Simple analogues of qinghaosu (artemisinin)

Article abstract of DOI:10.1002/asia.201200166

A series of 1,2,4-trioxanes were synthesized in which the key peroxy bonds were installed through a molybdenum-catalyzed perhydrolysis of the epoxy rings. A core structure was identified that may serve as a promising lead structure for further investigations because of its high antimalarial activity (comparable to that of artesunate and chloroquine), apparent potential for scale-up and derivatization, and facile monitoring/tracing by using UV light.

Full text of DOI:10.1002/asia.201200166

DOI: 10.1002/asia.201200166
Simple Analogues of Qinghaosu (Artemisinin)
Yun Li,[a] Hong-Dong Hao,[a] Sergio Wittlin,[b, c] and Yikang Wu*[a]
Abstract: A series of 1,2,4-trioxanes were synthesized in which the key peroxy
bonds were installed through a molybdenum-catalyzed perhydrolysis of the epoxy
Keywords: cyclization · epoxides ·
peroxides · ring-opening · terpe-
noids
rings. A core structure was identified that may serve as a promising lead structure
for further investigations because of its high antimalarial activity (comparable to
that of artesunate and chloroquine), apparent potential for scale-up and derivatiza-
tion, and facile monitoring/tracing by using UV light.
Introduction
The sesquiterpenoid qinghaosu[1] (QHS, artemisinin, 1;
Scheme 1), which was first isolated in the 1970s from the
Chinese herb qinghao (Artemisia annuua L.), was a mile-
stone[2] compound in the chemotherapy of malaria. This or-
ganic peroxide does not contain any nitrogen atoms or aro-
matic rings in its structure and hence its potent antimalarial
activity cannot be explained by previous theories, thereby
strongly suggesting a new mode of action. At a time when
cases of multi-drug-resistant malaria were increasing at an
alarming rate and began to create a global panic, the ap-
pearance of QHS and its derivatives as antimalarial drugs
that were highly effective against even the “drug-resistant
strains” naturally raised enormous interest in the scientific
community around the world.
In most cases, synthetic studies on QHS have been direct-
ed towards developing new bioactive derivatives and ana-
logues. Pioneering efforts in this area have led to the ap-
pearance of many synthetic organic peroxides with potent
antimalarial activity,[3] including simple 1,2,4-trioxanes that
were closely related to QHS (2–8).
Scheme 1. Structures of QHS (1) and several (synthetic) simplified ana-
logues (2–8) that have been reported to have significant in vitro antima-
larial activity. For the sake of comparison, the atom numbering of QHS
was also used in the analogues when appropriate.
ozone during the installation of the key peroxy bond, as in
all previous approaches. Herein, we prepared a range of
simplified QHS analogues from their corresponding epoxy
precursors by using the same perhydrolysis-based methodol-
ogy. Some of these products were particularly interesting be-
cause of their facile accessibility and high antimalarial activ-
ity, which was comparable to that of chloroquine and artesu-
nate.
In a continuation of our long-standing interest in the syn-
thesis of organic peroxides, we recently developed a novel
route to QHS,[4] which did not involve singlet oxygen or
[a] Dr. Y. Li, Dr. H.-D. Hao, Prof. Dr. Y. Wu
State Key Laboratory of Bioorganic and
Natural Products Chemistry
Shanghai Institution of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: yikangwu@sioc.ac.cn
Results and Discussion
[b] Dr. S. Wittlin
The QHS analogues that were investigated herein all con-
tained a bicyclic core structure that was similar to that in
compounds 2–8, but with fewer substituents attached onto
the fused-ring framework. To explore the scope and limita-
tions of molybdenum complex 9, which was formed from
the reaction of Na2MoO4 and glycine,[4] the catalyzed-perhy-
drolysis and subsequent trioxane-formation procedure that
Swiss Tropical and Public Health Institute,
Socinstrasse 57, CH-4002 Basel (Switzerland)
[c] Dr. S. Wittlin
University of Basel
CH-4051 Basel (Switzerland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200166.
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was recently developed in our laboratories, and to examine
the effects of structural variation on antimalarial activity, we
performed several structural changes that included:
1) changing the alkyl group at the C-3 position; 2) introduc-
ing a hydroxy group at the C-5 or C-7 positions; 3) replacing
the C-5 CH2 group with an oxygen atom; and 4) switching
the positions of the C-12 and O-13 moieties (see below). Be-
cause of the convenience of our synthetic procedure and be-
cause of the potential advantages in biomedical studies that
are associated with the introduction of a UV chromophore
onto the trioxane structure, a substrate that contained a ben-
zene ring was also investigated, which turned out to be the
most promising drug candidate (see below).
The relative configuration of the C-7 atom with respect to
the C-5a atom in compounds 12d–12g was confirmed by
NOESY experiments on the precursors. In the case of com-
pound (À)-12h, the selectivity of the well-established aldol
reaction and the Mosher method allowed us to establish the
configurations at the C-5 and C-5a positions. In the case of
compound 12i, two diastereomers were isolated, but their
relative configurations were not identified.
Because of its high antimalarial potency, the synthesis of
compound 12k appeared to merit particular attention. As
shown in Scheme 3, alkylation of alcohol 13[8] with bromide
14[9] under NaH/THF/HMPA[10] conditions afforded benzyl
ether 15. Then, the Heck reaction of compound 15 with Pd-
The starting epoxy substrates (10a–10k) are shown in
Scheme 2. O’Neill, Posner, and co-workers[3h] have shown
that the absolute configuration of the organic peroxides did
not significantly affect their antimalarial activity; therefore,
to speed up the synthesis, racemic epoxy substrates were
used (except for compound 10h[5]).
ACHTUNGRTENUN(NG OAc)2 in MeCN at 808C for 36 hours in the presence of
[10]
Ph3P/K2CO3 afforded the desired alkene (16). Higher re-
action temperatures (>1108C) did not afford any improve-
ments but rather caused an undesired partial migration of
À
the C C double bond and hydrolysis of the ketal protecting
group. Notably, if the reaction was performed in N,N-dime-
thylformamide (DMF) instead of MeCN, the yield of com-
pound 16 was dramatically reduced (41%).
À
The C C double bond was then converted into the corre-
sponding epoxide, thereby setting a stage for the key trans-
formation step: the incorporation of a hydroperoxy group
into the carbon framework. The perhydrolysis[11] of com-
pound 10k proceeded smoothly under our previously re-
ported conditions for the synthesis of QHS.[4] Intermediate
compound 11k readily underwent acid-catalyzed cyclization,
thereby delivering compound 12k in 75% yield.
Inspired by the conversion[12] of deoxo-QHS into QHS
and by the literature synthesis of artemether,[13] we also per-
formed similar transformations on compound 12k. The oxi-
dation of compound 12k was realized by using a more re-
cently reported procedure (KMnO4/FeCl3).[14] The resulting
lactone (12l) was then reduced with DIBAL-H into a hemia-
cetal intermediate, which, on exposure to p-TsOH/MeOH,
yielded acetal 12m as an inseparable mixture of two epi-
mers.
The in vitro antimalarial activity of the synthesized triox-
anes are given in Table 1. From the simplest compounds
considered herein (12a–12c), a larger alkyl group at the C-3
position was beneficial (Table 1, entries 1–3). The introduc-
tion of an OBn group at the C-7 position (12d and 12e) led
to an enhancement in activity that was comparable to that
caused by the replacement of the C-3 methyl group with an
n-butyl or iso-propyl group (Table 1, entries 4 and 5). This
result, together with the observation that the stereochemis-
try at the C-7 position that was associated with the attach-
ment of a substituent did not seem to make much difference
in terms of antimalarial activity, revealed that this position
could be potentially useful for further structural modifica-
tion. In contrast, an unprotected hydroxy group at the C-7
position (12 f and 12g) decreased the antimalarial activity
significantly (Table 1, entries 6 and 7). Perhaps the presence
of a free hydroxy group made the substrate more sensitive
towards oxidation and other reactions that lead to decompo-
sition of these molecules. Indeed, the attachment of a hy-
Scheme 2. Starting epoxides for the perhydrolysis reaction; for the sake
of comparison, the atom numbering of QHS (see Scheme 1) was also
used.
The perhydrolysis of 10a–10k was performed under the
same conditions as in our synthesis of QHS (9/H2O2/Et2O).
Because the epoxy groups were installed through a Corey–
Chaykovsky[6] reaction of the corresponding ketones without
much diastereoselectivity, only a percentage of the epoxy
substrates were of the correct relative configuration for per-
hydrolysis. Therefore, the yields of the resulting b-hydroxy
hydroperoxides (Table 1)[7] were typically lower than those
of the corresponding conversion in the synthesis of QHS
(74%).[4]
The conversion of compounds 11a–11k into compounds
12a–12k proceeded rather smoothly, although their yields
were heavily dependent on the structure. In many cases, the
isolated trioxanes were enriched in, or predominated by,
one diastereomer, but the configuration of the C-12a posi-
tion (where H2O2 opened the epoxy ring) with respect to
the ring conjuncture could not be established experimental-
ly. Nevertheless, judging from the striking structural similari-
ty, the relative configurations in these cases were likely to
be the same as that in QHS (Table 1).
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Simple Analogues of Qinghaosu (Artemisinin)
Table 1. Conversion of the epoxides into trioxanes and the IC50 values of the products.[a]
Entry
Epoxide
10
b-Hydroxy perhydroxide
11 Yield [%]
Trioxane
12
IC50
[b]
R
Yield [%] [ngmLÀ1
]
1
2
3
10a
10b
10c
Me
iPr
iBu
11a
11b
11c
61
68
61
12a
12b
12c
74
74
78
1.8ꢁ102
5.3ꢁ10
4.8ꢁ10
4
5
6
7
10d
10e
10 f
10g
a-OBn
ß-OBn
a-OTBS
ß-OTBS
11d
11e
11 f
11g
42
49
59
52
12d
12e
12 f
12g
78
58
62
68
4.8ꢁ10
4.9ꢁ10
7.0ꢁ102
4.8ꢁ102
2.1ꢁ103[c]
8
10h
10i
11h
11i
53
54
12h
92
ACHTUNGTRENUNG
12i
12iꢀ
20
20
3.7ꢁ102[e]
5.3ꢁ102[f]
9
10
10j
11j
71
50
12j
30
75
1.6ꢁ103
11
12
13
10k
10l
11k
11l
12k
12l
3.9
5.7
5.0
10m
11m
12m
14
15
artesunate
chloroquine diphosphate
1.2
6.7
[a] All of the compounds were racemic except for compounds (À)-12h and its precursors; the relative configurations (see text) are shown when major
diastereomers were observed. [b] Tested on P. falciparum (strain NF45); these data are the averages of 2–3 independent experiments (for further details
of the procedure, see Ref. [7]). [c] For compound (Æ)-12h. [d] For compound (À)-12h. [e] The less-polar diastereomer. [f] The more-polar diastereomer.
droxy group at the C-5 position (12h) also showed similar
adverse effects (Table 1, entry 8).
The trioxanes that contained a fused benzene ring (12k–
12m) were significantly dissimilar to QHS than the other tri-
oxanes considered herein. Nevertheless, these three perox-
ides all showed much higher potency (Table 1, entries 12–
14) than those that were expected to be the most active be-
cause of their stronger structural resemblance to QHS.
These results, together with the potential advantages of
their facile synthesis and UV-detectable nature owing to the
presence of a benzene ring, strongly suggested that the core
structure that was shared by compounds 12k–12m may be
a promising lead structure for further studies.
Substitution of the C-5 CH2 group with an oxygen atom
greatly facilitated the reaction (12i and 12i’). However, un-
fortunately, this change in what was seemingly a non-func-
tional unit resulted in substantially reduced antimalarial ac-
tivity compared to that of compound 12a (Table 1, entry 9).
If the C-5 oxy substituent was accompanied by a switch of
the C-12 CH2 group and the C-13 oxygen atom (12j), even
poorer activity was observed (Table 1, entry 10). Thus, struc-
tural variation along this line was not pursued further.
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MeCN were distilled over CaH2 prior to use. HMPA and DMSO were
stirred with CaH2 at ambient temperature for several days (in a sealed
flask with a flat balloon to collect the H2 gas evolved), distilled under
a vacuum, and kept over activated 4 ꢂ molecular sieves under an argon
[15]
atmosphere. Ethereal H2O2
and molybdenum catalyst 9[4] were pre-
pared according to literature procedures.
Alkylation of Compound 13 with Compound 14 to Afford Compound 15
A solution of alcohol 13 (103 mg, 0.60 mmol) in dry THF (2 mL) was
added to NaH (60% in mineral oil, 77 mg, 1.92 mmol, washed 3ꢁpetrole-
um ether). The mixture was stirred at ambient temperature for 1 h. Dry
HMPA (0.24 mL, 1.2 mmol) was added, followed by a solution of bro-
mide 14 (300 mg, 1.2 mmol) in dry THF (1 mL). The orange–yellow mix-
ture was stirred at ambient temperature overnight. The mixture was por-
tioned between Et2O (10 mL) and saturated aqueous NH4Cl (5 mL). The
phases were separated and the aqueous layer was back-extracted with
Et2O (3ꢁ30 mL). The combined organic layers were washed with brine
(2ꢁ15 mL) and dried over anhydrous Na2SO4. Removal of the solvent by
rotary evaporation and column chromatography on silica gel (EtOAc/pe-
troleum ether, 1:50) gave ether 15 as a colorless oil (160 mg, 0.47 mmol,
78% from compound 13). 1H NMR (300 MHz, CDCl3): d=7.51 (t, J=
7.0 Hz, 2H), 7.30 (t, J=7.3 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 5.70–5.82
(m, 1H), 5.27 (d, J=6.4 Hz, 1H), 5.23 (s, 1H), 4.61 (d, J=13 Hz, 1H),
4.43 (d, J=13 Hz, 1H), 3.90–3.95 (m, 4H), 3.80 (dd, J=5.3, 7.5 Hz, 1H),
1.74–1.88 (m, 2H), 1.62–1.74 (m, 2H), 1.32 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=138.6, 138.1, 132.4, 129.1, 128.7, 127.3, 122.6, 117.5,
109.9, 81.1, 69.5, 64.6, 34.7, 29.8, 23.9 ppm; FTIR (film): n˜ =2981, 2876,
1568, 1470, 1441, 1376, 1207, 1066, 927, 750 cmÀ1; MS (ESI): m/z: 363.1
[M+Na]+; elemental analysis calcd (%) for C16H21O3Br: C 56.32, H 6.20;
found: C 56.49, H 66.20.
Scheme 3. Synthesis of compounds 12k–12m. HMPA=hexamethyl-phos-
phoramide, p-TsOH=para-toluenesulfonic acid, DIBAL-H=diisobutyla-
luminum hydride, m-CPBA=meta-chloroperbenzoic acid.
Cyclization of Compound 15 to Afford Compound 16
PPh3 (60 mg, 0.23 mmol), K2CO3 (480 mg, 3.50 mmol), and PdACHTUNGTRENNUNG(OAc)2
(26 mg, 0.12 mmol) were added sequentially to a solution of compound
15 (200 mg, 0.58 mmol) in degassed MeCN (12 mL). The red–orange mix-
ture was frozen in liquid N2, evacuated with an oil pump, and warmed to
ambient temperature after releasing the vacuum with argon gas (repeated
three times). The mixture was then stirred at 808C under an argon at-
mosphere for 36 h. After cooling to ambient temperature, Et2O (50 mL)
was added, followed by water (20 mL). The phases were separated and
the aqueous layer was back-extracted with Et2O (3ꢁ30 mL). The com-
bined organic layers were washed with brine (2ꢁ15 mL) and dried over
anhydrous Na2SO4. Removal of the solvent by rotary evaporation and
column chromatography on silica gel (EtOAc/petroleum ether, 1:20)
gave ether 16 as a yellowish oil (114 mg, 0.44 mmol, 76% from 15).
1H NMR (300 MHz, CDCl3): d=7.62–7.65 (m, 1H), 7.20–7.26 (m, 2H),
7.00–7.03 (m, 1H), 5.64 (s, 1H), 5.08 (s, 1H), 4.87 (d, J=15.2 Hz, 1H),
4.75 (d, J=15.3 Hz, 1H), 4.33 (t, J=6.2 Hz, 1H), 3.89–3.98 (m, 4H),
1.72–2.06 (m, 4H), 1.37 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=
141.7, 134.3, 131.4, 127.7, 126.9, 124.3, 123.8, 109.9, 107.0, 65.6, 64.6, 34.8,
26.9, 23.9 ppm; FTIR (film): n˜ =2980, 2880, 1635, 1485, 1449, 1375, 1255,
1065, 891, 776 cmÀ1; MS (EI): m/z: 260 [M]+; HRMS (EI): m/z calcd for
C16H20O3: 260.1412 [M]+; found: 260.1425.
Conclusions
A series of simplified QHS analogues were synthesized with
remarkable ease by using hydrogen peroxide in the key for-
mation of the peroxy bonds. The incorporation of the inor-
ganic peroxy unit into the organic frameworks was achieved
through perhydrolysis of the epoxy rings under very mild
conditions that were recently developed in our laboratories.
Apart from demonstrating the distinct potential of this pro-
cedure in the synthesis of other organic peroxides, these
newly accessed trioxanes also helped to unveil some previ-
ously unknown facets of the structure–activity relationship
(SAR) of QHS-related antimalarial compounds, thereby
contributing to the existing knowledge of SAR of organic
peroxy antimalarial compounds. A new core structure that
was remarkably dissimilar to QHS compared with the other
trioxanes studied herein was identified, which might serve as
a promising lead compound for further investigation be-
cause of its unexpectedly high antimalarial activity (compa-
rable to that of artesunate and chloroquine), apparent po-
tential for scale-up and derivatization, and facile monitor-
ing/tracing by using UV light.
Epoxidation of Alkene 16 into Epoxide 10k
Na2CO3 (8.0 mg, 0.07 mmol) and m-CPBA (75%, 34 mg, 0.15 mmol)
were added to a stirring solution of alkene 16 (35 mg, 0.13 mmol) in dry
CH2Cl2 (2 mL) in an ice-water bath. The mixture was then stirred at am-
bient temperature until TLC showed the complete consumption of the
alkene. Saturated aqueous NaHCO3 (2 mL) was added and the mixture
was extracted with Et2O (3ꢁ30 mL). The combined organic layers were
washed with saturated aqueous Na2SO3 (15 mL) and brine (2ꢁ20 mL)
before being dried over anhydrous Na2SO4. Removal of the solvent by
rotary evaporation and column chromatography on silica gel (EtOAc/pe-
troleum ether, 1:10) gave epoxide 10k as a colorless sticky oil (32 mg,
0.12 mmol, 89% from compound 16). 1H NMR (300 MHz, CDCl3): d=
7.21–7.31 (m, 2H), 7.13 (t, J=3.8 Hz, 1H), 7.03 (t, J=3.7 Hz, 1H), 4.92
(s, 2H), 3.82–4.03 (m, 5H), 3.31 (d, J=4.4 Hz, 1H), 2.92 (d, J=4.7 Hz,
Experimental Section
General
THF and Et2O (for the moisture-sensitive reactions) were distilled over
Na/benzophenone under an argon atmosphere prior to use. CH2Cl2 and
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Simple Analogues of Qinghaosu (Artemisinin)
1H), 1.94–2.08 (m, 1H), 1.55–1.78 (m, 2H), 1.39–1.54 (m, 1H), 1.34 ppm
(s, 3H); 13C NMR (75 MHz, CDCl3): d=137.5, 133.6, 127.7, 127.1, 123.5,
123.2, 109.8, 68.1, 64.7, 64.6, 55.9, 54.0, 35.1, 23.9, 23.7 ppm; FTIR (film):
Conversion of Lactone 12l into Acetal 12m
DIBAL-H (1m, in cyclohexane, 0.13 mL, 0.13 mmol) was added to a stir-
ring solution of lactone 12l (15 mg, 0.057 mmol) in dry CH2Cl2 (2 mL) at
À788C under N2. The mixture was stirred at À788C until TLC showed
complete consumption of the lactone. MeOH (1 mL) was carefully added
to quench the excess hydride, followed by saturated aqueous potassium
sodium tartrate (5 mL) and Et2O (5 mL). Stirring was continued at ambi-
ent temperature until the mixture became transparent. The mixture was
extracted with Et2O (3ꢁ15 mL) and the combined organic layers were
washed with brine (5 mL) and dried over anhydrous Na2SO4. The drying
agent was removed by filtration and the filtrate was concentrated on
a rotary evaporator. The crude material was dissolved in anhydrous
MeOH (4 mL) that contained p-TsOH (2 mg, 0.01 mmol) and the solu-
tion was stirred at ambient temperature for 2 h, after which time TLC
analysis showed that the reaction had gone to completion. Saturated
aqueous NaHCO3 (3 mL) was added and the mixture was extracted with
Et2O (3ꢁ15 mL). The combined organic layers were washed with brine
(5 mL) and dried over anhydrous Na2SO4. Removal of the solvent by
rotary evaporation and column chromatography on silica gel (EtOAc/pe-
troleum ether, 1:50) gave compound 12m as a colorless oil (15 mg,
n˜ =2979, 2878, 1696, 1494, 1447, 1375, 1256, 1207, 1062, 869, 757 cmÀ1
;
MS (EI): m/z: 276 [M]+; HRMS (EI): m/z calcd for C16H20O4: 276.1362
[M]+; found: 276.1358.
Perhydrolysis of Compound 10k to Afford Compound 11k
Catalyst 7 (4 mg, 0.009 mmol) was added to a stirring solution of epoxide
10k (37 mg, 0.13 mmol) in ethereal H2O2 (1m, 1.5 mL) at ambient tem-
perature. The mixture was stirred at ambient temperature for 4 h then
water (5 mL) was added to the reaction mixture. The mixture was ex-
tracted with EtOAc (3ꢁ20 mL) and the combined organic layers were
washed with brine and dried over anhydrous Na2SO4. The drying agent
was removed by filtration and the filtrate was concentrated on a rotary
evaporator and column chromatography on silica gel (petroleum ether/
EtOAc, 1:1) gave compound 11k as a colorless oil (20 mg, 0.063 mmol,
50% from compound 10k) along with recovered compound 10k (10 mg,
1
0.035 mmol, 27%). H NMR (300 MHz, CDCl3): d=8.24 (s, 1H), 7.63 (d,
J=7.3 Hz, 1H), 7.27–7.39 (m, 2H), 7.06 (d, J=7.8 Hz, 1H), 4.85 (s, 2H),
4.15 (dd, J=2.3, 9.9 Hz, 1H), 3.90–4.04 (m, 5H), 3.83 (dd, J=8.3,
11.2 Hz, 1H), 1.99–2.19 (m, 3H), 1.67–1.89 (m, 2H), 1.37 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=136.1, 134.2, 127.7, 127.1, 126.4, 123.6,
109.9, 82.3, 67.6, 64.5, 64.0, 40.6, 35.7, 23.8, 22.9 ppm; FTIR (film): n˜ =
3360, 2927, 1455, 1377, 1211, 1099, 1060, 762, 728 cmÀ1; MS (ESI): m/z:
333.2 [M+Na]+; HRMS (ESI): m/z calcd for C16H22O6: 333.13086
[M+Na]+; found: 333.12989.
1
0.054 mmol, 95% from compound 12l). H NMR (300 MHz, CDCl3): d=
7.68 (d, J=7.6 Hz, 0.7H), 7.57 (d, J=7.6 Hz, 0.3H), 7.43–7.29 (m, 2H),
7.25–7.17 (m, 1H), 5.45 (s, 0.3H), 5.43 (s, 0.7H), 4.42 (d, J=7.6 Hz,
0.3H), 4.34–4.14 (m, 2.4H), 3.56 (s, 3H), 3.53 (d, J=7.6 Hz, 0.3H), 2.53–
2.39 (m, 1H), 2.20–2.04 (m, 2H), 2.01–1.82 (m, 1H), 1.59 (s, 1H),
1.44 ppm (s, 2H); FTIR (film): n˜ =2934, 2887, 1453, 1271, 1257, 1149,
1094, 1053, 1039, 1013, 759 cmÀ1; MS (EI): m/z (%): 278 (2) [M]+, 262
(16), 246 (3), 149 (48), 43 (100); HRMS (EI): m/z calcd for C15H18O5:
278.1154 [M]+; found: 278.1158.
Cyclization of Compound 11k to Afford Trioxane 12k
p-TsOH (4 mg, 0.02 mmol) was added into a solution of 11k (12 mg,
0.038 mmol) in CH2Cl2 (1 mL). The mixture was stirred at ambient tem-
perature overnight until TLC showed complete consumption of the start-
ing compound 11k. Saturated aqueous NaHCO3 (3 mL) was added and
the mixture was extracted with Et2O (3ꢁ25 mL). The combined organic
layers were washed with brine and dried over anhydrous Na2SO4. The
drying agent was removed by filtration, the filtrate was concentrated on
a rotary evaporator, and column chromatography on silica gel (EtOAc/
Acknowledgements
This work was supported by the National Basic Research Program of
China (the 973 Program, 2010CB833200), the National Natural Science
Foundation of China (21172247, 21032002, 20921091, 20672129, 20621062,
20772143), and the Chinese Academy of Sciences (KJCX2.YW.H08). We
thank Christian Scheurer for his assistance in performing the antimalarial
assays.
petroleum ether, 1:20) gave trioxane 12k as
a white solid (7 mg,
0.028 mmol, 75%). M.p.: 74–768C; 1H NMR (300 MHz, CDCl3): d=7.70
(d, J=6.8 Hz, 1H), 7.23–7.38 (m, 2H), 6.98 (d, J=6.4 Hz, 1H), 4.81 (s,
2H), 4.27 (d, J=11.7 Hz, 1H), 4.21 (dd, J=11.6, 1.7 Hz, 1H), 3.69–3.90
(m, 1H), 2.31–2.52 (m, 1H), 1.84–2.19 (m, 3H), 1.43 ppm (s, 3H);
13C NMR (125 MHz, CDCl3): d=136.0, 134.1, 128.6, 127.8, 127.2, 123.5,
103.7, 78.5, 73.4, 68.1, 65.2, 35.8, 34.4, 25.9, 25.4 ppm; FTIR (KBr): n˜ =
2927, 2853, 1490, 1448, 1372, 1255, 1215, 1147, 1104, 1078, 756 cmÀ1; MS
(EI): m/z: 248 (0.5) [M]+, 216 (18), 204 (21); HRMS (EI): m/z calcd for
C14H16O4: 248.1049 [M]+; found: 248.1042.
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Oxidation of Compound 12k to Afford Lactone 12l
FeCl3 (77 mg, 0.48 mmol) and KMnO4 (122 mg, 0.77 mmol) were added
to a stirring solution of compound 12k (21 mg, 0.077 mmol) in acetone
(6 mL) at À788C. The bath was allowed to warm to ambient temperature
and stirring was continued for 12 h before Et2O (10 mL) and water
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to afford compound 12l as a colorless oil (20 mg, 0.076 mmol, 99% from
compound 12k). 1H NMR (300 MHz, CDCl3): d=8.07–8.14 (m, 1H),
7.64–7.82 (m, 2H), 7.47–7.58 (m, 1H), 4.56–4.67 (m, 1H), 4.50 (d, J=
7.9 Hz, 0.3H), 4.14–4.26 (m, 1.3H), 3.52 (d, J=7.9 Hz, 0.3H), 2.25–2.55
(m, 2H), 2.11–2.53 (m, 1.3H), 1.84–2.06 (m, 0.7H), 1.63 (s, 2H),
1.46 ppm (s, 1H); FTIR (film): n˜ =2935, 1736, 1603, 1458, 1275, 1150,
1136, 1076, 1039, 845, 757 cmÀ1; MS (EI): m/z (%): 267 (2) [M]+, 230
(28), 189 (55), 104 (100), 76 (57); HRMS (EI): m/z calcd for C14H14O5:
262.0841 [M]+; found: 262.0838.
Chem. Asian J. 2012, 00, 0 – 0
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Yikang Wu et al.
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Received: February 1, 2012
Published online: && &&, 0000
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ÝÝ These are not the final page numbers!

FULL PAPERS
Terpenoids
Yun Li, Hong-Dong Hao,
Sergio Wittlin, Yikang Wu* &&&& — &&&&
Simple Analogues of Qinghaosu (Arte-
misinin)
The temple of artemisinin: The key
peroxy bonds in a series of 1,2,4-triox-
anes were installed by molybdenum-
catalyzed perhydrolysis of the epoxy
rings. A novel core structure with
potent antimalarial activity was identi-
fied.
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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