Synthesis and antimalarial activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes

Article abstract of DOI:10.1021/jm010026g

CsOH- or Ag₂O-mediated cycloalkylation of (alkylidene)bisperoxides 3 and 1,n-dihaloalkanes (n = 3-8) provided the corresponding medium-sized 1,2,4,5-tetraoxacycloalkanes 4-8 in moderate yields. Subsequent evaluation of the antimalarial activity of the cyclic peroxides 4-8 in vitro and in vivo revealed that 1,2,6,7-tetraoxaspiro[7.11]nonadecane 4a has considerable potential as a new, inexpensive, and potent antimalarial drug.

Full text of DOI:10.1021/jm010026g

J . Med. Chem. 2001, 44, 2357-2361
2357
Syn th esis a n d An tim a la r ia l Activity of Novel Med iu m -Sized
1,2,4,5-Tetr a oxa cycloa lk a n es
Hye-Sook Kim,† Yukiko Nagai,† Kanako Ono,† Khurshida Begum,† Yusuke Wataya,*,† Yoshiaki Hamada,‡
Kaoru Tsuchiya,‡ 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 J anuary 19, 2001
CsOH- or Ag2O-mediated cycloalkylation of (alkylidene)bisperoxides 3 and 1,n-dihaloalkanes
(n ) 3-8) provided the corresponding medium-sized 1,2,4,5-tetraoxacycloalkanes 4-8 in
moderate yields. Subsequent evaluation of the antimalarial activity of the cyclic peroxides 4-8
in vitro and in vivo revealed that 1,2,6,7-tetraoxaspiro[7.11]nonadecane 4a has considerable
potential as a new, inexpensive, and potent antimalarial drug.
Sch em e 1
In tr od u ction
Because malaria parasites are rapidly developing
multidrug resistance to the more common chemothera-
peutic alkaloidal drugs, interest in the antimalarial
properties of nonalkaloidal compounds such as the
sesquiterpene artemisinin and the related endoperox-
ides is rapidly growing.1 Particularly interesting is the
fact that dispiro-1,2,4,5-tetroxanes, easily prepared by
the acid-catalyzed condensation of cycloalkanones and
hydrogen peroxide, exhibit remarkable antimalarial
activities in vitro and in vivo.2 This observation had led
us to speculate that other cyclic peroxide systems having
two peroxide groups within the same ring could also
possess significant antimalarial activity.3 In this respect,
we now report that CsOH- or Ag2O-mediated cyclization
of (alkylidene)bishydroperoxides 3 and 1,n-dihaloal-
kanes offers a promising procedure for the synthesis of
novel 1,2,4,5-tetraoxacycloalkanes 4-8.4 Moreover, these
cyclic peroxides have been found to show remarkable
antimalarial activity not only in vitro but also in vivo.
Resu lts a n d Discu ssion
Syn th esis of 1,2,4,5-Tetr a oxa cycloa lk a n es. Ozo-
nolysis of the vinyl ethers 2a ,i in the presence of excess
hydrogen peroxide (ca. 2 equiv) in diethyl ether5 at -70
°C, followed by column chromatography on silica gel,
gave the expected bis(hydroperoxide)s 3a ,i in yields of
33 and 43%, respectively (Scheme 1).3b The bis(hydro-
peroxide)s, 3j and 3k , were prepared by the ozonolysis
of 1-octene and 1-decene, respectively, under similar
reaction conditions. Alternatively, bis(hydroperoxide) 3a
could be prepared by the reaction of cyclododecanone
and 30% aqueous hydrogen peroxide in formic acid (ca.
50%).6 By using the latter method, the bis(hydroperox-
ide)s 3b-h were also prepared (Scheme 1).
Cycloalkylation of the bis(hydroperoxide)s 3a -k was
attempted by treatment with 1,n-diiodoalkanes in the
presence of cesium hydroxide monohydrate in DMF.7
Thus the reaction of 3a with 1,3-diiodopropane (1.5 mol
equiv) and CsOH‚H2O (2 mol equiv) in DMF for 15 h,
followed by column chromatography on silica gel, af-
forded the desired 1,2,4,5-tetroxocane derivative 4a
(40% yield) as the first fraction. Cyclododecanone 1a was
obtained subsequently (40%) (Scheme 2). Bis(hydrop-
* Address correspondence to Yusuke Wataya, Faculty of Pharma-
ceutical Sciences, Okayama University, Tsushima, Okayama 700-8530,
Japan.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/jm010026g CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/02/2001

2358 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14
Kim et al.
Sch em e 2a
Ta ble 1. Synthesis of 1,2,4,5-Tetroxocanes by the Reaction of
Bishydroperoxides and 1,3-Diiodopropane
tetroxocane
promotera
solvent
% yield
4b
4b
4b
4c
4d
4e
4f
CsOH
Cs2CO3
Ag2O
CsOH
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
CsOH
Ag2O
Ag2O
Ag2O
DMF
26
18
54
19
53
54
69
58
63
19
21
32
27
DMF
CH2Cl2
DMF
MeCO2Et
MeCO2Et
MeCO2Et
MeCO2Et
MeCO2Et
DMF
4g
4h
4i
4i
CH2Cl2
MeCO2Et
MeCO2Et
4j
4k
a
Except for Cs2CO3, 2 mol equiv of a promoter was used.
Sch em e 4
a
A considerable amount of cyclododecanone was also isolated.
bA total of 2 mol equiv of promoter was used.
Sch em e 3
eroxide) 3a was found to be labile toward CsOH‚H2O
because treatment of 3a with CsOH‚H2O in DMF for
15 h resulted in its complete decomposition into 1a . Cs2-
CO3 was found to be a less efficient promoter than CsOH
in the synthesis of 4a .
Since Ag2O is reported to be an excellent catalyst for
the synthesis of dialkyl peroxides by the alkylation of
organic hydroperoxides,8 the cycloalkylation reaction
between 3a and 1,3-diiodopropane was attempted in the
presence of freshly prepared Ag2O in dichloromethane
(Scheme 2). The ratio of 3a to Ag2O exerts a small but
important influence on the efficiency of the reaction:
using equimolar amounts of Ag2O provided tetroxocane
4a in 42% yield, whereas with 2 mol equiv of Ag2O, 4a
was isolated in an improved 56% yield. Changing the
solvent from dichloromethane to ethyl acetate resulted
in a further increase in the yield of peroxide 4a (61%).
The chain length in the 1,n-diiodoalkanes plays an
important role in the CsOH-promoted cyclization reac-
tion (Scheme 3). First, 1,n-diiodoalkanes (n ) 3-6, 8)
could be used for cycloalkylation of the bis(hydroperox-
ide) 3a , thereby providing the corresponding 1,2,4,5-
tetraoxacycloalkanes 4a -8a . The analogous reaction
with 1,2-diiodoethane yielded only cyclododecanone 1a
rather than the expected 1,2,4,5-tetroxepane derivative.
Second, under normal conditions, the cyclization reac-
tion between 3a and the longer chain 1,n-diiodoalkanes
(n ) 5, 6, and 8) produced only a complex mixture of
products containing cyclododecanone. Simultaneous ad-
dition of more dilute solutions of the reactants over
extended addition times resulted in the preparation of
the 10- to 13-membered tetraoxacyclolalkanes 6a -8a
albeit in moderate to low yields (see Experimental
Section). Finally, the Ag2O-promoted cyclization was
less successful for the synthesis of the 9- to 13-
membered tetraoxacycloalkanes 5a -8a . For example,
the reaction of 3a with 1,4-diiodobutane gave 5a in a
low yield of 12% together with 1a (70%), whereas the
analogous reaction with 1,6-diiodohexane resulted in the
production of only oligomeric products.
The procedures used for the synthesis of a variety of
1,2,4,5-tetroxocane derivatives 4b-k are summarized
in Table 1 and Scheme 4. A slight modification of the
procedure is required for the synthesis of 4d -h because
of difficulties in separating the desired tetroxocane from
the reaction byproducts by column chromatography on
silica gel column. Thus, a mixture of 4g and 1g was
treated with NH2OH‚HCl to convert 1g to the highly
polar oxime 9g (Scheme 4). On subsequent column
chromatography of this mixture on silica gel, the
tetroxocane 4g was easily isolated (58%). The teraox-
ecanes 4d -f,h were isolated in a similar fashion. It was
found that it was difficult to separate the cyclic peroxide
8a from ketone 1a and unreacted 1,8-diiodooctane. By
using only 0.7 equiv of the diiodide in the reaction with
3a , and subsequent treatment of the product mixture
with NH2OH‚HCl, 13-membered 1,2,4,5-tetraoxacyclo-
tridecane derivative 8a was conveniently purified by
column chromatography on silica gel.

Antimalarial Tetraoxacycloalkanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14 2359
Ta ble 2. In Vitro Antimalarial Activities of Peroxides 4-8
against P. falciparum and Cytotoxicities against FM3A Cellsa
Ta ble 3. In Vivo Antimalarial Activities of Peroxides against
P. berghei Infected Mice
EC50 values (M)
intraperitoneal
oral
peroxide
P. falciparumb
FM3Ac
selectivityd
ED50
,
ED90
,
ED50
,
ED90,
peroxides
mg/kga
mg/kga
mg/kga
20
mg/kga
40
3a
1.0 × 10-4
2.5 × 10-8
1.0 × 10-7
2.8 × 10-7
1.0 × 10-8
1.7 × 10-6
3.0 × 10-9
5.0 × 10-8
2.0 × 10-7
2.0 × 10-7
2.8 × 10-7
3.1 × 10-7
2.0 × 10-7
2.0 × 10-7
1.0 × 10-8
4.4 × 10-5
8.0 × 10-6
1.7 × 10-5
1.2 × 10-5
1.6 × 10-5
2.9 × 10-5
3.0 × 10-5
5.8 × 10-5
3.2 × 10-5
1.1 × 10-4
5.6 × 10-5
3.4 × 10-5
1.9 × 10-5
1.9 × 10-5
1.0 × 10-5
4a
320
170
43
1600
17
4a
12
48
160
15
100
72
21
50
30
60
5
20
65
5a
5a
6a
7a
>200
7a
4b
30
52
84
8a
4c
4b
10000
1160
160
550
200
110
95
4d
>100
75
4c
4e
4d
4f
90
4e
4g
4h
58
4f
91
4g
artemisinin
32
13
89
4h
4i
a
Various concentrations of the test compounds were prepared
in olive oil. The test compounds were administered to groups of
five mice once a day starting on day 0 and continued on day 1,
day 2, and day 3. Parasitemia levels were determined on the day
following the last treatment (on day 4), and ED values of the
antimalarial activities indicated above were determined by the
previously reported protocol.3a
95
1000
artemisinin
a
In vitro antimalarial activities and cytotoxicities were reported
previously.3a
Chloroquine sensitive (FCR-3 strain). c Mouse
b
mammary tumor FM3A cells in culture as a control for mam-
malian cell cytotoxicity. Selectivity ) mean of EC50 value for
FM3A cells/mean of EC50 value for P. falciparum.
d
with this, five out of the five infected mice were cured
and experienced no cytotoxic effects for more than 60
days afterward. Furthermore, all infected mice, treated
orally (po) with 4a (160 mg/kg/day) once a day for three
consecutive days beginning on the day of 1% parasit-
emia were cured with no parasite reincrease or toxicity.
Conversely, on similar treatment of infected mice with
artemisinin, the malaria parasites were still observed
in their blood streams, and as a result, five out of the
five mice treated with artemisinin died during 18 days
due to P. berghei infection (po, 160 mg/kg/day; 3 days).
The low toxicity of the tetroxocane 4a is also notewor-
thy; no death or no cytotoxicity was observed at dose
levels of 1600 mg/kg/day (ip). It is concluded, therefore,
that this new and easily prepared tetroxocane 4a
represents a promising candidate for further clinical
evaluation.
An tim a la r ia l Activity of 1,2,4,5-Tetr a oxa cycloa l-
k a n es in Vitr o. With a series of 1,2,4,5-tetraoxacy-
cloalkanes 4-8 in hand, we tested their antimalarial
activities and cytotoxicities against P. falciparum and
FM3A cells, respectively (Table 2).3a The results are
summarized as follows: (a) All the tetroxocanes 4a -i
showed substantial antimalarial activity with EC50
values against P. falciparum in the range 3.1 × 10-7
-
3.0 × 10-9 M, and the selectivity was determined by
the 50% inhibitory concentration against mouse mam-
mary FM3A cells in the range 43-10000. It is worth
noting that the antimalarial activities of 4a -c are
comparable to that of artemisinin (the EC50 value
against P. falciparum and the selectivity are 1.0 × 10-8
M and 1000, respectively).1e,9 (b) For the series of cyclic
peroxides 4a -8a , the peroxide ring size exerts a re-
markable influence on the EC50 values, the activity
decreasing in the order 7a > 4a > 5a > 6a > 8a . (c)
3,3-Dialkyl-substituted 1,2,4,5-tetroxocanes 4f-h with
different alkyl chains showed moderate antimalarial
activity. (d) In contrast, the antimalarial activity of the
monoalkyl-substituted 1,2,4,5-tetroxocanes 4i was very
low. Tetroxocanes 4j-k exhibited no significant cyto-
toxicity at 5 × 10-5 M for P. falciparum. These results
suggest that minor changes in the structure of the cyclic
peroxides 4-8 exerts a remarkable influence on the
antimalarial activity in vitro.
Exp er im en ta l Section
Gen er a l P r oced u r e. 1H (270 MHz) and 13C NMR (67.5
MHz) spectra were obtained in CDCl3 with SiMe4 as standard.
The bis(hydroperoxide) 3i3b and Ag2O10 were prepared by
literature methods.
Ca u tion : Since organic peroxides are potentially hazardous
compounds, they must be handled with due care; avoid
exposure to strong heat or light, mechanical shock, oxidizable
organic materials, or transition metal ions.
P r ep a r a tion of Bis(h yd r op er oxid e)s by th e Ozon olysis
of a Vin yl Eth er in th e P r esen ce of Hyd r ogen P er oxid e
in Dieth yl Eth er . Ozonolysis of methoxymethylenecyclodode-
cane (2a ) is representative. The diethyl ether solution (2.5 M)
of anhydrous H2O2 was prepared by extraction of the 30%
aqueous H2O2 solution with diethyl ether. The diethyl ether
extracts were dried over anhydrous MgSO4 and standardized
iodometrically. To the solution of H2O2 in diethyl ether (25 mL)
was added vinyl ether 2a (630 mg, 3.0 mmol), and then a slow
stream of ozone (1 equiv; flow for 9 min) was passed into the
resulting reaction mixture at -70 °C. After adding diethyl
ether (70 mL), the organic layer was washed with ice-cold
potassium dihydrogen phosphate and saturated brine and
dried over anhydrous MgSO4. After evaporation of the solvent
under reduced pressure, the residue was separated by column
chromatography on silica gel. Elution with diethyl ether-
hexane (1:10) gave cyclododecanone 1a (215 mg, 39%). Sub-
sequent elution with diethyl ether-hexane (3:7) gave the
bis(hydroperoxide) 3a (232 mg, 33%).
An tim a la r ia l Activity of 1,2,4,5-Tetr a oxa cycloa l-
k a n es in Vivo. In vivo antimalarial activities for
peroxides against the P. berghei NK 65 strain were also
determined.3a The results compiled in Table 3 indicate
that the 1,2,4,5-tetroxocanes, 4a and 4b, exhibited po-
tent antimalarial activity (ED50: 12-15 mg/kg), al-
though their potency is lower than that of artemisinin
(ED50: 5.0 mg/kg) on intraperitoneal administration.
More important is the fact that the peroxide 4a was
found to be orally active (ED50: 20 mg/kg) whereas cyclic
peroxides 7a and 4c, which showed similar activities
in vitro, were found to exert only moderate activities
even in intraperitoneal administration (ED50: 100-160
mg/kg).
On administration of 4a to infected mice by intrap-
eritoneal injection (ip) (50 mg/kg/day; 4 days), the mal-
aria parasites could not be observed in their blood-
streams after the 4 day suppressive test. Consistent
(Cyclod od ecylid en e)bish yd r op er oxid e 3a :6 mp 140-
1
141 °C (from benzene); H NMR δ 1.2-1.8 (m, 22 H), 8.06 (s,
2 H); 13C NMR δ 19.28, 21.86, 22.15, 26.02, 26.19, 26.29,
112.64.

2360 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14
Kim et al.
r-Hyd r op er oxyh ep tyl h yd r op er oxid e 3j: an oil; 1H NMR
δ 0.88 (t, J ) 5.2 Hz, 3 H), 1.2-1.8 (m, 10 H), 5.29 (t, J ) 6.1
Hz, 1 H), 9.40 (br s, 2 H); 13C NMR δ 14.02, 22.48, 24.64, 28.56,
28.61, 31.52, 111.36. Anal. (C7H16O4) C, H.
r-Hyd r op er oxyn on yl h yd r op er oxid e 3k : an oil; 1H NMR
δ 0.87 (t, J ) 6.6 Hz, 3 H), 1.2-1.9 (m, 14 H), 5.28 (t, J ) 6.1
Hz, 1 H), 9.44 (br s, 2 H); 13C NMR δ 14.07, 22.63, 24.67, 28.54,
29.15, 29.22, 29.29, 31.79, 111.32. Anal. (C9H20O4) C, H.
P r ep a r a tion of Bis(h yd r op er oxid e)s by th e Rea ction
of a Keton e w ith 30% Aqu eou s Hyd r ogen P er oxid e in
F or m ic Acid . The preparation of 3g is representative. To a
stirred solution of 6-undecanone 1g (5.10 g, 30 mmol) in formic
acid (20 mL) was added 30% aqueous hydrogen peroxide (10
mL), and the mixture was stirred at room temperature for 3
min. The mixture was then poured into ice-cold water, and
the organic products were extracted by diethyl ether (300 mL).
After conventional workup, the residue was separated by
column chromatography on silica gel. Elution with diethyl
ether-hexane (1:20) gave the unreacted undecanone 1g (3.00
g). Elution with diethyl ether-hexane (1:9) gave a bis-
(hydroperoxide) 3g (1.76 g, 27%).
4-ter t-Bu tyl-7,8,12,13-tetr a oxa sp ir o[5.7]tr id eca n e 4b:
mp 58-59 °C (from hexane); 1H NMR δ 0.86 (s, 9 H), 1.1-1.8
(m, 9 H), 2.18 (m, 2 H), 4.10 (m, 2 H), 4.35 (m, 2 H); 13C NMR
δ 23.34, 23.61, 27.64, 28.59, 30.35, 31.93, 32.37, 47.44, 73.76,
74.02, 107.92. Anal. (C13H24O4) C, H.
Sp ir o[t r icyclo[3.3.1.13,7]d eca n e-2,3′-[1,2,4,5]t et r oxo-
ca n e] 4c: mp 34-35 °C (from hexane); 1H NMR δ 1.6-2.3 (m,
16 H), 4.12 (dt, J ) 12.9, 5.6 Hz, 2 H), 4.35 (dt, J ) 12.5, 4.8
Hz, 2 H); 13C NMR δ 27.06, 30.30, 31.81, 33.67, 33.98, 37.25,
73.94, 109.95. Anal. (C13H20O4) C, H.
3-Cycloh exyl-1,2,4,5-tetr oxoca n e 4i: an oil; 1H NMR δ
1.1-1.8 (m, 12 H), 2.6-2.8 (m, 1 H), 4.0-4.2 (m, 2 H), 4.43
(dd, J ) 12.9 and 3.6 Hz, 2 H), 5.12 (d, J ) 6.3 Hz, 1 H). Anal.
(C10H18O4) C, H.
CsOH-Med ia ted Syn th esis of 1,2,4,5-Tetr a oxa cycloa l-
k a n es 6a a n d 7a . The synthesis of 7a is representative. To a
stirred solution of CsOH‚H2O (1008 mg, 6.00 mmol) in DMF
(20 mL) were added a solution of bis(hydroperoxide) 3a (696
mg, 3.00 mmol) in DMF (20 mL) and a solution of 1,6-
diiodohexane (1521 mg, 4.50 mmol) in DMF (20 mL) simul-
taneously via syringe over 1 h at room temperature. The
reaction was continued for more than 16 h. The products were
separated by column chromatography on silica gel. Elution
with diethyl ether-hexane (1:100) gave the cyclic peroxide 7a
(168 mg, 18%).
6,6-Dih yd r op er oxyu n d eca n e 3g: mp 85-86 °C (from
methanol); 1H NMR δ 0.90 (t, J ) 6.1 Hz, 6 H), 1.3-1.7 (m, 16
H), 8.83 (br s, 2 H); 13C NMR δ 13.95, 22.39, 23,22, 29.44, 31.79,
114.72. Anal. (C11H24O4) C, H.
1,2,8,9-Tetr a oxa sp ir o[9.11]h en icosa n e 6a : mp 51-52 °C
(from hexane); 1H NMR δ 1.3-1.8 (m, 24 H), 2.0-2.1 (m, 4
H), 4.1-4.2 (m, 4 H); 13C NMR δ 19.26, 21.92, 22.25, 24.89,
25.97, 26.06, 26.65, 28.45, 76.64, 110.89. Anal. (C17H32O4) C,
H.
1,1-Dih yd r op er oxy-(4-ter t-bu tyl)cycloh exa n e 3b: mp
83-84 °C (from ether-hexane); 1H NMR δ 0.87 (s, 9 H), 1.1-
1.8 (m, 9 H), 9.27 (s, 2 H); 13C NMR δ 23.32, 27.58, 29.70, 32.31,
47.39, 110.00. Anal. (C10H20O4) C, H.
4,4-Dih ydr oper oxyadam an tan e 3c: mp 144-145 °C (from
ether-hexane); 1H NMR δ 1.7-2.1 (m, 14 H), 8.82 (s, 2 H);
13C NMR δ 26.94, 31.14, 33.68, 36.98, 112.88. Anal. (C10H16O4)
C, H.
1,2,9,10-Tetr a oxa sp ir o[10.11]d ocosa n e 7a : mp 48-49 °C
1
(from hexane); H NMR δ 1.3-1.8 (m, 30 H), 4.02 (t, J ) 4.8
Hz, 4 H); 13C NMR δ 19.35, 21.89, 22.23, 25.00, 26.02, 26.13,
26.43, 26.99, 74.63, 112.06. Anal. (C18H34O4) C, H.
(Cycloh ep t ylid en e)b ish yd r op er oxid e 3d : an oil; 1H
NMR δ 1.5-1.6 (m, 8 H), 1.9-2.0 (m, 4 H), 9.39 (s, 2 H); 13C
NMR δ 22.59, 29.96, 32.46, 115.98. Anal. (C7H14O4) C, H.
CsOH-Med ia ted Syn th esis of 1,2,4,5-Tetr a oxa cyclot-
r id eca n e 8a . To a stirred solution of CsOH‚H2O (1220 mg,
7.14 mmol) in DMF (25 mL) were added a solution of 3a (829
mg, 3.57 mmol) in DMF (20 mL) and a solution of 1,8-
diiodooctane (915 mg, 2.50 mmol) simultaneously via syringe
over 1 h at room temperature. The reaction was continued for
more than 16 h under argon atmosphere. After workup as
described above, the residue was separated by column chro-
matography on silica gel (elution with diethyl ether-hexane
(1:20)) to give a mixture of 8a and 1a (714 mg), which was
reacted with a mixture of NH2OH‚HCl (300 mg, 4.31 mmol)
and Na2CO3 (300 mg, 2.83 mmol) in 70% aqueous ethanol (10
mL) at room temperature for 15 h. After conventional workup,
the residue was separated by column chromatography on silica
gel. Elution with diethyl ether-hexane (1:90) gave the tet-
raoxacyclotridecane 8a (112 mg, 13% based on diiodooctane).
13,14,23,24-Tetr a oxa sp ir o[11.12]tetr a cosa n e 8a : mp 37
(Cyclooctylid en e)bish yd r op er oxid e 3e: an oil; 1H NMR
δ 1.4-2.0 (m, 14 H), 9.35 (s, 2 H); 13C NMR δ 21.69, 24.82,
27.12, 27.82, 115.08. Anal. (C8H16O4) C, H.
1
5,5-Dih yd r op er oxyn on a n e 3f: an oil; H NMR δ 0.92 (t,
J ) 6.6 Hz, 6 H), 1.2-1.5 (m, 8 H), 1.69 (t, J ) 7.4 Hz, 4 H),
9.39 (s, 2 H); 13C NMR δ 13.86, 22.77, 25.59, 28.88, 114.77.
Anal. (C9H20O4) C, H.
1
7,7-Dih yd r op er oxytr id eca n e 3h : an oil; H NMR δ 0.89
(t, J ) 6.3 Hz, 6 H), 1.2-1.4 (m, 16 H), 1.6-1.7 (m, 4 H), 9.20
(br s, 2 H); 13C NMR δ 14.02, 22.55, 23.47, 29.18, 29.36, 31.59,
114.59. Anal. (C13H28O4) C, H.
CsOH-Med ia ted Syn th esis of 1,2,4,5-Tetr a oxa cycloa l-
k a n es 4a , 5a , 4b, 4c, a n d 4i. The synthesis of tetroxocane
4a is representative. To a stirred solution of the bis(hydrop-
eroxide) 3a (348 mg, 1.50 mmol) and CsOH‚H2O (504 mg, 3
mmol) in DMF (25 mL) was added 1,3-diiodopropane (666 mg,
2.25 mmol) by syringe over 10 min. The resulting reaction
mixture was stirred for 16 h at room temperature under argon
atmosphere. The mixture was then poured into diethyl ether
(100 mL), and the organic layer was washed in turn with 3%
aqueous sodium thiosulfate (50 mL), aqueous NaHCO3, and
saturated brine and dried over anhydrous MgSO4. After
evaporation of the solvent under reduced pressure, the residue
was separated by column chromatography on silica gel. Initial
elution with diethyl ether-hexane (1:49) gave the tetroxocane
4a (164 mg, 40%). Further elution with diethyl ether-hexane
(1:20) gave cyclododecanone 1a (122 mg, 45%).
1,2,6,7-Tetr a oxa sp ir o[7.11]n on a d eca n e 4a : mp 83-84 °C
(from hexane); 1H NMR δ 1.3-1.7 (m, 22 H), 2.1-2.2 (m, 2
H), 4.12 (dt, J ) 12.5 and 5.6 Hz, 2 H), 4.31 (dt, J ) 12.5 and
4.7 Hz, 2 H); 13C NMR δ 19.36, 21.90, 22.17, 25.91, 26.07,
26.25, 30.40, 73.94, 112.13. Anal. (C15H28O4) C, H.
1,2,7,8-Tetr a oxa sp ir o[8.11]icosa n e 5a : mp 97-98 °C
(from hexane); 1H NMR δ 1.3-1.7 (m, 24 H), 2.2-2.3 (m, 2
H), 3.66 (t, J ) 12.2 Hz, 2 H), 4.26 (dd, J ) 12.2 and 3.9 Hz,
2 H); 13C NMR δ 19.30, 21.89, 22.17, 25.95, 26.11, 26.43, 30.93,
32.51, 73.85, 111.82. Anal. (C16H30O4) C, H.
1
°C (from hexane); H NMR δ 1.3-1.7 (m, 34 H), 4.11 (t, J )
5.6 Hz, 4 H); 13C NMR δ 19.27, 21.85, 22.18, 24.17, 26.00,
26.15, 26.56, 26.97, 74.84, 112.79. HRMS [M+] m/z calcd for
C
20H38O4, 342.2770; found, 342.2768.
Cs2CO3-Med ia ted Syn th esis of 1,2,4,5-Tetr a oxa cycloa l-
k a n es 4a a n d 4b. The synthesis of a tetroxocane 4a is
representative. To a stirred solution of Cs2CO3 (652 mg, 2.00
mmol) and 3a (464 mg, 2.00 mmol) in DMF (20 mL) was added
a solution of 1,3-diiodopropane (888 mg, 3.00 mmol) in DMF
(10 mL) via syringe over 5 min at 0 °C. The reaction was
continued for a further 16 h at room temperature. After
workup as described above, the residue was separated by
column chromatography on silica gel. Elution with diethyl
ether-hexane (1:100) gave the cyclic peroxide 4a (166 mg,
31%).
Ag2O-Med ia ted Syn th esis of 1,2,4,5-Tetr oxoca n es. The
preparation of a tetroxocane 4g is representative. To a solution
of Ag2O (1392 mg, 6 mmol) and a bis(hydroperoxide) 3g (660
mg, 3.00 mmol) in dichloromethane (20 mL) was added a
solution of 1,3-diiodopropane (1332 mg, 4.5 mmol) in dichlo-
romethane (10 mL) via a syringe over 5 min at 0 °C. The
reaction was continued at room temperature for more than
15 h. After filtration of the solid material over Celite, diethyl

Antimalarial Tetraoxacycloalkanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14 2361
ether (100 mL) was added to the filtrate, and the organic layer
was washed with 3% aqueous sodium thiosulfate (50 mL),
aqueous NaHCO3, and saturated brine and dried over anhy-
drous MgSO4. After evaporation of the solvent under reduced
pressure, the residue was separated by column chromatogra-
phy on silica gel. Elution with diethyl ether-hexane (1:20)
gave a 5:2 mixture of a peroxide 4g and undecanone 1g (562
mg), which was reacted with a mixture of NH2OH‚HCl (104
mg, 1.50 mmol) and Na2CO3 (212 mg, 2.00 mmol) in 70%
aqueous ethanol (10 mL) at room temperature for 15 h. After
conventional workup, the residue was separated by column
chromatography on silica gel. Elution with diethyl ether-
hexane (1:90) gave the tetroxocane 4g (447 mg, 57%).
Refer en ces
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tetraoxadispiro[5.2.5.2]hexadecanes substituted at the 1 and 10
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3,3-Dip en tyl-1,2,4,5-tetr oxoca n e 4g: an oil; 1H NMR δ
0.84 (t, J ) 5.4 Hz, 6 H), 1.2-1.7 (m, 16 H), 2.0-2.1 (m, 2 H),
4.0-4.3 (m, 4 H); 13C NMR δ 13.89, 22.45, 23.22, 29.49, 60.41,
31.88, 73.53, 113.34; EIMS m/z 342 (M+, 1), 183 (100). Anal.
(C14H28O4) C, H.
1
8,9,13,14-Tetr a oxa sp ir o[6.7]tetr a d eca n e 4d : an oil; H
NMR δ 1.4-2.3 (m, 14 H), 4.07 (dt, J ) 12.9 and 5.9 Hz, 2 H),
4.34 (dt, J ) 12.9 and 4.7 Hz, 2 H); 13C NMR δ 22.57, 30.12,
30.46, 32.28, 73.42, 113.19. Anal. (C10H18O4) C, H.
1,2,6,7-Tetr a oxa sp ir o[7.7]p en ta d eca n e 4e: an oil; 1H
NMR δ 1.2-2.4 (m, 16 H), 4.07 (dt, J ) 12.9 and 5.7 Hz, 2 H),
4.34 (dt, J ) 12.9 and 5.2 Hz, 2 H); 13C NMR δ 21.85, 24.89,
27.53, 27.93, 30.48, 73.48, 112.18. Anal. (C11H20O4) C, H.
3,3-Dibu tyl-1,2,4,5-tetr oxoca n e 4f: an oil; 1H NMR δ 0.91
(t, J ) 6.9 Hz, 6 H), 1.2-1.8 (m, 12 H), 2.0-2.2 (m, 2 H), 4.08
(dt, J ) 12.9 and 5.8 Hz, 2 H), 4.33 (dt, J ) 12.9 and 4.7 Hz,
2 H); 13C NMR δ 13.91, 22.86, 25.72, 29.33, 73.60, 111.41. Anal.
(C12H24O4) C, H.
3,3-Dih exyl-1,2,4,5-tetr oxoca n e 4h : an oil; 1H NMR δ 0.88
(t, J ) 5.8 Hz, 6 H), 1.2-1.8 (m, 20 H), 2.1-2.2 (m, 2 H), 4.08
(dt, J ) 12.5 and 5.8 Hz, 2 H), 4.33 (dt, J ) 12.9 and 4.6 Hz,
2 H); 13C NMR δ 14.05, 22.57, 23.58, 29.45, 29.63, 30.44, 31.66,
73.64, 111.47. Anal. (C16H32O4) C, H.
3-Hexyl-1,2,4,5-tetr oxoca n e 4j: an oil; 1H NMR δ 0.87 (t,
J ) 6.5 Hz, 3 H), 1.2-1.8 (m, 11 H), 2.6-2.8 (m, 1 H), 4.13
(ddd, J ) 2.8, 7.6, 11.9 Hz, 2 H), 4.44 (ddd, J ) 3.5, 3.8, 13.3
Hz, 2 H), 5.37 (t, J ) 5.6 Hz, 1 H); 13C NMR δ 14.00, 22.45,
24.64, 26.54, 28.77, 28.92, 31.47, 74.22 (2C), 108.21. Anal.
(C10H20O4) C, H.
3-Octyl-1,2,4,5-tetr oxoca n e 4k : an oil; 1H NMR δ 0.86 (t,
J ) 6.6 Hz, 3 H), 1.2-1.8 (m, 15 H), 2.6-2.8 (m, 1 H), 4.13
(ddd, J ) 2.9, 12.0, 12.0 Hz, 2 H), 4.43 (ddd, J ) 3.5, 3.5, 12.0
Hz, 2 H), 5.36 (t, J ) 5.8 Hz, 1 H); 13C NMR δ 14.07, 22.61,
24.71, 26.60, 28.79, 29.11, 29.26 (2 C), 31.79, 74.25 (2 C),
108.25. Anal. (C12H24O4) C, H.
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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.3a In vivo antimalarial activity
was assessed using ICR mice infected with P. berghei (NK 65
strain) following the protocol described previously.3a Various
concentrations of the test compounds, prepared in olive oil,
were administered daily via two routes, either ip or po, to
groups of five mice for four consecutive days beginning on the
day of infection (to determine the ED value and survival time).
To determine the curative effect, the test compounds were
administered to the mice orally once a day for 3 consecutive
days beginning on the day of 1% parasitemia in the infected
mice. Parasitemia levels were monitored every day for 2
months. Treatment was considered to be curative when no
parasites were detected after 60 days. On average, mice in the
control group survived for 6.5 days after infection.
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid for Scientific Research on Priority
Areas (08281105, 11147216, 11140244, 12307007, and
12217088) from the Ministry of Education, Science,
Culture and Sports of J apan.
(10) J anssen, D. E.; Wilson, C. V. Org. Synth. 1963, Coll. Vol. 4,
547-549.
J M010026G