JPH1017518A - Production of optically active alpha-hydroxyketal - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for easily producing an optically active α- hydroxyketal useful as an intermediate for a physiologically active substance such as a medicine or an agrochemical, or a fine chemical compound in high yield by oxidizing a specific enol ether compound in the presence of a specified optically active manganese complex catalyst. SOLUTION: (A) A compound of formula I R<5> is a 1-6C alkyl; R<6> and R<7> are each a 1-6C alkyl [substituted by a group (Z) of a 1-4C alkyl, a 1-4C alkoxy, etc.], a phenyl [substituted by a group (Z)], or R<6> and R<7> may be bonded to each other to form a 4-8C member ring} is oxidized in the presence of an optically active catalyst of formula II [R<1> to R<4> are each H, a 1-4C alkyl (substituted by a 1-4C alkyl or a halogen), a phenyl (substituted by a halogen, a 1-4C alkyl, etc.), or two of the R<1> to R<4> may form a 4-8C member ring by being combined with each other; R is same as the R<1> , etc.; X<-> is an anionic pair capable of forming a salt; Y is H, a halogen, a 1-4C alkyl, etc.; a binaphthyl group may be a racemic body or an optically active substance] to provide the objective compound of formula III [R<8> is same as the R<5> ; (*) represents that the absolute configuration of the C is R or S] in the method for producing an optically active α-hydroxyketal.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an optically active α-hydroxyketal compound which asymmetrically oxidizes an enol ether compound in the presence of an optically active manganese complex catalyst.

[0002]

2. Description of the Related Art Optically active .alpha.-hydroxyketal compounds are important intermediates between physiologically active substances such as medical and agricultural chemicals and various fine chemical compounds. The asymmetric oxidation of enol ether compounds is described in J. Chem. Soc., Chem.
Commun. 172 (1992) and JP-A-7-247238, a method for synthesizing optically active α-hydroxyketone compounds from trimethylsilyl enol ether compounds, Tetrahedron Lett. 35 ,
669 (1994), a method of synthesizing an optically active acetoxyenone compound from enol acetate is known.

[0003]

However, the asymmetric oxidation reaction of the above-mentioned trimethylsilyl enol ether compound is not yet satisfactory in asymmetric yield, and the substrate is limited to the silyl enol ether compound. In addition, the asymmetric oxidation reaction of an enol acetate compound is limited to an olefin having a conjugated substrate, although the asymmetric yield can be satisfied to some extent.

[0004]

Means for Solving the Problems The present inventors have made intensive studies on the asymmetric oxidation reaction of an enol ether compound, and as a result, have found that an optically active α-hydroxyketal compound can be easily obtained in good yield. The present invention has been completed. That is, the present invention relates to formula (1)

[0005]

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[0006] wherein, R ⁵ is C ₁ -C means ₆ alkyl group, R ⁶ and R ⁷ are optionally substituted independently C ₁
-C ₆ alkyl group (the substituent is a C ₁ -C ₄ alkyl group,
A C ₁ -C ₄ alkoxy group, a C ₂ -C ₅ alkanoyl group, a C ₂
-C ₅ alkylcarbonyloxy group, C ₂ -C ₅ alkoxycarbonyl group, a phenyl group, a halogen atom, a cyano group, means a nitro group. ), A phenyl group which may be substituted (the substituent is a C ₁ -C ₄ alkyl group, a C ₁ -C ₄
Alkoxy groups, C ₂ -C ₅ alkanoyl group, C ₂ -C ₅ alkylcarbonyloxy group, C ₂ -C ₅ alkoxycarbonyl group, a phenyl group, a halogen atom, a cyano group, means a nitro group. ) Means that R ⁶ and R ⁷ are bonded to form C ₄ -C ₈
May form a ring. Is represented by the formula (2)

[0007]

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[Wherein, R ¹ , R ² , R ³ and R ⁴ independently represent a hydrogen atom or an optionally substituted C ₁ -C ₄ alkyl group (the substituent is a C ₁ -C ₄ alkyl group) group, means a halogen atom.), a substituted optionally substituted phenyl group (the substituent also is meant halogen atom, C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, a cyano group, a nitro group Any two of which may together form a C _{4 to} C ₈ ring.

R is a hydrogen atom, an optionally substituted C
₁~ C_FourAn alkyl group (the substituent is C ₁~ C_FourAlkyl group,
It means a halogen atom. ), Optionally substituted
Enyl group (the substituent is a halogen atom, C₁~ C_FourArchi
Group, C₁~ C_FourAlkoxy, cyano, and nitro groups
To taste. ), C₁~ C_FourAlkoxy group, C_Two~ C_FiveAlkano
Il group, C_Two~ C_FiveAlkylcarbonyloxy group, C_Two~
C_FiveMeans alkoxycarbonyl group or substituted silyl group
Then X^-Represents an anion pair capable of forming a salt, and Y represents water
Elemental atom, halogen atom, C₁~ C_FourAlkyl group, C₁~ C_Four
Alkoxy, nitro or cyano means binaf
The tyl group may be racemic or optically active. ]
Oxidation in the presence of an optically active manganese complex catalyst
Equation (3) characterized by

[0010]

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Wherein R ⁸ represents a C ₁ -C ₆ alkyl group, the absolute configuration of the carbon atom indicated by * represents R or S , and R ⁵ , R ⁶ and R ⁷ are Same as above. ] The method for producing an optically active α-hydroxy ketal compound represented by the formula:

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. First, the substituents R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ and Y will be described. Examples of the C ₁ -C ₄ alkyl group include a methyl group, an ethyl group, an n-propyl group, and an i-
Examples include a propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, and a tert-butyl group.

As the C ₁ -C ₆ alkyl group, a methyl group,
Ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, tert-butyl group, n-amyl group, i-amyl group, neopentyl group, n-hexyl group And a cyclohexyl group. C ₁ -C ₄ alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, te
rt-butoxy group and the like.

The C ₂ -C ₅ alkanoyl groups include acyl, ethylcarbonyl, n-propylcarbonyl,
i-propylcarbonyl group, n-butylcarbonyl group,
i-butylcarbonyl group, sec-butylcarbonyl group, n-amylcarbonyl group, i-amylcarbonyl group, neopentylcarbonyl group and the like. C ₂ ~
The C ₅ alkylcarbonyloxy group, a methyl carbonyloxy group, ethyl carbonyloxy group, n- propyl carbonyloxy group, i- propyl carbonyloxy group, n- butyl carbonyloxy group, i- butyl carbonyloxy group, sec- butyl Carbonyloxy group,
Examples include a tert-butylcarbonyloxy group, an n-amylcarbonyloxy group, an i-amylcarbonyloxy group, and a neopentylcarbonyloxy group.

The C ₂ -C ₅ alkoxycarbonyl group includes a methoxycarbonyl group, an ethoxycarbonyl group, n
-Propoxycarbonyl group, i-propoxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-amyloxycarbonyl group, i-
Examples include an amyloxycarbonyl group and a neopentyloxycarbonyl group.

The C ₄ -C ₈ ring includes a cyclobutane ring,
Examples include a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, and a cyclooctane ring. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the substituted silyl group include a trimethylsilyl group, a triethylsilyl group, a tri-n-propylsilyl group, a tri-i-propylsilyl group, a tri-n-butylsilyl group, a tri-i-butylsilyl group, and a dimethylethylsilyl group. Dimethyl-n-propylsilyl group, dimethyl-n-butylsilyl group, dimethyl-i-butylsilyl group, dimethyl-t-butylsilyl group and the like.

[0017] X ^- is the anion pairs salt capable of forming ^{the, OH -, F -, Cl} -, Br -, I -, CH 3 CO 2 -, PF 6 -, ClO 4 -, B
F ₄ ⁻ , CO ₃ ²⁻ , SO ₄ ²⁻ , PO ₄ ^{3− and the} like. Next, the asymmetric oxidation reaction of the enol ether compound of the formula (1) will be described. Examples of the enol ether compound of the formula (1) include 1-methoxycyclopentene, 1-ethoxycyclopentene, 1-methoxycyclohexene, 1-ethoxycyclohexene, 1-methoxycycloheptene, 1-ethoxycycloheptene, and 1-methoxycyclooctene. ,
1-ethoxycyclooctene, 1-methoxy-3,4-
Dihydronaphthalene, 1-ethoxy-3,4-dihydronaphthalene, α-methoxy-β-methylstyrene, α-
Ethoxy-β-methylstyrene and the like.

Examples of the oxidizing agent include iodosylbenzene, iodosylmesitylene, iodosobenzoic acid, sodium hypochlorite, calcium hypochlorite and the like. The oxidizing agent is used in an amount of 1 to 20 moles, preferably 1 to 10 moles, per mole of the enol ether compound of the formula (1).
A molar range of 2 times is preferred. In the optically active manganese complex catalyst of the formula (2), preferable catalysts include the following optically active manganese complexes and their enantiomers.

[0019]

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Wherein Ph is a phenyl group and OAc is an acetoxy group. The amount of the optically active manganese complex catalyst used is expressed by the formula (1)
Is preferably in the range of 0.01 to 50 mol%, and more preferably in the range of 0.1 to 10 mol%, based on the enol ether compound. In the present invention, a tertiary amine, a tertiary amine N-oxide and the like can be coexisted as a reaction accelerator.

These compounds include imidazole,
1-methylimidazole, 2-methylimidazole, pyridine, 4-t-butylpyridine, 4-phenylpyridine, 4-phenylpropylpyridine, α-picoline, β
-Picoline, γ-picoline, 4-dimethylaminopyridine, imidazole-N-oxide, 1-methylimidazole-N-oxide, 2-methylimidazole-N
-Oxide, pyridine-N-oxide, 4-t-butylpyridine-N-oxide, 4-phenylpyridine-N-oxide, 4-phenylpropylpyridine-N
-Oxide, α-picoline-N-oxide, β-picoline-N-oxide, γ-picoline-N-oxide, 4-dimethylaminopyridine-N-oxide and the like.

The amount of the tertiary amine and the tertiary amine N-oxide used is in the range of 0.01 to 2 moles per mol of the enol ether compound of the formula (1). Examples of the reaction solvent include alcohol solvents, and specific examples include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, and cyclohexanol.

The reaction temperature is usually in the range of -50 ° C to 100 ° C, preferably in the range of -20 ° C to 30 ° C. The reaction time is usually 0.1 to 1000 hours, depending on the types of the enol ether compound of the formula (1), the optically active manganese complex catalyst of the formula (2) and the oxidizing agent used.

After completion of the reaction, the organic solvent is concentrated under reduced pressure, and the optically active α-hydroxyketal compound of the formula (2) can be obtained by operations such as silica gel column chromatography or distillation. The optical purity of the obtained target product is
It can be measured by an optical activity chromatography column or optical rotation.

[0025]

The present invention will be described in more detail with reference to the following examples.
The present invention is not limited to these. Example 1 1-ethoxycyclooctene 15.4 m under a nitrogen atmosphere
g (0.10 mmol), optically active manganese complex 2.8
mg (2.5 μmol) and 1.2 ml of ethanol were charged and stirred, and cooled to 0 ° C.

To the above mixture was added 22.0 mg (0.10 mmol) of iodosylbenzene at 0 ° C., and the mixture was stirred for 4 hours. Further, 22.0 mg of iodosylbenzene (0.1
(0 mmol) and stirred at 0 ° C. for 4 hours. After completion of the reaction, dimethyl sulfide was added, and the mixture was stirred for 20 minutes. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 9/9).
Purified according to 1) to obtain optically active 2-hydroxy-1,1
12.1 mg of diethoxycyclooctane (yield 56
%).

After benzoylation of this compound, the mixture was subjected to liquid chromatography (Daicel Chiralcel O).
F, hexane / isopropanol = 400/1) and the optical purity was 88% ee. _{^{1 H NMR (CDCl 3 270MHz)}} : 3.95 (1H, br d), 3.59-3.27 (4H,
m), 2.25 (1H, br d), 2.16-1.38 (12H, m), 1.05 (3H, t, J = 7.1H
z), 1.04 (3H, t, J = 7.1Hz)

[0028]

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Examples 2-3 A reaction and after-treatment were carried out in the same manner as in Example 1 except that 1-ethoxycyclohexene or 1-ethoxycycloheptene was used instead of 1-ethoxycyclooctene. The results are shown in the table below.

[0030]

Table 1 Example 1 Substrate Yield (%) Optical Purity (% ee) ────────────────────────────── 2 1-ethoxycyclohexene 46 89 3 1-ethoxycycloheptene 55 81 Example 4 to 5 The reaction and post-treatment were carried out in the same manner as in Example 1 except that the amount of ethanol was changed to methanol, the amount of 1-ethoxycyclooctene was changed to 1-methoxycyclohexene and the amount of iodosylbenzene was changed to 1 equivalent. The results are shown in the table below.

However, the optical purity is determined by ¹ HNMR (270M
Hz, chiral shift agent: [Eu (hfc) ₃ ]). Table 2 Example substrate Yield (%) Optical purity (% ee) ４ 41-ethoxy Cyclohexene 38 85 5 1-ethoxycycloheptene 60 83

[0032]

According to the method of the present invention, the enol ether compound of the formula (1) is oxidized in the presence of the optically active manganese complex catalyst of the formula (2) to obtain the optically active α of the formula (3). -Hydroxyketal compounds can be produced.

Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location C07M 7:00

Claims (4)

[Claims] (1) Formula (1)[Wherein, R^FiveIs C₁~ C₆An alkyl group, R⁶as well as
R⁷Is an optionally substituted C₁~ C₆Alkyl
Group (the substituent is C₁~ C_FourAlkyl group, C₁~ C_FourArco
Xy group, C_Two~ C_FiveAlkanoyl group, C_Two~ C_FiveAlkylka
Rubonyloxy group, C_Two~ C_FiveAn alkoxycarbonyl group,
Means phenyl group, halogen atom, cyano group and nitro group
I do. ), An optionally substituted phenyl group (the substituent
Is C₁~ C_FourAlkyl group, C₁~ C_FourAlkoxy group, C_Two
~ C_FiveAlkanoyl group, C_Two~ C_FiveAlkylcarbonyl
Xy group, C_Two~ C_FiveAlkoxycarbonyl group, phenyl
Group, halogen atom, cyano group and nitro group. )
Means R⁶And R⁷Is combined with C_Four~ C₈To form a ring
May be. ] The enol ether compound represented by
With the formula (2)[Wherein, R¹, R^Two, R^ThreeAnd R^FourIs independently a hydrogen atom,
C which may be replaced₁~ C_FourAn alkyl group (the substituent is
C₁~ C_FourIt means an alkyl group or a halogen atom. ), Place
Optionally substituted phenyl group (the substituent is halogen
Atom, C₁~ C_FourAlkyl group, C₁~ C_FourAlkoxy group,
It means ano group and nitro group. ) Means either 2
One together C_Four~ C₈May be formed. R
Is a hydrogen atom, an optionally substituted C₁~ C_FourAlkyl
Group (the substituent is C ₁~ C_FourAlkyl group and halogen atom
means. ), An optionally substituted phenyl group (the
The substituent is a halogen atom, C₁~ C_FourAlkyl group, C₁~ C_Four
It means an alkoxy group, a cyano group or a nitro group. ), C
₁~ C_FourAlkoxy group, C_Two~ C_FiveAlkanoyl group, C_Two~
C_FiveAlkylcarbonyloxy group, C_Two~ C_FiveAlkoxy
X represents a carbonyl group or a substituted silyl group;^-Represents an anion pair capable of forming a salt, Y represents a hydrogen atom, a halogen atom, C₁~ C_FourAlkyl group, C
₁~ C_FourMeans an alkoxy group, a nitro group or a cyano group,
The binaphthyl group may be racemic or optically active. ]
Oxidation in the presence of an optically active manganese complex catalyst represented by
Equation (3) characterized by the following:[Wherein, R⁸Is C₁~ C₆Indicates an alkyl group and is indicated by *
The absolute configuration of the carbon atomROrSMeans R^Five, R⁶
And R⁷Is the same as above. Optical activity α-
A method for producing a hydroxyketal compound. 2. The method according to claim 1, wherein the reaction solvent is an alcohol solvent. 3. Use of an optically active manganese complex catalyst wherein R, R ¹ and R ³ are phenyl groups, R ² and R ⁴ are hydrogen atoms, X is an acetoxy group, and Y is a hydrogen atom, or an enantiomer thereof. The method according to claim 1, wherein: 4. R is a phenyl group and R ¹ and R ³ are 3,5-
A dimethylphenyl group, R ² and R ⁴ are hydrogen atoms, X is an acetoxy group, and Y is a hydrogen atom.
2. The method according to claim 1, wherein the enantiomer is used.