Total synthesis of mallotophilippen C

Article abstract of DOI:10.1016/j.tetlet.2006.04.064

The first total synthesis of mallotophilippen C (1), a bioactive chalcone natural product recently isolated from Mallotus philippinensis MUELL. ARG., is described. The synthesis has been accomplished in 11 linear steps from a commercially available materi

Full text of DOI:10.1016/j.tetlet.2006.04.064

Tetrahedron Letters 47 (2006) 4153–4155
Total synthesis of mallotophilippen C
Yunfei Li,a Yu Luo,a Weigang Huang,a Jingli Wangb and Wei Lub,*
aShanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
bInstitute of Medicinal Chemistry, Department of Chemistry, East China Normal University, 3663 North Zhongshan Road,
Shanghai 200062, China
Received 8 March 2006; revised 10 April 2006; accepted 13 April 2006
Available online 9 May 2006
Abstract—The first total synthesis of mallotophilippen C (1), a bioactive chalcone natural product recently isolated from Mallotus
philippinensis MUELL. ARG., is described. The synthesis has been accomplished in 11 linear steps from a commercially available
material, with an overall yield of 28%.
Ó 2006 Elsevier Ltd. All rights reserved.
Mallotus philippinensis MUELL. ARG. (Euphorbia-
ceae) is a deciduous tree widely distributed throughout
tropical Asia, Australia and the Philippines. The granu-
lar hairs on the surface of its fruits are called kamala,
and have long been used as both an anthelmintic and
a cathartic in traditional medicine.1
OH
R
O
HO
O
1: R = H
2: R = OH
Mallotophilippens C (1), D (2) and E (3) are three novel
chalcone natural products (Fig. 1), first isolated by Dai-
konya et al.2 from the fruits of the Mallotus philippinen-
sis MUELL. ARG. They were shown to inhibit the
production of nitric oxide (NO) induced by interferon-
c (IFN-c) and lipopolysaccharide (LPS) in murine mac-
rophage-like cell line, RAW 264.7. Furthermore, they
also inhibit inducible nitric oxide synthase (iNOS),
cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and
interleukin-1b (IL-1b) mRNA expression. These results
suggest that they have anti-inflammatory and immuno-
regulatory effects, and may be candidates for drugs to
treat diseases due to iNOS over expression.
OH
OH
OH
O
HO
O
3
OH
Figure 1. Structures of mallotophilippens C, D and E.
Mallotophilippen C (1) is an attractive target, exhibiting
the best inhibitory activity (IC50 = 3.6 lg/ml) of the
three chalcone natural products (2, IC50 = 4.7 lg/ml;
3, IC50 = 18.9 lg/ml) against NO production, and
exhibiting stronger inhibition activity than that of the
positive control Quercetin3 (IC50 = 8.1 lg/ml). As we
were intrigued by the potent bioactivity of mallotophil-
ippen C (1) and interested in the new structure, we began
the synthetic study and achieved the first total synthesis
of this novel chalcone natural product.
According to our retrosynthetic analysis (Scheme 1),
mallotophilippen C (1) synthesis could be envisaged
through the Claisen–Schmidt condensation of 4-meth-
oxymethoxy-benzaldehyde with 13, which could in turn
be derived from 8 through directed ortho metalation
(DoM) methodology to install the geranyl chain. Com-
pound 8 could be converted from readily accessible
phloroacetophenone (4).
Keywords: Inhibit NO production; Mallotophilippen C; Total
synthesis.
*
Corresponding author. Tel./fax: +86 21 62602475; e-mail: wlu@
chem.ecnu.edu.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.064

4154
Y. Li et al. / Tetrahedron Letters 47 (2006) 4153–4155
OH
O
O
O
O
HO
OH
MOMO
O
MOMO
O
HO
O
OH
OMOM
OMOM
OH
8
13
4
1
Scheme 1. Retrosynthetic analysis.
O
O
O
O
HO
O
HO
OH
HO
OMOM
HO
OH
a
b
c
d
OMOM
OMOM
OMOM
OH
6
7
5
4
RO
MOMO
RO
MOMO
O
O
O
MOMO
O
g
e
i
OMOM
OMOM
OMOM
9 R = H
8
11 R = TBS
12 R = H
f
h
10 R = TBS
OH
OMOM
k
O
j
MOMO
O
O
O
HO
O
MOMO
O
OMOM
13
OH
OMOM
14
1
Scheme 2. Reagents and conditions: (a) MOMCl, DIPEA, CH2Cl2, 0 °C to rt, 1 h, 84%; (b) I2 (1 wt/vol % I2/MeOH), MeOH (0.1 M), rt, 16 h, 82%;
(c) 3-methyl-2-butenal, pyridine, reflux, 16 h, 83%; (d) MOMCl, NaH, DMF, rt, 2 h; (e) LiAlH4, THF, rt, 4 h; (f) TBSCl, imidazole, DMF, rt, 0.5 h,
95% (over three steps); (g) n-BuLi, TMEDA, CuCN, THF, À20 °C; geranyl bromide, THF, À78 °C, 12 h, 80%; (h) TBAF, THF, reflux, 3 h; (i) PDC,
CH2Cl2, rt, 24 h, 93% (over two steps); (j) 4-methoxymethoxy-benzaldehyde, 55% KOH (230 equiv), EtOH, 0 °C to rt, 16 h, 87%; (k) 3 N HCl,
MeOH, reflux, 25 min, 81%.
To initiate the sequence (shown in Scheme 2), phloro-
acetophenone (4) was protected with methoxymethyl
chloride (MOMCl) to give 5,4 which was followed by
selective cleavage of the ortho-MOM ether with iodine
in methanol5 to afford 66 in 82% yield. Treatment of 6
with 3-methyl-2-butenal in refluxing pyridine7 provided
chromene 7 in 83% yield. Prolonging the reaction time
led to the cleavage of para-MOM ether and octandren-
olone8 was obtained as a major byproduct.
was reduced by LiAlH4 in THF to give the correspond-
ing alcohol 9. The two steps proceeded smoothly with-
out the detection of any byproducts. After the
protection of the alcoholic group of 9 with tert-butyl-
dimethylsilyl chloride (TBSCl), the crude product was
purified by flash column chromatography on silica gel
to give 10 in 95% yield over three steps.
With the key intermediate 10 in hand, the next step
required the introduction of the geranyl chain into the
phenyl moiety. This compound was subjected to DoM
conditions, followed by lithium–copper exchange and
alkylation with geranyl bromide. The reaction pro-
ceeded slowly to afford the product 11 and a small quan-
tity of the starting material 10. After workup, the crude
product was purified by column chromatography to ob-
tain 11 in 80% yield, based on unrecovered 10 as a clear
oil. Cleavage of the silyl ether 11 by tetrabutylammo-
We then focused on the introduction of the geranyl
chain to the phenyl moiety. The strategy of directed
ortho metalation (DoM),9 which has been proved to be
an efficient method to install a geranyl chain, was used
to achieve this goal.
The free phenol of 7 was etherified with MOMCl and so-
dium hydride in DMF to afford acetophenone 8, which

Y. Li et al. / Tetrahedron Letters 47 (2006) 4153–4155
4155
nium fluoride (TBAF) in refluxing THF gave alcohol 12.
Acknowledgements
Compound 12 was oxidized with pyridinium dichromate
(PDC) in CH2Cl2 to provide 13 after 24 h stirring at
room temperature, in 93% yield over two steps.
Financial support from the National Natural Science
Foundation of China (30572232) is gratefully acknowl-
edged.
Prior work has shown that the Claisen–Schmidt conden-
sation10 can be achieved with excess of KOH or NaOH
in an alcoholic aqueous solution from 0 °C up to reflux-
ing temperature. Condensation of acetophenone 13 with
4-methoxymethoxy-benzaldehyde11 was accomplished
in a mixture of aqueous KOH and ethanol at 0 °C to
room temperature under nitrogen for 16 h. The
3MOM-protected chalcone 14 was thus obtained in
87% yield without the evidence of the undesired cis
enone. Almost no product was detected when 13 was
reacted with 4-hydroxy-benzaldehyde under the same
condition after 24 h, although a similar reaction pro-
ceeded smoothly when 13 was replaced with 1-(2,4-bis-
methoxymethoxy-phenyl)-ethanone.12
Supplementary data
Experimental data for compounds 1 and 6–14 are in-
cluded. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2006.04.064.
References and notes
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With the core chalcone framework established, the final
step was to remove the protective groups to give the tar-
get material mallotophilippen C (1). All the MOM
groups of 14 were removed by hydrolysis using 3 N
HCl in methanol to afford 1 in 81% yield. Increasing
the concentration of HCl or prolonging the reaction
time led to a decrease in yield, due to the instability of
1 in acidic environment. The spectral data (shown in
Supplementary data) of compound 1 were in agreement
with that of the reference.2
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In conclusion, an efficient first total synthesis of the
bioactive natural product, mallotophilippen C (1), has
been achieved. Starting from the readily accessible
phloroacetophenone (4), a linear sequence of 11 steps
allowed us to obtain 1 in 28% overall yield. The
synthetic route outlined here, with steps of procedural
simplicity and high efficiency, facilitates our further
structural modification and biological studies of this
kind of compounds.
12. Shimamura, T.; Arakawa, Y.; Hikita, K.; Niwa, M.
Heterocycles 1996, 43, 2223.