Malaria-infected mice live until at least day 30 after a new artemisinin-derived thioacetal thiocarbonate combined with mefloquine are administered together in a single, low, oral dose

Article abstract of DOI:10.1021/jm3009986

In only three steps and in 21-67% overall yields from the natural trioxane artemisinin, a series of 21 new trioxane C-10 thioacetals was prepared. Upon receiving a single oral dose of only 6 mg/kg of the monomeric trioxane 12c combined with 18 mg/kg of mefloquine hydrochloride, Plasmodium berghei-infected mice survived on average 29.8 days after infection. Two of the four mice in this group had no parasites detectable in their blood on day 30 after infection, and they behaved normally and appeared healthy. One of the mice had 11% blood parasitemia on day 30, and one mouse in this group died on day 29. Of high medicinal importance, the efficacy of this ACT chemotherapy is much better than (almost double) the efficacy under the same conditions using as a positive control the popular trioxane drug artemether plus mefloquine hydrochloride (average survival time of only 16.5 days).

Full text of DOI:10.1021/jm3009986

Article
pubs.acs.org/jmc
Malaria-Infected Mice Live Until at Least Day 30 after a New
Artemisinin-Derived Thioacetal Thiocarbonate Combined with
Mefloquine Are Administered Together in a Single, Low, Oral Dose
Alexander M. Jacobine,† Jennifer R. Mazzone,† Rachel D. Slack,† Abhai K. Tripathi,‡,§ David J. Sullivan,‡,§
and Gary H. Posner*,†,§
†Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore,
Maryland 21218, United States
‡W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, Maryland 21205, United States
§The Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205,
United States
S
* Supporting Information
ABSTRACT: In only three steps and in 21−67% overall
yields from the natural trioxane artemisinin, a series of 21 new
trioxane C-10 thioacetals was prepared. Upon receiving a
single oral dose of only 6 mg/kg of the monomeric trioxane
12c combined with 18 mg/kg of mefloquine hydrochloride,
Plasmodium berghei-infected mice survived on average 29.8
days after infection. Two of the four mice in this group had no
parasites detectable in their blood on day 30 after infection,
and they behaved normally and appeared healthy. One of the
mice had 11% blood parasitemia on day 30, and one mouse in this group died on day 29. Of high medicinal importance, the
efficacy of this ACT chemotherapy is much better than (almost double) the efficacy under the same conditions using as a positive
control the popular trioxane drug artemether plus mefloquine hydrochloride (average survival time of only 16.5 days).
dosing often is not followed faithfully, leading to ineffective
chemotherapy and to increased likelihood of resistance
developing.22−24 To overcome such nonadherence to a
repeated dosing regimen, curing malaria patients with a single
oral dose of drug is a very important goal.25−29 Toward that
goal, we have reported that malaria-infected mice are cured by a
single, oral, 6 mg/kg dose of several new artemisinin derivatives
combined with 18 mg/kg of mefloquine hydrochloride.30,31
Some thioacetal glycosides32 and thiosugar hemithioacetals33
have potent biological activities, and a thioacetal has been
developed as a thiol protecting group.34 Here, we disclose a
new series of artemisinin-derived monomeric C-10 thioacetal
carbonates, thiocarbonates, nitrogen-heterocycles, and a
dimeric trioxane C-10 thioacetal amide. A trioxane monomer
carbonate35 as well as a dimer carbonate have been reported,36
as well as some C-10 thioacetal derivatives of artemisinin.37−41
INTRODUCTION
■
Malaria kills approximately one million people, mostly children,
each year.1−4 No vaccine is yet a fully effective prophylactic
against malaria.5,6 Widespread resistance of Plasmodium
falciparum malaria parasites to chloroquine,7,8 until recently
the most popular malaria chemotherapeutic agent, catapulted
rapidly acting artemisinin (1) trioxanes like artemether (2) and
sodium artesunate (3) into use. Typically, the trioxane is
combined with slower-acting nitrogen-aromatics like meflo-
quine (4), lumefantrine (5), and pyronaridine (6, Figure 1).
Indeed, the World Health Organization (WHO) urges
worldwide use of such Artemisinin Combination Therapy
(ACT) as the best chemotherapy for malaria patients.9 Much
research has been focused on increasing the efficacy of
artemisinin-derived antimalarial drugs through synthetic
chemistry.10−13
One of the most promising synthetic (not derived from
artemisinin) peroxides is trioxolane OZ439 (7), which is now
in advanced human clinical trials.14 Some semisynthetic
artemisinin derivatives also are in clinical trials.15 Antimalarial
drugs now on the market include the following: a fixed
combination of 2 and 5;16 a fixed combination of 3 and 4;17,18
and a fixed combination of 3 and 6.19,20 Each of these three
combinations requires patients to take pills daily for several
days.16−21 Adherence to such a schedule of ACT multiple
RESULTS AND DISCUSSION
■
Chemistry. Thioacetals are known to be more hydrolytically
stable than the corresponding acetals.42,43 Since some trioxane
acetals are efficacious antimalarial drugs, like 2 and 3, trioxane
thioacetals were expected to be of potential value as new
Received: July 10, 2012
Published: August 14, 2012
© 2012 American Chemical Society
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Figure 1.
Scheme 1
antimalarials. Thus, our interest was to synthesize easily and to
test some trioxane thioacetals for antimalarial activity in
Plasmodium berghei-infected mice.
The stereochemistry at the C-10 position in thioacetals 9 and
10 was determined to establish the diastereoselectivity of the
thioacetalization reaction. Since the reactive C-10 site of the
intermediate oxocarbenium ion is planar, the nucleophile could
attack from either face of the molecule. Consequently, each
synthesized thioacetal could be a mixture of both C-10α and C-
10β diastereomers. Determination of the stereochemistry of the
We prepared a series of C-10α thioacetals in the yields
shown in Scheme 1 in three facile steps from 1. The first step is
reduction of 1 into dihydroartemisinin (8)44 without destroying
the crucial trioxane peroxide pharmacophore.45 Introduction of
the Lewis acid boron trifluoride diethyl etherate to 8 generates
an intermediate oxocarbenium ion. A variety of nucleophiles are
known to react with oxocarbenium ions, and, as predicted, the
reaction with thiols proceeds smoothly to produce the desired
C-10 thioacetals. The thiols used are commercially available
bifunctional mercaptoalcohols and a mercaptocarboxylic acid,
which leaves a synthetic handle, the hydroxyl or carboxylic acid
group, for further manipulation and SAR studies.
1
major diastereomer formed was achieved by comparing H
NMR coupling constants between the C-10 proton and the
adjacent C-9 proton in the crude thioacetals (4−9:1 ratio of
diastereomers). After column chromatography purification, the
major diastereomers 9a, 9b, and 10 were isolated in the yields
shown. In each case, the major diastereomer formed was the C-
10α thioacetal based on its C-10 to C-9 coupling constant of
9−11 Hz. These values were characteristic of C-10α thioacetals
in previous reports.37−41 Several C-10α and C-10β phenyl-
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thioacetals have been shown to be antimalarially efficacious in
mice, with the C-10α thioacetals being more potent than the C-
10β thioacetals.37−41
Scheme 3
Carbonates are more stable than esters,46,47 and the
carbonate functional group has been used effectively before as
a prodrug, subsequent hydrolysis of which releases the parent
alcohol.46,47 The steps in Scheme 2 are high-yielding and
Scheme 2
provide access to a small library of thioacetal carbonates.
Thioacetal carbonates 11 (Table 1) were synthesized from the
Since the development of chloroquine in the 1940s, nitrogen-
containing heterocycles have been a cornerstone of antimalarial
drug research.49−51 These moieties possess unique acid/base
properties and mimic many important biological molecules.
With these characteristics in mind, we prepared nitrogen-
heterocycle-containing C-10 thioacetal ethers 13 (Scheme 4)
and benzimidazole-containing C-10 thioacetal amides 14
(Scheme 5).
Table 1. C-10 Thioacetal Carbonates 11
a
compd
n
R
log P
yield
11a
11b
11c
11d
11e
11f
3
3
3
3
3
6
6
6
6
Me
4.6
5.9
5.5
6.4
4.9
5.9
6.3
6.1
6.6
91%
81%
85%
77%
54%
82%
88%
64%
n-Bu
t-Bu
PhF-4
CH2CCH
Me
Scheme 4
11g
11h
11i
Et
CH2CCH
b
O(CH2)2S(O)2Ph
63%
a
b
The log P values were calculated using ChemOffice Ultra 11.0. This
reaction was run in dichloromethane with pyridine as the base.
parent alcohol 9 by reaction with base and a chloroformate
(Scheme 2). Besides aliphatic and aromatic carbonates 11a−
11h, sulfone carbonate 11i was of interest because of a report
demonstrating the usefulness of this particular functionality in a
prodrug.48
With the intention to test some compounds that were similar
in structure to the thioacetal carbonates, we synthesized the
series C-10α thioacetal thiocarbonates 12a−c (Table 2) as well
Table 2. C-10 Thioacetal Thiocarbonates 12
a
compd
X
R
log P
yield
12a
12b
12c
12d
O
O
O
S
Me
5.2
6.0
6.1
5.6
81%
77%
82%
70%
n-Pr
t-Bu
Me
Making dimers of drug molecules is a common practice in
medicinal chemistry; for every one molecule of drug, two
pharmacophore moieties reach the active site within the
body.52,53 Therefore, dimer drug compounds are sometimes
considerably more efficacious than their monomer counter-
parts.52,53 Because of recent success with amide-containing
monomeric trioxanes as antimalarials,30,54 we synthesized bis-
amide bisthioacetal dimer 15 (Scheme 6).
On the basis of our previous in vivo results, we have observed
some trends between log P values and antimalarial efficacy.30,31
Typically, monomeric trioxanes are most efficacious when the
log P value is between 4 and 6 (Table 3). Dimeric trioxanes
have displayed optimal results when the log P value is between
7 and 9.
a
The log P values were calculated using ChemOffice Ultra 11.0.
as C-10α thioacetal xanthate ester 12d from diastereomerically
pure thioacetal alcohol 9a. Preparation of 12a−c involved
chemistry similar to that for the thioacetal carbonates, although
change of solvent as well as base was necessary to optimize
reaction conditions. In the case of 12d, 9a was treated with
base, carbon disulfide, and methyl iodide in tetrahydrofuran
(Scheme 3).
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stability of lead trioxane 12c at 60 °C, neat, for 7 days; TLC as
well as H NMR showed no decomposition.
Scheme 5
1
Biology. To each thioacetal trioxane (0.64 mg), 100 μL of
7:3 Tween 80/ethanol with mefloquine hydrochloride (1.92
mg) was added. This mixture was then diluted with 965 μL of
water for oral administration to 5-week old C57BL/6J male
mice (from the Jackson Laboratory) weighing about 20 g that
were infected with P. berghei ANKA strain (2 × 107 parasitized
erythrocytes). Each of four mice in a group was treated orally
24 h post-infection with a single dose of 200 μL of diluted
compound solution, corresponding to a dose of 6 mg/kg
trioxane combined with 18 mg/kg of mefloquine hydro-
chloride. Determining blood parasitemia levels and monitoring
the duration of animal survival compared to survival time of
animals receiving no drug are both widely accepted as measures
of a drug’s antimalarial efficacy. An average of 8.8% blood
parasitemia was observed in the control (no drug) group on
day 3 post-infection. Infected animals receiving no drug died on
an average of 8 days post-infection. The antimalarial efficacy
results of our C-10 thioacetals as well as controls are
summarized in Table 4, which includes the parasitemia levels
for mice on day 3 post-infection.
Scheme 6
Table 4. In Vivo Antimalarial Efficacy Using a Single Oral
Dose of 6 mg/kg Trioxane and 18 mg/kg Mefloquine
Hydrochloride in P. berghei-Infected Mice
average survival
(days) after infection
% suppression of parasitemia
(on day 3 post infection)
trioxane
11a
11b
11c
11d
11e
11f
12.8 (13, 13, 13, 12)
18.5 (30, 16, 15, 13)
17.8 (28, 17, 13, 13)
19.3 (29, 17, 17, 14)
18.8 (30, 17, 15, 13)
21.8 (30, 30, 15, 12)
16.5 (28, 14, 12, 12)
25.3 (30, 29, 27, 15)
14.5 (17, 15, 13, 13)
24.5 (30, 30, 21, 17)
19.3 (30, 17, 15, 15)
29.8 (30, 30, 30, 29)
22.0 (30, 28, 17, 13)
23.0 (30, 29, 17, 16)
22.3 (30, 29, 17, 13)
26.3 (29, 28, 27, 21)
19.5 (29, 20, 15, 14)
19.8 (30, 17, 17, 15)
Controls
>99.9%
>99.9%
>99.9%
>99.9%
99.9%
Table 3. Calculated log P Values for C-10 Thioacetals 13−15
a
compd
log P
13a
13b
14a
14b
15
4.7
5.3
4.8
4.5
7.4
>99.9%
>99.9%
>99.9%
99.9%
11g
11h
11i
a
The log P values were calculated using MarvinSketch and a calculator
12a
12b
12c
12d
13a
13b
14a
14b
15
>99.9%
>99.9%
99.9%
plug-in by ChemAxon Kft.
99.9%
Although the literature suggested that our new C-10
thioacetals 9−15 would be much more stable to acid than
the analogous acetals,42,43 we subjected lead trioxane 12c to a
series of stability tests since it was the most efficacious of our
antimalarial thioacetals. First, hydrolytic stability was tested
based on a published protocol that simulated stomach acidic
conditions, which is important for a drug that is administered
orally.55 Trioxane 12c was dissolved in a solution of aqueous
hydrochloric acid and acetonitrile (pH 2) and heated in a
temperature-controlled oil bath set to 37 °C. This solution was
allowed to stir for 24 h and was periodically analyzed by TLC.
Additionally, the solution was analyzed by 1H NMR after
completion of the 24 h. Since we knew that the product formed
through hydrolysis of the C-10 thioacetal functionality would
be 8, we compared the 1H NMR spectrum of 12c after 24 h to
that of 8 and to that of parent alcohol 9a. Less than 2%
hydrolysis of 12c had occurred. Similarly, 9a and 9b were stable
to hydrolysis under the same conditions. Full experimental
details of the hydrolysis study are included in the Supporting
Information.
>99.9%
>99.9%
>99.9%
>99.9%
99.9%
infected (no drug) 8.0 (10, 8, 7, 7)
0%
artemether +
mefloquine-HCl
16.5 (28, 13, 13, 12)
>99.9%
mefloquine-HCl
only
14.0 (17, 13, 13, 13)
>99.9%
On the basis of these data and as expected for artemisinin-
derived trioxanes,10−13 all of our new C-10α thioacetals acted
rapidly to suppress parasitemia, with almost complete
suppression of parasitemia as determined on day 3 post-
infection. However, not all of the parasites were killed after 3
days which leads to a difference, sometimes substantial, in
efficacy for each individual analogue over the full 30 day
experiment.
Because ACT is used predominantly in tropical areas where
malaria is endemic, it was important to determine the thermal
Also based on these data, it is clear that each of the four C-10
thioacetals 11h (25.3 days), 12a (24.5 days), 12c (29.8 days),
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added dropwise via a needle and plastic syringe, and the reaction was
stirred for 20 min. The reaction was quenched with water (2 mL) and
extracted with dichloromethane (3 × 2 mL). The organic layers were
pooled, dried with magnesium sulfate, vacuum filtered, and
concentrated via rotary evaporation at room temperature. The crude
residue was purified by flash column chromatography on silica, eluting
with a gradient mobile phase (5−10% ethyl acetate in hexane) to yield
and 14a (26.3 days) in combination with mefloquine
hydrochloride prolonged the mouse average survival time by
more than one week (>23.5 days) compared to the survival
time of the artemether plus mefloquine hydrochloride control
(16.5 days). Mefloquine hydrochloride alone at 18 mg/kg gave
an average survival time of only 14 days.
Most impressively, trioxane 12c produced a partial cure with
an average survival time of 29.8 days. Two of the four mice in
this group showed no signs of parasitemia in their blood on day
30 post-infection and behaved normally. One mouse in this
group had 11% parasitemia on day 30, and one mouse died on
day 29.
24.0
9b as a clear amorphous solid (45 mg, 64%). [α]D +14.6 (c. 0.65,
CHCl3); IR (thin film) ν 3458, 2927, 2871, 1455, 1377, 1128, 1037,
928, 879, 829, 666 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.28 (s, 1H),
4.51 (d, J = 10.7 Hz, 1H), 3.63 (br t, J = 6.6 Hz, 2 H), 2.78 (ddd, J =
12.5, 8.3, 6.3 Hz, 1H), 2.72−2.51 (m, 2H), 2.36 (ddd, J = 14.6, 13.3,
4.0 Hz, 1H), 2.01 (ddd, J = 14.5, 4.9, 2.9 Hz, 1H), 1.90−1.83 (m, 1H),
1.77−1.15 (m, including a singlet at 1.41, 19 H), 1.07−0.99 (m, 1H),
0.95 (d, J = 6.0 Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ104.4, 92.4, 80.7, 80.6, 63.0, 52.0, 46.2, 37.5, 36.4, 34.2, 32.7,
31.9, 29.9, 28.8, 28.3, 26.1, 25.4, 24.9, 21.4, 20.4, 15.2; HRMS (FAB)
m/z calcd for C21H36O5S (M + H)+ 401.2362; found, 401.2355.
Thioacetal Carboxylic Acid 10. An oven-dried, 2 dram vial,
equipped with a magnetic stir bar, under argon was charged with 8
(100 mg, 0.35 mmol, 1.0 equiv) and anhydrous dichloromethane (4
mL). 3-Mercaptopropionic acid (40 mg, 0.39 mmol, 1.1 equiv) was
added and allowed to stir for 10 min at 50 °C, under argon. Boron
trifluoride diethyl etherate (49.6 μL, 0.35 mmol, 1.0 equiv) was added
dropwise, and the reaction was allowed to stir under argon at 0 °C for
30 min. After 30 min, the reaction was quenched with water (5 mL),
extracted with dichloromethane (3 × 10 mL). The organic layers were
combined, dried over MgSO4, filtered, and concentrated on a rotary
CONCLUSIONS
■
In conclusion, several artemisinin-derived C-10α thioacetals
were found to be more efficacious as antimalarials than
artemether. Four of the new thioacetals (11h, 12a, 12c, and
14a) combined with mefloquine hydrochloride prolonged the
life of P. berghei-infected mice by at least one week longer than
the artemether plus mefloquine hydrochloride control.
Remarkably, when administered only once as a single, oral
dose of 6 mg/kg plus 18 mg/kg of mefloquine hydrochloride,
trioxane 12c was highly efficacious with an average survival time
of 29.8 days, almost double the average survival time (16.5
days) achieved by the popular antimalarial drug artemether plus
the mefloquine positive control using the same protocol.
1
evaporator at room temperature. The H NMR of the crude reaction
mixture indicated a mixture of 10-α and 10-β diastereomers in a ratio
of 6:1 (α:β). The crude amorphous solid was purified via column
chromatography (5−10% ethyl acetate in hexanes) to afford 10 as an
EXPERIMENTAL SECTION
■
The purity of compounds 11h, 12a, 12c, and 14a was determined to
be >98% by HPLC. HPLC data were acquired using a Varian ProStar
210 two-pump system with a Sedex Model 75 Evaporative Light
Scattering Detector (ELSD). A Varian 250 × 4.6 mm × 1/4″
Microsorb-MV 100-5 Si column was used. All other instrumentation
details are included in the Supporting Information.
Thioacetal Alcohol 9a. An oven-dried, 5 dram vial, equipped with
a magnetic stir bar, under argon was charged with 844 (250 mg, 0.88
mmol, 1.0 equiv) and anhydrous dichloromethane (10 mL). 3-
Mercaptopropanol (89 mg, 0.97 mmol, 1.1 equiv) was added and
allowed to stir for 10 min at 50 °C, under argon. Boron trifluoride
diethyl etherate (0.125 mL, 0.88 mmol, and 1.0 equiv) was added
dropwise, and the reaction was allowed to stir under argon at 50 °C for
30 min. After 30 min, the reaction was quenched with water (5 mL)
and extracted with dichloromethane (3 × 10 mL). The organic layers
were combined, dried over MgSO4, and concentrated on a rotary
22.6
amorphous solid (96 mg, 73% yield). [α]D +26.08 (c 1.1, CHCl3);
IR (thin film) ν 2926, 2872, 1707, 1449, 1378, 1268, 1230, 1195, 1128,
1
1086, 1069, 1036, 959, 928, 900, 879 cm−1; H NMR (300 MHz,
CDCl3) δ 5.29 (s, 1H), 4.57 (d, J = 10.8 Hz, 1H), 3.16−2.94 (m, 1H),
2.95−2.75 (m, 3H), 2.73−2.55 (m, 1H), 2.36 (ddd, J = 14.5, 13.2, 4.0
Hz, 1H), 2.01 (ddd, J = 14.5, 4.9, 2.9 Hz, 1H), 1.95−1.80 (m, 1H),
1.80−1.54 (m, 3H), 1.54−1.15 (m, 7H), 1.13−0.98 (m, 1H), 0.94 (dd,
J = 9.2, 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 176.8, 104.7, 92.3,
81.1, 80.6, 51.9, 46.1, 37.5, 36.4, 35.7, 34.2, 31.4, 25.9, 24.9, 23.6, 21.4,
20.4, 15.1; HRMS (FAB) m/z calcd for C18H28O6S [M + H]+
373.1685; found, 373.1669.
Thioacetal Carbonate 11h. An oven-dried 2-dram vial, equipped
with magnetic stir bar and argon gas inlet needle, was charged with 9b
(17.7 mg, 0.044 mmol, 1 equiv) in dry CH3CN (1 mL). Sodium
hydride (2 mg, 0.088 mmol, 2 equiv) was added as a solid in one
portion and the reaction was stirred at room temperature for 30 min.
Propargyl chloroformate (21 mg, 0.176 mmol, 4 equiv) was added
dropwise via a syringe. The reaction was stirred for 24 h at room
temperature, and then more sodium hydride (2 mg, 0.088 mmol, 2
equiv) and propargyl chloroformate (21 mg, 0.176 mmol, 2 equiv)
were added. After 12 h, the reaction was quenched with water (2 mL)
and extracted with CH2Cl2 (3 × 2 mL). The organic layers were
pooled, dried with MgSO4 (ca. 1 g), vacuum filtered, and concentrated
via rotary evaporation at room temperature. The crude residue was
1
evaporator at room temperature. The H NMR of the crude reaction
mixture indicated a mixture of 10-α and 10-β diastereomers in a ratio
of 9:1 (α:β). The crude amorphous solid was purified via column
chromatography (5−10% ethyl acetate in hexanes) to afford 9a as a
23.3
white solid (268 mg, 85% yield). Mp = 108.6−110.0 °C; [α]D
+31.49 (c. 0.58, CHCl3); IR (thin film) ν 3445, 2926, 2871, 2363,
1716, 1586, 1446, 1378, 1279, 1195, 1126, 1035, 928, 900, 878 cm−1;
1H NMR (400 MHz, CDCl3) δ 5.28 (s, 1H), 4.52 (d, J = 10.7 Hz,
1H), 3.87−3.76 (m, 2H), 2.94 (ddd, J = 13.5, 7.7, 5.8 Hz, 1H), 2.80 (s,
1H), 2.70 (ddd, J = 13.3, 7.1, 5.9 Hz, 1H), 2.59 (ddd, J = 11.1, 7.3, 4.3
Hz, 1H), 2.33 (ddd, J = 14.6, 13.4, 4.0 Hz, 1H), 1.98 (ddd, J = 14.6,
4.8, 2.8 Hz, 1H), 1.92−1.63 (m, 4H), 1.57 (dt, J = 13.5, 4.3 Hz, 1H),
1.50−1.15 (m, 7H), 1.10−0.95 (m, 1H), 0.91 (dd, J = 12.2, 6.7 Hz,
7H); 13C NMR (100 MHz, CDCl3) δ 104.7, 92.6, 80.8, 80.7, 59.8,
51.9, 46.1, 37.6, 36.4, 34.2, 32.2, 31.9, 25.9, 24.9, 24.1, 21.5, 20.4, 15.2;
HRMS (FAB) m/z calcd for C18H30O5S [M + H]+ 359.1892; found,
359.1888.
purified by flash chromatography on silica gel to yield 11h as a clear oil
22.7
(13.4 mg, 64%). [α]D
+11.8 (c. 0.59, CHCl3); IR (thin film) ν
3279, 2973−2851, 1751, 1377, 1279, 1259, 1229, 1128, 1051, 1037,
1
1017, 928, 880, 678 cm−1; H NMR (300 MHz, CDCl3) δ 5.27 (s,
1H), 4.71 (d, J = 2.4 Hz, 2H), 4.51 (d, J = 10.7 Hz, 1H), 4.16 (t, J =
6.6 Hz, 2H), 2.77 (ddd, J = 12.5, 8.2, 6.3 Hz, 1H), 2.68−2.59 (m, 2H),
2.52 (t, J = 2.4 Hz, 1H), 2.36 (ddd, J = 14.6, 13.3, 4.0 Hz, 1H), 2.00
(ddd, J = 14.4, 4.9, 2.9 Hz, 1H), 1.92−1.81 (m, 1H), 1.75−1.52 (m,
8H), 1.50−1.19 (m, 10H), 1.10−0.98 (m, 1H), 0.96−0.90 (m, 7H);
13C NMR (75 MHz, CDCl3) δ 154.8, 104.4, 92.4, 80.7, 80.6, 75.7,
75.7, 68.8, 55.2, 52.0, 46.2, 37.5, 36.4, 34.2, 31.9, 29.9, 28.7, 28.6, 28.3,
26.1, 25.4, 24.9, 21.5, 20.4, 15.2; HRMS (FAB) m/z calcd for
C25H39O7S (M + H)+ 483.2417; found, 483.2408.
Thioacetal Alcohol 9b. A 2-dram vial, equipped with magnetic
stir bar and argon inlet adaptor, was charged with 8 (0.18 mmol, 50
mg) in anhydrous dichloromethane (2 mL). 6-Mercaptohexanol (0.19
mmol, 26 mg) was added in one portion neat directly to the stirring
solution. Boron trifluoride diethyl etherate (0.18 mmol, 25 mg) was
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Thioacetal Thiocarbonate 12a. An oven-dried, 2 dram vial,
equipped with a magnetic stir bar, under argon was charged with 9a
(10 mg, 0.028 mmol, 1.0 equiv) and dichloromethane (1.0 mL).
Pyridine (3 mg, 0.42 mmol, 1.5 equiv) was added, and the mixture was
allowed to stir for 15 min. After 15 min, S-methyl chlorothioformate
(5 mg, 0.042 mmol, 1.5 equiv) was added, and the reaction was
allowed to stir under argon for 24 h. After 24 h, the reaction was
quenched with water (5 mL) and extracted with dichloromethane (3 ×
10 mL). The organic layers were combined, dried over MgSO4, and
concentrated on a rotary evaporator at room temperature. The crude
amorphous solid was purified via column chromatography (10% ethyl
acetate in hexanes) to afford 12a as a white amorphous solid (9.8 mg,
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional experimental details, analytical data, and copies of
1H and 13C NMR spectra for all reported compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Phone: 410-516-4670. Fax: 410-516-8420. E-mail: ghp@jhu.
22.1
81% yield). [α]D −2.40 (c. 0.55, CHCl3); IR (thin film) ν 2925,
edu.
1
2871, 1709, 1452, 1377, 1149, 1033, 926, 877, 826 cm−1; H NMR
Notes
(300 MHz, CDCl3) δ 5.27 (s, 1H), 4.52 (d, J = 10.8 Hz, 1H), 4.35 (td,
J = 6.3, 1.0 Hz, 2H), 2.87 (dt, J = 13.6, 6.9 Hz, 1H), 2.76−2.53 (m,
2H), 2.33 (s, 4H), 2.14−1.96 (m, 3H), 1.87 (ddt, J = 13.5, 6.7, 3.3 Hz,
1H), 1.77−1.65 (m, 2H), 1.64−1.21 (m, 8H), 1.11−0.98 (m, 1H),
0.93 (dd, J = 9.8, 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 171.7,
104.4, 92.4, 80.8, 80.5, 66.4, 51.9, 46.2, 37.5, 36.4, 34.2, 31.8, 29.3,
26.1, 24.9, 21.4, 20.4, 15.2, 13.6; HRMS (FAB) m/z calcd for
C20H32O6S2 [M + Na]+ 455.1538; found, 455.1532.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (AI 34885), the Johns Hopkins Malaria
Research Institute, and the Bloomberg Family Foundation for
financial support. We also thank Bryan T. Mott for help in
obtaining some HRMS data.
Thioacetal Thiocarbonate 12c. An oven-dried, 2 dram vial,
equipped with a magnetic stir bar, under argon was charged with 9a
(10 mg, 0.028 mmol, 1.0 equiv) and dichloromethane (1.0 mL).
Pyridine (3 mg, 0.042 mmol, 1.5 equiv) was added, and the mixture
was allowed to stir for 15 min. After 15 min, S-t-butyl
chlorothioformate (6 mg, 0.042 mmol, 1.5 equiv) was added, and
the reaction was allowed to stir under argon for 24 h. After 24 h, the
reaction was quenched with water (5 mL) and extracted with
dichloromethane (3 × 5 mL). The organic layers were combined,
dried over MgSO4, and concentrated on a rotary evaporator at room
temperature. The crude amorphous solid was purified via column
chromatography (10% ethyl acetate in hexanes) to afford 12c as a
ABBREVIATIONS USED
■
ACT, artemisinin combination therapy; WHO, world health
organization; DHA, dihydroartemisinin; EDC, N-(3-dimethy-
laminopropyl)-N′-ethylcarbodiimide hydrochloride; DMAP, 4-
dimethylaminopyridine
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22.1
white solid (10.9 mg, 82% yield). Mp = 102.4−103.9 °C; [α]D
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[α]D = −69.6 (c = 1.550, CHCl3); FTIR (thin film) ν 3341, 2926,
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