JP2003260366A - New chiral copper catalyst and method for manufacturing n-acylated amino acid derivative by using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a catalyst system which makes easy, efficient and stereoselective Mannich reaction possible from an N-acylimino ester having an aromatic cyclic substituent at the molecular end as the starting substance. <P>SOLUTION: A new chiral copper catalyst obtained by mixing a compound expressed by CuClO<SB>4</SB>4CH<SB>3</SB>CN with (S)-xylyl-Bis[bis(R<SP>1</SP>)phosphino]-1,1'-binaphthyl expressed by formula (II) is used. In formula (II), R<SP>1</SP>represents an aromatic group which may have a substituent. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a new copper catalyst and a method for producing an N-acylated amino acid derivative using the same. More specifically, the invention of this application relates to a novel chiral copper complex and an asymmetric Ma which produces an N-acylated amino acid derivative with high enantioselectivity.
It is related to the nnich type reaction.

[0002]

2. Description of the Related Art In the natural world, many important N-
There are acetyl amino acid derivatives. For example, the cyanobacteria Scytonema sp. (Strain U-3-3), which has calcium antagonistic properties
Scytonemin A (Helms, GL; Mo
ore, RE, Niemczura, WP, Patterson, GML, Tom
er, KB, Gross, MLJOrg.Chem. 1998, 53, 129
8), Theonellamide F (Matusnaga, S., Fusetani, N., which is an antimicrobial peptide derived from the spongiosa of the genus Theonella.
Hashimoto, K., Walchli, MJAm.Chem.Soc. 1989, 11
1, 2582), sphingolipid (Dickson, RC Annu. Re
v. Biochem. 1998, 67, 27) and many others have been isolated and reported (Humphrey, .M., Chamberlin,
AR Chem. Rev. 1997, 97, 2243; von Dohren, H., Ke
ller, U., Vater, J., Zocher, R. Chem. Rev. 1997, 9
7, 2675; Koltr, T., Sandhoff, K. Angew. Chem., Int.
Ed. 1999, 38, 1532).

High physiological activity is expected for these natural substances and their analogs. Therefore, if such compounds can be synthesized with high stereoselectivity, it will be possible to obtain important knowledge for elucidation of the action mechanism of natural substances and development of new drugs.

As a method for producing a natural compound or a similar compound by chemical synthesis, a stereoselective Mannich-type reaction between an α-imino ester and an enolate (Kobayashi, S.,
Ishitani, H. Chem. Rev. 1999, 99, 1069) is effective. The inventors have recently developed and reported a zirconium-catalyzed stereoselective Mannich-type reaction method (Ish
itani, H., Ueno, M., Kobayashi, SJAm.Chem.SOc.
1997, 119, 7153; Kobayashi, S., Ishitani, H., Uen
o, MJAm.Chem.Soc. 1998, 120, 431; Ishitani, H.,
Ueno, M., Kobayashi, SJAm.Chem.Soc. 2000, 122,
8180; Kobayashi, S., Ishitani, H., Yamashita, Y.,
Ueno, M., Shimizu, H. Tetrahedron 2001, 57, 86
1). In addition, many reports have been made on the asymmetric Mannich reaction of α-iminoesters (for example, Hagiwa
ra, E., Fujii, A., Sodeoka, MJAm.Chem.Soc. 199
8, 120, 2474; Ferraris, D., Young, B., Dudding,
T., Lectka, TJOrg.Chem. 1999, 64, 2168 et al.).

However, in these known reaction methods, it is necessary to remove the N-protecting group from the product and further acylate, which requires a complicated operation.

Therefore, as a more efficient reaction method, N
-Reacting an acyl imino ester with an enolate to give N-
A method for directly obtaining an acylated amino acid derivative was investigated.
However, many of the N-acyliminoesters used as starting materials are unstable and their application range to organic synthesis is limited. Furthermore, the inventors have reported a novel chiral copper complex obtained from copper trifluoromethanesulfonate and a ligand. Even in such a novel chiral copper complex, an aromatic group such as a phenyl group is added to the terminal. Have N-
When an acylimino ester is used as a starting material, an asymmetric
The fact is that stereoselective N-acylated amino acid derivative synthesis by the Mannich type reaction has not been realized.

Therefore, the invention of this application solves the above problems and is a simple and efficient stereoselective Mannich starting from an N-acyl imino ester having an aromatic cyclic substituent at the terminal. It is an object to provide a catalyst system that enables a mold reaction.

[0008]

Means for Solving the Problems The invention of this application is intended to solve the above-mentioned problems. First, the invention is represented by the following formula (I): CuClO ₄ .4CH ₃ CN (I) And a compound of the following formula (II)

[0009]

[Chemical 8]

(Wherein R ¹ is an aromatic group which may have a substituent) (S) -xylyl-Bis [bis
Provided is a novel chiral copper catalyst which is obtained by mixing (R ¹ ) phosphino] -1,1′-binaphthyl.

Secondly, the invention of this application is based on R ¹
There is provided the above novel chiral copper catalyst, wherein is a 3,5-dimethylphenyl group.

A third aspect of the present invention is a method for enantioselectively producing an N-acylated amino acid derivative, which comprises the following formula (III):

[0013]

[Chemical 9]

(Wherein R ² is an aromatic group which may have a substituent and R ³ is a hydrocarbon group which may have a substituent). , The following formula (IV)

[0015]

[Chemical 10]

(Wherein R ⁴ is an aromatic hydrocarbon group which may have a substituent, R ⁵ is a trialkylsilyl group, R ⁶
Is a hydrogen atom or a hydrocarbon group which may have a substituent) and a silyl enol ether represented by the following formula (I) CuClO ₄ .4CH ₃ CN (I) Formula (II)

[0017]

[Chemical 11]

(Wherein R ¹ is an aromatic group which may have a substituent), and is represented by (S) -xylyl-Bis [bis
N- characterized by reacting in the presence of a chiral copper catalyst obtained by mixing (R ¹ ) phosphino] -1,1′-binaphthyl
A method for producing an acylated amino acid derivative is provided.

A fourth aspect of the present invention is a method for enantioselectively producing an N-acylated amino acid derivative, which comprises the following formula (III):

[0020]

[Chemical 12]

(Wherein R ² is an aromatic group which may have a substituent and R ³ is a hydrocarbon group which may have a substituent). , The following formula (IV)

[0022]

[Chemical 13]

(However, R ⁴ is an aromatic hydrocarbon group which may have a substituent, R ⁵ is an alkyl group, and R ⁶ is a hydrogen atom or a hydrocarbon group which may have a substituent. ) Is an alkyl vinyl enol ether represented by the following formula (I) CuClO ₄ .4CH ₃ CN (I) and the following formula (II)

[0024]

[Chemical 14]

(Wherein R ¹ is an aromatic group which may have a substituent) (S) -xylyl-Bis [bis
(R ¹ ) phosphino] -1,1′-binaphthyl is reacted in the presence of a chiral copper catalyst obtained by mixing, and then treated with an acid to provide a method for producing an N-acylated amino acid derivative. To do.

Fifthly, the invention of this application also provides a method for producing a N-acylated amino acid derivative as described above, wherein R ¹ is a 3,5-dimethylphenyl group in a chiral copper catalyst. .

[0027]

BEST MODE FOR CARRYING OUT THE INVENTION In the invention of this application, the following formula (II
I)

[0028]

[Chemical 15]

(Wherein R ² is an aromatic group which may have a substituent and R ³ is a hydrocarbon group which may have a substituent). , The following formula (IV)

[0030]

[Chemical 16]

(Wherein R ⁴ is an aromatic hydrocarbon group which may have a substituent, R ⁵ is a trialkylsilyl group, R ⁶
Is a hydrogen atom or a hydrocarbon group which may have a substituent) and is reacted with a silyl enol ether in the presence of a novel chiral copper catalyst to produce an N-acylated amino acid enantioselectively. The derivative is prepared.

When an alkyl vinyl ether in which R ⁵ in the above (IV) is an alkyl group is used instead of the silyl enol ether, the reaction is carried out in the presence of the N-acyl imino ester and the above chiral copper catalyst. After that, if treated with an acid, an N-acylated amino acid derivative is produced with high enantioselectivity.

This novel chiral copper catalyst comprises a compound represented by the following formula (I) CuClO ₄ .4CH ₃ CN (I) and the following formula (II)

[0034]

[Chemical 17]

[S] -xylyl-Bis [bis (R ¹ ) phosphi represented by
no] -1,1'-binaphthyl ((S) -R ¹ -BINAP), for example, is obtained by mixing in a solution, and the isolated one may be used as a catalyst or a reaction solution. The complex may be formed in situ.

In the novel chiral copper catalyst of the invention of the present application, if the compound represented by the formula (I), CuClO ₄ .4CH ₃ CN (I), is commercially available as a reagent, such compound is used. May be used, for example, Kubas, GJ Inorgan
ic Synthesis; Shriver, DF, Ed .; Plenum: New Yor
k, 1979; Vol. XIX, p90 and the like may be used as the one synthesized by the known method. As (S) -R ¹ -BINAP, commercially available products may be used, or those synthesized by various known or novel methods may be used.

In the novel chiral copper complex of the invention of this application,
As R ¹ , those having a xylyl group, particularly an m-xylyl group are preferable. That is, the compound of the above (I) and the following formula

[0038]

[Chemical 18]

(S) -xylyl-Bis [bis (3,5-dimeth
ylphenyl) phosphino] -1,1'-binaphthyl ((S) -xylyl-BIN
A new chiral copper complex obtained by mixing
In the N-acylated amino acid derivative obtained by the nnich reaction, high yield and stereoselectivity can be obtained. This is clear from the examples described below.

As (S) -xylyl-BINAP, those commercially available from Takasago Chemical Co., Ltd. may be used, or Mash
ima, K., Kusano, K., Sato, N., Matsumura, Y., Noza
ki, K., Kumobayashi, H., Sayo, N., Hori, Y., Ishiza
ki, T., Akutagawa, S., Takaya, HJOrg. Chem. 199
You may use what was synthesize | combined by the well-known method as described in 4, 59, 3064.

A solvent capable of dissolving both (I) and (II) (for example, chloroform, dichloromethane,
The novel chiral copper catalyst of the invention of this application can be obtained by dissolving it in toluene etc.) and mixing.

In the method for producing an N-acylated amino acid derivative of the invention of this application, the following formula (III)

[0043]

[Chemical 19]

R ² in the N-acylimino ester of
An aromatic group which may have a substituent and R ³ is a hydrocarbon group which may have a substituent. Examples of R ² include phenyl, 1-naphthyl, 2-naphthyl, 3,5-dimethylphenyl, 4-chlorophenyl and the like. on the other hand,
R ³ may be any as long as it does not inhibit the asymmetric Mannich reaction, and is an alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and among others, methyl or ethyl. It is preferable to use a short-chain alkyl group such as Since these substituents are reflected in the N-acylated amino acid derivative which is the product of the asymmetric Mannich type reaction, they may be appropriately selected according to the desired N-acylated amino acid derivative. Of these, a short-chain alkyl group such as methyl or ethyl that does not hinder the reaction can be used.

In the method for producing an N-acylated amino acid derivative of the invention of this application, the N-acyl imino ester is represented by the following formula (IV):

[0046]

[Chemical 20]

Is reacted with a compound of At this time, (IV)
Where R^FourIs an aromatic carbon which may have a substituent
A hydrogen group, specifically, phenyl, 1-naphthyl,
2-naphthyl, 4-methylphenyl, 3,5-dimethyl
Examples include phenyl and 4-chlorophenyl. Also,
R⁷May be a hydrogen atom, methyl, ethyl, n
-Propyl, i-propyl, n-butyl, i-butyl,
Alkyl group such as t-butyl, cyclohexyl group, phenyl group
Hydrocarbon groups such as chloro groups, halogens, S, N, O
Etc. are selected from a hetero atom or a group to which a substituent is bonded.
On the other hand, R^FiveFor the trimethylsilyl group, triethly
It can also be a trialkylsilyl group such as a rusilyl group.
Rushi, methyl, ethyl, n-propyl, i-propyl,
With an alkyl group such as n-butyl, i-butyl, t-butyl, etc.
You may. R^FiveIs a trialkylsilyl ether
The (IV) becomes a silyl enol ether,
In the case of a vinyl group, (IV) should be an alkyl vinyl ether.
It In (IV), especially R ^FourLive after the asymmetric Mannich reaction
Is it left in the N-acylated amino acid derivative of the product?
Depending on the desired N-acylated amino acid derivative.
^FourMay be selected appropriately.

In the method for producing an N-acylated amino acid derivative of the invention of this application, the reaction products, N-acyl imino ester and silyl enol ether (or alkyl vinyl ether), are commercially available as reagents or known organic compounds. Those which are synthesized and isolated by the synthetic method may be used, and those for which the compound is difficult to isolate or unstable may be synthesized in situ during the Mannich reaction.

Furthermore, in the method for producing an N-acylated amino acid derivative of the invention of this application, the Mannich type reaction is
The reaction condition is not particularly limited as long as it is carried out in the presence of the novel chiral copper catalyst. For example,
The reaction is preferably carried out in various organic solvents.
The solvent is not particularly limited as long as it can dissolve the N-acylimino ester as a starting material, the silyl enol ether (or alkyl vinyl ether), and the catalyst, as long as it does not solidify or decompose at the reaction temperature. For example, a halogen-containing solvent such as chloroform or dichloromethane is exemplified. The reaction temperature may be in a temperature range in which each reactant is stable and the catalyst acts particularly efficiently, and preferably a low temperature of room temperature or lower,
More preferably, the temperature is set to about -100 ° C to room temperature. Furthermore, for specific reaction operations, operations such as stirring, separation, and purification that are carried out in general chemical reactions can be applied.

Hereinafter, the invention of this application will be described in more detail with reference to Examples. Needless to say, the invention of this application is not limited to the following examples.

[0051]

EXAMPLES In the following examples, melting points are shown without correction.

¹ H and ¹³ C NMR spectra are also based on JEOL JNM-LA300, J in CDCl ₃ unless otherwise stated.
It was measured with a NM-LA400 or JNM-LA500 spectrometer. ^{At 1} H, tetramethylsilane (TMS) was used as an internal standard (δ = 0). Also, at ¹³ C, CDC
l ₃ was used as an internal standard (δ = 77.0).

The IR spectrum was measured using a JASCO FT / IR-610 spectrometer.

Circular optical rotation was measured with a JASCO P-1010 polarimeter.

High Performance Liquid Chromatography is SHIMADZU
LC-10AT (liquid chromatograph), SHIMADZU SPD-10A
(UV detector) and SHIMADZU C-R6A Chromatopack.

Gas chromatography and mass spectrum were measured using SHIMADZU GC-17A and SHIMADZU GCMS-QP5050A.

Column chromatography is performed by Silica gel.
60 (Merck), and thin-layer chromatography with Wak
It was performed using ogel B-5F (Wako Pure Chemical Industries).

All reactions were carried out using a glass instrument dried under argon.

N-acyliminoester 2 is a polymer-immobilized amine (Kobayashi, S., Kitagawa, H., Matsubara,
RJComb.Chem. 2001, 3, 401).
Bromoglycine derivative (Ueno, M. Kitagawa, H. Ishitan
i, H., Yasuda, S., Nishijima, K., Hanada, K., Koba
yashi, S. Tetrahedron Lett. 2001, 42, 7863). <Example 1> Asymmetric Mannich using a novel chiral copper catalyst
Type Reaction According to the following formula (A), an N-acylated amino acid derivative was produced by an asymmetric Mannich type reaction using a novel chiral copper catalyst.

[0060]

[Chemical 21]

CuClO ₄ .4CH ₃ CN (3.2 mg, 0.010 mmol) was dried under vacuum at room temperature for 1 hour. To this, (S) -xylyl-BINA
A solution of P (8.1 mg, 0.011 mmol) (Takasago Chemical Co., Ltd.) in dichloromethane (1.0 mL) was added under argon, and the obtained pale yellow solution was stirred for 0.5 hours.

After cooling the solution to -78 ° C, N-benzoyl-α-iminoester (Compound 2) (0.1 mmol)
Was added in dichloromethane (1.0 mL).

Next, a solution of silyl enol ether or vinyl enol ether (0.15 mmol) in dichloromethane (1.0 mL) was added over 10 minutes, and the mixture was added at -78 ° C for 18 minutes.
The reaction was carried out with stirring for an hour.

THF-water was added to the reaction solution to stop the reaction, and the mixture was stirred for 2 minutes and then warmed to room temperature. Saturated NH ₄ C
The aqueous solution was added to the solution, extracted with dichloromethane, the organic layer was washed with brine, then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.

In the system using silyl enol ether,
Dichloromethane (3.0 mL) and 0.2 N HCl solution in dichloromethane (1.0 mL) were added to the residue and the reaction was stirred at room temperature for 10 min.
After stirring for a minute, the solvent was removed and dried.

The mixture was stirred at room temperature for 1 hour, then water (5 mL)
And the reaction was stopped with AcOEt (5 ml). AcOEt the mixture
After extraction with, the organic layer was washed with brine and dried over anhydrous magnesium sulfate.

For systems using alkyl vinyl ether, instead of adding dichloromethane (3.0 mL) and 0.2N HCl in dichloromethane (1.0 mL) to the residue, THF was added.
(5.0 ml) and 1N HCl aqueous solution (0.25 mL) were added to the residue, the reaction solution was stirred at room temperature for 10 minutes, then the solvent was removed and dried to obtain a product.

After removing the solvent, the crude product was purified by silica gel chromatography to obtain compounds 5a-5c.

The reaction conditions, yields, and optical purities of 5a to 5c are shown in Table 1.

[0070]

[Table 1]

The results of identification of 5a-5c are shown in Tables 2-4.

[0072]

[Table 2]

[0073]

[Table 3]

[0074]

[Table 4]

From Table 2, by using the novel chiral copper catalyst of the invention of this application, even when an N-acylated imino ester having an aromatic substituent at the terminal is used as a starting material, high enantioselectivity and yield are obtained. It was shown that the N-acylated amino acid derivative was obtained at a rate.

[0076]

As described in detail above, according to the invention of this application, a novel chiral copper catalyst and N-containing the same are described.
A method for producing an acylated amino acid derivative is provided. INDUSTRIAL APPLICABILITY The method of the present invention makes it possible to produce an N-acylated amino acid derivative in high yield and enantioselectively with a small number of steps.
Alternatively, it is highly useful in the synthesis of its intermediate.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07B 61/00 300 C07B 61/00 300 C07M 7:00 C07M 7:00 F term (reference) 4G069 AA06 BA27A BA27B BC31A BC31B BE27A BE27B BE37A BE37B BE46A BE46B CB25 CB57 CB59 CB77 4H006 AA02 AC48 AC53 AC60 AC81 BA05 BA46 BA53 BJ50 BR30 BT12 BV72 TN40 TN60 4H039 CA62 CA66 CA71 CF40 CG90

Claims (5)

[Claims] 1. A compound represented by the following formula (I), CuClO ₄ .4CH ₃ CN (I), and a compound represented by the following formula (II): (However, R ¹ is an aromatic group which may have a substituent) (S) -xylyl-Bis [bis (R ¹ ) phosphino]-
A novel chiral copper catalyst, which is obtained by mixing 1,1'-binaphthyl. 2. The novel chiral copper catalyst according to claim 1, wherein R ¹ is a 3,5-dimethylphenyl group. 3. A method for enantioselectively producing an N-acylated amino acid derivative, which comprises the following formula (III): (However, R ² is an aromatic group which may have a substituent,
R ³ is an optionally substituted hydrocarbon group) and an N-acyl imino ester represented by the following formula (IV): (However, R ⁴ is an aromatic hydrocarbon group which may have a substituent, R ⁵ is a trialkylsilyl group, and R ⁶ is a hydrogen atom or a hydrocarbon group which may have a substituent) A silyl enol ether represented by the following formula (I) CuClO ₄ .4CH ₃ CN (I) and a compound represented by the following formula (II) (However, R ¹ is an aromatic group which may have a substituent) (S) -xylyl-Bis [bis (R ¹ ) phosphino]-
A method for producing an N-acylated amino acid derivative, which comprises reacting in the presence of a chiral copper catalyst obtained by mixing 1,1'-binaphthyl. 4. A method for enantioselectively producing an N-acylated amino acid derivative, which comprises the following formula (III): (However, R ² is an aromatic group which may have a substituent,
R ³ is a hydrocarbon group which may have a substituent) and an N-acyl imino ester represented by the following formula (IV): (However, R ⁴ is an aromatic hydrocarbon group which may have a substituent, R ⁵ is an alkyl group, and R ⁶ is a hydrogen atom or a hydrocarbon group which may have a substituent) And a compound represented by the following formula (I) CuClO ₄ .4CH ₃ CN (I), and an alkyl vinyl enol ether represented by the following formula (II) (However, R ¹ is an aromatic group which may have a substituent) (S) -xylyl-Bis [bis (R ¹ ) phosphino]-
N- characterized by reacting in the presence of a chiral copper catalyst obtained by mixing 1,1'-binaphthyl and then acid-treating
A method for producing an acylated amino acid derivative. 5. In the chiral copper catalyst, R ¹ is 3,5
-A dimethylphenyl group, The method for producing an N-acylated amino acid derivative according to claim 3.