JP2012210623A - METAL CATALYST AND METHOD FOR PRODUCING PHOTOACTIVE α-AMINO ACID DERIVATIVE - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a technique not needing externally added base when producing photoactive α-amino acid derivative.SOLUTION: A metal catalyst constitutes M(OR1)2 (M represents an alkaline earth metal element and R1 represents an alkyl group) and a ligand bonded to M, and is a compound of a structure represented by a following formula [I] or an enantiomer of the same. Here, R2 is an aliphatic hydrocarbon group or an aromatic hydrocarbon group, all the R2s may be the same or different; R3 is H, an aliphatic hydrocarbon group or an aromatic hydrocarbon group, all the R3 are the same or different; and R4 is a substituted group or a cyano group in which a bonding atom with H, an alkyl group, an aryl group or carbon is a hetero atom.

Description

  The present invention relates to an optically active α-amino acid derivative. In particular, it relates to a technique for producing optically active α-amino acid derivatives. For example, it relates to a chiral calcium catalyst.

  In recent years, catalytic asymmetric 1,4-addition reactions using glycine ester derivatives and α, β-unsaturated carbonyl compounds have attracted attention. This is because, in the catalytic asymmetric reaction, an optically active glutamic acid derivative is obtained, and highly efficient synthesis of optical isomers that are difficult to supply from nature is possible by appropriate selection of optically active ligands.

Regarding glycine ester derivatives, Sorensen used the following compounds for DL-α-amino acid synthesis in 1903 (Figure 3-1-1), and several Schiff base derivatives have been synthesized. However, many of them are unstable compounds and require a strong base such as LDA for enolization. However, in 1978, O'Donnell et al. Synthesized a more stable glycine Schiff base derived from benzophenone rather than an unstable aldehyde-derived imine, and phase transfer utilizing the characteristics of the glycine Schiff base compound that is stable even in aqueous solution. A two-phase reaction using a catalyst has been developed (Scheme3-1-7). Since this research was published, this stable benzophenone-derived glycine ester derivative has been used by many researchers in various reactions including asymmetric alkylation.

  In recent years, many optically active phase transfer catalysts have been developed and developed into catalytic asymmetric alkylation reactions and the like. In the alkylation reaction, glycine is used to make other amino acid ester derivatives regardless of the D and L forms, and it has been characterized that various reaction systems have been constructed. On the other hand, the following catalyst systems in the catalytic asymmetric 1,4-addition reaction have already been developed.

Corey et al. Announced a catalytic asymmetric alkylation reaction of a glycine ester derivative in 1997 using a catalyst derived from cinchonidine, and reported the catalytic asymmetric 1,4-addition reaction in 1998 the following year ( Scheme3-1-8). Although there are few reaction examples, high enantioselectivity is expressed.

In addition, Ishikawa et al. And O'Donnell et al. Reported similar catalytic asymmetric 1,4-addition reactions in succession in 2001. In particular, the report of Ishikawa et al. Uses a catalyst having a guanidine moiety, and the reaction proceeds with a catalytic amount of base, although the substrate must be used in excess. The reaction time is from half a day to a week or so, but it is an interesting report. On the other hand, Shibasaki et al. Reported a relatively good result (Scheme3-1-9), using a new catalyst derived from tartaric acid having two cationic quaternary ammonium moieties. .

Arai et al. Reported an asymmetric reaction using a unique cationic quaternary ammonium catalyst. In 2002, only one example was reported, but the reaction proceeded with only a catalytic amount of base, and the reaction proceeded with moderate enantioselectivity. Thereafter, in 2006, a catalytic asymmetric 1,4-addition reaction using other α-amino acid ester derivatives other than glycine was reported. Although studies have been conducted using a relatively large number of substrates, most of them remain low in selectivity. On the other hand, Akiyama et al. Conducted an asymmetric reaction in 2003 using a catalyst prepared from a crown ether and an alkali metal, and reported a relatively high enantioselectivity in 6 reports. The substrate is also reported to be about 1.5 equivalents. In 2005, Lygo et al. Conducted a reaction using a unique quaternary ammonium phase transfer catalyst. Although only five cases were reported, high yield and high selectivity were realized (Scheme3-1-10) is doing.

  The above example is an example of prior research, and the problem of these reactions is that an excessive amount of substrate must be used in the reaction, and an excessive amount of base is required.

The reaction between azomethine ylide and alkene is one of the most efficient methods for synthesizing pyrrolidine compounds (Scheme 4-1-2 below).

This synthetic method has been extensively studied to understand the reaction pathways, selectivity and influence of Lewis acid metal. Among them, Kanemasa et al., In the reaction study of lithium enolates of N-alkylideneglycine derivatives and α, β-unsaturated esters, the reaction proceeds stepwise by computational chemistry using MNDO and PM3. I reported it in 1994 (Figure 4-1-4).

Here, first, the anti-selective 1,4-addition reaction becomes C via transition state B. From here, an intramolecular Mannich-type reaction proceeds via the transition state D to give the pyrrolidine compound E. The size of the energy B and D are feeling that steric bulk of the substituents R ^4, the transition state energy is different by a substituent R ^4.

In the field of reaction development, since diastereoselective reactions were reported by Padwa et al. (Schemes 4-1-3) in 1985, several diastereoselective reactions have been developed to synthesize optically active compounds. Has been proposed (Scheme4-1-4).

  In addition, examples of performing a diastereoselective reaction using a substrate having an asymmetric point toward the 1,3-dipole such as Husson et al., And an asymmetric auxiliary group at the alkene site as in Grigg et al. In some cases, the reaction is carried out by introducing a chiral auxiliary group.

As for asymmetric reactions, this is the first example of a reaction using a ligand derived from cobalt and optically active ephedrine by Grigg et al.
(Scheme4-1-5).

  This example of Grigg et al. Is an equivalent reaction, requires two equivalents of an optically active ligand relative to the metal, and requires a solvent amount of α, β-unsaturated ester for high enantioselectivity. Although there are some problems, the achievement of extremely high enantioselectivity and the possibility of enantioselective reaction is great. At the same time, Grigg et al. Report that manganese salts and silver acetate can also be used. In particular, in the case of silver acetate, it has been reported that enantioselectivity of 70% Ee is expressed by using a bidentate phosphine ligand. However, there is no disclosure about the equivalents and reaction conditions used.

On the other hand, as for catalytic asymmetric reaction, 2002 report using Zhang et al. With silver acetate and optically active bidentate phosphine ligand (Scheme4-1-6)
Is the first example.

In this report, it is said that azomethine compounds derived from various aromatic aldehydes and aliphatic aldehydes can be used, and the target product can be obtained with medium to high yield and enantioselectivity. Also, some α, β-unsaturated esters can be used, and the reaction has a wide variety of substrate generalities, but an externally added amine is required although it is a catalytic amount. Starting with this report, catalytic asymmetric reactions have been reported by several research groups (Schemes 4-1-7, 4-1-8).

  Jogensen et al. Reported in 2002 a catalytic asymmetric [3 + 2] cycloaddition reaction of an azomethine compound using zinc triflate and a neutral tert-uBox ligand. In this reaction, externally added triethylamine is essential. Schreiber et al. Reported a catalytic asymmetric reaction using silver acetate and QUINAP in 2003, and not only glycine ester derivatives but also other α-amino acid ester derivatives have moderate enantioselectivity. However, it is reported that it can be used. Komatsu et al. Reported that the reaction proceeds with high exo selectivity in a reaction system using copper triflate (II) and BINAP or SEGPHOS as optically active ligands. Jogensen et al. Reported a reaction system using an asymmetric base catalyst derived from silver fluoride and cinchonine in 2005, but the enantioselectivity remains moderate. Furthermore, in 2005, Zhang, Carretero et al. Reported a reaction system using a copper (I) perchlorate-ferrocene type optically active ligand, and showed that it has wide substrate generality. Has been. In these reaction systems, although high yield and high stereoselectivity are realized, an externally added amine is essential, and the reaction system is not always satisfactory from the viewpoint of atomic efficiency.

Under such circumstances, one reaction system (Scheme4-1-9) has recently been reported that does not require an externally added amine.

They found that when silver triflate was used as a catalyst, the enantioselectivity was high, but the reaction proceeded slowly, and at that time, an externally added amine had a reaction acceleration effect. In addition, when silver acetate is used, it has been found that the enantioselectivity is slightly reduced, but no amine is added externally and the reaction proceeds smoothly. In addition, it has been found that the yield and enantioselectivity are improved by using a ligand having an electron-withdrawing group as an optically active ligand, and the subtle Lewis acidity of the metal used greatly affects the reaction. Reporting that. Recently, an interesting result has been reported that the absolute configuration of the resulting product is reversed with respect to a ligand into which a hydrogen bonding site (—NH ₂ ) has been introduced while maintaining the absolute configuration of the optically active ligand. (Scheme4-1-10)

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As described above, in the techniques proposed so far, an externally added base is required, and there remains a problem that the generality of the substrate is not necessarily satisfied.
Therefore, the problem to be solved by the present invention is to provide a technique that does not require an externally added base and provides high enantioselectivity in the production of an optically active α-amino acid derivative.

By the way, the present inventor believes that if the alkaline earth metal alkoxide pulls out the active proton at the methylene crosslinking site of the optically active ligand, the metal and the ligand are bonded with a covalent bond radius, and two nitrogen atoms and We thought that a strong optically active metal complex bound in bidentate could be constructed. Furthermore, by using an alkaline earth metal, one of the two covalent bonds can be constituted as an optically active ligand and the other as an enolate component, which is considered to be a strong optically active enolate. Although such a complex itself is used as an optically active reagent in an equivalent reaction such as an alkylzinc reagent or a Grignard reagent, there are almost no examples of using it as a catalyst (Schemes 3-2-2, 3-2). -3).

Nakamura et al. Prepared a chiral allylzinc compound by deprotonating a methylene-bridged optically active Box ligand with n-butyllithium and then reacting it with an allylzinc compound, followed by cyclopropene ring-opening reaction and imine allylation reaction. Used for. Regarding the allylation reaction of imine, high stereoselectivity can be expressed by using cyclic imine.

  On the other hand, Hoffman et al. Prepared the desired optically active alkyl by reacting alkylmagnesium with the optically active Box ligand, directly preparing the optically active alkylmagnesium complex, and allowing alkyl iodide to act on it. A magnesium complex is obtained and this is allowed to act on benzaldehyde to obtain the target product with a moderate enantioselectivity.

As an example used as a catalyst, there is an example developed as a Lewis acid catalyst using magnesium, but there is no example of a carbon-carbon generation reaction used as a Bronsted base catalyst (Scheme 3-2-4) .

  On the other hand, complexes prepared from Group 3 lanthanides have been developed in recent years and have already been used as catalysts for alkenes amination reaction.

However, this reaction provides only moderate enantioselectivity (Scheme 3-2-5).

Typical papers other than these complex structures are as follows (Scheme 3-2-6).

Based on the above, the present inventor started a study using an alkaline earth metal alkoxide (Table 3-2-4).

  And after examining the kind of alkaline-earth metal alkoxide, it discovered that reaction advanced when Ca, Sr, and Ba were used. Among them, it has been found that when Ca, which is a particularly small metal, is used, and when calcium isopropoxide is used, the target product can be obtained with a good enantioselectivity of 73% Ee, although the yield is moderate. It was. The absolute configuration of the obtained product was determined by comparison with HPLC data described in the literature. Furthermore, in order to confirm whether or not the assumed catalyst structure is correct, since the enantioselectivity was not obtained at all in the examination using the normal neutral box ligand, the metal-anion type was used. It is presumed that the Box complex has the correct structure.

The present invention has been made based on the above findings.
That is, the above-described problem has M (OR ¹ ) ₂ (where M is an alkaline earth metal element and R ¹ is an alkyl group) and a ligand that binds to M of M (OR ¹ ) _2. ,
This is solved by a metal catalyst characterized in that the compound constituting the ligand is a compound having a biaryl skeleton or a bisoxazoline skeleton.

Also, M (OR ¹ ) ₂ (where M is an alkaline earth metal element and R ¹ is an alkyl group) and a compound constituting a ligand that binds to M of M (OR ¹ ) ₂ are mixed. Being
This is solved by a metal catalyst characterized in that the compound constituting the ligand is a compound having a biaryl skeleton or a bisoxazoline skeleton.

M (OR ¹ ) ₂ (where M is an alkaline earth metal element and R ¹ is an alkyl group) and a compound constituting a ligand that binds to M of M (OR ¹ ) ₂ are the former. : The latter = 1: 0.5 to 3 (more preferably 1: 1 to 2, especially 1: 1 to 1.5)
This is solved by a metal catalyst characterized in that the compound constituting the ligand is a compound having a biaryl skeleton or a bisoxazoline skeleton.

  Moreover, it is solved by the metal catalyst described above, which further has a molecular sieve.

In the above metal catalyst, M (OR ¹ ) ₂ is preferably an alkyl group having 1 to 10 carbon atoms in R ¹ (a linear or branched alkyl group). For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert-butyl group and the like. However, when a linear alkyl group is compared with a branched alkyl group, a branched alkyl group (having 3 or more carbon atoms) is preferable. Most preferred is an isopropyl group.

In the above metal catalyst, M (OR ¹ ) ₂ is an alkaline earth metal such as Ca, Mg, Sr or Ba. However, among these, Ca is most preferable.

That is, as M (OR ¹ ) ₂ , Ca (OiPr) ₂ is most preferable.

但し、式［Ｉ］中、Ｒ^２は脂肪族炭化水素基または芳香族炭化水素基で、全てのＲ^２は同一でも異なっていても良く、Ｒ^３はＨ若しくは脂肪族炭化水素基または芳香族炭化水素基で、全てのＲ^３は同一でも異なっていても良く、Ｒ^４はＨ、アルキル基、アリール基、炭素との結合原子がヘテロ原子である置換基またはシアノ基である。
尚、上記式［Ｉ］中でも、Ｒ^２は芳香族炭化水素基（中でも、特に、フェニル基）、Ｒ^３はＨ又は芳香族炭化水素基（中でも、特に、Ｈ又はフェニル基）で、Ｒ^４はＨである化合物が好ましい。 In the present invention, the compound constituting the ligand that forms a coordinate bond to M of M (OR ¹ ) ₂ is a compound having a biaryl skeleton or a bisoxazoline skeleton. Among such compounds, a preferable compound is a compound having a structure represented by the following formula [I] or an enantiomer thereof.
Formula [I]

However, in the formula [I], R ² is an aliphatic hydrocarbon group or an aromatic hydrocarbon group, all R ² may be the same or different, and R ³ is H, an aliphatic hydrocarbon group or an aromatic group. In the hydrocarbon group, all R ^{3 s} may be the same or different, and R ⁴ is H, an alkyl group, an aryl group, a substituent having a hetero atom as a bonding atom to carbon, or a cyano group.
In the above formula [I], R ² is an aromatic hydrocarbon group (in particular, a phenyl group), R ³ is H or an aromatic hydrocarbon group (in particular, H or a phenyl group), and R ⁴ A compound in which is H is preferred.

Moreover, as a preferable ligand, a compound having a structure represented by the following formula [II] or an enantiomer thereof may be mentioned.
Formula [II]

  The catalyst of the present invention is particularly a catalyst for the synthesis of optically active α-amino acid derivatives. For example, it is a catalyst used for reaction of the compound represented by the following formula [III] and the compound represented by the following formula [IV]. Or it is a catalyst used for reaction of the compound represented by the following formula [III], and the compound represented by the following formula [V]. Or it is a catalyst used for reaction of the compound represented by the following formula [VI], and the compound represented by the following formula [VII]. Or it is a catalyst used for reaction with the compound represented by the following formula [VIII], and the compound represented by the following formula [IX].

但し、式［ＩＩＩ］中、Ｒ^５はＨ、アルキル基またはアリール基（好ましくは、フェニル基）、Ｒ^６はＨ、アルキル基またはアリール基（好ましくは、フェニル基）、Ｒ^７はＨ、脂肪族炭化水素基または芳香族炭化水素基（好ましくは、Ｈ）、Ｒ^８は脂肪族炭化水素基（好ましくは、メチル基、エチル基、tert−ブチル基などの炭素数が１〜１０のアルキル基）である。 Formula [III]

In the formula [III], R ⁵ is H, an alkyl group or an aryl group (preferably a phenyl group), R ⁶ is H, an alkyl group or an aryl group (preferably a phenyl group), R ⁷ is H, an aliphatic group An aromatic hydrocarbon group or an aromatic hydrocarbon group (preferably H), R ⁸ is an aliphatic hydrocarbon group (preferably an alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a tert-butyl group, etc. ).

但し、式［ＩＶ］中、Ｒ^９は−ＣＯＯＲ（但し、Ｒは脂肪族炭化水素基（好ましくは、Ｒがメチル基、エチル基、プロピル基、イソプロピル基、tert−ブチル基などの炭素数が１〜１０のアルキル基）），−ＣＯＮ（Ｒ’）Ｒ’’（但し、Ｒ’，Ｒ’’は脂肪族炭化水素基（好ましくはメチル基またはエチル基、特に、メチル基）又は何れか一方がアルコキシ基），−ＳＯ_２Ｒ’’’
（但し、Ｒ’’’は脂肪族炭化水素基（好ましくは、Ｒがメチル基、エチル基、プロピル基、イソプロピル基、tert−ブチル基などの炭素数が１〜１０のアルキル基）又は芳香族炭化水素基（好ましくは、フェニル基））、Ｒ^１０はＨ，Ｘ（ハロゲン原子）、脂肪族炭化水素基（好ましくは、Ｒがメチル基、エチル基、プロピル基、イソプロピル基、tert−ブチル基などの炭素数が１〜１０のアルキル基）又は芳香族炭化水素基（好ましくは、フェニル基）である。 Formula [IV]

However, in the formula [IV], R ⁹ is —COOR (where R is an aliphatic hydrocarbon group (preferably R is a carbon group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group). 1 to 10 alkyl groups)), —CON (R ′) R ″ (where R ′ and R ″ are aliphatic hydrocarbon groups (preferably methyl groups or ethyl groups, particularly methyl groups) or any One is an alkoxy group), —SO ₂ R ′ ″
(Where R ′ ″ is an aliphatic hydrocarbon group (preferably R is an alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group) or an aromatic group. Hydrocarbon group (preferably phenyl group)), R ¹⁰ is H, X (halogen atom), aliphatic hydrocarbon group (preferably R is methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group) Such as an alkyl group having 1 to 10 carbon atoms) or an aromatic hydrocarbon group (preferably a phenyl group).

但し、式［Ｖ］中、Ｒ^９は−ＯＲ（但し、Ｒは脂肪族炭化水素基（好ましくは、Ｒがメチル基、エチル基、プロピル基、イソプロピル基、tert−ブチル基などの炭素数が１〜１０のアルキル基））又は−Ｎ（Ｒ’）Ｒ’’（但し、Ｒ’，Ｒ’’は脂肪族炭化水素基または芳香族炭化水素基（好ましくは、ジメチルアミノ基、ジシクロヘキシルアミノ基、ピペリジノ基、モルフォリノ基）、或いは何れか一方がアルコキシ基）、Ｒ^１０はＨ又は脂肪族炭化水素基（好ましくは、Ｒがメチル基、エチル基、プロピル基、イソプロピル基、tert−ブチル基などの炭素数が１〜１０のアルキル基）である。 Formula [V]

However, in formula [V], R ⁹ is —OR (where R is an aliphatic hydrocarbon group (preferably R is a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group or the like). 1-10 alkyl groups)) or -N (R ') R "(where R', R" are aliphatic hydrocarbon groups or aromatic hydrocarbon groups (preferably dimethylamino groups, dicyclohexylamino groups). R ¹⁰ is H or an aliphatic hydrocarbon group (preferably R is a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, etc.) Is an alkyl group having 1 to 10 carbon atoms.

但し、式［ＶＩ］中、Ｒａは炭化水素基または複素環基である。好ましくは芳香族基である。ＺはＳ又はＯである。Ｒｂは炭化水素基である。好ましくは脂肪族炭化水素基である。中でも、炭素数が１〜１０のアルキル基である。 Formula [VI]

However, in formula [VI], Ra is a hydrocarbon group or a heterocyclic group. An aromatic group is preferred. Z is S or O. Rb is a hydrocarbon group. An aliphatic hydrocarbon group is preferred. Especially, it is a C1-C10 alkyl group.

但し、式［ＶＩＩ］中、Ｒ^１，Ｒ^２はＨ又は炭化水素基である。炭化水素基は、好ましくは脂肪族炭化水素基である。中でも、炭素数が１〜１０のアルキル基である。Ｒ^３はアルコキシ基またはアミノ基である。 Formula [VII]

However, in the formula [VII], R ¹ and R ² are H or a hydrocarbon group. The hydrocarbon group is preferably an aliphatic hydrocarbon group. Especially, it is a C1-C10 alkyl group. R ³ is an alkoxy group or an amino group.

但し、式［ＶＩＩＩ］中、Ｒ^１はＨ又はアルキル基である。アルキル基の場合、好ましくは炭素数が１〜１０のアルキル基である。Ｒ^２は炭化水素基である。好ましくは炭素数が１〜１０のアルキル基である。 Formula [VIII]

However, in the formula [VIII], R ¹ is H or an alkyl group. In the case of an alkyl group, it is preferably an alkyl group having 1 to 10 carbon atoms. R ² is a hydrocarbon group. Preferably it is a C1-C10 alkyl group.

但し、式［ＩＸ］中、Ｒ^３は炭化水素基である。好ましくは炭素数が１〜１０のアルキル基である。 Formula [IX]

However, in the formula [IX], R ³ is a hydrocarbon group. Preferably it is a C1-C10 alkyl group.

In addition, the object is to react the compound represented by the formula [III] with the compound represented by the formula [IV] in the presence of the metal catalyst. It is solved by the method for producing amino acid derivatives.

In addition, the object is to react the compound represented by the above formula [III] with the compound represented by the above formula [V] in the presence of the above metal catalyst. This is solved by a method for producing an amino acid derivative.

Further, the above object is to provide an optically active α-characteristic comprising reacting a compound represented by the above formula [VI] with a compound represented by the above formula [VII] in the presence of the above metal catalyst. This is solved by a method for producing an amino acid derivative.

Further, the above object is to provide an optically active α-characteristic comprising reacting a compound represented by the formula [VIII] with a compound represented by the formula [IX] in the presence of the metal catalyst. It is solved by the method for producing amino acid derivatives.

  The above reaction is preferably performed at a temperature of -80 ° C to 20 ° C. More preferably, it is carried out at -45 ° C to 20 ° C. In particular, in the case of the reaction between the compound represented by the formula [III] and the compound represented by the formula [IV], −45 ° C. to 0 ° C. is preferable, and the compound represented by the formula [III] and the formula [III] In the case of the reaction with the compound represented by V], −30 ° C. to 20 ° C. is preferable.

  The above reaction is preferably carried out in a solvent. As the solvent, diethyl ether, tert-butyl methyl ether, toluene, methylene chloride, dimethoxyethane, acetonitrile or the like can be used. However, tetrahydrofuran was most preferred from the viewpoint of yield and selectivity.

  The amount of the catalyst used in the above reaction is preferably 0.1 to 20 mol% with respect to the substrate. Most preferably, it is 0.1-10 mol%.

In the above reaction, when a molecular sieve such as MS3A, MS4A, MS5A or the like is used in addition to a metal catalyst in which a compound having a biaryl skeleton or a bisoxazoline skeleton is coordinated to M (OR ¹ ) ₂ , a high yield is obtained.・ Selectivity was obtained. The amount of molecular sieve used is preferably 6 to 700 in weight / volume ratio with respect to the amount of solvent. More preferably, it is 30-140.

  An optically active α-amino acid derivative can be obtained with high yield and selectivity without requiring an externally added base. For example, a catalytic asymmetric Michael reaction (1,4-addition reaction) or [3 + 2] -cyclization reaction of a glycine derivative becomes possible, and an optically active α-amino acid derivative can be obtained efficiently.

  In addition, since Ca is used as a central metal, for example, there is also an advantage that it is an environment-friendly reaction as compared with a case where heavy metal such as copper is used.

  It is particularly useful in the field of fine chemicals such as pharmaceutical intermediates.

The catalyst of the present invention has M (OR ¹ ) ₂ (where M is an alkaline earth metal element and R ¹ is an alkyl group) and a ligand that binds to M of M (OR ¹ ) _2. It is. Such a catalyst comprises M (OR ¹ ) ₂ (where M is an alkaline earth metal element and R ¹ is an alkyl group) and a ligand that forms a coordinate bond with M of M (OR ¹ ) _2. Obtained by mixing with the compound to be obtained. For example, the former can be obtained by mixing at a ratio of 1: 0.5 to 3, particularly 1: 1 to 2, especially 1: 1 to 1.5. The compound constituting the ligand is a compound having a biaryl skeleton or a bisoxazoline skeleton. It also has a molecular sieve.

R ¹ of M (OR ¹ ) ₂ is, for example, an alkyl group having 1 to 10 carbon atoms (a linear or branched alkyl group). Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, and a tert-butyl group. Preferred groups are branched alkyl groups having 3 to 10 carbon atoms. In particular, an isopropyl group. M in M (OR ¹ ) ₂ is an alkaline earth metal such as Ca, Mg, Sr, or Ba, and is particularly Ca. Therefore, the most preferred M (OR ¹ ) ₂ is Ca (OiPr) ₂ .

A compound constituting a ligand that forms a coordinate bond to M in M (OR ¹ ) ₂ is a compound having a biaryl skeleton or a bisoxazoline skeleton. Among such compounds, a preferred compound is a compound having a structure represented by the above formula [I] or an enantiomer thereof. However, in the formula [I], R ² is an aliphatic hydrocarbon group or an aromatic hydrocarbon group, all R ² may be the same or different, and R ³ is H, an aliphatic hydrocarbon group or an aromatic group. In the hydrocarbon group, all R ^{3 s} may be the same or different, and R ⁴ is H, an alkyl group, an aryl group, a substituent having a hetero atom as a bonding atom to carbon, or a cyano group. Among the formulas [I], R ² is an aromatic hydrocarbon group (particularly, a phenyl group), R ³ is H or an aromatic hydrocarbon group (particularly, H or a phenyl group), and R ⁴ is H. Certain compounds are preferred. Moreover, the compound of the structure represented by said Formula [II], or its enantiomer is also mentioned as a preferable ligand.

The catalyst of the present invention is particularly a catalyst used for the synthesis of optically active α-amino acid derivatives. For example, it is a catalyst used for the reaction of the compound represented by the above formula [III] and the compound represented by the above formula [IV]. Or it is a catalyst used for reaction of the compound represented by said Formula [III], and the compound represented by said Formula [V]. Or it is a catalyst used for reaction of the compound represented by said formula [VI], and the compound represented by said formula [VII]. Or it is a catalyst used for reaction of the compound represented by said Formula [VIII], and the compound represented by said Formula [IX]. In the formula [III], R ⁵ is H or an aryl group (preferably a phenyl group), R ⁶ is H or an aryl group (preferably a phenyl group), R ⁷ is H, an aliphatic hydrocarbon group or an aromatic carbon group A hydrogen group (preferably H) and R ⁸ are an aliphatic hydrocarbon group (preferably an alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group and a tert-butyl group). In formula [IV], R ⁹ is —COOR (where R is an aliphatic hydrocarbon group (preferably R is a methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group or the like). 10 alkyl groups)), —CON (R ′) R ″ (where R ′, R ″ are aliphatic hydrocarbon groups (preferably methyl groups or ethyl groups, particularly methyl groups) or one of them is Alkoxy group), —SO ₂ R ′ ″
Where R ′ ″ is an aliphatic hydrocarbon group (preferably R is an alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group) or an aromatic group Any one selected from the group of hydrocarbon groups (preferably a phenyl group), wherein R ¹⁰ is H, X (halogen atom), an aliphatic hydrocarbon group (preferably R is a methyl group, an ethyl group, An alkyl group having 1 to 10 carbon atoms such as a propyl group, an isopropyl group, and a tert-butyl group) and an aromatic hydrocarbon group (preferably a phenyl group). In the formula [V], R ⁹ is —OR (where R is an aliphatic hydrocarbon group (preferably R is a methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group or the like). 10 alkyl groups)), —N (R ′) R ″ (where R ′, R ″ are aliphatic hydrocarbon groups or aromatic hydrocarbon groups (preferably dimethylamino group, dicyclohexylamino group, piperidino group). R ¹⁰ is H or an aliphatic hydrocarbon group (preferably, R is a methyl group, an ethyl group, a propyl group, an isopropyl group), or any one selected from the group of an alkoxy group). Group, an alkyl group having 1 to 10 carbon atoms such as a tert-butyl group). In the formula [VI], Ra is a hydrocarbon group such as an aliphatic hydrocarbon group or an aromatic hydrocarbon group or a heterocyclic group. An aromatic group is preferred. Z is S or O. Rb is a hydrocarbon group. An aliphatic hydrocarbon group is preferred. Especially, it is a C1-C10 alkyl group. In the formula [VII], R ¹ and R ² are H or a hydrocarbon group. The hydrocarbon group is preferably an aliphatic hydrocarbon group. Especially, it is a C1-C10 alkyl group. R ³ is an alkoxy group or an amino group. In the formula [VIII], R ¹ is H or an alkyl group. In the case of an alkyl group, it is preferably an alkyl group having 1 to 10 carbon atoms. R ² is a hydrocarbon group. Preferably it is a C1-C10 alkyl group. In the formula [IX], R ³ is a hydrocarbon group. Preferably it is a C1-C10 alkyl group.

  The method for producing an optically active α-amino acid derivative according to the present invention comprises reacting the compound represented by the above formula [III] with the compound represented by the above formula [IV] in the presence of the above metal catalyst. It is. Alternatively, it is a method in which the compound represented by the formula [III] is reacted with the compound represented by the formula [V] in the presence of the metal catalyst. Or it is the method of making the compound represented by the said formula [VI], and the compound represented by the said formula [VII] react in presence of said metal catalyst. Alternatively, in the presence of the metal catalyst, the compound represented by the formula [VIII] is reacted with the compound represented by the formula [IX]. This reaction is performed at a temperature of, for example, -80 ° C to 20 ° C. It is preferable to be performed at −45 ° C. to 20 ° C. In particular, in the case of the reaction between the compound represented by the formula [III] and the compound represented by the formula [IV], −45 ° C. to 0 ° C. is preferable, and the compound represented by the formula [III] and the formula [III] In the case of the reaction with the compound represented by V], −30 ° C. to 20 ° C. is preferable. The above reaction is preferably carried out in a solvent. A solvent is used in the reaction. A particularly preferable solvent is tetrahydrofuran from the viewpoint of yield and selectivity. The amount of the catalyst is, for example, 0.1 to 20 mol% with respect to the substrate. Particularly, it is 0.1 to 10 mol%. In the reaction, it is preferable to use molecular sieves such as MS3A, MS4A and MS5A in addition to the metal catalyst. In particular, the weight / volume ratio with respect to the amount of solvent is preferably 6 to 700, and more preferably 30 to 140.

This will be described in more detail below.
[Catalytic 1,4-addition reaction using M (OR ¹ ) ₂ ]
The reaction vessel heated and dried under reduced pressure was replaced with argon, and this reaction vessel was brought into a glove box, and 0.03 mmol of alkaline earth metal alkoxide and 100 mg of molecular sieve MS5A were weighed in.

  And the reaction container taken out from the glove box was stirred at room temperature.

  Thereafter, 0.5 mL of tetrahydrofuran (THF) was added at room temperature, and the mixture was stirred at the same temperature for 10 minutes.

  After stirring, a THF solution (1.0 mL) of glycine ester derivative (1b, 0.36 mmol) and methyl acrylate (0.30 mmol) were sequentially added at 0 ° C. Then, after stirring for 2 hours at the same temperature, saturated ammonium chloride solution (10 mL) was added with stirring at 0 ° C. to stop the reaction.

  Thereafter, methylene chloride (10 mL) was added for liquid separation, and extraction was performed three times with methylene chloride (20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The obtained crude product was filtered, concentrated under reduced pressure, and then purified by silica gel thin layer chromatography (Hexane: Ethyl acetate = 3: 1) to obtain the desired product.

[Catalytic 1,4-addition reaction using Ca (OiPr) ₂ ]
The reaction vessel heated and dried under reduced pressure was replaced with argon, and this reaction vessel was brought into a glove box, and 0.03 mmol of Ca (OiPr) ₂ and 100 mg of molecular sieve MS4A were weighed in.

  And the reaction container taken out from the glove box was stirred at room temperature.

  Thereafter, a solution of (S) -2,2'-Methylenebis (4-phenyl-2-oxazoline) in THF (0.5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours.

  After stirring, the reaction vessel was cooled to −30 ° C., and a THF solution (0.5 mL) of a glycine ester derivative (0.36 mmol) in THF (0.5 mL) and an α, β-unsaturated carbonyl compound (0.30 mmol). ) Were added sequentially. Then, after stirring for 12 hours at the same temperature, a saturated ammonium chloride solution (10 mL) was added with stirring at 0 ° C. to stop the reaction.

  This was followed by the addition of methylene chloride (10 mL), liquid separation, and extraction with methylene chloride (20 mL) three times. The organic layers were combined and dried over anhydrous sodium sulfate.

  The obtained crude product was filtered, concentrated under reduced pressure, and then purified by silica gel thin layer chromatography (Hexane: Ethyl acetate = 3: 1) to obtain the desired product.

The barium alkoxide, strontium alkoxide and magnesium alkoxide were purchased from High Purity Chemical Co., Ltd., and calcium isopropoxide (Ca (OiPr) ₂ ) was purchased from Aldrich in the glove box. Stored and used as is. Various optically active ligands are purchased from Aldrich or synthesized according to methods in known literature. The glycine ester derivative is synthesized according to a method in a known literature. Various α, β-unsaturated carbonyl compounds are purchased from Tokyo Chemical Industry Co., Ltd., purified by distillation. In addition, mass analysis of the obtained product was observed as a protonated product or a 2-aminopentane diester in which the ketoimine moiety was deprotected.

[Physical Properties of Catalytic Asymmetric 1,4-Addition Reaction Products Using Glycine Ester Derivatives]
dimethyl
2- (diphenylmethyleneamino) pentanedioate
IR [cm ^-1 ] 3361, 3060, 3026, 2952, 2845, 1968, 1905, 1741, 1659, 1623,
1598, 1576, 1491, 1442, 1362, 1280, 1158, 1074, 1030, 1004.
1H NMR (CDCl3) d 7.82-7.80 (m, 1H), 7.65-7.63
(m, 2H), 7.46-7.43 (m, 3H), 7.35-7.32
(m, 2H), 7.19-7.17 (m, 2H), 4.13 (t, 1H, J = 6.2 Hz), 3.71 (s, 3H), 3.58 (s, 3H), 2.38-2.35
(m, 2H), 2.26-2.23 (m, 2H).
13C NMR (CDCl3) d 173.4, 172.1, 171.2, 130.5, 130.1, 128.8, 128.7, 128.6,
128.3, 128.1, 127.8, 64.1, 52.2, 51.5, 30.3, 28.6.
HPLC, Daicel Chiralcel OD-H, Hexane / iPrOH = 40/1, Flow rate = 1.00 mL / min, Detection wavelength = 254 nm:
tR = 12.3 min (major), tR = 15.0 min (minor).
ESI-HRMS (m / z) calcd.for C20H22NO4 ((M + H) +): 340.1543; found: 340.1542.
(R) -1-tert-butyl 5-methyl
2- (diphenylmethyleneamino) pentanedioate
IR [cm ^-1 ] 3358, 2977, 2948, 1738,
1659, 1623, 1443, 1368, 1278, 1259, 1149.
1H NMR (CDCl3) d 7.82-7.80 (m, 1H), 7.65-7.63 (m, 2H), 7.50-7.43 (m, 3H), 7.34-7.31 (m, 2H), 7.18-7.17
(m, 2H), 3.96 (dd, 1H, J = 7.2, 5.2 Hz), 3.59 (s, 3H), 2.39−2.36 (m, 2H), 2.24−2.20
(m, 2H), 1.44 (s, 9H).
13C NMR (CDCl3) d 173.6, 170.7,
170.7, 130.3, 130.1, 128.8, 128.6, 128.4, 128.4, 128.0, 127.8, 81.2, 64.8,
51.5, 30.5, 28.6, 28.0.
HPLC, Daicel Chiralcel OD-H, Hexane / iPrOH = 40/1, Flow rate = 0.25 mL / min, Detection wavelength = 254 nm:
tR = 27.1 min (R), tR = 36.9 min (S).
ESI-HRMS (m / z) calcd.for C10H20NO4 ((MC ₁₃ H ₇ ) +): 218.1387; found: 218.1386.
(R) -1- tert-butyl
5-ethyl 2- (diphenylmethyleneamino) pentanedioate
IR [cm ^-1 ] 3367, 2979, 2931, 1734, 1659, 1599, 1449, 1370, 1316, 1279,
1154, 1030.
1H NMR (CDCl3) d 7.82-7.16
(m, 10H), 4.04 (q, 2H, J = 6.8 Hz), 3.96 (t, 1H, J = 6.0 Hz), 2.37−2.33
(m, 2H), 2.24−2.21 (m, 2H), 1.42 (s, 9H), 1.19 (t, 3H, J = 6.8 Hz).
13C NMR (CDCl3) d 173.1, 170.7,
170.6, 132.4, 130.0, 128.8, 128.5, 128.4, 128.2, 128.0, 127.7, 81.1, 64.8,
60.3, 30.7, 28.6, 28.0, 14.1.
HPLC, Daicel Chiralcel OD-H, Hexane / iPrOH = 40/1, Flow rate = 0.25 mL / min, Detection wavelength = 254 nm:
tR = 23.2 min (R), tR = 28.5 min (S).
ESI-HRMS (m / z) calcd.for C11H22NO4 ((M-C13H7) +): 232.1543; found: 232.1541.
di-tert-butyl 2- (diphenylmethyleneamino)) pentanedioate
IR [cm ^-1 ] 2978, 1730, 1660, 1622, 1450, 1368, 1278,
1254, 1152
1H NMR (CDCl3) d 7.82-7.16
(m, 10H), 3.95 (t, 1H, J = 6.4 Hz), 2.37−2.17 (m, 4H), 1.44 (s,
9H), 1.39 (s, 9H).
13C NMR (CDCl3) d 172.5, 170.9,
170.6, 132.4, 130.1, 128.8, 128.5, 128.4, 128.3, 128.0, 127.8, 81.1, 80.2,
65.0, 32.0, 28.9, 28.0, 27.4.
HPLC, Daicel Chiralcel OD-H, Hexane / iPrOH = 40/1, Flow rate = 0.25 mL / min, Detection wavelength = 254 nm:
tR = 18.6 min (major), tR = 23.3 min (minor).
ESI−HRMS (m / z) calcd.for C26H34NO4 ((M + H) +):
424.2482; found: 424.2478.
tert-butyl2- (diphenylmethyleneamino) -5- (methoxy (methyl) amino) -5-oxopentanoate
IR [cm ^-1 ] 3253, 2979, 1737,
1661, 1449, 1365, 1315, 1279, 1222, 1148.
1H NMR (CDCl3) d 7.58-7.57
(m, 2H), 7.36-7.35 (m, 3H), 7.32-7.29 (m, 1H), 7.25-7.23
(m, 2H), 7.11−7.09 (m, 2H), 3.93 (t, 1H, J = 5.5 Hz),
3.57 (s, 3H), 3.05 (s, 3H), 2.49−2.37
(m, 2H), 2.19−2.09 (m, 2H), 1.36 (s, 9H).
13C NMR (CDCl3) d 174.0, 171.0,
170.3, 139.5, 136.5, 130.2, 128.8, 128.5, 128.4, 127.9, 127.7, 81.0, 65.0,
61.1, 32.1, 28.5, 28.0, 27.9.
HPLC: Daicel Chiralpak OD-H, Hexane / iPrOH = 40/1, Flow rate = 1.00 mL / min,
Detection wavelength = 254 nm: tR = 12.8 min (major), tR = 37.7 min (minor).
ESI-HRMS (m / z) calcd.for C11H23N2O4 ((MC ₁₃ H ₇ ) +): 247.1652; found: 247.1657.
1-tert-butyl 5-methyl 2- (diphenylmethyleneamino) -4-methylpentanedioate
(major)
IR [cm ^-1 ] 3453, 2977, 1734, 1623, 1573, 1450, 1369, 1155.
1H NMR (CDCl3) d 7.61-7.60
(m, 2H), 7.40-7.35 (m, 4H), 7.31-7.29 (m, 2H), 7.16-7.14
(m, 2H), 3.93 (dd, 1H, J = 9.6, 4.1 Hz), 3.48 (s, 3H), 2.60−2.54
(m, 1H), 2.31-2.26 (m, 1H), 2.02-1.98 (m, 1H), 1.42 (s, 9H), 1.14 (d,
3H, J = 6.9 Hz).
13C NMR (CDCl3)
d
176.6, 171.0, 170.7, 139.6, 136.4, 130.2, 128.8, 128.6, 128.2, 128.0, 128.0,
81.1, 64.0, 51.4, 37.3, 36.2, 28.0, 18.4.
HPLC: Daicel Chiralpak OD-H, Hexane / iPrOH = 100/1, Flow rate = 0.50 mL / min,
Detection wavelength = 254 nm: tR = 13.6 min (major), tR = 15.5 min (minor).
ESI-RMS (m / z) calcd.forC11H22NO4 ((MC ₁₃ H ₇ ) +): 232.1543; found: 232.1552
1-tert-butyl5-methyl2- (diphenylmethyleneamino) -4-methylpentanedioate (major)
IR [cm ^-1 ] 3059, 2976, 2933,
2878, 1735, 1623, 1444, 1369, 1286, 1154, 1079.
1H NMR (CDCl3) d 7.63-7.62
(m, 2H), 7.44-7.35 (m, 4H), 7.31-7.29 (m, 2H), 7.20-7.18
(m, 2H), 3.92 (dd, 1H, J = 9.6, 5.5 Hz), 3.50 (s, 3H), 2.45−2.41
(m, 1H), 2.34-2.29 (m, 1H), 2.01-1.97 (m, 1H), 1.42 (s, 9H), 1.00 (d,
3H, J = 6.9 Hz).
13C NMR (CDCl3) d 176.7, 170.9,
170.6, 139.4, 136.4, 130.3, 128.8, 128.6, 128.4, 128.0, 127.9, 81.2, 64.1,
51.5, 37.1, 36.6, 28.0, 17.0.
HPLC: Daicel Chiralpak OD-H, Hexane / iPrOH = 100/1, Flow rate = 0.50 mL / min,
Detection wavelength = 254 nm: tR = 15.3 min (major), tR = 27.2 min (minor).
ESI−HRMS (m / z) calcd.for C11H22NO4 ((MC ₁₃ H ₇ ) +): 232.1543; found: 232.1534.
1-tert-butyl5-methyl2- (diphenylmethyleneamino) -4-ethylpentanedioat (major)
IR [cm ^-1 ] 2969, 2933, 1734,
1623, 1446, 1368, 1153.
1H NMR (CDCl3) d 7.55-7.54 (m, 2H), 7.34-7.29
(m, 4H), 7.25−7.23 (m, 2H), 7.10−7.09
(m, 2H), 3.82 (dd, 1H, J = 8.9, 3.4 Hz), 3.40 (s, 3H), 2.37−2.32 (m, 1H), 2.20−2.15
(m, 1H), 2.04−2.00 (m, 1H), 1.56−1.42
(m, 2H), 1.36 (s, 9H), 0.81 (t, 3H, J = 7.6 Hz).
13C NMR (CDCl3) d 176.1, 171.0, 170.7, 139.6, 136.4, 130.2, 128.8, 128.5,
128.2, 127.9, 127.9, 81.1, 64.0, 51.2, 43.4, 35.5, 28.0, 26.4, 11.7.
HPLC: Daicel Chiralpak OD-H, Hexane / iPrOH = 200/1, Flow rate = 0.30 mL / min, Detection wavelength
= 254 nm: tR =
71.1 min (minor), tR = 77.2 min (major).
ESI-HRMS (m / z) calcd.for C12H24NO4 ((MC ₁₃ H ₇ ) +): 246.1700; found: 246.1703.
1-tert-butyl5-methyl2- (diphenylmethyleneamino) -4-ethylpentanedioate (minor)
IR [cm ^-1 ] 2969, 2923, 1735, 1622,
1446, 1368, 1152.
1H NMR (CDCl3) d 7.62-7.60 (m, 2H), 7.45-7.41
(m, 3H), 7.37-7.34 (m, 1H), 7.31-7.28
(m, 2H), 7.20-7.18 (m, 2H), 3.90 (dd, 1H, J = 7.9, 5.8 Hz),
3.44 (s, 3H), 2.27-2.07 (m, 3H), 1.52-1.36
(m, 11H), 0.81 (t, 3H, J = 7.2 Hz).
13C NMR (CDCl3) d 176.1, 170.8, 170.4, 139.4, 136.5, 130.3, 128.8, 128.5,
128.4, 128.0, 127.9, 81.2, 64.7, 51.3, 44.3, 35.6, 28.0, 25.6, 11.6.
HPLC: Daicel Chiralpak OD-H, Hexane / iPrOH = 100/1, Flow rate = 0.30 mL / min, Detection wavelength
= 254 nm: tR =
26.9 min (major), tR = 47.7 min (minor).
ESI-HRMS (m / z) calcd.for C12H24NO4 ((MC ₁₃ H ₇ ) +): 246.1700; found: 246.1698.
1-tert-butyl5-methyl2- (diphenylmethyleneamino) -4-phenylpentanedioate (majar)
IR [cm ^-1 ] 3341, 2978, 1735, 1660,
1623, 1443, 1368, 1279, 1154.
1H NMR (CDCl3) d 7.54-7.53 (m, 2H), 7.38-7.30
(m, 4H), 7.25−7.23 (m, 2H), 7.13−7.11
(m, 2H), 4.47 (dd, 1H, J = 7.9, 5.8 Hz), 4.03 (t, 1H, J = 5.8 Hz), 3.54 (s,
3H), 2.65−2.60 (m, 1H), 2.46−2.42
(m, 1H), 1.36 (s, 9H).
13C NMR (CDCl3) d 171.5, 169.9, 169.7, 139.2, 136.0, 130.5, 128.8, 128.7,
128.4, 128.0, 127.7, 81.7, 62.8, 54.0, 52.8, 38.4, 28.0.
HPLC: Daicel Chiralpak AD-H, Hexane / iPrOH = 100/1, Flow rate = 1.00 mL / min, Detection wavelength
= 254 nm: tR =
8.7 min (major), tR = 9.9 min (minor).
ESI-HRMS (m / z) calcd.for C10H19ClNO4 ((MC ₁₃ H ₇ ) +): 252.0997; found: 252.0996.
1-tert-butyl5-methyl2- (diphenylmethyleneamino) -4-phenylpentanedioate (majar (2,4-syn)
IR [cm ^-1 ] 3438, 2980, 2936, 1730, 1625, 1446, 1369, 1352, 1292, 1237,
1214, 1156.
1H NMR (CDCl3) d 7.63-7.62 (m, 2H), 7.39-7.36
(m, 4H), 7.32-7.30 (m, 2H), 7.26-7.19
(m, 5H), 7.13-7.11 (m, 2H), 3.94 (dd, 1H, J = 7.6, 4.8 Hz),
3.76 (dd, 1H, J = 9.6, 4.8 Hz), 3.48 (s, 3H), 2.76−2.71 (m, 1H), 2.27−2.23
(m, 1H), 1.42 (s, 9H).
13C NMR (CDCl3) d 173.7, 170.8, 170.7, 139.5, 139.3, 136.2, 130.2, 128.8,
128.6, 128.5, 128.2, 127.9, 127.7, 127.7, 127.2, 81.2, 63.9, 51.8, 47.9, 37.2,
28.0.
HPLC: Daicel Chiralpak AD-H, Hexane / iPrOH = 200/1, Flow rate = 1.00 mL / min, Detection wavelength
= 254 nm: tR =
30.9 min (minor), tR = 33.1 min (major).
ESI-HRMS (m / z) calcd.for C16H24NO4 ((MC ₁₃ H ₇ ) +): 294.1700; found: 294.1695.
1-tert-butyl4- (N-methoxy-N-methylcarbamoyl) -2- (diphenylmethylenamino) pentanoate (majar)
IR [cm ^-1 ] 2974, 2934, 1730, 1660,
1450, 1153.
1H NMR (CDCl3) d 7.56 (m, 2H), 7.36-7.29
(m, 4H), 7.27-7.23 (m, 2H), 7.12-7.10
(m, 2H), 3.89 (dd, 1H, J = 7.6, 4.8 Hz), 3.57 (s, 3H), 3.09 (m, 1H), 3.02 (s,
3H), 2.35−2.31 (m, 1H), 1.92−1.88
(m, 1H), 1.38 (s, 9H), 1.06 (d, 3H, J = 7.6 Hz).
13C NMR (CDCl3) d 177.1, 171.4, 170.3, 139.8, 136.5, 130.0, 128.7, 128.5,
128.2, 127.8, 127.7, 80.8, 63.9, 61.2, 37.2, 31.9, 31.9, 27.9, 18.5.
HPLC: Daicel Chiralpak IA, Hexane / iPrOH = 40/1, Flow rate = 0.50 mL / min, Detection
wavelength = 254 nm: tR = 22.1 min (major), tR = 25.6 min (minor).
ESI−HRMS (m / z) calcd.for C12H25N2O4 ((MC ₁₃ H ₇ ) +): 261.1809; found: 261.1810.
tert-butyl
4- (phenylsulfonyl) -2- (diphenylmethyleneamino) butanoate
IR [cm ^-1 ] 3451, 3061, 2978, 1729,
1658, 1446, 1371, 1313, 1149, 1086.
1H NMR (CDCl3) d 7.83-7.82
(m, 2H), 7.75−7.73 (m, 1H), 7.59−7.23 (m, 10H), 7.06−7.04
(m, 2H), 3.93 (dd, 1H, J = 6.9, 4.8 Hz), 3.23−3.13 (m, 2H), 2.17−2.09
(m, 2H), 1.30 (s, 9H).
13C NMR (CDCl3) d 171.4, 169.8,
139.0, 138.8, 136.0, 133.6, 130.6, 130.0, 129.2, 128.8, 128.6, 128.1, 128.0,
127.6, 81.7, 63.5, 52.8, 27.9, 27.0.
HPLC: Daicel Chiralpak OD-H, Hexane / iPrOH
= 40/1, Flow rate = 1.00 mL / min: tR = 23.9 min (major), tR = 30.0 min (minor).
ESI−HRMS (m / z) calcd.for C14H22NO4S
((MC ₁₃ H ₇ ) +): 300.1264; found: 300.1278.

[Catalytic asymmetric [3 + 2] cycloaddition reaction using (Ca (OiPr) ₂ ]
The reaction vessel heated and dried under reduced pressure was replaced with argon, and this reaction vessel was brought into a glove box, and 0.03 mmol of Ca (OiPr) ₂ and 100 mg of molecular sieve MS4A were weighed into the reaction vessel.

  And the reaction container taken out from the glove box was stirred at room temperature.

  Thereafter, a solution of (S) -2,2'-Methylenebis (4-phenyl-2-oxazoline) in THF (0.5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours.

  After the stirring, the reaction vessel was cooled to 0 ° C., and a 0.33 mmol solution of an azomethine compound in THF (0.5 mL) and a 0.30 mmol solution of an α, β-unsaturated carbonyl compound in THF (0.5 mL). Were added sequentially. And it stirred at the same temperature for 3 hours. Thereafter, a saturated ammonium chloride solution (10 mL) was added under stirring at 0 ° C. to stop the reaction.

  This was followed by the addition of methylene chloride (10 mL), liquid separation, and extraction with methylene chloride (20 mL) three times. The organic layers were combined and dried over anhydrous sodium sulfate.

  The obtained crude product was filtered, concentrated under reduced pressure, and then purified by silica gel thin layer chromatography (Hexane: Ethyl acetate = 3: 1) to obtain the desired product.

The target product obtained by the above-described method is shown below (Table 4-2-5, 4-2-6, 4-2-7, 4-3-1, 4-3-2, Scheme 4-3-2. ). Enantioselectivity (Ee) was determined using HPLC.

The calcium isopropoxide Ca (OiPr) ₂ purchased from Aldrich was stored in a glove box and used as it was. Various optically active ligands are purchased from Aldrich or synthesized according to methods in known literature. The glycine ester derivative is synthesized according to a method in a known literature. Various α, β-unsaturated carbonyl compounds are purchased from Tokyo Chemical Industry Co., Ltd. and purified by distillation.

[Synthesis of azomethine ylide compounds]
(E) -methyl 2- (benzylideneamino) acetate
Bp 250 ℃ (0.8 mmHg, bulb-to-bulb)
IR [cm ^-1 ] 3366, 3061, 3030, 2951, 2882, 1963, 1741,
1646, 1601, 1582, 1493, 1435, 1376, 1272, 1204, 1093, 1026.
1H NMR (CDCl3) d 8.30 (s, 1H),
7.80-7.77
(m, 2H), 7.48-7.40 (m, 3H), 4.42 (s, 2H), 3.78 (s, 3H).
13C NMR (CDCl3) d 170.6, 165.5, 131.3, 135.5, 128.6, 128.5,
61.9, 52.2.
ESI−HRMS (m / z) calcd. For
C10H12NO2 ((M + H) +): 178.0863; found: 178.0869.
(E) -ethyl 2- (benzylideneamino) acetate
Bp 250 ℃ (0.8 mmHg, bulb-to-bulb)
IR [cm ^-1 ] 3364, 3062, 3029, 2982, 2935, 1964, 1890,
1740, 1646, 1601, 1582, 1492, 1451, 1374, 1337, 1268, 1188, 1095, 1028.
1H NMR (CDCl3) d 8.30 (s, 1H), 7.80-7.77 (m, 2H), 7.44-7.42 (m, 3H), 4.40
(s, 2H), 4.24 (q, 2H, J = 7.2 Hz), 1.31 (t, 3H, J = 7.2 Hz).
13C NMR (CDCl3) d 170.2, 165.4, 135.6, 131.2, 128.6, 128.5,
62.1, 61.1, 14.2.
ESI−HRMS (m / z) calcd. For
C11H14NO2 ((M + H) +): 192.1019; found: 192.1012.
(E) -tert-butyl 2- (benzylideneamino) acetate
Bp 250 ℃ (0.5 mmHg, bulb-to-bulb)
IR [cm ^-1 ] 3289, 3062, 2977, 2932, 2876, 1963, 1739,
1647, 1580, 1454, 1389, 1369, 1344, 1286, 1218, 1155, 1053.
1H NMR (CDCl3) d 8.26 (s, 1H), 7.79-7.77 (m,
2H), 7.43-7.40 (m, 3H), 4.31 (s, 2H), 1.49 (s, 9H).
13C NMR (CDCl3) d 169.3, 165.1,
135.6, 131.0, 128.5, 128.4, 81.4, 62.6, 28.0.
ESI−HRMS (m / z) calcd. For
C13H18NO2 ((M + H) +): 220.1332; found: 220.1328.
DL- (E) -methyl 2- (benzylideneamino) propanoate
Bp 240 ° C (0.8 mmHg, bulb-to-bulb).
IR [cm ^-1 ] 3385, 3061, 3027, 1987, 1950, 1872, 1961,
1742, 1643, 1579, 1493, 1450, 1383, 1341, 1268, 1205, 1175, 1126, 1050.
1H NMR (CDCl3) d 8.31 (s, 1H), 7.79-7.77 (m, 2H), 7.45-7.39 (m, 3H), 4.16
(q, 1H, J = 6.8 Hz), 3.75 (s, 3H), 1.53 (d, 3H, J = 6.8 Hz).
13C NMR (CDCl3) d 173.0, 162.9,
135.7, 131.1, 128.5, 128.4, 68.0, 52.2, 19.5.
ESI−HRMS (m / z) calcd. For
C11H14NO2 ((M + H) +): 192.1019; found: 192.1011.
DL − (E) −ethyl 2- (benzylideneamino) propanoate
Bp 250 ° C (0.7 mmHg, bulb-to-bulb).
IR [cm ^-1 ] 3454, 3062, 3027, 2983, 2936, 2872, 2051,
1964, 1893, 1821, 1738, 1644, 1579, 1450, 1382, 1335, 1291, 1262, 1190, 1125,
1048, 1021.
1H NMR (CDCl3) d 8.32 (s, 1H), 7.79-7.77 (m, 2H), 7.44-7.39 (m, 3H), 4.24-4.17 (m, 1H), 4.14
(q, 2H, J = 6.8 Hz), 1.53 (d, 3H, J = 6.9 Hz), 1.27 (t, 3H, J = 6.9 Hz).
13C NMR (CDCl3) d 172.5, 162.8, 135.8,
131.0, 128.6, 128.5, 68.0, 61.0, 19.4, 14.2.
ESI−HRMS (m / z) calcd. For
C12H16NO2 ((M + H) +): 206.1176; found: 206.1186.
DL − (E) −benzyl 2− (benzylideneamino) propanoate
Bp 300 ° C (0.6 mmHg, bulb-to-bulb)
IR [cm ^-1 ] 3450, 3062, 3031, 2983, 2936, 1873,
1960, 1741, 1643, 1580, 1495, 1452, 1379, 1334, 1260, 1178, 1123, 1046.
1H NMR (CDCl3) d 8.31 (s, 1H), 7.79-7.76 (m, 2H), 7.45-7.28 (m, 8H), 5.22-5.15 (m, 2H), 4.20
(q, 1H, J = 6.8 Hz), 1.54 (d, 3H, J = 6.8 Hz).
13C NMR (CDCl3) d 172.3, 162.9, 135.8, 135.7, 131.1, 128.6,
128.5, 128.4, 128.1, 128.0, 67.8, 66.6, 19.3.
ESI−HRMS (m / z) calcd. For
C17H18NO2 ((M + H) +): 268.1332; found: 268.1333.

[Physical properties of [3 + 2] cycloaddition reaction product]
(2R, 4R, 5S) -dimethyl 5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ]
3349, 2951, 1738, 1655, 1493, 1438, 1377, 1206, 1170, 1088, 1032.
1H NMR (CDCl3) d 7.36−7.22 (m, 5H), 4.54 (d, 1H, J = 7.6 Hz), 3.95 (t, 1H, J =
8.0 Hz), 3.83 (s, 3H), 3.33 (dt, 1H, J = 8.0, 7.6 Hz), 3.22 (s, 3H), 2.43 (dd,
(2H, J = 8.0, 8.0 Hz).
13C NMR (CDCl3) d 173.8, 173.1,
139.0, 128.2, 127.7, 126.6, 65.9, 60.0, 52.3, 51.3, 49.8, 33.4.
HPLC, Daicel Chiralpak AS, Hexane / iPrOH = 9/1, Flow rate = 1.00 mL / min, Detection wavelength = 220 nm: tR = 13.2 min (2S, 4S, 5R), tR = 21.6 min (2R, 4R, 5S ).
ESI−HRMS (m / z) calcd. For
C14H18NO4 ((M + H) +): 264.1230; found: 264.1290.
4-ethyl 2-methyl 5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ]
3341, 2953, 1735, 1653, 1452, 1378, 1201, 1093, 1034.
1H NMR (CDCl3) d 7.35−7.22 (m, 5H), 4.53 (d, 1H, J = 7.6 Hz), 3.98 (t, 1H, J =
8.2 Hz), 3.82 (s, 3H), 3.73-3.60 (m, 2H), 3.29
(dt, 1H, J = 7.6, 6.8 Hz), 2.41 (m, 2H), 0.82 (t, 3H, J = 7.2 Hz).
HPLC, Daicel Chiralcel OB-H, Hexane / iPrOH = 19/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 32.4 min (major), tR = 42.4 min (minor).
ESI−HRMS (m / z) calcd. For
C15H20NO4 ((M + H) +): 278.1387; found: 278.1403.
(2R, 4R, 5S) -4-tert-butyl 2-methyl 5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3749, 3341, 3029, 2977, 2952, 2372, 1738,
1454, 1370, 1250, 1210, 1151, 1095, 1026.
1H NMR (CDCl3) d 7.4−7.2 (m, 5H), 4.42 (d, 1H, J = 7.9 Hz), 3.91 (dd, 1H, J = 8.7, 8.3 Hz), 3.76 (s, 3H), 3.23 ( ddd, 1H, J = 7.9, 7.5, 6.8
Hz), 2.84 (br, 1H), 3.0−2.3 (m, 2H), 0.99 (s, 9H).
13C NMR (CDCl3) d 173.2, 171.4,
139.0, 128.0, 127.6, 126.8, 79.9, 65.5, 59.3, 51.6, 49.7, 33.6, 27.0.
HPLC, Daicel Chiralpak AS, Hexane / iPrOH
= 9/1, Flow rate = 1.00 mL / min, Detection
wavelength = 220 nm: tR =
6.8 min (2S, 4S, 5R), tR = 11.2 min (2R, 4R,
5S).
ESI−HRMS (m / z) calcd.for C17H24NO4 ((M + H) +):
306.1700; found: 306.1694.
2-tert-butyl 4-methyl 5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3749,
3349, 2978, 2376, 2307, 1733, 1454, 1370, 1250, 1204, 1155, 1036
1H NMR (CDCl3) d 7.32−7.23 (m, 5H), 4.53 (d, 1H, J = 7.8 Hz), 3.86 (t, 1H, J = 8.2
Hz), 3.32 (dt, 1H, J = 15, 7.8 Hz), 3.23 (s, 3H), 2.35 (m, 2H), 1.53 (s, 9H).
13C NMR (CDCl3) d 172.9, 172.5,
139.3, 128.2, 127.6, 126.8, 81.6, 65.9, 60.8, 51.2, 49.9, 33.6, 28.1.
HPLC, Daicel Chiralpak AD-H, Hexane / iPrOH = 19/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 27.2 min (minor), tR = 37.6 min (major).
ESI−HRMS (m / z) calcd. For
C17H24NO4 ((M + H) +): 306.1700; found: 306.1699.
di-tert-butyl 5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3281, 2973, 2374, 1725, 1704, 1454, 1370,
1288, 1253, 1217, 1151, 1105
1H NMR (CDCl3) d 7.36−7.21 (m, 5H), 4.46 (d, 1H, J = 8.0 Hz), 3.82 (t, 1H, J =
8.4 Hz), 3.25 (dt, 1H, J = 8.0, 6.8 Hz), 2.46−2.38
(m, 1H), 2.17-2.26 (m, 1H), 1.52 (s, 9H), 1.02 (s, 9H).
13C NMR (CDCl3) d 172.5, 171.9,
137.8, 128.1, 127.3, 127.2, 81.4, 80.5, 65.5, 60.7, 50.4, 34.5, 28.1, 27.5.
HPLC, Daicel Chiralpak ASx2, Hexane / iPrOH = 40/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 31.9 min (minor), tR = 36.9 min (major).
ESI−HRMS (m / z) calcd.for C20H30NO4 ((M + H) +):
348.2169; found: 348.2183.
dimethyl 3-methyl-5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3365,
3028, 2953, 2876, 2377, 2309, 1737, 1494, 1436, 1378, 1075, 1020
1H NMR (CDCl3) d 7.44−7.21 (m, 5H), 4.62 (d, 1H, J = 8.6 Hz), 3.83 (s, 3H), 3.55
(d, 1H, J = 8.7 Hz), 3.23 (s, 3H), 3.01 (dd, 1H, J = 8.6, 8.2 Hz), 2.72 (ddq, 1H, J = 8.7, 8.2, 6.6 Hz), 2.65
(br, 1H), 1.24 (d,
3H, J = 6.6 Hz).
13C NMR (CDCl3) d 173.7, 172.3,
140.0, 128.2, 127.6, 126.9, 67.3, 64.4, 58.3, 52.3, 51.3, 41.4, 17.8.
HPLC, Daicel Chiralpak AS, Hexane / iPrOH = 19/1, Flow rate = 0.25 mL / min, Detection wavelength = 220 nm: tR = 35.7 min (minor), tR = 46.9 min (major).
ESI−HRMS (m / z) calcd. For
C15H20NO4 ((M + H) +): 278.1386; found: 278.1390.
4-tert-butyl 2-methyl 3-methyl-5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3858, 3301, 3062, 3030, 2951,
2380, 2307, 1960, 1739, 1601, 1492, 1454, 1434, 1372, 1333, 1273, 1204, 1173,
1094, 1027.
1H NMR (CDCl3) d 7.45-7.20 (m, 5H), 4.55
(d, 1H, J = 8.6 Hz), 3.83 (s, 3H), 3.49 (d, 1H, J = 8.8 Hz), 2.9 (m, 2H), 2.65
(ddq, 1H, J = 8.8, 7.9, 6.7 Hz), 1.26 (d, 1H, J = 6.7 Hz), 1.02 (s, 9H).
13C NMR (CDCl3) d 173.5, 170.9,
140.2, 128.0, 127.3, 127.3, 80.4, 67.2, 64.1, 58.8, 52.1, 42.3, 27.4, 18.0.
HPLC, Daicel Chiralpak AS-H, Hexane / iPrOH = 19/1, Flow rate =
1.0 mL / min, Detection
wavelength = 220 nm: tR =
11.6 min (major), tR = 23.1 min (minor).
ESI−HRMS (m / z) calcd.for C18H26NO4 ((M + H) +):
320.1856; found: 320.1865.
2-tert-butyl 4-methyl 3-methyl-5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3749, 3652, 3363, 3062, 2975, 2877, 2376,
2298, 1734, 1602, 1496, 145, 1438, 1372, 1332, 1249, 1159, 1073, 1023.
1H NMR (CDCl3) d 7.32−7.23 (m, 5H), 4.60 (d, 1H, J = 8.6 Hz), 3.41 (d, 1H, J =
9.1 Hz), 3.24 (s, 3H), 3.01 (dd, 1H, J = 8.7, 8.6 Hz), 2.81 (br, 1H), 2.61−2.65 (m, 1H), 1.54 (s, 9H), 1.22 ( d, 3H, J = 6.7 Hz).
13C NMR (CDCl3) d 172.4, 172.2,
140.4, 128.2, 127.6, 126.9, 81.7, 67.9, 64.4, 58.2, 51.2, 41.6, 28.1, 17.6.
HPLC, Daicel Chiralpak AD-H, Hexane / iPrOH = 19/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 21.6 min (minor), tR = 24.9 min (major).
ESI−HRMS (m / z) calcd. For
C18H26NO4 ((M + H) +): 320.1856; found: 320.1847.
di-tert-butyl 3-methyl-5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3354, 3062, 2975, 2931, 2344, 1726, 1455,
1370, 1331, 1250, 1152, 1033.
1H NMR (CDCl3) d 7.36−7.22 (m, 5H), 4.54 (d, 1H, J = 8.6 Hz), 3.36 (d, 1H, J =
9.1 Hz), 2.91 (dd, 1H, J = 8.4, 8.4 Hz), 2.57 (ddq, 1H, J = 9.1, 8.6, 6.9 Hz),
2.85 (br, 1H), 1.24 (d, 3H, J = 6.9 Hz), 1.52 (s, 9H), 1.02 (s, 9H).
13C NMR (CDCl3) d 172.4, 171.0,
142.0, 128.1, 127.5, 127.4, 81.5, 80.5, 68.0, 64.2, 59.2, 42.8, 28.1, 27.5,
18.1.
HPLC, Daicel Chiralpak AD-H, Hexane / iPrOH = 19/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 35.2 min (major), tR = 56.7 min (minor).
ESI−HRMS (m / z) calcd. For
C21H32NO4 ((M + H) +): 362.2325; found: 362.2337.
2-tert-butyl 4-ethyl 3,5-diphenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3353,
3030, 2977, 2932, 2378, 1731, 1601, 1495, 1455, 1369, 1336, 1260, 1219, 1156,
1092, 1029
1H NMR (CDCl3) d 7.40−7.23 (m, 10H), 4.84 (d, 1H, J = 9.0 Hz), 3.90 (d, 1H, J =
9.6 Hz), 3.75 (dd, 1H, J = 9.2, 9.0 Hz), 3.65−3.52
(m, 3H), 2.92 (br, 1H), 1.34 (s, 9H), 0.78 (t, 3H, J = 7.1 Hz).
13C NMR (CDCl3) d 171.7, 171.4,
140.2, 139.9, 128.5, 128.2, 127.9, 127.7, 127.3, 127.0, 81.6, 68.6, 65.4, 60.3,
59.2, 53.2, 27.9, 13.6.
HPLC, Daicel Chiralcel OD-H, Hexane / iPrOH = 19/1, Flow rate = 0.50
mL / min, Detection wavelength
= 220 nm: tR =
17.4 min (minor), tR = 18.9 min (major).
ESI−HRMS (m / z) calcd.for C24H30NO4 ((M + H) +):
396.2169; found: 396.2180.
dimethyl 2-methyl-5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3360,
3028, 2951, 2379, 2344, 1734, 1604, 1495, 1437, 1376, 1259, 1202, 1134, 1087,
1031
1H NMR (CDCl3) d 7.31−7.21 (m, 5H), 4.66 (d, 1H, J = 7.6 Hz), 3.84 (s, 3H), 3.38−3.33 (m, 1H), 3.21 (s, 3H), 3.16 (br, 1H), 2.73 (dd, 1H, J
= 14, 5.3 Hz), 2.06 (dd, 1H, J = 14, 7.6 Hz), 1.51 (s, 3H).
13C NMR (CDCl3) d 176.6, 173.1,
139.1, 128.2, 127.6, 126.7, 65.8, 65.0, 52.6, 51.2, 50.6, 40.4, 27.6.
HPLC, Daicel Chiralpak AD-H, Hexane / iPrOH = 19/1, Flow rate = 0.25 mL / min, Detection wavelength = 220 nm: tR = 47.9 min (major), tR = 51.7 min (minor).
ESI−HRMS (m / z) calcd. For
C15H20NO4 ((M + H) +): 278.1386; found: 278.1445.
dimethyl 2,3-dimethyl-5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3365,
3062, 3028, 2951, 1955, 1733, 1603, 1494, 1437, 1378, 1256, 1195, 1118, 1027.
1H NMR (CDCl3) d 7.31-7.21 (m, 5H), 4.68 (d, 1H, J = 9.6 Hz), 3.82 (s, 3H), 3.17
(s, 3H), 3.12 (dd, 1H, J = 10.9, 9.6 Hz), 2.87 (br, 1H), 2.87 (dq, 1H, J =
10.9, 6.7 Hz), 1.35 (s, 3H), 1.10 (d, 1H, J = 6.7 Hz).
13C NMR (CDCl3) d 175.9, 172.1,
141.1, 128.1, 127.6, 127.3, 67.6, 62.5, 57.1, 52.5, 51.2, 42.7, 20.4, 13.8.
HPLC, Daicel Chiralpak AD-H, Hexane / iPrOH = 40/1, Flow rate = 0.25 mL / min, Detection wavelength = 220 nm: tR = 63.4 min (major), tR = 66.6 min (minor).
ESI−HRMS (m / z) calcd.for C16H22NO4 ((M + H) +):
292.1543; found: 292.1544.
4-tert-butyl 2-methyl 2-methyl-5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3357,
2976, 2359, 1731, 1452, 1369, 1295, 1254, 1213, 1148
1H NMR (CDCl3) d 7.33-7.21 (m, 5H), 4.61 (d, 1H, J = 7.9 Hz), 3.81 (s, 3H), 3.32
(ddd, 1H, J = 7.9, 7.8, 6.0 Hz), 3.18 (br, 1H), 2.62 (dd, 1H, J = 14, 6.0 Hz),
2.27 (dd, 1H, J = 14, 7.8 Hz), 1.49 (s, 3H), 1.01 (s, 9H).
13C NMR (CDCl3) d 176.4, 171.7,
139.5, 128.1, 127.3, 127.2, 80.5, 65.6, 64.4, 52.5, 50.8, 40.9, 27.5, 27.1.
HPLC, Daicel Chiralpak AD-H, Hexane / iPrOH = 19/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 14.6 min (major), tR = 17.3 min (minor).
ESI−HRMS (m / z) calcd. For
C18H26NO4 ((M + H) +): 320.1856; found: 320.1872.
4-tert-butyl 2-ethyl 2-methyl-5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3360,
3062, 2977, 2934, 1729, 1604, 1452, 1369, 1295, 1254, 1214, 1147, 1024
1H NMR (CDCl3) d 7.33−7.21 (m, 5H), 4.61 (d, 1H, J = 7.7 Hz), 4.29−4.24 (m, 2H), 3.33 (ddd, 1H, J = 7.8, 7.7, 6.2 Hz ), 3.21
(br, 1H), 2.62 (dd, 1H, J = 14, 6.2 Hz), 2.07 (dd, 1H, J = 14, 7.8 Hz), 1.49
(s, 3H), 1.32 (t, 3H, J = 7.1 Hz), 1.02 (s, 9H).
13C NMR (CDCl3) d 175.9, 171.7,
139.7, 128.1, 127.3, 127.3, 80.5, 65.5, 64.5, 61.3, 50.8, 40.9, 27.5, 27.1,
14.2.
HPLC, Daicel Chiralcel OD-H, Hexane / iPrOH = 19/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 13.4 min (minor), tR = 23.4 min (major).
ESI−HRMS (m / z) calcd. For
C19H28NO4 ((M + H) +): 334.2012; found: 334.2009.
2-benzyl 4-tert-butyl 2-methyl-5-phenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3358, 3062, 3031, 2975, 2934, 1953,
1728, 1604, 1496, 1453, 1370, 1254, 1215, 1147, 1082, 1028, 1000.
1H NMR (CDCl3) d 7.40-7.21 (m, 10H), 5.29-5.21 (m, 2H), 4.61
(d, 1H, J = 7.7 Hz), 3.32 (ddd, 1H, J = 7.8, 7.7, 6.0 Hz), 3.21 (br, 1H), 2.65
(dd, 1H, J = 14, 6.0 Hz), 2.07 (dd, 1H, J = 14, 7.8 Hz), 1.51 (s, 3H), 1.00 (s,
9H).
13C NMR (CDCl3) d 175.8, 171.7,
139.6, 135.9, 128.6, 128.2, 128.1, 128.1, 127.3, 127.2,
80.5, 66.9, 65.6, 64.5, 50.9, 40.8,
27.5, 27.3.
HPLC, Daicel Chiralcel OD-H, Hexane / iPrOH = 19/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 19.4 min (minor), tR = 30.0 min (major).
ESI−HRMS (m / z) calcd. For
C24H30NO4 ((M + H) +): 396.2169; found: 396.2178.
2-tert-butyl 4-methyl 3-methyl-5,5-diphenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3650, 3368, 3305, 3059, 2975, 2932, 2877,
2360, 1959, 1733, 1661, 1598, 1492, 1449, 1391, 1367, 1343, 1263, 1158, 1080,
1030.
1H NMR (CDCl3) d 7.8−7.1 (m, 10H), 3.68 (d, 1H, J = 6.4 Hz), 3.47 (br, 1H), 3.30
(m, 4H), 2.67 (ddq, 1H, J = 8.4, 6.8, 6.4 Hz), 1.51 (s, 9H), 1.05 (d, 3H, J =
(6.8 Hz).
13C NMR (CDCl3) d 173.5, 172.3,
146.4, 145.3, 132.4, 130.0, 128.3, 127.9, 126.9, 126.5, 81.4, 74.6, 66.4, 62.7,
51.4, 44.8, 28.1, 18.2.
HPLC, Daicel Chiralpak AD-H, Hexane / iPrOH = 40/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 12.6 min (minor), tR = 14.9 min (major).
ESI−HRMS (m / z) calcd. For
C24H30NO4 ((M + H) +): 396.2169; found: 396.2187.
2-tert-butyl 4-ethyl 3-methyl-5,5-diphenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3746,
3059, 2975, 2932, 1728, 1598, 1492, 1450, 1369, 1342, 1244, 1156, 1033.
1H NMR (CDCl3) d 7.8−7.1 (m, 10H), 3.7−3.8 (m, 2H), 3.67 (d,
1H, J = 5.8 Hz), 3.53 (br, 1H), 3.29 (d, 1H, J = 8.6 Hz), 2.65 (ddq, 1H, J =
8.6, 7.0, 5.8 Hz), 1.51 (s, 9H), 1.04 (d, 3H, J = 7.0 Hz), 0.88 (t, 3H, J = 7.1
Hz).
13C NMR (CDCl3) d 173.1, 172.3,
146.4, 145.4, 132.4, 130.1, 128.3, 127.9, 126.9, 126.5, 81.4, 74.7, 66.5, 62.9,
60.5, 45.2, 28.1, 18.5, 13.6.
HPLC, Daicel Chiralpak AD-H, Hexane / iPrOH = 19/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 17.8 min (minor), tR = 21.6 min (major).
ESI−HRMS (m / z) calcd. For
C25H32NO4 ((M + H) +): 410.2325; found: 410.2334.
di-tert-butyl 3-methyl-5,5-diphenylpyrrolidine-2,4-dicarboxylate
IR [cm ^-1 ] 3320, 30059, 2974, 2931, 2876, 2359,
1959, 1726, 1663, 1598, 1489, 1451, 1392, 1368, 1338, 1284, 1250, 1211, 1156,
1082, 1035.
1H NMR (CDCl3) d 7.8−7.1 (m, 10H), 3.58 (d, 1H, J = 5.2 Hz), 3.26 (d, 1H, J =
8.0 Hz), 2.56 (ddq, 1H, J = 8.0, 6.8, 5.2 Hz), 1.51 (s, 9H), 1.07 (s, 9H), 1.01
(d, 3H, J = 6.8 Hz).
13C NMR (CDCl3) d 172.4, 172.3,
146.3, 146.9, 132.4, 130.1, 128.4, 128.1, 126.7, 126.4, 81.2, 80.9, 74.6, 66.5,
64.0, 45.9, 28.1, 27.4, 19.2.
HPLC, Daicel Chiralpak AD-Hx2, Hexane / iPrOH = 19/1, Flow rate = 0.25 mL / min, Detection wavelength = 220 nm: tR = 30.7 min (minor), tR = 33.1 min (major).
ESI−HRMS (m / z) calcd. For
C27H36NO4 ((M + H) +): 438.2638; found: 438.2616.
tert-butyl 4- (dimethylcarbamoyl) -5,5-diphenylpyrrolidine-2-carboxylate
IR [cm ^-1 ] 3445, 3270, 2978, 2932,
1732, 1627, 1491, 1451, 1396, 1367, 1344, 1243, 1161,
1116.
1H NMR (CDCl3) d 7.58-7.57 (m, 2H), 7.27-7.06 (m, 8H), 4.08
(d, 1H, J = 6.2 Hz), 4.00 (m, 1H), 3.53 (m, 1H), 2.77 (s, 3H), 2.55 (s, 3H),
2.18 (dd, 1H, J = 12.7, 4.5 Hz), 2.12−2.08 (m, 1H), 1.43 (s, 9H).
13C NMR (CDCl3) d 173.7, 172.5,
145.0, 143.3, 128.4, 127.7, 126.9, 126.7, 126.7, 126.3, 81.0, 76.4, 59.2, 47.0,
37.6, 35.4, 35.1, 28.1.
HPLC, Daicel Chiralpak AD-H, Hexane / iPrOH = 19/1, Flow rate =
0.50 mL / min, Detection wavelength = 220 nm: tR =
12.7 min (major), tR = 19.9 min (minor).
ESI−HRMS (m / z) calcd. For
C24H31N2O3 ((M + H) +): 395.2329; found: 395.2338.
tert-butyl 4- (morpholine-4-carbonyl) -5,5-diphenylpyrrolidine-2-carboxylate
IR [cm ^-1 ] 3443, 2976, 2858, 1728,
1624, 1442, 1368, 1344, 1233, 1160, 1117, 1066, 1017.
1H NMR (CDCl3) d 7.65-7.64 (m, 2H), 7.36-7.34 (m, 2H), 7.27-7.17 (m, 6H), 4.10
(d, 1H, J = 6.9 Hz), 4.04 (brs, 1H), 3.61−3.23 (m, 8H), 3.12−3.03 (m, 2H), 2.30 (dd, 1H, J = 12.7, 4.5 Hz), 1.52 (s, 9H).
13C NMR (CDCl3) d 172.5, 172.4,
144.7, 142.7, 128.4, 128.0, 127.1, 127.0, 126.9, 126.6, 81.1, 76.2, 66.4, 66.0,
59.0, 46.6, 46.1, 41.6, 35.4, 28.1
HPLC: Daicel Chiralpak AD-H, Hexane / iPrOH = 9/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 19.4 min
(major), tR =
30.3 min (minor).
ESI−HRMS (m / z) calcd.for C26H33N2O4 ((M + H) +):
437.2435; found: 437.2436.
tert-butyl 5,5-diphenyl-4- (piperidine-1-carbonyl) pyrrolidine-2-carboxylate
IR [cm ^-1 ] 3271, 3064, 2973, 2933, 2859, 1735, 1619,
1448, 1366, 1338, 1286, 1247, 1223, 1158, 1117, 1029, 1009.
1H NMR (CDCl3) d 7.64-7.62 (m, 2H), 7.32-7.08 (m, 8H), 4.14
(d, 1H, J = 6.9 Hz), 4.12 (brs, 1H), 3.61−3.57 (m, 1H), 3.45−3.37 (m, 2H), 3.10−3.03 (m, 2H), 2.26−2.14 (m , 2H), 1.48 (s, 9H), 1.40−1.21 (m, 6H).
13C NMR (CDCl3) d 172.4, 172.0,
145.1, 143.3, 128.3, 127.8, 126.8, 126.7, 126.5, 126.5, 80.9, 76.2, 59.1, 46.8,
46.4, 42.3, 35.4, 28.1, 26.0, 25.0, 24.2.
HPLC: Daicel Chiralpak OD-H, Hexane / iPrOH = 100/1, Flow rate = 0.30 mL / min, Detection wavelength
= 220 nm: tR =
41.6 min (minor), tR = 47.7 min (major).
ESI−HRMS (m / z) calcd.for C27H35N2O3 ((M + H) +):
435.2642; found: 435.2652.
ert-butyl 4- (dicyclohexylcarbamoyl) -5,5-diphenylpyrrolidine-2-carboxylate
IR [cm ^-1 ] 3441, 2928, 2853, 1735,
1631, 1443, 1367, 1236, 1160.
1H NMR (CDCl3) d 7.58-7.57 (m, 2H), 7.37-7.34 (m, 3H), 7.32-7.29 (m, 1H), 7.25-7.23 (m, 2H), 7.11-7.09 (m, 2H) , 4.05
(brs, 1H), 3.88 (m, 1H), 3.62-3.60 (m, 1H), 3.47 (m, 1H), 2.64 (m, 1H), 2.36 (m, 1H), 2.10 (m,
3H), 1.79-1.00 (m, 27H).
13C NMR (CDCl3) d 172.5, 172.5,
145.6, 144.0, 128.3, 127.8, 127.6, 126.6, 126.4, 126.3, 80.9, 76.2, 59.3, 58.2,
56.1, 48.3, 36.0, 31.6, 30.6, 29.6, 28.0, 26.6, 26.5, 26.1, 25.2, 25.1.
HPLC: Daicel Chiralpak AD-H, Hexane / iPrOH = 40/1, Flow rate = 0.25 mL / min, Detection wavelength = 220 nm: tR = 18.9 min (major), tR = 37.9 min
(minor).
ESI−HRMS (m / z) calcd.for C34H47N2O3 ((M + H) +):
531.3581; found: 531.3599.
2-tert-butyl 3,4-dimethyl 5-phenylpyrrolidine-2,3,4-tricarboxylate
IR [cm ^-1 ] 3649, 3454, 3351, 2979, 2952,
1736, 1438, 1372, 1336, 1239, 1158, 1070, 1021.
1H NMR (CDCl3) d 7.33-7.24 (m, 5H), 4.68
(d, 1H, J = 8.4 Hz), 4.02 (d, 1H, J = 8.6 Hz), 3.77 (s, 3H), 3.64 (dd, 1H, J =
8.4, 7.1 Hz), 3.52 (dd, 1H, J = 8.6, 7.1 Hz), 3.21 (s, 3H), 2.79 (br, 1H), 1.52
(s, 9H).
13C NMR (CDCl3) d 172.8, 171.5, 170.7, 138.6, 128.3, 127.9, 126.9, 82.2, 65.4,
64.7, 54.4, 52.4, 51.1, 28.0, 28.0.
HPLC, Daicel Chiralcel OD-H, Hexane / iPrOH = 19/1, Flow rate = 0.50 mL / min, Detection wavelength = 220 nm: tR = 28.7 min (minor), tR = 30.5 min (major).
ESI−HRMS (m / z) calcd. For
C19H26NO6 ((M + H) +): 364.1754; found: 364.1743.

アルゴン雰囲気下で良く乾燥した30mLのナスフラスコにCa(OⁱPr)₂ (0.03 mmol)と不斉配位子(0.03 mmol)、及びモレキュラーシーブス4A (100 mg)を量り取り、室温にて無水THF (0.5 mL)を加えて２時間攪拌した。
０℃に冷却後、システイン誘導体(0.30 mmol)のTHF溶液(0.5 mL)及びアクリル酸メチル(0.36 mmol)のTHF溶液(0.5 mL)を加えた。
そして、そのままの温度で２４時間攪拌後、飽和塩化アンモニウム溶液(10 mL)を加えて反応を停止した。
この混合物に塩化メチレン10 mLを加えて分液し、水槽より塩化メチレン(15 mL x 2)で抽出した。そして、有機層を合わせ、無水硫酸ナトリウム上で乾燥した。濾過、濃縮後、得られた粗生成物をシリカゲル薄層クロマトグラフィーで精製し（ヘキサンー酢酸エチル＝３：１）、下記の構造式で示される目的物を得た。尚、光学純度は光学活性カラムを用いた高速液体クロマトグラフィーで決定した。
Methyl
4-(3-methoxy-3-oxopropyl) -2-phenyl-4,5-
dihydrothiazole-4-carboxylate:

IR [cm^−１] 3632, 3454, 2952, 2846, 1734, 1601, 1435, 1375, 1091.
1H NMR (CDCl3)
d7.85-7.84 (m, 2H), 7.49-7.27
(m, 3H), 3.85(d, 1H, J = 11.3 Hz), 3.80 (s, 3H), 3.65 (s, 3H) 3.35 (d,
1H, J = 11.3 Hz), 2.63-2.29 (m, 4H).
¹³C NMR (CDCl₃) d 173.2, 173.1, 169.3, 132.7, 131.7, 128.6, 128.4,
87.3, 52.9, 51.7, 40.4, 33.1, 29.4.
HPLC
Daicel Chiralpack OJ-H, hexane/ⁱPrOH = 9/1, flow rate = 0.7 mL/min,
Detection wavelength = 254 nm, t_R = 45.1 (major), t_R =
49.6 (minor).
[a]_D ¹⁵
+24.7 (c 0.68).
FAB-HRMS
(m/z) calcd. for C₁₅H₁₈NO₄S (M+H): 308.0951;
found: 308.0953.
尚、アミノ酸エステルのSchiff塩基を用いる立体選択的α置換アミノ酸合成は多くの研究者によって様々な高立体選択的触媒反応が開発され来てており、例えばアラニンやセリンなどのα置換基を有する基質を用いた不斉４級炭素生成も報告されている。しかしながら、これらの反応にあっては過剰量の強塩基や過剰量の基質を必要とし、基質一般性も含め未だ改善の余地を多く残していた。又、これまで報告されているシステイン誘導体に対するアルキル基導入反応では、キラル４級アンモニウム塩を用いるアルキルハライドによる触媒的不斉アルキル化反応が報告されているが、触媒的不斉１，４−付加反応で高エナンチオ選択的にアルキル基を導入した報告はない。これに対して、本発明者は、グリシンエステルから誘導されるSchiff塩基とα，β−不飽和エステルとの不斉１，４−付加反応において、本発明のキラルカルシウム錯体が有効な触媒となることを見出し、不斉４級炭素生成を目的にシステインから誘導される化合物とα，β−不飽和エステルとの反応による光学活性なα−置換グルタミン酸誘導体の合成を検討した結果、高収率・高立体選択的に目的物を得ることが判ったのである。又、置換基を有するα，β−不飽和エステルの場合も良好なジアステレオ選択性を示すことが明らかになった。 [Catalytic asymmetric 1,4-addition reaction of a cysteine derivative with an α, β-unsaturated carbonyl compound]

Weigh Ca (O ⁱ Pr) ₂ (0.03 mmol), asymmetric ligand (0.03 mmol), and molecular sieves 4A (100 mg) in a well-dried 30 mL eggplant flask under an argon atmosphere, and dry at room temperature. THF (0.5 mL) was added and stirred for 2 hours.
After cooling to 0 ° C., a THF solution (0.5 mL) of a cysteine derivative (0.30 mmol) and a THF solution (0.5 mL) of methyl acrylate (0.36 mmol) were added.
Then, after stirring at the same temperature for 24 hours, a saturated ammonium chloride solution (10 mL) was added to stop the reaction.
The mixture was partitioned by adding 10 mL of methylene chloride, and extracted with methylene chloride (15 mL × 2) from a water bath. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting crude product was purified by silica gel thin layer chromatography (hexane-ethyl acetate = 3: 1) to obtain the desired product represented by the following structural formula. The optical purity was determined by high performance liquid chromatography using an optically active column.
Methyl
4- (3-methoxy-3-oxopropyl) -2-phenyl-4,5-
dihydrothiazole-4-carboxylate:

IR [cm ^-1 ] 3632, 3454, 2952, 2846, 1734, 1601, 1435, 1375, 1091.
1H NMR (CDCl3)
d7.85-7.84 (m, 2H), 7.49-7.27
(m, 3H), 3.85 (d, 1H, J = 11.3 Hz), 3.80 (s, 3H), 3.65 (s, 3H) 3.35 (d,
1H, J = 11.3 Hz), 2.63-2.29 (m, 4H).
¹³ C NMR (CDCl ₃ ) d 173.2, 173.1, 169.3, 132.7, 131.7, 128.6, 128.4,
87.3, 52.9, 51.7, 40.4, 33.1, 29.4.
HPLC
Daicel Chiralpack OJ-H, hexane / ⁱ PrOH = 9/1, flow rate = 0.7 mL / min,
Detection wavelength = 254 nm, t _R = 45.1 (major), t _R =
49.6 (minor).
[a] _D ¹⁵
+24.7 (c 0.68).
FAB-HRMS
(m / z) calcd.for C ₁₅ H ₁₈ NO ₄ S (M + H): 308.0951;
found: 308.0953.
In addition, various highly stereoselective catalytic reactions have been developed by many researchers for the synthesis of stereoselective α-substituted amino acids using Schiff bases of amino acid esters. For example, substrates having α-substituents such as alanine and serine. Asymmetric quaternary carbon production using has also been reported. However, these reactions require an excessive amount of strong base and an excessive amount of substrate, and there is still much room for improvement including the generality of the substrate. In the alkyl group introduction reaction to cysteine derivatives reported so far, catalytic asymmetric alkylation reaction with alkyl halide using chiral quaternary ammonium salt has been reported, but catalytic asymmetric 1,4-addition. There is no report of introducing an alkyl group with high enantioselectivity in the reaction. On the other hand, the present inventors have found that the chiral calcium complex of the present invention is an effective catalyst in the asymmetric 1,4-addition reaction between a Schiff base derived from a glycine ester and an α, β-unsaturated ester. As a result of studying the synthesis of optically active α-substituted glutamic acid derivatives by the reaction of a compound derived from cysteine with an α, β-unsaturated ester for the purpose of asymmetric quaternary carbon formation, It was found that the object was obtained with high stereoselectivity. In addition, it has been clarified that α, β-unsaturated esters having a substituent also show good diastereoselectivity.

アルゴン雰囲気下で良く乾燥した30mLのナスフラスコにCa(OⁱPr)₂ (0.03 mmol)と不斉配位子(0.03 mmol)、及びモレキュラーシーブス4A (100 mg)を量り取り、室温にて無水THF (0.5 mL)を加えて２時間攪拌した。
１０℃に冷却後、グリシンSchiff塩基(0.30
mmol)のTHF溶液(0.3
mL)およびフマル酸ジメチル(0.36 mmol)のTHF溶液(0.9 mL)を加えた。
そして、そのままの温度で３時間攪拌後、飽和塩化アンモニウム溶液(10 mL)を加えて反応を停止した。
この混合物に塩化メチレン10 mLを加えて分液し、水槽より塩化メチレン(15 mL x 2)で抽出した。そして、有機層を合わせ、無水硫酸ナトリウム上で乾燥した。濾過、濃縮後、得られた粗生成物をシリカゲル薄層クロマトグラフィーで精製し（ヘキサンー酢酸エチル＝３：１）、下記の構造式で示される目的物を得た。尚、光学純度は光学活性カラムを用いた高速液体クロマトグラフィーで決定した。
2-tert-butyl 3,4-dimethyl 5-phenylpyrrolidine-2,3,4-triboxylate

IR [cm^-1] 3649, 3454, 3351, 2979,
2952, 1736, 1438, 1372, 1336, 1239, 1158, 1070, 1021.
¹H NMR
(CDCl₃) d 7.33-7.24 (m, 5H), 4.68 (d, 1H, J = 8.4 Hz), 4.02 (d, 1H, J = 8.6
Hz), 3.77 (s, 3H), 2.79 (br, 1H), 1.52 (s, 9H).
¹³C NMR
(CDCl₃) d 172.8, 171.5, 170.7, 138.6, 128.3, 127.9, 126.9, 82.2, 65.4, 64.7,
54.4, 52.4, 51.1, 28.0, 28.0.
Daicel Chiralcel OD-H,
hexane/ⁱPrOH = 19/1, flow rate = 0.50 mL/min, Detection wavelength =
220 nm, t_R = 28.7 (minor), t_R = 30.5 (major).
ESI-HRMS (m/z) calcd.
for C₂₆ H ₄₂ NO ₅((M+H)⁺): 364.1754; found: 364.1743.
尚、ピロリジン化合物は生理活性を有する化合物の母核となる骨格であり、その効率的合成法の開発が望まれて来た。その中でも本骨格の触媒的不斉合成は、光学活性医薬品を合成する際の中間体供給において重要な手法である。そして、本発明者は、キラルカルシウム触媒を用いるアゾメチンイミンとα，β−不飽和エステルとの高エナンチオ選択的[3+2]付加環化反応を報告している。そして、この手法の適用拡大を目指し、アゾメチンイミンとエチレン−1，２−ジカルボン酸エステルとの不斉[3+2]付加環化反応について検討を行った結果、例えばカルシウムアルコキシドとキラルビスオキサゾリンから調製されるキラルカルシウム触媒が有効に機能し、対応する[3+2]付加環化体を良好な収率、選択性をもって与えることが見出された。又、これまで、α−グリシン誘導体とフマル酸やマレイン酸誘導体との不斉［3+2］付加環化反応は高ジアステレオ、高エナンチオ選択的な例が報告されていたが、触媒の原子効率などにおいて問題が残っていた。しかしながら、本発明になる触媒を用いれば、より原子効率に優れた系になり得る。又、α位に置換基を有するアミノ酸誘導体との触媒的不斉反応の報告例は限られているのに対して、本発明により不斉４級炭素を有するピロリジン誘導体の合成が可能になった。

[Asymmetric [3 + 2] cycloaddition reaction between α-amino acid ester Schiff base and ethylenedicarboxylic acid derivative]

Weigh Ca (O ⁱ Pr) ₂ (0.03 mmol), asymmetric ligand (0.03 mmol), and molecular sieves 4A (100 mg) in a well-dried 30 mL eggplant flask under an argon atmosphere, and dry at room temperature. THF (0.5 mL) was added and stirred for 2 hours.
After cooling to 10 ° C., glycine Schiff base (0.30
mmol) in THF (0.3
mL) and a THF solution (0.9 mL) of dimethyl fumarate (0.36 mmol) were added.
Then, after stirring at the same temperature for 3 hours, a saturated ammonium chloride solution (10 mL) was added to stop the reaction.
The mixture was partitioned by adding 10 mL of methylene chloride, and extracted with methylene chloride (15 mL × 2) from a water bath. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting crude product was purified by silica gel thin layer chromatography (hexane-ethyl acetate = 3: 1) to obtain the desired product represented by the following structural formula. The optical purity was determined by high performance liquid chromatography using an optically active column.
2-tert-butyl 3,4-dimethyl 5-phenylpyrrolidine-2,3,4-triboxylate

IR [cm ^-1 ] 3649, 3454, 3351, 2979,
2952, 1736, 1438, 1372, 1336, 1239, 1158, 1070, 1021.
¹ H NMR
(CDCl ₃ ) d 7.33-7.24 (m, 5H), 4.68 (d, 1H, J = 8.4 Hz), 4.02 (d, 1H, J = 8.6
Hz), 3.77 (s, 3H), 2.79 (br, 1H), 1.52 (s, 9H).
¹³ C NMR
(CDCl ₃ ) d 172.8, 171.5, 170.7, 138.6, 128.3, 127.9, 126.9, 82.2, 65.4, 64.7,
54.4, 52.4, 51.1, 28.0, 28.0.
Daicel Chiralcel OD-H,
hexane / ⁱ PrOH = 19/1, flow rate = 0.50 mL / min, Detection wavelength =
220 nm, t _R = 28.7 (minor), t _R = 30.5 (major).
ESI-HRMS (m / z) calcd.
for C ₂₆ H ₄₂ NO ₅ ((M + H) ⁺ ): 364.1754; found: 364.1743.
The pyrrolidine compound is a skeleton serving as a mother nucleus of a compound having physiological activity, and development of an efficient synthesis method thereof has been desired. Among them, catalytic asymmetric synthesis of this skeleton is an important technique for supplying intermediates when synthesizing optically active pharmaceuticals. The present inventor has reported a highly enantioselective [3 + 2] cycloaddition reaction of azomethine imine with an α, β-unsaturated ester using a chiral calcium catalyst. Aiming to expand the application of this method, we studied the asymmetric [3 + 2] cycloaddition reaction of azomethine imine with ethylene-1,2-dicarboxylic acid ester. As a result, for example, from calcium alkoxide and chiral bisoxazoline. It has been found that the prepared chiral calcium catalyst functions effectively and gives the corresponding [3 + 2] cycloaddition with good yield and selectivity. In the past, asymmetric [3 + 2] cycloaddition reactions of α-glycine derivatives with fumaric acid and maleic acid derivatives have been reported as examples of high diastereo and high enantioselectivity. Problems remained in efficiency. However, if the catalyst according to the present invention is used, the system can be more excellent in atomic efficiency. In addition, while there are limited reports of catalytic asymmetric reactions with amino acid derivatives having a substituent at the α-position, the present invention has made it possible to synthesize pyrrolidine derivatives having asymmetric quaternary carbons. .

Claims (11)

A catalyst used for the reaction of a compound represented by the formula [III] and a compound represented by the formula [IV],
M (OR ¹ ) ₂ (where M is an alkaline earth metal element, R ¹ is an alkyl group) and a ligand that binds to M of M (OR ¹ ) ₂ ;
A metal catalyst, wherein the compound constituting the ligand is a compound having a biaryl skeleton or a bisoxazoline skeleton.
Formula [III]

[In the formula [III], R ⁵ is H, an alkyl group or an aryl group, R ⁶ is H, an alkyl group or an aryl group, R ⁷ is H, an aliphatic hydrocarbon group or an aromatic hydrocarbon group, R ⁸ Is an aliphatic hydrocarbon group. ]
Formula [IV]

[In the formula [IV], R ⁹ is —COOR (where R is an aliphatic hydrocarbon group), —CON (R ′) R ″ (where R ′ and R ″ are aliphatic hydrocarbon groups) Or one of them is an alkoxy group) or —SO ₂ R ′ ″
(Where R ′ ″ is an aliphatic hydrocarbon group or an aromatic hydrocarbon group), and R ¹⁰ is H, X (halogen atom), an aliphatic hydrocarbon group or an aromatic hydrocarbon group. ] The metal catalyst according to claim 1, wherein the compound constituting the ligand is a compound having a structure represented by the following formula [I] or an enantiomer thereof.
Formula [I]

[In the formula [I], R ² is an aliphatic hydrocarbon group or an aromatic hydrocarbon group, all R ² may be the same or different, and R ³ is H, an aliphatic hydrocarbon group or an aromatic group. In the group hydrocarbon group, all R ^{3 s} may be the same or different, and R ⁴ is H, an alkyl group, an aryl group, a substituent whose carbon bond atom is a hetero atom or a cyano group. ] R ^{2 in the} formula [I] is an aromatic hydrocarbon group, all R ² may be the same or different, R ³ is H or an aromatic hydrocarbon group, and all R ³ are the same or different. The metal catalyst according to claim 2, wherein R ⁴ is H. The metal catalyst according to claim 1, wherein the compound constituting the ligand is a compound having a structure represented by the following formula [II] or an enantiomer thereof.
Formula [II]

M (OR ¹ ) ₂ (wherein M is an alkaline earth metal element and R ¹ is an alkyl group) and a compound constituting a ligand that binds to M of M (OR ¹ ) ₂ are mixed to form a catalyst The metal catalyst according to any one of claims 1 to 4, wherein The metal catalyst according to any one of claims 1 to 5, wherein R ^{1 in} M (OR ¹ ) ₂ is an alkyl group having 1 to 10 carbon atoms. The metal catalyst according to claim 6, wherein R ¹ of M (OR ¹ ) ₂ is a branched alkyl group having 3 to 10 carbon atoms. The metal catalyst according to any one of claims 1 to 7, wherein M in M (OR ¹ ) ₂ is Ca. 9. An optically active α-amino acid characterized by reacting a compound represented by the formula [III] with a compound represented by the formula [IV] in the presence of the metal catalyst according to any one of claims 1 to 8. A method for producing a derivative.
Formula [III]

[In the formula [III], R ⁵ is H, an alkyl group or an aryl group, R ⁶ is H, an alkyl group or an aryl group, R ⁷ is H, an aliphatic hydrocarbon group or an aromatic hydrocarbon group, R ⁸ Is an aliphatic hydrocarbon group. ]
Formula [IV]

[In the formula [IV], R ⁹ is —COOR (where R is an aliphatic hydrocarbon group), —CON (R ′) R ″ (where R ′ and R ″ are aliphatic hydrocarbon groups) Or one of them is an alkoxy group) or —SO ₂ R ′ ″
(Where R ′ ″ is an aliphatic hydrocarbon group or an aromatic hydrocarbon group), and R ¹⁰ is H, X (halogen atom), an aliphatic hydrocarbon group or an aromatic hydrocarbon group. ] The method for producing an optically active α-amino acid derivative according to claim 9, wherein the reaction is carried out at a temperature of -80 ° C to 20 ° C. The method for producing an optically active α-amino acid derivative according to claim 9 or 10, wherein the amount of the metal catalyst is 0.1 to 20 mol% based on the substrate.