JP2004196793A - Transition metal complex having diphosphine compound as ligand - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a transition metal complex having a diphosphine compound as a ligand. <P>SOLUTION: A target compound of an absolute configuration can be efficiently obtained by making the transition metal complex having 2,2'-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-1,1'-binaphthyl as the ligand present in an asymmetric reaction system. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

  The present invention provides 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl, which can be a useful catalyst for various asymmetric synthesis reactions. The present invention relates to a transition metal complex as a ligand.

In asymmetric reduction and asymmetric isomerization using a catalyst in which an optically active phosphine is coordinated to a transition metal, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (hereinafter, referred to as an optically active phosphine) BINAP) is commonly used, but various types of optically active phosphines have been produced and reported because their reactivity, stereoselectivity, catalytic efficiency, etc. are not sufficient depending on the type of substrate. (For example, see Non-Patent Document 1). For example, Patent Document 1 discloses that a ruthenium complex having 2,2′-bis (di (p-toluyl) phosphino) -1,1′-binaphthyl as a ligand is used for asymmetric reduction of a carbon-carbon double bond. Patent Document 2 discloses that a ruthenium complex having 2,2′-bis (di (3,5-dialkylphenyl) phosphino) -1,1′-binaphthyl as a ligand is disclosed in Patent Document 2. It is described as being useful in the asymmetric reduction of ketoesters.
However, in the reaction using these transition metal catalysts, optical selection may be insufficient depending on the reaction substrate.

JP-A-61-63690 JP-A-3-255090 Handbook of Enantioselective Catalysis with Transition Metal Compounds, VCH Publisher, 1993

  The present invention provides a novel transition metal complex having excellent reaction substrate selectivity and conversion in various asymmetric synthesis reactions, and having a long reaction duration.

を配位子とする遷移金属錯体が不斉合成反応、特に不斉還元反応において、反応基質の選択性および転化率に優れていることを見出し、これらに基づいて本発明を完成するに至った。 The present inventors have proposed 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl (hereinafter, referred to as the following structural formula) Abbreviated as compound (I))

It has been found that a transition metal complex having as a ligand is excellent in the selectivity and conversion of a reaction substrate in an asymmetric synthesis reaction, particularly in an asymmetric reduction reaction, and based on these, the present invention has been completed. .

〔式中、R¹は置換基を有していてもよい炭化水素基または置換基を有していてもよい複素環基、R’はハロゲン原子、置換基を有していてもよいアルキルスルホニルまたは置換基を有していてもよいアリールスルホニル、R²は置換基を有していてもよい炭化水素基を示す。〕で表される化合物またはその塩を、2,2'-ビス[ビス(3,5-ジ-tert-ブチル-4-メトキシフェニル)ホスフィノ]-1,1'-ビナフチルを配位子とする遷移金属錯体の存在下、還元反応を行うことを特徴とする、式：

〔式中、*は不斉炭素の位置を示し、その他の記号は前記と同意義である。〕で表される化合物またはその塩の製造法、
〔１１〕式：

〔式中、R¹は置換基を有していてもよい炭化水素基または置換基を有していてもよい複素環基、R’’は塩素原子、臭素原子、ヨウ素原子、置換基を有していてもよいアルキルスルホニルオキシまたは置換基を有していてもよいアリールスルホニルオキシ、R²は置換基を有していてもよい炭化水素基を示す。〕で表される化合物またはその塩を、遷移金属錯体の存在下、アルコール系溶媒、炭化水素系溶媒、エーテル系溶媒、エステル系溶媒、ケトン系溶媒、ニトリル系溶媒、スルホキシド系溶媒およびアミド系溶媒から選ばれる溶媒中あるいはこれら二種以上の混合溶媒中で還元反応を行うことにより、式：

〔式中、*は不斉炭素の位置を示し、その他の記号は前記と同意義である。〕で表される化合物またはその塩を得、さらに無機塩基の存在下で環化反応を行うことを特徴とする式：

〔式中、各記号は前記と同意義である。〕で表される化合物またはその塩の製造法、
〔１２〕式：

〔式中、R¹は置換基を有していてもよい炭化水素基または置換基を有していてもよい複素環基、R²は置換基を有していてもよい炭化水素基を、*は不斉炭素の位置を示す。〕で表される化合物が

〔式中、各記号は前記と同意義である。〕または

〔式中、各記号は前記と同意義である。〕で表される光学活性化合物である前記〔１１〕記載の製造法、
〔１３〕式：

〔式中、R¹は置換基を有していてもよい炭化水素基または置換基を有していてもよい複素環基、R’’は塩素原子、臭素原子、ヨウ素原子、置換基を有していてもよいアルキルスルホニルオキシまたは置換基を有していてもよいアリールスルホニルオキシ、R²は置換基を有していてもよい炭化水素基を、*は不斉炭素の位置を示す。〕で表される化合物が、

〔式中、各記号は前記と同意義である。〕または、

〔式中、各記号は前記と同意義である。〕で表される光学活性化合物である前記〔１１〕記載の製造法、
〔１４〕R’’が塩素原子、臭素原子またはヨウ素原子である前記〔１１〕記載の製造法、
〔１５〕無機塩基がアルカリ金属の炭酸塩である前記〔１１〕記載の製造法、
〔１６〕還元反応を行う溶媒がアルコール系溶媒である前記〔１１〕記載の製造法、
〔１７〕遷移金属錯体が2,2'-ビス[ビス(3,5-ジ-tert-ブチル-4-メトキシフェニル)ホスフィノ]-1,1'-ビナフチルを配位子とする遷移金属錯体である前記〔１１〕記載の製造法、
〔１８〕式：

〔式中、R³は水素原子または置換基を有していてもよいアルキルを示す。〕で表される化合物またはその塩を、2,2'-ビス[ビス(3,5-ジ-tert-ブチル-4-メトキシフェニル)ホスフィノ]-1,1'-ビナフチルを配位子とする遷移金属錯体の存在下、式：R⁴-R’’’〔式中、R⁴は置換基を有していてもよいフェニル、R’’’は脱離基を示す。〕で表される化合物またはその塩と反応させることを特徴とする式：

〔式中、*は不斉炭素の位置を示し、その他の記号は前記と同意義である。〕で表される化合物またはその塩の製造法等に関する。 That is, the present invention
[1] a transition metal complex having 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl as a ligand,
[2] The transition metal complex according to the above [1], wherein the transition metal is rhodium, ruthenium, iridium, palladium, nickel or copper,
[3] the transition metal complex according to [1], wherein the transition metal is rhodium, ruthenium, iridium, palladium or nickel;
[4] The transition metal complex according to the above [1], wherein the transition metal is rhodium,
[5] The transition metal complex according to [1], wherein the transition metal is ruthenium,
[6] Ru (L) (AcO) ₂ [L is 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl, Ac is Indicates acetyl. ] The transition metal complex according to the above [1],
[7] Ru (L) Cl ₂ [L represents 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl. ] The transition metal complex according to the above [1],
[8] Ru (L) Cl ₂ (dmf) _n [L is 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl, dmf represents N, N-dimethylformamide. ] The transition metal complex according to the above [1],
[9] [Rh (L) (cod)] OTf [L is 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl, cod represents 1,5-cyclooctadiene, and Tf represents trifluoromethylsulfonyl. ] The transition metal complex according to the above [1],
Formula [10]:

Wherein R ¹ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, R ′ is a halogen atom, an alkylsulfonyl which may have a substituent Or an arylsulfonyl which may have a substituent, and R ² represents a hydrocarbon group which may have a substituent. Or a salt thereof, with 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl as a ligand Wherein the reduction reaction is carried out in the presence of a transition metal complex;

[In the formula, * indicates the position of the asymmetric carbon, and the other symbols are as defined above. The method for producing a compound represented by the formula or a salt thereof,
[11] Formula:

(In the formula, R ¹ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R '' has a chlorine atom, a bromine atom, an iodine atom, and a substituent. R ² represents an optionally substituted alkylsulfonyloxy or an optionally substituted arylsulfonyloxy, and R ² represents an optionally substituted hydrocarbon group. A compound represented by the formula: or a salt thereof, in the presence of a transition metal complex, an alcohol solvent, a hydrocarbon solvent, an ether solvent, an ester solvent, a ketone solvent, a nitrile solvent, a sulfoxide solvent and an amide solvent. By performing the reduction reaction in a solvent selected from the following or in a mixed solvent of two or more of these, the formula:

[In the formula, * indicates the position of the asymmetric carbon, and the other symbols are as defined above. Or a salt thereof, and further subjecting the compound to a cyclization reaction in the presence of an inorganic base.

Wherein each symbol is as defined above. The method for producing a compound represented by the formula or a salt thereof,
[12] Formula:

(In the formula, R ¹ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, R ² is a hydrocarbon group which may have a substituent, * Indicates the position of the asymmetric carbon. The compound represented by

Wherein each symbol is as defined above. ] Or

Wherein each symbol is as defined above. The method according to the above [11], which is an optically active compound represented by the formula:
[13] Formula:

(In the formula, R ¹ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R '' has a chlorine atom, a bromine atom, an iodine atom, and a substituent. Optionally substituted alkylsulfonyloxy or optionally substituted arylsulfonyloxy, R ² represents an optionally substituted hydrocarbon group, and * represents an asymmetric carbon position. The compound represented by

Wherein each symbol is as defined above. ] Or

Wherein each symbol is as defined above. The method according to the above [11], which is an optically active compound represented by
[14] The method of the above-mentioned [11], wherein R '' is a chlorine atom, a bromine atom or an iodine atom,
[15] The method of the above-mentioned [11], wherein the inorganic base is an alkali metal carbonate,
[16] The method of the above-mentioned [11], wherein the solvent for performing the reduction reaction is an alcohol solvent,
[17] The transition metal complex is a transition metal complex having 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl as a ligand The production method according to the above [11],
[18] Expression:

[In the formula, R ³ represents a hydrogen atom or an alkyl which may have a substituent. Or a salt thereof, with 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl as a ligand In the presence of a transition metal complex, a compound represented by the formula: R ⁴ -R ′ ″ wherein R ⁴ represents phenyl which may have a substituent, and R ″ ″ represents a leaving group. A compound represented by the formula:

[In the formula, * indicates the position of the asymmetric carbon, and the other symbols are as defined above. And a method for producing the compound or a salt thereof.

  The compound (I) includes an (R) form, an (S) form and a mixture of the (R) form and the (S) form (the ratio of both is not limited), but an optically active form is preferable.

〔式中Xは臭素、ヨウ素、トリフルオロメタンスルホニル、メタンスルホニル等の脱離基を示す〕
化合物(II)は、ジャーナル・オブ・オーガニック・ケミストリー、33巻、3690頁、1968年記載の方法に従って製造することができる。
化合物(III)は、化合物(II)を塩化セリウム、水素化ホウ素ナトリウムおよび水素化リチウムアルミニウムの存在下で反応させることで製造できる。
塩化セリウムの使用量は、化合物(II)1モルに対して約1ないし6モル、好ましくは約3ないし5モルである。
水素化ホウ素ナトリウムの使用量は、化合物(II)1モルに対して約2ないし10モル、好ましくは約3ないし5モルである。
水素化リチウムアルミニウムの使用量は、化合物(II)1モルに対して約0.25ないし5モル、好ましくは約1ないし3モルである。
前記反応は、不活性な有機溶媒中で行うことができる。該有機溶媒としては、炭化水素系溶媒（例、ヘキサン、ペンタン、シクロヘキサンなど）、アミド系溶媒（例、N,N-ジメチルホルムアミド（DMF）、N,N-ジメチルアセトアミド、N-メチルピロリドン、1,3-ジメチル-2-イミダゾリジノンなど）、芳香族炭化水素系溶媒（例、トルエン、ベンゼン、クロロベンゼンなど）、エーテル系溶媒（例、ジイソプロピルエーテル、ジエチルエーテル、テトラヒドロフラン（THF）、1,4-ジオキサン、1,2-ジメトキシエタンなど）、リン酸アミド系溶媒（例、ヘキサメチルリン酸アミドなど）等が挙げられる。これらの溶媒は単独で用いても、また混合溶媒として用いてもよい。好ましい溶媒はエーテル系溶媒、炭化水素系溶媒、芳香族炭化水素系溶媒などである。さらに好ましくはエーテル系溶媒（例、ジイソプロピルエーテル、ジエチルエーテル、テトラヒドロフラン（THF）、1,4-ジオキサン、1,2-ジメトキシエタンなど）である。
該反応における反応温度は、約-20ないし50℃、好ましくは約-10ないし35℃である。該反応における反応時間は、約1ないし48時間、好ましくは約1ないし20時間である。 The production method of compound (I) is shown below.

[Wherein X represents a leaving group such as bromine, iodine, trifluoromethanesulfonyl, methanesulfonyl, etc.]
Compound (II) can be produced according to the method described in Journal of Organic Chemistry, 33, 3690, 1968.
Compound (III) can be produced by reacting compound (II) in the presence of cerium chloride, sodium borohydride and lithium aluminum hydride.
The amount of cerium chloride to be used is about 1-6 mol, preferably about 3-5 mol, per 1 mol of compound (II).
The amount of sodium borohydride to be used is about 2 to 10 mol, preferably about 3 to 5 mol, per 1 mol of compound (II).
The amount of lithium aluminum hydride to be used is about 0.25-5 mol, preferably about 1-3 mol, per 1 mol of compound (II).
The reaction can be performed in an inert organic solvent. Examples of the organic solvent include hydrocarbon solvents (eg, hexane, pentane, cyclohexane, etc.), amide solvents (eg, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, , 3-dimethyl-2-imidazolidinone), aromatic hydrocarbon solvents (eg, toluene, benzene, chlorobenzene, etc.), ether solvents (eg, diisopropyl ether, diethyl ether, tetrahydrofuran (THF), 1,4 -Dioxane, 1,2-dimethoxyethane, etc.), and phosphoric acid amide solvents (eg, hexamethyl phosphoric acid amide, etc.). These solvents may be used alone or as a mixed solvent. Preferred solvents are ether solvents, hydrocarbon solvents, aromatic hydrocarbon solvents and the like. More preferred are ether solvents (eg, diisopropyl ether, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, etc.).
The reaction temperature in the reaction is about -20 to 50 ° C, preferably about -10 to 35 ° C. The reaction time in the reaction is about 1 to 48 hours, preferably about 1 to 20 hours.

Compound (IV) can be produced according to a method known per se, for example, the method described in Tetrahedron Letters, vol. 31, p. 985, 1990, Journal of Organic Chemistry, vol. 58, p. 1945, 1993, etc. . The compound (IV) thus obtained may be used in the reaction with the compound (III) as a reaction mixture without isolation.
Compound (I) can be produced by reacting compound (III) with compound (IV) in a solvent in the presence of an amine and a nickel catalyst.
Examples of the “amine” used include 1,4-diazabicyclo [2.2.2] octane (abbreviation: DABCO), triethylamine, diisopropylethylamine, tri (n-propyl) amine, tri (n-butyl) amine, 8-diazabicyclo [5.4.0] -7-undecene (abbreviation: DBU), tetramethylethylenediamine, dimethylaniline, 1,4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrolidine, 4-dimethylaminopyridine, pyridine, Examples include amines such as diethylamine. Of these, tertiary amines such as 1,4-diazabicyclo [2.2.2] octane, triethylamine and diisopropylethylamine are preferred. Particularly preferred is 1,4-diazabicyclo [2.2.2] octane.
The “nickel catalyst” used is NiCl ₂ bis (diphenyl) phosphino C _1-4 alkane, NiBr ₂ , NiCl ₂ , NiCl ₂ bis (diphenyl) phosphinyl ferrocene, NiCl ₂ bis (triphenylphosphine) , Ni · tetrakistriphenylphosphine, Ni · tetrakistriphenylphosphine phosphite, Ni · dicarbonyl bis (triphenyl) phosphine, NiBr ₂ · bis (triphenylphosphine), Ni · bis (1,5-cyclooctadiene), Ni.bis (cyclopentadienyl), Ni.bis (ethylcyclopentadienyl), NiCl ₂ .dimethoxyethane, Ni (BF ₄ ) ₂ or Ni (PF ₃ ) ₄ are exemplified. Among them, NiCl ₂ bis (diphenyl) phosphino C _1-4 alkane, NiBr ₂ , NiCl ₂ , NiCl ₂ bis (diphenyl) phosphinylferrocene, NiCl ₂ bis (triphenylphosphine), Ni tetrakistriphenyl Phosphine, Ni.tetrakistriphenylphosphite, Ni.dicarbonylbis (triphenyl) phosphine and the like are preferable. Especially preferably such NiCl ₂ · bis (diphenyl) phosphino C _1-4 alkane, particularly NiCl ₂ · bis (diphenyl) Hosufinoetan preferred.

The amount of compound (III) to be used is about 2 to 5 mol, preferably about 2 to 3 mol, per 1 mol of compound (IV).
The amount of the amine to be used is about 2 to 10 mol, preferably about 2 to 8 mol, per 1 mol of compound (IV).
The amount of the nickel catalyst to be used is about 0.01 to 10 mol, preferably about 0.05 to 1 mol, per 1 mol of compound (IV).
The reaction can be performed in an inert organic solvent. Examples of the organic solvent include hydrocarbon solvents (eg, hexane, pentane, cyclohexane, etc.), amide solvents (eg, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, , 3-dimethyl-2-imidazolidinone), aromatic hydrocarbon solvents (eg, toluene, benzene, chlorobenzene, etc.), aliphatic ester solvents (eg, ethyl acetate, n-propyl acetate, n-butyl acetate) ), Ether solvents (eg, diisopropyl ether, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbon solvents (eg, chloroform, dichloromethane, 1, 2-dichloroethane, carbon tetrachloride, etc.), alcoholic solvents (eg, methanol, ethanol, isopropanol, tert-butanol, etc.), Solvent (eg, acetone, ethyl methyl ketone, etc.), sulfoxide solvent (eg, dimethyl sulfoxide, etc.), nitrile solvent (eg, acetonitrile, propionitrile, etc.), phosphate amide solvent (eg, hexamethyl phosphorus Acid amide and the like). These solvents may be used alone or as a mixed solvent. Preferred solvents are amide solvents, sulfoxide solvents, phosphoric acid amide solvents and the like. More preferred are amide solvents (N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone).
The reaction temperature in the reaction is about 30 to 180 ° C, preferably about 80 to 120 ° C. The reaction time in the reaction is about 1 to 240 hours, preferably about 24 to 168 hours.
The product can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography.

  The “transition metal” in the transition metal complex of the present invention includes, for example, rhodium, ruthenium, iridium, palladium, nickel, copper and the like. Of these, rhodium and ruthenium are preferred.

The transition metal complex of the present invention can be produced according to a known method.
For example, when producing a rhodium complex, the compound (I) is prepared according to the method described in The Chemical Society of Japan (Maruzen), “4th Edition, Experimental Chemistry Course”, Vol. 18, Organometallic Complexes, pp. 341-344, 1991. It can be produced by reacting bis (cycloocta-1,5-diene) rhodium (I) tetrafluoroborate.
When a ruthenium complex is produced, the compound (I) and [Ru (cod) Cl] are prepared according to the method described in Journal of Chemical Society (J. Chem. Soc., Chem. Commun.), Page 922, 1988. ₂ ] _n can be produced by heating to reflux in a toluene solvent in the presence of triethylamine. Also, according to the method described in Journal of Chemical Society (J. Chem. Soc., Chem. Commun.), P. 1208, 1989, compound (I) and (Ru (p-cymene) I ₂ ) ₂ Can be produced by heating and stirring in methylene chloride and ethanol.
When producing an iridium complex, the compound (I) and (Ir (cod) (Ir (cod) (J.Organomet.Chem.), Vol. 428, p. 213, 1992) are used according to the method described in Journal of Organometal Chemistry. CH ₃ CN) ₂ ] BF ₄ in tetrahydrofuran with stirring.
When producing a palladium complex, compound (I) and π-allyl are prepared according to the method described in Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 113, p. 9887, 1991. It can be produced by reacting palladium chloride.
In the case of producing a nickel complex, compound (I) and nickel chloride are prepared according to the method described in “The 4th Edition Experimental Chemistry Course”, Vol. 18, Organometallic Complex, p. 376 (1991), edited by The Chemical Society of Japan (Maruzen). Can be produced by heating and stirring in the presence of a solvent.
In the case of producing a copper complex, compound (I) and copper chloride (copper chloride) can be produced according to the method described in “The 4th Edition Experimental Chemistry Course”, Vol. 18, Organometallic Complex, p. 444 (1991), edited by The Chemical Society of Japan (Maruzen). It is prepared by reacting I).

Specific examples of the rhodium complex include, for example, the following (where L is the compound (I) of the present invention, cod is 1,5-cyclooctadiene, and Tf is trifluoromethyl Sulfonyl, nbd is norbornadiene, Ph is phenyl, Ac is acetyl, Et is ethyl, dmf is N, N-dimethylformamide, en is ethylenediamine, dpen is 1,2-diphenylethylenediamine, daipen is 1,1-di (4- Anisyl) -2-isopropyl-1,2-ethylenediamine, n represents a number of 1 or more).
(Rh (cod) (L)) OTf, Rh (L) Cl, Rh (L) Br, Rh (L) I, (Rh (cod) (L)) BF ₄ , (Rh (cod) (L)) ClO ₄ , (Rh (cod) (L)) PF ₆ , (Rh (cod) (L)) BPh ₄ , (Rh (nbd) (L)) OTf, (Rh (nbd) (L)) BF ₄ , [Rh (nbd) (L)] ClO _4, [Rh (nbd) (L)] PF _6, [Rh (nbd) (L)] BPh _{4, [Rh (L) (CH 3 OH} ) 2 ] OTf, (Rh (L) (CH ₃ OH) ₂ ) BF ₄ , (Rh (L) (CH ₃ OH) ₂ ) ClO ₄ , (Rh (L) (CH ₃ OH) ₂ ) PF ₆ , (Rh (L) (CH ₃ OH) ₂ ) BPh ₄
The following are specific examples of the ruthenium complex.
RuCl ₂ (L) , RuBr ₂ (L), RuI ₂ (L), Ru (OAc) ₂ (L), Ru (O ₂ CCF ₃ ) ₂ (L), (NH ₂ Et ₂ ) [{RuCl (L)} ₂ (μ -Cl) ₃ ], [Ru ₂ Cl ₄ (L)] (NEt ₃ ), Ru (L) Cl ₂ (dmf) _n , Ru (L) (methylallyl) ₂ , [RuCl (benzene) (L)] Cl , (RuCl (benzene) (L)) Br, (RuCl (benzene) (L)) I, (RuCl (benzene) (L)) OTf, (RuCl (benzene) (L)) ClO ₄ , (RuCl (benzene) ) (L)) PF ₆ , (RuCl (benzene) (L)) BF ₄ , (RuCl (benzene) (L)) BPh ₄ , (RuBr (benzene) (L)) Cl, (RuBr (benzene) (L )) Br, (RuBr (benzene) (L)) I, (RuI (benzene) (L)) Cl, (RuI (benzene) (L)) Br, (RuI (benzene) (L)) I, (RuCl (p-cymene) (L)) Cl, (RuCl (p-cymene) (L)) Br, (RuCl (p-cymene) (L)) I, (RuBr (p-cymene) (L)) Cl, (RuBr (p-cymene) (L)) Br, (RuBr (p-cymene) (L)) I, (RuI (p-cymene) (L)) Cl, (RuI (p-cymene) (L)) br, [RuI (p-cymene) (L ) ] I, [Ru (L)] (OTf) _2, [Ru (L)] (BF _{4) 2,} [Ru (L)] (ClO _{4) 2,} [Ru (L)] (PF _{6) 2,} [Ru (L)] (BPh _{4) 2,} [RuH (L) _2] Cl, [RuH (L) _2] OTf , (RuH (L) ₂ ) BF ₄ , (RuH (L) ₂ ) ClO ₄ , (RuH (L) ₂ ) PF ₆ , (RuH (L) ₂ ) BPh ₄ , (RuH (CH ₃ CN) (L )) Cl, (RuH (CH ₃ CN) (L)) OTf, (RuH (CH ₃ CN) (L)) BF ₄ , (RuH (CH ₃ CN) (L)) ClO ₄ , (RuH (CH ₃ CN) (CN) (L)) PF ₆ , (RuH (CH ₃ CN) (L)) BPh ₄ , (Ru (L) Cl) OTf, (Ru (L) Cl) BF ₄ , (Ru (L) Cl) ClO _4, [Ru (L) Cl] PF _6, [Ru (L) Cl] BPh _4, [Ru (L) Br] OTf, [Ru (L) (Br) BF ₄ , (Ru (L) Br) ClO ₄ , (Ru (L) Br) PF ₆ , (Ru (L) Br) BPh ₄ , (Ru (L) I) OTf, (Ru (L) I ] BF _4, [Ru (L) I] ClO _4, [Ru (L) I] PF _6, [Ru (L) I] _{BPh 4, RuCl 2 (L)} (en), RuCl 2 (L) (dpen _{), RuCl 2 (L) (} daipen), RuH (BH 4) (L) (en), RuH (BH 4) (L) (daipen), RuH (BH 4) (L) (dpen)

Specific examples of the iridium complex include the following.
Ir (L) Cl, Ir (L) Br, Ir (L) I, (Ir (cod) (L)) OTf, (Ir (cod) (L)] BF ₄ , (Ir (cod) (L)) ClO ₄ , (Ir (cod) (L)) PF ₆ , (Ir (cod) (L)) BPh ₄ , (Ir (nbd) (L)) OTf, (Ir (nbd) (L)) BF ₄ , (Ir (nbd) (L)) ClO ₄ , (Ir (nbd) (L)) PF ₆ , (Ir (nbd) (L)) BPh ₄
The following are specific examples of the palladium complex.
PdCl ₂ (L), PdBr ₂ (L), PdI ₂ (L), (π-allyl) Pd (L), (Pd (L)) OTf, (Pd (L)) BF ₄ , (Pd (L) ) ClO ₄ , (Pd (L)) PF ₆ , (Pd (L)) BPh ₄
Specific examples of the nickel complex include the following.
NiCl ₂ (L), NiBr ₂ (L), NiI ₂ (L), (π-allyl) Ni (L)
Specific examples of the copper complex include, for example, the following.
CuCl (L), CuBr (L ), CuI (L), CuH (L), Cu (BH 4) (L), Cu (C 5 H 5) (L), Cu (C 5 (CH 3) 5) (L)

Of the transition metal complexes of the present invention, particularly preferred are Ru (L) (AcO) ₂ , Ru (L) Cl ₂ , Ru (L) Cl ₂ (dmf) _n , [Rh (L) (cod)] OTf, etc.

  By using the transition metal complex of the present invention for a reduction reaction, a Heck reaction, or the like, it is possible to produce a compound having a desired stereo configuration. Hereinafter, a reaction example is shown.

〔式中、R¹は置換基を有していてもよい炭化水素基または置換基を有していてもよい複素環基、R’はハロゲン原子、置換基を有していてもよいアルキルスルホニルまたは置換基を有していてもよいアリールスルホニル、R²は置換基を有していてもよい炭化水素基を示す。〕
化合物(V)を本発明の遷移金属錯体の存在下、水素化反応に付すことにより、光学活性化合物(VI)を得ることができる。 1. Asymmetric reduction of β-ketoester

Wherein R ¹ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ′ is a halogen atom, an alkylsulfonyl which may have a substituent. Or an arylsulfonyl which may have a substituent, and R ² represents a hydrocarbon group which may have a substituent. ]
By subjecting compound (V) to a hydrogenation reaction in the presence of the transition metal complex of the present invention, optically active compound (VI) can be obtained.

Examples of the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ¹ and R ² include alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- C _1-6 alkyl such as butyl, tert-butyl, pentyl, hexyl), cycloalkyl (eg, C _3-8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), aryl (example) , Phenyl, 1-naphthyl, C _6-10 aryl such as 2-naphthyl), aralkyl (eg, C _7-11 aralkyl such as benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl) and the like. can give.
Examples of the substituent of the “optionally substituted hydrocarbon group” represented by R ¹ and R ² include, for example, hydroxy, alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, carbonyl - sec-butoxy, tert- butoxy, pentoxy, C _1-6 alkoxy, such as hexyloxy), formyl, C _1-6 alkyl alkylcarbonyl (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl ), Alkoxycarbonyl (eg, C _1-6 such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, etc.) Alkoxy-carbonyl), carboxyl, N-mono-lower alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-tert- N-mono C _1-6 alkyl-carbamoyl such as butylcarbamoyl), N, N-di-lower alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N N, N-diC _1-6 alkyl-carbamoyl such as N, N-diisopropylcarbamoyl, N-ethyl-N-methylcarbamoyl), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and the like. And may have 1 to 3 selected from these substituents at substitutable positions.
The heterocyclic group of the `` heterocyclic group optionally having substituent (s) '' represented by R ¹ includes, besides a carbon atom, a nitrogen atom, a sulfur atom and an oxygen atom selected from 1 or 2 5- to 14-membered heterocyclic group containing two heteroatoms (eg, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3 -Quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3 -Pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 2-benzo [b] furanyl Aromatic heterocyclic groups such as 3-, 3-benzo [b] furanyl; 2-pyro Non-aromatic heterocyclic groups such as dinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 2-piperazinyl, etc.) .

Examples of the substituent of the “heterocyclic group optionally having substituent (s)” represented by R ¹ include, for example, hydroxy, alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy) , tert- butoxy, pentoxy, C _1-6 alkoxy, such as hexyloxy), formyl, alkylcarbonyl (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, C _1-6 alkyl, such as pivaloyl - carbonyl), alkoxy Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, C _1-6 alkoxy such as hexyloxycarbonyl -Carbonyl), carboxyl, N-mono-lower alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-tert-butyl) N-mono C _1-6 alkyl-carbamoyl such as rucarbamoyl), N, N-di-lower alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N, N-diC _1-6 alkyl-carbamoyl such as N-diisopropylcarbamoyl, N-ethyl-N-methylcarbamoyl), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and the like. And one or three selected from these substituents may be present at substitutable positions.
As R ¹ , aryl is preferable, and phenyl is particularly preferable.
As R ² , alkyl is preferable, and ethyl is particularly preferable.

The “halogen atom” represented by R ′ includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
As the "alkylsulfonyloxy" of the "alkylsulfonyloxy optionally having substituent (s)" for R ', for example, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy And C _1-4 alkylsulfonyloxy such as isobutylsulfonyloxy, sec-butylsulfonyloxy and tert-butylsulfonyloxy.
Examples of the substituent of the “alkylsulfonyloxy optionally having substituent (s)” represented by R ′ include a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom) and the like.
Represented by R 'in the "optionally arylsulfonyloxy optionally having substituents" as a "arylsulfonyloxy" is, for example, phenylsulfonyloxy, 1-naphthyl sulfonyloxy, such as 2-naphthylsulfonyl oxy C _{6 -10} arylsulfonyloxy.
Examples of the substituent of the “arylsulfonyloxy optionally having substituent (s)” represented by R ′ include a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom) and a halogen atom (eg, Alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) _1-6 alkyl) and the like.
R ′ is preferably a chlorine atom, a bromine atom or an iodine atom, and particularly preferably a chlorine atom.

In the asymmetric reduction reaction of compound (V), the amount of the transition metal complex of the present invention to be used is about 0.01 mmol to about 1 mol, preferably about 1 mmol to about 10 mmol, per 1 mol of compound (V). .
In the asymmetric reduction reaction of compound (V), hydrogen gas is used as a hydrogen source. The hydrogen pressure during the reaction is about 0.1 MPa to 10 MPa, preferably about 0.8 MPa to 5 MPa.
The asymmetric reduction reaction of compound (V) is performed in a solvent. Examples of the solvent used include alcohol solvents (eg, methanol, ethanol, n-propanol, isopropanol, etc.), hydrocarbon solvents (eg, hexane, benzene, toluene, xylene, etc.), ether solvents (eg, diethyl ether, Diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, etc.), ester solvents (eg, ethyl acetate, isopropyl acetate), ketone solvents (eg, acetone, methyl ethyl ketone, etc.), nitrile solvents (eg, acetonitrile, propio, etc.) A solvent selected from nitriles and the like, a sulfoxide-based solvent (eg, dimethylsulfoxide, etc.) and an amide-based solvent (eg, N, N-dimethylformamide, etc.), or a mixed solvent of two or more thereof. Of these, alcohol solvents (eg, methanol, ethanol, n-propanol, isopropanol, etc.), particularly ethanol, are preferred.
The reaction temperature in the asymmetric reduction of compound (V) is preferably from about 0 ° C to about 180 ° C, particularly preferably from about 20 ° C to about 100 ° C.

〔式中、各記号は前記と同意義である。〕の4種類の立体構造を有するが、特に

〔式中、各記号は前記と同意義である。〕または、

〔式中、各記号は前記と同意義である。〕である立体構造を有する化合物（syn体）を優先的に得ることができる。
また、化合物(V)の不斉還元反応は、同条件下で、本発明の遷移金属錯体以外の通常用いられる遷移金属錯体を用いて行うこともできる。本発明以外の遷移金属錯体としては、例えば、遷移金属がロジウム、ルテニウム、ニッケル、コバルトである遷移金属錯体があげられる。 The optically active compound (VI) obtained by the asymmetric reduction reaction of the compound (V) is

Wherein each symbol is as defined above. ] Has four types of three-dimensional structure,

Wherein each symbol is as defined above. ] Or

Wherein each symbol is as defined above. ] (Syn-form) having a steric structure can be preferentially obtained.
In addition, the asymmetric reduction reaction of compound (V) can also be carried out under the same conditions using a commonly used transition metal complex other than the transition metal complex of the present invention. Examples of the transition metal complex other than the present invention include a transition metal complex in which the transition metal is rhodium, ruthenium, nickel, or cobalt.

〔式中、R’’は塩素原子、臭素原子、ヨウ素原子、置換基を有していてもよいアルキルスルホニルまたは置換基を有していてもよいアリールスルホニル、その他の各記号は前記と同意義である。〕
化合物(VI’)の環化反応は、無機塩基の存在下、溶媒中で行う。
化合物(VI’)の環化反応において用いられる無機塩基としては、例えば、アルカリ金属の炭酸塩（例、炭酸ナトリウム、炭酸カリウム等）、アルカリ土類金属の炭酸塩（例、炭酸マグネシウム、炭酸カルシウム等）、アルカリ金属の水酸化物（例、水酸化ナトリウム、水酸化カリウム等）、アルカリ金属のリン酸塩（例、リン酸三カリウム等）、アルカリ金属の重炭酸塩（例、炭酸水素ナトリウム、炭酸水素カリウム等）等があげられる。なかでもアルカリ金属の炭酸塩（例、炭酸ナトリウム、炭酸カリウム等）が好ましい。
化合物(VI’)の環化反応において、無機塩基の使用量は化合物(VI’)1モルに対し、約1モルないし約10モル、好ましくは、約2モルないし約4モルである。
化合物(VI’)の環化反応において、用いられる溶媒は、アルコール系溶媒（例、メタノール、エタノール、n-プロパノール、イソプロパノール等）、炭化水素系溶媒（例、ヘキサン、ベンゼン、トルエン、キシレン等）、ハロゲン化炭化水素系溶媒（例、ジクロロメタン、クロロホルム、1,2-ジクロロエタン等）、エーテル系溶媒（例、ジエチルエーテル、ジイソプロピルエーテル、tert-ブチルメチルエーテル、ジオキサン、テトラヒドロフラン等）、エステル系溶媒（例、酢酸エチル、酢酸イソプロピル）、ケトン系溶媒（例、アセトン、メチルエチルケトン等）、ニトリル系溶媒（例、アセトニトリル、プロピオニトリル等）、スルホキシド系溶媒（例、ジメチルスルホキシド等）、水およびアミド系溶媒（例、N,N-ジメチルホルムアミド等）から選ばれる溶媒あるいはこれら二種以上の混合溶媒があげられる。なかでも、スルホキシド系溶媒（例、ジメチルスルホキシド等）およびアミド系溶媒（例、N,N-ジメチルホルムアミド等）が好ましい。
化合物(VI’)の環化反応における反応温度は、約-50℃ないし約180℃、なかでも約0℃ないし約100℃で行うのが好ましい。 Among the compounds (VI), R 'is a chlorine atom, a bromine atom, an iodine atom, an alkylsulfonyl optionally having a substituent or an arylsulfonyl optionally having a substituent (VI') Further, the compound (VII) useful as a synthetic intermediate of a medicine can be obtained by further performing a cyclization reaction.

Wherein R '' is a chlorine atom, a bromine atom, an iodine atom, an alkylsulfonyl which may have a substituent or an arylsulfonyl which may have a substituent, and other symbols are as defined above. It is. ]
The cyclization reaction of compound (VI ′) is performed in a solvent in the presence of an inorganic base.
Examples of the inorganic base used in the cyclization reaction of the compound (VI ′) include alkali metal carbonates (eg, sodium carbonate, potassium carbonate, etc.) and alkaline earth metal carbonates (eg, magnesium carbonate, calcium carbonate ), Alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), alkali metal phosphates (eg, tripotassium phosphate, etc.), alkali metal bicarbonates (eg, sodium bicarbonate) , Potassium bicarbonate, etc.). Of these, alkali metal carbonates (eg, sodium carbonate, potassium carbonate, etc.) are preferred.
In the cyclization reaction of compound (VI ′), the amount of the inorganic base to be used is about 1 mol to about 10 mol, preferably about 2 mol to about 4 mol, per 1 mol of compound (VI ′).
In the cyclization reaction of compound (VI ′), the solvent used is an alcohol solvent (eg, methanol, ethanol, n-propanol, isopropanol, etc.), a hydrocarbon solvent (eg, hexane, benzene, toluene, xylene, etc.) , Halogenated hydrocarbon solvents (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ether solvents (eg, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, etc.), ester solvents ( Examples: ethyl acetate, isopropyl acetate), ketone solvents (eg, acetone, methyl ethyl ketone, etc.), nitrile solvents (eg, acetonitrile, propionitrile, etc.), sulfoxide solvents (eg, dimethyl sulfoxide, etc.), water and amide solvents Solvent (eg, N, N-dimethylformamide, etc.) Et solvent or a mixed solvent of two or more of them selected the like. Of these, sulfoxide-based solvents (eg, dimethylsulfoxide, etc.) and amide-based solvents (eg, N, N-dimethylformamide, etc.) are preferred.
The reaction temperature in the cyclization reaction of compound (VI ') is preferably about -50 ° C to about 180 ° C, particularly preferably about 0 ° C to about 100 ° C.

〔式中、R³は水素原子または置換基を有していてもよいアルキル、R⁴は置換基を有していてもよいフェニル、R’’’は脱離基を示す。〕
化合物(VIII)を本発明の遷移金属錯体の存在下、化合物(IX)と反応させることにより、医薬の合成中間体として有用な光学活性化合物(X)を得ることができる。 2. Heck reaction

[In the formula, R ³ represents a hydrogen atom or an optionally substituted alkyl, R ⁴ represents an optionally substituted phenyl, and R ′ ″ represents a leaving group. ]
By reacting compound (VIII) with compound (IX) in the presence of the transition metal complex of the present invention, optically active compound (X) useful as an intermediate for the synthesis of a drug can be obtained.

Examples of the “optionally substituted alkyl group” represented by R ³ include, for example, hydroxy, alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy) , pentoxy, C _1-6 alkoxy), formyl, C _1-6 alkyl alkylcarbonyl (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, such as hexyloxy - carbonyl), alkoxycarbonyl (e.g., Cal - methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, tert- butoxycarbonyl, pentoxycarbonyl, C _1-6 alkoxy such as hexyl oxycarbonyl Nyl), carboxyl, N-mono-lower alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-tert-butylcarbamoyl Such as N-mono C _1-6 alkyl-carbamoyl), N, N-di-lower alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N 1 to 3 substituents selected from N, N-diC _1-6 alkyl-carbamoyl such as -diisopropylcarbamoyl and N-ethyl-N-methylcarbamoyl) C _1-6 alkyl and the like (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, etc.)
R ³ is particularly preferably a hydrogen atom.

Examples of the substituent of “phenyl which may have a substituent” represented by R ⁴ include, for example, hydroxy, alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butyl - butoxy, pentoxy, C _1-6 alkoxy), formyl, C _1-6 alkyl alkylcarbonyl (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, such as hexyloxy - carbonyl), alkoxycarbonyl ( examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, tert- butoxycarbonyl, pentoxycarbonyl, C _1-6 alkoxy such as hexyl oxycarbonyl -Carbonyl), carboxyl, N-mono-lower alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-tert-butyl) N-mono C _1-6 alkyl-carbamoyl such as rucarbamoyl), N, N-di-lower alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N, N-diC _1-6 alkyl-carbamoyl such as N-diisopropylcarbamoyl and N-ethyl-N-methylcarbamoyl), halogen atoms (eg, fluorine, chlorine, bromine, iodine), cyano, etc. And the number of substituents is one to three.
As R ⁴ , unsubstituted phenyl is particularly preferred.

  Examples of the "leaving group" represented by R "" include a halogen atom, an alkylsulfonyloxy optionally having a substituent, an arylsulfonyloxy optionally having a substituent, and the like. The “halogen atom”, “alkylsulfonyloxy optionally having substituent (s)”, and “arylsulfonyloxy optionally having substituent (s)” are “halogen atom” represented by R ′ above. And "alkylsulfonyloxy optionally having substituent (s)" and "arylsulfonyloxy optionally having substituent (s)". Of these, alkylsulfonyloxy optionally having a halogen atom is preferable, and trifluoromethylsulfonyloxy is particularly preferable.

The Heck reaction between compound (VIII) and compound (IX) is usually performed in a solvent. Examples of the solvent used include alcohol solvents (eg, methanol, ethanol, n-propanol, isopropanol, etc.), hydrocarbon solvents (eg, hexane, benzene, toluene, xylene, etc.), halogenated hydrocarbon solvents (eg, Examples: dichloromethane, chloroform, 1,2-dichloroethane, etc.), ether solvents (eg, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, etc.), ester solvents (eg, ethyl acetate, isopropyl acetate) , Ketone solvents (eg, acetone, methyl ethyl ketone, etc.), nitrile solvents (eg, acetonitrile, propionitrile, etc.), sulfoxide solvents (eg, dimethylsulfoxide, etc.) and amide solvents (eg, N, N-dimethylformamide) Etc.) The solvent mixtures of two or more of them and the like. Among them, hydrocarbon solvents (eg, hexane, benzene, toluene, xylene, etc.), ether solvents (eg, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, etc.) and amide solvents (eg, N, N-dimethylformamide and the like) are preferred. Further, ether solvents (eg, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, etc.) are preferred.
In the Heck reaction of compound (VIII) and compound (IX), the amount of the transition metal complex of the present invention is about 0.01 mmol to about 1 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (IX). Is a mole.
In the Heck reaction between compound (VIII) and compound (IX), the amount of compound (VIII) used is about 1 mol to about 10 mol, preferably about 3 mol to about 5 mol, per 1 mol of compound (IX). is there.
The reaction temperature in the Heck reaction of compound (VIII) with compound (IX) is preferably from about 0 ° C to about 180 ° C, particularly preferably from about 30 ° C to about 110 ° C.

  In addition to the above reaction, the transition metal complex of the present invention can be used for asymmetric hydrogenation of α, β-unsaturated ester (Example 1 described below), asymmetric hydrogenation of olefins and ketones, and the like. Thus, the production of an optically active compound useful as an intermediate for the synthesis of pharmaceuticals was made possible.

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. In the present specification, room temperature indicates 10 ° C to 35 ° C. In addition, the following equipment was used for the measurement of each physical property of the Example. ¹ H nuclear magnetic resonance spectrum ( ¹ H-NMR): DPX300 (manufactured by Bruker), internal reference substance: tetramethylsilane. ¹³ C nuclear magnetic resonance spectrum ( ¹³ C-NMR): DPX300 (manufactured by Bruker), internal reference substance: CDCl ₃ . ³¹ P nuclear magnetic resonance spectrum ( ³¹ P-NMR): DPX300 (manufactured by Bruker), external reference substance: 85% H ₃ PO ₄ aqueous solution. Mass spectrometry: JMS-700T (manufactured by JEOL Ltd.). Melting point: 530 (manufactured by Buchi).

Reference Example 1
(S) -2,2'-bis (trifluoromethanesulfonyloxy) -1,1'-binaphthyl
To a solution of (S) -1,1′-bi-2-naphthol (26.2 g, 91 mmol) in acetonitrile (130 mL) was added pyridine (19.5 g, 2.7 equivalents) at room temperature. Then, trifluoromethanesulfonic anhydride (64.2 g, 2.5 equivalents) was added at 5 ° C, and the mixture was stirred at 5 to 10 ° C for 2 hours. Water (100 mL) was added at 3 ° C., then ethyl acetate (130 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was separated, and the organic layer was washed with water (50 mL) and concentrated under reduced pressure. Diisopropyl ether (150 mL) and activated carbon (0.25 g) were added to the residue, and the mixture was stirred at 60 ° C for 30 minutes. The activated carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from heptane to give the title compound (48.9 g, white crystals). 97% yield
¹ H-NMR (300 MHz, CDCl ₃ , TMS) δ: 7.33 (d, 2H, J = 8.14 Hz), 7.34-7.46 (m, 2H), 7.57-7.63 (m, 2H), 7.68 (d, 2H, J = 9.09 Hz), 8.03 (d, 2H, J = 8.23 Hz), 8.16 (d, 2H, J = 9.08 Hz).

アルゴン雰囲気下、4-ブロモ-2,6-ジ-tert-ブチルフェノール(50 g, 0.175 moL)および炭酸カリウム(96.7 g, 4.0 当量)のアセトン(750 mL)溶液に硫酸ジメチル(38.6 g, 1.75 当量)を22℃で加えた後、還流下で13時間攪拌した。不溶物をろ去後、溶媒を減圧留去した。酢酸エチル(150 mL)、水(100 mL)を加え、分液し、有機層を水(100 mL)、5%NaHCO₃水溶液(100 mL)、5%NaCl水溶液(100 mL)で順次洗浄した。ついで有機層を無水硫酸マグネシウムで乾燥後、自然ろ過し、ろ液を減圧濃縮した。表題化合物(56.1 g,褐色オイル)を得た。収率95.2%
¹H-NMR (300MHz, CDCl₃, TMS) δ: 1.41 (s, 18H), 3.68 (s, 3H), 7.33 (s, 2H). Reference Example 2
4-bromo-2,6-di-tert-butylanisole

Under an argon atmosphere, dimethyl sulfate (38.6 g, 1.75 equivalent) was added to a solution of 4-bromo-2,6-di-tert-butylphenol (50 g, 0.175 mol) and potassium carbonate (96.7 g, 4.0 equivalent) in acetone (750 mL). ) Was added at 22 ° C, and the mixture was stirred under reflux for 13 hours. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure. Ethyl acetate (150 mL) and water (100 mL) were added, the layers were separated, and the organic layer was washed sequentially with water (100 mL), 5% aqueous NaHCO ₃ (100 mL), and 5% aqueous NaCl (100 mL). . Then, the organic layer was dried over anhydrous magnesium sulfate, filtered naturally, and the filtrate was concentrated under reduced pressure. The title compound (56.1 g, brown oil) was obtained. 95.2% yield
¹ H-NMR (300 MHz, CDCl ₃ , TMS) δ: 1.41 (s, 18H), 3.68 (s, 3H), 7.33 (s, 2H).

アルゴン雰囲気下、マグネシウム(4.0 g, 0.95 当量)および少量のヨウ素のTHF(50 mL)溶液を室温で1時間撹拌した。参考例２で合成した4-ブロモ-2,6-ジ-tert-ブチルアニソール(52 g, 0.175 moL)を46℃ないし53℃で加えた後、5℃で1時間攪拌した。ついで5℃で亜リン酸ジエチル(11.4 g, 0.52 当量)を加えた後、5℃で1時間撹拌した。3℃で水(50 mL)を加え、ついでトルエン(50 mL)、6M-HCl(20 mL)を加えた後、室温で30分間攪拌した。反応液を分液し、有機層を水(20 mL)、5%NaHCO₃水溶液(20 mL)、5%NaCl水溶液(20 mL)で順次洗浄した。ついで有機層を無水硫酸マグネシウムで乾燥後、自然ろ過し、ろ液を減圧濃縮した。残渣をヘプタンより再結晶し、表題化合物(11.6 g,薄黄白色結晶)を得た。収率20.5%。融点166.1℃。
¹H-NMR (300 MHz, CDCl₃, TMS) δ: 1.38 (s, 36H), 3.68 (s, 6H), 7.49 (s, 2H), 7.54 (s, 2H), 8.01 (d, 1H, J = 474.4 Hz).
³¹P-NMR (121 MHz, CDCl₃, 85%H₃PO₄) δ: 23.57 (dquint, J = 474.1 Hz, 14.0 Hz).
元素分析 C₃₀H₄₇O₃Pとして
計算値; C: 74.04, H: 9.73, P:6.36.
実測値; C: 74.13, H: 9.93, P:6.20. Reference Example 3
Bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphine oxide

Under an argon atmosphere, a solution of magnesium (4.0 g, 0.95 equivalent) and a small amount of iodine in THF (50 mL) was stirred at room temperature for 1 hour. After 4-bromo-2,6-di-tert-butylanisole (52 g, 0.175 mol) synthesized in Reference Example 2 was added at 46 ° C to 53 ° C, the mixture was stirred at 5 ° C for 1 hour. Then, after adding diethyl phosphite (11.4 g, 0.52 equivalent) at 5 ° C, the mixture was stirred at 5 ° C for 1 hour. Water (50 mL) was added at 3 ° C., and then toluene (50 mL) and 6M-HCl (20 mL) were added, followed by stirring at room temperature for 30 minutes. The reaction solution was separated, and the organic layer was sequentially washed with water (20 mL), a 5% aqueous NaHCO ₃ solution (20 mL), and a 5% aqueous NaCl solution (20 mL). Then, the organic layer was dried over anhydrous magnesium sulfate, filtered naturally, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from heptane to give the title compound (11.6 g, pale yellow-white crystals). Yield 20.5%. 166.1 ° C.
¹ H-NMR (300 MHz, CDCl ₃ , TMS) δ: 1.38 (s, 36H), 3.68 (s, 6H), 7.49 (s, 2H), 7.54 (s, 2H), 8.01 (d, 1H, J = 474.4 Hz).
³¹ P-NMR (121 MHz, CDCl ₃ , 85% H ₃ PO ₄ ) δ: 23.57 (dquint, J = 474.1 Hz, 14.0 Hz).
Elemental analysis as C ₃₀ H ₄₇ O ₃ P
Calculated; C: 74.04, H: 9.73, P: 6.36.
Found: C: 74.13, H: 9.93, P: 6.20.

アルゴン雰囲気下、塩化セリウム(4.55 g, 3.0 当量)のTHF(25 mL)溶液を室温(25℃)で30分間攪拌した。水素化ホウ素ナトリウム(0.72 g, 3.1 当量)を加えた後、室温で1時間攪拌した。ついで5℃にて参考例３で合成したビス(3,5-ジ-tert-ブチル-4-メトキシフェニル)ホスフィンオキサイド(3.0 g, 6.16 mmoL)および水素化リチウムアルミニウム(0.28 g, 1.2 当量)を順次加えた後、室温で18時間攪拌した。3℃で水(10 mL)を加え、ついでトルエン(30 mL)、6M-HCl(20 mL)を加えた後、室温で30分間攪拌した。反応液を分液し、水層をトルエン(30 mL)で抽出した。合わせた有機層を5%NaCl水溶液(20 mL)で順次洗浄した。ついで有機層を無水硫酸マグネシウムで乾燥、自然ろ過し、ろ液を減圧濃縮した。残渣をカラムクロマトグラフィー（アルミナ 25 g、n-ヘキサン）で精製した。残渣をヘプタンより再結晶し、表題化合物(1.18 g,白色結晶)を得た。収率39.6 %。融点134.7℃。
¹H-NMR (300 MHz, CDCl₃, TMS) δ: 0.37-1.08 (m, 3H), 1.39 (s, 36H), 3.69 (s, 6H), 6.23 (dq, 1H, J = 376.2 Hz, 6.78 Hz), 7.50 (d, 4H, J = 12.18 Hz).
³¹P-NMR (121 MHz, CDCl₃, 85%H₃PO₄) δ: -3.33- -1.46 (m), -0.13-1.80 (m). Reference example 4
Bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphine-borane complex

Under an argon atmosphere, a solution of cerium chloride (4.55 g, 3.0 equivalents) in THF (25 mL) was stirred at room temperature (25 ° C.) for 30 minutes. After adding sodium borohydride (0.72 g, 3.1 equivalents), the mixture was stirred at room temperature for 1 hour. Then, at 5 ° C., bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphine oxide (3.0 g, 6.16 mmol) synthesized in Reference Example 3 and lithium aluminum hydride (0.28 g, 1.2 equivalent) were added. After the addition, the mixture was stirred at room temperature for 18 hours. Water (10 mL) was added at 3 ° C., and then toluene (30 mL) and 6M-HCl (20 mL) were added, followed by stirring at room temperature for 30 minutes. The reaction solution was separated, and the aqueous layer was extracted with toluene (30 mL). The combined organic layers were sequentially washed with a 5% aqueous NaCl solution (20 mL). Then, the organic layer was dried over anhydrous magnesium sulfate, filtered naturally, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (25 g of alumina, n-hexane). The residue was recrystallized from heptane to give the title compound (1.18 g, white crystals). Yield 39.6%. 134.7 ° C.
¹ H-NMR (300 MHz, CDCl ₃ , TMS) δ: 0.37-1.08 (m, 3H), 1.39 (s, 36H), 3.69 (s, 6H), 6.23 (dq, 1H, J = 376.2 Hz, 6.78 Hz), 7.50 (d, 4H, J = 12.18 Hz).
³¹ P-NMR (121 MHz, CDCl ₃ , 85% H ₃ PO ₄ ) δ: -3.33- -1.46 (m), -0.13-1.80 (m).

アルゴン雰囲気下、[1,2-ビス(ジフェニルホスフィノ)-エタン]ジクロロニッケル(48 mg, 0.1 当量)と参考例１で合成した(S)-2,2'-ビス（トリフルオロメタンスルホニルオキシ）-1,1'-ビナフチル(507 mg, 0.91 mmoL)および1,4-ジアザビシクロ[2,2,2]オクタン(620 mg, 6.0 当量)のDMF溶液(5 mL)に、参考例４で合成したビス（3,5-ジ-tert-ブチル-4-メトキシフェニル）ホスフィン-ボラン錯体(1.03 g, 2.3 当量)を室温で加えた後、室温で30分間攪拌した。ついで110℃で153時間攪拌した。DMFを減圧留去し、残渣にメタノールを加えて、表題化合物(737 mg, 黄白色結晶)を得た。収率69%。融点 129.5℃。旋光度：[α]_D = -232°(25℃, c = 1.0, CHCl₃)
¹H-NMR (300 MHz, CDCl₃, TMS) δ: 1.21 (s, 36H), 1.24 (s, 36H), 3.58 (s, 6H), 3.64 (s, 6H), 6.64 (d, 2H, J = 7.60 Hz), 6.77 (d, 2H, J = 7.10 Hz), 6.92-7.00 (m, 4H), 7.13-7.20 (m, 4H), 7.30-7.37 (m, 2H), 7.42-7.51 (m, 2H), 7.77 (d, 2H, J = 6.91 Hz), 7.86 (d, 2H, J = 8.02 Hz).
¹³C-NMR (75 MHz, CDCl₃, CDCl₃) δ: 33.34, 33.49, 36.96, 37.19, 65.44, 65.53, 126.64, 127.23, 128.76, 128.80, 128.92, 131.84, 132.95, 134.51, 144.02, 160.37, 161.31.
³¹P-NMR (121 MHz, CDCl₃, 85%H₃PO₄) δ: -15.02 (s).
質量分析(ESI-HR); 計算値; 1189.7332
実測値; 1189.7350(M-H) Reference example 5
(S) -2,2'-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl

[1,2-Bis (diphenylphosphino) -ethane] dichloronickel (48 mg, 0.1 equivalent) and (S) -2,2'-bis (trifluoromethanesulfonyloxy) synthesized in Reference Example 1 under an argon atmosphere. It was synthesized in Reference Example 4 in a DMF solution (5 mL) of -1,1′-binaphthyl (507 mg, 0.91 mmoL) and 1,4-diazabicyclo [2,2,2] octane (620 mg, 6.0 equivalents). After adding bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphine-borane complex (1.03 g, 2.3 equivalents) at room temperature, the mixture was stirred at room temperature for 30 minutes. Then, the mixture was stirred at 110 ° C for 153 hours. DMF was distilled off under reduced pressure, and methanol was added to the residue to obtain the title compound (737 mg, yellow-white crystals). Yield 69%. 129.5 ° C. Optical rotation: [α] _D = -232 ° (25 ° C, c = 1.0, CHCl ₃ )
¹ H-NMR (300 MHz, CDCl ₃ , TMS) δ: 1.21 (s, 36H), 1.24 (s, 36H), 3.58 (s, 6H), 3.64 (s, 6H), 6.64 (d, 2H, J = 7.60 Hz), 6.77 (d, 2H, J = 7.10 Hz), 6.92-7.00 (m, 4H), 7.13-7.20 (m, 4H), 7.30-7.37 (m, 2H), 7.42-7.51 (m, 2H), 7.77 (d, 2H, J = 6.91 Hz), 7.86 (d, 2H, J = 8.02 Hz).
¹³ C-NMR (75 MHz, CDCl ₃ , CDCl ₃ ) δ: 33.34, 33.49, 36.96, 37.19, 65.44, 65.53, 126.64, 127.23, 128.76, 128.80, 128.92, 131.84, 132.95, 134.51, 144.02, 160.37, 161.31.
³¹ P-NMR (121 MHz, CDCl ₃ , 85% H ₃ PO ₄ ) δ: -15.02 (s).
Mass spectrometry (ESI-HR); calculated; 1189.7332
Found; 1189.7350 (MH)

Rh(cod)₂OTf(4.27 mg、0.0091mmoL)のメタノール(1 mL)溶液に参考例５で合成した(S)-2,2'-ビス[ビス（3,5-ジ-tert-ブチル-4-メトキシフェニル）ホスフィノ]-1,1'-ビナフチル(12.65 mg、0.011 mmoL)を加えた後、室温(25℃)で30分間攪拌した。反応混合物の³¹P-NMRを測定した。(³¹P-NMR (121 MHz, CD₃OD, 85%H₃PO₄) δ: 27.9(s), 29.1(s).) メチル (Z)-α-アセトアミドシンナメート(0.10 g、0.456 mmoL)のメタノール(4 mL)溶液に上記で調整したRh錯体溶液を加え、水素圧1.0 MPa、25℃で24時間水素化を行った。反応混合物をGC（カラム：CHIRASIL VAL、0.25mm×30 m）にて測定し、変換率 >99.9%、光学純度 91.43%ee(R)であった。 Example 1
Asymmetric hydrogenation of methyl (Z) -α-acetamidocinnamate

(S) -2,2'-bis [bis (3,5-di-tert-butyl-) synthesized in Reference Example 5 in a methanol (1 mL) solution of Rh (cod) ₂ OTf (4.27 mg, 0.0091 mmol). After adding 4-methoxyphenyl) phosphino] -1,1′-binaphthyl (12.65 mg, 0.011 mmol), the mixture was stirred at room temperature (25 ° C.) for 30 minutes. The ³¹ P-NMR of the reaction mixture was measured. ( ³¹ P-NMR (121 MHz, CD ₃ OD, 85% H ₃ PO ₄ ) δ: 27.9 (s), 29.1 (s).) Methyl (Z) -α-acetamidocinnamate (0.10 g, 0.456 mmoL) The Rh complex solution prepared above was added to a methanol (4 mL) solution of, and hydrogenation was performed at 1.0 MPa of hydrogen pressure and 25 ° C for 24 hours. The reaction mixture was measured by GC (column: CHIRASIL VAL, 0.25 mm × 30 m), and the conversion was> 99.9% and the optical purity was 91.43% ee (R).

Rh(cod)₂OTf(4.27 mg、0.0091mmoL)のメタノール(1 mL)溶液に(S)-2,2'-ビス（ジフェニルホスフィノ）-1,1'-ビナフチル(6.79 mg、0.011 mmoL)を加えた後、室温(25℃)で30分間攪拌した。メチル (Z)-α-アセトアミドシンナメート(0.10 g、0.456 mmoL)のメタノール(4 mL)溶液に上記で調整したRh錯体溶液を加え、水素圧1.0 MPa、25℃で24時間水素化を行った。反応混合物をGC（カラム：CHIRASIL VAL、0.25mm×30 m）にて測定し、変換率 >99.9%、光学純度 15.33%ee(R)であった。 Comparative Example 1
Asymmetric hydrogenation of methyl (Z) -α-acetamidocinnamate

_{Rh (cod) 2 OTf (4.27} mg, 0.0091mmoL) methanol (1 mL) was added (S)-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (6.79 mg, 0.011 mmoL) Was added, and the mixture was stirred at room temperature (25 ° C.) for 30 minutes. The above-prepared Rh complex solution was added to a methanol (4 mL) solution of methyl (Z) -α-acetamidocinnamate (0.10 g, 0.456 mmoL), and hydrogenation was performed at a hydrogen pressure of 1.0 MPa and 25 ° C. for 24 hours. . The reaction mixture was measured by GC (column: CHIRASIL VAL, 0.25 mm × 30 m), and the conversion was> 99.9% and the optical purity was 15.33% ee (R).

Example 2
Synthesis of diacetato {(S) -2,2'-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl} ruthenium (II) Bis (η ⁶ -benzene) -tetra-μ-chloro diruthenium (II) (100.0 mg, 0.200 mmol) and (S) -2,2′-bis [bis (3,5-di -tert-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl (453.1 mg, 0.380 mmol) was added with N, N-dimethylformamide (4 mL), and the mixture was stirred at 100 ° C for 10 minutes. The solvent of the reaction solution was distilled off, and a solution of sodium acetate (640.4 mg, 7.80 mmoL) in methanol (6 mL) was added to the residue. The mixture was irradiated with ultrasonic waves and reacted for 20 minutes. Toluene (3 mL) and water (6 mL) were added to the reaction solution to carry out a liquid separation, and toluene (3 mL) was added to the aqueous layer to carry out a liquid separation. Water (6 mL) was added to all the organic layers to carry out liquid separation, and the solvent of the organic layers was distilled off. Toluene (1 mL) and methanol (6 mL) were added to the residue, and after standing at room temperature for 15 hours and at 4 ° C for 5 days, insolubles were filtered. The title compound (450 mg, brown powder) was obtained from the filtrate. Yield 80%.
¹ H-NMR (300 MHz, CD ₂ Cl ₂ , TMS) δ: 1.0 (s, 36H), 1.3 (s, 36H), 1.5 (s, 6H), 3.2 (s, 6H), 3.7 (s, 6H) ), 6.0 (d, 2H, J = 8.4 Hz), 6.6-6.7 (m, 2H), 6.9 (t, 4H, J = 5.6 Hz), 7.0-7.1 (m, 2H), 7.3-7.4 (m, 4H), 7.5 (d, 2H, J = 8.1 Hz), 7.6 (d, 2H, J = 8.5 Hz), 7.8-7.9 (m, 2H)
³¹ P-NMR (121 MHz, CD ₂ Cl ₂ , 85% H ₃ PO ₄ ) δ: 67.5 (s)

Example 3
{[(S) -2,2'-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl] dichlororuthenium (II)} (N, N Synthesis of-(dimethylformamide) _n Under an argon atmosphere, bis (η ⁶ -benzene) -tetra-μ-chlorodiruthenium (II) (101.7 mg, 0.203 mmoL) and (S) -2,2 synthesized in Reference Example 5 Add N, N-dimethylformamide (4 mL) to '-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl (454.8 mg, 0.382 mmol). And stirred at 100 ° C. for 60 minutes. The solvent of the reaction solution was distilled off to obtain the title compound (469 mg, red-brown powder). Yield 80%.
³¹ P-NMR (121 MHz, CD ₂ Cl ₂ , 85% H ₃ PO ₄ ) δ: 56.8 (s), 70.1 (s)

Example 4
Synthesis of ｛(S) -2,2'-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyldichlororuthenium (II) Under argon atmosphere, Diacetato {(S) -2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl} ruthenium (II) synthesized in Example 2 To a solution of (237 mg, 0.168 mmol) in methylene chloride (4 mL) was added 5% hydrochloric acid-methanol (0.3 mL), and the mixture was stirred at room temperature for 93 hours. The solvent of the reaction solution was distilled off to obtain the title compound (22 mg, brown powder). 96% yield.
³¹ P-NMR (121 MHz, CD ₂ Cl ₂ , 85% H ₃ PO ₄ ) δ: 62.2 (s).

実施例２で合成したジアセタト｛(S)-2,2'-ビス[ビス（3,5-ジ-tert-ブチル-4-メトキシフェニル）ホスフィノ]-1,1'-ビナフチル｝ ルテニウム（II） (30.1 mg, 0.021 mmol)、2-クロロ-3-オキソ-3-フェニル-プロピオン酸エチルエステル(0.966 g, 4.261 mmol)のエタノール（9 mL）溶液を、水素圧 1 MPa、反応温度 80℃で 17.5 時間水素化を行った。この反応混合物につき、GC（カラム：α-DEX 120, 0.25 mm×30m）を測定し、変換率 >99.9% であった。さらにこの反応混合液の溶媒を留去し、N,N-ジメチルホルムアミド（含水 1.8%, 18 mL）及び炭酸カリウム(1.79 g, 13.0 mmol) を加え 6 時間攪拌した。イソプロピルエーテル (30 mL) 及び水（30 mL）を加えて抽出分液し、水層にイソプロピルエーテル（30 mL）を加えて再度抽出し、合わせた有機層を1N 塩酸（30 mL）、水（30 mL）、水（30 mL）で順次洗浄した。この有機層につきGC（カラム：α-DEX 120, 0.25 mm×30 m）を測定し、光学純度 77.5%ee (2R,3R), 82.7%de (cis) であった。 Example 5
Asymmetric hydrogenation of ethyl 2-chloro-3-oxo-3-phenyl-propionate

Diacetato {(S) -2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl} ruthenium (II) synthesized in Example 2 (30.1 mg, 0.021 mmol) and a solution of 2-chloro-3-oxo-3-phenyl-propionic acid ethyl ester (0.966 g, 4.261 mmol) in ethanol (9 mL) at a hydrogen pressure of 1 MPa and a reaction temperature of 80 ° C. Hydrogenation was performed for 17.5 hours. GC (column: α-DEX 120, 0.25 mm × 30 m) of this reaction mixture was measured, and the conversion was> 99.9%. Further, the solvent of the reaction mixture was distilled off, N, N-dimethylformamide (1.8% in water, 18 mL) and potassium carbonate (1.79 g, 13.0 mmol) were added, and the mixture was stirred for 6 hours. Isopropyl ether (30 mL) and water (30 mL) were added to carry out extraction and separation. The aqueous layer was extracted again with isopropyl ether (30 mL), and the combined organic layers were combined with 1N hydrochloric acid (30 mL), water ( 30 mL) and water (30 mL). GC (column: α-DEX 120, 0.25 mm × 30 m) of this organic layer was measured, and the optical purity was 77.5% ee (2R, 3R) and 82.7% de (cis).

ジアセタト｛(R)-2,2'-ビス（ジフェニルホスフィノ）-1,1'-ビナフチル｝ ルテニウム（II）(30.6 mg, 0.036 mmol)、2-クロロ-3-オキソ-3-フェニル-プロピオン酸エチルエステル (1.62 g, 7.17 mmol)のエタノール（15 mL）溶液を、水素圧 1 MPa、反応温度 80℃で 17.5 時間水素化を行った。反応混合物につき、GC（カラム：α-DEX 120, 0.25 mm×30m）を測定したところ、変換率 >99.9% であった。さらにこの反応混合液の溶媒を留去し、N,N-ジメチルホルムアミド（含水 1.8%, 30 mL）及び炭酸カリウム(2.98 g, 21.56 mmol) を加え 6時間攪拌した。イソプロピルエーテル (30 mL)及び水（30 mL）を加えて抽出分液し、水層にイソプロピルエーテル（30 mL）を加えて再度抽出し、合わせた有機層を1N 塩酸（30 mL）、水（30 mL）、水（30 mL）で順次洗浄した。この有機層につきGC（カラム：α-DEX 120, 0.25 mm×30m）を測定し、光学純度 3.9%ee(2R,3R), 85.7%de(cis) であった。 Comparative Example 2
Asymmetric hydrogenation of ethyl 2-chloro-3-oxo-3-phenyl-propionate

Diacetato ｛(R) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl｝ ruthenium (II) (30.6 mg, 0.036 mmol), 2-chloro-3-oxo-3-phenyl-propion A solution of acid ethyl ester (1.62 g, 7.17 mmol) in ethanol (15 mL) was hydrogenated at a hydrogen pressure of 1 MPa and a reaction temperature of 80 ° C. for 17.5 hours. GC (column: α-DEX 120, 0.25 mm × 30 m) of the reaction mixture was measured, and the conversion was> 99.9%. Further, the solvent of the reaction mixture was distilled off, N, N-dimethylformamide (1.8% in water, 30 mL) and potassium carbonate (2.98 g, 21.56 mmol) were added, and the mixture was stirred for 6 hours. Isopropyl ether (30 mL) and water (30 mL) were added to carry out extraction and separation. The aqueous layer was extracted again with isopropyl ether (30 mL), and the combined organic layers were combined with 1N hydrochloric acid (30 mL) and water ( 30 mL) and water (30 mL). GC (column: α-DEX 120, 0.25 mm × 30 m) of this organic layer was measured, and the optical purity was 3.9% ee (2R, 3R), 85.7% de (cis).

実施例３で合成した｛[(S)-2,2'-ビス[ビス（3,5-ジ-tert-ブチル-4-メトキシフェニル）ホスフィノ]-1,1'-ビナフチル]ジクロロ ルテニウム(II)｝ (N,N-ジメチルホルムアミド)_n (50.5 mg, 0.036 mmol)のエタノール溶液(5 mL) に2-クロロ-3-オキソ-3-フェニル-プロピオン酸エチルエステル (1.57 g, 6.928 mmol) のエタノール溶液(10 mL)を加え、水素圧 1 MPa、反応温度 80℃で 16.5時間水素化を行った。この反応混合物につき、GC（カラム：α-DEX 120, 0.25 mm×30 m）を測定し、変換率 >99.9% であった。さらにこの反応混合液の溶媒を留去し、N,N-ジメチルホルムアミド（含水 1.8%, 30 mL）及び炭酸カリウム(2.90 g, 20.9 mmol) を加え 6時間攪拌した。イソプロピルエーテル (30 mL)及び水（30 mL）を加えて抽出分液し、水層にイソプロピルエーテル（30 mL）を加えて再度抽出し、合わせた有機層を1N 塩酸（30 mL）、水（30 mL）、水（30 mL）で順次洗浄した。この有機層につきGC（カラム：α-DEX 120, 0.25 mm×30 m）を測定し、光学純度 79.4%ee (2R,3R), 82.4%de(cis)であった。 Example 6
Asymmetric hydrogenation of ethyl 2-chloro-3-oxo-3-phenyl-propionate

{[(S) -2,2'-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl] dichlororuthenium (II) synthesized in Example 3 )｝ (N, N-dimethylformamide) _n (50.5 mg, 0.036 mmol) in ethanol (5 mL) was added with 2-chloro-3-oxo-3-phenyl-propionic acid ethyl ester (1.57 g, 6.928 mmol). An ethanol solution (10 mL) was added, and hydrogenation was performed at a hydrogen pressure of 1 MPa and a reaction temperature of 80 ° C for 16.5 hours. GC (column: α-DEX 120, 0.25 mm × 30 m) of this reaction mixture was measured, and the conversion was> 99.9%. Further, the solvent of the reaction mixture was distilled off, N, N-dimethylformamide (1.8% in water, 30 mL) and potassium carbonate (2.90 g, 20.9 mmol) were added, and the mixture was stirred for 6 hours. Isopropyl ether (30 mL) and water (30 mL) were added to carry out extraction and separation. The aqueous layer was extracted again with isopropyl ether (30 mL), and the combined organic layers were combined with 1N hydrochloric acid (30 mL) and water ( 30 mL) and water (30 mL). GC (column: α-DEX 120, 0.25 mm × 30 m) of this organic layer was measured, and the optical purity was 79.4% ee (2R, 3R), 82.4% de (cis).

｛[(R)-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル]ジクロロ ルテニウム(II)｝ (N,N-ジメチルホルムアミド)_n (27.8 mg, 0.033 mmol)及び2-クロロ-3-オキソ-3-フェニル-プロピオン酸エチルエステル（1.586 g, 6.998 mmol）のエタノール（15 mL）溶液を、水素圧 1 MPa、反応温度 80℃で 16.5時間水素化を行った。この反応混合物につき、GC（カラム：α-DEX 120, 0.25 mm×30m）を測定し、変換率 >99.9% であった。さらにこの反応混合液の溶媒を留去し、N,N-ジメチルホルムアミド（含水 1.8%, 30 mL）及び炭酸カリウム(2.95 g, 21.3 mmol)を加え 6時間攪拌した。イソプロピルエーテル (30 mL)及び水（30 mL）を加えて抽出分液し、水層にイソプロピルエーテル（30 mL）を加えて再度抽出し、合わせた有機層を1N 塩酸（30 mL）、水（30 mL）、水（30 mL）で順次洗浄した。この有機層につきGC（カラム：α-DEX 120, 0.25 mm×30m）を測定し、光学純度 4.5%ee (2R,3R) , 87.7%de(cis) であった。 Comparative Example 3
Asymmetric hydrogenation of ethyl 2-chloro-3-oxo-3-phenyl-propionate

{[(R) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] dichlororuthenium (II)} (N, N-dimethylformamide) _n (27.8 mg, 0.033 mmol) and 2- A solution of ethyl chloro-3-oxo-3-phenyl-propionate (1.586 g, 6.998 mmol) in ethanol (15 mL) was hydrogenated at a hydrogen pressure of 1 MPa and a reaction temperature of 80 ° C. for 16.5 hours. GC (column: α-DEX 120, 0.25 mm × 30 m) of this reaction mixture was measured, and the conversion was> 99.9%. Further, the solvent of the reaction mixture was distilled off, N, N-dimethylformamide (1.8% in water, 30 mL) and potassium carbonate (2.95 g, 21.3 mmol) were added, and the mixture was stirred for 6 hours. Isopropyl ether (30 mL) and water (30 mL) were added to carry out extraction and separation. The aqueous layer was extracted again with isopropyl ether (30 mL), and the combined organic layers were combined with 1N hydrochloric acid (30 mL) and water ( 30 mL) and water (30 mL). GC (column: α-DEX 120, 0.25 mm × 30 m) of this organic layer was measured, and the optical purity was 4.5% ee (2R, 3R), 87.7% de (cis).

アルゴン雰囲気下、ジクロロ（η²,η²-1,5-シクロオクタジエン）ルテニウム(II) (100.9 mg, 0.396 mmol) 及び 参考例５で合成した(S)-2,2'-ビス[ビス（3,5-ジ-tert-ブチル-4-メトキシフェニル）ホスフィノ]-1,1'-ビナフチル(467.0 mg, 0.392 mmol) のトルエン(6 mL)溶液にトリエチルアミン(0.3 mL) を加え、135℃で3時間攪拌還流した。反応液の溶媒を留去し、褐色の粉末 (440 mg)を得た。ここで得た褐色の粉末(50.0 mg, 0.035 mmol)及び2-クロロ-3-オキソ-3-フェニル-プロピオン酸エチルエステル (1.61 g, 7.12 mmol)のエタノール（15 mL）溶液を、水素圧 1 MPa、反応温度 80℃で 15時間水素化を行った。この反応混合物につき、GC（カラム：α-DEX 120, 0.25 mm×30 m）を測定し、変換率 86.5% であった。さらにこの反応混合液の溶媒を留去し、N,N-ジメチルホルムアミド（含水 1.8%, 30 mL）及び炭酸カリウム(2.93 g, 21.2 mmol) を加え 6時間攪拌した。イソプロピルエーテル (30 mL)及び水（30 mL）を加えて抽出分液し、水層にイソプロピルエーテル（30 mL）を加えて再度抽出し、合わせた有機層を1N 塩酸（30 mL）、水（30 mL）、水（30 mL）で順次洗浄した。この有機層につきGC（カラム：α-DEX 120, 0.25 mm×30m）を測定し、光学純度 85.1%ee (2R,3R), 87.8%de (cis)であった。 Example 7
Asymmetric hydrogenation of ethyl 2-chloro-3-oxo-3-phenyl-propionate

Under an argon atmosphere, dichloro (η ² , η ² -1,5-cyclooctadiene) ruthenium (II) (100.9 mg, 0.396 mmol) and (S) -2,2′-bis [bis Triethylamine (0.3 mL) was added to a solution of (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl (467.0 mg, 0.392 mmol) in toluene (6 mL), and the mixture was added at 135 ° C. For 3 hours under reflux. The solvent of the reaction solution was distilled off to obtain a brown powder (440 mg). A solution of the brown powder obtained here (50.0 mg, 0.035 mmol) and 2-chloro-3-oxo-3-phenyl-propionic acid ethyl ester (1.61 g, 7.12 mmol) in ethanol (15 mL) was added under a hydrogen pressure of 1 Hydrogenation was carried out at a reaction temperature of 80 ° C. for 15 hours. GC (column: α-DEX 120, 0.25 mm × 30 m) of this reaction mixture was measured, and the conversion was 86.5%. Further, the solvent of the reaction mixture was distilled off, N, N-dimethylformamide (1.8% in water, 30 mL) and potassium carbonate (2.93 g, 21.2 mmol) were added, and the mixture was stirred for 6 hours. Isopropyl ether (30 mL) and water (30 mL) were added to carry out extraction and separation. The aqueous layer was extracted again with isopropyl ether (30 mL), and the combined organic layers were combined with 1N hydrochloric acid (30 mL) and water ( 30 mL) and water (30 mL). GC (column: α-DEX 120, 0.25 mm × 30 m) of this organic layer was measured, and the optical purity was 85.1% ee (2R, 3R) and 87.8% de (cis).

実施例７と同様の方法で合成したルテニウム-[(R)-2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル]錯体(33.6 mg, 0.040 mmol)及び2-クロロ-3-オキソ-3-フェニル-プロピオン酸エチルエステル(1.64 g, 7.24 mmol)のエタノール（15 mL）溶液を、水素圧 1 MPa、反応温度 80℃で 15 時間水素化を行った。この反応混合物につき、GC（カラム：α-DEX 120, 0.25 mm×30 m）を測定し、変換率 >99.9% であった。さらにこの反応混合液の溶媒を留去し、N,N-ジメチルホルムアミド（含水 1.8%, 30 mL）及び炭酸カリウム(3.02 g, 21.9 mmol) を加え6時間攪拌した。イソプロピルエーテル (30 mL)及び水（30 mL）を加えて抽出分液し、水層にイソプロピルエーテル（30 mL）を加えて再度抽出し、合わせた有機層を1N 塩酸（30 mL）、水（30 mL）、水（30 mL）で順次洗浄した。この有機層につきGC（カラム：α-DEX 120, 0.25 mm×30 m）を測定し、光学純度 3.1%ee (2R,3R), 86.6%de (cis)であった。 Comparative Example 4
Asymmetric hydrogenation of ethyl 2-chloro-3-oxo-3-phenyl-propionate

Ruthenium-[(R) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] complex (33.6 mg, 0.040 mmol) and 2-chloro-3 synthesized in the same manner as in Example 7. A solution of -oxo-3-phenyl-propionic acid ethyl ester (1.64 g, 7.24 mmol) in ethanol (15 mL) was hydrogenated at a hydrogen pressure of 1 MPa and a reaction temperature of 80 ° C for 15 hours. GC (column: α-DEX 120, 0.25 mm × 30 m) of this reaction mixture was measured, and the conversion was> 99.9%. Further, the solvent of the reaction mixture was distilled off, N, N-dimethylformamide (1.8% in water, 30 mL) and potassium carbonate (3.02 g, 21.9 mmol) were added, and the mixture was stirred for 6 hours. Isopropyl ether (30 mL) and water (30 mL) were added to carry out extraction and separation. The aqueous layer was extracted again with isopropyl ether (30 mL), and the combined organic layers were combined with 1N hydrochloric acid (30 mL) and water ( 30 mL) and water (30 mL). GC (column: α-DEX 120, 0.25 mm × 30 m) of this organic layer was measured, and the optical purity was 3.1% ee (2R, 3R), 86.6% de (cis).

参考例５で合成した(S)-2,2'-ビス[ビス（3,5-ジ-tert-ブチル-4-メトキシフェニル）ホスフィノ]-1,1'-ビナフチル (54.7 mg, 0.046 mmol)、（η²,η²-1,5-シクロオクタジエン）ビス-(2-メチルアリル) ルテニウム(II) (12.8 mg, 0.040 mmol)及び2-クロロ-3-オキソ-3-フェニル-プロピオン酸エチルエステル (1.71 g, 7.53 mmol) のエタノール (15 mL)溶液を、水素圧 1 MPa、反応温度 80℃で 14時間水素化を行った。この反応混合物につき、GC（カラム：α-DEX 120, 0.25 mm×30 m）を測定し、変換率 4.6% であった。さらにこの反応混合液の溶媒を留去し、N,N-ジメチルホルムアミド（含水 1.8%, 18 mL）及び炭酸カリウム(3.15 g, 22.8 mmol)を加え6時間攪拌した。イソプロピルエーテル (30 mL)及び水（30 mL）を加えて抽出分液し、水層にイソプロピルエーテル（30 mL）を加えて再度抽出し、合わせた有機層を1N 塩酸（30 mL）、水（30 mL）、水（30 mL）で順次洗浄した。この有機層につきGC（カラム：α-DEX 120, 0.25 mm×30 m）を測定し、光学純度 67.6%ee (2R,3R), 69.1%de (cis) であった。 Example 8
Asymmetric hydrogenation of ethyl 2-chloro-3-oxo-3-phenyl-propionate

(S) -2,2'-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl synthesized in Reference Example 5 (54.7 mg, 0.046 mmol) , (Η ² , η ² -1,5-cyclooctadiene) bis- (2-methylallyl) ruthenium (II) (12.8 mg, 0.040 mmol) and ethyl 2-chloro-3-oxo-3-phenyl-propionate A solution of the ester (1.71 g, 7.53 mmol) in ethanol (15 mL) was hydrogenated at a hydrogen pressure of 1 MPa and a reaction temperature of 80 ° C. for 14 hours. GC (column: α-DEX 120, 0.25 mm × 30 m) of this reaction mixture was measured, and the conversion was 4.6%. Further, the solvent of the reaction mixture was distilled off, N, N-dimethylformamide (1.8% in water, 18 mL) and potassium carbonate (3.15 g, 22.8 mmol) were added, and the mixture was stirred for 6 hours. Isopropyl ether (30 mL) and water (30 mL) were added to carry out extraction and separation. The aqueous layer was extracted again with isopropyl ether (30 mL), and the combined organic layers were combined with 1N hydrochloric acid (30 mL) and water ( 30 mL) and water (30 mL). GC (column: α-DEX 120, 0.25 mm × 30 m) of this organic layer was measured, and the optical purity was 67.6% ee (2R, 3R), 69.1% de (cis).

(R)-2,2'-ビス（ジフェニルホスフィノ）-1,1'-ビナフチル (30.3mg, 0.049mmol) 、（η²,η²-1,5-シクロオクタジエン）ビス-(2-メチルアリル) ルテニウム(II) (13.6mg, 0.042mmol) 及び2-クロロ-3-オキソ-3-フェニル-プロピオン酸エチルエステル（1.71g, 7.543mmol）のエタノール（15mL）溶液を、水素圧 1 MPa、反応温度 80℃で 14 時間水素化を行った。この反応混合物につき、GC（カラム：α-DEX 120, 0.25 mm×30m）を測定し、変換率 >99.9% であった。さらにこの反応混合液の溶媒を留去し、N,N-ジメチルホルムアミド（含水 1.8%, 18mL）及び炭酸カリウム(3.18g, 23.0mmol) を加え 6 時間攪拌した。イソプロピルエーテル (30mL) 及び水（30mL）を加えて抽出分液し、水層にイソプロピルエーテル（30mL）を加えて再度抽出し、合わせた有機層を1N 塩酸（30mL）、水（30mL）、水（30mL）で順次洗浄した。この有機層につきGC（カラム：α-DEX 120, 0.25 mm×30m）を測定し、光学純度 1.1%ee (2S,3S), 84.9%de (cis) であった。 Comparative Example 5
Asymmetric hydrogenation of ethyl 2-chloro-3-oxo-3-phenyl-propionate

(R) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (30.3 mg, 0.049 mmol), (η ² , η ² -1,5-cyclooctadiene) bis- (2- Methylallyl) Ruthenium (II) (13.6 mg, 0.042 mmol) and 2-chloro-3-oxo-3-phenyl-propionic acid ethyl ester (1.71 g, 7.543 mmol) in ethanol (15 mL) were treated with a hydrogen pressure of 1 MPa, Hydrogenation was carried out at a reaction temperature of 80 ° C. for 14 hours. GC (column: α-DEX 120, 0.25 mm × 30 m) of this reaction mixture was measured, and the conversion was> 99.9%. Further, the solvent of the reaction mixture was distilled off, N, N-dimethylformamide (1.8% in water, 18 mL) and potassium carbonate (3.18 g, 23.0 mmol) were added, and the mixture was stirred for 6 hours. Isopropyl ether (30 mL) and water (30 mL) were added to carry out extraction and liquid separation. The aqueous layer was extracted again with isopropyl ether (30 mL), and the combined organic layers were combined with 1N hydrochloric acid (30 mL), water (30 mL), and water. (30 mL). GC (column: α-DEX 120, 0.25 mm × 30 m) of this organic layer was measured, and the optical purity was 1.1% ee (2S, 3S), 84.9% de (cis).

酢酸パラジウム(II) (2.2 mg, 0.0099 mmoL)の1,4-ジオキサン(2.5 mL)溶液にジイソプロピルエチルアミン (0.25 mL, 11.46 mmoL)および参考例５で合成した (S)-2,2'-ビス[ビス（3,5-ジ-tert-ブチル-4-メトキシフェニル）ホスフィノ]-1,1'-ビナフチル(35.6 mg, 0.030 mmoL)を加えた後、60℃で1時間攪拌した。反応混合物の³¹P-NMRを測定した。(³¹P-NMR (121 MHz, CDCl₃, 85%H₃PO₄) δ: 29.24- 29.54 (m).) 2,3-ジヒドロフラン(0.19 mL、2.50 mmoL)、フェニル トリフルオロメタンスルホネート(0.079 mL、0.488 mmoL)を順次加え、105℃で24時間反応を行った。反応混合物をGC（カラム：CP-Chirasil-DEX CB、0.32mm×25 m）にて測定し、変換率 >99.9%、光学純度 64.9%ee(S)、生成比(1/2) 33:1であった。 Example 9
Asymmetric Heck reaction

Diisopropylethylamine (0.25 mL, 11.46 mmoL) was added to a solution of palladium (II) acetate (2.2 mg, 0.0099 mmol) in 1,4-dioxane (2.5 mL) and (S) -2,2'-bis synthesized in Reference Example 5. After adding [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl (35.6 mg, 0.030 mmol), the mixture was stirred at 60 ° C. for 1 hour. The ³¹ P-NMR of the reaction mixture was measured. ( ³¹ P-NMR (121 MHz, CDCl ₃ , 85% H ₃ PO ₄ ) δ: 29.24- 29.54 (m).) 2,3-dihydrofuran (0.19 mL, 2.50 mmoL), phenyl trifluoromethanesulfonate (0.079 mL , 0.488 mmoL), and the mixture was reacted at 105 ° C. for 24 hours. The reaction mixture was measured by GC (column: CP-Chirasil-DEX CB, 0.32 mm × 25 m), conversion rate> 99.9%, optical purity 64.9% ee (S), production ratio (1/2) 33: 1 Met.

酢酸パラジウム (II) (2.2 mg, 0.0099 mmoL)の1,4-ジオキサン(2.5 mL)溶液にジイソプロピルエチルアミン (0.25 mL, 11.46 mmoL)および (S)-2,2'-ビス（ジフェニルホスフィノ）-1,1'-ビナフチル(18.6 mg, 0.030 mmoL)を加えた後、60℃で1時間攪拌した。2,3-ジヒドロフラン(0.19 mL, 2.50 mmoL)、フェニル トリフルオロメタンスルホネート(0.079 mL, 0.488 mmoL)を順次加え、105℃で24時間反応を行った。反応混合物をGC（カラム：CP-Chirasil-DEX CB、0.32 mm×25 m）にて測定し、変換率 >99.9%、光学純度 48.8%ee(S)、生成比(1/2) 6:1であった。 Comparative Example 6

To a solution of palladium (II) acetate (2.2 mg, 0.0099 mmol) in 1,4-dioxane (2.5 mL) was added diisopropylethylamine (0.25 mL, 11.46 mmol) and (S) -2,2'-bis (diphenylphosphino)- After adding 1,1′-binaphthyl (18.6 mg, 0.030 mmol), the mixture was stirred at 60 ° C. for 1 hour. 2,3-Dihydrofuran (0.19 mL, 2.50 mmoL) and phenyl trifluoromethanesulfonate (0.079 mL, 0.488 mmoL) were sequentially added and reacted at 105 ° C. for 24 hours. The reaction mixture was measured by GC (column: CP-Chirasil-DEX CB, 0.32 mm × 25 m), conversion rate> 99.9%, optical purity 48.8% ee (S), production ratio (1/2) 6: 1 Met.

  The asymmetric reaction of the transition metal complex of the present invention having 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl as a ligand ( In particular, the compound having the desired absolute configuration can be efficiently obtained by using the compound for asymmetric reduction).

Claims (18)

A transition metal complex having 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl as a ligand. The transition metal complex according to claim 1, wherein the transition metal is rhodium, ruthenium, iridium, palladium, nickel or copper. The transition metal complex according to claim 1, wherein the transition metal is rhodium, ruthenium, iridium, palladium or nickel. The transition metal complex according to claim 1, wherein the transition metal is rhodium. The transition metal complex according to claim 1, wherein the transition metal is ruthenium. Ru (L) (AcO) ₂ [L is 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl, Ac represents acetyl . The transition metal complex according to claim 1, which is represented by the formula: Ru (L) Cl ₂ [L represents 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl. The transition metal complex according to claim 1, which is represented by the formula: Ru (L) Cl ₂ (dmf) _n [L is 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl, dmf is N , N-dimethylformamide. The transition metal complex according to claim 1, which is represented by the formula: [Rh (L) (cod)] OTf [L is 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl, cod is 1 , 5-cyclooctadiene and Tf represent trifluoromethylsulfonyl. The transition metal complex according to claim 1, which is represented by the formula: formula:

Wherein R ¹ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ′ is a halogen atom, an alkylsulfonyl which may have a substituent. Or an arylsulfonyl which may have a substituent, and R ² represents a hydrocarbon group which may have a substituent. Or a salt thereof, with 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl as a ligand Wherein the reduction reaction is carried out in the presence of a transition metal complex;

[In the formula, * indicates the position of the asymmetric carbon, and the other symbols are as defined above. ] Or a salt thereof. formula:

(In the formula, R ¹ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R '' has a chlorine atom, a bromine atom, an iodine atom, and a substituent. R ² represents an optionally substituted alkylsulfonyloxy or an optionally substituted arylsulfonyloxy, and R ² represents an optionally substituted hydrocarbon group. A compound represented by the formula: or a salt thereof, in the presence of a transition metal complex, an alcohol solvent, a hydrocarbon solvent, an ether solvent, an ester solvent, a ketone solvent, a nitrile solvent, a sulfoxide solvent and an amide solvent. By performing the reduction reaction in a solvent selected from the following or in a mixed solvent of two or more of these, the formula:

[In the formula, * indicates the position of the asymmetric carbon, and the other symbols are as defined above. Or a salt thereof, and further subjecting the compound to a cyclization reaction in the presence of an inorganic base.

Wherein each symbol is as defined above. ] Or a salt thereof. formula:

(In the formula, R ¹ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, R ² is a hydrocarbon group which may have a substituent, * Indicates the position of the asymmetric carbon. The compound represented by

Wherein each symbol is as defined above. ] Or

Wherein each symbol is as defined above. The method according to claim 11, which is an optically active compound represented by the formula: formula:

(In the formula, R ¹ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R '' has a chlorine atom, a bromine atom, an iodine atom, and a substituent. Optionally substituted alkylsulfonyloxy or optionally substituted arylsulfonyloxy, R ² represents an optionally substituted hydrocarbon group, and * represents an asymmetric carbon position. The compound represented by

Wherein each symbol is as defined above. ] Or

Wherein each symbol is as defined above. The method according to claim 11, which is an optically active compound represented by the formula: The method according to claim 11, wherein R "is a chlorine atom, a bromine atom or an iodine atom. The method according to claim 11, wherein the inorganic base is an alkali metal carbonate. The production method according to claim 11, wherein the solvent for performing the reduction reaction is an alcohol solvent. The transition metal complex is a transition metal complex having 2,2'-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl as a ligand. 12. The production method according to 11. formula:

[In the formula, R ³ represents a hydrogen atom or an alkyl which may have a substituent. Or a salt thereof, with 2,2′-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphino] -1,1′-binaphthyl as a ligand In the presence of a transition metal complex, a compound represented by the formula: R ⁴ -R ′ ″ wherein R ⁴ represents phenyl which may have a substituent, and R ″ ″ represents a leaving group. A compound represented by the formula:

[In the formula, * indicates the position of the asymmetric carbon, and the other symbols are as defined above. ] Or a salt thereof.