Method for synthesizing spiro compound by oxidation dearomatization
Through the method of oxidizing and dehuminating synthetic threading compounds, the problem of difficulty in synthesizing the key intermediates of the existing technology in the existing technology has been solved, and the high -efficiency intermediate system is realized. Aterior body compound.
Patent Information
- Application Number
- CN202411459992.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-18
- Publication Date
- 2025-01-21
AI Technical Summary
The prior art is difficult to efficiently synthesize key intermediates of trisapine, which affects the efficiency of bionic synthesis of trisapine.
The method of oxidizing and dehuminating synthetic threading compounds is used to build a C-C key through Suzuki coupling reaction to build a C-N key to oxidize dehuminogenic reactions, and synthesize the precursor compounds of the three-pointer iconic biological synthetic intermediate.
Efficient preparation of hahcephalomannine biomimetic synthesis intermediates was achieved, with a total yield of 39%, and key precursor compounds were provided for subsequent synthesis.
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Figure CN119331010A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of catalytic synthesis, and in particular relates to a method for synthesizing a spiro compound by utilizing oxidative dearomatization. Background Art
[0002] Natural products have novel structures and important physiological functions. How to efficiently complete the total synthesis of complex natural products is a problem that needs to be solved. Natural products come from nature, where they can be efficiently and mildly synthesized. Therefore, this study can draw on and simulate the pathways of biogenic synthesis of natural products in nature, such as enzyme catalysis, substrate structure, and bonding mode, to perform biomimetic synthesis and improve the synthesis efficiency of natural products. The existing biomimetic synthesis route of Cephalotaxine is to construct a ten-membered macrocyclic compound and perform an intramolecular cyclization reaction to obtain the Cephalotaxine skeleton structure or to construct a nitrogen-containing six-membered ring and obtain the Cephalotaxine skeleton structure through a trans-ring rearrangement reaction.
[0003] In 1980, Parry used 14 Phenylalanine and tyrosine were labeled with C isotopes, radioactive cephalosporin was collected, and it was chemically degraded to verify the hypothesis of the biogenic synthesis pathway of cephalosporin and propose a possible biogenic synthesis pathway. Starting from phenylalanine and tyrosine, a dibenzazepine ten-membered macrocyclic compound was synthesized through an intermediate: 1-phenethyl-1,2,3,4-tetrahydroisoquinoline derivative, and the compound was obtained through pathway a or pathway b to obtain a diketone compound. Pathway a: a nitrogen-containing five-membered heterocyclic ring is formed in the compound molecule, and pathway b: after a nitrogen-containing six-membered heterocyclic ring is formed in the molecule, electron transfer occurs to form a compound. The compound is then decarboxylated to obtain cephalosporin through an azacyclopentane rearrangement reaction. The strategy for designing a reverse synthetic route for the compound obtained by pathway b and synthesizing cephalosporin is as follows:
[0004]
[0005] Therefore, how to synthesize the key intermediates for the biomimetic synthesis of Cephalotaxine is of great significance for the biomimetic synthesis of Cephalotaxine. Summary of the invention
[0006] In order to prepare the key intermediate of the biomimetic synthesis of Cephalotaxine, the present invention provides a method for synthesizing a spiro compound by oxidative dearomatization, using Suzuki coupling reaction to construct CC bond, and oxidative dearomatization reaction to construct CN bond as the key synthesis strategy to synthesize the precursor compound of the biomimetic synthesis intermediate of Cephalotaxine. The synthesis route uses commercial reagent ferulic acid as a raw material, and synthesizes compound 1 through catalytic hydrogenation and Fischer esterification reaction. Compound 1 reacts with pivaloyl chloride to obtain compound 2, and then reacts with NIS to obtain compound 3. Compound 3 and compound 4 undergo Suzuki coupling reaction to obtain biphenyl compound 5 with a yield of 60%. Compound 5 is subjected to Piv protecting group removal, DIBAL reduction, condensation with tert-butylsulfenamide, and sodium borohydride reduction of C=N bond to obtain oxidative dearomatization reaction substrate 8, and compound 8 reacts with PIDA to obtain a spiro compound. The synthesis route has 9 steps in total, and the total yield is 39%
[0007] The present invention discloses a method for synthesizing a spiro compound by utilizing oxidative dearomatization, which is carried out according to the following steps:
[0008] 1. Mix ferulic acid, Pd / C and methanol, add PhCl after the ferulic acid is completely dissolved, and then charge with hydrogen. After the reaction is completed, remove the methanol by rotary evaporation under reduced pressure, filter the obtained crude product, elute, and then evaporate under reduced pressure to remove the eluent to obtain compound 1;
[0009] 2. Compound 1 and 4-dimethylaminopyridine were mixed, CH2Cl2 was added, triethylamine was added, and pivaloyl chloride was added dropwise. After the reaction was completed, the reaction was quenched, extracted, and the solvent was removed by evaporation under reduced pressure. The obtained crude product was filtered with dichloromethane to obtain compound 2;
[0010] 3. Compound 2 and N-iodosuccinimide were mixed, acetonitrile was then added, TFA was added dropwise after dissolution, the reaction was quenched after the reaction was completed, the organic phase was extracted, the organic solvent was removed by rotary evaporation, and then separated and purified to obtain compound 3;
[0011] 4. Compound 3, compound 4, potassium carbonate and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride were added to a reaction tube, nitrogen was filled after the anhydrous and oxygen-free treatment was completed, and then 1,4-dioxane was added, and then H2O was added. The reaction temperature was raised, and after the reaction was complete, the reaction was quenched, extracted, and the obtained organic phase was rotary evaporated to remove the solvent, separated and purified to obtain compound 5;
[0012] 5. Compound 5 and potassium carbonate were added to a reaction tube. After the anhydrous and oxygen-free treatment was completed, nitrogen was filled, and then MeOH solvent was added. After the reaction was complete, MeOH was concentrated in vacuo and removed. H2O and excess KHSO4 solution were added to the reaction tube, stirred, extracted, and the obtained organic phase was subjected to rotary evaporation to remove the organic solvent, separated and purified to obtain compound 6;
[0013] 6. Compound 6 is added to a reaction tube, and after the anhydrous and oxygen-free treatment is completed, nitrogen is filled, and then CH2Cl2 is added, and stirred to dissolve at room temperature, and then placed in anhydrous ethanol at -78°C, stirred, and then diisobutylaluminum hydride is added dropwise. After the reaction is complete, extraction and rotary evaporation are performed to remove the organic solvent, and then suction filtration is performed to obtain a mixture of compound 6 and compound 7;
[0014] 7. Add a mixture of compound 6 and compound 7 to a reaction tube, then add tert-butylsulfenamide, tetraethyl titanate and dry tetrahydrofuran to the reaction tube, add sodium borohydride after the reaction is complete, continue the reaction, add H2O to quench the reaction after the reaction is complete, stir, extract, and rotary evaporate to remove the organic solvent, and obtain compound 8 after separation and purification;
[0015] 8. Add compound 8 and iodophenyldiacetic acid into a glass bottle, then add tetrafluoroethylene, stir at room temperature, after the reaction is complete, remove tetrafluoroethylene by rotary evaporation, and obtain a spiro compound after separation and purification;
[0016] The specific preparation method of compound 4 is as follows:
[0017] a. Mix piperoacetic acid, methanol and acetyl chloride, stir at room temperature, and after the reaction is complete, remove methanol by rotary evaporation, and filter on a silica gel column to obtain product A;
[0018] b. Add N-bromosuccinimide and product A to a reaction bottle, add acetonitrile, add water to quench the reaction after the reaction is complete, extract, rotary evaporate, separate and purify to obtain product B;
[0019] c. Mix product B and dichloromethane, and after all of them are dissolved, add diisobutylaluminum hydride dropwise in an ice bath. After the reaction is complete, add water and a saturated sodium tartrate solution, stir at room temperature, extract, and rotary evaporate to separate and purify to obtain product C;
[0020] d. Add tert-butyldimethylsilyl chloride and CH2Cl2 to product C in an ice bath, then transfer to room temperature until the reaction is complete, quench the reaction, and filter through a silica gel column to obtain a compound protected by a TBS protecting group;
[0021] e. Add pinacol borate, palladium acetate and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl to the TBS-protected alcohol compound, add solvent 1,4-dioxane under nitrogen, heat to 60°C, add water to quench the reaction after the reaction is complete, extract, and pass through a column to obtain compound 4.
[0022] The reaction route is:
[0023]
[0024] Beneficial effects of the present invention:
[0025] In order to prepare a key intermediate of the biomimetic synthesis of cephalotaxine, the present invention uses ferulic acid as a starting material, undergoes catalytic hydrogenation and Fischer esterification reaction, and obtains a compound 1 with a yield of 98%; the compound 1 reacts with pivaloyl chloride to obtain a compound 2 with a yield of 100%; the compound 2 reacts with iodine imide to obtain an iodide 3 with a yield of 99%; the compound 3 and the compound 4 undergo a Suzuki coupling reaction to obtain a biphenyl compound 5, and the reaction step is carried out under different solvents (Dioxane, THF), different temperatures (80°C, 110°C), and different equivalents of the compound 4 (1.2 equiv., 1.5 equiv.), and finally determines the reaction conditions: 1.5 equiv. of the compound 4, 110°C, Dioxane:H2O=10:1, PdCl2dppf as a catalyst, K2CO3 as a base, and the compound 5 is obtained with a yield of 80%. Under the action of K2CO3, a deprotection reaction occurs to obtain compound 6 with a yield of 84%. Compound 6 reacts with DIBAL to reduce the ester group to an aldehyde group to obtain compound 7. Compound 7 undergoes a condensation reaction with tert-butylsulfenamide, followed by sodium borohydride reduction to obtain compound 8. The total yield of the three-step reaction is 79%. Compound 8 undergoes an oxidative dearomatization reaction with iodophenyl diacetic acid (PIDA) to obtain a spiro compound with a yield of 60%. The spiro compound can continue to undergo a deprotection reaction and then undergo an intramolecular Mitsunobu reaction to close the ring to obtain a key intermediate for biomimetic synthesis. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 is the H NMR spectrum of compound 8 obtained in Example 1;
[0027] Figure 2 is the C NMR spectrum of compound 8 obtained in Example 1;
[0028] Figure 3 is the H NMR spectrum of the spirocyclic compound obtained in Example 1;
[0029] Figure 4 This is the C NMR spectrum of the spirocyclic compound obtained in Example 1. DETAILED DESCRIPTION
[0030] Specific implementation method 1: This implementation method is a method for synthesizing spiro compounds by oxidative dearomatization, which is carried out according to the following steps:
[0031] 1. Mix ferulic acid, Pd / C and methanol, add PhCl after the ferulic acid is completely dissolved, and then charge with hydrogen. After the reaction is completed, remove the methanol by rotary evaporation under reduced pressure, filter the obtained crude product, elute, and then evaporate under reduced pressure to remove the eluent to obtain compound 1;
[0032] 2. Compound 1 and 4-dimethylaminopyridine were mixed, CH2Cl2 was added, triethylamine was added, and pivaloyl chloride was added dropwise. After the reaction was completed, the reaction was quenched, extracted, and the solvent was removed by evaporation under reduced pressure. The obtained crude product was filtered with dichloromethane to obtain compound 2;
[0033] 3. Compound 2 and N-iodosuccinimide were mixed, acetonitrile was then added, TFA was added dropwise after dissolution, the reaction was quenched after the reaction was completed, the organic phase was extracted, the organic solvent was removed by rotary evaporation, and then separated and purified to obtain compound 3;
[0034] 4. Compound 3, compound 4, potassium carbonate and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride were added to a reaction tube, nitrogen was filled after the anhydrous and oxygen-free treatment was completed, and then 1,4-dioxane was added, and then H2O was added. The reaction temperature was raised, and after the reaction was complete, the reaction was quenched, extracted, and the obtained organic phase was rotary evaporated to remove the solvent, separated and purified to obtain compound 5;
[0035] 5. Compound 5 and potassium carbonate were added to a reaction tube. After the anhydrous and oxygen-free treatment was completed, nitrogen was filled, and then MeOH solvent was added. After the reaction was complete, MeOH was concentrated in vacuo and removed. H2O and excess KHSO4 solution were added to the reaction tube, stirred, extracted, and the obtained organic phase was subjected to rotary evaporation to remove the organic solvent, separated and purified to obtain compound 6;
[0036] 6. Compound 6 is added to a reaction tube, and after the anhydrous and oxygen-free treatment is completed, nitrogen is filled, and then CH2Cl2 is added, and stirred to dissolve at room temperature, and then placed in anhydrous ethanol at -78°C, stirred, and then diisobutylaluminum hydride is added dropwise. After the reaction is complete, extraction and rotary evaporation are performed to remove the organic solvent, and then suction filtration is performed to obtain a mixture of compound 6 and compound 7;
[0037] 7. Add a mixture of compound 6 and compound 7 to a reaction tube, then add tert-butylsulfenamide, tetraethyl titanate and dry tetrahydrofuran to the reaction tube, add sodium borohydride after the reaction is complete, continue the reaction, add H2O to quench the reaction after the reaction is complete, stir, extract, and rotary evaporate to remove the organic solvent, and obtain compound 8 after separation and purification;
[0038] 8. Add compound 8 and iodophenyldiacetic acid into a glass bottle, then add tetrafluoroethylene, stir at room temperature, after the reaction is complete, remove tetrafluoroethylene by rotary evaporation, and obtain a spiro compound after separation and purification;
[0039] The specific preparation method of compound 4 is as follows:
[0040] a. Mix piperoacetic acid, methanol and acetyl chloride, stir at room temperature, and after the reaction is complete, remove methanol by rotary evaporation, and filter on a silica gel column to obtain product A;
[0041] b. Add N-bromosuccinimide and product A to a reaction bottle, add acetonitrile, add water to quench the reaction after the reaction is complete, extract, rotary evaporate, separate and purify to obtain product B;
[0042] c. Mix product B and dichloromethane, and after all of them are dissolved, add diisobutylaluminum hydride dropwise in an ice bath. After the reaction is complete, add water and a saturated sodium tartrate solution, stir at room temperature, extract, and rotary evaporate to separate and purify to obtain product C;
[0043] d. Add tert-butyldimethylsilyl chloride and CH2Cl2 to product C in an ice bath, then transfer to room temperature until the reaction is complete, quench the reaction, and filter through a silica gel column to obtain a compound protected by a TBS protecting group;
[0044] e. Add pinacol borate, palladium acetate and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl to the TBS-protected alcohol compound, add solvent 1,4-dioxane under nitrogen, heat to 60°C, add water to quench the reaction after the reaction is complete, extract, and pass through a column to obtain compound 4.
[0045] Specific embodiment 2: This embodiment differs from specific embodiment 1 in that a saturated sodium bicarbonate solution is added in step 2 to quench the reaction. The rest is the same as specific embodiment 1.
[0046] Specific embodiment 3: This embodiment differs from specific embodiment 1 or 2 in that dichloromethane is used for extraction in step 2. The rest is the same as specific embodiment 1 or 2.
[0047] Specific embodiment 4: This embodiment is different from specific embodiments 1 to 3 in that ethyl acetate is used for extraction in steps 3, 4 and 5. The rest is the same as specific embodiments 1 to 3.
[0048] Specific embodiment 5: This embodiment differs from specific embodiments 1 to 4 in that the water-free and oxygen-free treatment is to remove water and oxygen by heating at 400° C. with a drying gun under vacuum conditions. The rest is the same as specific embodiments 1 to 4.
[0049] Specific embodiment 6: This embodiment is different from specific embodiments 1 to 5 in that: in step 4, the reaction temperature is raised to 110° C. The rest is the same as specific embodiments 1 to 5.
[0050] Specific embodiment 7: This embodiment differs from specific embodiments 1 to 6 in that water is added to the reaction system in steps 3 and 4 to quench the reaction. The rest is the same as specific embodiments 1 to 6.
[0051] Specific embodiment 8: This embodiment differs from specific embodiments 1 to 7 in that ethyl acetate is used for extraction in steps b, c and e. The rest is the same as specific embodiments 1 to 7.
[0052] Specific embodiment 9: This embodiment is different from specific embodiments 1 to 8 in that the temperature of the ice bath is 0° C. The rest is the same as specific embodiments 1 to 8.
[0053] Specific embodiment 10: This embodiment differs from specific embodiments 1 to 9 in that: in step d, after reacting for 5 minutes, the mixture is transferred to room temperature until the reaction is completed. The rest is the same as specific embodiments 1 to 9.
[0054] The content of the present invention is not limited to the content of the above-mentioned embodiments. The combination of one or several specific embodiments can also achieve the purpose of the invention.
[0055] Example 1: A method for synthesizing spirocyclic compounds by oxidative dearomatization, comprising the following steps:
[0056] 1. Add compound ferulic acid (10.0g, 51.0mmol), Pd / C (0.1g, 0.2mol%), and methanol (50mL) into a 250mL round-bottom flask and mix. When ferulic acid is completely dissolved, add PhCl (30μL, 5mol%) using a micro syringe, and then fill with hydrogen. The solution is gray and the reaction progress is monitored by TLC. After 18h of reaction, the solution changes from gray to black. TLC monitoring of the reaction reveals that the raw material disappears and the reaction is over. Post-treatment: First, vacuum evaporation is performed to remove methanol. The crude product is filtered with a suction funnel to remove the Pd / C catalyst. The eluent with a polarity of PE / EtOAc = 4:1 is used for elution, and then the eluent is removed by vacuum evaporation to obtain the target compound 1 (10.6g, 50.0mmol, 98%). The product is a white solid.
[0057] The reaction route is:
[0058]
[0059] Its NMR data analysis is: Compound 1: R f=0.2(silica gel,PE / EtOAc=4:1,UV,I2)
[0060] 1 H NMR (400MHz, Chloroform-d) δ6.83(d,J=7.9Hz,1H),6.73-6.58(m,2H),3.87(s,3H),3.67(s,3H),2.88(t,J=7.8Hz,2H),2.60(t,J=7.8Hz,2H).
[0061] 2. Compound 1 (10.6 g, 50.0 mmol) and DMAP (0.30 g, 5 mol%) were added to a 250 mL round-bottom flask, CH2Cl2 (50 mL) was added to dissolve the compound, Et3N (11 mL, 80.0 mmol) was added by syringe at room temperature, and then pivaloyl chloride (6.3 mL, 55 mmol) was slowly added dropwise. At this time, white substance appeared in the solution. The reaction progress was monitored by TLC spot plate, and the developing agent polarity PE / EtOAc = 4:1. After 6 hours of reaction, the solution turned slightly yellow, and the raw material disappeared and the reaction was over. After treatment, saturated sodium bicarbonate solution was added, and dichloromethane was extracted. The solvent was removed by evaporation under reduced pressure. The crude product was filtered with dichloromethane to obtain the target compound 2 (14.7 g, 50.0 mmol, 100%), and the product was a light yellow oily liquid.
[0062] The reaction route is:
[0063]
[0064] Compound 2:R f =0.5(silica gel,PE / EtOAc=4:1,UV,I2)
[0065] 1 H NMR(400MHz,Chloroform-d)δ6.90(d,J=7.9,2.2Hz,1H),6.81-6.73(m,2H),3.79(s,J=2.2Hz,3H), 3.67(s,J=2.2Hz,3H),2.93(t,J=7.8,2.1Hz,2H),2.63(t,J=9.9,4.9Hz,2H),1.35(s,J=2.4Hz,9H).
[0066] 3. Compound 2 (1.8 g, 6.3 mmol) and NIS (1.4 g, 6.3 mmol) were added to a 20 mL reaction bottle, followed by 10 mL of acetonitrile solution. After the compound was completely dissolved, TFA (15 μL, 10 mol%) was added dropwise, and the solution turned dark red. TLC and NMR monitored the reaction structure. After 24 hours of reaction, the reaction was completed. After treatment, water was added to quench the reaction, ethyl acetate was extracted 3 times, and the organic phase was washed with saturated sodium thiosulfate 2 times. The obtained organic phases were combined and the organic solvent was removed by rotary evaporation to obtain a crude reaction product. Subsequently, the target compound 3 (2.5 g, 5.8 mmol, 93%) was obtained as a white solid by separation and purification on a silica gel column, using a polarity-size PE / EtOAc=10:1 eluent for elution.
[0067] The reaction route is:
[0068]
[0069] Compound 3:R f =0.3(silica gel,PE / EtOAc=20:1,UV,I2)
[0070] 1 H NMR (400MHz, Chloroform-d) δ7.39(s,1H),6.87(s,1H),3.77(s,3H),3.69(s,3H),3.02(t,J=8.7,6.9Hz,2H),2.62(t,J=7.8Hz,2H),1.34(s,9H).
[0071] 4. Add a magnetic particle and piperoacetic acid (1.8 g, 10 mmol) into a 20 ml reaction bottle, add 20 mL of methanol (MeOH), add acetyl chloride (AcCl, 20 μL, 10 mol%) with a syringe, stir at room temperature, monitor the reaction progress by TLC, and after reacting overnight, the raw material reacts completely, remove the methanol by rotary evaporation, and filter on a silica gel column to obtain product A;
[0072] NBS (1.82 g, 10.2 mmol) and the product obtained in the previous step were placed in a 20 mL reaction bottle, 10 mL of acetonitrile solution (MeCN) was added, and the reaction progress was monitored by TLC. The reaction was allowed to proceed overnight at room temperature. The reaction raw materials disappeared, and water was added to quench the reaction. The mixture was extracted with ethyl acetate (EA). Acetonitrile (MeCN) and EA were removed by rotary evaporation. The crude product was separated by column to obtain compound 2 (2.5 g, 9 mmol). The yield of the two-step reaction was 90% in total, and product B was obtained.
[0073] After evacuating and replacing nitrogen with 50mL of Schlenk flask three times, the obtained product B (1.38g, 5mmol) was added, and dichloromethane (CH2Cl2, 10mL) was added at room temperature. After all the solids were dissolved, it was placed in an ice bath at 0℃, and then DIBAL (1.0M, 15mL) was slowly added dropwise. The reaction progress was monitored by TLC. After 5h of reaction, the raw materials were completely consumed, and water and sodium tartarate solution were added. The mixture was stirred at room temperature for 2h, and EA was added for extraction. The solvent was removed by rotary evaporation to obtain a crude product, which was separated by column to obtain product C (1.1g, 4.5mmol, 89%).
[0074] Product C (1.1 g, 4.5 mmol) was added to a 20 mL reaction bottle, and TBSCl (1.0 g, 6.75 mmol) and CH2Cl25 mL were added to an ice bath. After reacting for 5 minutes, the mixture was transferred to room temperature. After 2 h, the reaction was completed, and water was added to quench the reaction. The compound protected by the TBS protecting group was obtained by filtering through a silica gel column.
[0075] After vacuuming and replacing nitrogen three times, the TBS-protected alcohol compound (360 mg, 1.0 mmol) was added into a 25 mL Schlenk tube, and diboric acid pinacol ester (500 mg, 2.0 mmol), palladium acetate (11.0 mg, 5 mol%), SPhos (41.0 mg, 10 mol%) were added. Under nitrogen, solvent 1,4-dioxane (4 mL) was added, and the mixture was heated to 60 ° C. The reaction was allowed to react overnight. The reaction was monitored by TLC. When the raw material was completely consumed, water was added for extraction reaction, EA was extracted, and the mixture was passed through a column to obtain compound 4.
[0076] The reaction route is:
[0077]
[0078] NMR data of compound 4: 1 H NMR(400MHz,Chloroform-d)δ6.73(s,1H),6.59(s,1H),5.95(dd,J=10.7,1.4Hz,2H),3.45(t,2H),2.56(t,2H),1.35(s,12H),0.80(s,9H),-0.08(S,6H)
[0079] 5. Add compound 3 (0.63 g, 1.5 mmol), compound 4 (0.63 g, 2.25 mmol), potassium carbonate (0.62 g, 4.5 mmol) and PdCl2dppf (22 mg, 2 mol%) to a 10 mL Schlenk reaction tube with a piston. After the anhydrous and oxygen-free treatment is completed, nitrogen is filled into the system. Use a syringe to take a dry 1,4-dioxane solution (1.5 mL) and inject it into the reaction tube, then add H2O (150 μL), the solution is brown-red. Use a heating block to raise the reaction temperature to 110 ° C, react overnight, and the solution turns black. TLC monitors the progress of the reaction. The experimental reaction is complete. Add H2O to the reaction system, extract with ethyl acetate three times, and remove the obtained organic phase by rotary evaporation to obtain a crude product. Then use a silica gel column to separate and purify the crude product by column chromatography to obtain compound 5 (0.68 g, 1.2 mmol, 80%), the product is a yellow oily liquid.
[0080]
[0081] Compound 5:R f =0.25(silica gel,PE / EtOAc=10:1,UV)
[0082] 1 H NMR(400MHz,Chloroform-d)δ6.84(s,1H),6.80(s,1H),6.73(s,1H),6.59(s,1H),5.95(dd,J=10.7,1.4Hz,2H),3 .82(s,3H),3.61(s,3H),3.59-3.37(m,2H),2.82-2.23(m,6H),1.34(s,9H),0.82(s,9H),-0.08(d,J=5.0Hz,6H).
[0083] 6. Compound 5 (0.57 g, 1.0 mmol) and potassium carbonate (0.41 g, 3.0 mmol) were added to a 10 mL Schlenk reaction tube with a piston. After the anhydrous and oxygen-free treatment was completed, nitrogen was filled into the system. The reaction does not require anhydrous and oxygen-free solvents, so ordinary MeOH solvent (5 mL) was added. The solution was light yellow. TLC monitored the progress of the reaction. After about 4 hours, the reaction raw materials reacted completely. First, MeOH was concentrated and removed in vacuo, H2O and an excess of 2 mol / L KHSO4 solution were added to the reaction tube, stirred, and ethyl acetate was added for extraction three times. The organic phase obtained was subjected to rotary evaporation to remove the organic solvent, and the crude product was separated and purified by silica gel column chromatography to obtain product 6 (0.48 g, 0.99 mmol, 99%). Since the stability of the compound is not very good, the next step of the reaction was directly carried out after the product was obtained.
[0084] VII. Compound 6 (0.60 g, 1.2 mmol) was added to a 25 mL Schlenk reaction tube with a piston. After the anhydrous and oxygen-free treatment was completed, nitrogen was filled into the system. Dry CH2Cl2 (7.0 mL) was added thereto. The compound was stirred and dissolved at room temperature, and then placed in an ethanol solution at -78°C and stirred for five minutes. After the temperature stabilized, DIBAL (1.24 mL, 1.86 mmol) was drawn with a syringe and slowly dripped into the reaction tube using a syringe pump. The time for dripping DIBAL was about 30 min. After the addition of DIBAL, the reaction progress was monitored by TLC. After about 2 h, the reaction was treated. Add excess sodium potassium tartrate aqueous solution and a small amount of ethyl acetate to the reaction tube to neutralize excess DIBAL reagent. Stir for about 3 hours until the solution becomes clear. Add CH2Cl2 and extract three times. The organic phase is rotary evaporated to remove the organic solvent to obtain a crude product. Since the reaction raw materials cannot react completely, only the crude product is filtered. Silica gel is added to a suction funnel and filtered using a solvent with a polarity of PE / EtOAc = 4:1 to obtain a mixture of compound 6 and compound 7.
[0085] The reaction routes of compounds 6 and 7 are:
[0086]
[0087] 8. The mixture of compound 6 and compound 7 was added to a 10 mL Schlenk reaction tube with a piston, and the mixture was evacuated and replaced with nitrogen three times. Then, tert-butylsulfenamide (0.16 g, 1.3 mmol), Ti(OEt)4 (0.51 mL, 2.4 mmol), and dry THF solution (1 mL) were added to the reaction tube. The solution was a yellow solution. TLC was used to monitor the reaction process. After about 5 hours, the solution became turbid, and the raw material 7 had reacted completely. Then, sodium borohydride (55 mg, 1.4 mmol) was added. The reaction process was continued to be monitored by TLC. After about 2 hours, all the generated imine compounds were reacted. H2O was added to the reaction tube, and the mixture was stirred for about 2 hours. The reaction tube turned white. Ethyl acetate was added for extraction three times, and the organic solvent was removed by rotary evaporation to obtain a crude product. The crude product was then purified and separated by column chromatography using a silica gel column to obtain compound 8 (0.4 g, 0.7 mmol) and compound 6 (0.16 g, 0.3 mmol). The three-step yield was 79%.
[0088] The reaction route is:
[0089]
[0090] The H NMR spectrum of compound 8 is shown in Figure 1 As shown, the NMR C spectrum is as follows Figure 2 As shown;
[0091] NMR data: R f =0.2(silica gel,PE / EtOAc=1:1,UV)
[0092] 1 H NMR(400MHz,Chloroform-d)δ6.76(s,1H),6.71(s,1H),6.63(s,2H),6.55(s,1H),5.92(d,J=1.5Hz,2H),5.77(s,1H),3.89(s,5H),3.5 8-3.47(m,3H),3.18-2.78(m,5H),2.56-2.23(m,6H),1.70-1.53(m,3H),1.12(d,J=4.9Hz,15H),0.80(s,10H),-0.11(d,J=2.3Hz,6H).
[0093] IX. Compound 8 (45 mg, 0.08 mmol) and iodophenyl diacetic acid (28 mg, 0.09 mmol) were added to a 4 mL glass bottle, TFE (0.2 mL) was added, and the mixture was stirred at room temperature. TLC and iodine color development were used to monitor the progress of the reaction, and the solution was brown. The raw materials reacted completely in about 30 min. After treatment, TFE was removed by rotary evaporation, and the crude product was purified and separated by column chromatography using a silica gel column to obtain compound 9 (27 mg, 0.05 mmol, 60%). The product was a colorless oily liquid, which was a spirocyclic compound.
[0094]
[0095] The H NMR spectrum of compound 9 is shown in Figure 3 As shown, the NMR C spectrum is as follows Figure 4 As shown;
[0096] NMR data::R f =0.30(silica gel,PE / EtOAc=1:1,UV)
[0097] 1H NMR (400MHz, Chloroform-d) δ7.82 (s, 1H), 6.78 (s, 1H), 6.09 (s, 1H), 5.93 (d, J = 7. 1Hz,2H),5.48(s,1H),3.69(m,5H),3.67-3.56(m,1H),3.10(q,J=8.5Hz,1H),2.64 (dp,J=20.4,7.1Hz,2H),2.21(dd,J=13.4,7.2Hz,1H),1.96(td,J=12.4,7.9Hz,1H ),1.71(dt,J=14.9,8.3Hz,2H),1.25(s,12H),0.85(s,9H),-0.01(d,J=2.4Hz,6H).
[0098] The spirocyclic compound successfully prepared by the present invention can continue to undergo a deprotection reaction, and then undergo an intramolecular Mitsunobu reaction to close the ring to obtain a key intermediate in the biogenic synthesis route for synthesizing cephalotaxine.
Claims
1. A method for synthesizing spiro compounds by oxidative dearomatization, characterized in that The method is specifically carried out in the following steps 1. Mix ferulic acid, Pd / C and methanol, add PhCl after the ferulic acid is completely dissolved, and then charge with hydrogen. After the reaction is completed, remove the methanol by rotary evaporation under reduced pressure, filter the obtained crude product, elute, and then evaporate under reduced pressure to remove the eluent to obtain compound 1; 2. Compound 1 and 4-dimethylaminopyridine were mixed, CH2Cl2 was added, triethylamine was added, and pivaloyl chloride was added dropwise. After the reaction was completed, the reaction was quenched, extracted, and the solvent was removed by evaporation under reduced pressure. The obtained crude product was filtered with dichloromethane to obtain compound 2; 3. Compound 2 and N-iodosuccinimide were mixed, acetonitrile was then added, TFA was added dropwise after dissolution, the reaction was quenched after the reaction was completed, the organic phase was extracted, the organic solvent was removed by rotary evaporation, and then separated and purified to obtain compound 3; 4. Compound 3, compound 4, potassium carbonate and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride were added to a reaction tube, nitrogen was filled after the anhydrous and oxygen-free treatment was completed, and then 1,4-dioxane was added, and then H2O was added. The reaction temperature was raised, and after the reaction was complete, the reaction was quenched, extracted, and the obtained organic phase was rotary evaporated to remove the solvent, separated and purified to obtain compound 5; 5. Compound 5 and potassium carbonate were added to a reaction tube. After the anhydrous and oxygen-free treatment was completed, nitrogen was filled, and then MeOH solvent was added. After the reaction was complete, MeOH was concentrated and removed in vacuo. H2O and KHSO4 solutions were added to the reaction tube, stirred, extracted, and the obtained organic phase was subjected to rotary evaporation to remove the organic solvent, separated and purified to obtain compound 6; 6. Compound 6 is added to a reaction tube, and after the anhydrous and oxygen-free treatment is completed, nitrogen is filled, and then CH2Cl2 is added, and stirred to dissolve at room temperature, and then placed in anhydrous ethanol at -78°C, stirred, and then diisobutylaluminum hydride is added dropwise. After the reaction is complete, extraction and rotary evaporation are performed to remove the organic solvent, and then suction filtration is performed to obtain a mixture of compound 6 and compound 7; 7. Add a mixture of compound 6 and compound 7 to a reaction tube, then add tert-butylsulfenamide, tetraethyl titanate and dry tetrahydrofuran to the reaction tube, add sodium borohydride after the reaction is complete, continue the reaction, add H2O to quench the reaction after the reaction is complete, stir, extract, and rotary evaporate to remove the organic solvent, and obtain compound 8 after separation and purification; 8. Add compound 8 and iodophenyldiacetic acid into a glass bottle, then add tetrafluoroethylene, stir at room temperature, after the reaction is complete, remove tetrafluoroethylene by rotary evaporation, and obtain a spiro compound after separation and purification; The specific preparation method of compound 4 is as follows: a. Mix piperoacetic acid, methanol and acetyl chloride, stir at room temperature, and after the reaction is complete, remove methanol by rotary evaporation, and filter on a silica gel column to obtain product A; b. Add N-bromosuccinimide and product A to a reaction bottle, add acetonitrile, add water to quench the reaction after the reaction is complete, extract, rotary evaporate, separate and purify to obtain product B; c. Mix product B and dichloromethane, and after all of them are dissolved, add diisobutylaluminum hydride dropwise in an ice bath. After the reaction is complete, add water and a saturated sodium tartrate solution, stir at room temperature, extract, and rotary evaporate to separate and purify to obtain product C; d. Add tert-butyldimethylsilyl chloride and CH2Cl2 to product C in an ice bath, then transfer to room temperature until the reaction is complete, quench the reaction, and filter through a silica gel column to obtain a compound protected by a TBS protecting group; e. Add pinacol borate, palladium acetate and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl to the TBS-protected alcohol compound, add solvent 1,4-dioxane under nitrogen, heat to 60°C, add water to quench the reaction after the reaction is complete, extract, and pass through a column to obtain compound 4.
2. A method for synthesizing spiro compounds by oxidative dearomatization according to claim 1, characterized in that In step 2, saturated sodium bicarbonate solution was added to quench the reaction.
3. A method for synthesizing spiro compounds by oxidative dearomatization according to claim 1, characterized in that In step 2, dichloromethane is used for extraction.
4. The method for synthesizing spiro compounds by oxidative dearomatization according to claim 1, characterized in that In steps 3, 4 and 5, ethyl acetate is used for extraction.
5. The method for synthesizing spiro compounds by oxidative dearomatization according to claim 1, characterized in that The water-free and oxygen-free treatment is to remove water and oxygen by heating at 400° C. with a drying gun under vacuum conditions.
6. The method for synthesizing spiro compounds by oxidative dearomatization according to claim 1, characterized in that Step 4: Raise the reaction temperature to 110°C.
7. The method for synthesizing spiro compounds by oxidative dearomatization according to claim 1, characterized in that In steps 3 and 4, water is added to the reaction system to quench the reaction.
8. The method for synthesizing spiro compounds by oxidative dearomatization according to claim 1, characterized in that In steps b, c and e, ethyl acetate is used for extraction.
9. The method for synthesizing spiro compounds by oxidative dearomatization according to claim 1, characterized in that The ice bath temperature was 0°C.
10. The method for synthesizing spiro compounds by oxidative dearomatization according to claim 1, characterized in that In step d, after reacting for 5 minutes, the mixture was transferred to room temperature until the reaction was completed.