KR101206123B1 - Synthesis method of compound having stilbene skeleton - Google Patents
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Abstract
The present invention relates to an efficient and simple method for synthesizing a compound having a stilbene skeleton exhibiting various physiological activities, and more particularly, to Kirikanin A, arachibine-1, and trans-araki, which occur naturally and exhibit various physiological activities. The present invention relates to a synthetic method capable of easily synthesizing a compound having a stilbene skeleton such as dean-2, trans-arachidine-3, and arachibine-5 with greater efficiency.
Description
The present invention relates to an efficient and simple method for synthesizing a compound having a stilbene skeleton exhibiting various physiological activities.
Peanuts are grown worldwide and are known to be economically and nutritionally important. Approximately 50 species of fungus are parasitic in peanuts, of which Aspergillus flavus and Aspergillus parasiticus are known to be harmful and important because they produce carcinogenic aflatoxins. Peanut plants, however, produce stilbene-induced phytoalexins immediately and can therefore resist this fungal attack.
Peanut resistance mechanism against this fungus is important for new mold-resistant peanut cultivation, so the research on peanut resistance based on natural phytolensin has attracted attention. Recently, several types of stilbene derivatives have been isolated from peanuts as mold-resistant materials. Among them, resveratrol is known to be important for human health because it has various physiological activities. Kirikanin A isolated from Lonchocarpus chiricanus is also known for its antimicrobial activity against Cladosporium cucumerinum .
In particular, polyphenols with stilbene skeletons are widely found in nature and are antimicrobial, antimalarial, antioxidant, anti-leukemia, antiplatelet aggregation, anticancer, anti-HIV, protein tyrosine kinase inhibitory, anti-inflammatory, antimutagenic, antifungal And various physiological activities such as hepatoprotective effects.
However, it is still very important to develop a synthetic method capable of easily and efficiently preparing a compound having a stilbene skeleton such as Kirikanin A, which shows various physiological activities.
Accordingly, the present inventors have conducted research to efficiently synthesize compounds having stilbene skeletons such as Kirikanin A, Arahipin-1, Trans-Arachidin-2, Trans-Arachidin-3, and Arahipin-5. It is possible to synthesize compounds having the stilbene skeleton as described above efficiently and conveniently by using pinosylbin or ( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystilbene as starting materials. The present invention was completed by finding out.
An object of the present invention is a synthetic method capable of efficiently and conveniently synthesizing a compound having a stilbene skeleton, such as Kirikanin A, Arahipin-1, Trans-Arachidin-2, Trans-Arachidin-3, and Arahipin-5. To provide.
In order to achieve the above object, the present invention provides a method for preparing a compound having a stilbene skeleton comprising the step of preparing a compound of formula (2) using the pinosylbin represented by the formula (1) as a starting material:
[Formula 1]
[Formula 2]
In Formula 2, R 1 may be any one of 3-methylbut-2-enyl or (E) -3-methylbut-1-enyl.
As the compound having the stilbene skeleton, it may be any one selected from Kirikanin A or Arahipin-1.
As the starting material, the pinosylbin represented by Formula 1 is a Horner-Words-Emons reaction between 3,5-dimethoxybenzaldehyde (7) and benzyl phosphonate (8), as shown in Scheme 1-1. After the -Emmons Reaction, a demethylation reaction can be used to synthesize pinosylbin with stilbene backbone:
[Reaction Scheme 1-1]
More specifically, the Kirikanin A is reacted with the pinocylbin (10) and methoxymethyl chloride in the presence of NaH, as shown in Scheme 1 below to (E) -3,5-dimethoxymethoxystilbene (11) Synthesizing; (E) -3,5-dimethoxymethoxy-2- (3-methylbut) by reacting ( E ) -3,5-dimethoxymethoxystilbene (11) with n-butyllithium and prenyl bromide Synthesizing 2-enyl) stilbene (12); And treating ( E ) -3,5-dimethoxymethoxy-2- (3-methylbut-2-enyl) stilbene (12) with hydrochloric acid in the presence of methanol:
[Reaction Scheme 1]
In addition, the arachino-1 is reacted with the pinocylbin (10) and methoxymethyl chloride in the presence of NaH, as shown in Scheme 2-1 to (E) -3,5-dimethoxymethoxystilbene (11) Synthesizing; (E) -3,5-dimethoxymethoxy-2- (1-hydroxy) by reacting the ( E ) -3,5-dimethoxymethoxystilbene (11) with n-butyllithium and isovaleraldehyde Synthesizing -3-methylbutyl) stilbene (13); ( E ) -3,5-dimethoxymethoxy-2- (1-hydroxy-3-methylbutyl) stilbene (13) is reacted with POCl 3 to ( E ) -3,5-dimethoxymethoxy Synthesizing -2-{( E ) -3-methylbut-1-enyl)} stilbene (14); And ( E ) -3,5-dimethoxymethoxy-2-{( E ) -3-methylbut-1-enyl)} stilbene (14) with hydrochloric acid in the presence of methanol Can:
Scheme 2-1
In addition, the arachidin-1 may be prepared by reacting the pinocylbin (10) and isovalealdehyde in the presence of ethylenediamine diacetate in the presence of NaH, as shown in Scheme 2-2:
Scheme 2-2
In addition, the present invention is to prepare a compound of the formula (4) using ( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxy stilbene represented by the formula (3) as a starting material Provided are methods for preparing a compound having a stilbene skeleton comprising:
(3)
[Formula 4]
In Formula 4, R 1 may be any one of 3-methylbut-2-enyl or (E) -3-methylbut-1-enyl.
The compound having the stilbene skeleton may be any one selected from trans-arachidine-2 or trans-arachidine-3.
( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystillbene represented by Chemical Formula 3 is a benzaldehyde (15) having a methoxymethyl ether group and a benzyl phosphonate (16) having a TIPS group. Can be synthesized via the Horner-Wadsworth-Emmons Reaction between:
Scheme 3
In addition, the trans-arachidine-2 is a Horner-Wordworth-Emones reaction between benzaldehyde 15 having a methoxymethyl ether group and benzyl phosphonate 16 having a TIPS group, as shown in Scheme 4-1. Synthesizing ( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystilbene (17) via Wadsworth-Emmons Reaction); ( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystillbene (17) is reacted with n-butyllithium and prenyl bromide to ( E ) -3,5-dimethoxymethoxy Synthesizing oxy-2- (3-methylbut-2-enyl) -4'-triisopropylsilyloxystilbene (18); ( E ) -3,5-dimethoxymethoxy-2- (3-methylbut-2-enyl) -4'-triisopropylsilyloxystilbene (18) was treated with hydrochloric acid in the presence of methanol ( E Synthesizing) -3,5-dihydroxy-2- (3-methylbut-2-enyl) -4'-triisopropylsilyloxystilbene (19); And ( E ) -3,5-dihydroxy-2- (3-methylbut-2-enyl) -4'-triisopropylsilyloxystilbene (19) with tetrabutylammonium fluoride (TBAF) The reaction can be synthesized, including:
Scheme 4-1
In addition, the trans-arachidine-3 is a Horner-Wadsworth-Emmons reaction between benzaldehyde (15) having a methoxymethyl ether group and benzyl phosphonate (16) having a TIPS group as shown in Scheme 5 below. Reaction) to synthesize ( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystillbene (17); ( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystilbene (17) was treated with hydrochloric acid in the presence of methanol ( E ) -3,5-dihydroxy-4'- Synthesizing triisopropylsilyloxystilbene (20); The ( E ) -3,5-dihydroxy-4'-triisopropylsilyloxystilbene (20) is reacted with isovalealdehyde in the presence of ethylenediamine diacetate (EDDA) to ( E ) -3,5- Synthesizing dihydroxy-2-{( E ) -3-methylbut-1-enyl} -4'-triisopropylsilyloxystilbene (21); And tetrabutylammonium fluoride ( E ) -3,5-dihydroxy-2-{( E ) -3-methylbut-1-enyl} -4'-triisopropylsilyloxystilbene (21). Reaction with (TBAF) can be synthesized, including:
Scheme 5
In addition, the present invention using the ( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxy stilbene represented by the formula (3) as a starting material to prepare arachib-5 of the formula (5) It provides a method for preparing a compound having a stilbene skeleton comprising the steps of:
(3)
[Chemical Formula 5]
More specifically, the arachif-5 is a Horner-Words-Emons reaction between benzaldehyde 15 having a methoxymethyl ether group and benzyl phosphonate 16 having a TIPS group, as shown in Scheme 6 below. Synthesizing ( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystilbene (17) through -Emmons Reaction; ( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystilbene (17) was treated with hydrochloric acid in the presence of methanol ( E ) -3,5-dihydroxy-4'- Synthesizing triisopropylsilyloxystilbene (20); The ( E ) -3,5-dihydroxy-4'-triisopropylsilyloxystilbene (20) is reacted with 3-methyl-2-butenal in the presence of ethylenediamine diacetate (EDDA) ( E ) Synthesizing -2,2-dimethyl-7 [2- (4-triisopropylsilanyloxyphenyl) vinyl] -2H-chromen-5-ol (22); And ( E ) -2,2-dimethyl-7 [2- (4-triisopropylsilanyloxyphenyl) vinyl] -2H-chromen-5-ol (22) with tetrabutylammonium fluoride (TBAF) Can be synthesized, including the steps of:
[Reaction Scheme 6]
Therefore, according to the present invention, it has a stilbene skeleton such as Kirikanin A, arachidin-1, trans-arachidine-2, trans-arachidine-3, and arachib-5, which occur naturally and exhibit various physiological activities. Compounds can be easily synthesized with greater efficiency.
According to the present invention, stilbenes such as Kirikanin A, arachibine-1, trans-arachidine-2, trans-arachidine-3 and arachib-5, which occur naturally and exhibit various physiological activities, according to the present invention. Compounds having a skeleton can be easily synthesized with greater efficiency.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.
All experiments below were performed under a nitrogen atmosphere. To measure analytical TLC, pre-coated silica gel plates (Art. 5554) with a Merck fluorescent indicator were used. Flash column chromatography was performed using silica gel 9385 (Merck). And 1 H NMR and 13 C NMR analyzes were recorded via Bruker Model ARX (300 and 75 MHz) spectroscopy in CDCl 3, CD 3 OD or acetone-d 6 as solvent chemical shifts. IR analysis was measured using a Jasco FTIR 5300 spectrometer. HRMS analysis was performed by Korea Basic Science Institute.
Example 1 Synthesis of Kirikanin A
One. ( E ), 3,5-dimethoxymethoxystilbene (11) synthesis
To a solution containing pinocylbin (10; 0.509 g, 2.4 mmol) and NaH (0.288 g, 12.0 mmol) dissolved in dimethylformamide (DMF), methoxymethyl chloride (0.51 g, 6.3 mmol) was added at 0 ° C. . The reaction mixture was stirred for 12 hours at room temperature, then water (40 mL) was added at 0 ° C. The reaction mixture was extracted with ethyl acetate (3 × 30 mL), and the organic extract obtained was washed with saturated NH 4 Cl solution (30 mL), water (30 mL), dried over MgSO 4 , and the solvent was evaporated under reduced pressure. Flash chromatography on silica gel using hexanes / ethyl acetate (20: 1) gave oily compound 11 (0.591 g, 82%).
1 H NMR (300 MHz, CDCl 3 ) δ 7.41 (2H, d, J = 7.2 Hz), 7.26 (2H, dd, J = 7.5,7.2 Hz), 7.17 (1H, t, J = 7.5 Hz), 7.01 ( 1H, d, J = 16.0 Hz), 6.93 (1H, d, J = 16.0 Hz), 6.79 (2H, s), 6.57 (1H, s), 5.01 (4H, s), 3.41 (6H, s);
13 C NMR (75 MHz, CDCl 3 ) δ 158.5, 139.5, 137.0, 129.3, 128.6, 128.3, 127.7, 126.5, 107.8, 104.2, 94.4, 56.0;
IR (neat) 2953, 2825, 1591, 1454, 1400, 1282, 1213, 1147, 1084, 1035, 962, 923, 841, 752 cm −1 ;
HRMS m / z (M + ) calcd for C 18 H 20 O 4 : 300.1362. Found: 300.1364.
2. ( E Synthesis of) -3,5-dimethylmethoxymethoxy-2- (3-methylbut-2-enyl) stilbene (12)
A solution obtained by adding n- BuLi (0.72 mL, 2.5 M in hexane, 1.8 mmol) to a solution (0.451 g, 1.5 mmol) dissolved in tetrahydrofuran (THF; 20 mL) prepared above at 0 ° C. Stir at C for 2 hours. Prenyl bromide (0.238 g, 1.6 mmol) was added to the reaction mixture at 0 ° C., followed by stirring at room temperature for 10 hours. The reaction mixture was quenched with saturated NH 4 Cl solution (20 mL) and extracted with ethyl acetate (3 × 30 mL). The resulting extract was washed with water (30 mL), dried over MgSO 4 , and the solvent was evaporated under reduced pressure. Flash chromatography on silica gel using hexanes / ethyl acetate (20: 1) gave oily compound 12 (0.337 g, 61%).
1 H NMR (300 MHz, CDCl 3 ) δ 7.49 (2H, d, J = 7.2 Hz), 7.34 (2H, dd, J = 7.5,7.2 Hz), 7.23 (1H, t, J = 7.5 Hz), 7.03 ( 2H, s), 6.94 (2H, s), 5.24 (4H, s), 5.21 (1H, t, J = 7.2 Hz), 3.50 (6H, s), 3.39 (2H, d, J = 7.2 Hz), 1.79 (3H, s), 1.67 (3H, s);
13 C NMR (75 MHz, CDCl 3 ) δ 155.8, 137.3, 136.3, 131.1, 128.8, 128.6, 128.3, 127.5, 126.5, 122.7, 119.9, 106.2, 94.5, 56.0, 25.8, 22.8, 17.5;
IR (neat) 2912, 1600, 1576, 1438, 1394, 1316, 1211, 1153, 1102, 1048, 944, 750 cm −1 ;
HRMS m / z (M + ) calcd for C 23 H 28 O 4 : 368.1988. Found: 368.1990.
3. Synthesis of Kirikanin A (2)
The reaction mixture obtained by adding c-hydrochloric acid (0.2 mL) to a solution (0.184 g, 0.5 mmol) in which Compound 12 synthesized above was dissolved in methanol (5 mL) was stirred at room temperature for 10 hours. The reaction mixture was diluted with saturated NaHCO 3 solution (30 mL) and extracted with EtOAc (3 × 30 mL). The solvent was removed under reduced pressure to leave an oil residue, which was then purified by column chromatography on silica gel using hexane / ethyl acetate (4: 1) to give an oily compound 2 (0.094 g, 67%).
1 H NMR (300 MHz, CDCl 3 ) δ 7.46 (2H, d, J = 7.2 Hz), 7.34 (2H, t, J = 7.2 Hz), 7.24 (1H, t, J = 7.2 Hz), 6.99 (1H, d, J = 16.5 Hz), 6.91 (1H, d, J = 16.5 Hz), 6.57 (2H, s), 5.27 (1H, t, J = 6.9 Hz), 3.42 (2H, d, J = 6.9 Hz) , 1.82 (3H, s), 1.76 (3H, s);
13 C NMR (75 MHz, CDCl 3 ) δ 155.0, 137.2, 136.8, 135.6, 128.7, 128.6, 128.0, 127.6, 126.5, 121.3, 113,2, 106.5, 25.8, 22.5, 17.9;
IR (neat) 3412, 2973, 2925, 1611, 1584, 1445, 1352, 1264, 1158, 1051, 963, 826, 743 cm −1 ;
HRMS m / z (M + ) calcd for C 19 H 20 O 2 : 280.1463. Found: 280.1466.
[Reaction Scheme 1]
Example 2 Arahiffin-1 Synthesis
One. ( E Synthesis of) -3,5-dimethoxymethoxy-2- (1-hydroxy-3-methylbutyl) stilbene (13)
A solution obtained by adding n- BuLi (0.8 mL, 2.5 M in hexane, 2.0 mmol) to a solution (0.541 g, 1.8 mmol) dissolved in tetrahydrofuran (THF; 20 mL) prepared above at 0 ° C. Stir at C for 2 hours. Isovalaldehyde (0.164 g, 1.9 mmol) was added to the reaction mixture at 0 ° C., followed by stirring at room temperature for 10 hours. The reaction mixture was quenched with saturated NH 4 Cl solution (20 mL) and extracted with ethyl acetate (3 × 30 mL). The obtained extract was washed with water (30 mL), dried over MgSO 4 , and evaporated under reduced pressure. Flash chromatography on silica gel using hexanes / ethyl acetate (4: 1) gave oily compound 13 (0.494 g, 71%).
1 H NMR (300MHz, CDCl 3 ) δ 7.49 (2H, d, J = 7.2 Hz), 7.34 (2H, t, J = 7.2 Hz), 7.24 (1H, t, J = 7.2 Hz), 7.01 (1H, d, J = 16.2 Hz), 7.07 (1H, d, J = 16.2 Hz), 6.97 (2H, s), 5.28-5.25 (1H, m), 5.26 (3H, s), 3.50 (6H, s), 1.93-1.84 (1H, m), 1.80-1.71 (1H, m), 1.67-1.58 (1H, m), 0.99 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6 Hz) ;
13 C NMR (75 MHz, CDCl 3 ) δ 155.5, 137.5, 137.0, 129.0, 128.6, 128.2, 127.6, 126.5, 121.3, 106.3, 94.5, 66.3, 56.2, 47.0, 25.0, 23.2, 22.4;
IR (neat) 2953, 1603, 1576, 1448, 1215, 1152, 1100, 1042, 921, 751 cm −1 ;
HRMS m / z (M + ) calcd for C 23 H 30 O 5 : 386.2093. Found: 386.2097.
2. ( E ) -3,5-dimethoxymethoxy-2-{( E ) -3-methylbut-1-enyl)} Stilbene (14) Synthesis
The reaction mixture obtained by dissolving compound 13 (0.425 g, 1.1 mmol) in pyridine (10 mL), was cooled to 0 ° C., and a few drops of POCl 3 (0.506 g, 3.3 mmol) was added dropwise. The resulting reaction mixture was stirred at room temperature for 1 hour and then heated at 100 ° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and poured into 2N HCl (50 mL) to separate phases. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The resulting extract was washed with 2N HCl (50 mL), brine (50 mL), dried over MgSO 4 , and concentrated under reduced pressure. Flash chromatography on silica gel using hexanes / ethyl acetate (4: 1) gave 14 (0.259 g, 64%) in oil phase.
1 H NMR (300 MHz, CDCl 3 ) δ 7.50 (2H, d, J = 7.2 Hz), 7.34 (2H, t, J = 7.2 Hz), 7.25 (1H, t, J = 7.2 Hz), 7.01 (1H, d, J = 16.2 Hz), 7.07 (1H, d, J = 16.0 Hz), 6.95 (2H, s), 6.60-6.58 (2H, m), 5.24 (3H, s), 3.52 (6H, s), 2.53-2.43 (1 H, m), 1.10 (6 H, d, J = 6.6 Hz);
13 C NMR (75 MHz, CDCl 3 ) δ 155.9, 143.1, 137.2, 136.5, 128.6, 128.5, 127.6, 126.5, 117.2, 107.2, 94.9, 56.2, 33.1, 22.7;
IR (neat) 2955, 1600, 1447, 1393, 1152, 1044, 965, 824, 739 cm −1 ;
HRMS m / z (M + ) calcd for C 23 H 28 O 4 : 368.1988. Found: 368.1985.
3. Synthesis of Arahipin-1 (3) from Compound 14
The reaction mixture obtained by adding c-hydrochloric acid (0.5 mL) to a solution (0.184 g, 0.5 mmol) in which Compound 14 synthesized above was dissolved in methanol (5 mL) was stirred at room temperature for 10 hours. The reaction mixture was diluted with saturated NaHCO 3 solution (30 mL) and extracted with EtOAc (3 × 30 mL). The solvent was removed under reduced pressure to leave an oil residue, which was then purified by column chromatography on silica gel using hexanes / ethyl acetate (4: 1) to afford 3 (0.035 g, 25%) in oil phase.
1 H NMR (300 MHz, CDCl 3 ) δ 7.46 (2H, d, J = 7.6 Hz), 7.33 (2H, t, J = 7.6 Hz), 7.24 (1H, t, J = 7.6 Hz), 7.03 (1H, d, J = 16.2 Hz), 6.93 (1H, d, J = 16.2 Hz), 6.63 (2H, s), 6.31 (1H, d, J = 16.5 Hz), 6.15 (1H, dd, J = 16.5,6.6 Hz), 5.34 (1H, brs), 2.60-2.49 (1H, m), 1.13 (6H, d, J = 7.2 Hz);
13 C NMR (75 MHz, CDCl 3 ) δ 153.8, 145.6, 137.6, 137.0, 129.1, 128.6, 127.9, 127.6, 126.5, 117.2, 111.8, 105.8, 32.2, 22.3;
IR (neat) 3409, 2949, 1624, 1574, 1433, 1360, 1301, 1028, 975, 828 cm −1 ;
HRMS m / z (M + ) calcd for C 19 H 20 O 2 : 280.1463. Found: 280.1466.
4. Synthesis of Arahipin-1 (3) from Compound 10
Ethylenediamine diacetate (36 mg, 0.2 mmol) was added to a solution of previously synthesized compound 10 (0.212 g, 1.0 mmol) and isovalealdehyde (0.129 g, 1.5 mmol) in benzene (20 mL) at room temperature. . The reaction mixture was refluxed for 10 hours and then cooled to room temperature. The solvent was evaporated and purified via column chromatography on silica gel using hexanes / ethyl acetate (4: 1) to afford 3 (0.151 g, 54%) in oil phase. At this time, the analysis data of the obtained compound 3 is the same as before.
Scheme 2
Example 3 Trans-Arachidin-2 Synthesis
One. ( E Synthesis of) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystilbene (17)
To a solution of aldehyde (15; 0.679 g, 3.0 mmol) and benzyl phosphonate (16; 1.202 g, 3.0 mmol) in THF (30 mL) was added t- BuOK (0.717 g, 6.4 mmol) at 0 ° C. . The reaction mixture was stirred at 0 ° C. for 5 hours. The reaction mixture was quenched by addition of water (30 mL) and extracted with EtOAc (3 × 30 mL). The resulting organic layer was washed with NH 4 Cl solution (30 mL), water (30 mL), brine (30 mL), dried over MgSO 4 and concentrated under reduced pressure. The solvent was removed under reduced pressure to leave an oil residue, which was then purified by column chromatography on silica gel using hexane / ethyl acetate (4: 1) to give an oily compound 17 (1.163 g, 82%).
1 H NMR (300 MHz, CDCl 3 ) δ 7.35 (2H, d, J = 9.0 Hz), 7.01 (1H, d, J = 16.2 Hz), 6.88-6.81 (5H, m), 6.60 (1H, t, J = 2.0 Hz), 5.17 (4H, s), 3.48 (6H, s), 1.41-1.20 (3H, m), 1.09 (18H, d , J = 7.2 Hz);
13 C NMR (75 MHz, CDCl 3 ) δ 158.2, 155.7, 139.7, 129.8, 128.8, 127.5, 126.0, 119.8, 107.4, 94.2, 55.7, 17.6, 12.4;
IR (neat) 2952, 2868, 1597, 1509, 1463, 1396, 1275, 1151, 1037, 918, 841 cm −1 ;
HRMS m / z (M + ) calcd for C 27 H 40 O 5 Si: 472.2645. Found: 472.2646.
2. ( E Synthesis of -3,5-dimethoxymethoxy-2- (3-methylbut-2-enyl) -4'-triisopropylsilyloxystilbene (18)
A solution obtained by adding n- BuLi (0.44 mL, 2.5 M in hexanes, 1.1 mmol) at 0 ° C. to a solution (0.473 g, 1.0 mmol) dissolved in tetrahydrofuran (THF; 20 mL) prepared before was added to 0 Stir at C for 2 hours. Prenyl bromide (0.164 g, 1.1 mmol) was added to the reaction mixture at 0 ° C. and stirred at room temperature for 10 hours. The reaction mixture was quenched with saturated NH 4 Cl solution (20 mL) and extracted with ethyl acetate (3 × 30 mL). The obtained extract was washed with water (30 mL), dried over MgSO 4 , and evaporated under reduced pressure. Flash chromatography on silica gel using hexanes / ethyl acetate (5: 1) gave 18 (0.433 g, 80%) in oil phase.
1 H NMR (300 MHz, CDCl 3 ) δ 7.36 (2H, d, J = 7.8 Hz), 7.01-6.84 (6H, m), 5.23 (4H, s), 5.22 (1H, t, J = 6.5 Hz), 3.50 (6H, s), 3.39 (2H, d, J = 6.5 Hz), 1.78 (3H, s), 1.67 (3H, s), 1.38-1.19 (3H, m), 1.11 (18H, d , J = 6.6 Hz);
13 C NMR (75 MHz, CDCl 3 ) δ 155.8, 155.7, 136.8, 131.0, 130.4, 128.0, 127.6, 126.7, 122.8, 120.1, 119.5, 106.0, 94.5, 56.0, 25.8, 22.8, 17.9, 12.7;
IR (neat) 2947, 1599, 1511, 1452, 1271, 1156, 1053, 916 cm −1 ;
HRMS m / z (M + ) calcd for C 32 H 48 O 5 Si: 540.3271. Found: 540.3268.
3. ( E Synthesis of -3,5-dihydroxy-2- (3-methylbut-2-enyl) -4'-triisopropylsilyloxystilbene (19)
The reaction mixture obtained by adding c-hydrochloric acid (0.5 mL) to a solution (0.27 g, 0.5 mmol) in which Compound 18 synthesized above was dissolved in methanol (5 mL) was stirred at room temperature for 10 hours. The reaction mixture was diluted with saturated NaHCO 3 solution (30 mL) and extracted with EtOAc (3 × 30 mL). The solvent was removed under reduced pressure to leave an oil residue, which was then purified by column chromatography on silica gel using hexanes / ethyl acetate (4: 1) to afford 19 (0.181 g, 80%) in oil phase.
1 H NMR (300 MHz, CDCl 3 ) δ 7.33 (2H, d, J = 8.7 Hz), 7.01 (1H, d, J = 16.2 Hz), 6.85 (2H, d, J = 8.7 Hz), 6.76 (1H, d, J = 16.8 Hz), 6.53 (2H, s), 5.40 (1H, brs), 5.27 (1H, t, J = 6.6 Hz), 3.41 (2H, d, J = 6.6 Hz), 1.82 (3H, s), 1.75 (3H, s), 1.34-1.20 (3H, m), 1.11 (18H, d , J = 6.9 Hz);
13 C NMR (75 MHz, CDCl 3 ) δ 155.8, 155.0, 137.2, 135.3, 130.2, 128.3, 127.6, 125.9, 121.5, 120.1, 112.8, 106.2, 25.7, 22.5, 17.8, 12.6;
IR (neat) 2946, 2865, 1598, 1509, 1456, 1391, 1269, 1155, 1103, 1051, 916, 838 cm −1 ;
HRMS m / z (M + ) calcd for C 28 H 40 O 3 Si: 452.2747. Found: 452.2745.
4. Synthesis of trans-arachidine-2 (4)
TBAF (0.6 mL, 0.6 mmol, 1.0 M in THF) was added at 0 ° C. to a solution (0.136 g, 0.3 mmol) in which Compound 19 synthesized above was dissolved in THF (10 mL). The reaction mixture was quenched by addition of saturated NH 4 Cl solution (30 mL) and extracted with EtOAc (3 × 30 mL). The obtained organic layer was washed with water (30 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The obtained material was purified by column chromatography using hexane / ethyl acetate (4: 1) to give an oily 4 (0.067 g, 75%).
1 H NMR (300 MHz, acetone- d 6 ) δ 8.41 (1H, s), 8.07 (1H, s), 7.38 (2H, d, J = 8.7 Hz), 6.93 (1H, d, J = 16.2 Hz), 6.84-6.79 (3H, m), 6.59 (2H, s), 5.30 (1H, t, J = 7.2 Hz), 3.35 (2H, d, J = 7.2 Hz), 1.76 (3H, s), 1.64 (3H , s);
13 C NMR (75 MHz, acetone- d 6 ) δ 158.0, 157.0, 137.3, 130.8, 130.1, 128.6, 128.2, 127.0, 124.4, 116.5, 115.3, 105.8, 26.0, 23.2, 18.0;
IR (neat) 3389, 2926, 1599, 1513, 1437, 1358, 1250, 1166, 1047, 819 cm −1 ;
HRMS m / z (M + ) calcd for C 19 H 20 O 3 : 296.1412. Found: 296.1414.
Scheme 4
Example 4 Trans-Arachidin-3 Synthesis
One. ( E Synthesis of) -3,5-dihydroxy-4'-triisopropylsilyloxystilbene (20)
The reaction mixture obtained by adding c-hydrochloric acid (1.0 mL) to a solution (0.473 g, 1.0 mmol) in which Compound 17 synthesized above was dissolved in methanol (5 mL) was stirred at room temperature for 10 hours. The reaction mixture was diluted with saturated NaHCO 3 solution (30 mL) and extracted with EtOAc (3 × 30 mL). The solvent was removed under reduced pressure to leave an oil residue, which was then purified by column chromatography on silica gel using hexane / ethyl acetate (4: 1) to give 20 (0.308 g, 80%) in oil phase.
1 H NMR (300 MHz, CDCl 3 ) δ 7.33 (2H, d, J = 8.7 Hz), 6.97 (1H, d, J = 16.2 Hz), 6.84 (2H, d, J = 8.7 Hz), 6.79 (1H, d, J = 16.2 Hz), 6.52 (2H, d, J = 2.1 Hz), 6.23 (1H, t, J = 2.1 Hz), 1.30-1.22 (3H, m), 1.09 (18H, d , J = 7.2 Hz);
13 C NMR (75 MHz, CDCl 3 ) δ 156.7, 156.0, 140.4, 130.0, 129.2, 127.8, 125.8, 120.1, 106.0, 101.9, 17.9, 12.6;
IR (neat) 3389, 2946, 1602, 1510, 1270, 1156, 1007, 911 cm −1 ;
HRMS m / z (M + ) calcd for C 23 H 32 O 3 Si: 384.2121. Found: 384.2118.
2. ( E ) -3,5-dihydroxy-2-{( E ) -3-methylbut-1-enyl)}-4'-triisopropylsilyloxystilbene (21) synthesis
Ethylenediamine diacetate (14 mg, 0.08 mmol) was added to a solution of previously prepared compound 20 (0.154 g, 0.4 mmol) and isovalealdehyde (0.043 g, 0.5 mmol) in benzene (20 mL) at room temperature. The reaction mixture was refluxed for 10 hours and then cooled to room temperature. The solvent was removed and purified via column chromatography on silica gel using hexanes / ethyl acetate (5: 1) to afford 21 (0.094 g, 52%) in oil phase.
1 H NMR (300 MHz, CDCl 3 ) δ 7.34 (2H, d, J = 8.7 Hz), 7.32 (1H, brs), 6.97 (1H, d, J = 16.2 Hz), 6.86 (2H, d, J = 8.7 Hz), 6.78 (1H, d, J = 16.2 Hz), 6.60 (2H, s), 6.31 (1H, d, J = 16.5 Hz), 6.13 (1H, dd, J = 16.5,6.6 Hz), 5.30 ( 1H, brs), 2.60-2.48 (1H, m), 1.30-1.22 (3H, m), 1.10 (18H, d , J = 7.2 Hz);
13 C NMR (75 MHz, CDCl 3 ) δ 156.0, 153.8, 145,5, 130.1, 128.8, 128.3, 127.7, 125.8, 120.1, 117.4, 111.3, 105.5, 32.3, 22.4, 17.9, 12.6;
IR (neat) 3422, 2945, 2871, 1601, 1510, 1447, 1268, 1168, 1036, 909 cm −1 ;
HRMS m / z (M + ) calcd for C 28 H 40 O 3 Si: 452.2747. Found: 452.2743.
3. Trans-Arachidin-3 (5) Synthesis
TBAF (0.2 mL, 0.2 mmol, 1.0 M in THF) was added to a solution (0.045 g, 0.1 mmol) in which Compound 21, previously synthesized, was dissolved in THF (10 mL), and stirred at room temperature for 3 hours. The reaction mixture was quenched by addition of saturated NH 4 Cl solution (30 mL) and extracted with EtOAc (3 × 30 mL). The obtained organic layer was washed with water (30 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The obtained material was purified by column chromatography using hexanes / ethyl acetate (4: 1) to give an oily 5 (0.022 g, 74%).
1 H NMR (300 MHz, CDCl 3 ) δ 7.36 (2H, d, J = 8.7 Hz), 6.97 (1H, d, J = 16.2 Hz), 6.80 (2H, d, J = 8.7 Hz), 6.77 (1H, d, J = 16.2 Hz), 6.60 (2H, s), 6.29 (1H, d, J = 16.5 Hz), 6.12 (1H, dd, J = 16.5,6.6 Hz), 5.09 (1H, s), 2.60- 2.49 (1 H, m), 1.13 (6 H, d, J = 6.6 Hz);
13 C NMR (75 MHz, acetone- d 6 ) δ 158.2, 157.1, 141.3, 137.7, 130.0, 128.7, 128.6, 126.6, 119.3, 116.5, 112.7, 106.1, 34.0, 23.3;
IR (neat) 3393, 2931, 1598, 1512, 1435, 1246, 1034, 821 cm −1 ;
HRMS m / z (M + ) calcd for C 19 H 20 O 3 : 296.1412. Found: 296.1409.
Scheme 5
Example 5 Arahipine-5 Synthesis
One. ( E ) -2,2-dimethyl-7 [2- (4-triisopropylsilanyloxyphenyl) vinyl] -2H-chromen-5-ol (22) Synthesis
Ethylenediamine diacetate (11 mg, 0.06 mmol) was dissolved in a solution of 20 (0.115 g, 0.3 mmol) and 3-methyl-2-butenal (0.034 g, 0.4 mmol) prepared in benzene (20 mL). Was added. The reaction mixture was refluxed for 10 hours and then cooled to room temperature. The solvent was removed and purified via column chromatography on silica gel using hexanes / ethyl acetate (5: 1) to afford 22 (0.074 g, 55%) in oil phase.
1 H NMR (300 MHz, CDCl 3 ) δ 7.32 (2H, d, J = 8.4 Hz), 6.95 (1H, d, J = 16.2 Hz), 6.83 (2H, d, J = 8.4 Hz), 6.74 (1H, d, J = 16.2 Hz), 6.63 (1H, d, J = 9.9 Hz), 6.57 (1 H, s), 6.46 (1 H, s), 5.56 (1 H, d, J = 9.9 Hz), 1.34 (6 H, s), 1.26-1.11 (3H, m), 1.01 (18H, d , J = 6.9 Hz);
13 C NMR (75 MHz, CDCl 3 ) δ 155.9, 154.0, 151.6, 138.8, 130.2, 128.9, 128.6, 127.7, 126.1, 120.1, 116.6, 109.0, 106.9, 106.1, 76.0, 29.7, 27.8, 17.9, 12.7;
IR (neat) 3396, 3028, 2943, 2865, 1600, 1565, 1509, 1462, 1271, 1168, 1139, 1115, 1060, 912, 884 cm −1 ;
HRMS m / z (M + ) calcd for C 28 H 38 O 3 Si: 450.2590. Found: 450.2593.
2. Synthesis of arachin-5 (6)
TBAF (0.2 mL, 0.2 mmol, 1.0 M in THF) was added to a solution (0.045 g, 0.1 mmol) in which Compound 22, previously synthesized, was dissolved in THF (10 mL), and stirred at room temperature for 3 hours. The reaction mixture was quenched by addition of saturated NH 4 Cl solution (30 mL) and extracted with EtOAc (3 × 30 mL). The obtained organic layer was washed with water (30 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The resulting material was purified by column chromatography using hexanes / ethyl acetate (5: 1) to give 6 (0.028 g, 95%) in oily form.
1 H NMR (300 MHz, CD 3 OD) δ 7.35 (2H, d, J = 8.7 Hz), 6.96 (1H, d, J = 16.2 Hz), 6.80-6.76 (3H, m), 6.64 (1H, d, J = 9,9 Hz), 6.51 (1 H, s), 6.46 (1 H, s), 5.57 (1 H, d, J = 9.9 Hz), 4.87 (1 H, s), 1.40 (6 H, s);
13 C NMR (75 MHz, CD 3 OD) δ 158.4, 155.3, 154.4, 140.3, 130.5, 129.5, 129.2, 128.9, 126.9, 118.3, 116.6, 110.3, 106.9, 106.7, 76.8, 28.1;
IR (neat) 3412, 1655, 1512, 1441, 1252, 1010, 819, 761 cm −1 ;
HRMS m / z (M + ) calcd for C 19 H 18 O 3 : 294.1256. Found: 294.1256.
[Reaction Scheme 6]
While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
Claims (12)
[Formula 1]
(2)
In Formula 2, R 1 is any one of 3-methylbut-2-enyl or (E) -3-methylbut-1-enyl.
Reacting the pinocylbin (10) with methoxymethyl chloride in the presence of NaH to synthesize (E) -3,5-dimethoxymethoxytilbene (11);
(E) -3,5-dimethoxymethoxy-2- (3-methylbut) by reacting ( E ) -3,5-dimethoxymethoxystilbene (11) with n-butyllithium and prenyl bromide Synthesizing 2-enyl) stilbene (12); And
Treating ( E ) -3,5-dimethoxymethoxy-2- (3-methylbut-2-enyl) stilbene (12) with hydrochloric acid in the presence of methanol
Method for producing a compound having a stilbene skeleton, characterized in that it comprises:
[Reaction Scheme 1]
Reacting the pinocylbin (10) with methoxymethyl chloride in the presence of NaH to synthesize (E) -3,5-dimethoxymethoxytilbene (11);
(E) -3,5-dimethoxymethoxy-2- (1-hydroxy) by reacting the ( E ) -3,5-dimethoxymethoxystilbene (11) with n-butyllithium and isovaleraldehyde Synthesizing -3-methylbutyl) stilbene (13);
( E ) -3,5-dimethoxymethoxy-2- (1-hydroxy-3-methylbutyl) stilbene (13) is reacted with POCl 3 to ( E ) -3,5-dimethoxymethoxy Synthesizing -2-{( E ) -3-methylbut-1-enyl)} stilbene (14); And
( E ) -3,5-dimethoxymethoxy-2-{( E ) -3-methylbut-1-enyl)} steelbene (14) treatment with hydrochloric acid in the presence of methanol
Method for producing a compound having a stilbene skeleton, characterized in that it comprises:
Scheme 2-1
A process for preparing a compound having a stilbene skeleton, comprising reacting pinocylbin (10) and isovalealdehyde in the presence of ethylene in the presence of ethylenediamine diacetate:
Scheme 2-2
(3)
[Chemical Formula 4]
In Formula 4, R 1 is one of 3-methylbut-2-enyl or (E) -3-methylbut-1-enyl.
[Reaction Scheme 3]
( E ) -3,5-dimethoxymethoxy via the Horner-Wadsworth-Emmons Reaction between benzaldehyde 15 having a methoxymethyl ether group and benzyl phosphonate 16 having a TIPS group Synthesizing oxy-4'-triisopropylsilyloxystillbene (17);
( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystillbene (17) is reacted with n-butyllithium and prenyl bromide to ( E ) -3,5-dimethoxymethoxy Synthesizing oxy-2- (3-methylbut-2-enyl) -4'-triisopropylsilyloxystilbene (18);
( E ) -3,5-dimethoxymethoxy-2- (3-methylbut-2-enyl) -4'-triisopropylsilyloxystilbene (18) was treated with hydrochloric acid in the presence of methanol ( E Synthesizing) -3,5-dihydroxy-2- (3-methylbut-2-enyl) -4'-triisopropylsilyloxystilbene (19); And
Reaction of ( E ) -3,5-dihydroxy-2- (3-methylbut-2-enyl) -4'-triisopropylsilyloxystilbene (19) with tetrabutylammonium fluoride (TBAF) Letting step
Method for producing a compound having a stilbene skeleton, characterized in that it comprises:
Scheme 4-1
( E ) -3,5-dimethoxymethoxy via the Horner-Wadsworth-Emmons Reaction between benzaldehyde 15 having a methoxymethyl ether group and benzyl phosphonate 16 having a TIPS group Synthesizing oxy-4'-triisopropylsilyloxystillbene (17);
( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystilbene (17) was treated with hydrochloric acid in the presence of methanol ( E ) -3,5-dihydroxy-4'- Synthesizing triisopropylsilyloxystilbene (20);
The ( E ) -3,5-dihydroxy-4'-triisopropylsilyloxystilbene (20) is reacted with isovalealdehyde in the presence of ethylenediamine diacetate (EDDA) to ( E ) -3,5- Synthesizing dihydroxy-2-{( E ) -3-methylbut-1-enyl} -4'-triisopropylsilyloxystilbene (21); And
Tetrabutylammonium fluoride ( E ) -3,5-dihydroxy-2-{( E ) -3-methylbut-1-enyl} -4'-triisopropylsilyloxy stilbene (21) TBAF)
Method for producing a compound having a stilbene skeleton, characterized in that it comprises:
Scheme 5
(3)
[Chemical Formula 5]
( E ) -3,5-dimethoxymethoxy via the Horner-Wadsworth-Emmons Reaction between benzaldehyde 15 having a methoxymethyl ether group and benzyl phosphonate 16 having a TIPS group Synthesizing oxy-4'-triisopropylsilyloxystillbene (17);
( E ) -3,5-dimethoxymethoxy-4'-triisopropylsilyloxystilbene (17) was treated with hydrochloric acid in the presence of methanol ( E ) -3,5-dihydroxy-4'- Synthesizing triisopropylsilyloxystilbene (20);
The ( E ) -3,5-dihydroxy-4'-triisopropylsilyloxystilbene (20) is reacted with 3-methyl-2-butenal in the presence of ethylenediamine diacetate (EDDA) ( E ) Synthesizing -2,2-dimethyl-7 [2- (4-triisopropylsilanyloxyphenyl) vinyl] -2H-chromen-5-ol (22); And
( E ) -2,2-dimethyl-7 [2- (4-triisopropylsilanyloxyphenyl) vinyl] -2H-chromen-5-ol (22) with tetrabutylammonium fluoride (TBAF) Reaction
Method for producing a compound having a stilbene skeleton, characterized in that it comprises:
[Reaction Scheme 6]
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