Synthesis of rhynchines a-e compounds

Abstract

The application discloses a synthesis method of Rhynchines A-E compounds, which comprises the following steps: taking 3-(2-bromoethyl)indole as raw material, carrying out nucleophilic substitution and nucleophilic addition to obtain a dihydropyridine intermediate, carrying out electrophilic bromination and Pictet-Spengler cascade cyclization on the dihydropyridine intermediate and Br2 to obtain a cyclization product, treating the cyclization product with NaBH3CN to successfully rearrange, and then carrying out DIBAL-H reduction, Wittig, Swern oxidation, aldol and oxidation reactions to construct a core skeleton, and carrying out Krapcho de-carbalkoxy reaction and hydrogenation reaction to realize synthesis of Rhynchine E. The product obtained through the Krapcho de-carbalkoxy reaction is subjected to isomerization and hydrogenation to realize synthesis of Rhynchines A-E. The synthesis route is simple and efficient, and provides a material basis for biological activity evaluation of natural products Rhynchines A-E.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of natural product synthesis, and particularly relates to a synthesis method of Rhynchines A-E compounds. BACKGROUND

[0002] Rhynchophyllaceae plants are a kind of traditional cultivated and widely consumed Chinese medicinal materials, which have rich secondary metabolites. So far, more than 350 molecules have been isolated and identified from the genus. The monoterpenoid indole alkaloids and oxidized monoterpenoid indole alkaloids are considered to be the main components. These alkaloid molecules exhibit a wide range of biological activities in vivo and in vitro. Including anti-acetylcholinesterase (AChE) activity, anti-hypertensive, anti-inflammatory, anti-cancer, anti-oxidative, anti-viral, anti-epileptic, anti-depressive, neuroprotective, etc. Therefore, they have the potential as drug development or lead compounds. In order to find natural inhibitors of T-type voltage-gated calcium channel subfamily Cav3.1, Zhao Qianshi's research group isolated and identified a class of structurally unique monoterpenoid indole alkaloids from Uncaria in 2021, named Rhynchines A-E. Preliminary study on their biological activity showed that Rhynchines A and B had strong inhibitory effect on calcium ion channel, with IC 50 So far, there is no related chemical synthesis method reported at home and abroad. SUMMARY

[0003] This section aims to summarize some aspects of the embodiments of the application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of the specification to avoid obscuring the purpose of this section, abstract and title, and such simplifications or omissions cannot be used to limit the scope of the application.

[0004] In view of the above and / or problems existing in the prior art, the present application is proposed.

[0005] Therefore, the purpose of the present application is to overcome the deficiencies in the prior art, and to provide a synthesis method of the compound Rhynchine E shown in formula (14);

[0006] To solve the above technical problems, the present application provides the following technical scheme: including,

[0007] The compound shown in formula (1) is subjected to S N 2 nucleophilic substitution reaction with methyl nicotinate to obtain the compound shown in formula (2);

[0008] The compound shown in formula (2) is subjected to nucleophilic addition reaction with sodium salt of methyl malonate to obtain a crude product of the compound shown in formula (3), the crude product is subjected to electrophilic bromination / Pictet-Spengler cascade cyclization reaction with liquid bromine in the presence of N,N-diisopropyl ethylamine at-78℃ to obtain the cyclization compound shown in formula (4);

[0009]

[0010] The compound shown in formula (4) is dissolved in acetic acid and reduced by adding sodium cyanoborohydride to obtain the rearrangement compounds shown in formula (5) and formula (6);

[0011]

[0012] The mixture of the rearrangement compounds shown in formula (5) and formula (6) is reacted with diisobutylaluminum hydride at-78℃ to obtain a mixture of the aldol compound shown in formula (7) and the compound shown in formula (8);

[0013]

[0014] The mixture of the compound shown in formula (7) and formula (8) is reacted with phosphorus ylide prepared from methyl triphenylphosphonium bromide and potassium tert-butoxide to obtain the compound shown in formula (9), and the compound shown in formula (9) is reacted with dimethyl sulfoxide, oxalyl chloride and triethylamine at-78℃ to obtain the olefin compound shown in formula (10);

[0015]

[0016] The olefin compound shown in formula (10) is dissolved in tetrahydrofuran, ytterbium trifluoromethanesulfonate and polyformaldehyde are added, and the reaction is carried out at room temperature to obtain the aldol compound shown in formula (11), and the aldol compound shown in formula (11) is oxidized with potassium ferricyanide to obtain the cyclization compound shown in formula (12);

[0017]

[0018] The cyclization compound shown in formula (12) is dissolved in N,N-dimethylacetamide and water, and lithium chloride is added to obtain the de-carbonyl compound shown in formula (13);

[0019]

[0020] The de-carbonyl compound shown in formula (13) is dissolved in ethanol, and hydrogenation reaction is carried out with palladium / carbon under hydrogen atmosphere to obtain the compound Rhynchine E shown in formula (14);

[0021]

[0022] As a preferred scheme of the synthesis method of the compound Rhynchine E shown in formula (14) of the present application, wherein: the rearrangement compound shown in formula (5) and formula (6), wherein the mass ratio of the compound shown in formula (5) and the compound shown in formula (6) is 1:1.

[0023] As a preferred scheme of the synthesis method of the compound Rhynchine E shown in formula (14) of the present application, wherein: the mixture of the hydroxy aldehyde compound shown in formula (7) and the compound shown in formula (8), wherein the mass ratio of the compound shown in formula (7) and the compound shown in formula (8) is 5:1.

[0024] As a preferred scheme of the synthesis method of the compound Rhynchine E shown in formula (14) of the present application, wherein: the cyclization compound shown in formula (12) is reacted with lithium chloride in a microwave reactor, the reaction temperature is 130℃, and the reaction time is 2h.

[0025] Another object of the present application is to provide a synthesis method of a compound Rhynchine D shown in formula (15).

[0026] To solve the above technical problems, the present application provides the following technical scheme: comprising,

[0027] The dealkoxycarbonylation compound shown in formula (13) is dissolved in tetrahydrofuran, and then lithium bis-trimethylsilylamide is added for reaction to obtain the compound Rhynchine D and the compound Rhynchine B shown in formula (15) and formula (16);

[0028]

[0029] The compound Rhynchine D shown in formula (15) is obtained by reverse semi-preparative HPLC purification, wherein the reverse semi-preparative HPLC purification time t R is 31.5min.

[0030] Another object of the present application is to provide a synthesis method of a compound Rhynchine B shown in formula (16).

[0031] To solve the above technical problems, the present application provides the following technical scheme: comprising,

[0032] The dealkoxycarbonylation compound shown in formula (13) is dissolved in tetrahydrofuran, and then lithium bis-trimethylsilylamide is added for reaction to obtain the compound Rhynchine D and the compound Rhynchine B shown in formula (15) and formula (16);

[0033]

[0034] The compound Rhynchine B shown in the structural formula as formula (16) is obtained by reverse semi-preparative HPLC purification, wherein the reverse semi-preparative HPLC purification time t R is 40.4 min.

[0035] Another object of the present application is to provide a synthesis method of the compound Rhynchine C shown in formula (17).

[0036] To solve the above technical problems, the present application provides the following technical scheme: comprising,

[0037] The compound Rhynchine C shown in formula (17) is obtained by dissolving the compound Rhynchine D shown in formula (15) in ethanol, hydrogenation reaction under hydrogen atmosphere by using palladium-carbon, and reverse semi-preparative HPLC purification;

[0038]

[0039] As a preferred scheme of the synthesis method of the compound Rhynchine E shown in formula (14), wherein the reverse semi-preparative HPLC purification time t R is 47.8 min.

[0040] Another object of the present application is to provide a synthesis method of the compound Rhynchine A shown in formula (18).

[0041] To solve the above technical problems, the present application provides the following technical scheme: comprising,

[0042] The compound Rhynchine A shown in formula (18) is obtained by dissolving the compound Rhynchine B shown in formula (16) in ethanol, hydrogenation reaction under hydrogen atmosphere by using palladium-carbon, and reverse semi-preparative HPLC purification;

[0043]

[0044] As a preferred scheme of the synthesis method of the compound Rhynchine E shown in formula (14), wherein the reverse semi-preparative HPLC purification time t R is 47.8 min.

[0045] The present application has the following beneficial effects:

[0046] The present application takes commercially available 3-(2-bromoethyl)indole as a synthetic raw material, and is subjected to SN 2 nucleophilic substitution reaction, and then nucleophilic addition reaction to obtain a 1,4-dihydropyridine intermediate, which, in the presence of N,N-diisopropylethylamine, undergoes electrophilic bromination / Pictet-Spengler cascade cyclization reaction with liquid bromine to obtain a 1,2-migration rearrangement precursor, which, by treatment with sodium cyanoborohydride in acetic acid, gives a rearrangement product, which, by diisobutylaluminum hydride reduction, Wittig reaction, Swern oxidation reaction, aldol condensation reaction and oxidation in the presence of potassium ferricyanide, gives a target molecule five-ring core skeleton compound, and finally, by Krapcho de-carbalkoxylation reaction and hydrogenation reaction, the first chemical synthesis of Rhynchine E is realized, and the compound obtained by Krapcho de-carbalkoxylation reaction, by isomerization reaction and hydrogenation reaction, the first chemical synthesis of Rhynchines A-E can be realized. The synthetic route of the present application has the advantages of simplicity, high efficiency, easy operation and low cost, and is suitable for the synthesis of Rhynchines A-E in large quantities, and provides an important material basis for the biological activity evaluation of natural products Rhynchines A-E. BRIEF DESCRIPTION OF DRAWINGS

[0047] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiment description 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. Among them:

[0048] Figure 1 It is a synthetic route diagram of the present application embodiment 1.

[0049] Figure 2 It is the hydrogen spectrum of the synthetic product Rhynchine E of the present application.

[0050] Figure 3 It is the carbon spectrum of the synthetic product Rhynchine E of the present application.

[0051] Figure 4 It is the hydrogen spectrum of the synthetic product Rhynchine D of the present application.

[0052] Figure 5 It is the carbon spectrum of the synthetic product Rhynchine D of the present application.

[0053] Figure 6 It is the hydrogen spectrum of the synthetic product Rhynchine C of the present application.

[0054] Figure 7 It is the carbon spectrum of the synthetic product Rhynchine C of the present application.

[0055] Figure 8 The hydrogen spectrum of Rhynchine B, a synthetic product of the present application.

[0056] Figure 9 The carbon spectrum of Rhynchine B, a synthetic product of the present application.

[0057] Figure 10 The hydrogen spectrum of Rhynchine A, a synthetic product of the present application.

[0058] Figure 11 The carbon spectrum of Rhynchine A, a synthetic product of the present application. DETAILED DESCRIPTION

[0059] In order to make the above objectives, features and advantages of the present application more obvious and comprehensible, the specific embodiments of the present application will be described in detail below with reference to the description and embodiments.

[0060] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present application, but the present application can also be implemented in other ways different from those described herein, and those skilled in the art can make similar generalizations without departing from the concept of the present application, so the present application is not limited to the specific embodiments disclosed below.

[0061] Secondly, "one embodiment" or "embodiment" referred to herein means that a specific feature, structure or characteristic can be included in at least one implementation of the present application. "In one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an embodiment that is separate or alternative to other embodiments.

[0062] The raw materials used in the present application are commercially available in the art without special instructions.

[0063] Example 1

[0064] The present embodiment provides a synthesis method of Rhynchines A-E compounds, and the synthesis route is as shown in Figure 1 Specifically:

[0065] 1) Add 10.0 g (44.6 mmol) of 3-(2-bromoethyl)indole shown in formula (1), 6.15 g (44.6 mmol) of methyl nicotinate, and then 45 mL of anhydrous methanol into a 100 mL dry round-bottom flask, and stir the reaction at room temperature for 72 hours. After the solution is dried, the crude product is washed with methyl tert-butyl ether (30 mL x 5 times), and after the solvent is removed under vacuum, 12.9 g of the compound shown in formula (2) is obtained with a yield of 80%.

[0066]

[0067] 2) Under nitrogen atmosphere, 84 mg (2.09 mmol, 60%) of sodium hydride was added to a 50 mL dry round bottom flask, then 8 mL of tetrahydrofuran solution was added thereto, after cooling to 0°C, 0.24 mL (0.29 mmol) of dimethyl malonate was added dropwise thereto, after stirring for 30 minutes at 0°C, the solution was spun dry, then 500 mg (1.39 mmol) of the compound represented by formula (2) was added to the flask, followed by 7 mL of ethylene glycol dimethyl ether solution, and it was stirred at room temperature for 12 hours under nitrogen protection, the reaction solution was filtered with a sand core funnel and washed with dichloromethane (100 mL), and the filtrate was spun dry to obtain about 343 mg of the crude product of the compound represented by formula (3), which was directly used in the next step without purification.

[0068]

[0069] 3) The crude product of the compound represented by formula (3) was dissolved in 3 mL of dichloromethane solution, and the system was placed at -78°C, 0.75 mL of 1.45 mol / L bromine solution in dichloromethane was added dropwise with a syringe while stirring, followed by 0.15 mL (0.84 mmol) of N,N-diisopropyl ethylamine, after stirring for 30 minutes at -78°C, it was quenched with saturated aqueous sodium thiosulfate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated and columned to obtain 157 mg of the cyclization compound represented by formula (4) with a two-step yield of 23%;

[0070] The structural characterization data thereof are as follows:

[0071] 1 H NMR (400 MHz, Deuterated dimethyl sulfoxide) δ (ppm): 11.07 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 5.49 (s, 1H), 5.15 (s, 1H), 4.10-4.06 (m, 1H), 3.91-3.72 (m, 1H), 3.68 (d, J = 6.8 Hz, 1H), 3.58 (s, 3H), 3.52 (s, 3H), 3.48-3.45 (m, 1H), 3.34 (s, 3H), 2.80-2.72 (m, 2H), 2.26-2.23 (m, 1H);

[0072] 13C NMR (100 MHz, Deuterated dimethyl sulfoxide) d (ppm): 167.8, 167.2, 166.7, 144.9, 136.1, 131.6, 126.5, 121.8, 119.2, 118.3, 111.5, 107.4, 94.0, 57.4, 56.1, 52.4, 52.3, 50.5, 50.4, 46.5, 38.2, 22.8.

[0073] 4) Dissolve 1.0 g (2.04 mmol) of the compound represented by formula (4) in 100 mL of acetic acid, then add 769 mg (12.2 mmol) of sodium cyanoborohydride, stir at 30°C for 2 hours, quench with saturated aqueous sodium bicarbonate solution, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate and pass through a column to obtain 718 mg of the compounds represented by formula (5) and formula (6) together, with a yield of 75%.

[0074]

[0075] The structural characterization data of the compound represented by formula (5) are as follows:

[0076] 1 H NMR (600 MHz, Deuterated dimethyl sulfoxide) d (ppm): 10.89 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.96 (t, J = 7.3 Hz, 1H), 3.90 (d, J = 2.94 Hz, 1H), 3.70 (s, 3H), 3.65 (s, 3H), 3.57 (s, 3H), 3.27-3.22 (m, 2H), 3.04 (d, J = 5.7 Hz, 1H), 2.92-2.79 (m, 5H), 2.61-2.56 (m, 2H), 2.05 (s, 3H);

[0077] 13 C NMR (151 MHz, Deuterated dimethyl sulfoxide) d (ppm): 172.2, 170.6, 168.5, 168.4, 134.8, 131.7, 127.4, 121.8, 118.6, 118.4, 113.3, 111.6, 69.7, 68.7, 58.0, 54.3, 52.8, 52.6, 51.8, 51.7, 43.6, 42.5, 24.5, 20.9;

[0078] The structural characterization data of the compound represented by formula (6) are as follows:

[0079] 1H NMR (600 MHz, Chloroform-d) d (ppm): 8.55 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.12 (s, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.68 (d, J = 7.4 Hz, 1H), 3.51-3.50 (m, 1H), 3.33-3.24 (m, 3H), 3.17-3.09 (m, 3H), 2.99-2.94 (m, 2H), 2.12 (s, 3H);

[0080] 13 C NMR (151 MHz, Chloroform-d) d (ppm): 173.7, 172.5, 168.7, 168.6, 135.1, 131.3, 127.6, 123.1, 119.6, 118.9, 116.1, 111.3, 71.0, 68.3, 58.9, 54.7, 53.7, 52.9, 52.8, 52.4, 45.1, 44.6, 23.5, 21.3;

[0081] 5) Dissolve 1.0 g (2.12 mmol) of the mixture represented by formula (5) and formula (6) in 20 mL of dichloromethane solution, and drop 6.1 mL of 1.5 mol / L diisobutylaluminum hydride solution in toluene into the system under nitrogen protection, stir the reaction at -78°C for 1 hour, then quench with saturated aqueous potassium sodium tartrate solution, extract with dichloromethane, dry over anhydrous sodium sulfate and concentrate to column to obtain 382 mg of compounds represented by formula (7) and formula (8).

[0082]

[0083] 6) Add 848 mg (2.38 mmol) of methyltriphenylphosphonium bromide and 245 mg (2.19 mmol) of potassium tert-butoxide into a 25 mL dry round-bottom flask, and add 7 mL of toluene solution into the system under nitrogen protection, stir the reaction at room temperature for 30 minutes, then drop 380 mg (0.95 mmol) of compounds represented by formula (7) and formula (8) dissolved in 3.5 mL of tetrahydrofuran solution into the system, stir at room temperature for 1.5 hours, quench with saturated aqueous ammonium chloride solution, extract with dichloromethane, dry over anhydrous sodium sulfate and concentrate to column to obtain 271 mg of compounds represented by formula (9) with a yield of 72%;

[0084]

[0085] Structural characterization data of the compound shown as formula (9) are as follows:

[0086] 1 H NMR (600 MHz, deuterated chloroform) δ (ppm): 8.38 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.07-6.01 (m, 1H), 5.11 (d, J = 16.8 Hz, 1H), 5.06 (d, J = 10.2 Hz, 1H), 4.69 (s, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 3.59 (d, J = 8.3 Hz, 1H), 3.32-3.30 (m, 1H), 3.15 (d, J = 9.4 Hz, 1H), 3.00-2.89 (m, 5H), 2.75 (s, 1H), 2.64-2.57 (m, 2H);

[0087] 13 C NMR (151 MHz, deuterated chloroform) δ (ppm): 168.9 (two carbons), 141.2, 137.0, 134.7, 128.7, 122.0, 119.5, 118.4, 114.3, 111.4, 111.2, 72.9, 67.8, 62.3, 56.4, 55.1, 52.7, 48.3, 43.8, 29.4, 24.8.

[0088] 7) Dissolve 71 μL (1.00 mmol) of dimethyl sulfoxide in 1.2 mL of dichloromethane solution, and slowly drop 55 μL (0.65 mmol) of oxalyl chloride into the system under nitrogen protection, and stir for 30 minutes. Then, add 99 mg (0.25 mmol) of the compound shown as formula (9) in 0.2 mL of dichloromethane solution drop by drop, continue to stir for 1 hour at -78°C, then add 0.14 mL (1.00 mmol) of triethylamine into the system, stir for 30 minutes, and then warm to room temperature. Extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate and pass through a column to obtain 79 mg of the compound shown as formula (10) with a yield of 78%.

[0089]

[0090] Structural characterization data of the compound shown as formula (10) are as follows:

[0091] 1H NMR (600 MHz, Chloroform-d) d (ppm): 8.89 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.37-7.33 (m, 2H), 7.14-7.12 (m, 1H), 5.85-5.79 (m, 1H), 4.99 (d, J = 17.4 Hz, 1H), 4.92 (d, J = 9.6 Hz, 1H), 4.03 (d, J = 6.1 Hz, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.69 (d, J = 6.5 Hz, 1H), 3.36-3.30 (m, 2H), 3.14-3.07 (m, 3H), 3.03-3.01 (m, 1H), 2.93-2.87 (m, 2H);

[0092] 13 C NMR (151 MHz, Chloroform-d) d (ppm): 194.4, 169.2 (two carbons), 141.2, 136.9, 131.9, 127.9, 127.0, 124.4, 121.5, 120.4, 114.4, 112.1, 74.7, 59.9, 54.0, 52.5, 52.4, 52.0, 48.1, 44.2, 26.4.

[0093] 8) Into a 25 mL round bottom flask, 200 mg (0.51 mmol) of the compound shown in formula (10) and 626 mg (1.01 mmol) of ytterbium triflate were added, followed by 5 mL of tetrahydrofuran solution, and then 910 mg (10.1 mmol) of paraformaldehyde was added. The reaction solution was stirred at room temperature for 2 hours, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated and column chromatography to obtain 192 mg of the compound shown in formula (11) with a yield of 89%.

[0094]

[0095] The structural characterization data of the compound shown in formula (11) are as follows:

[0096] 1H NMR (600 MHz, Chloroform-t^) d (ppm): 8.98 (s, 1 H), 7.64 (d, J = 8.1 Hz, 1 H), 7.39 - 7.36 (m, 2 H), 7.16 - 7.13 (m, 1 H), 5.92 - 5.87 (m, 1 H), 5.05 (d, J = 17.1 Hz, 1 H), 4.93 (d, J = 10.2 Hz, 1 H), 4.17 - 4.15 (m, 1 H), 4.11 - 4.06 (m, 2 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.49 (s, 1 H), 3.37 - 3.32 (m, 1 H), 3.27 - 3.09 (m, 4 H), 2.94 (s, 2 H), 2.77 - 2.76 (m, 1 H);

[0097] 13 C NMR (151 MHz, Chloroform-t^) d (ppm): 194.9, 170.6, 170.1, 141.0, 137.0, 132.1, 127.7, 127.4, 125.6, 121.5, 120.6, 114.3, 112.2, 73.0, 64.1, 62.1, 58.9, 53.5, 52.8, 52.2, 48.3, 43.5, 25.8.

[0098] 9) Dissolve 50 mg (0.12 mmol) of the compound represented by formula (11) in 2 mL of potassium tert-butoxide and 1 mL of water, then add 316 mg (0.96 mmol) of potassium ferricyanide thereto, warm to 65°C, stir for 12 hours, then extract with dichloromethane and saturated aqueous sodium chloride solution, collect the organic phase, dry over anhydrous sodium sulfate, concentrate, and pass through a column to obtain 43 mg of the compound represented by formula (12) at a yield of 86%.

[0099]

[0100] The structural characterization data of the compound represented by formula (12) are as follows:

[0101] 1H NMR (600 MHz, deuterated chloroform) δ (ppm): 8.80 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.37-7.32 (m, 2H), 7.14-7.12 (m, 1H), 5.80-5.72 (m, 1H), 5.05 (d, J = 17.0 Hz, 1H), 4.99 (d, J = 10.2 Hz, 1H), 4.57 (d, J = 9.4 Hz, 1H), 4.53 (d, J = 9.4 Hz, 1H), 4.02 (d, J = 7.0 Hz, 1H), 3.80 (s, 3H), 3.69 (s, 3H), 3.58-3.54 (m, 1H), 3.27-3.18 (m, 3H), 3.06-3.03 (m, 1H), 2.84-2.82 (m, 1H), 2.78-2.73 (m, 1H);

[0102] 13 C NMR (151 MHz, deuterated chloroform) δ (ppm): 187.7, 169.7, 168.1, 138.6, 137.1, 131.2, 127.5, 126.9, 125.9, 121.4, 120.5, 115.9, 112.1, 107.5, 72.3, 64.5, 57.6, 56.4, 53.4, 52.4, 47.6, 42.2, 24.3.

[0103] 10) 50 mg (0.12 mmol) of the compound represented by formula (12) was dissolved in 3 mL of N,N-dimethylacetamide and 0.3 mL of water, then 15 mg (0.36 mmol) of lithium chloride was added, the system was placed in a microwave reactor, heated to 130°C, and stirred for 2 hours. After cooling to room temperature, extraction was performed with dichloromethane and saturated aqueous sodium chloride solution, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated and column chromatography to obtain 22 mg of the compound represented by formula (13) with a yield of 53%.

[0104]

[0105] The structural characterization data of the compound represented by formula (13) are as follows:

[0106] 1H NMR (600 MHz, Chloroform-d) d (ppm): 8.84 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.35-7.33 (m, 2H), 7.13-7.11 (m, 1H), 5.89-5.83 (m, 1H), 5.11 (d, J = 17.2 Hz, 1H), 4.98 (d, J = 10.3 Hz, 1H), 4.24-4.18 (m, 2H), 3.78 (s, 3H), 3.64-3.62 (m, 1H), 3.55-3.54 (m, 1H), 3.42 (dd, J = 8.8 Hz and 6.0 Hz, 1H), 3.23-3.18 (m, 2H), 3.09-3.02 (m, 2H), 2.98-2.94 (m, 1H), 2.64-2.61 (m, 1H);

[0107] 13 C NMR (151 MHz, Chloroform-d) d (ppm): 188.3, 172.2, 139.5, 137.1, 130.7, 127.8, 126.9, 124.5, 121.5, 120.4, 115.3, 112.0, 105.8, 69.7, 58.2, 55.7, 52.4, 50.4, 45.8, 45.2, 26.0.

[0108] 11) 2.9 mg (0.008 mmol) of the compound represented by formula (13) was dissolved in 1 mL of ethyl acetate solution, then 1.7 mg of 10% palladium-carbon was added, then the reaction solution was bubbled with hydrogen for 10 minutes, and then the system was stirred under a hydrogen atmosphere for 1 hour. The filtrate was filtered with diatomite and washed with a mixed solution of dichloromethane and methanol (5 mL x 3 times), and the filtrate was concentrated by rotary evaporation, and then was rapidly passed through a short silica gel column to obtain 2.6 mg of the natural product Rhynchine E represented by formula (14) at a yield of 94%.

[0109]

[0110] The structural characterization data of Rhynchine E are as follows:

[0111] 1H NMR (600 MHz, Chloroform-d) d (ppm): 8.82 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.37-7.32 (m, 2H), 7.12 (dd, J = 6.7 Hz and 6.6 Hz, 1H), 4.21 (dd, J = 8.6 Hz and 7.5 Hz, 1H), 4.15 (dd, J = 8.4 Hz and 8.0 Hz, 1H), 3.78 (s, 3H), 3.62 (ddd, J = 13.8 Hz, 10.4 Hz and 3.6 Hz, 1H), 3.40-3.34 (m, 2H), 3.15-3.35 (m, 2H), 3.04 (dt, J = 13.3 Hz and 4.4 Hz, 1H), 2.96-2.90 (m, 2H), 1.88-1.82 (m, 1H), 1.49-1.40 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H);

[0112] 13 C NMR (151 MHz, Chloroform-d) d (ppm): 188.6, 172.5, 137.1, 130.8, 127.9, 126.9, 124.5, 121.6, 120.4, 112.1, 105.9, 69.7, 58.1, 55.5, 52.3, 51.3, 45.1, 44.1, 26.9, 26.2, 12.5.

[0113] 12) Dissolve 10 mg (0.028 mmol) of compound shown in formula (13) in 1 mL of anhydrous tetrahydrofuran solution, cool to -78 °C, and under nitrogen protection, add 140 μL of 1.0 mol / L lithium bis-trimethylsilyl amide tetrahydrofuran solution dropwise, stir for 40 minutes at -78 °C, then quench with 0.1 mL of methanol, raise to room temperature, extract with dichloromethane and saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate and concentrate over column to obtain 5.2 mg (4 / 7 = 1:1.6) of natural product Rhynchine D and natural product Rhynchine B shown in formula (15) and formula (16) with a yield of 48% (purified by reversed-phase semi-preparative HPLC [66% MeOH-H2O, v / v, 2 mL / min, Waters Sunfire C18 OBD Prep Column, 15 (t C18 OBD TM Prep Column] 15 (t R 31.5 min) 16 (t R 40.4 min) to obtain high-purity samples of natural products shown in formula (15) and formula (16).

[0114]

[0115] Structural characterization data of Rhynchine D are as follows:

[0116] 1 H NMR (600 MHz, Chloroform-d) δ (ppm): 8.83 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.11-7.12 (m, 1H), 5.72 (ddd, J = 17.5 Hz, 9.2 Hz and 9.2 Hz, 1H), 5.01 (d, J = 17.3 Hz, 1H), 4.96 (d, J = 10.4 Hz, 1H), 4.27-4.20 (m, 2H), 3.66 (s, 3H), 3.64-3.60 (m, 1H), 3.60-3.56 (m, 1H), 3.31 (dd, J = 8.3 Hz and 7.6 Hz, 1H), 3.28-3.24 (m, 1H), 3.22 (t, J = 7.0 Hz, 1H), 3.19-3.11 (m, 2H), 2.98-2.94 (m, 1H), 2.80-2.75 (m, 1H);

[0117] 13 C NMR (151 MHz, Chloroform-d) δ (ppm): 189.5, 171.2, 139.6, 137.3, 131.0, 127.8, 127.3, 125.9, 121.7, 120.6, 115.4, 112.2, 106.9, 69.6, 58.9, 55.6, 51.6, 48.0, 46.5, 41.5, 25.5;

[0118] Structural characterization data of Rhynchine B are as follows:

[0119] 1H NMR (400 MHz, Deuterated chloroform) δ (ppm): 8.84 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.35-7.32 (m, 2H), 7.11 (ddd, J = 8.0 Hz, 6.0 Hz and 1.8 Hz, 1H), 5.95-5.85 (m, 1H), 5.17 (dt, J = 10.6 Hz and 1.5 Hz, 1H), 5.10 (dt, J = 17.4 Hz and 1.6 Hz, 1H), 4.20 (t, J = 8.5 Hz, 1H), 4.01 (t, J = 8.8 Hz, 1H), 3.89 (t, J = 7.9 Hz, 1H), 3.75 (s, 3H), 3.68 (ddd, J = 13.2 Hz, 8.4 Hz and 6.3 Hz, 1H), 3.25 (dd, J = 8.3 Hz and 6.6 Hz, 1H), 3.24-3.19 (m, 2H), 3.19-3.16 (m, 1H), 3.16-3.12 (m, 1H), 3.04 (dt, J = 13.4 Hz and 4.7 Hz, 1H), 3.01-2.97 (m, 1H);

[0120] 13 C NMR (100 MHz, Deuterated chloroform) δ (ppm): 187.5, 172.4, 137.2, 135.0, 130.5, 128.0, 126.9, 123.6, 121.5, 120.4, 117.4, 112.1, 106.3, 70.7, 57.4, 52.4, 52.3, 46.1, 44.2, 41.9, 26.8.

[0121] 13) 2.8 mg (0.008 mmol) of the compound shown in formula (15) was dissolved in 1 mL of ethyl acetate solution, then 1.7 mg of 10% palladium-carbon was added, then the reaction was bubbled with hydrogen for 10 minutes, and then the system was stirred under hydrogen atmosphere for 1 hour. The system was filtered with diatomite, washed with a mixed solution of dichloromethane and methanol (5 mL x 3 times), and the filtrate was concentrated by rotary evaporation. The residue was purified by reverse-phase semi-preparative HPLC (66% MeOH-H2O, v / v, 2 mL / min, Waters C18 OBD TM preparative column, t R 47.8 min) to obtain 2.6 mg of the natural product Rhynchine C shown in formula (17) with a yield of 94%.

[0122]

[0123] The structural characterization data of Rhynchine C are as follows:

[0124] 1 H NMR (600 MHz, Deuterated chloroform) δ (ppm): 8.83 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.38-7.33 (m, 2H), 7.14-7.10 (m, 1H), 4.25-4.20 (m, 1H), 4.17 (dd, J = 9.6 Hz and 9.6 Hz, 1H), 3.72 (s, 3H), 3.71-3.67 (m, 1H), 3.65 (dd, J = 12.2 Hz and 12.2 Hz, 1H), 3.32 (dd, J = 8.7 Hz and 7.0 Hz, 1H), 3.25-3.19 (m, 1H), 3.16-3.10 (m, 1H), 3.08-3.02 (m, 2H), 2.92-2.88 (m, 1H), 1.89-1.82 (m, 1H), 1.48-1.41 (m, 1H), 1.39-1.32 (m, 1H), 0.86 (t, J = 7.0 Hz, 3H);

[0125] 13 C NMR (151 MHz, Deuterated chloroform) δ (ppm): 189.6, 171.7, 137.2, 131.0, 127.9, 127.2, 125.4, 121.7, 120.5, 112.1, 106.9, 70.4, 59.7, 55.6, 51.8, 49.3, 45.6, 38.9, 28.4, 26.4, 12.4.

[0126] 13) 2.8 mg (0.008 mmol) of the compound shown in formula (16) was dissolved in 1 mL of ethyl acetate solution, then 1.7 mg of 10% palladium-carbon was added, then the reaction was bubbled with hydrogen for 10 minutes, and then the system was stirred under hydrogen atmosphere for 1 hour. The system was filtered with diatomite, washed with a mixture of dichloromethane and methanol (5 mL x 3 times), and the filtrate was concentrated by rotary evaporation. The residue was purified by reverse-phase semi-preparative HPLC (66% MeOH-H2O, v / v, 2 mL / min, Waters C18 OBD TM preparative column, t R 47.8 min) to obtain 2.6 mg of the natural product Rhynchine A shown in formula 18, with a yield of 94%.

[0127]

[0128] The structural characterization data of Rhynchine A are as follows:

[0129] 1H NMR (600 MHz, Chloroform-d) d (ppm): 8.84 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 7.7 Hz and 7.7 Hz, 1H), 7.10 (dd, J = 7.0 Hz and 7.0 Hz, 1H), 4.18 (t, J = 7.9 Hz, 1H), 4.02 (t, J = 8.7 Hz, 1H), 3.85 (t, J = 7.8 Hz, 1H), 3.77 (s, 3H), 3.64 (dt, J = 13.1 Hz and 7.4 Hz, 1H), 3.25 (dd, J = 7.3 Hz and 6.8 Hz, 1H), 3.22-3.18 (m, 2H), 3.16 (dt, J = 8.6 Hz and 7.7 Hz, 1H), 3.04-2.99 (m, 1H), 2.86 (dd, J = 10.0 Hz and 9.6 Hz, 1H), 2.22-2.15 (m, 1H), 1.55-1.51 (m, 1H), 1.43-1.37 (m, 1H), 0.93 (t, J = 7.0 Hz, 3H);

[0130] 13 C NMR (151 MHz, Chloroform-d) d (ppm): 187.7, 172.7, 137.2, 130.6, 128.0, 126.8, 123.4, 121.5, 120.3, 112.0, 106.5, 71.1, 59.1, 52.4, 52.4, 45.3, 44.1, 40.7, 26.6, 21.3, 13.2.

[0131] By comparison, Rhynchines A-E are successfully synthesized in the application, which are consistent with Rhynchines A-E separated from Uncariae Ramulus-cruciformis by Zhao Qinshi's research group in 2021, the first chemical synthesis of Rhynchines A-E is realized, the synthesis route has the advantages of simple and efficient, simple operation, low cost and the like, and is suitable for large-scale synthesis of Rhynchines A-E, and provides an important material basis for the biological activity evaluation of natural products Rhynchines A-E.

[0132] It should be noted that the above examples are only used to illustrate the technical solutions of the present application, not to limit the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the spirit and scope of the present application, which should be covered in the scope of the claims of the present application.

Claims

1. A method for synthesizing the compound Rhynchine E shown in formula (14), characterized in that: comprising, The compound represented by formula (1) is subjected to S N 2nucleophilic substitution reaction to obtain a compound represented by formula (2); a compound shown in formula (2) is subjected to nucleophilic addition reaction with sodium salt of malonic acid methyl ester to obtain a crude product of a compound shown in formula (3), the crude product is subjected to electrophilic bromination / Pictet-Spengler cascade cyclization reaction with liquid bromine in the presence of N,N-diisopropylethylamine at-78℃ to obtain a cyclization compound shown in formula (4); the compound shown in formula (4) is dissolved in acetic acid and sodium cyanoborohydride is added for reduction to obtain rearrangement compounds shown in formula (5) and formula (6); the rearrangement compounds shown in formula (5) and formula (6) are reacted with diisobutylaluminum hydride at-78℃ to obtain a mixture of a compound shown in formula (7) and a compound shown in formula (8); the mixture of the compound shown in formula (7) and the compound shown in formula (8) is reacted with phosphorus ylide prepared from methyltriphenylphosphonium bromide and potassium tert-butoxide to obtain a compound shown in formula (9), and the compound shown in formula (9) is reacted with dimethyl sulfoxide, oxalyl chloride and triethylamine at-78℃ to obtain an olefin compound shown in formula (10); the olefin compound shown in formula (10) is dissolved in tetrahydrofuran, ytterbium triflate and polyformaldehyde are added and reacted at room temperature to obtain an aldol compound shown in formula (11), and the aldol compound shown in formula (11) is oxidized with potassium ferricyanide to obtain a cyclization compound shown in formula (12); the cyclization compound shown in formula (12) is dissolved in N,N-dimethylacetamide and water, and lithium chloride is added to react to obtain a de-carbonyl compound shown in formula (13); the de-carbonyl compound shown in formula (13) is dissolved in ethanol, and hydrogenation reaction is carried out with palladium / carbon under hydrogen atmosphere to obtain a compound Rhynchine E shown in formula (14); 2. The process for the synthesis of Rhynchine E as claimed in claim 1, wherein the compound of formula (14) is ###00004### (14) the rearrangement compounds shown in formula (5) and formula (6), wherein the mass ratio of the compound shown in formula (5) to the compound shown in formula (6) is 1:

1.

3. The process for the synthesis of Rhynchine E as claimed in claim 1, wherein the compound of formula (14) is ###00006### (14) the mixture of the aldol compound shown in formula (7) and the compound shown in formula (8), wherein the mass ratio of the compound shown in formula (7) to the compound shown in formula (8) is 5:

1.

4. The process for the synthesis of Rhynchine E as claimed in claim 1, wherein the compound of formula (14) is ###00009### (14) the cyclization compound shown in formula (12) is reacted with lithium chloride in a microwave reactor, the reaction temperature is 130℃, and the reaction time is 2h.

5. A process for the synthesis of a compound of formula (15) Rhynchine D, characterized in that: comprising, synthesizing the de-carbonyl compound shown in formula (13) by using the synthesis method of claim 1; the de-carbonyl compound shown in formula (13) is dissolved in tetrahydrofuran, and lithium bis(trimethylsilyl)amide is added to react to obtain compounds Rhynchine D and Rhynchine B shown in formula (15) and formula (16); The compound Rhynchine D having the structural formula as shown in formula (15) is purified by reverse phase semi-preparative HPLC, wherein the reverse phase semi-preparative HPLC purification time t R is 31.5 min.

6. A method for synthesizing Rhynchine B, a compound of formula (16), characterized in that: comprising, synthesizing the de-carbonyl compound shown in formula (13) by using the synthesis method of claim 1; The dealkoxycarbonyl compound shown in formula (13) is dissolved in tetrahydrofuran, and then lithium bis-trimethylsilylamide is added to react to obtain the compound Rhynchine D and the compound Rhynchine B shown in formula (15) and formula (16); The compound Rhynchine B having the structural formula as shown in formula (16) is purified by reverse phase semi-preparative HPLC, wherein the reverse phase semi-preparative HPLC purification time t R is 40.4 min.

7. A method of synthesizing a compound of formula (17) Rhynchine C, characterized by: comprising, The dealkoxycarbonyl compound shown in formula (13) is synthesized by using the synthetic method of claim 1; The compound Rhynchine D shown in formula (15) is synthesized by using the synthetic method of claim 5 again; The compound Rhynchine C shown in formula (17) is obtained by dissolving the compound Rhynchine D shown in formula (15) in ethanol, hydrogenating with palladium-carbon under a hydrogen atmosphere, and purifying by reverse-phase semi-preparative HPLC; 8. The process for synthesis of compound Rhynchine C as claimed in claim 7, wherein: The reverse phase semi-preparative HPLC purification time t R was 47.8 min.

9. A method of synthesizing a compound of formula (18) Rhynchine A, characterized by: comprising, the dealkoxycarbonyl compound shown in formula (13) is synthesized by using the synthetic method of claim 1; The compound Rhynchine B shown in formula (16) is synthesized by using the synthetic method of claim 5 again; The compound Rhynchine A shown in formula (18) is obtained by dissolving the compound Rhynchine B shown in formula (16) in ethanol, hydrogenating with palladium-carbon under a hydrogen atmosphere, and purifying by reverse-phase semi-preparative HPLC; 10. The process for synthesis of compound Rhynchine A as claimed in claim 9, wherein: The reverse phase semi-preparative HPLC purification time t R was 47.8 min.

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