JP2734457B2 - Asymmetric epoxidation reaction - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to optically active benzopyran compounds which are effective for treating hypertension, asthma, etc.
The present invention relates to a method for producing an optically active epoxy compound which is an important synthetic intermediate of a medicine.

[0002]

BACKGROUND OF THE INVENTION The most common method in which an epoxy compound is used for the production of optically active pharmaceuticals is obtained at a more advanced stage (for example, by reaction with ammonia). Diamines), specifically the optical resolution of pyranobenzoxadiazole compounds described in JP-A-3-114286, EP 409165 and US Pat. No. 5,097,037. Law and J. Med. Chem., 35, 1
Examples of the synthesis of optically active indene oxide described in the literature of 685-1701 (1992) can be mentioned. The second method is to derivatize a halohydrin compound, which is a precursor of an epoxy compound, and then diastereomerically separate at that stage, or use the stereoselectivity of an enzyme. Specifically, Circulation Research, 62 , 4, 679-686 (198
The optical resolution method of the benzopyran compound described in 8) can be mentioned. Each of these two methods has a major economic problem that the unnecessary enantiomer is totally wasted because the racemate is separated.

[0003] On the other hand, recently, an asymmetric catalyst synthesis method using an optically active manganese complex has been found, and has attracted attention as an efficient method for producing an optically active epoxy compound.
For example, Jacobsen et al.'S catalyst described in J. Am. Chem. Soc., 113, 7063-7064, (1991) and Katsuki described in JP-A-5-301878 and European Patent Publication 535377. These catalysts. This method solves the problem that the enantiomer on the unnecessary side is wasted unlike the racemic separation method,
An efficient production method is provided to provide good chemical and optical yields depending on the type of olefin as a raw material.
However, the catalysts reported so far do not always give good results in the production of all optically active epoxies, and the current situation is that active research is being carried out to measure improvements. .

[0004]

Means for Solving the Problems The present inventors have developed an olefin compound [II] having no vicinal functional group.

[0005]

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Wherein R ⁵ and R ⁶ are each independently
An amino group which may be protected by a protecting group such as a hydrogen atom, a cyano group, a nitro group, or an acetyl group, a halogen atom, C ₁
-C ₄ alkyl group, C ₁ -C ₄ alkoxy group, halo C ₁ -C ₄ alkyl group, a carboxy group, a formyl group, C ₁ -C ₄ alkanoyl group, aroyl group, halo C ₁ -C ₄ alkanoyl group, a carbamoyl group, C ₁ -C ₄ alkylsulfinyl group, an arylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, an arylsulfonyl group, a sulfonamido group, or means a mono- or di-C ₁ -C ₄ alkylsulfonamido group, or When R ⁵ and R ⁶ are in the ortho position, they are joined together,

[0007]

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(Wherein, n represents an integer of 0 or 1). R ⁷ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group. R ⁸ is a C ₁ -C ₄ alkyl group or C ₁ -C ₄
It means an alkoxy group. Or R ⁷ and R ⁸ together

[0009]

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(R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group). ] As the starting material [II
I]

[0011]

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As a result of intensive studies on the production method of (R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as above. The absolute configuration of the carbon atom indicated by * means R or S.) [I] or [I ']

[0013]

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[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, a phenyl group (the phenyl group is a halogen atom, C ₁ -C 4 ₄ alkyl group, C ₁ -C ₄ alkoxy group, cyano group or nitro group), and any two of them may form a ring together. X ^- represents an anion pair capable of forming a salt.

Y represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a nitro group or a cyano group. R represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a phenyl group (the phenyl group may be substituted with a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group) or substitution It means a silyl group. It has been found that by using the optically active manganese complex represented by the formula (1) as an asymmetric catalyst, the desired optically active epoxy compound represented by the formula [III] can be obtained with a high asymmetric yield. Was.

The substituents R ¹ , R ² , R ³ and R ⁴ of the optically active manganese complexes [I] and [I ′] are hydrogen, methyl, ethyl, normal propyl, isopropyl and normal. C ₁ -C ₄ alkyl group such as butyl group, isobutyl group, secondary butyl group, tertiary butyl group, or fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, normal propyl group, isopropyl group, normal Butyl group, isobutyl group, secondary butyl group, tertiary butyl group, methoxy group, ethoxy group, normal propoxy group, isopropoxy group, normal butoxy group, isobutoxy group, secondary butoxy group, tertiary butoxy group, cyano group and nitro group And a phenyl group which may be substituted with a substituent selected from Details, a hydrogen atom, an ethyl group, a tertiary butyl group, a phenyl group, 3,5-dimethylphenyl group.

Further, any ^{two of} R ¹ , R ² , R ³ and R ⁴ together form a C ₄ -C ₈ ring such as cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. Is also good.

R is a phenyl group, fluorophenyl, chlorophenyl, bromophenyl, tolyl, ethylphenyl, tertiarybutylphenyl, 3,5-dimethylphenyl group, methoxyphenyl (all ortho,
There are meta field and para field. ), Hydrogen atom, methyl group,
Ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, secondary butyl group,
Examples include a tertiary butyl group and substituted silyl.

As the substituted silyl, for example, trimethylsilyl, triethylsilyl, trinormalpropylsilyl, triisopropylsilyl, trinormalbutylsilyl, triisobutylsilyl, trinormalhexylsilyl, dimethylethylsilyl, dimethylnormalpropylsilyl, dimethylnormalbutyl Silyl, dimethyl isobutylsilyl, dimethyl tertiary butylsilyl, dimethyl normal pentyl silyl, dimethyl normal octyl silyl, dimethyl cyclohexyl silyl, dimethyl texyl silyl, dimethyl-2,3-dimethylpropyl silyl, dimethyl-2- (bicycloheptyl) silyl , Dimethylbenzylsilyl, dimethylphenylsilyl, dimethylparatolylsilyl, dimethylfurofemesylsilyl, methyldiphenylsilyl, It can be mentioned Li triphenylsilyl, diphenyl-tert-butylsilyl, tribenzylsilyl, diphenyl vinyl silyl, diphenyl n-butyl silyl, phenyl methyl vinyl silyl and the like.

Y is a hydrogen atom, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom), a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group,
It means an isobutyl group, a secondary butyl group, a tertiary butyl group, a methoxy group, an ethoxy group, a normal propoxy group, an isopropoxy group, a normal butoxy group, an isobutoxy group, a secondary butoxy group, a tertiary butoxy group, a nitro group or a cyano group. .

The optically active manganese complexes [I] and [I '] form various anion pair (X ⁻ ) salts because manganese, which is the central metal, can take an oxidation state from monovalent to pentavalent. Can be. As a salt-forming ion pair, a monovalent
^{OH -, F -, Cl -} , Br -, I -, CH 3 CO 2 -, PF 6 -, ClO 4 -, B
Examples thereof include F ₄ ⁻ , divalent CO ₃ ²⁻ , SO ₄ ²⁻ , and trivalent PO ₄ ³⁻ ions, all of which can be used as the asymmetric catalyst for the purpose of the present invention.

A typical synthesis example of the optically active manganese complexes [I] and [I '] will be described below. The scheme includes [I]
｛R ¹ = R ³ = R = Ph (phenyl group), R ² = R ⁴ = H, X = CH
₃ CO ₂ ^-} is shown only synthesis of, [I] and [I '] Because the relationship of the antipodes each ^{other, [I'] R 1 =} R 3 = R = Ph ( phenyl group), ^{R 2 = R 4 = H,} X = CH 3 CO 2 - to synthesize} need only change the optically active binaphthol compound and a diamine compound as a starting material to those with the opposite configuration.

That is, an optically active binaphthol compound having molecular asymmetry is reacted with N-phenyltrifluoromethanesulfonimide in the presence of (a) collidine to convert one hydroxyl group to triflate, and (b) [1,2-chloride] Bis (diphenylphosphino) ethane] nickel (II) is replaced by phenyl Grignard reagent as catalyst. Next, (c) methoxymethylation with chloromethyl methyl ether under basic conditions, (d) lithiation with t-butyllithium, (e) formylation with dimethylformamide, (f) demethylation with trimethylsilyl bromide A salicylaldehyde compound is synthesized via methoxymethylation. R
In the synthesis of a compound having a different portion, the kind of the Grignard reagent may be changed in the step (b). (Scheme 1)

There are many other diamine compounds which are commercially available, but examples of the synthesis of diamine compounds which are not commercially available include R ¹ = R ³ = 3,5-dimethylphenyl group and R ²
= R ⁴ = H is shown in Scheme 2. That is,
(G) 3,5-dimethylbenzoic acid is converted into an alcohol form by lithium aluminum hydride reduction, and (h) oxidized with manganese dioxide to synthesize an aldehyde form. This is dimerized with (i) titanium tetrachloride and zinc dust, and (j)
By the asymmetric diolation reaction of osmium tetroxide with hydroquinidine 4-chlorobenzoate as an asymmetric source, the compound is converted into a high-purity optically active diol form, and (k) hydroxyl group formation by mesyl chloride under basic conditions Mesylation,
This is a method of obtaining a target diamine compound through (l) a substitution reaction with sodium azide and (m) reduction of azide with lithium aluminum hydride. However, the method for synthesizing the diamine compound varies depending on the type of the substituent, and is not necessarily limited to this method.

The salicylaldehyde compound and the diamine compound obtained as described above are converted into an alcohol solvent such as ethanol and methanol, a nitrile solvent such as acetonitrile and propionitrile, dichloromethane,
Imine mixed in a halogen solvent such as chloroform, an aromatic hydrocarbon solvent such as benzene and toluene, an ether solvent such as tetrahydrofuran and diethyl ether, and a hydrocarbon solvent such as hexane and heptane Form the compound. Preferred solvents include ethanol, methanol, acetonitrile, dichloromethane, toluene and the like. At this time, if necessary, an equimolar amount or more of a dehydrating agent such as anhydrous magnesium sulfate, boric anhydride or molecular sieve may be allowed to coexist. Alternatively, the generated water may be removed by azeotropic dehydration with a solvent. There is no particular limitation on the reaction temperature,
The temperature can be from -20 ° C to the boiling point of the solvent used, but it is preferably carried out in the range of 0 ° C to 50 ° C. It is not always necessary to take out the imine compound from the reaction system, and it can be carried out continuously with the next manganese complex synthesis.

The obtained imine compound is treated with an alcoholic solvent such as ethanol and methanol, acetonitrile,
It is dissolved or suspended in a nitrile-based solvent such as propionitrile or a halogen-based solvent such as dichloromethane or chloroform, and 0.5 to 10 molar equivalents, preferably 0.8 to 2 molar equivalents. The desired optically active manganese complex [I] can be obtained by adding manganese acetate and reacting in the presence of oxygen. If necessary
It is also possible to replace CH ₃ CO ₂ ^- ions with Cl ^- and PF ₆ ^- other anions, for example by exchanging Cl ^- ions by adding equimolar or more lithium chloride in the reaction system. be able to. Preferred solvents include ethanol, methanol, acetonitrile, dichloromethane and the like. The reaction temperature is not particularly limited and can be from -20 ° C to the boiling point of the solvent used, but is preferably in the range of 0 ° C to 50 ° C. Oxygen is supplied by blowing a large excess of air or oxygen gas into the reaction system, or by stirring in an open system in the atmosphere.

As a specific example, Scheme 3 shows that the diamine compound is (1S, 2S) -1,2-diphenyl-1,2
-Active manganese complex which is ethanediamine [I]
｛R ¹ = R ³ = R = Ph (phenyl group), R ² = R ⁴ = H, X = CH
₃ CO ₂ ^- shows an example of the synthesis of}.

[0028]

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[0029]

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Wherein Ph is phenyl and Tf ₂ NPh is N-
Phenyltrifluoromethanesulfonimide, PhMgBr
Replaces phenylmagnesium bromide with NiCl ₂ (dppe)
Is [1,2-bis (diphenylphosphino) ethane] nickel (II) chloride, MOMCl is chloromethyl methyl ether, (i-Pr) ₂ NEt is diisopropylethylamine, THF is tetrahydrofuran, DMF Is dimethylformamide, TMSBr is trimethylsilyl bromide, LAH
Represents lithium aluminum hydride, and Et ₂ O represents diethyl ether. ]

Next, a specific method of the asymmetric epoxidation reaction will be described.

[0032]

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The amount of the optically active manganese complexes [I] and [I '] used as the asymmetric catalyst is usually 0.1 mol% to 100 mol with respect to the starting olefin compound [II].
%, Preferably in the range of 1 mol% to 5 mol%. Examples of the oxidizing agent include iodosylbenzene, 2
-Iodosylbenzoic acid, sodium hypochlorite, tetrabutylammonium periodate, hydrogen peroxide, oxygen, air and the like can be used. When the oxidizing agent is iodosylbenzene or 2-iodosylbenzoic acid, the amount used is usually 1 equivalent to 1 equivalent to the olefin compound [II] as the raw material.
It is in a range of 0 equivalent, preferably 1 equivalent to 3 equivalents. When the oxidizing agent is sodium hypochlorite, tetrabutylammonium periodate or hydrogen peroxide, the amount used is usually in the range of 1 equivalent to 100 equivalents, preferably 3 equivalents to the olefin compound [II] as the raw material. It is in the range of 30 equivalents.
When air or oxygen gas is used as the oxidizing agent, the air or oxygen gas is supplied by blowing a large excess of air or oxygen gas into the reaction system or by stirring in an open system in the atmosphere.

As the reaction solvent, water, acetonitrile,
Dichloromethane, dichloroethane, a mixed solvent thereof and the like can be used. Particularly when the oxidizing agent is sodium hypochlorite, it may be preferable to carry out the reaction in a two-phase system such as water and dichloromethane.

In the reaction system, pyridine N-oxide,
A component having coordination ability can coexist with a manganese complex such as phenylpyridine N-oxide, lutidine N-oxide or 2-methylimidazole. There is no particular limitation on the amount used.

The reaction temperature is usually in the range of -50 ° C to 50 ° C,
Preferably, the temperature is in the range of -20C to 25C.

After completion of the reaction, the objective optically active compound [III] can be isolated by concentrating the organic solvent under reduced pressure and separating and purifying it by silica gel column chromatography or distillation. Their optical purity can be analyzed by an optically active liquid chromatography column (Daicel Chemical Industries, Inc., Chiralcel OJ, etc.) or by optical rotation (see Examples for analysis conditions).

The olefin compound [II] to which the present asymmetric epoxidation reaction can be applied is represented by the formula [IV]

[0039]

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(Wherein R ⁵ and R ⁶ are each independently
An amino group which may be protected by a protecting group such as a hydrogen atom, a cyano group, a nitro group, or an acetyl group, a halogen atom, C ₁
-C ₄ alkyl group, C ₁ -C ₄ alkoxy group, halo C ₁ -C ₄ alkyl group, a carboxy group, a formyl group, C ₁ -C ₄ alkanoyl group, aroyl group, halo C ₁ -C ₄ alkanoyl group, a carbamoyl group, C ₁ -C ₄ alkylsulfinyl group, an arylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, an arylsulfonyl group, a sulfonamido group, or means a mono- or di-C ₁ -C ₄ alkylsulfonamido group, or R ⁵ and R ⁶ together form a ring

[0041]

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(Wherein, n represents an integer of 0 or 1). R ⁹ and R ¹⁰ each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group. Benzopyran derivative represented by the formula [VI]

[0043]

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The indene derivatives shown above are exemplified.

The benzopyran derivative is preferably

[0046]

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(Wherein R ⁵ and R ⁶ are each independently
An amino group which may be protected by a protecting group such as a hydrogen atom, a cyano group, a nitro group, or an acetyl group, a halogen atom, C ₁
-C ₄ alkyl group, C ₁ -C ₄ alkoxy group, halo C ₁ -C ₄ alkyl group, a carboxy group, a formyl group, C ₁ -C ₄ alkanoyl group, aroyl group, halo C ₁ -C ₄ alkanoyl group, a carbamoyl means group, C ₁ -C ₄ alkylsulfinyl group, an arylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, an arylsulfonyl group, a sulfonamido group, a mono- or di-C ₁ -C ₄ alkylsulfonamido group. )as well as

[0048]

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(Wherein, n represents an integer of 0 or 1).

As the indene derivative, a compound of the formula

[0051]

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The indene represented by

For each compound, the desired epoxy compound can be obtained by the above-mentioned method.

[0054]

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R ⁵ and R ⁶ which are substituents of the compounds represented by the formulas [IV] and [V] are each independently a hydrogen atom,
A cyano group, a nitro group, an amino group which may be protected with a protecting group such as an acetyl group, a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a halo C ₁ -C ₄ alkyl group, Carboxy group, formyl group, C ₁ -C ₄ alkanoyl group, aroyl group, halo C ₁ -C ₄ alkanoyl group, carbamoyl group, C _1-
C ₄ alkylsulfinyl group, an arylsulfinyl group,
C ₁ -C ₄ alkylsulfonyl group, arylsulfonyl group,
Means a sulfonamide group, a mono- or di-C ₁ -C ₄ alkylsulfonamide group, or R ⁵ and R ⁶ together

[0056]

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(Wherein, n represents an integer of 0 or 1). R ⁹ and R ¹⁰ each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group.

Examples of the amino-protecting group include acyl groups such as acetyl group, propionyl group, trifluoroacetyl group and benzoyl group, and alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group and tert-butoxycarbonyl group. Examples include a tosyl group and a benzyl group. Preferably, they are an acetyl group and a tertiary butoxycarbonyl group.

The halogen atom is a fluorine atom, a chlorine atom,
Bromine and iodine.

The C ₁ -C ₄ alkyl group means a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group, a secondary butyl group and a tertiary butyl group.

The C ₁ -C ₄ alkoxy group means a methoxy group, an ethoxy group, a normal propoxy group, an isopropoxy group, a normal butoxy group, an isobutoxy group, a secondary butoxy group or a tertiary butoxy group.

The halo C ₁ -C ₄ alkyl group means the above C ₁ -C ₄ alkyl group substituted by a halogen atom, and includes a trifluoromethyl group, a monochloromethyl group, a pentafluoroethyl group and the like.

Examples of the C ₁ -C ₄ alkanoyl group include an acetyl group and a propionyl group.

Examples of the aroyl group include a benzoyl group, a toluoyl group and a naphthoyl group.

Examples of halo C ₁ -C ₄ alkanoyl groups include trifluoroacetyl, monochloroacetyl, pentafluoropropionyl and the like.

[0066] The C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkyl in C ₁ -C ₄ alkylsulfonyl group, and a mono- or di-C ₁ -C ₄ alkylsulfonamido group is as defined above, arylsulfinyl Examples of the aryl in the arylsulfonyl include a phenyl group and a tolyl group.

[0067]

As described above, the present invention has a novel structure for producing an optically active pharmaceutical product or an optically active epoxy compound useful as an intermediate thereof from an olefin compound having no nearby functional group as a raw material. It is possible to provide a suitable catalyst.

[0068]

【Example】

Reference Example 1

[0070]

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[Wherein Ph is phenyl and Tf ₂ NPh is N-
Phenyltrifluoromethanesulfonimide, PhMgBr
Replaces phenylmagnesium bromide with NiCl ₂ (dppe)
Is [1,2-bis (diphenylphosphino) ethane] nickel (II) chloride, MOMCl is chloromethyl methyl ether, (i-Pr) ₂ NEt is diisopropylethylamine, THF is tetrahydrofuran, DMF Is dimethylformamide, TMSBr is trimethylsilyl bromide, DMAP
Represents dimethylaminopyridine, and Et ₂ O represents diethyl ether. ]

Synthesis of 1 (R)-(+)-binaphthol (286 mg, 1.0 m
mol) in dichloromethane solution (4 mL).
-Collidine (132 μL, 1.0 mmol), dimethylaminopyridine (15 mg, 0.12 mmol), N-
Phenyltrifluoromethanesulfonimide (357m
g, 1.0 mmol), and the mixture was refluxed for 12 hours.
After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (elution solvent: toluene). Yield of 1 (yield): 378 mg (90%). Colorless crystals.

Synthesis 1 of 2 (209 mg, 0.5 mmol) and [1,2-bis (diphenylphosphino) ethane] nickel (II) chloride
To a mixture of (5.3 mg, 0.01 mmol) was slowly added phenylmagnesium bromide (2.5 mL, 0.8 M in diethyl ether, 2.0 mmol). After refluxing for 1 hour, the mixture was cooled to room temperature, and a saturated aqueous ammonium chloride solution was added to stop the reaction. The reaction mixture was extracted with diethyl ether, and the organic layer was washed successively with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (elution solvent: hexane / toluene = 4/6). Yield of 2 (Yield): 15
6 mg (90%). Colorless crystals.

¹ H NMR (400 MHz): 8.10 (d, J = 8.30 Hz, 1 H),
7.79 (d, J = 8.30Hz, 1H), 7.78 (d, J = 9.28Hz, 2H), 7.72
(d, J = 8.79Hz, 1H), 7.54-7.50 (m, 1H), 7.36-7.20 (m,
4H), 7.15-7.04 (m, 7H).

Synthesis 2 of 3 To a dichloromethane solution (4 mL) of 365 mg (1.1 mmol) was added diisopropylethylamine (530 μl).
L, 3.0 mmol) and chloromethyl methyl ether (230 μL, 3.0 mmol) were sequentially added, and the mixture was stirred at room temperature for 1 day. After washing the reaction mixture with water, it was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (elution solvent: hexane / diethyl ether = 19/1). Yield of 3 (yield): 346 mg (83%). Colorless crystals.

¹ H NMR (90 MHz): 7.00-8.22 (m, 18H), 4.90
(ABq, J = 7.07Hz, 2H), 2.11 (s, 3H).

Synthesis 3 of 4 (140 mg, 0.36 mmol) was dissolved in tetrahydrofuran (1.5 mL) and cooled to −78 ° C. t-Butyllithium (530 μL, 1.
5M, 0.8 mmol) and stirred at −78 ° C. for 3 hours, and then dimethylformamide (140 μL, 1.8 m
mol) was added, the cooling bath was removed, and stirring was continued for another hour. The reaction was stopped by dropwise addition of a saturated aqueous solution of ammonium chloride, and the reaction mixture was extracted with diethyl ether. The organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (elution solvent: hexane / diethyl ether = 19 /
Purified according to 1). Yield of 4 (Yield): 139 mg
(91%). Yellow crystals.

¹ H NMR (90 MHz): 10.42 (s, 1 H), 8.50-7.00
(m, 17H), 4.53 (ABq, J = 6.17Hz, 2H), 2.94 (s, 3H).

To a mixture of Synthesis 4 of 5 (154 mg, 0.37 mmol) and Molecular Sieves 4A was added dichloromethane (1.5 mL), and the mixture was cooled to 0 ° C., and trimethylsilyl bromide (1
95 μL, 1.5 mmol) and stirred for 4 hours.
After the reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate, the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (elution solvent: hexane / toluene = 3/7). Yield of 5 (Yield): 13
2 mg (95%). Yellow crystals.

¹ H NMR (400 MHz): 10.41 (s, 1 H), 10.10 (s,
1H), 8.17 (s, 1H), 8.05 (d, J = 8.30Hz, 1H), 7.97 (d, J
= 8.30Hz, 1H), 7.85 (d, J = 7.81Hz, 1H), 7.49 (t, J = 3.4
2Hz, 1H), 7.34-7.19 (m, 6H), 7.02-7.00 (m, 3H).

Reference Example 2

[0082]

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[Wherein, LAH means lithium aluminum hydride, THF means tetrahydrofuran, Et ₂ O means diethyl ether, MsCl means mesyl chloride, and DMF means dimethylformamide. ]

Synthesis of 6 3,5-dimethylbenzoic acid (4.5 g, 30 mmol)
Of tetrahydrofuran (120 mL) was cooled to 0 ° C., and lithium aluminum hydride (1.7 g, 45 m
mol) was added slowly. After refluxing for 2 hours, methanol (8 mL) and 3N hydrochloric acid (50 mL) were added to stop the reaction. The reaction mixture was extracted with diethyl ether,
The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 8/2). 6 yield (yield): 3.0 g (74%). Colorless oil.

[0085] 7 Synthesis of 6 (8.60g, 63mmol) in diethyl ether solution γ- manganese oxide (54.8 g, 630 mmol)
Was added and stirred at room temperature for 16 hours. The reaction mixture was filtered through celite and concentrated. The obtained crude product (8.05
g) was used in the next reaction without purification.

Synthesis of 8 Titanium tetrachloride (9.9 ml, 90 mL) was added to a dioxane solution (400 mL) of the crude product 7 (8.05 g, 60 mmol).
mmol) and zinc powder (11.8 g, 180 mmol)
Was suspended in dioxane (200 mL), and the mixture was refluxed for 4 hours. After partitioning the reaction mixture between water and diethyl ether, the organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethanol. 8 yield (yield): 3.45 g (48 from 6 )
%). Colorless crystals.

¹ H NMR (90 MHz): 7.24 (s, 4H), 7.14 (s, 2
H), 7.00 (s, 2H), 2.36 (s, 12H).

Synthesis of 9 Hydroquinidine 4-chlorobenzoate (186 mg, 0.
4 mmol), potassium ferricyanide (2.96 g,
9.0 mmol), potassium carbonate (1.24 g, 9.0
mmol) in a mixture of t-butanol (20 mL), water (20 mL), and potassium osmate dihydrate (11.
1 mg, 0.03 mmol) and 8 (709 mg, 3.0
mmol) was added in sequence, and the mixture was stirred at room temperature for 24 hours. After adding sodium sulfite (15 g, 0.12 mmol) and further stirring for 30 minutes, the two layers were separated, the aqueous layer was extracted with dichloromethane, and the organic layers were combined and concentrated. The residue was diluted with ethyl acetate, washed sequentially with 1 M sulfuric acid, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 9/1 to 7/3). 9 yield (yield): 550 mg (67%). Colorless crystals. The optical purity of 9 was determined by high performance liquid chromatography analysis using a chiral column (DAICEL CHIRALCEL OD,
Elution solvent: hexane / isopropanol = 15/1) to give 99% e. e. It was decided above.

¹ H NMR (90 MHz): 6.96 (m, 6H), 4.76 (s, 2
H), 2.63 (br s, 2H), 2.30 (s, 12H).

Synthesis 9 of 10 To a dichloromethane solution (8 mL) of 9 (550 mg, 2.0 mmol) was added triethylamine (610 μL, 4.4).
mmol), mesyl chloride (340 μL, 4.4 mm
ol) were sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water and concentrated. The residue is subjected to silica gel column chromatography (elution solvent: diethyl ether)
And purified. Yield (yield) of 10 : 839 mg (9
8%). Colorless crystals.

¹ H NMR (90 MHz): 6.80-7.10 (m, 6H), 5.74
(s, 2H), 2.86 (s, 6H), 2.23 (s, 12H).

Synthesis 10 of 11 To a mixture of 10 (1.7 g, 4.0 mmol) and sodium azide (572 mg, 8.8 mmol) was added dimethylformamide (16 mL), and the mixture was stirred at 80 ° C. for 7 hours. After partitioning the reaction mixture between water and ethyl acetate, the organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (elution solvent: hexane). Yield of 11 (yield): 568 mg (48%). Colorless crystals.

¹ H NMR (90 MHz): 7.00 (br s, 2H), 6.84 (br
s, 2H), 4.63 (s, 2H), 2.28 (s, 12H).

Embodiment 1

[0095]

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[Wherein, EtOH means ethanol. ]

Synthesis of [I-1] A solution of 11 (32 mg, 0.1 mmol) in tetrahydrofuran (1 mL) was cooled to 0 ° C., and lithium aluminum hydride (7.6 mg, 0.2 mmol) was added.
After the mixture was stirred at room temperature for 30 minutes, a saturated aqueous potassium fluoride solution (380 μL, 1.59 N, 0.6 mmol) was used.
Was added to stop the reaction. The reaction mixture was filtered through celite, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The obtained crude products 12 and 5 (75.
8 mg, 0.2 mmol) was dissolved in ethanol (4 mL) and stirred at room temperature for 1 hour. After once concentrating the reaction mixture, manganese acetate tetrahydrate (24.6 mg, 0.1
mmol) and ethanol (4 mL).
Stirred for hours. The resulting crystals were collected by filtration and washed with ethanol and then hexane to give [I-1] 39.3.
mg. After the filtrate was further concentrated, the residue was recrystallized from dichloromethane-hexane to obtain 7.7 mg of [I-1]. Total yield (yield) of [I-1]: 47.0 mg ( 11
43%). IR (KBr): 3053, 2920, 1599, 1493, 1425, 1333, 1296,
1223, 1188, 1148, 1128, 1045, 1028, 953, 860, 733,
700, 575, 548 cm ^-1 .

The same reaction was carried out to obtain the compounds of the present invention [I-2] to
[I-8] was obtained.

[0099]

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[I-2] IR (KBr): 3447, 3422, 3049, 3013, 2916, 2680, 1655,
1603, 1558, 1506, 1420, 1387, 1333, 1296, 1257, 12
23, 1186, 1148, 1117, 1057, 1024, 953, 887,851, 81
8, 785, 746, 706, 683 cm ^-1 . [I-3] IR (KBr): 3431, 3053, 1599, 1493, 1443, 1425, 1385,
1333, 1296, 1223, 1188, 1148, 1128, 1090, 1072, 10
45, 1028, 999, 982, 953, 860, 733, 700, 681cm ^-1 . [I-4] IR (KBr): 3447, 3422, 3057, 3041, 2928, 1611, 1558,
1491, 1452, 1420, 1389, 1342, 1310, 1281, 1229, 12
13, 1188, 1150, 1126, 1016, 955, 799, 775, 746, 70
0 cm ^-1 . [I-5] IR (KBr): 3053, 2922, 2853, 1609, 1555, 1508, 1454,
1423, 1387, 1344, 1327, 1300, 1227, 1188, 1148, 81
0, 746, 702 cm ^-1 .Calcd. For C ₆₀ H ₄₅ N ₂ O ₄ Mn: C, 78.94; H, 4.97; N, 3.07
%. Found: C, 79.80; H, 5.32; N, 3.07%. [I-6] IR (KBr): 3051, 2920, 1605, 1555, 1508, 1454, 1389,
1344, 1327, 1300, 1221, 1188, 1150, 1126, 810, 77
0, 704, 687 cm ^-1 .Calcd. For C ₆₀ H ₄₅ N ₂ O ₄ Mn ・ 1.5H ₂ O: C, 76.67; H, 5.15;
N, 2.98%. Found: C, 76.50; H, 5.22; N, 3.06%. [I-7] IR (KBr): 3422, 3053, 2932, 2858, 1609, 1583, 1558,
1493, 1423, 1346, 1327, 1223, 1188, 1150, 1124, 10
28, 951, 866, 820, 760, 700, 658 cm ^-1 . [I-8] IR (KBr): 3447, 3051, 2936, 2860, 1611, 1583, 1558,
1508, 1489, 1448, 1423, 1394, 1346, 1329, 1304, 12
73, 1225, 1190, 1169, 1150, 1124, 810, 783,760, 68
7 cm ^-1 .

Example 2-1 Epoxidation of indene

[0102]

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Indene (10 μL, 86 μmol) was added to a solution of pyridine N-oxide in acetonitrile (0.02
M, 1.1 mL, 22 μmol), and then [I-
1] (2.3 mg, 2.1 μmol). To this solution was added iodosylbenzene (37.8 mg, 0.17 mm
ol) in one portion and stirred at room temperature for 24 hours. After carefully concentrating the reaction mixture, the residue was purified by silica gel column chromatography (eluent: pentane to pentane / diethyl ether 10/1). Epoxide yield (yield): 6.0 mg (53%). Asymmetric yield: 9
2% e. e.

Example 2-2 Epoxidation of Benzopyran Compound

[0105]

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[IV-1] (26.2 mg, 0.10 mmol
l) and [I-1] (2.6 mg, 2.5 μmol) were added to a solution of pyridine N-oxide in acetonitrile (0.02
M, 1.25 mL, 0.025 mmol) and cooled to 0 ° C. To this solution was added iodosylbenzene (44.0 mg, 0.20 mmol) at a time under a nitrogen atmosphere, and the mixture was stirred at 0 ° C. for 24 hours. After the insolubles were removed by filtration through Celite, the filtrate was concentrated and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 8: 2 to 4: 6). Epoxide yield (yield): 20.1 mg (72%). Asymmetric yield: 98% e. e. (DAICEL CHIRALCE
LOJ, hexane / isopropanol = 1: 1, flow rate = 0.5 mL / min).

Example 2-3 Epoxidation of Benzopyran Compound

[0108]

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[IV-1] (20.0 mg, 76.3 μmo
l) and [I-1] (1.7 mg, 1.6 μmol)
Acetonitrile solution of methyl imidazole (0.02
M, 760 μL, 7.6 μmol).
% Hydrogen peroxide (86 μL, 0.76 mmol) was added dropwise over 5 minutes. After stirring at room temperature for 24 hours, the residue obtained by concentrating the reaction mixture was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1: 1).
Purified according to 1). 6. Epoxide yield (yield):
1 mg (33%). Asymmetric yield: 94% e. e. (DAI
(CEL CHIRALCEL OJ, hexane / isopropanol = 1: 1, flow rate = 0.5 mL / min).

Example 2-4 In the same manner as in Example 2-3, using compound [I] of the present invention as a catalyst for various olefins, iodosylbenzene (PhIO), sodium hypochlorite (NaOCl) or acetonitrile was used. The test results obtained when asymmetric epoxidation was performed with 2-iodosylbenzoic acid (IBA) are shown in the following table.

[0111]

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[0112]

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Claims (5)

(57) [Claims] 1. Formulas [I] and [I '] [Wherein, R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, a phenyl group (the phenyl group is
Halogen atom, C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group,
It may be substituted with a cyano group or a nitro group. ), And any two may be taken together to form a C ₄ -C ₈ ring. X ^- represents an anion pair capable of forming a salt. Y represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a nitro group or a cyano group. R represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a phenyl group (the phenyl group is a halogen atom, a C ₁ -C ₄ alkyl group,
It may be substituted with ₁ -C ₄ alkoxy group. ) Or substituted silyl groups. (However, when R ¹ and R ³ are phenyl groups and R ² and R ⁴ are hydrogen atoms, and when R ¹ and R ³ are hydrogen atoms and R ² and R ⁴ are phenyl groups, R is a hydrogen atom and An optically active manganese complex represented by the formula: 2. A compound of the formula [II] Wherein R ⁵ and R ⁶ are each independently a hydrogen atom, an amino group which may be protected by a protecting group such as a cyano group, a nitro group, and an acetyl group, a halogen atom, a C ₁ -C ₄ alkyl Group, C ₁ -C ₄ alkoxy group, halo C ₁ -C ₄ alkyl group, carboxy group, formyl group, C ₁ -C ₄ alkanoyl group, aroyl group, halo C ₁ -C ₄ alkanoyl group, carbamoyl group, C ₁ -C ₄
Alkylsulfinyl group, arylsulfinyl group, C ₁
-C ₄ alkylsulfonyl group, arylsulfonyl group, sulfonamide group, mono- or di-C ₁ -C ₄ alkylsulfonamide group, or together when R ⁵ and R ⁶ are in the ortho position, With the linking ring (Where n represents an integer of 0 or 1). R ⁷
Represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group. R ⁸ represents a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group. Or R ⁷ and R ⁸ together (R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group). ]
An asymmetric epoxidation reaction is carried out on the olefin compound represented by the formula [I] or the optically active manganese complex represented by the formula [I '] according to claim 1 as a catalyst to obtain a compound represented by the formula [III]: Formula 5 (Wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as above). 3. A compound of the formula [IV] (Wherein, R ⁵ and R ⁶ are each independently a hydrogen atom, an amino group which may be protected by a protecting group such as a cyano group, a nitro group, an acetyl group, a halogen atom, a C ₁ -C ₄ alkyl Group, C ₁ -C ₄ alkoxy group, halo C ₁ -C ₄ alkyl group, carboxy group, formyl group, C ₁ -C ₄ alkanoyl group, aroyl group, halo C ₁ -C ₄ alkanoyl group, carbamoyl group, C ₁ -C ₄
Alkylsulfinyl group, arylsulfinyl group, C ₁
-C ₄ alkylsulfonyl group, arylsulfonyl group, sulfonamide group, mono- or di-C ₁ -C ₄ alkylsulfonamide group, or R ⁵ and R ⁶ together with the ring to be bonded 7] (Where n represents an integer of 0 or 1). R ⁹
And R ¹⁰ each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group. Asymmetric epoxidation reaction of the olefin compound represented by the formula [V] with one of the optically active manganese complexes represented by the formula [I] or [I '] according to claim 1 as a catalyst. Embedded image (Wherein R ⁵ , R ⁶ , R ⁹ and R ¹⁰ are the same as above. The absolute configuration of the carbon atom indicated by * means R or S.) how to. 4. A compound of the formula [VI] (Wherein, R ⁹ and R ¹⁰ each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group) with respect to a compound represented by the formula [I] or [I ′] ] [Wherein, R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, a phenyl group (the phenyl group is
Halogen atom, C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group,
It may be substituted with a cyano group or a nitro group. ), And any two may be taken together to form a C ₄ -C ₈ ring. X ^- represents an anion pair capable of forming a salt. Y represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a nitro group or a cyano group. R represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a phenyl group (the phenyl group is a halogen atom, a C ₁ -C ₄ alkyl group,
It may be substituted with ₁ -C ₄ alkoxy group. ) Or substituted silyl groups. An asymmetric epoxidation reaction is carried out using any of the optically active manganese complexes represented by the formula [VII] as a catalyst. (Wherein R ⁹ and R ¹⁰ are the same as above. The absolute configuration of the carbon atom indicated by * means R or S.) 5. A compound of the formula [VIII] Is subjected to an asymmetric epoxidation reaction using one of the optically active manganese complexes represented by the formula [I] or [I '] according to claim 4 as a catalyst to give the indene represented by the formula [IX] ] (Absolute configuration of carbon atom indicated by * means R or S.) A method for producing an optically active epoxy compound represented by the formula: