Antimalarial activity of yingzhaosu A analogues

Article abstract of DOI:10.1021/jm020208q

Iodonium ion mediated cyclization of unsaturated hydroperoxides 1 afforded the expected yingzhaosu A analogues 2. In some cases, however, the corresponding cyclic ethers 5 were formed competitively with the cyclic peroxides 2, the ratios of these two prod

Full text of DOI:10.1021/jm020208q

4732
J . Med. Chem. 2002, 45, 4732-4736
An tim a la r ia l Activity of Yin gzh a osu A An a logu es
Hye-Sook Kim,† Khurshida Begum,† Naoki Ogura,† Yusuke Wataya,*,† Takahiro Tokuyasu,‡ Araki Masuyama,‡
Masatomo Nojima,‡ and Kevin J . McCullough§
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, J apan, Department of Materials
Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, J apan, and Department of Chemistry,
Heriot-Watt University, Edinburgh EH14 4AS, Scotland
Received May 14, 2002
Iodonium ion mediated cyclization of unsaturated hydroperoxides 1 afforded the expected
yingzhaosu A analogues 2. In some cases, however, the corresponding cyclic ethers 5 were
formed competitively with the cyclic peroxides 2, the ratios of these two products being a marked
function of the structure of the starting materials. Some of the cyclic peroxides 2 showed
significant antimalarial activities in vitro and in vivo.
Sch em e 1
In tr od u ction
Recently, antimalarial activities of artemisinin, ying-
zhaosu A, and other natural endoperoxides have
attracted considerable attention.1 Total synthesis of
yingzhaosu A, possessing the unusual 2,3-dioxabicyclo-
[3.3.1]nonane skeleton, has been independently achieved
by Xu2 and Bachi.3a In addition, several 2,3-dioxabicyclo-
[3.3.1]nonane derivatives with excellent antimalarial
activity have been prepared.3,4 We have also reported
the preparation of yingzhaosu A analogues by ozone-
mediated cyclization of unsaturated hydroperoxides.5 As
an alternative synthetic approach to this kind of en-
doperoxide, we report herein the bis(collidine)iodine
hexafluorophosphate (BCIH) mediated cyclization of a
series of unsaturated hydroperoxides yielding the 4-io-
domethyl-substituted 2,3-dioxabicyclo[3.3.1]nonane de-
rivatives and their antimalarial activities.6
Resu lts a n d Discu ssion
P r ep a r a tion of Un sa tu r a ted Hyd r op er oxid es. A
variety of unsaturated hydroperoxides 1a -j were used
as starting materials for cyclization. The methods for
preparation of 1a -d ,f,g have been reported previously.5
The unsaturated isomeric sec-hydroperoxides cis-1h
(23%) and trans-1h (17%) were prepared from 3-(2-
methyl-2-propenyl)cyclohexanone as outlined in Scheme
1.7 Similarly, the hydroperoxides cis- and trans-1e were
prepared from 2-(2-methyl-2-propenyl)cyclohexanone
(Scheme 1).
Sch em e 2
R-Methoxy-substituted hydroperoxide 1i was obtained
as an inseparable mixture of diastereoisomers (52%; 1:1)
by the regioselective mono-ozonolysis of the correspond-
ing enol ether in MeOH-CH2Cl2 at -70 °C (Scheme 2).
Hydroperoxide 1j was prepared from 1-methoxymeth-
ylene-3-(2-methyl-1-propenyl)cyclohexane by a similar
method.
BCIH-Med ia ted Cycliza tion of Un sa tu r a ted Hy-
d r op er oxid es. The reaction of an unsaturated hydro-
peroxide 1a (a 1:1 mixture of isomers) with BCIH in
CH2Cl2 gave the expected yingzhaosu A analogue 2a as
a 3:2 mixture of diastereoisomers together with the
ketone 3a (Scheme 3); the latter is formed by the
intramolecular migration of the methoxy group as
discussed previously.6 From the reaction of 1b under
similar reaction conditions, cyclic peroxide 2b was
obtained in 33% yield as a 5:2 mixture of diastereoiso-
mers together with several unidentified polar products.
Under similar conditions for the formation of the
endoperoxides 2a ,b from 1a ,b, the reaction of 1c with
* To whom correspondence should be addressed. Phone: +81-86-
251-7976. Fax: +81-86-251-7974. E-mail: wataya@cc.okayama-u.ac.jp
† Okayama University.
‡ Osaka University.
§ Heriot-Watt University.
10.1021/jm020208q CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002

Antimalarial Yingzhaosu A Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21 4733
Sch em e 3
Sch em e 5
Sch em e 4
gave mainly the 2,3-dioxabicyclo[4.4.0]decane derivative
trans-2e (43%) together with trans-5e (23%). These
observations are consistent with the notion that in cis-
4e the terminal oxygen of the hydroperoxy group is
directed away from the cyclohexane ring, allowing the
nucleophilic attack of the inner oxygen to occur pre-
dominantly.
With these notions in mind, we designed unsaturated
hydroperoxides 1f,g. In the reactions of these substrates,
the resulting iodonium ion intermediates 4f,g should
cyclize through sterically less hindered conformations
with only one axial substituent. Moreover, the flexibility
of the tethered hydroperoxy group in 4f,g should favor
nucleophilic attack of the terminal oxygen on the
iodonium ion moiety. Consistent with this proposal, the
reaction of 1f with BCIH afforded the expected endop-
eroxide 2f in a moderate yield (53%; 1:1 mixture of
diastereoisomers). In an analogous manner, the endop-
eroxide 2g (52% yield) was obtained as the predominant
product from 1g (Scheme 6).
Finally, the reactions of unsaturated hydroperoxides
1h -j, each having a homologated side chain with BCIH,
were investigated. In each case, the bicyclic 1,2-diox-
epanes 2h -j were obtained in moderate yield (ca. 60%)
with no evidence for the formation of the corresponding
bicyclic ethers (Scheme 7). A priori, it is presumed that
the ease of formation of the bicyclic 1,2-dioxepanes 2h -j
must lie in the lower ring strain in the bicyclo[4.3.1]-
decane system compared to that of the bicyclo[3.3.1]-
nonane structure.
BCIH gave a cyclic ether 5c (27%), together with the
expected cyclic peroxide 2c (23%) (Scheme 4). From 1d ,
the corresponding oxolane 5d (47%) was obtained
exclusively. Regretfully, we failed to identify products
resulting from the residual “OH+”.7
To realize the intramolecular cyclization of 1a -d to
give 2a -d , it is clear that the iodonium ion intermediate
4a -d must adopt a 1,3-synaxial conformation. The
formation of 2a -c and 5c,d implies that two competitive
cyclization modes (paths a and b in Scheme 4) are in
operation. Because of the exclusive formation of the
oxolane 5d from 1d (R ) H), it is tentatively suggested
that in the sterically less-congested intermediate 4d , the
inner oxygen of the hydroperoxy group moiety lies
relatively close to the iodonium with the more nucleo-
philic terminal oxygen of the hydroperoxy group directed
away from the cyclohexane ring owing to the 1,3-
synaxial interactions.
To obtain further insight into the competitive forma-
tion of 1,2-dioxanes 2 and oxolanes 5, the reactions of
cis- and trans-1e with BCIH were examined (Scheme
5). It is interesting to note that the reaction of cis-1e
gave exclusively the 7-oxabicyclo[4.3.0]nonane deriva-
tive cis-5e (53% yield), while the reaction of trans-1e
An tim a la r ia l Activity of Yin gzh a osu A An a -
logu es in Vitr o. With several types of endoperoxides
in hand, their antimalarial activity and cytotoxicity
were tested against P. falciparum and FM3A cells,8
respectively (Table 1). The data showed the following
characteristics. First, of several 2,3-dioxabicyclo[3.3.1]-
nonane derivatives 2a -d and 2f,g, 2c,f,g exhibited

4734 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21
Kim et al.
Ta ble 1. In Vitro Antimalarial Activities of Yingzhaosu A
Sch em e 6
Analogues against P. falciparum and Cyctotoxicities against
FM3A Cellsa
EC50 (µM)
peroxide
2a
2b
2c
P. falciparumb
FM3Ac
selectivityd
1.7
2.0
0.013
1.5
>70 (19%)e
>54 (8%)e
>84 (10%)e
66
>41
>27
>6462
44
trans-2e
2f
2g
2h
2i
2j
5c
0.011
0.040
3.0
2.5
15
3.1
68
282
1700
>32
>32
>4
>48
>2
>14
1000
>96 (47%)e
>80 (6%)e
>64 (10%)e
>48 (0%)e
>210 (34%)e
>84 (10%)e
10
1
trans-5e
5g
artemisinin
120
5.8
0.01
a
In vitro antimalarial activities and cytotoxicities were deter-
mined by a previously reported protocol.8 Chloroquine-sensitive
b
(FCR-3 strain). c Mouse mammary tumor FM3A cells in culture
d
as a control for mammalian cell cytotoxicity. Selectivity ) (mean
of EC50 value for FM3A cells)/(mean of EC50 value for P. falci-
parum). e No activity at 10 µM. The value in parentheses is the
growth inhibition (%) in each concentration.
Ta ble 2. In Vivo Antimalarial Activities of Yingzhaosu A
Analogues against P. berghei Infected Micea
intraperitoneal
administration
intramuscular
administration
growth
growth
inhibitoin (%)
survivalb
inhibitoin (%)
survivalb
at 100 mg kg-1 day-1 (days) at 100 mg kg-1 day-1 (days)
2f
2g
20
32
6.5
7.0
80
99
9.8
9.6
a
Sch em e 7
The test compounds were prepared in olive oil, and these
compounds were administered to groups of five mice once a day
starting on day 0 and continuing on days 1-3. Growth inhibition
was determined on the day following the last treatment (on day
4). The details of the experimental procedure are described in ref
b
8. On average, mice in the control group survived for 6.0 days
after infection.
relatively inactive. This may imply that the presence
of ring strain within the 2,3-dioxabicyclo[3.3.1]nonane
structure is essential for antimalarial activity. Finally,
the activities of the cyclic ethers 5c, trans-5e, and 5g
were much lower than those of the corresponding cyclic
peroxides 2c, trans-2e, and 2g, as expected.1b
An tim a la r ia l Activity of Yin gzh a osu A An a -
logu es in Vivo.8 In vivo antimalarial activities against
P. berghei NK 65 strain8 were then determined for the
bicyclic peroxides 2f,g, which had shown such notable
activities in vitro. As indicated in Table 2, compounds
2f,g exhibited significant antimalarial activities (ED50
was 69 mg kg-1 day-1 for 2f and 50 mg kg-1 day-1 for
2g) on intramuscular (im) administration. In contrast,
the activities of 2f,g on intraperitoneal (ip) administra-
tion at a dose of 100 mg kg-1 day-1 were comparatively
poor. These results tend to suggest that most of the iodo-
substituted compounds 2f,g administered intraperito-
neally must have been metabolized in the liver into
compounds having little or no antimalarial activity by
a detoxification pathway.9 On the other hand, com-
pounds 2f,g administered into the thigh muscle of mice
(im) must have been delivered without modification into
the blood stream and consequentially retained substan-
tial antimalarial activity.9 The survival times of the P.
berghei infected mice treated with 2f,g (im, 100 mg kg-1
day-1) were found to be approximately 1.6 times longer
significant antimalarial activities similar to those for
arteflene4b and the related â-sulfonyl endoperoxides.3
Thus, although a minor change in the structure affects
remarkably the activities, yingzhaosu A analogues are
potentially promising as candidates of antimalarial
drugs. Second, the related 2,3-dioxabicyclo[4.3.1]decanes
2h -j and 2,3-dioxabicyclo[4.4.0]decane trans-2e were

Antimalarial Yingzhaosu A Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21 4735
83.33, 83.45; HRMS (EI) m/z calcd for C10H17IO 280.0324,
found 280.0304. Anal. Calcd for C10H17IO: C, 42.87; H, 6.12.
Found: C, 42.96; H, 6.18.
than those of the untreated ones. In addition, the
sample of mice treated with 2f,g (ip or im administra-
tion) did not exhibit either any of the usual effects of
toxicity (e.g., diarrhea, weight loss, convulsion) or
significant deviations from normal behavior. These
results led us to deduce that significant modification of
the functionalization of this series of bicyclic peroxides
2 would lead to the development of an attractive
antimalarial drug candidate. As a first approach, we are
now trying to transform the labile iodo group in 2f,g
into other functional groups such as hydroxyl and
carboxyl.
4-Iod om et h yl-1-m et h oxy-4-m et h yl-2,3-d ioxa b icyclo-
[3.3.1]n on a n e (2a ). An oil (a 3:2 mixture of two stereoiso-
1
mers); H NMR δ 1.2-2.5 (m, 9H), 1.35 (s, major) + 1.43 (s)
(3H), 3.3-3.5 (m, major) + 3.63 (s) + 3.66 (s) (2H), 3.38 (s) +
3.39 (s, major) (3H); 13C NMR δ 11.56 (CH2), 12.22 (CH2), 20.45
(CH2), 20.94 (CH3), 21.46 (CH2), 24.82 (CH2), 24.87 (CH3), 26.13
(CH2), 31.36 (CH2), 31.81 (CH2), 31.86 (CH2), 32.51 (CH2), 35.92
(CH), 37.97 (CH), 49.15 (CH3), 49.38 (CH3), 81.47 (C), 82.07
(C), 103.11 (C), 104.19 (C). Anal. Calcd for C10H17IO3: C, 38.48;
H, 5.49; I, 40.66. Found: C, 38.39; H, 5.37; I, 40.64.
4-Iodom eth yl-1-m eth oxy-4,8-dim eth yl-2,3-dioxabicyclo-
[3.3.1]n on a n e (2b) (Ma jor Isom er ). Mp 95-97 °C (ethyl
acetate-hexane); 1H NMR δ 0.91 (d, J ) 6.2 Hz, 3H), 1.2-2.0
(m, 6H), 1.36 (s, 3H), 2.3-2.6 (m, 2H), 3.31 (d, J ) 10.9 Hz,
1H), 3.43 (s, 3H), 3.65 (d, J ) 10.9 Hz, 1H); 13C NMR δ 11.49
(CH2), 13.91 (CH3), 25.29 (CH3), 25.39 (CH2), 29.27 (CH2), 30.86
(CH2), 38.12 (CH), 39.89 (CH), 49.56 (CH3), 81.85 (C), 104.89
(C). Anal. Calcd for C11H19IO3: C, 40.51; H, 5.87; I, 38.91.
Found: C, 40.45; H, 5.77; I, 38.63.
Su m m a r y
The BCIH-mediated cyclization of unsaturated hy-
droperoxides via the iodonium ion intermediates has
been found to provide the corresponding 2,3-dioxabicyclo-
[3.3.1]nonane or 2,3-dioxabicyclo[4.3.1]decane deriva-
tives. Some of the 2,3-dioxabicyclo[3.3.1]nonane deriva-
tives show significant antimalarial activity in vitro,
suggesting that the strained structure with a peroxide
bond in the ring is the essential factor for the appear-
ance of notable activity. The study in vivo demonstrates
that substantial modification of the functionalization of
this series of bicyclic peroxides 2 would be required in
order to produce a significant antimalarial drug candi-
date.
2b (Min or Isom er ). The minor isomer was obtained as an
admixture with 71% of the major one and is obtained as an
1
oil. H NMR δ 0.97 (d, J ) 5.6 Hz, 3H), 1.43 (s, 3H), 3.29 (d,
J ) 10.4 Hz, 1H), 3.39 (s, 3H), 3.46 (d, J ) 10.4 Hz, 1H); 13C
NMR δ 12.19 (CH2), 13.98 (CH3), 20.81 (CH3), 26.49 (CH2),
29.33 (CH2), 29.85 (CH2), 36.07 (CH), 39.75 (CH), 49.76 (CH3),
81.17 (C), 103.85 (C).
4-Iod om eth yl-4-m eth yl-2,3-d ioxa bicyclo[4.4.0]d eca n e
1
(tr a n s-2e). An oil (a 1:1 mixture of two isomers); H NMR δ
1.0-2.0 (m, 10.5H), 1.27 (s) + 1.54 (s) (3H), 2.1-2.2 (m, 0.5H),
3.12 (s) + 3.58 (d, J ) 10.2 Hz) + 3.67 (d, J ) 10.2 Hz) (2H),
3.6-3.8 (m, 1H); 13C NMR δ 12.24 (CH2), 13.75 (CH2), 21.62
(CH3), 24.87 (CH2), 24.91 (CH2), 25.34 (CH2), 25.43 (CH2), 26.51
(CH3), 28.30 (CH2), 28.48 (CH2), 30.37 (CH2), 30.48 (CH2), 36.71
(CH), 37.49 (CH2), 37.63 (CH), 39.30 (CH2), 78.91 (C), 79.91
(C), 85.36 (CH), 85.50 (CH). Anal. Calcd for C10H17IO2: C,
40.56; H, 5.79. Found: C, 40.61; H, 5.60.
8-Iodom eth yl-8-m eth yl-7-oxabicyclo[4.3.0]n on an e (tr a n s-
5e). An oil (a 1:1 mixture of two isomers); 1H NMR δ 1.0-2.2
(m, 11H), 1.42 (s) + 1.47 (s) (3H), 3.2-3.4 (m, 1H), 3.26 (s) +
3.31 (s) (2H); 13C NMR δ 17.90 (CH2), 18.85 (CH2), 24.17 (CH2),
25.57 (CH2), 25.64 (CH2), 27.35 (CH3), 27.48 (CH3), 28.79 (CH2),
28.88 (CH2), 31.34 (CH2), 31.52 (CH2), 42.59 (CH2), 43.42 (CH2),
45.57 (CH), 45.97 (CH), 80.20 (C), 80.56 (C), 83.43 (CH) 83.47
(CH); HRMS (CI) m/z calcd for C10H18IO 281.0403, found
281.0405. Anal. Calcd for C10H17IO: C, 42.87; H, 6.12. Found:
C, 42.75; H, 6.08.
(4,4-Dim eth yl-2,3-d ioxa bicyclo[3.3.1]n on -1-yl)iod oa ce-
tic Acid Eth yl Ester (2f). An oil (a 1:1 mixture of two
stereoisomers); 1H NMR δ 1.2-2.4 (m, 18H), 4.1-4.2 (m, 2H),
4.30 (s) + 4.31 (s) (1H); 13C NMR δ 13.73 (CH3), 13.77 (CH3),
20.29 (CH2), 20.34 (CH2), 23.04 (CH3), 23.22 (CH3), 24.87 (CH3),
25.05 (CH3), 25.90 (CH2), 26.11 (CH2), 29.04 (CH), 29.45 (CH),
30.71 (CH2), 31.25 (CH2), 32.29 (CH2), 32.76 (CH2), 35.76 (CH),
36.10 (CH), 61.85 (CH2), 61.91 (CH2), 78.47 (C), 78.65 (C), 81.38
(C), 81.58 (C), 168.88 (C), 169.07 (C); LRMS (EI) m/z (rel intens
%) 368 (M+) (8), 241 (M+ - I) (21), 155 (M+ - CHICO2Et) (61);
HRMS (EI) m/z calcd for C13H21IO4 368.0485, found 368.0483.
Anal. Calcd for C13H21IO4: C, 42.41; H, 5.75. Found: C, 42.75;
H, 6.00.
Exp er im en ta l Section s
Gen er a l P r oced u r es. 1H (270 MHz) and 13C (67.5 MHz)
NMR spectra were obtained in CDCl3 solution with SiMe4 as
the internal standard. The preparation of unsaturated hydro-
peroxides 1a -d ,f,g was previously reported.5
BCIH -Med ia t ed Cycliza t ion of Un sa t u r a t ed H yd r o-
p er oxid es. The reaction of the unsaturated hydroperoxide 1c
is representative. To CH2Cl2 (5 mL) were concurrently added
a CH2Cl2 (5 mL) solution of the unsaturated hydroperoxide
1c (100 mg, 0.59 mmol) and a CH2Cl2 (5 mL) solution of BCIH
(500 mg, 0.97 mmol) over 30 min, and then the reaction
mixture was stirred at room temperature for 2 h (the flask
was covered with aluminum foil). The reaction mixture was
poured into aqueous Na2S2O3 (20 mL) and extracted with ether
(30 mL × 2). The combined organic layer was washed with
0.2 N HCl (50 mL) and aqueous sodium bicarbonate (30 mL)
in turn and dried over anhydrous MgSO4. After evaporation
of the solvent under reduced pressure, the product was isolated
by column chromatography on silica gel. Elution with diethyl
ether-hexane (2:98) gave a mixture of the 1,2-dioxane 2c and
the oxolane 5c. These two products were separated by subse-
quent column chromatography on alumina. Elution with
diethyl ether-hexane (0.3:99.7) gave the oxolane 5c (45 mg,
27%) as a 1:1 mixture of two stereoisomers. Subsequent elution
with diethyl ether-hexane (0.4:99.6) gave the 1,2-dioxane 2c
(40 mg, 23%) as a 1:1 mixture of two stereoisomers.
4-Iod om e t h yl-1,4-d im e t h yl-2,3-d ioxa b icyclo[3.3.1]-
n on a n e (2c). An oil (a 1:1 mixture of two stereoisomers); H
1
NMR δ 0.99 (s) + 1.02 (s) + 1.24 (s) + 1.48 (s) (6H), 1.3-2.3
(m, 9H), 3.07 (s) + 3.08 (s) + 3.40 (d, J ) 10.4 Hz) + 3.73 (d,
J ) 10.4 Hz) (2H); 13C NMR δ 10.15, 13.43, 20.46, 21.06, 22.48,
22.96, 25.81, 25.97, 26.41, 26.79, 31.00, 33.21, 34.73, 35.65,
36.24, 36.28, 76.82, 77.15, 80.41, 80.68; HRMS (EI) m/z calcd
for C10H17IO2 296.0273, found 296.0276. Anal. Calcd for C10H17
IO2: C, 40.56; H, 5.79. Found: C, 40.77; H, 5.75.
7-Iod om et h yl-5,7-d im et h yl-6-oxa b icyclo[3.2.1]oct a n e
1-Iod om e t h yl-4,4-d im e t h yl-2,3-d ioxa b icyclo[3.3.1]-
n on a n e (2g). An oil; 1H NMR δ 1.2-2.4 (m, 9H), 1.22 (s, 3H),
1.39 (s, 3H), 3.10 (s, 1H), 3.11 (s, 1H); 13C NMR δ 13.73 (CH2),
20.49 (CH2), 23.42 (CH3), 24.69 (CH3), 26.31 (CH2), 33.57 (CH2),
34.31 (CH2), 35.55 (CH), 75.74 (C), 80.67 (C). Anal. Calcd for
-
C
10H17IO2: C, 40.56; H, 5.79. Found: C, 40.17; H, 5.59.
1
(5c). An oil (a 1:1 mixture of two stereoisomers); H NMR δ
5-Iod om et h yl-7,7-d im et h yl-6-oxa b icyclo[3.2.1]oct a n e
1.2-2.2 (m, 8.5H), 1.20 (s) + 1.22 (s) + 1.39 (s) + 1.46 (s) (6H),
2.3-2.5 (m, 0.5H), 3.12 (d, J ) 9.9 Hz) + 3.20 (d, J ) 9.9 Hz)
+ 3.24 (d, J ) 9.6 Hz) + 3.51 (d, J ) 9.6 Hz) (2H); 13C NMR
δ 11.47, 18.24, 19.14, 19.86, 20.40, 25.82, 26.67, 27.21, 27.37,
27.98, 37.47, 37.83, 41.44, 43.16, 43.34, 43.61, 82.10, 82.98,
(5g). Mp 48-49 °C (hexane); 1H NMR δ 1.2-2.1 (m, 8H), 1.28
(s, 3H), 1.36 (s, 3H), 2.2-2.4 (m, 1H), 3.30 (s, 2H); 13C NMR δ
16.64, 19.56, 23.04, 26.62, 30.51, 35.44, 42.21, 44.19, 81.10,
83.81. Anal. Calcd for C10H17IO: C, 42.87; H, 6.12. Found: C,
42.82; H, 6.04.

4736 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21
Kim et al.
4-Iod om eth yl-4-m eth yl-2,3-d ioxa bicyclo[4.3.1]d eca n e
(2h ). An oil; H NMR δ 1.2-2.2 (m, 10H), 1.42 (s, 3H), 2.50
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Metabolism of Novel, Potent C-10-Phenoxy Derivatives of Di-
hydroartemisinin. J . Med. Chem. 2001, 44, 58-68. (f) Ma, J .;
Weiss, E.; Kyle, D. E.; Ziffer, H. Acid Catalyzed Michael
Additions to Artemisitene. Bioorg. Med. Chem. Lett. 2000, 10,
1601-1603. (g) Li, Y.; Zhu, Y.-M.; J iang, H.-J .; Pan, J .-P.; Wu,
G.-S.; Wu, J .-M.; Shi, Y.-L.; Yang, J .-D.; Wu, B.-A. Synthesis
and Antimalarial Activity of Artemisinin Derivatives Containing
an Amino Group. J . Med. Chem. 2000, 43, 1635-1640. (h)
Posner, G. H.; J eon, H. B.; Parker, M. H.; Krasavin, M.; Paik,
I.-H.; Shapiro, T. A. Antimalarial Simplified 3-Aryltrioxanes:
Synthesis and Preclinical Efficacy/Toxicity Testing in Rodents.
J . Med. Chem. 2001, 44, 3054-3058. (i) McCullough, K. J .;
Nojima, M. Recent Advances in the Chemistry of Cyclic Perox-
ides. Curr. Org. Chem. 2001, 5, 601-636.
(br d, J ) 13.9 Hz, 1H), 3.24 (d, J ) 10.2 Hz, 1H), 3.30 (d, J
) 10.2 Hz, 1H), 4.4-4.5 (m, 1H); 13C NMR δ 10.25 (CH2), 15.80
(CH2), 26.45 (CH3), 28.23 (CH and CH2, 2C), 30.80 (CH2), 31.22
(CH2), 36.30 (CH2), 79.26 (CH), 84.98 (C); LRMS (EI) m/z (rel
intens %) 296 (M+) (14), 155 (M+ - CH2I) (100); HRMS (EI)
m/z calcd for C10H17IO2 296.0273, found 296.0270. Anal. Calcd
for C10H17IO2: C, 40.56; H, 5.79. Found: C, 40.62; H, 5.76.
4-Iod om et h yl-1-m et h oxy-4-m et h yl-2,3-d ioxa b icyclo-
[4.3.1]d eca n e (2i). An oil (a 7:3 mixture of two stereoisomers);
1H NMR δ 1.4-2.0 (m, 9H), 1.37 (s) + 1.48 (s, major) (3H),
2.2-2.4 (m, 1.3H), 2.4-2.6 (m, 0.7H), 3.18 (d, J ) 9.9 Hz,
major) + 3.2-3.4 (m) + 3.36 (d, J ) 9.9 Hz, major) (2H), 3.31
(s) + 3.32 (s, major) (3H); 13C NMR (major isomer) δ 9.31 (CH2),
18.12 (CH2), 27.44 (CH), 28.25 (CH3), 30.73 (CH2), 30.78 (CH2),
34.70 (CH2), 35.08 (CH2), 48.47 (CH3), 85.05 (C), 106.56 (C).
The following additional signals were assigned to the minor
isomer. 13C NMR δ 17.22 (CH2), 18.08 (CH2), 21.48 (CH3), 27.69
(CH), 30.57 (CH2), 30.95 (CH2), 34.86 (CH2), 35.00 (CH2), 48.35
(CH3), 84.60 (C), 106.42 (C). Anal. Calcd for C11H19IO3: C,
40.51; H, 5.87. Found: C, 40.70; H, 5.76.
5-Iod o-1-m eth oxy-4,4-d im eth yl-2,3-d ioxa bicyclo[4.3.1]-
d eca n e (2j). An oil; 1H NMR δ 1.4-2.2 (m, 7H), 1.52 (s, 3H),
1.56 (s, 3H), 2.7-2.9 (m, 2H), 3.31 (s, 3H), 4.55 (d, J ) 8.0 Hz,
1H); 13C NMR δ 18.42 (CH2), 23.38 (CH3), 28.81 (CH2), 29.07
(CH3), 30.87 (CH2), 36.50 (CH2), 40.43 (CH), 42.75 (CH), 48.62
(CH3), 86.95 (C), 106.11 (C). HRMS (EI) m/z calcd for C11H19
-
(2) Xu, X.-X.; Zhu, J .; Haung, D.-Z.; Zhou, W.-S. Total Synthesis of
(+)-Yingzhaosu A. Tetrahedron Lett. 1991, 32, 5785.
IO3 326.0379, found 326.0393. Anal. Calcd for C11H19IO3: C,
40.51; H, 5.87. Found: C, 40.92; H, 6.02.
(3) (a) Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M.
Synthesis and Reactions of Antimalarial Bicyclic Peroxides. J .
Heterocycl. Chem. 2000, 37, 639-646. (b) Szpilman, A. M.;
Korshin, E. E.; Hoos, B.; Posner, G. H.; Bachi, M. D. Iron(II)-
Induced Degradation of Antimalarial â-Sulfonyl Endperoxides.
Evidence for the Generation of Potentially Cytotoxic Carboca-
tions. J . Org. Chem. 2001, 66, 6531-6540.
(4) (a) O’Neill, P. M.; Searle, N. L.; Raynes, K. J .; Maggs, J . L.; Ward,
S. A.; Storr, R. C.; Park, B. K.; Posner, G. H. A Carbonyl Oxide
Route to Antimalarial Yingzhaosu A Analogues: Synthesis and
Antimalarial Activity. Tetrahedron Lett. 1998, 39, 6065. (b)
Hofheinz, W.; Bu¨rgin, H.; Gocke, E.; J aquet, C.; Masciadri, R.;
Schmid, G.; Stohler, H.; Urmyler, H. Ro 42-1611 (Arteflene), a
New Effective Antimalarial: Chemical Structure and Biological
Activity. Trop. Med. Parasitol. 1994, 45, 261.
In Vitr o a n d in Vivo An tim a la r ia l Activity. In vitro
antimalarial activity against P. falciparum (FCR-3 strain) and
cytotoxicity against mouse mammary cell (FM3A) was deter-
mined as described previously.8 In vivo antimalarial activity
was assessed using ICR mice infected with P. berghei (NK 65
strain) following the protocol described previously.8 In brief,
various concentrations of the test compounds, prepared in olive
oil, were administered daily, ip or im, to groups of five mice
for 4 consecutive days beginning on the day of infection (to
determine the ED value and survival days). To evaluate the
antimalarial activity of the compounds, we prepared tail blood
smears and stained them with Giemsa (E. Merck, Germany).
A total of 1 × 104 erythrocytes per one thin blood film were
examined under a microscope. On day 4, parasitemia of control
mice were between 18% and 22%. The suppression of para-
sitemia for the dose of the 2f,g was calculated by the formula
(5) Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough, K. J .;
Kim, H.-S.; Wataya, Y. Yingzhaosu A Analogues: Synthesis by
the Ozonolysis of Unsaturated Hydroperoxides, Structural Analy-
sis and Determination of Anti-malarial Activity. Tetrahedron
2001, 57, 5979.
(6) A part of this work was published in preliminary form. Toku-
yasu, T.; Masuyama, A.; Nojima, M.; Kim, H.-S.; Wataya, Y.
Synthesis and Anti-malarial Activity of Yingzhaosu A Analogues
from Unsaturated Hydroperoxy Acetals. Tetrahedron Lett. 2000,
41, 3145-3146. Tokuyasu, T.; Masuyama, A.; Nojima, M.;
McCullough, K. J . Halonium Ion-Mediated Unsaturated Hydro-
peroxy Acetals. Competition between the Formation of Cyclic
Peroxide and the Migration of the Methoxy (or Hydroxy) Group.
J . Org. Chem. 2000, 65, 1069-1075.
(7) Formation of a bicyclic ether from the reaction of 5-hydroper-
oxycyclooctene with N-bromosuccinimide via a similar ejection
of “OH+” has already been reported. Bloodworth, A. J .; Melvin,
T.; Mitchell, J . C. Oxygen Transfer by Dialkylperoxonium Ions.
J . Org. Chem. 1986, 51, 2612-2613.
average % parasitemia
-
average % parasitemia
in treated mice
in controls (sham-treated)
× 100
average % parasitemia in controls (sham treated)
Five infected dimethyl sulfoxide dosed mice were used as a
control. The data shown are the mean values from five mice
in one test.
Ack n ow led gm en t. This work was supported in part
by Grant-in-Aid for Scientific Research on Priority Areas
(Grants 12307007, 13226079, 13650904, 14021072, and
14021066) from the Ministry of Education, Science,
Culture and Sports of J apan.
(8) Kim, H.-S.; Nagai, Y.; Ono, K.; Begum, K.; Wataya, Y.; Hamada,
Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M. McCullough, K. J .
Synthesis and Antimalarial Activity of 1,2,4,5-Tetraoxacycloal-
kanes. J . Med. Chem. 2001, 44, 2357-2361.
(9) Benet, L. Z.; Kroetz, D. L.; Sheiner, L. W. Pharmacolinetics: The
dynamics of drug absorption, distribution, and elimination. In
Goodman & Gilman’s the Pharmacological Basis of Therapeutics,
9th ed.; Hardman, J . G., Limbird, L. E., Eds.; McGraw-Hill
Health Professions Division Ltd.: New York, 1996; pp 3-27.
Su p p or tin g In for m a tion Ava ila ble: Synthetic methods
and spectroscopic data of unsaturated hydroperoxides, cis- and
trans-1e, cis- and trans-1h , 1i, and 1j and spectroscopic data
for products 3a , 5d , and cis-5e. This material is available free
of charge via the Internet at http://pubs.acs.org.
J M020208Q