JP2001106690A - Bisisoxazoline derivative, production therefor and metallic complex catalyst therefrom - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an asymmetric synthesis catalyst having higher activity in order to obtain optically active compounds useful as a synthetic intermediate for medicines, agrochemicals and the like. SOLUTION: The objective compound is a bisisoxazoline derivative represented by general formula [I] (R is H, an alkyl, an alkenyl, an aralkyl which may be substituted, or an aryl which may be substituted; the four Rs may be all identical or at least one may differ from the others; R' is a single bond or an alkylene). In a preferred embodiment, all of the Rs are Hs or methyls and R' is methylene. In addition, an optically active bisisoxazoline derivative of formula [I] is provided as an asymmetric synthesis catalyst and the asymmetric synthesis catalyst is the complex of the optically active bisisoxazoline derivative of formula [I] including a transition metal as a ligand.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a bisisoxazoline derivative having a spiro ring skeleton, a method for producing the same, a complex in which a transition metal is coordinated to the bisisoxazoline derivative, the complex or the bisisoxazoline derivative. And a method for performing an asymmetric synthesis reaction using the catalyst.

[0002]

BACKGROUND OF problem of the invention In recent years, those with C ₂ symmetry axis as a catalyst for asymmetric synthesis is used extensively. Among them, Corey et al. (J. Am. Chem. Soc., 113,
728 (1991)), Pfaltz et al. (Tetrahedron 48, 2143 (199
2)), Evans et al. (J. Am. Chem. Soc., 113, 726 (1991)
The bisoxazoline derivative according to) has a high catalytic activity,
It is used in many asymmetric synthesis reactions.

[0003] In order to obtain an optically active compound useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like, an asymmetric synthesis catalyst exhibiting higher activity is required.

[0004]

Means for Solving the Problems The present inventors have found that an optically active bisisoxazoline derivative having a spiro ring skeleton or a transition metal complex thereof effectively works as a catalyst for asymmetric synthesis, and completed the present invention. I came to.

The present invention relates to a novel bisisoxazoline derivative represented by the general formula [I].

[0006]

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Wherein R is a hydrogen atom, a lower alkyl group,
A lower alkenyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group, wherein all four R's may be the same or at least one different . R 'is a single bond or a lower alkylene group. A bisisoxazoline derivative in which all four R's are hydrogen atoms or lower alkyl groups, especially methyl groups, is preferred. Preferred R 'is a methylene group. Further, the bisisoxazoline derivative [I] may be a racemic mixture or an optically active substance.

The bisisoxazolines according to the present invention are very unique in that they contain a rigid spiro ring skeleton and, in addition to the chirality at the base of the spiro ring side chain, have an axial asymmetry derived from the spiro ring skeleton. This is considered to be a reason why it works effectively as a catalyst for an asymmetric synthesis reaction.

The structure of the bisisoxazoline according to the present invention will be described in more detail.

Regarding R in the general formula [I], the lower alkyl group includes a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, sec
And a C1-C4 alkyl group, such as -butyl group and tert-butyl group. Examples of the lower alkenyl group include alkenyl groups having 2 to 4 carbon atoms, such as a vinyl group, an isopropenyl group, an allyl group, and a methallyl group. The aralkyl group which may have a substituent includes a benzyl group and m-
Examples thereof include a chlorobenzyl group, a p-bromobenzyl group, an o-methylbenzyl group, and a p-cyanobenzyl group. The aryl group which may have a substituent includes a phenyl group, an m-chlorophenyl group, a p-bromophenyl group,
-Tolyl group, m-tolyl group, p-tolyl group, p-cyanophenyl group, 1-naphthyl group, 2-naphthyl group, 6-bromo-1-naphthyl group, 6-chloro-2-naphthyl group,
6-methyl-1-naphthyl group and the like.

Regarding R 'in the general formula [I], examples of the lower alkylene group include alkylene groups having 1 to 3 carbon atoms such as methylene, ethylene and n-propylene, and methylene is particularly preferred.

Next, the bisisoxazoline derivative according to the present invention can be produced by the following method.

First step: A halogenated olefin represented by the general formula [II] is reacted with a malonic acid diester in the presence of a base to obtain a dialkenyl malonic ester represented by the general formula [III].

Second step: The dialkenyl malonic ester [III] obtained in the previous step is reduced to obtain a diol represented by the general formula [IV].

Third step: The diol obtained in the previous step [I
V] to obtain a dialdehyde represented by the general formula [V].

Fourth step: The dialdehyde [V] obtained in the preceding step is reacted with hydroxylamine to give a compound of the general formula [V
I] is obtained.

Fifth step: The dioxime [VI] obtained in the previous step is cyclized under oxidizing conditions to obtain a racemic mixture of a bisisoxazoline derivative [I].

Sixth step: The racemic mixture bisisoxazoline derivative [I] obtained in the previous step is optically resolved as required.

The diol [IV] obtained in the second step, the third
The dialdehyde [V] obtained in the step and the dioxime [VI] obtained in the fourth step are both novel compounds. Among these intermediates, those in which R 'is a methylene group are particularly preferred.

The process for producing the bisisoxazoline derivative according to the present invention is shown by the following process flow.

[0021]

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(Wherein R and R ′ have the same meaning as defined above. R ″ is a lower alkyl group. X is a halogen atom.) Each step of the process for producing bisisoxazoline according to the present invention is further described. Give a detailed explanation.

In the first step of reacting a halogenated olefin [II] with a malonic acid diester in the presence of a base to obtain a dialkenylmalonic acid ester [III], dimethyl malonate, diethyl malonate, Ditert-butyl malonate and dibenzyl malonate are preferably used. R of halogenated olefin [II]
And R 'are the bisisoxazoline derivatives of the present invention [I]
Corresponding to Halogen atoms X are preferably chlorine and bromine.

The base used in this step includes alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and alkali metal or alkaline earth metal hydrides such as sodium hydride, potassium hydride and calcium hydride. Alkali metal alcoholates such as sodium methylate, sodium ureate and potassium tert-butoxide; and particularly preferably potassium hydroxide.

It is also preferable to add trifluoromethanesulfonic acid or the like as a catalyst to the reaction system.

As the solvent in this step, alcohol solvents such as methanol, ethanol, isopropanol and butanol; diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran,
Ether solvents such as 1,4-dioxane and 1,2-dimethoxyethane; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; N, N-dimethylformamide, dimethyl sulfoxide and the like Aprotic polar solvents, and
Particularly, aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide are preferred.

The reaction temperature in this step is preferably from room temperature to the reflux temperature of the solvent. The reaction pressure is usually normal pressure, but the reaction can be carried out under pressure.

In the second step of reducing the dialkenyl malonic ester [III] to obtain the diol [IV], examples of the reducing agent include lithium aluminum hydride, diisobutylaluminum hydride, bitride and sodium borohydride. In particular, lithium aluminum hydride is preferably used.

As the solvent in this step, halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4- Dioxane, 1,2
Ether solvents such as dimethoxyethane; benzene,
Aromatic hydrocarbon solvents such as toluene and xylene are used. In the case of sodium borohydride, alcohol solvents such as methanol, ethanol, isopropanol and butanol are also used.

The reaction temperature in this step is from -80 ° C to the reflux temperature of the solvent. The reaction pressure is usually normal pressure, but the reaction can be carried out under pressure.

In the third step of obtaining the dialdehyde [V] by oxidizing the diol [IV], the reaction may be carried out under ordinary conditions for oxidizing a primary alcohol to an aldehyde.
For example, there is a method in which a reagent prepared from oxalic acid dichloride and dimethyl sulfoxide is reacted with diol [IV] in dichloromethane at a low temperature in the presence of triethylamine.

The reaction temperature in this step is generally preferably low. For example, in the case of a reaction using oxalic acid dichloride and dimethyl sulfoxide, the reaction temperature is from -80 ° C to -30 ° C.
It is about. The reaction pressure is usually normal pressure, but the reaction can be carried out under pressure.

In the fourth step of reacting dialdehyde [V] with hydroxylamine to obtain dioxime [VI], the reaction may be carried out under ordinary conditions for reacting aldehyde with hydroxylamine.

As the solvent in this step, alcohol solvents such as methanol, ethanol, isopropanol and butanol; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; diethyl ether, diisopropyl ether ,
t-butyl methyl ether, tetrahydrofuran, 1,
Ether solvents such as 4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide. This reaction can be performed without a solvent. Organic bases such as pyridine and triethylamine to promote the reaction; sodium carbonate, potassium carbonate, sodium acetate,
It is also preferable to add an inorganic weak base such as potassium acetate. The reaction temperature ranges from -20 ° C to the reflux temperature of the solvent. The reaction pressure is usually normal pressure, but the reaction can be carried out under pressure.

In the fifth step of cyclizing the dioxime [VI] under oxidizing conditions to obtain the bisisoxazoline derivative [I], nitrile oxide is formed from the dioxime to give 2 + 3
A spiro ring and an isoxazoline ring are constructed at once by a cycloaddition reaction.

The oxidizing agent used in this step is not particularly restricted but includes, for example, halogens such as chlorine and bromine; N-chlorosuccinimide, N-bromosuccinimide and the like.
-Halogenated amides; hypochlorites such as sodium hypochlorite and sodium hypochlorite; halogenates such as sodium periodate and the like are used.

As the solvent in this step, halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide; Can be

The reaction temperature in this step is preferably from -50 to
50 ° C. The reaction pressure is usually normal pressure, but the reaction can be carried out under pressure.

Thus, a diastereomer represented by the following formula, ie, a racemic mixture of the (M, S, S) form and its enantiomer, a racemic mixture of the (M, R, R) form and its enantiomer, and ( A racemic mixture of the (M, R, S) form and its enantiomer is obtained.

[0040]

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Racemic Mixture The sixth step of optically resolving the bisisoxazoline derivative [I] into each enantiomer can be carried out by a conventional method of optically resolving a racemic body. For example, a method using a liquid chromatograph equipped with a chiral stationary phase column, a method of forming a salt of a racemate with an optically active sulfonic acid or carboxylic acid, and then recrystallizing the racemate to optical resolution are exemplified.

The present invention also relates to a complex obtained by coordinating a metal to the racemic or optically active bisisoxazoline derivative [I]. The metal used to form the complex is preferably a transition metal, more preferably C
r, Mn, Fe, Co, Ni, Cu, Zn, Ru, R
h, and a metal selected from the group consisting of Pd, and more preferably Cu. As an example of a complex of the bisisoxazoline derivative [I] and a transition metal, a hexadentate Cu complex represented by the following formula (R in formula [I], R = hydrogen atom, R ′ = methylene group) may be mentioned. .

[0043]

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The complex can be synthesized by mixing a metal salt and a bisisoxazoline derivative in an organic solvent. The solvent used for this synthesis is preferably a solvent used for the next asymmetric synthesis reaction, but is not limited at all if it is a solvent inert to the asymmetric synthesis reaction. After the complex is synthesized, the complex may be isolated and then used for an asymmetric synthesis reaction. Further, the reaction substrate may be added to a mixed solution of the metal salt and the bisisoxazoline derivative, or the metal salt and the bisisoxazoline derivative may be added to the reaction substrate solution.

The present invention further relates to an asymmetric synthesis catalyst comprising the above complex and an asymmetric synthesis reaction catalyst comprising the above optically active bisisoxazoline derivative [I].

An asymmetric synthesis reaction, for example, an asymmetric nucleophilic addition reaction can be carried out using the above catalyst. Especially in that,
A method for performing an asymmetric Michael addition reaction to a conjugated enone and an asymmetric Wacker reaction to an olefin using an asymmetric synthesis reaction catalyst comprising the above complex, and a catalyst comprising the above optically active bisisoxazoline derivative [I] To carry out an asymmetric ring opening reaction of the epoxy compound.

The nucleophile used for the asymmetric Michael addition reaction to the conjugated enone and the asymmetric ring opening reaction of the epoxy compound include dialkyl zinc such as dimethyl zinc, diethyl zinc, dipropyl zinc and diisopropyl zinc; phenyl lithium, n An organolithium reagent such as butyllithium;
Grignard reagents such as methylmagnesium chloride, ethylmagnesium bromide, phenylmagnesium chloride, allylmagnesium bromide and vinylmagnesium bromide can be mentioned, and diethyl zinc and phenyllithium are preferably used. Examples of the nucleophile used in the asymmetric Wacker reaction to an olefin include an aliphatic alcohol, more preferably a substituted ethanol, and preferably a 2-allyl-1,3-propanediol derivative or 2,2-diallyl-2 -A substituted ethanol having an olefin in a molecule such as an ethanol derivative is used.

The amount of the catalyst of the present invention to be used is preferably 0.5 to 50 mol%, more preferably 1 to 50 mol%, based on the substrate such as conjugated enone, epoxy compound and olefin.
25 mol%.

The conjugated enone for the asymmetric Michael addition reaction is not particularly limited as long as it has a skeleton in which an olefin and a ketone are conjugated. For example, 3-penten-2-one, 4-hexen-3-one ON, 5-methyl-3
Aliphatic unsaturated ketones such as -hexen-2-one and 3-nonen-2-one; aromatics such as 4-phenyl-3-buten-2-one, chalcone, 4'-methoxychalcone and 4-nitrochalcone Unsaturated ketone; 1-acetyl-1-
Cyclohexene, 2-cyclopenten-1-one, 2-
Methyl-2-cyclopenten-1-one, 2-cyclohexen-1-one, 3-methyl-2-cyclohexene-
And cyclic ketones such as 1-one.

Epoxy compounds for the asymmetric ring opening reaction include:
The compound is not particularly limited as long as it has an epoxy group. For example, chain epoxy compounds such as 2,3-epoxybutane, 3,4-epoxyhexane, 4,5-epoxyoctane, and stilbene oxide; cyclopentene oxide, cyclohexene oxide And cyclic epoxy compounds such as cyclooctene oxide.

The olefin for the asymmetric Wacker reaction is
The diol or monool derivative having one or two allyl groups at the 2-position is not particularly limited. For example, a 2-allyl-1,3-propanediol derivative or 2,2
2-diallyl-2-ethanol derivatives and the like. When an ethanol derivative having two allyl groups in the molecule, such as a 2,2-diallyl-2-ethanol derivative, is used, after one of the allyl groups reacts with the hydroxyl group, the other allyl group is formed on the formed ring. Upon reaction, a cage-like cyclic ether is obtained.

Solvents for the asymmetric synthesis reaction using the catalyst of the present invention include aromatic hydrocarbon solvents such as toluene, xylene and mesitylene; aliphatic hydrocarbons such as hexane, heptane, octane, decane, undecane, dodecane and cyclohexane. Diethyl ether, diisopropyl ether, t-butyl methyl ether tetrahydrofuran;
Ether solvents such as 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dichloromethane, chloroform, 1,2-dichloroethane,
Halogenated hydrocarbon solvents such as chlorobenzene; and mixed solvents thereof. In particular, in the asymmetric Michael addition reaction to a conjugated enone and the asymmetric ring opening reaction of an epoxy compound, diethyl ether, diisopropyl ether, t-butylmethyl Ether, tetrahydrofuran,
Ether solvents such as 1,4-dioxane, dimethoxyethane and diethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as toluene, xylene and mesitylene are preferred. In the asymmetric Wacker reaction to olefins,
Halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane and chlorobenzene are preferred.

In the asymmetric Wacker reaction to an olefin, it is preferable to use a Pd complex as a catalyst. However, since this is used in a catalytic amount, Pd (0) generated after the reaction is converted to Pd (0) using an oxidizing agent. It is necessary to oxidize to II). The oxidizing agent used at this time is not particularly limited as long as it is an oxidizing agent usually used for the Wacker reaction.
I), iron (III) chloride, p-benzoquinone and molecular oxygen, and more preferably p-benzoquinone.

The reaction temperature of the asymmetric synthesis reaction is preferably -1.
The temperature is from 00 ° C to the reflux temperature of the solvent, more preferably from -60 ° C to room temperature. The reaction pressure is usually normal pressure, but the reaction can be carried out under pressure.

[0055]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Example 1 i) 2,2-bis (1-butenyl) propane-1,3
Synthesis of diethyl ester of dicarboxylic acid Trifluoromethanesulfonic acid CF ₃ SO ₂ OH (3.0 m) was added to a mixture of dimethyl sulfoxide (132 ml) and potassium hydroxide (10.4 g, 185 mmol).
1,19.8 mmol) and 3 minutes later, further added 4-bromo-1-butene and diethyl malonate (6.7 ml, 6 ml).
6.0 mmol) was added at room temperature. The mixture was warmed to 50 ° C. and stirred for 16 hours. The reaction was terminated by adding 1N hydrochloric acid, and the reaction solution was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product is subjected to column chromatography (silica gel; hexane /
(Acetone = 30/1). 4.9 g of the title compound was obtained as a colorless oil in a yield of 92%.

¹ H-NMR (270 MHz, CDCl ₃ ): δ1.25 (t,
J = 7.0Hz, 6H), 1.90-2.05 (m, 8H), 4.19 (q, J = 7.0Hz, 4
H), 4.97 (d, J = 11.0Hz, 2H), 5.04 (d, J = 17.0Hz, 2H),
5.78 (ddt, J = 17.0, 11.0 and 5.5Hz, 2H); MS: m / z 269

Ii) 2,2-bis (1-butenyl)-
Synthesis of 1,3-propanediol 2,2-bis (1-butenyl) propane-1,3-dicarboxylic acid diethyl ester (31.9 g, 119 mmol)
l) in a THF solution of lithium aluminum hydride (9.
(0 g, 158 mmol) at 0 ° C. The mixture was stirred at room temperature for 3.5 hours and quenched with sodium sulfate decahydrate. A 10% aqueous sulfuric acid solution was added, and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography (silica gel; hexane / ethyl acetate = 2/1) to give the title compound as colorless crystals.
0.1 g was obtained in a yield of 92%.

¹ H-NMR (270 MHz, CDCl ₃ ): δ 1.97-2.
02 (m, 4H), 1.34 (t, J = 8.5Hz, 2H), 1.34 (dd, J = 7.0 and
5.0Hz, 2H), 2.35 (brs, 2H), 3.60 (s, 4H), 4.96 (dd,
J = 10.0 and 2.0Hz, 2H), 5.04 (ddd, J = 17.0, 2.0 and
1.0Hz, 2H), 5.82 (ddt, J = 17.0, 10.0 and 7.0Hz, 2H)
; MS: m / z 185

Iii) Synthesis of 2,2-bis (1-butenyl) malonaldehyde Dimethyl sulfoxide (20.8 ml, 294 mmol)
To a solution of 1) in dichloromethane (56 ml), a solution of oxalic acid dichloride (18.3 ml, 56.5 mmol) in dichloromethane (179 ml) was slowly added at -78 ° C, and the mixture was stirred as it was for 30 minutes. 2,2-bis (1-butenyl) -1,3-propanediol (10.4 g, 5
6.5 mmol) in dichloromethane at -78 ° C and the mixture was stirred for a further 30 minutes. Triethylamine (70.6 ml, 508 mmol) was added at -78 ° C and the reaction temperature was raised to room temperature. After 1.5 hours, the reaction was terminated with a saturated aqueous solution of ammonium chloride, and the reaction solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained product, ie, the title compound, was used for the next reaction without purification.

¹ H-NMR (270 MHz, CDCl ₃ ): δ1.54-2.
06 (m, 8H), 5.00 (d, J = 10.5Hz, 2H), 5.15 (d, J = 17.4H
z, 2H), 5.75 (ddt, J = 17.4, 10.5 and 5.2Hz, 2H), 9.7
5 (s, 2H)

Iv) Synthesis of 2,2-bis (1-butenyl) malonodioxime Hydroxylamine hydrochloride (15.7 g, 226 mmol)
A mixture of 1) and pyridine (150 ml) was cooled to 0 ° C., and the crude 2,2-bis (1-butenyl) malonaldehyde obtained in step iii) was added, and the whole was stirred at room temperature for 7 days. Meanwhile, more hydroxylamine hydrochloride (9.0 g, 130 mmol) was added every two days. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline in this order, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product is subjected to column chromatography (silica gel;
Hexane / ethyl acetate = 4/1). 9.93 g of the title compound were obtained as colorless crystals in a yield of 87% (in two steps).

¹ H-NMR (270 MHz, CDCl ₃ ): δ1.66-1.
82 (m, 4H), 1.94-2.11 (m, 4H), 4.94 (dd, J = 10.2 and
1.8Hz, 2H), 4.99 (dd, J = 17.1 and 1.6Hz, 2H), 6.01 (d
dt, J = 17.1, 10.2 and 6.4Hz, 2H), 7.34 (s, 2H), 8.76
(brs, 2H); MS: m / z 211

V) Synthesis of Spirobisisoxazoline Derivative (VII)

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To a solution of 2,2-bis (1-butenyl) malonodioxime (4.78 g, 22.7 mmol) in dichloromethane (455 ml) was added an aqueous solution of sodium hypochlorite (ca. 5%, 34 ml) at 0 ° C. Stir for 2 hours. The reaction was terminated by adding water. The reaction was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography (silica gel; hexane / ethyl acetate = 2/1 → 1/1 → 1/2). The desired title compound was obtained as colorless crystals at 3.46.
g, 74% yield. The breakdown of diastereomers is
The racemic mixture of the (M, S, S) form and its enantiomer is 36
%, A racemic mixture of the (M, R, R) form and its enantiomer is 1%
3%, and 25% of a racemic mixture of the (M, R, S) form and its enantiomer.

Racemic mixture of (M, S, S) form and its enantiomer: ¹ H-NMR (270 MHz, CDCl ₃ ): δ1.70-1.88 (m, 2H),
2.05-2.27 (m, 4H), 2.63 (dd, J = 19.8 and 7.3Hz, 2H),
3.77-4.00 (m, 4H), 4.55 (m, 2H); MS: m / z 207

The racemic mixture was obtained from Daicel Chiralpak.
AD (EtOH, 3.0 ml / min) splits each enantiomer, and the optical rotation of the (+) isomer is [α] _D ²² + 234 ° (c
0.406, CHCl ₃ ).

Racemic mixture of (M, R, R) form and its enantiomer: ¹ H-NMR (270 MHz, CDCl ₃ ): δ1.50-1.68 (m, 2H),
2.16-2.33 (m, 4H), 2.73-2.84 (m, 2H), 3.88-4.03 (m, 4
H), 4.52-4.66 (m, 2H); MS: m / z 207

The racemic mixture was obtained from Daicel Chiralpak.
AD (EtOH, 4.5 ml / min) splits into each enantiomer, and the optical rotation of the (+) body is [α] _D ²⁶ + 121 ° (c
0.148, CHCl ₃ ).

Racemic mixture of (M, R, S) form and its enantiomer: ¹ H-NMR (270 MHz, CDCl ₃ ): δ1.54-1.84 (m, 2H),
2.02-2.35 (m, 4H), 2.40-2.55 (m, 1H), 2.84 (dd, J = 13.
2 and 7.6Hz, 1H), 3.80-4.00 (m, 3H), 4.11-4.22 (m, 1
H), 4.50-4.70 (m, 2H); MS: m / z 207

The racemic mixture was obtained from Daicel Chiralpak.
AD (EtOH, 3.0 ml / min) splits into each enantiomer, and the optical rotation of the (+) body is [α] _D ²⁶ + 133 ° (c
0.286, CHCl ₃ ).

Example 2 i) Synthesis of 2,2-bis (2-methyl-2-pentenyl) propane-1,3-dicarboxylic acid diethyl ester 5-bromo-butene instead of 4-bromo-1-butene Step i) of Example 1 except that 2-methyl-2-pentene was used.
The title compound was obtained in a yield of 98% in the same manner as in.

¹ H-NMR (270 MHz, CDCl ₃ ): δ1.25 (t,
J = 7.0Hz, 6H), 1.58 (s, 6H), 1.67 (s, 6H), 1.80-1.92
(m, 8H), 4.18 (q, J = 7.0Hz, 4H), 5.03- 5.15 (m, 2H); MS: m / z 325

Ii) Synthesis of 2,2-bis (2-methyl-2-pentenyl) -1,3-propanediol 2,2-bis (2-methyl-2-pentenyl) propane-1,3-dicarboxylic acid The title compound was obtained in a yield of 94% by the same operation as in step ii) of Example 1 using diethyl ester as a substrate.

¹ H-NMR (270 MHz, CDCl ₃ ): δ1.25-1.
36 (m, 4H), 1.61 (s, 6H), 1.68 (s, 6H), 1.85-2.10 (m, 4
H), 2.85-3.10 (brs, 2H), 3.57 (s, 4H), 5.05-5.15 (m,
2H); MS: m / z 241

Iii) 2,2-bis (2-methyl-2-
Synthesis of pentenyl) malonaldehyde 2,2-bis (2
-Methyl-2-pentenyl) propane-1,3-propanediol was used as a substrate, and the title compound was obtained as an unpurified product by the same operation as in step iii) of Example 1 and used as it was in the next reaction.

¹ H-NMR (270 MHz, CDCl ₃ ): δ1.56 (s,
6H), 1.67 (s, 6H), 1.80-2.03 (m, 8H), 4.85-5.12 (m,
2H), 9.74 (s, 2H)

Iv) Synthesis of 2,2-bis (2-methyl-2-pentenyl) malonodioxime Using the crude 2,2-bis (2-methyl-2-pentenyl) malonaldehyde as a substrate, the process of Example 1 By the same operation as in iv), the title compound was obtained in a yield of 87% (in two steps).

¹ H-NMR (270 MHz, CDCl ₃ ): δ1.58 (s,
6H), 1.67 (s, 6H), 1.55-1.70 (m, 4H), 1.90-2.10 (m, 4
H), 4.98-5.10 (m, 2H), 7.42 (s, 2H), 8.93 (brs, 2H); MS: m / z 267

V) Synthesis of spirobisisoxazoline derivative (VIII)

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Using 2,2-bis (2-methyl-2-pentenyl) malonodioxime as a substrate, the desired title compound was obtained by the same procedure as in step v) of Example 1.
% Yield. The breakdown of diastereomers is (M,
36% of a racemic mixture of (S, S) form and its enantiomer,
The racemic mixture of the (M, R, R) form and its enantiomer is 10
%, A racemic mixture of the (M, R, S) form and its enantiomer is 2%
1%.

Racemic mixture of (M, S, S) form and its enantiomer: ¹ H-NMR (270 MHz, CDCl ₃ ): δ 1.27 (s, 6 H), 1.54
(s, 6H), 1.74-1.88 (m, 2H), 1.92 (ddd, J = 6.4, 11.0 an
d 18.2Hz, 2H), 2.15 (ddd, J = 6.4, 11.9 and 18.2Hz, 2
H), 2.53 (ddd, J = 1.6, 6.4 and 11.9Hz, 2H), 3.48 (dd,
J = 7.3 and 11.0Hz, 2H); MS: m / z 262

Racemic mixture of (M, R, R) form and its enantiomer: ¹ H-NMR (270 MHz, CDCl ₃ ): δ1.23 (s, 6H), 1.54
(s, 6H), 1.55-1.72 (m, 2H), 1.94 (dddd, J = 3.3, 7.2,
8.7 and 11.9Hz, 2H), 2.19 (ddd, J = 3.3, 7.9 and 9.7H
z, 2H), 2.69 (ddd, J = 7.2, 9.5 and 9.7Hz, 2H), 3.62
(dd, J = 7.9 and 8.7Hz, 2H); MS: m / z (FAB ⁺ ) 263 (M + H)

Racemic mixture of (M, R, S) form and its enantiomer: ¹ H-NMR (270 MHz, CDCl ₃ ): δ1.22 (s, 3H), 1.26
(s, 3H), 1.54 (s, 3H), 1.55 (s, 3H), 1.62-1.75 (m, 1
H), 1.75-2.05 (m, 3H), 2.10-2.25 (m, 2H), 2.47 (ddd,
J = 6.5, 7.9 and 11.1Hz, 1H), 2.74 (ddd, J = 1.6, 6.3 a
nd 12.7Hz, 1H), 3.52 (dd, J = 7.9 and 10.8Hz, 1H), 3.
78 (dd, J = 7.9 and 9.5Hz, 1H); MS: m / z 262

The racemic mixture was optically resolved into each enantiomer using Chiralpak AD manufactured by Daicel in the same manner as in step v) of Example 1.

Example 3 i) Synthesis of 2,2-bis (4,4-diphenyl-3-butenyl) propane-1,3-dicarboxylic acid diethyl ester 4-bromo-1-butene was replaced by 4-bromo-1-butene Bromo-1,1
The title compound was obtained as colorless crystals in a yield of 87% by the same procedure as in step i) of Example 1 except that -diphenyl-1-butene was used.

IR (KBr): 2970, 1724, 1596, 1493, 1443,
1277, 1177, 1092, 1026, 883, 760, 702cm -1 1 H-NMR (270MHz, CDCl 3): δ1.08 (t, J = 7.1Hz, 6
H), 1.88-1.95 (m, 8H), 3.98 (q, J = 7.1Hz, 4H), 5.89-
6.00 (m, 2H), 7.08-7.40 (m, 20H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 13.964, 24.521, 3
2.028, 56.850, 61.045, 126.785, 126.809, 126.933,
127.905, 128.021, 129.529, 139.608, 142.138, 171.0
06 EI-MS m / z (relative intensity): 572 (M ⁺ , 40), 527
(20), 366 (20), 193 (100, bp) EI-HRMS: calcd for C ₃₉ H ₄₀ O ₄ (M ⁺ ), 572.292
7, found 572.2911 Mp: 69-71 ℃

Ii) Synthesis of 2,2-bis (4,4-diphenyl-3-butenyl) -1,3-propanediol 2,2-bis (4,4-diphenyl-3-butenyl) propane-1, Using 3-dicarboxylic acid diethyl ester as a substrate and the same operation as in step ii) of Example 1,
The title compound was obtained as colorless crystals in a yield of 66%.

IR (KBr): 3275, 2862, 1597, 1493, 1420,
^{1065, 1030, 760, 702cm -1} 1 H-NMR (270MHz, CDCl 3): δ1.22-1.38 (m, 4H),
1.90-2.03 (m, 4H), 2.15 (s, 2H), 3.41 (s, 4H), 5.98
(t, J = 7.5Hz, 2H), 7.10-7.40 (m, 20H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ23.441, 30.619, 4
1.390, 68.405, 126.768, 126.958, 127.971, 128.136,
129.282, 129.636, 139.863, 141.577, 142.270 EI-MS m / z (relative intensity): 488 (M ⁺ , 63), 457
(35), 440 (47), 115 (100, bp) EI-HRMS: calcd for C ₃₅ H ₃₆ O ₂ (M ⁺ ) 488.271
5, found 488.2704 Mp: 127-128 ℃

Iii) Synthesis of 2,2-bis (4,4-diphenyl-3-butenyl) malonaldehyde 2,2-bis (4,4-diphenyl-3-butenyl) propane-1,3-propanediol Used as a substrate,
The title compound was obtained as an unpurified compound by the same operation as in step iii) of Example 1 and used as it was in the next reaction.

¹ H-NMR (270 MHz, CDCl ₃ ): δ1.80-
1.92 (m, 4H), 1.92-2.05 (m, 4H), 5.89 (t, J = 7.25Hz, 2
H), 7.07-7.42 (m, 20H), 9.52 (s, 2H)

Iv) Synthesis of 2,2-bis (4,4-diphenyl-3-butenyl) malonodioxime Using unpurified 2,2-bis (4,4-diphenyl-3-butenyl) malonaldehyde as a substrate Example 1
The title compound was obtained as colorless crystals in a yield of 56% (in 2 steps) by the same operation as in step iv).

IR (KBr): 3356, 3024, 1493, 1443, 1281,
^{1072, 937, 764, 698cm -1} 1 H-NMR (270MHz, CDCl 3): δ1.62-1.78 (m, 4H),
1.90-2.12 (m, 4H), 5.82-6.00 (m, 2H), 7.08-7.40 (m, 2
4H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ24.364, 35.638, 4
5.544, 126.826, 126.925, 127.048, 127.938, 128.02
1, 128.111, 128.260, 129.562, 139.624, 142.212, 14
2.253, 153.469 EI-MS m / z (relative intensity): 514 (M ⁺ , 10), 496
(24), 481 (47), 452 (92), 178 (100, bp) EI-HRMS: calcd for C ₃₅ H ₃₄ N ₂ O ₂ (M ⁺ ) 51
4.6567, found 514.6567 Mp: 50-53 ℃

V) Synthesis of spirobisisoxazoline derivative (IX)

Embedded image

2,2-bis (4,4-diphenyl-3-
Using butenyl) malonodioxime as a substrate, the title compound was obtained in a yield of 18% by the same procedure as in step v) of Example 1. The breakdown of diastereomers is (M, S,
8% racemic mixture of (S) -isomer and its enantiomer, (M, R,
S) The racemic mixture of the isomer and its enantiomer was 11%.

Racemic mixture of (M, R, S) form and its enantiomer: colorless crystal IR (KBr): 3059, 2928, 1720, 1493, 1447, 1072, 1034,
^{837cm -1 1 H-NMR (270MHz} , CDCl 3): δ1.18-1.50 (m, 2H),
1.76-2.18 (m, 4H), 2.38 (dt, J = 7.2, 12.8Hz, 1H), 2.5
3 (dd, J = 5.9, 12.8Hz, 1H), 4.47 (dd, J = 7.6,11.7Hz, 1
H), 4.78 (t, J = 8.8 Hz, 1H), 7.16-7.42 (m, 20H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 22.49, 25.56, 41.
04, 42.16, 42.72, 60.79, 62.77, 95.77, 96.78, 126.
46, 126.87, 127.12, 127.25, 127.46, 127.83, 127.9
5, 128.19, 128.40, 140.02, 140.49, 142.81, 143.11,
171.34, 172.67 CI-MS m / z: 511 (MH ⁺ )

Racemic mixture of (M, S, S) form and its enantiomer: colorless crystal ¹ H-NMR (270 MHz, CDCl ₃ ): δ 1.39 (ddd, J = 7.0, 1
1.7, 23.6Hz, 2H), 1.85-1.95 (m, 2H), 2.10-2.25 (m, 2
H), 2.39 (dd, J = 5.43, 13.2Hz, 2H), 4.38 (dd, J = 7.6,
11.7Hz, 2H), 7.20-7.45 (m , 20H) 13 C-NMR (67.5MHz, CDCl 3): δ 25.27, 41.56, 43.5
6, 62.75, 95.43, 126.87, 127.38, 127.63, 127.96, 1
28.23, 140.05, 143.11, 173.09 CI-MS m / z: 511 (MH ⁺ ) Mp (decomposition): 145 ℃ (M, S, S)

Example 4 i) Synthesis of 2,2-bis (4-ethyl-3-hexenyl) propane-1,3-dicarboxylic acid diethyl ester 6-bromo-butene instead of 4-bromo-1-butene Step i) of Example 1 except that 3-ethyl-3-hexene was used.
90% yield of the title compound as a colorless liquid
I got it.

IR (neat): 2970, 1728, 1458, 1204, 117
^{3, 1088, 910, 733cm -1} 1 H-NMR (270MHz, CDCl 3): δ0.94 (t, J = 7.7Hz, 6
H), 0.97 (t, J = 7.5Hz, 6H), 1.25 (t, J = 7.1Hz, 6H), 1.8
2-2.07 (m, 16H), 4.18 (q, J = 7.1Hz, 4H), 5.00-5.09 (m,
2H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 12.63, 13.19, 14.0
2, 22.24, 23.09, 28.99, 32.56, 57.12, 60.82, 121.0
2, 143.21, 171.33

Ii) Synthesis of 2,2-bis (4-ethyl-3-hexenyl) -1,3-propanediol 2,2-bis (4-ethyl-3-hexenyl) propane-1,3-dicarboxylic acid The title compound was obtained as colorless crystals in a yield of 88% by the same operation as in step ii) of Example 1 using diethyl ester as a substrate.

IR (neat): 3348, 2963, 2955, 2878, 145
8, 1373, 1242, 1049, 849cm -1 1 H-NMR (270MHz, CDCl 3): δ0.96 (t, J = 7.6Hz, 6
H), 0.98 (t, J = 7.3Hz, 6H), 1.27-1.40 (m, 4H), 1.84 (s,
2H), 1.89-2.12 (m, 12H), 3.61 (s, 4H), 5.06 (t, J = 7.
0Hz, 2H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 12.84, 13.34, 14.1
9, 21.04, 21.14, 23.23, 29.10, 31.16, 41.17, 68.6
3, 122.43, 142.69 Mp: 31-35 ℃

Iii) 2,2-bis (4-ethyl-3-
Synthesis of hexenyl) malonaldehyde 2,2-bis (4-ethyl-3-hexenyl) -1,3
-The process of Example 1 using propanediol as substrate
By the same operation as in iii), the title compound was obtained as an unpurified product, and used as it was in the next reaction.

Iv) Synthesis of 2,2-bis (4-ethyl-3-hexenyl) malonodioxime Using the crude 2,2-bis (4-ethyl-3-hexenyl) malonaldehyde as a substrate, the procedure of Example 1 iv)
In the same manner as in the above, the title compound was converted into colorless crystals by 81
% (In two steps).

IR (neat): 3356, 2967, 2936, 2874, 145
8, 1292, 1080, 941, 760cm -1 1 H-NMR (270MHz, CDCl 3): δ0.84-1.05 (m, 12H),
1.41-1.80 (m, 4H), 1.90-2.12 (m, 12H), 4.94-5.07 (t,
J = 7.2Hz, 2H), 7.44 (s, 2H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 13.18, 14.14, 22.1
6, 23.19, 29.02, 36.38, 45.77, 121.53, 143.56, 15
4.10 EI-MS m / z (relative intensity): 322 (M ⁺ , 13), 278
(14), 195 (69), 55 (100, bp) EI-HRMS: calcd for C ₁₉ H ₃₄ N ₂ O ₂ (M ⁺ ) 32
2.2620, found 322.2619 Mp: 32-33 ° C

V) Spirobisisoxazoline (X)
Synthesis of

Embedded image

Using 2,2-bis (4-ethyl-3-hexenyl) malonodioxime as a substrate, the desired title compound was obtained by the same operation as in step V) of Example 1.
% Yield. The breakdown of diastereomers is (M,
31% of a racemic mixture of (S, S) form and its enantiomer,
7% of racemic mixture of (M, R, R) form and its enantiomer,
22% racemic mixture of (M, R, S) form and its enantiomer
Met.

Racemic mixture of (M, S, S) form and its enantiomer: IR (KBr): 2966, 2870, 1512, 1458, 1350, 1265, 1157,
1072, 980, 903, 833, 748, 548cm -1 1 H-NMR (270MHz, CDCl 3): δ0.90 (t, J = 4.6, 7.3H
z, 6H), 0.92 (t, J = 4.6, 7.5Hz, 6H), 1.38 (dq, J = 7.3,
14.3Hz, 2H), 1.60-2.05 (m, 10H), 2.12 (dt, J = 5.9, 1
2.3Hz, 2H), 2.50 (ddt, J = 1.2, 6.1, 12.3Hz, 2H), 3.4
6 (dd, J = 7.3, 11.8Hz, 2H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ7.46, 9.23, 23.44,
23.62, 28.40, 41.30, 43.27, 61.53, 92.75, 175.79 EI-MS m / z (relative intensity): 318 (M ⁺⁺ 1, 47), 2
90 (63), 147 (22), 91 (100, bp) EI-HRMS: calcd for C ₁₉ H ₃₀ N ₂ O ₂ (M ⁺ ) 31
8.2307, found 318.2322 Mp: 88-92 ℃ (M, S, S)

Racemic mixture of (M, R, R) form and its enantiomer: IR (CCl ₄ ): 2963, 2878, 1636, 1458, 1381, 1273, 1
^{119, 1057cm -1 1 H-NMR} (270MHz, CDCl 3): δ0.83 (t, J = 7.1Hz, 6
H), 0.86 (t, J = 7.1Hz, 6H), 1.27-1.43 (dq, J = 7.1, 14.3
Hz, 2H), 1.49-1.73 (m, 6H), 1.74-1.90 (m, 4H), 2.09
(ddd, J = 3.1, 8.1, 13.2Hz, 2H), 2.60 (ddd, J = 7.4, 9.
7, 13.2 Hz, 2H), 3.54 (dd, J = 8.6, 10.4 Hz, 2H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 7.78, 8.97, 21.77,
24.62, 29.09, 41.72, 59.82, 93.25, 172.49 EI-MS m / z (relative intensity): 318 (M ⁺ , 9), 288
(100, bp), 218 (19), 57 (97) EI-HRMS: calcd for C ₁₉ H ₃₀ N ₂ O ₂ (M ⁺ ) 31
8.2307, found 318.2291 Mp: 79-85 ℃ (M, R, R)

Racemic mixture of (M, R, S) form and its enantiomer: IR (KBr): 2970, 2878, 1458, 1381, 1350, 941, 864, 8
^{33cm -1 1 H-NMR (270MHz} , CDCl 3): δ0.84-1.03 (m, 12H),
1.24-1.51 (m, 2H), 1.51-2.07 (m, 10H), 2.07-2.24 (m,
2H), 2.48 (dt, J = 7.6, 13.0Hz, 1H), 2.70 (dd, J = 6.0, 1
2.6Hz, 1H), 3.51 (dd, J = 7.6, 11.6Hz, 1H), 3.70 (t, J
= 9.2 Hz, 1H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 7.42,
7.63, 9.08, 9.24, 20.81, 23.49,23.90, 24.19, 28.5
4, 28.97, 41.51, 41.87, 42.44, 59.5, 61.37, 92.92,
93.32, 172.58, 174.42 EI-MS m / z (relative intensity): 318 (M ⁺ , 46), 301
(13), 289 (100, bp), 57 (58) EI-HRMS: calcd for C ₁₉ H ₃₀ N ₂ O ₂ (M ⁺ ) 31
8.2307, found 318.2285 Mp: 89-92 ℃ (M, R, S)

The racemic mixture was optically resolved into each enantiomer using Chiralpak AD manufactured by Daicel in the same manner as in step v) of Example 1.

Example 5 i) 2,2-bis (5-methyl-4-isopropyl-
Synthesis of diethyl ester of 3-hexenyl) propane-1,3-dicarboxylic acid Example 1 was repeated except that 1-bromo-5-methyl-4-isopropyl-3-hexene was used instead of 4-bromo-1-butene. The title compound was obtained in the same operation as in step i) in a yield of 9
Obtained at 3%. Pale yellow liquid.

IR (neat): 2963, 2870, 1732, 1462, 136
6, 1261, 1238, 1211, 1180, 1034,864, 664cm -1 1 H-NMR (270MHz, CDCl 3): δ0.98 (d, J = 6.9Hz, 24
H), 1.25 (t, J = 7.1Hz, 6H), 1.90 (s, 2H), 1.92 (s, 2H),
2.26 (sept, J = 6.9Hz, 2H), 2.72 (sept, J = 6.9Hz, 2H),
4.19 (q, J = 7.1Hz, 4H), 5.08 (t, J = 3.0Hz, 2H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 14.20, 21.30, 22.1
3, 24.56, 28.83, 29.35, 32.79, 57.43, 61.05, 119.6
7, 151.97, 171.62 CI-MS m / z: 437 (MH +) EI-HRMS: calcd for C 27 H 48 O 4 (M +) 436.355
3, found 436.3542

Ii) Synthesis of 2,2-bis (5-methyl-4-isopropyl-3-hexenyl) -1,3-propanediol 2,2-bis (5-methyl-4-isopropyl-3-hexenyl) The title compound was obtained as colorless crystals in a yield of 91% in the same manner as in Step ii) of Example 1 using diethyl propane-1,3-dicarboxylate as a substrate.

IR (KBr): 3287, 2959, 2928, 2870, 1462,
1381, 1362, 1246, 1115, 1050, 1007, 853, 664cm
^{-1 1 H-NMR (270MHz,} CDCl 3): δ0.99 (d, J = 6.8Hz, 12
H), 1.01 (d, J = 6.9Hz, 12H), 1.26-1.37 (m, 4H), 1.93-
2.06 (m, 4H), 2.27 (sept, J = 6.8Hz, 2H), 2.78 (sept, J
= 6.9Hz, 2H), 3.61 ( s, 4H), 5.09 (t, J = 7.2Hz, 2H) 13 C-NMR (67.5MHz, CDCl 3): δ20.96, 21.34, 24.6
6, 28.62, 29.43, 31.50, 69.28, 120.81, 120.88, 15
1.45 CI-MS m / z: 351 (M-1) Mp: 69-72 ℃

Iii) 2,2-bis (5-methyl-4-)
Synthesis of isopropyl-3-hexenyl) malonodioxime Using 2,2-bis (5-methyl-4-isopropyl-3-hexenyl) -1,3-propanediol as a substrate, steps iii) and iv) of Example 1 and By the same operation, the title compound was obtained as colorless crystals in a yield of 90% (in two steps).

IR (KBr): 3310, 2959, 2928, 2870, 1470,
 1362, 1296, 1030, 949, 667cm^{− 1 1} H-NMR (270MHz, CDCl₃ ): δ0.98 (d, J = 6.9Hz, 12
H), 0.99 (d, J = 6.9Hz, 12H), 1.62-1.75 (m, 4H), 1.97-
2.10 (m, 4H), 2.26 (sept, J = 7.0Hz, 2H), 2.73 (sept, J
= 6.9 Hz, 2H), 5.04 (t, J = 7.1Hz, 2H), 6.89 (s, 2H),
7.44 (s, 2H) ¹³C-NMR (67.5MHz, CDCl₃ ): δ21.28,
22.02, 24.62, 28.70, 29.44, 36.55, 45.81, 120.01,
151.96, 154.40 EI-MS m / z (relative intensity): 378 (M⁺ , 14), 363
(10), 320 (34), 69 (100, bp) EI-HRMS: calcd for C₂₃H₄₂N₂ O₂ (M⁺ ), 37
8.3246, found 378.3257 Mp: 94-97 ℃

Iv) Spirobisisoxazoline (XI
) Synthesis

Embedded image

Using 2,2-bis (5-methyl-4-isopropyl-3-hexenyl) malonodioxime as a substrate, the title compound of interest was obtained in a yield of 60% by the same procedure as in step V) of Example 1. I got it. The breakdown of the diastereomer is 31% of a racemic mixture of the (M, S, S) form and its enantiomer, 7% of a racemic mixture of the (M, R, R) form and its enantiomer, (M, R, S) The racemic mixture of the isomer and its enantiomer was 22%.

Racemic mixture of (M, S, S) form and its enantiomer: IR (reflection method): 2961, 2933, 2897, 2876, 1466, 1385, 1
373, 1364, 1005, 889, 868, 783, 704cm -1 1 H-NMR (270MHz, CDCl 3): δ0.91 (d, J = 6.8Hz, 6
H), 0.94 (d, J = 7.1Hz, 6H), 1.00 (d, J = 6.8Hz, 6H), 1.0
7 (d, J = 6.8Hz, 6H), 1.78-1.81 (m, 2H), 1.87-2.34 (m,
8H), 2.47-2.61 (m, 2H), 3.64 (dd, J = 7.5, 11.4 Hz, 2H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 17.94, 18.36, 18.8
3, 18.91, 24.12, 31.19, 31.53, 40.66, 44.60, 56.8
3, 95.49, 172.68 CI-MS m / z: 375 (MH ⁺ ) Mp (decomposition): 160 ℃ (M, S, S)

Racemic mixture of (M, R, R) isomer and its enantiomer: IR (reflection method): 2961, 2878, 1466, 1385, 1342, 1007, 9
22, 899, 868, 841, 795cm -1 1 H-NMR (270MHz, CDCl 3): δ0.82-1.04 (m, 24H),
1.81-1.98 (m, 6H), 2.17-2.34 (m, 4H), 2.73 (dt, J = 8.
4, 13.4 Hz, 2H), 3.78 (t, J = 9.8 Hz, 2H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 17.44, 17.99, 18.3
7, 18.88, 21.96, 31.64, 31.85, 41.68, 41.95, 54.5
4, 96.69, 170.88 CI-MS m / z: 375 (MH ⁺ )

Racemic mixture of (M, R, S) form and its enantiomer: IR (reflection method): 2955, 2932, 1458, 1382, 1340, 995, 89
^{1, 860, 831, 800cm -} 1 1 H-NMR (270MHz, CDCl 3): δ0.82-1.04 (m, 24H),
1.65-1.95 (m, 5H), 2.02-2.48 (m, 6H), 2.73-2.86 (m, 1
H), 3.70 (dd, J = 7.7, 11.4Hz, 1H), 4.03 (t, J = 9.4Hz,
1H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 17.00, 17.64, 17.7
6, 17.96, 18.40, 18.55, 18.92, 20.26, 23.74, 31.1
1, 31.55, 31.57, 31.78, 40.15, 40.86, 42.40, 53.0
7, 56.10, 95.73, 96.93, 169.68, 172.19 CI-MS m / z: 375 (MH ⁺ )

The racemic mixture was optically resolved into each enantiomer using Chiralpak AD manufactured by Daicel in the same manner as in step v) of Example 1.

Example 6 Synthesis of Optically Active 3-Ethylcyclohexanone (M, S, S) Form (7.6 mg, 0.037) of Optically Active Bisisoxazoline Derivative [VII] Obtained in Example 1
mmol) and copper (II) triflate (9.4 mg, 0.
026 mmol) and a solution of cyclohexenone (51 μl, 0.52 mmol) in toluene (1.
(65 ml) was added with a toluene solution (0.61 ml) of diethyl zinc (0.68 mmol), and the whole was stirred at -50 ° C for 4.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ether. The resulting product was purified by silica gel column chromatography (hexane: acetone = 30: 1), and its optical purity was determined by Daicel's Chiralpak AS (hexane: isopropyl alcohol 98: 2). 68% yield, 2
2% ee.

Example 7 Synthesis of Optically Active 3-Ethylcyclohexanone The optically active bisisoxazoline derivative [VIII] (9.7 mg, 0.037 mmol) obtained in Example 2 and copper (II) triflate (9. 4mg, 0.026mmo
1) and cyclohexenone (51 μl,
0.52 mmol) in a toluene solution (1.65 ml) of diethylzinc (0.68 mmol) (0.61 m
l) was added and the mixture was stirred at -50 ° C for 2 hours. The product was obtained in the same manner as in Example 6, and the optical purity was determined. Yield 92
%, 31% ee.

Example 8 Synthesis of Optically Active 3-Ethylcyclohexanone (M, S, S) Form (10.3 mg, 0.05) of Optically Active Bisisoxazoline Derivative [VII] Obtained in Example 1
0 mmol) and copper (II) acetylacetonate (9.3).
mg, 0.0356 mmol) and diethyl zinc (0.926 m 2) in a toluene solution (2.3 ml) of cyclohexenone (70 μl, 0.713 mmol).
mol) of toluene solution (0.85 ml),
Stirred at 0 ° C. for 2 hours. The product was obtained in the same manner as in Example 6, and the optical purity was determined. Yield 79%, 45% ee.

Example 9 Synthesis of Optically Active 3-Isopropylcyclohexanone (M, S, S) Form (6.4 mg, 0.031) of Optically Active Bisisoxazoline Derivative [VII] Obtained in Example 1
mmol) and copper (II) triflate (9.4 mg, 0.
026 mmol) and a solution of cyclohexenone (51 μl, 0.52 mmol) in toluene (1.
65 ml) in diisopropyl zinc (0.68 mmol)
Of toluene (0.61 ml) was added,
Stirred for hours. The product was obtained by the same treatment as in Example 6,
Optical purity was determined. Yield 79%, 49% ee.

Example 10 Synthesis of Optically Active 1,3-Diphenylpentan-1-one The (M, S, S) form of the optically active bisisoxazoline derivative [VII] obtained in Example 1 (7. 4 mg, 0.035
7 mmol) and copper (II) triflate (9.2 mg,
0.0255 mmol) and diethyl zinc (0.663 mmol) in a toluene solution (2.2 ml) of the complex and chalcone (107 mg, 0.51 mmol).
Of toluene solution (0.6 ml) was added and the whole was -30 ° C.
For 7 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ether. The resulting product was purified by silica gel column chromatography (hexane: acetone = 30: 1), and its optical purity was determined by Daicel's Chiralpak AD (hexane: isopropyl alcohol 98: 2). Yield 69%, 3
6% ee.

Example 11 Synthesis of Optically Active trans-trans-2-phenylcyclohexanol The (M, S, S) form of the optically active bisisoxazoline derivative [VII] obtained in Example 1 (14 mg, 0 .07mm
ol) and cyclohexene oxide (0.1 ml, 1.0 ml
mmol) in diethyl ether (2.2 ml) was added a solution of phenyllithium (0.86 M in hexane) (3.0 ml), and the whole was stirred at 0 ° C. for 12 hours. After the reaction was stopped by adding 1N hydrochloric acid to the reaction mixture, the mixture was extracted with ethyl acetate. The obtained product is subjected to silica gel column chromatography (hexane: ethyl acetate =
5: 1) and the optical purity was determined by Daicel Chi
ralcel OD (hexane: isopropyl alcohol = 9
8: 2). Yield 58%, 16% ee.

Example 12 Optically active 3-hydroxymethyl-3,6-dihydro-2
Synthesis of H-pyran (General Procedure) The optically active spirobisisoxazoline derivative (18 μmo) shown in Table 1 and obtained as a ligand in the above example.
l) and palladium (II) triflate (15 μmol)
Was stirred in methylene chloride (0.40 ml) at room temperature for 2 hours to form a complex. To this solution was added a group R ² shown in Table 1.
(A) (0.10 mmol) having
Benzoquinone (43 mg, 0.40 mmol) was added at room temperature and stirred. After completion of the reaction for the time shown in Table 1, the reaction was stopped by adding water, extracted with ethyl acetate, washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was analyzed by silica gel column chromatography (hexane-ethyl acetate =
7: 1 to 2: 1) to obtain a cyclic product (b) with the yield and optical purity (ee) shown in Table 1. The optical purity was determined by converting to p-nitrobenzoyl ester and then
Determined by ralpak AD (hexane-isopropyl alcohol). These are summarized in Table 1.

[0130]

Embedded image

[Table 1]

3-Hydroxymethyl-3,6,6-trimethyl-3,6-dihydro-2H-pyran: colorless liquid IR (neat): 3420, 2972, 2870, 1466, 1360, 1232, 119
0, 1074, 1043, 916, 820, 750cm -1 1 H-NMR (270MHz, CDCl 3): δ0.90 (s, 3H), 1.25
(s, 3H), 1.27 (s, 3H), 2.20-2.50 (bro-s, 1H), 3.50 (s,
2H), 3.52 (d, J = 11.5Hz, 1H), 3.75 (dd, J = 11.5, 1.2H
z, 1H), 5.47 (dd, J = 10.2, 1.2Hz, 1H), 5.72 (d, J = 10.
2, 1H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ20.18, 25.62, 28.6
2, 36.31, 68.38, 69.61, 72.21, 129.08, 135.69 CI-MS m / z: 157 (MH ⁺ ), 156 (M ⁺ )

6,6-dimethyl-3-ethyl-3-hydroxymethyl-3,6-dihydro-2H-pyran: colorless liquid IR (neat): 3421, 2974, 2926, 2878, 1461, 1360, 121
7, 1184, 1074, 984, 746cm -1 1 H-NMR (270MHz, CDCl 3): δ0.87 (t, J = 7.6Hz, 3
H), 1.25 (s, 3H), 1.26 (s, 3H), 1.22-1.40 (m, 4H), 3.
50 (d, J = 10.5Hz, 1H), 3.54 (d, J = 10.5Hz, 1H), 3.63 (d,
J = 11.6Hz, 1H), 3.72 (dd, J = 11.6, 1.2Hz, 1H), 5.48
(dd, J = 10.2, 1.2Hz, 1H), 5.77 (d, J = 10.2Hz, 1H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ7.96, 25.72, 26.3
8, 28.53, 39.06, 66.70, 68.15, 72.20, 127.40, 136.
53

3-Benzyl-6,6-dimethyl-3-hydroxymethyl-3,6-dihydro-2H-pyran: colorless crystal IR (reflection method): 3410, 2976, 2918, 2898, 1495, 1454, 1
362, 1140, 1055, 1038, 818, 739, 704cm -1 1 H-NMR (270MHz, CDCl 3): δ1.19 (s, 3H), 1.24
(s, 3H), 2.20 (bro-s, 1H), 2.62 (d, J = 13.3Hz, 1H),
2.73 (d, J = 13.3Hz, 1H), 3.49 (s, 2H), 3.64 (d, J = 11.6
Hz, 1H), 3.72 (dd, J = 11.6, 0.8Hz, 1H), 5.50 (d, J = 1
0.3Hz, 1H), 5.72 (d, J = 10.3Hz, 1H), 7.10-7.35 (m, 5
H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 26.25, 27.94, 40.0
4, 40.09, 66.58, 66.73, 72.35, 126.21, 127.22, 12
7.92, 130.30, 136.34, 136.96 Example 13 Synthesis of Optically Active 3-Oxabicyclo [3.2.1] octane (General Procedure) The optically active spiro obtained in the above example, shown as a ligand in Table 2, Bisisoxazoline derivative (24 μmo
l) and palladium (II) triflate (20 μmol)
Was stirred in methylene chloride (0.40 ml) at room temperature for 2 hours to form a complex. Diolefin (c)
(0.10 mmol) and p-benzoquinone (43 mg,
0.40 mmol) at room temperature and stirred. After completion of the reaction for the time shown in Table 2, the reaction was stopped by adding water, extracted with ethyl acetate, washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 30: 1).
(D) and cyclic products (e) and (f) were obtained with the yield and optical purity (ee) shown in (1). The optical purity is Daicel Chi
Determined by ralpak AD (hexane-isopropyl alcohol). These are summarized in Table 2.

[0134]

Embedded image

[Table 2]

1-benzoyloxy-4,4-dimethyl-6-isopropenyl-3-oxabicyclo [3.2.
1] Octane: colorless liquid IR (neat): 2939, 2870, 1720, 1450, 1381, 1315, 127
3, 1115, 1069, 887, 714cm -1 1 H-NMR (270MHz, CDCl 3): δ1.26 (s, 3H), 1.27
(s, 3H), 1.50-1.62 (m, 2H), 1.77 (s, 3H), 1.77-1.93
(m, 2H), 2.01 (ddd, J = 13.0, 10.9, 3.0Hz, 1H), 2.85-
2.97 (m, 1H), 3.57 (dd, J = 12.0, 2.4Hz, 1H), 3.75 (dd,
J = 12.0, 0.98Hz, 1H), 4.20 (d, J = 12.0Hz, 1H), 4.24
(d, J = 12.0Hz, 1H), 4.71 (s, 1H), 4.74 (s, 1H), 7.40-
7.50 (m, 2H), 7.52-7.60 (m, 1H), 8.00-8.06 (m, 2H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ22.35, 22.71, 27.4
4, 32.56, 36.01, 44.26, 44.42, 48.90, 68.82, 70.2
9, 74.81, 107.80, 128.40, 129.51, 129.52, 130.11,
133.00, 149.14, 166.43 EI-MS m / z (relative intensity): 314 (M ⁺ , 20), 299
(13), 192 (82) , 105 (100, bp) EI-HRMS: calcd for C 20 H 26 O 3 (M +), 314.188
2, found 314.1874

3-Benzoyloxymethyl-6,6-dimethyl-3- (3-methyl-3-butenyl) -3,6-
Dihydro-2H-pyran: colorless liquid IR (neat): 2974, 2931, 1720, 1450, 1377, 1273, 111
5, 1176, 1076, 1026,752, 710cm -1 1 H-NMR (270MHz, CDCl 3): δ1.27 (s, 6H), 1.62
(d, J = 8.1Hz, 1H), 1.64 (d, J = 7.9Hz, 1H), 1.72 (s, 3
H), 1.95-2.20 (m, 2H), 3.66 (d, J = 11.5Hz, 1H), 3.80
(d, J = 11.5Hz, 1H), 4.21 (d, J = 10.5Hz, 1H), 4.26 (d,
J = 10.5Hz, 1H), 4.69 (s, 2H), 5.58 (d, J = 10.2Hz, 1H),
5.75 (d, J = 10.2Hz, 1H), 7.40-7.48 (m, 2H), 7.56 (tt,
J = 7.0, 1.1Hz, 1H), 7.99-8.07 (m, 2H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ22.57, 26.48, 27.7
3, 31.79, 32.33, 37.87, 65.39, 67.46, 72.14, 109.8
6, 126.60, 128.40, 129.53, 130.23, 132.96,136.85,
145.86, 166.41 EI-MS m / z (relative intensity): 314 (25), 299 (98), 2
45 (45), 193 (98), 79 (100, bp) EI-HRMS: calcd for C ₂₀ H ₂₆ O ₃ (M ⁺ ), 314.188
2, found 314.1893

3-benzoyloxymethyl-6,6-dimethyl-3- (3-methyl-2-butenyl) -3,6-
Dihydro-2H-pyran: colorless liquid IR (neat): 2974, 2928, 1724, 1450, 1377, 1273, 117
7, 1115, 1027, 1026,752, 710cm -1 1 H-NMR (270MHz, CDCl 3): δ1.26 (s, 6H), 1.58
(s, 3H), 1.70 (s, 3H), 2.19 (d, J = 7.6Hz, 2H), 3.60 (d,
J = 11.5Hz, 1H), 3.77 (d, J = 11.5Hz, 1H), 4.20 (s, 2
H), 5.10-5.22 (m, 1H), 5.58 (d, J = 10.2Hz, 1H), 5.71
(d, J = 10.2Hz, 1H), 7.44 (t, J = 7.4Hz, 2H), 7.53-7.59
(m, 2H), 8.30 (d, J = 7.3 Hz, 1H) ¹³ C-NMR (67.5 MHz, CDCl ₃ ): δ 17.99, 26.08, 26.5
9, 27.86, 32.44, 38.77, 65.38, 67.23, 72.20, 118.4
7, 126.95, 128.27, 129.41, 130.21, 132.79,134.71,
136.25, 166.24 EI-MS m / z (relative intensity): 314 (M ⁺ , 13), 299
(52), 245 (17) , 229 (33), 123 (100, bp) EI-HRMS: calcd for C 20 H 26 O 3 (M +), 314.188
2, found 314.1851

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) C07C 33/28 C07C 33/28 35/21 35/21 45/29 45/29 45/69 45/69 47 / 21 47/21 47/238 47/238 49/403 49/403 E 249/08 249/08 251/40 251/40 C07D 309/24 C07D 309/24 // C07B 61/00 300 C07B 61/00 300 C07D 493/08 C07D 493/08 C

Claims (25)

[Claims] 1. A bisisoxazoline derivative represented by the general formula [I]. Embedded image (In the formula, R is a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. It may be the same or at least one different. R 'is a single bond or a lower alkylene group.) 2. The bisisoxazoline derivative according to claim 1, wherein each of the four Rs is a hydrogen atom or a methyl group. 3. The bisisoxazoline derivative according to claim 1, wherein R ′ is a methylene group. 4. The bisisoxazoline derivative according to claim 1, which is an optically active substance. 5. A bisisoxazoline derivative [I] obtained by cyclizing a dioxime represented by the general formula [VI] under oxidizing conditions.
The process for producing a bisisoxazoline derivative according to claim 1, wherein Embedded image (Wherein, R and R ′ have the same meaning as defined in claim 1) 6. The method for producing a bisisoxazoline derivative according to claim 5, wherein the obtained bisisoxazoline derivative is optically resolved. 7. A dioxime represented by the general formula [VI]. Embedded image (In the formula, R is a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. It may be the same or at least one different. R 'is a single bond or a lower alkylene group.) 8. The dioxime according to claim 7, wherein R ′ is a methylene group. 9. The process for producing a dioxime according to claim 7, wherein the dialdehyde represented by the general formula [V] is reacted with hydroxylamine to obtain a dioxime [VI]. Embedded image (Wherein R and R ′ have the same meaning as defined in claim 7) 10. A dialdehyde represented by the general formula [V]. Embedded image (In the formula, R is a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. It may be the same or at least one different. R 'is a single bond or a lower alkylene group.) 11. The dialdehyde according to claim 10, wherein R ′ is a methylene group. 12. The method for producing a dialdehyde according to claim 10, wherein the diol represented by the general formula [IV] is oxidized to obtain a dialdehyde [V]. Embedded image (Wherein, R and R ′ have the same meaning as defined in claim 10) 13. A diol represented by the general formula [IV]. Embedded image (In the formula, R is a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. It may be the same or at least one different. R 'is a single bond or a lower alkylene group.) 14. The diol according to claim 13, wherein R ′ is a methylene group. 15. The method for producing a diol according to claim 13, wherein the dialkenyl malonic ester represented by the general formula [III] is reduced to obtain a diol [IV]. Embedded image Wherein R and R ′ have the same meaning as defined in claim 13. R ″ is a lower alkyl group. 16. A dialkenyl malonic ester [III
] Is obtained by reacting a halogenated olefin represented by the general formula [II] with a malonic acid diester in the presence of a base. Embedded image (Wherein, R, R ′ and R ″ have the same meaning as defined in claim 15. X is a halogen atom.) 17. A complex obtained by coordinating a metal to the bisisoxazoline derivative [I] according to any one of claims 1 to 4. 18. An asymmetric synthesis reaction catalyst comprising the optically active bisisoxazoline derivative [I] according to claim 4. 19. An asymmetric synthesis catalyst comprising a complex obtained by coordinating a transition metal with the optically active bisisoxazoline derivative [I] according to claim 4. 20. A transition metal comprising Cr, Mn, Fe, C
20. The catalyst according to claim 19, wherein the catalyst is selected from the group consisting of o, Ni, Cu, Zn, Ru, Rh, and Pd. 21. A method for performing an asymmetric synthesis reaction using the catalyst according to any one of claims 18 to 20. 22. The method according to claim 21, wherein the asymmetric synthesis reaction is an asymmetric nucleophilic addition reaction. 23. A method for performing an asymmetric ring-opening reaction of an epoxy compound using the catalyst according to claim 18. 24. A method for performing an asymmetric Michael-type nucleophilic addition reaction to a conjugated enone using the catalyst according to claim 19 or 20. 25. A method for performing an asymmetric Wacker reaction using the catalyst according to claim 19 or 20.