JP4807751B2 - Novel chiral catalyst and method for producing chiral carboxylic acid compound using the same - Google Patents

Description

  The present invention relates to a novel chiral catalyst and a method for producing a chiral carboxylic acid compound using the same, and more particularly to a chiral sulfonamide derivative and a method for producing an optically active carboxylic acid compound using the same.

Known methods for producing optically active compounds include enzymatic methods, optical resolution methods using optical resolution agents, and asymmetric synthesis methods. Among these methods, the former two methods have the restriction that half of the racemate is not used, whereas the asymmetric synthesis method is superior in that there is no such restriction.
Many of the catalysts usually used in asymmetric synthesis methods have a metal as the active center. However, depending on the type of metal, it is often expensive, toxic, difficult to dispose, or the catalyst is unstable to water or oxygen. For this reason, in recent years, research on reactions using organic molecules themselves as catalysts without using metals has been actively conducted for reasons such as stability, low cost, and environmental friendliness (Non-Patent Documents 1 and 2).

On the other hand, optically inactive dicarboxylic acid derivatives are useful as raw materials for production of physiologically active substances and pharmaceuticals. Conventionally, organic sulfonamide catalysts are produced from prochiral dicarboxylic acid anhydrides that are optically inactive with symmetrical molecular structures. There is no known method for producing an optically active carboxylic acid compound.
Angev. Chem. Int. Ed. 2005, 44, p. 1369-1371 J. et al. Am. Chem. Soc. 2004, 126, p. 12212-12213

  An object of the present invention is to provide a novel organic molecular catalyst used in an asymmetric synthesis method. Another object of the present invention is to provide a method for producing an optically active carboxylic acid or an ester thereof from a prochiral dicarboxylic acid anhydride that is optically inactive with a symmetric molecular structure using the organic molecular catalyst. . Still another object of the present invention is to provide a novel zinc catalyst derived from the organic molecular catalyst, and an optically active 1,3-diol compound from an optically inactive prochiral 1,3-diol compound using the zinc catalyst. -To provide a method for producing a diol monoester compound.

  In order to solve the above-mentioned problems, the present inventors have made extensive studies focusing on chiral sulfonamide compounds, and as a result, dialkylamino groups that are basic groups and secondary sulfonamide groups that are acidic groups are formed in the same molecule. Succeeded in creating a bifunctional compound, i.e., chiral 1,2-diphenyl-1- (N, N-dialkylamino) -2-N-arylsulfonamide, and using a catalytic amount of this chiral sulfonamide derivative The prochiral dicarboxylic acid anhydride can be thiolized (thiolyzed) or alcoholically decomposed (alcoholized) with high enantioselectivity, and optically active carboxylic acid compounds can be obtained in high yield and high optical yield. A zinc complex of a sulfonamide derivative is formed and used as a catalyst to form a prochiral 1,3-diol derivative Reaction of Le agent, a high yield of chiral mono esters together found to be obtained at a high optical yield, and have completed the present invention by further investigations.

［式中、Ｐｈはフェニル基を示し、Ａｒはアリール基を示し、Ｒ^１およびＲ^２はそれぞれアルキル基を示すか、あるいは両者が末端で結合して隣接する窒素原子と一緒になって異項環基を形成していることを示す。］
で示されるキラルスルホンアミド誘導体、
［２］ Ａｒが置換基を有するフェニル基であり、Ｒ^１およびＲ^２はそれぞれ炭素数１〜３のアルキル基である前記［１］に記載のキラルスルホンアミド誘導体、
［３］ Ａｒが炭素数１〜３のアルキル基もしくは炭素数１〜３のハロゲン化アルキル基で置換されたフェニル基である前記［１］または［２］に記載のキラルスルホンアミド誘導体、
［４］ Ａｒがメチルフェニル基または３，５−ビス（トリフルオロメチル）−フェニル基である前記［１］または［２］に記載のキラルスルホンアミド誘導体、 That is, the present invention
[1] Formula (I):

[In the formula, Ph represents a phenyl group, Ar represents an aryl group, and R ¹ and R ² each represent an alkyl group, or both are bonded together at the terminal and combined with an adjacent nitrogen atom to form a different group. It shows that a cyclic group is formed. ]
A chiral sulfonamide derivative represented by:
[2] The chiral sulfonamide derivative according to [1], wherein Ar is a phenyl group having a substituent, and R ¹ and R ² are each an alkyl group having 1 to 3 carbon atoms.
[3] The chiral sulfonamide derivative according to the above [1] or [2], wherein Ar is a phenyl group substituted with an alkyl group having 1 to 3 carbon atoms or a halogenated alkyl group having 1 to 3 carbon atoms,
[4] The chiral sulfonamide derivative according to the above [1] or [2], wherein Ar is a methylphenyl group or a 3,5-bis (trifluoromethyl) -phenyl group,

［式中、Ａは対称分子構造となる位置に置換基を１〜２個有するアルキレン基、または対称分子構造となる位置に置換基を１〜２個有していてもよいシクロアルキレン基もしくはシクロアルケニレン基を示す。］
で示されるプロキラルなジカルボン酸無水物と式（ＩＩＩ）：

［式中、Ｒはアルキル基、アリール基またはアラルキル基を示し、Ｘは硫黄原子または酸素原子を示す。］
で示されるチオールもしくはアルコール化合物とを、式（Ｉ）：

［式中、Ｐｈはフェニル基を示し、Ａｒはアリール基を示し、Ｒ^１およびＲ^２はそれぞれアルキル基を示すか、あるいは両者が末端で結合して隣接する窒素原子と一緒になって異項環基を形成していることを示す。］
で示されるキラルスルホンアミド誘導体の存在下に反応させ、ついで必要によりエステル化することを特徴とする、式（ＩＶ）：

［式中、ＲおよびＸは上記と同意義を、Ｒ^ａは水素またはエステル残基を、Ａ^＊はＡと平面構造が同一でかつ分子全体が非対称な絶対構造をとることを示す。］
で示される光学活性カルボン酸またはそのエステルの製造方法、 [5] Formula (II):

[Wherein, A represents an alkylene group having 1 to 2 substituents at a position where a symmetric molecular structure is formed, or a cycloalkylene group or cyclohexane optionally having 1 to 2 substituents at a position where a symmetric molecular structure is formed. An alkenylene group is shown. ]
A prochiral dicarboxylic acid anhydride represented by formula (III):

[Wherein, R represents an alkyl group, an aryl group or an aralkyl group, and X represents a sulfur atom or an oxygen atom. ]
A thiol or alcohol compound represented by formula (I):

[In the formula, Ph represents a phenyl group, Ar represents an aryl group, and R ¹ and R ² each represent an alkyl group, or both are bonded together at the terminal and combined with an adjacent nitrogen atom to form a different group. It shows that a cyclic group is formed. ]
Wherein the reaction is carried out in the presence of a chiral sulfonamide derivative represented by formula (IV), followed by esterification if necessary:

[Wherein, R and X are as defined above, R ^a represents hydrogen or an ester residue, and A ^* represents an absolute structure having the same planar structure as A and an asymmetric molecule as a whole. ]
A process for producing an optically active carboxylic acid or ester thereof represented by

［式中、Ｐｈはフェニル基を示し、Ａｒはアリール基を示し、Ｒ^１およびＲ^２はそれぞれアルキル基を示すか、あるいは両者が末端で結合して隣接する窒素原子と一緒になって異項環基を形成していることを示す。］
で示されるキラルスルホンアミド誘導体・Ｚｎ錯体、
［１２］ 式（Ｉ）：

［式中、Ｐｈはフェニル基を示し、Ａｒはアリール基を示し、Ｒ^１およびＲ^２はそれぞれアルキル基を示すか、あるいは両者が末端で結合して隣接する窒素原子と一緒になって異項環基を形成していることを示す。］
で示されるキラルスルホンアミド誘導体とジアルキル亜鉛とを反応させることを特徴とする、式（Ｉ−ａ）：

［式中、Ｐｈ、Ａｒ、Ｒ^１およびＲ^２は上記と同意義を示す。］
で示されるキラルスルホンアミド誘導体・Ｚｎ錯体の製造方法、
［１３］ 式（ＶＩＩ）：

［式中、Ｒ^３はアミノ基の保護基を示し、Ｒ^４はアルキル基、アルケニル基、またはアラルキル基を示す。］
で示される１，３−ジオール化合物と、式（ＶＩＩＩ）：

［式中、Ｒ^５はアルキル基、またはアリール基を示す。］
で示される酸無水物とを、 式（Ｉ−ａ）：

［式中、Ｐｈはフェニル基を示し、Ａｒはアリール基を示し、Ｒ^１およびＲ^２はそれぞれアルキル基を示すか、あるいは両者が末端で結合して隣接する窒素原子と一緒になって異項環基を形成していることを示す。］
で示されるキラルスルホンアミド誘導体・Ｚｎ錯体の存在下に反応させることを特徴とする、式（ＩＸ）：

［式中、Ｒ^３、Ｒ^４およびＲ^５は上記と同意義を示す。］
で示されるキラル１，３−ジオール・モノエステル化合物の製造方法、および
［１４］ 式（ＶＩＩ）：

［式中、Ｒ^３はアミノ基の保護基を示し、Ｒ^４はアルキル基、アルケニル基、またはアラルキル基を示す。］
で示される１，３−ジオール化合物と、式（ＶＩＩＩ）：

［式中、Ｒ^５はアルキル基、またはアリール基を示す。］
で示される酸無水物とを、 式（Ｉ）：

［式中、Ｐｈはフェニル基を示し、Ａｒはアリール基を示し、Ｒ^１およびＲ^２はそれぞれアルキル基を示すか、あるいは両者が末端で結合して隣接する窒素原子と一緒になって異項環基を形成していることを示す。］
で示されるキラルスルホンアミド誘導体とジアルキル亜鉛の存在下に反応させることを特徴とする、式（ＩＸ）：

［式中、Ｒ^３、Ｒ^４およびＲ^５は上記と同意義を示す。］
で示されるキラル１，３−ジオール・モノエステル化合物の製造方法、
に関する。 [6] The production method according to [5], wherein Ar is a phenyl group having a substituent, and R ¹ and R ² are each an alkyl group having 1 to 3 carbon atoms.
[7] The production method according to [5] or [6], wherein Ar is a phenyl group substituted with an alkyl group having 1 to 3 carbon atoms or a halogenated alkyl group having 1 to 3 carbon atoms,
[8] The production method according to [5] or [6], wherein Ar is a methylphenyl group or a 3,5-bis (trifluoromethyl) -phenyl group.
[9] The production method according to any one of [5] to [8], wherein R ^a is hydrogen, an alkyl group, or an aralkyl group.
[10] The production method according to the above [5], wherein Ar is a phenyl group having a substituent, and R is a benzyl group.
[11] Formula (Ia):

[In the formula, Ph represents a phenyl group, Ar represents an aryl group, and R ¹ and R ² each represent an alkyl group, or both are bonded together at the terminal and combined with an adjacent nitrogen atom to form a different group. It shows that a cyclic group is formed. ]
A chiral sulfonamide derivative / Zn complex represented by
[12] Formula (I):

[In the formula, Ph represents a phenyl group, Ar represents an aryl group, and R ¹ and R ² each represent an alkyl group, or both are bonded together at the terminal and combined with an adjacent nitrogen atom to form a different group. It shows that a cyclic group is formed. ]
Wherein the chiral sulfonamide derivative represented by formula (Ia) is reacted with a dialkylzinc:

[Wherein, Ph, Ar, R ¹ and R ² are as defined above. ]
A process for producing a chiral sulfonamide derivative / Zn complex represented by the formula:
[13] Formula (VII):

[Wherein, R ³ represents an amino-protecting group, and R ⁴ represents an alkyl group, an alkenyl group, or an aralkyl group. ]
A 1,3-diol compound represented by formula (VIII):

[Wherein, R ⁵ represents an alkyl group or an aryl group. ]
An acid anhydride represented by formula (Ia):

[In the formula, Ph represents a phenyl group, Ar represents an aryl group, and R ¹ and R ² each represent an alkyl group, or both are bonded together at the terminal and combined with an adjacent nitrogen atom to form a different group. It shows that a cyclic group is formed. ]
The reaction is carried out in the presence of a chiral sulfonamide derivative / Zn complex represented by formula (IX):

[Wherein R ³ , R ⁴ and R ⁵ are as defined above. ]
And a method for producing a chiral 1,3-diol monoester compound represented by the formula (VII):

[Wherein, R ³ represents an amino-protecting group, and R ⁴ represents an alkyl group, an alkenyl group, or an aralkyl group. ]
A 1,3-diol compound represented by formula (VIII):

[Wherein, R ⁵ represents an alkyl group or an aryl group. ]
An acid anhydride represented by formula (I):

[In the formula, Ph represents a phenyl group, Ar represents an aryl group, and R ¹ and R ² each represent an alkyl group, or both are bonded together at the terminal and combined with an adjacent nitrogen atom to form a different group. It shows that a cyclic group is formed. ]
Wherein the compound is reacted with a chiral sulfonamide derivative represented by formula (IX):

[Wherein R ³ , R ⁴ and R ⁵ are as defined above. ]
A process for producing a chiral 1,3-diol monoester compound represented by:
About.

  According to the present invention, a novel chiral organic molecular catalyst having excellent catalytic ability is provided. According to the present invention, the chiral organic molecular catalyst is used to convert an optically active carboxylic acid compound from a prochiral dicarboxylic acid anhydride, and from a prochiral 1,3-diol compound to an optically active 1,3-diol monoester. The ester compound can be obtained with high yield and high optical yield.

［式中、Ｐｈはフェニル基を示し、Ａｒはアリール基を示し、Ｒ^１およびＲ^２はそれぞれアルキル基を示すか、あるいは両者が末端で結合して隣接する窒素原子と一緒になって異項環基を形成していることを示す。］
で示されるキラルスルホンアミド誘導体である。 One aspect of the invention is a compound of formula (I):

[In the formula, Ph represents a phenyl group, Ar represents an aryl group, and R ¹ and R ² each represent an alkyl group, or both are bonded together at the terminal and combined with an adjacent nitrogen atom to form a different group. It shows that a cyclic group is formed. ]
It is a chiral sulfonamide derivative | guide_body shown by these.

In the chiral sulfonamide derivative (I), examples of the aryl group represented by Ar include an aromatic hydrocarbon group (for example, phenyl group, naphthyl group, etc.) which may have a substituent. Examples of the substituent include an alkyl group (for example, a methyl group, an ethyl group, a propyl group, and an isopropyl group), an alkoxy group (for example, a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group), and a halogen (for example, Fluorine, chlorine, bromine, iodine, etc.), halogenated alkyl groups (monofluoromethyl group, difluoromethyl group, trifluoromethyl group, difluoroethyl group, trifluoroethyl group, trichloromethyl group etc.), halogenated alkoxy groups ( For example, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a trifluoroethoxy group, etc.) may be mentioned, and 1 to 3 of these substituents may be present at any position of the aromatic hydrocarbon group.
In the above substituent, the alkyl group, alkoxy group, halogenated alkyl group, and halogenated alkoxy group preferably have 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms.

Examples of the alkyl group represented by R ¹ and R ² include an alkyl group having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, and an isopropyl group. Etc. In addition, when R ¹ and R ² are bonded together at the end to form a hetero ring group together with an adjacent nitrogen atom, examples of the hetero ring group include an aziridino group, an azetidino group, and a pyrrolidino group. And nitrogen-containing heterocyclic groups such as piperidino group and morpholino group.

［式中、Ｐｈは前記と同意義を示す。Ｒ^１およびＲ^２は、それぞれ前記と同意義を示す。］
で示される化合物を式（ＶＩ）：

［式中、Ａｒは前記と同意義を示す。］
で示される化合物と反応させることにより製造することができる。 The chiral sulfonamide derivative (I) of the present invention has the formula (V):

[In the formula, Ph is as defined above. R ¹ and R ² are as defined above. ]
A compound represented by formula (VI):

[In the formula, Ar is as defined above. ]
It can manufacture by making it react with the compound shown by these.

  This reaction can be carried out by a method known per se, for example, preferably by reacting compound (V) and compound (VI) in a suitable solvent in the presence of a base. Examples of the solvent include dichloromethane, chloroform, ethyl acetate, diethyl ether, tetrahydrofuran, toluene, pyridine, N, N-dimethylformamide and the like. Examples of the base include triethylamine, N-methylpiperidine, N-methylmorpholine, pyridine and the like. This reaction is preferably carried out at 0 ° C. to 10 ° C., but can be carried out at a lower temperature (˜−10 ° C.) or higher temperature (˜30 ° C.) if necessary. The amount of compound (VI) to be used is generally 1 to 1.5 mol, preferably 1 to 1.1 mol, per 1 mol of compound (V). The compound (I) thus produced can be isolated and purified by a method known per se, for example, extraction, recrystallization, chromatography and the like.

  Another aspect of the present invention is a method using the chiral sulfonamide derivative (I) obtained above as a catalyst. That is,

［式中、Ａは、対称分子構造となる位置に置換基を１〜２個有するアルキレン基、または対称分子構造となる位置に置換基を１〜２個有していてもよいシクロアルキレン基もしくはシクロアルケニレン基を示す。］
で示されるプロキラルなジカルボン酸無水物と式（ＩＩＩ）：

［式中、Ｒはアルキル基、アリール基またはアラルキル基を示し、Ｘは硫黄原子または酸素原子を示す。］
で示されるチオールもしくはアルコール化合物を、前記キラルスルホンアミド誘導体（Ｉ）の存在下に反応させ、ついで必要によりエステル化することにより式（ＩＶ）：

［式中、ＲおよびＸは上記と同意義を、Ｒ^ａは水素またはエステル残基を、Ａ^＊はＡと平面構造が同一でかつ分子全体が非対称な絶対構造をとることを示す。］
で示される光学活性カルボン酸またはそのエステルを製造する方法である。 Formula (II):

[Wherein, A represents an alkylene group having 1 to 2 substituents at a position where a symmetric molecular structure is formed, or a cycloalkylene group which may have 1 to 2 substituents at a position where a symmetric molecular structure is formed, or A cycloalkenylene group is shown. ]
A prochiral dicarboxylic acid anhydride represented by formula (III):

[Wherein, R represents an alkyl group, an aryl group or an aralkyl group, and X represents a sulfur atom or an oxygen atom. ]
Is reacted in the presence of the chiral sulfonamide derivative (I), followed by esterification if necessary, to give a compound of formula (IV):

[Wherein, R and X are as defined above, R ^a represents hydrogen or an ester residue, and A ^* represents an absolute structure having the same planar structure as A and an asymmetric molecule as a whole. ]
Is a method for producing an optically active carboxylic acid or an ester thereof.

  In the prochiral dicarboxylic acid anhydride (II) which is a raw material compound, an alkylene group having 1 to 2 substituents at a position where the symmetric molecular structure is represented by A, or a substituent which is 1 to 2 at a position where the symmetric molecular structure is formed. Examples of the cycloalkylene group or cycloalkenylene group which may have two include 2-substituted-1,3-propylene group, 1,3-cis-disubstituted-1,3-propylene group, 4,6- cis-disubstituted-1,3-cyclohexylene group, 2-substituted-1,3-cyclohexylene group, 5-substituted-1,3-cyclohexylene group, 3-cyclohexene-1,2-cis-diyl group, etc. Is mentioned. Here, the substituent is not particularly limited as long as it is inert to the reaction. For example, an alkyl group, an aryl group, an arylalkyl group (= aralkyl group), an alkyloxy group (= alkoxy group), an arylalkyloxy group (= Arylalkoxy groups), trisubstituted silyloxy groups and the like. Examples of the alkyl moiety in these substituents include linear, branched or cyclic alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Examples thereof include a butyl group, a tert-butyl group, a pentyl group, a cyclopentyl group, a cyclopentylmethyl group, a hexyl group, a cyclohexyl group, a cyclohexylmethyl group, a heptyl group, and an octyl group. Examples of the aryl moiety in the substituent include the same aryl groups (Ar) as described in the compound (I). Further, examples of the tri-substituted silyloxy group include a trimethylsilyloxy group, a tributyrylsilyloxy group, a dimethylphenylsilyloxy group, and a tert-butyldimethylsilyloxy group.

  In the other thiol or alcohol compound (III) as the raw material compound, examples of the alkyl group represented by R include a linear, branched or cyclic alkyl group having 1 to 16 carbon atoms. Specifically, For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, cyclopentyl group, cyclopentylmethyl group, hexyl group, cyclohexyl group, cyclohexylmethyl group, Examples include heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group and the like. Examples of the aryl group represented by R include the same aryl groups (Ar) as described in the compound (I). Examples of the aralkyl group (= arylalkyl group) represented by R include those in which the aryl group (Ar) is substituted on an alkyl group having 1 to 3 carbon atoms. Specific examples include benzyl group and phenylethyl group. , Phenylpropyl group, naphthylmethyl group, or those having 1 to 3 substituents similar to those described above at any position of the phenyl group or naphthyl group in these groups.

The reaction of the prochiral dicarboxylic acid anhydride (II) with the thiol or alcohol compound (III) is carried out in the presence of the chiral sulfonamide derivative (I) in an appropriate solvent at 0 to 40 ° C., preferably around room temperature (15 ˜30 ° C.). Any solvent may be used as long as it is inert to the reaction. For example, n-hexane, n-pentane, cyclohexane, diethyl ether, dibutyl ether, toluene, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, acetone, methyl ethyl ketone, methyl butyl ketone. N, N-dimethylformamide, dimethyl sulfoxide and the like are used.
The usage-amount of chiral sulfonamide derivative (I) is 0.001-0.1 mol normally with respect to a catalyst amount, ie, 1 mol of (II), Preferably it is 0.03-0.06 mol. Moreover, the usage-amount of compound (III) is 1.0-5.0 mol normally with respect to 1 mol of compound (II), Preferably it is 1.2-5.0 mol.

［式中、Ｍｅはメチル基を示し、Ｐｈは前記と同意義を示す。］ Thus, the compound (II) is thiol-decomposed or alcohol-degraded with high enantioselectivity to obtain an optically active carboxylic acid (compound in which R ^a is hydrogen in the compound (IV)).
What should be noted here is that in the above reaction, instead of the compound (I) as a catalyst, for example, in the compound (I), a hydrogen atom on a nitrogen atom is substituted with an alkyl group or the like as shown below. In the compound (A) and the compounds (B) to (C) in which both nitrogen atoms are substituted with the same substituent, the thiol (or alcohol) decomposition reaction does not occur, and the yield and the asymmetric yield are extremely high. This is a very low point.

[Wherein, Me represents a methyl group, and Ph has the same meaning as described above. ]

The optically active carboxylic acid obtained above is esterified as desired to obtain an optically active carboxylic acid ester (a compound in which ^Ra is an ester residue in compound (IV)). The esterification reaction is carried out by a known esterification method such as an alkyl esterification method (alkanol + acid catalyst), an aralkyl esterification method (aralkyl alcohol + acid catalyst), or a methylation method using diazomethane or trimethylsilyldiazomethane. be able to. In the compound (IV) thus obtained, examples of the ester residue represented by ^Ra include an alkyl group and an aralkyl group (= arylalkyl group), and the alkyl group is a straight chain having 1 to 8 carbon atoms. A branched or cyclic alkyl group, and examples of the aralkyl group include those in which the aryl group (Ar) is substituted on an alkyl group having 1 to 5 carbon atoms.

  The compound (IV) thus obtained can be isolated and purified by methods known per se, such as extraction, recrystallization, chromatography and the like, and is useful as a synthetic raw material or synthetic intermediate for bioactive compounds such as pharmaceuticals. It is.

［式中、Ｐｈ、Ａｒ、Ｒ^１およびＲ^２は前記と同意義を示す。］
で示されるキラルスルホンアミド誘導体・Ｚｎ錯体である。 Yet another aspect of the present invention is a compound of formula (Ia):

[Wherein, Ph, Ar, R ¹ and R ² are as defined above. ]
It is a chiral sulfonamide derivative and Zn complex shown by these.

［式中、Ｐｈ、Ａｒ、Ｒ^１およびＲ^２は前記と同意義を示す。］
で示される化合物をジアルキル亜鉛と反応させることにより製造することができる。 The chiral sulfonamide derivative / Zn complex (Ia) of the present invention has the formula (I):

[Wherein, Ph, Ar, R ¹ and R ² are as defined above. ]
It can manufacture by making the compound shown by react with dialkyl zinc.

  This reaction can be preferably carried out by reacting compound (I) with dialkylzinc in a suitable solvent. Examples of the solvent include dichloromethane, chloroform, ethyl acetate, diethyl ether, tetrahydrofuran, toluene, pyridine, N, N-dimethylformamide, n-hexane, and mixed solvents thereof. This reaction is preferably performed at room temperature. The amount of dialkylzinc used is usually 0.55 to 2.0 mol, preferably 0.6 to 1.0 mol, per 1 mol of compound (I). The compound (Ia) thus produced can be isolated and purified by a method known per se, for example, extraction, recrystallization and the like.

  Examples of the alkyl moiety in the dialkyl zinc used in the above reaction include an alkyl group having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms. Specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, etc. Is mentioned.

  Yet another aspect of the present invention is a method of using the chiral sulfonamide derivative / Zn complex (Ia) obtained above as a catalyst. That is,

［式中、Ｒ^３はアミノ基の保護基を示し、Ｒ^４はアルキル基、アルケニル基、またはアラルキル基を示す。］
で示される１，３−ジオール化合物と、式（ＶＩＩＩ）：

［式中、Ｒ^５はアルキル基、またはアリール基を示す。］
で示される酸無水物を、前記キラルスルホンアミド誘導体・Ｚｎ錯体（Ｉ−ａ）の存在下に反応させることにより、式（ＩＸ）：

［式中、Ｒ^３、Ｒ^４およびＲ^５は前記と同意義を示す。］
で示されるキラル１，３−ジオール・モノエステル化合物を製造する方法である。 Formula (VII):

[Wherein, R ³ represents an amino-protecting group, and R ⁴ represents an alkyl group, an alkenyl group, or an aralkyl group. ]
A 1,3-diol compound represented by formula (VIII):

[Wherein, R ⁵ represents an alkyl group or an aryl group. ]
Is reacted in the presence of the chiral sulfonamide derivative / Zn complex (Ia) to form the formula (IX):

[Wherein, R ³ , R ⁴ and R ⁵ are as defined above. ]
In which a chiral 1,3-diol monoester compound is produced.

In the prochiral 1,3-diol compound (VII) which is the starting compound, examples of the protecting group for the amino group represented by R ³ include benzyloxycarbonyl group, tert-butoxycarbonyl group, 3-nitro-2-pyridinesulfuryl group. Examples include a phenyl group, an allyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, and a p-methoxyphenyl group. In the 1,3-diol compound (VII), examples of the alkyl group represented by R ⁴ include linear, branched, or cyclic alkyl groups having 1 to 18 carbon atoms. A linear, branched or cyclic alkyl group having 2 to 16 carbon atoms is exemplified, and examples of the aralkyl group include those in which an aryl group (for example, a phenyl group) is substituted on an alkyl group having 1 to 3 carbon atoms.

In the acid anhydride (VIII) that is the other raw material compound, examples of the alkyl group represented by R ⁵ include a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms. Moreover, as an aryl group, the phenyl group which may have a substituent is mentioned, for example.

The reaction of the prochiral 1,3-diol compound (VII) with the acid anhydride (VIII) is carried out in the presence of the chiral sulfonamide derivative / Zn complex (Ia) in an appropriate solvent, under cooling or at room temperature. It can carry out suitably. Any solvent may be used as long as it is inert to the reaction. For example, t-butyl methyl ether, diethyl ether, t-amyl methyl ether, dibutyl ether, toluene, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, acetone, methyl ethyl ketone, methyl Butyl ketone, N, N-dimethylformamide, dimethyl sulfoxide, n-hexane, n-pentane, cyclohexane or a mixed solvent thereof may be used.
The amount of the chiral sulfonamide derivative / Zn complex (Ia) to be used is usually 0.01 to 0.1 mol, preferably 0.05 to 0.1, per 1 mol of the catalyst amount, that is, compound (VII). Is a mole. Moreover, the usage-amount of acid anhydride (VIII) is 1.0-3.0 mol normally with respect to 1 mol of compounds (VII), Preferably it is 1.5-3.0 mol.

  Thus, compound (VII) is mono-esterified with high enantioselectivity to obtain optically active 1,3-diol monoester compound (IX).

  Still another one of the present invention is a method for producing a chiral 1,3-diol monoester compound by producing it in a reaction system without isolating the chiral sulfonamide derivative / Zn complex. That is,

［式中、Ｒ^３、Ｒ^４は前記と同意義を示す。］
で示される１，３−ジオール化合物と、式（ＶＩＩＩ）：

［式中、Ｒ^５は前記と同意義を示す。］
で示される酸無水物を、前記キラルスルホンアミド誘導体（Ｉ）：

［式中、Ｐｈ、Ａｒ、Ｒ^１およびＲ^２は前記と同意義を示す。］
とジアルキル亜鉛の存在下に反応させることにより、式（ＩＸ）：

［式中、Ｒ^３、Ｒ^４およびＲ^５は前記と同意義を示す。］
で示されるキラル１，３−ジオール・モノエステル化合物を製造する方法である。 Formula (VII):

[Wherein R ³ and R ⁴ are as defined above. ]
A 1,3-diol compound represented by formula (VIII):

[Wherein, R ⁵ has the same meaning as described above. ]
An acid anhydride represented by the above-mentioned chiral sulfonamide derivative (I):

[Wherein, Ph, Ar, R ¹ and R ² are as defined above. ]
By reacting with dialkylzinc in the presence of formula (IX):

[Wherein, R ³ , R ⁴ and R ⁵ are as defined above. ]
In which a chiral 1,3-diol monoester compound is produced.

As the chiral sulfonamide derivative (I) and dialkylzinc used in this reaction, those described above are used. The reaction of 1,3-diol compound (VII) and acid anhydride (VIII) is carried out in the presence of chiral sulfonamide derivative (I) and dialkylzinc in an appropriate solvent at 0 to 40 ° C., preferably room temperature. It is preferably carried out in the vicinity (15 to 30 ° C.). Any solvent may be used as long as it is inert to the reaction. For example, diethyl ether, dibutyl ether, toluene, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, acetone, methyl ethyl ketone, methyl butyl ketone, N, N-dimethylformamide, dimethyl sulfoxide. , N-hexane, n-pentane, cyclohexane or a mixed solvent thereof.
The amount of the chiral sulfonamide derivative (I) to be used is generally 0.01 to 0.2 mol, preferably 0.05 to 0.1 mol, per 1 mol of the catalyst amount, that is, compound (VII). The usage-amount of dialkyl zinc is 0.01-0.2 mol normally with respect to 1 mol of chiral sulfonamide derivatives (I), Preferably it is 0.02-0.1 mol. Moreover, the usage-amount of acid anhydride (VIII) is 1.0-3.0 mol normally with respect to 1 mol of compounds (VII), Preferably it is 1.0-2.0 mol.

  Thus, compound (VII) is mono-esterified with high enantioselectivity to obtain optically active 1,3-diol monoester compound (IX).

  The compound (IX) thus obtained can be isolated and purified by methods known per se, such as extraction, recrystallization, chromatography, etc., and is useful as a synthetic raw material or synthetic intermediate for bioactive compounds such as pharmaceuticals. It is.

［式中、Ｍｅは前記と同意義を示す。］
（１Ｒ，２Ｒ）−Ｎ，Ｎ−ジメチル−１，２−ジフェニル−１，２−エタンジアミン（７２ｍｇ、０．３０ｍｍｏｌ）とｐ−トルエンスルホニルクロリド（５７ｍｇ、０．３０ｍｍｏｌ）のジクロロメタン（５ｍＬ）溶液に、アルゴン雰囲気下、トリエチルアミン（４２μＬ、０．３０ｍｍｏｌ）を室温で加え、同温で１時間撹拌した。反応液に水を加え、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去し、得られた粗生成物をカラムクロマトグラフィー（クロロホルム：メタノール＝２５：１）に付し、題記化合物（１０５ｍｇ、８９％収率）を得た。 [Example 1]
Synthesis of (1R, 2R) -N, N-dimethyl-N′-p-toluenesulfonyl-1,2-diphenyl-1,2-ethanediamine

[Wherein Me represents the same meaning as described above. ]
A solution of (1R, 2R) -N, N-dimethyl-1,2-diphenyl-1,2-ethanediamine (72 mg, 0.30 mmol) and p-toluenesulfonyl chloride (57 mg, 0.30 mmol) in dichloromethane (5 mL). Under an argon atmosphere, triethylamine (42 μL, 0.30 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to column chromatography (chloroform: methanol = 25: 1) to obtain the title compound (105 mg, 89% yield).

Melting point: 109-110 ° C
[Α] _D ¹⁹ 53.0 ° (c = 0.50, CHCl ₃ )
¹ HNMR (400 MHz, DMSO-d ₆ ) δ: 7.54-7.42 (3H, m), 7.25-6.86 (12H, m), 4.67-4.57 (1H, m) 3.77 (1H, d, J = 11.0 Hz), 2.31 (3H, s), 1.89 (6H, s)
Elemental _{analysis: C 23 H 26 N 2 O} 2 S
Calculated values: C, 70.02; H, 6.64; N, 7.10
Found: C, 69.74; H, 6.66; N, 7.02

［式中、Ｍｅは前記と同意義を示す。］
（１Ｒ，２Ｒ）−Ｎ，Ｎ−ジメチル−１，２−ジフェニル−１，２−エタンジアミン（７５２ｍｇ、３．１３ｍｍｏｌ）と３，５−ビス（トリフルオロメチル）ベンゼンスルホニルクロリド（９７８ｍｇ、３．１３ｍｍｏｌ）のジクロロメタン（３０ｍＬ）溶液に、アルゴン雰囲気下、トリエチルアミン（４３６μＬ、３．１３ｍｍｏｌ）を室温で加え、同温で１時間撹拌した。反応液に水を加え、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去し、得られた粗製物をカラムクロマトグラフィー（クロロホルム：メタノール＝２５：１）に付し、題記化合物（１．２３ｇ、７６％収率）を得た。本品をクロロホルム−ヘキサンで再結晶することにより無色針状晶を得た。 [Example 2]
Synthesis of (1R, 2R) -N, N-dimethyl-N′-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine (part 1):

[Wherein Me represents the same meaning as described above. ]
(1R, 2R) -N, N-dimethyl-1,2-diphenyl-1,2-ethanediamine (752 mg, 3.13 mmol) and 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (978 mg, 3. To a solution of 13 mmol) in dichloromethane (30 mL), triethylamine (436 μL, 3.13 mmol) was added at room temperature under an argon atmosphere, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to column chromatography (chloroform: methanol = 25: 1) to obtain the title compound (1.23 g, 76% yield). The product was recrystallized from chloroform-hexane to obtain colorless needle crystals.

Melting point: 168-169 ° C
[Α] _D ¹⁸ 131.5 ° (c = 1.21, CHCl ₃ )
¹ HNMR (400 MHz, DMSO-d ₆ ) δ: 8.61 (1H, bs), 8.20 (1H, s), 8.05 (2H, s), 7.15-6.93 (7H, m ), 6.84-6.73 (3H, m), 4.95 (1H, d, J = 11.2 Hz), 3.86 (1H, d, J = 11.2 Hz), 1.96 (6H , S)
Elemental _{analysis: C 24 H 22 F 2 N} 2 O 2 S
Calculated value: C, 55.81; H, 4.29; N, 5.42
Found: C, 55.61; H, 4.35; N, 5.37

（１Ｒ，２Ｒ）−１，２−ジフェニル−１，２−エタンジアミン（１．７ｇ、８．０ｍｍｏｌ）および３，５−ビス（トリフルオロメチル）ベンゼンスルホニルクロリド（２．５ｇ、８．０ｍｍｏｌ）のジクロロメタン（８０ｍＬ）溶液にトリエチルアミン（１．１５ｍＬ、８．０ｍｍｏｌ）を室温で加え、同温で３０分間撹拌した。反応液を１Ｎ ＮａＯＨ水溶液（１５０ｍＬ）で処理した後、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去し、得られた粗製物をテトラヒドロフラン（８０ｍＬ）に溶かし、その溶液にＮａＨ（ミネラルオイル中に６０％ｗ／ｗ含有、８００ｍｇ、２０ｍｍｏｌ）およびＭｅＩ（１．２４５ｍＬ、２０ｍｍｏｌ）を室温で撹拌しながら加えた。その混合液を１時間煮沸し、水を加えた後、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去し、得られた粗製物をカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：３）に付し、題記化合物（２．８ｇ、６８％収率）を得た。本品をクロロホルム−ヘキサンで再結晶することにより無色針状晶を得た。 Synthesis of (1R, 2R) -N, N-dimethyl-N′-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine (Part 2):

(1R, 2R) -1,2-diphenyl-1,2-ethanediamine (1.7 g, 8.0 mmol) and 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (2.5 g, 8.0 mmol) Triethylamine (1.15 mL, 8.0 mmol) was added to a dichloromethane (80 mL) solution at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was treated with 1N aqueous NaOH (150 mL), extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was dissolved in tetrahydrofuran (80 mL), and NaH (containing 60% w / w in mineral oil, 800 mg, 20 mmol) and MeI (1.245 mL, 20 mmol) were dissolved in the solution. ) Was added at room temperature with stirring. The mixture was boiled for 1 hour, water was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound (2.8 g, 68% yield). The product was recrystallized from chloroform-hexane to obtain colorless needle crystals.

[Example 3]
Catalytic enantioselective thiolysis of 3-phenylglutaric anhydride 3-phenylglutaric anhydride (190 mg, 1.0 mmol) and (1R, 2R) -N, N-dimethyl-N ′ obtained in Example 2 Benzyl mercaptan was added to a diethyl ether solution (10 mL) of 3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine (25.8 mg, 0.05 mmol) under an argon atmosphere. (141 μL, 1.2 mmol) was added at room temperature and stirred at the same temperature for 20 hours. To the reaction solution was added 10% hydrochloric acid, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product [(S) -5- (benzylthio) -5-oxo-3-phenylpentanoic acid] was dissolved in benzene-methanol (7: 2) (9 mL), Trimethylsilyldiazomethane (2.0 M in ether, 1 mL, 2.0 mmol) was added at room temperature and stirred at the same temperature for 15 minutes. Thereafter, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to column chromatography (ethyl acetate: hexane = 1: 4) to give (S) -5- (benzylthio) -5-oxo-3. -Phenylpentanoic acid methyl ester (312 mg, 95% yield, 91% ee) was obtained as white crystals. The% ee indicates an enantio excess.

Melting point: 34.5-35 ° C
[Α] _D ²⁰ 43.7 ° (c = 1.10, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.34-7.07 (10H, m), 4.05 (2H, s), 3.77-3.67 (1H, m), 3.57 (3H , S), 2.96 (1H, dd, J = 15.1 and 7.1 Hz), 2.91 (1H, dd, J = 15.1 and 7.8 Hz), 2.73 (1H, dd, J = 15.6 and 6.8 Hz), 2.65 (1H, dd, J = 15.6 and 8.1 Hz)
Elemental analysis value: C ₁₉ H ₂₀ O ₃ S
Calculated value: C, 69.48; H, 6.14
Found: C, 69.22; H, 6.12
The enantiomeric excess was determined by a Daicel chiral OD-H column (hexane: isopropanol = 19: 1, flow rate = 1 mL / min). The absolute configuration of the product was determined by converting it into a known keto ester (see Reference Example 1 described later).

[Example 4]
In Example 3, (1R, 2R) -N, N-dimethyl-N′-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine (25) was used as a catalyst. (1R, 2R) -N, N-dimethyl-N′-p-toluenesulfonyl-1,2-diphenyl-1,2-ethanediamine obtained in Example 1 instead of .8 mg, 0.05 mmol) (39.4 mg, 0.05 mmol) was used and the same treatment as in Example 3 was carried out except that toluene was used in place of diethyl ether as a solvent to give 3-phenylglutaric anhydride (190 mg, 1.0 mmol). And mercaptan (141 μL, 1.2 mmol) from (S) -5- (benzylthio) -5-oxo-3-phenylpentanoic acid to (S) -5- (benzylthiol). E) Methyl 5-oxo-3-phenylpentanoate (256 mg, 78% yield, 83% ee) was obtained.

[Examples 5a to 5h]
In Example 3, the amount of (1R, 2R) -N, N-dimethyl-N′-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine as a catalyst In the same manner as in Example 3 except that the type of solvent and the reaction temperature were as shown in Table 1 below, 3-phenylglutaric anhydride (190 mg, 1.0 mmol) and benzyl mercaptan (141 μL, 1.. 2 mmol) to (S) -5- (benzylthio) -5-oxo-3-phenylpentanoic acid to give (S) -5- (benzylthio) -5-oxo-3-phenylpentanoic acid methyl ester in the following table. 1 and the enantio excess was obtained.
As a comparative example, the results when the following compounds A to C were used instead of the catalyst of the present invention are also shown in Table 1 below.

［式中、ＭｅおよびＰｈはそれぞれ前記と同意義を示す。］

[Wherein, Me and Ph are as defined above. ]

なお、表１中、Ｂｎはベンジル基を、ＰｈおよびＭｅは、それぞれ前記と同意義を示す。また、ＴＭＳＣＨＮ_２は、トリメチルシリルジアゾメタンを意味し、Ｅｔはエチル基を意味し、ＴＨＦはテトラヒドロフランを意味する。

In Table 1, Bn is a benzyl group, and Ph and Me are as defined above. TMSCHN ₂ means trimethylsilyldiazomethane, Et means an ethyl group, and THF means tetrahydrofuran.

[Example 6]
In Example 3, except that 3-methylglutaric anhydride was used instead of 3-phenylglutaric anhydride, the same procedure as in Example 3 was performed, whereby (S) -5- (benzylthio)- 3-Methyl-5-oxopentanoic acid methyl ester was obtained as a colorless oil (87% yield, 91% ee).
[Α] _D ²⁰ 5.4 ° (c = 1.24, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.34-7.19 (5H, m), 4.12 (2H, s), 3.66 (3H, s), 2.69-2.45 (3H) M), 2.39 (1H, dd, J = 15.4 and 5.9 Hz), 2.23 (1H, dd, J = 15.4 and 7.3 Hz), 1.01 (3H, d, J = 6.3Hz)
Elemental analysis value: C ₁₄ H ₁₈ O ₃ S
Calculated value: C, 63.13; H, 6.81
Found: C, 63.05; H, 6.85
The enantiomeric excess was determined with a Daicel chiral OD-H column (hexane: isopropanol = 15: 1, flow rate = 0.7 mL / min). In addition, the absolute configuration of the product was converted to (R) -3-methyl-5-oxophenylpentanoic acid methyl ester ester and determined by comparison with literature values of known corresponding (S) isomers (see below) Example 2).

[Example 7]
In Example 3, (2S, 4R) -5-5 was performed in the same manner as in Example 3 except that 2,4-dimethylglutaric anhydride was used instead of 3-phenylglutaric anhydride. (Benzylthio) -2,4-dimethyl-5-oxopentanoic acid methyl ester was obtained as a colorless oil (100% yield, 90% ee).
[Α] _D ²⁰ −17.2 ° (c = 1.05, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.33-7.20 (5H, m), 4.11 (2H, s), 3.66 (3H, s), 2.76-2.65 (1H M), 2.56-2.45 (1H, m), 2.20-2.11 (1H, m), 1.54-1.44 (1H, m), 1.20 (3H, d) , J = 7.1 Hz), 1.17 (3H, J = 7.1 Hz)
Elemental analysis value: C ₁₅ H ₂₀ O ₃ S
Calculated value: C, 64.26; H, 7.19
Found: C, 64.09; H, 7.15

[Example 8]
In Example 3, instead of 3-phenylglutaric anhydride, 3- (tert-butyldimethylsiloxy) glutaric anhydride was used except that (S)- 5- (Benzylthio) -3- (tert-butyldimethylsiloxy) -5-oxopentanoic acid methyl ester was obtained as a colorless oil (88% yield, 93% ee).
[Α] _D ²⁰ 16.6 ° (c = 1.38, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.32-7.21 (5H, m), 4.62-4.53 (1H, m), 4.14 (1H, d, J = 13.7 Hz) 4.09 (1H, d, J = 13.7 Hz), 3.66 (3H, s), 2.83 (1H, dd, J = 14.9 and 6.6 Hz), 2.77 (1H, dd, J = 14.9 and 5.7 Hz), 2.56 (1H, dd, J = 15.1 and 5.9 Hz), 2.51 (1H, dd, J = 15.1 and 6.6 Hz) , 0.83 (9H, s), 0.05 (3H, s), 0.04 (3H, s)
Elemental analysis value: C ₁₉ H ₃₀ O ₄ SSi
Calculated value: C, 59.65; H, 7.90
Found: C, 59.39; H, 7.85

[Example 9]
In Example 3, (1R, 3S) -3 was carried out in the same manner as in Example 3 except that cyclohexane-1,3-dicarboxylic acid anhydride was used instead of 3-phenylglutaric acid anhydride. -(Benzylthio) carbonyl-cyclohexanecarboxylic acid methyl ester was obtained as a colorless oil (90% yield, 98% ee).
[Α] _D ²⁰ −22.6 ° (c = 1.42, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.35-7.20 (5H, m), 4.11 (2H, s), 3.66 (3H, s), 2.58-2.48 (1H M), 2.38-2.28 (1H, m), 2.6-2.18 (1H, m), 2.03-1.85 (3H, s), 1.68-1.56. (1H, m), 1.49-1.24 (3H, m)
Elemental analysis value: C ₁₆ H ₂₀ O ₃ S
Calculated value: C, 65.72; H, 6.89
Found: C, 65.42; H, 6.90

[Example 10]
In Example 3, except that 3-cyclohexene-1,6-dicarboxylic anhydride was used instead of 3-phenylglutaric anhydride, the same procedure as in Example 3 was carried out to obtain (1R, 6S). -6- (Benzylthio) carbonyl-cyclohex-3-enecarboxylic acid methyl ester was obtained as a colorless oil (90% yield, 83% ee).
[Α] _D ²⁰ −15.6 ° (c = 1.17, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.32-7.19 (5H, m), 5.74-5.64 (2H, m), 4.16 (1H, d, J = 13.7 Hz) 4.10 (1H, d, J = 13.7 Hz), 3.65 (3H, s), 3.22-3.15 (1H, m), 3.10-3.03 (1H, m) 2.66-2.31 (4H, m)
Elemental analysis value: C ₁₆ H ₁₈ O ₃ S
Calculated value: C, 66.18; H, 6.25
Found: C, 65.94; H, 6.29

なお、上記表２において、ＴＢＳＯはｔｅｒｔ−ブチルジメチルシリルオキシ基を意味し、Ｂｎ、Ｍｅはぞれぞれ前記と同意義を意味する。 Table 2 summarizes the results of Examples 6-10.

In Table 2, TBSO means a tert-butyldimethylsilyloxy group, and Bn and Me have the same meanings as described above.

[Reference Example 1]
(S) -5- (Benzylthio) -5-oxo-3-phenylpentanoic acid methyl ester obtained in Example 3 (100 mg, 0.30 mmol) and iron (III) acetylacetonate (21.5 mg, .0. To a solution of (061 mmol) in tetrahydrofuran (5 mL) was added ethylmagnesium bromide (0.98 M in tetrahydrofuran, 747 mmol) at −78 ° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 4 hours. To the reaction solution was added 10% hydrochloric acid, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to column chromatography (ethyl acetate: hexane = 1: 4) to give (R) -5-oxo-3-phenylpentanoic acid methyl ester (59 mg). 83% yield, 91% ee) as white crystals.

Melting point: 36-36.5 ° C
[Α] _D ²⁰ 31.5 ° (c = 0.75, C ₆ H ₆ ) [(R) literature value: [α] _D ²⁰ 35.3 ° (c = 2-3, C ₆ H ₆ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.32-7.16 (5H, m), 3.72-3.65 (1H, m), 3.58 (3H, s), 2.82 (1H , Dd, J = 16.6 and 7.1 Hz), 2.77 (1H, dd, J = 16.6 and 7.3 Hz), 2.69 (1H, dd, J = 15.3 and 7.2 Hz). ) 2.61 (1H, dd, J = 15.3 and 7.7 Hz), 2.41-2.23 (2H, m), 0.96 (3H, t, J = 7.3 Hz)
Elemental analysis value: C ₁₄ H ₁₈ O ₃
Calculated value: C, 71.77; H, 7.74
Found: C, 71.49; H, 7.72

[Reference Example 2]
The (S) -5- (benzylthio) -3-methyl-5-oxopentanoic acid methyl ester obtained in Example 6 was treated in the same manner as in Reference Example 1 to give (R) -3-methyl-5-oxo. Phenylpentanoic acid methyl ester was obtained as a colorless oil.
^{_{[Α] D 18 3.14 ° (}} c = 1.05, C 6 H 6) [ literature value of S form corresponding to the ^{_{product: [α] D 18 -5.65 °}} (c = 1.24, C ₆ H ₆ )]
¹ HNMR (400 MHz, CDCl ₃ ) δ: 8.01-7.91 (2H, m), 7.61-7.52 (1H, m), 7.51-7.41 (2H, m), 3 .68 (3H, s), 3.11 (1H, dd, J = 16.4 and 5.9 Hz), 2.85 (1H, dd, J = 16.4 and 7.6 Hz), 2.73− 2.61 (1H, m), 2.45 (1H, dd, J = 15.1 and 6.6 Hz), 2.33 (1H, dd, J = 15.1 and 7.1 Hz), 1.05 (3H, d, J = 6.8Hz)

[Example 11]
Catalytic enantioselective alcoholysis of 3-phenylglutaric anhydride 3-phenylglutaric anhydride (190 mg, 1.0 mmol) and (1R, 2R) -N, N-dimethyl-N ′ obtained in Example 2 -3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine (25.8 mg, 0.05 mmol) in diethyl ether (10 mL) was added to benzyl alcohol under an argon atmosphere. (125 mL, 1.2 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 20 hours. To the reaction solution was added 10% hydrochloric acid, extracted with chloroform, and dried over anhydrous magnesium sulfate. The crude product [(S) -5-benzyloxy-3-phenyl-5-oxopentanoic acid] obtained by distilling off the solvent under reduced pressure was dissolved in benzene-methanol (7: 2) (9 mL), and trimethylsilyl was dissolved. Diazomethane (2.0 M in Et ₂ O, 1 mL, 2.0 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Thereafter, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to column chromatography (ethyl acetate: hexane = 1: 4) to give (S) -5-benzyloxy-3-phenyl-5-oxo. Pentanoic acid methyl ester (286 mg, 92% yield, 87% ee) was obtained as a colorless oil.
[A] _D ²⁰ 2.4 ° (c = 1.05, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.34-7.15 (10H, m), 5.01 (2H, s), 3.71-3.61 (1H, m), 3.58 (3H , S), 2.79 (1H, dd, J = 15.6 and 6.8 Hz), 2.72 (1H, dd, J = 15.6 and 7.1 Hz), 2.70 (1H, dd, J = 15.6 and 8.3 Hz), 2.64 (1H, dd, J = 15.6 and 8.1 Hz)
Elemental analysis value: C ₁₉ H ₂₀ O ₄
Calculated value: C, 73.06; H, 6.45
Found: C, 72.82; H, 6.54
In addition, the enantio excess of the product is a Daicel Chiralcel AD-H column (hexane: isopropanol = 15.1, flow rate = 1 mL / min, retention time: 14.4 minutes [major, (S) -enantiomer], 16. 1 min [minor, (R) -enantiomer]). The absolute configuration of the product was converted to a known thiol ester [ie, (S) -5-benzylthio-3-phenyl-5-oxopentanoic acid methyl ester] and determined by HPLC retention time (Reference Example 3 described later). reference).

[Example 12]
(S) -5-benzyloxy-3 was carried out in the same manner as in Example 11 except that 3-methylglutaric anhydride was used in place of 3-phenylglutaric anhydride. -Methyl-5-oxopentanoic acid methyl ester (86% yield, 83% ee) was obtained as a colorless oil.
[Α] _D ²⁶ 3.1 ° (c = 1.05, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.39-7.29 (5H, m), 5.12 (2H, s), 3.66 (3H, s), 2.54-2.35 (3H M), 2.29 (1H, dd, J = 15.1 and 7.3 Hz), 2.24 (1H, dd, J = 15.1 and 7.6 Hz), 1.02 (3H, d, J = 6.6Hz)
Elemental analysis value: C ₁₄ H ₁₈ O ₄
Calculated value: C, 67.18; H, 7.25
Found: C, 66.91; H, 7.34
In addition, the enantio excess of the product is a Daicel Chiralcel OB-H column (hexane: isopropanol = 4: 1, flow rate = 0.5 mL / min, retention time: 18.8 minutes [major, (S) -enantiomer], 24.7 min [minor, (R) -enantiomer] and the absolute configuration of the product is known thiol ester [ie methyl (S) -5-benzylthio-3-methyl-5-oxopentanoate. Ester] and determined by HPLC retention time.

[Example 13]
In Example 11, in place of 3-phenylglutaric anhydride, 3- (tert-butyldimethylsiloxy) glutaric anhydride was used except that (S)- 5-Benzyloxy-3- (tert-butyldimethylsiloxy) -5-oxopentanoic acid methyl ester (86% yield, 91% ee) was obtained as a colorless oil.
[A] _D ²⁵ -1.4 ° (c = 0.98, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.42-7.29 (5H, m), 5.13 (1H, d, J = 12.5 Hz), 5.10 (1H, d, J = 12. 5Hz), 4.61-4.53 (1H, m), 3.66 (3H, s), 2.65-2.53 (4H, m), 0.83 (9H, s), 0.05 (3H, s), 0.04 (3H, s)
Elemental analysis value: C ₁₉ H ₃₀ O ₅ Si
Calculated value: C, 62.26; H, 8.25
Found: C, 62.00; H, 8.30
The enantiomeric excess of the product was converted to a known thiol ester [ie (S) -5-benzylthio-3- (tert-butyldimethylsiloxy) -5-oxopentanoic acid methyl ester] and determined by HPLC. The absolute configuration of the product was determined by the HPLC retention time of the thiol ester.

[Example 14]
In Example 11, (1R, 3S) -3 was carried out in the same manner as in Example 11 except that cyclohexane-1,3-dicarboxylic acid anhydride was used instead of 3-phenylglutaric acid anhydride. -Benzyloxycarbonyl-cyclohexanecarboxylic acid methyl ester (90% yield, 98% ee) was obtained as a colorless oil.
[Α] _D ²⁶ -9.0 ° (c = 0.98, CHCl ₃ )
¹ HNMR (400 MHZ, CDCl ₃ ) σ: 7.42-7.28 (5H, m), 5.11 (2H, s), 3.67 (3H, s), 2.55-2.20 (3H , M), 2.08-1.82 (3H, m), 1.70-1.51 (1H, m), 1.47-1.23 (3H, m)
Elemental analysis value: C ₁₆ H ₂₀ O ₄
Calculated value: C, 69.54; H, 7.30
Analytical value: C, 69.28; H, 7.45
The enantiomeric excess of the product was converted to the known thiol ester [ie (1R, 3S) -3- (benzylthio) carbonyl-cyclohexanecarboxylic acid methyl ester] and determined by HPLC. The absolute configuration of the product was determined by the HPLC retention time of known thiol esters.

[Example 15]
In Example 11, except that 3-cyclohexene-1,6-dicarboxylic acid anhydride was used instead of 3-phenylglutaric anhydride, the same procedure as in Example 11 was carried out to give (1R, 6S ) -6-benzyloxycarbonyl-cyclohex-3-ene-carboxylic acid methyl ester (95% yield, 98% ee) was obtained as a colorless oil.
[Α] _D ²⁶ −1.6 ° (c = 1.23, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.41-7.28 (5H, m), 5.68 (2H, br. S), 5.13 (2H, s), 3.57 (3H, s ), 3.14-3.03 (2H, m), 2.67-2.50 (2H, m), 2.45-2.30 (2H, m)
Elemental analysis value: C ₁₆ H ₁₈ O ₄
Calculated value: C, 70.06; H, 6.61
Found: C, 70.05; H, 6.72
The enantiomeric excess of the product is a Daicel Chiralcel OD-H column (hexane: isopropanol = 15: 1, flow rate = 0.5 mL / min, retention time: 15.8 min [minor, (1S, 6R) -enantiomer. ] 17.5 minutes [major, (1R, 6S) -enantiomer]). The absolute configuration of the product was converted to a known amide [ie (1S, 2R) -2-methoxycarbonyl-cyclohexanecarboxylic acid N-phenylamide] and determined by HPLC retention time (see Reference Example 4 below). .

[Example 16]
In Example 11, (1R, 2S) -2 was carried out in the same manner as in Example 11 except that cyclohexane-1,2-dicarboxylic anhydride was used instead of 3-phenylglutaric anhydride. -Benzyloxycarbonyl-cyclohexane-1-carboxylic acid methyl ester (99% yield, 98% ee) was obtained as a colorless oil.
[Α] _D ²⁶ −0.53 ° (c = 0.08, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.39-7.28 (5H, m), 5.13 (1H, d, J = 12.5 Hz), 5.11 (1H, d, J = 12. 5Hz), 3.57 (3H, s), 2.90-2.82 (2H, m), 2.08-1.96 (2H, m), 1.84-1.72 (2H, m) , 1.57-1.46 (2H, m), 1.45-1.34 (2H, m)
Elemental analysis value: C ₁₆ H ₂₀ O ₄
Calculated value: C, 69.54; H, 7.30
Analytical value: C, 69.26; H, 7.35
The enantiomeric excess of the product is the Daicel Chiralcel OJ-H column (hexane: isopropanol = 15: 1, flow rate = 0.75 mL / min, retention time: 14.6 min [minor, (1S, 2R) -enantiomer], 16.4 min [major, (1R, 2S) -enantiomer] and the absolute configuration of the product is known amide [ie (1S, 2R) -2-methoxycarbonyl-cyclohexane-1-carboxylic acid N-phenylamide] and determined by HPLC retention time.

[Example 17]
In Example 11, it replaces with 3-phenylglutaric anhydride and it uses like cyclohexanic acid except that bicyclo [2.2.1] hepta-5-ene-2,3-dicarboxylic anhydride is used. By carrying out, (2R, 3S) -3-endo-benzyloxycarbonyl-bicyclo [2.2.1] hept-5-en-2-endo-carboxylic acid methyl ester was obtained as a colorless oil (91 % Yield, 98% ee).
[Α] _D ²⁸ 3.8 ° (c = 1.05, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.38-7.28 (5H, m), 6.30-6.20 (2H, m), 5.07 (1H, d, J = 12.5 Hz) , 5.01 (1H, d, J = 12.5 Hz), 3.51 (3H, s), 3.37-3.25 (2H, m), 3.21-3.13 (2H, m) , 1.50-1.43 (1H, m), 1.35-1.29 (1H, m)
Elemental analysis value: C ₁₇ H ₁₈ O ₄
Calculated value: C, 71.31; H, 6.34
Found: C, 71.03; H, 6.34
It should be noted that the enantiomeric excess of the product is a known diester [ie (2R, 3S) -3-endo- (4-bromophenyloxycarbonyl) -bicyclo [2.2.1] hept-5-en-2- Endo-carboxylic acid methyl ester] and determined by HPLC. The absolute configuration of the product was determined by the HPLC retention time of a known diester (see Reference Example 5).

[Example 18]
In Example 11, Example 7 was used except that 7-oxabicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic anhydride was used instead of 3-phenylglutaric anhydride. By carrying out in the same manner, (2S, 3R) -3-exo-benzyloxycarbonyl-7-oxabicyclo [2.2.1] hept-5-en-2-exo-carboxylic acid methyl ester (89% Yield, 97% ee) was obtained as a colorless oil.
[Α] _D ²⁷ -13.7 ° (c = 0.89, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.42-7.30 (5H, m), 6.47-6.43 (2H, m), 5.29-5.26 (2H, m), 5 .15 (1H, d, J = 12.5 Hz), 5.13 (1H, d, J = 12.5 Hz), 3.55 (3H, s), 2.87-2.80 (2H, m)
Elemental analysis value: C ₁₆ H ₁₆ O ₅
Calculated value: C, 66.66; H, 5.59
Found: C, 66.24; H, 5.67
The enantiomeric excess of the product is a Daicel Chiralcel OJ-H column (hexane: isopropanol = 4: 1, flow rate = 1.5 ml / min, retention time: 25.8 min [minor, (2R, 3S) -enantiomer. 31.8 min [major, (2S, 3R) -enantiomer] and the absolute configuration of the product is known carboxylic acid [ie (2S, 3R) -3-exo-carboxyl-7-oxa Bicyclo [2.2.1] hept-5-ene-2-exo-carboxylic acid methyl ester] and determined by optical rotation (see Reference Example 6).

なお、上記表３において、Ｐｈ、ＴＢＳＯ、ＢｎおよびＭｅはそれぞれ前記と同意義を意味する。 Table 3 summarizes the results of Examples 11-18.

In Table 3, Ph, TBSO, Bn, and Me have the same meaning as described above.

[Reference Example 3]
(S) -5-Benzyloxy-3-phenyl-5-oxopentanoic acid methyl ester (165 mg, 0.528 mmol) and Pd · C (10% w / w, 28 mg, 0.0264 mmol) obtained in Example 11 ) In ethanol (5 mL) under hydrogen atmosphere at room temperature for 1.5 hours. The reaction mixture was filtered, the solvent was distilled off under reduced pressure, and the resulting crude product was dissolved in dichloromethane (5 mL). Under an argon atmosphere, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( EDC.HCl) (152 mg, 0.79 mmol), 4-dimethylaminopyridine (DMAP) (19 mg, 0.158 mmol), and benzyl mercaptan (BnSH) (68 mL, 0.579 mmol) were added. After stirring at room temperature for 2 hours, 10% hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to column chromatography (ethyl acetate: hexane = 1: 4) to give (S) -5-benzylthio- 3-Phenyl-5-oxopentanoic acid methyl ester (141 mg, 82%) was obtained.
Melting point: 34.5-35 ° C
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.34-7.07 (10H, m), 4.05 (2H, s), 3.77-3.67 (1H, m), 3.57 (3H , S), 2.96 (1H, dd, J = 15.1 and 7.1 Hz), 2.91 (1H, dd, J = 15.1 and 7.8 Hz), 2.73 (1H, dd, J = 15.6 and 6.8 Hz), 2.65 (1H, dd, J = 15.6 and 8.1 Hz)
HPLC: Daicel Chiralcel OD-H column (hexane: isopropanol = 19: 1, flow rate = 1.0 mL / min, retention time: 14.7 min [major, (S) -enantiomer], 24.8 min [minor, (R) -enantiomer]) (absolute configuration determined by comparison with HPLC retention time of a sample synthesized by the method described in the literature.)

[Reference Example 4]
(1R, 6S) -6-Benzyloxycarbonyl-cyclohex-3-enecarboxylic acid methyl ester (35.6 mg, 0.130 mmol) and Pd.C (10% w / w, 6.9 mg, 0.006 mmol) Stir in ethanol (5 mL) solvent at room temperature under hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered, the solvent was distilled off under reduced pressure, and the resulting crude product was dissolved in dichloromethane (5 mL). Under an argon atmosphere, EDC.HCl (37.4 mg, 0.195 mmol), DMAP (4. 8 mg, 0.039 mmol) and aniline (13 mL, 0.143 mmol) were added. After stirring at room temperature for 2 hours, 10% hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to column chromatography (ethyl acetate: hexane = 1: 2) to give (1S, 2R) -2- Methoxycarbonyl-cyclohexane-1-carboxylic acid N-phenylamide (24.7 mg, 73%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.59 (1H, brs), 7.54-7.44 (2H, m), 7.38-7.27 (2H, m), 7.13- 7.05 (1H, m), 3.67 (3H, s), 3.01-2.92 (1H, m), 2.84-2.75 (1H, m), 2.24-2. 04 (2H, m), 1.95-1.16 (8H, m)
HPLC: Daicel Chiralcel OJ-H column (hexane: isopropanol = 4: 1, flow rate = 0.5 mL / min, retention time: 16.2 minutes [minor, (1R, 2S) -enantiomer], 18.0 minutes [ Major, (1S, 2R) -enantiomer]) (absolute configuration determined by comparison with HPLC retention time of a standard synthesized by the method described in the literature)

[Reference Example 5]
(2R, 3S) -3-endo-benzyloxycarbonyl-bicyclo [2.2.1] hept-5-en-2-endo-carboxylic acid methyl ester (41.7 mg, 0.146 mmol) and Pd · C ( 10% w / w, 7.8 mg, 0.007 mmol) in ethanol (5 mL) solvent was stirred for 1.5 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered, the solvent was distilled off under reduced pressure, and the resulting crude product was dissolved in dichloromethane (5 mL). Under an argon atmosphere, EDC · HCl (41.9 mg, 0.219 mmol), DMAP (5. 3 mg, 0.044 mmol) and 4-bromophenol (30.3 mg, 0.175 mmol) were added. After stirring at room temperature for 2 hours, 10% hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to column chromatography (ethyl acetate: hexane = 1: 4) to give (2R, 3S) -3- Endo- (4-bromophenyloxycarbonyl) -bicyclo [2.2.1] hept-5-en-2-endo-carboxylic acid methyl ester (47.2 mg, 92%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.50-7.44 (2H, m), 7.05-6.99 (2H, m), 3.66 (3H, s), 3.21-3 .08 (2H, m), 2.70-2.60 (2H, m), 2.04-1.95 (1H, m), 1.69-1.59 (1H, m), 1.58 -1.41 (4H, m)
HPLC: Daicel Chiralcel OD-H column (n-heptane: isopropanol = 98: 2, flow rate = 0.5 mL / min, retention time: 15.4 minutes [major, (2S, 3R) -enantiomer], 18.8 Min [minor, (2R, 3S) -enantiomer])

[Reference Example 6]
(2S, 3R) -3-exo-benzyloxycarbonyl-7-oxabicyclo [2.2.1] hept-5-ene-2-exo-carboxylic acid methyl ester (148.1 mg, 0.518 mmol) and Pd -C (10% w / w, 27.5 mg, 0.025 mmol) in ethanol (5 mL) was stirred for 1 hour at room temperature in a hydrogen atmosphere. The reaction mixture was filtered, and the solvent was distilled off under reduced pressure. (2S, 3R) -3-exo-carboxyl-7-oxabicyclo [2.2.1] hept-5-en-2-exo-carboxylate methyl The ester (98 mg, 95%) was obtained.
Melting point: 101.5-102.5 ° C
[Α] _D ²⁸ 4.1 ° (c = 2.52, MeOH) (2S, 3R-enantiomer: 93% ee: literature value [α] _D ^rt 4.7 ° (c = 2.11, MeOH))
¹ HNMR (400 MHz, CDCl ₃ ) δ: 4.99-4.85 (2H, m), 3.67 (3H, s), 3.07-2.96 (2H, m), 1.89-1 .75 (2H, m), 1.59-1.47 (2H, m)

［式中、Ｍｅ、Ｅｔ、Ｐｈは前記と同意義を示す。］
（１Ｒ，２Ｒ）−Ｎ，Ｎ−ジメチル−Ｎ’−３，５−ビス（トリフルオロメチル）ベンゼンスルホニル−１，２−ジフェニル−１，２−エタンジアミン（５１６ｍｇ、１．０ｍｍｏｌ）のクロロホルム（５ｍＬ）溶液に、ジエチル亜鉛（１．０Ｍ ｎ−ヘキサン溶液、５５０μＬ、０．５５ｍｍｏｌ）を加え、室温で１分間撹拌した。減圧下溶媒を留去し、生成した白色粉末にメタノール（５ｍＬ）を加え、メタノールに不溶性の白色不純物を濾取することで取り除いた。メタノールを減圧下留去することによって題記化合物（５４８ｍｇ、１００％）を得た。 [Example 19]
Synthesis of (1R, 2R) -N, N-dimethyl-N′-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine-Zn complex

[Wherein, Me, Et and Ph are as defined above. ]
(1R, 2R) -N, N-dimethyl-N′-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine (516 mg, 1.0 mmol) in chloroform ( 5 mL), diethylzinc (1.0 M n-hexane solution, 550 μL, 0.55 mmol) was added and stirred at room temperature for 1 minute. The solvent was distilled off under reduced pressure, methanol (5 mL) was added to the resulting white powder, and white impurities insoluble in methanol were removed by filtration. Methanol was distilled off under reduced pressure to give the title compound (548 mg, 100%).

Melting point: 201.5-203 ° C
[Α] _D ²⁵ + 35.4 ° (c = 1.05, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.91 (4H, s), 7.62 (2H, s), 7.30-7.20 (10H, m), 7.03-6.94 (4H M), 6.81-6.75 (6H, m), 5.05 (2H, d, J = 11.5 Hz), 4.67 (2H, d, J = 11.5 Hz), 2.77. (6H, s), 2.73 (6H, s)
Elemental _{analysis: C 48 H 42 F 12 N} 4 O 4 S 2 Zn
Calculated values: C, 52.58; H, 3.86; N, 5.11
Found: C, 52.29; H, 3.89; N, 5.05

[Example 20]
Synthesis of (S) -2-[(tert-butoxycarbonyl) amino] -2-methyl-3-acetoxy-propanol 2-[(tert-butoxycarbonyl) amino] -2-methyl-1,3-propanediol ( 205 mg, 1.0 mmol) and (1R, 2R) -N, N-dimethyl-N′-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1, which was obtained in Example 19. Acetic anhydride (142 μL, 1.5 mmol) was added to a solution of 2-ethanediamine-Zn complex (54.8 mg, 0.05 mmol) in t-butyl methyl ether (10 mL) at 0 ° C., and the mixture was stirred at the same temperature for 20 hours. . To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to column chromatography (n-hexane: ethyl acetate = 1: 1) to give (S) -2-[(tert-butoxycarbonyl) amino]- 2-Methyl-3-acetoxy-propanol (227 mg, 92% yield, 88% ee) was obtained as a white powder.

Melting point: 63.5-65 ° C
[Α] _D ²⁵ + 12.8 ° (c = 1.25, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 4.90 (1H, br s), 4.25 (1H, d, J = 11.2 Hz), 4.19 (1H, d, J = 11.2 Hz), 3.93 (1H, br s), 3.65 (1 H, d, J = 11.7 Hz), 3.59 (1 H, d, J = 11.7 Hz), 2.11 (3H, s), 1 .44 (9H, s), 1.25 (3H, s)
Elemental analysis value: C ₁₁ H ₂₁ NO ₅
Calculated values: C, 53.43; H, 8.56; N, 5.66
Found: C, 53.30; H, 8.49; N, 5.66
The enantiomeric excess is a Daicel chiral pack IA column (n-hexane: isopropanol = 50: 1, flow rate = 1.0 mL / min, wavelength 220 nm, retention time: 18.8 min [major, (S) -enantiomer], 25.2 min [minor, (R) -enantiomer]). In addition, the absolute configuration of the product is a known methyl (R) -N- (tert-butoxycarbonyl) -2-methylselinate [= (2R) -2-methyl-2-[(tert-butoxycarbonyl) amino] To -3-hydroxy-propionic acid methyl ester] (see Reference Example 7 below).

[Example 21]
In Example 20, instead of 2-[(tert-butoxycarbonyl) amino] -2-methyl-1,3-propanediol, 2-[(tert-butoxycarbonyl) amino] -2-ethyl-1,3 -(S) -2-[(tert-butoxycarbonyl) amino] -2-ethyl-3-acetoxy was carried out in the same manner as in Example 20 except that propanediol (219 mg, 1.0 mmol) was used. -Propanol (227 mg, 87% yield, 86% ee) was obtained as a white powder.

Melting point: 81-83 ° C
[Α] _D ²⁵ + 26.5 ° (c = 1.00, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 4.77 (1H, br s), 4.28 (1H, d, J = 11.2 Hz), 4.14 (1H, d, J = 11.2 Hz), 3.99 (1H, br s), 3.70 (1 H, dd, J = 12.0 Hz and 6.6 Hz), 3.64 (1 H, dd, J = 12.0 Hz and 7.1 Hz), 2. 11 (3H, s), 1.83-1.72 (1H, m), 1.67-1.57 (1H, m), 1.44 (9H, s), 0.90 (3H, t, J = 7.6Hz)
Elemental analysis value: C ₁₂ H ₂₃ NO ₅
Calculated: C, 55.16; H, 8.87; N, 5.36
Found: C, 55.04; H, 8.79; N, 5.38
The enantiomeric excess is a Daicel Chiral Pack IA column (n-hexane: isopropanol = 50: 1, flow rate = 1.0 mL / min, wavelength 220 nm, retention time: 17.9 min [major, (S) -enantiomer], 22.5 min [minor, (R) -enantiomer]). The absolute configuration of the product was estimated from the absolute configuration of the product of Example 20.

[Example 22]
In Example 20, instead of 2-[(tert-butoxycarbonyl) amino] -2-methyl-1,3-propanediol, 2-[(tert-butoxycarbonyl) amino] -2-allyl-1,3 -(S) -2-[(tert-butoxycarbonyl) amino] -2-allyl-3-acetoxy was carried out in the same manner as in Example 20 except that propanediol (231 mg, 1.0 mmol) was used. -Propanol (192 mg, 70% yield, 82% ee) was obtained as a colorless oil.

[Α] _D ²⁵ + 22.8 ° (c = 1.00, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 5.84-5.72 (1H, m), 5.21-5.11 (2H, m), 4.84 (1H, brs), 4.29 ( 1H, d, J = 11.2 Hz), 4.13 (1H, d, J = 11.2 Hz), 4.05 (1H, br s), 3.68 (2H, d, J = 6.6 Hz) 2.54 (1H, dd, J = 13.9 and 6.8 Hz), 2.32 (1H, dd, J = 13.9 and 8.3 Hz), 2.11 (3H, s), 1. 44 (9H, s)
The enantiomeric excess is determined by the Daicel Chiral Pack IA column (n-hexane: isopropanol = 50: 1, flow rate = 1.0 mL / min, wavelength 220 nm, retention time: 17.2 min [major, (S) -enantiomer] 20.2 min [minor, (R) -enantiomer]). The absolute configuration of the product was determined by converting to known ethyl (R) -N- (benzyloxycarbonyl) -2-allyl serinate and comparing the optical rotation with literature values.

[Example 23]
In Example 20, instead of 2-[(tert-butoxycarbonyl) amino] -2-methyl-1,3-propanediol, 2-[(tert-butoxycarbonyl) amino] -2-n-hexyl-1 , 3-propanediol (275 mg, 1.0 mmol) was carried out in the same manner as in Example 20 to obtain (S) -2-[(tert-butoxycarbonyl) amino] -2-n-hexyl. -3-Acetoxy-propanol (266 mg, 84% yield, 83% ee) was obtained as a colorless oil.

[Α] _D ²⁵ + 8.5 ° (c = 1.20, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 4.77 (1H, br s), 4.27 (1H, d, J = 11.2 Hz), 4.13 (1H, d, J = 11.2 Hz), 4.03 (1H, br s), 3.69 (1H, dd, J = 12.0 and 6.6 Hz), 3.64 (1H, dd, J = 12.0 and 7.1 Hz), 2. 10 (3H, s), 1.74-1.49 (2H, m), 1.44 (9H, s), 1.37-1.18 (8H, m), 0.95-0.84 ( 3H, m)
The enantio excess was determined by converting the product to (+)-methoxy-α- (trifluoromethyl) phenylacetate. The absolute configuration of the product was estimated from the absolute configuration of the product of Example 20.

[Example 24]
In Example 20, instead of 2-[(tert-butoxycarbonyl) amino] -2-methyl-1,3-propanediol, 2-[(tert-butoxycarbonyl) amino] -2-benzyl-1,3 -(S) -2-[(tert-butoxycarbonyl) amino] -2-benzyl-3-acetoxy was carried out in the same manner as in Example 20 except that propanediol (281 mg, 1.0 mmol) was used. -Propanol (228 mg, 70% yield, 70% ee) was obtained as a colorless oil.

[Α] _D ²⁵ −2.8 ° (c = 5.50, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.35-7.15 (5H, m), 4.67 (1H, br s), 4.21 (1H, d, J = 11.2 Hz), 4. 07 (1H, d, J = 11.2 Hz), 3.87 (1H, br s), 3.69 (1 H, dd, J = 11.7 and 6.6 Hz), 3.60 (1 H, dd, J = 11.7 and 7.6 Hz), 3.13 (1H, d, J = 13.7 Hz), 2.95 (1H, d, J = 13.7 Hz), 2.11 (3H, s), 1.47 (9H, s)
In addition, the enantio excess ratio is a Daicel Chiral Pack AD-H column (n-hexane: ethanol = 15: 1, flow rate = 0.5 mL / min, wavelength 254 nm, retention time: 21.5 min [Major, (S) − Enantiomer], 26.6 min [minor, (R) -enantiomer]). The absolute configuration of the product was determined by converting to known ethyl (R) -N- (benzyloxycarbonyl) -2-benzyl serinate and comparing the optical rotation with literature values.

なお、上記表４において、Ｂｏｃはベンジルオキシカルボニル基を意味し、Ａｃはアセチル基を意味し、Ｍｅ、Ｅｔ、Ｐｈはぞれぞれ前記と同意義を意味する。 Table 4 summarizes the results of Examples 20-24.

In Table 4, Boc means a benzyloxycarbonyl group, Ac means an acetyl group, and Me, Et, and Ph each have the same meaning as described above.

[Examples 25a to 25i]
In Example 20, the catalyst (1R, 2R) -N, N-dimethyl-N′-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine-Zn Except that the amount of the complex, the type of the solvent and the reaction temperature were as shown in Table 5 below, the same treatment as in Example 20 was carried out to give 2-[(tert-butoxycarbonyl) amino] -2-methyl-1,3- Table 5 below shows (S) -2-[(tert-butoxycarbonyl) amino] -2-methyl-3-acetoxy-propanol from propanediol (205 mg, 1.0 mmol) and acetic anhydride (142 μL, 1.5 mmol). Obtained with the indicated yield and enantiomeric excess.

なお、上記表５において、Ｅｔ、ＭｅおよびＡｃは、それぞれ前記と同意義を示す。また、Ｂｏｃはｔｅｒｔ−ブトキシカルボニル基を意味し、ＣＰＭＥはシクロペンチルメチルエーテルを意味し、ｉＰｒはイソプロピル基を意味し、ｔ−Ｂｕはｔｅｒｔ−ブチル基を意味し、ｔ−Ａｍｙｌはｔｅｒｔ−ペンチル基を意味する。

In Table 5, Et, Me and Ac have the same meanings as described above. Boc means tert-butoxycarbonyl group, CPME means cyclopentylmethyl ether, iPr means isopropyl group, t-Bu means tert-butyl group, and t-Amyl means tert-pentyl group. Means.

[Example 26]
In Example 20, 2-[(tert-butoxycarbonyl) amino] -2-methyl-1,3-propanediol (205 mg, 1.0 mmol) and (1R, 2R) -N, obtained in Example 19 were used. N-dimethyl-N′-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine-Zn complex (27.4 mg, 0.025 mmol) in diethyl ether (10 mL) (S) -2-[(tert-Butoxycarbonyl) amino] -2 was carried out in the same manner as in Example 20 except that benzoic anhydride (339 mg, 1.5 mmol) was added to the solution at room temperature. -Methyl-3- (benzoyloxy) propanol (205 mg, 66% yield, 71% ee) was obtained as a white powder.

Melting point: 79-82 ° C
[Α] _D ²⁵ + 17.8 ° (c = 1.20, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 8.08-8.01 (2H, m), 7.62-7.55 (1H, m), 7.50-7.42 (2H, m), 4 .96 (1H, br s), 4.50 (1 H, d, J = 11.2 Hz), 4.47 (1H, d, J = 11.2 Hz), 3.96 (1H, br s), 3 .73 (1H, dd, J = 11.7 and 6.6 Hz), 3.65 (1H, dd, J = 11.7 and 6.3 Hz), 1.44 (9H, s), 1.35 ( 3H, s)
Elemental analysis value: C ₁₆ H ₂₃ NO ₅
Calculated values: C, 62.12; H, 7.49; N, 4.53
Found: C, 61.99; H, 7.44; N, 4.56
The enantiomeric excess is a Daicel chiral cell OD-H column (n-hexane: isopropanol = 15: 1, flow rate = 0.5 mL / min, wavelength 254 nm, retention time: 17.8 min [minor, (R) -enantiomer. ] 20.7 min [major, (S) -enantiomer]). The absolute configuration of the product was estimated from the absolute configuration of the product of Example 20.

[Example 27]
In Example 20, 2-[(benzyloxycarbonyl) amino] -2-methyl-1,3-propanediol (239 mg, 1.0 mmol) and (1R, 2R) -N, N obtained in Example 19 -Diethyl-N'-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine-Zn complex (27.4 mg, 0.025 mmol) in diethyl ether (10 mL) (S) -2-[(benzyloxycarbonyl) amino] -2-methyl-3 by carrying out in the same manner as in Example 20 except that acetic anhydride (142 μL, 1.5 mmol) was added to the solution at room temperature. -Acetoxy-propanol (230 mg, 82% yield, 70% ee) was obtained as a colorless oil.

[Α] _D ²⁵ + 5.7 ° (c = 1.20, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.42-7.31 (5H, m), 5.17 (1H, br s), 5.07 (2H, s), 4.26 (1H, d, J = 11.2 Hz), 4.21 (1H, d, J = 11.2 Hz), 3.66 (1H, dd, J =
11.7 and 4.4 Hz), 3.60 (1 H, dd, J = 11.7 and 3.4 Hz), 3.48 (1 H, br s), 2.09 (3 H, s), 1.30 (3H, s)
Elemental analysis value: C ₁₄ H ₁₉ NO ₅
Calculated: C, 59.78; H, 6.81; N, 4.98
Found: C, 59.55; H, 6.70; N, 4.94
The enantiomeric excess is a Daicel chiral OD-H column (n-hexane: isopropanol = 15: 1, flow rate = 0.5 mL / min, wavelength 254 nm, retention time: 14.2 min [major, (S) -enantiomer] 20.5 min [minor, (R) -enantiomer]). The absolute configuration of the product was determined by converting to known ethyl (R) -N- (benzyloxycarbonyl) -2-methylselinate and comparing the optical rotation with literature values.

[Examples 28a to 28d]
In Example 27, (S) -2-[(benzyloxycarbonyl) amino] -2-methyl- was carried out in the same manner as in Example 27 except that the type of solvent was as shown in Table 6 below. 3-Acetoxy-propanol was obtained with the yield and enantiomeric excess shown in Table 6 below.

なお、上記表６において、Ｍｅ、ＡｃおよびＴＨＦは、それぞれ前記と同意義を示す。また、Ｚはベンジルオキシカルボニル基を意味し、ＭｅＣＮはアセトニトリルを意味し、ＣＨ_２Ｃｌ_２はジクロロメタンを意味する。

In Table 6, Me, Ac, and THF have the same meanings as described above. Z represents a benzyloxycarbonyl group, MeCN represents acetonitrile, and CH ₂ Cl ₂ represents dichloromethane.

[Example 29]
In Example 20, 2-[(benzyloxycarbonyl) amino] -2-methyl-1,3-propanediol (239 mg, 1.0 mmol) and (1R, 2R) -N, N obtained in Example 19 -Diethyl-N'-3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine-Zn complex (27.4 mg, 0.025 mmol) in diethyl ether (10 mL) To (S) -2-[(benzyloxycarbonyl) amino] -2-methyl by carrying out in the same manner as in Example 20, except that benzoic anhydride (339 mg, 1.5 mmol) was added to -3- (Benzoyloxy) propanol (206 mg, 60% yield, 60% ee) was obtained as a white powder.

Melting point: 57-59 ° C
[Α] _D ²⁵ + 9.31 ° (c = 1.30, CHCl ₃ )
¹ HNMR (400 MHz, CDCl ₃ ) δ: 8.07-7.98 (2H, m), 7.64-7.28 (8H, m), 5.26 (1H, br s), 5.09 ( 2H, s), 4.53 (1H, d, J = 11.2 Hz), 4.49 (1H, d, J = 11.2 Hz), 3.74 (1H, d, J = 12.0 Hz), 3.66 (1H, d, J = 12.0 Hz), 3.54 (1H, br s), 1.40 (3H, s)
In addition, the enantio excess is a Daicel chiral cell OD-H column (n-hexane: ethanol = 5: 1, flow rate = 0.5 mL / min, wavelength 254 nm, retention time: 13.3 min [major, (S) -enantiomer. ], 14.6 min [minor, (R) -enantiomer]). The absolute configuration of the product was estimated from the absolute configuration of the product of Example 27.

[Example 30]
2-[(Benzyloxycarbonyl) amino] -2-methyl-1,3-propanediol (239 mg, 1.0 mmol) and (1R, 2R) -N, N-dimethyl-N ′ obtained in Example 2 To a diethyl ether solution of −3,5-bis (trifluoromethyl) benzenesulfonyl-1,2-diphenyl-1,2-ethanediamine was added diethyl zinc and acetic anhydride (142 μL, 1.5 mmol) at room temperature, The mixture was stirred at the same temperature for 20 hours. After completion of the reaction, post-treatment was performed in the same manner as in Example 20 to obtain (S) -2-[(benzyloxycarbonyl) amino] -2-methyl-3-acetoxy-propanol (82% yield, 69% ee). Was obtained as a colorless oil.

[Reference Example 7]
Dimethyl sulfoxide (218 μL, 3.07 mmol) was added to a solution of oxalyl chloride (132 μL, 1.537 mmol) in dichloromethane (7.5 mL) at −60 ° C. under an argon atmosphere. After stirring at the same temperature for 15 minutes, dichloromethane of (S) -2-[(tert-butoxycarbonyl) amino] -2-methyl-3-acetoxy-propanol (190 mg, 0.768 mmol) obtained in Example 20 was used. (2.5 mL) solution was added and stirred for an additional 40 minutes at the same temperature. Thereafter, triethylamine (536 μL, 3.84 mmol) was added to the reaction solution at the same temperature, and then the mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The aldehyde is a crude product obtained by distilling off the solvent under reduced pressure t- butanol - water (4: 1) was dissolved in _{(10mL), NaH 2 PO 4} · 2H 2 O (210mg, 1.34mmol) 2-methyl-2-butene (572 μL, 5.38 mmol), NaClO ₂ (320 mg, 3.53 mmol) were added at room temperature. The mixture was stirred at the same temperature for 1 hour, acidified with 4% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The crude product 2-[(tert-butoxycarbonyl) amino] -2-methyl-3-acetoxy-propionic acid obtained by distilling off the solvent under reduced pressure was added to benzene-methanol (7: 2) (9 mL). After dissolution, trimethylsilyldiazomethane (2.0 M diethyl ether solution, 768 μL, 1.537 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Thereafter, the solvent was distilled off under reduced pressure to obtain 2-[(tert-butoxycarbonyl) amino] -2-methyl-3-acetoxy-propionic acid methyl ester. The ester was dissolved in methanol (10 mL), potassium carbonate (106 mg, 0.768 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 15 min. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Column chromatography obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (n-hexane: ethyl acetate = 1: 1) to give methyl (R) -N- (tert-butoxycarbonyl) -2-methyl. Serinate [= (2R) -2-methyl-2-[(tert-butoxycarbonyl) amino] -3-hydroxy-propionic acid methyl ester] (115 mg, 64% yield, 77% ee) as a colorless oil Obtained.

[Α] _D ²⁵ −2.7 ° (c = 0.90, CHCl ₃ ) [literature value of (R): [α] _D ¹⁸ −2.0 ° (c = 0.81, CHCl ₃ )]
¹ HNMR (400 MHz, CDCl ₃ ) δ: 5.30 (1H, br s), 3.98 (1H, dd, J = 11.2 Hz and 5.6 Hz), 3.81-3.73 (1H, m ), 3.78 (3H, s), 3.27 (1H, br s), 1.47 (3H, s), 1.45 (9H, s)
The enantiomeric excess is a Daicel chiral cell OJ-H column (n-hexane: isopropanol = 30: 1, flow rate = 1.0 mL / min, wavelength 220 nm, retention time: 11.6 min [minor, (S) -enantiomer. ], 14.4 min [major, (R) -enantiomer]). The absolute configuration of the product was determined by comparing the optical rotation with literature values.

  The asymmetric organic catalyst of the present invention can be used as a catalyst for thiol decomposition (thiolysis) or alcohol decomposition (alcolysis) with high enantioselectivity. A zinc complex derived from the asymmetric organic catalyst can also be used as a catalyst for asymmetric synthesis.

Claims (9)

Formula (I):

[In the formula, Ph represents a phenyl group, Ar represents a phenyl group or a naphthyl group, 1 to 3 alkyl groups having 1 to 3 carbon atoms, or 1 to 3 halogenated alkyl groups having 1 to 3 carbon atoms, or a carbon number. 1 to 3 or a phenyl group or a naphthyl group substituted with 1 to 3 alkoxy groups or 1 to 3 halogen atoms at any position of the benzene ring , wherein R ¹ and R ² are each an alkyl group having 1 to 3 carbon atoms A group, or both bonded together at the end to form an aziridino group, an azetidino group, a pyrrolidino group, a piperidino group or a morpholino group together with the adjacent nitrogen atom. ]
A chiral sulfonamide derivative represented by: The chiral sulfonamide derivative according to claim 1, wherein R ¹ and R ² are each an alkyl group having 1 to 3 carbon atoms.   The chiral sulfonamide derivative according to claim 1 or 2, wherein Ar is a 4-methylphenyl group or a 3,5-bis (trifluoromethyl) -phenyl group. Formula (II):

[Wherein A represents an alkylene group having one or two substituents at the position where the compound of formula (II) has a symmetric molecular structure, or the compound of formula (II) has a symmetric molecular structure. A cycloalkylene group or a cycloalkenylene group which may have one substituent or two identical substituents at the position is shown. ]
A dicarboxylic acid anhydride having a symmetric molecular structure represented by formula (III):

[Wherein, R represents an alkyl group, an aryl group or an aralkyl group, and X represents a sulfur atom or an oxygen atom. ]
A thiol or alcohol compound represented by formula (I):

[In the formula, Ph represents a phenyl group, Ar represents a phenyl group or a naphthyl group, 1 to 3 alkyl groups having 1 to 3 carbon atoms, or 1 to 3 halogenated alkyl groups having 1 to 3 carbon atoms, or a carbon number. 1 to 3 or a phenyl group or a naphthyl group substituted with 1 to 3 alkoxy groups or 1 to 3 halogen atoms at any position of the benzene ring , wherein R ¹ and R ² are each an alkyl group having 1 to 3 carbon atoms A group, or both bonded together at the end to form an aziridino group, an azetidino group, a pyrrolidino group, a piperidino group or a morpholino group together with the adjacent nitrogen atom. ]
Further characterized in that esterification After Rukoto or reaction, in reacted in the presence of a chiral sulfonamide derivative represented the formula (IV):

[Wherein, R and X are as defined above, R ^a represents hydrogen or an ester residue, and A ^* represents an absolute structure having the same planar structure as A and an asymmetric molecule as a whole. ]
A process for producing an optically active carboxylic acid or ester thereof represented by The production method according to claim 4 , wherein R ¹ and R ² are each an alkyl group having 1 to 3 carbon atoms. The production method according to claim 4 or 5 , wherein Ar is a 4-methylphenyl group or a 3,5-bis (trifluoromethyl) -phenyl group. The process according to any one of claims 4 ~ 6 R ^a is hydrogen, alkyl or aralkyl group. R is a benzyl group, The manufacturing method of Claims 4-7 . Formula (Ia):

[In the formula, Ph represents a phenyl group, Ar represents a phenyl group or a naphthyl group, 1 to 3 alkyl groups having 1 to 3 carbon atoms, or 1 to 3 halogenated alkyl groups having 1 to 3 carbon atoms, or a carbon number. 1 to 3 or a phenyl group or a naphthyl group substituted with 1 to 3 alkoxy groups or 1 to 3 halogen atoms at any position of the benzene ring , wherein R ¹ and R ² are each an alkyl group having 1 to 3 carbon atoms A group, or both bonded together at the end to form an aziridino group, an azetidino group, a pyrrolidino group, a piperidino group or a morpholino group together with the adjacent nitrogen atom. ]
A chiral sulfonamide derivative / Zn complex represented by the formula: