JP2001252569A - Polymer fixed chiral zirconium catalyst - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an asymmetric aza Diels-Alder reaction method by which high stereoselectivity and yield can be obtained under normal conditions as well as a catalyst series which enables performing this method. SOLUTION: The polymer-fixed chiral zirconium catalyst is characterized in that it is represented by formula (wherein, R1 is a polymer chain; R2 is a hydrogen atom, a halogen atom or an alkyl group having a substituent group or having no substituent group, or a polymer chain; R3 is an aryl group having a substituent group or having no substituent group; and R4 is an alkyl group, an aryl group or an alkoxy group which has a substituent group or has no substituent group, or a substituent group having nitrogen, sulfur or oxygen). The asymmetric aza Diels-Alder reaction method uses this catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a polymer-immobilized chiral zirconium catalyst. More specifically, the invention of this application relates to a method for asymmetric aza Diels-Alder reaction using a polymer-immobilized chiral zirconium catalyst.

[0002]

2. Description of the Related Art In nature, many substances such as proteins are optically active substances,
It is known to express a specific physiological activity according to its three-dimensional structure. Therefore, it is considered essential to establish a stereoselective synthesis method in the total synthesis of physiologically active substances, which are important issues in the fields of medicines, agricultural chemicals, fragrances and the like.

Hitherto, a Diels-Alder reaction has been known as a cycloaddition reaction between a diene and a dienophile.
This method has been used in pharmaceutical production and the like as an effective method for synthesizing chiral nitrogen-containing compounds such as piperidine derivatives. And recently, asymmetric Di using various catalysts
The els-Alder reaction is studied as a means of stereoselective reaction,
It has been reported.

However, in practice, for example, the catalyst system reported by Kagan et al. (Chem. Rev., 1992, 92, 100
As in 7), the reaction often proceeded only to some limited compounds.

The inventors have previously reported an aza Diels-Alder reaction using a chiral ytterbium (Yb) catalyst,
That is, an example of a reaction using an azadiene (for example, iminodiene) is reported (Tetrahedron Lett., 1996, 37,
7357). Further, a method of reacting an azadienofil (for example, iminodienofil) with a diene of Danishefsky using a chiral zirconium-binaphthol complex (Angew Chem. Int. Ed. Engl., 1998, 37, 979;
Org. Chem., 1999, 64, 4220). In all of these systems, the reaction proceeds in a stereoselective and stereospecific manner, and the product is obtained in high yield, but the application range is narrow, and it is not always sufficient. In addition, in any of the above methods, 10 to 20 mol%
It has been pointed out that a high concentration of catalyst is required. Therefore, further optimization of these catalyst systems was needed.

[0006] The invention of this application has been made in view of the above circumstances, and overcomes the limitations of the prior art.
It is an object of the present invention to provide a method of asymmetric aza Diels-Alder reaction capable of obtaining high stereoselectivity and a yield under ordinary conditions, and an optimized catalyst system that enables the method. .

[0007]

Means for Solving the Problems In order to solve the above-mentioned problems, the invention of this application firstly solves the following general formula (1):

[0008]

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(Wherein R ¹ represents a polymer chain, and R ² is
A hydrogen atom, a halogen atom, an alkyl group having or not having a substituent, or a polymer chain;
³ is an aryl group having or not having a substituent, R
⁴ represents a substituted or unsubstituted alkyl group, an aryl group, an alkoxyl group, or a substituted group having nitrogen, sulfur, and oxygen).

[0010] Secondly, the invention of this application provides a method of asymmetric aza-Diels-Alder reaction for reacting an imine with a diene in the presence of the above-mentioned chiral zirconium catalyst.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION As described above, the invention of this application relates to an asymmetric aza-Diels-catalyst in which an imine and a diene are subjected to a cycloaddition reaction in a stereoselective and stereospecific manner using a novel chiral zirconium catalyst. Regarding the Alder reaction, its implementation will be described below.

The chiral zirconium catalyst represented by the general formula (1) is obtained by binding, for example, (R) -1,1'-binaphthol (BINOL) to a polymer to form a polymer-immobilized BI.
After synthesizing the NOL, it is reacted with Zr (O ^t Bu) ₄ and the like may be polymer-supported zirconium catalyst. At this time, R ¹ in the general formula (1) is a polymer chain, R ² is a hydrogen atom, R ³ is an aryl group such as a phenyl group,
And R ⁴ is a t-Bu group. This is merely an example, and in each of the substituents R ^{1 to} R ⁴ , the structure and length of the polymer chain of R ¹ and the structure of R ^{2 to} R ⁴ are not limited thereto.

Preferred examples of each substituent of R ^{1 to} R ⁴ in the formula (1) are as follows.

R ¹ is a polymer chain such as PCH ₂ O (CH ₂ ) _n (wherein P is a polymer chain whose structure and chain length are not limited as long as it does not inhibit the Diels-Alder reaction) Is exemplified. A chiral zirconium catalyst immobilized on a polymer chain represented by PCH ₂ O (CH ₂ ) _n is known as Diels-Alde
r After the reaction, it can be recovered by simple filtration and can be easily reused, which is preferable.
Such a polymer chain can be introduced into BINOL by reacting a polymer chain having a halogenated terminal with BINOL having a reactive group at the R ¹ site, such as PCH ₂ Cl. Thereafter, by mixing with Zr (OtBu) or the like, BINOL coordinates to Zr, and the chiral zirconium catalyst of the invention of this application is obtained.

R ² represents a hydrogen atom, a halogen atom,
Or an alkyl group having or not having a substituent,
Alternatively, the same polymer chain as that of R ¹ can be applied, but most preferably a hydrogen atom.

R ³ represents an ortho position, a meta position,
An OH group, a halogen atom, methyl,
Ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, alkyl group such as hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or methoxy, alkoxyl group such as ethoxy, or sulfur atom, mercapto group, An aryl group such as phenyl, toluyl, and xylyl which may or may not have one or more substituents such as a sulfonyl group, an amino group, a cyano group, a nitro group, and a nitroso group is applied. For example, m-toluyl group, o-toluyl group, 3,5-xylyl group, 3-trifluoromethylphenyl group, 4-methoxyphenyl group and the like can be mentioned.

Further, as R ⁴ , methyl, ethyl,
Alkyl groups such as n-propyl, i-propyl, n-butyl, sec-butyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or methoxy, ethoxy, etc., or sulfur atom, mercapto group, sulfonyl group , An amino group, a cyano group, a nitro group, a substituent such as a nitroso group, or an alkyl group, an aryl group, or a heterocyclic ring which may or may not have a substituent exemplified by these. Is done. For example, t-B
Examples include a uO group and a cyano group.

According to the invention of this application, furthermore, by reacting an imine with a diene using the above-mentioned chiral zirconium catalyst, which is a novel substance, aza-diamine with high stereoselectivity is obtained.
An els-Alder reaction can be performed.

As the imine, compounds having various chain or cyclic structures are conceivable. In addition to N, for example, an imine having an O or S atom or a substituent containing these atoms can be applied. . Preferably, the following chemical formula (2):

[0020]

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In (2), R ⁵
Is an alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, an alkylene group such as ethylene, propylene, butylene, amylene, or phenyl, toluyl And aryl groups such as xylyl. Further, these substituents may further have a substituent, for example, a halogenated phenyl group, a benzyl group, an o-methylphenyl group, a p-methoxyphenyl group, α
-A naphthyl group, a 2-thiophene group and the like are considered. Further, R ⁵ may be a heterocyclic group having or not having a substituent.

As the diene, various chain and cyclic compounds can be considered, and the structure is not particularly limited, but is preferably the following chemical formula (3):

[0023]

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The Danishefsky diene represented by (J. Am. Che
m. Soc., 1974, 96, 7807) is preferably used. In this case, R ⁶ in the formula is selected from an alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or a hydrogen atom. .

When such an imine and a diene are reacted in the presence of the above-mentioned chiral zirconium catalyst, the aza Diel
An s-Alder reaction occurs and cycloaddition yields a piperidine derivative as shown in the following formula (4).

[0026]

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In such a Diels-Alder reaction, the reaction conditions are not particularly limited. For example, as a reaction solvent,
Water and various organic solvents are considered. Preferably, benzene is used. At this time, the polymer-immobilized chiral zirconium catalyst can be used as a dispersion. The reaction temperature is not particularly limited, but can be appropriately changed depending on the solvent and the starting material. Preferably, -50 to 10
At 0 ° C., more preferably around room temperature. The reaction time is
It can be changed depending on the catalyst concentration and temperature,
Preferably, the time is about 24 hours. The concentration of the catalyst to be added is not particularly limited. However, if the concentration is too low, the effect hardly appears, and the reaction becomes difficult to progress, and if the concentration is higher than a certain concentration, the effect does not increase any more. It is preferred to be mol%. More preferably, it is 1 to 20 mol%. Of course, as long as sufficient reaction efficiency and recovery can be obtained, the lower the catalyst concentration, the better.

Hereinafter, the present invention will be described in more detail with reference to examples. Note that the present invention is not limited to these examples.

[0029]

EXAMPLES In the following Reference Examples and Examples, ¹ H,
^{The 13} C and ¹⁵ N NMR spectra were all JE
Unless otherwise specified, CD using OL JNM-LA300, JNM-LA400, or JMN-LA500
It was measured using Cl ₃ as a solvent. SR-MAS NM
R was measured using a JEOL JNM-LA400 FT-NMR system. ^{In 1} HNMR, tetramethylsilane (TMS) was used as an internal standard (δ = 0), and ¹³ C
In NMR, C ₂ Cl _{2 was} used unless otherwise specified.
DCL ₃ was used as an internal standard (δ = 77.0), and ¹⁵ NN
In MR, nitromethane was used as an external standard (δ = 0).

The IR spectrum was measured by JASCO FT / I
It measured using R-610.

High performance liquid chromatography (HPLC)
Was performed using a SHIMADZU LC-10AT (liquid chromatograph), SHIMADZU SPD-10A (UV detector), and SHIMADZU C-R6A chromatopack.

Column chromatography was carried out using silica gel 60 (manufactured by Merck), and thin-layer chromatography was carried out using Wakogel B-5F.

All the reagents were used after being purified by a method performed in a usual chemical laboratory operation. <Reference Example 1> Synthesis of polymer-immobilized BINOL (1) (R) -Ethyl-4- (2,2'-dimethoxy-1,1'-binaphth-6-
yl) butanoate (compound 5) was prepared by a known method (J. Org. Che).
m., 1998, 63, 3137). Hereinafter, a polymer-immobilized BINOL was synthesized according to the chemical formula [A].

[0034]

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(2) NaH (60% solution in mineral oil, 367 mg, 11.0 mmol) in DMF (10 ml)
Was dispersed in the solution in which Compound 5 (1.47 g, 3.67 g) was added.
(mmol) in DMF (5 ml) and stirred at room temperature for 1 hour. The mixture was cooled to 0 ° C.
OMCl (886 mg, 11.0 mmol) was added.
After stirring for an additional hour, water was added to stop the reaction.
The organic layer was separated and the aqueous layer was extracted by washing with ethyl acetate. The obtained crude product was purified by chromatography on silica gel (solvent: hexane / AcOEt = 9/1). (R) -Ethyl-4- [2,2'-bis (methoxymethyloxy)-
1,1'-binaphth-6-yl] butanoate (compound 6) was 1.71.
g, 95% yield. Table 1 shows the identification results.

[0036]

[Table 1]

(3) LiAlH ₄ (80 mg, 2.1 mmol) was added to Et ₂ O / THF (5 ml each),
To this, compound 6 (1.65 g, 3.38 mmol)
l) in THF (5 ml) was added at room temperature. After stirring for 45 minutes, water (0.16 ml) and 1N NaOH
(0.33 ml) was added and filtered. The filtrate was washed with Na ₂ SO ₄
After drying on the above, the crude product obtained is chromatographed on silica gel (solvent: hexane / AcOEt = 2
/ 1). (R) -4- [2,2'-Bis (methoxymethy
loxy) -1,1'-binaphth-6-yl] -1-butanol (compound 7)
(1.51 g) was obtained. Table 2 shows the identification results.

[0038]

[Table 2]

(4) Next, compound 7 (1.39 g, 3.
11 mmol) and imidazole (529 mg, 7.78)
mmol) in DMF (4.7 ml) was added to t-butyldimethylsiloxycyclolide (TBSCl) (563 m).
g, 3.73 mmol) at room temperature. After stirring for 2 hours, water was added to stop the reaction, and the aqueous layer was separated with ethyl acetate. The obtained crude product is chromatographed on silica gel (solvent: hexane / AcOEt =
30/1). (R) -1- (tert-Butyldimethy
lsiloxy) -4- [2,2'-bis (methoxymethyloxy) -1,1'-binaph
th-6-yl] -butane (compound 8) (1.73 g) was obtained. Table 3 shows the identification results.

[0040]

[Table 3]

(5) Further, compound 8 (1.5 g, 2.
N-Bu (67 mmol) in a solution of Et ₂ O (45 ml).
Li (1.57M, 5.1 ml, 8.0 mmol) was added at room temperature and stirred for 3 hours. Then, the mixture was cooled to 0 ° C.
And cooled to BrF ₂ CCF ₂ Br (2.43 g, 9.35 g).
mmol) in THF (15 ml). After stirring for 4 hours, the reaction was stopped by adding a saturated aqueous NH ₄ Cl solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The obtained crude product is chromatographed on silica gel (solvent: hexane / AcOEt = 30/1).
And purified. (R) -1- (tert-Butyldimethylsiloxy) -4
-[3,3'-dibromo-2,2'-bis (methoxymethyloxy) -1,1'-bin
aphth-6-yl] butane (compound 9) (1.70 g, 90
%)was gotten. Table 4 shows the identification results.

[0042]

[Table 4]

(6) At 0 ° C., compound 6 (1.53 g,
In THF 2.10 mmol) (12 ml) was added Bu ₄
NF (4.2 ml (1M THF solution), 4.2 mmol
l) was added. After stirring at room temperature for 4 hours, the reaction was stopped by adding water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The obtained crude product was chromatographed on silica gel (solvent: hexane / AcOEt = 3).
0/1). (R) -4- [3,3'-Dibromo-2,2'-b
is (methoxymethyloxy) -1,1'-binaphth-6-yl] -1-butanol
(Compound 10) (1.20 g, 95%) was obtained. Table 5 shows the identification results.

[0044]

[Table 5]

(7) NaH (60% solution in mineral oil, 79.0 mg, 1.97 mmol) in DMF (10 ml)
Compound 10 (1.19 g,
1.97 mmol) in DMF (5 ml) was added,
The mixture was stirred at room temperature for 1.5 hours. To this mixture was added Merrifield resin (1.19 g, 1.97 mmol) and B
u ₄ NI (24.5 mg, 0.066 mmol) was added, and the mixture was further stirred at room temperature for 24 hours. After adding a water / THF solution and stirring for 10 minutes, the solution was filtered. The obtained resin was washed with water (20 ml × 3 times) and THF (20 ml ×
3 times), and Et ₂ O (20 ml × 3 times),
Furthermore, it dried under reduced pressure (1 mmHg) at 60 degreeC. (R) -4-
[3,3'-Dibromo-2,2'-bis (methoxymethyloxy) -1,1'-bina
phth-6-yl] -butoxymethylpolystyrene (Compound 11)
(0.375 mmol / g) was determined by elemental analysis of bromine. The identification results are shown in Table 6.

[0046]

[Table 6]

(8) Compound 11 (500.0 mg, 0.1
375 mmol / g) and Pd (PPh _Three)_Four(43.0m
g, 0.037 mmol) in DMF (5 ml).
Phenyl boric acid (9.17 mg, 0.75 mmol) and charcoal
Aqueous sodium acid solution (2M, 0.46 ml) was added and 2
The mixture was stirred under reflux for 4 hours. NH_FourCOOH solution
After addition, the mixture was filtered. The obtained resin was washed with water (2
0 ml × 3 times), THF (20 ml × 3 times), and E
t_TwoWash with O (20 ml × 3 times), and add MOM ether
((R) -4- [3,3'-Diphenyl-2,2'-bis (methoxymethyloxy)-
1,1'-binaphth-6-yl] -butoxymethylpolystyrene (compound
Compound 12) was obtained. Table 7 shows the identification results.

[0048]

[Table 7]

(9) Compound 12 and saturated HCl / MeOH
(1/25, 11 ml) and stirred at 60 ° C. for 6 hours. After filtration, the resin was washed with water (20 ml × 3 times), TH
F (20 ml × 3 times), CH ₂ Cl ₂ (20 ml × 3)
Times) and Et ₂ O (20 ml × 3 times), (R)
-4- (3,3'-Diphenyl-2,2'-dihydroxy-1,1'-binaphth-6-y
l) Butoxymethyl polystyrene (compound 13) was obtained. Table 8 shows the results of the identification.

[0050]

[Table 8]

Various polymer-immobilized BINOLs as shown in Tables 9 to 15 were synthesized in the same manner as described above.

[0052]

[Table 9]

[0053]

[Table 10]

[0054]

[Table 11]

[0055]

[Table 12]

[0056]

[Table 13]

[0057]

[Table 14]

[0058]

[Table 15]

[0059] <Reference Example 2> polymer-immobilized chiral zirconium catalyst Synthesis of Compound 13 and allowed to react with Zr (O ^t Bu), to give a polymer-immobilized chiral zirconium catalyst. Example 1 Aza Diels-A of aldoimine and Danishefsky diene using a polymer-immobilized chiral zirconium catalyst
lder Reaction An aza Diels-Alder reaction was performed according to the chemical formula [B] using various compounds having R ³ (13 to 20 and others) as catalysts. Table 16 shows the yield and optical purity (ee%) of the obtained compound.

[0060]

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[0061]

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[0062]

[Table 16]

From these results, it is found that in the catalyst having a 4-tert-butylphenyl group, the selectivity (optical purity) of the enantiomer is low, but the 3,5-xylyl group, 4-biphenyl group, 4-fluorophenyl group, and For a catalyst having a 3-trifluoromethylphenyl group as R ⁴ , the yield,
It became clear that both selectivity was high. As a result, the catalyst was optimized.

Further, in the reaction of 1-methoxy-2-methyl-3-trimethylsiloxy-1,3-butadiene, a catalyst having a 3-trifluoromethylphenyl group as R ⁴ was added in an amount of 20 mol% to carry out the reaction. If
After the catalyst was used in the first reaction, filtered briefly and reused, the yield and selectivity were <first time: yield> 99%, selectivity 91% ee, second time: yield 97%, selectivity 90% ee, third time: yield 97%, selectivity 90% ee>. Therefore, it was found that the polymer-immobilized chiral zirconium catalyst of the invention of this application maintains high yield and selectivity even when used repeatedly.

[0065]

As described in detail above, the present invention provides a new polymer-immobilized chiral zirconium catalyst. By using this polymer-immobilized chiral zirconium catalyst, an asymmetric aza-Diels-Alder reaction capable of achieving high selectivity and yield has become possible. Further, the polymer-immobilized chiral zirconium catalyst of the invention of this application does not deteriorate even after repeated use, and can contribute to the reaction while maintaining high yield and stereoselectivity.

 ──────────────────────────────────────────────────続 き Continuing on the front page F term (reference) 4C054 AA03 CC07 DD05 DD08 EE01 FF23 4G069 AA02 AA08 BA22A BA22B BA27A BA27B BB02A BB02B BC51A BC51B BD02A BD06A BD08A BD08B BD11A BD15B BE05A BE05 BE34BE05 BE33 BE36 BE33

Claims (2)

[Claims] 1. The following general formula (1): (Wherein R ¹ represents a polymer chain, R ² represents a hydrogen atom, a halogen atom, an alkyl group having or not having a substituent, or a polymer chain, and R ³ represents a substituent An aryl group with or without a substituent, R ⁴ represents an alkyl group, an aryl group, an alkoxyl group with or without a substituent, or a substituent having nitrogen, sulfur, or oxygen) A polymer-immobilized chiral zirconium catalyst characterized by the following: 2. A method for asymmetric aza-Diels-Alder reaction, comprising reacting an imine with a diene in the presence of the chiral zirconium catalyst immobilized on a polymer according to claim 1.