JP2001252570A - Chiral rare earth metal catalyst and asymmetric aldol reaction method - Google Patents

Abstract

(57) [Summary] [Problem] High yield, high optical selectivity, versatility,
In addition, the present invention provides a new asymmetric synthesis catalyst which enables simple reaction operation and an asymmetric synthesis method using the same. SOLUTION: A rare earth metal compound represented by the following formula M (OR _f ) ₃ (M represents at least one kind of rare earth element, and R _f represents a fluorine-containing alkylsulfonyl group), and a compound represented by the following formula: ] And a chiral rare earth metal catalyst containing a chiral pyridine bisoxazoline compound having a skeleton represented by the formula: and performing an asymmetric aldol reaction using the catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The invention of this application relates to a chiral rare earth metal catalyst and a method for asymmetric aldol reaction. More specifically, the invention of this application relates to a novel chiral rare earth metal catalyst having a Lewis acid catalyst function and useful as an asymmetric synthesis catalyst, and a method for asymmetric aldol reaction using the same.

[0002]

2. Description of the Related Art In recent years, in chemical synthesis in various fields such as pharmaceuticals and fragrances, it has become an important issue to realize asymmetric synthesis with high yield and excellent optical selectivity. In particular, in asymmetric synthesis reactions, attention has been paid to a method using a catalyst.

[0003] As such a catalyst, those in which a chiral ligand compound is coordinated to a metal element have been proposed so far, but the reaction to be applied to these conventional chiral catalysts is considerably limited. In addition, there has been a problem that the operation conditions such as reaction conditions are largely restricted.

On the other hand, the inventors of the present application took advantage of the characteristic that a unique rare earth metal compound is stably present in water and has a function as a Lewis acid. In organic synthesis such as the Diels-Alder reaction, the basic and important carbon-carbon bond formation reaction has been found to proceed smoothly in water and other water-containing solvents, and new catalyst systems and synthetic reactions based on this have been found. Has been proposed.

Therefore, the invention of this application solves the problems of the conventional asymmetric synthesis in view of the knowledge and new proposals by the inventors of this application as described above,
It is an object of the present invention to provide a new asymmetric synthesis catalyst which has high optical selectivity, is versatile, and enables simple reaction operation, and an asymmetric synthesis method using the same.

[0006]

Means for Solving the Problems According to the invention of the present application, as a solution to the above problems, first, the following formula M (OR _f ) ₃ (where M is at least one kind of rare earth element) R _f represents a fluorinated alkylsulfonyl group) and a rare earth metal compound represented by the following formula:

[0007]

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A chiral rare earth metal catalyst comprising a chiral pyridine bisoxazoline compound having a skeleton represented by the following formula:
providing the chiral rare earth metal catalyst of one of c to Lu.

Further, the invention of this application is, thirdly, a method for producing the catalyst, which comprises mixing a rare earth metal compound and a chiral pyridine oxazoline compound in a polar solvent and then removing the polar solvent. A method for producing a chiral rare earth metal catalyst is provided.

Further, the invention of this application is, fourthly, a method for asymmetric aldol reaction using the catalyst, wherein the silyl enol ether compound of an aldehyde reactant is contained in a water-containing solvent in the presence of the catalyst. The present invention provides a method for asymmetric aldol reaction characterized by synthesizing a hydroxyketone compound by reacting the compound with acetonitrile. Fifth, the present invention provides a method for asymmetric aldol reaction comprising a water-containing solvent comprising water and an alcohol.

[0011]

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

First, the chiral rare earth metal catalyst of the invention of the present application is basically composed of a rare earth metal compound and a chiral pyridine bisoxazoline compound as described above. Among these, the rare earth metal compound is yttrium, lanthanide or the like. And various kinds of rare-earth fluorine-containing aluminosulfonates.

Among the rare earth elements, Yb (ytterbium), Y (yttrium), Dy (dysprosium), Nd (neodymium) and the like are shown as preferable examples. The fluorine-containing alkylsulfonyl group connecting these rare earth elements is a portion or all of the hydrogen atoms of the alkyl group are substituted by fluorine atoms, among _{them, -SO 2 -C n F 2n +} 1 (N ≦ 1
The perfluoroalkyl group of 0) is exemplified as a preferable example. A typical example is a triflate group.

The above-mentioned chiral pyridine bisoxazoline compound has various substituents such as hydrocarbon group, alkoxy group, amino group, heterocyclic group and the like which do not inhibit the chiral catalytic activity in each of the pyridine ring and oxazoline ring. May be appropriately provided. Further, the hydrogen atom of the hydroxyl group of —CH ₂ —OH bonded to the oxazoline ring may be substituted with an alkoxy group, an acyl group, a sulfonyl group, or the like.

The chiral rare earth metal catalyst of the present invention containing the above rare earth metal compound and a chiral pyridine bisoxazoline compound can be prepared by mixing each of them in a polar solvent and then removing the solvent. .

As the polar solvent, various solvents such as nitriles, sulfoxides, and acids may be used. The preparation can be performed, for example, under a temperature condition of about −10 ° C. to 10 ° C.

The amounts of the rare earth metal compound and the chiral pyridine bisoxazoline compound used are prepared by using the chiral pyridine bisoxazoline compound as a ligand in a ratio of 0.1 to 10 mol per 1 mol of the rare earth metal compound. can do.

The prepared chiral rare earth metal catalyst of the invention of the present application has Lewis acidity, enables formation of carbon-carbon bonds as the basis of organic synthesis, and enables asymmetric synthesis.

The invention of this application specifically provides an asymmetric aldol reaction method as one of such asymmetric syntheses. That is, in the present invention, an aldehyde compound and a silyl enol ether compound are reacted in a water-containing solvent in the presence of a catalyst as described above, thereby enabling asymmetric synthesis of a hydroxyketone compound.

The asymmetric synthesis of this hydroxyketone compound can be exemplified, for example, by the following reaction formula.

[0021]

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In the formula, R ¹ , R ² and R ³ represent a hydrocarbon group which may have a substituent or a substituent which is bonded via a hetero atom such as an oxygen atom or a sulfur atom. A hydrocarbon group which may have R ⁴ , R ⁵ , R
⁶ represents a hydrocarbon group.

In this reaction, a water-containing solvent is used. As the water-containing solvent, water or water and an alcohol, for example, an aliphatic or alicyclic alcohol,
Alternatively, it is used as a mixture with THF or the like. The mixed solvent of water and alcohol is suitably used, and the ratio of water in this case is preferably 0.9 or less as a volume ratio to alcohol.

The amount of the catalyst used in the reaction can be, for example, about 4 to 40 mol% for each of the rare earth metal compound and the chiral pyridine bisoxazoline compound. The amount of the aldehyde compound and the silyl enol ether compound used is from 1/10 to 10
It may be about 10/1.

The reaction can be performed under mild conditions. For example, a temperature range of -5 ° C to 15 ° C.

In the asymmetric aldol reaction method of the present invention as described above, not only the reaction operation is simple, but also
A hydrous solvent which is also advantageous in terms of the environment can be used, and further, there is an advantage in synthesis such as not requiring an extremely low temperature. In addition, the yield and the asymmetric yield are good.

Therefore, the present invention will be described below in more detail with reference to Examples. Of course, the invention is not limited by the following examples.

[0028]

<Example 1> 200 ° C / under argon atmosphere
To a solution of ytterbium (m) triflate (0.04 mmol, 20 mol%) in acetonitrile (0.8 ml) dried at 1 mmHg for 1 hour, pyridinebisoxazoline-CH ₂ OH represented by the following formula (1, 0.048 m)
mol, 24 mol%) at 0 ° C. and stirred for 1 hour,
Acetonitrile was distilled off under reduced pressure and dried to prepare a chiral ytterbium catalyst.

[0029]

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Subsequently, benzaldehyde (0.
2 mmol), 1-phenyl-1-trimethylsiloxy-1-H ₂ O-EtOH propene (0.3 mmol)
(1: 9, 1.0 ml in total) The mixed solution was added at 0 ° C. After stirring for 24 hours, a saturated aqueous solution of NaHCO ₃ (7 ml) was added, and the organic layer was separated. The product was extracted from the aqueous layer with methylene chloride (10 ml × 2). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel thin-layer chromatography to give 1,3-diphenyl-3-hydroxy-2-.
Methyl-1-propanone was obtained (93% yield, sy)
n: anti = 72: 83, 35% ee (syn)).

The ratio of diastereomers is determined by proton NMR.
Decided. The optical purity of the Syn form was determined by using an optical isomer separation column (CHIRALPAK AD, manufactured by Daicel Chemical Industries, hexane / 2-propanol = 30/1, retention time 17.88,
22.64 min (syn), 32.54, 36.54
min (anti)) was determined by HPLC analysis.

The identification physical properties of the product are as shown in the following table.

[0033]

[Table 1]

Example 2 An asymmetric aldol reaction with another aldehyde compound or enolate compound was carried out in the same manner as in Example 1.

The results are shown in the following table.

[0036]

[Table 2]

The identified physical properties of the reaction products are as shown in the following table.

[0038]

[Table 3]

[0039]

[Table 4]

[0040]

[Table 5]

<Example 3> In Example 1, the reaction was carried out as shown in the following table by changing the reaction solvent. The results are shown in the table.

[0042]

[Table 6]

<Example 4> In Example 1, Y (OT _f ) ₃ and D were used as rare earth metal compounds in place of CH _3- (CH ₂ ) ₆ -CH ₂ -CHO for the aldehyde compound.
An asymmetric aldol reaction was performed for each of y (OT _f ) ₃ .

As a result, in Y (OT _f ) ₃ , the product 3-hydroxy-2-methyl-1-phenyl-1
-Undecanone is Syn / anti = 59/41,
Syn = 41% ee. In the case of Dy (OT _f ) ₃ , Syn / anti = 57/43, syn = 39%
ee. <Example 5> Example 1 The reaction was carried out using the compound of -CH ₂ -OH and the -CH ₂ -OTBS that binds to the oxazoline ring of the chiral pyridine bisoxazoline compound ligand.

As a result, the yield was 53% and the syn / anti
= 62/38, syn = 18% ee.

[0046]

As described in detail above, the invention of the present application provides a new process which has high yield, high optical selectivity, is versatile, and allows simple and mild reaction operation. A catalyst for asymmetric synthesis and an asymmetric synthesis method using the same are provided.

──────────────────────────────────────────────────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 C07M 7:00 C07M 7:00 F term (reference) 4G069 AA06 BA21A BA21B BA27A BA27B BC38A BC39A BC40A BC40B BC41A BC42A BC43A BC44A BC44B CB25 CB57 DA02 FB06 4H006 AA02 AC27 AC41 AD17 BA08 BA47 BB14 BB31 BC10 BC19 BC31 TN30 TN40 4H039 CA60 CB20 CG90

Claims (5)

[Claims] 1. A rare earth metal compound represented by the following formula: M (OR _f ) ₃ (M represents at least one kind of rare earth element, and R _f represents a fluorine-containing alkylsulfonyl group); 1) And a chiral pyridinebisoxazoline compound having a skeleton represented by the formula: 2. The chiral rare earth metal catalyst according to claim 1, wherein the rare earth element includes all of Sc to Lu. 3. The method for producing a catalyst according to claim 1, wherein the rare earth metal compound and the chiral pyridine oxazoline compound are mixed in a polar solvent, and then the polar solvent is removed. Method for producing catalyst. 4. A method for asymmetric aldol reaction using a catalyst according to claim 1 or 2, comprising reacting an aldehyde reactant with a silyl enol ether compound in a water-containing solvent in the presence of the catalyst. An asymmetric aldol reaction method comprising synthesizing a ketone compound. 5. The asymmetric aldol reaction method according to claim 4, wherein the aqueous solvent comprises water and an alcohol.