Facile synthesis of flavonoid 7-O-glycosides

Article abstract of DOI:10.1021/jo034553e

Highly regioselective removal of the 7-O-acyl groups of the peracylated flavones, isoflavones, and flavonols (PhSH, imidazole, NMP) followed by effective glycosylation with glycosyl trifluoroacetimidates (BF ₃·Et₂O) and cautious deprotection of the acyl groups under basic conditions afforded the desired 7-O-flavonoid glycosides in satisfactory yields.

Full text of DOI:10.1021/jo034553e

tion (IC50 at the ng/mL level) against R-glucosidases I and
II occurring in endoplasmic reticulum and participating
in the processing of secretory-, cell membrane-, and virus
surface-glycoproteins.3 Daidzein 7-O-â-D-glucopyranoside
(daidzin, 2) is a characteristic isoflavone in the Legumi-
nosae plants possessing a range of bioactivities, such as
a potent selective inhibition against hamster liver mito-
chondria aldehyde dehydrogenase (IC50 ) 0.04 µM).4
Daidzin 2 has been added to commercial formulations to
act as a radical scavenger, dermal angiogenesis inhibitor,
and antiproliferic agent against melanomas.5 Quercetin
7-O-â-D-glucopyranoside (Quercimeritrin, 3) shows in-
hibitory effects on IL-5 (IC50 ) 27.3 µM),6 cAMP PDE
(IC50 ) 13.9 × 10-5 M),7 and rat aldose reductase (44.4%
at 10-5 M).8 In contrast to the wide occurrence and
importance of flavonoid O-glycosides, synthetic studies
toward those molecules are only sporadic and mostly rely
on conventional transformations.9 Here we report an
efficient procedure for the synthesis of flavonoid 7-O-
glycosides, including compounds 1-3.
F a cile Syn th esis of F la von oid
7-O-Glycosid es
Ming Li,† Xiuwen Han,† and Biao Yu*,‡
State Key Laboratory of Catalyst, Dalian Institute of
Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, China, and State Key Laboratory of
Bio-organic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
byu@mail.sioc.ac.cn
Received April 30, 2003
Abstr a ct: Highly regioselective removal of the 7-O-acyl
groups of the peracylated flavones, isoflavones, and flavonols
(PhSH, imidazole, NMP) followed by effective glycosylation
with glycosyl trifluoroacetimidates (BF3‚Et2O) and cautious
deprotection of the acyl groups under basic conditions
afforded the desired 7-O-flavonoid glycosides in satisfactory
yields.
The flavonoids are a very large and important group
of polyphenolic natural products, which are united by
their derivation from the aromatic heterocycle, flavone,
namely, 2-phenyl-4H-1-benzopyran-4-one.1,2 Conjugation
with sugars is a common form for the natural occurrence
of flavonoids. Flavonoid glycosides, as well as their
aglycones, play a variety of essential roles in the growth
and development of plants. Besides their contribution to
attract pollination (via the plant color) and protect
against UV-B radiation and microbial and animal feed-
ing, these molecules transfer signals between species
such as in the infection of legume roots by Rhizobium
bacteria and in the feeding of silkworms on mulberry
leaves. Flavonoids and flavonoid glycosides are also
important to human health, not only because those in
fruits and vegetables make up the human diet but also
because a number of those molecules have exhibited
significant biological activities such as antitumor, anti-
microbial, and radical-scavenging properties. Flavonoid
O-glycosides often bear the sugar moiety at the 7-hydroxy
position.1,2 Notably, among the over 500 flavone O-
glycosides and over 100 isoflavone O-glycosides so far
recorded, the majority are 7-O-glycosides.2 Among the
over l000 flavonol glycosides recorded, some 40% contain
a 7-O-glycosidic linkage.2 Compounds 1-3 are selected
as examples. 4′,8-Dihydroxyisoflavone 7-O-R-D-arabino-
furanoside (A-76202, 1) is isolated from Rhodococcus sp.
SANK 61694, which demonstrates a very strong inhibi-
The 7-hydroxyl group on the polyphenolic flavonoids,
which is para to the electron-withdrawing pyrone car-
bonyl function, possesses the highest acidity in the
molecule and therefore generates most easily the corre-
sponding phenolate.9e Taking advantage of this fact,
conventional methods distinguished the 7-OH by a
preferential nucleophilic substitution-upon-deprotection
of the flavonoid acetates.9c-f Recently, Needs et al.10 and
(3) (a) Shiozaki, M. Tetrahedron: Asymmetry 1999, 10, 1477. (b)
Watanabe, Y.; Shiozaki, M.; Kamegai, R. Carbohydr. Res. 2001, 335,
283.
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43, 4169.
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Chem. Abstr. 1984, 100, 126730. (b) Brunke, R. A. GP 443 2947/1996;
Chem. Abstr. 1996, 124, 2411803.
(6) Park, K. Y.; Lee, S.-H.; Min, B.-K.; Lee, K.-S.; Choi, J .-S.; Chung,
S. R.; Min, K. R.; Kim, Y. Planta Med. 1999, 65, 457.
(7) Sakamoto, Y.; Ohmoto, T.; Nikaido, T.; Koike, K.; Tomimori, T.
Bull. Chem. Soc. J pn. 1989, 62, 2450.
(8) Shimizu, M.; Ito, T.; Terrashima, S.; Hayashi, T.; Arisawa, M.;
Morita, N.; Kurokawa, S.; Ito, K.; Hashimoto, Y. Phytochemistry 1984,
23, 1885.
(9) (a) Farkas, L.; Mezey-Va´ndor, G.; No´gra´di, M. Chem. Ber. 1969,
102, 2583. (b) Farkas, L.; Vermes, B.; No´gra´di, M. Chem. Ber. 1972,
105, 3505. (c) Farkas, L.; Mezey-Va´ndor, G.; No´gra´di, M. Chem. Ber.
1974, 107, 1518. (d) Farkas, L.; Mezey-Va´ndor, G.; No´gra´di, M. Chem.
Ber. 1974, 107, 3878. (e) Mezey-Va´ndor, G.; Farkas, L.; No´gra´di, M.
In Flavonoids and Bioflavonoids Current Research Trends; Farkas, L.,
Ga´bor, M., Ka´llay, F., Eds.: Elsevier: Amsterdam, 1977; pp 187-192.
(f) Mezey-Va´ndor, G.; Farkas, L.; Kanzel, I.; No´gra´di, M. Chem Ber.
1980, 113, 1945. (g) Demetzos, C.; Skaltsounis, A. L.; Tillequin, F.;
Koch, M. Carbohydr. Res. 1990, 207, 131. (h) Alluis, B.; Dangles, O.
Helv. Chim. Acta 1999, 82, 2201. (i) Alluis, B.; Dangles, O. Helv. Chim.
Acta 2001, 84, 1133. (j) Kondo, T.; Oyama, K.-I.; Yoshida, K. Angew.
Chem., Int. Ed. 2001, 40, 894.
* Fax: (86)21-64166128.
† Dalian Institute of Chemical Physics.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Harborne, J . B. The Flavonoids: Advances in Research since
1986; Chapman and Hall: London, 1994. (b) Harborne, J . B. The
Flavonoids: Advances in Research since 1980; Chapman and Hall:
London, 1988. (c) Harborne, J . B.; Mabry, T. J . The Flavonoids:
Advances in Research; Chapman and Hall: London, 1982. (d) Har-
borne, J . B.; Mabry, T. J .; Mabry, H. The Flavonoids; Chapman and
Hall: London, 1975.
(2) Harborne, J . B.; Baxter, H. The Handbook of Natural Fla-
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(10) Needs, P. W.; Williamson, G. Carbohydr. Res. 2001, 330, 511.
10.1021/jo034553e CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/31/2003
6842
J . Org. Chem. 2003, 68, 6842-6845

TABLE 1. Regioselective Dep r otection of th e 7-O-Hexa n oyl Gr ou p of Isofla von e 4
entry
base
solvent
T (°C)
time (h)
yielda (%, 5)
recovery yielda (%, 4)
1
2
3
4
5
6
7b
8
9
DBU
K2CO3
NMP
NMP
NMP
NMP
NMP
NMP
NMP
THF
0
0
25
0
25
-25
25
25
25
2.5
6
24
4.5
2
5
5
24
24
52
67
35
90
87
63
87
68
43
no
no
57
no
no
30
no
12
19
2,6-lutidine
imidazole
imidazole
imidazole
imidazole
imidazole
imidazole
CH2Cl2
a
b
Isolated yields. Used 0.18 equiv of imidazole.
supports the transesterification mechanism.12b Therefore,
the effect of bases in this reaction is well correlated to
their basicity: 2,6-lutidine (pKa ) 6.7)14 < imidazole
(pKa ) 7.1)14 < DBU (pKa ) 24.1315 or 23.916), which
determines the effectiveness for the initial generation of
PhS- for transesterification. Expectedly, temperature,
solvent, and the amount of imidazole had remarkable
effects on the selective deprotection reaction using the
combination of PhSH and imidazole (entries 5-9). Thus,
the reaction at 25 °C finished within 2 h, generating 5
in 87% yield, while at -25 °C, the reaction proceeded very
slowly (cf. entries 4-6). The reactions in THF or CH2Cl2
solvent were very sluggish (entries 8-9). Reducing the
amount of the imidazole by one-half (from 0.35 to 0.18
equiv) more than doubled the time required to bring the
reaction to completion (cf. entries 5 and 7).
To investigate the scope and limitation of the present
protocol for selective 7-O-deprotection of flavonoid esters,
chrysin (flavone) esters (6a -c), daidzein (isoflavone)
esters (8a ,b), quercetin (flavonol) esters (10a ,b), pera-
cylated isoflavone glycoside 12, and chromone hexanoate
14 were subjected to the above optimized conditions (1.2
equiv of PhSH, 0.35 equiv of imidazole, NMP, rt). The
reactions were monitored by TLC and stopped after the
disappearance of the starting flavonoid esters (Figure 1).
Chrysin esters (6a -c) and daidzein esters (8a ,b), which
bear only two acyloxy groups, gave the corresponding
7-OH products (7a -c and 9a ,b) in excellent yields (90-
96%). Acetate and benzoate, in addition to hexanoate,
were well deprotected regioselectively, albeit requiring
different reaction times (Bz > hexanoyl g Ac) to bring
the reaction to completion. Remarkably, the 7-O-acyl
group, from the other four, on quercetin esters (10a ,b)
was well distinguished by the present transesterification
conditions, affording the 7-O-monodeprotected 11a ,b in
satisfactory yields (81 and 84%, respectively), while an
inseparable mixture containing two diols, as shown by
1H NMR, was isolated in about 10% yield. For isoflavone
glycoside 12, the 7-O-hexanoate was selectively cleaved
over the neighboring 8-O-hexanoate as well as the three
O-benzoate on the sugar moiety, providing 13 in 80%
yield. Thus, further modifications on the 7-OH of this
isoflavonoid glycoside become straightforward such as
methylation and sulfonation that are common ways of
SCHEME 1
Kim et al.11 were able to selectively hydrolyze the 7-O-
acetate in the presence of the 4′-O- or 5-O-acetate of
daidzein and chrysin (substrates 8b and 6b), respectively.
These results encouraged us to explore a general proce-
dure for selective release of the 7-OH on the peracylated
flavonoids. More recently, Chakraborti et al. demon-
strated that aromatic thiols in the presence of K2CO3 in
dipolar aprotic solvents constituted an efficient protocol
for the selective cleavage of aryl esters over alkyl esters.12
Furthermore, we found that using DBU as a base was
more efficient for the selective deprotection of an aryl
ester in the presence of an alkyl ester.13 Therefore, we
envisioned the combination of an aromatic thiol and a
base with suitable basicity a choice for selective removal
of the most electrophilic 7-O-acyl group on the peracy-
lated flavoinoids. Isoflavone trihexanoate 4 was selected
as a substrate for screening the conditions for selective
deprotection of 7-O-hexanoate over the neighboring 8-O-
as well as the 4′-O-hexanoate on the B ring (Scheme 1).
Some results are listed in Table 1.
The choice of base was crucial for the regioselective
deprotection of isoflavone 4. Employing PhSH (1.2 equiv)
as the thiol and NMP (N-methyl pyrolidinone) as the
solvent at 0 °C, the presence of DBU (0.35 equiv) or K2-
CO3 (0.35 equiv) produced the desired 7-OH product 5
in 52 and 67% isolated yields, respectively, after the
disappearance of the starting 4. The over-deprotected
diols were detected as byproducts (entries 1 and 2). When
2,6-lutidine was used as a base (0.35 equiv), the reaction
hardly took place at 0 °C. Upon raising the temperature
to 25 °C, the reaction proceeded, albeit sluggishly,
producing 5 in 35% yield with 57% of 4 being recovered
after 24 h (entry 3). Imidazole was found to be ideal for
the present purpose and (0.35 equiv) prompted the
reaction to be complete within 4.5 h, generating the
desired 5 in an excellent 90% yield (entry 4). Phenyl-
thiohexanoate was isolated in a comparable yield, which
(14) Reich, H. J .; Rigby, J . H. Handbook of Reagents for Organic
Synthesis: Acidic and Basic Reagents; J ohn Wiley & Son: Chichester,
UK, 1999.
(15) Kaljurand, I.; Rodima, T.; Leito, I.; Koppel, I. A.; Schwesinger,
R. J . Org. Chem. 2000, 66, 6202.
(16) Leffek, K.; Przuszynski, P.; Thanapaalasingham, K. Can. J .
Chem. 1989, 67, 590.
(11) Shin, J .-S.; Kim, K.-S.; Kim, M.-B.; J eong, J .-H.; Kim, B.-K.
Bioorg. Med. Chem. Lett. 1999, 9, 869.
(12) (a) Chakraborti, A. K.; Nayak, M. K.; Sharma, L. J . Org. Chem.
1999, 64, 8027. (b) Chakraborti, A. K.; Sharma, L.; Nayak, M. K. J .
Org. Chem. 2002, 67, 2541.
(13) Li, M.; Han, X.-W.; Yu, B. Tetrahedron Lett. 2002, 43, 9467.
J . Org. Chem, Vol. 68, No. 17, 2003 6843

SCHEME 2. Syn th esis of F la von oid
7-O-Glycosid esa
F IGURE 1. Regioselective deprotection of the 7-O-acyl Groups
of flavonoids. Enclosed in the parentheses are isolated yields
for the corresponding 7-O-deprotection products. Reagents and
conditions: PhSH (1.2 equiv), imidazole (0.35 equiv), NMP,
rt.
natural decoration of flavonoids.2 Finally, subjection of
chromone hexanoates 14, which bear only two hexanoates
but are in fact not flavonoids, to the above standardized
conditions afforded the 7-O-monodeprotected 15 in a
lower yield of 73%. These results demonstrate that the
present protocol is ideal for the regioselective deprotec-
tion of the 7-O-acyl groups of the peracylated flavones,
isoflavones, and flavonols, which possess the conjugated
ABC ring system.
With this efficient method in hand to regioselectively
free the 7-OH of flavonoid esters, we set out to effect the
7-O-glycosidic coupling. Compared to aliphatic hydroxyls,
phenolic hydroxyls are weaker nucleophiles and thus
usually require activation, in the presence of a hindered
organic base17 or via the formation of a stannyl ether18
or a butyl ether,19 to effect the coupling with glycosyl
donors under the promotion of Lewis acids. J oyfully, we
disclosed that our newly developed glycosyl trifluoroace-
timidates,20 under the promotion of BF3‚Et2O (0.3 equiv),
served as effective donors for the glycosylation of the
7-OH of flavonoid esters. The results for the coupling
reactions between flavonoid derivatives (5, 9a , and 11a )
and glycosyl trifluoroacetimidates (16-18) are depicted
in Scheme 2 and Table 2.
a
Reagents and conditions: (a) 16-18 (2.5 equiv), BF3‚OEt2 (0.3
equiv), 4Å MS, CH2Cl2, rt, overnight. (b) K2CO3, MeOH-THF
(1:1), 40°C; or NaOMe, MeOH- CHCl3, 6°C.
TABLE 2. Syn th esis of F la von oid 7-O-Glycosid es
glycosidation
product
deprotection
product
entry
acceptor
donor
(yield)a
(yield)a,b
1
2
3
5
5
5
9a
9a
11a
16
17
18
16
18
16
19 (64%)c
20 (72%)
21 (64%)c
22 (90%)
23 (75%)
24 (82%)
25 (100%)
26 (100%)
1 (64%)
2 (100%)
27 (68%)
3 (50%)
4d
5d
6
a
b
Isolated yields. Compounds 25-27 are artificial flavonoid
glycosides. c Compounds 19a and 21a were isolated in ∼15%
d
yields. Reaction was carried out in the absence of 4 Å MS.
Glycosylation of 4′,8-dihexanoxy-7-hydroxy isoflavone
5 with perbenzoylated D-glucopyranosyl-, peracetylated
L-rhamnopyranosyl-, and perbenzoylated D-arabinofura-
nosyl-(N-phenyl)trifluoroacetimidate (16-18, 2.5 equiv)
provided the corresponding coupling products (19-21) in
64-72% yields (Table 2, entries 1-3). An unexpected
8f7 acyl migration took place during the glycosylation,
as evidenced by the isolation of the 8-O-glycosides 19a
and 21a (∼15% yield). Acyl migration from a hydroxyl
of stronger acidity to a hydroxyl of weaker acidity under
basic conditions is known.21 However, a reverse migration
(17) (a) Yamaguchi, M.; Horiguchi, A.; Fukuda, A.; Minami, T. J .
Chem. Soc., Perkin Trans. 1 1990, 1079. (b) Oyama, K.-I.; Kondo, T.
Synlett 1999, 1627. (c) Lee, Y. S.; Rho, E. S.; Min, Y. K.; Kim, B. T.;
Kim, K. H. J . Carbohydr. Chem. 2001, 20, 503.
(18) Clerici, F.; Gelmi, M. L.; Mottadelli, S. J . Chem. Soc., Perkin
Trans. 1 1994, 985.
(19) (a) J ensen, K. J .; Meldal, M.; Bock, K. J . Chem. Soc., Perkin
Trans. 1 1993, 2119. (b) Vargas-Berenguel, A.; Meldal, M.; Paulsen,
H.; J ensen, K. J .; Bock, K. J . Chem. Soc., Perkin Trans. 1 1994, 3287.
(20) (a) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405. (b) Yu, B.;
Tao, H. J . Org. Chem. 2002, 67, 9099.
(21) (a) J urd, L.; Rolle, L. A. J . Am. Chem. Soc. 1958, 80, 5527. (b)
Simpson, T. H.; Wright, R. S. J . Org. Chem. 1961, 26, 4686. (c) Vermes,
B.; Farkas, L.; No´gra´di, M. In Topics in Flavonoid Chemistry and
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Budapest; Elsevier: Amsterdam, 1975; pp 162-170. (d) Kurosawa, K.
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6844 J . Org. Chem., Vol. 68, No. 17, 2003

under acidic conditions on flavonoids has not been
reported. The coupling of 4′-hexanoxy-7-hydroxy isofla-
vone 9a with trifluoroacetimidates 16 and 18 hardly
proceeded under similar conditions for the coupling of 5;
however, the reaction took place readily in the absence
of the 4 Å molecular sieves (entries 4-5), giving the
desired products (22 and 23) in good to excellent yields.
Coupling of the quercetin derivative 11a with 18 met
with no problem, affording 24 in 82% yield. All the
glycosidic linkages generated were confirmed by 1H NMR
analysis to be 1,2-trans configurations due to the neigh-
boring participation of the donors in the glycosylation.
Final removal of the acyl groups to elaborate the
flavonoid glycosides was effected under the action of K2-
CO3 in MeOH-THF (1:1) (Table 2). For isoflavone
glycosides, especially the furanosides (i.e., 21 and 23),
the basic conditions were found to cause the partial
cleavage of the sugar moieties, leading to the lower yields
of 1 and 27 (Table 2, entries 3 and 5). Caution was
especially taken in treating flavanol derivatives with a
free 3-OH (i.e., 24f3); an inert atmosphere was found
to be essential to prevent the plausible oxygenation of
the resulting flavonol glycosides under basic conditions.22
In summary, the combination of PhSH and imidazole
in NMP was found to be ideal for the highly regioselective
deprotection of the 7-O-acyl groups of the peracylated
flavones, isoflavones, and flavonols. Glycosylation of the
resulting 7-OH of the flavonoid derivatives with glycosyl
trifluoroacetimidates gave satisfactory yields of the cou-
pling products under the promotion of BF3‚Et2O. Cau-
tious removal of the acyl protecting groups under basic
conditions afforded the desired 7-O-flavonoid glycosides.
Ack n ow led gm en t. The work described in this paper
was supported by the National Natural Science Foun-
dation of China (20172068, 29925203) and the Commit-
tee of Science and Technology of Shanghai (01J C14053).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all new compounds and refer-
ences for all known compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O034553E
(22) (a) Rajananda, V.; Brown, S. B. Tetrahedron Lett. 1981, 22,
4331. (b) Balogh-Hergovich, EÄ .; Speier, G. J . Org. Chem. 2001, 66, 7974.
J . Org. Chem, Vol. 68, No. 17, 2003 6845