JP2007238525A - METHOD FOR PRODUCING OPTICALLY ACTIVE beta-HYDROXYIMINE COMPOUND - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a technique for carrying out an addition reaction of an enecarbamate with an aldehyde in high diastereoselectivity and high enantioselectivity. <P>SOLUTION: A method for producing an optically active β-hydroxyimine compound comprises carrying out the addition reaction of the enecarbamate with the aldehyde in the presence of a compound represented by formula (I) (wherein, Ar represents an aryl group which may have a substituent; R<SP>6</SP>sand R<SP>7</SP>represent each independently a hydrogen atom or an alkyl group or an aryl group which may have a substituent; and R<SP>6</SP>and R<SP>7</SP>together may form the same ring) and a rhodium complex. In the method for production, the optically active β-hydroxyimine compound can be produced under the high diastereoselectivity and good enantioselectivity. An asymmetric reaction can be carried out under relatively mild conditions such that the reaction can be conducted at about 0°C reaction temperature. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing an optically active β-hydroxyimine compound selectively using an asymmetric catalyst.

  The diastereoselective and enantioselective carbon-carbon bond formation reaction is one of important reactions in the fields of synthetic chemistry and medicinal chemistry, and many studies have been made so far. In such processes, aldol reactions have been developed in which substituted silyl enol ethers nucleophilically react with aldehydes, but syn-form products and anti-form products can be synthesized in a highly diastereoselective manner. It has been considered difficult (Patent Document 1, Patent Document 2).

  In recent years, in the asymmetric reaction with ethyl glyoxylate using a substituted enecarbamate as a nucleophile in the presence of a chiral diimine-copper catalyst, the product of the Z form ene carbamate to the syn form is changed from the E form of the encarbamate to the anti form. It has been found that the following products can be obtained with high diastereoselectivity and high enantioselectivity, respectively (Non-patent Document 3).

In recent years, asymmetric reactions using optically active P, N-ligands have been actively studied (Non-Patent Document 4), and are also derived from 1-phenylphosphorane-2-carboxylic acid by the present inventors. Catalytic asymmetric synthesis reactions using chiral ligands have been reported. (Non-Patent Document 5)
Mikami, K .; Matsukawa SJ Am. Chem. Soc., 116, 4077-4078 (1994). Evans, DA; Masse, CE; Wu, J. Org. Lett. 4, 3375-3378 (2002). Matsubara, R .; Vital, P .; Nakamura, Y .; Kiyohara, H .; Kobayashi, S. Tetrahedron, 60, 9769-9784 (2004). Tang, W .; Wang, W .; Zhang, X. Angew. Chem., Int. Ed. 42, 943 (2003). Sun, X .; Manabe, K .; Lam, WW? L .; Shiraishi, N .; Kobayashi, J .; Shiro, M .; Utsumi, H .; Kobayashi, S. Chem. Eur. J., 11, 361-368 (2005).

  The present invention provides a technique for performing a higher diastereoselective and higher enantioselective encarbamate and aldehyde addition reaction using a catalyst different from the conventional method.

  The present invention uses an optically active [phosphorus, nitrogen] -ligand and a rhodium complex to provide an optically active β-hydroxyimine compound with higher diastereoselectivity and higher enantioselectivity. The present invention relates to the following manufacturing method based on the finding that it can be manufactured.

  The present invention can produce an optically active β-hydroxyimine with high diastereoselectivity and good enantioselectivity. Also, the asymmetric reaction can be carried out under relatively mild conditions such as a reaction temperature of about 0 ° C.

  The β-hydroxyimine compound produced by the reaction of the present invention can be converted into an optically active β-hydroxycarbonyl compound by acid hydrolysis, or optically active 1,3-3- An amino alcohol compound can be obtained. Therefore, it is an important method as a process for producing such an optically active β-hydroxycarbonyl compound or an optically active 1,3-aminoalcohol compound.

ここで、式中のＲ^１及びＲ^２は水素原子又は置換基を有していてもよい炭化水素基又は複素環基を表し、Ｒ^３及びＲ^４は置換基を有していてもよい炭化水素基を表す。 The encarbamate used in the present invention is a compound having a structure represented by the following formula (III).

Here, R ¹ and R ² in the formula represent a hydrogen atom or a hydrocarbon group or a heterocyclic group which may have a substituent, and R ³ and R ⁴ may be a carbon atom which may have a substituent. Represents a hydrogen group.

  The hydrocarbon group which may have a substituent is an unsubstituted hydrocarbon group, or a heterocyclic group, a halogen, a carboxyl group, a hydroxyl group, an ester group, a nitro group, a cyano group, an ether group, a thiol group, an amide group. , A hydrocarbon group optionally having one or more substituents such as an amino group and a thioether group.

  The hydrocarbon group includes a linear or branched alkyl group having 10 or less carbon atoms (for example, a methyl group, an ethyl group, a propyl group, an i-propyl group, a butyl group, etc.), an alkenyl group (for example, an ethenyl group). 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group or 2-pentenyl group, alkynyl group (for example, ethynyl group, 2-propynyl group, 2-butynyl group) Group, 3-butynyl group, 2-methyl-3-butynyl group, phenylethynyl group, etc.), cycloalkyl group (such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group), or aryl group. it can.

  Such an encarbamate can be appropriately prepared or obtained by those skilled in the art with reference to the method of Matsubara et al. (Angew. Chem. Int. Ed. 43, 3258-3260 (2004).).

ここで、式中のＲ^５は置換基を有していてもよい炭化水素基、アシル基またはエステル基を示す。置換基を有していてもよい炭化水素基は前述の通りであり、置換基を有していてもよいアシル基とは、前記の様な置換基を一以上有していてもよい直鎖又は分岐鎖状の脂肪族アシル基を意味する。アシル基としては、例えばホルミル基、アセチル基、プロピオニル基、イソプロピオニル基、ブチリル基、ピバロイル基等を挙げることができる。また、置換基を有していてもよいエステル基とは、前記の様な置換基を一以上有していてもよいエステル基を意味する。 The aldehyde used in the present invention is a compound having a structure represented by the following formula (IV).

Here, R ⁵ in the formula represents a hydrocarbon group, an acyl group or an ester group which may have a substituent. The hydrocarbon group which may have a substituent is as described above, and the acyl group which may have a substituent is a straight chain which may have one or more substituents as described above. Alternatively, it means a branched aliphatic acyl group. Examples of the acyl group include formyl group, acetyl group, propionyl group, isopropionyl group, butyryl group, and pivaloyl group. Moreover, the ester group which may have a substituent means the ester group which may have one or more of the above substituents.

  A particularly preferred aldehyde is glyoxylate.

ここで、式中のＡｒは置換基を有していてもよいアリール基を表し、Ｒ^６及びＲ^７はそれぞれ独立して水素原子もしくは置換基を有していてもよいアルキル基又はアリール基を表し、またＲ^６とＲ^７は一緒になって一の環を形成してもよい。 The present invention is characterized in that the above addition reaction of enecarbamate and aldehyde is carried out in the presence of a compound represented by the following formula (I) and a transition metal complex.

Here, Ar in the formula represents an aryl group which may have a substituent, and R ⁶ and R ⁷ each independently represents a hydrogen atom or an alkyl group or aryl group which may have a substituent. R ⁶ and R ⁷ together may form a ring.

The alkyl group which may have a substituent is an alkyl group which may have a substituent as described above, and the ring formed by combining R ⁶ and R ⁷ is N, S, It is a 5-membered or 6-membered ring optionally containing a heteroatom selected from O, and the ring may further have a substituent as described above.

本発明では、上記式（Ｉ）で表される化合物のうち、次式（II）の構造を有する化合物とロジウム錯体との存在下で反応を行うことが好ましい。

本発明で使用するロジウム錯体は、１価のロジウム錯体である。本発明における好ましいロジウム錯体は、ビス（１，５−シクロオクタジエン）−μ，μ’−ジクロロ ジロジウム｛［RhCl(COD)］_２｝である。 The compound having the above structure is a so-called [phosphorus, nitrogen] -ligand, which can be synthesized based on the scheme represented by the following formula according to the method described in Non-Patent Document 5 described above. .

In the present invention, among the compounds represented by the above formula (I), the reaction is preferably performed in the presence of a compound having the structure of the following formula (II) and a rhodium complex.

The rhodium complex used in the present invention is a monovalent rhodium complex. A preferred rhodium complex in the present invention is bis (1,5-cyclooctadiene) -μ, μ′-dichloro dirhodium {[RhCl (COD)] ₂ }.

  The addition reaction of enecarbamate and aldehyde in the presence of the above [phosphorus, nitrogen] -ligand and rhodium complex is not particularly required to be carried out in a special solvent or atmosphere. Can be carried out under mild conditions such that the reaction proceeds at -20 ° C to 40 ° C. The mixing ratio of enecarbamate and aldehyde may be about 0.5 to 10 equivalents of aldehyde with respect to 1 equivalent of enecarbamate, and the mixing amount of [phosphorus, nitrogen] -ligand and rhodium complex is enecarbamate. What is necessary is just to select in the range of 0.5-10 mol% with respect to 1 equivalent.

  By the above method, an optically active β-hydroxyimine compound can be produced from encarbamate and aldehyde with high diastereoselectivity and high enantioselectivity.

またエンカルバメートが次式（VI−Ｂ）（Ｒ^１は水素原子以外を表す）で表されるＺ−体であるときは、次式（VII−Ｂ）（Ｘの定義は前記と同じ）で表されるａｎｔｉ−体のアルドール付加体が得られる。

この様にして得られる光学活性な１，３−イミノアルコールは、その後の酸加水分解により、光学活性なβ−ヒドロキシカルボニル化合物に変換することができる。あるいは酸加水分解の変わりに水添反応を行うことによって、光学活性な１，３−アミノアルコール化合物を得ることができる（下式）。

特にアルデヒドとしてグリオキシル酸エステルを利用した場合、本発明の方法による生成物は、光学活性なα−ヒドロキシ−γ−アミノ酸、又はα−ヒドロキシ−γ−ケト酸誘導体であり、これらは種々の生理活性物質の前駆体として有用である。 In the reaction according to the present invention, when the encarbamate is an E-form represented by the following formula (VI-A) (R ² represents other than a hydrogen atom), the following formula (VII-A) (X is imino). A syn-aldol adduct represented by the following formula is obtained as the main product.

When the encarbamate is a Z-form represented by the following formula (VI-B) (R ¹ represents other than a hydrogen atom), the following formula (VII-B) (the definition of X is the same as described above) The resulting anti-aldol adduct is obtained.

The optically active 1,3-iminoalcohol thus obtained can be converted into an optically active β-hydroxycarbonyl compound by subsequent acid hydrolysis. Alternatively, an optically active 1,3-aminoalcohol compound can be obtained by performing a hydrogenation reaction instead of acid hydrolysis (the following formula).

Particularly when glyoxylate is used as an aldehyde, the product of the method of the present invention is an optically active α-hydroxy-γ-amino acid or α-hydroxy-γ-keto acid derivative, which has various physiological activities. Useful as a precursor for materials.

  EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.

クロロ（１,５−シクロオクタジエン）ロジウム(I) ダイマー（2.4 mg、0.00493 mmol）（アルドリッチ）及び次式（IＸ）に示す構造を有する［リン、窒素］−配位子（2.9 mg、0.00985 mmol）をアルゴン雰囲気下室温でトルエン（1 ml）中2時間撹拌後、氷冷下20分間撹拌し、エチルグリオキシレート（80 mg、ポリマー型、４５〜５０％トルエン溶液、東京化成工業株式会社）のトルエン（0.5 ml）溶液を加え、更に氷冷下10分撹拌した。

その後、エンカルバメート（50 mg、0.197 mmol）のトルエン（0.5 ml）溶液を加え、氷冷下17時間半撹拌し、飽和炭酸水素ナトリウム水溶液を加えた。室温に戻した後、酢酸エチルで3回抽出し、有機相を飽和食塩水で1回洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、粗ヒドロキシイミン体を得た。

Chloro (1,5-cyclooctadiene) rhodium (I) dimer (2.4 mg, 0.00493 mmol) (Aldrich) and [phosphorus, nitrogen] -ligand (2.9 mg, 0.00985) having the structure shown in the following formula (IX) mmol) in toluene (1 ml) at room temperature under an argon atmosphere for 2 hours and then for 20 minutes under ice-cooling, ethyl glyoxylate (80 mg, polymer type, 45-50% toluene solution, Tokyo Chemical Industry Co., Ltd.) ) In toluene (0.5 ml) was added, and the mixture was further stirred for 10 minutes under ice cooling.

Thereafter, a toluene (0.5 ml) solution of encarbamate (50 mg, 0.197 mmol) was added, and the mixture was stirred for 17 and a half hours under ice cooling, and a saturated aqueous sodium hydrogen carbonate solution was added. After returning to room temperature, the mixture was extracted 3 times with ethyl acetate, and the organic phase was washed once with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude hydroxyimine compound.

The obtained residue was dissolved in ethanol (3 ml), 47% aqueous hydrobromic acid solution (0.3 ml) was added, and the mixture was stirred at room temperature for 90 seconds. Subsequently, a saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling, the mixture was returned to room temperature, and extracted three times with ethyl acetate. The organic phase was washed once with saturated brine and then dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was purified by preparative silica gel thin layer chromatography (developing solvent: benzene: acetone = 4: 1) to give (S) -ethyl 2- Hydroxy-4-oxo-4-phenylbutanoate formula (X) {(33.2 mg, 75.8% yield, 64.3% ee (S)} was obtained. Optical purity was determined by chiral HPLC. HPLC: Daicel Chiralpak ADH , hexane / ⁱ PrOH = 4/1, flow rate = 0.5 mL / min: t _R = 19.9 min (S), t _R = 22.2 min (R)

式（IＸ）に示した構造の配位子を式（ＸII）に示す化合物に変え（式中のＡｒは表１に示した構造である）、他の条件は実施例１と同様にして反応を実施した。ヒドロキシイミン体は単離せず、酸加水分解を行い化合物（Ｘ）を得た。

６種類の［リン、窒素］−配位子を用いて得られた(S)-エチル 2-ヒドロキシ-4-オキソ-4-フェニルブタナートの収率ならびに光学純度を表１に示す。

The ligand having the structure shown in formula (IX) is changed to the compound shown in formula (XII) (Ar in the formula is the structure shown in Table 1), and the other conditions are the same as in Example 1. Carried out. Hydroxyimine was not isolated, and acid hydrolysis was performed to obtain compound (X).

Table 1 shows the yield and optical purity of (S) -ethyl 2-hydroxy-4-oxo-4-phenylbutanate obtained using six kinds of [phosphorus, nitrogen] -ligands.

クロロ（１,５−シクロオクタジエン）ロジウム(I) ダイマー（2.4 mg、0.00493 mmol）、下記式（ＸIV）で表される構造を有する［リン、窒素］−配位子（2.9 mg、0.00985 mmol）をアルゴン雰囲気下室温でトルエン（1 ml）中2時間撹拌後、氷冷下20分間撹拌し、エチルグリオキシレート （80 mg、ポリマー型、４５〜５０％トルエン溶液、東京化成工業株式会社）のトルエン溶液（0.5 ml）を加え、更に氷冷下10分間撹拌した。

その後、エンカルバメート（50 mg、0.197 mmol）のトルエン(0.5 ml) 溶液を加え、氷冷下17時間半撹拌し、飽和炭酸水素ナトリウム水溶液を加えた。室温に戻した後、酢酸エチルで3回抽出し、有機層を飽和食塩水で1回洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、粗ヒドロキシイミン体を得た。

Chloro (1,5-cyclooctadiene) rhodium (I) dimer (2.4 mg, 0.00493 mmol), [phosphorus, nitrogen] -ligand (2.9 mg, 0.00985 mmol) having a structure represented by the following formula (XIV) ) In toluene (1 ml) at room temperature under an argon atmosphere for 2 hours, then stirred for 20 minutes under ice cooling, and ethyl glyoxylate (80 mg, polymer type, 45-50% toluene solution, Tokyo Chemical Industry Co., Ltd.) Toluene solution (0.5 ml) was added, and the mixture was further stirred for 10 minutes under ice cooling.

Thereafter, a toluene (0.5 ml) solution of encarbamate (50 mg, 0.197 mmol) was added, and the mixture was stirred for 17 hours and half under ice cooling, and a saturated aqueous sodium hydrogen carbonate solution was added. After returning to room temperature, the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed once with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude hydroxyimine compound.

This was dissolved in ethanol (3 ml), 47% aqueous hydrobromic acid solution (0.3 ml) was added, and the mixture was stirred at room temperature for 90 seconds. Subsequently, a saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling, the mixture was returned to room temperature, and extracted three times with ethyl acetate. The organic phase was washed once with saturated brine and then dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by preparative silica gel thin layer chromatography (developing solvent: benzene: acetone = 4: 1) to give (2S) -2-hydroxy which is a β-hydroxycarbonyl compound. -3-Methyl-4-oxo-4-phenylbutanoic acid ethyl ester was obtained as a diastereomeric mixture. The diastereomeric ratio and optical purity were determined by chiral HPLC. {(33.2 mg, 76% yield, syn / anti = 97/3, optical purity: 64% ee (syn)}. HPLC: Daicel Chiralpak ADH, hexane / ⁱ PrOH = 4/1, flow rate = 0.5 mL / min: t _R = 19.9 min (2S, 3S), t _R = 22.2 min (2R, 3R)
(2S) -2-Hydroxy-3-methyl-4-oxo-4-phenyl-butyric acid ethyl ester (5f, syn / anti mixture): ¹ H NMR syn (CDCl ₃ ) δ = 1.26 (t, 3H, J = 7.0 Hz), 1.29 (d, 3H, J = 7.0 Hz), 3.28 (br, 1H), 3.93 (dq, 1H, J = 4.2, 7.0 Hz), 4.25 (q, 2H, J = 7.0 Hz), 4.58 (d, 1H, J = 4.2 Hz), 7.40-7.65 (m, 3H), 7.90-8.05 (m, 2H); anti (CDCl ₃ ) δ = 1.20 (t, 3H, J = 7.1 Hz), 1.36 (d, 3H, J = 7.3 Hz), 3.61 (d, 1H, J = 8.3 Hz), 3.98 (dq, 1H, J = 4.6, 7.1 Hz), 4.10-4.25 (m, 2H), 4.39 (dd, 1H, J = 4.6, 8.3 Hz), 7.40-7.65 (m, 3H); ¹³ C NMR syn (CDCl ₃ ) δ = 12.1, 14.0, 44.3, 61.9, 71.6, 128.4, 128.7, 133.3, 135.7, 173.1, 201.6 ; anti (CDCl ₃ ) δ = 14.0, 14.1, 44.0, 61.5, 73.1, 128.3, 128.7, 133.4, 135.9, 173.1; IR (neat) syn 3480, 3063, 2978, 2936, 1734, 1678, 1596, 1579, 1449 , 1369, 1217, 1133, 1062, 1023, 1001, 975, 952, 862, 794, 708; anti 3481, 3059, 2981, 2941, 1738, 1685, 1588, 1454, 1372, 1255, 1209, 1144, 1092, 1024, 973, 701 cm ^-1 ; HRMS (FAB); Exact mass calcd for C ₁₃ H ₁₇ O ₄ [M + H] ⁺ , 237.1127. Found 237.1118 .; HPLC, Daicel Chiralcel AS + ADH + AD, hexane / ⁱ PrOH = 4/1, flow rate = 0.5 mL / min: t _R = 46.7 min (2S, 3S ), t _R = 50.6 min (2R, 3R), t _R = 54.3 min (2S, 3R), t _R = 61.9 min (2R, 3S).

Claims (6)

A method for producing an optically active β-hydroxyimine compound, wherein an addition reaction of an encarbamate and an aldehyde is carried out in the presence of a compound represented by the following formula (I) and a rhodium complex.

(In the formula, Ar represents an optionally substituted aryl group, R ⁶ and R ⁷ each independently represents a hydrogen atom or an optionally substituted alkyl group or aryl group, R ⁶ and R ⁷ may form the same ring together). The manufacturing method of Claim 1 whose compound represented by Formula (I) is a compound represented by the following Formula (II).

The production method according to claim 1, wherein the encarbamate is a compound represented by the following formula (III).

(Wherein R ¹ and R ² represent a hydrogen atom, an alkoxy group or an optionally substituted hydrocarbon group, and R ³ and R ⁴ represent an optionally substituted hydrocarbon group. To express). The manufacturing method of Claim 1 whose aldehyde is a compound represented by following formula (IV).

(In the formula, R ⁵ represents a hydrocarbon group, acyl group or ester group which may have a substituent). The manufacturing method of Claim 4 whose aldehyde is glyoxylic acid ester. The production method according to claim 1, wherein the rhodium complex is bis (1,5-cyclooctadiene) -μ, μ′-dichloro dirhodium.