Bridged phloroglucinol antibacterial compound as well as preparation method and application thereof

Abstract

The invention discloses a bridged ring phloroglucinol antibacterial compound as well as a preparation method and application thereof, and belongs to the field of medicinal chemistry and anti-infection pharmacy. The structural general formula of the bridged ring phloroglucinol antibacterial compound is shown in the specification. The preparation method specifically comprises the following steps: (1) preparing a compound B by taking methyl iodide, sodium methoxide and a compound A as raw materials; (2) preparing a compound C by taking diisobutylaluminium hydride, the compound B, 2, 6-dimethyl pyridine and trifluoromethanesulfonic anhydride as raw materials; (3) preparing a compound D by taking palladium acetate, triphenylphosphine, the compound C, triethylamine and formic acid as raw materials; and (4) preparing a target product by taking the compound D, hexafluoroisopropanol, p-toluenesulfonic acid, the compound E, chiral phosphoric acid and ytterbium trifluoromethanesulfonate as raw materials. The compound disclosed by the invention shows high selectivity, low drug resistance risk and a potential new action mechanism, and provides a new leading structure and a technical path for overcoming drug resistance of existing antibacterial drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry and anti-infective pharmacy, and particularly relates to a kind of bridged cyclophellatriene antibacterial compound, its pharmaceutically acceptable salt, stereoisomer, prodrug, crystal form and preparation method. BACKGROUND

[0002] In recent years, the global detection rate of "super bacteria" such as Methicillin-resistance Staphylococcus aureus (MRSA) and Vancomycin-Resistant Enterococcus (VRE) continues to rise. However, existing antibacterial drugs (such as vancomycin, linezolid, daptomycin) have shown decreased sensitivity, increased clinical failure rate, and accumulated side effects, leading to high mortality rate of drug-resistant bacterial infection; combined with the continuous emergence of drug-resistant mutations, single-target drugs are difficult to maintain long-term efficacy. Currently, traditional antibiotic research and development relies on the "new target-new drug" strategy, but bacterial targets are conservative and poorly drugable, resulting in long development cycle, high cost, and high failure rate.

[0003] Natural bridged cyclophellatriene derivatives have a unique polycyclic skeleton, a multi-hydroxyl / carbonyl hydrogen bond network, and a hydrophobic cavity, which can form multi-site reversible binding with bacterial membrane proteins, lipid II cycle enzymes, or metal ions, thereby reducing the frequency of drug-resistant mutations. However, the low content, complex structure, and difficulty of total synthesis of natural products limit their drugability.

[0004] Therefore, how to develop an efficient, low-drug, and novel mechanism of action antibacterial drug is a problem that needs to be solved by those skilled in the art. SUMMARY

[0005] Therefore, the purpose of the present application is to provide a bridged cyclophellatriene antibacterial compound and its preparation method and application to solve the deficiencies in the prior art.

[0006] To achieve the above purpose, the technical scheme adopted by the present application is as follows:

[0007] A bridged cyclophellatriene antibacterial compound, the general structure of which is

[0008] wherein R 1 is selected from methyl or unsubstituted C1-C3 alkyl; R 2 is selected from isopropyl or unsubstituted C4-C7 cycloalkyl; and n is selected from 1, 2, 3, or 4.

[0009] Further, the structure of the above-mentioned bridged cyclophellatriene antibacterial compound is:

[0010]

[0011] A preparation method of the above-mentioned bridged resorcinol antibacterial compound, specifically comprising the following steps:

[0012] (1) At 0℃, iodomethane is added to a methanol solution of sodium methoxide and compound A , warmed to 64℃ and stirred for 8h, cooled to room temperature, concentrated under reduced pressure, quenched with hydrochloric acid, extracted with ethyl acetate, combined organic phases, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound B

[0013] (2) At -78℃, diisobutylaluminum hydride is added to a tetrahydrofuran solution of compound B and stirred for 30min, quenched with distilled water, extracted with ethyl acetate, combined organic phases, dried with anhydrous sodium sulfate, filtered, concentrated, and obtained as a crude product; under the condition of room temperature and argon protection, 2,6-dimethylpyridine is added to a 1,2-dichloroethane solution of the above-mentioned crude product, warmed to reflux, and after adding triflic anhydride for 30min, cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, combined organic phases, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound C in yellow oil

[0014] (3) Under the condition of room temperature and argon protection, palladium acetate and triphenylphosphine are added to a tetrahydrofuran solution of compound C and stirred for 10min, and then tetrahydrofuran solutions of triethylamine and formic acid are slowly added, warmed to reflux, and reacted overnight, cooled to room temperature, quenched with saturated sodium chloride aqueous solution, extracted with ethyl acetate, combined organic phases, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain diene compound D

[0015] (4) Compound D is dissolved in hexafluoroisopropanol, and at 25℃, p-toluenesulfonic acid is added, warmed to 50℃ and continuously stirred for 1h, then directly filtered and vacuum concentrated, added to a toluene solution containing compound E chiral phosphoric acid and ytterbium triflate, the reaction is carried out at 25℃, quenched with saturated sodium bicarbonate aqueous solution when the reaction is completed according to thin layer chromatography, extracted with ethyl acetate, combined organic phases, dried with anhydrous sodium sulfate, filtered, vacuum concentrated, and purified by silica gel flash column chromatography to finally obtain the target product.

[0016] The synthesis reaction equation of the bridged resorcinol antibacterial compound of the present application is as follows:

[0017]

[0018] Further, in the above step (1), the molar ratio of methyl iodide, sodium methoxide and compound A is 10:8:1; the concentration of the methanol solution is 0.5M; the concentration of the hydrochloric acid is 1N; and the condition of the silica gel column chromatography is EtOAc / n-hexane = 1:100-1:20.

[0019] Further, in the above step (2), the molar ratio of diisobutylaluminum hydride, compound B, 2,6-lutidine and trifluoromethanesulfonic anhydride is 1.5:1:1.5:1.5; the concentration of the tetrahydrofuran solution is 0.2M; and the condition of the silica gel column chromatography is EtOAc / n-hexane = 1:200-1:70.

[0020] Further, in the above step (3), the molar ratio of palladium acetate, triphenylphosphine, triethylamine and formic acid is 0.02:0.04:2:2.1; the concentration of the tetrahydrofuran solution is 0.13M; and the condition of the silica gel column chromatography is EtOAc / n-hexane = 1:100.

[0021] Further, in the above step (4), the molar ratio of compound D, hexafluoroisopropanol, p-toluenesulfonic acid, compound E, chiral phosphoric acid and ytterbium trifluoromethanesulfonate is 1:0.1:1.2:1.1:0.05:0.05; and the concentration of the toluene solution is 0.02M.

[0022] The application also claims the use of the above-mentioned bridged cyclophelland antibacterial compound or the bridged cyclophelland antibacterial compound prepared by the above-mentioned preparation method in the preparation of a medicament for treating infectious diseases caused by gram-positive bacteria (including methicillin-resistant Staphylococcus aureus MRSA, vancomycin-resistant Enterococcus VRE, etc.).

[0023] According to the above technical solution, compared with the prior art, the application has the following beneficial effects:

[0024] The application provides a kind of bridged cyclophelland antibacterial compound with novel structure, four-step synthesis route and high atom economy, wherein, the MIC of representative compound 12 to MRSA is 2-4 μg / mL, and the activity is in the same order of magnitude with vancomycin sensitive strain quality control upper limit (≤2 μg / mL);Gram-positive bacteria such as Enterococcus faecium and Enterococcus faecalis also maintain the same activity, and there is no obvious inhibition to common gram-negative bacteria (MIC>128 μg / mL), which shows high selectivity, low drug resistance risk and potential new mechanism of action, providing a new lead structure and technical path for overcoming the drug resistance of existing antibacterial drugs. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.

[0026] Embodiment 1

[0027] Preparation method of bridged resorcinol antibacterial compound 1 , specifically comprising the following steps:

[0028] (1) At 0°C, iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (43.2 g, 0.8 mol, 8.0 eq.) and compound A (19.6 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL), warmed to 64°C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1N hydrochloric acid, extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100-1:20) to obtain compound B

[0029] (2) At -78°C, diisobutylaluminum hydride (1.5M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a solution of compound B (5.0 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) and stirred for 30 min, quenched with distilled water, extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated to obtain a crude product; under room temperature and argon protection, 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a solution of the above crude product in 1,2-dichloroethane, warmed to reflux, and trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added and reacted for 30 min, then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:200-1:70) to obtain compound C as yellow oil

[0030] (3) Pd(OAc)2(40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a solution of compound C (3.3 g, 9 mmol, 1.0 eq.) in THF (36 mL) at room temperature under argon, and stirred for 10 min, then a solution of triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) in THF (36 mL) was slowly added, and the reaction was heated to reflux overnight, cooled to room temperature, quenched with saturated aqueous NaCl solution, extracted with ethyl acetate, combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:100) to give diene compound D

[0031] (4) Compound D (22 mg, 0.1 mmol, 1.0 eq.) was dissolved in HFIP (1 mL), and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C, and the reaction was heated to 50 °C and stirred for 1 h, then directly filtered and concentrated under vacuum, and added to a solution containing compound E (23 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium triflate (3.1 mg, 0.005 mmol, 0.05 eq.) in toluene (PhMe, 5 mL), and the reaction was carried out at 25 °C, and when the reaction was completed according to thin layer chromatography, quenched with saturated aqueous NaHCO3 solution, and extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and purified by silica gel flash column chromatography to finally obtain the target product

[0032] Compound 1:

[0033] (c = 0.4, CH2Cl2);

[0034] R f = 0.60 (ethyl acetate / n-hexane = 1 / 4);

[0035] IR (film) λ max 3434, 2980, 2946, 2870, 1705, 1622, 1431, 1384, 1252, 1092, 879, 843 cm -1 ;

[0036] 1H NMR (400 MHz, CDC13) δ 14.35 (s, 1H), 7.21 (s, 1H), 6.28 (s, 1H), 4.19 (m, 1H), 3.42 (m, 1H), 3.32 (d, J = 3.1 Hz, 1H), 2.38 (m, 2H), 2.24 (m, 2H), 1.97 (m, 1H), 1.86 (m, 2H), 1.57 (t, J = 12.3 Hz, 1H), 1.41 (s, 3H), 1.38 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H), 1.25 (s, 3H), 1.03 (s, 3H);

[0037] 13 C NMR (100 MHz, CDC13) δ 218.0, 206.5, 165.1, 159.4, 157.9, 112.5, 103.6, 101.3, 94.2, 86.4, 54.1, 50.7, 46.4, 39.1, 37.4, 35.4, 30.2, 29.0, 28.9, 25.3, 24.8, 24.5, 24.0, 19.2, 17.8;

[0038] HRMS (ESI-TOF) m / z: [M + H] + calcd. for C 25 H 33 O6 + 429.2277; found: 429.2270.

[0039] Example 2

[0040] Preparation method of bridged resorcinol antibacterial compound 2 , specifically comprising the following steps:

[0041] (1) At 0 °C, iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (43.2 g, 0.8 mol, 8.0 eq.) and compound A (19.6 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL), warmed to 64 °C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1 N hydrochloric acid, extracted with ethyl acetate, combined organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100 ~ 1:20) to give compound B

[0042] (2) Diisobutylaluminum hydride (1.5 M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a stirred solution of compound B (5.0 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) at -78 °C for 30 min, quenched with distilled water, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. 2,6-Dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a stirred solution of the above crude product in 1,2-dichloroethane at room temperature under argon protection, heated to reflux, and trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added. After 30 min, the reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc / n-hexane = 1:200 to 1:70) gave compound C as a yellow oil.

[0043] (3) Palladium acetate (40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a stirred solution of compound C (3.3 g, 9 mmol, 1.0 eq.) in tetrahydrofuran (THF, 36 mL) at room temperature under argon protection, and stirred for 10 min. Then, triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) in tetrahydrofuran (THF, 36 mL) were added slowly, heated to reflux, and stirred overnight. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc / n-hexane = 1:100) gave diene compound D.

[0044] (4) Compound D (22 mg, 0.1 mmol, 1.0 eq.) was dissolved in hexafluoroisopropanol (HFIP, 1 mL), and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C. The reaction mixture was heated to 50 °C and stirred for 1 h, then directly filtered and concentrated under vacuum. The residue was added to a stirred solution of compound E (24 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium triflate (3.1 mg, 0.005 mmol, 0.05 eq.) in toluene (PhMe, 5 mL) was carried out at 25 °C, the reaction was observed to be complete by thin layer chromatography, quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by flash column chromatography on silica gel to finally obtain the target product

[0045] Compound 2:

[0046] (c = 0.4, CH2Cl2);

[0047] R f = 0.61 (ethyl acetate / n-hexane = 1 / 4);

[0048] IR (film) λ max 3420, 2974, 2946, 2870, 1702, 1622, 1601, 1429, 1382, 1240, 1162, 865, 841 cm -1 ;

[0049] 1 H NMR (400 MHz, CDCl3) δ 14.37 (s, 1H), 6.60 (s, 1H), 6.14 (s, 1H), 4.04 (m, 1H), 3.41 (m, 1H), 3.32 (d, J = 3.1 Hz, 1H), 1.89 (m, 5H), 1.72 (m, 2H), 1.58 (m, 3H), 1.41 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H), 1.29 (s, 3H), 1.26 (s, 3H), 1.02 (s, 3H);

[0050] 13 C NMR (100 MHz, CDCl3) δ 217.9, 209.1, 165.2, 159.0, 157.9, 112.6, 104.4, 101.7, 94.3, 87.9, 54.1, 50.7, 50.6, 39.1, 37.5, 35.4, 30.5, 30.3, 30.0, 29.0, 28.9, 26.4, 26.4, 24.8, 24.1, 19.3;

[0051] HRMS (ESI-TOF) m / z: [M + H] + calcd. for C26 H 35 O6 + 443.2434; found: 443.2432.

[0052] Example 3

[0053] Preparation of bridged resorcinol antibacterial compound 3 comprises the following steps:

[0054] (1) Iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (43.2 g, 0.8 mol, 8.0 eq.) and compound A (19.6 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL) at 0 °C, warmed to 64 °C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1 N hydrochloric acid, extracted with ethyl acetate, combined the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1 : 100 ~ 1 : 20) to give compound B

[0055] (2) Diisobutylaluminum hydride (1.5 M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a solution of compound B (5.0 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) at -78 °C and stirred for 30 min, quenched with distilled water, extracted with ethyl acetate, combined the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product; 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a solution of the above crude product in 1,2-dichloroethane under room temperature and argon protection, warmed to reflux, triflic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added and reacted for 30 min, cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography (EtOAc / n-hexane = 1 : 200 ~ 1 : 70) to give compound C as yellow oil

[0056] (3) Pd(OAc)2(40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a solution of compound C (3.3 g, 9 mmol, 1.0 eq.) in THF (36 mL) at room temperature under argon, and stirred for 10 min, then a solution of triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) in THF (36 mL) was slowly added, and the reaction was heated to reflux overnight, cooled to room temperature, quenched with saturated aqueous NaCl solution, extracted with ethyl acetate, combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:100) to give diene compound D

[0057] (4) Compound D (22 mg, 0.1 mmol, 1.0 eq.) was dissolved in HFIP (1 mL), and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C, and the reaction was heated to 50 °C and stirred for 1 h, then directly filtered and concentrated under vacuum, and added to a solution containing compound E (26 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium triflate (3.1 mg, 0.005 mmol, 0.05 eq.) in toluene (PhMe, 5 mL), and the reaction was carried out at 25 °C, and when the reaction was completed according to thin layer chromatography, quenched with saturated aqueous NaHCO3 solution, and extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and purified by silica gel flash column chromatography to finally obtain the target product

[0058] Compound 3:

[0059] (c = 0.4, CH2Cl2);

[0060] R f = 0.68 (ethyl acetate / n-hexane = 1 / 4);

[0061] IR (film) λ max 3420, 2977, 2929, 2853, 1705, 1622, 1431, 1382, 1254, 1165, 875, 822 cm -1 ;

[0062] 1H NMR (400 MHz, CDC13) δ 14.41 (s, 1H), 7.32 (s, 1H), 6.33 (s, 1H), 3.62 (m, 1H), 3.42 (m, 1H), 3.32 (d, J = 3.1 Hz, 1H), 1.94 (m, 2H), 1.89 (m, 1H), 1.81 (m, 2H), 1.70 (m, 1H), 1.57 (t, J = 12.3 Hz, 1H), 1.47 (m, 2H), 1.41 (s, 3H), 1.37 (s, 3H), 1.35 (m, 3H), 1.34 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H), 1.03 (s, 3H);

[0063] 13 C NMR (100 MHz, CDC13) δ 218.1, 209.9, 165.4, 159.2, 157.7, 112.5, 104.1, 101.5, 94.4, 86.4, 54.1, 50.7, 49.8, 39.1, 37.4, 35.4, 30.2, 30.2, 29.4, 29.1, 28.9, 26.4, 26.3, 26.2, 24.8, 24.0, 19.2;

[0064] HRMS (ESI-TOF) m / z: [M+H] + calcd. for C 27 H 37 O6 + 457.2590; found: 457.2583.

[0065] Example 4

[0066] Preparation method of bridged resorcinol antibacterial compound 4 , specifically comprising the following steps:

[0067] (1) At 0°C, iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (43.2 g, 0.8 mol, 8.0 eq.) and compound A (19.6 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL), warmed to 64°C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1N hydrochloric acid, extracted with ethyl acetate, combined organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100~1:20) to obtain compound B

[0068] (2) Diisobutylaluminum hydride (1.5 M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a stirred solution of compound B (5.0 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) at -78 °C for 30 min, quenched with distilled water, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product; 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a stirred solution of the above crude product in 1,2-dichloroethane at room temperature under argon protection, heated to reflux, and trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added to the solution, which was stirred at reflux for 30 min, cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / n-hexane = 1:200 to 1:70) to give compound C as a yellow oil

[0069] (3) Palladium acetate (40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a stirred solution of compound C (3.3 g, 9 mmol, 1.0 eq.) in tetrahydrofuran (THF, 36 mL) at room temperature under argon protection, and stirred for 10 min. Then triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) in tetrahydrofuran (THF, 36 mL) were added slowly to the solution, which was heated to reflux overnight, cooled to room temperature, quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / n-hexane = 1:100) to give diene compound D

[0070] (4) Compound D (22 mg, 0.1 mmol, 1.0 eq.) was dissolved in hexafluoroisopropanol (HFIP, 1 mL), and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C. The solution was heated to 50 °C and stirred for 1 h, then directly filtered and concentrated in vacuo. The residue was added to a solution of compound E (28 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium triflate (3.1 mg, 0.005 mmol, 0.05 eq.) in toluene (PhMe, 5 mL) was carried out at 25 °C, the reaction was observed to be complete by thin layer chromatography, quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by flash column chromatography on silica gel to give the target product

[0071] Compound 4:

[0072] (c = 0.4, CH2Cl2);

[0073] R f = 0.68 (ethyl acetate / n-hexane = 1 / 4);

[0074] IR (film) λ max 3334, 2977, 2926, 2858, 1705, 1617, 1599, 1435, 1377, 1254, 1136, 914, 865 cm -1 ;

[0075] 1 H NMR (400 MHz, CDCl3) δ 14.38 (s, 1H), 7.12 (s, 1H), 6.23 (s, 1H), 3.79 (m, 1H), 3.41 (m, 1H), 3.32 (d, J = 3.1 Hz, 1H), 1.98 (m, 2H), 1.89 (m, 2H), 1.78 (m, 2H), 1.64 (m, 2H), 1.59 (m, 2H), 1.57 (m, 2H), 1.54 (m, 2H), 1.41 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H), 1.02 (s, 3H);

[0076] 13 C NMR (100 MHz, CDCl3) δ 218.0, 210.7, 165.4, 159.1, 157.7, 112.5, 103.8, 101.5, 94.3, 86.2, 54.0, 50.7, 50.3, 39.0, 37.4, 35.3, 32.0, 31.5, 30.2, 29.0, 28.8, 28.2, 28.2, 27.4, 27.2, 24.7, 24.0, 19.2;

[0077] HRMS (ESI-TOF) m / z: [M+H] + calcd. for C 28 H 39 O6 + 471.2747; found: 471.2733.

[0078] Example 5

[0079] Preparation method of bridged resorcinol antibacterial compound 5 , specifically comprising the following steps:

[0080] (1) At 0 °C, iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (142.0 g, 1 mol, 10.0 eq.) and compound A (20.8 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL), warmed to 64 °C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1 N hydrochloric acid, extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100-1:20) to give compound B

[0081] (2) At -78 °C, diisobutylaluminum hydride (1.5 M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a solution of compound B (5.3 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) and stirred for 30 min, quenched with distilled water, extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product; under room temperature and argon protection, 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a solution of the above crude product in 1,2-dichloroethane, warmed to reflux, and trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added and reacted for 30 min, then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:200-1:70) to give compound C as yellow oil

[0082] (3) Under the condition of room temperature and argon protection, palladium acetate (40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to the tetrahydrofuran solution (THF, 36 mL) of compound C (3.4 g, 9 mmol, 1.0 eq.) respectively and stirred for 10 min, then the tetrahydrofuran solution (THF, 36 mL) of triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) was slowly added, warmed to reflux, reacted overnight, cooled to room temperature, quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, combined organic phase, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100) to obtain diene compound D

[0083] (4) Compound D (23 mg, 0.1 mmol, 1.0 eq.) was dissolved in hexafluoroisopropanol (HFIP, 1 mL), p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C, warmed to 50 °C and stirred for 1 h, then directly filtered and concentrated under vacuum, added to the toluene solution (PhMe, 5 mL) containing compound E (22 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium trifluoromethanesulfonate (3.1 mg, 0.005 mmol, 0.05 eq.), the reaction was carried out at 25 °C, quenched with saturated aqueous sodium bicarbonate solution when the reaction was completed according to thin layer chromatography, and extracted with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel flash column chromatography to finally obtain the target product

[0084] Compound 5:

[0085] (c = 0.4, CH2Cl2);

[0086] R f = 0.61 (ethyl acetate / n-hexane = 1 / 4);

[0087] IR (film) λ max 3440, 2978, 2934, 2874, 1620, 1547, 1429, 1365, 1250, 1162, 1035, 922, 846 cm -1 ;

[0088] 1 H NMR (400 MHz, CDC13) δ 14.37 (s, 1H), 6.88 (s, 1H), 5.94 (s, 1H), 3.90 (m, 1H), 3.34 (d, J = 3.1 Hz, 1H), 3.24 (m, 1H), 2.47 (q, J = 10.4 Hz, 1H), 2.32 (m, 2H), 2.22 (dd, J = 12.3, 6.9 Hz, 1H), 1.70 (m, 2H), 1.51 (m, 2H), 1.39 (s, 3H), 1.25 (s, 6H), 1.19 (s, 3H), 1.17 (s, 3H), 1.01 (s, 3H);

[0089] 13C NMR (100 MHz, CDC13) δ 217.8, 210.7, 165.3, 158.8, 157.8, 112.1, 103.8, 101.7, 94.3, 86.6, 53.9, 50.8, 39.4, 37.7, 37.3, 36.9, 36.7, 34.8, 28.9, 24.7, 24.0, 19.5, 19.4, 19.1, 12.8;

[0090] HRMS (ESI-TOF) m / z: [M+H] + calcd. for C 25 H 33 O6 + 429.2277; found: 429.2269.

[0091] Example 6

[0092] Preparation of bridged resorcinol antibacterial compound 6 , specifically comprising the following steps:

[0093] (1) At 0 °C, iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (142.0 g, 1 mol, 10.0 eq.) and compound A (22.2 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL), warmed to 64 °C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1 N hydrochloric acid, extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100 ~ 1:20) to give compound B

[0094] (2) Diisobutylaluminum hydride (1.5 M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a stirred solution of compound B (5.6 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) at -78 °C for 30 min, quenched with distilled water, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product; 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a stirred solution of the above crude product in 1,2-dichloroethane at room temperature under argon protection, heated to reflux, and trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added to the solution, which was stirred for 30 min, cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / n-hexane = 1:200 to 1:70) to give compound C as a yellow oil

[0095] (3) Palladium acetate (40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a stirred solution of compound C (3.5 g, 9 mmol, 1.0 eq.) in tetrahydrofuran (THF, 36 mL) at room temperature under argon protection, and stirred for 10 min. Then, triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) in tetrahydrofuran (THF, 36 mL) were slowly added to the solution, which was heated to reflux, and stirred overnight. The solution was cooled to room temperature, quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / n-hexane = 1:100) to give diene compound D

[0096] (4) Compound D (25 mg, 0.1 mmol, 1.0 eq.) was dissolved in hexafluoroisopropanol (HFIP, 1 mL), and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C. The solution was heated to 50 °C and stirred for 1 h, then directly filtered and concentrated in vacuo. The residue was added to a solution of compound E (22 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium triflate (3.1 mg, 0.005 mmol, 0.05 eq.) in toluene (PhMe, 5 mL) was carried out at 25 °C, the reaction was observed to be complete by thin layer chromatography, quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by flash column chromatography on silica gel to give the target product

[0097] Compound 6:

[0098] (c = 0.4, CH2Cl2);

[0099] R f = 0.69 (ethyl acetate / n-hexane = 1 / 4);

[0100] IR (film) λ max 3415, 2985, 2959, 2877, 1695, 1604, 1459, 1426, 1379, 1235, 1096, 875, 841 cm -1 ;

[0101] 1 H NMR (400 MHz, CDCl3) δ 14.40 (s, 1H), 7.14 (s, 1H), 6.25 (s, 1H), 3.89 (m, 1H), 3.36 (d, J = 13.5 Hz, 2H), 1.98 (m, 1H), 1.93 (m, 2H), 1.81 (m, 1H), 1.75 (m, 2H), 1.67 (m, 2H), 1.60 (m, 2H), 1.41 (s, 3H), 1.28 (d, J = 10.4 Hz, 3H), 1.26 (d, J = 10.4 Hz, 3H), 1.18 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H);

[0102] 13 C NMR (100 MHz, CDCl3) δ 218.0, 210.7, 165.4, 159.0, 157.9, 112.1, 103.8, 101.5, 96.0, 94.2, 54.0, 50.8, 39.6, 39.6, 39.3, 37.4, 37.3, 35.6, 29.0, 24.8, 24.0, 23.9, 23.5, 19.5, 19.4, 19.1;

[0103] HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 26 H 35 O6 + 443.2434; found: 443.2439.

[0104] Example 7

[0105] Bridged-ring phloroglucinol antibacterial compounds 7 The preparation method of [the substance] specifically includes the following steps:

[0106] (1) At 0 °C, 142.0 g, 1 mol, 10.0 eq. of iodomethane was added to sodium methoxide (142.0 g, 1 mol, 10.0 eq.) and compound A. The compound B was prepared by heating (23.6 g, 100 mmol, 1.0 eq.) in a methanol solution (MeOH, 200 mL) to 64 °C and stirring for 8 h, then cooling to room temperature, concentrating under reduced pressure, quenching with 1 N hydrochloric acid, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and purifying by silica gel column chromatography (EtOAc / n-hexane = 1:100–1:20) to obtain compound B.

[0107] (2) Under conditions of -78℃, diisobutylaluminum hydride (1.5M in) THF (20 mL, 30 mmol, 1.5 eq.) was added to a tetrahydrofuran solution (THF, 100 mL) of compound B (5.8 g, 20 mmol, 1.0 eq.), and stirred for 30 min. The mixture was quenched with redistilled water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Under argon protection at room temperature, 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a 1,2-dichloroethane solution of the crude product, and the mixture was heated to reflux. Trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added, and the mixture was reacted for 30 min. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:200–1:70) to obtain a yellow oily compound C.

[0108] (3) Pd(OAc)2(40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a solution of compound C (3.7 g, 9 mmol, 1.0 eq.) in THF (36 mL) at room temperature under argon, and stirred for 10 min, then a solution of triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) in THF (36 mL) was slowly added, and the reaction was heated to reflux overnight, cooled to room temperature, quenched with saturated aqueous NaCl solution, extracted with ethyl acetate, combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:100) to give diene compound D

[0109] (4) Compound D (26 mg, 0.1 mmol, 1.0 eq.) was dissolved in HFIP (1 mL), and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C, and the reaction was heated to 50 °C and stirred for 1 h, then directly filtered and concentrated under vacuum, and added to a solution of compound E (22 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium triflate (3.1 mg, 0.005 mmol, 0.05 eq.) in toluene (PhMe, 5 mL), and the reaction was carried out at 25 °C, and when the reaction was completed according to thin layer chromatography, quenched with saturated aqueous NaHCO3 solution, and extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and purified by silica gel flash column chromatography to finally obtain the target product

[0110] Compound 7:

[0111] (c = 0.4, CH2Cl2);

[0112] R f = 0.71 (ethyl acetate / n-hexane = 1 / 4);

[0113] IR (film) λ max 3460, 2972, 2934, 2861, 1712, 1620, 1594, 1419, 1382, 1228, 1093, 898, 848 cm -1 ;

[0114] 1 H NMR (400 MHz, CDC13) δ 14.37 (s, 1H), 6.94 (s, 1H), 6.08 (s, 1H), 3.90 (m, 1H), 3.34 (d, J = 15.2 Hz, 2H), 2.00 (m, 1H), 1.75 (m, 2H), 1.64 (m, 2H), 1.63 (m, 2H), 1.59 (m, 2H), 1.43 (m, 2H), 1.39 (s, 3H), 1.37 (m, 1H), 1.27 (s, 3H), 1.27 (s, 3H), 1.18 (d, J = 3.0 Hz, 3H), 1.17 (d, J = 3.0 Hz, 3H), 1.02 (s, 3H);

[0115] 13 C NMR (100 MHz, CDC13) δ 218.2, 210.8, 165.4, 158.9, 158.1, 111.9, 103.9, 101.8, 94.4, 88.4, 54.1, 50.7, 40.1, 39.4, 37.5, 37.3, 36.2, 35.0, 29.0, 25.3, 24.9, 24.3, 24.1, 23.9, 19.5, 19.4, 19.3;

[0116] HRMS (ESI-TOF) m / z: [M+H] + calcd. for C 27 H 37 O6 + 457.2590; found: 457.2589.

[0117] Example 8

[0118] Preparation method of bridged resorcinol antibacterial compound 8 , specifically comprising the following steps:

[0119] (1) At 0°C, iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (142.0 g, 1 mol, 10.0 eq.) and compound A (25.0 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL), warmed to 64°C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1N hydrochloric acid, extracted with ethyl acetate, combined organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100 ~ 1:20) to obtain compound B

[0120] (2) Diisobutylaluminum hydride (1.5 M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a solution of compound B (6.1 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) at -78 °C and stirred for 30 min, quenched with distilled water, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product; 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a solution of the above crude product in 1,2-dichloroethane at room temperature under argon protection, heated to reflux, and trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added and reacted for 30 min, cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:200 ~ 1:70) to give compound C as a yellow oil

[0121] (3) Palladium acetate (40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a solution of compound C (3.8 g, 9 mmol, 1.0 eq.) in tetrahydrofuran (THF, 36 mL) at room temperature under argon protection and stirred for 10 min, and then a solution of triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) in tetrahydrofuran (THF, 36 mL) was slowly added, heated to reflux, and reacted overnight, cooled to room temperature, quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:100) to give diene compound D

[0122] (4) Compound D (27 mg, 0.1 mmol, 1.0 eq.) was dissolved in hexafluoroisopropanol (HFIP, 1 mL), and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C, heated to 50 °C, and stirred for 1 h, then directly filtered and concentrated in vacuo, and added to a solution of compound E (22 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium triflate (3.1 mg, 0.005 mmol, 0.05 eq.) in toluene (PhMe, 5 mL) was carried out at 25 °C, the reaction was observed to be complete by thin layer chromatography, quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by flash column chromatography on silica gel to give the target product

[0123] Compound 8:

[0124] (c = 0.4, CH2Cl2);

[0125] R f = 0.72 (ethyl acetate / n-hexane = 1 / 4);

[0126] IR (film) λ max 3403, 2980, 2931, 2863, 1702, 1627, 1604, 1464, 1429, 1237, 1096, 876, 841 cm -1 ;

[0127] 1 H NMR (400 MHz, CDCl3) δ 14.36 (s, 1H), 6.60 (s, 1H), 6.01 (s, 1H), 3.89 (m, 1H), 3.32 (m, 2H), 1.95 (m, 2H), 1.83 (m, 2H), 1.77 (m, 1H), 1.71 (m, 4H), 1.57 (m, 2H), 1.44 (m, 2H), 1.39 (s, 3H), 1.32 (m, 1H), 1.26 (s, 6H), 1.19 (d, J = 2.7 Hz, 3H), 1.17 (d, J = 2.7 Hz, 3H), 1.01 (s, 3H);

[0128] 13 C NMR (100 MHz, CDCl3) δ 218.2, 210.7, 165.4, 158.7, 158.2, 112.3, 103.8, 102.0, 94.3, 91.8, 54.2, 50.7, 42.9, 40.7, 39.4, 38.5, 37.5, 34.7, 29.4, 29.3, 29.0, 24.9, 24.1, 22.9, 22.7, 19.5, 19.5, 19.3;

[0129] HRMS (ESI-TOF) m / z: [M+H] + calcd. for C 28 H 39 O6 + 471.2747; found: 471.2733.

[0130] Example 9

[0131] Preparation method of bridged resorcinol antibacterial compound 9, specifically comprising the following steps:

[0132] (1) At 0 °C, iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (142.0 g, 1 mol, 10.0 eq.) and compound A (20.8 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL), warmed to 64 °C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1 N hydrochloric acid, extracted with ethyl acetate, combined the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100 ~ 1:20) to obtain compound B

[0133] (2) At -78 °C, diisobutylaluminum hydride (1.5 M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a solution of compound B (5.3 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) and stirred for 30 min, quenched with distilled water, extracted with ethyl acetate, combined the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated to obtain a crude product; under the condition of room temperature and argon protection, 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a solution of the above-mentioned crude product in 1,2-dichloroethane, warmed to reflux, and trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added and reacted for 30 min, then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:200 ~ 1:70) to obtain compound C as yellow oil

[0134] ​(3) Pd(OAc)2(40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a solution of compound C (3.4 g, 9 mmol, 1.0 eq.) in THF (36 mL) at room temperature under argon, and stirred for 10 min, then a solution of triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) in THF (36 mL) was slowly added, and the reaction was heated to reflux overnight, cooled to room temperature, quenched with saturated aqueous NaCl solution, extracted with ethyl acetate, combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:100) to give diene compound D

[0135] (4) Compound D (23 mg, 0.1 mmol, 1.0 eq.) was dissolved in HFIP (1 mL), and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C, and the reaction was heated to 50 °C and stirred for 1 h, then directly filtered and concentrated under vacuum, and added to a solution containing compound E (23 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium triflate (3.1 mg, 0.005 mmol, 0.05 eq.) in toluene (PhMe, 5 mL), and the reaction was carried out at 25 °C, and when the reaction was completed according to thin layer chromatography, quenched with saturated aqueous NaHCO3 solution, and extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and purified by silica gel flash column chromatography to finally obtain the target product

[0136] Compound 9:

[0137] (c = 0.4, CH2Cl2);

[0138] R f = 0.69 (ethyl acetate / n-hexane = 1 / 4);

[0139] IR (film) λ max 3441, 2980, 2943, 2872, 1700, 1608, 1431, 1353, 1247, 1162, 1077, 876, 818 cm -1 ;

[0140] 1 H NMR (400 MHz, CDC13) δ 14.26 (s, 1H), 5.98 (s, 1H), 5.75 (s, 1H), 4.16 (m, 1H), 3.33 (d, J = 3.2 Hz, 1H), 3.23 (m, 1H), 2.46 (m, 1H), 2.37 (m, 2H), 2.23 (m, 4H), 2.08 (m, 1H), 1.97 (m, 2H), 1.77 (m, 4H), 1.39 (s, 3H), 1.25 (s, 6H), 1.01 (s, 3H);

[0141] 13 C NMR (100 MHz, CDC13) δ 217.8, 206.4, 165.0, 158.9, 157.8, 112.1, 103.5, 101.6, 94.1, 86.6, 53.9, 50.8, 46.4, 37.7, 37.3, 36.9, 36.7, 34.8, 28.9, 25.1, 24.7, 24.6, 24.0, 19.1, 17.8, 12.8;

[0142] HRMS (ESI-TOF) m / z: [M + H] + calcd. for C 26 H 33 O6 + 441.2277; found: 441.2269.

[0143] Example 10

[0144] Preparation method of bridged resorcinol antibacterial compound 10 , specifically comprising the following steps:

[0145] (1) At 0 °C, iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (142.0 g, 1 mol, 10.0 eq.) and compound A (22.2 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL), warmed to 64 °C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1 N hydrochloric acid, extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100 ~ 1:20) to obtain compound B

[0146] (2) Diisobutylaluminum hydride (1.5 M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a stirred solution of compound B (5.6 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) at -78 °C for 30 min, quenched with distilled water, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product; 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a stirred solution of the above crude product in 1,2-dichloroethane at room temperature under argon protection, heated to reflux, and trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added to the solution, which was stirred at reflux for 30 min, cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / n-hexane = 1:200 to 1:70) to give compound C as a yellow oil

[0147] (3) Palladium acetate (40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a stirred solution of compound C (3.5 g, 9 mmol, 1.0 eq.) in tetrahydrofuran (THF, 36 mL) at room temperature under argon protection, and stirred for 10 min. Then, triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) in tetrahydrofuran (THF, 36 mL) were added slowly to the solution, which was heated to reflux, and stirred overnight. The solution was cooled to room temperature, quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / n-hexane = 1:100) to give diene compound D

[0148] (4) Compound D (25 mg, 0.1 mmol, 1.0 eq.) was dissolved in hexafluoroisopropanol (HFIP, 1 mL), and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C. The solution was heated to 50 °C and stirred for 1 h, then directly filtered and concentrated in vacuo. The residue was added to a solution of compound E (24 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium triflate (3.1 mg, 0.005 mmol, 0.05 eq.) in toluene (PhMe, 5 mL) was carried out at 25 °C, the reaction was observed to be complete by thin layer chromatography, quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by flash column chromatography on silica gel to give the target product

[0149] Compound 10:

[0150] (c = 0.4, CH2Cl2);

[0151] R f = 0.71 (ethyl acetate / n-hexane = 1 / 4);

[0152] IR (film) λ max 3440, 2959, 2870, 1705, 1620, 1426, 1365, 1237, 1162, 1084, 919, 836 cm -1 ;

[0153] 1 H NMR (400 MHz, CDCl3) δ 14.40 (s, 1H), 7.06 (s, 1H), 6.22 (s, 1H), 4.06 (m, 1H), 3.36 (m, 2H), 1.96 (m, 1H), 1.91 (m, 2H), 1.88 (m, 2H), 1.83 (m, 1H), 1.76 (m, 2H), 1.73 (m, 2H), 1.70 (m, 2H), 1.64 (m, 2H), 1.60 (m, 2H), 1.58 (m, 2H), 1.41 (s, 3H), 1.28 (s, 3H), 1.26 (s, 3H), 1.03 (s, 3H);

[0154] 13 C NMR (100 MHz, CDCl3) δ 218.1, 209.1, 165.2, 159.1, 157.8, 112.1, 104.4, 101.4, 95.9, 94.2, 54.0, 50.7, 50.5, 39.6, 39.6, 37.4, 37.2, 35.6, 30.3, 30.2, 29.0, 26.3, 26.3, 24.8, 24.0, 23.9, 23.5, 19.2;

[0155] HRMS (ESI-TOF) m / z: [M+H] + calcd. for C 28 H 37 O6 + 469.2590; found: 469.2588.

[0156] Example 11

[0157] Preparation of bridged resorcinol antibacterial compound 11 The preparation method specifically comprises the following steps:

[0158] (1) At 0 °C, iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (142.0 g, 1 mol, 10.0 eq.) and compound A (23.6 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL), warmed to 64 °C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1 N hydrochloric acid, extracted with ethyl acetate, combined the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100~1:20) to obtain compound B

[0159] (2) At -78 °C, diisobutylaluminum hydride (1.5 M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a solution of compound B (5.8 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) and stirred for 30 min, quenched with distilled water, extracted with ethyl acetate, combined the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated to obtain a crude product; under the condition of room temperature and argon protection, 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a solution of the above-mentioned crude product in 1,2-dichloroethane, warmed to reflux, and trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added and reacted for 30 min, then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:200~1:70) to obtain compound C as yellow oil

[0160] (3) Under the condition of room temperature and argon protection, palladium acetate (40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a tetrahydrofuran solution (THF, 36 mL) of compound C (3.7 g, 9 mmol, 1.0 eq.) respectively and stirred for 10 min, then a tetrahydrofuran solution (THF, 36 mL) of triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) was slowly added, warmed to reflux, reacted overnight, cooled to room temperature, quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, combined organic phase, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100) to obtain diene compound D

[0161] (4) Compound D (26 mg, 0.1 mmol, 1.0 eq.) was dissolved in hexafluoroisopropanol (HFIP, 1 mL), p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25°C, warmed to 50°C and stirred for 1 h, then directly filtered and concentrated under vacuum, added to a toluene solution (PhMe, 5 mL) containing compound E (26 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium trifluoromethanesulfonate (3.1 mg, 0.005 mmol, 0.05 eq.), the reaction was carried out at 25°C, quenched with saturated aqueous sodium bicarbonate solution when the reaction was completed according to thin layer chromatography, and extracted with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel flash column chromatography to finally obtain the target product

[0162] Compound 11:

[0163] (c = 0.4, CH2Cl2);

[0164] R f = 0.74 (ethyl acetate / n-hexane = 1 / 4);

[0165] IR (film) λ max 3426, 2979, 2931, 2853, 1705, 1620, 1594, 1429, 1384, 1254, 1079, 917, 818 cm -1 ;

[0166] 1 H NMR (400 MHz, CDC13) δ 14.36 (s, 1H), 6.33 (s, 1H), 5.98 (s, 1H), 3.59 (t, J = 10.8 Hz, 1H), 3.32 (m, 2H), 2.01 (m, 1H), 1.84 (m, 4H), 1.71 (m, 2H), 1.65 (m, 1H), 1.63 (m, 4H), 1.50 (m, 4H), 1.40 (s, 3H), 1.34 (m, 4H), 1.27 (s, 6H), 1.24 (m, 2H), 1.02 (s, 3H);

[0167] 13 C NMR (100 MHz, CDC13) δ 218.1, 209.7, 165.4, 158.6, 158.1, 112.0, 103.9, 102.0, 94.4, 88.2, 54.0, 50.7, 49.9, 40.1, 37.6, 37.3, 36.4, 35.0, 30.0, 29.6, 29.0, 26.4, 26.3, 26.3, 25.3, 24.9, 24.3, 24.1, 23.9, 19.3;

[0168] HRMS (ESI-TOF) m / z: [M+H] + calcd. for C 30 H 41 O6 + 497.2903; found: 497.2895.

[0169] Example 12

[0170] A method for preparing bridged resorcinol antibacterial compound 12 specifically comprises the following steps:

[0171] (1) At 0°C, iodomethane (142.0 g, 1 mol, 10.0 eq.) was added to a solution of sodium methoxide (142.0 g, 1 mol, 10.0 eq.) and compound A (25.0 g, 100 mmol, 1.0 eq.) in methanol (MeOH, 200 mL), warmed to 64°C and stirred for 8 h, cooled to room temperature, concentrated under reduced pressure, quenched with 1N hydrochloric acid, extracted with ethyl acetate, combined organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (EtOAc / n-hexane = 1:100 ~ 1:20) to obtain compound B

[0172] (2) Diisobutylaluminum hydride (1.5 M in THF, 20 mL, 30 mmol, 1.5 eq.) was added to a solution of compound B (6.1 g, 20 mmol, 1.0 eq.) in tetrahydrofuran (THF, 100 mL) at -78 °C and stirred for 30 min, quenched with distilled water, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product; 2,6-dimethylpyridine (3.2 g, 30 mmol, 1.5 eq.) was added to a solution of the above crude product in 1,2-dichloroethane at room temperature under argon protection, heated to reflux, and trifluoromethanesulfonic anhydride (8.5 g, 30 mmol, 1.5 eq.) was added and reacted for 30 min, cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:200 ~ 1:70) to give compound C as a yellow oil

[0173] (3) Palladium acetate (40 mg, 0.18 mmol, 0.02 eq.) and triphenylphosphine (94 mg, 0.36 mmol, 0.04 eq.) were added to a solution of compound C (3.8 g, 9 mmol, 1.0 eq.) in tetrahydrofuran (THF, 36 mL) at room temperature under argon protection and stirred for 10 min, and then a solution of triethylamine (2.53 mL, 18 mmol, 2.0 eq.) and formic acid (0.72 mL, 18.9 mmol, 2.1 eq.) in tetrahydrofuran (THF, 36 mL) was slowly added, heated to reflux, and reacted overnight, cooled to room temperature, quenched with saturated aqueous sodium chloride solution, extracted with ethyl acetate, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / n-hexane = 1:100) to give diene compound D

[0174] (4) Compound D (27 mg, 0.1 mmol, 1.0 eq.) was dissolved in hexafluoroisopropanol (HFIP, 1 mL), and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 1.2 eq.) was added at 25 °C, heated to 50 °C, and stirred for 1 h, then directly filtered and concentrated in vacuo, and added to a solution of compound E (28 mg, 0.11 mmol, 1.1 eq.), chiral phosphoric acid (3.3 mg, 0.005 mmol, 0.05 eq.) and ytterbium triflate (3.1 mg, 0.005 mmol, 0.05 eq.) in toluene (PhMe, 5 mL) was carried out at 25 °C, the reaction was observed to be complete by thin layer chromatography, quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by flash column chromatography on silica gel to give the target product

[0175] Compound 12:

[0176] (c = 0.4, CH2Cl2);

[0177] R f = 0.79 (ethyl acetate / n-hexane = 1 / 4);

[0178] IR (film) λ max 3408, 2980, 2931, 2858, 1702, 1625, 1601, 1426, 1387, 1235, 1084, 914, 876 cm -1 ;

[0179] 1 H NMR (400 MHz, CDCl3) δ 14.35 (s, 1H), 6.70 (s, 1H), 6.08 (s, 1H), 3.78 (m, 1H), 3.31 (m, 2H), 1.96 (m, 4H), 1.86 (m, 1H), 1.81 (m, 4H), 1.69 (m, 4H), 1.62 (m, 4H), 1.59 (m, 4H), 1.52 (m, 4H), 1.42 (m, 1H), 1.39 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H), 1.01 (s, 3H);

[0180] 13 C NMR (100 MHz, CDCl3) δ 218.2, 210.6, 165.4, 158.8, 158.0, 112.2, 103.7, 102.0, 94.3, 92.0, 54.2, 50.7, 50.4, 42.8, 40.7, 38.5, 37.5, 34.7, 31.9, 31.7, 29.4, 29.4, 29.0, 28.2* (two carbons), 27.4, 27.3, 24.9, 24.1, 22.9, 22.7, 19.3;

[0181] HRMS (ESI-TOF) m / z: [M+H] + calcd. for C 32 H 45 O6 + 525.3216; found: 525.3204.

[0182] Performance test

[0183] The broth microdilution method was used to evaluate the in vitro antibacterial activity of the synthesized natural products and intermediates.

[0184] Experimental strains: The standard strains used in this study were all from the American Type Culture Collection (ATCC), covering both Gram-positive and Gram-negative bacteria.

[0185] Gram-positive bacteria: Staphylococcus aureus S. aureus ATCC 29213 (MSSA), Staphylococcus aureus S. aureus ATCC 48900 (MRSA), Staphylococcus aureus S. aureus ATCC 49025 (MRSA), Enterococcus faecium E. faecium ATCC 50545, Enterococcus faecalis E. faecalis ATCC 50602;

[0186] Gram-negative bacteria: Pseudomonas aeruginosa Ps. aeruginosa ATCC 27853, Klebsiella pneumoniae K. peneumoniae ATCC 13883, etc.

[0187] All strains are ISO 11133 certified standard reference strains, and their antibiotic resistance characteristics are consistent with the official quality control report of ATCC.

[0188] Preparation of medium and reagent: a. Preparation of CAMHB medium: accurately weigh 22.0 g of CAMHB dry powder (error ± 0.1 g) and dissolve in 1 L of ultrapure water. After the standard wet heat sterilization process, it is divided into sterile conical bottles and sealed for storage. Preparation of sample stock solution: the positive drug vancomycin is dissolved in sterile water for injection, and the test sample is dissolved in DMSO as the solvent, and the concentration of the mother liquor is 12.8 mg / mL. All solutions are sterile filtered through a 0.22 μm filter membrane, and then divided into cryotubes and stored in a -80°C deep freezer (validity period 180 days). b. Standard strain recovery and subculture: the frozen strain is taken out from the -80°C ultra-low temperature freezer, and the recovery operation is completed in the biological safety cabinet. Using a sterile inoculation loop to dip the cryopreservation solution, streaked onto 5% sheep blood agar plates, and incubated in a 37°C constant temperature incubator for 18-24 h until single colonies formed (first generation strain). Typical colonies with uniform morphology were picked from the first generation colonies and inoculated into fresh blood agar plates for secondary culture under the same conditions to obtain the second generation strain (used for subsequent MIC detection). c. Standardization of bacterial suspension: 0.5 McFarland standard turbidity (≈1×10 8 CFU / mL) of bacterial suspension was prepared using sterile saline, and the final concentration was adjusted to 5×10 5 CFU / mL by gradient dilution method for drug sensitivity test. A single colony with uniform morphology was taken from the secondary plate, and the bacterial density was calibrated using a standard turbidity tube (0.5 McFarland). The bacterial suspension was diluted to a working concentration of 1×10 6 CFU / mL within 15 min of preparation to ensure activity. Vancomycin standard and test compound mother liquor were serially diluted with CAMHB. 100 μL of gradient drug solution and an equal volume of bacterial suspension were sequentially injected into a 96-well plate to achieve a final system of 5×10 5 CFU / mL, and the final concentration of the test sample was configured to be 128-0.125 μg / mL. At the same time, 200 μL of CAMHB medium was prepared as a blank control, and 100 μL of CAMHB medium and an equal amount of bacterial suspension were prepared as a negative control. The inoculation plate was placed in a 37°C constant temperature incubator for 18-24 h, and the special strain was adjusted according to the CLSIM07 guidelines. d. MIC endpoint interpretation: under the premise that the negative control group formed a uniform bacterial lawn (MacFarland turbidity ≥0.5) and the blank control group remained sterile, the lowest drug concentration after adding the prepared test sample was the MIC of the test sample when the bacteria in the plate were visibly inhibited without turbidity / bacterial plaque. All concentration gradients were repeated three times to ensure data reproducibility.

[0189] The results are shown in Table 1.

[0190] Antibacterial activity of compounds 1-2 (Minimum inhibitory concentration MIC: μg / mL)

[0191]

[0192] From Table 1, it can be seen that:

[0193] (1) All compounds have antibacterial activity against the tested Gram-positive bacteria (MSSA ATCC 29213, MRSA ATCC 48900, MRSA ATCC 49025, Enterococcus faecalis ATCC 50602, Enterococcus faecium ATCC 50545) with MIC ranging from 2 to 32 μg / mL.

[0194] (2) No activity was detected (MIC > 128 μg / mL) against Gram-negative bacteria (Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumoniae ATCC 13883) at the upper limit of the test (128 μg / mL), suggesting that the antibacterial spectrum is limited to Gram-positive bacteria.

[0195] (3) For the three strains of Staphylococcus aureus (MRSA ATCC 48900, MRSA ATCC 49025, MSSA ATCC 29213), the MIC of all compounds is ≤ 8 μg / mL, reaching the same order of magnitude as the CLSI for vancomycin-sensitive strains (MIC ≤ 2 μg / mL), but has not yet reached the clinical breakpoint, and is highly active in vitro.

[0196] (4) Compound 12 has a MIC of 2-4 μg / mL against MRSA, and also has a MIC of 2-4 μg / mL against Enterococcus faecium and Enterococcus faecalis, and the activity is significantly better than that of the remaining intermediates, and is closest to the upper limit of the quality control of vancomycin against MRSA (≤ 2 μg / mL), and can be used as the preferred lead compound for subsequent structure optimization and in vivo efficacy evaluation.

[0197] The above description of disclosed embodiments enables one of ordinary skill in the art to make or use the application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein can be applied to other embodiments without departing from the spirit or scope of the application. Thus, the present application is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A bridged-ring phloroglucinol-based antibacterial compound, characterized in that, The general structural formula is Among them, R 1 Selected from methyl or unsubstituted C1-C3 alkyl groups; R 2 Selected from isopropyl or unsubstituted C4-C7 cycloalkyl; n is selected from 1, 2, 3 or 4.

2. The bridged-ring phloroglucinol antibacterial compound according to claim 1, characterized in that, The structural formula is 3. A method for preparing the bridged-ring phloroglucinol antibacterial compound as described in claim 1, characterized in that, Specifically, the following steps are included: (1) Iodomethane was added to sodium methoxide and compound A at 0°C. In a methanol solution, the mixture was heated to 64°C and stirred for 8 hours, then cooled to room temperature, concentrated under reduced pressure, quenched with hydrochloric acid, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound B. (2) At -78℃, diisobutylaluminum hydride was added to a tetrahydrofuran solution of compound B and stirred for 30 min. The mixture was then quenched with redistilled water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Under ambient temperature and argon protection, 2,6-dimethylpyridine was added to a 1,2-dichloroethane solution of the above crude product, heated to reflux, and reacted with trifluoromethanesulfonic anhydride for 30 min. The mixture was then cooled to ambient temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow oily compound C. (3) Under ambient temperature and argon protection, palladium acetate and triphenylphosphine were added separately to a tetrahydrofuran solution of compound C and stirred for 10 min. Then, a tetrahydrofuran solution of triethylamine and formic acid was slowly added, the mixture was heated to reflux, and the reaction was allowed to proceed overnight. The mixture was then cooled to ambient temperature, quenched with saturated sodium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain diene compound D. (4) Compound D was dissolved in hexafluoroisopropanol, p-toluenesulfonic acid was added at 25°C, the temperature was raised to 50°C and stirred continuously for 1 hour, then directly filtered and concentrated under vacuum, and added to a solution containing compound E. The reaction was carried out in a toluene solution of chiral phosphoric acid and ytterbium trifluoromethanesulfonate at 25°C. When the reaction was observed to be complete by thin-layer chromatography, it was quenched with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to finally obtain the target product.

4. The method for preparing a bridged-ring phloroglucinol antibacterial compound according to claim 3, characterized in that, In step (1), the molar ratio of iodomethane, sodium methoxide and compound A is 10:8:1; the concentration of the methanol solution is 0.5M; the concentration of the hydrochloric acid is 1N; and the conditions for the silica gel column chromatography are EtOAc / n-hexane = 1:100 to 1:

20.

5. The method for preparing a bridged-ring phloroglucinol antibacterial compound according to claim 3, characterized in that, In step (2), the molar ratio of diisobutylaluminum hydride, compound B, 2,6-dimethylpyridine and trifluoromethanesulfonic anhydride is 1.5:1:1.5:1.5; the concentration of the tetrahydrofuran solution is 0.2M; and the conditions for the silica gel column chromatography are EtOAc / n-hexane = 1:200 to 1:

70.

6. The method for preparing a bridged-ring phloroglucinol antibacterial compound according to claim 3, characterized in that, In step (3), the molar ratio of palladium acetate, triphenylphosphine, triethylamine and formic acid is 0.02:0.04:2:2.1; the concentration of the tetrahydrofuran solution is 0.13M; and the conditions for silica gel column chromatography are EtOAc / n-hexane = 1:

100.

7. The method for preparing a bridged-ring phloroglucinol antibacterial compound according to claim 3, characterized in that, In step (4), the molar ratio of compound D, hexafluoroisopropanol, p-toluenesulfonic acid, compound E, chiral phosphoric acid and ytterbium trifluoromethanesulfonate is 1:0.1:1.2:1.1:0.05:0.05; and the concentration of the toluene solution is 0.02M.

8. The use of a bridged-ring phloroglucinol antibacterial compound as described in claim 1 or 2, or a bridged-ring phloroglucinol antibacterial compound prepared by any one of claims 3-7, in the preparation of a medicament for treating infectious diseases caused by Gram-positive bacteria.

Images