A method for the synthesis of amphotericin A

Abstract

The application discloses a synthesis method of angustmycin A and belongs to the field of organic synthesis. After a donor and an acceptor are reacted, a protecting group is removed to obtain angustmycin A, R2 is an acyl protecting group, the glycosyl donor is simple to operate, the condition is mild, the reaction has high stereoselectivity and regioselectivity, and angustmycin A is synthesized in an environment-friendly manner.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for synthesizing stenomycin A. Background Technology

[0002] Nucleoside antibiotics are a large class of structurally diverse compounds that typically exert their biological effects by mimicking naturally occurring nucleosides or nucleotides. They are usually composed of modified bases linked to ribose residues via N-glycosidic bonds, exhibiting structural characteristics similar to purine or pyrimidine ribonucleotides in living organisms. Angustmycin A, an antibiotic isolated in 1958 by Japanese scientist Yuntsen from the metabolites of *Streptomyces hygroscopicus*, has been shown to be a potent inhibitor of GMP (guanylic acid) synthesis in Gram-positive bacteria. It has been demonstrated to have significant biological activity in plants and is considered a novel plant growth regulator. Recent studies have shown that the inhibition of GMP synthase in mice by stenoxamycin A can prevent melanoma cell invasion and tumorigenesis in immunocompromised mice, suggesting that stenoxamycin A has the potential to be developed into an anti-tumor drug (Khan, N.; Shah, PP; Ban, D.; Trigo-Mourino, P.; Carneiro, MG; De Leeuw, L.; Dean, WL; Trent, JO; Beverly, LJ; Konrad, M.; Lee, D.; Sabo, TMJ Biol. Chem. 2019, 294, 11920–11933.).

[0003] Despite the promising applications of stenomycin A, prompting ongoing research, most stenomycin A used for activity testing is currently extracted from bacterial metabolites. Due to its low natural abundance, extraction is challenging. Furthermore, while commercially available, stenomycin A is expensive, costing approximately 700 RMB per milligram. Therefore, the availability of stenomycin A has become a bottleneck in studying its biological functions and structure-activity relationships, and chemical synthesis is an effective way to overcome this bottleneck.

[0004] Narrow-skinned amycin A possesses a fascinating chemical structure, formed by the rare C5'-C6' double bond connecting allulose and adenine via an N-glycosidic bond. The exocyclic double bond (C5'-C6' double bond) is acid-sensitive, increasing the difficulty of its chemical synthesis. Furthermore, the N7-position regioselective glycosylation of adenine presents significant challenges. To date, only one study has reported the chemical synthesis of narrow-skinned amycin A (McCarthy, JR, Jr.; Robins, RK; Robins, MJJAm. Chem. Soc. 1968, 90, 4993-4999.). The artificial synthesis of narrow-skinned amycin A to obtain sufficient quantities of this compound will contribute to further research on its biological and pharmacological activities, possessing high academic and socioeconomic value. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing stenomycin A.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for synthesizing stenomycin A, the synthetic route is as follows:

[0008]

[0009] R1 is a hydroxyl protecting group, R2 is an acyl protecting group, and X is Cl, Br, or I;

[0010] The specific process is as follows:

[0011] (1) Compound 3 and 3,3-dimethyl-1-butyne were subjected to a Sonogashira reaction to give compound 4;

[0012] (2) Remove the protecting group R1 from compound 4; then react it with a halogen to obtain compound 5;

[0013] (3) Compound 5 was subjected to a haloalkane elimination reaction to obtain compound 6;

[0014] (4) Compounds 2a and 6 were dissolved in an organic solvent and compounds 7, 7' and 7” were obtained in the presence of a drying agent and a catalyst;

[0015] (5) Compound 7 was debonded under acid and then debonded under base to obtain stenomycin A.

[0016] Preferably, R1 is selected from Bz, Ac, CA, Lev, TBDPS, TBS, Ts, All, Nap, or Bn, and R2 is selected from Bz, Ac, Boc, CA, or Lev. TBDPS is tert-butyldiphenylsilyl, TBS is tert-butyldimethylsilyl, Ts is p-toluenesulfonyl, All is allyl, Nap is 2-methylnaphthyl, Bn is benzyl, Ac is acetyl, Bz is benzoyl, CA is chloroacetyl, Lev is acetylpropionyl, and Boc is tert-butyloxycarbonyl.

[0017] Further, in step (1), the Sonogashira reaction includes the following steps: dissolving compound 3, Ph3P, Pd(PPh3)2Cl2, and CuI in an organic solvent, cooling to -78℃ to -40℃ in an inert gas atmosphere, adding 3,3-dimethyl-1-butyne, heating to 50 to 100℃, and reacting until TLC shows complete reaction. The organic solvent is selected from one or more of N,N-dimethylformamide, diisopropanolamine, tetrahydrofuran, dichloromethane, and toluene.

[0018] Preferably, the molar ratio of compound 3, 3,3-dimethyl-1-butyne, (PPh3)2PdCl2, CuI and PPh3 is 1:(2.5-3.5):(0.08-0.12):(0.01-0.1):(0.1-0.3); the organic solvent is a mixed solvent of N,N-dimethylformamide and diisopropanolamine, and the volume ratio of N,N-dimethylformamide and diisopropanolamine is 1:(1-3).

[0019] Further, the specific process of step (2) is as follows: Compound 4 is dissolved in a mixed solvent consisting of an organic solvent and a buffer solution, DDQ is added, and the mixture is stirred at room temperature until the reaction is complete. The compound with the Nap protecting group removed is then obtained through post-treatment. The compound with the Nap protecting group removed, Ph3P and imidazole are dissolved in toluene, and a toluene solution containing elemental iodine is added dropwise. The mixture is stirred at 50-60°C until the reaction is complete to obtain compound 5. The organic solvent is selected from one or more of N,N-dimethylformamide, diisopropanolamine, tetrahydrofuran, dichloromethane and toluene.

[0020] Preferably, in step (2), the molar ratio of compound 4 to DDQ is 1:(2-3); the molar ratio of the compound with R1 protecting group removed, Ph3P, imidazole and elemental iodine is 1:(2-3):(4.5-5.5):(2-3); the pH of the buffer solution is 6.5-7.5, and the volume ratio of DCM to the buffer solution is (4-6):1.

[0021] Further, the specific process of step (3) is as follows: Dissolve compound 5 in an organic solvent, add DBU, and stir at room temperature to react completely to obtain compound 6; preferably, the molar ratio of compound 5 to DBU is 1:(2.5~3.5); the organic solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, THF, triethylamine, ethyl acetate, acetone, DMSO or diethyl ether.

[0022] Further, in step (4), the catalyst is a monovalent gold complex, and the drying agent is a molecular sieve; preferably, the molar ratio of compound 6 to compound 2a is (1.3-1.1):1, and the molar ratio of compound 6 to catalyst is 1:(0.02-0.2); the concentration of compound 6 in the organic solvent is 30-60 mM; and the amount of molecular sieve added, based on compound 2a, is 3-8 g / mmol. The organic solvent is preferably one or more of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, DMF, toluene, benzene, dioxane, tetrahydrofuran, pyridine, ethyl acetate, DMSO, or diethyl ether. The catalyst is preferably PPh3AuNTf2 or PPh3AuOTf. The molecular sieve is preferably... Molecular sieves or acid-washed molecular sieves are preferred. Molecular sieve.

[0023] Further, in step (5), the acid is TFA, the base is at least one of K2CO3, KHCO3, Na2CO3 and NaHCO3, the molar ratio of compound 7 to acid is 1:(15-25); the molar ratio of the product after Boc protecting group removal to base is 1:(4.5-5.5); the organic solvent is one or more of toluene, dichloromethane, diethyl ether, acetone and THF.

[0024] The synthesis process of compound 3 is as follows:

[0025]

[0026] (1) Compound 1 was prepared by introducing a hydroxyl protecting group R1 into the hydroxyl position of compound 1. Compound 1a was then reacted with 2-halogenated thiophenol in the presence of a Lewis acid to obtain compound 2.

[0027] (2) Compound 2 was introduced into protecting group R2 to prepare compound 3.

[0028] Furthermore, the Lewis acid is boron trifluoride ether, and the molar ratio of compound 1a, 2-halogenated thiophenol and Lewis acid is 1:(2.5–3.5):(1.5–2).

[0029] Further, when R1 is TBDPS, TBS, or Ts: Compound 1 is dissolved in an organic solvent, a base and a silanizing agent are added, the reaction is stirred until complete, and then post-processed to obtain 1a, wherein the organic solvent is at least one of THF, DMF, pyridine and dichloromethane, the base is at least one of imidazole, triethylamine and pyridine; the silanizing agent is TBDPSCl or TBSOTf or TBSCl or TsCl; the molar ratio of compound 1, base and silanizing agent is 1:(1~2):(1~2);

[0030] When R1 is All / Nap / Bn, compound 1 is dissolved in DMF or THF, and NaH (more than 1 times the molar amount of hydroxyl groups in compound 1) and NapBr or AllBr or BnBr (more than 1 times the molar amount of hydroxyl groups in compound 1) are added. The reaction is completed, and the product is then post-treated to obtain 1a.

[0031] When R1 or R2 is Bz, Ac, CA, or Boc, the amount of BzCl, AcCl, CACl, or Boc2O added should be more than 1 times the molar amount of the alcohol hydroxyl group in compound 1 or compound 2. The solvent is pyridine or dichloromethane. When using dichloromethane as the solvent, pyridine or triethylamine should be added (the amount added should be more than 1 times the molar amount of compound 2). When R1 or R2 is Lev, compound 1 or compound 2, LevOH, and DCC (or EDCI) are dissolved in dichloromethane. After the reaction is complete, the mixture is separated and purified to obtain the product. The molar amount of LevOH added should be more than 1 times the molar amount of the hydroxyl group in compound 2.

[0032] This invention provides a novel glycosyl donor, which is simple to operate under mild conditions and exhibits high stereoselectivity and regioselectivity, making it environmentally friendly for the synthesis of stenomycin A. Detailed Implementation

[0033] The technical solution of the present invention will be further described in detail below with reference to the embodiments.

[0034] Example 1

[0035]

[0036] Compound 1 (1.50 g, 5.76 mmol) (Compound 1 is a known compound: Cucumbero, II; Plaza López-Espinosa, MTJ Carbohydr. Chem. 1986, 5, 299-311.) was dissolved in dry DMF (15 mL). NaH (stored in kerosene, 60% sodium hydride content, 415 mg, 10.38 mmol) and NapBr (2.548 g, 11.5 mmol) were slowly added under ice bath conditions. The mixture was then slowly heated to room temperature and stirred for 4 hours. TLC showed complete reaction of the starting material. The mixture was diluted with ethyl acetate, extracted with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Column chromatography (PE / EA = 10:1) was used to separate the compound into a white solid (2.283 g, 99%).

[0037] The intermediate obtained above (500 mg, 1.25 mmol) was dissolved in dry dichloromethane (8 mL), and 2-bromothiophenol (0.45 mL, 3.75 mmol) and boron trifluoride diethyl ether (0.33 mL, 2.25 mmol, BF3-Et2O) were added at 0 °C. The system was then slowly heated to room temperature and stirred until TLC showed complete reaction of the starting material. Triethylamine was added to the system at 0 °C to neutralize it. The system was then diluted with dichloromethane and extracted successively with saturated sodium bicarbonate and saturated sodium chloride, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give a white, foamy solid compound 2 (465 mg, 70% yield in two steps). [α] D 25 = +173.5 (c 1.0, CHCl3); δ 1 H NMR (400MHz, CDCl3) δ7.85-7.80(m,3H),7.76(s,1H),7.67(dd,J=7.2,1.6Hz,1H),7.63(dd ,J=7.6,1.6Hz,1H),7.50-7.44(m,3H),7.23-7.14(m,2H),5.03(d,J=7.6Hz,1H),4.78(dd,J =7.6,5.2Hz,1H),4.74(s,2H),4.71-4.67(m,1H),3.81(dd,J=10.4,3.2Hz,1H),3.74(dd,J= 10.8,4.4Hz,1H),3.61(d,J=12.0Hz,1H),3.42(d,J=12.0Hz,1H),1.69(s,3H),1.39(s,3H); 13C NMR (100MHz, CDCl3) δ139.0,135.2,133.3,133.2,133.2,132.6,131.3,130.3,128.5,128.0,127.9,127. 6,126.7,126.4,126.2,125.7,116.9,99.9,84.6,82.4,81.6,73.8,69.6,65.5,26.0,25.3; HRMS(ESI)m / z calcd for C 26 H 31 BrO5NS[M+NH4] + :548.1101; found:548.1118.

[0038] Compound 2 (500 mg, 0.94 mmol) was dissolved in 70% HOAc (16 mL), and the system was heated to 70 °C and stirred for 1 h. A saturated NaHCO3 solution was then added to quench the reaction. The system was then extracted three times with dichloromethane and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration, and separated by column chromatography (petroleum ether / ethyl acetate = 4:1) to give a colorless syrupy compound (185 mg, 40%).

[0039] The obtained compound was dissolved in dry dichloromethane (2 mL), and DMAP (9 mg, 0.076 mmol), BzCl (0.22 mL, 1.9 mmol), and Et3N (0.63 mL, 4.56 mmol) were added under ice bath conditions. The system was slowly heated to room temperature and the reaction was continued until TLC showed the reaction was complete. The reaction system was diluted with ethyl acetate, and then extracted successively with 2M dilute hydrochloric acid, washed with saturated sodium bicarbonate, and washed with saturated sodium chloride. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give a white foamy solid compound 3 (302 mg, 99%). [α] D 25 = +86.0 (c 0.7, CHCl3); 1H NMR(400MHz,CDCl3)δ8.10-8.07(m,4H),8.00-7.93(m,2H),7.84-7.73(m,5H),7.68(dd,J=8.0,1.6Hz,1H),7.58-7.51(m,2H),7.47-7.45(m,2H),7.41-7.35(m,6H),7.29(td,J=7.6,1.6Hz,1H),7.22(td,J=7.6,1.6Hz,1H),7.15(t,J=8.0Hz,2H),6.13(d,J=6.8Hz,1H),5.93(dd,J=6.8,3.6Hz,1H),4.91(dd,J=6.4,3.2Hz,1H),4.66-4.61(m,4H),3.88(dd,J=10.8,1.6Hz,1H),3.83(dd,J=10.8,2.8Hz,1H); 13 C NMR(100MHz,CDCl3)δ165.9,165.9,164.9,138.8,135.3,133.7,133.6,133.4,133.4,133.1,131.6,131.4,130.6,130.2,130.1,129.9,129.7,129.5,129.0,128.6,128.5,128.4,128.3,128.1,127.9,127.8,126.4,126.2,126.0,125.5,96.3,83.0,73.7,73.7,71.8,69.2,65.1;HRMS(ESI)m / z calcd for C 44 H 39 BrO8NS[M+NH4] + :820.1574;found:820.1534.

[0040] In a sealed tube, compound 3 (200 mg, 0.25 mmol), PPh3PdCl2 (17.5 mg, 0.025 mmol), PPh3 (13 mg, 0.05 mmol), and CuI (19 mg, 0.01 mmol) were dissolved in 3 mL of a mixed solvent of DMF / DIPA (1:2). The mixture was purged with nitrogen three times at -78 °C. 3,3-Dimethyl-1-butyne (0.073 mL, 0.75 mmol) was added, and the system was then slowly heated to 80 °C. After 8 hours, TLC showed complete reaction. The system was diluted with ethyl acetate, and the reaction was quenched with saturated ammonium chloride solution. The mixture was then extracted sequentially with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (ethyl acetate / petroleum ether = 1:6) yielded a white, foamy solid, compound 4 (168 mg, 83%). [α] D 25 = +83.6 (c 1.25, CHCl3); 1 H NMR (400MHz, CDCl3) δ8.10-8.05(m,4H),8.01-7.99(m,2H),7.81-7.73(m,5H),7 .55-7.51(m,2H),7.48-7.44(m,3H),7.39-7.33(m,6H),7.29-7.21(m,2H),7.18 -7.14(m,2H),6.09(d,J=7.2Hz,1H),5.93(dd,J=7.2,4.0Hz,1H),4.93(dd,J=6. 8,3.2Hz,1H),4.77-4.67(m,4H),3.94-3.86(m,2H),1.23(s,9H).HRMS(ESI)m / z calcd for C 50 H 44 O8SNa[M+Na] + :827.2649; found:827.2652.

[0041] Compound 4 (250 mg, 0.31 mmol) was dissolved in DCM and a buffer solution at pH 7 (8.4 mL / v:v = 5:1), and DDQ (180 mg, 0.79 mmol) was added. After reacting at room temperature for three hours, TLC showed that the reaction was complete. The reaction mixture was diluted with dichloromethane and extracted successively with saturated sodium bicarbonate and saturated sodium chloride. The product was dried over anhydrous sodium sulfate, filtered, and concentrated to give the product (206 mg, 99%) with the Nap protecting group removed at position 6. It was a white, foamy solid.

[0042] The obtained compound (206 mg, 0.31 mmol), Ph3P (203 mg, 0.77 mmol), and imidazole (106 mg, 1.56 mmol) were dissolved in dichloromethane (2 mL). Then, a toluene solution containing elemental iodine (197 mg I2 in 3 mL toluene, 0.78 mmol) was slowly added dropwise at room temperature. The system was then heated to 55 °C and the reaction continued for 2 hours. After the reaction was complete, ethyl acetate was added to dilute the reaction mixture. The mixture was then extracted successively with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Column chromatography (petroleum ether / ethyl acetate = 5:1) was then used to separate the crude product into a white, foamy solid compound 5 (230 mg, 96%). [α] D 25 = +54.3 (c 1.6, CHCl3); δ 1 H NMR (400MHz, CDCl3) δ8.10-7.93 (m, 6H), 7.73 (dd, J = 6.8, 2.0Hz, 1H), 7.57-7. 51(m,3H),7.49-7.47(m,1H),7.40-7.34(m,6H),7.32-7.25(m,2H),6.00(d,J= 7.6Hz,1H),5.56(dd,J=7.6,4.4Hz,1H),4.80-4.75(m,2H),4.69(d,J=12.4Hz ,1H),3.72(dd,J=10.8,4.0Hz,1H),3.63(dd,J=11.2,4.0Hz,1H),1.24(s,9H); 13 C NMR (100MHz, CDCl3) δ165.8,165.8,164.8,136.7,133.7,133.6,133.3,133.2,131.3,130.3,130.2,130.1,130.1,129. 8,129.2,128.8,128.8,128.6,128.5,128.4,128.0,104.1,96.0,81.1,74.6,72.6,64.5,30.9,28.3,6.1; HRMS(ESI)m / z calcd forC 39 H 39 O7IS[M+NH4] + :792.1487; found:792.1476.

[0043] Compound 5 (205 mg, 0.27 mmol) was dissolved in dry DMF (8 mL), and DBU (119 μL, 0.78 mmol) was added. The mixture was reacted at room temperature for 8 hours. After the reaction was complete, ethyl acetate was added to dilute the solution, followed by extraction with water and saturated sodium chloride. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give a white, foamy solid, compound 6 (169 mg, 99%). [α] D 25 = +73.9 (c 0.9, CHCl3); 1 HNMR(400MHz, CDCl3)δ8.19-8.16(m,2H),8.01-7.98(m,4H),7.78(dd,J=7.6,1.6Hz,1H),7.58-7.48(m,4H),7.43-7.39(m,4H),7.34-7.28(m,4H), 6.35(d,J=7.2Hz,1H),6.07(d,J=6.4Hz,1H),4.86-4.85(m,1H),4.79(d,J =12.8Hz,1H),4.71(d,J=2.4Hz,1H),4.60(d,J=12.8Hz,1H),1.21(s,9H); 13 C NMR (100MHz, CDCl3) δ165.6,164.9,157.1,137.9,133.8,133.5,133.3,133.0,130.7,130.7,130.3,130.2,129.9 ,129.7,129.5,129.2,128.6,128.6,128.5,127.9,104.4,95.7,91.5,71.7,69.4,65.0,30.9,28.3; HRMS(ESI)m / z calcdfor C 39 H 34 O7SNa[M+Na]+:669.1918; found:669.1932.

[0044] Receptor 2a (34 mg, 0.1 mmol) and donor 6 (78 mg, 0.12 mmol) were dissolved in dry dichloromethane (4 mL), and freshly activated [substance / material] was added to the solution. Molecular sieve (300 mg). After stirring at room temperature for 15 minutes, catalyst PPh3AuNTf2 (17.6 mg, 0.024 mmol) was added. The system was heated to 45 °C and the reaction was stirred until the reaction was complete as detected by TLC. The crude product was obtained by filtration and concentration, and then separated by column chromatography (ethyl acetate: petroleum ether: dichloromethane = 1:2:1 to 2:1:1) to obtain white solid products 7 (41 mg, 52%), 7' (14 mg, 20%) and 7" (7 mg, 12%). [α] D 25 = -16.4 (c 1.4, CHCl3), 1 H NMR (400MHz, CDCl3) δ8.80 (s, 1H), 8.44 (s, 1H), 8.10-7.96 (m, 2H), 7.89 (dd, J = 8.2 ,1.4Hz,2H),7.76(dd,J=8.1,1.4Hz,2H),7.66-7.57(m,1H),7.57-7.40(m,4H),7.3 3(dt,J=9.7,7.7Hz,4H),7.06(d,J=5.4Hz,1H),6.20(dt,J=5.5,1.7Hz,1H),5.37-5 .11(m,2H),5.01(dd,J=3.3,1.8Hz,1H),4.64(dd,J=3.2,1.5Hz,1H),1.39(s,18H). 13 C NMR (100MHz, CDCl3) δ165.3,165.0,164.6,155.6,152.6,152.1,151.0,150.3,142.5,134.1,133.8,133.7,130.1 ,129.9,129.9,129.8,128.8,128.7,128.6,128.5,128.5,96.3,90.6,83.9,73.3,69.6,63.6,27.8.HRMS(ESI)m / z calcd for C 44 H 39 BrO8NS[M+NH4] + :820.1574; found:820.1534.;

[0045] Characterization data for 7' [α] D 25 = -8.6 (c 0.85, CHCl3), 1H NMR(400MHz, CDCl3)δ8.70(s,1H),8.28(s,1H),8.20 -7.98(m,3H),7.98-7.83(m,2H),7.83-7.71(m,2H),7.60(d,J=7.4Hz,1H),7.56-7.40(m,4H),7.40-7.27(m,4H),7.09(d,J=5.4Hz,1H),6. 18(dt,J=5.4,1.8Hz,1H),5.26(d,J=12.2Hz,1H),5.20(d,J=12.2Hz,1H),5.00(t,J=2.6Hz,1H),4.60(dd,J=3.2,1.7Hz,1H),1.56(s,9H). 13 C NMR (100MHz, CDCl3) δ165.4,165.0,164.7,155.7,153.5,150.3,150.2,149.7,140.2,134.1,133.8,133.7,1 30.1,130.0,129.8,128.8(2C),128.6,128.6,122.8,96.2,90.1,82.5,73.2,69.6,63.6,28.3.HRMS(ESI)m / z calcd forC 44 H 39 BrO8NS[M+NH4] + :820.1574; found:820.1534.

[0046] Compound 7 (40 mg, 0.051 mmol) was dissolved in dichloromethane (3 mL), and TFA (89 μL, 1.02 mmol) was added at room temperature. The reaction was stirred for 8 h, and then the reaction was quenched with solid NaHCO3. The mixture was filtered and concentrated, and column chromatography (CH2Cl2 / PE / EA = 2:1:2) was performed to give the product with the Boc protecting group removed (26 mg, 84%).

[0047] The above product (26 mg, 0.044 mmol) was dissolved in a mixed solution of THF / MeOH (0.9 mL, V / V = 1:2), and K2CO3 (29 mg, 0.21 mmol) was added. The reaction was continued with stirring at room temperature for 8 hours. After the reaction was completed, the pH of the reaction system was adjusted to approximately 7 using a cation exchange resin (Amberlite IR120, Na-form). The mixture was then filtered and concentrated, and separated by column chromatography (CH2Cl2 / CH3OH = 5:1) to obtain a white, foamy solid compound 8 (12 mg, 99%). [α] D 25=+73.9(c0.9,CHCl3), 1 H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.86(s,1H),7.27(s,2H),5.84(d,J=4.6Hz,1H),5.35(d,J=7.7Hz,1H),5.06(t,J=3.8Hz,1H),4.97(t,J=6.0Hz,1H),4.53(d,J=2.2Hz,1H),4.29(s,1H),4.22-4.11(m,2H),3.97(dd,J=12.3,5.2Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ162.2,156.1,152.1,148.2,138.6,119.9,98.4,83.5,71.5,69.7,61.0.HRMS(ESI)m / z calcd for C 44 H 39 BrO8NS[M+NH4] + :820.1574;found:820.1534。

Claims

1. A method of synthesis of amphotericin A, characterized by, The synthetic route is as follows: R1 is Nap, R2 is selected from Bz, Ac, Boc, CA or Lev, and X is Cl, Br or I; The specific process is as follows: (1) Compound 3 and 3,3-dimethyl-1-butyn are subjected to a Sonogashira reaction to obtain compound 4; (2) removing the protecting group R1 from compound 4; and then reacting with halogen element to obtain compound 5; the halogen element is elemental iodine, and the specific process of step (2) is as follows: dissolving compound 4 in a mixed solvent composed of an organic solvent and a Buffer solution, adding DDQ, stirring at room temperature until the reaction is complete, and then treating to obtain a compound from which the Nap protecting group is removed; dissolving the compound from which the Nap protecting group is removed, Ph3P and imidazole in toluene, adding dropwise a toluene solution containing elemental iodine, and stirring at 50~60 o C stirring until the reaction is complete to obtain compound 5, and the organic solvent is one or more selected from N,N-dimethylformamide, diisopropanolamine, tetrahydrofuran, dichloromethane and toluene; (3) Compound 5 is subjected to a halogenated hydrocarbon elimination reaction to obtain compound 6; (4) Compound 2a and compound 6 are dissolved in an organic solvent in the presence of a drying agent and a catalyst to obtain compounds 7, 7' and 7'', the catalyst is a monovalent gold complex, and the drying agent is molecular sieves; (5) Compound 7 is subjected to Boc removal under the action of an acid and then to removal of the protecting group R2 under the action of a base to obtain narbomycin A.

2. The method of claim 1, wherein the narbomycin A is synthesized by the method comprising the steps of: In step (1), the Sonogashira reaction comprises the following steps: compounds 3, Ph3P, Pd(PPh3)2Cl2, CuI are dissolved in an organic solvent, an inert gas atmosphere is provided, the temperature is lowered to-78℃ to-40℃, then 3,3-dimethyl-1-butyn is added, the temperature is raised to 50-100℃, and the reaction is carried out until TLC shows that the reaction is complete; the organic solvent is selected from one or more of N,N-dimethylformamide, diisopropanolamine, tetrahydrofuran, dichloromethane and toluene.

3. The method for synthesizing stenomycin A according to claim 1, characterized in that, The specific process of step (3) is as follows: compound 5 is dissolved in an organic solvent, DBU is added, and the reaction is stirred at room temperature until it is complete to obtain compound 6; the molar ratio of compound 5 to DBU is 1: (2.5-3.5).

4. The method of claim 1, wherein the streptomycin A is synthesized by the steps of: In step (4), the catalyst is a monovalent gold complex, and the drying agent is molecular sieves; the molar ratio of compound 6 to compound 2a is (1.3-1.1):1, the molar ratio of compound 6 to the catalyst is 1: (0.02-0.2); the concentration of compound 6 in the organic solvent is 30-60 mM; and the amount of molecular sieves added is 3-8 g / mmol based on compound 2a.

5. The method for synthesizing stenomycin A according to claim 1, characterized in that, In step (5), the acid is TFA, the base is at least one of K2CO3, KHCO3, Na2CO3 and NaHCO3, the molar ratio of compound 7 to the acid is 1: (15-25), the molar ratio of the product after removal of the Boc protecting group to the base is 1: (4.5-5.5), and the organic solvent is one or more of methanol, toluene, dichloromethane, diethyl ether, acetone and THF.

6. The method for synthesizing stenomycin A according to claim 1, characterized in that, The process of synthesizing compound 3 is as follows: (1) Compound 1 is subjected to introduction of a hydroxyl protecting group R1 at the alcohol hydroxyl group to obtain compound 1a, and compound 1a is subjected to reaction with 2-halogen thiophenol in the presence of a Lewis acid to obtain compound 2, the Lewis acid is boron trifluoride etherate; (2) Compound 2 is subjected to introduction of a protecting group R2 to obtain compound 3.

7. The method for synthesizing stenomycin A according to claim 2, characterized in that, The molar ratio of compound 3, 3,3-dimethyl-1-butyn, (PPh3)2PdCl2, CuI and PPh3 is 1: (2.5-3.5): (0.08-0.12): (0.01-0.1): (0.1-0.3).

8. The method for synthesizing stenomycin A according to claim 1, characterized in that, The molar ratio of compound 4 and DDQ is 1: (2~3); the molar ratio of the compound after removal of the R1 protecting group, Ph3P, imidazole and elemental iodine is 1: (2~3): (4.5~5.5): (2~3); the pH of the buffer solution is 6.5~7.5; and the volume ratio of the organic solvent and the buffer solution is (4~6):

1.

9. The method for synthesizing stenomycin A according to claim 6, characterized in that, The molar ratio of compound 1a, 2-halogen benzene thiol and Lewis acid is 1: (2.5~3.5): (1.5~2).

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