JP2001328993A - Optically active phosphine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an optically active phosphine compound capable of being synthesized in a short processes and useful as a ligand capable of achieving a high asymmetric yield in various asymmetric syntheses e.g. an allylic position asymmetric substitution reaction of an allylic compound. SOLUTION: This optically active phosphine compound is expressed by the general formula (I) (wherein R is H or hydroxyl that may be protected; and *is an asymmetric carbon atom) and the general formula (II) (wherein, *is the asymmetric carbon atom).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an optically active phosphine compound. The 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 allylic asymmetric substitution reaction.

[0002]

2. Description of the Related Art Development of various asymmetric synthesis reactions using transition metal complex catalysts is an area in which research is being actively conducted as a selective synthesis method of various optically active compounds. It is known that as one of the factors for achieving a high asymmetric yield in such an asymmetric synthesis reaction, the molecular design of a ligand constituting a catalyst used in the reaction is important. For example, in optically asymmetric substitution reactions of allyl compounds using transition metal complex catalysts, various optically active compounds having a phosphorus atom or a nitrogen atom have been developed as ligands giving high asymmetric yields [Chemical Review (Chem. Re
v. ), 96, 395-422 (1996)].

[0003]

SUMMARY OF THE INVENTION The present inventors have studied the synthesis of a novel optically active compound applicable as a new ligand in various asymmetric synthesis reactions using a transition metal complex catalyst. Have been. As a result, it has a phosphorus atom and a nitrogen atom in the same molecule, acts as a ligand constituting a catalyst in various asymmetric synthesis reactions using a transition metal complex catalyst, and has an optical activity that can be synthesized in a short process. The inventors have found compounds and completed the present invention.

[0004]

That is, the present invention provides a compound of the general formula (I)

[0005]

Embedded image

(Wherein R represents a hydrogen atom or a hydroxyl group which may be protected, and * represents an asymmetric carbon atom) (hereinafter abbreviated as optically active phosphine (I)). And the general formula (II)

[0007]

Embedded image

(Wherein * represents an asymmetric carbon atom) (hereinafter abbreviated as optically active phosphine (II)).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, the protecting group of a hydroxyl group in the optionally protected hydroxyl group represented by R includes:
For example, it has a substituent such as a methyl group, a methylthiomethyl group, a 2,2,2-trichloroethyl group, a 1- (2-chloroethoxy) ethyl group, a methoxymethyl group, a 1-ethoxyethyl group, or a benzyloxymethyl group. An aralkyl group 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 or a trifluoroacetyl group An alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group; a trimethylsilyl group;
Examples include trisubstituted silyl groups such as dimethylisopropylsilyl group and t-butyldimethylsilyl group.

The optically active phosphine (I) of the present invention can be produced, for example, according to the following scheme.

[0011]

Embedded image

For example, L-proline (R
= Hydrogen atom), L-proline is treated with trifluoroacetic anhydride or the like to protect its amino group, and then the carboxyl group is halogenated using phosphorus pentachloride, thionyl chloride, benzoyl chloride, oxalyl chloride or the like. After the reaction, the compound is reacted with aniline in the presence of a base such as an amine such as triethylamine, diethylamine, diisopropylamine, pyridine, picoline, lutidine, etc. to obtain the corresponding L-proline-2-phenylamide. The compound is reacted with a base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide; or an alkali metal carbonate such as lithium carbonate, sodium carbonate, or potassium carbonate to remove the trifluoroacetyl group. After protection, 2- (diphenylphosphino) benzaldehyde is reacted to give (3R, 7aS) -3- (diphenylphosphino) phen-2-yl-2-phenyl-, which is optically active phosphine (I). 2,3
5,6,7,7a-Hexahydro-1H-pyrrolo [1,
2-c] imidazol-1-one can be obtained.

In the above, when D-proline is used as a starting material, (3S, 7aR) -3- (diphenylphosphino), which is optically active phosphine (I), is used.
Phen-2-yl-2-phenyl-2,3,5,6
7,7a-Hexahydro-1H-pyrrolo [1,2-c]
Imidazol-1-one is obtained. Furthermore, when trans-4-hydroxy-L-proline is used as a starting material, it is an optically active phosphine (I) (3R, 6
R, 7aS) -3- (Diphenylphosphino) phen-
2-yl-6-hydroxy-2-phenyl-2,3,
5,6,7,7a-Hexahydro-1H-pyrrolo [1,
2-c] Imidazol-1-one is obtained. In addition, the hydroxyl group of such a compound can be protected by a method generally used in protecting a hydroxyl group.

The isolation and purification of the optically active phosphine (I) from the reaction solution can be carried out by the same method as that generally used in the synthesis of organic compounds. For example, the mixture is poured into water, benzene, toluene,
Hydrocarbons such as xylene; ethers such as diethyl ether and diisopropyl ether; extraction with an organic solvent such as a halogenated hydrocarbon such as dichloromethane and chloroform, and concentrating the extract to recrystallize a crude product obtained as necessary. , Chromatography and the like.

On the other hand, the optically active phosphine (I) of the present invention
I) can be produced, for example, according to the following scheme.

[0016]

Embedded image

For example, L-indoline-2-carboxylic acid is treated with t-butyl dicarbonate or the like to protect its amino group, and then dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl A) carbodiimide or a hydrochloride thereof; N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-
By reacting with aniline in the presence of a dehydrating agent such as 3,4-dihydro-1,2,3-benzotriazine,
The corresponding Nt-butoxycarbonyl-L-indoline-2-phenylamide is obtained. The compound is reacted with an acid such as hydrochloric acid, sulfuric acid, or trifluoroacetic acid to deprotect the t-butoxycarbonyl group, and then reacted with 2- (diphenylphosphino) benzaldehyde to give an optically active phosphine (II). Yes, (3R, 9aS)-
3- (diphenylphosphino) phen-2-yl-2-
Phenyl-2,3,9,9a-tetrahydro-1H-indolino [1,2-c] imidazol-1-one can be obtained.

In the above, D-indoline-2
When a carboxylic acid is used as a starting material, (3S, 9aR) -3- (diphenylphosphino) phen-2-yl-2-phenyl- which is an optically active phosphine (II) is used.
2,3,9,9a-Tetrahydro-1H-indolino [1,2-c] imidazol-1-one is obtained.

The isolation and purification of the optically active phosphine (II) from the reaction solution can be carried out by the same method as that generally used in the synthesis of organic compounds. For example, the mixture is poured into water and extracted with an organic solvent such as a hydrocarbon such as benzene, toluene, or xylene; an ether such as diethyl ether or diisopropyl ether; a halogenated hydrocarbon such as dichloromethane or chloroform;
The crude product obtained by concentrating the extract is purified by recrystallization, chromatography or the like, if necessary.

The optically active phosphine (I) and the optically active phosphine (II) can be used as ligands in various asymmetric synthesis reactions using a transition metal complex catalyst. When applied to substitution reactions, high asymmetric yields can be achieved.

[0021]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

Example 1 [Step (a)] 1.7 g of L-proline in a nitrogen atmosphere
(15 mmol) was suspended in 20 ml of chloroform and cooled to 0 ° C.
5 ml (75 mmol) were added. The mixture was heated to room temperature, stirred for 1 hour, and then concentrated under reduced pressure. The resulting residue was dissolved in 20 ml of diethyl ether under a nitrogen atmosphere and cooled to 0 ° C., and 3.2 g (15 mmol) of phosphorus pentachloride was added to this solution. After the addition was completed, the temperature was raised to room temperature. And stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 20 ml of benzene.
This solution was added to a solution prepared by dissolving 1.3 ml (14 mmol) of aniline and 4 ml (30 mmol) of triethylamine in 10 ml of ethyl acetate under a nitrogen atmosphere while maintaining the internal temperature of the reaction solution at 0 ° C. or lower, and the addition was completed. rear,
The mixture was heated to room temperature and stirred for 1 hour. The reaction solution was poured into 20 ml of water, and the organic layer was separated. The organic layer was washed with 10 ml of water, dried over anhydrous sodium sulfate, and concentrated. To the obtained crude product, diethyl ether (10 ml) and hexane (10 ml) were added, and the mixture was stirred for 10 minutes in a suspended state, and washed.
The solid was filtered off to give 3.0 g of N-trifluoroacetyl-L-proline-2-phenylamide (10.
5 mmol, yield 75%).

[Step (b)] 29 mg (0.1 mmol) of N-trifluoroacetyl-L-proline-2-phenylamide and 69 mg (0.5 mmol) of potassium carbonate obtained in the above step (a) were covered with a lid. Into a test tube,
After purging with nitrogen, 1 ml of methanol was added and the mixture was stirred at room temperature for 1 hour. Then, 29 mg (0.1 mmol) of 2- (diphenylphosphino) benzaldehyde was added to this solution.
Was added, and the mixture was heated to 100 ° C. and stirred for 1 hour. The reaction solution was poured into 5 ml of water, extracted with 5 ml of chloroform, and the extract was dried over anhydrous sodium sulfate and concentrated. The obtained residue is purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/5 (volume ratio)) to have the following physical properties (3R, 7aS) -3.
-(Diphenylphosphino) phen-2-yl-2-phenyl-2,3,5,6,7,7a-hexahydro-1
H-pyrrolo [1,2-c] imidazol-1-one <optically active phosphine (I)> 36 mg (0.078 mmol
1, 78% yield).

[0024] Specific _{rotation: [α] D = + 44} ° (c1.4, CHCl 3) EIMS (m / z): 462 (M) + 1 H-NMR (400MHz, CDCl 3, TMS, pp
m) δ: 1.42-1.56 (m, 1H, 6-CH),
1.65-1.76 (m, 1H, 6-CH), 1.97.
-2.15 (m, 2H, 7- CH 2), 2.63-2.
70 (m, 1H, 5-CH), 3.09-3.14
(M, 1H, 5-CH), 3.92 (dd, J = 4.
4,9.0 Hz, 1H, 7a-CH), 6.53 (d,
J = 6.1 Hz, 1H, 3-CH), 6.99-7.0.
7 (m, 2H, Ar), 7.14-7.39 (m, 15
H, Ar), 7.44 (d, = 8.1 Hz, 2H, A
r) ³¹ P-NMR (270 MHz, CDCl ₃ , P (OC
H ₃ ) ₃ (external standard), ppm) δ: −18.0 (s)

Example 2 In Example 1, 1.7 g of L-proline (15 mm
Example 1 except that 2.0 g (15 mmol) of trans-4-hydroxy-L-proline was used instead of 1).
3.2 g of trans-4-hydroxy-N-trifluoroacetyl-L-proline-2-phenylamide was obtained by performing the same reaction and isolation operation as in step (a) of
(10.5 mmol, yield 75%) was obtained. Then, in step (b) of Example 1, 29 mg of N-trifluoroacetyl-L-proline-2-phenylamide (0.
1 mmol) instead of the trans-4 obtained above.
By performing the same reaction and isolation operation as in step (b) of Example 1 except for using 30 mg (0.1 mmol) of -hydroxy-N-trifluoroacetyl-L-proline-2-phenylamide, (3)
R, 6R, 7aS) -3- (Diphenylphosphino) phen-2-yl-6-hydroxy-2-phenyl-2,
3,5,6,7,7a-Hexahydro-1H-pyrrolo [1,2-c] imidazol-1-one <optically active phosphine (I)> 34 mg (0.071 mmol, yield 7)
1%).

Specific rotation: [α] _D = + 9.2 ° (c1.
_{6, CHCl 3) EIMS (m} / z): 478 (M) + 1 H-NMR (400MHz, CDCl 3, TMS, pp
m) δ: 1.94-2.00 (m, 1H, 7-CH),
2.32-2.38 (m, 1H, 7-CH), 2.67
(Dd, J = 3.6, 10 Hz, 1H, 5-CH),
3.13 (d, J = 10 Hz, 1H, 5-CH);
82 (dd, J = 4.5, 9.6 Hz, 1H, 7a-C
H), 4.10 (br, s, 1H, 6-CH), 6.5.
8 (d, J = 5.9 Hz, 1H, 3-CH), 7.05
-7.13 (m, 2H, Ar), 7.19-7.38
(M, 15H, Ar), 7.57 (d, J = 7.8H)
z, 2H, Ar) ³¹ P-NMR (270 MHz, CDCl ₃ , P (OC
H ₃ ) ₃ (external standard), ppm) δ: −18.4 (s)

Example 3 (3R, 6R, 7aS) -3 obtained by the method of Example 2
-(Diphenylphosphino) phen-2-yl-6-hydroxy-2-phenyl-2,3,5,6,7,7a-
10 mg (0.02 mmol) of hexahydro-1H-pyrrolo [1,2-c] imidazol-1-one and 11 mg (0.16 mmol) of imidazole were dissolved in 5 ml of dimethylformamide under a nitrogen atmosphere, and cooled to 0 ° C. To this solution was added t-butyldimethylsilyl chloride 1
After adding 8 mg (0.12 mmol), the mixture was heated to room temperature and stirred for 3 hours. The reaction solution was cooled to 0 ° C., 5 ml of a saturated aqueous solution of sodium hydrogen carbonate was added, and then 5 ml of chloroform was added for extraction. The extract was washed five times with 5 ml of water, dried over anhydrous sodium sulfate and concentrated. The obtained residue is purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/8 (volume ratio)) to have the following physical properties (3R, 6R, 7a).
S) -3- (Diphenylphosphino) phen-2-yl-6-t-butyldimethylsilyloxy-2-phenyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolo [1,2 -C] Imidazol-1-one <optically active phosphine (I)> 12 mg (0.02 mmol, 100% yield) was obtained.

Specific rotation: [α]_D= + 71 ° (c2.1, CHCl_Three) EIMS (m / z): 592 (M)^{+ 1} H-NMR (400 MHz, CDCl_Three, TMS, pp
m) δ: 0.01 (d, J = 4.2 Hz, 6H, Si
(CH_Three)_Two), 0.85 (s, 9H, SiC (C
H_Three)_Three), 1.99-2.06 (m, 1H, 7-C
H), 2.38-2.44 (m, 1H, 7-CH),
2.85-2.95 (m, 2H, 5-CH _Two), 4.1
3 (dd, J = 3.8, 8.9 Hz, 1H, 7a-C
H), 4.30-4.36 (m, 1H, 6-CH),
6.51 (d, J = 7.1 Hz, 1H, 3-CH),
6.96-7.06 (m, 2H, Ar), 7.14-
7.37 (m, 15H, Ar), 7.41 (d, J =
8.5Hz, 2H, Ar)³¹ P-NMR (270 MHz, CDCl_Three, P (OC
H_Three)_Three(External standard), ppm) δ: −18.7 (s)

Example 4 [Step (a)] L-Indoline-2-carboxylic acid 816
5 mg of 1,4-dioxane and 10 ml of a 0.5N aqueous sodium hydroxide solution were added to and dissolved in mg (5.0 mmol), and the mixture was cooled to 0 ° C. 2.2 g (10 mmol) of t-butyl dicarbonate was added to this solution, and after completion of the addition, the mixture was heated to room temperature and stirred for 15 hours. The reaction solution was cooled to 0 ° C., adjusted to pH 3 by adding an aqueous citric acid solution, and then extracted three times with 10 ml of ethyl acetate. The extract was concentrated and the resulting residue was dissolved in 15 ml of dimethylformamide, and 0.72 ml (7.5 mmol) of aniline and 1
1.35 g of hydroxybenzotriazole (10 mm
ol) and cooled to 0 ° C. Add one more to this solution
After adding 1.44 g (7.5 mmol) of -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, the mixture was heated to room temperature and stirred for 12 hours. 10 ml of ethyl acetate was added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (10 ml) and a citric acid solution (1).
0 ml, saturated aqueous sodium hydrogen carbonate solution 10 ml, water 1
The extract was sequentially washed with 0 ml, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane =
By purifying in 1/3), 1.14 g of Nt-butoxycarbonyl-L-indoline-2-phenylamide was obtained.
(3.5 mmol, 70% yield).

[Step (b)] 200 mg (0.62 mmol) of Nt-butoxycarbonyl-L-indoline-2-phenylamide obtained in the above step (a) are dissolved in 4 ml of trifluoroacetic acid, and the mixture is dissolved at room temperature. Stir for 1 hour.
The reaction solution was concentrated under reduced pressure, and 5 ml of chloroform was added to the residue.
And washed with 5 ml of a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 121 mg of L-indoline-2-phenylamide.
(0.51 mmol, yield 82%). Next, 30 mg (0.13 mmol) of L-indoline-2-phenylamide obtained above was placed in a test tube with a lid purged with nitrogen.
l), 36 mg (0.12 mmol) of 2- (diphenylphosphino) benzaldehyde and 2 ml of methanol
And heated to 100 ° C. and stirred for 1 hour. The reaction solution is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane =
(3R, 9aS) -3- (diphenylphosphino) having the following physical properties by purifying with (1/8 (volume ratio)).
Phen-2-yl-2-phenyl-2,3,9,9a-
Tetrahydro-1H-indolino [1,2-c] imidazol-1-one <optically active phosphine (II)> 14
mg (0.03 mmol, 23% yield).

Specific rotation: [α] _D = + 180.7 ° (c
_{0.5, CHCl 3) EIMS (m} / z): 510 (M) + 1 H-NMR (400MHz, CDCl 3, TMS, pp
m) δ: 3.12 (dd, J = 10, 16 Hz, 1
H), 3.54 (d, J = 16 Hz, 1H), 4.39
(Dd, J = 1.6, 10 Hz, 1H), 6.90 −
7.63 (m, 24H, Ar) ³¹ P NMR (270 MHz, CDCl ₃ , P (OC
H ₃ ) ₃ (external standard), ppm) δ: -20.0 (s)

Next, using the optically active phosphine (I) and the optically active phosphine (II) obtained above,
An allyl position asymmetric substitution reaction of 1,3-diphenylpropenylmethyl carbonate was performed.

[0033]

Embedded image

Test Example 1 Tris (dibenzylideneacetone) dipalladium / chloroform (Pd ₂ (dba) ₃ .CHCl) in a nitrogen atmosphere
₃ ) 10 mg (0.01 mmol) and (3R, 6R, 7aS) -3- (diphenylphosphino) phen-2-yl-6-t-butyldimethylsilyloxy-2- obtained by the method of Example 3. Phenyl-2,3,5,6
7,7a-Hexahydro-1H-pyrrolo [1,2-c]
12 mg (0.02 mmol) of imidazol-1-one
Was dissolved in 1 ml of dichloromethane, and 54 mg of 1,3-diphenylpropenylmethyl carbonate (0.2 mm
ol) and stirred at room temperature for 1 hour. Next, 0.068 ml of dimethyl malonate (0.6 mmo) was added to the reaction solution.
l) was added and the mixture was stirred at room temperature for 1 week. 5 ml of ethyl acetate was added to the reaction solution, and the mixture was washed twice with 5 ml of a saturated aqueous solution of ammonium chloride. The organic layer was dried over magnesium sulfate and concentrated. The obtained residue is subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/10).
To give (S) -dimethyl-2- (1,3-
45 mg of diphenyl-2-propenyl) malonic acid (0.
14 mmol, yield 70%, optical purity 94% e. e. )
I got In addition, the obtained (S) -dimethyl-2- (1,
The optical purity of 3-diphenyl-2-propenyl) -malonic acid was determined by high performance liquid chromatography analysis (column: DA
ICEL CHIRALCEL OD-H, developing solvent:
Hexane / isopropanol = 98/2).

Test Example 2 The procedure of Test Example 1 was repeated except that (3R, 6R, 7aS) -3- (diphenylphosphino) phen-2-yl-6-tert-butyldimethylsilyloxy-2-phenyl-2,3,5. ,
6,7,7a-Hexahydro-1H-pyrrolo [1,2-
c] 12 mg of imidazol-1-one (0.02 mmol
(3R, 7a) obtained by the method of Example 1 instead of 1)
S) -3- (Diphenylphosphino) phen-2-yl-2-phenyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolo [1,2-c] imidazole-1-
Using 11 mg (0.02 mmol) of ON, 0.068 ml (0.6 mmol) of dimethyl malonate was added.
The same operation as in Test Example 1 was performed except for stirring at room temperature for 12 hours. Table 1 shows the results.

Test Example 3 The procedure of Test Example 1 was repeated except that (3R, 6R, 7aS) -3- (diphenylphosphino) phen-2-yl-6-t-butyldimethylsilyloxy-2-phenyl-2,3,5. ,
6,7,7a-Hexahydro-1H-pyrrolo [1,2-
c] 12 mg of imidazol-1-one (0.02 mmol
(3R, 9a) obtained by the method of Example 4 instead of 1)
S) -3- (Diphenylphosphino) phen-2-yl-2-phenyl-2,3,9,9a-tetrahydro-1
Test example except that 12 mg (0.02 mmol) of H-indolino [1,2-c] imidazol-1-one was added, and 0.068 ml (0.6 mmol) of dimethyl malonate was added, followed by stirring at room temperature for 12 hours. The same operation as in Example 1 was performed. Table 1 shows the results.

[0037]

[Table 1]

[0038]

The optically active phosphine compound provided by the present invention can be synthesized in a short step, and can be used for various asymmetric synthesis reactions using a transition metal complex catalyst, for example, an allyl position asymmetric substitution reaction of an allyl compound. In such cases, a high asymmetric yield can be achieved by using the compound as a ligand.

Claims (2)

[Claims] 1. A compound of the general formula (I) (In the formula, R represents a hydrogen atom or a hydroxyl group which may be protected, and * represents an asymmetric carbon atom.) 2. A compound of the general formula (II) (In the formula, * represents an asymmetric carbon atom.)