JP2003261544A - Method for producing optically active isoxazolidine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new method for the production of an optically active isoxazolidine compound useful as a component or an important intermediate of pharmaceuticals or agrochemicals, and an intermediate useful for synthesis of fine chemicals. <P>SOLUTION: The method for the production of the optically active isoxazolidine compound contains the reaction of nitrones with olefins in the presence of an optically active cobalt complex catalyst or an optically active chromium complex catalyst. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active isoxazolidines, and particularly to optically active isoxazolidines which are intermediates useful in the synthesis of fine chemicals, such as drug substances, agricultural chemicals, and other important intermediates. In asymmetric 1,3-dipolar cycloaddition reaction.

[0002]

2. Description of the Related Art As a method for synthesizing optically active isoxazolidines, a method using an asymmetric 1,3-dipolar cycloaddition reaction using nitrone as a substrate is known as a method for producing three asymmetric centers on a 5-membered ring. Is considered to be a useful technique. Although a large number of diastereoselective reactions have been reported so far, enantiomerically selective enantiomers using a catalytic amount of an asymmetric source, which requires a small amount of an asymmetric source that is generally expensive and has a wide range of applications, have been reported. There are not many reports of simultaneous 1,3-dipolar cycloaddition reactions, and the development of practical methods is urgently needed (Chem, Rev., 98, 863 (1998)). The asymmetric 1,3-dipolar cycloaddition reaction of nitrone that has been known so far is a method using an optically active Lewis acid catalyst. As the catalyst, an optically active titanium complex catalyst or an optically active titanium complex catalyst is used. Known magnesium complex catalysts, optically active palladium complex catalysts, optically active ytterbium complex catalysts, optically active nickel complex catalysts, and the like are known.

For example, in J.Org.Chem., 59,5687 (1994), an asymmetric 1,3-dipolar cycloaddition reaction of a nitrone using a titanium complex is described in J.Org.Chem., 61,346 ( 1996) described the asymmetric 1,3-dipolar cycloaddition reaction using magnesium complex by Tetrah.
edron Lett., 37, 5947 (1996) describes asymmetric 1,3-dipolar cycloaddition reaction using a palladium complex by Tetrahedron Let.
t., 38,7923 (1997) and J. Am. Chem. Soc, 120, 5840 (1998).
The asymmetric 1,3-dipolar cycloaddition reaction using a ytterbium complex was carried out for J. Am. Chem. Soc, 120, 12355 (1998), and the asymmetric 1,3 was carried out using a nickel complex. -Dipolar cycloaddition reactions have been reported respectively.

Up to now, the above-mentioned asymmetric cycloaddition reaction has been
In order to prevent the coordination of nitrone to the Lewis acid catalyst, which is a factor that inhibits the reaction, and to activate the dipolar parent compound more, α, β-unsaturation modified with oxazolidinone as shown in the following reaction formula (l) There has been a need to use amide compounds as parent dipole compounds. Therefore, modification of the substrate
Since the steps for (protection) and deprotection had to be incorporated, the whole process had to be complicated.

[0005]

[Chemical 15]

A new catalyst system was developed to solve this problem, and an application example to the reaction represented by the following reaction formula (m) was recently reported. Asymmetric 1,3-dipolar cycloaddition reaction of nitrones and crotonaldehydes using an optically active imidazolidinone as an asymmetric catalyst instead of a metal catalyst (J. Am. Chem. So.
c ,, 122,9874 (2000)) by MacMillan et al., and asymmetric 1,3-dipolar cycloaddition reaction of nitrone and acrolein using an optically active bisoxazoline / zinc complex as an asymmetric catalyst (Nippon Kagaku). Kinsei et al. Reported the 78th Annual Meeting of the Society, 4G108 (2000); the 80th Annual Meeting of the Chemical Society of Japan, 2H608, 2H609 (2001), respectively, which are all excellent methods.

[0007]

[Chemical 16]

[0008]

However, various improvements have been made to the asymmetric catalyst in the above-mentioned asymmetric 1,3-dipolar cycloaddition reaction, and the regioselectivity of the reaction, endo / exo reaction are still being improved. Not only selectivity, enantioselectivity, but also a wide range of substrates, substrate / catalyst ratio, reduction of environmental load, etc. The current situation is that development is actively carried out.

As described above, the optically active isoxazolidines, which are useful intermediates in the synthesis of fine chemicals such as drug substances and agricultural chemicals, and important intermediates, can be efficiently produced by a catalytic amount of an asymmetric source. It is desired to provide a novel method capable of achieving the above, and the present invention has an object to satisfy these needs.

[0010]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors have conducted extensive studies on a complex having a catalytic ability in an asymmetric 1,3-dipolar cycloaddition reaction, and as a result, The present invention has been completed. That is, the present invention is
When a nitrone and a dipole-philic compound are subjected to a 1,3-dipolar cycloaddition reaction using an optically active Lewis acid catalyst to produce optically active isoxazolidines, a tetradentate as a Lewis acid catalyst is used. The present invention relates to a method for producing an optically active isoxazolidine compound, which comprises using an optically active cobalt complex or an optically active chromium complex composed of the optically active ligand.

That is, the present invention includes the following inventions. (1) The following general formula (a):

[0012]

[Chemical 17]

[R ¹ , R ² and R ³ each independently represent a hydrogen atom, a linear, branched or cyclic alkyl group or an aryl group, and at least one of the alkyl group and the aryl group is It may have a substituent,
R ¹ and R ² or R ² and R ³ may form a ring together with the atom to which they are bonded. ] And the following general formula (b):

[0014]

[Chemical 18]

[In the formula, R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom, a formyl group, a carboxyl group, a linear, branched or cyclic alkyl group or aryl. A group, an alkoxy group, an aryloxy group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aminocarbonyl group, a cyano group, or a nitro group, the alkyl group or the aryl group. At least one of an alkoxy group, an aryloxy group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group and an aminocarbonyl group may have a substituent, and R ⁴ and R ⁵ combination, R ⁵ and R ⁶ combination, R ⁶ and R ⁷ combination Each of one or more combinations selected from the group consisting of combinations and combinations of R ⁷ and R ⁴ ,
The substituents constituting the combination and the atom to which they are bound may cooperate to form a ring. Also,
At least one of R ⁴ , R ⁵ , R ⁶ and R ⁷ is an electron withdrawing substituent. And an olefin represented by the following general formula (c):

[0016]

[Chemical 19]

[In the formula, Y ¹ and Y ² are different groups, and each is a hydrogen atom, a linear, branched, or cyclic alkyl group or an aryl group (the aryl group is a halogen atom, an alkyl group, Which may be substituted with at least one of an alkoxy group, a cyano group and a nitro group).
At least one of the two Y ^{1 s} and the two Y ^{2 s} is
They may be bonded to each other to form a ring. Also, Y ³ ,
Y ⁴ and Y ⁵ are each independently a hydrogen atom, a linear, branched, or cyclic alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, Or an aralkyloxycarbonyl group, and at least one of the alkyl group, alkenyl group, aryl group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group, and aralkyloxycarbonyl group may have a substituent, Further, Y ⁴ and Y ⁵ may be linked to each other to form a ring in cooperation with the carbon atom to which they are bonded. Further, M represents cobalt or chromium ion, Z represents an anion pair capable of forming a salt when the valence of these metal ions and the valence of the ligand are different, and the valence of the metal ion and the ligand When the valences are the same, Z does not exist. ] The following general formula (d) including a step of reacting in the presence of an optically active metal complex compound consisting of a tetradentate ligand represented by:

[0018]

[Chemical 20]

[In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined above. * Represents an asymmetric carbon atom, and means that the absolute configuration of the carbon atom is (R) or (S). ] The manufacturing method of optically active isoxazolidines represented by these.

(2) The following general formula (a):

[0021]

[Chemical 21]

[R ¹ , R ² and R ³ each independently represent a hydrogen atom, a linear, branched or cyclic alkyl group or aryl group, and at least one of the alkyl group and aryl group is It may have a substituent,
R ¹ and R ² or R ² and R ³ may form a ring together with the atom to which they are bonded. ] And the following general formula (e):

[0023]

[Chemical formula 22]

[Wherein X ¹ represents a hydrogen atom, a hydroxyl group, an amino group, a linear, branched or cyclic alkyl group, an aryl group, an alkoxy group, an aryloxy group, an alkylamino group or an arylamino group. At least one of the above-mentioned alkyl group, aryl group, alkoxy group, aryloxy group, alkylamino group, and arylamino group
May have a substituent, X ² , X ³ and X ⁴ each independently represent a hydrogen atom, a halogen atom, a linear, branched or cyclic alkyl group, or an aryl group, At least one of the alkyl group and the aryl group may have a substituent, and a combination of X ¹ and X ² ,
Each of one or two or more combinations selected from the group consisting of a combination of X ² and X ^3, a combination of X ³ and X ⁴ , and a combination of X ⁴ and X ¹ , and the substituents that form the combination It may be one which forms a ring in cooperation with the atom to which it is bonded. ] Α, β-unsaturated carbonyls represented by
The following general formula (c):

[0025]

[Chemical formula 23]

[In the formula, Y ¹ and Y ² are different groups, and each is a hydrogen atom, a linear, branched, or cyclic alkyl group, or an aryl group (the aryl group is a halogen atom, an alkyl group, Which may be substituted with at least one of an alkoxy group, a cyano group and a nitro group).
At least one of the two Y ^{1 s} or the two Y ^{2 s} may be bonded to each other to form a ring. Also, Y
³ , Y ⁴ and Y ⁵ are each independently a hydrogen atom, a straight chain,
A branched or cyclic alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group, the alkyl group,
At least one of an alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, and an aralkyloxycarbonyl group may have a substituent, and Y ⁴ and Y ⁵ are connected to each other. And may form a ring in cooperation with the carbon atom to which they are bonded. Also, M represents cobalt or chromium ion,
When the valence of these metal ions and the valence of the ligand are different, Z
Represents an anion pair capable of forming a salt, and Z does not exist when the valence of the metal ion and the valence of the ligand are the same. ] The following general formula (f) including a step of reacting in the presence of an optically active metal complex compound consisting of a tetradentate ligand represented by:

[0027]

[Chemical formula 24]

[Wherein R ¹ , R ² , R ³ , X ¹ , X ² , X ³ ,
X ⁴ and * are the same as above. ] The manufacturing method of optically active isoxazolidines represented by these.

(3) The following general formula (g):

[0030]

[Chemical 25]

[Wherein W ¹ and W ² are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a formyl group, a carboxyl group, a linear, branched or cyclic alkyl group, a linear chain, Alternatively, a branched alkenyl group, aryl group, alkoxy group, aryloxy group, alkylcarbonyloxy group, arylcarbonyloxy group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group, aminocarbonyl group, sulfonyl group, phosphinyl group, nitro Represents a group or a cyano group, and is an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an aryloxy group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aminocarbonyl group. , A sulfonyl group, And at least one of the phosphonyl groups may have a substituent. In addition, m and n are each independently an integer of 1 to 5, and m or n is 2 to 4
When at least one of the plurality of W ^{1 s} and the plurality of W ^{2 s} is an integer of at least two different substituents may be contained. In addition, two W ^1's may be linked to each other to form a ring in cooperation with the atoms respectively bonded. ] The nitrone represented by the following general formula
(e):

[0032]

[Chemical formula 26]

[In the formula, X ¹ represents a hydrogen atom, a hydroxyl group, an amino group, a linear, branched, or cyclic alkyl group, an aryl group, an alkoxy group, an aryloxy group, an alkylamino group, or an arylamino group. At least one of the above-mentioned alkyl group, aryl group, alkoxy group, aryloxy group, alkylamino group, and arylamino group
May have a substituent, X ² , X ³ and X ⁴ each independently represent a hydrogen atom, a halogen atom, a linear, branched or cyclic alkyl group, or an aryl group, At least one of the alkyl group and the aryl group may have a substituent, and a combination of X ¹ and X ² ,
Each of one or two or more combinations selected from the group consisting of a combination of X ² and X ^3, a combination of X ³ and X ⁴ , and a combination of X ⁴ and X ¹ , and the substituents that form the combination It may be one which forms a ring in cooperation with the atom to which it is bonded. ] Α, β-unsaturated carbonyls represented by
The following general formula (c):

[0034]

[Chemical 27]

[In the formula, Y ¹ and Y ² are different groups, and each is a hydrogen atom, a linear, branched, or cyclic alkyl group, or an aryl group (the aryl group is a halogen atom, an alkyl group, Which may be substituted with at least one of an alkoxy group, a cyano group and a nitro group).
At least one of the two Y ^{1 s} or the two Y ^{2 s} may be bonded to each other to form a ring. Also, Y
³ , Y ⁴ and Y ⁵ are each independently a hydrogen atom, a straight chain,
A branched or cyclic alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group, the alkyl group,
At least one of an alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, and an aralkyloxycarbonyl group may have a substituent, and Y ⁴ and Y ⁵ are connected to each other. And may form a ring in cooperation with the carbon atom to which they are bonded. Also, M represents cobalt or chromium ion,
When the valence of these metal ions and the valence of the ligand are different, Z
Represents an anion pair capable of forming a salt, and Z does not exist when the valence of the metal ion and the valence of the ligand are the same. ] The following general formula (h) including a step of reacting in the presence of an optically active metal complex compound consisting of a tetradentate ligand represented by:

[0036]

[Chemical 28]

[Wherein W ¹ , W ² , X ¹ , X ² , X ³ , X ⁴ ,
m, n and * are the same as above. ] The manufacturing method of optically active isoxazolidines represented by these.

(4) The method for producing an optically active isoxazolidine according to the above (2) or (3), wherein X ^{1 in} the formula (e) is a hydrogen atom.

(5) An optically active metal complex compound comprising a tetradentate ligand represented by the general formula (c) is represented by the following general formula
(i):

[0040]

[Chemical 29]

[Wherein Y ¹ and Y ² are the same as defined above,
Y ⁶ represents a linear, branched, or cyclic alkyl group, aryl group, alkoxy group, or aryloxy group, and at least one of the alkyl group, aryl group, alkoxy group, and aryloxy group is a substituent. You may have. Z ⁻ means an anion pair capable of forming a salt. ] The manufacturing method of the optically active isoxazolidines in any one of (1)-(4) which is an optically active cobalt (III) complex represented by these.

(6) The general formula (f) or (h) produced according to claim 4, wherein X ¹ is a hydrogen atom. ] The optically active isoxazolidines represented by the following general formula (j) or a step including a step of directly reacting with sodium borohydride without isolation / purification after the reaction
(k):

[0043]

[Chemical 30]

[Wherein R ¹ , R ² , R ³ , X ² , X ³ , X ⁴ ,
W ¹ , W ² , m, n and * are the same as above. ] The manufacturing method of optically active isoxazolidines represented by these.

[0045]

BEST MODE FOR CARRYING OUT THE INVENTION The method for producing the optically active isoxazolidines of the present invention (hereinafter referred to as the "method of the present invention") will be described in detail below.

The method of the present invention comprises the following formula (a):

[0047]

[Chemical 31]

Nitrons represented by the following formula (b):

[0049]

[Chemical 32]

It is suitable for the production of the corresponding optically active oxazolidines by using the olefins represented by as a starting material.

In the general formula (a), R ¹ , R ² and R
³ each independently represents a hydrogen atom, a linear, branched, or cyclic alkyl group, or an aryl group, and at least one of the alkyl group and the aryl group does not impair the intended reaction in the present invention. You may have a substituent in the range.

Typical examples of the linear, branched or cyclic alkyl group are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and sec.
-Butyl group, tert-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 1,1,2-trimethyl-n-propyl group, 1,2,2-trimethyl-n-propyl group, and 3,3-
Examples thereof include a dimethyl-n-butyl group, and typical examples of the cyclic alkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

Typical examples of the aryl group are phenyl group, o-hydroxyphenyl group, o-methoxyphenyl group, o-chlorophenyl group, o-bromophenyl group and p-
Hydroxyphenyl group, p-methoxyphenyl group, p-chlorophenyl group, p-bromophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 2,3,5-trichlorophenyl Group, α-
Examples thereof include a naphthyl group, a β-naphthyl group, and a substituted or unsubstituted aromatic heterocyclic group such as a furan ring, a thiophene ring and a pyridine ring.

R ¹ and R ² or R ² and R ³ are connected to each other to form a ring in cooperation with the atom (nitrogen atom or carbon atom) to which they are bonded. Good. For example, when both R ¹ and R ² represent a phenyl group and the ortho positions on both benzene rings are linked to each other via a methylene chain, a 7-membered ring is formed together with the molecular chain to be replaced. It Alternatively, R ² and R ³ are linked to each other to form-(CH
₂ ) When _5- , a cyclohexane ring is formed. A ring such as a cyclohexane ring formed in this manner is, for example,
Alkyl group such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and tert-butyl group; substituted with one or more substituents selected from aryl groups such as phenyl group and naphthyl group May be.

Next, in the general formula (b), R ⁴ , R ⁵ ,
R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom, a formyl group, a carboxyl group, a linear, branched or cyclic alkyl group, an aryl group, an alkoxy group,
Represents an aryloxy group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aminocarbonyl group, a cyano group, or a nitro group, wherein the alkyl group, the aryl group, the alkoxy group, the aryl At least one of an oxy group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, and an aminocarbonyl group has a substituent as long as the reaction intended in the present invention is not impaired. May be.

As a typical example of the halogen atom, fluorine,
Examples thereof include chlorine, bromine and iodine atoms.

Typical examples of the linear or branched alkyl group are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, 1 -Pentyl group, 2-pentyl group,
3-pentyl group, isopentyl group, neopentyl group, ter
t-pentyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 1,1,2-trimethyl-n-propyl group, 1,
2,2-trimethyl-n-propyl group and 3,3-dimethyl
Examples of the cyclic alkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

Typical examples of the aryl group are phenyl group, o-hydroxyphenyl group, o-methoxyphenyl group, o-chlorophenyl group, o-bromophenyl group and p-
Hydroxyphenyl group, p-methoxyphenyl group, p-chlorophenyl group, p-bromophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 2,3,5-trichlorophenyl Group, α-
Examples thereof include a naphthyl group, a β-naphthyl group, and a substituted or unsubstituted aromatic heterocyclic group such as a furan ring, a thiophene ring and a pyridine ring.

Typical examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group and a sec-butoxy group.

Typical examples of the aryloxy group include a phenoxy group, an α-naphthyloxy group and a β-naphthyloxy group.

As typical examples of the alkylcarbonyloxy group, acetoxy group, ethylcarbonyloxy group, n-
Examples thereof include a propylcarbonyloxy group, an isopropylcarbonyloxy group, an n-butylcarbonyloxy group, an isobutylcarbonyloxy group and a sec-butylcarbonyloxy group.

Representative examples of the arylcarbonyloxy group include a benzoyloxy group, an α-naphthylcarbonyloxy group and a β-naphthylcarbonyloxy group.

As a typical example of the acyl group, an acetyl group,
Examples thereof include ethylcarbonyl group, n-propylcarbonyl group, isopropylcarbonyl group, n-butylcarbonyl group, isobutylcarbonyl group and sec-butylcarbonyl group.

Typical examples of the alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, n
Examples include-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group and the like.

Typical examples of the aryloxycarbonyl group include a phenoxycarbonyl group, an α-naphthoxycarbonyl group and a β-naphthoxycarbonyl group.

Typical examples of the aminocarbonyl group include a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a phenylmethylaminocarbonyl group, a 1-pyrrolidinylcarbonyl group, a 1-piperidinylcarbonyl group and a dibenzylaminocarbonyl group. Can be mentioned.

R ⁴ and R ⁵ , R ⁵ and R ⁶ , R ⁶ and R ⁷ or R ⁷ and R ⁴ may be connected to each other to form a ring together with the atom (carbon atom) to which they are bonded. Good. Further, two or more ring structures may be formed together with the substituted molecular chain by two or more of the combinations selected from these four combinations (consisting of two substituents). The ring structures may be the same, or at least two different ring structures may be formed. For example, when R ⁵ and R ⁶ are linked to each other to give — (CH ₂ ) ₃ — or — (CH ₂ ) ₄ —, a cyclopentene ring or a cyclohexene ring is formed, respectively. The thus formed rings such as a cyclopentene ring and a cyclohexene ring are, for example, methyl group, ethyl group, n-
It may be substituted with one or more substituents selected from alkyl groups such as propyl group, isopropyl group, n-butyl group and tert-butyl group; aryl groups such as phenyl group and naphthyl group.

Further, at least one of R ⁴ , R ⁵ , R ⁶ and R ⁷ is an electron-withdrawing substituent, and representative examples thereof include a formyl group, a carboxyl group, a phenyl group, a cyano group, a nitro group and an acyl group. Groups, alkoxycarbonyl groups and the like.

Further, the method of the present invention has the following formula (e):

[0070]

[Chemical 33]

Α, β-unsaturated carbonyls represented by: and the following formula (g):

[0072]

[Chemical 34]

It is more preferable to use a nitrone represented by the following as a starting material.

In the general formula (e), X ¹ , X ² , X ³
And X ⁴ are independent of each other, and among them, X ¹ is a hydrogen atom, a hydroxyl group, an amino group, a linear, branched or cyclic alkyl group, an aryl group, an alkoxy group, an aryloxy group, an alkylamino group or An arylamino group is shown, and at least one of the above alkyl group, aryl group, alkoxy group, aryloxy group, alkylamino group and arylamino group has a substituent within a range that does not impair the intended reaction in the present invention. May be.

Typical examples of the linear or branched alkyl group are methyl group, ethyl group, n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-hexyl group Group, 2-hexyl group, 3-hexyl group, 1,1,2-trimethyl-n-propyl group, 1,2,2-trimethyl-n-propyl group, and 3,3-
Examples thereof include a dimethyl-n-butyl group, and typical examples of the cyclic alkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

Typical examples of the aryl group are phenyl group, o-hydroxyphenyl group, o-methoxyphenyl group, o-chlorophenyl group, o-bromophenyl group and p-
Hydroxyphenyl group, p-methoxyphenyl group, p-chlorophenyl group, p-bromophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 2,3,5-trichlorophenyl Group, α-
Examples thereof include a naphthyl group, a β-naphthyl group, and a substituted or unsubstituted aromatic heterocyclic group such as a furan ring, a thiophene ring and a pyridine ring.

Typical examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group and a sec-butoxy group.

Typical examples of the aryloxy group include a phenoxy group, an α-naphthyloxy group and a β-naphthyloxy group.

As a typical example of the alkylamino group, N,
Examples thereof include N-dimethylamino group, N, N-diethylamino group, 1-pyrrolidinyl group, 1-piperidinyl group and N, N-dibenzylamino group.

As a typical example of the arylamino group, N-
Examples thereof include a phenylamino group and an N-methyl-N-phenylamino group.

Further, X ² , X ³ and X ⁴ each independently represent a hydrogen atom, a halogen atom, a linear, branched or cyclic alkyl group or an aryl group, and the alkyl group and the aryl group At least one of the groups may have a substituent within a range that does not impair the intended reaction in the present invention.

Typical examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms.

Typical examples of the linear or branched alkyl group are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, 1 -Pentyl group, 2-pentyl group,
3-pentyl group, isopentyl group, neopentyl group, ter
t-pentyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 1,1,2-trimethyl-n-propyl group, 1,
2,2-trimethyl-n-propyl group and 3,3-dimethyl
Examples of the cyclic alkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

Typical examples of the aryl group are phenyl group, o-hydroxyphenyl group, o-methoxyphenyl group, o-chlorophenyl group, o-bromophenyl group and p-
Hydroxyphenyl group, p-methoxyphenyl group, p-chlorophenyl group, p-bromophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 2,3,5-trichlorophenyl Group, α-
Examples thereof include a naphthyl group, a β-naphthyl group, and a substituted or unsubstituted aromatic heterocyclic group such as a furan ring, a thiophene ring and a pyridine ring.

X ¹ and X ² , X ² and X ³ , X ³ and X ⁴ or X ⁴ and X ¹ may be linked to each other to form a ring with the atom (carbon atom) to which they are bonded. Good. Further, two or more ring structures may be formed together with the molecular chain on the side to be replaced by two or more of the combinations selected from these four combinations (consisting of two substituents), in which case two or more The ring structures may be the same, or at least two different ring structures may be formed.

For example, when X ² and X ³ are linked to each other,-(CH
_{2) 3} - or - (CH _{2) 4} - and may become, respectively cyclopentene ring, cyclohexene ring is formed. The thus formed ring such as a cyclopentene ring or a cyclohexene ring is, for example, an alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a tert-butyl group; a phenyl group or a naphthyl group. It may be substituted with one or more substituents selected from aryl groups such as groups.

As a particularly preferred specific example of the α, β-unsaturated carbonyls represented by the general formula (e), the following formula (e-
Examples thereof include those represented by 1) to (e-10).

[0088]

[Chemical 35]

In the general formula (g), W ¹ and W ² are each independently a hydrogen atom, a halogen atom,
Hydroxyl group, amino group, formyl group, carboxyl group, linear, branched or cyclic alkyl group, linear or branched alkenyl group, aryl group, alkoxy group, aryloxy group, alkylcarbonyloxy group, arylcarbonyloxy A group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aminocarbonyl group, a sulfonyl group, a phosphinyl group, a nitro group, or a cyano group, and the alkyl group, an alkenyl group, an aryl group, an alkoxy group, an aryloxy group, At least one of an alkylcarbonyloxy group, an arylcarbonyloxy group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aminocarbonyl group, a sulfonyl group, and a phosphonyl group does not impair the intended reaction in the present invention. It may have a substituent enclosed.
Further, m and n are each independently an integer of 1 to 5. Further, when m or n is an integer of 2 to 4, the plurality of groups in at least one of the plurality of W ¹ and the plurality of W ² may be the same or may include at least two different groups. . For example, when having three W ¹ , it may be a case where at least two different substituents are included so that two of them have the same substituent and one of them has a different substituent. .

As a typical example of the halogen atom, fluorine,
Examples thereof include chlorine, bromine and iodine atoms.

Typical examples of the linear, branched or cyclic alkyl group are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and sec.
-Butyl group, tert-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 1,1,2-trimethyl-n-propyl group, 1,2,2-trimethyl-n-propyl group, and 3,3-
Examples thereof include a dimethyl-n-butyl group, and typical examples of the cyclic alkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

Typical examples of the linear or branched alkenyl group include vinyl group, 1-propenyl group and isopropenyl group.

Typical examples of the aryl group are phenyl group, o-hydroxyphenyl group, o-methoxyphenyl group, o-chlorophenyl group, o-bromophenyl group and p-
Hydroxyphenyl group, p-methoxyphenyl group, p-chlorophenyl group, p-bromophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 2,3,5-trichlorophenyl Group, α-
Examples thereof include a naphthyl group, a β-naphthyl group, and a substituted or unsubstituted aromatic heterocyclic group such as a furan ring, a thiophene ring and a pyridine ring.

Typical examples of the alkoxy group include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group and sec-butoxy group.

Typical examples of the aryloxy group include a phenoxy group, an α-naphthyloxy group and a β-naphthyloxy group.

As typical examples of the alkylcarbonyloxy group, acetoxy group, ethylcarbonyloxy group, n-
Examples thereof include a propylcarbonyloxy group, an isopropylcarbonyloxy group, an n-butylcarbonyloxy group, an isobutylcarbonyloxy group and a sec-butylcarbonyloxy group.

Representative examples of the arylcarbonyloxy group include a benzoyloxy group, an α-naphthylcarbonyloxy group and a β-naphthylcarbonyloxy group.

As a typical example of the acyl group, an acetyl group,
Examples thereof include ethylcarbonyl group, n-propylcarbonyl group, isopropylcarbonyl group, n-butylcarbonyl group, isobutylcarbonyl group and sec-butylcarbonyl group.

Typical examples of the alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, n
Examples include-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group and the like.

Typical examples of the aryloxycarbonyl group include a phenoxycarbonyl group, an α-naphthoxycarbonyl group and a β-naphthoxycarbonyl group.

Typical examples of the aminocarbonyl group include a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a phenylmethylaminocarbonyl group, a 1-pyrrolidinylcarbonyl group, a 1-piperidinylcarbonyl group and a dibenzylaminocarbonyl group. Can be mentioned.

Typical examples of the sulfonyl group include a methanesulfonyl group, a p-toluenesulfonyl group, a p-fluorophenylsulfonyl group and a p-trifluoromethylphenylsulnonyl group.

Typical examples of the phosphonyl group include a dimethylphosphonyl group, a methylphenylphosphonyl group and a diphenylphosphonyl group.

At least one of the ^two W ^{1 s} and W ^{2 s} may be connected to each other to form a ring in cooperation with the atoms respectively bonded. For example, when two adjacent W ¹ 's are linked to each other,-(CH ₂ ) ₃ -,-(CH ₂ ) ₄
In the case of -or-(CH ₂ ) ₂ O-, an indane ring, a tetrahydronaphthalene ring and a dihydrobenzofuran ring are respectively formed. Rings such as the indane ring, the tetrahydronaphthalene ring and the dihydrobenzofuran ring formed in this way are, for example, a methyl group, an ethyl group, an n-propyl group
It may be substituted with one or more substituents selected from an alkyl group such as an isopropyl group, an n-butyl group and a tert-butyl group; and an aryl group such as a phenyl group and a naphthyl group. In addition, when two or more cyclic structures are formed, at least two different cyclic structures may be formed for the same phenyl group.

Specific examples of the nitrones represented by the general formula (g) include those represented by the following formulas (g-1) to (g-20).

[0106]

[Chemical 36]

Among these, (g-5), (g-6), (g-7),
(g-8), (g-13), (g-14), (g-15), (g-1
6) and (g-20), isoxazolidine can be produced with extremely high optical purity from nitrones having a halogen atom at the ortho position of the benzene ring.

The nitrones represented by the general formula (g) are
It can be prepared according to a known method. For example, O.
It can be prepared according to the method reported by H. Wheeler et al., J. Am. Chem. Soc., 78, 3363 (1956). That is, N-
It can be synthesized by reacting phenylhydroxylamine and an aromatic aldehyde in ethanol.

In the method of the present invention, the following formula (c):

[0110]

[Chemical 37]

It is preferable to use the optically active metal complex compound represented by as a catalyst because an optically active oxazolidine compound can be obtained in high yield with high optical yield.

In the general formula (c) representing the optically active metal complex compound, Y ¹ and Y ² are different groups, and each is a hydrogen atom, a linear, branched or cyclic alkyl group, or an aryl group. And at least one of these substituents may further have a substituent within a range that does not impair the intended reaction in the present invention.

Typical examples of the linear, branched or cyclic alkyl group include a methyl group, an ethyl group, an isopropyl group, a tert-butyl group and a cyclohexyl group.

Typical examples of the aryl group include phenyl group, p-methoxyphenyl group, p-chlorophenyl group, p
-Fluorophenyl group, 3,5-dimethylphenyl group, 2,
Examples thereof include substituted or unsubstituted aromatic hydrocarbon groups such as 4,6-trimethylphenyl group, 2,6-diisopropylphenyl group, α-naphthyl group and β-naphthyl group.

At least one of the two Y ^{1 s} and the two Y ^{2 s} may be bonded to each other to form a ring together with the molecular chain to be substituted, and for example,-(CH ₂ ) ₄ - ring may a to form a 6-membered ring or the like bonded to each other via a group, and the like.

Further, Y ³ , Y ⁴ and Y ⁵ are each independently a hydrogen atom, a linear, branched or cyclic alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group or an alkoxy group. A carbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group, the alkyl group, an alkenyl group, an aryl group,
At least one of an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, and an aralkyloxycarbonyl group may have a substituent as long as it does not impair the intended reaction in the present invention.

Typical examples of the linear, branched or cyclic alkyl group include methyl group, ethyl group, isopropyl group, tert-butyl group, cyclopentyl group and cyclohexyl group.

Typical examples of the linear or branched alkenyl group include vinyl group and isopropenyl group.

Typical examples of the aryl group are phenyl group, p-methoxyphenyl group, p-chlorophenyl group, p
-Fluorophenyl group, 3,5-dimethylphenyl group, 2,
Examples thereof include substituted or unsubstituted aromatic hydrocarbon groups such as 4,6-trimethylphenyl group, 2,6-diisopropylphenyl group, α-naphthyl group and β-naphthyl group.

As a typical example of the acyl group, an acetyl group,
Aliphatic acyl groups such as trifluoroacetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group; benzoyl group, 3,5-dimethylbenzoyl group, 2,
4,6-trimethylbenzoyl group, 2,6-dimethoxybenzoyl group, 2,4,6-trimethoxybenzoyl group, 2,6
Examples thereof include aromatic acyl groups such as -diisopropoxybenzoyl group, α-naphthylcarbonyl group, β-naphthylcarbonyl group and 9-anthrylcarbonyl group.

Typical examples of the alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, n
-Butoxycarbonyl group, n-octyloxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cyclooctyloxycarbonyl group, tert-butoxycarbonyl group and the like can be mentioned. As typical examples of the aryloxycarbonyl group, Examples thereof include a phenoxycarbonyl group, and typical examples of the aralkyloxycarbonyl group include a benzyloxycarbonyl group and a phenethyloxycarbonyl group.

[0122] Also, Y ⁴ and Y ⁵ are linked to each other, it may be in conjunction with the carbon atom to which Y ⁴ and Y ⁵ are each bonded to form a ring. For example, when R ⁴ and R ⁵ are linked to each other to give — (CH ₂ ) ₄ — or —CH═CH—CH═CH—, a cyclohexane ring or a benzene ring is formed, respectively, and thus formed. Rings such as cyclohexane ring and benzene ring are, for example, alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, sec-butyl group and tert-butyl group; aryl groups such as phenyl group and naphthyl group. It may be substituted with one or more substituents selected from, and the benzene ring may be condensed to form a condensed polycycle such as a naphthalene ring.

M represents a divalent or trivalent cobalt ion or a trivalent chromium ion, and when the valence of these metal ions and the valence of the ligand are different, Z is an anion pair capable of forming a salt. When the valence of the metal ion is the same as the valence of the ligand, Z does not exist.

When Z represents an anion pair, an anion
As a representative example of the pair, F^-, Cl^-, Br^-, I^-, O
H^-, CH₃CO₂ ^-, P-CH₃C₆H_FourSO₃ ^-, CF₃SO₃
^-, PF₆ ^-, BF_Four ^-, BPh_Four ^-, SbF₆ ^-, ClO_Four ^-etc
Can be mentioned.

The optically active cobalt (I) represented by the above formula (c)
Specific examples of the I) complex, cobalt (III) complex, and chromium (III) complex include those represented by the following formulas (c-1) to (c-10).

[0126]

[Chemical 38]

Further, in the method of the present invention,
(i):

[0128]

[Chemical Formula 39]

The use of the optically active cobalt complex compound represented by the formula as a catalyst is particularly preferable because the reaction can be completed in a shorter time and the optically active oxazolidines can be obtained in high yield with a high optical yield.

The above formula representing this optically active metal complex compound
In (i), Y ¹ and Y ² are the same as in the optically active metal complex compound represented by the general formula (c), and each of them is a hydrogen atom, a linear, branched or cyclic alkyl group, or aryl. At least one of these alkyl groups and aryl groups may further have a substituent as long as the intended reaction in the present invention is not impaired.

Typical examples of the linear, branched or cyclic alkyl group include methyl group, ethyl group, isopropyl group, tert-butyl group and cyclohexyl group.

Typical examples of the aryl group are phenyl group, p-methoxyphenyl group, p-chlorophenyl group and p
-Fluorophenyl group, 3,5-dimethylphenyl group, 2,
Examples thereof include substituted or unsubstituted aromatic hydrocarbon groups such as 4,6-trimethylphenyl group, 2,6-diisopropylphenyl group, α-naphthyl group and β-naphthyl group.

At least one of the two Y ^{1 s} and the two Y ^{2 s} may be bonded to each other to form a ring. For example, a group such as — (CH ₂ ) ₄ — They may be bonded to each other via a ring to form a ring such as a 6-membered ring.

Next, Y ⁶ represents a linear, branched, or cyclic alkyl group, aryl group, alkoxy group, or aryloxy group, and at least the alkyl group, aryl group, alkoxy group, and aryloxy group One may have a substituent within a range that does not impair the intended reaction in the present invention.

Typical examples of the linear, branched or cyclic alkyl group are methyl group, isopropyl group and te group.
Examples thereof include rt-butyl group, cyclopentyl group and cyclohexyl group.

Typical examples of the aryl group include phenyl group, p-methoxyphenyl group, p-chlorophenyl group and p
-Fluorophenyl group, 3,5-dimethylphenyl group, 2,
Substituted or unsubstituted aromatic hydrocarbon group such as 4,6-trimethylphenyl group, 2,6-diisopropylphenyl group, 3,5-dimethoxyphenyl group, α-naphthyl group, β-naphthyl group and 9-anthranyl group Can be mentioned.

Typical examples of the alkoxy group include a methoxy group, an ethoxy group, an n-butoxy group, an n-octyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cyclooctyloxy group and a tert-butoxy group. As a typical example of the aryloxy group,
Phenoxy group, 2,6-dimethylphenoxy group, 2,6-di
Examples thereof include -tert-butylphenoxy group and the like.

Also, Z^-Is an anion pair capable of forming a salt
means. A typical example of this anion pair is F^-, C
l^-, Br^-, I^-, OH^-, CH₃CO₂ ^-, P-CH₃C₆H
_FourSO ₃ ^-, CF₃SO₃ ^-, PF₆ ^-, BF_Four ^-, BPh_Four ^-, S
bF₆ ^-, ClO_Four ^-Etc. can be mentioned.

The optically active cobalt (I) represented by the above formula (i)
Specific examples of the II) complex include those represented by the following formulas (i-1) to (i-12).

[0140]

[Chemical 40]

[0141]

[Chemical 41]

The optically active cobalt (III) complex represented by the general formula (i) can be prepared according to a known method. For example, Y. Nishida et al., Inorg.Chim.Acta, 38,213.
(1980); L. Claisen, Ann.Chem., 297,57 (1897); EGJage
r, Z. Chem., 8, 30, 392, and 475 (1968), and can be prepared according to the method described in JP-A-9-15114.
No. 3, gazette, Bull. Chem. Soc. Jpn., 74, 1333 (2001) and the like.

Next, a specific method of the asymmetric 1,3-dipole cycloaddition reaction of the present invention will be described. The reaction is carried out in the absence of a solvent or in the presence of a suitable solvent, with the nitrones represented by the formula (a) or (g), and the parent dipole compound represented by the formula (b) or (e). Is represented by the formula (c) or the formula
The optically active metal complex compound represented by (i) is used.

The amount of the parent dipole compound of the formula (b) or formula (e) used is 1 to 10 times mol, preferably 1 to 5 times the mol of the nitrones of the formula (a) or formula (g). Mol is good. formula
The amount of the optically active metal complex compound of (c) or formula (i) to be used is generally 1 mol% to 15 mol%, preferably 1 to 10 mol, based on the nitrone of formula (a) or formula (g). It is in the range of mol%. The reaction solvent is not particularly limited as long as it is inert to the reaction, for example, dichloromethane, dichloroethane, halogenated hydrocarbons such as carbon tetrachloride, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, dimethoxyethane and the like. Ethers, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol,
Alcohols such as cyclohexanol, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, chlorobenzene and o-dichlorobenzene, n-hexane,
Aliphatic hydrocarbons such as cyclohexane, n-octane and n-decane, esters such as methyl acetate, ethyl acetate and butyl acetate, nitriles such as acetonitrile and butyronitrile, N, N-dimethylformamide, N, N-dimethyl Amides such as acetamide and N-methylpyrrolidone 1,3
-Ureas such as dimethylimidazolidinone and tetramethylurea are listed.

These may be used alone or in combination. The reaction temperature is usually in the range of -100 ° C to 50 ° C, preferably -78 ° C to 0 ° C. After completion of the reaction, the organic solvent is concentrated under reduced pressure and separated by silica gel chromatography, distillation or the like, whereby the product optically active isoxazolidines can be isolated. In the formula (e), when a compound in which X ¹ is a hydrogen atom is used as a raw material, thin-phase chromatography (T
After confirming the completion of the reaction by (LC) etc., a reducing agent such as an ethanol solution of sodium borohydride is directly added to the reaction system, and post-treatment is carried out to isolate a stable alcohol form from the aldehyde. You can also

The optical purity of the obtained optically active isoxazolidines can be analyzed as it is or after converting it into a derivative by an optically active chromatography column or optical rotation.

[0147]

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

Reference Example 1 N, N′-bis [2- (2,4,6-trimethylbenzoyl) -3-oxobutylidene]-(1R, 2R) -cyclohexane-1,2-diaminatocobalt (III ) Complex hexafluoroantimonate (the above formula (i-
1)) Synthesis: N, N'-bis [2- (2,4,6-trimethylbenzoyl) -3-oxobutylidene]-(1R, 2R) -cyclohexane-1,2-diaminatocobalt iodide under nitrogen atmosphere (III) Complex (91
Silver hexafluoroantimonate (434.4 mg, 1.264 mmol) was added to a methylene chloride solution (20.0 mL) of 3.8 mg, 1.258 mmol). After stirring at room temperature for 1 hour, the produced silver iodide and excess silver hexafluoroantimonate were filtered. The product obtained by distilling off the filtrate under reduced pressure was dissolved in a minimum amount of methylene chloride, and a large amount of hexane was added to this solution for reprecipitation purification, and N, N '.
-Bis [2- (2,4,6-trimethylbenzoyl) -3-oxobutylidene]-(1R, 2R) -Cyclohexane-1,2-diaminatocobalt (III) complex hexafluoroantimonate is a green solid Was quantitatively obtained as (977.7 mg).

Reference Example 2 N, N'-bis [2- (2,4,6-trimethylbenzoyl) -3-oxobutylidene]-(1S, 2S) -1,2-bis (3,5-dimethyl) (Phenyl)
Synthesis of ethylenediaminatocobalt (III) complex hexafluoroantimonate (optical isomer of the above formula (i-3)): N, N'-bis [2- (2,4,6- (Trimethylbenzoyl) -3-
Oxobutylidene]-(1S, 2S) -1,2-bis (3,5-dimethylphenyl) ethylenediaminatocobalt (III) iodide complex (1
Silver hexafluoroantimonate (58.0 mg, 0.169 mmol) was added to a methylene chloride solution (8.0 mL) of 32.6 mg, 0.151 mmol).
After stirring at room temperature for 1.5 hours, the produced silver iodide and excess silver hexafluoroantimonate were filtered. The product obtained by evaporating the filtrate under reduced pressure was dissolved in a minimum amount of methylene chloride,
A large amount of hexane was added to this solution for reprecipitation purification,
N, N'-bis [2- (2,4,6-trimethylbenzoyl) -3-oxobutylidene]-(1S, 2S) -1,2-bis (3,5-dimethylphenyl)
Ethylenediaminatocobalt (III) complex hexafluoroantimonate was obtained as a green solid (140.0 mg, yield 94
%).

Example 1 Synthesis of (1R ^* , 4S ^* , 5S ^* )-3,4-diphenyl-2-oxo-3-azabicyclo [3.3.0] -octane-5-carbaldehyde: under nitrogen atmosphere , N, N'-bis [2- (2,4,6-trimethylbenzoyl) -3-
Oxobutylidene]-(1R, 2R) -Cyclohexane-1,2-diaminatocobalt (III) complex Hexafluoroantimonate (12.4
mg, 0.015 mmol, 5.0 mol%; Formula (i-1); synthesized according to Reference Example 1), 1-cyclopentene-1-carbaldehyde (46.7 m
g, 0.49 mmol) in methylene chloride (1.0 mL) was added at room temperature, and the temperature was lowered to -40 ° C, and then benzylidenephenylamine-
N-oxide (58.2 mg, 0.30 mmol) in methylene chloride
(1.5 mL) was slowly added dropwise, and the mixture was stirred for 51 hours. Then, add 10% aqueous hydrochloric acid to stop the reaction, and
Stir for about 0 minutes. Then, it was extracted with methylene chloride, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the resulting crude product was separated and purified by silica gel column chromatography (Hex: AcOEt = 4: 1), (1R ^* ,
4S ^* , 5S ^* )-3,4-diphenyl-2-oxo-3-azabicyclo [3.
3.0] -Octane-5-carbaldehyde to diastereomeric ratio
Obtained at 99/1 (70.2 mg, yield 81%, 51% ee (Endo)). Although the absolute configuration of the product has not been confirmed so far, it was confirmed in Example 2 that the relative configuration of the compound obtained as the main product is (1R ^* , 4S ^* , 5S ^* ). Derived into the alcohol form shown in (1) and determined by NMR (NOE) and X-ray structural analysis. Also, when inducing alcohol,
It was also confirmed that there was no change in the diastereomeric ratio. Endo
The structure of the body / Exo body is shown in the following formula (h-1).

[0151]

[Chemical 42]

(Example 2) (1R^*, 4S^*, 5R^*) -3,4-Diphenyl-2-oxo-3-azavic
Synthesis of [3.3.0] -octane-5-methanol: Required for reaction
The stirring time should be 48 hours instead of 51 hours.
The reaction was carried out in the same manner as in Example 1 except for the above. Then carry out
Amount to stop the reaction by adding the 10% aqueous hydrochloric acid solution used in Example 1.
Instead, sodium borohydride (21.0 mg, 0.56 mmol)
Stop the reaction by adding the ethanol solution of
Stir for 1 hour. Then add water to the reaction solution and
The extract was dried over ren and the extract was dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the obtained crude product was washed with silica gel.
Separation and purification by Lamb chromatography (Hex: AcOEt = 4: 1)
After doing, (1R^*, 4S^*, 5R^*) -3,4-Diphenyl-2-oxo-
Single 3-azabicyclo [3.3.0] -octane-5-methanol
Obtained as the diastereomer of (79.5 mg, yield 89%, 5
1% ee (Endo)). The absolute configuration of the product is
Although not confirmed, the compound obtained as the main product
The relative configuration of objects is (1R^*, 4S^*, 5R^*) About being
As shown in Example 1, NMR (NOE) and X-ray
It was determined by building analysis. For the structure of Endo body / Exo body
It is shown in the following formula (k-1). Below, the absolute configuration has not been confirmed.
About things, (1R^*, 4S^*, 5R ^*)
R and S shown are marked with *.

[0153]

[Chemical 43]

Examples 3 to 5 In each Example, the reaction was carried out in the same manner as in Example 2 except that the solvent shown in Table 1 was used instead of dichloromethane. Obtained (1R ^* , 4
S ^* , 5R ^* )-3,4-diphenyl-2-oxo-3-azabicyclo [3.
Table 1 shows the yield of 3.0] -octane-5-methanol, the diastereomer ratio and the optical purity of the Endo form.

[0155]

[Table 1]

Examples 6 to 12 In each example, the optically active cobalt complex catalyst shown in Table 2 was used in place of the optically active cobalt (III) complex catalyst (i-1). The reaction was carried out in the same manner as in 2. Obtained (1R ^* , 4
S ^* , 5R ^* )-3,4-diphenyl-2-oxo-3-azabicyclo [3.
Table 2 shows the yield of 3.0] -octane-5-methanol, the diastereomeric ratio, and the optical purity of the Endo form.

[0157]

[Table 2]

Example 13 (1R ^* , 4S ^* , 5R ^* )-3-Phenyl-4- (2-bromophenyl) -2-oxo-3-azabicyclo [3.3.0] -octane-5-methanol Synthesis of N, N'-bis [2- (2,4,6-trimethylbenzoyl) -3-oxobutylidene]-(1S, 2S) -1,2-bis (3,5) under nitrogen atmosphere
-Dimethylphenyl) ethylenediaminatocobalt (III)
Complex hexafluoroantimonate (14.8 mg, 0.015 mmol, 5.0 m
ol%; Formula (i-3) synthesized according to Reference Example 2), a solution of 1-cyclopentene-1-carbaldehyde (49.0 mg, 0.49 mmol) in methylene chloride (1.0 mL) was added at room temperature, and the mixture was heated to -78 ° C. After cooling, 2-bromobenzylidenephenylamine-N-oxide (8
1.9 mg, 0.30 mmol; formula (g-7)) in methylene chloride (1.0
(mL) was slowly added dropwise, and the mixture was stirred for 96 hours. Then, an ethanol solution of sodium borohydride (32.1 mg, 0.85 mmol) was added to stop the reaction, and the mixture was further stirred at room temperature for 1 hour. Subsequently, water was added to the reaction solution and extracted with methylene chloride,
The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting crude product was separated and purified by silica gel column chromatography (Hex: AcOEt = 4: 1),
(1R ^* , 4S ^* , 5R ^* ) -3-phenyl-4- (2-bromophenyl) -2-oxo-3-azabicyclo [3.3.0] -octane-5-methanol as a single diastereomer Obtained (19.7 mg, yield 1
8%, 91% ee (Endo)).

Example 14 The reaction was performed in the same manner as in Example 13 except that the reaction temperature was changed to −40 ° C. instead of −78 ° C. As a result, (1R ^* , 4S ^* , 5R ^* )-3-phenyl
-4- (2-Bromophenyl) -2-oxo-3-azabicyclo [3.3.
0] -Octane-5-methanol has a diastereomeric ratio of 99 (End
O) / 1 (Exo), yield 88%. Endo body has an optical purity of 85
It was% ee.

Examples 15 to 18 In each example, the nitrones 2-bromobenzylidenephenylamine-N-
The reaction was performed in the same manner as in Example 14 except that the nitrones shown in Table 3 were used instead of the oxide (g-7). Table 3 shows the yield of the obtained optically active isoxazolidines, the diastereomer ratio, and the optical purity of the Endo form.

[0161]

[Table 3]

(Example 19) A reaction was carried out in the same manner as in Example 14 except that the above α, β-unsaturated carbonyls (e-1) were used and the stirring time was 24 hours. The yield of the obtained optically active isoxazolidines was 82%, the diastereomer ratio was 96 (Endo) / 4 (Exo), and the optical purity of the Endo form was 61% ee. The structure of the product is shown in the following formula (k-2).

[0163]

[Chemical 44]

Example 20 Using the nitrones (g-6) and the α, β-unsaturated carbonyls (e-2), the formula (I-3) was used as the optically active metal complex compound. The reaction was performed in the same manner as in Example 14 except that the above was performed. The yield of the optically active isoxazolidines obtained was 97%, the diastereomer ratio was 98 (Endo) / 2 (Exo), and the optical purity of the Endo form was 63% ee. The structure of the product is shown in the following formula (k-3).

[0165]

[Chemical formula 45]

[0166]

INDUSTRIAL APPLICABILITY According to the method of the present invention, an asymmetric dipole addition is carried out from nitrones and various parent dipole compounds by using an optically active cobalt complex catalyst or an optically active chromium complex which is easy to prepare as a catalyst. The corresponding optically active oxazolidines can be produced by the cyclization reaction. These optically active isoxazolidines are useful intermediates in the synthesis of fine chemicals, such as drug substances, agricultural chemicals, and other important intermediates.

Continued front page    F term (reference) 4C056 AA01 AB01 AC01 AD01 AD02                       AE01 AF01 FA03 FA04 FA08                       FB01 FC02                 4G069 AA06 AA08 BA27A BA27B                       BC26B BC58A BC58B BC67A                       BC67B BE13A BE13B BE22B                       BE31B BE33A BE33B BE34B                       BE35B BE36A BE38A BE38B                       BE43A CB25 CB38 DA02                       FA01                 4H039 CA41 CF10

Claims (6)

[Claims] 1. The following general formula (a): [R ¹ , R ² and R ³ are each independently a hydrogen atom,
A linear, branched, or cyclic alkyl group or aryl group is shown, and at least one of the alkyl group and the aryl group may have a substituent, and R ¹ and R ²
Alternatively, R ² and R ³ may together with the atom to which they are attached form a ring. ] And the following general formula (b): [In the formula, R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently
Hydrogen atom, halogen atom, formyl group, carboxyl group, linear, branched or cyclic alkyl group, aryl group, alkoxy group, aryloxy group, alkylcarbonyloxy group, arylcarbonyloxy group, acyl group, alkoxycarbonyl group , An aryloxycarbonyl group, an aminocarbonyl group, a cyano group, or a nitro group, and the alkyl group, aryl group, alkoxy group,
At least one of an aryloxy group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group and an aminocarbonyl group may have a substituent,
Also, a combination of R ⁴ and R ^5, a combination of R ⁵ and R ^6, a combination of R ⁶ and R ⁷
And one or more combinations selected from the group consisting of the combination of R ⁷ and R ⁴ and each of the substituents constituting the combination and the atom to which they are bonded form a ring. It may be one that does. In addition, R ⁴ , R ⁵ , R
^At least one of ⁶ and R ⁷ is an electron withdrawing substituent. ] The olefins represented by
(c): [Chemical formula 3] [In the formula, Y ¹ and Y ² are different groups, and each is a hydrogen atom, a linear, branched, or cyclic alkyl group, or an aryl group (the aryl group is a halogen atom, an alkyl group, an alkoxy group, Optionally substituted with at least one of a cyano group and a nitro group), and at least one of the two Y ^{1 s} and the two Y ^{2 s} are bonded to each other to form a ring. Good. In addition, Y ³ , Y ⁴ and Y ⁵ are each independently a hydrogen atom, a linear, branched or cyclic alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group,
An aryloxycarbonyl group or an aralkyloxycarbonyl group, wherein the alkyl group, alkenyl group,
At least one of an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, and an aralkyloxycarbonyl group may have a substituent,
Further, Y ⁴ and Y ⁵ may be linked to each other to form a ring in cooperation with the carbon atom to which they are bonded. Further, M represents cobalt or chromium ion, Z represents an anion pair capable of forming a salt when the valence of these metal ions and the valence of the ligand are different, and the valence of the metal ion and the ligand When the valences are the same, Z does not exist. ] The following general formula (d): including the step of reacting in the presence of an optically active metal complex compound consisting of a tetradentate ligand represented by: [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined above. * Represents an asymmetric carbon atom, and means that the absolute configuration of the carbon atom is (R) or (S). ] The manufacturing method of optically active isoxazolidines represented by these. 2. The following general formula (a): [R ¹ , R ² and R ³ are each independently a hydrogen atom,
A linear, branched, or cyclic alkyl group or aryl group is shown, and at least one of the alkyl group and the aryl group may have a substituent, and R ¹ and R ²
Alternatively, R ² and R ³ may together with the atom to which they are attached form a ring. ] And the following general formula (e): [In the formula, X ¹ represents a hydrogen atom, a hydroxyl group, an amino group, a straight chain,
Indicates a branched or cyclic alkyl group, aryl group, alkoxy group, aryloxy group, alkylamino group or arylamino group, wherein the alkyl group, aryl group, alkoxy group, aryloxy group, alkylamino group and aryl At least one of the amino groups may have a substituent, and X ² , X ³ and X ⁴ are each independently a hydrogen atom, a halogen atom, a linear, branched or cyclic alkyl group, or Represents an aryl group, at least one of the alkyl group and the aryl group may have a substituent, and a combination of X ¹ and X ^2, a combination of X ² and X ^3, a combination of X ³ and X ⁴ each of one or more combinations selected from the group consisting of combinations of the combination and X ⁴ and X ¹ is an atom such a substituent group constituting the combination are attached are jointly Ring may be configured to form. ]
Α, β-unsaturated carbonyls represented by the following general formula
(c): [Chemical 7] [In the formula, Y ¹ and Y ² are different groups, and each is a hydrogen atom, a linear, branched, or cyclic alkyl group, or an aryl group (the aryl group is a halogen atom, an alkyl group, an alkoxy group, It may be substituted with at least one of a cyano group and a nitro group.) And at least one of the two Y ^{1 s} or the two Y ^{2 s} is bonded to each other to form a ring. Good. Also, Y ³ , Y ⁴ and Y ⁵
Are each independently a hydrogen atom, a linear, branched, or cyclic alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group,
An aryloxycarbonyl group or an aralkyloxycarbonyl group, wherein the alkyl group, alkenyl group,
At least one of an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, and an aralkyloxycarbonyl group may have a substituent,
Further, Y ⁴ and Y ⁵ may be linked to each other to form a ring in cooperation with the carbon atom to which they are bonded. Further, M represents cobalt or chromium ion, Z represents an anion pair capable of forming a salt when the valence of these metal ions and the valence of the ligand are different, and the valence of the metal ion and the ligand When the valences are the same, Z does not exist. ] The following general formula (f): including a step of reacting in the presence of an optically active metal complex compound consisting of a tetradentate ligand represented by: [In the formula, R ¹ , R ² , R ³ , X ¹ , X ² , X ³ , X ⁴ and * are the same as defined above. ] The manufacturing method of optically active isoxazolidines represented by these. 3. The following general formula (g): [In the formula, W ¹ and W ² are each independently a hydrogen atom,
Halogen atom, hydroxyl group, amino group, formyl group, carboxyl group, linear, branched, or cyclic alkyl group,
Linear or branched alkenyl group, aryl group, alkoxy group, aryloxy group, alkylcarbonyloxy group, arylcarbonyloxy group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group, aminocarbonyl group, sulfonyl group, phosphinyl group , A nitro group or a cyano group, and is an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an aryloxy group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, amino. At least one of the carbonyl group, the sulfonyl group, and the phosphonyl group may have a substituent. In addition, m and n are each independently an integer of 1 to 5, and when m or n is an integer of 2 to 4, at least one of a plurality of W ^{1 s} and at least one of a plurality of W ² are different from each other. Substituents may be included. In addition, two W ^1's may be linked to each other to form a ring in cooperation with the atoms respectively bonded. ] And a nitrone represented by the following general formula (e): [In the formula, X ¹ represents a hydrogen atom, a hydroxyl group, an amino group, a straight chain,
Indicates a branched or cyclic alkyl group, aryl group, alkoxy group, aryloxy group, alkylamino group or arylamino group, wherein the alkyl group, aryl group, alkoxy group, aryloxy group, alkylamino group and aryl At least one of the amino groups may have a substituent, and X ² , X ³ and X ⁴ are each independently a hydrogen atom, a halogen atom, a linear, branched or cyclic alkyl group, or Represents an aryl group, at least one of the alkyl group and the aryl group may have a substituent, and a combination of X ¹ and X ^2, a combination of X ² and X ^3, a combination of X ³ and X ⁴ each of one or more combinations selected from the group consisting of combinations of the combination and X ⁴ and X ¹ is an atom such a substituent group constituting the combination are attached are jointly Ring may be configured to form. ]
Α, β-unsaturated carbonyls represented by the following general formula
(c): [Chemical 11] [In the formula, Y ¹ and Y ² are different groups, and each is a hydrogen atom, a linear, branched, or cyclic alkyl group, or an aryl group (the aryl group is a halogen atom, an alkyl group, an alkoxy group, It may be substituted with at least one of a cyano group and a nitro group.) And at least one of the two Y ^{1 s} or the two Y ^{2 s} is bonded to each other to form a ring. Good. Also, Y ³ , Y ⁴ and Y ⁵
Are each independently a hydrogen atom, a linear, branched, or cyclic alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group,
An aryloxycarbonyl group or an aralkyloxycarbonyl group, wherein the alkyl group, alkenyl group,
At least one of an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, and an aralkyloxycarbonyl group may have a substituent,
Further, Y ⁴ and Y ⁵ may be linked to each other to form a ring in cooperation with the carbon atom to which they are bonded. Further, M represents cobalt or chromium ion, Z represents an anion pair capable of forming a salt when the valence of these metal ions and the valence of the ligand are different, and the valence of the metal ion and the ligand When the valences are the same, Z does not exist. ] The following general formula (h): including a step of reacting in the presence of an optically active metal complex compound consisting of a tetradentate ligand represented by: [Wherein, W ¹ , W ² , X ¹ , X ² , X ³ , X ⁴ , m, n and *
Is the same as above. ] The manufacturing method of optically active isoxazolidines represented by these. 4. The method for producing an optically active isoxazolidine according to claim 2, wherein X ¹ is a hydrogen atom in the formula (e). 5. An optically active metal complex compound comprising a tetradentate ligand represented by the general formula (c) has the following general formula (i): [Wherein Y ¹ and Y ² are the same as defined above, Y ⁶ is a straight chain,
It represents a branched or cyclic alkyl group, aryl group, alkoxy group, or aryloxy group, and at least one of the alkyl group, aryl group, alkoxy group, and aryloxy group may have a substituent. . Z ⁻ means an anion pair capable of forming a salt. ] An optically active cobalt (III) complex represented by
5. The method for producing the optically active isoxazolidines according to any one of 4 above. 6. The formula (f) or (h) produced according to claim 4, wherein X ¹ is a hydrogen atom. ] The following general formula (j) or (k) including the step of reacting the optically active isoxazolidines represented by the following directly with sodium borohydride without isolation and purification after the reaction: [In the formula, R ¹ , R ² , R ³ , X ² , X ³ , X ⁴ , W ¹ , W ² ,
m, n and * are the same as above. ] The manufacturing method of optically active isoxazolidines represented by these.