Concise synthesis of chafurosides A and B

Article abstract of DOI:10.1021/ol900689m

The regioselective synthesis of chafurosides A (1) and B (2) from the same methyl ketone 5 was accomplished using a novel protecting group strategy. Both flavone rings were constructed from β-diketone intermediate 4, which was readily obtained by condensation of an acyl donor and ketone 5. Construction of the dihydrofuran ring was achieved via an intramolecular Mitsunobu reaction.

Full text of DOI:10.1021/ol900689m

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2233-2236
Concise Synthesis of Chafurosides A
and B
Takumi Furuta,† Miho Nakayama, Hirotaka Suzuki, Hiroko Tajimi, Makoto Inai,
Haruo Nukaya, Toshiyuki Wakimoto,* and Toshiyuki Kan*
School of Pharmaceutical Sciences, UniVersity of Shizuoka and Global COE Program,
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
wakimoto@u-shizuoka-ken.ac.jp; kant@u-shizuoka-ken.ac.jp
Received March 2, 2009
ABSTRACT
The regioselective synthesis of chafurosides A (1) and B (2) from the same methyl ketone 5 was accomplished using a novel protecting group
strategy. Both flavone rings were constructed from ꢀ-diketone intermediate 4, which was readily obtained by condensation of an acyl donor
and ketone 5. Construction of the dihydrofuran ring was achieved via an intramolecular Mitsunobu reaction.
Oolong tea extract exhibits a suppressive effect for type I
and IV reactions related to atopic dermatitis.1 A novel flavone
C-glycoside, chafuroside A (1),2 which displays potent
inhibitory activity against DNFB (2,4-dinitrofluorobenzene)
induced contact hypersensitivity in mice, at a concentration
of 1.0-10 µg/kg, has been isolated as the active ingredient.
Flavonoids typically exhibit moderate anti-inflammatory
activity, but 1 shows significantly potent anti-inflammatory
activity compared to other flavonoids, including isovitexin,
vitexin, and apigenin.3 Although oolong tea has a particularly
Figure 1.
Structures of 1 and 2.7
high content of 1, the compound provided by the natural
source is not enough for further study of its biological
functions.
posed of a dihydrofuran ring between the 2′ and 7-OH and
a C-glycoside bond at the C8 position, efficient total
syntheses of 1 and 2 are highly desired. Because 1 and 2
possess similar skeleta, an efficient synthetic method for
construction of the flavone ring should be a key step for the
synthesis of these minor nutritional ingredients. Since we
could not achieve efficient formation of the flavone ring in
the previous study in 2004,5 we have continuously made
efforts to develop an efficient synthetic method for obtaining
the flavone ring6 and we succeeded in applying a new
protocol in the second generation of total synthesis of 1 and
Due to the remarkable bioactivity of 1 and the regioiso-
meric skeleton of newly isolated chafuroside B (2)4 com-
† Present Address: Institute for Chemical Research, Kyoto University,
Uji, Kyoto 611-0011, Japan.
(1) Uehara, M.; Sugiura, H.; Sakurai, K. Arch. Dermatol. 2001, 137,
42.
(2) Ishikura, Y.; Tsuji, K.; Nukaya, H. Jpn. Kokai Tokkyo Koho 2002,
194828.
(3) (a) Whiting, D. A. Nat. Prod. Rep. 2001, 18, 583. (b) Marinova, K.;
Kleinschmidt, K.; Weissenbo¨ck, G.; Klein, M. Plant Physiol. 2007, 144,
432.
(4) Detailed data of isolation and structure elucidation of chafuroside B
are described in Supporting Information sections II and III.
10.1021/ol900689m CCC: $40.75
Published on Web 04/27/2009
 2009 American Chemical Society

2. Herein we report the details of these synthetic investiga-
tions.
of isovitexin (3a) and vitexin (3b). Because the conversion
of the flavone ring from a ꢀ-diketone intermediate has been
reported,9,10 3a and 3b could be derived from appropriately
protected 4a and 4b, respectively.11 To construct ꢀ-diketone
4, an alkylation reaction between acyl donor equivalent 9
and methyl ketone 5 would be suitable because C-glycoside
5 is readily available from O-glycosidation and a subsequent
O-C rearrangement between glucosyl imidate 6 and an
acetophenone derivative 7.12
Scheme 1. Retrosynthetic Analysis of 1 and 2
As shown in Scheme 2, the synthesis of chafuroside A
(1) began from tetra-O-benzyl-D-glucosyl imidate (6)12a and
acetophenone derivative 7, which was synthesized according
to Cairns’ method.13 Upon treatment of 6 and 7 with
TMSOTf, O-glycosidation and successive O-C rearrange-
ment (Fries rearrangement)14 proceeded smoothly to give
an aryl C-glucoside 5. In this reaction, O-glucoside 8 was
detected by terminating the reaction after a short time.12
Because of the different reactivity for each phenolic hydroxyl
group of 5, various protecting groups were incorporated in
a stepwise manner.15 The less hindered 8a-OH of 5 was
selectively protected by treatment with TBDPSCl and
imidazole to give mono-TBDPS ether. The reactivity of the
remaining free phenol was low due to hydrogen bonding with
the neighboring carbonyl group as well as steric hindrance
from both substituents at the ortho positions. After several
attempts to protect the phenol,15 we found that the Mitsunobu
conditions were suitable for alkylation of the remaining
phenol. Thus, treatment of the phenol with benzyl alcohol
(7) Numbering for 1 and 2 was according to flavone style.
(8) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
(9) Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192.
(10) (a) Baker, W. J. Chem. Soc. 1933, 1381. (b) Mahal, H. S.;
Venkataraman, K. J. Chem. Soc. 1934, 1767. (c) von Kostanecki, S.;
Ro´zycki, A. Ber. Dtsch. Chem. Ges. 1901, 34, 102.
(11) While preparing this manuscript, a similar strategy for ring
formation of prenylflavones has been reported. In their method, a prenyl
group and protecting group such as TBS and Pivaloyl groups were
regioselectively introduced on the flavone A ring: Minassi, A.; Giana, A.;
Ech-Chahad, A.; Appendino, G. Org. Lett. 2008, 10, 2267.
(12) For the synthesis of flavone glycosides, see: (a) Mahling, J.-A.;
Jung, K.-H.; Schmidt, R. R. Liebigs Ann. Chem. 1995, 461. (b) Mahling,
J.-A.; Schmidt, R. R. Synthesis 1993, 325. (c) Ohmori, K.; Hatakeyama,
K.; Ohrui, H.; Suzuki, K. Tetrahedron 2004, 60, 1365. (d) Oyama, K.;
Kawaguchi, S.; Yoshida, K.; Kondo, T. Tetrahedron. Lett. 2007, 48, 6005.
(e) Seijas, J. A.; Va`zquez-Tato, M. P.; Carballido-Reboredo, R. J. Org.
Chem. 2005, 70, 2855. (g) Li, M.; Han, X.; Yu, B. J. Org. Chem. 2003, 68,
6842. (h) Urgaonkar, S.; Shaw, J. T. J. Org. Chem. 2007, 72, 4582. (i)
Shan, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 5149. (j) Maloney, D. J.;
Hecht, S. M. Org. Lett. 2005, 7, 1097. (k) Du, Y.; Wei, G.; Linhardt, R. J.
Tetrahedron Lett. 2003, 44, 6887. (l) Zhu, C.; Peng, W.; Li, Y.; Han, X.;
Yu, B. Carbohydr. Res. 2006, 341, 1047. (n) Sato, S.; Akiya, T.; Suzuki,
T.; Onodera, J. Carbohydr. Res. 2004, 339, 2611. (m) Oyama, K.; Kondo,
T. J. Org. Chem. 2004, 69, 5240. (o) Chen, Z.; Hu, Y.; Wu, H.; Jiang, H.
Bioorg. Med. Chem. Lett. 2004, 14, 3949.
Scheme 1 illustrates our synthetic plan. According to our
previous synthetic investigation of 1,5a the dihydrofuran ring
of 1 and 2 could be constructed by Mitsunobu conditions8
at a late stage in the synthesis. Thus, the crucial step in the
syntheses of 1 and 2 would be regioselective construction
(13) Cairns, H. Tetrahedron 1972, 28, 359. Phloroglucinol was acetylated
with a boron trifluoride-acetic acid complex to afford C-diacetylphloroglu-
cinol. Subsequent benzylation with BnBr and K2CO3 resulted in mono-
benzylation. Then hydrolysis of an acetyl group with 1 M NaOH gave
desired acetophenone derivative 7. For experimental details, see Supporting
Information section IV.
(14) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1988,
29, 6935.
(5) (a) Furuta, T.; Kimura, T.; Kondo, S.; Mihara, H.; Wakimoto, T.;
Nukaya, H.; Tsuji, K.; Tanaka, K. Tetrahedron 2004, 60, 9375. (b)
Nakatsuka, T.; Tomimori, Y.; Fukuda, Y.; Nukaya, H. Bioorg. Med. Chem.
Lett. 2004, 14, 3201. (c) Kan, T.; Furuta, T. Jpn. Kokai Tokkyo Koho 2008,
13.
(15) To protect the remaining free phenol, allyl bromide was tentatively
selected as the smaller protective group due to the expected steric hindrance
of this phenol group. However, using a strong base such as NaH or LiHMDS
removed the TBDPS group. On the other hand, conditions with a milder
base such as K2CO3 did not result in a reaction. Subsequently, the desired
compound was afforded in high yield using Mitsunobu conditions, which
served as neutral protecting conditions using an allyl alcohol, PPh3, and
DEAD. This method was also applicable to benzyl alcohol.
(6) Furuta, T.; Hirooka, Y.; Abe, A.; Sugata, Y.; Ueda, M.; Murakami,
K.; Suzuki, T.; Tanaka, K.; Kan, T. Bioorg. Med. Chem. Lett. 2007, 17,
3095.
2234
Org. Lett., Vol. 11, No. 11, 2009

Scheme 2. Synthesis of Chafuroside A (1)
in the presence of PPh3 and DEAD proceeded smoothly, and
the protection reaction gave key intermediate 5a. For the
acyl donor unit, we selected a 1-acylbenzotriazole 916 due
to its stability under several conditions. Upon treatment of
5a and 9 using KHMDS, the desired acylation reaction
predominantly produced desired ꢀ-diketone 4a. Treatment
with TBAF removed the TBDPS group. Sequential cycliza-
tion and dehydration were performed by heating in toluene
with p-TsOH to afford selectively protected isovitexin
derivative 10. Although a concomitant deprotection of benzyl
group at 5-OH occurred during the cyclization reaction,12h
the ring closure product with a hindered phenol such as the
vitexin type was not detected in this step. Removal of the
benzyl groups of 10 was carried out by hydrogenolysis
conditions to provide the isovitexin 3a in good yield. The
critical dihydrobenzofuran ring was formed by the Mitsunobu
reaction. Upon treatment of 3a with DEAD and PPh3, the
desired ring was successfully formed, and 1 was afforded in
81% yield in two steps. Furthermore, intermolecular reactions
and/or polymerized products were not observed even if free
alcohol compound 3a was employed (Scheme 2).
was not affected by p-TsOH. Subsequently, removal of the
benzyl groups followed by a Mitsunobu reaction of vitexin
(3b) afforded 2 in 63% yield.
Thus, we accomplished the regioselective synthesis of
1 and 2 with 6- and 8-C-glycoside bonds, respectively.
Scheme 3. Synthesis of Chafuroside B (2)
Next, we focused on the selective synthesis of chafuroside
B (2) (Scheme 3). After selective protection of the reactive
phenol of 5 as a benzyl group, 5b was subjected to acylation
with 1-acylbenzotriazole 9. Upon treatment of 5b and 9 with
KHMDS, the acylation reaction afforded desired ꢀ-diketone
4b in 95% yield, even with the free hydroxyl group in 5b.
The ring closing reaction of ꢀ-diketone 4b was performed
under acidic conditions with TsOH as well as Amberlyst 15
to give flavone 11. In this reaction, the benzyl ether at C-5
(16) (a) Katritzky, A. R.; Shobana, N.; Pernak, J.; Afridi, A. S.; Fan,
W.-Q. Tetrahedron 1992, 48, 7817. (b) Katritzky, A. R.; Pastor, A. J. Org.
Chem. 2000, 65, 3679.
Org. Lett., Vol. 11, No. 11, 2009
2235

The synthesis employs a ꢀ-diketone intermediate, which
can be readily obtained by selective protection of 1 and
2. Consequently, we developed a seven step sequence to
1 beginning from aryl-C-glycoside (5) in 32% overall
yield. Moreover, newly identified 2 could be synthesized
in 13% yield in five steps from 5, and its stereochemistry
was confirmed. Furthermore, considering the compatibility
of this synthesis with a variety of functional groups, our
synthetic strategy should be applicable to various flavone
derivatives. Further synthetic investigation and biological
evaluation of 1 and 2 are currently under investigation in
our laboratory.
Acknowledgment. This work was financially supported by
Takeda Science Foundation, Naito Foundation, Nagase Science
and Technology Foundation, and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT) of Japan.
Supporting Information Available: General procedures
and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL900689M
2236
Org. Lett., Vol. 11, No. 11, 2009