WO2002038535A1

WO2002038535A1 - Optically active cobalt (ii) or (iii) complexes, process for the preparation thereof and intermediates therefor

Info

Publication number: WO2002038535A1
Application number: PCT/JP2001/003697
Authority: WO
Inventors: Takushi Nagata; Tohru Yamada
Original assignee: Mitsui Chemicals, Inc.
Priority date: 2000-11-10
Filing date: 2001-04-27
Publication date: 2002-05-16
Also published as: JP2002145842A

Abstract

Optically active cobalt (II) complexes represented by the general formulae (1) and (1'): (1) (1') wherein R?1 and R2¿ are each independently hydrogen, linear or branched alkyl, linear or branched alkenyl, aryl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkyloxycarbonyl, these groups being each optionally substituted; or alternatively R?1 and R2¿ together with the carbon atoms to which R?1 and R2¿ are bonded respectively may form a ring.

Description

Specification

Optically active cobalt (Π) and cobalt (III) complexes,

Production method and production intermediate, Technical field

The present invention relates to a method for producing an optically active isomer of an optically active cobalt complex having an optically active ketoimine compound and an optically active salen compound as a ligand, an optically active alcohol, an optically active amine and an optically active cyclopropane. The present invention relates to an optically active cobalt complex catalyst whose absolute structure has been confirmed to be useful as a catalyst used in the production of an optically active compound such as The present invention also relates to an intermediate for producing an optically active cobalt complex. Background art

Many asymmetric synthesis reactions using optically active transition metal complexes as catalysts have been developed so far, and have been used for the production of important intermediates such as pharmaceuticals and agricultural chemicals. In particular, since it was reported that a transition metal complex catalyst having an optically active phosphine compound as a ligand was effective for an asymmetric hydrogenation reaction, a great deal of research has been conducted, There have been many reports of the use of asymmetric isomerization / asymmetric hydrogenation in industrial production.

On the other hand, in recent years, there has been remarkable progress in the development of metal complex catalysts using a tetradentate ligand consisting of two atoms of nitrogen and two atoms of oxygen, and highly practical asymmetric catalysis has been reported. For example, Japanese Unexamined Patent Publication (Kokai) No. 5-301878 discloses that a tetradentate ligand called a salen type obtained by a condensation reaction between two molecules of a salicylaldehyde derivative and one molecule of an ethylenediamine derivative is used. The asymmetric epoxidation reaction of olefins with an optically active manganese complex is described in Japanese Patent Application Laid-Open No.

(13)

The asymmetric cyclopropanation reaction with a cobalt complex represented by the following formula is described in WO 00/09463 as the following formula (Ji)

(14)

And the synthesis reaction of an optically active epoxide by optical resolution of a racemic epoxide using a cobalt complex represented by the formula (1).

Further, the present invention relates to an asymmetric metal complex catalyst obtained by a condensation reaction of two molecules of an S-diketon derivative and one molecule of an ethylenediamine derivative and using a tetradentate ligand called a -ketimine type. Various asymmetric reactions have been developed by the inventors. For example, Japanese Patent Application Laid-Open No. 6-247993 discloses a method for producing an optically active epoxide by asymmetric oxygen oxidation of olefins. Japanese Patent Application Laid-Open No. 9-151143 discloses a method for producing ketones. A method for producing an optically active alcohol by an asymmetric reduction reaction is disclosed in W098 / 39276, and a method for producing an optically active amine by an asymmetric reduction reaction of imines is disclosed in JP-A-11-11.

Japanese Patent No. 246501 discloses asymmetric 1,4-reduction reaction of -unsaturated carboxylic acid amides. Discloses a method for producing an optically active carboxylic acid amide, and Heterocycles, 51, 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, enena selectivity, etc., or the catalytic efficiency is insufficient, and the ligand, metal, It may be necessary to improve or change the counter ion or the like.

The present inventors have been studying to develop an optically active cobalt complex catalyst having a higher enantioselectivity, and have obtained a ketoimine type cobalt complex derived from sterically bulky diamine. (15)

(

It has been found that the optically active cobalt complex represented by the formula (1) exhibits high enantioselectivity and was reported in Synlett, 1996, 1076 (1996). However, this complex is unsuitable for a sterically bulky substrate near the reaction point, and in some cases, the problem remains that the asymmetric reduction reaction does not proceed at all. As a result of further study, the following formula (½) or (½L)

(4a) The optically active cobalt (II) complex represented by (4a,) was found to be effective for various substrates. In other words, it is clear that this ancient form has high performance as a catalyst for asymmetric cyclopropanation reaction and asymmetric porohydride reduction reaction, and shows high steric (enantiomer and diastereo) selectivity in these reactions. Became. These results are reported in Japanese Patent Application Laid-Open No. 2000-355557, Japanese Patent Application No. 2000-70712, and Chew. Lett., 1999, 1345 (1999), Synlett, 20M, 535 (2000). Have been

However, the optically active diamine which is an asymmetric source of the above complex,

(1Q) or

(10) (10

As for the optically active 1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine represented by the following formula, an example of its use as a raw material for a manganese complex for asymmetric oxidation is shown in the University of Illinois in the United States. Ph.D. thesis, University of Zhang, Wei

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 one of the bioactive agents with high bioactivity. In the synthesis of pharmaceuticals that require only the nantiomer, there was a problem that the absolute structure of the catalyst used at the time of synthesis was not known, resulting in significant inconvenience in production control.

, Disclosure of the invention

As described above, it has been desired to provide a complex having high selectivity for various substrates as a catalyst for asymmetric reduction and asymmetric cyclopropanation reactions, and to clarify the absolute structure of the catalyst. There is a strong need for easy management of development, development and manufacturing. An object of the present invention is to satisfy these needs. In order to solve the above problems, the present inventors have proposed an optically active trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine as an asymmetric source. We have been conducting intensive studies using a tetradentate cobalt complex having As a result, the optically active Ν, Ν'-bis (2-acetyl-3-age-isobutylidene) -1,2-bis (2,4,6-trimethylphenyl) ethylenediaminatocobalt (III) complex X-ray structure analysis revealed the absolute structure of optically active 1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine, and this optically active N, N'-bis ( 2-Acetyl-3-year-old oxobutylidene) -1,2-bis (2,4,6-trimethylphenyl) ethylenediamine, and optically active ,, Ν, bis (salicylidene) -1,2-bis (2,4) The present inventors have found that a cobalt complex catalyst containing a tetradentate ligand such as (6,6-trimethylphenyl) ethylenediamine is effective for an asymmetric borohydride reduction reaction and an asymmetric cyclopropanation reaction, and arrived at the present invention. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a structural diagram obtained by an X-ray structural analysis of the optically active cobalt (III) complex represented by the formula.

FIG. 2 is a 0RTEP diagram showing the structure of another independent cobalt complex contained in the same crystal as the complex shown in FIG.

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

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

(D CD

[In the formula, R ¹ and R ² may be the same or different, and represent a hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, a linear or branched aryl group, Or an alkoxycarbonyl group, an aryloxycarboxy group or an aralkyloxycarbonyl group, wherein the alkyl group, alkenyl group, aryl group, acryl group, alkoxycarbonyl group, aryloxycarbonyl group and aralkyl The xycarbonyl group may have a substituent, and R ¹ and R ² are mutually connected to form a ring together with the carbon atom to which R ¹ and R ² are bonded. May be formed. ] Is represented.

Examples of the alkyl group R ¹ and R ^2, a methyl group, Echiru group, an isopropyl group, tert - heptyl group, sec- butyl group, n- propyl group, n - heptyl group and the like as _c Ariru group is a representative Are phenyl, p-methoxyphenyl, P-chlorophenyl, p-fluorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxyphenyl, 2,4,6 -Substituted or unsubstituted aromatic hydrocarbon groups such as trimethylphenyl group and naphthyl group; furyl group, chenyl group, pyridyl group, pyrrolyl group, oxazolyl group, isoxaxol group, thiazolyl group, isothiazolyl group, imidazolyl group, Pyrazo Representative examples include a substituted or unsubstituted aromatic heterocyclic group such as a luyl group, a pyrimidyl group, a pyridazinyl group, a bilaridinyl group, a quinolyl group, and an isoquinolyl group.

Examples of the acetyl group include fatty acetyl group, trifluroylacetyl group, propionyl group, butyryl group, isoptyryl group, and fatty acid 55 ouidosil group such as bivaloyl group; benzoyl group, 3,5-dimethylbenzoyl group, 2,4,6 -Trimethylbenzoyl group, 2,6-dimethoxydibenzoyl group, 2,4,6-trimethoxybenzoyl group, 2,6-diisopropoxybenzoyl group, 1-naphthylcarbonyl group, 2-naphthyl Aromatic acyl groups such as a carbonyl group and a 9-anthrylcarbonyl group are typical, and typical examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-butoxycarbonyl group, n-octyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexylcarbonyl, tert-butoxy Typical examples of aryloxycarbonyl groups include phenoxycarbonyl groups. Typical examples of aralkyloxycarbonyl groups include benzyloxycarbonyl groups and phenethyloxycarbonyl groups. Is mentioned.

R ¹ and R ² may be mutually connected to form a ring in cooperation with the carbon atom to which R ¹ and R ² are respectively bonded. For example, when R ¹ and R ² are interconnected to form — (CH ₂ ) ₄ — or —CH 2 CH—CH = CH—, a cyclohexane ring or a benzene ring is formed, respectively. The cyclohexane ring and benzene ring formed on the alkyl group include, for example, an alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a sec-butyl group and a tert-butyl group; Aryl groups such as benzyl, naphthyl, etc .; alkyl groups such as methoxy, ethoxy, isopropyl, etc .; aryl groups such as phenoxy, 2,6-dimethylphenoxy; benzyl Optionally substituted with one or more substituents selected from aralkyl groups such as methoxy group, phenethyl group and the like; halogen atoms such as fluorine, chlorine and bromine; cyano groups; and nitro groups. The benzene ring is fused It may form a condensed polycyclic ring such as naphthalene ring.

A further preferred embodiment of the optically active cobalt (Π) complex represented by the general formula (丄) or (J 丄) is represented by the following formula (JJ or The following formula (A) or

Wherein R ³ is a linear or branched alkyl group, aryl group, or alkoxy group, aryl group, and the alkyl group, aryl group, alkoxy group, and aryl group have a substituent. May be. ]

Alternatively, the following formula (e) or (i-ii)

[In the formula, R ⁴ , RR ⁶ , and R ⁷ may be the same or different, and represent a hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, a linear or branched If it is an aryl group, an alkoxy group, a cyano group, or a nitro group, or a halogen atom, the alkyl group, alkenyl group, aryl group, and alkoxy group may have a substituent. And any two of R ^{4 to} R ⁷ may be mutually connected to form a ring in cooperation with the carbon atom to which they are bonded, and may form a condensed ring such as a naphthyl ring. Is also good. ]

And an optically active cobalt (II) complex represented by the following formula (4a)

(4i) s (la) to (! I), and their enantiomers.

Further, the optically active cobalt (III) complex of the present invention has the following general formula (2) or (21)

(twenty two

[Wherein, R ¹ and R ² are as defined for the above general formula (1) or 01), wherein X— is a salt-forming anion pair. ] Is represented.

The X- Examples, F -, C 1 \ B r -, Γ, OH -, CH 3 C0 2 -, pC H 3 C 6 H 4 S0 3 -, CF 3 S0 3 \ PF 6 -, BF 4 _ , BP h ₄ _{one, S b F 6 -, C} 1 0 4 Chief is Ru representative and Iota¾.

As a more preferred embodiment of the optically active cobalt (III) complex represented by the formula (2) or (2_2), the following formula () or (D)

(5) (5 :)

[Wherein, R ³ and X— are as defined above. ]

Or the following formula (and) or (8,)

Wherein R ⁴ , RR \ R ⁷ and X— are as defined above. ]

An optically active cobalt (III) complex represented by the following formula.

(And those represented by () to (), and their enantiomers, etc.

An optically active cobalt (Π) complex represented by the general formula a) or oi), and a general formula

The optically active cobalt (II) complex represented by (2) or () can be prepared according to a known method. For example, Y. Nishida et al., Inorg. Chim. Acta, 38, 213 (1980); L. Claisen, Ann. Chem., 222, 57 (1897); EG Jager, Z. Chem., 8, 30, 392, And 475 (1968), which is also disclosed in Japanese Patent Application Laid-Open No. 9-151143.

That is, the following formula (15) or (101)

(Ten)

The optically active diamine represented by (3) or)

(Sa) (3 :)

[Wherein, R ¹ and R ² are as defined above. The optically active intermediate compound represented by the formula is produced, and the optically active intermediate compound is reacted with a compound containing divalent cobalt ion in the presence of a basic compound.

For example, an S-ketoimine compound represented by the formula (Sa), and an optically active cobalt (II) complex represented by the formula Ua), and an optically active cobalt (II) represented by the formula (): III) The complex can be prepared according to the process shown in the following formula (A).

Production process of the ^ -ketomine type optically active cobalt complex To prepare 3-methoxymethylene-2,4-pentanedine (compound () in formula (A)), for example, 1 to 5 molar equivalents of trimethyl orthoformate are added to acetylacetone, It can be carried out by heating and refluxing in an acetic anhydride solvent.

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

Examples of the basic compound used in the ligand complexing step include sodium hydroxide, potassium hydroxide, and the like. The amount of the basic compound used is not less than 2.0 molar equivalents relative to the ligand. Preferably it is 2.0 to 2.5 molar equivalents.

Examples of the source of peritocation include compounds containing divalent ions of \ relet, such as cobalt salt (Π) and cobalt acetate (Π), and these can be used as an aqueous solution. It is sufficient to add 1.0 mole equivalent or more of cobalt to the stake, and preferably an amount of 1.0 to 1.5 mole equivalent is used.

The complex formation reaction is carried out in an atmosphere of an inert gas such as nitrogen or argon, and the base, cobalt cation, water for dissolving the ligand, and the solvent used are degassed. 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., preferably 40 to 60 ° C.

As the solvent, alcohol solvents such as methanol, ethanol, and 2-propanol are preferable.

In the complex formation step represented by the above formula (A), the cobalt (II) complex starts to precipitate in about 1 to 10 minutes shortly after the addition of the aqueous solution of cobalt (II) chloride. Continue for about 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 the desired 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 method, a corresponding halogenated optically active cobalt (II) can be obtained. It can be converted to ruto (III) complex. For example, in a dichloromethane solvent, 0.5 mole equivalent of bromine (Br ₂ ) is added to the optically active conorelet (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, a salen compound represented by the formula (Sa), an optically active cobalt (II) complex represented by the formula (la), and an optically active cobalt (II) represented by the formula () III) The complex can be prepared according to the process represented by the following formula (and) in the same manner as in the formula (A).

Expression (

The production of this salen-type optically active cobalt complex is carried out by using the compound represented by the above formula (A).

A salicylaldehyde (compound 02a) in the formula (and) can be used as a starting material instead of (113), and can be produced through a similar process.

The optically active Koval (II) complex represented by the formula (4a) or (la) and the optically active cobalt (III) complex represented by the formula () or () thus obtained are both It is effective as a catalyst for an asymmetric borohydride reduction reaction using a ketone or imine as a substrate, or as a catalyst for an asymmetric cyclopropanation reaction of birefin. In addition, these complexes are very stable in air, and can be used as catalysts without problems even if they are stored for 3 to 5 years. In particular, in the case of the conoreto (III) complex, it is so stable that there is no problem even when it is dissolved in a solvent and exposed to water or air. Due to its 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 an X-ray-analysable crystal, which can be subjected to X-ray structure analysis. Actually, X-ray analysis was performed using a single crystal of the optically active cobalt (ΠΙ) complex represented by the formula () to determine the absolute configuration of the optically active diamine moiety, which had not been clarified until now. Was completed.

Next, the optically active diamine (1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanol represented by the above formula, which is used as an asymmetric source of the optically active cobalt complex of the present invention. The method for the synthesis of Ndamine and the method for determining the absolute configuration of the optically active cobalt (III) complex are described for reference.

Synthesis method of optically active diamine:

First, the method for producing racemic trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine will be described. Racemic trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine can be prepared by the process shown by the following formula (_QJ (Method by Pedersen et al .: J. Am. Chem. Soc, It can be prepared according to 1Q9, 3152 (1987).

Expression (£)

That is, 2,4,6-trimethylbenzaldehyde is reacted with lithium bis (trimethylsilyl) amide, trimethylsilane chloride is added, stirring is continued, and the salt that is concentrated and precipitated is removed by filtration. When the filtrate is distilled under reduced pressure, silylimine (II) is obtained. Next, in the presence of an equimolar amount of niobium tetrachloride tetrahydrofuran complex,

In 1,2-dimethoxyethane solvent, the silylimine 01) obtained above was reacted at room temperature, By treating with a base, the desired racemic trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine ((Sat)-) is obtained in good yield. . Next, optical resolution with optically active mandelic acid can be performed to isolate optically active diamine. That is, when (+)-mandelic acid is used as a resolving agent, (1)-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine is used, whereas (1-)- When mandelic acid is used, (+)-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine is obtained.

Principle of absolute configuration determination:

When X-ray scattering and absorption occur simultaneously, abnormal X-ray scattering occurs. By using this, the absolute structure of a crystal without a center of symmetry can be determined. Recently, a method of refining a variable X defined by the following equation as a parameter of the least squares method is commonly used.

The variable x is called the parameter of Flack overnight. (Flack, H.D., Acta Cryst.m, 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. If you use this Flack parameter, you can make an absolutely edgy horn. When determining the absolute configuration, two conditions must be satisfied: (1) the parameter X of Flack is -0.2 or more and 0.3 or less, and (2) its standard deviation is 0.5 or less. In the present invention, it was possible to clarify the absolute configuration of the complex using the Flack parameter. In order to determine the absolute configuration, full Riedel pairs (hkl and -h, - - 1 reflection set) must be possible tags measure _c

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

(Reference example 1)

Synthesis of 3-methoxymethylene-2,4-pentanedine 01 ^):

A solution of 21.6 g (0.216 mol) of acetylacetone and 40.0 g (0.377 mol) of trimethyl orthoformate in acetic anhydride (66.0 g, 0.647 mol) in a reactor was heated at 120 ° C for 5 hours. After distilling off the by-product low-boiling components, distillation under reduced pressure yielded 29.8 g of 3-methoxyxylene-2,4-pentanedione (96% yield).

Boiling point 110-112 ° C / 0.7 mmHg ₀

¹ H concealed (CDC1 ₃ ) 0 = 7.63 (1H, s), 4.05 (3H, s), 2.38 (3H, s), 2.33 (3H, s); IR 2998, 2946, 2852, 1678, 1623, 1587, 1388, 1360, 1292, 1134 cm— ¹ . (Example 1)

Synthesis of ^ -ketoimine-type ligand:

Stir in ethanol solution (60 ml) of 2.96 g (10 ol) of 1,2-bis (2,4,6-trimethylphenyl) ethylenediamine, which shows a positive optical rotation for sodium D-line. At the same time, an ethanol solution (40 ml) of 3.98 g (21 mmol) of 3-methoxymethylene-2,4-pentanedine was added dropwise at room temperature. 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; 4.88 g of 8-ketoimine type ligand (fia) was obtained as a white powder (isolation yield: 95 %) o

^{_{] W NMR (CDC1 3) (}} 5 = 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 [] _ΰ ²⁷ _—186 ° (c 1.02, CHC1 ₃ )

(Example 2)

Synthesis of ^ -ketiminate cobalt (II) complex (43):

Methanol (HO ml) was added to 4.1 g (8 mmol) of the -ketoimine-type ligand placed in the reactor, and the mixture was stirred and dissolved under a flow of nitrogen. After stirring for 30 minutes, an aqueous solution (2.8 ml) of 0.72 g (18 mmol) of sodium hydroxide was added, and the mixture was stirred at 50 ° C. 30 minutes later, salt A 2.1 g (9 mL) aqueous solution (3.7 ml) of cobalt chloride hexahydrate was added dropwise, and a yellow-brown precipitate was deposited. After further stirring for 30 minutes, the mixture was cooled to room temperature and water was added (40 ml × 2 times). _{C The} reaction solution was filtered under a nitrogen atmosphere, and 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 (^) (93% yield).

276-282 ° C

(Example 3)

Synthesis of j8-ketiminatocobalt (III) complex ():

; Dichloromouth methane (23 ml) was added to 1.15 g (2 mmol) of 5-ketoiminatokonopereto (II) complex (4a), and a dichloromethane solution containing 168 mg (1.05 mmol) of bromine under nitrogen flow. (5 ml) was added dropwise. 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 2 30/1). After concentrating the fraction containing the desired product, 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 desired cobalt (III) bromide (IIIa) complex (5aB) was recovered (yield 90%).

(Example 4)

(-). -/?-Ketoiminato cobalt bromide (ΙΠ) complex () (Ν, Νbis (2-acetyl-2-butenedyl-3-orato) -1, 2-bis (2,4,6-trimethylphenyl) Determination of absolute configuration of ethylenediamine-cobalt bromide (臭)) by X-ray crystal structure analysis X-ray structure analysis:

In the X-ray structure analysis, Ν, Ν'-bis (2-acetyl-2-butenediyl-3-year-old) -1,2-bis (2,4,6- Trimethylphenyl) Ethylenediamine-cobalt (III) bromide complex, or its enantiomer, shows a negative optical rotation ([HI] = -1440; (c 0.022, THF)) with respect to the sodium D line. Was used. The single crystals used for the analysis were prepared by adding a small amount of hexane to a solution of the complex in THF (tetrahydrofuran) and diffusing it. Brown columnar crystals obtained

(0.5x0.3x0.1 mm) together with the mother liquor in a capillaries, and a 4-axis X-ray diffractometer

Rigaku AFC-7R Using MoK (wavelength λ = 0.71073Α) as the source,

The X-ray diffraction intensity of the reflection of + h, + k, ± l was measured up to 2S _max = 55 °. Also, 2S≤40 ° For the region of, the reflection of + h, 1 k, ± l was also measured. A total of 12278 reflections were measured and 11744 independent reflections were obtained. This also includes 39 Friedel pairs. Table 1 shows the crystallographic data.

table 1

Crystallographic demata Chemical formula: (I) _D -trans- [Co (C ₃₂ H ₃₈ N ₂ 〇4) Br (H ₂₀ )] 'C4H ₈₀

Crystal system: monoclinic, space group:

Lattice constant: a = 13.667 (2), b = 15.046 (2), c = 17.764 (2) &, ^ = 100.32 (1) ° V = 3593.8 (8) A ³ , Z = 4, Measurement temperature T = 297K ,

Mo Κα line absorption coefficient μ = 1.638 mm- ¹

The structure was solved using the direct method. Two independent THF molecules were included as a crystallization solvent, but the atomic displacement parameter was so large that non-hydrogen atoms in THF were analyzed using isotropic temperature factors, and the CC and C-0 bond distances were appropriate. Bounded to be a reasonable value. The assignment of the oxygen atom in THF was judged from the fact that if it was a carbon atom, an unusually short {-'·} distance would occur between the complex and an adjacent complex. 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. Hydrogen temperature factor U _is . (H) was _fixed at 1.2 times the equivalent isotropic temperature factor U _eq of the non-hydrogen atom to which it was bonded. Since the crystal structure was a structure with an approximate symmetry center (the space group was pseudo P2c), the correlation between atomic parameters was strong, and the least squares method (SHELXL97 Sheldric GM, Program for tne Refinement. Or Crystal Structure, University of Goettingen, Germany, 1997) had difficulty converging. To prevent the anisotropic temperature factor from becoming non-positive or abnormal (max / min ADP is 4 or more), six additional non-hydrogen atoms (08, 013, C31, C63, C71, C72 atoms) For), the isotropic temperature factor was used. The absorption correction was performed by numerical integration of the polyhedron (the range of the transmission factor T was 0.619 to 0.854). There was no effect of the extinction effect. The number of parameters refined is 749, compared to the number of reflections 11744 used for refinement. R (F) = 0.064, wR (F ² ) = 0.186, S = 1.035, (A /) _max = 0.020, △ O _max = 0.70 eA- ³ , Δ ρ = -0.60 eA- 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. 3. The parameters of Flack (0.04 (2)) are in the normal range (-0.2 x X 0.3 and standard deviation 0.5), and their standard deviations are small enough. The accuracy of structural analysis has also reached a standard level (R = 0.064). Therefore, for this complex, which has a negative optical rotation with respect to the sodium D line, the absolute configuration of the ligand around the asymmetric carbon atom can be clearly determined to be (R, R).

From this, the absolute configuration of the corresponding optically active ligand and optically active diamine, which had not been elucidated before, was revealed, and as shown in Table 2, it could be correlated with the optical rotation. Was.

Table 2 Compounds Specific rotation diamine

((+) — (10)

Ligand

(?, ¾-(+)-(9a)

Cobalt (m) complex

(/ ?, ¾-(-)-(5aB) (Example 5)

Synthesis of optically active cobalt (III) complex (5aE):

To 327 mg (0.501 mmol) of the optically active cobalt (III) bromide complex represented by the formula (1), dik □□ methane (15 ml) is added, and the flask is shielded from light with silver paper. After confirming that the complex has dissolved, add 210 mg (0.862 rnmol, 1.66 equivalents) of hexaflu-year-old silver phosphate (I) and stir for 90 minutes. Thereafter, the formed precipitate was separated by filtration and washed with dik □ methane. 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 for reprecipitation / purification. The optically active cobalt (III) complex represented by the formula () (light brown solid 327 mg, yield 91%).

(Example 6)

Synthesis of salen-type ligand (Sa):

While stirring with a solution of 296 mg (1 mmol) of 1,2-bis (2,4,6-trimethylphenyl) ethylenediamine in ethanol (6 ml), which has a positive optical rotation with respect to the D-line of sodium, At room temperature, a solution of salicylaldehyde (244 mg, 2 mmol) in ethanol (6 ml) was added dropwise. 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, separated by filtration, washed, and dried under vacuum to obtain 485 mg of salen-type ligand (Sa) as pale yellow powder (isolation yield: 96%). ) ₀

¹ H NMR (CDC1 ₃₎ 5 two 1.85 (6H, s), 2.20 (6H, s), 2.66 (6H, s), 5.65 (2H, s), 6.63-7.27 (12H, m), 8.40 (2, s), 13.16 (2H, s); specific rotation [h]. ²⁷ + 214 ° (c 0.60, CHC1 ₃ )

(Example 7)

Synthesis of salen cobalt (Π) complex (2a):

Methanol (30 ml) was added to 404 mg (0.8 mmol) of the salen-type ligand (Sa) placed in the reactor, and dissolved by stirring under a nitrogen flow. After stirring for 30 minutes, an aqueous solution (0.4 ml) of sodium hydroxide 80 mg (2.0 mmol) was added, and the mixture was stirred at 60 ° C. After 30 minutes, an aqueous solution (0.6 ml) of cobalt chloride ■ hexahydrate (228 mg, 0.96 mmol) was added dropwise, and a brown precipitate was deposited. After stirring for an additional 30 minutes, the mixture was cooled to room temperature and water was added (10 ml). The reaction solution was filtered under a nitrogen atmosphere, and the precipitate was washed with water and dried by flowing nitrogen. Nitrogen port The product was taken out in a box and dried under reduced pressure at 120 ° C. for 2 hours to obtain 451 mg of a light brown conorelet (II) complex (la) (yield> 99%).

(Reference example 2)

Asymmetric reduction reaction using optically active cobalt (II) complex catalyst Oa):

To a chloroform suspension (22 ml) of 28 mg (0.75 ol) of hydrogenated borohydride, was added 0.13 ml (2.25 mmol) _s of ethanol at -20 ° C under a nitrogen atmosphere, followed by tetrahydrofuran. 1.0 ml (10.5 mmol) of furyl alcohol was added dropwise and stirred for 15 minutes to prepare a modified borohydride reducing agent.

A solution of 1.4 mg (0.0025 mmol) of an optically active cobalt (II) complex having an absolute configuration of (R, R) represented by the above formula (4) in the form ml) and 56 mg (0.25 mmol) of dibenzoylmethane in chloroform (4 ml) were added dropwise and 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 a saturated saline solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvent was distilled off under reduced pressure. The resulting 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 was determined by high-performance liquid chromatography. (Optically active column: CHIRALPAK AD, manufactured by Daicel Chemical Industries, Ltd .; Ethanol 1.2% in Hexane, flow rate 1.0 ml / min, retention time 32.4 min, 52.9 min) was 98 ee. The dl / meso ratio was found to be 84/16 from the ¹ HNMR integral 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 reaction was carried out in the same manner as in Reference Example 2, except that the following cobalt (II) complex (18) was used instead of the cobalt (II) complex catalyst (). As a result, the desired product was obtained quantitatively, but the dl / meso ratio of the product was 29/71, and the optical yield of the dl form was 61% ee.

(18)

(Reference example 3)

Asymmetric reduction reaction using optically active cobalt (III) complex catalyst ():

The reaction was carried out in the same manner as in Reference Example 2, except that the cobalt (III) complex (SaB) was used instead of the cobalt (II) complex catalyst Oa). As a result, the desired product was obtained quantitatively, the dl / meso ratio was 82 828, and the optical yield of the dl form was 98 ° /. ee.

(Reference example 4)

Asymmetric reduction reaction using optically active cobalt (II) complex (la):

In Reference Example 2, the optically active cobalt (II) complex (la) was used as a catalyst instead of the cono \ lireto (II) complex catalyst (4a), and acetophenone was used instead of dibenzoylmethane. The reaction was carried out in the same manner as in Reference Example 2 except that the reaction temperature was 0 ° C. As a result, the reaction was completed within 1 hour, and the desired product was obtained quantitatively. The optical yield was 84% ee.

(Comparative Examples 2, 3)

In each example, instead of cobalt (II) complex catalyst (Za), _c except for using cobalt (II) complex OS) or (2Q) shown in Table 3, the reaction was carried out in the same manner as in Reference Example 4 In Comparative Example 2, the reaction was completed within 1 hour, and the desired product was obtained quantitatively. In Comparative Example 3, the reaction was not completed even after 3 hours. Table 3 shows the optical purity of the obtained product. Table 3

Catalyst Reaction time Yield /% Optical yield /% ee

Reference Example 4 Quantitative 84

(7a)

Comparative Example 2 Quantitative 19

(1 9)

Comparative Example 3 39 11

(20)

(Reference example 5)

Reference Example 2 was the same as Reference Example 2 except that the cobalt (II) complex catalyst (R, R)-(knob) was used at 2 mol% based on the substrate, and 2-phenacylpyridine was used instead of dibenzoylmethane. The reaction was performed in the same manner for 12 hours. Table 4 shows the yield, optical purity and absolute configuration of the main enantiomer obtained from the obtained alcohol.

(Reference Examples 6 to 8)

In each case, the cobalt (II) complex catalyst (4a)

(II) The reaction was carried out in the same manner as in Reference Example 5 except that the complexes (4s), (4d), and (15) were used. I got it. Table 4 shows the yield, optical purity and absolute configuration of the obtained alcohol. (Comparative Example 4)

The reaction was carried out in the same manner as in Reference Example 5, except that the cobalt (II) complex (21) shown in Table 4 was used instead of the cobalt (II) complex catalyst (Aa). Table 4 shows the yield and optical purity of the obtained alcohol.

(/??)-(4d)

Reference Example 8

(/?, /?)-(15)

Comparative Example 4 22

( ?,?)-(twenty one) (Reference Example 9)

Asymmetric cyclopropanation reaction using optically active cobalt (II) complex catalyst (4a): 29 mg (0.05 mmol) of cobalt (Π) complex catalyst Oa) was weighed into a reactor, and the inside of the reaction vessel was replaced with a nitrogen gas atmosphere. Thereafter, 1 ml of tetrahydrofuran is added to dissolve the cobalt complex. The container was immersed in an oil bath adjusted to 25 ° C in advance, and 0.57 ml (5.0 mmol) of styrene was further added to the container, followed by dropwise addition of tert-butyl diazoacetate 148β ^ (1.0 mmol), and N-methylimidazole jul (0.1 mmol) 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 the excess styrene, complex catalyst and N-methylimidazole were removed by silica gel column chromatography to obtain the product as an oil (174 mg, 80% yield). rate). The isomer ratio (trans: cis) of the obtained tert-butyl 2-phenylcyclopropylcarboxylate was 83:17 as a result of analysis by gas chromatography. The product was subjected to preparative thin-layer chromatography to separate the trans / cis form. The optical yield of the trans form was determined by treating it with lithium aluminum hydride and producing it by column chromatography. The resulting reduced form was analyzed by high-performance liquid chromatography (optically active column: Daicel Chemical Industries, Chiralcel OB-H). As a result, it was 96% ee. The optical yield of the cis form was 91 ee after separation and purification by thin-layer chromatography and analysis by high-performance liquid chromatography (optically active column: Chiralcel 0B-H).

(Reference Example 10)

The reaction was carried out in the same manner as in Reference Example 9 except that the cobalt (II) complex was used instead of the cobalt (II) complex catalyst (4a). The yield of the obtained tert-butyl 2-phenylcyclopropylcarboxylate 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. • Industrial availability

The optically active cobalt complex of the present invention is excellent in catalytic activity and enantioselectivity in asymmetric borohydride reduction reaction and asymmetric cyclic propanation reaction, and has high stability in air and is easy to handle. It is. 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.

Claims

The scope of the claims

1. The following formula (丄) or (J2)

(D CD

Wherein R ¹ and R ² may be the same or different and each represent a hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, a linear or branched aryl group, An alkyl group, an alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an aryl group, or an aralkyl group. The group may have a substituent, and R ¹ and R ² are mutually connected to form 璟 together with the carbon atom to which R ¹ and R ² are bonded. Is also good. ] The optically active cobalt (II) complex represented by these.

2. The following formula (_2J or (ii)

(twenty two:) [Wherein, R ¹ and R ² are as defined above, and are an anion pair that can form a salt. ] The optically active cobalt (III) complex represented by these.

3. The following formula (A) or (1)

(In the formula, R ³ is a linear or branched alkyl group, aryl group, or alkoxy group, aryl group, and the alkyl group, aryl group, alkoxy group, and aryl group have a substituent. It may be. The optically active cobalt (II) complex according to claim 1, which is represented by the following formula:

4. The following formula (_5_) or (_5 丄)

(δ)

[Wherein, R ^{3 has the same} meaning as above. 3. The optically active cobalt (III) complex according to claim 2, which is represented by the following formula:

5. The following formula () or (4a

(4a) (4 :)

4. The optically active cobalt (II) complex according to claim 3, represented by the formula:

6. The following formula (_ ^) or (5 a

(5a) (5)

[Wherein, X- is as defined above. The optically active cobalt (II) complex according to claim 4, which is represented by the following formula:

7. The following formula (ヱ) or U 丄)

[In the formula, "" R ⁴ R \ R ⁶ and R ⁷ may be the same or different, and include a hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, and a linear chain. Or a branched or aryl group, an alkoxy group, a cyano group, or a nitro group, or a halogen atom, and the alkyl group, alkenyl group, aryl group, or alkoxy group may have a substituent; And any two of R ⁴ to R ⁷ may be connected to each other to form a ring in cooperation with the carbon atom to which they are bonded, or may form a condensed ring such as a naphthyl ring. Good. 2. The optically active cobalt (II) complex according to claim 1, which is represented by the following formula:

8. The following formula () or (_ai)

Wherein R ⁴ R \ R ⁶ R ⁷ and X— are as defined above. 3. The optically active cobalt (III) complex according to claim 2, which is represented by the formula:

9 · The following formula Z ^) or (JLal)

(Za) (§ :)

The optically active cobalt (II) complex according to claim 7, represented by:

1 0. The following formula (_S— § or (8 a ')

(8a) (8§ :)

[Wherein, it is as defined above. 9. The optically active cobalt (III) complex according to claim 8, which is represented by the following formula:

1 1. The optically active cobalt (II) complex according to any one of claims 1, 3, 5, 7, and 9, wherein the absolute configuration of the ligand around the asymmetric carbon atom is (R, R).

1 2. The absolute configuration of the ligand around the asymmetric carbon atom is (R, R).

11. The optically active cobalt (III) complex according to any one of 6, 8, and 10.

1 3. The following formula (_υυ or (1 ο ')

(I © (10

The optically active diamine represented by is subjected to a dehydration condensation reaction with an aldehyde compound,

(3) (3 :)

[Wherein, R ¹ and R ² are as defined above. Wherein the optically active intermediate compound is reacted with a compound containing divalent cobalt in the presence of a basic compound. Expression (丄) or

A method for producing an optically active cobalt (II) complex represented by (JL 丄).

14. The optically active diamine represented by the above formula LQJ or (10,) and the following formula (丄丄

And the following formula (J_a_) or

(6a) ()

After obtaining the optically active ketoimine compound represented by the formula, the optically active ketoimine conjugate is reacted with a compound containing a divalent cobalt ion in the presence of a basic conjugate. 14. The production method according to claim 13, wherein the optically active cobalt (II) complex represented by the formula (_) or (4a ') according to item 5 is produced.

1 5. The optically active diamine represented by the above formula ("_Ώ_") or (10 ') and the following formula (丄

By dehydration condensation with salicylaldehyde represented by the following formula or

(9a) (93 :)

After obtaining the optically active salen compound represented by the formula, the optically active salen compound is reacted with a compound containing a divalent cobalt ion in the presence of a basic compound, and the formula CLaJ. The production method according to claim 13, for producing an optically active cobalt (II) complex represented by 7a ').

16. The optically active diamine represented by L ^) or (10 ') in the above formula of the starting material is optically resolved by using optically active mandelic acid. The manufacturing method according to any one of the above.

17 7. The optically active diamine represented by LQJ or M 0 ′) in the above formula of the starting material, wherein the absolute configuration around the asymmetric carbon atom is (R, R). The production method according to the paragraph.

1 8. The following formula (_!) Or (3,)

() (3 :)

[Wherein, R ¹ and R ² are as defined above. ] Optically active intermediate compound _c represented by

1 9. The following formula or (6 a ')

(6a) (6 :)

19. The intermediate compound according to claim 18, which is an optically active ketomine compound represented by the formula:

20. The following formula (_2) aJ or (_9Lal)

(9a) (93 :)

19. The intermediate compound according to claim 18, which is an optically active salen compound represented by the formula:

21. The intermediate compound according to any one of claims 18 to 20, wherein the absolute configuration around the asymmetric carbon atom is (R, R).