JPH1180070A - Production of chiral beta-hydroxyketone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To enable to directly produce the subject compound useful as an intermediate raw material for medicines, agrochemicals, perfumes and the like in a high optical purity without using a silyl compound such as a silylenol ether as a substrate by using a specific metal complex as a catalyst. SOLUTION: This method for producing a chiral beta-hydroxyketone comprises an asymmetic aldole reaction, such as the asymmetic aldole reaction of a compound of formula II [R1 is a (cyclo)alkyl or the like] with a compound of formula III (R2 is R1 ), in the presence of a metal complex obtained by reacting an optically active binaphthol (derivative) [e.g. a compound obtained by reacting a compound of formula I (R3 , R4 are each H, an alkali, a halogen or the like) with an alkali metal compound] with a rare earth metal compound. The asymmetic aldole reaction is preferably carried out at a temperature of -80 to 50 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active (chiral) β-hydroxyketone. More specifically, the present invention relates to a method for producing an optically active β-hydroxyketone by an asymmetric aldol reaction using an asymmetric synthesis catalyst, and a novel β-hydroxyketone obtained thereby.

[0002]

2. Description of the Related Art The present inventors have previously conducted various studies on asymmetric synthesis reactions using rare earth complexes having an optically active ligand, for example, Japanese Patent Application Laid-Open Nos. 6-154618 and 6-25.
6270, JP-A-6-306026, WO-95
/ 0132, J.M. Am. Chem. Soc. , 114,
4418 (1992), Tetrahedron Le
tt. , 34, 851 (1993), Tetrahe.
drone Lett. , 34, 855 (1993),
Tetrahedron Lett. , 34,2657
(1993); Am. Chem. Soc. , 11
5, 10372 (1993); Org. Che
m. , 60, 7388 (1995).
The above references include lanthanum chloride and optically active dilithium 1,
A method in which 1'-bi-2-naphthoxide is mixed in tetrahydrofuran and water and sodium hydroxide are added, or an optically active 1,1'-bi-2-naphthol, water Using a rare earth metal complex catalyst prepared by a method of sequentially adding lithium chloride, a nitroaldol compound having high optical purity is obtained by a catalytic asymmetric nitroaldol reaction between various aldehydes and a nitroalkane. In addition, they have found that rare earth complexes having an optically active ligand are useful catalysts for asymmetric Michael addition reaction, hydrophosphonylation reaction, and asymmetric synthesis of α-aminophosphonic acid.

On the other hand, development of a method for producing optically active β-hydroxyketone is important in supplying raw materials for medicines, agricultural chemicals, fragrances, and liquid crystal intermediates. Among the production methods, the catalytic asymmetric aldol reaction is It is possible to obtain a large amount of optically active substance from a small amount of asymmetric source, and it is being actively studied as a method for efficiently obtaining an optically active substance. Many studies have been made on the asymmetric aldol reaction catalyzed by an optically active Lewis acid, and it has been found that optically active β-hydroxyketone derivatives having high optical purity can be obtained. For example, a catalyst is prepared from an optically active ligand using divalent tin, boron, titanium, copper, or the like as a catalyst metal. Representative papers are described below. Chem. Lett. , 129 (19
90); Am. Chem. Soc. , 113104
1 (1191); Am. Chem. Soc. , 11
3 9365 (1991), Tetrahedron.
Lett. , 33 4927 (1992), Tetr.
ahedron. Lett. , 33 4927 (19
92), Tetrahedron. Lett. , 33
6907 (1992), Tetrahedron. Le
tt. , 34 1507 (1993); Am. Ch
em. Soc. , 115 7039 (1993).

[0004] These catalytic reactions are based on the asymmetric aldol reaction of an aldehyde with a silyl compound such as silyl enol ether, ketene silyl acetal or ketene silyl thioacetal, and the product is silylated β-hydroxyl. Obtained as a ketone compound.

Since a transition metal complex is expected to proceed a catalytic reaction by a reaction mechanism different from that of a Lewis acid catalyst, much research has been conducted on a catalytic asymmetric aldol reaction using a transition metal complex. I have. For example, the following paper can be cited. Tetrahedron Let
t. , 28 793 (1987), Synth. Co
mmun. , 23 1251 (1993). The present inventors have proposed using a palladium complex prepared from an optically active bidentate phosphine ligand as a transition metal complex to produce a catalytically asymmetric aldol such as an aldehyde and silyl enol ether, ketene silyl acetal, or ketene silyl thioacetal. It has been found that a highly pure optically active β-hydroxyketone derivative can be obtained by the reaction (J. Org. C).
hem. 60, 2648 (1995);
No. 83787).

The asymmetric aldol reaction using these catalysts requires an aldehyde and a silyl compound such as silyl enol ether, ketene silyl acetal, or ketene silyl thioacetal as a substrate. The silyl compound is a relatively expensive raw material because it is produced in several steps from the carbonyl compound.In addition, the silylated hydroxyketone product, which is a product, is hydrolyzed in several steps to produce an optically active compound. A step of synthesizing a β-hydroxyketone derivative is required. Therefore, in comparison with the conventional synthesis method of optically active β-hydroxyketone derivative, the catalytic asymmetric aldol reaction can produce a large amount of optically active β-hydroxyketone derivative from a small amount of asymmetric source from an inexpensive raw material in a short process. There is a need for a manufacturing method.

As an example of performing an asymmetric aldol reaction between an aldehyde and a ketone without using a silyl compound such as silyl enol ether, ketene silyl acetal or ketene silyl thioacetal as a substrate, Chem. Le
tt. , 391 (1985). Where,
Using a zinc complex of an amino acid ester as a catalyst, p-
Optically active 4-hydroxy-4-phenyl- by asymmetric aldol reaction of nitrobenzaldehyde and acetone
The synthesis of 2-butanone has been described. However, only a benzaldehyde derivative as an aldehyde and acetone as a methyl ketone have been studied, but they have not provided a method for producing β-hydroxyketone, which is an object of the present invention.

[0008]

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned problems associated with the prior art, and is intended to directly provide a high optical purity β in a single step by an asymmetric aldol reaction. -To provide a production method capable of synthesizing hydroxyketone.

[0009]

Means for Solving the Problems As a result of intensive studies on the above-mentioned problems, the present inventors have found that by using a metal complex obtained by reacting an optically active binaphthol or a binaphthol derivative with a rare earth compound, silyl enol can be used as a substrate. We have established a novel reaction system that can directly obtain optically active β-hydroxyketone by catalytic asymmetric aldol reaction without using silyl compounds such as ether, ketene silyl acetal, and ketene silyl thioacetal. The invention has been completed.

(1) A method for producing a chiral β-hydroxyketone, comprising subjecting an asymmetric aldol reaction in the presence of a metal complex obtained by reacting an optically active binaphthol or a binaphthol derivative with a rare earth compound. (2) An asymmetric aldol reaction is carried out in the presence of a metal complex obtained by reacting an aldehyde compound represented by the following general formula 1 and a methyl ketone compound represented by the following general formula 2 with an optically active binaphthol or a binaphthol derivative and a rare earth compound. A method for producing a chiral β-hydroxy ketone, comprising:

[0011]

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[In the formula 1, R ₁ represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group (each of these substituents is a halogen atom, a hydroxyl group, an alkoxy group, an aminoalkyl group, a thioalkyl group, an aromatic group) Or an aromatic group or a heterocyclic group (all of the aromatic group and the heterocyclic group may be an alkyl group, an alkoxy group, a halogen group, a nitro group, a cyano group, an alkoxycarbonyl group). Group, alkanoyl group, amino group, N-monoalkylamino group, N, N-dialkylamino group, carbamoyl group, N-monoalkylcarbamoyl group, N, N-
A dialkylcarbamoyl group, an aminoalkyl group, an N-monoalkylaminoalkyl group, or an N, N-dialkylaminoalkyl group, which may have 1 to 3 identical or different substituents). ]

[0013]

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[In the formula 2, R ₂ represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group (all of these substituents are a halogen atom, a hydroxyl group, an alkoxy group, an aminoalkyl group, a thioalkyl group, an aromatic group) Or an optionally substituted heterocyclic group), an alkoxy group, a thioalkoxy group, or an aromatic group (the aromatic group is an alkyl group,
Alkoxy, halogen, nitro, cyano, alkoxycarbonyl, alkanoyl, amino, N-
Monoalkylamino group, N, N-dialkylamino group,
A carbamoyl group, an N-monoalkylcarbamoyl group,
1-3 selected from the group consisting of N, N-dialkylcarbamoyl, aminoalkyl, N-monoalkylaminoalkyl, and N, N-dialkylaminoalkyl
May have the same or different substituents). ]

(3) The metal complex is obtained by reacting a rare earth metal compound with an optically active 1,1′-bi-2-naphthol represented by the following general formula 3 or 4 and an alkali metal compound. The method for producing an optically active β-hydroxyketone according to the above (1) or (2), wherein the metal complex is a metal complex.

[0016]

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(In the formulas 3 and 4, R ₃ and R ₄ may be the same or different and represent a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, a halogen atom, a trialkylsilylethynyl group or a cyano group. (4) The asymmetric aldol reaction is carried out at -80 ° C to 50 ° C.
(1) to (3), which are performed in a temperature range of
The method for producing an optically active β-hydroxyketone according to any one of (3).

(5) (S) -6,6-dimethyl-5
Hydroxy-7-phenyl-3-heptanone. (6) (S) -4,4-dimethyl-3-hydroxy-
1'-naphthyl-1-pentanone. (7) (S) -4,4-dimethyl-1,5-diphenyl-3-hydroxy-1-pentanone. (8) (S) -5,5-dimethyl-4-hydroxy-
6-phenyl-2-hexanone.

The chiral β-hydroxyketone compounds described in the above (5) to (8) are novel compounds and have been found for the first time by the production method of the present invention. These novel chiral β-hydroxyketone compounds are useful as intermediates for pharmaceuticals, agricultural chemicals, fragrances, and raw materials for liquid crystal intermediates, and are particularly useful as intermediates in the production of pharmaceuticals.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION The metal complex used in the present invention is obtained by reacting an optically active binaphthol or a binaphthol derivative with a rare earth compound.

As the optically active binaphthol or binaphthol derivative, any one can be used, but only one of the R-form or the S-form is used. As the optically active binaphthol or the binaphthol derivative, the optically active 1,1′-bi-2 represented by the general formula 3 or 4 is used.
-Naphthols are preferred. The position of R ₃ is 3rd, 4th,
Any of the fifth, sixth and seventh positions may be used, and R ₄ may also be 3 ′
Position, 4 'position, 5' position, 6 'position and 7' position. R ₃ and R ₄ each represent a hydrogen atom, an alkyl group (eg, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl or t-butyl), a phenyl group, an alkenyl group (ethenyl, -Propenyl,
3-butenyl and the like), a trialkylsilylethynyl group (here, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl and t-butyl, etc.), a cyano group and a halogen atom Represents R ₃ and R ₄ are preferably a hydrogen atom,
6,6′-substituted trialkylsilylethynyl group.

Further, as the rare earth metal of the rare earth compound,
Are Y, La, Nd, Sm, Eu, Gd, Tb, Dy,
Pr, Yb, etc., and any of them may be used, but it is preferable.
Are La, Yb, and Sm. As rare earth compounds, rare
Earth metal alkoxides (methoxide, ethoxa
Id, propoxide, isopropoxide, n-but
Oxide, s-butoxide and t-butoxide, etc.
), Chloride (anhydride and hydrate)
Or a nitrate. Rare earth
Preferably, the compound is La (OR)_Three(Where R is
Represents an isopropyl group or a t-butyl group. ), La
Cl_Three(It can be either anhydrous or hydrated),
Yb (OR)_Three(Where R is as defined above), Y
bCl _Three(Either anhydrous or hydrate is acceptable.
I), Sm (OR)_Three(Where R is as defined above)
You. ).

The metal complex in the present invention is preferably
A compound obtained by reacting a rare earth metal compound with an optically active 1,1′-bi-2-naphthol represented by the above general formula 3 or 4 and an alkali metal compound is preferable.
Here, as the alkali metal compound, alkyl alkali metals, alkali metal hydroxide and the like can be used. Here, examples of the alkali metal include lithium, sodium, and potassium. Examples of the alkyl alkali metals include methyl lithium and t-butyl lithium, and examples of the alkali metal hydroxide include lithium hydroxide, sodium hydroxide, and potassium hydroxide.
As the alkali metal compound, alkyl alkali metals are preferable, and n-butyllithium and methyllithium are more preferable. In the production of the metal complex according to the present invention, the molar ratio of the optically active binaphthol or binaphthol derivative, rare earth compound and alkali metal compound in the reaction system is preferably from 2: 1: 3 to 3: 1: 5,
More preferably, the ratio is from 3: 1: 3 to 3: 1: 4.

As the solvent that can be used in preparing the metal complex in the present invention, any solvent can be used as long as the structure of the rare earth metal complex is not changed. For example, tetrahydrofuran (THF), ether solvents (diethyl ether, 1,4-dioxane, etc.), halogen solvents (methylene chloride, chloroform, 1,1,1-
Trichloroethane and monochlorobenzene, etc., hydrocarbon solvents (benzene, toluene, n-hexane and n-
Heptane) and fatty acid esters (ethyl acetate, methyl acetate, etc.). In addition, polar solvents such as dimethyl sulfoxide and N, N′-dimethylformamide can be used. These solvents may be used alone or in combination of two or more.

Of these solvents, tetrahydrofuran is preferred. When a rare earth chloride is used as the rare earth compound, a metal complex prepared from aqueous THF can be used. In dry THF, rare earth alkoxide, alkali metal compound, optically active 1,1'-bi-
In a catalyst solution prepared from 2-naphthols, a catalyst solution obtained by adding water to this catalyst, and a hydrated THF, a rare earth chloride, an alkali metal compound, an optically active 1,1′-bi-2-
Catalysts that can be adjusted from naphthols can be used.

Metal complexes are disclosed in JP-A-6-154618, JP-A-6-256270 and JP-A-30602.
The compound can be synthesized by the detailed preparation method described in JP-A-6. Here, an example (the following reaction formula) will be briefly described.

[0027]

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Here, more specifically, an optically active 1,1′-bi-2-naphthol represented by the general formula 3 or 4 is dissolved in a solvent such as THF, and lanthanum triisopropoxide [ _{la (O- (i) C 3} H 7) 3 ]
After stirring at room temperature, a solution of an alkali metal compound such as butyl lithium is added at 0 ° C.
After stirring at room temperature overnight, the metal complex of the present invention can be obtained in the form of a solution. This preparation method is representative, and is not particularly limited as a method for preparing the metal complex used in the present invention. The metal complex in the present invention,
Due to the various bonding modes unique to rare earth elements, dimers, trimers, oligomers, polymers, or dimers, such as monomers, bridging atoms such as halogen atoms, lanthanum atoms, or alkali metal atoms, etc. It can be a mixture. Although the metal complex in the present invention is obtained in this way, it is presumed that the metal complex will have a structure represented by the following general formula 5 or 6. However, the content of the present invention is not limited to these.

[0029]

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In the formula (5) or (6), X represents an alkali metal, and Ln represents a lanthanoid metal. The metal complex that can be used in the present invention is, for example, when Ln is La and X is Li in the above general formula 5, LaL
i ₃ Tris (R) -binaphthoxide complex [(R) -LL
B).

The metal complex as described above in the present invention is
The optically active β-hydroxyketone as a product can be obtained in about 0.005 to 0.3 molar equivalents to the aldehyde compound which is a raw material of the asymmetric aldol reaction. In order to further shorten the reaction time under mild conditions, an amount exceeding 0.3 molar equivalent may be used.

In the present invention, the asymmetric aldol reaction comprises
It refers to a reaction for producing a chiral β-hydroxyketone compound using an aldehyde compound and a carbonyl compound having a hydrogen atom at the α-position as raw materials. As the carbonyl compound having a hydrogen atom at the α-position, which is one of the raw materials, any one can be used as long as it is used for an asymmetric aldol reaction, but preferably a methyl ketone compound represented by the general formula 2 is used. is there.

As the aldehyde compound as another raw material, any one can be used as long as it is used in an asymmetric aldol reaction, but an aldehyde compound represented by the above general formula 1 is preferable.

In general formula 1 or 2, as an alkyl group
Is C_1-10An alkyl group; _1-10As an alkyl group
Is methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, s-butyl, t-butyl,
-Pentyl, 2-pentyl, 3-pentyl, i-pliers
, Neopentyl, t-pentyl, 1-hexyl, 2-
Hexyl, 3-hexyl, 1-methyl-1-ethyl-n
-Pentyl, 1,1,2-trimethyl-n-propyl,
1,2,2-trimethyl-n-propyl, 3,3-dimethyl
Tyl-n-butyl, 1-heptyl, 2-heptyl, 1-
Ethyl-1,2-dimethyl-n-propyl, 1-ethyl
-2,2-dimethyl-n-propyl, 1-octyl, 3
-Octyl, 4-methyl-3-n-heptyl, 6-methyl
2-n-heptyl, 2-propyl-1-n-hepti
2,4,4-trimethyl-1-n-pentyl, 1-
Nonyl, 2-nonyl, 2,6-dimethyl-4-n-hep
Chill, 3-ethyl-2,2-dimethyl-3-n-pent
3,5,5-trimethyl-1-n-hexyl, 1-
Decyl, 2-decyl, 4-decyl, 3,7-dimethyl-
1-n-octyl and 3,7-dimethyl-3-n-oct
And methyl, ethyl, n-propyl.
Ropyl, i-propyl, n-butyl, i-butyl, s-
Butyl, t-butyl, 1-pentyl, 1-hexyl, 1
-Heptyl, 1-octyl, 1-nonyl, 1-decyl
is there.

[0035] The cycloalkyl group in the general formula 1 or 2, include C _3-10 cycloalkyl group, C _3-10
Examples of the cycloalkyl group include cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl, 4-methylcyclohexyl, cyclobutyl, cyclopentyl,
Examples include cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like, and preferred are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In formulas 1 and 2, the alkenyl group includes a C _2-10 alkenyl group, and the C _2-10 alkenyl group includes ethenyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl , 2-butenyl,
3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1
-Ethyl-2-vinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl , 1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1-methyl-2
-Butenyl, 2-methyl-1-butenyl, 1-i-propylvinyl, 2,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-methyl-1-pentenyl, 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl and the like, preferably ethenyl, 1-propenyl, 3-butenyl, 1-
Methyl-1-propenyl, 1-pentenyl, 4-pentenyl, 1-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl and 1-decenyl.

In the general formulas 1 and 2, examples of the alkynyl group include C _2-10 alkynyl groups, and examples of the C _2-10 alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl and 2-butynyl. , 3-butynyl, 1
-Pentynyl, 2-pentynyl, 3-pentynyl, 4-
Pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, 1-noninyl, 1-decynyl and the like, preferably ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, 4-pentynyl,
1-hexynyl, 5-hexynyl, 1-heptynyl, 1
-Octynyl, 1-noninyl and 1-decynyl.

[0038] Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0039] The alkoxy group in the general formula 1 or 2, include C _1-10 alkoxy group, the C _1-10 alkoxy group, for example, methoxy, ethoxy, n- propoxy, i- propoxy, n- butoxy , Sec-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy,
n-nonyloxy and n-decyloxy and the like,
Preferably methoxy, ethoxy, n-propoxy, i-
Propoxy, n-butoxy, sec-butoxy, t-butoxy.

[0040] The aromatic group in the general formula 1 or 2, include C _6-10 aromatic group, and the C _{6- 10} aromatic radical, e.g., phenyl, 1-indenyl, 2-indenyl, 3 Indenyl, 4-indenyl, 5-indenyl, 6-indenyl, 7-indenyl, 1-naphthyl,
2-naphthyl, 1-tetrahydronaphthyl, 2-tetrahydronaphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl and the like, preferably phenyl, 1-naphthyl, 2-naphthyl, 1-tetrahydronaphthyl and 2-tetrahydronaphthyl is there.

In the general formula 1, examples of the heterocyclic group include an aromatic heterocyclic group and a non-aromatic heterocyclic group. Examples of the aromatic heterocyclic group include a monocyclic heterocyclic group having 5 to 7 membered rings and a condensed bicyclic heterocyclic group having 8 to 10 constituent atoms, and include an oxygen atom, a nitrogen atom, and a sulfur atom. The atoms may contain one to three atoms alone or two or more.

Examples of the non-aromatic heterocyclic group include a monocyclic heterocyclic group having 5 to 7 membered rings and a condensed bicyclic heterocyclic group having 6 to 10 constituent atoms. A nitrogen atom and a sulfur atom may contain one to three atoms alone or two or more.

Examples of the aromatic heterocyclic group include, for example, 2-
Thienyl, 3-thienyl, 2-furyl, 3-furyl, 2
-Pyranyl, 3-pyranyl, 4-pyranyl, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl,
5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5- Benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-isobenzothienyl, 4-isobenzothienyl, 5-isobenzothienyl, 2-chromenyl, 3-chromenil, 4-chromenil, 5-chromenil, 6-chromenyl , 7-chromenyl, 8-chromenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl,
2-imidazolyl, 4-imiazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-isothiazolyl
Oxazolyl, 4-oxazolyl, 5-oxazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-
Pyridazinyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-idridinyl, 1-isoindolyl, 4-isoindolyl, 5-isoindolyl, 1-indolyl, 2-indolyl, 3-
Indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5
-Indazolyl, 6-indazolyl, 7-indazolyl, 1-purinyl, 2-purinyl, 3-purinyl, 6-
Purinyl, 7-purinyl, 8-purinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-
Quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-
Isoquinolyl, 1-phthalazinyl, 5-phthalazinyl,
6-phthalazinyl, 2-naphthyridinyl, 3-naphthyridinyl, 4-naphthyridinyl, 2-quinoxalinyl, 5
-Quinoxalinyl, 6-quinoxalinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 3-
Cinnolinyl, 4-cinnolinyl, 5-cinnolinyl,
6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-ptenidinyl, 4-ptenidinyl, 6-ptenidinyl, 7-ptenidinyl, 3-furzanil and the like.

The aromatic heterocyclic group is preferably 2-
Thienyl, 3-thienyl, 2-furyl, 3-furyl, 2
-Pyranyl, 3-pyranyl, 4-pyranyl, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl,
5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5- Benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-isobenzothienyl, 4-isobenzothienyl, 5-isobenzothienyl, 2-chromenyl, 3-chromenil, 4-chromenil, 5-chromenil, 6-chromenyl , 7-chromenyl, 8-chromenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl,
2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-isothiazolyl
Oxazolyl, 4-oxazolyl, 5-oxazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-
Pyridazinyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-indolizinyl, 1-isoindolyl, 4-isoindolyl, 5-isoindolyl, 1-indolyl, 2-indolyl, 3-
Indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl.

As the non-aromatic heterocyclic ring, for example, t-
Pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
1-pyrolinyl, 2-pyrolinyl, 3-pyrolinyl, 4
-Pyrolinyl, 5-pyrolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1
-Imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4
-Pyrazolidinyl, 1-pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl , 1-indolinyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5
-Indolinyl, 6-indolinyl, 7-indolinyl, 1-isoindolinyl, 2-isoindolinyl,
-Isoindolinyl, 5-isoindolinyl, 2-quinuclidinyl, 3-quinuclidinyl, 4-quinuclidinyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-azetidinyl, 2-azetidinyl,
Examples thereof include 3-azetidinyl, 1-azetidinonyl, 3-azetidinonyl, and 4-azetidinonyl.

The non-aromatic heterocyclic ring is preferably 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
-Pyrrolinyl, 2-pyrolinyl, 3-pyrolinyl, 4-
Pyrrolinyl, 5-pyrolinyl, 1-imidazolidinyl,
2-imidazolidinyl, 4-imidazolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 1-pyrazolinyl, 2-pyrazolinyl,
3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 2-morpholinyl, 3-morpholinyl, 4- And morpholinyl.

[0047] As the thioalkoxy group in the general formula 2 include C _1-10 thioalkoxy group, and the C _1-10 thioalkoxy group, such as methylthio, ethylthio,
n-propylthio, i-propylthio, n-butylthio, sec-butylthio, t-butylthio, n-pentylthio, n-hexylthio, n-heptylthio, n-octylthio, n-nonylthio, n-decylthio and the like, and are preferred. Methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, sec
-Butylthio and t-butylthio.

R ₁ and R in the general formula 1 or 2
₂ is an alkyl group, a cycloalkyl group, an alkenyl group,
When representing an alkynyl group, any of these substituents may be optionally substituted with a halogen atom, a hydroxyl group, an alkoxy group, an aminoalkyl group, a thioalkyl group, an aromatic group or a heterocyclic group. R ₁ in the general formula 1 or 2
When represents an aromatic group or a heterocyclic group, when R ₂ represents an aromatic group, the aromatic group or the heterocyclic group is an alkyl group, an alkoxy group, a halogen group, a nitro group, a cyano group,
Alkoxycarbonyl group, alkanoyl group, amino group,
N-monoalkylamino group, N, N-dialkylamino group, carbamoyl group, N-monoalkylcarbamoyl group, N, N-dialkylcarbamoyl group, aminoalkyl group, N-monoalkylaminoalkyl group, N, N-dialkyl 1 to 1 selected from the group consisting of aminoalkyl groups
It may have three identical or different substituents.

Preferred substituents for R ₁ in formula 1 are an alkyl group, a cycloalkyl group, an alkynyl group, an aromatic group,
Alternatively, it is a heterocyclic group. Preferred substituents for R ₂ in Formula 2 are an alkyl group, a cycloalkyl group, an alkynyl group, a thioalkoxy group, or an aromatic group.

In the present invention, the methyl ketone compound used in the asymmetric aldol reaction is used in an optically active β-
Hydroxy ketone can be obtained. In particular, when an aldehyde compound having hydrogen at the α-position is used as a substrate, the excess use of a methyl ketone compound is particularly effective because a by-product self-condensate of the aldehyde compound is suppressed.

An excess amount of the methyl ketone compound is recovered together with the solvent at the end of the reaction, and can be reused directly or by separating and purifying from the solvent.

As the solvent used in the asymmetric aldol reaction in the present invention, the solvents used during the preparation of the catalyst, for example, tetrahydrofuran, ether solvents (diethyl ether, 1,4-dioxane, etc.), halogen solvents (methylene chloride, Chloroform, 1,1,1-trichloroethane, monochlorobenzene, etc.), hydrocarbon solvents (benzene, toluene, n-hexane, n-heptane, etc.), fatty acid esters (ethyl acetate, methyl acetate, etc.)
And dimethyl sulfoxide, N,
Polar solvents such as N'-dimethylformamide can be used,
These solvents may be used alone or in combination of two or more.

The asymmetric aldol reaction according to the present invention comprises-
It is preferable to carry out the reaction in a temperature range of 80 ° C to 50 ° C. In addition, the reaction time of the asymmetric aldol reaction in the present invention varies depending on the amount of the catalyst used, but generally 10 to 500 hours is appropriate. Specifically, a methyl ketone compound is added to the solution of the metal catalyst, and the mixture is stirred in the above temperature range. Then, the aldehyde compound is added, and the mixture is stirred for 50 to 300 hours.
A hydroxyketone can be obtained.

In the present invention, the specific asymmetric aldol reaction as described above is directly carried out in a single step.
High-purity optically active β-hydroxyketone was synthesized, and the above-mentioned novel chiral β-hydroxyketone was obtained. These novel chiral β-hydroxy ketones are useful as intermediates for pharmaceuticals, agricultural chemicals, perfumes, and raw materials for liquid crystal intermediates, and particularly useful as intermediates for pharmaceuticals.

[0055]

The following examples are representative experimental results.
It does not limit the content of the present invention. The optical purity was determined by liquid chromatography (HPLC) analysis (CHIRALPAK AD or CHILPAK manufactured by Daicel Chemical Industries, Ltd.).
RALCEL OD). ¹ H-NMR was measured at (270 MHz). Absolute configuration is Moshe
r (J. Am. Chem. Soc., 9551).
2 (1973)) and known substances (Chem. Let
t. 1399 (1984), Tetrahedoro
nLett. , 374911 (1996)).

Reference Example 1 Preparation of Rare Earth Metal Complex Solution A0 515 mg (1.8 mmol) of (R) -1,1′-dihydroxy-2,2′-binaphthalene was vacuum dried at 50 ° C. for 2 hours. Under an argon stream, (R) -1,1′-dihydroxy-2,2′-binaphthalene was added to THF 40 ml.
Lanthanum triisopropoxide [L
a (Oi-Pr) ₃ ] 190 mg (0.6 mmol)
Of THF (3 ml) is added dropwise. After stirring at room temperature for 30 minutes, a hexane solution of 1.8 mmol of n-butyllithium (n-BuLi) (1.12 ml) is added dropwise at 0 ° C. Then, the mixture was stirred overnight at room temperature, THF was added,
A 0.06 mmol / dm ³ complex catalyst THF solution (A
0) was prepared. The metal complex obtained here is considered to have a structure in which Ln in the above general formula 5 is La (lanthanum) and X represents lithium, and a LaLi ₃ tris (R) -binaphthoxide complex [(R) -LLB and Omitted)
It is expressed as

Reference Example 2 Preparation of Rare Earth Metal Complex Solution A1 A THF solution (0.6 ml) containing water (0.6 mmol) was added to the rare earth metal complex solution A0, and THF was further added to obtain 0.06 mmol / dm ^3. Of the above complex catalyst THF
Solution (A1) was prepared.

Reference Example 3 Preparation of Rare-Earth Metal Complex Solution A2 In the same manner as in Reference Example 1, (R) -1,1′-dihydroxy-2,2′-binaphthalene and ytterbium isopropoxide [Yb ( Oi-Pr) ₃ ] to prepare a complex catalyst THF solution (A2). The metal complex obtained here is considered to have a structure in which Ln in the above general formula 5 is Yb and X represents lithium, and is represented by YbLi ₃ tris (R) -binaphthoxide complex [abbreviated as (R) -YbLB]. expressed.

Example 1 Synthesis of (S) -6,6-dimethyl-5-hydroxy-7-phenyl-3-heptanone Catalyst solution A0 prepared in Reference Example 1 (0.10 mmol,
1.67 ml) in 2-butanone (25 mmol, 1.8).
g) was mixed with stirring at -20 ° C. After 30 minutes, 2,2-dimethyl-3-phenyl-1-propanal (0.5 mmol, 181 mg) was added to the solution, and -2 was added.
Stirred at 0 ° C. for 185 hours. After treatment with 1 M HCl (2 ml), the mixture was extracted three times with 10 ml of diethyl ether. The extract was washed with saturated saline, washed and dried over Na ₂ SO ₄ . The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (diethyl ether: hexane =
1:12) to give the β-hydroxyketone (83 mg, yield 71%) as a colorless oil. Optical purity was 94% as a result of analysis by high performance liquid chromatography.

IR (neat) 3502, 2968, 1
^{705cm -1 1 H-NMR (270MHz} , CDCl 3): δ0.8
(S, 3H), 0.90 (s, 3H), 1.06 (t,
j = 7.3 Hz, 3H), 2.42-2.82 (m, 6
H), 3.18 (br, 1H), 3.77 (dd, j =
10.2, 2.3 Hz, 1H), 7.17-7.30
(M, 5H) ¹³ NMR (67.8 MHz, CDCl ₃ ) δ 7.5, 22.2, 23.2, 36.9,
37.8, 43.3, 44.4, 72.9, 12
5.9, 127.7, 130.8, 138.6,
231.3 [α] _D ²⁴ = −25.7 (c = 1.2, CHCl ₃ (94%
e. e. ) Where e. e. Represents the enantiomeric excess. )

Example 2 Synthesis of (S) -4,4-dimethyl-3-hydroxy-1′-naphthyl-1-pentanone Catalyst solution A0 prepared in Reference Example 1 (0.10 mmol,
1′-acenaphthone (4 mmol, 6
80 mg) were mixed at −20 ° C. with stirring. After 30 minutes, the solution was added to trimethylacetaldehyde (0.5 m
mol, 51 mg) and stirred at -20 ° C for 253 hours. After treatment with 1 M HCl (2 ml), the mixture was extracted three times with 10 ml of diethyl ether. The extract was washed with saturated saline, washed and dried over Na ₂ SO ₄ . The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (diethyl ether: hexane = 1: 12), and the β-hydroxyketone (70 mg, yield 55) was obtained.
%) As a white solid. Optical purity was determined by high performance liquid chromatography to be 76% e.g. e. Met.

M.p. ^{60~64 ℃ IR (KBr) 3473,2957,1686cm -1} 1 H-NMR (270MHz, CDCl 3): δ1.00
(S, 9H), 3.09 (dd, j = 17.0, 1
0.2 Hz, 1 H), 3.27 (dd, j = 17.0,
2.0 Hz, 1 H), 3.98 (dd, j = 10.2)
2.0 Hz, 1 H), 7.49-7.63 (m, 3
H), 7.87-7.90 (mm, 2H), 7.99-
8.02 (m, 1H), 8.57-8.60 (m, 1
H) ¹³ NMR (67.8 MHz, CDCl ₃ ) δ 25.8, 34.5, 43.7, 75.6.
124.3, 125.7, 126.5, 12
7.7, 128.0, 128.4, 132.8,
133.9, 126.1, 205.8, [α] _D ²⁴ = −68.4 (c = 0.27, CHCl ₃ (7
6% e. e. )

Example 3 (S) -4,4-Dimethyl-1,5-diphenyl-3-
Synthesis of hydroxy-1-pentanone Catalyst solution A0 prepared in Reference Example 1 (0.10 mmol,
Acetophenone (3.7 mmol, 4.67 ml)
45 mg) were mixed at −20 ° C. with stirring. After 30 minutes, the solution was added with 2,2-dimethyl-3-phenyl-1-.
Add propanal (0.5 mmol, 81 mg)
The mixture was stirred at -20 ° C for 87 hours. 1M-HCl (2ml)
And extracted three times with 10 ml of diethyl ether. The extract was washed with saturated saline, washed and dried over Na ₂ SO ₄ . The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (diethyl ether: hexane =
1:12) to give the β-hydroxyketone (127 mg, yield 90%) as a white solid. Optical purity was determined by high performance liquid chromatography to be 69% e.g. e. Met.

M.p. 35.5-36.5 ° C. IR (KBr) 3536, 3262, 2963, 167
^{8cm -1 1 H-NMR (270MHz} , CDCl 3): δ0.90
(S, 3H), 0.99 (s, 3H), 2.58 (d,
j = 13.9 Hz, 1H), 2.88 (d, j = 13.
9, 2H), 3.03 (dd, j = 17.5, 9.
9Hz, 1H), 3.23 (dd, j = 17.5,
2.0 Hz, 1 H), 3.96 (dd, j = 9.9,
2.0 Hz, 1H) 7.18-7.31 (m, 5
H), 7.45-7.62 (m, 3H), 7.94-
7.97 (m, 2H); ¹³ NMR (67.8 MHz, CDCl ₃ ) δ 22.4, 23.5, 38.1, 39.7,
44.6, 73.0, 125.9, 127.8,
128.1, 128.7, 130.9, 133.
5, 137.0, 138.7, 201.7, [α] _D ²⁵ = −50.6 (c = 0.27, CHCl ₃ (6
9% e. e. )

Example 4 Synthesis of (S) -5,5-dimethyl-4-hydroxy-6-phenyl-2-hexanone Catalyst solution A0 prepared in Reference Example 1 (0.10 mmol,
1.67 ml) in acetone (5 mmol, 290 mg)
Were mixed at −20 ° C. with stirring. After 30 minutes, 2,2-dimethyl-3-phenyl-1-propana-
(0.5 mmol, 81 mg), and the mixture was stirred at -20 ° C for 185 hours. After treatment with 1 M HCl (2 ml), the mixture was extracted three times with 10 ml of diethyl ether. The extract was washed with saturated saline, washed and dried over Na ₂ SO ₄ . The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (diethyl ether: hexane = 1: 12).
And purified by the above β-hydroxyketone (90 mg,
(82% yield) as a white solid. Optical purity was 74% as a result of analysis by high performance liquid chromatography.
e. e. Met.

. [0066] m.p 35.5~36.5 ℃ IR (neat) 3502,2964,1708cm -1 1 H-NMR (270MHz, CDCl 3): δ0.80
(S, 3H), 0.90 (s, 3H), 2.18 (s,
3H), 2.49 (d, j = 12.9, 1H), 2.
54 (dd, j = 17.5, 9.9 Hz, 1H),
2.66 (dd, j = 17.5, 2.6 Hz, 1
H), 2.79 (d, j = 12.9 Hz, 1H), 2.
9 (br, 1H), 3.77 (dd, j = 9.9,
2.6 Hz, 1H), 7.17-7.30 (m, 5
H) ¹³ NMR (67.8 MHz, CDCl ₃ ) δ 21.7, 22.8, 30.4, 37.3.
43.9, 44.2, 72.3, 125.4, 1
27.3, 130.3, 138.1, 210.1 [α] _D ²⁴ = −25.1 (c = 1.3, CHCl ₃ (74%
e. e. )

Example 5 (S) -3-Hydroxy-4-methyl-1-phenyl-
Synthesis of 1-pentanone The catalyst solution A0 prepared in Reference Example 1 (0.10 mmol,
1.67 ml) to which acetophenone (4.0) was added.
mmol, 480 mg), isobutyraldehyde (0.
5 mmol, 36 mg), and the mixture was stirred at −30 ° C. for 277 hours, and the β-hydroxyketone (59 mg, yield 5
9%). The optical purity was determined by high performance liquid chromatography to be 54% e.g. e. Met.

Example 6 Synthesis of (S) -1,5-diphenyl-3-hydroxy-1-pentanone Catalyst solution A0 prepared in Reference Example 1 (0.10 mmol,
Acetophenone (4.07 ml).
mmol, 480 mg) and hydrocinnamaldehyde (0.5 mmol, 36 mg).
After stirring for an hour, the β-hydroxyketone (36 mg, yield 28%) was obtained. The optical purity was determined by high performance liquid chromatography to be 54% e.g. e. Met.

Example 7 Synthesis of (R) -1,3-diphenyl-3-hydroxy-propanone Catalyst solution A2 prepared in Reference Example 3 (0.10 mmol,
Acetophenone (4.07 ml).
mmol, 480 mg), benzaldehyde (0.5 m
mol, 53 mg), and the mixture was stirred at −20 ° C. for 198 hours.
%). The optical purity was determined by high performance liquid chromatography to be 36% e.g. e. Met.

Example 8 Synthesis of (S) -3-hydroxy-phenyl-1-pentanone Catalyst solution A1 prepared in Reference Example 2 (0.10 mmol,
1.67 ml), and acetophenone (2.5
mmol, 300 mg) and trimethylacetaldehyde (0.5 mmol, 50 mg).
After stirring for an hour, the β-hydroxyketone (44 mg, yield 43%) was obtained. The optical purity was 89% e.g. as a result of analysis by high performance liquid chromatography. e. Met.

Example 9 Synthesis of (S) -3-hydroxy-phenyl-1-pentanone Catalyst solution A0 prepared in Reference Example 1 (0.10 mmol,
1.67 ml), and acetophenone (2.5
mmol, 300 mg) and trimethylacetaldehyde (0.5 mmol, 50 mg).
After stirring for an hour, the above β-hydroxyketone (78 mg, yield 76%) was obtained. Optical purity was determined by high performance liquid chromatography to be 88% e.g. e. Met.

Example 10 Synthesis of (S) -3-hydroxy-phenyl-1-pentanone Catalyst solution A0 prepared in Reference Example 1 (0.10 mmol,
Acetophenone (0.77 ml).
5 mmol, 90 mg) and trimethylacetaldehyde (0.5 mmol, 50 mg).
After stirring for 5 hours, the β-hydroxyketone (44 mg,
Yield 43%). The optical purity was analyzed by high performance liquid chromatography, and as a result, 87% e. e. Met.

Example 11 Synthesis of (S) -3-hydroxy-phenyl-1-pentanone Catalyst solution A0 prepared in Reference Example 1 (0.10 mmol,
Acetophenone (5.0.1 ml).
mmol, 600 mg) and trimethylacetaldehyde (0.5 mmol, 50 mg).
After stirring for an hour, the above β-hydroxyketone (84 mg, yield 81%) was obtained. Optical purity was determined by high performance liquid chromatography to be 91% e.g. e. Met.

[0074]

According to the present invention, an optically active β-hydroxy ketone is directly produced in a single step by an asymmetric aldol reaction using a metal complex obtained by reacting an optically active binaphthol or a binaphthol derivative with a rare earth compound. Can be obtained. In addition, a novel optically active β-hydroxyketone useful as a pharmaceutical intermediate can be obtained by the production method of the present invention.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 61/00 300 C07B 61/00 300 C07M 7:00

Claims (8)

[Claims] 1. A process for producing a chiral β-hydroxyketone, comprising subjecting an asymmetric aldol reaction in the presence of a metal complex obtained by reacting an optically active binaphthol or a binaphthol derivative with a rare earth compound. 2. An asymmetric aldol in the presence of a metal complex obtained by reacting an aldehyde compound represented by the following general formula 1 and a methyl ketone compound represented by the following general formula 2 with an optically active binaphthol or a binaphthol derivative and a rare earth compound. A method for producing a chiral β-hydroxy ketone, which comprises reacting. Embedded image [In the formula 1, R ₁ represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group (all of these substituents are a halogen atom, a hydroxyl group, an alkoxy group, an aminoalkyl group, a thioalkyl group, an aromatic group, or a heterocyclic group. An aromatic group or a heterocyclic group (the aromatic group and the heterocyclic group each may be an alkyl group, an alkoxy group, a halogen group, a nitro group, a cyano group, an alkoxycarbonyl group, or an alkanoyl group). Group, amino group, N-monoalkylamino group, N, N-dialkylamino group, carbamoyl group,
1 to 3 identical or different substituents selected from the group consisting of N-monoalkylcarbamoyl, N, N-dialkylcarbamoyl, aminoalkyl, N-monoalkylaminoalkyl, and N, N-dialkylaminoalkyl Which may have a group). [Chemical formula 2] [In the formula 2, R ₂ represents an alkyl group, a cycloalkyl group, an alkenyl group, or an alkynyl group (all of these substituents are a halogen atom, a hydroxyl group, an alkoxy group, an aminoalkyl group, a thioalkyl group, an aromatic group, or a heterocyclic group. Optionally substituted with a group), an alkoxy group, a thioalkoxy group,
Or an aromatic group (the aromatic group is an alkyl group, an alkoxy group, a halogen group, a nitro group, a cyano group, an alkoxycarbonyl group, an alkanoyl group, an amino group, an N-monoalkylamino group, an N, N-dialkylamino group, 1 to 3 identical members selected from the group consisting of carbamoyl, N-monoalkylcarbamoyl, N, N-dialkylcarbamoyl, aminoalkyl, N-monoalkylaminoalkyl, and N, N-dialkylaminoalkyl Or may have a different substituent). ] 3. The method according to claim 1, wherein the metal complex comprises a rare earth metal compound,
Optical activity 1,1 ′ represented by the following general formula 3 or 4
The method for producing an optically active β-hydroxy ketone according to claim 1 or 2, wherein the metal complex is a metal complex obtained by reacting a bi-2-naphthol with an alkali metal compound. Embedded image (In Formulas 3 and 4, R ₃ and R ₄ may be the same or different and represent a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, a halogen atom, a trialkylsilylethynyl group, or a cyano group.) 4. The method according to claim 1, wherein the asymmetric aldol reaction is carried out at -80 ° C.
2. The method according to claim 1, wherein the heating is performed in a temperature range of 50 ° C.
4. The method for producing an optically active β-hydroxy ketone according to any one of claims 1 to 3. 5. An (S) -6,6-dimethyl-5-hydroxy-7-phenyl-3-heptanone. 6. (S) -4,4-Dimethyl-3-hydroxy-1′-naphthyl-1-pentanone. 7. (S) -4,4-Dimethyl-1,5-diphenyl-3-hydroxy-1-pentanone. 8. An (S) -5,5-dimethyl-4-hydroxy-6-phenyl-2-hexanone.