Method for constructing naphthenic alcohol through asymmetric hydrogenation of tri-substituted ketene under catalysis of nickel

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a method for constructing naphthenic alcohol through asymmetric hydrogenation of tri-substituted ketene under the catalysis of nickel and chiral alcohol prepared through the method. Alpha, beta-unsaturated ketones with different molecular structures are adopted as substrates, hydrogenation is carried out to construct chiral alcohol with a double chiral center, and the chiral alcohol with the double chiral center is obtained. According to the method, alkenyl is firstly subjected to hydrogenation reduction, carbonyl is then subjected to hydrogenation reduction, a good reduction effect can be obtained under the condition that hydrogen on carbon on a conjugated ring is substituted by different substituent groups, the catalyst is simple in preparation mode and stable in performance, and a good chiral selection effect and conversion rate can still be obtained under the condition of a high substrate / catalyst.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a method for constructing a cycloalkanol with two consecutive stereo centers by asymmetric hydrogenation of a trisubstituted enone catalyzed by nickel, and a chiral alcohol prepared by the method. Background Art

[0002] Chiral indanol derivatives are the core structures of various natural products and synthetic bioactive compounds. For example, Caulerpal A and Caulerprenylols B are two new sesquiterpenes isolated from green algae with antifungal activity. Pterosin C is a natural product molecule isolated from Pteris fasciata, used as an antitumor and anti-inflammatory drug. Chiral indole structures such as beztifan, which is used to treat renal cell carcinoma, and donepezil, which is used as an acetylcholinesterase inhibitor.

[0003] Since the asymmetric reduction of α, β-unsaturated ketones has three different results: selective reduction of C=C or C=O, and complete reduction of C=C and C=O. Therefore, it is a major challenge to construct a chiral center in one step by asymmetric reduction of α, β-unsaturated ketones. According to literature research, the asymmetric reduction of α, β-unsaturated ketones is currently mainly concentrated on noble metal catalysis.

[0004] In 2013, Glorius developed a chiral ruthenium-NHC complex to catalyze the asymmetric hydrogenation of 2-substituted flavones and chromones to form enantiomerically enriched flavanones, flavanols, chromanones and chromanols (81:19-99:1 ER, 1.3:1-8.3:1 DR).

[0005]

[0006] In 2016, Zhang Wanbin's research group reported a method for the efficient synthesis of chiral cyclotrans-β-amino alcohols through rhodium-catalyzed one-pot sequential asymmetric hydrogenation of α-dehydroaminoketones with excellent enantioselectivity and diastereoselectivity (89%-99% ee, 3:1-16:1 dr).

[0007]

[0008] In 2022, Zhang Xumu's team reported a dynamic kinetic resolution (DKR) method for the asymmetric sequential hydrogenation of α, β-unsaturated ketones (86%->99% ee, 8:1->20:1dr) catalyzed by Ir / fampha complexes.

[0009]

[0010] Although the research on asymmetric hydrogenation of α, β-unsaturated ketones catalyzed by precious metals is relatively mature, there is only one report on asymmetric hydrogenation of α, β-unsaturated ketones catalyzed by cheap metal nickel. S , S )-Ph-BPE catalyzes the asymmetric hydrogenation of cyclohexadienone derivatives. The selective reduction of olefins is achieved by implementing an asymmetric strategy to achieve a one-step reduction to construct a single chiral center (92%-99% ee).

[0011]

[0012] However, there are no reports on the nickel-catalyzed asymmetric sequential hydrogenation of α,β-unsaturated ketones to construct a chiral center in one step. Summary of the invention

[0013] In view of the problem that there are few technical routes for synthesizing chiral alcohols from α,β-unsaturated ketones in the prior art, and the problem that α,β-unsaturated ketones are prone to selective reduction during the hydrogenation process to construct chiral alcohols, the first aspect of the present invention provides a method for constructing a cycloalkanol having two consecutive stereocenters by asymmetric hydrogenation of trisubstituted ketones catalyzed by nickel, as shown in reaction formula (A):

[0014] The R 1 is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyloxy, haloalkyl, halogen, hydroxyl, amino, nitro, cyano, and aryl; said R 2 is selected from substituted or unsubstituted monocyclic carbocyclic group, substituted or unsubstituted condensed ring carbocyclic group, substituted or unsubstituted spirocyclic group, substituted or unsubstituted bridged ring, substituted or unsubstituted monocyclic heterocyclic group, substituted or unsubstituted condensed ring heterocyclic group, substituted or unsubstituted monocyclic aryl group, substituted or unsubstituted branched alkyl group, substituted or unsubstituted straight chain alkyl group; The catalyst Cat is prepared from a metal nickel compound and a diphosphorus chiral ligand, and the diphosphorus chiral ligand has the structure shown below: , , ,or Any of the following: The ring W is selected from an unsaturated monocyclic carbocyclic group and an unsaturated monocyclic heterocyclic group; The above * represents a carbon chiral center, and the multiple carbon chiral centers are each independently of the other in R configuration or S configuration.

[0015] In some specific embodiments of the first aspect, the R 1is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyloxy, haloalkyl, halogen, hydroxy, amino, nitro, cyano, and aryl; In some specific embodiments of the first aspect, the R 2 It is a heterocyclic fused ring group, wherein R includes two or more fused ring groups in which the first rings are fused to each other; the first ring is selected from a pyrrole group, a furan group, a thiophene group, a pyrrole group, a silole group, an indene group, a benzofuran group, a benzothiophene group, an indole group, and a benzosilole group.

[0016] In some specific embodiments of the first aspect, the R 2 It is a heterocyclic fused ring group, wherein R includes a fused ring group in which at least one first ring is fused to at least one second ring; the first ring is selected from a pyrrole group, a furan group, a thiophene group, a pyrrole group, a thiole group, an indene group, a benzofuran group, a benzothiophene group, an indole group, and a benzothiole group, and the second ring is selected from a cyclohexane group, a cyclopentane group, and a monocyclic aromatic group.

[0017] In some specific embodiments of the first aspect, the R 2 is a fused-ring carbocyclic group, wherein the fused-ring carbocyclic group is a fused-ring group in which two or more second rings are fused to each other; the second ring is selected from a cyclohexane group, a cyclopentane group, and a monocyclic aromatic group.

[0018] In some specific embodiments of the first aspect, the ring W is selected from a 3-10 membered heterocyclic group containing one or more carbon-carbon double bonds.

[0019] In some specific embodiments of the first aspect, the ring W is selected from a 3-10 membered heterocyclic group containing one carbon-carbon double bond and multiple carbon-carbon triple bonds.

[0020] In some specific embodiments of the first aspect, the ring W is selected from a C3-C10 carbocyclic group containing one or more carbon-carbon double bonds.

[0021] In some specific embodiments of the first aspect, the ring W is selected from a C3-C10 carbocyclic group containing one carbon-carbon double bond and multiple carbon-carbon triple bonds.

[0022] In some specific embodiments of the first aspect, the heterocyclic group has 1 to 3 heteroatoms selected from N, O, and S.

[0023] In some specific embodiments of the first aspect, the H on R is arbitrarily substituted by one or more Ra, and each of the multiple Ra is selected from nitro, alkyl, halogen, haloalkyl or alkoxy.

[0024] In some specific embodiments of the first aspect, Ra is selected from C1~C6 substituted or unsubstituted straight-chain alkyl, or, Ra is selected from C1~C6 substituted or unsubstituted branched-chain alkyl, or, Ra is selected from C1~C6 halogenated straight-chain alkyl, or, Ra is selected from C1~C6 halogenated branched-chain alkyl, or, Ra is selected from C1~C6 alkoxy.

[0025] In other specific embodiments of the first aspect, the R is such as:

[0026] The ring A is selected from phenyl, naphthyl, cyclohexyl or quinolyl, furanyl, thienyl, pyrrolyl; The n is selected from any positive integer of 1 to 9, and the multiple Ra are each independently selected from F, Cl, Br, methoxy, methyl, ethyl, -CF3 or nitro.

[0027] In some specific embodiments of the first aspect, the metal iridium complex includes Ni(OAc)2, Ni(OTf)2, NiCl2(DME), NiBr2(DME), Ni(OAc)2·4H2O, NiSO4·6H2O, Ni(ClO4)2·6H2O, Ni(BF4)2·4H2O, Ni(acac)2, Ni(COD)2. In some specific embodiments of the first aspect, the metal nickel complex and the diphosphorus chiral ligand are reacted in a solvent Solvent at room temperature for 12 hours to prepare the metal catalyst.

[0028] In some specific embodiments of the first aspect, the molar ratio of the metal nickel complex to the diphosphorus chiral ligand is 1.0:1.0-1.10.

[0029] In some specific embodiments of the first aspect, the solvent Solvent is methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, hexafluoroisopropanol, dichloromethane, toluene, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, n-hexane or cyclohexane, or a combination thereof.

[0030] In some specific embodiments of the first aspect, the reaction temperature of the asymmetric reduction is 30°C to 80°C. In some preferred embodiments of the first aspect, the reaction temperature of the asymmetric reduction is 50°C.

[0031] In some specific embodiments of the first aspect, the reaction time of the asymmetric reduction is 1 h to 48 h. In some preferred embodiments of the first aspect, the reaction time of the asymmetric reduction is 48 h.

[0032] In some specific embodiments of the first aspect, the asymmetric reduction is carried out in a hydrogen atmosphere at 50 to 80 atmospheres of pressure.

[0033] In the present invention: "Mol %" indicates the molar percentage of the substance relative to the α,β-unsaturated ketone.

[0034] “S / C” refers to the ratio of substrate to catalyst.

[0035] The H on the hydroxyl group of the compound 1b of the present invention is an active hydrogen.

[0036] The structure of the ligand in the present invention is as follows: , , ,or Any of the following: In the present invention, DMF is N,N-dimethylformamide, THF is tetrahydrofuran, Hexane is n-hexane, Toluene is toluene, TFE is trifluoroethanol, and HFIP is hexafluoroisopropanol.

[0037] The advantages of the present invention are as follows: the present invention uses α,β-unsaturated ketones with different molecular structures as substrates for hydrogenation to construct chiral alcohols, and when hydrogen at specific positions of the conjugated ring is replaced by different substituents, a good reduction effect can be obtained. In the reduction process, 1.2-reduction of C=C is first performed, and then 1,2-reduction of C=O is performed. The catalyst used in the method is simple to prepare and has stable performance, and good chiral selection effect and conversion rate can still be obtained under the condition of a higher substrate / catalyst. DETAILED DESCRIPTION

[0038] Through the following further detailed description of the embodiments of the present invention in combination with specific implementation modes, those skilled in the art will more clearly and thoroughly understand the further features, advantages and effects of the present invention.

[0039] Example 1: (1 S , 2 R )-2-Benzyl-2,3-dihydro-1 H -Inden-1-ol

[0040] In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand ( S )-Binapine (0.22×10 -2mmol) was dissolved in trifluoroethanol (1 mL) and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of the solution was added to a mixture of compound 1a (0.2 mmol) and hexafluoroisopropanol (250 uL). The reaction system was placed in an autoclave and stirred at 50 °C and H2 (50 atm) for 48 hours. The solvent was removed under reduced pressure and separated by column chromatography (using a silica gel column, the eluent was petroleum ether: ethyl acetate = 20:1) to obtain product 1b. The product was analyzed by HPLC, and the er value was 91.5:8.5. The product was 1 H NMR analysis showed that the dr value was 8:1. HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0041] 1 H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.37 (m, 4.8 Hz, 1H), 7.35 –7.34 (m, 2H), 7.30 – 7.24 (m, 5H), 7.21 – 7.18 (m, 1H), 4.95 (t, J = 5.4 Hz,1H), 3.11 (dd, J = 13.4, 5.9 Hz, 1H), 3.01 (dd, J = 15.1, 7.1 Hz, 1H), 2.79 (dd, J = 13.5, 8.6 Hz, 1H), 2.62 – 2.48 (m, 2H). 13 C NMR (100MHz, Chloroform-d) δ 144.4, 141.5, 140.6, 128.9, 128.5, 128.1, 126.7, 126.1, 124.7, 123.9, 80.7, 76.7, 52.2, 39.2, 35.7. Example 2: (1 S , 2 R )-2-(2-methylbenzyl)-2,3-dihydro-1 H -Inden-1-ol

[0042] In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand ( S )-Binapine (0.22×10 -2mmol) was dissolved in trifluoroethanol (1 mL) and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of the solution was added to a mixture of compound 2a (0.2 mmol) and hexafluoroisopropanol (250 uL). The reaction system was placed in an autoclave and stirred at 50 °C and H2 (50 atm) for 48 hours. The solvent was removed under reduced pressure and separated by column chromatography (using a silica gel column, the eluent was petroleum ether: ethyl acetate = 20:1) to obtain product 2b. The product was analyzed by HPLC, and the er value was 93.5:6.5. The product was 1 H NMR analysis showed that the dr value was 8:1. HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0043] 1 H NMR (400 MHz, Chloroform-d) δ 7.45 – 7.41 (m, 1H), 7.30 – 7.27 (m,J = 7.4, 3H), 7.25 – 7.21 (m, 4H), 4.99 (d, J = 6.6 Hz, 1H), 3.15 (dd, J =13.8, 6.1 Hz, 1H), 3.07 (dd, J = 15.2, 7.2 Hz, 1H), 2.83 (dd, J = 13.8, 8.7Hz, 1H), 2.67 – 2.54 (m, 2H), 2.42 (s, 3H). 13 C NMR (100 MHz, Chloroform-d) δ 144.6, 141.6, 138.9, 136.3, 130.6,129.5, 128.2, 126.8, 126.4, 126.1, 124.8, 124.0, 36.6, 36.0, 19.6. Example 3: (1 S , 2 R )-2-(3-methylbenzyl)-2,3-dihydro-1 H -Inden-1-ol

[0044] In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand ( S )-Binapine (0.22×10 -2mmol) was dissolved in trifluoroethanol (1 mL) and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of the solution was added to a mixture of compound 3a (0.2 mmol) and hexafluoroisopropanol (250 uL). The reaction system was placed in an autoclave and stirred at 50 °C and H2 (50 atm) for 48 hours. The solvent was removed under reduced pressure and separated by column chromatography (using a silica gel column, the eluent was petroleum ether: ethyl acetate = 20:1) to obtain product 3b. The product was analyzed by HPLC, and the er value was 89.5:10.5. The product was 1 H NMR analysis showed that the dr value was 14:1. HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0045] 1 H NMR (400 MHz, Chloroform-d) δ 7.43 – 7.38 (m, 1H), 7.29– 7.25 (m,3H), 7.23 – 7.18 (m, 1H), 7.15 – 7.07 (m, 3H), 4.97 (d, J = 6.4 Hz, 1H), 3.10– 3.01 (m, 2H), 2.88 – 2.74 (m, 1H), 2.63 – 2.49 (m, 2H), 2.39 (s, 3H). 13 C NMR (100 MHz, Chloroform-d) δ 144.5, 141.5, 140.5, 138.1, 129.7,128.4, 128.1, 126.9, 126.7, 125.9, 124.7, 123.9, 80.8, 52.2, 39.2, 35.8,21.4. Example 4: (1 S , 2 R )-2-(3-bromobenzyl)-2,3-dihydro-1 H -Inden-1-ol

[0046] In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand ( S )-Binapine (0.22×10 -2mmol) was dissolved in trifluoroethanol (1 mL) and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of the solution was added to a mixture of compound 4a (0.2 mmol) and hexafluoroisopropanol (250 uL). The reaction system was placed in an autoclave and stirred at 50 °C and H2 (50 atm) for 48 hours. The solvent was removed under reduced pressure and separated by column chromatography (using a silica gel column, the eluent was petroleum ether: ethyl acetate = 20:1) to obtain product 4b. The product was analyzed by HPLC, and the er value was 95:5. The product was 1 H NMR analysis showed that the dr value was 10:1. HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 97:3 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0047] 1 H NMR (400 MHz, Chloroform-d) δ 7.48 – 7.42 (m, 1H), 7.39 – 7.35 (m,2H), 7.28 – 7.22 (m, 2H), 7.20 – 7.16 (m, 3H), 4.91 (d, J = 6.3 Hz, 1H), 3.09(dd, J = 13.6, 5.6 Hz, 1H), 2.99 (dd, J = 15.2, 7.2 Hz, 1H), 2.85 – 2.68 (m,1H), 2.58 – 2.43 (m, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 144.3, 143.0, 141.3, 131.9, 130.0,129.2, 128.2, 127.5, 126.8, 124.8, 123.9, 122.5, 80.7, 51.9, 38.8, 35.5. Example 5: (1 S , 2 S )-2-Benzyl-1,2,3,4-tetrahydronaphthalen-1-ol

[0048] In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand ( S )-Binapine (0.22×10 -2mmol) was dissolved in trifluoroethanol (1 mL) and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of the solution was added to a mixture of compound 5a (0.2 mmol) and hexafluoroisopropanol (250 uL). The reaction system was placed in an autoclave and stirred at 50 °C and H2 (50 atm) for 48 hours. The solvent was removed under reduced pressure and separated by column chromatography (using a silica gel column, the eluent was petroleum ether: ethyl acetate = 20:1) to obtain product 5b. The product was analyzed by HPLC, and the er value was 83.5:16.5. The product was 1 H NMR analysis showed that the dr value was 3:1. HPLC separation conditions: chiral AS-H column, mobile phase: n-hexane / isopropanol = 99:1 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0049] 1 H NMR (400 MHz, Chloroform-d) δ 7.32 – 7.23 (m, 3H), 7.22 – 7.12 (m,6H), 4.92 – 4.70 (m, 1H), 3.23 – 3.06 (m, 1H), 2.82 – 2.77 (m, 1H), 2.73 –2.61 (m, 1H), 2.42 -2.30 (m, 1H), 2.22 – 2.12 (m, 1H), 2.00 – 1.93 (m, 1H), 1.84 – 1.71 (m, 2H), 1.63 – 1.56 (m, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 141.9, 141.2, 140.8, 129.6, 129.1,129.0, 128.2, 127.3, 125.9, 125.7, 60.6, 44.9, 37.1, 35.5, 31.0, 23.1. Example 6: (3 R , 4 S )-3-Benzylchroman-4-ol

[0050] In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand ( S )-Binapine (0.22×10 -2mmol) was dissolved in trifluoroethanol (1 mL) and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of the solution was added to a mixture of compound 6a (0.2 mmol) and hexafluoroisopropanol (250 uL). The reaction system was placed in an autoclave and stirred at 50 °C and H2 (50 atm) for 48 hours. The solvent was removed under reduced pressure and separated by column chromatography (using a silica gel column, the eluent was petroleum ether: ethyl acetate = 20:1) to obtain product 6b. The product was analyzed by HPLC, and the er value was 91.5:8.5. The product was 1 H NMR analysis showed that the dr value was 4:1. HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 96:4 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0051] 1 H NMR (400 MHz, Chloroform-d) δ 7.33 – 7.27 (m, 3H), 7.24 – 7.21 (m,2H), 7.21 – 7.16 (m, 2H), 6.95 – 6.92 (m, 1H), 6.89 – 6.82 (m, 1H), 4.45 (d,J = 4.0 Hz, 1H), 4.19 (dd, J = 11.2, 2.6 Hz, 1H), 3.94 (dd, J = 11.1, 4.3 Hz,1H), 2.68 (dd, J = 13.9, 6.5 Hz, 1H), 2.54 – 2.48 (m, 1H), 2.34 – 2.15 (m, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 154.2, 139.1, 130.1, 129.7, 129.1,128.5, 126.3, 123.2, 120.8, 116.9, 67.6, 64.5, 41.4, 34.6. Example 7: (3 R , 4 S )-3-Benzyl-6-methylchroman-4-ol

[0052] In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand ( S )-Binapine (0.22×10-2 mmol) was dissolved in trifluoroethanol (1 mL) and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of the solution was added to a mixture of compound 7a (0.2 mmol) and hexafluoroisopropanol (250 uL). The reaction system was placed in an autoclave and stirred at 50 °C and H2 (50 atm) for 48 hours. The solvent was removed under reduced pressure and separated by column chromatography (using a silica gel column, the eluent was petroleum ether: ethyl acetate = 20:1) to obtain product 7b. The product was analyzed by HPLC, and the er value was 97:3. The product was 1 H NMR analysis showed a dr value of 4:1. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 97:3 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0053] 1 H NMR (400 MHz, Chloroform-d) δ 7.38 – 7.27 (m, 3H), 7.25 – 7.21 (m,2H), 7.16 – 7.15 (m, 1H), 7.09 – 7.03 (m, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.47(d, J = 3.9 Hz, 1H), 4.21 (dd, J = 11.1, 2.6 Hz, 1H), 3.97 (dd, J = 11.2, 4.2Hz, 1H), 2.73 (dd, J = 13.9, 6.5 Hz, 1H), 2.56 (dd, J = 13.8, 9.2 Hz, 1H), 2.33 (s, 3H), 2.25 – 2.18 (m, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 152.0, 139.3, 130.5, 130.3, 130.1,129.1, 128.5, 126.3, 122.8, 116.6, 67.7, 64.5, 41.6, 34.6, 20.5. Example 8: (3 S , 4 S )-3-Benzylthiochroman-4-ol

[0054] In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand (S )-Binapine (0.22×10 -2 mmol) was dissolved in trifluoroethanol (1 mL) and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of the solution was added to a mixture of compound 8a (0.2 mmol) and hexafluoroisopropanol (250 uL). The reaction system was placed in an autoclave and stirred at 50 °C and H2 (50 atm) for 48 hours. The solvent was removed under reduced pressure and separated by column chromatography (silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to obtain product 8b. The product was analyzed by HPLC, and the er value was 79:21. The product was 1 H NMR analysis showed that the dr value was 1:1. HPLC separation conditions: chiral OD-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0055] 1 H NMR (400 MHz, Chloroform-d) δ 7.35 – 7.18 (m, 7H), 7.17 – 7.13 (m,1H), 7.11 – 7.01 (m, 1H), 4.51 (d, J = 3.9 Hz, 1H), 3.46 – 3.17 (m, 1H), 3.02– 2.77 (m, 1H), 2.69 – 2.55 (m, 2H), 2.54 – 2.23 (m, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 139.5, 133.3, 132.6, 131.7, 129.1,128.6, 128.4, 126.6, 126.3, 124.4, 70.5, 38.9, 35.3, 25.1. Example 9 Metal Screening: Step 1: In a high-purity argon atmosphere, add metal nickel compounds (0.2×10 -2 mmol) and ligand ( S )-Binapine (0.22×10 -2 mmol) was dissolved in 1 mL of trifluoroethanol and stirred at room temperature for 12 hours to obtain a catalyst solution.

[0056] Step 2: 1 mL of the clear solution was added to compound 1a (0.2 mmol), and the reaction system was placed in an autoclave and stirred at 30 °C and H2 (50 atm) for 48 h.

[0057] Step 3: Remove the solvent under reduced pressure, separate by column chromatography (using silica gel column, eluent is petroleum ether: ethyl acetate = 20:1), and obtain product 1b. The product is analyzed by HPLC to measure the ee value. 1 H NMR analysis, measured dr value. Metal screening table 1: HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0058]

[0059] Table 1: Metal screening table

[0060] Example 16 shows that for the use of [Ni] / ( S )-Binapine catalytic system, under the same substrate / catalyst ratio, reaction temperature and hydrogen pressure, different metal precursors produce different enantiomer amounts, and Ni(OAc)2 can obtain better results.

[0061] Example 10 Ligand Screening: Step 1: In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand (0.22×10 -2 mmol) was dissolved in 1.0 mL of the ligand shown in Table 2, and the mixture was stirred at room temperature for 12 hours to obtain a catalyst solution.

[0062] Step 2: 1 mL of the clear solution was added to compound 1a (0.2 mmol), and the reaction system was placed in an autoclave and stirred at 30 °C and H2 (50 atm) for 48 h.

[0063] Step 3: Remove the solvent under reduced pressure, separate by column chromatography (using silica gel column, eluent is petroleum ether: ethyl acetate = 20:1), and obtain product 1b. The product is analyzed by HPLC to measure the ee value. 1 H NMR analysis, measured dr value. The ligand screening table 2 is obtained: HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0064]

[0065] Table 2: Ligand screening table

[0066] Example 17 shows that for the Ni(OAc)2 / Ligand catalytic system, under the same substrate / catalyst ratio, reaction temperature and hydrogen pressure, different bisphosphine chiral ligands produce different enantiomeric amounts. S )-Binapine was able to achieve better results.

[0067] Example 11 Solvent screening: Step 1: In a high-purity argon atmosphere, Ni(OAc)2 (0.2×10 -2 mmol) and ligand ( S )-Binapine (0.22×10 -2 mmol) was dissolved in 1.4 mL of the solvent Solvent shown in Table 1, and stirred at room temperature for 12 hours to obtain a catalyst solution.

[0068] Step 2: Take 100 μL of the clear solution and add it to compound 1a (0.2 mmol) and 1 mL of the same solvent Solvent as in step 1. Place the reaction system in an autoclave and stir at 30 °C and H2 (50 atm) for 48 hours.

[0069] Step 3: Remove the solvent under reduced pressure, separate by column chromatography (using silica gel column, eluent is petroleum ether: ethyl acetate = 20:1), and obtain product 1b. The product is analyzed by HPLC to measure the ee value. 1 H NMR analysis, measured dr value. Solvent screening table 3: HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0070]

[0071] Table 3: Solvent screening table

[0072] a: 50 o C Example 18 shows that for the use of Ni(OAc)2 / ( S )-Binapine catalytic system, under the same substrate / catalyst ratio, reaction temperature and hydrogen pressure, different solvents produce different enantiomer amounts, and THF and HFIP can obtain better results.

[0073] Example 12: Ni(OAc)2 / ( S )-Binapine Catalyst Applicability Step 1: In a high-purity argon atmosphere, Ni(OAc)2 and ( S )-Binapine was dissolved in 1 ml of trifluoroethanol and stirred at room temperature for 12 hours to obtain a white solution.

[0074] Step 2: Take 1 mL of the clear solution and add it to compound 1a-25a (0.2 mmol) and hexafluoroisopropanol (250 uL). Place the reaction system in an autoclave and stir at 50°C and H2 (50 atm) for 48 hours.

[0075] Step 3: Remove the solvent under reduced pressure, separate by column chromatography (using silica gel column, eluent is petroleum ether: ethyl acetate = 20:1), and obtain products 1b~25b respectively. The products are analyzed by HPLC to measure the ee values ​​of 1b~25b respectively. 1 H NMR analysis was used to measure the dr values ​​of 1b~25b respectively.

[0076] HPLC separation conditions: chiral AD-H column, mobile phase: n-hexane / isopropanol = 95:5 (volume ratio), flow rate: 1.0 mL / min, wavelength: 210 nm, column temperature: 30°C.

[0077] Table 4: Effects of different structural substrates on the reaction

[0078] Ni(OAc)2 / ( S )-Binapine catalyst has different applicability for different substrates. The results are shown in Table 4. Various ketones of substrates 1a~25a gave corresponding chiral alcohols 1b~25b with good conversion and enantioselectivity. Ni(OAc)2 / ( S )-Binapine catalyst tolerates different electronic properties (electron neutral, electron-rich and electron-deficient) on the phenyl group, and has good effects on different phenyl substituents. At the same time, when the H at a specific position on the α, β-unsaturated ketone ring is replaced by a chain alkyl group, it can also hydrogenate with high conversion rate and high selectivity to produce specific chiral alcohols.

[0079] The embodiments described above are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. Such modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present application, and should all be included in the protection scope of the present application.

Claims

1. A method for constructing a cycloalkanol by asymmetric hydrogenation of a trisubstituted ketone catalyzed by nickel, characterized in that: The reaction formula is as follows (A): ， The compound represented by formula (I) is asymmetrically hydrogenated under the action of catalyst Cat. to obtain the compound represented by formula (II); The R 1 is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyloxy, haloalkyl, halogen, hydroxyl, amino, nitro, cyano, and aryl; said R 2 is selected from substituted or unsubstituted monocyclic carbocyclic group, substituted or unsubstituted condensed ring carbocyclic group, substituted or unsubstituted spirocyclic group, substituted or unsubstituted bridged ring, substituted or unsubstituted monocyclic heterocyclic group, substituted or unsubstituted condensed ring heterocyclic group, substituted or unsubstituted monocyclic aryl group, substituted or unsubstituted branched alkyl group, substituted or unsubstituted straight chain alkyl group; The catalyst Cat is prepared from a metal nickel compound and a diphosphorus chiral ligand, and the diphosphorus chiral ligand has the structure shown below: , , ,or Any of the following: The ring W is selected from an unsaturated monocyclic carbocyclic group and an unsaturated monocyclic heterocyclic group; The above * represents a carbon chiral center, and the multiple carbon chiral centers are each independently of the other in R configuration or S configuration.

2. The method according to claim 1, characterized in that: The R 1 is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyloxy, haloalkyl, halogen, hydroxy, amino, nitro, cyano, and aryl; In the definitions of compounds I, II and III given above, the terms used, whether used alone or in compound words, represent the following substituents: Halogen: refers to fluorine, chlorine, bromine, and iodine; Alkyl: refers to a straight chain or branched chain alkyl; Haloalkyl: refers to a straight-chain or branched alkyl group in which some or all of the hydrogen atoms are replaced by halogen atoms.

3. The method according to claim 1, characterized in that : The R 2 is a heterocyclic fused ring group, wherein R 2 A fused ring group comprising two or more first rings fused to each other, or, said R 2 is a heterocyclic fused ring group, wherein R 2 A fused ring group comprising at least one first ring fused to at least one second ring; Or, the R 2 is a fused-ring carbocyclic group, wherein the fused-ring carbocyclic group is a fused-ring group in which two or more second rings are fused to each other; The first ring is a pyrrole group, a furan group, a thiophene group, a pyrrole group, a silole group, an indene group, a benzofuran group, a benzothiophene group, an indole group, or a benzosilole group, The second ring mentioned above is a cyclohexane group, a cyclopentane group, or a monocyclic aromatic group.

4. The method according to claim 1, characterized in that: The ring W is selected from a 3-10 membered heterocyclic group containing one or more carbon-carbon double bonds, or, the ring W is selected from a 3-10 membered heterocyclic group containing one carbon-carbon double bond and multiple carbon-carbon triple bonds, or, the ring W is selected from a C3-C10 carbocyclic group containing one or more carbon-carbon double bonds, or, the ring W is selected from a C3-C10 carbocyclic group containing one carbon-carbon double bond and multiple carbon-carbon triple bonds, and / or, the heterocyclic group is mixed with 1-3 heteroatoms, and the heteroatoms are selected from N, O, and S.

5. The method according to any one of claims 1 to 4, characterized in that: The H on the benzene ring is arbitrarily substituted by one or more Ra, and the multiple Ra are each selected from nitro, alkyl, halogen, haloalkyl or alkoxy.

6. The method according to claim 5, characterized in that: The Ra is selected from C1~C6 substituted or unsubstituted straight-chain alkyl, or, the Ra is selected from C1~C6 substituted or unsubstituted branched-chain alkyl, or, the Ra is selected from C1~C6 halogenated straight-chain alkyl, or, the Ra is selected from C1~C6 halogenated branched-chain alkyl, or, the Ra is selected from C1~C6 alkoxy, or, the Ra is selected from F, Cl, Br or I.

7. The method according to claim 6, characterized in that: The R is as follows: The ring A is selected from phenyl, naphthyl, cyclohexyl or quinolyl, furanyl, thienyl, pyrrolyl; The n is selected from any positive integer of 1 to 9, and the multiple Ra are each independently selected from F, Cl, Br, methoxy, methyl, ethyl, -CF3 or nitro.

8. The method according to claim 1, characterized in that: The metal nickel compound comprises any one of Ni(OAc)2, Ni(OTf)2, and Ni(OAc)2·4H2O. The metal nickel compound reacts with the diphosphorus chiral ligand in a solvent Solvent at room temperature for 10-12 hours to prepare a metal catalyst, and / or the molar ratio of the metal nickel compound to the diphosphorus chiral ligand is 1.0:1.0-1.

10.

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

10. The method according to any one of claims 1 to 9, characterized in that: The reaction temperature of the asymmetric reduction is 30° C. to 80° C., preferably 50° C.; and / or, the reaction time of the asymmetric reduction is 24 h to 48 h, preferably 48 h; and / or, the asymmetric reduction is carried out in a hydrogen atmosphere at 50 to 80 atmospheres of pressure.

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