JP5453003B2 - Catalyst for stereoselective asymmetric nitroaldol reaction - Google Patents

Description

  The present invention relates to a stereoselective catalytic asymmetric nitroaldol reaction and a catalyst for the reaction.

  In the field of organic synthetic chemistry, especially pharmaceutical synthetic chemistry, optically active anti-1,2-aminoalcohol compounds are widely used as chiral building blocks with extremely high utility. For example, optically active anti-1,2-aminoalcohol is included as a basic unit in pharmaceuticals such as β-agonists and many natural physiologically active compounds, and optically active anti-1,2-aminoalcohol compounds are used as starting compounds and By using it as a reaction reagent, these compounds can be produced efficiently and inexpensively. For these reasons, development of a method for efficiently producing an optically active anti-1,2-aminoalcohol compound is required.

  As a method for producing an optically active anti-1,2-nitroalkanol compound useful as a precursor of an optically active anti-1,2-aminoalcohol compound by selective catalytic asymmetric reaction, various aldehyde compounds and nitroalkanes are used. Is known in the presence of an optically active tetraaminophosphonium salt (Uraguchi, D., et al., J. Am. Chem. Soc., 129, pp. 12392, 2007). However, this method needs to be carried out at an extremely low temperature of -78 ° C., and has a problem that it cannot be applied as an industrial production method.

を配位子として含むランタン錯体が不斉アミノ化反応用触媒として有用であることが知られている(Mashiko, T., et al., J. Am. Chem. Soc., 129, pp.11342, 2007)。しかしながら、上記刊行物には上記のアミド化合物において水酸基の位置が異なる異性体は開示されておらず、上記化合物について不斉アミノ化反応用触媒以外の用途について示唆ないし教示はない。また、上記のアミド化合物とは水酸基の位置が異なる異性体を配位子とするネオジム錯体が立体選択的な触媒的不斉ニトロアルドール反応に有用であることが知られている(Tetrahedron Letters, 49, pp.272-276, 2008)。しかしながら、上記のアミド化合物の芳香環にフッ素原子などのハロゲン原子や他の官能基を導入した化合物を配位子として含む錯体が立体選択的な触媒的不斉ニトロアルドール反応に有用であることは従来知られていない。 On the other hand, the following amide compounds:

Is known to be useful as a catalyst for asymmetric amination reaction (Mashiko, T., et al., J. Am. Chem. Soc., 129, pp. 11342 , 2007). However, the publication does not disclose isomers having different hydroxyl positions in the amide compound, and there is no suggestion or teaching about the use of the compound other than the catalyst for asymmetric amination reaction. In addition, neodymium complexes having isomers with different hydroxyl positions as ligands from the above amide compounds are known to be useful for stereoselective catalytic asymmetric nitroaldol reactions (Tetrahedron Letters, 49 , pp.272-276, 2008). However, the complex containing a compound in which a halogen atom such as a fluorine atom or other functional group is introduced into the aromatic ring of the amide compound as a ligand is useful for a stereoselective catalytic asymmetric nitroaldol reaction. It is not known so far.

J. Am. Chem. Soc., 129, 12392, 2007 J. Am. Chem. Soc., 129, 11342, 2007 Tetrahedron Letters, 49, pp.272-276, 2008

  An object of the present invention is to provide a stereoselective catalytic asymmetric nitroaldol reaction and a catalyst for the reaction. More specifically, a method for anti-selectively producing an optically active anti-1,2-nitroalkanol compound useful as a precursor of an optically active anti-1,2-aminoalcohol compound by catalytic asymmetric reaction, and the method It is an object of the present invention to provide a catalyst for use in the reaction.

  As a result of diligent research to solve the above problems, the inventors of the present invention produced a compound in which a functional group such as a halogen atom was introduced on the aromatic ring in the amide compound described in Non-Patent Document 3, Carry out nitroaldol reaction using various aldehyde compounds and nitroalkanes using a heterogeneous metal complex complex coordinated with lanthanoids such as neodymium and alkali metals such as sodium as ligands with this compound as a ligand. Makes it possible to efficiently produce an optically active anti-1,2-nitroalkanol compound, which is a precursor of an optically active anti-1,2-aminoalcohol compound, and this reaction can be carried out rapidly even at about -40 ° C cooling. It has been found that the target product can be produced with high anti-selectivity and extremely high asymmetric yield. The present invention has been completed based on the above findings.

（式中、R¹はC_3-8アルキル基又はアラルキル基を示し、X¹及びX²はそれぞれ独立にハロゲン原子、水酸基、アミノ基、ニトロ基、又はカルボキシル基を示す）で表される化合物を配位子として含む異種金属複合型の錯体（ただし2種の金属のうちの1種はランタノイドから選択され、もう1種の金属はアルカリ金属である）の存在下で反応させる工程を含む方法が提供される。 That is, according to the present invention, there is provided a method for producing an optically active anti-1,2-nitroalkanol compound, wherein an aldehyde compound and a nitroalkane compound having 2 or more carbon atoms are represented by the following general formula (I):

(Wherein R ¹ represents a C _3-8 alkyl group or an aralkyl group, and X ¹ and X ² each independently represent a halogen atom, a hydroxyl group, an amino group, a nitro group, or a carboxyl group) A method comprising a step of reacting in the presence of a heterogeneous metal complex complex containing 1 as a ligand, wherein one of the two metals is selected from lanthanoids and the other metal is an alkali metal Is provided.

According to a preferred method of the present invention, the compound represented by the above general formula (I) wherein R ¹ is an isobutyl group, lanthanum (La), neodymium (Nd), samarium (Sm), praseodymium ( Pr), europium (Eu), gadolinium (Gd), dysprosium (Dy), and a metal selected from the group consisting of ytterbium (Yb) and the above method, which is a heterogeneous metal complex complex containing an alkali metal; The above method, wherein the compound represented by the general formula (I) is a compound in which R ¹ is an isobutyl group, a heterogeneous metal complex complex containing neodymium (Nd) and sodium;
The above method which is a heterometallic complex containing samarium (Sm) and sodium; the above method which is a heterometallic complex containing praseodymium (Pr) and sodium; the nitroalkane is R ¹¹ —CH ₂ —NO ₂ ( Wherein R ¹¹ represents a C ₁ -C ₂₀ alkyl group, and the alkyl group may have a substituent, and the reaction temperature is -50 to -30 There is provided the above method carried out in the range of ° C .; the above method comprising the step of isolating and resuspending the prepared complex; and the above method carried out in the presence of approximately the same amount of water as the lanthanoid.

From another viewpoint, the present invention provides the above heterogeneous metal complex complex containing the compound represented by the general formula (I) as a ligand. A reaction catalyst for producing an optically active anti-1,2-nitroalkanol compound by reacting an aldehyde compound with a nitroalkane compound having 2 or more carbon atoms, the reaction catalyst comprising the complex; A method for producing a 1,2-aminoalcohol compound, wherein (A) an aldehyde compound and a nitroalkane compound are reacted in the presence of the above complex to produce an optically active anti-1,2-nitroalkanol compound The present invention also includes a method comprising the steps of: (B) reducing the optically active anti-1,2-nitroalkanol compound obtained in the above step (A) to produce an optically active anti-1,2-aminoalcohol compound. Provided by the invention.
From another point of view, the present invention also provides a compound represented by the above general formula (I).

  According to the method of the present invention, an optically active anti-1,2-nitroalkanol compound useful as a precursor of an optically active anti-1,2-aminoalcohol compound useful for the production of pharmaceuticals and natural physiologically active compounds can be relaxed. It can be produced efficiently under conditions. Since the method of the present invention can be performed at a low temperature of about −40 ° C., it can be used as an industrial production method. In the method of the present invention, the precipitate produced in the complex preparation can be isolated and then resuspended to be used as a catalyst suspension. By simply preparing and using a high-purity catalyst, high anti-selection can be achieved. In particular, it has an excellent feature that the target product can be produced with an extremely high asymmetric yield.

  The method of the present invention is a method for producing an optically active anti-1,2-nitroalkanol compound by a nitroaldol reaction using an aldehyde compound and a nitroalkane compound having 2 or more carbon atoms. In the above reaction, the above general formula (I ) Is used as a reaction catalyst.

  The kind of aldehyde compound is not particularly limited, and either an aromatic aldehyde compound or an aliphatic aldehyde compound may be used. The aldehyde compound may have one or more arbitrary substituents such as an alkyl group, an alkoxy group, a carboxyl group, a hydroxyl group, and a halogen atom. When using an aldehyde compound as a raw material in the method of the present invention, the method of the present invention can be suitably carried out by protecting a reactive functional group other than the aldehyde with a protecting group as necessary. For protecting groups, reference can be made to, for example, Green et al., Protective Groups in Organic Synthesis, 3rd Edition, 1999, John Wiley & Sons, Inc. Examples of the aldehyde compound include aromatic aldehyde compounds such as benzaldehyde, halogenobenzaldehyde (chlorbenzaldehyde, bromobenzaldehyde, etc.), alkoxybenzaldehyde (methoxybenzaldehyde, ethoxybenzaldehyde, etc.), alkylbenzaldehyde (methylbenzaldehyde, ethylbenzaldehyde, etc.), and naphthylaldehyde. Aliphatic aldehydes such as alkyl aldehydes (butyraldehyde, cyclopropyl aldehyde, etc.) or aromatic substituted aliphatic aldehydes such as aralkyl aldehydes (phenethyl aldehyde, benzyl aldehyde, etc.) can be used, but are not limited thereto. There is no.

  The type of the nitroalkane compound is not particularly limited as long as it has 2 or more carbon atoms. For example, a nitroalkane compound having an alkyl chain with about 2 to 20 carbon atoms can be used. The alkyl group constituting the main chain of the nitroalkane compound may have one or more arbitrary substituents such as an alkyl group, an alkoxy group, a carboxyl group, a hydroxyl group, and a halogen atom. Any number of double bonds or triple bonds may be included. The method of the present invention can be suitably performed by protecting reactive functional groups other than the nitro group with a protecting group as necessary. For the protecting group, refer to the above-mentioned book by Green et al. As the nitroalkane, nitroethane, nitropropane, nitrobutane and the like can be preferably used, but are not limited thereto.

In the complex represented by the general formula (I), R ¹ represents a C _3-8 alkyl group or an aralkyl group. As the C _3-8 alkyl group represented by R ¹ , an alkyl group consisting of a linear, branched, cyclic, or combination thereof can be used, but a branched, cyclic, or a combination thereof can be used. An alkyl group consisting of is preferable, and a branched or cyclic alkyl group is more preferable. For example, a branched C _3-4 alkyl group such as isopropyl group, sec-butyl group, isobutyl group (—CH ₂ —CH (CH ₃ ) ₂ ), or tert-butyl group, or cyclopentyl group, cyclohexyl group, Alternatively, a cyclic C _5-7 alkyl group such as a cycloheptyl group is preferable. Of these, an isopropyl group, an isobutyl group, or a tert-butyl group is more preferable, and an isobutyl group is particularly preferable.

As the aralkyl group represented by R ¹ , for example, a linear or branched C _1-4 alkyl group substituted by one or several, preferably one aryl group or heteroaryl group is used. Can do. As the aryl group constituting the aralkyl group represented by R ¹ , a monocyclic or condensed polycyclic aromatic hydrocarbon group can be used, for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an anthranyl group Or a phenanthryl group and the like, but is not limited thereto. As the heteroaryl group, a monocyclic or condensed polycyclic aromatic heterocyclic group can be used. The number of ring-constituting heteroatoms is not particularly limited, but is about 1 to several, preferably about 1 to 5. When two or more ring heteroatoms are contained, they may be the same or different. Examples of the hetero atom include, but are not limited to, an oxygen atom, a nitrogen atom, or a sulfur atom.

Examples of the monocyclic heteroaryl group constituting the aralkyl group represented by R ¹ include, for example, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 5-pyrazolyl group, (1,2,3-oxadiazol) -4-yl group, (1,2,3-oxadiazol) -5-yl group, (1,2,4-oxadiazole) -3-yl group, (1,2,4-oxadiazol) -5-yl group, (1,2,5-oxadiazol) -3-yl group, (1,2,5-oxadiazol) -4-yl group, (1,3,4-oxadiazol) -2-yl group, (1,3,4-oxadiazol) -5-yl group , Furazanyl group, (1,2,3-thiadiazol) -4-yl group, (1,2,3-thiadiazol) -5-yl group, (1,2,4-thiadiazol) -3-yl group, 1,2,4-thiadiazol) -5-yl group, (1,2,5-thiadiazol) -3-yl group, (1,2,5-thiadiazol) -4-yl group, (1,3,4 -Thiadiazolyl) -2-yl group, (1,3,4-thiadiazolyl) -5-yl group, (1H-1,2,3-triazol) -1-yl group, (1H-1,2,3- (Triazol) -4-yl group, (1H-1,2,3-triazol) -5-yl group, (2H-1,2,3-triazol) -2-yl group, (2H-1,2,3 -Triazol) -4-yl group, (1H-1,2,4-triazol) -1-yl group, (1H-1,2,4-triazol) -3-yl group, (1H-1,2, 4-triazol) -5-yl group, (4H-1,2,4-triazol) -3-yl group, (4H-1,2,4-triazol) -4-yl group, (1H-tetrazole)- 1-yl group, (1H-te Razol) -5-yl group, (2H-tetrazol) -2-yl group, (2H-tetrazol) -5-yl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 2-pyrazinyl group, (1,2,3-triazin) -4-yl group, (1,2,3-triazine)- 5-yl group, (1,2,4-triazine) -3-yl group, (1,2,4-triazine) -5-yl group, (1,2,4-triazine) -6-yl group, (1,3,5-triazine) -2-yl group, 1-azepinyl group, 1-azepinyl group, 2-azepinyl group, 3-azepinyl group, 4-azepinyl group, (1,4-oxazepine) -2- Yl group, (1,4-oxazepine) -3-yl group, (1,4-oxazepine) -5-yl group, (1,4-oxazepine) -6-yl group, (1,4-oxazepine)- 7-yl group, (1,4-thiazepine) -2-yl group, (1,4-thiazepine) -3-yl group, (1,4-thiazepine) -5-yl group, (1,4-thiazepine) ) -6-yl group (1,4-thiazepine) -7-yl, but 5 to 7-membered monocyclic heteroaryl group such groups are not limited thereto.

Examples of the condensed polycyclic heteroaryl group constituting the aralkyl group represented by R ¹ include a 2-benzofuranyl group, a 3-benzofuranyl group, a 4-benzofuranyl group, a 5-benzofuranyl group, a 6-benzofuranyl group, and a 7-benzofuranyl group. 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzo [b] thienyl group, 3-benzo [b] thienyl group, 4-benzo [b] thienyl Group, 5-benzo [b] thienyl group, 6-benzo [b] thienyl group, 7-benzo [b] thienyl group, 1-benzo [c] thienyl group, 4-benzo [c] thienyl group, 5-benzo [c] thienyl group, 1-indolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl group, 4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group, (2H-iso Indol) -1-yl group, (2H-isoindole) -2-yl group, (2H-isoindole) -4-yl group, (2H-isoi group) Dole) -5-yl group, (1H-indazol) -1-yl group, (1H-indazol) -3-yl group, (1H-indazol) -4-yl group, (1H-indazol) -5-yl Group, (1H-indazol) -6-yl group, (1H-indazol) -7-yl group, (2H-indazol) -1-yl group, (2H-indazol) -2-yl group, (2H-indazole) ) -4-yl group, (2H-indazol) -5-yl group, 2-benzoxazolyl group, 2-benzoxazolyl group, 4-benzoxazolyl group, 5-benzoxazolyl group, 6-benzoxazolyl group, 7-benzoxazolyl group, (1,2-benzisoxazol) -3-yl group, (1,2-benzisoxazol) -4-yl group, (1,2 -Benzoisoxazol) -5-yl group, (1,2-benzisoxazol) -6-yl group, (1,2-benzisoxazol) -7-yl group, (2,1-benzisoxazole) -3-yl group, (2,1-benzoisoxazol) -4-yl group, (2,1- Nzoisoxazol) -5-yl group, (2,1-benzisoxazol) -6-yl group, (2,1-benzisoxazol) -7-yl group, 2-benzothiazolyl group, 4-benzothiazolyl group , 5-benzothiazolyl group, 6-benzothiazolyl group, 7-benzothiazolyl group, (1,2-benzisothiazol) -3-yl group, (1,2-benzisothiazol) -4-yl group, (1,2 -Benzoisothiazol) -5-yl group, (1,2-benzisothiazol) -6-yl group, (1,2-benzisothiazol) -7-yl group, (2,1-benzoisothiazole) -3-yl group, (2,1-benzoisothiazol) -4-yl group, (2,1-benzoisothiazol) -5-yl group, (2,1-benzisothiazol) -6-yl group , (2,1-Benzisothiazol) -7-yl group, (1,2,3-Benzoxadiazol) -4-yl group, (1,2,3-Benzoxadiazol) -5-yl Group, (1,2,3-benzooxadiazole) -6-yl group, (1,2,3 -Benzoxadiazol) -7-yl group, (2,1,3-benzooxadiazol) -4-yl group, (2,1,3-benzooxadiazol) -5-yl group, (1 , 2,3-benzothiadiazol) -4-yl group, (1,2,3-benzothiadiazole) -5-yl group, (1,2,3-benzothiadiazol) -6-yl group, (1,2 , 3-Benzothiadiazole) -7-yl group, (2,1,3-benzothiadiazole) -4-yl group, (2,1,3-benzothiadiazole) -5-yl group, (1H-benzotriazole) -1-yl group, (1H-benzotriazol) -4-yl group, (1H-benzotriazol) -5-yl group, (1H-benzotriazol) -6-yl group, (1H-benzotriazole) -7 -Yl group, (2H-benzotriazol) -2-yl group, (2H-benzotriazol) -4-yl group, (2H-benzotriazol) -5-yl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group, 1- Soquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 3-cinnolinyl group, 4-cinnolinyl group, 5-cinnolinyl group, 6- Cinnolinyl group, 7-cinnolinyl group, 8-cinnolinyl group, 2-quinazolinyl group, 4-quinazolinyl group, 5-quinazolinyl group, 6-quinazolinyl group, 7-quinazolinyl group, 8-quinazolinyl group, 2-quinoxalinyl group, 5- Quinoxalinyl group, 6-quinoxalinyl group, 1-phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 2-naphthyridinyl group, 3-naphthyridinyl group, 4-naphthyridinyl group, 2-purinyl group, 6-purinyl group, 7- Purinyl group, 8-prinyl group, 2-pteridinyl group, 4-pteridinyl group, 6-pteridinyl group, 7-pteridinyl group, 1-carbazolyl group, 2-carbazolyl group, 3-carbazolyl group , 4-carbazolyl group, 9-carbazolyl group, 2- (α-carbolinyl) group, 3- (α-carbolinyl) group, 4- (α-carbolinyl) group, 5- (α-carbolinyl) group, 6- ( α-Carboninyl) group, 7- (α-Carborinyl) group, 8- (α-Carborinyl) group, 9- (α-Carborinyl) group, 1- (β-Carbonylyl) group, 3- (β-Carbonylyl) group 4- (β-Carbonylyl) group, 5- (β-Carbonylyl) group, 6- (β-Carbonylyl) group, 7- (β-Carbonylyl) group, 8- (β-Carbonylyl) group, 9- (β -Carbonylyl) group, 1- (γ-Carborinyl) group, 2- (γ-Carborinyl) group, 4- (γ-Carborinyl) group, 5- (γ-Carborinyl) group, 6- (γ-Carborinyl) group, 7- (γ-Carborinyl) group, 8- (γ-Carborinyl) group, 9- (γ-Carborinyl) group, 1-Acridinyl group, 2-Acridinyl group, 3-Acridinyl group, 4-Acridinyl group, 9-Acridinyl group Group, 1-phenoxazinyl group, 2-phenoxazinyl group, 3-phenyl Noxazinyl group, 4-phenoxazinyl group, 10-phenoxazinyl group, 1-phenothiazinyl group, 2-phenothiazinyl group, 3-phenothiazinyl group, 4-phenothiazinyl group, 10-phenothiazinyl group, 1-phenazinyl group, 2- Phenazinyl group, 1-phenanthridinyl group, 2-phenanthridinyl group, 3-phenanthridinyl group, 4-phenanthridinyl group, 6-phenanthridinyl group, 7-phenanthridinyl group 8-phenanthridinyl group, 9-phenanthridinyl group, 10-phenanthridinyl group, 2-phenanthrolinyl group, 3-phenanthrolinyl group, 4-phenanthrolinyl group, 5 -Phenanthrolinyl group, 6-phenanthrolinyl group, 7-phenanthrolinyl group, 8-phenanthrolinyl group, 9-phenanthrolinyl group, 10-phenanthrolinyl group, 1-thianthrenyl group Group, 2-thianthenyl group, 1-i Doridinyl group, 2-indolidinyl group, 3-indolidinyl group, 5-indolidinyl group, 6-indolidinyl group, 7-indolidinyl group, 8-indolidinyl group, 1-phenoxathinyl group, 2-phenoxathinyl group, 3 -Phenoxathiinyl group, 4-phenoxathiinyl group, thieno [2,3-b] furyl group, pyrrolo [1,2-b] pyridazinyl group, pyrazolo [1,5-a] pyridyl group, imidazo [ 11,2-a] pyridyl group, imidazo [1,5-a] pyridyl group, imidazo [1,2-b] pyridazinyl group, imidazo [1,2-a] pyrimidinyl group, 1,2,4-triazolo [ Examples include, but are not limited to, 8- to 14-membered fused polycyclic heteroaryl groups such as 4,3-a] pyridyl group and 1,2,4-triazolo [4,3-a] pyridazinyl group. There is no.
Examples of the aralkyl group represented by R ¹ include, but are not limited to, a benzyl group or a 3-indolylmethyl group.

X ¹ and X ² each independently represent a halogen atom, a hydroxyl group, an amino group, a nitro group, or a carboxyl group. In the present specification, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. As the halogen atom represented by X ¹ and X ² , for example, a fluorine atom, a chlorine atom, or a bromine atom is preferable. , A fluorine atom or a chlorine atom is more preferable, and a fluorine atom is particularly preferable. The amino group may have 1 or 2 substituents. For example, it may be a monoalkylamino group, a dialkylamino group, an aralkylamino group, or an acylamino group. X ¹ and X ² are preferably both halogen atoms, and both X ¹ and X ² are particularly preferably fluorine atoms.

The substitution positions of X ¹ and X ² are not particularly limited. For example, X ¹ is preferably para to the hydroxyl group substituted on the benzene ring. X ² is preferably in the meta position relative to the hydroxyl group substituted on the benzene ring. More preferably, X ¹ is para to the hydroxyl group and X ² is para to the amino group. More preferably, as X ¹ , the halogen atom is located in the para position with respect to the hydroxyl group, and as X ² , it is further preferred that the halogen atom is located in the para position with respect to the amino group. Particularly preferably, as X ¹ , the fluorine atom is located in the para position with respect to the hydroxyl group, and as X ² , it is further preferred that the fluorine atom is located in the para position with respect to the amino group.

  In the heterogeneous metal complex complex containing the compound represented by the general formula (I) as a ligand, one type of metal can be selected from lanthanoids. Lanthanoids are also called lanthanum series and contain 15 elements with atomic numbers 57-71. More specifically, lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb) , Dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), and lutetium (Lu). Of these metals, a metal selected from the group consisting of lanthanum, neodymium, samarium, praseodymium, europium, gadolinium, dysprosium, and ytterbium is preferred, more preferred is neodymium, samarium, or praseodymium, and particularly preferred is neodymium or Samarium. In the heterogeneous metal complex, an alkali metal such as sodium, potassium, or lithium is used as the other metal. Sodium is preferred as the alkali metal. The combination of sodium and neodymium and sodium and samarium is most preferred from the viewpoint of diastereoselectivity and enantioselectivity.

The compound represented by the general formula (I) is a 2-aminophenol derivative having an optically active L or D-amino acid having R ¹ as a side chain as a raw material and having a carboxyl group of the amino acid and X ² as a substituent. It can be produced by condensing a salicylic acid derivative having X ¹ as a substituent to a compound obtained by condensing with an amino group. If necessary, the amino group of the amino acid or the hydroxyl group of 2-aminophenol can be protected with an appropriate protecting group. For protecting groups, reference can be made to books such as Green et al., Protective Groups in Organic Synthesis, 3rd Edition, 1999, John Wiley & Sons, Inc. Examples of the amino-protecting group include an alkoxycarbonyl group, an aryloxycarbonyl group, an alkanoyl group, and an arylcarbonyl group (in the above aryloxycarbonyl group or arylcarbonyl group, the aryl ring is substituted or unsubstituted). It may be substituted, and when it has a substituent, examples thereof include a halogen atom and an alkoxy group). Of these, alkoxycarbonyl groups are preferred. The alkoxycarbonyl group is preferably an alkoxycarbonyl group composed of a linear or branched C _1-6 alkoxy group, more preferably a methoxycarbonyl group, an ethoxycarbonyl group, or a tert-butoxycarbonyl group. Particularly preferred is a tert-butoxycarbonyl group. As the hydroxyl-protecting group, an aralkyl group such as a benzyl group, a benzoyl group, a trialkylsilyl group, and the like can be used, and a benzyl group is preferable.

  This condensation reaction can be performed by a normal amide formation reaction in which an amino group and a carboxyl group are reacted. For example, the condensation reaction is performed by an appropriate method such as an active esterification method, a mixed acid anhydride method, or a condensation method. The active esterification method is carried out by reacting a carboxylic acid with an active esterifying agent in a solvent to produce an active ester and then reacting with an amino group. The solvent used is not particularly limited as long as it is inert. For example, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as ether and tetrahydrofuran, dimethylformamide, dimethylacetamide and the like. Preference is given to amides, aromatic hydrocarbons such as benzene, toluene, xylene, esters such as ethyl acetate, or mixed solvents thereof. Examples of the active esterifying agent include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide; 1,1′- Diimidazole compounds such as oxalyldiimidazole, N, N'-carbonyldiimidazole; disulfide compounds such as 2,2'-dipyridyl disulfide; such as N, N'-disuccinimidyl carbonate Succinic acid compounds; phosphinic chloride compounds such as N, N′-bis (2-oxo-3-oxazolidinyl) phosphinic chloride; N, N′-disuccinimidyl oxalate (DSO), N , N'-Diphthalimide oxalate (DPO), N, N'-bis (norbornenylsuccinimidyl) oxalate (BNO), 1,1'-bis (benzotriazolyl) oxalate (BBTO), 1 , 1'- screw ( Examples include oxalate compounds such as 6-chlorobenzotriazolyl) oxalate (BCTO) and 1,1′-bis (6-trifluoromethylbenzotriazolyl) oxalate (BTBO). Mention may be made of diimidazole compounds such as N, N′-carbonyldiimidazole.

  The reaction of an active ester with an amino group is, for example, azodicarboxylic acid di-lower alkyl-triphenylphosphine such as diethyl azodicarboxylate-triphenylphosphine, N-ethyl-5-phenylisoxazolium-3′- N-lower alkyl-5-arylisoxazolium-3'-sulfonates such as sulfonate, oxydiformates such as diethyloxydiformate (DEPC), N ', N'-dicyclohexylcarbodiimide (DCC ) N ', N'-dicycloalkylcarbodiimides, diheteroaryl diselenides such as di-2-pyridyl diselenide, triaryl phosphines such as triphenylphosphine, p-nitrobenzenesulfonyl Arylsulfonyl triazolides such as triazolide, 2-chloro-1-methylpyridinium 2- B-1-Lower alkyl pyridinium halides and diarylphosphoryl azides such as diphenylphosphoryl azide (DPPA), imidazole derivatives such as N, N'-carbodiimidazole (CDI), and 1-hydroxybenzotriazole (HOBT) Benzotriazole derivatives, dicarboximide derivatives such as N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) In the presence of a condensing agent such as a phosphonic acid cyclic anhydride such as 1-propanephosphonic acid cyclic anhydride (T3P). Preferably, a carbodiimide derivative such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or a phosphonic acid cyclic anhydride such as 1-propanephosphonic acid cyclic anhydride (T3P) is used. it can. The reaction temperature for the preparation of the active ester is −10 ° C. to room temperature, the reaction between the active ester compound and the amino group is around room temperature, and the reaction time is about 30 minutes to 10 hours.

  The mixed acid anhydride method is carried out by reacting an amino group after producing a mixed acid anhydride of a carboxylic acid. The condensation method can be carried out by directly reacting a carboxylic acid and an amine in the presence of the condensing agent, and is carried out in the same manner as in the reaction for producing the active ester. Condensation can also be carried out by converting the carboxyl group to an acid halide in an inert solvent and then reacting the resulting acid halide with an amine.

One embodiment of the method of the present invention is specifically shown by a reaction formula. In the following reaction, the heterogeneous metal complex complex containing a compound represented by the general formula (I) as a ligand, preferably R ¹ in the general formula (I) is an isopropyl group, and X ¹ and X ² are A neodymium / sodium complex containing a halogen atom compound as a ligand can be used as a reaction catalyst. Particularly preferably, in general formula (I), R ¹ is an isobutyl group, X ¹ is a fluorine atom located in the para position relative to the hydroxyl group, and X ² is a fluorine atom located in the para position relative to the amino group. A neodymium / sodium complex containing the compound as a ligand can be used as a reaction catalyst.

  In the present specification, the “anti” configuration means that in the 1,2-nitroalkanol compound represented by the general formula (II), a hydroxyl group and a nitro group are in an anti configuration. In the method of the present invention, the target 1,2-nitroalkanol compound can be obtained as an optically active compound by using the heterogeneous metal complex complex as a reaction catalyst. The steric notation shown in the following chemical formulas indicates a relative configuration, and the same applies to other chemical formulas shown in this specification.

（上記スキーム中、R¹⁰は炭素数1以上の脂肪族炭化水素基又は炭素数5以上の芳香族炭化水素基、あるいはそれらの組合せからなる基を示し、上記の基を構成する任意の個数の炭素原子は窒素原子、酸素原子、又はイオウ原子などのヘテロ原子で置き換えられていてもよく、上記の基は任意の置換基（該置換基は保護基で保護されていてもよい）を1個又は2個以上有していてもよく；R¹¹は水素原子又はC₁-C₂₀アルキル基を示し、該アルキル基は任意の置換基を1個又は2個以上有していてもよく、該アルキル基のアルキル鎖は1個又は2個以上の不飽和結合を含んでいてもよい）

(In the above scheme, R ¹⁰ represents an aliphatic hydrocarbon group having 1 or more carbon atoms, an aromatic hydrocarbon group having 5 or more carbon atoms, or a group consisting of a combination thereof, and an arbitrary number of groups constituting the above group) The carbon atom may be replaced with a heteroatom such as a nitrogen atom, an oxygen atom, or a sulfur atom, and the above group has one optional substituent (the substituent may be protected with a protecting group). R ¹¹ represents a hydrogen atom or a C ₁ -C ₂₀ alkyl group, and the alkyl group may have one or more arbitrary substituents, and The alkyl chain of the alkyl group may contain one or more unsaturated bonds)

  The method of the present invention is generally carried out in an inert solvent such as tetrahydrofuran, toluene, xylene, or a mixed solvent thereof at a low temperature of about -50 ° C to -30 ° C, preferably at a low temperature of about -40 ° C. Can be done. Generally, a lanthanoid alkoxide or a complex prepared by mixing a compound represented by the lanthanoid aralkyl oxide / alkali metal / general formula (I) with a mixing ratio of 1/2/2 is used as a catalyst, and the amount of catalyst in the reaction system is 5 The reaction can be carried out by sequentially adding a nitroalkane compound and an aldehyde compound at about 20 mol%, preferably about 8-10 mol%, particularly preferably about 9 mol%. The order of addition can be selected as appropriate. In the method of the present invention, a complex obtained by mixing a lanthanoid alkoxide or a lanthanoid aralkyl oxide / alkali metal / a compound represented by the general formula (I) at a mixing ratio of 1/2/2 is isolated as a precipitate. Can be resuspended and used as a catalyst suspension depending on the conditions, but a high-purity complex can be easily prepared and used as a catalyst by this means, and a high-purity catalyst is used. This embodiment is a preferred embodiment of the process of the present invention because very high anti-selectivity and asymmetric yield can be achieved.

  In addition, the above reaction is carried out in the presence of approximately the same amount of lanthanoid, for example, 5 to 20 mol%, preferably about 8 to 10 mol%, particularly preferably about 9 mol%, for efficient reaction. In some cases, and may improve isolation yield, diastereoselectivity, and enantioselectivity. But the ratio of the aldehyde compound and nitroalkane compound which are raw material compounds, and the addition amount of the complex as a reaction catalyst are not specifically limited, It can select suitably. In addition, it is easily understood by those skilled in the art that the reaction conditions described above can be appropriately changed, and the reaction can be performed while referring to typical methods specifically shown in the examples of the present specification. The method of the present invention can be preferably carried out by appropriately selecting, changing or modifying the conditions.

  By reducing the optically active anti-1,2-nitroalkanol compound obtained by the method of the present invention, an optically active anti-1,2-aminoalcohol compound useful for the production of pharmaceuticals and natural physiologically active substances can be obtained. it can. It goes without saying that the type of the reduction reaction is not particularly limited and can be appropriately selected by those skilled in the art depending on the type of the functional group present. For example, a catalytic reduction method using a palladium carbon catalyst can be exemplified, but the method is not limited thereto.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples.
Example 1: Ligand synthesis

4-fluoroanisole (3.40 mL, 30 mmol) was dissolved in tetrahydrofuran (THF, 30 mL) and cooled to -70 ° C. To this solution, a THF solution (24 mL) of lithium tetramethylpiperidine (33 mmol) was added dropwise over 5 minutes and then stirred at -70 ° C for 13 hours. Subsequently, crushed dry ice (140 g) was added and stirred at room temperature until gas evolution ceased. THF was distilled off under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained after filtration and concentration was recrystallized from hexane / ethyl acetate to obtain 2-fluoro-5-methoxybenzoic acid (Compound 1, 2.74 g, yield 54%) as a white solid.
Compound 1
¹ H NMR (CDCl ₃ ): δ 3.82 (s, 3H), 7.06-7.11 (m, 2H), 7.46-7.48 (m, 1H)

  The obtained compound 1 (1.70 g, 10 mmol) was suspended in methylene chloride (30 mL), N, N-dimethylformamide (3 drops) was added and cooled to 0 ° C., and oxalyl chloride (1.29) was added to this solution. mL, 15 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent and oxalyl chloride were distilled off under reduced pressure and dissolved in methylene chloride (10 mL) to obtain 2-fluoro-5-methoxybenzoyl chloride (10 mL, 10 mmol, 1.0 M methylene chloride solution) as a yellow liquid.

N-tert-butyloxycarbonyl-L-leucine (2.99 g, 12 mmol) was suspended in toluene (60 mL), and triethylamine (1.99 mL, 14 mmol) and pivaloyl chloride (1.61) were added under ice cooling. mL, 13 mmol) was sequentially added, and the mixture was stirred at room temperature for 15 minutes. The filtrate obtained by Celite filtration was cooled to 0 ° C., 2-benzyloxy-4-fluoroaniline (2.17 g, 10 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. 1N Hydrochloric acid was added, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained after filtration and concentration was purified by flash column chromatography (hexane / ethyl acetate = 4/1) to give compound 2.
Compound 2
¹ H NMR (CDCl ₃ ): δ 0.91 (d, J = 6.4 Hz, 6H), 1.38 (s, 9H), 1.46-1.54 (m, 1H), 1.64-1.76 (m, 2H), 4.20 (brs, 1H), 4.87 (brs, 1H), 5.09 (s, 2H), 6.63-6.67 (m, 2H), 7.32-7.40 (m, 5H), 8.27 (brs, 1H), 8.29 (dd, J = 1.4, (8.6 Hz, 1H)

  The obtained compound 2 was dissolved in methylene chloride (10 mL), 4N hydrogen chloride cyclopentyl methyl ether solution (40 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and the resulting solid residue was dissolved in methanol. After adding diethyl ether, the insoluble component obtained was collected by filtration and washed thoroughly with diethyl ether. After drying under reduced pressure, (2S) -2-amino-N- (2-benzyloxy-4-fluoro) phenyl-2-isobutylacetamide hydrochloride (3.34 g, 2-step yield 91%) was obtained as a colorless powder. It was.

A suspension of the obtained hydrochloride (1.65 g, 4.5 mmol) in methylene chloride (30 mL) was cooled to 0 ° C., and 2-fluoro-5-methoxybenzoyl chloride (5.0 mL, 5.0 mmol, 1.0 M in methylene chloride) ) And triethylamine (1.39 mL, 10 mmol) were sequentially added. After stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted twice with methylene chloride. The combined organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained after filtration and concentration was purified by flash column chromatography (hexane / ethyl acetate = 4/1) to obtain compound 3 (2.0 g, yield 92%).
Compound 3
¹ H NMR (CDCl ₃ ): δ 0.93 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H), 1.66-1.74 (m, 2H), 1.83-1.88 (m, 1H) , 3.77 (s, 3H), 4.75-4.78 (m, 1H), 5.07 (s, 2H), 6.64-6.68 (m, 2H), 6.97-7.04 (m, 2H), 7.16 (dd, J = 8.0, 14.3 Hz, 1H), 7.29-7.33 (m, 3H), 7.38 (dd, J = 1.8, 7.9 Hz, 2H), 7.51 (dd, J = 3.4, 6.1 Hz, 1H), 8.28 (dd, J = 6.1 , 8.9 HZ, 1H), 8.32 (s, 1H)

The obtained compound 3 (2.0 g, 4.1 mmol) was dissolved in methylene chloride (10 mL), and boron tribromide (23 mL, 23 mmol, 1.0 M methylene chloride solution) was added at 0 ° C. After stirring at 0 ° C. for 3 hours, water (70 mL) was added, the mixture was stirred at room temperature for 30 minutes, and the mixed solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained after filtration and concentration was purified by flash column chromatography (hexane / ethyl acetate = 1/1) and recrystallized from hexane / chloroform to give Compound 4 (1.30 g, 84% yield) as colorless amorphous crystals. Obtained as a mass.
Compound 4
¹ H NMR (CD ₃ OD): δ 1.00 (d, J = 6.5 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H), 1.77-1.83 (m, 3H), 4.75-4.78 (m, 1H ), 6.54 (dd, J = 8.8, 8.9 Hz, 1H), 6.58 (dd, J = 2.8, 10.1 Hz, 1H), 6.88-6.92 (m, 1H), 7.04 (dd, J = 9.2, 10.1 Hz, 1H), 7.11 (dd, J = 3.1, 5.5 Hz, 1H), 7.75 (dd, J = 6.4, 8.9 Hz, 1H)

Moreover, the following compounds were manufactured for the comparison of a ligand.

Compound 5
¹ H NMR (CDCl ₃ ): δ 0.96 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H), 1.52-1.58 (m, 1H), 1.82-1.88 (m, 2H) , 2.87-2.91 (m, 2H), 3.56 (t, J = 6.4 Hz, 2H), 5.49 (t, J = 8.6 Hz, 1H), 6.81 (dd, J = 7.9, 7.9 Hz, 1H), 6.93- 6.97 (m, 2H), 7.04-7.09 (m, 3H), 7.60 (brs, 1H), 8.79 (s, 1H)
Compound 6
¹ H NMR (CDCl ₃ ): δ 0.97 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.3 Hz), 1.71-1.79 (m, 2H), 1.87-1.93 (m, 1H), 4.81 -4.86 (m, 1H), 6.57 (d, J = 7.5 Hz, 1H), 6.83 (dd, J = 7.5, 7.5 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 7.08-7.12 ( m, 2H), 7.21-7.26 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 8.84 (brs, 1H)

Compound 7
¹ H NMR (CD ₃ OD): δ 0.99 (d, J = 5.5 Hz, 3H), 1.02 (d, J = 5.8 Hz, 3H), 1.76-1.86 (m, 3H), 4.74-4.77 (m, 1H ), 6.66 (ddd, J = 3.1, 8.6, 8.6 Hz, 1H), 6.76 (dd, J = 5.2, 8.6 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 7.27-7.33 (m, 3H), 7.83 (dd, J = 3.1, 10.7 Hz, 1H)
Compound 8
¹ H NMR (CD ₃ OD): δ 1.00 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H), 1.79-1.83 (m, 3H), 4.76-4.79 (m, 1H ), 6.80 (ddd, J = 1.5, 7.9, 7.9 Hz, 1H), 6.84 (dd, J = 1.2, 7.9 Hz, 1H), 6.89-6.92 (m, 1H), 6.97 (ddd, J = 1.5, 7.9 , 7.9 Hz, 1H), 7.04 (dd, J = 8.9, 10.4 Hz, 1H), 7.10-7.12 (m, 1H), 7.80 (dd, J = 1.5, 7.9 Hz, 1H)

加熱真空乾燥した試験管に化合物4（6.8 mg, 0.018 mmol）を加え、10分間真空乾燥した後、アルゴン雰囲気下にてTHF（0.30 mL）、Nd(OⁱPr)₃（0.2 M/THF溶液, 45 μL, 0.009 mmol）を加え10分間攪拌した。この懸濁液に氷冷下NaHMDS（1.0 M/THF溶液, 18 μL, 0.018 mmol）を加え、室温にてニトロエタン（0.21 ml, 3.0 mmol）、水（0.2 M/THF溶液, 45 μL, 0.009 mmol）、THF（1.1 mL）を順次加えた。試験管を-40 ℃の恒温槽に移し、ベンズアルデヒド（30 μL, 0.30 mmol）を加えて15時間攪拌した後、1N塩酸（3 mL）を加え、その混合溶液をジエチルエーテル（30mL）にて抽出し、飽和重曹水、飽和食塩水で洗い、硫酸ナトリウムで乾燥した。目的物の化学収率98%（¹H NMR, 内部標準1,4-dioxane）、anti/syn = >40/1、ee 88%。 Example 2

Compound 4 (6.8 mg, 0.018 mmol) was added to a test tube that had been vacuum-dried by heating, dried in vacuo for 10 minutes, and then THF (0.30 mL), Nd (O ⁱ Pr) ₃ (0.2 M / THF solution) under an argon atmosphere , 45 μL, 0.009 mmol) and stirred for 10 minutes. NaHMDS (1.0 M / THF solution, 18 μL, 0.018 mmol) was added to this suspension under ice-cooling, and nitroethane (0.21 ml, 3.0 mmol) and water (0.2 M / THF solution, 45 μL, 0.009 mmol) were added at room temperature. ) And THF (1.1 mL) were sequentially added. Transfer the test tube to a -40 ° C thermostatic bath, add benzaldehyde (30 μL, 0.30 mmol), stir for 15 hours, add 1N hydrochloric acid (3 mL), and extract the mixed solution with diethyl ether (30 mL). The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. 98% chemical yield of the desired product ⁽¹ H NMR, the internal standard 1,4-dioxane), anti / syn => 40/1, ee 88%.

Example 3
The same reaction as in Example 2 was performed using a catalyst suspension prepared using the isolated catalyst. Compound 4 (6.8 mg, 0.018 mmol) was added to a heated and vacuum-dried glass tube, vacuum-dried for 10 minutes, then THF (0.30 mL), Nd (O ⁱ Pr) ₃ (0.2 M / THF solution) under an argon atmosphere. , 45 μL, 0.009 mmol), and vigorously stirred with a vortex mixer. NaHMDS (1.0 M / THF solution, 18 μL, 0.018 mmol), nitroethane (40 μL, 0.57 mmol) and water (0.2 M / THF solution, 45 μL, 0.009 mmol) at room temperature were added to this suspension under ice cooling. Sequentially added and vigorously stirred with a vortex mixer. After 30 minutes, the solution was transferred to an Eppendorf tube, centrifuged for 1 minute (13750 rpm), and the supernatant was discarded to isolate the complex. THF (1.0 mL) was added thereto, and the mixture was vigorously stirred with a vortex mixer and centrifuged again for 1 minute (13750 rpm). As above, the supernatant was discarded to isolate the complex, and THF (1.3 mL) was added to form a catalyst suspension. Add nitroethane (0.21 mL, 3.0 mmol) and the prepared catalyst suspension to a separately prepared heated and vacuum-dried test tube in an argon atmosphere, transfer the test tube to a -40 ° C thermostatic bath, and add benzaldehyde (30 μL, 0.30 mmol) was added. After stirring at −40 ° C. for 7 hours, 1N hydrochloric acid (3 mL) was added, and the mixed solution was extracted with diethyl ether (30 mL), washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. Chemical yield 99% ( ¹ H NMR, internal standard 1,4-dioxane), anti / syn => 40/1, 93% ee. The anti / syn ratio and optical yield (ee.%) Obtained by this reaction were significantly higher than when the corresponding compound having no fluorine atom introduced was used as the ligand ( (See Entry 5 in Table 2 of Tetrahedron Letters, 49, pp.272-276, 2008).

Example 4
The reaction was carried out in the same manner as in Example 2 or Example 3 by changing the reaction conditions, the aldehyde compound, and / or the nitroalkane. The results are shown in Table 1. Entry number 1 shows the result of Example 3 above, entry numbers 3 and 4 show the result of changing the amount of nitroethane (usually 10 equivalents) to 4 or 1 equivalent, and entry number 5 sets the reaction temperature to 0 ° C. Entry number 6 shows the result when nitropropane was used instead of nitroethane, entry number 8 shows the result when the substrate concentration was changed from 0.2 M to 0.5 M, and entry 10 And 11 show the results when using the supernatant and the precipitate at the time of catalyst preparation, respectively, and entry numbers 12 and 13 are when the precipitate obtained at the time of catalyst preparation is washed once and dried (entry number 12) and similarly The results when the prepared catalyst was used undried (entry number 13) are shown.

Example 5
For comparison, a catalyst was prepared using compounds 5 to 8 in the same manner as in Example 2, and the same nitroaldol reaction was performed at a catalyst amount of 9 mol% and a reaction temperature of -40 ° C. The results are shown in Table 2.

Example 6
A catalyst was prepared in the same manner as in Example 2 or Example 3 using a rare earth metal other than Compound 4 and Nd, and a similar nitroaldol reaction was performed at a catalyst amount of 3 mol% and a reaction temperature of -40 ° C. The results are shown in Table 3.

Claims (9)

A method for producing an optically active anti-1,2-nitroalkanol compound, wherein an aldehyde compound and a nitroalkane compound having 2 or more carbon atoms are represented by the following general formula (I):

(Wherein R ¹ represents a C _3-8 branched chain alkyl group , and X ¹ and X ² represent a fluorine atom ) One of the metal species is selected from lanthanoids and the other metal is an alkali metal). 2. The method according to claim 1, wherein the complex is a heterogeneous metal complex containing neodymium (Nd) or samarium (Sm) as a lanthanoid and sodium as an alkali metal. The method according to claim 1 or 2, wherein R ¹ is an isobutyl group. The nitroalkane is a nitroalkane represented by R ¹¹ —CH ₂ —NO ₂ (wherein R ¹¹ represents a C ₁ -C ₂₀ alkyl group, and the alkyl group may have a substituent). 4. A method according to any one of claims 1 to 3 . The process according to any one of claims 1 to 4 , wherein the reaction temperature is in the range of -50 to -30 ° C. 6. The method according to any one of claims 1 to 5 , comprising the step of isolating and resuspending the prepared complex. The method according to any one of claims 1 to 6 , wherein the method is carried out in the presence of an approximately equal amount of water to the lanthanoid. The dissimilar metal complex complex according to claim 1, comprising a compound represented by the general formula (I) as a ligand. A compound represented by the general formula (I) according to claim 1.