Efficient synthesis of a bisglycosyl kaempferol from fagonia taeckholmiana

Article abstract of DOI:10.1246/cl.2011.324

The first total synthesis of kaempferol-3-O-β-L-arabinopyranosyl-( 1→4)-α-L-rhamnopyranoside-7-O-α-L-rhamnopyranoside (1), a 3, 7-triglycosylflavone, which was isolated from the aerial parts of Fagonia taeckholmiana, was accomplished in 13 steps and 9.2% overall yield from commercially available kaempferol. We efficiently employed phase-transfer- catalyzed (PTC) glycosylation for the construction of phenol glycosides. Applying this approach will allow the preparation of derivatives for further study of structureactivity relationships (SAR).

Full text of DOI:10.1246/cl.2011.324

doi:10.1246/cl.2011.324
324
Published on the web February 23, 2011
Efficient Synthesis of a Bisglycosyl Kaempferol from Fagonia taeckholmiana
Qingchao Liu,*1 Wenhong Li,1 Tiantian Guo,2 Dong Li,1 Zhen Fan,1 and Suihong Yan1
1Department of Pharmaceutical Engineering, Northwest University, Xi’an 710069, Shaanxi, P. R. China
2Department of Medical Science, Xi’an Creation College, Yanan University, Xi’an 710100, Shaanxi, P. R. China
(Received November 29, 2010; CL-101008; E-mail: liuqc21@nwu.edu.cn)
The first total synthesis of kaempferol-3-O-¢-L-arabinopyr-
OH
4'
6'
3
anosyl-(1¼4)-¡-L-rhamnopyranoside-7-O-¡-L-rhamnopyrano-
side (1), a 3,7-triglycosylflavone, which was isolated from the
aerial parts of Fagonia taeckholmiana, was accomplished in 13
steps and 9.2% overall yield from commercially available
kaempferol. We efficiently employed phase-transfer-catalyzed
(PTC) glycosylation for the construction of phenol glycosides.
Applying this approach will allow the preparation of derivatives
for further study of structure-activity relationships (SAR).
8
7
O
O
O
2'
1''
O
HO
6
O
5
HO
1'''
OH
HO
HO
OH
O
1''''
O
OH
OH
O
OH
1
Figure 1. Chemical structure of bisglycosyl kaempferol 1.
Glycosylated flavonoids are a specific class of natural
products widely distributed in the plant kingdom, which consist
of a flavonol skeleton bearing one or more sugar chains.1-4 They
exhibit a wide range of biological activities such as protection
against UV light,5 flower color development,6 insect stimulants,7
and more interestingly, present a variety of medicinal properties
which might be beneficial to humans, including anticancer,8,9
antimicrobial,10 anti-inflammatory,11 inhibitors against influenza
virus sialidase,12 radical scavenging,1,2 hepatoprotectant,13 anti-
diabetic,14 neuroprotective,15 and inhibition of HIV reverse
transcriptase and DNA topoisomerase I.16 In contrast to the
widespread distribution and important biological activities of
glycosylated flavonoids, access to this class of natural products
via facile chemical synthesis presents a formidable task. The
major bottleneck to the synthesis of flavonoid glycosides are the
poor solubility of most flavonoids in common organic solvents
and the lack of sophisticated protecting-group strategies. Despite
the considerable attention to synthesis of monoglycosyl flavones
has attracted in the last decade,9,17-25 preparation of bisglycosyl
flavones has been scarcely reported to date.26-30
Recently, kaempferol-3-O-¢-L-arabinopyranosyl-(1¼4)-¡-
L-rhamnopyranoside-7-O-¡-L-rhamnopyranoside (1), a 3,7-tri-
glycosylflavone (Figure 1), was isolated from the aerial parts of
Fagonia taeckholmiana. The cytotoxic activity of the alcohol
and water extracts including bisglycosyl kaempferol 1 against
MCF7 human breast tumor cells in culture exhibited an IC50 of
8.72 and 9.80 ¯g mL¹1, respectively.31 Bisglycosyl kaempferol
1 may be one of the major active components of Fagonia
taeckholmiana, yet the difficulties in obtaining compound 1
(12 mg from 2 kg of the dried powdered plant) have hindered
further pharmacological studies, so chemical synthesis is needed
and appears to be a rational way to gain access to adequate
amounts for thorough pharmacological research and further SAR
investigation. We report here the first total synthesis of this
natural product.
OH
OH
AllO
O
HO
AllO
AllO
O
a
OH
OH
OH
O
2
OH
O
kaempferol
b
OH
OAc
O
c
AllO
O
OAc
OAc
OAc
O
4
OAc
O
3
d
OBn
OBn
O
AllO
O
e
OAc
OH
OAc
O
OH
O
6
5
Scheme 1. Synthesis of acceptor 5. Reagents and conditions: (a)
allyl bromide (AllBr), TBAB, K2CO3, DMF-H2O (v:v, 1:1), 50 °C,
69%; (b) Ac2O, pyridine, 89%; (c) PhSH, imidazole, NMP, ¹20 °C,
85%; (d) BnBr, K2CO3, KI, DMF, 71%; (f) 10% aq NaOH, MeOH,
reflux, 100%.
was treated with allyl bromide under PTC (phase-transfer-
catalyzed) conditions, namely, in the presence of tetrabutylam-
monium bromide (TBAB) and K2CO3 in 1:1 DMF-H2O at 50 °C,
affording 7-O-allylkaempferol (2) in 69% yield.25 Observing the
NOE correlation between H-6 or H-8 and the allyl OCH2 protons
in compound 2 confirmed the position of the allylation.
Acetylation of 2 with acetic anhydride in pyridine then provided
7-O-allylkaempferol triacetate (3) in 89% yield. With the 7-OH
being blocked with an allyl group, compound 3, upon treatment
with PhSH and imidazole in N-methylpyrrolidone (NMP) at low
temperature (¹20 °C), gave the free 4¤-OH product 4 in high
selectivity (85%).19 Finally benzylation of the 4¤-OH followed by
removal of the remaining 3- and 5-O-acetyl groups provided
4¤-O-benzyl-7-O-allylkaempferol (6) conveniently.
We envisioned that bisglycosyl kaempferol 1 could be
constructed from the suitably protected 7,4¤-dihydroxyflavone 6,
a disaccharide donor 12, and easily prepared rhamnopyranosyl
donor 14. As shown in Scheme 1, our synthetic approach to 6
commenced with the commercially available kaempferol, which
Disaccharide bromide 12 was prepared through conven-
tional glycosylation and protecting group manipulation. As
Chem. Lett. 2011, 40, 324-325
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

325
OAc
BnO
glycosides. Further study on preparation and bioactivity evalua-
tion of analogs and derivatives is in progress and will be
reported in due course.
O
NH
CCl3 AcO
OAc
AcO
O
R1
STol
O
8
BnO
O
O
O
HO
a
R2O
OR3
O
O
This work was financially supported by the Scientific
Research Foundation of Northwest University (No. PR10035).
9 R1 = STol, R2, R3 = isopropylidene
b
c
7
10 R1 = STol, R2 = R3 = H
11 R1 = STol, R2 = R3 = Ac
References and Notes
1
B. A. Bohm, Introduction to Flavonoids: Chemistry and Biochem-
istry of Organic Natural Products, Harwood Academic Publishers,
Amsterdam, 1998.
OBn
AllO
O
OAc
2
The Handbook of Natural Flavonoids, ed. by J. B. Harborne, H.
Baxter, John Wiley & Sons, Chichester, 1999, Vol. 1.
J. B. Harborne, C. A. Williams, Nat. Prod. Rep. 2001, 18, 310.
N. C. Veitch, R. J. Grayer, Nat. Prod. Rep. 2008, 25, 555.
M. Mori, K. Yoshida, Y. Ishigaki, T. Matsunaga, O. Nikaido, K.
Kameda, T. Kondo, Bioorg. Med. Chem. 2005, 13, 2015.
Ø. M. Andersen, M. Jordheim, in Flavonoids: Chemistry, Bio-
chemistry and Applications, ed. by Ø. M. Andersen, K. R.
Markham, CRC Press, Boca Raton, 2006, pp. 471-551.
P. Feeny, K. Sachdev, L. Rosenberry, M. Carter, Phytochemistry
1988, 27, 3439.
OH
O
O
Br
AcO
OH
O
6
d
BnO
O
3
4
5
e
AcO
OAc
12
Br
OBn
BzO
OBn
O
6
R4O
O
O
O
O
BzO
OBz
15
O
BzO
O
O
e
BzO
OH
O
O
O
7
8
9
OBz
OH
O
O
O
AcO
AcO
f
OAc
OAc
AcO
AcO
J. A. Smith, C. E. Poteet-Smith, Y. Xu, T. M. Errington, S. M.
Hecht, D. A. Lannigan, Cancer Res. 2005, 65, 1027.
J. A. Smith, D. J. Maloney, S. M. Hecht, D. A. Lannigan, Bioorg.
Med. Chem. 2007, 15, 5018.
OAc
OAc
O
OBn
OBn
13 R4
16
1
= All
g
14 R4
= H
10 M. M. Cowan, Clin. Microbiol. Rev. 1999, 12, 564.
11 K. Marinova, K. Kleinschmidt, G. Weissenböck, M. Klein, Plant
Physiol. 2007, 144, 432.
12 T. Nagai, Y. Miyaichi, T. Tomimori, Y. Suzuki, H. Yamada, Chem.
Pharm. Bull. 1990, 38, 1329.
13 A. S. Awaad, D. J. Maitland, G. A. Soliman, Bioorg. Med. Chem.
Lett. 2006, 16, 4624.
14 A. P. Jorge, H. Horst, E. de Sousa, M. G. Pizzolatti, F. R. M. B.
Silva, Chem. Biol. Interact. 2004, 149, 89.
Scheme 2. Synthesis of target compound 1. Reagents and con-
ditions: (a) TMSOTf, CH2Cl2, ¹78 °C, 79%; (b) 80% AcOH, reflux,
87%; (c) Ac2O, pyridine, 90%; (d) Br2, CH2Cl2, 0 °C, 85%; (e)
K2CO3, TBAB, CHCl3-H2O, 50 °C, 79% for 13; 80% for 16; (f)
PdCl2, MeOH, 87%; (g) H2, 10% Pd-C, EtOH-EtOAc, 40 °C;
NaOMe, MeOH-CH2Cl2, rt, 86% for two steps.
15 S. H. Kim, C. N. Kumar, H. J. Kim, D. H. Kim, J. Cho, C. Jin, Y. S.
Lee, Bioorg. Med. Chem. Lett. 2009, 19, 6009.
16 J. Ma, S. H. Jones, R. Marshall, X. Wu, S. M. Hecht, Bioorg. Med.
Chem. Lett. 2005, 15, 813.
depicted in Scheme 2, coupling of p-tolyl 2,3-O-isopropylidene-
1-thio-¡-L-rhamnopyranoside (7)32 with 2-O-benzyl-3,4-di-O-
acetyl-¢-L-alabinopyranosyl trichloroacetimidate (8)33 under the
promotion of TMSOTf stereoselectively provided disaccharide
9 in 79% yield. The isopropylidene of 9 was readily cleaved
using 80% HOAc at 80 °C, and the free hydroxy groups were
then acetylated with acetic anhydride in pyridine affording 11.
Finally, bromination of the anomeric position using elemental
bromine at 0 °C gave disaccharide bromide 12 in 85% yield.
With efficient synthetic access to 4¤-O-benzyl-7-O-allyl-
kaempferol (6) and disaccharide bromide 12, we next turned
our attention to the synthesis of natural product 1 via PTC
glycosylation, which was used for flavonoid glycosides by Li
et al. and Du et al.17,18,26 Treatment of diol 6 with disaccharide
bromide 12 under PTC conditions regioselectively provided
the desired 3-O-¢-glycoside 13 in 79% isolation yield. After
deprotection of the allyl group with PdCl2, similar PTC
conditions described above were employed for the coupling of
diol 14 with easily prepared rhamnopyranosyl bromide 15,
affording the corresponding 7,4¤-diglycoside 16 in a satisfactory
80% yield. Finally, removal of the benzyl group (H2, 10%
Pd-C) and all acyl groups (NaOMe) cleanly furnished the target
kaempferol glycoside 1 in 86% yield,34 whose analytical data
are identical in all respects to those reported in the literature.31
In conclusion, we succeeded in the first total synthesis of
bisglycosyl kaempferol 1 from commercially available kaemp-
ferol in 13 steps and 9.2% overall yield. The PTC glycosylation
strategy proved to be very efficient for the construction of phenol
17 M. Li, X. W. Han, B. Yu, Tetrahedron Lett. 2002, 43, 9467.
18 Y. Du, G. Wei, R. J. Linhardt, J. Org. Chem. 2004, 69, 2206.
19 W. Peng, Y. Li, C. Zhu, X. Han, B. Yu, Carbohydr. Res. 2005, 340,
1682.
20 J. A. Smith, D. J. Maloney, D. E. Clark, Y. M. Xu, S. M. Hecht,
D. A. Lannigan, Bioorg. Med. Chem. 2006, 14, 6034.
21 S. T. Caldwell, H. M. Petersson, L. J. Farrugia, W. Mullen, A.
Crozier, R. C. Hartley, Tetrahedron 2006, 62, 7257.
22 M. D. Shan, G. A. O’Doherty, Org. Lett. 2006, 8, 5149.
23 K. Oyama, S. Kawaguchi, K. Yoshida, T. Kondo, Tetrahedron Lett.
2007, 48, 6005.
24 W. Yang, J. Sun, W. Lu, Y. Li, L. Shan, W. Han, W.-D. Zhang, B.
Yu, J. Org. Chem. 2010, 75, 6879.
25 L. Zhang, G. Wei, Y. Du, Carbohydr. Res. 2010, 345, 2714.
26 Y. Du, G. Wei, R. J. Linhardt, Tetrahedron Lett. 2003, 44, 6887.
27 C. Zhu, W. Peng, Y. Li, X. Han, B. Yu, Carbohydr. Res. 2006, 341,
1047.
28 S. Urgaonkar, J. T. Shaw, J. Org. Chem. 2007, 72, 4582.
29 Q. Gao, G. Lian, F. Lin, Carbohydr. Res. 2009, 344, 511.
30 J. Chen, W. Huang, G. Lian, F. Lin, Carbohydr. Res. 2009, 344,
2245.
31 L. F. Ibrahim, S. A. Kawashty, A. M. El-Hagrassy, M. I. Nassar, T. J.
Mabry, Carbohydr. Res. 2008, 343, 155.
32 Z. Zhang, P. Wang, N. Ding, G. Song, Y. Li, Carbohydr. Res. 2007,
342, 1159.
33 For the synthesis of donor 8, see ref. 34.
34 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2011, 40, 324-325
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/