Facile Syntheses of 3-Isopentenyl Flavone and 3-Geranyl Flavone

Transcription

1 CHEM. RES. CHINESE UNIVERSITIES 2012, 28(6), Facile Syntheses of 3-Isopentenyl Flavone and 3-Geranyl Flavone HUANG Chu-sheng 1*, SHI Jian-cheng 1, LIU Hong-xing 1, CHEN Qian 1 and DUAN Hong-xia 2 1. College of Chemistry and Life Sciences, Guangxi Teachers Education University, Nanning , P. R. China; 2. Department of Applied Chemistry, College of Science, China Agricultural University, Beijing , P. R. China Abstract Although there was a strong steric effect, isopentenyl and geranyl moieties were successfully introduced into C3 position in flavone skeleton so as to synthesize the 3-isopentenyl flavone and 3-geranyl flavone under two cyclization conditions(acoh/hcl and concentrated H 2 SO 4 /MeOH) in this report. It was found that the optimum cyclization conditions for 3-isopentenyl flavone and 3-geranyl flavone were, respectively, AcOH/HCl and H 2 SO 4 /MeOH. Furthermore, the donating electron ability is in the sequence 3-geranyl flavone>3-isopentenyl flavone according to the density functional theory(dft) calculations, suggesting the longer alkyl chain at 3-position would be more favorable for enhancing the donating electron ability. The present synthetic routes might reveal potential applicability in our continued studies on the total syntheses of other natural 3-alkyl flavonoids. Keywords 3-Isopentenyl flavone; 3-Geranyl flavone; 3-Alkyl flavonoid Article ID (2012) Introduction 3-Alkyl flavonoids are interesting natural products, isolated from some traditional medicinal plants, e.g., the Moraceae family, their major constituents are various types of prenylated flavonoids [1 3]. Prenylated flavonids are chemical entities having an isoprenyl, a geranyl, a 1,1-dimethylallyl, and/or a lavandulyl moiety as part of their flavonoid backbone structure [4]. They are important components of a variety of traditional Chinese medicines and phyto medicines, bearing a C 6 C 3 C 6 skeleton with diverse pharmacological properties, such as anticancer, antioxidant, anti-aging, anti-inflammatory and antibacterial effects [5 8]. 3-Geranyl flavones(3) and 3-isopentenyl flavone(5)(fig.1) are important 3-alkyl flavonoids, and they are usually more hydrophobic than the conventional flavonoids, suggesting easy penetration through the cell membrane and skin barrier when used topically [9]. Thus they may have advantages for topical use as anticancer, antioxidant, anti- aging and antibacterial agents. To our knowledge, 3-isopentenyl flavone(5) and 3-geranyl flavones(3) have limited distribution in the plant kingdom [9,10], especially, with the prenyl structural relative among other flavonoid natural products, 3-isopentenyl flavone and 3-geranyl flavone occupy an unique position in the realm of flavonoid chemistry [11]. So it is of significance for us to carry out the total synthesis studies on them. However, the isopentenyl and geranyl moieties are difficult to introduce into C3 position in flavone skeleton due to the strong steric effect, few researches have been focused on total synthesis of them up to now [11,12]. Our goal in this work is, therefore, to synthesize 3-isopentenyl flavone and 3-geranyl flavone via the appropriate routes. We expect that the results in present work can lay good foundations for successfully synthesizing other natural 3-alkyl flavonoids, e.g., heterophyllin, artocarpin, cudraflavone C, and studying the structure-activity relationship of 3-alkyl flavonoids [13 16]. R=H(flavones); (3); (5) Fig.1 Molecular structures of flavones and compounds 3 and 5 2 Experimental 2.1 Apparatus Melting points were determined on a WRS-2 melting point apparatus and were uncorrected. 1 H NMR and 13 C NMR spectra were obtained on Bruker Avance 300(300 MHz) and Bruker Avance 500(500 MHz) spectrometers with CDCl 3 as solvent, and tetramethylsilane as an internal standard. The GF254 silica gel was used as thin layer chromatography(tlc). Column chromatography was performed on Qingdao silica gel 60 ( mesh). *Corresponding author. wsf668@sina.cn Received January 10, 2012; accepted June 4, Supported by the National Natural Science Foundation of China(No ) and the Natural Science Foundation of Guangxi Zhuang Autonomous Region, China(Nos and ).

2 No.6 HUANG Chu-sheng et al Syntheses The synthetic routes for target compounds 3 and 5 were outlined in Scheme 1. As was shown in Scheme 1, two possible cyclization methods I(AcOH/HCl, 100 C) [17] and II (concentrated H 2 SO 4 /MeOH) [18] would be pursued to determining which strategy was viable. For our purpose, we started with the known O-hydroxy acetophenone, which was converted to ester firstly, followed by rearrangement in the presence of potassium hydroxide and pyridine, then the 1-(2-hydroxyphenyl)-3-phenyl-propane-1,3-dione(the precursor compound 1) was obtained. Scheme 1 Synthetic routes of compounds 3 and 5 a. RBr, K 2 CO 3, acetone(54%); b. cyclization method II(62%); c. RBr, K 2 CO 3, acetone(75%); d. cyclization method I(91%); e. cyclization method II(50%). Cyclization method I: AcOH/HCl, 100 C, 3 h; cyclization method II: MeOH/H 2 SO 4, reflux, 3 h. For the synthesis of target compound 3, compound 1 and geranyl bromide were submitted to subsequent alkylation and cyclization. One could see from Scheme 1 that cyclization method I was not viable. To overcome the technical difficulty, we switched from cyclization method I to cyclization method II, and compound 3 was synthesized in a moderate yield 62%. To synthesize target compound 5, compound 1 was also C3 alkylated with isopentenyl bromide firstly, then cyclized to afford desired compound 5. It was found from Scheme 1 that compound 5 was obtained with a high yield(91%) via cyclization method I, while only moderate yield(50%) was obtained via cyclization method II. It should be worth noting that the reported method was the best among the well established methods by comparing thoroughly with other methods (2-Hydroxyphenyl)-3-phenyl-propane-1,3-dione(1) A mixture of O-hydroxy acetophenone( g) and anhydrous pyridine(20 ml) was added to 21.1 ml of benzoyl chloride. After 15 min, the content was poured into an ice cold HCl solution. The solid formed was washed with water, evaporated and crystallized from MeOH to afford a white solid ( g). The mixture of the white solid( g) and dry powdered KOH(4.550 g) in anhydrous pyridine(50 ml) was heated at 50 C with stirring for 15 min. A yellow solid was obtained and then poured into aqueous HCl. The content was washed with water, dried and crystallized from MeOH to afford yellow needle crystals of compound 1( g, 44%); m. p C; 1 H NMR(500 MHz, CDCl 3 ), δ: 15.57(s, 1H, OH), 12.13(s, 1H, OH), 8.01(dd, J=34.46, 8.14 Hz, 2H, ArH), 7.81(t, J=9.59 Hz, 1H, ArH), (m, 4H, ArH), (m, 3H, ArH), 4.67(s, 1H, CH 2 ); 13 C NMR(125 MHz, CDCl 3 ), δ: , , , , , , , , , , , , , 92.31; mass spectroscopy/electron ionization(ms/ei), m/z: 240[M + ](50%), 223 (12%), 121(24%), 105(100%), 77(21%) [(E)-3,7-Dimethylocta-2,6-dienyl]-1-{2-[(E)- 3,7-dimethylocta-2,6-dienyloxy]phenyl}-3-phenyl-propane-1,3-dione(2) Compound 1 of 240 mg was dissolved in anhydrous acetone(3 ml), then added to 1-bromo-3,7-dimethyl-2,6-octadiene (800 mg) and anhydrous K 2 CO 3 (350 mg). The mixture was refluxed for 2 h, diluted with ice water and washed with acetone. The residue was separated over silica gel(pe/ea=10/1, volume ratio), affording a light yellow oil, compound 2(284 mg, 54%); 1 H NMR(500 MHz, CDCl 3 ), δ: 8.01(t, J=9.62 Hz, 2H, ArH), 7.76(t, J=7.10 Hz, 1H, ArH), 7.48(td p, J=10.68, 4.38, 2.39 Hz, 5H, ArH), (m, 2H, OH), (m, 1H, OCCHCO), 5.30(t, J=5.97 Hz, 1H), 5.18(t, J=6.89 Hz, 1H, OH), (m, 2H, ArH), 4.49(t, J=7.99 Hz, 2H, CH 2 ), (m, 2H, CH 2 ), (m, 9H, CH 3 ), (m, 17H, CH 3 and CH 2 ); 13 C NMR(125 MHz, CDCl 3 ), δ: , , , , , , , , , , , , , , , , , , , 65.34, 60.37, 39.72, 39.46, 27.97, 26.58, 26.25, 25.62, 25.58, 17.66, 17.63, 16.56, (E)-3-(3,7-Dimethylocta-2,6-dienyl)-2-phenyl-4Hchromen-4-one(3) Compound 2 of 100 mg was dissolved in MeOH(5 ml), to which was added concentrated H 2 SO 4 (0.05 ml) and stirred for 2 h. The content was extracted with AcOEt, then the combined extract was washed with water twice and dried over Na 2 SO 4. After evaporation, the residue was separated on a silica gel column(pe/ea=20/1, volume ratio), affording a light yellow oil, compound 3(40 mg, 62%); 1 H NMR(500 MHz, CDCl 3 ), δ: 8.29(d, 1H, J=7.3Hz, H5), 7.68(m, 3H, ArH), 7.53(m, 3H, ArH), 7.46(d, 1H, J=8.4 Hz, H6), 7.41(t, 1H, J=7.3 Hz, ArH), 5.02(t, 1H, J=6.5 Hz, =CH), 4.86(t, 1H, J=6.5 Hz, =CH), 3.29(d, 2H, J=6.5 Hz, CH 2 ), 2.07(m, 2H, CH 2 ), 1.98(t, 4H, J=6.8 Hz), 1.71(s, 3H, CH 3 ), 1.58(s, 6H, CH 3 ); 13 C NMR(125 MHz, CDCl 3 ), δ: 178.4(C4), 161.8(C2), 156.1(C8α), 133.5(C7), 133.4(=C), 132.3(C1'), 130.2(C5), 128.8(C3'), 128.4(C2'), 125.9(C4'), 124.7(C6), 123.0(C4α), (=CH), 121.4(C3), 117.9(C8), 26.5(CH 2 ), 25.7(CH 3 ), 25.2 (CH 2 ), 17.8(CH 3 ); MS/EI, m/z: 358[M + ], 289(100%), 271 (24%), 247(50%), 235(50%), 223(94%), 121(87%), 105(39%), 69(26%). Electron spray ionization(esi)-ms, m/z: [M+H] [2-(Allyloxy)phenyl]-2-(3-methylbut-2-enyl)- butane-1,3-dione(4) Compound 1 of 480 mg was dissolved in anhydrous acetone(5 ml), then added to 3-dimethylallyl bromide(630 mg) and anhydrous K 2 CO 3 (630 mg). The mixture was refluxed for 2 h, diluted with ice water and washed with acetone. The

3 996 CHEM. RES. CHINESE UNIVERSITIES Vol.28 residue was separated on a silica gel column(pe/ea=10:1, volume ratio), affording a light yellow oil, compound 4(558 mg, 75%); 1 H NMR(500 MHz, CDCl 3 ), δ: 8.01(d, 2H, J=7.8 Hz, ArH), 7.76(dd, 1H, J=7.8, 1.8 Hz, ArH), 7.57(t, 1H, J=7.4 Hz, ArH), 7.45(m, 3H), 7.02(t, 1H, J=7.6 Hz, ArH), 6.92(d, 1H, J=8.4 Hz, ArH), 5.57(t, 1H, J=6.4 Hz, CH), 5.29(m, 1H, =CH), 5.16(m, 1H, CH), 4.47(d, 2H, J=6.7 Hz, OCH 2 ), 2.74(m, 1H, CH 2 ), 2.70(m, 1H, CH 2 ), 1.71(s, 3H, CH 3 ), 1.66(s, 3H, CH 3 ), 1.61(s, 3H, CH 3 ), 1.57(s, 3H, CH 3 ); 13 C NMR(125 MHz, CDCl 3 ), δ: 197.9, 196.8, 157.4, 138.2, 136.7, 133.4, 132.8, 131.3, 128.9, 128.7, 128.5, 128.4, 121.6, 120.8, 119.0, 112.5, 65.2, 60.4, 28.4, 27.9, 25.6, 18.1, 17.7; MS/EI, m/z: 376[M + ], 203(87%), 187(100%), 129(64%), 105(84%) (3-Methylbut-2-enyl)-2-phenyl-4H-chromen- 4-one(5) Method I, AcOH/HCl cyclization: 344 mg of compound 4 was dissolved in a 10% AcOH solution(3 ml), to which was then added concentrated HCl(0.15 ml). The mixture was stirred at 100 C for 3 h, then extracted with AcOEt. The combined extract was washed with a 5% NaHCO 3 solution and water, respectively, dried over Na 2 SO 4. After evaporation, the residue was separated on a silica gel column(pe/ea=20/1, volume ratio), affording a light yellow oil, compound 5(246 mg, 91%). Method II, MeOH/H 2 SO 4 cyclization: 232 mg of compound 4 was dissolved in MeOH(5 ml), and concentrated H 2 SO 4 (0.05 ml) was added to it. The mixture was refluxed for 3 h, then extracted with AcOEt. The combined extract was washed with water twice, dried over Na 2 SO 4. After evaporation, the residue was separated on a silica gel column(pe/ea=20/1, volume ratio), affording a light yellow oil, compound 5 (91 mg, 50%); 1 H NMR(500 MHz, CDCl 3 ), δ: 8.29(d, 1H, J=7.3 Hz, H5), 7.68(m, 3H, ArH), 7.53(m, 3H, ArH), 7.46(d, 1H, J=8.4 Hz, H6), 7.41(t, 1H, J=7.3 Hz, ArH), 5.26(t, 1H, J=6.5 Hz, =CH), 3.29(d, 2H, J=6.5 Hz, CH 2 ), 1.71(s, 3H, CH 3 ), 1.58(s, 3H, CH 3 ); 13 C NMR(CDCl 3 ), δ: 178.4(C4), 161.8(C2), (C8α), 133.5(C7), 133.4(=C), 132.3(C1'), 130.2(C5), (C3'), 128.4(C2'), 125.9(C4'), 124.7(C6), 123.0(C4α), (=CH), 121.4(C3), 117.9(C8), 25.7(CH 3 ), 25.2(CH 2 ), 17.8 (CH 3 ); MS/EI, m/z: 290[M + ], 187(10%), 121(10%), 105(100%), 77(22%). ESI-MS, m/z: [M+H] +. 3 Results and Discussion In the present work, various cyclization methods for compound 2 compound 3 and compound 4 compound 5 were tried. For example, H 2 SO 4 /C 2 H 5 OH and NaOOCCH 3 / CH 3 COOH [16], DBU/pyridine [19]. However, cyclization procedures of compound 2 compound 3 and compound 4 compound 5 were always unsuccessful under these reaction conditions. Riva et al. [17] reported that 3-[1,3-dioxo-3-(1- phenylcyclopentyl)-propyl]-2-hydroxybenzoate was cyclized to methyl benzopyran-8-carboxylate by acid catalysis with 37% HCl and AcOH in a yield of 64%. Malolanarasimhan et al. [18] stated that 2-(4-nitrophenyl)-8-prop-2-enylchromen-4-one was obtained by the cyclization of (2Z)-3-hydroxy-1-(2-hydroxy- 3-prop-2-enylphenyl)-3-(4-nitrophenyl)prop-2-en-1-one with H 2 SO 4 and MeOH in a yield of 90%. Enlightened by Riva s [17] and Malolanarasimhan s [18] cyclization methods, catalysts AcOH/HCl [17] (method I) and H 2 SO 4 /MeOH [18] (method II) were employed as shown in Scheme 1. It was seen that H 2 SO 4 /MeOH could both achieve the cyclization procedures for 3-isopentenyl flavone and 3-geranyl flavone(i.e., compound 2 compound 3 and compound 4 compound 5 in Scheme 1) in yields of 50% and 62%, respectively, which were lower than Malolanarasimhan s yield of 90%. The reason might lie in the fact that the isopentenyl and geranyl groups in our work were difficult to introduce into C3 position in flavone skeleton due to their strong steric effect. Furthermore, AcOH/HCl could only carry out the cyclization procedure for 3-isopentenyl flavone(i.e., compound 4 compound 5 in Scheme 1) in a yield of 91%, which is higher than Riva s yield of 64%. It might be because the presence of an alternative reaction pathway in Riva s work, in which the alkylation O versus that of C during the Baker-Venkataraman rearrangement step could be preferred due to the lesser steric hindrance and /or electronic factors [17]. It was demonstrated that the introduction of a prenyl substituent into flavonoids could remarkably improve the various biological activities, including anticancer, antioxidant, antiaging and antibacterial activities [4,20,21]. Importantly, in this report, we extended Riva s [17] and Malolanarasimhan s [18] ideas to introduce the isopentenyl and geranyl moieties into C3 position in flavone skeleton although there was strong steric effect, and synthesize natural 3-alkyl flavonoids, which were cyclized in the presence of catalysts AcOH/HCl [17] and H 2 SO 4 / MeOH [18]. Based on above results, it should be suggested that the optimum cyclization catalyst for 3-isopentenyl flavone was AcOH/HCl, while it was H 2 SO 4 /MeOH for 3-geranyl flavone. The reason is still not clear and the mechanism researches are in progress. We think that our synthetic routes for target compounds 3(3-geranyl flavone) and 5(3-isopentenyl flavone) in the present work have potential applicability in our continued studies on the total synthesis of other natural 3-alkyl flavonoids. To predict the biological activities of 3-isopentenyl flavone and 3-geranyl flavone, the density functional theory(dft) and semi-empirical quantum chemical method(am1) are often used. It is worth pointing out that density functional theory(dft) methods often produce reliable results with relatively reasonable computational cost [22,23]. Considering the accuracy and conveniency of DFT method [24], the original structures of 3-isopentenyl flavone and 3-geranyl flavone molecules were optimized by AM1 [25], then a full optimization to these structures were performed at 6-31G(d) basis set by B3LYP method. In order to describe the molecule properties, the energies and popluation of the frontier orbitals HOMO and LUMO were employed because they are important parameters to characterize the biological activity. All the calculations were carried out with the program Gaussian 03 [26]. As in the presentation in Refs.[26,27], the lower was the E HOMO, the weaker was the molecule donating electron ability. On the contrary, the higher E HOMO implied that the molecule was a good electron donor. E LUMO presented the ability of a

4 No.6 HUANG Chu-sheng et al. 997 molecule receiving electron. It should be noted that the E HOMO and E LUMO of flavone was shown here in order to compare its molecule properties with those of 3-isopentenyl flavone and 3-geranyl flavone molecules. As was shown in Table 1, the E HOMO values of flavone, 3-isopentenyl flavone and 3-geranyl flavone were , and a.u., Table 1 respectively. It might suggest that the donating electron ability would be in the sequence 3-geranyl flavone>3-isopentenyl flavone>flavone. The result might reflect that the longer alkyl chain at 3-position would be more favorable for enhancing the donating electron ability of 3-alkyl flavonoids. Total energies and frontier orbital energies of 3-isopentenyl flavone and 3-geranyl flavone molecules Compound E Total /a.u. E HOMO /a.u E LUMO /a.u E gap /a.u Flavone Isopentenyl flavone Geranyl flavone To further show the active sites of donating electron, the HOMO electron densities of flavone molecule, 3-isopentenyl flavone molecule and 3-geranyl flavone molecule are shown in Fig.2. From the comparison of the HOMO electron densities, it was found that they gradually shifted to 3-position substituent from Fig.2(A) to Fig.2(C). The result suggests that the 3-position substituent played an important role in the distribution of the HOMO electron density, and the longer alkyl chain at 3-position would be more favorable for donating electron. Moreover, the longer alkyl chain at 3-position would play a more important role in providing electrons to coordinate to some metal irons, and inhibiting those free radicals aroused by the metal iron reactions [28]. Fig.2 HOMO electron densities of flavone molecule(a), 3-isopentenyl flavone molecule(b) and 3-geranyl flavone molecule(c) In order to strengthen our arguments, in what follows, we focused on the antioxidant activities of 3-isopentenyl flavone and 3-geranyl flavone. In recent years, phenolic antioxidants (ArOH) have received much attention due to their wide application in chemical industry, pharmaceutical industry and food industry [29 31]. Though the factors, which affect the H-abstraction reaction between the phenolic antioxidant and the free radicals, are complicated, it is universally considered that the scavenging free radical would be from the H-abstraction reactions [32,33]. It can be seen from Fig.1 that OH moiety did not exist in 3-isopentenyl flavone and 3-geranyl flavone molecules, so there should not exist the antioxidant activities of the two molecules. To confirm our theoretical prediction, a highthroughput method of 2,2-diphenyl-1-picrylhydrazyl(DPPH) free radical scavenging for evaluating the antioxidant activities of the extracts from 3-isopentenyl flavone and 3-geranyl flavone was established [34,35]. One can see from Fig.3 the antioxidant activity of 3-isopentenyl flavones is nearly identical to that of 3-geranyl flavone, and the antioxidant activities of the two molecules are both remarkably weaker than that of Vc. The result reflects that there nearly did not exist the antioxidant activities of 3-isopentenyl flavone and 3-geranyl flavone, which is in agreement with our theoretical prediction. 4 Conclusions The isopentenyl and geranyl moieties were introduced into C3 position in flavone skeleton although there was strong steric effect in the present work. It was found that the optimum cyclization conditions for 3-isopentenyl flavone and 3-geranyl flavone were, respectively, the AcOH/HCl and H 2 SO 4 /MeOH. In addition, the donating electron abilities were in the sequence 3-geranyl flavone>3-isopentenyl flavone by the density functional theory(dft) calculations, suggesting the longer alkyl chain at 3-position would be more favorable for enhancing their donating electron ability. We expect that the results in the present work could lay good foundations for synthesizing other natural 3-alkyl flavonoids, and studying the structure-activity relationship of 3-alkyl flavonoids. Fig.3 DPPH free radical scavenging of extract from compound 3(a), compound 5(b) and Vc(c) References [1] Jiyamas K., Emizuy A., Iraga U., J. Nat. Prod., 1992, 55, 1197 [2] Phillips W. R., Baj N. J., Gunatilaka A. A. L., Kingston D. G. I., J. Nat. Prod., 1996, 59, 495 [3] Chung M. I., Lu C. M., Huang P. L., Phytochemistry, 1995, 40, 1279 [4] Sohn H. Y., Son K. H., Kwon C. S., Kang S. S., Phytomedicine, 2004, 11, 666

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