A synthetic process of (-)-a-lycorane alkaloid
By catalytically synthesizing asymmetric tandem Michael addition reactions and other steps, the synthetic route of (-)-α-lycorane was simplified, solving the problem of lengthy and time-consuming processes in existing technologies. This resulted in a highly efficient and high-yield synthesis, laying the foundation for the development of (-)-α-lycorane as an anti-tumor drug.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- QUJING NORMAL UNIV
- Filing Date
- 2025-07-10
- Publication Date
- 2026-04-10
AI Technical Summary
Existing methods for synthesizing (-)-α-lycorane suffer from lengthy routes and time-consuming inefficiency, making it difficult to achieve efficient and concise synthesis.
(-)-α-lycorane was finally obtained by using a catalytic asymmetric tandem Michael addition reaction, Bischler-Napieralski cyclization reaction, Comins' reagent reaction and reductive hydrogenolysis reaction, through the transformation of compounds 4, 8, 9 and 10a and 10b.
The efficient and concise synthesis of (-)-α-lycorane was achieved, with high product yield and high purity, making it suitable for large-scale production and providing a foundation for the development of anti-tumor drugs.
Smart Images
Figure CN120682239B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of organic synthesis chemistry, and particularly relates to a synthesis process of (-)-alpha-lycorane alkaloid. BACKGROUND
[0002] In the field of bioactive molecules, Lycorine has attracted much attention due to its inhibitory effect on melanoma angiogenesis and various biological activities such as anti-tumor, antibacterial, analgesic and the like. As an important member of Lycorine alkaloids, (-)-alpha-lycorane inherits the core advantages of this class of alkaloids and exhibits good in vitro tumor inhibition activity and cell proliferation and growth inhibition activity, which has great potential for drug development.
[0003] At present, the synthesis method of (-)-alpha-lycorane has obvious limitations, and most of them have problems such as long route, time-consuming and low efficiency. In view of the importance of Lycorine alkaloids in the field of drug research and development due to their excellent anti-tumor activity, it is of great significance to develop a novel and efficient catalytic asymmetric synthesis method to realize the efficient and simple synthesis of (-)-alpha-lycorane. This not only can significantly improve the synthesis efficiency, but also is expected to further promote the research and development of this class of drugs, and provide a solid foundation for the in-depth research and application of related drugs. SUMMARY
[0004] The purpose of the present application is to provide a simple and efficient synthesis process of (-)-alpha-lycorane alkaloid to solve the problems existing in the prior art.
[0005] In order to achieve the above purpose, the present application provides the following technical scheme:
[0006] The present application provides a synthesis process of (-)-alpha-lycorane alkaloid, comprising the following steps:
[0007] (1) using known (2Z, 4E)-7, 7-diethoxy-3-hydroxyhepta-2, 4-dienoic acid methyl ester (compound 1) and 3, 4-methylenedioxy-beta-nitrostyrene (compound 2) as starting materials, compound 4 is obtained by catalytic asymmetric tandem Michael addition reaction, and the structural formula of the compound 4 is:
[0008] (2) compound 4 is first subjected to de-acetal protection in a mixed solvent of acetic acid and water; after cooling, zinc powder is added to perform reductive amination; after the reaction is completed, the zinc powder is removed, concentrated and extracted, the solvent is removed, hydrochloric acid is added to perform heating decarboxylation; after the reaction is completed, concentration, neutralization, dichloromethane extraction, and the extraction liquid is directly added to di-tert-butyl dicarbonate and triethylamine to obtain compound 8, and the structural formula of the compound 8 is:
[0009] (3) Compound 8 is subjected to Bischler-Napieralski cyclization reaction in 2-chloropyridine / triflic anhydride / boron trifluoride etherate reaction system to prepare compound 9, the structural formula of which is as follows:
[0010] (4) Compound 9 is subjected to reaction with Comins' reagent under the action of LiHMDS to prepare enol triflate mixture compounds 10a and 10b, the structural formula of which is as follows: and
[0011] (5) The mixture of compounds 10a and 10b is subjected to reductive hydrolysis reaction and amide reduction reaction to obtain product (-)-α-lycorane.
[0012] The synthetic route map is as follows:
[0013]
[0014] Preferably, the catalytic asymmetric tandem Michael addition reaction of step (1) is carried out at room temperature, the reaction time is 120 h, and the solvent is toluene.
[0015] Preferably, in step (2), the de-acetal protection is carried out under nitrogen protection, the reaction temperature is 90℃, and the reaction time is 2 h; and / or, the reductive amination is carried out under nitrogen protection, the reaction temperature is room temperature; and / or, the reaction temperature of the heating decarboxylation is 100℃, the concentration of hydrochloric acid is 2N-8N, and the reaction time is 10-24 h; and / or, the reaction time after adding di-tert-butyl dicarbonate is 4 h, the reaction solvent is dichloromethane, and triethylamine provides an alkaline environment.
[0016] Further preferably, the volume ratio of glacial acetic acid to water in the mixed solvent of acetic acid and water is 10:1.
[0017] Preferably, the reaction of step (3) is carried out under nitrogen protection, the reaction temperature is -78℃, and the reaction time is 6 h.
[0018] Preferably, step (4) comprises, under nitrogen protection, using tetrahydrofuran to dissolve compound 9 and Comins' reagent, adding LiHMDS, extracting after the reaction is completed, concentrating, and purifying to obtain a mixture of compound 10a and compound 10b.
[0019] Further preferably, the molar ratio of compound 9, Comins' reagent and LiHMDS is 2.28:2.73:2.96.
[0020] Preferably, in step (5), the reductive hydrolysis comprises the following steps: dissolving mixture 10a and compound 10b in methanol, adding catalyst Pd / C, placing the reaction under normal temperature in a hydrogen atmosphere for 12h, filtering, washing, and concentrating the filtrate under reduced pressure.
[0021] Preferably, in step (5), the step of amide reduction reaction is as follows: adding the product of reductive hydrolysis delipidation reaction into tetrahydrofuran, adding lithium aluminum hydride thereto, reacting at 70℃ for 5h, extracting, concentrating, and purifying to obtain product (-)-a-lycorane.
[0022] The present application discloses the following beneficial effects:
[0023] The synthetic process of the present application is simplified, the reaction conditions are easy to achieve, high temperature and high pressure are not needed, the synthetic process is efficient and simple, mass production of (-)-a-lycorane can be realized, the yield of product (-)-a-lycorane is high, the purity is high, and necessary conditions are created for promoting development of lycorine as a good antitumor drug. BRIEF DESCRIPTION OF DRAWINGS
[0024] In order to more clearly illustrate the technical solutions of the embodiments of the present application or the prior art, the drawings needed in the embodiments will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor.
[0025] Figure 1 NMR hydrogen spectrum of compound 4;
[0026] Figure 2 NMR carbon spectrum of compound 4;
[0027] Figure 3 NMR hydrogen spectrum of compound 8;
[0028] Figure 4 NMR carbon spectrum of compound 8;
[0029] Figure 5 NMR hydrogen spectrum of compound 9;
[0030] Figure 6 NMR carbon spectrum of compound 9;
[0031] Figure 7NMR of hydrogen for compound 10a and 10b mixture;
[0032] Figure 8 NMR of carbon for compound 10a and 10b mixture;
[0033] Figure 9 NMR of hydrogen for compound (-)-a-lycorane;
[0034] Figure 10 NMR of carbon for compound (-)-a-lycorane. DETAILED DESCRIPTION
[0035] Various exemplary embodiments of the present application will now be described in detail, which should be considered to be illustrative of certain aspects, features and embodiments of the present application, but not limiting of the same.
[0036] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application.
[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although preferred methods and materials are described, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All documents mentioned herein are incorporated by reference to disclose and describe in further detail the methods and / or materials associated with the documents. In the case of conflict between the present specification and any document incorporated by reference, the present specification will control.
[0038] Various modifications and changes can be made to the specific embodiments of the present application described herein without departing from the scope or spirit of the application. Other embodiments of the application will be apparent to those of ordinary skill in the art from the description and examples presented herein. The description and examples are illustrative of the application and are not intended to limit the scope of the application in any way.
[0039] The embodiment of the present application provides a synthesis process of (-)-a-lycorane alkaloid, which comprises the following steps:
[0040] (1) using (2Z, 4E)-7, 7-diethoxy-3-hydroxyhepta-2, 4-dienoic acid methyl ester (compound 1) and 3, 4-methylenedioxy-β-nitrostyrene (compound 2) as starting materials, compound 4 is obtained by catalytic asymmetric tandem Michael addition reaction, and the reaction route is as follows:
[0041]
[0042] (2) Compound 4 is first subjected to de-acetal protection in a mixed solvent of acetic acid and water, then subjected to reductive amination after zinc powder is added, after the reaction is completed, the zinc powder is removed, concentrated and extracted, the solvent is removed, hydrochloric acid is added and heated to remove the carboxyl group, after the reaction is completed, it is concentrated, neutralized, extracted with dichloromethane, and the extract is directly added to di-tert-butyl dicarbonate and triethylamine to obtain Compound 8, and the reaction route is as follows:
[0043]
[0044] (3) Compound 8 is subjected to Bischler-Napieralski cyclization reaction in a 2-chloropyridine / triflic anhydride / boron trifluoride etherate reaction system to obtain Compound 9, and the reaction route is as follows:
[0045]
[0046] (4) Compound 9 is reacted with Comins' reagent (N,N-bistrifluoromethanesulfonyl-5-chloro-2-aminopyridine) under the action of LiHMDS (lithium hexamethyldisilazide) to obtain enol triflate mixture 10a and Compound 10b, and the reaction route is as follows:
[0047]
[0048] (5) Compound 10a and Compound 10b are subjected to reductive hydrolysis reaction and reductive reaction of amide to obtain product (-)-α-lycorane, and the reaction route is as follows:
[0049]
[0050] In some embodiments, the catalytic asymmetric tandem Michael addition reaction of step (1) is carried out at room temperature, the reaction time is 120 h, and the solvent is toluene.
[0051] In some embodiments, in step (2), the de-acetal protection is carried out under nitrogen protection, the reaction temperature is 90°C, and the reaction time is 2 h; and / or, the reductive amination is carried out under nitrogen protection, the reaction temperature is room temperature; and / or, the reaction temperature of the heating decarboxylation is 100°C, the concentration of hydrochloric acid is 2-8N (equivalent concentration), and the reaction time is 10-24 h; and / or, the reaction time after di-tert-butyl dicarbonate is added is 4 h, the reaction solvent is dichloromethane, and triethylamine provides an alkaline environment.
[0052] In some embodiments, the volume ratio of glacial acetic acid to water in the mixed solvent of acetic acid and water is 10:1.
[0053] In some embodiments, the reaction of step (3) is carried out under nitrogen protection, the reaction temperature is -78°C, and the reaction time is 6 h.
[0054] In some embodiments, the step (4) comprises, under the protection of nitrogen, using tetrahydrofuran to dissolve compound 9, Comins’ reagent, adding LiHMDS, extracting after the reaction is completed, concentrating, purifying, to obtain a mixture of compound 10a and compound 10b.
[0055] In some preferred embodiments, the molar ratio of compound 9, Comins’ reagent and LiHMDS is 2.28:2.73:2.96.
[0056] In preferred embodiments, the step (5) specifically comprises the following steps: dissolving the mixture 10a and compound 10b with methanol, adding a catalyst Pd / C, placing the reaction under the condition of hydrogen atmosphere, and carrying out the reaction at room temperature for 12 h, then filtering, washing, concentrating the filtrate under reduced pressure, dissolving with tetrahydrofuran, adding lithium aluminum hydride (reducing agent) thereto, reacting at 70℃ for 5 h, extracting, concentrating, purifying, to obtain the product (-)-α-lycorane.
[0057] In the following examples, the raw materials used are obtained through conventional commercial channels. Among them, (2Z,4E)-7,7-diethoxy-3-hydroxyhepta-2,4-dienoic acid methyl ester is prepared by the method reported in our previous literature (Yuxiang Zhao; Yanren Zhu; Guolan Ma; Qi Wei; Shaoxiong Yang; Xiaoyu Zeng; Hongbin Zhang; Jingbo Chen; Short, enantioselective, gram-scale synthesis of (-)-zephyranthine Chemical Science, 2021, 12(27): 9452-9457.), 3,4-methylenedioxy-β-nitrostyrene (compound 2), Zn powder, di-tert-butyl dicarbonate, 2-chloropyridine and lithium aluminum hydride are purchased from Titan Exploration Platform Adamas brand reagent.
[0058] Example 1
[0059] A synthesis process of (-)-α-lycorane alkaloid, comprising the following steps: (1)
[0061]
[0062] Compound 1 ((2Z,4E)-7,7-diethoxy-3-hydroxyhepta-2,4-dienoic acid methyl ester) (7.00 g, 28.65 mmol) was weighed into a single-necked round-bottom flask, to which was added compound 2 (3,4-methylenedioxy- -nitrostyrene) (5.71 g, 30.09 mmol), 0.02 equivalent of catalyst Evens' (462.71 mg, 573 μmol) was weighed into it, then toluene (80 mL) was added, and the reaction was carried out at room temperature on a constant-temperature magnetic stirrer for 120 h. TLC monitoring showed that the reaction was complete. After the reaction was complete, an appropriate amount of base Triton B (trimethylbenzylammonium hydroxide) methanol solution (10 mL, 40% concentration, 27.85 mmol) was slowly added to the reaction system under ice-bath conditions, and the reaction was continuously stirred for 15 min. After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the crude product was subjected to silica gel column chromatography (DCM) to obtain compound 4 (10.8 g, 86% yellow oily compound).
[0063] 1 H NMR (400 MHz, CDCl3) δ 12.52 (s, 1H), 6.77-6.65 (m, 3H), 5.95 (s, 2H), 4.72 (dd, J = 3.0, 2.1 Hz, 1H), 4.50-4.43 (m, 2H), 3.59 (s, 3H), 3.52 (ddd, J = 9.4, 8.4, 7.1 Hz, 2H), 3.32 (ddd, J = 21.7, 9.3, 7.1 Hz, 1H), 2.53 (d, J = 9.2 Hz, 2H), 2.33 (ddd, J = 9.3, 5.9, 2.3 Hz, 1H), 1.87-1.65 (m, 2H), 1.06 (t, J = 7.0 Hz, 3H), 0.99 (t, J = 7.0 Hz, 3H).
[0064] 13 C NMR (101 MHz, CDCl3) δ 172.28, 171.96, 148.15, 147.02, 135.03, 121.05, 108.55, 108.24, 101.37, 100.57, 95.93, 89.23, 62.03, 61.94, 51.99, 43.69, 35.51, 31.36, 27.06, 15.24, 15.10.
[0065] The nuclear magnetic resonance hydrogen spectrum of compound 4 is as shown in Figure 1 ; and the nuclear magnetic resonance carbon spectrum of compound 4 is as shown in Figure 2 . (2)
[0067]
[0068] To compound 4 (3.00 g, 6.86 mmol) in a 100 mL round bottom flask, add glacial acetic acid: water = 10: 1 solvent (33 mL), and stir at 90 °C under nitrogen protection for 2 h. After TLC detection, the reaction is complete. Cool to room temperature, add activated Zn powder (4.48 g, 68.58 mmol) to the flask, and stir at room temperature under nitrogen protection overnight. After TLC detection, the reaction is complete. Filter the Zn powder and insoluble residue, concentrate to remove the solvent, add aqueous HC1 (4 N, 50 mL), and stir at 100 °C for 24 h. After TLC detection, the reaction is complete. Dry the solvent, dilute with DCM, neutralize with potassium carbonate solution, extract with DCM (3 x 20 mL), combine the organic layers, add di-tert-butyl dicarbonate (1.80 g, 8.24 mmol) and triethylamine (1.43 mL, 10.30 mmol), and stir for 4 h. Dry the solvent, and purify the residue by column chromatography (dichloromethane:methanol = 100: 1) to obtain 1.78 g of product, compound 9. From compound 4 to compound 8, the total yield of the five-step reaction is as high as 72%.
[0069] 1 H NMR (400 MHz, CDC13) δ 6.76 - 6.68 (m, 2H), 6.64 - 6.57 (m, 1H), 5.94 - 5.90 (m, 2H), 4.19 (dd, J = 9.5, 6.2 Hz, 1H), 3.55 (s, 1H), 3.43 (td, J = 9.1, 4.8 Hz, 1H), 2.93 (s, 1H), 2.80 - 2.68 (m, 3H), 2.46 (d, J = 13.3 Hz, 2H), 2.24 - 1.96 (m, 1H), 1.80 (tt, J = 13.0, 9.1 Hz, 1H), 1.33 - 1.05 (m, 9H).
[0070] 13 C NMR (101 MHz, CDC13) δ 209.52, 154.53, 147.78, 146.63, 135.23, 121.27, 108.35, 108.25, 101.06, 79.39, 61.67, 44.42, 41.83, 28.17.
[0071] The nuclear magnetic resonance hydrogen spectrum of compound 8 is as shown in Figure 3 ; and the nuclear magnetic resonance carbon spectrum of compound 8 is as shown in Figure 4 . (3)
[0073]
[0074] Compound 8 (300 mg, 0.905 mmol) was taken in a 50 ml round bottom flask, dissolved in dry DCM (10 mL), taken in a -78 °C ultra-low temperature reactor under nitrogen atmosphere, 2-chloropyridine (157.95 μL, 1.67 mmol), Tf20 (triflic anhydride) (423 μL, 2.50 mmol), OEt2.BF3(trifluoroboron-ethanol complex) (2.18 mL, 8.35 mmol) were added sequentially and allowed to react for 6 h, monitored by TLC, reaction was over; saturated sodium bicarbonate solution (10 mL) was added to the reaction mixture, organic layer was separated, aqueous layer was extracted with DCM (3 x 10 mL), combined organic layers were washed with saturated brine (3 x 10 mL); organic layer was separated and concentrated under reduced pressure, crude residue was purified by column chromatography (dichloromethane:methanol = 100:1) to get the product (compound 9) 186 mg, yield 78%.
[0075] 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 6.59 (s, 1H), 6.02 (s, 2H), 4.28 (dd, J = 12.0, 7.6 Hz, 1H), 3.69 (dd, J = 13.5, 9.8 Hz, 1H), 3.34 (dtd, J = 32.3, 12.3, 5.3 Hz, 2H), 2.95 (dd, J = 18.6, 4.9 Hz, 1H), 2.86 - 2.70 (m, 2H), 2.58 - 2.45 (m, 1H), 2.40 (dt, J = 12.6, 6.4 Hz, 1H), 2.21 (dd, J = 18.6, 12.8 Hz, 1H), 1.99 - 1.73 (m, 1H).
[0076] 13 C NMR (101 MHz, CDCl3) δ 209.58, 162.08, 150.93, 147.19, 134.81, 124.65, 108.94, 104.20, 101.90, 59.80, 45.09, 44.08, 38.90, 35.59, 34.98, 33.90.
[0077] NMR of compound 9 is as shown in Figure 5 ; NMR of compound 9 is as shown in Figure 6 . (4)
[0079]
[0080] Compound 9 (650 mg, 2.28 mmol) and Comins' reagent (N,N-ditrifluoromethanesulfonyl-5-chloro-2-aminopyridine) (1.07 g, 2.73 mmol) were added to a 50 mL round-bottom flask and dissolved in anhydrous THF (20 mL). Under nitrogen protection, the reaction was carried out at an ultra-low temperature of -78 °C. LiHMDS (bis(trimethylsilylamino)lithium) was added using a syringe.
[0081] After reacting with 2.96 mL (2.96 mmol) for 2 h, the reaction was monitored by TLC. After the reaction was complete, saturated ammonium chloride solution (10 mL) was added to separate the organic layer. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with saturated brine (3 × 10 mL) and concentrated under reduced pressure. The crude residue was purified by column chromatography (dichloromethane:methanol = 200:1) to give 886 mg of the product (a mixture of compounds 10a and 10b), with a yield of 87%.
[0082] 1 H NMR (400MHz, CDCl3) δ7.50(d,J=1.2Hz,1H),7.46(d,J=1.3Hz,1H),6.76(d,J=1.3Hz,1H),6.61(d,J=1.2Hz,1H),6.26(d,J=3.2Hz,1H ),6.03(d,J=1.2Hz,2H),6.02(d,J=1.3Hz,3H),5.97(t,J=2.1Hz,2H),4.23(dt,J=12.3,8.4Hz,3H),3.68(td,J=12.7,9.2Hz,3H),3.4 9–3.37(m,2H),3.33(td,J=12.5,5.3Hz,3H),3.23–3.08(m,1H),2.98(td,J=12.0,5.0Hz,1H),2.93–2.83(m,1H),2.80–2.75(m,1H), 2.73(d,J=5.0Hz,1H),2.62–2.53(m,1H),2.47(dtt,J=16.6,7.0,3.1Hz,1H),2.26(ddt,J=18.3,12.0,6.1Hz,3H),1.86–1.66(m,4H).
[0083] 13C NMR (101 MHz, CDC13) δ 162.67, 162.22, 151.21, 150.94, 150.85, 148.15, 147.22, 147.20, 134.61, 132.89, 124.98, 124.65, 120.22, 120.20, 119.11, 117.02, 116.22, 109.33, 108.87, 103.78, 101.98, 101.95, 101.90, 61.02, 58.40, 45.96, 45.93, 38.58, 38.46, 36.46, 36.41, 32.54, 32.34, 30.84, 28.84.
[0084] The nuclear magnetic resonance hydrogen spectrum of the mixture of compounds 10a and 10b is as follows: Figure 7 The nuclear magnetic resonance carbon spectrum of the mixture of compounds 10a and 10b is as follows: Figure 8 . (5)
[0086]
[0087] The mixture of compounds 10a, 10b (300 mg, 0.718 mmol) was added to a 50 ml flask, dissolved with methanol (MeOH), then Pd / C (catalyst palladium / carbon) (50 mg, 469.84 mmol) was added, and the reaction was carried out at room temperature under hydrogen for 12 h, and the reaction was monitored by TLC; after filtration, washing, and concentration of the filtrate under reduced pressure, tetrahydrofuran (20 mL) was added for dissolution; after the addition of LiAlH4 (reducing agent lithium aluminum hydride) (37.66 mg, 1.08 mmol), the reaction was carried out at 70°C for 5 h, and the reaction was monitored by TLC; after the reaction was completed, saturated potassium carbonate solution (5 mL) was added for quenching, and ethyl acetate extraction (3 x 20 mL) was carried out; after the organic phase was washed with saturated brine (3 x 15 mL), it was concentrated; column chromatography (dichloromethane:methanol:triethylamine = 20:1:0.1) was used for separation and purification, and the product (-)-a-Lycorane 144.28 mg, i.e., compound (-)-a-Lycorane (compound 11), was obtained, with a yield of 78%.
[0088] 1H NMR (400 MHz, CDC13) δ 6.71 (s, 1H), 6.60 (s, 1H), 5.90 (s, 2H), 4.13 (d, J = 15.1 Hz, 1H), 3.77 (d, J = 15.1 Hz, 1H), 3.15 (dd, J = 17.6, 8.0 Hz, 1H), 2.84 (dt, J = 9.4, 3.4 Hz, 1H), 2.51 - 2.35 (m, 3H), 2.26 - 2.20 (m, 1H), 1.93 - 1.57 (m, 6H), 1.23 - 1.14 (m, 1H);
[0089] 13 C NMR (101 MHz, CDC13) δ 146.29, 145.49, 135.05, 128.81, 107.06, 104.57, 100.78, 64.64, 54.70, 54.30, 37.02, 34.02, 28.02, 26.22, 25.00, 20.96.
[0090] The nuclear magnetic resonance hydrogen spectrum of compound (-)-a-lycorane is as follows: Figure 9 The nuclear magnetic resonance carbon spectrum of compound (-)-a-lycorane is as follows: Figure 10 .
[0091] The above-described embodiments are merely preferred modes of the present application and are not intended to limit the scope of the present application. Various modifications and improvements to the technical solutions of the present application made by those of ordinary skill in the art without departing from the design spirit of the present application shall fall within the scope of protection of the present application as defined by the claims.
Claims
1. A process for the synthesis of a (-)-a-lycorane alkaloid, characterized in that, The method comprises the following steps: (1) with (2Z,4E)-7,7-diethoxy-3-hydroxyhepta-2,4-dienoic acid methyl ester and 3,4-methylenedioxy-β-nitrostyrene as starting materials, a compound 4 is obtained by catalytic asymmetric tandem Michael addition reaction, and the structural formula of the compound 4 is: ; (2) Compound 4 is first deprotected in a mixed solvent of acetic acid and water; after cooling, zinc powder is added to perform reductive amination; after the reaction is completed, the zinc powder is removed, concentrated and extracted, the solvent is removed, hydrochloric acid is added to perform heating decarboxylation; after the reaction is completed, concentration, neutralization, dichloromethane extraction, and the extraction liquid is directly added to di-tert-butyl dicarbonate and triethylamine to obtain compound 8, and the structural formula of the compound 8 is: ; (3) Compound 8 is subjected to Bischler-Napieralski cyclization reaction in a 2-chloropyridine / triflic anhydride / boron trifluoride etherate reaction system to prepare compound 9, the structural formula of which is: ; (4) Compound 9 reacts with Comins' reagent under the action of LiHMDS to prepare enol triflate mixture compounds 10a and 10b, whose structural formulas are as follows: and ; (5) the mixture of compound 10a and compound 10b is subjected to a reductive hydrolysis reaction and an amide reduction reaction to obtain the product (-)-α-lycorane; The reaction of step (3) is carried out under nitrogen protection, at a reaction temperature of -78 °C, and for a reaction time of 6 h. Step (4) comprises, under nitrogen protection, at an ultra-low temperature of -78 °C, dissolving compound 9 and Comins' reagent in tetrahydrofuran, adding LiHMDS, and reacting for 2 h, after which extraction, concentration and purification are carried out to obtain the mixture of compound 10a and compound 10b. In step (5), the reductive hydrolysis comprises the following steps: dissolving compound 10a and compound 10b in methanol, adding a catalyst Pd / C, and reacting at room temperature under a hydrogen atmosphere for 12 h, after which filtration, washing and concentration of the filtrate under reduced pressure are carried out. In step (5), the amide reduction reaction comprises the following steps: adding the product of the reductive hydrolysis reaction to tetrahydrofuran, adding lithium aluminum hydride thereto, and reacting at 70 °C for 5 h, after which extraction, concentration and purification are carried out to obtain the product (-)-α-lycorane.
2. The process for synthesis of (-)-a-lycorane alkaloid according to claim 1, wherein, The catalytic asymmetric tandem Michael addition reaction in step (1) is carried out at room temperature, for a reaction time of 120 h, and using toluene as the solvent.
3. The process for synthesis of (-)-a-lycorane alkaloid as claimed in claim 1, wherein, In step (2), the de-acetal protection is carried out under nitrogen protection, at a reaction temperature of 90 °C, and for a reaction time of 2 h; and / or, the reductive amination is carried out under nitrogen protection, at room temperature; and / or, The reaction temperature of the heating decarboxylation is 100 °C, the concentration of hydrochloric acid is 2N-8N, the reaction time is 10-24 h, and / or, the reaction time after adding di-tert-butyl dicarbonate is 4 h, the reaction solvent is dichloromethane, and triethylamine provides an alkaline environment.
4. The process for synthesis of (-)-a-lycorane alkaloid as claimed in claim 1, wherein, The volume ratio of glacial acetic acid to water in the mixed solvent of acetic acid and water in step (2) is 10:
1.
5. The process for synthesis of (-)-a-lycorane alkaloid as claimed in claim 1 wherein, The molar ratio of compound 9, Comins' reagent and LiHMDS is 2.28:2.73:2.96.