Synthesis process of (-)-alpha-lycolane alkaloid

Abstract

The invention discloses a synthesis process of (-)-alpha-lycolane alkaloid, and belongs to the technical field of organic synthetic chemistry. According to the preparation method, (2Z, 4E)-7, 7-diethoxy-3-hydroxyheptyl-2, 4-dienoic acid methyl ester and 3, 4-methylenedioxy-beta-nitrostyrolene are taken as initial raw materials, and the raw materials are subjected to a one-pot reaction so as to obtain the 3, 4-methylenedioxy-beta-nitrostyrolene. According to the method, (-)-alpha-lycolane is obtained through a catalytic asymmetric series Michael addition reaction, a nitro reductive amination reaction, a Boc amidation reaction, a Bischler-Napieralski cyclization reaction, an enolation series esterification reaction of ketone, a reductive hydrogenolysis reaction of enol trifluoromethanesulfonate and an amide reduction reaction in sequence. The (-)-alpha-lycolane has a four-membered ring core skeleton of a pyrrole-phenanthridine ring, and has good in-vitro tumor inhibition activity and cell proliferation and growth inhibition activity. According to the synthesis process disclosed by the invention, efficient and simple total synthesis of the (-)-alpha-lycolane can be realized.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthetic chemistry, in particular to a synthesis process of (-)-α-lycorane alkaloid. Background Art

[0002] In the field of bioactive molecules, lycorine has attracted considerable attention due to its inhibitory effects on melanoma angiogenesis, as well as its diverse bioactivities, including anti-tumor, antibacterial, and analgesic properties. As a key member of the lycorine alkaloid class, (-)-α-lycorane inherits the core advantages of this class of alkaloids, exhibiting excellent in vitro tumor suppression and cell proliferation inhibition activities, and holds great potential for drug development.

[0003] Current synthetic methods for (-)-α-lycorane have significant limitations, with most routes being lengthy, time-consuming, and inefficient. Given the importance of Amaryllidaceae alkaloids in drug development due to their excellent antitumor activity, developing a novel and efficient catalytic asymmetric synthesis method to achieve the efficient and concise total synthesis of (-)-α-lycorane is of paramount importance. This approach would not only significantly improve synthetic efficiency but also potentially further promote the development of this class of drugs, providing a solid foundation for their in-depth research and application. Summary of the Invention

[0004] The purpose of the present invention is to provide a simple and efficient synthesis process for (-)-α-lycorane alkaloids to solve the problems existing in the above-mentioned prior art.

[0005] In order to achieve the above-mentioned purpose, the present invention provides the following technical solutions:

[0006] The present invention provides a synthesis process of (-)-α-lycorane alkaloids, comprising the following steps:

[0007] (1) Using known (2Z,4E)-7,7-diethoxy-3-hydroxyhept-2,4-dienoic acid methyl ester (Compound 1) and 3,4-methylenedioxy-β-nitrostyrene (Compound 2) as starting materials, a catalytic asymmetric tandem Michael addition reaction was performed to obtain Compound 4, the structural formula of which is:

[0008] (2) Compound 4 is first subjected to deacetalization in a mixed solvent of acetic acid and water; after cooling, zinc powder is added and reductive amination is performed; after the reaction is completed, the zinc powder is removed, the mixture is concentrated and extracted, the solvent is removed, and hydrochloric acid is added to perform heating decarboxylation; after the reaction is completed, the mixture is concentrated, neutralized, and extracted with dichloromethane, and the extract is directly added with di-tert-butyl dicarbonate and triethylamine to react to obtain Compound 8, the structural formula of which is:

[0009] (3) Compound 8 was subjected to Bischler-Napieralski cyclization reaction in a 2-chloropyridine / trifluoromethanesulfonic anhydride / boron trifluoride etherate reaction system to prepare compound 9, the structural formula of which is:

[0010] (4) Compound 9 was reacted with Comins' reagent in the presence of LiHMDS to prepare enol trifluoromethanesulfonate mixtures Compound 10a and Compound 10b. The structural formulas of Compound 10a and Compound 10b are: and

[0011] (5) The mixture of compound 10a and compound 10b was subjected to reductive hydrogenolysis and amide reduction to obtain the product (-)-α-lycorane.

[0012] The synthetic route is as follows:

[0013]

[0014] Preferably, the catalytic asymmetric tandem Michael addition reaction in step (1) is carried out at room temperature, the reaction time is 120 h, and the solvent is toluene.

[0015] Preferably, in the step (2), the deacetalization 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 hydrochloric acid concentration is 2N to 8N, and the reaction time is 10 to 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] More 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 in step (3) is carried out under nitrogen protection, at a reaction temperature of -78°C, and for a reaction time of 6 hours.

[0018] Preferably, step (4) comprises dissolving compound 9 and Comins' reagent in tetrahydrofuran under nitrogen protection at an ultra-low temperature of -78°C, adding LiHMDS, extracting, concentrating, and purifying after the reaction to obtain a mixture of compound 10a and compound 10b.

[0019] More 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 hydrogenolysis comprises the following steps: dissolving the mixture 10a and compound 10b in methanol, adding a Pd / C catalyst, reacting at room temperature under a hydrogen atmosphere for 12 hours, filtering, washing, and concentrating the filtrate under reduced pressure.

[0021] Preferably, in step (5), the step of the amide reduction reaction is: adding tetrahydrofuran to dissolve the product of the reduction hydrogenation degreasing reaction, then adding lithium aluminum hydride thereto, reacting at 70° C. for 5 hours, extracting, concentrating, and purifying to obtain the product (-)-α-lycorane.

[0022] The present invention discloses the following beneficial effects:

[0023] The synthesis process of the present invention is simplified, reaction conditions are easily achieved, high temperature and high pressure are not required, the synthesis process is efficient and concise, and large-scale production of (-)-α-lycorane can be achieved; the product (-)-α-lycorane has a high yield and high purity, creating necessary conditions for promoting the development of lycorine as a good anti-tumor drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0025] Figure 1 is the H NMR spectrum of compound 4;

[0026] Figure 2 is the carbon NMR spectrum of compound 4;

[0027] Figure 3 is the H NMR spectrum of compound 8;

[0028] Figure 4 is the carbon NMR spectrum of compound 8;

[0029] Figure 5 is the H NMR spectrum of compound 9;

[0030] Figure 6 is the carbon NMR spectrum of compound 9;

[0031] Figure 7This is the H NMR spectrum of the mixture of compounds 10a and 10b;

[0032] Figure 8 This is the C NMR spectrum of the mixture of compounds 10a and 10b;

[0033] Figure 9 is the H NMR spectrum of compound (-)-α-lycorane;

[0034] Figure 10 This is the carbon NMR spectrum of the compound (-)-α-lycorane. DETAILED DESCRIPTION

[0035] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0036] It should be understood that the terms used in the present invention are only used to describe particular embodiments and are not intended to limit the present invention.

[0037] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0038] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be exemplary only.

[0039] The embodiment of the present invention provides a synthesis process of (-)-α-lycorane alkaloids, comprising the following steps:

[0040] (1) Using (2Z,4E)-7,7-diethoxy-3-hydroxyhept-2,4-dienoic acid methyl ester (Compound 1) and 3,4-methylenedioxy-β-nitrostyrene (Compound 2) as starting materials, compound 4 was obtained by catalytic asymmetric tandem Michael addition reaction. The reaction scheme is as follows:

[0041]

[0042] (2) Compound 4 is first deacetalized in a mixed solvent of acetic acid and water; then zinc powder is added for reductive amination; after the reaction is completed, the zinc powder is removed, the mixture is concentrated and extracted, the solvent is removed, hydrochloric acid is added for heating and decarboxylation; after the reaction is completed, the mixture is concentrated, neutralized, and extracted with dichloromethane, and the extract is directly added with di-tert-butyl dicarbonate and triethylamine to react to obtain compound 8. The reaction scheme is as follows:

[0043]

[0044] (3) Compound 8 was subjected to Bischler-Napieralski cyclization reaction in a 2-chloropyridine / trifluoromethanesulfonic anhydride / boron trifluoride etherate reaction system to prepare compound 9. The reaction scheme is as follows:

[0045]

[0046] (4) Compound 9 reacts with Comins' reagent (N,N-ditrifluoromethanesulfonyl-5-chloro-2-aminopyridine) in the presence of LiHMDS (lithium hexamethyldisilazide) to prepare enol trifluoromethanesulfonate mixture 10a and compound 10b. The reaction scheme is as follows:

[0047]

[0048] (5) Compound 10a and compound 10b were subjected to reductive hydrogenolysis and amide reduction to obtain the product (-)-α-lycorane. The reaction scheme 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 the step (2), the deacetalization 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, and the reaction temperature is room temperature; and / or, the reaction temperature of the heating decarboxylation is 100° C., the hydrochloric acid concentration is 2-8N (equivalent concentration), and the reaction time is 10-24 h; and / or, the reaction time is 4 h after adding di-tert-butyl dicarbonate, 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 in step (3) is carried out under nitrogen protection, at a reaction temperature of -78°C, and for 6 hours.

[0054] In some embodiments, step (4) comprises dissolving compound 9 and Comins' reagent in tetrahydrofuran under nitrogen protection at an ultra-low temperature of -78°C, adding LiHMDS, extracting, concentrating, and purifying after the reaction 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 a preferred embodiment, step (5) specifically includes the following steps: dissolving the mixture 10a and compound 10b in methanol, adding a Pd / C catalyst, reacting at room temperature for 12 hours under a hydrogen atmosphere, filtering, washing, and concentrating the filtrate under reduced pressure, adding tetrahydrofuran to dissolve, and then adding lithium aluminum hydride (reducing agent) thereto. After reacting at 70° C. for 5 hours, extraction, concentration, and purification are performed to obtain the product (-)-α-lycorane.

[0057] In the following examples, the raw materials used were obtained through conventional commercial routes. Among them, (2Z,4E)-7,7-diethoxy-3-hydroxyhept-2,4-dienoic acid methyl ester was obtained from our previous reports (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 were purchased from Adamas brand reagents on the Titan Exploration Platform.

[0058] Example 1

[0059] A process for synthesizing a (-)-α-lycorane alkaloid comprises the following steps: (1)

[0061]

[0062] Compound 1 ((2Z,4E)-7,7-diethoxy-3-hydroxyhept-2,4-dienoic acid methyl ester) (7.00 g, 28.65 mmol) was weighed on an analytical balance and placed in a single-necked round-bottom flask. Compound 2 (3,4-methylenedioxy-β-nitrostyrene) (5.71 g, 30.09 mmol) was added thereto. 0.02 equivalents of catalyst Evens' (462.71 mg, 573 μmol) was weighed and added thereto. Then, toluene (80 mL) was added. ), reacted at room temperature on a constant temperature magnetic stirrer for 120 hours. After the completion of the reaction, monitored by TLC thin-layer chromatography, an appropriate amount of a methanol solution of Triton B (trimethylbenzylammonium hydroxide) (10 mL, 40% concentration, 27.85 mmol) was slowly added to the reaction system in an ice bath to treat the reaction solution. The reaction was stirred for 15 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM) to obtain compound 4 (10.8 g, 86% yellow oily compound).

[0063] 1 H NMR (400MHz, CDCl3) δ12.52 (s, 1H), 6.77-6.65 (m, 3H), 5.95 (s, 2H), 4.72 (dd, J= 3.0,2.1Hz,1H),4.50-4.43(m,2H),3.59(s,3H),3.52(ddd,J=9.4,8.4,7.1Hz,2 H),3.32(ddd,J=21.7,9.3,7.1Hz,1H),2.53(d,J=9.2Hz,2H),2.33(ddd,J=9.3, 5.9,2.3Hz,1H),1.87-1.65(m,2H),1.06(t,J=7.0Hz,3H),0.99(t,J=7.0Hz,3H).

[0064] 13 C NMR (101MHz, CDCl3) δ172.28,171.96,148.15,147.02,135.03,121.05,108.55,108.24,101 .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 H NMR spectrum of compound 4 is as follows Figure 1 ; The C NMR spectrum of compound 4 is as follows Figure 2 . (2)

[0067]

[0068] Compound 4 (3.00 g, 6.86 mmol) was added to a 100 mL round-bottom flask, and then glacial acetic acid: water = 10:1 solvent (33 mL) was added. The mixture was reacted at 90 ° C for 2 h under nitrogen protection. After TLC detection, the reaction was completed; it was then cooled to room temperature, activated Zn powder (4.48 g, 68.58 mmol) was added to the bottle, and the mixture was stirred at room temperature under nitrogen protection overnight. After TLC detection, the reaction was completed; the Zn powder and insoluble residue were filtered, the solvent was concentrated to remove, and HCl aqueous solution (4N, 50 mL) was added. The mixture was reacted at 100 ° C for 24 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was dried, diluted with DCM, neutralized with potassium carbonate solution, and extracted with DCM (3×20 mL, i.e., extracted three times with 20 mL of dichloromethane, the same below). After combining the organic layers, di-tert-butyl dicarbonate (1.80 g, 8.24 mmol) and triethylamine (1.43 mL, 10.30 mmol) were added. The reaction was stirred for 4 hours, the solvent was evaporated, and the residue was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 1.78 g of the product, i.e., compound 9. From compound 4 to compound 8, the total yield was as high as 72% in five steps.

[0069] 1 H NMR (400MHz, CDCl3) δ6.76-6.68(m,2H),6.64-6.57(m,1H),5.94-5.90(m,2H),4.19(dd,J=9.5,6.2Hz,1H),3.55(s,1H),3.43(td,J=9.1 ,4.8Hz,1H),2.93(s,1H),2.80-2.68(m,3H),2.46(d,J=13.3Hz,2H),2.24-1.96(m,1H),1.80(tt,J=13.0,9.1Hz,1H),1.33-1.05(m,9H).

[0070] 13 C NMR (101MHz, CDCl3) δ209.52,154.53,147.78,146.63,135.23,121.27,108.35,108.25,101.06,79.39,61.67,44.42,41.83,28.17.

[0071] The H NMR spectrum of compound 8 is as follows Figure 3 ; The C NMR spectrum of compound 8 is as follows Figure 4 . (3)

[0073]

[0074] Compound 8 (300 mg, 0.905 mmol) was placed in a 50 ml round-bottom flask and dissolved in anhydrous DCM (10 mL). The mixture was placed in a -78 °C ultra-low temperature reactor under nitrogen protection, and 2-chloropyridine (157.95 μL, 1.67 mmol), Tf2O (trifluoromethanesulfonic anhydride) (423 μL, 2.50 mmol), OEt2·BF3 (boron trifluoride-diethyl ether complex) (2.18 mL, 8.35 mmol) was added, and the reaction was carried out for 6 h. The reaction was completed as monitored by TLC. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, the organic layer was separated, the aqueous layer was extracted with DCM (3×10 mL), and the organic layers were combined and washed with saturated brine (3×10 mL). The organic layer was separated and concentrated under reduced pressure. The crude residue was purified by column chromatography (dichloromethane:methanol=100:1) to obtain 186 mg of the product (Compound 9) in a yield of 78%.

[0075] 1 H NMR (400MHz, CDCl3) δ7.53 (s, 1H), 6.59 (s, 1H), 6.02 (s, 2H), 4.28 (dd, J = 12. 0,7.6Hz,1H),3.69(dd,J=13.5,9.8Hz,1H),3.34(dtd,J=32.3,12.3,5.3Hz, 2H),2.95(dd,J=18.6,4.9Hz,1H),2.86–2.70(m,2H),2.58–2.45(m,1H),2.4 0(dt,J=12.6,6.4Hz,1H),2.21(dd,J=18.6,12.8Hz,1H),1.99–1.73(m,1H).

[0076] 13 C NMR (101MHz, CDCl3) δ209.58,162.08,150.93,147.19,134.81,124.65,108.94,104.20,101.90,59.80,45.09,44.08,38.90,35.59,34.98,33.90.

[0077] The H NMR spectrum of compound 9 is as follows Figure 5 The C NMR spectrum of compound 9 is as follows: 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 anhydrous THF (20 mL) was added to dissolve them. Under nitrogen protection, the reaction was placed in an ultra-low temperature environment of -78 ° C, and LiHMDS (lithium bis(trimethylsilyl)amide) was added with a syringe.

[0081] )(2.96 mL, 2.96 mmol) and reacted for 2 h. After the reaction was completed, monitored by TLC; saturated ammonium chloride solution (10 mL) was added, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (3×15 mL), the combined organic layers were washed with saturated brine (3×10 mL), and the organic layer was concentrated under reduced pressure; the crude residue was purified by column chromatography (dichloromethane:methanol=200:1) to obtain 886 mg of the product (a mixture of compounds 10a and 10b) in 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 (101MHz, CDCl3) δ162.67,162.22,151.21,150.94,150.85,148.15,14 7.22,147.20,134.61,132.89,124.98,124.65,120.22,120.20,119.11,11 7.02,116.22,109.33,108.87,103.78,101.98,101.95,101.90,61.02,58. 40,45.96,45.93,38.58,38.46,36.46,36.41,32.54,32.34,30.84,28.84.

[0084] The H NMR spectrum of the mixture of compounds 10a and 10b is as follows Figure 7 The C NMR spectrum of the mixture of compounds 10a and 10b is as follows: Figure 8 . (5)

[0086]

[0087] A mixture of compounds 10a and 10b (300 mg, 0.718 mmol) was added to a 50 ml flask and dissolved in methanol (MeOH). Pd / C (catalyst palladium / carbon) (50 mg, 469.84 mmol) was then added. The reaction was allowed to proceed at room temperature for 12 h under the condition of hydrogen gas. The reaction was completed as monitored by TLC. The mixture was filtered, washed, and the filtrate was concentrated under reduced pressure and then dissolved in tetrahydrofuran (20 mL). LiA was added. After adding lH4 (reducing agent lithium aluminum hydride) (37.66 mg, 1.08 mmol), the reaction was placed at 70°C for 5 hours. After completion of the reaction, monitored by TLC, saturated potassium carbonate solution (5 mL) was added for quenching, and the mixture was extracted with ethyl acetate (3×20 mL). The organic phase was washed with saturated brine (3×15 mL) and concentrated. After separation and purification by column chromatography (dichloromethane:methanol:triethylamine=20:1:0.1), 144.28 mg of the product (-)-α-Lycorane, i.e., compound (-)-α-Lycorane (Compound 11), was obtained in a yield of 78%.

[0088] 1H NMR (400MHz, CDCl3) δ6.71(s,1H),6.60(s,1H),5.90(s,2H),4.13(d,J=15.1Hz,1H),3.77(d,J=15.1Hz,1H),3.15(dd,J=1 7.6,8.0Hz,1H),2.84(dt,J=9.4,3.4Hz,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 (101MHz, CDCl3) δ146.29,145.49,135.05,128.81,107.06,104.57,100.78,64.64,54.70,54.30,37.02,34.02,28.02,26.22,25.00,20.96.

[0090] The H NMR spectrum of compound (-)-α-lycorane is as follows Figure 9 The C NMR spectrum of compound (-)-α-lycorane is as follows: Figure 10 .

[0091] The embodiments described above are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by persons skilled in the art should fall within the scope of protection defined by the claims of the present invention.

Claims

1. A process for synthesizing a (-)-α-lycorane alkaloid, characterized in that: The following steps are involved: (1) Using (2Z,4E)-7,7-diethoxy-3-hydroxyhept-2,4-dienoic acid methyl ester and 3,4-methylenedioxy-β-nitrostyrene as starting materials, a catalytic asymmetric tandem Michael addition reaction was performed to obtain compound 4, the structural formula of which is: (2) Compound 4 is first subjected to deacetalization in a mixed solvent of acetic acid and water; after cooling, zinc powder is added and reductive amination is performed; after the reaction is completed, the zinc powder is removed, the mixture is concentrated and extracted, the solvent is removed, and hydrochloric acid is added to perform heating decarboxylation; after the reaction is completed, the mixture is concentrated, neutralized, and extracted with dichloromethane, and the extract is directly added with di-tert-butyl dicarbonate and triethylamine to react to obtain Compound 8, the structural formula of which is: (3) Compound 8 was subjected to Bischler-Napieralski cyclization reaction in a 2-chloropyridine / trifluoromethanesulfonic anhydride / boron trifluoride etherate reaction system to prepare compound 9, the structural formula of which is: (4) Compound 9 was reacted with Comins' reagent in the presence of LiHMDS to prepare enol trifluoromethanesulfonate mixtures Compound 10a and Compound 10b. The structural formulas of Compound 10a and Compound 10b are: (5) The mixture of compound 10a and compound 10b was subjected to reductive hydrogenolysis and amide reduction to obtain the product (-)-α-lycorane.

2. The synthesis process of (-)-α-lycorane alkaloid according to claim 1, characterized in that The catalytic asymmetric tandem Michael addition reaction in step (1) is carried out at room temperature, the reaction time is 120 h, and the solvent is toluene.

3. The synthesis process of (-)-α-lycorane alkaloid according to claim 1, characterized in that In step (2), the deacetalization 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 at room temperature; and / or, The reaction temperature of the heating decarboxylation is 100° C., the concentration of hydrochloric acid is 2N to 8N, the reaction time is 10 to 24 hours, and / or, After adding di-tert-butyl dicarbonate, the reaction time is 4 hours, the reaction solvent is dichloromethane, and triethylamine provides an alkaline environment.

4. The synthesis process of (-)-α-lycorane alkaloid according to claim 1, characterized in that 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 synthesis process of (-)-α-lycorane alkaloid according to claim 1, characterized in that The reaction in step (3) was carried out under nitrogen protection, at a temperature of -78°C, and for 6 hours.

6. The synthesis process of (-)-α-lycorane alkaloid according to claim 1, characterized in that Step (4) comprises dissolving compound 9 and Comins' reagent in tetrahydrofuran under nitrogen protection at an ultra-low temperature of -78°C, adding LiHMDS, and reacting for 2 hours. After the reaction, extraction, concentration, and purification are performed to obtain a mixture of compound 10a and compound 10b.

7. The process for synthesizing the (-)-α-lycorane alkaloid according to claim 6, wherein: The molar ratio of compound 9, Comins' reagent and LiHMDS is 2.28:2.73:2.

96.

8. The process for synthesizing the (-)-α-lycorane alkaloid according to claim 1, wherein In step (5), the reductive hydrogenolysis comprises the following steps: dissolving the mixture 10a and compound 10b in methanol, adding a Pd / C catalyst, reacting at room temperature under a hydrogen atmosphere for 12 hours, filtering, washing, and concentrating the filtrate under reduced pressure.

9. The process for synthesizing the (-)-α-lycorane alkaloid according to claim 8, wherein In step (5), the amide reduction reaction comprises the following steps: adding tetrahydrofuran to dissolve the product of the reduction hydrogenolysis reaction, adding lithium aluminum hydride thereto, reacting at 70° C. for 5 h, extracting, concentrating, and purifying to obtain the product (-)-α-lycorane.

Images