JPH02131493A - New phosphinopyrrolidine compound and method for asymmetric synthesis using the same - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I or II [R<1> is H, -COR', -COOR'', -CONHR''', -SO2R<4>' or -PO(R<5>')2 (R' to R<5> are alkyl or aryl); R<2> is phenyl having 1-3 substituent groups, such as lower alkyl or alkoxy; R<3> is cyclohexyl]. EXAMPLE:(2S,4S)-N-tert-Butoxycarbonyl-2-bis(2-methoxyphenyl)phosphinom ethyl-4- dicyclohexylphosphinopyrrolidine. USE:A ligand for a metallic complex compound as a catalyst for asymmetric synthesis. PREPARATION:(2S,4S)-N-Methanesulfonyl-4-dicyclohexylphosphinyl-2- methanesulfonyloxymethylpyrrolidine is produced from L-hydroxyproline, then reacted with bis(2-methoxyphenyl)phosphinolithium, oxidized, demesylated, reduced and subsequently reacted with a carboxylic acid, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel phosphinopi-lysine compound and a novel asymmetric synthesis method using the same.

More specifically, the present invention provides compounds having asymmetric carbon atoms by catalytically reducing a carbon-carbon double bond structure, a carbon-monocarbon double bond structure, and/or a carbon-oxygen double bond structure. In carrying out the reaction to produce
, -CON}IR"'-SO2R" or one PO(R
"2) 2, Rt, R'", R"'R" and R
"ゝrepresents an alkyl group or an aryl group, respectively,
R2 is a phenyl group having 1 to 3 substituents selected from a lower alkyl group, an alkoxy group, and a dialkylamino group, and R3 is a cyclohexyl group. This paper relates to asymmetric synthesis by catalytic reduction.

Conventionally, in the field of synthetic chemistry, many studies have been conducted on asymmetric reduction reactions that can directly synthesize optically active compounds. As one of these, many bisphosphine ligands have been synthesized, and asymmetric reduction reactions have been attempted using combinations of these ligands and various metals. ) and reaction yield (Note: Regarding the reaction rate, the slower the reaction rate, the larger the amount used, so one way to show the relationship is to express it in terms of the molar ratio of substrate and ligand) at the same time. A satisfying ligand has not yet been found [B. “Asymmetric Catalysis” by Martinus Nijhoff Publ.
ishers Boston, 1986, p. 19~
3l page.

Conventionally, as an asymmetric bisphosphine compound, BP P M
[Rhodium (BPPMX1.5- cyclooctadiene)]Cl04 monocomplex as substrate/Rh=10
Hydrogenation was performed in methanol at 20 atm and 20°C for 20 hours in the presence of triethylamine to obtain (-)-methylsuccinic acid with a yield of 96% and an asymmetric yield of 92%. JP-A-54-128511).

In addition, in a follow-up experiment conducted by the present inventors, at substrate/Rh: 1000 (mole ratio), the asymmetric yield was approximately 9 in 20 hours at 1 atm and room temperature.
2%, but the conversion rate was less than 10% (Che
m. Lett. , Box, 1921. ).

The present inventor considered the coordination structure of bisphosphine-rhodium complexes and found that the phosphine group (2nd position), which is coordinated to the cis position of the functional group that undergoes the asymmetric reaction, dominates the asymmetric yield, while the trans We synthesized various phosphinopyrrolidine compounds based on the idea that the phosphine group (4th position) coordinating with the functional group could control the reaction efficiency (reaction rate) of the functional group.

As a result, B C P M [(2S,4S)-N-te
rt-Butoxycarbonyl-4-dicyclohexylphosphino-2-diphenylphosphinomethylpyrrolidine was synthesized, and itaconic acid was synthesized as [rhodium (B C P M) (L5-cyclooctadiene) co+C10a monocomplex. The asymmetric reduction was carried out with substrate/Ri = 1000 (molar ratio), and (1) monomethylconocic acid was obtained with a conversion rate of 100% and an asymmetric yield of 92%. It was found that it is excellent in both aspects for industrial implementation (Chem. Lett., 19
87, 1921. ).

Further, as a result of intensive studies on the synthesis of better ligands, the present inventors have determined that the novel phosphinobi-lysine compound represented by the above general formula [■] or [■'] is suitable for the purpose. I found it.

To explain this in more detail, in the above formula, P(
The phosphine group represented by R'')2 is a site that affects improving the asymmetric yield, and the phosphine group represented by P(R3)2 is a site that affects improving reaction efficiency. This became clear as a result of research by the present inventor.

In the phosphinobimouth lysine compound represented by the general formula CI] or [■'], R', R", R"' in the formula
Examples of each alkyl group of R"R"2 are C1 to C6
alkyl groups, such as methyl, ethyl, probyl, isobrobyl, n-butyl, seC-butyl, tert-
Examples of the aryl group include butyl and phenyl and biridyl groups. These alkyl groups or aryl groups can have a halogen atom such as fluorine or chlorine, a hydroxyl group, an alkyl group, an alkoxy group, etc. as a substituent.

R2 is a phenyl group having 1 to 3 substituents selected from a lower alkyl group, an alkoxy group, and a dialkylamino group, such as a 2-methoxyphenyl group, a 3-methoxyphenyl group, and a 4-methoxyphenyl group. group, 4-dimethylaminophenyl group and 3,5-dimethyl-4-methoxyphenyl group.

R3 is a cyclohexyl group.

In the asymmetric synthesis method for using the novel phosphinobi-lysine compound as a ligand according to the present invention, the catalytic reduction reaction will be explained by taking as an example the case where (-)monomethylsuccinic acid is produced from itaconic acid. Common solvents used in reduction reactions, such as water, methanol,
Using ethanol, isobrobyl alcohol, etc. as a solvent, a rhodium metal complex compound, such as rhodium-dinorbornadiene-perchlorate, and a phosphinobi-lysine compound [11] as a ligand are dissolved therein. Add triethylamine 0.5 to 3 times the mole of the substrate and the substrate,
At normal pressure or under increased pressure, preferably at a reaction temperature of 0°C
The hydrogenation reaction is carried out at ~1500C. The substrate/rhodium molar ratio ranges from 200 to 1,000,000, and the ligand/rhodium molar ratio is preferably from 1 to 3.

After the reaction is completed, the solvent is distilled off and the residue is appropriately treated to obtain (1) monomethylsuccinic acid in a high yield as a reaction product.

The phosphinopic lysine compound represented by the general formula [1] or [I'] according to the present invention can be used, for example, in Examples 1 to
It can be manufactured by the method shown in 5.

To explain Example 1, (25.45)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2-methanesulfonyloxymethylpyrrolidine [2] was prepared from L-hydroxyproline, and this was (2-
(2S,4S)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2-
Bis(2-methoxyphenyl)phosphinylmethylpyrrolidine [3a] is obtained.

Demesylation was performed with hydrobromic acid in the presence of phenol (
2S,4S)-4-dicyclohexylphosphinyl-2
-Bis(2-methoxyphenyl)phosphinylmethylpyrrolidine [4a] is obtained. This is isolated and purified, and after reduction with trichlorosilane, various substituents are easily added to the 1-position by reacting with carboxylic acid, sulfonic acid, or phosphonic acid halide, anhydride, or isocyanate. CI] can be obtained.

For example, when reacting with Di-Boc, (2S,4S)-N
-(tert-butoxycarbonyl)-4-dicyclohexylbosphino-2-bis(2-methoxyphenyl)
Phosphinomethylpyrrolidine [1a] can be obtained.

The (2R,4R) monophosphinopi-lysine compound represented by the general formula [1'] can be produced in a similar manner using D-hydroxyproline as a starting material.

Examples of the production of the novel phosphinobi-lysine compound according to the present invention and examples of asymmetric reduction using the same are listed below to further explain the present invention, but are not intended to limit the present invention.

Reference Example 1 Magnesium (3.57 g) was placed in THF (5 ml) under an argon atmosphere, and 0-promoanisole (25.0 g) was added to THF (5 ml).
0 g) of T H F (80i+1) solution is added dropwise.

After stirring for 2 hours, add phosphorus trichloride (3.04 g) under water cooling.
A solution of T H F (70 ml) is added dropwise. Stir overnight at room temperature. While cooling with water, 5% hydrochloric acid (25 ml) was added dropwise. The crystals were collected in a furnace and recrystallized from ethanol to obtain 12.39 g of tris(2-methoxyphenyl)phosphine.

Melting point: 203-204'C Under an argon atmosphere, potassium (945 mg) and sodium (228 mg) are added to degassed dioxane (101) and heated. After cooling on ice, tris(2-methoxyphenyl)phosphine (4.0Og) and dioxane (40ml
) and stir at room temperature for 3 hours.

After cooling with water, tert-butanol (10 ml) and methanol are added. After concentration under reduced pressure, benzene is added and the mixture is washed with degassed saturated saline. The mixture was dried over magnesium sulfate, concentrated under reduced pressure, and dried to obtain 2.40 g of bis(2-methoxyphenyl)phosphine as a white solid.

Reference Example 2 ■-Anisole (25.0 g) was reacted and post-treated in the same manner as in Reference Example 2 to obtain 11.76 g of bis(3-methoxyphenyl)phosphine as a white solid.

Melting point: 113 to 115'C Reference Example 3 Magnesium (3.22 g) was placed in THF (5 ml) under an argon atmosphere, and p-promoanisole (22
．． A solution of 44 g) in T H F (60 ml) is added dropwise.

After stirring for 1 hour, diethyl phosphite (5.5
2 g) in T H F (20 ml) is added dropwise.

Stir overnight at room temperature. Under water cooling, 5% hydrochloric acid (25ml
) and extracted with benzene.

The benzene layer was washed with degassed saturated saline, dried over magnesium sulfate, concentrated under reduced pressure, dried and then recrystallized from benzene to obtain 10.00 g of bis(4-methoxyphenyl)phosphine oxide.

2.80 g of this is dissolved in degassed toluene (36 ml) under an argon atmosphere. After cooling with water, add trichlorosilane (5.0 ml), boil under reflux, and stir for 5 hours.
After cooling with water, 2N caustic soda (16 ml) is added. Separate the toluene layer and extract the aqueous layer with toluene. Combine the toluene layers, dry with magnesium sulfate, concentrate under reduced pressure,
Distilled under reduced pressure, bp 200-210"C (bulb-t
1.45 g of bis(4-methoxyphenyl)phosphine (white solid upon cooling) was obtained.

Reference Example 4 Under an argon atmosphere, tetrahydrofuran (hereinafter referred to as T H
Magnesium (abbreviated as F) (5 ml) (4.25 g)
) and 4-bromoN,N-dimethylaniline (2
5.0 g) in T H F (150 ml) is added dropwise. After boiling under reflux for 30 minutes, dichlorophenylphosphine (io.74g) was dissolved in THF (50m
l) Add solution dropwise. Stir overnight at room temperature.

After adding saturated ammonium chloride aqueous solution, concentrate under reduced pressure and extract with benzene. Wash the benzene layer with saturated saline,
The residue was concentrated to dryness under reduced pressure and recrystallized from ethanol under an argon atmosphere to obtain 31 g of bis(4-dimethylaminophenyl)phenylphosphine. Melting point: 85°C To 6.97 g of this, diisobutyramine (2.85
g), T H F (40 ml) was added to create an argon atmosphere, and then lithium (389 mg) was added. 6 at room temperature
After stirring for an hour, ice-cooled and degassed saturated brine was added, followed by extraction with benzene. The benzene layer was dried over magnesium sulfate, concentrated under reduced pressure, and distilled under reduced pressure.
Distillation of the target product, bis(4-dimethylaminophenyl)phosphine, at a temperature of 1./3 torr. Obtained Og.

mp 80-90@C (sealed tube) Reference Example 5 Caustic soda (12.6 g) was dissolved in water (250 ml) and cooled to 15°C. Methylene chloride (250ml), 2
, 6-dimethyl-4-promofdenol (40.21
g), tetrabutylammonium bromide (3.22 g) and dimethyl sulfate (64.35 g) were added, and the mixture was stirred at room temperature for 5.5 hours.

Caustic soda (8.0 g) was added and the mixture was further stirred for 1 hour. The layers were separated and the aqueous layer was extracted with methylene chloride. The methylene chloride layers were combined and concentrated. This was dissolved in isobrobyl ether and washed successively with 2N ammonia water, 2N caustic soda aqueous solution, and saturated saline. The layers were separated and the aqueous layer was extracted with isobrobyl ether. The organic layers were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and distilled under reduced pressure to obtain 2,6-
Dimethyl-4-bromoanisole (40.15 g) was obtained.

bp 129-130”C/42Torr.

Under an argon atmosphere, magnesium (4.68 g) was added to T H F (5 ml), and 2,6-dimethyl-4-promoanisole (37.64 g) was added to T H F (11
0 ml) solution was added dropwise.

After stirring for 3 hours, diethyl phosphite (8.0
A solution of 6 g) in T H F (20 ml) was added dropwise.

After stirring at room temperature overnight, the mixture was boiled under reflux for 4 hours. Under water cooling, 5%
Hydrochloric acid (40 ml) was added dropwise, and the mixture was extracted with benzene.

The benzene layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.

This was purified by silica gel column chromatography,
13.68 g of bis(3,5-dimethyl-4-methoxyphenyl)phosphine oxide was obtained.

3.40 g of this was dissolved in degassed toluene (40 ml) under an argon atmosphere. After cooling with water, trichlorosilane (5.0 ml) was added, boiled under reflux, and stirred for 5 hours.

After cooling with water, 2N caustic soda (100 ml) is added. Separate the toluene layer and extract the aqueous layer with toluene. The toluene layers were combined, washed with sharp saturated saline, dried over magnesium sulfate, concentrated under reduced pressure, and distilled under reduced pressure.
~210'C/2Torr (bulb-to-bulk
1.70 g of bis(3,5-dimethyl-4-methoxyphenyl)phosphine of the fraction b) was obtained.

Example 1 Under an argon atmosphere, bis(2-methoxyphenyl)phosphine (3.69 g) was dissolved in THF (60 ml) and cooled to -35@C. Add 1.6M n-butyllithium-hexane solution (10.3ml),
Stir for 5 minutes. (2S,4S)N-methanesulfonyl-4-dicyclohexylphosphinyl-2-methanesulfonyloxymethylpyrrolidine (1.41 g) 4
Drop the solution dissolved in THF (10ml) -3
The mixture was stirred at 5°C for 3 hours. After concentrating the reaction solution, ethyl acetate was added, and the mixture was washed with cold saturated brine and cold water.

The organic layer was dried over anhydrous magnesium sulfate and then concentrated. This was dissolved in methanol (75 ml), cooled to 0°C, 10% hydrogen peroxide solution (4.5 ml) was added, and the mixture was stirred for 2 hours. After concentrating the reaction solution, methylene chloride was added and the mixture was washed with cold saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to give (25,4S)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2-bis(2-
methoxyphenyl)phosphinylmethylpyrrolidine (3
a) was obtained as an amorphous solid. Add this to phenol (3.0 ml) and 48% hydrobromic acid (15 ml).
The mixture was stirred and boiled under reflux in a nitrogen atmosphere for 10 hours.

After the reaction is completed, the mixture is made alkaline with a 30% aqueous sodium hydroxide solution and extracted with ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. Dissolved in ethyl acetate (200 ml) and silica gel (75 g
), stirred, filtered, and washed with ethyl acetate (LOOML). The furnace residue was mixed with ethanol (200ml'
), stirred, filtered in a furnace, and ethanol (300ml)
).

The five liquids and washing liquid were combined and concentrated to yield 641 mg of (25,4S)-4-dicyclohexylphosphinyl-2-bis(2-methoxyphenyl)phosphinylmethylpyrrolidine (4a) as an amorphous solid. Obtained.

Compound (4a, 558 mg) and triethylamine (4
20 mg) in acetonitrile (40 ml) and create a nitrogen atmosphere. Trichlorosilane (540mg) under water cooling
was dissolved in acetonitrile (10 ml) and added dropwise. 3
After refluxing and boiling for a period of time, the mixture is concentrated under reduced pressure. The product is converted into benzene (
1501) and 30% caustic soda (loO
ml) and stirred for 30 minutes at 50-60°C under nitrogen atmosphere. The benzene layer is separated, and the aqueous layer is further extracted with benzene. The benzene layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated. This was dissolved in methylene chloride (10 ml) under a nitrogen atmosphere, and triethylamine (110 ml) was dissolved in methylene chloride (10 ml).
mg), then ditertiary butyl dicarbonate}
(D i −B oc , 240 mg ethyl acid/benzene = 1/9) L/, (25,45)-N-tert
-Butoxycarbonyl-2-bis(2-methoxyphenyl)phosphinomethyl-4-dicyclohexylphosphinolysine (1a) as an amorphous solid 26
Obtained 0 mg.

[α]%'-88.1' (CO.72, benzene). Example 2 Bis(3-methoxyphenyl)phosphine (3.69g
) and (25.4S)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2-methanesulfonyloxymethylpyrrolidine (1.41 g) were reacted and worked up in the same manner as in Example 1. ,4S)-4-dicyclohexylphosphinyl-2-bis(3-methoxyphenyl)phosphinylmethylpyrrolidine (4b) was obtained in an amount of 1042 mg. 558 mg of this was reacted, worked up and purified in the same manner as in Example 1, and (25,4S)-N-tert-butoxycarbonyl-2-bis(3-methoxyphenyl)phosphinomethyl-4-dicyclohexylphosphino 374 mg of picolysine (lb) was obtained as an amorphous solid.

[α偕-63.3” (c O.6, benzene). Example 3 Bis(4-methoxyphenyl)phosphine (3.69 g
) and (2S,4S)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2-methanesulfonyloxymethylpyrrolidine (1.41 g) were reacted and post-treated in the same manner as in Example 1, resulting in (2S, 1344 mg of 4S)-4-dicyclohexylphosphinyl-2-bis(3-methoxyphenyl)phosphinylmethylpyrrolidine (4c) was obtained. 558 mg of this was subjected to reaction, post-treatment and purification in the same manner as in Example 1. 315 mg of finobinolysine (lc) was obtained as an amorphous solid.

[αco r-50.4° (c O.7, benzene). Example 4 Bis(4-dimethylaminophenyl)phosphine (4.
08g) and (2S,4S)-N-methanesulfonyl-4
-dicyclohexylphosphinyl-2-methanesulfonyhexylphosphinyl-2-bis(4-dimethylaminophenyl)phosphinylmethyl and loridine (4d) in 8
88 mg was obtained. 584 mg of this was subjected to reaction, post-treatment, and purification in the same manner as in Example 1, and (2S,4S)-N-tert
-Butoxycarbonyl-2-bis(4-dimethylaminophenyl)phosphinomethyl-4-dicyclohexylphosphinobimouth lysine (ld) in syrup form 349mg
Obtained.

[αko'o'-33.3' (c O.62, Hensen). Example 5 Bis(3,5-dimethyl-4-methoxyphenyl)phosphine (4.54 g) and (2S,4S)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2
-methanesulfonyloxymethylpyrrolidine (1.41
g) was reacted and post-treated in the same manner as in Example 1 to obtain (2S,
45) 1,177 mg of -4-dicyclohexylphosphinyl-2-bis(3,5-dimethyl-4-methoxyphenyl)phosphinylmethylpyrrolidine (4e) was obtained.

This 614 mg was subjected to reaction, post-treatment, and purification in the same manner as in Example 1. 331 mg of 4-dicyclohexylphosphinopinolysine (le) was obtained as an amorphous solid.

[α co%'-24.1" (c O.62, benzene). Examples 6-9 Rhodium-dinorbornadiene monoperchlorate o.oos
0.0065 mmol of the asymmetric ligand and 15 mmol of triethylamine were dissolved in methanol 301, 5 mmol or 15 mmol of itaconic acid was added, and the mixture was stirred at room temperature under 1 atmosphere of hydrogen pressure for 20 hours. The reaction solution was concentrated under reduced pressure, converted into an acidic aqueous solution of hydrochloric acid, and extracted with ether. After drying the organic layer, the solvent was distilled off to obtain optically active (-)monomethylsuccinic acid.

The conversion rate is 'H-NMR (CD30D-CD
The optical purity was determined by HPLC (Chiralcel OB manufactured by Daicel) after conversion to dimethyl ester with diazomethane.
, hexane/isobrobanol = 10/1, UV
220 nm). The results are shown in Table 1. N
o. Asymmetric ligand 6 lb 7 1c 8 1d 9 1e Table 1 Raw material/Rh Conversion rate Asymmetric yield 93%ee 9l The IR and NMR measurement results of compounds 4a to 4e are shown in Table 2.

Compounds 1a-le! It is shown in Table 3.

The R and NMR measurement results are Table 3 Table 2

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] Or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ′] (In the formula, R^1 is a hydrogen atom , -COR', -COOR
″, -CONHR″′, -SO_2R″″ or -PO(
R″″′)_2, R′, R″, R″′, R″″ and R″″ each represent an alkyl group or an aryl group, and R^2 is a lower alkyl group, an alkoxy group, A phosphinopyrrolidine compound represented by a phenyl group having 1 to 3 substituents selected from dialkylamino groups, R^3 represents a cyclohexyl group. 2. When performing a reaction to produce a compound having an asymmetric carbon atom by catalytic hydrogen reduction of a carbon-carbon double bond structure, a carbon-nitrogen double bond structure, and/or a carbon-oxygen double bond structure As a ligand in a metal complex compound used as a catalyst, there are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] or ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [ I ′] (in the formula, R^ 1 is a hydrogen atom, -COR', -COOR
″, -CONHR″′, -SO_2R″″ or -PO(
R″″′)_2, R′, R″, R″′, R″″ and R″″ each represent an alkyl group or an aryl group, and R^2 is a lower alkyl group, an alkoxy group, An asymmetric synthesis method by catalytic reduction characterized by using a phosphinopyrrolidine compound represented by a phenyl group having 1 to 3 substituents selected from dialkylamino groups, R^3 represents a cyclohexyl group.