Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore

Article abstract of DOI:10.1016/j.bmcl.2006.02.059

A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.

Full text of DOI:10.1016/j.bmcl.2006.02.059

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2991–2995
Diels–Alder/thiol–olefin co-oxygenation approach
to antimalarials incorporating the
2
,3-dioxabicyclo[3.3.1]nonane pharmacophore
a,
a
b
b
c
*
Paul M. O’Neill, Edite Verissimo, Stephen A. Ward, Jill Davies, Edward E. Korshin,
d
a
d
Nuna Araujo, Matthew D. Pugh, M. Lurdes S. Cristiano,
a
c,
*
Paul A. Stocks and Mario D. Bachi
a
Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK
Department of Organic Chemistry, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
b
c
The Weizmann Institute of Science, Rehovot 76100, Israel
d
University of the Algarve, FCT, Faro P-8000, Portugal
Received 11 January 2006; revised 22 February 2006; accepted 22 February 2006
Available online 9 March 2006
Abstract—A Diels–Alder/thiol–olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a–22b is reported.
Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of
the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEM-
PO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive
C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.
Ó 2006 Elsevier Ltd. All rights reserved.
1
2
The 2,3-dioxabicyclo[3.3.1]nonane system 1 was first
identified in the naturally occurring antimalarial yingz-
than 25 nM against Plasmodium falciparum (NF54).
Upon subcutaneous administration, four b-sulfonyl
endoperoxides were shown to be highly active antimala-
1
,2
haosu A 2. It was subsequently incorporated into syn-
3
thetic antimalarials as Hoffmann LaRoche’s arteflene 3,
4
endoperoxides 4 synthesized by O’Neill et al. b-sulfanyl
OH
O
O
HO
and b-sulfonyl-endoperoxides 5–9b synthesized by Bachi
and co-workers, and related cyclic peroxides synthe-
O
5
–8
O
O
9
O
O
sized by Nojima and co-workers, to become a well-
Ar
3, Ar= 2, 4-
CF -Ph
established pharmacophore. C(4)-Methyl-substituted
b-sulfanyl- and b-sulfonyl-2,3-dioxabicyclo[3.3.1]non-
ane derivatives such as 5–8 are now readily available
by a useful method based on the adaptation of the
1
2
3
OR2
OR2
1
0
thiol–olefin co-oxygenation (TOCO) reaction to limo-
5
–8
nene. This method proved to be particularly efficient
in a key step of the synthesis of C(4)-phenyl-substituted
1
1
R O S
SO R
n
O
n
O
RO
O
O
O
1
1
O
benzylidene endoperoxides like 10 and 11 (Fig. 1).
O
4
, R = Alkyl
5, n = 0
7, n = 0
8, n = 2
More than 50 compounds of types 5–8 have been
1
6
, n = 2
2
screened for in vitro activity. Ten of the b-sulfonyl-
endoperoxides of types 6 and 8 have IC50 values lower
1
2
R = Ar, R = H or Bn or PMB
5
7
, 6 - obtained from R-(+)-limonene
, 8 - obtained from S-(-)-limonene
Keywords: Artemisinin; Arteflene; Endoperoxide; Malaria; Mechanism
of action.
Figure 1. Bicyclic endoperoxides based on the 2,3-dioxabicy-
clo[3.3.1]nonane pharmacophore.
*
Corresponding authors. E-mail: P.M.oneill01@liv.ac.uk
0
960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.02.059

2992
P. M. O’Neill et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2991–2995
O
Ph
OAc
O
Ph
SO Ph
2
O
O
O
O
O
O
Ar
Ph
SO Ph
2
9
a. IC50 = 6.5 nM (NF54)
9b. IC50 = 9.4 nM (NF54)
Artemisinin IC50 = 8.9 nM
ED50 = 0.43 mg/kg
1
0. Ar
=
Ph
Artemisinin IC50 = 8.9 nM
ED50 = 0.8 mg/kg
IC50 = 34 nM (K1)
11. Ar = p-Cl-Ph
IC50 = 23 nM (K1)
Artemisinin ED50 = 0.95 mg/kg Artemisinin ED50 = 0.95 mg/kg
Figure 2. Structures and antimalarial activities of lead endoperoxides 9a, 9b, 10 and 11.
rials in vivo against Plasmodium yoelii and Plasmodium
berghei strains of malaria parasites. Relative to artemis-
inin, the most potent compounds 9a and 9b (Fig. 2) were
about two times more efficacious against chloroquine-
sensitive P. berghei and 3–5 times more efficacious
against chloroquine-resistant P. yoelii. Thus, the poten-
cy of the endoperoxides 9a and 9b is comparable to
those of some of the best currently used antimalarial
drugs, including artemether and arteether. The benzyl-
oxy derivative 9b (Fig. 2) exhibits also a reasonable oral
antimalarial efficacy about twice the level of arteflene.
Antimalarial benzylidene endoperoxides, such as com-
pounds 10 and 11, have been shown to liberate chal-
cones following iron-dependent bioactivation of the
endoperoxide bridge within isolated digestive vacuoles
of P. falciparum. Such compounds are considered as
Enone 15 was prepared from 3-chloropropiophenone 14
by base-catalysed elimination of HCl in 90% yield. The
enone product was used immediately in the Diels–Alder
reaction with isoprene; the Kobayashi protocol gave the
desired product 16 in 76% yield following purification
by flash column chromatography; only minor quantities
(<2%) of the regioisomeric 1,3-adduct could be detected.
Compound 16 was subjected to a Wittig reaction, with
methyl triphenyl phosphonium bromide and potassium
tert-butoxide as base, to give the desired product 12 in
90% yield. Exposure of 12 to optimised conditions for
the TOCO reaction gave a mixture of two diastereomers
1
4
15
11
17a and 17b in yields of 70% on a 2g scale. The
individual racemic diastereomers were separated by col-
umn chromatography and oxidised with m-CPBA to
1
6
17
give the corresponding sulfones 19a and 19b in excel-
lent yields. The TOCO reaction of 12, performed using
p-chlorothiophenol instead of phenylthiol, afforded the
p-chloro-substituted analogues 18a and 18b, although
in lower yields.
1
1
pro-drug prototypes.
In this paper, we report on the synthesis of a new series
of bicyclic C(4)-phenyl-substituted b-sulfanyl/sulfonyl
endoperoxides and the assessment of their antimalarial
activity.
Since previous SAR studies involving C(4) methyl-
substituted endoperoxides like 5–8 of both the ‘a’ and
‘b’ diastereomeric series revealed that acetylation of
the tertiary alcohol led to improvement in antimalarial
1
1
The key intermediate in our earlier synthesis of pro-
drug prototypes 10 and 11 was the phenyl limonene
derivative 12 prepared in four steps from the unsaturat-
ed epoxide 13 (Scheme 1). We decided to investigate a
more direct and flexible synthesis of 12 by employing a
1
2
activity both in vitro and in vivo; hydroxy endoperox-
ides 17a and 17b were transformed in good overall yield
into the corresponding acetoxy sulfides 21a and 21b as
shown in Scheme 3. The corresponding sulfones 22a
and 22b were obtained as before, by the use of m-CPBA
as oxidant. The assignment of stereochemistry at the C-4
position for 22b has previously been confirmed by a
combination of NMR spectroscopy and X-ray
Sc(OTf) -catalysed Diels–Alder reaction of 1-phenyl-
3
prop-2-en-1-one (15) with isoprene. Studies by Kobay-
ashi have shown that scandium perfluoroalkane
sulfonates catalyse the reaction of vinyl ketones with
isoprene leading to excellent yields of the corresponding
1
3
7,11
cycloadducts with very high levels of regioselectivity.
crystallography.
Prior to testing, we considered the issue of enantiomeric
purity since all of the compounds prepared in this study
are racemic. Previously, several studies have confirmed
that enantiomeric pairs of endoperoxides have identical
antimalarial activity; these compounds include antimal-
OAc
OH
TOCO
O
O
O
O
Ph
SPh
Ph
SO Ph
PhSH/AIBN/UV
2 O2
18a,b
18c
arially potent 1,2,4-trioxanes,
analogues of the present series of bicyclic endoperox-
endoperoxides and
2
1
2
ides.
Thus, for the purposes of identifying lead
Ph
endoperoxides, we note that many papers in the litera-
ture have employed primary screening of racemic
endoperoxides and feel that this is a validated approach
O
key intermediate
4 steps
1
8a–c
to antimalarial lead compound discovery.
The
1
2
13
antimalarial activity of selected endoperoxides was mea-
sured in red blood cell-based assays. Efficacy was mon-
itored by parasite { H}-hypoxanthine incorporation
Scheme 1. Retrosynthetic analysis on sulfone endoperoxides to
limonene epoxide 13.
3

P. M. O’Neill et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2991–2995
2993
a
b
Ph
Cl
Ph
Ph
O
O
O
6, 76%
14
15, 90%
1
c
d
OH
OH
12, 90%
O
SAr
O
O
Ph
SAr
17b, Ar =Ph, 40%
O
Ph
7a, Ar = Ph, 30%
8a, Ar = p-Cl-Ph, 7% 18b, Ar = p-Cl-Ph, 14%
1
1
e
e
OH8
OH8
1
10
1
9
10
9
7
3
7
3
2
5
2
O 5 Ph
O
SO Ar
2
O
4
O
4
Ph
SO Ar
2
1
9a, Ar = Ph, 81%
19b, Ar =Ph, 70%
2
0a, Ar = p-Cl-Ph, 92% 20b, Ar = p-Cl-Ph, 75%
˚
, 5 A molecular sieves, CH
Scheme 2. Reagents and conditions: (a) potassium acetate, EtOH, reflux, 3 h; (b) isoprene, Sc(OTf)
methyl triphenyl phosphonium bromide, potassium tert-butoxide, THF, rt; (d) PhSH (1.2 equiv), AIBN (0.07 equiv), O
Ph P (1.6 equiv), CH CN, CH Cl Cl , rt.
, 0 °C to rt (Ar = Ph, ratio 17b/17a ca. 4:3); (e) m-CPBA, CH
3
2
Cl
2
, ꢀ20 °C, 3 h; (c)
2
3
(excess), hm, 0 °C, CH CN;
3
3
2
2
2
2
OH
OAc
OAc
a, b
c
O
O
SAr
O
O
SAr
O
O
SO Ar
2
Ph
Ph
Ph
17a
21a, Ar = Ph, 80%
22a, Ar = Ph, 97%
OH
OAc
OAc
a, b
c
O
O
Ph
SAr
O
Ph
SO Ar
O
Ph
SAr
21b, Ar =Ph, 50%
O
O
2
17b
22b, Ar =Ph, 90%
Scheme 3. Reagents and condition: (a) TMSOTf (2 equiv), 2,6-lutidine (2.75 equiv), CH
2 2 2 2
Cl ; (b) neat AcCl; (c) m-CPBA (1.1 equiv), CH Cl , 0 °C.
1
9,20
using parasite-infected human erythrocytes.
All
performed an iron(II)-mediated degradation of sulfone
19b in the presence of the spin-trapping agent TEMPO
compounds were assayed in triplicate against the chloro-
quine-resistant parasite, K1 and data are recorded in
Table 1.
21,22
(2,2,6,6-tetramethylpiperidine-1-oxyl) (Scheme 4).
Following column chromatography of the reaction
mixture, a major product (40%) was identified as
2
3a
The endoperoxides 17a–22b have a broad range of IC s
5
b-ketosulfone 23.
was analysed by LCMS and several products were
The residual complex mixture
0
versus the K1 strain with the two most potent com-
pounds expressing equivalent activity to arteflene. Apart
from analogues 18a and 18b, compounds of the ‘b’ series
tend to be more potent than compounds of the ‘a’ series
(see 17b, 19b, 20b and 22b vs 17a, 19a, 20a and 22a). In
line with previous SAR work on C(4)-methyl analogues
of types 5–8, acetylation of the 8-hydroxyl function
and oxidation of the sulfide group to a sulfone enhance
activity for this class of endoperoxide. It is apparent that
the incorporation of the phenyl group at the C(4)
position in place of the C(4) methyl group of previous
analogues (5–8) provides no advantage in terms of
enhancing antimalarial activity.
identified including the spin-trapped TEMPO adduct
2
3b
25.
The formation of these products is consistent
with the mechanism depicted in Scheme 4 whereby
association of oxygen O2 with reducing Fe(II)
provides an oxyl radical by homolytic cleavage of the
endoperoxide bridge. The intermediate oxyl radical spe-
cies fragments to produce the secondary carbon cen-
tered radical species 24 in tandem with the sulfone 23.
1
2
Although in vitro antimalarial assessment of the ‘poten-
tially protein reactive 23’ revealed that it is inactive, we
have no knowledge about its potential activity if re-
2
4a
leased within the parasite’s food vacuole or cytosol
through iron-induced degradation of the parent perox-
ide. Nevertheless, by analogy to the mode of action of
In order to gain insight into potential antimalarial
mechanisms of action of these endoperoxides, we

2994
P. M. O’Neill et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2991–2995
Table 1. Antimalarial activities of bicyclic endoperoxides
OR
8
10
1
9
7
2
5
O
Y
3
O
4
Z
a
Compound
Y
Z
R
IC50 (nM)
17a
17b
18a
18b
19a
19b
20a
20b
21a
21b
22a
22b
CH
Ph
2
2
2
2
2
2
SPh
Ph
H
298
81
CH
Ph
2
2
2
2
2
2
SPh
H
CH
Ph
S–p-Cl–Ph
H
247
541
230
92
CH
Ph
S–p-Cl–Ph
H
CH
Ph
SO
2
2
Ph
H
CH
Ph
SO
SO
2
Ph
H
CH
Ph
SO
–p-Cl–Ph
H
225
107
164
124
72
CH
Ph
2
–p-Cl–Ph
H
CH
Ph
SPh
SO
Ac
Ac
Ac
Ac
CH
Ph
SPh
SO
CH
Ph
2
Ph
CH
2
Ph
42
Arteflene
76
1000
23
a
18
Parasites were maintained in continuous culture according to the method of Trager and Jensen. IC50 values were measured according to the
19
methods described by Desjardins.
on a Diels–Alder reaction and a TOCO reaction. It fol-
lows a protocol that should allow a variety of structural
modifications on the 1,3-diene and on the vinyl ketone
participating in the Diels–Alder reaction as well as in
the arylthiol participating in the TOCO reaction
OH
OH
a
O
Ph
(III)Fe O
O
Ph
SO Ph
O
SO Ph
2
2
1
9b
(
Scheme 2). Consequently in addition to possible manip-
ulations of the group ‘R,’ also groups ‘Y’ and ‘Z’ of the
endoperoxides (17a–22a) reported in Table 1 should be
prone to changes required for SAR studies. The best
compounds from the present series are obtained in good
yields and have equivalent activity to arteflene. Further
work in this area will continue.
OH
Ph
O
SO Ph
2
O
(III)Fe
2
3, 40%
24
TEMPO
OH
Acknowledgments
HO
O N
The authors thank the EPSRC (M.P.), the BBSRC
(S.A.W., P.O.N., P.A.S., Grants BB/C006321/1 and
2
5
2
6/B13581) and the FCT (Funda c¸ a˜ o para a Ci eˆ ncia e
LCMS [M+1] 286
a Tecnologia) Portugal, for funding this work. We also
thank Dr. J. L. Maggs (Department of Pharmacology,
University of Liverpool) for carrying out the LCMS
study on analogue 19b.
Scheme 4. Reagents: (a) Iron(II) acetate (2 equiv) TEMPO, (3 equiv),
CH CN.
3
2
4b,c
other antimalarial endoperoxides,
it is expected that
the activity of the peroxides described in Table 1 is med-
iated by the secondary carbon centered radical 24, gen-
erated by iron-mediated bioactivation in the vicinity of
References and notes
2
4b
1. Zhou, W. S.; Xu, X. X. Acc. Chem. Res. 1994, 27, 211.
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one or more key parasite protein targets. It is also fea-
2
4c
sible, based on previous observations, that this radical
species can also form potentially protein reactive carbo-
cations via radical oxidation with ferric iron (generated
through the initial SET-mediated cleavage of the endo-
peroxide bridge).
3
4
In conclusion, we have developed a novel and efficient
approach to antimalarial endoperoxides that is based
5. Bachi, M. D.; Korshin, E. E. Synlett 1998, 122.

P. M. O’Neill et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2991–2995
2995
6
. Bachi, M. D.; Korshin, E. E.; Ploypradith, P.; Cumming,
J. N.; Xie, S. J.; Shapiro, T. A.; Posner, G. H. Bioorg.
Med. Chem. Lett. 1998, 8, 903.
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novski, L.; Posner, G. H.; Bachi, M. D. Tetrahedron 2002,
(C(10)), 23.0. Anal. Calcd for C21
6.23. Found: C, 64.44; H, 6.18. MS m/z (CI, +ve) 388
H
24SO
5
: C, 64.93; H,
+
+
([M ], 6), 406 ([M+NH ] , 9), 278 (100), 371(3). Found
4
+
7
4
]
28 5
[M+NH 406.16787, C21H O SN requires 406.16882.
6), 146 (16), 138 (10), 104 (12).
ꢀ
1
5
8, 2449.
17. Compound 19b: mmax (nujol)/cm 3499 (OH), 1715, 1584
8
. Szpilman, A. M.; Korshin, E. E.; Rozenberg, H.; Bachi,
M. D. J. Org. Chem. 2005, 70, 3618.
. (a) Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCul-
lough, K. J.; Kim, H. S.; Wataya, Y. Tetrahedron 2001, 57,
(Ar), 1305 (C–O), 1284 (S@O), 1132 (S@O), 752, 698, 684.
1
H NMR (400 MHz, CDCl
3.68 (d, J = 14.6 Hz, 1H, C(11)H ), 3.56 (br s, 1H, C(1)H),
3
) d 7.48–7.22 (m, 10H, Ar),
0
9
3.50 (d, J = 14.7 Hz, 1H, C(11)H), 2.84 (m, 1H, C(5)H),
2.38–1.51 (m, 6H), 1.38 (s, 3H, C(10)H
1
3
5
979; (b) Kim, H.-S.; Begum, K.; Ogura, N.; Wataya, Y.;
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732.
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979, 101, 7099.
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Ploypradith, P.; Xie, S. J.; Shapiro, T. A.; Posner, G. H.
J. Med. Chem. 2003, 46, 2516.
3. Kobayashi, S.; Hachiya, I.; Araki, M.; Ishitani, H.
Tetrahedron Lett. 1993, 34, 3755.
3
). C NMR
(100 MHz, CDCl ) d 141.1, 138.9, 133.4, 129.2, 128.5,
3
4
128.2, 127.7, 127.6, 85.9 (C(1)), 82.8 (C(4)), 71.7 (C(8)),
62.9 (C(11)), 36.0 (C(5)), 29.9, 28.5, 24.1 (C(10)), 23.9.
1
1
1
Anal. Calcd for C21
64.76; H, 6.27. MS m/z (CI, +ve) 388 ([M ], 6), 406
5
H24SO : C, 64.93; H, 6.23. Found: C,
+
+
4
([M+NH ] , 1), 278 (100), 232 (9).
18. (a) O’Neill, P. M.; Rawe, S. L.; Borstnik, K.; Miller, A.;
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1
1
ꢀ
1
1
4. Compound 17a: mmax (neat)/cm 3520 (OH), 2922 (C–H),
1
1
709, 1583 (C@C, Ar), 1305 (C–O), 1151 (C–O). H NMR
(
J = 12.7 Hz, 1H, C(11)H ), 3.81 (br s, 1H, C(1)H), 3.64 (d,
400 MHz, CDCl
3
) d 7.32–7.10 (m, 10H, Ar), 3.98 (d,
0
J = 12.7 Hz, 1H, C(11)H), 2.37–2.17 (m, 4H), 1.73–1.61 (m,
2
1
3
H), 1.45 (s, 3H, C(10)H
3
), 1.37 (m, 1H). C NMR
(
(
(
(
100 MHz, CDCl ) d 130.1, 129.0, 128.4, 127.6, 124.7, 86.1
3
C(4)), 82.4 (C(1)), 71.7 (C(8)), 42.7 (C(11)), 35.8, 32.1
C(5)), 28.6 (C(10)), 24.7, 24.3. MS m/z (CI) [M+NH ] 374
+
22. Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman,
S. A.; Chiu, F. C. K.; Chollet, J.; Dong, Y. X.; Dorn, A.;
Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam,
M.; Tomas, J. S.; Scheurer, C.; Scorneaux, B.; Tang, Y.
Q.; Urwyler, H.; Wittlin, S.; Charman, W. N. Nature 2004,
430, 900.
4
6), 339 (47), 246 (31), 235 (100), 229 (17), 217 (16) 105 (5).
S requires 357.15244.
+
Found [M+H ] 357.15325 C21
H
25
1
O
3
ꢀ
1
5. Compound 17b: mmax (neat)/cm 3425 (OH), 2924 (C–H),
1
H
1
583 (ArC@C), 1490, 1461 (ArC@C), 1375 (OH).
NMR (400 MHz, CDCl ) d 7.30–7.02 (m, 10H, Ar), 3.60
3
0
ꢀ1
(
(
br s, 1H, C(1)H), 3.24 (d, J = 12.3 Hz, 1H, C(11)H ), 3.12
d, J = 12,4 Hz, 1H, C(11)H), 2.60–2.58 (m, 1H, C(5)H),
23. (a) Compound 23: mmax (nujol)/cm 1725 (C@O), 1670
(Ar), 1597 (Ar), 1581 (Ar), 1307 (S@O), 1227, 1155 (S@O),
1
1083, 1005, 902, 744, 684. H NMR (400 MHz, CDCl
2
1
.53–2.43 (m, 1H), 2.00–1.93 (m, 2H), 1.92–1.60 (m, 2H),
3
) d
1
3
13
.43 (s, 3H, C(10)H
) d 141.5, 130.3, 130.0, 129.95, 129.9, 129.0, 129.0,
28.4, 128.4, 127.7, 127.6, 126.9, 126.5, 125.1, 87.4 (C(4)),
2.5 (C(1)), 71.8 (C(8)), 43.5 (C(11)), 36.2, 29.4 (C(5)), 28.6
3
), 1.33 (m, 1H). C NMR (100 MHz,
7.92 (m, 4H), 7.89–7.45 (m, 6H), 4.74 (s, 2H). C NMR
(100 MHz, CDCl ) d 188.3, 139.2, 134.7, 134.6, 129.6,
129.5, 129.2, 129.0, 63.9. MS m/z (CI, +ve) 261 ([M+H] ,
CDCl
1
8
3
3
+
+
8), 278 ([M+NH
4
] , 94), 138(100), 121 (71), 105 (78), 94
: C, 64.60; H, 4.65. Found: C,
(
[
(
C(10)), 24.8, 23.4, 23.3, 22.6. (Ar). MS m/z (CI)
M+NH4] 374 (6), 356 (10), 339 (82), 235 (100), 229
(22), 78 (21). For C14H12SO
3
+
64.24; H, 4.71; (b) The column used in LCMS studies was
a Waters Symmetry 5-micron, C-8. The eluent was a
gradient of acetonitrile in formic acid (0.1%): 10% for
+
32), 217 (52), 157 (11), 123 (34). Found [M+Na]
79.1362 for C21 Na, requires 379.1344.
6. Compounds 19a and 19b were purified by flash column
3
H24SO
3
1
R
10 min, 10% to 85% over 5 min; 0.9 mL/min. t = 2 min
+
chromatography using 50–70% ethyl acetate/hexane.
3494 (OH), 2920,
9 s and 2 min 45 s. MS m/z 286([M+H] , 100), 158 (9), 126
(10).
ꢀ1
Compound 19a: mmax (nujol)/cm
1
1
704, 1583 (Ar), 1459, 1377, 1305 (C–O), 1278 (S@O),
24. For studies implicating the enzyme PfATP6, see: (a)
Eckstein-Ludwig, U.; Webb, R. J.; van Goethem, I. D. A.;
East, J. M.; Lee, A. G.; Kimura, M.; O’Neill, P. M.; Bray,
P. G.; Ward, S. A.; Krishna, S. Nature 2003, 424, 957; For
a recent review on iron(II) triggered antimalarial activity
of peroxides, see: (b) Posner, G. H.; O’Neill, P. M. Acc.
Chem. Res. 2004, 37, 397; (c) Szpilman, A. M.; Korshin, E.
E.; Hoos, R.; Posner, G. H.; Bachi, M. D. J. Org. Chem.
2001, 66, 6531.
1
192 (S@O), 1081 (–C–O–), 1052, 779, 784. H NMR
(400 MHz, CDCl ) d 7.61–7.18 (m, 10H, Ar), 4.27 (d,
J = 14.8 Hz, 1H, C(11)H , 4.03 (d, J = 14.8 Hz, 1H,
C(11)H), 3.80 (br d, J = 2.8 Hz, 1H, C(1)H), 2.41 (m,
1
3
0
H, C(5)H), 2.29–1.54 (m, 5H), 1.39 (s, 3H, C(10)H), 1.33
1
3
(
m, 1H). C NMR (100 MHz, CDCl ) d 141.05, 133.5,
3
1
(
30.2, 129.0, 128.4, 127.6, 126.2, 124.8, 86.0 (C(1)), 82.5
C(4)), 71.8 (C(8)), 42.7 (C(5)), 35.9, 31.9 (C(9)), 28.6, 24.3