JP3010756B2 - Method for producing optically active alcohol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing an optically active alcohol using a chiral ferrocene derivative as a catalyst, and more particularly, to reacting an aldehyde compound with a dialkyl zinc in the presence of a chiral ferrocene derivative. And a method for producing an optically active alcohol comprising:

[0002] Optically active alcohols are compounds useful as synthetic intermediates for pharmaceuticals and agricultural chemicals, and as asymmetric sources of ferroelectric liquid crystals. The method for producing an optically active alcohol of the present invention is a method capable of efficiently asymmetrically alkylating an aldehyde compound which is a kind of carbonyl compound.

[0003]

2. Description of the Related Art Asymmetric synthesis catalysts, which are one of the methods for producing optically active compounds, often employ asymmetric synthesis catalysts. Well-known catalysts include compounds derived from natural products such as ephedrine and prolinol derivatives.

[0004] However, these compounds derived from natural products often have substrate specificity, and some substrates exhibit high enantioselectivity and others do not. Therefore, there are reactions that are not applicable or inefficient.

[0005] Therefore, for the purpose of lowering the substrate specificity and improving characteristics such as reaction efficiency, improvement of a catalyst for asymmetric synthesis derived from natural products has been attempted. However, it is often not easy to change the substituent on the asymmetric carbon, and in many cases, an asymmetric synthesis catalyst having desired characteristics cannot be obtained.

It is known to produce optically active alcohols by asymmetric alkylation of carbonyl compounds with dialkylzinc in the presence of an optically active catalyst [see, for example, N. Oguni et al., J. Am. Chem. Soc., Volume 110, 7877 (198
8); K. Soai et al., J. Am. Chem. Soc., Volume 109,
7111 (1987); G. Muchow et al., Tetrahedron Le
tt., 28, 6163 (1987); EJ Corey et al., Te
rahedron Letl., Vol. 28, 5233 (1987); M. Kitamura (Kit)
amura) et al., J. Am. Chem. Soc., 108, 6071 (1986)].

[0007]

However, any of these methods has a problem that it is not easy to obtain an optically active catalyst to be used. Furthermore, the manufacturing method itself was not suitable for industrial use.

An object of the present invention is to provide a method for producing an optically active alcohol with high enantioselectivity suitable for industrial use.

[0009]

The present invention provides a method for producing an optically active alcohol, comprising reacting an aldehyde compound with a dialkyl zinc in the presence of a chiral ferrocene derivative represented by the following general formula [I]. About.

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(In the formula, R ¹ represents a lower alkyl group having 1 to 6 carbon atoms, and R ² and R ³ are the same or different and represent a lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group. Or R ² and R ³ form a heterocyclic ring having 4 to 6 carbon atoms with the nitrogen atom to which they are bonded, R ⁴ and R ⁵ are the same or different, and are hydrogen, a lower alkyl group having 1 to 6 carbon atoms. ,
Aryl group, anthracenyl group or either shows a ferrocenyl group, to form a cycloalkyl group or a 10-hydro-anthracenyl group R ⁴ and R ⁵ carbon atoms and having 5 to 7 carbon atoms, each of which binds. )

Hereinafter, the present invention will be described in detail. The lower alkyl group having 1 to 6 carbon atoms of R ¹ , R ² and R ^{3 in} the general formula [I] includes, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-
Pentyl, n-hexyl and the like can be mentioned. Particularly, R ¹ is preferably methyl and propyl, and R ² and R ³ are preferably methyl, ethyl and iso-propyl. Examples of the heterocyclic ring formed by R ² and R ³ together with the nitrogen atom to be bonded include pyrrolidyl, piperidyl, and the like, and piperidyl is particularly preferable.

The lower alkyl group having 2 to 6 carbon atoms represented by R ⁴ and R ⁵ includes, for example, ethyl, n-propyl,
iso-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl and the like. Especially iso
-Propyl and tert-butyl are preferred. Examples of the aryl group include a phenyl group, an o-tolyl group, a p-tolyl group, a mesityl group, a 2,6-dimethoxyphenyl group,
Examples thereof include a p-chlorophenyl group. Also, R ⁴ and R ⁵
Examples of the cycloalkyl group formed together with the carbon atom to be bonded include cyclopentyl, cyclohexyl, and cycloheptyl, with cyclohexyl being particularly preferred.

Table 1 shows R ^{1 to} R ⁵ of specific examples of the compound which can be used as a catalyst in the present invention.

[0014]

[Table 1]

First, a method for producing the compound of the general formula [I] used as a catalyst in the present invention will be described below. The compound of the present invention comprises a ferrocene iodide represented by the general formula [II] and n
-Lithium is reacted by reacting -butyllithium, and then the lithiated product is reacted with a ketone (or aldehyde) represented by the general formula [III] R ⁴ COR ⁵ .

[0016]

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Examples of the organic lithium compound used for the lithiation include, in addition to n-butyllithium, sec-butyllithium, t-butyllithium, methyllithium and phenyllithium. The amount of these organolithium compounds used is 0.1 to 2.0 with respect to the ferrocene iodide [II].
It is appropriate to use 0 equivalent, preferably 0.7 to 1.5 equivalent. These organolithium compounds are preferably used as a 5 to 30% solution of hexane or ether. Further, the lithiation reaction is carried out by a solvent (for example, ethers such as ethyl ether and tetrahydrofuran; hydrocarbons such as pentane, hexane and heptane; benzene,
In the presence of aromatic hydrocarbons such as toluene, xylene and dichlorobenzene; or one or a mixture of two or more of these solvents), the reaction is suitably performed under the following conditions.

Reaction temperature: -30 ° to 50 ° C., preferably -10 ° to 3 °
0 ° C. Reaction time: 0.1 to 5 hours Reaction pressure: from normal pressure to pressurized, preferably 1 to 3 atm Atmosphere: under nitrogen or argon

Next, the reaction between the lithiated product and the ketone (or aldehyde) [III] is preferably carried out by adding an ether solution of the ketone (or aldehyde) [III] to the reaction system. The amount of the ketone (or aldehyde) [III] used is the iodide [II] of ferrocene used in the lithiation.
It is appropriate that the amount is 0.1 to 2.0 equivalents, preferably 0.7 to 1.5 equivalents. This reaction is preferably performed under the following conditions.

Reaction temperature: −40 to 70 ° C., preferably −20 to 40 ° C. Reaction time: 1 to 3 hours Reaction pressure: from normal pressure to pressurized, preferably 1 to 3 atm Atmosphere: under nitrogen or argon

At the end of the reaction, the reaction is stopped by adding an aqueous solution of phosphoric acid to the reaction system, washed with ether, the aqueous layer is made alkaline, and extracted with ether. The compound of [I] can be fractionated.

When the compound [III] is an aldehyde, an asymmetric center is newly formed, so that two kinds of diastereomers are formed. Each diastereomer can be separated by chromatography. Alternatively, since one diastereomer has a more stable structure, the literature (J.
According to the method described in Am. Chem. Soc., 95, 482 (1973), one diastereomer can be isolated after acid treatment to isomerize the other diastereomer.

In the above reaction, the starting compound represented by the general formula [III
The ketone (or aldehyde) is commercially available. Further, the compound of the general formula [II] is synthesized as follows.

A compound represented by the general formula [IV] (J. Am. Che
m. Soc., Vol. 92, 5389 (1970)), reacting with methyl iodide to form a quaternary ammonium salt, and then reacting with a primary or secondary amine derivative or ammonia to obtain an appropriate R
Ferrocene derivatives [V] in which ² and R ³ are other than methyl can be synthesized [G. Gokel et al., Angew. Chem., Int. Ed. Engl., 9
Vol. 64 (1970).

[0025]

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Reaction MeI to form quaternary ammonium salt : 0.5 to 40 equivalents Solvent: ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile and benzonitrile Temperature: -30 to 80 ° C, preferably -10 to 40 C. Time: 0.1 to 5 hours Pressure: From normal pressure to pressurized, preferably 1 to 3 atm Atmosphere: Under nitrogen or argon Isolation: Filtration when the product is crystallized, otherwise ethyl ether or After adding hexane to precipitate crystals, the mixture is filtered.

Reaction with amine or ammonia HNR ² R ³ : 1 to 30 equivalents Solvent: nitriles such as acetonitrile and benznitrile, ethers such as ethyl ether and tetrahydrofuran Temperature: 0 to 100 ° C., preferably 10 to 90 ° C. Time: 0.5 to 100 hours Pressure: From normal pressure to pressurized, preferably 1 to 3 atm Atmosphere: Under nitrogen or argon Isolation: Recrystallization or column chromatography

The ferrocene derivative of the general formula [V] is converted to Tetrah
By applying the method described in edron, 26 , 5453 (1970), the general formula [I
I] can be synthesized.

[0029]

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Apart from the above method, a haloferrocene derivative represented by the general formula [II] is produced by lithiation of a ferrocene derivative represented by the general formula [V] with an organolithium compound, followed by reaction with a halogenating agent. be able to.

Examples of the organic lithium compound used for the lithiation include n-butyllithium, sec-butyllithium, t-butyllithium, methyllithium and phenyllithium. The amount of the organic lithium compound to be used is suitably 0.1 to 2.0 equivalents, preferably 0.7 to 1.5 equivalents to the ferrocene derivative [V]. Further, these organic lithium compounds are preferably used as a 5 to 30% solution of hexane or ether. Further, the lithiation reaction is carried out by a solvent (for example, ethers such as ethyl ether and tetrahydrofuran; hydrocarbons such as pentane, hexane and heptane; benzene,
In the presence of aromatic hydrocarbons such as toluene, xylene and dichlorobenzene; or one or a mixture of two or more of these solvents), the reaction is suitably performed under the following conditions.

Reaction temperature: −30 to 50 ° C., preferably −10 to 3
0 ° C. Reaction time: 0.1 to 5 hours Reaction pressure: from normal pressure to pressurized, preferably 1 to 3 atm Atmosphere: under nitrogen or argon

The lithiation reaction is carried out by a known method (Ugi et al.
Am. Chem. Soc., Vol. 92, 5389 (1970)).

Next, halogenation of the lithiated compound can be carried out using, for example, iodine, bromine, chlorine, N-iodosuccinimide, N-bromosuccinimide, or N-chlorosuccinimide as a halogenating agent. These halogenating agents can be added to the reaction system as it is or as a solution dissolved in a solvent.

As the solvent, those exemplified as the lithiation solvent can be used, and those exemplified as the lithiation solvent can also be used as the halogenation reaction solvent. The amount of the halogenating agent used is 0.1 to 2.0 equivalents, preferably 0.1 equivalent, to the ferrocene derivative [V] used for the lithiation.
It is appropriate to use 7 to 1.5 equivalents.

The halogenation reaction is preferably performed under the following conditions. Reaction temperature: -120 ° to 0 ° C, preferably -100 ° to -30 ° C Reaction time: 0.1 to 10 hours Reaction pressure: from normal pressure to pressurized, preferably 1 to 3 atm Atmosphere: under nitrogen or argon

The progress of the halogenation can be judged by thin layer chromatography. At the end of the reaction,
After terminating the reaction by adding water to the reaction system, ether extraction is performed, and the target product can be collected by column chromatography.

The compound of the formula [II] wherein R ² and R ³ are methyl groups can be obtained by quaternary ammonium salification with methyl iodide and subsequent reaction with a primary or secondary amine. , Primary and secondary amines can be appropriately selected to convert R ² and R ³ into compounds other than methyl groups [I. Ugi et al., J. Org.
m., 37, 3052 (1972); T. Hayashi et al., Bull.
Chem. Soc. Jpn, 53, 1138 (1980); G. Goke
1 et al., Angew. Chem., Int. Ed. Engl, 9 , 64 (1970)].

Many of the haloferrocene derivatives [II] thus obtained crystallize. Therefore, a diastereomer (J.
Am. Chem. Soc., Vol. 92, 5389 (1970)). Thereby, optically pure ferrocene derivatives [II] and [I] can be obtained.

Hereinafter, the production method of the present invention will be described.
The carbonyl compound to be asymmetrically alkylated in the present invention is an aldehyde compound. As the aldehyde compound, an aromatic aldehyde, an aliphatic aldehyde, and a conjugate aldehyde are used.

The aromatic aldehyde has 7 to 7 carbon atoms.
11, for example, benzaldehyde, o- and p-
Tolualdehyde, o- and p-chlorobenzaldehyde, o- and p-anisaldehyde, furfural, α
-Naphthaldehyde and β-naphthaldehyde.

The aliphatic aldehyde has 2 to 2 carbon atoms.
10, for example, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde,
Heptaldehyde, octylaldehyde, cyclohexanecarboxaldehyde, 2-ethylbutyraldehyde, pivalaldehyde, isovaleraldehyde, 3-phenylpropionaldehyde and the like can be mentioned.

The conjugated aldehyde has a carbon number of 3 to 1
0, for example, acrolein, methacrolein,
Cinnamaldehyde, crotonaldehyde and the like can be mentioned.

The alkylating agent used in the production method of the present invention is a dialkyl zinc. Specifically, dimethyl zinc, diethyl zinc, dipropyl zinc, dibutyl zinc and the like are used. These dialkyl zincs are preferably used as a 0.5 to 3.0 M solution of hexane or toluene. Further, the dialkyl zinc obtained by reacting zinc chloride with 2 equivalents of an organic lithium compound in ether can be used as it is.

In the production method of the present invention, it is preferable to use a solvent. The solvent is inert to the reaction, and specific examples thereof include hydrocarbons such as pentane, hexane, heptane, cyclohexane, benzene, toluene and xylene, and ethers such as ethyl ether, butyl ether and tetrahydrofuran. .

These solvents can be used as one kind or two kinds of mixed solvents. These solvents are generally present in an amount of 1 to 100 parts by weight, preferably 5 to 40 parts by weight, based on 1 part by weight of the aldehyde compound.

When reacting the aldehyde compound with the dialkyl zinc, the dialkyl zinc is
It is appropriate to use 0.5 to 3.0 equivalents, preferably 0.7 to 2.0 equivalents.

The ferrocenyl derivative represented by the general formula [I], which is an optically active catalyst, is used in an amount of usually 0.5 to 30 mol%, more preferably 1 to 1 mol%, based on the aldehyde compound.
5 mol%.

The reaction temperature varies depending on the type of the catalyst, but is usually -20 to 80 ° C, more preferably -10 to 60 ° C.
It is. This reaction is rare in an asymmetric synthesis reaction, and can be carried out at a high temperature of 0 ° C. or higher without impairing the optical purity of the product.

The reaction time is appropriately selected depending on conditions such as the type of the catalyst and the amount of the catalyst, and is suitably 0.5 to 48 hours.
The reaction pressure may be any of normal pressure to pressurization, but is preferably performed at 1 to 3 atm. The reaction is performed in an atmosphere of an inert gas such as nitrogen and argon.

The progress of the reaction can be determined by gas chromatography. After the reaction, a dilute acidic aqueous solution is added to stop the reaction, extraction is performed, and the target product can be collected by column chromatography. The optical purity of the product can be determined by optical rotation comparison if optically pure optical rotation values are known, otherwise by high performance liquid chromatography (HPLC) using a chiral column. Alternatively, optically active α-methoxy-α-trifluoromethylphenylacetic acid ester (MT
PA ester) and determined from the diastereo ratio of gas chromatography.

On the other hand, the catalyst can be recovered by extraction after making the acidic liquid after extraction of the target product alkaline.
The recovered catalyst can be reused in the present reaction after purification by chromatography.

The compounds thus produced by the method of the present invention include, for example, (S) -1-phenylpropanol, (R) -1-phenylpropanol,
(S) -1-phenylethanol, (R) -1-phenylethanol, (S) -1-phenylpentanol,
(R) -1-phenylpentanol, (S) -1-p-
Chlorophenylpropanol, (S) -1-o-methylphenylpropanol, (R) -1-p-methoxyphenylpropanol, (S) -3-nonanol, (S)-
2-octanol, (S) -3-decanol, (S)-
1-phenyl-1-penten-3-ol, (R) -1
-Phenyl-1-buten-3-ol, (S) -2-hexen-4-ol, (S) -2-penten-4-ol, (S) -1-cyclohexylpropanol, (R)
-1-cyclohexylpropanol, (S) -1-phenylpentan-3-ol, (S) -1- (2-furyl) propanol, (R) -1- (2-furyl) propanol, (S) -2 -Methyl-1-penten-3-ol, (S) -1-penten-3-ol, (R) -2-
Methyl-1-penten-3-ol, (S) -2-methyl-pentan-3-ol, (S) -1-β-naphthylpropanol, (S) -4-ethyl-3-hexanol, (S) -2,2-dimethyl-3-pentanol,
(R) -2,2-dimethyl-3-pentanol, (S)
Suitable examples include -2-methyl-4-hexanol, (S) -2-methyl-3-heptanol, (R) -2-methyl-3-heptanol and the like.

[0054]

According to the present invention, an optically active alcohol having high optical purity can be obtained by using a ferrocene derivative represented by the general formula [I] as a catalyst.

It is difficult to convert a substituent on a catalyst when a compound derived from a natural product is used as a catalyst. Therefore, when a compound derived from a natural product is used as a catalyst, substrate specificity is a problem. Became. However, in the catalyst used in the present invention, the substituents on the asymmetric carbon and on the nitrogen atom can be easily converted. Can solve the problem of substrate specificity.

Further, by using the catalyst of the present invention, an asymmetric alkylation reaction which has generally been required to be carried out generally at 0 ° C. or lower can be carried out at a temperature near room temperature or higher. Became. This means that when the method of the present invention is industrially scaled up and carried out, the optical purity of the target substance does not decrease even if the reaction temperature increases due to the heat of reaction, and therefore, the method of the present invention. Is an industrially advantageous method.

Further, the ferrocene derivative represented by the general formula [I] used as a catalyst in the present invention has an advantage that it can be easily synthesized.

[0058]

EXAMPLES The present invention will be further described below with reference examples and examples.

Reference Example 1 Under an argon atmosphere, (+)-(R) -N, N-dimethyl-1- was added to a 100 ml glass atmospheric pressure reactor having a stirrer.
2.66 g (10.3 mmol) of ferrocenylethylamine were added and dissolved in 25 ml of ether. After cooling with ice, 12.4 ml of a solution of secondary butyllithium in cyclohexane (0.94 ml) was added.
M, 11.7 mmol) was added dropwise. The reaction was performed for 1 hour under ice cooling. After cooling in a dry ice-acetone bath, iodine 3.00
g (11.7 mmol) dissolved in 25 ml of tetrahydrofuran was added dropwise. After reacting for 1 hour under cooling,
The reaction was stopped by adding water. Make the aqueous layer alkaline,
Extracted with ether. The organic layer was dried with anhydrous sodium sulfate. After evaporating the solvent, the residue was separated by alumina column chromatography to obtain (-)-(R)
-N, N-dimethyl-1-[(S) -2-iodoferrocenyl] ethylamine was obtained in an amount of 3.12 g (production yield 79%). Further, it was recrystallized from acetonitrile.

[0060]

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[Α] _D ²² −8.98 ゜ (C 1.0, EtOH) Melting point 78-9 ° C. 60 MHz ¹ H NMR (δ, CDCl ₃ ); 1.50 (3H, d, J = 8.0 Hz), 2.
15 (6H, s), 3.15 (1H, q, J = 7.5Hz), 4.13 (7H, s), 4.40
~ 4.60 (1H, m) IR (KBr) 3100、2970、2940、2802、2760、1100、1000cm
^-1

Reference Example 2 Under an argon atmosphere, the (R) -N, N-dimethyl-1- obtained in Reference Example 1 was placed in a normal pressure reactor made of glass having a stirrer.
[(S) -2-iodoferrocenyl] ethylamine 3.83
g (10.0 mmol) was added and dissolved in 20 ml of acetone. At room temperature, 2.86 ml (46 mmol) of methyl iodide was added and reacted for 10 minutes. A precipitate was formed by adding 100 ml of ethyl ether, followed by filtration to obtain a quaternary ammonium salt.
5.25 g (10.0 mmol) were obtained. Subsequently, the resulting quaternary ammonium salt was dissolved in 130 ml of acetonitrile and then dissolved in 26 ml (250 mmol) of diethylamine.
Was added and stirred at 30 ° C. for 48 hours. Ethyl ether was added and washed with water. The ethyl ether solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was recrystallized using ethyl alcohol, and 3.70 g of (R) -N, N-diethyl-1-[(S) -2-iodoferrocenyl] ethylamine (9.0 mmol, production yield) 90%).

[0063]

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[Α] _D ²⁷ -58.6 ^o (C 0.596, EtOH) Melting point 49 ° C. 90 MHz ¹ H NMR (δ, CDCl ₃ ); 0.98 (6H, t, J = 7.2 Hz) 1.39
(3H, d, J = 6.6Hz) 2.39 (2H, q, J = 6.9Hz) 2.42 (2H, q, J =
6.9Hz) 3.90 (1H, q, J = 6.6Hz) 4.09 (5H, s) 4.15 〜
4.21 (2H, m) 4.38 to 4.44 (1H, m) IR (KBr) 3100, 2980, 2820, 1104, 1001, 820 cm ^-1

Reference Examples 3 and 4 The same procedure as in Reference Example 2 was repeated, except that the amines shown in Table 2 were used instead of diethylamine, to obtain the products shown in Table 2.

[0066]

[Table 2]

The product of Reference Example 3 90 MHz ¹ H NMR (δ, CDCl ₃ ); 1.16 to 1.50 (6H, m) 1.50
(3H, d, J = 6.3Hz) 2.36 (3H, t, J = 5.1Hz) 3.70 (1H, q, J = 7.
2Hz) 4.10 (5H, s) 4.16-4.25 (2H, m) 4.39-4.49 (1
(H, m) IR (KBr) 3100, 2950, 2860, 2805, 2760, 1108, 100
2,820 cm ^-1

The product of Reference Example 4 90 MHz ¹ H NMR (δ, CDCl ₃ ); 0.96 (6H, d, J = 6.0 Hz) 1.06
(6H, d, J = 6.0Hz) 1.49 (3H, d, J = 6.3Hz) 2.89 to 3.37 (2
H, m) 4.03 (1H, q, J = 6.6Hz) 4.06 (5H, s) 4.10-4.28 (2H,
m) 4.36 to 4.45 (1H, m) IR (KBr) 3105, 2995, 2898, 13
65, 1195, 1109, 1002, 820 cm ^-1

Reference Example 5 Under an argon atmosphere, (R) -1-[(S) -2-iodoferrocenyl] -1-piperidinoethane 2 obtained in Reference Example 3 in a glass-made atmospheric pressure reactor having a stirrer. .12 g (5.0 m
mol) was dissolved in 12 ml of ethyl ether. After cooling on ice, 3.13 ml of a hexane solution of n-butyllithium (1.
60M, 5.0 mmol) was added dropwise. After reacting for 5 minutes under ice cooling, 911 mg (5.0 mmol) of benzophenone in 15 ml of ethyl ether was added. The reaction was performed at room temperature for 1 hour. The reaction was stopped by adding an 8% aqueous phosphoric acid solution. After washing the acidic solution with ethyl ether, a concentrated alkaline aqueous solution was added to make the acidic solution strongly alkaline. Extracted with ethyl ether and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was separated by alumina column chromatography (hexane: AcOEt) to give (-)-
1.80 g of (R) -1-[(S) -2- (diphenylhydroxymethyl) ferrocenyl] -1-piperidinoethane
(3.75 mmol, production yield 75%).

[0070]

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[Α] _D ²¹ -209.9 ^o (C 0.49, EtOH) Melting point 62-69 ° C. 90 MHz ¹ H NMR (δ, CDCl ₃ ); 0.29-1.70 (6H, m) 1.24
(3H, d, J = 6.3Hz) 2.25 (4H, t, J = 5.7Hz) 3.80 (5H, s) 3.8
9 ~ 4.01 (1H, m) 4.03 ~ 4.20 (1H, m) 4.20 ~ 4.37 (1H, m)
4.40 (1H, q, J = 6.9Hz) 6.98 ~ 7.45 (8H, m) 7.50 ~ 7.75 (2
(H, m) 8.72 (1H, s, OH) IR (KBr) 3460, 3100, 3070, 2950, 2840, 1600, 144
4, 1104, 1002, 820, 762, 753, 703 cm ^-1

Reference Examples 6 to 10 (R) -1-[(S) -2-iodoferrocenyl] -1
Table 3 and Table 4 by repeating the same operation as in Reference Example 5 except that the starting materials shown in Tables 3 and 4 were used instead of benzophenone as piperidinoethane and ketone.
Was obtained.

[0073]

[Table 3]

[0074]

[Table 4]

Product of Reference Example 6 90 MHz ¹ H NMR (δ, CDCl ₃ ); 0.37 (3H, d, J = 6.6 Hz) 0.85
(3H, d, J = 6.3Hz) 1.29 (6H, d, J = 6.6Hz) 1.45 (3H, d, J =
6.6Hz) 1.60 to 1.97 (1H, m) 2.10 (6H, s) 2.30 to 2.68 (1
(H, m) 3.78 to 3.95 (1H, m) 4.09 (5H, s) 4.11 to 4.23 (3
(H, m) 7.69 (1H, s, -OH) IR (KBr) 3420, 3100, 2998, 2898, 2800, 1108, 100
4,828,820cm- ¹

Product of Reference Example 7 90 MHz ¹ H NMR (δ, CDCl ₃ ); 1.21 (3H, d, J = 6.3 Hz) 1.30
~ 2.42 (10H, m) 2.09 (6H, s) 3.90 ~ 4.09 (3H, m) 4.12 (5
H, s) 4.29 (1H, q, J = 6.3Hz) 7.18 (1H, s, -OH) IR (KBr) 34
50, 3100, 2950, 2800, 1105, 822cm ^-1

The product of Reference Example 8 90 MHz ¹ H NMR (δ, CDCl ₃ ); 0.63 (6H, t, J = 7.2 Hz) 1.20
(3H, d, J = 6.0Hz) 1.89 to 2.58 (4H, m) 3.78 (5H, s) 3.89
~ 4.03 (1H, m) 4.07 ~ 4.20 (1H, m) 4.20 ~ 4.31 (1H, m)
4.65 (1H, q, J = 6.9Hz) 6.98 ~ 7.48 (8H, m) 7.53 ~ 7.76 (2
(H, m) 8.70 (1H, s, -OH) IR (KBr) 3450, 3100, 3060, 2995, 2860, 1598, 110
9, 1003, 820, 755, 702 cm ^-1

The product of Reference Example 9 90 MHz ¹ H NMR (δ, CDCl ₃ ); 1.32 (3H, d, J = 6.0 Hz) 1.35
~ 1.95 (6H, m) 2.64 (4H, t, J = 5.4Hz) 3.20 ~ 3.39 (1H, m)
3.50 (5H, s) 3.70 to 3.90 (1H, m) 3.90 to 4.02 (1H, m)
4.02 to 4.18 (1H, m) 4.20 to 4.60 (2H, m) 7.06 to 7.50 (4H, m)
m) 7.60-7.83 (1H, m) 7.89-8.09 (1H, m) IR (KBr) 3460, 3100, 3150, 2950, 2830, 1108, 100
1,820,760,747cm- ¹

Product of Reference Example 10 90 MHz ¹ H NMR (δ, CDCl ₃ ); 0.69 (6H, d, J = 6.0 Hz) 1.09
(6H, d, J = 6.0Hz) 1.38 (3H, d, J = 6.3Hz) 2.85 to 3.22 (2
H, m) 3.70 (5H, s) 3.90-4.10 (1H, m) 4.10-4.23 (1H,
m) 4.23 ~ 4.37 (1H, m) 4.82 (1H, q, J = 6.9Hz) 6.98 ~ 7.
47 (8H, m) 7.60 to 7.83 (2H, m) 8.45 (1H, s, -OH) IR (KBr) 3450, 3100, 3070, 2990, 2890, 1600, 110
5, 1000, 819, 750, 700 cm ^-1

Reference Examples 11 to 13 (R) -1-[(S) -2-iodoferrocenyl] -1
-The same operation as in Reference Example 5 was repeated, except that the raw materials shown in Table 5 were used instead of piperidinoethane, and the aldehydes shown in Table 5 were used instead of benzophenone as the carbonyl compound. The products were two kinds of diastereomers, and were separated by chromatography on alumina or silica gel to obtain each product, and the physical properties of each product were shown. Table 5 shows the results.

[0081]

[Table 5]

Reference Example 11 Product 1 90 MHz ¹ H NMR (δ, CDCl ₃ ); 1.36 (3H, d, J = 6.6 Hz) 2.22
(6H, s) 3.38 to 3.58 (1H, m) 3.80 to 4.40 (3H, m) 4.03 (5
H, s) 5.94 (1H, s) 7.12 to 7.68 (5H, m) 7.70 to 8.02 (1H,
s, OH) .IR (neat) 3102, 3049, 2998, 2849, 2800, 1605, 110
5, 1000, 819, 738, 700 cm ^-1

Product 2 90 MHz ¹ H NMR (δ, CDCl ₃ ); 1.23 (3H, d, J = 6.0 Hz) 2.19
(6H, s) 3.80 (5H, s) 3.90 to 4.35 (4H, m) 5.47 (1H, s)
6.00-6.70 (1H, -OH) 7.09-7.68 (5H, m) IR (neat) 3370, 3100, 3040, 2998, 2798, 1600, 110
4, 1000, 818, 719, 700 cm ^-1

Reference Example 12 Product 1 90 MHz ¹ H NMR (δ, CDCl ₃ ); 0.94 (9H, s) 1.29 (3H, d, J =
6.6Hz) 2.07 (6H, s) 2.62 (1H, -OH) 3.80 (1H, q, J = 7.5H
z) 3.97-4.17 (4H, m) 4.16 (5H, s) IR (KBr) 3480, 3105, 2999, 2970, 2840, 2800, 110
6, 1102, 818cm ^-1

Product 2 90 MHz ¹ H NMR (δ, CDCl ₃ ); 1.18 (9H, s) 1.29 (3H, d, J =
6.0Hz) 2.15 (6H, s) 4.00 (5H, s) 4.05 to 4.18 (3H, m)
4.19 to 4.34 (1H, m) 4.52 (1H, s) 7.40 to 7.80 (1H, -OH) IR (KBr) 3450, 3102, 3000, 2960, 2850, 2800, 110
8, 1005, 820cm ^-1

Reference Example 13 Product 1 90 MHz ¹ H NMR (δ, CDCl ₃ ); 0.99 (9H, s) 1.27 (3H, d, J =
5.4Hz) 1.18 to 1.55 (6H, m) 2.20 to 2.60 (4H, m) 3.79 (1
(H, q, J = 7.2Hz) 3.97-4.37 (4H, m) 4.11 (5H, s) IR (neat) 3100,3000,2950,2820,1105,1000,820
cm ^-1

Product 2 90 MHz ¹ H NMR (δ, CDCl ₃ ); 1.20 (9H, s) 1.33 (3H, d, J =
6.0Hz) 1.29 to 1.56 (6H, m) 2.32 to 2.57 (4H, m) 4.0
0 (5H, s) 4.03 to 4.20 (3H, m) 4.20 to 4.37 (1H, m) 4.50 (1
H, s) IR (neat) 3250, 3105, 3000, 2960, 2840, 1112, 100
9, 822 cm ^-1

Reference Examples 14, 15 (R) -1-[(S) -2-iodoferrocenyl] -1
(R) -N, N-dimethyl-1-[(S) -2-iodoferrocenyl] ethylamine was used in place of -piperidinoethane, and the aldehyde shown in Table 6 was used in place of benzophenone as the carbonyl compound. Except for this, the same operation as in Reference Example 5 was repeated. In addition, although the product of Reference Example 15 becomes two kinds of diastereomers,
Each product was obtained by separation by chromatography on alumina or silica gel, and the respective physical properties were shown. Table 6 shows the results.

[0089]

[Table 6]

Reference Example 14 90 MHz ¹ H NMR (δ, CDCl ₃ ); 1.35 (3H, d, J = 6.6 Hz) 2.20
(6H, s) 3.78 (6H, s) 3.70 to 4.00 (2H, m) 3.93 (5H, s) 4.
02 to 4.20 (1H, m) 4.30 (1H, q, J = 7.0Hz) 6.58 (1H, s)
6.68 (2H, d, J = 3.3Hz) 7.23 (1H, dd, J = 8.4Hz, J = 7.0Hz) IR (KBr) 3450,3100,2998,2950,2848,2800,159
5, 1475, 1245, 1180, 1100, 1004, 920, 808, 730c
m ^-1

Reference Example 15 Product 1 90 MHz ¹ H NMR (δ, CDCl ₃ ); 1.35 (3H, d, J = 6.8 Hz) 2.27
(6H, s) 3.52 to 3.65 (1H, m) 3.87 to 3.99 (1H, m) 3.97 (5H,
s) 4.15 〜 4.24 (1H, m) 4.47 (1H, q, J = 6.8Hz) 6.05 (1H, O
H) 7.17 (1H, s) 7.30 to 7.60 (4H, m) 7.88 to 8.10 (2H, m)
8.40 (1H, s) 8.85 to 9.10 (2H, m) IR (neat) 3440, 3100, 3050, 2970, 2940, 2815, 277
5, 1620, 1520, 1365, 1260, 1104, 1040, 1000, 88
0, 732cm ^-1

Product 2 90 MHz ¹ H NMR (δ, CDCl ₃ ); 1.47 (3H, d, J = 6.8 Hz) 2.34
(6H, s) 3.30 to 3.42 (1H, m) 3.83 (5H, s) 4.04 to 4.16 (1H,
m) 4.18 to 4.30 (1H, m) 4.51 (1H, q, J = 6.8Hz) 7.25 to 7.53
(4H, m) 7.55 (1H, s) 7.89-8.10 (2H, m) 8.44 (1H, s) 8.60
~ 8.90 (2H, m) IR (KBr) 3440, 3100, 2990, 2930, 2785, 1600, 151
0, 1350, 1265, 1108, 1035, 1005, 880, 730cm ^-1

Example 1 Under an argon atmosphere, the (R) -N, N-dimethyl-1- obtained in Reference Example 11 was placed in a glass-made atmospheric pressure reactor having a stirrer.
[(S) -2-{(S) -phenylhydroxymethyl}
Ferrocenyl] ethylamine (Product 1 of Reference Example 11)
431 mg (1.19 mmol, catalyst concentration 4.9 mol%) was added and dissolved in 25 ml of hexane. Benzaldehyde 2.
20 g of a hexane solution of 60 g (24.5 mmol) was added,
Stirred at room temperature for 15 minutes. 26 ml of diethylzinc (1.47
M hexane solution, 38 mmol), and the mixture was stirred at room temperature for 3 hours, and 1N hydrochloric acid was added under ice cooling to stop the reaction. After extraction with ether, the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The ether was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. After further distillation under reduced pressure, (S) -1-phenylpropanol
3.18 g (23.3 mmol, production yield 95%) were obtained.

[Α] _D ²⁵ -44.4 ° (C5.28, CHCl ₃ ) The optical purity determined by high performance liquid column chromatography (HPLC) using a chiral column was 91% ee.

On the other hand, the acidic aqueous solution after ether extraction was made alkaline by adding a concentrated aqueous sodium hydroxide solution.
Extracted with ether. After drying over anhydrous sodium sulfate and distilling off ether under reduced pressure, (R) -N, N-dimethyl-
1-[(S) -2-{(S) -phenylhydroxymethyl} ferrocenyl] ethylamine is 409 mg (1.13 mm
ol, 95% recovery).

Examples 2 to 7 (S) -1-phenylpropanol was obtained by repeating the same operation as in Example 1 except that the asymmetric catalyst, the reaction temperature and the reaction time were changed to the compounds and conditions shown in Table 7. Was. Table 7 shows the results.

[0097]

[Table 7]

Examples 8 to 13 The same operation as in Example 1 was carried out except that n-heptaldehyde was used instead of benzaldehyde, and the asymmetric catalyst, solvent and reaction time were the compounds and conditions shown in Table 8. Repeated to give 3-nonanol. The optical purity of 3-nonanol was determined by optical rotation [T. Mukaiyama (Mukoyama)
Chem. Lett., 1976, 893, literature value [α] _D ²⁴ + 9.6 ° (CHCl ₃ )]. Table 8 shows the results.

[0099]

[Table 8]

Examples 14 to 23 (R) -1-[(S)-obtained in Reference Example 5 as an asymmetric catalyst
2-diphenylhydroxymethyl @ ferrocenyl] -1
-An optically active alcohol was obtained by repeating the same operation as in Example 1 except that piperidinoethane was used and aldehydes shown in Tables 9 and 10 were used instead of benzaldehyde. The optical purity of the obtained optically active alcohol is
Depending on the product, optical rotation comparison, HPLC
Alternatively, it was determined as an MTPA ester, and determined by gas chromatography or ¹ H NMR diastereo ratio.
The absolute configuration was determined from the sign of the optical rotation. The results are shown in Tables 9 and 10.

[0101]

[Table 9]

[0102]

[Table 10]

Examples 24 and 25 (R) -1-[(S)-obtained in Reference Example 5 as an asymmetric catalyst.
2- (diphenylhydroxymethyl) ferrocenyl]-
An optically active alcohol was obtained by repeating the same operation as in Example 1 except that 1-piperidinoethane was used, di (n-butyl) zinc was used instead of diethylzinc, and aldehydes shown in Table 11 were used. . Table 11 shows the results.

[0104]

[Table 11]

────────────────────────────────────────────────── ─── Continuation of front page (56) References JP-A-3-112996 (JP, A) JP-A 64-68 (JP, A) JP-A 2-133 (JP, A) (58) Field (Int.Cl. ⁷ , DB name) B01J 31/22 C07B 53/00 C07C 29/40 C07F 17/00-17/02 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A method for producing an optically active alcohol, comprising reacting an aldehyde compound with a dialkyl zinc in the presence of a chiral ferrocene derivative represented by the following general formula [I]. Embedded image (Wherein, R ¹ represents a lower alkyl group having 1 to 6 carbon atoms,
R ² and R ³ are the same or different, and represent a lower alkyl group, a phenyl group or a benzyl group having 1 to 6 carbon atoms, R ²
And R ³ are the nitrogen atom and the carbon number of 4 to 6
R ⁴ and R ⁵ are the same or different,
Hydrogen, lower alkyl group having 1 to 6 carbon atoms, an aryl group, or anthracenyl group or represents a ferrocenyl group, R ⁴ and R
⁵ forms a cycloalkyl group having 5 to 7 carbon atoms or a 10-hydroanthracenyl group with a carbon atom to which each is bonded. )