JP3464432B2 - Chiral rare earth metal catalyst and asymmetric aldol reaction method - Google Patents

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art Recently, in chemical synthesis in various fields such as pharmaceuticals and fragrances, realization of asymmetric synthesis with high yield and excellent optical selectivity has become an important issue. In particular, in the asymmetric synthesis reaction, a method using a catalyst is drawing attention.

As such a catalyst, a catalyst in which a chiral ligand compound is coordinated to a metal element has been proposed so far, but these conventional chiral catalysts have considerably limited applicable reactions. However, it 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 take advantage of the characteristic that a unique rare earth metal compound is stably present in water and have a function as a Lewis acid. In organic synthesis such as Diels-Alder reaction, we found that the basic and important carbon-carbon bond formation reaction proceeds smoothly in a water-containing solvent such as water, and based on this, new catalyst systems and synthetic reactions Is proposed.

Therefore, the invention of this application solves the problems of conventional asymmetric synthesis in view of the findings 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 having high optical selectivity, versatility, and simple reaction operation, and an asymmetric synthesis method using the same.

[0006]

[Means for Solving the Problems] This application invention, as to solve the problem as described above, the first, the following formula M (OR _{f) 3} (M is the rare earth element less Do Kutomo 1 shows the species, R _f is, bet
A rare earth metal compound represented by showing a trifluoromethane sulfonyl group), the following equation

[0007]

[Chemical 4]

The present invention provides a chiral rare earth metal catalyst containing a chiral pyridinebisoxazoline compound having a skeleton represented by the following. Secondly, the rare earth element is S
There is provided the chiral rare earth metal catalyst, which is one of c to Lu.

A third aspect of the invention of this application is a method for producing the above catalyst, which comprises mixing a rare earth metal compound and a chiral pyridineoxazoline compound in a polar solvent, and then removing the polar solvent. A method for producing a characteristic chiral rare earth metal catalyst is provided.

A fourth aspect of the invention of this application is a method of asymmetric aldol reaction using the above-mentioned catalyst, wherein the following formula R ¹ CHO (provided that R ¹ is a hydrocarbon which may have a substituent
A group, or a substituent bonded through a heteroatom
And an aldehyde compound represented by the following formula:

[Chemical 5] (However, R ² and R ³ may have a substituent.
Bonded through a hydrocarbon group or a heteroatom,
A hydrocarbon group which may have a substituent is represented by R ⁴ , R ⁵
And R ⁶ each represent a hydrocarbon group) and a silyl enol ether compound represented by the following formula

[Chemical 6] (However, R ¹ , R ² , and R ³ are the same as above)
The present invention provides a method for asymmetric aldol reaction characterized by synthesizing a hydroxyketone compound as described above. Fifthly, a method for asymmetric aldol reaction in which a water-containing solvent comprises water and alcohol.

[0011]

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

First, the chiral rare earth metal catalyst of the invention of this application is basically composed of a rare earth metal compound and a chiral pyridinebisoxazoline compound as described above. Among them, the rare earth metal compound is yttrium, lanthanide or the like. Various kinds of the rare earth element-containing fluorine-containing aluminum sulfonates may be used.

Among the rare earth elements, Yb (ytterbium), Y (yttrium), Dy (dysprosium), Nd (neodymium) and the like are shown as preferable examples .

The above-mentioned chiral pyridinebisoxazoline compound has various substituents on each of its pyridine ring and oxazoline ring which do not inhibit the chiral catalytic activity, such as hydrocarbon group, alkoxy group, amino group and heterocyclic group. May be appropriately included. 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 the chiral pyridinebisoxazoline compound can be prepared by mixing each of them in a polar solvent and then removing the solvent. .

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

Regarding the amounts of the rare earth metal compound and the chiral pyridine bisoxazoline compound used, the chiral pyridine bisoxazoline compound as a ligand is used in a proportion 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 present invention has Lewis acidity and enables formation of a carbon-carbon bond as a basis of organic synthesis, and further 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, the aldehyde compound and the silyl enol ether compound are reacted with each other in the water-containing solvent in the presence of the catalyst as described above to enable the asymmetric synthesis of the hydroxyketone compound.

The asymmetric synthesis of the hydroxyketone compound can be exemplified by the following reaction formula.

[0021]

[Chemical 7]

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

In this reaction, a water-containing solvent is used, and the water-containing solvent may be water, or water and alcohol, such as an aliphatic or alicyclic alcohol.
Alternatively, it is used as a mixture with THF or the like. A mixed solvent of water and alcohol is preferably 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 may be, for example, about 4 to 40 mol% for each of the rare earth metal compound and the chiral pyridinebisoxazoline compound. The aldehyde compound and the silyl enol ether compound are used in a molar ratio of 1/10 to 10
It may be about 10/1.

As the reaction temperature, mild conditions can be adopted. For example, the temperature range is from -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
From the environmental point of view, it is possible to use a water-containing solvent which is advantageous, and has a synthetic advantage such as not requiring extremely low temperature. Moreover, the yield and the asymmetric yield are also good.

Therefore, the invention of this application will be described in more detail with reference to the following examples. Of course, the invention is not limited to the following examples.

[0028]

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

[0029]

[Chemical 8]

Subsequently, benzaldehyde (0.
2 mmol), 1-phenyl-1-trimethylsiloxy-1-propene (0.3 mmol) H ₂ O-EtOH
(1: 9, 1.0 ml in total) The mixed solution was added under the condition of 0 ° C. After stirring for 24 hours, saturated NaHCO ₃ aqueous solution (7 ml) was added to separate the organic layer, and 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 produced by silica gel thin layer chromatography to give 1,3-diphenyl-3-hydroxy-2-
Methyl-1-propanone was obtained (yield 93%, sy
n: anti = 72: 83, 35% ee (syn)).

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

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

[0033]

[Table 1]

<Example 2> In the same manner as in Example 1, an asymmetric aldol reaction was carried out with another aldehyde compound or enolate compound.

The results are shown in the following table.

[0036]

[Table 2]

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

[0038]

[Table 3]

[0039]

[Table 4]

[0040]

[Table 5]

<Example 3> In Example 1, the reaction solvent was changed and the reactions shown in the following table were carried out. The results are shown in the table.

[0042]

[Table 6]

[0043] <Example 4> Example 1, the aldehyde compound CH ₃ - instead of _{(CH 2) 6 -CH 2 -CHO} , as the rare earth metal compound Y (OT _{f) 3} and D
Asymmetric aldol reactions were 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-
Undecanon is Syn / anti = 59/41, S
It was yn = 41% ee. In the case of Dy (OT _f ) ₃ , Syn / anti = 57/43, syn = 39% e
It was e. Reference Example 5 In Example 1, —CH ₂ —O bonded to the oxazoline ring of the chiral pyridinebisoxazoline compound as the ligand.
The reaction was carried out using a compound in which H was —CH ₂ —OTBS.

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

[0046]

As described in detail above, according to the invention of this application, a new yield which is high in yield and optical selectivity, has general versatility, and enables a reaction operation under simple and mild conditions. A simultaneous synthesis catalyst and an asymmetric synthesis method using the same are provided.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI // C07B 61/00 300 C07B 61/00 300 C07M 7:00 C07M 7:00 (56) Reference JP-A-6-256248 ( JP, A) JP 2000-42404 (JP, A) JP 9-248463 (JP, A) JP 6-166652 (JP, A) JP 56-108726 (JP, A) Seiji Iwasa, et al. , A SYNTHESIS OF 2,6-BIS (4R-HYDROXY METHYLOXAZOLYL) PYR IDINE AS A WATERS OLUBLE LIGAND, HETE ROCYCLES, 2000, Vol. 52, No. 2, p. 939-944 (58) Fields surveyed (Int.Cl. ⁷ , DB name) B01J 21/00-38/74 C07B 61/00 CA (STN) JISC file (JOIS)

Claims (5)

(57) [Claims] 1. A following formula M (OR _{f) 3} (where M indicates a low Do Kutomo one rare earth element, R _f represents a trifluoromethanesulfonyl group) and a rare earth metal compound represented by the following formula [ Chemical 1] A chiral rare earth metal catalyst containing a chiral pyridine bisoxazoline compound having a skeleton represented by 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 pyridineoxazoline 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 the catalyst according to claim 1 or 2, which comprises the following formula R ¹ CHO (where R ¹ is a substituent group) in a water-containing solvent in the presence of the catalyst. Hydrocarbons which may have
A group, or a substituent bonded through a heteroatom
An aldehyde compound represented by the formula ( which represents a hydrocarbon group which may have), and a compound represented by the following formula : (However, R ² and R ³ may have a substituent.
Bonded through a hydrocarbon group or a heteroatom,
A hydrocarbon group which may have a substituent is represented by R ⁴ , R ⁵
And R ⁶ are each a serial <br/> Le enol ether compound represented by a hydrocarbon group) is reacted, following formula: 3] (However, R ¹ , R ² , and R ³ are the same as above)
A method for asymmetric aldol reaction, which comprises synthesizing a hydroxyketone compound. 5. The asymmetric aldol reaction method according to claim 4, wherein the water-containing solvent comprises water and alcohol.