Preparation method of quinazoline [3, 2-a] [1, 4]-benzodiazepine natural product

Abstract

The invention relates to a preparation method of a quinazoline [3, 2-a] [1, 4]-benzodiazepine natural product. Aiming at the defects of an existing synthesis strategy and an existing synthesis route, on the basis of a large number of experiments, a carbonylation synthesis strategy and a novel synthesis route are innovatively adopted, the novel preparation method of the novel, simple and reliable quinazoline [3, 2-a] [1, 4]-benzodiazepine compound is developed, and through adjustment of reagents used in related reactions, the yield of the quinazoline [3, 2-a] [1, 4]-benzodiazepine compound is increased, and the yield of the quinazoline [3, 2-a] [1, 4]-benzodiazepine compound is increased. A series of quinazoline [3, 2-a] [1, 4]-benzodiazepine alkaloids can be more conveniently synthesized, so that the structure-function relationship or related biological research of the quinazoline [3, 2-a] [1, 4]-benzodiazepine alkaloids is facilitated.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical synthesis, and particularly relates to a preparation method of quinazoline [3,2-a] [1,4]-benzodiazepine natural products. BACKGROUND

[0002] Quinazolinone is a nitrogen-rich heterocycle, and is a common structural unit of natural products. One type of natural products has quinazoline [3,2-a] [1,4]-benzodiazepine as a core skeleton, presents diversity in molecular structure (as shown in Figure 1 ), and has various important biological activities, such as antiviral (HCV), anti-AD, inhibition of indoleamine 2,3-dioxygenase (IDO) or phospholipase-1B, and has further pharmaceutical development value.

[0003] Therefore, the synthesis of these quinazoline [3,2-a] [1,4]-benzodiazepine alkaloids has also attracted widespread attention, and the key synthesis strategies are as shown in Figure 2 For example, strategy 1: the quinazoline [3,2-a] [1,4]-benzodiazepine skeleton is constructed by reduction and cyclization of 2-nitrobenzamide; strategy 2: a tripeptide containing methyl anthranilate is subjected to microwave reaction, and under the catalysis of scandium triflate, intramolecular cyclization is first carried out to construct a quinazolinone ring, and then intramolecular amide exchange reaction is continuously carried out to finally construct a quinazoline [3,2-a] [1,4]-benzodiazepine skeleton; strategy 3: an o-iodobenzamide precursor is reacted with benzo[D][1,3]oxazin-2,4(1H)-dione in the presence of iron chloride to construct a quinazolinone skeleton, and then intramolecular coupling reaction is carried out by Buchwald-Hartwig to construct a benzodiazepine skeleton; strategy 4: a quinazolinone compound with a terminal carboxyl group is subjected to oxidative or light-induced decarboxylation to generate a free radical, and then cyclization is carried out to construct the heterocycle. Although these methods have achieved good application effects in the synthesis of quinazoline [3,2-a] [1,4]-benzodiazepine alkaloids, these methods still have some shortcomings, including harsh reaction conditions, long reaction time, sometimes difficult preparation of substrates, and low total reaction yield.

[0004] Therefore, the present application provides a brand-new synthesis strategy and approach, which can conveniently realize the preparation of quinazoline [3,2-a] [1,4]-benzodiazepine compounds. SUMMARY

[0005] To solve the above technical problems, the application provides a preparation method of quinazoline [3,2-a] [1,4]-benzodiazepine natural products. Based on a large number of experiments, the synthesis strategy and novel synthesis route of carbonylation are used to develop a novel, simple and reliable preparation method of quinazoline [3,2-a] [1,4]-benzodiazepine compounds. By adjusting the reagents used in the reaction, a series of quinazoline [3,2-a] [1,4]-benzodiazepine alkaloids can be synthesized more conveniently, thereby facilitating the structure-activity relationship or related biological research.

[0006] The object of the application can be achieved by the following scheme: In a first aspect, the application provides a preparation method of quinazoline [3,2-a] [1,4]-benzodiazepine natural products, comprising the following steps: S1, under the condition of an ice water bath, mixing compound 1 with compound 2-Fmoc to obtain compound 3-Fmoc through condensation reaction ; S2, deprotecting the amino group of compound 3-Fmoc to obtain compound 4 ; S3, mixing compound 4 with compound 3 to perform amide reaction and obtain compound 5 ; S4, performing nitro reduction reaction on compound 5 to obtain compound 6 ; S5, introducing CO gas, mixing compound 6 with a base, and performing carbonylation reaction under the catalysis of a catalyst; after the reaction is completed, an acid is added to obtain the quinazoline [3,2-a] [1,4]-benzodiazepine natural product ; the catalyst is a combination of palladium acetate and phosphine ligand with a molar ratio of 1:1-4; the catalyst is selected from one or more of Pd(OAc)2 / PPh3, Pd(OAc)2 / Dppf, Pd(OAc)2 / CyJohnPhos, Pd(OAc)2 / XantPhos, Pd(OAc)2 / JohnPhos, Pd(OAc)2 / tBuXPhos, Pd(OAc)2 / XPhos, Pd(OAc)2 / RuPhos, Pd(OAc)2 / BrettPhos and Pd(OAc)2 / BINAP; wherein R 1 and R 4is one of H, C1-C7 alkyl, benzyl, C1-C7 alkoxy; R 2 is one of H, C1-C7 alkyl, benzyl, C1-C7 alkyl substituted with indole; R 3 is one of H, C1-C7 alkyl, benzyl; R 2 and R 3 A fatty ring can be formed.

[0007] The preparation method of the present application is carried out according to the following synthetic route:

[0008] Specifically, o-iodoaniline (compound 1) substituted with R 1 and Fmoc-protected amino acid (compound 2-Fmoc) in R- or S- configuration are used as starting materials, compound 3-Fmoc is prepared by condensation reaction in the first step, the amino group of compound 3-Fmoc is deprotected to prepare compound 4 in the second step, compound 5 is prepared by amidation reaction with o-nitrobenzoyl chloride (compound 3) substituted with R 4 in the third step, the nitro group of compound 5 is converted into compound 6 containing a free amino group by nitro reduction reaction in the fourth step, and quinazoline [3,2-a] [1,4]-benzodiazepine compound is prepared from 6 by “one-pot method” in the fifth step.

[0009] In the fifth step, compound 6 is used as raw material, carbonylation reaction occurs under the action of a suitable base in the presence of a suitable catalyst and CO atmosphere in a suitable solvent at a suitable temperature for a suitable reaction time to prepare the key intermediate; wherein the CO atmosphere refers to the filling of CO gas in the reaction system, and the gas pressure in the reaction system is 1-6 atm; the catalyst refers to the combination of Pd(OAc)2 / PPh3, Pd(OAc)2 / Dppf, Pd(OAc)2 / CyJohnPhos, Pd(OAc)2 / XantPhos, Pd(OAc)2 / JohnPhos, Pd(OAc)2 / tBuXPhos, Pd(OAc)2 / XPhos, Pd(OAc)2 / RuPhos, Pd(OAc)2 / BrettPhos or Pd(OAc)2 / BINAP, wherein the molar ratio of Pd(OAc)2 to the above phosphine ligand is 1 / 1-4, and the molar amount of the combination of Pd(OAc)2 and the above phosphine ligand is 1-20% of compound 6; the solvent is selected from methanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, acetonitrile or a combination thereof; the temperature is 0-80 ℃; the suitable base is DMAP, Et3N or DIPEA; and the reaction time is 1-12 hours.

[0010] Subsequently, the freshly prepared key intermediate reaction solution is directly added with a suitable acid, at a suitable temperature, for a suitable reaction time, to prepare quinazoline [3, 2-a] [1, 4]-benzodiazepine compounds by one-pot method; the acid is formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid or camphorsulfonic acid; the temperature is 0-80 ℃; and the reaction time is 1-24 hours.

[0011] As an embodiment of the present application, the compound 1 , wherein R 1 is one of H, C1-C4 alkyl, benzyl, C1-C4 alkoxy.

[0012] Further, the compound 1 is selected from one of the following structural compounds: , .

[0013] As an embodiment of the present application, the compound 2-Fmoc , wherein R 2 is one of H, C1-C4 alkyl, benzyl, C1-C4 alkyl substituted with indole; R 3 is one of H, C1-C4 alkyl, benzyl; R 2 and R 3 may form an aliphatic ring.

[0014] Further, the compound 2-Fmoc is selected from one of the following structural compounds: , , , .

[0015] Further, the compound 3-Fmoc is selected from one of the following structural compounds: , , , .

[0016] Further, the compound 4 is selected from one of the following structural compounds: , , , .

[0017] As an embodiment of the present application, the compound 3 , wherein R 4 is one of H, C1-C4 alkyl, benzyl, C1-C4 alkoxy.

[0018] Further, the compound 3 is selected from one of the following structural compounds: , .

[0019] Further, the compound 5 is selected from one of the following structural compounds: , , , , .

[0020] Further, the compound 6 is selected from one of the following structural compounds: , , , , .

[0021] As an embodiment of the present application, the configuration general formula of the quinazoline [3, 2-a] [1, 4]-benzodiazepine natural product is as shown in formula I: ; wherein, * represents R- or S- configuration.

[0022] Further, the quinazoline [3, 2-a] [1, 4]-benzodiazepine natural product is selected from one of the following structural compounds: .

[0023] As an embodiment of the present application, the specific steps of step S1 include: after dissolving compound 1 under ice water bath condition, adding triphosgene and 2, 4, 6-trimethylpyridine and stirring, then adding compound 2-Fmoc and mixing, and then performing condensation reaction to obtain compound 3-Fmoc. The condensation reaction temperature is 18-30℃, and the time is 8-10 h.

[0024] As an embodiment of the present application, the specific steps of step S2 include: after dissolving compound 3-Fmoc, adding diethylamine to deprotect the amino group of compound 3-Fmoc to obtain compound 4. The deprotection reaction temperature is 18-30℃, and the time is 20-35 min.

[0025] As an embodiment of the present application, the specific steps of step S3 include: under argon protection, first dissolving compound 3 to form compound 3 solution, then dissolving compound 4, adding triethylamine, and mixing with compound 3 solution to perform amidation reaction to obtain compound 5. The temperature of the amidation reaction is 18-30 DEG C, and the time is 4-8 h.

[0026] As an embodiment of the present application, the specific steps of step S4 include: under argon protection, dissolving compound 5 after mixing with tetrahydroxy diboron, adding 4,4'-dipyridine to perform nitro reduction reaction to obtain compound 6. The temperature of the nitro reduction reaction is 18-30 DEG C, and the time is 20-35 min.

[0027] As an embodiment of the present application, the specific steps of step S5 include: under argon protection, passing CO gas, mixing and dissolving compound 6 with a catalyst, and adding a base to perform carbonylation reaction; after the reaction is completed, an acid is further added to obtain quinazoline [3,2-a] [1,4]- benzodiazepine natural product; the solvent used for the dissolving is selected from one or more of methanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, acetonitrile; The pressure of the CO gas is 1-6 atm; The molar amount of the catalyst is 1-20% of compound 6; The base is selected from one or more of DMAP, Et3N, DIPEA; and the acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid; The temperature of the carbonylation reaction is 0-80 DEG C, and the time is 1-24 h.

[0028] Compared with the prior art, the present application has the following beneficial effects: The preparation method has the following advantages: 1. novel and simple synthesis route; 2. mild reaction conditions; 3. conventional and readily available reaction reagents; 4. stable reaction intermediates; 5. the key synthesis step (the fifth step) is a "one-pot" reaction, which is simple to operate. Therefore, the present application not only has obvious innovation and novelty, but also provides important technical support for the development of new drugs of quinazoline [3,2-a] [1,4]- benzodiazepine alkaloids, and has great application value. BRIEF DESCRIPTION OF DRAWINGS

[0029] Other features, objects and advantages of the present application will become more apparent from the following detailed description of non-limiting embodiments, with reference to the following drawings: Figure 1 The molecular structure of the quinazoline [3,2-a] [1,4]- benzodiazepine natural product; Figure 2 The synthesis strategy of the known quinazoline [3,2-a] [1,4]- benzodiazepine compound; Figure 3 The key synthetic strategy and synthetic route of the present application. DETAILED DESCRIPTION

[0030] The present application will be described in detail below with reference to the accompanying drawings and specific examples. The following examples are implemented on the premise of the technical solutions of the present application, and the detailed implementation and specific operation process are provided, which will help those skilled in the art to further understand the present application. It should be pointed out that the protection scope of the present application is not limited to the following examples, and several adjustments and improvements made on the premise of the concept of the present application also belong to the protection scope of the present application.

[0031] The present application improves a preparation method of a quinazoline [3, 2-a] [1, 4]- benzodiazepine natural product, and the synthetic strategy and synthetic route thereof are as shown in Figure 3

[0032] Example 1 Synthesis of Sclerotigenin Step 1: Preparation of compound 3a-Fmoc

[0033] In a clean and dry single-mouth 250 mL tomato-shaped reaction bottle filled with argon protection, a magnetic stirrer was placed, Fmoc-glycine (1.34 g, 4.50 mmol, 1.0 eq.) was added, then 50 mL of anhydrous tetrahydrofuran was added to dissolve the solid, and the reaction bottle was placed in an ice water bath for stirring. After adding triphosgene (0.445 g, 1.50 mmol, 0.33 eq.) to the reaction bottle, 2, 4, 6-trimethylpyridine (1.20 mL, 9.00 mmol, 2.0 eq.) was slowly added dropwise. After stirring for 10 min under the condition of ice water bath, o-iodoaniline (0.986 g, 4.50 mmol, 1.0 eq.) was added, and then the reaction was carried out at room temperature for 9 hours. After the reaction was completed, the reaction solution was rotary evaporated, dissolved in dichloromethane, and then saturated ammonium chloride solution (100 mL) was added to quench the reaction, extracted with dichloromethane (150 mL x 3), the organic phase was combined, washed with water (300 mL) and saturated NaCl solution (300 mL), dried over anhydrous sodium sulfate, then concentrated by suction filtration, and the crude product was purified by column chromatography with dichloromethane / ethyl acetate (DCM / EA=30 / 1) as the eluent to obtain white powder solid 3a-Fmoc (1.77 g, 79%).

[0034] TLC: R f = 0.19 (DCM / EA=30 / 1). 1 ​H NMR (400 MHz, DMSO-) d 6) δ 9.26 (s, 1H, N H ), 7.91-7.85 (m, 3H, Ar H ),7.77 (brs, 1H, N H ), 7.73 (m, 2H, Ar H ), 7.59 (d, J = 8.1 Hz, 1H, Ar H ), 7.44-7.31(m, 5H, Ar H ), 6.97 (m, 1H, Ar H ), 4.34 (d, J = 6.9 Hz, 2H, OC H 2CH), 4.26 (d, J =6.9 Hz, 1H, OCH2C H ), 3.83 (d, J = 6.1 Hz, 2H, C H 2NH). 13 C NMR (150 MHz, DMSO-) d 6) δ 168.6, 157.1, 144.31, 141.2, 139.4, 139.3,129.3, 128.1, 127.8, 127.6, 125.7, 121.9, 120.6, 79.4, 66.3, 47.1, 44.6. HRMS(ESI): calculated for C 24 H 21 IN2NaO3 + [M+Na] + : 521.0333, found:521.0328. Step 2: Preparation of compound 4a

[0035] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and 3a-Fmoc (1.49 g, 3.00 mmol, 1.0 eq.) was added and dissolved in anhydrous acetonitrile (40 mL). Then, diethylamine (20 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, some of the solvent was removed by rotary evaporation, the reaction was quenched with saturated ammonium chloride (50 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with water (150 mL), then with saturated NaCl solution (100 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography using ethyl acetate / dichloromethane (EA / DCM = 4 / 1) as the eluent, yielding a pale yellow oil, 4a (0.737 g, 89%).

[0036] TLC: R f = 0.25 (EA / DCM=4 / 1). 1 H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H, CON H Ph), 8.34 (d, J = 8.2 Hz, 1H,Ar H ), 7.78 (d, J = 8.0 Hz, 1H, Ar H ), 7.34 (m, 1H, Ar H ), 6.83 (m, 1H, Ar H ), 3.52(s, 2H, NH2C H 2), 1.74 (brs, 2H, N H 2CH2). ESI-MS m / z ): calculated for C8H 10 IN2O + [M+H] + : 276.98, found: 276.93. Step 3: Preparation of compound 5a

[0037] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and o-nitrobenzoic acid (0.718 g, 4.3 mmol, 1.2 eq.) was added, followed by 7 mL of thionyl chloride. The mixture was reacted in an oil bath at 50 °C for 30 min, and the remaining thionyl chloride was removed by vacuum distillation. The solution was then dissolved in 10 mL of dichloromethane and set aside for later use. In another reaction flask, 4a (0.995 g, 3.6 mmol, 1.0 eq.) was added, followed by 30 mL of dichloromethane to dissolve the solid. Triethylamine (1.0 mL, 7.2 mmol, 2.0 eq.) was then added, followed by the previously prepared dichloromethane solution. The mixture was reacted at room temperature for 6 hours. The reaction was quenched by adding saturated ammonium chloride solution (50 mL), and extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed with water (200 mL), washed with saturated NaCl solution (200 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with dichloromethane / ethyl acetate (DCM / EA = 2 / 1) as the eluent to give a yellow powder solid 5a (1.15 g, 75%).

[0038] TLC: R f = 0.20 (DCM / EA=2 / 1). 1 H NMR (400 MHz, DMSO-) d 6) δ 9.43 (s, 1H, CON H Ar), 9.14 (brs, 1H,CH2N H CO), 8.05 (d, J = 8.1 Hz, 1H, Ar H ), 7.90 (d, J = 7.9 Hz, 1H, Ar H ), 7.82(m, 1H, Ar H ), 7.75-7.69 (m, 2H, Ar H ), 7.56 (d, J = 8.1 Hz, 1H, Ar H ), 7.40 (m, 1H, Ar H ), 6.99 (m, 1H, Ar H ), 4.10 (d, J = 5.9 Hz, 2H,C H 2NH). 13 C NMR (150 MHz, DMSO-) d6) δ 168.0, 166.5, 147.6, 139.5, 134.1, 132.3,131.5, 130.3 129.8, 129.2, 128.0, 126.9, 124.6, 96.0, 43.5. HRMS(ESI): calculated for C 15 H 12 IN3O4Na + [M+Na] + : 477.9765, found:477.9762. Step 4: Preparation of compound 6a

[0039] In a clean, dry, single-necked 50 mL eggplant-shaped reaction flask under argon protection, a magnetic stirrer was placed, and 5a (0.425 g, 1.00 mmol, 1.0 eq.) and tetrahydroxydiboron (0.268 g, 3.00 mmol, 3.0 eq.) were added. After dissolving the solid in 10 mL of anhydrous DMF, 4,4′-bipyridine (0.008 g, 0.05 mmol, 0.05 eq.) was added to the reaction solution, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, 100 mL of ethyl acetate was added to dilute the reaction solution, and the organic phase was washed with saturated NaCl solution (30 mL × 3), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography using petroleum ether / ethyl acetate (PE / EA = 4 / 1) as the eluent to obtain a white powder solid 6a (0.292 g, 74%).

[0040] TLC: R f = 0.15 (PE / EA=3 / 1). 1 H NMR (400 MHz, DMSO-) d 6) δ9.33 (s, 1H, ArN H CO), 8.65 (brs, 1H, CH2N) H CO), 7.87 (d, J = 7.9 Hz, 1H, Ar H ), 7.66-7.57 (m, 2H, Ar H ), 7.39 (m, 1H,Ar H ), 7.20-7.12 (m, 1H, Ar H ), 6.96 (m, 1H, ArH ), 6.71 (d, J = 8.3 Hz, 1H, Ar H ),6.56 -6.51 (m, 1H, Ar H ), 6.47 (s, 2H, ArN H 2), 4.04 (d, J = 5.8 Hz, 2H, C H 2NH). 13 C NMR (150 MHz, DMSO-) d 6) δ 168.8, 167.7, 149.2, 138.4, 131.4, 128.2,127.7, 126.6, 125.0, 115.8, 114.0, 113.2, 94.0, 42.5. HRMS(ESI): calculated for C 15 H 14 IN3O2Na + [M+Na] + : 418.0023, found:418.0020. Step 5: Synthesis of Sclerotigenin

[0041] In a clean, dry 50 mL two-necked reaction flask under argon protection, a magnetic stirrer was placed inside. 6a (0.198 g, 0.50 mmol, 1.0 eq.), palladium acetate (0.011 g, 0.05 mmol, 0.10 eq.), and XantPhos (0.058 g, 0.10 mmol, 0.20 eq.) were added, followed by 5 mL of anhydrous dichloromethane to dissolve the solid. Finally, triethylamine (0.20 mL, 1.25 mmol, 2.50 eq.) was added. A carbon monoxide balloon was prepared using a three-way valve and connected to the reaction flask. The gas in the reaction flask was replaced with carbon monoxide gas using a pump. After three replacements, the reaction flask was placed in an oil bath at 40°C and stirred. After 2 h of reaction, trifluoroacetic acid (0.5 mL, TFA / DCM = 10 / 100) was added dropwise to the reaction flask. After the reaction was completed, 10 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane (15 mL × 3), and the organic phases were combined. The organic phases were washed with water (50 mL) and saturated NaCl solution (50 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with petroleum ether / ethyl acetate (PE / EA = 1 / 3) as the eluent to obtain a white powder solid (0.067 g, 48%).

[0042] TLC: R f = 0.29 (PE / EA=1 / 4). 1 H NMR (400 MHz, DMSO-) d 6) δ 8.97 (t, J = 6.0 Hz, 1H, N H ),8.19 (d, J = 9.5Hz, 1H, Ar H ), 7.93-7.88 (m, 1H, Ar) H ),7.79 (d, J = 7.2 Hz, 1H, Ar H ), 7.72 (d, J =7.6 Hz, 1H, Ar H ), 7.67-7.56 (m, 4H, Ar H ), 4.18 (dd, J = 15.1, 5.2 Hz, 1H,C H 2NH), 4.00 (dd, J = 15.1, 6.8 Hz, 1H, C H2NH). ESI-MS m / z ): calculated for C 16 H 12 N3O2 + [M+H] + : 278.1, found: 278.2. Example 2: Synthesis of Asperlicin C Step 1: Preparation of compound 3b-Fmoc

[0043] In a clean, dry, single-necked 250 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and L-Fmoc-tryptophan (3.84 g, 9.00 mmol, 1.0 eq.) was added. Then, 90 mL of anhydrous tetrahydrofuran was added to dissolve the solid, and the flask was placed in an ice-water bath with stirring. Triphosgene (1.07 g, 3.60 mmol, 0.5 eq.) was added to the reaction flask, followed by the slow dropwise addition of 2,4,6-trimethylpyridine (2.40 mL, 18.00 mmol, 2.0 eq.). After stirring for 10 min in an ice-water bath, o-iodoaniline (1.97 g, 9.00 mmol, 1.0 eq.) was added to the solution, and the reaction was then allowed to proceed at room temperature for 9 hours. After the reaction was completed, the reaction solution was evaporated to dryness, dissolved in dichloromethane, and then quenched with saturated ammonium chloride solution (150 mL). The solution was extracted with dichloromethane (150 mL × 3), and the organic phases were combined. The organic phases were washed with water (300 mL) and saturated NaCl solution (300 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with dichloromethane / petroleum ether (DCM / PE = 15 / 1) as the eluent to obtain a white powder solid 3b-Fmoc (4.83 g, 86%).

[0044] TLC: R f = 0.48 (DCM). = -43.0 (c=0.20, MeOH) 1 H NMR (400 MHz, CDCl3) δ8.22 (d, J = 8.2 Hz, 1H, Ar H ), 8.11 (brs, 1H,ArN H CH), 7.89 (brs, 1H, ArN HCO), 7.78-7.64 (m, 4H, Ar H ), 7.57-7.51 (m, 2H,Ar H ), 7.41-7.27 (m, 6H, Ar H ), 7.24 – 7.19 (m, 1H, Ar H ), 7.13 (m, 1H, Ar H ),7.05 (s, 1H, CHN H CO), 6.82 (m, 1H, Ar H ), 5.52 (s, 1H, CC H NH), 4.75 (s, 1H, COC) H NH), 4.49-4.41 (m, 2H, OC H 2CH), 4.21 (t, J = 6.8 Hz, 1H, OCH2C H ),3.66 (m,1H, CHC H 2C), 3.32 (m, 1H, CHC H 2C). ESI-MS m / z ): calculated for C 32 H 27 IN3O3 + [M+H] + : 628.1, found: 628.3. 6.6 Hz, 3H). Step 2: Preparation of compound 4b

[0045] In a clean, dry, single-necked 250 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and 3b-Fmoc (4.83 g, 7.70 mmol, 1.0 eq.) was added and dissolved in anhydrous acetonitrile (80 mL). Then, diethylamine (40 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, some of the solvent was removed by rotary evaporation, the reaction was quenched with saturated ammonium chloride (100 mL), and extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with water (300 mL), then with saturated NaCl solution (300 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (EA / PE = 1 / 2) as the eluent to give a pale yellow oil, 4b (2.52 g, 81%).

[0046] TLC: R f = 0.20 (EA / PE=1 / 2). = -39.2 (c=0.30, MeOH) 1 H NMR (400 MHz, CDCl3) δ 9.99 (brs, 1H, CHN H Ar), 8.43-8.37 (m, 2H,Ar H ), 7.79 (d, J = 7.9 Hz, 1H, Ar H ), 7.71 (d, J = 7.9 Hz, 1H, Ar H ), 7.40-7.34 (m,2H, Ar H ), 7.22 (m, 1H, CC H NH), 7.14 (m, 1H, Ar H ), 7.07 (brs, 1H, ArN H CO), 6.85 (m, 1H, Ar) H ), 3.89 (dd, J = 9.3, 3.9 Hz, 1H,C H NH2), 3.51 (dd, J = 14.5, 3.9Hz, 1H, CHC H 2C), 3.04 (dd, J = 14.5, 9.2 Hz, 1H, CHC H 2C). ESI-MS m / z ): calculated for C 17 H 17 IN3O + [M+H] + : 406.0, found: 406.1. Step 3: Preparation of compound 5b

[0047] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and o-nitrobenzoic acid (1.24 g, 7.4 mmol, 1.2 eq.) was added, followed by 10 mL of thionyl chloride. The mixture was reacted in an oil bath at 50 °C for 30 min, and the remaining thionyl chloride was removed by vacuum distillation. The crude o-nitrobenzoyl chloride was dissolved in 10 mL of dichloromethane and set aside for later use. In another reaction flask, 4b (2.52 g, 6.2 mmol, 1.0 eq.) was added, followed by 40 mL of dichloromethane to dissolve the solid. Triethylamine (1.7 mL, 12.4 mmol, 2.0 eq.) was then added, followed by the previously prepared dichloromethane solution of o-nitrobenzoyl chloride. The reaction was carried out at room temperature for 6 hours. The reaction was quenched by adding saturated ammonium chloride solution (60 mL), and extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed with water (200 mL), washed with saturated NaCl solution (200 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with dichloromethane / petroleum ether (DCM / PE = 50 / 1) as the eluent to give a yellow powder solid 5b (1.75 g, 51%).

[0048] TLC: R f = 0.27 (DCM). = -35.3 (c=0.10, MeOH) 1 H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H, CHN H Ar), 8.06 (m, 2H, ArN H CO,Ar H ), 7.78 (d, J = 7.9 Hz, 1H, Ar H ), 7.71-7.66 (m, 2H, Ar H ), 7.63-7.53 (m, 2H,Ar H ), 7.43 (d, J = 7.4 Hz, 1H, Ar H ), 7.36-7.27 (m, 2H, Ar H ), 7.20-7.15 (m, 1H,Ar H ), 7.13-7.06 (m, 2H, Ar H ), 6.88-6.79 (m, 2H, CC H NH, Ar H), 5.23 (m, 1H, COC H NH), 3.65 (dd, J = 14.7, 5.1 Hz, 1H, CHC H 2C), 3.37 (dd, J = 14.6, 8.2 Hz, 1H, CHC H 2C). ESI-MS m / z ): calculated for C 24 H 20 IN4O4 + [M+H] + : 555.1, found: 555.0. Step 4: Preparation of compound 6b

[0049] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed inside. 5b (1.11 g, 2.00 mmol, 1.0 eq.) and tetrahydroxydiboron (0.538 g, 600 mmol, 3.0 eq.) were added. After dissolving the solid in 12 mL of anhydrous DMF, 4,4′-bipyridine (0.016 g, 0.10 mmol, 0.05 eq.) was added to the reaction solution, and the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, 150 mL of ethyl acetate was added to dilute the reaction solution. The organic phase was washed with saturated NaCl solution (50 mL × 3), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography using ethyl acetate / dichloromethane (EA / DCM = 1 / 50) as the eluent, yielding a yellow powder solid 6b (0.828 g, 79%).

[0050] TLC: R f = 0.21 (EA / DCM=1 / 40). = -39.3 (c=0.20, MeOH) 1 H NMR (400 MHz, CDCl3) δ 8.25-8.17 (m, 2H, Ar H ArN H ), 7.97 (brs, 1H,CHN H CO), 7.77 (d, J = 7.9 Hz, 1H, Ar H ), 7.67 (d,J = 6.4 Hz, 1H, Ar H ), 7.39-7.30(m, 2H, Ar H ), 7.23-7.09 (m, 5H, Ar H ), 6.86-6.78 (m, 2H, Ar H CC H NH), 6.68-6.64 (m, 1H, Ar H ), 6.58-6.52 (m, 1H, Ar H ), 5.13 (td, J = 7.2, 5.5 Hz, 1H,C H CH2), 3.59 (dd, J = 14.7, 5.5 Hz, 1H, CHC H 2), 3.38 (dd, J = 14.6, 7.2 Hz, 1H, CHC H 2). 13 C NMR(150 MHz, CDCl3) δ 168.9, 168.3, 148.2, 137.8, 136.8, 135.4,131.9, 128.1, 126.5, 125.1, 122.2, 121.5, 120.8, 119.1, 117.8, 116.4, 115.5,113.4, 110.5, 109.2, 88.8, 53.8, 26.9. HRMS(ESI): calculated for C 24 H 22 IN4O2 + [M+H] + : 525.0782, found: 525.0784. Step 5: Synthesis of Asperlicin C

[0051] In a clean, dry 100 mL two-necked reaction flask under argon protection, a magnetic stirrer was placed, and 6b (0.451 g, 0.90 mmol, 1.0 eq.), palladium acetate (0.020 g, 0.09 mmol, 0.10 eq.), and XantPhos (0.104 g, 0.18 mmol, 0.20 eq.) were added. Then, 10 mL of anhydrous dichloromethane was added to dissolve the solid, and finally, triethylamine (0.31 mL, 2.25 mmol, 2.50 eq.) was added. A carbon monoxide balloon was prepared using a three-way valve and connected to the reaction flask. The gas in the reaction flask was replaced with carbon monoxide gas using a pump. After three replacements, the reaction flask was placed in an oil bath at 40 °C and stirred. After 2 h of reaction, trifluoroacetic acid (1.0 mL, TFA / DCM = 10 / 100) was added dropwise to the reaction flask. After the reaction was completed, 25 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane (25 mL × 3). The organic phases were combined and washed with 100 mL of water and 100 mL of saturated NaCl solution. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated. The crude product was purified by column chromatography with dichloromethane / ethyl acetate (DCM / EA = 5 / 1) as the eluent to obtain a yellow powder solid Asperlicin C (0.091 g, 25%).

[0052] TLC: R f = 0.25 (DCM / EA=5 / 1). = -89.0 (c=0.02, MeOH) 1 H NMR (400 MHz, DMSO-) d 6) δ 10.86 (brs, 1H, N H ), 8.90 (d, J = 6.4 Hz, 1H,Ar H ), 8.21 (d, J = 7.9 Hz, 1H, Ar H ), 7.94 (m, 1H, Ar H ), 7.85 (d, J = 8.5 Hz, 1H,Ar H ), 7.68 (d, J = 7.4 Hz, 1H, Ar H ), 7.65-7.60 (m, 3H, Ar H ), 7.57-7.50 (m, 2H,ArH ), 7.34-7.28 (m, 2H, Ar H ), 7.02 (t, J = 8.2 Hz, 1H, Ar H ), 6.93-6.87 (m, 1H,Ar H ), 4.42-4.36 (m, 1H, NHC H C), 3.63 (dd, J = 14.8, 5.0 Hz, 1H, indolyl-C H 2),3.43- 3.40 (m, 1H, indolyl-C H 2, partially overlapped with H2O signal). ESI-MS m / z ): calculated for C 25 H 19 IN4O2 + [M+H] + 407.2, found: 407.4. Example 3: Synthesis of Circumdatin H Step 1: Preparation of compound 3c-Fmoc

[0053] In a clean, dry, single-necked 250 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed inside. L-Fmoc-proline (3.04 g, 9.00 mmol, 1.0 eq.) was added, followed by the addition of 90 mL of anhydrous tetrahydrofuran to dissolve the solid. The reaction flask was then placed in an ice-water bath with stirring. Triphosgene (1.07 g, 3.60 mmol, 0.5 eq.) was added to the reaction flask, followed by the slow dropwise addition of 2,4,6-trimethylpyridine (2.40 mL, 18.00 mmol, 2.0 eq.). After stirring for 10 min in an ice-water bath, 4-methoxy-2-iodoaniline (2.24 g, 9.00 mmol, 1.0 eq.) was added to the solution, and the reaction was then allowed to proceed at room temperature for 9 hours. After the reaction was completed, the reaction solution was evaporated to dryness, dissolved in dichloromethane, and then quenched with saturated ammonium chloride solution (150 mL). The solution was extracted with dichloromethane (150 mL × 3), and the organic phases were combined. The organic phases were washed with water (300 mL) and saturated NaCl solution (300 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with dichloromethane / petroleum ether (DCM / PE = 15 / 1) as the eluent to obtain a white powder solid 3c-Fmoc (3.99 g, 78%).

[0054] TLC: R f = 0.25 (DCM / PE=10 / 1). = -63.5 (c=0.20, MeOH) 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H, N H ), 8.16-7.87 (m, 2H, Ar H ), 7.82-7.29 (m, 7H, Ar H ), 7.12 (s, 1H, Ar H ), 6.92 (s, 1H, Ar H ), 4.61-4.15 (m,4H, COC H N, OC H 2CH, OCH2C H ), 3.77 (s, 3H, OC H 3), 3.71-3.39 (m, 2H, C H 2CHN), 2.47-1.93 (m, 4H, CHC) H 2CH2, CHCH2C H2). ESI-MS m / z ): calculated for C 27 H 26 IN2O4 + [M+H] + : 569.1, found: 569.0. Step 2: Preparation of compound 4c

[0055] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, 3c-Fmoc was added, and anhydrous acetonitrile (50 mL) was added to dissolve it. Then, diethylamine (25 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, part of the solvent was removed by rotary evaporation, the reaction was quenched with saturated ammonium chloride (60 mL), and extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed with water (200 mL), washed with saturated NaCl solution (200 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with ethyl acetate / dichloromethane (EA / DCM = 1 / 3) as the eluent to give a pale yellow oily substance 4c (2.07 g, 85%).

[0056] TLC: R f = 0.16 (EA / DCM=1 / 5). = -55.6 (c=0.21, MeOH) 1 H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H, ArN H ), 8.11 (m, 1H, Ar H ), 7.31(m, 1H, Ar H ), 6.90 (m, 1H, Ar H ), 3.90 (m, 1H, COC H NH), 3.76 (s, 3H, OC H 3), 3.13-3.07 (m, 2H, CHN) H C H 2NH), 2.24-2.16 (m, 1H, C H 2NH), 2.10-2.02 (m, 2H,CHC H 2CH2), 1.86-1.72 (m, 2H, CHCH2CH 2). ESI-MS m / z ): calculated for C 12 H 16 IN2O2 + [M+H] + : 347.0, found: 347.3. Step 3: Preparation of compound 5c

[0057] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and o-nitrobenzoic acid (0.582 g, 3.5 mmol, 1.2 eq.) was added, followed by 6 mL of thionyl chloride. The mixture was reacted in an oil bath at 50 °C for 30 min, and the remaining thionyl chloride was removed by vacuum distillation. The solution was then dissolved in 10 mL of dichloromethane and set aside for later use. In another reaction flask, 4c (1.00 g, 2.9 mmol, 1.0 eq.) was added, followed by 20 mL of dichloromethane to dissolve the solid. Triethylamine (0.81 mL, 5.8 mmol, 2.0 eq.) was then added, followed by the previously prepared dichloromethane solution. The mixture was reacted at room temperature for 6 hours. The reaction was quenched by adding saturated ammonium chloride solution (50 mL), and extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed with water (200 mL), washed with saturated NaCl solution (200 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with dichloromethane / ethyl acetate (DCM / EA = 25 / 1) as the eluent to give a yellow powder solid 5c (1.23 g, 86%).

[0058] TLC: R f = 0.21 (DCM / EA=25 / 1). = -61.0 (c=0.30, MeOH) 1 H NMR (400 MHz, CDCl3) δ 8.70 (brs, 1H, N H ), 8.22 (d, J = 8.3 Hz, 1H,Ar H ), 7.85-7.74 (m, 2H, Ar H ), 7.63-7.55 (m, 2H, Ar H ), 7.32 (m, 1H, Ar H,rotamer), 6.91 (m, 1H, Ar H , rotamer), 5.03 (m, 1H, COC H N), 3.78 (s, 3H, C H 3), 3.41-3.34 (m, 1H, C) H 2N), 3.28-3.19 (m, 1H, C H 2N), 2.33-1.96 (m, 4H, CHC H 2CH2,CHCH2C H 2). ESI-MS m / z ): calculated for C 19 H 19 IN3O5 + [M+H] + : 496.0, found: 496.1. Step 4: Preparation of compound 6c

[0059] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and 5c (1.23 g, 2.50 mmol, 1.0 eq.) and tetrahydroxydiboron (0.672 g, 7.5 mmol, 3.0 eq.) were added. After dissolving the solid in 15 mL of anhydrous DMF, 4,4′-bipyridine (0.019 g, 0.13 mmol, 0.05 eq.) was added to the reaction solution, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, 150 mL of ethyl acetate was added to dilute the reaction solution, and the organic phase was washed with saturated NaCl solution (50 mL × 3), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography using ethyl acetate / dichloromethane (EA / DCM = 1 / 15) as the eluent to obtain a white powder solid 6c (0.895 g, 77%).

[0060] TLC: R f = 0.17 (EA / DCM=1 / 20). = -49.0 (c=0.15, MeOH) 1 H NMR (400 MHz, CDCl3) δ 8.38 (brs, 1H, ArN H ), 7.86 (d, J= 8.4 Hz, 1H,Ar H ), 7.33-7.27 (m, 2H, Ar H ), 7.20-7.13 (m, 1H, Ar H ), 6.88 (m, 1H, Ar H ), 6.73-6.66 (m, 2H, Ar) H ), 4.93 (s, 1H, COC H N), 3.78-3.54 (m, 5H, OC H 3, C H 2N), 2.40 (m, 1H, CHC) H 2CH2), 2.23 (m, 1H, CHC H 2CH2), 2.06 (m, 1H, CHCH2C H 2), 1.90(m, 1H, CHCH2C H 2). 13 C NMR(150 MHz, CDCl3) δ 170.3, 168.9, 156.0, 144.9, 130.6, 130.2,127.2, 123.3, 122.8, 118.5, 116.1, 115.7, 113.7, 91.1, 59.6, 54.7, 49.3,27.3, 24.4. HRMS(ESI): calculated for C 19 H 21 IN3O3 + [M+H] + : 466.0622, found: 466.0625. Step 6: Synthesis of Circumdatin H

[0061] In a clean, dry 100 mL two-necked reaction flask under argon protection, a magnetic stirrer was placed, and 6C (0.418 g, 0.9 mmol, 1.0 eq.), palladium acetate (0.020 g, 0.09 mmol, 0.10 eq.), and XantPhos (0.104 g, 0.18 mmol, 0.20 eq.) were added. Then, 10 mL of anhydrous dichloromethane was added to dissolve the solid, and finally, triethylamine (0.32 mL, 2.25 mmol, 2.50 eq.) was added. A carbon monoxide balloon was prepared using a three-way valve and connected to the reaction flask. The gas in the reaction flask was replaced with carbon monoxide gas using a pump. After three replacements, the reaction flask was placed in an oil bath at 40 °C and stirred. After 2 h of reaction, trifluoroacetic acid (1.0 mL, TFA / DCM = 10 / 100) was added dropwise to the reaction flask. After the reaction was completed, 25 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane (25 mL × 3). The organic phases were combined and washed with 100 mL of water and 100 mL of saturated NaCl solution. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated. The crude product was purified by column chromatography with dichloromethane / ethyl acetate (DCM / EA = 10 / 1) as the eluent to obtain a yellow powder solid Circumdatin H (0.203 g, 65%).

[0062] TLC: R f = 0.64 (DCM / EA=5 / 1). = -32.0 (c=0.05, MeOH) 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.0 Hz, 1H, Ar H ), 7.68-7.63 (m,2H, Ar H ), 7.60-7.50 (m, 3H, Ar H ), 7.37 (dd, J = 8.9, 3.0 Hz, 1H, Ar H ), 4.54 (d, J = 8.1 Hz, 1H, CC H N), 3.92 (s, 3H, OCH3), 3.83-3.76 (m, 1H, C H 2N), 3.66-3.57 (m, 1H, C) H2N), 3.21-3.13 (m, 1H, CHC H 2CH2), 2.31 (m, 1H, CHC H 2CH2), 2.21-2.03(m, 2H, CHCH2C H 2). ESI-MS m / z ): calculated for C 20 H 17 IN3O7Na + [M+Na] + 370.1, found: 370.3. Example 4: Synthesis of Circumdatin J The steps of steps 1 and 2 are the same as in Example 3, resulting in compound 4c; Step 3: Preparation of compound 5d

[0063] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and 4-methoxy-2-nitrobenzoic acid (0.615 g, 3.12 mmol, 1.2 eq.) was added, followed by 6 mL of thionyl chloride. The mixture was reacted in an oil bath at 50 °C for 30 min, and the remaining thionyl chloride was removed by vacuum distillation. The solution was then dissolved in 10 mL of dichloromethane and set aside for later use. In another reaction flask, 4c (0.901 g, 2.6 mmol, 1.0 eq.; prepared as described in step 2 of Example 3) was added, followed by 20 mL of dichloromethane to dissolve the solid. Triethylamine (0.72 mL, 5.2 mmol, 2.0 eq.) was then added, followed by the previously prepared dichloromethane solution, and the reaction was carried out at room temperature for 6 hours. The reaction was quenched by adding saturated ammonium chloride solution (50 mL), and extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed with water (200 mL), washed with saturated NaCl solution (200 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with dichloromethane / ethyl acetate (DCM / EA = 25 / 1) as the eluent, to give a pale yellow powder solid 5d (1.06 g, 78%).

[0064] TLC: R f = 0.26 (DCM / EA=20 / 1). = -49.0 (c=0.10, MeOH) 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H, ArN H ), 8.20 (m, 1H, Ar H ,rotamer), 7.97-7.79 (m, 1H, Ar H , rotamer), 7.32 (m, 1H, Ar H , rotamer), 7.06-6.88 (m, 3H, Ar H , rotamer), 5.04-4.97 (m, 1H, COC H N), 3.91 (s, 3H, OC H 3), 3.77 (s, 3H, OC) H 3), 3.41-3.34 (m, 1H, C H 2N), 3.22 (m, 1H, C H 2N), 2.58 (m, 1H, CHC) H 2CH2), 2.43-2.29 (m, 1H, CHC H 2CH2), 2.17-2.13 (m, 1H, CHCH2C H 2), 1.97 (m, 1H, CHCH2C) H 2). ESI-MS m / z ): calculated for C 20 H 21 IN3O6 + [M+H] + : 526.0, found: 526.3. Step 4: Preparation of compound 6d In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed inside. 5d (0.733 g, 1.40 mmol, 1.0 eq.) and tetrahydroxydiboron (0.377 g, 4.2 mmol, 3.0 eq.) were added. After dissolving the solid in 12 mL of anhydrous DMF, 4,4′-bipyridine (0.011 g, 0.07 mmol, 0.05 eq.) was added to the reaction solution, and the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, 120 mL of ethyl acetate was added to dilute the reaction solution. The organic phase was washed with saturated NaCl solution (40 mL × 3), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography using ethyl acetate / dichloromethane (EA / DCM = 1 / 8) as the eluent, yielding a white powder solid 6d (0.499 g, 72%).

[0065] TLC: R f = 0.25 (EA / DCM=1 / 5). = -57.3 (c=0.20, MeOH) 1 H NMR (400 MHz, CDCl3) δ 8.41 (brs, 1H, ArN H ), 7.96 (m, 1H, Ar H ,rotamer), 7.38 (m, 1H, Ar H , rotamer), 7.01-6.77 (m, 3H, Ar H , rotamer), 6.66m, 1H, Ar H , rotamer), 4.93 (s, 1H, COC H N), 3.85-3.49 (m, 8H, , OC H 3, OC H 3,C H 2N), 2.44 (m, 1H, CHC H 2CH2), 2.29-2.18 (m, 1H, CHC H 2CH2), 2.13-1.91 (m, 2H,CHCH2C H 2). 13C NMR(150 MHz, CDCl3) δ 169.8, 168.9, 164.2, 155.7, 151.7, 139.8,127.6, 122.8, 121.7, 119.2, 116.8, 115.1, 112.3, 91.4, 55.7, 55.0, 54.7,46.3, 25.2, 22.5. HRMS(ESI): calculated for C 20 H 23 IN3O4 + [M+H] + : 496.0728, found: 496.0732. Step 5: Synthesis of Circumdatin J

[0066] In a clean, dry 100 mL two-necked reaction flask under argon protection, a magnetic stirrer was placed, and 6 d (0.248 g, 0.50 mmol, 1.0 eq.), palladium acetate (0.011 g, 0.05 mmol, 0.10 eq.), and XantPhos (0.058 g, 0.10 mmol, 0.20 eq.) were added. Then, 5 mL of anhydrous dichloromethane was added to dissolve the solid, and finally, triethylamine (0.17 mL, 1.25 mmol, 2.50 eq.) was added. A carbon monoxide balloon was prepared using a three-way valve and connected to the reaction flask. The gas in the reaction flask was replaced with carbon monoxide gas using a pump. After three replacements, the reaction flask was placed in an oil bath at 40°C and stirred. After 2 h of reaction, trifluoroacetic acid (0.5 mL, TFA / DCM = 10 / 100) was added dropwise to the reaction flask. After the reaction was completed, 15 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined and washed with 60 mL of water and 60 mL of saturated NaCl solution. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated. The crude product was purified by column chromatography with dichloromethane / ethyl acetate (DCM / EA = 10 / 1) as the eluent to obtain a yellow powder solid Circumdatin J (0.142 g, 75%).

[0067] TLC: R f = 0.3 (DCM / EA=8 / 1). = -33.0 (c=0.05, MeOH) 1H NMR (400 MHz, CDCl3) δ 7.68-7.61 (m, 2H, Ar H ), 7.49-7.44 (m, 2H,Ar H ), 7.36 (dd, J = 8.9, 2.9 Hz, 1H, Ar H ), 7.10 (dd, J = 8.9, 3.1 Hz, 1H, Ar H ),4.56 (d, J = 7.9 Hz, 1H, CC H N), 3.93-3.89 (m, 6H, OC H 3, OC H 3), 3.81-3.73 (m, 1H,C H 2CH2CH2N), 3.64-3.56 (m, 1H, C H 2CH2CH2N), 3.19-3.12 (m, 1H, CH2CH2C H 2N), 2.35-2.23 (m, 1H, CH2C H 2CH2N), 2.16-2.02 (m, 2H, CH2CH2C H 2N). ESI-MS m / z ): calculated for C 21 H 20 IN3O4 + [M+H] + 378.1, found: 378.2. Example 5: Synthesis of Benzomalvin A Step 1: Preparation of compound 3e-Fmoc

[0068] In a clean, dry, single-necked 250 mL eggplant-shaped reaction flask purged with argon gas, a magnetic stir bar was placed, and L- N-Me-Fmoc-phenylalanine (3.61 g, 9.00 mmol, 1.0 eq.) was dissolved in 90 mL of anhydrous tetrahydrofuran, and the reaction flask was stirred in an ice-water bath. Triphosgene (1.07 g, 3.60 mmol, 0.5 eq.) was added to the reaction flask, followed by the slow dropwise addition of 2,4,6-trimethylpyridine (2.40 mL, 18.00 mmol, 2.0 eq.). After stirring in an ice-water bath for 10 min, o-iodoaniline (1.97 g, 9.00 mmol, 1.0 eq.) was added to the solution, and the reaction was then allowed to proceed at room temperature for 9 hours. After the reaction was completed, the reaction solution was evaporated to dryness, dissolved in dichloromethane, and then quenched with saturated ammonium chloride solution (150 mL). The reaction was extracted with dichloromethane (150 mL × 3), and the organic phases were combined. The organic phases were washed with water (300 mL) and saturated NaCl solution (300 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with dichloromethane / petroleum ether (DCM / PE = 1 / 1.5) as the eluent to obtain a white powder solid 3e-Fmoc (4.87 g, 90%).

[0069] TLC: R f = 0.25 (DCM / PE=1 / 1). = -89.5 (c=0.11, MeOH) 1 H NMR(400 MHz, CDCl3) δ 8.21-7.65(m, 5H, Ar H , N H ), 7.60-7.27 (m, 9H,Ar H ), 7.24-7.06 (m, 2H, Ar H ), 7.00-6.82 (m, 2H, Ar H ), 5.26-4.11 (m, 4H, OC) H 2CH, OCH2C H NC H CH2), 3.57-3.28 (m, 1H, NCHC H 2, major rotamer), 3.10 (m,0.6H, NCHC H 2, minor rotamer), 2.91-2.82 (m, 3H, NC H 3,rotamer), 2.77 (m, 0.4H,NCHCH 2, minor rotamer). ESI-MS m / z ): calculated for C 31 H 28 IN2O3 + [M+H] + : 603.1, found: 603.3. Step 2: Preparation of compound 4e

[0070] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and 3e-Fmoc (4.87 g, 8.10 mmol, 1.0 eq.) was added and dissolved in anhydrous acetonitrile (70 mL). Then, diethylamine (35 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, some of the solvent was removed by rotary evaporation, the reaction was quenched with saturated ammonium chloride (70 mL), and extracted with dichloromethane (70 mL × 3). The organic phases were combined, washed with water (200 mL), then with saturated NaCl solution (200 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography using petroleum ether / dichloromethane (PE / DCM = 1 / 1.5) as the eluent, yielding a pale yellow oil, 4e (2.97 g, 96%).

[0071] TLC: R f = 0.30 (PE / DCM=1 / 2). = -56.0 (c=0.18, MeOH) 1 H NMR (400 MHz, CDCl3) δ 9.88 (brs, 1H, ArN H ), 8.35 (d, J = 8.2 Hz, 1H,Ar H ), 7.76 (d, J = 8.0 Hz, 1H, Ar H ), 7.37-7.29 (m, 3H, Ar H ), 7.28-7.22 (m, 3H,Ar H ), 6.81 (m, 1H, Ar H ), 3.36-3.28 (m, 2H, CHC H 2), 2.81-2.71 (m, 1H, CH CH2), 2.38 (s, 3H, NC) H 3), 1.51 (brs, 1H, CHN H ). ESI-MS m / z ): calculated for C 16 H 18 IN2O + [M+H] + : 381.0, found: 381.1. Step 3: Preparation of compound 5e

[0072] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and o-nitrobenzoic acid (1.56 g, 9.4 mmol, 1.2 eq.) was added. Then, 10 mL of thionyl chloride was added. The mixture was reacted in an oil bath at 50 °C for 30 min, and the remaining thionyl chloride was removed by vacuum distillation. The solution was then dissolved in 10 mL of dichloromethane and set aside for later use. In another reaction flask, 4e (2.97 g, 7.8 mmol, 1.0 eq.) was added, followed by the dissolution of the solid in 60 mL of dichloromethane. Triethylamine (2.17 mL, 15.6 mmol, 2.0 eq.) was added, and then the previously prepared dichloromethane solution was slowly added. The reaction was carried out at room temperature for 6 hours. The reaction was quenched by adding saturated ammonium chloride solution (80 mL), and extracted with dichloromethane (80 mL × 3). The organic phases were combined, washed with water (250 mL), washed with saturated NaCl solution (250 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with dichloromethane / petroleum ether (DCM / PE = 2 / 1) as the eluent to give a white powder solid 5e (3.50 g, 85%).

[0073] TLC: R f = 0.24 (DCM / PE=2 / 1). = -23.4 (c=0.23, MeOH) 1 H NMR (400 MHz, CDCl3) δ 8.34 (brs, 1H, ArN H ), 8.14 (d, J = 8.2 Hz, 1H,Ar H ), 8.05 (d, J = 8.1 Hz, 1H, Ar H), 7.80 (d, J = 7.9 Hz, 1H, Ar H ), 7.60-7.48 (m,2H, Ar H ), 7.40-7.26 (m, 7H, Ar H ), 6.88 (m, 1H, Ar H ), 5.87 (s, 1H, C H CH2), 3.57 (dd, J = 15.8, 6.6 Hz, 1H, CHC H 2), 3.22 (dd, J = 15.5, 9.6 Hz, 1H, CHC H 2), 2.82 (s, 3H, NC) H 3). ESI-MS m / z ): calculated for C 23 H 21 IN3O4 + [M+H] + : 530.1, found: 530.0. Step 4: Preparation of compound 6e

[0074] In a clean, dry, single-necked 100 mL eggplant-shaped reaction flask under argon protection, a magnetic stir bar was placed, and 5e (2.35 g, 4.40 mmol, 1.0 eq.) and tetrahydroxydiboron (1.183 g, 13.2 mmol, 3.0 eq.) were added. After dissolving the solid in 25 mL of anhydrous DMF, 4,4′-bipyridine (0.034 g, 0.22 mmol, 0.05 eq.) was added to the reaction solution, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, 250 mL of ethyl acetate was added to dilute the reaction solution, and the organic phase was washed with saturated NaCl solution (85 mL × 3), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography using petroleum ether / dichloromethane (PE / DCM = 1 / 6) as the eluent to obtain a white powder solid 6e (1.86 g, 84%).

[0075] TLC: R f = 0.18 (PE / DCM=1 / 5). = -51.0 (c=0.11, MeOH) 1 1H NMR (400 MHz, CDCl3) δ 8.69 (brs, 1H, ArN H ), 8.20 (s, 1H, Ar H ), 7.81m, 1H, Ar H ), 7.40 - 7.25 (m, 6H, Ar H ), 7.11 (m, 1H, Ar H ), 6.88 (m, 1H, Ar H ), 6.75 (s, 1H, Ar H ), 6.63 - 6.55 (m, 2H, Ar H ), 5.80 (s, 1H, C H CH2), 4.01 (brs, 2H, N H 2), 3.51 - 2.83 (m, 5H, CHC H 2, NC H 3). 13 13C NMR (150 MHz, CDCl3) δ 172.1, 167.5, 144.7, 138.1, 137.4, 135.9, 130.4, 128.0, 127.9, 127.8, 125.9, 125.3, 121.7, 117.1, 116.2, 115.4, 89.4, 57.1, 32.4, 28.7. HRMS (ESI): calculated for C 23 H[[ID=�3]] 23 IN3O2 + [M + H] + : 500.0830, found: 500.0830. Step 5: Synthesis of Benzomalvin A

[0076] In a clean, dry 100 mL two-necked reaction flask under argon protection, a magnetic stirrer was placed, and 6e (0.674 g, 1.40 mmol, 1.0 eq.), palladium acetate (0.032 g, 0.14 mmol, 0.10 eq.), and XantPhos (0.162 g, 0.28 mmol, 0.20 eq.) were added. Then, 15 mL of anhydrous dichloromethane was added to dissolve the solid, and finally, triethylamine (0.49 mL, 3.5 mmol, 2.50 eq.) was added. A carbon monoxide balloon was prepared using a three-way valve and connected to the reaction flask. The gas in the reaction flask was replaced with carbon monoxide gas using a pump. After three replacements, the reaction flask was placed in an oil bath at 40 °C and stirred. After 2 h of reaction, trifluoroacetic acid (1.5 mL, TFA / DCM = 10 / 100) was added dropwise to the reaction flask. After the reaction was completed, 25 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane (25 mL × 3). The organic phases were combined, washed with 100 mL of water and 100 mL of saturated NaCl solution, dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was purified by column chromatography with dichloromethane / ethyl acetate (DCM / EA = 30 / 1) as the eluent to obtain a yellow powder solid Benzomalvin A (0.368 g, 69%). Benzomalvin A has two diastereomers, which were further purified by column chromatography to obtain two pure diastereomers (major isomer: 0.206 g; minor isomer: 0.105 g).

[0077] Major isomers: TLC: R f = 0.34 (DCM / EA=20 / 1). = -89.0 (c=0.10, MeOH) 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.0 Hz, 1H, Ar H ), 7.96-7.92 (m, 1H, Ar) H ), 7.83-7.80 (m, 2H, Ar H ), 7.63-7.51 (m, 4H, Ar H ), 7.26-7.16 (m, 5H,Ar H ), 4.91 -4.85 (m, 1H, C H CH2Ph), 3.80 (dd,J = 14.6, 7.9 Hz, 1H, CHC H 2Ph), 3.42 (dd, J = 14.6, 6.9 Hz, 1H, CHC H 2Ph), 3.09 (s, 3H, NC H 3). 13 C NMR(150 MHz, CDCl3) δ 167.4, 161.3, 151.9, 146.1, 136.8, 135.0, 133.0, 131.6, 131.0, 130.0, 129.1, 129.1, 129.0, 128.8, 127.8, 127.8, 127.7, 127.0, 121.8, 58.4, 33.3, 28.0. ESI-MS( m / z ): calculated for C 24 H 20 IN3O2 + [M+H] + : 382.2, found: 382.4. Minor isomer: TLC: R f = 0.28 (DCM / EA = 20 / 1). = 55.0 (c = 0.05, MeOH) 1 H NMR(400 MHz, CDCl3) δ 8.33 (d, J = 8.0 Hz, 1H, Ar H ), 8.04 (d, J = 7.5Hz, 1H, Ar H ), 7.83 - 7.77 (m, 1H, Ar H ), 7.68 - 7.61 (m, 3H, Ar H ), 7.54 (m, 1H,Ar H ), 7.29 - 7.19 (m, 4H, Ar H ), 7.01 - 6.96 (m, 2H, Ar H ), 4.78 (dd, J = 11.2, 5.9Hz, 1H, C HCH2Ph), 2.94 (s, 3H, C H 3), 2.78 (dd, J = 13.9, 5.9 Hz, 1H, CHC H 2Ph), 2.36 (dd, J = 13.9, 11.2 Hz, 1H, CHC H 2Ph). 13 C NMR(150 MHz, CDCl3) δ 165.6, 161.7, 153.9, 146.5, 136.0, 135.2,133.1, 132.3, 131.3, 130.8, 129.3, 129.0, 128.8, 128.3, 127.9, 127.7, 127.5,127.4, 121.5, 70.5, 38.4, 36.0. ESI-MS m / z ): calculated for C 24 H 20 IN3O2 + [M+H] + : 382.2, found: 382.2. The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for the preparation of quinazoline [3, 2-a] [1, 4]- benzodiazepine natural products, characterized in that, The method comprises the following steps: S1, under ice water bath condition, compound 1 is mixed with compound 2-Fmoc to give compound 3-Fmoc ; S2, for compound 3-Fmoc The amino group was deprotected to give compound 4. ; S3, compound 4 with compound 3 The amidation reaction is carried out by mixing to obtain compound 5 ; S4, compound 5 is reacted with compound 6 a nitro reduction reaction is performed to obtain compound 6 ; S5, CO gas is introduced, compound 6 mixed with a base, and a carbonylation reaction is carried out under catalysis of a catalyst; after the reaction is completed, an acid is added to obtain the quinazoline [3, 2-a] [1, 4]-benzodiazepine natural product ; the catalyst is a combination of palladium acetate and a phosphine ligand in a molar ratio of 1:1-4; the catalyst is one or more selected from Pd(OAc)2 / PPh3, Pd(OAc)2 / Dppf, Pd(OAc)2 / CyJohnPhos, Pd(OAc)2 / XantPhos, Pd(OAc)2 / JohnPhos, Pd(OAc)2 / tBuXPhos, Pd(OAc)2 / XPhos, Pd(OAc)2 / RuPhos, Pd(OAc)2 / BrettPhos, Pd(OAc)2 / BINAP. wherein R 1 and R 4 are one of H, C1-C7 alkyl, benzyl, C1-C7 alkoxy; R 2 is one of H, C1-C7 alkyl, benzyl, a substituent on C1-C7 alkyl bearing an indole; R 3 is one of H, C1-C7 alkyl, benzyl; R 2 and R 3 may form an aliphatic ring.

2. The production method according to claim 1, characterized by, said compound 1 R 1 is one of H, C1-C4 alkyl, benzyl, C1-C4 alkoxy; said compound 2-Fmoc R 2 is one of H, C1-C4 alkyl, benzyl, C1-C4 alkyl substituted with indole; R 3 is one of H, C1-C4 alkyl, benzyl; R 2 and R 3 may form an aliphatic ring; said compound 3 R 4 is one of H, C1-C4 alkyl, benzyl, C1-C4 alkoxy.

3. The preparation method according to claim 1, characterized in that, The compound 1 is selected from one of the following structural compounds: 、 ； The compound 2-Fmoc is selected from one of the following structural compounds: 、 、 、 ； The compound 3-Fmoc is selected from one of the following structural compounds: 、 、 、 ； The compound 4 is selected from one of the following structural compounds: 、 、 、 ； The compound 3 is selected from one of the following structural compounds: 、 ； The compound 5 is selected from one of the following structural compounds: 、 、 、 、 ； The compound 6 is selected from one of the following structural compounds: 、 、 、 、 。 4. The method of claim 1, wherein, The quinazoline [3, 2-a] [1, 4]-benzodiazepine natural product has a general formula as shown in formula I: ; wherein * represents R- or S-configuration.

5. The preparation method according to claim 4, characterized in that, The quinazoline [3, 2-a] [1, 4]-benzodiazepine natural product is selected from one of the following structural compounds: 。 6. The method of claim 1, wherein, The specific steps of step S1 include: under the condition of ice water bath, after dissolving compound 1, adding triphosgene and 2, 4, 6-trimethylpyridine and stirring, then adding compound 2-Fmoc and mixing to obtain compound 3-Fmoc through condensation reaction; The condensation reaction is carried out at a temperature of 18-30 DEG C for 8-10 h.

7. The preparation method according to claim 1, characterized in that, The specific steps of step S2 include: after dissolving compound 3-Fmoc, adding diethylamine to deprotect the amino group of compound 3-Fmoc to obtain compound 4; The deprotection reaction is carried out at a temperature of 18-30 DEG C for 20-35 min.

8. The method of claim 1, wherein, The specific steps of step S3 include: under the protection of argon, first dissolving compound 3 to form compound 3 solution, then dissolving compound 4, adding triethylamine, and mixing with compound 3 solution to carry out amidation reaction to obtain compound 5; The amidation reaction is carried out at a temperature of 18-30 DEG C for 4-8 h.

9. The method of claim 1, wherein, The specific steps of step S4 include: under the protection of argon, dissolving compound 5 and tetrahydroxyboron after mixing, adding 4, 4'-dipyridyl to carry out nitro reduction reaction to obtain compound 6; The nitro reduction reaction is carried out at a temperature of 18-30 DEG C for 20-35 min.

10. The method of claim 1, wherein, The specific steps of step S5 include: under the protection of argon, passing in CO gas, dissolving compound 6 and catalyst after mixing, adding base to carry out carbonylation reaction; after the reaction is completed, adding acid to obtain quinazoline [3, 2-a] [1, 4]-benzodiazepine natural product; the solvent used for dissolving is selected from one or more of methanol, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, N, N-dimethylformamide, acetonitrile; The pressure of the CO gas is 1-6 atm; The molar amount of the catalyst is 1-20% of compound 6; The base is selected from one of DMAP, Et3N, DIPEA; the acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid; The carbonylation reaction is carried out at a temperature of 0-80 DEG C for 1-24 h.

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