Method for preparing spirooxindole alkaloid Coerulescine natural product
Through the tandem reaction of chiral sulfinamide with metal copper coordination and cuprous iodide catalyzed tandem reaction, the key chiral center of spiroepoxidized indole alkaloid Coerulescine was successfully constructed, solving the problems of high energy consumption and low yield in traditional methods, and achieving efficient and environmentally friendly alkaloid synthesis.
Patent Information
- Application Number
- CN202411412343.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-11
- Publication Date
- 2025-02-25
AI Technical Summary
The prior art is difficult to efficiently synthesize natural products of spiroepoxidized indole alkaloids, and traditional methods have problems of high energy consumption, environmental pollution and low yield.
Through the coordination induced by chiral sulfinamide as a co-group and metal copper, cuprous iodide catalyzes the cyclization reaction of methyl chloroformate in tandem in methyl chloroformate in a spiroepoxidized indole alkaloid Coerulescine, the key aryl quaternary carbon chiral center of the spiroepoxidized indole alkaloid Coerulescine, and the alkaloid and its analogue were synthesized in large quantities through subsequent chemical transformation.
Coerulescine and its analogs were efficiently prepared under the catalysis of cheap metal cuprous iodide, with mild reaction conditions, low energy consumption and low environmental pollution, with high yield and good atomic economy.
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Figure CN119504767A_ABST
Abstract
Description
Technical Field
[0001] The patent of this invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product. Background Art
[0002] All-carbon quaternary carbon stereo centers are widely present in natural products, drugs and bioactive molecules. The construction of chiral quaternary carbon is a hot topic in international cutting-edge research. In 2011, 12% of the top 200 drugs sold in the United States had chiral quaternary carbon centers. Quaternary carbon chiral centers are widely present in bioactive compounds such as drugs and natural products, and they play an important role in the fields of biomedicine and pharmacy. Their synthesis has always been a hot spot and difficulty in the field of organic synthetic chemistry, and is extremely challenging. The development of efficient methods for constructing quaternary carbon chiral centers will obviously help synthesize these drugs and their analogs. The spirooxidindole alkaloids Horsfiline and Coerulescine natural products were isolated by the Bodo research group and the Colegate research group from the Myristicaceae plant and Canary Herb, respectively. They have typical all-carbon quaternary carbon chiral centers in their chemical structure. At the same time, spiro-oxoindole alkaloid natural products have rich and diverse biological activities. For example, the spiro-oxoindole alkaloid Horsfiline natural product is used as a substance to anesthetize the sense of smell; Coerulescine has good antibacterial activity; Spiro-oxoindole alkaloid Spirotryprostatin B can inhibit mouse breast cancer cells (tsFT2l0) in the G2 / M phase, and at the same time confirms that it has cytotoxic activity against human chronic myeloid leukemia (K562) cells and human promyelocytic leukemia (HL-60) cells; Strychnofoline has the function of inhibiting various cell lines. In recent years, due to the special chemical structure, important biological activity and high drug-making rate of spiro-oxoindole alkaloids, they have an important position in the fields of biomedicine and pharmacy, and continue to receive extensive attention from synthetic chemists and pharmacists. The development of new reactions for the efficient synthesis of spiro-oxoindole compounds is particularly important and has always been a hot topic in the field of organic synthetic chemistry, which is of great significance for drug research and development. In 2005, Professor Shaomeng Wang, a famous American medicinal chemist, developed a new anti-tumor drug MDM2 inhibitor based on the core skeleton of the key spiro-oxidized indole structure in the spiro-oxidized indole alkaloids Spirotryprostatin A and Alstonisine natural products. The patent of his MDM2 inhibitor was transferred to Sanofi-Aventis, a well-known European pharmaceutical company, at a high price of US$398 million. This is a successful case of developing a new drug based on the core skeleton unit of the key spiro-oxidized indole structure in the natural product Spirotryprostatin A.
[0003] Therefore, based on the chiral sulfenamide as the auxiliary group and the coordination induction of metallic copper, we catalyzed the cuprous iodide-catalyzed arylation of the amide a-position and the cyclization of methyl chloroformate. Through a one-step inexpensive metal cuprous iodide-catalyzed cascade reaction, we constructed the key aromatic quaternary carbon chiral center of the spirocyclic indole alkaloid Coerulescine natural product. Then, through subsequent chemical transformation, we synthesized a large amount of spirocyclic indole alkaloid natural product Coerulescine and its skeleton analogues, providing sufficient samples for clinical trial research, which has important theoretical and practical significance. Summary of the invention
[0004] The object of the present invention is to provide a method for preparing a natural product of spirocyclic oxidized indole alkaloid Coerulescine. The disclosed preparation method uses only cheap metal cuprous iodide as a catalyst, causes less pollution to the environment, has fewer reaction steps, and has a high yield.
[0005] To achieve the above object, the present invention provides the following technical solutions: A method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product comprises the following steps: S1. Dissolve the chiral sulfenyl imide compound with an anhydrous solvent, then slowly add a reducing agent for reduction for 5 hours in an ice-water bath, and obtain an amide compound after purification; wherein the molecular structure 2 of the amide compound is: ; S2, dissolving the amide compound with an anhydrous solvent, then slowly adding an inorganic base and an alkylating agent in an ice-water bath, continuing the reaction for 10 hours, and obtaining a chiral sulfenamide compound after purification; wherein the molecular structure 3 of the chiral sulfenamide compound is: ; S3, dissolving the chiral sulfenamide compound with a solvent, then adding cuprous iodide and lithium bis(trimethylsilyl)amide, then degassing three times under the protection of high-purity inert gas, heating and reacting for 6 hours, then adding methyl chloroformate in an ice-water bath and reacting for 4 hours, and obtaining an oxidized indole compound containing an aromatic quaternary carbon center after purification; wherein the molecular structure 4 of the oxidized indole compound containing an aromatic quaternary carbon center is: ; S4, dissolving the oxidized indole compound containing an aromatic quaternary carbon center in anhydrous methanol, then adding a dilute hydrochloric acid solution to react for 5 hours, and obtaining a spirocyclic oxidized indole compound after purification; wherein the molecular structure 5 of the spirocyclic oxidized indole compound is: ; S5, dissolving the spirocyclic indole oxide compound in an anhydrous solvent, adding trifluoromethanesulfonic acid under ice-water bath conditions for 2 hours, then placing the reaction at room temperature, continuing the reaction for 10 hours, and obtaining a spirocyclic indole oxide compound after purification; wherein the molecular structure 6 of the spirocyclic indole oxide compound is: ; S6, dissolving the spirocyclic oxidized indole compound in anhydrous tetrahydrofuran, then adding n-butyl lithium at -78 degrees Celsius to react for 1 hour, then adding a reducing agent to react for 12 hours, and obtaining a spirocyclic oxidized indole alkaloid Coerulescine natural product after purification; wherein the molecular structure 7 of the spirocyclic oxidized indole alkaloid Coerulescine natural product is: .
[0006] Preferably according to the present invention, the anhydrous solvent in S1 is anhydrous methanol, and the reducing agent is sodium borohydride.
[0007] Preferably according to the present invention, the anhydrous solvent in S2 is tetrahydrofuran, the inorganic base is sodium hydride, and the alkylating agent is iodomethane.
[0008] Preferably according to the present invention, the solvent in S3 is anhydrous toluene, the heating temperature is 80° C., the high-purity inert gas is nitrogen, and the methyl chloroformate is used as a series reagent.
[0009] Preferably according to the present invention, the concentration of the dilute hydrochloric acid used in S4 is 4 mmol / mL.
[0010] Preferably according to the present invention, the anhydrous solvent in S5 is anhydrous dichloromethane.
[0011] Preferably according to the present invention, the reducing agent in S6 is lithium aluminum hydride.
[0012] Preferably, according to the present invention, the purification method included in S1 to S6 is: concentrating the crude product initially obtained in each step, followed by chromatography separation and purification, and finally obtaining a compound with high purity.
[0013] The beneficial technical effects of the present invention are as follows: 1. The preparation method provided by the present invention has mild reaction conditions, uses cheap metal cuprous iodide as a catalyst, has low energy consumption, is beneficial to environmental protection, and is conducive to the large-scale preparation of spirocyclic oxidized indole alkaloid Coerulescine natural products and their analogs; 2. The preparation method provided by the present invention has good atom economy and high product yield; 3. The preparation method provided by the present invention has a short synthetic route and a relatively simple reaction operation process. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the drawings required for describing the embodiment are briefly introduced below. Those skilled in the art can also obtain other drawings based on these drawings without paying any creative work.
[0015] Figure 1 It is a schematic diagram of the preparation process of the present invention; DETAILED DESCRIPTION
[0016] The following will be combined with the accompanying drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.
[0017] In order to synthesize a large amount of spirocyclic indole alkaloid Coerulescine natural product and its analogs, and provide sufficient samples for clinical trial research.
[0018] The inventors provide a method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product, comprising the following steps: S1, dissolving a chiral sulfinyl imide compound in an anhydrous solvent, then slowly adding a reducing agent for reduction for 5 hours in an ice-water bath, and obtaining an amide compound after purification; The anhydrous solvent in S1 is anhydrous methanol, and the reducing agent is sodium borohydride.
[0019] S2, dissolving the amide compound with an anhydrous solvent, then slowly adding an inorganic base and an alkylating agent in an ice-water bath, continuing the reaction for 10 hours, and obtaining a chiral sulfenamide compound after purification; Among them, the anhydrous solvent in S2 is tetrahydrofuran, the inorganic base is sodium hydride, and the alkylating agent is iodomethane.
[0020] S3, dissolving the chiral sulfenamide compound with a solvent, then adding cuprous iodide and lithium bis(trimethylsilyl)amide, then degassing three times under the protection of high-purity inert gas, heating and reacting for 6 hours, then adding methyl chloroformate in an ice-water bath and reacting for 4 hours, and obtaining an oxidized indole compound containing an aromatic quaternary carbon center after purification; The solvent in S3 is anhydrous toluene, the heating temperature is 80° C., the high-purity inert gas is nitrogen, and the methyl chloroformate is used as a series reagent.
[0021] S4, dissolving the oxidized indole compound containing an aromatic quaternary carbon center in anhydrous methanol, then adding a dilute hydrochloric acid solution to react for 5 hours, and obtaining a spirocyclic oxidized indole compound after purification; The concentration of the dilute hydrochloric acid used in S4 is 4 mmol / mL.
[0022] S5, dissolving the spirocyclic oxidized indole compound in an anhydrous solvent, adding trifluoromethanesulfonic acid under ice-water bath conditions for 2 hours, then placing the reaction at room temperature for 10 hours, and obtaining the spirocyclic oxidized indole compound after purification; Wherein, the anhydrous solvent in S5 is anhydrous dichloromethane.
[0023] S6, dissolving the spirocyclic oxidized indole compound in anhydrous tetrahydrofuran, then adding n-butyl lithium in an ice water bath at 0° C. to react for 1 hour, then adding a reducing agent to react for 12 hours, and obtaining the spirocyclic oxidized indole alkaloid Coerulescine natural product after purification; Wherein, the reducing agent in S6 is lithium aluminum hydride; Furthermore, the purification method included in S1 to S6 is: concentrating the crude product initially obtained in each step, followed by chromatography separation and purification, and finally obtaining a compound with high purity.
[0024] The preparation method provided by the invention has mild reaction conditions, low cost, low energy consumption, is beneficial to environmental protection and is conducive to the large-scale preparation of spirocyclic oxidized indole alkaloid Coerulescine natural products and analogs thereof.
[0025] In the process of studying the preparation of the spirocyclic oxidized indole alkaloid Coerulescine natural product, the inventors also made the following specific examples: Example
[0026] A method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product (preparation process as shown in Figure 1 shown): S1, the synthesis of compound 2, the reaction formula is as follows: ; The specific implementation steps are as follows: In a 100 mL double-necked round-bottom flask, compound 1 (5.26 g, 10.0 mmol) was weighed and dissolved in 100 mL of anhydrous methanol solvent, then sodium borohydride solid (1.14 g, 30.0 mmol, 3.0 equiv) was slowly added in an ice-water bath at 0°C, and the reaction was continued with stirring for 5 hours. Post-treatment: After evaporating most of the organic solvent, 60 mL of water was added, and the mixture was extracted with ethyl acetate (3 ´ 100 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (petroleum ether 60-90°C: ethyl acetate = 2:1→1:1) was performed to obtain a light yellow liquid compound 2 (4.1 g, 93%).
[0027] The characterization data of compound 2 are as follows: 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.92 (dt, J =7.9, 1.4 Hz, 1H), 7.22 (td, J = 7.6, 1.2 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H),7.04 (t, J = 7.7 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.72 – 6.67 (m, 1H), 5.57(d, J = 14.0 Hz, 1H), 3.87 (dd, J = 14.0, 2.4 Hz, 1H), 3.76 (s, 3H), 3.66 –3.56 (m, 1H), 3.21 – 3.15 (m, 1H), 3.08 – 3.00 (m, 1H), 2.07 – 1.91 (m, 2H),1.89 – 1.84 (m, 2H), 1.15 (s, 9H). 13C NMR (100 MHz, CDCl3) δ (ppm): 171.51,171.45, 158.74, 143.47, 139.97, 139.91, 130.71, 130.66, 130.49, 130.48,129.69, 129.10, 129.06, 128.79, 128.75, 113.47, 100.34, 100.31, 55.31, 54.95,50.71, 44.72, 44.70, 31.62, 25.84, 22.47. HRMS (ESI-TOF) m / z [M+H] + Calculate for C 22 H 30 IN2O3S: 529.1017, found 529.1015. S2, the synthesis of compound 3, the reaction formula is as follows: ; The specific implementation steps are as follows: In a 100 mL double-necked round-bottom flask, compound 2 (5.28 g, 10.0 mmol) was weighed and dissolved in 100 mL of anhydrous tetrahydrofuran solvent, then in an ice-water bath at 0°C, 60% sodium hydride solid (1.20 g, 30.0 mmol, 3.0 equiv) and iodomethane reagent were slowly added, and the reaction was continued with stirring for 10 hours. Post-treatment: After evaporating most of the organic solvent, 60 mL of water was added, and extracted with ethyl acetate (3 ´ 80 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (petroleum ether 60-90°C: ethyl acetate = 2:1) gave a light yellow liquid compound 3 (4.1 g, 93%).
[0028] The characterization data of compound 3 are as follows: 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.90 (dd, J =7.9, 1.4 Hz, 1H), 7.20 (tt, J = 7.6, 1.5 Hz, 1H), 7.09 – 7.05 (m, 2H), 7.01(td, J = 7.6, 1.6 Hz, 1H), 6.78 – 6.73 (m, 2H), 6.66 (td, J= 7.6, 1.6 Hz,1H), 5.57 (dd, J = 14.2, 1.8 Hz, 1H), 3.83 (dd, J = 14.2 Hz, 1H), 3.75 (s,3H), 3.05 – 2.85 (m, 1H), 2.55 (s, 1.5H), 2.54 (s, 1.5H), 2.00 – 1.80 (m, 4H), 1.07 (s, 4.5H), 1.06 (s, 4.5H). HRMS (ESI-TOF) m / z [M+H] + Calculate for C 23 H 32 IN2O3S: 543.1173, found 543.1174. S3, the synthesis of compound 4, the reaction formula is as follows: ; Cuprous iodide (CuI, 190 mg, 1.0 mmol, 0.1 equiv) and compound 3 (5.42 g, 10.0 mmol) were weighed into a 250 mL double-necked round-bottom flask, degassed three times with dry high-purity nitrogen, anhydrous toluene (100 mL, lithium aluminum hydride reflux treatment) was added, and lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 20 mL, 20 mmol, 2.0 equiv) was added under stirring at room temperature, and then heated in an oil bath at 80°C for 6 hours. High-purity nitrogen protection was required throughout the reaction process. After heating for 6 hours, the heating was stopped, the temperature was restored to room temperature, and then cooled to 0°C with an ice-water bath, and methyl chloroformate reagent (1.55 mL, 20 mmol, 2.0 equiv) was slowly added, and then reacted at 0°C for 4 hours. Post-treatment: Add saturated Na2S2O3 solution (20 mL) and saturated ammonium chloride solution (20 mL) and stir for 20 minutes, then add 80 mL of water, extract with ethyl acetate (3 ´ 100 mL), dry over anhydrous sodium sulfate, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (petroleum ether 60-90℃: ethyl acetate = 2:1→1:1) to obtain light yellow liquid compound 4 (4.1 g, 87%).
[0029] The characterization data of compound 4 are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.27 –7.19 (m, 4H),7.04 (t,J = 7.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 7.8 Hz, 1H),5.02 (dd, J = 15.5, 5.7 Hz, 1H), 4.75 (d, J = 15.5 Hz, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 2.94 – 2.70 (m, 2H), 2.60 (s, 3H), 2.65 – 2.43 (m, 2H), 1.11 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 173.79, 173.75, 169.62, 169.58, 159.27,159.23, 143.34, 143.24, 129.49, 129.46, 128.78, 128.68, 127.59, 127.47,127.18, 127.08, 123.26, 123.23, 123.18, 123.14, 114.32, 114.29, 109.95,109.91, 58.28, 58.14, 57.72, 57.68, 55.36, 53.29, 48.96, 48.82, 43.57, 33.44,33.25, 32.31, 32.20, 23.44, 23.40. HRMS (ESI-TOF) m / z [M+H] + Calculate for C 25 H 33 N2O5S: 473.2105, found 473.2108. S4, the synthesis of compound 5, the reaction formula is as follows: ; Compound 4 (472 mg, 1.0 mmol) was dissolved in 10 mL of anhydrous methanol, and then HCl (4mmol / mL, 1.0 mL, 4.0 mmol, 4.0 equiv.) was added and reacted at room temperature for 5 hours. Post-treatment: saturated sodium bicarbonate solution was added until its pH >7, and 5 mL of water was added to dilute, most of the organic solvent was evaporated, and then extracted with ethyl acetate (3´ 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, and then chromatographed on a silica gel column (petroleum ether 60-90 ℃: ethyl acetate = 1:1) to obtain a light yellow liquid, compound 5 (286 mg, 85%).
[0030] The characterization data of compound 5 are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.28 –7.22 (m, 2H),7.21 – 7.13 (m, 2H), 7.03 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 6.72(d, J = 7.8 Hz, 1H), 4.96 (d, J = 15.6 Hz, 1H), 4.78 (d, J = 15.6 Hz, 1H),3.86 – 3.79 (m, 1H), 3.76 (s, 3H), 3.66 – 3.59 (m, 1H), 3.00 (s, 3H), 2.79 –2.71 (m, 1H), 2.48 – 2.40 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 176.00, 170.65,159.10, 143.68, 130.11, 129.01, 128.56, 127.46, 123.15, 122.92, 114.32,109.73, 57.97, 55.38, 47.40, 43.51, 30.71, 29.46. HRMS (ESI-TOF) m / z [M+H] + Calculate for C 20 H 21 N2O3: 337.1547, found 337.1546. S5. Synthesis of compound 6, the reaction formula is as follows: ; Compound 5 (340 mg, 1.0 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and the reaction was placed in an ice-water bath at zero degrees, then 0.5 mL of trifluoromethanesulfonic acid was added to continue the reaction for 2 hours, and then the reaction was warmed to room temperature and continued to react for 10 hours. Post-treatment: saturated sodium bicarbonate solution was added until its pH >7, 10 mL of water was added to dilute, and then extracted with dichloromethane (3 ´ 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, and then chromatographed on a silica gel column (petroleum ether 60-90°C: ethyl acetate = 1:3) to obtain a light yellow liquid, compound 6 (160 mg, 76%).
[0031] The characterization data of compound 6 are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.28 (brs, 0.34H), 8.20 (brs, 0.66H), 7.25 – 7.17 (m, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.06 – 7.00(m, 1H), 6.87 (d, J = 7.8 Hz, 0.34H), 6.83 (d, J = 7.8 Hz, 0.66H), 3.81 –3.74 (m, 1H), 3.65 – 3.56 (m, 1H), 3.00 (s, 3H), 2.76 – 2.68 (m, 1H), 2.45 –2.36 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 177.53, 177.42, 170.68, 170.65,141.71, 130.49, 129.13, 123.21, 123.08, 123.04, 110.41, 110.38, 58.32, 47.39,30.73, 29.51. HRMS (ESI-TOF) m / z [M+H] + Calculate for C 12 H 13 N2O2: 217.0972, Found217.0972. S6, the synthesis of compound 7, the reaction formula is as follows: .
[0032] Compound 6 (216 mg, 1.0 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and the reaction was placed under the reaction conditions of -78 degrees, and then 0.68 mL of n-butyl lithium (1.6M in THF, 1.1eq) was added, and then the reaction was continued at -78 degrees for 1 hour, and then 0.8 mL of lithium aluminum hydride solution (2.5 M in Toluene, 2.0 eq) was added, and then the reaction was continued for 12 hours. Post-treatment: 20 mL of saturated sodium potassium tartrate solution was added, and the reaction was continued to stir for 2 hours, and then extracted with dichloromethane (3 ´ 40 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, and then chromatographed on a silica gel column (dichloromethane: methanol = 30: 1) to obtain a light yellow liquid, spirocyclic indole alkaloid Coerrulescine natural product 7 (85 mg, 42%).
[0033] The characterization data of compound 7 are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.86 (brs, 1H), 7.45(d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.88(d, J = 8.0 Hz, 1H), 3.23 – 3.13 (m, 1H), 3.12 – 3.00 (m, 1H), 2.99 – 2.94(m, 2H), 2.60 (s, 3H), 2.45 – 2.39 (m, 1H), 2.19 – 2.14 (m, 1H). 13 C NMR (100MHz, CDCl3) δ 182.09, 139.98, 136.20, 128.32, 123.75, 123.38, 109.64, 65.57,56.78, 53.46, 42.02, 37.96. HRMS (ESI-TOF) m / z [M+H] + Calculate for C 12 H 15 N2O:203.1184, Found 203.1183. It can be seen from the above examples that the preparation method provided by the present invention has a high product yield, a short synthesis route, a simple reaction operation process, and good atom economy.
[0034] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.
[0035] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.
Claims
1. A method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product, comprising the following steps: S1. Dissolve the chiral sulfenyl imide compound with an anhydrous solvent, then slowly add a reducing agent for reduction for 5 hours in an ice-water bath, and obtain an amide compound after purification; wherein the molecular structure 2 of the amide compound is: ； S2, dissolving the amide compound with an anhydrous solvent, then slowly adding an inorganic base and an alkylating agent in an ice-water bath, continuing the reaction for 10 hours, and obtaining a chiral sulfenamide compound after purification; wherein the molecular structure 3 of the chiral sulfenamide compound is: ； S3, dissolving the chiral sulfenamide compound with a solvent, then adding cuprous iodide and lithium bis(trimethylsilyl)amide, then degassing three times under the protection of high-purity inert gas, heating and reacting for 6 hours, then adding methyl chloroformate in an ice-water bath and reacting for 4 hours, and obtaining an oxidized indole compound containing an aromatic quaternary carbon center after purification; wherein the molecular structure 4 of the oxidized indole compound containing an aromatic quaternary carbon center is: ； S4, dissolving the oxidized indole compound containing an aromatic quaternary carbon center in anhydrous methanol, then adding a dilute hydrochloric acid solution to react for 5 hours, and obtaining a spirocyclic oxidized indole compound after purification; wherein the molecular structure 5 of the spirocyclic oxidized indole compound is: ； S5, dissolving the spirocyclic indole oxide compound in an anhydrous solvent, adding trifluoromethanesulfonic acid under ice-water bath conditions for 2 hours, then placing the reaction at room temperature, continuing the reaction for 10 hours, and obtaining a spirocyclic indole oxide compound after purification; wherein the molecular structure 6 of the spirocyclic indole oxide compound is: ； S6, dissolving the spirocyclic oxidized indole compound in anhydrous tetrahydrofuran, then adding n-butyl lithium at -78°C to react for 1 hour, then adding a reducing agent to react for 12 hours, and obtaining a spirocyclic oxidized indole alkaloid Coerulescine natural product after purification; wherein the molecular structure 7 of the spirocyclic oxidized indole alkaloid Coerulescine natural product is: 。 2. A method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product according to claim 1, characterized in that: The anhydrous solvent in S1 is anhydrous methanol, and the reducing agent is sodium borohydride.
3. A method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product according to claim 1, characterized in that: In the S2, the anhydrous solvent is tetrahydrofuran, the inorganic base is sodium hydride, and the alkylating agent is methyl iodide.
4. A method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product according to claim 1, characterized in that: The solvent in S3 is anhydrous toluene, the heating temperature is 80° C., the high-purity inert gas is nitrogen, and the methyl chloroformate is used as a series reagent.
5. A method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product according to claim 1, characterized in that: The concentration of the dilute hydrochloric acid used in S4 is 4 mmol / mL.
6. A method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product according to claim 1, characterized in that: The anhydrous solvent in S5 is anhydrous dichloromethane.
7. A method for preparing a spirocyclic oxidized indole alkaloid Coerulescine natural product according to claim 1, characterized in that: The reducing agent in S6 is lithium aluminum hydride.
8. The method for preparing the spirocyclic oxidized indole alkaloid Coerulescine natural product according to claim 1, characterized in that: The purification method included in S1 to S6 is: concentrating the crude product initially obtained in each step, followed by chromatography separation and purification, and finally obtaining a compound with high purity.