JPH11269183A - Method for producing phosphine compound, intermediate thereof, and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject optically pure compound useful for asymmetric synthesis as a ligand for asymmetric catalysts by utilizing a unique reactivity of phosphine borane. SOLUTION: This phosphine compound which is either of enantiomers of formula V is obtained by reacting a dichlorophenylphosphine of the structural formula, Ph-P-Cl2 (Ph is phenyl) with a Grignard reagent of formula I (X is a halogen), preferably, at -50 to -80 deg.C, then, reacting the resultant product with (-)-menthol in the presence of a base, further, reacting the reaction product with a borane-tetrahydrofuran complex to make a mixture of diastereomers of formula II, reacting the mixture with a lithium compound of the structural formula, CH3 -Li to obtain either of enantiomers of formula III, reacting the resultant product with an alkyllithium of the formula, R-Li (R is a lower alkyl) in the presence of a copper chloride to obtain either of enantiomers of formula IV and then reacting the resultant compound with a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a phosphine compound useful as a ligand of an asymmetric catalyst for various asymmetric syntheses, an intermediate thereof, and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Since the usefulness of optically active phosphine ligands as asymmetric catalysts was reported by Horner, Kagan, Knowles et al., A number of optically active phosphine ligands have been synthesized.
Asymmetric catalysis has been studied. To date, more than 500 ligands have been published, and many of them have extremely high selectivity. However, not only is the selectivity high, but also very high catalytic activity (substrate / catalyst> 100
00) and reduction, hydrosilylation, isomerization, carbon-
Very few ligands can be widely applied to carbon bond formation reactions and the like.

[0003]

As a ligand giving an extremely high asymmetric yield, an optically active bisphosphine having an asymmetric center at a phosphorus atom itself, for example, (S, S) -1,4
-Bis (o-anisylphenylphosphino) ethane (D
IPAMP), but the synthesis of this type of ligand by conventional methods is extremely difficult, and the development of a simple synthesis method is strongly desired.

[0004]

Means for Solving the Problems The present inventors have proposed the above DIP.
A phosphine ligand having an asymmetric center on a phosphorus atom can be synthesized at an optical purity of 100% by conducting intensive research to find a new method for producing AMP and making use of the unique reactivity of phosphine / borane. The present inventors have developed a method for producing optically pure phosphine borane and completed the present invention. The present invention relates to dichlorophenylphosphine represented by the structural formula (X) Ph-P-Cl ₂ (X) (wherein Ph represents a phenyl group) represented by the general formula (VII):

[0005]

Embedded image (Wherein X represents a halogen atom), and then reacted with a Grignard reagent represented by the formula (-)-in the presence of a base.
Menthol is reacted, and further reacted with a borane-tetrahydrofuran complex (BH ₃ -THF complex) to obtain a compound represented by the structural formula (VI).

Embedded image (Wherein Ph is the same as described above), and the mixture (VI) is separated or separated to obtain a diastereomer mixture or a diastereomer represented by the structural formula (VI). Or reacting dichlorophenylphosphine represented by the structural formula (X) with (−)-menthol in the presence of a base, then reacting with a borane-tetrahydrofuran complex, and further performing a reduction reaction with a reducing agent to obtain a structure The formula (I
X)

[0006]

Embedded image (Wherein Ph is the same as described above), and the mixture is separated or separated without separation to obtain a compound represented by the general formula (VIII):

Embedded image (Wherein, Y represents a halogen atom), and reacted in the presence of a catalyst to obtain a diastereomer mixture or a separation product represented by the structural formula (VI). )
Is the structural formula (V)

Reaction with a lithium compound represented by CH ₃ -Li (V)

Embedded image (Wherein Ph is the same as described above), and any compound in the enantiomer represented by the general formula (III) R-Li (III) (in the formula, R represents a lower alkyl group), and reacted with an alkyl lithium represented by the formula (II):

[0008]

Embedded image (Wherein Ph is the same as described above), and any one of the compounds in the enantiomer represented by the formula (I), wherein the compound (II) is reacted with a base.

[0009]

Embedded image (In the formula, Ph is the same as described above.) The present invention relates to a method for producing any of the phosphine compounds in the enantiomer represented by the formula, an intermediate which is a novel compound not described in any literature, and a method for producing them.

The production method of the present invention can be schematically shown as follows, for example.

Embedded image

[0011]

Embedded image

[0012]

Embedded image (In the formula, Ph represents a phenyl group, R represents a lower alkyl group, Men represents (-)-menthol, X and Y
Represents a halogen atom which may be the same or different. )

That is, the dichlorophenol represented by the structural formula (X)
General formula (VII) in the presence of an inert solvent for phenylphosphine
Reaction of the Grignard reagent represented by
(-)-Menthol is reacted in the presence of
Tetrahydrofuran complex (BH _Three-THF complex)
Diastereomeric mixture represented by structural formula (VI)
The mixture (VI) is separated and represented by the structural formula (VI-1) or (VI-2).
Diastereomer isomers or represented by structural formula (X)
Dichlorophenylphosphine and (-)-menthol
Is reacted in the presence of an inert solvent and a base.
_Three-THF complex reacts and is further reduced with a reducing agent
To form a mixture of diastereomers represented by Structural Formula (IX).
And the mixture (IX) is represented by the general formula (VIII):
Diastereomer represented by the structural formula (VI)
And a mixture of the structural formula
(VI-1) or (VI-2) or a structural formula
Dichlorophenylphosphine represented by (X) and (−)-
Reacting menthol in the presence of an inert solvent and a base,
Then BH_Three-THF complex and further reduced by reducing agent
By reacting, the diastere represented by the structural formula (IX)
Omer mixture, the mixture (IX) was separated, and the compound represented by the structural formula (IX-
1) and as a separated product represented by (IX-2), the compound (IX-1),
(IX-2) and an inert solvent represented by the general formula (VIII)
Reaction in the presence of a medium and a base, the structural formula (VI-1) or (VI-
The diastereomer isolate represented by 2) is produced.

Reacting any of the diastereomeric isolates represented by Structural Formula (VI-1) or (VI-2) produced by the above method with a lithium compound represented by Structural Formula (V) To produce an enantiomer isolate of any of the structural formulas (IV-1) and (IV-2). Also, a diastereomer mixture obtained in each step by the above method was not isolated from the structural formula (X) to produce an enantiomeric mixture represented by the structural formula (IV), and at this stage, the enantiomers were separated to form a structure. It is also possible to produce an enantiomeric isolate represented by the formula (IV-1) or (IV-2). Next, the enantiomer isolate (IV-1) or (IV-2) is reacted with a lithium compound represented by the structural formula (III) in the presence of copper chloride, and the structural formula represented by the structural formula (II) ( (IV-1) or any of the enantiomers separated from (IV-2), and reacting the separated with a base to produce a phosphine compound which is any of the enantiomers represented by the structural formula (I) can do.

A. (X) → (VI) The inert solvent that can be used in the present reaction may be any solvent that does not hinder the progress of the present reaction, and examples thereof include linear or cyclic ethers such as diethyl ether and tetrahydrofuran. . The Grignard reagent used in this reaction can be prepared and used by a commonly used method. The amount of the Grignard reagent to be used may be selected from the range of equimolar to 2 times the molar amount of the dichlorophenylphosphine represented by the structural formula (X), and is preferably in the range of 1 mole to 1.3 times the molar amount. The temperature at which the Grignard reagent is dropped is a temperature of 0 ° C. or lower, preferably −50 ° C.
To -80 ° C. This reaction is preferably performed under an argon atmosphere. After completion of the dropwise addition, (-)-menthol, one of the optically active alcohols, may be added in the presence of a base.

[0016] The optically active alcohol is not particularly limited to (-)-menthol. The amount of (-)-menthol to be used may be selected from the range of equimolar to 1.5 times mol, preferably 1.0 to 1.3 times mol, of dichlorophenylphosphine represented by the structural formula (X). Range. As a base that can be used in this reaction, an organic base or an inorganic base can be used, and an organic base such as triethylamine or pyridine is preferably used. This reaction may be carried out at a temperature in the range of -80 ° C to room temperature.
The reaction may be carried out in the range of from -80 ° C to -80 ° C, and gradually up to room temperature after the addition. The reaction time is not fixed depending on the reaction amount, the reaction temperature and the like, but may be in the range of several minutes to 48 hours.

After completion of the reaction, the desired product can be produced by removing the salt generated from the reaction system, and adding and reacting with a BH ₃ -THF complex. As the BH ₃ -THF complex, a commercially available one may be used, and its amount may be in the reaction system at least equimolar to dichlorophenylphosphine represented by the general formula (X). The reaction temperature may be selected from the range of 0 ° C. to room temperature. The reaction time is not fixed depending on the reaction amount, the reaction temperature and the like, but may be in the range of several minutes to 48 hours. After completion of the reaction, the diastereomer is isolated from the reaction solution containing the target substance by a conventional method, and the diastereomer is separated by, for example, a recrystallization method, a column chromatography method, a liquid column chromatography method, a thin layer chromatography method, or the like. be able to.

B. (X) → (IX) → (IX-1),
(IX-2) As the inert solvent that can be used in this reaction, the inert solvents exemplified for A can be used. (-)-Menthol, one of the optically active alcohols, may be added in the presence of a base, but the optically active alcohol is not limited to this. The amount of (-)-menthol to be used may be selected from the range of equimolar to 1.5 times the molar amount of dichlorophenylphosphine represented by the structural formula (X), and is preferably in the range of equimolar to slightly excess molar. is there. As a base that can be used in this reaction, an organic base or an inorganic base can be used, and an organic base such as triethylamine or pyridine is preferably used. This reaction may be carried out at a temperature in the range of 0 ° C. to room temperature, preferably at a temperature around room temperature. The reaction time is not fixed depending on the reaction amount, the reaction temperature and the like, but may be in the range of several minutes to 48 hours. Next, the reaction may be carried out by adding a BH ₃ -THF complex and a reducing agent, excluding salts generated from the reaction system.

The addition of the BH ₃ -THF complex and the reducing agent is preferably carried out at a temperature of about 0 ° C. After the addition, the reaction may be carried out gradually at a temperature near room temperature. As the BH ₃ -THF complex, a commercially available one may be used, and its amount may be in the reaction system at least equimolar to dichlorophenylphosphine represented by the general formula (X). As the reducing agent, for example, a reducing agent such as lithium aluminum hydride (LiAlH ₄ ) may be used, and the amount of the reducing agent is from equimolar to 1 to 1 mol of dichlorophenylphosphine represented by the general formula (X).
What is necessary is just to add in the range of 5 times amount. This reaction is preferably performed under an argon atmosphere. After completion of the reaction, the desired product is isolated by a conventional method and, if necessary, separated by, for example, silica gel thin-layer chromatography, to isolate each diastereomer.

C. (IX-1), (IX-2) → (VI
-1), (VI-2) As the inert solvent that can be used in this reaction, for example, chain or cyclic ethers such as diethyl ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene, toluene, and xylene can be used. it can. As the catalyst used in this reaction, a palladium-phosphine compound can be used. For example, tetrakis (triphenylphosphine) palladium can be used.
The amount may be selected from the range of 0.0001 to 0.5 mol, preferably 0.01 to 0.1 mol, based on the compound represented by X). The reaction temperature may be appropriately selected from room temperature to the boiling point range of the inert solvent used. Since this reaction is an equimolar reaction, each reactant may be used in an equimolar amount, but any one of them may be used in excess.

D. (IX) → (VI) The reaction can be carried out in the same manner as in C to produce the desired product. E. (VI-1), (VI-2) → (IV-1), (I
V-2) As the inert solvent that can be used in this reaction, for example, the inert solvents exemplified for C can be used. Since this reaction is an equimolar reaction, the alkyllithium represented by the structural formula (V) may be used in an equimolar amount with respect to the compound represented by the structural formula (VI-1) or (VI-2). However, any of the reaction reagents can be used in excess. The reaction temperature may be selected from the range of 0 ° C. to room temperature. The reaction time is the reaction amount,
It is not fixed depending on the reaction temperature and the like, but may be selected from a range of several minutes to 48 hours. After completion of the reaction, the target product can be obtained by isolating the reaction solution containing the target product from the reaction solution by a conventional method and separating the product by, for example, silica gel thin layer chromatography.

F. Structural formulas (IV-1), (IV-2) →
Structural formulas (II-1) and (II-2) The inert solvent that can be used in the present reaction may be any solvent that does not inhibit the progress of the present reaction. For example, the inert solvent exemplified in the reaction of C is used. be able to. As the alkyllithium represented by the general formula (III) used in this reaction, for example, alkyllithiums such as n-butyllithium, sec-butyllithium, t-butyllithium and the like can be used. It is preferable to use anhydrous cupric chloride as the copper chloride used simultaneously in this reaction, and its use amount is not particularly limited, but it is preferable that the structural formula (IV-
The compound represented by the formula (1) or (IV-2) is equimolar to 1.
It is in the range of 5 moles. The reaction temperature may be selected from the range of -80 ° C to room temperature, preferably -50 ° C to -8.
It is in the range of 0 ° C. The reaction time is not fixed depending on the reaction amount, the reaction temperature and the like, but may be selected from a range of several minutes to 48 hours. After the completion of the reaction, the desired product corresponding to any of the enantiomers of the structural formula (IV) as a raw material can be produced by isolating from the reaction solution containing the desired product by a conventional method.

G. (II─1), (II-2) → (I−
1), (I-2) As the inert solvent usable in the present reaction, for example, in addition to the inert solvents exemplified in C, a base used in the present reaction can also be used. The base that can be used in this reaction may be any base that performs deboration, and for example, an organic base such as ethylamine, diethylamine, triethylamine, morpholine, and N-methylmorpholine can be used. The amount of the base used may be a 2-fold molar amount or an excess amount with respect to the compound represented by the structural formula (II-1) or (II-2), but is preferably used in an excess amount, and may be used as an inert solvent. Good to use. After the completion of the reaction, the desired product can be isolated from the reaction solution containing the desired product by a conventional method and, if necessary, purified by, for example, column chromatography. Hereinafter, typical examples of the present invention will be described, but the present invention is not limited thereto.

Embodiment 1 FIG. 1─1.

Embedded image

Dichlorophenylphosphine 1.1 ml
(8.1 mmol) was dissolved in 40 ml of tetrahydrofuran, and o-anisylmagnesium bromide 40 was added to this solution.
ml (0.25 mol / 1 L tetrahydrofuran solution) was added dropwise at −78 ° C. over 50 minutes with vigorous stirring under an argon atmosphere. After dropping, (-)-menthol
56 g (10 mmol) and 0.8 ml (10 mmol) of pyridine were added at a temperature of -78 ° C, and the reaction mixture was stirred overnight at room temperature except for a cooling bath. After the reaction, the reaction mixture was quickly filtered to remove the pyridinium salt, and the filtrate was further cooled to 0 ° C. Then, 30 ml of BH ₃ -THF complex
(1.0 mol / 1 L tetrahydrofuran solution) was added, and the mixture was reacted at room temperature for 1 hour, and then 100 ml of 1N hydrochloric acid was added. After completion of the reaction, the reaction solution containing the desired product was extracted with ether, the extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Benzene: n-hexane =
1: 1). Although the target product was obtained as a viscous substance, 2.83 g of a white powder crystal was obtained as a mixture of each diastereomer from hexane. (Yield 90%) Diastereomers were separated by preparative silica gel thin-layer chromatography (toluene: cyclohexane = 1: 4).

[0026] Physical properties (VI-1): oil [α] ^{D 25 -75.6 ° (c 0.9,} C 6 H 6) IR (neat) 2950, 2390, 1590, 1480, 1280cm -1 1 H-NMR (500MHz, CDCl ₃ ) δ value (ppm) 0.49 (d, 3H, J = 6.87H
z), 0.80-1.64 (m, 16H), 1.92-1.96 (m, 1H), 2.09 (d, 1H, J =
11.8Hz), 3.53 (s, 3H), 4.23-4.25 (m, 1H), 6.80-7.96 (m,
9H), 100% de (VI-2): mp. 85.0-87.5 ° C. [α] D ²⁵ −49.0 ° (c 1.0, C ₆ H ₆ ) IR (neat) 2940, 2390, 1480, 1280, 1015 ^{, 765 cm -1 1 H-NMR} (500MHz, CDCl 3) δ value (ppm) 0.55 (d, 3H , J = 6.87H
z), 0.79-1.64 (m, 16H), 1.87-1.91 (m, 1H), 2.06 (d, 1H, J =
13.2Hz), 3.53 (s, 3H), 4.26-4.29 (m, 1H), 6.82-7.93 (m,
9H), 93% de

1-2.

Embedded image

25 ml of dichlorophenylphosphine (0.
185 mol) was dissolved in 100 ml of dry benzene, and 28.8 g (0.185 mol) of (-)-menthol dissolved in 100 ml of dry benzene were added to 15 ml of pyridine.
(0.185 mol) was added dropwise at room temperature under an argon atmosphere for 2 hours. After reacting for 12 hours after the dropwise addition, the reaction solution was quickly filtered to remove the pyridinium salt, and 8.42 g (0.222 mol) of lithium aluminum hydride and B
After adding 225 ml (1.0 mol / 1 L tetrahydrofuran solution) of H ₃ -THF complex at 0 ° C. and reacting at room temperature for 3 minutes, the reaction solution was concentrated with 40 ml of concentrated hydrochloric acid, about 200 g of ice and 100 ml of water.
The organic layer was separated, and the aqueous layer was extracted four times with ether. The organic layer and the ether layer were combined, washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (benzene: n-hexane = 1: 1). As a result, 20.6 g of a diastereomer mixture (IX) was obtained as white crystals. (40% yield). Further, the obtained crystal was recrystallized three times from hexane to obtain 5.7 g of a pure diastereomer. Diastereomers were separated by preparative silica gel thin layer chromatography (toluene: cyclohexane).

Physical properties (IX-1): colorless crystals, mp 94-
96 ° C. [α] ^{D 25 -117.6 ° (c 1.0,} ClCH 2 CH 2 Cl) IR (KBr, cm -1) 2900, 2375, 1445, 1135, 1060, 970. 1 H-NMR (500MHz, CDCl ₃ ) δ value (ppm) 0.63 (d, 3H, J = 7.15H
z), 0.888 (d, 3H, 6.60Hz), 0.893 (d, 3H, J = 6.88Hz), 2.01-
2.08 (m, 2H), 3.85-3.94 (m, 1H), 7.48-7.81 (m, 5H). ³¹ P-NMR (121 MHz) (CDCl ₃ : (PhO) ₃ PO ext), δ value 109.5 (q, J
^{. (PB) = 58.96Hz) 11} B-NMR (96MHz) (CDCl 3: (CH 3 O) B ext), δ values -58.90 (d, J (P
B) = 58.96Hz) .MS (70eV) m / e 264 (M -BH ₃ ) 100ee

(IX-2): colorless crystal, mp 81-83 ° C. [α] D ²⁵ −62.8 ° (c 1.0, ClCH ₂ CH ₂ Cl) IR (KBr, cm ⁻¹ ) 2900, 2390, 1435 ^{, 1130, 1060, 970. 1 H} -NMR (500MHz, CDCl 3) δ value (ppm) 0.70 (d, 3H , J = 6.87H
z), 0.85 (d, 3H, 6.87Hz), 0.91 (d, 3H, J = 6.32Hz), 1.92-2.
08 (m, 2H), 3.97-4.40 (m, 1H), 7.49-7.82 (m, 5H). ³¹ P-NMR (121MHz) (CDCl ₃ : (PhO) ₃ PO ext), δ value 111.1 (q, J
^{. (PB) = 58.96Hz) 11} B-NMR (96MHz) (CDCl 3: (CH 3 O) B ext), δ values -59.90 (d, J (P
B) = 58.96Hz) .100ee

1-3.

Embedded image 278 mg (1 mmol) of (IX-1) in 2 ml of toluene, o
468 mg (2 mmol) of iodoanisole are tetrakis (triphenylphosphine) palladium (0) 11
5 mg (0.1 mmol) and 553 m of sodium carbonate
g (4 mmol) was added, and the mixture was reacted at 70-80 ° C. for 1 day with stirring under an argon atmosphere, and 1N-hydrochloric acid was added to stop the reaction. After the reaction, the organic layer was separated, and the aqueous layer was further extracted three times with ether. The organic layer and the ether layer were combined, washed with an aqueous solution of sodium thiosulfate and brine, dried over magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was separated by silica gel thin layer chromatography. Yield: 234 mg Physical property (IV-1): oil

1-4.

Embedded image

(VI-2) 83 mg (0.2 mmol)
Was dissolved in 3 ml of dry benzene, and 0.5 ml of an ether solution of methyllithium (1.3 mol / 1 L ether solution) was added to the solution at room temperature. A stirring reaction was performed at the same temperature for 3 hours, and 1N-hydrochloric acid was added to stop the reaction. After the reaction, the organic layer was separated, and the aqueous layer was extracted four times with ether. After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure.
The obtained residue is separated by preparative silica gel thin-layer chromatography (benzene: n-hexane) to obtain 50 mg of o-anisylmethylphenylphosphine-borane represented by (IV-2) which is a target substance. (Yield: 95%). Similarly, the other enantiomer was obtained from (VI-1). Physical property (IV-1): [α] D ²⁵ -27.0 ° (c 1.5, MeOH) 100% de (IV-2): [α] ²⁵ + 25.2 ° (c 1.6, MeOH) 93% de

1-5.

Embedded image 488 mg of optically active phosphine-borane (2 mmol,
89% ee) was dissolved in dry tetrahydrofuran under an argon atmosphere and cooled to -78 ° C. Sec-
2.2 ml (1.0 mol / 1 L tetrahydrofuran solution) of butyllithium was added, and the reaction was carried out with stirring for 2 hours. 404 mg (3 mmol) of anhydrous copper chloride under further vigorous stirring
Was added, and the reaction temperature was gradually raised to room temperature over 1.5 hours. Thereafter, the reaction was carried out at room temperature for 1 hour, and dilute hydrochloric acid was added to stop the reaction. After the reaction, the reaction mixture containing the desired product was extracted with chloroform, the extract was dried over magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to preparative silica gel thin-layer chromatography (ethyl acetate: hexane: dichloromethane =
1: 4: 1) to give the desired product. Physical properties mp 162.5-163.0 ℃ [α] D ²⁵ -70.2 ° (c 1.3, CHCl ₃ ) 1-6

[0035]

Embedded image Bis-phosphine-borane 100 obtained in 1-5 above
mg (0.21 mmol) was dissolved in degassed diethylamine and the solution was kept at 50 ° C. for 10 hours under an argon atmosphere. After completion of the reaction, excess diethylamine was distilled off under reduced pressure, and the residue was passed through a short column of basic alumina with degassed benzene under an argon atmosphere to give 81 mg of a substantially pure target product (yield: 84%). I got Further, the product was recrystallized from hot methanol under an argon atmosphere to obtain a pure target product. Properties mp 102-103 ℃ (α) D ²⁵ +87.0 (c 1.0, CHCl ₃ )

Claims (4)

[Claims] 1. Dichlorophenylphosphine represented by the structural formula (X) Ph-P-Cl ₂ (X) (wherein Ph represents a phenyl group) is represented by the general formula (VII): (Wherein X represents a halogen atom), and then reacted with a Grignard reagent represented by the formula (-)-in the presence of a base.
Menthol is reacted, and further reacted with a borane-tetrahydrofuran complex to obtain a compound represented by the structural formula (VI). (Wherein Ph is the same as described above), and the mixture (VI) is separated or separated without separation to give a diastereomer mixture represented by the structural formula (VI). Or by reacting dichlorophenylphosphine represented by Structural Formula (X) with (−)-menthol in the presence of a base, then reacting with a borane-tetrahydrofuran complex, and further subjected to a reduction reaction with a reducing agent. (IX) (Wherein Ph is the same as described above), and the mixture (IX) is separated or separated without separation to give a general formula (VIII) (Wherein, Y represents a halogen atom) to react with a halide represented by the formula (VI) in the presence of a catalyst to obtain a diastereomeric mixture or a separated product represented by the structural formula (VI), and the mixture or the separated product (VI) Is reacted with a lithium compound represented by the structural formula (V) CH ₃ -Li (V) to obtain a compound represented by the structural formula (IV): (Wherein Ph is the same as described above), and any of the compounds (IV) in the enantiomer represented by the general formula (III) R-Li (III) in the presence of copper chloride. , R represents a lower alkyl group.) With an alkyllithium represented by the formula (II): (Wherein Ph is the same as described above), and the compound (II) is reacted with a base as any compound in the enantiomer represented by the formula (I): (In the formula, Ph is the same as described above.) A method for producing any phosphine compound in the enantiomer represented by the formula: 2. Structural formula (II) (In the formula, Ph represents a phenyl group.) Any compound in the enantiomer represented by the formula: 3. Structural formula (IV) (In the formula, Ph is the same as described above.) The enantiomer separated product represented by the general formula (III) R-Li (III) (where R represents a lower alkyl group) in the presence of copper chloride. Which is reacted with an alkyllithium compound represented by the following structural formula (II): (Wherein Ph is the same as described above). 4. Structural formula (II) (Wherein Ph is the same as described above), and any one of the compounds in the enantiomer represented by the formula (I) is reacted with a base. (In the formula, Ph is the same as described above.) A method for producing any phosphine compound in the enantiomer represented by the formula: