Malaria-infected mice are cured by oral administration of new artemisinin derivatives

Article abstract of DOI:10.1021/jm701168h

In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 x 30 mg/kg. The clinically used trioxane drug sod

Full text of DOI:10.1021/jm701168h

J. Med. Chem. 2008, 51, 1035–1042
1035
Malaria-Infected Mice Are Cured by Oral Administration of New Artemisinin Derivatives
Gary H. Posner,*,†,‡ Wonsuk Chang,† Lindsey Hess,† Lauren Woodard,† Sandra Sinishtaj,† Aimee R. Usera,† William Maio,†
Andrew S. Rosenthal,† Alvin S. Kalinda,† John G. D’Angelo,† Kimberly S. Petersen,† Remo Stohler,† Jacques Chollet,§
Josefina Santo-Tomas,§ Christopher Snyder,§ Matthias Rottmann,§ Sergio Wittlin,§ Reto Brun,§ and Theresa A. Shapiro‡,|
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins UniVersity, 3400 North Charles Street,
Baltimore, Maryland 21218-2685, The Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health,
Baltimore, Maryland 21205, Swiss Tropical Institute, Basel, Switzerland, and DiVision of Clinical Pharmacology, Department of Medicine,
School of Medicine, The Johns Hopkins UniVersity, Baltimore, Maryland 21205
ReceiVed September 18, 2007
In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has
been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 × 30
mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.2 days
with this oral dose regimen. In comparison, animals receiving no drug die typically on day 6–7 postinfection.
At only 3 × 10 mg/kg oral dosing, seven dimers prolong the lifetime of malaria-infected mice to days
14–17, more than double the chemotherapeutic effect of sodium artesunate. Ten new trioxane dimers at
only a single oral dose of 30 mg/kg prolong mouse average survival to days 8.7–13.7, and this effect is
comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase
II clinical trials.
Introduction
lipophilicity (log P ≈ 8),16,19 we designed and prepared the
following lipophilic trioxane dimers,20 each in only one additional
chemical step: hydrazone LH-isobu-ketone-isoniaz-hydrazone (6),
ketals LH-isobudiol-acetal-form (7), WC-isobudiol-ketal-CB (8),
LH-isobudiol-ketal-cyclohex-4-one (9), LW-isobudiol-ketal-4-THP
(10), SS-isobudiol-ketal-4-pipC(O)Ph (11), LW-isobudiol-ketal-4-
pipC(O)OEt (12), AU-isobudiol-ketal-pipC(O)NHCH3 (13), and
LH-isobudiol-ketal-4-SO2-pyran (14), ethers WC-isobudiol-
OCH2Pyr (15)16 and ASK-isobudiol-C(O)Ph (16), carboxylate ester
KSP-isobudiol-OCH2CCCH2OBn-pF (17), ether WC-isobu-
OCH2Tol (18),16 thiophosphate ester WM-isobu-CH2OP(S)(OEt)2
(19), carbamate AU-isobu-OC(O)NEt2 (20), amides AU-isobu-
C(O)NHCH2Cyc-hex (21), SS-isobu-C(O)NH-Neop (22), ASR-
isobuCONHCH2Pyr (23), JGD-isobu-C(O)NHCH2(4-C(O)OMe)Ph
(24), WC-isobuC(O)NH-Bn-pMe (25), and WC-isobuC(O)NH-(S)-
CH(Me)-(Ph-pF) (26), and oxadiazoles RS-isobu-3-Me-1,2,4-
oxadiazole (27) and RS-isobu-5-p-FPh-1,3,4-oxadiazole (28). Of
critical importance, none of these final transformations destroyed
the essential peroxide pharmacophore within these dimer 1,2,4,-
trioxanes. All of these new trioxane dimers are amorphous solids.
All are stable neat at 60 °C for g24 h. All are stable for at least
12 h at room temperature in 80/20 DMSO/water at pH 7.4, and
all except 6 are also stable in 80/20 DMSO/water at pH 2.0.
Biology. Following standard procedure,21 trioxane dimers
6–28 were formulated in 70/30 Tween 80/ethanol and diluted
10× with water before oral administration to NMRI mice
that were infected intravenously on day 0 with the Plasmo-
dium berghei GFP ANKA malaria strain (2 × 107 parasitized
erythrocytes, donation from AP Waters and CJ Janse, Leiden
University). The mice (n ) 3 per group) were treated orally
with either three doses (24, 48, and 72 h postinfection) or a
single dose (24 h postinfection) of trioxane dimer with a
volume of 10 mL/kg. Two widely accepted measures of the
efficacy of a drug are lowering blood parasitemia levels and
raising animal survival times as compared to animals
receiving no drug. Animals receiving no drug die typically
6–7 days postinfection. An accepted yardstick of cure (i.e.,
100% efficacy) is survival of animals to day 30 postinfection,
Malaria still causes widespread morbidity and mortality.1–3
Standard antimalarial drugs such as chloroquine are rapidly
becoming ineffective due to malaria parasite widespread
resistance.4 A new class of antimalarial 1,2,4-trioxane drugs
has emerged from traditional Chinese herbal remedies.5–11
Although extremely fast-acting, the antimalarial effect of
natural trioxane artemisinin (1) and its daughter trioxanes
artemether (1b) and sodium artesunate (1c) is not long lasting;
when these trioxanes are used as monotherapy, recrudescence
of malaria parasites often occurs.5–11 Therefore, the World
Health Organization (WHO) has recommended, and most
countries where malaria is endemic have adopted, use of
artemisinin combination therapy (ACT), combining a trioxane
with an alkaloidal antimalarial such as lumefantrine or
amodiaquine.12–15 Recently, we have discovered that the
antimalarial effect of some artemisinin-derived trioxane
dimers strongly prolongs mouse survival.16 Even when used
in vivo as monotherapy, these trioxane dimers cure malaria-
infected mice after only a single subcutaneous dose.16 Curing
malaria-infected animals via oral administration of an anti-
malarial is an even more demanding and more desirable goal.
Now we report on a series of 23 new trioxane dimers 6–28,
11 of which cure 100% of the malaria-infected mice when
administered orally at 3 × 30 mg/kg.
Results and Discussion
Chemistry. Scheme 1 outlines the chemical conversions17
of natural trioxane 1 into previously described18 dimeric
trioxane ketone 2, diol 3, primary alcohol 4, and carboxylic
acid 5. Based on recent reports that optimal antimalarial oral
efficacy was achieved with trioxanes of relatively high
* To whom correspondence should be addressed. Phone: 410-516-4670.
Fax: 410-516-8420. E-mail: ghp@jhu.edu.
†
Department of Chemistry, The Johns Hopkins University.
The Johns Hopkins Malaria Research Institute.
Swiss Tropical Institute.
Division of Clinical Pharmacology, The Johns Hopkins University.
‡
§
|
10.1021/jm701168h CCC: $40.75
2008 American Chemical Society
Published on Web 01/31/2008

1036 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4
Posner et al.
Scheme 1. First Generation Artemisinin Dimers and Scheme for Synthesis of New Artemisinin Dimers
with no detectable malaria parasites in the animals’ blood at
that time. Average mouse survival times using two different
oral dosing regimens are summarized in Table 1. The
clinically used trioxane drug 1c is included as a standard.15
At an oral dose regimen of 3 × 30 mg/kg of trioxane dimers
7–10, 12–15, 18, 20, and 21, all cured the malaria-infected
mice; no parasites were detected in the blood of the surviving
mice by using standard flow cytometry techniques.21 To
confirm the reliability of such flow cytometry for establishing
cure on day 30 postinfection, blood from the surviving mice
in two curative experiments (e.g., with dimers 10 and 21)
was inoculated into uninfected mice; no parasitemia devel-
oped in these mice even after 30 days. Neither overt toxicity
nor behavioral changes attributable to trioxane drug admin-
istration were observed visually in any of the cured animals.
The clinically used trioxane drug 1c gave mouse average
survival of 7.2 days with this oral dose regimen of 3 × 30
mg/kg. At a lower oral dose regimen of 3 × 10 mg/kg,
trioxane dimers 6–7, 9–13, 15, 20, and 24 all prolonged
mouse average survival to at least day 10, compared to day
6.5 average survival with the trioxane drug 1c under this
multiple dose regimen. At only a single oral dose of 1 × 30
mg/kg, trioxane dimers 6, 9–12, 15, 20, and 25-28 all
prolonged mouse average survival at least as effectively as
the fully synthetic trioxolane peroxide drug development
candidate OZ277 maleate (29), which is in phase II clinical
trials (Table 2).22,23
In summary, many of the artemisinin-derived antimalarial
trioxane dimers described here are highly efficacious even
when administered orally. When administered using three oral
doses of 30 mg/kg, 11 of these dimers cure malaria-infected
mice. These trioxane dimers are stable both thermally and
hydrolytically. Further chemical structure-biological activity

New Artemisinin DeriVatiVes To Treat Malaria
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4 1037
(thin film) 2951, 2871, 1675, 1375, 1050, 1004, 754 cm-1; 1H NMR
(400 MHz, acetone-d6) δ 10.73 (s, 1H), 8.76 (d, J ) 5.6 Hz, 2H),
7.79 (d, J ) 5.6 Hz, 2H), 5.66 (s, 1H), 5.48 (s, 1H), 4.66–4.65 (m,
1H), 2.97–2.24 (m, 8H), 2.18–1.66 (m, 8H), 1.57–1.22 (m including
singlets at 1.33 and 1.31, 16H), 1.10–0.93 (m, 14H); 13C NMR
(100 MHz, CDCl3) δ 192.3, 163.9, 162.6, 150.4, 121.9, 104.2,
103.9, 92.3, 92.2, 80.9, 80.8, 75.4, 72.9, 51.9, 51.8, 46.2, 45.9, 37.3,
37.2, 36.9, 36.3, 36.1, 34.1, 33.9, 33.6, 32.3, 31.5, 26.2, 25.3, 24.7,
24.6, 22.6, 21.6, 21.5, 20.3, 14.1, 13.9; HRMS (FAB) calculated
for C39H56N3O9 [(M + H)+] 710.4017, found 710.4009.
Table 1. Antimalarial Oral Efficacy of Trioxane Dimers in P.
berghei-Infected Mice
avg survival (days) after infection
trioxane
dimer
dose:
3 × 30 mg/kg
dose:
3 × 10 mg/kg
log P (calc)
6
7
8
9
17.7 (17, 18, 18)a
11.0 (11, 11, 11)
7.0 (7, 7, 7)
7.0
6.3
7.1
7.1
6.9
8.1
7.4
6.4
5.9
5.9
7.7
9.2
8.9
7.7
8.0
7.8
6.6
8.0
g30
g30
g30
g30
16.3 (17, 14, 18)
15.7 (16, 15, 16)
15.7 (16, 15, 16)
14.0 (14, 14, 14)
13.3 (12, 14, 14)
8.3 (8, 9, 8)
14.7 (30, 7, 7)
6.0 (6, 6, 6)
8.0 (8, 8, 8)
7.7 (8, 8, 7)
14.0 (14, 14, 14)
7.0 (7, 7, 7)
6.0 (6, 6, 6)
7.0 (7, 7, 7)
10
11
12
13
14
15
16
18
19
20
21
22
23
24
Acetal 7. To a solution of trioxane dimer diol 3 (50 mg, 0.08
mmol) in CH2Cl2 (2 mL) was added paraformaldehyde (5 mg, 0.16
mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.02 mmol).
The reaction was stirred at rt for 12 h. It was quenched with
saturated aqueous NaHCO3 (5 mL), and the layers were separated.
The aqueous layer was extracted with EtOAc (3 × 10 mL). The
combined organic solution was washed with brine, dried (MgSO4),
and concentrated in vacuo. The purification of the crude product
by column chromatography (elution with 25% EtOAc in hexane)
g30
g30
g30
g30
20.7
g30
24.7
g30
g30
27.7
11.3
25
gave 7 (38 mg, 72%) as an amorphous solid: [R]D ) +91 (c
0.53, CHCl3); IR (thin film) 2946, 2849, 1377, 1094, 1052, 1010,
941, 755 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.37 (s, 1H), 5.34
(s, 1H), 4.99 (s, 1H), 4.96 (s, 1H), 4.50–4.46 (m, 1H), 4.29 (m,
1H), 3.86 (s, 2H), 2.73–2.64 (m, 1H), 2.35–2.20 (m, 3H), 2.02–1.96
(m, 3 H), 1.90–1.71 (m, 6H), 1.65–1.17 (m including singlets at
1.38 and 1.37, 19H), 0.97–0.83 (m including doublets at 0.94 with
J ) 6.4 Hz, 0.93 with J ) 6.4 Hz, 0.87 with J ) 7.6 Hz, and 0.84
with J ) 7.6 Hz, 14H); 13C NMR (100 MHz, CDCl3) δ 103.2,
103.1, 94.6, 88.5, 82.2, 81.09, 81.07, 73.4, 72.2, 71.3, 52.4, 52.3,
44.6, 44.5, 37.3, 37.2, 36.7, 36.6, 35.4, 34.5, 34.4, 33.8, 30.7, 30.6,
26.1, 26.09, 24.6, 24.6, 24.5, 24.4, 20.2, 20.1, 13.4, 13.2; HRMS
(FAB) calculated for C35H55O10 [(M + H)+] 635.3795, found
635.3765.
10.0 (11, 7, 12)
Control
vehicle (no drug)
1c
6–7
7.2
6–7
6.5
3.0
a Actual mouse survival until day.
Table 2. Antimalarial Efficacy Using a Single Oral Dose of Trioxane
Dimers in P. berghei-Infected Mice
avg survival (days)
trioxane
dimer
after infection dose: % suppression of parasitemia
1 × 30 mg/kg
(on day 3 post infection)
6
9
10.0 (10, 10, 10)a
8.3 (9, 9, 7)
99.4
99.6
99.5
99.0
99.6
99.2
88.0
99.3
99.0
98.9
98.9
98.8
Ketal 8. To a solution of trioxane dimer diol 3 (70 mg, 0.11
mmol) in CH2Cl2 (1 mL) was added cyclobutanone (100 µL, 1.30
mmol) and p-toluenesulfonic acid monohydrate (2 mg, 0.01 mmol).
The reaction was stirred at rt for 48 h. It was concentrated and
purified by flash column chromatography (elution with EtOAc/
hexane ) 1:10) on silica gel to give 8 (73 mg, 96%) as an
10
11
12
15
17
20
25
26
27
28
9.0 (9, 9, 9)
10.0 (10, 10, 10)
8.7 (8, 9, 9)
10.0 (10, 10, 10)
6.3 (7, 5, 7)
24
amorphous solid: [R]D ) +74 (c 0.50, CHCl3); IR (thin film)
11.7 (9, 13, 13)
10.3 (9, 8, 14)
12.7 (14, 14, 10)
13.7 (13, 13, 14)
10.0 (15, 7, 8)
1
2944, 2873, 1377, 1282, 1052, 1008, 879 cm-1; H NMR (400
MHz, CDCl3) δ 5.52 (s, 1H), 5.40 (s, 1H), 4.86 (m, 1H), 4.53 (m,
1H), 4.24 (d, J ) 8.4 Hz, 1H), 3.98 (d, J ) 8.0 Hz, 1H), 2.90 (m,
1H), 2.78 (m, 1H), 2.63–2.27 (m, 6H), 2.13 (d, J ) 13.6 Hz, 2H),
1.85–0.55 (m including a singlet at 1.40, 42H); 13C NMR (100
MHz, C6D6) δ 109.7, 103.2, 102.9, 101.1, 89.2, 89.2, 83.6, 81.0,
80.9, 73.0, 72.0, 71.3, 52.7, 52.6, 45.1, 44.8, 38.0, 37.9, 37.5, 37.4,
37.3, 37.1, 35.5, 34.8, 34.7, 31.2, 26.3, 25.2, 24.8, 24.8, 20.3, 20.2,
13.5, 13.2, 12.1; HRMS (FAB) calculated for C38H59O10 [(M +
H)+] 675.4108, found 675.4084.
Ketal 9. To a solution of trioxane dimer diol 3 (50 mg, 0.08
mmol) in CH2Cl2 (3 mL) was added 1,4-cyclohexanedione (90 mg,
0.80 mmol) and p-toluenesulfonic acid monohydrate (3 mg, 0.02
mmol). The reaction was stirred at rt for 12 h. The reaction was
quenched with saturated aqueous NaHCO3 (5 mL), and the layers
were separated. The aqueous layer was extracted with EtOAc (3
× 10 mL). The combined organic solution was washed with brine,
dried (MgSO4), and concentrated. The purification of the crude
Control
vehicle (no drug)
6–7
0
1c
29
7.6
92.0
8.2, 10.7b
99.7, 99.95b
a Actual mouse survival until day. b Data from Supporting Information
in ref 22.
relationship (SAR) study is ongoing, aimed at developing
trioxane dimers able to achieve the goal of a single oral dose
cure.
Experimental Section18
The purity of all trioxane dimers was judged to be >98% based
on HPLC analysis. Log P values were calculated by using
MarvinSketch and a calculator plug-in by ChemAxon Kft.
product by column chromatography (elution with 25% EtOAc in
21
hexane) gave 9 (45 mg, 78%) as an amorphous solid: [R]D
)
+70 (c 0.75, CHCl3); IR (thin film) 2938, 2880, 2359, 2320, 1712,
1635, 1587, 1558, 1442, 1374, 1316, 1249, 1220, 1181, 1114, 1046,
1008, 959, 921, 872, 834, 747 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.36 (s, 1H), 5.35 (s, 1H), 4.62–4.58 (m, 1H), 4.26–4.23 (m, 1
H), 4.08 (d, J ) 8.8 Hz, 1H), 3.96 (d, J ) 8.8 Hz, 1H), 2.75 (sextet,
J ) 7.2 Hz, 1 H), 2.68–2.55 (m, 3H), 2.48–2.40 (m, 2 H), 2.36–2.22
(m, 3H), 2.11–1.69 (m, 12H), 1.65–1.21 (m including singlets at
1.37 and 1.35, 19H), 0.92–0.80 (m including a doublet at 0.93 with
J ) 6.0 Hz, 14H); 13C NMR (100 MHz, CDCl3) δ 210.8, 107.2,
103.3, 102.8, 88.8, 88.2, 83.4, 81.1, 81.0, 73.3, 72.6, 70.8, 52.4,
52.2, 44.7, 44.2, 38.22, 38.2, 37.3, 37.2, 37.1, 36.59, 36.55, 35.9,
Hydrazone 6. An oven-dried 10 mL flask was charged sequen-
tially with trioxane dimer ketone 2 (151 mg, 0.25 mmol), EtOH (5
mL), isoniazid (105 mg, 0.76 mmol), and p-toluenesulfonic acid
monohydrate (24 mg, 0.13 mmol). The reaction was stirred at room
temperature (rt) for 2 h, and then the reaction was quenched with
H2O (10 mL). EtOAc (20 mL) was added to the mixture, and the
layers were separated. The aqueous layer was extracted with EtOAc
(3 × 20 mL), and the combined organic layer was dried (MgSO4)
and concentrated in vacuo. The purification of the crude product
by column chromatography (1% Et3N in EtOAc) gave 6 (156 mg,
21
86%) as an amorphous solid: [R]D ) -109 (c 1.30, CHCl3); IR

1038 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4
Posner et al.
34.7, 34.5, 34.4, 34.3, 30.9, 30.7, 30.3, 26.1, 26.0, 24.6, 24.59, 24.4,
20.2, 13.4, 13.2, 11.1; HRMS (FAB) calculated for C40H61O11 [(M
+ H)+] 717.4214, found 717.4181.
were separated, and the aqueous layer was extracted with CH2Cl2
(3 × 10 mL). The combined organics were washed with H2O (1 ×
10 mL), dried (MgSO4), and concentrated. Purification of the crude
product by column chromatography (10% hexane in EtOAc) gave
4-oxo-piperidine-1-carboxylic acid methylamide (43 mg, 45%) as
a slightly yellow solid: mp 76–80 °C; IR (thin film) 3348, 2962,
2909, 2874, 1713, 1630, 1547, 1484, 1419, 1392, 1353, 1312, 1266,
Ketal 10. p-Toluenesulfonic acid monohydrate (3 mg, 0.02
mmol) was added to a solution of trioxane dimer diol 3 (50 mg,
0.08 mmol) and tetrahydro-4H-pyran-4-one (15 µL, 0.16 mmol)
in CH2Cl2 (2 mL). The reaction was stirred overnight at rt. The
solution was washed with saturated aqueous NaHCO3 (5 mL), water
(5 mL), and brine (5 mL), dried (MgSO4), and concentrated. The
crude product was purified by flash chromatography (silica gel, 33%
EtOAc in hexane) to afford 10 (30 mg, 54%) as an amorphous
1
1151, 1080, 982, 825, 767 cm-1; H NMR (400 MHz, CDCl3) δ
5.14 (s, 1H), 3.65 (t, J ) 5.6 Hz, 4H), 2.83–2.68 (m, 3H), 2.42 (t,
J ) 6.0 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 207.8, 158.1,
42.9, 40.9, 27.7; HRMS (FAB) calculated for C7H13N2O2 [(M +
H)+] 157.0977, found 157.0969. To a solution of trioxane dimer
diol 3 (20 mg, 0.03 mmol) in CH2Cl2 (1.50 mL) was added 4-oxo-
piperidine-1-carboxylic acid methylamide (41 mg, 0.26 mmol) and
p-toluenesulfonic acid monohydrate (2 mg, 0.01 mmol). The
reaction was stirred for 16 h at rt and then quenched with H2O (3
mL). Layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 10 mL). The combined organic layer was dried
(MgSO4) and concentrated. Purification of the crude product by
column chromatography (100% EtOAc) gave 13 (19 mg, 76%) as
an amorphous white solid: [R]D22 ) +55 (c 0.90, CHCl3); IR (thin
film) 3346, 2956, 2926, 2873, 2850, 1629, 1544, 1449, 1379, 1350,
25
solid: [R]D ) +74 (c 0.42, CHCl3); IR (thin film) 2953, 2873,
1
1712, 1453, 1376 cm-1; H NMR (400 MHz, CDCl3) δ 5.36 (s,
1H), 5.35 (s, 1H), 4.59 (m, 1H), 4.19 (m, 1H), 4.00 (d, J ) 8.8 Hz,
1H), 3.89 (d, J ) 8.8 Hz, 1H), 3.75 (m, 4H), 2.79–2.64 (m, 2H),
2.37–2.27 (m, 3H), 2.04–1.16 (m including singlets at 1.38 and
1.36, 31H), 0.94–0.81 (m including a doublet at 0.95 with J ) 6.4
Hz, 14H); 13C NMR (100 MHz, CDCl3) δ 106.2, 103.1, 102.8,
88.2, 87.9, 82.7, 80.9, 80.8, 72.6, 72.5, 71.2, 65.8, 65.7, 52.3, 52.1,
44.6, 44.3, 37.9, 37.0, 36.9, 36.7, 36.7, 36.4, 36.4, 34.6, 34.3, 34.2,
30.7, 30.4, 25.9, 25.9, 24.4, 24.1, 20.0, 20.0, 13.5, 13.3; HRMS
(FAB) calculated for C39H61O11 [(M + H)+] 705.4214, found
705.4214.
1
1251, 1119, 1092, 1051, 1009, 935, 877, 829, 769, 664 cm-1; H
Ketal 11. To a solution of trioxane dimer diol 3 in THF (2 mL)
at 0 °C was added N-benzoyl piperidinone (41 mg, 0.20 mmol)
and triethylorthoformate (1.0 mL, 6.0 mmol). The mixture was
warmed to rt and stirred for 24 h. It was quenched by addition of
cold water (10 mL), and layers were separated. The aqueous layer
was extracted with ethyl acetate (3 × 30 mL). The combined
organic solution was washed with water (5 mL) and 5% aqueous
NaHCO3 (5 mL), dried (Na2SO4), and filtered. The filtrate was
concentrated to give the crude product that was purified by flash
column chromatography (eluted with 50% EtOAc in hexane) to
afford 11 (27 mg, 85%) as an amorphous solid: [R]D25 ) +234 (c
0.75, CHCl3); IR (thin film) 2947, 2876, 1631, 1437, 1379, 1350,
1293, 1113, 1092, 1048, 1013, 934, 868, 747 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.39 (s, 5H), 5.34 (s, 2H), 4.60–4.56 (dd, J ) 6.0,
10.4 Hz, 1H), 4.23–4.21 (m, 1H), 4.05–3.91 (m, 3H), 3.8–3.69 (s,
1H), 3.50–3.47 (m, 2H), 2.79–2.61 (m, 2H), 2.32–2.28 (m, 2H),
2.01–1.19 (m including a singlet at 1.36, 32H), 0.95–0.88 (m, 14H);
13C NMR (100 MHz, CDCl3) δ 170.3, 136.1, 129.5, 128.4, 126.8,
107.1, 103.3, 102.9, 88.7, 88.2, 83.3, 81.1, 81.3, 77.3, 73.0, 72.7,
71.0, 53.5, 52.4, 52.3, 45.7, 44.8, 44.3, 40.2, 37.3, 37.2, 36.6, 35.8,
34.5, 34.4, 30.9, 30.7, 26.1, 24.6, 24.4, 20.2, 20.2, 13.7, 13.3; HRMS
(FAB) calculated for C46H66N3O11 [(M + H)+] 808.4636, found
808.4655.
NMR (400 MHz, CDCl3) δ 5.33 (s, 1H), 5.32 (s, 1H), 4.57–4.53
(m, 1H), 4.46–4.44 (m, 1H), 4.20–4.15 (m, 1H), 3.99 (d, J ) 9.2
Hz, 1H), 3.88 (d, J ) 9.2 Hz, 1H), 3.48–3.35 (m, 4H), 2.78–2.77
(d, J ) 4.4 Hz, 3H), 2.75–2.70 (m, 1H), 2.67–2.62 (m, 1H),
2.34–2.19 (m, 3H), 2.19–1.92 (m, 4H), 1.88–1.83 (m, 2H),
1.77–1.71 (m, 4H), 1.68–1.60 (m, 3H), 1.56–1.44 (m, 5H),
1.40–1.29 (m including singlets at 1.37 and 1.33, 10H), 1.25–1.17
(m, 3H), 0.96–0.91 (m, 7H), 0.85–0.82 (m, 7H); 13C NMR (100
MHz, CDCl3) δ 158.1, 107.3, 103.4, 103.0, 88.6, 88.3, 83.1, 81.1,
81.1, 72.9, 72.7, 71.2, 52.5, 52.3, 44.8, 44.5, 42.1, 37.3, 37.2, 37.1,
36.9, 36.7, 35.7, 34.7, 34.5, 34.4, 30.9, 30.8, 30.7, 27.7, 26.2, 26.1,
24.6, 24.4, 20.3, 20.2, 19.1, 13.7, 13.4; HRMS (FAB) calculated
for C41H65N2O11 [(M + H)+] 761.4588, found 761.4610.
Ketal 14. To a solution of trioxane dimer diol 3 (50 mg, 0.08
mmol) in CH2Cl2 (1 mL) was added tetrahydrothiopyran-4-one (18
mg, 0.16 mmol) and p-toluenesulfonic acid monohydrate (3 mg,
0.02 mmol), and it was stirred at rt for 12 h. The reaction was
quenched with saturated aqueous NaHCO3 (3 mL), and the layers
were separated. The aqueous layer was extracted with EtOAc (3
× 5 mL). The combined organic solution was washed with brine,
dried (MgSO4), and concentrated. The residue was purified by
column chromatography (elution with 25% EtOAc in hexane) to
give a crude solid. To a mixture of oxone (410 mg, 0.69 mmol) in
H2O (2 mL) was cannulated the crude solid (49 mg, 0.07 mmol) in
MeOH (4 mL). The reaction stirred at rt for 1.5 h. The insoluble
solid was filtered off, and the filtrate was extracted with EtOAc (3
× 5 mL). The combined organic layer was washed with brine, dried
(MgSO4), and concentrated. Purification by column chromatography
(30% EtOAc in hexane) gave 14 (46 mg, 88%) as an amorphous
Ketal 12. p-Toluenesulfonic acid monohydrate (1 mg, 5 µmol)
was added to a solution of trioxane dimer diol 3 (20 mg, 0.03 mmol)
and 1-carbethoxy-4-piperidone (10 µL, 0.06 mmol) in CH2Cl2 (1
mL). The reaction was stirred overnight at rt. The solution was
washed with saturated aqueous NaHCO3 (5 mL), water (5 mL),
and brine (5 mL), dried (MgSO4), and concentrated. The crude
product was purified by flash chromatography (silica gel, 29%
EtOAc in hexane) to afford 12 (17 mg, 67%) as an amorphous
24
solid: [R]D ) +62 (c 0.34, CHCl3); IR (thin film) 2938, 2880,
2851, 2465, 2224, 1712, 1587, 1558, 1452, 1374, 1326, 1287, 1249,
24
1
solid: [R]D ) +75 (c 0.62, CHCl3); IR (thin film) 2927, 2875,
1220, 1191, 1104, 1056, 1017, 940, 901, 882, 747, 660 cm-1; H
1
1697, 1435, 1378, 1350, 1279, 1240, 1112, 1055, 1011 cm-1; H
NMR (400 MHz, CDCl3) δ 5.28 (s, 1H), 5.28 (s, 1H), 4.57–4.53
(m, 1H), 4.28–4.25 (m, 1H), 4.04 (d, J ) 9.0 Hz, 1H), 3.91 (d, J
) 9.0 Hz, 1H), 3.43–3.37 (m, 1H), 3.33–3.27 (m, 1H), 3.08–3.00
(m, 2H), 2.74–2.69 (m, 1 H), 2.49–2.44 (m, 1 H), 2.35–2.22 (m, 5
H), 2.03–1.89 (m, 5H), 1.89–1.47 (m, 10H), 1.47–1.15 (m including
singlets at 1.38 and 1.36, 14H), 0.92–0.80 (m including doublets
at 0.87 with J ) 7.6 Hz and 0.84 with J ) 7.6 Hz, 14H); 13C
NMR (100 MHz, CDCl3) δ 104.8, 103.1, 102.3, 89.3, 88.0, 83.7,
80.8, 80.7, 73.3, 71.9, 68.9, 51.9, 51.6, 49.0, 48.7, 44.3, 43.3, 37.2,
37.14, 37.10, 36.2, 36.1, 34.2, 34.1, 33.9, 33.8, 33.6, 30.6, 30.4,
25.7, 25.6, 24.5, 24.4, 24.3, 24.1, 19.9, 19.7, 13.1, 12.2; HRMS
(FAB) calculated for C39H61O12S [(M + H)+] 753.3883, found
753.3875.
NMR (400 MHz, CDCl3) δ 5.36 (s, 1H), 5.35 (s, 1H), 4.58 (m,
1H), 4.20 (m, 1H), 4.11 (q, J ) 7.2 Hz, 2H), 4.01 (d, J ) 8.8 Hz,
1H), 3.89 (d, J ) 8.8 Hz, 1H), 3.61–3.47 (m, 4H), 2.77–2.65 (m,
2H), 2.37–2.23 (m, 3H), 2.04–1.14 (m including singlets at 1.39
and 1.36, 34H), 0.95–0.84 (m including a doublet at 0.94 with J )
6.0 Hz, 14H); 13C NMR (100 MHz, CDCl3) δ 155.4, 107.2, 103.4,
103.0, 88.5, 88.2, 83.1, 81.1, 81.1, 72.8, 71.3, 61.3, 52.5, 52.3, 44.8,
44.5, 41.8, 37.3, 37.2, 37.0, 36.7, 36.6, 35.7, 34.5, 34.4, 30.9, 30.7,
29.7, 26.1, 26.1, 24.6, 24.4, 20.2, 20.2, 14.7, 14.2, 13.7, 13.4; HRMS
(FAB) calculated for C42H66NO12 [(M + H)+] 776.4585, found
776.4597.
Ketal 13. 4-Oxo-piperidine-1-carbonyl chloride (0.100 g, 0.620
mmol) was dissolved in CH2Cl2 (1.50 mL). Methyl amine (2.0 M
in THF, 1.50 mL, 3.09 mmol) was added to the solution. It was
stirred for 16 h at rt and then quenched with H2O (5 mL). Layers
Ester 16. A 25 mL round-bottom flask was charged with trioxane
dimer diol 3 (70 mg, 0.11 mmol), CH2Cl2 (5 mL), pyridine (22
µL, 0.56 mmol), and benzoyl chloride (0.33 µL, 0.56 mmol). The

New Artemisinin DeriVatiVes To Treat Malaria
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4 1039
reaction was stirred at rt for 2 h. Then, it was quenched with ice
cold water (5 mL). The aqueous layer was extracted with Et2O (3
× 5 mL), and the combined organics were washed with aqueous
citric acid (5%, 5 × 5 mL). The organic layer was dried (MgSO4)
and concentrated. The crude product was purified by flash silica
gel column chromatography (40% EtOAc in hexane) to give 16
9.2 Hz, 1H), 2.64 (m, 2H), 2.31 (m, 2H), 1.88 (m, 9H), 1.62 (m,
5H), 1.4–1.19 (m including a singlet at 1.38, 14H), 0.97–0.79 (m
including doublets at 0.94 with J ) 6.0 Hz, 0.87 with J ) 7.2 Hz,
and 0.87 with J ) 7.6 Hz, 14H); 13C NMR (100 MHz, CDCl3) δ
162.5 (d, J ) 244 Hz), 133.4 (d, J ) 3 Hz), 129.9 (d, J ) 8 Hz),
115.2 (d, J ) 22 Hz), 103.1, 102.9, 89.4, 88.9, 83.5, 81.6, 81.1,
81.1, 74.0, 74.0, 71.2, 71.1, 70.7, 58.7, 57.5, 52.4, 52.2, 44.4, 44.0,
37.4, 37.4, 36.63, 36.63, 36.0, 35.3, 34.5, 34.5, 30.82, 30.82, 26.1,
26.0, 24.8, 24.8, 20.2, 20.1, 13.0, 12.7; 19F NMR (282 MHz, CDCl3)
δ -115.16 (septet, J ) 5.6 Hz); HRMS (FAB) calculated for
C45H63FO11 [(M + H)+] 799.4433, found 799.4445.
Thiophosphate ester 19. To a solution of trioxane dimer
primary alcohol 4 (0.080 g, 0.13 mmol) in THF at 0 °C was
added lithium hexamethyldisilane (1.0 M in THF, 0.20 mL, 0.20
mmol) dropwise over 1 min. After stirring for 10 min, diethyl
chloro thiophosphate (52 µL, 0.33 mmol) was added neat. The
reaction mixture was allowed to warm to rt and stir for 2 h before
the reaction was quenched by the slow addition of H2O (5 mL).
The contents of the flask were extracted with CH2Cl2 (2 × 25
mL), washed with saturated aqueous NaHCO3 (5 mL) and H2O
(5 mL), dried (MgSO4), and concentrated in vacuo. The crude
product was purified by silica gel chromatography (20% EtOAc
in hexane) to give 19 as an amorphous white solid (56 mg, 56%):
[R]D23 ) +59.2 (c 3.30, CHCl3); IR (thin film) 2943, 2872, 1737,
1443, 1378, 1102, 1002, 967 cm-1; 1H NMR (300 MHz, CDCl3)
δ 5.31 (s, 1H), 5.28 (s, 1H), 4.42–4.32 (m, 1H), 4.27–4.15 (m,
3H), 4.15–4.04 (m, 4H), 2.74–2.50 (m, 2H), 2.37–2.13 (m, 3H),
2.02–1.17 (m including singlets at 1.38 and 1.37, and a triplet
at 1.30 with J ) 6.9 Hz, 34H), 0.97–0.77 (m including doublets
at 0.93 with J ) 6.0 Hz, 0.85 with J ) 7.5 Hz, and 0.84 with
J ) 7.5 Hz, 14H); 13C NMR (75 MHz, CDCl3) δ 103.1, 102.8,
89.3, 88.6, 81.14, 81.07, 73.9, 71.2, 70.3 (d, J ) 5 Hz), 64.1 (d,
J ) 5 Hz), 52.5, 52.2, 44.5, 44.2, 37.4, 37.3, 36.63, 36.57, 35.2,
35.1, 34.5, 34.4, 30.5, 30.4, 30.2, 29.6, 26.1 (d, J ) 3 Hz), 24.82,
24.75, 24.70, 24.6, 20.2, 20.1, 15.9 (d, J ) 5 Hz), 15.2, 13.2;
HRMS (FAB) calculated for C38H64O11PS [(M + H)+] 759.3907,
found 759.3896.
23
(64 mg, 80%) as an amorphous solid: [R]D ) +70 (c 1.00,
CHCl3); IR (thin film) 3498, 2943, 2870, 1718, 1446, 1372, 1310,
1
1274, 1112, 907, 730, 710 cm-1; H NMR (400 MHz, CDCl3) δ
8.05–8.02 (m, 2H), 7.55–7.51 (m, 1H), 7.43–7.34 (m, 2H), 5.34
(s, 1H), 5.31 (s, 1H), 4.71 (dd, J ) 8.0, 10.0 Hz, 1H), 4.61 (dd, J
) 8.0, 10.0 Hz, 1H), 4.55 (s, 2H), 4.24 (bs, 1H), 2.66–2.54 (m,
2H), 2.32–2.24 (m, 2H), 2.15–1.75 (m, 10H), 1.68–1.62 (m, 4H),
1.42–1.18 (m including two singlets at 1.40 and 1.37, 14H),
0.96–0.86 (m, 14H); 13C NMR (100 MHz, CDCl3) δ 166.1, 132.5,
130.7, 129.5, 128.1, 103.6, 102.9, 89.4, 89.1, 80.9, 80.9, 73.8, 70.5,
70.4, 52.1, 51.9, 43.9, 43.8, 37.4, 37.4, 36.5, 36.5, 36.3, 35.0, 34.3,
34.3, 30.8, 30.7, 30.2, 25.9, 25.8, 24.8, 24.8, 24.6, 24.6, 20.0, 20.0,
12.7, 12.6; HRMS (FAB) calculated for C41H59O11 [(M + H)+]
727.4057, found 727.4031; Anal. calculated for C41H58O11 C, 67.75,
H, 8.04, found C, 67.24, H, 8.09.
Ether 17. To a solution of 2-butyne-1,4-diol (500 mg, 5.81
mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral
oil, 140 mg, 3.48 mmol), and it was stirred at rt for 30 min. The
mixture was cooled to 0 °C, and 4-fluorobenzyl bromide (428 µL,
3.48 mmol) was added dropwise. The solution was stirred for 14 h
and then added to ice cold water (10 mL). The aqueous layer was
extracted with EtOAc (3 × 15 mL). The combined organic layers
were rinsed with ice–water (3 × 20 mL) and brine, dried (MgSO4),
and concentrated. Flash column chromatography (10–25% EtOAc
in hexane) yielded mono 4-fluorobenzyl ether (320 mg, 28%) as a
colorless oil: IR (thin film) 3440, 2871, 1603, 1510, 1349, 1223,
1073, 1029, 1007, 823, 707 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.32 (m, 2H), 7.03 (m, 2H), 4.52 (s, 2H), 4.30 (m, 2H), 4.19 (m,
2H), 2.26 (bs, 1H); 13C NMR (100 MHz, CDCl3) δ 162.5 (d, J )
244 Hz), 133.0 (d, J ) 3 Hz), 129.8 (d, J ) 8 Hz), 115.3 (d, J )
22 Hz), 84.9, 81.4, 70.9, 57.4, 50.9; HRMS (FAB) calculated for
C11H11FO2 [(M + H)+] 193.0665; found, 193.0666. To a solution
of the mono 4-fluorobenzyl ether alcohol (295 mg, 1.52 mmol) in
THF (20 mL) was added freshly ground KOH (681 mg, 12.16
mmol). The mixture was cooled to -30 °C, and tosylchloride (319
mg, 1.67 mmol) was added in one portion. After stirring at -30
°C for 3 h, the mixture was added to water (10 mL), and the aqueous
layer was extracted with EtOAc (3 × 15 mL). The combined
organic layers were rinsed with brine, dried (MgSO4), concentrated,
and purified by flash column chromatography (25% EtOAc in
hexane) to give 2-butyne-1-tosylate-4-p-fluorobenzyl ether (495 mg,
94%) as a colorless oil: IR (thin film) 2857, 1602, 1508, 1446,
1358, 1222, 1179, 1083, 1008, 947, 815, 662 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.79 (m, 2H), 7.31 (m, 2H), 7.25 (m, 2H), 7.00
(m, 2H), 4.74 (t, J ) 1.6 Hz, 2H), 4.42 (s, 2H), 4.05 (t, J ) 1.6
Hz, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5 (d, J
) 244 Hz), 145.1, 133.0 (d, J ) 3 Hz), 129.8 (d, J ) 8 Hz), 129.8,
Carbamate 20. Trioxane dimer primary alcohol 4 (40 mg,
0.07 mmol) was dissolved in CH2Cl2 (0.8 mL). Sodium hydride
(60% dispersion in mineral oil, 4 mg, 0.10 mmol) was added to
the solution. After 1 h, diethylcarbamyl chloride (9 mg, 0.07
mmol) was added. The reaction was stirred for 16 h at rt, and
then more sodium hydride (60% dispersion in mineral oil, 4 mg,
0.10 mmol) was added. After 16 h, the reaction was quenched
with H2O (10 mL). The reaction mixture was extracted with
CH2Cl2 (10 mL) and ethyl acetate (2 × 10 mL). The combined
organic layer was dried (MgSO4) and concentrated. Purification
of the crude product by column chromatography (60% EtOAc
21
in hexane) gave 20 (32 mg, 70%) as an amorphous solid: [R]D
) +49.3 (c 2.43, CHCl3); IR (thin film) 2928, 2870, 1693, 1480,
1423, 1374, 1268, 1230, 1191, 1114, 1056, 998, 958, 950, 872,
766 cm-1 1H NMR (400 MHz, CDCl3) δ 5.29 (m, 2H),
;
4.37–4.33 (m, 1H), 4.26–4.15 (m, 3H), 3.24 (m, 4H), 2.69
(sextet, J ) 6.4 Hz, 1H), 2.59 (sextet, J ) 6.8 Hz, 1H), 2.31–2.27
(m, 2H), 2.16 (m, 1H), 2.00–1.93 (m, 2H), 1.88–1.82 (m, 2H),
1.81–1.71 (m, 3H), 1.64–1.50 (m, 5H), 1.44–1.36 (m including
singlets at 1.38 and 1.37, 9H), 1.33–1.17 (m, 6H), 1.09 (t, J )
6.8 Hz, 6H), 0.95–0.92 (m, 7H), 0.86–0.82 (m, 8H); 13C NMR
(100 MHz, CDCl3) δ 156.0, 103.2, 103.0, 88.2, 88.6, 81.2, 81.1,
73.6, 72.1, 67.4, 52.5, 52.3, 44.6, 44.4, 37.4, 37.3, 36.7, 36.6,
34.5, 34.4, 34.3, 30.8, 30.5, 30.4, 29.8, 26.1, 26.0, 24.8, 24.7,
24.6, 20.3, 20.2, 14.2, 13.3, 12.9; HRMS (FAB) calculated for
C39H64NO10 [(M + H)+] 706.4530, found 706.4540.
Amide 21. Trioxane dimer acid 5 (35 mg, 0.06 mmol) was
dissolved in CH2Cl2 (1.5 mL). 1-(3-(Dimethylamino)propyl)-3-
ethylcarbodiimide hydrochloride (13 mg, 0.07 mmol) and 1-hy-
droxybenzotriazole (10 mg, 0.07 mmol) were added. After 1 h,
cyclohexanemethyl amine (23 mg, 0.17 mmol) was added to the
reaction mixture. It was stirred for 3 h, and then the reaction was
quenched with saturated aqueous NH4Cl (3 mL). The aqueous layer
was extracted with CH2Cl2 (10 mL) and EtOAc (2 × 10 mL). The
128.1, 115.3 (d, J ) 22 Hz), 85.3, 78.5, 70.9, 57.8, 57.0, 21.6; 19
F
NMR (282 MHz, CDCl3) δ -114.72 (septet, J ) 5.6 Hz); HRMS
(FAB) calculated for C18H16FO4S [(M - H+)] 347.0753, found
347.0746. To a solution of trioxane dimer diol 3 (35 mg, 0.056
mmol) in THF (1 mL) was added KH (30% dispersion in mineral
oil, rinsed with hexane prior to use, 30 mg, 0.225 mmol), and the
mixture was stirred at rt for 1 h. The mixture was cooled to 0 °C,
and a solution of 2-butyne-1-tosylate-4-p-fluorobenzyl ether (130
mg, 0.373 mmol) in THF (1 mL) was added dropwise. The solution
was warmed slowly to rt and stirred for 10 h. The reaction was
added to ice cold water and extracted with CH2Cl2 (3 × 5 mL),
dried (MgSO4), and concentrated. The crude oil was purified by
flash column chromatography (25% EtOAc in hexane) to give 17
(16 mg, 36% yield) as an amorphous white solid: [R]D27 ) +80 (c
0.08, CHCl3); IR (thin film) 3673, 2940, 2889, 1513, 1377, 1348,
1223, 1091, 1014, 844, 825, 720 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.33 (m, 2H), 7.03 (m, 2H), 5.36 (s, 1H), 5.34 (s, 1H),
4.55 (m, 4H), 4.30 (m, 4H), 3.74 (d, J ) 9.2 Hz, 1H), 3.66 (d, J )

1040 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4
Posner et al.
combined organic solution was dried (MgSO4) and concentrated.
Purification of the crude product by column chromatography (30%
EtOAc in hexane) gave 21 (39 mg, 93%) as an amorphous solid:
Amide 24. To a solution of trioxane dimer acid 5 (50 mg, 0.08
mmol) in CH2Cl2 (5 mL) was added N-[3-(dimethylamino)propyl]-
N′-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol) and
1-hydroxybenzotriazole hydrate (12 mg, 0.09 mmol). After 1.5 h,
methyl 4-(aminomethyl)benzoate hydrochloride (65 mg, 0.32 mmol)
and Et3N (44 µL, 0.39 mmol) were added. The reaction mixture
was stirred overnight, and then the reaction was quenched by
the addition of 1 N HCl (5 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were washed with brine, dried (MgSO4),
filtered, and concentrated. The crude product was purified by flash
gradient column chromatography (silica gel, 3:2 then, 3:1 ether/
petroleum ether) to give 24 (47 mg, 78%) as an amorphous solid:
22
[R]D ) +102 (c 1.25, CHCl3); IR (thin film) 2872, 2880, 2861,
1654, 1529, 1452, 1355, 1268, 1258, 1230, 1201, 1191, 1094, 1075,
1
1056, 1017, 959, 930, 863, 824, 815, 757 cm-1; H NMR (400
MHz, CDCl3) δ 6.05 (t, J ) 5.6 Hz, 1H), 5.25 (s, 1H), 5.22 (s,
1H), 4.09–3.99 (m, 2H), 3.07 (t, J ) 6.0 Hz, 2H), 2.75–2.65 (m,
2H), 2.55–2.49 (m, 1H), 2.34–2.25 (m, 2H), 2.14–2.04 (m, 1H),
2.03–1.95 (m, 3H), 1.90–1.78 (m, 3H), 1.77–1.59 (m, 11H),
1.54–1.41 (m, 6H), 1.39–1.34 (m including singlets at 1.38 and
1.36, 6H), 1.31–1.14 (m, 8H), 0.96–0.90 (m, 9H), 0.85–0.79 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 175.7, 103.4, 88.5, 88.4, 81.2,
81.1, 76.1, 74.3, 52.6, 52.5, 46.0, 45.0, 44.7, 44.1, 37.7, 37.4, 37.3,
36.5, 34.7, 34.5, 32.8, 32.6, 31.6, 31.1, 31.0, 30.2, 29.9, 26.5, 26.3,
26.2, 25.9, 25.9, 25.3, 24.9, 24.8, 24.7, 24.6, 20.2, 14.3, 13.5, 13.2;
HRMS (FAB) calculated for C41H66NO9 [(M + H)+] 716.4638,
found 716.4745.
25
[R]D ) +56 (c 0.50, CHCl3); IR (thin film) 2950, 2360, 1722,
1672, 1279, 1106, 1052, 1012 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.95–7.93 (d, J ) 8.1 Hz, 2H), 7.41–7.39 (d, J ) 8.1 Hz, 2H),
6.41–6.39 (t, J ) 4.8 Hz, 1H), 5.26 (s, 1H), 5.15 (s, 1H), 4.48 (d,
J ) 5.3 Hz, 2H), 4.15–4.06 (m, 2H), 3.87 (s, 3H), 2.74–2.57 (m,
3H), 2.31–2.11 (m, 3H), 2.01–1.16 (m including singlets at 1.39
and 1.29, 27H), 0.93–0.82 (m, 14H); 13C NMR (75 MHz, CDCl3)
δ 176.1, 166.9, 144, 129.8, 129, 127.9, 103.4, 103.3, 88.7, 88.5,
81.2, 81.1, 76.3, 73.7, 52.5, 52.4, 52.0, 44.6, 44.5, 44.2, 43.7, 37.4,
37.2, 36.5, 34.5, 33.3, 33.0, 30.2, 30.0, 26.2, 26.1, 24.9, 24.8, 24.7,
24.5, 20.2, 13.5, 13.0; HRMS (FAB) calculated for C43H62NO11
[(M + H)+] 768.4323, observed 768.4349.
Amide 22. To a solution of trioxane dimer acid 5 (50 mg, 0.10
mmol) in CH2Cl2 (2 mL) at 0 °C was added 1-(3-(dimethylami-
no)propyl)-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol)
and hydroxybenzotriazole (16 mg, 0.12 mmol). The mixture was
stirred for 2 h. The neopentylamine (0.041 mL, 0.49 mmol) was
then added to the reaction mixture at 0 °C, and it was stirred
overnight as it warmed to rt. The reaction was quenched by addition
of H2O (10 mL). It was extracted with EtOAc (3 × 30 mL). The
combined extracts were washed with H2O (5 mL) and brine (5 mL),
dried (Na2SO4), and concentrated to give the crude product, which
was purified by flash column chromatography (eluted with 50%
EtOAc in hexane to afford 22 (52 mg, 77%) as an amorphous solid:
Amide 25. To a solution of trioxane dimer acid 5 (25 mg, 0.040
mmol) in CH2Cl2 (1 mL) were added N-[3-(dimethylamino)propyl]-
N′-ethylcarbodiimide hydrochloride (9 mg, 0.05 mmol) and 1-hy-
droxybenzotriazole (7 mg, 0.05 mmol). It was stirred at rt for 1 h.
To the reaction was added 4-methylbenzylamine (15 µL, 0.12
mmol), and the solution was stirred for 3 h. Then, water (1 mL)
was added, and the layers were separated. The aqueous layer was
extracted with EtOAc (3 × 2 mL). The combined organic solution
was dried (MgSO4) and concentrated. The residue was purified by
25
[R]D ) +110 (c 0.50, CHCl3); IR (thin film) 3338, 2953, 2870,
1664, 1447, 1380, 1212, 1094, 1011, 936, 877, 752 cm-1; 1H NMR
(400 MHz, CDCl3) δ 6.11–6.08 (t, J ) 6.0 Hz, 1H), 5.27 (s, 1H),
5.25 (s, 1H), 4.14–4.10 (m, 1H), 4.07–4.04 (m, 1H), 3.15 (dd, J )
6.8, 13.6 Hz, 1H), 2.97 (dd, J ) 6.0, 13.6 Hz, 1H), 2.78–2.70 (m,
2H), 2.59–2.52 (m, 1H), 2.36–2.26 (m, 2H), 2.18–2.07 (m, 1H),
2.03–1.97 (m, 2H), 1.90–1.71 (m, 6H), 1.68–1.61 (m, 2H),
1.55–1.18 (m including two singlets at 1.39 and 1.36, 17H),
0.96–0.90 (m including a singlet at 0.91, 17H), 0.85 (d, J ) 7.6
Hz, 3H), 0.82 (d, J ) 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 175.7, 103.5, 103.4, 88.4, 88.2, 81.2, 81.0, 76.0, 74.5, 52.6, 52.5,
50.8, 44.8, 44.7, 44.2, 37.4, 37.3, 36.5, 36.5, 34.5, 34.5, 32.4, 31.5,
30.2, 29.8, 27.4, 26.2, 26.1, 24.9, 24.7, 24.6, 24.5, 20.2, 20.2, 13.5,
13.3; HRMS (FAB) calculated for C39H64NO9 [(M + H)+]
690.4581, found 690.4595.
flash column chromatography (elution with EtOAc/hexane ) 1:2)
22
to give 25 (26 mg, 89%) as an amorphous white solid: [R]D
)
+82 (c 0.59, CHCl3); IR (thin film) 2928, 2870, 1665, 1514, 1377,
1052 cm-1; H NMR (400 MHz, CDCl3) δ 7.22 (d, J ) 8.0 Hz,
1
2H), 7.09 (d, J ) 8.0 Hz, 2H), 6.18 (t, J ) 5.2 Hz, 1H), 5.27 (s,
1H), 5.20 (s, 1H), 4.40 (dd, J ) 4.8, 15.2 Hz, 2H), 4.11 (m, 2H),
2.74 (sextet, J ) 7.2 Hz, 1H), 2.67 (sextet, J ) 7.2 Hz, 1H), 2.53
(m, 1H), 2.31 (dt, J ) 4.0, 14.0 Hz, 2H), 2.31 (s, 3H), 2.17 (m,
1H), 2.03–1.17 (m including singlets at 1.37 and 1.27, 27H),
0.99–0.80 (m including doublets at 0.95 with J ) 5.2 Hz, 0.94
with J ) 6.0 Hz, 0.85 with J ) 8.0 Hz, and 0.83 with J ) 8.4 Hz,
14H); 13C NMR (100 MHz, CDCl3) δ 175.7, 136.7, 135.4, 129.1,
128.1, 103.4, 103.3, 88.6, 88.4, 81.2, 81.0, 76.3, 73.9, 52.6, 52.4,
44.8, 44.6, 44.4, 43.8, 37.4, 37.2, 36.6, 36.5, 34.5, 34.5, 33.1, 32.9,
30.2, 30.0, 26.2, 26.0, 24.9, 24.8, 24.7, 24.5, 21.1, 20.2, 20.2, 13.5,
13.0; HRMS (FAB) calculated for C42H62NO9 [(M + H)+]
724.4425, found 724.4439.
Amide 23. Trioxane dimer acid 5 (50 mg, 0.08 mmol), N-[3-
(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (19
mg, 0.10 mmol), and 1-hydroxybenzotriazole (13 mg, 0.10
mmol) were added to CH2Cl2 (4 mL). After stirring at 0 °C for
2 h, 4-(aminomethyl)pyridine (17 µL, 0.16 mmol) and triethyl-
amine (45 µL, 0.32 mmol) were added. The reaction mixture
was stirred at rt for 30 min, and then the reaction was quenched
with 1% aqueous HCl (5 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 10 mL). The combined organic layer was
dried (MgSO4) and concentrated in vacuo. The crude product
was purified by flash column chromatography (100% EtOAc)
to yield 23 (31 mg, 54%) as an amorphous solid: [R]D22 ) +100
(c 0.05, CHCl3); IR (thin film) 3311, 2938, 2875, 1669, 1603,
1530, 1453, 1417, 1377, 1253, 1187, 1093, 1052, 1012, 878,
Amide 26. To a solution of trioxane dimer acid 5 (25 mg, 0.040
mmol) in CH2Cl2 (1 mL) were added N-[3-(dimethylamino)propyl]-
N′-ethylcarbodiimide hydrochloride (9 mg, 0.05 mmol) and 1-hy-
droxybenzotriazole (7 mg, 0.05 mmol). It was stirred at rt for 1 h.
To the reaction was added (S)-(-)-1-(4-fluorophenyl)ethylamine
(15 µL, 0.12 mmol), and the solution was stirred for 3 h. Then,
water (1 mL) was added, and the layers were separated. The aqueous
layer was extracted with EtOAc (3 × 2 mL). The combined organic
solution was dried (MgSO4) and concentrated. The crude was
purified by flash column chromatography (elution with EtOAc/
hexane ) 1:2) to give 26 (30 mg, 99%) as an amorphous white
1
734 cm-1; H NMR (400 MHz, CDCl3) δ 8.63–8.48 (m, 2H),
7.35–7.28 (m, 2H), 6.35 (t, J ) 5.6 Hz, 1H), 5.32 (s, 1H), 5.20
(s, 1H), 4.53 (dd, J ) 5.6, 16.0 Hz, 1H), 4.41 (dd, J ) 5.6, 16.0
Hz, 1H), 4.19–4.15 (m, 1H), 4.13–4.09 (m, 1H), 2.72–2.61 (m,
3H), 2.38–2.30 (m, 3H), 2.40–2.17 (m, 1H), 2.04–1.23 (m
including singlets at 1.36 and 1.27, 26H), 0.97 (m, 8H),
0.90–0.82 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 176.3, 149.8,
147.9, 123.5, 103.4, 88.7, 88.6, 81.2, 81.1, 73.5, 52.5, 52.4, 44.6,
44.5, 44.4, 42.9, 37.5, 37.3, 36.5, 34.5, 33.6, 33.0, 30.2, 29.9,
26.2, 26.2, 24.9, 24.8, 24.7, 24.6, 20.2, 13.5, 13.0; HRMS (FAB)
calculated for C40H59N2O9 [(M + H)+] 711.4221, found 711.4245.
22
solid: [R]D ) +98 (c 0.70, CHCl3); IR (thin film) 2934, 2869,
1
1665, 1509, 1378, 1132, 1052, 1008 cm-1; H NMR (400 MHz,
CDCl3) δ 7.37 (dd, J ) 7.2, 12.4 Hz, 2H), 6.99 (t, J ) 8.4 Hz,
2H), 6.34 (d, J ) 7.6 Hz, 1H), 5.28 (s, 1H), 5.27 (s, 1H), 5.07 (t,
J ) 7.2 Hz, 1H), 4.09 (m, 1H), 3.84 (m, 1H), 2.77 (sextet, J ) 6.0
Hz, 1H), 2.59 (sextet, J ) 6.4 Hz, 1H), 2.50 (m, 1H), 2.38–2.15
(m, 3H), 2.06–1.97 (m, 2H), 1.93–1.17 (m including d at 1.47 with
J ) 6.8 Hz, and singlets at 1.41 and 1.34, 28H), 0.99–0.89 (m
including doublets at 0.95 with J ) 4.0 Hz and 0.93 with J ) 3.6

New Artemisinin DeriVatiVes To Treat Malaria
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4 1041
Hz, 8H), 0.83 (d, J ) 12.4 Hz, 3H), 0.66 (d, J ) 7.6 Hz, 3H); 13
C
26.1, 26.1, 25.4, 25.4, 25.4, 25.2, 20.5, 20.4, 13.5, 12.9; 19F
NMR (282 MHz, CD2Cl2) δ –109.1; HRMS (FAB) calculated
for C41H56FN2O9 [(M + H)+] 739.3970, found 739.3967.
NMR (100 MHz, CDCl3) δ 174.8, 161.8 (d, J ) 243 Hz), 140.0
(d, J ) 3 Hz), 127.9 (d, J ) 8 Hz), 115.0 (d, J ) 21 Hz), 103.6,
103.5, 88.4, 88.3, 81.2, 81.0, 76.9, 74.0, 52.6, 52.4, 48.5, 44.8, 44.7,
44.6, 37.4, 37.2, 36.6, 36.5, 34.5, 34.5, 33.5, 32.5, 30.1, 29.6, 26.2,
26.1, 24.8, 24.7, 24.7, 24.6, 22.4, 20.2, 13.7, 13.0; 19F NMR (282
MHz, CDCl3) δ -116.5; HRMS (FAB) calculated for C42H61FNO9
[(M + H)+] 742.4330, found 742.4313.
Acknowledgment. We thank the NIH (AI 34885), the Johns
Hopkins Malaria Research Institute, and the Novartis Institute
for Tropical Diseases for financial support.
Supporting Information Available: 1H and 13C NMR spectra
for all of the new trioxane dimers. This material is available free
of charge via the Internet at http://pubs.acs.org.
Oxadiazole 27. To a solution of trioxane dimer acid 5 (80
mg, 0.13 mmol) in dimethylformamide (1 mL) at –10 °C was
added a solution of N,N′-diisopropylcarbodiimide (24 µL, 0.15
mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), and N-
hydroxyethanimidamide (11 mg, 0.15 mmol) in dimethylforma-
mide (3 mL) over 20 min. The reaction was stirred for 20 min
at –10 °C and slowly warmed to rt overnight. Volatile compo-
nents were removed under reduced pressure, and the residue was
dissolved in EtOAc (10 mL). The organic solution was subse-
quently washed with saturated aqueous NaHCO3 (6 mL), H2O
(6 mL), aqueous KHSO4 (0.5 M, 2 × 6 mL), and brine (6 mL)
and dried (MgSO4). The crude product was dissolved in THF
(3 mL), and n-Bu4NF in THF (1.0 M, 170 µL, 0.17 mmol) was
added to the solution dropwise. The reaction mixture was stirred
overnight and then poured into EtOAc (10 mL). It was washed
with water (6 mL) and brine (6 mL) and dried (MgSO4). The
crude product was purified by column chromatography (EtOAc/
hexane ) 1:4) to give 27 (53 mg, 62%) as an amorphous white
solid: [R]D26 ) +97 (c 0.41, CHCl3); IR (thin film) 2953, 2934,
2874, 1611, 1581, 1462, 1379, 1329, 1278, 1222, 1102, 1054,
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(s, 1H), 5.11 (s, 1H), 4.21–4.25 (m, 1H), 4.09–4.15 (m, 1H),
3.51 (bs, 1H), 2.71–2.62 (m, 1H), 2.53–2.43 (m, 1H), 2.34 (s,
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26
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1499, 1450, 1377, 1226, 1094, 1053, 1011, 941, 879, 844, 751
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