Asymmetric synthesis method of bicyclo [2.2. 2] octane-2, 5-diketone

Abstract

The invention discloses an asymmetric synthesis method of bicyclo [2.2. 2] octane-2, 5-diketone, which comprises the following steps: taking 2-cyclohexene-1-ketone as a reaction substrate to react with triphenylchlorosilane, reacting the obtained intermediate 1 with trifluoroethyl acrylate under the action of a pre-catalyst and trifluoromethanesulfonic acid to generate an intermediate 2, and reacting the intermediate 2 with trifluoroethyl acrylate under the action of a pre-catalyst and trifluoromethanesulfonic acid to generate the bicyclo [2.2. 2] octane-2, 5-diketone. Mixing and reacting the intermediate 2 with ethylene glycol and p-toluenesulfonic acid monohydrate to obtain an intermediate 3, reducing the intermediate 3 under the action of an organic reducing agent to generate an intermediate 4, reacting the intermediate 4 with reactants of oxalyl chloride and dimethyl sulfoxide, adding triethylamine, stirring to generate an intermediate 5, and carrying out oxidative deformylation and acid hydrolysis reaction on the intermediate 5 to obtain an intermediate 2; and reacting to generate the bicyclo [2.2. 2] octane-2, 5-diketone. The synthesis method is short in synthesis step, simple to operate and high in product generation rate.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and particularly relates to an asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione. Background Art

[0002] As a new type of advantageous ligand for asymmetric catalysis, the research and application of chiral dienes in asymmetric synthesis have attracted widespread attention from organic chemists. In many cases, chiral dienes show unique advantages over other types of traditional chiral ligands (such as phosphorus and nitrogen ligands) in terms of catalytic activity and enantioselectivity. So far, chiral diene ligands have made important progress in metal-catalyzed asymmetric reactions, mainly including the addition reaction of organoboron reagents to C=X (X=N, O) bonds or Michael acceptors, carbene insertion into YH (Y=C, N, O, S, B, Si) bonds, cyclopropanation reactions and allylic substitution reactions (see Chem. Rev. 2022, 122, 14346). At the same time, the development of practical synthesis methods for chiral diene ligands is crucial for in-depth exploration of their applications in asymmetric synthesis. The bicyclo[2.2.2]octadiene ligand developed by Hayashi's group (J.Am.Chem.Soc.2004,126,13584; J.Org.Chem.2005,70,2503) is a very useful chiral diene ligand with good enantioselectivity in some metal-catalyzed asymmetric reactions. In recent years, this ligand has achieved great success in many asymmetric syntheses. Chiral bicyclo[2.2.2]octane-2,5-dione is an important precursor for the synthesis of this type of ligand. The development of a simple asymmetric synthesis method for bicyclo[2.2.2]octane-2,5-dione is of great significance for expanding the application of this type of ligand in asymmetric synthesis and developing new catalytic asymmetric reactions in the future.

[0003] How to prepare optically active bicyclo[2.2.2]octane-2,5-dione has always been a hot topic among organic chemists. However, the methods for obtaining this compound are still very limited. There are mainly the following methods: a) chemically resolving the racemic raw material or directly splitting it with a chiral chromatographic column (J. Org. Chem. 2005, 70, 2503; Tetrahedron Lett. 1990, 31, 4057; J. Org. Chem. 1985, 50, 5528); b) splitting the racemic raw material with a biological enzyme (J. Org. Chem. 2010, 75, 2057; Org. Biomol. Chem. 2006, 4, 2304; J. Chem. Soc., Perkin Trans. 1 1992, 2337); c) asymmetric reduction of the meso-racemic raw material with a biological enzyme, followed by multi-step chemical transformation (J. Org. Chem. 1996, 61, 3794).

[0004] The main disadvantages of the above methods are that, whether the racemic raw materials are chemically resolved or enzymatically resolved, the overall yield is low (at least half is lost) and the operation is cumbersome, which is not conducive to large-scale preparation. The use of biological enzymes for asymmetric reduction and then multi-step chemical transformation also has the problem of lengthy steps and low overall yield.

[0005] Based on the above problems, it is necessary to develop a simple method for synthesizing bicyclo[2.2.2]octane-2,5-dione. Summary of the invention

[0006] The object of the present invention is to provide an asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione to solve at least one of the above technical problems.

[0007] The present invention provides an asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione, comprising the following steps:

[0008] Step 1: 2-cyclohexene-1-one is subjected to silylation reaction with triphenylsilyl chloride to obtain intermediate 1, and intermediate 1 is dissolved in dichloromethane solvent to obtain a dichloromethane solution of intermediate 1;

[0009] Step 2: dissolving the precatalyst in dichloromethane solvent, cooling the solution to below -50°C under the protection of inert gas, adding a dichloromethane solution of trifluoromethanesulfonic acid and mixing thoroughly, then cooling the mixture to below -70°C, adding a dichloromethane solution of trifluoroethyl acrylate and intermediate 1, stirring until fully reacted, quenching the reactant, filtering, concentrating, and purifying to obtain intermediate 2;

[0010] Step 3: Dissolve the intermediate 2, ethylene glycol and p-toluenesulfonic acid monohydrate in benzene, heat to fully react and then cool to room temperature, quench the reactants, separate the layers, obtain the organic phase and purify it to obtain the intermediate 3;

[0011] Step 4: Dissolve the intermediate 3 in tetrahydrofuran solvent, slowly add an organic reducing agent in batches to fully react, then quench the reaction, extract the reaction solution, and purify the organic phase to obtain the intermediate 4;

[0012] Step 5: Under low temperature conditions, dimethyl sulfoxide is slowly added dropwise to a dichloromethane solvent of oxalyl chloride, and the mixture is allowed to stand for at least 5 minutes. A dichloromethane solution of intermediate 4 is then slowly added dropwise. After 15 to 30 minutes, triethylamine is added. The mixture is stirred and reacted at room temperature. The reactants are quenched, extracted, and the organic phase is purified to obtain intermediate 5.

[0013] Step 6: Dissolve the intermediate 5 in a mixed solution of THF / t-BuOH, add potassium tertiary butoxide, pass oxygen through it for sufficient reaction, add a strong acid aqueous solution for sufficient hydrolysis, dilute the reactant with ethyl acetate, and then wash with a salt solution, dry, concentrate, and purify in sequence to obtain bicyclo[2.2.2]octane-2,5-dione.

[0014] As a preferred embodiment, the step 1 specifically comprises the following steps:

[0015] Step 1.1: 2-cyclohexen-1-one is dissolved in tetrahydrofuran, and a strong base reagent is added dropwise at a temperature below -75°C, and stirred until the reaction is complete;

[0016] Step 1.2: Slowly add triphenylsilyl chloride and allow to react fully at room temperature;

[0017] Step 1.3: Quench with saturated salt solution, extract with ethyl acetate, wash the organic phase with saturated salt solution, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude intermediate 1;

[0018] Step 1.4: The crude intermediate 1 was purified by silica gel column to obtain yellow semisolid intermediate 1.

[0019] Preferably, in the step 1, the concentration of the intermediate 1 in the dichloromethane solution of the intermediate 1 obtained is 0.1 to 0.5 g / mL.

[0020] Preferably, in step 1.1, 2-cyclohexene-1-one is dissolved in tetrahydrofuran at a concentration of 0.1 to 2 M, and the strong base reagent comprises at least one of lithium hexamethyldisilazide, butyl lithium, phenyl lithium, lithium diisopropylamide, and sodium bis(trimethylsilyl)amide.

[0021] In addition, in some embodiments, the strong base reagent can also be selected from at least one of sodium hydride, potassium hydride, sodium methoxide, and sodium tert-butoxide.

[0022] As a preferred embodiment, the strong base reagent used in the step 1.1 is lithium hexamethyldisilazide, which is dissolved in tetrahydrofuran (THF). The preferred addition temperature of the strong base reagent is -76°C to -85°C. At this temperature, the strong base reagent is added dropwise. After the addition is completed, the mixture is stirred at this temperature for 0.5 to 1.5 hours until the reaction is complete.

[0023] In step 1, the molar ratio of 2-cyclohexene-1-one to triphenylsilyl chloride is 1:1-1.5. After adding triphenylsilyl chloride, the temperature is raised to room temperature, and the room temperature is between 20° C. and 30° C. The reaction is carried out within this temperature range for at least 0.5 h until the reaction is fully completed.

[0024] As a preferred embodiment, the temperature is controlled at 25° C. and stirred at a constant temperature. At this temperature, the reaction is more stable and more thorough.

[0025] In step 1.3, saturated salt solution is used for quenching, and the quenching temperature is not higher than 0°C. The saturated salt solution includes at least one of sodium bicarbonate solution, sodium chloride solution, ammonium chloride solution, sodium carbonate solution, sodium potassium tartrate solution, and potassium chloride solution. After quenching, ethyl acetate is used for extraction, and the combined organic phase is washed once with a saturated salt solution, and anhydrous Na 2 SO 4 Dry, filter and concentrate to obtain the crude intermediate 1.

[0026] In step 1.4, the crude intermediate 1 was purified by silica gel column chromatography using an eluent containing 1‰ Et 3 N-hexane to give a yellow semisolid intermediate 1.

[0027] The structural formula of intermediate 1 is shown in formula (1):

[0028]

[0029] Furthermore, in step 2, after the pre-catalyst is activated with trifluoromethanesulfonic acid, intermediate 1 reacts with trifluoroethyl acrylate to prepare intermediate 2, wherein the preparation step of the pre-catalyst includes:

[0030] Step 2.1: o-Tolylboronic acid is dissolved in toluene, and the reaction mixture is heated to reflux using a water separator. After sufficient reaction, the reaction mixture is cooled to room temperature;

[0031] Step 2.2: Add diphenyl-2-pyrrolidinemethanol and heat under reflux until the reaction is fully reacted;

[0032] Step 2.3: After cooling to room temperature, the solvent was distilled off to obtain a yellow oily precatalyst.

[0033] In step 2.2, the diphenyl-2-pyrrolidinemethanol is selected from (S)-diphenyl-2-pyrrolidinemethanol or (R)-diphenyl-2-pyrrolidinemethanol.

[0034] The detailed operation method is that in step 2, 1 to 5 mmol of o-tolylboronic acid is added to every 10 mL of toluene, and the reaction mixture is heated to reflux using a water separator. The reaction time is 5 to 10 hours. After sufficient reaction, the reaction mixture is cooled to room temperature, and (S)-diphenyl-2-pyrrolidinemethanol is added in an amount of 1 to 1.2 times the mass of o-tolylboronic acid. The heating and reflux are continued for 3 to 5 hours. After complete and sufficient reaction, it is cooled to room temperature, and the solvent is distilled off to obtain a yellow oily precatalyst, which is dissolved in a toluene solution to obtain a toluene solution of the precatalyst. The concentration of the precatalyst in the toluene solution is 0.2 to 1 mole.

[0035] The toluene solution of the obtained precatalyst is placed in a round-bottom flask, and the solvent is removed by rotary evaporation under reduced pressure, and then dichloromethane solvent is added. Under the protection of an inert gas such as argon or helium, the solution is cooled to below -50°C, preferably at a temperature of -55°C to -70°C, and a dichloromethane solution of trifluoromethanesulfonic acid is added dropwise. After sufficient mixing, the solution is cooled to -70°C to -85°C, and trifluoroethyl acrylate is added. Then, a dichloromethane solution of intermediate 1 is added dropwise within 4 hours through a syringe pump, and the mixture is stirred for 8 to 15 hours until the reaction is fully reacted. Triethylamine is added to the reactants to quench the reaction, and the mixture is naturally heated to room temperature, filtered on silica gel, concentrated, and purified by silica gel column chromatography to obtain intermediate 2 as a colorless oil.

[0036] Among them, the structural formula of intermediate 2 is shown in formula (2):

[0037]

[0038] In step 2, the volume ratio of the toluene solution of the precatalyst, the dichloromethane solution of trifluoromethanesulfonic acid, trifluoroethyl acrylate, and the dichloromethane solution of intermediate 1 is 5-7:10-12:5-6:40-45, the concentration of trifluoromethanesulfonic acid in the dichloromethane solution is 0.1-0.5 molar, and the temperature is raised to room temperature, the room temperature is 20°C-30°C, and preferably the room temperature is 25°C.

[0039] As a preferred embodiment, in the step 3, the molar ratio of intermediate 2, ethylene glycol and p-toluenesulfonic acid monohydrate is 1:5-100:0.01-2, and is added to a water separator and heated to reflux. The reaction temperature is 85°C to 95°C. After 3 to 5 hours of complete reaction, the reaction mixture is cooled to room temperature, preferably room temperature is 25°C, and slowly quenched with a saturated salt solution at 0°C or below. After separation, the aqueous phase is extracted with ethyl acetate, the combined organic phase is washed with a saturated salt solution, and then Na 2 SO 4 Drying, filtration and concentration followed by purification by silica gel column chromatography afforded Intermediate 3 as a yellow oil.

[0040] Among them, the structural formula of intermediate 3 is shown in formula (3):

[0041]

[0042] In step 3, the saturated salt solution includes at least one of sodium bicarbonate solution, sodium chloride solution, ammonium chloride solution, sodium carbonate solution, sodium potassium tartrate solution, and potassium chloride solution.

[0043] Specifically, in step 4, 2.5 g to 3.2 g of intermediate 3 is dissolved in every 10 mL of tetrahydrofuran solvent, cooled to 0° C., and an organic reducing agent is slowly added in batches, wherein the molar ratio of the organic reducing agent to the intermediate 3 is 1 to 1.5:1, and the reaction is fully reacted for 0.3 to 0.8 h, and then the reaction is quenched, the reaction solution is extracted with ethyl acetate, and the combined organic phase is washed with a saline solution, and the organic phase is taken and washed with Na 2 SO 4 Drying, filtration and concentration, and purification by silica gel column chromatography gave Intermediate 4 as a yellow oil.

[0044] Among them, the structural formula of intermediate 4 is shown in formula (4):

[0045]

[0046] In step 4, as a preferred embodiment, the organic reducing agent includes at least one of lithium aluminum hydride, sodium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride, lithium borohydride, lithium triethylborohydride, triethylsilane, dimethoxyethoxyaluminum hydride, and a borohydride ligand; the quencher and detergent used are both saturated salt solutions, and the salt solution includes at least one of sodium bicarbonate solution, sodium chloride solution, ammonium chloride solution, sodium carbonate solution, sodium potassium tartrate solution, and potassium chloride solution.

[0047] As a preferred embodiment, in the step 5, in the dichloromethane solvent of oxalyl chloride, the mixed volume ratio of oxalyl chloride and dichloromethane solvent is 5mL~8mL:130mL~140mL, the operating temperature is not higher than -70°C, in the dichloromethane solution of intermediate 4, the concentration of intermediate 4 in dichloromethane is 0.45g~0.5g / mL, and the volume ratio of the dichloromethane solution of intermediate 4 to the dichloromethane solvent of oxalyl chloride is 1:50~70.

[0048] In the step 5, the volume ratio of the added amount of the triethylamine to the dichloromethane solution of the intermediate 4 is 1 to 1.2:1; after the addition of triethylamine, the reaction solution is gradually heated to room temperature, preferably 25°C, and continued to be stirred at room temperature for 1 to 2 hours, the reaction solution is quenched at no higher than 0°C, and extracted with an organic solvent, the organic phases are combined, washed, dried, filtered, and concentrated to obtain a crude product, which is purified by silica gel column chromatography to obtain a yellow oily intermediate 5.

[0049] As a preferred embodiment, in step 5, the organic solvent used for extraction may be dichloromethane solvent.

[0050] In step 5, the quenching agent used to quench the reaction is a saturated salt solution, and the saturated salt solution includes at least one of a sodium bicarbonate solution, a sodium chloride solution, an ammonium chloride solution, a sodium carbonate solution, a potassium sodium tartrate solution, and a potassium chloride solution.

[0051] Among them, the structural formula of intermediate 5 is shown in formula (5):

[0052]

[0053] As a preferred embodiment, in step 6, at room temperature, the intermediate 5 is dissolved in a mixed solution of THF / t-BuOH, the concentration of the intermediate 5 in the mixed solution of THF / t-BuOH is 0.030 g to 0.04 g / mL, potassium tertiary butoxide is added, and the molar ratio of the addition amount of potassium tertiary butoxide to the intermediate 5 is 1 to 2:1, and then oxygen is bubbled for 0.8 to 1.5 hours. After sufficient reaction, an equal volume of strong acid aqueous solution is added to continue the reaction for 1 to 3 hours, and then the reaction solution is diluted with ethyl acetate, and the organic phase is washed with a saturated salt solution, and then dried, filtered and concentrated to obtain a crude product, which is purified by silica gel column chromatography to obtain bicyclo[2.2.2]octane-2,5-dione.

[0054] In step 6, the strong acid aqueous solution may be selected from at least one of hydrochloric acid aqueous solution or sulfuric acid aqueous solution, boron trifluoride solution, and hydroiodic acid solution.

[0055] Among them, if (R)-diphenyl-2-pyrrolidinemethanol is added in step 2.2, the product obtained is the enantiomer of intermediate 2. By applying the steps of this method, (S,S)-configured bicyclo[2.2.2]octane-2,5-dione can be finally obtained; if (S)-diphenyl-2-pyrrolidinemethanol is added in step 2.2, by applying the steps of this method, (R,R)-configured bicyclo[2.2.2]octane-2,5-dione can be finally obtained.

[0056] The molecular structure of the (R,R)-configured bicyclo[2.2.2]octane-2,5-dione is shown in formula (6):

[0057]

[0058] The molecular structure of the (S,S)-configured bicyclo[2.2.2]octane-2,5-dione is shown in formula (7):

[0059]

[0060] The invention provides a simple and practical asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione. The basic skeleton of bicyclo[2.2.2]octane-2,5-dione is constructed based on 2-cyclohexene-1-one. The raw materials are easily available and have high reaction activity, which helps to reduce the generation of by-products in the synthesis process and improve the purity and yield of the product. Moreover, the entire synthesis step is simple and easy to operate. The synthesized bicyclo[2.2.2]octane-2,5-dione has high purity, which is of great significance for expanding the application of such ligands in asymmetric synthesis and developing new catalytic asymmetric reactions in the future. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 This is the asymmetric synthesis route of bicyclo[2.2.2]octane-2,5-dione of the present invention;

[0062] Figure 2 is the hydrogen nuclear magnetic resonance spectrum of bicyclo[2.2.2]octane-2,5-dione of the present invention;

[0063] Figure 3 The carbon nuclear magnetic resonance spectrum of bicyclo[2.2.2]octane-2,5-dione of the present invention is shown in FIG. DETAILED DESCRIPTION

[0064] The present invention is further described in detail below in conjunction with the embodiments. The examples are only for explanation and are not intended to limit the present invention in any way. Unless otherwise specified, the raw materials and reagents used in the examples are conventional products that can be obtained commercially; the experimental methods in the examples without specifying the specific conditions are conventional methods and conventional conditions well known in the art.

[0065] This embodiment is just one of the implementation modes. The specific reaction parameters can be adjusted flexibly as needed. The specific adjustment range can refer to the above records.

[0066] Step 1: Synthesis of Intermediate 1

[0067]

[0068] Step 1.1: 2-Cyclohexen-1-one (10.0 g, 104 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (104 mL). Lithium hexamethyldisilazide (1.0 M in THF, 115 mL, 115 mmol, 1.1 equiv) was added dropwise at -78 °C. After the addition was complete, the mixture was stirred at this temperature for one hour until the reaction was complete.

[0069] Step 1.2: Slowly add triphenylsilyl chloride (33.8 g, 115 mmol, 1.1 equiv), raise the temperature to 25°C, and react for one hour;

[0070] Step 1.3: Quench with saturated sodium bicarbonate solution (100 mL), extract with ethyl acetate (2×100 mL), wash the combined organic phases once with saturated sodium chloride solution (100 mL), and dry with anhydrous Na 2 SO 4 Dry, filter and concentrate to obtain the crude intermediate 1;

[0071] Step 1.4: The crude intermediate 1 was purified by silica gel column chromatography (eluent: n-hexane containing 1‰ Et3N) to obtain a yellow semisolid intermediate 1.

[0072] According to the above steps, a total of 33.5 g of intermediate 1 was obtained, with a yield of 96%.

[0073] TLC:R f =0.6(1‰Et 3 N in hexane);

[0074] 1 H NMR(600MHz,C6D6)δ7.81–7.79(m,5H),7.18–7.14(m,10H),5.98(dq,J=9.9,2.0Hz ,1H),5.64–5.59(m,1H),5.04–4.99(m,1H),1.90–1.85(m,2H),1.81–1.75(m,2H);

[0075] 13C NMR (151MHz, C6D6) δ148.8,136.0,134.7,130.4,129.2,128.2,126.7,103.6,22.8,22.0;

[0076] HRMS(ESI):m / z calcd for C 24 H 23 OSi + [M+H] + 355.1513, found 355.1509.

[0077] Step 2: Synthesis of Intermediate 2

[0078]

[0079] The preparation steps of the precatalyst include:

[0080] Step 2.1: o-Tolylboronic acid (1.36 g, 10.0 mmol) was dissolved in toluene (20 mL), and the reaction mixture was heated to reflux for 8 hours using a water separator. After sufficient reaction, the reaction mixture was cooled to 25°C;

[0081] Step 2.2: Add (S)-diphenyl-2-pyrrolidinemethanol (2.53 g, 10 mmol), and heat under reflux to react for 4 hours;

[0082] Step 2.3: After cooling to 25°C, the solvent was distilled off to obtain a yellow oily precatalyst.

[0083] Preparation of Intermediate 2:

[0084] The prepared precatalyst was dissolved in a toluene solution (0.5 M in toluene, 6.34 mL, 3.17 mmol, 0.075 equiv) to obtain a toluene solution of the precatalyst. The toluene solution of the precatalyst was placed in a 250 mL dried round-bottom flask for reduced pressure evaporation. After removing the solvent, dichloromethane solvent (42 mL) was added. The solution was cooled to -60 ° C under argon protection, and a dichloromethane solution of trifluoromethanesulfonic acid (0.2 M in DCM, 10.6 mL, 2.11 mmol, 0.05 equiv) was fully mixed. After 10 min, the mixture was cooled to below -78 ° C, trifluoroethyl acrylate (5.87 mL, 46.5 mmol, 1.1 equiv) was added, and a solution of intermediate 1 (15.0 g, 42.3 mmol, 1 equiv) in dichloromethane (42 mL) was added dropwise via a syringe pump over 4 hours. The reaction mixture was stirred at -78 ° C for 12 hours until the reaction was fully reacted, and then Et3N (4 mL) was added to quench the reaction. The temperature was naturally raised to 25 ° C, filtered on silica gel, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 500:1 to 50:1) to obtain intermediate 2 as a colorless oil.

[0085] According to the above steps, a total of 18.3 g of intermediate 2 was obtained with a yield of 85% and >99% ee.

[0086] TLC:R f =0.4 (hexane / ethyl acetate=20:1);

[0087] = +16(c = 1.0, CHCl 3 );

[0088] 1 H NMR (500 MHz, C 6 D 6 )δ7.78–7.75(m,5H),7.22–7.15(m,10H),5.05(dd,J=7.1,2.3Hz,1H),4.09–3.94(m,2H),2.74(dd,J=6.9,2. 8Hz,1H),2.48(d,J=2.7Hz,1H),2.22–2.17(m,1H),2.04–1.96(m,1H),1.36–1.30(m,1H),1.12–0.94(m,4H);

[0089] 13 C NMR (126MHz, C 6 D 6)δ172.9,157.3,135.9,134.3,130.5,128.2,123.8(q,J CF =277.4Hz),103.9,60.0(q,J CF =36.0Hz),43.2,35.9,33.7,29.7,26.4,24.9;

[0090] HRMS(ESI):m / z calcd for C 29 H 28 F 3 O 3 Si + [M+H] + 509.1754, found 509.1747;

[0091] Chiral HPLC: Chiralpak OD-H column (4.6×250mm), hexane / i-propanol=99:1, flow rate=1.0mL / min, λ=230nm, tR(minor)=4.3min, tR(major)=4.7min.

[0092] Step 3: Synthesis of Intermediate 3

[0093]

[0094] Intermediate 2 (28.0 g, 55.0 mmol, 1 equiv), ethylene glycol (15.4 mL, 275 mmol, 5 equiv) and p-toluenesulfonic acid monohydrate (523 mg, 2.75 mmol, 0.05 equiv) were dissolved in benzene (AR, 55 mL), a water separator was added, and the mixture was heated to 90 °C. After 4 hours, the reaction mixture was cooled to 25 °C and slowly treated with saturated NaHCO at 0 °C. 3 The aqueous solution (50 mL) was quenched, and after separation, the aqueous phase was extracted with ethyl acetate (3×50 mL), and the combined organic phase was washed with sodium chloride solution (50 mL). 2 SO 4 After drying, filtering and concentration, the crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 100:1 to 10:1) to obtain Intermediate 3 as a yellow oil.

[0095] According to the above steps, a total of 15.7 g of intermediate 3 was obtained, with a yield of 97%.

[0096] TLC:R f =0.3 (hexane / ethyl acetate=10:1);

[0097] =-3.5(c=0.41,CHCl 3 );

[0098] 1 H NMR (500 MHz, CDCl 3 )δ4.58–4.49(m,1H),4.47–4.38(m,1H),3.99–3.91(m,2H),3.90–3.81(m,2H),2.67–2.54(m,1H),2.31–2.14(m,2H) ,1.98–1.92(m,1H),1.90–1.83(m,1H),1.83–1.74(m,2H),1.73–1.65(m,1H),1.61–1.55(m,2H),1.46–1.36(m,1H);

[0099] 13 C NMR (126 MHz, CDCl 3 )δ173.8,110.0,64.2,64.0,60.41(q,J CF =36.4Hz),40.1,37.2,32.5,29.5,24.8,24.8,20.8;

[0100] HRMS(ESI):m / z calcd for C 13 H 18 F 3 O 4 + [M+H] + 295.1152, found 295.1147.

[0101] Step 4: Synthesis of intermediate 4

[0102]

[0103] Intermediate 3 (15.6 g, 53.1 mmol, 1 equiv) was dissolved in tetrahydrofuran solvent (53 mL), cooled to 0 °C, and LiAlH 4 (2.02 g, 53.1 mmol, 1 equiv), after fully reacting for 0.5 h, the reaction was slowly quenched with a saturated sodium potassium tartrate solution (260 mL), the reaction solution was extracted with ethyl acetate (3×130 mL), the organic phases were washed with a saturated sodium chloride solution (100 mL), and the mixture was washed with Na 2 SO 4The reaction mixture was dried, filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (hexane / ethyl acetate = 10:1 to 1:1) to give 9.67 g of intermediate 4 as a yellow oil with a yield of 92%.

[0104] TLC:R f =0.4 (hexane / EtOAc=1:1);

[0105] =-54(c=1.0,CHCl 3 );

[0106] 1 H NMR (500 MHz, CDCl 3 )δ3.93–3.86(m,2H),3.86–3.77(m,2H),3.50(d,J=7.5Hz,2H),1.92(dt,J=14.6,2.6 Hz,1H),1.84–1.72(m,3H),1.66–1.51(m,4H),1.48–1.37(m,2H),1.32–1.24(m,1H);

[0107] 13 C NMR (126 MHz, CDCl 3 )δ110.7,65.6,64.0,63.7,37.2,36.1,32.7,27.5,25.7,25.6,21.2;

[0108] HRMS(ESI):m / z calcd for C 11 H 19 O 3 + [M+H] + 199.1329, found 199.1324.

[0109] Step 5: Synthesis of Intermediate 5

[0110]

[0111] To a solution of oxalyl chloride (6.16 mL, 72.7 mmol, 1.5 equiv) in dichloromethane (140 mL) was slowly added dropwise dimethyl sulfoxide (6.19 mL, 87.3 mmol, 1.8 equiv) at -78 °C. After standing for 10 minutes, a solution of intermediate 4 (9.60 g, 48.5 mmol, 1.5 equiv) in dichloromethane (20 mL) was slowly added dropwise. After 20 minutes, triethylamine (20.1 mL, 145 mmol, 3 equiv) was added. After 10 minutes, the reaction solution was gradually heated to 25 °C and stirred for 1 hour at 25 °C. The reaction mixture was heated to 40 °C with saturated NH 4 The reaction mixture was quenched with Cl solution (80 mL) and extracted with dichloromethane (3 × 80 mL). The organic phases were combined, washed with sodium chloride solution (80 mL), and washed with Na 2 SO 4 The reaction mixture was dried, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (hexane / ethyl acetate = 50:1 to 5:1) to obtain 9.12 g of yellow oily intermediate 5 with a yield of 96%.

[0112] TLC:R f =0.7 (hexane / EtOAc=1:1);

[0113] =-32(c=1.0,CHCl 3 );

[0114] 1 H NMR (500 MHz, CDCl 3 )δ9.69(s,1H),3.96–3.83(m,4H),2.41–2.34(m,1H),2.30–2.21(m,2H),1 .93–1.84(m,1H),1.80–1.74(m,2H),1.70–1.52(m,4H),1.50–1.42(m,1H);

[0115] 13 C NMR (126 MHz, CDCl 3 )δ204.8,110.0,64.1,63.9,47.9,37.4,32.4,27.9,25.0,22.1,21.3;

[0116] HRMS(ESI):m / z calcd for C 11 H 17 O 3 + [M+H] + 197.1172, found 197.1168.

[0117] Step 6: Synthesis of bicyclo[2.2.2]octane-2,5-dione (6)

[0118]

[0119] At 25°C, intermediate 5 (4.20 g, 21.4 mmol, 1 eq.) was dissolved in a mixed solution of THF / t-BuOH (80 mL / 40 mL), potassium tert-butoxide (3.60 g, 32.1 mmol, 1.5 eq.) was added, and then HO was used to obtain a 5% ethanol solution. 2 After bubbling for 1 hour, the reaction solution was cooled to 0°C, 4.0 M aqueous hydrochloric acid solution (20 mL) was slowly added, the temperature was raised to 25°C, stirring was continued for 12 hours, the reaction solution was diluted with ethyl acetate (250 mL), washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (n-hexane / ethyl acetate = 7:1 to 3:1) to obtain bicyclo[2.2.2]octane-2,5-dione as a white solid.

[0120] According to the above steps, a total of 2.01 g of bicyclo[2.2.2]octane-2,5-dione was obtained with a yield of 68%.

[0121] TLC:R f =0.3 (hexane / EtOAc=2:1);

[0122] =-40(c=0.2,CHCl 3 );

[0123] 1 H NMR (500 MHz, CDCl 3 )δ2.84–2.65(m,2H),2.60–2.43(m,4H),2.09–2.01(m,2H),2.00–1.90(m,2H);

[0124] 13 C NMR (126 MHz, CDCl 3 )δ211.8,45.2,40.6,22.4;

[0125] HRMS(ESI):m / z calcd for C 8 H 11 O 2 + [M+H] + 139.0754, found 139.0751.

[0126] The above are only some embodiments of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the creative concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for the asymmetric synthesis of bicyclo[2.2.2]octane-2,5-dione, characterized in that: The steps include: Step 1: 2-cyclohexene-1-one is subjected to silylation reaction with triphenylsilyl chloride to obtain intermediate 1, and intermediate 1 is dissolved in dichloromethane solvent to obtain a dichloromethane solution of intermediate 1; Step 2: dissolving the precatalyst in dichloromethane solvent, cooling the solution to below -50°C under the protection of inert gas, adding a dichloromethane solution of trifluoromethanesulfonic acid and mixing thoroughly, then cooling the mixture to below -70°C, adding a dichloromethane solution of trifluoroethyl acrylate and intermediate 1, stirring until fully reacted, quenching the reactant, filtering, concentrating, and purifying to obtain intermediate 2; Step 3: Dissolve the intermediate 2, ethylene glycol and p-toluenesulfonic acid monohydrate in benzene, heat to fully react and then cool to room temperature, quench the reactants, separate the layers, obtain the organic phase and purify it to obtain the intermediate 3; Step 4: Dissolve the intermediate 3 in tetrahydrofuran solvent, slowly add an organic reducing agent in batches to fully react, then quench the reaction, extract the reaction solution, and purify the organic phase to obtain the intermediate 4; Step 5: Under low temperature conditions, dimethyl sulfoxide is slowly added dropwise to a dichloromethane solvent of oxalyl chloride, and the mixture is allowed to stand for at least 5 minutes. A dichloromethane solution of intermediate 4 is then slowly added dropwise. After 15 to 30 minutes, triethylamine is added. The mixture is stirred and reacted at room temperature. The reactants are quenched, extracted, and the organic phase is purified to obtain intermediate 5. Step 6: Dissolve the intermediate 5 in a mixed solution of THF / t-BuOH, add potassium tertiary butoxide, pass oxygen through it for sufficient reaction, add a strong acid aqueous solution for sufficient hydrolysis, dilute the reactant with ethyl acetate, and then wash with a salt solution, dry, concentrate, and purify in sequence to obtain bicyclo[2.2.2]octane-2,5-dione.

2. The asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione according to claim 1, characterized in that: The step 1 specifically comprises the following steps: Step 1.1: 2-cyclohexen-1-one is dissolved in tetrahydrofuran, and a strong base reagent is added dropwise at a temperature below -75°C, and stirred until the reaction is complete; Step 1.2: Slowly add triphenylsilyl chloride and allow to react fully at room temperature; Step 1.3: Quench with saturated salt solution, extract with ethyl acetate, wash the organic phase with saturated salt solution, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude intermediate 1; Step 1.4: The crude intermediate 1 was purified by silica gel column to obtain yellow semisolid intermediate 1.

3. The asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione according to claim 2, characterized in that: In the step 1.1, the strong base reagent includes at least one of lithium hexamethyldisilazide, butyl lithium, phenyl lithium, lithium diisopropylamide, and sodium bis(trimethylsilyl)amide.

4. The asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione according to claim 1, characterized in that: In step 2, the preparation step of the precatalyst includes: Step 2.1: o-Tolylboronic acid is dissolved in toluene, and the reaction mixture is heated to reflux using a water separator. After sufficient reaction, the reaction mixture is cooled to room temperature; Step 2.2: Add diphenyl-2-pyrrolidinemethanol and heat under reflux until the reaction is fully reacted; Step 2.3: After cooling to room temperature, the solvent was distilled off to obtain a yellow oily precatalyst.

5. The asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione according to claim 3, characterized in that: In step 2, a dichloromethane solution of intermediate 1 was added dropwise via a syringe pump over 4 hours.

6. The asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione according to claim 3, characterized in that: The prepared precatalyst is dissolved in a toluene solution to obtain a toluene solution of the precatalyst. The toluene solution of the precatalyst is evaporated under reduced pressure, and after removing the solvent, a dichloromethane solvent is added.

7. The asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione according to claim 1, characterized in that: In the step 3, the molar ratio of the intermediate 2, ethylene glycol and p-toluenesulfonic acid monohydrate is 1:5-100:0.01-2, and the heating reaction temperature is 85°C-95°C.

8. The asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione according to claim 1, characterized in that: In step 4, the organic reducing agent includes at least one of lithium aluminum hydride, sodium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride, lithium borohydride, lithium triethylborohydride, triethylsilane, dimethoxyethoxyaluminum hydride, and a borohydride ligand.

9. The asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione according to claim 1, characterized in that: In the steps 2 to 5, the quenching temperature is not higher than 0°C, the quenching agent for the quenching reaction in step 2 is triethylamine, and the quenching agent for the quenching reaction in steps 3 to 5 is a saturated salt solution; in the step 5, the temperature of the low temperature condition is not higher than -70°C.

10. The asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione according to claim 9, characterized in that: The saturated salt solution includes at least one of a sodium bicarbonate solution, a sodium chloride solution, an ammonium chloride solution, a sodium carbonate solution, a potassium sodium tartrate solution, and a potassium chloride solution.

Images