Method for synthesizing cyclopentenyl ketone under catalysis of nickel and aluminum

Abstract

The invention relates to a method for synthesizing cyclopentenyl ketone under the catalysis of nickel and aluminum, which comprises the following steps: adding a secondary phosphine oxide ligand PO, a metal catalyst Ni (cod) 2, a solvent, cyclopropyl ketone and alkyne into a reaction container in a nitrogen atmosphere, then adding lewis acid, stirring at a specified reaction temperature, adding an ethylene diamine tetraacetic acid aqueous solution after the reaction is completed, washing, separating liquid, and drying to obtain the cyclopentenyl ketone. And carrying out drying and column chromatography separation on the organic phase to obtain chiral or achiral cyclopentenyl ketone. The method has the advantages of wide substrates, strong tolerance of reaction to functional groups of the substrates, no atom loss, high atom economy and step economy, capability of effectively inhibiting side reactions caused by enolation racemization of ketone and Lewis acid through coordinated regulation and control of the ligand and the solvent, and extremely high reaction efficiency and stereo control capability.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, and more specifically to a method for synthesizing cyclopentenyl ketones using nickel-aluminum catalysis. Background Technology

[0002] Enantioselective cycloaddition of cyclopropane to π-unsaturated compounds catalyzed by transition metals is an important strategy for constructing common chiral cyclic structures in medicinal chemistry. However, the high C–C bond energy of cyclopropane makes it difficult to activate, resulting in current successful cases mainly focusing on intramolecular reactions requiring multi-step preparation, while the development of intermolecular cycloaddition is significantly insufficient.

[0003] To achieve intermolecular cycloaddition, cyclopropanes typically require pre-activation to weaken the C–C bonds. This can be achieved by introducing highly ring-strained cyclopropenes or dicarboxylic acid esters like vinylcyclopropanes with strong electron-withdrawing groups. However, for more readily available, weakly activated cyclopropanes (such as cyclopropyl carbonyl / amine / alcohol / alkanes), achieving high enantioselectivity remains extremely challenging despite the existence of various racemic methods. The key challenge lies in the lack of chiral catalytic systems capable of precise stereocontrol under the drastic conditions of C–C bond breaking.

[0004] Cyclopropyl ketones have attracted considerable attention due to the synthetic utility of their carbonyl groups and their presence in numerous bioactive molecules. Despite their effectiveness, this radical pathway requires multi-substituted cyclopropanes to stabilize key radical intermediates, making it incompatible with more common, less substituted analogs. Therefore, developing highly efficient enantioselective cycloaddition catalytic systems for unmodified cyclopropyl ketones remains an unsolved challenge. Furthermore, the electrophilicity of the ketone carbonyl group in cyclopropyl ketones leads to rapid racemization of the α-tertiary chiral center under high-temperature / Lewis acid reaction conditions, making high enantioselectivity a significant hurdle despite the development of various racemic cycloaddition systems since 2006.

[0005] In summary, although the cycloaddition reactions of cyclopropylamides and polysubstituted cyclopropanes to construct cyclopentenyl ketones have been reported, the construction of cyclopentenyl ketones via the cycloaddition reaction of unmodified simple cyclopropyl ketones remains an unsolved problem. Summary of the Invention

[0006] The purpose of this invention is to provide a method for the synthesis of cyclopentenyl ketones using nickel-aluminum catalysis, in order to solve the problems of limited substrate structure, harsh reaction conditions, and easy racemization of products in existing technologies.

[0007] Therefore, the present invention adopts the following technical solution:

[0008] A method for synthesizing cyclopentenyl ketones using nickel-aluminum catalysis, characterized by the following reaction formula and reaction process:

[0009]

[0010] In a nitrogen atmosphere, secondary phosphine oxide ligand PO, metal catalyst Ni(cod)2, solvent, raw material A, and raw material B are added to a reaction vessel. Then, a Lewis acid is added, and the mixture is stirred at a specified reaction temperature. After the reaction is complete, an aqueous solution of disodium ethylenediaminetetraacetate is added for washing. The mixture is separated, and the organic phase is dried and separated by column chromatography to obtain the target product C or D.

[0011] R, R 1 and R 2 Each is independently selected from aryl and alkyl groups;

[0012] The molar ratio of the secondary phosphooxyligand PO, the metal catalyst, the Lewis acid, and the raw material A is (0.05-0.3):(0.05-0.3):(0.1-0.8):1.

[0013] Preferably, R is phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-chlorophenyl or cyclohexylphenyl.

[0014] Preferably, R 1 It can be n-propyl, acetoxypropyl, phenyl, 4-methoxyphenyl, 4-trimethylsilylphenyl, 4-chlorophenyl, or ethyl.

[0015] Preferably, R 2 It can be n-propyl, acetoxypropyl, phenyl, 4-methoxyphenyl, 4-trimethylsilylphenyl, 4-chlorophenyl, ethyl or methyl.

[0016] In the above reaction, the secondary phosphooxy ligand is a chiral dinitrogen-substituted secondary phosphooxy ligand with the following structural formula:

[0017] ,

[0018] Alternatively, a non-chiral dinitrogen-substituted secondary phosphooxy ligand may be used, with the following structural formula:

[0019] .

[0020] The Lewis acid is an organoaluminum compound, an organozinc compound, or an organomagnesium compound. Preferably, the organoaluminum compound is trimethylaluminum; the organozinc compound is diethylzinc; and the organomagnesium compound is dibutylmagnesium.

[0021] The solvents mentioned above are nonpolar, moderately polar, or polar solvents, and the amount of solvent used is 0.5–5 mL / mmolA. Preferably, the nonpolar solvent is toluene or n-hexane, the moderately polar solvent is tetrahydrofuran or 1,4-dioxane, and the polar solvent is dimethyl sulfoxide.

[0022] In the above reaction, the specified reaction temperature is 20–120 °C; the stirring time is 10–1440 minutes; and the organic phase is dried with anhydrous sodium sulfate.

[0023] Preferably, the molar ratio of raw material B to raw material A is (1-3):1.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. The substrates used in this invention have a wide range of applicability, including arylcyclopropyl ketones, heteroarylcyclopropyl ketones, alkylcyclopropyl ketones, as well as aryl alkynes, functionalized alkyl alkynes, and asymmetric alkynes. The reaction is highly tolerant to the functional groups of the substrates, and gram-scale reactions have been successfully carried out, making it suitable for the late-stage modification of complex molecules (such as drug molecules).

[0026] 2. This invention constructs cyclopentenyl ketones by activating the C-C bonds of cyclopropyl ketones without any atom loss, thus exhibiting high atom economy and step economy.

[0027] 3. The Ni–Al bimetallic synergistic catalytic system of this invention can achieve high enantioselectivity control under mild conditions. Through the synergistic regulation of ligands and solvents, it can effectively suppress the racemic enolization of ketones and the side reactions caused by Lewis acids, achieving a yield of up to 99% and an ee of 99%, demonstrating extremely high reaction efficiency and stereocontrol ability. Detailed Implementation

[0028] The synthesis method of the present invention will be described in detail below with reference to the embodiments. However, the present invention is not limited to the listed embodiments and should also include any other known modifications within the scope of the claims of the present invention.

[0029] In the following examples, product purity was determined by NMR, and product chirality was detected by high-performance liquid chromatography; the structural formulas of the secondary phosphonooxyligand PO used in Examples 1-12 are as follows:

[0030] ,

[0031] The secondary phosphonooxyligand rac-PO used in Example 13 has the following structural formula:

[0032] .

[0033] Example 1

[0034] A synthetic method for (S)-(2,3-Dipropylcyclopent-2-en-1-yl)(phenyl)methanone is described. The reaction formula and reaction procedure are as follows:

[0035]

[0036] Under a nitrogen atmosphere, secondary phosphooxy ligand PO (23.5 mg, 0.04 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), tetrahydrofuran (1.0 mL), A-1 (29.2 mg, 0.2 mmol), and B-1 (44.1 mg, 0.4 mmol) were added to the reaction flask, followed by the addition of trimethylaluminum (1 M, 60 μL, 30 mol%). The mixture was stirred at room temperature for 10 minutes, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a colorless oily liquid C-1 in 76% yield.

[0037] 1 H NMR (400 MHz, CDCl3) δ 8.00–7.98 (m, 2H), 7.56–7.52 (m, 1H), 7.47–7.43 (m, 2H), 4.50 (t, J = 7.2 Hz, 1H), 2.49–2.33 (m, 2H), 2.25 – 2.11 (m,2H), 1.96–1.89 (m, 2H), 1.52–1.31 (m, 3H), 1.27–1.15 (m, 1H), 0.92 (t, J =7.4 Hz, 1H), 0.80 (t, J = 7.3 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 203.2,140.4, 137.4, 134.4, 132.8, 128.6, 128.5, 55.3, 35.0, 30.7, 29.4, 28.2, 21.5,21.4, 14.2, 14.2. HRMS (ESI) m / z: [M+H] + Calculated for C 18 H 25 O 257.1905; Found257.1896. HPLC analysis: Chiracel OD-H column, n-Hex / i-PrOH = 99:1, 0.8 mL / min, 254 nm, minor enantiomer: 5.0 min, major enantiomer: 5.4 min, 97% ee;[α] = -5.3° (c = 0.1, CHCl3).

[0038] Example 2

[0039] A synthetic method for (S)-(2,3-Dipropylcyclopent-2-en-1-yl)(p-tolyl)methanone ((S)-(2,3-dipropylcyclopent-2-en-1-yl)(p-tolyl)methanone) is described. The reaction formula and reaction procedure are as follows:

[0040]

[0041] Under a nitrogen atmosphere, secondary phosphonooxyligand PO (5.9 mg, 0.01 mmol), Ni(cod)2 (2.8 mg, 0.01 mmol), toluene (1.0 mL), A-2 (32.0 mg, 0.2 mmol), and B-1 (44.1 mg, 0.4 mmol) were added to the reaction flask, followed by the addition of trimethylaluminum (1 M, 20 μL, 10 mol%). The mixture was stirred at room temperature for 24 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a pale yellow oily liquid C-2 in 74% yield.

[0042] 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.0Hz, 2H), 4.48 (t, J = 7.2 Hz, 1H), 2.50–2.33 (m, 5H), 2.26–2.10 (m, 4H), 1.96–1.86 (m, 2H), 1.52–1.30 (m, 3H), 1.26–1.15 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ HRMS (ESI) m / z: [M+Na] + Calculated for C 19 H26 NaO 293.1881; Found293.1871. HPLC analysis: Chiracel OJ-H column, n-Hex / i-PrOH = 99.5:0.5, 0.5mL / min, 254 nm, minor enantiomer: 9.3 min, major enantiomer: 8.8 min, 89% ee;[α] = -7.4° (c = 0.1, CHCl3).

[0043] Example 3

[0044] A synthetic method for (S)-(2,3-Dipropylcyclopent-2-en-1-yl)(m-tolyl)methanone ((S)-(2,3-dipropylcyclopent-2-en-1-yl)(m-tolyl)methanone) is described. The reaction formula and reaction procedure are as follows:

[0045]

[0046] Under a nitrogen atmosphere, secondary phosphonooxyligand PO (23.5 mg, 0.04 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), n-hexane (1.0 mL), A-3 (32.0 mg, 0.2 mmol), and B-1 (22.0 mg, 0.2 mmol) were added to a reaction flask, followed by the addition of trimethylaluminum (1 M, 60 μL, 30 mol%). The mixture was stirred at 50 °C for 24 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a pale yellow oily liquid C-3 in 60% yield.

[0047] 1 H NMR (400 MHz, CDCl3) δ 7.80–7.76 (m, 2H), 7.37–7.32 (m, 2H), 4.49 (t, J = 7.3 Hz, 1H), 2.51–2.33 (m, 5H), 2.23–2.11 (m, 4H), 1.96–1.86 (m, 2H), 1.52–1.29 (m, 3H), 1.26–1.17 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H), 0.81 (t, J =7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 203.4, 140.4, 138.4, 137.5, 134.5,133.6, 129.0, 128.5, 125.7, 55.4, 35.0, 30.7, 29.4, 28.2, 21.6, 21.5, 21.4,14.2, 14.2. HRMS (ESI) m / z: [M+Na] + Calculated for C 19 H 26 NaO 293.1881; Found293.1871. HPLC analysis: Chiracel OD-H column, n-Hex / i-PrOH = 99:1, 0.8 mL / min, 254 nm, minor enantiomer: 6.6 min, major enantiomer: 7.0 min, 94% ee;[α] = -11.7° (c = 0.1, CHCl3).

[0048] Example 4

[0049] A synthetic method for (S)-(2,3-Dipropylcyclopent-2-en-1-yl)(o-tolyl)methanone ((S)-(2,3-dipropylcyclopent-2-en-1-yl)(o-tolyl)methanone) is described. The reaction formula and reaction procedure are as follows:

[0050]

[0051] Under a nitrogen atmosphere, secondary phosphonooxyligand PO (23.5 mg, 0.04 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), tetrahydrofuran (1.0 mL), A-4 (32.0 mg, 0.2 mmol), and B-1 (44.1 mg, 0.4 mmol) were added to the reaction flask, followed by diethylzinc (1 M, 80 μL, 40 mol%). The mixture was stirred at room temperature for 24 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a pale yellow oily liquid C-4 in 86% yield.

[0052] 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.9 Hz, 1H), 7.37–7.33 (m, 1H), 7.26–7.23 (m, 2H), 4.33 (t, J = 6.3 Hz, 1H), 2.49–2.41 (m, 4H), 2.36–2.29 (m,1H), 2.18–2.09 (m, 4H), 2.20–1.96 (m, 1H), 1.85–1.81 (m, 1H), 1.50–1.31 (m,3H), 1.25–1.15 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H), 0.79 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 207.6, 104.7, 139.3, 137.8, 134.4, 131.8, 130.8,128.0, 125.6, 58.4, 35.0, 30.7, 29.3, 27.6, 21.5, 21.0, 14.2, 14.2. HRMS(ESI) m / z: [M+Na] + Calculated for C 19 H 26 NaO 293.1881; Found 293.1872. HPLCanalysis: Chiracel OD-H column, n-Hex / i-PrOH = 99.5:0.5, 0.5 mL / min, 254 nm, minor enantiomer: 8.4 min, major enantiomer: 9.2 min, 75% ee; [α] = -11.3° (c = 0.1, CHCl3).

[0053] Example 5

[0054] A synthetic method for (S)-(4-Chlorophenyl)(2,3-dipropylcyclopent-2-en-1-yl)methanone ((S)-(4-chlorophenyl)(2,3-dipropylcyclopent-2-en-1-yl)methanone) is described. The reaction formula and reaction procedure are as follows:

[0055]

[0056] Under a nitrogen atmosphere, secondary phosphonooxyligand PO (23.5 mg, 0.04 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), tetrahydrofuran (1.0 mL), A-5 (36.1 mg, 0.2 mmol), and B-1 (66.1 mg, 0.6 mmol) were added to the reaction flask, followed by dibutylmagnesium (1 M, 120 μL, 60 mol%). The mixture was stirred at 80 °C for 24 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a pale yellow oily liquid C-5 in a yield of 67%.

[0057] 1 H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6Hz, 2H), 4.43 (t, J = 6.8 Hz, 1H), 2.49–2.33 (m, 2H), 2.25–2.10 (m, 4H), 1.93–1.86 (m, 2H), 1.51–1.29 (m, 3H), 1.23–1.15 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 202.0, 140.8, 139.3,135.7, 134.2, 130.0, 129.0, 55.5, 35.0, 30.7, 29.4, 28.1, 21.6, 21.4, 14.2,14.2. HRMS (ESI) m / z: [M+H] + Calculated for C 18 H 24 ClO 291.1516; Found 291.1508.HPLC analysis: Chiracel OJ-H column, n-Hex / i-PrOH = 99:1, 0.6 mL / min, 254 nm, minor enantiomer: 8.3 min, major enantiomer: 8.0 min, 95% ee; [α] = -16.5° (c = 0.1, CHCl3).

[0058] Example 6

[0059] A synthetic method for (S)-Cyclohexyl(2,3-dipropylcyclopent-2-en-1-yl)methanone ((S)-cyclohexyl(2,3-dipropylcyclopent-2-en-1-yl)methanone) is described. The reaction formula and reaction procedure are as follows:

[0060]

[0061] Under a nitrogen atmosphere, secondary phosphonooxyligand PO (23.5 mg, 0.04 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), 1,4-dioxane (5.0 mL), A-6 (30.4 mg, 0.2 mmol), and B-1 (44.1 mg, 0.4 mmol) were added to the reaction flask, followed by the addition of trimethylaluminum (1 M, 60 μL, 30 mol%). The mixture was stirred at room temperature for 12 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a colorless liquid C-6 in 91% yield.

[0062] 1 H NMR (400 MHz, CDCl3) δ 3.72 (t, J = 6.9 Hz, 1H), 2.45–2.41 (m, 2H), 2.33–2.26 (m, 1H), 2.16–1.97 (m, 4H), 1.80–1.73 (m, 6H), 1.68–1.67 (m, 1H), 1.42-1.20 (m, 9H), 0.88 (t, J = 7.3 Hz, 3H), 0.84 (t, J = 7.3 Hz, 3H). 13 HRMS (ESI) m / z: [M+H] + Calcd. forC 18 H 31O 263.2375; Found 263.2369. HPLC analysis: Chiracel ID column, n-Hex / i-PrOH = 99.5:0.5, 0.5 mL / min, 254 nm, minor enantiomer: 10.1 min, majorenantiomer: 9.8 min, 90% ee; [α] = -2.3° (c = 0.1, CHCl3).

[0063] Example 7

[0064] A synthetic method for (S)-(3-Benzoylcyclopent-1-ene-1,2-diyl)bis(propane-3,1-diyl)diacetate is described. The reaction formula and reaction process are as follows:

[0065]

[0066] Under a nitrogen atmosphere, secondary phosphonooxyligand PO (23.5 mg, 0.04 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), dimethyl sulfoxide (0.5 mL), A-1 (29.2 mg, 0.2 mmol), and B-2 (90.5 mg, 0.4 mmol) were added to the reaction flask, followed by the addition of trimethylaluminum (1 M, 60 μL, 30 mol%). The mixture was stirred at room temperature for 24 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a colorless liquid C-7 in 63% yield.

[0067] 1H NMR (400 MHz, CDCl3) δ 8.01–7.99 (m, 2H), 7.60–7.57 (m, 1H), 7.51–7.47 (m, 2H), 4.52–4.54 (m, 1H), 4.10 (t, J = 6.6 Hz, 2H), 4.03–3.90 (m, 2H), 2.52–2.35 (m, 2H), 2.32–2.22 (m, 4H), 2.08 (s, 3H), 1.99–1.91 (m, 5H), 1.82–1.76 (m, 2H), 1.70–1.64 (m, 1H), 1.60–1.51 (m, 1H). 13 C NMR (100 MHz, CDCl3)δ HRMS (ESI) m / z: [M+Na] + Calcd. forC 22 H 28 NaO5 395.1834; Found 395.1827. HPLC analysis: Chiracel OD-H column, n-Hex / i-PrOH = 99:1, 0.6 mL / min, 254 nm, minor enantiomer: 13.2 min, majorenantiomer: 14.3 min, 96% ee; [α] = -23.7° (c = 0.1, CHCl3).

[0068] Example 8

[0069] A synthetic method for (S)-(2,3-Diphenylcyclopent-2-en-1-yl)(phenyl)methanone is described. The reaction formula and reaction procedure are as follows:

[0070]

[0071] Under a nitrogen atmosphere, secondary phosphooxy ligand PO (23.5 mg, 0.04 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), tetrahydrofuran (1.0 mL), A-1 (29.2 mg, 0.2 mmol), and B-3 (71.3 mg, 0.4 mmol) were added to the reaction flask, followed by the addition of trimethylaluminum (1 M, 60 μL, 30 mol%). The mixture was stirred at 120 °C for 24 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give a white solid C-8 in 81% yield.

[0072] 1 H NMR (400 MHz, CDCl3) δ 7.95–7.93 (m, 2H), 7.54–7.51 (m, 1H), 7.44–7.40 (m, 2H), 7.22–7.17 (m, 5H), 7.13–7.07 (m, 5H), 5.10–5.06 (m, 1H), 3.22–3.16 (m, 1H), 2.92–2.85 (m, 1H), 2.60–2.50 (m, 1H), 2.26–2.19 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ HRMS (ESI) m / z: [M+Na] + Calculated for C 24 H 20 NaO 347.1412; Found 347.1409. HPLC analysis: Chiracel OD-Hcolumn, n-Hex / i-PrOH = 98:2, 0.8 mL / min, 254 nm, minor enantiomer: 9.2 min, major enantiomer: 11.0 min, 92% ee; [α] = -12.3° (c = 0.1, CHCl3).

[0073] Example 9

[0074] A synthetic method for (S)-(2,3-Bis(4-methoxyphenyl)cyclopent-2-en-1-yl)(phenyl)methanone ((S)-2,3-bis(4-methoxyphenyl)cyclopent-2-en-1-yl methyl ketone) is described. The reaction formula and reaction procedure are as follows:

[0075]

[0076] Under a nitrogen atmosphere, secondary phosphonooxyligand PO (23.5 mg, 0.04 mmol), Ni(cod)2 (11.0 mg, 0.04 mmol), tetrahydrofuran (1.0 mL), A-1 (29.2 mg, 0.2 mmol), and B-4 (95.3 mg, 0.4 mmol) were added to the reaction flask, followed by the addition of trimethylaluminum (1 M, 120 μL, 60 mol%). The mixture was stirred at room temperature for 24 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a pale yellow oily liquid C-9 in 74% yield.

[0077] 1 H NMR (400 MHz, CDCl3) δ 7.96–7.94 (m, 2H), 7.55–7.51 (m, 1H), 7.45–7.41 (m, 2H), 7.18–7.15 (m, 2H), 7.07–7.05 (m, 2H), 6.76–6.74 (m, 2H), 6.70–6.67 (m, 2H), 5.04–5.01 (m, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.15–3.09 (m,1H), 2.88–2.80 (m, 1H), 2.57–2.47 (m, 1H), 2.23–2.15 (m, 1H). 13 C NMR (100MHz, CDCl3) δ MHz, CDCl3) δ 201.9, 158.5, 158.3, 139.8, 137.0, 134.9, 132.9,130.2, 130.0, 129.8, 129.5, 128.6, 113.7, 113.5, 58.7, 55.2, 55.1, 37.4,28.1. HRMS (ESI) m / z: [M+Na] + Calculated for C 26 H24 NaO3 407.1623; Found 407.1622.HPLC analysis: Chiracel OD-H column, n-Hex / i-PrOH = 99:1, 0.8 mL / min, 254 nm, minor enantiomer: 40.7 min, major enantiomer: 42.9 min, 93% ee; [α] = -28.0° (c = 0.1, CHCl3).

[0078] Example 10

[0079] A synthetic method for (S)-(2,3-Bis(4-(trimethylsilyl)phenyl)cyclopent-2-en-1-yl)(phenyl)methanone ((S)-2,3-bis(4-(trimethylsilyl)phenyl)cyclopent-2-en-1-yl methyl ketone) is described. The reaction formula and reaction procedure are as follows:

[0080]

[0081] Under a nitrogen atmosphere, secondary phosphooxy ligand PO (23.5 mg, 0.04 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), tetrahydrofuran (1.0 mL), A-1 (29.2 mg, 0.2 mmol), and B-5 (129.0 mg, 0.4 mmol) were added to the reaction flask, followed by the addition of trimethylaluminum (1 M, 60 μL, 30 mol%). The mixture was stirred at 50 °C for 10 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a pale yellow solid C-10 in 87% yield.

[0082] 1 H NMR (400 MHz, CDCl3) δ 8.02–8.00 (m, 2H), 7.59–7.55 (m, 1H), 7.49–7.44 (m, 4H), 7.37–7.35 (m, 2H), 7.32–7.30 (m, 2H), 5.15–5.12 (m, 1H), 3.29–3.20 (m, 1H), 2.99–2.91 (m, 1H), 2.65–2.55 (m, 1H), 2.32-2.25 (m, 2H), 0.32 (s, 9H), 0.27 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ201.3, 141.4, 139.1, 138.7,137.9, 137.0, 136.7, 133.3, 133.2, 132.9, 128.7, 128.6, 127.8, 127.6, 58.8,37.8, 28.2, -1.0, -1.0. HRMS (ESI) m / z: [M+Na] + Calculated for C 30 H 36 NaOSi2491.2202; Found 491.2199. HPLC analysis: Chiracel OD-H column, n-Hex / i-PrOH =99:1, 0.8 mL / min, 254 nm, minor enantiomer: 5.8 min, major enantiomer: 6.3min, 99% ee; [α] = -11.8° (c = 0.1, CHCl3).

[0083] Example 11

[0084] The synthetic method of (S)-(2,3-Bis(4-chlorophenyl)cyclopent-2-en-1-yl)(phenyl)methanone is described. The reaction formula and reaction procedure are as follows:

[0085]

[0086] Under a nitrogen atmosphere, secondary phosphooxy ligand PO (23.5 mg, 0.04 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), tetrahydrofuran (1.0 mL), A-1 (29.2 mg, 0.2 mmol), and B-6 (98.8 mg, 0.4 mmol) were added to the reaction flask, followed by the addition of trimethylaluminum (1 M, 60 μL, 30 mol%). The mixture was stirred at room temperature for 1 hour, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give a white solid C-11 in 99% yield.

[0087] 1 H NMR (400 MHz, CDCl3) δ 7.94–7.92 (m, 2H), 7.56–7.53 (m, 1H), 7.46–7.43 (m, 2H), 7.20–7.18 (m, 2H), 7.13–7.10 (m, 4H), 7.05–7.03 (m, 2H), 5.05–5.03 (m, 1H), 3.17–3.08 (m, 1H), 2.87–2.80 (m, 1H), 2.61–2.51 (m, 1H), 2.25–2.18 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 201.1, 141.1, 136.7, 136.2, 135.8,135.5, 133.3, 133.1, 132.9, 130.0, 129.7, 128.8, 128.7, 128.6, 128.5, 58.4,37.5, 28.3. HRMS (ESI) m / z: [M+H] + Calculated for C 24 H 19 Cl2O 393.0813; Found393.0814. HPLC analysis: Chiracel OD-H column, n-Hex / i-PrOH = 99:1, 0.6 mL / min, 254 nm, minor enantiomer: 14.8 min, major enantiomer: 16.4 min, 90% ee;[α] = -11.4° (c = 0.1, CHCl3).

[0088] Example 12

[0089] A synthetic method for (S)-(3-Methyl-2-phenylcyclopent-2-en-1-yl)(phenyl)methanone is described. The reaction formula and reaction procedure are as follows:

[0090]

[0091] Under a nitrogen atmosphere, secondary oxygen ligand PO (35.2 mg, 0.06 mmol), Ni(cod)2 (16.5 mg, 0.06 mmol), tetrahydrofuran (5.0 mL), A-1 (29.2 mg, 0.2 mmol), and B-7 (61.0 mg, 0.4 mmol) were added to the reaction flask, followed by the addition of trimethylaluminum (1 M, 160 μL, 80 mol%). The mixture was stirred at room temperature for 24 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a pale yellow oily liquid C-12 in 57% yield.

[0092] 1 H NMR (400 MHz, CDCl3) δ 8.05–8.03 (m, 2H), 7.60–7.56 (m, 1H), 7.51–7.47 (m, 2H), 7.38–7.33 (m, 4H), 7.26–7.23 (m, 1H), 4.60 (t, J = 7.4 Hz, 1H), 2.88–2.85 (m, 2H), 2.44–2.35 (m, 1H), 2.15–2.07 (m, 1H), 1.80 (d, J = 0.92Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 202.3, 139.2, 138.0, 137.3, 133.2, 133.1,128.8, 128.7, 128.2, 128.0, 126.8, 59.0, 36.5, 27.8, 15.0. HRMS (ESI) m / z: [M+Na] + Calculated for C 19 H 18NaO 285.1255; Found 285.1246. HPLC analysis: ChiracelOJ-H column, n-Hex / i-PrOH = 99:1, 0.6 mL / min, 254 nm, minor enantiomer: 37.6min, major enantiomer: 29.9 min, 96% ee; [α] = -10.6° (c = 0.1, CHCl3).

[0093] Example 13

[0094] A synthetic method for (S)-(2,3-Diethylcyclopent-2-en-1-yl)(phenyl)methanone is described. The reaction formula and reaction procedure are as follows:

[0095]

[0096] Under a nitrogen atmosphere, phosphooxyligand rac-PO (23.5 mg, 0.04 mmol), Ni(cod)2 (5.5 mg, 0.02 mmol), tetrahydrofuran (2.0 mL), A-1 (29.2 mg, 0.2 mmol), and B-8 (32.9 mg, 0.4 mmol) were added to the reaction flask, followed by the addition of trimethylaluminum (1 M, 60 μL, 30 mol%). The mixture was stirred at room temperature for 8 hours, then washed with an aqueous solution of disodium ethylenediaminetetraacetate. The mixture was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a pale yellow oily liquid C-13 in 84% yield.

[0097] 1 H NMR (400 MHz, CDCl3) δ 8.01–7.99 (m, 2H), 7.57–7.54 (m, 1H), 7.48–7.44 (m, 2H), 4.54 (t, J = 7.2 Hz, 1H), 2.52–2.36 (m, 2H), 2.29–2.09 (m, 4H), 1.98-1.86 (m, 2H), 1.02 (t, J = 7.6 Hz, 3H), 0.87 (t, J = 7.6 Hz, 3H). 13C NMR(100 MHz, CDCl3) δ 203.3, 141.2, 137.4, 135.1, 132.8, 128.6, 128.5, 55.1,34.6, 28.0, 21.6, 20.3, 13.2, 13.1. HRMS (ESI) m / z: [M+H] + Calcd. for C 16 H 21 O229.1592; Found 229.1597. HPLC analysis: Chiracel OD-H column, n-Hex / i-PrOH =99.5:0.5, 0.6 mL / min, 254 nm, minor enantiomer: 10.9 min, major enantiomer:11.6 min, 95% ee; [α] = -7.4° (c = 0.1, CHCl3)。

Claims

1. A method for synthesizing cyclopentenyl ketones using nickel-aluminum catalysis, characterized in that, The reaction formula and reaction process are as follows: ， In a nitrogen atmosphere, secondary phosphine oxide ligand PO, metal catalyst Ni(cod)2, solvent, raw material A, and raw material B are added to a reaction vessel. Then, a Lewis acid is added, and the mixture is stirred at a specified reaction temperature. After the reaction is complete, an aqueous solution of disodium ethylenediaminetetraacetate is added for washing. The mixture is separated, and the organic phase is dried and separated by column chromatography to obtain the target product C or D. R, R 1 and R 2 Each is independently selected from aryl and alkyl groups; The molar ratio of the secondary phosphooxyligand PO, the metal catalyst, the Lewis acid, and the raw material A is (0.05-0.3):(0.05-0.3):(0.1-0.8):

1.

2. The method according to claim 1, characterized in that: R is phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-chlorophenyl, or cyclohexylphenyl.

3. The method according to claim 1, characterized in that: R 1 It can be n-propyl, acetoxypropyl, phenyl, 4-methoxyphenyl, 4-trimethylsilylphenyl, 4-chlorophenyl, or ethyl.

4. The method according to claim 1, characterized in that: R 2 It can be n-propyl, acetoxypropyl, phenyl, 4-methoxyphenyl, 4-trimethylsilylphenyl, 4-chlorophenyl, ethyl or methyl.

5. The method according to claim 1, characterized in that: The secondary phosphooxy ligand is a chiral dinitrogen-substituted secondary phosphooxy ligand with the following structural formula: ， Alternatively, a non-chiral dinitrogen-substituted secondary phosphooxy ligand may be used, with the following structural formula: 。 6. The method according to claim 1, characterized in that: The Lewis acid is an organoaluminum compound, an organozinc compound, or an organomagnesium compound. Preferably, the organoaluminum compound is trimethylaluminum, the organozinc compound is diethylzinc, and the organomagnesium compound is dibutylmagnesium.

7. The method according to claim 1, characterized in that: The solvent is a non-polar solvent, a moderately polar solvent, or a polar solvent, and the amount of solvent used is 0.5 to 5 mL / mmol A.

8. The method according to claim 1, characterized in that: The nonpolar solvent is toluene or n-hexane; the moderately polar solvent is tetrahydrofuran or 1,4-dioxane; and the polar solvent is dimethyl sulfoxide.

9. The method according to claim 1, characterized in that: The specified reaction temperature is 20–120 °C; the stirring time is 10–1440 minutes; and the organic phase is dried with anhydrous sodium sulfate.

10. The method according to any one of claims 1-9, characterized in that: The molar ratio of raw material B to raw material A is (1-3):1.

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