JP2003321445A - Heterocyclic compound having asymmetric center and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for stereoselectively introducing an asymmetric center at the adjacent hetero-site. <P>SOLUTION: The heterocyclic compound having an asymmetric center and expressed by formula 1a (R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>are each independently hydrogen atom, a hydrocarbon group or the like; and A is a 5 to 11-membered heterocyclic group) is produced by the rearrangement reaction of an epoxy alcohol expressed by formula 5a in the presence of a Lewis acid. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a heterocyclic compound having an asymmetric center and a method for producing the same, and more particularly to a heterocyclic compound having an asymmetric center at a position adjacent to a heterocycle and a method for producing the same.

[0002]

2. Description of the Related Art Introduction of an asymmetric center at a heterocyclic ring adjacent position is important from the viewpoint of natural product synthesis. Previously, the introduction of a chiral center to the 3rd adjacent indole by the enzymatic method (T. Bando and K. Shishido, Heter
ocycles, 46, 111 (1997)) and the introduction of an asymmetric center at the adjacent position of pyrrole 2 by the asymmetric Michael reaction (NA Paras
and DWC MacMillan, J. Am. Chem. Soc., 123, 4
370 (2001)) was reported, but there was a problem that it was not always possible to obtain a product with almost perfect optical purity.

Therefore, there has been a demand for a method of stereoselectively introducing an asymmetric center into a hetero adjacent position.

[0004]

In the first aspect of the present invention,
A heterocyclic compound having an asymmetric center represented by the following formula (1a) or (1b) is provided.

[Chemical 15] [In the formula, R ¹ , R ² and R ³ are independently of each other,
They are the same or different and are C _{1 to} C ₂₀ hydrocarbon groups which may have a hydrogen atom or a substituent, and Ring A represents a 5 to 11 membered heterocyclic ring which may have a substituent. ]

In the second aspect of the present invention, in the presence of Lewis acid,
An epoxy alcohol represented by the following formula (5a)

[Chemical 16] [In the formula, R ¹ , R ² and R ³ are independently of each other,
They are the same or different and are C _{1 to} C ₂₀ hydrocarbon groups which may have a hydrogen atom or a substituent, and Ring A represents a 5 to 11 membered heterocyclic ring which may have a substituent. ] A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (1a), characterized by carrying out a rearrangement reaction,

[Chemical 17] [In formula, R < ¹ >, R < ² >, R < ³ > and A ring have the above-mentioned meaning. ] And an epoxy alcohol represented by the following formula (5b) in the presence of a Lewis acid:

[Chemical 18] [In the formula, R ¹ , R ² and R ³ are independently of each other,
They are the same or different and are C _{1 to} C ₂₀ hydrocarbon groups which may have a hydrogen atom or a substituent, and Ring A represents a 5 to 11 membered heterocyclic ring which may have a substituent. ] A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (1b), which comprises performing a rearrangement reaction is provided.

[Chemical 19] [In formula, R < ¹ >, R < ² >, R < ³ > and A ring have the above-mentioned meaning. ]

In the first and second aspects of the present invention, R¹
Is an optionally substituted C₁~ C ₂₀Alkyl group, C₂
~ C₂₀Alkenyl group, C₂~ C₂₀Alkynyl group, C₆~ C
₁₈Aryl group, C₆~ C₂₀An alkylaryl group, or
C₆~ C₂₀An arylalkyl group, R²Is a hydrogen atom
Is C₁~ C_TenAn alkyl group, R³Is C₁~ C_TenArchi
Ru radical or C_Four~ C_TenPreferably a cycloalkyl group
Good In addition, even if each ring A has a substituent,
Good, furan, thiophene, pyrrole, benzofuran,
Preferred is benzothiophene or indole
Good

The third aspect of the present invention provides a heterocyclic compound having an asymmetric center represented by the following formula (2).

[Chemical 20] [In the formula, R ⁴ is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent, and B ring is a 5 to 11 membered heterocyclic ring which may have a substituent. Indicates. ]

In the fourth aspect of the present invention, in the presence of Lewis acid,
The epoxy alcohol represented by the following formula (6)

[Chemical 21] [In the formula, R ⁴ is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent, and B ring is a 5 to 11 membered heterocyclic ring which may have a substituent. Indicates. ] A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (2), which comprises rearrangement reaction is provided.

[Chemical formula 22] [In the formula, R ⁴ and B ring have the above-mentioned meanings. ]

In the third and fourth aspects of the present invention, R ⁴
Is preferably a C ₁ -C ₁₀ alkyl group. Also,
Ring B is preferably furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole, each of which may have a substituent.

The fifth aspect of the present invention provides a heterocyclic compound having an asymmetric center represented by the following formula (3).

[Chemical formula 23] [In the formula, R ⁵ and R ⁶ are each independently, the same or different, and are a C _{1 to} C ₂₀ hydrocarbon group which may have a hydrogen atom or a substituent, and the C ring is a substituent. Represents a 5- to 11-membered heterocyclic ring which may have. ]

In the sixth aspect of the present invention, in the presence of Lewis acid,
The alcohol represented by the following formula (7)

[Chemical formula 24] [In the formula, R ⁵ and R ⁶ are each independently, the same or different, and are a C _{1 to} C ₂₀ hydrocarbon group which may have a hydrogen atom or a substituent, and A ¹ is C ₁ To C ₂₀ alkylsulfonyl group or C _{6 to} C ₁₈ arylsulfonyl group, and C ring represents a 5 to 11 membered heterocyclic ring which may have a substituent. ] A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (3), which comprises performing a rearrangement reaction is provided.

[Chemical 25] [In formula, R < ⁵ >, R < ⁶ > and C ring have a said meaning. ]

In the fifth and sixth aspects of the present invention, R^Five
Is an optionally substituted C₁~ C ₂₀Alkyl group, C₂
~ C₂₀Alkenyl group, C₂~ C₂₀Alkynyl group, C₆~ C
₁₈Aryl group, C₆~ C₂₀An alkylaryl group, or
C₆~ C₂₀An arylalkyl group, R⁶Is C₁~ C_Ten
Alkyl group or C_Four~ C_TenBe a cycloalkyl group
Is preferred. In addition, each C ring has a substituent,
Yes, furan, thiophene, pyrrole, benzoph
Orchid, benzothiophene, or indole
Is preferred.

The seventh aspect of the present invention provides a heterocyclic compound having an asymmetric center represented by the following formula (4).

[Chemical formula 26] [In the formula, R ⁷ is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent, and D ring is a 5 to 11 membered heterocyclic ring which may have a substituent. Indicates. ]

In the eighth aspect of the present invention, a ketone represented by the following formula (8) is added in the presence of a reducing agent.

[Chemical 27] [In the formula, R ⁷ is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent, and A ² is a C _{1 to} C ₂₀ alkylsulfonyl group or a C _{6 to} C ₁₈ aryl. A sulfonyl group, and the D ring may have a substituent 5 to 11
Indicates a member heterocycle. ] A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (4) is provided, which comprises performing a rearrangement reaction using a Lewis acid.

[Chemical 28] [In the formula, R ⁷ and D ring have the above-mentioned meanings. ]

In the seventh and eighth aspects of the present invention, R ⁷
It is preferred but is C ₁ -C ₁₀ alkyl or C ₄ -C _{1 0} cycloalkyl group. Further, it is preferable that each D ring is furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole which may have a substituent.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The first aspect of the present invention provides a heterocyclic compound having an asymmetric center represented by the following formula (1a) or (1b).

[Chemical 29] [In formula, R < ¹ >, R < ² >, R < ³ > and A ring have the above-mentioned meaning. ]

R ¹ , R ² and R ³ are each independently of the same or different and each is a hydrogen atom; a C ₁ -C ₂₀ hydrocarbon group which may have a substituent.

In the present specification, the hydrocarbon group of the "C ₁ -C ₂₀ hydrocarbon group" may be saturated or unsaturated acyclic, or saturated or unsaturated cyclic. Good. When the C ₁ -C ₂₀ hydrocarbon group is acyclic, it may be linear or branched. The "C ₁ -C ₂₀ hydrocarbon group", C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₄ -C ₂₀ alkadienyl group, C ₆ ~ C ₁₈ aryl group, C ₆ -C ₂₀ alkylaryl group, C ₆ -C ₂₀ arylalkyl group, C ₄ ~C _{2 0} cycloalkyl group, C ₄ -C ₂₀ cycloalkenyl group, (C ₃ -C
₁₀ cycloalkyl) C ₁ -C ₁₀ alkyl groups and the like are included.

In the present specification, the "C ₁ -C ₂₀ alkyl group" is preferably C ₁ -C ₁₀ alkyl group,
And more preferably a C ₁ -C ₆ alkyl group. Examples of alkyl groups include, but are not limited to, methyl,
Ethyl, propyl, isopropyl, n-butyl, sec
-Butyl, tert-butyl, pentyl, hexyl, dodecanyl and the like can be mentioned.

In the present specification, the "C ₂ -C ₂₀ alkenyl group" is preferably C ₂ -C ₁₀ alkenyl group, and more preferably C ₂ -C ₆ alkenyl group.
Examples of alkenyl groups include, but are not limited to,
Examples thereof include vinyl, allyl, propenyl, isopropenyl, 2-methyl-1-propenyl, 2-methylallyl, 2-butenyl and the like.

In the present specification, "C ₂ -C ₂₀ alkynyl group" is preferably C ₂ -C ₁₀ alkynyl group, more preferably a C ₂ -C ₆ alkynyl group.
Examples of alkynyl groups include, but are not limited to,
Examples include ethynyl, 2-propynyl, 2-butynyl and the like.

In the present specification, the "C ₄ -C ₂₀ alkyldienyl group" is preferably C ₄ -C ₁₀ alkyldienyl group, more preferably C ₄ -C ₆ alkyldienyl group. preferable. Examples of alkyldienyl groups include:
Examples include, but are not limited to, 1,3-butadienyl and the like.

In the present specification, the "C ₆ -C ₁₈ aryl group" is preferably C ₆ -C ₁₀ aryl group.
Examples of aryl groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, indenyl, biphenylyl, anthryl, phenanthryl and the like.

In the present specification, the "C ₆ -C ₂₀ alkylaryl group" is preferably C ₆ -C ₁₂ alkylaryl group. Examples of alkylaryl groups include, but are not limited to, o-tolyl, m-tolyl, p-
Trilyl, 2,3-xylyl, 2,4-xylyl, 2,5
-Xylyl, o-cumenyl, m-cumenyl, p-cumenyl, mesityl and the like can be mentioned.

In the present specification, the "C ₆ -C ₂₀ arylalkyl group" is preferably C ₆ -C ₁₂ arylalkyl group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl,
Examples thereof include 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and the like.

In the present specification, the "C ₄ -C ₂₀ cycloalkyl group" is preferably C ₄ -C ₁₀ cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

In the present specification, the "C ₄ -C ₂₀ cycloalkenyl group" is preferably C ₄ -C ₁₀ cycloalkenyl group. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, 2-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, and the like.

A substituent may be introduced into the "C ₁ -C ₂₀ hydrocarbon group" represented by R ¹ , R ² and R ³ . Examples of this substituent include a C _{1 to} C ₁₀ hydrocarbon group (eg, methyl, ethyl, propyl, butyl, phenyl, naphthyl, indenyl, tolyl, xylyl, benzyl, etc.), a C _{1 to} C ₁₀ alkoxy group (eg, , Methoxy, ethoxy, propoxy, butoxy), C ₆ -C ₁₀ aryloxy groups (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), amino groups, hydroxyl groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine). ) Or a silyl group. In this case, one or more substituents may be introduced at substitutable positions,
Preferably, 1 to 4 may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

In the first aspect of the present invention, R ¹ is C _1-
C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₆ -C ₁₈ aryl group, C ₆ -C ₂₀ alkylaryl group, or is the C ₆ -C ₂₀ arylalkyl group Preferably, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, phenyl, phenylmethyl,
More preferably phenylethyl.

R ² is preferably a hydrogen atom or a C ₁ -C ₁₀ alkyl group, more preferably a hydrogen atom, methyl, ethyl, propyl or isopropyl.

R ³ is a C ₁ -C ₁₀ alkyl group or C ₄ -C
₁₀ cycloalkyl groups are preferable, and methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl are more preferable.

In the above formulas (1a) and (1b), A ring is
It represents a 5- to 11-membered heterocyclic ring which may have a substituent.

In the present specification, "5- to 11-membered heterocycle"
Examples thereof include a monocyclic heterocycle and a polycyclic heterocycle.

In the present specification, the "monocyclic heterocycle" is furan, thiophene, pyrrole, pyran, thiopyran, pyridine, thiazole, imidazole, pyrimidine, 1,3,5-triazine, 1,2,3-. Examples thereof include triazole, 1,2,4-triazole, tetrazole, oxazole, oxadiazole, isoxazole, isothiazole, pyrazole, furazan, pyridazine, pyrazine and triazole.

In the present specification, "polycyclic heterocycle" means benzofuran, benzothiophene, indole,
Examples thereof include quinoline, purine, isoquinoline, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, 4H-quinolidine, phthalazine, naphthyridine, quinoxaline, quinazoline and cinnoline.

In the first embodiment of the present invention, the "5- to 11-membered heterocycle" represented by ring A may have a substituent introduced therein. Examples of this substituent include a C _{1 to} C ₁₀ hydrocarbon group (eg, methyl, ethyl, propyl, butyl, etc.), a C _{1 to} C ₁₀ alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc.), C ₆ -C ₁₀ aryloxy group (e.g., phenyloxy, naphthyloxy, biphenyloxy, etc.), an amino group, a hydroxyl group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine) may also have a substituent silyl Groups (eg trimethylsilyl, triethylsilyl, triisopropylsilyl, t
-Butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl), or a sulfonyl group which may have a substituent (for example, a phenylsulfonyl group,
p-toluenesulfonyl, methanesulfonyl) and the like. In this case, one or more substituents may be introduced at substitutable positions, and preferably 1 to
Four may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

In the first embodiment of the present invention, each ring A is preferably furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole, which may have a substituent. ,
Unsubstituted thiophene, unsubstituted pyrrole, 1-methylpyrrole, 1-triisopropylsilylpyrrole, unsubstituted benzofuran, unsubstituted benzothiophene, unsubstituted indole, 1-methylindole, 1-phenylsulfonylindole, 1-triisopropylsilylindole 1
More preferably it is acetylindole.

In a second aspect of the present invention, there is provided one aspect of a method for producing a heterocyclic compound according to the first aspect of the present invention,
A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (1a), which comprises subjecting an epoxy alcohol represented by the following formula (5a) to a rearrangement reaction in the presence of a Lewis acid; 5b) is a rearrangement reaction of the epoxy alcohol represented by the following formula (1
A method for producing a heterocyclic compound having an asymmetric center represented by b) is provided.

[Chemical 30] [In formula, R < ¹ >, R < ² >, R < ³ > and A ring have the above-mentioned meaning. ]

[Chemical 31] [In formula, R < ¹ >, R < ² >, R < ³ > and A ring have the above-mentioned meaning. ]

In the second embodiment of the present invention, the following formula (5
The epoxy alcohol represented by a) or (5b) is used.

[Chemical 32] [In formula, R < ¹ >, R < ² >, R < ³ > and A ring have the above-mentioned meaning. ]

[Chemical 33] [In formula, R < ¹ >, R < ² >, R < ³ > and A ring have the above-mentioned meaning. ]

R ¹ and R ^{2 in the} above formulas (5a) and (5b)
And R ³ are the same as those described for R ¹ , R ² and R ³ in the above formulas (1a) and (1b) in the first aspect of the present invention.

The ring A in the above formulas (5a) and (5b) is
In the first aspect of the present invention, it is the same as described for ring A in formulas (1a) and (1b) above.

The epoxy alcohol represented by the above formula (5a) or (5b) can be synthesized by a known method.

In the second aspect of the present invention, a Lewis acid is used. The Lewis acid is not particularly limited, and examples thereof include silver triflate, triethylaluminum, boron trifluoride diethyl ether, titanium tetrachloride, tin tetrachloride, diethylaluminum chloride, ethylaluminum dichloride, and the like. , Boron trifluoride diethyl ether, titanium tetrachloride, tin tetrachloride are preferred.

In the second embodiment of the present invention, the amount of Lewis acid is 0.01 mol to 10 mol, preferably 0.1 mol, relative to 1 mol of the epoxy alcohol represented by the above formula (5a) or (5b). It is 1 to 2 mol, and more preferably 0.1 to 1 mol.

In the second aspect of the present invention, the above formula (1
The heterocyclic compound represented by a) is typically produced by adding a Lewis acid to a solution of the epoxy alcohol represented by the above formula (5a) and carrying out a rearrangement reaction.
The epoxy alcohol (5a) does not need to be isolated, and the epoxy alcohol (5a) prepared in the solution may be used as it is.

In the second aspect of the present invention, the above formula (1
The heterocyclic compound represented by b) is typically produced by adding a Lewis acid to a solution of the epoxy alcohol represented by the above formula (5b) and carrying out a rearrangement reaction.
The epoxy alcohol (5b) does not need to be isolated, and the epoxy alcohol (5b) prepared in the solution may be used as it is.

In the second aspect of the present invention, by activating the epoxy group with a suitable Lewis acid, the 1,2-rearrangement of the heterocycle accompanied by steric inversion from the conformation of the epoxy group, which is always antiperiplanar. Happens. Therefore, it is presumed that an aldol having a single stereochemistry can be obtained regardless of the stereochemistry of the tertiary alcohol. In addition,
The above reaction mechanism is only a hypothesis, and the second aspect of the present invention is not limited to the above reaction mechanism.

In the second embodiment of the present invention, the reaction conditions (time, temperature, pressure, etc.) are appropriately determined so that the rearrangement reaction is completed. For example, in the second aspect of the present invention, the reaction is preferably −100 ° C. to 15 ° C.
It is carried out in a temperature range of 0 ° C, particularly preferably -80 ° C to 8 ° C.
It is carried out in a temperature range of 0 ° C, more preferably in a temperature range of -80 ° C to 40 ° C. In the second aspect of the present invention, the reaction time is preferably in the range of 1 minute to 48 hours, particularly preferably 10 minutes to 24 hours, and further preferably 1
It is performed in the range of 0 minutes to 1 hour.

In the second aspect of the present invention, the solvent is preferably a solvent capable of dissolving the epoxy alcohol represented by the above formulas (5a) and (5b). As the solvent, an aliphatic or aromatic organic solvent is used. Halogenated hydrocarbons such as methylene chloride; halogenated aromatic hydrocarbons such as o-dichlorobenzene; aromatic hydrocarbons such as benzene and toluene are used.

The third aspect of the present invention provides a heterocyclic compound having an asymmetric center represented by the following formula (2).

[Chemical 34] [In the formula, R ⁴ and B ring have the above-mentioned meanings. ]

R ⁴ is a hydrogen atom or a C ₁ -C ₂₀ hydrocarbon group which may have a substituent.

A substituent may be introduced into the "C ₁ -C ₂₀ hydrocarbon group" represented by R ⁴ . Examples of this substituent include a C _{1 to} C ₁₀ hydrocarbon group (eg, methyl,
Ethyl, propyl, butyl, phenyl, naphthyl, indenyl, tolyl, xylyl, benzyl, etc.), C ₁ -C ₁₀
Alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc.), C ₆ -C ₁₀ aryloxy group (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), amino group, hydroxyl group, halogen atom (eg, fluorine, chlorine) , Bromine, iodine) or a silyl group. In this case, one or more substituents may be introduced at the substitutable position, and preferably one to four substituents may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

In a third aspect of the invention R ⁴ is C ₁ -C
₁₀ alkyl groups are preferred, methyl, ethyl,
More preferably, they are propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl and hexyl.

In the above formula (2), ring B represents a 5- to 11-membered heterocyclic ring which may have a substituent.

In the third embodiment of the present invention, a substituent may be introduced into the "5- to 11-membered heterocycle" represented by ring B. Examples of this substituent include a C _{1 to} C ₁₀ hydrocarbon group (eg, methyl, ethyl, propyl, butyl,
Pentyl etc.), C ₁ -C ₁₀ alkoxy groups (eg methoxy, ethoxy, propoxy, butoxy etc.), C ₆ -C
₁₀ aryloxy groups (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), amino groups, hydroxyl groups,
Halogen atom (eg, fluorine, chlorine, bromine, iodine), optionally substituted silyl group (eg, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tri) Phenylsilyl), or a sulfonyl group which may have a substituent (for example, phenylsulfonyl group, p-toluenesulfonyl, methanesulfonyl), acetyl group, benzoyl group and the like. In this case, one or more substituents may be introduced at the substitutable position, and preferably one to four substituents may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

In the third embodiment of the present invention, each ring B is preferably furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole, which may have a substituent. ,
Unsubstituted thiophene, unsubstituted indole, 1-phenylsulfonylindole, 1-triisopropylsilylindole, 1-acetylindole, 1-methylindole, 1-benzylindole are more preferred.

In a fourth aspect of the present invention, there is provided one aspect of a method for producing a heterocyclic compound according to the third aspect of the present invention,
Provided is a method for producing a heterocyclic compound having an asymmetric center represented by the following formula (2), which comprises subjecting an epoxy alcohol represented by the following formula (6) to a rearrangement reaction in the presence of a Lewis acid.

[Chemical 35] [In the formula, R ⁴ and B ring have the above-mentioned meanings. ]

In the fourth aspect of the present invention, the following formula (6)
The epoxy alcohol represented by is used.

[Chemical 36] [In the formula, R ⁴ and B ring have the above-mentioned meanings. ]

R ⁴ in the above formula (6) is the same as described for R ⁴ in the above formula (2) in the third aspect of the present invention.

The ring B in the above formula (6) is the same as described for the ring B in the above formula (2) in the third aspect of the present invention.

The epoxy alcohol represented by the above formula (6) can be synthesized by a known method.

In the fourth aspect of the present invention, a Lewis acid is used. The Lewis acid is not particularly limited, and examples thereof include silver triflate, triethylaluminum, boron trifluoride diethyl ether, titanium tetrachloride, tin tetrachloride, and the like, and among them, triethylaluminum and boron trifluoride. It is preferably diethyl ether.

In the fourth embodiment of the present invention, the amount of the Lewis acid is 0.01 mol-10 mol, preferably 0.1 mol-2, relative to 1 mol of the epoxy alcohol represented by the above formula (6). Mol, and more preferably 0.1 mol to 1 mol.

In a fourth aspect of the present invention, the above formula (2)
The heterocyclic compound represented by is typically the above formula (6)
It is produced by adding a Lewis acid to a solution of the epoxy alcohol represented by and rearrangement reaction. The epoxy alcohol (6) does not need to be isolated, and the epoxy alcohol (6) prepared in the solution may be used as it is.

In the fourth embodiment of the present invention, by activating the epoxy group with a suitable Lewis acid, the 1,2-rearrangement of the heterocycle accompanied by steric inversion from the conformation of the epoxy group which is always antiperiplanar. Happens. Therefore, it is presumed that an aldol having a single stereochemistry can be obtained regardless of the stereochemistry of the tertiary alcohol. In addition,
The above reaction mechanism is only a hypothesis, and the fourth aspect of the present invention is not limited to the above reaction mechanism.

In the fourth aspect of the present invention, the reaction conditions (time, temperature, pressure, etc.) are appropriately determined so that the rearrangement reaction is completed. For example, in the fourth aspect of the present invention, the reaction is preferably −100 ° C. to 15 ° C.
It is carried out in a temperature range of 0 ° C, particularly preferably -80 ° C to 8 ° C.
It is carried out in a temperature range of 0 ° C, more preferably in a temperature range of -80 ° C to 40 ° C. In the fourth aspect of the present invention, the reaction time is preferably in the range of 1 minute to 48 hours, particularly preferably 10 minutes to 24 hours, and further preferably 1 minute.
It is performed in the range of 0 minutes to 1 hour.

In the fourth aspect of the present invention, the solvent is preferably a solvent capable of dissolving the epoxy alcohol represented by the above formula (6). As the solvent, an aliphatic or aromatic organic solvent is used. Halogenated hydrocarbons such as methylene chloride; halogenated aromatic hydrocarbons such as o-dichlorobenzene; aromatic hydrocarbons such as benzene and toluene are used.

The fifth aspect of the present invention provides a heterocyclic compound having an asymmetric center represented by the following formula (3).

[Chemical 37] [In formula, R < ⁵ >, R < ⁶ > and C ring have a said meaning. ]

R ⁵ and R ⁶ are each independently, the same or different, and are a C _{1 to} C ₂₀ hydrocarbon group which may have a hydrogen atom or a substituent.

A substituent may be introduced into the "C ₁ -C ₂₀ hydrocarbon group" represented by R ⁵ and R ⁶ . Examples of this substituent include a C _{1 to} C ₁₀ hydrocarbon group (for example,
Methyl, ethyl, propyl, butyl, phenyl, naphthyl, indenyl, tolyl, xylyl, benzyl, etc.), C
₁ -C ₁₀ alkoxy group (e.g., methoxy, ethoxy,
Propoxy, butoxy etc.), C ₆ -C ₁₀ aryloxy groups (eg phenyloxy, naphthyloxy, biphenyloxy etc.), amino groups, hydroxyl groups, halogen atoms (eg fluorine, chlorine, bromine, iodine) or silyl groups, etc. Can be mentioned. In this case, one or more substituents may be introduced at substitutable positions, preferably 1
It may be introduced by 4 to 4. When the number of substituents is 2 or more, each substituent may be the same or different.

In a fifth aspect of the invention, R ⁵ is C _1-
C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₆ -C ₁₈ aryl group, C ₆ -C ₂₀ alkylaryl group, or is the C ₆ -C ₂₀ arylalkyl group Preferably, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, phenyl, phenylmethyl,
More preferably phenylethyl.

R ⁶ is a C ₁ -C ₁₀ alkyl group or C ₄ -C
₁₀ cycloalkyl groups are preferable, and methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl are more preferable.

In the above formula (3), ring C represents a 5- to 11-membered heterocyclic ring which may have a substituent.

In the fifth embodiment of the present invention, the "5- to 11-membered heterocycle" represented by the C ring may have a substituent introduced therein. Examples of this substituent include a C _{1 to} C ₁₀ hydrocarbon group (eg, methyl, ethyl, propyl, butyl, etc.), a C _{1 to} C ₁₀ alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc.), C ₆ -C ₁₀ aryloxy group (e.g., phenyloxy, naphthyloxy, biphenyloxy, etc.), an amino group, a hydroxyl group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine) may also have a substituent silyl Groups (eg trimethylsilyl, triethylsilyl, triisopropylsilyl, t
-Butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl), or a sulfonyl group which may have a substituent (for example, a phenylsulfonyl group,
p-toluenesulfonyl, methanesulfonyl) and the like. In this case, one or more substituents may be introduced at substitutable positions, and preferably 1 to
Four may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

In the fifth aspect of the present invention, each C ring is preferably furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole, which may have a substituent. ,
Unsubstituted thiophene, unsubstituted indole, 1-phenylsulfonylindole, 1-triisopropylsilylindole, 1-acetylindole, 1-methylindole, 1-benzylindole are more preferred.

In a sixth aspect of the present invention, there is provided one aspect of a method for producing a heterocyclic compound according to the fifth aspect of the present invention,
Provided is a method for producing a heterocyclic compound having an asymmetric center represented by the following formula (3), which comprises subjecting an alcohol represented by the following formula (7) to a rearrangement reaction in the presence of a Lewis acid.

[Chemical 38] [In the formula, R ⁵ , R ⁶ , A ¹ , and C ring have the above meanings. ]

In a sixth aspect of the present invention, the following formula (7)
The alcohol shown by is used.

[Chemical Formula 39] [In formula, R < ⁵ >, R < ⁶ > and C ring have a said meaning. ]

In the above formula (7), A ¹ is a C ₁ -C ₂₀ alkylsulfonyl group or a C ₆ -C ₁₈ arylsulfonyl group. A ¹ is preferably a C ₁ -C ₁₀ alkylsulfonyl group, and methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n
-Butylsulfonyl, sec-butylsulfonyl, te
It is more preferably rt-butylsulfonyl, pentylsulfonyl or hexylsulfonyl.

R in the above formula (7)^FiveAnd R⁶The present invention
In a fifth aspect of R in the above formula (3) ^FiveAnd R⁶At
It is the same as revealed. The ring C in the above formula (7) is
In the fifth embodiment of the present invention, the ring C in the above formula (3)
It is the same as

The alcohol represented by the above formula (7) can be synthesized by a known method.

In the sixth aspect of the present invention, a Lewis acid is used. The Lewis acid is not particularly limited, and examples thereof include silver triflate, triethylaluminum, boron trifluoride diethyl ether, titanium tetrachloride, tin tetrachloride, diethylaluminum chloride, ethylaluminum dichloride, and the like. , Boron trifluoride diethyl ether, titanium tetrachloride, tin tetrachloride are preferred.

In the sixth aspect of the present invention, the amount of the Lewis acid is 1 mol of the alcohol represented by the above formula (7).
The amount is 0.01 mol to 10 mol, preferably 0.1 mol to 2 mol, and more preferably 0.1 mol to 1 mol.

In a sixth aspect of the present invention, the above formula (3)
The heterocyclic compound represented by is typically the above formula (7)
It is produced by adding a Lewis acid to a solution of an alcohol represented by and carrying out a rearrangement reaction. Alcohol (7)
It is not necessary to use the isolated one, and the alcohol (7) prepared in the solution may be used as it is.

In the sixth aspect of the present invention, by activating the sulfonyl group with a suitable Lewis acid, a heterocyclic ring having a stereoinversion from a conformation of the sulfonyl group which is a leaving group to always be antiperiplanar, 1,2-dislocation occurs. From this, it is presumed that an optically pure ketone can be obtained regardless of the stereochemistry of the tertiary alcohol. The above reaction mechanism is only a hypothesis, and the sixth aspect of the present invention is not limited to the above reaction mechanism.

In the sixth aspect of the present invention, the reaction conditions (time, temperature, pressure, etc.) are appropriately determined so that the rearrangement reaction is completed. For example, in the sixth aspect of the present invention, the reaction is preferably −100 ° C. to 15 ° C.
It is carried out in a temperature range of 0 ° C, particularly preferably -80 ° C to 8 ° C.
It is carried out in a temperature range of 0 ° C, more preferably in a temperature range of -80 ° C to 40 ° C. In the sixth aspect of the present invention, the reaction time is preferably in the range of 1 minute to 48 hours, particularly preferably 10 minutes to 24 hours, and further preferably 1
It is performed in the range of 0 minutes to 1 hour.

In the sixth aspect of the present invention, the solvent is preferably a solvent capable of dissolving the alcohol represented by the above formula (7). As the solvent, an aliphatic or aromatic organic solvent is used. Halogenated hydrocarbons such as methylene chloride; halogenated aromatic hydrocarbons such as o-dichlorobenzene; aromatic hydrocarbons such as benzene and toluene are used.

The seventh aspect of the present invention provides a heterocyclic compound having an asymmetric center represented by the following formula (4).

[Chemical 40] [In the formula, R ⁷ and D ring have the above-mentioned meanings. ]

R ⁷ is a hydrogen atom or a C ₁ -C ₂₀ hydrocarbon group which may have a substituent.

A substituent may be introduced into the "C ₁ -C ₂₀ hydrocarbon group" represented by R ⁷ . Examples of this substituent include a C _{1 to} C ₁₀ hydrocarbon group (eg, methyl,
Ethyl, propyl, butyl, phenyl, naphthyl, indenyl, tolyl, xylyl, benzyl, etc.), C ₁ -C ₁₀
Alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc.), C ₆ -C ₁₀ aryloxy group (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), amino group, hydroxyl group, halogen atom (eg, fluorine, chlorine) , Bromine, iodine) or a silyl group. In this case, one or more substituents may be introduced at the substitutable position, and preferably one to four substituents may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

In a seventh aspect of the present invention, R ⁷ is C _1-
It is preferably a C ₁₀ alkyl group or a C ₄ -C ₁₀ cycloalkyl group, and more preferably methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclohexyl. .

In the above formula (4), ring D represents a 5- to 11-membered heterocyclic ring which may have a substituent.

In the seventh embodiment of the present invention, the "5- to 11-membered heterocycle" represented by ring D may have a substituent introduced therein. Examples of this substituent include a C _{1 to} C ₁₀ hydrocarbon group (eg, methyl, ethyl, propyl, butyl, etc.), a C _{1 to} C ₁₀ alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc.), C ₆ -C ₁₀ aryloxy group (e.g., phenyloxy, naphthyloxy, biphenyloxy, etc.), an amino group, a hydroxyl group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine) may also have a substituent silyl Groups (eg trimethylsilyl, triethylsilyl, triisopropylsilyl, t
-Butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl), or a sulfonyl group which may have a substituent (for example, a phenylsulfonyl group,
p-toluenesulfonyl, methanesulfonyl) and the like. In this case, one or more substituents may be introduced at substitutable positions, and preferably 1 to
Four may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

In the seventh aspect of the present invention, ring D is preferably furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole, each of which may have a substituent, and unsubstituted benzofuran , Unsubstituted benzothiophene, unsubstituted indole, 1
-Methylindole, 1-phenylsulfonylindole, 1-triisopropylsilylindole and 1-acetylindole are more preferable.

In an eighth aspect of the present invention, there is provided one aspect of a method for producing a heterocyclic compound according to the seventh aspect of the present invention,
A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (4), which comprises rearrangement of a ketone represented by the following formula (8) with a Lewis acid in the presence of a reducing agent is provided. To be done.

[Chemical 41] [In formula, R < ⁷ >, A < ² > and D ring have a said meaning. ]

In the eighth aspect of the present invention, the following formula (8)
The ketone shown by is used.

[Chemical 42] [In the formula, R ⁷ and D ring have the above-mentioned meanings. ]

R ⁷ in the above formula (8) is the same as described for R ⁷ in the above formula (4) in the seventh aspect of the present invention.

In the above formula (8), A ² is a C ₁ -C ₂₀ alkylsulfonyl group or a C ₆ -C ₁₈ arylsulfonyl group. A ² is preferably a C ₁ -C ₁₀ alkylsulfonyl group, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n
-Butylsulfonyl, sec-butylsulfonyl, te
It is more preferably rt-butylsulfonyl, pentylsulfonyl or hexylsulfonyl.

The D ring in the above formula (8) is the same as described in the D ring in the above formula (4) in the seventh aspect of the present invention.

The ketone represented by the above formula (8) can be synthesized by a known method.

In the eighth aspect of the present invention, a reducing agent is used. The reducing agent is not particularly limited, for example,
Examples include diisobutylaluminum hydride (DIBAL) and triethylsilane. Among them, DIB
It is preferably AL.

In the eighth aspect of the present invention, the amount of the reducing agent is 1 to 1 mol of the ketone represented by the above formula (8).
The amount is 9 mol to 10 mol, preferably 1.9 mol to 3 mol, and more preferably 1.9 mol to 2.1 mol.

In the eighth aspect of the present invention, a Lewis acid is used. The Lewis acid is not particularly limited, for example, triethyl aluminum, boron trifluoride diethyl ether, titanium tetrachloride, tin tetrachloride, diethyl aluminum chloride and the like, among them, triethyl aluminum, diethyl aluminum chloride. Is preferred.

In the eighth aspect of the present invention, the amount of the Lewis acid is 0. 1 with respect to 1 mol of the ketone represented by the above formula (8).
01 mol to 10 mol, preferably 0.1 mol to 2
Mol, and more preferably 0.1 mol to 1 mol.

In an eighth aspect of the present invention, the above formula (4)
The heterocyclic compound represented by is typically represented by the above formula (8)
It is produced by adding a reducing agent to a solution of the ketone represented by and then adding a Lewis acid to cause a rearrangement reaction.
The ketone (8) does not need to be isolated, and the ketone (8) prepared in the solution may be used as it is.

In the eighth embodiment of the present invention, the ketone is reduced in situ with a suitable reducing agent, and then the sulfonyl group is activated with a suitable Lewis acid, so that the sulfonyl group, which is a leaving group, is always antiperiphered. The 1,2-rearrangement of the heterocycle accompanied by steric inversion occurs from the conformation that becomes the planar. It is presumed that this makes it possible to obtain an optically pure alcohol. The above reaction mechanism is only a hypothesis, and the eighth aspect of the present invention is not limited to the above reaction mechanism.

In the eighth aspect of the present invention, the reaction conditions (time, temperature, pressure, etc.) are appropriately determined so that the rearrangement reaction is completed. For example, in the eighth aspect of the present invention, the reaction is preferably −100 ° C. to 15 ° C.
It is carried out in a temperature range of 0 ° C, particularly preferably -80 ° C to 8 ° C.
It is carried out in a temperature range of 0 ° C, more preferably in a temperature range of -80 ° C to 40 ° C. In the eighth aspect of the present invention, the reaction time is preferably in the range of 1 minute to 48 hours, particularly preferably 10 minutes to 24 hours, and further preferably 1
It is performed in the range of 0 minutes to 1 hour.

In the eighth aspect of the present invention, the solvent is preferably a solvent capable of dissolving the ketone represented by the above formula (8). As the solvent, an aliphatic or aromatic organic solvent is used. Halogenated hydrocarbons such as methylene chloride; halogenated aromatic hydrocarbons such as o-dichlorobenzene; aromatic hydrocarbons such as benzene and toluene are used.

According to the present invention, many physiologically active substances (pharmaceutical compounds, agricultural chemicals, etc.) or their intermediates having an asymmetric center at the adjacent position of the heterocycle can be simply and efficiently provided. According to the invention, for example, indolmycin, Frondosin B, Chuangxinmycin, Decaroxychuangxin
The total synthesis of mycin etc. can be performed.

[0109]

EXAMPLES The present invention will be described below based on examples.
However, the present invention is not limited to the following examples.

Reference Example 1

[Chemical 43] 1-benzenesulfonyl-3-bromo-1H-indole (864mg,
2.57 mmol) of dehydrated THF (20 ml) at −78 ° C. with stirring under 1.5
1.69 m of 9 M normal butyl lithium (hexane solution)
l (2.69 mmol) was added. After 30 seconds, (4R ^* , 5S ^* )-4,5-epoxy-4-methyl-1-phenyl-3-hexanone (500 mg, 2.45
mmol) was added, and after stirring for 10 minutes, water was poured to stop the reaction. Add ethyl acetate and wash with water (water x 3, saturated saline x
1), dried (magnesium sulfate) and concentrated, then column chromatography (ethyl acetate / hexane = 1/30 to 1/2)
Purification was performed at 0 to 1/10) to obtain 1.05 g (86%) of colorless amorphous epoxy alcohol (03-114) represented by the above formula.

Reference Example 2

[Chemical 44] A solution of furan (0.53 ml, 7.3 mmol) in dehydrated THF (10 ml) was added dropwise with 3.77 ml (5.87 mmol) of 1.56 M n-butyllithiumhexane solution under stirring at -78 ° C, and the mixture was stirred at 20 ° C for 20 minutes. It was cooled to -78 ° C again and (4R *, 5S *)-4,5-epoxy-4-methyl-1-phenyl-3-hexanone (1.0g, 4.9mmo
l) was added and stirred for 10 minutes. Pour water to stop the reaction,
Add ethyl acetate and wash with water (water × 3, saturated saline × 1),
After drying (magnesium sulfate) and concentration, silica gel column chromatography (ethyl acetate / hexane = 1 / 30-
Purification was performed at 1/20 to 1/10) to obtain 1.28 g (96%) of colorless oily epoxy alcohol.

Reference Example 3

[Chemical formula 45] The same operation as in Reference Example 2 was performed. However, 1-methylpyrrole was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. White granular form.

Reference Example 4

[Chemical formula 46] The same operation as in Reference Example 2 was performed. However, thiophene was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. Colorless oil.

Reference Example 5

[Chemical 47] The same operation as in Reference Example 1 was performed. However, 3-bromofuran was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. Colorless oil.

Reference Example 6

[Chemical 48] The same operation as in Reference Example 1 was performed. However, 3-bromothiophene was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. Colorless oil.

Reference Example 7

[Chemical 49] The same operation as in Reference Example 2 was performed. However, 1-benzenesulfonyl-1H-indole was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. Colorless and amorphous.

Reference Example 8

[Chemical 50] The same operation as in Reference Example 2 was performed. However, 1-methyl-1H-indole was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. White powder.

Reference Example 9

[Chemical 51] The same operation as in Reference Example 1 was performed. However, 3-bromo-1-triisopropylsilylpyrrole was used instead of 1-benzenesulfonyl-3-bromo-1H-indole.
Colorless oil.

Reference Example 10

[Chemical 52] The same operation as in Reference Example 2 was performed. However, benzofuran was used in place of 1-benzenesulfonyl-3-bromo-1H-indole. Colorless oil.

Reference Example 11

[Chemical 53] The same operation as in Reference Example 2 was performed. However, benzothiophene was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. Colorless oil.

Reference Example 12

[Chemical 54] The same operation as in Reference Example 1 was performed. However, 3-bromo-1-methyl-1H-indole was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. Colorless oil.

Reference Example 13

[Chemical 55] The same operation as in Reference Example 1 was performed. However, 3-bromobenzothiophene was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. White powder.

Reference Example 14

[Chemical 56] The same operation as in Reference Example 1 was performed. However, 3-bromobenzofuran was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. White powder.

Example 1

[Chemical 57] Epoxy alcohol obtained in Reference Example 1 (50 mg, 0.108 m
(mol) in a dehydrated methylene chloride solution while stirring at -78 ° C to produce BF ₃ · O.
Et ₂ (27 microl, 0.217 mmol) was added, and the mixture was stirred for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to stop the reaction, ethyl acetate was added, and the mixture was washed with water (water x 3, saturated saline x 1), dried (magnesium sulfate), concentrated, and then subjected to column chromatography (ethyl acetate / ethyl acetate /
Purification was performed with hexane = 1/2) to obtain 48.5 mg (97%) of colorless and amorphous aldol represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.69 (3H, J = 6.3Hz), 1.53 (3H, s), 2.2
2-2.34 (1H, m), 2.55-2.68 (2H, m), 2.70-2.84 (1H, m),
3.57 (1H, d, J = 2.7Hz), 4.80 (1H, dq, J = 2.7,6.3Hz),
6.83-6.90 (2H, m), 7.08-7.18 (4H, m), 7.22-7.38 (4H,
m), 7.44-7.49 (1H, m), 7.52 (1H, s), 7.78-7.84 (2H,
m), 7.99 (1H, d, J = 8.4Hz).

The reaction scheme of Example 1 is shown below.

[Chemical 58]

Example 2

[Chemical 59] Using the epoxy alcohol obtained in Reference Example 2, the same operation as in Example 1 was carried out to obtain a white solid compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.86 (3H, d, J = 6.3 Hz), 1.41 (3H, s),
2.42-2.53 (1H, m), 2.59-270 (1H, m), 2.71-2.88 (2H,
m), 3.40 (1H, d, J = 3.2 Hz), 4.61 (1H, dq, J = 3.2, 6.3
Hz), 6.20 (1H, d, J = 3.2 Hz), 6.34 (1H, dd, J = 1.9,
3.2 Hz), 7.03-7.11 (2H, m), 7.13-7.28 (3H, m), 7.33
(1H, d, J = 1.9 Hz).

Example 3

[Chemical 60] Using the epoxy alcohol obtained in Reference Example 3, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.83 (3H, d, J = 6.5Hz), 1.46 (3H, s),
2.40-2.51 (1H, m), 2.66-2.78 (1H, m), 2.78-2.89 (2H,
m), 3.20 (3H, s), 3.40 (1H, d, J = 2.9Hz), 4.67 (1H, d
q, J = 2.9, 6.5Hz), 6.07-6.10 (1H, m), 6.10-6.17 (1H,
m), 6.46-6.51 (1H, m), 7.03-7.09 (2H, m), 7.13-7.27
(3H, m).

Example 4

[Chemical formula 61] Using the epoxy alcohol obtained in Reference Example 4, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.90 (3H, d, J = 6.5Hz), 1.57 (3H, s),
2.59-2.90 (4H, m), 3.30 (1H, D, J = 2.9Hz), 4.55 (1H, d
q, J = 2.9, 6.5Hz), 6.75, (1H, dd, J = 0.9, 3.6Hz), 6.
95 (1H, dd, J = 3.6, 5.1Hz), 7.00-7.06 (2H, m), 7.12-
7.26 (4H, m).

Example 5

[Chemical formula 62] Using the epoxy alcohol obtained in Reference Example 5, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.93 (3H, d, J = 6..5Hz), 1.43 (3H, s),
2.63-2.89 (4H, m), 3.14 (1H, d, J = 2.9Hz), 4.43 (1H,
dq, J = 29, 6.5Hz), 6.10-615 (1H, m), 7.06 (2H, d, J =
7.0Hz), 7.13-7.27 (4H, m), 7.34-7.38 (1H, m).

Example 6

[Chemical formula 63] Using the epoxy alcohol obtained in Reference Example 6, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.82 (3H, d, J = 6.5Hz), 1.52 (3H, s),
2.46-2.88 (4H, m), 3.28 (1H, d, J = 3.1Hz), 4.53 (1H, d
q, J = 3.1, 6.5Hz), 6.76-6.79 (1H, m), 6.98-7.06 (3H,
m), 7.12-7.29 (4H, m).

Example 7

[Chemical 64] Using the epoxy alcohol obtained in Reference Example 7, the same operation as in Example 1 was carried out to obtain a colorless amorphous compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.24 (3H, s), 1.37 (3H, d, J = 6.8Hz),
1.85 (1H, d, J = 3.1Hz), 1.94-2.07 (1H, m), 2.33-2.43
(1H, m), 2.55-2.76 (2H, m), 4.00 (1H, dq, 3.1, 6.8H
z), 6.77 (1H, s), 6.92 (2H, d, J = 7.0Hz), 7.10-7.28 (5
H, m), 740-7.46 (2H, m), 7.50-7.60 (2H, m), 7.67-7.7
3 (2H, m), 7.77-7.84 (1H, m).

Example 8

[Chemical 65] Using the epoxy alcohol obtained in Reference Example 8, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.82 (3H, d, J = 6.5Hz), 1.58 (3H, s),
2.40-2.50 (1H, m), 2.71-2.88 (3H, m), 3.33 (3H, s),
3.58 (1H, d, J = 1.7Hz), 4.78 (1H, dq, J = 2.7, 6.5Hz),
6.54 (1H, s), 6.95-7.04 (2H, m), 7.06-7.25 (6H, m),
7.58 (1H, d, J = 8.0Hz).

Example 9

[Chemical formula 66] Using the epoxy alcohol obtained in Reference Example 9, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.89 (3H, d, J = 6.3Hz), 1.07 (18H, d,
J = 7.5Hz), 1.42 (3H, heptet, J = 7.5Hz), 1.43 (3H, s),
2.50-2.72 (3H, m), 2.78-2.92 (1H, m), 3.28 (1H, d, J =
2.9Hz), 4.50 (1H, dq, J = 2.9, 6.3Hz), 6.02-6.06 (1H,
m), 6.51-6.55 (1H, m), 6.69-6.73 (1H, m), 6.69-6.73
(1H, m), 7.02 (2H, d, J = 7.0Hz), 7.10-7.24 (3H, m).

Example 10

[Chemical formula 67] Using the epoxy alcohol obtained in Reference Example 10, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.92 (3H, d, J = 6.1Hz), 1.51 (3H, s),
2.51-2.62 (1H, m), 2.68-2.89 (3H, m), 3.44 (1H, d, J =
3.2Hz), 4.75 (1H, dq, J = 3.1, 6.5Hz), 6.59 (1H, d, J =
1.0Hz), 6.99-7.05 (2H, m), 7.10-7.30 (5H, m), 7.41 (1
H, d, J = 8.2Hz), 7.50-7.55 (1H, m).

Example 11

[Chemical 68] Using the epoxy alcohol obtained in Reference Example 11, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.96 (3H, d, J = 6.3Hz), 1.64 (3H, s),
2.66-2.90 (4H, m), 3.32 (1H, d, J = 3.2Hz), 4.62 (1H, d
q, J = 3.2, 6.3Hz), 6.93-7.06 (3H, m), 708-7.20 (3H,
m), 7.27-7.40 (2H, m) 7.63-7.71 (1H, m), 7.77 (1H, d,
J = 7.7Hz).

Example 12

[Chemical 69] Using the epoxy alcohol obtained in Reference Example 12, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.82 (3H, d, J = 6.3Hz), 1.52 (3H, s),
1.37-2.50 (1H, m), 1.59-2.7 (2H, m), 2.77-289 (1H,
m), 3.69 (1H, brs), 3.75 (3H, s), 4.85-4.97 (1H, m),
6.89-7.00 (3H, m), 7.01-7.24 (5H, m), 7.28 (1H, d, J =
8.2Hz), 7.41 (1H, d, J = 8.0Hz).

Example 13

[Chemical 70] Using the epoxy alcohol obtained in Reference Example 13, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.74 (3H, d, J = 6.5Hz), 1.57 (3H, s),
2.23-2.40 (1H, m), 2.60-2.74 (2H, m), 2.76-2.91 (1H,
m), 3.84 (1H, s), 4.96 (1H, q, J = 6.5Hz), 6.89-6.97 (2
H, m), 7.04-7.19 (3H, m), 7.21-7.35 (2H, m), 7.36 (1
H, s), 7.53-7.62 (1H, m), 7.80-7.89 (1H, m).

Example 14

[Chemical 71] Using the epoxy alcohol obtained in Reference Example 14, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.88 (3H, d, J = 6.5Hz), 1.53 (3H, s),
2.42-2.56 (1H, m), 2.62-2.91 (3H, m), 3.51 (1H, brs),
4.81-4.92 (1H, m), 6.92-6.99 (2H, m), 7.06-7.20 (4H,
m), 7.25-7.32 (1H, m), 7.37 (1H, d, J = 8.0Hz), 7.45-
7.50 (1H, m), 7.54 (1H, s).

Reference Example 15

[Chemical 72] The same operation as in Reference Example 2 was performed. However, (4R ^* , 5S ^* )-
Instead of 4,5-epoxy-4-methyl-1-phenyl-3-hexanone, (4R ^* , 5S ^* )-4,5-epoxy-1-phenyl-3-hexanone was used. Furan was used instead of 1-benzenesulfonyl-3-bromo-1H-indole.

Reference Example 16

[Chemical formula 73] The same operation as in Reference Example 15 was performed. However, thiophene was used instead of furan. White solid.

Reference Example 17

[Chemical 74] The same operation as in Reference Example 1 was performed. However, (4R ^* , 5S ^* )-
Instead of 4,5-epoxy-4-methyl-1-phenyl-3-hexanone, (4R ^* , 5S ^* )-4,5-epoxy-1-phenyl-3-hexanone was used. Also, 3-bromo-1-triisopropylsilylpyrrole was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. Colorless oil.

Reference Example 18

[Chemical 75] The same operation as in Reference Example 17 was performed. However, 1-benzenesulfonyl-3-bromo-1H-indole was used instead of 1-benzenesulfonyl-3-bromo-1H-indole.
White powder.

Reference Example 19

[Chemical 76] The same operation as in Reference Example 17 was performed. However, 3-bromo-1-triisopropylsilyl-1H-indole was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. White powder.

Reference Example 20

[Chemical 77] The same operation as in Reference Example 17 was performed. However, 2-bromo-benzothiophene was used instead of 1-benzenesulfonyl-3-bromo-1H-indole.

Reference Example 21

[Chemical 78] The same operation as in Reference Example 17 was performed. However, thiophene was used instead of furan. White powder.

Reference Example 22

[Chemical 79] The same operation as in Reference Example 17 was performed. However, 3-bromo-1-methyl-1H-indole was used instead of 1-benzenesulfonyl-3-bromo-1H-indole. White powder.

Reference Example 23

[Chemical 80] The same operation as in Reference Example 17 was performed. However, instead of 1-benzenesulfonyl-3-bromo-1H-indole, 3-benzene
Bromobenzothiophene was used. Colorless oil.

Reference Example 24

[Chemical 81] The same operation as in Reference Example 17 was performed. However, instead of 1-benzenesulfonyl-3-bromo-1H-indole, 3-benzene
Benzofuran was used. Colorless oil.

Example 15

[Chemical formula 82] Using the epoxy alcohol obtained in Reference Example 15, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.06 (3H, d, J = 6.3Hz), 2.66-2.92 (4H,
m), 3.03 (1H, brs), 3.69 (1H, d, J = 8.9Hz), 4.35-4.49
(1H, m), 6.15 (1H, d, J = 3.2Hz), 6.33 (1H, dd, J = 1.8,
3.2Hz), 7.6-7.28 (5H, m), 7.34 (1H, d, J = 1.8Hz).

Example 16

[Chemical 83] Using the epoxy alcohol obtained in Reference Example 16, the same operation as in Example 1 was carried out to obtain an orange oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.08 (3H, d, J = 6.3Hz), 2.66-2.95 (5H,
m), 3.85 (1H, d, J = 8.9Hz), 4.28-4.44 (1H, m), 6.80-
6.85 (1H, m), 6.95 (1H, dd, J = 3.6, 5.1Hz), 7.02-7.30
(6H, m).

Example 17

[Chemical 84] Using the epoxy alcohol obtained in Reference Example 17, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.04 (3H, d, J = 6.3Hz), 1.07 (18H, d,
J = 7.5Hz), 1.41 (3H, heptet, J = 7.5Hz), 2.56-2.94 (4H,
m), 3.03 (1H, d, J = 2.4Hz), 3.51 (1H, d, J = 9.2Hz),
4.24-4.38 (1H, m), 6.06 (1H, dd, J = 1.4, 2.4Hz), 6.57
(1H, t, J = 1.4Hz), 6.69 (1H, t, J = 2.4Hz), 7.06 (2H,
d, J = 7.0Hz), 7.11-7.28 (3H, m).

Example 18

[Chemical 85] Using the epoxy alcohol obtained in Reference Example 18, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.95 (3H, d, J = 6.3Hz), 2.55-2.88 (4H,
m), 3.02 (1H, brs), 3.77 (1H, d, J = 8.9Hz), 4.42-4.57
(1H, m), 6.91-6.99 (2H, m), 7.09-7.51 (10H, m), 7.78-
7.85 (2H, m), 8.00 (1H, d, J = 8.4Hz).

Example 19

[Chemical 86] Using the epoxy alcohol obtained in Reference Example 19, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.02 (3H, d, J = 6.3Hz), 1.12 (18H, dd,
J = 1.4, 7.5Hz), 1.68 (3H, heptet, J = 7.5Hz), 2.61-2.
79 (3H, m), 2.81-2.95 (1H, m), 3.17 (1H, d, J = 3.2Hz),
3.84 (1H, d, J = 9.2Hz), 4.48-4.62 (1H, m), 6.95-7.22
(8H, m), 7.46-7.58 (2H, m).

Example 20

[Chemical 87] Using the epoxy alcohol obtained in Reference Example 20, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.13 (3H, d, J = 6.3Hz), 2.72-3.04 (5H,
m), 3.89 (1H, d, J = 8.9Hz), 4.38-4.54 (1H, m), 7.02-
7.22 (6H, m), 7.27-7.38 (1H, m), 7.63-7.84 (2H, m).

Example 21

[Chemical 88] Using the epoxy alcohol obtained in Reference Example 21, the same operation as in Example 1 was carried out to obtain a white solid compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.02 (3H, d, J = 6.3Hz), 2.61-3.06 (5H,
m), 3.74 (1H, d, J = 8.9Hz), 4.28-4.44 (1H, m), 6.87
(1H, dd, J = 1.2, 4.8Hz), 7.00-7.26 (6H, m), 7.28 (1H,
dd, J = 2.9, 4.8Hz).

Example 22

[Chemical 89] Using the epoxy alcohol obtained in Reference Example 22, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.04 (3H, d, J = 6.3Hz), 2.63-2.90 (4H,
m), 3.13 (1H, d, J = 3.1Hz), 3.69 (3H, s), 3.84 (1H,
d, J = 8.9Hz), 4.40-4.4 (1H, m), 6.73 (1H, s), 6.97-7.0
4 (2H, m), 7.06-7.33 (6H, m).

Example 23

[Chemical 90] Using the epoxy alcohol obtained in Reference Example 23, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.00 (3H, d, J = 6.3Hz), 2.57-2.92 (4H,
m), 3.1 (1H, brs), 4.04 (1H, d, J = 8.9Hz), 4.49-4.62
(1H, m), 6.99 (2H, d, J = 7.0Hz), 7.08-7.26 (4H, m),
7.32-7.4 (2H, m), 7.74-7.81 (1H, m), 7.83-7.92-1H,
m).

Example 24

[Chemical Formula 91] Using the epoxy alcohol obtained in Reference Example 24, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.08 (3H, d, J = 6.3Hz), 2.72-2.93 (4H,
m), 2.97 (1H, brs), 3.77 (1H, d, J = 8.9Hz), 4.46-4.62
(1H, m), 7.00-7.07 (2H, m), 7.10-7.36 (5H, m), 7.43-
7.55 (3H, m).

Reference Example 25

[Chemical Formula 92] The same operation as in Reference Example 1 was performed. However, (4R ^* , 5S ^* )-
Instead of 4,5-epoxy-4-methyl-1-phenyl-3-hexanone, (4R ^* , 5R ^* )-4,5-epoxy-4-methyl-1-phenyl-3-hexanone was used. Colorless and amorphous.

Reference Example 26

[Chemical formula 93] The same operation as in Reference Example 2 was performed. However, (4R ^* , 5S ^* )-
Instead of 4,5-epoxy-4-methyl-1-phenyl-3-hexanone, (4R ^* , 5R ^* )-4,5-epoxy-4-methyl-1-phenyl-3-hexanone was used. Colorless oil.

Reference Example 27

[Chemical 94] The same operation as in Reference Example 26 was performed. However, benzofuran was used instead of furan. Colorless oil.

Reference Example 28

[Chemical 95] The same operation as in Reference Example 26 was performed. However, 1-methylindole was used instead of furan. Colorless oil.

Reference Example 29

[Chemical 96] The same operation as in Reference Example 26 was performed. However, 1-methylpyrrole was used instead of furan. Colorless oil.

Reference Example 30

[Chemical 97] The same operation as in Reference Example 26 was performed. However, thiophene was used instead of furan. Colorless oil.

Example 25

[Chemical 98] Using the epoxy alcohol obtained in Reference Example 25, the same operation as in Example 1 was carried out to obtain a colorless amorphous compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.94 (3H, d, J = 6.3Hz), 1.44 (3H, s),
2.33-2.44 (1H, m), 2.53-2.72 (3H, m), 2.75-2.87 (1H,
m), 4.47 (1H, dq, J = 4.1, 6.3Hz), 6.88-6.94 (2H, m),
6.80-7.18 (4H, m), 7.24-7.50 (5H, m), 7.54 (1H, s),
7.79-7.86 (2H, m), 7.98, (1H, d, J = 8.4Hz).

Example 26

[Chemical 99] Using the epoxy alcohol obtained in Reference Example 26, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.02 (3H, d, J = 6.3Hz), 1.35 (3H, s),
2.48-2.90 (5H, m), 4.32 (1H, quintet, J = 6.3Hz), 6.22
-6.30 (1H, m), 6.34-6.42 (1H, m), 7.02-7.24 (5H, m),
7.37-7.45 (1H, m).

Example 27

[Chemical 100] Using the epoxy alcohol obtained in Reference Example 27, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.08 (3H, d, J = 6.5Hz), 1.45 (3H, s),
2.54-2.96 (5H, m), 4.42 (1H, quintet, J = 6.3Hz), 6.63
(1H, s), 6.98-7.32 (7H, m), 7.42-7.56 (2H, m).

Example 28

[Chemical 101] Using the epoxy alcohol obtained in Reference Example 28, the same operation as in Example 1 was carried out to obtain a pale yellow oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.00 (3H, d, J = 6.3Hz), 1.49 (3H, s),
2.42-2.54 (1H, m), 2.66-2.94 (4H, m), 3.46 (3H, s),
4.50 (1H, dq, J = 2.9, 6.3Hz), 6.54 (1H, s), 7.00-7.28
(8H, m), 7.59 (1H, d, J = 7.7Hz).

Example 29

[Chemical 102] Using the epoxy alcohol obtained in Reference Example 29, the same operation as in Example 1 was carried out to obtain a colorless oily compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.00 (3H, d, J = 6.3Hz), 1.39 (3H, s),
2.41-2.53 (1H, m), 2.62 (1H, d, J = 2.2Hz), 2.65-2.76
(1H, m), 2.76-2.92 (2H, m), 3.33 (, s), 4.41 (1H, dq,
J = 2.7, 6.3Hz), 6.06-6.18 (2H, m), 6.53 (1H, t, J = 2.
2Hz), 7.07 (2H, d, J = 6.8Hz), 7.12-7.28 (3H, m).

Example 30

[Chemical 103] Using the epoxy alcohol obtained in Reference Example 30, the same operation as in Example 1 was carried out to obtain a colorless amorphous compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 0.98 (3H, d, J = 6.3Hz), 1.46 (3H, s),
2.52-2.90 (4H, m), 2.99 (1H, d, J = 3.4Hz), 4.40 (1H, d
q, J = 3.4, 6.3Hz), 6.92-7.08 (4H, m), 7.12-7.30 (4H,
m).

Reference Example 31

[Chemical 104] 1-benzenesulfonyl-3-bromo-1H-indole (1.0 g,
A solution of 2.97 mmol) in dry THF (20 ml) at -78 ° C with stirring at 1.5
1.96 m of 9 M normal butyl lithium (hexane solution)
l (3.12 mmol) was added. After 30 seconds, 1-acetyl-1-cyclohexene (0.42 ml, 3.27 mmol) was added and stirred for 10 minutes, then water was added to stop the reaction. Add ethyl acetate and wash with water (water x 3, saturated saline x 1), dry (magnesium sulfate), concentrate and then column chromatography (ethyl acetate / hexane = 1 / 20-1 / 10-1).
/ 4) for purification, 0.905 g of colorless oily alcohol
(80%) obtained. The above alcohol obtained in this way
A solution of (700 mg, 1.83 mmol) in methylene chloride (10 ml) was stirred at 0 ° C with Na ₂ HPO ₄ (1.30 g, 9.17 mmol), 80% mCPBA (435 mg, 2.02 m).
(mol) and stirred for 20 minutes. After water was added to stop the reaction, ethyl acetate was added, washed with water (water × 3, saturated saline × 1), dried (magnesium sulfate), and concentrated. Column chromatography of the residue (ethyl acetate / hexane = 1 / 20-1 / 10-1 / 5)
To obtain 720 mg (99%) of colorless amorphous epoxy alcohol represented by the above formula.

Reference Example 32

[Chemical 105] While stirring a solution of furan (1.25 ml, 17.5 mmol) in dehydrated THF (20 ml) at -78 ° C, 9.0 ml (14 mmol) of 1.56M n-butyllithiumhexane solution was added dropwise, and the mixture was stirred at 20 ° C for 20 minutes. The mixture was again cooled to -78 ° C, 1-acetyl 1-cyclohexenone (1.5 ml, 11.7 mmol) was added, and the mixture was stirred for 10 minutes. Water was poured to stop the reaction, ethyl acetate was added, washed with water (water × 3, saturated saline × 1), dried (magnesium sulfate),
After concentration, the product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/30 to 1/20 to 1/10) to obtain 1.6 g (71%) of pale yellow oily epoxy alcohol.
Obtained. The above-obtained alcohol (1.0 g,
A solution of 5.2 mmol) in methylene chloride (10 ml) was stirred at 0 ° C with Na ₂ HP.
Add O ₄ (3.69 g, 26 mmol), 80% mCPBA (1.23 g, 5.7 mmol) and add 20
Stir for minutes. After water was added to stop the reaction, ethyl acetate was added, washed with water (water × 3, saturated saline × 1), dried (magnesium sulfate), and concentrated. The residue was purified by column chromatography (ethyl acetate / hexane = 1 / 20-1 / 10) to obtain 1.41 g of colorless oily epoxy alcohol represented by the above formula.
(87%) obtained.

Reference Example 33

[Chemical formula 106] The same operation as in Reference Example 32 was performed. However, thiophene was used instead of furan. Colorless oil.

Example 31

[Chemical formula 107] Epoxy alcohol obtained in Reference Example 31 (50 mg, 0.12
The dry methylene chloride solution of 6 mmol) under stirring -78 ° C., BF ₃
-OEt ₂ (32 micro l, 0.252 mmol) was added and stirred for 10 minutes.
Saturated aqueous sodium hydrogen carbonate was added to stop the reaction, ethyl acetate was added, and the mixture was washed with water (water x 3, saturated saline x 1), dried (magnesium sulfate), concentrated, and then subjected to column chromatography (ethyl acetate / ethyl acetate /
Purification was performed with hexane = 1/1) to obtain 48.8 mg (98%) of colorless and amorphous aldol represented by the above formula. Colorless and amorphous. ¹ H-NMR (CDCl ₃ ) 1.36-1.82 (6H, m), 1.86 (3H, s), 2.19
-2.36 (2H, m), 3.20 (1H, d, J = 5.3Hz), 4.45-4.53 (1H,
m), 7.16-7.23 (1H, m), 7.28-7.34 (1H, m), 7.42-7.50
(3H, m), 7.51-7.58 (1H, m), 7.62 (1H, s), 7.83-7.88
(2H, m), 8.00 (1H, d, J = 8.2Hz).

The reaction scheme of Example 31 is shown below.

[Chemical 108]

Example 32

[Chemical 109] Using the epoxy alcohol obtained in Reference Example 32, the same operation as in Example 31 was carried out to obtain a compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.32-1.44 (1H, m), 1.50-1.80 (5H, m),
2.01 (3H, s), 2.10-2.23 (2H, m), 3.26 (1H, d, J = 5.3H
z), 4.40-4.50 (1H, m), 6.28 (1H, d, J = 3.2Hz), 6.39 (1
H, dd, J = 1.7, 3.2Hz), 7.40 (1H, d, J = 1.7Hz).

Example 33

[Chemical 110] Using the epoxy alcohol obtained in Reference Example 33, the same operation as in Example 31 was carried out to obtain a compound represented by the above formula. ¹ H-NMR (CDCl ₃ ) 1.30-1.57 (2H, m), 1.66-1.86 (4H, m),
203 (3H, s), 2.08-2.23 (1H, m), 2.31-2.47 (1H, m),
3.35 (1H, d, J = 6.8Hz), 4.19 (1H, d, J = 3.6Hz), 6.99-7.
04 (2H, m), 7.28 (1H, dd, J = 2.4, 3.8Hz).

Reference Example 34

[Chemical 111] 1-benzenesulfonyl-3-bromo-1H-indole (1.5 g,
4.46 mmol) of dehydrated THF (20 ml) was stirred at -78 ° C for 1.59
M-n-butyllithium hexane solution (2.8ml, 4.46mmol)
Was added, and after stirring for 30 seconds, (S) -4-O- (1-ethoxyethyl) -1-phenyl-propan-3-one (1.06 g, 4.25 mmol) was added. After 10 minutes, water was added to stop the reaction, ethyl acetate was added, and the mixture was washed with water (water x 3, saturated saline x 1), dried (magnesium sulfate), concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/6) and got alcohol. This was made into an ethanol (20 ml) solution, and pyridinium-p-toluenesulfonate (0.17 g,
0.67 mmol) was added and the mixture was stirred for 30 minutes. After ethanol was distilled off under reduced pressure, ethyl acetate was added and washed with water (saturated sodium hydrogen sulfate aqueous solution x 1, saturated sodium hydrogen carbonate aqueous solution x 1, water x
3, saturated saline solution x 1), dried (magnesium sulfate), concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 10-1 / 5-1 / 3), and represented by the above formula 1.63 g (88%) of colorless amorphous diol was obtained.

Reference Example 35

[Chemical 112] Thiophene (1.0 ml, 12.5 mmol) dehydrated THF (10 ml)
The solution was added with 4.7 ml (7.5 mmol) of 1.59 M n-butyllithium hexane solution under stirring at -78 ° C, and stirred at 20 ° C for 20 minutes. It was cooled to -78 ° C again and (S) -4-O- (1-ethoxyethyl) -1-phenyl-propan-3-one (1.5 ml, 6.24 mmo
l) was added and stirred for 10 minutes. Pour water to stop the reaction,
Add ethyl acetate and wash with water (water × 3, saturated saline × 1),
After drying (magnesium sulfate) and concentration, silica gel column chromatography (ethyl acetate / hexane = 1 / 30-
Purification was carried out at 1/20 to 1/10) to obtain alcohol. This was made into an ethanol (10 ml) solution, and pyridinium-p-toluenesulfonate (0.23 g, 0.90 mmol) was stirred at room temperature.
Was added and stirred for 30 minutes. After ethanol was distilled off under reduced pressure, ethyl acetate was added and washed with water (saturated sodium hydrogensulfate aqueous solution x
1, saturated sodium hydrogen carbonate aqueous solution x 1, water x 3, saturated saline solution x 1), dried (magnesium sulfate), concentrated under reduced pressure and subjected to silica gel column chromatography (ethyl acetate / hexane = 1 / 10-1 / 5-1 / Purification in 3) yielded 1.45 g (89%) of the colorless amorphous diol represented by the above formula.

Reference Example 36

[Chemical 113] The same operation as in Reference Example 35 was performed. However, 1-methylindole was used instead of thiophene. Colorless oil.

Reference Example 37

[Chemical 114] The same operation as in Reference Example 35 was performed. However, benzofuran was used instead of thiophene. Colorless oil.

Reference Example 38

[Chemical 115] The same operation as in Reference Example 35 was performed. However, benzothiophene was used instead of thiophene. Colorless oil.

Example 34

[Chemical formula 116] A solution of the diol (500 mg, 1.15 mmol) obtained in Reference Example 34 in dehydrated methylene chloride (5 ml) was added with triethylamine (240 microl, 1.72 mmol) and methanesulfonyl chloride (107 microl, 1.38 mmol) under stirring at 0 ° C. . After 10 minutes, cool to −78 ° C. and add 0.92 M triethylaluminum / hexane solution.
3.74 ml (3.44 mmol) was added and stirred for 10 minutes. The reaction was stopped by pouring it into ice and an aqueous solution of sodium hydrogensulfate, adding ethyl acetate, washing with water (sodium hydrogensulfate × 1, water × 3, saturated saline × 1), drying (magnesium sulfate) and concentrating under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate
/ Hexane = 1 / 10-1 / 6) and colorless oily ketone 0
430 mg (90%) of 3-80 was obtained. Enantiomeric excess 99% [α] _D −39.7 (c 0.64 CHCl ₃ 20 ℃) ¹ H-NMR (CDCl ₃ ) 1.45 (3H, d, J = 7.2Hz), 2.54-2.86 (4H,
m), 3.86 (1H, q, J = 7.2Hz), 6.95-7.03 (2H, m), 7.10-
7.53 (10H, m), 7.80-7.87 (2H, m), 7.98 (1H, d, J = 8.5H
z).

The reaction scheme of Example 34 is shown below.

[Chemical 117]

Example 35

[Chemical 118] Using the diol obtained in Reference Example 35, the same operation as in Example 34 was carried out to obtain a pale yellow oily compound represented by the above formula. Enantiomeric excess 99% [α] _D −84.8 (c 0.69 CHCl ₃ 19 ℃) ¹ H-NMR (CDCl ₃ ) 1.45 (3H, d, J = 7.0Hz), 2.65-2.95 (4H,
m), 3.98 (1H, q, J = 7.0Hz), 6.83 (1H, d, J = 3.4Hz),
6.9 (1H, dd, J = 3.6, 5.3Hz), 7.06-7.29 (6H, m).

Example 36

[Chemical formula 119] Using the diol obtained in Reference Example 36, the same operation as in Example 34 was carried out to obtain a colorless oily compound represented by the above formula. Enantiomeric excess 99% [α] _D −38.2 (c 0.65 CHCl ₃ 24 ℃) ¹ H-NMR (CDCl ₃ ) 1.49 (3H, d, J = 7.0Hz), 2.61-2.69 (1H,
m), 2.69-2.87 (3H, m), 3.49 (3H, s), 3.86 (1H, q, J =
7.0Hz), 6.30 (1H, d, J = 0.8Hz), 6.98-7.29 (8H, m), 7.
50-7.60 (1H, m).

Example 37

[Chemical 120] Using the diol obtained in Reference Example 37, the same operation as in Example 34 was carried out to obtain a compound represented by the above formula. Enantiomeric excess 90% [α] _D −41.3 (c 0.67 CHCl ₃ 23 ℃) ¹ H-NMR (CDCl ₃ ) 1.48 (3H, d, J = 7.0Hz), 2.72-2.93 (4H,
m), 3.90 (1H, q, J = 7.0Hz), 6.48 (1H, s), 7.06-7.29
(7H, m), 7.38-7.45 (1H, m), 7.46-7.53 (1H, m).

Example 38

[Chemical 121] Using the diol obtained in Reference Example 38, the same operation as in Example 34 was carried out to obtain a colorless oily compound represented by the above formula. Enantiomeric excess 99% [α] _D +65 (c 0.67 CHCl3 24 ℃) ¹ H-NMR (CDCl ₃ ) 1.51 (3H, d, J = 7.0Hz), 2.72-2.94 (4H,
m), 4.02 (1H, d, J = 7.0Hz), 7.02 (1H, s), 7.06-7.38
(7H, m), 7.63-7.71 (1H, m), 7.73-7.80 (1H, m).

Reference Example 39

[Chemical formula 122] 1-benzenesulfonyl-3-bromo-1H-indole (6.0 g,
17.8 mmol) of dehydrated THF (120 ml) was stirred at -78 ° C for 1.59
M-n-butyllithium hexane solution (11.8ml, 18.7mmol)
Was added and stirred for 30 seconds (S) -2-O- (1-ethoxyethyl) -N, N-
Dimethyl lactamide (3.71 g, 19.6 mmol) was added. 1
After 0 minutes, water was added to stop the reaction, ethyl acetate was added, and the mixture was washed with water (water x 3, saturated saline x 1), dried (magnesium sulfate), concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/5) to obtain the ketone. This was made into an ethanol (60 ml) solution and pyridinium-p-toluenesulfonate (0.90 g, 3.6 mm) was stirred at room temperature.
ol) was added and stirred for 30 minutes. After distilling off the ethanol under reduced pressure,
Ethyl acetate was added and washed with water (saturated sodium hydrogen sulfate aqueous solution x 1, saturated sodium hydrogen carbonate aqueous solution x 1, water x 3, saturated saline solution x 1), dried (magnesium sulfate), concentrated under reduced pressure and subjected to silica gel column chromatography (ethyl acetate / ethyl acetate / Hexane = 1 / 10-1 / 5-1 / 3) to obtain 4.68 g (80%) of a colorless oily keto alcohol represented by the above formula.

Reference Example 40

[Chemical 123] Dehydration TH of 2,3-benzofuran (1.86 ml, 13 mmol)
While stirring the F (10 ml) solution at -78 ° C, 9.06 ml (14.3 mmol) of 1.56 M n-butyllithium hexane solution was added dropwise.
The mixture was stirred at 0 ° C for 20 minutes. It was cooled again to -78 ° C, and (S) -2-O-
(1-Ethoxyethyl) -N, N-dimethyllactamide (2.5m
(1, 13 mmol) was added and stirred for 10 minutes. The reaction was stopped by pouring water, ethyl acetate was added, washed with water (water × 3, saturated saline × 1), dried (magnesium sulfate), concentrated, and then subjected to silica gel column chromatography (ethyl acetate / hexane = 1.
/ 30 to 1/20 to 1/10) to obtain a ketone. This was made into an ethanol (20 ml) solution and stirred at room temperature with pyridinium-p-toluenesulfonate (0.65 g, 2.59 mmo
l) was added and stirred for 30 minutes. After ethanol was distilled off under reduced pressure, ethyl acetate was added and washed with water (saturated sodium hydrogensulfate aqueous solution x
1, saturated sodium hydrogen carbonate aqueous solution x 1, water x 3, saturated saline solution x 1), dried (magnesium sulfate), concentrated under reduced pressure and subjected to silica gel column chromatography (ethyl acetate / hexane = 1 / 10-1 / 5-1 / After purification in 3), 2.11 g (85%) of the pale yellow oily keto alcohol represented by the above formula was obtained.

Reference Example 41

[Chemical formula 124] The same operation as in Reference Example 40 was performed. However, benzothiophene was used instead of 2,3-benzofuran. White powder.

Reference Example 42

[Chemical 125] The same operation as in Reference Example 39 was performed. However, 1-methylindole was used instead of 2,3-benzofuran.
Pale yellow solid.

Reference Example 43

[Chemical formula 126] The same operation as in Reference Example 39 was performed. However, (S) -2-O- (1
Instead of -ethoxyethyl) -N, N-dimethyllactamide, (R) -2-O- (1-ethoxyethyl) -N, N-dimethyllactamide was used.

Example 39

[Chemical 127] Keto alcohol obtained in Reference Example 39 (3.0 g, 9.11 mmo
A solution of l) in dehydrated methylene chloride (30 ml) was stirred at 0 ° C., triethylamine (1.9 ml, 13.7 mmol) and methanesulfonyl chloride (0.85 ml, 11 mmol) were added, and the mixture was stirred for 10 minutes. Water was added to stop the reaction, ether was added, and the mixture was washed with water (water × 2, saturated saline solution × 1), dried (magnesium sulfate), concentrated under reduced pressure and then vacuum dried. This is dehydrated methylene chloride (30 ml)
27.3 ml (27.3 mmol) of 1.0 M diisobutylaluminum hydride / hexane solution was added to the solution under stirring with cooling to −78 ° C. and 0.9.
3M nodiethyl aluminum chloride / hexane solution 1
4.7 ml (13.7 mmol) was added continuously and the temperature was raised to 0 ° C over 10 minutes. The reaction was stopped by pouring it into ice and aqueous sodium hydrogensulfate, adding ethyl acetate, washing with water (sodium hydrogensulfate × 1, water × 3, saturated saline × 1), drying (magnesium sulfate) and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 10-1 / 4-1 / 2), and the colorless oily alcohol represented by the above formula was added to 2.
Obtained 5 g (87%). Enantiomeric excess 99% [α] _D +17.6 (c 0.81 CHCl ₃ 21 ℃) 1.36 (3H, d, J = 6.8Hz), 1.38-1.54 (1H, brs), 3.18 (1H,
sextet, J = 6.8Hz), 3.64-3.87 (2H, m), 7.20-7.57 (7H,
m), 7.83 + 7.89 (2H, m), 7.99 (1H, d, J = 8.2Hz).

The reaction scheme of Example 39 is shown below.

[Chemical 128]

Example 40

[Chemical formula 129] Using the keto alcohol obtained in Reference Example 40, the same operation as in Example 39 was carried out to obtain a colorless oily compound represented by the above formula. Enantiomeric excess 99% [α] _D −20.4 (c 0.51 CHCl ₃ 19 ℃) ¹ H-NMR (CDCl ₃ ) 1.36 (3H, d, J = 6.8Hz), 1.75 (1H, br
s), 3.16 (1H, sextet, J = 6.8Hz), 3.75-3.92 (2H, m),
6.47 (1H, s), 7.15-7.26 (2H, m), 7.38-7.45 (1H, m), 7.
45-7.55 (1H, m).

Example 41

[Chemical 130] Using the keto alcohol obtained in Reference Example 41, the same operation as in Example 39 was carried out to obtain a colorless oily compound represented by the above formula. Enantiomeric excess 99% [α] _D −22.9 (c 0.62 CHCl ₃ 20 ℃) ¹ H-NMR (CDCl ₃ ) 1.39 (3H, d, J = 6.8Hz), 1.60-1.80 (1H,
m), 3.28 (1H, sextet, J = 6.8Hz), 3.68-3.83 (2H, m),
7.10 (1H, s), 7.22-7.35 (2H, m), 7.68 (1H, d, J = 7.5H
z), 777 (1H, d, J = 7.8Hz).

Example 42

[Chemical 131] Using the keto alcohol obtained in Reference Example 42, the same operation as in Example 39 was carried out to obtain a pale yellow oily compound represented by the above formula. Enantiomeric excess 99% [α] _D −43.1 (c 0.52 CHCl ₃ 21 ℃) ¹ H-NMR (CDCl ₃ ) 1.31 (3H, d, J = 6.8Hz), 1.74 (1H, br
s), 3.18 (1H, sextet, J = 6.8Hz), 3.62-3.82 (5H, m),
6.30 (1H, s), 7.04-7.12 (1H, m), 7.14-7.22 (1H, m), 7.
27 (1H, d, J = 8.2Hz).

Example 43

[Chemical 132] Using the keto alcohol obtained in Reference Example 43, the same operation as in Example 39 was carried out to obtain a colorless oily compound represented by the above formula. Enantiomeric excess 99% [α] _D −17.4 (c 1.13 CHCl ₃ 22 ℃) 1.36 (3H, d, J = 6.8Hz), 1.38-1.54 (1H, brs), 3.18 (1H,
sextet, J = 6.8Hz), 3.64-3.87 (2H, m), 7.20-7.57 (7H,
m), 7.83 + 7.89 (2H, m), 7.99 (1H, d, J = 8.2Hz).

Examples 34, 35, 36, 37, 38, 3
Enantiomeric excess of 9,40,41,42,43 is chiral HPLC column with racemic body synthesized in the same way as chiral body
(DAICEL CHIRALCEL OD-H, i-PrOH / hexane = 9/1) Determined by analysis.

[0201]

INDUSTRIAL APPLICABILITY According to the present invention, many physiologically active substances (pharmaceutical compounds, agricultural chemicals, etc.) or their intermediates having an asymmetric center at the adjacent position of a heterocycle can be simply and efficiently provided.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 333/22 C07D 333/22 4H039 333/56 333/56 // C07B 61/00 300 C07B 61/00 300 C07M 7:00 C07M 7:00 F term (reference) 4C023 DA05 4C037 HA06 PA08 4C069 AC07 BB22 4C204 BB04 CB03 DB16 EB02 FB32 GB01 4H006 AA01 AA02 AB84 AC81 BA67 BB12 BC11 BC34 4H039 CA60 CA62 CJ00 CJ10

Claims (25)

[Claims] 1. A heterocyclic compound having an asymmetric center represented by the following formula (1a) or (1b). [Chemical 1] [In the formula, R ¹ , R ² and R ³ are independently of each other,
They are the same or different and are a C _{1 to} C ₂₀ hydrocarbon group which may have a hydrogen atom or a substituent, and the A ring represents a 5 to 11 membered heterocyclic ring which may have a substituent. ] 2. R ¹ which may have a substituent, C ₁ -C ₂₀
Alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₆ -C ₁₈ aryl group, C ₆ -C ₂₀ alkylaryl group, or a C ₆ -C ₂₀ arylalkyl group,
R ² is a hydrogen atom or a C ₁ -C _{1 0} alkyl group, R ³ is C ₁ -C ₁₀ alkyl or C ₄ -C ₁₀ cycloalkyl group, a heterocyclic compound of Claim 1. 3. Ring A, each of which may have a substituent, furan, thiophene, pyrrole, benzofuran,
A benzothiophene or an indole.
Or the heterocyclic compound according to item 2. 4. An epoxy alcohol represented by the following formula (5a) in the presence of a Lewis acid: [In the formula, R ¹ , R ² and R ³ are independently of each other,
They are the same or different and are a C _{1 to} C ₂₀ hydrocarbon group which may have a hydrogen atom or a substituent, and the A ring represents a 5 to 11 membered heterocyclic ring which may have a substituent. ] A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (1a), which comprises carrying out a rearrangement reaction. [Chemical 3] [In formula, R < ¹ >, R < ² >, R < ³ > and A ring have the above-mentioned meaning. ] 5. An epoxy alcohol represented by the following formula (5b) in the presence of a Lewis acid: [In the formula, R ¹ , R ² and R ³ are independently of each other,
They are the same or different and are a C _{1 to} C ₂₀ hydrocarbon group which may have a hydrogen atom or a substituent, and the A ring represents a 5 to 11 membered heterocyclic ring which may have a substituent. ] A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (1b), which comprises carrying out a rearrangement reaction. [Chemical 5] [In formula, R < ¹ >, R < ² >, R < ³ > and A ring have the above-mentioned meaning. ] 6. R ¹ is optionally substituted C ₁ -C ₂₀
Alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₆ -C ₁₈ aryl group, C ₆ -C ₂₀ alkylaryl group, or a C ₆ -C ₂₀ arylalkyl group,
R ² is a hydrogen atom or a C ₁ -C _{1 0} alkyl group, R ³ is C ₁ -C ₁₀ alkyl or C ₄ -C ₁₀ cycloalkyl group, a heterocyclic compound according to claim 4 or 5 Manufacturing method. 7. A ring A may have a substituent, furan, thiophene, pyrrole, benzofuran,
It is benzothiophene or indole.
7. The method for producing a heterocyclic compound according to any one of 6 to 6. 8. A heterocyclic compound having an asymmetric center represented by the following formula (2). [Chemical 6] [In the formula, R ⁴ is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent, and B ring is a 5 to 11 membered heterocyclic ring which may have a substituent. Indicates. ] 9. The heterocyclic compound according to claim 8, wherein R ⁴ is a C ₁ -C ₁₀ alkyl group. 10. The heterocyclic compound according to claim 8, wherein ring B is furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole, each of which may have a substituent. 11. An epoxy alcohol represented by the following formula (6) in the presence of a Lewis acid: [In the formula, R ⁴ is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent, and B ring is a 5 to 11 membered heterocyclic ring which may have a substituent. Indicates. ] A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (2), which comprises carrying out a rearrangement reaction. [Chemical 8] [In the formula, R ⁴ and B ring have the above-mentioned meanings. ] 12. The method for producing a heterocyclic compound according to claim 11, wherein R ⁴ is a C ₁ -C ₁₀ alkyl group. 13. The heterocyclic compound according to claim 11, wherein ring B is furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole, each of which may have a substituent. Production method. 14. A heterocyclic compound having an asymmetric center represented by the following formula (3). [Chemical 9] [In the formula, R ⁵ and R ⁶ are each independently, the same or different, and are a C _{1 to} C ₂₀ hydrocarbon group which may have a hydrogen atom or a substituent, and the C ring is a substituent. Represents a 5- to 11-membered heterocyclic ring which may have. ] 15. R ⁵ is an optionally substituted C ₁ -C
₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₆ -C ₁₈ aryl group, C ₆ -C ₂₀ alkylaryl group, or a C ₆ -C ₂₀ arylalkyl group, The heterocyclic compound according to claim 14, wherein R ⁶ is a C _{1 to} C ₁₀ alkyl group or a C _{4 to} C ₁₀ cycloalkyl group. 16. The heterocyclic compound according to claim 14, wherein ring C is furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole, each of which may have a substituent. 17. An alcohol represented by the following formula (7) in the presence of a Lewis acid: [In the formula, R ⁵ and R ⁶ are each independently, the same or different, and are a C _{1 to} C ₂₀ hydrocarbon group which may have a hydrogen atom or a substituent, and A ¹ is C ₁ To C ₂₀ alkylsulfonyl group or C _{6 to} C ₁₈ arylsulfonyl group, and C ring represents a 5 to 11 membered heterocyclic ring which may have a substituent. ] A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (3), which comprises carrying out a rearrangement reaction. [Chemical 11] [In formula, R < ⁵ >, R < ⁶ > and C ring have a said meaning. ] 18. R ⁵ is an optionally substituted C ₁ -C
₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₆ -C ₁₈ aryl group, C ₆ -C ₂₀ alkylaryl group, or a C ₆ -C ₂₀ arylalkyl group, The method for producing a heterocyclic compound according to claim 17, wherein R ⁶ is a C _{1 to} C ₁₀ alkyl group or a C _{4 to} C ₁₀ cycloalkyl group. 19. The heterocyclic compound according to claim 17, wherein the C ring is furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole, each of which may have a substituent. Production method. 20. A heterocyclic compound having an asymmetric center represented by the following formula (4). [Chemical 12] [In the formula, R ⁷ is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent, and D ring is a 5 to 11 membered heterocyclic ring which may have a substituent. Indicates. ] 21. R ⁷ is a C ₁ -C ₁₀ alkyl group or C ₄ -C
The heterocyclic compound according to claim 20, which is a ₁₀ cycloalkyl group. 22. The heterocyclic compound according to claim 20, wherein ring D is furan, thiophene, pyrrole, benzofuran, benzothiophene, or indole, each of which may have a substituent. 23. A ketone represented by the following formula (8) in the presence of a reducing agent: [In the formula, R ⁷ is a hydrogen atom or a C _{1 to} C ₂₀ hydrocarbon group which may have a substituent, and A ² is a C _{1 to} C ₂₀ alkylsulfonyl group or a C _{6 to} C ₁₈ aryl. It is a sulfonyl group, and Ring D represents a 5- to 11-membered heterocycle which may have a substituent. ] A method for producing a heterocyclic compound having an asymmetric center represented by the following formula (4), which comprises carrying out a rearrangement reaction using a Lewis acid. [Chemical 14] [In the formula, R ⁷ and D ring have the above-mentioned meanings. ] 24. R ⁷ is a C ₁ -C ₁₀ alkyl group or C ₄ -C
24. The method for producing a heterocyclic compound according to claim 23, which is a ₁₀ cycloalkyl group. 25. The heterocyclic compound according to claim 23 or 24, wherein each ring D is furan, thiophene, pyrrole, benzofuran, benzothiophene or indole which may have a substituent. Production method.