Ground state oxygen in synthesis of cyclic peroxides. Part 1: Benzo fused ketals

Article abstract of DOI:10.1016/j.tet.2006.02.008

A thiol-olefin-cooxygenation (TOCO) radical chain reaction involving ground state molecular oxygen converts 2′-isopropenyl acetophenones directly into cyclic peroxy hemiketal products with three new bonds. Starting with 4-t-butylbenzenethiol, this TOCO pr

Full text of DOI:10.1016/j.tet.2006.02.008

Tetrahedron 62 (2006) 4120–4127
Ground state oxygen in synthesis of cyclic peroxides. Part 1: Benzo
fused ketals
Junwon Kim,a Hong Bin Li,a Andrew S. Rosenthal,a Dongpei Sang,b Theresa A. Shapiro,b,c
Mario D. Bachid and Gary H. Posnera,c,
*
aDepartment of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA
bDivision of Clinical Pharmacology, Department of Medicine, School of Medicine, The Johns Hopkins University,
Baltimore, MD 21205, USA
cBloomberg School of Public Health, Johns Hopkins Malaria Research Institute, Baltimore, MD 21205, USA
dDepartment of Organic Chemistry, The Weizmann Institute of Research, Rehovot 76100, Israel
Received 15 November 2005; revised 30 January 2006; accepted 2 February 2006
Available online 3 March 2006
Abstract—A thiol-olefin-cooxygenation (TOCO) radical chain reaction involving ground state molecular oxygen converts 20-isopropenyl
acetophenones directly into cyclic peroxy hemiketal products with three new bonds. Starting with 4-t-butylbenzenethiol, this TOCO process
proceeds reproducibly on gram scale in 86% yield. Hemiketal/ketal and sulfide/sulfone transformations finally provide a series of
sulfonyl cyclic peroxy ketals. The in vitro antimalarial activities of some of these structurally simple benzo-fused cyclic peroxides are
reported.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
limonene (2) into some antimalarially potent sulfonyl
endoperoxides (Scheme 1 and Fig. 1).7,8
Among the methods for preparing dialkyl peroxides such as
1,2-dioxetanes and antimalarial 1,2,4-trioxanes, dioxygena-
tion using photochemically-generated singlet molecular
oxygen is the most popular.1–3 Unfortunately, however,
preparation of multigram amounts of antimalarial trioxanes
is not practical using singlet molecular oxygen due to the
short lifetime and high reactivity of this high energy species.
Thus, even though our research program of antimalarial
trioxane drug development successfully identified two safe,
efficacious, and structurally simple antimalarial trioxanes,
scale-up synthesis was unsuccessful.4,5 As part of a general
program eventually to synthesize trioxanes using ground
state molecular oxygen, we report here non-singlet (i.e.,
triplet, ground state) molecular oxygen synthesis of simple
benzo-fused cyclic peroxy ketals. This research builds on
our previous report about some potent antimalarial cyclic
peroxy ketals (e.g., sulfone 1 with IC50Z31 nM)6 and on the
recent successful application of thiol-olefin-cooxygenation
(TOCO) chemistry for rapid and efficient conversion of
2. Results and discussion
Starting with commercial 20-bromoacetophenone, Wittig
methylenation, lithium–bromide exchange, addition to
acetaldehyde, and oxidation produced 20-isopropenyl aceto-
phenone (5) in high yield (Scheme 2). Using a balloon filled
with molecular oxygen and a short irradiation time, as
recently described in a modified TOCO protocol,9 TOCO
chemistry produced the benzo-fused cyclic peroxy hemi-
ketal 7 in 57% yield asa 9:5 ratio ofdiastereomers (Scheme 2).
The high yield of this TOCO process is due in large part to the
ease with which the benzenethiolate radical adds to the
isopropenyl group to generate a tertiary benzylic carbon-
centered radical; this relatively stable radical reacts with
ground-state molecular oxygen to form a peroxy radical,
which can abstract a hydrogen atom from benzenethiol,
thereby propagating this radical chain reaction. The putative
intermediate hydroperoxy ketone 6 is not observed, but it
presumablyrapidlycyclizesintotheisolatedperoxyhemiketal
product 7.
Keywords: Endoperoxides; Molecular oxygen; Radical oxygenation;
Malaria.
*
Corresponding author. Address: Department of Chemistry, The Johns
Hopkins University, Baltimore, MD 21218, USA. Tel.: C1 410 516
4670; fax: C1 410 516 8420; e-mail: ghp@jhu.edu
Based on our previous finding that cyclic peroxy hemiketals
have considerably less antimalarial potency than the
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.008

J. Kim et al. / Tetrahedron 62 (2006) 4120–4127
4121
Scheme 1. Thiol olefin cooxygenation (TOCO) followed by sulfide oxidation.
trans-oriented. Dissolved in 40:60 DMSO/H2O buffered at
pH 7.4, sulfone 9 was stable; after 4 days at 25 8C, less than
1% decomposition was determined by calibrated HPLC
analysis. Finally, with the intention of further diminishing
any possible hydrolysis of the peroxy ketal functionality
under physiological (pH 7.4) conditions, the methoxy group
was replaced by a less basic (i.e., less easily protonated)
trifluoroethoxy group in the form of ketal sulfone 10
(Scheme 2). In this way, a series of commercial
benzenethiols led to the series of benzo-fused cyclic peroxy
ketals shown in Table 1. The most outstanding chemical
result in this series is that 4-t-butylbenzenethiol, a
mercaptan having almost no unpleasant odor, achieves the
3-bond-forming TOCO process in 86% yield even on gram
scale.
Figure 1.
corresponding ketals,6 hemiketal 7 was converted directly
into ketal 8 (Scheme 2). Based also on the previous finding
that sulfanyl endoperoxides have considerably less anti-
malarial potency than the corresponding sulfonyl endoper-
oxides,8 the major diastereomer of sulfide 8 was oxidized
into sulfone 9. Confirmation of the relative stereochemistry
of crystalline sulfone 9 by X-ray crystallography revealed
that the two methyl groups on the 1,2-dioxin ring are
Scheme 2. Synthesis of ketal endoperoxides via the TOCO process. Yields and ratios are for ArZPh.

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J. Kim et al. / Tetrahedron 62 (2006) 4120–4127
Table 1. Benzo fused ketal analogs via the TOCO process
Entry
HS-Ar
Yield (%)
80 majorC800 minor
100 majorC1000 minor
7
9
a
57% (1.8:1)
76% (9:1)
93
83
76% (5:1)a
b
60% (2:1)
76% (2.7:1)
74% (5:1)
c
d
e
86% (1.4:1)
71% (2.8:1)
72% (1.5:1)
89% (6:1)
97
89
94
65% (5:1)
90% (5:1)
91% (6:1)
84% (3.4:1)
83% (2.4:1)
a Inseparable mixture by HPLC.
The in vitro antimalarial potencies of several of these
sulfonyl cyclic peroxy ketals was determined using our
standard protocol10 and are shown in Table 2.
the methoxy is cis to the sulfonyl was only weakly active
as an antimalarial.
To encumber the ketal region and thus to retard possible
hydrolysis of the peroxy ketal functionality under
physiological conditions, a sterically hindered version
carrying a tertiary butyl group was prepared in good
yield as a 1:1 mixture of diastereomers (Scheme 3). The
sulfonyl t-butyl peroxy ketal 12 diastereomer where
3. Conclusions
In conclusion, TOCO radical chain reactions using ground
state molecular oxygen lead, in good yield, to a series of
benzo-fused cyclic peroxy ketals. These reactions are easily
scaled up to multigram quantities of products. The relatively
Table 2. Antimalarial activity against Plasmodium falciparum (NF54)
Ar
R
IC50 (nM)a
540
4-t-BuPh
4-BrPh
Me
Me
820
Phb
CF3CH2
480
Artemisinin
7.9G0.87
a The standard deviation for each set of quadruplicates was an average of 8.0% (%16%) of the mean. R2 values for the fitted curves were R0.983. Artemisinin
activity is the meanGstandard deviation of the concurrent control (nZ3).
b Mixture of isomers.
Scheme 3. Synthesis of a hindered ketal endoperoxide via the TOCO process.

J. Kim et al. / Tetrahedron 62 (2006) 4120–4127
4123
weak in vitro antimalarial activities of these cyclic peroxy
ketals, however, make them unpromising for chemotherapy
of malaria.
dichromate (PDC, 5.54 g, 14.7 mmol) and Celitew (5.50 g)
at 25 8C under argon atmosphere. After being stirred for
2 days, the reaction mixture was diluted with EtOAc and
filtered through a pad of silica gel. The filtrate was
concentrated in vacuo and then purified by flash column
chromatography (10% EtOAc in petroleum ether) to give
ketone 4 (1.11 g, 94%) as a colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.47 (ddd, JZ7.6, 1.2, 0.4 Hz, 1H),
7.39 (td, JZ7.6, 1.6 Hz, 1H), 7.29 (td, JZ7.6, 1.2 Hz, 1H),
7.25 (dd, JZ7.6, 1.2 Hz, 1H), 5.16–5.15 (m, 1H), 4.88 (m,
1H), 2.47 (m, 3H), 2.11 (m, 3H); 13C NMR (100 MHz,
CDCl3) d 203.6, 145.1, 142.5, 139.3, 130.6, 128.4, 127.8,
127.1, 116.2, 29.9, 23.9; IR (neat, film) 3062, 2973, 2918,
2855, 1691, 1635, 1595, 1441, 1355, 1275, 1243, 956, 904,
770, 758 cmK1; TLC Rf (hexane/Et2O)Z0.80; HRMS (EI)
m/z calcd for C11H12O (M)C160.0883, found 160.0888.
4. Experimental
4.1. General
4.1.1. 1-Bromo-2-isopropenyl-benzene 3. To a suspension
of methyltriphenylphosphonium bromide (8.57 g,
24.0 mmol) in THF (60 mL) at room temperature was
added a solution of potassium tert-butoxide (1.0 M in THF,
24.0 mL, 24.0 mmol). After being stirred for 5 min, the
reaction mixture was treated with a solution of 20-
bromoacetophenone (3.98 g, 20 mmol) in THF (40 mL)
via cannula. The reaction mixture was stirred for 3 h at room
temperature before it was quenched with the addition of
saturated aqueous ammonium chloride (40 mL). The
organic layer was separated, and the aqueous layer was
extracted with diethyl ether (3!40 mL). The combined
organic layers were washed with water and brine, dried over
MgSO4, filtered and concentrated in vacuo. The residue was
purified via flash column chromatography (100% hexanes)
to give 1-bromo-2-isopropenyl-benzene (3.78 g, 96% yield)
4.1.4. Hemiketal 7c. To a solution of ketone 5 (2.12 g,
13.2 mmol) in acetonitrile (220 mL) under argon was added
2,20-azobisisobutyronitrile (AIBN, 152 mg, 0.926 mmol)
and 4-tert-butylthiophenol (2.85 mL, 16.5 mmol). The
reaction vessel was flushed with oxygen for 10 min at
0 8C and then kept under a positive pressure of oxygen with
two balloons. The reaction mixture was stirred vigorously
and irradiated using a mercury UV lamp (450 W, Ace Glass)
at a distance of 10 cm at 0 8C. After 2 h, the reaction was
flushed with argon and then concentrated in vacuo. The
crude product was then purified by flash silica gel column
chromatography (10% EtOAc in hexanes) to yield hemi-
ketal 7c (4.06 g, 11.3 mmol, 86%) as a yellow oil as a
mixture of two diastereomers. 1H NMR (400 MHz, CDCl3)
d 7.46–7.44 (m, 1H), 7.33–7.26 (m, 7H), 3.78 (s, 1H), 3.70
(d, JZ13.6 Hz, 1H), 3.39 (d, JZ13.6 Hz, 1H), 1.69 (s, 3H),
1.60 (s, 3H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) d
149.3, 137.7, 135.3, 133.4, 129.6, 128.1, 127.6, 125.8,
125.8, 124.7, 99.2, 81.9, 43.4, 34.3, 31.2, 23.8, 22.4; IR
(CH2Cl2, film) 3415, 2962, 2862, 1492, 1444, 1364, 1148,
1120, 935, 892, 824, 764 cmK1; HRMS (EI) m/z calcd for
C21H26O3SNa (MCNa)C381.14948, found 381.14871.
1
as a colorless oil: H NMR (400 MHz, CDCl3) d 7.55 (dd,
JZ8.0, 1.2 Hz, 1H), 7.26 (dt, JZ7.2, 1.2 Hz, 1H), 7.19 (dd,
JZ7.6, 2.0 Hz, 1H), 7.13–7.09 (m, 1H), 5.24–5.22 (m, 1H),
4.94–4.93 (m, 1H), 2.10–2.09 (m, 3H); 13C NMR
(100 MHz, CDCl3) d 145.8, 144.8, 132.7, 129.7, 128.3,
127.2, 121.5, 116.0, 23.5; IR (CH2Cl2, film) 3081, 3053,
2970, 1917, 1805, 1641, 1469, 1433, 1371, 1025, 903, 758,
653 cmK1; TLC Rf (hexane)Z0.83; HRMS (CI) m/z calcd
for C9H9Br (M)C195.9888, found 195.9876.
4.1.2. Alcohol 4. To a solution of 1-bromo-2-isopropenyl-
benzene (1.97 g, 10 mmol) in THF (15 mL) at K78 8C, was
added a solution of n-BuLi (1.6 M in hexanes, 7.5 mL,
12 mmol). After being stirred for 30 min at K78 8C,
acetaldehyde (0.84 mL, 15 mmol) was added neat. The
reaction mixture was stirred at K78 8C for 30 min then at
room temperature for 1 h before it was quenched with the
addition of saturated aqueous ammonium chloride (25 mL).
The organic layer was separated, and the aqueous layer was
extracted with Et2O (3!40 mL). The combined organic
layers were washed with water and brine, dried over
MgSO4, filtered and concentrated in vacuo. The residue was
purified via flash column chromatography (20% ethyl
acetate in hexanes) to give alcohol (1.55 g, 96% yield) as
a colorless oil: 1H NMR (400 MHz, CDCl3) d 7.49 (ddd, JZ
7.6, 1.2, 0.4 Hz, 1H), 7.41 (td, JZ7.6, 1.6 Hz, 1H), 7.31 (td,
JZ7.6, 1.6 Hz, 1H), 7.27 (ddd, JZ7.6, 1.2, 0.4 Hz, 1H),
5.25–5.22 (m, 1H), 5.18 (quint, JZ1.6 Hz, 1H), 4.90 (m,
1H), 2.10 (br s, 1H), 2.09–2.07 (m, 3H), 1.49–1.45 (m, 3H);
13C NMR (100 MHz, CDCl3) d 144.9, 142.3, 142.0, 127.9,
127.4, 127.1, 125.2, 115.5, 66.6, 25.6, 25.0; IR (CH2Cl2,
film) 3746, 3076, 2971, 2929, 1640, 1486, 1445, 1434,
1372, 1299, 1196, 1073, 1004, 900, 759 cmK1; TLC Rf
(hexane/Et2O 2:1)Z0.64; HRMS (EI) m/z calcd for
C11H14O (M)C162.1039, found 162.1098.
4.1.5. Ketone 11. Ketone 11 was synthesized as above with
substitution of trimethylacetaldehyde in place of acet-
aldehyde. After three steps from 20-bromoacetophenone,
ketone 11 was isolated as a colorless oil (104 mg,
0.512 mmol, 36% from alcohol). 1H NMR (400 MHz,
CDCl3) d 7.37–7.26 (m, 3H), 7.11 (d, JZ7.2 Hz, 1H),
5.17 (m, 1H), 4.97 (s, 1H), 2.14 (s, 3H), 1.21 (s, 9H);
13C NMR (100 MHz, CDCl3) d 216.0, 144.4, 139.9, 135.8,
128.4, 127.3, 126.5, 125.7, 117.6, 78.6, 27.7, 24.1; IR
(CH2Cl2, film) 3488.6, 3061.9, 2968.8, 2870.0, 1987.1,
1633.4, 1478.5, 1460.0, 1392.0, 1363.6, 1278.6, 1259.5,
1191.1, 1173.0, 1035.9, 768.0, 734.4 cmK1; HRMS
(FAB-MS) m/z calcd for C14H18O (MCH)C203.14359,
found 203.14416.
4.2. General procedure for the TOCO process
A solution of ketone (1.0 mmol), 2,20-azobisisobutyronitrile
(AIBN, 0.07 mmol) and thiophenol (1.25 mmol) in aceto-
nitrile (17 mL) was thoroughly flushed with oxygen for
10 min at 0 8C and then kept under a positive pressure of
pure oxygen with the aid of two oxygen balloons. The
reaction mixture was stirred vigorously and UV irradiated at
4.1.3. Ketone 5. To a solution of alcohol 4 (1.19 g,
7.36 mmol) in CH2Cl2 (25 mL) was added pyridinium

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J. Kim et al. / Tetrahedron 62 (2006) 4120–4127
1
4.5.1.2. Compound 9a. White solid: mp 97–98 8C; H
0 8C using an externally mounted medium-pressure mercury
lamp (450 W, Ace Glass) at a distance of 15 cm. After 2 h at
0 8C, the reaction mixture was concentrated in vacuo and the
residue was subjected to flash column chromatography to
give corresponding hemiketals.
NMR (400 MHz, CDCl3) d 7.94 (dm, JZ7.6 Hz, 2H), 7.62
(tt, JZ7.6, 1.6 Hz, 1H),7.53 (tm, JZ7.6 Hz, 2H), 7.34–7.29
(m, 4H), 3.95 (d, JZ14.8 Hz, 1H), 3.58 (d, JZ14.8 Hz,
1H), 3.30 (s, 3H), 1.87 (s, 3H), 1.44 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 140.7, 137.5, 133.5, 133.5, 128.9,
128.5, 128.1, 125.9, 124.5, 101.5, 79.7, 61.9, 51.2, 22.5,
22.1; IR (CDCl3, film) 3066, 2996, 2940, 1448, 1375, 1308,
1147, 1085, 1043, 876, 761, 688 cmK1; HRMS (ESI) m/z
calcd for C18H20O5SNa (MCNa)C371.0924, found
371.0909.
4.3. General procedure for the methylation of the alcohol
To a solution of the above hemiketals (0.15 mmol) in
MeOH (3 mL) was added p-toluenesulfonic acid mono-
hydrate (0.015 mmol) at 25 8C. After being stirred for 24 h
at 25 8C, the reaction mixture was concentrated in vacuo and
the residue was subjected to flash column chromatography
to give the corresponding methoxy ketal sulfides.
4.5.1.3. Compound 100a. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.94–7.89 (m, 2H), 7.64 (tt, JZ7.6,
1.2 Hz, 1H), 7.56–7.51 (m, 2H), 7.42–7.33 (m, 4H), 3.66
(dq, JZ12.0, 8.4 Hz, 1H), 3.91 (d, JZ14.8 Hz, 1H), 4.02
(dq, JZ11.6, 8.8 Hz, 1H), 3.58 (d, JZ14.8 Hz, 1H),, 1.90
(s, 3H), 1.51 (s, 3H); 13C NMR (100 MHz, CDCl3) d 140.6,
137.9, 133.6, 131.4, 129.2, 129.0, 128.6, 128.1, 126.1,
124.6, 123.6 (q, JZ276 Hz), 102.0, 80.0, 62.4 (q, JZ
35 Hz), 61.6, 23.6, 22.5; IR (neat, film) 3067, 2996, 2942,
2835, 1586, 1448, 1378, 1321, 1286, 1151, 1085, 968, 902,
764, 688 cmK1; HRMS (ESI) m/z calcd for C19H19F3O5SNa
(MCNa)C439.0797, found 439.0808.
4.4. General procedure for oxidation of methoxy ketal
sulfides to methoxy ketal sulfones
To a solution of methoxy ketal sulfide (0.15 mmol) in
CH2Cl2 (6 mL), was added 3-chloroperoxybenzoic acid (m-
CPBA, 77% max, 0.36 mmol) and sodium bicarbonate
(0.86 mmol). After being stirred for 4 h at 25 8C, the
reaction was quenched by the addition of water and
extracted with CH2Cl2 (3!10 mL). The combined organic
layers were washed with water and brine, dried over
MgSO4. After filtration and concentration in vacuo, the
residue was purified via flash column chromatography (25%
ethyl acetate in hexanes). The products were further purified
using normal-phase high-performance liquid chromatog-
raphy (HPLC) prior to antimalarial testing [semi-prepara-
tive Silica gel column (1!25 cm), 5% EtOAc in hexanes,
2.0 mL/min, 264 nm].
4.5.1.4. Compound 80b. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.39–7.26 (m, 4H), 6.95 (s, 2H),
6.78 (s, 1H), 3.51 (d, JZ13.2 Hz, 1H), 3.43 (s, 3H), 3.38 (d,
JZ13.2 Hz, 1H), 2.25 (s, 6H), 1.63 (s, 3H), 1.61 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 138.3, 138.3, 136.6, 134.0,
128.0, 127.8, 127.6, 125.8, 124.6, 101.7, 81.5, 51.2, 43.0,
22.3, 22.3, 21.1; IR (CH2Cl2, film) 2989, 2937, 1599, 1582,
1447, 1370, 1298, 1274, 1131, 1043, 896, 875, 762 cmK1
;
TLC Rf (hexane/Et2O 2:1)Z0.58; HRMS (ESI) m/z calcd
for C20H24O3SNa (MCNa)C367.1338, found 367.1328.
This product was further purified using HPLC prior to
antimalarial testing [semi-preparative Silica gel column
(1!25 cm), 10% EtOAc in hexanes, 2.0 mL/min, 264 nm,
tR Z15.3 min].
4.5. Conversion of methoxy ketal sulfones to trifluoro-
ethoxy ketal sulfones
To a solution of methoxy ketal (0.13 mmol) in trifluoro-
ethanol (3 mL) at 0 8C, was added dropwise boron
trifluoride diethyl etherate (0.066 mmol, 0.5 equiv). After
stirring for 3 h at 0 8C, the reaction mixture was warmed to
room temperature and further stirred for 1 h. The reaction
was quenched by the addition of saturated aqueous NaHCO3
(3 mL) and extracted with Et2O (3!10 mL). The combined
organic layers were washed with brine and dried over
MgSO4. After filtration and concentration in vacuo, the
residue was purified via flash column chromatography (20%
ethyl acetate in hexanes). The products were further purified
using normal-phase HPLC prior to antimalarial testing
[semi-preparative Silica gel column (1!25 cm), 5% EtOAc
in hexanes, 2.0 mL/min, 264 nm].
4.5.2. From 3,5-dimethylthiophenol.
4.5.2.1. Compound 800b. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.37–7.31 (m, 3H), 7.22–7.20 (m,
1H), 6.97 (s, 2H), 6.79 (s, 1H), 3.57 (d, JZ13.6 Hz, 1H),
3.43 (d, JZ13.6 Hz, 1H), 3.33 (s, 3H), 2.26 (s, 6H), 1.69 (s,
3H), 1.67 (s, 3H); 13C NMR (100 MHz, CDCl3) d 139.2,
138.4, 136.6, 134.4, 128.0, 128.0, 127.4, 127.3, 125.8,
124.2, 102.9, 82.1, 51.9, 43.4, 24.4, 24.2, 21.2; IR (CH2Cl2,
film) 2987, 2929, 1594, 1575, 1445, 1369, 1268, 1128,
1042, 849, 762 cmK1; TLC Rf (hexane/Et2O 2:1)Z0.64;
HRMS (ESI) m/z calcd for C20H24O3SNa (MC
Na)C367.1338, found 367.1332. This product was further
purified using HPLC prior to antimalarial testing [semi-
preparative Silica gel column (1!25 cm), 10% EtOAc in
hexanes, 2.0 mL/min, 264 nm, tRZ13.5 min].
4.5.1. From thiophenol.
4.5.1.1. Compound 80a. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.39–7.22 (m, 8H), 7.18–7.13 (m,
1H), 3.69 (d, JZ17.6 Hz, 1H), 3.43 (s, 3H), 3.38 (d, JZ
18.0 Hz, 1H), 1.61 (s, 3H), 1.60 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 138.3, 137.1, 134.0, 129.4, 128.8,
128.1, 127.6, 126.0, 125.9, 124.5, 101.8, 81.5, 51.2, 43.1,
22.3, 22.3; IR (neat, film) 3060, 2990, 2937, 2832, 1583,
1480, 1439, 1371, 1298, 1275, 1154, 1131, 1043, 875, 763,
739, 691 cmK1; HRMS (ESI) m/z calcd for C18H20O3SNa
(MCNa)C339.1025, found 339.1024.
4.5.2.2. Compound 9b. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.51–7.50 (m, 2H), 7.35–7.29 (m,
4H), 7.21–7.20 (m, 1H), 3.90 (d, JZ14.8 Hz, 1H), 3.61 (d,
JZ14.8 Hz, 1H), 3.33 (s, 3H), 2.36 (br s, 6H), 1.87 (s, 3H),
1.47 (s, 3H); 13C NMR (100 MHz, CDCl3) d 140.5, 139.0,
137.3, 135.0, 133.5, 128.3, 128.0, 125.8, 125.4, 124.7,
101.5, 79.8, 61.9, 51.2, 22.7, 22.0, 21.1; IR (CH2Cl2, film)

J. Kim et al. / Tetrahedron 62 (2006) 4120–4127
4125
2972, 2941, 2835, 1608, 1456, 1378, 1318, 1302, 1139,
1104, 1046, 878, 768, 683 cmK1; TLC Rf (hexane/Et2O
2:1)Z0.14; HRMS (ESI) m/z calcd for C20H24O5SNa (MC
Na)C399.1237, found 399.1237. This product was further
purified using HPLC prior to antimalarial testing [semi-
preparative Silica gel column (1!25 cm), 30% EtOAc in
hexanes, 3.0 mL/min, 264 nm, tRZ9.5 min].
1044, 879, 825, 762 cmK1; TLC Rf (hexane/Et2O 2:1)Z
0.72; HRMS (ESI) m/z calcd for C22H28O3SNa (MC
Na)C395.1651, found 395.1648. This product was further
purified using HPLC prior to antimalarial testing [semi-
preparative Silica gel column (1!25 cm), 5% EtOAc in
hexanes, 2.0 mL/min, 264 nm, tRZ18.4 min].
4.5.3.3. Compound 9c. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.84–7.82 (m, 2H), 7.53–7.51 (m,
2H), 7.32–7.26 (m, 4H), 3.90 (d, JZ14.8 Hz, 1H), 3.58 (d,
JZ14.8 Hz, 1H), 3.30 (s, 3H), 1.87 (s, 3H), 1.44 (s, 3H),
1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) d 157.3, 137.7,
137.4, 133.5, 128.4, 128.0, 127.9, 125.9, 125.8, 124.6,
101.5, 79.7, 61.9, 51.0, 35.2, 31.0, 22.5, 21.9; IR (CH2Cl2,
film) 2964, 1595, 1398, 1319, 1151, 1108, 1085, 1043,
762 cmK1; TLC Rf (hexane/EtOAc 2:1)Z0.63; HRMS
(ESI) m/z calcd for C22H28O5SNa (MCNa)C427.1550,
found 427.1541. This product was further purified using
HPLC prior to antimalarial testing [semi-preparative Silica
gel column (1!25 cm), 30% EtOAc in hexanes,
3.0 mL/min, 264 nm, tRZ12.9 min].
4.5.2.3. Compound 100b. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.50 (br s, 2H), 7.41–7.33 (m, 4H),
7.22 (br s, 1H), 4.06 (dq, JZ11.8, 8.4 Hz, 1H), 3.85 (d, JZ
14.8 Hz, 1H), 3.68 (dq, JZ11.8, 8.8 Hz, 1H), 3.60 (d,
JZ14.8, 8.8 Hz, 1H), 2.37 (s, 6H), 1.88 (s, 3H), 1.54 (s,
3H); 13C NMR (100 MHz, CDCl3) d 140.4, 139.1, 137.8,
135.2, 131.4, 129.0, 128.5, 126.0, 125.4, 124.9, 123.6 (q,
JZ276 Hz), 62.4 (q, JZ35 Hz), 61.6, 23.6, 22.7, 21.1; IR
(CH2Cl2, film) 2987, 2929, 1608, 1453, 1378, 1321, 1286,
1144, 1083, 967, 902, 858, 765, 684 cmK1; TLC Rf (hexane/
EtOAc 2:1)Z0.68; HRMS (ESI) m/z calcd for C21H23F3-
O5SNa (MCNa)C467.1110, found 467.1093. This
product was further purified using HPLC prior to
antimalarial testing [semi-preparative Silica gel column
(1!25 cm), 30% EtOAc in hexanes, 2.0 mL/min, 264 nm,
tRZ13.0 min].
4.5.3.4. Compound 100c. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.84–7.81 (m, 2H), 7.55–7.51 (m,
2H), 7.38–7.32 (m, 4H), 4.03 (dq, JZ11.8, 8.8 Hz, 1H),
3.86 (d, JZ14.8 Hz, 1H), 3.67 (dq, JZ12.0, 8.4 Hz, 1H),
3.59 (d, JZ14.8 Hz, 1H), 1.88 (s, 3H), 1.52 (s, 3H), 1.34 (s,
9H); 13C NMR (100 MHz, CDCl3) d 157.6, 137.9, 137.7,
131.4, 129.1, 128.5, 127.9, 126.1, 124.8, 123.6 (q, JZ
280 Hz), 102.0, 80.1, 62.3 (q, JZ35 Hz), 61.7, 35.2, 31.1,
23.6, 22.6; IR (CH2Cl2, film) 2965, 2872, 1595, 1453, 1320,
1288, 1153, 1084, 968, 902, 842, 765, 573 cmK1; TLC Rf
(hexane/EtOAc 2:1)Z0.66; HRMS (ESI) m/z calcd for
C23H27F3O5SNa (MCNa)C495.1423, found 495.1426.
This product was further purified using HPLC prior to
antimalarial testing [semi-preparative Silica gel column
(1!25 cm), 30% EtOAc in hexanes, 3.0 mL/min, 264 nm,
tRZ7.9 min].
4.5.2.4. Compound 1000b. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.48–7.47 (m, 2H), 7.35–7.32 (m,
3H), 7.22–7.18 (m, 2H), 3.78–3.68 (m, 3H), 3.53 (dq, JZ
12.0, 8.8 Hz, 1H), 2.36 (s, 6H), 1.89 (s, 3H), 1.65 (s, 3H);
13C NMR (100 MHz, CDCl3) d 140.7, 139.2, 138.4, 135.3,
132.1, 128.9, 128.2, 125.9, 125.5, 124.1, 123.5 (q, JZ
276 Hz), 63.1, 62.0 (q, JZ35 Hz), 24.4, 24.3, 21.1; IR
(CH2Cl2, film) 2987, 2929, 1604, 1449, 1372, 1319, 1280,
1140, 966, 898, 855, 763, 681 cmK1; TLC Rf (hexane/
EtOAc 2:1)Z0.68; HRMS (ESI) m/z calcd for C21H23F3-
O5SNa (MCNa)C467.1110, found 467.1097. This product
was further purified using HPLC prior to antimalarial testing
[semi-preparative Silica gel column (1!25 cm), 30%
EtOAc in hexanes, 2.0 mL/min, 264 nm, tRZ13.7 min].
4.5.3.5. Compound 1000c. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.82–7.79 (m, 2H), 7.54–7.50 (m,
2H), 7.36–7.33 (m, 3H), 7.21–7.18 (m, 1H), 3.77 (d, JZ
15.2 Hz, 1H), 3.69 (d, JZ15.2 Hz, 1H), 3.68 (dq, JZ11.8,
8.8 Hz, 1H), 3.49 (dq, JZ11.8, 8.8 Hz, 1H), 1.91 (s, 3H),
1.64 (s, 3H), 1.56 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 157.7, 138.5, 138.0, 132.0, 129.0, 128.2, 127.9,
126.0, 126.0, 124.1, 123.5 (q, JZ276 Hz), 63.2, 62.0 (q, JZ
35 Hz), 35.2, 31.0, 24.3, 24.1; IR (CH2Cl2, film) 2966, 1595,
1493, 1453, 1399, 1375, 1319, 1286, 1152, 1084, 968, 903,
836, 790, 767 cmK1; TLC Rf (hexane/EtOAc 2:1)Z0.66;
HRMS (ESI) m/z calcd for C23H27F3O5SNa (MC
Na)C495.1423, found 495.1408. This product was further
purified using HPLC prior to antimalarial testing [semi-
preparative Silica gel column (1!25 cm), 30% EtOAc in
hexanes, 3.0 mL/min, 264 nm, tRZ8.2 min].
4.5.3. From 4-t-butylthiophenol.
4.5.3.1. Compound 80c. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.37–7.26 (m, 8H), 3.68 (d, JZ
13.2 Hz, 1H), 3.43 (s, 3H), 3.36 (d, JZ13.6 Hz, 1H), 1.62 (s,
3H), 1.61 (s, 3H), 1.30 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 149.3, 138.3, 134.0, 133.5, 129.6, 128.0, 127.5,
125.8, 124.5, 101.7, 81.5, 51.1, 43.6, 34.4, 31.2, 22.3; IR
(CH2Cl2, film) 2962, 1490, 1457, 1371, 1272, 1191, 1130,
1044, 875, 823, 762 cmK1; TLC Rf (hexane/Et2O 2:1)Z
0.64; HRMS (ESI) m/z calcd for C22H28O3SNa (MC
Na)C395.1651, found 395.1641. This product was further
purified using HPLC prior to antimalarial testing [semi-
preparative Silica gel column (1!25 cm), 10% EtOAc in
hexanes, 3.0 mL/min, 264 nm, tRZ9.5 min].
4.5.3.2. Compound 800c. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.38–7.35 (m, 1H), 7.33–7.26 (m,
6H), 7.21–7.18 (m, 1H), 3.58 (d, JZ13.6 Hz, 1H), 3.43 (d,
JZ13.6 Hz, 1H), 3.32 (s, 3H), 1.69 (s, 3H), 1.67 (s, 3H),
1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) d 149.5, 139.2,
134.4, 133.6, 130.0, 128.0, 127.4, 125.9, 125.8, 124.1,
102.8, 82.2, 51.9, 44.0, 34.4, 31.2, 24.3, 24.3; IR (CH2Cl2,
film) 2963, 2868, 1490, 1447, 1369, 1269, 1188, 1120,
4.5.3.6. Compound 80d. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.38–7.28 (m, 5H), 7.26–7.20 (m,
3H), 3.66 (d, JZ13.6 Hz, 1H), 3.42 (s, 3H), 3.32 (d, JZ
13.2 Hz, 1H), 1.61 (s, 3H), 1.60 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 138.0, 136.3, 133.9, 131.7, 130.9,
128.1, 127.7, 125.9, 124.3, 119.7, 101.7, 81.3, 51.2, 43.1,
22.2, 22.2; IR (CH2Cl2, film) 2989, 2927, 2826, 1473, 1368,

4126
J. Kim et al. / Tetrahedron 62 (2006) 4120–4127
1297, 1272, 1126, 1086, 1041, 1006, 870, 805, 760 cmK1
;
1084, 1010, 967, 824, 766 cmK1; TLC Rf (hexane/EtOAc
2:1)Z0.73; HRMS (ESI) m/z calcd for C19H18BrF3O5SNa
(MCNa)C516.9903, found 516.9902. This product was
further purified using HPLC prior to antimalarial
testing [semi-preparative Silica gel column (1!25 cm),
40% EtOAc in hexanes, 2.0 mL/min, 264 nm, tRZ
14.0 min].
TLC Rf (hexane/Et2O 2:1)Z0.58; HRMS (ESI) m/z calcd
for C18H19BrO3SNa (MCNa)C417.0130, found 417.0126.
This product was further purified using HPLC prior to
antimalarial testing [semi-preparative Silica gel column
(1!25 cm), 20% EtOAc in hexanes, 2.0 mL/min, 264 nm,
tRZ11.4 min].
4.5.4. From 4-bromothiophenol.
4.5.5. From 4-methoxythiophenol.
4.5.4.1. Compound 800d. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.38–7.29 (m, 5H), 7.22 (dt, JZ8.4,
2.0 Hz, 2H), 7.17–7.14 (m, 1H), 3.56 (d, JZ13.6 Hz, 1H),
3.39 (d, JZ14.0 Hz, 1H), 3.30 (s, 3H), 1.68 (s, 3H), 1.66 (s,
3H); 13C NMR (100 MHz, CDCl3) d 138.8, 136.4, 134.5,
131.8, 131.3, 128.1, 127.5, 125.8, 123.9, 120.0, 102.8, 82.1,
51.7, 43.5, 24.3, 24.0; IR (CH2Cl2, film) 2989, 2927, 1474,
1370, 1269, 1189, 1091, 1007, 866, 808, 762 cmK1; TLC Rf
(hexane/Et2O 2:1)Z0.64; HRMS (ESI) m/z calcd for
C18H19BrO3SNa (MCNa)C417.0130, found 417.0141.
This product was further purified using HPLC prior to
antimalarial testing [semi-preparative Silica gel column
(1!25 cm), 20% EtOAc in hexanes, 2.0 mL/min, 264 nm,
tRZ10.7 min].
4.5.5.1. Compound 80e. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.37–7.33 (m, 3H), 7.32–7.28 (m,
2H), 7.26–7.23 (m, 1H), 6.83–6.79 (m, 2H), 3.78 (s, 3H),
3.61 (d, JZ13.6 Hz, 1H), 3.41 (s, 3H), 3.27 (d, JZ13.6 Hz,
1H), 1.59 (s, 3H), 1.58 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 158.8, 138.4, 133.9, 133.0, 127.9, 127.5, 127.5,
125.8, 124.5, 114.5, 101.7, 81.6, 55.3, 51.2, 45.3, 22.3, 22.2;
IR (CH2Cl2, film) 2977, 2925, 2820, 1592, 1494, 1443,
1370, 1284, 1245, 1179, 1130, 1042, 875, 762 cmK1; TLC
Rf (hexane/Et2O 2:1)Z0.44; HRMS (ESI) m/z calcd for
C19H22O4SNa (MCNa)C369.1131, found 369.1129. This
product was further purified using HPLC prior to
antimalarial testing [semi-preparative Silica gel column
(1!25 cm), 20% EtOAc in hexanes, 2.0 mL/min, 264 nm,
tRZ12.2 min].
4.5.4.2. Compound 9d. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.80 (d, JZ8.8 Hz, 2H), 7.67 (d, JZ
8.4 Hz, 2H), 7.34–7.25 (m, 4H), 1.84 (s, 3H), 1.43 (s, 3H);
13C NMR (100 MHz, CDCl3) d 139.6, 137.3, 133.3, 132.1,
129.8, 128.7, 128.5, 128.1, 125.9, 124.2, 101.4, 79.5, 61.7,
51.1, 22.2, 21.9; IR (CH2Cl2, film) 2990, 2940, 2831, 1574,
4.5.5.2. Compound 800e. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.37–7.34 (m, 3H), 7.32–7.28 (m,
2H), 7.17–7.15 (m, 1H), 6.81–6.79 (m, 2H), 3.78 (s, 3H),
3.51 (d, JZ13.6 Hz, 1H), 3.35 (d, JZ13.6 Hz, 1H), 3.31 (s,
3H), 1.66 (s, 3H), 1.66 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 158.9, 139.2, 134.4, 133.4, 128.0, 127.6, 127.3,
125.8, 124.1, 102.8, 82.3, 55.3, 51.8, 45.6, 24.3, 24.2; IR
(CH2Cl2, film) 2984, 2937, 2834, 1592, 1494, 1442, 1369,
1284, 1245, 1180, 1129, 1034, 827, 763 cmK1; TLC Rf
(hexane/Et2O 2:1)Z0.44; HRMS (ESI) m/z calcd for
C19H22O4SNa (MCNa)C369.1131, found 369.1128. This
product was further purified using HPLC prior to
antimalarial testing [semi-preparative Silica gel column
(1!25 cm), 40% EtOAc in hexanes, 2.0 mL/min, 264 nm,
tRZ9.8 min].
1449, 1389, 1320, 1148, 1084, 1067, 1010, 876, 762 cmK1
;
TLC Rf (hexane/EtOAc 2:1)Z0.57; HRMS (ESI) m/z calcd
for C18H19BrO5SNa (MCNa)C449.0029, found 449.0031.
This product was further purified using HPLC prior to
antimalarial testing [semi-preparative Silica gel column
(1!25 cm), 30% EtOAc in hexanes, 2.0 mL/min, 264 nm,
tRZ14.1 min].
4.5.4.3. Compound 100d. White solid: mp 129–130 8C;
1H NMR (400 MHz, CDCl3) d 7.81–7.78 (m, 2H),
7.70–7.67 (m, 2H), 7.41–7.31 (m, 4H), 4.01 (dq, JZ11.8,
8.4 Hz, 1H), 3.91 (d, JZ14.8 Hz, 1H), 3.65 (dq, JZ11.6,
8.8 Hz, 1H), 3.54 (d, JZ14.8 Hz, 1H), 1.86 (s, 3H), 1.51 (s,
3H); 13C NMR (100 MHz, CDCl3) d 139.5, 137.8, 132.3,
131.2, 129.7, 129.3, 128.9, 128.6, 126.2, 124.4, 123.5 (q,
JZ276 Hz), 62.3 (q, JZ35 Hz), 61.5, 23.5, 22.3; IR
(CH2Cl2, film) 3078, 2991, 2933, 1575, 1451, 1390, 1322,
1277, 1150, 1125, 1083, 1068, 1010, 967 cmK1; TLC Rf
(hexane/EtOAc 2:1)Z0.73; HRMS (ESI) m/z calcd for
C19H18BrF3O5SNa (MCNa)C516.9903, found 516.9916.
This product was further purified using HPLC prior to
antimalarial testing [semi-preparative Silica gel column
(1!25 cm), 40% EtOAc in hexanes, 2.0 mL/min, 264 nm,
tRZ10.2 min].
4.5.5.3. Compound 9e. White solid: mp 134–135 8C; 1H
NMR (400 MHz, CDCl3) d 7.86–7.84 (m, 2H), 7.32–7.26
(m, 4H), 6.99–6.97 (m, 2H), 3.92 (d, JZ15.2 Hz, 1H), 3.86
(s, 3H), 3.53 (d, JZ14.8 Hz, 1H), 3.31 (s, 3H), 1.85 (s, 3H),
1.46 (s, 3H); 13C NMR (100 MHz, CDCl3) d 163.6, 137.6,
133.4, 132.4, 130.2, 128.4, 128.0, 125.9, 124.4, 114.1,
101.5, 79.7, 62.0, 55.6, 51.2, 22.4, 22.1; IR (CH2Cl2, film)
2983, 2934, 2834, 1596, 1498, 1444, 1320, 1260, 1142,
1087, 804, 741 cmK1; TLC Rf (hexane/EtOAc 2:1)Z0.35;
HRMS (ESI) m/z calcd for C19H22O6SNa (MC
Na)C401.1029, found 401.1029. This product was further
purified using HPLC prior to antimalarial testing [semi-
preparative Silica gel column (1!25 cm), 40% EtOAc in
hexanes, 2.0 mL/min, 264 nm, tRZ16.9 min].
4.5.4.4. Compound 1000d. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.76–7.73 (m, 2H), 7.66–7.63 (m,
2H), 7.36–7.33 (m, 3H), 7.15–7.13 (m, 1H), 3.74–3.69 (m,
3H), 3.54 (dq, JZ11.8, 8.4 Hz, 1H), 1.87 (s, 3H), 1.64
(s, 3H); 13C NMR (100 MHz, CDCl3) d 139.8, 137.9, 132.3,
132.2, 129.8, 129.1, 128.3, 127.6, 126.0, 123.9, 123.5 (q,
JZ276 Hz), 63.1, 61.8 (q, JZ35 Hz), 24.2, 23.9; IR
(CH2Cl2, film) 2920, 2854, 1574, 1390, 1324, 1282, 1150,
4.5.5.4. Compound 100e. Colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.86–7.82 (m, 2H), 7.42–7.33 (m,
4H), 7.01–6.97 (m, 2H), 4.05 (dq, JZ11.8, 8.4 Hz, 1H),
3.88 (s, 3H), 3.87 (d, JZ14.8 Hz, 1H), 3.66 (dq, JZ11.8,
8.8 Hz, 1H), 3.54 (d, JZ14.8 Hz, 1H), 1.86 (s, 3H), 1.54 (s,
3H); 13C NMR (100 MHz, CDCl3) d 163.7, 138.1, 132.3,
131.3, 130.3, 129.1, 128.5, 126.1, 124.6 (q, JZ276 Hz),

J. Kim et al. / Tetrahedron 62 (2006) 4120–4127
4127
114.2, 62.4 (q, JZ35 Hz), 61.8, 55.7, 23.7, 22.4; IR
References and notes
(CH2Cl2, film) 2992, 2938, 2839, 1596, 1498, 1377, 1321,
1286, 1143, 1085, 1024, 967, 901, 836 cmK1; TLC Rf
(hexane/EtOAc 2:1)Z0.57; HRMS (ESI) m/z calcd for
C20H21F3O6SNa (MCNa)C469.0903, found 469.0904.
This product was further purified using HPLC prior to
antimalarial testing [semi-preparative Silica gel column
(1!25 cm), 50% EtOAc in hexanes, 2.0 mL/min, 264 nm,
tRZ11.5 min].
1. For general review of 1,2-dioxetanes, see: (a) Chemical and
Biological Generation of Excited States; Adam, W.,
Cilento, G., Eds.; Academic: New York, 1982. (b) Adam, W.
InTheChemistryofFunctionalGroups,Peroxides;Patai, S., Ed.;
Wiley: New York, 1982. (c) Adam, W.; Baader, W. J.;
Babatsikos, C.; Schmidt, E. Bull. Soc. Chim. Belg. 1984, 93,
605. (d) Adam, W.; Yang, F. In Small Ring Heterocycles;
Hassner, A., Ed.; Wiley: New York, 1985; Part 3, Chapter 4.
2. For reviews of 1O2 chemistry, see: (a) Denny, R. W.; Nickon,
A. Org. React. 1973, 20, 133. (b) Singlet Oxygen; Wasserman,
H. H., Murray, R. W., Eds.; Academic: New York, 1979. (b)
Singlet Oxygen; Frimer, A., Ed.; CRC: Boca Raton, FL, 1985.
3. For a recent review of antimalarial 1,2,4-trioxanes, see:
O’Neill, P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945.
4. Posner, G. H.; Cumming, J. N.; Woo, S.-H.; Ploypradith, P.;
Xie, S.; Shapiro, T. A. J. Med. Chem. 1998, 41, 940.
4.5.5.5. Compound 12. White solid: mp 120–123 8C; 1H
NMR (400 MHz, CDCl3) d 7.89 (d, JZ8.8 Hz, 2H), 7.55 (d,
JZ8.4 Hz, 2H), 7.42 (d, JZ7.6 Hz, 1H), 7.36 (m, 2H), 7.30
(m, 1H), 3.95 (br d, JZ12.0 Hz, 1H), 3.71 (d, JZ15.2 Hz,
1H), 3.21 (br s, 3H), 1.81 (br s, 3H), 1.34 (s, 9H), 0.79 (s,
9H); 13C NMR (100 MHz, CDCl3) d 157.4, 141.7, 137.8,
128.2, 128.2, 128.0, 127.4, 126.9, 126.0, 124.8, 106.6, 79.5,
50.8, 41.4, 35.2, 31.1, 26.4, 26.2, 23.8; IR (CH2Cl2, film)
2964, 2360, 1726, 1595, 1462, 1393, 1319, 1291, 1199,
1150, 1107, 1084, 960, 845, 760, 576, 520 cmK1; HRMS
(FAB-MS) m/z calcd for C25H34O5S (MCNa)C469.20247,
found 469.20237.
5. Posner, G. H.; Jeon, H. B.; Parker, M. H.; Krasavin, M.; Paik,
I.-H.; Shapiro, T. A. J. Med. Chem. 2001, 44, 3054.
6. Posner, G. H.; O’Dowd, H.; Ploypradith, P.; Cumming, J. N.;
Xie, S.; Shapiro, T. A. J. Med. Chem. 1998, 41, 2164.
7. Korshin, E. E.; Hoos, R.; Szpilman, A. M.; Konstantinovski,
L.; Posner, G. H.; Bachi, M. D. Tetrahedron 2002, 58, 2449.
8. Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M.;
Ploypradith, P.; Xie, S.; Shapiro, T. A.; Posner, G. H. J. Med.
Chem. 2003, 46, 2516.
Acknowledgements
9. O’Neill, P. M.; Murkhtar, A.; Ward, S. A.; Bickley, J. F.;
Davies, J.; Bachi, M. D.; Stocks, P. A. Org. Lett. 2004, 6, 3035.
10. Posner, G. H.; Gonzalez, L.; Cumming, J. N.; Klinedienst, D.;
Shapiro, T. A. Tetrahedron 1997, 53, 37.
We thank the NIH (AI-34885 and RR00052) for financial
support and Suji Xie for help with the in vitro antimalarial
testing, and Dr. Amy Sarjeant for the X-ray crystallography.