A method for synthesizing aspergillus A and its analogs

Abstract

The application provides a synthesis method of aspergillus A and analogs thereof, a large amount of aziridine carboxylic acid ester is synthesized by using a one-pot method, then the aziridine carboxylic acid ester is subjected to a solvent-free nucleophilic ring-opening reaction in sequence, and a protecting group on an amino group is removed after each ring-opening, so as to obtain aspergillus A and analogs thereof. The synthesis process is simple, the condition is mild, aspergillus A and analogs thereof with specific chiral structures can be selectively synthesized, the yield of the target product is high, and industrialized production can be easily realized.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of natural product synthesis, and particularly relates to a synthesis method of aspergillomarasmine A and analogs thereof. BACKGROUND

[0002] In recent years, with the abuse of antibiotics, antibiotic resistance has become a more and more serious problem in the world. The evolution of bacteria secreting beta-lactamase is the main reason for the development of drug resistance. Beta-lactamase is divided into serine beta-lactamase and metal beta-lactamase. Some serine beta-lactamase inhibitors, such as the drug class of avibactam, have been successfully listed as drugs, but there is currently no safe and effective metal beta-lactamase inhibitor.

[0003] Aspergillomarasmine A has been proved to be a very promising metal beta-lactamase inhibitor (A.M. King, S.A. Reid-Yu, W. Wang, et al, Aspergillomarasmine A overcomes metallo-beta-lactamase antibiotic resistance, Nature, 2014, 510, 503-506.), which has a strong inhibitory effect on common metal beta-lactamase and is expected to solve the increasingly serious problem of antibiotic resistance caused by metal beta-lactamase. However, the current chemical synthesis method of aspergillomarasmine A has long steps and low yield, which greatly limits its industrial production.

[0004] The structure of aspergillomarasmine A and its analogs is as follows:

[0005] SUMMARY

[0006] The purpose of the present application is to provide a synthesis method of aspergillomarasmine A and its analogs, which has short steps, high yield and is easy to realize industrial production.

[0007] In order to achieve the above purpose of the present application, the following technical solutions are adopted:

[0008] A synthesis method of aspergillomarasmine A and its analogs, which adopts a one-pot method to synthesize a large amount of aziridine carboxylate, and then performs a solvent-free nucleophilic ring-opening reaction on the aziridine carboxylate in turn, and removes the protecting group on the amino group after each ring-opening to obtain aspergillomarasmine A and its analogs.

[0009] Preferably, the synthesis route is as follows:

[0010]

[0011] wherein R1, R2 are each independently tBu or Bn, and * represents a chiral center.

[0012] Preferably, the method comprises the following steps:

[0013] (1) dissolving compound 1 in an organic solvent, adding o-nitrobenzenesulfonyl chloride and sodium bicarbonate and a small amount of water, and reacting until compound 1 is substantially completely converted; then sequentially adding o-nitrobenzenesulfonyl chloride and sodium hydroxide, and obtaining compound 2 after reaction;

[0014] (2) mixing and reacting compound 2 and compound 3 to obtain compound 4;

[0015] (3) dissolving compound 4 in an organic solvent, adding sodium benzenethiolate, and obtaining compound 5 after reaction;

[0016] (4) mixing and reacting compound 5 and compound 2 to obtain compound 6;

[0017] (5) dissolving compound 6 in an organic solvent, adding sodium benzenethiolate, and obtaining compound 7 after reaction;

[0018] (6) dissolving compound 7 in an organic solvent, adding anisole and trifluoromethanesulfonic acid, and obtaining aspergillomarasmine A or an analogue thereof after reaction.

[0019] Preferably, the reaction temperature in step (1) is 10-40°C, and the reaction time is 4-16 hours.

[0020] Preferably, the organic solvent in step (1) is dichloromethane, and the molar ratio of o-nitrobenzenesulfonyl chloride to compound 1 is (1.0-3.0):1.

[0021] Preferably, the reactions in steps (2) and (4) are solvent-free reactions, the reaction temperature is 10-40°C, and the reaction time is 1-4 hours.

[0022] Preferably, the molar ratio of compound 3 to compound 2 in step (2) is (1.0-1.5):1, and the molar ratio of compound 5 to compound 2 in step (4) is (1.0-1.5):1.

[0023] Preferably, the organic solvent in step (3) is acetonitrile, the reaction temperature is 10-40°C, the reaction time is 0.5-4 hours, and the molar ratio of sodium benzenethiolate to compound 4 is (3.0-5.0):1.

[0024] Preferably, the organic solvent in step (5) is N,N-dimethylformamide, the reaction temperature is 10-40°C, the reaction time is 0.5-4 hours, and the molar ratio of sodium benzenethiolate to compound 6 is (3.0-5.0):1.

[0025] Preferably, the organic solvent in step (6) is dichloromethane, the molar ratio of anisole, trifluoromethanesulfonic acid and compound 7 is (5.0-13.0):(4.0-12.0):1, the reaction temperature and time are 0.5-2.0 hours at -10-10℃, and then 0.5-2.0 hours at 10-40℃.

[0026] Compared with the prior art, the present application has the following beneficial effects:

[0027] (1) The synthesis method of aspergillomarin A and its analogs has simple process and mild conditions, and can selectively synthesize aspergillomarin A and its analogs with specific chiral structure.

[0028] (2) The yield of aspergillomarin A and its analogs is high. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 The structure of aspergillomarin A in Example 1 of the present application is 1 H nuclear magnetic resonance spectrum. DETAILED DESCRIPTION

[0030] The raw materials and equipment used in the present application are known products, which can be obtained by purchasing commercially available products or referring to the preparation method in the public literature.

[0031] Example 1: Synthesis of aspergillomarin A (chiral SSS):

[0032]

[0033] The method comprises the following steps:

[0034] (1) In 400 mL of dichloromethane and 16 mL of water, compound 1 serine tert-butyl ester hydrochloride (7.9 g, 40 mmol), sodium bicarbonate (10.1 g, 120 mmol) and o-nitrophenylsulfonyl chloride (13.3 g, 60 mmol) were sequentially added, and the reaction was carried out at 25℃ for 12 hours. Then o-nitrophenylsulfonyl chloride (10.6 g, 48 mmol) and sodium hydroxide (9.6 g, 240 mmol) were sequentially added, and the reaction was carried out for 1 hour. After the reaction was completed, anhydrous magnesium sulfate was added for drying, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 12.2 g of compound 2 (yellowish oily liquid, which became white solid after standing for a long time), with a yield of 93%.

[0035] The structure characterization data of compound 2 are as follows:

[0036] 1H NMR (400 MHz, CDC13) δ 8.26 - 8.22 (m, 1H), 7.84 - 7.69 (m, 3H), 3.49 (dd, J = 7.1, 4.5 Hz, 1H), 3.00 (d, J = 7.1 Hz, 1H), 2.71 (d, J = 4.4 Hz, 1H), 1.46 (s, 9H). 13 C NMR (101 MHz, CDC13) δ 165.54, 148.46, 134.92, 132.60, 131.82, 131.55, 124.74, 83.42, 38.73, 34.09, 27.93.

[0037] (2) Compound 2 (6.6 g, 20 mmol) and compound 3 aspartic acid di-tert-butyl ester (5.9 g, 24 mmol) were mixed and reacted at 25 °C without solvent for 2 hours. The resulting mixture was directly purified by silica gel column chromatography to obtain 11.1 g of compound 4 (yellowish oily liquid which became white solid after standing for a long time), with a yield of 96%.

[0038] The structural characterization data of compound 4 are as follows:

[0039] 1 H NMR (400 MHz, CDC13) δ 8.26 - 8.22 (m, 1H), 7.84 - 7.69 (m, 3H), 3.49 (dd, J = 7.1, 4.5 Hz, 1H), 3.00 (d, J = 7.1 Hz, 1H), 2.71 (d, J = 4.4 Hz, 1H), 1.46 (s, 9H). 13 C NMR (101 MHz, CDC13) δ 165.54, 148.46, 134.92, 132.60, 131.82, 131.55, 124.74, 83.42, 38.73, 34.09, 27.93.

[0040] (3) Compound 4 (9.2 g, 16 mmol) was dissolved in 80 mL of acetonitrile, and sodium thiophenol (7.4 g, 56 mmol) was added. After being reacted at 25°C for 30 minutes, 80 mL of ethyl acetate and 80 mL of water were added, and the mixture was separated. The aqueous phase was extracted with 80 mL of ethyl acetate once, and the combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 5.3 g of compound 5 (yellowish oily liquid) at a yield of 85%.

[0041] The structural characterization data of compound 5 are as follows:

[0042] 1 H NMR (400 MHz, CDCl3) δ 3.43 (dd, J = 7.3, 5.7 Hz, 1H), 3.37 (dd, J = 7.0, 4.1 Hz, 1H), 2.87 (dd, J = 11.9, 7.0 Hz, 1H), 2.73 (dd, J = 11.9, 4.2 Hz, 1H), 2.57 (dd, J = 15.7, 5.7 Hz, 1H), 2.44 (dd, J = 15.7, 7.3 Hz, 1H), 2.09 (s, 3H), 1.49 - 1.40 (m, 27H). 13 C NMR (101 MHz, CDCl3) δ 173.94, 172.91, 170.26, 81.51, 81.31, 80.99, 58.73, 55.19, 51.30, 39.65, 28.17, 28.15, 28.13.

[0043] (4) Compound 5 (5.3 g, 13.6 mmol) and compound 2 (4.3 g, 13.2 mmol) were mixed and reacted at 25°C without solvent for 2 hours. The obtained mixture was directly purified by silica gel column chromatography to obtain 7.8 g of compound 6 (yellowish oily liquid) at a yield of 80%.

[0044] The structural characterization data of compound 6 are as follows:

[0045] 1 H NMR (400 MHz, CDCl3) δ 8.08 - 8.03 (m, 1H), 7.89 - 7.83 (m, 1H), 7.74 - 7.64 (m, 2H), 4.10 (t, J = 4.6 Hz, 1H), 3.42 (t, J = 6.4 Hz, 1H), 3.20 - 3.08 (m, 2H), 2.86 - 2.66 (m, 3H), 2.58 (dd, J = 16.0, 6.4 Hz, 1H), 2.51 (dd, J = 15.9, 6.5 Hz, 1H), 1.51 - 1.38 (m, 27H), 1.26 (s, 9H). 13C NMR (101 MHz, CDC13) δ 172.75, 172.67, 170.27, 169.09, 147.87, 134.81, 133.42, 132.73, 130.56, 125.42, 82.62, 81.68, 81.47, 80.89, 62.31, 58.63, 57.75, 50.25, 49.99, 39.44, 28.15, 28.11, 28.09, 27.80.

[0046] (5) Compound 6 (5.4 g, 7.5 mmol) was dissolved in 20 mL of N,N-dimethylformamide, sodium benzene thiol (3.5 g, 26.3 mmol) was added, and after reaction at 25°C for 30 minutes, 150 mL of ethyl acetate and 150 mL of water were added, the liquid was separated, the water phase was extracted with 150 mL of ethyl acetate once, and the organic phase was combined, washed with 150 mL of water 5 times, and 150 mL of saturated brine once, and the organic phase was dried with anhydrous sodium sulfate, filtered under suction, and the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography to obtain 3.3 g of compound 7 (yellowish oily liquid), with a yield of 83%.

[0047] The structural characterization data of compound 7 are as follows:

[0048] 1 H NMR (400 MHz, CDC13) δ 3.41 (t, J = 6.5 Hz, 1H), 3.38 (dd, J = 7.2, 4.5 Hz, 1H), 3.19 (dd, J = 7.4, 4.9 Hz, 1H), 2.81 - 2.65 (m, 4H), 2.55 (dd, J = 15.8, 6.2 Hz, 1H), 2.46 (dd, J = 15.8, 6.7 Hz, 1H), 2.01 (s, 4H), 1.47 - 1.34 (m, 36H). 13 C NMR (101 MHz, CDC13) δ 174.03, 173.18, 172.74, 170.26, 81.41, 81.37, 81.28, 80.90, 62.29, 58.62, 55.43, 51.34, 50.38, 39.56, 28.20, 28.17, 28.14, 28.13.

[0049] (6) Compound 7 (3.3 g, 6.2 mmol) was dissolved in 100 mL of dichloromethane, and benzyl methyl ether (4.1 mL, 37.4 mmol) and trifluoromethanesulfonic acid (2.7 mL, 31.2 mmol) were added at 0 °C. After 30 minutes of reaction, the reaction was continued at 25 °C for 1 hour. Then, an aqueous solution of sodium bicarbonate (3.7 g dissolved in 100 mL of water) was added at 0 °C for 1 hour, and the mixture was separated. The aqueous phase was washed with 100 mL of dichloromethane three times, and the aqueous phase was concentrated and purified by ion exchange column chromatography to obtain 1.1 g of compound 8, aspergillomarasmine A, at a yield of 57%.

[0050] The structural characterization data of aspergillomarasmine A are as follows:

[0051] 1 H NMR (600 MHz, D2O) δ 3.89-3.83 (m, 2H), 3.43 (dd, J = 9.8, 4.2 Hz, 1H), 3.31 (dd, J = 12.9, 4.3 Hz, 1H), 3.29 (dd, J = 13.5, 5.8 Hz, 1H), 3.16 (dd, J = 12.9, 9.8 Hz, 1H), 2.89 (dd, J = 13.5, 3.9 Hz, 1H), 2.84 (dd, J = 17.5, 3.7 Hz, 1H), 2.71 (dd, J = 17.6, 9.4 Hz, 1H). 13 C NMR (151 MHz, D2O) δ 177.43, 177.34, 173.26, 173.12, 59.79, 59.30, 54.54, 47.95, 47.06, 35.78.

[0052] The nuclear magnetic spectrum is shown in Figure 1 .

[0053] Example 2: Synthesis of aspergillomarasmine A analog (chiral RSS):

[0054]

[0055] The same method as in Example 1 was used by replacing the corresponding chiral raw material.

[0056] The structural characterization data of aspergillomarasmine A analog (chiral RSS) are as follows:

[0057] 1H NMR (600 MHz, D20) δ 3.82 (dd, J = 6.0, 4.0 Hz, 1H), 3.79 (dd, J = 9.1, 3.9 Hz, 1H), 3.41 (dd, J = 9.6, 4.3 Hz, 1H), 3.24 (dd, J = 13.4, 6.0 Hz, 1H), 3.27 - 3.17 (m, 1H), 3.06 (dd, J = 12.7, 9.6 Hz, 1H), 2.90 (dd, J = 13.4, 4.0 Hz, 1H), 2.79 (dd, J = 17.1, 4.0 Hz, 1H), 2.65 (dd, J = 17.1, 9.1 Hz, 1H).

[0058] Example 3: Synthesis of Aspermin A analogue (chiral SRS):

[0059]

[0060] The same method as Example 1 was used with the corresponding chiral starting material replaced.

[0061] The structural characterization data of Aspermin A analogue (chiral SRS) are as follows:

[0062] 1 H NMR (600 MHz, D20) δ 3.82 (dd, J = 6.0, 4.0 Hz, 1H), 3.79 (dd, J = 9.1, 3.9 Hz, 1H), 3.41 (dd, J = 9.6, 4.3 Hz, 1H), 3.24 (dd, J = 13.4, 6.0 Hz, 1H), 3.27 - 3.17 (m, 1H), 3.06 (dd, J = 12.7, 9.6 Hz, 1H), 2.90 (dd, J = 13.4, 4.0 Hz, 1H), 2.79 (dd, J = 17.1, 4.0 Hz, 1H), 2.65 (dd, J = 17.1, 9.1 Hz, 1H).

[0063] Example 4: Synthesis of Aspermin A analogue (chiral SSR):

[0064]

[0065] The same method as Example 1 was used with the corresponding chiral starting material replaced.

[0066] The structural characterization data of Aspermin A analogue (chiral SSR) are as follows:

[0067] 1H NMR (600 MHz, D20) δ 3.70 (dd, J = 7.0, 4.1 Hz, 1H), 3.61 (dd, J = 8.9, 4.4 Hz, 1H), 3.34 (dd, J = 9.2, 4.4 Hz, 1H), 3.07 (dd, J = 13.0, 7.0 Hz, 1H), 3.01 (dd, J = 12.5, 4.4 Hz, 1H), 2.88 (dd, J = 13.0, 4.1 Hz, 1H), 2.85 (dd, J = 12.4, 9.2 Hz, 1H), 2.67 (dd, J = 16.1, 4.4 Hz, 1H), 2.51 (dd, J = 16.2, 8.9 Hz, 1H).

[0068] Example 5: Synthesis of Aspermin A analogue (chiral RRS):

[0069]

[0070] The same procedure as in Example 1 was used with the corresponding chiral starting materials replaced.

[0071] The structural characterization data of Aspermin A analogue (chiral RRS) are as follows:

[0072] 1 H NMR (600 MHz, D20) δ 3.70 (dd, J = 7.0, 4.1 Hz, 1H), 3.61 (dd, J = 8.9, 4.4 Hz, 1H), 3.34 (dd, J = 9.2, 4.4 Hz, 1H), 3.07 (dd, J = 13.0, 7.0 Hz, 1H), 3.01 (dd, J = 12.5, 4.4 Hz, 1H), 2.88 (dd, J = 13.0, 4.1 Hz, 1H), 2.85 (dd, J = 12.4, 9.2 Hz, 1H), 2.67 (dd, J = 16.1, 4.4 Hz, 1H), 2.51 (dd, J = 16.2, 8.9 Hz, 1H).

[0073] Example 6: Synthesis of Aspermin A analogue (chiral RSR):

[0074]

[0075] The same procedure as in Example 1 was used with the corresponding chiral starting materials replaced.

[0076] The structural characterization data of Aspermin A analogue (chiral RSR) are as follows:

[0077] 1H NMR (600 MHz, D20) δ 3.69 (dd, J = 7.2, 4.1 Hz, 1H), 3.62 (dd, J = 9.1, 4.2 Hz, 1H), 3.34 (dd, J = 9.4, 4.3 Hz, 1H), 3.07 (dd, J = 13.1, 7.2 Hz, 1H), 3.03 (dd, J = 12.5, 4.3 Hz, 1H), 2.89 (dd, J = 13.2, 4.0 Hz, 1H), 2.88 - 2.82 (m, 1H), 2.68 (dd, J = 16.3, 4.2 Hz, 1H), 2.51 (dd, J = 16.3, 9.1 Hz, 1H).

[0078] Example 7: Synthesis of Aspermin A analogue (chiral SRR):

[0079]

[0080] The same procedure as in Example 1 was used with the corresponding chiral starting material.

[0081] The structural characterization data of Aspermin A analogue (chiral SRR) are as follows:

[0082] 1 H NMR (600 MHz, D20) δ 4.23 - 4.04 (m, 2H), 3.74 (dd, J = 8.2, 4.4 Hz, 1H), 3.50 (dd, J = 8.8, 6.2 Hz, 1H), 3.42 (dd, J = 13.7, 5.4 Hz, 1H), 3.04 (dd, J = 13.8, 5.8 Hz, 1H), 2.85 (dd, J = 13.8, 6.2 Hz, 1H), 2.75 - 2.59 (m, 2H).

[0083] Example 8: Synthesis of Aspermin A analogue (chiral RRR):

[0084]

[0085] The same procedure as in Example 1 was used with the corresponding chiral starting material.

[0086] The structural characterization data of Aspermin A analogue (chiral RRR) are as follows:

[0087] 1H NMR (600 MHz, D20) δ 4.49 (t, J = 5.1 Hz, 1H), 4.31 (t, J = 5.1 Hz, 1H), 4.15 (dd, J = 8.5, 4.8 Hz, 1H), 3.95 (dd, J = 14.9, 8.5 Hz, 1H), 3.90 - 3.80 (m, 2H), 3.75 (dd, J = 13.2, 5.0 Hz, 1H), 3.12 (dd, J = 18.1, 5.8 Hz, 1H), 2.98 (dd, J = 18.1, 4.3 Hz, 1H).

Claims

1. A method for synthesizing aspergillus A and its analogues, characterized by, A large amount of aziridine carboxylate is synthesized by "one-pot method", and then the aziridine carboxylate is subjected to a solvent-free nucleophilic ring-opening reaction in sequence, and the protecting group on the amino group is removed after each ring-opening to obtain aspergillomarasmine A and analogs thereof; the synthetic route is as follows: wherein R1 and R2 are tBu; the aspergillomarasmine A analog is chiral RSS, chiral SRS, chiral SSR, chiral RRS, chiral RSR, chiral SRR or chiral RRR; Specifically comprising the following steps: (1) Compound 1 is dissolved in an organic solvent, o-nitrobenzenesulfonyl chloride and sodium bicarbonate and a small amount of water are added, and the reaction is continued until compound 1 is substantially completely converted; then o-nitrobenzenesulfonyl chloride and sodium hydroxide are added in sequence, and compound 2 is obtained after reaction; (2) Compound 2 and compound 3 are mixed and reacted to obtain compound 4; (3) Compound 4 is dissolved in an organic solvent, and sodium benzenethiol is added, and compound 5 is obtained after reaction; (4) Compound 5 and compound 2 are mixed and reacted to obtain compound 6; (5) Compound 6 is dissolved in an organic solvent, and sodium benzenethiol is added, and compound 7 is obtained after reaction; (6) Compound 7 is dissolved in an organic solvent, anisole and trifluoromethanesulfonic acid are added, and aspergillomarasmine A or its analog is obtained after reaction.

2. The method of synthesis of claim 1, wherein, The reaction temperature in step (1) is 10-40℃, and the reaction time is 4-16 hours.

3. The method of synthesis of claim 2, wherein, The organic solvent in step (1) is dichloromethane, and the molar ratio of o-nitrobenzenesulfonyl chloride to compound 1 is (1.0-3.0):

1.

4. The method of synthesis according to claim 1 or 2 or 3, wherein, The reactions in steps (2) and (4) are solvent-free reactions, the reaction temperature is 10-40℃, and the reaction time is 1-4 hours.

5. The method of synthesis of claim 4, wherein, In step (2), the molar ratio of compound 3 to compound 2 is (1.0-1.5):1; in step (4), the molar ratio of compound 5 to compound 2 is (1.0-1.5):

1.

6. The method of synthesis of claim 5, wherein, In step (3), the organic solvent is acetonitrile, the reaction temperature is 10-40℃, the reaction time is 0.5-4 hours, and the molar ratio of sodium benzenethiol to compound 4 is (3.0-5.0):

1.

7. The method of synthesis of claim 6, wherein, In step (5), the organic solvent is N,N-dimethylformamide, the reaction temperature is 10-40℃, the reaction time is 0.5-4 hours, and the molar ratio of sodium benzenethiol to compound 6 is (3.0-5.0):

1.

8. The method of synthesis of claim 7, wherein, In step (6), the organic solvent is dichloromethane, the molar ratio of anisole, trifluoromethanesulfonic acid and compound 7 is (5.0-13.0):(4.0-12.0):1, and the reaction temperature and time are 0.5-2.0 hours at -10-10℃, and then 0.5-2.0 hours at 10-40℃.

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