Synthesis method of narrow mycin A

Abstract

The invention discloses a synthesis method of angustmycin A, and belongs to the field of organic synthesis. The preparation method comprises the following steps: taking a glycosyl donor as a raw material, taking # imgabs0 # as a donor to react with a receptor # imgabs1 #, removing a protecting group to prepare the narrow-mycin A, taking R2 as an acyl protecting group, and synthesizing the narrow-mycin A with the advantages of simple operation, mild conditions, high reaction stereoselectivity and regioselectivity and environment friendliness by utilizing the glycosyl donor.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and in particular relates to a method for synthesizing narrow mycin A. Background Art

[0002] Nucleoside antibiotics are a large class of structurally diverse compounds that usually exert biological effects by mimicking naturally occurring nucleosides or nucleotides. They are usually composed of modified bases and ribose residues connected by N-glycosidic bonds, and have structural characteristics similar to purine or pyrimidine ribonucleosides in organisms. Angustmycin A is an antibiotic isolated by Japanese scientist Yuntsen from the metabolites of Streptomyces hygroscopicus in 1958. Studies have shown that Angustmycin A is a potent inhibitor of GMP (guanylate) synthesis in Gram-positive bacteria. It has been shown to have significant biological activity on plants and is regarded as a new plant growth regulator. Recent studies have shown that the inhibition of GMP synthase in mice by stenomycin A can protect immunocompromised mice from melanoma cell invasion and tumorigenicity, indicating that stenomycin A has the potential to be developed into an anti-tumor drug (Khan, N.; Shah, PP; Ban, D.; Trigo-Mourino, P.; Carneiro, MG; DeLeeuw, L.; Dean, WL; Trent, JO; Beverly, LJ; Konrad, M.; Lee, D.; Sabo, TM. J Biol. Chem. 2019, 294, 11920–11933.).

[0003] Although the wide application prospects of stenomycin A have prompted people to continue to deepen their research on it, the stenomycin A currently used for activity testing is mostly separated and extracted from bacterial metabolites. Due to its low natural content, separation and extraction are relatively difficult. At the same time, although stenomycin A is commercially available, it is expensive, with a market price of about RMB 700 per mg. Therefore, the problem of obtaining stenomycin A has become a bottleneck in studying its biological function and structure-activity relationship, and chemical synthesis is an effective way to break this bottleneck.

[0004] Narrow mycin A has a fascinating chemical structure, which is composed of a rare C5'-C6' double bond of psicose and adenine connected by an N-glycosidic bond. Among them, its exocyclic double bond (C5'-C6' double bond) is sensitive to acid, which increases the difficulty of its chemical synthesis. At the same time, the selective glycosylation of the N7 position of adenine is also very challenging. So far, there is only one research report on the chemical synthesis of narrow mycin A (McCarthy, JR, Jr.; Robins, RK; Robins, MJJAm.Chem.Soc.1968,90,4993-4999.). Artificial synthesis of narrow mycin A to obtain a sufficient amount of this compound will help further advance the research on its biological and pharmacological activities, and has high academic and socio-economic value. Summary of the invention

[0005] The purpose of the present invention is to provide a method for synthesizing narrow mycin A.

[0006] Based on the above purpose, the present invention adopts the following technical solutions:

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

[0008]

[0009] R 1 is a hydroxyl protecting group, R 2 is an acyl protecting group, X is Cl, Br or I;

[0010] The specific process is as follows:

[0011] (1) subjecting compound 3 and 3,3-dimethyl-1-butyne to a Sonogashira reaction to obtain compound 4;

[0012] (2) Removing the protecting group R from compound 4 1 ; Then react with halogen element to obtain compound 5;

[0013] (3) subjecting compound 5 to a halogenated hydrocarbon elimination reaction to obtain compound 6;

[0014] (4) dissolving compound 2a and compound 6 in an organic solvent in the presence of a desiccant and a catalyst to obtain compounds 7, 7' and 7";

[0015] (5) Remove the Boc group from compound 7 under the action of an acid, and then remove the protecting group R under the action of a base. 2 Obtain narrow mycin A.

[0016] Preferably, R 1is selected from Bz, Ac, CA, Lev, TBDPS, TBS, Ts, All, Nap or Bn, R 2 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 levulinyl, and Boc is tert-butyloxycarbonyl.

[0017] Further, in step (1), the Sonogashira reaction comprises the following steps: compound 3, Ph 3 P、Pd(PPh 3 ) 2 Cl 2 , CuI is dissolved in an organic solvent, cooled to -78°C to -40°C in an inert gas atmosphere, 3,3-dimethyl-1-butyne is added, the temperature is raised to 50 to 100°C, and the reaction is continued until TLC shows that the reaction is complete, wherein the organic solvent is selected from one or more of N,N-dimethylformamide, diisopropanolamine, tetrahydrofuran, dichloromethane and toluene.

[0018] Preferably, compound 3, 3,3-dimethyl-1-butyne, (PPh 3 ) 2 PdCl 2 , CuI and PPh 3 The molar ratio 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: dissolving compound 4 in a mixed solvent consisting of an organic solvent and a buffer solution, adding DDQ, stirring at room temperature until the reaction is complete, and post-treating to obtain a compound with the Nap protecting group removed; the compound with the Nap protecting group removed, Ph 3 P and imidazole are dissolved in toluene, and a toluene solution containing elemental iodine is added dropwise, and the mixture is stirred at 50-60° C. to react completely to obtain compound 5, wherein 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); R 1 Compounds with removed protecting groups, Ph 3The molar ratio of P, 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 and the buffer solution is (4-6):1.

[0021] Furthermore, 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 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 ether.

[0022] Further, in step (4), the catalyst is a monovalent gold complex, and the desiccant 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; based on compound 2a, the amount of molecular sieve added 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 ether. The catalyst is preferably PPh 3 AHr 2 or PPh 3 AuOTf. The molecular sieve is preferably Molecular sieve or acid-washed molecular sieve, more preferably Molecular sieve.

[0023] Further, in step (5), the acid is TFA and the base is K 2 CO 3 , KHCO 3 、Na 2 CO 3 and NaHCO 3 At least one of the compounds 7 and the acid is in a molar ratio of 1:(15-25); the molar ratio of the product of the removal of the Boc protecting group and the base is 1:(4.5-5.5); and the organic solvent is one or more of toluene, dichloromethane, ether, acetone and THF.

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

[0025]

[0026] (1) Introducing a hydroxyl protecting group R into the alcoholic hydroxyl position of compound 1 1Prepare 1a, react compound 1a with 2-halogenbenzenethiol in the presence of Lewis acid to obtain compound 2;

[0027] (2) Introducing the protective group R into compound 2 2 Compound 3 was obtained.

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

[0029] Furthermore, R 1 When it is TBDPS, TBS, or Ts: compound 1 is dissolved in an organic solvent, a base and a silylation agent are added, the reaction is stirred until complete, and 1a is obtained by post-treatment, 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 silylation agent is TBDPSCl or TBSOTf or TBSCl or TsCl; and the molar ratio of compound 1, the base, and the silylation agent is 1:(1-2):(1-2);

[0030] R 1 When 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 to react completely, and then post-treatment is performed to obtain 1a;

[0031] R 1 or R 2 When it is Bz, Ac, CA, or Boc, BzCl, AcCl, CACl, or Boc 2 The amount of O added is more than 1 times the molar amount of the alcoholic hydroxyl group in compound 1 or compound 2, and the solvent is pyridine or dichloromethane. When dichloromethane is used as the solvent, pyridine or triethylamine (the amount added is more than 1 times the molar amount of compound 2) needs to be added. 1 or R 2 When Lev is used, compound 1 or compound 2, LevOH and DCC (or EDCI) are dissolved in dichloromethane, the reaction is completed, and the mixture is separated and purified. The molar amount of LevOH added is more than 1 times that of the hydroxyl group of compound 2.

[0032] The invention prepares a novel glycosyl donor, and utilizes the glycosyl donor to synthesize narrow mycin A which is simple in operation, mild in conditions, high in stereoselectivity and regioselectivity of the reaction and is environmentally friendly. DETAILED DESCRIPTION

[0033] The technical solution of the present invention is further described in detail below in conjunction with embodiments.

[0034] Example 1

[0035]

[0036] Compound 1 (1.50 g, 5.76 mmol) (Compound 1 is a known compound: Cubero, II; Plaza López-Espinosa, MTJ Carbohydr. Chem. 1986, 5, 299-311.) was dissolved in dry DMF (15 mL), and NaH (stored in kerosene, the content of sodium hydride is 60%, 415 mg, 10.38 mmol) and NapBr (2.548 g, 11.5 mmol) were slowly added thereto under ice bath. Then the temperature was slowly raised to room temperature and stirred for 4 hours. TLC showed that the raw material was completely reacted. Ethyl acetate was added thereto to dilute, and then extracted with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and dried. Column chromatography (PE / EA=10:1) was used for separation to obtain a white solid compound (2.283 g, 99%).

[0037] The intermediate obtained above (500 mg, 1.25 mmol) was dissolved in dry dichloromethane (8 mL), and 2-bromobenzenethiol (0.45 mL, 3.75 mmol) and boron trifluoride etherate (0.33 mL, 2.25 mmol, BF 3 -Et 2 O). Then the system was slowly warmed to room temperature and stirred until TLC showed that the raw material was completely reacted. At 0°C, triethylamine was added to the system to neutralize it. Then the system was diluted with dichloromethane, extracted with saturated sodium bicarbonate and saturated sodium chloride in turn, and dried over anhydrous sodium sulfate. Filtered and concentrated, column chromatography (petroleum ether / ethyl acetate = 5:1) was used to separate and purify to obtain white foamy solid compound 2 (465 mg, two-step yield 70%). [α] D 25 = +173.5 (c 1.0, CHCl 3 );δ 1 H NMR (400 MHz, CDCl 3)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=7.6,5.2 Hz,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); 13 C NMR (100 MHz, CDCl 3 )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 B O 5 NS[M+NH 4 ] + :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. Saturated NaHCO was then added to the system. 3 The solution was quenched, and then the system was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain a colorless syrupy compound (185 mg, 40%).

[0039] The compound obtained above was dissolved in dry dichloromethane (2 mL), and DMAP (9 mg, 0.076 mmol), BzCl (0.22 mL, 1.9 mmol) and Et 3N (0.63mL, 4.56mmol). The system was slowly heated to room temperature and the reaction continued until TLC showed that the reaction was complete. The reaction system was diluted with ethyl acetate, and then extracted with 2M dilute hydrochloric acid, washed with saturated sodium bicarbonate, and washed with saturated sodium chloride. Column chromatography (petroleum ether / ethyl acetate = 5:1) was used for separation and purification to obtain white foam solid compound 3 (302mg, 99%). [α] D 25 = +86.0 (c 0.7, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )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 (100 MHz, CDCl 3 )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 B O 8 NS[M+NH 4 ] + :820.1574; found:820.1534.

[0040] In a sealed tube, compound 3 (200 mg, 0.25 mmol), PPh3 PdCl 2 (17.5 mg, 0.025 mmol), PPh 3 (13mg, 0.05mmol) and CuI (19mg, 0.01mmol) were dissolved in 3mL DMF / DIPA (1:2) mixed solvent, nitrogen was replaced three times at -78℃, 3,3-dimethyl-1-butyne (0.073mL 0.75mmol) was added, and then the system was slowly heated to 80℃. After 8 hours of reaction, TLC showed that the reaction was complete, the system was diluted with ethyl acetate, and the reaction was quenched with saturated ammonium chloride solution, and then extracted with saturated sodium bicarbonate and saturated sodium chloride in turn, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (ethyl acetate / petroleum ether = 1:6) was used to separate the white foam solid compound 4 (168mg, 83%). [α] D 25 = +83.6 (c 1.25, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ8.10-8.05(m,4H),8.01-7.99(m,2H),7.81-7.73(m,5H),7.55-7.51(m,2 H),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 O 8 SNa[M+Na] + :827.2649; found:827.2652.

[0041] Compound 4 (250 mg, 0.31 mmol) was dissolved in DCM and pH = 7 Buffer solution (8.4 mL / v:v = 5:1), and DDQ (180 mg, 0.79 mmol) was added thereto. After three hours of reaction at room temperature, TLC showed that the reaction was complete. The reaction system was diluted with dichloromethane, and extracted with saturated sodium bicarbonate and saturated sodium chloride in turn. Drying with anhydrous sodium sulfate, filtering and concentrating gave the product with the 6-position Nap protecting group removed (206 mg, 99%). Its properties were white foamy solid.

[0042] The compound obtained above (206 mg, 0.31 mmol), Ph 3 P (203 mg, 0.77 mmol) and imidazole (106 mg, 1.56 mmol) were dissolved in dichloromethane (2 mL), and then a toluene solution (197 mg I iodine) containing elemental iodine was slowly added dropwise at room temperature. 2 in 3mL toluene, 0.78mmol). Then the system was heated to 55°C and the reaction was continued for 2 hours. After the reaction was completed, ethyl acetate was added to dilute the reaction, and then extracted with saturated sodium bicarbonate and saturated sodium chloride in sequence, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, and then separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain a white foam solid compound 5 (230mg, 96%). [α] D 25 = +54.3 (c 1.6, CHCl 3 );δ 1 H NMR (400 MHz, CDCl 3 )δ8.10-7.93(m,6H),7.73(dd,J=6.8,2.0Hz,1H),7.57-7.51(m,3H),7.4 9-7.47(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 (100 MHz, CDCl 3 )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 O 7 IS[M+NH 4 ] + :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 thereto. The mixture was reacted at room temperature for 8 hours. After the reaction was completed, ethyl acetate was added thereto for dilution, and then the mixture was extracted with water and saturated sodium chloride in turn. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by column chromatography (petroleum ether / ethyl acetate = 5:1). Compound 6 (169 mg, 99%) was obtained as a white foamy solid. [α] D 25 = +73.9 (c 0.9, CHCl 3 ); 1 HNMR (400MHz, CDCl 3 )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 (100 MHz, CDCl 3 )δ165.6,164.9,157.1,137.9,133.8,133.5,133.3,133.0,130.7,130.7,130.3,130.2,129.9,129.7,1 29.5,129.2,128.6,128.6,128.5,127.9,104.4,95.7,91.5,71.7,69.4,65.0,30.9,28.3; HRMS(ESI)m / z calcdfor C 39 H 34 O 7 SNa[M+Na]+:669.1918; found:669.1932.

[0044] The acceptor 2a (34 mg, 0.1 mmol) and the donor 6 (78 mg, 0.12 mmol) were dissolved in dry dichloromethane (4 mL) and freshly activated After stirring at room temperature for 15 minutes, the catalyst PPh 3 AHr 2(17.6 mg, 0.024 mmol). The system was heated to 45°C and stirred until the reaction was complete as detected by TLC. The crude product was filtered and concentrated to obtain a crude product. The crude product was 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,CHCl 3 ), 1 H NMR (400 MHz, CDCl 3 )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),7.33(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 (100 MHz, CDCl 3 )δ165.3,165.0,164.6,155.6,152.6,152.1,151.0,150.3,142.5,134.1,133.8,133.7,130.1,129.9,1 29.9,129.8,128.8,128.7,128.6,128.5,128.5,96.3,90.6,83.9,73.3,69.6,63.6,27.8.HRMS(ESI)m / z calcd for C 44 H 39 B O 8 NS[M+NH 4 ] + :820.1574; found:820.1534.;

[0045] Characterization data of 7'[α] D 25 =-8.6(c 0.85,CHCl 3 ), 1 H NMR (400 MHz, CDCl 3)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 (100 MHz, CDCl 3 )δ165.4,165.0,164.7,155.7,153.5,150.3,150.2,149.7,140.2,134.1,133.8,133.7,130.1,130 .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 B O 8 NS[M+NH 4 ] + :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 NaHCO 3 The solid was quenched, filtered and concentrated, and then column chromatography (CH 2 Cl 2 / PE / EA=2:1:2) to obtain the product after removal of the Boc protecting group (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 K 2 CO 3 (29 mg, 0.21 mmol), the reaction was continued to stir at room temperature for 8 hours. After the reaction was completed, a cation exchange resin (Amberlite IR120, Na-form) was added to the system to adjust the pH of the reaction system to about 7, filtered and concentrated, and column chromatography (CH2 Cl 2 / CH 3 OH=5:1) to obtain compound 8 (12 mg, 99%) as a white foamy solid. D 25 = +73.9 (c0.9, CHCl 3 ), 1 H NMR (400 MHz, DMSO-d 6 )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 B O 8 NS[M+NH 4 ] + :820.1574;found:820.1534.

Claims

1. A method for synthesizing narrow mycin A, characterized in that: The synthetic route is as follows: R1 is a hydroxyl protecting group, R2 is an acyl protecting group, and X is Cl, Br or I; The specific process is as follows: (1) subjecting compound 3 and 3,3-dimethyl-1-butyne to a Sonogashira reaction to obtain compound 4; (2) removing the protecting group R1 from compound 4; and then reacting with a halogen element to obtain compound 5; (3) subjecting compound 5 to a halogenated hydrocarbon elimination reaction to obtain compound 6; (4) dissolving compound 2a and compound 6 in an organic solvent in the presence of a desiccant and a catalyst to obtain compounds 7, 7' and 7"; (5) Compound 7 is treated with an acid to remove the Boc group, and then the base to remove the protecting group R2 to obtain stenotic mycin A.

2. The method for synthesizing narrow mycin A according to claim 1, characterized in that: In step (1), the Sonogashira reaction comprises the following steps: dissolving compound 3, Ph3P, Pd(PPh3)2Cl2 and CuI in an organic solvent, cooling the mixture to -78°C to -40°C in an inert gas atmosphere, adding 3,3-dimethyl-1-butyne, heating the mixture to 50 to 100°C, and reacting until TLC shows that the reaction is complete, wherein the organic solvent is selected from one or more of N,N-dimethylformamide, diisopropanolamine, tetrahydrofuran, dichloromethane and toluene.

3. The method for synthesizing narrow mycin A according to claim 1, characterized in that: The specific process of step (2) is as follows: dissolving compound 4 in a mixed solvent consisting of an organic solvent and a buffer solution, adding DDQ, stirring at room temperature until the reaction is complete, and post-treating to obtain a compound with the Nap protecting group removed; dissolving the compound with the Nap protecting group removed, Ph3P and imidazole in toluene, adding dropwise a toluene solution containing elemental iodine, stirring at 50 to 60° C. to react until the compound 5 is completely obtained, wherein the organic solvent is selected from one or more of N,N-dimethylformamide, diisopropanolamine, tetrahydrofuran, dichloromethane and toluene.

4. The method for synthesizing narrow mycin 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 to obtain compound 6; the molar ratio of compound 5 to DBU is 1:(2.5-3.5).

5. The method for synthesizing narrow mycin A according to claim 1, characterized in that: In step (4), the catalyst is a monovalent gold complex, the desiccant is a molecular sieve; the molar ratio of compound 6 to compound 2a is (1.3-1.1):1, 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; based on compound 2a, the amount of molecular sieve added is 3-8 g / mmol.

6. The method for synthesizing narrow mycin 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); the organic solvent is one or more of methanol, toluene, dichloromethane, ether, acetone and THF.

7. The method for synthesizing narrow mycin A according to claim 1, characterized in that: The synthesis process of compound 3 is as follows: (1) introducing a hydroxyl protecting group R1 into the alcoholic hydroxyl position of compound 1 to obtain 1a, and reacting compound 1a with 2-halogenbenzenethiol in the presence of a Lewis acid to obtain compound 2; (2) Compound 2 is introduced with a protecting group R2 to obtain compound 3.

8. The method for synthesizing narrow mycin A according to claim 2, characterized in that: 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).

9. The method for synthesizing narrow mycin A according to claim 3, characterized in that: The molar ratio of compound 4 and 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 the organic solvent and the buffer solution is (4-6):

1.

10. The method for synthesizing narrow mycin A according to claim 7, characterized in that: The molar ratio of compound 1a, 2-halogenbenzenethiol and Lewis acid is 1:(2.5-3.5):(1.5-2).

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