WO2006080576A1

WO2006080576A1 - METHOD FOR ASYMMETRIC ALLYLATION OF α-IMINO ACID

Info

Publication number: WO2006080576A1
Application number: PCT/JP2006/301920
Authority: WO
Inventors: Shu Kobayashi
Original assignee: Japan Science And Technology Agency
Priority date: 2005-01-31
Filing date: 2006-01-31
Publication date: 2006-08-03
Also published as: JPWO2006080576A1; JP4714730B2

Abstract

A method for the asymmetric allylation of an α-imino acid, wherein an allylsilane compound is reacted with an an α-imino acid having a structure in which an oxycarbonyl group is bonded to a nitrogen atom of the imino group in the presence of a chiral copper catalyst. The above method can be suitably employed for synthesizing an optically active allylglycine analogue by the use of a practical catalytic asymmetric allylation reaction which uses non-expensive raw materials and gives a high reaction yield and high stereoselectivity under mild conditions.

Description

Akira Akira A method for asymmetric arylation of α-imino acids

【Technical field】

[0 0 0 1]

The present invention relates to a method for enantioselective allylation of optically active allylglycine analogues useful as raw materials for pharmaceuticals, agricultural chemicals, fragrances, catalysts, etc. or synthetic intermediates.

[Background]

[0 0 0 2]

Optically active α-amino acids occupy a valuable position as raw materials or synthetic intermediates for fan chemicals such as natural product synthesis and pharmaceuticals. Various synthetic methods have been studied so far, especially for optically active α-amino acids that are difficult to obtain from nature. Such optically active non-natural α-amino acid synthesis methods have been used for a long time, and are still widely used today: derivatization from naturally abundant optically active compounds, optical resolution by enzymes, optical activity This method is based on optical resolution using a recrystallization method after derivatization to a salt with an acidic compound. There were problems such as volume byproduct. In recent years, techniques for obtaining optically active α-amino acids with high asymmetric yields have been reported with the progress of asymmetric synthesis reactions (Non-patent documents 1 and 2). Among them, the catalytic asymmetric synthesis method is advantageous in terms of cost because it requires a small amount of metal catalyst and asymmetric ligand, and also from the viewpoint of reducing industrial waste, which has become a major issue in recent years. Expected and actively researched.

[0 0 0 3]

In addition, allylglycine, a kind of non-natural α-amino acid, Since it is a useful synthetic intermediate that can be derivatized in various ways by chemical conversion of the double bond, its asymmetric synthesis method has been studied for a long time. In particular, asymmetric arylation reactions of α-iminoesters and N, Ο-acetals have recently attracted particular attention as methods for synthesizing optically active arylglycine analogs (Non-patent Documents 2 to 4).

[0 0 0 4]

However, as described above, many methods for catalytic asymmetric synthesis of optically active α-amino acids and araldaricin analogs as one of them have been proposed, but few have been put to practical use so far. . The reason is that the yield and stereoselectivity are insufficient, the catalyst is expensive (uses a precious metal catalyst), and the rotation (reuse rate) of the catalyst is low (reduction of the amount of catalyst). There are various problems such as severe reaction conditions (reaction temperature is 1 78, etc.) and low generality of substrates. Furthermore, in the case of synthesis of allyldaricin by asymmetric allylation reaction of imino ester, there is a problem that it is generally difficult to remove a substituent on the α-amino group of the produced allylic glycine derivative. That is, the tosyl group and the acyl group are often used as substituents for the nitrogen atom of the raw material imino ester, and since these removal conditions are harsh, it has been an obstacle when the amino group is converted to unprotected allylglycine.

[0 0 0 5]

On the other hand, the present inventors have developed many asymmetric reaction catalysts and asymmetric reaction methods. Among them, asymmetric catalysts prepared from Lewis acid metals and chiral diamine ligands effectively catalyze asymmetric nucleophilic addition reactions to aldehyde diamines, resulting in high yields and high stereoselective optical activity. (Patent Document 1) (Non-Patent Documents 5 to 9).

[Non-Patent Document 1] Bloch, R.. CheiL Rev. 98, 1407, 1998

[Non-Patent Document 2] Ferrr is, D .; Dudding, T .; Young, B; Druty I I I, W. J .;

Lec tka, T., J. Org. Chem. 64, 2 168, 1999 [Non-Patent Document 3] Ferraris, D .; Young, B; Cox, C .; Dudding, T ,;

III, W. J .; Ryzhkov, L .; Taggi, A. E .; Lecktka., T. J.

Am. Chem. Soc. 124, 67, 2002

[Non-Patent Document 4] Fang, X .; Johannsen,.; Yao, S .; Gathergood, N .;

Hazel 1, R. G .; Jorgensen, K. A., J. Org. Chem. 64, 4844, 1999

[Non-Patent Document 5] Kobayashi, S .; Matsubara, R .; Nakamura, Y .;

Kitagawa, H .; Sugiura.M., J. Am. Chem. Soc. 125, 2507, 2003

[Non-Patent Document 6] Hamada, T .; Manabe, K .; Kobayashi, S., Angew. Chem.

Int. Ed, 42, 3927, 2003

[Non-Patent Document 7] Nakamura, Y .; Matsubara, R .; Kiyohara, H .;

Kobayashi, S .;, Org. Lett. 5, 2481, 2003 [Non-Patent Document 8] Matsubara, R .; Nakamura, Y .; Kobayashi, S.;, Angew.

Chem., Int. Ed. 43, 1679, 2004

[Non-Patent Document 9] Matsubara, R .; Paulo, V .; Nakamura, Y .; Kiyohara, H.

Kobayashi, S., Tetrahedron 60, 9769, 2004 [Patent Document 1] JP 2003-260363 A

DISCLOSURE OF THE INVENTION

[Problems to be solved by the invention]

[0 0 0 6]

Therefore, the present invention is based on the background as described above, and is based on the development history of the present asymmetric reaction catalyst and the asymmetric reaction method as described above and the knowledge obtained therewith. To provide a catalytic asymmetric allylation reaction method as a practical method for synthesizing optically active allylglycine analogs, which can obtain high reaction yield and stereoselectivity under mild reaction conditions using raw materials. Is an issue. [Means for Solving the Problems]

[00 0 7]

The present invention is characterized by the following in order to solve the above problems.

[000 8]

First: Synthesis of optically active allyldaricin analogs by reacting α-imino acids with an oxycarbonyl group bonded to the nitrogen atom of the imino group in the presence of a chiral copper catalyst to synthesize optically active allyldaricin analogs Arylation reaction method.

[000 9]

Second: A chiral copper catalyst is an asymmetric allylation reaction method comprising a salt of an organic acid or an inorganic acid or a copper compound which is a complex or complex of this salt and a chiral diamine ligand.

[00 1 0]

Third: The chiral diamine ligand is an arylation reaction method having an ethylene diamine molecular structure as a part thereof.

[00 1 1]

Fourth: The following formula (1)

[Chemical 4]

0

(In the formula, R ¹ represents a hydrocarbon group which may have a substituent, R ² represents one OR, —SR or —NR ^a R ^b , and R has a substituent. And R ^a and R ^b each represents a hydrogen atom or a hydrocarbon group which may have a substituent)

Α-imino acids represented by the following formula (2) [0 0 1 2]

[Chemical 5]

(In the formula, R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a hydrocarbon group which may have a substituent, X represents a halogen atom, Represents an alkyl group or an alkoxy group)

The following formula (3A) (3 B) [00 1 3]

[Chemical 6]

(3 B)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above) An asymmetric allylation reaction method for synthesizing an optically active allylglycine analog represented by any one of the following:

[0 0 1 4] Fifth: In the above asymmetric arylation reaction method, R ¹ in formula (1) (3 A) (3 B) is a benzyl group, a trifluoromethyl group, a tertiary butyl group or a P-methoxybenzyl group. An asymmetric allylation reaction method which is a substituent selected from the group consisting of:

BEST MODE FOR CARRYING OUT THE INVENTION

[0 0 1 5]

The present invention has the features as described above, and an embodiment thereof will be described below.

Characteristic features of the present invention are as follows.

<A> A chiral copper catalyst is used in the reaction.

[00 1 6]

<B> α-Imino acids with an oxycarbonyl group bonded to the nitrogen atom of the imino group are used as reaction substrates.

A <C> aryl silane compound is reacted.

First, as for the chiral copper catalyst <A>, various types are considered in which a copper atom is indispensable for its constitution and a structure of a chiral organic molecule is added. Generally, it is composed of a copper compound and a chiral organic compound, but more practically, the reaction yield is

From the viewpoint of the selectivity, it is preferably considered to be composed of a copper compound and a chiral diamine ligand compound.

[00 1 7]

The copper compound may be selected from a variety of monovalent or divalent copper compounds such as salts, complex salts, and organic metal compounds. Among them, a salt with an organic acid or an inorganic acid, or a salt thereof. Organic complexes are preferable as the complex. Of these, salts with strong acids, for example, (per) fluoroalkylsulfonic acid, salts of perchloric acid, sulfuric acid and the like, and complexes thereof are exemplified as organic complexes. For example _{C u (OT f) 2,} C u C 10 4, C u C 10 4 · 4 CH 3 CN, C u (BF 4) 2 · XH 2 0 Hitoshidea Of these, Cu (OT f) ₂ is preferred.

[00 1 8]

As one chiral diamine ligand compound, a compound having an ethylene diamine structure as a part of the molecular structure is preferably used. In this case, the amino group may have an imine bond. For example, representative examples include various types of the following formula.

[00 1 9]

[Chemical 7]

Here, R in the formula represents a hydrocarbon group which may have a substituent, and the hydrocarbon group may be a chain or a cyclic group, and the substituent may be a halogen atom. In addition, it may have a hydrocarbon group such as an alkyl group or an alkoxy group. In addition, in P h (phenyl group) in the above formula, May also have a substituent.

[00 2 0]

Regarding the above-described chiral catalyst in the invention of this application, a complex may be prepared in advance from a copper compound and a chiral organic molecule and used as a catalyst, or a copper compound and a chiral organic molecule may be used in a reaction system. May be used in combination. Regarding the use ratio as a catalyst, it is considered that the ratio is usually about 0.5 to 30 mol% with respect to α-imino acids as a complex of a copper compound or a copper compound and a chiral organic molecule.

[00 2 1]

As the characteristic reaction substrate of the present invention, α-imino acid <Β> in which an oxyl group is bonded to the nitrogen atom of the imino group may be of various types. Those shown in (1) are shown. In this formula (1), the symbol R ¹ is a hydrocarbon group which may have a substituent. For example, it may be a chain or alicyclic hydrocarbon group, an aromatic hydrocarbon group, and various hydrocarbon groups as a combination thereof. As long as the substituent does not hinder the nucleophilic addition reaction, it has a hydrocarbon group such as an alkyl group, an alkoxy group, a sulfide group, a cyano group, a two-necked group, an ester group and the like as appropriate. Also good.

[00 2 2]

Specific examples of Ri include a benzyl group, a phenyl group, an ethyl group, a tertiary butyl group, a Me (methyl) group, a p-methoxybenzyl group, and a CF ₃ group. For example, when R ¹ is a benzyl group, the benzyloxycarbonyl group can be removed from the α-amino group by hydrogenolysis or using HB r Z acetic acid. In the case of tertiary butyl and ρ-methoxybenzyl, the tertiary butoxycarbonyl group or ρ-methoxybenzyloxycarbonyl group can be removed with an acid such as TFΑ. The symbol R ² is any one of —OR, — SR, —NR ^a R ^b as described above, and R is In the hydrocarbon group that may have a substituent, R ^a and R ^b each represent a hydrogen atom or a hydrocarbon group that may have a substituent. Among these, hydrocarbons that may have a substituent in R, R ^a , and R ^b are a chain or alicyclic hydrocarbon group, an aromatic hydrocarbon group, and various combinations thereof. It may be a hydrocarbon group. As a substituent, as long as the reaction of the present invention is not inhibited, various substituents such as a hydrocarbon group such as an alkyl group, an alkoxy group, a sulfido group, a cyano group, a nitro group, and an ester group may be appropriately included. Good.

[0 0 2 3]

By using the α-imino acids as described above, an asymmetric arylation reaction is realized, and in the optically active aryldaricin analog that is a product of the asymmetric arylation reaction, it binds to the nitrogen atom of the amino group. This oxycarbonyl group can be easily removed.

[0 0 2 4]

The gallium silane compound <C> may also be various, for example, those represented by the above formula (2). In this formula (2), R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen atoms or hydrocarbon groups which may have the same substituent as R ¹ described above. X is a halogen atom, an alkyl group, or an alcohol.

Of these, an alkyl group, particularly an alkyl group, particularly a lower alkyl group having about 1 to 6 carbon atoms, is considered suitable.

[0 0 2 5]

The asymmetric arylation reaction of α-imino acids of the present invention makes it possible to synthesize an optically active allylglycine analog represented by, for example, any one of the above formulas (3 Α) (3 、). For the asymmetric arylation reaction, an appropriate organic solvent such as halogenated hydrocarbon, diaryls, ethers and the like may be used, and the reaction temperature is appropriately in the range of about −40 to 40. Adopted. The atmosphere can be air or an inert atmosphere. The use ratio of the α-imino acids and the allylsilane compound as the reaction substrate can be appropriately set within a range of about 0.5 to 4.0 as a molar ratio.

[00 2 6]

In the reaction, it is also effective to carry out an acid treatment with TFΑ as a post-treatment.

Thereby, the silane group can be more effectively desorbed from the by-product added with the silane group.

Therefore, an example will be shown below and will be described in more detail. Of course, the following example

There is no limit.

【Example】

[00 2 7]

Example 1>

1) Synthesis of N- (benzyloxycarbonyl) imino ester

[Chemical 8]

Was synthesized according to Williams, RM; Aldous, DJ; Aldous, SCJ Org. Chem. 1990, 55, 4657.

Then the following reaction formula

[00 28]

[Chemical 9]

Then, piperidinomethyl polystyrene (3.50 mmol Zg, 216 mg, 0.80 mmo 1) was added to a solution of the above compound (0.4 mmo 1) in methylene chloride (4.0 mL) under an argon atmosphere. The mixture was stirred at room temperature for 10 minutes, then the stirring was stopped and the mixture was stopped for several minutes. As a result, the polymer was accumulated on top of the methylene chloride layer. From the bottom of the methylene chloride layer, using a gas syringe, a clear methylene chloride solution (2. OmL) of N- (benzyloxycarbonyl) iminoester was sucked and used as it was in the next reaction.

[0029]

2) Synthesis of optically active N- (benzyloxycarbonyl) arylglycine ester An asymmetric arylation reaction was performed according to the following reaction formula.

[Chemical formula 10]

^^ ^SiMe 3 (3.0 equiv)

slow a ton of iminoester

over 4 h

That is, divalent copper triflate (7.2 mg, 0.02 mmo 1), chiral diamine (10.8 mg, 0.0 0) synthesized by the method described in the literature (Non-patent Document 5) in an eggplant flask under argon. 2 2mmo 1) was weighed, and then tetradofuran (2. OmL) distilled as needed was added and stirred vigorously for several seconds (copper triflutter was completely dissolved, and the solution turned yellowish green). Stirring was stopped and molecular sieves 3 A (20. Omg) was added. Agitation was resumed and the suspension was cooled to zero. With a microsyringe, allyltrimethylsilane (0.62 mmo 1) was added, followed by tetrahydrofuran (1. OmL). Next, the methylene chloride solution (0.1 M, 2. OmL, 0.2 mMol) of the imino ester prepared in 1) above was added over 4 hours.

[0030]

1 After stirring for 5 minutes, saturated aqueous sodium hydrogen carbonate (8. OmL) was added and stirred vigorously. The mixture was extracted three times with methylene chloride, and the combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate.

[0 03 1]

After filtration, the solvent was distilled off, methylene chloride (2. OmL) was added to the resulting residue, and the solution was cooled to zero. Slowly trifluoroacetic acid (1.OmL) was added with vigorous stirring.

[00 3 2]

After 2 hours, saturated aqueous sodium hydrogen carbonate (8. OmL) was added and stirred vigorously. The mixture was extracted three times with methylene chloride, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel chromatography, to obtain the desired product (67% yield, 88% ee).

Example 2-4>

In the reaction 2) of Example 1, the same asymmetric arylation reaction was carried out by changing the addition time of the imino ester (Y) and the amount of chiral copper catalyst used, Optically active N- (benzyloxycarbonyl) aryl glycine ester was synthesized. The results are shown in Table 1.

[0 0 3 3]

【table 1】

Cu (OTf) ₂ diamine

Example Y (h) yield% ee%

(mmol%) (mmol%)

2 10 11 0.5 46 87

3 10 11 24 74 87

4 30 33 4 72 89

Example 5—8>

Under the same conditions as in Example 2, an asymmetric allylation reaction was carried out using various iminoesters represented by the above formula (1) and an arylating agent (2) to produce a photoactive allylglycine derivative (( 3 A) or (3 B)) was obtained. The results are shown in Table 2.

[Table 2]

(3A) or (3B) Yield (%) ee (%)

5 Bzl Et H H Me H Me 99 88

6 Boc ^a) Et HH SEt H Me 84 76

7 Boc Et H H SPh H Me 71 85

8 Teoc ^b) Et HH Me H Me 85 71 a) tert-Butoxycarbonyl group b) Trimethylsilylethoxycarbonyl group

【The invention's effect】

[0 034] According to the present invention, a raw material for pharmaceuticals, agricultural chemicals, fragrances, catalysts, etc. or an aryl metallicine analog useful as a synthetic intermediate, an inexpensive metal raw material, a high catalytic rotation, and a mild reaction condition Enables asymmetric synthesis. In addition, according to the present invention, by using a benzyl group, a trifluoromethyl group, a third butyl group, a p-methoxypentyl group or the like as the alkoxy group of the product N-alkoxycarbonylarylglycine ester, They are removed as normal amino protecting groups under mild conditions without side reactions such as racemization.

Claims

The scope of the claims

1. In the presence of a chiral copper catalyst, a photoactive allyldaricin analog is synthesized by reacting an α-imino acid with an oxycarbonyl group bonded to the nitrogen atom of the imino group with a allylic silane compound. —Method for asymmetric arylation of imino acids.

2. The chiral copper catalyst according to claim 1, wherein the chiral copper catalyst is composed of a salt of an organic acid or an inorganic acid, or a complex or complex of this salt, and a chiral diamine ligand. Chemical reaction method.

3. The method for asymmetric arylation according to claim 2, wherein the chiral diamine ligand has an ethylene diamine molecular structure as a part thereof.

4. The following formula (1)

[Chemical 1]

0

(In the formula, R ¹ represents a hydrocarbon group which may have a substituent, R ² represents —OR, —SR or —NR ^a R ^b , and R represents a substituent. And R ^a and R ^b each represents a hydrogen atom or a hydrocarbon group which may have a substituent)

In the α-imino acids represented by the following formula (2)

[Chemical 2]

Is reacted with a silane compound represented by the following formula (3A) (3 B)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above), an optically active arylglycine analog represented by any one of the following is synthesized: A method for asymmetric arylation according to any one of 1 to 3.

5. The method for asymmetric arylation according to claim 4, wherein R ¹ in the formula (1) (3A) (3 B) is a benzyl group, a trifluoromethyl group, a tert-butyl group or P-methoxybenzyl. A method for asymmetric arylation, which is a substituent selected from the group consisting of groups.