阅读说明：本技术 光学活性体的制造方法、光学活性体、手性分子的制造方法及手性分子 (Method for producing optically active body, method for producing chiral molecule, and chiral molecule ) 是由 友冈克彦 井川和宣 于 2018-05-16 设计创作，主要内容包括：本发明提供一种光学活性体的制造方法,其包括通过使不对称诱导剂作用于对映体过量的半衰期小于10小时的手性分子来提高所述手性分子的一个对映体的存在比的不对称诱导工序。根据该方法,能够选择性且高效地获得容易外消旋化的手性分子的一个对映体。(The present invention provides a method for producing an optically active form, which comprises an asymmetry inducing step of increasing the abundance ratio of one enantiomer of a chiral molecule by allowing an asymmetry inducing agent to act on the chiral molecule having an enantiomeric excess half-life of less than 10 hours. According to this method, one enantiomer of a chiral molecule which is easily racemized can be selectively and efficiently obtained.)

1. A method for producing an optically active form, which comprises an asymmetry inducing step of increasing the abundance ratio of one enantiomer of a chiral molecule by allowing an asymmetry inducing agent to act on the chiral molecule having an enantiomeric excess half-life of less than 10 hours at 50 ℃.

2. The method for producing an optically active body according to claim 1, wherein,

by allowing the asymmetry inducing agent to act on the chiral molecule, the abundance ratio of one enantiomer is increased without concomitant cleavage or reformation of the bond within the chiral molecule.

3. The method for producing an optically active body according to claim 1 or 2, wherein,

the spatial conformation of the chiral molecules differs from one enantiomer to the other.

4. The method of producing an optically active body according to claim 2 or 3, wherein the chiral molecule is a planar asymmetric molecule.

5. The method of producing an optically active body according to claim 2 or 3, wherein the chiral molecule is an axially asymmetric molecule, and wherein a substituted biphenyl molecule is excluded.

6. The method of producing an optically active body according to claim 2 or 3, wherein the chiral molecule is a helical asymmetric molecule.

7. The method for producing an optically active body according to any one of claims 1 to 6,

the chiral molecule has a structure represented by any one of the following general formulae (1) to (3), (4a), (4b), (5), (6), (7), (8), (9a) and (9b),

[ chemical formula 1]

In the general formula (1), R¹¹～R¹⁴Each independently represents a hydrogen atom or a substituent, X¹¹Denotes O, S or NR¹⁵，R¹⁵Represents a substituent, n1 represents an integer of 1 to 10,

[ chemical formula 2]

In the general formula (2), R²¹And R²²Each independently represents a hydrogen atom or a substituent, R²³～R²⁶Each independently represents a hydrogen atom or a substituent, X¹²Denotes O, S or NR²⁷，R²⁷Represents a substituent, n2 represents an integer of 1 to 10,

[ chemical formula 3]

In the general formula (3), R³¹And R³²Each independently represents a substituent, R³³～R³⁷Each independently represents a hydrogen atom or a substituent,

[ chemical formula 4]

In the general formula (4a), R⁴¹～R⁴³Each independently represents a substituent, n4 represents an integer of 1 to 10, a benzene ring may be fused to the cycloolefin skeleton in the general formula (4a),

[ chemical formula 5]

In the general formula (4b), R⁴⁴～R⁴⁸Each independently represents a substituent group, and each independently represents a substituent group,

[ chemical formula 6]

In the general formula (5), R⁵¹～R⁵⁵Each independently represents a substituent, wherein R⁵⁴And R⁵⁵Are groups which are different from each other and which,

[ chemical formula 7]

In the general formula (6), R⁶¹～R⁶⁴Are groups different from each other and each independently represents a substituent,

[ chemical formula 8]

In the general formula (7), R⁷¹And R⁷²Each independently represents a hydrogen atom or a substituent,

[ chemical formula 9]

In the general formula (8), R⁸¹And R⁸²Each independently represents a hydrogen atom orSubstituent, R⁸³Represents a substituent group, and a pharmaceutically acceptable salt thereof,

[ chemical formula 10]

In the general formulae (9a) and (9b), R⁹¹～R⁹⁶Each independently represents a substituent, and n91 and n92 each independently represents an integer of 1 to 10.

8. The method for producing an optically active body according to any one of claims 1 to 7,

the racemic energy of the chiral molecules is 20-27 kcal/mol.

9. The method for producing an optically active body according to any one of claims 1 to 8,

the asymmetric inducer is an optically active body.

10. The method for producing an optically active body according to any one of claims 1 to 9,

the asymmetry inducer is a sugar chain derivative.

11. The method for producing an optically active body according to claim 10, wherein,

the sugar chain derivative has a structure in which an aryl group is linked to a unit of a sugar chain via a linking group, the linking group containing an ester bond or a urethane bond.

12. The method for producing an optically active body according to any one of claims 1 to 11,

the asymmetry inducer is carried on a particulate carrier.

13. The method for producing an optically active body according to any one of claims 1 to 12,

after the asymmetry induction step, a separation step of separating the one enantiomer is further included.

14. The method for producing an optically active body according to any one of claims 1 to 13,

after the asymmetry induction step, an asymmetry stabilization step of converting the one enantiomer into one enantiomer of a 2 nd chiral molecule having an enantiomeric excess half-life longer than that of the chiral molecule by allowing a reactant to act on the chiral molecule is further included.

15. The method for producing an optically active body according to claim 14, wherein,

the half-life of the enantiomeric excess of the 2 nd chiral molecule is 10 hours or more at 50 ℃.

16. The method for producing an optically active body according to claim 14 or 15,

the reactant is an optically active body.

17. The method for producing an optically active body according to claim 14 or 15,

the reactant is an epoxidizing agent.

18. An optically active body produced by the production method according to any one of claims 1 to 17.

19. A method for producing a chiral molecule, comprising an asymmetric stabilization step of converting an optically active form of a 1 st chiral molecule having a half-life of enantiomeric excess of less than 10 hours at 50 ℃ into an optically active form of a 2 nd chiral molecule having a longer half-life of enantiomeric excess by allowing a reactant to act on the optically active form of the 1 st chiral molecule, wherein the optically active form has an enantiomeric excess of more than one enantiomer.

20. The method for producing a chiral molecule according to claim 19, which comprises the following steps before the asymmetric stabilization step:

increasing the presence ratio of one enantiomer of said chiral molecules by allowing an asymmetry inducing agent to act on said chiral molecules having a half-life of enantiomeric excess of less than 10 hours at 50 ℃, thereby obtaining said 1 st chiral molecule having one enantiomer of said chiral molecules present in excess of the other.

21. The method for producing a chiral molecule according to claim 19 or 20, wherein the enantiomeric excess of the 1 st chiral molecule is 40% ee or more.

22. A chiral molecule produced by the production method of any one of claims 19 to 21.

23. The chiral molecule of claim 22,

the half-life of the enantiomeric excess is more than 10 hours at 50 ℃.

Technical Field

The present invention relates to a method for selectively obtaining one enantiomer of a chiral molecule in which the interconversion between enantiomers is fast (hereinafter, dynamic chiral molecule), and a method for further producing a chiral molecule in which there is no interconversion between enantiomers (hereinafter, static chiral molecule) or a chiral molecule in which the interconversion between enantiomers is slower than that of dynamic chiral molecule (hereinafter, quasi-static chiral molecule) by using this method.

Background

Chiral molecules have a pair of enantiomers (enantiomers). These enantiomers are generally identical in chemical or physical properties to each other, but the signs of optical rotation are opposite and the physiological activities are greatly different, so that selectively using only one enantiomer is extremely important for the development of drugs and functional materials. Therefore, extensive research has been conducted to date on methods for selectively obtaining one enantiomer.

As the chiral molecule, for example, sp is typically known³Carbon atom as being asymmetricA central chiral carbon molecule. Here, since one enantiomer of a chiral carbon molecule has a different configuration from the other enantiomer around an asymmetric carbon, in order to convert the other enantiomer of a racemate into one enantiomer and obtain only one enantiomer, it is necessary to cleave and form a bond on the asymmetric carbon again, and thus, a very large amount of energy is required. Therefore, as a method for selectively obtaining one enantiomer of a chiral carbon molecule, the following methods are mainly used: optical resolution, which does not rely on such interconversion, of only one enantiomer from a readily available racemate (a mixture containing one pair of enantiomers in a 50: 50 ratio); an asymmetric synthesis method in which an achiral molecule is used as a starting material (substrate) for production, and the molecule is enantioselectively reacted to selectively synthesize one enantiomer (see, for example, non-patent document 1).

Prior art documents

Non-patent document

Non-patent document 1: "Asymmetric Synthesis", James D. Morrison editor, Academic Press, New York, published in 1983

Disclosure of Invention

Technical problem to be solved by the invention

However, in optical resolution, the yield of the target enantiomer is maintained at 50% at the maximum, and at least half of the chiral molecules are wasted, due to the resolution of the enantiomer from the racemate. Further, in the asymmetric synthesis method, since a specific chiral reagent for enantioselectively reacting the substrate must be used, there are many limitations on chiral molecules that can be used, and the versatility is poor.

Therefore, the present inventors have made studies to solve the above-mentioned problems of the prior art and have an object to provide a method for selectively and efficiently obtaining one enantiomer of a chiral molecule without using a chiral reactant.

Means for solving the technical problem

As a result of intensive studies to solve the above problems, the present inventors have found that when an asymmetry inducing agent is allowed to act on a dynamic chiral molecule having a half-life of less than 10 hours in which the enantiomer is excessive at 50 ℃ at room temperature, the other enantiomer of the chiral molecule is easily converted into one enantiomer, and the existence ratio of one enantiomer is remarkably improved. Further, it has also been found that when a reactant is reacted with an optically active substance including a chiral molecule, which is easily racemized, the reactant is converted into a static chiral molecule or a quasi-static chiral molecule while maintaining its optical purity, thereby obtaining these optically active substances. The present invention has been made based on these findings, and specifically has the following structure.

[1] A method for producing an optically active form, which comprises an asymmetry inducing step of increasing the abundance ratio of one enantiomer of a chiral molecule by allowing an asymmetry inducing agent to act on the chiral molecule having an enantiomeric excess half-life of less than 10 hours at 50 ℃.

[2] The method for producing an optically active body according to [1], wherein,

by allowing the asymmetry inducing agent to act on the chiral molecule, the abundance ratio of one enantiomer is increased without concomitant cleavage or reformation of the bond within the chiral molecule.

[3] The method for producing an optically active body according to [1] or [2], wherein,

the spatial conformation of the chiral molecules differs from one enantiomer to the other.

[4] The method for producing an optically active body according to [2] or [3], wherein,

the chiral molecules are planar asymmetric molecules.

[5] The method for producing an optically active body according to [2] or [3], wherein,

the chiral molecules are axisymmetric molecules (wherein, substituted biphenyl molecules are excluded).

[6] The method for producing an optically active body according to [2] or [3], wherein,

the chiral molecules are helical asymmetric molecules.

[7] The method for producing an optically active body according to any one of [1] to [6], wherein,

the chiral molecule has a structure represented by any one of the following general formulae (1) to (3), (4a), (4b), (5), (6), (7), (8), (9a), and (9 b).

[ chemical formula 1]

[ in the general formula (1), R¹¹～R¹⁴Each independently represents a hydrogen atom or a substituent. X¹¹Denotes O, S or NR¹⁵，R¹⁵Represents a substituent. n1 represents an integer of 1 to 10.]

[ chemical formula 2]

[ in the general formula (2), R²¹And R²²Each independently represents a substituent, R²³～R²⁶Each independently represents a hydrogen atom or a substituent. X¹²Denotes O, S or NR²⁷，R²⁷Represents a substituent. n2 represents an integer of 1 to 10.]

[ chemical formula 3]

[ in the general formula (3), R³¹And R³²Each independently represents a substituent, R³³～R³⁷Each independently represents a hydrogen atom or a substituent.]

[ chemical formula 4]

[ in the general formula (4a), R⁴¹～R⁴³Each independently represents a hydrogen atom or a substituent. n4 represents an integer of 1 to 10. The benzene ring may be fused to the cycloolefin skeleton in the general formula (4 a).]

[ chemical formula 5]

[ in the general formula (4b), R⁴⁴～R⁴⁸Each independently represents a substituent.]

[ chemical formula 6]

[ in the general formula (5), R⁵¹～R⁵⁵Each independently represents a substituent. Wherein R is⁵⁴And R⁵⁵Are groups different from each other.]

[ chemical formula 7]

[ in the general formula (6), R⁶¹～R⁶⁴Each of the groups different from each other independently represents a substituent.]

[ chemical formula 8]

[ in the general formula (7), R⁷¹And R⁷²Each independently represents a hydrogen atom or a substituent.]

[ chemical formula 9]

[ in the general formula (8), R⁸¹And R⁸²Each independently represents a hydrogen atom or a substituent, R⁸³Represents a substituent.]

[ chemical formula 10]

[ in the general formulae (9a) and (9b), R⁹¹～R⁹⁶Each independently represents a substituent, and n91 and n92 each independently represents a substituentIndependently represent an integer of 1 to 10.]

[8] The method for producing an optically active body according to any one of [1] to [7], wherein,

the activation energy (hereinafter, racemic energy) required for racemization of the chiral molecule is 20 to 27 kcal/mol.

[9] The method for producing an optically active body according to any one of [1] to [8], wherein,

the asymmetric inducer is an optically active body.

[10] The method for producing an optically active body according to any one of [1] to [9], wherein,

the asymmetry inducer is a sugar chain derivative.

[11] The method for producing an optically active body according to [10], wherein,

the sugar chain derivative has a structure in which an aryl group is linked to a unit of a sugar chain via a linking group, the linking group containing an ester bond or a urethane bond.

[12] The method for producing an optically active body according to any one of [1] to [11], wherein,

the asymmetry inducing agent is carried on a particulate carrier.

[13] The method for producing an optically active body according to any one of [1] to [12], wherein,

after the asymmetry induction step, a separation step of separating the one enantiomer is further included.

[14] The method for producing an optically active body according to any one of [1] to [13], wherein,

after the asymmetry induction step, an asymmetry stabilization step of converting the one enantiomer into one enantiomer of a 2 nd chiral molecule having an enantiomeric excess half-life longer than that of the chiral molecule by allowing a reactant to act on the chiral molecule is further included.

[15] The method for producing an optically active body according to [14], wherein,

the half-life of the enantiomeric excess of the 2 nd chiral molecule is 10 hours or more at 50 ℃.

[16] The method for producing an optically active body according to [14] or [15], wherein,

the reactant is an optically active body.

[17] The method for producing an optically active body according to [14] or [15], wherein,

the reactant is an epoxidizing agent.

[18] An optically active substance produced by the production method according to any one of [1] to [17 ].

[19] A process for producing a chiral molecule, which comprises a step (hereinafter referred to as an asymmetric stabilization step) of converting an optically active form of a 1 st chiral molecule (dynamic chiral molecule) having a half-life of less than 10 hours and one enantiomer present in an excess amount to the other enantiomer by allowing a reactant to act on the optically active form of the 1 st chiral molecule at 50 ℃ into an optically active form of a 2 nd chiral molecule (static chiral molecule or quasi-static chiral molecule) having a longer racemization half-life.

[20] The method for producing a chiral molecule according to [19], which comprises the following steps before the asymmetric stabilization step:

increasing the presence ratio of one enantiomer of said chiral molecule by allowing an asymmetry inducing agent to act on a chiral molecule having an enantiomeric excess half-life of less than 10 hours at 50 ℃, thereby obtaining said 1 st chiral molecule having one enantiomer of said chiral molecule present in excess of the other.

[21] The method for producing a chiral molecule according to [19] or [20], wherein,

the enantiomeric excess of the 1 st chiral molecule is above 40% ee.

[22] A chiral molecule produced by the production method of any one of [19] to [21 ].

[23] The chiral molecule according to [22], wherein,

the half-life of the enantiomeric excess is more than 10 hours at 50 ℃.

Effects of the invention

According to the method for producing an optically active form of the present invention, one enantiomer of a chiral molecule can be selectively and efficiently obtained. Further, according to the method for producing a chiral molecule of the present invention, an optically active form which is not easily interconverted between enantiomers of a chiral molecule and is stable in stereochemistry can be obtained. The optically active substance thus obtained is very useful as a raw material for pharmaceuticals and functional materials.

Detailed Description

The present invention will be described in detail below. The following description of the constituent elements may be based on representative embodiments or specific examples of the present invention, but the present invention is not limited to these embodiments or specific examples. In the present specification, the numerical range expressed by the term "to" means a range including the numerical values described before and after the term "to" as the lower limit value and the upper limit value. The isotope type of hydrogen atoms present in the molecule of the compound used in the present invention is not particularly limited, and for example, all hydrogen atoms in the molecule may be hydrogen atoms¹H may be partially or wholly represented by²H (deuterium D).

< method for producing optically active Material >

The method for producing an optically active form of the present invention comprises a step of increasing the abundance ratio of one enantiomer of a chiral molecule by allowing an asymmetry inducing agent to act on the chiral molecule having an enantiomeric excess half-life of less than 10 hours at 50 ℃. In the present invention, this step is referred to as an "asymmetry induction step". The enantiomer whose presence ratio is increased by this step is the optically active form produced by the production method of the present invention. Also, in the present invention, "chiral molecule" does not refer to a single molecule, but refers to an aggregate of molecules.

According to this production method, the existence ratio of one enantiomer in a chiral molecule can be significantly increased without using a chiral reactant or even without accompanying cleavage and reformation of a bond in the chiral molecule, and one enantiomer can be selectively and efficiently obtained. Therefore, the optical purity can be made very high (the enantiomeric excess is made very high). The production method can be applied to various chiral molecules, and is a general method. This production method is a novel method having a completely different concept from conventional racemization resolution methods and asymmetric synthesis methods.

Hereinafter, the chiral molecule, the asymmetry inducer and the conditions used in the asymmetry induction step of the present invention will be described in detail. In the present specification, room temperature refers to 25 ℃.

[ asymmetric Induction Process ]

In this step, the existence ratio of one enantiomer of the chiral molecule is increased by allowing the asymmetry inducing agent to act on the chiral molecule having an enantiomeric excess half-life of less than 10 hours.

(chiral molecules with a half-life of less than 10 hours with enantiomeric excess)

In the present invention, the "half-life of enantiomeric excess" of the chiral molecule used in the asymmetry induction step refers to the time until the enantiomeric excess of the chiral molecule becomes 1/2, which is the initial enantiomeric excess, at a certain temperature.

The enantiomeric excess is a value determined from the following formula (I).

[ numerical formula 1]

In the formula (I), A₁And A₂Represents the molar fraction of one and the other enantiomer contained in the chiral molecule of interest, A₁The mole fraction of the enantiomer having a large mole fraction, A₂Is the mole fraction of the enantiomer with small mole fraction.

The mole fractions of one and the other enantiomers can be determined by HPLC · GC analysis using a chiral stationary phase, optical rotation measurement, NMR analysis using a chiral shift reagent, or the like.

In addition, a chiral molecule in which one or the other enantiomer is present in excess exhibits optical activity, and therefore, in the present specification, such a chiral molecule is sometimes referred to as an "optically active form".

Chiral molecules readily interconvert enantiomers, the easier the racemization, the shorter the half-life of the enantiomeric excess. Thus, a chiral molecule with an enantiomeric excess half-life of less than 10 hours at 50 ℃ allows for the action of a suitable asymmetry inducer under mild conditions (0-50 ℃), whereby the other enantiomer is readily converted to one and the presence ratio of one enantiomer can be increased. The half-life of the enantiomeric excess of the chiral molecule (dynamic chiral molecule) used in the method for producing an optically active body of the present invention can be set to, for example, less than 5 hours, less than 3 hours, or less than 1 hour. The lower limit of the half-life of the enantiomeric excess of the chiral molecule is not particularly limited, and for example, may be 10 minutes or more, 1 hour or more, or 10 hours or more at a temperature lower than 0 ℃.

As the chiral molecule used in the asymmetry induction step, for example, a chiral molecule whose spatial conformations are different from each other among enantiomers, that is, a chiral molecule which exhibits chirality by a difference in spatial conformation can be used. In such a chiral molecule, the other enantiomer is changed into one enantiomer by a steric conformational transition of a relatively low energy barrier (for example, 20 kcal/mol) such as a rotation of a bond in the molecule and a change in bond angle. Therefore, by allowing an asymmetry inducing agent to act on a chiral molecule under mild conditions at about room temperature, the other enantiomer is easily changed into one enantiomer, and the existence ratio of one enantiomer can be remarkably increased. Examples of chiral molecules having different spatial conformations between enantiomers include planar asymmetric molecules, axially asymmetric molecules (for example, axially asymmetric molecules other than substituted biphenyl molecules can be selected), helical asymmetric molecules, and central asymmetric molecules. Examples of the plane asymmetric molecule include cyclic dienes and ortho-cyclic phenols (ortho-cyclic dienes). Examples of the axially asymmetric molecule include aniline, unsaturated amides, and substituted styrenes, and for example, axially asymmetric molecules other than substituted biphenyl molecules can be selected. Examples of the helical asymmetric molecule include a lactone and a lactam. Examples of the central asymmetric molecule include silane. Specifically, for example, compounds represented by the following general formulae (1) to (3), (4a), (4b), (5), (6), (7), (8), (9a), and (9b) can be used. All of the compounds represented by these general formulae are easy to interconvert enantiomers under mild temperature conditions (0 to 50 ℃), and therefore the temperature at which the asymmetry inducer acts can be set to mild temperature conditions (0 to 50 ℃).

First, as the cyclic diene used as the chiral molecule, a compound represented by the following general formula (1) can be used.

[ chemical formula 11]

In the general formula (1), R¹¹～R¹⁴Each independently represents a hydrogen atom or a substituent. R¹¹～R¹⁴The substituents may be the same or different from each other. X¹¹Denotes O, S or NR¹⁵，R¹⁵Represents a substituent. n1 represents an integer of 1 to 10.

The substituent is not particularly limited, and R is¹²The substituent represented can be, for example, a substituted or unsubstituted alkyl group or a halogen atom, and in the case of a substituted alkyl group, a halogen atom or an alkyl group substituted with a substituted or unsubstituted acyloxy group can be used. As R¹⁵Examples of the substituent include a protecting group such as tosyl group.

As the o-cyclofin used as the chiral molecule, a compound represented by the following general formula (2) can be used.

[ chemical formula 12]

In the general formula (2), R²¹And R²²Each independently represents a hydrogen atom or a substituent. R²¹And R²²When both represent a substituent, the substituents may be the same as or different from each other. As an embodiment, R can be mentioned²¹And R²²One of them is a hydrogen atom and the other is a substituent. R²³～R²⁶Are respectively provided withIndependently represents a hydrogen atom or a substituent. R²³～R²⁶The number of the substituent(s) in (1) is not particularly limited, and R²³～R²⁶All may be unsubstituted (hydrogen atoms). R²¹～R²⁶When 2 or more of them are substituents, the substituents may be the same or different from each other. X¹²Denotes O, S or NR²⁷，R²⁷Represents a substituent. n2 represents an integer of 1 to 10.

The kind of the substituent is not particularly limited, and R is²²As the substituent, for example, a substituted or unsubstituted alkyl group or a halogen atom can be used, and in the case of a substituted alkyl group, a halogen atom or an alkyl group substituted with an acyloxy group can be used. As R²⁷Examples of the substituent include a protecting group such as tosyl group.

Hereinafter, the spatial conformations of the R-form and S-form of an example of the compounds represented by the general formulae (1) and (2) are schematically shown. X, Y represents a substituent.

[ chemical formula 13]

As the aniline used as the chiral molecule, a compound represented by the following general formula (3) can be used.

[ chemical formula 14]

In the general formula (3), R³¹And R³²Each independently represents a substituent. R³¹And R³²The substituents may be the same or different from each other. R³³～R³⁷Each independently represents a hydrogen atom or a substituent. R³³～R³⁷The number of the substituent(s) in (1) is not particularly limited, and R³³～R³⁷All may be unsubstituted (hydrogen atoms). R³³～R³⁷When 2 or more of them are substituents, the substituents may be the same or different from each other.

The substituent is not particularly limited, and R is³¹The substituents represented, for example, can be substituted or unsubstituted alkyl groups, and in the case of substituted alkyl groups, substituted or unsubstituted aryl groups or alkyl groups substituted with substituted or unsubstituted heteroaryl groups can be used. As R³²The substituent represented can be, for example, a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkenyl group, and in the case of a substituted alkyl group or a substituted alkenyl group, an alkyl group substituted with a substituted or unsubstituted aryl group, an alkenyl group substituted with a substituted or unsubstituted aryl group can be used. As R³³、R³⁷The substituent represented can be, for example, a substituted or unsubstituted alkyl group or a halogen atom.

Hereinafter, the spatial conformations of the R-isomer and the S-isomer of an example of the compound represented by the general formula (3) are schematically shown. R, R' and X, Y represent substituents.

[ chemical formula 15]

As the unsaturated amide used as the chiral molecule, a compound represented by the following general formula (4a) or (4b) can be used.

[ chemical formula 16]

In the general formulae (4a) and (4b), R⁴¹～R⁴³、R⁴⁴～R⁴⁸Each independently represents a substituent. R⁴¹～R⁴³The substituents may be the same or different from each other. R⁴⁴～R⁴⁸The substituents may be the same or different from each other. n4 represents an integer of 1 to 10. The benzene ring may be fused to the cycloolefin skeleton in the general formula (4 a).

The substituent is not particularly limited, and R is⁴¹As the substituent, for example, a substituted or unsubstituted aroyloxy group can be usedThe substituted or unsubstituted siloxy group can be an arylacyloxy group substituted with a substituted or unsubstituted alkoxy group when the substituted siloxy group is a substituted arylacyloxy group, or a siloxy group substituted with 3 hydrogen atoms by at least one of a substituted or unsubstituted alkyl group and a substituted or unsubstituted aryl group when the substituted siloxy group is a substituted siloxy group. As R⁴²、R⁴³、R⁴⁷、R⁴⁸As the substituent, for example, a substituted or unsubstituted alkyl group can be used.

Hereinafter, the spatial conformations of the R-isomer and the S-isomer of an example of the compound represented by the general formula (4a) are schematically shown. R, X represents a substituent.

[ chemical formula 17]

As the substituted styrene used as the chiral molecule, a compound represented by the general formula (5) can be used.

[ chemical formula 18]

In the general formula (5), R⁵¹～R⁵⁵Each independently represents a substituent. Wherein R54 and R⁵⁵Are groups different from each other.

The substituent is not particularly limited, and R is⁵¹～R⁵³As the substituent, for example, a substituted or unsubstituted alkyl group can be used. As R⁵⁴And R⁵⁵The substituent represented can be, for example, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a halogen atom.

As the silane used as the chiral molecule, a compound represented by the general formula (6) can be used.

[ chemical formula 19]

In the general formula (6), R⁶¹～R⁶⁴Each of the groups different from each other independently represents a substituent.

The substituent is not particularly limited, and R is⁶¹And R⁶²As the substituent, for example, a substituted or unsubstituted alkyl group can be used. As R⁶³And R⁶⁴The substituent represented can be, for example, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a halogen atom.

As the lactone used as the chiral molecule, a compound represented by the general formula (7) can be used.

[ chemical formula 20]

In the general formula (7), R⁷¹And R⁷²Each independently represents a hydrogen atom or a substituent. R⁷¹And R⁷²The number of the substituent(s) in (1) is not particularly limited, and R⁷¹And R⁷²Two may be unsubstituted (hydrogen atoms). R⁷¹And R⁷²When two are substituents, 2 substituents may be the same as or different from each other.

R⁷¹、R⁷²The substituent is not particularly limited, and for example, a substituted or unsubstituted alkoxy group can be used, and in the case of a substituted alkoxy group, a substituted or unsubstituted aryl group or an alkoxy group substituted with a substituted or unsubstituted alkoxy group can be used. Examples of the substituent of the substituted alkoxy group in the alkoxy group substituted with the substituted alkoxy group include a substituted or unsubstituted alkoxy group and a silyl group substituted with 3 hydrogen atoms and substituted with an alkyl group.

Hereinafter, the spatial conformations of the R-isomer and the S-isomer of an example of the compound represented by the general formula (7) are schematically shown. X, Y represents a substituent.

[ chemical formula 21]

As the lactam used as the chiral molecule, a compound represented by the general formula (8) can be used.

[ chemical formula 22]

In the general formula (8), R⁸¹And R⁸²Each independently represents a hydrogen atom or a substituent. R⁸¹And R⁸²The number of the substituent(s) in (1) is not particularly limited, and R⁸¹And R⁸²Two may be unsubstituted (hydrogen atoms). R⁸¹And R⁸²When two are substituents, 2 substituents may be the same as or different from each other. R⁸³Represents a substituent.

The substituent is not particularly limited, and R is⁸¹、R⁸²The substituent represented can be, for example, a substituted or unsubstituted alkoxy group, and in the case of a substituted alkoxy group, a substituted or unsubstituted aryl group or an alkoxy group substituted with a substituted or unsubstituted alkoxy group can be used. Examples of the substituent of the substituted alkoxy group in the alkoxy group substituted with the substituted alkoxy group include a substituted or unsubstituted alkoxy group and a silyl group substituted with 3 hydrogen atoms and substituted with an alkyl group.

As the lactam used as the chiral molecule, a compound represented by the general formula (9a) or the general formula (9b) can also be used.

[ chemical formula 23]

In the general formulae (9a) and (9b), R⁹¹～R⁹⁶Each independently represents a substituent, and n91 and n92 each independently represents an integer of 1 to 10.

The substituent is not particularly limited, and R is⁹¹、R⁹²、R⁹⁴、R⁹⁵As the substituent, for example, a substituted or unsubstituted alkyl group can be used. As R⁹³、R⁹⁶The substituent represented can be, for example, a substituted or unsubstituted alkyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkoxycarbonyl group, or a sulfonyl group. As the acyl group, for example, acetyl group or benzyl group can be used. As the alkoxycarbonyl group, for example, a tert-butoxycarbonyl group (Boc group) can be used. Examples of the sulfonyl group include a p-toluenesulfonyl group (tosyl group, Ts group), a 2-nitrobenzenesulfonyl group (nonyl group, Ns group), and a methanesulfonyl group (methanesulfonyl group, Ms group).

R as formula (1)¹¹～R¹⁵R of the general formula (2)²¹～R²⁷R of the general formula (3)³¹～R³⁷R of the general formula (4a)⁴¹～R⁴³R of the general formula (4b)⁴⁴～R⁴⁸R of the general formula (5)⁵¹～R⁵⁵R of the formula (6b)⁶¹～R⁶⁴R of the general formula (7)⁷¹、R⁷²R of the general formula (8)⁸¹～R⁸³R of the formula (9a)⁹¹～R⁹³R of the formula (9b)⁹⁴～R⁹⁶Examples of the substituent which may be substituted on the substituent represented by each general formula include a hydroxyl group, a halogen atom, a cyano group, an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, an alkylthio group having 1 to 20 carbon atoms, an alkyl-substituted amino group having 1 to 20 carbon atoms, an acyl group having 2 to 20 carbon atoms, an aryl group having 6 to 40 carbon atoms, a heteroaryl group having 3 to 40 carbon atoms, a diarylamino group having 12 to 40 carbon atoms, a substituted or unsubstituted carbazolyl group having 12 to 40 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, an alkoxycarbonyl group having 2 to 10 carbon atoms, an alkylsulfonyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amide group, an alkylamide group having 2 to 10 carbon atoms, a trialkylsilyl group having 3 to 20 carbon atoms, a trimethylsilylalkyl group having 4 to 20 carbon atoms, and a trimethylsilylalkyl group having 5 to 20 carbon atoms, A C5-20 trimethylsilylalkynyl group, a nitro group, and the like. In these embodiments, a substituent which may be further substituted with a substituent may also be substituted with a substituent in these embodiments.

The "alkyl group" or an alkyl group in a substituent containing an alkyl group in a part thereof in the present specification may be any of a linear, branched, and cyclic group. The number of carbon atoms can be selected from, for example, 1 to 10, 1 to 6, 1 to 3, and the like. Examples thereof include methyl, ethyl and propyl. Specific examples of the "halogen atom" in the present specification include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The racemic energy of the chiral molecule used in the asymmetry induction step can be, for example, 27kcal/mol or less, 25kcal/mol or less, 24kcal/mol or less, or 23kcal/mol or less. The racemic energy of the chiral molecule used in the asymmetry induction step can be, for example, 20kcal/mol or more, 21kcal/mol or more, or 22kcal/mol or more. The racemization energy range includes, for example, a range of 21 to 23 kcal/mol. While a chiral molecule having a racemization energy in an appropriate range has appropriate stereochemical stability to the extent of slowly racemizing at room temperature, if an appropriate asymmetry inducer acts at room temperature, it is relatively easily changed from another enantiomer to one enantiomer. Therefore, by providing a chiral molecule having such racemization energy to the production method of the present invention, one enantiomer can be selectively and efficiently obtained, and the chiral molecule can be well handled.

The racemization energy of a chiral molecule can be determined by kinetic analysis experiments or density functional calculations (DFT calculations) of the racemic transition state.

Specific examples of chiral molecules having a half-life of less than 10 hours at 25 ℃ in enantiomeric excess that can be used in the present invention are exemplified below. However, the chiral molecules having a half-life of less than 10 hours at 25 ℃ in enantiomeric excess that can be used in the present invention should not be construed restrictively from these embodiments. In the following formula, Ts represents a tosyl group (p-tosyl group), Ac represents an acetyl group, iPr represents an isopropyl group, Ph represents a phenyl group, TBDPS represents a tert-butyldiphenylsilyl group, Bn represents a benzyl group, MEM represents a 2-methoxyethoxymethyl group, and SEM represents a 2- (trimethylsilyl) ethoxymethyl group.

[ chemical formula 24]

(asymmetric inducer)

In the present invention, the "asymmetry inducer" refers to a substance that acts to increase the abundance ratio of one enantiomer of a chiral molecule when acting on the chiral molecule. The asymmetry inducer is required to be a substance which, when acting on a chiral molecule, increases the abundance ratio of one enantiomer without accompanying cleavage and reformation of bonds in the chiral molecule, and can be recovered and reused. Further, the asymmetry inducer may be a substance having a function of preferentially interacting with the other enantiomer and converting the spatial conformation of the other enantiomer into the spatial conformation of the one enantiomer.

Examples of such an asymmetry inducer include sugar chain derivatives (sugar chain-derived polymers) such as cellulose derivatives and amylose derivatives, naturally-derived chiral polymers and derivatives thereof such as polypeptides, DNAs and antibodies, amino acid derivatives, and chiral mold polymers (artificial chiral polymers).

The asymmetry inducer may be supported on a particulate carrier such as silica gel. Thus, the asymmetry inducer acting on the chiral molecules in the solvent can be easily separated from the chiral molecules and reused by a simple operation such as filtration.

(method and conditions for allowing an asymmetry inducer to act on a chiral molecule)

As described above, in the method for producing an optically active form of the present invention, an asymmetry inducing agent is allowed to act on a chiral molecule having a half-life of less than 10 hours at 50 ℃.

The operation of allowing the asymmetry inducer to act on the chiral molecule can be performed by allowing the chiral molecule and the asymmetry inducer to coexist in a solvent and stirring the solvent, followed by standing. The chiral molecule is brought into sufficient contact with the asymmetry inducer by stirring of the solvent, and then left to stand, whereby the action of the asymmetry inducer can be exhibited and the equilibrium between enantiomers can be sufficiently biased. In addition, after stirring the solvent in which the chiral molecule and the asymmetry inducer coexist, the solvent may be distilled off, and instead of adding another solvent thereto, the chiral molecule and the asymmetry inducer may be allowed to stand in the solvent.

The solvent is not particularly limited as long as it does not adversely affect the chiral molecule and the asymmetry inducer and does not impair the action of the asymmetry inducer. Regarding the compatibility of the solvent, having compatibility with the chiral molecule, may be a solvent in which the asymmetry inducer or the carrier carrying the asymmetry inducer can exist in a solid state in the solvent. The asymmetric inducer or the carrier carrying the asymmetric inducer exists in a solid state while the chiral molecule is dissolved in the solvent, and thus the asymmetric inducer after having acted on the chiral molecule can be easily separated from the chiral molecule by a simple operation such as filtration. Also, the vapor pressure of the solvent may be higher (lower boiling point) than that of the chiral molecule. Thus, the solvent and the chiral molecule can be easily separated by a simple operation such as removal by distillation.

The amount of the solvent used for standing the chiral molecule and the asymmetry inducer can be set to 1 to 20 times the total amount of the chiral molecule and the asymmetry inducer.

The amount of the asymmetry inducer in the solvent can be, for example, 50 times or more, 100 times or more, 200 times or more, 1000 times or less, 500 times or less, and 300 times or less relative to the weight of the chiral molecule.

The temperature of the solvent at which the chiral molecule and the asymmetry inducer are allowed to stand can be set to, for example, 0 to

At 50 ℃. The method for producing an optically active body of the present invention can be carried out under such mild temperature conditions (0 to 50 ℃), and therefore, an apparatus, a device, and an operation for high-temperature heating are not required, and the production cost of the optically active body can be kept low.

From the viewpoint of work efficiency, the time for leaving the chiral molecule and the asymmetry inducer standing can be 72 hours or less.

[ other Processes ]

In the method for producing an optically active body of the present invention, after the asymmetry induction step, a step of separating the optically active body (separation step) and a step of converting the optically active body into an optically active body of the 2 nd chiral molecule having a longer half-life of an enantiomeric excess of the chiral molecule by allowing a reactant to act on the chiral molecule (asymmetry stabilization step) can be further performed. Hereinafter, each step will be explained.

[ separation Process ]

The optically active substance obtained in the asymmetry inducing step is co-present in a solvent together with an asymmetry inducing agent. In the separation step, the optically active substance is separated from these substances.

When the asymmetry inducer is in a solid state in a solvent or carried on a solid support, separation of the optically active species from the asymmetry inducer can be carried out by filtration of a mixture of the optically active species and the asymmetry inducer and the solvent. Thereby, the asymmetry inducing agent remains on the filter medium, and the optically active body is dissolved in the filtrate, so that the two are in a separated state. The separation of the optically active substance from the solvent can be performed by removing the solvent by distillation. Either one of filtration and distillation removal may be performed first, and when distillation removal is performed first, filtration may be performed by adding a solvent again to the concentrate after distillation removal.

In addition, the separated asymmetry inducing agent can be reused as an asymmetry inducing agent in the asymmetry inducing step.

Also, when the enantiomeric excess of one enantiomer of the filtrate is not 100% ee, i.e., the other enantiomer is contained in the filtrate, the separation of the other enantiomer from one enantiomer may be performed. The separation of one enantiomer from the other can be carried out using well-known optical resolution methods. The separation of one enantiomer from the other may be carried out after an asymmetric stabilization procedure.

[ asymmetric stabilization Process ]

In the above-mentioned asymmetry induction step, one enantiomer having a higher ratio may change into the other enantiomer with time. In this step, the reactant is allowed to act on the chiral molecule to be an optically active form in the asymmetry induction step, and the optically active form is converted into an optically active form of the 2 nd chiral molecule having a longer half-life of enantiomeric excess compared with the chiral molecule. Thus, an optically active body having high optical purity and stable optical activity can be obtained. The asymmetry stabilization step may be performed as a step subsequent to the asymmetry induction step, or may be performed after the separation step.

(reagent)

The "reactant" in the asymmetry stabilization step is a substance that reacts with the optically active substance obtained in the asymmetry induction step and is converted into an optically active substance of the 2 nd racemic molecule having a longer half-life of enantiomeric excess than the racemic molecule used in the asymmetry induction step. The reactant is not particularly limited as long as it has such a function. In addition, the object actually treated with the reagent may be a chiral molecule comprising only one enantiomer isolated, or may be a chiral molecule comprising one enantiomer and the other enantiomer, one enantiomer being present in excess of the other. When a mixture comprising one enantiomer and the other enantiomer is treated with an asymmetry inducing agent, the other enantiomer may also be subjected to the action of a reactant.

The reactant may be an epoxidizing agent, an alkyllithium reactant, an alkylmagnesium reactant, a metal alkoxide reactant, or the like.

The method and conditions for allowing the reactant to act on the optically active substance are not particularly limited. For example, when an epoxidizing agent is used as the reactant, the asymmetric stabilization can be carried out by the method and conditions of the asymmetric stabilization step described in the column of examples.

(chiral molecule 2)

The "half-life of enantiomeric excess" of the 2 nd chiral molecule used in the asymmetric stabilization step refers to the time until the enantiomeric excess of one enantiomer of the 2 nd chiral molecule becomes 1/2 of the initial enantiomeric excess at a certain temperature, where "one enantiomer" is the enantiomer (one enantiomer) that should be obtained for the purpose in the asymmetric stabilization step.

In the asymmetric stabilization step, the half-life of the enantiomeric excess of the 2 nd chiral molecule is the time until the initial enantiomeric excess of one enantiomer becomes 1/2 of the initial enantiomeric excess at a certain temperature, where "one enantiomer" is the enantiomer (one enantiomer) with a higher ratio present in the asymmetric induction step.

The half-life of the enantiomeric excess of the 2 nd chiral molecule can be set to, for example, 10 hours or more, 100 hours or more, or 1,000 hours or more at 50 ℃.

Examples of the compound that can be used as the 2 nd chiral molecule, that is, the chiral molecule having a relatively long half-life with an excess of an enantiomer include a planar asymmetric molecule, a 5-membered ring compound, a cyclohexane derivative, a tetrahydronaphthalene derivative, an epoxide, an ortho-cyclic aromatic (ortho-cyclic) compound, an indolone, and a binaphthyl compound.

As the plane asymmetric molecule of the 2 nd chiral molecule, a compound represented by the following general formula (10) or general formula (11) can be used.

[ chemical formula 25]

In the general formula (10), R¹⁰¹～R¹⁰³Each independently represents a hydrogen atom or a substituent. R¹⁰¹～R¹⁰³The number of the substituent(s) in (1) is not particularly limited, and R¹⁰¹～R¹⁰³All may be unsubstituted (hydrogen atoms). R¹⁰¹～R¹⁰³When 2 or more of them are substituents, the substituents may be the same or different from each other. X¹⁰¹Denotes O, S or NR¹⁰⁴，R¹⁰⁴Represents a substituent.

The substituent is not particularly limited, and R¹⁰⁴A protecting group such as tosyl group can be used.

[ chemical formula 26]

In the general formula (11), R¹¹¹Represents a hydrogen atom or a substituent. X¹¹¹Denotes O, S or NR¹¹²，R¹¹²Represents a substituent. R¹¹²A protecting group such as tosyl group can be used.

The 5-membered ring compound as the 2 nd chiral molecule can be a compound represented by the following general formula (12).

[ chemical formula 27]

In the general formula (12), R¹²¹～R¹²⁴Each independently represents a hydrogen atom or a substituent. R¹²¹～R¹²⁴The number of the substituent(s) in (1) is not particularly limited, and R¹²¹～R¹²⁴All may be unsubstituted (hydrogen atoms). R¹²¹～R¹²⁴When 2 or more of them are substituents, the substituents may be the same or different from each other. X¹²¹Denotes O, S or NR¹²⁵，R¹²⁵Represents a substituent.

The cyclohexane derivative as the 2 nd chiral molecule can be a compound represented by the following general formula (13).

[ chemical formula 28]

In the general formula (13), R¹³¹～R¹³⁴Each independently represents a hydrogen atom or a substituent. R¹³¹～R¹³⁴The number of the substituent(s) in (1) is not particularly limited, and R¹³¹～R¹³⁴All may be unsubstituted (hydrogen atoms). R¹³¹～R¹³⁴When 2 or more of them are substituents, the substituents may be the same or different from each other. X¹³¹Denotes O, S or NR¹³⁵，R¹³⁵Represents a substituent. n13 represents an integer of 1 to 10.

The substituent is not particularly limited, and R¹³²Watch with clockThe substituent can be an alkyl group substituted with a hydroxyl group, R¹³⁵The substituent may be a protecting group such as a tosyl group.

The tetrahydronaphthalene derivative as the 2 nd chiral molecule can be a compound represented by the following general formula (14).

[ chemical formula 29]

In the general formula (14), R¹⁴¹And R¹⁴²Each independently represents a hydrogen atom or a substituent. R¹⁴¹And R¹⁴²The number of the substituent(s) in (1) is not particularly limited, and R¹⁴¹And R¹⁴²Two may be unsubstituted (hydrogen atoms). R¹⁴¹And R¹⁴²When two are substituents, 2 substituents may be the same as or different from each other. X represents O, S or NR¹⁴³，R¹⁴³Represents a substituent. n14 represents an integer of 1 to 10.

The substituent is not particularly limited, and R¹⁴²The substituent represented can be, for example, an alkyl group substituted with a hydroxyl group, R¹⁴³The substituent may be a protecting group such as a tosyl group.

The epoxide as the 2 nd chiral molecule can be an epoxide represented by the general formula (15), (16), (17) or (18). Specific examples of the 2 nd chiral molecule include chiral molecules represented by the following general formula.

The ortho-cyclic aromatic group as the 2 nd chiral molecule can be a compound represented by the following general formulae (15) to (19).

[ chemical formula 30]

In the general formulae (15) to (19), R¹⁵¹～R¹⁵⁴、R¹⁶¹～R¹⁶⁵、R¹⁷¹～R¹⁷⁵、R¹⁸¹～R¹⁸³、R¹⁹¹～R¹⁹³Each independently represents a hydrogen atom or a substituent. R¹⁵¹～R¹⁵⁴、R¹⁶¹～R¹⁶⁵、R¹⁷¹～R¹⁷⁵、R¹⁸¹～R¹⁸³、R¹⁹¹～R¹⁹³The number of the substituents in (1) is not particularly limited, and all may be unsubstituted (hydrogen atom). When 2 or more substituents are present, the substituents may be the same or different from each other. X¹⁵¹、X¹⁶¹、X¹⁹¹Each independently of the other O, S or NR¹⁹⁴，R¹⁹⁴Represents a substituent. n18 and n19 each independently represent an integer of 1 to 10.

Indolone as the 2 nd chiral molecule can be a compound represented by the following general formula (20).

[ chemical formula 31]

In the general formula (20), R²⁰¹Represents a substituent group, R²⁰²～R²⁰⁶Each independently represents a hydrogen atom or a substituent. R²⁰²～R²⁰⁶The number of the substituent(s) in (1) is not particularly limited, and R²⁰²～R²⁰⁶All may be unsubstituted (hydrogen atoms). R²⁰¹～R²⁰⁶When 2 or more of them are substituents, the substituents may be the same or different from each other.

The binaphthyl compound as the 2 nd chiral molecule can be a compound represented by the general formula (21) or (22).

[ chemical formula 32]

In the general formulae (21) and (22), R²¹¹、R²²¹And R²²²Each independently represents a substituent. R²¹²、R²¹³、R²²³And R²²⁴Are respectively and independentlyRepresents a hydrogen atom or a substituent. For example, R can be²¹²And R²¹³And R²²³And R²²⁴At least one of them is provided as a substituent. R²¹¹～R²¹³、R²²¹～R²²⁴The substituents may be the same or different from each other.

The substituent is not particularly limited, and R²¹¹、R²²¹The substituent represented can be, for example, a substituted or unsubstituted alkyl group.

R for the general formula (10)¹⁰¹～R¹⁰⁴R of the general formula (11)¹¹¹、R¹¹²R of the general formula (12)¹²¹～R¹²⁵R of the general formula (13)¹³¹～R¹³⁵R of the general formula (14)¹⁴¹～R¹⁴³R of the general formula (19)¹⁹¹～R¹⁹⁴R of the general formula (20)²⁰¹～R²⁰⁶R of the general formula (21)²¹¹R of the general formula (22)²²¹、R²²²As for the range and specific examples of the substituent that can be used, R in the general formula (1) can be referred to¹¹～R¹⁵And the like, and specific examples and ranges of the substituents which can be employed.

Specific examples of the 2 nd chiral molecule that can be used in the present invention are shown below. However, the 2 nd chiral molecule that can be used in the present invention should not be construed restrictively from these specific examples. In the following formulae, Ac represents an acetyl group, Ts represents a tosyl group (p-tosyl group), TBDPS represents a t-butyldiphenylsilyl group, iPr represents an isopropyl group, Et represents an ethyl group, and SEM represents a 2- (trimethylsilyl) ethoxymethyl group.

[ chemical formula 33]

< optically active form >

Next, the optically active body of the present invention will be described.

The optically active body of the present invention is produced by the method for producing an optically active body of the present invention.

With regard to the explanation, the scope and the specific examples of the method for producing an optically active body of the present invention, reference can be made to the contents described in the column < method for producing an optically active body > above.

The optically active form of the present invention may be an optically active form obtained in the asymmetry induction step in the method for producing an optically active form of the present invention, an optically active form separated by performing a separation step after the asymmetry induction step, an optically active form of the 2 nd chiral molecule obtained by performing an asymmetry stabilization step after the asymmetry induction step, or an enantiomer of the 2 nd chiral molecule obtained by further performing an asymmetry stabilization step on an enantiomer separated by performing the separation step after the asymmetry induction step. When the optically active form of the present invention is an optically active form of the 2 nd chiral molecule, it is difficult to change to the other enantiomer of the 2 nd chiral molecule, and stable optical activity can be obtained. One enantiomer of the chiral molecule or one enantiomer of the 2 nd chiral molecule, which is the optically active form of the present invention, may be produced by the production method of the present invention in coexistence with the other enantiomer of the chiral molecule or the other enantiomer of the 2 nd chiral molecule, and thus have a higher existence ratio than these other enantiomers.

The enantiomeric excess of the optically active form (one enantiomer) of the present invention can be, for example, 40% ee or more, 60% ee or more, or 70% ee or more, and all can be one enantiomer. Thus, an optically active form having a large existence ratio of one enantiomer can efficiently exhibit asymmetric functions based on the presence ratio, and is very useful as a drug or various functional materials.

< method for producing chiral molecule >

Next, a method for producing chiral molecules will be described.

The method for producing a chiral molecule of the present invention comprises the following steps (asymmetric stabilization step): the half-life of the enantiomeric excess is less than 10 hours at 50 ℃, by reacting a reagent with a 1 st chiral molecule present in an enantiomeric excess of one enantiomer to thereby convert the 1 st chiral molecule to a 2 nd chiral molecule having a longer half-life of the enantiomeric excess.

According to this method for producing a chiral molecule, the 1 st chiral molecule having a half-life of an enantiomeric excess of less than 10 hours at 50 ℃ is converted into the 2 nd chiral molecule having a long half-life of an enantiomeric excess by allowing a reactant to act on the 1 st chiral molecule, and therefore, an optically active form of the 1 st chiral molecule (an optically active form which is easily racemized) can be converted into an optically active form which is difficult to racemize while maintaining its optical purity. Thus, an optically active substance having stable optical purity can be easily obtained.

With respect to the description, the range and specific examples of the 1 st chiral molecule, reference can be made to the description, the range and the specific examples of the chiral molecule in the column of the asymmetry induction step in the above < method for producing an optically active body >. With respect to the definition of the half-life of the enantiomeric excess of the 2 nd chiral molecule, the description and the ranges, and specific examples of the reactant and the 2 nd chiral molecule, reference can be made to the definition of the half-life of the enantiomeric excess of the 2 nd chiral molecule, the description and the ranges, and specific examples of the reactant and the 2 nd chiral molecule in the column of the asymmetric stabilization step in the above < method for producing an optically active substance >.

The "half-life of enantiomeric excess" of the 1 st chiral molecule used in the asymmetric stabilization step refers to the time until the initial enantiomeric excess of one enantiomer, which is the enantiomer (one enantiomer) present in excess in the 1 st chiral molecule, becomes 1/2 of the initial enantiomeric excess at a certain temperature.

"one enantiomer is present in excess of the other enantiomer" in chiral molecule 1 means that the enantiomeric excess of one enantiomer is greater than 0% ee, including the case where the enantiomeric excess is 100% ee. That is, the 1 st chiral molecule may comprise one enantiomer and the other enantiomer, one enantiomer being present in a larger ratio than the other enantiomer, or may comprise only one enantiomer of one and the other enantiomer.

The enantiomeric excess of one enantiomer in the 1 st chiral molecule can be set to, for example, 40% ee or more, 70% ee or more, or 100% ee.

The 1 st chiral molecule may be in any one of a solid state, a liquid state, and a solution state. Further, components other than the 1 st chiral molecule and the 2 nd chiral molecule may be mixed as long as the conversion reaction from the 1 st chiral molecule to the 2 nd chiral molecule is not adversely affected.

The 1 st chiral molecule can be obtained by any method, but can be obtained by applying the method for producing an optically active body of the present invention. Specifically, before the asymmetric stabilization step, the asymmetric induction step of obtaining the 1 st chiral molecule in which one enantiomer of the chiral molecule is present in excess of the other enantiomer is performed by allowing an asymmetric inducer to act on an optically active form of the chiral molecule having a half-life of less than 10 hours at 50 ℃ with an enantiomeric excess, thereby increasing the presence ratio of one enantiomer of the chiral molecule, and the 1 st chiral molecule obtained in this step can be used as the 1 st chiral molecule in the asymmetric stabilization step. Thus, the 1 st chiral molecule having a high enantiomeric excess of one enantiomer can be obtained by a simple operation under mild conditions at room temperature. For the definition of the half-life of the 1 st chiral molecule in terms of enantiomeric excess, the 1 st chiral molecule, the asymmetry inducer, and the method and conditions for allowing the asymmetry inducer to act on the 1 st chiral molecule, reference can be made to the corresponding descriptions in the section of the asymmetry induction step in the above < method for producing an optically active form >.

< chiral molecule >

The chiral molecule of the present invention is produced by the method for producing a chiral molecule of the present invention.

For the explanation, the scope and the specific examples of the method for producing chiral molecules of the present invention, reference can be made to the contents described in the column < method for producing chiral molecules > above. As for the range and specific examples of the chiral molecule of the present invention, reference can be made to the range and specific examples of the 2 nd chiral molecule in the column of the asymmetric stabilization step in < method for producing an optically active body >.

The chiral molecule of the present invention is produced by the method for producing a chiral molecule of the present invention, and thus an optically active form in which the interconversion between enantiomers is difficult and the enantiomeric excess hardly changes under mild temperature conditions (0 to 50 ℃) can be obtained.