Iodine-catalyzed one-pot synthesis and antimalarial activity evaluation of symmetrically and asymmetrically substituted 3,6-diphenyl[1,2,4,5]tetraoxanes

Article abstract of DOI:10.1016/j.bmcl.2009.01.103

A novel iodine-catalyzed one-pot synthesis of symmetrically and asymmetrically substituted 3,6-diphenyl-[1,2,4,5]tetraoxanes is described. The synthetic protocol is general with substituted benzaldehydes and proceeds well under acidic conditions. Total 17

Full text of DOI:10.1016/j.bmcl.2009.01.103

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1675–1677
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Iodine-catalyzed one-pot synthesis and antimalarial activity evaluation of
symmetrically and asymmetrically substituted 3,6-diphenyl[1,2,4,5]tetraoxanes
Nitin Kumar a, Shabana I. Khan b, Mukul Sharma a, Himanshu Atheaya a, Diwan S. Rawat a,
*
a Department of Chemistry, University of Delhi, Delhi 110 007, India
b National Centre for Natural Products Research, University of Mississippi, MS 38677, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel iodine-catalyzed one-pot synthesis of symmetrically and asymmetrically substituted 3,6-diphe-
nyl-[1,2,4,5]tetraoxanes is described. The synthetic protocol is general with substituted benzaldehydes
and proceeds well under acidic conditions. Total 17 tetraoxanes have been prepared during this study
and some of these compounds exhibit promising antimalarial activity. None of the compounds shows
any toxicity against vero cells.
Received 11 November 2008
Revised 28 January 2009
Accepted 30 January 2009
Available online 4 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Plasmodium falciparum
Artemisinin
Tetraoxane
Malaria affects over 40% of world’s population, causing deaths
of 1-3 million people every year.1–4 The incidence of malaria is
increasing because of many Plasmodium falciparum strains have be-
come resistant to most of the drugs. Over the last two decades
endoperoxide class of compounds have received considerable
attention of chemist and biologist due to their potent activity
against P. falciparum.5 Artemisinin, a 1,2,4-trioxane compound iso-
lated from Chinese plant Artemisia annua, has been one of the most
effective antimalarial against P. falciparum. However limited avail-
ability, high cost, and poor bioavailability have been the major
drawback of artemisinin.6 Artesunate and artemether, a semi-syn-
thetic derivatives of artemisinin, also shows poor pharmacokinetic
properties.7 Structure-activity relationship studies conducted on
artemisinin and its semi-synthetic derivatives revealed that the
peroxide linkage is the most crucial pharmacophore in these mol-
ecules.2,8 This discovery was the beginning of a significant effort to
identify synthetically accessible antimalarial peroxides.9,10 Dispi-
ro-tetraoxane is one such class of compounds which was found
to be equally potent as artemisinin.11 However, structural diversity
of this important class of compound is not available.12 Numerous
methods have been reported for the synthesis of symmetrical tet-
raoxane derivatives.13 The acid-catalyzed cyclocondensation of
hydrogen peroxide with ketones or aldehydes,13–16 ozonolysis of
olefins,17 enol-ethers,18 O-ether oxime,19 and cyclocondensation
of bis(trimethylsilyl) peroxide with carbonyl compounds catalyzed
by trimethylsilyl trifluoromethanesulfonate (TMSOTf)20 have been
the most commonly used methods. The unsymmetrical tetraox-
anes have been synthesized by cyclocondensation of ketones and
aldehydes with steroidal gem-bis-hydroperoxides (H2SO4 cata-
lyst),21 aliphatic and alicyclic gem-hydroperoxides (MeReO3–
HBF4 catalyst),21 and gem-bis(trimethylsilyldioxy)alkanes (TMSOTf
catalyst).22 Most of these methods are highly dependent on several
factors, such as the structure of the carbonyl compounds, temper-
ature, concentration, pH, mode of addition, solvent, and the equi-
librium between ketone and the precursors of cyclic peroxides,23
which lead to variable yields of the tetraoxanes. Most of these pro-
cedures involve cyclic ketones as a starting material, which pro-
vides limited opportunity for functionalization. So there is always
a need for the development of an easy, cost effective, and efficient
route to symmetrical and unsymmetrical tetraxoanes with func-
tional group diversity. Structural diversity in this class of com-
pounds can be generated if one uses aromatic aldehydes as a
starting material rather than cyclic ketones. Careful literature sur-
vey revealed that little over 25 tetraoxanes having aromatic ring as
a part of the active pharmacophore have been evaluated for their
antimalarial activity. As part of our ongoing efforts towards the
synthesis of biologically active compounds,24–26 we report herein
an efficient, cost effective, iodine-catalyzed simple one-pot synthe-
sis of symmetrically and asymmetrically substituted tetraoxanes,
and evaluation of their antimalarial activity.
Due to the possibility of selective incorporation of various func-
tional groups in the phenyl ring, we decided to use substituted
benzaldehydes as a starting material for the preparation of tetraox-
anes. Use of substituted benzaldehydes will not only generate wide
range of tetraoxanes, but this will help to study the structure activ-
ity relationship in this class of compounds. Recently, we have re-
ported synthesis and antimalarial activity of symmetrically and
* Corresponding author. Tel.: +91 11 27667465; fax: +91 11 27667501.
E-mail address: dsrawat@chemistry.du.ac.in (D.S. Rawat).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.01.103

1676
N. Kumar et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1675–1677
by TLC and 1H NMR. After this, same or different substituted benz-
aldehyde (1.0 equiv) was added followed by the addition of 1.0 mL
of HBF4ꢀEt2O (Scheme 1).
O O
O O
(i), (ii)
RCHO
1
Asymmetrical tetraoxanes (2m–q) have also been prepared by
this method, which are useful for the structure activity relationship
studies. It is important to mention here that during the preparation
of asymmetrical tetraoxanes, symmetrical tetraoxanes formation
was not observed by 1H NMR. This synthetic protocol is of partic-
ular interest, as the functional groups can be further manipulated
chemically, if required. Notably, electron withdrawing OMe group
favors the formation of tetraoxane (Table 1,26,31–33 entry 2g, litera-
ture yield 2%) while electron withdrawing NO2 group inhibit the
reaction, as bis-hydroperoxide formation was not observed in this
case.29,30 Using same reaction conditions cyclic ketones did not re-
act. All of the compounds were purified over SiO2 column, and
characterized spectroscopically.34
R
R`
2a-2q
Scheme 1. Reagents and conditions: (i) I2, H2O2, CH3CN; (ii) R0CHO, HBF4ꢀEt2O, rt.
Table 1
Symmetrical and asymmetrical tetraoxanes via Scheme 1
Ent
R
R0
Mp
Yield (%)
Reference
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
o-Me
m-Me
p-Me
p-Cl
p-Br
p-F
o-Me
m-Me
p-Me
p-Cl
p-Br
p-F
p-OMe
p-Et
p-n-Pr
p-i-Pr
p-n-But
p-t-But
p-Me
p-i-Pr
p-t-But
p-OMe
p-CO2Me
165–167
148–150
233–234
240 (dec)
>280
212–213
195–196
190–192
155
156–157
142–145
222–224
205
215–216
188–190
206
42
51
54
25
22
29
27
44
38
41
40
53
41
33
46
25
37
26,31–33
26
26
26,31–33
26
26,31–33
33
In vitro antimalarial activity and cytotoxicity. In vitro antimalarial
activity and cytotoxicity of these tetraoxanes were determined
against chloroquine sensitive (D6), and chloroquine resistant
(W2) strains of P. falciparum by literature methods.26,35–37 Among
the series, compounds 2h–j, and 2m–p, exhibited the most potent
p-OMe
p-Et
p-n-Pr
p-i-Pr
p-n-But
p-t-But
p-Et
p-Me
p-Me
p-Me
p-Me
antimalarial activity with IC50 values ranging from 0.38 to 0.99
for D6 and 0.45 to 1.08 M for W2 strain as shown in Table 2. Other
compounds (entries 2k, and 2l) also showed moderate to mild
antimalarial activities (IC50 2.19–3.79 M). None of these tetraox-
lM
l
l
207–208
anes showed any cytotoxicity (Table 2) to mammalian kidney
fibroblasts (vero cells). A higher selectivity index (S.I. > 20) for anti-
malarial activity was observed for compounds 2i, 2j, and 2m–p.
Among the series of 10 unknown compounds, symmetrical tetra-
oxanes having para n-butyl or p-tert-butyl group have shown poor
antimalarial activity (entries 2k and 2l). While in case of asymmet-
rical tetraoxanes p-ethyl group at one end and p-methyl or m-
methyl or p-isopropyl group at the other end of the tetraoxane,
were found to be most active compounds (entries 2m–o) in terms
of IC50 value and selectivity index. These three compounds (entries
2m–o) were effective against both strains of P. falciparum (D6 and
asymmetrically substituted tetraoxanes which have been prepared
under MTO/TFE reaction conditions21 using substituted benzalde-
hydes as a starting material.26 Some of the compounds, especially
tolyl based tetraoxanes exhibit good antimalarial activity.26 During
the course of this study we observed that the MTO-catalyzed reac-
tion has many limitations as MTO/TFE system is uneconomical,
non-selective for various functional groups, and yield was poor in
some cases.26 In continuation to this study, we developed a novel
cost effective method for the preparation of tetraoxanes and their
antimalarial activity was determined in an in vitro assay. Bis-
hydroperoxide has been used as an intermediate for the prepara-
tion of tetraoxanes in most of the cases, and it has been prepared
via various methods.22,27,28 Encouraged by a recent publication
by Iskra and co-workers29,30 that deals with the iodine-catalyzed
synthesis of bis-hydroperoxides, we speculated iodine may cata-
lyze the reaction of bis-hydroperxides and aromatic aldehydes that
may lead to tetraoxanes.
W2) with IC50 values in the range of 0.38–0.79 lM and selectivity
index of 25.1–43.6. However, ester functionality has negative effect
on the antimalarial activity (entry 2q). This study indicates that
substitution of methyl group in the previously reported tetraox-
anes26 by ethyl, n-propyl, i-propyl groups not only improves anti-
malarial activity, but selectivity index of the resulting
tetraoxanes was also better.
In conclusion, we have developed a new, convenient, simple
and efficient method for the synthesis of symmetrical and asym-
metrical tetraoxanes. Use of readily accessible and inexpensive
substituted aromatic aldehydes, iodine as a catalyst, and acetoni-
In a typical reaction conditions, substituted benzaldehyde was
added to a stirred solution of H2O2 (6 equiv) and I2 (0.1 equiv) in
10 mL of acetonitrile. Bis-hydroperoxide formation was confirmed
Table 2
Antimalarial activity and cytotoxicity of symmetrical and asymmetrical tetraoxanes via Scheme 1
Ent
R
R0
P. falciparum (D6 clone)
P. falciparum (W2 clone)
Cytotoxicity (vero cells)
IC50
(
lM)
S.I.
IC50
(l
M)
S.I.
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
CQ
Art
p-Et
p-Et
p-n-Pr
p-i-Pr
p-n-But
p-t-But
p-Et
0.99
0.61
0.67
3.65
2.19
0.38
0.59
0.60
0.76
3.79
0.05
>15.9
>23.8
>21.6
>3.7
0.99
0.76
1.03
4.77
3.93
0.45
0.77
0.79
1.08
6.01
0.41
>15.9
>19
>14
>2.8
>3.4
>36.7
>20.7
>19.0
>15.4
>2.5
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
p-n-Pr
p-i-Pr
p-n-But
p-t-But
p-Me
p-Me
p-Me
p-Me
p-Me
>6.1
>43.6
>26.4
>25.1
>21.6
>4.0
p-i-Pr
p-t-But
p-OMe
p-CO2Me
>298
>476
>42
>1400
0.035
0.015
NC: no cytotoxicity upto 16.72 lM.
SI: selectivity index (IC50 for cytotoxicity/IC50 for antimalarial activity).
CQ: chloroquine; Art: artemisinin.

N. Kumar et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1675–1677
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(2h): Yield: 44%; mp: 190–192 °C; IR (KBr, cmꢁ1): 2969, 1610, 1512, 1458,
1422, 1362, 1181, 1117, 1022, 1003, 909, 840; 1H NMR (300 MHz, CDCl3): 1.26
(t, J = 6 Hz, 6H), 2.66–2.94 (m, 4H), 6.91 (s, 2H), 7.28 (m, J = 8 Hz, 4H), 7.53 (m,
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(2l): Yield: 53%; mp: 222–224 °C; IR (KBr, cmꢁ1): 2924, 1614, 1461, 1370,
1312, 1267, 1187, 1021, 1003, 911, 838, 803; 1H NMR (300 MHz, CDCl3): 1.31
(s, 18H), 6.92 (s, 2H), 7.50–7.62 (m, 8H); 13C NMR (75.5 MHz, CDCl3): 31.16
(CH3), 34.91 (CH3), 108.10 (CH), 125.76 (CH), 127.57 (CH), 128.06 (C), 154.67
(C); MS–ESI (m/z): 356.4 (M+); Anal. Calcd for C22H28O4: C, 74.13; H, 7.92.
Found: C, 74.37; H, 7.73. 3-(4-Ethyl-phenyl)-6-p-tolyl-[1,2,4,5]tetroxane (2m):
Yield: 41%; mp: 205 °C; IR (KBr, cmꢁ1): 2949, 1610, 1361, 1180, 1021, 909, 840;
1H NMR (300 MHz, CDCl3): 1.26 (t, J = 6 Hz, 3H), 2.40 (s, s, 3H), 2.69 (q, J = 6 Hz,
2H), 6.90 (s, 1H), 6.91 (s, 1H), 7.27–7.30 (m, 4H), 7.41–7.47 (m, 4H); MS–ESI
(m/z): 286.1 (M+); Anal. Calcd for C17H18O4: C, 71.31; H, 6.34. Found: C, 71.61;
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