JP2002265481A - Polymer-supported optically active phosphine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polymer-supported optically active phosphine compound which does not require a complicated recovery operation of a catalyst having an optically active phosphine compound as a ligand after completion of an asymmetric synthesis reaction, and a transition metal. In a variety of asymmetric synthesis reactions using a complex catalyst, for example, an allyl-position asymmetric substitution reaction of an allyl compound, a polymer-supported optically active phosphine compound useful as a ligand capable of achieving a high asymmetric yield is obtained. To provide. SOLUTION: General formula (I) (In the formula, n represents an integer of 40 to 45, R represents a hydrogen atom or a hydroxyl group which may be protected, * represents an asymmetric carbon atom, and P represents polystyrene.) The supported optically active phosphine compound and a compound represented by the general formula (I)
I) (In the formula, n, * and P are as defined above.)
And a polymer-supported optically active phosphine compound represented by the formula:

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to relates to polymer-carrying optically active phosphine compound. The polymer-supported optically active phosphine compound of the present invention is useful as a ligand of a catalyst in various asymmetric synthesis reactions using a transition metal complex catalyst, for example, an asymmetric allyl substitution reaction.

[0002]

BACKGROUND OF THE INVENTION Transition metal complex catalysts various asymmetric synthesis reaction using research has been actively conducted research for selective synthesis of various optically active compounds. To achieve high asymmetric yield in such asymmetric synthesis, it is important molecular design of the ligand constituting the catalyst used in the reaction.
For example, in an allyl position asymmetric substitution reaction of an allyl compound using a transition metal complex catalyst, various optically active compounds having a phosphorus atom or a nitrogen atom have been developed as ligands that give high asymmetric yields [Chemicals Review (Ch
em. Rev .. 96, 395-422 (199).
6 years)].

[0003]

DISCLOSURE OF THE INVENTION The present inventors have studied the synthesis of a novel optically active compound applicable as a ligand in various asymmetric synthesis reactions using a transition metal complex catalyst. . As a result, it has a phosphorus atom and a nitrogen atom in the same molecule, acts as a bidentate ligand constituting a catalyst in various asymmetric synthesis reactions using a transition metal complex catalyst, and can be synthesized in a short process. An optically active phosphine compound was discovered and filed earlier (Japanese Patent Application 2000-19).
No. 4512).

However, in the conventional asymmetric synthesis reaction, a catalyst using a low molecular weight compound, an optically active phosphine compound, as a ligand has been used in a homogeneous system, and after the reaction is completed, the optically active phosphine compound is used as a ligand. A complicated separation and recovery operation of the catalyst is required, and there is room for improvement in the operability.

[0005] Thus, an object of the present invention does not require complicated recovery operation of the catalyst having a ligand an optically active phosphine compound after completion of asymmetric synthesis, to provide a polymer-carrying optically active phosphine compound It is in.

Another object of the present invention is to provide a ligand capable of achieving a high asymmetric yield in various asymmetric synthesis reactions using a transition metal complex catalyst, for example, an allyl position asymmetric substitution reaction of an allyl compound. To provide a polymer-supported optically active phosphine compound useful as a polymer.

[0007]

The present invention provides a compound represented by the general formula (I):

[0008]

Embedded image

(Wherein, n represents an integer of 40 to 45;
Represents a hydrogen atom or a hydroxyl group which may be protected,
* Represents an asymmetric carbon atom, P represents a polystyrene. )
(Hereinafter referred to as polymer-supported optically active phosphine (I)) represented by general formula (II):

[0010]

Embedded image

Wherein n, * and P are as defined above (hereinafter referred to as polymer-supported optically active phosphine (II)). .

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, examples of the protecting group for the hydroxyl group represented by R include a methyl group, a methoxymethyl group,
Benzyloxymethyl group, methylthiomethyl group, 2,
2,2-trichloroethyl group, 1-ethoxyethyl group,
An alkyl group which may have a substituent such as a 1- (2-chloroethoxy) ethyl group; an aralkyl which may have a substituent such as a benzyl group, a p-methoxybenzyl group or a p-nitrobenzyl group; An acyl group such as an acetyl group, a trichloroacetyl group and a trifluoroacetyl group; an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group and a t-butoxycarbonyl group; a trimethylsilyl group, a dimethylisopropylsilyl group and a t-
And a trisubstituted silyl group such as a butyldimethylsilyl group.

The polymer-supported optically active phosphine (I) of the present invention can be produced, for example, according to the following scheme. In the scheme, n, R, * and P are as defined above, TFA represents a trifluoroacetyl group, Me represents a methyl group, and Ph represents a phenyl group.

[0014]

Embedded image

When L-proline is used as a starting material, L-proline is treated with trifluoroacetic anhydride to protect its amino group, and then the carboxyl group is converted to phosphorus pentachloride, thionyl chloride, benzoyl chloride, oxalyl chloride and the like. And then halogenated in the presence of a base such as amines such as triethylamine, diethylamine, diisopropylamine, pyridine, picoline and lutidine.
- is reacted with (3- (methoxycarbonyl) propyl) aniline, N- trifluoroacetyl-2- (4-
(Methoxycarbonylpropyl) phenyl) aminocarbonyl) -L-proline is obtained. This compound includes an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide; lithium carbonate, sodium carbonate,
After deprotection of the trifluoroacetyl group by the action of a base such as an alkali metal carbonate such as potassium carbonate,
By reacting (diphenylphosphino) benzaldehyde, (3R, 7aS) -3- (diphenylphosphino) phen-2-yl-2- (4- (methoxycarbonylpropyl) phenyl) -2,3,5 6,7,
7a-Hexahydro-1H-pyrrolo [1,2-c] imidazol-1-one is obtained. A methoxycarbonyl group is hydrolyzed by allowing a base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide; and an alkali metal carbonate such as lithium carbonate, sodium carbonate and potassium carbonate to act on this compound. And (3R, 7aS) -3- (diphenylphosphino) phen-2-yl-2- (4- (hydroxycarbonylpropyl) phenyl) -2,3,5,6,7,
7a-Hexahydro-1H-pyrrolo [1,2-c] imidazol-1-one can be obtained.

When D-proline is used as a starting material, it is an optically active phosphine (3S, 7aR)-.
3- (diphenylphosphino) phen-2-yl-2-
(4- (hydroxycarbonylpropyl) phenyl)-
2,3,5,6,7,7a-Hexahydro-1H-pyrrolo [1,2-c] imidazol-1-one can be obtained.

Next, the above-mentioned optically active phosphine is converted into, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or a hydrochloride thereof,
N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-
The polymer-supported optically active phosphine (I) can be obtained by reacting with a polymer carrier having an amino group in the presence of a dehydrating agent such as dihydro-1,2,3-benzotriazine and a solvent.

[0018] Here, as the polymer carrier having an amino group, a carrier having a modified end of a polyoxyethylene also good polystyrene backbone have a crosslinked structure graft copolymer with amino groups, for example, Argonaut
Argo from Argonaut Technology
Gel-NH _{2 and the} like.

In the isolation and purification of the polymer-supported optically active phosphine (I) from the reaction mixture, the reaction mixture is filtered,
This is performed by washing with N, N-dimethylformamide, dichloromethane, or the like. The polymer-supported optically active phosphine (I) thus obtained can be used as it is as a ligand constituting a catalyst used in an asymmetric synthesis reaction.

The polymer-carrying optically active phosphine (II) of the present invention, for example, can be produced according to the following scheme. In the scheme, n, * and P are as defined above, BOC represents a t-butoxycarbonyl group, Me represents a methyl group, and Ph represents a phenyl group.

[0021]

Embedded image

When L-indoline-2-carboxylic acid is used as a starting material, t-butyl dicarbonate is allowed to act on L-indoline-2-carboxylic acid to protect its amino group, and then dicyclohexylcarbodiimide, diisopropylcarbodiimide , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or a hydrochloride thereof, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-
4- (3- (methoxycarbonyl) in the presence of a dehydrating agent such as 3,4-dihydro-1,2,3-benzotriazine
(L) -2- (4-)
(Methoxycarbonylpropyl) phenyl) aminocarbonyl) indoline is obtained. By reacting this compound with an acid such as hydrochloric acid, sulfuric acid, and trifluoroacetic acid to deprotect the t-butoxycarbonyl group, 2- (diphenylphosphino) benzaldehyde is reacted,
(3S, 9aS)-(2- (4- (methoxycarbonylpropyl) phenyl) -3- (2-diphenylphosphino) -phenyl) tetrahydro-1H-imidazo [1,
5-a] Indole-1-one is obtained. This compound
Lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide; lithium carbonate, sodium carbonate, then with a base such as an alkali metal carbonate such as potassium carbonate methoxycarbonyl group is hydrolyzed, the optically active (3S, 9aS)-(2- (4
-(Hydroxycarbonylpropyl) phenyl) -3-
(2-diphenylphosphino) - phenyl) tetrahydro -1H- imidazo [1,5-a] can be obtained indol-1-one.

When D-indoline-2-carboxylic acid is used as a starting material, the optically active phosphine (3R, 9aR)-(2- (4- (hydroxycarbonylpropyl) phenyl) -3- (2- Diphenylphosphino) -phenyl) tetrahydro-1H-imidazo [1,5-a] indol-1-one can be obtained.

Then, the above-mentioned optically active phosphine is converted to, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or a hydrochloride thereof,
N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-
By reacting with a polymer carrier having an amino group in the presence of a dehydrating agent such as dihydro-1,2,3-benzotriazine and a solvent, a polymer-supported optically active phosphine (II) can be obtained.

Here, examples of the polymer carrier having an amino group include the above-mentioned ArgoGel-NH _{2 and the} like.

In the isolation and purification of the polymer-supported optically active phosphine (II) from the reaction mixture, the reaction mixture is filtered,
This is performed by washing with N, N-dimethylformamide, dichloromethane, or the like. The polymer-supported optically active phosphine (II) thus obtained can be used as it is as a ligand constituting a catalyst used in an asymmetric synthesis reaction.

The polymer-supported optically active phosphine (I) and the polymer-supported optically active phosphine (II) can be subjected to various asymmetric synthesis reactions using a transition metal complex catalyst having these as ligands, for example, the production of allyl compounds. in allylic asymmetric substitution reaction, it is possible to achieve high optical yield.

[0028]

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

[0029] Example 1 [Step (a)] Under a nitrogen atmosphere, L- proline 0.86g
(7.5 mmol) was suspended in 10 ml of chloroform and cooled to 0 ° C., and 4.73 g (22.5 mmol) of trifluoroacetic anhydride was added to the resulting suspension. The reaction mixture was heated to room temperature, stirred for 1 hour, and then concentrated under reduced pressure. Under a nitrogen atmosphere, diethyl ether (20 ml) was added to the obtained residue to dissolve the mixture, the mixture was cooled to 0 ° C, and N, N-dimethylformamide (54.8 mg) was added to the obtained solution.
(0.75 mmol) and 8.93 g of thionyl chloride (7
5 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was
The suspension was then suspended in ml. 815 mg of 4- (3- (methoxycarbonyl) propyl) aniline (5 mg
mmol) and 3.03 g of triethylamine (30 m
The mol) to a solution obtained by dissolving in ethyl acetate 20 ml, under a nitrogen atmosphere, was added while maintaining the internal temperature at 0 ℃ below. After the addition was completed, the resulting reaction mixture was heated to room temperature and stirred for 1 hour. Pour the reaction mixture into 20 ml of water,
The organic layer was separated. The organic layer was washed three times with 10 ml of water and once with 10 ml of saturated saline, dried over anhydrous sodium sulfate and concentrated. Methanol 50 was added to the obtained crude product.
and dissolved in potassium carbonate (2.65 g, 25 ml).
mmol), and the mixture was stirred at room temperature for 3 hours, 10 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with 10 ml of chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure. 0.41 g of N-trifluoroacetyl-2- (4- (methoxycarbonylpropyl) phenyl) aminocarbonyl) -L-proline
(1.2 mmol, 24% yield).

[Step (b)] In a test tube with a lid, the N-trifluoroacetyl-2- (4
-(Methoxycarbonylpropyl) phenyl) aminocarbonyl) -L-proline 0.41 g (1.2 mmol
l) and 0.70 g (2.4 mmol) of 2- (diphenylphosphino) benzaldehyde were suspended in 5 ml of methanol and heated at 80 ° C. with stirring for 3 hours.
Thereafter, the reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate 10
Then, the mixture was extracted three times with 10 ml of chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure. The obtained residue was dissolved in 50 ml of methanol, and 1M aqueous sodium hydroxide solution 16
Then, the mixture was stirred at 25 ° C for 4 hours, and then cooled to 0 ° C. After 5% hydrochloric acid was added to the resulting reaction solution until the pH reached 1, extraction was performed three times with 10 ml of chloroform. The organic layers are combined, dried using anhydrous sodium sulfate, concentrated under reduced pressure and dried under reduced pressure, and have the following physical properties (3S, 7a).
S) -3- (Diphenylphosphino) phen-2-yl-2- (4- (hydroxycarbonylpropyl) phenyl-2,3,5,6,7,7a-hexahydro-1H-
Pyrrolo [1,2-c] imidazol-1-one 0.65
g (1.1 mmol, yield 92%).

¹ H-NMR (500 MHz, CDCl ₃ ,
TMS, ppm) δ: 1.54 (m, 1H), 1.72
(M, 1H), 1.87 (m, 2H), 2.07 (m, 1H)
2H), 2.30 (t, J = 7.5 Hz, 2H), 2.
55 (t, J = 7.6 Hz, 2H), 2.67 (m, 1
H), 3.14 (m, 1H), 4.00 (dd, J =
9.0 Hz, J = 4.3 Hz, 1H), 6.50 (d,
J = 6.1 Hz, 1H), 6.98 (m, 3H), 7.
15-7.40 (m, 15H)

[Step (c)] (3) obtained in step (b)
(S, 7aS) -3- (diphenylphosphino) phen-
2- yl-2- (4- (hydroxycarbonyl propyl) phenyl -2,3,5,6,7,7a- hexahydro -1H- pyrrolo [1,2-c] imidazol-1-one 0.24 g (0 .41 mmol), ArgoGel-
NH ₂ (Argonaut Tekunorojii Co., amino group content 0.27 mmol) 0.73 g, 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 0.15 g (0.81 mmol) and 1-hydroxybenzotriazole hydrate 0.15g (1.08mmo
l) was placed in a Merrifield vessel (Merrifield Vessel), suspended by adding 7 ml of N, N-dimethylformamide, and shaken at 25 ° C for 6 hours. The mixture was filtered, and the obtained resin was washed 5 times with 7 ml of N, N-dimethylformamide and 5 times with 7 ml of dichloromethane, each for 2 minutes, and then washed.
After drying under reduced pressure, the polymer-supported optically active phosphine (I) having the following physical properties [corresponding to the polymer-supported optically active phosphine compound in which R in Formula (I) is a hydrogen atom].
It was obtained 88g.

³¹ P-NMR (MAS NMR, 162M
Hz, CDCl ₃ , ppm) δ: -19.0 (s)

Example 2 [Step (a)] In Example 1, L-proline 0.8
Instead of 6 g (7.5 mmol), 0.98 g (7.5 mmol) of trans-4-hydroxy-L-proline
By the carrying out the reaction and isolation operation in the same manner except for using trans-4-hydroxy -N- trifluoroacetyl-2- (4- (methoxycarbonyl propyl) phenyl) aminocarbonyl) -L- proline 0 .
57 g (1.6 mmol, 31% yield) were obtained.

[Step (b)] In Example 1, instead of 0.41 g (1.2 mmol) of N-trifluoroacetyl-2- (4- (methoxycarbonylpropyl) phenyl) aminocarbonyl) -L-proline, Using 0.43 g (1.2 mmol) of trans-4-hydroxy-N-trifluoroacetyl-2- (4- (methoxycarbonylpropyl) phenyl) aminocarbonyl) -L-proline obtained in step (a). By carrying out the reaction and the isolation operation in the same manner except for the above, (3S, 7aS) -3- (diphenylphosphino) phen-2-yl-2- (4- (hydroxycarbonylpropyl) having the following physical properties is obtained. Phenyl-5-hydroxy-2,3,
5,6,7,7a- hexahydro -1H- pyrrolo [1,
2-c] imidazol-1-one 0.67 g (1.1 m
mol, yield 90%).

¹ H-NMR (500 MHz, CDCl ₃ ,
TMS, ppm) δ: 1.88 (m, 1H), 2.17
(M, 1H), 2.29 (t, J = 7.3 Hz, 2
H), 2.36 (m, 1H), 2.58 (t, J = 7.
6 Hz, 2H), 2.70 (dd, J = 10.0 Hz,
J = 3.7Hz, 1H), 3.20 (br d, J = 1
0.0Hz, 1H), 3.90 (dd, J = 9.8H
z, J = 4.6 Hz, 1H), 4.15 (brs, 1
H), 6.55 (d, J = 6.0 Hz, 1H), 7.0
6 (m, 3H), 7.15-7.45 (m, 15H)

[Step (c)] In Example 1, (3)
(S, 7aS) -3- (diphenylphosphino) phen-
2- yl-2- (4- (hydroxycarbonyl propyl) phenyl -2,3,5,6,7,7a- hexahydro -1H- pyrrolo [1,2-c] imidazol-1-one 0.24 g (0 (3S, 7aS) -3- (diphenylphosphino) phen-2-yl-2- (4- (hydroxycarbonylpropyl) phenyl-5-hydroxy-) obtained in step (b) instead of (.41 mmol).
0.25 g of 2,3,5,6,7,7a-hexahydro-1H-pyrrolo [1,2-c] imidazol-1-one
(0.41 mmol), the same reaction and isolation procedure was carried out to obtain a polymer-supported optically active phosphine (I) having the following physical properties (in the general formula (I), wherein R is a hydroxyl group). 0.88 g of a molecule-supported optically active phosphine compound) was obtained.

³¹ P-NMR (MAS NMR, 162M
Hz, CDCl ₃ , ppm) δ: −19.2 (s)

Example 3 [Step (a)] Nt-butoxycarbonyl-L-indoline-2-carboxylic acid 2.63 g (10.0 mmol)
l) and 2.70 g (20.0 mmol) of 1-hydroxybenzotriazole hydrate were dissolved in 20 ml of N, N-dimethylformamide, cooled to 0 ° C., and 1- (3-dimethylaminopropyl) was added to the resulting solution. ) -3-Ethylcarbodiimide hydrochloride 2.88 g (15.0 mmol)
l) and 3.86 g (20.0 mmol) of 4- (3- (methoxycarbonyl) propyl) aniline. Thereafter, the mixture was heated to 25 ° C. and stirred for 12 hours, and a 2M aqueous citric acid solution was added to the obtained reaction mixture for 15 m.
The aqueous layer was extracted three times with 20 ml of ethyl acetate. Combine the organic layers and add a saturated aqueous sodium hydrogen carbonate solution (10 ml)
, Dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 20 ml of trifluoroacetic acid and stirred at 25 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography, to give (developing solvent ethyl acetate / hexane = 1/2 (volume ratio)), it has the following physical properties (S) - 2- (4- (methoxycarbonyl propyl) phenyl) aminocarbonyl) indoline 3.15g
(9.3 mmol, 93% yield).

Specific rotation: [α] _D = −175 ° (c1.
^{_{0, CHCl 3) 1 H-}} NMR (500MHz, CDCl 3, TMS, pp
m) δ: 1.93 (q, J = 7.3 Hz, 2H);
31 (t, J = 7.3, 2H), 2.61 (t, J =
7.3, 2H), 3.21 (dd, J = 8.7 Hz, 1
6.6 Hz, 1 H), 3.66 (s, 3 H), 4.30
(Br d, J = 5.8Hz, 1H), 4.54 (m,
1H), 6.83 (d, J = 7.5 Hz, 1H), 6.
87 (d, J = 7.5 Hz, 1H), 7.14 (m, 4
H), 7.50 (d, J = 7.8 Hz, 2H), 8.9
6 (s, 1H)

[Step (b)] In a test tube with a lid, 676 mg (2.0 mmol) of (S) -2- (4- (methoxycarbonylpropyl) phenyl) aminocarbonyl) indoline obtained in step (a) and 1.16 g of 2- (diphenylphosphino) benzaldehyde (4.0 m
mol) was suspended in 5 ml of methanol and heated at 80 ° C. with stirring for 3 hours. Thereafter, the reaction mixture was cooled to room temperature, saturated sodium bicarbonate water 10ml was added, and extracted three times with chloroform 10ml. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure. The obtained residue was dissolved in 1,4-dioxane (20 ml), and a 1 M aqueous sodium hydroxide solution was added at 0 ° C. Thereafter, it warmed spontaneously to 25 ° C., after stirring for 7 hours, and then concentrated under reduced pressure and vacuum drying. 5 in the residue obtained
% Hydrochloric acid until pH 1 and chloroform 10ml
And extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure. The obtained residue is purified by silica gel column chromatography (developing solvent: acetone / hexane = 1/2 (volume ratio)) to have the following physical properties (3S, 9aS)-.
(2- (4- (hydroxycarbonylpropyl) phenyl-3- (2-diphenylphosphino) -phenyl) tetrahydro-1H-imidazo [1,5-a] indol-1-one 401 mg (0.68 mmol, yield) 34
%).

Specific rotation: [α] _D = −204 ° (c1.
0, CHCl ₃ ) ¹ H-NMR (500 MHz, CDCl ₃ , TMS, pp
m) δ: 1.84 (q, J = 7.3 Hz, 2H);
28 (t, J = 7.3, 2H), 2.52 (t, J =
7.3, 2H), 3.15 (dd, J = 10.0 Hz,
15.9Hz, 1H), 3.55 (d, J = 15.9H
z, 1H), 4.22 (dd, J = 1.7 Hz, 10.
0 Hz, 1H), 6.91 (m, 3H), 7.11-
7.40 (m, 19H), 7.59 (d, J = 8.0H)
^{z, 1H) 31 P-NMR} (202MHz, CDCl 3, ppm)
δ: -20.2 (s)

[Step (c)] (3) obtained in step (b)
S, 9aS)-(2- (4- (hydroxycarbonylpropyl) phenyl-3- (2-diphenylphosphino)
-Phenyl) tetrahydro-1H-imidazo [1,5-
a] indol-1-one 496mg (0.83mmo
l), ArgoGel-NH ₂ (manufactured by Argonaut Technology, amino group content 0.56 mmol) 1.5
1 g, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 319 mg (1.67 mmol)
1) and 1-hydroxybenzotriazole hydrate 3
00 mg (2.20 mmol) was placed in a Merrifield container, suspended in 20 ml of N, N-dimethylformamide, and shaken at 25 ° C. for 6 hours. Filtering the reaction mixture,
The obtained resin was treated with N, N-dimethylformamide 20m
After washing 5 times with 1 liter and 5 times with 20 ml of dichloromethane for 2 minutes each, the residue was dried under reduced pressure to obtain 1.84 g of a polymer-supported optically active phosphine (II) having the following physical properties.

¹³ C-NMR (MAS NMR, 100 M
Hz, CDCl ₃ , ppm) δ: 26.5, 31.0,
34.0, 38.6, 63.6, 70.0, 81.1,
113-115, 172.0, 173.4 ³¹ P-NMR (MAS NMR, 162 MHz, CDC
l ₃ , ppm) δ: -19.3 (s)

Example 4 0.84 g (0.26 mmol) of the polymer-supported optically active phosphine (I) obtained in Example 1 and (η ³ −
59 mg of allyl) palladium chloride dimer (0.
16 mmol) was placed in a Merrifield container, suspended in 7 ml of dichloromethane, and shaken at 25 ° C. for 15 minutes. The reaction mixture was filtered, and the obtained resin was washed 5 times with 7 ml of dichloromethane for 2 minutes each, dried under reduced pressure, and polymer-supported optically active phosphine (I) having the following physical properties.
0.89 g of (η ³ -allyl) palladium chloride (0.
26 mmol).

³¹ P-NMR (MAS NMR, 162M
Hz, CDCl ₃ , ppm) δ: 19.1 (s)

[0047] In Example 5 Example 4, instead of the polymer-carrying optically active phosphine obtained in Example 1 (I), using a polymer carrying optically active phosphine obtained in Example 2 (I) Other than the above, the reaction and isolation operations were carried out in the same manner to obtain the polymer-supported optically active phosphine (I) (η
0.89 g (0.26 g of ³ -allyl) palladium chloride
mmol).

³¹ P-NMR (MAS NMR 162 MH
_{z, CDCl 3, ppm) δ} : -19.2 (s)

Example 6 1.84 g of polymer-supported optically active phosphine (II)
(0.56 mmol) and 128 mg (0.34 mmol) of (η ³ -allyl) palladium chloride dimer
Into a Merrifield container,
and shaken at 25 ° C. for 10 minutes. The reaction mixture was filtered, and the obtained resin was washed three times with 20 ml of dichloromethane for 2 minutes each, dried under reduced pressure, and polymer-supported optically active phosphine (II) (η ³ -allyl) palladium chloride 1 having the following physical properties. .18g (0.56mmo
1) was obtained.

³¹ P-NMR (MAS NMR 162 MH
_{z, CDCl 3, ppm) δ} : -19.1 (s)

Next, the polymer-supported optically active phosphine (I) (η ³ -allyl) palladium chloride and the polymer-supported optically active phosphine (II) (η ^3-
Allyl) using palladium chloride, it was allylic asymmetric substitution reactions allyl esters.

Test Example 1 In a nitrogen atmosphere, 1.04 g (0.30 mmol) of the polymer-supported optically active phosphine (II) (η ³ -allyl) palladium chloride obtained in Example 6 and lithium carbonate 33
0 mg (4.5 mmol), 142 mg of 1-methoxycarbonyloxy-cyclopentan-2-ene (1.0 m
mol) and 396 mg of dimethyl malonate (nucleophile)
(3.0 mmol) was suspended in 5 ml of water, and 1
Stir for 2 hours. The reaction palladium complex is separated by filtration from the mixture, the resin (polymer-carrying optically active phosphine (II) (eta ³ - allyl) palladium chloride) was washed 3 times with chloroform 10 ml. The filtrate and the washing were combined, extracted three times with 10 ml of chloroform, and the organic layer was dried over sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography to give (S) -dimethyl (cyclopentan-2-yl) malonic acid (136 mg, 0.68 mmol, yield 68%, optical purity 92% ee). ) Got. Table 1 shows the results. In addition, the obtained (S) -dimethyl (cyclopentane-2-
The optical purity of il) malonic acid is determined by using tris [3- (heptafluoropropylhydroxymethylene) -d-camphorato] europium (Eu (hf
c) Determined by NMR analysis using ₃ ).

Test Example 2 In Test Example 1, 396 mg of dimethyl malonate (3.
0 mmol) instead of 480 mg of diethyl malonate
The same operation was performed except that (3.0 mmol) was used. Table 1 shows the results.

Test Example 3 In Test Example 1, 142 mg (1.0 mmol) of 1-methoxycarbonyloxy-cyclopentan-2-ene
Was performed in the same manner as above except that 156 mg (1.0 mmol) of 1-methoxycarbonyloxy-cyclohexane-2-ene was used. Table 1 shows the results. In addition, the obtained (S) -dimethyl (cyclohexane-2-
The optical purity of il) malonic acid is determined by chiral column (Cycl)
odexCB, Scientific (J & W Scie
ntific)).

Test Example 4 In Test Example 3, 396 mg of dimethyl malonate (3.
0 mmol) instead of 480 mg of diethyl malonate
The same operation was performed except that (3.0 mmol) was used. Table 1 shows the results.

Test Example 5 The same operation as in Test Example 3 was carried out except that the reaction was carried out at 25 ° C. Table 1 shows the results.

Test Example 6 In Test Example 1, 142 mg (1.0 mmol) of 1-methoxycarbonyloxy-cyclopentan-2-ene
The same operation was performed except that 170 mg (1.0 mmol) of 1-methoxycarbonyloxy-cyclooctane-2-ene was used instead of 1). Table 2 shows the results.
In addition, the obtained (S) -dimethyl (cycloheptane-2)
-Yl) malonic acid has a chiral column (Cyc
lodexCB, as described above).

Test Example 7 In Test Example 6, 396 mg of dimethyl malonate (3.
Diethyl malonate instead of 0 mmol) 480 mg
The same operation was performed except that (3.0 mmol) was used. Table 2 shows the results.

Test Example 8 In Test Example 1, 142 mg (1.0 mmol) of 1-methoxycarbonyloxy-cyclopentan-2-ene was used.
In place of cis-1-methoxycarbonyl-3-methoxycarbonyloxy-cyclohexane-4-ene 214
The same operation was performed except that mg (1.0 mmol) was used. Table 2 shows the results. The optical purity of the obtained cis-dimethyl- (1-methoxycarbonyl-3-methoxycarbonyloxy-4-cyclohexen-2-yl) malonic acid was determined by using a chiral column (Cyclodex CB,
(As described above).

[0060] In Test Example 9 Test Example 8, dimethyl malonate 396 mg (3.
0 mmol) instead of 480 mg of diethyl malonate
The same operation was performed except that (3.0 mmol) was used. Table 2 shows the results.

Test Example 10 In Test Example 9, the polymer-supported optically active phosphine (II) (η ³ -allyl) palladium chloride obtained in Example 6 was replaced with 104 mg (0.30 mmol) of Example 4 to obtain the same. Polymer supported optically active phosphine (I)
(Eta ³ - allyl) palladium chloride 103 mg (0.
The same operation was performed except that 30 mmol) was used. Table 2 shows the results.

Test Example 11 In Test Example 9, the polymer-supported optically active phosphine (II) (η ³ -allyl) palladium chloride obtained in Example 6 was replaced with 104 mg (0.30 mmol) of Example 5. Polymer supported optically active phosphine (I)
(Eta ³ - allyl) palladium chloride 103 mg (0.
The same operation was performed except that 30 mmol) was used. Table 3 shows the results.

Test Example 12 In Test Example 9, 5 ml of dichloromethane was used instead of 5 ml of water, and 330 mg (4.5 m) of lithium carbonate was used.
mol) instead of N, O-bis (trimethylsilyl)
The same operation was performed except that 914 mg (4.5 mmol) of acetamide and 297 mg (4.5 mmol) of lithium acetate were used. Table 3 shows the results.

Test Example 13 In Test Example 1, 142 mg (1.0 mmol) of 1-methoxycarbonyloxy-cyclopentan-2-ene
The same operation was carried out except that 252 mg (1.0 mmol) of 1,3-diphenyl-1-methoxycarbonyl-2-butene was used instead of 1) and the reaction was carried out at 25 ° C. Table 3 shows the results. Incidentally, the obtained (S) - dimethyl -1
The optical purity of-(1,3-diphenyl-buten-2-yl) malonic acid was determined by liquid chromatography analysis equipped with a chiral column (Chiral Cell OD-H, manufactured by Daicel Chemical Industries, Ltd.).

Test Example 14 In Test Example 1, 142 mg (1.0 mmol) of 1-methoxycarbonyloxy-cyclopentan-2-ene was used.
Was replaced with 294 mg (1.0 mmol) of 1,3-diphenyl-1-t-butoxycarbonyl-2-butene, and the same operation was performed except that the reaction was carried out at 25 ° C. Table 3 shows the results. Incidentally, the obtained (S) - dimethyl -1
The optical purity of-(1,3-diphenyl-buten-2-yl) malonic acid was determined by liquid chromatography analysis equipped with a chiral column (Chiral Cell OD-H, as described above).

[0066]

[Table 1]

[0067]

[Table 2]

[0068]

[Table 3]

In the table, n, * and P are as defined above, Me represents a methyl group, Et represents an ethyl group, and Ph represents a phenyl group.

[0070]

According to the present invention, there is provided a polymer-supported optically active phosphine compound which does not require a complicated recovery operation of a catalyst having an optically active phosphine compound as a ligand after completion of an asymmetric synthesis reaction. Polymer-supported optically active phosphine useful as a ligand capable of achieving a high asymmetric yield in various asymmetric synthesis reactions using a transition metal complex catalyst, such as an allyl asymmetric substitution reaction of an allyl compound. Compounds are provided.

Claims (2)

[Claims] 1. A compound of the general formula (I) (Wherein, n represents an integer of 40 to 45, R represents a hydroxyl group which may be a hydrogen atom or a protective, * represents an asymmetric carbon atom, P is represents a polystyrene.) Polymer represented by Supported optically active phosphine compound. 2. A compound of the general formula (II) (In the formula, n represents an integer of 40 to 45, * represents an asymmetric carbon atom, and P represents polystyrene.) A polymer-supported optically active phosphine compound represented by the following formula: