Antimalarial activity of novel 1,2,5,6-tetraoxacycloalkanes and 1,2,5-trioxacycloalkanes

Article abstract of DOI:10.1021/jm020387b

Photooxygenation of 2-phenylnorbornene 1 in the presence of 30% aqueous hydrogen peroxide afforded 1,2-bishydroperoxide 3, which could be cycloalkylated on treatment with silver oxide and a 1,ω-diiodoalkane to provide the tricyclic peroxides 12. Trimethyl

Full text of DOI:10.1021/jm020387b

J . Med. Chem. 2003, 46, 1957-1961
1957
An tim a la r ia l Activity of Novel 1,2,5,6-Tetr a oxa cycloa lk a n es a n d
1,2,5-Tr ioxa cycloa lk a n es
Hye-Sook Kim,† Khurshida Begum,† Naoki Ogura,† Yusuke Wataya,*,† Yuji Nonami,‡ Toyonari Ito,‡
Araki Masuyama,‡ Masatomo Nojima,‡ and Kevin J . McCullough§
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, J apan, Department of Materials
Chemistry & Frontier Research Center, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, J apan, and
Department of Chemistry, Heriot-Watt University, Edinburgh EH14 4AS, Scotland
Received September 10, 2002
Photooxygenation of 2-phenylnorbornene 1 in the presence of 30% aqueous hydrogen peroxide
afforded 1,2-bishydroperoxide 3, which could be cycloalkylated on treatment with silver oxide
and a 1,ω-diiodoalkane to provide the tricyclic peroxides 12. Trimethylsilylation of 3 followed
by TMSOTf-catalyzed cyclocondensation with carbonyl compounds led to the formation of the
tricyclic peroxides 14 containing a 1,2,4,5-tetroxepane structure. Photooxygenation of 1 in the
presence of either unsaturated hydroperoxides or unsaturated alcohols followed by bis(collidine)-
iodine hexafluorophosphate promoted cyclization gave the corresponding cyclic peroxides 15-
17. Several of these cyclic peroxides showed substantial antimalarial activity particularly in
vitro.
In tr od u ction
Since we had previously found that bis(collidine)-
iodine hexafluorophosphate (BCIH) promoted cycliza-
tion of unsaturated hydroperoxides provided a versatile
method for the synthesis of a variety of cyclic peroxides,7
we tried to prepare the appropriate unsaturated hydro-
peroxides. Photooxygenation of 1 in the presence of
either the unsaturated hydroperoxide 6 or unsaturated
alcohols 7 and 8 afforded the corresponding labile
unsaturated hydroperoxides 9-11, which could be
isolated in low yield (12-25%) by rapid chromatography
on silica gel but needed to be used without further
purification (Scheme 2).
Since malaria parasites are rapidly developing resis-
tance to the most commonly used chemotherapeutic
alkaloidal drugs, the antimalarial properties of nonal-
kaloidal compounds such as artemisinin and the related
endoperoxides have attracted considerable attention.1
We have recently reported that treatment of (alkyl-
idene)-1,1-bishydroperoxides with 1,ω-dihaloalkanes in
3
the presence of CsOH in DMF2 or Ag2O in CH2Cl2
affords a series of novel 1,2,4,5-tetraoxacycloalkanes
that exhibit remarkable antimalarial activity not only
in vitro but also in vivo.3 In the development of new
synthetic routes to cyclic peroxides containing two
peroxide groups within the same ring, the comparatively
rare vic-dihydroperoxide was identified as a promising
precursor.4 We report herein details of (i) the synthesis
of the tetraoxacycloalkanes, (ii) extension of this meth-
odology to the synthesis of novel 1,2,5-trioxacycloal-
kanes, and (iii) the antimalarial activities of the respec-
tive peroxidic compounds.
Syn th esis of 1,2,5,6-Tetr a oxycycloa lk a n es a n d
1,2,5-Tr ioxa cycloa lk a n es. With these starting materi-
als in hand, the synthesis of cyclic peroxides was at-
tempted. Treatment of a mixture of 3 and 1,3-diiodopro-
3
pane with Ag2O in CH2Cl2 gave the desired tricyclic
peroxide 12a , containing a 1,2,5,6-tetroxonane ring,
though the major product was again the keto aldehyde
13 (48%). The 1,2,5,6-tetroxecane derivative 12b was
obtained from the analogous cycloalkylation reaction
involving 1,4-diiodobutane (Scheme 3). In the crystal
structure of 12a , as determined by the X-ray analysis,
the nine-membered tetroxonane ring was found to adopt
the symmetrical boat-chair conformation.4
TMSOTf-catalyzed cyclocondensation of trimethylsi-
lyl-protected bishydroperoxide 5 with carbonyl com-
pounds6 provided a series of novel 1,2,4,5-tetroxepane
derivatives 14a -e (Scheme 4). The crystal structure of
14a , as determined by X-ray analysis, had demonstrated
that the seven-membered 1,2,4,5-tetroxepane ring of
14a is in a classical chair conformation as a consequence
of the structural rigidity imposed by the fused bicyclo-
[2.2.1]heptane ring system.4
Resu lts a n d Discu ssion
P r ep a r a tion of a 1,2-Bish yd r op er oxid e a n d th e
Rela ted Un sa tu r a ted Hyd r op er oxid es. 2-Phenyl-
norbornene 1 is known to react with singlet oxygen to
generate a zwitterionic intermediate that can be ef-
ficiently trapped by methanol to form 2.5 By analogy,
photooxygenation of a solution of 1 in acetonitrile con-
taining 30% aqueous hydrogen peroxide afforded the
1,2-bishydroperoxide 3 in essentially quantitative yield
(Scheme 1). Compound 3 was successfully transformed
using N,O-bis(trimethylsilyl)acetamide (BSA) into the
corresponding bis-trimethylsilylated derivative 5,6 which
could be isolated by column chromatography on silica
gel.
Treatment of the unsaturated hydroperoxide 9 with
BCIH afforded the tricyclic peroxide 15, containing a
1,2,5,6-tetroxonane ring, in 61% yield. Similarly, the
tricyclic peroxides 16 and 17, each containing a 1,2,5-
trioxacycloalkane ring, were prepared from the unsat-
urated hydroperoxides 10 and 11 in yields of 52% and
* 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/jm020387b CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/03/2003

1958 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Kim et al.
Sch em e 1
Sch em e 2
Sch em e 4
Sch em e 5
Sch em e 3
endo, and the iodomethyl group is in an axial position
and is syn to the bridging methine group of the norbor-
nane moiety.
60%, respectively (Scheme 5). Although tricyclic perox-
ide 16 provided weakly diffracting crystals, its structure
was unambiguously determined by X-ray crystallo-
graphic analysis (Figure 1). The central 1,2,5-trioxepane
ring adopts a classical chair conformation similar to that
of the peroxide ring in 14a . The phenyl group at C(4) is
An tim a la r ia l Activity of 1,2,5,6-Tetr a oxycycloa l-
k a n es a n d 1,2,5-Tr ioxa cycloa lk a n es. The antima-
larial activities of the derived cyclic peroxides in vitro

Antimalarial Tetraoxa- and Trioxacycloalkanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1959
Ta ble 2. In Vivo Antimalarial Activities of Peroxides against
P. berghei Infected Micea
ip
po
ED50
,
ED90
,
ED50
,
ED90,
peroxide
mg/kg
mg/kg
mg/kg
mg/kg
artemisinin
12a
14c
5.4
13
70
13
50
32
89
>100 (45%b)
>100 (70%b)
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 days 1-3.
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
b
protocol.3 The value in parentheses shows the growth inhibition
in each dose.
inactive in vivo (ip, 100 mg/kg). Thus, it is evident that
significant modification of the functionalization would
be required in order to produce a significant antima-
larial drug candidate based on the novel structure of
the tricyclic peroxides prepared in this study.
F igu r e 1. Crystal structure of compound 16 (two molecules
per asymmetric unit; only molecule one shown for clarity).
Su m m a r y
Ta ble 1. In Vitro Antimalarial Activities of Peroxides against
P. falciparum and Cyctotoxicities against FM3A Cellsa
Trapping of the zwitterionic intermediate, generated
from the reaction of 2-phenylnorbornene 1 and singlet
oxygen, by aqueous H2O2, unsaturated hydroperoxides,
or unsaturated alcohols provides a series of useful
precursors for the synthesis of novel cyclic peroxides
containing the 1,2,5,6-tetraoxacycloalkane and 1,2,5-
trioxacycloalkane ring systems. Several of the cyclic
peroxides prepared in this study showed significant
antimalarial activity particularly in vitro.
EC50 (µM)
peroxide
12a
14a
14b
14c
14d
14e
15
P. falciparumb
FM3Ac
selectivityd
0.19
1.5
1.0
0.21
0.45
0.13
0.15
1.0
45
13
11
11
11
5.9
11
11
15
10
237
9
11
52
24
45
73
11
3000
1000
16
17
Exp er im en ta l Section
0.005
0.01
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. Bis(collidine)iodine(I) hexafluorophos-
phate (BCIH) was prepared by the method reported by
Simonot and Rousseau.8
artemisinin
a
In vitro antimalarial activities and cytotoxicities were deter-
mined by the previously reported protocol.7 Chloroquine-sensi-
b
tive FCR-3 strain. c Mouse mammary tumor FM3A cells in culture
d
as a control for mammalian cell cytotoxicity. Selectivity ) (mean
of EC50 for FM3A cells)/(mean of EC50 for P. falciparum).
P h otooxid a tion of 2-P h en yln or bor n en e 1 in th e P r es-
en ce of Hyd r ogen P er oxid e. A cooled (0 °C), oxygenated
solution of 1 (290 mg, 1.71 mmol), 30% aqueous H2O2 (10 g),
and tetraphenylporphine (1 mg) in CH3CN (20 mL) was
irradiated for 1.5 h with a 350 W high-pressure mercury lamp
filtered through an aqueous CuSO4 solution (>400 m). After
extraction with Et2O (50 mL), the organic layer was washed
in turn with aqueous NaHCO3 and saturated brine. Removal
of solvent (room temp, 15 mmHg) yielded the crude 1,2-
bishydroperoxide 3 as the sole product. Treatment of a solution
of 3 in CH2Cl2 (404 mg, 1.71 mmol) with 3 equiv of triphen-
ylphosphine (1344 mg, 5.13 mmol) at room temperature for 3
h followed by column chromatography on silica gel (elution
with Et2O-hexane, 40:60) gave the diol 4 (272 mg, 78%).
3-Hyd r op er oxy-2-p h en yl-2-n or bor n yl h yd r op er oxid e,
were determined against P. falciparum (FCR-3 strain).3
A series of tetraoxacycloalkanes, 12a , 14a -e, and 15,
showed antimalarial activity against P. falciparum with
EC50 values in the range 1.5 × 10-6 to 1.3 × 10-7 M,
and the selectivity determined by the 50% inhibitory
concentration against mouse mammary FM3A cells
were in the range 9-237. As judged from a combination
of their respective activity and selectivity, compounds
12a and 14c were found to be the most attractive. For
trioxacycloalkane derivatives 16 and 17, it is noted that
the antimalarial activity of compound 17 (5.0 × 10-9
M) was comparable to that of artemisinin (Table 1).
1
3: an oil; H NMR δ 0.8-1.5 (m, 5 H), 2.1-2.2 (m, 1 H), 2.4-
2.5 (m, 1 H), 2.5-2.6 (m, 1 H), 4.77 (s, 1 H), 7.1-7.5 (m, 5 H),
8.52 (br s, 1 H), 10.12 (br s, 1 H); 13C NMR δ 23.56, 25.12,
34.81, 41.71, 46.18, 91.16, 95.65, 128.09, 128.27 (2 C), 128.52
(2 C), 138.54.
In vivo antimalarial activities against P. berghei NK
65 strain3 were then determined for the peroxides 12a ,
14c, and 17, which had shown significant activities in
vitro. As indicated in Table 2, the ED50 value of 12a
(ED50 ) 13 mg/kg) on intraperitoneal administration (ip)
was 2.4 times of that of artemisinin (ED50 ) 5.4 mg/kg)
whereas 14c showed only moderate activity (ED50 ) 70
mg/kg). However, 12a showed weak antimalarial activ-
ity on oral administration (po) (ED50 ≈ 100 mg/kg). Most
disappointing is the fact that the tricyclic peroxide 17,
the most active compound in vitro, was found to be
Rea ction of Bish yd r op er oxid e 3 w ith Diiod oa lk a n es.
The reaction with 1,3-diiodopropane is representative. To a
stirred solution of 1,3-diiodopropane (888 mg, 3 mmol) and
Ag2O (510 mg, 2.2 mmol) in CH2Cl2 (25 mL), was added
bishydroperoxide 3 (472 mg, 2.0 mmol) by syringe over 1 h.
The resulting mixture was stirred at room temperature for
16 h. After filtration of the solid material through Celite, Et2O
(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 was dried over anhydrous

1960 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Kim et al.
MgSO4. After evaporation of the solvent under vacuum, the
products were isolated by column chromatography on silica
gel, eluting initially with Et2O-hexane (4:96) to give tetroxane
12a (50 mg, 9%) followed by Et2O-hexane (3:7) to give cis-3-
benzoylcyclopentanecarbaldehyde 139 (194 mg, 48%): an oil;
1H NMR δ 1.9-2.4 (m, 6 H), 2.8-2.9 (m, 1 H), 3.8-3.9 (m, 1
H), 7.4-7.5 (m, 3 H), 7.9-8.0 (m, 2 H), 9.67 (s, 1 H); 13C NMR
δ 26.38, 29.63, 30.01, 46.11, 51.66, 128.39 (2 C), 128.59 (2 C),
133.06, 136.17, 201.24, 203.27.
2-P h en yl-3,4,8,9-t et r a oxa t r icyclo[9.2.1.02,10]t et r a d e-
ca n e, 12a : mp 140-142 °C (from methanol); 1H NMR δ 1.1-
1.6 (m, 6 H), 2.18 (d, J ) 10.2 Hz, 1 H), 2.3-2.4 (m, 1 H),
2.4-2.5 (m, 1 H), 2.9-3.0 (m, 1 H), 3.93 (d × t, J ) 10.2 and
10.2 Hz, 2 H), 4.42 (d, J ) 10.2 Hz, 2 H), 4.74 (s, 1 H), 7.2-7.6
(m, 5 H); 13C NMR δ 24.03, 24.82, 25.27, 35.65, 42.81, 47.93,
73.66, 73.96, 87.17, 93.82, 127.39 (2 C), 128.30 (2 C), 128.37,
140.17. Anal. Calcd for C16H20O4: C, 69.54; H, 7.30. Found:
C, 69.10; H, 7.26.
TMSOTf-Ca ta lyzed Cyclocon d en sa tion of Bisp er oxid e
5 w ith Ca r bon yl Com p ou n d s. The reaction with benzalde-
hyde is representative. Under an argon atmosphere, a solution
of BSA (1218 mg, 6 mmol) in THF was added to a CH2Cl2
solution of bishydroperoxide 3 (708 mg, 3 mmol) at 0 °C for
10 min, and the mixture was stirred at room temperature for
an additional 5 min. After concentration under reduced
pressure, the residue was separated by column chromatogra-
phy on silica gel. Elution with Et2O-hexane (2:98) gave the
bisperoxide 2,3-bis[(trimethylsilyl)dioxy]-2-phenylnorbornane
5 (638 mg, 56%): an oil; 1H NMR δ 0.15 (s, 9 H), 0.27 (s, 9 H),
1.0-1.6 (m, 5 H), 2.3-2.4 (m, 1 H), 2.6 (m, 1 H), 3.0-3.1 (m,
1 H), 4.48 (s, 1 H), 7.2-7.6 (m, 5 H); 13C NMR δ -1.62 (3 C),
-1.26 (3 C), 23.36, 25.70, 34.05, 40.30, 42.19, 94.56, 95.02,
127.30 (2 C), 127,44, 130.08 (2 C), 139.34.
To a stirred solution of bisperoxide 5 (322 mg, 0.85 mmol)
and benzaldehyde (180 mg, 1.70 mmol) in CH2Cl2 (25 mL) was
added TMSOTf (111 mg, 0.5 mmol) by syringe over 10 min at
-70 °C. Stirring was continued at 0 °C for an additional 1.5
h. The products were isolated by column chromatography on
silica gel, eluting initially with Et2O-hexane (1:25) to give the
tetroxepane 14a (64 mg, 23%) and subsequently with Et2O-
hexane (1:9) to give keto aldehyde 13 (62 mg, 36%).
2,5-Dip h en yl-3,4,6,7-t et r a oxa t r icyclo[7.2.1.02,8]d od e-
ca n e, 14a : mp 133 °C (from ethyl acetate-hexane); 1H NMR
δ 0.9-1.0 (m, 1 H), 1.1-1.4 (m, 3 H), 1.5-1.6 (m, 1 H), 2.3-
2.4 (m, 2 H), 2.5-2.6 (m, 1 H), 5.21 (s, 1 H), 6.65 (s, 1 H), 7.1-
7.7 (m, 10 H); 13C C NMR δ 23.76 (CH), 23.87 (CH), 35.08 (CH),
41.42 (CH), 47.12 (CH), 91.45 (CH), 98.62, 109.33 (CH), 127.12
(2C, CH), 127.42 (CH), 127.48 (CH), 127.69 (CH), 128.21 (CH),
128.41 (2 C, CH), 128.79 (CH), 130.05 (CH), 130.67, 139.87.
Anal. (C20H20O4) C, H.
P r ep a r a tion of Cyclic P er oxid e 15. By the procedure
described before, a solution of 2-phenylindene 1 (550 mg, 3.2
mmol), 3-methyl-3-butenyl hydroperoxide 6 (2.0 g, 20 mmol),
and rose bengal (5 mg) in CH3CN (10 mL) was irradiated at 0
°C for 5 h under oxygen atmosphere. After workup, the
products were separated by column chromatography on silica
gel. Elution with Et2O-hexane (5:95) gave the unsaturated
hydroperoxide 3-[(3-methyl-3-butenyl)dioxy]-3-phenyl-2-nor-
bornyl hydroperoxide 9 (241 mg, 25%): an oil; 1H NMR δ 0.9-
1.4 (m, 5 H), 1.39 (s, 3 H), 1.9-2.0 (m, 3 H), 2.1-2.2 (m, 1 H),
2.5-2.6 (m, 1H), 3.5-3.6 (m, 1 H), 3.7-3.8 (m, 1 H), 4.44 (s, 1
H), 4.56 (s, 1 H), 4.70 (s, 1 H), 7.2-7.7 (m, 5 H), 10.2 (s, 1 H);
13C NMR δ 22.0, 23.6, 26.0, 34.9, 35.7, 42.2, 46.2, 72.6, 91.2,
95.0, 112.0, 127.8, 127.9 (2 C), 129.1 (2 C), 138.9, 141.4.
To CH2Cl2 (5 mL) were concurrently added a CH2Cl2 (5 mL)
solution of the unsaturated hydroperoxide 9 (140 mg, 0.46
mmol) and a CH2Cl2 (5 mL) solution of BCIH (473 mg, 0.92
mmol) over 30 min, and then the reaction mixture was stirred
at room temperature for 1 h (the flask was covered with
aluminum foil). The reaction mixture was poured into aqueous
Na2S2O3 (20 mL) and extracted with Et2O (30 mL × 2). The
combined organic layer was washed with 0.2 N HCl (50 mL)
and aqueous sodium bicarbonate (30 mL) and was dried over
anhydrous MgSO4. After evaporation of the solvent under
reduced pressure, the product was isolated by column chro-
matography on silica gel. Elution with Et2O-hexane (4:96)
gave the cyclic peroxide 15 (120 mg, 61%).
7-I o d o m e t h y l-7-m e t h y l-2-p h e n y l-3,4,8,9-t e t r a o x a -
tr icyclo[9.2.1.02,10]tetr a d eca n e, 15: mp 150-152 °C (from
1
hexane); H NMR δ 0.8-1.4 (m, 5 H), 1.42 (s, 3 H), 2.0-2.1
(m, 1 H), 2.2-2.3 (m, 1 H), 2.4-2.5 (m, 1 H), 2.9-3.1 (m, 2 H),
2.94 (d, J ) 10.2 Hz, 1 H), 2.99 (d, J ) 10.2 Hz, 1 H), 3.6-3.7
(m, 1 H), 4.1-4.2 (m, 1 H), 4.63 (br s, 1 H), 7.2-7.5 (m, 5 H);
13C NMR δ 8.2, 24.0, 25.1, 25.4, 31.3, 35.4, 42.4, 47.7, 68.9,
81.6, 87.4, 93.6, 127.3, 128.0, 128.2, 128.4, 128.9, 139.6. Anal.
(C18H23IO4) C, H, I.
P r ep a r a tion of Un sa tu r a ted Hyd r op er oxid es 10 a n d
11. The preparation of 10 is representative. A solution of
2-phenylindene 1 (340 mg, 2.0 mmol), methallyl alcohol 7 (2.9
g, 40 mmol), and rose bengal (5 mg) in CH3CN (10 mL) was
irradiated at 0 °C for 5 h under an oxygen atmosphere. After
workup, the reaction products were isolated by column chro-
matography on silica gel. Elution with Et2O-hexane (5:95)
gave 10 (66 mg, 12%).
3-(2-Meth yl-2-p r op en yloxy)-3-p h en yl-2-n or bor n yl h y-
1
d r op er oxid e, 10: an oil; H NMR δ 1.1-1.4 (m, 3 H), 1.5-
1.7 (m, 2 H), 1.59 (s, 3 H), 2.3-2.4 (m, 2 H), 3.0-3.1 (m, 1 H),
3.24 (d, J ) 11.6 Hz, 1 H), 3.79 (d, J ) 11.6 Hz, 1 H), 4.53 (s,
1 H), 4.67 (s, 1 H), 4.88 (s, 1 H), 7.2-7.4 (m, 3 H), 7.6-7.7 (m,
2 H), 9.94 (s, 1 H); 13C NMR δ 19.79, 23.92, 25.48, 34.32, 40.18,
40.95, 66.52, 90.23, 93.26, 111.70, 128.03 (2 C), 127.91, 130.28
(2 C), 138.28, 141.96.
3-(3-Met h yl-3-b u t en yloxy)-3-p h en yl-2-n or b or n yl h y-
d r op er oxid e, 11: an oil; 1H NMR δ 0.9-2.1 (m, 9 H), 1.33 (s,
3 H), 2.9-3.0 (m, 2 H), 3.4-3.6 (m, 1 H), 4.46 (br s, 1 H), 4.63
(s, 1 H), 4.69 (s, 1 H), 7.2-7.4 (m, 3 H), 7.6-7.7 (m, 2 H), 9.94
(s, 1 H); 13C NMR δ 21.2, 24.1, 25.7, 34.2, 38.3, 39.9, 41.0, 59.0,
89.9, 92.9, 112.2, 127.7, 127.8 (2 C), 130.3 (2 C), 138.2, 143.1.
Rea ction of Un sa tu r a ted Hyd r op er oxid es 10 a n d 11
w ith BCIH. The reaction of 10 is representative. A solution
of the unsaturated hydroperoxide 10 (160 mg, 0.58 mmol) and
BCIH (600 mg, 1.2 mmol) in CH2Cl2 (20 mL) was stirred at
room temperature for 1 h. After workup, the products were
separated by column chromatography on silica gel. Elution
with Et2O-hexane (2:98) gave peroxide 16 (120 mg, 52%).
5-Iod om et h yl-5-m et h yl-8-p h en yl-3,4,7-t r ioxa b icyclo-
[7.2.1.02,8]d od eca n e, 16: mp 89-90 °C (from hexanes-Et2O);
1H NMR δ 0.6-1.6 (m, 5 H), 0.90 (s, 3 H), 2.2-2.5 (m, 3 H),
3.36 (d, J ) 13.5 Hz, 1 H), 3.53 (d, J ) 10.4 Hz, 1 H), 3.66 (d,
J ) 13.5 Hz, 1 H), 4.46 (d, J ) 10.4 Hz, 1 H), 4.89 (br s, 1 H),
7.5-7.5 (m, 5 H); 13C NMR δ 12.5, 20.8, 23.4, 24.0, 35.3, 41.7,
49.8, 71.3, 82.1, 90.7, 91.7, 127.5, 127.7, 127.9, 128.1, 129.1,
139.9. Anal. (C17H21IO3) C, H.
5-Iod om et h yl-5-m et h yl-9-p h en yl-3,4,8-t r ioxa t ir cyclo-
[8.2.1.02,9]tr id eca n e, 17: an oil (ca. 1:1 mixture of isomers);
1H NMR δ 0.7-1.6 (m, 5 H), 0.97 (s, 3 H), 2.2-2.5 (m, 3 H),
2.77 (d, J ) 10.4 Hz, 1 H), 2.89 (d, J ) 10.4 Hz, 1 H), 3.0-3.1
(m, 1 H), 3.3-3.4 (m, 1 H), 3.36 (d, J ) 10.2 Hz, 1 H), 3.62 (d,
J ) 10.2 Hz, 1 H), 4.66 (br s, 1 H), 7.3-7.5 (m, 5 H); 13C NMR
δ 10.7, 15.6, 22.6, 23.7, 25.2, 26.6, 35.1, 39.1, 41.3, 41.4, 50.7,
50.8, 60.6, 61.3, 80.0, 80.3, 86.5, 86.7, 91.7, 91.8, 127.36, 127.42,
127.44, 127.51, 128.32, 128.47, 128.51, 128.67, 128.71, 140.73.
HRMS (EI, M+) m/z calcd for C18H23IO3: 414.0692. Found:
414.0699. Anal. (C18H23IO3) C, H.
Deter m in a tion of th e X-r a y Cr ysta l Str u ctu r e of Com -
p ou n d 16. The X-ray diffraction data were collected on a
Brucker AXS P4 diffractometer at 160 K using graphite-
monochromated Mo KR, λ ) 0.710 73 Å. The structure was
solved by direct methods and refined using least-squares
techniques. All crystallographic calculations and preparation
of structure plots and tables were carried out using the
SHELXTL PC suite of programs.10
Cr ysta l Da ta for Com p ou n d 16: C17H21IO3, MW ) 400.24,
colorless needles, triclinic, space group P1h (No. 2), a ) 8.287(3)
Å, b ) 9.460(4) Å, c ) 22.137(8) Å, R ) 80.54(3)°, â ) 84.27(3)°,
γ ) 74.81(4)°, U ) 1649.1(11) Å3, Z ) 4, Dc ) 1.612 g cm-3
,
F(000) ) 800, µ(Mo KR) ) 1.949 mm-1, final discrepancy
factors R1 ) 0.084 and wR2 ) 0.240.

Antimalarial Tetraoxa- and Trioxacycloalkanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1961
A.; Alvim-Gaston, M.; Rodrigues, C. R.; Barreiro, E. J .; Cohen,
F. E.; Sabnis, Y. A.; Woolfrey, J . R. Structure-Activity Relation-
ships of the Antimalarial Agent Artemisinin. 6. The Develop-
ment of Predictive in Vitro Potency Models Using CoMFA and
HQSAR Methodologies. J . Med. Chem. 2002, 45, 292-303. (l)
Korshin, E. E.; Hoos, R.; Szpilman, A. M.; Konstantinovski, L.;
Posner, G. H.; Bachi, M. D. Tetrahedron 2002, 58, 2449-2469.
(2) Tsuchiya, K.; Hamada, Y.; Masuyama, A.; Nojima, M.; Mc-
Cullough, K. J .; Kim, H.-S.; Wataya, Y. Synthesis, Crystal
Structure and Anti-Malarial Activity of Novel Spiro-1,2,4,5-
Tetraoxacycloalkanes. Tetrahedron Lett. 1999, 40, 4077-4080.
(3) 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
(4) A part of this work was published in preliminary form. Mc-
Cullough, K. J .; Nonami, Y.; Masuyama, A.; Nojima, M.; Kim,
H.-S.; Wataya, Y. Synthesis, Crystal Structure and Antimalarial
Activity of Novel 1,2,5,6-Tetraoxacycloalkanes from 2,3-Dihy-
droperoxy-2-phenylnorbornane. Tetrahedron Lett. 1999, 40,
9151-9155.
(5) J efford, C. W. The Photo-Oxygenation of Olefins and the Role
of Zwitterionic Peroxides. Chem. Soc. Rev. 1993, 59-66.
(6) Kim, H.-S.; Tsuchuya, K.; Shibata, Y.; Wataya, Y.; Ushigoe, Y.;
Masuyama, A.; Nojima, M.; McCullough, K. J . Synthetic Meth-
ods for Unsymmetrically-Substituted 1,2,4,5-Tetroxanes and of
1,2,4,5,7-Pentoxocanes. J . Chem. Soc., Perkin Trans. 1 1999,
1867.
(7) (a) Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough, K. J .
Halonium Ion-Mediated Reaction of Unsaturated Hydroperoxy
Acetals. Competition between the Formation of Cyclic Peroxides
and the Migration of the Methoxy (or Hydroxy) Group. J . Org.
Chem. 2000, 65, 1069-1075. (b) Nonami, Y.; Tokuyasu, T.;
Masuyama, A.; Nojima, M.; McCullough, K. J .; Kim, H.-S.;
Wataya, Y. Synthesis, Crystal Structure and Antimalarial
Activity of Functionalized Spiro-1,2,4,5-Tetraoxacycloalkanes
from Unsaturated Hydroperoxy Acetals. Tetrahedron Lett. 1999,
40, 4681-4684.
Ack n ow led gm en t. This work was supported in part
by Grant-in-Aid for Scientific Research on Priority Areas
(Grant Nos. 12307007, 13226079, 13650904, 14021072,
and 14021066) from the Ministry of Education, Science,
Culture and Sports of J apan.
Su p p or tin g In for m a tion Ava ila ble: Physical properties
of compounds 4, 12b, and 14b-e, elemental analysis data for
all new cyclic peroxides, and X-ray crystallographic data for
compound 16. This material is available free of charge via the
Internet at http://pubs.acs.org.
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