Synthesis of mono- and di-O-β-D-glucopyranoside conjugates of (E)-resveratrol

Article abstract of DOI:10.1055/s-2006-926394

Starting from the commercially available natural product (E)-resveratrol (1), the four selectively tert-butyldimethylsilyl (TBS) protected (E)-resveratrols 6-9 were prepared by one reaction. Using 6-9 as glucosyl acceptors and trifluoroacetimidate 11 as glucosyl donor, three bioactive natural glucopyranoside conjugates of (E)-resveratrol 2-4 and one novel compound (5) were efficiently prepared in two steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926394

PAPER
1301
Synthesis of Mono- and Di-O-b-D-glucopyranoside Conjugates of
(
E)-Resveratrol
esveratrol n Zhang,*a,b,1 Biao Yu, Richard R. Schmidtb
a
M
Z
ono- and Di-
O
h
-
b
-
D
-glucop
a
yranoside
C
o
onjugate
s
o
j
(
E
)-R
u
a
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, P. R. of China
E-mail: zhangzj99@yahoo.com.cn
Fachbereich Chemie, Universität Konstanz, Universitätsstrasse 10, 78457 Konstanz, Germany
Fax +49(7531)883135
b
Received 20 September 2005; revised 28 November 2005
9
b
9c
has antioxidant and prolyl endopeptidase inhibitory ac-
Abstract: Starting from the commercially available natural product
tivities and compound 4 can inhibit xanthine oxidase.1
0b
(
(
E)-resveratrol (1), the four selectively tert-butyldimethylsilyl
TBS) protected (E)-resveratrols 6-9 were prepared by one reac- For systematic studies of the biological properties of com-
tion. Using 6-9 as glucosyl acceptors and trifluoroacetimidate 11 as
glucosyl donor, three bioactive natural glucopyranoside conjugates
of (E)-resveratrol 2-4 and one novel compound (5) were efficiently
prepared in two steps.
pounds 2-4, large quantities are necessary. However, it is
difficult to obtain sufficiently pure material from natural
sources. Chemical synthesis can solve this kind of prob-
lem in many cases. Up to now, to the best of our knowl-
edge, there are three chemical protocols for preparing 2,
one for 3, and none for 4. Orsini et al. described the first
five-step synthesis of 2 based on a Wittig olefination
strategy7 to afford the core stilbenic skeleton, which
produced Z- and E-isomers (1:2.3) thus greatly lowering
the synthetic efficiency. Additionally, both the subse-
quent glucosylation (32%) and demethylation (60%) steps
are not very efficient. Brandolini et al. reported a direct
glucosylation of 1, but the conversion yield of 1 to 2 was
Key words: carbohydrates, natural products, glycosides, glyco-
sylation, phenols
,11
(
E)-Resveratrol, (E)-1-(3,5-dihydroxyphenyl)-2-(4-hy-
droxyphenyl) ethene (1, Figure 1), is a naturally occurring
phytoalexin found in grapes, red wine, peanuts, olive oil,
2
,3
cranberries, and other food. (E)-Resveratrol has shown4
multiple biological effects, such as anti-inflammatory,
5
6
anti-platelet, and anti-cancer effects. Also, the b-D-glu-
copyranoside conjugates of (E)-resveratrol, 2, 3 and 4
(
12
quite low. Learmonth has recently reported an improved
7
,8
9
10
synthesis of 2 and 3 based on a convergent Heck-coupling
Figure 1) are natural products. Compound 2 possesses
13
strategy; however, this method is also not very efficient
7
,8d
9b
anti-platelet and antioxidant activities. Compound 3
because of the indirect access of one starting material for
HO
HO
OH
(E)-Resveratrol (1)
HO
HO
O
HO
HO
5
5
4
O
4
O
OH
OH
HO
OH
OH
3
HO
HO
O
3
3
2
OH
OH
HO
HO
O
5
HO
OH
O
HO
O
5
3
4
4
OH
O
O
OH
OH
HO
OH
O
HO
HO
HO
3
HO
HO
O
O
5
OH
OH
Figure 1 Chemical structures of (E)-resveratrol (1), and its mono- and di-O-b-D-glucopyranoside conjugates 2-5
SYNTHESIS 2006, No. 8, pp 1301–1306
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.03.2006
DOI: 10.1055/s-2006-926394; Art ID: T13005SS
Georg Thieme Verlag Stuttgart · New York
©

1
302
Z. Zhang et al.
PAPER
OH
OH
HO
TBSCl (2.1 equiv)
imidazole (2.5 equiv)
DMF, –5 °C to r.t., 6 h
1
OTBS
TBSO
OTBS
OTBS
1
0 27%
OTBS
OH
+
+
HO
+
TBSO
OTBS
7
10%
6
33%
OTBS
OH
OH
+
HO
TBSO
OH
8
16%
9 14%
Scheme 1 Synthesis of mono- and di-glycosyl acceptors 6-9 of (E)-resveratrol
each crucial Heck-coupling reaction and the low glucosyl- copyranosyl trifluoroacetimidate (11)15 was chosen to
ation yields (<40%).
glucosylate the acceptors 6-9. Coupling of acceptors 6
and 7 with donor 11 under trimethylsilyl triflate (TMSOTf)
catalysis gave (E)-resveratrol-3-O-b-D-glucopyranoside
conjugate 12 (64%) and (E)-resveratrol-4¢-O-b-D-gluco-
pyranoside conjugate 13 (80%), respectively (only b-ano-
mers were formed). The glucosylation reactions were not
optimized. The following deprotection of 12 and 13 with
aqueous 3 N NaOH in MeOH-THF (5:1) afforded the tar-
get compounds 2 (97%) and 3 (95%), respectively
Hence, efficient protocols for preparing the glycoconju-
gates of (E)-resveratrol are still desirable. We explored
and fortunately found that the four selectively TBS-pro-
tected (E)-resveratrols 6-9 (Scheme 1) could be prepared
by one reaction from commercially available (E)-resvera-
trol. Separation of 6-9 and the fully protected resveratrol
1
0 could be performed by column chromatography on sil-
ica gel with petroleum ether-ethyl acetate as eluent.Thus,
using 6-9 as glucosyl acceptors, three natural glucopyra-
noside conjugates of (E)-resveratrol 2-4 and one novel
compound (5) were smoothly and efficiently prepared, re-
spectively.
(
Scheme 2), whose optical rotation and spectral data are
all in accordance with those in the corresponding refer-
ences mentioned above.
Using the same protocol as for the preparation of 2 and 3,
(
E)-resveratrol-di-O-b-D-glucopyranoside conjugates 4
Since trifluoroacetimidates have demonstrated to be ex-
cellent glycosyl donors in the course of our synthesis of
Cassiaside C2,14 herein, 2,3,4,6-tetra-O-benzoyl-D-glu-
and 5 could also be prepared smoothly (Scheme 3), with
the exception that more equivalents of donor 11 (4.0
TBSO
TBSO
OTBS
OH
HO
6
TBSO
7
OBz
O
NPh
BzO
BzO
O
a
11
OBz
CF3
TBSO
OBz
TBSO
TBSO
BzO
O
O
OTBS
OBz
BzO
OBz
BzO
BzO
O
13
O
12
b
OBz
2
3
Scheme 2 Syntheses of (E)-resveratrol-mono-O-b-D-glucopyranoside conjugates 2 and 3. Reagents and conditions: a. i) for 6, 11 (1.4 equiv),
TMSOTf (0.15 equiv), CH Cl , 4 Å MS, 0 °C to r.t., 12 (64%); ii) for 7, 11 (1.4 equiv), TMSOTf (0.15 equiv), CH Cl , 4 Å MS, 0 °C to r.t.,
2
2
2
2
13 (80%); b. 3 N NaOH, MeOH-THF (5:1), 0 °C to r.t., 2 (97%), 3 (95%).
Synthesis 2006, No. 8, 1301–1306 © Thieme Stuttgart · New York

PAPER
Mono- and Di-O-b-D-glucopyranoside Conjugates of (E)-Resveratrol
1303
TBSO
HO
HO
OTBS
OH
HO
9
8
BzO
TBSO
O
O
OBz
OBz
O
BzO
a
OBz
BzO
BzO
O
14
BzO
OBz
O
OBz
O
BzO
BzO
O
BzO
BzO
O
BzO
OTBS
O
OBz
OBz
OBz
BzO
BzO
BzO
BzO
OBz
O
O
15
1
6
b
OBz
4
5
Scheme 3 Syntheses of (E)-resveratrol-di-O-b-D-glucopyranoside conjugates 4 and 5. Reagents and conditions: a. i) for 8, 11 (4.0 equiv),
TMSOTf (0.10 equiv), CH Cl , 4 Å MS, 0 °C to r.t., 14 (76%), 16 (10%); ii) for 9, 11 (4.0 equiv), TMSOTf (0.08 equiv), CH Cl , 4 Å MS, 0 °C
2
2
2
2
to r.t., 15 (50%), 16 (15%); b. 3 N NaOH, MeOH-THF (5:1), 0 °C to r.t., 4 (99%), 5 (98%).
Synthesis of Mono- and Di-glycosyl Acceptors 6-9 of
E)-Resveratrol
equiv) were used to afford 14 and 15 in good yields; a
common by-product in the reactions was octa-O-benzoyl-
a,b-trehalose (16).
(
To a suspension of (E)-resveratrol (1, 456 mg, 2.00 mmol) and im-
idazole (170 mg, 2.50 mmol) in anhyd DMF (2 mL), TBSCl (316
mg, 2.10 mmol) was added at –5 to 0 °C, then the mixture was
warmed to ambient temperature naturally. After 3 h, additional im-
idazole (170 mg, 2.50 mmol) and TBSCl (316 mg, 2.10 mmol) were
added. After additional 3 h, the mixture was diluted with EtOAc (80
16
In comparison with previous syntheses7,11-13 of (E)-res-
veratrol-mono-O-b-D-glucopyranoside conjugates 2 and
3
, a more concise and environmentally friendly methodol-
ogy for preparing these compounds has been developed. mL), washed with H O (3 × 30 mL), dried, filtrated, and concentrat-
2
Furthermore, two (E)-resveratrol-di-O-b-D-glucopyrano- ed under vacuo and flash column chromatography (PE-EtOAc,
1
2:1 → 3:1) afforded 6 (296 mg) in 33% yield as a brown solid, 7
side conjugates 4 and 5 were efficiently synthesized. The
successful synthesis of 2-5 with 6-9 as glucosyl accep-
tors not only demonstrates the good properties of 6-9 as
glucosyl acceptors, it also implies that they will be prom-
ising acceptors for preparing other glycoside conjugates
of (E)-resveratrol.
(
89 mg) in 10% yield as a slightly yellow solid, 8 (107 mg) in 16%
yield as a white solid, 9 (98 mg) in 14% yield as a slightly yellow
solid, and 10 (308 mg) in 27% yield as a colorless syrup (becoming
a white solid after a month at ambient temperature).
(E)-1-{[3-tert-Butyl(dimethyl)silyl]oxy}-5-hydroxyphenyl-2-
(
{[4-tert-butyl(dimethyl)silyl]oxy}-phenyl) Ethene (6)
Rf 0.34 (PE-EtOAc, 8:1).
(
E)-Resveratrol was purchased from Orchid Chemicals & Pharma-
IR: 3399, 2957, 2931, 2860, 1600, 1510, 1261, 1168, 915, 840, 782
cm .
ceuticals Ltd. and used without further purification. Solvents were
distilled from the appropriate drying agents before use. Petroleum
ether (PE) used had a boiling range of 60-90 °C. Organic extracts
were dried over anhyd Na SO . Commercially available 4 Å MS
were powdered and activated just before use. TMSOTf was used as
a 0.1 mmol/mL solution of anhyd CH Cl . All reactions were car-
ried out under a positive pressure of argon and monitored by TLC
on silica gel HF254 (0.5 mm, Qingdao, China). Spots were detected
under UV light or by charging with 10% H SO in MeOH. Flash
column chromatography was carried out on silica gel H (400 mesh,
Qingdao, China). Optical rotations were measured on a Perkin-Elm-
er 241 MC polarimeter at 18 °C. IR spectra were recorded with an
–
1
1
H NMR (300 MHz, CDCl ): d = 7.38 (d, J = 8.4 Hz, 2 H), 6.98 (d,
3
2
4
J = 16.5 Hz, 1 H), 6.83 (d, J = 8.4 Hz, 2 H), 6.83 (d, J = 16.2 Hz, 1
H), 6.59 (d, J = 1.2 Hz, 1 H), 6.55 (d, J = 1.2 Hz, 1 H), 6.25 (t,
J = 2.3 Hz, 1 H), 4.73 (s, 1 H), 1.00, 0.99 (2 s, 18 H), 0.23, 0.22,
2
2
0
.22, 0.21 (4 s, 12 H).
MS (EI, 70 eV): m/z (%) for C H O Si = 73 (52.4), 171 (18.3),
2
6
40
3
2
2
4
3
99 (49.5), 400 (53.9), 401 (25.1), 456 (100.0), 457 (95.9).
Anal. Calcd for C26
8.89.
H O Si : C, 68.42; H, 8.77. Found: C, 68.65; H,
40 3 2
1
13
FTS-185 spectrometer (KBr). H NMR and C NMR spectra were
recorded on a Bruker AM-300 spectrometer using CDCl as sol-
(E)-1-(3,5-Bis-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-
3
vent, unless stated otherwise, and tetramethylsilane as internal ref-
erence. Mass spectra were recorded on a HP5989A mass
spectrometer. Elemental analyses were measured on a Perkin-Elmer
(4-hydroxyphenyl) Ethene (7)
R
0.29 (PE-EtOAc, 8:1).
f
IR: 3365, 2955, 2930, 2858, 1595, 1579, 1515, 1261, 1160, 1028,
2
400 CHN analyzer.
–1
8
40, 779 cm .
Synthesis 2006, No. 8, 1301–1306 © Thieme Stuttgart · New York

1
304
Z. Zhang et al.
PAPER
1
H NMR (300 MHz, CDCl ): d = 7.40 (d, J = 8.4 Hz, 2 H), 6.96 (d,
rified by flash column chromatography (PE-EtOAc, 12:1) to afford
12 (210 mg) in 64% yield as white foam.
3
J = 16.8 Hz, 1 H), 6.83 (d, J = 14.1 Hz, 1 H), 6.82 (d, J = 8.7 Hz, 2
H), 6.60 (d, J = 1.8 Hz, 2 H), 6.24 (t, J = 1.7 Hz, 1 H), 4.86 (br s, 1
H), 1.00, 0.99 (2 s, 18 H), 0.22, 0.21 (2 s, 12 H).
R 0.58 (PE-EtOAc, 6:1); [a] +41.8 (c 1.04, CHCl ).
f
D
3
1
H NMR (300 MHz, CDCl ): d = 8.00-7.27 (m, 22 H), 6.91 (d,
3
MS (EI, 70 eV): m/z (%) for C H O Si = 73 (51.3), 399 (84.5),
4
(
2
6
40
3
2
J = 15.9 Hz, 1 H), 6.80 (d, J = 8.4 Hz, 2 H), 6.74 (d, J = 16.2 Hz, 1
H), 6.67 (br s, 2 H), 6.38 (t, J = 2.0 Hz, 1 H), 6.01 (t, J = 9.6 Hz, 1
H), 5.80 (t, J = 9.2 Hz, 1 H), 5.77 (t, J = 9.8 Hz, 1 H), 5.44 (d,
J = 7.2 Hz, 1 H), 4.71 (dd, J = 12.0, 2.9 Hz, 1 H), 4.53 (dd, J = 12.0,
5.9 Hz, 1 H), 4.36 (m, 1 H), 0.99, 0.94 (2 s, 18 H), 0.21, 0.14, 0.17
00 (100.0), 401 (44.1), 402 (14.9), 456 (88.0), 457 (96.6), 458
36.4).
Anal. Calcd for C H O Si : C, 68.42; H, 8.77. Found: C, 68.16; H,
8
26
40
3
2
.88.
(
3 s, 12 H).
(
(
E)-1-(3-{[tert-Butyl(dimethyl)silyl]oxy}-5-hydroxyphenyl)-2-
4-hydroxyphenyl) Ethene (8)
13
C NMR (75 MHz, CDCl ): d = 166.2, 165.8, 165.2, 165.1, 158.1,
3
1
1
56.8, 155.6, 139.9, 133.5, 133.3, 133.1, 130.3, 129.8, 129.7, 129.5,
29.1, 128.8, 128.4, 127.8, 126.1, 120.3, 113.3, 108.7, 108.1, 99.9,
Rf 0.34 (PE-EtOAc, 3:1).
–
1
IR: 3312, 2931, 2858, 1604, 1591, 1513, 1254, 1167, 840 cm .
72.8, 72.6, 71.8, 69.6, 63.3, 25.7, 25.6, 18.2, 18.1, -4.4.
1
+
H NMR (300 MHz, CDCl ): d = 7.34 (d, J = 8.7 Hz, 2 H), 6.92 (d,
ESI-MS: m/z (%) for C H O Si = 1058.4 [M + Na] .
3
60 66 12
2
J = 16.2 Hz, 1 H), 6.83 (d, J = 8.7 Hz, 2 H), 6.79 (d, J = 16.8 Hz, 1
H), 6.60 (d, J = 1.8 Hz, 1 H), 6.57 (d, J = 1.8 Hz, 1 H), 6.53 (br s, 1
H), 6.34 (br s, 1 H), 6.32 (t, J = 2.3 Hz, 1 H), 1.00 (s, 9 H), 0.22 (s,
Anal. Calcd for C H O Si : C, 69.63; H, 6.38. Found: C, 69.42;
H, 6.52.
6
0
66 12
2
6
H).
(
E)-1-(3-b-D-Glucopyranosyloxy-5-hydroxyphenyl)-2-
MS (EI, 70 eV): m/z (%) for C H O Si = 73 (16.1), 75 (40.6), 251
(4-hydroxyphenyl) Ethene (2)
2
0
26
3
(
20.4), 267 (23.6), 285 (65.5), 286 (33.1), 342 (100.0), 343 (27.5).
To a solution of 12 (200 mg, 0.19 mmol) in MeOH-THF (5:1, 12
mL), 3 N aq NaOH (0.8 mL) was added at 0 °C. The resulting solu-
Anal. Calcd for C H O Si: C, 70.18; H, 7.60. Found: C, 70.3; H,
7
20
26
3
tion was stirred for 5 h at 0-25 °C, diluted with H O (4 mL), neu-
2
.83.
+
tralized with Dowex 50-X (H ) resin, filtered, washed with H O
2
(
2.5 mL) and MeOH (2.5 mL), and concentrated. The residue was
(
E)-1-(3,5-Dihydroxyphenyl)-2-(4-{[tert-butyl(dimethyl)-
purified by flash column chromatography (CHCl -MeOH, 5:1) to
afford 2 (73 mg) in 97% yield as a slightly yellow solid.
3
silyl]oxy}phenyl) Ethene (9)
Rf 0.23 (PE-EtOAc, 3:1).
R 0.33 (CHCl -MeOH, 3:1); [a] -53.4 (c 1.01, MeOH).
f
3
D
IR: 3519, 3352, 2930, 2859, 1620, 1600, 1510, 1268, 1169, 917,
8
–1
1
39 cm .
H NMR (300 MHz, pyridine-d + 5% D O): d = 7.36 (d, J = 7.8
5
2
1
Hz, 2 H), 7.17, 7.11 (2 d, J = 17.7 Hz, 2 H), 7.07 (d, J = 7.2 Hz, 2
H), 7.05 (br s, 1 H), 7.01 (br s, 1 H), 6.92 (br s, 1 H), 5.46 (d, J = 7.2
Hz, 1 H), 4.36-3.92 (m, 5 H), 3.94 (br s, 1 H).
H NMR (300 MHz, CDCl ): d = 7.35 (d, J = 8.4 Hz, 2 H), 6.96 (d,
3
J = 15.9 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 2 H), 6.79 (d, J = 17.1 Hz, 1
H), 6.54 (d, J = 1.8 Hz, 2 H), 6.26 (t, J = 1.8 Hz, 1 H), 5.39 (s, 2 H),
0
1
3
.99 (s, 9 H), 0.20 (s, 6 H).
C NMR (75 MHz, pyridine-d ): d = 160.0, 158.7, 140.5, 129.3,
5
1
7
28.8, 128.4, 126.0, 116.3, 108.4, 105.7, 103.8, 102.1, 78.5, 78.2,
4.7, 71.0, 62.0.
MS (EI, 70 eV): m/z (%) for C H O Si = 73 (13.3), 75 (21.1), 251
(
2
0
26
3
15.8), 267 (17.0), 285 (100.0), 286 (44.2), 342 (97.8), 343 (27.8).
+
+
ESI-MS: m/z (%) for C H O = 391.3 [M] , 408.2 [M + NH ] .
2
0
22
8
4
Anal. Calcd for C H O Si: C, 70.18; H, 7.60. Found: C, 70.10; H,
20
26
3
7
.80.
Syntheses of Compounds 3-5 and 13-15; General Procedure
Compounds 3-5 were synthesized with the same protocol as for the
preparation of 2, respectively; compounds 13-15 were synthesized
with the same protocol as for the preparation of 12, respectively;
small differences are noted for each product.
(
E)-1-(3,5-Bis-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-(4-
[tert-butyl(dimethyl)silyl]oxy}phenyl) Ethene (10)
Rf 0.79 (PE-EtOAc, 8:1).
{
–
1
IR: 2956, 2930, 2858, 1584, 1509, 1437, 1259, 1167, 836, 781 cm .
1
(E)-1-(3,5-Bis-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-[4-
H NMR (300 MHz, CDCl ): d = 7.38 (d, J = 8.1 Hz, 2 H), 6.95 (d,
3
(
2,3,4,6-tetra-O-benzoyl-b-D-glucopyranosyloxy)phenyl]
J = 16.2 Hz, 1 H), 6.83 (d, J = 16.2 Hz, 1 H), 6.82 (d, J = 9.2 Hz, 2
H), 6.59 (d, J = 1.2 Hz, 2 H), 6.23 (t, J = 1.2 Hz, 1 H), 0.99 (s, 27
H), 0.20 (s, 18 H).
Ethene (13)
Stirring time: 5 h; white foam; yield: 250 mg (80%).
R 0.50 (PE-EtOAc, 6:1); [a] +33.0 (c 1.01, CHCl ).
MS (EI, 70 eV): m/z (%) for C H O Si = 73 (52.2), 151 (28.2),
f
D
3
3
2
54
3
3
1
71 (21.0), 400 (50.0), 456 (100.0), 457 (90.5), 571 (14.7).
1
H NMR (300 MHz, CDCl ): d = 8.06-7.25 (m, 22 H), 6.98 (d,
3
J = 8.1 Hz, 2 H), 6.90, 6.78 (d, J = 16.2 Hz, 2 H), 6.59 (br s, 2 H),
Anal. Calcd for C H O Si : C, 67.37; H, 9.47. Found: C, 67.12; H,
32
54
3
3
6
5
.26 (br s, 1 H), 6.01 (t, J = 9.5 Hz, 1 H), 5.82 (t, J = 8.7 Hz, 1 H),
.72 (t, J = 9.8 Hz, 1 H), 5.42 (d, J = 8.1 Hz, 1 H), 4.69 (dd,
9
.74.
J = 12.0, 2.6 Hz, 1 H), 4.56 (dd, J = 12.0, 6.6 Hz, 1 H), 4.36 (m, 1
H), 0.99 (s, 18 H), 0.22 (s, 12 H).
(
E)-1-[3-{[tert-Butyl(dimethyl)silyl]oxy}-5-(2,3,4,6-tetra-O-
benzoyl-b-D-glucopyranosyloxy)phenyl]-2-(4-{[tert-butyl(di-
methyl)silyl]oxy}phenyl) Ethene (12)
A suspension of the dried donor 11 (348 mg, 0.45mmol), the accep-
tor 6 (145 mg, 0.32 mmol), and 4 Å MS (200 mg) in anhyd CH Cl
13
C NMR (75 MHz, CDCl ): d = 166.0, 165.7, 165.3, 165.1, 156.7,
3
1
56.4, 155.6, 139.1, 133.5, 133.3, 133.2, 132.6, 129.9, 129.8, 129.6,
2
2
129.1, 128.7, 128.6, 128.4, 128.3, 127.9, 127.8, 127.6, 117.4, 111.6,
(3.5 mL) was vigorously stirred at ambient temperature. After 30
1
11.5, 99.6, 72.8, 72.6, 71.7, 69.7, 63.2, 25.7, 18.2, -4.4.
min, the suspension was cooled to 0 °C and TMSOTf (480 mL, 0.15
equiv) was slowly added. The resulting suspension was continu-
ously stirred at 0-25 °C for 3 h. Then the reaction was quenched
+
ESI-MS: m/z (%) for C H O Si = 1058.4 [M + Na] .
6
0
66 12
2
Anal. Calcd for C H O Si : C, 69.63; H, 6.38. Found: C, 69.58;
6
0
66 12
2
with 3 drops of Et N, filtered and concentrated. The residue was pu-
H, 6.42.
3
Synthesis 2006, No. 8, 1301–1306 © Thieme Stuttgart · New York

PAPER
Mono- and Di-O-b-D-glucopyranoside Conjugates of (E)-Resveratrol
1305
1
(
E)-1-(3,5-Dihydroxyphenyl)-2-(4-b-D-glucopyranosyl-
H NMR (300 MHz, CDCl ): d = 7.99-7.19 (m, 42 H), 6.87, 6.66
3
oxyphenyl) Ethene (3)
Yield: 51 mg (95%); slightly yellow solid.
(2 d, J = 16.2 Hz, 2 H), 6.85 (br s, 1 H), 6.84 (br s, 1 H), 6.78 (d,
J = 8.4 Hz, 2 H), 6.54 (br s, 1 H), 5.96 (t, J = 9.8 Hz, 2 H), 5.74 (t,
J = 9.2 Hz, 2 H), 5.71 (t, J = 9.8 Hz, 2 H), 5.34 (d, J = 7.8 Hz, 2 H),
R 0.33 (CHCl -MeOH, 5:1); [a] -52.3 (c 1.02, MeOH).
f
3
D
4
.66 (dd, J = 12.2, 2.9 Hz, 2 H), 4.49 (dd, J = 12.0, 4.0 Hz, 2 H),
1
H NMR (300 MHz, pyridine-d + 5% D O): d = 7.29 (d, J = 8.6
5
2
4.23 (m, 2 H), 1.00, 0.99 (2 s, 9 H), 0.22, 0.21 (2 s, 6 H).
1
Hz, 2 H), 7.14 (d, J = 8.6 Hz, 2 H), 7.10, 7.03 (2 d, J = 15.9 Hz, 2
H), 6.96 (br s, 2 H), 6.79 (br s, 1 H), 5.46 (d, J = 6.9 Hz, 1 H), 4.37-
4
3
C NMR (75 MHz, CDCl ): d = 166.1, 165.7, 165.2, 165.0, 158.0,
3
1
1
40.4, 133.5, 133.3, 133.1, 129.9, 129.8, 129.7, 129.4, 129.1, 128.7,
28.4, 128.3, 127.9, 125.4, 120.2, 110.0, 104.8, 99.4, 72.6, 72.4,
.12 (m, 5 H), 3.94 (br s, 1 H).
1
3
C NMR (75 MHz, pyridine-d ): d = 160.3, 157.9, 140.3, 131.6,
5
71.7, 69.6, 63.2, 25.7, 18.1, -4.4.
1
6
28.1, 128.0, 116.9, 105.7, 103.5, 101.7, 78.6, 78.2, 74.7, 71.0,
2.1.
+
ESI-MS: m/z (%) for C H O Si = 1522.3 [M + Na] .
8
8
78 21
+
+
Anal. Calcd for C88
.30.
H
78
O21Si: C, 70.49; H, 5.21. Found: C, 70.38; H,
ESI-MS: m/z (%) for C H O = 391.3 [M] , 408.2 [M + NH ] .
2
0
22
8
4
5
(
E)-1-[3-{[tert-Butyl(dimethyl)silyl]oxy}-5-(2,3,4,6-tetra-O-
(
E)-1-(3,5-Bis-b-D-glucopyranosyloxyphenyl)-2-(4-hydroxy-
benzoyl-b-D-glucopyranosyloxy)phenyl]-2-[4-(2,3,4,6-tetra-O-
benzoyl-b-D-glucopyranosyloxy)phenyl] Ethene (14)
The donor 11 (4.0 equiv); TMSOTf (0.10 equiv); stirring time: 12
h; separation by flash column chromatography (toluene-EtOAc,
6
phenyl) Ethene (5)
Separation by flash column chromatography (CHCl -MeOH, 3:1
3
→
sat. CHCl -MeOH-H O, 6:3:1 giving two layers and use of the
3
2
lower layer) to afford 5 (61 mg) in 98% yield as a slightly yellow
0:1) to afford 14 (270 mg, 76%) and 16 (56 mg) as white foams.
solid.
Compound 14
R 0.71 (sat. CHCl -MeOH-H O); [a] -71.5 (c 1.01, MeOH).
f
3
2
D
R 0.41 (toluene-EtOAc, 30:1); [a] +54.5 (c 1.03, CHCl ).
f
D
3
1
H NMR (300 MHz, DMSO-d + 5% D O): d = 7.41 (d, J = 8.4 Hz,
6
2
1
H NMR (300 MHz, CDCl ): d = 8.11-7.36 (m, 40 H), 7.30 (d,
3
2 H), 7.11, 6.92 (2 d, J = 16.2 Hz, 2 H), 6.87 (br s, 2 H), 6.77 (d,
J = 8.4 Hz, 2 H), 6.58 (br s, 1 H), 4.87 (d, J = 6.6 Hz, 2 H), 3.74-
3
J = 8.6 Hz, 2 H), 7.08 (d, J = 8.6 Hz, 2 H), 6.97, 6.81 (2 d, J = 16.4
Hz, 2 H), 6.90 (br s, 1 H), 6.79 (br s, 1 H), 6.53 (br s, 1 H), 6.15 (t,
J = 9.2 Hz, 1 H), 6.14 (t, J = 9.5 Hz, 1 H), 5.98-5.83 (m, 4 H), 5.58
.12 (m, 12 H).
1
3
C NMR (75 MHz, DMSO-d ): d = 158.8, 157.7, 139.7, 129.5,
6
(
1
d, J = 6.6 Hz, 1 H), 5.55 (d, J = 7.8 Hz, 1 H), 4.87-4.47 (m, 6 H),
.07, 1.06 (2 s, 9 H), 0.27, 0.26 (2 s, 6 H).
1
7
28.3, 128.2, 125.1, 115.9, 108.8, 103.3, 100.6, 77.3, 77.0, 73.5,
0.1, 61.1.
1
3
C NMR (75 MHz, CDCl ): d = 166.1, 166.0, 165.7, 165.2, 165.1,
3
ESI-MS: m/z (%) for C H O = 575.1 [M + Na]+.
26 32 13
1
1
1
2
65.0, 158.1, 156.8, 156.5, 139.6, 133.5, 133.3, 133.2, 133.1, 129.8,
+
29.6, 129.3, 129.1, 128.7, 128.6, 128.4, 128.3, 127.7, 127.1, 117.3,
13.4, 108.9, 108.2, 99.8, 99.5, 72.7, 72.6, 71.7, 69.7, 69.5, 63.2,
5.6, 18.1, -4.5.
HRESI-MS: m/z calcd for C H O [M + Na] : 575.1757; found:
26 32 13
575.1735.
+
ESI-MS: m/z (%) for C H O Si = 1522.4 [M + Na] .
8
8
78 21
Acknowledgment
Anal. Calcd for C H O Si: C, 70.49; H, 5.21. Found: C, 70.25; H,
88
78 21
We are grateful for the financial supports from the Chinese Acade-
my of Sciences (KGCX2-SW-213-05) and the German Fonds der
Chemischen Industrie.
5
.21.
(
E)-1-[3-b-D-(glucopyranosyloxy)-5-hydroxyphenyl]-2-(4-b-D-
glucopyranosyloxyphenyl) Ethene (4)
Separation by flash column chromatography (CHCl -MeOH, 3:1
3
References
→
sat. CHCl -MeOH-H O, 6:3:1 giving two layers and use of the
3 2
lower layer) to afford 4 (95 mg) in 99% yield as a slightly yellow
solid.
(1) Present address: Shanghai Medicilon Inc., 67 Libing Road,
Building 5, Zhangjiang High-Tech Park, Shanghai 201203,
P. R. of China.
R 0.47 (sat. CHCl -MeOH-H O); [a] -72.5 (c 1.03, MeOH).
f
3
2
D
(
2) Pervaiz, S. FASEB J. 2003, 17, 1975.
1
H NMR (300 MHz, DMSO-d + 5% D O): d = 7.51 (d, J = 8.7 Hz,
6
2
(3) Wang, Y.; Catana, F.; Yang, Y.; Roderick, R.; van Breemen,
2
6
1
H), 7.09, 6.96 (2 d, J = 16.4 Hz, 2 H), 7.02 (d, J = 8.7 Hz, 2 H),
.76 (br s, 1 H), 6.62 (br s, 1 H), 6.37 (br s, 1 H), 4.89 (d, J = 7.2 Hz,
H), 4.82 (d, J = 7.2 Hz, 1 H), 3.77-3.16 (m, 12 H).
R. B. J. Agric. Food Chem. 2002, 50, 431.
4) Frankel, E. N.; Waterhouse, A. L.; Kinsella, J. E. Lancet
(
1993, 341, 1103.
1
3
C NMR (75 MHz, DMSO-d ): d = 159.2, 158.7, 157.4, 139.4,
(5) Jang, M.; Cai, L.; Udeani, G. O.; Slowing, K. V.; Thomas,
C. F.; Beecher, C. W.; Fong, H. H.; Farnsworth, N. R.;
Kinghorn, A. D.; Mehta, R. G.; Moon, R. C.; Pezzuto, J. M.
Science 1997, 275, 218.
6
1
7
31.1, 128.4, 128.0, 127.1, 116.8, 107.8, 105.3, 103.4, 101.0, 100.6,
7.4, 77.3, 77.0, 76.9, 73.6, 70.1, 70.0, 61.1.
ESI-MS: m/z (%) for C H O = 575.1 [M + Na]+.
2
6
32 13
(
(
(
6) Fontecave, M.; Lepoivre, M.; Elleigand, E.; Gerez, C.;
Guittet, O. FEBS Lett. 1998, 421, 277.
7) Orsini, F.; Pelizzoni, F.; Verotta, L.; Aburjai, T. J. Nat. Prod.
(
E)-1-[3,5-Bis-(2,3,4,6-tetra-O-benzoyl-b-D-glucopyranosyl-
oxy)phenyl]-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)
Ethene (15)
1
997, 60, 1082.
8) (a) Hillis, W. E.; Hasegawa, M. Biochem. J. 1962, 83, 503.
b) Aritomi, M.; Donnelly, D. M. X. Phytochemistry 1976,
5, 2006. (c) Hanawa, F.; Tahara, S.; Mizutani, J.
The donor 11 (4.0 equiv); TMSOTf (0.08 equiv); stirring time: 12 h;
separation by flash column chromatography (toluene-EtOAc, 60:1)
to afford 15 (177 mg, 50%) and 16 (82 mg) as white foams.
(
1
Phytochemistry 1992, 31, 3005. (d) Aburjai, T. A.
Phytochemistry 2000, 55, 407.
Compound 15
R 0.40 (toluene-EtOAc, 30:1); [a] +47.6 (c 1.01, CHCl ).
f
D
3
Synthesis 2006, No. 8, 1301–1306 © Thieme Stuttgart · New York

1
306
Z. Zhang et al.
PAPER
(12) Brandolini, V.; Maietti, A.; Tedeschi, P.; Durini, E.;
(
9) (a) Nonaka, G.; Minani, M.; Nishioka, I. Chem. Pharm. Bull.
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G.; Huguet, F.; Vercauteren, J.; Merillon, J.-M. J. Nat. Prod.
998, 61, 655. (c) Fan, W.; Tezuka, Y.; Kadota, S. Chem.
Pharm. Bull. 2000, 48, 1055.
1
Vertuani, S.; Manfredini, S. J. Agric. Food Chem. 2002, 50,
7407.
1
(13) Learmonth, D. A. Synth. Commun. 2004, 34, 1565.
(14) Zhang, Z.; Yu, B. J. Org. Chem. 2003, 68, 6309.
(15) Yu, B.; Tao, H. J. Org. Chem. 2002, 67, 9099.
(16) Elias, C.; Gelpi, M. E.; Cadenas, R. A. J. Carbohydr. Chem.
1995, 14, 1209.
(
(
10) (a) Hano, Y.; Goi, K.; Nomura, T.; Ueda, S. Cell Mol. Life
Sci. 1997, 53, 237. (b) Zhou, C. X.; Kong, L. D.; Ye, W. C.;
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Synthesis 2006, No. 8, 1301–1306 © Thieme Stuttgart · New York