Method for efficiently synthesizing Macullaactone A skeleton based on Suzuki-Miyaura cross-coupling reaction

Abstract

The invention relates to a method for synthesizing a Macullatone A skeleton through Suzuki-Miyaura cross-coupling reaction, which comprises the following steps: in an organic solvent, in the presence of a palladium catalytic system catalysis and an additive, carrying out Suzuki-Miyaura cross-coupling reaction on a gamma-substituted-butyrolactone compound I and a benzyl substituted boric acid compound II or a trifluoroborate compound III to obtain a Macullatone A skeleton IV; the palladium catalysis system is composed of a palladium catalyst and a ligand. According to the method, a palladium catalyst which is simple, easy to obtain and low in price and a commercial ligand serve as a catalytic system, the Macullatone A framework is efficiently prepared through the Suzuki-Miyaura coupling reaction, and the method for synthesizing the Macullatone A framework through the Suzuki-Miyaura coupling reaction has the advantages that operation is convenient, the substrate application range is wide, reaction raw materials are low in price and easy to obtain and the like.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a Maculalactone A skeleton through a Suzuki-Miyaura cross-coupling reaction, and belongs to the technical field of organic synthesis. Background Art

[0002] Maculalactone A is a natural product isolated from the marine bacterium K. maculans, which has a multi-substituted-2(5H)-furanone skeleton and exhibits antibacterial and other biological activities. In addition, Maculalactone A can also be used as a biogenic precursor for a variety of natural products of the same family, maculalactones BM (GD Brown, H.-F. Wong, N. Hutchinson, S.-C. Lee, BKK Chan, G.A. Williams. Phytochemistry Reviews, 2004, 3, 381). Its unique structure and good biological activity have aroused great interest among synthetic chemists. In recent years, researchers have developed a variety of methods to synthesize Maculalactone A compounds (such as: Geoffrey D Brown, Ho-Fai WongRong, Tetrahedron, 2004, 60, 5439; Samuel L. Bader, Michael U. Luescher, Karl Gademann. Org. Biomol. Chem., 2015, 13, 199; Richard J. Duffy, Kay A. Morris, Ravikrishna Vallakati, Wei Zhang, Daniel Romo. J. Org. Chem. 2009, 74, 4772). However, the reported synthetic methods generally have limitations such as cumbersome synthetic steps and harsh reaction conditions, and the step economy and atom economy of the synthetic route are poor.

[0003] The palladium-catalyzed Suzuki-Miyaura cross-coupling reaction is an important reaction in modern organic synthesis and is widely used in the synthesis of compounds such as drug molecules and active natural products. Akira Suzuki won the 2010 Nobel Prize in Chemistry for his contribution to the study of this reaction. However, there are relatively few methods for constructing 2(5H)-furanone skeletons using the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction (Min Lei, Xianwen Gan, Kun Zhao, Anfeng Chen, Lihong Hu. Tetrahedron, 2015, 71, 7508). So far, there has been no report on a method for synthesizing the Maculalactone A skeleton in one step based on the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a method for efficiently synthesizing the Maculalactone A skeleton based on a palladium-catalyzed Suzuki-Miyaura coupling reaction. The method of the present invention uses a simple, easily available, low-cost palladium catalyst and a commercial ligand as a catalytic system to efficiently synthesize the Maculalactone A skeleton.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0006] The present invention provides a method for efficiently synthesizing a Maculalactone A skeleton based on a Suzuki-Miyaura cross-coupling reaction, comprising the following steps:

[0007] In an organic solvent, under the catalysis of a palladium catalyst system, in the presence of an additive and a base, a γ-substituted-butyrolactone compound I and a benzyl-substituted boronic acid compound II or a trifluoroborate compound III undergo a Suzuki–Miyaura cross-coupling reaction to obtain Maculalactone A and a skeleton compound IV thereof; the palladium catalyst system consists of a palladium catalyst and a ligand;

[0008]

[0009] in,

[0010] R is methyl, ethyl, phenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-methylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3,4-dimethoxyphenyl, allyl or benzyl;

[0011] The R 1 is a bromine atom, a chlorine atom or a trifluoromethanesulfonyl group;

[0012] The R 2 is hydrogen, halogen, trifluoromethyl, cyano, methoxy, tert-butyldimethylsilyloxy, ester or aryl.

[0013] As a preferred technical solution of the present invention, the organic solvent is one of dichloromethane, tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane, acetone, acetonitrile, toluene or p-xylene; the ratio of the molar number of the γ-substituted-butyrolactone compound I to the volume of the organic solvent is 0.05-1 mmol: 1 mL, and more preferably 0.2-0.5 mmol: 1 mL.

[0014] As a preferred technical solution of the present invention, the palladium catalyst is PdCl2(dppf) or Pd(OAc)2; the molar ratio of the palladium catalyst to the γ-substituted-butyrolactone compound I is 0.005-0.05:1; and the molar ratio of the palladium in the palladium catalyst to the ligand is 1:2.

[0015] As a preferred technical solution of the present invention, the additive is distilled water; the volume ratio of the additive to the organic solvent is 0.5 to 2:1, and more preferably 0.5 to 0.75:1.

[0016] As a preferred technical solution of the present invention, the base is cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, triethylamine or N,N-diisopropylethylamine, and the ligand is XPhos or RuPhos.

[0017] As a preferred technical solution of the present invention, the molar ratio of the benzyl substituted boronic acid compound II to the γ-substituted-butyrolactone compound I is 1 to 3:1, and more preferably 2 to 2.5:1; the molar ratio of the trifluoroborate compound III to the γ-substituted-butyrolactone compound I is 1 to 3:1, and more preferably 2 to 2.5:1.

[0018] As a preferred technical solution of the present invention, the Suzuki-Miyaura cross-coupling reaction is carried out under an inert gas atmosphere, and the inert gas is nitrogen or argon.

[0019] As a preferred technical solution of the present invention, the temperature of the Suzuki-Miyaura coupling reaction is 25 to 100° C., more preferably 50 to 80° C.; the time of the cycloaddition reaction is 20 to 50 hours, more preferably 40 to 48 hours.

[0020] As a preferred technical solution of the present invention, the post-treatment steps of the reaction solution obtained after the coupling reaction of γ-substituted-butyrolactone compound I and benzyl-substituted boronic acid compound II or trifluoroborate compound III are as follows: the reaction solution is separated by silica gel column chromatography to obtain Maculalactone A skeleton compound IV, and the eluent is a mixed solvent of ethyl acetate and petroleum ether, wherein the volume ratio of ethyl acetate to petroleum ether in the mixed solvent of ethyl acetate and petroleum ether is 0.05-0.2:1.

[0021] By adopting the above technical solution, the beneficial effects of the present invention are:

[0022] 1. The present invention uses γ-substituted-butyrolactone compound I substituted with different substituents and benzyl substituted boronic acid compound II or trifluoroborate compound III as raw materials, and uses a simple, easily available and inexpensive palladium catalyst and a commercial ligand as a catalytic system to efficiently prepare the Maculalactone A skeleton through a Suzuki-Miyaura coupling reaction.

[0023] 2. The catalyst used in the method of the present invention is a simple, easily available, low-cost palladium catalyst and a commercial RuPhos ligand as a catalytic system, which has the advantages of low catalyst cost and high catalytic efficiency. At the same time, the amount of catalyst used is small and can be reduced to 0.5%. The method of the present invention for preparing Maculalactone A skeleton by palladium-catalyzed Suzuki-Miyaura coupling reaction has the advantages of convenient operation, wide application range of substrates, and cheap and easy-to-obtain reaction raw materials. DETAILED DESCRIPTION

[0024] It should be noted that the following detailed descriptions are all illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0025] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0026] The yields described in the following examples are molar yields.

[0027] Example 1

[0028] Synthesis of 3,4-Benzhydryl-5-phenylfuran-2(5H)-one (IVaa)

[0029] Under nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ia) (159 mg), benzylboronic acid (IIa) (170 mg), palladium catalyst Pd(OAc)2 (5.6 mg), ligand (23.3 mg) and cesium carbonate (407.3 mg) were added to a 25 mL round-bottom flask, and then solvent (2.5 mL of toluene and 2.5 mL of water) was added, and then stirred at 80°C for 24 h. The crude product after the reaction was directly separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:10-1:20, v / v) to obtain 144.7 mg of 3,4-dibenzhydryl-5-phenylfuran-2(5H)-one (IVaa) in a yield of 85%.

[0030] The reaction scheme of this embodiment is as follows:

[0031]

[0032] The characterization data of the obtained product (IVaa) are as follows:

[0033] Light yellow oil (144.7 mg, 82%);

[0034] 1 H NMR (400MHz, CDCl3): δ7.30-7.03(m,15H)6.20(s,1H); 3.73(s,2H),3.72(s,2H);

[0035] 13 C NMR (100MHz, CDCl3): δ175.2,146.4,138.2,136.0,135.2,129.3,128.9,128.8,128.7,127.9,127.5,,84.0,33.7,29.9;

[0036] HRMS (ESI) m / z calcd.for C 25 H 20 O2[M+H] + :341.1542,found:341.1541.

[0037] Example 2

[0038] Synthesis of 3,4-bis(4-methylbenzyl)-5-phenylfuran-2(5H)-one (IVab)

[0039] Under nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ia) (159 mg), (4-methylbenzyl)boric acid (IIb) (187.5 mg), palladium catalyst Pd(OAc)2 (5.6 mg), ligand (23.3 mg) and cesium carbonate (407.3 mg) were added to a 25 mL round-bottom flask, and then solvent (2.5 mL of toluene and 2.5 mL of water) was added, and then stirred at 80°C for 24 h. The crude product after the reaction was directly separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:10-1:20, v / v) to obtain 144.7 mg of 3,4-di(4-methylbenzyl)-5-phenylfuran-2(5H)-one (IVab) in a yield of 82%.

[0040] The reaction scheme of this embodiment is as follows:

[0041]

[0042] The characterization data of the obtained product (IIIab) are as follows:

[0043] Light yellow oil (151.1 mg, 82%);

[0044] 1 H NMR (400MHz, CDCl3): δ7.30-7.18(m,4H)7.17-7.14(m,3H),7.11(d,J=7.9Hz,2H),7.09(d ,J=8.0Hz,2H),6.93(d,J=8.0Hz,2H),6.19(s,1H),3.74(s,2H),3.71(s,2H),2.32(s,2H);

[0045] 13 C NMR (100MHz, CDCl3): δ175.2,146.3,138.2,136.3,135.2,129.1,128.9,128.8,128.5,127.9,127.5,83.0,34.6,33.3,21.6,21.5;

[0046] HRMS (ESI) m / z calcd.for C 26 H 25 O2[M+H] + :369.1855,found:369.1857.

[0047] Example 3

[0048] Synthesis of 3,4-bis(2-methylbenzyl)-5-phenylfuran-2(5H)-one (IVac)

[0049] Under nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ia) (159 mg), (2-methylbenzyl)boric acid (IIc) (187.5 mg), palladium catalyst Pd(OAc)2 (5.6 mg), ligand (23.3 mg) and cesium carbonate (407.3 mg) were added to a 25 mL round-bottom flask, and then solvent (2.5 mL of toluene and 2.5 mL of water) was added, and then stirred at 80°C for 24 h. The crude product after the reaction was directly separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:10-1:20, v / v) to obtain 79.2 mg of 3,4-di(2-methylbenzyl)-5-phenylfuran-2(5H)-one (IVac) in a yield of 43%.

[0050] The reaction scheme of this embodiment is as follows:

[0051]

[0052] The characterization data of the obtained product (IVac) are as follows:

[0053] Light yellow oil (79.5 mg, 43%);

[0054] 1 H NMR (400MHz, CDCl3) δ7.30-7.23(m,5H)7.21-7.09(m,8H),6.17(s,1H),3.69(s,2H),3.56(s,2H),2.30(s,3H),2.12(s,3H);

[0055] 13 C NMR (100MHz, CDCl3) δ175.0,160.6,146.3,136.5,136.3,135.7,135.2,134.2,130.9,130 .6,129.3,129.0,128.9,127.7,127.1,126.7,126.3,126.0,81.7,30.6,28.8,20.1,19.5;

[0056] HRMS (ESI) m / z calcd.for C 26 H 25 O2[M+H] + :369.1855,found:369.1854.

[0057] Example 4

[0058] Synthesis of 3,4-bis(2-methylbenzyl)-5-phenylfuran-2(5H)-one (IVad)

[0059] Under nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ia) (159 mg), (4-methoxybenzyl)boric acid (IId) (207.5 mg), palladium catalyst Pd(OAc)2 (5.6 mg), ligand (23.3 mg) and cesium carbonate (407.3 mg) were added to a 25 mL round-bottom flask, and then solvent (2.5 mL of toluene and 2.5 mL of water) was added, and then stirred at 80°C for 24 h. The crude product after the reaction was directly separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:10-1:20, v / v) to obtain 152.1 mg of 3,4-di(2-methylbenzyl)-5-phenylfuran-2(5H)-one (IVad) in a yield of 76%.

[0060] The reaction scheme of the present embodiment is as follows:

[0061]

[0062] The characterization data of the obtained product (IVad) are as follows:

[0063] Light yellow oil (152.1 mg, 76%);

[0064] 1 H NMR (400MHz, CDCl3) δ7.30-7.18(m,7H),7.17(d,J=8.4Hz,2H),6.90(d,J=8.4Hz,2H),6.85( d,J=8.4Hz,2H),6.84(d,J=8.4Hz,2H),6.17(s,1H),3.78(s,6H),3.68(s,2H),3.63(s,2H);

[0065] 13 C NMR (100MHz, CDCl3) δ175.3,160.1,158.9,158.5,138.3,136.3,134.1,133.7,131.3,129.8,129.7,128.0,114.6,114.2,82.4,55.6,33.9,29.9;

[0066] HRMS (ESI) m / z calcd.for C 26 H 25 O4[M+H] + :401.1753,found:401.1752.

[0067] Example 5

[0068] Synthesis of 3,4-bis(4-chlorobenzyl)-5-phenylfuran-2(5H)-one (IVae)

[0069] Under nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ia) (159 mg), (4-chlorobenzyl)boric acid (IIe) (213 mg), palladium catalyst Pd(OAc)2 (5.6 mg), ligand (23.3 mg) and cesium carbonate (407.3 mg) were added to a 25 mL round-bottom flask, and then solvent (2.5 mL of toluene and 2.5 mL of water) was added, and then stirred at 80°C for 24 h. The crude product after the reaction was directly separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:10-1:20, v / v) to obtain 126.9 mg of 3,4-di(4-chlorobenzyl)-5-phenylfuran-2(5H)-one (IVae) in a yield of 62%.

[0070] The reaction scheme of this embodiment is as follows:

[0071]

[0072] The characterization data of the obtained product (IVae) are as follows:

[0073] Light yellow oil (126.9 mg, 62%);

[0074] 1 H NMR (400MHz, CDCl3): δ7.39(d,J=8.3Hz,2H),7.30-7.18(m,5H),7.27(d,J=8.3Hz,2H),7.20(d,J=8.3 Hz,2H),7.17(d,J=8.3Hz,2H),6.97(d,J=8.3Hz,2H),6.17(s,1H); (s,2H),3.71(s,2H),3.67(s,2H);

[0075] 13 C NMR (100MHz, CDCl3): δ175.2,159.4,146.3,138.2,136.3,134.2,133.6,129.5,128.9,128.8,128.5,127.9,127.4,81.4,34.1,29.2;

[0076] HRMS (ESI) m / z calcd.for C 24 H 19 Cl2O2[M+H] + :409.0762,found:409.0763.

[0077] Example 6

[0078] Synthesis of 3,4-Benzhydryl-5-methylfuran-2(5H)-one (IVba)

[0079] Under nitrogen atmosphere, 3,4-dibromo-5-methylfuran-2(5H)-one (Ia) (128 mg), benzylboronic acid (IIa) (170 mg), palladium catalyst Pd(OAc)2 (5.6 mg), ligand (23.3 mg) and cesium carbonate (407.3 mg) were added to a 25 mL round-bottom flask, and then solvent (2.5 mL of toluene and 2.5 mL of water) was added, and then stirred at 80°C for 24 h. The crude product after the reaction was directly separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:10-1:20, v / v) to obtain 3,4-dibenzhydryl-5-methylfuran-2(5H)-one (IVba) 97.4 mg, with a yield of 70%.

[0080] The reaction scheme of the present embodiment is as follows:

[0081]

[0082] The characterization data of the obtained product (IVba) are as follows:

[0083] Light yellow oil (97.4 mg, 70%);

[0084] 1 H NMR (400MHz, CDCl3): δ7.30-7.24(m,8H); 7.03-7.00(m,2H); 5.12(d,J=6.7Hz,1H); 3.72(s,2H),3.71(s,2H),1.60(d,J=6.7Hz,3H);

[0085] 13 C NMR (100MHz, CDCl3): δ176.0,138.2,136.0,129.4,128.9,128.8,128.7,127.9,127.5,127.1,126.9,71.5,33.8,29.8,78.0,33.7,29.8,17.6;

[0086] HRMS (ESI) m / z calcd.for C 19 H 19 O2[M+H] + :279.1385,found:279.1384.

[0087] Comparative Example 1

[0088] Synthesis of 3,4-Benzhydryl-5-phenylfuran-2(5H)-one (IVaa)

[0089] Under nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ia) (159 mg), benzylboronic acid (IIa) (170 mg), palladium catalyst Pd(OAc)2 (5.6 mg), cesium carbonate (407.3 mg) were added to a 25 mL round-bottom flask, and then solvent (2.5 mL of toluene and 2.5 mL of water) was added, and then stirred at 80°C for 24 h. The crude product after the reaction was directly separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:10-1:20, v / v) to obtain 3,4-dibenzhydryl-5-phenylfuran-2(5H)-one (IVaa) 5 mg, with a yield of <3%.

[0090] In this comparative example, no ligand was added, and the yield of the obtained target product was low.

[0091] The above are only some embodiments of the present invention, and do not limit the present invention in any form. Any simple modification, equivalent changes and modifications made to the above embodiments based on the technical essence of the invention are within the scope of the technical solution of the present invention.

Claims

1. A method for efficiently synthesizing Maculalactone A skeleton based on Suzuki-Miyaura cross-coupling reaction, characterized in that: The method comprises the following steps: in an organic solvent, under the catalysis of a palladium catalyst system, in the presence of an additive and a base, a γ-substituted-butyrolactone compound I and a benzyl-substituted boronic acid compound II or a trifluoroborate compound III undergo a Suzuki-Miyaura cross-coupling reaction to obtain Maculalactone A and a skeleton compound IV thereof; the palladium catalyst system comprises a palladium catalyst and a ligand; The γ-substituted-butyrolactone compound I, benzyl-substituted boronic acid compound II, trifluoroborate compound III, and skeleton compound IV are respectively: in, R is methyl, ethyl, phenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-methylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3,4-dimethoxyphenyl, allyl or benzyl; The R 1 is a bromine atom, a chlorine atom or a trifluoromethanesulfonyl group; The R 2 is hydrogen, halogen, trifluoromethyl, cyano, methoxy, tert-butyldimethylsilyloxy, ester or aryl.

2. The method according to claim 1, characterized in that The organic solvent is one of dichloromethane, tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane, acetone, acetonitrile, toluene or p-xylene; the ratio of the mole number of the γ-substituted-butyrolactone compound I to the volume of the organic solvent is 0.05-1 mmol:1 mL, and more preferably 0.2-0.5 mmol:1 mL.

3. The method according to claim 1, characterized in that The palladium catalyst is PdCl2(dppf) or Pd(OAc)2; the molar ratio of the palladium catalyst to the γ-substituted-butyrolactone compound I is 0.005-0.05:1; and the molar ratio of the palladium in the palladium catalyst to the ligand is 1:

2.

4. The method according to claim 1, characterized in that: The additive is distilled water; the volume ratio of the additive to the organic solvent is 0.5 to 2:1, and more preferably 0.5 to 0.75:

1.

5. The method according to claim 1, characterized in that The base is cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, triethylamine or N,N-diisopropylethylamine, and the ligand is XPhos or RuPhos.

6. The method according to claim 1, characterized in that The molar ratio of the benzyl substituted boronic acid compound II to the γ-substituted-butyrolactone compound I is 1 to 3:1, and more preferably 2 to 2.5:1; the molar ratio of the trifluoroborate compound III to the γ-substituted-butyrolactone compound I is 1 to 3:1, and more preferably 2 to 2.5:

1.

7. The method according to claim 1, characterized in that The Suzuki-Miyaura cross-coupling reaction is carried out under an inert gas atmosphere, and the inert gas is nitrogen or argon.

8. The method according to claim 1, characterized in that The temperature of the Suzuki-Miyaura coupling reaction is 25 to 100° C., more preferably 50 to 80° C.; the time of the cycloaddition reaction is 20 to 50 hours, more preferably 40 to 48 hours.

9. The method according to claim 1, characterized in that: The post-treatment steps of the reaction solution obtained after the coupling reaction of γ-substituted-butyrolactone compound I and benzyl-substituted boronic acid compound II or trifluoroborate compound III are as follows: the reaction solution is separated by silica gel column chromatography to obtain Maculalactone A skeleton compound IV, and the eluent is a mixed solvent of ethyl acetate and petroleum ether, wherein the volume ratio of ethyl acetate to petroleum ether in the mixed solvent of ethyl acetate and petroleum ether is 0.05-0.2:1.

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