Environmentally friendly C-glycosylation of phloroacetophenone with unprotected d-glucose using scandium(III) trifluoromethanesulfonate in aqueous media: Key compounds for the syntheses of mono- and di-C-glucosylflavonoids

Article abstract of DOI:10.1016/j.carres.2004.07.023

The direct C-glycosylation of phloroacetophenone with an unprotected d-glucose in aqueous media using scandium(III) trifluoromethanesulfonate (Sc(OTf)₃) as the catalyst, gave mono- and bis-C-β-glycosylic compounds in highest total yield of 81%.

Full text of DOI:10.1016/j.carres.2004.07.023

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 2611–2614
Note
Environmentally friendly C-glycosylation of
phloroacetophenone with unprotected D-glucose using scandium(III)
trifluoromethanesulfonate in aqueous media: key compounds for
the syntheses of mono- and di-C-glucosylflavonoids
*
Shingo Sato, Toshiki Akiya, Toshiyuki Suzuki and Jun-ichi Onodera
Department of Chemistry and Chemical Engineering, Faculty of Engineering, Yamagata University, 4-3-16 Jonan,
Yonezawa, Yamagata 992-8510, Japan
Received 27 April 2004; accepted 20 July 2004
Available online 18 September 2004
Abstract—The direct C-glycosylation of phloroacetophenone with an unprotected D-glucose in aqueous media using scandium(III)
trifluoromethanesulfonate (Sc(OTf) ) as the catalyst, gave mono- and bis-C-b-glycosylic compounds in highest total yield of 81%.
3
The second and third use of the recovered Sc(OTf)
2004 Elsevier Ltd. All rights reserved.
3
afforded them in total yields of 56% and 53%, respectively.
ꢀ
3
Keywords: C-Glycosylflavonoid; Direct C-glycosylation; Unprotected glucose; Sc(OTf) ; Aqueous media; Recycling
The availability of a variety of C-glycosylflavonoids,
which are found in low concentrations in plant tissue
such as citrus fruit peels, are attractive because they
did not proceed in good yield. One reason for this is that
O-demethylation by acid hydrolysis of methyl 2,3,4,6-
tetra-O-benzyl-a-D-glucopyranoside is low yield, and
C-alkylation tends to occur between the 1,3-diol groups
on the benzene ring under the protection reaction condi-
tions of the phenolic hydroxyl. As a result, the reaction
requires considerable operating time, and a number of
reagents be used in the protection reaction.
4
1
are nontoxic and have hypotensive activity. A number
of C-glycosylic aryl compounds (Ôaryl C-glycosidesÕ)
with antibiotic activity have also been isolated from
microorganisms, and some useful synthetic methods
for preparing these aryl C-glycoside antibiotics have
been reported. One such method is SuzukiÕs C-glycosyla-
tion technique, in which the reaction of a selectively
hydroxyl-protected polyphenol with per-O-benzylglyco-
syl fluoride proceeds via an O!C glycoside rearrange-
Toshima and co-workers recently reported on the
environmentally benign C-glycosylation of selective
hydroxyl-protected aryl compounds with unprotected
2-deoxy sugars using a solid acid in aqueous media, that
afforded aryl C-glycosides in good yields with good b-
2
ment. We also reported on the synthesis of some
3
5
C-glycosylflavonoids, using SuzukiÕs method. This reac-
selectivity. After C-glycosylation of the methyl-pro-
tected phenol, however, difficulties are encountered in
tion results in high yields and in high regio- and stereo-
selectivities, but requires the use of undesirable solvents
such as CH Cl . In addition, the selective protection
6
the deprotecting of the methoxyl group.
To the best of our knowledge, a reliable method for
the direct C-glycosylation of unprotected polyphenols
with unprotected general sugars such as a D-glucose in
2
2
reaction of hydroxyl groups of the glycosyl donor and
the polyphenol derivative such as phloroacetophenone
7
aqueous media has not been reported. Since C-glyco-
sylflavonoids are typically harmless, we attempted to
examine such environmentally friendly glycosylation
conditions as a route to their synthesis. The goal was
*
Corresponding author. Tel.: +81 238 26 3121; fax: +81 238 26 3413;
e-mail: shingo-s@yz.yamagata-u.ac.jp
0
008-6215/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.07.023

2612
S. Sato et al. / Carbohydrate Research 339 (2004) 2611–2614
to develop conditions for the glycosylation of an unpro-
tected polyphenol using an unprotected sugar in aque-
ous media.
the yield of bis-C-glucoside 2 was also increased (entries
5 and 10). When acetonitrile–water was used as a solvent
system, good yield and selectivity of the mono-C-gluco-
side was obtained (entries 6 and 7). An ethanol–water
solvent system gave a good yield but no selectivity (en-
8
Since Kobayashi and co-workers recently developed
a number of carbon–carbon bond-forming reactions
using rare-earth metal triflates, that function as Lewis
acids, even in aqueous media, we attempted the use of
ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3)
tries 9 and 10). The use of 0.2equiv of Sc(OTf) in 2:1
3
EtOH–H O gave the highest yield (81%) of C-glucosides
2
(1: 43%, 2: 38%) (entry 9). The best yield of the mono-
and bis-C-glucosides was 48% and 40%, respectively (en-
tries 6 and 10). In this reaction, the additional formation
of small amounts of phloroacetophenone dimers linked
via a D-glucose chain was confirmed. The use of more
and Sc(OTf) to satisfy the above reaction conditions
3
(
Table 1). We examined the C-glycosylation of phloro-
acetophenone, a key compound in C-glycosylflavonoid
synthesis, with D-glucose in aqueous acetonitrile solu-
tion. Detailed structural analyses of the sugar moieties
than 0.4equiv of Sc(OTf) and 3equiv of D-glucose, or
3
7
were carried out after acetylation of the products. A
structural analysis of the C-glucosides obtained indi-
cated that they were, in fact, the desired mono- and
an extension of the refluxing time, or the use of water
as a solvent (entry 11) did not lead to an improved
yield of mono- and bis-C-glucosides, and side reaction
products made the product separation by silica-gel chro-
matography difficult. Since phenol or 2,4-O-dimethyl-
protected phloroacetophenone was unreactive under
these reaction conditions, it is suggested that this direct
C-glycosylation of polyphenols proceeds regioselectively
only between the 1,3-diol. Thus, this reaction is a car-
bon–carbon bond-forming reaction of the 1,3-diketone
with an aldehyde. In entry 10, the second use of the
3
a,b 9,10
bis-C-b-D-glucopyranosides (1 , 2 ). As of this writ-
ing, the bis-C-glucoside 2 produced here could not be
synthesized by repeating the O!C glycoside rearrange-
1
0
ment method from phloroacetophenone. The reaction
barely proceeded at room temperature (entry 3). When
the temperature was increased to 65ꢁC, 80ꢁC, or to
reflux, the yield of the C-glycosides increased (entries
4
, 5 and 8). A higher yield was obtained using Sc(OTf)3,
rather than Yb(OTf) as a promoter (entry 2). The use
recovered glucose and Sc(OTf) gave the C-glycosides
3
3
of p-toluensulfonic acid as a promoter led to no reac-
7
tion, and the use of a Brønsted acid such as HCl and
in a total of 56% yield (1:2 = 68:32), and further the
third use in a total of 53% yield (1:2 = 81:19). Direct
recycling of the Sc(OTf) used in the reaction with excess
H SO also resulted in no yields of C-glucosides (entry
2
4
3
1
). When the amount of added Sc(OTf) was increased,
3
glucose permits excellent yields to be obtained.
Table 1. C-glycosylation of phloroacetophenone with D-glucose in aqueous media
OH
OH
O
OH
HO
HO
OH
Ac
HO
OH
Ac
HO
HO
HO
OH
HO
HO
O
+
O
D-Glucose (Glc)
HO
HO
Ac
OH
OH
OH
OH
OH
1
2
Entry
Glc (equiv)
Promoter (equiv)
Solvent
Temp (ꢁC).
Time (h)
Yield (%)
mono-C (1)
No reaction
bis-C (2)
1
2
3
4
5
6
7
8
9
3.0
3.0
1.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
5.0
3.0
3.0
p-TsOH (ꢀ0.4)
CH
CH
CH
CH
CH
CH
CH
3
CN:H
3
CN:H
3
CN:H
3
CN:H
3
CN:H
3
CN:H
3
CN:H
2
2
2
2
2
2
2
O (1:1)
O (1:1)
O (1:1)
O (1:1)
O (2:1)
O (2:1)
O (1:2)
Reflux
Reflux
rt
6
8
Yb(OTf)
3
(0.2)
(0.1)
(0.2)
(0.2)
(0.1)
(0.2)
(0.2)
(0.2)
(0.4)
(0.2)
(0.2)
(0.2)
13
3
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Se(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
3
24
20
8
No reaction
3
3
3
3
3
3
3
3
3
3
65
16
43
48
47
16
43
39
8
10
29
14
24
12
38
40
34
22
0
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
8
8
THF:H
2
O (2:1)
8
EtOH:H
EtOH:H
2
O (2:1)
O (2:1)
9
10
11
12
13
2
6.5
8
2
H O
CH CN
3
8
5
1,4-Dioxane
3
0

S. Sato et al. / Carbohydrate Research 339 (2004) 2611–2614
2613
Since the C-glycosylation method developed here is
very simple and environmentally friendly and proceeds
with high regio- and b-stereoselectively, we conclude
that this reaction has considerable potential for use in
the synthesis of nontoxic naturally occurring C-glyco-
sylflavonoids, especially di-C-glycosylflavonoids in
which most of the C-b-glycosyl residues are bonded be-
glucose were subjected to the same reaction to give the
C-glucosides in 56% yield (1:2 = 68:32). The same glyco-
sylation reaction in the third cycle also gave the C-gluco-
sides in 53% yield (1:2 = 81:19).
1.3. 3,5-di-C-b-D-Glucopyranosylphloroacetophenone (2)
1
tween the 1,3-diol of the polyphenol molecule.
22
White powder (from EtOH); mp 171–173ꢁC; ½aꢁ +105
D
(
c 1.12, MeOH); R 0.13 (30:30:5:1 Me CO–EtOAc–
f 2
H O–AcOH); IR (KBr) m 3346, 2931, 2881, 1621,
2
ꢀ
1
1
367, 1274, 1082, and 1026cm ; H NMR (DMSO-
1
1. Experimental
0
00
d +D O) d 2.61 (3H, s, ArAc), 3.27 (4H, m, H-3 , 3 ),
6
2
0 00 0 00
3.34 (2H, t, J 9.5Hz, H-4 , 4 ), 3.41 (2H, br s, 2 ,2 -
OH), 3.48 (2H, t, J 9.5Hz, H-2 , 2 ), 3.62 (4H, m, H-
6 a,b, 6 a,b), 4.72 (2H, d, J 9.5Hz, H-1 , 1 ), 4.75 (2H,
br s, 6 ,6 -OH), 5.01 (2H, br. s, 3 ,3 -OH), 5.05 (2H,
1
.1. General
0
00
0
0
0
0
0
0
The solvents used in this reaction were prepared by dis-
tillation. For separation and purification, at first, col-
umn chromatography was performed on MCI gel
CHP20Pꢂ (high porous polymer, 75–150lm, Mitsubi-
shi Chemical Corp.), and then, flash column chromato-
graphy was performed on silica gel (230–400 mesh,
Fuji-Silysia Co., Ltd., BW-300). Melting points were
determined on a Yanagimoto micro-melting point appa-
ratus and are uncorrected. Optical rotations were
recorded on a JASCO DIP-370 polarimeter. Mass spec-
tral data were obtained by fast-atom bombardment
0
00
0
00
0
00
br s, 4 ,4 -OH), 9.17 (1H, br s, 4-OH), 11.77 (2H, br s,
3
,6-OH); C NMR (DMSO-d ) d 32.8 (ArAc), 59.8
1
2
(
1
1
2
6
0 00 0 00 0 00 0
C-6 , 6 ), 69.1 (C-4 , 4 ), 71.9 (C-2 , 2 ), 74.5 (C-1 ,
0
0
0 00 0 00
), 77.7 (C-3 , 3 ), 81.0 (C-5 , 5 ), 103.8 (C-3, 5),
04.7 (C-1), 161.15 and 161.19 (C-2, 6), 172.0 (C-4),
03.4 (ArAc); FABMS (positive, glycerol, m/z) 493
+
M+H) ; Anal. Calcd for C H O : C, 48.78; H,
28 14
(
2
0
5.73. Found: C, 48.52; H, 5.86.
(
FAB) using 3-nitrobenzyl alcohol (NBA) as a matrix
on a JEOL JMS-AX505HA instrument. IR spectra were
recorded on a Horiba FT-720 IR spectrometer. NMR
spectra were recorded on a Varian Inova 500 spectro-
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.2. C-Glycosylation procedure
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.19mmol), D-glucose (643mg, 3.57mmol), and
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1
3
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(
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3
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3
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6
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00mg of phloroacetophenone and 300mg of additional

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