A short and efficient synthesis of licochalcone E

Article abstract of DOI:10.1055/s-0030-1258029

Licochalcone E was synthesized concisely via an abnormal Claisen rearrangement and Claisen-Schmidt condensation as the key reactions in a three-step sequence. The overall yield is 20% starting from prenyl bromide and 4-hydroxy-2-methoxybenzaldehyde. Georg

Full text of DOI:10.1055/s-0030-1258029

LETTER
2289
A Short and Efficient Synthesis of Licochalcone E
A
S
hort an
i
dEffic
z
ient
S
ynthe
h
sis of
L
icoc
e
E
n Li,*a Yuhua Mi,a Jianghua He,a Xuming Deng*b
a
College of Chemistry, Jilin University, 2519 Jiefang Road, Changchun 130023, P. R. of China
Fax +86(431)88499179; E-mail: ljz@jlu.edu.cn
College of Animal Science and Veterinary Medicine, Jilin University, 5333 Xi’an Road, Changchun 130062, P. R. of China
Fax +86(431)87836160; E-mail: xumingdeng@jluhp.edu.cn
b
Received 18 June 2010
total synthesis of licochalcone E have been reported by
Cheon and Na independently in 2009 and 2010.14 These
methods, however, suffered from limitations such as te-
dious protection and deprotection procedure of phenolic
hydroxy group, by employing Claisen rearrangement and
Claisen–Schmidt condensation reaction as the key steps.
For example, as depicted in Scheme 1, licochalcone E was
obtained in 15% overall yield via at least five steps from
the starting material 1-bromo-2-methyl-2E-butene (2), as
well as the formation of a side product which was tenta-
tively called licochalcone F was observed.14a
Abstract: Licochalcone E was synthesized concisely via an abnor-
mal Claisen rearrangement and Claisen–Schmidt condensation as
the key reactions in a three-step sequence. The overall yield is 20%
starting from prenyl bromide and 4-hydroxy-2-methoxybenzalde-
hyde.
Key words: licochalcone E, abnormal Claisen rearrangement,
Claisen–Schmidt condensation, total synthesis
Licorice is a traditional medicine used in the Northeast
Asia for the treatment of gastric and peptic ulcers, bron-
chial asthma, inflammation and other diseases.1,2 Six ret-
rochalcones, licochalcone A–E and echinatin (Figure 1)
have been isolated and characterized from the roots of G.
inflata, which is the main species in Chinese Xinjiang lic-
orice.3–6 These retrochalcones are comprised of two ben-
zene rings joined by an a,b-unsaturated carbonyl system,
structurally distinguishable from normal chalcones by the
lack of oxygen functionalities at C-2¢ and C-6¢ positions of
A ring. In particular, among many constituents, retrochal-
cones, chalcones, flavonoids are responsible for the yel-
low color of licorice. The series of retrochalcones family
have shown various biological properties, including anti-
tumor,3,7 antiparasitic,8 antileishmanial,9 antibacterial ac-
tivities.10 They also display antioxidative and superoxide
scavenging property.11
Our goal was to search for a shorter and more efficient
protocol for the synthesis of licochalcone E, and we sus-
pected that this may be achieved by overcoming the short-
coming of the above mentioned synthesis strategies.14a To
our best knowledge, an abnormal Claisen rearrangement
as the special rearrangement reaction usually happens af-
ter normal Claisen rearrangement of certain allyl vinyl
ether without protection of phenolic hydroxy group.15–17
Thus, functional allyl groups could be introduced into
suitable position directly by the utilization of this reaction.
Recently, its contribution to naturally occurring products
or relative compounds was explored.18 Additionally, even
though Claisen–Schmidt condensation was usually per-
formed under basic conditions, the greater advantage of
running the reaction under acidic conditions had been
demonstrated in the construction of retrochalcone such as
licochalcone A without hydroxy group protection.19,20
Therefore, we envisaged that a shorter route may be se-
cured through abnormal Claisen rearrangement and the
utilization of acidic conditions in the Claisen–Schmidt
condensation.
Among the reported retrochalcones, licochalcone E, as a
member of this family, was isolated in 2005 by Cheon’s
group.6 The initial biological activity study showed that
this compound exhibited a higher cytotoxicity compared
to the analogous licochalcone A and isoliquiritigenin.6
Furthermore, licochalcone E has also been reported to
modulate the nuclear factor (NF)-KB and Bc1-2 families
and to induce endothelial cell apoptosis.12 Recently, re-
search revealed that licochalcone E inhibited protein ty-
rosine phosphatase 1B (PTP1B) which played crucial role
in negative regulation of insulin and leptin signaling path-
ways.13
Herein, we present one short and efficient synthesis route
to licochalcone E, the reagents and reaction conditions for
which are depicted in Scheme 2. Our journey towards the
synthesis of licochalcone E began with prenyl bromide (8)
and 4-hydroxy-2-methoxybenzaldehyde (1), and the O-
alkenelated ether 9 was formed at room temperature using
K2CO3 and anhydrous acetone as solvent in 86% yield.
The abnormal Claisen rearrangement reaction proceeded
by heating ether 9 to 185 °C for 26 hours in anhydrous
N,N-dimethylaniline under nitrogen. After cooling to
room temperature, the reaction system was neutralized by
diluted HCl. The crude product was then extracted with
diethyl ether and purified via silica gel chromatography to
obtain the key intermediate 5-(1,2-dimethyl-2-propenyl)-
4-hydroxy-2-methoxy benzaldehyde (5) in 32% yield, ac-
Due to the demand of large amount of licochalcone E for
further biological activity studies and the low isolated
yield from natural product (yield: 0.0005% from 1 kg of
G. inflate), chemical synthesis of licochalcone E was
highly desirable. Several routes to the semi-synthesis or
SYNLETT 2010, No. 15, pp 2289–2292
x
x
.x
x
.2
0
1
0
Advanced online publication: 12.08.2010
DOI: 10.1055/s-0030-1258029; Art ID: W09910ST
© Georg Thieme Verlag Stuttgart · New York

2290
J. Li et al.
LETTER
O
OH
+
Br
a
OH
OH
OH
OHC
OHC
B
OMe
OMe
HO
HO
3
1
2
A
OMe
OMe
O
O
b
c
O
OH
licochalcone A
d
licochalcone B
O
OH
OHC
OHC
OMe
OMe
HO
4
5
OMe
OH
OH
O
HO
HO
licochalcone C
O
O
e
OMe
OMe
OHC
O
O
OMe
licochalcone D
6
7
Scheme 1 Synthesis route of licochalcone E from 1-bromo-2-
methyl-2E-butene as reported in the literature.14a Reagents and con-
ditions: (a) K2CO3, acetone; (b) N,N-dimethylaniline, n-butyric anhy-
dride; (c) (1) 10% NaOH–EtOH; (2) 2 M HCl; (d) THP, PTSA,
CH2Cl2; (e) (1) 4-hydroxyacetophenone, NaOH–EtOH; (2) 4 M HCl.
OH
OH
HO
HO
OMe
OMe
O
O
licochalcone E
licochalcone F
OH
O
Br
OH
a
+
HO
OHC
OHC
OMe
OMe
OMe
1
8
9
O
echinatin
Figure 1 Structure of the retrochalcones
OH
companied by the recovery of starting material 1 formed
from the decomposition of 9 in 4% yield. Finally, 1.5–2.0
M HCl in anhydrous ethanol was added slowly to a mix-
ture of 5 and 4-hydroxyacetophenone at 0–5 °C to pro-
mote the Claisen–Schmidt condensation. After workup,
the orange-colored title product licochalcone E (7) was
obtained in 72% yield after silica gel chromatography.
In comparison to reported literature,14a herein licochal-
cone E was synthesized efficiently by a three-step se-
quence from starting material prenyl bromide and 4-
hydroxy-2-methoxybenzaldehyde. The spectral data of
intermediate 5 and licochalcone E (7) were consistent
with the reported literature values.6,14 The trans configu-
ration of licochalcone E could also be confirmed by the
large coupling constant (J = 15.9 Hz) observed for the ole-
finic proton signals in its 1H NMR spectrum.
OH
HO
b
c
OMe
OHC
OMe
O
5
7
Scheme 2 Total synthesis route of licochalcone E from prenyl bro-
mide. Reagents and conditions: (a) K2CO3, acetone; (b) N,N-dime-
thylaniline; (c) 4-hydroxyacetophenone, HCl–EtOH.
A plausible reaction mechanism of the abnormal Claisen
rearrangement is shown in Scheme 3. The initial [3,3]-sig-
matropic reaction process produces the normal Claisen re-
arrangement compound 10 which is not isolable but
undergoes tautomerization to form quinone 11. Com-
pound 11 then undergoes an intramolecular oxy-ene reac-
tion to form cyclopropane 13. Subsequently, retro oxy-
ene reaction leads to the formation of the abnormal rear-
rangement product 5.
Synlett 2010, No. 15, 2289–2292 © Thieme Stuttgart · New York

LETTER
A Short and Efficient Synthesis of Licochalcone E
2291
(7) Park, E. J.; Park, H. R.; Lee, J. S.; Kim, J. W. Planta Med.
1998, 64, 464.
(8) Nielsen, S. F.; Chen, M.; Theander, T. G.; Kharazmi, A.;
Christensen, S. B. Bioorg. Med. Chem. Lett. 1995, 5, 449.
(9) Nielsen, S. F.; Christensen, S. B.; Cruciani, G.; Kharazmi,
A.; Liljefors, T. J. Med. Chem. 1998, 41, 4819.
OH
O
Claisen rearrangement
OHC
MeO
OMe
CHO
(10) Haraguchi, H.; Tanimoto, K.; Tamura, Y.; Mizutani, K.;
Kinoshita, T. Phytochemistry 1998, 48, 125.
10
9
(11) Haraguchi, H.; Ishikawa, H.; Mizutani, K.; Tamura, Y.;
Kinoshita, T. Bioorg. Med. Chem. 1998, 6, 339.
H
O
(12) Chang, H. J.; Yoon, G.; Park, J. S.; Kim, M. H.; Back, M. K.;
Kim, N. H.; Shin, B. A.; Ahn, B. W.; Cheon, S. H.; Jung,
Y. D. Biol. Pharm. Bull. 2007, 30, 2290.
O
H
– H+
+ H+
tautomerization
(13) Yoon, G.; Lee, W. J.; S, N.; Cheon, S. H. Bioorg. Med.
Chem. Lett. 2009, 19, 5155.
MeO
MeO
(14) (a) Na, Y.; Cha, J. H.; Yoon, H. G.; Kwon, Y. J. Chem.
Pharm. Bull. 2009, 57, 607. (b) Yoon, G.; Liu, Z.; Jeong,
H. J.; Cheon, S. H. Bull. Korean Chem. Soc. 2009, 30, 2959.
(c) Liu, Z.; Yoon, G.; Cheon, S. H. Tetrahedron 2010, 66,
3165. (d) Yoon, G.; Oak, M.; Lee, J.; Cheon, S. H. Bull.
Korean Chem. Soc. 2010, 31, 1085.
(15) Schobert, R.; Siegfried, S.; Gordon, G.; Mulholland, D.;
Nieuwenhuyzen, M. Tetrahedron Lett. 2001, 42, 4561.
(16) Roberts, R. M.; Landolt, R. G. J. Org. Chem. 1966, 31, 2699.
(17) Coombes, C. L.; Moody, C. J. J. Org. Chem. 2008, 73, 6758.
(18) Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem.
Soc. 2000, 122, 8131.
CHO
CHO
11
12
H
O
O
OH
MeO
CHO
MeO
CHO
OHC
OMe
13
13
5
(19) Xu, R. S.; Wen, G. L.; Jiang, S. F.; Wang, C. G.; Jiang, F. X.;
Xie, Y. Y.; Gao, Y. S. Acta Chim. Sinica 1979, 37, 289.
(20) Kromann, H.; Larsen, M.; Boesen, T.; Schonning, K.;
Nielsen, S. F. Eur. J. Med. Chem. 2004, 39, 993.
Scheme 3 The mechanism of abnormal Claisen rearrangement
reaction
In summary, we have developed an efficient and short ac-
cess to licochalcone E via a three-step procedure with an
overall yield of 20%.21 This simple and efficient route
makes the synthesis of licochalcone E in large scale pos-
sible. Furthermore, our result presented herein implies
that the synthesis of other analogues of this family may
also be carried out via the abnormal Claisen rearrange-
ment reaction. Further biological study of licochalcone E
and the synthesis of other modified analogues and deriva-
tives are currently underway in our group.
(21) Procedures for the Preparation of Licochalcone E and
Selected Spectral Data: At r.t., K2CO3 (2.8 g, 20.3 mmol)
which had been grinded carefully was added to the stirred
solution of 4-hydroxy-2-methoxybenzaldehyde (2.0 g, 13.2
mmol) in anhyd acetone. Then after 10 min, prenyl bromide
(1.80 mL, 15.3 mmol) was added to the reaction mixture by
pipette. The reaction was stirred for 24 h, until it was
complete (checked by TLC). K2CO3 was removed by
filtration, and the solvent was evaporated under vacuum.
The crude residue was recrystallized from PE to generate the
white-colored solid compound 9 (2.4 g, yield 86%).
Rf 0.41 (PE–acetone = 10:2). MS: m/z = 243.2 [M + Na]+.
1H NMR (300 MHz, CDCl3): d = 1.76 (s, 3 H), 1.81 (s, 3 H),
3.89 (s, 3 H), 4.57–4.59 (d, J = 6.9 Hz, 2 H), 5.46–5.51 (t,
J = 6.9 Hz, 1 H), 6.46–6.47 (d, J = 2.1 Hz, 1 H), 6.54–6.57
(dd, J = 2.1, 8.7 Hz, 1 H), 7.79–7.82 (d, J = 8.7 Hz, 1 H),
10.29 (s, 1 H). 13C NMR (75 MHz, CDCl3): d = 18.20, 25.79,
55.52, 65.11, 98.56, 106.20, 118.62, 118.86, 130.66, 139.25,
163.50, 165.45, 188.28. IR (KBr): 2970, 2940, 1680, 1620,
1580, 1500, 1450, 1420, 1390, 1310, 1290, 1270, 1200,
1120, 1030, 928, 818, 787, 642, 602 cm–1. Anal. Calcd for
C13H16O3: C, 70.89; H, 7.32. Found: C, 70.82; H, 7.29.
A solution of compound 9 (1.0 g, 4.54 mmol) in freshly
distilled N,N-dimethylaniline (5 mL) under nitrogen
atmosphere protection was stirred for 26 h at about 185 °C in
sealed tube. Then after cooling to r.t., the reaction mixture
was neutralized by dilute 10% HCl solution until its pH
changed to 5–7. The solution was extracted with Et2O. The
Et2O layer was washed with sat. NaHCO3 and NaCl solution
separately, and then dried with anhyd MgSO4. The residue
obtained after evaporation of the solvent was separated via
silica gel column chromatography using mixtures of PE and
acetone (30:1) as eluent to give the key intermediate 5 as a
white solid (0.32 g, 32%), accompanied by decomposed
starting material 4-hydroxy-2-methoxybenzaldehyde (1; 40
mg, yield: 4%).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This research was supported by funding from the Scientific Fore-
front and Interdisciplinary Innovation Project, JiLin University
(Grant, No 421031531412), P. R. of China.
References and Notes
(1) Huang, K. C. The Pharmacology of Chinese Herbs; CRC
Press: Florida, 1993, 277.
(2) Asl, M. N.; Hosseinzadeh, H. Phytother. Res. 2008, 22, 709.
(3) Saitoh, T.; Shibata, S. Tetrahedron Lett. 1975, 4461.
(4) Ayabe, S. I.; Kobayashi, M.; Hikichi, M.; Matsumoto, K.;
Furuya, T. Phytochemistry 1980, 19, 2179.
(5) Kajiyama, K.; Demizu, S.; Hiraga, Y.; Kinoshita, K.;
Koyama, K.; Takahashi, K.; Tamura, Y.; Okada, K.;
Kinoshita, T. Phytochemistry 1992, 31, 3229.
(6) Yoon, G.; Jung, Y. D.; Cheon, S. H. Chem. Pharm. Bull.
2005, 53, 694.
Synlett 2010, No. 15, 2289–2292 © Thieme Stuttgart · New York

2292
J. Li et al.
LETTER
using mixtures of PE and acetone (10:1) as eluent.:
Licochalcone E also may be purified according to the
following method: theg orange solid was precipitated
completely after cooled H2O was added slowly to the
reaction mixture. The precipitated solid was then filtered,
and recrystallized from cold EtOH–H2O to provide the target
compound.
Rf: 0.18 (PE–acetone = 10:2). MS: m/z = 221.3 [M + H]+.
1H NMR (300 MHz, CDCl3): d = 1.41–1.44 (d, J = 7.2 Hz,
3 H), 1.63 (s, 3 H), 3.46–3.53 (q, J = 7.2 Hz, 1 H), 3.86 (s, 3
H), 5.07 (s, 1 H), 5.16 (s, 1 H), 6.40 (s, 1 H), 6.43 (s, 1 H),
7.66 (s, 1 H), 10.29 (s, 1 H). 13C NMR (75 MHz, CDCl3):
d = 18.27, 20.66, 41.50, 55.65, 99.58, 111.96, 118.36,
122.31, 129.32, 149.64, 162.32, 162.76, 188.76. UV: lmax
(EtOH; log e) = 278 (0.32), 235 (0.46), 206 (0.43) nm. IR
(KBr): 3180, 1660, 1590, 1510, 1450, 1380, 1285, 1253,
1120, 1020, 891, 841, 694, 594 cm–1. Anal. Calcd for
C13H16O3: C, 70.89; H, 7.32. Found: C, 70.90; H, 7.33.
4-Hydroxyacetophenone (0.27 g, 2 mmol) and intermediate
5 (0.40 g, 1.82 mmol) were dissolved in anhyd EtOH (2 mL),
cooled by ice-water bath, then anhyd 1.5–2.0 M HCl–EtOH
(5 mL) was added slowly to the stirred solution. The mixture
was continuously stirred for 2 h at 0–5 °C until the reaction
was finished completely (checked by TLC). HCl and EtOH
solvent were removed under vacuum; the mixture was then
extracted with EtOAc, washed with H2O, sat. NaHCO3, then
H2O separately. The extracted layer was dried over MgSO4,
filtered, and the solvent was removed under vacuum. Then
the title compound licochalcone E (7) was obtained as an
orange solid (0.45 g, yield 72%) over silica gel column
Rf: 0.10 (PE–acetone = 10:4). MS: m/z = 337.3 [M + H]+.
1H NMR (300 MHz, CDCl3): d = 1.45–1.47 (d, J = 7.2 Hz, 3
H), 1.69 (s, 3 H), 3.47–3.54 (q, J = 7.2 Hz, 1 H), 3.88 (s, 3
H), 5.09 (s, 1 H), 5.16 (s, 1 H), 5.67 (s, 1 H), 6.06 (s, 1 H),
6.43 (s, 1 H), 6.92–6.95 (d, J = 9.0 Hz, 2 H), 7.37 (s, 1 H),
7.53–7.59 (d, J = 15.9 Hz, 1 H), 7.99–8.02 (d, J = 9.0 Hz, 2
H), 7.99–8.04 (d, J = 15.9 Hz, 1 H). 13C NMR (75 MHz,
CD3OD): d = 19.79, 22.54, 38.97, 56.09, 99.59, 110.16,
116.31, 116.48, 119.29, 125.74, 129.91, 131.44, 132.07,
141.98, 150.39, 160.38, 160.51, 163.52, 191.79. UV: lmax
(EtOH; log e) = 379 (1.33), 309 (0.94), 262 (0.84) nm. IR
(KBr): 3400, 2970, 1640, 1600, 1560, 1500, 1450, 1410,
1340, 1290, 1210, 1170, 1120, 1040, 984, 895, 837, 756,
638, 611, 575 cm–1. Anal. Calcd for C21H22O4: C, 74.54; H,
6.55. Found: C, 74.52; H, 6.56.
Synlett 2010, No. 15, 2289–2292 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.