Orally active antimalarial 3-substituted trioxanes: New synthetic methodology and biological evaluation

Article abstract of DOI:10.1021/jm970686e

On the basis of a mechanistic understanding of the mode of action of artemisinin-like antimalarials, a series of structurally simple 3-aryl- 1,2,4-trioxanes 5 was designed and was prepared in three to five operations from commercial reactants. The 3-aryl group was attached in each case as a nucleophile. In an electronically complementary fashion, 3-(fluoroalkyl)- trioxanes 6 were prepared via attachment of electrophilic fluoroalkyl esters. Both in vitro and in vivo antimalarial evaluations of these new trioxanes showed 12β-methoxy-3-aryltrioxanes 5g, 5j, 5k, and 5l to be highly potent, with crystalline fluorobenzyl ether trioxane 5k especially potent even when administered to rodents orally. As shown by rearrangement of hexamethyl Dewar benzene into hexamethylbenzene, iron-induced degradation of some of these 3- aryltrioxanes 5 involves generation of high-valent iron oxo species that might kill malaria parasites.

Full text of DOI:10.1021/jm970686e

940
J . Med. Chem. 1998, 41, 940-951
Or a lly Active An tim a la r ia l 3-Su bstitu ted Tr ioxa n es: New Syn th etic
Meth od ology a n d Biologica l Eva lu a tion
Gary H. Posner,*,† J ared N. Cumming,† Soon-Hyung Woo,†,‡ Poonsakdi Ploypradith,† Suji Xie,§ and
Theresa A. Shapiro§
Department of Chemistry, The J ohns Hopkins University, Baltimore, Maryland 21218, and Department of Medicine,
School of Medicine, The J ohns Hopkins University, Baltimore, Maryland 21205
Received October 9, 1997
On the basis of a mechanistic understanding of the mode of action of artemisinin-like
antimalarials, a series of structurally simple 3-aryl-1,2,4-trioxanes 5 was designed and was
prepared in three to five operations from commercial reactants. The 3-aryl group was attached
in each case as a nucleophile. In an electronically complementary fashion, 3-(fluoroalkyl)-
trioxanes 6 were prepared via attachment of electrophilic fluoroalkyl esters. Both in vitro
and in vivo antimalarial evaluations of these new trioxanes showed 12â-methoxy-3-aryltrioxanes
5g, 5j, 5k , and 5l to be highly potent, with crystalline fluorobenzyl ether trioxane 5k especially
potent even when administered to rodents orally. As shown by rearrangement of hexamethyl
Dewar benzene into hexamethylbenzene, iron-induced degradation of some of these 3-aryltri-
oxanes 5 involves generation of high-valent iron oxo species that might kill malaria parasites.
Approximately 300-400 million people worldwide
now have malaria, and each year 1-3 million, mostly
children, die from this infectious disease.1,2 Complicat-
ing chemotherapy treatment of malaria patients is the
rapidly spreading multidrug resistance of parasites to
standard quinoline-based antimalarial drugs such as
chloroquine and mefloquine.3,4 A new class of nonal-
kaloidal antimalarial compounds was identified by
organic chemists in the 1970s based on ancient Chinese
herbal medicine; characteristic of these potent and fast-
acting antimalarials is their chemically unusual 1,2,4-
trioxane pharmacophore unit.5-8 Clinically used ex-
amples of such trioxanes derived from Artemisia annua
(qinghao) are natural artemisinin (qinghaosu, 1) and
semisynthetic artemether (2) and artesunic acid (3) as
well as promising artelinic acid (4).5-7 Much structure-
activity relationship (SAR) study has been done,9 lead-
ing to an understanding of the fundamental biological10
and chemical mechanisms11 of action of such trioxanes.
of a trioxane, this process inadvertently causes the
parasites’ own death.10,11 This self-destruction of the
parasite schizonts in the human erythrocytic stage of
their life cycle involves a cascade of chemical reactions
triggered by the iron(II)12,13 liberated during hemoglobin
degradation.11 Iron(II) reduces the peroxide bond in the
trioxane antimalarial drug to form sequentially poten-
tially lethal oxygen-centered free radicals, carbon-
centered free radicals, high-valent iron oxo species, and
reactive epoxides;13 any one of these reactive intermedi-
ates, or a combination of them, may kill the parasite
by alkylating or oxidizing critical biomolecules,14,15
thereby disrupting vital biochemical processes.
On the basis of our understanding at the molecular
level of the chemical cascade leading from antimalarial
trioxane to these various cytotoxic intermediates,13 we
have designed a series of structurally simple 3-a r yltri-
oxanes (5). We anticipated that the 3-aryl substituent
would facilitate progression through this cascade by
Malaria parasites inside human erythrocytes digest
hemoglobin as a source of amino acids. In the presence
† Department of Chemistry.
‡ Current address: Research Institute of Industrial Science &
Technology, P.O. Box 135, Pohang, Korea 790-600.
§ Department of Medicine.
S0022-2623(97)00686-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/12/1998

Orally Active Antimalarial 3-Substituted Trioxanes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 941
Sch em e 1
Sch em e 3
Sch em e 2
variety of 3-substituents than can be incorporated into
such trioxanes. Thus, 3-(fluoroalkyl)trioxanes 6a and
6b were conveniently prepared via Scheme 3 using
readily available electr op h ilic fluorinated esters; cor-
responding fluorinated organometallic reagents for use
in Scheme 1 are neither readily available nor easy to
prepare. Finally, in Scheme 3, the commercially avail-
able phenyl vinyl sulfoxide serves effectively as the
synthetic equivalent of a 2-carbon synthon that is
electr op h ilic at one end and n u cleop h ilic at the
other.
resonance stabilization of adjacent unsaturation and,
therefore, would lead to larger amounts of cytotoxic
intermediates and thus to more potent antimalarial
trioxanes. The first 3-aryltrioxane reported was pre-
pared in the J efford group.16 Also, based on the often
pharmacologically beneficial effect of a drug having a
fluorine atom in place of a hydrogen atom17 and on the
established importance of 3-alkyl substituents for high
antimalarial activity,18,19 we have prepared 3-(fluoro-
aryl)trioxanes 5k -5n and 3-(flu or oa lk yl)trioxanes 6.20
Preparation of 3-(fluoroalkyl)trioxanes 6 illustrates new
synthetic methodology that significantly broadens the
scope of accessible fluorinated targets by allowing not
only fluorinated n u cleop h iles to be used (see Scheme
1) but now also more readily available fluorinated
electr op h iles (see Scheme 3).
Biology
Following our previously described protocol,22 we
evaluated in vitro the chemical structure-antimalarial
activity relationships of these 3-substituted trioxanes
in chloroquine-sensitive Plasmodium falciparum (NF54)23
parasites. The results of this evaluation are tabulated
in Table 1.
Many general observations arise from examination of
the in vitro antimalarial data in Table 1: (1) of the 29
3-substituted trioxanes, 23 have IC50 values of less than
100 nM, and 12 have IC50 values of less than 50 nM,
compared to the 9.2 nM IC50 value for artemisinin; (2)
several of these trioxanes have IC50 values ranging from
15 to 30 nM (in bold); (3) the 12â-methoxy diastereomers
are equally or more potent than the corresponding 12R-
methoxy diastereomers; (4) a p-fluoro substituent adds
very little to in vitro antimalarial activity (cf. trioxanes
5a and 5l); (5) the steric hindrance of an o-methyl
substituent as in 3-aryltrioxanes 5m does not change
antimalarial potency relative to its non-ortho-methy-
lated analogues 5l; (6) the nature of the halogen
substituent, fluoro or chloro, does not have a strong
effect (cf. 5d vs 5l); and (7) although oxygen-containing
3-aryltrioxanes such as anisole 5e and furan 5f are poor
antimalarials, oxygen-containing benzylic trioxanes 5g-k
are potent antimalarials.
Ch em istr y
Three-step syntheses of most of the 3-aryltrioxanes
5 are summarized in Scheme 1. For benzylic alcohol
trioxanes 5g, ketone precursor 7g was prepared as the
corresponding silyl ether and thus one more step was
needed to liberate the benzylic hydroxyl group directly
from silylated benzylic alcohol trioxanes 8. For those
3-aryltrioxanes 5i and 5j that were prepared by acyla-
tion of the primary alcohol group of 3-(p-hydroxymeth-
yl)phenyl trioxanes 5g, one additional step was used
(Scheme 2). Thus, in only three to five chemical
operations, 3-aryltrioxanes 5a -n were synthesized in
racemic form in quantities up to a few hundred mil-
ligrams. Scale-up should be feasible. The 12R- and 12â-
methoxy diastereomers were separated chromatographi-
cally and were distinguished by high-field H and 13C
1
NMR spectroscopy.21
In contrast to Scheme 1 in which an aryl n u cleop h ile
was used to attach the aryl group to the cyclohexane
side chain, Scheme 3 represents complementary syn-
thetic methodology in which a fluoroalkyl electr op h ile
was used. This flexibility in choice of either a nucleo-
phile or an electrophile considerably broadens the
At least one of these 3-aryltrioxanes is effective also
against another type of opportunistic infection. Pre-
liminary L929 cell studies24 with p-fluorophenyl-12â-
methoxytrioxane 5l indicate that it is as active as
artemisinin at inhibiting growth of Toxoplasma gondii,
a parasite that causes cerebral encephalitis in immu-

942 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Posner et al.
a
Ta ble 1. In Vitro Antimalarial Activitites
results demonstrate the high antimalarial efficacy of
simple 12â-methoxytrioxanes 5g, 5j, 5k , and 5l, and
recent preliminary in vivo acute toxicity testing results
highlight the relative safety of (fluorophenyl)trioxane
5l. These new and easily prepared trioxanes, therefore,
are promising lead compounds appropriate for clinical
evaluation.
trioxane
5a
Ar or Rf
C12-OMe
IC50 (nM)
Mech a n ism of Action
Ph
R
â
R
â
R
â
R
â
110
38
76
68
170
44
We have recently proposed a unified chemical mech-
anism to account for the ability of trioxanes to kill
malaria parasites selectively.11 According to this mech-
anism, the parasite’s digestion of hemoglobin releases
heme in which iron(II) reduces the trioxane’s peroxide
linkage to form oxy radicals. Critically for antimalarial
activity, one type of such oxy radical then rearranges
via a 1,5-hydrogen atom shift to form a carbon radical
at C4.13 Therefore, we designed the 3-aryl trioxanes
described here to facilitate the next â-scission step to
form the arene-conjugated new carbon-carbon double
bond shown in Scheme 4 and a strongly oxidizing and
possibly cytotoxic high-valent iron oxo species.
5b
5c
5d
p-PhPh
1-naphthyl
p-ClPh
49
55
5e
5f
p-MeOPh
2-furyl
>2500b
600
78
R
R
â
R
â
R
R
â
R
â
R
â
R
â
R
â
5g
p-HOCH2Ph
15
39
51
79
44
20
42
23
65
30
99
34
39
53
5h
p-MeOCH2Ph
5i
5j
p-MeOC(O)OCH2Ph
p-MeC(O)OCH2Ph
5k
5l
p-(p′-FPhCH2OCH2)Ph
p-FPh
Sch em e 4
5m
5n
p-F-o-MePh
p-CF3Ph
11
6a
6b
CH3
CF3CH2CH2
FCH2
â
â
R
â
960c
84c
320c
160c
artemisinin
9.2
a
Antimalarial activity was determined as reported previously.22
The standard deviation for each set of quadruplicates was an
average of 10% (e59%) of the mean. R2 values for the fitted curves
b
were g0.989. 12-Methoxy stereochemistry not unambiguously
determined. c Assay may underestimate the potency of these
volatile compounds.
nocompromised individuals. In this cell assay, the
therapeutic index (ratio of activity/toxicity) of fluorophe-
nyl trioxane 5l is better than that of atovaquone.
In the past, we have been successful in using in vitro
antimalarial activities as a guide to select peroxides for
in vivo antimalarial evaluation.25 Preliminary assay of
four 12â-methoxy-3-aryltrioxanes (5g, 5j, 5k , and 5l) in
a rodent system against chloroquine-sensitive Plasmo-
dium berghei (N) using a previously described protocol26
resulted in the data shown in Table 2. For convenience
in comparing relative potencies of antimalarials having
different molecular weights, ED50 and ED90 values are
presented not only in the standard mg/kg terms but here
also in µmol/kg values. Several observations emerge:
(1) these four simple synthetic trioxanes are potent
antimalarials; (2) high levels of in vitro antimalarial
activity correlate well with high in vivo antimalarial
potencies; (3) especially noteworthy for ease of admin-
istration ultimately in clinical settings is the or a l
a ctivity of these simple, crystalline trioxanes; and (4)
structurally simple benzylic alcohol trioxane 5g, acetate
trioxane 5j, and fluorobenzyl ether trioxane 5k are up
to twice as potent as the complex natural artemisinin
(1). All of these orally active trioxanes are stable at 60
°C for at least 36 h. Thus, these preclinical in vivo
Evidence to support operation of this mechanism in
iron(II)-initiated reduction of these 3-aryltrioxanes comes
from three sources. First, 4â-methyl-3-phenyltrioxane
12 (forming a C4-tertiary radical) has 5 times higher in
vitro antimalarial activity than the corresponding 4-un-
substituted system 12R-methoxytrioxane 5a (forming a

Orally Active Antimalarial 3-Substituted Trioxanes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 943
Ta ble 2. In Vivo Antimalarial Activities
ED50, mg/kg (µmol/kg)a
ED90, mg/kg (µmol/kg)
IC50, (nM)b
in vitro
C
12â-trioxane
R
subcutaneous
oral
subcutaneous
oral
5g
5j
5k
5l
HOCH2
3.4 (11)
2.8 (7.7)
3.5 (8.2)
6.8 (22)
3.0 (11)
1.0 (1.9)
5.5 (17)
14 (39)
3.8 (8.9)
10 (32)
8.5 (30)
1.2 (2.3)
6.8 (21)
6.0 (17)
7.1 (17)
13 (42)
9.2
12 (37)
22 (61)
6.8 (16)
23 (75)
15
20
23
30
MeC(O)OCH2
p′-FPhCH2OCH2
F
artemisinin
chloroquine
5.0
a
Four different doses (1, 3, 10, and 30 mg/kg) were administered each day for 4 days to five mice per dose regimen to establish the ED
values indicated above via a previously reported protocol.26 In vitro antimalarial activity was determined as reported previously.22
b
less stable C4-secondary radical).27 Second, iron(II)-
induced degradation of 3-phenyl- and 3-(p-fluorophenyl)-
12R-methoxytrioxanes 5a and 5l (see Scheme 4) in the
other biomolecules before reaching the parasite tar-
gets.19
In summary, mechanism-based design has led to a
series of structurally simple 3-aryl trioxanes that are
efficacious in vivo as potent antimalarials even when
administered orally to rodents. These trioxanes, there-
fore, are now excellent antimalarial drug candidates for
further clinical evaluations as part of the worldwide
effort to fight malaria via chemotherapy.
presence of hexamethyl Dewar benzene (HMDB) led to
considerable rearrangement into hexamethylbenzene.
This rearrangement is generally accepted as strong
evidence for the intermediacy of one or more high-valent
iron oxo species,13 formed presumably as outlined in
Scheme 4 via â-scission, along with a new styrene
carbon-carbon double bond. Third, iron(II)-induced
degradation of 12R-methoxytrioxane 5l produced 1-2%
of the C4-oxygenated, structurally reorganized aryl
ketone 13 as a single diastereomer.28 Formation of this
rearranged product, having the same molecular formula
as its parent trioxane 5l, may reasonably involve one
or both of the epoxide intermediates shown in Scheme
4. Independent synthesis of the penultimate C4-hydroxy
epoxide (dimethyldioxirane reacting with the corre-
sponding vinyl ether) showed that it rearranged spon-
taneously into aryl ketone 13.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, the following applies:
Reactions were run in flame-dried round-bottomed flasks
under an atmosphere of ultra-high-purity (UHP) argon. Di-
ethyl ether (ether) and tetrahydrofuran (THF) were distilled
from sodium benzophenone ketyl prior to use. Methylene
chloride (CH2Cl2) was distilled from calcium hydride prior to
use. All other compounds were purchased from Aldrich
Chemical Co. and used without further purification. Analyti-
cal thin-layer chromatography (TLC) was conducted with silica
gel 60 F254 plates (250 µm thickness, Merck). Column chro-
matography was performed using short path silica gel (particle
size <230 mesh), flash silica gel (particle size 400-230 mesh),
or Florisil (200 mesh). Yields are not optimized. Purity of
products was judged to be >95% based on their chromato-
graphic homogeneity. High-performance liquid chromatogra-
phy (HPLC) was carried out with a Rainin HPLX system
equipped with two 25 mL/min preparative pump heads using
Rainin Dynamax 10 mm × 250 mm (semipreparative) columns
packed with 60 Å silica gel (8 µm pore size), either as bare
silica or as C-18-bonded silica. Melting points were measured
using a Mel-Temp metal-block apparatus and are uncorrected.
Nuclear magnetic resonance (NMR) spectra were obtained
either on a Varian XL-400 spectrometer, operating at 400 MHz
for 1H and 100 MHz for 13C, or on a Varian XL-500 spectrom-
eter, operating at 500 MHz for 1H and 125 MHz for 13C.
Chemical shifts are reported in parts per million (ppm, δ)
downfield from tetramethylsilane. Splitting patterns are
described as singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m), and broad (br). Infrared (IR) spectra were
obtained using a Perkin-Elmer 1600 FT-IR spectrometer.
Resonances are reported in wavenumbers (cm-1). Low- and
high-resolution mass spectra (LRMS and HRMS) were ob-
tained with electronic or chemical ionization (EI or CI) either
(1) at J ohns Hopkins University on a VG Instruments 70-S
spectrometer run at 70 eV for EI and run with ammonia (NH3)
as a carrier gas for CI or (2) at the University of Illinois at
Champaign-Urbana on a Finnigan-MAT CH5, a Finnigan-
MAT 731, or a VG Instruments 70-VSE spectrometer run at
70 eV for EI and run with methane (CH4) for CI. Combustion
analyses were conducted by Atlantic Microlab (Norcross, GA).
Gen er a l P r oced u r e 1: F or m a tion of Lith iu m Diiso-
p r op yla m id e (LDA). To a -78 °C solution of diisopropy-
In contrast, iron(II)-mediated degradation of the 12â-
diastereomers of 3-phenyl- and 3-(p-fluorophenyl)triox-
anes did not produce any rearrangement of HMDB.
Major products of these reactions were 1,5-diketones
14.19 These results indicate a dependence of the deg-
radation pathway on the stereochemistry at C12. 12â-
Methoxy-3-aryltrioxanes may exert their antimalarial
activity by acting as prodrugs for electrophilic dike-
tones. The diketones arising from most of the 3-aryl-
trioxanes listed in Table 1 were thus tested for in vitro
efficacy. These potential alkylating agents were gener-
ally inactive, with the exception of those arising from
trioxane 5a (1400 nM) and trioxane 5l (1200 nM). The
low antimalarial activity of these reactive diketones
in unmasked form may be due to their reacting with

944 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Posner et al.
lamine (1.2 equiv based on 1.0 equiv of substrate) in THF
(volume needed to make the final concentration of LDA 0.25-
0.50 M) was added via syringe recently titrated n-butyllithium
(1.1 equiv, originally 1.6 M in hexanes). This mixture was
stirred at -78 °C for 5 min and then warmed to room
temperature and stirred for 20 min.
contained 2,6-di-tert-butyl-4-methylpyridine (0.25 equiv). The
reaction was quenched with Et3N (neat, 3.9 equiv).
Gen er a l P r oced u r e 4: Desilyla tion by F lu or id e Ion .
To a solution of starting silyl ether (1.0 equiv) in THF (0.33
M) at 0 °C was added a 0 °C solution of Bu4NF (monohydrate,
1.5 equiv) in THF (0.67 M). The resulting solution was stirred
at 0 °C until the starting material was consumed (generally
at least 1 h). The reaction was quenched with H2O (3 mL)
and then diluted with appropriate volumes of ether and H2O.
The organic phase was separated, and the aqueous phase was
extracted with appropriate volumes of ether. The organic
portions were combined, washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure.
p-Bip h en yl Keton e 7b. To a solution of 4-bromobiphenyl
(770 mg, 3.30 mmol) in ether (4 mL) at 0 °C was added n-BuLi
(1.25 M in hexanes, 2.5 mL, 3.1 mmol) via syringe. This
solution was stirred at 0 °C for 5 min, then warmed to room
temperature and stirred for 1 h. The resulting greenish gray
turbid mixture was added dropwise via cannula (without
cooling) to a -78 °C solution of (Z)-methoxyethylidene-2-(2′-
cyanoethyl)cyclohexanone16,29 (370 mg, 2.06 mmol) in ether (14
mL). The reaction mixture turned bright orange and fumed
extensively during the addition. The mixture was stirred at
-78 °C for 5 min, then warmed to room temperature and
stirred for 3 h. At that time, the reaction was quenched with
H2O (3 mL) and then diluted with ether (50 mL) and H2O (50
mL). The organic phase was separated, and the aqueous phase
was extracted with ether (50 mL × 2). The organic portions
were combined, washed with saturated aqueous NaCl, dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (short path, 1% f 10% EtOAc/hexanes) to
give the desired product 7b (282 mg, 2.53 mmol, 41%) as a
light pink solid: mp ) 93.0-94.5 °C.
Gen er a l P r oced u r e 2a : Keton e Syn th esis (Lith iu m -
Ha logen Exch a n ge). To a solution of aryl bromide (1.3
equiv) in ether (5 mL/mmol of nitrile) at -78 °C was added
via syringe recently titrated t-BuLi (2.5 equiv, originally 1.6
M in ether) over 1 min. This solution was stirred at -78 °C
for 30-60 min. To this mixture was added dropwise via
cannula a -78 °C solution of nitrile starting material (1.0
equiv) in ether (5 mL/mmol). The reaction was stirred at -78
°C for 15 min, then warmed to room temperature over 1 h and
stirred at that temperature until complete by TLC analysis
(at least 1 h). At that time, the reaction was cooled back to 0
°C and quenched with dropwise addition of H2O. The mixture
was then diluted with H2O and ether, the organic phase
separated, and the aqueous phase extracted twice with ether.
The organic portions were combined, washed with saturated
aqueous NaCl, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure.
Gen er a l P r oced u r e 2b: Keton e Syn th esis (Su lfoxid e
Alk yla tion /Red u ction ). To a freshly prepared solution of
LDA (1.1 equiv) in THF/hexanes (0.25 M) at -78 °C was added
dropwise by cannula a -78 °C solution of sulfoxide substrate
(1.0 equiv) in THF (0.67 M). The mixture was allowed to warm
to -35 °C over 2 h, was stirred for an additional hour, and
was cooled back to -78 °C. A solution of fluoroalkyl ester (1.4
equiv) in THF (3.3 M) was added via cannula. The resulting
reaction mixture was stirred at -78 °C for 1 h and then
warmed to -35 °C over 2 h. After being stirred at that
temperature for an additional 2 h, the reaction was quenched
with saturated aqueous NH4Cl. The mixture was extracted
with EtOAc, dried over anhydrous MgSO4, and concentrated
to give a crude acylated sulfoxide.
3-(p-Bip h en yl)tr ioxa n es C12r-5b a n d C12â-5b. p-Biphenyl
ketone 7b (190 mg, 0.565 mmol) was treated according to
general procedure 3a. The crude reaction mixture was purified
by column chromatography (Florisil, 1% f 10% EtOAc/
hexanes) to give 12R-methoxytrioxane 5b (90 mg, 0.24 mmol,
43%), 12â-methoxytrioxane 5b (45 mg, 0.324 mmol, 22%),
impure diketone 14b, and an impure mixture of mono- and
di-O-silylated species arising from 14b. The latter material
was treated according to general procedure 4 (excess Bu4NF).
The crude product from this reaction was combined with the
other portion of impure diketone 14b and purified by column
chromatography (flash gel, 5% f 50% EtOAc/hexanes) to give
diketone 14b (36 mg, 0.117 mmol, 21%).
Aluminum foil (10 equiv based on estimated yield of
sulfoxide) was cut into small strips, submerged for 15 s in an
aqueous mercury(II) chloride solution (2% w/v), and then
rinsed well with absolute ethanol and then with ether. The
resulting aluminum/mercury amalgam was snipped with
scissors into a 0 °C solution of the above acylated sulfoxide in
aqueous THF (90%, THF/H2O, 2.0 mL/mmol of aluminum foil).
This reaction was stirred at 0 °C for 1.5 h. Anhydrous MgSO4
was then added to the resulting gray slurry, and this mixture
was filtered with copious ether rinses. The combined organic
washes were concentrated under reduced pressure.
Gen er a l P r oced u r e 3a : Tr ioxa n e F or m a tion by Sin -
glet Oxygen a tion . A sulfonation (three-necked) flask was
fitted with a gas inlet line, an outlet line with stopcock, and a
septum. To this flask was added solid methylene blue (ca.5
mg) followed by a solution of the starting ketone (1.0 equiv)
in CH2Cl2 (0.01 M). The resulting solution was cooled to -78
°C while UHP oxygen passed through a drying column was
bubbled (ca. 2-3 mL/s) through the solution. The reaction
mixture was then irradiated with UV light (medium-pressure
Hg lamp) with continuous O2 bubbling ju st until TLC analysis
showed >95% consumption of starting material (typically 20-
60 min). After irradiation, an argon source was introduced
through the septum, the outlet stopcock was closed, and the
gas inlet line was replaced with a stopper. To this reaction
mixture, still at -78 °C, was then added by cannula a -78 °C
solution of TBDMSOTf (1.1 equiv) in CH2Cl2 (0.50 M). The
resulting solution was stirred for approximately 8 h at -78
°C. At that time, the reaction was quenched by addition via
syringe over 2 min of Et3N (neat, 3.3 equiv). The mixture was
allowed to warm to at least -20 °C slowly over at least 2 h
and was then concentrated under reduced pressure.
Further purification of trioxane C12R-5b by HPLC (silica,
85% CH2Cl2/hexanes, 2.5 mL/min, 274 nm, tR ) 15.8 min)
afforded a white solid: mp ) 163.5-165.0 °C.
Further purification of trioxane C12â-5b by HPLC (silica, 3%
EtOAc/hexanes, 3.0 mL/min, 274 nm, tR ) 9.9 min) afforded a
white solid: mp ) 146.0-147.0 °C.
Further purification of diketone 14b by HPLC (silica, 15%
EtOAc/hexanes, 3.0 mL/min, 274 nm, tR ) 18.9 min) afforded
a white solid: mp ) 76.0-76.5 °C.
1-Na p h th yl Keton e 7c. (Z)-Methoxyethylidene-2-(2′-cya-
noethyl)cyclohexanone16,29 (500 mg, 2.79 mmol) was treated
according general procedure 2a using 1-naphthyl bromide.
Analysis of the crude product by TLC and then by 1H NMR
revealed the almost exclusive presence of a stable imine
corresponding to the desired ketone. A small amount of
hydrolysis was evident by TLC. Accordingly, this material was
dissolved in 5% EtOAc/hexanes (20 mL) and slurried with
short path silica (10 g) for 8 h, at which time TLC analysis
indicated complete hydrolysis of imine to ketone. This solution
was filtered and concentrated and the resulting oil was purified
by column chromatography (flash gel, 1% f 10% EtOAc/
hexanes) to give the desired product 7c (695 mg, 2.25 mmol,
81%) as a pale yellow oil.
Gen er a l P r oced u r e 3b: Tr ioxa n e F or m a tion : P r oton
Sp on ge Mod ifica tion . This procedure is identical to general
procedure 3a, with the following modifications. CH2Cl2 (an-
hydrous, 99.8%, packaged in Sure/Seal bottle) was purchased
from Aldrich (27,099-7) and used without further purification.
The TBDMSOTf solution (1.3 equiv, 0.50 M in CH2Cl2) also
3-(1-Na p h th yl)tr ioxa n es C12r-5c a n d C12â-5c. 1-Naph-
thyl ketone 7c (310 mg, 1.00 mmol) was treated according to
general procedure 3a. The crude reaction mixture was purified

Orally Active Antimalarial 3-Substituted Trioxanes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 945
by column chromatography (Florisil, 1% f 10% EtOAc/
hexanes) to give 12R-methoxytrioxane 5c (138 mg, 0.405 mmol,
40%), 12â-methoxytrioxane 5c (66 mg, 0.19 mmol, 19%),
impure diketone 14c, and an impure mixture of mono- and
di-O-silylated species arising from 14c. The latter material
was treated according to general procedure 4 (excess Bu4NF).
The crude product from this reaction was combined with the
other portion of impure diketone 14c and purified by column
chromatography (flash gel, 5% f 50% EtOAc/hexanes) to give
diketone 14c (91 mg, 0.32 mmol, 32%).
Further purification of trioxane C12R-5c by HPLC (silica,
98% CH2Cl2/hexanes, 2.0 mL/min, tR ) 13.6 min) afforded a
white solid: mp ) 110-112 °C.
Further purification of trioxane C12â-5c by HPLC (silica, 40%
CH2Cl2/hexanes, 3.0 mL/min, 274 nm, tR ) 14.5 min) afforded
a white solid: mp ) 154.5-155.0 °C.
Further purification of trioxane C12â-5d by HPLC (silica,
80% CH2Cl2/hexanes, 2.0 mL/min, 264 nm, tR ) 9.5 min)
afforded a white solid: mp ) 93.0-95.0 °C.
Further purification of diketone 14d by HPLC (silica, 15%
EtOAc/hexanes, 3.0 mL/min, 264 nm, tR ) 17.1 min) afforded
a white solid: mp ) 71.5-73.5 °C.
p-Meth oxyp h en yl Keton e 7e. (Z)-Methoxyethylidene-2-
(2′-cyanoethyl)cyclohexanone16,29 (300 mg, 1.67 mmol) was
treated according general procedure 2a (1.6 equiv of aryl
bromide, 1.5 equiv of t-BuLi) using p-methoxyphenyl bromide.
The crude product was purified by column chromatography
(flash gel, 1% f 20% EtOAc/hexanes) to give the desired
product 7e (323 mg, 1.12 mmol, 67%) as a colorless oil.
3-(p-Meth oxyp h en yl)tr ioxa n e 5e. p-Methoxyphenyl ke-
tone 5 (300 mg, 1.04 mmol) was treated according to general
procedure 3a. The crude reaction mixture was purified by
column chromatography (Florisil, 1% f 10% EtOAc/hexanes)
to give trioxane 5e (140 mg, 0.437 mmol, 42%), with ambiguous
relative stereochemistry, impure diketone 14e, and an impure
mixture of mono- and di-O-silylated species arising from 14e.
The latter material was treated according to general procedure
4 (excess Bu4NF). The crude product from this reaction was
combined with the other portion of impure diketone 14e
and purified by column chromatography (flash gel, 5% f
50% EtOAc/hexanes) to give diketone 14e (94 mg, 0.36 mmol,
35%).
Further purification of trioxane 5e by HPLC (silica, 5%
EtOAc/hexanes, 3.0 mL/min, 254 nm, tR ) 19.0 min) afforded
a white solid: mp ) 84.5-85.0 °C. Anal. Calcd for C18H24O5:
C, 67.47; H, 7.57. Found: C, 67.54; H, 7.57. Note that this
combustion analysis rules out the deoxytrioxane product.
Anal. Calcd for C18H24O4: C, 71.02; H, 7.96.
Further purification of diketone 14e by HPLC (silica, 25%
EtOAc/hexanes, 3.0 mL/min, 274 nm, tR ) 16.6 min) afforded
a white solid: mp ) 104.0-105.0 °C.
2-F u r yl Keton e 7f. To a solution of furan (0.525 mL, 7.25
mmol) in THF (8 mL) at 0 °C was added via syringe n-BuLi
(5.6 mL, 1.25 M solution in hexanes, 7.0 mmol). The mixture
was stirred at 0 °C for 2 h, then warmed to room temperature,
and stirred for 1 h. This solution was then cooled back to 0
°C, and a solution of (Z)-methoxyethylidene-2-(2′-cyanoethyl)-
cyclohexanone16,29 (500 mg, 2.79 mmol) in THF (4 mL) at 0 °C
was added via cannula. The reaction immediately turned
bright orange. After 5 min at 0 °C, the mixture was warmed
to room temperature and stirred for 6 h, at which time it was
dark red. The reaction was then quenched with H2O (3 mL)
and diluted with ether (20 mL) and H2O (20 mL). The organic
phase was separated, and the aqueous phase was extracted
with ether (50 mL × 2). The organic portions were combined,
washed with saturated aqueous NaCl, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography (20 g
flash gel, 1% f 20% EtOAc/hexanes) to give the desired
product 7f (296 mg, 1.19 mmol, 43%) as a yellow oil.
3-(2-F u r yl)tr ioxa n e 5f. 2-Furyl ketone 7f (250 mg, 1.01
mmol) was treated according to general procedure 3a. The
crude reaction mixture was purified by column chromatogra-
phy (Florisil, 1% f 20% EtOAc/hexanes) to give 12R-methox-
ytrioxane 5f (45 mg, 0.16 mmol, 16%), impure diketone 14f,
and an impure mixture of mono- and di-O-silylated species
arising from 14f. The latter material was treated according
to general procedure 4 (excess Bu4NF). The crude product
from this reaction was combined with the other portion of
impure diketone 14f and purified by column chromatography
(flash gel, 5% f 50% EtOAc/hexanes) to give diketone 14f (121
mg, 0.549 mmol, 54%).
Further purification of diketone 14c by HPLC (silica, 15%
EtOAc/hexanes, 3.0 mL/min, 280 nm, tR ) 19.0 min) afforded
a white solid: mp ) 80.0-81.5 °C.
p-Ch lor op h en yl Keton e 7d . To a slurry of (methoxym-
ethyl)triphenylphosphonium chloride (16.7 g, 48.8 mmol) in
THF (200 mL) at -78 °C was added PhLi (1.8 M in 70%
cyclohexane/ether, 25.3 mL, 45.6 mmol) via syringe. The
resulting dark red mixture was stirred at -78 °C for 15 min,
warmed to room temperature, and stirred for 3 h. This
solution was cooled back to -78 °C, and a precooled solution
of 2-(2′-carbomethoxyethyl)cyclohexanone30 (6.00 g, 32.6 mmol)
in THF (100 mL) was added via cannula. The mixture was
stirred at -78 °C for 1 h, warmed to room temperature, and
stirred for 12 h. The reaction was quenched with H2O (10 mL)
and further diluted with H2O (100 mL). After 10 min of
stirring, the organic layer was decanted. The aqueous portion
was extracted with ether (2 × 50 mL). The organic portions
were combined, washed with saturated aqueous NaCl, dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (flash gel, 1% f 20% EtOAc/hexanes) to give
the desired enol ethers (5.68 g, 26.8 mmol, 82%), a 1:1 mixture
of diastereomers, as a colorless liquid.
To a 0 °C solution of (p-chlorophenyl)magnesium bromide
(1.0 M in ether, 5.65 mL, 5.65 mmol) in benzene (7.0 mL) was
added via syringe Et3N (2.35 mL, 17.0 mmol). This mixture
was stirred at 0 °C for 10 min, and then a precooled solution
of the above enol ethers (600 mg, 2.83 mmol) in benzene (14
mL) was added via cannula. The reaction was stirred at 0 °C
for 3 h, quenched with dropwise addition of H2O (3 mL), and
then diluted with ether (50 mL) and H2O (25 mL). The organic
phase was separated, and the aqueous phase was extracted
with ether (25 mL × 2). The organic portions were combined,
washed with saturated aqueous NaCl, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was filtered through a plug of short path silica
to afford the corresponding ketones (566 mg, 1.93 mmol, 68%)
as a 1:1 mixture of diastereomers. This mixture was separated
by column chromatography (short path, 1% f 10% EtOAc/
hexanes) to give the desired Z-enol ether isomer 7d , which
solidified slowly at room temperature over several days: mp
) 38.0-39.5 °C.
3-(p-Ch lor op h en yl)tr ioxa n es C12r-5d a n d C12â-5d . p-
Chlorophenyl ketone 7d (235 mg, 0.802 mmol) was treated
according to general procedure 3a. The crude reaction mixture
was purified by column chromatography (Florisil, 1% f 10%
EtOAc/hexanes) to give 12R-methoxytrioxane 5d (73 mg, 0.22
mmol, 28%), 12â-methoxytrioxane 5d (84 mg, 0.26 mmol, 32%),
impure diketone 14d , and an impure mixture of mono- and
di-O-silylated species arising from 14d . The latter material
was treated according to general procedure 4 (excess Bu4NF).
The crude product from this reaction was combined with the
other portion of impure diketone 14d and purified by column
chromatography (flash gel, 5% f 50% EtOAc/hexanes) to give
diketone 14d (45 mg, 0.17 mmol, 21%).
Further purification of trioxane 5f by HPLC (silica, 5%
EtOAc/hexanes, 4.0 mL/min, 254 nm, tR ) 14.2 min) afforded
a white solid: mp ) 110.5-112.0 °C.
Further purification of diketone 14f by HPLC (silica, 10%
i-PrOH/hexanes, 3.0 mL/min, 264 nm, tR ) 12.0 min) afforded
a white solid: mp ) 48.5-49.5 °C.
Further purification of trioxane C12R-5d by HPLC (silica,
100% CH2Cl2, 2.0 mL/min, 264 nm, tR ) 20.4 min) afforded a
white solid: mp ) 94.0-95.0 °C.
p-(Silyloxym eth yl)p h en yl Keton e 7g. To a solution of
p-hydroxymethylphenyl bromide (4.75 g, 25.4 mmol) and

946 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Posner et al.
imidazole (2.59 g, 38.0 mmol) in CH2Cl2 (100 mL) at 0 °C was
added via dropping funnel a solution of tert-butyldimethylsilyl
chloride (4.59 g, 30.5 mmol). The resulting solution was kept
for 5 min at 0 °C, then warmed to room temperature, and
stirred for 20 min. The reaction was then quenched with H2O
(10 mL) and diluted with 10% aqueous HCl (100 mL). The
organic phase was separated, and the aqueous phase was
extracted with CH2Cl2 (100 mL × 2). The organic portions
were combined, washed with saturated aqueous NaCl, dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by Ku¨gel-
rohr distillation (160-180 °C, 0.9 Torr) to give the desired silyl
ether (7.21 g, 23.9 mmol, 94%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 7.45 (m, 2 H), 7.20 (m, 2 H), 4.69 (s, 2 H), 0.95
(d, J ) 0.8 Hz, 9 H), 0.11 (d, J ) 0.8 Hz, 6 H); 13C NMR (100
MHz, CDCl3) δ 140.4, 131.2, 127.6, 120.5, 64.3, 25.9, 18.4, -5.2.
These spectroscopic data are consistent with those reported
previously.31,32
(Z)-Methoxyethylidene-2-(2′-cyanoethyl)cyclohexanone16,29 (500
mg, 2.79 mmol) was treated according to general procedure
2a with the above p-(silyloxymethyl)phenyl bromide. The
crude product was purified by column chromatography (flash
gel, 1% f 10% EtOAc/hexane) to give the desired product 7g
(776 mg, 1.92 mmol, 69%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 7.92 (m, 2 H), 7.39 (m, 2 H), 5.79 (d, J ) 1.6
Hz, 1 H), 4.78 (s, 2 H), 3.41 (s, 3 H), 2.99-2.83 (m, 3 H), 2.00
(m, 2 H), 1.80 (m, 1 H), 1.74 (m, 2 H), 1.65 (m, 1 H), 1.52 (m,
3 H), 1.26-1.15 (m, 1 H), 0.95 (s, 9 H), 0.11 (s, 6 H); 13C NMR
(100 MHz, CDCl3) δ 200.4, 146.3, 140.3, 136.0, 128.0, 125.6,
118.9, 64.4, 59.0, 36.8, 32.6, 31.6, 28.2, 26.4, 25.8, 21.6, 18.3,
-5.3; IR (neat) 3001, 2928, 2856, 1684, 1609, 1462, 1256, 1124,
1094, 839 cm-1; LRMS (EI, rel intensity) 402 (M+, 2), 370 (6),
249 (6), 223 (12), 138 (100); HRMS (EI) m/z calcd for (M+)
402.2590, found 402.2594.
(ddd, J ) 14.4, 4.4, 3.2 Hz, 1 H), 2.02-1.89 (m, 2 H), 1.81-
1.59 (m, 8 H), 1.30 (apparent dt, J d ) 4.8 Hz, J t ) 13.6 Hz, 1
H), 1.20 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 141.4, 140.1,
126.7, 125.5, 105.1, 105.0, 83.8, 64.9, 57.1, 47.4, 39.1, 35.6, 30.8,
26.8, 25.0, 23.8; IR (CHCl3) 3608, 3473, 3031, 3012, 2933, 2863,
1446, 1277, 1104, 1036, 960 cm-1; LRMS (CI, NH3, rel
intensity) 321 (M + H+, 100), 261 (68), 138 (34); HRMS (CI,
NH3) m/z calcd for C18H25O5 (M + H+) 321.1702, found
321.1700.
Further purification of diketone 14g by HPLC (silica, 20%
i-PrOH/hexanes, 3.0 mL/min, 270 nm, tR ) 10.6 min) afforded
a white solid: mp ) 50.0-51.0 °C; 1H NMR (400 MHz, CDCl3)
δ 7.96 (m, 2 H), 7.45 (m, 2 H), 4.77 (d, J ) 5.2 Hz, 2 H), 3.04
(ddABq, J d ) 8.4, 6.0 Hz, J AB ) 16.8 Hz, ∆νAB ) 64.4 Hz, 2
H), 2.43 (m, 2 H), 2.31 (m, 1 H), 2.19-2.03 (m, 3 H), 1.99 (br
m, 1 H), 1.87 (m, 1 H), 1.75-1.62 (m, 3 H), 1.46 (m, 1 H); 13C
NMR (100 MHz, CDCl3) δ 213.5, 200.0, 146.2, 135.8, 128.3,
126.5, 64.4, 49.9, 42.2, 36.3, 34.6, 28.1, 25.0, 24.5; IR (CHCl3)
3611, 3489, 3029, 3011, 2939, 2864, 1704, 1681, 1610, 1450,
1233, 1014 cm-1; LRMS (EI, rel intensity) 260 (M+, 5), 242
(10), 150 (84), 135 (100), 107 (13), 89 (15), 77 (11); HRMS (EI)
m/z calcd for C16H20O3 (M+) 260.1412, found 260.1417.
p-(Meth oxym eth yl)p h en yl Keton e 7h . To a room tem-
perature suspension of p-(hydroxymethyl)phenyl bromide (3.0
g, 16 mmol) in methyl iodide (10 g, 160 mmol) was added just
enough CH2Cl2 to dissolve ca. 90% of the solid (ca. 5 mL). To
this rapidly stirring mixture was added solid n-Bu4NI (300 mg,
0.80 mmol) followed immediately by NaOH (50% aqueous, 6.2
mL, 80 mmol). After 3 h, the mixture was diluted with H2O
(50 mL) and CH2Cl2 (50 mL). The organic phase was sepa-
rated, and the aqueous phase was washed with CH2Cl2 (50
mL). The organic portions were combined, washed with
saturated aqueous NaCl, dried over anhydrous MgSO4, fil-
tered, and concentrated under reduced pressure. The crude
product was purified by column chromatography (flash gel, 1%
f 5% EtOAc/hexanes) to give the desired methyl ether (3.0 g,
15 mmol, 93%) as a colorless oil. Its spectroscopic data are
consistent with those reported previously.33,34
3-(p-(Hydr oxym eth yl)ph en yl)tr ioxan es C12r-5g an d C12â
-
5g. p-(Silyloxymethyl)phenyl ketone 7g (430 mg, 1.07 mmol)
was treated according to general procedure 3b. The crude
reaction mixture was purified by column chromatography
(Florisil, 1% f 20% EtOAc/hexanes) to give a silylated 12R-
methoxytrioxane (115 mg, 0.264 mmol, 25%), a silylated 12â-
methoxytrioxane (129 mg, 0.296 mmol, 28%), an impure
p-(silyloxymethyl)phenyl diketone, and an impure mixture of
mono- and di-O-silylated species arising from this diketone.
Portions of the trioxanes (100 mg, 0.230 mmol of C12R analogue;
75 mg, 0.17 mmol of C12â analogue) were individually desily-
lated according to general procedure 4. The resulting crude
products were purified separately by column chromatography
(Florisil each, 5% f 50% EtOAc/hexanes) to give 12R-meth-
oxytrioxane 5g (60 mg, 0.19 mmol, 83%) and 12â-methoxytri-
oxane 5g (40 mg, 0.12 mmol, 71%). All diketone-containing
material was combined and was treated according to general
procedure 4 (excess Bu4NF). The crude product was purified
by column chromatography (flash gel, 5% f 50% EtOAc/
hexanes) to give diketone 14g (52 mg, 0.20 mmol, 19%).
(Z)-Methoxyethylidene-2-(2′-cyanoethyl)cyclohexanone16,29
(1.00 g, 5.58 mmol) was treated according to general procedure
2a with the above (methoxymethyl)phenyl bromide. The crude
product was purified by column chromatography (flash gel, 1%
f 20% EtOAc/hexane) to give the desired product 7h (925 mg,
3.06 mmol, 55%) as a colorless oil.
3-(p-(Meth oxym eth yl)ph en yl)tr ioxan es C12r-5h an d C12â
-
5h . p-(Methoxymethyl)phenyl ketone 7h (230 mg, 0.792
mmol) was treated according to general procedure 3b. The
crude reaction mixture was purified by column chromatogra-
phy (Florisil, 1% f 20% EtOAc/hexanes) to give 12R-methox-
ytrioxane 5h (39 mg, 0.12 mmol, 21%), 12â-methoxytrioxane
5h (19 mg, 0.057 mmol, 10%), impure diketone 14h , and an
impure mixture of mono- and di-O-silylated species arising
from 14h . The latter material was treated according to
general procedure 4 (excess Bu4NF). The crude product from
this reaction was combined with the other portion of impure
diketone 14h and purified by column chromatography (flash
gel, 5% f 50% EtOAc/hexanes) to give diketone 14h (99 mg,
0.36 mmol, 66%).
Further purification of trioxane C12R-5h by HPLC (silica, 5%
EtOAc/CH2Cl2, 3.0 mL/min, 254 nm, tR ) 11.4 min) afforded
a white solid: mp ) 96.0-97.0 °C. Further purification of
trioxane C12â-5h by HPLC (silica, 10% EtOAc/hexanes, 2.5 mL/
min, 254 nm, tR ) 16.0 min) afforded a white solid: mp )
69.0-70.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2 H), 7.32
(m, 2 H), 5.14 (d, J ) 1.2 Hz, 1 H), 4.46 (s, 2 H), 3.65 (s, 3 H),
3.37 (s, 3 H), 2.78 (ddd, J ) 14.4, 13.2, 3.6 Hz, 1 H), 2.30 (ddd,
J ) 13.6, 4.4, 3.2 Hz, 1 H), 2.02-1.89 (m, 2 H), 1.81-1.59 (m,
7 H), 1.30 (apparent dt, J d ) 4.8 Hz, J t ) 13.6 Hz, 1 H), 1.20
(m, 1 H); 13C NMR (100 MHz, CDCl3) δ 140.1, 138.6, 127.3,
125.2, 105.0, 104.9, 83.7, 74.1, 58.0, 57.1, 47.4, 39.1, 35.6, 30.7,
26.8, 25.0, 23.8; IR (CHCl3) 3032, 3012, 2933, 2862, 1447, 1277,
1104, 1016 cm-1; LRMS (CI, NH3, rel intensity) 335 (M + H+,
37), 275 (100); HRMS (CI, NH3) m/z calcd for C19H27O5 (M +
H+) 335.1858, found 335.1860.
Further purification of trioxane C12R-5g by HPLC (silica,
10% i-PrOH/hexanes, 3.0 mL/min, 254 nm, tR ) 14.4 min)
afforded a white solid: mp ) 140-142 °C (broad); 1H NMR
(400 MHz, CDCl3) δ 7.54 (m, 2 H), 7.34 (m, 2 H), 5.18 (s, 1 H),
4.68 (s, 2 H), 3.61 (s, 3 H), 2.83 (ddd, J ) 14.4, 13.6, 4.0 Hz, 1
H), 2.41 (m, 1 H), 2.26 (ddd, J ) 14.8, 4.8, 2.4 Hz, 1 H), 1.89
(m, 1 H), 1.82-1.69 (m, 5 H), 1.67-1.56 (m, 1 H), 1.33-1.15
(m, 4 H); 13C NMR (100 MHz, CDCl3) δ 141.4, 139.7, 126.5,
125.5, 103.8, 96.0, 83.6, 64.8, 55.9, 45.3, 37.5, 33.3, 32.5, 27.1,
25.2, 23.1; IR (CHCl3) 3608, 3506, 3031, 3012, 2934, 2864,
1451, 1347, 1272, 1100, 1012 cm-1; LRMS (CI, NH3, rel
intensity) 321 (M + H+, 63), 289 (22), 261 (100), 138 (24);
HRMS (CI, NH3) m/z calcd for C18H25O5 (M + H+) 321.1702,
found 321.1709.
Further purification of trioxane C12â-5g by HPLC (silica, 5%
i-PrOH/hexanes, 3.0 mL/min, 254 nm, tR ) 18.6 min) afforded
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 2 H),
7.35 (m, 2 H), 5.14 (d, J ) 1.2 Hz, 1 H), 4.69 (d, J ) 3.2 Hz, 2
H), 3.65 (s, 3 H), 2.78 (ddd, J ) 14.8, 13.2, 3.6 Hz, 1 H), 2.29

Orally Active Antimalarial 3-Substituted Trioxanes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 947
Further purification of diketone 14h by HPLC (silica, 25%
EtOAc/hexanes, 3.0 mL/min, 284 nm, tR ) 19.8 min) afforded
a white solid: mp ) 41.5-42.5 °C.
(6.6 mL, 53 mmol) was added NaOH (50% aqueous, 10.5 mL,
134 mmol) followed immediately by solid n-Bu4NI (494 mg,
1.34 mmol). After 1 h, the mixture was diluted with H2O (50
mL) and CH2Cl2 (50 mL). The organic phase was separated,
and the aqueous phase was washed with CH2Cl2 (50 mL). The
organic portions were combined, washed with saturated aque-
ous NaCl, dried over anhydrous MgSO4, filtered, and concen-
trated under reduced pressure. The crude product was
purified by Ku¨gelrohr distillation (175 °C, 0.9 Torr) to give
the desired ether (7.43 g, 25.2 mmol, 93%) as a white solid:
3-(p-(Ca r bom eth oxyoxym eth yl)p h en yl)tr ioxa n e 5i. To
a 0 °C slurry of C12R-methoxytrioxane benzyl alcohol 5g (32
mg, 0.10 mmol) and K2CO3 (414 mg, 3.00 mmol) in acetone
(10 mL) was added Me2SO4 (0.33 mL, 3.5 mmol). The resulting
mixture was warmed to room temperature. After 3 h, no
reaction was evident by TLC analysis. The mixture was then
heated to reflux. After 6 h, all acetone had boiled away. The
reaction had partially but cleanly proceeded according to TLC.
Additional Me2SO4 (0.33 mL, 3.5 mmol) was added, and the
mixture was refluxed for an additional 12 h. The reaction was
then cooled to room temperature and diluted with H2O (5 mL)
and CHCl3 (5 mL). The phases were separated, and the
aqueous phase was extracted with CHCl3 (5 mL). The
combined organic portions were washed with saturated aque-
ous NaCl (10 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure. The resulting crude product was
purified by column chromatography (Florisil, 1% f 20%
EtOAc/hexanes) to give C12R-methoxytrioxane carbonate 5i (19
mg, 0.050 mmol, 50%). Further purification of this material
by HPLC (silica, 10% EtOAc/CH2Cl2, 2.0 mL/min, 264 nm, tR
) 9.5 min) afforded a white solid: mp ) 113.5-114.0 °C.
1
mp ) 37.5-38.0 °C; H NMR (400 MHz, CDCl3) δ 7.48 (m, 2
H), 7.31 (m, 2 H), 7.24 (m, 2 H), 7.04 (m, 2 H), 4.50 (s, 2 H),
4.49 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 162.3 (d, J C-F
)
244 Hz), 137.1, 133.7 (d, J C-F ) 3.0 Hz), 131.5, 129.5 (d, J C-F
) 7.6 Hz), 129.3, 121.5, 115.2 (d, J C-F ) 21.3 Hz), 71.5, 71.3;
IR (neat) 3044, 2923, 2859, 1603, 1509, 1223, 1086, 1012, 824
cm-1; LRMS (EI, rel intensity) 294/296 (M+, 3), 185/187 (8),
169/171 (29), 109 (100), 91 (52); HRMS (EI) m/z calcd for
C
14H12O79BrF (M+) 294.0056, found 294.0054.
(Z)-Methoxyethylidene-2-(2′-cyanoethyl)cyclohexanone16,29
(1.00 g, 5.58 mmol) was treated according to general procedure
2a with the above p-(p′-fluorobenzyloxymethyl)phenyl bromide.
The crude product was purified by column chromatography
(flash gel, 1% f 20% EtOAc/hexane) to give the desired
product 7k (1.68 g, 4.24 mmol, 76%) as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 7.94 (m, 2 H), 7.43 (br d, 2 H), 7.33 (m, 2
H), 7.04 (m, 2 H), 5.79 (d, J ) 2.0 Hz, 1 H), 4.59 (s, 2 H), 4.53
(s, 2 H), 3.42 (s, 3 H), 2.92 (m, 3 H), 2.00 (m, 2 H), 1.83-1,70
(m, 3 H), 1.64 (m, 1 H), 1.60-1.48 (m, 4 H), 1.28-1.15 (m, 1
H); 13C NMR (100 MHz, CDCl3) δ 200.5, 162.3 (d, J C-F ) 244
Hz), 143.0, 140.4, 136.6, 133.6 (d, J C-F ) 3.1 Hz), 129.4 (d,
J C-F ) 8.4 Hz), 128.2, 127.3, 119.0, 115.3 (d, J C-F ) 51.1 Hz),
71.7, 71.5, 59.1, 36.9, 32.6, 31.7, 28.3, 26.4, 25.8, 21.6; IR (neat)
3058, 2927, 2854, 1681, 1608, 1510, 1224, 1124, 826; LRMS
(EI, rel intensity) 396 (M+, 1), 138 (100), 123 (11), 109 (20);
HRMS (EI) m/z calcd for C25H29O3F (M+) 396.2101, found
396.2101.
3-(p-(Acetoxym eth yl)p h en yl)tr ioxa n es 5j. C3-(p-(Hy-
droxymethyl)phenyl)trioxanes 5g were individually treated
according to the following procedure: To a solution of trioxane
alcohol (32 mg, 0.10 mmol C12R-5g; 29 mg, 0.091 mmol C12â
-
5g) in CH2Cl2 (0.10 M) was added DMAP (ca. 0.2 equiv,
catalytic) as a solid followed by Et3N (1.2 equiv) via syringe.
The resulting solution was cooled to 0 °C and acetyl chloride
(1.2 equiv) was added via syringe. The reaction was stirred
at 0 °C for 15-20 min, quenched with dropwise addition of
H2O (1 mL), then diluted with CH2Cl2 (2 mL) and H2O (2 mL).
The phases were separated, and the aqueous phase was
extracted with CH2Cl2 (2 mL). The combined organic portions
were washed with saturated aqueous NaCl (5 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
resulting crude products were purified separately by column
chromatography (Florisil each, 1% f 10% EtOAc/hexanes) to
give 12R-methoxytrioxane acetate 5j (28 mg, 0.077 mmol, 77%)
and 12â-methoxytrioxane acetate 5j (24 mg, 0.066 mmol, 73%).
Further purification of C12R-5j by HPLC (silica, 60% MeOt-
Bu/CH2Cl2, 2.5 mL/min, 264 nm, tR ) 8.5 min) afforded a white
solid: mp ) 71.0-72.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.54
(m, 2 H), 7.34 (br d, 2 H), 5.17 (s, 1 H), 5.10 (s, 2 H), 3.60 (s,
3 H), 2.82 (ddd, J ) 13.2, 13.6, 3.6 Hz, 1 H), 2.41 (m, 1 H),
2.24 (ddd, J ) 14.4, 4.8, 2.4 Hz, 1 H), 2.10 (s, 3 H), 1.89 (m, 1
H), 1.82-1.70 (m, 4 H), 1.68-1.55 (m, 1 H), 1.30-1.15 (M, 4
H); 13C NMR (100 MHz, CDCl3) δ 170.8, 140.5, 136.3, 127.9,
125.5, 103.8, 96.1, 83.7, 65.8, 56.0, 45.4, 37.6, 33.4, 32.5, 27.2,
25.3, 23.1, 21.0; IR (CHCl3) 3020, 2934, 2863, 1736, 1451, 1224,
1100, 1014, 754, 668 cm-1; LRMS (CI, CH4, rel intensity) 363
(M + H+, 4), 331 (17), 303 (89), 243 (100), 177 (23), 125 (33),
109 (66), 61 (53); HRMS (CI, CH4) m/z calcd for C20H27O6 (M
+ H+) 363.1808, found 363.1804.
Further purification of C12â-5j by HPLC (silica, 10% EtOAc/
hexanes, 2.5 mL/min, 264 nm, tR ) 11.0 min) afforded a white
solid: mp ) 85.0-85.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.55
(m, 2 H), 7.34 (m, 2 H), 5.13 (d, J ) 1.2 Hz, 1 H), 5.10 (s, 2 H),
3.64 (s, 3 H), 2.77 (ddd, J ) 14.8, 13.6, 4.0 Hz, 1 H), 2.28 (ddd,
J ) 14.8, 4.4, 3.2 Hz, 1 H), 2.10 (s, 3 H), 2.02-1.89 (m, 2 H),
1.81-1.59 (m, 7 H), 1.30 (apparent dt, J d ) 5.2 Hz, J t ) 13.6
Hz, 1 H), 1.21 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 170.7,
140.8, 136.4, 128.0, 125.4, 105.0, 104.9, 83.8, 65.8, 57.1, 47.4,
39.1, 35.6, 30.8, 26.8, 25.0, 23.8, 21.0; IR (CHCl3) 3030, 2934,
2862, 1736, 1446, 1380, 1234, 1104, 1016 cm-1; LRMS (CI,
NH3, rel intensity) 380 (M + NH4+, 12), 363 (M + H+, 81),
320 (M+ - O2, 15), 303 (100), 260 (36), 138 (20); HRMS (CI,
NH3) m/z calcd for C20H27O6 (M + H+) 363.1808, found
363.1814.
3-(p-(p′-Flu or oben zyloxym eth yl)ph en yl)tr ioxan es C12r
-
5k a n d C12â-5k . p-(p′-Fluorobenzyloxymethyl)phenyl ketone
7k (175 mg, 0.441 mmol) was treated according to general
procedure 3b. The crude reaction mixture was purified by
column chromatography (Florisil, 1% f 20% EtOAc/hexanes)
to give 12R-methoxytrioxane 5k (58 mg, 0.14 mmol, 13%), 12â-
methoxytrioxane 5k (65 mg, 0.15 mmol, 14%), impure diketone
14k , and an impure mixture of mono- and di-O-silylated
species arising from 14k . The latter material was treated
according to general procedure 4 (excess Bu4NF). The crude
product from this reaction was combined with the other portion
of impure diketone 14k and purified by column chromatogra-
phy (flash gel, 5% f 50% EtOAc/hexanes) to give diketone 14k
(217 mg, 0.589 mmol, 55%).
Further purification of trioxane C12R-5k by HPLC (silica,
20% EtOAc/CH2Cl2, 1.5 mL/min, 274 nm, tR ) 9.5 min)
afforded a white solid: mp ) 90.0-91.0 °C; 1H NMR (400 MHz,
CDCl3) δ 7.55 (m, 2 H), 7.33 (m, 4 H), 7.03 (m, 2 H), 5.18 (s, 1
H), 4.54 (s, 2 H), 4.49 (s, 2 H), 3.62 (s, 3 H), 2.84 (ddd, J )
14.8, 13.2, 3.6 Hz, 1 H), 2.42 (m, 1 H), 2.27 (ddd, J ) 14.4, 4.8,
2.4 Hz, 1 H), 1.90 (m, 1 H), 1.83-1.71 (m, 4 H), 1.70-1.59 (m,
1 H), 1.33-1.16 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 162.0
(d, J C-F ) 244 Hz), 139.8, 138.5, 133.7 (d, J C-F ) 3.0 Hz), 129.3
(d, J C-F ) 8.3 Hz), 127.2, 125.3, 115.0 (d, J C-F ) 21.3), 103.7,
95.9, 83.3, 71.5, 71.1, 55.8, 45.2, 37.4, 33.2, 32.3, 27.0, 25.1,
23.0; IR (CHCl3) 3019, 2933, 2863, 1511, 1210, 1100, 1013, 752
cm-1; LRMS (CI, CH4, rel intensity) 427 (M - H+, 3), 397 (15),
369 (33), 243 (58), 169 (24), 125 (29), 109 (100), 61 (81); HRMS
(CI, CH4) m/z calcd for C25H28O5F1 (M - H+) 427.1921, found
427.1910.
Further purification of trioxane C12â-5k by HPLC (silica, 5%
EtOAc/hexanes, 4.0 mL/min, 264 nm, tR ) 14.5 min) afforded
a white solid: mp ) 59.0-61.0 °C; 1H NMR (400 MHz, CDCl3)
δ 7.54 (m, 2 H), 7.32 (m, 4 H), 7.03 (m, 2 H), 5.14 (d, J ) 1.2
Hz, 1 H), 4.54 (s, 2 H), 4.48 (s, 2 H), 3.64 (s, 3 H), 2.78 (ddd,
J ) 14.4, 13.2, 3.6 Hz, 1 H), 2.29 (ddd, J ) 14.8, 4.4, 3.2 Hz,
1 H), 2.02-1.89 (m, 2 H), 1.81-1.59 (m, 5 H), 1.20 (apparent
p-(p′-F lu or oben zyloxym eth yl)p h en yl Keton e (7k ). To
a rapidly stirring room temperature slurry of p-hydroxymeth-
ylphenyl bromide (5.0 g, 27 mmol) in p-fluorobenzyl bromide

948 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Posner et al.
dt, J d ) 5.2 Hz, J t ) 13.6 Hz, 1 H) overlapping 1.21 (m, 1 H);
13C NMR (100 MHz, CDCl3) δ 162.3 (d, J C-F ) 244 Hz), 140.2,
138.6, 133.8 (d, J C-F ) 3.0 Hz), 129.5 (d, J C-F ) 8.4 Hz), 127.5,
125.4, 115.2 (d, J C-F ) 21.3 Hz), 105.1, 150.0, 83.8, 71.7, 71.3,
57.2, 47.5, 39.1, 65.6, 30.8, 26.8, 25.1, 23.8; IR (CHCl3) 3034,
(apparent dt, J d ) 4.8 Hz, J t ) 13.6 Hz, 1 H), 1.21 (m, 1 H);
13C NMR (100 MHz, CDCl3) δ 162.8 (d, J C-F ) 246 Hz), 136.7
(d, J C-F ) 3.0 Hz), 127.2 (d, J C-F ) 8.4 Hz), 115.0 (d, J C-F
)
21.2 Hz), 105.1, 104.7, 83.7, 57.1, 47.4, 39.1, 35.6, 30.8, 26.8,
25.0, 23.8; IR (CHCl3) 3034, 3012, 2934, 2863, 1604, 1512,
1447, 1235, 1139, 1106 cm-1; LRMS (CI, NH3, rel intensity)
326 (M + NH4+, 12), 309 (M + H+, 100), 277 (11), 249 (71),
138 (17); HRMS (CI, NH3) m/z calcd for C17H22O4F (M + H+)
309.1502, found 309.1506.
3011, 2933, 2862, 1604, 1511, 1230, 1139, 1104, 785 cm-1
;
LRMS (CI, NH3, rel intensity) 429 (M + H+, 20), 397 (5), 369
(100), 154 (14), 126 (13); HRMS (CI, NH3) m/z calcd for
C
25H30O5F (M + H+) 429.2077, found 429.2088.
Further purification of diketone 14l by HPLC (silica, 8%
EtOAc/hexanes, 4.0 mL/min, 270 nm, tR ) 18.2 min) afforded
a white solid: mp ) 63.0-64.0 °C; 1H NMR (400 MHz, CDCl3)
δ 8.02 (m, 2 H), 7.12 (m, 2 H), 3.02 (dd AB q, J d ) 8.8, 6.0 Hz,
J AB ) 16.8 Hz, ∆νAB ) 70.8 Hz, 2 H), 2.48-2.27 (m, 3 H), 2.18-
2.03 (m, 3 H), 1.88 (m, 1 H), 1.76-1.64 (m, 3 H), 1.46 (m, 1
H); 13C NMR (100 MHz, CDCl3) δ 213.2, 198.6, 165.6 (d, J C-F
) 253 Hz), 133.1 (d, J C-F ) 3.0 Hz), 130.7 (d, J C-F ) 9.1 Hz),
115.5 (d, J C-F ) 22.0 Hz), 49.9, 42.2, 36.3, 34.6, 28.1, 25.1,
24.6; IR (CHCl3) 3022, 2940, 2863, 1705, 1683, 1599, 1508,
1224, 1156, 764 cm-1; LRMS (EI, rel intensity) 248 (M+, 8),
138 (100), 123 (54), 95 (21); HRMS (EI) m/z calcd for C15H17O2F
(M+) 248.1213, found 248.1216.
p-F lu or o-o-m eth ylp h en yl Keton e 7m . (Z)-Methoxyeth-
ylidene-2-(2′-cyanoethyl)cyclohexanone16,29 (450 mg, 2.51 mmol)
was treated according to general procedure 2a (1.6 equiv of
aryl bromide, 1.5 equiv of t-BuLi) using p-fluoro-o-methylphe-
nyl bromide. The crude product was purified by column
chromatography (short path, 1% f 20% EtOAc/hexanes) to
give the desired product 7m (476 mg, 1.64 mmol, 65%) as a
pale yellow oil.
Further purification of diketone 14k by HPLC (silica, 30%
EtOAc/hexanes, 3.0 mL/min, 260 nm, tR ) 12.5 min) afforded
a cloudy film: 1H NMR (400 MHz, CDCl3) δ 7.97 (m, 2 H),
7.44 (br d, 2 H), 7.33 (m, 2 H), 7.05 (m, 2 H), 4.59 (s, 2 H), 4.53
(s, 2 H), 3.04 (ddABq, J d ) 8.4, 6.4 Hz, J AB ) 17.2 Hz, ∆νAB
)
64.8 Hz, 2 H), 2.43 (m, 2 H), 2.31 (m, 1 H), 2.19-2.04 (m, 3
H), 1.88 (m, 1 H), 1.75-1.64 (m, 3 H), 1.46 (m, 1 H); 13C NMR
(100 MHz, CDCl3) δ 213.2, 199.8, 162.3 (d, J C-F ) 244 Hz),
143.4, 136.1, 133.6 (d, J C-F ) 3.1 Hz), 129.4 (d, J C-F ) 8.3 Hz),
128.3, 127.4, 115.3 (d, J C-F ) 21.3), 71.7, 71.4, 50.0, 42.2, 36.4,
34.6, 28.1, 25.1, 24.6; IR (CHCl3) 3029, 3012, 2939, 2863, 1705,
1681, 1609, 1511, 1231, 1086, 826, 668 cm-1; LRMS (EI, rel
intensity) 368 (M+, 6), 258 (71), 242 (47), 148 (47), 133 (100),
123 (54), 109 (83), 77 (33); HRMS (EI) m/z calcd for C23H25O3F
(M+) 368.1788, found 368.1785.
p-F lu or op h en yl Keton e 7l. (Z)-Methoxyethylidene-2-(2′-
cyanoethyl)cyclohexanone16,29 (732 mg, 4.08 mmol) was treated
according to general procedure 2a (1.5 equiv of aryl bromide,
1.4 equiv of t-BuLi) using p-fluorophenyl bromide. The crude
product was purified by column chromatography (flash gel, 1%
f 5% EtOAc/hexanes) to give the desired product 7l (1.03 g,
3.73 mmol, 91%) as a pale yellow oil: 1H NMR (400 MHz,
CDCl3) δ 7.97 (m, 2 H), 7.11 (m, 2 H), 5.79 (d, J ) 2.0 Hz, 1
H), 3.41 (s, 3 H), 2.97-2.81 (m, 3 H), 2.00 (m, 2 H), 1.82 (m, 1
H), 1.74 (m, 2 H), 1.65 (m, 1 H), 1.53 (m, 3 H), 1.21 (m, 1 H);
13C NMR (100 MHz, CDCl3) δ 199.0, 165.3 (d, J C-F ) 253 Hz),
140.4, 133.7 (d, J C-F ) 3.0 Hz), 130.4 (d, J C-F ) 9.1 Hz), 118.8,
115.3 (d, J C-F ) 22.0 Hz), 59.0, 36.6, 32.5, 31.6, 28.2, 26.4,
25.7, 21.6; IR (neat) 3068, 2927, 2853, 1683, 1598, 1506, 1232,
1124, 836 cm-1; LRMS (EI, rel intensity) 276 (M+, 7), 244 (4),
138 (100), 123 (24), 95 (15); HRMS (EI) m/z calcd for C17H21O2F
(M+) 276.1525, found 276.1532.
3-(p-Flu or o-o-m eth ylph en yl)tr ioxan es C12r-5m an d C12â
-
5m . p-Fluoro-o-methylphenyl ketone 7m (230 mg, 0.792
mmol) was treated according to general procedure 2a. The
crude reaction mixture was purified by column chromatogra-
phy (Florisil, 1% f 20% EtOAc/hexanes) to give 12R-methox-
ytrioxane 5m (40 mg, 0.12 mmol, 16%), 12â-methoxytrioxane
5m (50 mg, 0.16 mmol, 20%), impure diketone 14m , and an
impure mixture of mono- and di-O-silylated species arising
from 14m . The latter material was treated according to
general procedure 4 (excess Bu4NF). The crude product from
this reaction was combined with the other portion of impure
diketone 14m and purified by column chromatography (flash
gel, 5% f 50% EtOAc/hexanes) to give diketone 14m (116 mg,
0.442 mmol, 56%).
Further purification of trioxane C12R-5m by HPLC (silica,
4% EtOAc/hexanes, 3.0 mL/min, 254 nm, tR ) 13.7 min)
afforded a white solid: mp ) 112.0-113.0 °C.
Further purification of trioxane C12â-5m by HPLC (silica,
1% EtOAc/hexanes, 3.0 mL/min, 254 nm, tR ) 10.4 min)
afforded a white solid: mp ) 97.0-99.0 °C.
Further purification of diketone 14m by HPLC (silica, 10%
EtOAc/hexanes, 4.0 mL/min, 264 nm, tR ) 18.8 min) afforded
a white solid: mp ) 38.5-39.5 °C.
p-Tr iflu or om eth ylp h en yl Keton e 7n . (Z)-Methoxyeth-
ylidene-2-(2′-cyanoethyl)cyclohexanone16,29 (400 mg, 2.23 mmol)
was treated according to general procedure 2a using methyl
p-(trifluoromethyl)phenyl bromide. The crude product was
purified by column chromatography (flash gel, 1% f 20%
EtOAc/hexanes) to afford the desired product 7n (557 mg, 1.71
mmol, 77%) as a yellow oil.
3-(p-F lu or op h en yl)tr ioxa n es
C12r-5l a n d C12â-5l. p-
Fluorophenyl ketone 3 (270 mg, 0.977 mmol) was treated
according to general procedure 3a. The crude reaction mixture
was purified by column chromatography (Florisil, 1% f 10%
EtOAc/hexanes) to give 12R-methoxytrioxane 5l (60 mg, 0.19
mmol, 20%), 12â-methoxytrioxane 5l (100 mg, 0.324 mmol,
33%), impure diketone 14l, and an impure mixture of mono-
and di-O-silylated species arising from 14l. The latter material
was treated according to general procedure 4 (excess Bu4NF).
The crude product from this reaction was combined with the
other portion of impure diketone 14l and purified by column
chromatography (flash gel, 5% f 50% EtOAc/hexanes) to give
diketone 14l (78 mg, 0.314 mmol, 32%).
Further purification of trioxane C12R-5l by HPLC (C-18, 10%
water/methanol, 3.0 mL/min, 260 nm, tR ) 9.3 min) afforded
a white solid: mp ) 97.0-98.0 °C; 1H NMR (400 MHz, CDCl3)
δ 7.54 (m, 2 H), 7.03 (m, 2 H), 5.17 (s, 1 H), 3.61 (s, 3 H), 2.83
(ddd, J ) 14.4, 13.2, 3.6 Hz, 1 H), 2.41 (m, 1 H), 2.25 (ddd, J
) 14.4, 4.8, 2.4 Hz, 1 H), 1.89 (m, 1 H), 1.82-1.70 (m, 4 H),
1.62 (m, 1 H), 1.30-1.15 (m, 4 H); 13C NMR (100 MHz, CDCl3)
δ 162.8 (d, J C-F ) 246 Hz), 136.4 (d, J C-F ) 3.0 Hz), 127.4 (d,
J C-F ) 8.3 Hz), 115.0 (d, J C-F ) 22.0 Hz), 103.6, 96.2, 83.6,
56.1, 45.3, 37.5, 33.3, 32.5, 27.1, 25.2, 23.1; IR (CHCl3) 3032,
2934, 2863, 1604, 1512, 1452, 1235, 1101 cm-1; LRMS (CI,
NH3, rel intensity) 326 (M + NH4+, 19), 309 (M + H+, 86), 277
(30), 249 (100), 138 (18); HRMS (CI, NH3) m/z calcd for
3-(p-(Tr iflu or om eth yl)p h en yl) tr ioxa n es C12r-5n a n d
C
12â-5n . p-(Trifluoromethyl)phenyl ketone 7n (390 mg, 1.09
mmol) was treated according to general procedure 3a. The
crude reaction mixture was purified by column chromatogra-
phy (Florisil, 1% f 20% EtOAc/hexanes) to give C12R-methox-
ytrioxane 5n (13 mg, 0.033 mmol, 3%), C12â-methoxytrioxane
5n (30 mg, 0.077 mmol, 7%) impure diketone 14n , and an
impure mixture of mono- and di-O-silylated species arising
from 14n . The latter material was treated according to
general procedure 4 (excess Bu4NF). The crude product from
this reaction was combined with the other portion of impure
diketone 14n and purified by column chromatography (flash
gel, 5% f 50% EtOAc/hexanes) to give diketone 14n (216 mg,
0.724 mmol, 66%).
C
17H22O4F (M + H+) 309.1502, found 309.1503.
Further purification of trioxane C12â-5l by HPLC (C-18, 2%
water/methanol, 3.0 mL/min, 270 nm, tR ) 6.3 min) afforded
a white solid: mp ) 87.0-88.0 °C; 1H NMR (400 MHz, CDCl3)
δ 7.53 (m, 2 H), 7.03 (m, 2 H), 5.13 (d, J ) 1.2 Hz), 3.64 (s, 3
H), 2.78 (ddd, J ) 14.4, 13.2, 3.6 Hz, 1 H), 2.28 (ddd, J ) 14.4,
4.8, 3.2 Hz, 1 H), 2.01-1.87 (m, 2 H), 1.80-1.59 (m, 7 H), 1.30

Orally Active Antimalarial 3-Substituted Trioxanes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 949
Further purification of trioxane C12R-5n by HPLC (silica, 5%
EtOAc/hexanes, 3.0 mL/min, 254 nm, tR ) 12.7 min) afforded
a white solid: mp ) 137.0-138.0 °C.
Further purification of trioxane C12â-5n by HPLC (silica, 3%
EtOAc/hexanes, 3.0 mL/min, 254 nm, tR ) 7.3 min) afforded a
white solid: mp ) 97.0-98.0 °C.
F lu or om eth yl Keton e 10b. Sulfoxide enol ether 9 (1.41
g, 5.07 mmol) was treated according to general procedure 2b
using ethyl fluoroacetate (acylated sulfoxide was used crude
in reduction). The crude product was purified by column
chromatography (flash gel, 90% EtOAc/hexanes) to afford pure
ketone 10b (286 mg, 1.33 mmol, 26%) as an oil.
3-(F lu or om eth yl)tr ioxa n es C12r-6b a n d C12â-6b. Fluo-
romethyl ketone 10b (281 mg, 1.31 mmol) was treated accord-
ing to general procedure 3a (20 mL CH2Cl2, irradiation for 2
h). The crude product was purified by column chromatography
(flash gel, 10% EtOAc/hexanes) to give C12R-methoxytrioxane
6b (17 mg, 0.069 mmol, 5%) and C12â-methoxytrioxane 6b (132
mg, 0.537 mmol, 41%).
Further purification of trioxane C12R-6b by recrystallization
afforded a white solid: mp ) 75.0-76.0 °C.
Further purification of trioxane C12â-6b by recrystallization
afforded a white solid: mp ) 80.0-81.0 °C.
Further purification of diketone 14n by HPLC (silica, 20%
EtOAc/hexanes, 3.0 mL/min, 284 nm, tR ) 12.6 min) afforded
a white solid: mp ) 53.5-54.0 °C.
Su lfoxid e En ol Eth er 9. To a suspension of (methoxym-
ethyl)triphenylphosphonium chloride (1.42 g, 4.14 mmol) in
THF (15 mL) at -78 °C was added dropwise via syringe PhLi
(1.77 M in 70% cyclohexane/ether, 2.34 mL, 4.14 mmol). This
mixture was warmed to room temperature and stirred for 3
h. The resulting dark red solution was cooled to -78 °C, and
a solution of 2-(2′-phenylsulfoxyethyl)cyclohexanone35 (0.650
g, 2.60 mmol) in THF (10 mL) was added dropwise by cannula.
The resulting mixture was then allowed to warm to room
temperature over 5 h and was stirred for an additional 5 h.
At that time, the reaction was quenched with H2O (25 mL),
extracted with EtOAc, dried over anhydrous MgSO4, and
concentrated. Purification by column chromatography (flash
gel, 50% EtOAc/hexanes) afforded the desired product 9 (644
mg, 2.32 mmol, 89%) as a roughly equal mixture of the four
diastereomers: 1H NMR (400 MHz, CDCl3) δ 7.60 (m, 8 H),
7.51 (m, 12 H), 5.81 (s, 1 H), 5.80 (s, 1 H), 5.71 (s, 1 H), 5.69
(s, 1 H), 3.53 (s, 3 H), 3.52 (s, 3 H), 3.49 (s, 3 H), 3.47 (s, 3 H),
2.96 (m, 1 H), 2.75 (m, 8 H), 2.25 (m, 2 H), 2.10-1.20 (m, 41
H); 13C NMR (100 MHz, CDCl3) δ 144.2, 143.99, 143.97, 143.88,
140.67, 140.65, 139.89, 139.86, 130.9, 130.8, 130.7, 130.6,
129.1, 129.0, 128.97, 124.1, 123.99, 123.98, 123.92, 118.8,
118.0, 117.9, 59.4, 59.21, 59.18, 55.8, 55.7, 55.5, 55.3, 38.3, 37.9,
33.4, 33.3, 32.4, 31.9, 31.53, 31.46, 28.1, 27.0, 26.3, 26.2, 24.1,
23.7, 23.5, 23.4, 22.8, 22.43, 22.38, 21.54, 21.51; IR (CHCl3)
2927, 2852, 1676, 1444, 1127, 1043, 748, 693 cm-1; LRMS (CI,
NH3, rel intensity) 279 (M + H+, 100), 265 (40); HRMS (CI,
NH3) m/z calcd for C16H23SO2 (M + H+) 279.1419, found
279.1423.
Tr iflu or op r op yl Keton e 10a . Sulfoxide enol ether 9 (1.20
g, 4.32 mmol) was treated according to general procedure 2b
using ethyl 4,4,4-trifluorobutyrate (acylated sulfoxide was
passed through silica before reduction). Purification of the
crude product by column chromatography (flash gel, 90%
EtOAc/hexanes) afforded pure ketone 10a (120 mg, 0.431
mmol, 37%): 1H NMR (400 MHz, CDCl3) δ 5.80 (d, J ) 2.0
Hz, 1 H), 3.48 (s, 3 H), 2.75 (m, 1 H), 2.67 (m, 2 H), 2.47-2.30
(m, 4 H), 1.96-1.49 (m, 9 H), 1.25-1.13 (m, 1 H); 13C NMR
(100 MHz, CDCl3) δ 207.6, 140.4, 127.0 (q, J C-F ) 276 Hz),
118.8, 59.1, 40.7, 35.0 (q, J C-F ) 2.2 Hz), 32.3, 31.7, 28.2, 27.9
(q, J C-F ) 29.8 Hz), 26.4, 25.2, 21.6; IR (CHCl3) 2929, 2855,
1720, 1678, 1442, 1307, 1255, 1237, 1127, 1104 cm-1; LRMS
(EI, rel intensity) 278 (M+, 9), 138 (100), 125 (44), 123 (12), 93
(10); HRMS (EI) m/z calcd for C14H21O2F3 (M+) 278.1494, found
278.1499.
4â-Met h yl-3-p h en yl-12r-m et h oxyt r ioxa n e 12. To a
freshly prepared solution of LDA (2.96 mmol) in THF/hexane
(3.5 mL/2.5 mL) at -78 °C was added a precooled solution of
(Z)-methoxyethylidene-2-(2′-cyanoethyl)cyclohexanone16,29 (483
mg, 2.69 mmol) in THF (20 mL). After 5 min of stirring at
-78 °C for 5 min, the reaction mixture was warmed to room
temperature and stirred for 15 min. This bright yellow enolate
solution was cooled to -78 °C, and methyl iodide (0.17 mL,
2.8 mmol) was added dropwise via syringe. After the addition,
the mixture was stirred at -78 °C for 1 h, warmed to room
temperature over 1 h, and stirred at room temperature for 2
h. The reaction was cooled to 0 °C and quenched by addition
of H2O (5 mL). The resulting mixture was diluted with H2O
(50 mL) and ether (50 mL). The organic phase was separated,
and the aqueous phase was extracted with ether (50 mL × 2).
The organic portions were combined, washed with saturated
aqueous NaCl, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. This crude product was
purified by column chromatography (short path, 1% f 5%
EtOAc/hexane) to give the desired alkylated nitriles (472 mg,
2.44 mmol, 91%), a 1:1 diastereomeric mixture, as a pale yellow
oil: 1H NMR (400 MHz, CDCl3) δ 5.84 (m, 2 H), 3.53 (s, 3 H),
3.51 (s, 3 H), 3.08 (m, 1 H), 2.96 (m, 1 H), 2.50 (m, 2 H), 2.10
(ddd, J ) 13.6, 11.2, 5.2 Hz, 1 H), 2.00-1.80 (m, 4 H), 1.74
(m, 3 H), 1.63-1.50 (m, 7 H), 1.45 (m, 3 H), 1.32 (d, J ) 2.8
Hz, 3 H), 1.30 (d, J ) 3.2 Hz, 3 H), 1.22 (m, 2 H); 13C NMR
(100 MHz, CDCl3) δ 141.1, 141.0, 124.0, 123.5, 117.4, 117.1,
59.09, 59.08, 36.7, 35.4, 31.7, 31.4, 31.2, 30.1, 28.07, 28.06, 26.4,
26.2, 23.9, 22.8, 21.8, 21.4, 18.6, 17.3; IR (neat) 3057, 2930,
2854, 2238, 1677, 1449, 1240, 1129, 839 cm-1; LRMS (EI, rel
intensity) 193 (M+, 11), 125 (100), 93 (24), 45 (12); HRMS (EI)
m/z calcd for C12H19NO (M+) 193.1467, found 193.1469.
To a solution of these 4-methylated nitriles (100 mg, 0.517
mmol) in ether (4.5 mL) at -78 °C was added via syringe a
solution of phenyllithium (1.8 M in 70% cyclohexane/ether,
0.86 mL, 2.6 mmol). This dark brown solution was stirred at
-78 °C for 15 min, then warmed to room temperature, and
stirred for 3 h. At that time, the reaction was cooled to 0 ° C
and quenched by dropwise addition of H2O (1 mL). The
resulting mixture was diluted with H2O (20 mL) and ether
(20 mL). The organic phase was separated, and the aqueous
phase was extracted with ether (20 mL × 2). The organic
portions were combined, washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. This crude product was purified by column
chromatography (short path, 1% f 10% EtOAc/hexane) to give
the desired ketones (138 mg, 0.507 mmol, 98%), a 2:1 diaster-
eomeric mixture, as a yellow oil: italics in NMR data indicate
minor isomer where discernible, 1H NMR (400 MHz, CDCl3) δ
7.97 (m, 2 H), 7.92 (m, 2 H), 7.53 (m, 3 H), 7.44 (m, 3 H), 5.69
(m, 2 H), 3.41 (m, 1 H) overlapping 3.37 (s, 3 H), 3.02 (m, 1 H)
overlapping 3.01 (s, 3 H), 2.83 (m, 1 H), 2.29 (ddd, J ) 13.6,
12.4, 5.2 Hz, 1 H), 2.03-1.90 (m, 3 H), 1.83-1.69 (m, 5 H),
1.63 (m, 2 H), 1.55-1.42 (m, 8 H), 1.27-1.12 (m, 2 H)
overlapping 1.22 (d, J ) 6.8 Hz, 3 H) and 1.17 (d, J ) 6.8 Hz,
3 H); 13C NMR (100 MHz, CDCl3) δ 204.2, 204.1, 140.9, 140.0,
136.9, 136.7, 132.4, 132.3, 128.4, 128.28, 128.27, 128.2, 118.9,
3-(Tr iflu or op r op yl)tr ioxa n e 6a . Trifluoropropyl ketone
10a (106 mg, 0.381 mmol) was treated according to general
procedure 3a (irradiation for 2 h). The crude reaction mixture
was purified by column chromatography (flash gel, 10% EtOAc/
hexanes) to give C12â-methoxytrioxane 6a (36 mg, 0.116 mmol,
30%).
Further purification of trioxane 6a by HPLC (silica, 0.6%
i-PrOH/hexanes, 3.0 mL/min, 235 nm, tR ) 5.4 min) afforded
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.90 (s, 1 H), 3.52
(s, 3 H), 2.38-2.14 (m, 3 H), 2.00 (ddd, J ) 14.4, 4.4, 3.2 Hz,
1 H), 1.93 (apparent dt, J d ) 10.8 Hz, J t ) 6.4 Hz, 1 H), 1.84
(m, 2 H), 1.70-1.53 (m, 8 H), 1.28-1.13 (m, 2 H); 13C NMR
(100 MHz, CDCl3) δ 127.0 (q, J C-F ) 274 Hz), 104.8 (q, J C-F
)
3.1 Hz),104.3, 83.8, 57.1, 47.4, 36.9, 35.5, 32.1 (q, J C-F ) 2.3
Hz), 30.8, 27.7 (q, J C-F ) 29.6 Hz), 26.5, 25.0, 23.7; IR (CHCl3)
2931, 2863, 1449, 1396, 1324, 1256, 1208, 1110, 1004, 968
cm-1; LRMS (CI, NH3, rel intensity) 328 (M + NH4+, 100), 311
(M + H+, 63), 293 (27), 279 (27), 278 (M+ - O2, 6), 268 (71),
251 (92), 138 (13), 118 (22), 100 (37); HRMS (CI, NH3) m/z
calcd for C14H22O4F3 (M + H+) 311.1470, found 311.1476.

950 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Posner et al.
(3) Peters, W. Chemotherapy and Drug Resistance in Malaria, 2nd
ed.; Academic Press: London, 1987.
118.7, 59.0, 58.4, 39.1, 38.6, 35.7, 34.5, 32.4, 31.7, 31.4, 30.9,
28.4, 26.54, 26.48, 21.63, 21.61, 19.2, 17.2; IR (neat) 3060, 2927,
2852, 1682 (2 peaks overlapping), 1579, 1448, 1205, 1128, 703
cm-1; LRMS (EI, rel intensity) 272 (M+, 2), 138 (100), 123 (16),
105 (23), 77 (28); HRMS (EI) m/z calcd for C18H24O2 (M+)
272.1776, found 272.1779.
(4) Hien, T. T.; White, N. J . Qinghaosu. Lancet 1993, 341, 603-
608.
(5) Klayman, D. L. Qinghaosu (Artemisinin): an Antimalarial Drug
from China. Science 1985, 228, 1049-1055.
(6) Zhou, W. S.; Xu, X. X. Total Synthesis of the Antimalarial
Sesquiterpene Peroxide Qinghaosu and Yingzhaosu A. Acc.
Chem. Res. 1994, 27, 211-216.
This mixture of 4-methylated 3-phenyl ketones (100 mg,
0.367 mmol) was treated according to general procedure 3a.
The crude reaction mixture was purified by column chroma-
tography (Florisil, 1% f 20% EtOAc/hexanes) to give 4â-
methyltrioxane 12 (23 mg, 0.076 mmol, 21%). Further puri-
fication of of this material by HPLC (silica, 3% EtOAc/hexanes,
2.0 mL/min, 254 nm, tR ) 26.1 min) afforded a white solid:
(7) J ung, M. Current Developments in the Chemistry of Artemisinin
and Related Compounds. Curr. Med. Chem. 1994, 1, 46-60.
(8) For a recent pharmacokinetic study of artemisinin used to treat
patients with malaria, see: De Vries, P. J .; Dien, T. K.; Khanh,
N. X.; Binh, L. N.; Yen, P. T.; Duc, D. D.; C. J ., V. B.; Kager, P.
A. The Pharmacokinetics of a Single Dose of Artemisinin in
Patients with Uncomplicated Falciparum Malaria. Am. J . Trop.
Med. Hyg. 1997, 56, 503-507.
(9) For a leading reference, see: Avery, M. A.; Fan, P.; Karle, J .
M.; Bonk, J . D.; Miller, R.; Goins, D. K. Structure-Activity
Relationships of the Antimalarial Agent Artemisinin. 3. Total
Synthesis of (+)-13-Carbaartemisinin and Related Tetra- and
Tricyclic Structures. J . Med. Chem. 1996, 39, 1885-1897.
(10) Meshnick, S. R.; Taylor, T. E.; Kamchonwongpaisan, S. Arte-
misinin and the Antimalarial Endoperoxides: from Herbal
Remedy to Targeted Chemotherapy. Microbiol. Rev. 1996, 60,
301-315.
1
mp ) 105.0-106.0 °C; H NMR (400 MHz, CDCl3) δ 7.46 (m,
2 H), 7.31 (m, 3 H), 5.14 (s, 1 H), 3.52 (s, 3 H), 7.85 (m, 1 H),
2.41 (m, 1 H), 1.83 (m, 2 H), 1.73 (m, 3 H), 1.40 (m, 1 H), 1.30-
1.13 (m, 4 H), 0.48 (d, J ) 7.2 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 139.1, 128.3, 127.8, 125.7, 106.6, 95.5, 82.9, 55.7, 44.5,
40.0, 37.6, 33.3, 32.5, 25.3, 23.1, 21.2; IR (CHCl3) 3032, 3012,
2933, 2861, 1450, 1262, 1094, 1010, 700 cm-1; LRMS (CI, NH3,
rel intensity) 322 (M + NH4+, 25), 305 (M + H+, 100), 245
(96), 168 (28), 138 (58), 105 (44); HRMS (CI, NH3) m/z calcd
for C18H25O4 (M + H+) 305.1753, found 305.1758.
F or m a tion of Ar yl Keton e 13 by Ir on -In d u ced Degr a -
d a tion of 5l. To a stirred suspension of iron(II) bromide (0.10
g, 0.46 mmol) in THF (3 mL) at 0 °C was added a 0 °C solution
of 5l (0.20 g, 0.65 mmol) in THF (3.5 mL) via cannula. The
reaction was stirred at 0 °C for 45 min and then slowly warmed
to room temperature. When TLC indicated that all starting
material was consumed (about 1 h), the reaction was quenched
with H2O (3 mL) and diluted with CHCl3 (15 mL). The two
layers were separated, and the aqueous was extracted with
CHCl3 (15 mL × 2). The combined organic phases were
washed with brine (30 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure to give a crude mixture
of products.28 Separation by column chromatography (Florisil,
1% f 30% EtOAc/hexanes) afforded impure 13 that was
combined with another portion of impure 13 from a second
degradation of 5l (0.15 g, 0.49 mmol). Column chromatogra-
phy of this combined sample (Florisil, 1% f 30% EtOAc/
hexanes) provided aryl ketone 13 (7.5 mg, 0.024 mmol, 2% for
both degradations). Further purification of this material by
(11) Cumming, J . N.; Ploypradith, P.; Posner, G. H. Antimalarial
Activity of Artemisinin (Qinghaosu) and Related Trioxanes:
Mechanism(s) of Action. Adv. Pharmacol. 1997, 37, 2253-297.
(12) For the first report on the importance of iron in triggering the
cytotoxic effects of trioxanes, see: Meshnick, S. R.; Thomas, A.;
Ranz, A.; Xu, C. M.; Pan, H. P. Artemisinin (Qinghaosu): the
Role of Intracellular Hemin in its Mechanism of Antimalarial
Action. Mol. Biochem. Parasitol. 1991, 49, 181-190.
(13) Posner, G. H.; Cumming, J . N.; Ploypradith, P.; Oh, C. H.
Evidence for Fe(IV)dO in the Molecular Mechanism of Action
of the Trioxane Antimalarial Artemisinin. J . Am. Chem. Soc.
1995, 117, 5885-5886.
(14) Imlay, J . A.; S. M., C.; Linn, S. Toxic DNA Damage by Hydrogen
Peroxide Through the Fenton Reaction in Vivo and in Vitro.
Science 1988, 240, 640-642.
(15) Robert, A.; Meunier, B. Characterization of the First Covalent
Adduct between Artemisinin and a Heme Model. J . Am. Chem.
Soc. 1997, 119, 5968-5969.
(16) J efford, C. W.; Velarde, J . A.; Bernardinelli, G.; Bray, D. H.;
Warhurst, D. C.; Milhous, W. K. 198. Synthesis, Structure, and
Antimalarial Activity of Tricyclic 1,2,4-Trioxanes Related to
Artemisinin. Helv. Chim. Acta 1993, 76, 2775-2788.
(17) Chemistry of Organic Fluorine Compounds. II. A Critical Review;
Hudlicky, M., Pavlath, A. E., Eds.; American Chemical Society
Monograph 187; American Chemical Society: Washington, DC,
1995.
(18) Avery, M. A.; Mehrotra, S.; Bonk, J . D.; Vroman, J . A.; Goins,
D. K.; Miller, R. Structure-Activity Relationships of the Anti-
malarial Agent Artemisinin. 4. Effect of Substitution at C-3. J .
Med. Chem. 1996, 39, 2900-2906.
(19) Posner, G. H.; Park, S. B.; Gonza´lez, L.; Wang, D.; Cumming, J .
N.; Klinedinst, D.; Shapiro, T. A.; Bachi, M. D. Evidence for the
Importance of High-Valent FedO and of a Diketone in the
Molecular Mechanism of Action of Antimalarial Trioxane Ana-
logues of Artemisinin. J . Am. Chem. Soc. 1996, 118, 3537-3538.
(20) Pu, Y. M.; Torok, D. S.; Ziffer, H. Synthesis and Antimalarial
Activities of Several Fluorinated Artemisinin Derivatives. J .
Med. Chem. 1995, 38, 4120-4124.
(21) Oh, C. H.; Wang, D.; Cumming, J . N.; Posner, G. H. Antimalarial
1,2,4-Trioxanes Related to Artemisinin: Rules for Assignment
of Relative Stereochemistry in Diversely Substituted Analogues.
Spectrosc. Lett. 1997, 30, 241-255.
HPLC (silica, 10% i-PrOH/hexanes, 3.0 mL/min, 245 nm, tR
)
10.8 min) afforded a white solid: mp ) 79.5-80.5 °C; 1H NMR
(400 MHz, CDCl3) δ 8.02 (m, 2 H), 7.15 (m, 2 H), 5.16 (dd, J )
11.6, 2.8 Hz, 1 H), 4.38 (s, 1 H), 3.52 (s, 3 H), 2.23 (d, J ) 2.0
Hz, 1 H), 2.10-2.00 (m, 4 H), 1.68 (m, 2 H), 1.45-1.39 (m, 5
H); 13C NMR (100 MHz, CDCl3) δ 196.1, 165.8 (d, J C-F ) 253
Hz), 131.5 (d, J C-F ) 3.7 Hz), 131.4 (d, J C-F ) 9.1 Hz), 115.8
(d, J C-F ) 22.0 Hz), 104.8, 71.2, 69.8, 56.4, 36.0, 30.9, 29.1,
26.1, 21.0, 20.1; IR (CHCl3) 3568, 3016, 2938, 2867, 1694, 1599,
+
1234, 1218, 758; LRMS (CI, NH3, rel intensity) 326 (M + NH4
,
7), 309 (M + H+, 6), 291 (4), 277 (100); HRMS (CI, NH3) m/z
calcd for C17H22O4F (M + H+) 309.1502, found 309.1506.
Ack n ow led gm en t. We thank the NIH (AI-34885
and NCRR OPD-GCRC RR00722) and the Burroughs
Wellcome Fund for financial support and Professor
Wallace Peters and Mr. Brian Robinson for the in vivo
antimalarial results reported here. We thank also the
NIAID contract services for the preliminary in vivo
acute toxicity experiments.
(22) Posner, G. H.; Gonza´lez, L.; Cumming, J . N.; Klinedinst, D.;
Shapiro, T. A. Synthesis and Antimalarial Activity of Heteroa-
tom-Containing Bicyclic Endoperoxides. Tetrahedron 1997, 53,
37-50.
(23) Ponnudurai, T.; Leeuwenberg, A. D. E. M.; Meuwissen, J . H. E.
T. Chloroquine Sensitivity of Isolates of Plasmodium falciparum
Adapted to In Vitro Culture. Trop. Geogr. Med. 1981, 33, 50-
54.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR,
IR, and mass spectral data for those compounds for which such
spectroscopic characterization is not provided in the experi-
mental section of this paper (11 pages). Ordering information
is given on any current masthead page.
(24) We thank Dr. Alexandra Fairfield, NIH Division of AIDS,
Therapeutic Research Program, for arranging these studies in
L929 cells.
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