JP5458528B2 - Optically active biphenyl phosphate derivative - Google Patents

Description

  The present invention relates to a novel optically active biphenyl phosphate derivative and use thereof.

  In recent years, organic catalyst reactions have attracted attention without using metal catalysts. In particular, in asymmetric organic catalytic reactions, metal catalysts that have been used so far are unstable and require attention to handling, and are also expensive. On the other hand, the organic catalyst has great advantages because it is inexpensive and stable to water and oxygen. Furthermore, when a metal catalyst is used, there is a problem of metal contamination in the product, and particularly in the field of pharmaceutical intermediate production and the like. Since the problem of metal contamination is also solved by using an organic catalyst, the organic catalyst is highly expected as a new catalyst that replaces the conventional metal catalyst.

As such an organic catalyst, the present inventors have disclosed a binaphthyl type optically active phosphoric acid compound, which is an optically active phosphoric acid catalyst (see, for example, Non-Patent Document 1). However, in order to use it as a catalyst for various asymmetric reactions, there has been a demand for the development of a catalyst that is superior in the ease of modification required for the reaction.
That is, since the binaphthyl type optically active phosphate compound does not have the benzyl position as in the optically active biphenyl phosphate derivative of the present invention, it has low reactivity and is disadvantageous in the variety of modifications. In addition, binaphthyl-type optically active phosphate compounds are not necessarily industrially suitable due to their large molecular weights, and the development of catalysts composed of compounds with lower molecular weights has also been demanded.

  Examples of disclosed optically active phosphorylated compounds other than binaphthyl type include biphenyl phosphate as an intermediate for optical resolution by acting cinchona alkaloid on racemic biphenyl phosphate for the purpose of obtaining optically active biphenol The compounds are only described (the biphenyl phosphate used here is substituted with a methyl group at the 5 and 5 ′ positions) (see, for example, Non-Patent Document 2 and Patent Document 1), and asymmetric There is no example of using this as a catalyst for the reaction.

  Examples of optically active phosphate derivatives having no biphenyl skeleton and binaphthyl skeleton are derived from optically active phosphate compounds derived from optically active tartaric acid (TAADDOL) (non-patent document 3) and biphenanthrol (VAPOL). An optically active phosphoric acid compound (Non-patent Document 4) is known, but there are very few examples used for asymmetric reaction as compared with an optically active phosphoric acid derivative having a binaphthyl skeleton. An optically active phosphate compound derived from tartaric acid is modified by a Grignard reaction, but a substrate that is not suitable for the Grignard reaction cannot be used. Moreover, the optically active phosphate compound derived from biphenanthrol (VAPOL) has no place where it can be modified due to its structure.

In addition, there is an example in which an optically active phosphorus compound is used as a complex with a transition metal and as an asymmetric reaction catalyst (see, for example, Patent Document 2), but the reaction can proceed only with an optically active phosphorus compound that does not contain a metal. Not done.
WO2002-040491 JP 2003-176293 A T. T. et al. Akiyama; Itoh; Yokota; Fuchibe; Angew. Chem. Int. Ed. , 43, 1566 (2004) John B. Alexander; Daniel S .; La; DustinR. Cefalo; AmirH. Hoveyda; RichardR. Schrock; Am. Chem. Soc. , 120, 4041 (1998) T. T. et al. Akiyama et al., Adv. Synth. Catal. , 347, 1523 (2005) GeraldB. Rowland et al. Am. Chem. Soc. , 127, 15696 (2005)

  The present invention is an asymmetric nucleophilic reaction that can obtain a target product with high reactivity and high optical purity, has a lower molecular weight than a known organic catalyst, is easily modified and required for the reaction, and is inexpensive. It is an object to provide a particularly advantageous catalyst.

  As a result of intensive studies to solve the above problems, the present inventors have found that an optically active biphenyl phosphate derivative having a specific structure has a low molecular weight and can be easily modified for a reaction. By using an optically active biphenyl phosphate derivative, it was found that the target product can be obtained by asymmetric nucleophilic reaction such as asymmetric Mannich reaction and asymmetric Friedel-Craft reaction with high reactivity and high optical purity. The invention has been completed.

  That is, the gist of the present invention is as follows.

[1] An optically active biphenyl phosphate derivative represented by the general formula (i) or (ii).

(Wherein, R _1, R ₂ are each independently represent a substituent which may have a hydrocarbon group or a substituted silyl group having 1 to 20 carbon atoms.)

[2] Using optically active 6,6′-dimethyl-1,1′-biphenyl-2,2′-diol represented by the following formula (3) or (4) as a starting material, its 3,3 ′ position The method for producing an optically active biphenyl phosphate derivative according to the above [1] , wherein the substituents R ₁ and R ₂ are introduced into and reacted with phosphorus oxychloride .

[3] An asymmetric nucleophilic reaction catalyst comprising the optically active biphenyl phosphate derivative according to [1].

[4] An asymmetric nucleophilic reaction, which is performed in the presence of the asymmetric nucleophilic reaction catalyst according to [3].

The novel optically active biphenyl phosphate derivative of the present invention can be advantageously used industrially because of its low molecular weight and easy modification. Thus, this optically active biphenyl phosphate derivative exhibits high reactivity in various asymmetric nucleophilic reactions and can give a reaction product with high optical purity.
The target product produced by the asymmetric nucleophilic reaction carried out in the presence of the optically active biphenyl phosphate derivative of the present invention is a compound useful as an intermediate or raw material for pharmaceuticals, agricultural chemicals and the like.

  Embodiments of the present invention will be described in detail below. However, the description of the constituent elements described below is an example (representative example) of the embodiments of the present invention, and the present invention does not exceed the gist thereof. These contents are not specified.

  In the present specification, the “carbon number” of various functional groups refers to the total number of carbon atoms including the substituent when the functional group has a substituent.

[Optically active biphenyl phosphate derivative]
The optically active biphenyl phosphate derivative of the present invention is represented by the following general formula (1) or (2), and R ₁ and R ₂ in the formula may have a carbon number 1 to 20 substituent. It is a hydrogen group or a substituted silyl group, and R ₁ and R ₂ may be the same or different from each other.

Examples of the hydrocarbon group optionally having a substituent having 1 to 20 carbon atoms represented by R ₁ and R ₂ include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, and the like. Of these, an aryl group is preferably used. Examples of the aryl group include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a biphenyl group, and a terphenyl group.

Further, these hydrocarbon groups may have a hydrocarbon group, an alkoxy group, an aryloxy group, a heterocyclic group, a hydroxyl group, an amino group, a substituted amino group, an alkylthio group, an arylthio group, an acyl group. Group, alkoxycarbonyl group, alkylthiocarbonyl group, aryloxycarbonyl group, carbamoyl group, substituted imino group, cyano group, nitro group, silyl group or halogen atom, etc., especially nitro or trifluoromethyl group It is preferable that it is a sex group. The substitution position of these substituents may be any as long as the optically active biphenyl phosphate derivative of the present invention has a catalytic activity for asymmetric nucleophilic reaction. For example, the hydrocarbon groups of R ₁ and R ₂ are phenyl groups, When the substituent is an electron-withdrawing group, the 2-position and / or 4-position of the phenyl group is preferable.

  Examples of the substituted silyl group include a trialkylsilyl group (the alkyl group preferably has 1 to 10 carbon atoms), a triarylsilyl group, a triaralkylsilyl group (the aralkyl group preferably has 2 to 10 carbon atoms), dialkyl Examples thereof include an arylsilyl group (the alkyl group preferably has 1 to 10 carbon atoms) and a diarylalkylsilyl group (the alkyl group preferably has 1 to 10 carbon atoms). Specific examples include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, diethylisopropylsilyl group, t-butyldimethylsilyl group, di-t-butylmethylsilyl group, tribenzylsilyl group, triphenyl. Examples thereof include a silyl group, a trixylsilyl group, a t-butyldiphenylsilyl group, and a diphenylmethylsilyl group. Among them, a triphenylsilyl group is particularly preferable.

Since R ₁ and R ₂ shown above often affect the yield and optical purity when used as a catalyst for asymmetric nucleophilic reaction, they can be used for the purpose of using optically active biphenyl phosphate derivatives. Accordingly, it can be appropriately selected with reference to the following example.

For example, when an optically active binaphthyl phosphate compound similar to the biphenyl skeleton represented by the following general formula (a) or (b) is used, in the asymmetric Mannich reaction using aldimine and silyl ketene acetal as reaction substrates, R _a = R _b = H yield 57%, optical purity 0% ee, R _a = R _b = Ph (phenyl group) 100% yield, optical purity 27% ee, R _a = R _b = 4-NO ₂ The yield of Ph is 96% and the optical purity is 87% ee (T. Akiyama et al., Angew. Chem. Int. Ed., 43, 1566 (2004)).

Similarly, when the optically active binaphthyl phosphate compound is used, in the asymmetric hydrophosphonylation reaction using aldimine and dialkyl phosphite as reaction substrates, a yield of 90% is obtained for R _a = R _b = 4-NO ₂ Ph. An optical purity of 23% ee and R _a = R _b = 3,5- (CF ₃ ) ₂ Ph gives a yield of 99% and an optical purity of 43% ee (T. Akiyama et al., Org. Lett., 7, 13, 2583 (2005)).

Since the substituents R ₁ and R ₂ in the optically active biphenyl phosphate derivative of the present invention show the same tendency as the substituents R _a and R _{b of} such an optically active binaphthyl phosphate compound, such information is also included. In addition, a catalyst configuration suitable for the target asymmetric nucleophilic reaction can be obtained.

The optically active biphenyl phosphate derivative of the present invention has a biphenyl skeleton as a basic skeleton, and has a molecular weight smaller than that of a conventional optically active binaphthyl phosphate compound or the like, and is industrially advantageous. Moreover, in the optically active biphenyl phosphate derivative of the present invention, various modifications can be made in R ₁ and R ₂ in the general formulas (1) and (2). Furthermore, since the optically active biphenyl phosphate compound of the present invention has a methyl group at the 6,6′-position of biphenyl and is a highly reactive benzyl position, it can be easily modified from the 6,6′-position. Is possible. On the other hand, since the conventional optically active binaphthyl phosphate compound does not have such a benzyl position, modification required for the reaction is not easy. Therefore, it can be said that the optically active biphenyl phosphate compound of the present invention is industrially advantageous also in the variety of modifications.

[Method for producing optically active biphenyl phosphate derivative]
Although there is no restriction | limiting in particular about the manufacturing method of the optically active biphenyl phosphate derivative of this invention, It can carry out based on the manufacturing method of a well-known optically active binaphthyl phosphate derivative. Specifically, for example, Angew. Chem. Int. Ed. 43, 1566 (2004), and Am. Chem. Soc. , 128, 84 (2006) can be applied.

In addition, the modification of the R ₁ position and the R ₂ position, that is, the introduction method of the substituents R ₁ and R ₂ can be carried out by a known and commonly used method. . Process Res. Dev. (2007), 11 (3), 628-632, etc. can be used. In addition, as Br formation and cyclization reaction, J. et al. Org. Chem. (2003), 68 (23), 8918-8, or J.A. Chem. Soc. Perkin Trans. 1 (1988), (6), 1305-11 can be used.

  An example of a specific manufacturing method will be described below.

<Production of 3,3′-diaryl-substituted optically active biphenyl phosphate derivative>
An optically active 6,6′-dimethyl-1,1′-biphenyl-2,2′-diol represented by the following general formula (3) or (4) described in JP-A No. 2004-189696 is used. As a starting material, 6,6′-dimethyl-1,1′-biphenyl-2,2′-bis (methoxymethyl) ether is prepared, and then a boron group is introduced at the 3,3 ′ position under a strong base.

  The reaction product is subjected to a coupling reaction in the presence of a halogen-substituted aryl compound and a palladium catalyst to introduce an aryl group at the 3,3 ′ position. Thereafter, the methoxymethyl group is deprotected, reacted with phosphorus oxychloride, and then hydrolyzed, whereby a 3,3′-diaryl-substituted optically active biphenyl phosphate derivative can be produced.

<Production of 3,3′-disilyl optically active biphenyl phosphate derivative>
Starting from the optically active 6,6′-dimethyl-1,1′-biphenyl-2,2′-diol represented by the general formula (3) or (4) described in JP-A-2004-189696 As a raw material, 6,3′-dimethyl-1,1′-biphenyl-2,2′-bis (methoxymethyl) ether was prepared and reacted with a halogen-substituted silyl compound under a strong base to produce 3,3 ′. A substituted silyl group is introduced at the position. Thereafter, a 3,3′-disilyl-substituted optically active biphenyl phosphate derivative can be produced by deprotecting the methoxymethyl group, reacting with phosphorus oxychloride and then hydrolyzing.

[Asymmetric nucleophilic reaction]
The optically active biphenyl phosphate derivative of the present invention can be suitably used as an organic catalyst for asymmetric nucleophilic reaction.
Examples of the asymmetric nucleophilic reaction to which the optically active biphenyl phosphate derivative of the present invention can be applied include an asymmetric Mannich reaction, an asymmetric Friedel-Craft reaction, an asymmetric Michael addition reaction, and the like.

  In this asymmetric nucleophilic reaction, the optically active biphenyl phosphate derivative of the present invention may be used alone or in combination of two or more. The optically active biphenyl phosphate derivative of the present invention may be used alone, but may be used in combination with various additives for the purpose of activating the reaction, for example.

Examples of additives that can be used in combination with the optically active biphenyl phosphate derivative of the present invention include, but are not limited to, dehydrating agents such as Molecular Sieves ^TM , anhydrous magnesium sulfate, and anhydrous sodium sulfate. These may be used alone or in combination of two or more.

  When the optically active biphenyl phosphate derivative of the present invention is used in an asymmetric nucleophilic reaction, generally, the amount used is preferably 0.1 to 50 mol% with respect to the raw material (electrophile), In particular, the content is preferably 0.5 to 20 mol%. Moreover, when using said dehydrating agent together, it is preferable to use a dehydrating agent 1 to 200 weight% with respect to a raw material (electrophile), especially about 5 to 100 weight%.

  Examples of raw materials, solvents, reaction conditions, and the like that can be used for the asymmetric nucleophilic reaction according to the present invention are given below, but the present invention is not limited to these.

<Asymmetric Mannich reaction>
Examples of the nucleophile for the asymmetric Mannich reaction include ketene silyl acetal compounds and ketones. In addition, an imine compound or the like is used as an electrophile, and the imine compound can be generated in a reaction system using an aldehyde compound and an amine compound as raw materials.

  The solvent used in the asymmetric Mannich reaction is not particularly limited as long as it does not participate in the reaction. For example, halogen solvents such as methylene chloride, chloroform and dichloroethane, ether solvents such as tetrahydrofuran and diethyl ether, benzene and toluene. An aromatic hydrocarbon such as xylene, an aliphatic hydrocarbon such as hexane and heptane, an alcohol solvent such as methanol, ethanol and 2-propanol, or water is used. These solvents can be used alone or as a co-solvent.

  Although reaction temperature changes with reaction substrates, it is preferable that it is the range of -78-80 degreeC. However, in order to achieve high optical purity, generally a lower temperature is better, and a range of −78 to 40 ° C. is particularly preferable.

<Asymmetric Friedel Craft Reaction>
Indole compounds, pyrrole compounds, furan compounds, aniline compounds, etc. are used as nucleophiles for asymmetric Friedel-Craft reaction, and nitroalkene compounds, α, β-unsaturated carbonyl compounds (ketones) are used as electrophiles. Aldehydes, esters), or imine compounds.

  The solvent used in the asymmetric Friedel-Craft reaction is not particularly limited as long as it does not participate in the reaction. For example, halogen solvents such as methylene chloride, chloroform and dichloroethane, ether solvents such as tetrahydrofuran and diethyl ether, benzene, Aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as hexane and heptane, alcohol solvents such as methanol, ethanol and 2-propanol, or water are used. These solvents can be used alone or as a co-solvent.

  Although reaction temperature changes with reaction substrates, it is preferable that it is the range of -78-80 degreeC. However, in order to achieve high optical purity, it is generally preferable that the temperature is low, and it is particularly preferably in the range of −78 to room temperature (for example, about 25 ° C.).

<Asymmetric Michael addition reaction>
Malonic acid diesters, diketones, β-ketoesters, nitroalkanes, cyanoalkanes, iminoacetic esters, alcohols, phenols, thiols, and other sulfur compounds and azides as nucleophiles for asymmetric Michael addition reactions Alternatively, hydroxydiarylphosphines and the like are used. Examples of electrophiles include α, β-unsaturated carbonyl compounds (ketones, aldehydes, esters), nitroalkene compounds, and the like.

  The solvent used in the asymmetric Michael addition reaction is not particularly limited as long as it does not participate in the reaction. For example, halogen solvents such as methylene chloride, chloroform and dichloroethane, ether solvents such as tetrahydrofuran and diethyl ether, benzene, Aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as hexane and heptane, or water are used. These solvents can be used alone or as a co-solvent.

  Although reaction temperature changes with reaction substrates, it is preferable that it is the range of -78-80 degreeC. However, in order to achieve high optical purity, it is generally preferable that the temperature is low, and it is particularly preferably in the range of −78 to room temperature (for example, about 25 ° C.).

  The reaction products obtained by these asymmetric nucleophilic reactions can be used as intermediates and raw materials for various useful compounds such as pharmaceuticals and agricultural chemicals.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by a following example, unless the summary is exceeded. In the following, only the (S) form of the optically active compound is shown, but the same applies to the (R) form, and the reaction of the (R) form proceeds in the same manner.

[Example 1: Production of optically active biphenyl phosphate derivative of R ₁ = R ₂ = p-nitrophenyl group]

<Methoxymethylation>

A glass three-necked flask was charged with 0.35 g (14.6 mmol, 2.3 eq.) Of NaH and 18 ml of dimethylformamide, and after ice cooling, 1.521 g (6. 6) of diol (i) dissolved in 12 ml of dimethylformamide. 31 mmol) was charged under a nitrogen atmosphere. Next, 1.1 ml (14.6 mmol, 2.3 eq.) Of methoxymethyl chloride (MeOCH ₂ Cl) was added dropwise under ice cooling. This was returned to room temperature and further stirred for 3 hours. After the reaction, the reaction solution was ice-cooled and 1N HCl aqueous solution was added. This was extracted three times with ethyl acetate, washed twice with 1N aqueous HCl and once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, evaporated to remove methoxymethyl protected (ii) (MOM = MeOCH ₂ -) was obtained in quantitative (1.90g, 6.31mmol).

<Boronation>

  A glass three-necked flask was charged with 1.90 g (6.31 mmol) of the protected methoxymethyl (ii), 3.8 ml of tetramethylethylenediamine (25.02 mmol, 4 eq.) And 40 ml of tetrahydrofuran, and cooled to -78 ° C. , N-BuLi hexane solution 16.1 ml (4 eq.) Was charged in a nitrogen atmosphere. This was warmed to 0 ° C. and stirred for 3 hours. Next, after cooling this to -78 ° C., 7.167 g (6 eq.) Of boric acid ester protected with pinacol was added under a nitrogen atmosphere. This was warmed to room temperature and stirred overnight. After the reaction, the reaction solution was subjected to gel filtration, washed with ethyl acetate, the solvent was distilled off, and the residue was purified by column chromatography (hexane / ethyl acetate) to obtain 1.820 g (3.28 mmol, 3.28 mmol, (Yield 52%).

<Coupling reaction (introduction of p-nitrophenyl group)>

  In a glass three-necked flask, 1.002 g (1.81 mmol) of boride (iii), 0.803 g (3.97 mmol, 2.2 eq.) Of p-nitrobromobenzene, 0.105 g (0. 09 mmol, 0.05 eq.), 1.713 g (5.43 mmol, 3.0 eq.) Of barium hydroxide octahydrate, 21 ml of dioxane and 7 ml of water were added, and the mixture was stirred for 40 hours while heating under reflux. After the reaction, Celite filtration was performed, the solvent was distilled off, and the obtained p-nitrophenyl-substituted product (iv) was used in the next step without purification.

<Deprotection>

  A glass three-necked flask was charged with 1.200 g (2.20 mmol) of p-nitrophenyl-substituted product (iv), a crude product of the coupling reaction, 8 ml of concentrated hydrochloric acid and 23 ml of dioxane, and stirred at 50 ° C. for 21 hours. After the reaction, 100 ml of water was added, extracted with dichloromethane three times, the solvent was distilled off, the residue was purified by column chromatography (hexane / ethyl acetate), and deprotected form (v) 0.609 g (1.33 mmol, cup) The total yield of the ring reaction and deprotection was 73%).

<Phosphorylation>

  A deprotection body (v) 384.1 mg (0.841 mmol) and pyridine 8 ml were placed in a glass three-necked flask, and 157 μl (1.684 mmol, 2 eq.) Of phosphorus oxychloride was added thereto at room temperature in a nitrogen atmosphere. Next, this was heated and stirred for 2 hours under heating to reflux. After the reaction, the reaction solution was cooled to room temperature, 2 ml of water was added, this was heated again, and stirred for 30 minutes under heating and refluxing. The solvent was distilled off, 6N HCl aqueous solution was added to the residue, extracted three times with methylene chloride, and dried over anhydrous sodium sulfate. This was purified by recrystallization from tetrahydrofuran / 6N HCl aqueous solution and then methylene chloride / hexane to give 415.3 mg of 6,6′-dimethyl-3,3′-bis (p-nitrophenyl) -substituted biphenyl phosphate (vi) ( 0.802 mmol, yield 95%). The analysis result of this is as follows.

¹ H-NMR (CDCl ₃ ): δ = 8.06-8.04 (m, 4H), 7.55-7.53 (m, 4H), 7.39-7.37 (m, 4H), 2.58 (s, 1H), 2.35 (s, 6H)

[Example 2: Production of optically active biphenyl phosphate derivative of R ₁ = R ₂ = 2,4-ditrifluoromethylphenyl group]
<Coupling reaction (introduction of 2,4-ditrifluoromethylphenyl group)>

  The same procedure as in Example 1 was conducted except that 1.190 g (4.06 mmol, 2.2 eq.) Of 2,4-ditrifluoromethylbromobenzene was coupled to the boride (iii) instead of p-nitrobromobenzene. The same operation as in the coupling reaction was performed to obtain 2,4-ditrifluoromethylphenyl-substituted product (vii).

<Deprotection>

  By performing the same operation as the deprotection in Example 1, 0.7714 g (1.208 mmol, coupling reaction and deprotection 2) from the 2,4-ditrifluoromethylphenyl-substituted product (vii) to the deprotected product (viii) The total yield of the process was 65%).

<Phosphorylation>

  The deprotected product (viii) was subjected to the same operation as in Example 1, and subjected to 6,6′-dimethyl-3,3′-bis (2,4-trifluoromethylphenyl) -substituted biphenyl phosphorus. 682.5 mg (0.9743 mmol, yield 81%) of acid (ix) was obtained. The analysis result of this is as follows.

¹ H-NMR (CDCl ₃ ): δ = 8.17 (s, 1H), 7.86 (s, 2H), 7.63-7.48 (m, 4H), 7.33-7.16 ( m, 4H), 2.35-2.26 (m, 6H)

[Example 3: Production of optically active biphenyl phosphate derivative of R ₁ = R ₂ = triphenylsilyl group]
<Triphenylsilylation>

  A glass three-necked flask was charged with 0.994 g (3.29 mmol) of the methoxymethyl protected product (ii) obtained by methoxymethylation in Example 1 and 47 ml of diethyl ether, and 5.2 ml of n-BuLi hexane solution at room temperature ( 4 eq.) Was charged under a nitrogen atmosphere. This was stirred for 1.5 hours. Next, 2.952 g (10.04 mmol, 3 eq.) Of triphenylsilyl chloride was dissolved in 40 ml of tetrahydrofuran and charged at 0 ° C. in a nitrogen atmosphere. This was warmed to room temperature and stirred for 45 hours. After the reaction, a saturated aqueous ammonium chloride solution was added at 0 ° C., this was extracted three times with ethyl acetate, and washed once with a saturated aqueous sodium chloride solution. Subsequently, it was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting triphenylsilyl-substituted product (x) was used in the next step without purification.

<Deprotection>

  The same operation as the deprotection in Example 1 was carried out to obtain 0.574 g (0.79 mmol, triphenylsilylation and deprotection) from the triphenylsilyl substitution product (x) and the deprotection product (xi). 24%).

<Phosphorylation>

  The deprotected product (xi) was subjected to the same operation as in Example 1, and subjected to 6,6′-dimethyl-3,3′-bis (triphenylsilyl) -substituted biphenyl phosphate (xii) 0. 533 g (0.73 mmol, 43% yield) was obtained. The analysis result of this is as follows.

¹ H-NMR (CDCl ₃ ): δ = 7.56-7.54 (m, 12H), 7.37-7.26 (m, 20H), 7.12-7.10 (m, 2H), 2.19 (s, 6H), 2.35 (s, 6H)

[Example 4: Asymmetric Mannich reaction]

  In a dried two-necked eggplant-shaped flask, an optically active biphenyl phosphate derivative (vi) (10.2 mg, 0.020 mmol), imine (A) (38.0 mg, 0.193 mmol) at −78 ° C. in a nitrogen atmosphere, And toluene (1 ml) was added and stirred for 20 minutes. Subsequently, ketene silyl acetal (B) (TMS: trimethylsilyl group) (70 μl, 0.291 mmol) was added dropwise at −78 ° C., followed by stirring for 29 hours. Thereafter, the reaction was stopped with a saturated aqueous sodium hydrogen carbonate solution, which was extracted three times with ethyl acetate, and washed once with a saturated aqueous sodium chloride solution. Next, after drying over anhydrous sodium sulfate and distilling off the solvent, the residue was purified by thin layer chromatography, and Mannich adduct (C) (54.0 mg, 0.181 mmol, yield 93.6%, optical purity 87.3%). ee) was obtained. The optical purity was determined by liquid high performance chromatography. The analysis result of this is as follows.

¹ H-NMR (CDCl ₃ ): δ = 7.29-7.19 (m, 5H), 6.69-6.49 (m, 3H), 6.39-6.37 (m, 1H), 5.80 (brs, 1H), 4.93 (brs, 1H), 4.57 (s, 1H), 3.68 (s, 3H), 1.24 (s, 3H), 1.21 (s , 3H)

[Example 5: Asymmetric Friedel-Craft reaction]

Molecular sieves 3A ^TM (19.9 mg) was placed in a two-necked eggplant-shaped flask, heated for 10 minutes with a heat gun under reduced pressure, and the atmosphere in the container was replaced with nitrogen. Optically active biphenyl phosphate derivative (xii) (16.2 mg, 0.020 mmol), nitrostyrene (E) (147.5 mg, 0.989 mmol), benzene (0.5 ml), 1,2-dichloroethane (0 0.5 ml) at −35 ° C. After stirring for 10 minutes, indole (D) was added and reacted for 47 hours. This was purified by column chromatography to obtain an indole adduct (F) (yield 100%, optical purity 84% ee). The optical purity was determined by high performance liquid chromatography. The analysis result of this is as follows.

¹ H-NMR (CDCl ₃ ): δ = 8.08 (brs, 1H), 7.45-7.43 (m, 1H), 7.38-7.17 (m, 7H), 7.09- 7.05 (m, 1H), 7.02-7.00 (m, 1H), 5.19 (dd, J = 7.6, 8.4 Hz, 1H), 5.06 (dd, J = 7 .6, 12.5 Hz, 1H), 4.93 (dd, J = 8.4, 12.5 Hz, 1H)

[Example 6: Asymmetric Michael addition reaction]

  Optically active biphenyl phosphate derivative (ix) (14.1 mg, 0.020 mmol), β-ketoester (H) (38.2 mg, 0.201 mmol), toluene (1 ml) at room temperature under a nitrogen atmosphere in a dried test tube The temperature was raised to 40 ° C. Subsequently, methyl vinyl ketone (G) (49 μl, 0.601 mmol) was added dropwise and stirred for 20 hours. This was purified by column chromatography to obtain Michael adduct (I) (47.0 mg, 0.181 mmol, yield 90%, optical purity 72% ee). The optical purity was determined by high performance liquid chromatography. The analysis result of this is as follows.

¹ H-NMR (CDCl ₃ ): δ = 7.79-7.77 (m, 1H), 7.61-7.62 (m, 1H), 7.49-7.47 (m, 1H), 7.44-7.40 (m, 1H), 3.70 (s, 3H), 3.67 (d, J = 17.4 Hz, 1H), 3.04 (d, J = 17.4 Hz, 1H) ), 2.68-2.59 (m, 1H), 2.56-2.48 (m, 1H), 2.30-2.14 (m, 1H), 2.13 (s, 3H)

[Comparative Example 1: Asymmetric Friedel-Craft Reaction (from Angelw. Chem. Int. Ed., 44, 6756 (2005))]
Using an optically active thiourea compound (xiv) in place of the optically active biphenyl phosphate derivative (xii), an asymmetric Friedel-Craft reaction was performed on the same substrate as in Example 5. As a result, the yield was 78% and the optical purity was 85. % Ee.

[Comparative Example 2: Asymmetric Mannich Reaction]
As a result of conducting an asymmetric Mannich reaction with the same substrate as in Example 4 using the optically active binaphthyl phosphate compound (xv) instead of the optically active biphenyl phosphate derivative (vi), the yield was 93% and the optical purity was 89. % Ee.

[Comparative Example 3: Asymmetric Friedel-Craft Reaction]
As a result of conducting an asymmetric Friedel-Craft reaction with the same substrate as in Example 5 using the optically active binaphthyl phosphate compound (xvi) instead of the optically active biphenyl phosphate derivative (xii), the yield was 98%. The purity was 92% ee.

[Comparative Example 4: Asymmetric Michael Addition Reaction]
As a result of performing an asymmetric Michael addition reaction with the same substrate as in Example 6 using the optically active binaphthyl phosphate compound (xvii) instead of the optically active biphenyl phosphate derivative (ix), the yield was 96% and the optical purity was It was 71% ee.

  From the above results, it can be seen that an asymmetric nucleophilic reaction product with high reaction efficiency and high optical purity can be obtained using the optically active biphenyl phosphate derivative of the present invention.

Claims (4)

An optically active biphenyl phosphate derivative represented by the general formula (1) or (2).

(Wherein, R _1, R ₂ are each independently represent a substituent which may have a hydrocarbon group or a substituted silyl group having 1 to 20 carbon atoms.) An optically active 6,6′-dimethyl-1,1′-biphenyl-2,2′-diol represented by the following formula (3) or (4) is used as a starting material, and the substituent is located at the 3,3 ′ position. The method for producing an optically active biphenyl phosphate derivative according to claim _1, wherein R ₁ and R ₂ are introduced and reacted with phosphorus oxychloride .

  An asymmetric nucleophilic reaction catalyst comprising the optically active biphenyl phosphate derivative according to claim 1.   An asymmetric nucleophilic reaction, which is carried out in the presence of the asymmetric nucleophilic reaction catalyst according to claim 3.