JPH0987258A - Oxazolines, their production and production of asymmetric cyclopropanecarboxylic acids - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce new oxazolines, useful as asymmetric ligands when producing asymmetric carboxylic acids by reacting olefins with diazoacetic esters in the presence of a copper salt and available from a readily synthesized raw material in good yield in one step. SOLUTION: The oxazolines are represented by formula I (X is a 1-hydroxy-1- cycloalkyl, a 1-hydroxy-1-cycloaryl, etc.; R<1> is H, an aryl, etc.; R<2> to R<5> are each H, an alkyl, etc., with the proviso that R<2> and R<3> are not same), e.g. (4 R)-2-((1R,2S,5R)-menthol-1-methylenyl)-4-phenyloxazoline. The compounds are obtained by reacting cyclic ketones such as cyclohexanone with 2- methyloxazolines of formula II such as (4R)-2-methyl-4-phenyloxazoline in the presence of a strong base such as t-butyl-lithium usually by using a solvent such as tetrahydrofuran, preferably at -90 to 0 deg.C.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to oxazolines,
The present invention relates to a method for producing the same and a method for producing asymmetric cyclopropanecarboxylic acids using the method.

[0002]

BACKGROUND OF THE INVENTION Asymmetric cyclopropanecarboxylic acids are useful as intermediates for medicines and agricultural chemicals, and olefins and diazoacetic acid esters are reacted in the presence of a copper salt and an asymmetric ligand. It is known to be manufactured by Optically active methylenebisoxazolines have been proposed as such chiral ligands (Tetrahedro).
n Letters, Vol. 32, No. 50, pp
7373-7376, 1991). However, methylenebisoxazolines are not only unstable and easily polymerized, but also produced in low yield through several steps using malononitrile as a raw material (Helvetica Chimica).
Acta, Vol. 74, p2, 1991), and the method for producing asymmetric cyclopropanecarboxylic acids using such methylenebisoxazolines as an asymmetric ligand has not been industrially advantageous.

[0003]

Therefore, the present inventor can produce a 2-methyloxazoline derivative, which is easily derived from a nitrile derivative, as a raw material in a high yield in one step, is stable, and is stable with olefins and diazoacetic acid. As a result of diligent studies to develop a new compound that can be used as an asymmetric ligand when producing an asymmetric cyclopropanecarboxylic acid by reacting an ester with a copper salt, the present invention has been achieved. It was

[0004]

That is, the present invention provides a compound represented by the following general formula (1): (In the formula, X is a 1-hydroxy-1-cycloalkyl group,
A 1-hydroxy-1-cycloaralkyl group or a 1-hydroxy-1-cycloaryl group, R ¹ is a hydrogen atom,
Or, an aryl group which may have a substituent is represented by R ² ,
R ³ , R ⁴ and R ^{5 each} represent a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or an aryl group which may have a substituent. . However, R ² and R ³ are not the same. )
To provide oxazolines represented by

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION In the oxazolines of the present invention, R ¹ is a hydrogen atom or an aryl group which may have a substituent, and the substituents R ² , R ³ , R ⁴ and R ⁵ are hydrogen atoms. , An alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent, respectively. Is, for example, a methyl group, an ethyl group,
n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-amyl group, neopentyl group, n-hexyl group, cyclohexyl group, 2,3,4-
Trimethyl-3-pentyl group, 2,4-dimethyl-3-
Examples of the aryl group include a pentyl group and the like, an aralkyl group such as a benzyl group, a 2-phenylethyl group, a 2-naphthylethyl group, and a diphenylmethyl group.
For example, a phenyl group, a naphthyl group, a biphenyl group, a furyl group, a thiophenyl group, a 2,6-di-t-butyl-p-tolyl group, etc. are respectively exemplified, and when these substituents are further substituted with a substituent As the substituent of, a halogen atom such as chlorine or bromine, a methyl group, an ethyl group,
Lower alkyl groups such as isopropyl group, n-butyl group, t-butyl group, n-amyl group, n-hexyl group, lower alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, t-butoxy group, phenoxy group Examples thereof include aryloxy groups such as groups, n-propylthio groups, lower alkylthio groups such as t-butylthio groups, arylthio groups such as phenylthio groups, nitro groups and hydroxyl groups.

The substituent X is 1-hydroxy-1-
A cycloalkyl group, a 1-hydroxy-1-cycloaralkyl group or a 1-hydroxy-1-cycloaryl group is shown. Examples of the 1-hydroxy-1-cycloalkyl group include a 1-hydroxy-1-cyclopropyl group. , 1-hydroxy-1-cyclohexyl group, 1-hydroxy-1-cycloheptyl group and the like, and the 1-hydroxy-1-cycloaralkyl group is, for example, 9-hydroxy-9-anthronyl group, 9-hydroxy-9- Examples of the 1-hydroxy-1-cycloaryl group such as phenanthryl group include 1-hydroxy-1-indenyl group, 9-hydroxy-9-fluorenyl group, 1-hydroxy-1-cyclopentacyclooctenyl group and the like. Each is listed.

Such oxazolines are compounds which have not been described in the literature and include cyclic ketones and general formula (2). (Produced by reacting with 2-methyloxazoline represented by the formula: R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the same meaning as described above in the presence of a strong base. can do.

As the cyclic ketones, cycloalkyl ketones such as cyclohexanone and cyclooctanone, 9
-Cyclic aryl ketones such as fluorenone, or D
-Camphor, L-camphor, (-)-menton,
(+)-Mentone, (-)-Norcamphor, (+)-
Illustrative examples include optically active cyclic ketones such as norcamphor, (−)-tujon, and (+)-tujon.

Examples of 2-methyloxazolines include (4R) -2-methyl-4-phenyloxazoline,
(4R) -2-Methyl-4-phenylmethyloxazoline, (4R) -2-methyl-4-isopropyloxazoline, (4R) -2-phenylmethyl-4-phenyloxazoline, (4R) -2-phenylmethyl- 4-phenylmethyloxazoline, (4R) -2-phenylmethyl-4-isopropyloxazoline, and compounds in which (4R) in each of the above compounds corresponds to (4S), and the like are used. It is usually in the range of 0.5 to 10 times by mole, preferably 0.9 to 3 times by mole.

All of such 2-methyloxazolines are known, for example, nitrile derivatives such as acetonitrile and phenylacetonitrile, and (R)-(-).
-Phenylglycinol, L-phenylalaninol,
It can be easily produced by reacting with optically active 2-aminoethanol such as L-norephedrine in the presence of a Lewis acid such as zinc chloride.

Examples of strong bases include alkyllithium compounds such as t-butyllithium, sec-butyllithium and n-butyllithium, alkali metal amide compounds such as lithium diisopropylamide, lithium amide and sodium amide, sodium methoxide, Examples thereof include alkali metal alkoxides such as potassium-t-butoxide, and the amount thereof is usually 0.8 to 10 mole times, preferably 1 to 2 times the amount of 2-methyloxazolines.
It is in the range of 1.5 molar times.

In the reaction, a solvent is usually used,
Examples of such a solvent include solvents inert to the reaction such as ether solvents such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethoxymethane, and hydrocarbon solvents such as hexane. These solvents may be used alone or as a mixture, and the amount thereof is usually 2 to 2 with respect to the cyclic ketones.
It is in the range of 100 times the weight.

In the reaction, for example, cyclic ketones, 2-methyloxazolines and strong bases may be mixed in a solvent, and the reaction temperature is usually -100 to 10 ° C, preferably -90 to 0 ° C. Is the range.

After the reaction, the reaction mixture is subjected to a conventional method, for example, the reaction mixture is mixed with an aqueous solution of ammonium chloride, and then, for example, toluene, ethyl acetate, diethyl ether,
Extraction treatment is carried out using an organic solvent insoluble in water such as dichloromethane, and the obtained organic layer is concentrated to obtain the desired oxazolines. Further, the obtained oxazolines may be purified by column chromatography or distillation operation.

Examples of the oxazolines thus obtained include (4R) -2-((1R, 2S, 5R)-
Menthol-1-methylenyl) -4-phenyloxazoline, (4R, 5S) -2-((2R) -2-camphanol 2-methylenyl) 4-methyl-5-phenyloxazoline, (4R) -2- (9 -Hydroxy-9-methylenyl) -4-benzyloxazoline, (4R) -2-
((1R, 2S, 5R) -Menthol-1-methylenyl) -4-phenyloxazoline, (4S) -2-
((2S) -2-camphanol-2-methylenyl)-
4-t-butyloxazoline, (4R) -2-((2
R) -2-camphanol-2-methylenyl) -4-t
-Butyloxazoline, (4R) -2-[((1R, 2
S, 5R) -Menthol-1-yl)-(phenyl-
(R) -methyl)]-4-oxazoline, (4R, 5
S) -2-[((2R) -2-camphanol-2-yl) -phenyl- (R) -methyl] -4-methyl-5-
Phenyloxazoline, (4R) -2-[(9-hydroxy-9-fluorenyl) -phenyl- (R) -methyl] -4-benzyloxazoline, (4R) -2-
[((1R, S, 5R) -Menthol-1-yl) -phenyl- (R) -methyl] -4-phenyloxazoline, (4S) -2-[((2S) -2-camphanol-2- Iyl) -phenyl- (R) -methyl] -4-t-
Butyloxazoline, (4R) -2-[((2R) -2
-Campanol-2-yl) -phenyl- (R) -methyl] -4-t-butyloxazoline and the like.

All of these oxazolines are stable and can be used as an asymmetric ligand. For example, in the presence of such oxazolines and a copper salt, the compound represented by the general formula (3) (In the formula, R ⁶ , R ⁷ , R ⁸ and R ⁹ are each a hydrogen atom,
The alkyl group which may have a substituent, the aralkyl group which may have a substituent or the aryl group which may have a substituent are shown. However, R ⁶ , R ⁷ , R ⁸ , R ⁹
Cannot be the same at the same time. ) And an olefin represented by the general formula (4) N ₂ CHCOOR ¹⁰ (4) (In the formula, R ¹⁰ is an alkyl group which may have a substituent,
The aralkyl group which may have a substituent or the aryl group which may have a substituent is shown. ) By reacting with a diazoacetic acid ester represented by the general formula (5) (In the formula, each of R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ has the same meaning as in the above.), And thus asymmetric cyclopropanecarboxylic acids can be produced.

In the substituents R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ in such olefins and diazoacetic acid esters, an alkyl group which may have a substituent or a substituent which may have a substituent Examples of the aralkyl group or the aryl group which may have a substituent include the substituents R ² and R described above.
Examples of the substituents are the same as those shown as ³ , R ⁴ and R ⁵ .

Examples of the diazoacetic acid esters include ethyl diazoacetic acid ester, isopropyl ester, and n.
-Propyl ester, t-butyl ester, isobutyl ester, n-butyl ester, benzyl ester, cyclohexyl ester, l-menthyl ester, n-pentyl ester, neopentyl ester, n-hexyl ester, n-heptyl ester and the like. .

Examples of the olefins include isobutylene, 2-methyl-2-butene, 3-methyl-1-butene, 3,3-dimethyl-1-butene, 2-pentene, 4
-Methyl-1-pentene, 2-methyl-2-pentene,
1-hexene, 2-hexene, 2-heptene, isoprene, 2,5-dimethyl-2,4-hexadiene, 1-methyl-1-cyclohexene, vinylcyclopentane, styrene, 4-phenyl-1-butene and the like can be mentioned. The amount used is usually 0.5 with respect to diazoacetic acid esters.
It is in the range of up to 30 mol times.

The amount of oxazolines used is usually in the range of 0.001 to 2 mole times, preferably 0.01 to 1 mole times, relative to the diazoacetic acid esters.

Examples of the copper salt include monovalent monofluorotrifluoromethanesulfonates such as copper (I) triacetate, copper (I) acetate, copper (I) bromide, copper (I) chloride, and copper (I) trifluoroacetate. Examples thereof include a copper salt and a divalent copper salt in which copper (I) in each of the above compounds corresponds to copper (II), and the amount thereof is usually 0.01 to 2 mole times with respect to the oxazolines, preferably. Is in the range of 0.1 to 1 mole times.

The reaction may be carried out in the absence of a solvent depending on the kind of the olefin, but it is usually carried out in a solvent, and examples of such a solvent include diethyl ether, diethoxymethane, tetrahydrofuran, dimethoxyethane, dioxane and the like. Examples of the solvent inert to the reaction include ether solvents, hydrocarbon solvents such as hexane, halogenated hydrocarbon solvents such as chloroform and dichloromethane, ester solvents such as ethyl acetate. The amount of such a solvent used is usually 2 to 20 relative to diazoacetic acid esters.
It is in the range of 0 times the weight.

In the reaction, for example, olefins, oxazolines, and copper salts may be mixed in a solvent, and then diazoacetic acid esters may be added. The reaction temperature is usually in the range of -50 to 200 ° C, preferably 0 to 50 ° C.

When a divalent copper salt is used as the copper salt, it is preferable to add the hydrazine compound before adding the diazoacetic acid ester, because the reaction rate of the olefins and the diazoacetic acid ester becomes faster. . Examples of such a hydrazine compound include phenylhydrazine and the like, and the amount thereof is usually 0.8 to 10 with respect to the copper salt.
The range is 1.2 times.

After completion of the reaction, the reaction mixture is treated in the usual manner,
For example, after mixing the mixture with an aqueous ammonium chloride solution, extraction treatment is performed with an organic solvent insoluble in water such as toluene, ethyl acetate, diethyl ether, or dichloromethane, and the obtained organic layer is concentrated,
The desired asymmetric cyclopropanecarboxylic acid can be obtained.

The asymmetric cyclopropanecarboxylic acids thus obtained are, for example, 1-S-ethoxycarbonyl-2-S-phenylcyclopropane, 1-R-ethoxycarbonyl-2,2-dimethylcyclopropane, 1-R.
-Ethoxycarbonyl-2,2-dimethylcyclopropane, 1-R-ethoxycarbonyl-2-R- (2-methyl-1-propenyl) cyclopropane, 1-S-ethoxycarbonyl-2-S-t-butylcyclo Propane etc. are mentioned.

[0027]

INDUSTRIAL APPLICABILITY The oxazolines of the present invention can be produced from 2-methyloxazolines in a high yield in one step and are stable, and in addition, olefins and diazoacetic acid esters can be prepared in the presence of a copper salt. It can be used as an asymmetric ligand in the production of asymmetric cyclopropanecarboxylic acids to be reacted.

[0028]

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

Example 1 10 g of (R)-(-)-phenylglycinol (72.
9 mmol) was dissolved in 300 g of acetonitrile, bead-shaped molecular sieve 4A (20 g) was added to this solution, and the mixture was stirred under a nitrogen stream for 30 minutes, then 10 g of zinc chloride was added.
(73.4 mmol) was added, and the mixture was further stirred with heating under reflux for 7 hours. After the reaction, the reaction mixture was filtered to remove the molecular sieves, the washing liquid obtained by washing the molecular sieves with acetonitrile (50 g × 2) was combined with the filtrate, 400 g of a saturated calcium carbonate aqueous solution was added, and the mixture was stirred for 30 minutes. The filtrate after stirring was filtered to remove the precipitated solid matter and then concentrated to obtain a residue. 400 g of this residue
The resulting organic layers were combined, washed with 100 g of water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (chloroform: acetone = 20: 1), and then (4R) -2-methyl-
4-phenyloxazoline 9.21 g (57.2 mmo
l) was obtained (yield 78.5%).

0.5 g of diisopropylamine (4.94)
mmol) in 10 ml of tetrahydrofuran,
0.5 g of n-butyllithium with stirring at 78 ° C
A hexane solution (3.1 ml) of (4.94 mmol) was added dropwise, and the mixture was further stirred at −78 ° C. for 5 minutes. After that, the temperature was raised to −15 ° C., and after stirring for 15 minutes, −78
It was cooled to 0 ° C. and 0.795 g (4,94 mmol) of (4R) -2-methyl-4-phenyloxazoline obtained above was obtained.
A tetrahydrofuran solution (5 ml) of was added dropwise. Then, after stirring for 30 minutes at −78 ° C., 0.752 g (4.94 mmol) of L-camphor in tetrahydrofuran (5 ml) was added dropwise, and the mixture was stirred at −78 ° C. for 15 minutes, and then at −10 ° C. for 30 minutes. Stir for minutes. To the reaction mixture after the reaction, 2 ml of a saturated aqueous solution of ammonium chloride was added, and after stirring for 5 minutes, 200 ml of water was added, followed by extraction with 150 g of chloroform twice. The obtained organic layers were combined, washed with 50 g of water, dried over anhydrous sodium sulfate and then concentrated, and the obtained residue was purified by silica gel chromatography (chloroform: acetone = 50: 1) to obtain (4R). -2-((2R) -2-camphanol-
2-Methylenyl) -4-phenyloxazoline 1.2
9 g (4.12 mmol) were obtained (83.5 yield from ((4R) -2-methyl-4-phenyloxazoline).
%). 1H-NMR (CDCl ₃ , TMS) δ 0.85 (S, 3H), 0.86 (S, 3H), 1.
17 (S, 3H), 1.38-1.57 (m, 4H),
1.60-1.79 (m, 2H) 2.10-2.24
(M, 1H), 2.50 (d, 1H), 2.67 (d,
1H), 4.04 (t, 1H), 4.54 (S, 1
H), 4.56 (t, 1H), 5.17 (t, 1H),
7.18-7.36 (m, 5H)

Example 2 The same operation as in Example 1 was carried out except that 0.726 g (4.94 mmol) of (-)-menthone was used in place of 0.752 g of L-camphor, and (4R) -2- ((1R, 2
1.32 g (4.18 mmol) of (S, 5R) -menthol-1-methylenyl) -4-phenyloxazoline was obtained (yield from (4R) -2-methyl-4-phenyloxazoline 84.7%). _{1H-NMR (CDCl 3, TMS} ) δ0.80-1.00 (m, 9H), 1.00-1.1
5 (m, 3H), 1.42 = 1.60 (m, 2H),
1.65-1.90 (m, 3H), 2.00-2.22
(M, 1H), 2.31 (d, 1H), 2.95 (d,
1H), 3.45 (S, 1H), 4.06 (t, 1
H), 4.62 (t, 1H), 5.22 (t, 1H),
7.20-7.40 (m, 5H)

Example 3 The procedure of Example 1 was repeated, except that 0.752 g (4.94 mmol) of D-camphor was used instead of 0.752 g of L-camphor, and (4R) -2-(( 2S)-
1.34 g (4.28 mmol) of 2-camphanol-2-methylenyl) -4-phenyloxazoline was obtained (yield from (4R) -2-methyl-4-phenyloxazoline: 86.6%). 1H-NMR (CDCl ₃ , TMS) δ 0.90 (S, 3H), 0.92 (S, 3H), 1.
15 (S, 3H), 1.28-1.41 (m, 4H),
1.62-1.80 (m, 2H), 2.15-2.25
(M, 1H), 2.57 (q, 2H), 4.05 (t,
1H), 4.60 (t, 1H), 4.85 (S, 1
H), 5.20 (t, 1H), 7, 17-7.40.
(M, 5H)

Example 4 (4R) -2- (9) was operated in the same manner as in Example 1 except that 0.890 g (4.94 mmol) of 9-fluorenone was used in place of 0.752 g of L-camphor. 1.37 g (4.02 mmol) of -hydroxy-9-fluorenylmethyl) -4-phenyloxazoline was obtained ((4
R) -2-Methyl-4-phenyloxazoline yield 81.3%). 1H-NMR (CDCl ₃ , TMS) δ 2.15 (S, 2H), 3.00 (q, 2H), 4.
05 (t, 1H), 4.60 (t, 1H), 5.30
(T, 1H), 5.64 (S, 1H), 7.20-7.
40 (m, 9H), 7.60-7.70 (m, 4H)

Example 5 10 g of (R)-(-)-phenylglycinol (72.
9 mmol) and 8.54 g of phenylacetonitrile (7
2.9 mmol) and 300 g of monochlorobenzene are dissolved in this solution, and bead-shaped molecular sieve 4A (2
0 g) and stirred for 30 minutes under a nitrogen stream, then 10 g (73.4 mmol) of zinc chloride is added and heated under reflux,
It was stirred for another 7 hours. After the reaction, the reaction mixture is filtered to remove the molecular sieve, and the washing solution obtained by washing the molecular sieve with acetonitrile (50 g × 2) is combined with the filtrate, and the filtrate is mixed with 400 g of a saturated aqueous solution of calcium carbonate.
Was added and stirred for 30 minutes. The filtrate after stirring is filtered,
After removing the precipitated solid matter, the solid matter was concentrated to obtain a residue.
This residue was dissolved in 400 g of water, and then 30 ml of ethyl acetate was added.
The organic layers obtained were extracted twice with 0 g, washed with 100 g of water, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by silica gel column chromatography (chloroform: acetone = 20: 1),
12.66 g (53.4 mmol) of (4R) -2-phenylmethyl-4-phenyloxazoline was obtained (yield 7
3.3%). 1 H-NMR (CDCl ₃ , TMS) δ 3.73 (S, 2H), 4.08 (t, 1H), 4.
59 (t, 1H), 5.17 (t, 1H), 7.20-
7.40 (m, 10H)

0.5 g of diisopropylamine (4.94)
mmol) in 10 ml of tetrahydrofuran,
0.5 g of n-butyllithium with stirring at 78 ° C
A hexane solution (3.1 ml) of (4.94 mmol) was added dropwise, and the mixture was further stirred at −78 ° C. for 5 minutes. After that, the temperature was raised to -15 ° C, and after stirring for 15 minutes,
It cooled to 0 degreeC, 1.17 g (4,94 mm) of (4R) -2-phenylmethyl-4-phenyloxazoline obtained previously.
ol) in tetrahydrofuran (5 ml) was added dropwise. Then, after stirring for 30 minutes at −78 ° C., L
-Add 0.752 g (4.94 mmol) of camphor tetrahydrofuran solution (5 ml) dropwise, and add 1 at -78 ° C.
After stirring for 5 minutes, the mixture was further stirred at -10 ° C for 30 minutes. To the reaction mixture after the reaction, 2 ml of a saturated aqueous solution of ammonium chloride was added, and after stirring for 5 minutes, 200 ml of water was added, followed by extraction with 150 g of chloroform twice. The obtained organic layers were combined, washed with 50 g of water, dried over anhydrous sodium sulfate and then concentrated, and the obtained residue was subjected to silica gel chromatography (chloroform: acetone = 50: 1).
Purified by (4R) -2-[((2R) -2-camphanol-2-yl) -phenyl- (R) -methyl]-
4-phenyloxazoline 1.25 g (3.21 mm
ol) was obtained (83.5% yield from (4R) -2-phenylmethyl-4-phenyloxazoline). 1H-NMR (CDCl ₃ , TMS) δ 0.61 (S, 3H), 0.72 (S, 3H), 0.
75 (S, 3H), 1.00-1.30 (m, 2H),
1.40-1.60 (m, 2H), 1.65-1.75
(M, 1H), 1.85-1.90 (m, 1H), 2.
05-2.20 (m, 1H), 3.52 (S, 1H),
3.65 (t, 1H), 4.36 (t, 1H), 5.5
0 (t, 1H), 5.73 (S, 1H), 6.90-
6.95 (m, 2H), 7.00-7.20 (m, 6
H), 7.35-7.46 (m, 2H)

Example 6 (4R) -2-[((2S) -2) was carried out in the same manner as in Example 5 except that D-camphor was used instead of L-camphor.
-Campanol-2-yl) -phenyl- (R) -methyl] -4-phenyloxazoline 1.46 g (3.
74 mmol) was obtained (yield from (4R) -2-phenylmethyl-4-phenyloxazoline 75.8%). 1H-NMR (CDCl ₃ , TMS) δ 0.81 (S, 3H), 0.88 (S, 3H), 1.
06 (S, 3H), 1.08-1.18 (m, 1H),
1.25-1.45 (m, 2H), 1.50-1.90
(M, 4H), 3.86 (t, 1H), 3.90 (S,
1H), 4.60 (t, 1H), 5.20 (t, 1
H), 5.25 (S, 1H), 7.10-7.15.
(M, 2H), 7.20-7.38 (m, 6H), 7.
57-7.65 (m, 2H)

Example 7 18.0 mg of copper (II) trifluoromethanesulfonate
(0.05 mmol) and (4R) -2-((2R) -2
-Campanol-2-methylenyl) -4-phenyloxazoline (78.3 mg, 0.25 mmol) was dissolved in 3 g of dichloromethane and stirred at 25 ° C for 15 minutes, and then 5 µl of phenylhydrazine (0.05 μl) was added to this solution.
mmol) and further stirred at 25 ° C. for 5 minutes,
2,5-dimedil-2,4-hexadiene 1.10 g
(10 mmol) was added, and the mixture was stirred at 25 ° C. for 10 minutes.
Then, at 25 ° C. with stirring, diazoacetic acid ethyl ester 0.1.
114 g (1 mmol) of dichloromethane solution (2 m
1) was added dropwise over 2 hours, and the mixture was further stirred at 25 ° C. for 3 hours. After stirring, the reaction mixture was concentrated and the residue was chromatographed on silica gel (hexane: ethyl acetate = 30:
1) and trans-1-R-ethoxycarbonyl-2
-R- (2-methyl-1-propenyl) cyclopropane 128.6 mg (0.656 mmol) (yield 65.5
%, 46.5% ee) and cis-1-R-ethoxycarbonyl-2-S- (2-methyl-1-propenyl) cyclopropane 55.3 mg (0.282 mmol) (yield 2
8.2%, 37.9% ee) was obtained.

Example 8 (4R) -2-((1R, 2S, 5R) was substituted for 78.3 mg of (4R) -2 ((2R) -2-camphanol-2-methylenyl) -4-phenyloxazoline. ) -Menthol-1-methylenyl) -4-phenyloxazoline 78.8 mg (0.25 mmol) was used in Example 7.
Is operated in the same manner as described above, trans-1-S-ethoxycarbonyl-2-S- (2-methyl-1-propenyl) cyclopropane 126.8 mg (0.647 mmol) (yield 64.7%, 40.2). % Ee) and cis-1-S-ethoxycarbonyl-2-R- (2-methyl-1-propenyl) cyclopropane 54.3 mg (0.277 mmo).
1) (yield 27.7%, 28.2% ee).

Example 9 (4R) -2 ((2R) -2-camphanol-2-methylenyl) -4-phenyloxazoline was replaced with (4
Example 7 using R) -2 ((2S) -2-camphanol-1-methylenyl) -4-phenyloxazoline.
By the same procedure as described above, trans-1-S-ethoxycarbonyl-2-S- (2-methyl-1-propenyl) cyclopropane 113.2 mg (0.578 mmol) (yield 57.8%, 27.1). % Ee) and cis-1-S-ethoxycarbonyl-2-R- (2-methyl-1-propenyl) cyclopropane 65.3 mg (0.333 mmo)
1) (yield 33.3%, 26.7% ee).

Example 10 (4R) -2-((2R) -2-camphanol-2-
Methylenyl) -4-phenyloxazoline 78.3 mg
Instead of (4R) -2- (9-hydroxy-9-fluorenylmethyl) -4-phenyloxazoline 85.3 m
g (0.25 mmol) to 2,5-dimethyl-2,4
-Styrene 1.04 instead of hexadiene 1.102 g
g (10 mmol) was used in the same manner as in Example 7 to prepare trans-1-S-ethoxycarbonyl-
2-S-phenylcyclopropane 90.4 mg (0.4
76 mmol) (yield 47.6%, 48.3% ee)
And cis-1-S-ethoxycarbonyl-2-R-phenylcyclopropane 47.7 mg (0.25 mmol)
(Yield 25.1%, 29.6% ee) were obtained.

Example 11 (4R) -2-((2R) -2-camphanol-2-
Methylenyl) -4-phenyloxazoline 78.3 mg
In place of (4R) -2-[((2R) -2-camphanol-2-yl) -phenyl- (R) -methyl] -4-
Phenyloxazoline 97.3 mg (0.25 mmo
l) was used and operated in the same manner as in Example 7, to
1-R-ethoxycarbonyl-2-R- (2-methyl-
1-Propenyl) cyclopropane 115.4 mg (0.
589 mmol) (yield 58.9%, 48.9% ee)
And cis-1-R-ethoxycarbonyl-2-S- (2
-Methyl-1-propenyl) cyclopropane 56.4m
g (0.280 mmol) (yield 28.0%, 51.5
% Ee) was obtained.

Example 12 (4R) -2-((2R) -2-camphanol-2-
Instead of methylenyl) -4-phenyloxazoline,
(4R) -2-[((2S) -2-camphanol-2
-Yl) -Phenyl- (R) -methyl] -4-phenyloxazoline 97.3 mg (0.25 mmol) was operated in the same manner as in Example 7 to give trans-1-R-ethoxycarbonyl-2-R. -(2-Methyl 1-propenyl) cyclopropane 108.2 mg (0.552 mmo
1) (yield 55.2%, 37.2% ee) and cis-1-
R-ethoxycarbonyl-2-S- (2-methyl-1-
Propenyl) cyclopropane 48.6 mg (0.248
mmol) (yield 24.8%, 39.5% ee).

Example 13 (4R) -2-((2R) -2-camphanol-2-
Methylenyl) -4-phenyloxazoline 78.3 mg
In place of (4R) -2-[((2R) -2-camphanol-2-yl) -phenyl- (R) -methyl] -4-
97.3 mg of phenyloxazoline was replaced with 1.102 g of 2,5-dimethyl-2,4-hexadiene, and 1.04 g (10 mmol) of styrene was used, respectively, and the same procedure as in Example 7 was conducted to prepare trans-1-. S-Ethoxycarbonyl-2-S-phenylcyclopropane 106.8
mg (0.562 mmol) (yield 56.2%, 49.
6% ee) and cis-1-S-ethoxycarbonyl-2-
R-phenylcyclopropane 54.9 mg (0.289
mmol) (yield 28.9%, 56.7% ee).

Example 14 (4R) -2-((2R) -2-camphanol-2-
Methylenyl) -4-phenyloxazoline 78.3 mg
In place of (4R) -2-[((2S) -2-camphanol-2-yl) -phenyl- (R) -methyl] -4-
97.3 mg of phenyloxazoline was replaced with 1.102 g of 2,5-dimethyl-2,4-hexadiene, and 1.04 g (10 mmol) of styrene was used, respectively, and the same procedure as in Example 7 was conducted to prepare trans-1-. S-Ethoxycarbonyl-2-S-phenylcyclopropane 97.5m
g (0.513 mmol) (yield 51.3%, 53.9
% Ee) and cis-1-S-ethoxycarbonyl-2-
R-phenylcyclopropane 40.5 mg (0.213
mmol) (yield 21.3%, 57.2% ee).

Claims (6)

[Claims] 1. A general formula (1) (In the formula, X is a 1-hydroxy-1-cycloalkyl group,
A 1-hydroxy-1-cycloaralkyl group or a 1-hydroxy-1-cycloaryl group, R ¹ is a hydrogen atom,
Or, an aryl group which may have a substituent is represented by R ² ,
R ³ , R ⁴ and R ^{5 each} represent a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent or an aryl group which may have a substituent. . However, R ² and R ³ are not the same. )
An oxazoline represented by. 2. Cyclic ketones and general formula (2) (Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ have the same meanings as described above), and the 2-methyloxazolines are reacted in the presence of a strong base. The method for producing the oxazolines represented by the general formula (1) according to claim 1. 3. The production method according to claim 2, wherein the strong base is an alkyllithium compound. 4. General formula (3) (In the formula, R ⁶ , R ⁷ , R ⁸ and R ⁹ are each a hydrogen atom,
The alkyl group which may have a substituent, the aralkyl group which may have a substituent or the aryl group which may have a substituent are shown. However, R ⁶ , R ⁷ , R ⁸ , R ⁹
Cannot be the same at the same time. ) And an olefin represented by the general formula (4) N ₂ CHCOOR ¹⁰ (4) (In the formula, R ¹⁰ is an alkyl group which may have a substituent,
The alkyl group which may have a substituent or the aryl group which may have a substituent is shown. ) Is reacted with a diazoacetic acid ester represented by the general formula (1) in the presence of an oxazoline represented by the general formula (1) and a copper salt. (In the formula, R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ have the same meanings as described above.) A process for producing an asymmetric cyclopropanecarboxylic acid. 5. The method according to claim 4, wherein the copper salt is a divalent copper salt. 6. The method according to claim 5, wherein the divalent copper salt is copper (II) trifluoromethanesulfonate.