JP2000297084A - Production of optically active norbornenealdehyde - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a haloether and eneacetal in high yield and high enantioselectivity by intramolecular haloetherification of a specific diastereo mixture in the presence of a halogenating agent and an alcohol or water. SOLUTION: This haloether of formula VI or VII (X is a halogen) is stereoselectively obtained and at the same time the other objective eneacetal of formula V is allowed to remain by such processes that (A) 2-endo forms of racemic norbornenealdehydes of formula I and II (R is H or a lower alkyl) are reacted with (B) optically active C2-symmetric 1,2-diols of formula III [R1 is a (substituted) aryl] to obtain (C) a diastereo mixture of eneacetals of formula IV and V; and the component C is intramolecularly haloetherified in the presence of (D) a halogenating agent and (E) an alcohol of the formula R2OH (R2 is a lower alkyl) or water.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing optically active norbornene aldehydes from racemic norbornene aldehydes, which are useful as intermediates for the synthesis of medicinal and agricultural chemicals and as optical resolution agents.

[0002]

BACKGROUND ART Conventionally, norbornene aldehydes have been easily synthesized in a racemic form by the Diels-Alder reaction, and many studies have been made on the selectivity between endo- and exo-forms. The purpose is to synthesize a racemate, and there is not much method for obtaining a pure optically active form. The asymmetric synthesis of norbornene aldehyde uses a complex of an asymmetric ligand and a titanium compound as a Lewis acid catalyst (Journal of Organic Chemistry, 5
8 , 2938-2939 (1993)), a method using a complex of an asymmetric ligand and a borane compound as a Lewis acid catalyst (Journal of Am.
erican Chemical Society, 120 , 6920-6930 (1998)). Further, an oxazolidinone ring is bonded to norbornene aldehyde, and as an amide compound as a derivative, a method described in the literature (Journal of American Chemical
(4S) -3-((3R, 4R, 5S, 6S) -5-methylbicyclo, which can be easily obtained by ciety, 110 , 1238-1256 (1988)).
[2.2.1] Method of obtaining norbornene aldehyde from heptene-4-carbonyl) -4- (1-methylethyl) -2-oxazolidinone in two steps (Japanese Patent Application No. 10-13039)
There is also 7).

[0003] When the target substance is a stable solid, purification is carried out by recrystallization by binding an asymmetric ligand thereto, or when the target substance is in a very small amount, by chiral column chromatography. A method of separating this is also possible.

[0004]

However, most of these conventional methods require expensive asymmetric ligands and reagents, require complicated reaction steps and strict reaction conditions, and are therefore not suitable for large-scale synthesis. Is not suitable.

[0005] In addition, when the norbornene aldehyde, which is the target substance, is liquid or more volatile,
Purification by ordinary recrystallization or chromatography is difficult. Further, in many cases, completely optically active substances cannot be obtained even by these methods.

[0006]

Means for Solving the Problems The present inventors converted the racemic norbornene aldehyde 2-end form into C
These diastereomers are led to these diastereomers by using a two-symmetric diol, and the optical resolution is achieved with high purity by utilizing the difference in the reactivity between these diastereomers. At the same time, the obtained optically active norbornene aldehyde is equivalent to norbornene It led to an acetal which showed more stable physical properties than aldehyde. Further, this acetal compound can be used as it is in a method for producing an optically active alcohol derivative from meso-1,2-diol (Japanese Patent Application No. 10-13973).

That is, the present invention relates to (a) a 2-end form of racemic norbornene aldehydes represented by the following general formulas [I] and [I ']: To form a diastereomeric mixture of eneacetals represented by the general formulas [III] and [III '] by reacting with a halogenating agent and an alcohol or water. An enoacetal represented by the general formula [III '] and a haloether represented by the general formula [IV] or [V] are stereoselectively separated by lower intramolecular haloetherification followed by separation of the product. And (b) reacting the haloethers [V] obtained in the above method (a) with meso-1,2-diols represented by the general formula [VI]. [V] is represented by the general formula [VII] And acetals,
A method of deriving this into an eneacetal represented by the general formula [VIII] by a dehaloetherification reaction, (c) converting the eneacetal [III ′] obtained by the above method (a) with a halogenating agent and water To give a haloether represented by the general formula [V '], which is reacted with a meso-1,2-diol represented by the general formula [VI] A method for producing optically active norbornene aldehydes, comprising a method of converting an acetal represented by [VII '] into an ene acetal represented by the general formula [VIII'] by a dehaloetherification reaction. It is.

[0008] The above method (a) comprises the general formulas [I] and [I ']

Embedded image To the 2-endo-form of racemic norbornene aldehydes represented by the general formula [II]

Embedded image By reacting an optically active C2-symmetric 1,2-diol represented by the general formulas [III] and [III ']

Embedded image To form a diastereomeric mixture of eneacetals represented by the formula
⁽ OH) to form a haloether represented by the general formula [IV] in a stereoselective manner while leaving the eneacetals [III '] or a mixture thereof. In the presence of a halogenating agent and water to produce a haloether represented by the general formula [V] in a stereoselective manner while leaving the eneacetal [III ']. It is.

[0009]

Embedded image Haloethers [IV] and haloethers [V] which are the final products of the method (a), and eneacetals [III] and eneacetals [III '] which are synthetic intermediates thereof, Acetals [III] [II
Each of the diastereomeric mixtures of I ′] is a novel substance.

In the above method (b), the haloethers [V] obtained in the above method (a) are added to the general formula [VI]

Embedded image And reacting the same haloethers [V] with the general formula [VII]

Embedded image Acetals represented by the general formula [VIII]

Embedded image Is a method for producing eneacetals, which leads to eneacetals represented by

Acetals [VII], which are synthetic intermediates in method (b), are novel compounds.

In the above method (c), the eneacetals [III '] obtained in the above method (a) are subjected to intramolecular haloetherification in the presence of a halogenating agent and water to give a compound of the general formula [V']

Embedded image Represented by the general formula [VI]

Embedded image By reacting with a meso-1,2-diol represented by the general formula [VII ']

Embedded image Acetals represented by the general formula [VIII ']

Embedded image Is a method for producing eneacetals, which leads to eneacetals represented by

In the above formula, R, R ¹ and R
³ are the same, R is a hydrogen atom or a lower alkyl group, R ¹ is an aryl group which may have a substituent, R ² is a lower alkyl group,
R ³ is a lower alkyl group or a lower alkenyl group which may have a substituent, a lower alkoxycarbonyl group, an amino group protected by a protecting group, a cyano group, or an aryl group which may have a substituent. And X is a halogen atom.

The synthesis intermediates of the method (c), the haloethers [V '] and the acetals [VII'], are both novel compounds.

The above methods (a) to (c) are as shown by the following formulas.

[0016]

Embedded image

[0017]

Embedded image

[0018]

Embedded image

[0019]

In the process according to the invention, the radicals R are identical and are lower alkyl radicals. Examples of the lower alkyl group as the group R include those having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isobutyl, t-butyl and sec-butyl.
Linear or branched alkyl groups. Particularly, a methyl group is preferable.

The two groups R ¹ in the compound are the same and are an optionally substituted aryl group. Here, as the aryl group which may have a substituent, a phenyl group, a tolyl group, a methoxyphenyl group, and a chlorophenyl group are representative examples.

The two groups R ³ in the compound are the same, and may be a lower alkyl or lower alkenyl group which may have a substituent, a lower alkoxycarbonyl group, or an amino group protected by a protecting group. , A cyano group, or an aryl group which may have a substituent.

The lower alkyl group or lower alkenyl group which may have a substituent as the group R ³ is, for example, an aralkyloxy group, a lower alkoxyl group, a lower alkoxycarbonyl group, a halogen atom, a protecting group. It may be a lower alkyl group or a lower alkenyl group having a protected amino group, a cyano group, and / or an aryl group which may have a substituent. As an aralkyloxy group as a substituent of a lower alkyl group or a lower alkenyl group, benzyloxymethyl, methoxyethyl as a lower alkoxyl group, methoxycarbonyl, ethoxycarbonyl as a lower alkoxycarbonyl group, chlorine as a halogen atom, Bromine is an amino group protected with a protecting group as an amino group protected with a benzyloxycarbonyl group, and an aryl group optionally having a substituent is a phenyl group, tolyl group, methoxyphenyl group, chlorophenyl The groups are each exemplified. Examples of lower alkyl group as radicals R ³ are methyl, ethyl, propyl, isobutyl, t-
It is a linear or branched alkyl group having 1 to 6 carbon atoms such as butyl and sec-butyl. Examples of lower alkenyl as R ³ are vinyl, allyl, isopropenyl, 1
-A linear or branched alkenyl group having 1 to 6 carbon atoms such as propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, and 3-methyl-2-butenyl.

The lower alkoxycarbonyl group as the group R ³ is methoxycarbonyl or ethoxycarbonyl, and the amino group protected by the protecting group as the group R ³ is an amino group protected by a benzyloxycarbonyl group. and the aryl group as group R ³ include a respective representative example a phenyl group.

X is a halogen atom such as fluorine, chlorine, bromine and iodine.

The above method (a) will be described in more detail.

First, in the first step of the method (a), the 2-endo-form [I] of racemic norbornene aldehydes
[I ′] is converted to a chain optically active 1,2-diol [II]
To give a diastereomeric mixture [III] [III '] of eneacetals, respectively.

This reaction is usually carried out in an organic solvent in the presence of an acid catalyst. Examples of the acid catalyst to be used include organic acids such as p-toluenesulfonic acid pyridine salt (PPTS), p-toluenesulfonic acid and camphorsulfonic acid; Lewis acids such as trifluoroborane ether complex and trimethylsilyl trifluoromethanesulfonic acid; hydrochloric acid; Mineral acids such as sulfuric acid and phosphoric acid can be mentioned, and among them, PPTS is preferable. The addition amount of the acid catalyst is preferably 0.05 to 0.5 equivalent to 1 equivalent of norbornene aldehyde.

Examples of the organic solvent include aromatic solvents such as benzene and toluene; ether solvents such as diethyl ether and tetrahydrofuran; ketone solvents such as acetone; nitrile solvents such as acetonitrile; N, N-dimethylformamide and the like. Aprotic polar solvents,
Among them, aromatic solvents are particularly preferred. Reaction temperature is 0 ° C
To the reflux temperature of the solvent, but is preferably room temperature.

Subsequently, in the second step of the method (a), the first step
The diastereomer mixture [III] [III '] of the eneacetals obtained in the step is prepared in an organic solvent in the presence of a halogenating agent, an alcohol (R ² OH) or water, and optionally in the presence of a base. And haloetherification. Thus, when an alcohol is used, the haloethers [I
V] is produced, and eneacetals [III ′] remain.
When water is used, haloethers [V] are generated, and eneacetals [III '] remain. Thus, the haloethers [IV] or the haloethers [V] and the eneacetals [III '] are stereoselectively obtained. Haloethers [IV] or haloethers [V] and eneacetals [III '] can be obtained by separating them by a common separation method such as distillation or recrystallization, silica gel column chromatography or the like.

Examples of the halogenating agent used in this reaction include N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS), and among them, NBS is preferable. . The amount of the halogenating agent to be used is 0.5 equivalent to 1 equivalent of eneacetals.

When an alcohol (R ² OH) is used in this reaction, R ² is a lower alkyl group and is a straight-chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isobutyl, t-butyl, sec-butyl and the like. Examples are a chain or branched alkyl group. As the alcohol, methanol, ethanol, isopropanol and the like are preferable, and among them, methanol is particularly preferable. The amount of the alcohol used is 0.5 equivalent or more with respect to 1 equivalent of the ene acetal, but preferably about 5 equivalent. When water is used for the reaction, the amount used is preferably about 1% based on the solvent.

When a base is used in this reaction, examples of the base include pyridine, lutidine, γ-collidine and the like, among which γ-collidine is preferable. The amount of the base used is about 0.5 equivalent to 1 equivalent of eneacetals.

Examples of the organic solvent include nitrile solvents such as acetonitrile; aromatic solvents such as benzene and toluene;
Ether solvents such as diethyl ether and tetrahydrofuran; ketone solvents such as acetone; aprotic polar solvents such as N, N-dimethylformamide;
Of these, nitrile solvents are particularly preferred.

Next, the method (b) will be described in detail.

First, in the first step of the method (b), the haloethers [V] obtained in the second step of the method (a) are
By reacting the meso-1,2-diols [VI], the haloethers [V] are converted to acetals [VII].

This reaction is usually carried out in an organic solvent in the presence of an acid catalyst. Examples of the acid catalyst to be used include organic acids such as p-toluenesulfonic acid pyridine salt (PPTS), p-toluenesulfonic acid and camphorsulfonic acid; Lewis acids such as trifluoroborane ether complex and trimethylsilyl trifluoromethanesulfonic acid; hydrochloric acid; Mineral acids such as sulfuric acid and phosphoric acid can be mentioned, and among them, PPTS is preferable. The addition amount of the acid catalyst is preferably 0.05 to 0.5 equivalent based on 1 equivalent of the haloethers [V].

Examples of the organic solvent include aromatic solvents such as benzene and toluene; ether solvents such as diethyl ether and tetrahydrofuran; ketone solvents such as acetone; nitrile solvents such as acetonitrile; N, N-dimethylformamide and the like. Aprotic polar solvents,
Among them, aromatic solvents are particularly preferred. Reaction temperature is 0 ° C
To the reflux temperature of the solvent, but is preferably room temperature.

Subsequently, in the second step of the method (b), the acetal [VII] obtained in the first step of the method (b) is dehaloetherified to lead to an eneacetal [VIII].

This dehaloetherification reaction is usually carried out reductively by reflux in an organic solvent in the presence of a reducing agent and a Lewis acid catalyst.

As the reducing agent used, zinc is preferred. Examples of the Lewis acid catalyst include trifluoroborane ether complex, titanium tetrachloride, tin tetrachloride aluminum chloride, magnesium bromide ether complex, diethylaluminum chloride, zinc bromide, zinc chloride, zinc trifluoromethanesulfonate, and zinc tetrafluoroborane. But
Among them, zinc trifluoromethanesulfonate is preferred. The amount of the reducing agent and the Lewis acid catalyst to be used is at least 1 equivalent to 1 equivalent of the acetal [VII], but preferably about 30 equivalents of the reducing agent and about 10 equivalents of the Lewis acid. Most preferably, N, N-dimethylacetamide is used as the solvent.

Finally, the method (c) will be described in detail.

First, in the first step of the method (c), the eneacetals [III '] obtained in the second step of the method (a) are used.
Are converted into haloethers [V '] by an intramolecular haloetherification reaction.

This reaction is usually carried out in an organic solvent in the presence of a halogenating agent and water.

As the halogenating agent to be used, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS)
And the like, among which NBS is preferable. The amount of the halogenating agent to be used is preferably about 1.2 equivalents to 1 equivalent of eneacetals [III ']. The amount of water used for the reaction is preferably about 5% based on the solvent.

Examples of the organic solvent include nitrile solvents such as acetonitrile; aromatic solvents such as benzene and toluene;
Ether solvents such as diethyl ether and tetrahydrofuran; ketone solvents such as acetone; aprotic polar solvents such as N, N-dimethylformamide;
Of these, nitrile solvents are particularly preferred.

Subsequently, in the second step of the method (c), the haloethers [V '] obtained in the first step of the method (c) are acetalized with the meso-1,2-diols [VI]. By reacting, acetal [VII '] is obtained.

This reaction is usually carried out in an organic solvent in the presence of an acid catalyst. The acid catalyst used in this reaction includes:
p-Toluenesulfonic acid pyridine salt (PPTS), p-
Organic acids such as toluenesulfonic acid and camphorsulfonic acid; Lewis acids such as trifluoroborane ether complex and trimethylsilyl trifluoromethanesulfonate; hydrochloric acid;
Mineral acids such as sulfuric acid and phosphoric acid;
S is preferred. The addition amount of the acid catalyst is preferably 0.05 to 0.5 equivalent to 1 equivalent of the haloether.

Examples of the organic solvent include aromatic solvents such as benzene and toluene; ether solvents such as diethyl ether and tetrahydrofuran; ketone solvents such as acetone; nitrile solvents such as acetonitrile; N, N-dimethylformamide and the like. Aprotic polar solvents,
Among them, aromatic solvents are particularly preferred. Reaction temperature is 0 ° C
To the reflux temperature of the solvent, but is preferably room temperature.

Finally, in the third step of the method (c), the acetal [VII '] obtained in the second step of the method (c) is dehaloetherified to lead to an eneacetal [VIII'].

This dehaloetherification reaction is usually carried out reductively by reflux in an organic solvent in the presence of a reducing agent and a Lewis acid catalyst. As a reducing agent used in this reaction, zinc is preferable. Examples of the Lewis acid catalyst include trifluoroborane ether complex, titanium tetrachloride, tin tetrachloride aluminum chloride, magnesium bromide ether complex, diethylaluminum chloride, zinc bromide, zinc chloride, zinc trifluoromethanesulfonate, and zinc tetrafluoroborane. Among them, zinc trifluoromethanesulfonate is preferable. The amount of the reducing agent and the Lewis acid catalyst to be used is at least 1 equivalent to 1 equivalent of the acetal [VII '], preferably about 30 equivalents of the reducing agent and about 1 equivalent of the Lewis acid.
It is 0 equivalent. Most preferably, N, N-dimethylacetamide is used as the solvent.

Thus, the method according to the invention makes it possible to optically resolve norbornene aldehydes.

[0052]

According to the present invention, it is possible to obtain optically active norbornene aldehydes useful as intermediates for various chemical products such as medicines and agricultural chemicals and as optical resolution aids in very high yield and high enantioselectivity. it can. In particular, this method is industrially useful because it does not require a special chiral ligand and has no complicated reaction mechanism. In addition, the present method can be used in the synthesis of optically active alcohols, since the method can be shifted to the optical resolution method of meso-1,2-diol without isolating highly volatile norbornene aldehyde.

[0053]

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

In the following examples, step i) is a method for synthesizing eneacetals [III] and [III '] by acetalization of racemic enaldehydes [I] and [I'], and step ii) is eneacetal Classes [III] and [II
Haloethers [IV] and eneacetals [III '] by haloetherification reaction of I'] in the presence of alcohol
Step iii) of the synthesis and isolation of
II] and [III '] by the haloetherification reaction in the presence of water to synthesize and isolate haloethers [V] and eneacetals [III']. Method for synthesizing acetal [VII] by acetalization with meso-1,2-diols [VI], step v)
Is a method for synthesizing eneacetals [VIII] by dehaloetherification of acetal [VII], and step vi) is a method for synthesizing haloethers [V '] by haloetherification of eneacetals [III']. Step vii) is a method for synthesizing acetal [VII '] by an acetalization reaction between haloether [V'] and meso-1,2-diol [VI].
viii) corresponds to the synthesis reaction of the eneacetals [VIII '] by the dehaloetherification reaction of the acetals [VII'], respectively.

Example 1 Optical Resolution of 3-Methylbicyclo [2.2.1] hept-5-ene-2-carboxaldehyde Step i) (4S, 5S) -4,5-diphenyl-2-[(1S, 2S, 3R, 4R) −
3-methylbicyclo [2.2.1] hept-5-en-2-yl] -1,3-dioxolane and (4S, 5S) -4,5-
Synthesis of a mixture of diphenyl-2-[(1R, 2R, 3S, 4S) -3-methylbicyclo [2.2.1] hept-5-en-2-yl] -1,3-dioxolane

Embedded image

Under a nitrogen atmosphere, (1S, 2S, 3R, 4R) -3-methylbicyclo [2.2.1] hept-5-ene-2-carboxaldehyde and (1R, 2R, 3S, 4S) -3- Methyl bicyclo [2.
2.1] To a benzene solution (42 ml) of a mixture of hept-5-en-2-carboxaldehyde (578 mg, 4.24 mmol) was added (1S, 2S) -1,2-diphenyl-1,
2-ethanediol (909 mg, 4.24 mmol)
And a catalytic amount of pyridine p-toluenesulfonate (PPTS) was added, and the whole was stirred at room temperature for 12 hours. Thereafter, aqueous sodium bicarbonate was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by flash chromatography (hexane: ethyl acetate = 10: 1), and (4S,
5S) -4,5-diphenyl-2-[(1S, 2S, 3R, 4R) -3-
Methylbicyclo [2.2.1] hept-5-en-2-yl]
-1,3-dioxolane and (4S, 5S) -4,5-diphenyl-2-[(1R, 2R, 3S, 4S) -3-methylbicyclo [2.
2.1] Hept-5-en-2-yl] diastereo mixture of 1,3-dioxolane (1.38 g, 4.15 mm
ol).

Colorless oily compound ¹ H-NMR δ (CDCl ₃ ): 7.37-7.18, 6.28, 6.1
4, 6.07, 4.90, 4.71, 3.04, 2.47, 1.92, 1.61-1.44,
1.27-1.19

Step ii) (1S, 2S, 3S, 5S, 6S, 8S, 9S, 10R, 12S) -2-bromo-8-methoxy-12-methyl-5,6-diphenyl-4,7-
Dioxatricyclo [7.2.1.0 ^{3, 10]} dodecane, and (4S, 5
S) -4,5-diphenyl-2-[(1R, 2R, 3S, 4S) -3-
Methylbicyclo [2.2.1] hept-5-en-2-yl]
Synthesis of -1,3-dioxolan

Embedded image

Under a nitrogen atmosphere, (4S, 5S) -4,5-diphenyl-2-[(1S, 2S, 3R, 4R) -3-methylbicyclo [2.2.
1] Hept-5-en-2-yl] -1,3-dioxolane and (4S, 5S) -4,5-diphenyl-2-[(1R, 2R,
To a solution (6.1 ml) of a diastereomeric mixture of (3S, 4S) -3-methylbicyclo [2.2.1] hept-5-en-2-yl] -1,3-dioxolane (202 mg, 0.608 mmol) in acetonitrile. , Methanol (0.12m
1, 2.96 mmol) and γ-collidine (2,4,4).
6-trimethylpyridine, 0.04 ml, 0.303 m
mol) was added and the whole was cooled to -40 ° C. To the solution was added N-bromosuccinimide (NBS, 54 mg, 0.1 mL).
303 mmol), and the whole was gradually heated to room temperature while stirring.

After confirming the completion of the reaction by TLC, hypo water (saturated thiosulfuric acid aqueous solution) was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (hexane: ethyl acetate = 15: 1), and (1S, 2S, 3S, 5S, 6S, 8S, 9S, 10R, 12
S) -2-Bromo-8-methoxy-12-methyl-5,6
-Diphenyl-4,7-dioxatricyclo [7.2.1.0
^{3, 10]} dodecane (93.3mg, 0.210mmol)
And (4S, 5S) -4,5-diphenyl-2-[(1R, 2R, 3
(S, 4S) -3-Methylbicyclo [2.2.1] hept-5-ene-
2-yl] -1,3-dioxolane (102.8 mg,
0.310 mmol, diastereomer excess 99% or more).

(1S, 2S, 3S, 5S, 6S, 8S, 9S, 10R, 12S) -2-bromo-8-methoxy-12-methyl-5,6-diphenyl-4,7-dioxatricyclo [ 7.2.1.0 ^{3, 10]} dodecane white solid

¹ H-NMR δ (CDCl ₃ ): 7.16-6.8
6 (10H, m), 5.19 (1H, d), 4.45 (1H, t), 4.42 (1H, d), 4.34
(1H, d), 3.85 (1H, t), 3.28 (3H, s), 3.00 (1H, bs), 2.22
(1H, bs), 1.94-1.90 (2H, m), 1.71-1.59 (2H, m), 1.10 (3
H, d)

¹³ C-NMR δ (CDCl ₃ ): 138.25,
137.87, 127.77, 127.67, 127.55, 127.47, 127.35, 12
7.13, 110.10, 91.51, 88.35, 86.73, 57.85, 54.89, 5
4.36,52.94, 45.36, 41.40, 32.08, 21.39

(4S, 5S) -4,5-diphenyl-2-[(1
(R, 2R, 3S, 4S) -3-methylbicyclo [2.2.1] hept-5-
En-2-yl] -1,3-dioxolane

Colorless oily compound ¹ H-NMR δ (CDCl ₃ ): 7.35-7.18 (10H, m), 6.
27 (1H, dd), 6.07 (1H, dd), 4.90 (1H, d), 4.70 (2H, m), 3.
04 (1H, bs), 2.46 (1H, bs), 1.91 (1H, m), 1.61-1.44 (3H,
m), 1.20 (3H, d)

¹³ C-NMR δ (CDCl ₃ ): 138.59,
138.19, 137.20, 133.04, 128.40, 128.37, 128.21, 12
7.88, 126.70, 126.30, 109.64, 86.63, 64.72, 52.99,
48.80, 46.15, 44.71, 36.38, 21.64

Step iii) (1R, 2S, 3S, 4S, 5S, 6S) -5-bromo-6-[(1S, 2S) -2
-Hydroxy-1,2-diphenylethyl] oxy-3
-Methylbicyclo [2.2.1] heptane-2-carbaldehyde and (4S, 5S) -4,5-diphenyl-2-[(1R, 2R,
Synthesis of 3S, 4S) -3-methylbicyclo [2.2.1] hept-5-en-2-yl] -1,3-dioxolan

Embedded image

Under a nitrogen atmosphere, (4S, 5S) -4,5-diphenyl-2-[(1S, 2S, 3R, 4R) -3-methylbicyclo [2.2.
1] Hept-5-en-2-yl] -1,3-dioxolane and (4S, 5S) -4,5-diphenyl-2-[(1R, 2R,
A 1% aqueous acetonitrile solution of a diastereomeric mixture of (3S, 4S) -3-methylbicyclo [2.2.1] hept-5-en-2-yl] -1,3-dioxolane (203 mg, 0.61 mmol) (6. N-bromosuccinimide (NBS, 54 mg, 0.305 mmol) was added to 1 ml), and the whole was stirred at room temperature for 6 hours.

After confirming the completion of the reaction by TLC, hypo-water (saturated thiosulfuric acid aqueous solution) was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (hexane: ethyl acetate = 5: 1) to give (1R, 2S, 3S, 4S, 5S, 6S) -5-bromo-6-[(1S, 2S) -2- Hydroxy-1,2-diphenylethyl] oxy-3-methylbicyclo [2.2.1] heptane-2-carbaldehyde (115.6 mg, 0.27
mmol) and (4S, 5S) -4,5-diphenyl-2-
[(1R, 2R, 3S, 4S) -3-methylbicyclo [2.2.1] hept-
5-en-2-yl] -1,3-dioxolane (10
2.2 mg, 0.31 mmol, diastereomer excess 95%).

(1R, 2S, 3S, 4S, 5S, 6S) -5-bromo-6
[(1S, 2S) -2-hydroxy-1,2-diphenylethyl] oxy-3-methylbicyclo [2.2.1] heptane-2
-Carbaldehyde colorless oily compound

¹ H-NMR δ (CDCl ₃ ): 10.02 (1
H, s), 7.24-6.96 (10H, m), 4.65 (1H, d), 4.34 (1H, d), 4.3
1 (1H, d), 3.36 (1H, t), 3.10-2.75 (2H, m), 2.19-2.18 (2
H, m), 2.08 (1H, s), 1.86 (1H, dd), 1.65-1.60 (1H, m), 1.
04 (3H, d)

¹³ C-NMR δ (CDCl ₃ ): 202.25,
138.83, 137.71, 128.19, 128.11, 127.99, 1 27.85, 1
27.72, 126.93, 91.25, 89.06, 78.36, 59.98, 55.91,
52.80, 45.97, 35.15, 32.32, 21.24.

(4S, 5S) -4,5-diphenyl-2-[(1
(R, 2R, 3S, 4S) -3-methylbicyclo [2.2.1] hept-5-
En-2-yl] -1,3-dioxolane colorless oily compound

¹ H-NMR δ (CDCl ₃ ): 7.35-7.1
8 (10H, m), 6.27 (1H, dd), 6.07 (1H, dd), 4.90 (1H, d), 4.
70 (2H, m), 3.04 (1H, bs), 2.46 (1H, bs), 1.91 (1H, m), 1.6
1-1.44 (3H, m), 1.20 (3H, d)

¹³ C-NMR δ (CDCl ₃ ): 138.59,
138.19, 137.20, 133.04, 128.40, 128.37, 128.21, 12
7.88, 126.70, 126.30, 109.64, 86.63, 64.72, 52.99,
48.80, 46.15, 44.71, 36.38, 21.64

Step iv) (1S, 2S) -2-[(1R, 2S, 3S, 4S, 5S, 6S) -3-bromo-6
-(C-4, c-5-Dimethyl-1,3-dioxolan-r-2-yl) -5-methylbicyclo [2.2.1] hept-2-yloxy] -1,2-diphenyl-1-ethanol Synthesis of

Embedded image

Under a nitrogen atmosphere, (1R, 2S, 3S, 4S, 5S, 6S) -5
-Bromo-6-[(1S, 2S) -2-hydroxy-1,2-
Diphenylethyl] oxy-3-methylbicyclo [2.2.
1] Heptane-2-carbaldehyde (91 mg, 0.21
(1 mmol) in a benzene solution (2.1 ml).
R, 3S) -butanediol (19 mg, 0.211 m
mol), a catalytic amount of PPTS was further added, and the whole was stirred at room temperature for 12 hours.

Thereafter, aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (hexane: ethyl acetate = 10: 1) to give (1S, 2S) -2-[(1R, 2S,
3S, 4S, 5S, 6S) -3-Bromo-6- (c-4, c-5-dimethyl-1,3-dioxolan-r-2-yl) -5
Methylbicyclo [2.2.1] hept-2-yloxy]-
1,2-diphenyl-1-ethanol (92 mg, 0.
18 mmol).

(1S, 2S) -2-[(1R, 2S, 3S, 4S, 5S, 6S) -3
-Bromo-6- (c-4, c-5-dimethyl-1,3-
Dioxolan-r-2-yl) -5-methylbicyclo
[2.2.1] Hept-2-yloxy] -1,2-diphenyl-1-ethanol Colorless oily compound

¹ H-NMR δ (CDCl ₃ ): 7.18-6.9
7 (10H, m), 5.39-5.34 (2H, m), 4.64 (1H, d), 4.26−4.15
(4H, m), 3.45 (1H, t), 2.76 (1H, bs), 2.05 (1H, bs), 1.71
−1.48 (4H, m), 1.17 (6H, t), 1.08 (3H, d)

¹³ C-NMR δ (CDCl ₃ ): 139.10,
138.31, 127.76, 127.69, 127.52, 127.22, 127.03, 10
5.31, 92.79, 91.15, 78.58, 74.77, 74.26, 58.05, 5
4.06, 53.78, 45.19, 39.72, 32.03, 21.00, 15.78, 1
5.26

Step v) c-4, c-5-dimethyl-r-2-[(1S, 2S,
3R, 4R) -3-Methylbicyclo [2.2.1] hept-5
-En-2-yl] -1,3-dioxolane

Embedded image

Under a nitrogen atmosphere, (1S, 2S) -2-[(1R, 2S, 3
(S, 4S, 5S, 6S) -3-bromo-6- (c-4, c-5-dimethyl-1,3-dioxolan-r-2-yl) -5
Methylbicyclo [2.2.1] hept-2-yloxy]-
1,2-diphenyl-1-ethanol (11.7 mg,
0.0233 mmol) to an N, N-dimethylacetamide solution (0.2 ml), zinc trifluoromethanesulfonate (85 mg, 0.234 mmol) was added, and the whole was heated to 40 ° C. and stirred for 50 minutes. Powder (46 mg, 0.70 mmol) was added and the whole was brought to 85 ° C.
For 10 hours.

After confirming the completion of the reaction by TLC, ethyl acetate was added, and the precipitated salt and zinc were separated by filtration. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate,
It was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (hexane: ethyl acetate = 15: 1), and c
-4, c-5-dimethyl-r-2-[(1S, 2S, 3R, 4R)-
3-methylbicyclo [2.2.1] hept-5-en-2-yl] -1,3-dioxolane (3.6 mg, 0.017
3 mmol) and (1S, 2S) -1,2-diphenyl-1,2-ethanediol (3.9 mg, 0.018)
2 mmol).

C-4, c-5-Dimethyl-r-2-[(1
(S, 2S, 3R, 4R) -3-Methylbicyclo [2.2.1] hept-5-
En-2-yl] -1,3-dioxolane colorless oily compound

¹ H-NMR δ (CDCl ₃ ): 6.19 (1H,
dd), 6.00 (1H, dd), 4.25 (1H, d), 4.05 (2H, qd), 2.90 (1
H, bs), 2.39 (1H, bs), 1.59-1.26 (4H, m), 1.17-1.14 (6H,
m), 1.12 (3H, d)

¹³ C-NMR δ (CDCl ₃ ): 138.17,
133.05, 107.08, 74.39, 74.29, 53.44, 48.63, 46.00,
44.69, 36.37, 21.40, 15.73, 15.46

(1S, 2S) -1,2-diphenyl-1,2-
Ethanediol white solid

¹ H-NMR δ (CDCl ₃ ): 7.25-7.1
0 (10H, m), 4.70 (2H, s), 2.91 (2H, s)

Step vi) (1S, 2R, 3R, 4R, 5R, 6R) -5-bromo-6-[(1S, 2S) -2
-Hydroxy-1,2-diphenylethyl] oxy-3
Of -Methylbicyclo [2.2.1] heptane-2-carbaldehyde

Embedded image

Under a nitrogen atmosphere, (4S, 5S) -4,5-diphenyl-2-[(1R, 2R, 3S, 4S) -3-methylbicyclo [2.2.
1] Hept-5-en-2-yl] -1,3-dioxolane (23.7 mg, 0.071 mmol) in 5% aqueous acetonitrile (0.7 ml) was added to N-bromosuccinimide (NBS, 15. 2mg, 0.085mmo
1) was added and the whole was stirred at room temperature for 6 hours.

After confirming the completion of the reaction by TLC, hypo-water (saturated thiosulfuric acid aqueous solution) was added to the reaction solution, and the solution was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (hexane: ethyl acetate = 5: 1) to give (1S, 2R, 3R, 4R, 5R, 6R) -5.
-Bromo-6-[(1S, 2S) -2-hydroxy-1,2-
Diphenylethyl] oxy-3-methylbicyclo [2.2.
1] Heptane-2-carbaldehyde (19 mg, 0.04
4 mmol) were obtained.

(1S, 2R, 3R, 4R, 5R, 6R) -5-bromo-6-
[(1S, 2S) -2-hydroxy-1,2-diphenylethyl] oxy-3-methylbicyclo [2.2.1] heptane-2
-Carbaldehyde colorless oily compound

¹ H-NMR δ (CDCl ₃ ): 10.00 (1
H, s), 7.25-6.95 (10H, m), 4.59 (1H, dd), 4.41 (1H, d),
4.08 (1H, d), 3.88 (1H, bs), 3.07 (1H, d), 2.93 (1H, bs),
2.46 (1H, m), 2.26-2.23 (2H, m), 1.88 (1H, d), 1.66 (1H,
d), 1.07 (3H, d)

¹³ C-NMR δ (CDCl ₃ ): 202.77,
138.53, 136.45, 128.18, 128.12, 127.96, 127.80, 12
7.68, 127.49, 126.96, 86.66, 86.21, 78.00, 60.73,
55.28,52.72, 45.72, 33.94, 32.88, 21.14

Step vii) (1S, 2S) -2-[(1S, 2R, 3R, 4R, 5R, 6R) -3-bromo-6
-(C-4, c-5-Dimethyl-1,3-dioxolan-r-2-yl) -5-methylbicyclo [2.2.1] hept-2-yloxy] -1,2-diphenyl-1-ethanol Synthesis of

Embedded image

Under a nitrogen atmosphere, (1S, 2R, 3R, 4R, 5R, 6R) -5
-Bromo-6-[(1S, 2S) -2-hydroxy-1,2-
Diphenylethyl] oxy-3-methylbicyclo [2.2.
1] Heptane-2-carbaldehyde (22.5 mg, 0.
052 mmol) in a benzene solution (0.5 ml).
(R, 3S) -butanediol (7.1 mg, 0.079 mm
ol), a catalytic amount of PPTS was further added, and the whole was stirred at room temperature for 12 hours. Thereafter, aqueous sodium bicarbonate was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (hexane: ethyl acetate = 10: 1) to give (1S, 2S)-
2-[(1S, 2R, 3R, 4R, 5R, 6R) -3-bromo-6- (c-
4, c-5-dimethyl-1,3-dioxolane-r-2
-Yl) -5-methylbicyclo [2.2.1] hept-2-yloxy] -1,2-diphenyl-1-ethanol (2
(3.3 mg, 0.046 mmol).

(1S, 2S) -2-[(1S, 2R, 3R, 4R, 5R, 6R) -3
-Bromo-6- (c-4, c-5-dimethyl-1,3-
Dioxolan-r-2-yl) -5-methylbicyclo
[2.2.1] Hept-2-yloxy] -1,2-diphenyl-1-ethanol Colorless oily compound

¹ H-NMR δ (CDCl ₃ ): 7.21-7.0
5 (10H, m), 5.40-5.39 (2H, m), 4.58 (2H, s), 4.16-4.01 (3
H, m), 3.88 (1H, t), 2.39 (1H, bs), 2.14-2.11 (2H, m), 1.
88 (1H, m), 1.69 (1H, dd), 1.52 (1H, d), 1.21-1.17 (6H,
m), 1.04 (3H, d)

¹³ C-NMR δ (CDCl ₃ ): 139.55,
137.20, 128.09, 127.96, 127.93, 127.83, 127.50, 12
7.16, 103.87, 87.32, 85.89, 78.46, 74.91, 73.74, 5
6.61,53.90, 51.81, 45.96, 35.59, 32.61, 21.80, 15.
85, 15.01

Step viii) c-4, c-5-dimethyl-r-2-[(1R, 2R, 3S, 4
S) -3-Methylbicyclo [2.2.1] hept-5-ene-2
-Yl] -1,3-Dioxolane

Embedded image

Under a nitrogen atmosphere, (1S, 2S) -2-[(1S, 2R, 3
R, 4R, 5R, 6R) -3-bromo-6- (c-4, c-5-dimethyl-1,3-dioxolan-r-2-yl) -5
Methylbicyclo [2.2.1] hept-2-yloxy]-
1,2-diphenyl-1-ethanol (5.0 mg,
0.010 mmol) to an N, N-dimethylacetamide solution (0.1 ml), zinc trifluoromethanesulfonate (36 mg, 0.10 mmol) was added, and
After heating to 0 ° C and stirring for 50 minutes, zinc dust (26
mg, 0.40 mmol).
Stirred at C for 10 hours.

After confirming the completion of the reaction by TLC, ethyl acetate was added to the reaction solution, and the precipitated salt and zinc were separated by filtration.
The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (hexane: ethyl acetate = 15: 1), and c-4, c-5-dimethyl-r-2-[(1R, 2R, 3
(S, 4S) -3-Methylbicyclo [2.2.1] hept-5-ene-
2-yl] -1,3-dioxolane (1.1 mg, 0.1 mg).
0053 mmol) and (1S, 2S) -1,2-diphenyl-1,2-ethanediol (1.1 mg, 0.005
1 mmol).

C-4, c-5-Dimethyl-r-2-[(1
(R, 2R, 3S, 4S) -3-methylbicyclo [2.2.1] hept-5-
En-2-yl] -1,3-dioxolane colorless oily compound

¹ H-NMR δ (CDCl ₃ ): 6.19 (1H,
dd), 6.00 (1H, dd), 4.25 (1H, d), 4.05 (2H, qd), 2.90 (1
H, bs), 2.39 (1H, bs), 1.59-1.26 (4H, m), 1.17-1.14 (6
H, m), 1.12 (3H, d)

¹³ C-NMR δ (CDCl ₃ ): 138.17,
133.05, 107.08, 74.39, 74.29, 53.44, 48.63, 46.00,
44.69, 36.37, 21.40, 15.73, 15.46

(1S, 2S) -1,2-diphenyl-1,2-
Ethanediol white solid ¹ H-NMRδ (CDCl ₃ ): 7.25-7.10 (10H, m),
4.70 (2H, s), 2.91 (2H, s)

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) C07D 321/12 C07D 321/12 // C07M 7:00 F term (reference) 4H006 AA01 AA02 AB84 AC41 AC43 AC45 AC81 BE60

Claims (19)

[Claims] 1. The compounds of the general formulas [I] and [I '] The 2-end form of racemic norbornene aldehydes represented by the general formula [II] By reacting an optically active C2-symmetrical 1,2-diol represented by the general formulas [III] and [III ']: To form a diastereomeric mixture of eneacetals represented by the formula
⁽ OH) to form a haloether represented by the general formula [IV] in a stereoselective manner while leaving the eneacetals [III '] or a mixture thereof. Is intramolecularly haloetherified in the presence of a halogenating agent and water to stereoselectively form a haloether represented by the general formula [V] and leave the eneacetals [III ']. Characteristic manufacturing method. Embedded image (Wherein, R and R ¹ are the same, and R is a hydrogen atom or a lower alkyl group;
¹ represents an aryl group which may have a substituent group, R ²
Is a lower alkyl group, and X is a halogen atom. ) 2. Formulas [III] and [III '] A diastereomeric mixture of eneacetals represented by the formula is converted into an intramolecular haloether in the presence of a halogenating agent and an alcohol (R ² OH) to stereoselectively produce a haloether represented by the general formula [IV] Or leaving the above eneacetals [III '], or by subjecting the mixture to intramolecular haloetherification in the presence of a halogenating agent and water to convert the haloethers represented by the general formula [V] into steric compounds. And the eneacetals [II
I ′]. Embedded image (Wherein, R and R ¹ are the same, and R is a hydrogen atom or a lower alkyl group;
¹ represents an aryl group which may have a substituent group, R ²
Is a lower alkyl group, and X is a halogen atom. ) 3. A compound of the general formula [IV] Haloethers represented by (Wherein, R is a hydrogen atom or a lower alkyl group, R ¹ is the same aryl group which may have a substituent, and R ²
Is a lower alkyl group, and X is a halogen atom. ) 4. A compound of the general formula [V] Haloethers represented by (In the formula, R is a hydrogen atom or a lower alkyl group, R ¹ is the same and may be an aryl group which may have a substituent, and X is a halogen atom.) 5. General formulas [I] and [I '] The 2-end form of racemic norbornene aldehydes represented by the general formula [II] By reacting an optically active C2-symmetrical 1,2-diol represented by the general formulas [III] and [III ']: A diastereomeric mixture of eneacetals represented by the formula: (Wherein, R and R ¹ are the same, R is a hydrogen atom or a lower alkyl group, and R ¹ is an aryl group which may have a substituent.) 6. A diastereomeric mixture of eneacetals represented by the general formulas [III] and [III ′]. Embedded image (In the formula, R ¹ is the same, R is a hydrogen atom or a lower alkyl group, and R ¹ is an aryl group which may have a substituent.) 7. A compound of the general formula [III ′] Enacetals represented by (In the formula, R ¹ is the same, R is a hydrogen atom or a lower alkyl group, and R ¹ is an aryl group which may have a substituent.) 8. A compound of the general formula [V] To the haloethers represented by the general formula [VI] The haloethers [V] are reacted with a meso-1,2-diol represented by the general formula [VII] Acetals represented by the general formula [VIII] are obtained by a dehaloetherification reaction. A method for producing eneacetals, which leads to eneacetals represented by the formula: Wherein R ¹ and R ³ are the same, R is a hydrogen atom or a lower alkyl group, R ¹ is an aryl group which may have a substituent, and R ³ is A lower alkyl group or a lower alkenyl group which may have a group, a lower alkoxycarbonyl group, an amino group protected by a protecting group, a cyano group, or an aryl group which may have a substituent, and X is It is a halogen atom.) 9. A compound of the general formula [VII] The acetal represented by the general formula [VIII] is obtained by a dehaloetherification reaction. A method for producing eneacetals, which leads to eneacetals represented by the formula: Wherein R ¹ and R ³ are the same, R is a hydrogen atom or a lower alkyl group, R ¹ is an aryl group which may have a substituent, and R ³ is A lower alkyl group or a lower alkenyl group which may have a group, a lower alkoxycarbonyl group, an amino group protected by a protecting group, a cyano group, or an aryl group which may have a substituent, and X is It is a halogen atom.) 10. The general formula [V] To the haloethers represented by the general formula [VI] The haloethers [V] are reacted with a meso-1,2-diol represented by the general formula [VII]. A method for producing an acetal, which is an acetal represented by the formula: (Wherein, R, R ¹ and R ³ are the same, R is a hydrogen atom or a lower alkyl group, R ¹ is an aryl group which may have a substituent, ³ is a lower alkyl group or a lower alkenyl group which may have a substituent, a lower alkoxycarbonyl group, an amino group protected by a protecting group, a cyano group, or an aryl group which may have a substituent. , X is a halogen atom.) 11. A compound of the general formula [VII] Acetals represented by (Wherein R ¹ and R
³ are the same, R is a hydrogen atom or a lower alkyl group, R ¹ is an aryl group which may have a substituent, and R ³ is a lower group which may have a substituent. An alkyl group or a lower alkenyl group, a lower alkoxycarbonyl group, an amino group protected by a protecting group, a cyano group, or an aryl group which may have a substituent, and X is a halogen atom. ) 12. A compound of the general formula [III ′] Is converted into an intramolecular haloether in the presence of a halogenating agent and water to give a general formula [V '] Represented by the general formula [VI]: By reacting with a meso-1,2-diol represented by the general formula [VII '] An acetal represented by the general formula [VIII ′] is obtained by a dehaloetherification reaction. A method for producing eneacetals, which leads to eneacetals represented by the formula: Wherein R ¹ and R ³ are the same, R is a hydrogen atom or a lower alkyl group, R ¹ is an aryl group which may have a substituent, and R ³ is A lower alkyl group or a lower alkenyl group which may have a group, a lower alkoxycarbonyl group, an amino group protected by a protecting group, a cyano group, or an aryl group which may have a substituent, and X is It is a halogen atom.) 13. A compound of the general formula [VII '] An acetal represented by the general formula [VIII '] is obtained by a dehaloetherification reaction. A method for producing eneacetals, which leads to eneacetals represented by the formula: Wherein R ¹ and R ³ are the same, R is a hydrogen atom or a lower alkyl group, R ¹ is an aryl group which may have a substituent, and R ³ is A lower alkyl group or a lower alkenyl group which may have a group, a lower alkoxycarbonyl group, an amino group protected by a protecting group, a cyano group, or an aryl group which may have a substituent, and X is It is a halogen atom.) 14. A compound of the general formula [V ′] A haloether represented by the general formula [VI] By reacting with a meso-1,2-diol represented by the general formula [VII '] A method for producing an acetal, which is an acetal represented by the formula: 15. A compound of the general formula [VII ′] Acetals represented by (Wherein R ¹ and R
³ is a what is the same, respectively, R is a hydrogen atom or a lower alkyl group, R ¹ is an aryl group which may have a substituent, R ³ is lower which may have a substituent An alkyl group or a lower alkenyl group, a lower alkoxycarbonyl group, an amino group protected by a protecting group, a cyano group, or an aryl group which may have a substituent, and X is a halogen atom. ) 16. A compound of the general formula [III ′] Is converted into an intramolecular haloether in the presence of a halogenating agent and water to give a general formula [V '] A method for producing haloethers, characterized by being a haloether represented by the formula: (In the formula, R is a hydrogen atom or a lower alkyl group, R ¹ is the same and may be an aryl group which may have a substituent, and X is a halogen atom.) 17. A compound of the general formula [V ′] Haloethers represented by (In the formula, R is a hydrogen atom or a lower alkyl group, R ¹ is the same and may be an aryl group which may have a substituent, and X is a halogen atom.) 18. Formulas [I] and [I '] Embedded image to a 2-end body of a racemic norbornene aldehyde represented by the general formula [II]: By reacting an optically active C2-symmetric 1,2-diol represented by the general formulas [III] and [III ']: A diastereomeric mixture of eneacetals represented by the following formula is formed, and the mixture is subjected to intramolecular haloetherification in the presence of a halogenating agent and water to give a general formula [V]. And the eneacetals [III '] are left, and the resulting haloethers [V] are represented by the general formula [VI]. By reacting a meso-1,2-diol represented by the formula, the haloethers [V] are converted to a general formula [VII]. Acetals represented by the general formula [VIII] are obtained by a dehaloetherification reaction. A method for producing eneacetals, which leads to eneacetals represented by the formula: (Wherein, R, R ¹ and R ³ are the same, R is a hydrogen atom or a lower alkyl group, R ¹ is an aryl group which may have a substituent, ³ is a lower alkyl group or a lower alkenyl group which may have a substituent, a lower alkoxycarbonyl group, an amino group protected by a protecting group, a cyano group, or an aryl group which may have a substituent. , X is a halogen atom.) 19. The compounds of the general formulas [I] and [I '] Embedded image to a 2-endo compound of a racemic norbornene aldehyde represented by the general formula [II]: By reacting an optically active C2-symmetric 1,2-diol represented by the general formulas [III] and [III '] To form a diastereomeric mixture of eneacetals represented by the formula
⁽ OH) to form a haloether represented by the general formula [IV] in a stereoselective manner while leaving the eneacetals [III '] or a mixture thereof. Is subjected to intramolecular haloetherification in the presence of a halogenating agent and water to generate stereoselectively the haloethers represented by the general formula [V] and to leave the eneacetals [III '], 48 The remaining eneacetals [III '] are subjected to intramolecular haloetherification in the presence of a halogenating agent and water to give a general formula [V'] A haloether represented by the general formula [VI]: By reacting with a meso-1,2-diol represented by the general formula [VII '] An acetal represented by the general formula [VIII '] is obtained by a dehaloetherification reaction. A method for producing eneacetals, which leads to eneacetals represented by the formula: (Wherein, R, R ¹ and R ³ are the same, R is a hydrogen atom or a lower alkyl group, R ¹ is an aryl group which may have a substituent, ² is a lower alkyl group, and R ³ has a lower alkyl group or a lower alkenyl group which may have a substituent, a lower alkoxycarbonyl group, an amino group protected by a protecting group, a cyano group, or a substituent. And X is a halogen atom.)