Isolation, synthesis, and antiplatelet aggregation activity of resveratrol 3-O-β-D-glucopyranoside and related compounds

Article abstract of DOI:10.1021/np970069t

Resveratrol 3-O-β-D-glucopyranoside (1) has been isolated from the seeds of Erythrophleum lasianthum (Caesalpinioidae, Leguminosae), a South African plant used in traditional medicine, and has shown antiplatelet aggregation activity. The synthesis of 1, related hydroxystilbenes, and their glucosides has been undertaken to provide larger quantities, for further biological evaluation, and has been accomplished via Wittig reactions followed by glucosylation under phase transfer catalysis.

Full text of DOI:10.1021/np970069t

1082
J . Nat. Prod. 1997, 60, 1082-1087
Isola tion , Syn th esis, a n d An tip la telet Aggr ega tion Activity of Resver a tr ol
3-O-â-D-Glu cop yr a n osid e a n d Rela ted Com p ou n d s†
Fulvia Orsini,* Francesca Pelizzoni, Luisella Verotta, and Talal Aburjai‡
Centro di Studio per le Sostanze Organiche Naturali del CNR, Dipartimento di Chimica Organica e Industriale,
Universita` degli Studi, via Venezian 21, 20133 Milano, Italy
Colin B. Rogers
Department of Chemistry, University of Durban-Westville, Durban 4000, Republic of South Africa
Received J anuary 29, 1997X
Resveratrol 3-O-â-D-glucopyranoside (1) has been isolated from the seeds of Erythrophleum
lasianthum (Caesalpinioidae, Leguminosae), a South African plant used in traditional medicine,
and has shown antiplatelet aggregation activity. The synthesis of 1, related hydroxystilbenes,
and their glucosides has been undertaken to provide larger quantities, for further biological
evaluation, and has been accomplished via Wittig reactions followed by glucosylation under
phase transfer catalysis.
Infusions of different parts of Erythrophleum lasian-
thum Corbishley (Caesalpinioidae, Leguminosae), a
South African plant, widely used both as a medicinal
plant and a poison, are reported to produce digitalis-
like effects on the heart.1 During the search for the
substances responsible for the toxicity of E. lasianthum,
we isolated two diterpene alkaloids and a phenolic
glucoside (1) (resveratrol 3-O-â-D-glucopyranoside).2 The
cassaine type diterpene alkaloids have been found to
be active on heart motility with a digitalis-like mecha-
nism;3,4 resveratrol 3-O-â-D-glucopyranoside (1, Figure
1) showed antiplatelet aggregation activity.5 The cor-
F igu r e 1. Chemical structure and atom numbering scheme
of resveratrol 3-O-â-D-glucopyranoside.
responding aglycon resveratrol, isolated from different
sources, has also shown antiplatelet aggregation activ-
The stilbene skeleton of (E)- and (Z)-resveratrol has
ity6,7 as well as coronary vasodilator action,8 anti-
been efficiently achieved by a Wittig reaction between
leukemic,9 antifungal,10 and protein-tyrosine kinase
the phosphonium salt of the commercially available
inhibitory action.11 Other dihydrostilbene compounds,
4-methoxybenzyl chloride and 3,5-bis[(tert-butyldimeth-
isolated from natural sources, have been reported as
ylsilyl)oxy]benzaldehyde (Scheme 1), followed by desi-
antiplatelet aggregation agents.12 Since these com-
lylation with tetrabutylammonium fluoride.14,15
pounds are available in small amounts from natural
Protection of the hydroxyl group at position 4′ as
sources, the synthesis of 1 and related hydroxystilbenes
methyl ether had the advantage that a methoxy group
and their glucosides has been undertaken to provide
at the 4′-position is present in several natural bioactive
larger quantities for further biological evaluation. In
compounds with a stilbene skeleton.16,17 The Wittig
this paper the results obtained in the evaluation of the
product, obtained in 98% yields as a 2.3:1 mixture of
antiplatelet aggregation activity of the natural and
the Z/E isomers 2b and 2a , was directly desilylated with
synthetic compounds are reported.
tetrabutylammonium fluoride to afford 3a and 3b,
which were purified by crystallization or flash chroma-
Resu lts a n d Discu ssion
tography.18
E. lasianthum Corbishley (Caesalpinoideae, Legumi-
nosae) is a large tree widely used by Zulu people in
medicine and magic.1 Detailed chemical investigation
of the poisonous seeds yielded two diterpene alkaloids,
namely 3-hydroxynorerythrosuamine and its 3-O-â-D-
glucopyranoside, which have been found to possess a
positive inotropic effect and inhibit the Na+,K+-
ATPase.2-4
A modified extraction procedure of the seeds yielded
1 which was characterized as resveratrol 3-O-â-D-
glucopyranoside by spectroscopic evidence and by com-
parison with literature data.10,13
The glucosylation, which can be troublesome with
phenols because of the very low reactivity of the phenolic
moiety as a glycosyl acceptor, was tested under a variety
of experimental conditions. Aqueous bases under phase
transfer catalysis gave the best results in terms of
convenience (use of a commercially available sugar) and
yield as reported for the synthesis of 4a (Scheme 2)
which was obtained in 32% yield from 3a , accompanied
by a small amount of the corresponding diglucoside
(13%) and unreacted aglycon (20%).15 Treatment of 4a
with a 7.5/1 molar ratio of sodium thioethoxide in
dimethylformamide19,20 afforded resveratrol 3-O-â-D-
glucopyranoside (1), identical in all respects to an
authentic isolated sample.21
† This paper is dedicated to the memory of Prof. G. J ommi.
* Author to whom correspondence should be adressed. Tel.: 02-
2367588. Fax: 02-2364369. E-mail: sellogui@imicilea.cilea.it.
‡ On leave from the University of J ordan, Dept. of Phytochemistry
and Pharmacognosy, Faculty of Pharmacy, Amman, J ordan.
X Abstract published in Advance ACS Abstracts, October 1, 1997.
The same sequence of reactions described above was
applied to the cis-aglycon (3b) to prepare a series of cis
derivatives and study the influence of the double bond
S0163-3864(97)00069-4 CCC: $14.00
© 1997 American Chemical Society and American Society of Pharmacognosy

Resveratrol 3-O-â-D-glucopyranoside and Related Compounds
J ournal of Natural Products, 1997, Vol. 60, No. 11 1083
Sch em e 1
Sch em e 2a
a
(a) Et3(PhCH2)N+Br-, R-bromo-tetra-O-acetyl-D-glucose, NaOH, CHCl3, 60 °C; (b) EtSNa (excess), DMF; (c) MeONa, MeOH, 25 °C;
(d) EtSNa, DMF.
Ta ble 1. Effects of (E)-Resveratrol 3-O-â-D-Glucopyranoside (1)
configuration both on the outcome of the synthetic
on the Platelet Aggregation Induced by Collagen, Adrenalin,
Arachidonic Acid (AA), and ADPa
sequence and on the biologic activity. Glucosylation of
3b under phase transfer catalysis afforded the mono-
glucoside 4b (32%) and a small amount of the digluco-
side 5b (4%). Unreacted aglycon (54%) was recovered
and recycled. By treatment with sodium methoxide and
methanol, 4b gave (Z)-3,5-dihydroxy-4′-methoxystilbene
3-O-â-D-glucopyranoside (6b) in quantitative yield. The
de-O-methylation sequence, when applied to the (Z)-
glucosides 4b and 6b, gave a mixture of (Z)- and (E)-
resveratrol 3-O-â-D-glucopyranoside (8b) and 1, due to
a sodium thioethoxide-promoted Z/E isomerization.22
inducer
IC50 (µg)
collagen
adrenaline
AA
32.55 ( 2.20b
49.27 ( 9.26b
57.21 ( 5.73c
84.90 ( 6.50c
ADP
a
Platelets were preincubated with (E)-resveratrol 3-O-â-D-
glucopyranoside or the solvent (0.25% DMSO, control) at 37 °C
for 3 min, and then collagen (2.5 g/mL), adrenalin (2 µM), AA (100
µM), or ADP (6 µM) was added. Results are expressed as means
b
( SE of five replicate experiments. p < 0.05 as compared with
control values. c p < 0.01 as compared with control values.
(E)-Resveratrol 3-O-â-D-glucopyranoside (1), tested in
vitro on human platelet-rich plasma (PRP), has shown
a significant inhibitory effect on platelet aggregation
induced by collagen (IC50 value of 69 µM), adrenalin
(IC50 value of 102 µM) and, to a minor extent, by
arachidonic acid (IC50 of 149 µM) and by ADP (IC50 of
218 µM) (Table 1).4,5
On the basis of these results, the antiplatelet ag-
gregation activity was then tested on several compounds

1084 J ournal of Natural Products, 1997, Vol. 60, No. 11
Orsini et al.
Ta ble 2. Effects of Compounds 3-13 on the Platelet
Aggregation Induced by Collagen and ADPa
IC50 (µg)
compound
collagen
ADP
3a
6a
7a
3b
6b
7b
8b
9
10
11
12
13
12.9 ( 0.84 (3)d
40.40 ( 5.40 (3)c
112.8 ( 20.5 (3)d
33.9 ( 6.4 (5)b
300
119.14 ( 9.5 (5)b
300
300
100.55 ( 5.74 (4)b
198.0 ( 16.5 (4)c
300
300
300
120.15 ( 27.3 (4)c
60.58 ( 6.87 (6)a
75.17 ( 26.73 (4)a
300
68.5 ( 22.1 (4)d
97.7 ( 19.7 (3)b
300
106.2 ( 9.08 (3)b
124.4 ( 16.93 (3)d
300
300
a
Platelets were preincubated with various agents or DMSO
(0.25%, control) at 37 °C for 3 min, then ADP (6 µM) or collagen
(2.5 g/mL) was added. Results are presented as means (SE.
b
Number of replicate experiments is shown in parentheses. p <
0.05 as compared with control values. c p < 0.01 as compared with
d
control values. p < 0.001 as compared with control values.
tion as observed by comparing 6a 15 with 3a . The
combined effects of a Z-configuration and glucosylation
made (Z)-3-(â-D-glucopyranosyloxy)-4′,5-dihydroxystil-
bene (8b), (Z)-3-(â-D-glucopyranosyloxy)-4′-methoxy-5-
hydroxystilbene (6b), and (Z)-3,5-di-(â-D-glucopyrano-
syloxy)-4′-methoxystilbene (7b) inactive. Similar obser-
vation can be made for platelet aggregation induced by
ADP. In particular, glycosylation significantly influ-
ences activity.
F igu r e 2. Chemical structure of combretastins derivatives.
derived from 3,4′,5-trihydroxystilbene (resveratrol se-
ries). To obtain further insight on the structure-
activity relationship, the analysis was extended to some
derivatives of the combretastatins series previously
synthesized,15 namely (Z)-2′,3′-dihydroxy-3,4,4′,5-tet-
ramethoxystilbene (9) (combretastatin A-1);23 (Z)-3′-
hydroxy-3,4,4′,5-tetramethoxystilbene (10) (combret-
astatin A-4);24 (E)-2′-hydroxy-3,4,4′,5-tetramethoxy-
stilbene (12) ((E)-combretastatin iso A-4); combretasta-
tin A-4, 3′-O-â-D-glucopyranoside (11); (E)-combretasta-
tin iso A-4, 2′-O-â-D-glucopyranoside (13).
As far as the tested compounds are concerned, some
parameters responsible for the activity can be sug-
gested: (a) the number and the location of the hydroxyl
groups; (b) the derivatization of the hydroxyl groups;
and (c) the configuration of the double bond. The effects
of these parameters can be further modulated by the
different substitution pattern found either within the
same series or in the two series.
When platelet aggregation was induced by collagen
the most active compounds were found in the resveratrol
series, whereas the opposite held true when the platelet
aggregation was induced by ADP. Concerning the
platelet aggregation induced by collagen, in both series
the maximum activity appears to be related to the
presence of two free hydroxyl groups as found in (E)-
3,5-dihydroxy-4′-methoxystilbene (3a), (Z)-3,5-dihydroxy-
4′-methoxystilbene (3b), (E)-(â-D-glucopyranosyloxy)-
4′,5-dihydroxystilbene (1) [resveratrol series], and 2′,3′-
dihydroxy-3,4,4′,5-tetramethoxystilbene (9) (combreta-
statin A-1, Figure 2). Differences in the activity of these
compounds could be related to the different substitution
pattern as well as to the different location (on the same
ring or on different rings) and orientation (meta, ortho)
of the hydroxyl groups (Table 2).
Exp er im en ta l Section
Gen er a l E xp er im en t a l P r oced u r es. Triphenyl-
phosphine, 4-methoxybenzyl chloride, benzyltriethylam-
monium chloride, and 4-hydroxybenzyl alcohol were
purchased from Aldrich and used as received. R-Bro-
motetra-O-acetyl-D-glucose was purchased from Sigma
and used as received. Reagents grade tetrahydrofuran,
1,2-dimethoxyethane, and pyridine were refluxed over
LiAlH4 and distilled. Reagent grade dichloromethane
was refluxed over P2O5 and distilled. Reagent grade
MeOH was refluxed over CaH2, distilled, refluxed over
Mg, distilled, and kept over 3 Å molecular sieves.
Reagent grade dimethylformamide was distilled at low
pressure under nitrogen and kept over 4 Å molecular
sieves. (E)-3,5-Dihydroxy-4′-methoxystilbene 3-O-â-D-
glucopyranoside (6a ); (E)-3,5-dihydroxy-4′-methoxystil-
bene 3,5-O-â-D-diglucopyranoside (7a); (Z)-2′,3′-dihydroxy-
3,4,4′,5-tetramethoxystilbene (9) (combretastatin A-1);
(Z)-3′-hydroxy-3,4,4′,5-tetramethoxystilbene (10) (com-
bretastatin A-4); (E)-2′-hydroxy-3,4,4′,5-tetramethoxy-
stilbene (11) ((E)-combretastatin iso A-4); combretasta-
tin A-4, 3′-O-â-D-glucopyranoside (12); and (E)-com-
bretastatin iso A-4, 2′-O-â-D-glucopyranoside (13) were
synthesized as reported in the literature.15 NMR spec-
tra were obtained with Varian L-200 and Bruker AC-
200 and AC-300 instruments. IR spectra were recorded
with a Perkin-Elmer 681 spectrometer and mass spectra
with a VG 7070 E 9 spectrometer. Melting points were
obtained by using Buchi 535 apparatus, optical rotations
were measured on a Perkin-Elmer 241 polarimeter, and
the microanalyses for the new compounds were deter-
mined on a Perkin-Elmer 240 elemental analyzer.
Flash-column chromatography was performed on Si gel
Merck Kieselgel 60 (230-400 mesh ASTM). Thin layer
chromatography (TLC) was carried out on Si gel plates
(60 F254, Merck): spots were detected visually by
Activity appeared to be related to the configuration
of the double bond and was lowered by changing the
configuration from E to Z, as observed by comparing
3a with 3b. Activity was also depressed by glucosyla-

Resveratrol 3-O-â-D-glucopyranoside and Related Compounds
J ournal of Natural Products, 1997, Vol. 60, No. 11 1085
ultraviolet absorption (254 nm) or by spraying with
MeOH/H2SO4, 9:1, followed by heating at 100 °C.
All reactions were carried out at 25 °C in a dry
nitrogen atmosphere, using glassware dried by flaming
in a stream of dry nitrogen.
THF (110 mL) at 15 °C. The resulting reddish solution
was allowed to warm at room temperature and stirred
for additional 30 min. 3,5-Bis[(tert-butyldimethylsilyl)-
oxy]benzaldehyde (2.64 g, 7.17 mmol) was added, and
the reaction mixture was stirred for 1 h, diluted with
ice-cold H2O (2 × 50 mL), and extracted with EtOAc (3
× 60 mL). The combined organic extracts were washed
with H2O (2 × 50 mL), and the solvent was removed
under reduced pressure to afford a mixture of E- and
Z-isomers 2a and 2b (E/Z, 2.3/1). Flash chromatogra-
phy over Si gel (n-hexane/EtOAc, 99/1) afforded a small
amount of pure Z isomer 2b (0.67 g, 1.43 mmol, 20%)
and a mixture of E and Z isomers (2.64 g, 5.6 mmol,
78.2%). Due to the difficult separation of the isomers
2a and 2b, the mixture was directly desilylated to 3a
and 3b.
P la n t Ma ter ia l. Seeds of E. lasianthum were col-
lected in False Bay (KwaZulu, Natal, South Africa) in
December 1991. A voucher specimen (no. 14122/1) is
deposited in the Ward Herbarium in Durban (South
Africa).
Extr a ction a n d Isola tion of Resver a tr ol 3-O-â-
D-glu cop yr a n osid e. Defatted seeds (800 g) were
extracted with H2O at room temperature (6 × 1.6 L).
The dark-brown solution was concentrated and ex-
tracted with EtOAc (3 × 400 mL; 1.3 g). This was
purified on Fractogel TSK HW 40 (3.5 cm i.d. × 90 cm)
eluted with MeOH (flow rate 1.9 mL/min), then on silica
gel (CHCl3/MeOH, 4:1), obtaining 180 mg of resveratrol
3-O-â-D-glucopyranoside (0.023%).1 The extraction pro-
cedure described in ref 4 did not allow the stilbenic
glucoside 1 to be isolated.
To a mixture of 2a and 2b (4.6 g, 9.6 mmol) in THF
(85 mL) was added tetrabutylammonium fluoride (25
mL of a 1 M solution in THF), and the mixture was
stirred at room temperature for 15 min. Et2O was
added (50 mL), the solution was washed with H2O (2 ×
30 mL), and the solvent was removed under reduced
pressure. The residue was filtered over silica gel to
afford a mixture of 3a and 3b (2.34 g, quantitative),
which was crystallized from CHCl3 and afforded pure
E isomer 3a (0.72 g, 2.98 mmol, 31%). The mother
liquors (1.62 g) were flash chromatographed over Si gel
(n-hexane/EtOAc, 99/1) and afforded 3b (0.68 g, 2.58
mmol, 29.6%).
Resver atr ol 3-O-â-D-glu copyr an oside (1): mp 220-
225 °C (from CHCl3-MeOH, 9:1) [lit.25 mp 228-230 °C];
[R]25D ) -56.4 (c 0.22, MeOH) [lit.26 [R]25D -65.26]; FAB
1
MS (positive) m/z 390 [M]+, 228 [M - 162]+; H NMR
(200 MHz, DMSO-d6) δ 9.58 (1H, bs, phenolic OH), 9.43
(1H, bs, phenolic OH), 7.39 (2H, d, J ) 8.6 Hz, H-2′ +
H-6′), 7.05 (1H, d, J ) 17.2 Hz, H-b), 6.85 (1H, J ) 17.2
Hz, H-a), 6.72 (2H, d, J ) 8.6 Hz, H-3′ + H-5′), 6.70
(1H, dd, J ) 1.8, 1.8 Hz, H-2), 6.55 (1H, dd, J ) 1.8, 1.8
Hz, H-6), 6.32 (1H, dd, J ) 1.8, 1.8 Hz, H-4), 5.29 (1H,
d, OH), 5.11 (1H, d, OH), 5.03 (1H, d, OH), 4.80 (1H, d,
J ) 7.0 Hz, H-1′′), 4.62 (1H, t, OH), 3.72 (1H, dd, J )
12.0, 1.8 Hz, H-6′′B), 3.6-3.12 (5H, m); 13C NMR (50.3
MHz, DMSO-d6) δ 158.9 (s, C-3 or C-5), 158.4 (s, C-3 or
C-5), 157.3 (s, C-4′), 139.4 (s, C-1), 130.0 (s, C-1′), 128.6
(d, C-â), 128.0 (d, C-2′ + C-6′), 125.2 (d, C-R), 115.6 (d,
C-3′ + C-5′), 107.2 (d, C-6), 104.7 (d, C-4), 102.8 (d, C-2),
100.7 (d, C-1′′), 77.2 (d, C-5′′), 76.7 (d, C-3′′), 73.3 (d,
C-2′′), 69.8 (d, C-4′′), 60.7 (t, C-6′′).
3a : colorless prisms: mp 176-178 °C (n-hexane/
1
EtOAc); H NMR (DMSO-d6, 300 MHz) δ 3.79 (3H, s,
OCH3), 6.18 (1H, dd, J 4,2 ) 1.5, J 4,6 ) 1.5 Hz, H-4), 6.45
(2H, d, H-2 and H-6), 6.93 (2H, d, J 3′,2′ ) J 5′,6′ ) 9.6 Hz,
H-3′ and H-5′), 6.94 and 6.98 (AB system, 2H, J ) 16.4
Hz, CHdCH), 7.51 (2H, d, H-2′ and H-6′), 9.22 (2H, bs
exchanges with D2O, OH); 13C NMR (DMSO-d6, 300
MHz) δ 55.36 (q), 102.06 (d), 2 × 104.63 (d), 113.90 (s),
2 × 114.40 (d), 126.80 (d), 2 × 127.98 (d), 129.84 (d),
139.35 (s), 2 × 158.53 (s), 159.14 (s); EIMS m/z 242 [M+];
anal. C 74.44%, H 5.90%, calcd for C15H14O3, C 74.35%,
H 5.83%.
3b: colorless syrup; 1H NMR (CDCl3 300 MHz) δ 3.76
(3H, s, OCH3), 5.68 (2H, bs, exchanges with D2O, OH),
6.19 (1H, dd, J 4,2 ) 2.1, J 4,6 ) 2.1 Hz, H-4), 6.31 (2H, d,
H-2 and H-6), 6.43 and 6.48 (AB system, 2 H, J ) 11.5
Hz, CHdCH), 6.75 (2H, d, J 3′,2′ ) J 5′,6′ ) 9.5 Hz, H-3′
and H-5′), 7.19 (2H, d, H-2′ and H-6′); 13C NMR (CDCl3,
300 MHz) δ 55.86 (q), 102.52 (d), 2 × 109.0 (d), 2 ×
114.40 (d), 129.0 (d), 130.37 (s), 2 × 130.95 (d), 131.0
(d), 140.75 (s), 2 × 157.54 (s), 159.37 (s); EIMS m/z 242
[M+]; anal. C 74.75%, H 5.98%, calcd for C15H14O3, C
74.35%, H 5.83%.
P la telet Aggr ega tion . The samples were dissolved
in DMSO at a final concentration of 0.25%. Platelet-
rich plasma (PRP) were obtained from human blood
taken from the forearm vein of volunteers. Blood was
then collected by free flow along the side of plastic tube
containing 3.8% sodium citrate (1:9) and was then
centrifuged at room temperature at 1250 rpm for 18
min. Platelets were counted under the microscope, and
the platelet count was adjusted to 300 000 platelets/mL
with platelet-poor plasma (PPP) obtained by centrifuga-
tion of the PRP at 13 000 rpm for 3 min.
Aggregation was measured by the turbidometric
method.27 The aggregometer was calibrated so that the
PRP gave 10% of light trasmission while the PPP from
the same donor gave 90% of light trasmission. The
aggregation was measured by an aggregometer (Elvi
Logos 840) connected to dual channel recorders. The
platelet suspension was stirred at 1000 rpm. Platelets
were preincubated with the test compounds or DMSO
for 3 min before the addition of aggregation inducer.
Typ ica l Glu cosyla tion P r oced u r es. A solution of
R-bromotetra-O-acetyl-D-glucose (1.06 g, 2.58 mmol) and
benzyltriethylammonium bromide (0.287 g, 1.05 mmol)
in CHCl3 (5.5 mL) was added to a solution of 3b (0.5 g,
2.07 mmol) in NaOH (1.25 M, 3.0 mL). The two-phase
reaction mixture was vigorously stirred at 60 °C for 5
h. After a second addition of NaOH solution (0.96 mL)
and sugar (0.49 g), the mixture was stirred at 60 °C for
5 h. EtOAc was added, and the resulting organic phase
was successively washed with H2O and dried (Na2SO4),
and the solvent was evaporated under reduced pressure.
The residue was purified by flash chromatography (n-
hexane/EtOAc, 70/30) to afford unreacted aglycon 3b
(0.367 g, 54%), tetra-O-acetyl-3-O-â-D-glucoside, (Z)-3,5-
(E)- a n d (Z)-3,5-Dih yd r oxy-4′-m eth oxystilben e
[(E)- a n d (Z)-4′-O-Meth ylr esver a tr ol] (3a ) a n d (3b).
3a and 3b were synthesized as previously described.15
Butyllithium (4.5 mL, 1.6 M in hexane, 7.17 mmol) was
added dropwise to a suspension of (4-methoxybenzyl)-
triphenylphosphonium chloride15 (3.9 g, 7.17 mmol) in

1086 J ournal of Natural Products, 1997, Vol. 60, No. 11
Orsini et al.
dihydroxy-4′-methoxystilbene tetra-O-acetyl-3-O-â-D-
glucopyranoside (4b) (0.472 g, 0.82 mmol, 32%), and a
small amount of diglucoside 5b (0.09 g, 0.103 mmol, 4%).
(2H, d, H-2′ and H-6′); FABMS m/z 902 [M+]; anal. C
57.10%, H 5.61%, calcd for C43H50O21, C 57.22%, H
5.58%.
1
(E)-3,5-Dih yd r oxy-4′-m eth oxystilben e Tetr a -O-
a cetyl-3-O-â-D-glu cop yr a n osid e (4a ). The title com-
pound 4a was synthesized from 3a by treatment with
R-bromotetra-O-acetyl-D-glucose as described for 3b.15
4b: amorphous solid; [R]D ) -0.9° (c 2, CHCl3); H
NMR (CDCl3, 300 MHz) δ 2.01 (6H, s, 2 × OAc), 2.04
(3H, s, OAc), 2.09 (3H, s, OAc), 3.58 (1H, m, H-5′′), 3.80
(3H, s, OCH3), 3.99 (1H, dd, J 6′′a,6′′b ) 13.4, J 6′′a,5′′ ) 2.4
Hz, H-6′′a), 4.22 (1H, dd, J 6′′b,5′′ ) 5.5 Hz, H-6′′b), 4.83
(1H, d, J 1′′,2′′ ) 7.9 Hz, H-1′′), 5.12 (1H, dd, J 3′′,2′′ ) 9.4,
J 3′′,4′′ ) 9.3 Hz, H-3′′), 5.19 (2H, m, H-2′′ and H-4′′), 5.31
1
4a : amorphous powder; H NMR (CDCl3) δ 1.98 (s,
3H, OAc), 2.0 (s, 3H, OAc), 2.01 (s, 3H, OAc), 2.04 (s,
3H, OAc), 3.78 (s, 3H, OCH3), 4.15 (ddd, 1H, J 5′′,4′′
)
8.0, J 5′′,6′′a ) 6.0, J 5′′,6′′b ) 3.0 Hz, H-5′′), 4.12 (dd, 1H,
J 6′′a,6′′b ) 12.0 Hz, H-6′′a), 4.22 (dd, 1H, H-6′′b), 4.90-
5.58 (m, 4H, H-1′′, H-2′′, H-3′′, and H-4′′), 6.42 (dd, 1H,
J 4,2 ) 2.6, J 4,6 ) 2.6 Hz, H-4), 6.69 (d, 2H, H-2 and H-6),
6.83 and 7.01 (AB system, 2H, J ) 15.7 Hz, CHdCH),
6.88 (d, 2H, J 3′,2′ ) J 5′,6′ ) 9.4 Hz, H-3′ and H-5′), 7.42
(d, 2H, H-2′ and H-6′); FABMS m/z 572 (M+); anal. C
60.98%, H 5.73%, calcd for C29H32O12, C 60.84%; H,
5.63%.
(1H, bs, exchanges with D2O, OH), 6.33 (1H, dd, J 4,2
)
1.5, J 4,6 ) 1.5 Hz, H-4), 6.37 and 6.53 (2H, d, J ) 12.6
Hz, CHdCH), 6.47 (2H, d, H-2 and H-6), 6.78 (2H, d,
J 3′2′ ) J 5′6′ ) 8.1 Hz, H-3′ and H-5′), 7.17 (2H, d, H-2′
and H-6′); 1H NMR (C6D6, 300 MHz) δ 1.68 (3H, s, OAc),
1.70 (6H, s, 2 × OAc), 1.73 (3H, s, OAc), 3.13 (1H, ddd,
J 5′′,4′′ ) 9.0, J 5′′,6′′b ) 5.2, J 5′′,6′′a ) 2.5 Hz, H-5′), 3.33 (3H,
s, OCH3), 3.84 (1H, d, J 6′′a,6′′b ) 14.0 Hz, H-6′a), 4.19
(1H, dd, H-6′′b), 4.79 (1H, d, J 1′′,2′′ ) 8.0 Hz, H-1′), 5.22
(1H, dd, J 3′′,2′′ ) 9.0, J 3′′,4′′ ) 9.0 Hz, H-3′′), 5.37 (1H,
dd, H-4′′), 5.46 (1H, dd, H-2′′), 6.34 and 6.45 (AB system,
2H, J ) 12.0 Hz, CHdCH), 6.42 (2H, s, H-2 and H-6),
6.47 (1H, s, H-4), 6.60 (2H, d, J 3′,2′ ) J 5′,6′ ) 8.6 Hz, H-3′
and H-5′), 6.72 (1H, s, exchanges with D2O, OH), 7.17
(2H, d, H-2′ and H-6′); 13C NMR (CDCl3, 300 MHz) δ
20.96 (q), 2 × 20.97 (q), 20.98 (q), 55.59 (q), 61.10 (t),
68.76 (d), 71.62 (d), 72.22 (d), 73.98 (d), 99.59 (d), 104.11
(d), 109.02 (d), 111.56 (d), 2 × 114.18 (d), 128.79 (d),
130.02 (s), 2 × 130.03 (d), 130.89 (d), 140.27 (s), 157.95
(s), 158.50 (s), 159.35 (s), 2 × 170.10 (s), 170.90 (s),
171.48 (s); 13C NMR (DMSO-d6) δ 4 × 20.35 (q), 55.03
(q), 61.50 (t), 68.03 (d), 2 × 70.75 (d), 71.95 (d), 97.69
(d), 103.01 (d), 107.38 (d), 110.26 (d), 2 × 113.71 (d),
128.08 (d), 128.86 (s), 2 × 129.98 (d), 130.0 (d), 139.25
(s), 157.63 (s), 158.39 (s), 158.40 (s), 169.08 (s), 169.1
(s), 169.5 (s), 169.97 (s); FABMS m/z 572 [M+]; anal. C
60.94%, H, 5.58%, calcd for C29H32O12, C 60.84%, H
5.63%.
(Z)-3,5-Dih yd r oxy-4′-m et h oxyst ilb en e 3-O-â-D-
glu cop yr a n osid e ((Z)-4′-O-m eth ylr esver a tr ol 3-O-
â-D-glu cop yr a n osid e, (Z)-4′-O-m eth ylp iceid ) (6b). A
0.2 M solution of sodium methoxide in MeOH (21 mL)
was added to a solution of 4b (0.4 g, 0.7 mmol) in MeOH
(27 mL). The solution was stirred at room temperature
for 2 h, and then Dowex 50Wx8 (H+ form) resins were
added until neutral pH. The resins were filtered and
washed with MeOH, and the solvent was evaporated
under reduced pressure to afford 6b in quantitative
yield.
6b: colorless needles; mp 143-145 °C (lit.12 mp 147-
148 °C); [R]D -33.0° (c 8, acetone); 1H NMR (DMSO-d6,
300 MHz) δ 3.1-3.5 (6H, H-2′′, H-3′′, H-4′′, H-5′′, and
H-6′′), 3.7 (3H, s, OCH3), 4.45 (1H, bs, exchanges with
D2O), 4.60 (1H, d, J 1′′,2′′ ) 7.8 Hz, H-1′′), 5.15 (1H, bs,
exchanges with D2O), 5.17 (1H, bs, exchanges with D2O),
5.30 (1H, bs, exchanges with D2O), 6.32 (2H, dd, J 2,4
)
J 6,4 ) 2.0 Hz, H-2 and H-6), 6.38 (1H, dd, H-4), 6.36
and 6.52 (AB system, 2H, J ) 12.0 Hz, CHdCH), 6.50
5b: colorless solid (n-hexane/EtOAc); mp 159-161 °C;
(1H, s, exchanges with D2O), 6.82 (2H, d, J 3′,2′ ) J 5′,6′
)
1
[R]D +2.3° (c 5, CHCl3); H NMR (CDCl3, 300 MHz) δ
1
7.9 Hz, H-3′ and H-5′), 7.18 (2H, d, H-2′ and H-6′); H
NMR (Py-d5) δ 3.65 (3H, s, OCH3), 3.88 (1H, ddd, J 5′′,4′′
) 7.0, J 5′′,6′′a ) 5.0, J 5′′,6′′b ) 2.0 Hz, H-5′′), 4.15-4.4 (5H,
m, H-2′′, H-3′′, H-6′′a, H-6′′b, and H-4′′), 4.3 (3H, s,
exchanges with D2O), 5.35 (1H, d, J 1′′,2′′ ) 6.7 Hz, H-1′′),
6.48 and 6.52 (AB system, 2H, J ) 13.5 Hz, CHdCH),
6.5 (2H, s, exchanges with D2O), 6.75 (2H, d, J 3′,2′ ) J 5′,6′
) 8.3 Hz, H-3′ and H-5′), 6.92 (2H, s, H-2 and H-6), 7.12
(1H, s, H-4), 7.32 (2H, d, H-2′ and H-6′); 13C NMR (Py-
d5, 300 MHz) δ 55.18 (q), 62.23 (t), 71.09 (d), 74.90 (d),
2 × 78.50 (d), 102.45 (d), 104.14 (d), 108.62(d), 110.62
(d), 2 × 114.20 (d), 129.41 (d), 129.85 (s), 130.28 (d), 2
× 130.79 (d), 140.07 (s), 159.37 (s), 2 × 160.07 (s);
FABMS m/z 404 [M+]; anal. C 62.28%, H 6.03%, calcd
for C21H24O8, C 62.37%, H 5.97%.
1.98 (6H, s, 2 × OAc), 2.01 (12H, s, 4 × OAc), 2.04 (6H,
s, 2 × OAc), 3.58 (2H, ddd, J 5′′,4′′ ) J 5′′′,4′′′ ) 9.0, J 5′′,6′′b
)
J 5′′′,6′′′b ) 5.4, J 5′′,6′′a ) J 5′′′,6′′′a ) 2.0 Hz, H-5′′ and H-5′′′),
3.82 (3H, s, OCH3), 3.99 (2H, dd, J 6′′a,6′′b ) J 6′′′a,6′′′b
)
12.3 H-6′′a and H-6′′′a), 4.21 (2H, dd, H-6′′b and H-6′′′b),
4.84 (2H, dd, J 1′′,2′′ ) J 1′′′,2′′′ ) 7.4, H-1′′ and H-1′′′), 5.08
(2H, dd, J 3′′,2′′ ) J 3′′′,2′′′ ) 9.0, J 3′′,4′′ )J 3′′′,4′′′ ) 9.0 Hz,
H-3′′ and H-3′′′), 5.17 (2H, dd, H-4′′ and H-4′′′), 5.21 (2H,
dd, H-2′′ and H-2′′′), 6.38 and 6.57 (AB system, 2H, J )
12.0 Hz, CHdCH), 6.42 (1H, dd, J 4,2 ) 1.5, J 4,6 ) 1.5
Hz, H-4), 6.58 (2H, d, H-2 and H-6), 6.82 (2H, d, J 3′,2′
)
J 5′,6′ ) 8.5 Hz, H-3′ and H-5′), 7.18 (2H, d, H-2′ and H-6′);
1H NMR (C6D6) δ 1.67 (6H, s, 2 × OAc), 1.70 (6H, s, 2
× OAc), 1.78 (6H, s, 2 × OAc), 1.82 (6H, s, 2 × OAc),
3.13 (2H, ddd, J 5′′,4′′ ) J 5′′′,4′′′ ) 9.0, J 5′′,6′′b ) J 5′′′,6′′′b
)
(Z)-3,5-Dih yd r oxy-4′-m eth oxystilben e 3, 5-O-â-D-
d iglu cop yr a n osid e (7b). The diglucoside 5b treated
with sodium methoxide in MeOH as described above for
4b afforded 7b in quantitative yield.
5.0, J 5′′,6′′a ) J 5′′′,6′′′a ) 2.0 Hz, H-5′′ and H-5′′′), 3.39 (3H,
s, OCH3), 3.85 (2H, dd, J 6′′a,6′′b ) J 6′′′a,6′′′b ) 12.0, J 6′′a,5′′
) J 6′′′b,5′′′ ) 2.0 Hz, H-6′′a and H-6′′′a), 4.18 (2H, dd,
H-6′′b and H-6′′′b), 4.82 (2H, d, J 1′′,2′′ ) J 1′′′,2′′′ 8.0 Hz,
H-1′′ and H-1′′′), 5.21 (dd, 2H, J 3′′,2′′ ) J 3′′′,2′′′ 9.0, J 3′′,4′′
) J 3′′′,4′′′ ) 9.0 Hz, H-3′′ and H-3′′′), 5.37 (2H, dd, Hz,
H-4′′ and H-4′′′), 5.47 (2H, dd, H-2′′ and H-2′′′), 6.32 and
6.42 (AB system, J ) 12.0 Hz, CHdCH), 6.61 (2H, d,
J 3′,2′ ) J 5′,6′ ) 8.2 Hz, H-3′ and H-5′), 6.77 (1H, dd, J 4,2
) 2.0, J 4,6 ) 2.0 Hz, H-4), 6.81 (2H, d, H-2, H-6), 7.12
1
7b: amorphous solid; [R]D -31.0° (c 2.7, MeOH); H
NMR (Py-d5, 300 MHz) δ 3.65 (3H, s), 4.08 (2H, m, H-5′,
H-5′′), 4.2-4.55 (10H, sugar protons), 5.2 (8H, bs,
exchanges with D2O), 5.5 (2H, d, J 1′′,2′′ ) J 1′′′,2′′′ ) 7.0
Hz, H-1′′ and H-1′′′), 6.5 and 6.52 (AB system, 2H, J )
12 Hz, CHdCH), 6.85 (2H, d, J 3′,2′ ) J 5′,6′ ) 9.0 Hz, H-3′
and H-5′), 7.1 (1H, dd, J 4,2 ) J 4,6 ) 2.1 Hz, H-4), 7.3

Resveratrol 3-O-â-D-glucopyranoside and Related Compounds
J ournal of Natural Products, 1997, Vol. 60, No. 11 1087
(1H, d, H-2, H-6), 7.32 (2H, d, H-2′ and H-6′); 13C NMR
(Py-d5, 300 MHz) δ 54.75 (q), 2 × 61.92 (t), 2 × 70.81
(d), 2 × 74.40 (d), 2 × 78.07 (d), 2 × 78.10 (d), 2 × 101.85
(d), 104.16 (d), 110.79 (d), 110.80 (d), 113.90 (d), 113.91
(d), 127.5 (d), 2 × 128.0 (d), 129.5 (s), 130.5 (d), 139.20
(s), 159,0 (s), 159.2 (s), 159.5 (s); FABMS m/z 589 [M+
+ Na]; anal. C 57.00%, H 6.11%, calcd for C27H34O13,
C 57.24%, H 6.01%.
(4) Verotta, L.; Rogers, B. C.; Dorigo, P.; Maragno, I.; Fraccarollo,
D.; Santostasi, G.; Gaion, R. M.; Floreani, M.; Carpenedo F.
Planta Med. 1995, 61 (3), 271-274.
(5) Verotta, L.; Rogers, B. C.; Aburjai, T.; Cignarella, A.; Colli, S.;
Puglisi, L. Giornate di Chimica delle Sostanze Naturali, III
Convegno Nazionale, Amalfi (SA) 29 maggio-1 giugno 1994, p
3.
(6) Chung, Mei-Ing; Teng, Che-Ming; Cheng, Kam-Lin; Ko, Feng-
Nien; Lin, Chun-Nan. Planta Med. 1992, 58, 274-275.
(7) Kimura, Y.; Okuda, H.; Arichi, S. Biochim. Biophys. Acta 1985,
175, 275-278.
(E)-3,4′,5-Tr ih yd r oxystilben e 3-O-â-D-glu cop yr a -
n osid e (Resver a tr ol 3-O-â-D-glu cop yr a n osid e, P i-
ceid , 1). A 0.5 M solution of sodium ethioethoxide in
dimethylformamide was prepared by adding thioethanol
(0.93 g, 1.1 mL, 15 mmol) to an ice-cooled and magneti-
cally stirred suspension of sodium hydride (0.4 g of a
60% oil dispersion, 10 mmol) in DMF (20 mL) and
stirring at room temperature for 15 min. Then 11 mL
(5.5 mmol) of this solution was added to 4a (0.3 g, 0.74
mmol), and the resulting solution was heated in an oil
bath at 140 °C. The reaction was monitored by TLC.
After 10 h, the cooled reaction mixture was acidified
with 10% HCl and extracted with EtOAc (3 × 10 mL)
and with BuOH (2 × 10 mL). The combined organic
extracts were washed with H2O and dried (Na2SO4).
Removal of the solvent under reduced pressure afforded
a residue which was purified by flash chromatography
and gave 1 (50%), which was identical in all respects to
an authentic isolated sample.
(Z)-3,4′,5-Tr ih yd r oxystilben e 3-O-â-D-glu cop yr a -
n osid e ((Z)-Resver a tr ol 3-O-â-D-glu cop yr a n osid e,
(Z)-P iceid , 8b). A 0.5 M solution of sodium thioethox-
ide in dimethylformamide (2 mL) was added to 6b (0.25
g, 0.62 mmol), and the solution was heated at 130 °C.
The reaction was monitored by TLC. The reaction was
cooled, acidified with 1% HCl and extracted with AcOEt
(3 × 10 mL) and BuOH (2 × 10 mL). The combined
organic extracts were dried, and the solvent removed
under reduced pressure to afford a mixture of (Z)- and
(E)-resveratrol (62%) (8 and 1) in a 2/1 ratio.
(8) Inamori, Y.; Kubo, M.; Tsujibo, H.; Ogawa, M.; Saito, Y.; Miki,
Y.; Takemura, S. Chem. Pharm. Bull. 1987, 35, 887-890.
(9) Mannila, E.; Talvitie, A.; Kolehmainen, E. Phytochemistry 1993,
33, 813-816.
(10) Langcake, P.; Cornford, C. A.; Pryce, R. J . Phytochemistry 1979,
18, 1025-1027.
(11) J ayatilake, G. S.; J ayasuriya, H.; Lee, Eung-Seok; Koonchanok,
N.M.; Geahlen, R. L.; Ashendel, C. L.; McLaughlin, J . L.; Chang,
Ching-J er. J . Nat. Prod. 1993, 56, 1805-1810.
(12) Chen, Chien-Chih; Wu, Li-Gin; Ko, Feng-Nien; Teng, Che-Ming.
J . Nat. Prod. 1994, 57, 1271-1274.
(13) Nyemba, A. M.; Ngando Mpondo, T.; Kimbu, S. F.; Connolly, J .
D. Phytochemistry 1995, 39, 895-898.
(14) Orsini, F., Pelizzoni, F., Bellini, B.; Miglierini, G. XIII Congresso
Nazionale SCI. Formazione, Ricerca, Innovazione, Milano, 27
Agosto-1 Settembre, 1995.
(15) Orsini, F.; Pelizzoni, F.; Bellini, B.; Miglierini, G. Carbohydr.
Res. 1997, in press.
(16) Kubo, I.; Murai, Y. J . Nat. Prod 1991., 54, 1115-1118.
(17) Kashiwada, Y.; Nonaka, G. I.; Nishioka, I. Chem. Pharm. Bull.
1984, 32, 3501-3517.
(18) In an alternative approach, 3,5-bis[(tert-butyldimethylsilyl)oxy]-
benzaldehyde was reacted with (4-acetoxybenzyl)triphenylphos-
phonium chloride, the latter obtained in 75% yield from tri-
phenylphosphine and 4-acetoxybenzyl chloride in refluxing
toluene. 4-Acetoxybenzyl chloride was synthetized by a “one pot”
reaction from the commercially available p-hydroxybenzyl alco-
hol and acetyl chloride.28 This approach, however, proved less
convenient since the protective acetyl group was partially
removed during both the Wittig and the glucosylation reactions
and the chemical yield of the Wittig reaction was lower (72%).
In addition, direct treatment of the Wittig adduct (E)-3,5-bis-
[(tert-butyldimethylsilyl)oxy]-4′-acetoxystilbene with 1-O-(tri-
methylsilyl)-2,3,4,6-tetra-O-acetylglucose29,30 which a priori ap-
peared to be the most straightforward glucosidation procedure,
led to recovery of starting material (48%), accompanied by a
mixture of the tetra-O-acetyl-3-â-O-glucopyranosides of (E)-3,5-
dihydroxy-4′-acetoxystilbene, (E)-4′-acetoxy-5-[(tert-butyldimeth-
ylsilyl)oxy]-3-hydroxystilbene, and (E)-3,4′-dihydroxy-5-[(tert-
butyldimethylsilyl)oxy]stilbene. Acetylation of the mixture gave
the tetra-O-acetyl-3-O-â-D-glucopyranoside of 4′,5-diacetoxy-3-
hydroxystilbene, identical in all respect to an authentic sample.
(19) Lal, K.; Ghosh, S.; Salomon, R. G. J . Org. Chem 1987, 52, 1072-
1078.
(20) Fentriel, J . I.; Mirrington, R. N. Tetrahedron Lett. 1970, 16,
1327-1328.
(21) Conversion of 4a to 1 was previously performed in two steps:
deacetylation with sodium hydroxide in MeOH to afford the
natural 4-methyl piceide {(E)-3,5-dihydroxy-4-methoxystilbene
3-O-â-D-glucopyranoside} followed by demethylation with a 1.2/1
molar ratio of sodium thioethoxide.15
(22) 4-Hydroxystilbenes have been reported to undergo a facile
isomerization process which depends on the substitution pat-
terns and, in some cases, occurs in all common laboratory
solvents.28
8b (identified in the Z/E mixture): 1H NMR (DMSO-
d6 + D2O, 300 MHz) δ 3.2-3.8 (6H, H-2′′, H-3′′, H-4′′,
H-5′′, H-6′′a, and H-6′′b), 4.7 (1H, d, J 1′′,2′′ ) 7.4 Hz,
H-1′′), 6.36 (2H, d, J 2,4 ) J 6,4 ) 2.0 Hz, H-2 and H-6),
6.39 (1H, dd, H-4), 6.39 and 6.48 (AB system, 2H, J )
12 Hz, CHdCH), 6.68 (2H, d, J 3′,2′ ) J 5′,6′ ) 8.4 Hz, H-3′
and H-5′), 7.12 (2H, d, H-2′ and H-6′); 13C NMR (DMSO-
d6, 300 MHz) δ 60.38 (t), 69.34 (d), 73.10 (d), 76.43 (d),
76.81 (d), 100.67 (d), 102.49 (d), 107.36 (d), 109.0 (d), 2
× 114.9 (d), 125.22 (d), 127.31 (s), 127.59 (d), 2 × 129.91
(d), 138.97 (s), 156.59 (s), 157.98 (s), 158.56 (s).
(23) Combretastatin A-1 is a very potent cell growth and tubulin
inhibitor: Pettit, G. R.; Singh S. B; Niven, M. L.; Hamel, E.;
Schmidtm J . M. J . Nat. Prod. 1987, 50, 119 -131.
(24) Combretastatin A-4 is a very potent cell growth and tubulin
inhibitor: Pettit, G. R.; Singh S. B; Hamel, E.; Lin, C. M.;
Alberts, D. S.; Garcia-Kendall. Experientia 1989, 45, 209-211.
(25) Hillis,W. E.; Ishikura, K. J . Chromatogr. 1968, 32, 323.
(26) Aritomi, M.; Donnelly, D. M. X. Phytochemistry 1976, 2006-
2008.
Ack n ow led gm en t. Financial support by Consiglio
Nazionale delle Ricerche (CNR, Roma) through “Pro-
getto Finalizzato Chimica Fine II”, Centro di Studio Per
le Sostanze Organiche Naturali (CNR, Milano), MURST
“Progetto Nazionale di Ricerca, 40%” is gratefully
acknowledged.
(27) Bertz, A.; Cazenave, J . P. Methods in Plant Biochemistry;
Hostettmann, K., Ed.; Academic Press: New York, 1991; Vol.
6, pp 235-260.
Refer en ces a n d Notes
(1) Watt, J . M.; Breyer-Brandwijk, M. G. The Medicinal and
Poisonous Plants of Southern and East Africa; Livingstone
Ltd.: Edinburgh and London, 1962; pp 602-606.
(2) Verotta, L.; Rogers, B. C. Phytochemistry of Plants used in
Traditional Medicine; Lausanne, September 29-October 1, 1993;
pp 71.
(3) Fraccarollo, D.; Santostasi, G.; Maragno, I.; Gaion, R. M.; Dorigo,
P.; Carpenedo, F.; Floreani, M.; Verotta L. VII Congresso
Nazionale della Societa` Italiana di Farmacognosia (SIPHAR),
Bologna 30 giugno-2 luglio, 1994, p 54.
(28) Taylor, L. D.; Grasshopp, J . M.; Pluhar, M. J . Org. Chem. 1978,
43, 1197-1198
(29) Tietze, F. L.; Fisher, R.; Guder, H. J . Tetrahedron Lett. 1982,
23, 4661-4664.
(30) Nashed, E. M.; Glaudemans, C. P. J . J . Org. Chem. 1989, 54,
6116-6118.
(31) Robertson, D. W.; Katzenellenbogen, J . A. J . Org. Chem. 1982,
47, 2387-2393.
NP970069T