Regiospecific synthesis of three quercetin O-β-glucosides of N-acetylglucosamine

Article abstract of DOI:10.3184/174751918X15232706115112

The regiospecific synthesis of three quercetin O-β-glucosides of N-acetylglucosamine has been achieved in good yield. Selective di- and tri-O-benzylation of quercetin followed by O-glycosylation with 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-d-glucopyranosyl chloride under phase-transfer catalysis conditions yielded, after deacetylation and debenzylation, 3-, 3′- and 4′-glycosylated quercetin.

Full text of DOI:10.3184/174751918X15232706115112

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 APRIL, 189–193
RESEARCH PAPER 189
Regiospecific synthesis of three quercetin O-β-glucosides of
N-acetylglucosamine
Zhiling Cao*, Jing Chen, Dandan Zhu, Zongnan Yang, Wenqi Teng, Gaofeng Liu, Bing Liu and
Chuanzhou Tao
Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Institute of Marine Resources, Huaihai Institute of Technology,
Lianyungang 222005, P.R. China
The regiospecific synthesis of three quercetin O-β-glucosides of N-acetylglucosamine has been achieved in good yield. Selective di-
and tri-O-benzylation of quercetin followed by O-glycosylation with 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-d-glucopyranosyl chloride
under phase-transfer catalysis conditions yielded, after deacetylation and debenzylation, 3-, 3′- and 4′-glycosylated quercetin.
Keywords: glucosamine, quercetin, glycosylation, regiospecific synthesis, N-acetylglucosamine, phase-transfer catalysis
Many natural products that contain sugar residues have
significant biological activity. Flavonoids are polyphenolic
compounds that are widely distributed in plants. Quercetin
(Fig. 1) and its glycosides are an important class of antioxidants
and dietary flavonoids and some are known to be common
components of traditional medicines.1,2 Furthermore, some
have exhibited pharmacological effects, such as anti-cancer,3
anti-inflammatory,4 and anti-ageing5 activity, in vivo and in
vitro. Quercetin can be linked to various sugars, including
glucose, galactose, arabinose or rhamnose.2 Both the structure
and linking position of the sugar moiety attached to quercetin
dramatically affect the biological activity.6–8
an O-glycosylation procedure. Obviously, the selective protection
of four of the five hydroxyl groups of quercetin is crucial for the
regiospecific O-glycosylation of one of them. The results showed
that quercetin phenolic functions have a preferential reactivity in the
order of 7 > 3 ≈ 4′ > 3′ > 5, which is in agreement with Rolando’s
tests.17 In previous work from this laboratory, the C3 isomer (1) was
synthesised by the direct glycosylation of 7,4′-di-O-benzylquercetin
(4) (Scheme 1).18 However, we found that it was difficult to avoid the
concurrent formation of the 3,3′-di-O-glycosylated product. It was
therefore clear that for the efficient synthesis of all three isomers
(1–3) (Fig. 1), all OH groups except the one to be glycosylated
should be protected to give the selectivity required.
Recently, some natural and unnatural flavonoid amino sugar
glycosides have been reported. Fenical and co-workers isolated
a novel 3-amino-ribopyranose flavonoid from Streptomyces
sp. that showed antibacterial activity against Bacillus subtilis9
and Ahn and co-workers reported the biological synthesis
of quercetin 3-O-N-acetylglucosamine glycoside (1) using
engineered Escherichia coli.10,11 Glucosamine and other amino
sugars are common structural units found in various biological
O-glycosides.12,13 Most glucosamine glycosides are N-acetylated
and characterised by β-glycosidic linkages.14 Quercetin
glycosides of glucosamine have interesting potential biological
effects. However, the efficient regioselective and stereoselective
synthesis of flavonoid glycosides remains challenging.15,16 What
is more, the production of them via biological synthesis has
been limited by the diversity of sugar type and position of sugar
links. This prompted us to develop a synthetic method for the
preparation of unusual flavonoid glycosides of N-acetyl amino
sugars. Here, we report the synthesis of three quercetin O-β-
glycosides of N-acetylglucosamine (1–3) (Fig. 1).
OBn
H
'
O
'
3
OBn
H
O
4
BnO
O
O
H
O
O
7
c
3
H
O
O rutinose
H
O
H
O
O
rutin
6
a
H
O
H
O
OBn
OBn
BnO
O
BnO
O
b
OBn
H
O
H
O
O
H
O
O
4
5
Scheme 1 Synthesis of tri- (5 and 6), and a di-benzylated quercetin (4)
from rutin. Path a: (i) BnBr (2 equiv.), K2CO3 (1.5 equiv.), DMF, 60 °C, 2
h; (ii) HCl/EtOH, reflux, 2 h. Path b: BnCl (1 equiv.), py, CH Cl2, r.t., 12
h, 85%. Path c: (i) BnBr (8 equiv.), K2CO3, DMF, r.t., 16 h; (ii)2HCl/EtOH,
reflux, 2 h, 85%.
Results and discussion
In this study, we aimed to introduce an N-acetylglucosamine
moiety into quercetin at its C3, C3′ and C4′ hydroxyl groups by
H
O
O
H
O
H
O
H
O
H
O
H
O
O
H
O
O
NH
H
O
H
O
O
H
O
H
O
H
O
O
HN
H
O
O
H
O
O
O
H
O
O
H
O
H
O
O
O
O
O
H
O
O
H
O
H
O
H
O
H
O
H
O
O
HN
H
O
H
O
O
H
O
O
1
Quercetin
2
3
Fig. 1 Structure of quercetin and its 3- (1), 3′- (2) and 4′-N-acetylglucosamine glycosides (3).
* Correspondent. E-mail: zhilingcao@outlok.com

190 JOURNAL OF CHEMICAL RESEARCH 2018
Accordingly, the selective glycosylation at the 3′-OH
group required a 3,7,4′-O-protected quercetin and the desired
tribenzoylated quercetin (5) was synthesised from the
3-O-glycosylated derivative of quercetin, rutin via the key
intermediate 4 (Scheme 1). (There was no need to protect the
5-hydroxy group as hydrogen bonding with the adjacent C=O
group rendered it inactive towards alkylation, except under
forcing conditions.) In the first step (path a), dibenzylation
of rutin was well controlled by the slow addition of 2 equiv.
of benzyl bromide in DMF and subsequent hydrolysis of
the rutinoside residue with HCl gave a good yield of the
dibenzylated compound (4). Further selective benzylation of
the 3-OH of 4 with 1 equiv. of benzyl chloride (path b) gave the
tribenzylated compound (5) required as glycosyl acceptor.
7,3′,4′-Tri-O-benzylquercetin (6) was the glycosyl acceptor
required for the synthesis of the quercetin 3-O-glycoside (1)
and we prepared it via benzylation of rutin with an increase (>3
equiv.) in the amount of benzyl bromide, as described by Zhao
and co-workers,19 followed by the hydrolysis of the C3 rutinose
residue (Scheme 1, path c).
bromide (TBAB) as catalysts) and found to be practical as well
as highly regioselective. In the aqueous two-phase reaction
system, degradation of the glycosyl donor and glycosylation
occurred at the same time. After optimisation of the stirring speed
and reaction temperature, quercetin amino glucosides 11, 12 and
13 were finally obtained in good yields (Scheme 3, path a).
Guoetal.reportedamethodusingFeCl3 tocatalyseglycosylation
of glucosamine pentaacetates with phenols.22 However, our
attempts to utilise FeCl3 in our experiments were unsuccessful.
We also tried the classic Schmidt’s trichloroacetimidate method,
but found that the phenolic hydroxyl groups of quercetin failed
to react with glucosamine trichloroacetimidate donor in the
presence of trifluoromethanesulfonate (TMSOTf) as catalyst.
TheresultingtribenzylatedquercetinN-acetylaminoglycoside
triacetates (11–13) were first deacetylated by treatment with
MeONa/MeOH and then debenzylated using 10% Pd–C/EtOH/
THF to afford 2, 1, and 3 in high yield (Scheme 3, path b).
Compounds 1–3 were identified as β-anomers because of the
large J1,2 value (7.5–7.8 Hz) observed for the anomeric proton
1
of the glucose residue in their H NMR spectra. In the HMBC
3,7-Di-O-benzylquercetin (9), which has 3′- and 4′-OH groups,
has been used previously for the synthesis of 4′-monomethylated
quercetin17 by taking advantage of the greater reactivity of the
4′ position compared with that of the 3′ position. We hoped a
similar synthetic strategy would lead to selective glycosylation
on 4′-OH. In the event, that proved to be the case (see below).
First, to protect effectively and temporarily the 3′,4′-diols of
quercetin, intermediate 7 was synthesised by reacting quercetin
with dichlorodiphenylmethane in bis(2-methoxyethyl)ether
(Scheme 2, path a). The subsequent benzylation afforded the
3,7-di-benzylated intermediate 8, the diphenylmethane ketal
moiety of which was deprotected with a mixture of HCl/EtOH
to yield 9 (Scheme 2, paths b and c).
spectrum of the N-acetyl amino glucoside 2, the correlation
between the glucose H1″ (δ 4.99) and quercetin C3′ (δ 146.1)
showed a glycosidic linkage of quercetin at the C3′ position. The
structural assignment of isomers 1 and 3 was also confirmed by
the HMBC correlation of glucose H1 with C3 or C4′ carbon,
respectively.23
Conclusion
We have achieved the regiospecific synthesis of three
quercetin O-β-glucosides of N-acetylglucosamine. The
three suitably protected glycosyl acceptors were 3,7,4′-di-
O-benzylquercetin (5), 7,3′,4′-di-O-benzylquercetin (6) and
3,7-di-O-benzylquercetin (9) and they were synthesised
from either quercetin or rutin by standard protecting-group
methodology. Glycosylation of these protected quercetins with
triacetylated glycosyl chloride 10 was efficiently achieved
under phase-transfer-catalysed conditions using TBAB as
catalyst and aqueous K2CO3 as base and the products (11–13)
were deprotected to give the three quercetin O-β-glucosides of
N-acetylglucosamine (1–3).
Of the many types of glycosyl donors,20 2-acetamido-3,4,6-
tri-O-acetyl-2-deoxy-α-d-glucopyranosyl chloride (10) was
the most effective as its glycosylation of protected quercetins
(5, 6 and 9) can be controlled by C2 acetamide neighbouring
participation to secure high 1,2-trans selectivity (Scheme 3).21
The glycosylation synthesis was achieved under phase-transfer-
catalysed conditions (K2CO3/CHCl3 with tetrabutylammonium
Ph
H
O
Ph
O
'
3
H
O
O
'
4
H
O
O
a
H
O
O
7
3
H
O
H
O
H
O
O
H
O
O
7
Quercetin
Ph
b
H
O
Ph
O
H
O
O
c
BnO
O
BnO
O
OBn
OBn
H
O
O
H
O
O
9
8
Scheme 2 Synthesis of 3,7-di-O-benzylquercetin (9). Path a: Ph2CCl2, bis(2-methoxyethyl)ether, reflux, 2 h, 56%. Path b: BnBr (2 equiv.), K2CO3, DMF,
r.t., 3 h, 90%. Path c: HCl/EtOH, 70 °C, 5 h, 95%.

JOURNAL OF CHEMICAL RESEARCH 2018 191
OAc
O
AcO
AcO
O
NH
OBn
O
BnO
O
R
O
1
R
O
OBn
2
BnO
O
O
H
O
O
(79%)
(80%)
11
R
O
3
b
H
O
2
5
6
9
R1=H, R2=R3=Bn
R1=R2=Bn, R3=H
OBn
OBn
OAc
,
R1=R2=H R3=Bn
BnO
O
O
a
+
O
OAc
OAc
O
H
O
HN
O
OAc
(72%)
O
12
AcO
AcO
HN
b
(77%)
l
C
1
OAc
O
H
O
O
OAc
OAc
10
O
HN
BnO
O
O
OBn
b
(69%)
(67%)
H
O
O
1
3
3
Scheme 3 Synthesis of quercetin O-β-glucosides of N-acetylglucosamine (1–3). Path a: 0.13 M K2CO3, CHCl3, TBAB, 52 °C, 6 h. Path b: (i) NaOMe,
MeOH, 30 °C, 10 h; (ii) H2, Pd/C, THF/EtOH, 25 °C, 4 h.
Experimental
1H, 3OH), 7.76 (d, J = 2.2 Hz, 1H, H2′), 7.63 (dd, J = 8.6, 2.2 Hz, 1H,
H6′), 7.54–7.28 (m, 10H, 2 × Ph), 7.17 (d, J = 8.8 Hz, 1H, H5′), 6.81 (d,
J = 2.1 Hz, 1H, H8), 6.44 (d, J = 2.1 Hz, 1H, H6), 5.23 (s, 2H, CH2Ph),
5.21 (s, 2H, CH2Ph).
All reagents for synthesis were provided by J&K Scientific Co. unless
otherwise specified. Melting points were measured on an XPR-400
melting point apparatus. NMR spectra were obtained on a Bruker
AQS Avance spectrometer (1H NMR at 400 or 300 Hz, 13C NMR
at 100 or 75 Hz) in CDCl3 or DMSO-d6 using TMS as an internal
standard. Chemical shifts (δ) are given in ppm and coupling constants
(J) are given in Hz. Mass spectra were performed with an Agilent
Technologies MSD SL Trap mass spectrometer with an ESI source
coupled with a 1100 Series HPLC system.
Synthesis of 3,7,4′-tri-O-benzylquercetin (5)
A solution of 4 (1.00 g, 2.1 mmol), pyridine (0.41 g, 5.2 mmol), and
BnCl (0.25 g, 2.1 mmol) in CH2Cl2 (10 mL) was stirred for 12 h at
room temperature. The obtained solution was diluted with CH2Cl2
(15 mL) and washed with HCl (1 M, 3 × 50 mL). The organic layer
was then dried over MgSO4 and filtered. The solvent was evaporated
under reduced pressure and the residue was crystallised from ether to
afford 5 as a yellow solid; yield 0.91 g (77%); m.p. 147–150 °C (lit.17
Synthesis of 7,4′-di-O-benzylquercetin (4)
Rutin (1.22 g, 2.0 mmol) was dissolved in DMF (20 mL), and K2CO3
(0.41 g, 3.0 mmol) was added to this solution under stirring. The
mixture was warmed to 60 °C and a solution of BnBr (0.48 mL, 4.0
mmol) in DMF (10 mL) was slowly added. After further stirring for
2 h, the reaction mixture was evaporated under reduced pressure.
Ethanol (30 mL) and concentrated HCl (3 mL) were added to the
residue, and the stirred solution was refluxed for 2 h. The solution
was cooled and filtered, yielding a bright yellow precipitate, which
was recrystallised from ethanol to give 4 as a yellow solid; yield 0.53
1
150–152 °C); H NMR (300 MHz, CDCl3): δ 12.70 (s, 1H, 5OH),
7.67–7.58 (m, 2H, H2′, H6′), 7.49–7.33 (m, 12H, Ph), 7.27 (m, 3H, Ph),
6.97–6.93 (m, 1H, H5′), 6.50 (d, J = 2.1 Hz, 1H, H8), 6.44 (d, J = 2.2
Hz, 1H, H6), 5.76 (s, 1H, 3′OH), 5.19, 5.13, 5.07 (s, 3 × 2H, CH2Ph).
Synthesis of 7,3’,4’-tri-O-benzylquercetin (6)
A mixture of rutin (1.22 g, 2.0 mmol), BnBr (1.9 mL, 16.0 mmol)
and K2CO3 (2.20 g, 16.0 mmol) in DMF (20 mL) was stirred at room
temperature for 16 h. The reaction mixture was evaporated under
reduced pressure. Ethanol (30 mL) and concentrated HCl (3 mL) were
added to the residue, and the solution was refluxed for 2 h. The solution
g (58%); m.p. 182–183 °C (lit.17 181–182 °C); H NMR (300 MHz,
DMSO): δ 12.43 (d, J = 9.0 Hz, 1H, 5OH), 9.61 (s, 1H, 3′OH), 9.42 (s,
1

192 JOURNAL OF CHEMICAL RESEARCH 2018
was cooled and filtered to give 6 as a yellow solid; yield 0.97 g (85%);
127.1, 125.0, 123.2, 120.3, 113.1, 105.8, 99.8, 98.4, 92.7, 74.0, 71.9, 71.6,
70.6, 70.1, 67.9, 61.4, 54.0, 22.5, 20.3, 20.2. HRMS (ESI) m/z calcd for
C50H47NO15Na [M + Na]+: 924.2838; found: 924.2847.
1
m.p. 186–188 °C (lit.17 188–190 °C); H NMR (300 MHz, DMSO): δ
12.42 (s, 1H, 5OH), 9.71 (s, 1H, 3OH), 7.89 (d, J = 2.0 Hz, 1H, H2′),
7.84 (dd, J = 8.7, 2.0 Hz, 1H, H6′), 7.51–7.30 (m, 15H, Ph) 7.26 (d, J =
8.7 Hz, 1H, H5′), 6.86 (d, J = 2.1 Hz, 1H, H8), 6.45 (d, J = 2.1 Hz, 1H,
H6), 5.20–5.24 (m, 3 × 2H, CH2Ph).
3-O- (2″-acetamido-3″,4″,6’’-tri-O-acetyl-2″-deoxy) -β-d -
glucopyranosyl-7,3′,4′-tri-O-benzylquercetin (12): Yellow solid; yield
1.30 g (72%); m.p. 198–200 °C; 1H NMR (300 MHz, CDCl3): δ 12.24
(s, 1H, 5OH), 7.82 (d, J = 2.1 Hz, 1H, H2′), 7.73 (dd, J = 8.7, 2.1 Hz,
1H, H6′), 7.55–7.28 (m, 15H, Ph), 6.95–7.05 (m, 2H, H5′, NH), 6.51
(d, J = 2.2 Hz, 1H, H8), 6.46 (d, J = 2.2 Hz, 1H, H6), 5.27–5.20 (m,
4H, 2 × CH2Ph), 5.15 (s, 2H, CH2Ph), 5.13–5.08 (m, 3H, H1′, H3′, H4′),
4.25–4.40 (m, 1H, H2′), 4.06 (dd, J = 12.3, 4.8 Hz, 1H, H6″), 3.91 (dd,
J = 12.3, 2.5 Hz, 1H, H6″), 3.62–3.50 (m, 1H, H5″), 2.07, 2.02, 2.00,
1.81 (s, 4 × 3H, CH3C=O); 13C NMR (75 MHz, CDCl3): δ 177.2, 170.6,
170.5, 170.1, 168.9, 164.5, 161.3, 156.9, 156.3, 151.4, 147.8, 136.6, 136.2,
135.2, 134.7, 128.4, 128.3, 128.1, 127.6, 127.6, 127.1, 127.0, 126.8,
123.1, 122.1, 115.4, 112.9, 105.4, 100.9, 98.6, 92.9, 73.5, 72.1, 71.1, 70.4,
70.2, 67.8, 61.4, 54.0, 23.1, 20.4, 20.2, 20.0. HRMS (ESI) m/z calcd for
C50H47NO15Na [M + Na]+: 924.2838; found: 924.2834.
Synthesis of 2-(2,2-diphenylbenzo[1,3]dioxol-5-yl)-3,5,7-trihydroxy-
4H-chromen-4-one (7)
Quercetin (2.0 g, 6.6 mmol) and 1,1-dichlorodiphenylmethane(2.0 mL,
10.4 mmol) were dissolved in bis(2-methoxyethyl) ether (20 mL). The
mixture was warmed to reflux under an atmosphere of nitrogen for
2 h. The reaction solution was concentrated in vacuo to give a yellow
solid which was purified on silica gel eluting with hexane/EtOAc to
afford 7 as a yellow solid; yield 1.73 g (56%); m.p. 230–232 °C (lit.17
1
222–224 °C); H NMR (300 MHz, CDCl3): δ 11.77 (s, 1H, 5OH),
7.83–7.75 (m, 2H, H6′, H2′), 7.66–7.52 (m, 4H, Ph), 7.47–7.32 (m, 6H,
Ph), 7.02 (d, J = 8.2 Hz, 1H, H5′), 6.43 (d, J = 2.1 Hz, 1H, H8), 6.29 (d,
J = 2.1 Hz, 1H, H6).
4′-O- (2″-acetamido-3″,4″,6″-tri-O-acetyl-2″-deoxy) -β-d -
glucopyranosyl-3,7-tri-O-benzylquercetin (13): Yellow solid; yield
1.12 g (69%); m.p. 228–230 °C; 1H NMR (300 MHz, CDCl3): δ 12.62
(s, 1H, 5OH), 7.51–7.62 (m, 2H, H2′, H6′), 7.46–7.18 (m, 10H, Ph), 6.95
(d, J = 8.8 Hz, 1H, H5′), 7.60–7.71 (m, 1H, NH), 6.48 (s, 1H, H8), 6.44
(s, 1H, H6) 5.99 (d, J = 7.5 Hz, 1H, H1″), 5.27–5.16 (m, 1H, H4″), 5.13
(s, 2H, CH2Ph), 5.05 (s, 2H, CH2Ph), 4.93 (d, J = 8.1 Hz, 1H, H3″),
4.45–4.28 (m, 2H, H6″, H2″), 4.22 (d, J = 11.9 Hz, 1H, H6″), 3.79–3.95
(m, 1H, H5″), 2.18–1.91 (m, 12H, 4 × CH3C=O); 13C NMR (75 MHz,
CDCl3): δ 178.4, 172.0, 171.3, 170.2, 168.9, 164.2, 161.5, 156.2, 155.5,
146.2, 146.1, 137.4, 135.9, 135.4, 128.4, 128.3, 128.0, 127.9, 127.9, 127.1,
125.8, 120.8, 115.6, 114.1, 105.7, 101.6, 98.3, 92.6, 73.8, 71.8, 71.4,
70.1, 67.5, 61.5, 54.5, 23.1, 20.3, 20.3, 20.2. HRMS (ESI) m/z calcd for
C43H42NO15 [M + H]+: 812.2549; found: 812.2559.
Synthesis of 2-(2,2-diphenylbenzo[1,3]dioxol-5-yl)-3,7-dibenzyloxy-
5-hydroxy-4H-chromen-4-one (8)
A mixture of compound 7 (1.0 g, 2.1 mmol), BnBr (0.74 mL, 4.3
mmol) and K2CO3 (0.58 g, 4.2 mmol) was stirred in DMF (20 mL)
at room temperature until the reaction was complete (TLC). Then
the solution was diluted with CH2Cl2 (20 mL), washed with water
and dried (MgSO4). After evaporation of the solvent, the residue was
recrystallised from ethanol/CHCl3 to yield 8 as a yellow solid; yield
1.25 g (90%); m.p. 133–135 °C; 1H NMR (300 MHz, CDCl3): δ 12.69
(s, 1H, 5OH), 7.65–7.54 (m, 5H, Ph), 7.50 (d, J = 1.6 Hz, 1H, H2′),
7.48–7.08 (m, 16H, Ph, H6′), 6.92 (d, J = 8.3 Hz, 1H, H5′), 6.48 (d,
J = 2.2 Hz, 1H, H8), 6.45 (d, J = 2.1 Hz, 1H, H6), 5.13 (s, 2H, CH2Ph),
5.04 (s, 2H, CH2Ph); 13C NMR (75 MHz, CDCl3): δ 178.4, 164.1, 161.7,
156.3, 156.3, 148.9, 146.9, 139.4, 136.9, 135.8, 135.4, 129.0, 128.6,
128.4, 128.0, 127.8, 127.1, 125.9, 123.9, 123.7, 108.6, 108.0, 105.8, 98.3,
92.6, 74.1, 70.1. HRMS (ESI) m/z calcd for C42H30O7Na [M + Na]+:
669.1884; found: 669.1895.
Synthesis of quercetin glycosides of N-acetylglucosamine (1–3);
general procedure
NaOMe (2.2 mmol) was added to a solution of a glucoside 11–13
(1.5 mmol) in MeOH (15 mL) and the resulting solution was stirred at
30 °C for 10 h. The solvent was removed under vacuum. Then ethanol
(30 mL) and acetic acid (0.5 mL) were added to the residue. After
refluxing for 0.5 h, the reaction was cooled to room temperature. The
yellow precipitate was filtered off, washed with water, dried and dissolved
in THF/EtOH (16 mL:16 mL). Then Pd/C 10% (0.19 g) was added to the
solution and the mixture was stirred for 4 h in a hydrogen atmosphere at
ambient pressure. The catalyst was filtered off, the filtrate evaporated and
the residue recrystallised from acetone to give compounds 1–3.
Synthesis of 3,7-di-O-benzylquercetin (9)
A mixture of 7 (0.5 g, 0.8 mmol), ethanol (15 mL) and concentrated
HCl (2 mL) was refluxed for 5 h. After cooling, the precipitate was
filtered off, washed with water and dried to yield 9 as a yellow solid;
1
yield 0.35 g (95%); m.p. 206–208 °C (lit.9 202–204 °C); H NMR
(300 MHz, DMSO): δ 12.73 (s, 1H, 5OH), 9.83 (s, 1H, 4′OH), 9.35 (s,
1H, 3′OH), 7.54 (d, J = 2.1 Hz, 1H, H2′), 7.51–7.24 (m, 11H, H6′, Ph),
6.87 (d, J = 8.5 Hz, 1H, H5′), 6.80 (d, J = 2.1 Hz, 1H, H8), 6.47 (d,
J = 2.1 Hz, 2H, H6), 5.24 (s, 2H, CH2Ph), 5.01 (s, 2H, CH2Ph).
3-O-(2″-acetamido-2″-deoxy)-β-d-glucopyranosylquercetin
(1):
Yellow solid; yield 0.58 g (77%); m.p. 212–214 °C (lit.18 210–212 °C);
1H NMR (400 MHz, DMSO): δ 12.71 (s, 1H, 5OH), 10.83 (s, 1H, 7OH),
9.71 (s, 1H, 3′OH), 9.09 (s, 1H, 4′OH), 8.03 (d, J = 9.3 Hz, 1H, NH),
7.71–7.57 (m, 2H, H2′, H6′), 6.84 (d, J = 8.4 Hz, 1H, H5′), 6.41 (d,
J = 2.0 Hz, 1H, H8), 6.19 (d, J = 2.0 Hz, 1H, H6), 5.63 (d, J = 8.5 Hz,
1H, H1″), 5.03 (s, 2H, OH), 4.26 (s, 1H, OH), 3.75 (dt, J = 10.2, 8.9 Hz,
1H, H2″), 3.56 (dd, J = 11.3, 4.2 Hz, 1H, H6″), 3.44–3.24 (m, 2H, H6″,
H3″), 3.14–3.03 (m, 2H, H4″, H5″), 1.86 (s, 3H, CH3CO).
Synthesis of glycosides 11–13; general procedure
A mixture of a protected quercetin 5, 6 or 9 (2.0 mmol), tetrabutyl
ammonium bromide (TBAB, 1.0 mmol) and 0.13
(20 mL) in CHCl3 (20 mL) was vigorously stirred at 52 °C for 1 h.
Then 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-d-glucopyranosyl
M K2CO3
chloride 10 (4.0 mmol) was added in one portion, then stirred for 5 h.
The reaction mixture was diluted with CH2Cl2 (20 mL), washed with
water, dried and concentrated. The residue was purified by column
chromatography (silica gel) to give compounds 11–13.
4′-O-(2″-acetamido-2″-deoxy)-β-d-glucopyranosylquercetin
1
(3): Yellow solid; yield 0.51 g (67%); m.p. 218–220 °C; H NMR
3′-O- (2″-acetamido-3″,4″,6’’-tri-O-acetyl-2″-deoxy) -β-d -
glucopyranosyl-3,7,4′-tri-O-benzylquercetin (11): Yellow solid; yield
1.42 g (79%); m.p. 200–202 °C; 1H NMR (300 MHz, CDCl3): δ 12.64
(s, 1H, 5OH), 7.91 (d, J = 1.9 Hz, 1H, H2′), 7.78 (dd, J = 8.7, 1.9 Hz,
1H, H6′), 7.52–7.30 (m, 15H, Ph), 7.01 (d, J = 8.7 Hz, 1H, H5′), 6.55 (d,
J = 1.9 Hz, 1H, H8), 6.44 (d, J = 1.9 Hz, 1H, H6), 5.34 (d, J = 8.8 Hz,
1H, H1″), 5.24–5.01 (m, 7H, 3 × CH2Ph, H3″), 4.85–4.95 (m, 2H, H4″,
NH), 4.21–4.08 (m, 2H, H2″, H6″), 4.02 (d, J = 10.3 Hz, 1H, H6″),
3.31 (dd, J = 7.1, 2.5 Hz, 1H, H5″), 2.05, 2.03, 1.94, 1.62 (s, 4 × 3H,
CH3C=O); 13C NMR (75 MHz, CDCl3): δ 178.3, 170.4, 170.3, 169.8,
169.0, 164.2, 161.6, 156.3, 155.2, 151.2, 145.5, 137.4, 136.3, 135.7,
135.4, 128.9, 128.7, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.4,
(400 MHz, DMSO-d6): δ 12.41 (s, 1H, 5OH), 7.97 (d, J = 8.3 Hz, 1H,
NH), 7.70 (s, 1H, H2′), 7.61 (d, J = 8.4 Hz, 1H, H6′), 7.19 (d, J = 8.7 Hz,
1H, H5′), 6.40 (s, 1H, H8), 6.17 (s, 1H, H6), 5.14 (bs, 2H, OH), 5.02
(d, J = 8.4 Hz, 1H, H1″), 4.65 (bs, 1H, OH), 3.74 (d, J = 11.3 Hz, 1H,
H6″), 3.67 (dd, J = 18.0, 8.8 Hz, 1H, H2″), 3.57–3.43 (m, 2H, H6″,
H3″), 3.39–3.27 (m, 1H, H5″), 3.26–3.18 (m, 1H, H4″), 1.84 (s, 3H,
CH3C=O); 13C NMR (100 MHz, DMSO-d6): δ 176.0, 170.5, 165.2,
160.8, 156.4, 146.8, 145.7, 136.5, 125.4, 119.5, 116.2, 115.0, 102.8,
100.3, 98.6, 93.6, 77.4, 73.7, 70.3, 60.8, 56.1, 23.3. HRMS (ESI) m/z
calcd for C23H23NO12Na [M + Na]+: 528.1112; found: 528.1117.
3′-O-(2″-acetamido-2″-deoxy)-β-d-glucopyranosylquercetin
1
(2): Yellow solid; yield 0.61 g (80%); m.p. 210–212 °C; H NMR

JOURNAL OF CHEMICAL RESEARCH 2018 193
References
(400 MHz, DMSO-d6): δ 12.45 (s, 1H, 5OH), 7.95 (d, J = 8.4 Hz,
1H, NH), 7.90 (d, J = 2.1 Hz, 1H, H2′), 7.83 (dd, J = 8.6, 2.1 Hz,
1H, H6′), 6.98 (d, J = 8.6 Hz, 1H, H5′), 6.48 (d, J = 2.0 Hz, 1H, H8),
6.20 (d, J = 2.0 Hz, 1H, H6), 5.12 (bs, 2H, OH), 4.99 (d, J = 8.4 Hz,
1H, H1″), 4.61 (s, 1H, OH), 3.79 (d, J = 11.3 Hz, 1H, H6″), 3.68 (dd,
J = 18.5, 8.4 Hz, 1H, H2″), 3.60 (dd, J = 11.8, 4.5 Hz, 1H, H6″), 3.51
(t, J = 8.4 Hz, 1H, H3″), 3.39–3.23 (m, 2H, H4″, H5″), 1.87 (s, 3H,
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m/z calcd for C23H23NO12Na [M + Na]+: 528.1112; found: 528.1105.
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The work described in this paper was supported by the National
Natural Science Foundation of China (21402062), the Natural Science
Foundation of Jiangsu Province (BK20141246), the PAPD Program
(a project funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions), the Open-end Funds of Jiangsu
Key Laboratory of Marine Pharmaceutical Compound Screening
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Received 25 March 2018; accepted 27 March 2018
Paper 1805343
https://doi.org/10.3184/174751918X15232706115112
Published online: 18 April 2018