A method for efficiently synthesizing Maculalactone A skeleton based on Suzuki-Miyaura cross-coupling reaction

Abstract

The present application relates to a kind of Maculalactone A skeleton by Suzuki-Miyaura cross coupling reaction synthesis method, comprising the following steps: in organic solvent, in the presence of additive, under the catalysis of palladium catalytic system, γ-substituted-butyrolactone compound I and benzyl substituted boronic acid compound II or trifluoroborate compound III occur Suzuki-Miyaura cross coupling reaction, obtain Maculalactone A skeleton IV;The palladium catalytic system is composed of palladium catalyst and ligand.The method of the present application uses simple and easily available, low-cost palladium catalyst and commercial ligand as catalytic system, and Maculalactone A skeleton is efficiently prepared by Suzuki-Miyaura coupling reaction, and the method for synthesizing Maculalactone A skeleton by Suzuki-Miyaura coupling reaction of the present application has the advantages of convenient operation, wide substrate application range, reaction raw material is cheap and easy to obtain.

Description

Technical Field

[0001] This invention relates to a method for synthesizing the Maculalactone A skeleton via the Suzuki–Miyaura cross-coupling reaction, belonging to the field of organic synthesis technology. Background Technology

[0002] Maculalactone A is a type of marine... K. maculans A natural product was isolated from the bacteria, possessing a polysubstituted -2(5H)-furanone skeleton, exhibiting antibacterial and other biological activities. Furthermore, Maculalactone A can serve as a biosynthetic precursor for several other family-related natural products, maculalactones BM (GD Brown, H.-F. Wong, N. Hutchinson, S.-C. Lee, BKK Chan, GA Williams. Phytochemistry Reviews, 2004, 3, 381). The unique structure and excellent bioactivity of Maculalactone have attracted great interest from synthetic chemists. In recent years, researchers have developed various methods to synthesize Maculalactone Class A compounds (e.g., 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 suffer from limitations such as cumbersome synthetic steps and harsh reaction conditions, and the synthetic routes are not very economical in terms of step economy and atom economy.

[0003] Palladium-catalyzed Suzuki-Miyaura cross-coupling is an important reaction in modern organic synthesis, widely used in the synthesis of drug molecules, bioactive natural products, and other compounds. Akira Suzuki was awarded the 2010 Nobel Prize in Chemistry for his contributions to this research. However, methods for constructing the 2(5H)-furanone skeleton using palladium-catalyzed Suzuki-Miyaura cross-coupling are relatively few (Min Lei, Xianwen Gan, Kun Zhao, Anfeng Chen, Lihong Hu. Tetrahedron, 2015, 71, 7508). To date, no method has been reported for a one-step synthesis of the Maculalactone A skeleton based on palladium-catalyzed Suzuki-Miyaura cross-coupling. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a method for the efficient synthesis of the Maculalactone A skeleton based on a palladium-catalyzed Suzuki–Miyaura coupling reaction. The method of this invention uses readily available and inexpensive palladium catalysts and commercially available ligands as the catalytic system for the efficient synthesis of the Maculalactone A skeleton.

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

[0006] This invention provides a method for the efficient synthesis of the Maculalactone A skeleton based on the Suzuki–Miyaura cross-coupling reaction, comprising the following steps:

[0007] In an organic solvent, under palladium catalysis and in the presence of additives and a base, γ-substituted butyrolactone compound I and benzyl-substituted boric acid compound II or trifluoroborate compound III undergo a Suzuki–Miyaura cross-coupling reaction to yield Maculalactone A and its skeletal compound IV; the palladium catalysis system consists of a palladium catalyst and ligands.

[0008]

[0009] in,

[0010] The 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 It can be a bromine atom, a chlorine atom, or a trifluoromethanesulfonyl group;

[0012] The R 2 It can be hydrogen, halogen, trifluoromethyl, cyano, methoxy, tert-butyldimethylsiloxy, ester or aryl.

[0013] As a preferred embodiment 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 molar ratio of the γ-substituted butyrolactone compound I to the volume of the organic solvent is 0.05~1 mmol:1 mL, more preferably 0.2~0.5 mmol:1 mL.

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

[0015] As a preferred embodiment 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, more preferably 0.5 to 0.75:1.

[0016] As a preferred embodiment of the present invention, the alkali 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 embodiment of the present invention, the molar ratio of the benzyl-substituted boric acid compound II to the γ-substituted butyrolactone compound I is 1 to 3:1, 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, more preferably 2 to 2.5:1.

[0018] As a preferred embodiment of the present invention, the Suzuki–Miyaura cross-coupling reaction is carried out in an inert gas atmosphere, wherein the inert gas is nitrogen or argon.

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

[0020] As a preferred embodiment of the present invention, the post-processing steps of the reaction solution obtained after the coupling reaction of γ-substituted butyrolactone compound I and benzyl-substituted boric 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 is 0.05 to 0.2:1.

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

[0022] 1. This invention uses γ-substituted butyrolactone compound I with different substituents and benzyl-substituted boric acid compound II or trifluoroborate compound III as raw materials, and uses a simple, readily available and inexpensive palladium catalyst and commercially available ligands as catalytic systems to efficiently prepare the Maculalactone A skeleton via the Suzuki–Miyaura coupling reaction.

[0023] 2. The catalyst used in the method of the present invention is a simple, readily available, and inexpensive palladium catalyst and a commercially available RuPhos ligand as the catalytic system. It 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 the Maculalactone A skeleton by palladium-catalyzed Suzuki–Miyaura coupling reaction has the advantages of convenient operation, wide range of applicable substrates, and inexpensive and readily available reaction raw materials. Detailed Implementation

[0024] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0025] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments of the invention. For example, as used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0026] The yields described in the following examples are molar yields. Example 1

[0027] Synthesis of 3,4-diphenylmethyl-5-phenylfuran-2(5H)-one (IVaa)

[0028] Under a 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. Then, solvent (toluene 2.5 mL and water 2.5 mL) was added, and the mixture was stirred at 80 °C for 24 h. The crude product was then purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10~1:20, v / v) to obtain 144.7 mg of 3,4-diphenylmethyl-5-phenylfuran-2(5H)-one (IVaa), with a yield of 85%.

[0029] The reaction route in this embodiment is as follows:

[0030]

[0031] The characterization data of the obtained product (IVaa) are as follows:

[0032] A pale yellow oily substance (144.7 mg, 82%);

[0033] 1 H NMR (400 MHz, CDCl3): δ 7.30-7.03 (m, 15H) 6.20 (s, 1H); 3.73 (s, 2H), 3.72 (s, 2H);

[0034] 13 C NMR (100 MHz, CDCl3): δ 175.2, 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;

[0035] HRMS (ESI) m / z calcd. for C 25 H 20 O2 [M+H] + : 341.1542, found: 341.1541. Example 2

[0036] Synthesis of 3,4-bis(4-methylbenzyl)-5-phenylfuran-2(5H)-one (IVab)

[0037] Under a nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ia) (159 mg), (4-methylbenzyl)boronic 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. Then, solvent (2.5 mL toluene and 2.5 mL water) was added, and the mixture was stirred at 80 °C for 24 h. The crude product was then purified by column chromatography (eluting 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), with a yield of 82%.

[0038] The reaction route in this embodiment is as follows:

[0039]

[0040] The characterization data of the obtained product (Ⅲab) are as follows:

[0041] A pale yellow oily substance (151.1 mg, 82%);

[0042] 1 H NMR (400 MHz, CDCl3): δ 7.30-7.18 (m, 4H) 7.17-7.14 (m, 3H), 7.11 (d, J=7.9 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 6.19 (s, 1H), 3.74 (s, 2H), 3.71 (s, 2H), 2.32 (s, 2H);

[0043] 13 C NMR (100 MHz, CDCl3): δ 175.2, 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;

[0044] HRMS (ESI) m / z calcd. for C 26 H 25 O2 [M+H] + : 369.1855, found: 369.1857. Example 3

[0045] Synthesis of 3,4-bis(2-methylbenzyl)-5-phenylfuran-2(5H)-one (IVac)

[0046] Under a nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ia) (159 mg), (2-methylbenzyl)boronic 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. Then, solvent (2.5 mL toluene and 2.5 mL water) was added, and the mixture was stirred at 80 °C for 24 h. The crude product was then purified by column chromatography (eluting 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), with a yield of 43%.

[0047] The reaction route in this embodiment is as follows:

[0048]

[0049] The characterization data of the obtained product (IVac) are as follows:

[0050] A pale yellow oily substance (79.5 mg, 43%);

[0051] 1 H NMR (400 MHz, CDCl3) δ 7.30-7.23(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);

[0052] 13 C NMR (100 MHz, CDCl3) δ 175.0, 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;

[0053] HRMS (ESI) m / z calcd. for C 26 H 25 O2 [M+H] +: 369.1855, found: 369.1854. Example 4

[0054] Synthesis of 3,4-bis(2-methylbenzyl)-5-phenylfuran-2(5H)-one (IVad)

[0055] Under a nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ⅰa) (159 mg), (4-methoxybenzyl)boronic 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. Then, solvent (toluene 2.5 mL and water 2.5 mL) was added, and the mixture was stirred at 80 °C for 24 h. The crude product was then purified by column chromatography (eluting 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), with a yield of 76%.

[0056] The reaction route in this embodiment is as follows:

[0057]

[0058] The characterization data of the obtained product (IVad) are as follows:

[0059] A pale yellow oily substance (152.1 mg, 76%);

[0060] 1 H NMR (400 MHz, CDCl3) δ 7.30-7.18 (m, 7H), 7.17 (d,J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.84 (d,J=8.4 Hz, 2H), 6.17(s, 1H), 3.78 (s, 6H), 3.68 (s, 2H), 3.63 (s, 2H);

[0061] 13 C NMR (100 MHz, CDCl3) δ 175.3, 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;

[0062] HRMS (ESI) m / z calcd. for C 26 H 25 O4 [M+H] + : 401.1753, found: 401.1752. Example 5

[0063] Synthesis of 3,4-bis(4-chlorobenzyl)-5-phenylfuran-2(5H)-one (IVae)

[0064] Under a nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ia) (159 mg), (4-chlorobenzyl)boronic 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. Then, solvent (toluene 2.5 mL and water 2.5 mL) was added, and the mixture was stirred at 80 °C for 24 h. The crude product was then purified by column chromatography (eluting 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), with a yield of 62%.

[0065] The reaction route in this embodiment is as follows:

[0066]

[0067] The characterization data of the obtained product (IVae) are as follows:

[0068] A pale yellow oily substance (126.9 mg, 62%);

[0069] 1 H NMR (400 MHz, CDCl3): δ 7.39 (d, J=8.3 Hz, 2H), 7.30-7.18 (m, 5H), 7.27 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 6.97(d, J=8.3 Hz,2H), 6.17 (s, 1H); (s, 2H), 3.71 (s, 2H), 3.67 (s, 2H);

[0070] 13C NMR (100 MHz, CDCl3): δ 175.2, 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;

[0071] HRMS (ESI) m / z calcd. for C 24 H 19 Cl2O2 [M+H] + :409.0762, found: 409.0763. Example 6

[0072] Synthesis of 3,4-diphenylmethyl-5-methylfuran-2(5H)-one (IVba)

[0073] Under a nitrogen atmosphere, 3,4-dibromo-5-methylfuran-2(5H)-one (Ia) (128 mg), benzyl boric 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. Then, solvent (toluene 2.5 mL and water 2.5 mL) was added, and the mixture was stirred at 80 °C for 24 h. The crude product was then purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10~1:20, v / v) to obtain 97.4 mg of 3,4-diphenylmethyl-5-methylfuran-2(5H)-one (IVba), with a yield of 70%.

[0074] The reaction route in this embodiment is as follows:

[0075]

[0076] The characterization data of the obtained product (IVba) are as follows:

[0077] A pale yellow oily substance (97.4 mg, 70%);

[0078] 1 H NMR (400 MHz, CDCl3): δ 7.30-7.24 (m, 8H); 7.03-7.00 (m, 2H); 5.12 (d,J = 6.7 Hz, 1H); 3.72 (s, 2H), 3.71 (s, 2H), 1.60 (d, J = 6.7 Hz, 3H);

[0079] 13C NMR (100 MHz, CDCl3): δ 176.0, 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;

[0080] HRMS (ESI) m / z calcd. for C 19 H 19 O2 [M+H] + : 279.1385, found: 279.1384. Comparative Example 1

[0081] Synthesis of 3,4-diphenylmethyl-5-phenylfuran-2(5H)-one (IVaa)

[0082] Under a nitrogen atmosphere, 3,4-dibromo-5-phenylfuran-2(5H)-one (Ia) (159 mg), benzyl boric acid (IIa) (170 mg), palladium catalyst Pd(OAc)2 (5.6 mg), and cesium carbonate (407.3 mg) were added to a 25 mL round-bottom flask. Then, solvent (toluene 2.5 mL and water 2.5 mL) was added, and the mixture was stirred at 80 °C for 24 h. The crude product was then purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10~1:20, v / v) to obtain 5 mg of 3,4-diphenylmethyl-5-phenylfuran-2(5H)-one (IVaa), with a yield of <3%.

[0083] No ligand was added in this comparative example, resulting in a lower yield of the target product.

[0084] The above are only some embodiments of the present invention and are not intended to limit the present invention in any way. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the invention shall fall within the scope of the technical solution of the present invention.

Claims

1. A method for the efficient synthesis of the Maculalactone A skeleton based on the Suzuki–Miyaura cross-coupling reaction, characterized in that, The steps include the following: In an organic solvent, under the catalysis of a palladium catalytic system, and in the presence of additives and a base, γ-substituted butyrolactone compound I and benzyl-substituted boric acid compound II undergo a Suzuki–Miyaura cross-coupling reaction to yield Maculalactone A skeleton compound IV; the palladium catalytic system consists of a palladium catalyst and ligands; The γ-substituted butyrolactone compound I, the benzyl-substituted boric acid compound II, and the Maculalactone A skeleton compound IV are respectively: ； in, The palladium catalyst is Pd(OAc)2; The ligand is XPhos or RuPhos; The additive is distilled water; The 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 It can be a bromine atom, a chlorine atom, or a trifluoromethanesulfonyl group; The R 2 It can be hydrogen, halogen, trifluoromethyl, cyano, methoxy, tert-butyldimethylsiloxy, 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 molar ratio of the γ-substituted butyrolactone compound I to the volume of the organic solvent is 0.05~1 mmol:1 mL.

3. The method according to claim 1, characterized in that, The molar ratio of the palladium catalyst to γ-substituted butyrolactone compound I is 0.005~0.05∶1; the molar ratio of palladium to ligand in the palladium catalyst is 1∶2.

4. The method according to claim 1, characterized in that, The volume ratio of the additive to the organic solvent is 0.5 to 2:

1.

5. The method according to claim 1, characterized in that, The alkali is cesium carbonate, potassium carbonate, sodium carbonate, or potassium phosphate.

6. The method according to claim 1, characterized in that, The molar ratio of the benzyl-substituted boric acid compound II to the γ-substituted butyrolactone compound I is 1 to 3:

1.

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

8. The method according to claim 1, characterized in that, The temperature for the Suzuki–Miyaura coupling reaction is 25–100 °C.

9. The method according to claim 1, characterized in that, The post-processing steps of the reaction solution obtained after the coupling reaction of γ-substituted butyrolactone compound I and benzyl-substituted boric acid compound II are as follows: the reaction solution is separated by silica gel column chromatography to obtain Maculalactone A skeleton compound IV. 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 is 0.05 to 0.2:1.

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