JP2001039995A - Method for producing metal complex and amino acid-modified metal complex - Google Patents

Abstract

(57) [Problem] To surely produce metal complexes each having a different bipyridine-based ligand under mild conditions. SOLUTION: The following formula [M (D) A ₂ ] ₂ (M represents a transition metal atom, D represents a gen or aromatic ring compound ligand, and A represents a monovalent anion group. ) Is reacted with a bipyridine-based compound (L ₁ ) to give the following formula [M (L ₁ ) A (D)] (A) (where M, D and A are as defined above, ₁ represents a bidentate ligand of a bipyridine-based compound), and then a bipyridine-based compound (L ₂ )
And the following formula M (L ₁ ) (L ₂ ) A ₂ (M, L ₁ , and A are as described above, and L ₂ is L
₁ shows a bidentate ligand of a bipyridine compound different from ₁ . ) Is produced.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a metal complex and a metal complex modified with an amino acid. More specifically, the invention of this application relates to a metal complex having a plurality of bipyridine-based compound bidentate ligands, which is useful as an optically functional substance, and a method for producing these optically active substances, and a functional substance by molecular design. The present invention relates to these metal complexes modified with amino acids, which are attracting attention as the creation of the metal complex.

[0002]

2. Description of the Related Art A technique for connecting a peptide to a bipyridine ligand and coordinating the peptide with a transition metal complex to associate the peptide and construct a secondary structure similar to a protein is a de novo design of protein function. Has been used as one of the methods. However, in these studies, multiple bipyridine ligands are modified with the same peptide chain, and the molecular design of highly functional molecules similar to proteins requires the development of a method to connect different peptide chains. I was
As a synthesis of a tris-type complex in which a plurality of, for example, three different ligands are coordinated, [Ru (CO) ₂ Cl ₂ ] n
Is used as a starting material to obtain a bis complex having different ligands [R
a method of synthesizing u (L ₁ ) (L ₂ ) (CO) ₂ ] ²⁺ and converting it into a tris form, and synthesizing a tris form having the same ligand, and desorbing the photoligand The method of exchanging ligands one by one by the reaction is known as a typical one, but none of them is suitable for peptide or amino acid-modified ligand.

[0003] A more specific example will be described.
For the synthesis of reported triple-ligand ruthenium complexes
As mentioned above, there are two main methods.
You. The first method was reported by Keene et al.
In the following method, [Ru (CO)_TwoCl_TwoDeparture n
As a substance, one by one bidentate pyridine-based ligand
One has been introduced. The introduction of the first ligand in methanol
Relatively mild conditions because it is performed by refluxing
It is. However, as the precursor of the bis-form, [Ru (L
₁) (CO)_Two(CF_ThreeSO_Three)_Two] To obtain C
F_ThreeSO_ThreeH or Ag (CF_ThreeSO_ThreeH) reacted
When using a peptide-modified ligand for the ligand,
The side chain protecting group may be eliminated. Second configuration
The introduction of the child was carried out in ethanol [Ru (L₁) (CO)_Two(CF
_ThreeSO_Three)_Two] And the second ligand (L _TwoReflux)
Is a bis form [Ru (L₁) (L_Two) (CO)_Two]²⁺Get
Can be performed under relatively mild conditions.
Is stable, so the third ligand L_ThreeWhen introducing
It is necessary to perform reflux at 125 ℃ in toxic ethanol
is there. This condition is severe for using peptide-modified ligands.
It is.

[0004]

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A second method is the following method reported by Ross et al. In this way, once after the ruthenium tris (bipyridine) type complex, an excess of Cl ^- presence of, after isolation of ligands allowed desorbed by performing light irradiation, sequentially introducing another ligand are doing. In this method, the ligand is desorbed and then reintroduced in ethylene glycol.
In order to reflux, it must be heated to 200 ° C, and the ligand used in the synthesis must be quite stable. Therefore, it cannot be applied to peptide-modified ligands. Furthermore, this is a synthesis method that is not possible unless there is a certain difference in the coordination ability of each ligand, and all peptide-modified ligands used in this study have a carboxyl group at the 4,4'-position of bipyridine. Since it has been introduced, it is not expected that there will be such a large difference in coordination ability. From this point too, Ross's method is not suitable.

[0006]

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Accordingly, the invention of this application overcomes the above-mentioned drawbacks of the prior art, and provides a plurality of different bipyridine-based ligands capable of introducing a peptide-modified ligand under mild conditions. Another object of the present invention is to provide a method for producing a metal complex having the following. In this case, it is also an object to consider the following points.

[0008] i) Conditions that can withstand a ligand modified with a peptide chain ii) Isolation of each intermediate can be performed iii) Use of a reagent which does not affect the side chain protecting group of the peptide iv ) No need to consider coordination ability

[0009]

Means for Solving the Problems According to the invention of the present application, as a solution to the above problems, first, the following formula (I) [M (D) A ₂ ] ₂ (M is a transition metal atom) Wherein D represents a gen-based or aromatic ring-based compound ligand, and A represents a monovalent anion group), and a bipyridine-based compound (L ₁ ) is reacted with the complex represented by the following formula ( II) Complex compound of [M (L ₁ ) A (D)] (A) (where M, D and A are as described above, and L ₁ is a bidentate ligand of a bipyridine-based compound) And then a bipyridine compound (L ₂ )
And the following formula (III): M (L ₁ ) (L ₂ ) A ₂ (M, L ₁ and A are as described above, and L ₂ is L
₁ shows a bidentate ligand of a bipyridine compound different from ₁ . The present invention provides a method for producing a metal complex, which comprises producing the metal complex represented by the formula (1).

Also, the invention of this application is based on the following formula (III): M (L ₁ ) (L ₂ ) A ₂ (M is a transition metal atom, A is a monovalent anion group) And L ₁ and L ₂ each represent a different bidentate ligand of a bipyridine-based compound.) With a bipyridine-based compound (L ₃ ) to react with a metal complex represented by the following formula ( IV) [M (L ₁ ) (L ₂ ) (L ₃ )] ²⁺ (M, L ₁ , and L ₂ are as described above, and L ₃ is
It shows a bidentate ligand of a bipyridine compound different from L ₁ and L ₂ . The present invention provides a method for producing a metal complex, which comprises producing a complex of a cation represented by the formula:

The invention of this application is, thirdly, the first invention in which at least one of the bidentate ligands L ₁ and L ₂ of the bipyridine compound has an amino acid group or a peptide group. Fourth, at least one of the bidentate ligands L ₁ , L ₂ and L ₃ of the bipyridine compound has an amino acid group or a peptide group. A method for producing the metal complex according to the second invention is provided. Fifth, a method for producing any one of the metal complexes described above, wherein the monovalent anion group A is a halogen anion, The present invention also provides a method for producing any one of the above-mentioned metal complexes in which the metal atom M is a noble metal atom belonging to Group 8 of the periodic table.

Furthermore, the invention of this application, the seventh, the following formula (V) _{[M (L A) (L B} ) (L C) ] ²⁺ (M represents a transition metal atom, L _A, L _B and L _C are each a bidentate ligand of a different bipyridine compound,
At least one of them is an amino acid-modified metal complex having an amino acid group or a peptide group. Eighth, the transition metal atom M
A metal complex as defined above, which is a group noble metal atom.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The invention of this application has the features as described above, and the embodiments will be described below.

First, the manufacturing method of the invention of this application will be described.
Is based on the following ideas for conventional technologies.
You. That is, in the conventional technology, for example,
For the synthesis of tris (bipyridine) -type complexes
An important and easy-to-handle bis (bipyridine) intermediate is R
u (L₁) (L_Two) Cl_TwoIs considered to be
Is [Ru (L₁) (L_Two) (CO)_Two]
²⁺Only the synthesis and isolation of Ru (L₁)
(L_Two) Cl_TwoThere are no reports on the synthesis and isolation of
is there. [Ru (L ₁) (L_Two) (CO)_Two]²⁺Is a stable complex
In order to make it into a tris form, as reported by Keene et al.
Severe conditions (reflux at 125 ° C) are required.
(L₁) (L _Two) Cl_TwoIf you can get mild conditions
It is already known that can be converted to Tris form by that's all
Therefore, the bis complex with these two different ligands
Body (Ru (L₁) (L_Two) Cl_Two) Is obtained under relatively mild conditions
The invention including a method capable of doing so has been completed.

Ru (L₁) (L_Two) Cl_TwoScrew type complex like
In order to produce the body, the invention of this application
Formula (I) wherein the compound is a ligand: [M (D) A_Two]_Two Starting from the complex compound of
Bipyridine compound (L ₁) (L_Two). the first
In the formula (II): [M (L₁) A (D)] (A) was synthesized, and then the compound of formula (III): M (L₁) (L_Two) A_Two Is synthesized.

In this method, the transition metal atom M may be any of various polyvalent transition metals, for example, metals of Group 8 of the periodic table, among which Ru, Pd, Rh, P
Noble metals such as t are indicated as desirable. The most typical one is Ru (ruthenium).

The monovalent anionic group may be of various types,
Typical and desirable are halogen atoms.
Among them, a chlorine atom anion is exemplified. And L₁You
And L_TwoIs also the aforementioned L_ThreeAre different bipyridi
This indicates a compound or its bidentate ligand.
Here, the definition of “bipyridine type” means that the bipyridine skeleton
And two nitrogen (N) atoms constituting the skeleton are
Various compounds that are bidentately coordinated with the transition metal M
Means For example, a 2,2'-bipyridine skeleton
With a carbocyclic ring fused to this skeleton
1,10-phenanthroline and the like can be used in the present invention.
Lysine ". In other words, the bipyridine skeleton has various
May be substituted. L ₁and
L_Two, And even L_ThreeAre different from each other,
Means that the overall molecular structure is different
I have.

In the synthesis reaction, the compounds represented by the formulas (I) to (I)
The role of the complex of the formula I) and the complex of the formula (III) from the formula (II) may be a gen-based or aromatic ring compound ligand:
The presence of D is important. The gen-based compound may be cyclic or chain-like, and suitable examples thereof include alicyclic gen compounds such as cyclohexadiene, cyclopentadiene and cyclooctadiene. Examples of the aromatic ring compound include compounds such as benzene, toluene, xylene, and naphthalene. Of course, it is not limited to this. Introduction of ligands L ₁ and L ₂ is generally carried out by using alcohol, THF, DMF, DMS.
Using an organic solvent such as O and nitrile, the temperature in the range from room temperature to 90 ° C. proceeds under mild conditions. The amount of the ligand compound to be used for L ₁ and L ₂ is based on an equivalent, and may be smaller or larger.

In the present invention, the complex of the formula (III): M (L ₁ ) (L ₂ ) A ₂ is further reacted with another kind of bipyridine compound under the same conditions as described above to obtain the above-mentioned compound. can be derived formula (V) _{[M (L a) (L B} ) (L C) ] complex compound of the ²⁺ cations.

The cation of the invention of this application has three different types of cations.
Ligand (L₁) (L_Two) (L_Three), But composite
Alternatively, various anions used in the purification process
Will be obtained as a combined state of In this case,
Nions are, for example, PF₆ ^-, Cl^-, I^-, ClO
_Four ^-, Br^-And the like.

The bipyridine-based compounds or their bidentate ligands as L _1, L ₂ and L ₃ will be further described. Various substituents may be bonded to the bipyridine skeleton of these compounds. Examples include various groups such as hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, and aryl, alkoxy groups, ester groups, cyano groups, carboxyl groups, amide groups, carbamate groups, amino groups, and peptide groups.

In particular, in the present invention, as a bipyridine compound bidentate ligand, a complex of the formula (III) wherein one of L ₁ and L ₂ has an amino acid group or a peptide group; L _1, one at least of the L ₂ and L ₃ are include complexes of the formula (IV) having the amino acid group or a peptide group. This latter is a metal complex which also corresponds to formula (V). L _1, L ₂ and L
₃ corresponds to L _A, L _B, and L _C.

In these complexes, the definition of “having an amino acid group or a peptide group” means that the bipyridine skeleton has an amino group constituting an amino acid or a peptide,
It means that the hydroxyl group, carboxyl group, amide group, or even a case where a carbon atom or the like is directly bonded, or a case where it is bonded through a bond with another atom or a substituent may be used. are doing.

The amino acid group, the peptide group and the amino group, the hydroxy group, the carboxyl group and the like constituting the amino acid group and the peptide group may be protected by a protecting group in a general sense. For example, the metal complex of the present invention as described above can be subjected to optical resolution (ΔΛ) by means such as HPLC.

[0025] And the metal complex of the invention of this application
Including the photo-functional substance, and the ligand L₁, L_Two, L_Three(Also
Is L_A, L_B, L_C) For different things, etc.
Therefore, the core of dendrimers that have been attracting attention recently
Nucleus).

The present invention will now be described in more detail with reference to examples.

[0027]

EXAMPLES Example 1 <a> [Ru (C ₆ H ₆ ) Cl ₂ ] ₂ RuCl ₃ .nH ₂ Ol. 70 g (8.20 mmol)
l) 1,3-cyclohexadiene 6 ml (63 mmo
l) and 100 ml ethanol / water (9: 1, v /
v) into a 200 ml eggplant flask,
Stirred for hours. After completion of the stirring, the solvent was filtered to remove impurities, and the filtrate was removed by evaporation. When this was recrystallized from methanol / ether, orange-yellow crystals were obtained. Yield 1.57 g Yield 76.6%

[0028]

[Table 1]

<B> [Ru (bpy) (C ₆ H ₆ ) C
l] Cl [Ru (C ₆ H ₆ ) Cl ₂ ] ₂ 0.20 g (0.40 m
mol), 0.16 g of 2,2'-bipylidyl (bpy) (1.
0 mmol) and 25 ml methanol were put into a 100 ml eggplant flask and stirred at room temperature for 1 hour. After completion of the stirring, the mixture was filtered to remove unreacted raw materials, and the filtrate was evaporated. This was recrystallized from methanol / ether.
The obtained compound is an orange-yellow needle-like crystal. Yield 250
mg yield 76.9%

[0030]

[Table 2]

<C> Ru (bpy) (dmbpy) Cl
0.15 g of ₂ [Ru (bpy) (C ₆ H ₆ ) Cl] Cl
(0.37 mmol), 4,4'-dimethyl-2,2 '
-Bipyridyl (dmbpy) 0.10g (0.55mmo
l), 0.05 g (1.11 mmol) of LiCl in 20
The mixture was stirred at 80-90 ° C for 24 hours in a nitrogen stream in ml of DMF. The solution changed from orange-yellow to dark purple. After completion of the stirring, the DMF was evaporated and concentrated to about 15 ml.
150 ml of acetone was added thereto, and the mixture was allowed to stand in a refrigerator overnight. The obtained crystals were filtered, sufficiently washed with acetone, and dried under vacuum. Yield 92 mg Yield 48.5%

[0032]

[Table 3]

Example 2 According to the following reaction scheme,
It can be expected that the ternary mixed ligand ruthenium complex can change the pKa of the carboxylic acid in the ligand by photoexcitation [Ru (Asp (OcHex) bpy) (Ser)
(Bzl) bpy) (dcbpy)] ²⁺ complex was synthesized.

[0034]

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<a> [Ru (Asp (OcHex) bp
y) Cl (C ₆ H ₆ )] Cl (mono complex) [RuCl ₂ (C ₆ H) synthesized according to <a> of Example 1.
₆ )] ₂ 0.108 g (0.22 mmol), Asp (OcHex) bpy 0.300 represented by the following formula:
g (0.43 mmol), 25 ml of Ethanol and chlo
Put 15 ml of roform into a 50 ml eggplant flask and add about 5
Stirred at room temperature for hours. After completion of the stirring, the solvent was evaporated to dryness, and column chromatography (Wakogel; C-
200, chloroform / methanol = 9/1). Yield 0.36 g Yield 88.6%

[0036]

[Table 4]

[0037]

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<B> [Ru (Asp (OcHex) bp
y) (Ser (Bzl) bpy) Cl _Two] (Bis complex) [Ru (Asp (OcHex) bpy) (C₆H₆) C
l_Two150 mg (0.16 mmol) by the following formula
Ser (Bzl) bpy 115.2 mg represented
(0.18 mmol) and 20.3 mg of LiCl
(0.48 mmol) into a 50 ml eggplant flask
Was dissolved in 30 ml of DMF. This is placed under a stream of nitrogen 2
Stirred at 80-90 ° C for 0 hours. Solution is orange-yellow to black-green
Change to color. After completion of the stirring, the solvent is evaporated to 10 ml.
After concentrating to the extent, dissolve in 50 ml of acetone,
The mixture was crystallized by adding ether. 213.6 g of crude yield
 Crude yield 88.4%

[0039]

[Table 5]

[0040]

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<C> [Ru (Asp (OcHex) bp
y) (Ser (Bzl) bpy) (dcbpy)] (P
F ₆ ) ₂ (Tris complex) [Ru (Asp (OcHex) bpy) (Ser (Bz
l) bpy) Cl _2] 199.35mg (0.13mm
ol), dcbpy 38.41 represented by the following formula:
mg (0.16 mmol), ethanol 20 ml 100
0.62 g (7.5 mmol)
l) H ₃ PO ₃ and 0.30 g (7.5 mmol) NaO
H was dissolved in 5 ml of water, and the mixture was added slowly. This is 80-90 days under nitrogen stream for 2 days
Reflux at ° C. At this time, the solution changed from dark purple to blood red. After completion of the stirring, the solvent was removed by evaporation, and a colorless and transparent oily substance was formed. However, the oily substance was insoluble in methanol and was separated by decantation. After evaporating methanol, purification by column chromatography was performed. However, the usual silica gel column chromatography, Se
Since there is a limit in the purification method using phadex, purification using a preparative column was performed. 20mg completely separated,
22 mg was obtained with a purity of about 80-90%. Crude yield 44 mg Crude yield 19.0%

[0042]

[Table 6]

[0043]

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FIG. 1 shows the synthesized [Ru (Asp (Oc
Hex) bpy) (Ser (Bzl) bpy) (dcb
py)] ²⁺ and its NMR spectrum. (Example 3) A synthesized ruthenium complex ([Ru (Asp
(OcHex) bpy) (Ser (Bzl) bpy)
(Dcbpy)] ²⁺ ) optically active form (ΔΛ) was obtained by high performance liquid chromatography (HPL) using a chiral column.
Optical division was successfully performed by C). FIG. 2 shows the CD spectrum of the obtained optically active substance. The ligand is L-
Since the amino acid was modified and the optically active form was a diastereomer, the CD spectrum was not expected to be a mirror image. In fact, a characteristic of a diastereomer was observed, which was almost a mirror image on the long wavelength side of 300 nm or more but did not become a mirror image in a short wavelength region of 300 nm or less.

[0045]

As described above in detail, according to the invention of this application, it is possible to reliably produce metal complexes having different bipyridine-based ligands under mild conditions.

More specifically, it is possible to design a compound in which an amino acid is connected to a bipyridine ligand for the purpose of adding a protein-like function to the photocatalytic ability of a ruthenium tris (bipyridine) complex, A novel synthesis method for synthesizing a ruthenium complex having three different bipyridine-type ligands to which amino acids are connected under mild conditions is provided. Further, optical resolution (Δ · Λ) of the synthesized ruthenium complex by HPLC becomes possible.

[Brief description of the drawings]

FIG. 1 shows NMR of a cation complex synthesized in Example 2.
It is a spectrum diagram.

FIG. 2 is a CD spectrum diagram of an optically active substance according to Example 3.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 213/81 C07D 213/81 H01L 31/04 H01L 31/04 Z F-term (Reference) 4C055 AA01 BA02 BA25 CA01 DA58 DB02 DB11 EA01 EA03 FA01 FA37 GA02 4H050 AB92 5F051 AA14 CB29 DA20

Claims (8)

[Claims] 1. The following formula (I) [M (D) A ₂ ] ₂ (M is a transition metal atom, D is a ligand of a gen or aromatic ring compound, and A is a monovalent anion. Is reacted with a bipyridine-based compound (L ₁ ) to give the following formula (II) [M (L ₁ ) A (D)] (A) (where M, D and A are In the above, L ₁ represents a bidentate ligand of a bipyridine-based compound), and a bipyridine-based compound (L ₂ ) is further reacted to obtain the following formula (III) M (L ₁ ) (L ₂ ) A ₂ (M, L ₁ and A are as described above, and L ₂ is
L ₁ illustrates a bidentate ligand different bipyridine-based compounds and. A method for producing a metal complex, which comprises producing the metal complex represented by the formula (1). 2. The following formula (III): M (L ₁ ) (L ₂ ) A ₂ (M represents a transition metal atom, A represents a monovalent anion group, and L ₁ and L ₂ are different from each other. Represents a bidentate ligand of a bipyridine-based compound.)
The bipyridine compound (L ₃ ) is reacted, and the following formula (IV) [M (L ₁ ) (L ₂ ) (L ₃ )] ²⁺ (M, L ₁ , and L ₂ are as defined above) , L
₃ represents a bidentate ligand of a bipyridine compound different from L ₁ and L ₂ . A method for producing a metal complex, which comprises producing a complex of a cation represented by the formula: 3. The method for producing a metal complex according to claim 1, wherein at least _{one of the} bidentate ligands L ₁ and L ₂ of the bipyridine compound has an amino acid group or a peptide group. 4. A bidentate ligand L _{1 of} a bipyridine compound,
L at least one of the ₂ and L _3, the manufacturing method of the metal complex according to claim 2 having an amino acid group or a peptide group. 5. The method for producing a metal complex according to claim 1, wherein the monovalent anion group A is a halogen anion. 6. The method according to claim 1, wherein the transition metal atom M is a noble metal atom belonging to Group 8 of the periodic table. 7. A following formula (V) _{[M (L A) (L B} ) (L C) ] ²⁺ (M is a transition metal _{atom, L A, L B, L} C , respectively, another A bidentate ligand of a different bipyridine compound,
At least one of them is an amino acid-modified metal complex having an amino acid group or a peptide group. 8. The metal complex according to claim 7, wherein the transition metal atom M is a noble metal atom belonging to Group 8 of the periodic table.