Efficient synthesis of kaempferol 3,7-O-bisglycosides via successive glycosylation with glycosyl ortho-alkynylbenzoates and trifluoroacetimidates

Article abstract of DOI:10.1016/j.tetlet.2012.03.103

Selective glycosylation of the 3-OH of 5,4′-di-O-acetyl-kaempferol was achieved with glycosyl ortho-alkynylbenzoates as donors under the catalysis of Ph₃PAuNTf₂, and subsequent glycosylation of the remaining 7-OH with glycosyl triflu

Full text of DOI:10.1016/j.tetlet.2012.03.103

Tetrahedron Letters 53 (2012) 2773–2776
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Efficient synthesis of kaempferol 3,7-O-bisglycosides via successive
glycosylation with glycosyl ortho-alkynylbenzoates and trifluoroacetimidates
Weizhun Yang a,b, Jiansong Sun b, , Zhongyi Yang b, Wei Han a, , Wei-Dong Zhang c, Biao Yu b,
⇑
⇑
⇑
a School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
b State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
c Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Selective glycosylation of the 3-OH of 5,40-di-O-acetyl-kaempferol was achieved with glycosyl ortho-
alkynylbenzoates as donors under the catalysis of Ph3PAuNTf2, and subsequent glycosylation of the
remaining 7-OH with glycosyl trifluoroacetimidates under the catalysis of BF3ꢀOEt2, after global deprotec-
tion, afforded the kaempferol 3,7-O-bisglycosides conveniently.
Article history:
Received 30 January 2012
Revised 20 March 2012
Accepted 27 March 2012
Available online 30 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Selective glycosylation
Kaempferol
Glycosyl ortho-alkynylbenzoate
Glycosyl trifluoroacetimidate
As a major type of the flavonol O-glycosides, over 450 of the
kaempferol glycosides have been identified from plant kingdom;
many of them have their saccharide residues attached at the 3,7-
OH.1 Kaempferol 3,7-O-bisglycosides have shown a broad spectrum
of bioactivities, including antioxidant,2 antifungal,3 glucosidase
inhibition,4 antitumor,5 and hypoglycemic activities.6 However,
there are only two reports on the synthesis of kaempferol 3,7-O-bis-
glycosides,7–9 both employing the glycosylation method with glyco-
syl bromides as donors and silver salt or potassium carbonate as
promoter. For the synthesis of kaempferol 3,7-O-bisglycosides
flanked with different saccharide residues, tedious protecting
groups manipulation was required to differentiate these two hydro-
xyl groups prior to each glycosylation.8 Herein, we report a concise
approach to synthesize kaempferol 3,7-O-bisglycosides, taking
advantage of a selective glycosylation of the 3-OH of 5,40-di-O-acet-
yl-kaempferol with glycosyl ortho-alkynylbenzoates as donors un-
der the catalysis of Ph3PAuNTf2.
We have recently found that glycosyl ortho-alkynylbenzoates
could be effectively applied to glycosylate the 3-OH of 5,7,40-tri-
O-benzyl-kaempferol.10,11 However, attempts at glycosylation of
the 7-OH of kaempferol or quercetin derivatives under similar con-
ditions were not successful. It is known that the 7-OH in flavonol
derivatives is deactivated due to its para position to the electron-
withdrawing 4-carbonyl group.12 These results prompted us to
examine the feasibility of a selective glycosylation of the kaempf-
erol 3-OH in the presence of the free 7-OH with glycosyl ortho-
alkynylbenzoates as donors.
The required 5,40-di-O-acetyl-kaempferol (2) was synthesized
as shown in Scheme 1. Thus, treatment of the commercially avail-
able kaempferol with BnBr (2.1 equiv) and K2CO3 (2.5 equiv) led to
3,7-di-O-benzyl-kaempferol (1)11 in 40% yield. Although the yield
is moderate, this transformation can be easily scaled up to provide
1 in grams quantity. The free 40,5-OHs in 1 were then blocked with
acetyl groups, and the two benzyl groups were removed via
hydrogenolysis (H2, Pd/C) to furnish the kaempferol derivative 2
in high yield (80% for two steps).
Perbenzoyl glucopyranosyl o-hexynylbenzoate 3a (1.5 equiv to 2)
was applied first to couple with 5,40-di-O-acetyl-kaempferol (2) un-
der standard conditions (0.2 equiv Ph3PAuNTf2, CH2Cl2, 4 Å MS, rt).13
The desired kaempferol 3-O-glucoside 4 was isolated in 20% yield,
with the remaining 2 being fully recovered. To enhance the coupling
yield to a practically useful level, the donor quantity was increased to
6.0 equiv; to our delight, a good 78% yield of the 3-O-glucoside 4 was
obtained, without detection of the 7-O-glucosides (Scheme 2, entry
1). Such a tactic has been used successfully in our synthesis of cassia-
side C2.14 Glucopyranosyl o-cyclopropylethynylbenzoates 3b and 3c
also coupled with 2 smoothly to afford the kaempferol 3-O-gluco-
sides 5 and 6 in 70% and 66% yields, respectively (entries 2 and 3).
Glucosyl donors 3b and 3c which bear electron-donating protecting
groups on the 3,4,6-positions are much more reactive than 3a, how-
ever, only trace amounts of the 3,7-O-bisglycosides were detected on
⇑
Corresponding authors. Fax: +86 21 4166128.
E-mail addresses: jssun@sioc.ac.cn (J. Sun), byu@mail.sioc.ac.cn (B. Yu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.103

2774
W. Yang et al. / Tetrahedron Letters 53 (2012) 2773–2776
OAc
OH
OH
HO
O
HO
O
O
BnO
O
O
1) Ac2O, pyridine,
DMAP, rt;
BnBr (2.1 eq), K2CO3,
DMF, rt, 2 h; 40%
OH
OBn
OH
2) H2, 10% Pd/C,
80% for 2 steps
OAc O
OH
OH
2
Kaempferol
1
Scheme 1. Synthesis of 5,40-di-O-acetyl-kaempferol 2.
OAc
O
O
O
R
HO
O
2
(OP)n
(OP)n
O
PPh3AuNTf2 (0.2 equiv),
CH2Cl2, 4A MS, rt
O
OAc O
3a-f (6.0 equiv)
Donor
4-9
Entry
1
Product
Isolated Yield
78%
nBu
OAc
HO
O
O
BzO
O
BzO
BzO
O
O
BzO
OBz
O
OAc O
OBz
4
3a
OBz
OBz
OAc
HO
O
TBDPSO
BnO
BnO
O
BzO
O
70%
66%
O
2
3
O
OBn
OBn
OTBDPS
O
OAc O
O
OBz
5
6
3b
OAc
HO
TBDPSO
AllylO
AllylO
O
O
BzO
O
O
OAllyl
OAllyl
OTBDPS
O
O
OAc
OBz
3c
OAc
HO
O
O
O
O
O
82%
4
OAc O
OBz
OBz
O
BzO
BzO
OBz
7
3d
BzO
OAc
HO
O
O
O
O
65%
77%
O
5
6
OAc O
BnO
BzO
O
3e
OBz
OBz
OBz
8
BnO
OAc
nBu
O
HO
O
O
O
AcO
O
O
OAc
O
OAc
OAc
AcO
OAc
AcO
9
3f
Scheme 2. Regioselective 3-O-glycosylation of 5,40-di-O-acetyl-kaempferol 2 with glycosyl ortho-alkynylbenzoates.
TLC when coupling with 2. Rhamnosyl o-cyclopropylethynylbenzo-
ates 3d and 3e, were also proved to be good donors for the selective
glycosylation of 2, providing the 3-O-rhamnosides 7 and 8 in good
yields (entries 4 and 5). Ribofuranosyl donor 3f coupled with 2 under
similar conditions to furnish the 3-O-furanoside 9 in a satisfactory
77% yield (entry 6). The resulting coupled glycosides 4–8 were

W. Yang et al. / Tetrahedron Letters 53 (2012) 2773–2776
2775
subjected to deprotection under conventional conditions to provide
kaempferol 3-O-glucoside (from 4–6) and 3-O-rhamnoside (from 7
and 8), which showed identical analytical data to those reported
for the natural products.15,16 The glycosylation position in compound
9 was confirmed by acetylation of the remaining 7-OH in 9, which
led to the down-field shift of the H-6 and H-8 from 6.50 and
6.63 ppm to 6.78 and 7.20 ppm, respectively.
We have previously shown that the poorly nucleophilic flavo-
noid 7-OH could be effectively glycosylated with glycosyl trifluoro-
acetimidates17 under the catalysis of BF3ꢀEt2O.18 However, this
protocol has not been applied to the glycosylation of the 7-OH of
the flavonoid 3-O-glycosides, which bear the acidic labile 3-O-gly-
cosidic linkage.10 Thus, glycosylation of kaempferol 3-O-glucoside
4 with perbenzoyl glucopyranosyl trifluoroacetimidate 10a was
examined first under the action of 0.2 equiv of BF3ꢀEt2O (CH2Cl2,
4 Å MS, rt); the reaction could not reach completion. Upon increas-
ing the amount of BF3ꢀEt2O to 0.5 equiv, the reaction proceeded
smoothly to provide the coupled disaccharide 11 in a good 75%
yield (Scheme 3, entry 1), and no cleavage of the 3-O-glycosidic
linkage was detected. However, further increasing the catalyst
amount to 1.0 equiv resulted in apparent decomposition of the
resulting disaccharide. In the presence of 0.5 equiv of BF3ꢀEt2O,
10a also coupled with kaempferol 3-O-rhamnoside 7 smoothly to
give a satisfactory yield of 12 (entry 2). Under the similar condi-
tions, rhamnosyl trifluoroacetimidate 10b coupled with kaempfer-
ol 3-O-glucosides 4, 7 and 5 effectively, leading to the desired 3,
7-O-bisglycosides 13, 14, and 15 in 75–79% yields (entries 3, 4,
and 5). The 7-O-glycosylation brought about the evident down-
field shift of the kaempferol H-6 and H-8 from around 6.5 and
6.6 ppm to 6.8 and 7.1 ppm, respectively.18
After the successive glycosylation protocol has been success-
fully established,19 the resulting 3,7-O-bisglycosides 13 and 14
were subjected to deprotection under basic conditions (K2CO3,
MeOH, THF, rt), leading to the desired kaempferol 3,7-O-bisglyco-
sides 16 and 17 in 86–96% yields (Scheme 4). The analytical data
of these compounds were in good accordance with those reported
for the natural products.7,20 In addition, compounds 16 and 17
have been reported to posses interesting bioactivities.7,21,22 Com-
pound 17, namely kaempferitrin, showed significant hypoglycemic
effect, has been synthesized in nine steps and in 5.5% total yield.7
OAc
BF3EtO2 (0.5 equiv),
OAc
O
Sugar2O
O
O
O
O
HO
O
NPh
+
OSugar1
OSugar1
CH2Cl2, 4A MS, rt
(OP)n
CF3
OAc
OAc
10a 10b
or
(3 equiv)
Donor
4, 5, or 7
11-15
Entry
Product
Isolated Yield
75%
Acceptor
OBz
OAc
BzO
O
BzO
BzO
NPh
CF3
BzO
BzO
BzO
O
O
O
1
2
OBz
O
4
7
O
OBz
10a
OBz
OBz
OBz
OAc
O
OAc O
11
OBz
O
BzO
BzO
O
O
10a
OBz
70%
O
OAc O
BzO
O
12
OBz
OAc
OBz
NPh
CF3
O
O
O
O
BzO
O
AcO
AcO
3
4
O
79%
75%
AcO
AcO
4
7
OBz
OBz
OBz
OAc
O
OAc O
OAc
OAc
13
10b
O
O
O
AcO
AcO
10b
O
OAc O
OAc
O
OBz
OBz
14 BzO
OAc
O
O
O
BzO
AcO
AcO
5
10b
5
O
79%
OBn
OBn
OTBDPS
O
OAc O
15
OAc
Scheme 3. 7-O-Glycosylation of the kaempferol 3-O-glycosides 4, 5, and 7 with glycosyl trifluoroacetimidates.

2776
W. Yang et al. / Tetrahedron Letters 53 (2012) 2773–2776
4. Phuwapraisirisan, P.; Puksasook, T.; Kokpol, U.; Suwanboriux, K. Tetrahedron
OH
Lett. 2009, 50, 5864–5867.
5. Ibrahim, L. F.; Kawashty, S. A.; El-Hagrassy, A. M.; Nassar, M. I.; Mabry, T. J.
Carbohydr. Res. 2008, 343, 155–158.
O
O
O
HO
HO
O
6. de Sousa, E.; Zanatta, L.; Seifriz, I.; Creczynski-Pasa, T. B.; Pizzolatti, M. G.;
Szpoganicz, B.; Silva, F. R. M. B. J. Nat. Prod. 2004, 67, 829–832.
7. Urgaonkar, S.; Shaw, J. T. J. Org. Chem. 2007, 72, 4582–4585.
8. Liu, Q.; Li, W.; Guo, T.; Li, D.; Fan, Z.; Yan, S. Chem. Lett. 2011, 40, 324–325.
9. For the synthesis of quercetin 3,7-O-bisglycosides, see: Du, Y.; Wei, G.;
Linhardt, R. J. Tetrahedron Lett. 2003, 44, 6887–6890.
10. For the synthesis of kaempferol monoglycosides, see: Yang, W.; Sun, J.; Lu, W.;
Li, Y.; Shan, L.; Han, W.; Zhang, W.-D.; Yu, B. J. Org. Chem. 2010, 75, 6879–6888.
and references cited therein.
HO
O
HO
OH
OH
OH
OH
O
16
(93%)
K2CO3, MeOH, THF
rt
13
14
OH
O
O
O
HO
11. Li, Y.; Yang, W.; Ma, Y.; Sun, J.; Shan, L.; Zhang, W.-D.; Yu, B. Synlett 2011, 915–
918.
12. Kajjout, M.; Rolando, C. Tetrahedron 2011, 67, 4731–4741.
13. (a) Li, Y.; Yang, Y.; Yu, B. Tetrahedron Lett. 2008, 49, 3604–3608; (b) Li, Y.; Yang,
X. Y.; Liu, Y. P.; Zhu, C. S.; Yang, Y.; Yu, B. Chem. Eur. J. 2010, 16, 1871–1882; (c)
Zhu, Y.; Yu, B. Angew. Chem., Int. Ed. 2011, 50, 8329–8332.
O
HO
OH
O
OH
O
OH
OH
17
(96%)
HO
14. Zhang, Z.; Yu, B. J. Org. Chem. 2003, 68, 6309–6313.
15. Chen, L.; Wang, J.-J.; Zhang, G.-G.; Song, H.-T. Nat. Prod. Res. 2009, 23, 1330–
1336.
Scheme 4. Synthesis of kaempferol 3,7-O-bisglycosides.
16. Yang, N.-Y.; Tao, W.-W.; Duan, J.-A. Nat. Prod. Res. 2010, 24, 1843–1849.
17. (a) Yu, B.; Sun, J. Chem. Commun. 2010, 46, 4668–4679; (b) Yu, B.; Tao, H.
Tetrahedron Lett. 2001, 42, 2405–2407.
The present synthesis of 17 requires six steps and in 19% overall
yield, starting from kaempferol, rhamnosyl ortho-alkynylbenzoate
3d and rhamnosyl trifluoroacetimidate 10b.
18. Li, M.; Han, X.; Yu, B. J. Org. Chem. 2003, 68, 6842–6845.
19. General procedure for the regioselective glycosylation of the 3-OH of 2 with
glycosyl ortho-alkynylbenzoates donors: To a stirred mixture of glycosyl o-
alkynylbenzoate (0.49 mmol), 2 (30 mg, 0.081 mmol), and 4 Å MS in CH2Cl2
(2.5 mL) was added Ph3PAuNTf2 (12 mg, 0.016 mmol). After being stirred at rt
overnight, the mixture was filtered through a pad of Celite. The filtrate was
concentrated and the residue was purified by silica gel column
chromatography to give the corresponding glycoside. General procedure for
In summary, a facile approach to the synthesis of kaempferol
3,7-O-bisglycosides has been developed, taking advantage of the
selective glycosylation of the 3-OH of 5,40-di-O-acetyl-kaempferol
with glycosyl ortho-alkynylbenzoates under the catalysis of
Ph3PAuNTf2 and subsequent glycosylation of the remaining 7-OH
with glycosyl trifluoroacetimidates under the promotion of
BF3ꢀOEt2. A panel of the natural flavonol glycosides, including
kaempferol 3-O-glucopyranoside, 3-O-rhamnopyranoside, 3,7-O-
bisrhamnopyranoside (17), and 3-O-glucopyranosyl-7-O-rhamno-
pyranoside (16), have thus been conveniently synthesized.
the
glycosylation
of
kaempferol
3-O-monoglycosides
with
(N-
phenyl)trifluoroacetimidate:
To
a
suspension of the
kaempferol
monoglycosides acceptor (0.05 mmol), glycosyl trifluoroacetimidate donor
(0.15 mmol), and 4 Å molecular sieves in CH2Cl2 (2.5 mL) was added a solution
of BF3ꢀEt2O in CH2Cl2 (0.1 M, 0.25 mL). After stirring at room temperature
overnight, the reaction was quenched with Et3N. The mixture was then
filtrated and concentrated, and the residue was purified by silica gel column
chromatography to give the corresponding glycoside.
20. (a) Kamiya, K.; Yoshioka, K.; Saiki, Y.; Ikuta, A.; Satake, T. Phytochemistry 1997,
44, 141–144; (b) Ozden, S.; Durust, N.; Toki, K.; Saito, N.; Honda, T.
Phytochemistry 1998, 49, 241–245.
Acknowledgment
21. (a) Marin, C.; Ramirez-Macias, I.; Lopez-Cespedes, A.; Olmol, F.; Villegas, N.;
Diaz, J. G.; Rosales, M. J.; Gutierrez-Sanchez, R.; Sanchez-Moreno, M. J. Nat.
Prod. 2011, 74, 744–750; (b) Tselepi, M.; Papachristou, E.; Emmanouilidi, A.;
Angelis, A.; Aligiannis, N.; Skaltsounis, A.-L.; Kouretas, D.; Liadaki, K. J. Nat.
Prod. 2011, 74, 2362–2370.
Financial support from the National Major Project of China
(Grants 2009ZX09311-001 and 2008ZXJ09004-007) and the Na-
tional Natural Science Foundation of China (20921091 and
20621062) are gratefully acknowledged.
22. Analytic data for compound 16 and 17: For compound 16: 1H NMR (300 MHz,
DMSO-d6): d 8.09 (d, J = 8.4 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 6.82 (s, 1 H), 6.44
(d, J = 1.8 Hz, 1 H), 5.55 (s, 1 H), 5.50 (d, J = 6.9 Hz, 1 H), 3.84 (s, 1 H), 3.65 (m, 9
H), 1.12 (d, J = 5.4 Hz, 3 H); 13C NMR (100 MHz, DMSO-d6): d 177.5, 161.6,
161.0, 156.8, 156.0 , 133.4, 131.0, 120.2, 115.3, 105.7, 100.8, 99.4, 98.4, 94.4,
79.2, 77.5, 76.5, 74.2, 71.6, 70.3, 70.0, 69.9, 69.8, 60.9, 17.9. For compound 17:
1H NMR (400 MHz, CD3OD): d 7.80 (d, J = 8.4 Hz, 2 H), 6.94 (d, J = 8.4 Hz, 2 H),
6.72 (s, 1 H), 6.46 (s, 1 H), 5.56 (s, 1 H), 5.39 (s, 1 H), 4.22 (s, 1 H), 4.02 (s, 1 H),
3.84 (m, 1 H), 3.73 (m, 1 H), 3.60 (m, 1 H), 3.50 (t, J = 9.6 Hz, 1 H), 3.34 (m, 1 H)
1.27 (d, J = 6.0 Hz, 3 H), 0.94 (d, J = 6.4 Hz, 3 H); 13C NMR (100 MHz, DMSO-d6):
d 178.4, 162.2, 161.6, 161.1, 158.3, 156.6, 135.0, 131.2, 120.7, 116.0, 106.3,
102.4, 100.0, 99.0, 95.0, 72.2, 71.7, 71.2, 70.9, 70.8, 70.6, 70.3, 18.4, 18.0.
References and notes
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