JPH0658881A - Method, reagent, and device for judging absolute configuration of optical active compound - Google Patents

Abstract

(57) [Summary] (Correction) [Structure] The helical orientation of the chiral nematic phase of the compound obtained by chemically bonding the compound represented by Chemical formula 1 to the optically active compound to be tested, or represented by Chemical formula 1 The compound obtained by chemically bonding the compound and the optically active compound to be inspected is judged from the direction of the helix of the chiral nematic phase of the composition added to the liquid crystal compound having a nematic phase, and the absolute value of the optically active compound to be inspected is judged. Determine the placement. (However, in the formula, n, p, and q are independently 0 or 1, and R
Represents an alkyl group having 1 to 18 carbon atoms, and when n = 0, X
₁ is any _one of a hydrogen atom, a halogen atom, a cyano group, a nitro group, a hydroxy group, or a trifluoromethyl group, and when n = 1, X ₁ is a single bond. [Effect] The amount of the optically active compound to be inspected can be sufficiently measured even in a small amount of about 100 μg, and if the bond with Chemical formula 1 is changed to an ester bond, it can be recovered later by hydrolysis.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for determining an absolute configuration of an optically active compound used in medicines, agricultural chemicals, functional materials, etc., an absolute configuration determination reagent, and an absolute configuration determination device.

[0002]

2. Description of the Related Art The exciton chirality method (Nobuyuki Harada, Kaji Nakanishi,
"Circular dichroism spectrum-application to organic stereochemistry", Tokyo Kagaku Dojin (1982), MTPA esterification method (J.
A. Dale, H.A. S. Mosher, J .; Am. Ch
em. Soc. , 95 , 512 (1973)) and the like.

However, the exciton chirality method is an absolute configuration measurement method only for diols, and the MTPA esterification method is a secondary alcohol, or at most two methylenes between a hydroxyl group and an asymmetric carbon. It was a method of predicting the absolute configuration of primary alcohols.

An attempt to predict the absolute configuration using liquid crystals is described in G. Gottarelli et al. (Tetrahedr
on Lett. 1975, 1981, Tetrah
edron 37 (1981) 395), an optically active compound is directly added to a compound having a nematic phase and the direction of the helix of the resulting chiral nematic phase is measured. It could not be a prediction method. Therefore, there has been a demand for a method capable of predicting the absolute configuration with few exceptions even if the asymmetric carbon is separated from the functional group.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to control the arrangement of optically active groups by chemically bonding an optically active compound to be inspected with a liquid crystalline group, and to precisely determine the absolute configuration of the optically active compound. An object is to provide a determination method, an absolute configuration determination reagent, and an absolute configuration determination device.

[0006]

Means for Solving the Problems As a result of intensive investigations by the present inventors, if the optically active compound to be inspected is chemically bonded to a liquid crystalline group to control the arrangement of the optically active groups, this object can be obtained. It was found to be effective in achieving this, and the present invention was completed.

That is, the absolute configuration determination method for an optically active compound, the absolute configuration determination reagent, and the absolute configuration determination device of the present invention chemically bond the compound shown in Chemical formula 1 to the test optically active compound. Direction of the helix of the chiral nematic phase of the obtained compound, or the chiral of the composition obtained by adding the compound obtained by chemically bonding the compound represented by Chemical formula 1 and the optically active compound to be inspected to the liquid crystal compound having the nematic phase A method for judging the absolute configuration of an optically active compound to be inspected by judging from the direction of the helix of a nematic phase; an absolute configuration determination reagent shown in Chemical formula 1 used for the purpose of utilizing the absolute configuration determination method; It is characterized by an apparatus using a judgment method.

[Chemical 1] (However, in the formula, n, p, and q are independently 0 or 1, and R
Represents an alkyl group having 1 to 18 carbon atoms, and when n = 0, X
₁ is any _one of a hydrogen atom, a halogen atom, a cyano group, a nitro group, a hydroxy group, or a trifluoromethyl group, and when n = 1, X ₁ is a single bond,

[Chemical 2] Z _A , Z _B and Z _C are each a hydrogen atom, a halogen atom, a cyano group, a nitro group, a methyl group,
It is either a methoxy group or a trifluoromethyl group. )

[0008]

First, the absolute placement determination method will be described. A feature of the absolute configuration determination method of the present invention is that the optically active compound to be inspected exhibits a liquid crystallinity by chemically bonding with a liquid crystalline group, and even if the liquid crystallinity itself does not show a liquid crystallinity,
Since sufficient linearity is maintained by chemically bonding with a compound as shown in, and by adding itself to a liquid crystal compound having a nematic phase, a liquid crystal state can be realized,
The point is that the arrangement of optically active groups can be controlled.

That is, the spiral of the chiral nematic phase is
The steric interaction of the absolute configuration of the optically active group determines the twisting direction.

In the case of one asymmetric carbon, the opposite of the absolute configuration always causes the opposite direction of the helix. It is considered empirically ascertaining whether the twist direction corresponds to R or S asymmetry by systematically examining the molecular structures and twist directions of many samples.

Among them, particularly those in which the optically active compound has a linear structure are described in the Gray and McDonnell rule (Mo
l. Cryst. Liq. Cryst. Lett. , 3
4, 211 (1977)), "Is empirically the number of carbons away from the core and the asymmetry may uniquely determine the absolute configuration of the asymmetry and the orientation of the chiral nematic phase helix?" Therefore, the experiment shown in the example was conducted. As a result, all odd-numbered asymmetries from functional groups are S
Or if the even-numbered asymmetry from the functional group is R, the direction of the helix of the chiral nematic phase is R
It turned out that it can correspond to. Further, it was found that when the even-numbered asymmetry from the functional group is S, or when the odd-numbered asymmetry from the functional group is R, the helical direction of the chiral nematic phase can correspond to L.

That is, if the direction of the helix of the chiral nematic phase and the planar structure of the optically active compound are known, the absolute configuration will be uniquely determined. As a result of being applied to the pheromone of the actual natural compound, this is all applicable to this rule, and it can be seen that it is also applied to the pheromone of which the absolute configuration is unknown.

For compounds having two asymmetric carbons,
It is the sum of the twisting forces of the chiral nematic phase corresponding to each asymmetry, and the twisting force is stronger near the core part, and the direction of the chiral nematic phase helix is determined by the asymmetric absolute configuration near the core part. It

By measuring the twisting force, information on the other asymmetry can be obtained.

Here, the case where the optically active compound is linear is given as an example, but as described above, other optically active compounds can also be systematically examined for the molecular structure and the twisting direction of the helix. , It is considered possible to associate the absolute configuration with the twisting direction of the helix.

The characteristic of this method is that the optically active compound to be inspected can be sufficiently measured even in a small amount of about 100 μg. Many of the natural compounds are not available in large quantities, and the fact that they can be measured in small quantities is sufficiently significant. Further, if the bond with Chemical formula 1 is changed to an ester bond, it can be recovered later by hydrolysis.

Next, the absolute configuration determination reagent will be described.

The compound represented by Chemical formula 1 used for the purpose of the present invention is a compound for facilitating the development of a liquid crystal phase when chemically bound to the optically active compound to be inspected.

Here, when the asymmetric carbon of the optically active compound to be inspected is separated from the functional group by 5 carbons or more, the compound obtained by chemically bonding with the optically active compound to be inspected is a chiral nematic phase. Since it is possible to use without diluting the compound having the above, the twisting power is not weakened, which is preferable, but of course, even when the asymmetric carbon of the optically active compound to be inspected is separated from the functional group by 4 carbons or less, The compound obtained by chemically bonding the optically active compound and the compound represented by Chemical formula 1 preferably has a chiral nematic phase.

As described above, among the compounds represented by Chemical formula 1, compounds which exhibit a chiral nematic phase when chemically bonded to various optically active compounds to be tested can be preferably used. As a particularly preferable example, the compound shown in Chemical formula 3 can be mentioned.

[Chemical 3]

When the asymmetric carbon of the optically active compound to be inspected is separated from the functional group by 4 carbon atoms or less, the compound represented by Chemical formula 1 is chemically bonded to the optically active compound to be inspected. The obtained compound itself does not necessarily have a chiral nematic phase.

In this case, a compound obtained by compounding the compound represented by Chemical formula 1 with the optically active compound to be inspected is added to the liquid crystal compound having a nematic phase, and the spiral of the induced chiral nematic phase is added. The direction of should be measured. However, the addition amount of the compound at that time is preferably 0.1 to 20 mol% because the helical direction may be reversed when added in a large amount.

When the amount of the optically active compound to be inspected is small, the above method is superior.

The compound shown in Chemical formula 1 is a compound for facilitating the expression of a liquid crystal phase when chemically bonded to the optically active compound to be inspected, that is, for facilitating the control of the arrangement of the optically active groups. As a typical compound used for such a purpose, among the compounds represented by Chemical formula 1, particularly preferably, the compound represented by Chemical formula 4 can be mentioned.

[Chemical 4]

Further, even in the optically active substance to be inspected in which the asymmetric carbon is separated from the functional group by 5 or more carbon atoms, the method of adding to the liquid crystal having the nematic phase is particularly effective when the amount of the optically active substance itself is small. It can be used satisfactorily although the sensitivity is slightly lowered.

The absolute placement determining device will be described below.

The spiral orientation of the chiral nematic phase can be measured by the contact method (J. Billard, C. et al.
R. Acad. Sci. , Paris, 274B , 33
3 (1972)) is simple and the measurement cell using the principle is shown in FIG.

The absolute configuration measuring device of the present invention means that the measuring cell is placed on a heater equipped with a temperature controller,
A liquid crystal compound whose chiral nematic phase helix direction is known is injected from one inlet of the measurement cell by capillarity, and the optically active compound to be inspected and the compound shown in Chemical formula 1 are chemically bonded from the other inlet. The resulting compound, or a composition obtained by adding the compound to a liquid crystalline compound having a nematic phase is injected, and observed with a microscope having a polarizing plate in which the contact regions are orthogonal to the upper and lower sides of the measurement cell, By rotating the direction of the measurement cell, when the black region of the nematic phase is observed, it is determined that the spiral direction of the compound or composition on the tested side is opposite to the spiral direction of the known liquid crystal compound, An apparatus for determining the absolute configuration of the optically active compound to be inspected from the determination result is shown.

In addition, in order to measure the direction of the helix of the chiral nematic phase, a method of measuring from the sign of the Cotton effect of optical dispersion and circular dichroism (FD Saeva, et.
al, J .; Am. Chem. Soc. , 93 , 5928
(1971)) or a method in which the light passing through the liquid crystal cell is made into linearly polarized light by inserting a Berek compensator into the optical system, and the polarization direction is measured (Ozawaguchi,
Wada, Applied Physics, 8 , 771 (1976)), and as a method for measuring a longer helical pitch, one glass was rubbed concentrically and liquid crystal was injected into a cell in which one glass was rubbed in parallel. There is a method of measuring the direction of the helix from the direction of the disclination (Uchida et al., IEICE Transactions, 62-C , 629 (1979)), and the like. The absolute configuration of the optically active compound to be inspected can be determined from the orientation.

[0030]

【Example】

[Example 1]

[Chemical 5] Ethyl p-hydroxybenzoate (2.3 g) and diisopropylethylamine (2.2 g) were dissolved in dichloromethane (20 ml), and chloromethyl methyl ether (1.2 g) was added dropwise at 0 ° C, followed by stirring for 1 hour. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate, extracted with ether, washed with a saline solution,
It was dried over magnesium sulfate and purified by silica gel column chromatography.

The ethyl 4-methoxymethoxybenzoate thus obtained was dissolved in 50 ml of ethanol, 30 ml of 4N KOH solution was added, and the mixture was stirred at room temperature for 16 hours. 1N hydrochloric acid was added to this solution until the pH reached 3, and the resulting crystals were filtered, washed with water and dried under reduced pressure.
1.3 g of methoxymethoxybenzoic acid was obtained.

1.17 g of this product and S. A. The method of Haut et al. (J. Org. Chem., 37 , 1425 (1
972)) 4- (4-methoxybenzoyloxy) phenol 1.73 g, N, N'-dicyclohexylcarbodiimide 1.26 g, and dichloromethane 3
After dissolving in 0 ml and stirring for 10 minutes, 0.37 g of N, N-dimethylaminopyridine was added and stirred for 16 hours.

After the solvent was distilled off, the product was purified by silica gel column chromatography to obtain an ester product, 0.82 g of this product was dissolved in 50 ml of tetrahydrofuran,
30 ml of 6N hydrochloric acid was added with stirring, and the mixture was stirred for 2 days and nights. The reaction solution was poured into 400 ml of water, extracted with ethyl acetate, washed with an aqueous solution of sodium hydrogencarbonate and brine, dehydrated over magnesium sulfate, the solvent was distilled off, and the residue was thoroughly washed with dichloromethane and dried to obtain target compound 5. Obtained 0.59 g.

[Embodiment 2]

[Chemical 6] S. The method of Krishnaswamy et al. (Mol. Cr
yst. Liq. Cryst. , 38 , 353 (197)
7)) to 1 equivalent of commercially available Chemical 7, 1 equivalent of N, N′-dicyclohexylcarbodiimide, 0.3 equivalent of N, N-dimethylaminopyridine, and 10 equivalents of dichloromethane. The reaction was carried out at room temperature for 16 hours, the solvent was distilled off, and the product was purified by silica gel column chromatography to obtain the corresponding ester form.

Corresponding ester compounds were obtained in the same manner as in Chemical formulas 8 to 14.

[Chemical 7]

[Chemical 8]

[Chemical 9]

[Chemical 10]

[Chemical 11]

[Chemical 12]

[Chemical 13]

[Chemical 14]

[Chemical 15]

The method of Zaschke et al. (Z. Chem.
No. 7,293 (1977)), a chiral nematic phase was induced by doping 10 wt% of the ester compound into the compound 15, and the direction of the helix was measured at 50 ° C.

As a result, the helical direction of the chiral nematic phase of the ester-doped composition corresponding to Chemical formula 7, Chemical formula 9, Chemical formula 10, and Chemical formula 11 is L, and Chemical formula 8, Chemical formula 12, Chemical formula 1
3, the helical direction of the chiral nematic phase of the composition doped with the ester corresponding to Chemical formula 14 was R.

That is, when the absolute configuration of the asymmetric carbon is the S configuration, when the number of carbon atoms from the hydroxyl group to the asymmetric carbon is an odd number, the direction of the chiral nematic phase helix is R; Corresponds to L.

[Embodiment 3] [Formula 5] synthesized in Embodiment 1
With respect to the equivalents, 1 equivalent of Chemical formula 7, 1 equivalent of triphenylphosphine, and 1 equivalent of diethyl azodicarboxylate were reacted in 10 equivalents of anhydrous benzene for 16 hours at room temperature, the solvent was distilled off, and silica gel column chromatography was performed. The corresponding ether form was obtained by purification. The corresponding ethers were obtained in the same manner as in Chemical formulas 8 to 14.

All of the obtained ethers were in a chiral nematic phase at 150 ° C. The orientation of the helix was measured to find that the chiral nematic phase of the ethers corresponding to Chemical formula 7, Chemical formula 9, Chemical formula 10 and Chemical formula 11 The direction of the helix was R, and the direction of the helix of the chiral nematic phase of the ether corresponding to Chemical formula 8, Chemical formula 12, Chemical formula 13, and Chemical formula 14 was L.

That is, when the absolute configuration of the asymmetric carbon is S, when the number of carbon atoms from the oxygen atom to the asymmetric carbon is odd, the helical direction of the chiral nematic phase is L, and when it is even, it is R. It corresponds.

[Embodiment 4]

[Chemical 16] Mori et al.'S method (Liebigs Ann. Chem., 1
985 , 2083), 102 mg of the pheromone represented by Chemical formula 16 was dissolved in 5 ml of anhydrous methanol and 10 ml of anhydrous methylene chloride, and ozone was injected at -78 ° C under stirring in a container in which nitrogen and oxygen were replaced in this order.

When the reaction solution turned purple, the vessel was replaced again with oxygen and nitrogen in this order, and sodium borohydride (14.5 m) was added.
Add a solution of g in 3 ml of ethanol and add -78 ° C.
It was stirred for 1 hour. Further sodium borohydride 7
A methanol solution (4.3 mg) was added, and the mixture was further stirred at −78 ° C. for 1 hr and then at room temperature for 2 hr.

The reaction solution was poured into saturated saline solution, extracted with methylene chloride, washed with saline solution, and dried with magnesium sulfate.
The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 78 mg of the alcohol shown in Chemical formula 17. [Α] _D ^18.5 = -1.6 (C = 0.84, Et
₂ O)

[Chemical 17]

[Embodiment 5]

[Chemical 18] Mori et al.'S method (Tetrahedron, 38 , 2291)
(1982)), 7.2 mg of the pheromone represented by Chemical formula 18 was dissolved in 1 ml of ethanol, and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hours using platinum oxide as a catalyst. After filtering the solvent, the solvent was distilled off to quantitatively obtain the alcohol represented by Chemical formula 19.

[Chemical 19]

[Embodiment 6]

[Chemical 20] Method of Senda et al. (Agric. Biol. Chem., 4
8 , 795 (1983)) was dissolved in 6 ml of 1,4-dioxane and 1.8 ml of water, and cooled to 8 ° C. Separately, a solution of 231 mg of sodium hydroxide in 2 ml of water was added dropwise at -5 ° C with 236 mg of bromine.
1.3 ml of 1,4-dioxane was added, and this was added dropwise to the previously prepared pheromone solution at 10 ° C. or lower, followed by stirring for 3 hours.

0.6 ml of water in which 55 mg of sodium sulfite was dissolved was added to the reaction solution, and the mixture was heated under reflux for 15 minutes. Concentrated hydrochloric acid was added, the mixture was extracted with ethyl acetate, washed with brine, and the solvent was evaporated.

0.5 ml of anhydrous tetrahydrofuran was added to the residue.
Lithium aluminum hydride 76m
g was added dropwise to a solution suspended in 1.5 ml of anhydrous ether and then gently refluxed for 30 minutes. 10 in an ice bath
% Aqueous sodium hydrogencarbonate solution 0.5 ml and 20% aqueous sodium hydroxide solution 1 ml, ether extraction, washing with brine, evaporation of the solvent and purification by silica gel column chromatography gave 78 mg of the alcohol represented by Chemical formula 21. Obtained. [Α] _D ^21.5 = -1.54
(C = 0.88, CHCl ₃ )

[Chemical 21]

[Example 7] The pheromones obtained in Examples 4 to 6 were converted into ethers in the same manner as in Example 3, and the helical orientation of the chiral nematic phase was measured at 150 ° C. It is suggested that the absolute configuration is uniquely determined by knowing the orientation of the helix with respect to the natural pheromone and the number of carbon atoms from the oxygen atom, similar to the result obtained in Example 3.

[Embodiment 8]

[Chemical formula 22]

[Chemical formula 23] Mori et al.'S method (Libigs Ann. Chem., 19
88 , 717), the pheromones represented by Chemical formulas 22 and 23 are subjected to haloform reaction in the same manner as in Example 6, and then reduced with lithium aluminum hydride to give the corresponding alcohols represented by Chemical formulas 24 and 25. Got 24 [α] _D ^18.5 = -6.2 (C = 0.34,
Et ₂ O), Chemical ^formula 25 [α] _D ^18.5 = 0.0 (C = 0.4
2, Et ₂ O)

[0052]

[Chemical formula 24]

[Chemical 25]

[Example 9] The pheromone obtained in Example 8 was converted to an ether form in the same manner as in Example 3, and the helical orientation of the chiral nematic phase thereof was measured at 150 ° C. It can be seen that the law obtained in Example 3 is applied asymmetrically to the one closer to the oxygen atom. Further, 10 wt% of an ether compound was added to the compound represented by Chemical formula 15, and the helical pitch (P) of the chiral nematic phase was measured at 50 ° C. by the Cano-Wedge method (B).
all. Soc. Fr. Mineral, 91 , 20
(1968)), the chemical formula 24 was 4.6 μm and the chemical formula 25 was 3.2 μm.

From the viewpoint of the twisting force (β) (β = 1 / ρ × 1 / concentration (mol%)), β of
Is 3.4 μm ⁻¹ · mol ⁻¹ , and β in Chemical formula 25 is 5.0 μm ⁻¹
It can be seen that the law of mol ⁻¹ and obtained in Example 2 is expressed as the sum of the twisting forces of two asymmetric carbons (β corresponding to the asymmetry at the 5-position is 4.2 μm ^−1.・ Mol ^-1 ,
Β corresponding to the 11th asymmetry is 0.8 μm ^-1 · mo
l ^-1 ).

That is, it is suggested that by measuring both the direction of the helix and the pitch of the helix, the absolute configuration of both asymmetries is uniquely determined.

INDUSTRIAL APPLICABILITY As described above, the absolute configuration determination method, the absolute configuration determination reagent, and the absolute configuration determination device of the present invention can sufficiently measure an optically active compound to be inspected in a small amount of about 100 μg. If the bond with Chemical formula 1 is changed to an ester bond, there is an excellent effect that it can be recovered by hydrolysis later.

[Brief description of drawings]

FIG. 1 is a view of a chiral nematic measurement cell viewed from above, which uses the principle of a measurement method using a conventional contact method.

FIG. 2 is a cross-sectional view of a chiral nematic measuring cell using the principle of the conventional measuring method using a contact method.

[Explanation of symbols]

 1: Spacer 2: Glass 3: Polyimide alignment film

Claims (3)

[Claims] 1. A compound represented by the chemical formula 1 is chemically bound to an optically active compound to be inspected, and the helical orientation of a chiral nematic phase of the compound is obtained, or the compound represented by the chemical formula 1 and the optically active compound to be inspected. A method of determining the absolute configuration of an optically active compound to be inspected by determining the compound obtained by chemical bonding of and from the direction of the helix of the chiral nematic phase of the composition in which a liquid crystal compound having a nematic phase is added. [Chemical 1] (However, in the formula, n, p, and q are independently 0 or 1, and R
Represents an alkyl group having 1 to 18 carbon atoms, and when n = 0, X
₁ is any _one of a hydrogen atom, a halogen atom, a cyano group, a nitro group, a hydroxy group, or a trifluoromethyl group, and when n = 1, X ₁ is a single bond, Z _A , Z _B and Z _C are each a hydrogen atom, a halogen atom, a cyano group, a nitro group, a methyl group,
It is either a methoxy group or a trifluoromethyl group. ) 2. A compound represented by Chemical formula 1 according to claim 1, which is used for the purpose of utilizing the absolute configuration determination method according to claim 1. 3. The direction of the helix of the chiral nematic phase of the compound obtained by chemically bonding the compound represented by Chemical formula 1 according to claim 1 to the optically active compound to be inspected, or the compound represented by Chemical formula 1 and the compound A compound obtained by chemically bonding to the optically active compound to be inspected is added to a liquid crystal compound having a nematic phase, a means for detecting the helical orientation of the chiral nematic phase, and the absolute configuration is determined from the orientation of the helical. Absolute position determination device comprising: