A method for constructing cycloalkanol by nickel-catalyzed asymmetric hydrogenation of trisubstituted enone

Abstract

The application relates to the technical field of chemical synthesis, and particularly discloses a method for constructing cycloalkanol by nickel-catalyzed asymmetric hydrogenation of tri-substituted enone, and a chiral alcohol prepared by the method. The method uses alpha, beta-unsaturated ketone with different molecular structures as a substrate to construct chiral alcohol with double chiral centers, hydrogen is added to reduce the enyl group first, and then hydrogen is added to reduce the carbonyl group. In the case that the hydrogen on the carbon in the conjugated ring is replaced by different substituents, good reduction effect can be obtained. The catalyst has simple preparation mode and stable performance, and good chiral selection effect and conversion rate can still be obtained under the condition of high substrate / catalyst.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical synthesis, in particular to a method for constructing a cycloalkanol with two consecutive stereogenic centers by nickel-catalyzed asymmetric hydrogenation of a trisubstituted enone, and a double chiral alcohol prepared by the method. BACKGROUND

[0002] Chiral indenyl alcohol derivatives are the core structure of various natural products and synthetic bioactive compounds. For example,

[0003] Caulerpal A and Caulerprenylols B are two novel sesquiterpenes isolated from green algae, which have antifungal activity. Pterosin C is a natural product molecule isolated from Pteris multifida, which is used for antitumor and anti-inflammatory drugs. Chiral indenyl alcohol structures such as bevacizumab for the treatment of renal cell carcinoma and donepezil as acetylcholinesterase inhibitors.

[0004] Because the asymmetric reduction of α,β-unsaturated ketones has three different results: selective reduction of C=C or C=O, and total reduction of C=C and C=O. Therefore, it is a major challenge to construct double chiral centers in one step by asymmetric reduction of α,β-unsaturated ketones. According to literature research, the asymmetric reduction of α,β-unsaturated ketones is mainly focused on noble metal catalysis.

[0005] In 2013, Glorius developed a chiral ruthenium-NHC complex to catalyze the asymmetric hydrogenation of 2-substituted flavones and chromones, forming enantiomerically enriched flavanones, flavanols, chromanones and chromanols (81:19-99:1 er, 1.3:1-8.3:1 dr).

[0006]

[0007] In 2016, Zhang Wanbin's research group reported a method for efficient synthesis of chiral cyclo-trans-β-amino alcohols by one-pot sequential asymmetric hydrogenation of α-dehydroamino ketones catalyzed by rhodium, with excellent enantioselectivity and diastereoselectivity (89%-99% ee, 3:1-16:1 dr).

[0008]

[0009] In 2022, Zhang Xumou's team reported a method for asymmetric sequential hydrogenation of α,β-unsaturated ketones catalyzed by Ir / fampha complex (86%->99% ee, 8:1->20:1 dr), which is a dynamic kinetic resolution (DKR) method.

[0010]

[0011] Although the research on noble metal catalyzed asymmetric hydrogenation of α,β-unsaturated ketones is relatively mature, there is only one report on inexpensive nickel catalyzed asymmetric hydrogenation of α,β-unsaturated ketones. In 2019, Zhang Xumou's team studied the asymmetric hydrogenation of cyclohexadienone derivatives catalyzed by Ni / ( S , S )-Ph-BPE. The selective reduction of olefins is achieved by implementing an asymmetric strategy to construct a single chiral center in one step (92%-99% ee).

[0012]

[0013] However, there is no report on nickel catalyzed asymmetric sequential hydrogenation of α,β-unsaturated ketones to construct double chiral centers in one step. SUMMARY

[0014] In view of the problem of less technical path for synthesizing chiral alcohol from α,β-unsaturated ketone in the prior art, and the problem of easy selective reduction of α,β-unsaturated ketone in the process of hydrogenation to construct chiral alcohol, the first aspect of the present application provides a method for nickel catalyzed asymmetric hydrogenation of trisubstituted enone to construct cycloalkanol with two consecutive stereogenic centers, as shown in reaction formula (A):

[0015]

[0016] The R 1 is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyloxy, halogenated alkyl, halogen, hydroxyl, amino, nitro, cyano, aryl; the R 2 is selected from substituted or unsubstituted monocyclic carbocyclyl, substituted or unsubstituted fused ring carbocyclyl, substituted or unsubstituted spirocyclyl, substituted or unsubstituted bridged ring, substituted or unsubstituted monocyclic heterocyclyl, substituted or unsubstituted fused ring heterocyclyl, substituted or unsubstituted monocyclic aryl, substituted or unsubstituted branched alkyl, substituted or unsubstituted straight chain alkyl;

[0017] The catalyst Cat is prepared from a metal nickel compound and a double phosphorus chiral ligand, and the double phosphorus chiral ligand has any one of the following structures,

[0018] 、 、 , or

[0019] The ring W is selected from unsaturated monocyclic carbocyclyl and unsaturated monocyclic heterocyclyl.

[0020] The above-mentioned * represents a carbon chiral center, and each of the plurality of carbon chiral centers is independently in R configuration or S configuration.

[0021] ​In some embodiments of the first aspect, R is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyl oxy, haloalkyl, halogen, hydroxyl, amino, nitro, cyano, aryl. 1 is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyl oxy, haloalkyl, halogen, hydroxyl, amino, nitro, cyano, aryl;

[0022] In some embodiments of the first aspect, R is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyl oxy, haloalkyl, halogen, hydroxyl, amino, nitro, cyano, aryl. 2 is a heterocyclic fused ring group, said R comprising a fused ring group of two or more first rings fused to each other; said first ring is selected from a pyrrole group, a furan group, a thiophene group, a pyrrole group, a thiopyrrole group, an indene group, a benzofuran group, a benzothiophene group, an indole group, a benzothiopyrrole group.

[0023] In some embodiments of the first aspect, R is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyl oxy, haloalkyl, halogen, hydroxyl, amino, nitro, cyano, aryl. 2 is a heterocyclic fused ring group, said R comprising a fused ring group of at least one first ring and at least one second ring fused to each other; said first ring is selected from a pyrrole group, a furan group, a thiophene group, a pyrrole group, a thiopyrrole group, an indene group, a benzofuran group, a benzothiophene group, an indole group, a benzothiopyrrole group, said second ring is selected from a cyclohexane group, a cyclopentane group, a monocyclic aryl group.

[0024] In some embodiments of the first aspect, R is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyl oxy, haloalkyl, halogen, hydroxyl, amino, nitro, cyano, aryl. 2 is a fused ring carbocyclic group, said fused ring carbocyclic group is a fused ring group of two or more second rings fused to each other; said second ring is selected from a cyclohexane group, a cyclopentane group, a monocyclic aryl group.

[0025] In some 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.

[0026] In some 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.

[0027] In some embodiments of the first aspect, the ring W is selected from a C3-C10 carbocyclic group containing one or more carbon-carbon double bonds.

[0028] In some 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.

[0029] In some embodiments of the first aspect, the heterocyclic group has 1-3 heteroatoms, said heteroatoms are selected from N, O, S.

[0030] In some embodiments of the first aspect, any H on R is optionally substituted with one or more Ra, each Ra is selected from nitro, alkyl, halogen, haloalkyl, or alkoxy.

[0031] In some embodiments of the first aspect, the Ra is selected from C1-C6 substituted or unsubstituted linear alkyl, or, the Ra is selected from C1-C6 substituted or unsubstituted branched alkyl, or, the Ra is selected from C1-C6 halogenated linear alkyl, or, the Ra is selected from C1-C6 halogenated branched alkyl, or, the Ra is selected from C1-C6 alkoxy.

[0032] In some embodiments of the first aspect, the R is selected from:

[0033]

[0034] the ring A is selected from phenyl, naphthyl, cyclohexyl, or quinolinyl, furanyl, thienyl, pyrrolyl;

[0035] the n is selected from any positive integer from 1 to 9, and each of the plurality of Ra is independently selected from F, Cl, Br, methoxy, methyl, ethyl, -CF3, or nitro.

[0036] In some 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.

[0037] In some embodiments of the first aspect, the metal nickel complex and the biphosphine chiral ligand are reacted in a solvent Solvent at room temperature for 12 hours to prepare the metal catalyst.

[0038] In some embodiments of the first aspect, the molar ratio of the metal nickel complex to the biphosphine chiral ligand is 1.0:1.0-1.10.

[0039] In some 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.

[0040] In some embodiments of the first aspect, the reaction temperature of the asymmetric reduction is 30 ℃-80 ℃, and in some preferred embodiments of the first aspect, the reaction temperature of the asymmetric reduction is 50 ℃.

[0041] In some embodiments of the first aspect, the reaction time of the asymmetric reduction is 1h-48h, and in some preferred embodiments of the first aspect, the reaction time of the asymmetric reduction is 48h.

[0042] In some embodiments of the first aspect, the asymmetric reduction is performed in a hydrogen atmosphere of 50-80 atmospheres.

[0043] In the present application:

[0044] "Mol%" means the molar percentage of the substance relative to the α,β-unsaturated ketone.

[0045] "S / C" means the ratio of the amount of substrate and catalyst.

[0046] The H on the hydroxyl group of compound 1b in the present application is a reactive hydrogen.

[0047] The structure of the ligand in the present application is any one of the following formulae:

[0048] , , , or

[0049] In the present application, DMF is N,N-dimethylformamide, THF is tetrahydrofuran, Hexane is n-hexane, Toluene is toluene, TFE is trifluoroethanol, and HFIP is hexafluoroisopropanol.

[0050] The present application has the advantages that: the present application uses α,β-unsaturated ketones with different molecular structures as substrates to construct chiral alcohols by hydrogenation. In the case that the hydrogen at a specific position of the conjugated ring is substituted by different substituents, good reduction effects can be obtained. In the reduction process, the C=C is first reduced by 1.2, and then the C=O is reduced by 1.2. The catalyst used in the method is simple to prepare and stable in performance, and good chiral selection effect and conversion rate can still be obtained in the case of a relatively high substrate / catalyst. DETAILED DESCRIPTION

[0051] The further features, advantages and effects of the present application will be more clearly and thoroughly understood by the person skilled in the art through the further detailed description of the embodiments of the present application in conjunction with the specific embodiments.

[0052] Example 1: (1 S ,2 R )-2-benzyl-2,3-dihydro-1 H -inden-1-ol

[0053]

[0054] Under an atmosphere of high-purity argon, Ni(OAc)2(0.2×10 -2 mmol) and the ligand S )-Binapine (0.22×10​-2 mmol) in trifluoroethanol (1 mL) at room temperature for 12 h to give a white solution. 1 mL of this solution was added to a mixture of compound 1a (0.2 mmol), hexafluoroisopropanol (250 uL). The reaction mixture was placed in a high-pressure vessel and stirred at 50 °C under H2(50 atm) for 48 h. The solvent was removed under reduced pressure and the product was isolated by column chromatography (silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to give product 1b. The product was analyzed by HPLC to give an er value of 91.5:8.5. The product was analyzed by H NMR to give a dr value of 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. 1 H NMR analysis to give a dr value of 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.

[0055] 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).

[0056] 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.

[0057] Example 2: (1 S ,2 R )-2- (2-methylbenzyl)-2,3-dihydro-1 H -inden-1-ol

[0058]

[0059] Ni(OAc)2(0.2 x 10 -2mmol) and ligand ( S )-Binapine (0.22×10 -2 mmol) in trifluoroethanol (1 mL) at room temperature for 12 h to give a white solution. 1 mL of this solution was added to a mixture of compound 2a (0.2 mmol), hexafluoroisopropanol (250 uL). The reaction mixture was placed in an autoclave and stirred at 50 °C under H2(50 atm) for 48 h. The solvent was removed under reduced pressure and the product was isolated by column chromatography (silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to give product 2b. The product was analyzed by HPLC and the er value was measured to be 93.5:6.5. The product was analyzed by1H NMR and the dr value was measured to be 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. 1 H NMR analysis, the dr value was measured to be 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.

[0060] 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).

[0061] 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.

[0062] Example 3: (1 S ,2 R )-2- (3-methylbenzyl)-2,3-dihydro-1 H -inden-1-ol

[0063]

[0064] Under a high-purity argon atmosphere, Ni(OAc)₂ (0.2 × 10⁻⁶) was... -2 mmol) and ligands ( S )-Binapine (0.22×10 -2 0.2 mmol) of compound 3a was dissolved in 1 mL of trifluoroethanol and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of this solution was added to a mixture of compound 3a (0.2 mmol) and hexafluoroisopropanol (250 μL). The reaction mixture 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 the product was separated by column chromatography (silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to obtain product 3b. HPLC analysis of the product yielded an ER value of 89.5:10.5. 1 ¹H NMR analysis showed a dr ratio of 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℃.

[0065] 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).

[0066] 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.

[0067] Example 4: (1) S ,2 R )-2-(3-bromobenzyl)-2,3-dihydro-1 H -indole-1-ol

[0068]

[0069] Ni(OAc)2(0.2 x 10 -2 mmol) and ligand ( S )-Binapine (0.22 x 10 -2 mmol) were dissolved in trifluoroethanol (1 mL) and stirred at room temperature for 12 h to give 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 h. The solvent was removed under reduced pressure and the product was separated by column chromatography (silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to give product 4b. The er value of the product was measured by HPLC analysis to be 95:5, and the dr value of the product was measured by1H NMR analysis to be 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. 1

[0070] 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).

[0071] 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.

[0072] Example 5: (1 S ,2 S )-2-benzyl-1,2,3,4-tetrahydronaphthalen-1-ol

[0073] ​

[0074] Under a high-purity argon atmosphere, Ni(OAc)₂ (0.2 × 10⁻⁶) was... -2 mmol) and ligands ( S )-Binapine (0.22×10 -2 0.2 mmol) of compound 5a was dissolved in 1 mL of trifluoroethanol and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of this solution was added to a mixture of compound 5a (0.2 mmol) and hexafluoroisopropanol (250 μL). The reaction mixture 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 the product was separated by column chromatography (silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to obtain product 5b. HPLC analysis of the product yielded an ER value of 83.5:16.5. 1 ¹H NMR analysis showed a dr ratio of 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℃.

[0075] 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).

[0076] 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.

[0077] Example 6: (3) R 4 S 3-Benzylchroman-4-ol

[0078]

[0079] Under a high-purity argon atmosphere, Ni(OAc)₂ (0.2 × 10⁻⁶) was... -2 mmol) and ligands ( S )-Binapine (0.22×10 -2 0.2 mmol) of compound 6a was dissolved in 1 mL of trifluoroethanol and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of this solution was added to a mixture of compound 6a (0.2 mmol) and hexafluoroisopropanol (250 μL). The reaction mixture 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 the product was separated by column chromatography (silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to obtain product 6b. HPLC analysis of the product yielded an ER value of 91.5:8.5. 1 ¹H NMR analysis showed a dr ratio of 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℃.

[0080] 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).

[0081] 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.

[0082] Example 7: (3) R 4 S)-3-benzyl-6-methylchroman-4-ol

[0083]

[0084] Ni(OAc)2(0.2 x 10 -2 mmol) and ligand ( S )-Binapine (0.22 x 10 -2 mmol) were dissolved in trifluoroethanol (1 mL) and stirred at room temperature for 12 h to give 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 h. The solvent was removed under reduced pressure and the product was separated by column chromatography (silica gel column, eluent petroleum ether: ethyl acetate = 20:1) to give product 7b. The er value of the product was measured by HPLC analysis to be 97:3, and the dr value of the product was measured by1H NMR analysis to be 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. 1

[0085] 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).

[0086] 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.

[0087] Example 8: (3) S 4 S 3-Benzylthiochroman-4-ol

[0088]

[0089] Under a high-purity argon atmosphere, Ni(OAc)₂ (0.2 × 10⁻⁶) was... -2 mmol) and ligands ( S )-Binapine (0.22×10 -2 0.2 mmol) of compound 8a was dissolved in 1 mL of trifluoroethanol and stirred at room temperature for 12 hours to obtain a white solution. 1 mL of this solution was added to a mixture of compound 8a (0.2 mmol) and hexafluoroisopropanol (250 μL). The reaction mixture 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 the mixture was separated by column chromatography (silica gel column, eluent: petroleum ether: ethyl acetate = 20:1) to obtain product 8b. HPLC analysis of the product showed an ER value of 79:21. 1 ¹H NMR analysis showed a dr ratio of 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℃.

[0090] 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).

[0091] 13C 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.

[0092] Example 9 Metal Screening:

[0093] Step 1: Under a high-purity argon atmosphere, add 0.2 × 10⁻⁶ nickel compounds respectively. -2 mmol) and ligands ( S )-Binapine (0.22×10 -2 Dissolve mmol) in 1 mL of trifluoroethanol and stir at room temperature for 12 hours to obtain a catalyst solution.

[0094] Step 2: Add 1 mL of the clear solution to compound 1a (0.2 mmol), place the reaction system in an autoclave, and stir for 48 hours at 30 °C and H2 (50 atm).

[0095] 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 1b. The product is analyzed by HPLC, and the ee value is determined. 1 ¹H NMR analysis yielded the dr value. Metal sieve table 1 is obtained:

[0096] 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℃.

[0097]

[0098] Table 1: Metal Screening Table

[0099]

[0100] As can be seen in Example 16, for the use of [Ni] / ( S In the )-Binapine catalytic system, under the same substrate / catalyst ratio, reaction temperature and hydrogen pressure, different metal precursors produce different enantiomeric amounts, with Ni(OAc)2 yielding better results.

[0101] Example 10 Ligand Screening:

[0102] Step 1: Under a high-purity argon atmosphere, Ni(OAc)₂ (0.2 × 10⁻⁶) was added separately.-2 mmol) and ligand (0.22 x 10 -2 mmol) was dissolved in 1.0 mL of the ligand shown in Table 2, and stirred at room temperature for 12 hours to obtain a catalyst solution.

[0103] 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 hours.

[0104] Step 3: The solvent was removed under reduced pressure, and column chromatography was used for separation (a silica gel column was used, and petroleum ether: ethyl acetate = 20:1 was used as the eluent) to obtain product 1b. The product was analyzed by HPLC to determine the ee value, and the product was analyzed by H NMR to determine the dr value. Table 2 shows the ligand screening table: 1 H NMR analysis, the dr value was determined. Table 2 shows the ligand screening table:

[0105] 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.

[0106]

[0107] Table 2: Ligand screening table

[0108]

[0109] As can be seen from Example 17, for the Ni(OAc)2 / Ligand catalytic system, different chiral ligands of bisphosphine produce different amounts of enantiomers under the same substrate / catalyst ratio, reaction temperature, and hydrogen pressure, S (-Binapine can achieve better results.

[0110] Example 11: Solvent screening:

[0111] Step 1: Ni(OAc)2(0.2 x 10 -2 mmol) and ligand ( S )-Binapine (0.22 x 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.

[0112] Step 2: 100 μL of the clear solution was added to compound 1a (0.2 mmol) and 1 mL of the same solvent Solvent as in Step 1, and the reaction system was placed in an autoclave and stirred at 30°C and H2(50 atm) for 48 hours.

[0113] 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 1b. The product is analyzed by HPLC, and the ee value is determined. 1 ¹H NMR analysis was performed to obtain the dr value. Solvent screening table 3 is obtained:

[0114] 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℃.

[0115]

[0116] Table 3: Solvent Screening Table

[0117]

[0118] a: 50 o C

[0119] Example 18 shows that for the use of Ni(OAc)2 / ( S In the )-Binapine catalytic system, under the same substrate / catalyst ratio, reaction temperature, and hydrogen pressure, different solvents produce different enantiomeric amounts, with THF and HFIP yielding better results.

[0120] Example 12: Ni(OAc)2 / ( S Suitability of )-Binapine catalysts

[0121] Step 1: Under 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.

[0122] Step 2: Add 1 mL of the clarified solution to compounds 1a-25a (0.2 mmol) and hexafluoroisopropanol (250 μL). Place the reaction system in an autoclave and stir for 48 hours at 50 °C and H2 (50 atm).

[0123] 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 products 1b~25b. The products were analyzed by HPLC, and the ee values ​​of 1b~25b were determined. 1 ¹H NMR analysis was performed, and dr values ​​were measured at 1b to 25b.

[0124] 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℃.

[0125] Table 4: Effect of different substrate structures on the reaction

[0126]

[0127] Ni(OAc)2 / ( S The )-Binapine catalyst exhibits different applicability to different substrates, as shown in Table 4. Various ketones from substrates 1a to 25a yielded corresponding chiral alcohols 1b to 25b with good conversion and enantioselectivity. Ni(OAc)2 / ( S The )-Binapine catalyst is tolerant to different electronic properties (electron neutral, electron-rich, and electron-deficient) on the phenyl group. It has good effects on different substituents of the phenyl group. At the same time, it can also hydrogenate specific chiral alcohols with high conversion and high selectivity when the H at a specific position on the α,β-unsaturated ketone ring is replaced by a chain alkyl group.

[0128] 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 method for the construction of cyclic alkanols by asymmetric hydrogenation of a trisubstituted enone catalyzed by nickel, characterized in that, The reaction is shown as (A): The compound represented by formula (I) is asymmetrically hydrogenated in the presence of a catalyst to obtain a compound represented by formula (II). R1 is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyloxy, haloalkyl, halogen, hydroxyl, amino, nitro, cyano, aryl; R2 is selected from unsubstituted monocyclic carbocyclyl, unsubstituted fused ring carbocyclyl, unsubstituted spirocyclyl, unsubstituted bridged ring, unsubstituted monocyclic heterocyclyl, unsubstituted fused ring heterocyclyl, unsubstituted branched alkyl, unsubstituted straight chain alkyl; The catalyst is prepared from a metal nickel compound and a double phosphorus chiral ligand, the double phosphorus chiral ligand has the structure shown below, , , , or any of The ring W is selected from unsaturated monocyclic carbocyclyl, unsaturated monocyclic heterocyclyl; the above-mentioned represents a carbon chiral center, each of the plurality of carbon chiral centers is independently R configuration or S configuration; the metal nickel compound is any one of Ni(OAc)2, Ni(OAc)2·4H2O, the metal nickel compound and the double phosphorus chiral ligand are reacted in a solvent at room temperature for 10-12 hours to prepare a metal catalyst, the molar ratio of the metal nickel compound to the double phosphorus chiral ligand is 1.0:1.0-1.10; the solvent is trifluoroethanol, hexafluoroisopropanol, or a combination thereof.

2. The method of claim 1, wherein, The R 1 is any one of hydrogen, C1-C10 alkyl, C1-C10 alkyl oxy, haloalkyl, halogen, hydroxyl, amino, nitro, cyano, aryl; In the definitions of compounds I, II, III given above, the terms used, whether used alone or in a combination, represent the following substituents: halogen: means fluorine, chlorine, bromine, iodine; alkyl: means straight chain or branched chain alkyl; haloalkyl: means straight chain or branched chain alkyl, in which some or all of the hydrogen atoms in these alkyl groups are replaced by halogen atoms.

3. The method of claim 1, wherein : said R 2 is a fused ring heterocyclyl group, said R 2 comprises a fused ring group of two or more first rings which are fused to one another, or, said R 2 is a heterocyclic fused ring group, said R 2 comprises a fused ring group of at least one first ring and at least one second ring which are fused to one another; or, said R 2 is a fused ring carbocyclyl, said fused ring carbocyclyl being a fused ring group of two or more second rings which are fused to one another; The first ring mentioned above is a pyrrole group, a furan group, a thiophene group, a pyrrole group, a thiol group, an indene group, a benzofuran group, a benzothiophene group, an indole group, or a benzothiol group, The second ring mentioned above is a cyclohexane group, a cyclopentane group, a monocyclic aryl group.

4. The method of claim 1, wherein, The reaction temperature of the asymmetric hydrogenation is 30℃ ~ 80℃; and / or, the reaction time of the asymmetric hydrogenation is 24h ~ 48h; and / or, the asymmetric hydrogenation is carried out in a hydrogen atmosphere of 50 ~ 80 atm.

5. The method of claim 1, wherein, The reaction temperature of the asymmetric hydrogenation is 50℃, and the reaction time of the asymmetric hydrogenation is 48h.

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