JP2001252567A - Chiral metallic catalyst and asymmetric michael addition reaction process of thiol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new chiral metallic catalyst which shows high yield and superb optical selectivity and can be controlled for chemical reaction under simple and mild conditions and further, effects asymmetric synthesis of thiol in the Michael addition reaction as well as the asymmetric Michael addition reaction process of the thiol using the chiral metallic catalyst. SOLUTION: The chiral metallic catalyst contains a metallic compound represented by formula (I): M(ORf)4 (wherein, M is an element of metals and Rf is an alkylsulfonyl group containing fluorine and a chiral prolinol compound represented by formula (II): (wherein, R1, R2,R3 and R4 are each a hydrocarbon group which may have a substituent group). This chiral merallic catalyst is used for the asymmetric Michael addition reaction process of the thiol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for asymmetric Michael addition reaction of a thiol with a chiral metal catalyst. More specifically, the invention of this application provides a novel chiral metal catalyst that enables an asymmetric addition reaction of an aliphatic thiol compound with good yield and optical selectivity,
The present invention relates to a method for asymmetric Michael addition reaction of thiol using this.

[0002]

2. Description of the Related Art Since many natural organic compounds and physiologically active substances contain a sulfur atom, in organic synthesis, the Michael addition reaction of a thiol compound is useful for forming a carbon-sulfur bond. It is considered a means.

[0003] This Michael addition reaction comprises α, β
-A nucleophilic addition reaction of a carbanion to an unsaturated carbonyl compound, which is regarded as an important technique for organic synthesis together with the aldol reaction.

However, the application of this Michael addition reaction method to enantioselective reactions has hitherto mostly been based on chiral amines, and is practically satisfactory in terms of chemical yield and optical selectivity. There are few things that can be done, and very low temperature is required as the reaction temperature.
The complicated structure of the catalyst and its handling have been regarded as the drawbacks.

[0005] In view of the above-mentioned conventional problems, the invention of the present application has good yield and optical selectivity.
To provide a new chiral metal catalyst that enables simple and gentle reaction operation under mild conditions and enables asymmetric synthesis in Michael addition reaction of thiol, and to provide a method for asymmetric Michael addition reaction of thiol using the same. That is the task.

[0006]

Means for Solving the Problems The present invention solves the above-mentioned problems. First, the following formula M (OR _f ) ₄ (where M represents a metal element and R _f represents a fluorinated alkylsulfonyl group);
Next formula

[0007]

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(R ¹ , R ² , R ³ and R ⁴ are each
A hydrocarbon group which may have a substituent).

[0009] The invention of this application, the second metal element provides a H _f, the chiral metal catalyst is a T _i or Zr, in the first 3, R ^1, R ² and R Each of the ³ hydrocarbon groups is a chiral metal catalyst which is one of a branched aliphatic hydrocarbon group, a monocyclic or polycyclic alicyclic hydrocarbon group or an aromatic hydrocarbon. Provides a chiral metal catalyst wherein the hydrocarbon group of R ⁴ is one of the aliphatic hydrocarbon groups. And the invention of this application is
Fifthly, there is provided a method for asymmetric Michael reaction of thiol using any of the above-mentioned chiral metal catalysts, wherein an α, β-unsaturated carbonyl compound is reacted with a thiol compound in the presence of the catalyst to form a thiol compound. Provided is a method for asymmetric Michael addition reaction of thiol, characterized by asymmetric synthesis of an addition compound.

[0010]

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.

The chiral metal catalyst provided by the invention of this application is basically composed of the above-mentioned metal compound and a chiral prolinol compound. Of these, the metal compound has a valence of four. , A metal such as Hf (hafnium), Ti (titanium), or Zr (zirconium) is preferably used. Among them, Hf is a typical example.

The fluorine-containing alkylsulfonyl group bonded to these metal elements is a fluoroalkylsulfonyl group in which some or all of the hydrogen atoms of the alkyl group have been replaced by fluorine atoms. More preferably,-
An example is a perfluoroalkylsulfonyl group represented by SO ₂ —C _n F _{2n + 1} (n ≦ 10). A typical example is a triflate group.

Further, in the chiral prolinol compound, the symbols R ¹ , R ² and R ³ are a hydrocarbon group which may have a substituent, but the hydrocarbon is more sterically bulky. Preferred are a hydrogen group, for example, a branched alkyl group such as a tert-butyl group, an alicyclic group such as a cycloalkyl group and an adamantyl group, and an aromatic group such as a phenyl group and a naphthyl group.

On the other hand, R ⁴ is preferably an aliphatic hydrocarbon group having a relatively low carbon number.

It is needless to say that in the chiral prolinol compound, the pyrrolidine ring may further have a hydrocarbon or other substituent.

The above-mentioned chiral metal catalyst is prepared, for example, by mixing the above-mentioned metal compound and a chiral prolinol compound in a solvent. The solvent at this time may be used as it is as a solvent for the synthesis reaction using the catalyst, or may be replaced by another reaction solvent.

And, in the chiral metal catalyst of the present invention,
Further, if necessary, another kind of ligand compound may coexist with the reaction promoting compound. In the preparation of the chiral metal catalyst, the metal compound and the chiral prolinol compound can be used in a molar ratio of, for example, 1/10 to 10/1.

The chiral metal catalyst of the present invention has Lewis acidity as a feature, is effectively used in Lewis acid catalyzed reactions such as Michael addition reaction and aldol reaction, and enables asymmetric synthesis. Is emphasized.

In general, when a ligand is introduced into a Lewis acid,
Although the Lewis acidity decreases and the reactivity decreases, in the present invention, the reactivity of the metal compound as the Lewis acid is accelerated in the presence of the asymmetric ligand as compared with the case of the unit of the metal compound. It has the feature of

A method for asymmetric Michael addition of thiols is provided in particular in the invention of this application. In this asymmetric synthesis, a reaction with a high yield and selectivity using an aliphatic thiol which has hardly been reported hitherto is also possible.

In the asymmetric Michael addition reaction method using the thiol compound, the thiol compound may be various kinds of aliphatic, aromatic or heterocyclic compounds,
The same applies to α, β-unsaturated carbonyl compounds.

For example, in the present invention, the asymmetric Michael addition reaction described in the examples is shown as a specific example.

The α, β-unsaturated carbonyl compound in these examples may further have various substituents such as a hydrocarbon group on the oxazoline ring or the α, β-unsaturated carbon chain. Needless to say.

The feature of the reaction method of the present invention is that a high yield and a high optical selectivity are realized under mild reaction temperature conditions of about -5 ° C. to 15 ° C. For the reaction, a solvent can be appropriately used, and the use ratio of the aldehyde compound and the α, β-unsaturated carbonyl compound is, for example, 1/10 to 10 /
1 can be used as a guideline as appropriate.

The amount of chiral metal catalyst used can also be varied over a wide range if desired. For example, 1 to 30 mol
% Is practically considered.

Then, the following examples are shown and the invention of this application will be described in more detail. Of course, the invention is not limited by the following examples.

[0027]

<Example 1> 50 ° C / under argon atmosphere
H dried at 0.5 mmHg for 1 hour_f(OT_f)
_Four(0.04 mmol, 10 mol%) and N-benzoy
2-diphenylmethoxymethylpyrrolidine (0.0
5 mmol, 12 mol%), and MS4A (125
mg) in dichloromethane (1 mL) for 1 hour at room temperature
The mixture was stirred to prepare a chiral metal catalyst. Then the reaction solution was
C. and cooled to N-crotonoyloxazodinone (0.4
mmol) in dichloromethane (0.5 mL) and
Of dichloromercaptan (0.42 mmol)
A tan solution (0.5 mL) was added and stirred for 20 hours. Bored
After adding sodium bicarbonate aqueous solution to stop the reaction,
Extracted with dichloromethane. Wash the extract with saturated saline
And dried over anhydrous magnesium sulfate. Evaporate the solvent
After that, it was purified by silica gel thin layer chromatography.
However, 3- (3-benzylthiobutanoyl) -2-o
Xazolidinone obtained in 82% yield and 67% ee optical yield
Was. Optical yield was determined by HPLC.

The fixed physical properties of the reaction product were as follows.

[0029]

[Table 1]

In the same manner as above, the reaction was carried out using the following various chiral prolinol compounds as ligands. Ligand 4
Represents the aforementioned N-benzoyl-2-diphenylmethoxymethylpyrrolidine.

[0031]

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The results of the reaction are shown in Table 1 below.

[0033]

[Table 2]

Example 2 (A) Synthesis of Ligand The following reaction formula

[0035]

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(2S) -1-N-pivaloyl-2- (methoxy-diphenylmethyl) pyrrolidine was synthesized according to (where Z represents a benzyloxycarbonyl group).

That is, the following procedure was adopted.

N- (Z)-(2S) -2- (Hydroxy-diphenylmethy) pyrrolidine: Magnesium (300 mmol, 1
(0 eq) in a diethyl ether solution (100 mL) was added dropwise over 1 hour at room temperature a diethyl ether solution (60 mL) of benzene bromide (315 mmol, 10.5 eq) (at this time, heating and reflux occurred spontaneously). After completion of the dropwise addition, the mixture was further stirred for 1 hour. After confirming that magnesium was completely dissolved, the reaction solution was cooled to 0 ° C. Z-L
A solution of proline methyl ester (30 mmol) in diethyl ether (50 mL) was added dropwise over 30 minutes, and the mixture was stirred overnight while gradually warming to room temperature. A 1N aqueous hydrochloric acid solution (200 mL) was added to stop the reaction, followed by extraction with diethyl ether. After washing the extract with saturated saline,
It was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain N- (Z)-(2S)-with a yield of 83%.
2- (Hydroxy-diphenylmethyl) pyridine was obtained.

[0039]

[Table 3]

(2S) -2- (Hydroxy-diphenylmethy) pyrrolid
ine: 10% palladium activated carbon (200 mg) in a THF solution (50 mL) of the above amino alcohol (20 mmol)
Was added and stirred at room temperature for 5 hours under a hydrogen atmosphere. After filtering off the palladium catalyst, the solvent was distilled off under reduced pressure, and the residue was recrystallized with hexane to give (2S) -2 as white crystals.
-(Hydroxy-diphenylmethyl) pyridine was obtained quantitatively.

[0041]

[Table 4]

(2S) -1-N-Pivaloyl-2- (diphenylmethanol) pyrrolidine: Under an argon atmosphere, a dichloromethane solution (5 mL) of (2S) -2- (hydroxy-diphenylmethyl) pyrrolidine (5 mmol) was brought to 0 ° C. After cooling, pivaloyl chloride (10 mmol) and pyridine (10 mmol) were added and stirred for 1 hour. After stopping the reaction by adding water, the mixture was extracted with dichloromethane. The extract was washed with a 1N aqueous solution of hydrochloric acid, water and saturated saline in this order, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain (2S) -1-N-pivaloyl-2- (diphenylmethanol) pyridine at a yield of 80%.

[0043]

[Table 5]

(2S) -1-N-Pivaloyl-2- (methoxy-diphenylm
ethyl) pyrrolidine: THF solution of (2S) -1-N- (pivaloyl-2- (diphenylmethanol) pyrrolidine (2 mmol) (5
mL), potassium tert-butoxide (4 mmol) and methyl iodide (4 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After adding water, the mixture was extracted with dichloromethane and washed with saturated saline. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain (2S) -1-N-pivaloyl-2- (methoxy) with a yield of 84%. -Diphenylmethyl) prolysine was obtained. Recrystallization from hexane gave white crystals.

[0045]

[Table 6]

(B) Asymmetric Michael Addition Reaction Using (2S) -1-N-pivaloyl-2- (methoxy-diphenylmethyl) prolidine (ligand 6) synthesized by the above procedure, Similarly, a chiral metal catalyst was prepared, and an asymmetric Michael addition reaction was performed using various thiol compounds.

The results are shown in the following table. In Entry 2, it can be seen that excellent results with a yield of 92% and 71% ee were obtained.

[0048]

[Table 7]

<Example 3> In the case where the chiral metal catalyst of the present invention was used and the case where no catalyst was used, H _f (OT
_f ) The reaction was performed when only ₄ was used, and further, when only the ligand was used.

The results are shown in the following table. H _f (OT _f )
_It can be seen that the reaction was accelerated in the chiral metal catalyst of the present invention to which the ligand was added, as compared with the reaction of only ₄ .

[0051]

[Table 8]

Example 4 The following formula was used as a ligand:

[0053]

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An asymmetric synthesis reaction was carried out using (2S) -1-N-adamantanoyl-2- (diphenylmethoxy) methylpyrrolidine (ligand 11) represented by the following formula:

The results are shown in the following table.

Although the reaction yield was slightly lowered, the optical yield was greatly improved. From this, it was confirmed that stereoselectivity was improved by partially converting the ligand structure.

[0057]

[Table 9]

<Example 5> In Example 4, thiophenol (PhSH) and Ph-CH = CH-C were added to the N atom.
When reacted with an O-linked oxazolidinone compound, 3-phenylthio-butanoyloxazoline-2 was obtained.
-One was obtained with a yield of 73% and 43% ee.

[0059]

As described in detail above, according to the invention of the present application, the reaction operation can be performed easily and under mild conditions with good yield and optical selectivity, and the asymmetric reaction in the Michael addition reaction of thiol can be achieved. A new chiral metal catalyst which enables synthesis and a method for asymmetric Michael addition reaction of thiol using the same are provided.

 ──────────────────────────────────────────────────の Continued on the front page F term (reference) 4C056 AA01 AB01 AC02 AD01 AE02 BA01 BA10 BB04 BC05 4C069 AA05 BB02 BB16 CC16 4G069 AA06 BA21A BA21B BA27A BA27B BC50A BC51A BC52A BC52B BE19A BE19B BE20B BEB37B CB59 DA02 4H039 CA61 CF10

Claims (5)

[Claims] 1. A metal compound represented by the following formula: M (OR _f ) ₄ (where M represents a metal element and R _f represents a fluorinated alkylsulfonyl group);
The following formula: (Wherein R ¹ , R ² , R ³ and R ⁴ each represent a hydrocarbon group which may have a substituent) and a chiral prolinol compound represented by the formula: . 2. The chiral metal catalyst according to claim 1, wherein the metal element is H _f , T _i or Zr. ^3. The hydrocarbon group for R ¹ , R ² and R ³ is
3. The chiral metal catalyst according to claim 1, which is one of a branched aliphatic hydrocarbon group, a monocyclic or polycyclic alicyclic hydrocarbon group and an aromatic hydrocarbon, respectively. 4. The chiral metal catalyst according to claim 1, wherein the hydrocarbon group of R ⁴ is one of aliphatic hydrocarbon groups. 5. A method for asymmetric Michael reaction of a thiol using the chiral metal catalyst according to any one of claims 1 to 4, wherein the α, β-unsaturated carbonyl compound and the thiol compound are reacted in the presence of the catalyst. Asymmetric thiol Michael addition reaction method comprising reacting and asymmetrically synthesizing a thiol addition compound.