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NMR screening approach for discovery of new 6-methylpyridinone derivatives from the marine-derived fungus Leptosphaerulina sp.
⁎Corresponding authors at: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China (W.-J. Lan); School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China (H.-J. Li). lanwj@mail.sysu.edu.cn (Wen-Jian Lan), ceslhj@mail.sysu.edu.cn (Hou-Jin Li)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
By the method of 1H NMR prescreening and tracing the diagnostic signals, 6-methylpyridinone derivatives, (8R,9S)-dihydroisoflavipucine (1), (8S,9S)-dihydroisoflavipucine (2), 3-(1-hydroxy-4-methyl-2-oxopentylidene)-6-methylpyridine-2,4(1H,3H)-dione (3), 4-hydroxy-3-(2-hydroxy-4-methylpentanoyl)-6-methylpyridin-2(1H)-one (4), 4-hydroxy-3-[(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)methyl]-6-methylpyridin-2(1H)-one (5) and a known 6-methylpyranone derivative 3,3′-methylenebis(4-hydroxy-6-methyl-2H-pyran-2-one) (6) were isolated from the marine fungus Leptosphaerulina sp., which was collected from the starfish Acanthaster planci from the South China Sea. Compounds 2 and 3 are new compounds. Their structures were elucidated on the basis of MS, 1D and 2D NMR, and X-ray single crystal diffraction data. The absolute configurations of compounds 1 and 2 were determined by analysis on the experimental circular-dichroism spectra.
Keywords
Marine fungus
Leptosphaerulina sp.
6-Methylpyridinone derivatives
Metabolites
1 Introduction
The starfish Acanthaster planci is found easily in the coral reefs of the South China Sea. It feeds on coral polyps and large populations of A. planci have permanent disastrous effects on the coral communities. Our investigation on the microorganisms associated with A. planci led to the purification of large number of fungi, bacteria, and actinomycetes. In our previous researches on the metabolites of the marine fungi associated with A. planci, a variety of metabolites with chemodiversity and biodiversity were obtained (Lan et al., 2012, 2014; Zhao et al., 2013; Xie et al., 2013; Yan et al., 2015).
Marine fungus Leptosphaerulina sp. was isolated from the inner tissue of A. planci from the South China Sea. The comprehensive literature survey indicates the metabolites research on the fungus Leptosphaerulina is still rare. This finding prompted us to investigate the metabolites of the fungus. This fungus was cultured in a glucose–peptone–yeast extract (GPY) medium, and the EtOAc extract of the culture broth was subjected to chemical structure prescreening by 1H and 13C NMR analysis. The 1H NMR spectra of the crude extract and the following fractions showed diagnostic singlet signals at δH 11.5, 6.0 and 2.3. The metabolites purification guided by tracking these signals afforded five 6-methylpyridinone derivatives (8R,9S)-dihydroisoflavipucine (1), (8S,9S)-dihydroisoflavipucine (2), 3-(1-hydroxy-4-methyl-2-oxopentylidene)-6-methylpyridine-2,4(1H,3H)-dione (3), 4-hydroxy-3-(2-hydroxy-4-methylpentanoyl)-6-methylpyridin-2(1H)-one (4), 4-hydroxy-3-[(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)methyl]-6-methylpyridin-2(1H)-one (5) and a known 6-methylpyranone derivative 3,3′-methylenebis(4-hydroxy-6-methyl-2H-pyran-2-one) (6) (Fig. 1). Compounds 2 and 3 are new compounds. Herein, we describe the isolation, structure determination and cytotoxic activity evaluation of these compounds.
Chemical structures of compounds 1–6.
2 Experimental
2.1 General
Melting points were measured on X-6 micro-melting-point apparatus (Beijing Fukai Science and Technology Development, Beijing, PR China) and were uncorrected. Optical rotations were measured using a Schmidt and Haensch Polartronic HNQW5 optical rotation spectrometer. CD spectra were measured on a JASCO J-810 circular dichroism spectrometer. IR spectra were recorded on a PerkinElmer Frontier FT-IR spectrophotometer. UV spectra were recorded on a Shimadzu UV–Vis–NIR spectrophotometer. 1D and 2D NMR spectra were recorded on a Varian Inova 500, a Bruker Avance II 400 spectrometers and a Varian Mercury-Plus 300 spectrometers. The chemical shifts are relative to the residual solvent signals (CDCl3: δH 7.26 and δC 77.0; DMSO-d6: δH 2.50 and δC 39.51). The low- and high-resolution EI mass spectra were obtained on Thermo DSQ and Thermo MAT95XP mass spectrometers, respectively. LR ESI-MS and HR ESI-MS analyses were performed with Thermo LCQ DECA XP liquid chromatography-mass spectrometry and Thermo Fisher LTQ Orbitrap Elite High Resolution liquid chromatography-mass spectrometry. Preparative HPLC was performed on a Shimadzu LC-20AT pumping system equipped with a SPD-20A dual λ absorbance detector and a Shim-pack PRC-ODS HPLC column (250 × 20 mm, 5 μm). The single crystal data were collected on a Agilent Technologies Gemini A Ultra system, with Cu Kα radiation (λ = 1.54178 Å).
2.2 Fungal strain and culture method
The marine fungus Leptosphaerulina sp. (collection Number 2012F7-1B) was isolated from the inner tissue of the starfish A. planci collected from Hainan Sanya National Coral Reef Reserve, China. This fungal strain was maintained in 15% glycerol aqueous solution at −80 °C. A voucher specimen was deposited in the School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, China. The fermentation medium was glucose 10 g/L, peptone 5 g/L, yeast extract 2 g/L, seawater 1 L, and pH 7.5 (GPY medium). The liquid medium was sterilized at 120 °C for 30 min. The mycelia were aseptically transferred to 500 mL Erlenmeyer flasks containing 200 mL liquid medium. The flasks were then incubated at 28 °C on a rotary shaker (120 rpm) for 20 days.
2.3 Extraction and isolation
60 liter of growth culture broth was filtered through cheesecloth. The culture broth was successively extracted three times with EtOAc. The EtOAc extract was concentrated by low-temperature rotary evaporation. The extract (18.3 g) was chromatographed on a silica gel column with light petroleum–EtOAc (100:0–0:100, v/v) followed by EtOAc—MeOH (100:0–0:100, v/v) as the eluent to afford 28 fractions (code Fr. 1–Fr. 28). The chemical structures of the metabolites in Fr. 1–Fr. 28 were prescreened by 1H NMR. Fr. 3–Fr. 8 was inferred to contain 6-methylpyridinone derivatives according to the diagnostic signals at δH 2.3, 6.0 and 11.5. Therefore, Fr. 3 and Fr. 4 were further purified by on a normal-phase silica gel column to obtain 5 (12 mg) and 6 (25 mg), respectively. Fr. 5 was further purified by RP-HPLC eluted with H2O—MeOH (60:40, v/v) to yield 4 (10 mg). Fr. 6 was further purified by repeated RP-HPLC eluted with H2O—MeOH (60:40, v/v) to yield 3 (6 mg). Fr. 7 and Fr. 8 were purified by RP-HPLC eluted with H2O—MeOH (50:50, v/v) to yield 1 (32 mg) and 2 (16 mg).
2.4 Cytotoxicity assay
The in vitro cytotoxicities of 1–6 were screened using the colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay. The tested human cancer cell lines were seeded in 96-well plates at a density of 3 × 107 cells/L, and the compounds were added at various concentrations (0.125–50 mg/L). After 48 h, MTT was added to the culture medium at a final concentration of 0.5 mg/mL, and the plates were incubated for 4 h at 37 °C. The supernatant was removed. The formazan crystals were dissolved in DMSO (150 μL) with gentle shaking at r.t. The absorbance at 570 nm was recorded with a microplate reader (Bio-Rad), and the data were analyzed with the SPSS 13.0 software package.
2.5 (8R,9S)-dihydroisoflavipucine (1)
Colorless crystal; mp 170–171 °C; [α]20D −282 (c 0.011, MeOH); UV (MeOH) λmax (ε) 308 nm (7557), 254 nm (2681), 217 nm (23,298); IR υmax 3280, 3020, 2962, 2932, 1670, 1617, 1520, 1470, 1423, 1290, 1208, 1176, 1148, 1108, 1080, 1025, 1007, 986, 924, 795 cm−1; 1H and 13C NMR data, see Tables 1 and 2; LREIMS m/z 239 [M]+, 224, 208, 196, 182, 168, 152, 141, 124, 112, 96, 84, 68, 57. HREIMS m/z 239.1151 [M]+ (calcd for C12H17NO4, 239.1152). Crystal of 1 was obtained from MeOH solution. C12H17NO4, M = 239.27, colorless block, monoclinic, space group P2(1)/n, a = 13.7719(5) Å, b = 5.7096(2) Å, c = 16.7688(6) Å, β = 109.255(4)°, V = 1244.80(8), Z = 4, Dcalcd. = 1.277 g/cm3, crystal size 0.46 × 0.41 × 0.38 mm3, F(0 0 0) = 512, T = 293(2) K.
Position
1a
2a
3b
4c
5a
1 NH
11.52 (brs)
11.51 (brs)
11.92 (brs)
11.51 (brs)
11.96 (brs)
5
6.01 (s)
6.00 (d, 0.8)
5.90 (s)
5.94 (s)
5.97 (s)
7
2.13 (s)
2.14 (s)
2.30 (s)
2.33 (s)
2.16 (s)
8
5.99 (d, 3.2)
5.95 (d, 3.0)
3.43 (s)
9
3.71 (ddd, 13.4, 6.4, 3.2)
3.71 (dt, 10.0, 3.0)
5.91 (d, 9.6)
10
α: 1.40 (ddd, 13.4, 10.0, 4.0); β: 1.19 (ddd, 13.4, 10.0, 3.2)
α: 1.40 (ddd, 14.0, 10.0, 4.0); β: 1.19 (ddd, 14.0, 10.0, 3.0)
2.61 (d, 6.5)
α: 1.44 (ddd, 14.0, 9.6, 4.8); β: 1.19 (ddd, 14.0, 9.6, 4.8)
11
1.80 (m)
1.81 (m)
2.25 (nine peaks, 6.5)
1.99 (m)
12
0.86 (d, 6.4)
0.86 (d, 6.8)
1.01 (d, 6.5)
1.00 (d, 6.4)
13
0.91 (d, 6.4)
0.91 (d, 6.8)
1.03 (d, 6.5)
1.01 (d, 6.4)
5.97 (s)
15
2.13 (s)
4-OH
15.01 (brs)
10.39 (brs)
8-OH
13.46 (brs)
9-OH
5.22 (d, 6.4)
5.20 (brs)
2.19 (brs)
12-OH
10.39 (brs)
Position
1a
2a
3b
4c
5a
2
154.1
154.0
177.5
164.7
168.7
3
130.5
130.6
102.7
103.5
107.0
4
152.8
152.8
199.1
178.4
166.2
5
91.8
91.9
100.6
101.6
102.1
6
141.3
141.3
155.8
153.3
144.3
7
18.4
18.4
20.0
19.8
18.2
8
113.3
113.4
164.9
207.4
17.4
9
68.1
68.2
201.0
74.4
10
39.3
39.3
47.1
42.6
165.5
11
23.6
23.6
23.7
25.0
100.7
12
21.4
21.4
23.0
23.7
166.5
13
23.5
23.5
23.0
21.7
101.0
14
160.3
15
19.0
2.6 (8S,9S)-dihydroisoflavipucine (2)
Colorless crystal; mp 166–167 °C; [α]20D + 173 (c 0.031, MeOH); UV (MeOH) λmax (ε) 306 nm (1308), 254 nm (502), 217 nm (4157); IR υmax 3280, 3020, 2962, 2932, 1670, 1617, 1520, 1470, 1423, 1290, 1208, 1176, 1148, 1108, 1080, 1025, 1007, 986, 924, 795 cm−1; 1H and 13C NMR data, see Tables 1 and 2; LREIMS m/z 239 [M]+, 224, 208, 196, 182, 168, 152, 141, 124, 112, 96, 84, 68, 57; HREIMS m/z 239.1151 [M]+ (calcd for C12H17NO4, 239.1152). Compound 2 was crystallized from methanol to afford some crystals which were suitable for single-crystal X-ray crystallographic analysis. C12H21NO5, M = 271.31, colorless block. Monoclinic, space group P2(1)/c, a = 8.5655(3) Å, b = 18.8084(5) Å, c = 9.6519(3) Å, β = 116.124(4)°, V = 1396.10(8), Z = 4, Dcalcd. = 1.291 g/cm3, crystal size 0.42 × 0.36 × 0.36 mm3, F(0 0 0) = 584, T = 173(2) K.
2.7 3-(1-Hydroxy-4-methyl-2-oxopentylidene)-6-methylpyridine-2,4(1H,3H)-dione (3)
White solid; mp 182–183 °C; [α]20D + 206.5 (c 0.026, MeOH); UV (MeOH) λmax (ε): 318 nm (19,779), 275 nm (4381), 232 nm (18,243), 206 nm (21,567). IR υmax 3385, 3075, 2956, 1718, 1675, 1634, 1608, 1568, 1490, 1467, 1450, 1354, 1286, 1249, 1182, 1158, 823, 753 cm−1; 1H and 13C NMR data, see Tables 1 and 2; LR(+)ESIMS: m/z 497 [2 M + Na]+, 260 [M + Na]+, 238 [M + H]+, 224, 208, 196, 182, 168, 152, 141, 124, 112, 96, 84, 68, 57; HR(−)ESIMS m/z 236.0927[M − H]− (calcd for C12H14NO4, 236.0928).
2.8 4-Hydroxy-3-(2-hydroxy-4-methylpentanoyl)-6-methylpyridin-2(1H)-one (4)
White solid; 1H and 13C NMR data, see Tables 1 and 2; LREIMS m/z 239 [M]+, 221, 208, 198, 182, 173, 159, 152, 138, 125, 108, 96, 84, 68, 53.
2.9 4-Hydroxy-3-[(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)methyl]-6-methylpyridin-2(1H)-one (5)
White solid; 1H and 13C NMR data, see Tables 1 and 2; LR(+)ESIMS m/z 264 [M + H]+; HR(+)ESIMS m/z 286.0676 [M + Na]+, 264.0810 [M + H]+ (calcd for C13H14NO5, 264.0872).
2.10 3,3′-Methylenebis(4-hydroxy-6-methyl-2H-pyran-2-one) (6)
Colorless crystals; mp 161–162 °C; 1H NMR (CDCl3, 300 MHz): δH 10.71 (s, OH-4 and OH-4′, 2H), 5.99 (s, H-5 and H-5′, 2H), 3.50 (s, H-8, 2H), 2.25 (s, H-7 and H-7′, 6H). 13C NMR (CDCl3, 75 MHz): δC 169.8 (C-2, and C-2′), 168.4 (C-4, and C-4′), 161.0 (C-6, and C-6′), 101.5 (C-3, and C-3′), 102.5 (C-5, and C-5′), 18.6 (C-8), 19.8 (C-7, and C-7′). LREIMS: m/z 264 [M]+, 236, 221, 203, 194, 180, 179, 152, 151, 139, 137, 124, 111, 98, 85, 69. Compound 6 was crystallized from EtOAc to afford some crystals which were suitable for single crystal X-ray crystallographic analysis. C13H12O6, M = 264.23, colorless block, Monoclinic, space group P2(1)/c, a = 13.8506 (3) Å, b = 11.7211 (2) Å, c = 7.2516 (2) Å, β = 91.766(2)°, V = 1176.70(5), Z = 4, Dcalcd. = 1.491 g/cm3, crystal size 0.45 × 0.39 × 0.38 mm3, F(0 0 0) = 552, T = 293(2) K.
3 Results and discussion
Compounds 1 and 2 were isolated from the fractions 7 and 8 by normal-phase silica gel column chromatography followed by RP-HPLC eluted with H2O—MeOH (50:50, v/v). In the HPLC trace, compounds 1 and 2 showed two independent peaks with the retention time 65.66 and 70.97 min, respectively, eluted with H2O—MeOH (50:50, v/v) (Fig. 2). However, their MS, 1D and 2D NMR, including HMQC, HMBC, 1H—1H COSY and NOESY (Tables 1 and 2), are almost identical. So, we conceive that compounds 1 and 2 are conformational isomers.
The HPLC trace of compounds 1 and 2.
Compound 1 was identified as (8R,9S)-dihydroisoflavipucine, which was previously reported in 1977 as a artificial degradation product of the fungal metabolite isoflavipucine (Findlay et al., 1977), and it was firstly obtained in 2011 as a natural product from an endophytic fungus Phoma sp. (Loesgen et al., 2011). The single crystals of 1 were obtained from the MeOH solution. In the crystal, the molecules are joined together by strong O—H⋯O⚌C hydrogen bonds to form a highly puckered layer-type structure (Fig. 3a). The experimental CD spectrum of 1 (Fig. 4a) was identical to the reference data (Loesgen et al., 2011).
Crystal structures of compounds 1 (a) and 2 (b). Thermal ellipsoids are plotted at a 30% probability level.
Circular dichroism (CD) spectra of compounds 1 (a) and 2 (b) in MeCN solution.
Compound 2 was obtained as a colorless crystal. Its molecular formula was established as C12H17NO4 based on the HREIMS peak at m/z 239.1151 [M]+, the 1H and 13C NMR spectroscopic data (Tables 1 and 2). The UV spectrum showed the characteristic absorption bands at λmax 306 and 254 nm indicated the presence of a conjugated system. The strong IR absorption at 1670 cm−1 indicated the presence of a carbonyl group. The 13C NMR and DEPT spectra displayed three methyls, one methylene, four methines, and four quaternary carbons. In the 1H—1H COSY spectrum, the cross peaks of H-8/H-9, H-9/H-10, H-10/H-11, H-11/H-12 and H-11/H-13 indicated the presence of a partial structure —CHCHCH2CH(CH3)2 in this molecule (Fig. 5). The methyl singlet at δH 2.13 showing a weak cross peak with the olefinic proton at δH 6.01 in 1H—1H COSY spectrum, combined with the HMBC correlations of H-7/C-6, H-5/C-6, H-5/C-4 and H-5/C-3, revealed the other partial structure —C(CH3)⚌CH—C⚌C—. The amide and the partial structure —C(CH3)⚌CH—C⚌C— established the 6-methylpyridinone skeleton. The partial structure —CHCHCH2CH(CH3)2 connected with 6-methylpyridinone skeleton at C-3 and C-4 by the two oxygen bridges. The hydroxyl group at δH 5.22 was connected to C-9 (δC 68.1) based on the HMBC correlations with C-8, C-9 and C-10. Therefore, the planar structure of compound 2 was determined as dihydroisoflavipucine.
1H—1H COSY (bold line) and main HMBC (arrow) correlations of compound 2.
Fortunately, the single crystals of 2 were also obtained from the MeOH solution. The molecules are joined together by strong O—H⋯O⚌C hydrogen bonds. Additional strong O—H⋯O hydrogen bonds are formed between MeOH molecule and the OH group of the molecule to form a wavy layer-type structure (Fig. 3b). The CD spectrum of 2 (Fig. 4b) was also fit to the quantum-chemically calculated CD spectrum of (8S,9S)-dihydroisoflavipucine (2) (Loesgen et al., 2011).
Compound 3 was isolated as a white solid. The molecular formula was assigned as C12H15NO4 by HR(−)ESIMS peak at m/z 236.0927 [M − H]− and NMR data (Tables 1 and 2), comprising six degrees of unsaturation. The 13C NMR and DEPT spectra displayed three methyls, one methylene, two methines, and six quaternary carbons. In the 1H NMR spectrum, the characteristic signals at δH 11.92, 5.90, and 2.30 suggest compound 3 is also a 6-methylpyridinone derivative. In 1H—1H COSY spectrum, the two methyl groups at δH 1.01 (d, 6.5 Hz) and 1.03 (d, 6.5 Hz), and a methene at δH 2.61 (d, 6.5 Hz) showed correlations with the methine at δH 2.25 (nine, 6.5 Hz), so, the partial structure —CH2CH(CH3)2 was established (Fig. 6). The H-10 showed HMBC correlations with the carbonyl carbon at δC 201.0 (C-9) and the quaternary carbon at δC 164.9 (C-8). In addition, olefinic proton at δH 5.90 (s, H-5) showed HMBC correlations with the carbonyl carbons at δC 199.1 (C-4) and 177.4 (C-2), and quaternary carbons at δC 102.7 (C-3) and 155.8 (C-6). The hydroxyl group at δH 13.46 was connected at C-8. Based on the analysis above, compound 3 was elucidated as 3-(1-hydroxy-4-methyl-2-oxopentylidene)-6-methylpyridine-2,4(1H,3H)-dione. The NMR data are not enough to determine the E/Z configuration of the double bound between C-3 and C-8. It is also very difficult to obtain a suitable crystal for X-ray single diffraction experiment, so, the configuration remains uncertain.
1H—1H COSY (bold line) and main HMBC (arrow) correlations of compound 3.
Compound 4 was obtained as a white solid. The molecular formula was assigned as C12H17NO4 by HREIMS peak at m/z 239.1151 [M]+ and NMR data (Tables 1 and 2), comprising five degrees of unsaturation. The 13C NMR and DEPT spectra displayed three methyls, one methylene, three methines, and five quaternary carbons. In 1H NMR spectrum, the characteristic signals at δH 11.51, 5.94, and 2.33 suggest compound 4 is also a 6-methylpyridinone derivative. In 1H—1H COSY spectrum, the correlations of H-9/H-10, H-10/H-11, H-11/H-12, and H-11/H-13 established the side chain of —CHCH2CH(CH3)2. The phenolic hydroxyl group at δH 15.01 was attached at C-4 and formed an intramolecular hydrogen bond with the carbonyl group at C-8. The other hydroxyl group at δH 2.19 was connected at C-9, however, its stereochemistry was not determined due to the limited sample. Compound 4 was elucidated as 4-hydroxy-3-(2-hydroxy-4-methylpentanoyl)-6-methylpyridin-2(1H)-one. Compound 4 was previously obtained in 1978 as a synthesized product by Girotra and Wendler (1978). However, this is the first time of presenting the detailed 1H and 13C NMR assignment.
Compound 5 was identified as 4-hydroxy-3-[(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)methyl]-6-methylpyridin-2(1H)-one (the other name is penicipyrone), which was previously isolated from marine fungus Penicillum sp. PSU-F40 (Trisuwan et al., 2010). However, our NMR data recorded in DMSO-d6 (Tables 1 and 2) were slightly different from the reference values recorded in CDCl3 + CD3OD.
Compound 6 is 3,3′-methylenebis(4-hydroxy-6-methyl-2H-pyran-2-one). Its NMR data were identical to the reference value (Minassi et al., 2012). The single crystals of 6 were obtained from the EtOAc solution. In the crystal, a pair of very strong O—H⋯O⚌C intramolecular hydrogen bonds fixs the orientation of the molecule. Neighboring molecules are joined together by weak C—H⋯O⚌C hydrogen bonds to form a puckered layer (Fig. 7).
Crystal structure of compound 6. Thermal ellipsoids are plotted at a 30% probability level.
Fifteen cancer cell lines, including SW620, SW480, LoVo, Hep3B, A549, HepG2, Bel-7402, CNE1, CNE2, SUNE1, MCF7, MDA-MB-231, MDA-MB-435, MDA-MB-453 and HeLa were used to examine the cytotoxic activities of compounds 1–6 in vitro. Unfortunately, this assay revealed that these compounds are inactive (IC50 > 20 μg/mL).
4 Conclusions
Most of the marine fungi can produce prolific metabolites with various biosynthetic pathways. Some of those compounds can only be found at very low levels, so that massive harvesting is needed to obtain sufficient amounts, and various advanced technologies, including the bioassay and chemical structure prescreening are developed to promote the efficiency of metabolites isolation. 6-methylpyridinone derivatives showed the characteristic singlet signals around δH 11.5, 6.0 and 2.13. Tracing these diagnostic signals, compounds 1–6 were obtained with a high efficiency.
CCDC 1047171–1047173 contains crystallographic data for (8R,9S)-dihydroisoflavipucine (1), (8S,9S)-dihydroisoflavipucine (2) and 6-methylpyranone derivative 3,3′-methylenebis(4-hydroxy-6-methyl-2H-pyran-2-one) (6), respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
This project was financially supported by the National Natural Science Foundation of China (Nos. 30973633 and J1103305), the Guangdong Provincial Science and Technology Research Program (Nos. 2012A031100005, 2013B021100010, and 2013B021100012), the Guangdong Natural Science Foundation (No. S2012010010653), the Guangzhou Science and Technology Research Program (No. 2014J4100059), and the Research Foundation of IARC-SYSU (Nos. 2013-06 and 2014-05).
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Appendix A
Supplementary material
Supplementary data associated with this article can be found, in online version, at http://dx.doi.org/10.1016/j.arabjc.2015.06.015.
Appendix A
Supplementary material
Supplementary Figures S1–S44
Supplementary Figures S1–S44