JP2003207444A - Method for determining absolute appangement of chiral compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for determining the absorlute arrangement of a chiral compound without using any solvents. <P>SOLUTION: In a method for determining the absolute arrangement of the chiral compound concerned by performing a circular dichromatic spectrophtometric analysis of a forming body containing a chiral compound, a metal porphyrin dimer-hexamer, and halogenation alkali, the metal porphyrin dimer-haxmer is a metal porphyrin dimer-hexamer that is crosslinked by a carbon chain and has a substituent that is bulkier than an ethyl group at least at one of the second carbons along the outer periphery of a porphyrin ring from a carbon that is linked to a crosslinking carbon chain in at least one porphyrin ring of a dimer-hexamer (1), and the chiral compound is a chiral compound that can be coordinated to the metal porphyrin dimer-hexamer, and a group that can be coordinated to the metal porphyrin dimer-hexamer and an asymmetric carbon are directly coupled, or one carbon atom is included between a group that can be coordinated and the asymmetric carbon (2). <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for determining the absolute configuration of a chiral compound.

[0002]

2. Description of the Related Art Conventionally, as a method for determining the absolute configuration of a chiral compound, a circular dichroism (CD) spectrophotometric analysis has been carried out on a complex (for example, a complex) of the chiral compound and a specific compound, and the Cotton effect A method of determining the absolute configuration of a chiral compound by utilizing the correlation between the sign of and the absolute configuration of the chiral compound is used. For example, the documents of Inoue et al. Described below can be exemplified. (1) J. Am. Chem. Soc., 2000, 122, 4403-4407, VV
Borovkov, JM Linituluoto, M. Fujiki and Y. Ino
ue. (2) Org. Lett., 2000, 2, 1565-1568, VV Borovko
v, JM Linituluoto and Y. Inoue. (3) J. Phys. Chem. A, 2000, 104, 9213-9219, VV
Borovkov, JM Linituluoto and Y. Inoue. (4) J. Am. Chem. Soc., 2001, 123, 2379-2989, VV
Borovkov, JM Linituluoto, and Y. Inoue. (5) Chirality, 2001, 13, 329-335, VV Borovkov,
N. Yamamoto, JM Linituluoto and Y. Inoue. However, all of the above references disclose only a method for determining the absolute configuration of a chiral compound in a solution state, and the absolute configuration of a chiral compound that is unstable in a solution cannot be determined. Not applicable to decisions. Further, in the above literature, since the nonpolar solvent is used as the solvent, it is not possible to determine the absolute configuration of the chiral compound that does not dissolve in the nonpolar solvent.

As described above, there is a demand for the development of a method for determining the absolute configuration of a chiral compound which can be applied to a chiral compound which is unstable in a solution, a chiral compound which is hardly soluble, a compound which is soluble only in a polar solvent, and the like.

[0004]

SUMMARY OF THE INVENTION The present invention has been made in view of the problems of the prior art, and mainly provides a method for determining the absolute configuration of a chiral compound without using a solvent. To aim.

[0005]

As a result of earnest research, the present inventor has found that the above object can be achieved by using a metalloporphyrin dimer having a specific structure, and has completed the present invention. It was

That is, the present invention relates to the following method for determining the absolute configuration of a chiral compound. 1. A method for determining the absolute configuration of a chiral compound by performing circular dichroism spectrophotometric analysis on a molded product containing a chiral compound, a metal porphyrin dimer and an alkali halide, and (1) the metal porphyrin dimer. The body is a metal porphyrin dimer cross-linked with a carbon chain, and in at least one porphyrin ring of the dimer, at least one of carbons bonded to the cross-linked carbon chain and a second carbon along the outer periphery of the porphyrin ring. On the other hand, it has a bulky substituent at least an ethyl group, and (2) the chiral compound is (i) a chiral compound capable of coordinating with the metalloporphyrin dimer, and (ii) the metalloporphyrin 2 The coordinating group and the asymmetric carbon are directly bonded to the monomer, or 1 carbon atom is present between the coordinating group and the asymmetric carbon.
A method for determining the absolute configuration of an asymmetric carbon of a chiral compound, which is characterized by interposing atoms. 2. The method according to 1 above, wherein the chiral compound is one selected from the group consisting of 1) primary amine, 2) secondary amine, 3) primary diamine, and 4) secondary diamine. 3. The above-mentioned 1 in which the metal porphyrin dimer cross-linked with a carbon chain is a metal porphyrin dimer represented by the following formula (1):
Alternatively, the method for determining the absolute configuration of the chiral compound according to item 2.

[0007]

[Chemical 3]

[Wherein M ²⁺ and M ′ ²⁺ are the same or different and are at least selected from the group consisting of Zn ²⁺ , Fe ²⁺ , Mn ²⁺ , Mg ²⁺ and Ru ^2+. R ^{a to} R ^d and R ¹
R 1 to R ¹² are the same or different and each represents a bulky substituent at the hydrogen atom or higher. However, at least one of R ^{a to} R ^d represents a bulky substituent that is higher than the ethyl group. ] 4. At least one of R ^{a to} R ^d in the formula (1) is
1) a hydrocarbon group having 2 or more carbon atoms, 2) an oxygen-containing substituent,
The method according to 2 above, which is one selected from the group consisting of 3) a nitrogen-containing substituent, 4) a halogen atom, and 5) a halogenated hydrocarbon group. 5. The above-mentioned 1 in which the metal porphyrin dimer cross-linked with a carbon chain is a metal porphyrin dimer represented by the following formula (2):
Alternatively, the method for determining the absolute configuration of the chiral compound according to item 2.

[0009]

[Chemical 4]

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The method for determining the absolute configuration of a chiral compound of the present invention is carried out by performing circular dichroism spectrophotometric analysis on a molded product containing a chiral compound, a metalloporphyrin dimer and an alkali halide. A method for determining the absolute configuration of a chiral compound, wherein (1) the metalloporphyrin dimer is a metalloporphyrin dimer cross-linked with a carbon chain, and at least one porphyrin ring of the dimer, At least one of the second carbon along the outer circumference of the porphyrin ring from the carbon bonded to the bridging carbon chain has a bulky substituent group of ethyl group or more, (2) the chiral compound, (i) the metal porphyrin It is a chiral compound capable of coordinating to a dimer, and (ii) the group capable of coordinating to the metalloporphyrin dimer is directly bonded to an asymmetric carbon, or Groups and the carbon atoms between the asymmetric carbon is interposed 1 atom, characterized in that.

The metalloporphyrin dimer that can be used in the method of the present invention is not particularly limited as long as the above-mentioned conditions are satisfied, and examples thereof include compounds represented by the following formula (1).

[0012]

[Chemical 5]

In the formula (1), M ²⁺ and ^{M'2 +} represent a metal center. As M ²⁺ and M ′ ²⁺ , for example, Zn ²⁺ , F
Examples thereof include e ²⁺ , Mn ²⁺ , Mg ²⁺ , Ru ²⁺ , and among these, Zn ²⁺ is preferable. M ²⁺ and M ′ ²⁺ may be the same or different.

The metal porphyrin dimer is --CH ₂ --CH _2-
Are crosslinked by carbon chains such as. The number of carbon atoms contained in the carbon chain is not particularly limited. For example, in the formula (1), the number of carbon atoms contained in the carbon chain is 2.

Metal porphyrin 2 used in the present invention
The monomer has a bulky substituent group more than an ethyl group on at least one of the carbons bonded to the bridging carbon chain and the second carbon along the outer circumference of the porphyrin ring. For example, equation (1)
In R ^a to R ^d is a substituent were all along the outer periphery of the porphyrin ring from the carbon bonded to the crosslinking carbon chain attached to the carbon wherein for the second. In the formula (1), R ^{a to} R ^d are the same or different and each represents a hydrogen atom or a bulky substituent above a methyl group. However, at least one of R ^{a to} R ^d is a bulky substituent that is more than the ethyl group.

The term “bulky substituent group higher than a methyl group” means a bulky substituent group equivalent to or more than a methyl group. Examples of the bulkier substituent than the methyl group include 1) a hydrocarbon group, 2) an oxygen-containing substituent,
Examples thereof include 3) nitrogen-containing substituents, 4) halogen atoms, 5) halogenated hydrocarbon groups, and the like.

1) Methyl group As a bulky hydrocarbon group, a methyl group, an ethyl group, a propyl group,
Examples thereof include a butyl group. The number of carbon atoms of the hydrocarbon group as a bulky substituent more than a methyl group is not particularly limited, but is usually about 1 to 10, preferably 1 to
It is about 5.

2) Examples of the oxygen-containing substituent include an ester group and a carboxyalkyl group. Examples of the ester group include alkyl ester groups such as methyl ester group and ethyl ester group. Examples of the carboxyalkyl group include a carboxymethyl group and a carboxyethyl group. The alkyl portion of the alkyl ester group and the alkyl portion of the carboxylalkyl group have, for example, about 1 to 10 carbon atoms, preferably 1 carbon atom.
Alkyl of about 5 can be exemplified.

3) Examples of the nitrogen-containing substituent include an amino group, an amide group, a 2-aminoethyl group and the like.

4) Examples of the halogen atom include C
l, Br, F and the like can be exemplified.

5) As the halogenated hydrocarbon group, for example, a methyl chloride group, an ethyl chloride group, a propyl chloride group, a butyl chloride group or the like having about 1 to 10 carbon atoms, preferably about 1 to 5 carbon atoms. A hydrocarbon group can be exemplified.

A bulky substituent group which is equal to or greater than an ethyl group means a substituent group which is as bulky as or equivalent to an ethyl group. Examples of bulky substituents that are more than ethyl groups include 1) hydrocarbon groups having 2 or more carbon atoms, 2)
An oxygen-containing substituent, 3) a nitrogen-containing substituent, 4) a halogen atom,
5) Examples thereof include halogenated hydrocarbon groups.

1) As the hydrocarbon group having 2 or more carbon atoms,
For example, an ethyl group, a propyl group, a butyl group and the like can be exemplified. The carbon number of the hydrocarbon group as a bulkier substituent than the ethyl group is not particularly limited, but is usually
It is about 2 to 10, preferably about 2 to 5.

For 2) oxygen-containing substituents, 3) nitrogen-containing substituents, 4) halogen atoms and 5) halogenated hydrocarbon groups, which are bulky substituents above the ethyl group, refer to "bulky substitution above the methyl group. Substituents similar to the groups exemplified as the "group" can be exemplified.

In the formula (1), R ^{1 to} R ¹² are the same or different and each represents a hydrogen atom or a bulky substituent group having a methyl group or more. Examples of the bulky substituent above the methyl group include the substituents described above, and R ^{1 to} R ¹² include a methyl group, an ethyl group, a propyl group, a butyl group, or the like having 1 carbon atom.
A hydrocarbon group of about 10 (more preferably about 1 to 5) is preferable.

As the metalloporphyrin dimer used in the present invention, for example, a compound represented by the following formula (2) can be preferably used. Hereinafter, the compound of formula (2) may be referred to as compound 1.

[0027]

[Chemical 6]

Metalloporphyrin 2 used in the present invention
The monomer itself can be synthesized according to a known production method (for example, JP-A No. 11-255790).

On the other hand, the chiral compound whose absolute configuration is determined by the method of the present invention has the following characteristics. That is; (i) a chiral compound capable of coordinating to the metalloporphyrin dimer, and (ii) a chiral compound in which an asymmetric carbon is directly bonded to a group capable of coordinating to the metalloporphyrin dimer, Alternatively, it is a chiral compound having one carbon atom interposed between the aforesaid coordinating group and the asymmetric carbon.

The chiral compound may be either liquid (including oily) or solid. Preferred examples of the chiral compound include amine compounds such as 1) primary amine, 2) secondary amine, 3) primary diamine, and 4) secondary diamine. As the primary amine, for example,
Examples thereof include 1-phenylethylamine, 1-cyclohexylethylamine, bornylamine and isopinocampheylamine. When there are a plurality of groups capable of coordinating to a metalloporphyrin dimer such as primary diamine and secondary diamine, an asymmetric carbon to which the group coordinating to the metal center of the metalloporphyrin is bonded, or The absolute configuration can be determined for an asymmetric carbon that is attached to the coordinating group via one carbon atom.

According to the method of the present invention, a chiral compound in which a group capable of coordinating to a metalloporphyrin dimer and an asymmetric carbon are directly bonded to each other, or a carbon atom between the group capable of coordinating and the asymmetric carbon. The absolute configuration can be determined for chiral compounds with one atom intervening.

Metal porphyrin 2 having multiple asymmetric carbons
In the case of a chiral compound in which the asymmetric carbon is directly bonded to the group capable of coordinating to the monomer, the absolute configuration of the asymmetric carbon directly bonded to the group coordinated to the metalloporphyrin can be determined. . For example, bornylamine corresponds to a chiral compound in which a group capable of coordinating to a central metal of a metal porphyrin dimer and an asymmetric carbon are directly bonded, and an amino group among three asymmetric carbons is bonded. The absolute configuration of the asymmetric carbon can be determined.

Metal porphyrin 2 having multiple asymmetric carbons
In the case of a chiral compound in which one carbon atom is present between the asymmetric carbon and the group capable of coordinating to the monomer, the group coordinated to the metalloporphyrin is bonded via one carbon atom. The absolute configuration can be determined for the asymmetric carbons that are present.

The molded product used in the method of the present invention contains the above metal porphyrin dimer, a chiral compound, and an alkali halide. Examples of the alkali halide include KBr, NaBr, NaCl, CsI and the like, and among these, KBr is preferable. The molded product may contain an additive component within a range in which a desired effect is obtained.

The method for preparing the molded body is not particularly limited, and for example, a method of preparing a transparent tablet by milling and mixing the metalloporphyrin dimer, the chiral compound and the alkali halide and press molding. Can be shown. The order of milling and mixing is not particularly limited, and for example, the metal porphyrin dimer and the chiral compound are first milled and mixed,
Then, a method of grinding and mixing with an alkali halide can be exemplified. The exemplified order is preferable because the chiral compound is more surely coordinated to the metal center of the metalloporphyrin dimer. The method of pressure molding is not particularly limited,
It can be appropriately selected according to the circular dichroism measuring device to be used, and for example, a hydraulic pressing method can be exemplified.

The temperature at which circular dichroism spectrophotometry is performed is not particularly limited as long as the cotton effect can be detected. The lower the temperature, the more sensitive the analysis can be performed, but the cotton effect can be sufficiently detected at about 0 to 30 ° C. without cooling the molded body.

The mixing ratio of the metalloporphyrin dimer and the chiral compound is not particularly limited as long as the first Cotton effect can be detected in the CD spectrum of the molded product. The metal porphyrin dimer: chiral compound (molar ratio) is usually 1: 500-
It is about 1: 3000, preferably about 1: 1000 to 1: 2000.

The amount of the alkali halide to be mixed is not particularly limited, but for example, in the ultraviolet-visible absorption spectrum of the molded product, the absorbance of the porphyrin in the B absorption band (Soley band) is usually about 0.5 to 2, preferably 1 It should be set to be about 2 or so.

The molded body used in the present invention is usually 15
It contains about 0 to 160 mg of alkali halide. In addition, the molded body usually contains about 1.5 × 10 ^{−4 to} 3 × 10 ⁻⁴ mmol, preferably about 2 × 10 ^{−4 to} 2.4 × 10 ⁻⁴ mmol of the chiral compound.

The circular dichroism spectrum of the molded product shows two peaks (one maximum and one minimum) (see FIG. 1). Hereinafter, the code indicated by the peak on the longer wavelength side may be referred to as the “code for the first Cotton effect”, and the code indicated by the peak on the shorter wavelength side may be referred to as the “code for the second Cotton effect”.
The sign of each peak may be positive or negative, and the sign of the first Cotton effect and the sign of the second Cotton effect are different. For example, taking the CD spectrum of (1R, 2S)-(+)-bornylamine shown in FIG. 1 as an example, the sign of the first Cotton effect is negative (minus) and the sign of the second Cotton effect is positive (plus). ). Further, the optical effects of the optical isomers (for example, R-isomer and S-isomer) have opposite signs. For example, when (1S, 2R)-(−)-bornylamine is used, the sign is opposite to that in FIG. 1, the first Cotton effect has a positive sign, and the second Cotton effect has a negative sign. The sign of any of the peaks may be used to determine the absolute arrangement, but the first Cotton effect is easier to detect, and therefore can be preferably used.

In order to clarify that a certain correspondence is established between the sign of each Cotton effect in the molded body and the absolute configuration of the asymmetric carbon of the chiral compound (whether it is the R form or the S form), the absolute configuration is established. CD spectra were measured using various chiral compounds known to be. Table 1 below shows the absolute configuration and sign of various chiral compounds and the sign of each Cotton effect in the shaped body. As the metal porphyrin dimer, a metal porphyrin (compound 1) having Zn ²⁺ as a metal center represented by the above formula (2) was used. The molded body was prepared in the same manner as in Example 1 described later. Note that isophenylethylamine, isopinocampheylamine, and cyclohexylethylamine are liquids, and bornylamine is a solid. For reference, the structural formula of isopinocampheylamine is shown below.

[0042]

[Table 1]

[0043]

[Chemical 7]

As is clear from Table 1, there is a certain correspondence between the configuration of the amino group around the α carbon and the sign of the first Cotton effect. That is, when the sign of the first Cotton effect is positive, the absolute configuration of the asymmetric carbon in the chiral compound is (R). On the other hand, when the sign of the first Cotton effect is negative, the absolute configuration of the asymmetric carbon in the chiral compound is (S). By using this correlation and the sign of the Cotton effect of the unknown sample, the absolute configuration of the chiral compound in the unknown sample can be determined.

In the method of the present invention, a circular dichroism (CD) spectrophotometric method is used to analyze a molded article containing a chiral compound, a metalloporphyrin, an alkali halide and the like. That is, in the method of the present invention, the absolute configuration of the chiral compound is determined by the sign of the Cotton effect in the circular dichroism spectrum obtained when the chiral compound to be measured is coordinated with the metalloporphyrin dimer. be able to.

[0046]

According to the present invention, the absolute configuration of a chiral compound can be determined without using a solvent. Therefore, the absolute configuration of a chiral compound that is unstable in a solvent, a chiral compound that is sparingly soluble, a compound that is soluble only in a polar solvent, and the like can be determined.

Conventionally, a method using X-ray crystal structure analysis has been known as a method for determining the absolute configuration of a chiral compound in a solid state, but this method can be applied only to a crystalline compound. According to the method of the present invention, the absolute configuration can be determined regardless of whether the chiral compound is crystalline or not.

According to the present invention, the absolute configuration of chiral compounds can be rapidly determined. The time required for sample preparation and CD spectrum measurement is about 20 to 25 minutes depending on the conditions.

[0049]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples of the present invention. The present invention is not limited to the examples below.

Example 1 The metalloporphyrin dimer represented by the formula (2) (about 10 ⁻⁷ mol) and (1
R, 2S)-(+)-bornylamine (crystalline powder, about 1.5 × 10
^-4 mol) was mixed by milling for about 10 minutes using an agate mortar. A small amount of this mixture was collected, added to KBr (about 150 mg), and further ground for about 10 minutes using an agate mortar, and a tablet was prepared according to a conventional method using this mixture. Specifically, tablets were prepared by the following method. After the mixture is transferred onto a metal disk mounted in a metal cylinder to make the thickness uniform, another metal disk is placed on the powder layer, and the cylinder is kept so that the two disks do not move in that state. Fixed to. After depressurizing the inside of the cylinder with a vacuum pump, place the metal piston on the upper disc while depressurizing it, and press 6
A transparent tablet was prepared by pressurizing to ~ 8 t / cm ² and molding. The amount of the mixture added was adjusted so that the absorbance in the B absorption band of porphyrin was in the range of 1 to 2 in the ultraviolet-visible absorption spectrum of the tablet.

The CD spectrum of the tablets prepared as described above was measured at 20 ° C. The CD spectrum is shown in FIG. As is clear from FIG. 1, the first
The sign of the cotton effect was "negative".

Example 2 A CD spectrum was measured in the same manner as in Example 1 except that (R)-(+)-1-phenylethylamine (oil substance, about 1.5 × 10 ^-4 mol) was used as the amine. The results are shown in Figure 2.

As is apparent from FIG. 2, the sign of the first Cotton effect was "positive".

[Brief description of drawings]

FIG. 1 is a diagram showing a CD spectrum of (1R, 2S)-(+)-bornylamine measured in Example 1. The horizontal axis represents wavelength (nm) and the vertical axis represents ellipticity (mdeg).

FIG. 2 is a diagram showing a CD spectrum of (R)-(+)-1-phenylethylamine measured in Example 2. The horizontal axis represents wavelength (nm) and the vertical axis represents ellipticity (mdeg).

Claims (5)

[Claims] 1. A method for determining the absolute configuration of a chiral compound by performing circular dichroism spectrophotometric analysis on a molded product containing the chiral compound, a metalloporphyrin dimer and an alkali halide, The metal porphyrin dimer is a metal porphyrin 2 cross-linked with a carbon chain.
In at least one porphyrin ring of the dimer, at least one of the carbon bonded to the bridging carbon chain and the second carbon along the outer periphery of the porphyrin ring has a bulky substituent group of ethyl group or more. And (2) the chiral compound is (i) a chiral compound capable of coordinating to the metalloporphyrin dimer, and (ii) a group capable of coordinating to the metalloporphyrin dimer and an asymmetric carbon atom. Is directly bonded, or one carbon atom is interposed between the aforesaid coordinating group and the asymmetric carbon, and a method for determining the absolute configuration of the asymmetric carbon in a chiral compound. 2. The method according to claim 1, wherein the chiral compound is one selected from the group consisting of 1) primary amine, 2) secondary amine, 3) primary diamine and 4) secondary diamine. 3. The method for determining the absolute configuration of a chiral compound according to claim 1, wherein the metal porphyrin dimer cross-linked with a carbon chain is a metal porphyrin dimer represented by the following formula (1). [Chemical 1] [ ^Wherein M ²⁺ and M ′ ²⁺ are the same or different and
at least one selected from the group consisting of n ²⁺ , Fe ²⁺ , Mn ²⁺ , Mg ²⁺ and Ru ²⁺ , and R ^{a to} R ^d and R ^{1 to} R
^12's are the same or different and each represents a bulky substituent on a hydrogen atom or a methyl group or more. However, at least one of R ^{a to} R ^d represents a bulky substituent that is higher than the ethyl group. ] 4. At least one of R ^{a to} R ^d in the formula (1) is 1) a hydrocarbon group having 2 or more carbon atoms, 2) an oxygen-containing substituent, 3) a nitrogen-containing substituent, and 4) a halogen atom. And 5) one method selected from the group consisting of halogenated hydrocarbon groups. 5. The method for determining the absolute configuration of a chiral compound according to claim 1, wherein the metal porphyrin dimer cross-linked with a carbon chain is a metal porphyrin dimer represented by the following formula (2). [Chemical 2]