Preparation method for simultaneously synthesizing four coumarin natural products

Abstract

The invention provides a preparation method for simultaneously synthesizing four coumarin natural products, which comprises the following steps: by taking cheap and easily available 2-hydroxy-4-methoxybenzaldehyde as a raw material, carrying out selective bromination reaction in the presence of Lewis acid, cyclizing the product through Perkin reaction to obtain a brominated coumarin compound, and then carrying out palladium-catalyzed Heck dehydration reaction to obtain the four coumarin natural products. The preparation method comprises the following steps of: obtaining trans-Dehydrostol under a reflux condition, and carrying out epoxidation on the trans-Dehydrostol to generate Phebalosin; and carrying out ring opening and rearrangement on the Phebalosin to synthesize the natural products, namely Murraxocin, Murrangitin and Murralongin, wherein the natural products are Murraxocin, Murrangitin and Murralongin. The method has the advantages of simple synthetic route, simple and easily available raw materials, simple operation, low preparation cost and high yield, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology of natural products, specifically relating to a method for simultaneously synthesizing four coumarin-type natural products. Background Technology

[0002] Phebalosin is a naturally occurring isopropylated coumarin, first isolated in 1966 from *Phebalalium* spp., discovered in Western Australia. It is also found in extracts of many other plants in the Rutaceae and Apiaceae families, which are used in folk medicine in China and other Asian countries as analgesics, astringents, and antidiuretics.

[0003] Leishmania panamaensis (Viannia) is the causative agent of most cutaneous leishmaniasis in Central and South America, accounting for approximately 50% of all cases in eight endemic countries. Chemotherapy is primarily based on antimony compounds, such as pentoses and dextran; however, nephrotoxicity and cardiotoxicity, as well as clinical resistance to these commonly used antimony preparations, have prompted the search for new chemicals to overcome these drawbacks. Phebalosin was tested on sterile, non-flagellated bodies of Leishmania panamaensis at a 50% effective concentration (EC50). 50 The concentrations were 14.1 μg / mL and 20.7 μg / mL, respectively, and also showed cytotoxicity (IC50) to human U-937 cells. 50 Phebalosin exhibited significant antiproliferative activity and antiparasitic activity against Leishmania protozoa.

[0004] Phebalosin can be generated from the isopropenylated natural coumarin trans-Dehydroosthol via an epoxidation reaction. Phebalosin can be rearranged to generate three other isopropenylated natural coumarins: Murracarpin, Murragatin, and Murralongin. Murraxocin, an ethyl alkaloid of Murracarpin, was first isolated from the exotic plant Murraya in 1987. All of these natural products have been reported to possess a variety of biological activities. The non-conjugated sp at C-2 of the 7-methoxycoumarin nucleus... 2 Hydroxyl substituents on the C5 isoprene moiety at C-2 or C-8 play a crucial role in promoting antitumor activity. In particular, some of these coumarins, such as Murrangatin, are valuable antitumor promoters in several carcinogenicity assays. In in vivo initiation-promoting assays of these compounds, Murrangatin exhibited significant antitumor activity.

[0005] In 2009, Long-huo et al. (Long-huo, W.; Pei, L.; Ruian, X. Hecheng Huaxue 2009, 17, 761-763.) used resorcinol and 2-hydroxysuccinic acid (1) as raw materials to achieve the total synthesis of Phebalosin (6) through a four-step reaction. First, 7-hydroxycoumarin (2) was synthesized by the Pechmann reaction with a yield of 53%. 7-hydroxycoumarin (2) was then subjected to the Reimer-Tiemann reaction to introduce a formyl group at the 8-position of 7-hydroxycoumarin (2) to obtain compound 3 with a yield of 30%. Subsequently, compound 3 was methylated to methoxy group at the 7-position to obtain compound 4 with a yield of 85%. Finally, compound 4 underwent a Darzens condensation reaction to synthesize compound 5 with a yield of 50%. Finally, compound 5 underwent a Wittig reaction to finally obtain Phebalosin (6) with a yield of 19%, and the total yield of the four steps was 1.3%. The method has an extremely low overall yield of only 1.3%, which limits its practical application. Furthermore, the Wittig reaction requires stringent conditions; a strongly alkaline environment easily damages the coumarin parent ring structure, leading to a further decrease in yield. In addition, this synthetic method uses expensive reagents (such as LDA and Ph3PCH3Br), is complex to operate, and is not conducive to scale-up production.

[0006]

[0007] In 2015, Sen et al. (Sen I, Sasmal S, Ghorai KS, et al. Tetrahedron Letters, 2015, 56(31): 4590-4592) synthesized Phebalosin (6) efficiently through a four-step reaction using 7-hydroxycoumarin (2) as the starting material. First, 7-hydroxycoumarin (2) was acetylated under the catalysis of acetic anhydride and pyridine to generate acetylated product (7) in 95% yield; acetylated product (7) was reacted with hexamethylenetetramine (HMTA) in trifluoroacetic acid (TFA) to undergo Duff formylation, introducing a formyl group at the 7-position in 60% yield to obtain compound (3); compound (3) was methylated under the action of iodomethane and potassium carbonate, methylating the 7-hydroxyl group in 80% yield to obtain compound (4). Compound (4) underwent a Corey-Chaykovsky epoxidation reaction with thioyl ylide in a lithium tert-butoxide (LiOtBu) and DMSO system to construct isopentenyl epoxy units in one step, yielding the final product Phebalosin (6) in approximately 47.5% yield, with an overall four-step yield of 22.8%. Although the overall yield (22.8%) of this method is a significant improvement over the previously reported (1.3%), it is still considered moderate. The thioyl ylide used in the key Corey-Chaykovsky reaction is highly hygroscopic, requiring stringent operating and storage conditions (nitrogen protection), which is not conducive to large-scale production. The route uses highly corrosive reagents such as trifluoroacetic acid (TFA) and high-boiling solvents such as DMSO, leading to difficulties in post-processing and environmental problems.

[0008]

[0009] In 1991, Allison et al. (Allison S, Burks SJ, Taylor R T. Tetrahedron, 1991, 47(47): 9737-9742.) used 7-hydroxycoumarin (2) as the starting material and achieved the total synthesis of Murralongin (12) in five steps. First, 7-hydroxycoumarin (2) and (E)-1-bromo-2-methyl-4-acetoxy-2-butene underwent alkylation in a K2CO3 and acetone system to produce compound (8) in 32% yield. Compound (8) was then heated under reflux in butyric anhydride, undergoing a Claisen rearrangement to generate intermediate (9). Intermediate (9) was then hydrolyzed in a K2CO3 and methanol system to give compound (10). Compound (10) was then methylated in iodomethane and acetone to directly give compound (11) in 59% overall yield. Finally, compound (11) was oxidized by Swern oxidation in oxalyl chloride, DMSO, and triethylamine to give the final product Murralongin (12) in 75% yield, resulting in an overall yield of 14% for the five steps. The low yield of the initial alkylation step (32%) limited the overall synthetic efficiency, resulting in an overall yield of only 14%. While this route successfully synthesized the target molecule, its overall atom economy and step economy are only average, particularly the total conversion efficiency from inexpensive starting materials to the final product, which needs improvement. The critical Claisen rearrangement requires harsh conditions (reflux in butyric anhydride) and easily generates difficult-to-separate byproducts. The method uses irritating, corrosive, and malodorous reagents such as oxalyl chloride and butyric anhydride, posing operational hazards and environmental problems.

[0010]

[0011] It is evident that current methods for synthesizing Phebalosin mostly suffer from low yields, use highly toxic reagents which are not environmentally friendly, have long reaction times, require harsh reaction conditions, or use solvents that are difficult to remove. In short, they fail to meet practical application needs. Therefore, obtaining a preparation method with mild reaction conditions, a simple preparation route, high yield, and environmental friendliness is an urgent technical problem to be solved in this field. Summary of the Invention

[0012] To address the shortcomings of existing technologies, the present invention adopts the following technical solution:

[0013] The first aspect of this invention provides a method for simultaneously synthesizing four coumarin-type natural products, comprising the following steps:

[0014] S1: 2-hydroxy-4-methoxybenzaldehyde (13) reacts with liquid Br2 in the presence of Lewis acid to undergo selective bromination to give the brominated compound 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14);

[0015] S2: The brominated compound 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14) undergoes a Perkin cyclization reaction with acetic anhydride catalyzed by a catalyst to give a bromocoumarin compound (15);

[0016] S3: Bromocoumarin compounds (15) and 2-methyl-3-buten-2-ol were reacted via Heck dehydration to give trans-Dehydroosthol (16);

[0017] S4: trans-Dehydroosthol (16) reacts with m-chloroperoxybenzoic acid (m-CPBA) via a cyclization reaction to generate Phebalosin (6);

[0018] S5: Phebalosin (6) ring-opening rearrangement synthesizes natural products Murraxocin (17), Murrangatin (18) and Murralongin (12);

[0019] The reaction is shown in Formula I:

[0020]

[0021] Furthermore, in S1, the catalyst is a Lewis acid; even further, in S1, the catalyst is selected from any one or more of TiCl4, AlCl3, FeCl3, BF3, FeBr3, SO3, and NbF5.

[0022] Furthermore, in S1, the equivalence ratio of 2-hydroxy-4-methoxybenzaldehyde, liquid Br2, and Lewis acid is 1:1:1 to 1.4; even further, in S1, the equivalence ratio of 2-hydroxy-4-methoxybenzaldehyde, liquid Br2, and Lewis acid is 1:1:1.2.

[0023] Furthermore, in S2, the catalyst is cesium acetate (AcOCs);

[0024] Furthermore, in S2, the equivalent ratio of the brominated compound 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14), acetic anhydride, and cesium acetate (AcOCs) is 1:8 to 9:1; even further, in S2, the equivalent ratio of the brominated compound 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14), acetic anhydride, and cesium acetate (AcOCs) is 1:8.5:1;

[0025] Furthermore, in S3, the reaction is carried out under the catalysis of a palladium catalyst; even further, the palladium catalyst is bis(tri-tert-butylphosphine)palladium;

[0026] Furthermore, in S3, butylated hydroxytoluene (BHT), anhydrous 1,3-dichloropropane, and triethylamine are also added to the reaction.

[0027] Furthermore, in S3, the equivalent ratio of the reaction of bromocoumarin compound (15), butylated hydroxytoluene (BHT), bis(tri-tert-butylphosphine)palladium, anhydrous 1,3-dichloropropane, triethylamine, and 2-methyl-3-buten-2-ol is 1:0.1:0.1:80:1:4-5; even further, in S3, the equivalent ratio of the reaction of bromocoumarin compound (15), butylated hydroxytoluene (BHT), bis(tri-tert-butylphosphine)palladium, anhydrous 1,3-dichloropropane, triethylamine, and 2-methyl-3-buten-2-ol is 1:0.1:0.1:80:1:4.5;

[0028] Furthermore, in S4, the reaction is carried out under alkaline conditions; even further, the base is NaHCO3;

[0029] Furthermore, in S4, the equivalence ratio of trans-Dehydroosthol (16) to m-chloroperoxybenzoic acid (m-CPBA) is 1:0.8 to 1.2; even further, in S4, the equivalence ratio of trans-Dehydroosthol (16) to m-chloroperoxybenzoic acid (m-CPBA) is 1:1;

[0030] Further, step S5 includes: dissolving Phebalosin (6) in an 8-12 v / v% H2SO4:EtOH aqueous solution with a volume ratio of H2SO4:EtOH of 1:1, and then heating the reaction system under reflux at 50-70°C for 4-6 hours to generate the target products Murraxocin (17), Murrangatin (18) and Murralongin (12);

[0031] Compared with existing technologies, this patented approach has the following significant advantages:

[0032] This invention innovatively synthesizes four novel coumarin compounds through epoxidation and ring-opening rearrangement reactions, and also possesses the following advantages:

[0033] 1. The preparation method of this invention avoids the use of highly toxic reagents in traditional methods, and the reagents used in the reaction are green, environmentally friendly, and have low toxicity;

[0034] 2. The reaction conditions of this invention are mild and the operation is simple, avoiding complex and environmentally harmful processes;

[0035] 3. The catalyst used in this invention is in small quantities and is inexpensive and readily available, thus reducing production costs;

[0036] 4. This invention uses a "one-pot method" to simultaneously prepare four kinds of coumarin natural products, with a high yield, making it suitable for large-scale production.

[0037] The natural coumarin compounds synthesized by this method contain fused structures of multi-substituted aromatic rings and oxygen heterocycles. These compounds show significant application potential in the development of antitumor lead compounds and organic optoelectronic materials. The establishment of this efficient synthesis method not only has methodological innovation value, but also provides key molecular building blocks for subsequent structure-activity relationship studies. Attached Figure Description

[0038] Figure 1 The 1H NMR spectrum of 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14)

[0039] Figure 2 Carbon spectrum of 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14)

[0040] Figure 3 The 1H NMR spectrum of 8-bromo-7-methoxycoumarin (15)

[0041] Figure 4 Carbon spectrum of 8-bromo-7-methoxycoumarin (15)

[0042] Figure 5 Trans-Dehydroosthol (16) hydrogen spectrum

[0043] Figure 6 Carbon spectrum of trans-Dehydroosthol(16)

[0044] Figure 7 The hydrogen spectrum of Phebalosin(6)

[0045] Figure 8 Carbon spectrum of Phebalosin (6)

[0046] Figure 9 The hydrogen spectrum of Murraxocin (17)

[0047] Figure 10 Carbon spectrum of Murraxocin (17)

[0048] Figure 11 The hydrogen spectrum of Murrangatin (18)

[0049] Figure 12 Carbon spectrum of Murrangatin (18)

[0050] Figure 13 The proton spectrum of Murralongin (12)

[0051] Figure 14 Carbon spectrum of Murralongin (12) Detailed Implementation

[0052] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0053] Example 1

[0054] Synthesis of 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14):

[0055]

[0056] Substrate (13) (2 g, 1.0 eq., 13.14 mmol) was dissolved in DCM (41 mL, 0.32 M) and stirred at -78 °C. TiCl4 (1.8 mL, 1.2 eq., 15.76 mmol) was then added and stirred thoroughly for half an hour. Diluted and dried liquid bromine (0.68 mL, 1.0 eq., 13.14 mmol) was then slowly added dropwise. After the addition of liquid bromine was complete, the reaction was allowed to return to room temperature for 4 hours. The reaction was quenched with 10 mL of saturated sodium bisulfite. The reaction solution was extracted with DCM (2 × 250 mL), and the organic phase was washed with saturated brine (1 × 10 mL). An appropriate amount of anhydrous Na2SO4 was added to the organic phase for drying, and the organic phase was concentrated by vacuum distillation. Finally, the sample was loaded dry, and the eluent PE:EA was used to elute sequentially from 100:1 to 15:1 to obtain the pure target compound 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14) as a white powder solid (88.7%).

[0057] NMR and mass spectrometry data of 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14):

[0058] 1 H NMR (400MHz, CHCl3): δ11.93 (s, 1H), 9.71 (s, 1H), 7.51 (d, J = 8.7Hz, 1H), 6.62 (d, J = 8.7Hz, 1H), 3.99 (s, 3H); 13 C NMR (100MHz, CHCl3): δ194.43,162.83,160.20,134.69,116.19,103.87,99.69,56.96; HRMS(EI)calcd for C8H7BrO3[MH] - 228.9506,found228.9506.

[0059] Example 2

[0060] Synthesis of 8-bromo-7-methoxycoumarin (15):

[0061]

[0062] Substrate (14) (1 g, 1.0 eq., 4.32 mmol) was weighed and added to a sealing tube, followed by cesium acetate (831 mg, 1.0 eq., 4.32 mmol), and finally redistilled acetic anhydride (3.46 mL, 8.5 eq., 36.6 mmol). The reaction was carried out at 160 °C for 12 h. The reaction solution was transferred to a separatory funnel with 400 mL of industrially redistilled EA, and the organic phase was washed with water (5 × 10 mL) and saturated brine (1 × 10 mL). An appropriate amount of anhydrous Na2SO4 was added to the organic phase for drying, and then the organic phase was concentrated by vacuum distillation. The sample was loaded using a dry method, and eluents PE:EA were used sequentially from 10:1 to 5:1 to obtain the pure target compound 8-bromo-7-methoxycoumarin (15) as a yellow powder (70%).

[0063] NMR and mass spectrometry data of 8-bromo-7-methoxycoumarin (15):

[0064] 1 H NMR (400MHz, CHCl3): δ7.62 (d, J = 9.5Hz, 1H), 7.41 (d, J = 8.7Hz, 1H), 6.87 (d, J = 8.7Hz, 1H), 6.28 (d, J = 9.5Hz, 1H), 3.99 (s, 3H); 13 C NMR (100MHz, CHCl3): δ160.31,159.30,152.43,143.30,127.68,113.96,113.91,108.09,99.87,56.99; HRMS(EI)calcdfor C 10 H7O3Br[M+Na] + 276.9497, found 276.9477.

[0065] Example 3

[0066] Synthesis of trans-Dehydroosthol(16):

[0067]

[0068] Weigh substrate (15) (50 mg, 1.0 eq., 0.196 mmol), BHT (4.3 mg, 0.1 eq., 0.0196 mmol), and bis(tri-tert-butylphosphine)palladium (10 mg, 0.1 eq., 0.0196 mmol) into a 5 mL two-necked flask, attach a suitable condenser, and seal. Vacuum the sealed reaction system three times using a double-row tube, an oil pump, and nitrogen, with 2-minute intervals between each evacuation. Add anhydrous 1,3-dichloropropane (1.5 mL, 80 eq., 15.7 mmol), diluted triethylamine (81.6 μL, 1.0 eq., 0.196 mmol), and 2-methyl-3-buten-2-ol (92 μL, 4.5 eq., 0.882 mmol) sequentially. After addition, insert a nitrogen-filled balloon of suitable size above the condenser. React at 110 °C for 26 h. The reaction solution was quenched by adding 2 mL of saturated sodium bicarbonate solution. The solution was then transferred to a short silica gel column using EA to filter out insoluble solids. The filtrate was collected directly using a separatory funnel. The organic phase was washed with water (1 × 10 mL) and then with saturated brine (1 × 10 mL). An appropriate amount of anhydrous Na₂SO₄ was added to the organic phase for drying. The organic phase was then concentrated by vacuum distillation. The sample was loaded using the DCM wet method, and eluents PE:EA were used sequentially from 8:1 to 2:1 to obtain the pure target compound trans-Dehydroosthol (16) as a yellow powder solid (90%).

[0069] NMR and mass spectrometry data of trans-Dehydroosthol(16):

[0070] 1 H NMR (400MHz, CHCl3): δ7.62(d,J=9.4Hz,1H),7.49(d,J=16.5Hz,1H),7.30(d,J=8.7Hz,1H),6.95–6 .83(m,2H),6.27(d,J=9.4Hz,1H),5.16(dd,J=21.8,1.8Hz,2H),3.97(s,3H),2.03(s,J=1.0Hz,3H); 13 C NMR (100MHz, CHCl3): δ161.12,160.36,152.67,144.06,143.20,138.25,127.08 ,118.56,117.28,114.35,113.22,113.10,107.68,56.28,18.47; HRMS(EI)calcd for C 15 H 14 O3[M+Na] + 265.0837, found 265.0835.

[0071] Example 4

[0072] Synthesis of compound Phebalosin(6):

[0073]

[0074] Substrate (16) (90 mg, 0.37 mmol, 1.0 eq.) was placed in a pre-dried round-bottom flask and dissolved in redistilled DCM (4.4 mL, 0.085 M). The reaction mixture was then pre-cooled at 0 °C for 10 min, followed by the slow addition of NaHCO3 (31.2 mg, 0.371 mmol, 1.0 eq.). After the addition was complete, the mixture was stirred at 0 °C for 10 min, followed by the dropwise addition of m-CPBA (85%, 75.3 mg, 0.371 mmol, 1.0 eq.) in redistilled DCM (1.5 mL, 0.255 M), which took approximately 5 min. The reaction mixture was allowed to return to room temperature and then stirred at room temperature for 1 h. The reaction was monitored by TLC (PE:EA = 2:1). After the reaction was complete, the reaction mixture was diluted with DCM (100 mL) and washed with water (1 × 5 mL). The aqueous phase was then extracted with DCM (2×50mL), and the organic phase was washed with saturated NaCl aqueous solution (1×5mL). The organic phases were combined, transferred to an Erlenmeyer flask, dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a pale yellow solid crude product. After purification by silica gel column chromatography, the pure target compound Phebalosin (6) was obtained as a white solid (63%).

[0075] NMR data for compound Phebalosin(6):

[0076] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=9.5Hz,1H),7.42(d,J=8.7Hz,1H),6.87(d,J=8.7Hz,1H),6.26(d,J=9.5Hz,1H),5.30(dd, J=1.8,0.9Hz,1H),5.08(t,J=1.6Hz,1H),3.99(d,J=2.4Hz,1H),3.96(s,3H),3.91(d,J=2.4Hz,1H),1.86(d,J=1.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ162.07,160.53,153.96,143.59,141.40,129.14,113.73,113.58,112.93,112.63,107.69,60.84,56.48,51.88,17.57.

[0077] Example 5

[0078] Synthesis of compounds Murraxocin (17), Murrangatin (18), and Murralongin (12):

[0079]

[0080] The substrate Phebalosin(6) (120 mg, 0.465 mmol, 1.0 eq.) was placed in a round-bottom flask and dissolved in a 10% H₂SO₄:EtOH mixture (2 mL, 0.232 M, 1:1). The reaction was then heated to reflux at 60 °C. TLC (PE:EA = 1:2) was used for monitoring. After the reaction was complete (approximately 5 h), the reaction mixture was brought to room temperature, and 1-2 mL of water was added to quench the reaction. The mixture was then diluted with EA and extracted with EA, washed with water (2 × 10 mL), and washed with saturated NaCl aqueous solution (1 × 5 mL). The organic phases were combined, transferred to an Erlenmeyer flask, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. Purification by silica gel column chromatography yielded compounds 17, 18, and 12 in yields of 20%, 35%, and 17%, respectively.

[0081] NMR data for compound Murraxocin (17): (17) 1 H NMR (400MHz, CDCl3) δ7.62(d,J=9.4Hz,1H),7.39(d,J=8.6Hz,1H),6.86(d,J=8.7Hz,1H),6.25(d,J=9.5Hz,1H),5.13(d,J=8.8Hz,1H) ,4.90(d,J=8.9Hz,1H),4.72–4.56(m,2H),3.92(s,3H),3.56–3.34(m,2H),3.14(s,1H),1.69(d,J=1.2Hz,3H),1.18(t,J=7.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ161.47,160.70,153.93,143.86,143.43,129.01,114.3 9,114.27,113.40,112.91,108.05,76.46,75.93,65.31,56.33,17.41,15.43.

[0082] NMR data for compound Murrangatin (18): 1HNMR (400MHz, CDCl3) δ7.65(d,J=9.5Hz,1H),7.41(d,J=8.6Hz,1H),6.89(d,J=8.7Hz,1H),6.25(d,J=9.5 Hz,1H),5.34–5.29(m,1H),4.64(t,J=1.7Hz,1H),4.61–4.53(m,2H),3.97(s,3H),1.77(t,J=1.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ160.28,160.19,152.92,143.87,143.82,128.77,115.92,114.04,113.67,107.90,78.55,69.74,56.43,20.84,17.52.

[0083] NMR data for compound Murralongin(12): 1 H NMR (400MHz, CDCl3) δ10.22(s,1H),7.65(d,J=9.5Hz,1H),7.44(d,J=8.7Hz,1H),6 .89(d,J=8.6Hz,1H),6.22(d,J=9.5Hz,1H),3.82(s,3H),2.42(s,3H),1.78(s,3H). 13 C NMR (100MHz, CDCl3) δ189.02,161.33,160.17,160.06,152.66,143.83,129.32,128.76,113.35,113.22,113.13,107.74,56.36,25.06,20.01.

[0084] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art may make various modifications and alterations without departing from the spirit and scope of the present invention, and all such modifications and alterations shall be within the protection scope of the present invention.

Claims

1. A method for simultaneously synthesizing four coumarin-type natural products, characterized in that, Includes the following steps: S1: 2-hydroxy-4-methoxybenzaldehyde (13) reacts with liquid Br2 in the presence of Lewis acid to undergo selective bromination to give the brominated compound 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14); S2: The brominated compound 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14) undergoes a Perkin cyclization reaction with acetic anhydride catalyzed by a catalyst to give a bromocoumarin compound (15); S3: Bromocoumarin compounds (15) and 2-methyl-3-buten-2-ol were reacted via Heck dehydration to give trans-Dehydroosthol (16); S4: trans-Dehydroosthol (16) reacts with m-chloroperoxybenzoic acid (m-CPBA) via a cyclization reaction to generate Phebalosin (6); S5: Phebalosin (6) ring-opening rearrangement synthesizes natural products Murraxocin (17), Murrangatin (18) and Murralongin (12); The reaction is shown in Formula I:

2. The method for simultaneously synthesizing four coumarin-type natural products according to claim 1, characterized in that, In S1, the catalyst is a Lewis acid; furthermore, in S1, the catalyst is selected from any one or more of TiCl4, AlCl3, FeCl3, BF3, FeBr3, SO3, and NbF5.

3. The method for simultaneously synthesizing four coumarin-type natural products according to claim 1, characterized in that, In S1, the equivalence ratio of 2-hydroxy-4-methoxybenzaldehyde, liquid Br2, and Lewis acid is 1:1:1 to 1.4; furthermore, in S1, the equivalence ratio of 2-hydroxy-4-methoxybenzaldehyde, liquid Br2, and Lewis acid is 1:1:1.

2.

4. The method for simultaneously synthesizing four coumarin-type natural products according to claim 1, characterized in that, In S2, the catalyst is cesium acetate (AcOCs).

5. The method for simultaneously synthesizing four coumarin-type natural products according to claim 1, characterized in that, In S2, the equivalent ratio of the brominated compound 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14), acetic anhydride, and cesium acetate (AcOCs) is 1:8 to 9:1; furthermore, in S2, the equivalent ratio of the brominated compound 3-bromo-2-hydroxy-4-methoxybenzaldehyde (14), acetic anhydride, and cesium acetate (AcOCs) is 1:8.5:

1.

6. The method for simultaneously synthesizing four coumarin-type natural products according to claim 1, characterized in that, In S3, the reaction is carried out under the catalysis of a palladium catalyst; furthermore, the palladium catalyst is bis(tri-tert-butylphosphine)palladium.

7. The method for simultaneously synthesizing four coumarin-type natural products according to claim 1, characterized in that, In S3, butylated hydroxytoluene (BHT), anhydrous 1,3-dichloropropane, and triethylamine are also added to the reaction.

8. The method for simultaneously synthesizing four coumarin-type natural products according to claim 1, characterized in that, In S3, the equivalent ratio of the reaction of bromocoumarin compound (15), butylated hydroxytoluene (BHT), bis(tri-tert-butylphosphine)palladium, anhydrous 1,3-dichloropropane, triethylamine, and 2-methyl-3-buten-2-ol is 1:0.1:0.1:80:1:4-5; furthermore, in S3, the equivalent ratio of the reaction of bromocoumarin compound (15), butylated hydroxytoluene (BHT), bis(tri-tert-butylphosphine)palladium, anhydrous 1,3-dichloropropane, triethylamine, and 2-methyl-3-buten-2-ol is 1:0.1:0.1:80:1:4.

5.

9. The method for simultaneously synthesizing four coumarin-type natural products according to claim 1, characterized in that, In S4, the reaction is carried out under alkaline conditions; furthermore, the base is NaHCO3.

10. The method for simultaneously synthesizing four coumarin-type natural products according to claim 1, characterized in that, In S4, the equivalence ratio of trans-Dehydroosthol(16) to m-chloroperoxybenzoic acid (m-CPBA) is 1:0.8 to 1.2; furthermore, in S4, the equivalence ratio of trans-Dehydroosthol(16) to m-chloroperoxybenzoic acid (m-CPBA) is 1:

1.

11. The method for simultaneously synthesizing four coumarin-type natural products according to claim 1, characterized in that, Step S5 includes: dissolving Phebalosin (6) in an 8-12 v / v% H2SO4:EtOH aqueous solution with a volume ratio of 1:1, and then heating the reaction system under reflux at 50-70°C for 4-6 h to generate the target products Murraxocin (17), Murrangatin (18) and Murralongin (12).

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