JP2002145842A - Optically active cobalt (ii), cobalt (iii) complex and production complex thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a cobalt (II) complex and a cobalt (III) complex useful as a catalyst for obtaining high asymmetric yield and a β-ketoimine compound for producing these complexes and a salen compound. SOLUTION: This optically active (II) complex is represented by the following formula (1) or (1') [R1 and R2 may be same or different and each represent hydrogen atom, a straight-chain or branched alkyl group, a straight-chain or branched alkenyl group, a straight-chain or branched aryl group, acyl group or alkoxycarbonyl group, an aryloxycabonyl group or aralkyloxycarbonyl group and the above-mentioned alkyl group, alkenyl group, aryl group, acyl group, alkoxycarbonyl group, arhyoxycarbonyl group and aralkyloxycarbonyl group each may have a substituent group and R1 and R2 nay mutually be connected and may form a ring together with a carbon atom to which R1 and R2 are each bonded].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active β-ketoimine compound, an optically active cobalt complex having an optically active salen compound as a ligand, and an optically active alcohol, an optically active amine, an optically active cyclopropane and the like. The present invention relates to an optically active cobalt complex catalyst useful as a catalyst used in the production of a compound.

[0002]

2. Description of the Related Art Hitherto, many asymmetric synthesis reactions using an optically active transition metal complex as a catalyst have been developed and utilized for producing important intermediates such as pharmaceuticals and agricultural chemicals. In particular, since the report was made that a transition metal complex catalyst having an optically active phosphine compound as a ligand was effective for asymmetric hydrogenation, a great deal of research has been carried out, and asymmetric isomerization of olefins using asymmetric catalysts has been carried out. There have been many reports of the use of reactions and asymmetric hydrogenation reactions for industrial production.

On the other hand, in recent years, the development of metal complex catalysts using a tetradentate ligand consisting of two atoms of nitrogen and two atoms of oxygen has been remarkably progressed, and highly practical asymmetric catalysis has been reported. . For example, Japanese Unexamined Patent Publication (Kokai) No. 5-301878 discloses an olefin comprising an optically active manganese complex using a tetradentate ligand called salen type obtained by a condensation reaction of two molecules of a salicylaldehyde derivative and one molecule of an ethylenediamine derivative. Asymmetric epoxidation reaction of JP-A-9-6
No. 7312 discloses the following formula ( 9 ):

[0004]

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An asymmetric cyclopropanation reaction using a cobalt complex represented by a cobalt complex is described in WO 00/09463 in the following formula ( 10 ):

[0006]

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[0007] A synthesis reaction of an optically active epoxide by optical resolution of a racemic epoxide using a cobalt complex typified by, for example, is disclosed.

The asymmetric metal complex catalyst using a tetradentate ligand called β-ketoimine type, which is obtained by a condensation reaction of two molecules of β-diketone derivative and one molecule of ethylenediamine derivative, is disclosed by the present inventors. Have developed various asymmetric reactions. For example, JP-A-6-247
Japanese Patent Application Laid-Open No. 9-1511 discloses a method for producing an optically active epoxide by asymmetric oxygen oxidation of olefins.
No. 43 discloses a method for producing an optically active alcohol by an asymmetric reduction reaction of ketones, and WO 98/39276 discloses a method for producing an optically active amine by an asymmetric reduction reaction of imines, which is disclosed in JP-A-11-246501. The publication discloses a method for producing optically active carboxylic acid amides by asymmetric 1,4-reduction reaction of α, β-unsaturated carboxylic acid amides, and Heterocycles, 5
2 , 1041 (2000) discloses a method for producing an optically active dihydropyran derivative by an asymmetric hetero Diels-Alder reaction.

However, depending on the target reaction or the substrate, the selectivity such as chemoselectivity, diastereoselectivity, and enantioselectivity, and the catalytic efficiency are insufficient. In some cases, it is necessary to make improvements or changes to ions or the like. The present inventors have been studying to develop an optically active cobalt complex catalyst having higher enantioselectivity, and have obtained a β-ketoimine type cobalt complex derived from a sterically bulky diamine, that is, the following formula ( 11 ) [Formula 15]

[0010]

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It has been found that the optically active cobalt complex represented by the formula (1) exhibits high enantioselectivity, and is described in Synlett, 1996 ,
1076 (1996). However, this complex is unsuitable for a substrate whose reaction point is sterically bulky in the vicinity, and in some cases, there remains a problem that the asymmetric reduction reaction does not proceed at all. As a result of further study, the following formula ( 3a ) or ( 3a ' ) [Formula 16]

[0012]

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It has been found that the optically active cobalt (II) complex represented by the formula is effective for various substrates. That is, it was revealed that this complex has high performance as a catalyst for asymmetric cyclopropanation reaction and asymmetric borohydride reduction reaction, and shows high steric (enantio- and diastereo-) selectivity in these reactions. . These results are disclosed in Japanese Patent Application Nos. 11-163426 and 2000
-70712, and Chem. Lett., 1999 , 1345 (1
999), Synlett, 2000 , 535 (2000).

However, the optically active diamine which is an asymmetric source of the above complex, ie, the following formula ( 12 ) or ( 1 )
2 ' ) [Formula 17]

[0015]

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With respect to the optically active 1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine represented by the following formula, an example used as a raw material of a manganese complex for an asymmetric oxidation reaction is shown. Ph.D. dissertation by Zhang, Wei, University of Illinois, USA
D. thesis, University of Illinois, 1991), but the absolute structure (absolute configuration) was not disclosed. For this reason, it is not only difficult to systematically develop a catalyst using this diamine as an asymmetric source, but also in the synthesis of a drug that requires only one enantiomer having high physiological activity, However, there is a problem that the absolute structure of the catalyst is not known, resulting in significant inconvenience in production control.

[0017]

As described above, as a catalyst for an asymmetric reduction reaction and an asymmetric cyclopropanation reaction,
It is desired to provide a complex having high selectivity for various substrates, and together with clarifying the absolute structure of the catalyst,
There is a strong demand for easy management in manufacturing. An object of the present invention is to satisfy these needs.

[0018]

In order to solve the above-mentioned problems, the present inventors have developed an optically active transformer as an asymmetric source.
Intensive studies have been conducted using a tetradentate cobalt complex having -1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine as a catalyst. As a result, the optically active N, N'-bis (2-
Acetyl-3-oxobutylidene) -1,2-bis (2,4,6-trimethylphenyl) ethylenediaminatocobalt bromide (I
II) The X-ray structure analysis of the complex reveals the optically active 1,2-bis (2,
After clarifying the absolute structure of 4,6-trimethylphenyl) -1,2-ethanediamine, the optically active N, N′-bis (2-acetyl-3-oxobutylidene) -1,2-bis (2, 4,6-trimethylphenyl) ethylenediamine and optically active N, N '
Asymmetric borohydride reduction reaction and asymmetric cyclopropanation reaction using cobalt complex catalysts containing tetradentate ligands such as -bis (salicylidene) -1,2-bis (2,4,6-trimethylphenyl) ethylenediamine And found that the present invention was effective.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The optically active cobalt (II) complex of the present invention has the following general formula ( 1 ) or ( 1 ′ ):

[0020]

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[In the formula, R ¹ and R ² may be the same or different and each represents a hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, a linear or branched aryl group. A group, an acyl group or an alkoxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group, wherein the alkyl group, alkenyl group, aryl group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group and aralkyloxycarbonyl group are And R ¹
And R ² may be linked to each other to form a ring in cooperation with the carbon atom to which R ¹ and R ² are each bonded. ]
It is represented by

The alkyl groups for R ¹ and R ² include a methyl group, an ethyl group, an isopropyl group, a tert-butyl group,
Typical examples include a sec-butyl group, an n-propyl group, and an n-butyl group.

The aryl group includes a phenyl group, a p-methoxyphenyl group, a p-chlorophenyl group, a p-fluorophenyl group, a 3,5-dimethylphenyl group, a 3,5-dimethoxyphenyl group, a 2,4,6- A substituted or unsubstituted aromatic hydrocarbon group such as a trimethylphenyl group or a naphthyl group; a furyl group,
Substituted or unsubstituted aromatic groups such as thienyl group, pyridyl group, pyrrolyl group, oxazolyl group, isoxazole group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, pyrimidyl group, pyridazinyl group, pyraridinyl group, quinolyl group, isoquinolyl group Heterocyclic groups are representative.

Examples of the acyl group include aliphatic acyl groups such as acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, and pivaloyl; benzoyl, 3,5-dimethylbenzoyl, 2,4,6 -Trimethylbenzoyl group, 2,6-dimethoxybenzoyl group, 2,4,6-trimethoxybenzoyl group, 2,6-diisopropoxybenzoyl group, 1-naphthylcarbonyl group, 2-naphthylcarbonyl group, 9-anthryl Aromatic acyl groups such as a carbonyl group are typical, and typical examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group,
-Butoxycarbonyl group, n-octyloxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cyclooctyloxycarbonyl group, tert-butoxycarbonyl group, and a typical example of the aryloxycarbonyl group is a phenoxycarbonyl group. And a benzyloxycarbonyl group, a phenethyloxycarbonyl group and the like are typical examples of the aralkyloxycarbonyl group.

R ¹ and R ² are linked to each other to form R 1
¹ and R ² may form a ring together with the carbon atom to which they are attached. For example, when R ¹ and R ² are linked together to form-(CH ₂ ) ₄ -or -CH = CH-CH = CH-, a cyclohexane ring or a benzene ring is formed, respectively. Rings such as cyclohexane ring and benzene ring are, for example, alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, sec-butyl group and tert-butyl group; aryl groups such as phenyl group and naphthyl group. An alkyloxy group such as a methoxy group, an ethoxy group, and an isopropyloxy group; an aryloxy group such as a phenoxy group and a 2,6-dimethylphenoxy group; a benzyloxy group;
An aralkyloxy group such as a phenethyloxy group; fluorine,
A halogen atom such as chlorine or bromine; a cyano group; a nitro group, which may be substituted with one or more substituents, and the benzene ring is condensed to form a condensed polycyclic ring such as a naphthalene ring. You may.

As specific examples of the optically active cobalt (II) complex represented by the general formula ( 1 ) or ( 1 ' ), the following formulas ( 3a ) to ( 3f ), ( 6a ) to ( 6j ) ( 1
9] to [Formula 22]), their enantiomers, and the like.

[0027]

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[0028]

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[0029]

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[0030]

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The optically active cobalt (II) of the present invention
I) The complex is represented by the following general formula ( 2 ) or ( 2 ′ )
3]

[0032]

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[In the formula, R ¹ and R ² are the same as those in the general formula ( 1 ).
Or (1 ') are as defined for in formula X ^-
Is an anion pair capable of forming a salt. ] Is represented.

The above X^-As F^-, Cl^-, Br^-,
I^-, OH^-, CH_ThreeCO_Two ^-, P-CH_ThreeC ₆H_FourSO_Three ^-, CF
_ThreeSO_Three ^-, PF₆ ^-, BF_Four ^-, BPh_Four ^-, SbF₆ ^-, Cl
O_Four ^-Etc. are typical.

As specific examples of the optically active cobalt (III) complex represented by the above formula ( 2 ) or ( 2 ' ), the following formulas ( 4aA ) to ( 4aH ), ( 7aB ) to ( 7aE )
([Chemical Formula 24] to [Chemical Formula 26]) and their enantiomers.

[0036]

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[0037]

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[0038]

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The optically active cobalt (II) complex represented by the general formula ( 1 ) or ( 1 ′ ) and the optically active cobalt (III) complex represented by the general formula ( 2 ) or ( 2 ′ ) It can be prepared according to a known method. See, for example, Y. Nishida et al., Inorg. Chim. Acta, 38 , 213 (198
0); L. Claisen, Ann. Chem., 297 , 57 (1897); EG
It can be prepared according to the method reported in Jager, Z. Chem., 8 , 30, 392, and 475 (1968).
It is also disclosed in JP-A-151143. For example, the β-ketoimine compound represented by the formula ( 5a ) and the corresponding optically active cobalt (I) represented by the formula ( 3a )
I) The complex and the optically active cobalt (III) complex represented by the formula ( 4aB ) can be prepared according to the steps shown in the following formula ( A ).

[0040]

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In the production of the β-ketoimine type optically active cobalt complex, 3-methoxymethylene-2,4-pentanedione (compound ( 13)
a )) can be prepared, for example, by adding 1 to 5 molar equivalents of trimethyl orthoformate to acetylacetone and heating and refluxing in an acetic anhydride solvent.

The dehydration-condensation reaction with an optically active diamine is carried out by adding 2 equivalents of 3-methoxymethylene-2,4-pentanedione ( 13a ) in an alcohol solvent, stirring the mixture at room temperature for 1 to 2 hours, and then heating at 50 ° C. It can be performed by heating. The crude product obtained by concentration can be purified by a conventional purification method such as silica gel column chromatography, reprecipitation, and recrystallization.

Examples of the basic compound used in the ligand complex formation step include sodium hydroxide, potassium hydroxide and the like. The amount of the basic compound to be used is at least 2.0 molar equivalents to the ligand, and is preferably 2.0 to 2.5 molar equivalents.

Examples of the cobalt cation source include compounds containing divalent ions of cobalt, such as cobalt (II) chloride and cobalt (II) acetate, and these can be used as an aqueous solution. It is sufficient to add 1.0 molar equivalent or more of the cobalt cation to the ligand, and preferably, an amount that gives 1.0 to 1.5 molar equivalent is used.

The complex formation reaction is carried out in an atmosphere of an inert gas such as nitrogen or argon, and degassed water is used for dissolving the base, the cobalt cation and the ligand, and the solvent is used. The reaction proceeds when the reaction temperature is 0 ° C. or higher, but the reaction time can be shortened by heating to about 30 to 80 ° C., and preferably 40 to 60 ° C.

As the solvent, methanol, ethanol,
Alcohol solvents such as 2-propanol are preferred.

In the complex forming step represented by the above formula (A),
Shortly after the addition of the aqueous cobalt (II) chloride solution, 1-10
The cobalt (II) complex starts to precipitate in about a minute, but heating and stirring are further continued for about 30 minutes to 2 hours. Thereafter, the reaction mixture is cooled to room temperature, and water is added as necessary to precipitate a reaction product. Next, the mixture is filtered off under an inert gas such as nitrogen, washed with water or a mixed solution of water-alcohol, and then dried under vacuum to obtain a target optically active cobalt (II) complex.

By adding a halogen such as chlorine, bromine or iodine to the optically active cobalt (II) complex obtained by the above-mentioned method, it can be converted to the corresponding halogenated optically active cobalt (III) complex. . For example, in a dichloromethane solvent, 0.5 mol equivalent of bromine (Br ₂ ) is added to the optically active cobalt (II) complex, reacted at room temperature with stirring, and concentrated to obtain a crude product. This crude product can be purified by purification operations such as silica gel column chromatography, reprecipitation, and recrystallization.

On the other hand, for example, the salen compound represented by the formula ( 8a ), the corresponding optically active cobalt (II) complex represented by the formula ( 6a ), and the optically active compound represented by the formula ( 7aB ) The cobalt (III) complex can be prepared according to the process shown in the following formula ( B ) [Formula 28] in the same manner as in the above formula ( A ).

[0050]

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The salen type optically active cobalt complex is produced by replacing the compound ( 13 ) in the above formula ( A ) with salicylaldehyde (the compound ( 14a ) in the formula ( B )).
Can be produced as a starting material through the same steps.

The above formula ( 3a ) thus obtained is obtained.
Or optically active cobalt (II) represented by ( 6a )
The complex and the optically active cobalt (III) complex represented by the formula ( 4aB ) or ( 7aB ) are both used as a catalyst for an asymmetric borohydride reduction reaction using a ketone or imine as a substrate, or for asymmetric cyclopropanation of an olefin. It is effective as a catalyst for the reaction. In addition, these complexes are very stable in the air, and can be used without problems even if stored for 3 to 5 years as a catalyst.

Particularly, in the case of the cobalt (III) complex, it is stable so that there is no problem even when it is dissolved in a solvent and exposed to water or air. Since it has the characteristics of being stable and easy to handle, it is easy to perform structural analysis using X-rays. That is, the optically active cobalt (III) complex is crystallized in a tetrahydrofuran (THF) -hexane solution to obtain a single crystal capable of X-ray analysis, which can be subjected to X-ray structural analysis. Actually, X-ray analysis is performed using a single crystal of the optically active cobalt (III) complex represented by the formula ( 4aB ) to determine the absolute configuration of the optically active diamine moiety, which has not been clarified until now. Was completed.

Next, the optically active diamine (1,2-bis (2,4,6-trimethylphenyl)-) represented by the above formula ( 12 ), which is used as an asymmetric source of the optically active cobalt complex of the present invention.
A method for synthesizing (1,2-ethanediamine) and a method for determining the absolute configuration of an optically active cobalt (III) complex will be described for reference. Synthesis method of optically active diamine ( 12 ): First, racemic trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-
A method for producing ethanediamine will be described. Racemic trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-
Ethanediamine can be obtained by a process represented by the following formula ( C ) (Method by Pedersen et al .: J. Am. Chem. Soc., 109 , 3).
152 (1987)).

[0055]

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That is, 2,4,6-trimethylbenzaldehyde ( 15 ) was reacted with lithium bis (trimethylsilyl) amide, trimethylsilane chloride was added, stirring was continued, and the salt precipitated by concentration was separated by filtration. The filtrate is distilled off under reduced pressure to obtain silylimine ( 16 ). Next, in the presence of an equimolar amount of a niobium tetrachloride-tetrahydrofuran complex, the silylimine ( 16 ) obtained above is reacted in a 1,2-dimethoxyethane solvent at room temperature and treated with a base to obtain the desired compound. racemic trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine ((±) - 12) are obtained in good yield. Next, optical resolution with optically active mandelic acid is performed to isolate the optically active diamine. That is, when (+)-mandelic acid is used as a resolving agent, (−)-1,2-bis (2,4,6-
Trimethylphenyl) -1,2-ethanediamine,
When (-)-mandelic acid is used, (+)-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine is obtained.

Principle of determining the absolute configuration: If X-ray scattering and absorption occur simultaneously, abnormal X-ray scattering occurs. By utilizing this, the absolute structure of a crystal having no center of symmetry can be determined. Recently, a method of refining a variable x defined by the following equation [Equation 1] as a parameter of the least squares method has been used as a standard.

[Formula 1] The variable x is called a Flack parameter. (Flack, HD,
Acta Cryst. A39 , 876-881 (1983).) If x is close to 0, the absolute structure is correct, but if it is close to 1, the inverted structure is correct. Using these Flack parameters, you can analyze the absolute structure.
When determining the absolute configuration, the Flack parameter x
It is necessary to satisfy two conditions, that is, -0.2 or more and 0.3 or less and its standard deviation is 0.5 or less. In the present invention, the absolute configuration of the complex could be clarified using the Flack parameter. In addition,
To determine the absolute configuration, the Friedel pair (hkl and -h,
-k, -l reflection set) must be measured as much as possible.

[0058]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 Synthesis of 3-methoxymethylene-2,4-pentanedione ( 13a ): 21.6 g (0.216 g) of acetylacetone in a reactor
mol) and 40.0 g (0.377 mol) of trimethyl orthoformate in acetic anhydride (66.0 g, 0.647 mol) were heated at 120 ° C. for 5 hours. After distilling off low-boiling components produced as by-products, distillation under reduced pressure gives 3-methoxymethylene-2,4-pentanedione 29.8 g
Was obtained (96% yield). Boiling point 110-112 ° C / 0.7 mmHg. ¹ H NMR (CDCl ₃ ) δ = 7.63 (1H, s), 4.05 (3H, s), 2.3
8 (3H, s), 2.33 (3H, s); IR 2998, 2946, 2852, 167
8, 1623, 1587, 1388, 1360, 1292, 1134 cm ^-1 .

Example 1 Synthesis of β-ketoimine type ligand ( 5a ): D of sodium
1,2-bis (2,4,6-trimethylphenyl) ethylenediamine 2.96 g (10 mmol) in ethanol solution (60 ml) showing a positive optical rotation with respect to the line Methylene-2,4-pentanedione 2.98 g (21 mmol)
An ethanol solution (40 ml) was added dropwise. After stirring at room temperature for 1 hour, the temperature was raised to 50 ° C., and stirring was continued for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was recrystallized from dichloromethane / ether / hexane, filtered, washed and dried under vacuum to obtain 4.88 g of β-ketoimine type ligand ( 5a ) as a white powder (isolation yield: 95%) . ¹ H NMR (CDCl ₃ ) δ = 1.73 (6H, br), 2.21 (6H, s), 2.
22 (6H, s), 2.46 (6H, s), 2.72 (6H, br), 5.20 (2H,
m), 6.60-6.90 (4H, m), 7.65 (2H, d, J = 12.2 Hz);
Specific rotation [α] _D ²⁷ −186 ° (c 1.02, CHCl ₃ )

Example 2 Synthesis of β-ketoiminatocobalt (II) complex ( 3a ): β-ketoimine type ligand ( 5a ) placed in a reactor 4.
Methanol (140 ml) was added to 1 g (8 mmol), and dissolved by stirring under a nitrogen flow. After stirring for 30 minutes, an aqueous solution (2.8 ml) of sodium hydroxide 0.72 g (18 mmol) was added, and the mixture was added at 50 ° C.
And stirred. After 30 minutes, 2.1 g of cobalt chloride hexahydrate (9
mmol) aqueous solution (3.7 ml) was added dropwise to precipitate a tan precipitate. After further stirring for 30 minutes, the mixture was cooled to room temperature and water was added (40 ml × 2). The reaction solution was filtered under a nitrogen atmosphere, the precipitate was washed with water, and dried by flowing nitrogen. The product was taken out in a nitrogen box, and dried under reduced pressure at 120 ° C. for 2 hours to obtain 4.3 g of a yellow-brown cobalt (II) complex ( 3a ) (93% yield). Melting point 276-282 ℃

Example 3 β-ketoiminate cobalt (III) bromide complex ( 4aB )
Synthesis of β-ketoiminatocobalt (II) complex ( 3
a ) Dichloromethane (23 ml) was added to 1.15 g (2 mmol), and a dichloromethane solution (5 ml) containing 168 mg (1.05 mmol) of bromine was added dropwise under nitrogen flow. After stirring at room temperature for 1 hour, the solvent was distilled off, and purification was performed by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 30/1). After concentrating the fraction containing the target substance, it was further dissolved in a small amount of dichloromethane, and hexane was added, whereby a brown precipitate was obtained. By performing filtration, washing and drying operations, 1.17 g of the target cobalt (III) bromide complex ( 4aB ) was recovered (yield 90%).

(Example 4) (-) _D -β-ketiminato cobalt (III) bromide complex ( 4aB ) (N, N'-bis (2-acetyl-2-butenediyl-3-orato) -1,2 -Bis (2,4,6-trimethylphenyl) ethylenediamine-cobalt bromide (II
I)) Determination of absolute configuration by X-ray crystal structure analysis

X-ray structure analysis: For X-ray structure analysis, N, N'-bis (2-acetyl-2-butenediyl-3-orato) -1,2-bis () represented by the above formula ( 4aB ) was used. 2,4,6-trimethylphenyl) ethylenediamine-cobalt (III) bromide complex,
Alternatively, among its enantiomers, a negative optical rotation ([α] _D ²⁷ = -1440 ° (c 0.022, T
HF)). The single crystal used for the analysis was prepared by adding a small amount of hexane to a THF (tetrahydrofuran) solution of the complex and diffusing it. The obtained brown columnar crystals (0.5 × 0.3 × 0.1 mm) were sealed in a capillary together with the mother liquor, and placed on a 4-axis X-ray diffractometer Rigaku AFC-7R. Using MoKα (wavelength λ = 0.71073Å) as the source, 2
θ _{m ax} = 55 ° to + h, + k, measurement of X-ray diffraction intensity of the reflection of ± l. In addition, for the region of 2θ ≦ 40 °, + h, −k, ±
l reflection measurements were also made. A total of 12278 reflections were measured and 11
744 independent reflections were obtained. This includes 3169 Friedel pairs. The crystallographic data is shown in Table 1 [Table 1].

[0065]

[Table 1]

The structure was solved using the direct method. Two independent molecules of THF were included as a crystallization solvent, but the non-hydrogen atoms of THF were analyzed using the isotropic temperature factor because the atomic displacement parameter was very large, and the CC and CO bond distances were reasonable values. Tied up. The assignment of oxygen atoms in THF was judged from the fact that if it was a carbon atom, an unusually short distance between H and H would occur between adjacent complexes. The hydrogen position of the coordinated water molecule was idealized by calculation (assuming sp ² hybridization) based on the peak of D synthesis.
Other hydrogen atoms were introduced and fixed by geometric calculation. The hydrogen temperature factor U _iso (H) was fixed at 1.2 times the equivalent isotropic temperature factor U _eq of the non-hydrogen atom to which it was bonded. The crystal structure is a structure with an approximate symmetry center (space group is pseudo P2 ₁ /
c), the correlation between the atomic parameters is strong, and the least squares method (SHELXL97; Sheldrick, GM, Program for
the Refinement of Crystal Structure, University of
Goettingen, Germany, 1997).
Non-positive or abnormal value of anisotropic temperature factor (max / min AD
In order to avoid P becoming 4 or more), an isotropic temperature factor was used for 6 more non-hydrogen atoms (O8, O13, C31, C63, C71, C72 atoms). The absorption correction was performed by numerical integration of the polyhedron (the transmission factor T ranged from 0.619 to 0.854).
There was no effect of the extinction effect.

The number of refined parameters is 749 for the number of reflections 11744 used for refinement. R (F) = 0.064, wR (F ² ) = 0.1
86, S = 1.035, (Δ / σ) _max = 0.020, Δρ _max = 0.70 e
Å ^-3 , Δρ _min = -0.60 eÅ ^-3 , Flack parameter is 0.
04 (2).

From the above results, the structure of this complex was clarified as follows. Although there are two independent cobalt complexes (FIGS. 1 and 2) in the crystal, the molecular structure including the absolute configuration is essentially the same, as shown in FIG. Flack's parameter (0.04 (2)) is in the normal range (-0.2 <x <0.3 and standard deviation <0.5), and its standard deviation is small enough. The accuracy of structural analysis has also reached the standard level (R = 0.064). Therefore, for this complex that exhibits a negative optical rotation for the sodium D line, the absolute configuration of the ligand around the asymmetric carbon atom is (R, R)
Was clearly determined.

From this, the absolute configuration of the corresponding optically active ligand and the corresponding optically active diamine, which had not been clarified, was determined. As shown in Table 2, the optical rotation was shown. Could be linked to degrees.

[0070]

[Table 2]

Example 5 Synthesis of Optically Active Cobalt (III) Complex ( 4aF ): Optically active cobalt (II) bromide (II) represented by the above formula ( 4aB )
I) Dichloromethane (15 ml) was added to 327 mg (0.501 mmol) of the complex.
And shield the flask from light with silver paper. After confirming that the complex was dissolved, the silver (I) hexafluorophosphate 210 m
g (0.862 mmol, 1.66 equivalents) and stir for 90 minutes.
Thereafter, the formed precipitate was separated by filtration and washed with dichloromethane. The filtrate is concentrated, the residue is dissolved in a minimum amount of dichloromethane, and this solution is added to a large amount of hexane to reprecipitate and purify the optically active cobalt (II) represented by the formula ( 4aF ).
I) A complex (327 mg of a light brown solid, yield 91%) was obtained.

Example 6 Synthesis of salen-type ligand ( 8a ): 296 mg of 1,2-bis (2,4,6-trimethylphenyl) ethylenediamine showing a positive optical rotation for sodium D line A solution of salicylaldehyde (244 mg, 2 mmol) in ethanol (6 ml) was added dropwise with stirring to a solution of ethanol (1 mmol) in ethanol (6 ml) at room temperature. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was recrystallized from dichloromethane / ether / hexane, filtered, washed and dried under vacuum to obtain 485 mg of a salen-type ligand ( 8a ) as a pale yellow powder (isolation yield: 96%). ¹ H NMR (CDCl ₃ ) δ = 1.85 (6H, s), 2.20 (6H, s), 2.6
6 (6H, s), 5.65 (2H, s), 6.63-7.27 (12H, m), 8.40
(2H, s), 13.16 (2H, s); specific rotation [α] _D ²⁷ + 214 °
(c 0.60, CHCl ₃ )

Example 7 Synthesis of Salen Cobalt (II) Complex ( 6a ): Methanol (30 ml) was added to 404 mg (0.8 mmol) of salen type ligand ( 8a ) placed in a reactor, and the mixture was allowed to flow under nitrogen. To dissolve. After stirring for 30 minutes, sodium hydroxide 80 mg (2.0 m
mol) aqueous solution (0.4 ml) and stirred at 60 ° C. After 30 minutes, 228 mg (0.96 mmol) aqueous solution of cobalt chloride hexahydrate
(0.6 ml) was added dropwise to precipitate a brown precipitate. After stirring for another 30 minutes, it was cooled to room temperature and water was added (10 ml). The reaction solution was filtered under a nitrogen atmosphere, the precipitate was washed with water, and dried by flowing nitrogen. The product was taken out in a nitrogen box and dried under reduced pressure at 120 ° C. for 2 hours to obtain 451 mg of a light brown cobalt (II) complex ( 6a ) (yield).
> 99%).

Reference Example 2 Asymmetric reduction reaction using an optically active cobalt (II) complex catalyst ( 3a ): sodium borohydride 28 mg (0.75 mmo)
l) in a chloroform suspension (22 ml) under a nitrogen atmosphere under -20.
0.13 ml (2.25 mmol) of ethanol and then 1.0 ml (10.5 mmol) of tetrahydrofurfuryl alcohol were added dropwise at ℃, and the mixture was stirred for 15 minutes to prepare a modified borohydride reducing agent. This reducing agent solution is represented by the above formula ( 3a ).
Optically active cobalt (I) having the absolute configuration of (R, R)
I) A solution of 1.4 mg (0.0025 mmol) of the complex in chloroform (4
ml) and a chloroform solution (4 ml) of 56 mg (0.25 mmol) of dibenzoylmethane were added dropwise, and the mixture was reacted at -20 ° C for 40 hours. The reaction was stopped by adding a phosphate buffer, and the product was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Filter the solution,
The solvent was distilled off under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography to give 1,3-diphenyl-1,3-propanediol quantitatively (57 mg).
The optical purity of this product is determined by high performance liquid chromatography.
(Optically active column: Daicel Chemical Industries, CHIRALPAK A
D; Ethanol 1.2% in Hexane, flow rate 1.0 ml / min, retention time 32.4 min, 52.9 min), it was 98% ee. The dl / meso ratio was found to be 84/16 from the ¹ H NMR integrated value of the derivative obtained by acetylating the hydroxyl group of the product. The absolute configuration of the product was found to be (R, R) by comparison of the optical rotation with literature values.

(Comparative Example 1) The same procedure as in Reference Example 2 was carried out except that the cobalt (II) complex ( 17 ) shown below was used instead of the cobalt (II) complex catalyst ( 3a ). The reaction was carried out in the same manner as in Example 2. as a result,
Although the desired product was obtained quantitatively, the dl / meso ratio of the product was 29/71, and the optical yield of the dl form was 61% ee.

[0076]

Embedded image

Reference Example 3 Asymmetric reduction reaction using an optically active cobalt (III) complex catalyst ( 4aB ):
I) Instead of the complex catalyst ( 3a ), the cobalt (II)
I) The reaction was carried out in the same manner as in Reference Example 2 except that the complex ( 4aB ) was used. As a result, the desired product was obtained quantitatively, the dl / meso ratio was 82/18, and the optical yield of the dl form was 98% ee.

Reference Example 4 Asymmetric reduction reaction using optically active cobalt (II) complex ( 6a ): In the above-mentioned Reference Example 2, instead of the cobalt (II) complex catalyst ( 3a ), the optically active cobalt (I) was used.
I) The reaction was carried out in the same manner as in Reference Example 2 except that the complex ( 6a ) was used as a catalyst, acetophenone was used instead of dibenzoylmethane, and the reaction temperature was set to 0 ° C. as a result,
The reaction is completed within 1 hour and the desired product is obtained quantitatively.
The optical yield was 84% ee.

(Comparative Examples 2 and 3) In each of the examples, a cobalt (II) complex ( 18 ) or ( 19 ) shown in Table 3 was used instead of the cobalt (II) complex catalyst ( 6a ). The reaction was carried out in the same manner as in Example 4. In Comparative Example 2, the reaction was completed within 1 hour, and the target product was obtained quantitatively. In Comparative Example 3, the reaction was not completed even after 3 hours. The optical purity of the obtained product is shown in Table 3 [Table 3].

[0080]

[Table 3]

(Reference Example 5) In Reference Example 2, the cobalt (II) complex catalyst (R, R)-( 3a ) was added to the substrate.
The reaction was performed for 12 hours in the same manner as in Reference Example 2 except that 2 mol% was used and 2-phenacylpyridine was used instead of dibenzoylmethane. Table 4 [Table 4] shows the yield, optical purity, and absolute configuration of the main enantiomer of the obtained alcohol.

Reference Examples 6 to 8 In each of the examples, instead of the cobalt (II) complex catalyst ( 3a ), the cobalt (II) complexes ( 3c ), ( 3d ), and ( 3d ) shown in Table 4 [Table 4] were used. The reaction was carried out in the same manner as in Reference Example 5, except that 11 ) was used. Table 4 [Table 4] shows the yield, optical purity and absolute configuration of the obtained alcohol.

Comparative Example 4 Instead of the cobalt (II) complex catalyst ( 3a ), cobalt (I) shown in Table 4 was used.
I) The reaction was carried out in the same manner as in Reference Example 5 except that the complex ( 20 ) was used. Table 4 [Table 4] shows the yield and optical purity of the obtained alcohol.

[0084]

[Table 4]

(Reference Example 9) Asymmetric cyclopropanation reaction using optically active cobalt (II) complex catalyst ( 3a ): 29 mg (0.05 mmol) of cobalt (II) complex catalyst ( 3a ) was measured in a reactor, and the reaction was carried out. After replacing the atmosphere in the vessel with a nitrogen gas atmosphere, 1 ml of tetrahydrofuran is added to dissolve the cobalt complex. 2 in advance
Immerse the container in an oil bath adjusted to 5 ° C.
0.57 ml (5.0 mmol) of styrene was added, followed by 148 μl (1.0 mmol) of tert-butyl diazoacetate dropwise, 8 μl (0.1 mmol) of N-methylimidazole was added, and the mixture was stirred at the same reaction temperature for 2 hours. The progress of the reaction was confirmed by gas chromatography analysis, and excess styrene, the complex catalyst and N-methylimidazole were removed by silica gel column chromatography to obtain the product as an oil (174 mg, 80% yield).
The isomer ratio (trans: cis) of the obtained 2-phenylcyclopropylcarboxylic acid tert-butyl ester was 83:17 as a result of analysis by gas chromatography.
The product was separated in trans / cis form by preparative thin-layer chromatography. The optical yield of the trans form is determined by treating with lithium aluminum hydride and producing the reduced form by column chromatography.
The result of analysis by cel OB-H) was 96% ee. The optical yield of the cis form was 91% ee as a result of separation and purification by thin layer chromatography and analysis by high performance liquid chromatography (optically active column: Chiralcel OB-H).

Reference Example 10 Instead of the cobalt (II) complex catalyst ( 3a ), the cobalt (II) complex ( 3
The reaction was carried out in the same manner as in Reference Example 9 except that e ) was used. The obtained 2-phenylcyclopropylcarboxylic acid tert
The yield of -butyl ester was 99%, and the isomer ratio (trans: cis) was 91: 9. The optical yields of the trans form and the cis form were 96% ee and 77% ee, respectively.

[0087]

The optically active cobalt complex of the present invention has excellent catalytic activity and enantioselectivity in asymmetric borohydride reduction reaction and asymmetric cyclopropanation reaction, and has high stability in the air, and is easy to handle. It's easy. Therefore, this optically active cobalt complex and a ligand which is an intermediate for producing the optically active cobalt complex are useful for producing optically active physiologically active compounds such as pharmaceuticals and agricultural chemicals.

[Brief description of the drawings]

FIG. 1 shows an optically active cobalt (I) represented by the formula ( 4aB ).
II) Structural diagram obtained by X-ray structural analysis of the complex.

FIG. 2 is contained in the same crystal as the complex shown in FIG. 1,
ORTEP representing the structure of the other independent cobalt complex
FIG.

FIG. 3 is a schematic diagram of the cobalt complex shown in FIGS. 1 and 2.

FIG. 4 is an a-axis projection view showing an arrangement state of the complexes in the single crystal containing the cobalt complex shown in FIGS. 1 and 2;

FIG. 5 is a b-axis projection view showing an arrangement state of the complexes in the single crystal containing the cobalt complex shown in FIGS. 1 and 2.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 69/753 C07C 69/753 A 251/16 251/16 C07F 15/06 C07F 15/06 // C07B 41 / 02 C07B 41/02 Z 53/00 53/00 B 61/00 300 61/00 300 C07M 7:00 C07M 7:00 F term (reference) 4G069 AA02 BA21A BA21B BA27A BA27B BC67A BC67B BE10A BE10B BE13A BE13B BE37A BE37B BE38A BE38B CB57 4H006 AA01 AB84 4H039 CA60 CB20 4H050 AB40 WB13 WB14 WB21

Claims (12)

[Claims] 1. A compound represented by the following formula ( 1 ) or ( 1 ′ ): Wherein R ¹ and R ² may be the same or different;
A hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, a linear or branched aryl group, an acyl group or an alkoxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group, The alkyl group, alkenyl group, aryl group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group or aralkyloxycarbonyl group may have a substituent, and R ¹ and R ² are mutually linked. , R ¹ and R ² may form a ring together with the carbon atom to which each is attached. ] The optically active cobalt (II) complex represented by these. 2. A compound represented by the following formula ( 2 ) or ( 2 ′ ): [Wherein, R ¹ and R ² are as defined above, and X ⁻ is an anion pair capable of forming a salt. ] The optically active cobalt (III) complex represented by these. 3. The compound represented by the following formula ( 3 ) or ( 3 ′ ): [In the formula, R ³ is a linear or branched alkyl group, aryl group, or alkoxy group, aryloxy group, and the alkyl group, aryl group, alkoxy group, and aryloxy group have a substituent. Is also good. ] The optically active cobalt (II) complex represented by these. 4. The compounds of the following formulas ( 4 ) and ( 4 ′ ): [Wherein, R ³ and X ⁻ are as defined above. ] The optically active cobalt (III) complex represented by these. 5. A compound represented by the following formula ( 3a ) or ( 3a ′ ): An optically active cobalt (II) complex represented by the formula: 6. A compound represented by the following formula ( 4a ) or ( 4a ′ ): [Wherein, X ^- has the same meaning as described above. ] The optically active cobalt (III) complex represented by these. 7. A compound represented by the following formula ( 5a ) or ( 5a ′ ): An optically active β-ketoimine compound represented by 8. A compound represented by the following formula ( 6 ) or ( 6 ′ ): [In the formula, R ⁴ , R ⁵ , R ⁶ , and R ⁷ may be the same or different and are each a hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, a linear or branched or aryl group, an alkoxy group, a cyano group or a nitro group, or a halogen atom, the alkyl group, an alkenyl group, an aryl group, an alkoxy group may have a substituent, and, R ^4, Any two of R ⁷ to R ⁷ may be mutually connected to form a ring together with the carbon atoms to which they are bonded, or may form a condensed ring such as a naphthyl ring. ] The optically active cobalt (II) complex represented by these. 9. A compound represented by the following formula ( 7 ) or ( 7 ′ ): [Wherein, R ⁴ , R ⁵ , R ⁶ , R ⁷ and X ⁻ are as defined above. ] The optically active cobalt (III) complex represented by these. 10. A compound represented by the following formula ( 6a ) or ( 6a ′ ): An optically active cobalt (II) complex represented by the formula: 11. A compound represented by the following formula ( 7a ) or ( 7a ′ ): [Wherein, X ^- has the same meaning as described above. ] The optically active cobalt (III) complex represented by these. 12. A compound represented by the following formula ( 8a ) or ( 8a ′ ): An optically active salen compound represented by the formula: