pH is preferably 7-8.

Examples of the lipase include Pseudomonas, Arthrobacter, Alcaligenes, Aspergillus, Chromobacterium, Candida, Mucor, Rhizopus and the like. This bacterium itself can be used or its extract can be used. It may be further fixed and used. It can also be extracted from the internal organs of animals, for example, from the liver of pigs or cattle, or the pancreas. In addition, commercially available products can be used. For example, lipase PS, OF, AY, AK
(Above, manufactured by Amano Pharmaceutical Co., Ltd.), MY (name sugar), PPL (Wako Pure Chemical Industries), Paratase A, Lipozyme IM, SP435 (above, manufactured by Novo Nordisk). Of these, particularly preferred are those derived from Pseudomonas.

The immobilization carrier may be chromosolve, celite, cellulose, carrageenan, various polymers or the like as long as it does not inhibit the activity of lipase.

[0014]

Industrial Applicability According to the method described above, a novel optically active 2-phenylthio-2-cycloalkene-1-ol which is stable as a building block for physiologically active substances such as agricultural chemicals and pharmaceuticals and has high versatility, and , 2-phenylthio-1
-Acyloxy-2-cycloalkene and its synthetic method could be provided.

[0015]

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

Example 1 Synthesis of (±) -2-phenylthio-2-cyclopentenol: 2-phenylthio-2-cyclopentenone (2.72
g, 14.3 mmol) was dissolved in methanol (70 ml), and cerium trichloride heptahydrate (5.85 g, 15.7 mmol) was added at room temperature. 0 ° C
Cooled to sodium borohydride (544.0mg, 14.3mmo
l) was added dropwise. After the completion of dropping, the mixture was stirred at 0 ° C. for 1 hour.
Then, acetone (1 ml) was added and the solvent was distilled off under reduced pressure. Water was added to the residue, extracted with ether, washed with saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and a yellow oily (±) -2-phenylthio-2 was obtained from a fraction of diethyl ether / n-hexane (20% v / v). -Cyclopentenol (2.61 g, 94.9%) was obtained. IR (neat):. 3500-3100, 1582cm -1 1 H-NMR (300MHz, CDCl 3) δ: 1.84-2.03 (2H, m, 1Hexchangeab
le with D ₂ O), 2.25-2.43 (2H, m), 2.46-2.61 (1H, m), 4.6
8 (1H, t, J = 3.3,2.9Hz), 5.92 (1H, t, J = 2.6,1.8Hz), 7.21
-7.35 (3H, m), 7.37-7.44 (2H, m). MS: m / z = 192 (M ⁺ , 100%). HRMS: Calcd: C ₁₁ H ₁₂ OS: 192.0609. FOUND: 192.0623. C ₁₁ H ₁₂ OS: Calcd: C, 68.73, H, 6.30, S, 16.65 Found: C, 68.65, H, 6.27, S, 16.56

Example 2 Synthesis of (±) -2-phenylthio-2-cyclohexenol: 2-phenylthio-2-cyclohexenone (3.63
g, 17.8 mmol) was dissolved in methanol (90 ml), and cerium trichloride heptahydrate (7.27 g, 19.6 mmol) was added at room temperature. 0 ° C
Cooled to sodium borohydride (679.1mg, 17.8mmo
l) was gradually added. After the completion, the mixture was stirred at 0 ° C for 1 hour.
Then, acetone (2 ml) was added and the solvent was distilled off under reduced pressure. Water (2 ml) was added to the residue, the mixture was extracted with diethyl ether, washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, and a yellow oily (±) -2-phenylthio-2- was obtained from a fraction of diethyl ether / n-hexane (15% v / v). Cyclohexenol (3.47 g, 94.6%) was obtained. IR (neat):. 3600-3100, 1581cm -1 1 H-NMR (300MHz, CDCl 3) δ: 1.50-2.00 (4H, m), 2.15-2.30 (2
H, m), 2.28 (1H, br s, exchangeable withD ₂ O), 4.05 (1
H, br s), 6.26 (1H, t, J = 4.0, 3.7Hz), 7.20-7.40 (5H, m) .MS: m / z = 206 (M ⁺ ), 110 (100%). HRMS: Calcd : C ₁₂ H ₁₄ OS: 206.0766. FOUND: 206.0744. C ₁₂ H ₁₄ OS: Calcd: C, 69.88, H, 6.85, S, 15.51 Found: C, 69.59, H, 6.67, S, 15.29

Example 3 Synthesis of (±) -1-acetoxy-2-phenylthio-2-cyclopentene: (±) -2-phenylthio-2-cyclopentenol (889.8 mg, 4.63 mm) obtained in Example 1
ol), acetic anhydride (1.31 ml, 13.9 mmol), triethylamine
(1.93 ml, 13.9 mmol) and 4-N, N-dimethylaminoaminopyridine (16.9 mg, 0.14 mmol) were stirred in methylene chloride (23 ml) at room temperature for 12 hours. Then, the reaction mixture was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and diethyl ether / n-hexane (20% v / v)
The colorless oily substance (±) -1-acetoxy-2-phenylthio-2-cyclopentene (1.18 g, 93.8%) was obtained from the above stream. IR (neat):. 1735, 1581cm -1 1 H-NMR (300MHz, CDCl 3) δ: 1.96 (3H, s), 1.83-2.00 (1H, m) 2.30-2.44 (2H, m), 2.44-2.62 (1H, m), 5.66 (1H, t, J = 4.7,
2.6Hz), 5.94 (1H, br s), 7.23-7.37 (3H, m), 7.38-7.48
(2H, m) .MS: m / z = 234 (M ⁺ ), 174 (100%). HRMS: Calcd: C ₁₃ H ₁₄ O ₂ S: 234.0715. FOUND: 234.0715. C ₁₃ H ₁₄ O ₂ S: Calcd: C, 66.65, H, 6.03, S, 13.66 Found: C, 66.48, H, 5.92, S, 13.51

Example 4 Synthesis of (±) -1-acetoxy-2-phenylthio-2-cyclohexene: (±) -2-phenylthio-2-cyclohexenol (918.6 mg, 4.45) obtained in Example 2. mm
ol), acetic anhydride (1.25 ml, 13.3 mmol), triethylamine
(1.85 ml, 13.3 mmol) and 4-N, N-dimethylaminopyridine (16.2 mg, 0.13 mmol) were stirred in methylene chloride (22 ml) at room temperature for 12 hours. Then, the reaction mixture was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, diethyl ether / n-hexane (15% v / v)
A colorless oily (±) -1-acetoxy-2-phenylthio-2-cyclohexene (1.08 g, 97.9%) was obtained from the above stream. IR (neat):. 1731, 1581cm -1 1 H-NMR (300MHz, CDCl 3) δ: 1.60-1.90 (4H, m), 1.93 (3H, s) 2.10-2.40 (2H, m), 5.29 (1H , br s), 6.34 (1H, t, J = 4.6,3.
7Hz), 7.20-7.40 (5H, m) .MS: m / z = 248 (M ⁺ ), 188 (100%). HRMS: Calcd: C ₁₄ H ₁₆ O ₂ S: 248.0871. FOUND: 248.0858. C ₁₄ H ₁₆ O ₂ S: Calcd: C, 67.72, H, 6.50, S, 12.89 Found: C, 67.69, H, 6.51, S, 12.86

Example 5 Transesterification of (±) -2-phenylthio-2-cyclopentenol with lipase: (±) -2-phenylthio-2-cyclopentenol obtained in Example 1
(1.04g, 5.44mmol), vinyl acetate (5.0ml, 54.4mmol), lipase PS (manufactured by Amano Pharmaceutical Co., Pseudomonas origin, 544m
g) was stirred in methylene chloride (27 ml) at 30 ° C. for 12 days. Then, the reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and diethyl ether / n-hexane (10 to 20% v
R-(+)-1-acetoxy-2-phenylthio-2-cyclopentene ((644 mg, 50.
5%), [α] _D ²⁹ + 80.0 ° (c = 1.28, CHCl ₃ )) and colorless oily S-(−)-2-phenylthio-2-cyclopenteno-
((487.6mg, 46.6%), [α] _D ³² -153.8 ° (c = 1.02, CHC
l ₃ )). The optical purity of R-(+)-1-acetoxy-2-phenylthio-2-cyclopentene was determined by optical resolution HPLC (chiralcel OD, effluent solvent i-PrOH / n).
-Hexane (1% v / v)) was 93.2% ee. S-
The optical purity of (-)-2-phenylthio-2-cyclopentenol was 100% by optical resolution HPLC (chiralcel OD, eluent i-PrOH / n-hexane (5% v / v)).
It was ee.

Example 6 Transesterification of (±) -2-phenylthio-2-cyclohexenol with lipase: (±) -2-phenylthio-2-cyclohexenol obtained in Example 2
(1.02g, 4.97mm ol), vinyl acetate (4.58ml, 54.4mmol),
Lipase PS (Amano Pharmaceutical, Pseudomonas origin, 49
7 mg) was stirred in methylene chloride (25 ml) at 30 ° C for 12 days. Then, the reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and diethyl ether / n-hexane (5-15% v
R-(+)-1-acetoxy-2-phenylthio-2-cyclohexene ((599.3 mg, 4
8.5%), [α] _D ³¹ + 191.2 ° (c = 1.29, CHCl ₃ )) and colorless oily S-(−)-2-phenylthio-2-cyclohexenol ((47 7.6 mg, 46.6 %), [Α] _D ³¹ -283.3 ° (c = 1.29, CHC
l ₃ )). The optical purity of R-(+)-1-acetoxy-2-phenylthio-2-cyclohexene was determined by optical resolution HPLC (chiralcel OD, effluent solvent i-PrOH / n).
-Hexane (99% v / v)) gave 98.0% ee. S-
The optical purity of (−)-2-phenylthio-2-cyclohexenol was 100% by optical resolution HPLC (chiralcel OD, eluent i-PrOH / n-hexane (5% v / v)).
It was ee.

Example 7 Hydrolysis of (±) -1-acetoxy-2-phenylthio-2-cyclopentene with lipase: (±) -1-acetoxy-2-phenylthio-obtained in Example 3
2-Cyclopentene (965.6mg, 4.12mmol), Lipase P
S (Amano Pharmaceutical Co., Pseudomonas origin, 412 mg) was added with 0.1 M phosphate buffer / acetone (1: 9 v / v, 20 ml).
The mixture was stirred at 30 ° C. for 12 days. Then, the reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and a colorless oily S-(-)-1-acetoxy-2-phenylthio-2- was obtained from a stream of diethyl ether / n-hexane (10 to 20% v / v).
Cyclopentene ((460.1mg, 47.6%), [α] _D ³⁰ -84.0 °
(c = 1.12, CHCl ₃ )) and colorless oily R-(+)-2-phenylthio-2-cyclopentenol ((367.6 mg, 46.3%)
, [Α] _D ³² + 154.1 ° (c = 1.10, CHCl ₃ )) were obtained. S-
The optical purity of (−)-1-acetoxy-2-phenylthio-2-cyclopentene was determined by optical resolution HPLC (chiralcel OD, eluent i-PrOH / n-hexane (1% v / v).
) Was 93.2% ee. The optical purity of R-(+)-2-phenylthio-2-cyclopentenol was measured by optical resolution HPLC (chiralcel OD, eluent i-PrOH).
/ N-hexane (5% v / v)) was 100% ee.

Example 8 Hydrolysis reaction of (±) -1-acetoxy-2-phenylthio-2-cyclohexene with lipase: (±) -1-acetoxy-2-phenylthio-obtained in Example 3
2-Cyclohexene (103.0mg, 0.42mmol), Lipase P
S (Amano Pharmaceutical, Pseudomonas origin, 41.5 mg) was added with 0.1 M phosphate buffer / acetone (1: 9 v / v, 2 ml).
The mixture was stirred at 30 ° C. for 12 days. Then, the reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and a colorless oily S was obtained from a stream of diethyl ether / n-hexane (5 to 15% v / v).
-(-)-1-acetoxy-2-phenylthio-2-cyclohexene ((49.2 mg, 47.7%), [α] _D ²⁸ -194.8 ° (c = 0.
47, CHCl ₃ )) and colorless oily R-(+)-2-phenylthio-2-cyclohexenol ((38.4 mg, 44.8%), [α] _D
³¹ + 277.6 ° (c = 1.32, CHCl ₃ )) was obtained. S-(-)-1-
The optical purity of acetoxy-2-phenylthio-2-cyclohexene was 100% by optical resolution HPLC (chiralcel OD, eluent i-PrOH / n-hexane (1% v / v)).
It was ee. The optical purity of R-(+)-2-phenylthio-2-cyclohexenol was determined by optical resolution HPLC (chiralcel OD, eluent i-PrOH / n-hexane (5
% v / v)) was 100% ee.

Claims (7)

[Claims] 1. A compound represented by the general formula (1): (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) An optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the formula: 2. A general formula (2): (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
An optically active 2-phenylthio-2-cycloalkene-1-ol represented by: 3. A compound represented by the general formula (3): (In the formula, n represents 1 to 4.) Racemic 2-phenylthio-2-cycloalkene-1-ol represented by the general formula by transesterification with an acylating agent in the presence of lipase. (1) [Chemical 4] (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) And an optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the general formula (2) (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
A method for producing an optically active 2-phenylthio-2-cycloalkene derivative, which comprises obtaining the optically active 2-phenylthio-2-cycloalkene-1-ol represented by 4. A compound represented by the general formula (4): (In the formula, R represents an alkyl group, and n represents 1 to 4.) Hydrolyzing a racemic 2-phenylthio-1-acyloxy-2-cycloalkene represented by the formula in the presence of lipase. According to the general formula (1) (In the formula, * represents an asymmetric carbon, R represents an alkyl group,
n represents 1 to 4. ) And an optically active 2-phenylthio-1-acyloxy-2-cycloalkene represented by the general formula (2) (In the formula, * represents an asymmetric carbon, and n represents 1 to 4.)
A method for producing an optically active 2-phenylthio-2-cycloalkene derivative, which comprises obtaining the optically active 2-phenylthio-2-cycloalkene-1-ol represented by 5. The method for producing an optically active 2-phenylthio-2-cycloalkene derivative according to claim 3, wherein the acylating agent is a vinyl ester. 6. The method for producing an optically active 2-phenylthio-2-cycloalkene derivative according to claim 3, wherein the lipase is derived from Pseudomonas. 7. The method for producing an optically active 2-phenylthio-2-cycloalkene derivative according to claim 4, wherein the lipase is derived from Pseudomonas.