JP2006035125A - Asymmetric catalyst, method for producing optically active alcohol, and binaphthol derivative - Google Patents

Abstract

【選択図】なしThe chemical yield and the asymmetric yield are both high, there is no need to use a titanium-based activator, and the chemical yield and the asymmetric yield are not significantly lowered even under heating conditions. The present invention provides a method for producing an asymmetric catalyst and an optically active alcohol that can significantly reduce the time and requires a small amount of the asymmetric catalyst.
The following compound in which a diphenylphosphine oxide unit is bonded to the 3-position and 3'-position of a binaphthol skeleton is used as an asymmetric catalyst.
[Chemical 1]

[Selection figure] None

Description

  The present invention relates to an asymmetric catalyst for producing an optically active alcohol from an aldehyde, a method for producing an optically active alcohol using the asymmetric catalyst, and a binaphthol derivative usable for the asymmetric catalyst.

  Many physiologically active substances and functional substances are chiral molecules having asymmetric carbon atoms. For this reason, the development of asymmetric synthesis reactions that selectively synthesize optical isomers having the desired absolute configuration is an important issue in the organic chemical industry such as pharmaceuticals.

  One such asymmetric synthesis reaction is an asymmetric addition reaction to an aldehyde with dialkylzinc. In this asymmetric addition reaction, the asymmetric catalyst plays an important role. That is, the asymmetric catalyst used in this reaction not only provides an asymmetric field, but also promotes the rate-limiting step by newly providing a zinc active site in the periphery of the catalyst core. For this reason, according to this reaction, an optically active alcohol can be produced with a high chemical yield and a high asymmetric yield.

  Conventionally, an asymmetric catalyst having a binaphthol skeleton is known as an asymmetric catalyst in an asymmetric addition reaction to an aldehyde with dialkylzinc. In this asymmetric catalyst, it is considered that the coordination unit bonded to the 3rd position and the 3 'position of the binaphthol skeleton has a function of newly providing a zinc active site, thereby promoting the reaction. For this reason, asymmetric catalysts in which various coordination units are introduced at the 3-position and 3'-position of the binaphthol skeleton have been synthesized, and their properties as asymmetric catalysts have been investigated.

H. Kitajima, K. Ito, Y. Aoki, T. Katsuki Bull. Chem. Soc. Jpn. 1997, 70, 207-217 H. Kitajima, K. Ito, Y. Aoki, T. Katsuki Chem. Lett. 1996, 343-344 特開２００２−３１６９６１号公報 For example, Non-Patent Documents 1 and 2 and Patent Document 1 report the synthesis of optically active alcohols using the following compound A in which an amide is introduced as a coordination unit as an asymmetric catalyst.

H. Kitajima, K. Ito, Y. Aoki, T. Katsuki Bull. Chem. Soc. Jpn. 1997, 70, 207-217 H. Kitajima, K. Ito, Y. Aoki, T. Katsuki Chem. Lett. 1996, 343-344 JP 2002-316916 A

  In Non-Patent Documents 1 and 2, in the asymmetric addition reaction to an aromatic aldehyde using diethylzinc, if 10 mol% of Compound A is used, the reaction is performed with a chemical yield of 88% and an asymmetric yield of 91 to 99%. It has been reported to progress. In addition, since the complex C is detected by X-ray structural analysis, the chelation model of the compound B has been proposed as an intermediate.

K. Kodama, J. Ito, A. Nagaki, T. Ohta, I. Furukawa Appl. Organometal. Chem. 2000, 14, 709-714 特開２００２−３１６９６６号公報 Non-Patent Document 3 reports an asymmetric synthesis using the following compound D and compound E in which an oxazoline derivative is introduced as a coordination unit.

K. Kodama, J. Ito, A. Nagaki, T. Ohta, I. Furukawa Appl. Organometal. Chem. 2000, 14, 709-714 JP 2002-316966 A

  In the above document, it is reported that an optically active alcohol was obtained by performing an asymmetric addition reaction of diethylzinc to an aromatic aldehyde using the compound D or compound E as an asymmetric catalyst.

W.-S. Huang, Q.-S. Hu, L. Pu J. Org. Chem. 1998, 63, 1364-1365 W.-S. Huang, Q.-S. Hu, L. Pu J. Org. Chem. 1999, 64, 7940-7956 米国特許第５８８９１３４号 米国特許第６０２０４５２号 Furthermore, Non-Patent Documents 4 and 5 and Patent Documents 3 and 4 report asymmetric synthesis by the following compound F in which polyphenol or polyphenol ether is introduced as a coordination unit.

W.-S. Huang, Q.-S. Hu, L. Pu J. Org. Chem. 1998, 63, 1364-1365 W.-S. Huang, Q.-S. Hu, L. Pu J. Org. Chem. 1999, 64, 7940-7956 US Pat. No. 5,889,134 US Pat. No. 6,020,452

  In an asymmetric addition reaction to an aldehyde with dialkylzinc, only 5 mol% of this compound F is present with respect to the substrate, and optically obtained with a high asymmetric yield of 99% without using a titanium-based activator. It has been reported that active alcohols can be obtained.

  However, the asymmetric catalyst comprising a chiral compound having coordination units at the 3 and 3 'positions of the conventional binaphthol skeleton has the following problems.

  That is, in the asymmetric catalyst in which amide is introduced as a coordination unit, the chemical yield is as low as 88% even under the optimum conditions. In addition, it is difficult to introduce amides at the 3-position and 3'-position of the binaphthol skeleton, which makes it difficult to synthesize.

  In addition, an asymmetric catalyst using an oxazoline derivative as a coordination unit has low chemical yield and asymmetric yield. This disadvantage can be solved to some extent by coexisting a titanium-based activator, but the titanium-based activator is required to be equimolar or more with respect to the substrate, leading to an increase in manufacturing cost. To do.

  Furthermore, in the conventional asymmetric catalyst in which a coordination unit is introduced at the 3rd and 3 ′ positions of the binaphthol skeleton, if the reaction is promoted by increasing the reaction temperature, the chemical yield and the asymmetric yield are reduced. descend. For this reason, it is necessary to proceed the reaction at a low temperature, and there is a problem that the reaction time becomes long.

This invention is made | formed in view of the said conventional situation, Comprising: It aims at providing the manufacturing method of the asymmetric catalyst and optically active alcohol which solve at least 1 of the following subjects. That is,
Increase both chemical and asymmetric yields.
No need for titanium-based activators.
The chemical yield and asymmetric yield should not decrease so much even under heating conditions.
The reaction time can be greatly shortened.
Use less asymmetric catalysts.

  The inventors selected a phosphine oxide unit and a phosphine sulfide unit, which had not been studied conventionally, as coordination units to be modified at the 3rd and 3 'positions of the binaphthol skeleton, and investigated the characteristics as an asymmetric synthesis catalyst. As a result, it was found that these compounds can solve the above problems in the asymmetric addition of dialkylzinc to aldehyde, and the present invention has been made.

  That is, the asymmetric catalyst of the present invention is an asymmetric catalyst comprising a chiral compound having coordination units at the 3rd and 3 ′ positions of the binaphthol skeleton, wherein the coordination unit is a phosphine oxide unit or a phosphine sulfide unit. It is characterized by.

  In addition, the method for producing an optically active alcohol according to the present invention includes an optically active alcohol in which a dialkylzinc is asymmetrically added to an aldehyde using a chiral compound having coordination units at the 3 and 3 ′ positions of the binaphthol skeleton as an asymmetric catalyst. In the production method, the coordination unit is a phosphine oxide unit or a phosphine sulfide unit.

  According to the test results of the inventors, if a compound in which a phosphine oxide unit or a phosphine sulfide unit is modified at the 3-position and 3′-position of the binaphthol skeleton is used as an asymmetric catalyst in the case of asymmetric addition of dialkylzinc to an aldehyde. The asymmetric catalyst can coordinate strongly to zinc and provide a strong zinc activation site. For this reason, an optically active alcohol can be synthesized with a high asymmetric yield and a high chemical yield without using a titanium-based activator. In addition, since this asymmetric catalyst is strongly coordinated with zinc and a strong asymmetric field is formed, its ability as an asymmetric catalyst does not decrease so much even at high temperatures. For this reason, the reaction can be accelerated by heating, the reaction time can be greatly shortened, and the amount of the asymmetric catalyst used can be reduced.

  In the asymmetric catalyst of the present invention, the phosphine oxide unit or phosphine sulfide unit bonded to the 3rd and 3 ′ positions of the binaphthol skeleton and the hydroxyl group bonded to the 2nd and 2 ′ positions have a great influence on the catalytic activity. Therefore, although it is limited to them, in other site | parts, you may have a substituent.

As the asymmetric catalyst of the present invention, a binaphthol derivative represented by the following formula, in which a diphenylphosphine oxide unit is introduced as a coordination unit bonded to the 3rd and 3 ′ positions of the binaphthol skeleton, can be used.

  According to the test results of the inventors, this compound is extremely high in asymmetric addition with dialkylzinc of various aromatic aldehydes and aliphatic aldehydes having electron-withdrawing substituents and electron-donating substituents. An optically active alcohol can be obtained with a uniform yield and a very high chemical yield.

In addition, as the asymmetric catalyst of the present invention, a compound represented by the following formula in which a diphenylphosphine sulfide unit is introduced as a coordination unit bonded to the 3-position and 3′-position of the binaphthol skeleton can also be used.

  According to the test results of the inventors, this compound can also provide an optically active alcohol with high asymmetric yield and high chemical yield in the asymmetric addition of aromatic aldehydes with dialkylzinc.

  Hereinafter, Examples 1 to 3 embodying the present invention will be described in comparison with Comparative Examples 1 to 3.

Example 1
In Example 1, (R) -3,3′-bis (diphenylphosphinoyl) -BINOL was used as an asymmetric catalyst as a chiral compound having coordination units at the 3rd and 3 ′ positions of the binaphthol skeleton. This compound was synthesized by the following two-step reaction.

  That is, in a 500 mL three-necked eggplant type flask purged with nitrogen, sodium hydride (ca. 60% oil suspension) (0.880 g, 22 mmol) was added, and 50 mL of THF was added in an ice bath at 0 ° C. Stir for 5 minutes to make a suspension. When (R) -BINOL (2.86 g, 10 mmol) is added to this suspension at 0 ° C, it gradually becomes a yellow transparent solution. Next, diphenylphosphinic chloride (4.19 mL, 22 mmol) is slowly added dropwise at 0 ° C., followed by further stirring at 0 ° C. for 15 minutes, followed by stirring at room temperature for 3 hours. After confirming the completion of the reaction by TLC, the reaction solution is brought to 0 ° C., and diethyl ether (100 mL) and pure water (100 mL) are slowly added in this order. Then, normal separation treatment is performed, and diethyl ether extraction (30 mL) is performed twice from the aqueous layer. The extracted organic layer is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give (R) -3,3'-bis (diphenylphosphinoyl) -BINOL as a white solid in a yield of 99% or more. Got.

  Using the compound 1 thus obtained without any particular purification, the following operation was performed. That is, 50 mL of diisopropylamine (19.2 mL, 137 mmol) and THF are added to a nitrogen-substituted 500 mL three-necked eggplant type flask. This is cooled to -78 ° C and n-butyllithium (1.58N hexane solution) (86.7 mL, 137 mmol) is added. After stirring at −78 ° C. for 30 minutes, a THF (100 mL) solution of Compound 1 is slowly added dropwise with a cannula, and the reaction mixture is stirred at −78 ° C. for 3 hours. After confirming the completion of the reaction by TLC, diethyl ether (50 mL), saturated aqueous sodium chloride solution (50 mL), and 1N hydrochloric acid (200 mL) are added in this order at -78 ° C. After confirming that the pH is 1 or less, normal separation treatment is performed. The aqueous layer is further extracted twice with diethyl ether (30 mL). The extracted organic layer is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to obtain a white solid. The obtained crude product was recrystallized with a mixed solvent of toluene / hexane (ca. 1/5) to give pure (R) -3,3'-bis (diphenylphosphinoyl)-with a yield of 99% or more. Got BINOL.

Using (R) -3,3′-bis (diphenylphosphinoyl) -BINOL thus obtained, asymmetric addition to benzaldehyde with diethylzinc was performed as shown in the following chemical reaction formula.

  That is, a 20 mL Schlenk tube was heated and dried under reduced pressure, and then purged with nitrogen, and (R) -3,3'-bis (diphenylphosphinoyl) -BINOL (68.6 mg, 0.10 mmol), THF (3 mL), and diethylzinc Add 1.0N toluene or hexane solution (3.00mmol, 3mL) and stir at room temperature for 30 minutes. Cool the mixture to −78 ° C. and add benzaldehyde (1.00 mml, 106.0 mg). After sufficiently stirring, the mixed solution is set to a predetermined temperature. After confirming the completion of the reaction by TLC, 1N hydrochloric acid (10 ml) is added, and the mixture is stirred at room temperature for 10 minutes. Furthermore, ethyl acetate (10 mL) is added, and a normal liquid separation treatment is performed. Extract two more times from the aqueous layer with ethyl acetate (10 mL). The extract is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further, the product was fractionated with a mixed solvent of hexane: ethyl acetate = 5: 1 through a neutral silica gel column to obtain 1-phenylpropanol as a colorless liquid.

Moreover, it replaced with the benzaldehyde and performed the same operation about various aromatic aldehydes, and obtained the corresponding asymmetric secondary alcohol. The results are shown in Table 1.

  As shown in Table 1, by using (R) -3,3'-bis (diphenylphosphinoyl) -BINOL as an asymmetric catalyst, various aromatic aldehydes having electron-withdrawing substituents and electron-donating substituents As a raw material, an optically active alcohol could be obtained with an extremely high asymmetric yield and an extremely high chemical yield without using a titanium-based activator.

(Example 2)
In Example 2, the asymmetric addition reaction of diethylzinc was carried out at 50 ° C., and the amount of (R) -3,3′-bis (diphenylphosphinoyl) -BINOL added as an asymmetric catalyst was half that in Example 1. Of 5 mol%. Other conditions are the same as those in the first embodiment, and a description thereof will be omitted. The results are shown in Table 2.

  As can be seen from Table 2, even though the reaction temperature is as high as 50 ° C., the corresponding optically active alcohol is synthesized from any aromatic aldehyde with high asymmetric yield and high chemical yield. I was able to. Moreover, although the addition amount of the asymmetric catalyst was half that of Example 1, the reaction time could be greatly shortened. Therefore, (R) -3,3'-bis (diphenylphosphinoyl) -BINOL does not deactivate even at high temperatures above room temperature, and has constructed a precise asymmetric field with dinuclear zinc with strong binding force. Is suggested. In addition, when a zinc complex crystal of (R) -3,3'-bis (diphenylphosphinoyl) -BINOL was synthesized and its crystal structure was examined by X-ray diffraction, it was found to have the structure shown in FIG. . 1A is an actual measurement diagram including all atoms, and FIG. 1B is a schematic diagram in which the central portion of the complex is picked up.

  From the above crystal structure, the chelation structure hypothesis that phosphine oxide is effective in forming a zinc activation site was demonstrated. In addition, the structure is not a conventionally known trinuclear zinc complex but a tetranuclear zinc complex and does not contain a chelation structure (ArO-Zn-OAr) of a naphthol site in one molecule. It became clear that.

(Comparative Example 1)
In Comparative Example 1, asymmetric addition to benzaldehyde with diethylzinc was performed in the same manner as in Example 1 using (R) -3,3′-bis (diphenylphosphanyl) -BINOL having no oxide moiety. . (R) -3,3′-bis (diphenylphosphanyl) -BINOL was synthesized by reducing (R) -3,3′-bis (diphenylphosphinoyl) -BINOL synthesized in Example 1 by the following chemical reaction.

That is, (R) -3,3'-bis (diphenylphosphinoyl) -BINOL (85.2 mg, 0.124 mmol), dimethylaniline (0.629 mL, 4.96 mmol) in a 20 mL two-necked eggplant-shaped flask equipped with a nitrogen-substituted condenser Toluene (2 mL) is added. The mixture is cooled to 0 ° C., trichlorosilane (0.125 mL, 1.24 mmol) is added, and the mixture is stirred at 0 ° C. for 30 minutes. The reaction mixture is then heated at 130 ° C. for 17 hours. After confirming the completion of the reaction by TLC, add methylene chloride (2 mL) and a small amount of saturated aqueous sodium hydrogen carbonate solution at 0 ° C. The white solid produced by the treatment was filtered, the filtrate was concentrated, and the product was fractionated on a neutral silica gel column (hexane: ethyl acetate = 10: 1) to give a yellowish white solid in a yield of 39% ( R) -3,3′-bis (diphenylphosphanyl) -BINOL was obtained. As a result of asymmetric addition to benzaldehyde with diethylzinc using this compound, it was found that the asymmetric yield was remarkably reduced to 66% as shown in the following reaction formula.

(Comparative Example 2)
In Comparative Example 2, diethyl zinc was obtained in the same manner as in Example 1 using a catalyst that apparently had no zinc activation ability (coordination ability) and was substituted at the 3,3 ′ position with a phenyl group. Asymmetric addition to benzaldehyde was performed. As a result, as shown in the following reaction formula, it was found that the asymmetric yield was further lowered to 49%. From this, it was found that there is a limit to the improvement of the asymmetric yield only by the three-dimensional control relying only on the bulkiness.

(Comparative Example 3)
In Comparative Example 3, as shown in the following reaction formula, a catalyst in which only one of the 3,3 ′ positions was substituted with a diphenylphosphine oxide unit using (R) -BINOL as a starting material was synthesized in two steps. Asymmetric addition to benzaldehyde with diethylzinc was carried out in the same manner as in Example 1.

As a result, as shown in the following reaction formula, it was found that the chemical yield was dramatically reduced to 34% and the asymmetric yield was 21%. From this, it was found that the diphenylphosphine oxide unit had a poor ability as an asymmetric catalyst unless it was bonded to both the 3,3 ′ positions of binaphthol.

Example 3
In Example 3, (R) -3,3′-bis (diphenylphosphinoyl) -BINOL into which diphenylphosphine sulfide was introduced as a coordination unit at the 3rd and 3 ′ positions of the binaphthol skeleton was used as an asymmetric catalyst. This compound was synthesized by the reaction shown below.

  That is, after replacing the inside of a 20 mL two-necked eggplant flask equipped with a condenser with nitrogen, (R) -3,3'-bis (diphenylphosphinoyl) -BINOL (65.4 mg, 0.10 mmol) and sulfur (7.0 mg, 0.22 mmol) and freeze degassed benzene (5 mL). The reaction mixture is then heated at 110 ° C. for 24 hours. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated, and the product was fractionated on a neutral silica gel column (hexane: ethyl acetate = 5: 1) to obtain 3,3 ′ as a white solid in 69% yield. -bis (diphenylphosphanyl) -BINOL was obtained.

Using 3,3′-bis (diphenylphosphanyl) -BINOL thus obtained, asymmetric addition to benzaldehyde with diethylzinc was carried out in the same manner as in Example 1 (see the following reaction formula). A similar asymmetric addition reaction was also performed on parachlorobenzaldehyde and paramethoxybenzaldehyde.

As a result, as shown in Table 3, the corresponding optically active alcohol could be obtained with a high asymmetric yield at a catalyst amount of 10 mol% at room temperature. From this, 3,3'-bis (diphenylphosphanyl) -BINOL, like (R) -3,3'-bis (diphenylphosphanyl) -BINOL, forms a zinc activation site, which has a high chemical yield and a high concentration. It was found that a uniform yield can be realized.

  By carrying out the method for producing an optically active alcohol of the present invention using the asymmetric catalyst of the present invention, the optically active alcohol can be produced with a high chemical yield and a high asymmetric yield. In addition, it is not necessary to use a titanium-based activator at that time, and further, the reaction time can be greatly shortened by reducing the chemical yield and the asymmetric yield by performing the reaction under heating. And the amount of asymmetric catalyst used can be reduced.

Fig. 1 shows the structure of the zinc complex crystal of (R) -3,3'-bis (diphenylphosphinoyl) -BINOL. Fig. 1A is an actual measurement including all atoms, and Fig. 1B shows the atoms at the center of the complex. It is the schematic diagram which picked up.

Claims (7)

In an asymmetric catalyst comprising a chiral compound having coordination units at the 3rd and 3 ′ positions of the binaphthol skeleton,
The asymmetric catalyst, wherein the coordination unit is a phosphine oxide unit or a phosphine sulfide unit. The asymmetric catalyst according to claim 1, comprising a binaphthol derivative represented by the following formula.

The asymmetric catalyst according to claim 1, comprising a binaphthol derivative represented by the following formula.

In a method for producing an optically active alcohol in which a chiral compound having a coordination unit at the 3-position and 3′-position of a binaphthol skeleton is used as an asymmetric catalyst and a dialkylzinc is asymmetrically added to an aldehyde,
The method for producing an optically active alcohol, wherein the coordination unit is a phosphine oxide unit or a phosphine sulfide unit. The method for producing an optically active alcohol according to claim 4, wherein a binaphthol derivative represented by the following formula is used as the asymmetric catalyst.

The method for producing an optically active alcohol according to claim 4, wherein a binaphthol derivative represented by the following formula is used as the asymmetric catalyst.

A binaphthol derivative represented by the following formula:

Images