A method for synthesizing the natural product Pancratinine C

Abstract

This invention discloses a method for preparing natural products Pancratinine B and C and their intermediates. The preparation method of the key intermediate compound 8 includes the following steps: 1) Compound 1 reacts with a nitrogen-iodine compound to obtain compound 2; 2) Compound 2 undergoes a cycloaddition reaction with compound 2' protected by a silicon-based protecting group R1 to obtain compound 3; 3) Compound 3 forms an enol silyl ether, which then undergoes a Saegusa-Ito oxidation reaction to obtain compound 4; 4) Compound 4 undergoes a reduction reaction to obtain compound 5; 5) Compound 5 is protected by a hydroxyl group to obtain compound 6; 6) Compound 6 is deprotected by the protecting group R to obtain compound 7; 7) Compound 7 undergoes a Pictet-Spengler condensation reaction to obtain compound 8. Then, Pancratinine C and B are obtained from compound 8 via compounds 9 and 10, respectively. This method is a novel synthetic approach with a simple reaction route, mild reaction conditions, and ease of operation.

Description

[0001] This application is a divisional application of application number 202110543312.7, filed on May 19, 2021, entitled "A method for synthesizing natural products Pancratinine B and C". Technical Field

[0002] This invention belongs to the field of organic chemical synthesis, specifically relating to a method for the total synthesis of natural products Pancratinine B and C. Background Technology

[0003] Pancratinine B and C are alkaloids first isolated from *Pancratium canariense*, a plant in the Amaryllidaceae family, in 2009. They possess antitumor, antiviral, and antibacterial physiological activities, and their molecular skeletons belong to the montanine type of alkaloids. These alkaloids have a 5,11-methylenemorphinidine structure and contain a common five-membered bridged heterocycle (as shown in Formula I). ​​The main differences lie in the substituents and stereoconfigurations on the E ring.

[0004]

[0005] In 1955, Wildam's group first isolated montanine, coccinine, and manthine from *Haemanthus*. In the decades that followed, numerous chemists isolated various montanine-type alkaloids. Due to their rich physiological activity and novel, complex, and challenging structures, chemists have been attracted to study the synthesis of montanine-type natural products. In 1991, Overman's group reported the first total synthesis, and many chemists have since conducted research on the synthesis of these natural products. The most recent reports are from Fan's group in 2013 and Zhai Hongbin's group in 2017, which reported the synthesis of the core skeleton of montanine-type alkaloids using Rh-catalyzed cycloaddition reactions. However, since their initial isolation in 2009, there have been no reports on the synthesis of pancratinine B and C. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing the natural products Pancratinine B and C. This method is a novel approach for the first complete synthesis of Pancratinine B and C, featuring a simple synthetic route, mild reaction conditions, and ease of operation. This invention also provides a method for preparing novel intermediate compounds of Pancratinine B and C.

[0007] This invention provides the following technical solutions:

[0008] In a first aspect, the present invention provides a method for synthesizing an intermediate compound 8 of Pancratinine B and C, comprising the steps of:

[0009] 1) Compound 1 reacts with nitrogen-iodine compounds to give compound 2;

[0010] 2) Compound 2 undergoes a cycloaddition reaction with compound 2' (a six-membered ring diene) to give compound 3;

[0011] 3) Compound 3 forms an enol silyl ether, which then undergoes a Saegusa-Ito oxidation reaction to give compound 4;

[0012] 4) Compound 4 undergoes a reduction reaction to give compound 5;

[0013] 5) Compound 5 was protected with a hydroxyl group to give compound 6;

[0014] 6) Compound 6 is deprotected by protecting group R to give compound 7;

[0015] 7) Compound 7 undergoes Pictet-Spengler condensation to give compound 8;

[0016] The reaction formula is as follows:

[0017]

[0018] Where R represents p-methylbenzenesulfonyl (Ts) or p-nitrobenzenesulfonyl (Ns); R1 and R2 represent hydroxyl protecting groups.

[0019] In one implementation, the method may include one or more of the following features with respect to steps 1)-7):

[0020] In step 1), compound 1 reacts with a nitrogen-iodine compound in the presence of copper acetylacetonate to obtain compound 2. The nitrogen-iodine compound can be p-methylbenzenesulfonylimide iodobenzene or p-nitrobenzenesulfonylimide iodobenzene. Accordingly, the protecting group R attached to N in compounds 2-6 is p-methylbenzenesulfonyl (Ts) or p-nitrobenzenesulfonyl (Ns).

[0021] In step 1), the reaction solvent can be acetonitrile.

[0022] In step 1), the molar ratio of the nitrogen-iodine compound to the olefin is in the range of 1:(1-4); the molar ratio of the nitrogen-iodine compound to copper acetylacetonate is in the range of 1:(0.03-0.08), preferably 1:0.08.

[0023] In step 1), the nitrogen-iodine compound can be prepared by reacting p-toluenesulfonamide or p-nitrobenzenesulfonamide with iodophenyl diacetic acid in the presence of a base (such as potassium hydroxide).

[0024] In step 2), compound 2 and compound 2' undergo a [3+2] cycloaddition reaction under Lewis acid catalysis to obtain compound 3. The Lewis acid may be selected from at least one of the following: copper tetrafluoroborate, copper trifluoromethanesulfonate, copper trifluoromethanesulfonate, copper hexafluorophosphate, copper acetate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, cuprous iodide, copper chloride, copper trifluoroacetate hydrate, silver tetrafluoroborate, silver perchlorate, silver trifluoromethanesulfonate, silver acetate, and silver trifluoroacetate.

[0025] In step 2), the hydroxyl protecting group R1 in compound 2' can be selected from silicon-based protecting groups, such as triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), triethylsilyl (TES), etc.; preferably triisopropylsilyl (TIPS).

[0026] In step 2), the reaction solvent can be selected from at least one of dichloromethane, tetrahydrofuran, chloroform, dioxane, and toluene, preferably dichloromethane.

[0027] In step 2), the molar ratio of compound 2 to the six-membered ring diene compound 2' is 1:(1-2), the molar ratio of compound 2 to Lewis acid is 1:(0.1-0.5), and the reaction temperature is 25°C-80°C.

[0028] In one embodiment, compound 2' is prepared by reacting cyclohexenone in the presence of lithium bis(trimethylsilyl)amino (LiHMDS) and a silicon-based protecting group reagent to obtain (cyclohexane-1,3-dien-1-yloxy)triisopropylsilane, i.e., compound 2'. The silicon-based protecting group reagent (enol silyl ether protecting group reagent) can be isopropyl silyl trifluoromethanesulfonate (TIPSOTf), triethyl silyl trifluoromethanesulfonate (TESOTf), tert-butyldimethyl silyl trifluoromethanesulfonate (TBSOTf), etc., preferably triisopropyl silyl trifluoromethanesulfonate (TIPSOTf). The reaction is carried out at a low temperature, for example, -78°C. The reaction solvent can be tetrahydrofuran.

[0029] In step 3), compound 3 forms an enol silyl ether in the presence of a base and trimethylsilyltrifluoromethanesulfonate, and then undergoes a Saegusa-Ito oxidation reaction under the action of an oxidant to obtain compound 4. The base may be diisopropylethylamine. The oxidant may be selected from at least one of the following: high-valent iodine reagents such as 2-iodobenzoic acid, pyridinium chlorochromate, and palladium acetate, preferably palladium acetate.

[0030] In step 3), the reaction solvent can be selected from at least one of toluene, dichloromethane, acetonitrile, and tetrahydrofuran; the reaction temperature range can be -78°C to 65°C.

[0031] In step 4), compound 4 undergoes a reduction reaction under the action of a reducing agent to obtain compound 5. The reducing agent is selected from at least one of sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, cerium trichloride, and sodium borohydride; preferably, it undergoes a Luche reduction reaction under the action of cerium trichloride and sodium borohydride.

[0032] In step 4), the reaction solvent can be selected from alcohol solvents (including methanol, ethanol, isopropanol, n-propanol, etc.), or dichloromethane, tetrahydrofuran, and mixed solvents of dichloromethane and ethanol, with methanol being preferred.

[0033] In step 5), compound 5 undergoes a hydroxyl protection reaction under the action of a hydroxyl protecting agent to obtain compound 6. The hydroxyl protecting agent may be selected from at least one of chloromethyl methyl ether, trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, etc.; preferably chloromethyl methyl ether. The hydroxyl protecting group R2 in compound 6 represents methoxymethyl (MOM), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethyl (TBS), etc., preferably methoxymethyl (MOM).

[0034] In step 5), the reaction solvent can be selected from commonly used solvents such as dichloromethane and tetrahydrofuran.

[0035] In step 6), compound 6 undergoes deprotection of the protecting group R under the action of sodium naphthalene or lithium aluminum hydride to obtain compound 7. Preferably, compound 6 undergoes deprotection of the protecting group R under the action of sodium naphthalene to obtain compound 7, and the reaction temperature under this condition is -78°C.

[0036] In step 7), compound 7 undergoes a Pictet-Spengler reaction in the presence of paraformaldehyde and formic acid to obtain compound 8.

[0037] In step 7), the reaction solvent can be selected from methanol, formic acid, acetonitrile, or N,N-dimethylformamide, and the reaction temperature can be 50°C-90°C, for example, 80°C. Compound 8 is an important intermediate in the synthesis of Pancratinine B and C.

[0038] In a second aspect, the present invention further provides a method for synthesizing Pancratinine C, comprising the steps of:

[0039] 8) Compound 9 is obtained by protecting compound 8 with a hydroxyl group and then oxidizing it.

[0040] 9) Compound 9 was dehydroxylated, and then subjected to oxidation and reduction reactions to obtain Pancratinine C;

[0041] The reaction formula is as follows:

[0042]

[0043] Compound 8 undergoes a hydroxyl protection reaction under the action of a hydroxyl protecting agent, followed by an oxidation reaction under the action of an oxidizing agent, to yield compound 9 (a tertiary hydroxyl compound). The hydroxyl protecting agent is selected from at least one of trimethylsilyltrifluoromethanesulfonate, triethylsilyltrifluoromethanesulfonate, tert-butyldimethylsilyltrifluoromethanesulfonate, triisopropylsilyltrifluoromethanesulfonate, chloromethyl ether, methanesulfonate, etc., preferably triisopropylsilyltrifluoromethanesulfonate. In compound 9, R3 represents a hydroxyl protecting group, which can be methoxymethyl (MOM), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethyl (TBS), etc., preferably methoxymethyl (MOM). The oxidizing agent is selected from at least one of pyridinium chlorochromate, ruthenium trichloride, sodium periodate, selenium dioxide, etc., preferably selenium dioxide, and the reaction temperature is 100°C. The reaction solvent can be selected from common solvents such as dichloromethane, tetrahydrofuran, and dioxane.

[0044] In this reaction, compound 9 undergoes a process where it loses its hydroxyl protecting group under the action of an acid, followed by oxidation (oxidizing the hydroxyl group to a carbonyl group) under the action of an oxidant, and then reduction (achieving hydroxyl configuration inversion) under the action of a reducing agent to yield Pancratinine C. The acid is selected from at least one of hydrofluoric acid, trifluoroacetic acid, ammonium bifluoride, etc., preferably ammonium bifluoride. The oxidant is preferably manganese dioxide. The reducing agent is selected from at least one of sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, etc., preferably diisobutylaluminum hydride. The reaction temperature range is 0°C-50°C. The reaction solvent can be selected from tetrahydrofuran, pyridine, dichloromethane, water, or mixtures thereof.

[0045] This invention also provides a method for synthesizing Pancratinine B, comprising the steps of:

[0046] 1) Compound 8 was subjected to a nucleophilic substitution (SN2) reaction to yield compound 10;

[0047] 2) Compound 10 undergoes an oxidation reaction to yield Pancratinine B;

[0048] The reaction route is as follows:

[0049]

[0050] Compound 8 undergoes a nucleophilic substitution (SN2) reaction in the presence of a methylating agent to yield compound 10. The methylating agent is selected from iodomethane / sodium cyanide, methyl trifluoromethanesulfonate / sodium hexamethyldisilanediazo, iodomethane / sodium hexamethyldisilanediazo, iodomethane / lithium bis(trimethylsilyl)amino, iodomethane / silver oxide, trimethyloxonium tetrafluoroborate, carbonyl chloride / sodium methoxide, and thioyl chloride / sodium methoxide, with thioyl chloride / sodium methoxide being preferred. For example, compound 8 undergoes an SN2 reaction in SOCl2 and sodium methoxide at a reaction temperature of 70°C to yield compound 10. The reaction solvent is selected from common solvents such as dichloromethane, methanol, chloroform, and tetrahydrofuran.

[0051] Compound 10 is oxidized by an oxidizing agent to yield Pancratinine B (a tertiary hydroxy compound). The oxidizing agent is selected from pyridinium chlorochromate, ruthenium trichloride, sodium periodate, and selenium dioxide; selenium dioxide is preferred. Under these conditions, the reaction temperature is 100°C. The reaction solvent can be selected from common solvents such as dichloromethane, tetrahydrofuran, and dioxane.

[0052] In a third aspect, the present invention further provides intermediate compounds for the preparation of Pancratinine B and C. These intermediate compounds are all newly synthesized compounds, including compounds 2, 4, 5, 6, 7, 8, 9, and 10 as described above. The present invention also provides the use of said intermediate compounds 2 to 8, 9, and 10 for the synthesis of Pancratinine B or C.

[0053] The beneficial effects of this invention are as follows: 1) This invention provides a novel method for the total chemical synthesis of Pancratinine B and C, with a novel and short synthetic route; 2) The raw materials are inexpensive and readily available, and the reagents used are all commonly used industrial reagents; 3) The reaction conditions are mild and the operation is simple; 4) The synthesis of the key intermediate compound 3 is a one-step construction of a tetracyclic skeleton through a Lewis acid-catalyzed [3+2] cycloaddition reaction, which is simple, efficient, and suitable for large-scale preparation. Detailed Implementation

[0054] The features and advantages of the present invention are further described below through examples. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention or the claims. Reaction conditions not detailed in the invention summary (e.g., reaction temperature, time, material ratio, etc.) are conventional operations that can be performed by those skilled in the art based on common sense or by referring to the examples. The raw materials used in the examples are all known and available compounds. The abbreviations of chemical groups or structures used in the specification are all well-known to those skilled in the art. For example, Me-methyl, Et-ethyl, Ac-acetyl, Ph-phenyl, MOM-methoxymethyl, TBS-tert-butyldimethylsilyl, TIPS-triisopropylsilyl, TMS-trimethylsilyl, Ts-p-toluenesulfonyl, etc.

[0055] Example 1 Preparation of Compound 1'

[0056]

[0057] Under argon protection, 4 g of p-toluenesulfonamide, 2.5 eq of potassium hydroxide, and 39 ml of methanol were added to a dry round-bottom flask. The mixture was stirred in an ice bath for 10 minutes until it solidified. Then, 1.1 eq of iodophenyldiacetic acid was added in portions to dissolve the solid. The mixture was stirred in an ice bath for 1 hour and then reacted at room temperature for 1 hour. After adding 93 ml of ice water, the mixture was reacted in an ice bath for 1 hour. The reaction mixture was filtered through a Buchner funnel. The resulting solid was washed successively with 60 ml of ice water, 60 ml of methanol, and 60 ml of diethyl ether. After drying the solvent, 6.52 g of p-toluenesulfonylimide iodobenzene PhI=NTs (compound 1') was obtained, with a yield of 76%.

[0058] Example 2 Preparation of Compound 2

[0059] Under argon protection, acetonitrile-dissolved p-methylbenzenesulfonylimide iodobenzene (PhI=NTs) (653.11 mg, 1.75 mmol) was added to a dry round-bottom flask, followed by the addition of compound 1 (1 g, 6.99 mmol) and copper acetylacetonate (36.64 mg, 0.14 mmol). After stirring at room temperature for 30 min, the solution became clear. Triethylamine was added, followed by diatomaceous earth filtration. The solution was concentrated and then separated by column chromatography (petroleum ether, ethyl acetate system 8:1 → 2:1, containing triethylamine) to obtain 388 mg of 2-(benzo[d][1,3]dioxa-5-yl)-1-toluenesulfonylpropidine (compound 2), with a yield of 70%.

[0060] Compound 2: 1H NMR (400 MHz, Acetone–d6) δ: 7.86 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 6.84 (dd, J = 8.0, 2.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.72 HRMS (ESI, m / z) calcdfor C 16 H 15 NNaO4S[M+Na] + : 340.0614, found 340.0634.

[0061] Example 3 Preparation of compound 2'

[0062]

[0063] Under argon protection, cyclohexenone (2 g) and tetrahydrofuran (0.4 M) solution were added. Hexamethylphosphoric triamine (HMPA, 2.5 eq) was added at -78 °C, followed by dropwise addition of bis(trimethylsilyl)aminolithium (LiHMDS, 1 eq) dissolved in tetrahydrofuran (1 M), and the reaction was stirred for 1 hour. After reacting at 0 °C for 1 hour, triisopropylsilyl trifluoromethanesulfonate (TIPSOTf, 1.1 eq) was added dropwise at -78 °C, and the reaction was stirred for 0.5 hours. The reaction solution was restored to room temperature and quenched with sodium bicarbonate. The solution was extracted with dichloromethane, dried, concentrated, and the crude product was separated by column chromatography (eluent) to obtain 4.77 g of (cyclohexane-1,3-dien-1-yloxy)triisopropylsilane (compound 2'), with a yield of 91%.

[0064] Compound 2': 1 H NMR (400 MHz, CDCl3) δ: 5.84-5.80 (m, 1 H), 5.43-5.39 (m,1 H), 5.13 (d, J = 5.6 Hz, 1 H), 2.30-2.26 (m, 4 H), 1.22-1.18 (m, 3 H), 1.10(d, J = 6.8 Hz, 18 H).

[0065] Example 4 Preparation of Compound 3

[0066] Under argon protection, copper trifluoromethanesulfonate (43.4 mg, 0.12 mmol) and dry dichloromethane were added to a dry round-bottom flask. Then, 2-(benzo[d][1,3]dioxa-5-yl)-1-toluenesulfonylpropidine (478 mg, 1.51 mmol) and (cyclohexane-1,3-dien-1-yloxy)triisopropylsilane (579 mg, 2.26 mmol) dissolved in dichloromethane were added dropwise. The mixture was stirred at room temperature for 2.5 hours (TLC monitoring). Potassium carbonate (15.1 mmol) and ethanol (30 mL) were added, and the mixture was heated to 60 °C and reacted for 10 hours (TLC monitoring). The reaction was terminated by adding water. After dichloromethane extraction, the mixture was dried, filtered, concentrated, and separated by column chromatography (petroleum ether and ethyl acetate system 6:1 → 2:1) to obtain 3413 mg of the compound, with a yield of 77%.

[0067] Compound 3: 1 H NMR (400 MHz, CDCl3) δ: 7.73 (d, J = 8.4 Hz, 2H), 7.36 (d,J = 8.4 Hz, 2H), 6.72 (d, J = 8.0 Hz, 1H), 6.56 (dd, J = 8.0, 2.0 Hz, 1H), 6.49 (d, 3.07 (dd, J =10.8, 9.6 Hz, 1H), 2.98 (dd, J = 15.6 Hz, 5.6 Hz, 1H), 2.70 (dd, J = 16.0 Hz, 10.4 Hz, 1H), 2.47 (s, 3H), 2.37 (dt, J = 8.4, 5.2 Hz, 1H), 2.25-2.17 (m,1H), 2.15-2.08 (m, 1H), 1.91-1.83 (m, 1H), 1.72-1.63 (m, 1H); HRMS (ESI, m / z)calcd for C 22 H 23 NNaO5S[M+Na] + : 436.1189, found 436.1222.

[0068] Example 5 Preparation of Compound 4

[0069] Under argon protection, compound 3 (800 mg, 1.94 mmol) dissolved in dry dichloromethane and DIPEA (N,N-diisopropylethylamine) (3.36 mL, 19.4 mmol) were added dropwise to a dry round-bottom flask. Trimethylsilyltrifluoromethanesulfonate (TMSOTf, 1.76 mL, 9.68 mmol) was added dropwise at room temperature, and the reaction was carried out for 4 hours. The reaction was quenched with saturated sodium bicarbonate at 0°C and extracted with n-pentane. The combined organic phases were washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and concentrated to obtain the crude product.

[0070] The crude product from the first step was dissolved in acetonitrile, and palladium acetate (Pd(OAc)₂, 568 mg, 2.52 mmol) was added at room temperature with stirring for 4 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether and ethyl acetate system 5:1 → 3:1) to obtain 4632 mg of the compound, with a yield of 78%.

[0071] Compound 4: 1H NMR (400 MHz, CDCl3) δ: 7.75 (d, J = 8.0 Hz, 2H), 7.37 (d,J = 8.0 Hz, 2H), 6.73 (d, J = 7.6 Hz, 1H), 6.57 (dd, J = 8.0, 1.6 Hz, 1H), 6.50 (d, J = 1.6 Hz, 1H), 6.48 – 6.46 (m, 1H), 6.00 (d, J = 10.4 Hz, 1H), 5.95 (s, 2H), 4.38 (td, J = 11.6, 6.8 Hz, 1H), 3.89 (dd, J = 9.6, 7.2 Hz,1H), 3.37 (td, J = 10.4, 7.2 Hz, 1H), 3.26 (t, J = 10.0 Hz, 1H), 3.01 (dd, J= 16.8, 6.4 Hz, 1H), 2.69 (dd, J = 16.8, 11.6 Hz, 1H), 2.63-2.57 (m, 1H),2.47 (s, 3H); HRMS (ESI, m / z) calcd for C 22 H 21 NNaO5S[M+Na] + : 434.1033, found434.0898.

[0072] Example 6 Preparation of Compound 5

[0073] Under argon protection, dry methanol and dichloromethane (2:1) were added to a dry round-bottom flask, followed by compound 4 (551 mg, 1.34 mmol) and CeCl3 (cerium trichloride) (990 mg, 4.02 mmol). The mixture was stirred at room temperature for 20 min, and then NaBH4 (sodium borohydride) (101 mg, 2.68 mol) was added at 0°C. The reaction was continued at room temperature for 30 min. The mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether and ethyl acetate system 4:1 → 2:1) to obtain compound 5, 405 mg, in 73% yield.

[0074] Compound 5: 1 H NMR (400 MHz, CDCl3) δ: 7.76 (d, J = 8.0 Hz, 2H), 7.36 (d,J = 8.0 Hz, 2H), 6.71 (d, J = 8.0 Hz, 1H), 6.52 (dd, J = 8.0, 1.6Hz, 1H), 6.45 (d, J = 1.6 Hz, 1H), 5.92 (s, 2H), 5.74 (d, J = 10.0 Hz, 1H), 5.36-5.32(m, 1H), 4.35 (d, J = 4.4 Hz, 1H), 4.04-3.98 (m, 1H), 3.79 (td, J = 6.0, 2.4Hz 1H), 3.15-3.07 (m, 2H), 2.60-2.55 (m, 1H), 2.46 (s, 3H), 2.25 (t, J = 7.2Hz, 1H), 1.93 (s, 1H), 1.72-1.63 (m, 1H); HRMS (ESI, m / z) calcd forC 22 H 23 NNaO5S [M+Na] + : 436.1189, found 436.0880.

[0075] Example 7 Preparation of Compound 6

[0076] Under argon protection, compound 5 (332 mg, 0.8 mmol) dissolved in dry dichloromethane was added to a dry round-bottom flask. Then, DIPEA (N,N-diisopropylethylamine) (0.7 mL, 4.0 mmol) and MOMCl (0.18 mL, 2.4 mmol) were added sequentially at 0°C, and the mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated brine, dried with magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether and ethyl acetate system 10:1 → 5:1) to obtain compound 6, 342 mg, in 93% yield.

[0077] Compound 6: 1 H NMR (400 MHz, CDCl3) δ: 7.76 (d, J = 8.0 Hz, 2H), 7.37 (d,J = 8.0 Hz, 2H), 6.71 (d, J = 8.0 Hz, 1H), 6.51 (dd, J = 7.6, 1.6Hz, 1H), 6.42 (d, J = 2.0 Hz, 1H), 5.93 (s, 2H), 5.75 (dd, J = 10.4, 1.2Hz, 1H), 5,38-5.34 (m, 1H), 4.73 (dd, J = 20.8, 6.8 Hz, 2H), 4.27-4.23 (m, 1H), 4.03-3.97(m, 1H), 3.79 (td, J = 6.0, 2.0 Hz 1H), 3.40 (s, 3H), 3.18-3.07 (m, 2H), 2.63-2.58 (m, 1H), 2.47 (s, 3H), 2.25-2.21 (m, 1H), 1.73-1.64 (m, 1H); HRMS(ESI, m / z) calcd for C 24 H 27 NNaO6S [M+Na] + : 480.1451, found 480.1471.

[0078] Example 8 Preparation of Compound 7

[0079] Under argon protection, compound 6 (170 mg, 0.37 mmol) dissolved in dry dichloroethane was added to a dry round-bottom flask. Sodium naphthalene was added at -78°C until the solution turned dark green, then stirred for 30 min. At the same temperature, saturated ammonium chloride solution was added to quench the stirring for two minutes. After returning to room temperature, potassium carbonate (1.6 g, 11.5 mmol) was added and stirred for 30 min. Extraction was performed with dichloromethane, followed by washing with saturated ammonium chloride solution and brine, drying with magnesium sulfate, filtration, and concentration to obtain the crude product. Column chromatography (dichloromethane and methanol system 20:1) yielded 112 mg of compound 7 (89% yield), which was directly used in the next reaction.

[0080] Example 9 Preparation of Compound 8

[0081] Under argon protection, compound 7 (112 mg, 0.37 mmol) dissolved in formic acid was added to a dry round-bottom flask. Paraformaldehyde (110.7 mg, 3.69 mmol) was added at room temperature, and the mixture was heated to 80°C for 2 hours. After cooling to room temperature, the mixture was quenched with saturated sodium bicarbonate solution until the pH reached 7-8. Extraction was performed using dichloromethane and chloroform:isopropanol (10:1 ratio). The extract was washed with saturated brine, dried with magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was dissolved in methanol, and potassium carbonate (77 mg, 0.55 mmol) was added at room temperature. The mixture was stirred for 30 min, filtered, concentrated, and separated by column chromatography (dichloromethane and methanol system 20:1) to obtain compound 8 (83 mg, yield 83%).

[0082] Compound 8: 1 H NMR (600 MHz, CDCl3) δ: 6.56 (s, 1H), 6.46 (s, 1H), 6.05 (ddd, J = 6.0, 4.2, 2.4 Hz, 1H), 5.88 (s, 2H), 5.73 (dd, J = 9.6, 2.4 Hz, 1H), 4.21 – 4.19 (m, 2H), 3.75 (d, J = 18.6 Hz, 1H), 3.34 (dd, J = 11.4, 2.4Hz, 1H), 3.29 (dd, J = 12.0, 5.4 Hz, 1H), 2.82 (d, J = 7.2 Hz, 1H), 2.79-2.76 (m, 2H), 2.03-1.98 (m, 1H), 1.95-1.91 (m, 1H); HRMS (ESI, m / z) calcd forC 16 H 17 NO3[M+H] +: 272.1281, found 272.1301.

[0083] Example 10 Preparation of Compound 9

[0084] Under argon protection, compound 8 (90 mg, 0.332 mmol) dissolved in dichloromethane was added to a dry round-bottom flask. Triethylamine (0.15 mL, 0.664 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (TBSOTf, 0.14 mL, 0.996 mmol) were added at room temperature, and the mixture was stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. Column chromatography yielded 118 mg of the product (92% yield), which was then used in the next step.

[0085] Under argon protection, the product from the previous step (58 mg, 0.15 mmol) of dioxane dissolved in a dry round-bottom flask was added, followed by the addition of selenium dioxide at room temperature. The compound was reacted with (SeO2, 50 mg, 0.45 mmol) and heated to 100°C for 8 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, filtered through diatomaceous earth, washed with dichloromethane, concentrated, and separated by column chromatography (dichloromethane and methanol system 20:1→10:1) to obtain 9.36 mg of the compound, with a yield of 60%.

[0086] Compound 9: 1 H NMR (400 MHz, CDCl3) δ: 6.57 (s, 1H), 6.53 (s, 1H), 6.12 (dd, J = 10.0, 2.0Hz, 1H), 5.93 (s, 2H), 5.80 (dd, J = 10.0, 2.0 Hz, 1H), 4.40 (d, J = 17.6 Hz, 1H), 4.36-4.32 (m, 1H), 3.88 (d, J = 17.2 Hz, 1H), 3.37(dd, J = 12.0, 2.0 Hz, 1H), 3.02 (t, J = 7.6 Hz, 1H), 2.88 (dd, J = 12.0, 2.4Hz, 1H), 2.69 (d, J = 2.8 Hz, 1H), 2.34-2.28 (m, 1H), 1.67-1.59 (m, 1H), 0.90(s, 9H), 0.09 (s, 6H); HRMS (ESI, m / z) calcd for C 22 H 32 NO4Si[M+H]+ : 402.2095, found 402.2127.

[0087] Example 11 Preparation of compound Pancratinine C

[0088] Under argon protection, compound 9 dissolved in tetrahydrofuran (15 mg, 0.037 mmol) was added to a dry round-bottom flask, followed by the addition of NH4HF2 (ammonium hydrogen fluoride) (32 mg, 0.56 mmol) at room temperature. The mixture was heated to 50°C and reacted for 5 hours. After cooling to room temperature, the product was purified by preparative thin-layer chromatography to obtain 9 mg of the product, which was then added to the next step.

[0089] Under argon protection, the product from the previous step (8.1 mg, 0.028 mmol) dissolved in dichloromethane and manganese dioxide (49 mg, 0.56 mmol) were added to a dry round-bottom flask, and the mixture was stirred at room temperature for 30 min. After dilution with dichloromethane, the crude product was filtered through diatomaceous earth to obtain crude product. Tetrahydrofuran was added, followed by the addition of diisobutylaluminum hydride (DIBAL-H, 35 μL, 1.2 M dissolved in toluene, 0.04 mmol) at -78°C. After stirring for 10 min, methanol was added to quench the reaction, followed by extraction with dichloromethane, washing with saturated brine, drying with magnesium sulfate, filtering, and concentrating. Column chromatography (chloroform, methanol, ammonia system: 80:4:1) yielded 3.6 mg of Pancratinine C, 44% yield.

[0090] Pancratinine C: 1 H NMR (600 MHz, CD3OD) δ: 6.60 (s, 1H), 6.55 (s, 1H), 6.00 (d, J = 10.4 Hz, 1H), 5.89 (s, 2H), 5.74 (d, J = 10.0 Hz, 1H), 4.29 (m,1H), 4.24 (d, J = 16.8 Hz, 1H), 3.86 (d, J = 16.4 Hz, 1H), 2.98 (dd, J =12.4, 2.8 Hz, 1H), 2.84 (d, J = 11.6 Hz, 1H), 2.67 (d, J = 2.4 Hz, 1H), 2.25(d, J = 13.2 Hz, 1H), 1.58 (m, 1H). HRMS (ESI, m / z) calcd for C 16 H 18 NO4[M+H] + :288.1236, found 288.1237.

[0091] Example 12 Preparation of Compound 10

[0092] Under argon protection, compound 8 (40 mg, 0.147 mmol) dissolved in dichloromethane and SOCl2 (75 μL, 1.03 mmol) were added to a dry round-bottom flask. The mixture was stirred at room temperature for 30 min and then concentrated. After dissolving in methanol, sodium methoxide (0.28 mL, 1.47 mmol) was added at room temperature, and the mixture was heated to 100°C and stirred for 8 hours. The reaction was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. Column chromatography (dichloromethane and methanol system 30:1 → 10:1) yielded compound 10 9.7 mg, 23% yield.

[0093] Compound 10: 1 H NMR (600 MHz, CDCl3) δ: 6.56 (s, 1H), 6.46 (s, 1H), 5.99 (dd, J = 10.2, 1.2 Hz, 1H), 5.89 (s, 2H), 5.71 (ddd, J = 6.0, 4.2, 2.4 Hz, 1H), 4.24 (d, J = 16.2 Hz, 1H), 3.89-3.87 (m, 1H), 3.80 (d, J = 16.2 Hz, 1H), 3.42 (s, 3H), 3.33-3.32 (m, 1H), 2.90 (s br, 1H), 2.83 (s, 2H), 2.75 (s, 1H),2.47 (d, J =12.0 Hz, 1H), 1.46-1.41 (m, 1H); HRMS (ESI, m / z) calcd forC 17 H 20 NO3[M+H] + : 286.1438, found 286.1446.

[0094] Example 13 Preparation of compound Pancratinine B

[0095] Under argon protection, compound 13 (5.5 mg, 0.02 mmol) dissolved in dioxane was added to a dry round-bottom flask. SeO2 (6.4 mg, 0.058 mmol) was added at room temperature, and the mixture was heated to 100°C and stirred for 8 hours. The mixture was filtered through diatomaceous earth, washed with dichloromethane, concentrated, and then separated by column chromatography (dichloromethane and methanol system 20:1 → 10:1) to obtain 3.5 mg of Pancratinine B, with a yield of 60%.

[0096] Pancratinine B: 1 H NMR (600 MHz, CDCl3) δ: 6.63 (s, 1H), 6.55 (s, 1H), 6.15 (d, J = 10.2 Hz,

[0097] 1H), 5.94 (s, 2H), 5.78 (d, J = 10.8 Hz, 1H), 4.29 (d, J = 16.8 Hz,1H), 3.96 (m, 1H), 3.84 (d, J = 16.8 Hz, 1H), 3.44 (s, 3H), 3.00 (d, J = 12.0Hz, 1H), 2.93 (s, 1H), 2.86 (d, J = 11.4 Hz, 1H), 2.65 (s, 1H), 2.37 (d, J =12.6 Hz, 1H), 1.59 (dt, J = 4.8, 12.6 Hz, 1H);HRMS (ESI, m / z) calcd forC 17 H 20 NO4[M+H] + 302.1387 was found, and 302.1396 was also found.

[0098] The above description is for illustrative and explanatory purposes only. Any modifications and alterations made by those skilled in the art to the invention and its embodiments without departing from the spirit of the invention are within the scope of protection of the invention.

Claims

1. An intermediate compound 9, having the following structural formula: wherein R3 represents a hydroxyl protecting group, and R3 is selected from methoxymethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl.

2. A method of preparing compound 9, comprising: Compound 8 is subjected to hydroxyl protection and oxidation to obtain compound 9, The reaction scheme is as follows: Compound 8 is subjected to hydroxyl protection and oxidation to obtain compound 9, wherein the hydroxyl protection reagent is selected from at least one of trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, and triisopropylsilyl trifluoromethanesulfonate; and the oxidizing agent is selenium dioxide.

3. A process for the preparation of Pancratinine C comprising: Compound 9 is subjected to deprotection, oxidation, and reduction to obtain Pancratinine C; The reaction scheme is as follows: R3 represents a hydroxyl protecting group, and R3 is selected from methoxymethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl. Compound 9 is subjected to deprotection, oxidation, and reduction to obtain Pancratinine C, wherein the acid is ammonium hydrogen fluoride; the oxidizing agent is manganese dioxide; and the reducing agent is diisobutylaluminum hydride.

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