A method for the asymmetric hydrogenation of 2,5-disubstituted cyclopentanones and derivatives thereof catalyzed by nickel

Abstract

This invention relates to the field of chemical synthesis technology, specifically disclosing a nickel-catalyzed study of the chemoselectivity and stereoselectivity of multi-reduction-site conjugated enone hydrogenation, and the preparation of monochiral α-unsaturated ketones, α,β-bichiral ketones, and α,β-bichiral alcohol derivatives by this method. This invention uses 2,5-disubstituted cyclopentanones and their derivatives with different molecular structures as substrates for hydrogenation to construct chiral ketones and chiral alcohols. The catalyst preparation method is simple, the performance is stable, and it can achieve good chiral selectivity and conversion. The metal catalyst consists of a nickel complex and a diphosphorus chiral ligand (…). S The method provided by this invention is characterized by high chemoselectivity, enantioselectivity, and high yield. This method can synthesize various substituted chiral ketones and chiral alcohols, which can serve as important intermediates for the preparation of various drugs, and are of great significance to the pharmaceutical industry.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a method for constructing chiral 2,5-disubstituted cyclopentanone and its derivatives by nickel-catalyzed asymmetric hydrogenation, and the chiral ketone derivatives prepared by this method. Background Technology

[0002] 2,5-Disubstituted chiral cyclopentanones and their derivatives are core structural units of certain bioactive molecules, such as cyclopentanone A with antischistosome activity and cyclopentanol B as a plant growth inhibitor, as well as some chiral ligands with a cyclohexylspirocyclic skeleton:

[0003]

[0004] Because chiral carboxylic acids and their derivatives have great industrial value in pharmaceuticals and other fields, people have conducted in-depth research on their synthetic methods and developed many synthetic routes. Among them, the asymmetric reduction of prochiral 2,5-disubstituted chiral cyclopentanones and their derivatives is one of them. However, to date, no simple and efficient nickel-catalyzed non-equivalent reduction method has been applied to the asymmetric reduction of 2,5-disubstituted chiral cyclopentanols and their derivatives. Summary of the Invention

[0005] To address the limited number of existing technical pathways for chiral 2,5-disubstituted chiral cyclopentanols and their derivatives, the first aspect of this invention provides a method for the asymmetric hydrogenation of α,β-unsaturated 2,5-disubstituted chiral cyclopentanones and their derivatives to construct chiral 2,5-disubstituted chiral cyclopentanone alcohols and their derivatives. The compound shown in formula (I) is asymmetrically hydrogenated under the action of the catalyst Cat to obtain the compound shown in formula (II), as shown in the following reaction formula:

[0006] It is understood that, in order to provide a reaction medium, the reaction also includes the solvent.

[0007] The solvent used in the reaction process is the same as the solvent used for the catalyst, which simplifies the reaction steps.

[0008] The R, R ’ The catalyst is selected from any one of hydrogen, cyclohexyl, methyl, ethyl, tert-butyl, furanyl, thiophene, pyridyl, naphthyl, phenyl, and substituted phenyl groups, wherein the phenyl substituent is selected from one or more independent nitro groups, halogens, C1-C4 haloalkyl groups and C1-C4 alkoxy groups, methyl groups, ethyl groups, and tert-butyl groups; the catalyst Cat is prepared from a nickel compound and a bisphosphine chiral ligand, wherein the bisphosphine chiral ligand has any one of the following structures: .

[0009] It will be understood by those skilled in the art that the nickel compound is obtained by mixing the biphosphorus chiral ligand in a solvent.

[0010] The solvents include methanol, ethanol, dichloromethane, isopropanol, n-hexane, acetonitrile, ethyl acetate, toluene, 1,4-dioxane, trifluoroethanol, hexafluoroisopropanol, tert-butanol, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, difluoroethanol, or cyclohexane, or combinations thereof.

[0011] The above The carbon chiral center is represented by the fact that each of the multiple carbon chiral centers is independently configured in either the R or S configuration.

[0012] The R, R ’ Selected from substituted or unsubstituted monocyclic aryl groups, substituted or unsubstituted branched alkyl groups, and substituted or unsubstituted straight-chain alkyl groups; In some specific embodiments of the first aspect, the R, R ’ It is selected from any one of hydrogen, cyclohexyl, methyl, ethyl, tert-butyl, furanyl, thiophene, pyridyl, naphthyl, phenyl and substituted phenyl, wherein the phenyl substituent is selected from one or more independent nitro, halogen, C1-C4 haloalkyl and C1-C4 alkoxy, methyl, ethyl, tert-butyl; Preferably, the R, R ’ It is any one of hydrogen, methyl, ethyl, alkoxy, tert-butyl, fluorine, chlorine, bromine, and haloalkyl; And / or, the R, R ’ The alkylene ring is 2-methylphenyl, 3-methylphenyl, 3-ethylphenyl, 3-methoxyphenyl, 4-methylphenyl, 4-ethylphenyl, 2,4,6-trimethylphenyl, 2-chlorophenyl, 2-bromophenyl, 2-trifluoromethylphenyl, 3-fluorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 2,6-difluorophenyl; in some specific embodiments of the first aspect, the cyclon n is selected from 1 to 3 straight-chain alkyl groups.

[0013] As a preferred embodiment, n is a straight-chain alkyl group of 1 to 3, with the structure shown below: .

[0014] R, R' is any one of hydrogen, cyclohexyl, methyl, ethyl, tert-butyl, furanyl, thiophene, pyridyl, naphthyl, phenyl, and substituted phenyl, wherein the phenyl substituent is selected from one or more independent nitro, halogen, C1-C4 haloalkyl and C1-C4 alkoxy, methyl, ethyl, tert-butyl.

[0015] In the aforementioned raw materials, the 2,5-disubstituted cyclopentanone and its derivatives have one of the following structures:

[0016]

[0017] .

[0018] In some specific embodiments of the first aspect, the nickel complex includes any one of Ni(OAc)2·4H2O, Ni(OAc)2, NiCl2(DME), NiBr2(DME), Ni(OTf)2, Ni(acac)2, Ni(OCOCF3)2·6H2O, and NiI2.

[0019] In some specific embodiments of the first aspect, the metal catalyst is prepared by reacting the nickel complex with the diphosphorus chiral ligand in the solvent Solvent at room temperature for 0.5 to 12 hours.

[0020] In some specific embodiments of the first aspect, the molar ratio of the nickel complex to the diphosphorus chiral ligand is 1.0:1.0-1.2.

[0021] In some specific embodiments of the first aspect, the solvent Solvent is methanol, ethanol, isopropanol, tert-butanol, dichloromethane, toluene, acetonitrile, ethyl acetate, trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, n-hexane or cyclohexane, or a combination thereof.

[0022] In some specific embodiments of the first aspect, the reaction temperature of the asymmetric reduction is 0 ℃ to 50 ℃, and in some preferred embodiments of the first aspect, the reaction temperature of the asymmetric reduction is below 50 ℃.

[0023] In some specific embodiments of the first aspect, the reaction time of the asymmetric reduction is 1 h to 48 h, and in some preferred embodiments of the first aspect, the reaction time of the asymmetric reduction is 48 h.

[0024] In some specific embodiments of the first aspect, the asymmetric reduction is carried out in a hydrogen atmosphere at a pressure of 45 to 55 atmospheres.

[0025] In this invention: "mol%" indicates the molar percentage of the substance relative to 2,5-disubstituted cyclopentanone.

[0026] "S / C" indicates the ratio of substrate to catalyst.

[0027] "Room temperature" in some embodiments represents 40°C to 10°C, in some embodiments it represents 35°C to 15°C, in some embodiments it represents 30°C to 20°C, in some embodiments it represents 25°C to 20°C, and in other embodiments it represents 25°C.

[0028] In this invention, DMF is N,N-dimethylformamide, EA is ethyl acetate, THF is tetrahydrofuran, Hexane is n-hexane, Toluene is toluene, TFE is trifluoroethanol, and HFIP is hexafluoroisopropanol.

[0029] The advantages of this invention are as follows: This invention uses 2,5-disubstituted cyclopentanones and their derivatives with different molecular structures as substrates to construct chiral cyclopentanol derivatives by hydrogenation. The catalysts used in the method are simple to prepare and have stable performance. Even with a high substrate / catalyst ratio, good chiral selectivity and conversion rate can still be obtained. Detailed Implementation

[0030] Through the detailed description of the embodiments of the present invention below, those skilled in the art will gain a clearer and more thorough understanding of the further features, advantages and effects of the present invention.

[0031] Example 1: Ligand screening: Step 1: Under a high-purity nitrogen atmosphere, Ni(OAc)₂ (2.0 × 10⁻⁶) -3 mmol) and ligand 2.2 × 10 -3 mmol was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a catalyst solution.

[0032] Step 2: Add 1 mL of the solution to compound 1a (0.2 mmol), place the reaction system in an autoclave, and stir for 48 hours at 50 °C and H2 (50 bar).

[0033] Step 3: Remove solvent under reduced pressure, then separate by column chromatography (using silica gel column, eluent: petroleum ether: ethyl acetate = 10:1) to obtain product 4d. The product is analyzed by HPLC, and the ee value is determined. Ligand screening table 1 is obtained: HPLC separation conditions: chiral IB-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃.

[0034] Table 1: Ligand and Metal Screening Table

[0035]

[0036] Example 1 shows that, for the Ni / Ligand catalytic system, under the same substrate / catalyst ratio, reaction temperature, and hydrogen pressure, different bisphosphine chiral catalysts produce different enantiomeric amounts, Ni(OTf)2 / ( S Binapine can achieve better results.

[0037] Example 2 Solvent Screening: Step 1: Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) -3 mmol) and ligands ( S )-Binapine(2.2×10 -3 The catalyst solution was obtained by dissolving mmol) in 1.0 mL of Solvent (as shown in Table 2) and stirring at room temperature for 12 hours.

[0038] Step 2: Add 1.0 mL of catalyst solution to compound 1a (0.2 mmol), place the reaction system in an autoclave, and stir for 48 hours at 50 °C and H2 (50 bar).

[0039] Step 3: Remove solvent under reduced pressure, then separate by column chromatography (using silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to obtain product 1d. The product is analyzed by HPLC, and the ee value is determined. Solvent screening table 2 is obtained. HPLC separation conditions: chiral IB-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃.

[0040] Table 2: Solvent Screening Table

[0041]

[0042] As can be seen from Example 2, for the use of Ni(OTf)2 / ( S In the )-Binapine catalytic system, under the same substrate / catalyst ratio, reaction temperature, and hydrogen pressure, different solvents produce different product ratios and enantiomeric amounts, with TFE yielding better results.

[0043] Example 3: Additive Screening Step 1: Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) -3 mmol) and ligands ( S )-Binapine(2.2×10 -3Dissolve mmol) in 1.0 mL TFE and stir at room temperature for 12 hours to obtain a catalyst solution.

[0044] Step 2: Take 1.0 mL of catalyst solution and the additives shown in Table 3 and add them to compound 1a (0.2 mmol). Place the reaction system in an autoclave and stir for 48 hours at 50 °C and H2 (50 bar).

[0045] Step 3: Remove solvent under reduced pressure, then separate by column chromatography (using silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to obtain product 1d. The product is analyzed by HPLC, and the ee value is determined. Solvent screening table 3 is obtained. HPLC separation conditions: chiral IB-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃.

[0046] Table 3: Additive Screening Table

[0047]

[0048] Example 3 shows that for the use of Ni(OTf)2 / ( S In the )-Binapine catalytic system, under the same substrate / catalyst ratio / solvent, reaction temperature and hydrogen pressure, different additives produce different product ratios and enantiomeric amounts, with 4A MS and NaOAc yielding better results.

[0049] Example 4: Ni(OTf)2 / ( S Suitability of )-Binapine catalysts Step 1: Under a high-purity nitrogen atmosphere, Ni(OTf)2 / ( S )-Binapine was dissolved in 1.0 mL of TFE and stirred at room temperature for 12 hours to obtain a light yellow solution.

[0050] Step 2: Add 1.0 mL of the clear solution to compounds 1a-1z (0.1 mmol). Place the reaction system in an autoclave and stir for 48 hours at 50 °C and H2 (50 bar).

[0051] Step 3: Remove the solvent under reduced pressure, and separate by column chromatography (using a silica gel column, with petroleum ether: ethyl acetate = 10:1 as the eluent) to obtain products 4a~4z. The products are analyzed by HPLC, and the ee values ​​of 4a~4z are measured respectively.

[0052]

[0053] [a] Reaction conditions: 0.1 mmol substrate, 0.002 mmol Ni(OTf)2 / (S)-Binapine, 4A molecular sieve (10 mol%), 1.0 mL TFE. The catalyst was pre-complexed in TFE. Yields were determined by separation yield, ee value, and trans:cis ratio by HPLC analysis.

[0054] [b] 0.1 mmol substrate, 0.002 mmol Ni(OTf)2 / (S)-Binapine, CH3COONa (10 mol%), 1.0 mL TFE.

[0055] Ni(OTf)2 / ( S The )-Binapine catalyst exhibits varying applicability to different substrates, as shown above. Substrates 1a~1z, various triconjugated enones, after asymmetric hydrogenation, yielded 4a~4z with good yields and enantioselectivity. Ni(OTf)2 / ( S The )-Binapine catalyst is tolerant to different electronic properties (electron neutral, electron-rich, and electron-deficient) on the phenyl group and has good effects on different substituents of the phenyl group.

[0056] Example 5: Asymmetric reduction of 2,5-di((E)-benzylidene)cyclopentan-1-one

[0057] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0058] 1.0 ml of the catalyst was added to compound 1a (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4a. HPLC analysis showed an ee value of 94% and a yield of 99%. across : this way= 4:1. HPLC separation conditions: chiral IB-H column, mobile phase: n-hexane / isopropanol = 95:5 (v / v), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =13.8 min (major), 17.1 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.30 (dd, j = 7.4,5.2 Hz, 4H), 7.26 – 7.19 (m, 6H), 3.87 (dd, j = 5.5, 3.3 Hz, 1H), 2.95 – 2.89(m, 1H), 2.75 (dd, j = 13.7, 7.3 Hz, 1H), 2.67 – 2.52 (m, 2H), 2.29 – 2.18 (m,2H), 1.98 – 1.90 (m, 1H), 1.74 (dt, j = 11.9, 3.6 Hz, 1H), 1.58 – 1.48 (m, 1H), 1.35 – 1.19 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 141.7, 140.9, 128.8, 128.8, 128.7, 128.3, 125.9, 125.7, 78.7, 49.5, 45.4, 40.7, 35.3, 29.0, 28.8. Example 6: Asymmetric reduction of 2,5-bis((E)-2-methylbenzylidene)cyclopentan-1-one

[0059] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0060] 1.0 ml of the catalyst was added to compound 1b (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4b. HPLC analysis showed an ee value of 97% and a yield of 94%. across : this way = 20:1. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =40.6 min (major), 52.2 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.22 – 7.10 (m,8H), 3.90 (dd, j = 5.4, 3.3 Hz, 1H), 2.93 (dd, j = 13.9, 6.3 Hz, 1H), 2.71 (dd, j =14.0, 7.7 Hz, 1H), 2.64 – 2.53 (m, 2H), 2.36 – 2.32 (m, 6H), 2.29 – 2.20 (m,2H), 2.08 – 1.95 (m, 1H), 1.81 – 1.71 (m, 1H), 1.61 – 1.51 (m, 1H), 1.32 –1.22 (m, 1H). 13 C NMR(101 MHz, CDCl3) δ 139.9, 139.2, 136.1, 136.0, 130.3,130.2, 129.2, 129.2, 126.0, 125.8, 125.8, 79.0, 48.1, 43.9, 38.0, 32.2, 29.3,28.8, 19.5, 19.5. Example 7: Asymmetric reduction of 2,5-bis((E)-3-methylbenzylidene)cyclopentan-1-one

[0061] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands (S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0062] 1.0 ml of the catalyst was added to compound 1c (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1 as the developing solvent) to obtain product 4c. HPLC analysis showed an ee value of 93% and a yield of 96%. across : this way = 4:1. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 95:5 (v / v), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =8.6 min (major), 11.3 min (minor). 1 H NMR (600 MHz, CDCl3) δ 7.24 (t, J = 7.4 Hz,2H), 7.10 – 7.04 (m, 6H), 3.91 (t, J = 4.4 Hz, 1H), 2.93 – 2.89 (m, 1H), 2.75(dd, J = 13.6, 7.4 Hz, 1H), 2.66 – 2.53 (m, 2H), 2.42 – 2.38 (m, 7H), 2.30 –2.24 (m, 2H), 2.01 – 1.95 (m, 1H), 1.82 – 1.74 (m, 1H), 1.60 – 1.53 (m, 1H),1.39 – 1.25 (m, 2H). 13 C NMR(151 MHz, CDCl3) δ 141.6, 140.9, 137.8, 129.6,129.5, 128.2, 128.2, 126.6, 126.6, 126.5, 125.8, 125.7, 78.7, 49.3, 45.2,40.6, 35.1, 29.0, 28.8, 21.4, 21.4. Example 8: Asymmetric reduction of 2,5-bis((E)-3-ethylbenzylidene)cyclopentan-1-one

[0063] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0064] 1.0 ml of the catalyst was added to compound 1d (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4d. HPLC analysis showed an ee value of 86% and a yield of 96%. across : this way = 3:1. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 98:2 (volume ratio), flow rate: 1.2 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =9.6 min (major), 14.5 min (minor). 1 H NMR (600 MHz, CDCl3) δ 7.20 (q, J = 7.5 Hz,2H), 7.07 – 6.99 (m, 6H), 3.86 (dd, J = 5.4, 3.3 Hz, 1H), 2.88 – 2.85 (m, 1H), 2.70 (dd, J = 13.7, 7.4 Hz, 1H), 2.66 – 2.60 (m, 5H), 2.58 – 2.50 (m, 2H), 2.26 – 2.19 (m, 2H), 2.07 – 2.02 (m, 1H), 1.96 – 1.91 (m, 1H), 1.77 – 1.69 (m,1H), 1.55 – 1.48 (m, 1H), 1.34 – 1.22 (m, 9H). 13C NMR (151 MHz, CDCl3) δ 144.4,144.3, 141.7, 141.0, 128.4, 128.3, 128.3, 128.3, 126.1, 126.0, 125.4, 125.3,78.8, 49.5, 45.3, 40.7, 35.2, 29.1, 28.9, 28.8, 28.8, 28.8, 15.6. Example 9: Asymmetric reduction of 2,5-bis((E)-3-methoxybenzylidene)cyclopentan-1-one

[0065] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0066] 1.0 ml of the catalyst was added to compound 1e (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4e. HPLC analysis showed an ee value of 96% and a yield of 94%. across : this way = 4:1. HPLC separation conditions: chiral IC-H column, mobile phase: n-hexane / isopropanol = 97:3 (v / v), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =12.8 min (major), 15.0 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.22 – 7.09 (m,4H), 6.96 – 6.77 (m, 4H), 3.84 (d, J = 8.4 Hz, 4H), 3.68 (s, 2H), 3.62 (d, J=4.2 Hz, 1H), 2.96 – 2.84 (m, 1H), 2.66 – 2.56 (m, 2H), 2.42 (dd, J = 13.8, 8.2Hz, 1H), 2.32 (p, J = 7.7 Hz, 1H), 2.18 – 2.07 (m, 1H), 2.01 – 1.93 (m, 1H), 1.82 – 1.74 (m, 1H), 1.65 – 1.55 (m, 1H), 1.27 (qt, J = 8.4, 4.8 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 157.5, 156.7, 130.8, 130.2, 127.0, 126.9, 121.1, 120.2,120.4, 110.6, 110.3, 110.1, 77.6, 55.5, 55.0, 46.9, 46.2, 34.7, 29.4, 29.1,28.9. Example 10: Asymmetric reduction of 2,5-bis((E)-4-ethylbenzylidene)cyclopentan-1-one

[0067] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0068] 1.0 ml of the catalyst was added to compound 1f (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4f. HPLC analysis showed an ee value of 90% and a yield of 92%. across : this way = 4:1. HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 95:5 (v / v), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: tR =7.3 min (major), 9.0 min (minor). 1 H NMR (600 MHz, CDCl3) δ 7.16 – 7.10 (m, 8H), 3.86 (dd, J = 5.4, 3.4 Hz, 1H), 2.88 – 2.84 (m, 1H), 2.72 – 2.49 (m, 7H), 2.24 – 2.18 (m, 2H), 1.96 – 1.90 (m, 1H), 1.78 – 1.69 (m, 1H), 1.54 – 1.47 (m,1H), 1.36 – 1.19 (m, 9H). 13 C NMR(151 MHz, CDCl3) δ 141.7, 141.6, 138.8, 138.2,128.7, 128.6, 127.9, 127.8, 78.8, 49.4, 45.3, 40.3, 34.8, 29.1, 28.9, 28.4,28.4, 15.6, 15.5. Example 11: Asymmetric reduction of 2,5-bis((E)-2,4,6-trimethylbenzylidene)cyclopentan-1-one

[0069] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0070] 1.0 ml of the catalyst was added to 1 g (0.1 mmol) of the compound, followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred for 48 hours at 50 °C and H2 (50 bar). The solvent was removed under reduced pressure, and the mixture was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1 as the developing solvent) to obtain 4 g of the product. HPLC analysis showed an ee value of 95% and a yield of 86%. across : this way= 3:1. HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 98:2 (v / v), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =15.8 min (major), 18.4 min (minor). 1 H NMR (400 MHz, CDCl3) δ 6.88 (d, J = 5.0 Hz, 4H), 3.90 (dd, J = 5.0, 3.1 Hz, 1H), 2.90 (dd, J = 13.8, 4.8 Hz, 1H), 2.75 – 2.59(m, 3H), 2.37 – 2.17 (m, 21H), 2.06 – 1.98 (m, 1H), 1.76 – 1.68 (m, 1H), 1.32– 1.21 (m, 2H). 13 C NMR(101 MHz, CDCl3) δ 136.3, 136.2, 135.7, 135.1, 134.8,134.8, 129.1, 129.0, 79.4, 48.1, 44.4, 33.9, 29.4, 28.6, 27.8, 20.7, 20.4,20.3. Example 12: Asymmetric reduction of 2,5-bis((E)-2-chlorobenzylidene)cyclopentan-1-one

[0071] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0072] 1.0 ml of the catalyst (0.1 mmol) was added to the compound for 1 h, followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 h. The solvent was removed under reduced pressure, and the mixture was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain the product for 4 h. The product was analyzed by HPLC, and the ee value was found to be 98%, with a yield of 96%. across : this way = 5:1. HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 90:10 (v / v), flow rate: 2.0 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =3.2 min (major), 3.7 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.37 – 7.32 (m, 2H), 7.30 – 7.25 (m, 1H), 7.24 – 7.11 (m, 5H), 3.86 (dd, J = 5.2, 2.9 Hz, 1H), 3.07– 3.02 (m, 1H), 2.86 – 2.72 (m, 2H), 2.64 (dd, J = 14.0, 8.1 Hz, 1H), 2.40 –2.29 (m, 2H), 2.02 – 1.93 (m, 1H), 1.74 – 1.70 (m, 1H), 1.62 – 1.52 (m, 2H),1.33 – 1.28 (m, 1H). 13 C NMR(101 MHz, CDCl3) δ 139.3, 138.6, 134.1, 133.9,131.0, 130.7, 129.5 129.5, 127.4, 127.2, 126.7, 126.6, 78.4, 47.9, 43.6,38.0, 32.7, 28.9, 28.5. Example 13: Asymmetric reduction of 2,5-bis((E)-2-bromobenzylidene)cyclopentan-1-one

[0073] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0074] 1.0 ml of the catalyst was added to compound 1i (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1 as the developing solvent) to obtain product 4i. HPLC analysis showed an ee value of 96% and a yield of 91%. across : this way = 5:1. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 95:5 (v / v), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =9.2 min (major), 11.0 min (minor). H NMR (400 MHz, CDCl3) δ 7.54 (t, J = 8.6 Hz, 2H), 7.29 (dd, J = 7.6, 1.8 Hz, 1H), 7.24 – 7.21 (m, 3H), 7.08 – 7.03 (m, 2H), 3.87 (dd, J = 5.2, 2.9 Hz, 1H), 3.13 – 3.03 (m, 1H), 2.86 – 2.70 (m, 2H), 2.65(dd, J = 13.9, 8.0 Hz, 1H), 2.41 – 2.30 (m, 2H), 2.03 – 1.96 (m, 1H), 1.77 –1.69 (m, 2H), 1.59 – 1.53 (m, 1H), 1.42 – 1.28 (m, 1H). 13 C NMR(101 MHz, CDCl3)δ 141.0, 140.2, 132.8, 132.8, 131.0, 130.8, 127.6, 127.5, 127.3, 127.3,124.7, 124.6, 78.3, 48.1, 43.7, 40.5, 35.2, 28.9, 28.5. Example 14: Asymmetric reduction of 2,5-bis((E)-3-(trifluoromethyl)benzylidene)cyclopentan-1-one

[0075] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0076] 1.0 ml of the catalyst was added to compound 1j (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4j. HPLC analysis showed an ee value of 88% and a yield of 93%. across : this way = 2:1. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 98:2 (volume ratio), flow rate 1.2 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =9.9 min (major), 8.6 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.50 – 7.36 (m, 8H), 3.84 (dd, J = 5.5, 3.3 Hz, 1H), 3.06 – 2.96 (m, 1H), 2.81 (dd, J = 13.8, 7.1 Hz, 1H), 2.67 (dd, J = 13.7, 8.4 Hz, 1H), 2.60 – 2.54 (m, 1H), 2.27 – 2.18 (m, 1H), 2.11 – 2.01 (m, 1H), 1.97 – 1.89 (m, 1H), 1.78 – 1.68 (m, 2H), 1.51 (dd, J =9.4, 3.6 Hz, 1H), 1.33 – 1.22 (m, 1H). 13C NMR(151 MHz, CDCl3) δ 142.6, 141.8,141.7, 132.2, 132.2, 132.1, 132.1, 128.8, 128.7, 125.5, 125.5, 125.4, 125.4,125.4, 122.9, 122.9, 122.9, 122.9, 122.8, 78.3, 49.5, 45.2, 40.3, 35.1, 28.9,28.7. Example 15: Asymmetric reduction of 2,5-bis((E)-4-fluorobenzylidene)cyclopentan-1-one

[0077] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0078] 1.0 ml of the catalyst was added to compound 1k (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4k. HPLC analysis showed an ee value of 92% and a yield of 97%. across : this way = 3:1. HPLC separation conditions: chiral IA-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate 1.0 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =30.1 min (major), 33.6 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.19 – 7.10 (m,4H), 7.00 – 6.94 (m, 4H), 3.81 (dd, J = 5.5, 3.3 Hz, 1H), 2.90 – 2.83 (m, 1H), 2.69 (dd, J= 13.8, 7.3 Hz, 1H), 2.60 – 2.45 (m, 2H), 2.21 – 2.08 (m, 2H), 2.05 – 1.86 (m, 2H), 1.70 – 1.66 (m, 1H), 1.53 – 1.43 (m, 1H), 1.24 – 1.13 (m,1H). 13 C NMR(101 MHz, CDCl3) δ 162.4, 160.1, 137.2, 136.5, 130.1, 130.1, 130.0,130.0, 129.9, 115.2, 115.1, 115.0, 114.9, 78.5, 49.7, 45.5, 39.8, 34.4, 28.9,28.8. Example 16: Asymmetric reduction of 2,5-bis((E)-4-chlorobenzylidene)cyclopentan-1-one

[0079] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0080] 1.0 ml of the catalyst was added to compound 1 l (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the mixture was separated by column chromatography (using silica gel plates, with petroleum ether:ethyl acetate = 10:1 as the developing solvent) to obtain product 4 l. HPLC analysis showed an ee value of 86% and a yield of 95%. across : this way = 13:1. HPLC separation conditions: chiral IB-H column, mobile phase: n-hexane / isopropanol = 98:2 (v / v), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =24.5 min (major), 22.6 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.26 – 7.20 (m,4H), 7.11 (dd,J = 8.4, 2.4 Hz, 3H), 7.02 (d, J = 8.1 Hz, 1H), 3.49 (dd, J = 5.9, 3.3 Hz, 1H), 3.17 (dd, J = 13.3, 3.7 Hz, 1H), 2.79 (dt, J = 12.5, 6.0 Hz, 1H),2.56 – 2.43 (m, 2H), 2.34 (dd, J = 13.3, 9.0 Hz, 1H), 1.99 – 1.87 (m, 2H), 1.74 – 1.64 (m, 2H), 1.61 – 1.52 (m, 2H), 1.40 – 1.37 (m, 1H), 1.20 – 1.13 (m, 1H), 0.94 – 0.85 (m, 1H). 13 C NMR(101 MHz, CDCl3) δ 139.6, 139.1, 139.0, 131.6,131.5, 130.6, 130.4, 130.3, 128.3, 128.3, 128.3, 72.9, 47.0, 42.0, 40.4,38.5, 36.9, 35.3, 30.3, 26.4, 25.0, 20.0. Example 17: Asymmetric reduction of 2,6-di((E)-benzylidene)cyclohexan-1-one

[0081] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0082] 1.0 ml of the catalyst was added to compound 1m (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4m. HPLC analysis showed an ee value of 78% and a yield of 93%. across : this way = 3:1. HPLC separation conditions: chiral IA-H column, mobile phase: n-hexane / isopropanol = 99:1 (v / v), flow rate 1.0 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =21.7 min (major), 31.2 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.28 (m,3H), 7.24 – 7.11 (m, 7H), 3.56 (dd, J = 5.8, 3.2 Hz, 1H), 3.22 (dd, J = 13.4, 3.7Hz, 1H), 2.86 – 2.81 (m, 1H), 2.61 – 2.35 (m, 3H), 2.08 – 1.94 (m, 2H), 1.77– 1.56 (m, 3H), 1.43 – 1.40 (m, 1H), 1.24 – 1.18 (m, 1H), 0.99 – 0.81 (m, 1H). 13 C NMR(101 MHz, CDCl3) δ 140.8, 140.7, 129.3, 129.1, 128.2, 128.2, 128.2,125.8, 73.3, 47.0, 42.2, 39.4, 37.7, 30.5, 26.6, 20.1. Example 18: Asymmetric reduction of 2,6-bis((E)-4-(tert-butyl)benzylidene)cyclohexan-1-one

[0083] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0084] 1.0 ml of the catalyst was added to compound 1n (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1 as the developing solvent) to obtain product 4n. HPLC analysis showed an ee value of 93%, indicating a yield of 90%. across : this way = 20:1. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 95:5 (v / v), flow rate 1.0 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R = 7.5min (major), 6.9min (minor). 1 H NMR(400 MHz, CDCl3) δ 7.35 – 7.28 (m, 4H),7.17 – 7.06 (m, 4H), 3.60 (dd, J = 5.7, 3.3 Hz, 1H), 2.86 – 2.78 (m, 2H), 2.60 – 2.46 (m, 2H), 2.11 – 1.96 (m, 2H), 1.78 – 1.57 (m, 3H), 1.37 – 1.33 (m, 20H), 1.12 – 0.91 (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 148.6, 148.5, 148.5,138.1, 137.7, 137.7, 129.0, 128.8, 128.7, 125.1, 125.1, 125.1, 78.9, 46.9,39.0, 37.2, 34.3, 31.4, 31.4, 30.6, 26.6, 20.2. Example 19: Asymmetric reduction of 2,6-bis((E)-2-chlorobenzylidene)cyclohexan-1-one

[0085] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands (S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0086] 1.0 ml of the catalyst was added to compound 1o (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4o. HPLC analysis showed an ee value of 89% and a yield of 96%. across : this way = 4:1. HPLC separation conditions: chiral IA-H column, mobile phase: n-hexane / isopropanol = 99:1 (v / v), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =32.0 min (major), 25.7 min (minor). 1 H NMR(600 MHz, CDCl3) δ 7.37 – 7.30 (m,2H), 7.23 – 7.06 (m, 6H), 3.55 (dd, J = 5.1, 3.1 Hz, 1H), 2.96 – 2.91 (m, 1H), 2.74 – 2.63 m, 2H), 2.18 – 2.07 (m, 2H), 1.77 – 1.54 (m, 4H), 1.46 – 1.39 (m, 1H), 1.30 – 1.25 (m, 1H), 1.05 – 0.99 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 138.8,138.5, 134.1, 134.1, 131.7, 131.6, 131.3, 129.5, 127.3, 127.3, 126.5, 126.4,79.4, 46.0, 40.6, 36.9, 35.0, 30.4, 26.4, 20.4. Example 20: Asymmetric reduction of 2,6-bis((E)-2-(trifluoromethyl)benzylidene)cyclohexan-1-one

[0087] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0088] 1.0 ml of the catalyst was added to compound 1p (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1 as the developing solvent) to obtain product 4p. HPLC analysis showed an ee value of 96% and a yield of 95%. across : this way = 9:1. HPLC separation conditions: chiral IA-H column, mobile phase: n-hexane / isopropanol = 98:2 (v / v), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =20.0 min (major), 25.4 min (minor). 1 H NMR(400 MHz, CDCl3) δ 7.67 – 7.60 (m,2H), 7.45 (q, J = 7.2 Hz, 1H), 7.39 – 7.25 (m, 4H), 7.18 (d, J = 7.7 Hz, 1H), 3.66 (dd, J = 5.2, 3.1 Hz, 1H), 3.05 – 2.95 (m, 1H), 2.78 (dd, J = 14.2, 8.4 Hz, 1H), 2.69 (dd, J = 14.2, 8.4 Hz, 1H), 2.11 – 2.03 (m, 1H), 1.77 – 1.65 (m, 2H), 1.54 – 1.38 (m, 4H), 1.36 – 1.25 (m, 1H), 1.07 – 0.98 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 139.9, 139.7, 139.6, 139.6, 132.1, 131.7, 131.5, 131.4, 131.4,131.3, 131.3, 126.2, 126.2, 126.2, 126.2, 126.0, 126.0, 125.9, 79.8, 47.0,41.7, 35.7, 33.8, 30.3, 26.2, 20.2. Example 21: Asymmetric reduction of 2,6-bis((E)-3-chlorobenzylidene)cyclohexan-1-one

[0089] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0090] 1.0 ml of the catalyst was added to compound 1q (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred at 50 °C and H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4q. HPLC analysis showed an ee value of 96% and a yield of 84%. across : this way = 3:1. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 97:3 (v / v), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =22.3 min (major), 32.6 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.23 – 7.12 (m,6H), 7.06 (dd, J = 7.0, 1.7 Hz, 1H), 6.98 – 6.96 (m, 1H), 3.49 (dd, J = 5.9, 3.4Hz, 1H), 3.19 (dd, J= 13.3, 3.6 Hz, 1H), 2.80 (dd, J = 13.5, 6.2 Hz, 1H), 2.56 –2.43 (m, 2H), 2.33 (dd, J = 13.3, 9.1 Hz, 1H), 2.01 – 1.89 (m, 1H), 1.75 – 1.65(m, 1H), 1.62 – 1.51 (m, 3H), 1.41 – 1.36 (m, 1H), 1.21 – 1.14 (m, 1H), 0.96– 0.84 (m, 1H). 13 C NMR(101 MHz, CDCl3) δ 143.2, 142.8, 134.0, 129.5, 129.4,129.4, 129.4, 129.1, 127.5, 127.2, 126.1, 126.0, 46.9, 41.9, 38.9, 37.3,30.3, 26.5, 20.0. Example 22: Asymmetric reduction of 2,6-bis((E)-3-(trifluoromethyl)benzylidene)cyclohexan-1-one

[0091] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0092] 1.0 ml of the catalyst was added to compound 1r (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred for 48 hours at 50 °C and H2 (50 bar). The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4r. HPLC analysis showed an ee value of 82% and a yield of 92%. across : this way = 2:1. HPLC separation conditions: chiral OJ-H column, mobile phase: n-hexane / isopropanol = 98:2 (v / v), flow rate 1.0 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R=13.8 min (major), 18.9 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.25 (m,8H), 3.51 (dd, J = 6.0, 3.4 Hz, 1H), 3.29 (dd, J = 13.3, 3.4 Hz, 1H), 2.93 – 2.87(m, 1H), 2.65 – 2.52 (m, 1H), 2.42 (dd, J = 13.4, 9.1 Hz, 1H), 2.06 – 1.93 (m,1H), 1.76 – 1.59 (m, 3H), 1.53 – 1.36 (m, 3H), 1.22 – 1.14 (m, 1H), 1.09 –0.9(m, 1H). 13 C NMR(101 MHz, CDCl3) δ 142.1, 141.6, 141.5, 132.7, 132.5, 132.4,128.7, 128.6, 128.6, 126.0 125.9, 125.6, 122.8, 122.7, 78.1, 47.0, 42.0,39.0, 37.5, 30.3, 26.5, 20.0. Example 23: Asymmetric reduction of 2,6-bis((E)-4-chlorobenzylidene)cyclohexan-1-one

[0093] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0094] 1.0 ml of the catalyst was added to compound 1s (0.1 mmol), followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred for 48 hours at 50 °C and H2 (50 bar). The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain product 4s. HPLC analysis showed an ee value of 91% and a yield of 93%. across : this way = 16:1. HPLC separation conditions: chiral IA-H column, mobile phase: n-hexane / isopropanol = 99:1 (v / v), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =24.6 min (major), 31.4 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.26 – 7.19 (m,4H), 7.11 (dd, J = 8.4, 2.3 Hz, 3H), 7.03 – 7.01 (m, 1H), 3.49 (dd, J = 5.9, 3.3Hz, 1H), 3.16 (dd, J = 13.3, 3.7 Hz, 1H), 2.81 – 2.75 (m, 1H), 2.55 – 2.43 (m,2H), 2.34 (dd, J = 13.4, 9.0 Hz, 1H), 1.98 – 1.87 (m, 2H), 1.73 – 1.65 (m, 1H), 1.61 – 1.50 (m, 3H), 1.43 – 1.37 (m, 1H), 1.20 – 1.13 (m, 1H), 0.94 – 0.85(m, 1H). 13 C NMR(101 MHz, CDCl3) δ 139.6, 139.0, 130.6, 130.4, 130.3, 128.3,128.3, 128.3, 78.1, 47.0, 42.0, 38.6, 36.9, 30.3, 26.5, 20.0. Example 24: Asymmetric reduction of 2,6-bis((E)-4-(trifluoromethyl)benzylidene)cyclohexan-1-one

[0095] Under a high-purity nitrogen atmosphere, Ni(OTf)₂ (2.0 × 10⁻⁶) was... -3 mmol) and ligands ( S )-Binapine (2.2×10 -3 The catalyst (1 mmol) was dissolved in trifluoroethanol (1.0 mL) and stirred overnight at room temperature to obtain a pale yellow solution (i.e., the catalyst).

[0096] 1.0 ml of the catalyst was added to 1 t (0.1 mmol) of compound, followed by 8.8 mg of 4A MS. The reaction mixture was placed in an autoclave and stirred for 48 hours at 50 °C and H2 (50 bar). The solvent was removed under reduced pressure, and the mixture was separated by column chromatography (silica gel plate, petroleum ether:ethyl acetate = 10:1) to obtain 4 t of product. HPLC analysis showed an ee value of 85% and a yield of 75%. across : this way = 3:1. HPLC separation conditions: chiral IA-H column, mobile phase: n-hexane / isopropanol = 97:3 (v / v), flow rate: 0.5 mL / min, wavelength: 210 nm, column temperature: 30℃, elution time: t R =20.3 min (major), 16.7 min (minor). 1 H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 23.1,7.8 Hz, 4H), 7.31 – 7.27 (m, 3H), 7.19 (d, J = 7.9 Hz, 1H), 3.48 (dd, J = 5.9, 3.3 Hz, 1H), 3.28 (dd, J = 13.3, 3.5 Hz, 1H), 2.92-2.86 (m, 1H), 2.65-2.52 (m,2H), 2.43 (dd, J = 13.3, 9.0 Hz, 1H), 2.06-1.94 (m, 1H), 1.77 – 1.56 (m, 4H), 1.41 (dd, J = 11.2, 6.7 Hz, 1H), 1.23 – 1.16 (m, 1H), 1.08 – 0.91 (m, 1H). 13 CNMR(101 MHz, CDCl3) δ 145.4, 144.9, 144.7, 129.6, 129.3, 129.3, 125.2, 125.2,125.2, 125.1, 125.1, 78.2, 47.0, 42.0, 39.1, 37.5, 30.3, 26.5, 20.0. The above-described embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of this application, and should all be included within the protection scope of this application.

Claims

1. A process for the asymmetric hydrogenation of 2,5-disubstituted cyclopentanones and derivatives thereof catalyzed by nickel, characterized in that, Includes the following steps: The compound shown in formula (Ⅰ) is asymmetrically hydrogenated in the presence of the catalyst Cat to produce the compound shown in formula (Ⅱ), as shown in the following reaction formula: The catalyst Cat is prepared from a nickel compound and a diphosphorus chiral ligand, wherein the diphosphorus chiral ligand is selected from any of the following structural formulas. The above The carbon chiral center is represented by the fact that each of the multiple carbon chiral centers is independently configured in either the R or S configuration.

2. The method according to claim 1, characterized in that, The R is selected from any one of hydrogen, cyclohexyl, methyl, ethyl, tert-butyl, furanyl, thiophene, pyridyl, naphthyl, phenyl and substituted phenyl, wherein the phenyl substituent is selected from one or more independent nitro, halogen, C1-C4 haloalkyl, C1-C4 alkoxy, methyl, ethyl or tert-butyl. R' is selected from any one of hydrogen, cyclohexyl, methyl, ethyl, tert-butyl, furanyl, thiophene, pyridyl, naphthyl, phenyl and substituted phenyl, wherein the phenyl substituent is selected from one or more independent nitro, halogen, C1-C4 haloalkyl, C1-C4 alkoxy, methyl, ethyl, tert-butyl; The alkane is of the range of 1 to 3.

3. The method according to claim 1, characterized in that, R and R' are any one of hydrogen, cyclohexyl, methyl, ethyl, tert-butyl, furanyl, thiophene, pyridyl, naphthyl, phenyl, and substituted phenyl, wherein the phenyl substituent is selected from one or more independent nitro, halogen, C1-C4 haloalkyl, C1-C4 alkoxy, methyl, ethyl, and tert-butyl. In the definition of compound I given above, the terms used, whether alone or in compound terms, represent the following substituents: Halogens: refer to fluorine, chlorine, bromine, and iodine; Alkyl: refers to straight-chain or branched alkyl groups; Halogenated alkyl: refers to straight-chain or branched alkyl groups in which some or all of the hydrogen atoms are replaced by halogen atoms.

4. The method according to any one of claims 1-3, characterized in that, The n is a straight-chain alkyl group of 1-3, with the structure shown below: R and R' are any one of hydrogen, cyclohexyl, methyl, ethyl, tert-butyl, furanyl, thiophene, pyridyl, naphthyl, phenyl, and substituted phenyl, wherein the phenyl substituent is selected from one or more independent nitro groups, halogens, C1-C4 haloalkyl and C1-C4 alkoxy groups, methyl, ethyl, tert-butyl, C1-C4 alkyl, alkyloxy, haloalkyl, and halogens.

5. The method according to claim 1, characterized in that: The 2,5-disubstituted cyclopentanone and its derivatives have one of the following structures: 。 6. The method according to claim 1, characterized in that, The nickel compound includes any one of Ni(OTf)2, Ni(OAc)2, NiCl2(DME), NiBr2(DME), Ni(OAc)2·4H2O, Ni(acac)2, and Ni(OCOCF3)2·6H2O.

7. The method according to claim 1, characterized in that, The metallic catalyst was prepared by reacting the nickel compound with the diphosphorus chiral ligand in the solvent Solvent at room temperature for 0.5-12 hours.

8. The method according to claim 7, characterized in that, The solvent Solvent is methanol, ethanol, dichloromethane, isopropanol, n-hexane, acetonitrile, ethyl acetate, toluene, 1,4-dioxane, trifluoroethanol, hexafluoroisopropanol, tert-butanol, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, difluoroethanol, or cyclohexane, or a combination thereof.

9. The method according to claim 7, characterized in that, The molar ratio of the nickel compound to the diphosphorus chiral ligand is 1.0:1.

1.

10. The method according to claim 1, characterized in that, The reaction temperature of the asymmetric reduction is 30 ℃ to 60 ℃, preferably 50 ℃; and / or, the reaction time of the asymmetric reduction is 1 h to 48 h, preferably 48 h; and / or, the asymmetric reduction is carried out in a hydrogen atmosphere at a pressure of 30 to 80 atm.

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