Fluoroartemisinin: Trifluoromethyl Analogues of Artemether and Artesunate

Article abstract of DOI:10.1021/jm0310333

The synthesis of a series of C-10 trifluoromethyl ethers of artemisinin has been achieved from key bromide 8, itself carried out in two steps from artemisinin. The substitution of 8 with methanol, ethanol, or succinic acid allowed the access of C-10 CF₃ analogues of β-artemether, β-arteether, or artesunate, respectively, in good yields (up to 89%). The presence of the CF₃ group at C-10 of artemisinin clearly increased the chemical stability under simulated stomach acid conditions. For example, the CF₃ analogue of arteether was found to be around 45 times more stable than arteether itself. The influence of the CF₃ moiety on biological activity was also highlighted. CF₃ analogues of artemether and arteether exhibited a high in vivo antimalarial activity on mice infected with Plasmodium berghei NK173, with a complete clearance of the parasitemia during the entire observation period (25 days).

Full text of DOI:10.1021/jm0310333

2694
J . Med. Chem. 2004, 47, 2694-2699
F lu or oa r tem isin in : Tr iflu or om eth yl An a logu es of Ar tem eth er a n d Ar tesu n a te
Guillaume Magueur,† Benoit Crousse,† Se´bastien Charneau,‡ Philippe Grellier,‡ J ean-Pierre Be´gue´,† and
Danie`le Bonnet-Delpon*,†
Faculte´ de Pharmacie, BIOCIS UPRES A 8076 CNRS, 92296 Chaˆtenay-Malabry, France, and De´partement RDDM,
Laboratoire de Biologie Parasitaire, USM 504, Muse´um National d’Histoire Naturelle, 61 Rue Buffon, 75231 Paris, France
Received September 15, 2003
The synthesis of a series of C-10 trifluoromethyl ethers of artemisinin has been achieved from
key bromide 8, itself carried out in two steps from artemisinin. The substitution of 8 with
methanol, ethanol, or succinic acid allowed the access of C-10 CF3 analogues of â-artemether,
â-arteether, or artesunate, respectively, in good yields (up to 89%). The presence of the CF3
group at C-10 of artemisinin clearly increased the chemical stability under simulated stomach
acid conditions. For example, the CF3 analogue of arteether was found to be around 45 times
more stable than arteether itself. The influence of the CF3 moiety on biological activity was
also highlighted. CF3 analogues of artemether and arteether exhibited a high in vivo
antimalarial activity on mice infected with Plasmodium berghei NK173, with a complete
clearance of the parasitemia during the entire observation period (25 days).
Ch a r t 1
In tr od u ction
Endoperoxides are a promising class of antimalarial
drugs. Artemisinin (ART), the lead natural compound,
is a sesquiterpenic lactone.1 Because of its poor phar-
macological profile, scientists rapidly developed deriva-
tives from dihydroartemisinin (DHA) 1 (Chart 1) with
better properties, in particular better solubility in oil
or water.2 The semisynthetic ethers or esters, such as
artemether 2,3 arteether,4 and artesunate 3,5 are being
widely used for therapy in Asia and in Africa.6 Artelinate
is still in clinical development.7 These endoperoxides
have several advantages over existing antimalarial
drugs. First, they clear the peripheral blood from
parasites very rapidly, and second, there is no cross-
resistance with other antimalarial drugs. However, they
also have some disadvantages, such as short plasmatic
half-lives, and the effective concentrations in plasma are
sustained for only relatively brief periods. Artemisinin
derivatives undergo in vivo cytochrome P450 oxidation
(artemether, arteether) and/or are hydrolyzed under
mild acidic conditions (in particular artesunate). Both
processes provide active dihydroartemisin, which has
itself a short plasmatic half-life.8 As a result, a short-
course treatment is generally associated with a high
rate of recrudescent parasitemia.9 An urgent objective
is thus to design new artemisinin derivatives that
enable prolonged efficiency and to target a reasonable
plasmatic half-life that should be long enough to avoid
the unacceptable recrudescence of parasitemia, to allow
shorter treatments or smaller doses while preventing
the emergence of resistance.
roalkyl group onto a crucial position for metabolism of
artemisinin derivatives, for instance, on carbon C-10
(compound 4) or on the alkoxy chain of ethers of DHA
(compound 5), resulted in excellent in vitro and in vivo
activities by both intraperitoneal and oral routes,
surpassing those of DHA and its ethers 2 and 3.11,12
Comparative measurement of plasmatic half-lives of CF3
hemiketal 4 (T1/2 ) 85.9 min) and DHA (T1/2 ) 26.3 min)
after intravenous administration to rats seems to indi-
cate that the CF3 group at C-10 effectively protects ART
derivatives against oxidation or hydrolytic metabolism.13
Considering the facile cleavage of the acetal function
of DHA ethers in acidic solution, we decided to use the
fluorine approach to design hydrolytically stable ana-
logues of artemether and arteether. The easy hydrolysis
of DHA acetals and esters is the consequence of the easy
formation and the great stability of oxonium ion 6a
(Chart 2). The destabilization of this oxonium ion by an
electron-withdrawing substituent should strongly dis-
favor any pathway where it could be involved. In
connection with this process, we have already shown
that on more simple molecules the formation of oxonium
ion 7a is strongly destabilized by the presence of a
trifluoromethyl group compared to 6a .14 In an artemisi-
Fluorinated substituents (Rf) are known to impart
greater protection to molecules from metabolic (oxida-
tive and hydrolytic) degradation,10 due to a strong C-F
bond. We have shown that the introduction of a fluo-
* To whom correspondence should be addressed. Phone: +33
1/46835739. Fax: +33-1/46835740. E-mail: daniele.bonnet-delpon@cep.u-
psud.fr.
† BIOCIS UPRES A 8076 CNRS.
‡ Muse´um National d’Histoire Naturelle.
10.1021/jm0310333 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/06/2004

Analogues of Artemether and Artesunate
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10 2695
Ch a r t 2
Ch a r t 3
nin series, oxonium ion 7b would be much more difficult
to generate by hydrolysis from the CF3 analogue of
artemether 8 than the ion 6b from artemether itself.
Moreover, the presence of a trifluoromethyl group
could also slow the rate of the oxidative dealkylation of
the alkoxyl at C-10, since it has been demonstrated that
the protection of oxidative processes, provided by a
fluoroalkyl group, could extend to â and even γ CH or
CH2 groups.10
In this paper, we report our findings on the acid
stability and the high in vitro and in vivo antimalarial
activities of the C-10 trifluoromethyl analogues of
artemether and other ethers and esters.
Ch em istr y
Trifluoromethyl-substituted artemether and other
parent compounds were prepared from the bromo
derivative 8, available itself in 80% yield from trifluo-
rohemiketal 4 through a reaction with thionyl bromide
followed by an intramolecular substitution.15 Bromide
8 was first substituted with methanol through a silver
salt assisted solvolysis. Under these conditions, com-
pound 9 was obtained in a 55% yield as a 52/48 mixture
of both diastereoisomers 9R (where OMe is R) and 9â,
accompanied by a large amount (43%) of an elimination
product, glycal 10. The yield was improved to 79% when
1,1,1,3,3,3-hexafluoroisopropanol (HFIP) was used as a
bromide activator in place of silver salt (as a cosolvent
with CH2Cl2).16 A better chemical selectivity was also
obtained with only 5% of glycal 10 observed. Moreover,
with HFIP, 9â was formed as the major diastereoisomer
(>95% de). These conditions were then applied to
introduce various other alcohols, one acid, one amine,
and even hydrogen peroxide (Chart 3). Yields in sub-
stitution were moderate to good. In all cases except for
the amine 17, only a small amount of glycal was
obtained and the substitution reaction was completely
stereoselective with only the â isomer formed.
Although the role of HFIP as an activating agent has
not been well elucidated, its use as a cosolvent clearly
improved the rate and the course of the reaction.
Subsequent basic hydrolysis of methyl ester 12 pro-
vided the trifluoromethyl analogue 19 of artelinic acid
in a 53% overall yield from 8. The allyl ether 13 was
also submitted to various conversions to obtain water-
soluble compounds. Dihydroxylation with a catalytic
amount of OsO4 afforded the corresponding diol 20 in
60% yield (Scheme 1). Compound 13 was also readily
converted into carboxylic acid 21 using RuO4, generated
in situ from RuCl3 and NaIO4, as an oxidant system, or
oxidized by ozonolysis into the corresponding aldehyde
22 (80% yield).
Sch em e 1
gastric pH conditions and often lead to inactive
metabolites.8c,12b Their half-lives did not exceed 20 h at
pH 2.17 The stability of their fluorinated analogues 4,
9, 11, 16, and 19 was evaluated to check if the trifluo-
romethyl substituent is actually able to improve the
stability of artemisinin compounds, as postulated. Since
fluorinated compounds can be detected by 19F NMR, the
analysis described in the literature17 was simplified. The
fluorinated derivative 4 (C-10 trifluoromethyl analogue
of DHA) was first placed under the described simulated
stomach acid conditions (1 mg/mL in 0.01 N HCl (pH
2) at 37 °C) in an NMR tube in which trifluoromethane-
sulfonic acid was added as an internal standard. Its
stability was evaluated by following the disappearance
of its 19F NMR signal. The half-life of compound 4 was
found to be around 40 times higher (∼700 h) than the
DHA itself (17 h) (Figure 1). However, because of the
lower solubility of other fluorinated compounds in water,
conditions were slightly modified with the addition of
acetonitrile. The pH was then adjusted in order to
obtain the same degradation rate for 4 (760 h) as in the
previous conditions: 1:1 v/v mixture of 0.1 N HCl
solution (pH 1) and acetonitrile at 37 °C. All other
fluorinated compounds (2 mg/mL) were thus completely
soluble and analyzable by 19F NMR. Compounds 9, 11,
and 19 also exhibited high acid stability with half-lives
Ch em ica l Sta bility
DHA, artemether, arteether, sodium artesunate, and
artelinic acid are known to be sensitive to moisture and

2696 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10
Magueur et al.
Ta ble 1. In Vitro Antimalarial Activity against Plasmodium falciparum FCB1 Strain
compound
2 (ref)
4
9
11
14
15
16
17
18
19
20
21
22
IC50 (nM)
SD (()
3.5
1.2
9.4
2.7
0.8
0.3
3.3
1.1
0.9
0.2
8.3
2.4
4.1
1.2
12.3
2.8
13.2
0.9
10.6
3.0
0.9
0.3
30.4
6.0
21.4
3.0
Ta ble 2. In Vivo Antimalarial Activity against P. berghei NK
173 at 35.5 µmol/kg
% parasitemia (% infected erythrocytes)
drug
day 4
day 7
day 9
39.2
day 11
day 13
48.1
day 25a
2 (ref)
4
9
2.2
4.0
0
0
8.8
0
5.5
10.7
0
0
14.8
0
3.9
0
28.3
26.8
12.1
22.1
0
0
27.3
0
0
11
14
15
16
17
18
19
20
21
22
3.8b
0
0
0.5
0
36.8
0.1
41.7
34.9
28.8
8.1
36.8
25.6
5.5
25.9
2.1c
47.5
0.2
46.3
7.8
26.8
46.8
29.6d
a
b
Values only for experiments where all mice survived. 0% of
parasitemia for 80% of mice. c Measured on day 3. Measured on
d
day 23.
Ta ble 3. In Vivo Antimalarial Activity of 9 and 2
ED50
ED90
F igu r e 1. Stability of C-10 trifluoromethyl compounds under
drug
mg/kg
µmol/kg
mg/kg
µmol/kg
acidic conditions.
2
9
2.5
1.25
8.4
3.4
8.5
6.4
28.5
17.5
of 660, 500, and 680 h, respectively. Compound 15 was
a little less stable, with a half-life of 215 h. Conversely
compounds 16 and 17 were found to be much less stable
under these acid conditions (pH 1) than C-10 trifluo-
romethyl ethers, with half-lives of 30 h. However,
trifluoromethyl-substituted artesunic acid 16 was found
to be more stable at pH 2 (80 h) or at pH 1 (30 h) than
artesunate at pH 7-8 (∼10 h), which decomposed
mainly into DHA.18 It must be noted that similarly the
19F NMR signal of 16 was in part replaced by the signal
corresponding to 4. For 17, the short half-life suggests
that the first step of hydrolysis occurs at a different site
where the CF3 substituent has no influence.
is a complete clearance of parasitemia in mice treated,
not only at the end of the treatment but from day 4 to
day 25.
A striking result is that compounds bearing a polar
functionality, except amine 17, did not ensure a pro-
longed antimalarial activity, even when they were able
to clear parasitemia at the end of the treatment,
exhibiting thus a profile similar to that of artemether.
For example, compound 14 was not able to suppress
parasitemia or to maintain it at a low level while
compound 11, which differs from 14 only by an alcohol
function, completely cured mice from day 4 to day 25.
While compound 16 protected mice against P. Berghei
until day 7 (3.9% of parasitemia), a rapid increase of
parasitemia suggests a rapid metabolism and/or elimi-
nation of the drug. The difference between 21 (acid
functionality) and 22 (aldehyde functionality) is also
striking and could be due to the inadequate intraperi-
toneal route of the administration of the acid. The
addition of another peroxide site onto artemisinin (18)
did not bring any beneficial effect compared to 4.
The improvement of antimalarial activity when a
trifluoromethyl group is incorporated at C-10 on the
artemisinin skeleton is also indicated with the ED50 and
ED90 values, evaluated for artemether and its 10-
trifluoromethyl analogue (on P. Berghei NK 173, ip
administration) (Table 3). The CF3-artemether was
found to be approximately 2 times more active than
artemether. It is worth noting that ED50 and ED90
values, which are measured at day 4 (at the end of
treatment), cannot give any information on the recru-
descence of parasitemia, which is the main drawback
of artemether.
Biologica l Eva lu a tion
The in vitro antimalarial activities of compounds 4,
9, 11, and 14-22 were determined using the FCB1
strain of Plasmodium falciparum. This strain is resis-
tant to chloroquine (IC50 ) 115 ( 25 nM). IC50 values
are shown in Table 1.
All derivatives exhibited good in vitro activity com-
pared to artemether. All these compounds were sub-
jected to in vivo assays in mice according to Peters’
protocol (Plasmodium berghei NK 173 infected mice,
intraperitoneal administration for 4 days at 35.5
µmol‚kg-1).19 Results are reported in Table 2. By use of
this procedure, artemether ensured a nearly complete
clearance of parasitemia at the end of the treatment
(day 4), but the parasitemia then gradually increased.
Most of the fluorinated derivatives were more efficient
than artemether in decreasing parasitemia. More im-
portantly, with the C-10 trifluoromethyl analogues of
artemether and arteether (9 and 11) and with 15, there

Analogues of Artemether and Artesunate
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10 2697
parasites was measured using a scintillation counter. The
growth inhibition for each drug concentration was determined
by comparison of the radioactivity incorporated in the treated
culture with that in the control culture (without drug). The
drug concentration causing 50% inhibition (IC50) was deter-
mined by nonlinear regression analysis of log(dose)-response
curves. Values are the average of three experiments. DMSO
and methanol introduced into the cultures never exceeded 0.1%
and did not affect parasite growth.
In Vivo Assa ys. The antimalarial activity was studied in
mice (female ICR (CD-1), 18-20 g; Harlan, Gannat, France)
infected with P. berghei (NK 173 strain) (15-106 red cells)
according to the protocol of Peters.19 Each group contained four
to five mice. Treatments with drugs were performed over 4
days, beginning with the day of infection, by intraperitoneal
route. The drugs were given once a day at 0.0355 mmol‚kg-1
as a suspension in an aqueous solution of carboxymethyl
cellulose (1%). The untreated group received the same amount
of DMSO in 1% carboxymethyl cellulose. Efficient doses to
inhibit 50% and 90% of parasite growth (ED50 and ED90) were
determined according to Peters by counting parasitemia at day
4 for drug concentrations ranging from 0.5 to 10 mg/kg.19 The
percentage of inhibition was calculated by comparison to the
parasitemia determined in control infected mice.
Sta bility Tests of Ar tem isin in An a logu es in Sim u la ted
Stom a ch Acid . Sa m p le P r ep a r a tion a n d Mea su r em en t
of Sta bility. 1. Wa ter -Solu ble Com p ou n d s. A 50 µL portion
of an artemisinin prodrug (0.5 mg) stock solution (in acetoni-
trile) was added to 500 µL of a freshly prepared 0.01 N HCl
aqueous solution (pH 2). An amount of 20 µL of a freshly
prepared internal standard solution (10 mg of trifluoromethane-
sulfonic acid per milliliter of D2O) was also added to the
mixture.
2. In solu ble Com p ou n d s. A 250 µL portion of an arte-
misinin prodrug (1 mg) stock solution (in acetonitrile) was
added to 250 µL of a freshly prepared 0.1 N HCl aqueous
solution (pH 1). An amount of 40 µL of a freshly prepared
internal standard solution (10 mg of trifluoromethanesulfonic
acid per milliliter of D2O) was also added to the mixture.
Better antimalarial activity can be attributed to
several phenomena such as the demonstrated hydrolytic
stability and a decreased rate of oxidation by cytochrome
P450 enzymes, due to the influence of CF3 on a
metabolism course or a different distribution. Further-
more, considering the calculated values of log P, C10-
trifluoromethyl artemether 9 (ClogP ) 4.19)20 is very
likely more lipophilic than artemether itself (ClogP )
2.91).20 This change in the lipophilic character can
induce a greater accumulation of fat cells and thus
modify the distribution of the drug.
Con clu sion
In conclusion, new C-10 trifluoromethyl substituted
artemisinin derivatives were easily obtained in a three-
step process from artemisinin, thus giving the op-
portunity to evaluate more quantitatively the incidence
of the introduction of a trifluoromethyl group at C-10
on the stability and antimalarial activity. C-10 trifluo-
romethyl hydroartemisinin 4 was found to be 40 times
more stable than DHA under acid conditions (pH 2), and
the trifluoromethyl analogue of arteether was found to
be 45 times more stable than arteether itself. This study
demonstrated the increased hydrolytic stability brought
to the ketal function by the trifluoromethyl substituent.
Higher stability of these compounds under acidic condi-
tions should increase their half-lives in stomach and in
the acidic parasite food vacuole, where artemisinin
derivatives function as alkylating agents, reacting with
heme and parasite proteins.9 The beneficial effect of the
trifluoromethyl group was also observed in the biological
evaluations. All new prepared compounds exhibited
good in vitro activities against a chloroquine-resistant
strain. In vivo, three of them, in particular the 10-CF3
analogues of artemether and arteether, completely
cleared parasitemia in mice infested with Plasmodium
berghei, from the end of treatment to day 25, which, to
our knowledge, has never been observed with arte-
mether itself at the concentration tested of 35.5 µmol/
kg, whatever the strain used. This improvement in
biological activity could be attributed to several fac-
tors: better hydrolytic stability, higher oxidative me-
tabolism stability, and higher lipophilic character. These
compounds deserve further evaluation and additional
biological data in order to exploit their remarkable
activity and to have a better appreciation of the influ-
ence of the CF3 group.
The NMR tube was sealed to prevent evaporation and
maintained at 37 °C in a water bath. 19F NMR (128 scans)
measurements were made at regular time intervals up to 30
days. The disappearance of the artemisinin derivative was
evaluated by comparing integration with that of the internal
standard.
Ch em istr y. NMR spectra were recorded using Bruker AC
200 and ARX 400 (1H, 200 or 400 MHz; 19F, 188 MHz; 13C, 50
or 100 MHz) spectrometers, in CDCl3 solutions. Chemical
shifts are reported in ppm relative to Me4Si and CFCl3 (for
19F NMR) as internal standards. In the 13C NMR data,
reported signal multiplicities are related to C-F coupling. For
the determination of fine coupling constants, an acquisition
of 16K data points, a Lorentz-Gauss transformation of the
free induction decay (FID), and a zero filling to 64K were
performed in order to obtain a minimum of resolution of 0.2
Hz/point (1H) or 0.5 Hz/point (13C). Complete assignments in
NMR resulted from J module, COSY, HMQC, and HMBC
experiments performed on a multinuclear probe head equipped
with a Z-gradient coil. Optical rotations were measured at 589
nm on a Polartronic E-Schmidt-Haensch apparatus. TLC was
performed on Merck 60 F254 silica plates (vanilin-MeOH-H2-
SO4). Column chromatography was carried out on Merck
SiO2 (70-230 mesh). The IUPAC nomenclature of 6 is
(1S,4R,5R,8R,9R,10R,12R,13R)-1,5,9-trimethyl-10-(trifluoro-
methyl)-11,14,15,16-tetraoxatetracyclo[10.3.1.0.4,13.08,13]-
hexadecane-10-ol. However, for commodity reasons we have
opted for the usual nomenclature 10â-hydroxy-10R-trifluoro-
methyldeoxoartemisinin for 6 and similar nomenclature for
all other compounds described below. Compounds 9, 11-16,
18, and 19 were prepared as previously described.16
Exp er im en ta l Section
In Vit r o Assa ys. Chloroquine-resistant P. falciparum
strain FCB1 (Colombia) was maintained in a continuous
culture of human erythrocytes as described by Trager and
J ensen.21 In vitro antiplasmodial activity of our compounds
was determined using a modification of the semiautomated
microdilution technique of Desjardins et al.22 Stock solutions
of tested compounds were prepared in methanol or DMSO.
Drug solutions were serially diluted with the culture medium
and added to parasite cultures synchronized at the ring stage
(1% parasitemia and 1% final hematocrit) in 96-well plates.
Parasite growth was assessed by adding 0.5 µCi of [3H]-
hypoxanthine (10-30 Ci/mmol, Amersham Biosciences Europe
Gmbh) to each well. Plates were incubated for 48 h at 37 °C
in the appropriate atmosphere. Immediately after incubation,
the plates were frozen and thawed to lyse erythrocytes. The
contents of each well were collected on filter microplates,
washed using a cell harvester, and dried. Scintillation cocktail
was added to each filter, and radioactivity incorporated by the
P r ep a r a tion of 10â-(4-Meth oxyp h en yla m in o)-10r-tr i-
flu or om eth yld eoxoa r tem isin in (17). Bromide 8 (1.128 g,
2.72 mmol) was dissolved in CH2Cl2 (15 mL). The solution was
stirred under an Ar stream at room temperature, and p-

2698 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10
Magueur et al.
1
anisidine (3.34 g, 27.2 mmol) and HFIP (1.4 mL, 13.6 mmol)
were successively added. After being stirred for 1 night at room
temperature, the mixture was diluted with ethyl acetate,
washed with a saturated aqueous solution of NaHCO3, and
dried over MgSO4. Evaporation of the solvent afforded the
crude product, which was purified on an SiO2 column (9:1
petroleum ether/AcOEt). Compound 16 was obtained (315 mg,
25%) as a brown foam. [R]D +93.6 (c 0.34, MeOH); 1H NMR δ
0.95 (3H, d, J ) 5.5 Hz), 1.11 (3H, d, J ) 7.5 Hz), 1.47 (3H, s),
0.83-2.17 (10H, m), 2.39 (1H, m), 3.05 (1H, m), 3.63 (1H, s
broad), 3.75 (3H, s), 5.56 (1H, s), 6.81 (2H, m), 7.04 (2H, m);
13C NMR δ 12.6, 20.0, 23.5, 24.5, 25.7, 30.1, 34.3, 36.2, 37.2,
46.3, 52.2, 55.2, 80.1, 88.3 (q, J C-F ) 28 Hz), 90.0, 104.3, 114.2,
119.2, 123.8 (q, J C-F ) 294 Hz), 136.4, 154.0; 19F NMR δ -75.5
(s, 3F, CF3). Anal. (C23H30F3NO5) C, H, N.
80%) as a white foam. [R]D +94.0 (c 0.32, MeOH); H NMR δ
0.94 (3H, d, J ) 5.5 Hz), 1.04 (3H, d, J ) 7.0 Hz), 1.39 (3H, s),
2.35 (1H, m), 2.88 (1H, m), 4.35 (1H, dm, J ) 18.5 Hz), 4.54
(1H, d, J ) 18.5 Hz), 5.28 (1H, s), 9.6 (1H, s); 13C NMR δ 12.0,
20.1, 23.1, 24.5, 25.6, 29.4, 34.5, 36.0, 37.3, 45.6, 51.8, 68.4,
79.9, 89.4, 98.8 (q, J C-F ) 29 Hz), 104.6, 122.2 (q, J C-F ) 292
Hz), 197.8; 19F NMR δ -76.3 (s, 3 F, CF3); IR νmax 1740 cm-1
.
Anal. (C18H25F3O6) C, H.
Ack n ow led gm en t. We thank MENRT for financial
support (PAL+ program) and a fellowship (G.M.) and
CNRS (GDR etude des protozoaires pathoge`nes: cibles
the´rapeutiques et vaccinales) for financial support. We
are grateful to Drs. V. D. Hoang, P. G. Dien, and N. V.
Hung at the Institute of Natural Products (CNST,
Hanoi, Vietnam) for supplying of artemisinin, and we
are grateful to Central Glass for supplying HFIP. We
thank Miche`le Oure´vith for NMR experiments, Sophie
Mairesse-Lebrun for the elementary analysis, and Nath-
alie Dogna for animal care.
P r ep a r a t ion of 10â-(2,3-d ih yd r oxyp r op oxy)-10r-t r i-
flu or om eth yld eoxoa r tem isin in (20). Compound 13 (396
mg, 1.0 mmol) was dissolved in a mixture of tert-butanol (20
mL) and water (2 mL). 4-Methylmorpholine N-oxide (150 mg,
1.1 mmol) was then added to the solution, followed by osmium
tetroxide (13 mg, 0.05 mmol). After being stirred for 3 h at
room temperature, the mixture was diluted with AcOEt,
successively washed with an aqueous solution of NaHSO3 and
NaHCO3, and dried over MgSO4 and the solvents were
removed under vacuum. Purification of the crude on silica gel
(petroleum ether/AcOEt 8:2) afforded a white foam of 20 (257
mg, 60%) as a mixture (40:60) of two diastereoisomers. 1H
NMR δ 0.95 (3H, d, J ) 6.0 Hz), 0.99 (3H, d, J ) 7.5 Hz), 1.41
(3H, s), 2.37 (1H, ddd, J ) 14.5 Hz, J ) 14.0 Hz, J ) 4.5 Hz),
0.76-2.59 (12H, m), 2.86 (1H, m), 3.41-4.05 (5H, m), 5.48
(Hmino, s), 5.55 (Hmajo, s); 13C NMR δ 11.7, 19.7, 22.6, 22.8, 24.3,
25.2, 29.3, 34.4, 35.8, 36.85, 36.90, 45.6, 45.7, 51.8, 63.3, 63.5,
Refer en ces
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63.6, 64.2, 70.6, 71.0, 79.7, 79.8, 88.7, 88.8, 98.22 (q, J C-F
)
29 Hz), 98.25 (q, J C-F ) 29 Hz), 104.0, 122.2 (q, J C-F ) 293
Hz); 19F NMR δ -76.1 (40%), -76.2 (60%). Anal. (C19H29F3O7)
C, H.
P r ep a r a t ion of 10â-ca r b oxym et h oxy-10r-t r iflu or o-
m eth yld eoxoa r tem isin in (21). Compound 13 (595 mg, 1.5
mmol) was dissolved in a mixture of CCl4 (3 mL), CH3CN (3
mL), and water (5 mL). Sodium periodate (1.6 g, 7.6 mmol)
was then added to the solution, followed by ruthenium(III)
chloride (8 mg, 0.03 mmol). After being stirred for 1 night at
room temperature, the mixture was filtered over Celite, diluted
with AcOEt, successively washed with an aqueous solution of
NaHSO3 and NaHCO3, and dried over MgSO4 and the solvents
were removed under vacuum. Purification of the crude on silica
gel (petroleum ether/AcOEt 7:3) afforded 21 (353 mg, 60%) as
a white foam. [R]D +71.2 (c 0.80, MeOH); 1H NMR δ 0.90 (1H,
m, H-7ax), 0.95 (3H, d, J 15-6 ) 6.0 Hz, CH3-15), 1.05 (3H, d,
J 16-9 ) 7.0 Hz, CH3-16), 1.05 (1H, m, H-5a), 1.35 (1H, m, H-6),
1.40 (3H, s, CH3-14), 1.45 (1H, m, H-5), 1.55 (1H, m, H-8a),
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Activity of New Water-Soluble Dihydroartemisinin Derivatives.
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Physiol. 1991, C99, 391-396. (c) Baker, J . K.; McChesney, J .
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Pharm. Res. 1993, 10, 662-666. (d) Grace, J . M.; Aguilar, A. J .;
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1.65 (1H, dq, J 7eq-7ax ) 13.0 Hz, J 7eq-6 ) J 7eq-8ax ) J 7eq-8eq
)
2.5 Hz, H-7eq), 1.75 (1H, m, H-8), 1.9 (1H, m, H-5), 2.00 (1H,
dt, J 4eq-4ax ) 14.5 Hz, J 4eq-5ax ) J 4eq-5eq ) 3.0 Hz, H-4eq), 2.15
(1H, m, H-8), 2.40 (1H, ddd, J 4ax-4eq ) 14.5 Hz, J 4ax-5a ) 14.0
Hz, J 4ax-5eq ) 4.0 Hz, H-4ax), 2.90 (1H, dq, J 9-16 ) J 9-8a ) 6.0
Hz, H-9), 4.20 (1H, d, J 17-17 ) 16.5 Hz, H-17), 4.50 (1H, s, OH),
4.55 (1H, d, J 17-17 ) 16.5 Hz, H-17), 5.50 (1H, s, H-12); 13C
NMR δ 12.1 (C-16), 20.2 (C-15), 22.8 (C-8), 24.7 (C-5), 25.7
(C-14), 29.5 (C-9), 34.7 (C-7), 36.2 (C-4), 37.3 (C-6), 45.9 (C-
8a), 52.1 (C-5a), 60.7 (C-17), 80.2 (C-12a), 89.6 (C-12), 98.9 (q,
J C-F ) 29 Hz, C-10), 104.7 (C-3), 122.4 (q, J C-F ) 292 Hz, CF3),
175.5 (C-18); 19F NMR δ -76.1 (s, 3 F, CF3); IR νmax 3200, 1728
cm-1. Anal. (C18H25F3O7) C, H.
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mmol) in dichloromethane (40 mL) was cooled at -78 °C.
Ozone gas was passed through the solution at that tempera-
ture until it became light-blue. The color was diminished as
oxygen gas was bubbled through the solution. The reaction
was quenched with methyl sulfide (85 µL, 1.14 mmol), and the
resultant reaction solution was evaporated under reduced
pressure to give a colorless oil. Purification of the crude on
silica gel (petroleum ether/AcOEt 9:1) afforded 22 (238 mg,
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J M0310333