JP4496100B2 - Optically active phosphorane compound, method for producing the same, ligand for asymmetric reaction, and asymmetric reaction method using the same - Google Patents

Description

  The present invention relates to an optically active phosphorane compound useful as an asymmetric reaction ligand in the synthesis of pharmaceuticals, agricultural chemicals, fragrances, and other various fine chemicals, a method for producing the same, and an asymmetric reaction ligand comprising the same. It relates to the asymmetric reaction method used.

  In an asymmetric synthesis reaction using a transition metal complex, an optically active phosphine is considered to be effective as a ligand, and many optically active diphosphines represented by BINAP have been developed so far (Non-patent Document 1). . On the other hand, there are many examples of catalytic asymmetric synthesis reactions using an asymmetric metal catalyst with a nitrogen-containing compound as a ligand. Among them, optically active diamine-metal complexes derived from proline include Mukaiyama aldol reaction, alkylation reaction, High selectivity is achieved in reduction reactions and the like (Non-Patent Documents 2 to 4).

  Accordingly, the present inventors have developed a phosphorane-2-carboxylic acid in which the nitrogen atom of proline is replaced with a phosphorus atom as an asymmetric source in place of proline, and its synthesis and application to an asymmetric ligand. Application is proposed (Patent Document 1).

  In this phosphorane-2-carboxylic acid, a substituent is present on the phosphorus atom, so that

As shown in Fig. 4, (1R, 2R), (1R, 2S), (1S, 2R), and (1S, 2S) four types of stereoisomers exist depending on the 1- and 2-positions of the 5-membered ring. To do.

  For these all isomers, the present inventors have also developed a method that can be obtained purely by asymmetric reaction or diastereolysis and optical resolution after synthesis of the racemate (Patent Document 1, Non-Patent Document 1). Literature 5-6).

  Zhang et al. Synthesized a derivative of the above-described phospholane-2-carboxylic acid using a phosphorane having a phosphorus atom protected with sulfur, and developed an asymmetric reaction using the derivative (Non-Patent Documents 7 to 8). .

However, as described above, phosphorane-2-carboxylic acid and its derivatives are attracting attention as molecules having a phosphorus atom as an asymmetric source. However, higher reaction yield and selectivity in asymmetric reaction. The molecular structure to realize it, its production method, and its practical application to asymmetric reactions have just been pioneered.
Catalytic Asymmetric Synthesis, 2nd.ed; Ojima, I., Ed: Weinheim, 2000. Kobayashi, S .; Horibe, M. Chem. Eur. J. 3, 1472 (1997). Minowa, N .; Mukaiyama, T. Bull. Chem. Soc. Jon., 60, 3697 (1987). Falorni, M., Giacomelli, G .; Marchetti, M .; Culeddu, N .; Lardicci, L. Tetrahedron: Asymmetry 2, 287 (1991). Sun, K. Manabe, WW-L. Lam, N. Shiraishi, J. Kobayashi, M. Shiro, H. Utsumi, S. Kobayashi, Chem. Eur. J., 11, 361-368 (2005). Kobayashi, S .; Shiraishi, N .; Lam, WW-L .; Manabe, K. Tetrahedron Lett. 2000, 42, 7303. Tang, W .; Zhang, X. Angew. Chem. Int. Ed. 2002, 41, 1612. Tang, W .; Wang, W .; Zhang, X. Angew. Chem. Int. Ed. 2003, 42, 943. JP 2002-69086

  The present invention is based on the background as described above, and based on the results of the studies by the present inventors and the knowledge thereof, an asymmetric ligand capable of performing an asymmetric reaction with high reaction yield and selectivity. More specifically, a new P, N-type asymmetric ligand and an asymmetric reaction method using the same are attached to a nitrogen atom as well as a phosphorus atom as an asymmetric source. It is an issue.

  The present invention is characterized by the following in order to solve the above problems.

  1: The following formula (1) (2)

(In the formula, R ¹ represents an aryl group having 6 to 14 carbon atoms, and R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are any two of these adjacent to each other bonded to each other to form a benzene ring. , And each other represents a pair of hydrogen atoms. )
An optically active phosphorane compound represented by any one of the following:

  Second: A method for producing an optically active phosphorane compound represented by the above formula (1), wherein the following formula (3)

（式中のＲ ² 〜Ｒ ⁶ は前記のものを示す。）
で表わされるアミンと反応させる工程と、アミンとの反応により得られたボラン錯体を脱ボラン化する工程とを含むことを特徴とする光学活性なホスホラン化合物の製造方法。 (Wherein R ¹ represents the same as above, and X represents a hydroxyl group or a halogen atom)
A borane complex of optically active phosphoranecarboxylic acids represented by

(In the formula, R ^{2 to} R ⁶ are as defined above.)
A process for producing an optically active phosphorane compound, comprising a step of reacting with an amine represented by the formula: and a step of deborating a borane complex obtained by the reaction with an amine.

  Third: A method for producing an optically active phosphorane compound represented by the above formula (2), wherein the following formula (3)

(In the formula, R ¹ and X are as defined above.)
A borane complex of an optically active phospholane carboxylic acid represented by the following formula: HNR ² R ³
(Wherein R ² and R ³ are as defined above.)
The following formula (4) obtained by reacting with an amine represented by the formula

（式中のＲ ² 〜Ｒ ⁶ は前記のものを示す。）
で表わされるアミンと反応させ得られた次式（４）

（式中のＲ ¹ 〜Ｒ ⁶ は前記のものを示す。）
で表わされるボラン錯体のカルボニル基を還元する工程と、これにより得られたボラン錯体を脱ボラン化する工程とを含むことを特徴とする光学活性なホスホラン化合物の製造方法。 (Wherein R ¹ represents the same as above, and X represents a hydroxyl group or a halogen atom)
A borane complex of optically active phosphoranecarboxylic acids represented by

(In the formula, R ^{2 to} R ⁶ are as defined above.)
The following formula (4) obtained by reacting with an amine represented by the formula

(In the formula, R ^{1 to} R ⁶ are as defined above.)
A process for reducing the carbonyl group of the borane complex represented by formula (1), and a process for deboraneating the borane complex obtained thereby.

  Fourth: A ligand for asymmetric reaction which is the above-mentioned optically active phosphorane compound.

  5th: An asymmetric reaction method in which the above optically active phosphorane compound is present in the reaction system as an asymmetric ligand.

  Sixth: The above asymmetric reaction method, which is a palladium-catalyzed asymmetric allylation reaction.

  According to the invention of this application as described above, an asymmetric ligand that enables an asymmetric reaction to be carried out with high reaction yield and selectivity is provided, and a nitrogen atom together with a phosphorus atom as an asymmetric source is provided. As a new P, N-type asymmetric ligand with attention paid to the above, it is effectively used in the asymmetric reaction method.

  The present invention has the features as described above, and an embodiment thereof will be described below.

In the optically active phosphorane compound of the present invention represented by any one of the above formulas (1) and (2), the symbol R ¹ is an aryl group having 6 to 14 carbon atoms, and R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are bonded to each other to form a benzene ring, and each of the others represents a pair of hydrogen atoms.

The aryl group as R ¹ may be monocyclic or polycyclic such as a phenyl group, a naphthyl group , a biphenyl group, and an anthranyl group .

（式中のＲ ² 〜Ｒ ⁶ は前記のものを示す。）
で表わされるアミンを反応させて式（１）のホスホラン化合物を導くことや、上記アミンとの反応により生成する式（４）の反応中間体を経由して、このものを還元することで製造することができる。 With respect to the phosphorane compounds (1) and (2) as described above of the present invention, for example, in accordance with the method of Examples described later, a borane complex of a phosphoranecarboxylic acid represented by the formula (3) is used as a starting material. Next formula

(In the formula, R ^{2 to} R ⁶ are as defined above.)
To produce a phosphorane compound of formula (1) by reacting with an amine represented by formula (1), or by reducing this through a reaction intermediate of formula (4) generated by reaction with the amine. be able to.

  In addition, about the borane complex of the phospholane carboxylic acid represented by Formula (3) as said reaction starting material, according to the method (Nonpatent literature 5, Patent literature 1) which this inventor has already developed, for example, Next formula

It can be prepared by introducing a carboxyl group by reacting a 1-aryl (R ¹ ) phosphorane borane complex represented by the following formula with carbon dioxide (CO ₂ ).

  The optically active phosphorane compound of the present invention is used as a ligand for asymmetric reaction. It is a ligand for catalytic asymmetric reactions.

  The asymmetric reaction to be applied may be various, for example, an asymmetric ligand for an asymmetric allylation reaction using a palladium catalyst as exemplified in the examples described later. The palladium-catalyzed allylation reaction is a method known from literature (for example, Chem. Rev., 1996, 96, 395; Catalytic Asymmetric Synthesis, 2nd, ed, 2000).

  Therefore, an example will be shown below and will be described in more detail. Of course, the invention is not limited by the following examples.

<Example 1>
The following reaction formula

(1R, 2S) -1-phenylphosphorane-2-carboxylic acid-borane complex (222.1 mg, 1.0 mmol) and 1,2, To a solution of 3,4-tetrahydroisoquinoline (199.8 mg, 1.5 mmol) in methylene chloride (5 mL) was cooled to 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC) (EDC) ( 287.6 mg, 1.5 mmol) was added little by little, and the mixture was stirred for 4 hours under ice cooling. Water and methylene chloride were added to stop the reaction, and the organic phase and the aqueous phase were separated. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the solution under reduced pressure is purified by silica gel column chromatography to obtain (1R, 2R) -1-phenylphosphorane-2-carboxylic acid-1, which is a cis form. 2,3,4-tetrahydroisoquinolinamide-borane complex (14.5 mg, 4% yield) and trans form (1R, 2S) -1-phenylphosphorane-2-carboxylic acid-1,2,3,4 -Tetrahydroisoquinolinamide-borane complex (275.5 mg, 82% yield) was obtained. The resulting (1R, 2R) -1-phenylphosphorane-2-carboxylic acid-1,2,3,4-tetrahydroisoquinolinamide-borane complex and (1R, 2S) -1-phenylphosphorane-2-carboxylic acid The acid-1,2,3,4-tetrahydroisoquinolinamide-borane complex was a mixture of its rotamers.

Under the same reaction conditions, from (1R, 2R) -1-phenylphosphorane-2-carboxylic acid-borane complex (222.1 mg, 1.0 mmol), (1R, 2S) -1-phenylphosphorane-2-carboxylic acid- A 1,2,3,4-tetrahydroisoquinolinamide-borane complex was synthesized. (1R, 2R) -1-phenylphosphorane-2-carboxylic acid-1,2,3,4-tetrahydroisoquinolinamide-borane complex (258.4 mg, 77% yield), (1R, 2S) -1-phenyl Phosphorane-2-carboxylic acid-1,2,3,4-tetrahydroisoquinolinamide-borane complex (8.0 mg, 2% yield)
The physical property values are as follows.
(1R, 2S) -body: viscous colorless oil; 1H-NMR (600 MHz, CDCl3) d 0.71 (3H, J = 149.8 Hz), 2.11-6.39 (13H, m), 7.03-7.86 (9H, m); 13C-NMR (150 MHz, CDCl3) d 25.76 (d, J = 4.3 Hz), 28.22 (d, J = 7.2 Hz), 28.45, 28.50, 29.43, 31.67 (d, J = 4.3 Hz), 31.73 (d, J = 4.3 Hz), 40.31, 43.35, 43.54, 44.19, 44.36, 44.87, 47.79, 125.70, 125.97, 126.41, 126.54, 126.68, 126.72, 127.91, 128.82, 129.22, 129.29, 130.68 (d, J = 17.2 Hz), 130.96 (d, J = 17.2 Hz), 131.67, 131.73, 131.81, 131.87, 131.93, 133.28, 133.96, 135.15, 167.57, 168.06; 31P-NMR (243 MHz, CDCl3) d 39.40 (d, J = 46.0 Hz), 41.54 (d, J = 46.0 Hz); IR (KBr) 2938, 2381, 1642, 1434 cm-1; MS (ESI) m / z 360 (M + Na +); Anal.Calcd for C20H25BNOP: C, 71.24; H , 7.47; N, 4.15; Found: C, 71.20; H, 7.56; N, 4.08.
(1R, 2R) -body: colorless prism; mp 75.7-76.9 oC; 1H-NMR (600 MHz, CDCl3) d 1.00 (3H, J = 111 Hz), 1.73-4.78 (13H, m), 6.86-7.76 ( 9H, m); 13C-NMR (150 MHz, CDCl3) d 26.56, 26.73, 27.12, 27.38, 27.66, 27.68, 29.16, 31.28, 31.54, 39.85, 43.26, 43.34, 43.48, 43.65, 44.39, 47.04, 125.41 (d , J = 44.5 Hz), 126.23 (d, J = 44.5 Hz), 126.19, 126.30, 126.45, 128.00, 128.10 (d, J = 10.1 Hz), 128.32 (d, J = 10.1 Hz), 128.57, 131.53, 131.89 , 132.08, 132.68, 132.81, 132.87, 132.92, 133.96, 134.32, 167.15 (d, J = 4.3 Hz), 167.69 (d, J = 4.3 Hz); 31P-NMR (243 MHz, CDCl3) d 37.37 (d, J = 72.4 Hz), 37.67 (d, J = 72.4 Hz); IR (KBr) 3051, 2938, 2394, 2360, 2332, 1641, 1497, 1433 cm ^-1 ; MS (ESI) m / z 360 (M + Na + ); Anal.Calcd for C20H25BNOP: C, 71.24; H, 7.47; N, 4.15; Found: C, 71.12; H, 7.62; N, 4.06.
Further, the (1R, 2S) -1-phenylphosphorane-2-carboxylic acid-1,2,3,4-tetrahydroisoquinolinamide derivative-borane complex synthesized above was treated with diethylamine to give (1R, 2S) A -1-phenylphosphorane-2-carboxylic acid-1,2,3,4-tetrahydroisoquinolinamide derivative was obtained. Similarly, (1R, 2R) -1-phenylphosphorane-2-carboxylic acid-1,2,3,4-tetrahydroisoquinolinamide derivative-borane complex was treated with diethylamine to give (1R, 2R) -1- Phenylphosphorane-2-carboxylic acid-1,2,3,4-tetrahydroisoquinolinamide derivative was obtained.
<Example 2>
The following reaction formula

  (1R, 2S) -phenylphosphorane-carboxylic acid amide derivative-borane complex (160.8 mg, 0.48 mmol) synthesized in Example 1 in THF (5 mL) solution and borane in THF solution (1.0 M, 4.7 mL) , 4.7 mmol) was added dropwise, followed by stirring at 40 ° C. for 14 hours. After cooling to room temperature, water and methylene chloride were added to stop the reaction, and the organic phase and the aqueous phase were separated. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the solution under reduced pressure is purified by silica gel column chromatography, whereby the (1R, 2S) -1-phenylphosphoran-2-amine derivative-borane complex is converted into a rotational isomer. And 82.6 mg was obtained as a mixture of N-borane complex and non-N-borane complex.

  Subsequently, the obtained (1R, 2S) -phenylphosphorane-amine derivative-borane complex was dissolved in diethylamine (1.2 mL) and stirred at 45 ° C. for 5 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography to obtain (1R, 2S) -phenylphosphoran-amine derivative (45.7 mg, 0.18 mmol, yield 39% (2 Step)) was obtained as a white solid.

Under the same reaction conditions, (1R, 2R) -phenylphosphorane-amine derivative was synthesized from (1R, 2R) -phenylphosphorane-carboxylic acid amide derivative-borane complex (221.7 mg, 0.66 mmol). (1R, 2R) -Phenylphosphorane-amine derivative (87.2 mg, 0.28 mmol, 43% yield (2 steps))
The physical properties of the product are as follows.
(1R, 2S) -body: colorless oil; [a] 20D -52.3o (c 1.0, EtOH); 1H-NMR (400 MHz, CDCl3) d 1.46-1.56 (1H, m), 1.73-1.85 (1H, m), 1.87-2.11 (4H, m), 2.52-2.61 (1H, m), 2.67-2.89 (6H, m), 3.62 (1H, d, J = 15.1 Hz), 3.74 (14.7 Hz), 6.97- 7.14 (4H, m), 7.22-7.30 (3H, m), 7.44-7.48 (2H, m); 13C-NMR (100 MHz, CDCl3) d 26.03 (d, J = 11.4 Hz), 27.88 (d, J = 2.9 Hz), 28.91, 33.35, 42.99 (d, J = 10.49 Hz), 50.83, 56.32, 62.68 (d, J = 36.2 Hz), 126.02, 126.56, 127.50, 128.28 (d, J = 5.9 Hz), 128.59 , 130.73, 130.89, 134.44, 141.84 (d, J = 21.9 Hz); 31P-NMR (243 MHz, CDCl3) d 4.18; IR (neat) 3068, 2929, 2795, 1585, 1497, 1430, 1372, 1193, 740 cm-1; HRMS (ESI) calcd for C11H13O2P (M + H +) 310.1719, Found 310.1718.
(1R, 2R) -body: white solid; mp 64.1-64.2 oC; [a] 20D -113.6o (c 0.60, EtOH); 1H-NMR (600 MHz, CDCl3) d 1.36-1.41 (1H, m), 1.72-1.76 (1H, m), 1.96-2.38 (7H, m), 2.55-2.66 (2H, m), 2.88 (2H, m), 3.43 (1H, d, J = 14.4 Hz), 3.61 (1H, d, J = 15.1 Hz), 6.98-7.31 (7H, m), 7.51 (2H, m); 13C-NMR (100 MHz, CDCl3) d 23.03 (d, J = 11.4 Hz), 26.37 (d, J = 2.9 Hz), 28.82, 31.85 (d, J = 4.3 Hz), 40.36 (d, J = 12.4 Hz), 50.67, 55.83, 58.30, 125.58, 126.05, 126.56, 127.72 (d, J = 6.7 Hz), 128.44, 128.57, 133.84, 134.02, 134.34, 136 .; 31P-NMR (162 MHz, CDCl3) d 9.82; IR (KBr) 3064, 2935, 2861, 2786, 2753, 1425, 1375, 744 cm-1 ,; HRMS (ESI) calcd for C11H13O2P (M + H +) 310.1719, Found 310.1706.
<Example 3>
The following reaction formula

Then, an asymmetric allylation reaction of diethyl malonate using a palladium catalyst was carried out. As the asymmetric ligand, optically active phosphorane compounds (1R, 2S) -10 and (1R, 2R) -10 were used at a ratio of 4 mol%, respectively. As a result, in the case of ligand (1R, 2S) -10, an optically active allylation reaction product was obtained in a 96% yield and 45% ee. On the other hand, in the case of the ligand (1R, 2R) -10, it was obtained with a high yield and selectivity of 97% yield and 94% ee.

In the case of the (1R, 2R) -10 ligand, it was confirmed that the reaction yield and selectivity were better when the amount used was at least twice that of the palladium catalyst.

Claims (6)

The following formula (1) (2)

(In the formula, R ¹ represents an aryl group having 6 to 14 carbon atoms, and R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are any two of these adjacent to each other bonded to each other to form a benzene ring. , And each other represents a pair of hydrogen atoms. )
An optically active phosphorane compound represented by any one of the following: A method for producing an optically active phosphorane compound represented by the formula (1) of claim 1, wherein the formula (3)

(Wherein R ¹ represents the same as above, and X represents a hydroxyl group or a halogen atom)
A borane complex of optically active phosphoranecarboxylic acids represented by

(In the formula, R ^{2 to} R ⁶ are as defined above.)
A process for producing an optically active phosphorane compound, comprising a step of reacting with an amine represented by the formula: and a step of deborating a borane complex obtained by the reaction with an amine. A method for producing an optically active phosphorane compound represented by the formula (2) of claim 1, wherein the formula (3)

( Wherein R ¹ represents the same as above, and X represents a hydroxyl group or a halogen atom)
A borane complex of optically active phosphoranecarboxylic acids represented by

(In the formula, R ^{2 to} R ⁶ are as defined above.)
The following formula (4) obtained by reacting with an amine represented by the formula

(In the formula, R ^{1 to} R ⁶ are as defined above.)
A process for reducing the carbonyl group of the borane complex represented by formula (1), and a process for deboraneating the borane complex obtained thereby.   A ligand for an asymmetric reaction, which is the optically active phosphorane compound according to claim 1.   An asymmetric reaction method, wherein the optically active phosphorane compound of claim 1 is present as an asymmetric ligand in a reaction system.   6. The asymmetric reaction method according to claim 5, which is a palladium-catalyzed asymmetric allylation reaction.