Total synthesis of phenylpropanoid glycosides, grayanoside A and syringalide B, through a common intermediate

Article abstract of DOI:10.1016/j.carres.2007.06.022

Phenylpropanoid glycosides are known as bioactive natural products. Two of them, grayanoside A (1) and syringalide B (2), were synthesized through a common intermediate, using benzyl as temporary protecting group following a shorter route.

Full text of DOI:10.1016/j.carres.2007.06.022

Carbohydrate Research 342 (2007) 2309–2315
Note
Total synthesis of phenylpropanoid glycosides, grayanoside A
and syringalide B, through a common intermediateI
Saibal Kumar Das,a,* K. Anantha Reddya,b and K. Mukkantib
aDiscovery Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
bChemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, AP, India
Received 18 April 2007; received in revised form 15 June 2007; accepted 19 June 2007
Available online 28 June 2007
Abstract—Phenylpropanoid glycosides are known as bioactive natural products. Two of them, grayanoside A (1) and syringalide B
(2), were synthesized through a common intermediate, using benzyl as temporary protecting group following a shorter route.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Phenylpropanoid glycosides; Grayanoside A; Syringalide B; Synthesis; Monosaccharide; Feruloyl
Phenylpropanoid glycosides are naturally occurring gly-
cosides acylated with a substituted cinnamoyl residue
having a substituted phenethyl group as aglycon.1 Most
of them possess biological activities such as antiviral,
antimicrobial, hepato-protective, antitumour, anti-
fungal, improved immune function and sedative
effects.1–8 Very recently, Lin and co-workers suggested
that the inhibition of reactive oxygen species (ROS) pro-
duction, possibly through modulation of NADPH oxi-
dase (NOX) activity and/or the radical scavenging
effect, as well as b2 integrin expression in leucocytes,
indicated that the phenylpropanoid glycosides had the
potential to serve as anti-inflammatory agents during
oxidative stress.9 More than 100 phenylpropanoid gly-
cosides have already been isolated and characterized
by spectral and chemical conversions. However, the
low content of phenylpropanoid glycosides in most of
the plant species has limited further investigation of
their activities. Thus, it becomes important to provide
a synthetic route to these phenylpropanoid glycosides.
Grayanoside A (1, Fig. 1), a monosaccharide phenyl-
propanoid glycoside, was isolated from the bark of Pra-
nus grayana10 and syringalide B (2, Fig. 1), an isomer of
OR1
R2O
HO
O
O
OH
OH
1: R = feruloyl, R = H; grayanoside A
1
2
1
2
2: R = H, R = feruloyl; syringalide B
Figure 1. Structures of grayanoside A and syrigalide B.
grayanoside A, was isolated from Syringa reticulata
leaf.11 Cai and co-workers have reported12,13 the synthe-
ses of these two phenylpropanoid glycosides following
two different routes and through different intermediates.
Here we wish to report the syntheses of both the phenyl-
propanoid glycosides through a common intermediate,
thereby reducing the number of steps.
Protecting group manipulation plays an important
role in organic synthesis. After considering the struc-
tures of both the phenylpropanoid glycosides, it ap-
peared that the benzyl group could possibly impart the
necessary assistance to obtain two compounds through
a common, late-stage intermediate, although selective
removal of benzyl groups without affecting the double
bond was a challenge. A literature search provided the
confidence that the acteoside had been synthesized14
using benzyl protection and bearing a similar kind of
q DRL Publication No. 608.
*
Corresponding author. Fax: +91 40 23045438;
saibalkumardas@drreddys.com
e-mail:
0008-6215/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.06.022

2310
S. K. Das et al. / Carbohydrate Research 342 (2007) 2309–2315
cinnamoyl residue. The literature survey also indicated
that Cai and co-workers12 already used allyl or allyloxy-
carbonyl groups for the synthesis of grayanoside A. This
was another reason to choose benzyl as protective
group. After we started the work, there was a report13
on the synthesis of syringalide B, the other isomer, fol-
lowing a similar allyl protective group strategy.
Our strategy for the total syntheses of the two isomers
1 and 2 involved a convergent route from phenethyl gly-
coside 6, obtained from glucose pentaacetate15 and the
phenethyl derivative 5 (Scheme 1). Initially we wanted
to follow Schmidt’s trichloroacetimidate procedure to
obtain phenethyl glycoside 6. Accordingly, 2,3,4,6-
tetra-O-acetyl-D-glucopyranose (3) was obtained from
glucose pentaacetate15 using hydrazine acetate.16 Com-
pound 3 was then converted to the trichloroacetimidate
derivative 4 following literature procedure.17 TMSOTf-
promoted18 glycosylation of 4 using 2-(4-benzyloxy-
phenyl)ethyl alcohol afforded phenethyl glycoside 6 in
only 34% yield. The overall yield seemed to be unsatis-
factory, and we turned our interest to a single-step pro-
cedure. Thus, glucose pentaacetate was reacted with
boron trifluoride etherate to afford phenethyl glycoside
6 in 60% yield (see Scheme 1).
Compound 6 was then treated with sodium methoxide
in methanol to remove the acetyl groups, followed by
benzylidination using a,a-dimethoxytoluene19 in the
presence of a catalytic amount of p-toluenesulfonic acid
(Scheme 2) to afford benzylidene derivative 8 in 95%
yield over two steps. Compound 8 was then converted
to its dibenzyl derivative 9 (90% yield) using benzyl bro-
mide in DMF in the presence of sodium hydride, which
on hydrolysis using aqueous acetic acid furnished crucial
intermediate 10 in 82% yield.
In the next step, protected ferulic acid derivative 13
was prepared starting from 4-hydroxy-3-methoxy
cinnamic acid (11) following a reported procedure20
(Scheme 3).
The ferulic acid derivative 13 was then reacted with
the synthesized glycoside 10 using 3-ethyl-1-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride (EDCI)21
in the presence of 4-(dimethylamino)pyridine (DMAP)
in dichloromethane where both 6-O-acyl as well as 4-
O-acyl derivatives 14 and 15, respectively, were obtained
OAc
O
OAc
OAc
b
AcO
AcO
a
O
O
AcO
AcO
AcO
AcO
OH
OAc
OAc
NH
OAc
OAc
O
4
3
CCl3
c
OAc
d
O
AcO
AcO
O
OAc
O
HO
6
O
5
Scheme 1. Reagents and conditions: (a) Hydrazine acetate, DMF, 60 ꢁC, 40 min, 93%; (b) CCl3CN, DBU, CH2Cl2, rt, 30 min, 76%; (c) 5, TMSOTf,
Et2O, rt, 1 h, 34%; (d) 5, CH2Cl2, BF3ÆOEt2, rt, 6 h, 60%.
OH
O
c
Ph
O
b
a
O
HO
HO
O
6
OR
OR
HO
OH
OH
8
7
OH
O
Ph
O
O
d
HO
O
OR
OR
BnO
BnO
OBn
OBn
10
9
R=
O
Scheme 2. Reagents and conditions: (a) NaOMe, MeOH, rt, 4 h, quant.; (b) a,a-dimethoxytoluene, p-TsOH, DMF, rt, 24 h, 95%; (c) BnBr, NaH,
DMF, rt, 20 h, 90%; (d) 80% AcOH, 80 ꢁC, 90 min, 82%.

S. K. Das et al. / Carbohydrate Research 342 (2007) 2309–2315
2311
MeO
HO
COOH
MeO
BnO
COOH
MeO
BnO
COOBn
b
a
11
12
13
Scheme 3. Reagents and conditions: (a) BnBr, K2CO3, DMF, rt, overnight, 96%; (b) LiOH, THF–MeOH–H2O, rt, 40 h, 92%.
in 35% and 39% yields as shown in Scheme 4. The
reason for obtaining a marginally higher yield for the
4-O-acyl derivative is not clear to us, although before
assigning the structures through 1D and 2D NMR
experiments, we assumed the opposite result, since a pri-
mary hydroxyl group generally shows greater reactivity.
These two compounds were easily separated by normal
silica gel column chromatography method. The 1H,
The protons of H-4, H-5, H-6a and H-6b were as-
signed at d 5.06 (d 70.8), d 3.40 (d 74.6), d 3.61 and d
3.70 (d 61.7), respectively. Through the same HMBC
experiment, the carbon chemical shift of the cinnamoyl
carbonyl was assigned at d 167.0 from its long-range
heteronuclear correlations with the olefinic protons at
d 7.60 and d 6.15. Further the cinnamoyl carbonyl car-
bon at d 167.0 showed long-range heteronuclear correla-
tions with the proton at d 5.06, which was assigned for
H-4 on the sugar moiety. This shows that the substitu-
tion (cinnamoyl group) is at C-4 in 15.
The last step was the debenzylation of compounds 14
and 15. We first tried the ammonium formate–10% Pd/C
transfer hydrogenolysis method.22 To our surprise, the
analysis indicated that the double bond got reduced
along with three of the four benzyl groups. The BCl3
method23 afforded only 10% conversion, and the iso-
lated product contained three benzyl protections intact.
When we tried the FeCl3 method,24 a very highly polar
product formed that was not characterized. Finally the
desired products were obtained when we used 1,4-cyclo-
hexadiene in the presence of Pd/C in a DMF–EtOH
mixture, following a known protocol for the transfer
hydrogenolysis.14 It is pertinent to say that the yields
of the reaction were poor mainly due to incomplete
1
1H–1H COSY and H–13C HSQC NMR experiments
were used to assign the protons and carbons in com-
pounds 14 and 15. The protons H-4, H-5, H-6a and
H-6b were assigned at d 3.52 (d 70.2), d 3.46 (83.9), d
4.38 and d 4.58 (d 63.3), respectively; the figures in the
parentheses being the position of corresponding C. To
confirm the position of substitution of the cinnamoyl
group on the sugar moiety, the HMBC experiment
was performed, the results of which are shown in Figure
2. The carbon chemical shift of the cinnamoyl carbonyl
was easily assigned at d 168.2 from its long-range hetero-
nuclear correlations with the olefinic protons at d 7.63
and d 6.34. Further the cinnamoyl carbonyl carbon at
d 168.2 showed long-range heteronuclear correlations
with protons at d 4.38 and d 4.58, which were assigned
for H-6a and H-6b on the sugar moiety. This shows that
the substitution (cinnamoyl group) is at C-6 in 14.
OR2
OH
OH
MeO
BnO
COOH
R2O
BnO
O
O
HO
BnO
O
a
OR1
OR1
HO
BnO
OR1
+
+
OBn
OBn
OBn
15; 39%
14; 35%
13
10
28%
b
b
29%
MeO
OH
O
OH
MeO
HO
O
O
HO
O
O
OH
O
OH
O
HO
2
O
HO
OH
OH
MeO
BnO
CO
R1=
R2=
1
OBn
Scheme 4. Reagents and conditions: (a) EDCI, DMAP, CH2Cl2, rt, 1 h; (b) 1,4-cyclohexadiene, 5% Pd/C, DMF–EtOH, rt, 10 h.

2312
S. K. Das et al. / Carbohydrate Research 342 (2007) 2309–2315
H3CO
H
OBn
7.63 (145.0)
O
7.60 (146.6)
5.06 (70.8)
OH
H
168.2
O
6.34 (115.6)
H3CO
H
O
O
H
4.58 (63.3)
H
H
4.38 (63.3)
H
O
H 3.46 (83.9)
BnO
3.52 (70.2)
HO
O
O
BnO
H
O
OBn
BnO
6.15 (114.9)
OBn
OBn
14
OBn
15
Figure 2. Structures and chemical shifts for 14 and 15.
removal of benzyl protections. Even after several days,
the reaction did not go for completion.
The advantage of this synthetic strategy is that both
grayanoside A and syringalide B can be synthesized in
reasonably good yields through a common intermediate
through less number of reaction steps.
then was diluted with CH2Cl2 (50 mL). The organic
phase was washed successively with water and brine,
dried (anhyd Na2SO4) and evaporated to dryness under
reduced pressure. The crude product was purified by col-
umn chromatography using 35:65 EtOAc–petroleum
ether to afford a colourless gummy mass of 6: yield
0.86 g (60%); Rf 0.32 (1:3 EtOAc–petroleum ether);
[a]D À1.8 (c 0.5, CHCl3); IR (Neat): 2940, 1766, 1512,
1
1368, 1223, 1040 cmÀ1; H NMR (400 MHz, CDCl3):
1. Experimental
d 1.89 (s, 3H, Ac), 1.99 (s, 3H, Ac), 2.02 (s, 3H, Ac),
2.08 (s, 3H, Ac), 2.82 (t, 2H, J 6.4 Hz, OCH2–CH2-
Ph), 3.60–3.78 (m, 2H, H-5 and OCH2–CH2-Ph), 4.05–
4.09 (m, 1H, OCH2–CH2-Ph), 4.13 (dd, 1H, J 2.4 and
12.4 Hz, H-6a), 4.25 (dd, 1H, J 4.8 and 12.4 Hz, H-
6b), 4.48 (d, 1H, J 8.0 Hz, H-1), 4.98 (t, 1H, J 8.8 Hz,
H-2), 5.04 (s, 2H, OCH2-Ph), 5.07 (t, 1H, J 9.6 Hz, H-
4), 5.17 (t, 1H, J 9.4 Hz, H-3), 6.88 (d, 2H, J 8.8 Hz,
Ph), 7.01 (d, 2H, J 8.4 Hz, Ph), 7.29–7.43 (m, 5H, Ph).
13C NMR (50 MHz, CDCl3): d 20.6 (2CH3), 20.7
(2CH3), 35.0, 61.9, 68.5, 70.0, 70.9, 71.2, 71.8, 72.8,
100.8 (C-1), 114.8 (2C), 127.4 (2C), 127.9, 128.6 (2C),
129.9 (2C), 130.8, 137.1, 157.4, 169.3, 169.4, 170.3,
170.7. ESIMS: m/z 576.4 (M++18). HRMS m/z: calcd
for C29H34O11Na, 581.1999; found 581.1979. Anal.
Calcd for C29H34O11: C, 62.36; H, 6.13. Found: C,
62.05; H, 5.91.
1.1. General methods
The 1H NMR spectra were recorded with tetramethylsi-
lane (TMS, d 0.00) as the internal standard and calibra-
tion of 13C NMR spectra were done with residual
solvent peaks on a Varian Gemini 200 or 400 MHz FT
NMR spectrometer. Mass spectra were measured on
Hewlett-Packard 5989A mass spectrometer [chemical
ionization, (CI), 20 eV] or on a Perkin–Elmer Sciex
model API 3000 [electrospray ionization, (ESI), capil-
lary voltage between +5000 and À4500 V]. The HRMS
studies were performed on a Waters LCT premier XE
instrument. The FTIR spectra were recorded using a
Perkin–Elmer 1650 fourier-transform infrared spectro-
photometer. Optical rotations were measured using a
JASCO DIP-370 polarimeter at room temperature
(25 ꢁC). Melting points were measured in glass capillary
tubes on a digital melting point apparatus model No.
1.3. 2-(4-Benzyloxyphenyl)ethyl b-D-glucopyranoside (7)
Buchi-535 and were uncorrected. All the chromatogra-
¨
phy solvents were distilled before use. Silica gel (100–
200 mesh, SRL, India) was used for column
chromatography.
To a solution of compound 6 (0.95 g, 1.70 mmol) in
MeOH (3.5 mL) was added 1 M NaOMe (0.19 mL),
and the reaction mixture was stirred at room tempera-
ture for 4 h. The reaction mixture was diluted with
MeOH and neutralized with Dowex-50W (H+) resin.
The reaction mixture was filtered through cotton, evap-
orated to dryness under reduced pressure, flashed with
toluene and dried to afford 7 as a white solid: yield
0.65 g (quant); Rf 0.2 (EtOAc); mp 96–98 ꢁC; [a]D
+0.4 (c 0.5, MeOH); IR: 3264, 2913, 1659, 1512, 1250,
1.2. 2-(4-Benzyloxyphenyl)ethyl 2,3,4,6-tetra-O-acetyl-
b-D-glucopyranoside (6)
To an ice cooled solution of glucose pentaacetate (1.0 g,
2.56 mmol) and 2-(4-benzyloxyphenyl)-1-ethanol (1.17
g, 5.13 mmol) in CH2Cl2 (10 mL) boron trifluoride eth-
erate (0.64 mL) was added dropwise with stirring at
room temperature. The mixture was stirred for 6 h and
1105, 1028 cmÀ1
;
1H NMR (400 MHz, CD3OD): d
2.87 (t, 2H, J 7.7 Hz, OCH2–CH2-Ph), 3.18 (dd, 1H, J

S. K. Das et al. / Carbohydrate Research 342 (2007) 2309–2315
2313
7.8 and 8.9 Hz, H-2), 3.22–3.32 (m, 2H, H-4 and H-5),
3.35 (t, 1H, J 7.8 and 8.9 Hz, H-3), 3.66 (dd, 1H, J 5.4
and 11.8 Hz, H-6a), 3.68–3.75 (m, 1H, OCH2–CH2-
Ph), 3.86 (dd, 1H, J 2.0 and 11.9 Hz, H-6b), 4.01–4.08
(m, 1H, OCH2–CH2-Ph), 4.29 (d, 1H, J 7.6 Hz, H-1),
5.04 (s, 2H, OCH2-Ph), 6.89 (dd, 2H, J 2.2 and
6.7 Hz, Ph), 7.16 (dd, 2H, J 2.0 and 6.6 Hz, Ph), 7.28–
7.30 (m, 1H, Ph), 7.35 (t, 2H, J 6.6 Hz, Ph), 7.41 (dd,
2H, J 1.6 and 7.3 Hz, Ph). 13C NMR (50 MHz, CDCl3):
d 36.5, 62.9, 71.2, 71.8, 72.1, 75.3, 78.1, 78.3, 104.5 (C-1),
116.0 (2C), 128.6 (2C), 128.9, 129.6 (2C), 131.1 (2C),
132.6, 139.1, 158.9. ESIMS: m/z 408.1 (M++18); HRMS
m/z: calcd for C21H26O7Na, 413.1576; found, 413.1578.
Anal. Calcd for C21H26O7: C, 64.60; H, 6.71. Found: C,
64.43; H, 6.98.
1.9 mmol; 60% oil coated) was added portionwise with
stirring for 15 min. Benzyl bromide (0.21 mL) was then
added dropwise, and the mixture was stirred at room
temperature for 20 h. The mixture was diluted with
EtOAc (ꢀ50 mL) and washed with water. The aqueous
layer was extracted with EtOAc (2 · 50 mL), and the
combined organic extracts were washed with water
and brine, then dried (anhyd Na2SO4) and evaporated
to dryness under reduced pressure. The crude product
was purified by column chromatography using 15:85
EtOAc–petroleum ether to afford 9 as an off-white solid:
yield 434 mg (90%); Rf 0.58 (1:4 EtOAc–petroleum
ether); mp 110–112 ꢁC; [a]D À22.6 (c 0.5, CHCl3); IR:
2879, 1512, 1239, 1089, 1006 cmÀ1
;
1H NMR
(400 MHz, CDCl3): d 2.90 (t, 2H, J 7.0 Hz, OCH2–
CH2-Ph), 3.36–3.41 (m, 1H, H-5), 3.44 (t, 1H, J
8.1 Hz, H-2), 3.67 (t, 2H, J 9.0 Hz, H-3), 3.70–3.80 (m,
3H, H-4, H-6a and OCH2–CH2-Ph), 4.11–4.16 (m, 1H,
OCH2–CH2-Ph), 4.34 (dd, 1H, J 5.2 and 10.6 Hz, H-
6b), 4.51 (d, 1H, J 7.6 Hz, H-1), 4.64 and 4.69 (2d,
2H, J 11.0 Hz, OCH2Ph), 4.78 (d, 1H, J 11.2 Hz,
OCH2Ph), 4.89 (d, 1H, J 11.6 Hz, OCH2Ph), 4.97 (s,
2H, OCH2Ph), 5.55 (s, 1H, PhCH), 6.86 (dd, 2H, J 2.0
and 6.7 Hz, Ph), 7.14 (dd, 2H, J 2.1 and 6.7 Hz, Ph),
7.22–7.40 (m, 18H, Ph), 7.47–7.50 (m, 2H, Ph); 13C
NMR (50 MHz, CDCl3): d 30.9, 61.6, 64.3, 65.5, 66.7,
70.6, 70.7, 71.9, 72.6, 73.2, 96.7, 99.6 (C-1), 110.4 (2C),
121.5 (2C), 122.9 (2C), 123.1 (2C), 123.4 (2C), 123.5
(2C), 123.6 (2C), 123.76 (2C), 123.79 (2C), 124.1 (2C),
124.4 (2C), 125.4 (2C), 126.3, 132.7, 132.9, 133.9,
134.1, 153.0; ESIMS: m/z 676.5 (M++18); HRMS m/z:
calcd for C42H42O7Na, 681.2828; found, 681.2819. Anal.
Calcd for C42H42O7: C, 76.57; H, 6.43. Found: C, 76.89;
H, 6.77.
1.4. 2-(4-Benzyloxyphenyl)ethyl 4,6-O-benzylidene-b-D-
glucopyranoside (8)
To a solution of compound 7 (1.1 g, 2.82 mmol) and p-
toluenesulfonic acid (50 mg) in DMF (10 mL) was
added dropwise benzaldehyde dimethyl acetal (1 mL)
with stirring. The reaction mixture was stirred at room
temperature for 24 h and then diluted with EtOAc
(100 mL). The organic layer was washed with water,
and the aqueous layer was extracted with EtOAc
(2 · 100 mL). The combined organic extracts were
washed with water and brine, then dried (anhyd
Na2SO4) and evaporated to dryness under reduced
pressure. The crude product was purified by column
chromatography using 3:7 EtOAc–petroleum ether to
afford 8 as a white solid: yield 1.28 g (95%); Rf 0.7 (9:1
EtOAc–petroleum ether); mp 106–108 ꢁC; [a]D À31.6
(c 0.5, CHCl3); IR (Neat): 3507, 2870, 1512, 1242,
1
1082, 1028 cmÀ1; H NMR (400 MHz, CDCl3): d 2.90
(t, 2H, J 7.9 Hz, OCH2–CH2-Ph), 3.43–3.50 (m, 2H,
H-2 and H-5), 3.55 (t, 1H, J 9.3 Hz, H-3), 3.69–3.83
(m, 3H, H-4, H-6a and OCH2–CH2-Ph), 4.09–4.16 (m,
1H, OCH2–CH2-Ph), 4.33 (dd, 1H, J 4.8 and 10.5 Hz,
H-6b), 4.38 (d, 1H, J 7.8 Hz, H-1), 5.04 (s, 2H, OCH2-
Ph), 5.53 (s, 1H, PhCH), 6.91 (dd, 2H, J 2.0 and
6.6 Hz, Ph), 7.14 (dd, 2H, J 1.9 and 6.7 Hz, Ph), 7.30–
7.40 (m, 10H, Ph). 13C NMR (50 MHz, CDCl3): d
35.1, 66.3, 68.6, 70.0, 71.2, 73.0, 74.5, 80.5, 101.8,
103.2 (C-1), 114.9 (2C), 126.2 (2C), 127.4 (2C), 127.9,
128.3 (2C), 128.5 (2C), 129.2, 129.8 (2C), 130.3, 136.9,
137.0, 157.4. ESIMS: m/z 496.3 (M++18), 479.2
(M++1); HRMS m/z: calcd for C28H30O7Na,
501.1889; found, 501.1897. Anal. Calcd for C28H30O7:
C, 70.28; H, 6.32. Found: C, 70.20; H, 6.50.
1.6. 2-(4-Benzyloxyphenyl)ethyl 2,3-di-O-benzyl-b-D-
glucopyranoside (10)
A solution of compound 9 (1.2 g, 1.82 mmol) in 80%
aqueous HOAc (15 mL) was stirred at 80 ꢁC for
90 min. The HOAc was evaporated under reduced pres-
sure. The residue was dissolved in EtOAc (100 mL) and
successively washed with water, satd aq NaHCO3, water
and brine, dried (anhyd Na2SO4) and evaporated to dry-
ness under reduced pressure. The crude product was
purified by column chromatography using 1:1 EtOAc–
petroleum ether to afford 10 as a white solid; yield
276 mg (82%); Rf 0.62 (1:4 EtOAc–petroleum ether);
mp 112–114 ꢁC; [a]D À15.4 (c 0.5, CHCl3); IR: 3352,
2850, 1513, 1455, 1249, 1121, 1071, 1036 cmÀ1 1H
;
NMR (400 MHz, CDCl3): d 2.90 (t, 2H, J 7.0 Hz,
OCH2–CH2-Ph), 3.28–3.32 (m, 1H, H-5), 3.40–3.42
(m, 2H, H-2 and H-6a), 3.53 (t, 1H, J 8.8 Hz, H-4),
3.70–3.78 (m, 2H, H-6b and OCH2–CH2-Ph), 3.85–
3.97 (m, 1H, H-3), 4.11–4.17 (m, 1H, OCH2–CH2-Ph),
4.45 (d, 1H, J 7.2 Hz, H-1), 4.59 (d, 1H, J 10.8 Hz,
1.5. 2-(4-Benzyloxyphenyl)ethyl 4,6-O-benzylidene-2,3-
di-O-benzyl-b-D-glucopyranoside (9)
To an ice-cooled solution of compound 8 (0.35 g,
0.73 mmol) in DMF (5 mL), sodium hydride (76 mg,

2314
S. K. Das et al. / Carbohydrate Research 342 (2007) 2309–2315
OCH2-Ph), 4.64 (d, 1H, J 11.6 Hz, OCH2-Ph), 4.74 (d,
1H, J 10.8 Hz, OCH2-Ph), 4.94 (d, 1H, J 11.8 Hz,
OCH2-Ph), 4.97 (s, 2H, OCH2-Ph), 6.87 (dd, 2H, J 1.9
and 6.7 Hz, Ph), 7.14 (d, 2H, J 8.8 Hz, Ph), 7.21–7.40
(m, 15H, Ph); 13C NMR (50 MHz, CDCl3): d 35.3,
62.4, 69.9, 70.3, 71.0, 74.5, 74.9, 75.1, 81.8, 83.8, 103.7
(C-1), 114.8 (2C), 127.3 (2C), 127.6, 127.81 (2C),
127.83 (2C), 128.0 (2C), 128.2 (2C), 128.5 (4C), 129.8
(2C), 130.8, 137.0, 138.3, 138.5, 157.4; ESIMS: m/z
588.5 (M++18), 571.4 (M++1); HRMS m/z: calcd for
C35H38O7Na, 593.2515; found, 593.2521. Anal. Calcd
for C35H38O7: C, 73.66; H, 6.71. Found: C, 73.50; H,
6.88.
(2C), 130.8, 136.5, 137.1, 138.4, 138.5, 145.5, 149.8,
150.4, 151.4, 167.6; ESIMS: m/z 854.5 (M++18), 831.5
(M++1); HRMS m/z: calcd for C52H52O10Na,
859.3458; found, 859.3482. Anal. Calcd for C52H52O10:
C, 74.62; H, 6.26. Found: C, 74.29; H, 6.55.
1.7.2. Data for 15. Yield: 172 mg (39%); Rf 0.66 (1:1
EtOAc–petroleum ether); mp 91–93 ꢁC; [a]D À56.8 (c
0.5, CHCl3); IR: 3414, 2919, 1713, 1514, 1255, 1139,
1027 cmÀ1 1H NMR (400 MHz, CDCl3): d 2.92 (t,
;
2H, J 7.0 Hz, OCH2–CH2-Ph), 3.36–3.41 (m, 1H,
H-5), 3.51 (t, 1H, J 8.6 Hz, H-2), 3.57–3.63 (m, 1H,
H-6a), 3.68–3.78 (m, 3H, H-3, H-6b and OCH2–CH2-
Ph), 3.93 (s, 3H, OCH3), 4.15–4.21 (m, 1H, OCH2–
CH2-Ph), 4.48 (d, 1H, J 7.8 Hz, H-1), 4.62 (d, 1H, J
11.0 Hz, OCH2-Ph), 4.66 (d, 1H, J 11.3 Hz, OCH2-
Ph), 4.74 (d, 1H, J 11.0 Hz, OCH2-Ph), 4.80 (d, 1H,
J 11.5 Hz, OCH2-Ph), 4.98 (s, 2H, OCH2-Ph), 5.05
(t, 1H, J 9.6 Hz, H-4), 5.20 (s, 2H, OCH2-Ph), 6.14
and 7.59 (2d, 2H, J 15.8 Hz, CH@CH–C@O), 6.86–
6.90 (m, 3H, Ph), 7.00–7.04 (m, 2H, Ph), 7.15 (d,
2H, J 8.6 Hz, Ph), 7.18–7.44 (m, 20H, Ph); 13C
NMR (50 MHz, CDCl3): d 35.3, 56.0, 61.5, 69.9,
70.4, 70.8, 70.9, 74.3, 74.8, 75.0, 81.3, 82.0, 103.6 (C-
1), 110.4, 113.4, 114.6, 114.8 (2C), 122.7 (2C), 127.2
(2C), 127.4 (2C), 127.5, 127.6, 127.8, 127.98 (2C),
128.0, 128.1 (2C), 128.2 (2C), 128.3 (2C), 128.5 (2C),
128.6 (2C), 129.8 (2C), 130.8, 136.4, 137.1, 138.2,
138.3, 146.2, 149.8, 150.6, 157.4, 166.8; ESIMS: m/z
854.5 (M++18); HRMS m/z: calcd for C52H52O10Na,
859.3458; found, 859.3453. Anal. Calcd for
C52H52O10: C, 74.62; H, 6.26. Found: C, 74.40; H,
6.60.
1.7. 2-(4-Benzyloxyphenyl)ethyl 2,3-di-O-benzyl-6-O-
[(E)-4-O-benzylferuloyl]-b-D-glucopyranoside (14) and 2-
(4-Benzyloxyphenyl)ethyl 2,3-di-O-benzyl-4-O-[(E)-4-O-
benzylferuloyl]-b-D-glucopyranoside (15)
To a solution of 4-benzyloxy-3-methoxycinnamic acid
(13, 148 mg, 0.526 mmol) and 4-dimethylaminopyridine
(DMAP, 64 mg, 0.526 mmol) in CH2Cl2 (5 mL) was
added compound 10 (0.3 g, 0.526 mmol) at room tem-
perature with stirring for 10 min. 1-(3-Dimethylamino-
propyl)-3-ethyl carbodiimide hydrochloride (EDCI,
101 mg, 0.526 mmol) was added with stirring at room
temperature for a further 1 h. The reaction mixture
was diluted with CH2Cl2 (100 mL), washed with water
and brine, dried (anhyd Na2SO4) and then evaporated
to dryness under reduced pressure. The crude product
was purified by column chromatography using 1:9
EtOAc–petroleum ether to afford 14 and 15 as white
solids.
1.7.1. Data for 14. Yield: 155 mg (35%); Rf 0.66 (1:1
EtOAc–petroleum ether); mp 109–111 ꢁC; [a]D À9.6 (c
0.5, CHCl3); IR: 3503, 2870, 1702, 1512, 1258, 1138,
1.8. Preparation of 2-(4-hydroxyphenyl)ethyl 6-O-[(E)-
feruloyl]-b-D-glucopyranoside (1)
1067 cmÀ1
;
1H NMR (400 MHz, CDCl3): d 2.91 (t,
A mixture of 14 (130 mg, 155 lmol), 5% Pd/C (155 mg)
and 1,4-cyclohexadiene (291 lL, 3.11 mmol) in 1:1
DMF–EtOH (1.09 mL) was stirred at 40 ꢁC for 10 h.
The reaction mixture was filtered through Celite and
the filtrate was concentrated to give a yellow residue.
The residue was purified on preparative TLC using
CHCl3–MeOH to give 21.4 mg (29%) of grayanoside
A. The physical constants of the product were in agree-
ment with those reported in the literature.12
2H, J 7.2 Hz, OCH2–CH2-Ph), 3.43 (t, 1H, J 7.9 Hz,
H-2), 3.45–3.55 (m, 3H, H-3, H-4, H-5), 3.72 (dd, 1H,
J 5.7 and 9.1 Hz, OCH2–CH2-Ph), 3.91 (s, 3H, OCH3),
4.13–4.19 (m, 1H, OCH2–CH2-Ph), 4.38 (dd, 1H, J 1.8
and 12.2 Hz, H-6a), 4.44 (d, 1H, J 7.5 Hz, H-1), 4.58
(dd, 1H, J 4.4 and 12.1 Hz, H-6b), 4.60 (d, 1H, J
11.6 Hz, OCH2-Ph), 4.72 (d, 1H, J 8.6 Hz, OCH2-Ph),
4.75 (d, 1H, J 8.3 Hz, OCH2-Ph), 4.92 (d, 1H, J
11.6 Hz, OCH2-Ph), 4.95 (s, 2H, OCH2-Ph), 5.18 (s,
2H, OCH2-Ph), 6.34 and 7.63 (2d, 2H, J 15.8 Hz,
CH@CH–C@O), 6.81–6.88 (m, 3H, Ph), 7.01 (dd, 1H,
J 1.9 and 8.3 Hz, Ph), 7.06 (d, 1H, J 1.9 Hz, Ph), 7.13
(d, 2H, J 8.8 Hz, Ph), 7.23–7.43 (m, 20H, Ph); 13C
NMR (50 MHz, CDCl3): d 35.3, 55.94, 55.97, 63.1,
69.9, 70.8, 71.0, 73.8, 74.6, 75.3, 81.7, 83.6, 103.9 (C-
1), 110.2, 113.4, 114.8 (2C), 115.3, 119.0 (2C), 122.6,
127.2 (2C), 127.4 (2C), 127.58, 127.6, 127.8 (2C), 127.9
(2C), 128.0 (2C), 128.3 (2C), 128.5 (4C), 128.6, 129.8
1.9. Preparation of 2-(4-hydroxyphenyl)ethyl 4-O-[(E)-
feruloyl]-b-D-glucopyranoside (2)
A mixture of 15 (140 mg, 167 lmol), 5% Pd/C (167 mg),
and 1,4-cyclohexadiene (314 lL, 3.36 mmol) in 1:1
DMF–EtOH (1.17 mL) was stirred at 40 ꢁC for 10 h.
The reaction mixture was filtered through Celite and
the filtrate was concentrated to give a yellow residue.
The residue was purified on preparative TLC using

S. K. Das et al. / Carbohydrate Research 342 (2007) 2309–2315
2315
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K.-T.; Chou, Y.-C.; Wang, W.-Y.; Shen, Y.-C. J. Pharm.
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10. Shimomura, H.; Sashida, Y.; Adachi, T. Phytochemistry
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CHCl3–MeOH to give 22 mg (28%) of syringalide B.
The physical constants were in agreement with those
recorded earlier13 for this compound.
11. Kikuchi, M.; Yamauchi, Y.; Tanabe, F. Yakugaku Zasshi
1987, 107, 350–354; Chem. Abstr. 1987, 107, 130903.
12. Zhang, S.-Q.; Li, Z.-J.; Wang, A.-B.; Cai, M.-S.; Feng, R.
Carbohydr. Res. 1997, 299, 281–285.
13. Li, Q.; Li, S.-C.; Li, H.; Cai, M.-S.; Li, Z.-J. Carbohydr.
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14. Kawada, T.; Asano, R.; Hayashida, S.; Sakuno, T. J. Org.
Chem. 1999, 64, 9268–9271.
15. Das, S. K.; Reddy, K. A.; Krovvidi, V. L. N. R.;
Mukkanti, K. Carbohydr. Res. 2005, 340, 1387–1392.
Acknowledgements
We are thankful to Professor J. Iqbal and Dr. R.
Rajagopalan for their continuous encouragement to this
work. We also thank the members of the Department of
Analytical Research and Development, especially Mr.
Vasudev R., for the analyses.
´
´ ´
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