Determination of absolute structure of (+)-davidiol A

Article abstract of DOI:10.3987/com-05-10577

The absolute configurations of stilbenetrimers, (+)-davidiol A and (-)-davidiol A were determined on the basis of the enzymatic chemical transformations.

Full text of DOI:10.3987/com-05-10577

HETEROCYCLES, Vol. 68, No. 1, 2006
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HETEROCYCLES, Vol. 68, No. 1, 2006, pp. 93 – 100. © The Japan Institute of Heterocyclic Chemistry
Received, 26th September, 2005, Accepted, 11th November, 2005, Published online, 15th November, 2005. COM-05-10577
DETERMINATION OF ABSOLUTE STRUCTURE OF (+)-DAVIDIOL A
Yue-Hua He, Yoshiaki Takaya, Kenji Terashima, and Masatake Niwa*
Faculty of Pharmacy, Meijo University, Tempaku, Nagoya 468-8503, Japan
Abstract – The absolute configurations of stilbenetrimers, (+)-davidiol A and
(–)-davidiol A were determined on the basis of the enzymatic chemical
transformations.
INTRODUCTION
Many oligostilbenes with various types of the molecular skeleton have been isolated mainly from the
following families: Vitaceae, Dipterocarpaceae, Leguminosae, Cyperaceae, Gnetaceae, and
Umbelliferae.1 But the oligostilbenes isolated from the Vitaceaeous plants are chemically different from
those from other families as shown in case of ε-viniferin (a resveratrol-dimer) and hopeaphenol (a
resveratrol-tetramer). (+)-ε-Viniferin (1) and (+)-hopeaphenol (2) were isolated only from Vitaceaeous
plants,2 while the enantiomers of these compounds were from other families. So Vitaceaeous plants are
estimated to have a specific biosynthetic pathway to generate oligostilbenes. As we described
previously,3 ε-viniferin, which would be synthesized enzymatically in plant tissues, seems to be a
biogenetically important precursor of many oligostilbenes in plants. But we can propose several
patterns of oxidative dimerization of resveratrol (3) as shown in our previous report,4 and a characteristic
type of compound is supposed to be obtained in each pathway.

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On the other hand, we previously reported lignan glycosides,5 oligostilbenes and flavonoids6 as the
constituents of Vitis thunbergii, a wild Vitaceaeous plant mainly distributed in Japan, Korea and China.
Recently, Chen et al. reported on the structures and biological activity of oligostilbenes from the roots of
V. thunbergii.7 In the course of our further exploration of the compounds contained in the plant, we
isolated a stilbenetrimer, (+)-davidiol A (4) from the aerial part of V. thunbergii. This is the first report
of (+)-davidiol A and the structure including the absolute configuration was deduced from the spectral
data and the enzymatic transformation of resveratrol (3) and (+)-ε-viniferin (1).
RESULTS AND DISCUSSION
Isolation
The methanol extract of the aerial part of V. thunbergii collected in Aichi Prefecture was successively
partitioned between water and ethyl acetate, and n-butanol to give the corresponding solubles. The ethyl
acetate soluble was subjected to silica gel column chromatography using a mixture of chloroform –
methanol as an eluent to give four fractions. One of the fractions eluted with the mixture of chloroform
– methanol (70:30) was fractionated using repeated normal and reversed-phase silica gel, and (+)-davidiol
A (4) was isolated.
From the ethyl acetate soluble, (+)-ε-viniferin (1),8 (+)-cis-ε-viniferin,9
(+)-trans-miyabenol C,10 (+)-cis-miyabenol C,11 (–)-vitisin B,12 (+)-hopeaphenol (2),13
(–)-isohopeaphenol,13 (+)-ampelopsin C,14 and (+)-ampelopsin E15 were also isolated. It is interesting
that (+)-trans-miyabenol C10 and (+)-cis-miyabenol C11 were also obtained from Umbelliferaeous and
Cyperaceaeous plants. This evidence demonstrated that the biogenetic pathways to generate these
oligostilbenes are different by the plants.
Structure of (+)-davidiol A
(+)-Davidiol A (4), [α]D +144.0° (c 0.19, MeOH) was found to have the molecular formula C42H32O9
1
determined by high-resolution FABMS spectrum. The H NMR spectrum in acetone-d6 of 4 exhibited
signals for three sets of ortho-coupled aromatic hydrogens at δH 7.20 and 6.77 (each 2H, d, J=8.5 Hz); 7.03
and 6.58 (each 2H, d, J=8.5 Hz); 6.73 and 6.59 (each 2H, d, J=8.5 Hz); one set of meta-coupled aromatic
hydrogens at δ 6.42 and 6.54 (each 1H, br. s); one set of AX2 type meta-coupled aromatic hydrogens at δ
6.42 (2H, d, J=2.2 Hz) and, 6.17 (1H, t, J=2.2 Hz), one isolated aromatic hydrogen at δ 6.00 (1H, s), one
set of aliphatic hydrogens at δ 6.07 (1H, d, J=3.3 Hz) and 4.39 (1H, m), and four aliphatic hydrogens at δ
5.26 (1H, brs, H-7b), 4.21 (1H, d, J=11.3 Hz, H-8b), 2.95 (1H, dd, J=11.3, 9.6 Hz, H-8c), and 4.38 (1H, d,
J=9.6 Hz, H-8c). These data, along with those of HMBC and NOESY spectra and the sign of the
specific rotation, suggested that this compound should be the enantiomer of (–)-davidiol A (5).16

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Absolute configuration of davidiol A
(+)-Davidiol A (4) would be generated by either of the pathways shown in Figure 1. In pathway A,
resveratrol (3) oxidatively couples with (+)-ε-viniferin (1) followed by cyclization to afford (+)-davidiol
A (4). On the other hand, pathway B demonstrates that two molecules of resveratrol (3) dimerize in the
first step to give (–)-quadrangularin A (6),17 and then another resveratrol (3) couples to (–)-quadrangularin
A to form (+)-davidiol A (4).
We have recently reported the biomimic transformation of resveratrol (3)
Figure 1 Possible biogenetic pathways of (+)-davidiol A (4) from (+)-ε-viniferin (1) and resveratrol (3).
HO
HO
HO
HO
OH
O
OH
O
OH
OH
OCH3
+
H
OH
OH
OCH3
CH3O
OCH3
OH
OH
1
8
9
MeI
HO
HO
CH3O
CH3O
CH3
O
O
OH
OH
O
OCH3
OCH3
CH3I
OH
H
H
OH
CH3O
OH
OCH3
OH
OCH3
4
10
Figure 2 Confirmation of the absolute structure of (+)-davidiol A (4).

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with several commercially available peroxidases.4 In this study, we tried again to treat only resveratrol
(3) with horseradish peroxidase (HRP), but we could get neither ε-viniferin, quadrangularin A, nor
davidiol A just like our previous report, even though we analyzed the product precisely by using HPLC.
ε-Viniferin was obtained both from Vitaceaeous and other plants, though, to the best of our knowledge,
(–)-quadrangularin A (6) has never been detected in Vitaceaeous plants. Accordingly, pathway A seems
to be the promising route to (+)-davidiol A (4). Then we treated (+)-ε-viniferin (1) and resveratrol (3)
with HRP to give (+)-davidiol A (4) in the yield of 1.1% along with resveratrol-trans-dihydrodimer (7)
(8.5%), resveratrol-cis-dehydrodimer (2.0%) and (+)-hopeaphenol (1.5%). The synthetic (+)-davidiol A
was identical with natural (+)-davidiol A (4) including the optical rotation.
As mentioned above, (+)-davidiol A (4) was synthesized from resveratrol (3) and (+)-ε-viniferin (1),
whose absolute configuration is known,18 and its absolute configuration was estimated to be the antipode
of that for (–)-davidiol A (5) shown in the paper by Tanaka et al.16 But we further investigated an
enzymatic coupling of (+)-ε-viniferin (1) and pterostilbene (4´-hydroxy-3,5-dimethoxystilbene) (8)19 so as
to confirm that (+)-davidiol A (4) is really generated from (+)-ε-viniferin (1) and resveratrol (3), since we
could not deny perfectly that three molecules of resveratrol (3) were transformed to (+)-davidiol A (4).
Prior to the coupling, pterostilbene (8) was synthesized by the modified route for the synthesis of
resveratrol shown in our previous paper4 using methyl 3,5-dimethoxybenzoate as the starting material.
As shown in Figure 2, (+)-ε-viniferin (1) and pterostilbene (7) were treated with HRP to give dimethoxy
compound (9) in the yield of 2.7%. This result demonstrated that pathway A in Figure 1 is responsible
for the formation of (+)-davidiol (4), and the stereochemistry of the product (9) was regulated by that of
(+)-ε-viniferin (1). Compound (9) was further methylated with methyl iodide, to give methylated
davidiol A (10). All spectral data were identical with those of methylated davidiol A (10) prepared from
the natural (+)-davidiol A (4), and thus the absolute configuration of (+)-davidiol A (4) was confirmed.
EXPERIMENTAL
General
UV and IR spectra were recorded on JASCO Ubest V-560 (cell length 10 mm) and FT/IR-410
spectrophotometers, respectively. Optical rotations were measured with a JASCO P-1020 polarimeter
1
13
(cell length 100 mm). H and C NMR spectra were recorded on JEOL ALPHA-600 (1H: 600 MHz and
13C: 150 MHz) and JEOL ALPHA-400 (1H: 400 MHz and C: 100 MHz) spectrometers. Chemical
13
1
13
shifts for H and C NMR are given in parts per million (δ) relative to solvent signal (chloroform-d: δH
7.26 and δC 77.0, acetone-d6: δH 2.04 and δC 24.9, and methanol-d4: δH 3.30 and δC 49.0) as internal
standards, respectively. LR and HR FAB-MS were obtained with JEOL JMS HX-110 using

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m-nitrobenzyl alcohol as matrix. Analytical TLC was performed on silica gel 60 F254 (Merck).
Column chromatography was carried out on silica gel BW-820MH (Fuji Silysia Chemicals, Co. Ltd).
ODS (Develosil ODS HG-5, φ20 x 250 mm, Nomura Chemical, Seto, Japan), and C-8 (Develosil C8-5,
φ20 x 250 mm, Nomura Chemical, Seto, Japan) columns were used for preparative HPLC. Peroxidases
from horseradish were from Wako Pure Chemicals, Osaka, Japan. Synthetic resveratrol (3)4 and natural
(+)-ε-viniferin (1) from the roots of Vitis vinifera ‘Kyoho’ were used for the starting material of the
enzymatic transformation. All spectral data of these compounds were completely identical with those
reported.20
Isolation of (+)-davidiol A (4)
A part of the ethyl acetate solubles (1.23 g) prepared from the methanol extract of the aerial part of V.
thunbergii in our previous paper5 was fractionated by silica-gel column chromatography using a mixed
solvent system of chloroform – methanol (95:5 – 50:50) to give four fractions (F1 – F4). F3 (429 mg,
chloroform – methanol (70:30)) was further separated by medium pressure column chromatography
(MPCC) using an ODS column (Develosil Lop ODS 30/50 φ50 x 320 mm, Nomura Chemical, Seto,
Japan) with a mixture of methanol – water (70:30 – 50:50) to give six fractions (F31 – F36). F34 (57
mg, methanol – water (60:40)) was fractionated by silica-gel column chromatography using a mixture of
chloroform – methanol (85:15 – 70:30) to give three fractions (F341 – F343). F342 (35 mg, chloroform
– methanol (80:20)) was purified by HPLC equipped with C-8 column by using a mixed solvent of
methanol – water (4:6), and (+)-davidiol A (4) (2.7 mg) was obtained.
(+)-Davidiol A (4). [α]D +144.0° (c 0.19, MeOH);21 a brown oil; UV λmax (MeOH) [nm (log ε)] 284
(3.75); IR νmax (film) 3321, 1613 cm-1; 1H NMR (600 MHz, acetone-d6) δ 7.20 (2H, d, J=8.5 Hz; H-2a,6a),
7.03 (2H, d, J=8.5 Hz; H-2b,6b), 6.77 (2H, d, J=8.5 Hz; H-3a,5a), 6.73 (2H, d, J=8.5 Hz; H-2c,6c), 6.59
(2H, d, J=8.5 Hz; H-3c,5c), 6.58 (2H, d, J=8.5 Hz; H-3b,5b), 6.54 (1H, br s; H-14a), 6.42(1H, br s;
H-12a), 6.42 (2H, d, J=2.2 Hz; H-10c,14c), 6.17 (1H, t, J=2.2 Hz; H-12c), 6.07 (1H, d, J=3.3 Hz; H-7a),
6.00 (1H, s; H-12b), 5.26 (1H, br s; H-7b), 4.39 (1H, m; H-8a), 4.38 (1H, d, J=9.6 Hz; H-7c), 4.21 (1H, d,
13
J=11.3 Hz; H-8b), 2.95 (1H, dd, J=11.3, 9.6 Hz; H-8c); C NMR (150 MHz, acetone-d6) δ 159.5
(C-11c,13c), 159.4 (C-11b), 158.4 (C-4b), 158.0 (C-11a), 156.9 (C-4c), 156.8 (C-13a), 155.8 (C-4a),
152.1 (C-13b), 147.1 (C-9a), 143.9 (C-9c), 143.3 (C-9b), 137.5 (C-1b), 134.4 (C-1a), 134.1 (C-1c), 129.9
(C-2c,6c), 129.6 (C-2b,6b), 128.1 (C-2a,6a), 124.2 (C-14b), 119.2 (C-10b), 118.1 (C-10a), 116.0
(C-3a,5a), 115.5 (C-3b,5b), 115.3 (C-3c,5c), 108.3 (C-10c,14c), 103.8 (C-14a), 102.1 (C-12c), 101.5
(C-12a), 95.7 (C-12b), 85.8 (C-7a), 67.5 (C-8c), 56.2 (C-7c), 51.4 (C-8b), 50.4 (C-8a), 36.5 (C-7b);
HRFAB-MS: m/z 681.2122 [M+H]+ (681.2125 calculated for C42H33O9).

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Peroxidase reaction of (+)-ε-viniferin (1) and resveratrol (3)
To a solution of (+)-ε-viniferin (1) (50 mg) and resveratrol (3) (50 mg) in 50% aqueous acetone (9 mL), a
suspension of horseradish peroxidase (HRP) (0.1 mg) in 50% aqueous acetone (1 mL) was added at 25 °C.
After 5 min stirring, 30% hydrogen peroxide (25 µL) was added. The reaction solution was kept stirring
for 15 min, extracted with ethyl acetate, and the organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and evaporated. The residue was purified by column chromatography
over silica gel using a mixture of chloroform – methanol (90:10 – 50:50) followed by preparative HPLC
using C8 column with a mixed solvent of methanol – water (40:60) to afford (+)-davidiol A (4) (0.8 mg,
1.1%). [α]D +135.3° (c 0.16, MeOH).
Resveratrol-trans-dihydrodimer (7) (8.5%), resveratrol-cis-dehydrodimer (2.0%), and (+)-hopeaphenol
(1.5%) were also obtained, and their spectral data were identical with those reported.13,17
Peroxidase reaction of (+)-ε-viniferin (1) and pterostilbene (8)
Pterostilbene (8)19 was synthesized in the modified manner of route for resveratrol (3) using methyl
3,5-dimethoxybenzoate as a starting material.4
Peroxidase reaction of (+)-ε-viniferin (1) and
pterostilbene (8) was carried out in the same manner described above using (+)-ε-viniferin (1) (38 mg),
pterostilbene (8) (41 mg) and 20 µL of 30% hydrogen peroxide. The product was purified by repeated
preparative HPLC using ODS column with a mixed solvent of acetonitrile – water (60:40) to give
dimethoxy compound (9) (1.6 mg, 2.7%).
Pterostilbene (8). 1H NMR (400 MHz, CD3OD) δ 7.38 (2H, d, J=8.8 Hz; H-2,6), 7.05 (1H, d, J=16.1
Hz; H-7), 6.89 (1H, d, J=16.1 Hz; H-8), 6.76 (2H, d, J=8.8 Hz; H-3,5), 6.66 (2H, d, J=2.2 Hz; H-10,14),
6.34 (1H, t, J=2.2 Hz; H-12), 3.78 (6H, s; –OCH3 x 2); 13C NMR (100 MHz, CD3OD) δ 162.4 (C-11,13),
158.5 (C-4), 141.3 (C-9), 130.3 (C-1), 130.0 (C-7), 128.9 (C-2,6), 126.8 (C-8), 116.5 (C-3,5), 107.8
(C-10,14), 100.3 (C-12), 55.7 (–OCH3); FAB-MS: m/z 257 [M+H]+.
Compound (9). [α]D +153.3° (c 0.054, CHCl3); a brown oil; UV λmax (MeOH) [nm (log ε)] 284 (4.94);
IR νmax (film) 3357, 1609 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.20 (2H, d, J=8.4 Hz; H-2a,6a), 7.01 (2H,
d, J=8.4 Hz; H-2b,6b), 6.79 (2H, d, J=8.4 Hz; H-2c,6c), 6.77 (2H, d, J=8.4 Hz; H-3a,5a), 6.68 (2H, d,
J=2.2 Hz; H-10c,14c), 6.61 (2H, d, J=8.4 Hz; H-3c,5c), 6.58 (2H, d, J=8.4 Hz; H-3b,5b), 6.56 (1H, d,
J=2.4 Hz; H-14a), 6.41 (1H, d, J=2.4 Hz; H-12a), 6.27 (1H, t, J=2.2 Hz; H-12c), 6.08 (1H, d, J=3.0 Hz;
H-7a), 6.01 (1H, s; H-12b), 5.26 (1H, br s; H-7b), 4.54 (1H, d, J=9.9 Hz; H-7c), 4.37 (1H, d, J=3.0 Hz;
13
H-8a), 4.21 (1H, d, J=11.7 Hz; H-8b), 3.05 (1H, dd, J=11.7, 9.9 Hz; H-8c), 3.70 (6H, s; –OCH3 x 2); C
NMR (150 MHz, CDCl3) δ 161.5 (C-11c,13c), 159.6 (C-11b), 158.1 (C-4a), 158.0 (C-11a), 158.0 (C-13a),
156.9 (C-4c), 155.9 (C-4b), 154.9 (C-13b), 147.2 (C-9a), 144.0 (C-9b), 143.0 (C-9c), 137.3 (C-1b), 134.4

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(C-1a), 134.1 (C-1c), 129.9 (C-2c,6c), 129.6 (C-2b,6b), 128.1 (C-2a,6a), 122.2 (C-14b), 119.2 (C-10b),
118.1 (C-10a), 116.0 (C-3a,5a), 115.7 (C-3c,5c), 115.4 (C-3b,5b), 107.8 (C-10c,14c), 104.2 (C-14a),
101.4 (C-12a), 99.3 (C-12c), 96.0 (C-12b), 85.9 (C-7a), 67.5 (C-8c), 55.4 (C-7c), 51.8 (C-8b), 50.4 (C-8a),
36.5 (C-7b), 55.4 (–OCH3 x 2); HRFAB-MS: m/z 709.2460 [M+H]+ (709.2438 calculated for C44H37O9).
Methylation of (+)-davidiol A (4) and compound (9)
To a solution of (+)-davidiol A (4) (2.0 mg) in acetone (3 mL), methyl iodide (26 µL) and anhydrous
potassium carbonate (55 mg) were added. The reaction mixture was refluxed for 21 h, filtered, and
evaporated. The resulted residue was purified by silica gel column chromatography using a mixture of
benzene – acetone (10:0.2) to give methylated davidiol A (10) (1.5 mg). By the same method,
compound (10) (1.1 mg) was obtained from compound (9) (1.6 mg).
Compound (10) (from natural product (4)). [α]D +130.2° (c 0.07, CHCl3); a brown oil; UV λmax
1
(MeOH) [nm (log ε)] 284 (4.03), 241 (4.54); IR νmax (film) 2922, 2835, 1605, 1510 cm-1; H NMR (600
MHz, CDCl3) δ 7.29 (2H, d, J=8.8 Hz; H-2a,6a), 7.04 (2H, d, J=8.8 Hz; H-2b,6b), 6.87 (2H, d, J=8.8 Hz;
H-3a,5a), 6.75 (1H, d, J=2.4 Hz; H-14a), 6.74 (2H, d, J=8.8 Hz; H-2c,6c), 6.67 (2H, d, J=8.8 Hz;
H-3b,5b), 6.64 (2H, d, J=8.8 Hz; H-3c,5c), 6.62 (2H, d, J=2.2 Hz; 10c,14c), 6.59 (1H, d, J=2.4 Hz;
H-12a), 6.33 (1H, t, J=2.2 Hz; H-12c), 6.29 (1H, d, J=2.9 Hz; H-7a), 6.23 (1H, s; H-12b), 5.25 (1H, br s;
H-7b), 4.53 (1H, d, J=9.7 Hz; H-7c), 4.36 (1H, d, J=2.9 Hz; H-8a), 4.30 (1H, d, J=11.7 Hz; H-8b), 2.93
(1H, dd, J=11.7, 9.9 Hz; H-8c), 3.87 (3H, s; 11a-OCH3), 3.84 (3H, s; 13a-OCH3), 3.77 (3H, s; 4a-OCH3),
3.74 (6H, s; 11c,13c-OCH3), 3.68 (3H, s; 4c-OCH3), 3.64 (3H, s; 4b-OCH3), 3.39 (3H, s; 13b-OCH3); 13C
NMR (150 MHz, CDCl3) δ 161.7 (C-11c,13c), 160.7 (C-11a), 160.4 (C-11b), 160.2 (C-4a), 159.6 (C-13a),
158.8 (C-4c), 158.6 (C-4b), 158.2 (C-13b), 146.8 (C-9a), 143.9 (C-9b), 142.8 (C-9c), 137.8 (C-1b), 136.3
(C-1c), 135.5 (C-1a), 129.5 (C-2b,6b), 129.4 (C-2c,6c), 128.0 (C-2a,6a), 124.4 (C-14b), 120.5 (C-10a),
119.3 (C-10b), 114.6 (C-3a,5a), 114.1 (C-3b,5b), 113.7 (C-3c,5c), 108.0 (C-10c,14c), 103.3 (C-14a), 99.0
(C-12c), 96.7 (C-12a), 93.2 (C-12b), 85.5 (C-7a), 67.5 (C-8c), 56.2 (C-7c), 51.5 (C-8b), 50.8 (C-8a), 36.4
(C-7b), 56.5, 56.2, 55.8, 55.54, 55.4, 55.2 (each –OCH3), 55.49 (2C, –OCH3); HRFAB-MS: m/z 793.3378
[M+H]+ (793.3377 calculated for C50H49O9).
Compound (10) (from compound (9)). [α]D +123.2° (c 0.08, CHCl3); HRFAB-MS: m/z 793.3400
[M+H]+ (793.3377 calculated for C50H49O9).
ACKNOWLEDGEMENTS
This research was financially supported by a Grant-in-Aid for High-Tech Research Center Project and for
The Advancement of Graduate School from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, which are gratefully acknowledged. We are also grateful to Matsu-Ura Yakugyo

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Co. Ltd. for financial support. We are thankful to Dr. T. Ito of Gifu Prefectural Institute of Health and
Environmental Sciences for providing the 1H NMR spectrum of (–)-davidiol A.
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21. The absolute value of the specific optical rotation of 4 was different from that of (–)-davidiol A (5)
reported ([α]D –272°) in the reference 16. But the values of natural and synthetic 4 were very
similar, and these compounds seemed to be pure judging from the NMR spectra of them. So we
report our value in this paper.