JP2001252568A - Chiral zirconium catalyst and method for synthesizing optically active antialdol material using this catalyst - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for synthesizing an optically active antialdol material by which high antiselectivity and yield can be achieved under milder conditions than by a conventional method. SOLUTION: This chiral zirconium catalyst is characterized in that it is represented by formula (1): (wherein, X is a halogen atom or a hydrogen atom and R1 is an alkyl group or an aryl group). The method for synthesizing the optically active antialdol material is to make aldehyde chemically react with a silylenol ether using this catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a chiral zirconium catalyst. For more information,
The invention of this application relates to a method for synthesizing an optically active anti-aldol compound using a 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.

The aldol reaction conventionally known as the reaction between a ketone having an α hydrogen and an aldehyde has been regarded as a very important reaction in the production of pharmaceuticals and has been used. And in recent years, systems using various catalysts,
It has been studied and reported as a means of stereoselective reactions.

For example, reaction of silyl enol ether with aldehyde using Lewis acid (Mukoyama aldol reaction)
Is known as an effective method for selectively forming a carbon-carbon bond in organic chemistry, and various compounds using tin, boron, titanium, copper and the like have been reported as Lewis acid catalysts (Comprehensive Asymmetric Catalysi
s, 1999, Vol. 3, p. 998; Chem. Rev., 1999, 99, 109.
5, Chem. Eur. J. 1998, 4,1137, Tetrahedron: Asy
m., 1998, 9, 357; Angew. Chem. Int. Ed. Engl., 199
4, 33, 417).

[0005] These methods have high stereoselectivity in the reaction and have been considered as one of the most efficient reactions in the synthesis of chiral β-hydroxyketone and ester derivatives. However, in practice, there is a problem that a low reaction temperature of −78 ° C. and severe conditions of complete anhydrous state are required.

Although many syndol-selective aldol reactions have been studied, anti-selective aldol reactions are not well known. At present, what has been reported (Tetrahedron Lett., 1992, 33, 1729, J. Am. Chem.
Soc., 1994, 116, 4077) have problems such as low product yields and limited usable compounds, and are not practical.

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 for synthesizing an optically active anti-aldol compound capable of obtaining high anti-selectivity and a yield under ordinary conditions.

[0008]

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):

[0009]

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(X in the formula represents a halogen atom or a hydrogen atom, and R ¹ represents an alkyl group or an aryl group).

The invention of this application also provides, secondly, a method for synthesizing an optically active anti-aldol compound, which comprises reacting an aldehyde with a silyl enol ether in the presence of the above-mentioned chiral zirconium catalyst. provide.

Thirdly, the present invention provides, as an embodiment, that the synthesis of the above-mentioned optically active anti-aldol compound is carried out in the presence of an alcohol.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION As described above, the invention of this application is to carry out aldol reaction of aldehyde and silyl enol ether with high anti-selectivity using a novel chiral zirconium catalyst. Will be described.

[0014] Chiral zirconium catalyst represented by the general formula (1) may, for example Zr (O ^t Bu) ₄ and (R) -
It is obtained by mixing 3,3′-dibromo-1,1′-bi-2-naphthol ((R) -3,3′-BrBINOL).
At this time, X in the general formula (1) is Br, and R ¹ is t-
It becomes a butyl group. Of course, X is not limited to Br, and may be, for example, a halogen atom such as I or Cl, or a hydrogen atom. Further, R ¹ is not limited to a t-Bu group, and an alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or An aryl group such as phenyl, toluyl, and xylyl, and the like are applied.

In the invention of this application, an optically active aldol compound can be obtained with high anti-selectivity by reacting an aldehyde with silyl enol ether using the above-mentioned chiral zirconium catalyst which is a novel substance.

The aldehyde is represented by the following chemical formula (2): R ² CHO (2), wherein R ² is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, An alkyl group such as hexyl, cyclopropyl, cyclobutyl and cyclopentyl, an alkylene group such as ethylene, propylene, butylene and amylene, or an aryl group such as phenyl, toluyl and xylyl are applied. Further, these substituents may further have a substituent, for example, a halogenated phenyl group, a p-methoxyphenyl group, a benzyl group and the like. Of course, R ² is not limited to the substituents listed above.

The silyl enol is not particularly limited, but is preferably represented by the following chemical formula (3):

[0018]

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The following is an example. At this time,
In the formula, R ³ , R ⁴ and R ⁵ are each the same or different,
Shows various substituents. Specifically, an alkyl group having or not having a substituent, an alkylene group, an amino group, a cyano group, a nitro group, a thiol group, a sulfone group, a carbonyl group, a carboxyl group, an alkoxycarbonyl group, or a hydrogen atom Is selected from For example, a methyl group,
Examples thereof include an ethyl group, a propyl group, a phenyl group, a benzyl group, a methoxy group, and a phenoxy group. Of course, R
^{3 to} R ⁵ are not limited to these substituents, and silyl enol ethers having various structures can be applied.

The reaction conditions are not particularly limited.
Water and various organic solvents are considered as the reaction solvent.
Preferably, toluene is used. At this time, it becomes a dispersion. The reaction temperature is not particularly limited, but can be appropriately changed depending on the solvent and the starting material. Preferably, it is -10 to 50 ° C. The concentration of the catalyst to be added is not particularly limited. However, if the concentration is too low, the effect is hardly exhibited, and the anti-selective reaction becomes difficult to progress. If the concentration is more than a certain concentration, the effect is not further increased. Therefore, the catalyst concentration is preferably 0.1 to 100 mol%, more preferably 1 to 20 mol%.

In the aldol reaction of the invention of this application, it is preferable to add an alcohol to the reaction system. By the addition of the alcohol, the alcohol acts as a proton generation source, and the monotrimethylsilylated BINOL derivative generated as an intermediate product can be converted into a BINOL derivative, thereby improving the yield and selectivity. Various types of alcohol can be applied, but preferably, a monohydric primary alcohol such as ethanol, methanol, propanol, or butanol is used. Of course, other alcohols such as diols and triols may be used.

The amount of alcohol to be added is as follows:
Although not particularly limited, if the amount is too large, the reaction may be adversely affected. Therefore, the content is preferably set to 1 to 100 mol%.

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.

[0024]

EXAMPLES In the following Reference Examples and Examples,¹H
And¹³The CNMR spectra are all JEOL J
NM-LA300, JNM-LA400, or JMN
-Using LA500, CDCl unless otherwise specified_ThreeTo
It was measured as a solvent. ¹In HNMR, tetramethy
Lusilane (TMS) as an internal standard (δ = 0)¹³CN
In MR, CD_TwoCl_TwoCD unless otherwise noted
Cl_ThreeWas used as an internal standard (δ = 77.0).

High performance liquid chromatography (HPLC)
Was performed using a SHIMADZU LC-10AT (liquid chromatograph), SHIMADZU SPD10-A (UV detector), and SHIMADZU C-R6A chromatopack.

The column chromatography was performed using silica gel 60 (manufactured by Merck), and the thin layer chromatography was performed using Wakogel B-5F.

The dichloromethane used in the experiment was P ₂
O ₅ under and then distilled under CaH _2, was dried under MS 4A, it was used. Toluene was used after drying under MS 4A. Also, alcohol is distilled under Mg,
Dried under MS 4A and stored under argon. The aldehyde was purified before use by distillation or sublimation.

All silyl enol ethers are Ho
Synthesized according to the method of use (J. Org. Chem., 1969, 34, 2324). Furthermore, the 3,3′-BINOL derivative was prepared according to the method of Sneekus (Tetrahedron Lett., 1
992, 33, 2253). <Reference Example> Preparation of chiral zirconium catalyst (NMR measurement)
At room temperature, (R) -3,3'-diiodo-1,1 '
-Bi-2-naphthol (3,3'-IBINOL) (44
mg, 0.08 mmol) to CD ₂ Cl ₂ (0.5 ml),
After the _{^{dispersion, Zr (O t Bu) 4}} (30.6 mg, 0.04
mmol) in CD ₂ Cl ₂ (0.50 ml) and further propanol (24.1 mg, 0.4 mmol). After stirring this solution for 60 minutes, it was introduced into a sample tube for NMR.

CD ₂ Cl ₂ (δ ¹ = 5.32 ppm in ¹ H NMR,
NMR measurement was performed using ¹³ C NMR as δ = 53.1 ppm) as a standard. Table 1 shows the results.

[0030]

[Table 1]

The obtained chiral zirconium catalyst was (naphthalenediolato) -dialkoxyzirconium, which was a compound of the general formula (1) where X was I and R ¹ was ^t Bu. <Example 1> Effect of catalyst and alcohol species on anti-selective asymmetric aldol reaction Benzaldehyde (2a) according to chemical formula [A]
And silyl enolate (3a) were subjected to an aldol reaction. The catalyst is a compound represented by the following chemical formulas (1a to d):
Alcohol, n- propanol (PrOH), i-propanol ⁽ⁱ PrOH), n- butanol (BuO
H), were selected from t- butanol ^(t BuOH).

[0032]

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[0033]

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The yield and optical activity (ee%) of the obtained product
Are shown in Table 2.

[0035]

[Table 2]

From the results, it was shown that the addition of propanol improves the yield in the reaction and the optical purity of the product. Also, BuOH is more than ^t BuOH, ⁱ
It was confirmed that PrOH exhibited a higher effect on improving the yield and the optical purity than PrOH. <Example 2> (R) -3,3'-diiodo-1,1'-
Bi-2-naphthol (0.044 mmol) was dissolved in toluene (0.25 m
was added to l), after the suspension, Zr (O ^t Bu)
_A solution of ₄ (0.04 mmol) in toluene (0.50 ml) was added and mixed at room temperature. The obtained mixture was stirred at room temperature for 30 minutes, and toluene (1.0 mmol) of n-propanol (0.20 mmol) was added.
ml) solution was added. The mixture was stirred for a further 30 minutes and cooled to 0 ° C.

Benzaldehyde (0.80 mmol) and silyl enolate (3b) (0.96 mmol) in toluene (0.50 m
l) Add solution, stir for 18 hours, then add saturated NaHCO
_The reaction was stopped by adding ₃ .

The aqueous layer was washed with dichloromethane and separated.
The obtained crude product was washed at 0 ° C. with THF-1N HCl (2
0: 1) for 1 hour to hydrolyze a small amount of the silylated product. The obtained crude product was separated and purified on silica gel.

The obtained product was identified by NMR.
Table 3 shows the identification results.

[0040]

[Table 3]

The product yield and optical purity (ee
%) Are shown in Table 4. <Examples 3 to 12> In the same manner as in Example 2, aldol reactions of each aldehyde and silyl enolate in Table 3 were performed.

In Examples 2 to 12, the yield, syn / anti ratio, and optical purity (ee%) of the obtained product were determined.
The results are shown in Table 4.

[0043]

[Table 4]

The structure of each product (4a to 4k) is represented by N
Confirmed by MR. The identification results are shown in Tables 5 to 14.

[0045]

[Table 5]

[0046]

[Table 6]

[0047]

[Table 7]

[0048]

[Table 8]

[0049]

[Table 9]

[0050]

[Table 10]

[0051]

[Table 11]

[0052]

[Table 12]

[0053]

[Table 13]

[0054]

[Table 14]

From the above, it has been shown that the use of the chiral zirconium catalyst of the invention of this application allows the asymmetric aldol reaction to proceed anti-selectively. It has also been confirmed that this reaction is applicable not only to specific starting materials but also to reactions of various aldehydes with silyl enolates.

[0056]

As described in detail above, the present invention provides a new chiral zirconium catalyst. And, by using this chiral zirconium catalyst, a higher an
It is possible to synthesize an optically active anti-aldol compound that can achieve ti-selectivity and yield. In this method of synthesizing an optically active anti-aldol compound, not only limited compounds but also many compounds can be applied as starting materials.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) // C07B 61/00 300 C07B 61/00 300 F term (reference) 4G069 AA06 BA27A BC51A BE33A BE37A CB57 DA02 4H006 AA02 AC48 AC80 AC81 AD17 BA10 BA45 BB11 BB14 BC10 BC19 BC33 BC36 BJ50 BM30 BM72 BN10 BP30 KA36 4H039 CA66 CB20 CL25

Claims (3)

[Claims] 1. The following general formula (1): (X in the formula represents a halogen atom or a hydrogen atom;
¹ represents an alkyl group or an aryl group. A chiral zirconium catalyst represented by the formula: 2. A method for synthesizing an optically active anti-aldol compound, comprising reacting an aldehyde with a silyl enol ether in the presence of the chiral zirconium catalyst according to claim 1. 3. The method for synthesizing an optically active anti-aldol compound according to claim 2, which is carried out in the presence of an alcohol.