JP2002326992A - N-spiro asymmetric phase transfer catalyst containing binaphthayl group and biphenyl group - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a binaphthyl group-containing N-spiro asymmetric phase transfer catalyst which is used for asymmetrically synthesizing various kinds of amino acid derivative without regard to natural or non-natural amino acid derivatives. SOLUTION: This new N-spiro asymmetric phase transfer catalyst contains a binaphthyl group and a biphenyl group in the structure and is useful for the selective synthesis, the so-called asymmetric synthesis, of optically active compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an N-spiro asymmetric phase transfer catalyst containing a binaphthyl group and a biphenyl group.
More specifically, the present invention relates to a novel phase transfer catalyst useful in so-called asymmetric synthesis for selectively synthesizing organic synthetic chemistry, particularly, an optically active compound.

[0002]

BACKGROUND OF THE INVENTION The present inventors have already synthesized a chiral N-spiro quaternary ammonium salt in which the conformation is fixed by two binaphthyl structures having axial asymmetry, and this is a steric N-protected glycine derivative. They have been found to act as effective asymmetric phase transfer catalysts for selective monoalkylation. This is well known to those skilled in the art (J.A.
m. Chem. Soc. 1999, 121, 6519-
6520).

Furthermore, it has been revealed that, for example, when 3,4,5-trifluorophenyl is introduced as a substituent on a binaphthyl ring, it is also effective for stereoselective dialkylation of an N-protected glycine derivative. (JA
m. Chem. Soc. 2000, 122, 5228-
5229).

Here, in order to ensure the stereoselectivity of the alkylation reaction, the conformation of a chiral N-spiro quaternary ammonium salt must be fixed by two binaphthyl structures having axial asymmetry. Was considered indispensable.

[0005]

SUMMARY OF THE INVENTION The present inventors have pursued the effect of the structure of the asymmetric phase transfer catalyst on the stereoselectivity of the alkylation reaction, and as a result of repeated studies, have reached the present invention. That is, an object of the present invention is to provide a novel phase transfer catalyst used in asymmetric synthesis of various amino acid derivatives, whether natural or unnatural. In particular, it is an object of the present invention to provide an N-spiro asymmetric phase transfer catalyst in which one of the binaphthyl structures of a conventional catalyst is replaced with a biphenyl structure, and also provides a method for stereoselective synthesis of amino acids using the novel catalyst. It is in.

[0006]

SUMMARY OF THE INVENTION The present invention is an N-spiro quaternary ammonium salt compound represented by formula (I):

[0007]

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In the formula, R ¹ is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; which may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom. Aryl group; or lower alkyl group, lower alkoxy group,
Or a heteroaryl group which may be substituted with a halogen atom, wherein R ² is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; a lower alkyl group, a lower alkoxy group; Or an aryl group optionally substituted with a halogen atom; an aryl group substituted with a lower alkyl group, a lower alkoxy group, or an aryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group,
Or an aryl group substituted with a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group A heteroaryl group substituted with an aryl group optionally substituted with a halogen atom; or a heteroaryl group substituted with a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom And X is a halogen atom.

In a preferred embodiment, in the above formula (I), R ¹ is a hydrogen atom or an organic residue having 4 to 10 carbon atoms, and R ² is a hydrogen atom or 4 to 20 carbon atoms. Is an organic residue having a carbon atom of

In a further preferred embodiment, the organic residue having 4 to 10 carbon atoms and the organic residue having 4 to 10 carbon atoms.
Organic residues having from 20 to 20 carbon atoms are both aromatic hydrocarbons.

In a preferred embodiment, X is Br.

In a preferred embodiment, in the above formula (I), R ¹ is a hydrogen atom or a phenyl group, and R ² is a β-naphthyl group or a 3,5-diphenylphenyl group.

The present invention is also a compound represented by formula (II):

[0014]

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In the formula, R ¹ is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; a lower alkyl group, a lower alkoxy group, and an aryl which may be substituted with a halogen atom. A lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom; R ² is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; A halogen atom; an aryl group optionally substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; an aryl substituted with an aryl group optionally substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom Group; substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom Even if it substituted with heteroaryl group, an aryl group, a lower alkyl group, a lower alkoxy group or optionally substituted with a halogen atom, a heteroaryl group; a lower alkyl group, a lower alkoxy group,
Or a heteroaryl group substituted with an aryl group optionally substituted with a halogen atom; or a heteroaryl group substituted with a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom. X (except when both R ¹ and R ² are hydrogen atoms), and X is a halogen atom.

The present invention also relates to a process for producing the compound represented by the above formula (I), which comprises the compound represented by the formula (II)

[0017]

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(Wherein R ¹ is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; even if it is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom). Good aryl groups; or lower alkyl groups, lower alkoxy groups,
Or a heteroaryl group which may be substituted with a halogen atom, wherein R ² is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; a lower alkyl group, a lower alkoxy group; Or an aryl group optionally substituted with a halogen atom; an aryl group substituted with a lower alkyl group, a lower alkoxy group, or an aryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group,
Or an aryl group substituted with a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group Or a heteroaryl group substituted with an aryl group optionally substituted with a halogen atom; or a heteroaryl group substituted with a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom. X is an aryl group, and X is a halogen atom. ) And a compound of formula (III):

[0019]

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Is reacted in an organic solvent in the presence of an acid scavenger.

In a preferred embodiment, X is Br.

In a preferred embodiment, R ¹ is a hydrogen atom and R ² is β-naphthyl or 3,5-diphenylphenyl.

In a preferred embodiment, R ¹ is phenyl and R ² is 3,5-diphenylphenyl.

The present invention also provides a compound represented by the formula (IV) in the presence of the compound represented by the above formula (I):

[0025]

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(Where R³And R⁴Are the same or different
Is a hydrogen atom or C₁~ C₃Archi
Group, C₁~ C₃With an alkoxy group or a halogen atom
An aryl group which may be substituted (provided that R³You
And R⁴Unless both are simultaneously hydrogen atoms);
R⁵Is a hydrogen atom or C₁~ C₃Alkyl group, C
₁~ C₃Substituted with an alkoxy group or a halogen atom
Is an optionally substituted aryl group or forms a branch or ring
C that may be₁~ C₆Is an alkyl group or
Is C₁~ C₃Alkyl group, C₁~ C₃An alkoxy group
Or an aralkyl group optionally substituted with a halogen atom
And R⁶Is C₁~ C₄Is an alkyl group)
With a compound of formula (V) in a solvent in the presence of an inorganic base:

[0027]

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(Where R⁷Is C₁~ C₆Branch of
Is an alkyl group which may form a ring;₃~ C₉Minute
Allyl group which may form a branch or ring or substitution
Allyl group; C₁~ C₄An alkyl group of C₁~ C₃Al
Coxy group, halogen atom or C₁~ C₄Archi
Group, C₁~ C₃An alkoxy group or a halogen atom
An aryl group optionally substituted with₁~ C
₄An alkyl group of C₁~ C₃An alkoxy group, or
A heteroaryl group which may be substituted with a
An optionally substituted aralkyl group; C₁~ C₃Al
Kill group, C₁~ C ₃An alkoxy group, a halogen atom,
Or C₁~ C₄An alkyl group of C₁~ C ₃Alcoqui
Ants which may be substituted with
Or C₁~ C₄An alkyl group of C₁~ C₃
Is substituted with an alkoxy group or a halogen atom,
Hetero which may be substituted with a heteroaryl group
An aralkyl group; or C₃~ C₉Even if it branches
Good propargyl or substituted propargyl;
And W is a functional group capable of leaving)
Formula (VI):

[0029]

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Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are the same as described above, and the asterisk indicates an asymmetric carbon atom. How to

The present inventors have conducted further studies on the stereoselectivity of the axially asymmetric N-spiro phase transfer catalyst and the alkylation reaction of the N-protected glycine derivative, and as a result, have accomplished the present invention. The main points are as follows.

Conventionally, in order to stereoselectively alkylate N-protected glycine derivatives using an axially asymmetric N-spiro phase transfer catalyst, the conformation is fixed by two binaphthyl structures having axial asymmetry. As described above, it was considered that a chiral N-spiro quaternary ammonium salt was required.

[0033]

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[0034]

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However, when the catalytic activities of the compound represented by the formula (VII) and the compound represented by the formula (VIII) were examined, the following facts were found. That is, the compound represented by the formula (VII) was used at 1 mol%, and a 50% aqueous solution of potassium hydroxide and toluene (1:
In the two-phase mixture of 3), the glycine derivative (IX) was added with 1: 1.
After reaction of 2 equivalents of benzyl bromide at 0 ° C. for 3 hours, the resulting compound (X) is subjected to a post-treatment involving hydrolysis, and then (R) -phenylalanine (XI) having an optical purity of 94% ee is obtained in a yield of 91%. Could be obtained. On the other hand, in the case of the compound of formula (VIII), the reaction progresses only 53% even if the reaction is continued for 62 hours under the same conditions, and the (R) -phenylalanine obtained after work-up The optical purity was also only 18% ee.

[0036]

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Based on these results, the compound (VI
The same reaction was carried out using a mixture of 0.5 mol% each of I) and the compound (VIII) as a catalyst. After 13 hours, (R) having an optical purity of 94% ee was obtained.
-Phenylalanine was obtained in a yield of 88%.

That is, among chiral N-spiro quaternary ammonium salts composed of two binaphthyl groups, it was found that only the axial asymmetry of one binaphthyl group contributed to high catalytic activity and stereoselectivity. It was. The present invention has been made based on such findings.

[0039]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

The terms used in this specification are defined as follows.

The term "lower alkyl" refers to C ₁ -C.
C ₆ , preferably a C _{1 to} C ₄ alkyl group which may form a branch or a ring, and is a linear, branched or cyclic C _{1 to} C 6 (preferably 1 to 4) carbon group The term includes alkyl. Examples of such lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert.
-Butyl, cyclobutyl, pentyl, cyclopentyl,
Hexyl, and cyclohexyl. In the present invention, methyl, isopropyl and tert-butyl are particularly preferred.

The term “lower alkoxy” refers to C ₁ -C
₆ , preferably a C ₁ -C ₄ alkoxy group which may form a branch or a ring, having 1 to 6 (preferably 1 to 4) carbon atoms of a linear, branched or cyclic alkoxy group Including. Examples of such lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t
tert-butoxy, and phenoxy. In the present invention, methoxy and ethoxy are particularly preferred.

The term “lower alkenyl” refers to C ₂ -C
₆ , preferably a C ₂ -C ₄ alkenyl group which may form a branch or a ring, having 2 to 6 (preferably 2 to 4) carbon atoms of a linear, branched or cyclic alkenyl group Including. Examples of such lower alkenyl groups include ethenyl, propenyl, isopropenyl, cyclopropenyl, butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl -2-propenyl, cyclobutenyl, pentenyl, cyclopentenyl, hexenyl, and cyclohexenyl. In the present invention,
Propenyl and butenyl are particularly preferred.

The term "lower alkynyl" refers to C ₂ -C
₆ , preferably an alkynyl group optionally having a C _{2 to} C ₄ branched or cyclic structure, and having 2 to 6 (preferably 2 to 4) carbon atoms of a linear, branched or cyclic alkynyl group Including. Examples of such lower alkynyl groups include ethynyl, propynyl, cyclopropylethynyl, butynyl, 1-methyl-2-propynyl, pentynyl, cyclobutylethynyl, hexynyl, and trimethylsilylethynyl. In the present invention, ethynyl and trimethylsilylethynyl are particularly preferred.

Examples of the “halogen atom” in the present invention include chlorine, bromine, iodine and fluorine.

The term "organic residue having 4 to 10 carbon atoms" refers to a bulky aliphatic hydrocarbon, such as t-butyl, neopentyl, and 2,2-dimethylhexyl. Aliphatic hydrocarbons containing tertiary or quaternary carbon atoms, or aromatic hydrocarbons such as phenyl, naphthyl and pyridyl, and some of these may be halogen atoms. And those substituted with an aliphatic alkyl group or an aliphatic alkoxy group.

The term "organic residue having 4 to 20 carbon atoms" refers to a bulky aliphatic hydrocarbon, such as t-butyl, neopentyl, and 2,2-dimethylhexyl. Aliphatic or long chain aliphatic hydrocarbons containing such tertiary or quaternary carbon atoms, or aromatic hydrocarbons such as phenyl, naphthyl, anthryl, phenanthryl, phenyl substituted phenyl, and pyridyl. And some of these are halogen atoms,
Those substituted with an aliphatic alkyl group or an aliphatic alkoxy group are also included.

Examples of the "aryl group" in the present invention include phenyl, biphenyl, naphthyl and anthracenyl.

Examples of the "heteroaryl group" in the present invention include pyridyl, quinonyl, pyrrolyl, imidazolyl, furyl, indolyl, thienyl, oxazolyl and thiazolyl.

[0050] Examples of the "aralkyl group" in the present invention include benzyl, phenethyl, naphthylmethyl and anthracenylmethyl.

Examples of the heteroaralkyl group in the present invention include pyridylmethyl, quinonylmethyl, indolylmethyl, furylmethyl, thienylmethyl, and pyrrolylmethyl.

The term "C ₃ -C ₉ optionally branched propargyl group or substituted propargyl group" means a propargyl group or a C ₄ -C ₉ substituted or unsubstituted propargyl group having a substituent at the 1- and / or 3-position. A substituted propargyl group means, for example, 2-butynyl, 3-trimethylsilyl-2
-Propynyl and the like. In the present invention, propargyl and 3-trimethylsilyl-2-propynyl are preferred.

The term "functional group capable of leaving" refers to an atom or an atomic group leaving a reaction substrate in a substitution reaction or elimination reaction, that is, a leaving group, for example, a halogen atom and a sulfonyloxy group. Is mentioned.

"Sulfonyloxy group" in the present invention
Examples include methanesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy.

The N-spiro quaternary ammonium salt compound of the present invention has the formula (I):

[0056]

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(Wherein R ¹ is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; even if it is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom). Good aryl groups; or lower alkyl groups, lower alkoxy groups,
Or a heteroaryl group which may be substituted with a halogen atom, wherein R ² is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; a lower alkyl group, a lower alkoxy group; Or an aryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group, or an aryl group substituted with an aryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group, or a halogen An aryl group substituted with a heteroaryl group optionally substituted with an atom; a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group, or Substituted with an aryl group which may be substituted with a halogen atom, A heteroaryl group; or a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom,
A heteroaryl group and X is a halogen atom). This N-spiro quaternary ammonium salt compound can be used as a phase transfer catalyst.

The compound represented by the above formula (I) is produced as follows. That is, a compound represented by the formula (II):

[0059]

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(Wherein R ¹ is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; even if it is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom). Good aryl groups; or lower alkyl groups, lower alkoxy groups,
Or a heteroaryl group which may be substituted with a halogen atom, wherein R ² is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; a lower alkyl group, a lower alkoxy group; Or an aryl group optionally substituted with a halogen atom; an aryl group substituted with a lower alkyl group, a lower alkoxy group, or an aryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group,
Or an aryl group substituted with a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group Or a heteroaryl group substituted with an aryl group optionally substituted with a halogen atom; or a heteroaryl group substituted with a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom. X is an aryl group (unless both R ¹ and R ² are hydrogen atoms), and X is a halogen atom. ) And a compound of formula (III):

[0061]

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Can be obtained in a suitable organic solvent in the presence of an acid scavenger.

Here, the suitable organic solvent that can be used is not particularly limited as long as it does not participate in the reaction. For example, methanol, ethanol, propanol,
Alcohol solvents such as isopropanol, butanol and tert-butyl alcohol are exemplified. Examples of acid supplements that may be used include potassium carbonate and sodium carbonate.

The compound represented by the above formula (II) and the compound represented by the above formula (III) are used at room temperature in such a suitable organic solvent in the presence of an acid scavenger. By stirring at a suitable temperature up to the boiling point of the organic solvent, preferably at room temperature to 80 ° C., for 30 minutes to 12 hours, preferably 2 hours to 11 hours, more preferably 3 hours to 10 hours, The compounds represented can be obtained.

At this time, the reaction solvent is the compound (II)
It is preferably used in a volume (mL) / weight (g) ratio of 5 to 50 times, more preferably 10 to 40 times with respect to I), and the acid scavenger is preferably used for compound (III). It is sufficient to use 2 to 4 equivalents, more preferably 2 to 3 equivalents.

In the compound represented by the above formula (I),
A compound in which R ¹ is a hydrogen atom and R ² is β-naphthyl is produced as follows.

First, 2-iodo-6-nitrotoluene is prepared from 2-amino-6-nitrotoluene and subjected to a coupling reaction to obtain 2,2′-dimethyl-3,3′-dinitrobiphenyl. Can be Then
After reducing the nitro group of this 2,2'-dimethyl-3,3'-dinitrobiphenyl to an amino group, the resulting compound is converted to an iodine group via diazotization to give 2,2'-dimethyl-3,3. '-Iodobiphenyl is produced.

The obtained 2,2'-dimethyl-3,3'-
Iodobiphenyl was reacted with 2-naphthylboronic acid in the presence of a palladium catalyst and an acid scavenger (Suzuki coupling) to give 2,2′-dimethyl-3,3′-di (β-
Naphthyl) biphenyl, which was brominated with N-bromosuccinimide to form a methyl group to give 3,3′-di (β-
(Naphthyl) -2,2'-dibromomethylbiphenyl is obtained.

Further, the obtained 3,3′-di (β-naphthyl) -2,2′-dibromomethylbiphenyl is represented by the formula (III) in the presence of an acid scavenger.
3,5-dihydro-4H-dinaphtho [2,1-c:
1 ′, 2′-e] azepine compound. Thus, among the compounds represented by the formula (I), N-spirochiral C having a benzene ring substituted with a β-naphthyl group can be used.
It is possible to produce a ₂ axial asymmetry quaternary ammonium bromide.

On the other hand, in the compound represented by the above formula (I), the compound wherein R ¹ is a hydrogen atom and R ² is 3,5-diphenylphenyl is produced as follows.

First, 2,2'-dimethyl 3,3'-iodobiphenyl is produced in the same manner as described above. Then
The 2,2′-dimethyl-3,3′-iodobiphenyl is reacted with 3,5-diphenylphenylboronic acid,
2,2′-Dimethyl-3,3′-di (3,5-diphenylphenyl) biphenyl, and bromination of the methyl group with N-bromosuccinimide to give 3,3′-di (3 ″,
5 "-diphenylphenyl) -2,2'-dibromomethylbiphenyl is obtained.

The obtained 3,3′-di (3 ″, 5 ″ -diphenylphenyl) -2,2′-dibromomethylbiphenyl is represented by the formula (III) (S) -3,5-dihydro- 4H-dinaphtho [2,1-c: 1 ′, 2′-e]
React with azepine compound. Thus, among the compounds represented by the formula (I), 3,5-
N-spirochiral C ₂ substituted with a diphenylphenyl group
An axially asymmetric quaternary ammonium bromide is produced.

Further, R ¹ is phenyl and R ²
Is a 3,5-diphenylphenyl, the compound represented by the formula (I) is produced from 2,2′-dihydroxy-5,5′-diphenylbiphenyl as follows.

First, 2,2'-dihydroxy-5,5 '
-Diphenylbiphenyl is reacted with, for example, methoxymethyl chloride to give 2,2'-dimethoxymethoxy-
5,5′-diphenylbiphenyl was lithiated with n-butyllithium, reacted with trimethoxyborane, and finally oxidized with hydrogen peroxide to give 2,2′-dimethoxymethoxy-3,3. '-Dihydroxy-5,5'
To obtain diphenylbiphenyl.

Then, after O-alkylation with methyl halide (methyl iodide, methyl bromide, etc.), the mixture is treated with concentrated hydrochloric acid to give 2,2′-dihydroxy-3,3′-.
Dimethoxy-5,5'-diphenylbiphenyl is obtained.
The resulting compound is O-tolylylated and reacted with a methyl Grignard reagent (methyl magnesium iodide, methyl magnesium bromide, etc.) to give 2,2′-dimethyl-
3,3'-Dimethoxy-5,5'-diphenylbiphenyl is obtained.

The obtained compound was reacted with boron tribromide to change a methoxy group to a hydroxy group, and after O-trifurylation, reacted with 3,5-diphenylphenylboronic acid (Suzuki coupling). 2,2′-dimethyl-3,
3'-bis (3,5-diphenylphenyl) -5,5 '
To obtain diphenylbiphenyl.

The compound thus obtained was reacted with N-bromosuccinimide to convert it to a bromomethyl compound, and then (S) -3,5-dihydro-4H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine compound. Thus, among the compounds of formula (I), that the benzene ring to produce a substituted N- Supirokiraru C ₂ axial asymmetry quaternary ammonium bromide in a phenyl group and 3,5-diphenyl phenyl group it can.

The compound represented by the formula (I)
And R¹And R²Are both hydrogen atoms,
Using 2,2'-dimethylbiphenyl as a raw material,
R ¹Is phenyl and R²Is a hydrogen atom
The compound is 2,2'-dihydro-5,5'-diphenylbi
By using phenyl as a raw material, the above method
Can be appropriately applied to each of them for synthesis.

Formula (II) used in the above reaction
The (S) -3,5-dihydro-4H-dinaphtho [2,1-c: 1 ′, 2′-e] azepine compound represented by I) is published in Journal of the publication by the present inventors.
American Chemical Society
Vol. 121 6519-6520.

Further, in the compound represented by the formula (I), compounds having other substituents specified by R ¹ and R ² can also be produced according to the above-mentioned synthesis method. it can.

Thus, the compound represented by the formula (I) can be produced.

When the compound represented by the formula (I) of the present invention is used in the above-mentioned alkylation reaction of a glycine derivative, a reaction product having high optical purity can be obtained in high yield.

That is, using the compound represented by the above formula (I), the compound represented by the formula (VI):

[0084]

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(Where R³And R⁴Are the same or different
Is a hydrogen atom or C₁~ C₃Archi
Group, C₁~ C₃With an alkoxy group or a halogen atom
An aryl group which may be substituted (provided that R³You
And R⁴Unless both are simultaneously hydrogen atoms);
R⁵Is a hydrogen atom or C₁~ C₃Alkyl group, C
₁~ C₃Substituted with an alkoxy group or a halogen atom
Is an optionally substituted aryl group or forms a branch or ring
C that may be₁~ C₆Is an alkyl group or
Is C₁~ C₃Alkyl group, C₁~ C₃An alkoxy group
Or an aralkyl group optionally substituted with a halogen atom
And R⁶Is C₁~ C₄An alkyl group; and R
⁷Is C₁~ C₆May form a branch or ring of
Alkyl group; C₃~ C₉Form a branch or ring of
Optionally allyl or substituted allyl; C₁~ C₄of
Alkyl group, C₁~ C₃Alkoxy group, halogen source
Child or C₁~ C₄An alkyl group of C₁~ C₃No
May be substituted with a alkoxy group or a halogen atom
Aryl group or C₁~ C₄An alkyl group of C₁
~ C₃Is substituted with an alkoxy group or a halogen atom
Optionally substituted with a heteroaryl group
Aralkyl group; C₁~ C₃An alkyl group of C₁~ C₃of
An alkoxy group, a halogen atom, or C₁~ C₄No
Alkyl group, C₁~ C₃An alkoxy group, or halogen
An aryl group optionally substituted with an atom, or C₁
~ C₄An alkyl group of C₁~ C₃An alkoxy group of
Is a heteroaryl optionally substituted by a halogen atom
A heteroaralkyl group optionally substituted with a group; or
Is C₃~ C₉A propargyl group which may be branched
Or a substituted propargyl group, and * is an asymmetric carbon atom.
Can be produced stereoselectively.

Specifically, the compound represented by the formula (IV) in the presence of the compound represented by the above formula (I):

[0087]

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(Wherein R³And R⁴Are the same or different
Is a hydrogen atom or C₁~ C₃Archi
Group, C₁~ C₃With an alkoxy group or a halogen atom
An aryl group which may be substituted (provided that R³You
And R⁴Unless both are simultaneously hydrogen atoms);
R⁵Is a hydrogen atom or C₁~ C₃Alkyl group, C
₁~ C₃Substituted with an alkoxy group or a halogen atom
Is an optionally substituted aryl group or forms a branch or ring
C that may be₁~ C₆Is an alkyl group or
Is C₁~ C₃Alkyl group, C₁~ C₃An alkoxy group
Or an aralkyl group optionally substituted with a halogen atom
And R⁶Is C₁~ C₄Is an alkyl group)
With a compound of formula (V) in a solvent in the presence of an inorganic base:

[0089]

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(Where R⁷Is C₁~ C₆Branch of
Is an alkyl group which may form a ring;₃~ C₉Minute
Allyl group which may form a branch or ring or substitution
Allyl group; C₁~ C₄An alkyl group of C₁~ C₃Al
Coxy group, halogen atom or C₁~ C₄Archi
Group, C₁~ C₃An alkoxy group or a halogen atom
An aryl group optionally substituted with₁~ C
₄An alkyl group of C₁~ C₃An alkoxy group, or
A heteroaryl group which may be substituted with a
An optionally substituted aralkyl group; C₁~ C₃Al
Kill group, C₁~ C ₃An alkoxy group, a halogen atom,
Or C₁~ C₄An alkyl group of C₁~ C ₃Alcoqui
Ants which may be substituted with
Or C₁~ C₄An alkyl group of C₁~ C₃
Is substituted with an alkoxy group or a halogen atom,
Hetero which may be substituted with a heteroaryl group
An aralkyl group; or C₃~ C₉Even if it branches
Good propargyl or substituted propargyl;
And W is a functional group capable of leaving)
By doing so, it can be manufactured.

In the above reaction, the compound represented by the formula (I) plays a role as a phase transfer catalyst in a pure form with respect to axial asymmetry. Here, "pure with respect to axial asymmetry"
"It means that among various stereoisomers considered based on axial asymmetry, the abundance of one specific isomer is larger than that of the other isomer. The abundance of this one specific isomer is preferably at least 90%, more preferably at least 95%, even more preferably at least 98%.

According to the present invention, the compound (IV) is contained in a two-phase mixture comprising a hydrocarbon solvent and an aqueous alkali solution.
And preferably 1 equivalent to 1.5 equivalents to compound (IV).
An equivalent, more preferably 1.1 equivalent to 1.3 equivalent, most preferably 1.2 equivalent to 1.25 equivalent of compound (V) is added with 0.005 equivalent to 0.03 equivalent of compound (IV).
Equivalent, more preferably 0.0075 equivalent to 0.0125 equivalent
In the presence of the compound represented by the above formula (I), which acts as an equivalent phase transfer catalyst, preferably at an appropriate temperature between −10 ° C. and room temperature, more preferably −5 ° C. to + 5 ° C.
C., preferably 15 minutes to 3 hours, more preferably 0.5 hours to 2 hours, most preferably 0.5 hours to 1.
By stirring for 5 hours, an optically active compound represented by the formula (VI) can be obtained with high yield and high optical purity.

Specifically, for example, when synthesizing the (S) form of the compound represented by the formula (VI), a compound having the axial asymmetry of the formula (I) is used as the compound of the formula (I). Is done.
In the case of synthesizing the (R) form of the compound represented by the formula (VI), the compound represented by the formula (I) having the axial asymmetry of (S) is used.

In this specification, high optical purity is preferably 90% ee or more, more preferably 95% ee.
ee or higher optical purity.

When a hydrocarbon solvent is used as the solvent, any solvent may be used as long as it is immiscible with water. For example, hexane, toluene and the like are represented by the formula (IV). The volume (mL) / weight (g) ratio of the compound is preferably 5 to 30 times, more preferably 8 to 30 times.
Used 25 times to 25 times. Further, when an aqueous alkali solution is used as the solvent, a 10 to 60% aqueous solution of an alkali metal hydroxide such as lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, and rubidium hydroxide can be used. The volume can be preferably 4 to 20 times, more preferably 8 to 15 times, the volume (mL) / weight (g) ratio of the compound represented by the formula (IV).

The inorganic base which can be used in the stereoselective production method of the compound of the above formula (VI) of the present invention includes lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, rubidium hydroxide. And cesium hydroxide.

Thus, the compound represented by the formula (VI) can be stereoselectively produced using the compound represented by the formula (I).

[0098]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below by way of examples.
However, the present embodiment does not limit the present invention.

<Production Example 1> 2-Methyl-
3-nitroaniline compound 1 (4.66 g, 30 mmol
l):

[0100]

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And a mixture of 6N hydrochloric acid (15 mL).
An aqueous solution (30 mL) of sodium nitrite (3.15 g, 45 mmol) was added dropwise at 0 ° C, and the mixture was stirred for 30 minutes. Then, the reaction mixture was washed with potassium iodide (20.0 g, 120 mmol).
l) After dropwise adding to an aqueous solution (100 mL) at 0 ° C., the mixture was heated to room temperature and stirred for 2 hours. Then, the reaction mixture was poured into a saturated aqueous solution of sodium sulfite and extracted with dichloromethane. Wash the dichloromethane extract with saturated saline and dry
After (Na ₂ SO ₄ ), the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with dichloromethane: hexane (1:10) to give Compound 2 (7.
75 g (30 mmol) was obtained in 98% yield.

[0102]

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The analysis results on the obtained compound 2 were as follows.

400 MHz ¹ H-NMR (CDC
l ₃ ): δ 8.06 (1H, d, J = 8.0 Hz, Ar
-H), 7.72 (1H, d, J = 8.0 Hz, Ar-
H), 7.04 (1H, t, J = 8.0 Hz, Ar-
_{H), 2.60 (3H, s} , ArCH 3) ppm.

<Production Example 2> Production Example 1 under an argon atmosphere
A mixture of the compound 2 (7.75 g, 30 mmol) obtained in the above, active copper powder (15.0 g), and N, N-dimethylformamide (45 mL) was stirred under reflux with heating for 15 hours. After allowing to cool to room temperature, the mixture was filtered through Celite. Then, the filtrate was poured into water and extracted with dichloromethane. The dichloromethane extract was washed with water and saturated saline, dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with dichloromethane: hexane (1: 4) to give compound 3 shown below.
(3.63 g, 13 mmol) was obtained with a yield of 90%.

[0106]

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The analysis results on the obtained compound 3 were as follows.

400 MHz ¹ H-NMR (CDC
l ₃ ): δ 7.90 (2H, d, J = 7.6 Hz, Ar)
-H), 7.43 (2H, t, J = 7.6 Hz, Ar-
H), 7.35 (2H, d, J = 7.6 Hz, Ar−
_{H), 2.21 (6H, s} , ArCH 3) ppm.

<Production Example 3> Compound 3 obtained in Production Example 2
(3.63 g, 13 mmol), iron trichloride hexahydrate (7
After stirring a mixture of 1.9 mg, 2 mol%), activated carbon (1.0 g) and methanol (45 mL) for 10 minutes under reflux with heating, hydrazine monohydrate (3.87 mL, 80 mL) was added.
(mmol) was added dropwise and the mixture was further stirred for 5 hours. After allowing to cool to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.
After washing the residue with hexane and drying under reduced pressure, the following compound 4 (2.24 g, 11 mmol) was obtained in a yield of 80%.

[0110]

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The analysis results on the obtained compound 4 were as follows.

400 MHz ¹ H-NMR (CDC
l ₃ ): δ 7.04 (2H, t, J = 7.6 Hz, Ar
-H), 9.69 (2H, d, J = 7.6 Hz, Ar-
H), 6.59 (2H, d, J = 7.6 Hz, Ar-
H), 3.65 (4H, brs , ArNH 2), 1.8
_{7 (6H, s, ArCH 3} ) ppm.

<Production Example 4> Compound 4 obtained in Production Example 3
(2.24 g, 11 mmol) and concentrated sulfuric acid (10 m
L) at 0 ° C with sodium nitrite (2.23).
g, 32 mmol) in water (30 mL),
Stir for 30 minutes. Next, the reaction mixture was added dropwise to an aqueous solution (150 mL) of potassium iodide (14.1 g, 85 mmol) at 0 ° C., and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium sulfite and extracted with dichloromethane. The dichloromethane extract was washed with saturated saline, dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with dichloromethane: hexane (1:30) to give the compound 5 (2.90 g, 6.7 mmol) shown below in a yield of 63%.
I got it.

[0114]

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The analysis results on the obtained compound 5 were as follows.

[0116] 400 Hz¹H-NMR (CDC
l₃): Δ 7.85 (2H, d, J = 8.0 Hz, Ar
-H), 7.04 (2H, d, J = 8.0 Hz, Ar-
H), 6.90 (2H, t, J = 8.0 Hz, Ar−
H), 2.16 (6H, s, ArCH ₃) Ppm.

<Production Example 5> Production Example 4 under an argon atmosphere
Compound 5 (0.217 g, 0.50 mmol) obtained in
l), 2-naphthylboronic acid (0.206 g, 1.2 m
mol), barium hydroxide octahydrate (0.483 g,
1.5 mmol), ethylene glycol dimethyl ether (4.5 mL), water (0.5 mL), and tetrakis (triphenylphosphine) palladium (28.9).
mg, 5 mol%) was stirred for 24 hours under reflux with heating. The reaction mixture was poured into saturated saline and extracted with dichloromethane. Dry the dichloromethane extract (Na ₂ S
After O ₄ ), the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with dichloromethane: hexane (1:50) to give compound 6 (0.
217 g, 0.50 mmol) were obtained in quantitative yield.

[0118]

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The analysis results on the obtained compound 6 were as follows.

400 MHz ¹ H-NMR (CDC
l ₃ ): δ 7.89 (2H, t, J = 8.0 Hz, Ar
-H), 7.84 (2H, s, Ar-H), 7.50-
7.54 (6H, m, Ar-H), 7.33-7.35
(4H, m, Ar-H), 7.24-7.26 (2H,
m, Ar-H), 3.18 (6H, s, ArCH 3) p
pm.

Example 1 Compound 6 obtained in Production Example 5
(0.217 g, 0.50 mmol), 2,2′-azobis (isobutyronitrile) (8.4 mg, 10 mol)
%), N-bromosuccinimide (0.191 mg,
1.1 mmol) and benzene (5 mL) was stirred for 1 hour under heated reflux. The reaction mixture was poured into water and extracted with ether. Dry the ether extract (Na
_{After 2} SO ₄ ), the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with dichloromethane: hexane (1:30) to give compound 7 shown below.
(0.215 g, 0.36 mmol) in 73% yield.

[0122]

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The analysis results on the obtained compound 7 were as follows.

400 MHz ¹ H-NMR (CDC
_{1 3): δ8.00 (2H,} s, Ar-H), 7.90
-7.95 (6H, m, Ar-H), 7.65 (2H,
dd, J = 1.6, 8.4 Hz, Ar-H), 7.53
-7.55 (4H, m, Ar-H), 7.40-7.5
1 (6H, m, Ar-H), 4.40 (2H, d, J =
10.0 Hz, ArCH ₂ Br), 4.26 (2H,
d, J = 10.0 Hz, ArCH ₂ Br) ppm.

<Example 2> Compound 8 (7
(3.8 mg, 0.25 mmol):

[0126]

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To an acetonitrile solution (5 mL) of was added potassium carbonate (52.1 mg, 0.38 mmol),
After stirring at room temperature for 30 minutes, the compound 7 obtained in Example 1 was obtained.
(0.163 g, 0.28 mmol) was added. The reaction mixture was stirred for 7 hours under heated reflux, then poured into water and extracted with dichloromethane. Dry dichloromethane extract
After (Na ₂ SO ₄ ), the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with methanol: dichloromethane (1:20) to give compound 9 shown below.
(0.192 g, 0.24 mmol) in a yield of 95%.

[0128]

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The results of analysis of the obtained compound 9 are as follows.

[Α] _D ²² 174.2 ° (c = 0.2
5, CHCl ₃ ). 400 MHz ¹ H-NMR (CDCl ₃ ): δ7.8
0 (8H, t, J = 7.6 Hz, Ar-H), 7.35
(4H, t, J = 7.6 Hz, Ar-H), 7.20-
8.10 (16H, brm, Ar-H), 7.06
(4H, t, J = 7.6 Hz, Ar-H), 6.90
(2H, d, J = 8.4 Hz, Ar-H), 4.84
(2H, br, ArCH ₂ ), 4.57 (2H, br,
ArCH ₂ ), 4.55 (2H, d, J = 13.2H)
z, ArCH ₂ ), 3.00 (2H, br, ArC
H ₂₎ ppm. IR (KBr): ν _max 3383, 3051, 162
2,1595,1504,1456,1357,119
7,864,821,797,752 cm- ¹ . MS: m / z 726 (M ^<+> ) (100%), 266.1
65,154,136. Calculated HRMS C ₅₆ H ₄₀ N: 726.31
63 (M ^<+> ); found: 726.3167 (M ^<+> ).

<Production Example 6> Production Example 4 under an argon atmosphere
5 (0.109 g, 0.25 mmol
l), 3,5-diphenylphenylboronic acid (0.16
4g, 0.6mmol), barium hydroxide octahydrate (0.241g, 0.75mmol), ethylene glycol dimethyl ether (4.5mL), water (0.5m
L) and a mixture of tetrakis (triphenylphosphine) palladium (14.4 mg, 5 mol%) were stirred for 20 hours under reflux with heating. The reaction mixture was poured into saturated saline and extracted with dichloromethane. The dichloromethane extract was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with dichloromethane: hexane (1:50) to give the following compound 10 (0.160 g, 0.25 mmol) in a quantitative yield.

[0132]

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The analysis results on the obtained compound 10 were as follows.

200 MHz ¹ H-NMR (CDC
_{1 3): δ7.81 (2H,} s, Ar-H), 7.68
-7.73 (8H, m, Ar-H), 7.60 (4H,
d, J = 1.8 Hz, Ar-H), 7.34-7.49
(16H, m, Ar-H), 7.21-7.26 (2
H, m, Ar-H), 2.11 (6H, s, ArC
H ₃₎ ppm.

<Example 3> Compound 1 obtained in Production Example 6
0 (0.160 g, 0.25 mmol), 2,2'-azobis (isobutyronitrile) (4.2 mg, 10 mo
1%), N-bromosuccinimide (95.4 mg,
0.53 mmol) and benzene (5 mL) were stirred for 3 hours under heated reflux. The reaction mixture was poured into water and extracted with ether. Dry the ether extract (N
After a ₂ SO ₄ ), the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with dichloromethane: hexane (1:20) to obtain a compound 11 represented by the following.
(0.180 g, 0.23 mmol) in 91% yield.

[0136]

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The analysis results on the obtained compound 11 were as follows.

400 MHz ¹ H-NMR (CDC
_{1 3): δ7.88 (2H,} t, J = 1.80Hz, A
rH), 7.73-7.75 (12H, m, Ar-
H), 7.43-7.52 (14H, m, Ar-H),
7.38 (4H, t, J = 7.2 Hz, Ar-H) 4.
43 (2H, d, J = 10.0 Hz, ArCH ₂ B
r), 4.30 (2H, d, J = 10.0 Hz, ArC
H ₂ Br) ppm.

Example 4 Compound 8 (4
4.3 mg, 0.15 mmol):

[0140]

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To an acetonitrile solution (5 mL) of was added potassium carbonate (31.1 mg, 0.23 mmol),
After stirring at room temperature for 30 minutes, the compound 1 obtained in Example 3 was obtained.
1 (0.131 g, 0.17 mmol) was added. The reaction mixture was stirred under heated reflux for 16 hours, poured into water and extracted with dichloromethane. The dichloromethane extract was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with methanol: dichloromethane (1:20) to give the following compound 12 (0.120 g, 0.12 mmol) in a yield of 7
Obtained at 9%.

[0142]

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The analysis results of the obtained compound 12 were as follows.

[Α] _D ²⁴ 55.0 ° (c = 0.25,
CHCl ₃ ). 400 MHz ¹ H-NMR (CDCl ₃ ) δ 7.08
-7.80 (44H, brm, Ar-H), 4.83
(4H, d, J = 13.2 Hz, ArCH ₂ ), 4.5
7 (2H, d, J = 13.2 Hz, ArCH ₂ );
_{78 (2H, br, ArCH 2} ) ppm. IR (KBr): ν _max 3399, 3055, 295
9,1593,1574,1499,1454,141
4,1358,883,825,760,696cm
^-1 . MS: m / z 930 (M ^<+> ) (100%), 266,2
65,154,136. Calculated HRMS C ₇₂ H ₅₂ N: 930.41
03 (M ⁺ ); Found: 9304101 (M ⁺ ).

<Production Example 7> Sodium hydride (0.301 g, 7.5 mmol) and T
Compound 13 represented by the following was added to a mixture of HF (5 mL).
(0.981 g, 2.9 mmol):

[0146]

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A solution of THF (5 mL) was added dropwise at 0 ° C.
Stir for 30 minutes. Then, chloromethyl methyl ether (0.597 mL, 7.5 mmol) was added dropwise to the reaction mixture at 0 ° C., stirred for 2 hours, poured into water, and extracted with ethyl acetate. Wash the ethyl acetate extract with saturated saline,
After drying (Na ₂ SO ₄ ), the solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: hexane (1: 5) to give compound 14 shown below.
(1.22 g, 2.9 mmol) in 99% yield.

[0148]

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The analysis results on the obtained Compound 14 were as follows.

400 MHz ¹ H-NMR (CDC
_{1 3): δ7.56-7.60 (8H,} m, Ar-
H), 7.41 (4H, t, J = 8.04 Hz, Ar-
H), 7.28-7.33 (4H, m, Ar-H),
5.13 (4H, s, ArOCH ₂ ), 3.01 (6
_{H, s, OCH 3) ppm} .

<Production Example 8> Production Example 7 under an argon atmosphere
Compound 14 obtained in (1.22 g, 2.9 mmol)
Into an ether solution (10 mL) of n-butyllithium (1.56 M, 4.46 ml, 7.0 m)
mol) was added dropwise at room temperature and stirred for 3 hours. The reaction mixture was then cooled to −78 ° C. and THF (10 mL) was added, followed by trimethoxyborane (0.992 mL, 8.
7 mmol), and the mixture was heated to room temperature and stirred for 10 hours. After the reaction mixture was concentrated under reduced pressure using an evaporator, benzene (10 mL) was added, the mixture was cooled to 0 ° C., and aqueous hydrogen peroxide (30%, 2 mL) was added dropwise. The reaction mixture was stirred under reflux with heating for 2 hours, poured into a saturated aqueous solution of sodium nitrite, and extracted with ether. The ether extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: hexane (1: 2) to give Compound 15 (0.850 g, 1.9 mmol) represented below.
l) was obtained with a yield of 64%.

[0152]

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The analysis results on the obtained compound 15 were as follows.

400 MHz ¹ H-NMR (CDC
_{1 3): δ7.38-7.60 (4H,} m, Ar-
H), 7.34-7.44 (4H, m, Ar-H),
7.31-7.35 (2H, m, Ar-H), 7.28
(4H, d, J = 2.4 Hz, Ar-H), 7.08
(2H, d, J = 2.4 Hz, Ar-H), 4.48
(4H, s, ArOCH ₂ ), 3.50 (6H, s, O
CH ₃₎ ppm.

<Production Example 9> Compound 1 obtained in Production Example 8
A mixture of 5 (0.850 g, 1.9 mmol), potassium carbonate (0.729 g, 5.7 mmol), methyl iodide (0.747 mL, 11.4 mmol), and acetone (6 mL) was heated under reflux with heating. Stirred for hours. Then the reaction mixture was poured into water and extracted with ether. The ether extract was washed with saturated saline and dried (Na ₂
After SO ₄ ), the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate: hexane (1: 1).
Eluted with 3) to give compound 16 (0.84
3 g, 1.7 mmol) were obtained with a yield of 91%.

[0156]

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The analysis results on the obtained compound 16 were as follows.

400 MHz ¹ H-NMR (CDC
_{1 3): δ7.58-7.61 (4H,} m, Ar-
H), 7.42 (4H, t, J = 7.2 Hz, Ar-
H), 7.29-735 (4H, m, Ar-H), 7.
15 (2H, d, J = 2.0 Hz, Ar-H), 4.9
_{6 (4H, br s, ArOCH} 2), 3.05 (6
_{H, s, OCH 3) ppm} .

<Production Example 10> A mixture of compound 16 (0.843 g, 1.7 mmol) obtained in Production Example 9, 1,4-dioxane (5 mL), and concentrated hydrochloric acid (0.5 mL) was heated under heating. Stirred at 50 ° C. for 4 hours. Then the reaction mixture was poured into water and extracted with ether. The ether extract was washed with water and saturated saline, and dried (Na ₂ SO ₄ )
Then, the mixture was concentrated under reduced pressure. Then, the residue was treated with dichloromethane (5
Then, triethylamine (0.722 mL, 5.1 mmol) was added at room temperature under an argon atmosphere, and then cooled to -78 ° C. Next, trifluoromethanesulfonic anhydride (0.676 mL, 4.1 mmol)
After l) was added dropwise, the reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction mixture was poured into saturated aqueous NH ₄ Cl and extracted with dichloromethane. The dichloromethane extract was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with dichloromethane: hexane (1: 3) to give compound 17 (0.882 g, 1.3 mmol) represented by the following yield 72.
%.

[0160]

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The analysis results of the obtained compound 17 were as follows.

400 MHz ¹ H-NMR (CDC
_{1 3): δ7.57-7.59 (4H,} m, Ar-
H), 7.39-7.48 (6H, m, Ar-H),
7.25-7.29 (4H, m, Ar-H), 4.04
_{(6H, s, ArOCH 3)} ppm.

<Production Example 11> The compound 17 obtained in Production Example 10 (0.882 g, 1.3 mm
ol), [1,3-bis (diphenylphosphino) propane] nickel chloride [NiCl ₂ (dppp), 3
5.2 mg, 5 mol%], and ether (2 mL)
Was added to an ether solution of MeMgI (1.0 M,
(7.0 mL, 7.0 mmol) was added dropwise at 0 ° C. After the reaction mixture was stirred at room temperature for 30 hours, it was poured into saturated aqueous NH ₄ Cl. The nickel catalyst was filtered off, and the filtrate was extracted with ether. Wash the ether extract with saturated saline and dry
After (Na ₂ SO ₄ ), the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ether: hexane (1:10) to give compound 18 shown below.
(0.324 g, 0.82 mmol) in 63% yield.

[0164]

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The results of analysis of the obtained compound 18 are as follows.

400 MHz ¹ H-NMR (CDC
_{1 3): δ7.61-7.63 (4H,} m, Ar-
H), 7.40-7.44 (4H, m, Ar-H),
7.32 (2H, ddt, J = 1.2, 6.8, 8.0
Hz, Ar-H), 7.08 (4H, dd, J = 1.
6, 8.0 Hz, Ar-H), 3.95 (6H, s, A)
_{rOCH 3), 2.01 (6H,} s, ArCH 3) pp
m.

<Production Example 12> The compound 18 obtained in Production Example 11 (0.324 g, 0.82 m
mol) in dichloromethane solution (5 mL) at 0 ° C. was added dropwise boron tribromide (0.188 mL, 2.0 mmol). After the temperature of the reaction mixture was raised to room temperature and stirred for 2 hours, the mixture was cooled again to 0 ° C., and water was added dropwise. Extract with dichloromethane, wash the extract with saturated saline, and dry (Na ₂
After SO ₄ ), the mixture was concentrated under reduced pressure. Next, the residue was dissolved in a dichloromethane solution (5 mL), and triethylamine (0.348 mL, 2.5 mmol) was added at room temperature under an argon atmosphere, and then cooled to -78 ° C. Then, trifluoromethanesulfonic anhydride (0.326 mL,
(2.0 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture is washed with saturated NH ₄ Cl
It was poured into an aqueous solution and extracted with dichloromethane. The dichloromethane extract was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with dichloromethane: hexane (1: 5) to give the compound 19 (0.494 g, 0.78 mmol) shown below in a 96% yield.

[0168]

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The results of analysis of the obtained compound 19 are as follows.

400 MHz ¹ H-NMR (CDC
_{1 3): δ7.55-7.60 (6H,} m, Ar-
H), 7.45-7.49 (6H, m, Ar-H),
7.38-7.42 (2H, m, Ar-H), 2.15
_{(6H, s, ArCH 3)} ppm.

<Production Example 13> Production example under argon atmosphere
Compound 19 obtained in Example 12 (0.189 g, 0.30 m
mol), 3,5-diphenylphenylboronic acid (0.
197 g, 0.72 mmol), tetrakis (triphe
Nylphosphine) palladium (17.3 mg, 5 m
ol%), potassium phosphate hydrate (0.257 g, 0.1 g).
90 mmol), and N, N-dimethylformamide
(6 mL) is stirred under heating at 80 ° C. for 18 hours
did. Then, the reaction mixture was poured into saturated saline. Para
The indium catalyst was filtered off and the filtrate was extracted with ether. A
Dry the ter extract (Na₂SO ₄) Then, the mixture was concentrated under reduced pressure. Remaining
The silica gel was subjected to silica gel column chromatography.
Elution with dichloromethane: hexane (1:20)
Compound 20 represented (0.221 mg, 0.28 mmol
l) was obtained in 93% yield.

[0172]

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The analysis results of the obtained compound 20 were as follows.

400 MHz ¹ H-NMR (CDC
_{1 3): δ7.85 (2H,} t, J = 1.6Hz, Ar
-H), 7.65-7.73 (16H, m, Ar-
H), 7.59 (2H, d, J = 2.4 Hz, Ar-
H), 7.33-7.49 (20H, m, Ar-H),
_{1.91 (6H, s, ArCH 3} ) ppm.

Example 5 Compound 20 (0.221 g, 0.28 mmol) obtained in Production Example 13, 2,2'-
Azobis (isobutyronitrile) (4.7 mg, 10 m
ol%), N-bromosuccinimide (0.112 g,
0.62 mmol) and benzene (12 mL) were stirred for 1 hour under heated reflux. The reaction mixture was poured into water and extracted with ether. Dry ether extract
After (Na ₂ SO ₄ ), the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ether: hexane (1:20) to give compound 21 shown below.
(0.259 g, 0.27 mmol) was obtained with a yield of 97%.

[0176]

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The analysis results on the obtained compound 21 were as follows.

400 MHz ¹ H-NMR (CDC
_{1 3): δ7.91 (2H,} t, J = 1.6Hz, Ar
-H), 7.84 (4H, d, J = 1.6 Hz, Ar-
H), 7.71-7.79 (16H, m, Ar-H),
7.34-7.50 (18H, m, Ar-H), 4.5
4 (2H, d, J = 9.6 Hz, ArCH ₂ Br),
4.10 (2H, d, J = 9.6 Hz, ArCH ₂ B
r) ppm.

Example 6 Compound 8 (4
4.3 mg, 0.15 mmol):

[0180]

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Potassium carbonate (31.1 mg, 0.23 mmol) was added to an acetonitrile solution (10 mL) of the above, and the mixture was stirred at room temperature for 30 minutes. Then, the compound 21 obtained in Example 5 (0.157 g, 0.17 mmol) was obtained. ) Was added.
The reaction mixture was stirred for 9 hours under reflux, then poured into water and extracted with dichloromethane. The dichloromethane extract was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with methanol: dichloromethane (1:20) to give the following compound 22 (0.146 g, 0.13 mmol) in a yield of 8:
Obtained at 4%.

[0182]

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The analysis results of the obtained compound 22 were as follows.

[Α] _D ²⁵ 41.2 ° (c = 0.25,
CHCl ₃ ). 400 MHz ¹ H-NMR (CDCl ₃ ); δ 7.1
0-8.02 (52H, brm, Ar-H), 4.96
(2H, d, J = 13.2 Hz, ArCH ₂ ), 4.8
6 (2H, br, ArCH ₂ ), 4.65 (2H, d,
J = 13.2 Hz, ArCH ₂ ), 2.77 (2H, b
_r, ArCH 2) ppm. IR (KBr): ν _max 3895, 3047, 161
8, 1587, 1454, 897, 860, 825, 7
50 cm- ¹ . MS: m / z 1082 (M ^<+> ) (100%), 800,
266,265,136. Calculated HRMS C ₈₄ H ₆₀ N: 1082.4
729 (M ^<+> ); found: 1082.4713.
(M ⁺ ).

<Example 7> In place of compound 21, 2
2'-dibromomethylbiphenyl (57.8 mg, 0.1
Compound 23 shown below was obtained in the same manner as in Example 6 except that 17 mmol) was used.

[0186]

Embedded image

The results of analysis of the obtained compound 23 are as follows.

[Α] _D ²⁸ -110.2 ° (c = 0.2
5, CHCl ₃ ). 400 MHz ¹ H-NMR (CDCl ₃ ): δ 8.2
9 (2H, d, J = 8.4 Hz, Ar-H), 8.08
(2H, d, J = 8.0 Hz, Ar-H), 8.05
(2H, d, J = 8.4 Hz, Ar-H), 7.88
(2H, brd, J = 6.8 Hz, Ar-H), 7.
70-7.77 (6H, m, Ar-H) 7.63 (2
H, ddd, J = 1.2, 6.4, 8.0 Hz, Ar-
H), 7.50 (2H, d, J = 8.4 Hz, Ar−
H), 7.39 (2H, ddd, J = 1.2, 6.8,
8.0 Hz, Ar-H), 4.78 (2H, d, J = 1)
3.6 Hz, ArCH ₂ ), 4.33 (2H, d, J =
13.6 Hz, ArCH ₂ ), 4.04 (2H, d, J
= 13.2 Hz, ArCH ₂ ), 3.95 (2H, d,
_{J = 13.2Hz, ArCH 2) ppm} . IR (KBr): ν _max 3638, 3385, 305
3,2359,1622,1456,1354,120
0,1028,878,854,818,758cm
^-1 . MS: m / z 474 (M ^<+> ), 327, 266, 16
5,136 (100%). Calculated HRMS C ₃₆ H ₂₈ N: 474.22
23 (M ^<+> ); found: 474.2238 (M ^<+> ).

Example 8 Instead of compound 8, (J.
Am. Chem. Soc. 1999, 121, 6519
(S) -2,6-di (β-naphthyl)-(prepared from (S) -1,1′-bi-2- (bromomethyl) -3- (β-naphthyl) naphthalene) 3,5
-Dihydro-4H-dinaphtho [2,1-c; 1 ′, 2 ′
-E] 2,2′- as in Example 4, except that azepine (82.1 mg, 0.15 mmol) was used.
The compound 24 was reacted with dibromomethyl-bi-phenyl to obtain a compound 24 shown below.

[0190]

Embedded image

The results of analysis of the obtained compound 24 are as follows.

[Α]_D ²⁸−5.98 ° (c = 0.2
5, CHCl₃). 400MHz¹HNMR (CDCl₃): Δ7.07
-8.44 (30H, brm, Ar-H), 5.71
(2H, br, Ar-H), 5.27 (1.36H, b
r, ArCH₂, Homochiral), 4.91 (0.64
H, br, ArCH ₂, Heterochiral), 4.67.
(0.64H, br, ArCH₂, Heterochiral) 4.
43 (1.36H, br, ArCH₂, Homochiral),
4.32 (0.64H, br, ArCH₂, Heterokira
3.91 (1.36H, br, ArCH)₂, Homo
Chiral), 3.67 (1.36H, br, ArCH₂,
Heterochiral), 2.62 (0.64H, br, ArC
H₂, Heterochiral). IR (KBr): ν_max3895, 3047, 161
8, 1587, 1454, 897, 860, 825, 7
50cm^-1. MS: m / z 726 (M⁺) (100%), 518, 2
65,179,136. HRMS C₅₆H₄₀Calculated value 726.316 as N
3 (M⁺); Found 726.3156 (M⁺).

Example 9 (R) -Phenylalanine-
Preparation of tert-butyl ester benzophenone Schiff base>

Glycine-tert-butyl ester benzophenone Schiff base (148 mg, 0.5 mmol
l), the asymmetric transfer catalyst obtained in Example 6 (compound 22)
(5.51 mg, 0.005 mmol), toluene (3.25 mL) and a 50% aqueous potassium hydroxide solution (1.05 mL) were added to benzyl bromide (72.1.
μL, 0.6 mmol) was added dropwise at 0 ° C. 48 at 0 ° C
After stirring for an hour, the reaction mixture was poured into water. The mixture was extracted with ether, and the ether extract was washed with saturated saline,
After drying (Na ₂ SO ₄ ), the solution was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ether: hexane (1:10) to give (R) -phenylalanine-tert-butyl ester benzophenone Schiff base. Yield 156 mg (0.405 mmol). Yield 8
The optical purity of this product obtained at 1% was 95% ee as a result of HPLC analysis. (DAICEL CHIR
AL OD; Hexane: 2-propanol (100:
1); 0.5 mL / min; (R) -form: 14 minutes; (S)-
Body: 28.2 minutes).

<Embodiments 10 to 13> For each embodiment,
An alkylation reaction was carried out in the same manner as in Example 9, except that the catalyst and the amount thereof shown in Table 1 were used instead of the compound 22, and the reaction was carried out at the reaction temperature and time shown in Table 1. The product was obtained.

[0196]

[Table 1]

Table 2 shows the yield and optical purity of each product obtained.

[0198]

[Table 2]

As shown in Table 2, by using the asymmetric catalyst of the present invention, the alkylation reaction of the glycine derivative could be carried out with excellent yield and optical purity in any of the examples. I understand.

[0200]

According to the present invention, various α-amino acid derivatives, whether natural or non-natural, can be synthesized stereoselectively. Therefore, the present invention is useful in the field of asymmetric synthetic chemistry of α-amino acids.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) // C07B 53/00 C07B 53/00 B 61/00 300 61/00 300 C07M 7:00 C07M 7:00 F-term (reference) 4C050 AA04 BB09 CC10 EE01 FF05 GG01 HH01 4G069 AA06 AA08 BA21A BA21B BE14C BE17A BE17B BE19C BE20C BE21C BE33C BE37A BE37B BE37C BE38A BE38B BE45A BE45B CB57 AC01 BA02 BA01 AC02 CD20

Claims (11)

[Claims] An N-spiro quaternary ammonium salt compound represented by the formula (I): In the formula, R ¹ represents a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; a lower alkyl group, a lower alkoxy group, or an aryl group optionally substituted with a halogen atom; Or a lower alkyl group, a lower alkoxy group, or a heteroaryl group which may be substituted with a halogen atom,
R ² is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; a lower alkyl group, a lower alkoxy group, or an aryl group optionally substituted with a halogen atom; An aryl group substituted with an aryl group which may be substituted with a lower alkoxy group or a halogen atom;
An aryl group substituted with a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group,
Or a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group, a heteroaryl group substituted with an aryl group optionally substituted with a halogen atom; or a lower alkyl group, a lower alkoxy group, Or a heteroaryl group substituted with a heteroaryl group which may be substituted with a halogen atom, and X is a halogen atom. 2. R ¹ is a hydrogen atom or an organic residue having 4 to 10 carbon atoms, and R ² is a hydrogen atom or an organic residue having 4 to 20 carbon atoms.
A compound according to claim 1. 3. The compound according to claim 2, wherein the organic residue having 4 to 10 carbon atoms and the organic residue having 4 to 20 carbon atoms are both aromatic hydrocarbons. . 4. The compound according to claim 1, wherein X is Br. 5. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom or a phenyl group, and R ² is a β-naphthyl group or a 3,5-diphenylphenyl group. 6. A compound represented by the formula (II): In the formula, R ¹ is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; a lower alkyl group, a lower alkoxy group, an aryl group optionally substituted with a halogen atom; A lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom;
² is a hydrogen atom; a lower alkyl group; a lower alkoxy group;
Lower alkenyl group; lower alkynyl group; halogen atom;
An aryl group optionally substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; an aryl group substituted with a lower alkyl group, a lower alkoxy group, or an aryl group optionally substituted with a halogen atom; An aryl group substituted with an alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group,
Or a heteroaryl group optionally substituted with a halogen atom; a lower alkyl group, a lower alkoxy group, or a heteroaryl group substituted with an aryl group optionally substituted with a halogen atom; or a lower alkyl group or a lower alkoxy group Or a heteroaryl group substituted with a heteroaryl group which may be substituted with a halogen atom (except when both R ¹ and R ² are hydrogen atoms), and X is a halogen atom. 7. A method for producing the compound according to claim 1, wherein the compound is represented by the formula (II): (Wherein R ¹ is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a halogen atom; a lower alkyl group, a lower alkoxy group, or an aryl group optionally substituted with a halogen atom) Or a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom, wherein R ² is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; Atom; aryl group optionally substituted by lower alkyl group, lower alkoxy group, or halogen atom; aryl group substituted by lower alkyl group, lower alkoxy group, or aryl group optionally substituted by halogen atom ; Substituted by a lower alkyl group, a lower alkoxy group, or a halogen atom An aryl group substituted by a heteroaryl group which may be substituted; a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted by a halogen atom; a lower alkyl group, a lower alkoxy group, or a halogen atom A heteroaryl group substituted with an optionally substituted aryl group; or a heteroaryl group substituted with a lower alkyl group, a lower alkoxy group, or a heteroaryl group optionally substituted with a halogen atom, and X Is a halogen atom.)
And a compound represented by the formula (III): And a reaction in an organic solvent in the presence of an acid scavenger. 8. The method of claim 7, wherein X is Br. 9. R ¹ is a hydrogen atom, and R ² is β-
The method according to claim 7 or 8, wherein the method is naphthyl or 3,5-diphenylphenyl. 10. The method of claim 7, wherein R ¹ is phenyl and R ² is 3,5-diphenylphenyl.
The method described in. 11. In the presence of a compound according to claim 1, a compound of the formula
Compound represented by (IV):(Where R³And R⁴Is the same or different and is hydrogen
Is an atom or C₁~ C₃Alkyl group, C₁~
C₃Substituted with an alkoxy group or a halogen atom
An aryl group (where R³And R⁴Both
R and R are not hydrogen atoms at the same time);⁵Is hydrogen
Atom or C₁~ C₃Alkyl group, C ₁~ C₃Al
May be substituted with a oxy group or a halogen atom
May be an aryl group, or form a branch or ring
C₁~ C₆An alkyl group or C₁~ C₃
Alkyl group, C₁~ C₃Alkoxy group or halogen
An aralkyl group optionally substituted with an atom;
R⁶Is C₁~ C₄An alkyl group) in a solvent
In the presence of an organic base, a compound of formula (V):(Where R⁷Is C₁~ C₆Form a branch or ring of
An optionally substituted alkyl group; C₃~ C₉Branch or ring of
An allyl group or a substituted allyl group which may form
₁~ C₄An alkyl group of C₁~ C₃An alkoxy group, c
Logen atom or C₁~ C₄An alkyl group of C₁~
C₃Substituted with an alkoxy group or a halogen atom
Optionally an aryl group, or C₁~ C₄The alkyl of
Group, C₁~ C₃With an alkoxy group or a halogen atom
Substituted with an optionally substituted heteroaryl group
Aralkyl groups which may be substituted; C₁~ C₃An alkyl group of C₁
~ C ₃An alkoxy group, a halogen atom, or C₁~
C₄An alkyl group of C₁~ C ₃An alkoxy group, or
Some aryl groups which may be substituted by halogen atoms
I C₁~ C₄An alkyl group of C₁~ C₃The alkoxy of
Group or hetero optionally substituted with a halogen atom
Heteroaralkyl optionally substituted with an aryl group
Group; or C₃~ C₉Properties that may be branched
A Lugyl group or a substituted propargyl group; and W is
Alkylation with a functional group capable of leaving)
Including, formula (VI):(Where R³, R⁴, R⁵, R⁶, And R⁷Is
The same is true, and * indicates an asymmetric carbon atom).
To produce a compound stereoselectively.