JP2010209008A - Manufacturing method of optically active bisphosphinomethane - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for easily and economically manufacturing an optically active bis(alkylphosphino)methane. <P>SOLUTION: The manufacturing method comprises a step A of oxidizing a dialkylhydroxymethylphosphineborane (2) to obtain a dialkylphosphineboran (3), a step B, separately from the step A, of converting a hydroxy group in another dialkylhydroxymethylphosphineborane (2) into a releasable functional group to obtain a derivative (4), a step C of lithiating the dialkylphosphineboran (3) obtained in the step A to obtain a lithiated product (5), a step D of causing the lithiated product (5) obtained in the step C to react with the derivative (4) obtained in the step B to obtain a bis(alkylphosphino)methane-borane (1a) and a step E of deboranating the bis(alkylphosphino)methane-borane (1a) to prepare the bis(alkylphosphino)methane (1). <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing optically active bisphosphinomethane. The optically active bisphosphinomethane produced according to the present invention is particularly useful as a ligand of a metal complex used as an asymmetric synthesis catalyst, for example.

  An optically active phosphine ligand having an asymmetric center on a phosphorus atom plays an important role in a catalytic asymmetric synthesis reaction using a transition metal complex. As an optically active phosphine ligand having an asymmetric center on the phosphorus atom, for example, Patent Document 1 proposes 1,1-bis (alkylmethylphosphino) methane (hereinafter also referred to as MiniPHOS). This document describes the following reaction scheme as a production method of MiniPHOS.

In the above reaction scheme, first, alkyldimethylphosphine borane 21 is obtained using phosphorus trichloride 20 as a starting material. Subsequently, hydrogen in one of the two enantiotopic methyl groups is enantioselectively deprotonated with sec-butyllithium in the presence of (−)-sparteine. Subsequently, alkyldichlorophosphine, methylmagnesium bromide, and borane-tetrahydrofuran complex are successively reacted to obtain C ₂ symmetric bisphosphine-borane 22 as an intermediate. The synthesis of the bisphosphine / borane 22 involves the formation of a meso body 22a, which is removed by recrystallization using methanol or the like. The obtained optically pure intermediate 22 is deboranated by sequentially treating with trifluoromethanesulfonic acid and potassium hydroxide to obtain the target MiniPHOS23.

JP 2000-136193 A

  However, when the above reaction scheme is employed, when the bisphosphine-borane 22 is synthesized, half of the product must be removed as the meso form 22a, so that there is a disadvantage that the yield is lowered. Further, there is a drawback that it is difficult to isolate the bisphosphine-borane 22 when removing the meso body 22a. Furthermore, the alkyldichlorophosphine used for synthesizing the bisphosphine / borane 22 must be synthesized separately, which complicates the manufacturing process.

  The present invention provides a method by which MiniPHOS can be manufactured more easily than conventionally known methods.

一般式（２）で表されるジアルキルヒドロキシキメチルホスフィンボランを酸化して一般式（３）で表されるジアルキルホスフィンボランを得る工程Ａと、

工程Ａとは別に、一般式（２）で表されるジアルキルヒドロキシメチルホスフィンボランにおける水酸基を脱離可能な官能基に変換し、一般式（４）で表される誘導体を得る工程Ｂと、

工程Ａで得られた一般式（３）で表されるジアルキルホスフィンボランをリチオ化し、一般式（５）で表されるリチオ化物を得る工程Ｃと、

工程Ｃで得られた一般式（５）で表されるリチオ化物と、工程Ｂで得られた一般式（４）で表される誘導体とを反応させる工程Ｄと、

を有することを特徴とする、前記の一般式（１ａ）で表されるビス（アルキルホスフィノ）メタンボランの製造方法を提供するものである。 The present invention is a method for producing bis (alkylphosphino) methaneborane represented by the general formula (1a),

Step A for oxidizing the dialkylhydroxykimethylphosphine borane represented by the general formula (2) to obtain a dialkylphosphine borane represented by the general formula (3);

Separately from step A, step B is to convert the hydroxyl group in the dialkylhydroxymethylphosphine borane represented by general formula (2) to a detachable functional group to obtain a derivative represented by general formula (4);

Step C to obtain a lithiated product represented by the general formula (5) by lithiation of the dialkylphosphine borane represented by the general formula (3) obtained in the step A;

A step D in which the lithiated product represented by the general formula (5) obtained in the step C is reacted with the derivative represented by the general formula (4) obtained in the step B;

The process for producing bis (alkylphosphino) methaneborane represented by the general formula (1a) is provided.

Moreover, this invention has the process E which deboranates the bis (alkyl phosphino) methane borane represented by General formula (1a) obtained by the said method, It represents with General formula (1) characterized by the above-mentioned. And a method for producing optically active bis (alkylphosphino) methane.

  According to the present invention, optically active bis (alkylphosphino) methane that is suitably used as a ligand of a metal complex useful as a catalyst for an asymmetric synthesis reaction can be easily and economically produced.

  Hereinafter, the present invention will be described based on preferred embodiments thereof. The production method of the present invention is characterized by separately synthesizing two kinds of compounds from one kind of starting material, and using these two kinds of compounds, the optically active bis (alkyl) represented by the general formula (1) Phosphino) is to obtain methane. By adopting such a method, unlike the reaction scheme described in the background art section, the target compound (1) can be easily obtained in a high yield without the formation of a meso form.

The starting material used in this production method is an optically active dialkylhydroxymethylphosphine borane represented by the above general formula (2). In general formula (2), R ¹ and R ² are alkyl groups on the condition that they have different carbon numbers. Examples of the alkyl group include an acyclic alkyl group and an alicyclic alkyl group.

  Examples of the acyclic alkyl group include a linear alkyl group and a branched alkyl group. Examples of the linear alkyl group include those having 1 to 10 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-hexyl group, and an n-heptyl group. Examples of the branched alkyl group include those having 3 to 10 carbon atoms such as isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isohexyl group, isoheptyl group, 1,1,3,3-tetramethylbutyl. Can be mentioned.

  Examples of the alicyclic alkyl group include a monocyclic alkyl group and a bicyclic alkyl group. Examples of the monocyclic alkyl group include those having 3 to 10 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the bicyclic alkyl group include those having 4 to 10 carbon atoms such as an adamantyl group.

  These alkyl groups may be appropriately substituted with at least one monovalent substituent. As the substituent, a triphenylmethyl group, a diphenylmethyl group, a benzyl group, a methoxy group, a methoxyethyl group and the like are preferable.

In the general formula (1a), R ¹ is particularly preferably a bulky group having steric hindrance. From this viewpoint, when R ¹ is an acyclic alkyl group, a secondary alkyl group is preferable to a primary alkyl group, and a tertiary alkyl group is preferable to a secondary alkyl group. It is also preferred that R ¹ is an alicyclic alkyl group. Preferred alkyl groups include tert-butyl group, 1,1,3,3-tetrabutyl group, adamantyl group and the like.

On the other hand, R ² preferably has fewer carbon atoms than R ¹ . The difference in carbon number between R ¹ and R ² is at least 1. In view of the formation of a highly asymmetric space when the target compound (1) of this production method is used as a ligand for a metal complex for asymmetric synthesis catalysts, the steric R ¹ and R ² It is preferable that there is a large difference in obstacle. That is, R ¹ is preferably a bulky group having steric hindrance, that is, a maximal group, whereas R ² is preferably a minimal group. Therefore, R ¹ and R ² are more preferable as the difference between their carbon numbers is larger. Specifically, the difference in carbon number between R ¹ and R ² is preferably 2 or more, particularly 3 or more, particularly 4 or more. In view of the fact that R ² is a minimal group, R ² is preferably an acyclic alkyl group of an alicyclic alkyl group and an acyclic alkyl group having the same carbon number. Furthermore, among the acyclic alkyl groups having the same carbon number, a linear alkyl group is preferable to a branched alkyl group. Ultimately, the most preferred group for R ² can be said to be a methyl group. In general, however, the groups that can be used as R ² are determined relatively in relation to R ¹ . Preferred combinations of R ¹ and R ² include, for example, a combination of R ¹ = tert-butyl group, R ² = methyl group, R ¹ = 1,1,3,3-tetramethylbutyl group, R ² = methyl group The combination of is mentioned. In particular, according to the production method of the present invention, a compound having a combination of R ¹ = 1,1,3,3-tetramethylbutyl group and R ² = methyl group in general formula (1a) or general formula (1) is used. It can be obtained with high optical purity.

  The compound represented by the general formula (2) can be preferably synthesized by the following method. That is, according to the following step (A ′), the dialkylmethylphosphine borane represented by the general formula (2a) is enantioselectively deprotonated and then oxidized to obtain the general formula (2) having optical activity. The compounds represented can be obtained. The dialkylmethylphosphine borane (2a) is a commercially available compound manufactured and sold by the present applicant, for example.

  The enantioselective deprotonation of dialkylmethylphosphine borane (2a) can be carried out, for example, using an optically active amine as an asymmetric source in the presence of a base. As the optically active amine, an optically active tertiary diamine or triamine can be used. Examples of such amines include sparteine, 1,2-bis- (N, N-dimethylamino) cyclohexane, N, N, N ′, N′-tetramethyl-1,1′-binaphthyl-2,2 ′. -A diamine etc. are mentioned. Of these, sparteine ((-)-spartein) is preferably used. The amount of the optically active amine used is preferably 1.0 to 1.5 equivalents, particularly 1.05 to 1.15 equivalents, relative to the dialkylmethylphosphine borane (2a).

  The base used for deprotonation is used to deprotonate the hydrogen of the enantiotopic methyl group in dialkylmethylphosphine borane (2a). Such bases include organolithium compounds. Examples of organolithium compounds include methyllithium, ethyllithium, n-propyllithium, sec-propyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, dimethylaminolithium, diethylaminolithium, diisopropylaminolithium, Examples include diphenylamino lithium and dibenzylamino lithium. It is particularly preferable to use n-butyl lithium or sec-butyl lithium. The amount of the organolithium compound used is preferably 1.0 to 1.3 equivalents, more preferably 1.0 to 1.1 equivalents, relative to the dialkylmethylphosphine borane (2a).

  Oxidation after deprotonation can be performed, for example, by bubbling oxygen gas into the reaction system. Examples of the bubbling condition include a condition in which oxygen gas is supplied in an amount of 10 to 20 mL / min per 100 mL of the reaction solution. The bubbling time can be set to 1 to 5 hours, for example, and the temperature can be set to −80 to 0 ° C. on the condition that the amount is supplied.

  In this production method, a dialkylphosphine borane represented by the general formula (3) and a derivative represented by the general formula (4) are prepared using the dialkylhydroxykimethylphosphine borane represented by the general formula (2) as a raw material. Are synthesized separately. The order of synthesis of these two compounds is not essential in the present invention.

  First, in order to synthesize the dialkylphosphine borane (3), as shown in the step (A), the dialkylhydroxymethylphosphine borane (2) is oxidized using an oxidizing agent in the presence of a catalyst. Examples of the oxidizing agent include potassium peroxodisulfate and oxone (registered trademark). The amount of the oxidizing agent used is preferably 1 to 10 equivalents, particularly 1.2 to 1.5 equivalents, relative to the dialkylhydroxykimethylphosphine borane (2). As the catalyst, an appropriate amount of ruthenium chloride, ruthenium bromide, ruthenium iodide or the like can be used. This oxidation reaction can be performed, for example, in an aqueous phase. The reaction temperature can be, for example, 0 to 25 ° C., and the reaction time can be, for example, 1 to 5 hours.

  On the other hand, in order to synthesize the derivative (4), as shown in the step (B), the hydroxyl group in the dialkylhydroxykimethylphosphine borane (2) is converted into a detachable functional group (hereinafter referred to as “hydroxyl group”). (Also called “activation”). For the activation of the hydroxyl group, a known hydroxyl-activated functional group can be used. Such a functional group, that is, A in the general formula (4) is, for example, a tosyl group, a mesyl group, a trialkylsilyl group such as a trimethylsilyl group or a tert-butyldimethylsilyl group, or an arylalkyl group such as a benzyl group or a phenethyl group. And a trifluoromethanesulfonyl group.

  The activation of the hydroxyl group in the dialkylhydroxykimethylphosphine borane (2) is performed by, for example, activating the functional group of the dialkylhydroxykimethylphosphineborane (2) and the hydroxyl group in an organic solvent such as tetrahydrofuran under an inert atmosphere such as nitrogen gas. It can be performed by reacting with a hydroxyl group activator having a group. Specifically, hydroxyl group activation is performed by adding and mixing dialkylhydroxykimethylphosphine borane (2) and hydroxyl group activator p-toluenesulfonyl chloride or methanesulfonyl chloride in an organic solvent. Can do. The amount of the hydroxyl group activator used is preferably 1.2 to 3 equivalents, more preferably 1.5 to 2.5 equivalents, relative to the dialkylhydroxykimethylphosphine borane (2). The reaction temperature can be, for example, 0 to 25 ° C., and the reaction time can be, for example, 2 to 24 hours.

  In this way, two types of compounds (3) and (4) are obtained separately. In the obtained compounds (3) and (4), the steric configuration of the compound (2) which is a raw material compound is maintained. Next, as shown in the step (C), the compound (3), that is, the dialkylphosphine borane is lithiated to obtain a lithiated product represented by the general formula (5). An organolithium compound is used for lithiation. Examples of the organic lithium compound include methyl lithium, ethyl lithium, n-propyl lithium, sec-propyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and the like. It is particularly preferable to use n-butyl lithium or sec-butyl lithium. The amount of the organolithium compound used is preferably 1.0 to 1.3 equivalents, more preferably 1.0 to 1.1 equivalents, relative to the dialkylphosphine borane (3).

  Lithiation can be performed in an organic solvent such as tetrahydrofuran under an inert atmosphere such as nitrogen gas. Specifically, lithiation can be performed by adding and mixing an organic lithium compound in an organic solvent in which the dialkylphosphine borane (3) is dissolved. The reaction temperature can be, for example, −80 to −50 ° C., and the reaction time can be, for example, 0.2 to 0.5 hours.

  When the lithiated product (5) of dialkylphosphine borane (3) is formed, the derivative (4) is added to the reaction system. The derivative (4) can be added in a state dissolved in an organic solvent such as tetrahydrofuran. The addition is preferably performed under an inert atmosphere such as nitrogen gas. The amount of the derivative (4) added is preferably 1.0 to 1.5 equivalents, particularly 1.1 to 1.2 equivalents, relative to the charged dialkylphosphine borane (3).

  When the derivative (4) is added, the temperature of the reaction system is raised to 50 to 70 ° C., and the lithiated product (5) is caused to undergo nucleophilic attack on the derivative (4) as shown in the above step (D). By this reaction by nucleophilic attack, bis (alkylphosphino) methaneborane represented by the general formula (1a) having optical activity is obtained. The reaction time can be 3 to 4 hours, for example.

  The bis (alkylphosphino) methaneborane (1a) thus obtained is useful as a precursor of the compound (1) which is a ligand of the asymmetric catalyst in the asymmetric synthesis reaction.

  In order to use the compound (1) as a ligand of the asymmetric catalyst, as shown in the step (E), bis (alkylphosphino) methaneborane (1a) is deboraneated to obtain the compound (1). Just get.

  In order to perform deboraneation, for example, a method using a secondary amine such as diethylamine or morpholine, a base such as DABCO or triethylamine is known (J. Am. Chem. Soc., 112, p. 5244 (1990); J. Am. Chem. Soc., 121, p. 1090 (1999)). A method using an excess of tertiary amine is also known (J. Am. Chem. Soc., 121, p. 1090 (1999)). Furthermore, a method using a strong acid such as tetrafluoroboric acid, trifluoroacetic acid or trifluoromethanesulfonic acid (Tetrahedron Lett., 35, 9319 (1994); J. Organomet. Chem., 621, 120 (2001); J. Am Chem. Soc., 120, p.1635 (1998) In addition to these methods, phosphine in an alcohol solvent in the presence of molecular sieves described in JP-A-2005-97131 is also known. A method of liberating phosphine from borane can also be used.

An asymmetric catalyst is obtained by coordinating the optically active bis (alkylphosphino) methane (1) thus obtained to a metal such as rhodium or copper. In order to obtain an asymmetric catalyst from this compound (1), for example, the method described in Experimental Chemistry Course 4th edition (edited by the Chemical Society of Japan, published by Maruzen Co., Ltd.) Volume 18 pages 327-353 can be employed. Can do. For example, in order to obtain a rhodium complex, the compound (1) may be reacted with [RhX (diene) ₂ ]. Here, X represents halogen, BF ₄ ⁻ , PF ₆ ⁻ , ClO ₄ ⁻ or the like, and diene represents two compounds such as 1,5-cyclooctadiene and bicyclo [2,2,1] hepta-2,5-diene. It is a conformational compound. The molar ratio of the compound (1) and rhodium in this rhodium complex is preferably 1: 0.75-1.

  The obtained asymmetric catalyst is, for example, the production of an optically active saturated carboxylic acid or ester thereof by asymmetric hydrogenation of an unsaturated carboxylic acid, or the production of an optically active secondary alcohol by asymmetric hydrosilylation of a prochiral ketone. And can be suitably used for various asymmetric syntheses.

  The present invention will be described more specifically with reference to the following examples. However, the scope of the present invention is not limited to such examples.

[Example 1]
Synthesis of (R, R) -bis [(methyl) (1,1,3,3-tetramethylbutyl) phosphino] methane (1)

(1-1) Synthesis of (R) -hydroxymethyl (methyl) (1,1,3,3-tetramethylbutyl) phosphine-borane (2)

A solution of (−)-sparteine (7.6 mL, 33 mmol) in diethyl ketone (30 mL) was cooled to −78 ° C. and stirred under a nitrogen atmosphere with sec-butyllithium (cyclohexane and n -33 mL of a 1M solution containing hexane as a mixed solvent (33 mmol) was added. After 30 minutes, a solution of dimethyl (1,1,3,3-tetramethylbutyl) phosphine-borane (2a) (manufactured by Nippon Chemical Industry Co., Ltd., 5.64 g, 30 mmol) in diethyl ketone (30 mL) was added dropwise. .

  After dropping, stirring was continued for 3 hours while maintaining the temperature of the reaction system, and then the temperature was gradually increased to −40 ° C. After 1 hour, oxygen was blown into the solution while stirring vigorously, and stirring was continued for another hour. The solution was then stirred at 0 ° C. for 1 hour before the temperature was raised to room temperature. After 1 hour, 1M hydrochloric acid was added to stop the reaction. The reaction product was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. This was purified by silica gel chromatography (eluent: dichloromethane) to obtain the target compound (2) (5.24 g, 84% yield, 92% ee) as a white solid.

The analysis results of the compound (2) are as follows.
mp 67-68 ° C; [α] ^D = -7.53 (99% ee, c1.00, CHCl ₃ );
¹ H NMR (CDCl ₃ ) δ 0.12-0.68 (br m, 3H), 1.05 (s, 9H), 1.25 (d, J = 9.9Hz, 3H), 1.35 (d, J = 16.1Hz, 6H), 1.55 (dd, J = 7.7, 2.0Hz, 2H), 2.04 (m, 1H), 3.92 (ddd, J = 13.1, 7.0, 3.0Hz, 1H), 4.06 (dd, J = 12.9, 5.7Hz, 1H).
¹³ C NMR (CDCl ₃ ) δ 2.94 (d, J = 34.2Hz), 22.79, 22.85, 32.04, 32.19 (d, J = 29.2 Hz), 33.38 (d, J = 8.1Hz), 47.34, 56.75 (d, (J = 36.3Hz).
³¹ P NMR (CDCl ₃ ) δ 33.54 (m).
MS (FAB) m / z 201 (M ⁺ -3H), 191 (M ⁺ -BH ₃ + H).

(1-2) Synthesis of (S) -methyl (1,1,3,3-tetramethylbutyl) phosphine-borane (3)

  While stirring a solution of compound (2) (582 mg, 2.85 mmol) in acetone (5 mL), potassium hydroxide (1.68 g, 30 mmol) and potassium persulfate (2.31 g) dissolved in 6 mL of water were stirred. 8.55 mmol) was added. Ruthenium trichloride trihydrate (40 mg, 0.14 mmol) was then added and the solution was kept at 0 ° C. and stirred vigorously for 2 hours. Then it was gradually heated to bring the temperature to room temperature. After 2 hours, 1M hydrochloric acid was added to stop the reaction. The reaction product was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. This was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 5/1) to obtain the objective transparent oily compound (3) (370 mg, yield 75%).

The analysis results of the compound (3) are as follows.
[α] ^D = +4.74 (99% ee, c1.00, CHCl ₃ );
¹ H NMR (CDCl ₃ ) δ 0.21-0.77 (br m, 3H), 1.05 (s, 9H), 1.30 (dd, J = 10.6, 6.0 Hz, 3H), 1.34 (dd, J = 16.5, 7.2 Hz, 6H), 1.49 (dd, J = 14.5, 11.5 Hz, 1H), 1.63 (dd, J = 14.5, 9.7Hz, 1H), 4.41 (dm, J = 357Hz, 1H).
¹³ C NMR (CDCl ₃ ) δ 2.15 (d, J = 34.5Hz), 24.34, 24.64, 30.65 (d, J = 33.0Hz), 31.88, 33.24 (d, J = 11.1Hz), 49.22 (m).
³¹ P NMR (CDCl ₃ ) δ 18.44 (m).

(1-3) Synthesis of (R) -methanesulfonyloxymethyl (methyl) (1,1,3,3-tetramethylbutyl) phosphine-borane (4)

  While stirring a mixture of sodium hydride (72 mg, 3.0 mmol) and compound (2) (306 mg, 1.5 mmol) at 0 ° C., 4 mL of tetrahydrofuran was added under a nitrogen gas atmosphere at the same temperature. Subsequently, stirring was performed for 30 minutes. Methanesulfonyl chloride (0.231 mL, 3.0 mmol) was added thereto and stirred for 30 minutes. Then, it heated gradually and raised temperature to room temperature. After 2 hours, water was added to stop the reaction. The reaction product was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. This was purified by silica gel chromatography (eluent: dichloromethane / hexane = 20/1) to obtain the objective compound (4) (350 mg, yield 83%) as a transparent oil.

The analysis results of the compound (4) are as follows.
[α] ^D = -14.26 (99% ee, c1.00, CHCl ₃ );
¹ H NMR (CDCl ₃ ) δ 0.13-0.66 (br m, 3H), 1.06 (s, 9H), 1.37-1.40 (m, 9H), 1.54 (dd, J = 14.2, 7.8Hz, 1H), 1.62 ( dd, J = 14.2, 8.5Hz, 1H), 3.10 (s, 3H), 4.44 (dd, J = 13.0, 1.8Hz, 1H), 4.63 (dd, J = 13.0, 2.4 Hz, 1H).
¹³ C NMR (CDCl ₃ ) δ 2.73 (m), 3.00 (m), 22.82, 22.88, 32.01, 32.94 (d, J = 29.5 Hz), 33.42 (d, J = 13.1 Hz), 37.38, 47.11 (m) , 62.31 (d, J = 29.2Hz).
³¹ P NMR (CDCl ₃ ) δ 34.82 (m).
MS (FAB) m / z 281 (M ⁺ -H), 269 (M ⁺ -BH ₃ + H).

(1-4) Synthesis of (R, R) -bis [boranato (methyl) (1,1,3,3-tetramethylbutyl) phosphino] methane (1a)

  A solution of compound (3) (196 mg, 1.13 mmol) dissolved in tetrahydrofuran (0.5 mL) was cooled to −78 ° C., and n-butyllithium (hexane was used as a solvent in a nitrogen atmosphere while stirring the solution. 1.5M solution 0.75 mL, 1.13 mmol) was added to lithiate compound (3). After 30 minutes, a solution of compound (4) (350 mg, 1.24 mmol) in tetrahydrofuran (1.0 mL) was added, followed by heating at 60 ° C. for 3 hours to effect nucleophilic reaction of the lithiated compound with compound (4). went. Then, cooling was performed gradually to bring the temperature to room temperature. Then, water was added to stop the reaction. The reaction product was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. This was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 20/1) and further purified by recycle preparative HPLC to obtain the target compound (1a) (159 mg, 39% yield) as a white solid. Obtained.

The analysis results of the compound (1a) are as follows.
[α] ^D = -9.25 (99% ee, c1.00, CHCl ₃ );
^l H NMR (CDCl ₃ ) δ 0.27-0.80 (br m, 6H), 1.06 (s, 18H), 1.32 (d, J = 16.5 Hz, 12H), 1.50-1.52 (m, 10H), 1.77 (t, J = 11.8 Hz, 2H).
¹³ C NMR (CDCl ₃ ) δ 6.31 (d, J = 32.8Hz), 11.97 (t, J = 8.6Hz), 21.92 (d, J = 4.8Hz), 32.00, 33.21 (d, J = 12.1Hz), 33.49 (d, J = 3.8Hz), 33.73 (d, J = 4.5Hz), 46.65.
³¹ P NMR (CDCl ₃ ) δ 33.05.
MS (FAB) m / z 359 (M ⁺ -H), 355 (M ⁺ -6H + H), 345 (M ⁺ -BH ₃ -H), 333 (M ⁺ -2BH ₃ + H).

(1-5) Synthesis of (R, R) -bis [(methyl) (1,1,3,3-tetramethylbutyl) phosphino] methane (1) (R, R) -bis [boranato (methyl) ( [1,1,3,3-Tetramethylbutyl) phosphino] methane (1a) (36 mg, 0.1 mmol) was put into a 5 mL Schlenk tube, and the inside of the Schlenk tube was purged with nitrogen, and then dichloromethane (0.5 mL) was added and dissolved. I let you. The Schlenk tube was immersed in an ice bath, trifluoromethanesulfonic acid (53 μL, 0.6 mmol) was added, and the mixture was stirred for 20 minutes. Thereafter, the ice bath was removed and stirring was continued at room temperature. After 3 hours, the organic solvent was removed under reduced pressure, and a 2 mol / L potassium hydroxide aqueous solution was further added, followed by reaction at 60 ° C. for 2 hours. Under a nitrogen atmosphere, the reaction mixture was extracted three times with degassed diethyl ether. The extract was concentrated and subjected to silica gel chromatography filtration (eluent: degassed diethyl ether) under a nitrogen atmosphere. The filtrate was concentrated under reduced pressure to obtain the target product (R, R) -bis [(methyl) (1,1,3,3-tetramethylbutyl) phosphino] methane (1).

The analysis results of compound (1) are as follows.
¹ H NMR (CDCl ₃ ) δ 0.27-0.80 (br m, 6H), 1.06 (s, 18H), 1.32 (d, J = 16.5Hz, 12H), 1.50-1.52 (m, 10H), 1.77 (t, J = 11.8Hz, 2H).
¹³ C NMR (CDCl ₃ ) δ 6.31 (d, J = 32.8Hz), 11.97 (t, J = 8.6Hz), 21.92 (d, J = 4.8Hz), 32.00, 33.21 (d, J = 12.1Hz), 33.49 (d, J = 3.8Hz), 33.73 (d, J = 4.5Hz), 46.65.
³¹ P NMR (CDCl ₃ ) δ 33.05 (m).

(1-6) Synthesis of Rhodium Complex (R, R) -bis [(methyl) (1,1,3,3-tetramethylbutyl) phosphino] methane (1) was dissolved in 1 mL of tetrahydrofuran. This solution was added to a 1 mL tetrahydrofuran solution of [Rh (nbd) ₂ ] BF ₄ (33 mg, 0.09 mmol) separately prepared, and stirred for 5 hours under a nitrogen atmosphere. Concentrated. The obtained solid was filtered and washed with pentane to obtain a rhodium complex [Rh] of (R, R) -bis [(methyl) (1,1,3,3-tetramethylbutyl) phosphino] methane (1). (T-Oct-miniphos) ₂ ] BF ₄ (21 mg) was obtained as an orange powder.

(1-7) Asymmetric hydrogenation reaction Using the rhodium complex prepared in (1-6), asymmetric hydrogenation of N-acetylcinnamic methyl ester (substrate / catalyst ratio = 100, hydrogen pressure 2 atm, room temperature) 24 hours) in methanol solvent. As a result, (R) -N-acetylphenylalanine methyl ester was quantitatively obtained. As a result of analyzing this product by liquid chromatography (chiral column OJ-H), the enantiomeric ratio was 99.4% ee.

The analysis results of the obtained compound are as follows.
¹ H NMR (CDCl ₃ ) δ 1.95 (s, 3H), 3.11 (m, 2H), 3.73 (s, 3H), 4.89 (m, 1H), 5.97 (br s, 1H), 7.07-7.31 (m, 5H).

Claims (3)

A process for producing bis (alkylphosphino) methaneborane represented by the general formula (1a),

A step A of obtaining a dialkylphosphine borane represented by the general formula (3) by oxidizing the dialkylhydroxykimethylphosphine borane represented by the general formula (2);

Separately from step A, step B is to convert the hydroxyl group in the dialkylhydroxymethylphosphine borane represented by general formula (2) to a detachable functional group to obtain a derivative represented by general formula (4);

Step C to obtain a lithiated product represented by the general formula (5) by lithiation of the dialkylphosphine borane represented by the general formula (3) obtained in the step A;

A step D in which the lithiated product represented by the general formula (5) obtained in the step C is reacted with the derivative represented by the general formula (4) obtained in the step B;

The manufacturing method of the bis (alkyl phosphino) methane borane represented by the said general formula (1a) characterized by having. Further comprising step A ′ of enantiomerically deprotonating the dialkylmethylphosphine borane represented by the general formula (2a), followed by oxidation to obtain the dialkylhydroxymethylphosphine borane represented by the general formula (2). Item 2. The production method according to Item 1.

It is represented by the general formula (1), characterized by having a step E of deboranating the bis (alkylphosphino) methaneborane represented by the general formula (1a) obtained by the method according to claim 1. An optically active bis (alkylphosphino) methane production method.