Asymmetric Synthesis of Bicyclo[2.2.2]octane-2,5-dione

Abstract

The invention discloses an asymmetric synthesis method of bicyclo[2.2.2]octane-2,5-dione, wherein 2-cyclohexene-1-one is reacted with triphenylchlorosilane as a reaction substrate, the obtained intermediate 1 is reacted with trifluoroethyl acrylate under the action of a precatalyst and trifluoromethanesulfonic acid, and the generated intermediate 2 is mixed with ethylene glycol and p-toluenesulfonic acid monohydrate to obtain intermediate 3, which is reduced by an organic reducing agent to generate intermediate 4, which is reacted with the reactants of oxalyl chloride and dimethyl sulfoxide, and triethylamine is added and stirred to generate intermediate 5, which is oxidative deformylation and acid hydrolysis to generate bicyclo[2.2.2]octane-2,5-dione. The synthesis method has short synthesis steps, simple operation, and high product yield.

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, chiral dienes have attracted widespread attention from organic chemists for their research and application in asymmetric synthesis. In many cases, chiral dienes show unique advantages in catalytic activity and enantioselectivity over other types of traditional chiral ligands (such as phosphorus and nitrogen ligands). To date, chiral diene ligands have made significant progress in metal-catalyzed asymmetric reactions, mainly including the addition 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 synthetic methods for chiral diene ligands is crucial for in-depth exploration of their applications in asymmetric synthesis. The bicyclo[2.2.2]octadiene ligands developed by Hayashi's group (J.Am.Chem.Soc.2004,126,13584; J.Org.Chem.2005,70,2503) are a very useful class of chiral diene ligands, exhibiting excellent enantioselectivity in a variety of metal-catalyzed asymmetric reactions. In recent years, these ligands have achieved significant success in numerous asymmetric syntheses. Chiral bicyclo[2.2.2]octane-2,5-dione is an important precursor for the synthesis of this class of ligands. 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 class of ligands in asymmetric synthesis and for the future development of new catalytic asymmetric reactions.

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

[0004] The main drawbacks of these methods are that, whether chemical or enzymatic resolution of the racemic starting material, they all suffer from low overall yields (at least half is lost) and cumbersome procedures, making them unsuitable for large-scale production. Using enzymes for asymmetric reduction followed by multiple chemical transformations also results in lengthy steps and low overall yields.

[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-cyclohexen-1-one is subjected to a silylation reaction with triphenylsilyl chloride to obtain intermediate 1, which is then dissolved in dichloromethane to obtain a dichloromethane solution of intermediate 1;

[0009] Step 2: Dissolve the precatalyst in dichloromethane solvent, cool the solution to below -50°C under inert gas protection, add a dichloromethane solution of trifluoromethanesulfonic acid and mix thoroughly, then cool the mixture to below -70°C, add a dichloromethane solution of trifluoroethyl acrylate and intermediate 1, and stir until fully reacted. The reactant is quenched, filtered, concentrated, and purified to obtain intermediate 2;

[0010] Step 3: Dissolve intermediate 2, ethylene glycol, and p-toluenesulfonic acid monohydrate in benzene, heat to react fully, and then cool to room temperature. The reactants are quenched, and after separation, the organic phase is obtained and purified to obtain intermediate 3.

[0011] Step 4: Dissolve 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 intermediate 4;

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

[0013] Step 6: Dissolve intermediate 5 in a mixed solution of THF / t-BuOH, add potassium tertiary butoxide, pass oxygen through to allow for sufficient reaction, then 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 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: Dissolve 2-cyclohexen-1-one in tetrahydrofuran. Add a strong base dropwise at below -75°C and stir 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 saline solution, extract with ethyl acetate, wash the organic phase with saturated saline solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the 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 complete, 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 to 1.5. After adding triphenylsilyl chloride, the temperature is raised to room temperature, which is 20° C. to 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 complete.

[0025] In step 1.3, quenching is performed with a saturated salt solution at a temperature not exceeding 0°C. The saturated salt solution comprises 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, extraction is performed with ethyl acetate. The combined organic phases are washed once with a saturated salt solution, dried over anhydrous NaSO, filtered, and concentrated to obtain a crude intermediate 1.

[0026] In the step 1.4, the crude intermediate 1 is purified by silica gel column chromatography using n-hexane containing 1‰ Et3N as the eluent to obtain a yellow semi-solid 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, the intermediate 1 reacts with trifluoroethyl acrylate to prepare the intermediate 2, wherein the preparation step of the pre-catalyst includes:

[0030] Step 2.1: Dissolve o-tolylboronic acid in toluene, heat the reaction mixture to reflux using a water separator, and after sufficient reaction, cool the reaction mixture 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 as follows: 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-pyrrolidone methanol in an amount of 1 to 1.2 times the mass of o-tolylboronic acid is added. The heating and reflux are continued for 3 to 5 hours. After complete and sufficient reaction, the mixture 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. Dichloromethane solvent is then 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. A dichloromethane solution of trifluoromethanesulfonic acid is added dropwise. After thorough mixing, the solution is cooled to -70°C to -85°C. Trifluoroethyl acrylate is added, and a dichloromethane solution of intermediate 1 is added dropwise over 4 hours via a syringe pump. 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 warmed to room temperature. The mixture is filtered on silica gel, concentrated, and purified by silica gel column chromatography to obtain intermediate 2 as a colorless oil.

[0036] 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 to 30°C, preferably 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 the mixture is added to a water separator and heated to reflux. The reaction temperature is 85°C~95°C. After 3~5 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 dried with Na2SO4, filtered and concentrated, and purified by silica gel column chromatography to obtain intermediate 3 as a yellow oil.

[0040] 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, potassium sodium tartrate solution, and potassium chloride solution.

[0043] In detail, 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. The molar ratio of the organic reducing agent to the intermediate 3 is 1 to 1.5:1. 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. The organic phase is dried over Na2SO4, filtered and concentrated, and purified by silica gel column chromatography to obtain 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, potassium sodium 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 step 5, the volume ratio of the added amount of triethylamine to the dichloromethane solution of the intermediate 4 is 1 to 1.2:1; after adding triethylamine, the reaction solution is gradually heated to room temperature, preferably 25°C, and 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.

[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 sodium bicarbonate solution, sodium chloride solution, ammonium chloride solution, sodium carbonate solution, potassium sodium tartrate solution, and potassium chloride solution.

[0051] The structural formula of intermediate 5 is shown in formula (5):

[0052]

[0053] As a preferred embodiment, in the 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 and the reaction is continued 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, 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, the (S,S)-configuration bicyclo[2.2.2]octane-2,5-dione can be finally obtained; if (S)-diphenyl-2-pyrrolidinemethanol is added in step 2.2, the steps of this method can be finally obtained. (R,R)-configuration bicyclo[2.2.2]octane-2,5-dione.

[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 present invention provides a simple and practical asymmetric synthesis method for 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 readily 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. The method 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. 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. DETAILED DESCRIPTION

[0064] The present invention will be further described in detail below with reference to the following embodiments. The examples are provided for illustrative purposes only 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 commercially available conventional products; experimental methods without specific conditions in the examples are conventional methods and conditions well known in the art.

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

[0066] Step 1: Synthesis of Intermediate 1

[0067]

[0068] Step 1.1: Dissolve 2-cyclohexen-1-one (10.0 g, 104 mmol, 1.0 equiv) in tetrahydrofuran (104 mL). Add lithium hexamethyldisilazide (1.0 M in THF, 115 mL, 115 mmol, 1.1 equiv) dropwise at -78°C. After the addition is complete, stir at this temperature for 1 hour until the reaction is 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), dry over anhydrous Na2SO4, 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 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‰Et3N 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] 13 C 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: Dissolve o-tolylboronic acid (1.36 g, 10.0 mmol) in toluene (20 mL). Heat the reaction mixture under reflux using a water separator for 8 hours. After sufficient reaction, cool the reaction mixture 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 oven-dried round-bottom flask and evaporated under reduced pressure. 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 thoroughly mixed. After 10 min, the mixture was cooled to below -78 ° C and trifluoroethyl acrylate (5.87 mL, 46.5 mmol, 1.1 equiv) was added. 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 complete. Et3N (4 mL) was then added to quench the reaction, and the temperature was naturally raised to 25 ° C. Filtered on silica gel and concentrated to obtain a crude product, which 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,CHCl3);

[0088] 1 H NMR (500MHz, C6D6) 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, C6D6) 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 F3O3Si + [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) and a water separator was added. The mixture was heated to 90°C. After 4 hours, the reaction mixture was cooled to 25°C and slowly quenched with saturated aqueous NaHCO3 solution (50 mL) at 0°C. After separation, the aqueous phase was extracted with ethyl acetate (3×50 mL), and the combined organic phases were washed with sodium chloride solution (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 100:1 to 10:1) to give 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, CHCl3);

[0098] 1 H NMR (500MHz, CDCl3) 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 (126MHz, CDCl3) 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 F3O4 + [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 (53 mL) and cooled to 0°C. LiAlH4 (2.02 g, 53.1 mmol, 1 equiv) was slowly added in portions. After fully reacting for 0.5 h, the reaction was slowly quenched with saturated sodium potassium tartrate solution (260 mL). The reaction solution was extracted with ethyl acetate (3×130 mL), washed with saturated sodium chloride solution (100 mL), and the combined organic phases were dried over Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 10:1 to 1:1) to obtain 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, CHCl3);

[0106] 1 H NMR (500MHz, CDCl3) δ3.93–3.86(m,2H),3.86–3.77(m,2H),3.50(d,J=7.5Hz,2H),1.92(dt,J= 14.6,2.6Hz,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 (126MHz, CDCl3) 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 O3 + [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); after 10 minutes, the reaction solution was gradually warmed to 25°C and stirred at 25°C for 1 hour. The reaction solution was quenched with saturated NH4Cl solution (80 mL) at 0°C and extracted with dichloromethane (3×80 mL). The organic phases were combined, washed with sodium chloride solution (80 mL), dried over Na2SO4, 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 intermediate 5 as a yellow oil in a yield of 96%.

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

[0113] =-32 (c = 1.0, CHCl3);

[0114] 1 H NMR(500MHz, CDCl3)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 (126MHz, CDCl3) 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 O3 + [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 equ iv) was dissolved in a mixture of THF / t-BuOH (80 mL / 40 mL), and potassium tert-butoxide (3.60 g, 32.1 mmol, 1.5 equ iv) was added. O2 was then bubbled through the mixture for 1 hour. The reaction solution was then cooled to 0°C, and 4.0 M aqueous hydrochloric acid (20 mL) was slowly added. The temperature was raised to 25°C and 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 give the crude product, which was purified by silica gel column chromatography (n-hexane / ethyl acetate = 7:1 to 3:1) to give 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, CHCl3);

[0123] 1 H NMR (500MHz, CDCl3) 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 (126MHz, CDCl3) δ211.8, 45.2, 40.6, 22.4;

[0125] HRMS(ESI):m / z calcd for C8H 11 O2 + [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 inventive concept of the present invention, which all fall within the scope of protection 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-cyclohexen-1-one is subjected to a silylation reaction with triphenylsilyl chloride to obtain intermediate 1, which is then dissolved in dichloromethane to obtain a dichloromethane solution of intermediate 1; Step 2: The precatalyst is dissolved in dichloromethane solvent, and the solution is cooled to below −50° C. under inert gas protection. A dichloromethane solution of trifluoromethanesulfonic acid is added and mixed thoroughly. The mixture is then cooled to below −70° C., and a dichloromethane solution of trifluoroethyl acrylate and intermediate 1 is added and stirred until the reaction is fully reacted. The reactant is quenched, filtered, concentrated, and purified to obtain intermediate 2. The precatalyst is: ; Step 3: Dissolve intermediate 2, ethylene glycol, and p-toluenesulfonic acid monohydrate in benzene, heat to react fully, and then cool to room temperature. The reactants are quenched, and after separation, the organic phase is obtained and purified to obtain intermediate 3. Step 4: Dissolve 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 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. Then, a dichloromethane solution of intermediate 4 is slowly added dropwise. After 15 to 30 minutes, triethylamine is added. The reaction is stirred thoroughly at room temperature. The reactants are quenched, extracted, and the organic phase is purified to obtain intermediate 5. The temperature of the low temperature condition is not higher than -70°C. Step 6: Dissolve intermediate 5 in THF / t -BuOH mixed solution, add potassium tertiary butoxide, after oxygen is passed through to fully react, add strong acid aqueous solution to fully hydrolyze, dilute the reactant with ethyl acetate, and then wash with salt solution, dry, concentrate, and purify to obtain bicyclo[2.2.2]octane-2,5-dione; The synthesis process is as follows: 。 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: Dissolve 2-cyclohexen-1-one in tetrahydrofuran. Add a strong base dropwise at below -75°C and stir 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 saline solution, extract with ethyl acetate, wash the organic phase with saturated saline solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the 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 comprises 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: Dissolve o-tolylboronic acid in toluene, heat the reaction mixture to reflux using a water separator, and after sufficient reaction, cool the reaction mixture 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, the solvent is removed, and then 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 step 3, the molar ratio of 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, and dimethoxyethoxyaluminum hydride.

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.

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 sodium bicarbonate solution, sodium chloride solution, ammonium chloride solution, sodium carbonate solution, potassium sodium tartrate solution, and potassium chloride solution.

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