Synthesis of quercetin 3-O-[6"-O-(trans-p-coumaroyl)]-β-D- Glucopyranoside

Article abstract of DOI:10.1080/07328303.2011.616979

This report describes the efficient synthesis of quercetin 3-O-[6"-O-(trans-pcoumaroyl)]- β-D-glucopyranoside 1 (isoquercitrin coumarate), an acylated quercetin glycoside possessing antihypertensive, antidiabetic, and tyrosinase inhibitory activities. The synthesis is initiated from commercially available quercetin via regioselective benzylation of quercetin to produce 4', 7-di-O-benzylquercetin (4). Through 4, 1 was successfully achieved via selective β-glycosylation of the 3-OH, acylation of 6"-OH, and finally debenzylation via catalytic transfer hydrogenation. Taylor & Francis Group, LLC.

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Synthesis of Quercetin 3-O-[6″-O-(trans-
p-Coumaroyl)]-β-D-Glucopyranoside
Xuhong Ren a , Liu-lan Shen a , Osamu Muraoka b & Maosheng Cheng a
a The Key Laboratory of Structure-Based Drug Design & Discovery of
Ministry of Education, The School of Pharmaceutical Engineering,
Shenyang Pharmaceutical University, Liaoning, 110016, PR China
b School of Pharmaceutical Sciences, Kinki University, 3-4-1
Kowakae, Higashi-Osaka, Osaka, 577-8502, Japan
Published online: 17 Oct 2011.
To cite this article: Xuhong Ren , Liu-lan Shen , Osamu Muraoka & Maosheng Cheng (2011): Synthesis
of Quercetin 3-O-[6″-O-(trans-p-Coumaroyl)]-β-D-Glucopyranoside, Journal of Carbohydrate
Chemistry, 30:3, 119-131
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Journal of Carbohydrate Chemistry, 30:119–131, 2011
ꢀ
C
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2011.616979
Synthesis of Quercetin 3-O-
[6ꢁꢁ-O-(trans-p-Coumaroyl)]-
β-D-Glucopyranoside
Xuhong Ren,1 Liu-lan Shen,1 Osamu Muraoka,2
and Maosheng Cheng1
1The Key Laboratory of Structure-Based Drug Design & Discovery of Ministry
of Education, The School of Pharmaceutical Engineering, Shenyang Pharmaceutical
University, Liaoning 110016, PR China
2School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka,
Osaka 577-8502, Japan
This report describes the efficient synthesis of quercetin 3-O-[6ꢁꢁ-O-(trans-p-
coumaroyl)]-β-D-glucopyranoside 1 (isoquercitrin coumarate), an acylated quercetin
glycoside possessing antihypertensive, antidiabetic, and tyrosinase inhibitory activi-
ties. The synthesis is initiated from commercially available quercetin via regioselective
benzylation of quercetin to produce 4ꢁ, 7-di-O-benzylquercetin (4). Through 4, 1 was
successfully achieved via selective β-glycosylation of the 3-OH, acylation of 6ꢁꢁ-OH, and
finally debenzylation via catalytic transfer hydrogenation.
Keywords
Quercetin; Quercetin O-glycosides; Quercetin 3-O-[6ꢁꢁ-O-(trans-p-
coumaroyl)]-β-D-glucopyranoside; Synthesis
INTRODUCTION
Quercetin O-glycosides are important flavonol glycosides widely distributed
in the plant kingdom. They have been shown to possess a broad range of bi-
ological activities including antioxidant, anticancer, and radical scavenging
activities,[1] and hence are of great interest. Among the numerous quercetin
O-glycosides identified, most have a sugar linkage at the 3-OH, while some
possess one or more aromatic carboxylic acids attached at specific OH groups
Received June 23, 2011; accepted August 20, 2011.
Address correspondence to Maosheng Cheng, The Key Laboratory of Structure-Based
Drug Design & Discovery of Ministry of Education, The School of Pharmaceutical Engi-
neering, Shenyang Pharmaceutical University, Liaoning, 110016, PR China. E-mail:
mscheng@syphu.edu.cn; and Osamu Muraoka, School of Pharmaceutical Sciences,
Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan. E-mail:
muraoka@phar.kindai.ac.jp
119

X. Ren et al.
120
H
O
3'
H
O
4'
H
7
O
O
O
3
O
5
H
O
O
O
6"
O
1"
H
3'"
O
O
2'"
H
H
O
H
O
1
Figure 1: Structure of isoquercitrin coumarate 1.
in their sugar moieties.[2,3] The physiological functions such as UV resistance
and the radical scavenging ability of higher plants are possibly due to the ex-
istence of these acylated flavonol glycosides in the plant tissues.[4–6]
Quercetin 3-O-[6ꢁꢁ-O-(trans-p-coumaroyl)-β-D-glucopyranoside (isoquer-
citrin coumarate) is an acylated quercetin glycoside having a trans-coumaric
acid attached at the 6ꢁꢁ-OH (1, Fig. 1). It was isolated from Helichrysum kraus-
sii,[7] Melastoma candidum,[8] and Marrubium cylleneum,[9] and has shown
strong antihypertensive[8] and tyrosinase inhibitory activity.[9] Recently, our
laboratory has separated a series of isoquercitrin coumarates, including 1,
from the flower of Apocynum venetum. These compounds potently reduce
triglyceride (TG) accumulation in Hep G2 and have antidiabetic activity, mak-
ing them worthy of further evaluation. However, the quantities of these com-
pounds isolated from natural sources are limited. To get sufficient amounts of
these compounds for further biological investigations, we initiated a program
to synthesize 1.
RESULTS AND DISCUSSION
Although 1 has very important biological properties, to the best of our knowl-
edge, no report regarding the chemical synthesis of 1 has yet been published.
We plan to synthesize 1 from commercially available quercetin. Previously,
Jurd noted that when quercetin penta-acetate underwent substitution by ben-
zyl chloride in dry acetone solution, benzylation on the phenol group appeared
to have some regioselectivity with a preferential order of 7 > 4ꢁ > 3 > 5 >
3ꢁ.[10,11] Therefore, if we develop an efficient method to obtain 4ꢁ,7-di-O-
protected quercetin, selective glycosylation at the 3-OH and acylation of 6ꢁꢁ-OH
with derivatized coumaric acid for the synthesis of 1 should be easily achiev-
able. In the synthesis, protecting-group manipulation is also important since 1
contains not only a double bond, an ester linkage, but also multiple hydroxyl
groups at the sugar ring, at the aglycon, and at the p-coumarate. As discussed

Quercetin 3-O-[6ꢁꢁ-O-(trans-p-Coumaroyl)]-β-D-Glucopyranoside
121
by Jurd, the nucleophilicity of the phenol oxygen on flavone is variable.[11] For
more specific control of the phenol oxygen at the different positions, we chose
to use p-methoxybenzyl chloride (PMBCl), trimethylsilyl chloride (TMSCl),
and allyl bromide to produce 4ꢁ,7-di-O-protected quercetin. But all of these
methods could not provide ideal yields. Finally, we explored selective 4ꢁ,7-di-O-
benzylation, although specific deprotection of benzyl groups without reduction
of the double bond on coumarate skeleton was a challenge. Two reports about
synthesis of acteoside and grayanoside A had shown that benzyl protection was
possible to realize the total synthesis of isoquercitrin coumarate (1).[12,13] As
shown in Scheme 1, 1 is logically disconnected into three fragments, coumaric
acid derivative(3), 4ꢁ,7-di-O-benzyl quercetin (4), and peracetylated glucosyl
bromide (5).[14]
H
O
n
B
O
n
B
O
n
B
O
n
B
O
O
O
n
B
O
O
O
H
O
O
H
O
n
B
O
O
4
H
O
n
B
O
n
c
B
O
A
O
1
n
O
B
O
c
A
O
2
c
O
A
c
A
O
r
B
5
O
H
O
n
B
O
3
Scheme 1: Retrosynthetic analysis of 1.
For the synthesis of 4, Jurd’s procedure[10] was initially attempted, but 4ꢁ,7-
di-O-benzylquercetin acetate (7) was obtained from quercetin pentacetate (6)
as a low-yielding by-product, as was also found by Jurd (Table 1, entry 1). As we
progressed, the yield improved under moderate temperatures (Table 1, entries
2–4). Next, we applied an intermittent injection method with a higher concen-
tration of BnCl. After 72 h of total reaction time, 7 was obtained at a 70% yield
(Table 1, entry 6). Compound 7 was confirmed with the reported literature.[11]
At the same time, we found that when the reaction time of benzylation was
longer than 72 h, major product 7 was decreased and the by-product of 4ꢁ, 3,
7-substituted product was increased. Then, treatment of 7 in 5% NaOH pro-
duced 4. The total yield for the three steps was 57%, much greater than the
17% to 29% previously reported[15] (Sch. 2). The identity of 4 was confirmed

X. Ren et al.
122
H
O
c
A
O
c
A
O
c
A
O
H
O
n
B
O
c
A
O
H
O
O
O
O
n
B
O
O
a
b
c
A
O
H
O
c
A
O
c
A
O
H
O
O
c
A
O
O
uerce n
ti
Q
6
7
c
H
O
H
O
n
B
O
n
B
O
H
O
n
B
O
O
n
B
O
n
B
O
O
n
B
O
O
O
e
O
d
H
O
O
O
H
O
O
O
H
O
H
O
H
O
O
H
O
c
A
O
c
A
O
H
O
4
c
A
O
H
O
c
A
O
9
8
f
H
O
H
O
H
O
O
O
H
O
O
O
H
O
H
O
H
O
H
O
so uerc r n
it i
I
q
Scheme 2: Reagents and conditions: (a) Ac2O, pyridine,140–145◦C, 4 h, 97.5%; (b) PhCH2Cl,
acetone, K2CO3, KI, 35–40◦C, 70%; (c) 5% NaOH, acetone, 0◦C, 3 h, 82%; (d) 5, K2CO3, DMF,
rt, 32 h, 56%; (e) MeONa/MeOH, rt, 9.5 h, 94%; (f) H2, 10% Pd-C, EtOAc/EtOH (1:1), rt,
overnight, 98%.
Table 1: Preparation of 4ꢁ,7-di-O-benzylquercetin acetate 7 from quercetin
penta-acetate 6
Entry
Addition of BnCl
Equiv. of BnCl
Temp. (◦C)
Time (h)
Yield (%)
1
2
3
4
5
6
One-pot
2.0
2.0
2.5
2.5
2.0
2.0
Reflux
10–45
35–40
35–40
35–40
35–40
20
17
21
52
55
61
70
One-pot
20
One-pot
36
One-pot
60
1.0 → 0.6 → 0.4a (eq.)
1.0 → 0.6 → 0.4b (eq.)
60c
72c
aInterval of addition is 20 h.
bInterval of addition is 24 h.
cReaction time is in total hours.

Quercetin 3-O-[6ꢁꢁ-O-(trans-p-Coumaroyl)]-β-D-Glucopyranoside
123
1
1
1
1
by FT-IR, H and 13C NMR, H-1H COSY, H-13C HSQC, H-13C HMBC, and
ESI-MS, and all assigned data were compared and proven to be identical with
the reported literature. [11,15]
Next, we focused our attention on the introduction of glucose to the 3-OH of
4. For this purpose, 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (5) was
chosen as a glycosyl donor. With an acetyl group at 2-O-position, 5 ensures the
β-configuration of the glycosylation product via neighboring participation ef-
fect. Moreover, the mild glycosylation conditions with 5 will introduce glucose
efficiently and preferentially to the 3-OH of 4. Initially, the glycosylation reac-
tion with acceptor 4, donor 5, and Ag2O[16] (the commonly utilized activator for
a glycosyl bromide donor) was investigated and shown to be unsuccessful. After
multiple attempts, the glycosylation reaction was preceded with K2CO3 as an
activator and produced product 8 at approximately a 56% yield, with only trace
amounts of the 3ꢁ-glycosylated by-product (Sch. 2). The β-configuration species
on 8 was confirmed by the unique NMR signal of H-1ꢁꢁ, which shows the doublet
1
peak at δ 5.71 with a J value of approximately 7.8 Hz. The H NMR chemical
shifts of specific protons are consistent with reported literature.[17,18] Moreover,
the cross-peak from H-1ꢁꢁ (δ 5.71) to C-3 (δ 133.50) in the HMBC spectrum con-
firmed that the glucosylation took place at the 3-O-position. Compound 8 was
treated with 5% sodium methoxide in methanol to remove all the acetyl groups
and afforded compound 9 in a 94% yield. To further prove the identities of 8
and 9, debenzylation of 9 was next performed by 10% Pd/C-catalyzed hydro-
genation to produce another nature flavonol glycoside, isoquercitrin, in a 98%
yield. The analytical data for the synthesized isoquercitrin, including FT-IR,
1
optical rotation, H and 13C NMR, DEPT, and ESI-MS, were compared and
proven to be identical with the authentic, naturally derived sample.[19]
With 9 in hand, the synthesis of 1 was carried out. We first consid-
ered selective acylation on the 6ꢁꢁ-OH in 9 with the coumaric acid deriva-
tive 3 under the 1-ethyl-3-(3-dimethylaminopropyl) carbodimide hydrochloride
(EDCI•HCl) and 4-dimethylaminopyridine (DMAP) condition, but the result-
ing product was complicated, despite the reaction being carried out at low tem-
peratures. Therefore, a more reasonable and efficient synthetic approach was
developed. As shown in Scheme 3, the 6ꢁꢁ-OH in 9 was protected with the tert-
butyldiphenylsilyl (TBDPS) group by the reaction of 9 with TBDPS-Cl and
imidazole, while the OH groups at other positions were protected with ben-
zyl groups yielding compound 10 in 82% in two steps. Then, selective removal
of the TBDPS group in 10 with tetra-n-butylammonium fluoride (TBAF) pro-
duced compound 2, which was then condensed with 3 using EDCI•HCl as the
condensation reagent and DMAP as the catalyst to afford compound 11 in a
92% yield. The identity of 11 was confirmed by FT-IR, 1H and 13C NMR, DEPT,
and ESI-MS. Finally, the benzyl groups in 11 needed to be removed to form
1. It was reported that selective removal of the benzyl group without affect-
ing the double bond of coumaric acid can be achieved via catalytic transfer

X. Ren et al.
124
n
B
O
n
B
O
n
B
O
n
B
O
n
B
O
O
O
n
B
O
O
O
a
O
b
c
O
9
n
B
O
n
B
O
O
O
H
O
n
B
O
TBDP
SO
n
B
O
n
B
O
n
B
O
n
B
O
n
B
O
2
10
n
B
H
O
O
n
B
O
H
O
n
B
H
O
O
O
O
O
d
O
O
+
1
n
B
O
H
O
O
O
O
O
O
O
O
n
B
O
H
O
n
B
H
O
O
n
n
B
H
O
O
B
H
O
O
11
12
Scheme 3: Reagents and conditions: (a) (i) TBDPSCl, imidazole, DMF, rt, 17 h; (ii) NaH, BnBr,
DMF, rt, 24 h, 82%; (b) TBAF, THF, rt, 34 h, 83%; (c) 3, DMAP, EDCI, CH2Cl2, rt, 10 h, 92%; (d) 5%
Pd-C, 1,4-cyclohexadiene, DMF/EtOH (1:1), rt, 20 h, 40%.
hydrogenation using 1,4-cyclohexadiene/5% Pd-C at 40◦C.[12] However, this
reaction condition only afforded 1 from 11 in a 27% yield after purification
by flash column chromatography (CHCl3/MeOH/H2O, 7:3:1, v/v/v), alone with
the double bond reduced by-product, 3-O-[6ꢁꢁ-O-(p-hydroxyphenylpropionyl)-β-
1
D-glucopyranosyl] quercetin (12),[20] whose H NMR spectrum clearly shows
the disappearance of the double bond signals at δ 6.10 and 7.41 with a J value
of 16 Hz shown in the 1H NMR spectrum of 1. To avoid reduction of the double
bond on the p-coumaroyl group, reactions at low temperature were explored.
After several attempts, we found that the condition of reaction at rt for 20 h
was optimal for debenzylation. Using this condition we can get 1 (40%) con-
taining only trace amounts of 12. Additionally, a longer reaction time cannot
improve the yield of 1, but that of 12 was increased. The analytical data of the
1
synthesized 1, including FT-IR, optical rotation, H and 13C NMR, DEPT, and
ESI-MS, were compared and shown to be identical with those of the authentic,
naturally derived sample.[7]
In
summary,
quercetin
3-O-[6ꢁꢁ-O-(trans-p-coumaroyl)]-β-D-gluco
pyranoside (1), an acylated quercetin glycoside with interesting biological
activities, has been readily synthesized from commercially available quercetin.
The important intermediate, 4ꢁ,7-di-O-benzylquercetin 4, was prepared in
a high yield under the improved conditions. The successful method for the

Quercetin 3-O-[6ꢁꢁ-O-(trans-p-Coumaroyl)]-β-D-Glucopyranoside
125
selective glycosylation of the quercetin 3-OH and the final debenzylation step
in the presence of the double bond to form 1 are worth further exploration.
In a word, the present work paves the way to easily access various quercetin
3-O-glycosides and their 6ꢁꢁ-O-coumarates analogs.
EXPERIMENTAL
NMR spectra were recorded on a 400, 500, or 700 MHz instrument with chem-
ical shifts reported in ppm (δ) in reference to Me4Si (if not otherwise specified).
Coupling constants (J) are reported in hertz (Hz). Optical rotations were de-
termined using a Horiba SEPA-300 digital polarimeter (l–5 cm). IR spectra
were performed with a Shimadzu FT-IR-8100 spectrometer. Electrospray ion-
ization mass spectra (ESI-MS) were obtained with a Finnigan LCQ-MS, Agi-
lent 1100C, or Water HPLC-MS instrument. Thin layer chromatography (TLC)
was performed on silica gel GF254 plates with detection by phosphomolybdic
acid in EtOH or 2% H2SO4 in EtOH. Commercial anhydrous solvents and other
reagents were used without further purification.
Quercetin penta-acetate (6)
In a dry round-bottom flask equipped with a reflux condenser, the mixture
of quercetin (5.0 g, 3.31 mmol), acetic anhydride (50 mL), and pyridine (65 mL)
was refluxed for 4 h. The solution was concentrated, and the residue was
washed with water (50 mL × 3) and methanol (50 mL × 3) to give 6 as an off-
white solid (8.26 g, 97.5%). mp: 194–195◦C; Rf = 0.73 (EtOAc/hexane/MeOH,
1:1:0.02); IR (nujol,-cm): 2943, 2852, 2353, 1772, 1653, 1635, 1558, 1541, 1506,
1456, 1375, 1207, 1184; 1H NMR (CDCl3, 400 MHz): δ 2.33 (s, 6H), 2.34 (s, 3H),
2.35 (s, 3H), 2.44 (s, 3H), 6.88 (d, J = 2.0 Hz, 1H, H-6), 7.34 (d, J = 2.0 Hz,
1H, H-8), 7.35 (d, J = 8.8 Hz, 1H, H-5ꢁ), 7.69 (d, J = 2.0 Hz, 1H, H-2ꢁ), 7.72
(dd, J = 14.0, 2.2 Hz, 1H, H-6ꢁ); 13C NMR (CDCl3, 100 MHz): δ 20.5, 20.7, 21.0,
21.2, 109.0, 113.9, 114.8, 123.8, 123.9, 126.4, 127.8, 134.1, 142.2, 144.4, 150.4,
153.8, 154.3, 156.9, 167.7, 167.8, 167.82, 167.9, 169.3, 170.0; ESI-MS (m/z):
Calcd. 512.1; found: 513.3 (M + H)+, 535.3 (M + Na)+.
4ꢀ,7-Di-O-benzyl Quercetin Triacetate (7)
The mixture of 6 (8.0 g, 15.63 mmol), K2CO3 (16.5 g, 118.73 mmol), KI
(0.66 g, 3.94 mmol), and PhCH2Cl (1.8 ml, 15.63 mmol) in dry acetone (100 mL)
was stirred at 35◦C to 40◦C for 24 h and then another batch of PhCH2Cl
(1.1 mL, 9.378 mmol) was added. After 24 h, PhCH2Cl (0.72 mL, 6.252 mmol)
was added again. After a total of 72 h, the solvent was removed under vac-
uum, and the residue was extracted with CH2Cl2. The combined CH2Cl2 ex-
tracts were washed with brine (50 mL) and water (50 mL × 2), dried over

X. Ren et al.
126
anhydrous Na2SO4, and concentrated. The residue was recrystallized from
methanol to give 7 as a white solid (6.63 g, 70%). mp: 154–155◦C; Rf = 0.65
(EtOAc/hexane/MeOH, 1:1:0.01); IR (nujol,-cm): 2922, 2858, 1716, 1653, 1606,
1
1558, 1456, 1377, 1251, 1170, 1112, 1012; H NMR (CDCl3, 400 MHz): δ 2.32
(s, 6H), 2.42 (s, 3H), 5.15 (s, 2H), 5.17 (s, 2H), 6.70 (d, J = 2.4 Hz, 1H, H-6),
6.90 (d, J = 2.8 Hz, 1H, H-8), 7.08 (d, J = 8.8 Hz, 1H, H-5ꢁ), 7.34–7.43 (m,
10H), 7.56 (d, J = 2.4 Hz, 1H, H-2ꢁ), 7.67 (dd, J = 14.0, 2.2 Hz, 1H, H-6ꢁ);
13C NMR (CDCl3, 100 MHz): δ 20.57, 20.61, 21.1, 21.2, 70.7, 70.8, 99.8, 109.2,
111.2, 113.6, 122.5, 122.9, 127.1, 127.2, 127.5, 128.0, 128.1, 128.2, 128.7, 128.8,
133.3, 140.1, 150.7, 152.6, 153.8, 158.0, 162.8, 168.0, 168.7, 169.6, 170.1. ESI-
MS (m/z): Calcd. 608.1; found: 608.9 (M + H)+, 631.0 (M + Na)+.
4ꢀ,7-Di-O-benzyl Quercetin (4)
To a stirred solution of 7 (5.0 g, 8.55 mmol) in acetone (150 ml) at 0◦C
under N2 atmosphere, a solution of sodium hydroxide (2.5 M, 50 mL) was
added dropwise to maintain the temperature below 0◦C. After addition, the
mixture was stirred at 0◦C for 3 h and followed by the dropwise addition of
the diluted hydrochloric acid. The resultant mixture was stirred at 0◦C for
another 30 min; the solid was filtered off, washed with NaHCO3 aqueous so-
lution and water, and dried to give a yellow solid (3.9 g), which was further
purified by flash column chromatography (EtOAc/hexane, 8:1) to afford 4 as a
bright yellow solid (3.2 g, 82%). mp: 182◦C; Rf = 0.55 (EtOAc/hexane, 1:1); IR
(nujol,-cm): 3400–3300, 2924, 2856, 2370, 1716, 1699, 1653, 1558, 1541, 1506,
1
1462, 1377, 1159; H NMR (DMSO-d6, 500 MHz): δ 5.21 (s, 2H, CH2Ph), 5.23
(s, 2H, CH2Ph), 6.44 (d, J = 2.1 Hz, 1H, H-6), 6.81 (d, J = 2.4 Hz, 1H, H-8),
7.16 (d, J = 8.8 Hz, 1H, H-5ꢁ), 7.30–7.51 (m,10H), 7.63 (dd, J = 8.7, 2.4 Hz,
1H, H-6ꢁ), 7.78 (d, J = 2.5 Hz, 1H, H-2ꢁ), 9.41 (s, 1H, 3ꢁ-OH), 9.60 (s, 1H, 3-
OH), 12.4 (s, 1H, 5-OH); 13C NMR (DMSO-d6, 125 MHz): δ 69.9, 70.1, 93.0,
98.2, 104.4, 113.8, 115.3, 119.8, 123.8, 127.9, 128.0, 128.3, 128.4, 128.5, 128.6,
128.7, 136.4, 136.7, 137.1, 146.8, 146.9, 148.5, 156.2, 160.6, 164.2, 176.3; ESI-
MS (m/z): Calcd. 482.1; found: 480.8 (M-H)−, 482.9 (M+H)+.
4ꢀ,7-Di-O-benzyl-3-O-(β-D-tetra-acetylglucopyranosyl)
Quercetin (8)
A mixture of 4 (0.39 g, 0.85 mmol), 5 (0.42 g, 1.02 mmol), and K2CO3 (0.14 g,
1.02 mmol) in DMF (12 mL) was stirred under argon at rt for 32 h. The reac-
tion mixture was poured into H2O and extracted with EtOAc. The combined
organic layer was washed with brine and H2O, dried over anhydrous MgSO4,
and concentrated. The residue was purified by flash column chromatography
(EtOAc/hexane, 8:1) to provide 8 as a yellow solid (0.39 g, 56%). mp: 95–97◦C;
Rf = 0.40 (EtOAc/hexane, 2:3); [α]23.7 −6.70 (c 1.0, CHCl3); IR (nujol,-cm):
D

Quercetin 3-O-[6ꢁꢁ-O-(trans-p-Coumaroyl)]-β-D-Glucopyranoside
127
3400–3300, 2914, 2852, 2343, 1749, 1716, 1653, 1600, 1558, 1506, 1458, 1377,
1
1217, 1165, 1035; H NMR (DMSO-d6, 700 MHz): δ 1.97 (s, 3H), 1.98 (s, 3H),
1.99 (s, 3H), 2.09 (s, 3H), 3.89–3.98 (m, 3H, H-5ꢁꢁ, H-6ꢁꢁ), 5.04 (m, 1H, H-4ꢁꢁ), 5.17
(m, 1H, H-5ꢁꢁ), 5.22 (s, 2H), 5.23 (s, 2H), 5.37 (m, 1H, H-3ꢁꢁ), 5.71 (d, J = 7.8 Hz,
1H, H-1ꢁꢁ), 6.47 (d, J = 2.2 Hz, 1H, H-6), 6.83 (d, J = 2.2 Hz, 1H, H-8), 7.13
(d, J = 8.8 Hz, 1H, H-5ꢁ), 7.34–7.51 (m, 10H), 7.56 (dd, J = 9.0, 2.2 Hz, 1H,
H-6ꢁ), 7.69 (d, J = 2.2 Hz, 1H, H-2ꢁ), 9.50 (s, 1H, 3ꢁ-OH), 12.49 (s, 1H, 5-OH);
13C NMR (DMSO-d6, 175 MHz): δ 20.4, 20.5, 20.6, 20.9, 61.2, 67.9, 69.9, 70.2,
71.1, 71.6, 72.1, 93.5, 98.8, 105.3, 113.2, 116.7, 121.0, 122.4, 127.5, 127.8, 127.9,
128.0, 128.7, 128.9, 133.5, 136.2, 137.4, 146.5, 149.6, 156.4, 157.3, 161.1, 164.5,
169.3, 169.6, 169.8, 170.4, 177.1. ESI-MS (m/z): Calcd. 812.23; found: 810.7
(M-H)−.
4ꢀ,7-Di-O-benzyl-3-O-(β-D-glucopyranosyl) Quercetin (9)
To a solution of 8 (0.27 g, 0.33 mmol) in MeOH (44 mL), NaOMe (22 mg,
0.36 mmol) was added. The resultant solution was stirred at rt for 9.5 h
and then neutralized with Dowex 50 (H+) ion-exchange resin. The resin
was filtered and washed with MeOH; the filtrate and washings were com-
bined and concentrated to afford 9 (0.2 g, 94%). mp: 145–147◦C; Rf
=
0.55 (EtOAc/hexane/MeOH, 2:2:1); [α]24.2 −0.73 (c 0.15, acetone); IR
D
(nujol,-cm): 3400–3300, 2924, 2852, 2345, 2328, 1716, 1697, 1635, 1541,
1508, 1458, 1375, 1338; 1H NMR (CD3COCD3, 700 MHz): δ 3.19–3.58
(m, 7H), 4.11 (d, J = 4.2 Hz, 1H), 4.21 (d, J = 3.4 Hz, 1H), 4.87
(d, J = 2.8 Hz, 1H), 5.15 (s, 2H), 5.16 (s, 2H), 5.22 (d, J = 7.6 Hz,
1H, H-1ꢁꢁ), 6.33 (d, J = 2.2 Hz, 1H, H-6), 6.69 (d, J = 2.2 Hz,
1H, H-8), 7.06 (d, J = 8.6 Hz, 1H, H-5ꢁ), 7.23–7.40 (m, 10H), 7.60 (dd, J =
8.5, 2.2 Hz, 1H, H-6ꢁ), 7.79 (d, J = 2.2 Hz, 1H, H-2ꢁ), 8.29 (s, 1H, 3ꢁ-OH), 12.26
(s, 1H, 5-OH); 13C NMR (CD3COCD3, 175 MHz): δ 62.8, 71.2, 75.5, 77.9, 78.1,
93.9, 99.5, 104.6, 106.4, 113.4, 117.6, 122.5, 124.0, 128.5, 128.7, 128.8, 128.9,
129.2, 129.4, 136.0, 137.2, 137.7, 147.1, 150.0, 157.9, 158.6, 162.6, 165.9, 179.3;
ESI-MS (m/z): Calcd. 644.19; found: 642.8 (M-H)−, 644.9 (M+H)+.
Isoquercetin
The mixture of 9 (0.1 g, 0.155 mmol) and 10% Pd–C (0.02 g) in EtOAc
(2 mL) and EtOH (2 mL) was stirred under an atmosphere of H2 at ambient
temperature overnight. After removing the catalyst, the filtrate was concen-
trated to give isoquercetin as a yellow solid (73 mg, quant.). mp: 231–233◦C;
Rf = 0.40 (EtOAc/hexane/MeOH, 1:1:1); [α]24.0D −2.78 (c 0.9, MeOH); IR (nujol,
-cm): 3400–3300, 2924, 2850, 2345, 2360, 1658, 1602, 1462, 1377, 1303, 1201;
1H NMR (CD3OD, 400 MHz): δ 3.30–3.60 (m, 6H, H2ꢁꢁ–H6ꢁꢁ), 5.15 (d, J = 7.6 Hz,
1H, H-2ꢁꢁ), 6.10 (d, J = 1.6 Hz, 1H, H-6), 6.30 (d, J = 2.0 Hz, 1H, H-8), 6.71

X. Ren et al.
128
(d, J = 8.4 Hz, 1H, H-5ꢁ), 7.49 (dd, J = 8.4, 2.0 Hz, 1H, H-6ꢁ), 7.61 (d, J =
2.0 Hz, 1H, H-2ꢁ); 13C NMR(CD3OD, 100 MHz,): δ 62.6, 71.2, 75.7, 78.1, 78.4,
94.7, 99.9, 104.3, 105.7, 117.6, 120.0, 123.1, 123.2, 135.6, 145.9, 149.8, 158.5,
159.0, 163.0,165.9, 179.5; ESI-MS (m/z): Calcd. 464.1; found: 463.2 (M-H)−.
3ꢀ,4ꢀ,5,7-Tetra-O-benzyl-3-O-(2ꢀꢀ,3ꢀꢀ,4ꢀꢀ-O-benzyl-6ꢀꢀ-O-tert-butyl
diphenylsilyl-β-D-glucopyranosyl) Quercetin (10)
To a stirred solution of 9 (70 mg, 0.12 mmol) and imidazole (66 mg, 0.24
mmol) in DMF (1 mL) at 0◦C, a solution of TBDPSCl (17 mg, 0.24 mmol) in
DMF (1 mL) was added dropwise. After stirring at rt for 17 h, the reaction
mixture was diluted with H2O (12 mL) and extracted with EtOAc (20 mL × 3).
The combined organic layer was washed with brine and H2O, dried over an-
hydrous Na2SO4, and concentrated under vacuum to produce a yellow oil (100
mg), which was dissolved in DMF (2.5 mL) and cooled to 0◦C. Next, NaH (78
mg, 1.9 mmol, 60% oil coated) was added portion-wise during 15 min followed
by dropwise addition of BnBr (1 mL). The mixture was stirred at rt for 24 h and
then extracted with EtOAc (20 mL × 2). The combined organic extracts were
washed with brine and water, dried over anhydrous Na2SO4, and concentrated.
The residue was purified by flash column chromatography (EtOAc/hexane, 1:8)
to produce 10 as a yellow oil (101 mg, 82% yield for two steps). Rf = 0.50
(EtOAc/hexane, 1:2); [α]24.0 −20 (c 1.5, CHCl3); IR (nujol,-cm): 2935, 2837,
D
1
1716, 1614, 1585, 1514, 1456, 1301, 1247, 1076, 1035, 821; H NMR (CDCl3,
400 MHz): δ 0.8 (s, 9H), 3.77 (m, 2H), 3.81 (m, 2H), 4.58 (m, 1H), 4.82–4.85 (m,
4H), 5.02–5.08 (m, 3H), 5.11 (s, 2H), 5.12 (s, 2H), 5.17 (s, 2H), 5.26 (s, 2H), 6.16
(d, J = 8.0 Hz, 1H, H-1ꢁꢁ), 6.46 (d, J = 1.6 Hz, 1H, H-6), 6.58 (d, J = 2.0 Hz,
1H, H-8), 6.90 (d, J = 8.8 Hz, 1H, H-5ꢁ), 7.08–7.59 (m, 45H), 7.71 (dd, J = 8.8,
2.0 Hz, 1H, H-6ꢁ), 7.89 (d, J = 2.0 Hz, 1H, H-2ꢁ); 13C NMR (CDCl3, 100 MHz,): δ
26.5, 62.0, 65.3, 70.5, 70.78, 70.82, 71.5, 73.9, 74.9, 75.5, 75.8, 77.6, 82.6, 84.7,
93.8, 99.1, 100.6, 110.0, 113.6, 115.1, 123.4, 123.9, 126.6, 126.9, 127.0, 127.1,
127.2, 127.3, 127.4, 127.5, 127.6, 127.64, 127.69, 127.7, 127.8, 127.9, 128.0,
128.3, 128.4, 128.52, 128.54, 128.6, 128.66, 128.7, 128.8, 129.3, 129.4, 129.6,
132.7, 133.1, 135.5, 135.6, 135.7, 136.0, 136.3, 136.8, 137.1, 138.1, 138.6, 138.7,
148.2, 150.6, 153.1, 158.6, 159.9, 162.7, 173.1; ESI-MS (m/z): Calcd. 1332.54;
found: 1331.4 (M-H)−, 1333.5 (M+H)+.
3ꢀ,4ꢀ,5,7-Tetra-O-benzyl-3-O-(2ꢀꢀ,3ꢀꢀ,4ꢀꢀ-O-benzyl-β-
D-glucopyranosyl) Quercetin (2)
A solution of 10 (80 mg, 0.06 mmol) and TBAF•THF (1M, 0.4 mL) in
THF (1 mL) was stirred under an N2 atmosphere at rt for 32 h. The re-
action mixture was diluted with H2O (20 mL) and extracted with EtOAc
(20 mL × 3). The combined organic layer was dried over anhydrous Na2SO4

Quercetin 3-O-[6ꢀꢀ-O-(trans-p-Coumaroyl)]-β-D-Glucopyranoside
129
and concentrated under vacuum. The residue was purified by flash column
chromatography (EtOAc/hexane, 1:10) to yield 2 as a yellow oil (54 mg, 83%).
Rf = 0.30 (EtOAc/hexane, 1:3); [α]25.5 −6.50 (c 0.35, CHCl3); IR (nujol,-cm):
D
1
3400–3300, 2910, 2852, 2360, 2337, 1716, 1653, 1558, 1456, 1377; H NMR
(CDCl3, 400 MHz): δ 3.44–4.69 (m, 6H, H2ꢁꢁ −H6ꢁꢁ), 4.50 (m, 2H), 4.69 (d, J =
11 Hz, 1H), 4.72 (m, 2H), 4.89 (d, J = 11 Hz, 1H), 5.02 (s, 2H), 5.09 (s, 2H),
5.13 (s, 2H), 5.19 (s, 2H), 5.46 (d, J = 7.2 Hz, 1H, H-1ꢁꢁ), 6.40 (d, J = 2.4
Hz, 1H, H-6), 6.58 (d, J = 2.0 Hz, 1H, H-8), 6.87 (d, J = 8.8 Hz, 1H, H-5ꢁ),
7.13–7.40 (m, 33H), 7.52–7.54 (m, 2H), 7.57 (dd, J = 8.8, 2.8 Hz, 1H, H-6ꢁ),
7.66 (d, J = 2.0 Hz, 1H, H-2ꢁ); 13C NMR (CDCl3, 100 MHz): δ 61.5, 70.5, 70.8,
70.9, 71.6, 73.9, 74.5, 74.9, 75.4, 77.3, 82.1, 84.1, 93.9, 98.2, 100.9, 110.0, 113.8,
115.8, 122.7, 124.1, 126.6, 127.1, 127.2, 127.3, 127.4, 127.5, 127.6, 127.7, 127.8,
127.88, 127.9, 128.1, 128.2, 128.3, 128.4, 128.53, 128.57, 128.6, 128.74, 128.75,
134.8, 135.6, 136.63, 136.67, 137.0, 138.0, 138.6, 138.7, 148.2, 150.8, 154.1,
158.7, 159.8, 162.8, 172.9; ESI-MS (m/z): Calcd. 1094.42; found: 1093.4 (M-H)−,
1094.8 (M+H)+.
3ꢀ,4ꢀ,5,7-Tetra-O-benzyl-3-O-[2ꢀꢀ,3ꢀꢀ,4ꢀꢀ-O-benzyl-6ꢀꢀ-O-(trans-
p-benzyloxycoumaroyl)-β-D-glucopyranosyl] Quercetin (11)
To a solution of 2 (40.0 mg, 0.037 mmol), 3 (11.3 mg, 0.045 mmol),
and 4-dimethylaminopyridine (4-DMAP, 6.8 mg, 0.056 mmol) in dry CH2Cl2
(1 mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI,
14.2 mg, 0.074 mmol) was added and then the mixture was stirred at rt for 10
h. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with brine
and water, dried over anhydrous Na2SO4, and concentrated. The residue was
purified by flash column chromatography (EtOAc/hexane, 1:15) to afford 11 as
a yellow oil (43 mg, 92%). mp: 152–154◦C; Rf = 0.65 (EtOAc/hexane,1:3); [α]23.8
−74 (c 0.6, CHCl3); IR (nujol,-cm): 3400–3300, 2926, 2852, 2355, 2310, 1716,
D
1653, 1558, 1541, 1458, 1375; 1H NMR (CDCl3, 500 MHz): δ 3.48–3.74 (m, 4H),
4.53 (d, J = 11 Hz, 1H), 4.78 (d, J = 11 Hz, 1H), 4.82 (d, J = 11 Hz, 2H), 4.94
(s, 2H), 5.02 (s, 4H), 5.05 (s, 2H), 5.08–5.18 (m, 4H), 5.25 (s, 2H), 5.84 (d, J =
7.8 Hz, 1H, H-1ꢁꢁ), 6.06 (d, J = 16 Hz, 1H, H-2ꢁꢁꢁ), 6.43 (d, J = 2.3 Hz, 1H,
H-6), 6.47 (d, J = 2.3 Hz, 1H, H-8), 6.80 (d, J = 8.6 Hz, 2H, H-6ꢁꢁꢁ and 8ꢁꢁꢁ),
6.91 (d, J = 8.6 Hz, 1H, H-5ꢁ), 7.20–7.47 (m, 40H), 7.59–7.63 (m, 3H, H-5ꢁꢁꢁ,
H-9ꢁꢁꢁ, H-3ꢁꢁꢁ), 7.64 (dd, J = 8.9, 2.8 Hz, 1H, H-6ꢁ), 7.84 (d, J = 2.3 Hz, 1H, H-
2ꢁ); 13C NMR (CDCl3, 125 MHz): δ 62.3, 69.9, 70.4, 70.6, 70.8, 71.4, 72.5, 73.9,
74.9, 75.6, 82.1, 84.4, 87.8, 93.8, 98.8, 101.1, 109.9, 113.3, 114.9, 115.1, 116.3,
122.7, 124.0, 126.6, 127.0, 127.1, 127.2, 127.3, 127.4, 127.5, 127.6, 127.69,
127.7, 127.8, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.7, 129.5, 129.6,
129.8, 130.1, 132.2, 134.7, 135.2, 135.9, 136.3, 136.4, 136.8, 137.1, 137.7, 138.5,
138.6, 144.4, 148.0, 150.6, 154.6, 158.7, 159.7, 160.4, 162.7, 166.6, 173.0. ESI-
MS (m/z): Calcd. 1330.51; found: 1331.5 (M + H)+.

X. Ren et al.
130
Quercetin 3-O-[6ꢀꢀ-O-(trans-p-coumaroyl)-β-D-
glucopyranoside (1)
A mixture of 11 (47 mg, 0.035 mmol), 5% Pd-C (10 mg), and 1,4-
cyclohexadiene (66 µL, 0.707 mmol) in DMF/EtOH (1:1, v/v, 2.0 mL) was stirred
at rt for 20 h. The catalyst was filtered off, and the filtrate was concentrated
in vacuo to give a yellow oil, which was purified by flash column chromatogra-
phy (CHCl3/MeOH/H2O, 7:3:1) to yield 1 as a pale yellow waxy solid (8.3 mg,
40%). Rf = 0.45 (EtOAc/hexane/MeOH, 1:1:1); [α]24.5 +10 (c 0.1, MeOH); IR
D
(nujol,-cm): 3400–3300, 2926, 2854, 2359, 1716, 1653, 1558, 1458, 1377, 1259,
1
1089, 1028, 802; H NMR (CD3OD, 700 MHz): δ 3.42–3.51 (m, ꢁ4ꢁ H), 4.19 (dd,
ꢁꢁ
J = 11.5, 6.8 Hz, 1H, H-62 ), 4.30 (dd, J = 11.9, 2.2 Hz, 1H, H-61 ), 5.26 (d, J =
7.6 Hz, 1H, H-1ꢁꢁ), 6.10 (d, J = 16 Hz, 1H, H-2ꢁꢁꢁ), 6.13 (d, J = 2.0 Hz, 1H,
H-6), 6.30 (d, J = 2.4 Hz, 1H, H-8), 6.80 (d, J = 8.8 Hz, 2H, H-6ꢁꢁꢁ and 8ꢁꢁꢁ),
6.81 (d, J = 8.4 Hz, 1H, H-5ꢁ), 7.32 (d, J = 8.4 Hz, 2H, H-5ꢁꢁꢁ and H-9ꢁꢁꢁ), 7.41
(d, J = 16 Hz, 1H, H-3ꢁꢁꢁ), 7.58 (dd, J = 8.4, 2.4 Hz, 1H, H-6ꢁ), 7.59 (d, J =
2.4 Hz, 1H, H-2ꢁ); 13C NMR (CD3OD, 175 MHz): δ 64.3, 71.8, 75.7, 75.9, 78.1,
94.7, 99.9, 103.8, 105.6, 114.8, 114.9, 115.9, 116.7, 117.3, 123.1, 123.3, 127.2,
131.2, 135.2, 145.9, 146.5, 149.8, 158.4, 159.2, 159.7, 163.0, 165.9, 168.9, 179.5.
ESI-MS (m/z): Calcd. 610.13; found: 608.8 (M-H)−, 633.0 (M+Na)+.
ACKNOWLEDGEMENTS
We thank Kinki University in Japan and professor Lu Sun of Shenyang
Pharmaceutical University in China for help with the HRMS and NMR
measurements.
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20. Spectroscopic data for 12: a pale yellow waxy solid. Rf = 0.60 (CHCl3/MeOH, 6:1);
1
[α]23.0 +7 (c 0.1, MeOH); H NMR (CD3OD, 300 MHz): δ 2.35 (t, J = 7.3, 6.8 Hz, 1H,
D
H-2ꢁꢁꢁ), 2.60 (t, J = 7.0, 6.6 Hz, 1H, H-3ꢁꢁꢁ), 3.36–3.66 (m, 4H), 4.05(m, 1H), 4.23(m, 1H),
5.24 (d, J = 7.5 Hz, 1H, H-1ꢁꢁ), 6.19 (d, J = 2.1 Hz, 1H), 6.36 (d, J = 1.8 Hz, 1H), 6.65 (d,
J = 8.4 Hz, 2H), 6.87 (m,3H), 7.60 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 8.4, 2.2 Hz, 1H).
ESI-MS (m/z): Cald. 612.13, found 611.0 (M-H) −.