WO2025164594A1 - Ruthenium-diphosphine-carboxylate complex and method for producing same - Google Patents

Abstract

The present invention relates to a novel ruthenium complex useful as a catalyst in various organic synthesis reactions, including aromatic asymmetric hydrogenation, and an efficient method for producing the same. Namely, the present invention provides a ruthenium-diphosphine-carboxylate complex represented by general formula (1). The present invention further provides a method for producing a ruthenium-diphosphine-carboxylate complex represented by general formula (1), the method comprising reacting a diphosphine compound represented by general formula (2) with a ruthenium-alkylbenzene-carboxylate complex represented by general formula (3).

Description

Ruthenium-diphosphine-carboxylate complex and method for producing the same

The present invention relates to a novel ruthenium-diphosphine-carboxylate complex that is useful as a catalyst in various organic synthesis reactions, including aromatic asymmetric hydrogenation, and an efficient method for producing the same.

Optically active cyclic compounds are extremely important compounds for use in pharmaceuticals, agrochemicals, functional materials, fragrances, and synthetic intermediates, and research and development into their production methods is still underway. Among these, catalytic asymmetric hydrogenation of aromatic and heteroaromatic compounds, or aromatic asymmetric hydrogenation, has the advantage of being able to simultaneously introduce multiple asymmetric carbons into target molecules, while also being highly atom-efficient and capable of significantly reducing waste. Therefore, aromatic asymmetric hydrogenation is not only useful as a method for producing optically active cyclic compounds, but is also one of the most important catalytic reactions from the perspectives of the Sustainable Development Goals (SDGs), which have recently attracted attention, and green chemistry, which contributes to reducing environmental impact.

In order to commercialize this type of asymmetric aromatic hydrogenation, it is essential to have an asymmetric catalyst that is easy to manufacture and that exhibits excellent catalytic activity, chiral induction ability, substrate compatibility, reaction reproducibility, and air stability. Therefore, vigorous development of such catalysts has been underway for many years. Among these catalysts, catalytic systems prepared by combining the rare trans-chelate chiral diphosphine ligand 2,2"-bis[1-(diphenylphosphino)ethyl]-1,1"-biferrocene (commonly known as Ph-TRAP; Patent Document 1 and Non-Patent Document 1) with various transition metal sources are known to exhibit excellent chiral induction ability and substrate compatibility in aromatic asymmetric hydrogenation (Non-Patent Documents 2-4). Accordingly, research and development into the synthesis of Ph-TRAP, which is used to prepare such catalytic systems, has been actively pursued, and various methods have been reported to date (Non-Patent Documents 5-7).

On the other hand, the aforementioned catalytic systems sometimes fail to produce reproducible reactions. This is because the complex formation between Ph-TRAP and the transition metal source in the reaction system does not always proceed smoothly (Non-Patent Document 2). To address this issue, Ryoichi Kuwano et al. of Kyushu University developed a ruthenium complex of Ph-TRAP, [RuCl(p-cymene)(Ph-trap)]Cl. They demonstrated that reaction reproducibility was significantly improved by preparing this complex outside the reaction system, isolating it, and using it as a catalyst (Non-Patent Documents 2 and 8). Furthermore, asymmetric hydrogenation of indoles, naphthalenes, and quinolines using this ruthenium complex as a catalyst has enabled the efficient synthesis of optically active indolines, which are important as pharmaceutical and agrochemical intermediates, as well as optically active tetrahydronaphthalenes and tetrahydroquinolines, which are difficult to obtain using conventional methods (Non-Patent Documents 8-10). For reference, the following formula 1 shows the stereochemical structure of both enantiomers of [RuCl(p-cymene)(Ph-trap)]Cl, and the following formula 2 shows a schematic diagram of aromatic asymmetric hydrogenation using this complex as a catalyst.

Patent Document 1: Japanese Patent Application Laid-Open No. 4-283596

Non-Patent Document 1: Masaya Sawamura, Hitoshi Hamashima, and Yoshihiko Ito, Tetrahedron: Asymmetry, 1991, 7(2), 593-596.
Non-patent document 2: Ryoichi Kuwano, J. Synth. Org. Chem. , Jpn. , 2007, 65(2), 109-118.
Non-patent document 3: Ryoichi Kuwano, Nao Kameyama, and Ryuhei Ikeda, J. Am. Chem. Soc., 2011, 133(19), 7312-7315.
Non-patent document 4: Ryoichi Kuwano, J. Synth. Org. Chem. , Jpn. , 2021, 79(12), 1125-1135.
Non-Patent Document 5: Masaya Sawamura, Hitoshi Hamashima, Masanobu Sugawara, Ryoichi Kuwano, and Yoshihiko Ito, Organometallics, 1995, 14(10), 4549-4558.
Non-Patent Document 6: Ryoichi Kuwano, and Masaya Sawamura, Catalysts for Fine Chemical Synthesis: Vol. 5, Regio- and Stereo-Controlled Oxidations and Reductions, Wiley, Chicago, 2007, 5, 73-86.
Non-Patent Document 7: Michael A. Schmidt, Eric M. Simmons, Carolyn S. Wei, Hyunsoo Park, and Martin D. Eastgate, J. Org. Chem. , 2018, 83(7), 3928-3940.
Non-Patent Document 8: Ryoichi Kuwano and Manabu Kashiwabara, Org. Lett., 2006, 8(12), 2653-2655.
Non-Patent Document 9: Ryoichi Kuwano, Ryuichi Morioka, Manabu Kashiwabara, and Nao Kameyama, Angew. Chem. Int. Ed., 2012, 51(17), 4136-4139.
Non-Patent Document 10: Ryoichi Kuwano, Ryuhei Ikeda, and Kazuki Hirasada, Chem. Commun., 2015, 51, 7558-7561.

Until now, various catalysts have been vigorously developed to improve the efficiency of various organic synthesis reactions, including aromatic asymmetric hydrogenation, which is useful for producing optically active cyclic compounds. However, the aforementioned SDGs and green chemistry cannot necessarily be achieved by applying conventional catalysts, so new catalyst systems are always desired. The objective of the present invention is to provide a new catalyst that can be suitably used in various organic synthesis reactions, as well as an efficient method for producing the same.

From the perspective of developing such new catalysts, the aforementioned ruthenium complex of Ph-TRAP, i.e., [RuCl(p-cymene)(Ph-trap)]Cl, is considered. While this complex exhibits excellent performance as an aromatic asymmetric hydrogenation catalyst, various problems remain from the perspective of industrial use, as described below. First, the synthesis of Ph-TRAP used to produce this complex requires various reagents and solvents that are difficult to use industrially. Furthermore, Ph-TRAP takes the form of an amorphous compound that is unstable in air or a highly toxic benzene solvate, making it extremely difficult to produce industrially using conventional methods (Equation 3; Non-Patent Documents 5-7).

It is possible to synthesize the desired [RuCl(p-cymene)(Ph-trap)]Cl by reacting the thus obtained Ph-TRAP with dichloro(p-cymene)ruthenium(II) dimer ([RuCl ₂ (p-cymene)] ₂ ). However, this reaction requires an excess amount of dichloromethane, a halogenated solvent that is subject to strict legal restrictions. In addition, the complex is amorphous and has poor crystallinity, making industrial production difficult (Equation 4; Non-Patent Document 8).

Furthermore, while aromatic asymmetric hydrogenation using this complex as a catalyst has the advantage of eliminating the need for the highly toxic and corrosive fluorinated solvents commonly used in this type of reaction, it requires the coexistence of various strong bases, such as potassium carbonate, cesium carbonate, or 1,1,3,3-tetramethylguanidine (TMG). This makes it difficult to use compounds that decompose under basic conditions as substrates, and also requires a catalyst amount of 1 mol% or more, leaving room for further improvement (Equation 5; Non-Patent Documents 8-10).

In light of this background, the present inventors first investigated the industrialization of Ph-TRAP, which is difficult to synthesize, and developed an efficient method for producing a stable equivalent of Ph-TRAP (Ph-TRAP·(BH ₃ ) ₂ ) that avoids the various problems associated with conventional methods (WO 2024/203802). Furthermore, they discovered that this stable equivalent can be easily converted to Ph-TRAP·n-BuOH, an air-stable crystalline solvate, simply by heating it in n-butyl alcohol (n-BuOH) and then cooling it (WO 2024/203803). For reference, the following scheme 6 outlines the methods for producing Ph-TRAP·(BH ₃ ) ₂ and Ph-TRAP·n-BuOH (although the present invention is not limited by this scheme).

These manufacturing methods have made it possible to obtain Ph-TRAP, which was previously difficult to synthesize, in abundant quantities as a stable, crystalline solvate. Therefore, the inventors worked on the molecular design of a new catalyst to resolve the issues with the conventional catalyst, [RuCl(p-cymene)(Ph-trap)]Cl. As a result, they arrived at a molecular design that not only improves molecular symmetry and crystallinity but also anticipates the development of excellent catalytic activity without the addition of a strong base, if the p-cymene and chloride ligands could be removed from the conventional catalyst and instead acetate ligands, which can also function as a weak base, could be introduced (Equation 7).

Based on this strategic molecular design, the present inventors have conducted extensive research aimed at developing a novel catalyst. They have discovered that a novel ruthenium-diphosphine-acetate complex, i.e., Ru(O ₂ CMe) ₂ (Ph-trap), can be produced in good yield as a crystalline compound by reacting Ph-TRAP·n-BuOH with a known ruthenium-alkylbenzene-acetate complex, diacetato(p-cymene)ruthenium(II) (Ru(O ₂ CMe) ₂ (p-cymene)), in a non-halogenated solvent, toluene. Furthermore, by utilizing the excellent crystallinity of this complex, they have succeeded in determining its absolute configuration by single-crystal X-ray structural analysis. Surprisingly, it has been revealed that Ph-TRAP in this complex behaves as a cis-chelate chiral diphosphine ligand, rather than the conventional trans-chelate type. For reference, the outline of the method for producing Ru(O ₂ CMe) ₂ (Ph-trap) is shown in the following scheme 8 (it should be noted that the present invention is not limited to this outline in any way).

Therefore, the present inventors evaluated the performance of various catalysts using the asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole, a sterically bulky and poorly reactive heteroaromatic compound, as a model reaction. The results showed that the reaction proceeded almost completely without the addition of a base when using the conventional catalyst [RuCl(p-cymene)(Ph-trap)]Cl or the common catalyst Ru(O ₂ CMe) ₂ (binap). On the other hand, when using the newly developed Ru(O ₂ CMe) ₂ (Ph-trap) as a catalyst, the reaction proceeded rapidly to completion without the addition of a base, and the catalyst amount could be reduced to just 0.05 mol%. Furthermore, this reaction also demonstrated quantitative production of the desired N-Boc-2-phenylindoline with excellent optical purity. For reference, the following scheme 9 shows an outline of the asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole using various catalysts (it should be noted that the present invention is not limited to this scheme in any way).

Furthermore, we found that by replacing the acetate ligand (O ₂ CMe) on Ru(O ₂ CMe) ₂ (Ph-trap) with a bulkier carboxylate ligand, such as a pivalate ligand (O ₂ C ^t Bu) or a 1-adamantanecarboxylate ligand (O ₂ CAd), the molecular symmetry changes and the catalytic activity is significantly improved, enabling the reaction to be completed even using more practical low-pressure hydrogen gas.

Based on these findings, the present inventors have further investigated and completed the present invention. That is, the present invention includes the following [1] to [11].
[1] A ruthenium-diphosphine-carboxylate complex represented by the following general formula (1):

[In the formula,
A solid line represents a single bond, a double line represents a double bond, and a dashed line represents a coordinate bond;
H represents a hydrogen atom, C represents a carbon atom, O represents an oxygen atom, and P represents a phosphorus atom;
Me represents a methyl group;
Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the bold line represents six electrons donated by the cyclopentadienyl anion to Fe;
R ^P represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent;
Ru represents a divalent ruthenium ion;
R ^C represents a group selected from the group consisting of an alkyl group, a halogenoalkyl group, a cycloalkyl group, and an aryl group.
[2] The ruthenium-diphosphine-carboxylate complex according to [1] above, which is an optically active substance.
[3] The ruthenium-diphosphine-carboxylate complex according to the above [1] or [2], wherein R 1 ^P is an aryl group which may have a substituent.
[4] The ruthenium-diphosphine-carboxylate complex according to any one of the above [1] to [3], wherein R ^C is selected from the group consisting of alkyl groups and cycloalkyl groups.
[5] The following general formula (2)

[In the formula,
Solid lines represent single bonds;
H represents a hydrogen atom, C represents a carbon atom, and P represents a phosphorus atom;
Me represents a methyl group;
Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the bold line represents six electrons donated by the cyclopentadienyl anion to Fe;
R ^P represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent.
and a diphosphine compound represented by the following general formula (3):

[In the formula,
A solid line represents a single bond, a double line represents a double bond, and a dashed line represents a coordinate bond;
C represents a carbon atom and O represents an oxygen atom;
Ru represents a divalent ruthenium ion, AB represents alkylbenzenes, and the thick dashed line represents six-electron donation of the alkylbenzenes to Ru;
R ^C represents a group selected from the group consisting of an alkyl group, a halogenoalkyl group, a cycloalkyl group, and an aryl group.
[0023] The method for producing the ruthenium-diphosphine-carboxylate complex according to any one of [1] to [4] above, comprising reacting a ruthenium-alkylbenzene-carboxylate complex represented by the formula:
[6] The method according to the above [5], wherein the diphosphine compound represented by the general formula (2) is an optically active substance.
[7] The method according to the above [5] or [6], wherein R 1 ^P in the general formula (2) is an aryl group which may have a substituent.
[8] The method according to any one of the above [5] to [7], wherein R 3 ^C in the general formula (3) is selected from the group consisting of alkyl groups and cycloalkyl groups.
[9] The method according to any one of [5] to [8] above, wherein AB in the general formula (3) is selected from the group consisting of benzene, 1,3,5-trimethylbenzene, 1-methyl-4-isopropylbenzene, and hexamethylbenzene.
[10] A method for producing an optically active cyclic compound by asymmetric hydrogenation of a compound selected from the group consisting of aromatic compounds and heteroaromatic compounds using the ruthenium-diphosphine-carboxylate complex according to any one of [2] to [4] above as a catalyst.
[11] The method according to [10] above, wherein the compound selected from the group consisting of aromatic compounds and heteroaromatic compounds is selected from the group consisting of indoles, oxazoles, imidazoles, and naphthalenes.

The present invention provides a ruthenium-diphosphine-carboxylate complex represented by the general formula (1), i.e., Ru(O ₂ ^CRC ) ₂ (R ^P -trap) (hereinafter referred to as ruthenium complex (1) of the present invention). The ruthenium complex (1) of the present invention can be easily produced by reacting a diphosphine compound represented by the general formula (2) with a ruthenium-alkylbenzene-carboxylate complex represented by the general formula (3) in a non-halogenated solvent that is readily available for industrial use. Furthermore, a preferred form of ruthenium complex (1) of the present invention has excellent crystallinity, facilitating isolation and purification and long-term storage. Furthermore, it exhibits excellent catalytic activity, asymmetric induction ability, and substrate generality without the addition of a base, and therefore can contribute to the efficiency and practical application of various organic synthesis reactions, including aromatic asymmetric hydrogenation, which is useful for producing optically active cyclic compounds.

FIG. 1 shows the results of single crystal X-ray structural analysis of Ru(O ₂ CMe) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) produced in Example 1 below. FIG. 2 shows the results of single crystal X-ray structural analysis of Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) produced in Example 2 below. FIG. 3 shows the results of single crystal X-ray structural analysis of Ru(O ₂ C ^t Bu) ₂ ((R _C ,R _C ,S _P ,S _P )-Ph-trap) produced in Example 3 below. FIG. 4 shows the results of single crystal X-ray structural analysis of Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) produced in Example 4 below. FIG. 5 shows the results of single crystal X-ray structural analysis of Ru(O ₂ CAd) ₂ ((R _C ,R _C ,S _P ,S _P )-Ph-trap) produced in Example 5 below. FIG. 6 shows the results of single crystal X-ray structural analysis of Ru(O ₂ CAd) ₂ ((R _C ,R _C ,S _P ,S _P )-Ph-trap)·H ₂ O produced in Example 5 below. FIG. 7 shows the results of single crystal X-ray structural analysis of (S)-N-Boc-2-phenylindoline prepared in Example 9 below. FIG. 8 shows the results of single crystal X-ray structural analysis of (R)-N-Boc-2-phenylindoline prepared in Example 14 below. FIG. 9 shows the results of single crystal X-ray structural analysis of (S)-N-Boc-3-phenylindoline prepared in Example 17 below.

The ruthenium complex (1) of the present invention will be described in detail below. In the general formula (1), a solid line represents a single bond, a double line represents a double bond, and a dashed line represents a coordinate bond. H represents a hydrogen atom, C represents a carbon atom, O represents an oxygen atom, and P represents a phosphorus atom. Me represents a methyl group. Fe represents a divalent iron ion, the pentagon containing a circle represents a cyclopentadienyl anion, and the thick line represents six electrons donated by the cyclopentadienyl anion to Fe. R ^{1 P} represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent, preferably an aryl group which may have a substituent. Ru represents a divalent ruthenium ion. R ^{1 C} represents a group selected from the group consisting of an alkyl group, a halogenoalkyl group, a cycloalkyl group, and an aryl group, preferably an alkyl group or a cycloalkyl group. In the ruthenium complex (1) of the present invention, all four R 1 ^Ps present on the molecule represent the same group, and all two R 1 ^Cs present on the molecule represent the same group.

Next, the alkyl group, cycloalkyl group, heteroaryl group and optionally substituted aryl group in R 1 ^P will be described in more detail.

The alkyl group in R ^P may be linear or branched, and examples thereof include alkyl groups having 1 to 12 carbon atoms, preferably alkyl groups having 1 to 8 carbon atoms, and more preferably alkyl groups having 1 to 4 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group.

The cycloalkyl group for R ^P may be monocyclic or polycyclic, and examples thereof include a cycloalkyl group having 3 to 20 carbon atoms, preferably a cycloalkyl group having 3 to 15 carbon atoms, and more preferably a cycloalkyl group having 3 to 10 carbon atoms. Specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 1-adamantyl group, and a 2-adamantyl group.

The heteroaryl group in R 1 ^P includes heteroaryl groups derived from a 5-membered heteroaromatic ring containing an oxygen atom or a sulfur atom, and specific examples thereof include a 2-furyl group, a 3-furyl group, a 2-thienyl group, and a 3-thienyl group.

Examples of the aryl group in R ^P include aryl groups having 6 to 18 carbon atoms, preferably aryl groups having 6 to 14 carbon atoms, and more preferably aryl groups having 6 to 10 carbon atoms, and specific examples include phenyl groups, 1-naphthyl groups, and 2-naphthyl groups, and a preferred specific example is phenyl groups. The aryl groups may have a substituent.

Substituents that the aryl group in R 1 ^P may have include an alkyl group, a halogenoalkyl group, an aryl group, an alkoxy group, a dialkylamino group, and a halogeno group.

Examples of the alkyl group include the same alkyl groups as those detailed in the description of R 1 ^P , specifically methyl and tert-butyl groups, and a preferred specific example is methyl.

The halogenoalkyl group includes a halogenoalkyl group formed by replacing at least one hydrogen atom on the alkyl group with a halogen atom, and a specific example is a trifluoromethyl group.

Examples of the aryl group include the same aryl groups as those described in detail in the description of R 1 ^P , and specific examples include a phenyl group.

The alkoxy group may be linear or branched, and examples include alkoxy groups having 1 to 12 carbon atoms, preferably alkoxy groups having 1 to 8 carbon atoms, and more preferably alkoxy groups having 1 to 4 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy groups.

The dialkylamino group includes a dialkylamino group formed by substituting two hydrogen atoms on an amino group with the alkyl group, and specifically includes an N,N-dimethylamino group.

Specific examples of such halogeno groups include fluoro, chloro, bromo, and iodo groups.

Next, the alkyl group, halogenoalkyl group, cycloalkyl group and aryl group in R ^{3 C} will be described in more detail.

The alkyl group in R ^C may be linear or branched, and examples thereof include alkyl groups having 1 to 12 carbon atoms, preferably alkyl groups having 1 to 8 carbon atoms, and more preferably alkyl groups having 1 to 4 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group, and preferred specific examples thereof include a methyl group and a tert-butyl group.

The halogenoalkyl group for R 3 ^C includes a halogenoalkyl group formed by substituting at least one hydrogen atom on the alkyl group described above with a halogen atom, and a specific example thereof is a trifluoromethyl group.

The cycloalkyl group for R ^C may be monocyclic or polycyclic, and examples thereof include a cycloalkyl group having 3 to 20 carbon atoms, preferably a cycloalkyl group having 3 to 15 carbon atoms, and more preferably a cycloalkyl group having 3 to 10 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 1-adamantyl group, and a 2-adamantyl group, and a preferred specific example is a 1-adamantyl group.

The aryl group for R ^C includes, for example, an aryl group having 6 to 18 carbon atoms, preferably an aryl group having 6 to 14 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms, and specific examples thereof include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

The ruthenium complex (1) of the present invention has two carbon-centered asymmetries (hereinafter, the absolute configurations of these carbon-centered asymmetries will be represented by R _C and S _C ), two planar asymmetries (hereinafter, the absolute configurations of these planar asymmetries will be represented by R _P and S _P ), and one secondarily induced ruthenium-centered asymmetry (hereinafter, the absolute configurations of this ruthenium-centered asymmetry will be represented by Δ and Λ). Therefore, it may be a mixture of stereoisomers resulting from these various asymmetries, or a single stereoisomer. However, particularly from the viewpoint of application to aromatic asymmetric hydrogenation, a single stereoisomer, i.e., an optically active substance, is preferred.

Preferred forms of the optically active ruthenium complex (1) of the present invention, due to structural requirements, include Ru(O ₂ CR ^C ) ₂ ((S _C ,S _C ,R _P ,R _P )-R ^P -trap) ((S C ,S C ,R P ,R _P )-1) and Ru(O ₂ CR ^C ) ₂ ((R _C ,R _C ,S _P ,S _{P )} -R ^P -trap ₎ ((R _C ,R _C ,S _P , _{S P} )-1), which have the stereostructural formula shown in Formula 10 below (according to convention, in drawing the stereostructural formulas in this specification, secondarily induced ruthenium-centered asymmetry and the carbon atom C and hydrogen atom H are omitted).

[In the formula, the solid wedge line represents a carbon-carbon bond toward the front side of the paper, and the dashed wedge line represents a carbon-carbon bond toward the back side of the paper.]

Particularly preferred examples of the ruthenium complex (1) of the present invention include Ru(O ₂ CMe) ₂ ((S _{C ,S C} ,R P ,R _P )-Ph-trap), Ru(O 2 CMe) 2 ((R _C ,R _C ,S P ,S P )-Ph-trap), Ru(O ₂ C t Bu) ₂ ((S _C , _{S C} ,R _P ,R P )-Ph-trap), Ru(O _{2 C} ^{t Bu} ) ₂ ((R _C ,R _C ,S P ,S _P )-Ph-trap), and Ru _{( O 2} CAd) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) _, which have the stereostructural formula _{shown in} the following formula ₁₁ . )-Ph-trap) and Ru(O ₂ CAd) ₂ (( _RC , _RC , _SP , _SP )-Ph-trap), as well as Ru(O ₂ CMe) 2 (( _SC , _SC ,RP,RP)-Tol-trap), Ru(O ₂ CMe) ₂ ((RC, _RC ,SP, _SP )-Tol-trap), Ru(O 2 C _t Bu) ₂ (( _SC , _SC , _RP , _RP )-Tol-trap), and Ru(O ₂ C ^t Bu) ₂ (( _RC , _RC , _SP , _{SP ) -Tol} - ^trap ), _whose stereostructures are _shown in Formula 12 below _. )-Tol-trap), Ru(O ₂ CAd) ₂ ((S _C ,S _C ,R _P ,R _P )-Tol-trap) and Ru(O ₂ CAd) ₂ ((R _C ,R _C ,S _P ,S _P )-Tol-trap).

[In the formula, Ph represents a phenyl group, and Me represents a methyl group.]

[In the formula, Tol represents a 4-methylphenyl group, and Me represents a methyl group.]

Next, a method for producing the ruthenium complex (1) of the present invention (hereinafter referred to as the production method of the present invention) will be described. First, the ruthenium complex (1) of the present invention can be easily produced by reacting a diphosphine compound represented by the general formula (2) (hereinafter referred to as R ^P -TRAP (2)) with a ruthenium-alkylbenzene-carboxylate complex represented by the general formula (3), i.e., Ru(O ₂ CR ^C ) ₂ (AB) (3) (hereinafter referred to as the ruthenium source (3)), while dissociating the alkylbenzene, i.e., AB, as shown in formula 13 below.

R ^P -TRAP (2) in the production method of the present invention will be described in detail below. In the general formula (2), the solid line, H, C, P, Me, Fe, the pentagon containing a circle, the thick line, and R ^P are all the same as those defined and described in detail in the explanation of the general formula (1). In R ^P -TRAP (2), all four R ^Ps present on the molecule represent the same group.

Since R ^P -TRAP (2) has two carbon-center chiralities and two planar chiralities, it may be a mixture of stereoisomers resulting from these chiralities or a single stereoisomer. However, similar to the ruthenium complex (1) of the present invention, a single stereoisomer, i.e., an optically active form, is preferred, particularly from the viewpoint of application to aromatic asymmetric hydrogenation. Preferred forms of optically active R ^P -TRAP (2), based on structural requirements, include (S _C ,S C ,R P ,R P )-R ^P -TRAP((S C ,S _C ,R _P ,R _P )-2) and (R _C ,R _C ,S _P ,S _P )-R ^P -TRAP(( _{R C} ,R _C , _{S P} , _{S P )} -2), whose stereostructural formulas are shown _in Formula 14 below.

Particularly preferred examples of R ^P -TRAP (2) in the production method of the present invention include (S _C ,S C ,R _P ,R _P )-Ph-TRAP, (R C ,R _C ,S _P ,S P )-Ph-TRAP, (S _C ,S _C ,R _P ,R _P )-Tol-TRAP, and ( _{R C ,} R _C ,S _P ,S _P )-Tol-TRAP, which have the stereostructural formula shown in the _following formula ₁₅ .

[In the formula, Ph represents a phenyl group, and Tol represents a 4-methylphenyl group.]

The method for synthesizing R ^P -TRAP (2) is not particularly limited, but from a practical viewpoint, the methods described in WO 2024/203802 and WO 2024/203803 are preferred, and an outline of the method is shown in the following formula 16. That is, R ^P -TRAP (2) can be easily synthesized with good reproducibility from commercially available N,N-dimethyl-1-ferrocenylethylamine (commonly known as Ugi's Amine) through a multi-step reaction including lithiation and halogenation (Step 1), phosphination (Step 2), reaction with a borane source (Step 3), reaction with a magnesium source (Step 4), reaction with an oxidizing agent (Step 5), and deprotection reaction (Step 6). Furthermore, by making the Ugi's Amine used in this synthesis method optically active, it is possible to separately produce the above-mentioned (S _C ,S _C ,R _P ,R _P )-R ^P -TRAP ((S _C ,S _C ,R _P ,R _P )-2) and (R _C ,R _C ,S _P ,S _P ) ^{-R P -TRAP} ((R _C ,R _C ,S _P ,S _P )-2), which are preferred forms of optically active R P -TRAP (2). Furthermore, R ^P -TRAP (2) obtained by this synthesis method may form a stable solvate together with the solvent used in the deprotection reaction (Step 6), and preferred examples of such a solvent include n-propyl alcohol and n-butanol.

[In the formula, B represents a boron atom, Mg represents a magnesium atom, N represents a nitrogen atom, and X represents a halogen atom.]

The ruthenium source (3) in the production method of the present invention will be described in detail below. In the general formula (3), the solid line, double line, dashed line, C, O, Ru, and R ^C are all the same as those defined and described in detail in the explanation of the general formula (1). AB represents an alkylbenzene, and the thick dashed line represents six-electron donation of the alkylbenzene to Ru. In the ruthenium source (3), both of the two R ^Cs present on the molecule represent the same group.

Next, the alkylbenzenes in AB will be described in more detail. Examples of alkylbenzenes include benzene (C ₆ H ₆ ) and compounds in which at least one hydrogen atom on the benzene is substituted with an alkyl group, such as alkylbenzenes having 6 to 24 carbon atoms, preferably alkylbenzenes having 6 to 18 carbon atoms, and more preferably alkylbenzenes having 6 to 12 carbon atoms. Specific examples include benzene, 1,3,5-trimethylbenzene (mesitylene), 1-methyl-4-isopropylbenzene (p-cymene), and hexamethylbenzene, and a preferred specific example is 1-methyl-4-isopropylbenzene (p-cymene).

Particularly preferred specific examples of the ruthenium source (3) in the production method of the present invention include Ru(O ₂ CMe) ₂ (p-cymene), Ru(O ₂ C ^t Bu) ₂ (p-cymene), and Ru(O ₂ CAd) ₂ (p-cymene), whose structural formulas are shown in the following formula 17. Note that all of these ruthenium sources (3) can be easily synthesized following known methods.

[In the formula, Me represents a methyl group, ^t Bu represents a tert-butyl group, and Ad represents a 1-adamantyl group.]

Next, an embodiment of the production method of the present invention, i.e., the reaction conditions between R ^P -TRAP (2) and the ruthenium source (3), will be described in more detail. The amount of R ^P -TRAP (2) used in this reaction is not particularly limited, but from the viewpoint of atom efficiency, it is appropriately selected from the range of usually 0.5 to 1.5 equivalents, preferably 0.8 to 1.2 equivalents, and more preferably 0.9 to 1.1 equivalents relative to the ruthenium source (3).

The reaction of R ^P -TRAP (2) with the ruthenium source (3) can in principle be carried out in the absence of a solvent. However, this requires special equipment such as a ball mill or a kneader. Therefore, in practice, it is preferable to carry out the reaction in the presence of a solvent. Such a solvent is preferably one that is not involved in the decomposition reaction of the ruthenium complex (1) of the present invention. Specific examples of such a solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, n-decane, cyclohexane, and decalin; aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, p-cymene, and 1,4-diisopropylbenzene; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, and 1,4-dioxane; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; and water. More preferred are aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, p-cymene, and 1,4-diisopropylbenzene. Toluene is particularly preferred because it is inexpensive, easy to handle, and has excellent substrate solubility. These solvents may be used alone or in combination of two or more. The amount of the solvent used is not particularly limited, but is usually selected from the range of 1 to 200 times by volume, preferably 1.5 to 100 times by volume, and more preferably 2 to 50 times by volume relative to the weight of R ^P -TRAP (2) used.

The reaction between R ^P -TRAP (2) and the ruthenium source (3) is preferably carried out under an inert gas atmosphere to prevent decomposition of the substrate and reaction intermediates. Specific examples of inert gases include argon gas and nitrogen gas, with nitrogen gas being a preferred example. The reaction temperature is typically selected from the range of -20°C to 160°C, preferably 0°C to 140°C, and more preferably 20°C to 120°C. The reaction time depends on the structures of R ^P -TRAP (2) and the ruthenium source (3), the amount of R ^P -TRAP (2) used, the reaction solvent, and the reaction temperature, but is typically selected from the range of 5 minutes to 24 hours, preferably 10 minutes to 12 hours, and more preferably 20 minutes to 6 hours.

The reaction solution obtained from R ^P -TRAP (2), the ruthenium source (3), and the solvent may be post-treated as necessary, and the ruthenium complex (1) of the present invention may be isolated from the reaction solution and further purified. Specific post-treatment techniques include filtration of the reaction solution, concentration, and solvent substitution. Specific isolation techniques include drying and crystallization of the reaction solution, and filtration, washing, and drying of the crude crystals. Specific purification techniques include dissolution of the crude crystals, decolorization with an adsorbent, recrystallization, and filtration, washing, and drying of the purified crystals. These techniques may be used alone or in combination. Furthermore, the ruthenium complex (1) of the present invention may contain a solvent used in the reaction, post-treatment, isolation, or purification, or an alkylbenzene dissociated during the reaction. Preferred examples of such solvents and alkylbenzenes include toluene, n-heptane, acetone, water, and p-cymene.

Furthermore, when using the ruthenium complex (1) of the present invention as a catalyst, the reaction liquid may be used as is, or may be used after carrying out the above-mentioned post-treatment, isolation, and purification as necessary. On the other hand, the preferred form of the ruthenium complex (1) of the present invention is one that has excellent crystallinity and stability and can be stored for a long period of time, and therefore, from the perspective of utilizing these properties, it is preferable to use it as a catalyst after isolation. Furthermore, the ruthenium complex (1) of the present invention may be used as a catalyst either alone or in combination with two or more types, but from a practical perspective, it is preferable to use it as a catalyst alone.

The ruthenium complex (1) of the present invention produced in this manner can be suitably used as a catalyst in various organic synthesis reactions. These organic synthesis reactions are not particularly limited, but specific examples include oxidation reactions, reduction reactions, hydrogenation reactions, dehydrogenation reactions, hydrogen transfer reactions, addition reactions, conjugate addition reactions, pericyclic reactions, functional group transformation reactions, isomerization reactions, rearrangement reactions, polymerization reactions, bond formation reactions, and bond cleavage reactions. All of these organic synthesis reactions may be asymmetric, and a preferred example is the asymmetric hydrogenation of aromatic compounds and heteroaromatic compounds, i.e., aromatic asymmetric hydrogenation.

Particularly preferred examples of such aromatic asymmetric hydrogenation include the asymmetric hydrogenation of indoles, oxazoles, imidazoles, and naphthalenes under neutral conditions, and these reactions enable the efficient production of industrially useful optically active cyclic compounds.

The method for producing the ruthenium complex (1) of the present invention and the asymmetric aromatic hydrogenation using this complex as a catalyst are described in detail below with specific examples and comparative examples, but the present invention is in no way limited by these descriptions. Furthermore, unless otherwise noted, the substrate, reagents, and solvent were charged and added under a nitrogen stream, the reaction was carried out under a nitrogen atmosphere, and post-treatment, isolation, and purification were carried out in air. The instruments, measurement conditions, and analysis conditions used to measure physical properties in the examples are as follows:

1) Proton nuclear magnetic resonance spectroscopy ( ¹ H NMR): 400MR DD2 type instrument (resonance frequency 400 MHz; manufactured by Agilent Technologies)
2) Carbon-13 nuclear magnetic resonance spectroscopy ( ¹³ C NMR): 400 MR DD2 type instrument (resonance frequency 100 MHz; manufactured by Agilent Technologies)
3) Phosphorus-31 Nuclear Magnetic Resonance Spectroscopy ( ³¹ P NMR): 400 MR DD2 type instrument (resonance frequency 161 MHz; manufactured by Agilent Technologies)
4) High-performance liquid chromatography (HPLC): GL-7400 model (GL Sciences)
5) Single crystal X-ray structure analysis: XtaLAB Synergy-S type instrument (Rigaku Oxford Diffraction)
[Measurement conditions] X-ray source: CuKα ray, device control program: CrysAlis ^PRO .
[Analysis conditions] Structural analysis software: Olex ² 1.3-ac4, structural analysis program: SHELXS/SHELXL-2018/3, drawing software: Mercury 4.3.0.

[Example 1] Production of Ru(O ₂ CMe) ₂ ((S _C , S _C , R _P , R _P )-Ph-trap) (Formula 18)

Step 1: Preparation of Ru(O ₂ CMe) ₂ (p-cymene) solution

[Preparation and reaction] Dichloro(p-cymene)ruthenium(II) dimer ([RuCl ₂ (p-cymene)] ₂ ; 716 mg, 1.17 mmol, 1.0 equivalent) and silver acetate (AgOAc; 781 mg, 4.68 mmol, 4.0 equivalent) were sequentially placed in a 50 mL two-necked round-bottom flask, and a magnetic stirrer bar and a three-way stopcock were attached. The inside of the flask was then purged with nitrogen. Next, dehydrated toluene (15 mL) was added to the flask, and the flask was covered with aluminum foil to shield it from light, and the contents were stirred at room temperature for 2 hours.

[Post-treatment] The resulting orange suspension was filtered using diatomaceous earth under a nitrogen stream, and the filtered residue was washed with dehydrated toluene (15 mL) to obtain the target toluene solution (approximately 30 mL) of Ru(O ₂ CMe) ₂ (p-cymene) (<2.34 mmol) as a reddish-orange liquid. Note that this complex can also be isolated as hygroscopic reddish-brown crystals by concentrating the toluene solution and then adding n-heptane to cause crystallization. The NMR analysis results were as follows:

^1H NMR (400MHz, _CDCl3 ): δ=5.78 (d, J=5.6Hz, 2H), 5.57 (d, J=5.6Hz, 2H), 2.87 (sept, J=7.2Hz, 1H), 2.26 (s, 3H), 1.94 (s, 6H), 1.36 (d, J=7.2Hz, 6H).
^13C NMR (100MHz, _CDCl3 ): δ=184.37, 97.98, 92.59, 78.84, 77.68, 31.38, 23.77, 22.46, 18.50.

Step 2: Preparation of Ru(O ₂ CMe) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap)

[Preparation and reaction] A 100 mL four-necked round-bottom flask was charged with (S _C , S _C , R _P , R _P )-Ph-TRAP·n-BuOH (purity: 92.9 wt%, 2.0 g, 2.34 mmol, 1.0 equivalent), synthesized according to the method described in WO 2024/203803, and equipped with a magnetic stir bar, thermometer, dropping funnel, Claisen distillation apparatus, Dimroth condenser, and three-way stopcock. The inside was purged with nitrogen. Anhydrous toluene (40 mL) was added to the flask, and the resulting orange solution was stirred at 60 ° C. while gradually reducing the pressure to 60 Torr. After recovering approximately 30 mL of solvent, the inside of the apparatus was filled with nitrogen gas. Next, a toluene solution (approximately 30 mL) of Ru(O ₂ CMe) ₂ (p-cymene) (<2.34 mmol, 1.0 equivalent) prepared in Step 1 was placed in the dropping funnel and added dropwise to the reaction solution at room temperature, followed by stirring for 2 hours while heating in an oil bath at 70°C.

[Post-treatment, isolation, and purification] The dark brown reaction solution was heated at 70°C while gradually reducing the pressure to 60 Torr. Approximately 30 mL of solvent was recovered, and then the inside of the apparatus was filled with nitrogen gas. Anhydrous n-heptane (40 mL) was added to the concentrated solution while stirring at 60°C. The resulting brown slurry was cooled to 0°C in an ice-water bath and then suction filtered using a Kiriyama funnel under a nitrogen stream. The filtered crystals were washed twice with a mixed solvent of anhydrous n-heptane (8 mL) and anhydrous toluene (1 mL) cooled to 0°C, then heated to 60°C under a reduced pressure of 1 Torr and dried for 1 hour. 2.34 g of the target Ru(O ₂ CMe) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) was obtained as an air-stable light brown powder. Purity: 92.1% by weight (major impurities were 7.5% by weight of toluene and 0.4% by weight of n-heptane), Overall yield: 90.9%. Single crystals of this complex could be prepared by the solvent diffusion method using toluene as a good solvent and n-heptane as a poor solvent.

^1H NMR ₍ 400MHz, _C6D6 ): δ = 8.06 (bs, 4H), 7.47 (bs, 4H), 7.24-6.90 (m, 12H [Target] + 4.50H [Tol uene]), 4.69 (bs, 2H), 4.22 (bs, 2H), 4.17 (t, J=2.4Hz, 2H), 4.04 (bs, 2H) , 4.01 (s, 10H), 2.10 (s, 2.70H [Toluene]), 1.67 (s, 6H), 1.25-1.00 (bs, 6 H[Target]+0.40H[n-Heptane]), 0.87 (t, J=6.8Hz, 0.24H[n-Heptane]).
³¹ P NMR (161 MHz, C ₆ D ₆ ): δ=74.07 (s, 2P).

The results of single-crystal X-ray structural analysis (thermal ellipsoid diagram; atomic probability of 50%) of Ru(O ₂ CMe) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) prepared in Example 1 are shown in Figure 1 below. To facilitate understanding of the complex structure, hydrogen atoms have been omitted from the diagram. These results reveal that 1) this complex crystallizes while solvating one molecule of toluene, 2) it has _C2 symmetry in the crystalline state, 3) the secondarily induced ruthenium-centered asymmetry is Λ, and 4) surprisingly, Ph-TRAP in this complex behaves as a cis-chelate chiral diphosphine ligand (coordination angle: 91.42°), rather than the conventionally known trans-chelate type (coordination angle: approximately 180°). The main parameters that ensure the accuracy of the analysis results are as follows: _chemical formula: _{C59H58Fe2O4P2Ru} , crystal system: orthorhombic, space group: _P212121 ( _{# 19} ), lattice constants: a = _11.11914 ( ₁₅ ) Å, b = 17.4009 ( ₂ ) Å, c = 25.5514 (3) Å, α = β = γ = 90°, reliability factor ( _R1 ): 0.0407, weighted reliability factor ( _wR2 ): 0.0814, goodness of fit (GOF): 1.019, Flack parameter: -0.025 (4).

Example 2: Preparation of Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) (Equation 19)

Step 1: Synthesis of Ru(O ₂ C ^t Bu) ₂ (p-cymene)

[Preparation and reaction] Pivalic acid ( ^t BuCO ₂ H; 3.67 g, 35.9 mmol, 4.4 equivalents) and [RuCl ₂ (p-cymene)] ₂ (5.0 g, 8.16 mmol, 1.0 equivalents) were sequentially charged into a 200 mL four-neck round-bottom flask. A magnetic stirrer bar, thermometer, Claisen distillation apparatus, Dimroth condenser, and three-way stopcock were attached, and the inside atmosphere was purged with nitrogen. Anhydrous methanol (MeOH; 40 mL) and a methanol solution of sodium methoxide (NaOMe) (purity: 28.0 wt%, 6.89 mL, 34.3 mmol, 4.2 equivalents) were sequentially added to the flask, and the contents were stirred for 2 hours while being heated in an oil bath at 60°C.

[Post-treatment, isolation, and purification] Toluene (80 mL) was added to the reaction mixture, and the pressure was gradually reduced to 60 Torr while stirring at 60°C. After approximately 80 mL of solvent had been recovered, the apparatus was filled with nitrogen gas. Toluene (120 mL) was added to the resulting reddish-brown slurry, which was then filtered using diatomaceous earth under a nitrogen stream. The filtered residue was then washed with toluene (40 mL). The combined filtrate was transferred to a 500 mL four-neck round-bottom flask and equipped with a magnetic stir bar, thermometer, Claisen distillation apparatus, and a three-way stopcock. The filtrate was then gradually reduced to 50 Torr while stirring at 60°C. After approximately 130 mL of solvent had been recovered, the apparatus was filled with nitrogen gas. n-Heptane (90 mL) was added to the concentrated filtrate, and the pressure was gradually reduced to 70 Torr while stirring at 60°C. After approximately 90 mL of solvent had been recovered, the apparatus was filled with nitrogen gas. To the resulting orange slurry, n-heptane (90 mL) was added with stirring, and the mixture was cooled to 0°C in an ice-water bath and then suction filtered using a Kiriyama funnel. The filtered crystals were washed twice with n-heptane (10 mL) cooled to 0°C and then heated to 60°C under reduced pressure of 1 Torr and dried for 1 hour, yielding 6.79 g of the target Ru(O ₂ C ^t Bu) ₂ (p-cymene) as a yellow-orange powder that was stable even in air. Isolated yield: 95.1%.

^1H NMR (400MHz, _CDCl3 ): δ=5.72 (d, J=6.0Hz, 2H), 5.50 (d, J=6.0Hz, 2H), 2.89 (sept, J=7.2Hz, 1H), 2.26 (s, 3H), 1.35 (d, J=7.2Hz, 6H), 1.08 (s, 18H).
^13C NMR (100MHz, _CDCl3 ): δ=191.85, 98.59, 94.10, 78.21, 76.76, 39.86, 31.48, 27.60, 22.46, 18.47.

Step 2: Preparation of Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) [Charge and reaction] A 50 mL four-neck round-bottom flask was charged with (S _C ,S _C ,R _P ,R _P )-Ph-TRAP·n-BuOH (purity: 92.9 wt%, 1.0 g, 1.17 mmol, 1.0 equivalent), and equipped with a magnetic stir bar, thermometer, Claisen distillation apparatus, Dimroth condenser, and three-way stopcock. The inside of the flask was purged with nitrogen. Anhydrous toluene (20 mL) was added to the flask, and the resulting orange solution was stirred at 60°C while gradually reducing the pressure to 60 Torr. Approximately 15 mL of solvent was recovered, and the inside of the flask was then filled with nitrogen gas. Next, Ru(O ₂ C ^t Bu) ₂ (p-cymene) (512 mg, 1.17 mmol, 1.0 equivalent) synthesized in Step 1 was quickly added to the reaction solution at room temperature, and the mixture was stirred for 2 hours while being heated in an oil bath at 70°C.

[Post-treatment, isolation, and purification] The resulting brown slurry was allowed to cool to room temperature, after which anhydrous n-heptane (10 mL) was added and the mixture was suction-filtered using a Kiriyama funnel under a nitrogen stream. The filtered crystals were washed with a mixed solvent of anhydrous n-heptane (8 mL) and anhydrous toluene (2 mL) and then heated to 60°C under a reduced pressure of 1 Torr and dried for 1 hour. This afforded 1.16 g of the target Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) as an orange powder that was stable even in air. Purity: 96.8 wt% (the main impurity was toluene at 3.4 wt%), isolation yield: 87.4%. Single crystals of this complex could be prepared by the solution diffusion method using toluene as a good solvent and n-heptane as a poor solvent.

^1H NMR ₍ 400MHz, _C6D6 ): δ = 7.62 (bs, 4H), 7.45-7.37 (bt, 4H), 7.14-6.93 (m, 12H [Target] + 1.97H [Toluene]), 4.46 (bs, 2H), 4.06 (s, 1 0H), 4.04 (t, J=2.4Hz, 2H), 3.80 (bs, 2H), 3.74 (bs, 2H), 2.10 (s, 1.18H [Toluene]), 1.42 (bs, 6H), 1.12 (s, 18H).
³¹ P NMR (161 MHz, C ₆ D ₆ ): δ=72.13 (s, 2P).

The results of single-crystal X-ray structural analysis (thermal ellipsoid diagram; atomic probability of 50%) of Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) prepared in Example 2 are shown in Figure 2 below. Note that hydrogen atoms have been omitted in the figure to make the complex structure easier to understand. These results reveal that 1) this complex crystallizes while solvating one molecule of toluene for every two molecules of the complex, 2) it has _C1 symmetry in the crystalline state, 3) the secondarily induced ruthenium-centered asymmetry is Δ, and 4) surprisingly, Ph-TRAP in this complex behaves as a cis-chelate chiral diphosphine ligand (average included coordination angle: 107.43°), rather than the conventionally known trans-chelate type (included coordination angle: approximately 180°). The main parameters that ensure the accuracy of the analysis results are as follows: chemical formula: C ₁₂₃ H ₁₃₂ Fe ₄ O ₈ P ₄ Ru ₂ , crystal system: monoclinic, space group: P1 2 ₁ 1 (#4), lattice constants: a = 11.32810 (13) Å, b = 43.8943 (4) Å, c = 11.49857 (13) Å, α = γ = 90°, β = 111.2182 (13)°, R ₁ : 0.0450, wR ₂ : 0.1031, GOF: 1.034, Flack parameter: -0.013 (3).

Example 3: Preparation of Ru(O ₂ C ^t Bu) ₂ ((R _C , R _C , S _P , S _P )-Ph-trap) (Equation 20)

[Preparation and reaction] A 50 mL four-necked round-bottom flask was charged with (R _C , R _C , S _P , S _P )-Ph-TRAP·n-BuOH (purity: 93.8 wt%, 1.0 g, 1.18 mmol, 1.05 equivalents), synthesized according to the method described in WO 2024/203803, and equipped with a magnetic stir bar, thermometer, dropping funnel, Claisen distillation apparatus, Dimroth condenser, and three-way stopcock. The inside was purged with nitrogen. Anhydrous toluene (20 mL) was added to the flask, and the resulting orange solution was stirred at 60 °C while gradually reducing the pressure to 60 Torr. After recovering approximately 15 mL of solvent, the inside of the apparatus was filled with nitrogen gas. Next, Ru(O ₂ C ^t Bu) ₂ (p-cymene) (492 mg, 1.12 mmol, 1.0 equivalent) prepared in Step 1 of Example 3 and dehydrated toluene (15 mL) were sequentially charged into the dropping funnel, and the resulting suspension was added dropwise to the reaction solution at room temperature, followed by stirring for 2 hours while heating in an oil bath at 70°C.

[Workup, isolation, and purification] The dark red reaction solution was stirred at 60°C while gradually reducing the pressure to 60 Torr. Approximately 15 mL of solvent was recovered, and the inside of the apparatus was then filled with nitrogen gas. Anhydrous n-heptane (15 mL) was added to the resulting brown slurry while stirring at room temperature. The mixture was cooled to 0°C in an ice-water bath and then suction filtered using a Kiriyama funnel under a nitrogen stream. The filtered crystals were washed with a mixed solvent of anhydrous n-heptane (10 mL) and anhydrous toluene (1 mL) cooled to 0°C and then heated to 60°C under a reduced pressure of 1 Torr and dried for 1 hour. This yielded 1.21 g of the desired Ru(O ₂ C ^t Bu) ₂ ((R _C ,R _C ,S _P ,S _P )-Ph-trap) as an air-stable orange powder. Purity: 96.8 wt% (the main impurity was 3.4 wt% toluene), isolated yield: 95.2%. The NMR analysis results of this complex were consistent with the data for Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap), i.e., the enantiomer, prepared in Example 2. Single crystals of this complex could also be prepared in the same manner as its enantiomer.

The results of single crystal X-ray structural analysis (thermal ellipsoid diagram; atomic existence probability 50%) of Ru(O ₂ C ^t Bu) ₂ ((R _C ,R _C ,S _P ,S _P )-Ph-trap) produced in Example 3 are shown in Figure 3 below. To make the mirror image relationship easier to understand, hydrogen atoms are omitted from the diagram, and the structure of one molecule of this complex is shown in an excerpt. These results demonstrate that this complex is indeed an enantiomer of Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) produced in Example 2. The main parameters that ensure the accuracy of the analysis results are as follows: chemical formula: C ₁₂₃ H ₁₃₂ Fe ₄ O ₈ P ₄ Ru ₂ , crystal system: monoclinic, space group: P1 2 ₁ 1 (#4), lattice constants: a = 11.32740 (12) Å, b = 43.9161 (4) Å, c = 11.49891 (12) Å, α = γ = 90°, β = 111.1986 (12)°, R ₁ : 0.0415, wR ₂ : 0.0958, GOF: 1.047, Flack parameter: -0.015 (3).

Example 4: Preparation of Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) (Equation 21)

Step 1: Synthesis of Ru(O ₂ CAd) ₂ (p-cymene)

[Preparation and reaction] A 100 mL four-neck round-bottom flask was sequentially charged with [RuCl ₂ (p-cymene)] ₂ (5.4 g, 8.82 mmol, 1.0 equivalent) and 1-adamantanecarboxylic acid (AdCO ₂ H; 7.0 g, 38.8 mmol, 4.4 equivalent). The flask was equipped with a magnetic stirrer bar, a thermometer, a Dimroth condenser, and a three-way stopcock. The atmosphere was purged with nitrogen. Anhydrous methanol (35 mL) and a methanol solution of NaOMe (purity: 28.0 wt %, 7.44 mL, 37.0 mmol) were sequentially added to the flask, and the contents were stirred under reflux for 3 hours while being heated in an oil bath at 80°C.

[Post-treatment, isolation, and purification] The resulting reddish-orange slurry was cooled to 0°C in an ice-water bath and then filtered under suction using a separatory funnel to separate the crystals from the filtrate. The filtered crystals were washed sequentially with 0°C-cooled methanol (14 mL), tap water (35 mL), and 0°C-cooled methanol (14 mL). They were then heated to 80°C under reduced pressure of 1 Torr and dried for 2 hours, yielding 8.16 g of the target Ru(O ₂ CAd) ₂ (p-cymene) as an air-stable orange powder. Purity: 98.5 wt% (the main impurity was the reaction intermediate RuCl(O ₂ CAd)(p-cymene)), isolation yield: 76.7%. Meanwhile, tap water (35 mL) was added to the separated filtrate and stirred at 0°C for 2 hours. The resulting orange slurry was filtered under suction using a separatory funnel. The filtered crystals were washed three times with 50% aqueous methanol (14 mL) and then dried at 80°C under a reduced pressure of 1 Torr for 2 hours to obtain 2.17 g of additional Ru(O ₂ CAd) ₂ (p-cymene) as a yellow-orange powder. Purity: 97.1 wt% (the main impurity was RuCl(O ₂ CAd) (p-cymene)), isolated yield: 20.1%, total yield: 96.8%.

^1H NMR (400MHz, _CDCl3 ): δ=5.72 (d, J=6.0Hz, 2H), 5.49 (d, J=6.0Hz, 2H), 2.88 (sept, J=7.2Hz, 1H), 2.24 (s, 3H), 1.93 (bs, 6H), 1.78 (bs, 12H), 1.70-1.58 (m, 12H), 1.34 (d, J=7.2Hz, 6H).
^13C NMR (100MHz, _CDCl3 ): δ = 191.03, 98.57, 93.94, 78.14, 76.80, 41.90, 39.27, 36.71, 31.47, 28.19, 22.48, 18.48.

Step 2: Preparation of Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap)

[Preparation and reaction] A 100 mL four-neck round-bottom flask was charged with (S _C , S _C , R _P , R _P )-Ph-TRAP·n-BuOH (purity: 92.6 wt%, 2.5 g, 2.91 mmol, 1.05 equivalents), and equipped with a magnetic stirrer bar, a thermometer, a dropping funnel, a Claisen distillation apparatus, a Dimroth condenser, and a three-way stopcock. The atmosphere inside was replaced with nitrogen. Anhydrous toluene (40 mL) was added to the flask, and the resulting orange solution was stirred at 60°C while gradually reducing the pressure to 60 Torr. Approximately 30 mL of solvent was recovered, and the inside of the flask was then filled with nitrogen gas. Next, Ru(O ₂ CAd) ₂ (p-cymene) (purity: 98.5 wt %, 1.67 g, 2.77 mmol, 1.0 equivalent) prepared in Step 1 and dehydrated toluene (30 mL) were sequentially charged into the dropping funnel, and the resulting suspension was added dropwise to the reaction solution, followed by stirring for 2 hours while heating in an oil bath at 70°C.

[Workup, Isolation, and Purification] The dark brown reaction mixture was stirred at 70°C while gradually reducing the pressure to 60 Torr. Approximately 33 mL of solvent was recovered, and the reaction mixture was then filled with nitrogen gas. The concentrated solution was allowed to cool to room temperature. Anhydrous acetone (30 mL) was added to the resulting brown slurry while stirring. The mixture was then cooled to 0°C in an ice-water bath and suction filtered using a Kiriyama funnel under a nitrogen stream. The filtered crystals were washed three times with anhydrous acetone (10 mL) cooled to 0°C and then heated to 60°C under a reduced pressure of 1 Torr and dried for 1 hour. 3.14 g of the target Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) was obtained as an air-stable orange powder. Purity: 98.1 wt% (major impurities were 1.4 wt% toluene and 0.5 wt% acetone), isolation yield: 88.7%. The single crystal of this complex could be prepared by the solution diffusion method using toluene as a good solvent and n-heptane as a poor solvent.

^1H NMR ₍ 400MHz, _C6D6 ): δ = 7.68 (bs, 4H), 7.45 (bs, 4H), 7.20 (t, J = 7.2Hz, 4H), 7.11 (t, J = 7.2Hz, 2H), 7.08-6.97 (m, 6H [Target] + 0.95H [Toluene]), 4.52 (bs, 2H), 4.11 (t, J = 2.4Hz, 2 H), 4.07 (s, 10H), 3.94-3.60 (bm, 4H), 2.10 (s, 0.57H [Toluene]), 1.93 (bs, 12H ), 1.86 (bs, 6H), 1.63-1.51 (bm, 12H [Target] + 0.66H [Acetone]), 1.43 (bs, 6H).
³¹ P NMR (161 MHz, C ₆ D ₆ ): δ=72.06 (bs, 2P).

The results of single-crystal X-ray structural analysis (thermal ellipsoid diagram; atomic probability of 50%) of Ru(O ₂ CAd) ₂ ((SC ₁ ,SC ₂ ,RP ₃ ,RP ₃ )-Ph-trap) prepared in Example 4 are shown in Figure 4 below. Note that hydrogen atoms have been omitted in the figure to make the complex structure easier to understand. These results reveal that 1) this complex crystallizes without solvation, 2) it has _C1 symmetry in the crystalline state, 3) the secondarily induced ruthenium-centered asymmetry is Δ, and 4) surprisingly, Ph-TRAP in this complex behaves as a cis-chelate chiral diphosphine ligand (coordination angle: 104.56°), rather than the conventionally known trans-chelate type (coordination angle: approximately 180°). The main parameters that ensure the accuracy of the analysis results are as follows: chemical formula: C ₇₀ H ₇₄ Fe ₂ O ₄ P ₂ Ru ₂ , crystal system: triclinic system, space group: P1 (#1), lattice constants: a = 12.0194 (2) Å, b = 12.0812 (2) Å, c = 12.5546 (2) Å, α = 62.7282 (17) °, β = 65.4211 (16) °, γ = 67.5524 (16) °, R ₁ : 0.0438, wR ₂ : 0.1111, GOF: 1.044, Flack parameter: -0.024 (4).

Example 5: Preparation of Ru(O ₂ CAd) ₂ (( _RC , _RC , _SP , _SP )-Ph-trap) (Equation 22)

Starting materials were (R _C ,R _C ,S _P ,S _P )-Ph-TRAP·n-BuOH (purity: 93.8 wt %, 1.08 g, 1.28 mmol, 1.05 equivalents) and Ru(O ₂ CAd) ₂ (p-cymene) (purity: 98.5 wt %, 735 mg, 1.22 mmol, 1.0 equivalents) synthesized in Step 1 of Example 4. Following the procedure described in Example 4, 1.35 g of the target Ru(O ₂ CAd) ₂ ((R _C ,R _C ,S _P ,S _P )-Ph-trap) was obtained as an air-stable orange powder. Purity: 98.0 wt % (major impurities were 1.4 wt % toluene and 0.6 wt % acetone), isolated yield: 86.5%. The NMR analysis results of this complex, except for the difference in acetone content, were consistent with the data for Ru(O ₂ CAd) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap), i.e., the enantiomer, prepared in Example 4. Single crystals of this complex could also be prepared in the same manner as its enantiomer.

The results of single crystal X-ray structural analysis (thermal ellipsoid diagram; atomic existence probability 50%) of Ru(O ₂ CAd) ₂ (( _RC , _RC , _SP , _SP )-Ph-trap) produced in Example 5 are shown in Figure 5 below. Note that to make the enantiomer relationship of the complex easier to understand, hydrogen atoms have been omitted from the diagram. These results demonstrate that this complex is indeed an enantiomer of Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) produced in Example 4. The main parameters that ensure the accuracy of the analysis results are as follows: chemical formula: C ₇₀ H ₇₄ Fe ₂ O ₄ P ₂ Ru ₂ , crystal system: triclinic, space group: P1 (#1), lattice constants: a = 12.0321(2) Å, b = 12.07810(10) Å, c = 12.54670(10) Å, α = 62.7470(10)°, β = 65.4940(10)°, γ = 67.5930(10)°, R ₁ : 0.0518, wR ₂ : 0.1319, GOF: 1.096, Flack parameter: -0.012(5).

On the other hand, single crystals of this complex were prepared by the solution diffusion method using toluene as a good solvent and acetone as a poor solvent, and X-ray structural analysis was performed after exposing them to air under humid conditions. This revealed that one equivalent of water was encapsulated per complex molecule. The results of the single crystal X-ray structural analysis of the thus obtained Ru(O ₂ CAd) ₂ ((R _C , R _C , S _P , S _P )-Ph-trap)·H ₂ O (thermal ellipsoid diagram; atomic existence probability 50%) are shown in Figure 6 below. Note that to make the encapsulation state of water molecules easier to understand, hydrogen atoms on the complex molecule have been omitted from the diagram. The main parameters that ensure the accuracy of the analysis results are as follows: chemical formula: C ₇₀ H ₇₆ Fe ₂ O ₅ P ₂ Ru ₂ , crystal system: triclinic system, space group: P1 (#1), lattice constants: a = 12.0418(2) Å, b = 12.07310(10) Å, c = 12.5359(2) Å, α = 62.6800(10)°, β = 65.6630(10)°, γ = 67.6240(10)°, R ₁ : 0.0403, wR ₂ : 0.1044, GOF: 1.064, Flack parameter: -0.018(3).

Example 6: Preparation of Ru(O ₂ CMe) ₂ ((S _C ,S _C ,R _P ,R _P )-Tol-trap) (Equation 23)

[Preparation and reaction] A 20 mL Schlenk flask was sequentially charged with (S _C ,S _C ,R _P ,R _P )-Tol-TRAP (purity: 98.5 wt%, 500 mg, 0.579 mmol, 1.01 equivalent) synthesized according to the method described in WO 2024/203802, and Ru(O ₂ CMe) ₂ (p-cymene) (203 mg, 0.573 mmol, 1.0 equivalent) synthesized according to Step 1 of Example 1. A magnetic stirrer bar was attached, and the inside atmosphere was replaced with nitrogen. After adding anhydrous toluene (2.5 mL) to the flask, the contents were stirred for 2 hours while heating in an oil bath at 70°C.

[Post-treatment and isolation] The resulting reaction solution was stirred at 70°C and gradually reduced in pressure to 15 Torr, concentrating and drying the mixture. The flask was then filled with nitrogen gas. The resulting dark brown residue was crushed under a nitrogen atmosphere and then heated to 70°C under a reduced pressure of 1 Torr for 1 hour to dry, yielding 680 mg of the target Ru(O ₂ CMe) ₂ ((S _C ,S _C ,R _P ,R _P )-Tol-trap) as a dark brown powder. Purity: 90.7% by weight (the main impurities were 4.5% by weight of toluene and 4.8% by weight of p-cymene). Isolation yield: quantitative.

^1H NMR ₍ 400MHz, _C6D6 ): δ = 8.06 (bs, 4H), 7.50-7.38 (m, 4H), 7.14-6.97 (m, 2.90H [Toluene] + 1.68H [p-Cymene]), 7.05 (d, J = 8.0Hz, 4H), 6.89 (d, J = 8.0Hz, 4H), 4.75 (bs, 2H), 4.32 (bs, 2H), 4.22 (t, J = 2.4Hz, 2H), 4.15 (bs, 2H), 4 ．． 06 (s, 10H), 2.72 (sept, J = 6.8Hz, 0.42H [p-Cymene]), 2.15 (s, 1.26H [p-Cymene]), 2.10 (s, 1.74H [To luene]), 2.04 (s, 6H), 1.94 (s, 6H), 1.76 (s, 6H), 1.21 (bs, 6H), 1.15 (d, J = 6.8Hz, 2.52H [p-Cymene]).
^31P NMR (161MHz, C ₆ D ₆ ): δ = 73.36 (s, 2P)

Example 7: Preparation of Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Tol-trap) (Equation 24)

Ru(O ₂ C ^t Bu) ₂ (p-cymene) (251 mg, 0.573 mmol, 1.0 equivalent) synthesized in Step 1 of Example 2 was reacted with (S _C ,S _C ,R _P ,R _P )-Tol-TRAP (purity: 98.5 wt%, 500 mg, 0.579 mmol, 1.01 equivalent) according to the procedure described in Example 6. After further workup, 739 mg of the desired Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Tol-trap) was obtained as a dark brown powder. Purity: 91.7 wt% (major impurities were 3.0 wt% toluene and 5.3 wt% p-cymene), and the isolated yield was quantitative.

^1H NMR ₍ 400MHz, _C6D6 ): δ = 7.62 (bs, 4H), 7.35 (bs, 4H), 7.14-7.00 (m, 2.03H [Toluene] + 2.0H [p-Cymene]), 6.98 (d, J = 8.0 Hz, 4H), 6.84 (d, J = 8.0Hz, 4H), 4.56 (bs, 2H), 4.14 (t, J = 2.4Hz, 2H), 4.08 (s, 10H), 4.00 (bs, 2H), 3. 82 (bs, 2H), 2.72 (sept, J = 6.8 Hz, 0.5H [p-Cymene]), 2.15 (s, 1.5H [p-Cymene]), 2.10 (s, 1.22H [Tol uene]), 2.07 (s, 6H), 2.02 (s, 6H), 1.42 (bs, 6H), 1.23 (s, 18H), 1.15 (d, J=6.8Hz, 3.0H [p-Cymene]).
³¹ P NMR (161 MHz, C ₆ D ₆ ): δ=72.90 (s, 2P).

Example 8: Preparation of Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Tol-trap) (Equation 25)

Ru(O ₂ CAd) ₂ (p-cymene) (purity: 98.5 wt %, 346 mg, 0.573 mmol, 1.0 equivalent) synthesized in Step 1 of Example 4 was reacted with (S _C ,S _C ,R _P ,R _P )-Tol-TRAP (purity: 98.5 wt %, 500 mg, 0.579 mmol, 1.01 equivalent) according to the procedure described in Example 6. After further workup, 842 mg of the target Ru(O ₂ CAd) ₂ ((S _C ,S _C ,R _P ,R _P )-Tol-trap) was obtained as a dark brown powder. Purity: 91.4 wt % (the main impurities were 3.9 wt % toluene and 4.7 wt % p-cymene), and the isolated yield was quantitative.

^1H NMR ₍ 400MHz, _C6D6 ): δ = 7.68 (bs, 4H), 7.39 (bs, 4H), 7.14-6.97 (m, 3.07H [Toluene] + 2.0H [p-Cymene]), 7.05 (d, J = 7.6Hz, 4H), 6 .88 (d, J=7.6Hz, 4H), 4.63 (bs, 2H), 4.21 (t, J=2.4Hz, 2H), 4.10 (s, 10H), 4.04 (bs, 2H), 3.88 (bs, 2H), 2.72 (s ept. s, 12H), 2.04 (s, 6H), 1.90 (bs, 6H), 1.68-1.51 (bm, 12H), 1.44 (bs, 6H), 1.15 (d, J=6.8Hz, 3.0H [p-Cymene]).
³¹ P NMR (161 MHz, C ₆ D ₆ ): δ=72.86 (bs, 2P).

Example 9: Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole using Ru(O ₂ CMe) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) as a catalyst (Formula 26)

[Charge and reaction] Ru(O ₂ CMe) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) (purity: 92.1 wt %, 2.8 mg, 0.05 mol %) prepared in Example 1 and N-Boc-2-phenyl-1H-indole (1.47 g, 5.00 mmol, 1.0 equivalent) synthesized according to the method described in Non-Patent Document 8 were sequentially charged into a borosilicate glass test tube (φ20 mm × 130 mm), and a magnetic stirrer bar was attached. This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated isopropyl alcohol ( ⁱ PrOH; 12 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60°C for 6 hours.

[Post-treatment, isolation, and purification] After opening the autoclave, the reaction solution in the test tube was transferred to a 50 mL round-bottom flask and concentrated to dryness under reduced pressure using a rotary evaporator. Analysis of a portion of the resulting residue by ¹ H NMR revealed a conversion rate of >99.9%. Purification of this residue by silica gel column chromatography (eluent: n-hexane/toluene = 88/12 to 0/100) afforded 1.450 g of the desired (S)-N-Boc-2-phenylindoline as a white solid. Isolated yield: 98.2%, optical purity: 95.0% ee. The NMR analysis results of this compound were consistent with the data described in Non-Patent Document 8. Single crystals of this compound could be prepared by the solvent diffusion method using toluene as a good solvent and n-hexane as a poor solvent. The conditions for measuring the optical purity of this compound were as follows: column: CHIRALPAK IC-3 (manufactured by Daicel, 4.6 mmφ×250 mm), eluent: n-hexane/isopropanol=99/1, flow rate: 0.5 mL/min, detector: UV 254 nm, temperature: 20°C, retention time: 14.9 minutes (R-isomer), 21.1 minutes (S-isomer).

The results of single-crystal X-ray structural analysis (thermal ellipsoid diagram; atomic existence probability 50%) of (S)-N-Boc-2-phenylindoline synthesized in Example 9 are shown in Figure 7. From these results, the absolute configuration of this compound, which had been unknown until now (Non-Patent Document 8), was determined, and the steric relationship between the catalyst and the product was clarified. The main parameters that ensure the accuracy of the analysis results are as follows: chemical formula: C ₁₉ H ₂₁ NO ₂ , crystal system: orthorhombic, space group: P2 ₁ 2 ₁ 2 ₁ (#19), lattice constants: a = 5.85060 (4) Å, b = 16.35509 (11) Å, c = 16.49422 (10) Å, α = β = γ = 90°, R ₁ : 0.0281, wR ₂ : 0.0703, GOF: 1.075, Flack parameter: 0.00 (6).

Example 10: Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole catalyzed by Ru(O ₂ C ^t Bu) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap)

Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (1.47 g) was carried out at an internal pressure of 5 MPa using Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) (purity: 96.8 wt %, 2.8 mg, 0.05 mol %) prepared in Example 2 as a catalyst according to the procedure described in Example 9, to give 1.450 g of the desired (S)-N-Boc-2-phenylindoline. Reaction time: 2 hours, conversion: >99.9% (by ¹ H NMR analysis), isolated yield: 98.2%, optical purity: 94.9% ee.

Example 11: Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole catalyzed by Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap)

Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (1.47 g) was carried out at an internal pressure of 5 MPa using Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) (purity: 98.1 wt %, 3.2 mg, 0.05 mol %) prepared in Example 4 as a catalyst according to the procedure described in Example 9, to give 1.470 g of the desired (S)-N-Boc-2-phenylindoline. Reaction time: 1 hour, conversion: >99.9% (by ¹ H NMR analysis), isolated yield: 99.5%, optical purity: 94.4% ee.

Example 12: Low-pressure asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole catalyzed by Ru(O ₂ C ^t Bu) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap)

Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (1.47 g) was carried out at an internal pressure of 1 MPa using Ru(O ₂ C ^t Bu) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) (0.05 mol %) prepared in Example 2 as a catalyst according to the procedure described in Example 9, to give 1.453 g of the desired (S)-N-Boc-2-phenylindoline. Reaction time: 6 hours, conversion: >99.9% (by ¹ H NMR analysis), isolated yield: 98.4%, optical purity: 94.7% ee.

Example 13: Low-pressure asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole catalyzed by Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap)

Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (1.47 g) was carried out at an internal pressure of 1 MPa using Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) (0.05 mol %) prepared in Example 4 as a catalyst according to the procedure described in Example 9, to obtain 1.456 g of the desired (S)-N-Boc-2-phenylindoline. Reaction time: 6 hours, conversion: >99.9% (by ¹ H NMR analysis), isolated yield: 98.6%, optical purity: 94.9% ee.

Comparative Example 1: Attempt at asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole using [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl as a catalyst

Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole was carried out according to the procedure described in Example 9 using the conventional catalyst [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl (0.05 mol %), which was synthesized following the method described in Non-Patent Document 8. However, even after 6 hours of reaction at an internal pressure of 5 MPa, the conversion rate was only 2.2% (according to ¹ H NMR analysis).

Comparative Example 2: Attempt at asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole using Ru(O ₂ CMe) ₂ ((S)-binap) as a catalyst

Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole was attempted using the commercially available common catalyst Ru(O ₂ CMe) ₂ ((S)-binap) (0.05 mol%) according to the procedure described in Example 9. However, even after 6 hours of reaction at an internal pressure of 5 MPa, the conversion was less than 0.1% (according to ¹ H NMR analysis).

Table 1 below summarizes the results of Comparative Examples 1 and 2 and Examples 9 to 13. For reference, Formula 27 below shows the three-dimensional structural formulas of the various catalysts used in these Comparative Examples and Examples.

As is clear from the results summarized in Table 1, when the conventional catalyst [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl or the common catalyst Ru(O ₂ CMe) ₂ ((S)-binap) was used, the asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole, a bulky and poorly reactive heteroaromatic compound, hardly proceeded without the addition of a base (Comparative Examples 1 and 2).

On the other hand, when Ru(O ₂ CMe) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap), a preferred form of the ruthenium complex (1) of the present invention, was used as a catalyst, the target reaction proceeded smoothly without the addition of a base, and the optically active cyclic compound (S)-N-Boc-2-phenylindoline was quantitatively obtained with excellent optical purity (Example 9). These results demonstrate that the coexistence of the acetate ligand (O ₂ CMe) and (S _C ,S _C ,R _P ,R _P )-Ph-TRAP on a divalent ruthenium ion (Ru) enables catalytic activity to be expressed even under neutral conditions.

Furthermore, when the acetate ligand (O ₂ CMe) in this complex was replaced with a bulkier pivalate ligand (O ₂ C ^t Bu) or a 1-adamantanecarboxylate ligand (O ₂ CAd), it was possible to significantly shorten the reaction time while maintaining excellent optical purity and quantitative yield (Examples 10 and 11). Furthermore, when these highly active catalysts were used to investigate asymmetric hydrogenation at more practical low pressures, it was found that the reaction was completed within 6 hours even when the internal pressure was reduced from 5 MPa to 1 MPa (Examples 12 and 13). These results clearly demonstrate the superiority of the ruthenium complex (1) of the present invention over conventional and general catalysts.

Example 14: Low-pressure asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole catalyzed by Ru(O ₂ CAd) ₂ ((R _C ,R _C ,S _P ,S _P )-Ph-trap) (Scheme 28)

Asymmetric hydrogenation of N-Boc _{-2-phenyl-1H-indole (1.47 g) was carried out at an internal pressure of 1 MPa following the procedure described in Example 9 using Ru(O 2 CAd) 2 ((R C , R C ,} S _P ,S P )-Ph-trap) (purity: 98.0 wt %, 3.2 mg, 0.05 mol %) prepared in Example 5 as a catalyst. 1.475 g of the desired (R)-N-Boc-2-phenylindoline was obtained. Reaction time: 6 hours, conversion: >99.9% (by ¹ H NMR analysis), isolated yield: 99.9%, optical purity: 94.7% ee. The NMR analysis results of this compound were consistent with the data for (S)-N-Boc-2-phenylindoline synthesized in Example 9, i.e., the enantiomer. Single crystals of this compound could also be prepared in the same manner as its enantiomers.

The results of single crystal X-ray structural analysis (thermal ellipsoid diagram; atomic existence probability 50%) of (R)-N-Boc-2-phenylindoline synthesized in Example 14 are shown in Figure 8. These results demonstrate that this compound is indeed an enantiomer of (S)-N-Boc-2-phenylindoline synthesized in Example 9. The main parameters that ensure the accuracy of the analysis results are as follows: chemical formula: C ₁₉ H ₂₁ NO ₂ , crystal system: orthorhombic, space group: P2 ₁ 2 ₁ 2 ₁ (#19), lattice constants: a = 5.85762 (4) Å, b = 16.36040 (11) Å, c = 16.51152 (10) Å, α = β = γ = 90°, R ₁ : 0.0290, wR ₂ : 0.0733, GOF: 1.080, Flack parameter: -0.07 (4).

As can be seen from Examples 13 and 14, by carrying out aromatic asymmetric hydrogenation while selectively using both enantiomers of ruthenium complex (1) of the present invention, it is possible to easily produce both enantiomers of the desired optically active cyclic compound. These results clearly demonstrate the practical utility of ruthenium complex (1) of the present invention in aromatic asymmetric hydrogenation.

Example 15: Asymmetric hydrogenation of methyl N-Boc-1H-indole-2-carboxylate using Ru(O ₂ CMe) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap) as a catalyst (Formula 29)

[Charge and reaction] Ru(O ₂ CMe) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) (purity: 92.1 wt %, 2.8 mg, 0.05 mol %) prepared in Example 1 and N-Boc-1H-indole-2-methyl carboxylate (1.38 g, 5.00 mmol, 1.0 equivalent) synthesized according to the method described in Non-Patent Document 8 were sequentially charged into a borosilicate glass test tube (φ20 mm × 130 mm), and a magnetic stirrer bar was attached. This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated ^iPrOH (14 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60°C for 2 hours.

[Post-treatment, isolation, and purification] After opening the autoclave, the reaction mixture in the test tube was transferred to a 50 mL round-bottom flask and concentrated to dryness under reduced pressure using a rotary evaporator. Analysis of a portion of the resulting residue by ¹ H NMR revealed a conversion rate of >99.9%. Purification of this residue by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 98/2 to 82/18) afforded 1.357 g of the desired (S)-N-Boc-indoline-2-methyl carboxylate as a white solid. Isolated yield: 97.9%, optical purity: 89.7% ee. The NMR analysis results of this compound were consistent with those described in Non-Patent Document 8. The conditions for measuring the optical purity of this compound were as follows: column: CHIRALPAK AD (manufactured by Daicel, 4.6 mmφ×250 mm), eluent: n-hexane/isopropanol=90/10, flow rate: 0.5 mL/min, detector: UV 254 nm, temperature: 20°C, retention time: 9.9 minutes (R-isomer), 12.0 minutes (S-isomer).

[Comparative Example 3] Attempt at asymmetric hydrogenation of methyl N-Boc-1H-indole-2-carboxylate using a conventional catalyst

Asymmetric hydrogenation of methyl N-Boc-1H-indole-2-carboxylate was carried out using the conventional catalyst [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl (0.05 mol %) according to the procedure described in Example 15, but the conversion was only 4.1% (by ¹ H NMR analysis).

As can be seen from Example 15 and Comparative Example 3, by using a preferred form of the ruthenium complex (1) of the present invention in place of conventional catalysts, highly stereoselective asymmetric hydrogenation proceeded even for indoles containing functional groups that are easily decomposed under strongly basic conditions, resulting in quantitative production of industrially useful optically active cyclic amino acids. These results clearly demonstrate the usefulness of the ruthenium complex (1) of the present invention, which exhibits excellent catalytic activity without the addition of a base.

Example 16: Asymmetric hydrogenation of N-Boc-3-methyl-1H-indole using Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) as a catalyst (Equation 30)

[Charge and reaction] N-Boc-3-methyl-1H-indole (purity: 99.6 wt%, 500 mg, 2.15 mmol, 1.0 equivalent), synthesized according to the method described in Non-Patent Document 8, and Ru(O ₂ CAd) ₂ (( _SC , SC, _RP , _RP )-Ph-trap) (purity: 98.1 wt%, 5.5 mg, 0.2 mol%), prepared in Example 4, were sequentially charged into a borosilicate glass test tube (φ20 mm × 130 mm) _, and a magnetic stirrer bar was attached. This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated ^iPrOH (5 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60°C for 6 hours.

[Post-treatment, isolation, and purification] After opening the autoclave, the reaction mixture in the test tube was transferred to a 50 mL round-bottom flask and concentrated to dryness under reduced pressure using a rotary evaporator. A portion of the resulting residue was analyzed by ¹ H NMR, revealing a conversion rate of >99.9%. This residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain 484 mg of the desired (S)-N-Boc-3-methylindoline as a colorless viscous liquid. Isolated yield: 96.4%, optical purity: 81.4% ee. The NMR analysis results of this compound were consistent with those described in Non-Patent Document 8. The conditions for measuring the optical purity of this compound were as follows: column: CHIRALPAK IC-3 (manufactured by Daicel, 4.6 mmφ×250 mm), eluent: n-hexane/isopropanol=99/1, flow rate: 0.5 mL/min, detector: UV 254 nm, temperature: 20°C, retention time: 13.8 minutes (S-isomer), 15.1 minutes (R-isomer).

[Comparative Example 4] Attempt at asymmetric hydrogenation of N-Boc-3-methyl-1H-indole using a conventional catalyst

Asymmetric hydrogenation of N-Boc-3-methyl-1H-indole was attempted using the conventional catalyst [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl (0.2 mol %) according to the procedure of Example 16, but the conversion was less than 0.1% (by ¹ H NMR).

Example 17: Asymmetric hydrogenation of N-Boc-3-phenyl-1H-indole using Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) as a catalyst (Formula 31)

[Charge and reaction] Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) (purity: 98.1 wt %, 5.5 mg, 0.4 mol %) prepared in Example 4 and N-Boc-3-phenyl-1H-indole (316 mg, 1.08 mmol, 1.0 equivalent) synthesized according to the method described in Non-Patent Document 8 were sequentially charged into a borosilicate glass test tube (φ20 mm × 130 mm), and a magnetic stirrer bar was attached. This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated ^iPrOH (3 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60°C for 6 hours.

[Post-treatment, isolation, and purification] After opening the autoclave, the reaction solution in the test tube was transferred to a 50 mL round-bottom flask and concentrated to dryness under reduced pressure using a rotary evaporator. Analysis of a portion of the resulting residue by ¹ H NMR revealed a conversion rate of >99.9%. Purification of this residue by silica gel column chromatography (eluent: n-hexane/toluene = 88/12 to 0/100) afforded 313 mg of the desired (S)-N-Boc-3-phenylindoline as a white solid. Isolated yield: 98.0%, optical purity: 94.6% ee. The NMR analysis results of this compound were consistent with the data described in Non-Patent Document 8. Single crystals of this compound could be prepared by the solvent diffusion method using toluene as a good solvent and n-hexane as a poor solvent. The conditions for measuring the optical purity of this compound were as follows: column: CHIRALPAK AD-H (manufactured by Daicel, 4.6 mmφ×250 mm), eluent: n-hexane/isopropanol=99/1, flow rate: 0.5 mL/min, detector: UV 254 nm, temperature: 20°C, retention time: 11.3 minutes (S-isomer), 13.2 minutes (R-isomer).

The results of single-crystal X-ray structural analysis (thermal ellipsoid diagram; atomic existence probability 50%) of (S)-N-Boc-3-phenylindoline synthesized in Example 17 are shown in Figure 9. From these results, the absolute configuration of this compound (Non-Patent Document 8), which had been unknown until now, was determined, and the steric relationship between the catalyst and the product was clarified. The main parameters that ensure the accuracy of the analysis results are as follows: chemical formula: C ₁₉ H ₂₁ NO ₂ , crystal system: orthorhombic, space group: P2 ₁ 2 ₁ 2 ₁ (#19), lattice constants: a = 8.85782 (7) Å, b = 11.09725 (9) Å, c = 16.08239 (13) Å, α = β = γ = 90°, R ₁ : 0.0305, wR ₂ : 0.0765, GOF: 1.021, Flack parameter: -0.05 (8).

[Comparative Example 5] Attempt at asymmetric hydrogenation of N-Boc-3-phenyl-1H-indole using a conventional catalyst

Asymmetric hydrogenation of N-Boc-3-phenyl-1H-indole was attempted using the conventional catalyst [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl (0.4 mol %) according to the procedure described in Example 17, but the conversion was less than 0.1% (by ¹ H NMR).

Example 18: Asymmetric hydrogenation of 2,4-diphenyloxazole using Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) as a catalyst (Equation 32)

[Preparation and reaction] Ru(O ₂ CAd) ₂ ((SC ₁ ,SC 2, _RP 1, _RP 2)-Ph-trap) (purity: 98.1 wt %, 2.9 mg, 0.2 mol _% ) prepared in Example 4 and commercially available 2,4-diphenyloxazole (250 mg, 1.13 mmol, 1.0 equivalent) were sequentially placed in a borosilicate glass test tube (φ20 mm × 130 mm), and a magnetic stirrer bar was attached. This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated ^iPrOH (2.5 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 80°C for 6 hours.

[Post-treatment, isolation, and purification] After opening the autoclave, the reaction solution in the test tube was transferred to a 50 mL round-bottom flask and concentrated to dryness under reduced pressure using a rotary evaporator. A portion of the resulting residue was analyzed by ¹ H NMR, revealing a conversion rate of 98.9%. This residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 96/4 to 70/30) to obtain 247 mg of the target (R)-2,4-diphenyloxazoline as a colorless viscous liquid. Isolated yield: 97.9%, optical purity: 97.5% ee. The NMR analysis results of this compound were consistent with the data described in Non-Patent Document 3. The conditions for measuring the optical purity of this compound were as follows: column: CHIRALPAK IC-3 (manufactured by Daicel, 4.6 mmφ×250 mm), eluent: n-hexane/isopropanol=90/10, flow rate: 0.5 mL/min, detector: UV 254 nm, temperature: 20°C, retention time: 13.7 minutes (R-isomer), 16.7 minutes (S-isomer).

[Comparative Example 6] Attempt at asymmetric hydrogenation of 2,4-diphenyloxazole using a conventional catalyst

Asymmetric hydrogenation of 2,4-diphenyloxazole was attempted using the conventional catalyst [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl (0.2 mol %) according to the procedure described in Example 18, but the conversion was less than 0.1% (by ¹ H NMR).

Example 19: Asymmetric hydrogenation of 2,5-diphenyloxazole using Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) as a catalyst (Equation 33)

[Preparation and reaction] Ru(O ₂ CAd) ₂ ((SC ₁ ,SC 2, _RP 3,RP 3)-Ph-trap) (purity: _98.1 wt %, 2.9 mg, 0.2 mol _% ) prepared in Example 4 and commercially available 2,5-diphenyloxazole (250 mg, 1.13 mmol, 1.0 equivalent) were sequentially placed in a borosilicate glass test tube (20 mmφ×130 mm), and a magnetic stir bar was attached. This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated ^iPrOH (2.5 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 80°C for 6 hours.

[Post-treatment, isolation, and purification] After opening the autoclave, the reaction mixture in the test tube was transferred to a 50 mL round-bottom flask and concentrated to dryness under reduced pressure using a rotary evaporator. A portion of the resulting residue was analyzed by ¹ H NMR, revealing a conversion rate of >99.9%. This residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 94/6 to 50/50) to obtain 248 mg of the target (R)-2,5-diphenyloxazoline as a colorless viscous liquid. Isolated yield: 98.3%, optical purity: 94.7% ee. The NMR analysis results of this compound were consistent with the data described in Non-Patent Document 3. The conditions for measuring the optical purity of this compound were as follows: column: CHIRALPAK IC-3 (manufactured by Daicel, 4.6 mmφ×250 mm), eluent: n-hexane/isopropanol=90/10, flow rate: 0.5 mL/min, detector: UV 254 nm, temperature: 20°C, retention time: 15.6 minutes (S-isomer), 17.0 minutes (R-isomer).

[Comparative Example 7] Attempt at asymmetric hydrogenation of 2,5-diphenyloxazole using a conventional catalyst

Asymmetric hydrogenation of 2,5-diphenyloxazole was attempted using the conventional catalyst [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl (0.2 mol %) according to the procedure described in Example 19, but the conversion was less than 0.1% (by ¹ H NMR).

Example 20: Asymmetric hydrogenation of 1-Boc-4-methyl-2-phenylimidazole using Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) as a catalyst (Formula 34)

[Charge and reaction] 1-Boc-4-methyl-2-phenylimidazole (303 mg, 1.17 mmol, 1.0 equivalent), synthesized according to the method described in Non-Patent Document 3, and Ru(O ₂ CAd) ₂ ((SC _{, SC} , RP, _RP )-Ph-trap) (purity: 98.1 wt%, 15.0 mg, 1.0 mol%), prepared in Example 4, were sequentially charged into a borosilicate glass test tube (φ20 mm × 130 _mm ), and a magnetic stir bar was attached. This test tube was then attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated ^iPrOH (3 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60°C for 6 hours.

[Post-treatment, isolation, and purification] After opening the autoclave, the reaction mixture in the test tube was transferred to a 50 mL round-bottom flask and concentrated to dryness under reduced pressure using a rotary evaporator. A portion of the resulting residue was analyzed by ¹ H NMR, revealing a conversion rate of 93.8%. This residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 95/5 to 50/50) to obtain 229 mg of the target (R)-1-Boc-4-methyl-2-phenylimidazoline as a colorless viscous liquid. Isolated yield: 75.1%, optical purity: 97.3% ee. The NMR analysis results of this compound were consistent with the data described in Non-Patent Document 3. The conditions for measuring the optical purity of this compound were as follows: column: CHIRALPAK IC-3 (manufactured by Daicel, 4.6 mmφ×250 mm), eluent: n-hexane/isopropanol=90/10, flow rate: 0.5 mL/min, detector: UV 254 nm, temperature: 20°C, retention time: 24.8 minutes (R-isomer), 26.5 minutes (S-isomer).

[Comparative Example 8] Attempt at asymmetric hydrogenation of 1-Boc-4-methyl-2-phenylimidazole using a conventional catalyst

Asymmetric hydrogenation of 1-Boc-4-methyl-2-phenylimidazole was attempted using a conventional catalyst, [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl (1.0 mol %), according to the procedure described in Example 20. However, it was found that in this reaction system, the substrate decomposed while the Boc group dissociated.

Example 21: Asymmetric hydrogenation of diisobutyl naphthalene-2,6-dicarboxylate using Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) as a catalyst (Equation 35)

[Charge and reaction] Ru(O ₂ CAd) ₂ (( _SC , _SC , _RP , _RP )-Ph-trap) (purity: 98.1 wt %, 11.7 mg, 1.0 mol %) prepared in Example 4 and diisobutyl naphthalene-2,6-dicarboxylate (300 mg, 0.913 mmol, 1.0 equivalent) synthesized according to the method described in Non-Patent Document 9 were sequentially charged into a borosilicate glass test tube (φ20 mm × 130 mm), and a magnetic stirrer bar was attached. This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated ^iPrOH (4.5 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60°C for 6 hours.

[Post-treatment, isolation, and purification] After opening the autoclave, the reaction mixture in the test tube was transferred to a 50 mL round-bottom flask and concentrated to dryness under reduced pressure using a rotary evaporator. A portion of the resulting residue was analyzed by ¹ H NMR, revealing a conversion rate of 99.1%. This residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 98/2 to 82/18) to obtain 283 mg of the target diisobutyl (S)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate as a colorless viscous liquid. Isolated yield: 93.4%, optical purity: 73.2% ee. The NMR analysis results of this compound were consistent with the data described in Non-Patent Document 9. The conditions for measuring the optical purity of this compound were as follows: column: CHIRALPAK IC-3 (manufactured by Daicel, 4.6 mmφ×250 mm), eluent: n-hexane/isopropanol=99/1, flow rate: 0.5 mL/min, detector: UV 254 nm, temperature: 20°C, retention time: 7.3 minutes (R-isomer), 9.8 minutes (S-isomer).

[Comparative Example 9] Attempt at asymmetric hydrogenation of diisobutyl naphthalene-2,6-dicarboxylate using a conventional catalyst

Asymmetric hydrogenation of diisobutyl naphthalene-2,6-dicarboxylate was attempted using the conventional catalyst [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl (1.0 mol %) according to the procedure described in Example 21, but the conversion was less than 0.1% (by ¹ H NMR).

Table 2 below summarizes the results for Examples 16-21 and Comparative Examples 4-9 for each substrate. For reference, Formula 36 below shows the three-dimensional structural formula of the catalyst used in these Examples and Comparative Examples.

As can be seen from the results summarized in Table 2, when Ru(O ₂ CAd) ₂ ((S _C ,S _C ,R _P ,R _P )-Ph-trap), a particularly preferred form of the ruthenium complex (1) of the present invention, was used as a catalyst, the asymmetric hydrogenation of various aromatic and heteroaromatic compounds, such as indoles, oxazoles, imidazoles, and naphthalenes, proceeded smoothly without the addition of a base, and industrially useful optically active cyclic compounds were obtained in good yields (Examples 16 to 21). Instead, when the conventional catalyst [RuCl(p-cymene)((S _C ,S _C ,R _P ,R _P )-Ph-trap)]Cl was used, the reaction did not proceed without the addition of a base, and some substrates were decomposed (Comparative Examples 4 to 9). These results clearly demonstrate the usefulness of the ruthenium complex (1) of the present invention, which does not require a base and has an excellent range of substrate applications.

The ruthenium complex (1) of the present invention can be easily produced by reacting R ^P -TRAP (2) with a ruthenium source (3). The preferred form of the ruthenium complex (1) has excellent crystallinity, allowing for easy isolation and purification and long-term storage. Furthermore, it exhibits excellent catalytic activity, asymmetric induction ability, and substrate generality without the addition of a base, and therefore can contribute to the improvement of efficiency and practical application of various organic synthesis reactions, including aromatic asymmetric hydrogenation, which is useful for producing optically active cyclic compounds.

Claims (9)

A ruthenium-diphosphine-carboxylate complex represented by the following general formula (1):
[In the formula,
A solid line represents a single bond, a double line represents a double bond, and a dashed line represents a coordinate bond;
H represents a hydrogen atom, C represents a carbon atom, O represents an oxygen atom, and P represents a phosphorus atom;
Me represents a methyl group;
Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the bold line represents six electrons donated by the cyclopentadienyl anion to Fe;
R ^P represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent;
Ru represents a divalent ruthenium ion;
R ^C represents a group selected from the group consisting of an alkyl group, a halogenoalkyl group, a cycloalkyl group, and an aryl group. The ruthenium-diphosphine-carboxylate complex according to claim 1, which is optically active. 3. The ruthenium-diphosphine-carboxylate complex according to claim 1, wherein R 1 ^P is an aryl group which may have a substituent. The ruthenium-diphosphine-carboxylate complex according to any one of claims 1 to 3, wherein R 1 ^C is selected from the group consisting of alkyl groups and cycloalkyl groups. The following general formula (2)
[In the formula,
Solid lines represent single bonds;
H represents a hydrogen atom, C represents a carbon atom, and P represents a phosphorus atom;
Me represents a methyl group;
Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the bold line represents six electrons donated by the cyclopentadienyl anion to Fe;
R ^P represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent.
and a diphosphine compound represented by the following general formula (3):
[In the formula,
A solid line represents a single bond, a double line represents a double bond, and a dashed line represents a coordinate bond;
C represents a carbon atom and O represents an oxygen atom;
Ru represents a divalent ruthenium ion, AB represents alkylbenzenes, and the thick dashed line represents six-electron donation of the alkylbenzenes to Ru;
R ^C represents a group selected from the group consisting of an alkyl group, a halogenoalkyl group, a cycloalkyl group, and an aryl group.
5. A method for producing the ruthenium-diphosphine-carboxylate complex according to claim 1, comprising reacting a ruthenium-alkylbenzene-carboxylate complex represented by the formula: The manufacturing method described in claim 5, wherein the diphosphine compound represented by general formula (2) is optically active. The method according to claim 5 or 6, wherein R 1 ^P in general formula (2) is an aryl group which may have a substituent. The method according to any one of claims 5 to 7, wherein R 3 ^C in general formula (3) is selected from the group consisting of alkyl groups and cycloalkyl groups. The manufacturing method described in any one of claims 5 to 8, wherein AB in general formula (3) is selected from the group consisting of benzene, 1,3,5-trimethylbenzene, 1-methyl-4-isopropylbenzene, and hexamethylbenzene.