Ruthenium-diphosphine-carboxylate complex and method for producing same

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

[0001] The present invention relates to a novel ruthenium-diphosphine-carboxylate complex useful as a catalyst in various organic synthesis reactions, including aromatic asymmetric hydrogenation, and to an efficient method for producing the same.

[0002] Optically active cyclic compounds are extremely important compounds for use in pharmaceuticals, agrochemicals, functional materials, fragrances, and synthetic intermediates, and their production methods are still being actively researched and developed. Among these, catalytic asymmetric hydrogenation of aromatic compounds and heteroaromatic compounds, i.e., aromatic asymmetric hydrogenation, has the advantages of being able to simultaneously introduce multiple asymmetric carbons into target molecules and of being extremely atom-efficient, thereby 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.

[0003] For practical application of such aromatic asymmetric hydrogenation, asymmetric catalysts that are easy to prepare and have excellent catalytic activity, chiral induction ability, substrate compatibility, reaction reproducibility, and air stability are essential. Therefore, vigorous development of such catalysts has been underway for many years. Among these catalysts, catalytic systems prepared by combining a 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). Therefore, active research and development has been conducted on methods for synthesizing Ph-TRAP, which is used to prepare such catalytic systems, and various methods have been reported (Non-Patent Documents 5-7).

[0004] On the other hand, the aforementioned catalytic systems sometimes fail to achieve reproducible reactions. This is due to the fact that 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 the reproducibility of the reaction 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 intermediates for pharmaceuticals and agrochemicals, as well as optically active tetrahydronaphthalenes and tetrahydroquinolines, which are difficult to obtain by conventional methods (Non-Patent Documents 8-10). For reference, the stereochemical structures of both enantiomers of [RuCl(p-cymene)(Ph-trap)]Cl are shown in Formula 1 below, and a schematic diagram of aromatic asymmetric hydrogenation using this complex as a catalyst is shown in Formula 2 below.

[0005]

[0006]

[0007] Patent Document 1: Japanese Patent Application Laid-Open No. 4-283596

[0008] Non-patented document 1: Masaya Sawamura, Hitoshi Hamashima, and Yoshihiko Ito, Tetrahedron: Asymmetry, 1991, 7(2), 593-596. Non-patented document 2: Ryoichi Kuwanado, J. Synth. Org. Chem., Jpn., 2007, 65(2), 109-118. Non-patented document 3: Ryoichi Kuwanado, Nao Kameyeyama, and Ryuhei Ikeda, J. Am. Chem. Soc. , 2011, 133(19), 7312-7315. Non-patented literature 4: Ryoichi Kuwano, J. Synth. Org. Chem. , JPn. , 2021, 79(12), 1125-1135. Unauthorized Document 5: Masaya Sawamura, Hitoshi Hamashima, Masanobu Sugawara, Ryoichi Kuwano, and Yoshihiko Ito, Organometallics, 1995, 14(10), 4549-4558. Unauthorized Document 6: Ryoichi Kuwano, and Masaya Sawamura, Catalysts for Fine Chemical Synthesis: Vol. 5.Regio- and Stereo- Controlled Oxidation and Reductions, Wiley, Churcher, 2007, 5, 73-86. Unauthorized Document 7: Michael A. Schmidt, Eric M. Simons, Carolyn S. Wei, Hyunsoo Park, and Martin D. Eastgate, J. Org. Chem. , 2018, 83(7), 3928-3940. Unauthorized Document 8: Ryoichi Kuwano and Manabu Kashiwabara, Org. Lett. , 2006, 8(12), 2653-2655. Unauthorized Document 9: Ryoichi Kuwano, Ryuichi Morioka, Manabu Kashiwabara, and Nao Kameyama, Angew. Chem. Int. Ed. , 2012, 51(17), 4136-4139. Unauthorized Document 10: Ryoichi Kuwano, Ryuhei Ikeda,and Kazuki Hirasada, Chem. Commun. , 2015, 51, 7558-7561. ,

[0009] To date, 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, and new catalyst systems are always desired. In other words, the object of the present invention is to provide a novel catalyst that can be suitably used in various organic synthesis reactions and an efficient method for producing the same.

[0010] From the perspective of developing such novel 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 a catalyst for asymmetric aromatic hydrogenation, various problems remain from the viewpoint of industrial application, 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 is unstable in air in an amorphous form or in the form of a highly toxic benzene solvate, making its industrial production by conventional methods extremely difficult (Equation 3; Non-Patent Documents 5-7).

[0011]

[0012] The thus obtained Ph-TRAP and dichloro(p-cymene)ruthenium(II) dimer ([RuCl ２ (p-cymene)] ２ Although it is possible to synthesize the target [RuCl(p-cymene)(Ph-trap)]Cl by reacting [RuCl(p-cymene)(Ph-trap)]Cl with dichloromethane, which is a halogenated solvent subject to strict legal restrictions, this reaction requires an excess amount of dichloromethane, and the resulting complex is amorphous with poor crystallinity, making industrial production difficult (Equation 4; Non-Patent Document 8).

[0013]

[0014] Furthermore, aromatic asymmetric hydrogenation using this complex as a catalyst has the advantage of not requiring the use of highly toxic and corrosive fluorinated solvents that are commonly used in this type of reaction. However, since the complex requires the coexistence of various strong bases such as potassium carbonate, cesium carbonate, or 1,1,3,3-tetramethylguanidine (TMG), it is difficult to use compounds that decompose under basic conditions as substrates. In addition, the complex requires a catalyst amount of 1 mol % or more, leaving room for further improvement (Equation 5; Non-Patent Documents 8-10).

[0015]

[0016] In light of this background, the present inventors first investigated the industrialization of Ph-TRAP, which is difficult to synthesize, and discovered a stable equivalent of Ph-TRAP (Ph-TRAP·(BH ３ ) ２ We have developed an efficient method for producing Ph-TRAP·(BH) (International Publication No. WO 2024 / 203802). Furthermore, we have discovered that this stable equivalent can be easily converted into Ph-TRAP·n-BuOH, a crystalline solvate that is stable even in air, by simply heating it in n-butyl alcohol (n-BuOH) and then cooling it (International Publication No. WO 2024 / 203803). For reference, the above-mentioned Ph-TRAP·(BH) can be easily converted into Ph-TRAP·n-BuOH by simply heating it in n-butyl alcohol (n-BuOH) and then cooling it (International Publication No. WO 2024 / 203803). ３ ) ２ The present invention is not limited to these outlines, however.

[0017]

[0018] These production 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 present inventors worked on the molecular design of a new catalyst to resolve the problems of 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 leads to the expected 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 replaced with acetate ligands, which can also function as a weak base (Equation 7).

[0019]

[0020] Based on this strategic molecular design, the present inventors have conducted extensive research to develop a new catalyst. As a result, they have found that diacetato(p-cymene)ruthenium(II), a known ruthenium-alkylbenzene-acetate complex, can be easily synthesized using Ph-TRAP·n-BuOH. ２ CMe) ２ (p-cymene)) in toluene, a non-halogenated solvent, to give a novel ruthenium-diphosphine-acetate complex, namely, Ru(O ２ CMe) ２ We have found that (Ph-TRAP) can be produced as a crystalline compound with good yield. Furthermore, by utilizing the excellent crystallinity of this complex, we have succeeded in determining the absolute configuration by single-crystal X-ray structural analysis. As a result, it has become clear that Ph-TRAP in this complex behaves as a cis-chelate chiral diphosphine ligand, rather than the conventional trans-chelate type. For reference, in the following formula 8, Ru(O ２ CMe) ２ The outline of the production method of (Ph-trap) is shown below (it should be noted that the present invention is not limited to this outline in any way).

[0021]

[0022] 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. As a result, the performance of the conventional catalyst [RuCl(p-cymene)(Ph-trap)]Cl and the general catalyst Ru(O ２ CMe) ２ When using (binap), the reaction hardly proceeds without the addition of a base. ２ CMe) ２ When using (Ph-trap) as a catalyst, we found that the reaction was rapidly completed without the addition of a base, and the catalyst amount could be reduced to just 0.05 mol %. Furthermore, it was revealed that this reaction produced the target N-Boc-2-phenylindoline quantitatively with extremely high 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 (although the present invention is not limited by this scheme in any way).

[0023]

[0024] Furthermore, Ru(O ２ CMe) ２ Acetate ligand (O) on (Ph-trap) ２ CMe) with a bulkier carboxylate ligand, such as a pivalate ligand (O ２ C ｔ Bu) and 1-adamantanecarboxylate ligands (O ２ By replacing the catalyst with HCl, the molecular symmetry is changed and catalytic activity is significantly improved, and the reaction can be completed even with more practical low-pressure hydrogen gas.

[0025] 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):

[0026] [wherein, 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-electron donation of 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] R Ｐ [4] The ruthenium-diphosphine-carboxylate complex according to the above [1] or [2], wherein R is an aryl group which may have a substituent. Ｃ is selected from the group consisting of alkyl groups and cycloalkyl groups. [5] The ruthenium-diphosphine-carboxylate complex according to any one of [1] to [3] above,

[0027] [wherein, the solid line represents a single bond; H represents a hydrogen atom, C represents a carbon atom, 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-electron donation of 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):

[0028] [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, 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.]. [6] The method for producing a ruthenium-diphosphine-carboxylate complex according to any one of [1] to [4] above, comprising reacting a ruthenium-alkylbenzene-carboxylate complex represented by the general formula (2) with a diphosphine compound represented by the general formula (2) above. [7] The method for producing a ruthenium-diphosphine-carboxylate complex according to the general formula (2) above, wherein R Ｐ [8] The method according to the above [5] or [6], wherein R in general formula (3) is an aryl group which may have a substituent. Ｃ is selected from the group consisting of alkyl groups and cycloalkyl groups. [9] The production method according to any one of [5] to [8] above, wherein AB in 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 production 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.

[0029] The present invention relates to a ruthenium-diphosphine-carboxylate complex represented by the general formula (1), i.e., Ru(O ２ CR Ｃ ) 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 easy to use industrially. Furthermore, a preferred form of the ruthenium complex (1) of the present invention has excellent crystallinity, facilitating isolation and purification and long-term storage, and 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.

[0030] FIG. 1 shows the Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ 2 shows the results of single crystal X-ray structure analysis of Ru(O)-Ph-trap prepared in Example 2 below. ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ 3 shows the results of single crystal X-ray structure analysis of Ru(O)-Ph-trap prepared in Example 3 below. ２ C ｔ Bu) ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ 4 shows the results of single crystal X-ray structure analysis of Ru(O)-Ph-trap prepared in Example 4 below. ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ 5 shows the results of single crystal X-ray structure analysis of Ru(O)-Ph-trap prepared in Example 5 below. ２ C.A.d. ２ ((R Ｃ , R Ｃ , S Ｐ, S Ｐ 6 shows the results of single crystal X-ray structure analysis of Ru(O)-Ph-trap prepared in Example 5 below. ２ C.A.d. ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ )-Ph-trap)・H ２ 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.

[0031] 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, a pentagon containing a circle represents a cyclopentadienyl anion, and a thick 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 preferably represents 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, and preferably represents an alkyl group or a cycloalkyl group. Ｐ All represent the same group, and two R Ｃ represent the same group.

[0032] Next, R Ｐ The alkyl group, cycloalkyl group, heteroaryl group and optionally substituted aryl group in the above formula will be described in more detail below.

[0033] R Ｐ The alkyl group in 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.

[0034] R Ｐ The cycloalkyl group in 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.

[0035] R Ｐ The heteroaryl group in the formula (I) 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.

[0036] R Ｐ Examples of the aryl group in the formula (I) include 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 include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group, and a preferred specific example is a phenyl group. The aryl group may have a substituent.

[0037] R Ｐ The substituents that the aryl group in the formula (I) may have include an alkyl group, a halogenoalkyl group, an aryl group, an alkoxy group, a dialkylamino group, and a halogeno group.

[0038] The alkyl group may be R Ｐ Examples of alkyl groups include the same alkyl groups as those detailed in the explanation of 1., specifically methyl and tert-butyl groups, and a preferred specific example is methyl.

[0039] The halogenoalkyl group includes a halogenoalkyl group formed by substituting at least one hydrogen atom on the alkyl group described above with a halogen atom, and specifically includes a trifluoromethyl group.

[0040] The aryl group includes R Ｐ Examples of the aryl groups include the same aryl groups as those detailed in the explanation of 1., and specifically include a phenyl group.

[0041] The alkoxy group may be linear or branched, and includes, for example, an alkoxy group having 1 to 12 carbon atoms, preferably an alkoxy group having 1 to 8 carbon atoms, and more preferably an alkoxy group having 1 to 4 carbon atoms. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, an isobutoxy group, and a tert-butoxy group.

[0042] The dialkylamino group includes a dialkylamino group formed by substituting two hydrogen atoms on an amino group with the above-mentioned alkyl groups, and specifically includes an N,N-dimethylamino group.

[0043] Specific examples of the halogeno group include a fluoro group, a chloro group, a bromo group, and an iodo group.

[0044] Next, R Ｃ The alkyl group, halogenoalkyl group, cycloalkyl group and aryl group in the formula (I) will be described in more detail below.

[0045] R Ｃ The alkyl group in may be linear or branched, and includes, for example, an alkyl group having 1 to 12 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, and more preferably an alkyl group having 1 to 4 carbon atoms. Specific examples 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 include a methyl group and a tert-butyl group.

[0046] R ＣThe halogenoalkyl group in the formula (I) includes a halogenoalkyl group formed by substituting at least one hydrogen atom on the alkyl group with a halogen atom, and a specific example thereof is a trifluoromethyl group.

[0047] R Ｃ The cycloalkyl group in may be monocyclic or polycyclic and includes, for example, a cycloalkyl group having 3 to 20 carbon atoms, preferably a cycloalkyl group having 3 to 15 carbon atoms, 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.

[0048] R Ｃ The aryl group in the formula (I) 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.

[0049] The ruthenium complex (1) of the present invention has two carbon-center chiral structures (hereinafter, the absolute configuration of these carbon-center chiral structures is referred to as R Ｃ and S Ｃ ) and two planar chiral structures (hereinafter, the absolute configurations of these planar chiral structures are referred to as R Ｐ and S Ｐ and one secondarily induced ruthenium-centered asymmetry (hereinafter, the absolute configuration of this ruthenium-centered asymmetry will be represented by Δ and Λ). Therefore, the compound may be a mixture of stereoisomers resulting from these various asymmetries, or a single stereoisomer, but from the viewpoint of application to aromatic asymmetric hydrogenation in particular, it is preferably a single stereoisomer, i.e., an optically active substance.

[0050] A preferred embodiment of the optically active ruthenium complex (1) of the present invention is, from the structural requirements, Ru(O ２ CR Ｃ ) ２ ((S Ｃ , S Ｃ , R Ｐ , RＰ )-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) (Note that, according to convention, in the drawing of the stereostructure in this specification, the secondarily induced ruthenium-centered asymmetry and the carbon atom C and the hydrogen atom H are omitted).

[0051] [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.]

[0052] A particularly preferred example of the ruthenium complex (1) of the present invention is 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), Ru(O２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap) and Ru(O ２ C.A.d. ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ )-Ph-trap) and Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Tol-trap), Ru(O ２ CMe) ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ )-Tol-trap), Ru(O ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Tol-trap), Ru(O ２ C ｔ Bu) ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ )-Tol-trap), Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Tol-trap) and Ru(O ２ C.A.d. ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ )-Tol-trap).

[0053] [In the formula, Ph represents a phenyl group, and Me represents a methyl group.]

[0054] [In the formula, Tol represents a 4-methylphenyl group, and Me represents a methyl group.]

[0055] 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 is obtained by reacting a diphosphine compound represented by the general formula (2) (hereinafter referred to as R Ｐ -TRAP (2)) and a ruthenium-alkylbenzene-carboxylate complex represented by the general formula (3), i.e., Ru(O ２ CR Ｃ ) ２ It can be easily produced by reacting (AB)(3) (hereinafter referred to as ruthenium source (3)) with alkylbenzenes, i.e., AB, while dissociating the alkylbenzenes.

[0056]

[0057] Hereinafter, R in the production method of the present invention Ｐ In the general formula (2), the solid line, H, C, P, Me, Fe, a pentagon containing a circle, a thick line, and R Ｐ are the same as those defined and detailed in the explanation of the general formula (1). Ｐ In -TRAP(2), there are four R Ｐ all represent the same group.

[0058] Furthermore, R Ｐ Since R-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, as with the ruthenium complex (1) of the present invention, it is preferably a single stereoisomer, i.e., an optically active substance, particularly from the viewpoint of application to aromatic asymmetric hydrogenation. Ｐ A preferred form of -TRAP (2) is the one shown in the following formula 14, (S Ｃ , S Ｃ , R Ｐ , R Ｐ )-R Ｐ -TRAP ((S Ｃ , SＣ , 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) can be mentioned.

[0059]

[0060] R in the production method of the present invention Ｐ A particularly preferred example of -TRAP (2) is (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.

[0061] [In the formula, Ph represents a phenyl group, and Tol represents a 4-methylphenyl group.]

[0062] R Ｐ Although the synthesis method of -TRAP (2) is not particularly limited, from a practical viewpoint, the methods described in WO 2024 / 203802 and WO 2024 / 203803 are preferred, and the outline thereof is shown in the following formula 16. ＰN,N-dimethyl-1-ferrocenylethylamine (commonly known as Ugi's Amine) can be synthesized easily and reproducibly 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 (Step 6). Furthermore, by converting Ugi's Amine used in this synthesis method into an optically active form, it is possible to obtain an optically active R Ｐ The preferred form of -TRAP (2) is the (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) can be prepared separately. Ｐ -TRAP (2) may form a stable solvate with the solvent used in the deprotection reaction (Step 6), and preferred examples of such solvents include n-propyl alcohol and n-butanol.

[0063] [In the formula, B represents a boron atom, Mg represents a magnesium atom, N represents a nitrogen atom, and X represents a halogen atom.]

[0064] 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 Ｃare the same as those defined and detailed in the explanation of the general formula (1). AB represents an alkylbenzene, and the thick dashed line represents six electrons donated by the alkylbenzene to Ru. In the ruthenium source (3), two R Ｃ represent the same group.

[0065] 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 benzene is substituted with an alkyl group, for example, alkylbenzenes having 6 to 24 carbon atoms, preferably alkylbenzenes having 6 to 18 carbon atoms, 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).

[0066] A particularly preferred example of the ruthenium source (3) in the production method of the present invention is Ru(O ２ CMe) ２ (p-cymene), Ru(O ２ C ｔ Bu) ２ (p-cymene) and Ru(O ２ C.A.d. ２ (p-cymene). All of these ruthenium sources (3) can be easily synthesized according to known methods.

[0067] [In the formula, Me represents a methyl group, ｔ Bu represents a tert-butyl group, and Ad represents a 1-adamantyl group.

[0068] Next, an embodiment of the manufacturing method of the present invention, namely, R Ｐ The reaction conditions for the reaction of R-TRAP (2) with the ruthenium source (3) are described in more detail below. ＰThe amount of -TRAP (2) used is not particularly limited, but is appropriately selected from the range of usually 0.5 to 1.5 equivalents, preferably 0.8 to 1.2 equivalents, more preferably 0.9 to 1.1 equivalents relative to the ruthenium source (3) from the viewpoint of atom efficiency.

[0069] R Ｐ The reaction of -TRAP (2) with the ruthenium source (3) can in principle be carried out in the absence of a solvent. However, since this requires special equipment such as a ball mill or a kneader, it is practically 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 solvent used is not particularly limited. Ｐ The volume is usually selected from the range of 1 to 200 times, preferably 1.5 to 100 times, more preferably 2 to 50 times the weight of the -TRAP (2).

[0070] R ＰThe reaction between ruthenium-TRAP (2) and 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 gas include argon gas and nitrogen gas, and a preferred example is nitrogen gas. The reaction temperature is generally 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 is determined by the R Ｐ Structure of R-TRAP (2) and ruthenium source (3) Ｐ Although it depends on the amount of -TRAP (2) used, the reaction solvent and the reaction temperature, the reaction time is usually selected appropriately from the range of 5 minutes to 24 hours, preferably 10 minutes to 12 hours, more preferably 20 minutes to 6 hours.

[0071] R Ｐ The reaction solution obtained from .GAMMA.-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.

[0072] Furthermore, when the ruthenium complex (1) of the present invention is used as a catalyst, the reaction solution may be used as is, or may be used after 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 excellent in crystallinity and stability and can be stored for a long period of time, so from the viewpoint 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 of two or more kinds, but from a practical viewpoint, it is preferable to use it as a catalyst alone.

[0073] The ruthenium complex (1) of the present invention thus produced 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 conversion 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 thereof is the asymmetric hydrogenation reaction of aromatic compounds and heteroaromatic compounds, i.e., aromatic asymmetric hydrogenation.

[0074] Particularly preferred examples of such aromatic asymmetric hydrogenation include asymmetric hydrogenation of indoles, oxazoles, imidazoles, and naphthalenes under neutral conditions, and these reactions enable efficient production of industrially useful optically active cyclic compounds.

[0075] The method for producing the ruthenium complex (1) of the present invention and the aromatic asymmetric hydrogenation using this complex as a catalyst will be described in detail below with reference to specific examples and comparative examples, but the present invention is not limited by these examples. Furthermore, unless otherwise noted, the substrate, reagent, 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 apparatuses, measurement conditions, and analysis conditions used for measuring physical properties in the examples are as follows:

[0076] 1) Proton nuclear magnetic resonance spectroscopy ( １1H NMR): 400MR DD2 type apparatus (resonance frequency 400 MHz; manufactured by Agilent Technologies) 2) Carbon-13 nuclear magnetic resonance spectroscopy ( １３ C NMR): 400MR DD2 type apparatus (resonance frequency 100 MHz; manufactured by Agilent Technologies) 3) Phosphorus-31 nuclear magnetic resonance spectroscopy ( ３１ P NMR): 400MR DD2 type instrument (resonance frequency 161 MHz; manufactured by Agilent Technologies) 4) High-performance liquid chromatography (HPLC): GL-7400 type instrument (manufactured by GL Sciences) 5) Single crystal X-ray structural analysis: XtaLAB Synergy-S type instrument (manufactured by Rigaku Oxford Diffraction) [Measurement conditions] X-ray source: CuKα ray, instrument 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.

[0077] [Example 1] Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Preparation of )-Ph-trap (Equation 18)

[0078]

[0079] Step 1: Ru(O ２ CMe) ２ Preparation of (p-cymene) solution

[0080] [Preparation and reaction] Dichloro(p-cymene)ruthenium(II) dimer ([RuCl ２ (p-cymene)] ２ A magnetic stirrer bar and a three-way stopcock were attached, and the inside of the flask was purged with nitrogen. Next, dehydrated toluene (15 mL) was added to the flask, and the flask was covered with aluminum foil to shield from light. The contents were stirred at room temperature for 2 hours.

[0081] [Post-treatment] The obtained orange suspension was filtered under a nitrogen stream using diatomaceous earth, and the filtered residue was washed with dehydrated toluene (15 mL) to obtain the target Ru(O ２ CMe) ２ A toluene solution (approximately 30 mL) of (p-cymene) (<2.34 mmol) was obtained as a reddish-orange liquid. 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 are as follows:

[0082] １ H NMR (400MHz, CDCl ３ ): 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). １３ C NMR (100MHz, CDCl ３ ): δ=184.37, 97.98, 92.59, 78.84, 77.68, 31.38, 23.77, 22.46, 18.50.

[0083] Step 2: Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)

[0084] [Charge 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) was charged into the flask, and a magnetic stirrer bar, a thermometer, a dropping funnel, a Claisen distillation apparatus, a Dimroth condenser, and a three-way stopcock were attached, and the inside of the flask was replaced with nitrogen. Anhydrous toluene (40 mL) was added to the flask, and the resulting orange solution was gradually reduced in pressure to 60 Torr while stirring at 60°C. After recovering approximately 30 mL of solvent, the inside of the apparatus was filled with nitrogen gas. Next, the dropping funnel was charged with Ru(O ２ CMe) ２ A toluene solution (approximately 30 mL) of (p-cymene) (<2.34 mmol, 1.0 equivalent) was added dropwise to the reaction mixture at room temperature, and the mixture was stirred for 2 hours while being heated in an oil bath at 70°C.

[0085] [Post-treatment, isolation, and purification] The dark brown reaction solution was heated at 70°C while gradually reducing the pressure to 60 Torr. After recovering approximately 30 mL of the solvent, 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, and then heated to 60°C under a reduced pressure of 1 Torr and dried for 1 hour to obtain the target Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ 2.34 g of )-Ph-trap) was obtained as a light brown powder that was stable even in air. Purity: 92.1 wt% (major impurities were 7.5 wt% toluene and 0.4 wt% 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.

[0086] １ H NMR (400MHz, C ６ D ６): 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 (161MHz, C ６ D ６ ): δ=74.07(s, 2P).

[0087] Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ The results of single crystal X-ray structural analysis of )-Ph-trap (thermal vibration ellipsoid diagram; atomic existence probability 50%) are shown in Figure 1 below. Note that hydrogen atoms have been omitted in the diagram to make the structure of the complex easier to understand. From these results, it is clear that 1) this complex crystallizes while solvating one molecule of toluene, and 2) in the crystalline state, C ２ 3) the secondary induced ruthenium-centered chirality is Λ; 4) Ph-TRAP in this complex unexpectedly behaves as a cis-chelate chiral diphosphine ligand (coordination angle: 91.42°) rather than the conventionally known trans-chelate type (coordination angle: approximately 180°). Furthermore, the main parameters that ensure the accuracy of this analysis were as follows: Chemical formula: C ５９ H ５８ Fe ２ O ４ P ２ Ru, crystal system: rectangular system, space group: P2 １ 2 １ 2 １ (#19), lattice constant: 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 (wR ２ ): 0.0814, Goodness of Fit (GOF): 1.019, Flack parameter: −0.025 (4).

[0088] [Example 2] Ru(O ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Preparation of )-Ph-trap (Equation 19)

[0089]

[0090] Step 1: Ru(O ２ C ｔ Bu) ２ Synthesis of (p-cymene)

[0091] [Preparation and reaction] In a 200 mL four-neck round-bottom flask, add pivalic acid ( ｔ BuCO ２ H; 3.67 g, 35.9 mmol, 4.4 equivalents) and [RuCl ２ (p-cymene)] ２ The flask was sequentially charged with 5.0 g (8.16 mmol, 1.0 equiv.), a magnetic stir bar, a thermometer, a Claisen distillation apparatus, a Dimroth condenser, and a three-way stopcock, and the inside of the flask 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 equiv.) were sequentially added to the flask, and the contents were stirred for 2 hours while being heated in an oil bath at 60 °C.

[0092] [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. The resulting orange slurry was added with n-heptane (90 mL) while stirring, cooled to 0°C in an ice-water bath, and then subjected to suction filtration 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 to obtain the target Ru(O ２ C ｔ Bu) ２ 6.79 g of p-cymene was obtained as an air-stable yellow-orange powder. Isolated yield: 95.1%.

[0093] １ H NMR (400MHz, CDCl ３ ): 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). １３ C NMR (100MHz, CDCl ３ ): δ=191.85, 98.59, 94.10, 78.21, 76.76, 39.86, 31.48, 27.60, 22.46, 18.47.

[0094] Step 2: Ru(O ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , RＰ , R Ｐ Preparation of (S)-Ph-trap) [Preparation and reaction] In a 50 mL four-necked round-bottom flask, Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-TRAP·n-BuOH (purity: 92.9 wt%, 1.0 g, 1.17 mmol, 1.0 equivalent) was charged, and a magnetic stirrer bar, thermometer, Claisen distillation apparatus, Dimroth condenser, and three-way stopcock were attached, and the inside of the flask was purged with nitrogen. Dehydrated 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, the Ru(O ２ C ｔ Bu) ２ (p-Cymene) (512 mg, 1.17 mmol, 1.0 equivalent) 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.

[0095] [Post-treatment, isolation, and purification] The resulting brown slurry was allowed to cool to room temperature, and then dehydrated n-heptane (10 mL) was added. The mixture was then suction filtered using a Kiriyama funnel under a nitrogen stream. The filtered crystals were washed with a mixed solvent of dehydrated n-heptane (8 mL) and dehydrated toluene (2 mL), and then heated to 60°C under a reduced pressure of 1 Torr and dried for 1 hour to obtain the target Ru(O ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap) was obtained as an orange powder (1.16 g) 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.

[0096] １ H NMR (400MHz, C ６ D ６): 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 (161MHz, C ６ D ６ ): δ=72.13(s, 2P).

[0097] Ru(O ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ The results of single crystal X-ray structural analysis of )-Ph-trap (thermal vibration ellipsoid diagram; atomic existence probability 50%) are shown in Figure 2 below. Note that hydrogen atoms have been omitted in the diagram to make the structure of the complex easier to understand. From these results, it is clear that 1) this complex crystallizes while solvating one molecule of toluene for every two molecules of the complex, and 2) in the crystalline state, C １ 3) the secondary induced ruthenium-centered chirality is Δ; 4) Ph-TRAP in this complex unexpectedly behaves as a cis-chelate chiral diphosphine ligand (average coordination angle: 107.43°), rather than the conventionally known trans-chelate type (coordination angle: approximately 180°). Furthermore, the main parameters that ensure the accuracy of this analysis were 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 constant: 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).

[0098] [Example 3] Ru(O ２ C ｔ Bu) ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ Preparation of )-Ph-trap (Equation 20)

[0099]

[0100] [Charge and reaction] A 50 mL four-necked round-bottom flask was charged with 100 ml of 100% methyl 2-methylpropional (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) was charged into the flask, and a magnetic stirrer bar, a thermometer, a dropping funnel, a Claisen distillation apparatus, a Dimroth condenser, and a three-way stopcock were attached, and the inside of the flask was purged with nitrogen. Anhydrous toluene (20 mL) was added to the flask, and the resulting orange solution was gradually reduced in pressure to 60 Torr while stirring at 60°C. After recovering about 15 mL of solvent, the inside of the apparatus was filled with nitrogen gas. Next, the dropping funnel was charged with Ru(O ２ C ｔ Bu) ２ (p-Cymene) (492 mg, 1.12 mmol, 1.0 equivalent) and dehydrated toluene (15 mL) were sequentially charged, 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.

[0101] [Post-treatment, isolation, and purification] The dark red reaction solution was stirred at 60°C while gradually reducing the pressure to 60 Torr. After recovering approximately 15 mL of the solvent, the inside of the apparatus was filled with nitrogen gas. The resulting brown slurry was stirred at room temperature while adding dehydrated n-heptane (15 mL). The mixture was cooled to 0°C in an ice-water bath, and then filtered under suction using a Kiriyama funnel under a nitrogen stream. The filtered crystals were washed with a mixed solvent of dehydrated n-heptane (10 mL) and dehydrated 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 to obtain the target Ru(O ２ C ｔ Bu) ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ 1.21 g of Ru(O)-Ph-trap was obtained as an orange powder that was stable in air. Purity: 96.8 wt % (the main impurity was toluene at 3.4 wt %), isolated yield: 95.2%. NMR analysis of this complex showed that it was identical to the Ru(O) complex prepared in Example 2. ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap), i.e., the data for the enantiomers were consistent. Single crystals of this complex could also be prepared in the same manner as for its enantiomers.

[0102] Ru(O ２ C ｔ Bu) ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ The results of single crystal X-ray structural analysis of Ru(O)-Ph-trap (thermal vibration ellipsoid diagram; atomic existence probability 50%) 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. From these results, it is clear that this complex is indeed the same as the Ru(O)-Ph-trap prepared in Example 2. ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , RＰ The main parameters that ensure the accuracy of the analytical results are as follows: Chemical formula: C １２３ H １３２ Fe ４ O ８ P ４ Ru ２ , Crystal system: monoclinic system, Space group: P1 2 １ 1 (#4), lattice constant: 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).

[0103] [Example 4] Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Preparation of )-Ph-trap (Equation 21)

[0104]

[0105] Step 1: Ru(O ２ C.A.d. ２ Synthesis of (p-cymene)

[0106] [Preparation and reaction] In a 100 mL four-neck round-bottom flask, add [RuCl ２ (p-cymene)] ２ (5.4 g, 8.82 mmol, 1.0 equivalent) and 1-adamantanecarboxylic acid (AdCO ２ The flask was sequentially charged with (H; 7.0 g, 38.8 mmol, 4.4 equivalents), a magnetic stirrer bar, a thermometer, a Dimroth condenser, and a three-way stopcock, and the inside of the flask was replaced 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.

[0107] [Post-treatment, isolation, and purification] The obtained reddish-orange slurry was cooled to 0°C in an ice-water bath, and then subjected to suction filtration using a Kiriyama funnel to separate the crystals from the filtrate. The filtered crystals were washed successively with methanol (14 mL) cooled to 0°C, tap water (35 mL), and methanol (14 mL) cooled to 0°C, and then heated to 80°C under a reduced pressure of 1 Torr and dried for 2 hours to obtain the target Ru(O ２ C.A.d. ２ 8.16 g of p-cymene was obtained as an orange powder that was stable in air. 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, and the resulting orange slurry was suction filtered using a Kiriyama funnel. The filtered crystals were washed three times with 50% aqueous methanol (14 mL) and then heated to 80°C under a reduced pressure of 1 Torr and dried for 2 hours to obtain additional Ru(O ２ C.A.d. ２ 2.17 g of (p-cymene) was obtained 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%.

[0108] １ H NMR (400MHz, CDCl ３ ): 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). １３ C NMR (100MHz, CDCl ３ ): 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.

[0109] Step 2: Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , RＰ , R Ｐ )-Ph-trap)

[0110] [Preparation and reaction] In a 100 mL four-neck round-bottom flask, (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) was charged into the flask, and a magnetic stirrer bar, a thermometer, a dropping funnel, a Claisen distillation apparatus, a Dimroth condenser, and a three-way stopcock were attached, and the inside of the flask 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, the dropping funnel was charged with Ru(O ２ C.A.d. ２ (p-Cymene) (purity: 98.5 wt%, 1.67 g, 2.77 mmol, 1.0 equivalent) and dehydrated toluene (30 mL) were sequentially charged, 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.

[0111] [Post-treatment, isolation, and purification] The dark brown reaction solution was stirred at 70°C while gradually reducing the pressure to 60 Torr. Approximately 33 mL of solvent was recovered, and then the inside of the apparatus was filled with nitrogen gas. The concentrated solution was allowed to cool to room temperature, and 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 then 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 to obtain the target Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ)-Ph-trap) was obtained as an orange powder, 3.14 g, which was stable even in air. Purity: 98.1 wt% (major impurities were 1.4 wt% toluene and 0.5 wt% acetone), isolation yield: 88.7%. 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.

[0112] １ H NMR (400MHz, C ６ D ６ ): 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 (161MHz, C ６ D ６ ): δ=72.06 (bs, 2P).

[0113] Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ The results of single crystal X-ray structural analysis of )-Ph-trap (thermal ellipsoid diagram; atomic existence probability 50%) are shown in Figure 4 below. Note that hydrogen atoms have been omitted in the diagram to make the structure of the complex easier to understand. From these results, it can be seen that 1) this complex crystallizes without solvation, 2) in the crystalline state, C １3) the secondary induced ruthenium-centered chirality is Δ; 4) Ph-TRAP in this complex unexpectedly behaves as a cis-chelate chiral diphosphine ligand (coordination angle: 104.56°) rather than the previously known trans-chelate type (coordination angle: approximately 180°). Furthermore, the main parameters that ensure the accuracy of this analysis were as follows: Chemical formula: C ７０ H ７４ Fe ２ O ４ P ２ Ru ２ , Crystal system: triclinic, Space group: P1 (#1), Lattice constant: 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).

[0114] [Example 5] Ru(O ２ C.A.d. ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ Preparation of )-Ph-trap (Equation 22)

[0115]

[0116] As a starting material, (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 C.A.d. ２ Using p-cymene (purity: 98.5 wt %, 735 mg, 1.22 mmol, 1.0 equivalent), a series of operations was carried out according to the procedure described in Example 4 to obtain the target Ru(O ２ C.A.d. ２ ((R Ｃ , R Ｃ, S Ｐ , S Ｐ 1.35 g of Ru(O)-Ph-trap was obtained as an orange powder that was stable in air. Purity: 98.0 wt% (major impurities were 1.4 wt% toluene and 0.6 wt% acetone), isolated yield: 86.5%. NMR analysis of this complex showed that, except for the difference in acetone content, it was identical to the Ru(O) complex prepared in Example 4. ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap), i.e., the data for the enantiomers were consistent. Single crystals of this complex could also be prepared in the same manner as for its enantiomers.

[0117] Ru(O ２ C.A.d. ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ The results of single crystal X-ray structural analysis (thermal vibration ellipsoid diagram; atomic existence probability 50%) of Ru(O)-Ph-trap) are shown in Figure 5 below. Note that hydrogen atoms have been omitted in the diagram to make the mirror image relationship of the complex easier to understand. From these results, it is clear that this complex is indeed the same as the Ru(O)-Ph-trap prepared in Example 4. ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ The main parameters that ensure the accuracy of the analytical 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 constant: 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).

[0118] 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. It was found that one equivalent of water was included per complex molecule. ２ C.A.d. ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ )-Ph-trap)・H ２ The results of single-crystal X-ray structural analysis of O (thermal vibration ellipsoid diagram; atomic existence probability 50%) are shown in Figure 6 below. Note that to make the inclusion state of water molecules easier to understand, the hydrogen atoms on the complex molecules are omitted in the diagram. The main parameters that ensure the accuracy of this analysis result are as follows: Chemical formula: C ７０ H ７６ Fe ２ O ５ P ２ Ru ２ , Crystal system: triclinic, Space group: P1 (#1), Lattice constant: 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).

[0119] Example 6: Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Preparation of )-Tol-trap) (Equation 23)

[0120]

[0121] [Charge and reaction] A 20 mL Schlenk flask was charged with 100 mL of 100% methyl 2-methyl-1-propanol (S Ｃ, S Ｃ , R Ｐ , R Ｐ )-Tol-TRAP (purity: 98.5 wt %, 500 mg, 0.579 mmol, 1.01 equivalents) and Ru(O ２ CMe) ２ p-cymene (203 mg, 0.573 mmol, 1.0 equivalent) was then added, a magnetic stirrer bar was attached, and the inside of the flask was purged with nitrogen. After adding dehydrated toluene (2.5 mL), the contents were stirred for 2 hours while being heated in an oil bath at 70°C.

[0122] [Post-treatment and isolation] The reaction solution obtained was stirred at 70°C and gradually reduced in pressure to 15 Torr to concentrate and dry the solution. The flask was then filled with nitrogen gas. The dark brown residue obtained was crushed under a nitrogen atmosphere and then heated to 70°C under a reduced pressure of 1 Torr and dried for 1 hour to obtain the target Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ 680 mg of )-Tol-trap) was obtained as a dark brown powder with a purity of 90.7% by weight (the main impurities were 4.5% by weight of toluene and 4.8% by weight of p-cymene), and quantitative isolated yield.

[0123] １ H NMR (400MHz, C ６ D ６): 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]). ３１ P NMR (161MHz, C ６ D ６ ): δ=73.36(s, 2P)

[0124] Example 7: Ru(O ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Preparation of )-Tol-trap) (Equation 24)

[0125]

[0126] Ru(O) synthesized in Step 1 of Example 2 ２ C ｔ Bu) ２ (p-cymene) (251 mg, 0.573 mmol, 1.0 equivalent) and (S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Tol-TRAP (purity: 98.5 wt %, 500 mg, 0.579 mmol, 1.01 equivalents) was reacted according to the procedure described in Example 6, and further post-treatment was carried out to obtain the target Ru(O ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ739 mg of )-Tol-trap) was obtained as a dark brown powder with a purity of 91.7% by weight (the main impurities were 3.0% by weight of toluene and 5.3% by weight of p-cymene), and quantitative isolated yield.

[0127] １ H NMR (400MHz, C ６ D ６ ): 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 (161MHz, C ６ D ６ ): δ=72.90(s, 2P).

[0128] Example 8: Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Preparation of )-Tol-trap) (Equation 25)

[0129]

[0130] Ru(O) synthesized in Step 1 of Example 4 ２ C.A.d. ２ (p-cymene) (purity: 98.5 wt%, 346 mg, 0.573 mmol, 1.0 equivalent) and (S Ｃ , S Ｃ , R Ｐ , R Ｐ)-Tol-TRAP (purity: 98.5 wt %, 500 mg, 0.579 mmol, 1.01 equivalents) was reacted according to the procedure described in Example 6, and further post-treatment was carried out to obtain the target Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ 842 mg of )-Tol-trap) was obtained as a dark brown powder with a purity of 91.4 wt % (the main impurities were 3.9 wt % toluene and 4.7 wt % p-cymene), and quantitative isolated yield.

[0131] １ H NMR (400MHz, C ６ D ６ ): 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 (161MHz, C ６ D ６ ): δ=72.86 (bs, 2P).

[0132] Example 9: Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)-catalyzed asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (Equation 26)

[0133]

[0134] [Preparation and reaction] In a borosilicate glass test tube (φ20 mm × 130 mm), Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap) (purity: 92.1 wt%, 2.8 mg, 0.05 mol%) 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, and a magnetic stirrer bar was further attached. The test tube was attached to a 50 mL autoclave, and the inside of the autoclave was replaced with nitrogen, followed by dehydrated isopropyl alcohol ( ｉ Then, the inside of the apparatus was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60° C. for 6 hours.

[0135] [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. １ Analysis by H NMR revealed a conversion rate of >99.9%. The residue was purified by silica gel column chromatography (eluent: n-hexane / toluene = 88 / 12 to 0 / 100) to obtain 1.450 g of the target (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).

[0136] The results of single crystal X-ray structural analysis of (S)-N-Boc-2-phenylindoline synthesized in Example 9 (thermal vibration ellipsoid diagram; atomic existence probability 50%) are shown in Figure 7 below. 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. In addition, the main parameters that ensure the accuracy of these analytical results were as follows; chemical formula: C １９ H ２１ NO ２ , Crystal system: Rectangular system, Space group: P2 １ 2 １ 2 １ (#19), lattice constant: 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).

[0137] Example 10: Ru(O ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)-Catalyzed Asymmetric Hydrogenation of N-Boc-2-phenyl-1H-indole

[0138] Ru(O ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (1.47 g) was carried out using (S)-Ph-trap) (purity: 96.8 wt %, 2.8 mg, 0.05 mol %) as a catalyst at an internal pressure of 5 MPa according to the procedure described in Example 9, yielding 1.450 g of the desired (S)-N-Boc-2-phenylindoline. Reaction time: 2 hours, conversion rate: >99.9% ( １ H NMR analysis), isolated yield: 98.2%, optical purity: 94.9% ee.

[0139] Example 11: Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)-Catalyzed Asymmetric Hydrogenation of N-Boc-2-phenyl-1H-indole

[0140] Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (1.47 g) was carried out using (S)-Ph-trap) (purity: 98.1 wt %, 3.2 mg, 0.05 mol %) as a catalyst at an internal pressure of 5 MPa according to the procedure described in Example 9, yielding 1.470 g of the desired (S)-N-Boc-2-phenylindoline. Reaction time: 1 hour, conversion rate: >99.9% ( １ H NMR analysis), isolated yield: 99.5%, optical purity: 94.4% ee.

[0141] Example 12: Ru(O ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)-Catalyzed Low-Pressure Asymmetric Hydrogenation of N-Boc-2-phenyl-1H-indole

[0142] Ru(O) prepared in Example 2 ２ C ｔ Bu) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (1.47 g) was carried out using (S)-Ph-trap (0.05 mol%) as a catalyst at an internal pressure of 1 MPa according to the procedure described in Example 9, yielding 1.453 g of the desired (S)-N-Boc-2-phenylindoline. Reaction time: 6 hours, conversion rate: >99.9% ( １H NMR analysis), isolated yield: 98.4%, optical purity: 94.7% ee.

[0143] Example 13: Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)-Catalyzed Low-Pressure Asymmetric Hydrogenation of N-Boc-2-phenyl-1H-indole

[0144] Ru(O) prepared in Example 4 ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (1.47 g) was carried out using (S)-Ph-trap (0.05 mol%) as a catalyst at an internal pressure of 1 MPa according to the procedure described in Example 9, yielding 1.456 g of the desired (S)-N-Boc-2-phenylindoline. Reaction time: 6 hours, conversion rate: >99.9% ( １ H NMR analysis), isolated yield: 98.6%, optical purity: 94.9% ee.

[0145] [Comparative Example 1] [RuCl (p-cymene) ((S Ｃ , S Ｃ , R Ｐ , R Ｐ Attempted asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole using [(N-Boc-Ph-trap)]Cl as a catalyst

[0146] The conventional catalyst [RuCl(p-cymene)((S Ｃ , S Ｃ , R Ｐ , R Ｐ Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole was carried out using 0.05 mol% N-Boc-2-phenyl-1H-indole according to the procedure described in Example 9. However, even after 6 hours of reaction at an internal pressure of 5 MPa, the conversion rate was only 2.2% ( １ by H NMR analysis).

[0147] [Comparative Example 2] Ru(O ２ CMe) ２ Attempted asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole using ((S)-binap) as a catalyst

[0148] A common catalyst, Ru(O ２ CMe) ２ Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole was attempted using the commercially available product ((S)-binap) (0.05 mol%) according to the procedure described in Example 9, but the conversion was less than 0.1% even after 6 hours of reaction at an internal pressure of 5 MPa. １ by H NMR analysis).

[0149] The results of Comparative Examples 1 and 2 and Examples 9 to 13 are summarized in Table 1 below. For reference, the three-dimensional structural formulas of the various catalysts used in these Comparative Examples and Examples are shown in Formula 27 below.

[0150]

[0151]

[0152] As is clear from the results summarized in Table 1, the conventional catalyst [RuCl(p-cymene)((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)]Cl and the common catalyst Ru(O ２ CMe) ２ When ((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).

[0153] On the other hand, Ru(O), which is a preferred form of the ruthenium complex (1) of the present invention, ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R ＰWhen the acetate ligand (O)-Ph-trap) 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). ２ CMe) and (S Ｃ , S Ｃ , R Ｐ , R Ｐ It was revealed that the coexistence of )-Ph-TRAP on divalent ruthenium ions (Ru) enabled the expression of catalytic activity even under neutral conditions.

[0154] In addition, the acetate ligand (O ２ CMe) with a bulkier pivalate ligand (O ２ C ｔ Bu) and 1-adamantanecarboxylate ligands (O ２ When the catalyst was replaced with ruthenium complex (1), 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.

[0155] Example 14: Ru(O ２ C.A.d. ２ ((R Ｃ , R Ｃ , S Ｐ , S Ｐ )-Ph-trap)-catalyzed low-pressure asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (Equation 28).

[0156]

[0157] Ru(O) prepared in Example 5 ２ C.A.d. ２ ((R Ｃ , R Ｃ , S Ｐ , S ＰAsymmetric hydrogenation of N-Boc-2-phenyl-1H-indole (1.47 g) was carried out using (R)-Ph-trap) (purity: 98.0 wt %, 3.2 mg, 0.05 mol %) as a catalyst at an internal pressure of 1 MPa according to the procedure described in Example 9, yielding 1.475 g of the desired (R)-N-Boc-2-phenylindoline. Reaction time: 6 hours, conversion rate: >99.9% ( 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, i.e., the enantiomer, synthesized in Example 9. Single crystals of this compound could also be prepared in the same manner as for its enantiomer.

[0158] The results of single crystal X-ray structural analysis of (R)-N-Boc-2-phenylindoline synthesized in Example 14 (thermal ellipsoid diagram; atomic probability of 50%) are shown in Figure 8 below. These results clearly demonstrate that this compound is indeed an enantiomer of (S)-N-Boc-2-phenylindoline synthesized in Example 9. Furthermore, the main parameters that ensure the accuracy of these analytical results are as follows: Chemical formula: C １９ H ２１ NO ２ , Crystal system: Rectangular system, Space group: P2 １ 2 １ 2 １ (#19), lattice constant: 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).

[0159] As can be seen from Examples 13 and 14, by carrying out aromatic asymmetric hydrogenation while selectively using both enantiomers of the ruthenium complex (1) of the present invention, it is possible to easily produce both enantiomers of the target optically active cyclic compound. These results clearly demonstrate the practical utility of the ruthenium complex (1) of the present invention in aromatic asymmetric hydrogenation.

[0160] Example 15: Ru(O ２ CMe)２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)-catalyzed asymmetric hydrogenation of methyl N-Boc-1H-indole-2-carboxylate (Equation 29)

[0161]

[0162] [Preparation and reaction] In a borosilicate glass test tube (φ20 mm × 130 mm), Ru(O ２ CMe) ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap) (purity: 92.1 wt%, 2.8 mg, 0.05 mol%) and N-Boc-1H-indole-2-carboxylate methyl (1.38 g, 5.00 mmol, 1.0 equivalent) synthesized according to the method described in Non-Patent Document 8 were sequentially charged, and a magnetic stirrer bar was attached. The test tube was attached to a 50 mL autoclave, the inside of which was replaced with nitrogen, and then dehydrated. ｉ PrOH (14 mL) was added, and then the inside of the apparatus was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60° C. for 2 hours.

[0163] [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. １Analysis by H NMR revealed a conversion rate of >99.9%. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 82 / 18) to obtain 1.357 g of the desired (S)-N-Boc-indoline-2-methyl carboxylate as a white solid. The isolated yield was 97.9%, and the optical purity was 89.7% ee. The NMR analysis results of this compound were consistent with those described in Non-Patent Document 8. The optical purity of this compound was measured under the following conditions: column: CHIRALPAK AD (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).

[0164] Comparative Example 3: Attempt at asymmetric hydrogenation of methyl N-Boc-1H-indole-2-carboxylate using a conventional catalyst

[0165] The conventional catalyst [RuCl(p-cymene)((S Ｃ , S Ｃ , R Ｐ , R Ｐ Asymmetric hydrogenation of methyl N-Boc-1H-indole-2-carboxylate was carried out using methyl N-Boc-1H-indole-2-carboxylate (0.05 mol%) according to the procedure described in Example 15, but the conversion was only 4.1% ( １ by H NMR analysis).

[0166] 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 instead of a conventional catalyst, even indoles having functional groups that are easily decomposed under strongly basic conditions were asymmetrically hydrogenated with high stereoselectivity, and industrially useful optically active cyclic amino acids were quantitatively obtained. 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.

[0167] Example 16: Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , RＰ )-Ph-trap)-catalyzed asymmetric hydrogenation of N-Boc-3-methyl-1H-indole (Equation 30)

[0168]

[0169] [Charge and reaction] N-Boc-3-methyl-1H-indole (purity: 99.6% by weight, 500 mg, 2.15 mmol, 1.0 equivalent) synthesized according to the method described in Non-Patent Document 8 and Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap) (purity: 98.1 wt%, 5.5 mg, 0.2 mol%) was sequentially charged, and a magnetic stirrer bar was further attached. The test tube was attached to a 50 mL autoclave, the inside of which was purged with nitrogen, and then dehydrated. ｉ PrOH (5 mL) was added, and then the inside of the apparatus was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60° C. for 6 hours.

[0170] [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. １ Analysis by H NMR revealed a conversion rate of >99.9%. The 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. The isolated yield was 96.4%, and the optical purity was 81.4% ee. The NMR analysis results of this compound were consistent with those described in Non-Patent Document 8. The optical purity of this compound was measured under the following conditions: column: CHIRALPAK IC-3 (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 min (S-isomer), 15.1 min (R-isomer).

[0171] [Comparative Example 4] Attempt at asymmetric hydrogenation of N-Boc-3-methyl-1H-indole using a conventional catalyst

[0172] The conventional catalyst [RuCl(p-cymene)((S Ｃ , S Ｃ , R Ｐ , R Ｐ Asymmetric hydrogenation of N-Boc-3-methyl-1H-indole was attempted using N-Boc-3-methyl-1H-indole (0.2 mol%) according to the procedure of Example 16, but the conversion was less than 0.1% ( １ by H NMR).

[0173] Example 17: Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)-catalyzed asymmetric hydrogenation of N-Boc-3-phenyl-1H-indole (Equation 31)

[0174]

[0175] [Preparation and reaction] In a borosilicate glass test tube (φ20 mm × 130 mm), Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap) (purity: 98.1 wt%, 5.5 mg, 0.4 mol%) 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, and a magnetic stirrer bar was attached. The test tube was attached to a 50 mL autoclave, the inside of which was replaced with nitrogen, and then dehydrated. ｉ PrOH (3 mL) was added, and then the inside of the apparatus was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60° C. for 6 hours.

[0176] [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. １ Analysis by H NMR revealed a conversion rate of >99.9%. The residue was purified by silica gel column chromatography (eluent: n-hexane / toluene = 88 / 12 to 0 / 100) to obtain 313 mg of the target (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).

[0177] The results of single crystal X-ray structural analysis of (S)-N-Boc-3-phenylindoline synthesized in Example 17 (thermal vibration ellipsoid diagram; atomic existence probability 50%) are shown in Figure 9 below. 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. In addition, the main parameters that ensure the accuracy of these analytical results were as follows; chemical formula: C １９ H ２１ NO ２ , Crystal system: Rectangular system, Space group: P2 １ 2 １ 2 １ (#19), lattice constant: 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).

[0178] [Comparative Example 5] Attempt at asymmetric hydrogenation of N-Boc-3-phenyl-1H-indole using a conventional catalyst

[0179] The conventional catalyst [RuCl(p-cymene)((S Ｃ , S Ｃ , R Ｐ , R Ｐ Asymmetric hydrogenation of N-Boc-3-phenyl-1H-indole was attempted using 2-Ph-trap)]Cl (0.4 mol %) according to the procedure described in Example 17, but the conversion was less than 0.1% ( １ by H NMR).

[0180] Example 18: Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)-catalyzed asymmetric hydrogenation of 2,4-diphenyloxazole (Equation 32)

[0181]

[0182] [Preparation and reaction] In a borosilicate glass test tube (φ20 mm × 130 mm), Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap) (purity: 98.1 wt%, 2.9 mg, 0.2 mol%) and commercially available 2,4-diphenyloxazole (250 mg, 1.13 mmol, 1.0 equivalent) were sequentially charged, and a magnetic stirrer bar was attached. The test tube was then placed in a 50 mL autoclave, the inside of which was replaced with nitrogen, and the autoclave was dehydrated. ｉ PrOH (2.5 mL) was added, and then the inside of the apparatus was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 80° C. for 6 hours.

[0183] [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.１ Analysis by H NMR revealed a conversion rate of 98.9%. The 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. The isolated yield was 97.9%, and the optical purity was 97.5% ee. The NMR analysis results of this compound were consistent with the data described in Non-Patent Document 3. The optical purity of this compound was measured under the following conditions: column: CHIRALPAK IC-3 (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).

[0184] [Comparative Example 6] Attempt at asymmetric hydrogenation of 2,4-diphenyloxazole using a conventional catalyst

[0185] The conventional catalyst [RuCl(p-cymene)((S Ｃ , S Ｃ , R Ｐ , R Ｐ Asymmetric hydrogenation of 2,4-diphenyloxazole was attempted using 2,4-diphenyloxazole (0.2 mol%) according to the procedure described in Example 18, but the conversion was less than 0.1% ( １ by H NMR).

[0186] Example 19: Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)-catalyzed asymmetric hydrogenation of 2,5-diphenyloxazole (Equation 33)

[0187]

[0188] [Preparation and reaction] In a borosilicate glass test tube (20 mmφ×130 mm), Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , RＰ )-Ph-trap) (purity: 98.1 wt%, 2.9 mg, 0.2 mol%) and commercially available 2,5-diphenyloxazole (250 mg, 1.13 mmol, 1.0 equivalent) were sequentially charged, and a magnetic stirrer bar was attached. The test tube was then placed in a 50 mL autoclave, the inside of which was replaced with nitrogen, and the autoclave was dehydrated. ｉ PrOH (2.5 mL) was added, and then the inside of the apparatus was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 80° C. for 6 hours.

[0189] [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. １ Analysis by H NMR revealed a conversion rate of >99.9%. The 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. The isolated yield was 98.3%, and the optical purity was 94.7% ee. The NMR analysis results of this compound were consistent with the data described in Non-Patent Document 3. The optical purity of this compound was measured under the following conditions: column: CHIRALPAK IC-3 (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 min (S-isomer), 17.0 min (R-isomer).

[0190] [Comparative Example 7] Attempt at asymmetric hydrogenation of 2,5-diphenyloxazole using a conventional catalyst

[0191] The conventional catalyst [RuCl(p-cymene)((S Ｃ , S Ｃ , R Ｐ , R Ｐ Asymmetric hydrogenation of 2,5-diphenyloxazole was attempted using 2,5-diphenyloxazole (0.2 mol%) according to the procedure described in Example 19, but the conversion was less than 0.1% ( １ by H NMR).

[0192] Example 20: Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap)-catalyzed asymmetric hydrogenation of 1-Boc-4-methyl-2-phenylimidazole (Equation 34)

[0193]

[0194] [Charge and reaction] In a borosilicate glass test tube (φ20 mm × 130 mm), 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 C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap) (purity: 98.1 wt%, 15.0 mg, 1.0 mol%) was sequentially charged, and a magnetic stirrer bar was further attached. The test tube was attached to a 50 mL autoclave, the inside of which was replaced with nitrogen, and then dehydrated. ｉ PrOH (3 mL) was added, and then the inside of the apparatus was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60° C. for 6 hours.

[0195] [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. １Analysis by H NMR revealed a conversion rate of 93.8%. The 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. The isolated yield was 75.1%, and the optical purity was 97.3% ee. The NMR analysis results of this compound were consistent with the data described in Non-Patent Document 3. The optical purity of this compound was measured under the following conditions: column: CHIRALPAK IC-3 (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).

[0196] [Comparative Example 8] Attempt at asymmetric hydrogenation of 1-Boc-4-methyl-2-phenylimidazole using a conventional catalyst

[0197] 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 20, the asymmetric hydrogenation of 1-Boc-4-methyl-2-phenylimidazole was attempted. However, it was found that in this reaction system the substrate decomposed while the Boc group dissociated.

[0198] Example 21: Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ )-Ph-trap) catalyzed asymmetric hydrogenation of diisobutyl naphthalene-2,6-dicarboxylate (Equation 35)

[0199]

[0200] [Preparation and reaction] In a borosilicate glass test tube (φ20 mm × 130 mm), Ru(O ２ C.A.d. ２ ((S Ｃ , SＣ , R Ｐ , R Ｐ )-Ph-trap) (purity: 98.1 wt%, 11.7 mg, 1.0 mol%) 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, and a magnetic stirrer bar was attached. The test tube was attached to a 50 mL autoclave, the inside of which was replaced with nitrogen, and then dehydrated. ｉ PrOH (4.5 mL) was added, and then the inside of the apparatus was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60° C. for 6 hours.

[0201] [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. １ Analysis by H NMR revealed a conversion rate of 99.1%. The 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. The isolated yield was 93.4%, and the optical purity was 73.2% ee. The NMR analysis results of this compound were consistent with the data described in Non-Patent Document 9. The optical purity of this compound was measured under the following conditions: column: CHIRALPAK IC-3 (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).

[0202] [Comparative Example 9] Attempt at asymmetric hydrogenation of diisobutyl naphthalene-2,6-dicarboxylate using a conventional catalyst

[0203] The conventional catalyst [RuCl(p-cymene)((S Ｃ , S Ｃ , R Ｐ , R ＰAsymmetric hydrogenation of diisobutyl naphthalene-2,6-dicarboxylate was attempted using 1.0 mol% of diisobutyl naphthalene-2,6-dicarboxylate according to the procedure described in Example 21, but the conversion was less than 0.1% ( １ by H NMR).

[0204] The results for each substrate in Examples 16 to 21 and Comparative Examples 4 to 9 are summarized in Table 2 below. For reference, the steric structural formula of the catalyst used in these Examples and Comparative Examples is shown in Formula 36 below.

[0205]

[0206]

[0207] As can be seen from the results summarized in Table 2, the particularly preferred form of the ruthenium complex (1) of the present invention, Ru(O ２ C.A.d. ２ ((S Ｃ , S Ｃ , R Ｐ , R Ｐ When [RuCl(p-cymene)((S)-Ph-trap] 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, the conventional catalyst [RuCl(p-cymene)((S)-Ph-trap] was used as a catalyst. Ｃ , S Ｃ , R Ｐ , R Ｐ It was found that when [(Ph-trap)]Cl was used, the reaction did not proceed without the addition of a base, and some of the 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 applicability.

[0208] The ruthenium complex (1) of the present invention is R ＰIt can be easily produced by reacting .GAMMA.-TRAP (2) with a ruthenium source (3). Its preferred form has excellent crystallinity, allowing for easy isolation and purification, and long-term storage. It also 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.

Claims

1. A ruthenium-diphosphine-carboxylate complex represented by the following general formula (1): [wherein, 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-electron donation of 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 claim 1, which is an optically active substance.

3. R Ｐ 3. The ruthenium-diphosphine-carboxylate complex according to claim 1, wherein is an aryl group which may have a substituent.

4. R Ｃ The ruthenium-diphosphine-carboxylate complex according to any one of claims 1 to 3, wherein is selected from the group consisting of alkyl groups and cycloalkyl groups.

5. The following general formula (2): [wherein, the solid line represents a single bond; H represents a hydrogen atom, C represents a carbon atom, 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-electron donation of 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, 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.

6. The method according to claim 5, wherein the diphosphine compound represented by formula (2) is an optically active compound.

7. R in general formula (2) Ｐ The method according to claim 5 or 6, wherein is an aryl group which may have a substituent.

8. R in general formula (3) Ｃ The method according to any one of claims 5 to 7, wherein is selected from the group consisting of alkyl groups and cycloalkyl groups.

9. The production method according to 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.

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