JPH02259481A - Chirality shift reagent - Google Patents

Abstract

PURPOSE:To simply and correctly determine the structure or optical purity of an optical antipode such as amino acid or the like by adding an optical antipode to a metal porphyrin complex. CONSTITUTION:An optical antipode is added to a metal porphyrin complex represented by the formula (wherein R1-R10 is H and a chain alkyl group such as methyl group, a branched alkyl group such as iso-propyl group, an unsaturat ed hydrocarbon group such as vinyl group or a benzil group which may contain a substituting group etc., and which is a group consisting of a monohydric group selected from hydrocarbon groups having 20 carbons or less or an acetic acid group etc., strap X is a chain alkyl group such as octamethylene group, nonamethylene group etc., a chain alkyl group containing phenylene group which may contain a substituting group, ester or the like, and which is a chain group selected from hydrocarbon groups having 30 carbons or less, and the porphyrin is such that is not reversed by the strap X.). The formula is preferable to be 2,12-bis(hexamethyleneaminocarbonylethyl)-7,17-dihexyl-3-8,-13,18- tetramethylporphyrin.

Description

Detailed Description of the Invention [Industrial Application Field] An optically active metal complex obtained by optically resolving a porphyrin having molecular asymmetry is useful as a chiral shift reagent or an optical resolving agent.

It can also be used as a catalyst for asymmetric synthesis and asymmetric polymerization of asymmetric substances and optically active polymers useful as physiologically active substances.

[Conventional technology]

H) The shift reagent introduced in 1979 by N.K.K.
Provides a method to broaden the R absorption pattern. That is, when a shift reagent is added to a sample with the appropriate functional group, the difference between the chemical shifts of non-equivalent protons is greatly expanded. When a chiral shift reagent forms a complex with an optical enantiomer, it forms diastereomers, each of which exhibits a different chemical shift, which can be used to determine the proportions, or optical purity, of a mixture of enantiomers.

The shift reagents currently in use are rare (lanthanide) series ions bound to chiral organic ligands; Eu (dew)
s〉, Tris (3-()lifluoromethylhydroxymethylene)-d-camphorate] europium (■) (hereinafter abbreviated as Eu(tfc)s) Tris [3
-(heptafluoropropylhydroxymethylene)-d-
Campfplate copraseodymium (hereinafter referred to as Pr(hfcL)
(abbreviated as ) are known.

[Problems to be solved by the present invention]

These chiral shift reagents such as Eu(dcm)s, Eu(tfc)* and Pr(hfc)* are used as chiral shift reagents for carboxylic acids (especially amino acids) and phenols, which have many compounds useful as optically active substances. Not only does it have the disadvantage of not being able to do it, but it also has chiral shift x
Because the drug itself has asymmetric selectivity, there are restrictions on how it can be used.

[Means for solving problems]

The present inventors have discovered that in the formula represented by the following general formula (1), R
1 to R+o are monovalent groups selected from hydrogen and hydrocarbon groups having 20 or less carbon atoms, or groups consisting of carboxylic acid derivatives, and X is a chain group selected from hydrocarbons having 30 or less carbon atoms. We discovered that strap porphyrins, in which strump I found it.

That is, the present invention can shift the resonance absorption of the optical antipode to a negative chemical shift where no resonance absorption exists in ordinary compounds by adding the optical antipode to the porphyrin metal complex, and The optical purity of a mixture of enantiomers can be accurately determined regardless of the amount of the optical pair being present.

The used porphyrin metal complex can be recovered and reused.

In the general formula (1), R, "R + o are hydrogen and a chain alkyl group such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, a 11-hentyl group, a 1so-propyl group,
Branched alkyl groups such as 1so-butyl group, 5eC-butyl group, and Lerk-butyl group; unsaturated hydrocarbon groups such as vinyl group and allyl group; phenyl group that may have a substituent; A monovalent group selected from hydrocarbon groups having 20 or less carbon atoms, preferably 10 or less carbon atoms, such as a benzyl group, which may have 20 or less carbon atoms, an acetate group, a propionate group, a butyrate group, etc. It is a group consisting of a carboxylic acid derivative which is an ester or amide such as.

Strump X is an occumethylene group, a nonamethylene group,
A chain alkyl group such as a decamethylene group, a chain alkyl group having a phenylene group which may have a substituent, a chain alkyl group having an ester, ether, amide, imino, or thioether bond, etc., with a carbon number of 30 It is a chain group selected from the following hydrocarbon groups, and is a porphyrin in which the strap X does not turn over the porphyrin surface.

Specific examples include 2.12-bis(hexamethyleneaminocarbonylethyl)-7,17-dihexyl3.8
Particularly preferred is 13,18-tetramethylporphyrin.

The method for optically resolving porphyrins having these asymmetric molecules is not particularly limited. Methods of dividing diastereomers or diastereomeric salts based on differences in physical properties such as solubility, methods of dividing by asymmetric crystallization (physical method), methods of dividing diastereomers or diastereomeric salts by asymmetric crystallization (physical method), asymmetric resolution method using enzymes or living organisms themselves (
There are methods using biological methods) and chromatography.

Among these, the method using chromatography is the most preferred.

Chromatography includes paper chromatography, gas chromatography and high performance liquid chromatography. In particular, recent techniques of high-performance liquid chromatography have become extremely sophisticated in both hardware and software, and direct optical resolution by high-performance liquid chromatography is a very simple method and is particularly preferred.

Direct optical resolution by chromatography requires the introduction of an asymmetric environment into the phase system, and there are two methods for this: one using a solution containing optically active additives and the other using an optically active stationary phase. be. The latter method is more advantageous when the purpose is preparative separation, since no treatment such as removal of additives from the eluate is required. As the stationary phase, cellulose tris (3,5-dimethylphenylcarbamate) (manufactured by Daicel) or the like is used.

The metal complex of porphyrin optically resolved in this manner is obtained by reacting porphyrin such as an organometallic compound, and has the structure shown below and is a halogen group. (
If M is magnesium or zinc, there is no X).

For example, 2,12-bis(hexamethyleneaminocarbonylethyl)-7,17-dihexyl3.8.13
．． 18-tetramethylborufinate aluminum hydroxide and the like are used.

[Effects of the Invention] By using the chiral shift reagent of the present invention, it is possible to easily and accurately determine the optical structure or optical purity of carboxylic acids (especially amino acids), phenols, alcohols, amines, etc., and , can be collected and reused.

(Example) Reference Example 1 Here, M is a metal atom such as aluminum, gallium, iron, cobalt, manganese, rhodium, magnesium, zinc, etc., and X is a hydroxyl group, an alkyl group, an alkoxy group, a carboxylate group, a phenoxy group, or 2, 1 expressed by the formula
2-bis(hexamethyleneaminocarbonylethyl)
Optical resolution of -7,17-dihexyl-3°8,13.18-tetramethylporphyrin (hereinafter abbreviated as strapporphyrin) was performed using cellulose tris (3,5-dimethylphenylcarbamate) adsorbed on silica gel as a chiral stationary phase. This was carried out by high-performance liquid chromatography using a column packed in a column. Fractionation was performed using hexane-isopropyl alcohol-chloroform (80:10:10 by volume) as an eluent to obtain two components with different retention times. It was confirmed from the circular dichroism spectrum that these two components were optical isomers.

Example 1 After putting 20 μ of the optically active strap porphyrin with the shorter retention time obtained in Reference Example 1 into a nitrogen-substituted eggplant-shaped flask, 2 J of methylene chloride,
Add 0.02 ml of trimethylaluminum and 1 ml at room temperature.
After 0.1 hours of reaction, 0.1 hours of methanol and 5.0 hours of water. L/! was added and separated, and the methylene chloride layer was dried under reduced pressure to obtain an aluminum porphyrin complex.

After adding 3 ml of an isopropyl alcohol solution containing 20 ml of this complex to 0.01 ml of the measurement sample 1) L-α-methoxypropionic acid (racemic form) at room temperature, the isopropyl alcohol solvent was removed under reduced pressure. After removing the solvent, it was dissolved in 0.5% deuterated chloroform (CDC13)-deuterated dimethyl sulfoxide CDMSO-d&) mixed solvent (9:1 by volume), and the solution was placed in a sample tube for NMR measurement. (270 old 1z,
22°C) was measured.

DL-α-methoxypropionic acid (C14°+
8+ C11(OCIlz)COOIi) in CDCI
(b) Protons attached to carbon are 63.95 ppm (quartet line) (C) Protons attached to carbon are 63.47 ppm
(- double line) (Figure 1), the resonance absorption corresponding to D-α-methoxypropionic acid in the complex (diastereomer) after addition is due to the proton attached to the <a> carbon. 1
,99pprin and -2,01ppm (each double line) (b
) Proton attached to carbon -0,401) $111 and -
〇, 91 ppm (each quartet) (C) Protons attached to carbon shifted to 0.95 ppm steel and 0.94 ppm each doublet. The integral ratio of the resonance absorption divided into two types is 1.0
Therefore, the optical purity of DL-α-methoxypropionic acid was calculated to be 0%. Figure 2 shows the 'H' of this complex.
- Shows a chart of NMR spectra.

Example 2 A sample was prepared in the same manner as in Example 1, except that DL-α-methoxypropionic acid (racemic form) was replaced with 1α-methoxypropionic acid, which has no optical activity, as the carboxylic acid. was measured.

After addition of mono-α-methoxypropionic acid (C
The resonance absorption corresponding to II3CH (OCH C00-) is (a) lal fcl (bl proton attached to carbon is -2,01 ppm (double line), (
b) Proton attached to carbon is δ-0,40pp+s (quartet) (C) Proton attached to carbon is 60.95ppm (-
(double line) was observed. The optical purity of L-α-methoxypropionic acid was calculated to be 100% since it was attributed to only one of each resonance absorption in the case of a racemate.

Example 3 Instead of OL-α-methoxypropionic acid (racemic form) as the carboxylic acid, α-methoxypropionic acid with L to D fJ <4:1 by weight (optical purity of L form: 60%) was used. Otherwise, the sample was prepared in the same manner as in Example 1, and 'I
I-NMR was measured.

α-methoxypropionic acid (CHt(
: If(OCII3)COO-), the resonance absorption corresponding to
ppm (each doublet) (b) The proton attached to carbon is δ
-0,40ppm and -0,91ppm (each quartet)
(C) Butons attached to carbon are 60.95 ppm and 0.
It was observed at 94pp111 (each double line). The chemical shift values of the resonance absorption split into two types were the same as in the case of the racemate, and the respective integral ratios were 4.0. Furthermore, the chemical shift value of the resonance absorption with larger integrated intensity is L
−α Since it is equal to the case of methoxypropionic acid, α
-The optical purity of methoxypropionic acid was calculated to be 60% of the L form.

Example 4 The sample subjected to NMR measurement in Example 1 was transferred to a separating funnel, and 5.5% of methylene chloride was added. mt, 0.5N sodium hydroxide 5 was added and the mixture was stirred for 0 minutes, then the methylene chloride layer was washed with water sJ, and the methylene chloride layer was dried under reduced pressure to recover the aluminum porphyrin complex.

The recovered complex and DL-α-methoxypropionic acid (racemic form) as the carboxylic acid were replaced with non-optically active monoα.
A sample was prepared in the same manner as in Example 1, except that methoxypropionic acid was used, and 'II-IJMR was measured.

Since the resonance absorption corresponding to L-α-methoxypropionic acid in the complex after addition is exactly the same as in Example 2, the optical purity of L-α-methoxypropionic acid is 100.
It was calculated as %.

[Brief explanation of drawings]

FIG. 1 shows an NMR chart of OL-methoxypropionic acid used in Example 1. FIG. 2 is an NMR chart of the OL-α-methoxypropionic acid to which an aluminum porphyrin complex is added, and the figures indicated by arrows at the bottom of the figure are enlarged views of each part. (a) attached to the NMR spectra in Figures 1 and 2
(b) The symbols in (c) have the following meanings. (a): Resonance absorption of protons attached to the (a) carbon of DL-α-methoxypropionic acid. (b): Resonant absorption of protons attached to (b) carbon of the same substance. (C): Resonant absorption of protons attached to (c) carbon of the same substance.

Claims (1)

[Scope of Claims] A chiral shift reagent comprising a metal complex of an optically active substance obtained by optically resolving a strap porphyrin in which the strap X does not invert the porphyrin plane in the following general formula (1). ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・(1)