Microwave-assisted ring opening of epoxides: A general route to the synthesis of 1-aminopropan-2-ols with anti malaria parasite activities

Article abstract of DOI:10.1021/jm070553l

A series of 1-aminopropan-2-ols were synthesized and evaluated against two strains of malaria, Plasmodium falciparum FCR3 (chloroquine-resistant) and 3D7 (chloroquine-sensitive). Microwave-assisted ring opening of epoxides (aryl and alkyl glycidyl ethers,

Full text of DOI:10.1021/jm070553l

J. Med. Chem. 2007, 50, 4243-4249
4243
Microwave-Assisted Ring Opening of Epoxides: A General Route to the Synthesis of
1-Aminopropan-2-ols with Anti Malaria Parasite Activities
Ae´lig Robin,† Fraser Brown,† Noem´ı Bahamontes-Rosa,‡ Binghua Wu,§ Eric Beitz,§ Ju¨rgen F. J. Kun,‡ and Sabine L. Flitsch*,†
Manchester Interdisciplinary Biocentre (MIB), The UniVersity of Manchester, 131 Princess street, Manchester M1 7ND, UK, Institute for
Tropical Medicine, Department of Parasitology, UniVersity of Tu¨bingen, Wilhelmstr. 27, 72074 Tu¨bingen, Germany, and Department of
Pharmaceutical Chemistry, UniVersity of Kiel, Gutenbergstrasse 76, Kiel, Germany
ReceiVed May 11, 2007
A series of 1-aminopropan-2-ols were synthesized and evaluated against two strains of malaria, Plasmodium
falciparum FCR3 (chloroquine-resistant) and 3D7 (chloroquine-sensitive). Microwave-assisted ring opening
of epoxides (aryl and alkyl glycidyl ethers, glycidol, epichlorohydrin) with various amines without catalysts
generated the desired library of â-amino alcohols rapidly and efficiently. Most of the compounds showed
micromolar potency against malaria, with seven of them having IC50 values between 1 and 10 µM against
both Plasmodium falciparum strains.
Introduction
Malaria is one of the three major infectious diseases, and
despite years of continual efforts, it is still one of the major
causes of morbidity and mortality affecting more than 40% of
the world’s population mainly in the developing world. There
are 300 to 500 million clinical cases each year, with up to two
Figure 1. Libraries of 1-aminopropan-2-ols.
million deaths predominantly among young children in Sub-
Saharan Africa. Rapidly increasing resistance to antimalarial
drugs, such as chloroquine and the synergistic combination of
In our efforts to target the aquaglyceroporin channel in
Plasmodium for chemotherapy3-6 we were interested in generat-
sulfadoxine and pyrimethamine used as first line treatment, calls
ing libraries of 1-aminopropan-2-ols (Figure 1) as glycerol
for novel focused strategies for combating malaria.1,2
analogues that might block the channel. It was proposed that a
robust and efficient route toward these compounds could be
The causative agent of malaria, Plasmodium falciparum, faces
the highly complex problem of obtaining nutrients and disposing
developed from the ring opening of epoxides, versatile starting
of waste products, while at the same time growing and
materials or intermediates in organic synthesis.
multiplying within a cell, which is merely a container for
Ring opening of epoxides is well-documented in the litera-
hemeoglobin. The delivery of substrates and disposal of
ture: the inherent polarity and strain of the three membered
metabolites to the parasite depends therefore upon parasite-
ring allows them to react with a wide number of reagents such
encoded transport proteins that facilitate exchange across the
as amines, alcohols, and thiols.7-10 For the aminolysis of
parasite plasma membrane. Identifying participating molecules
epoxides, a large variety of activators have been employed,
and mechanisms responsible for transport processes is of
including metal salts.11-18 Some of the reported methods suffer
potential importance because they may become new drug targets.
from disadvantages such as moisture sensitivity, inconvenient
The attractiveness of transporters as potential drug targets lies
handling procedures, expensive costs, or long reaction times.
in their unique essential function for parasite growth. One of
Previous studies have suggested that epoxide opening reactions
the potential targets is PfAQPa, a single copy gene in P.
can be conducted under microwave irradiation.19-22 We report
falciparum.
here the successful use of microwave irradiation to drive
Aquaporins, such as PfAQP, are integral membrane channel
nucleophilic ring-opening reactions of epoxide intermediates
proteins that selectively and efficiently facilitate the passage of
without the need for any catalyst. The methodology was used
water (orthodox aquaporins) and/or small uncharged molecules
for the rapid synthesis of a library of â-amino alcohols with
antimalarial activities.
(aquaglyceroporins) across cell membranes. Their functions are
as diverse as water homeostasis in the human body, regulation
of cellular osmolarity in yeast, uptake of nitrogen sources, such
as ammonia, in plant nodules, or involvement in lipid metabo-
Results and Discussion
Ring opening of epoxides such as benzyl glycidyl ether can
be achieved using Lewis acid catalysis (zinc chloride), but the
reaction times were long (24 h) and required lengthy column
purification. The ring opening of (()-benzyl glycidyl ether with
diethylamine (Table 1, product 1a) was therefore studied using
a variety of conditions (acidic, basic, and neutral) under
microwave irradiation. It was found that neutral conditions were
optimal for ring opening. The reaction proceeded cleanly with
1.5 equiv of amine in 4 min at 140 °C (80 W power), with no
trace of byproducts. This strategy was then applied to a broad
range of primary and secondary amines (Scheme 1, Table 1).
lism via glycerol facilitation. The latter function may be of
particular importance for Plasmodium parasites, which were
shown to excessively use glycerol from the host serum for the
rapid synthesis of membrane glycerolipids (see review by Beitz3
and references therein).
* Corresponding author. Tel.: +44(0)161 3065172; fax: +44(0)161
2751311; e-mail: sabine.flitsch@manchester.ac.uk.
† The University of Manchester.
‡ University of Tu¨bingen.
§ University of Kiel.
a Abbreviations: PfAQP, Plasmodium falciparum aquaglyceroporin.
10.1021/jm070553l CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/01/2007

4244 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Table 1. Synthesis of â-Amino Alcohols 1a-x
Robin et al.
Table 2. Synthesis of â-Amino Alcohols 2a-g and 3a-c
Scheme 3. Proposed Route for Formation of Unwanted Side
Products
Scheme 1. Ring Opening of Benzyl Glycidyl Ether with
Amines under Microwave Conditions
Scheme 2. Ring Opening of Alkyl/aryl Glycidyl Ethers or
Glycidol (R ) H) with Amines under Microwave Conditions
Scheme 4. Ring Opening of Epichlorohydrin with Amines
under Microwave Conditions
Products 1a-x were isolated in good yields by simple evapora-
tion of the reaction solvent or, if necessary, purification Via
Kugelrohr bulb to bulb distillation.
Apart from benzyl ethers, a large number of â-amino alcohols
could also be obtained depending on the amines and the
epoxides used as starting materials (Scheme 2). The method
was adapted to use various alkyl/aryl glycidyl ethers or glycidol
itself for the synthesis of 1-amino-3-alkoxy/aryloxypropan-2-
ols 2a-g or 3-aminopropan-1,2-diols 3a-c, respectively, with
good yields (Table 2).
The use of epichlorohydrin as starting material was also
investigated in order to facilitate further glycerol modifications,
such as nucleophile substitution of the chlorine. Reaction of
epichlorohydrin with morpholine using solvent free conditions
with montmorillonite K10 clay has been reported by Saidi et
al.21 The yield was 54% because of the formation of a byproduct
resulting from the nucleophilic attack at the more substituted
carbon of the epoxide. We investigated the reaction of epi-
chlorohydrin with diethylamine using the conditions developed
previously. Upon analysis by mass spectrometry, the desired
product and the expected chlorine isotope peak were not
observed. However, an intense molecular ion peak at m/z 203
(100%) and a smaller peak at m/z 130 (50%) were evident, and
a further peak at m/z 332 was also observed. It was postulated
that the microwave conditions used for this reaction could have
promoted further reaction of unwanted side products as shown
in Scheme 3 (product m/z 203 was isolated in 75% yield).
Optimization of the experimental conditions was conducted.
Altering the number of amine equivalent (0.9 equiv), the
temperature (20 °C), and the reaction time (1 min) prevented
formation of byproducts. Using these new conditions, a small
library of 1-chloro-3-aminopropan-2-ol was synthesized (Scheme
4, Table 3). Purification was achieved by removing the solvent
under reduced pressure using a low-temperature bath (keeping

1-Aminopropan-2-ols with Anti Malaria ActiVities
Table 3. Synthesis of â-Amino Alcohols 4a-h
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4245
Scheme 5. Synthesis of Analogues of 1l and Enantiopure
Analogues of 1p (8a and 9a) and 1t (8b and 9b)
Table 4. Results of Biological Tests against Plasmodium falciparum
FCR3 and 3D7
IC50 FCR3
IC50 3D7
IC50 FCR3
IC50 3D7
compd
(µM)
(µM)
compd
(µM)
(µM)
1a
1b
1c
1f
1h
1j
28.1
12.5
20.2
12.5
8.4
31.1
0.7
2.0
12.7
15.2
10.3
7.7
3.4
1.2
NEa
NE
NE
NE
NE
NE
NE
47
NE
NE
15.1
NE
NE
NE
1t
1w
4f
5.8
15.8
38.5
23.8
31.0
41.6
43.9
7.7
16.3
5.9
5.3
4.6
2.4
9.7
32.5
66
NE
15.6
15.4
43.5
3.7
9.3
5.1
2.9
3.9
4g
4h
6a
6b
6c
7
8a
8b
9a
9b
1k
1l
1n
1o
1p
1q
1r
1s
1.4
a NE: noneffective.
water bath temperature under 20 °C), and products 4a-h were
obtained in good yields.
All the compounds generated have been tested in Vitro against
two strains of Plasmodium falciparum: FCR3 (chloroquine-
resistant) and 3D7 (chloroquine-sensitive) (Table 4). Compounds
were first tested against the FCR3-resistant strain. Since the
objective is to find compounds with a broad antimalarial
spectrum, only those compounds showing activity against FCR3
were subsequently tested against the 3D7 strain.
Five of the most interesting compounds with inhibition of
both Plasmodium strains (4f, 4h, 1t, 6c, and 7) were also tested
in toxicity assays. The effect of these compounds on cell
viability (NALM-6, MONO-MAC-6, and Jurkat cell lines) was
measured in 96-well plates after 24 h (1 cell cycle) of exposure
of the cell suspension (25 cells/µL) to 100 µM compound
concentration at 37 °C. The experiments were done in duplicate,
and cell growth was monitored by incorporating the vital dye
Trypan Blue. None of the compounds showed any toxicity at
concentrations of 100 µM.
Of this first generation of compounds, all active compounds
included a benzyloxy or a chloro group in their structure and
had an IC50 under 50 µM against the FCR3 strain. Six
compounds (1l, 1p, 1t, 1w, 4f, and 4h) had inhibitory effects
for both strains, with 1l having the lowest IC50 among these
compounds for the FCR3 strain. Therefore, some derivatives
of 1l were synthesized in order to replace the benzyloxy group
with its sulfur (7) and nitrogen (6a-c) analogues. Compounds
6a-c and 7 were obtained under microwaves conditions by ring
opening of epoxide 5 (Scheme 5.). The most interesting
biological result was obtained with 6c. In fact, compared to 1l,
compound 6c showed a similar IC50 against FCR3 but a better
IC50 against 3D7 (3.7 µM). Enantiopure synthesis of two of
the most interesting compounds generated by the library (1p
and 1t) were also realized in order to know if one of the two
enantiomers could be more effective. The synthesis was
achieved by reacting the commercially available enantiopure
benzylglycidyl ethers (R) or (S) with the appropriate amine to
generate 8a,b and 9a,b (Scheme 5). The results of the biological
tests showed that both enantiomers have the same inhibitory
effect, similar to that of the racemic mixtures.
Conclusion
In summary, we have shown that it is possible to generate
focused libraries of 1-aminopropan-2-ols using microwave-
assisted ring opening of epoxides. Short reaction times and
simple procedures and purifications make this method applicable
for library synthesis, while liberating a free alcohol group useful
for further transformations. The biological tests against two
strains of malaria parasites (one resistant against chloroquine)
have shown some interesting results, with seven compounds
having an IC50 between 1 and 10 µM against the two strains of
Plasmodium falciparum. Synthesis of more analogues are
therefore currently under investigation.
Experimental Section
General. Solvents and reagents were obtained from commercial
sources and used as received. Proton and carbon NMR spectra were
obtained using Bruker AC250 or DPX-360 instruments. Chemical
shifts are reported in parts per million (ppm, δ) relative to TMS
using CDCl3 as solvent. The coupling constants are reported in hertz
Compounds 1b, 1h, 1k, 1l, 1t, and 6c were tested as inhibitors
of Plasmodium falciparum aquaglyceroporin function in a yeast-
based assay at concentrations up to 100 µM. None of the
compounds affected aquaglyceroporin function.

4246 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Robin et al.
(Hz) using the following abbreviations: s ) singulet, d ) doublet,
t ) triplet, q ) quadruplet, qu ) quintet and m ) multiplet. High-
resolution mass spectrometry fast atom bombardment (HRMS FAB)
was performed using a Kratos MS50TC instrument, and electrospray
(ES-MS) nominal mass spectra were recorded using a Micromass
Platform II instrument. All microwave-assisted reactions were
carried out in a CEM Discover Microwave Synthesizer with
Explorer Carousel. Analytical HPLC was performed on an Agilent
Series 1100. The methods used were (A) a normal phase system
and (B) a reverse phase system (see Supporting Information).
Parasite Cultures. The P. falciparum chloroquine-resistant (QR)
strain FCR3 and the chloroquine-sensitive (QS) strain 3D7 were
maintained in continuous culture with 5% fresh O+ erythrocytes
depleted of lymphocytes obtained from the University Hospital in
Tu¨bingen. Parasites were kept according to the standard procedure
in RPMI-1640 medium (Sigma, Steinheim, Germany) supplemented
with 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
(HEPES) (Sigma), 0.5% albumax (GIBCO, Paisley, Scotland), 2
mM L-glutamine (GIBCO), and 50 µM/mL gentamicin (GIBCO)
and incubated at 37 °C in a 5% CO2, 5% O2, and 90% N2
atmosphere. Parasites were maintained as highly synchronized
cultures by regular treatment with 5% D-sorbitol (SIGMA) twice a
week. The success of the synchronization was determined by thin
blood smears stained with 10% Giemsa stain solution (SIGMA) in
phosphate buffer pH 7.2.
(1.5 mmol) was added to the tube and placed in the CEM Discover
Microwave Synthesizer Explorer Carousel. Each sample was heated
at 140 °C with stirring for 4 min (80 W, 50 psi). A period of 5 min
was allowed for sample cooling. Each sample was concentrated in
Vacuo, and purification was performed if necessary, by using
Kugelrohr bulb to bulb distillation apparatus to yield the desired
products 1a-x, 2a-g, or 3a-c.
1-Benzyloxy-3-diethylaminopropan-2-ol (1a). Yield 96%, oil;
3
1H NMR(CDCl3); δ 1.10 (6H, t, J ) 7.0 Hz, 2 CH3), 2.51-2.78
(6H, m, 2 NCH2CH3, NCH2CH), 3.56 (2H, d, 3J ) 5.3 Hz,
CHCH2O), 3.90 (1H, qu, 3J ) 4.7 Hz, CHOH), 4.66 (2H, s,
OCH2Ar), 7.34-7.43 (5H, m, Har); 13C NMR(CDCl3) δ 11.8 (2
CH3), 46.9 (2 NCH2CH3), 55.8 (NCH2CH), 66.4 (CHOH), 72.7
(CHCH2O), 73.3 (OCH2Ar), 127.4 (CHar), 127.5 (2 CHar), 128.2
(2 CHar), 138.1 (Car); m/z; found (ES-MS+) [M + H]+ 238; found
(HRMS FAB) [M + H]+ 238.18086 C14H23NO2 requires 238.18070.
1-Benzylamino-3-benzyloxypropan-2-ol (1b). Yield 95%; oil;
1H NMR(CDCl3); δ 2.02 (1H, s, NH), 2.62-2.82 (2H, m,
NCH2CH), 3.42-3.56 (2H, m, CHCH2O), 3.79 (2H, s, ArCH2N),
3.84-4.12 (1H, m, CHOH), 4.55 (2H, s, OCH2Ar), 7.52-7.65
(10H, m, Har); 13C NMR(CDCl3) δ 52.1 (NCH2CH), 54.3 (ArCH2N),
68.8 (CHOH), 73.3 (CHCH2O), 73.8 (OCH2Ar), 127.4-129.6 (10
CHar), 138.5 (Car), 140.4 (Car); m/z; found (ES-MS+) [M + H]+
272; found (HRMS FAB) [M + H]+ 272.15723 C17H21NO2 requires
272.15730. HPLC 98% purity (A), 95% purity (B).
Drug Susceptibility Assay. P. falciparum drug sensitivity assays
were performed in 96-well plates by monitoring the accumulation
of the parasite protein histidine-rich protein 2 (HRPII) in the culture
supernatant after lysis of the parasite cells.23 Ring-stage parasites
were seeded at 0.05% parasitemia in 1.5% hematocrit.24 The cultures
were incubated for 72 h at 37 °C in complete culture medium
containing three-fold serial dilutions of the drugs starting at 100
µM. Since compounds were dissolved in DMSO or acetonitrile,
parasite viability was previously assessed. Parasites were frozen
and thawed twice to obtain complete lysis, and the samples were
stored at -20 °C. Parasite growth controls were obtained by
culturing parasites without drug harvesting at 0 and 72 h. Growth
inhibition in the presence of the test compounds is expressed as a
percent of the control cultures. Chloroquine was used as a positive
control for growth inhibition. The experiments were done in
duplicate, and IC50 values were calculated from the HRPII
production in the 72 h time interval. Drug sensitivities were assayed
as published previously.25
In Vitro Toxicity Assay. Human B cell precursor leukemia
NALM-6, monocytic leukaemia MONO-MAC-6, and Jurkat lym-
phoblastoid cell lines were routinely cultured at 37 °C in RPMI
1640 medium complemented with 1 mmol/L-glutamine and 10%
fetal calf serum (GIBCO) in 5% humidified CO2. The effect of the
drugs on cell viability was measured in 96-well plates after 24 h
(1 cell cycle) of exposure of 6000 cells/well to drug concentrations
of 100, 50, 25, 1 µM and 500 nM at 37 °C. The experiments were
done in duplicate, and cell growth was monitored by incorporating
Trypan Blue (SIGMA, Taufkirchen, Germany). The results are
expressed as the drug concentration resulting in 50% inhibition of
the cell growth.
1-Benzyloxy-3-pyrrolidin-1-ylpropan-2-ol (1c). Yield 62%; oil;
1H NMR(CDCl3); δ 1.62-1.68 (4H, m, 2 CH2 pyrrolidine), 2.24-
2.62 (6H, m, 2 NCH2 pyrrolidine, NCH2CH), 3.21-3.39 (2H, m,
CHCH2O), 3.79 (1H, qu, 3J ) 4.6 Hz, CHOH), 4.45 (2H, s,
OCH2Ar), 7.15-7.24 (5H, m, Har); 13C NMR(CDCl3) δ 23.6 (2
CH2 pyrrolidine), 54.3 (2 NCH2 pyrrolidine), 58.8 (NCH2CH), 68.1
(CHOH), 73.0 (CHCH2O), 73.5 (OCH2Ar), 127.7 (CHar), 127.8 (2
CHar), 128.4 (2 CHar), 138.2 (Car); m/z; found (ES-MS+) [M +
H]+ 236; found (HRMS FAB) [M + H]+ 236.16572 C14H21NO2
requires 236.16505.
1-Benzyloxy-3-morpholin-4-ylpropan-2-ol (1e). Yield 94%; oil;
1H NMR(CDCl3); δ 2.30-2.36 (4H, m, 2 NCH2 morpholine),
2.47-2.55 (2H, m, NCH2CH), 3.37-3.41 (2H, m, CHCH2O),
3
3.55-3.62 (4H, m, 2 OCH2 morpholine), 3.84 (1H, qu, J ) 4.6
Hz, CHOH), 4.47 (2H, s, OCH2Ar), 7.15-7.25 (5H, m, Har); 13C
NMR(CDCl3) δ 53.3 (NCH2CH), 57.7 (2 NCH2 morpholine), 65.6
(CHOH), 66.5 (2 OCH2 morpholine), 72.1 (CHCH2O), 73.1
(OCH2Ar), 127.2 (CHar), 127.3 (2 CHar), 128.0 (2 CHar), 137.6 (Car);
m/z; found (ES-MS+) [M + H]+ 252; found (HRMS FAB) [M +
H]+ 252.15970 C14H21NO3 requires 252.15997.
1-Benzyloxy-3-piperazin-1-ylpropan-2-ol (1f). Yield 85%, oil;
1H NMR(CDCl3); δ 2.28-2.33 (4H, m, 2 CH2 piperazine), 2.42-
2.48 (2H, m, NCH2CH), 2.73-2.77 (4H, m, 2 CH2 piperazine),
3.36-3.42 (2H, m, CHCH2O), 3.84 (1H, qu, 3J ) 4.6 Hz, CHOH),
4.46 (2H, s, OCH2Ar), 7.15-7.25 (5H, m, Har); 13C NMR(CDCl3)
δ 46.1 (2 CH2 piperazine), 47.1 (2 CH2 piperazine), 54.6 (NCH2CH),
66.0 (CHOH), 72.7 (CHCH2O), 73.5 (OCH2Ar), 127.7 (CHar), 127.8
(2 CHar), 128.4 (2 CHar), 138.1 (Car); m/z; found (ES-MS+) [M +
H]+ 251; found (HRMS FAB) [M + H]+ 251.17590 C14H22N2O2
requires 251.17595.
Yeast-Based Assay for PfAQP Inhibition. Efflux permeability
of cytotoxic methylamine was used to test for the functionality of
PfAQP and inhibition by the test compounds 1b, 1h, 1k, 1l, 1t,
and 6c. BY4742∆fps1 yeast cells expressing PfAQP were grown
in 1 mL of 20 mM MES-buffered (pH5.5) liquid minimal YNB
medium with 3% glucose, 0.1% proline, with and without addition
of 50 mM methylamine hydrochloride. The test compound con-
centration was 100 µM. Untreated cells were used as controls.
Cultures were set up with an initial OD600 of 0.1 and were incubated
for 48 h. A reduction in cell proliferation as determined by OD600
measurement would indicate PfAQP inhibition by the test com-
pounds. All experiments were done in duplicate.
1-Benzyloxy-3-(cyclopropylmethylamino)propan-2-ol (1h). Yield
89%, oil, H NMR(CDCl3); δ 0.09-0.13 (2H, m, CH2 cyclopro-
1
pane), 0.36-0.41 (CH2 cyclopropane), 0.78-0.87 (CH cyclopro-
pane), 1.89 (1H, s, NH), 2.32-2.41 (2H, m, cyclopropane CH2NH),
2.54-2.66 (2H, m, NCH2CH), 3.34-3.41 (2H, m, CHCH2O),
3.77-3.81 (1H, m, CHOH), 4.47 (2H, s, OCH2Ar), 7.19-7.29 (5H,
m, Har); 13C NMR(CDCl3) δ 3.8 (2 CH2 cyclopropane), 11.6 (CH
cyclopropane), 52.2 (NCH2CH), 55.3 (cyclopropaneCH2N), 68.8
(CHOH), 73.0 (CHCH2O), 73.8 (OCH2Ar), 127.9 (CHar), 128.1 (2
CHar), 128.8 (2 CHar), 138.4 (Car); m/z; found (ES-MS+) [M +
H]+ 236; found (HRMS FAB) [M + H]+ 236.16450 C14H21NO2
requires 236.16505.
General Procedure for the Synthesis of 1a-x, 2a-g, and 3a-
c. Benzyl glycidyl ether (for 1a-x), alkyl/aryl glycidyl ether (for
2a-g), or glycidol (for 3a-c) (1 mmol) was dispensed into a
microwave tube and dissolved in absolute ethanol (2.5 mL). Amine
1-Benzyloxy-3-(pyridin-2-ylamino)propan-2-ol (1j). Yield 82%,
oil, 1H NMR(CDCl3); δ 2.01 (1H, s, NH), 3.38-3.56 (4H, m,
NCH2CH, CHCH2O), 3.90-4.12 (1H, m, CHOH), 4.44 (2H, s,
3
OCH2Ar), 6.51 (1H, m, CH pyridine), 6.59 (1H, d, J ) 9.0 Hz,

1-Aminopropan-2-ols with Anti Malaria ActiVities
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4247
3
CH pyridine), 7.23-7.35 (5H, m, Har), 7.46 (1H, d, J ) 5.5 Hz,
CH pyridine), 7.81-7.89 (1H, m, CH pyridine); 13C NMR(CDCl3)
δ 54.5 (NCH2CH), 68.0 (CHOH), 73.8 (CHCH2O), 74.0 (OCH2Ar),
107.1 (CH pyridine), 114.2 (CH pyridine), 128.3-128.9 (5 CHar),
138.1 (CH pyridine), 139.6 (Car), 148.3 (CH pyridine) 158.9 (C
pyridine); m/z; found (ES-MS+) [M + H]+ 259; found (HRMS
FAB) [M + H]+ 259.14411 C15H18N2O2 requires 259.14465.
1-(Benzyl(ethyl)amino)-3-(benzyloxy)propan-2-ol (1k). Yield
57%, oil, 1H NMR(CDCl3); δ 0.94 (3H, t, 3J ) 7.1 Hz, CH3), 2.42-
2.59 (4H, m, NCH2CH, CH3CH2), 3.33-3.40 (3H, m, CHCH2O,
NMR(CDCl3) δ 25.8 (CH2 tetrahydrofuran), 29.1 (CH2 tetra-
hydrofuran), 52.0 (NCH2CH), 54.0 (tetrahydrofuran CH2), 67.9
(CH2 tetrahydrofuran), 68.8 (CHOH), 72.8 (CHCH2O), 73.4
(OCH2Ar), 78.2 (CH tetrahydrofuran), 127.7-128.4 (5 CHar), 138.1
(Car); m/z; found (ES-MS+) [M + H]+ 266.
1-Benzyloxy-3-[(2-furylmethyl)amino]propan-2-ol (1r). Yield
1
58%, oil; H NMR(CDCl3); 2.51-2.65 (3H, m, NCH2CH, NH),
3.34-3.44 (2H, m, CHCH2O), 3.68 (2H, s, furanCH2NH), 3.77-
3.82 (1H, m, CHOH), 4.45 (2H, s, OCH2Ar), 6.07 (1H, d, 3J ) 1.1
3
Hz, CH furan), 6.21 (1H, d, J ) 1.1 Hz, CH furan), 7.20-7.25
2
ArCH2N), 3.64 (1H, d, J ) 13.5 Hz, ArCH2N), 3.75-3.81 (1H,
(6H, m, 5 Har, CH furan); 13C NMR(CDCl3) δ 45.9 (furanCH2-
NH), 51.1 (NCH2CH), 68.8 (CHOH), 72.7 (CHCH2O), 73.3
(OCH2Ar), 106.9 (CH furan), 110.0 (CH furan), 127.6-128.3 (5
CHar), 137.9 (Car), 141.7 (CH furan), 153.5 (C furan); m/z; found
(ES-MS+) [M + H]+ 262.
m, CHOH), 4.44 (2H, s, OCH2Ar), 7.19-7.35 (10H, m, Har); 13C
NMR(CDCl3) δ 12.0 (CH3), 47.8 (CH2CH3), 56.4 (NCH2CH), 58.5
(ArCH2N), 67.1 (CHOH), 73.0 (CHCH2O), 73.8 (OCH2Ar), 127.4-
129.2 (10 CHar), 138.6 (Car), 139.3 (Car); m/z; found (ES-MS+) [M
+ H]+ 300. HPLC 96% purity (A), 95% purity (B).
1-Benzyloxy-3-[2-(2-thienylethyl)amino]propan-2-ol (1s). Yield
73%, oil; 1H NMR(CDCl3); 2.47-2.64 (2H, m, NCH2CH), 2.73-
2.89 (4H, m, CH2CH2NH, thiophene CH2CH2), 3.33-3.40 (2H,
m, CHCH2O), 3.74-3.78 (1H, m, CHOH), 4.43 (2H, s, OCH2Ar),
1-(Benzyl(methyl)amino)-3-(benzyloxy)propan-2-ol (1l). Yield
96%, oil, 1H NMR(CDCl3); δ 2.24 (3H, s, NCH3), 2.41-2.63 (2H,
2
m, NCH2CH), 3.46-3.57 (2H, m, CHCH2O), 3.52 (1H, d, J )
2
3
3
13.5 Hz, ArCH2N), 3.67 (1H, d, J ) 13.5 Hz, ArCH2N), 3.92-
6.70 (1H, d, J ) 2.1 Hz, CH thiophene), 6.81 (1H, dd, J ) 2.1
3 3
3.99 (1H, m, CHOH), 4.57 (2H, s, OCH2Ar), 7.25-7.37 (10H, m,
Har); 13C NMR(CDCl3) δ 42.2 (NCH3), 59.9 (NCH2CH), 62.6
(ArCH2N), 66.9 (CHOH), 72.7 (CHCH2O), 73.6 (OCH2Ar), 127.0-
129.1 (10 CHar), 138.5 (Car), 140.2 (Car); m/z; found (ES-MS+) [M
+ H]+ 286; found (HRMS FAB) [M + H]+ 286.18044 C18H23NO2
requires 286.18070. HPLC 99% purity (A), 97% purity (B).
1-Benzyloxy-3-(ethyl(isopropyl)amino)propan-2-ol (1m). Yield
87%, oil, 1H NMR(CDCl3); δ 0.79-0.92 (9H, m, CH3CH2,
(CH3)2CH), 2.24-2.41 (4H, m, CH3CH2, NCH2CH), 2.83 (1H,
Hz, J ) 3.0 Hz, CH thiophene), 7.02 (1H, d, J ) 3.0 Hz, CH
thiophene), 7.19-7.24 (5H, m, Har); 13C NMR(CDCl3) δ 30.2
(thiophene CH2CH2), 50.9 (CH2CH2NH), 51.5 (NCH2CH), 68.7
(CHOH), 72.7 (CHCH2O), 73.2 (OCH2Ar), 123.4 (CH thiophene),
124.8 (CH thiophene), 126.7 (CH thiophene), 127.6-128.2 (5 CHar),
137.9 (Car), 142.2 (C thiophene); m/z; found (ES-MS+) [M + H]+
292.
1-Benzyloxy-3-[(2-thienylmethyl)amino]propan-2-ol (1t). Yield
1
84%, oil; H NMR(CDCl3); 2.55-2.70 (3H, m, NCH2CH, NH),
3
septet, J ) 6.6 Hz, (CH3)2CH), 3.34-3.37 (2H, m, CHCH2O),
3.36-3.43 (2H, m, CHCH2O), 3.79-3.84 (1H, m, CHOH), 3.90
(2H, s, thiophene CH2NH), 4.46 (2H, s, OCH2Ar), 6.80-6.86 (2H,
m, CH thiophene), 7.11 (1H, d, 3J ) 3.0 Hz, CH thiophene), 7.20-
7.26 (5H, m, Har); 13C NMR(CDCl3) δ 48.6 (thiopheneCH2NH),
51.5 (NCH2CH), 69.3 (CHOH), 73.1 (CHCH2O), 73.7 (OCH2Ar),
124.8 (CH thiophene), 125.3 (CH thiophene), 126.9 (CH thiophene),
128.0-128.8 (5 CHar), 138.3 (Car), 144.1 (C thiophene); m/z; found
(ES-MS+) [M + H]+ 278. HPLC 97% purity (A), 92% purity (B).
1-Benzyloxy-3-(bicyclo[2.2.1]hept-2-ylamino)propan-2-ol (1x).
Yield 95%; oil; 1H NMR(CDCl3); δ 1.04-1.10 (4H, m, CH2
bicycle), 1.41-1.60 (4H, m, CH2 bicycle, 2 CH bicycle), 2.13-
2.20 (2H, m, CH2 bicycle), 2.53-2.75 (3H, m, NCH2CH, CH
bicycle), 2.97 (1H, s, NH), 3.45-3.49 (2H, m, CHCH2OH), 3.87-
3.92 (1H, m, CHOH), 4.56 (2H, s, OCH2Ar), 7.30-7.35 (5H, m,
Har); 13C NMR(CDCl3) δ 27.4 (CH2 bicycle), 28.9 (CH2 bicycle),
35.2 (CH2 bicycle), 36.0 (CH bicycle), 40.5 (CH2 bicycle), 41.4
(CH bicycle), 50.6 (NCH2CH), 62.4 (CH bicycle), 69.2 (CHOH),
73.5 (CHCH2O), 73.8 (OCH2Ar), 128.1-128.8 (5 CHar), 138.5
(Car); m/z; found (ES-MS+) [M + H]+ 276.
3.60-3.65 (1H, m, CHOH), 4.44 (2H, s, OCH2Ar), 7.11-7.24 (5H,
m, Har); 13C NMR(CDCl3) δ 14.6 (CH3CH2), 20.4 ((CH3)2CH), 44.2
(CH3CH2), 50.4 ((CH3)2CH), 52.0 (NCH2CH), 66.6 (CHOH), 73.1
(CHCH2O), 73.6 (OCH2Ar), 127.7 (CHar), 127.8 (2 CHar), 128.4
(2 CHar), 138.4 (Car); m/z; found (ES-MS+) [M + H]+ 252; found
(HRMS FAB) [M + H]+ 252.19624 C15H25NO2 requires 252.19635.
1-Benzyloxy-3-(tert-butylamino)propan-2-ol (1n). Yield 81%,
1
oil, H NMR(CDCl3); δ 0.99 (9H, s, (CH3)3), 2.44-2.60 (2H, m,
NCH2CH), 3.34-3.41 (2H, m, CHCH2O), 3.65-3.72 (1H, m,
CHOH), 4.44 (2H, s, OCH2Ar), 7.17-7.28 (5H, m, Har); 13C
NMR(CDCl3) δ 27.2 ((CH3)3), 44.9 (NCH2CH), 54.0 (C(CH3)3),
69.3 (CHOH), 72.8 (CHCH2O), 73.5 (OCH2Ar), 127.6 (CHar), 127.8
(2 CHar), 128.4 (2 CHar), 138.2 (Car); m/z; found (ES-MS+) [M +
H]+ 238; found (HRMS FAB) [M + H]+ 238.18058 C14H23NO2
requires 236.18070.
1-Benzyloxy-3-(cyclobutylamino)propan-2-ol (1o). Yield 59%,
oil; H NMR(CDCl3); δ 1.51-1.62 (4H, m, CH2 cyclobutane),
1
2.07-2.12 (2H, m, CH2 cyclobutane), 2.50-2.58 (2H, m, NCH2CH),
3.09-3.17 (1H, m, CH cyclobutane), 3.33-3.43 (2H, m, CHCH2O),
3.73-3.79 (1H, m, CHOH), 4.47 (2H, s, OCH2Ar), 7.18-7.26 (5H,
m, Har); 13C NMR(CDCl3) δ 14.6 (CH2 cyclobutane), 30.9 (2 CH2
cyclobutane), 49.1 (NCH2CH), 54.0 (CH cyclobutane), 68.9
(CHOH), 72.9 (CHCH2O), 73.3 (OCH2Ar), 127.6-128.3 (5 CHar),
138.0 (Car); m/z; found (ES-MS+) [M + H]+ 236.
1-[Benzyl(methyl)amino]-3-phenoxypropan-2-ol (2a). Yield
99%, oil, 1H NMR(CDCl3); δ 2.31 (3H, s, NCH3), 2.55-2.73 (2H,
2
m, NCH2CH), 3.57 (1H, d, J ) 12.9 Hz, ArCH2N), 3.72 (1H, d,
3
2J ) 12.9 Hz, ArCH2N), 4.00 (2H, d, J ) 4.8 Hz, CHCH2O),
4.12-4.18 (1H, m, CHOH), 6.92-6.98 (3H, m, Har), 7.32-7.37
(7H, m, Har); 13C NMR(CDCl3) δ 42.1 (NCH3), 59.6 (NCH2CH),
62.6 (ArCH2N), 66.1 (CHOH), 70.2 (CHCH2O), 114.4 (2 CHar),
120.8 (CHar), 127.2-129.4 (7 CHar), 138.2 (Car), 158.7 (Car); m/z;
found (ES-MS+) [M + H]+ 272.
1-Benzyloxy-3-(cyclopentylamino)propan-2-ol (1p). Yield 99%,
oil; 1H NMR(CDCl3); δ 1.21-1.93 (8H, 4 m, CH2 cyclopentane),
2.59-2.78 (3H, m, NCH2CH, NH), 3.07 (1H, qu, 3J ) 6.9 Hz, CH
cyclopentane), 3.48-3.52 (2H, m, CHCH2O), 3.87-3.93 (1H, m,
CHOH), 4.59 (2H, s, OCH2Ar), 7.23-7.36 (5H, m, Har); 13C
NMR(CDCl3) δ 23.8 (2 CH2 cyclopentane), 32.9 (2 CH2 cyclo-
pentane), 50.8 (NCH2CH), 59.7 (CH cyclopentane), 68.9 (CHOH),
72.9 (CHCH2O), 73.3 (OCH2Ar), 127.5-128.3 (5 CHar), 138.0
(Car); m/z; found (ES-MS+) [M + H]+ 250. HPLC 95% purity (A),
98% purity (B).
1-Benzyloxy-3-[(tetrahydrofuran-2ylmethyl)amino]propan-2-
ol (1q). Yield 79%, oil; H NMR(CDCl3); δ 1.44-1.51 (1H, m,
CH2 tetrahydrofuran), 1.76-1.91 (3H, m, CH2 tetrahydrofuran),
2.57-2.72 (4H, m, NCH2CH, tetrahydrofuran CH2NH), 3.37-3.45
(2H, m, CHCH2O), 3.66-3.77 (2H, 2 m, CH2 tetrahydrofuran),
3.78-3.82 (1H, m, CH tetrahydrofuran), 3.88-3.93 (1H, m,
CHOH), 4.48 (2H, s, OCH2Ar), 7.23-7.28 (5H, m, Har); 13C
3-[Benzyl(ethyl)amino]propan-1,2-diol (3a). Yield 99%, oil,
3
1H NMR(CDCl3); δ 0.89 (3H, t, J ) 7.1 Hz, CH3), 2.29-2.49
(4H, m, NCH2CH, CH3CH2), 3.34-3.61 (6H, m, CH2OH, ArCH2N,
CHOH), 7.08-7.17 (5H, m, Har); 13C NMR(CDCl3) δ 11.3 (CH3),
47.4 (CH2CH3), 55.4 (NCH2CH), 58.0 (ArCH2N), 64.5 (CH2OH),
67.2 (CHOH), 126.9-128.7 (5 CHar), 138.3 (Car); m/z; found (ES-
MS+) [M + H]+ 210.
General procedure for the synthesis of 4a-h. To a microwave
tube containing epichlorohydrin (1 mmol) dissolved in absolute
ethanol (2.5 mL) was added the amine (0.9 mmol). The reaction
was placed in the CEM Discover microwave for 1 min at 20 °C
(80 W, 50 psi). The crude product was allowed to cool and
concentrated in Vacuo (keeping water bath temperature <20 °C)
to yield the desired products 4a-h. Purification was achieved by
1

4248 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Robin et al.
placing the product under high vacuum for 1 h to remove any
residual solvent.
(50 mL) at 0 °C, and the mixture was stirred for 15 min. To the
mixture was added dropwise at 0 °C a solution of epibromohydrin
(1 mL, 11.7 mmol) in THF (5 mL) over a period of 15 min. The
solution was then stirred at reflux overnight. Under ice bath cooling,
30 mL of water was added. The aqueous phase was extracted with
dichloromethane (3 × 30 mL), and the organic layers were dried
over MgSO4 and concentrated in Vacuo. The residue was purified
by silica gel column chromatography (ethyl acetate as eluent) to
1-Chloro-3-diethylaminopropan-2-ol (4a). Yield 68%, oil, 1H
NMR(CDCl3); δ 1.03 (6H, t, 3J ) 7.2 Hz, 2 CH3), 2.40-2.68 (6H,
m, 2 NCH2CH3, NCH2CH), 3.50-3.61 (2H, m, CH2Cl), 3.80 (1H,
3
qu, J ) 5.1 Hz, CHOH); 13C NMR(CDCl3) δ 11.8 (2 CH3), 47.1
(CH2Cl), 56.2 (2 NCH2CH3, NCH2CH), 66.8 (CHOH); m/z; found
(ES-MS+) [M + H]+ 166; found (HRMS FAB) [M + H]+
166.09204 C7H16NOCl requires 166.09211.
1
give 5 (1.40 g, 68%) as a pale yellow oil. H NMR(CDCl3); δ
1-Chloro-3-[ethyl(isopropyl)amino]propan-2-ol (4b). Yield
12%, oil, 1H NMR(CDCl3); δ 0.82-0.95 (9H, m, CH3CH2,
(CH3)2CH), 2.20-2.38 (4H, m, CH3CH2, NCH2CH), 2.79 (1H,
2.33 (3H, s, NCH3), 2.33-2.48 (2H, m, NCH2CH), 2.74-2.78 (2H,
m, CH2O), 3.13 (1H, m, CHO), 3.52 (1H, d, 2J ) 13.5 Hz,
2
ArCH2N), 3.66 (1H, d, J ) 13.5 Hz, ArCH2N), 7.32-7.36 (5H,
3
septet, J ) 6.6 Hz, (CH3)2CH), 3.51-3.60 (2H, m, CH2Cl), 3.89
m, Har); 13C NMR(CDCl3) δ 43.4 (NCH3), 45.4 (CH2O), 51.2
(CHO), 60.1 (NCH2CH), 63.0 (ArCH2N), 127.5-129.4 (5 CHar),
139.1 (Car); m/z; found (ES-MS+) [M + H]+ 178.
(1H, qu, 3J ) 5.2 Hz, CHOH); 13C NMR(CDCl3) δ 15.1 (CH3CH2),
21.1 ((CH3)2CH), 44.2 (CH3CH2), 46.5 (CH2Cl), 50.4 (CH(CH3)2),
51.7 (NCH2CH), 66.3 (CHOH); m/z; found (ES-MS+) [M + H]+
180; found (HRMS FAB) [M + H]+ 180.11503 C8H18NOCl
requires 180.11560.
General Procedure for the Synthesis of 6a-c and 7. Epoxide
5 (1 mmol) was dispensed into a microwave tube and dissolved in
absolute ethanol (2.5 mL). Amine (1.5 mmol) for 6a-c or
benzylmercaptan (1.1 mmol) and NaOH (2 pellets) for 7 were added
to the tube and placed in the CEM Discover Microwave Synthesizer
Explorer Carousel. Each sample was heated at 140 °C with stirring
for 4 min (80 W, 50 psi). A period of 5 min was allowed for sample
cooling. For 6a-c, each sample was concentrated in Vacuo, and
purification was performed using Kugelrohr bulb to bulb distillation
apparatus to yield the desired products. For 7, the solution was
dissolved with dichloromethane (10 mL) and washed with water
(2 × 10 mL). The organic phase was dried over MgSO4 and
evaporated in Vacuo. The residue was purified by silica gel
chromatography column to yield 7 as a colorless oil.
1-Chloro-3-pyrrolidin-1-ylpropan-2-ol (4c). Yield 65%, oil, 1H
NMR(CDCl3); δ 1.73-1.78 (4H, m, 2 CH2 pyrrolidine), 2.42-
2.50 (4H, m, 2 CH2 pyrrolidine), 2.63-2.74 (2H, m, NCH2), 3.51-
3
3.60 (2H, m, CH2Cl), 3.88 (1H, qu, J ) 5.1 Hz, CHOH); 13C
NMR(CDCl3) δ 23.5 (2 CH2 pyrrolidine), 47.2 (CH2Cl), 54.5 (2
CH2 pyrrolidine), 56.2 (NCH2), 68.2 (CHOH); m/z; found (ES-
MS+) [M + H]+ 164; found (HRMS FAB) [M + H]+ 164.05937
C7H14NOCl requires 164.06562.
1-Chloro-3-piperidin-1-ylpropan-2-ol (4d). Yield 72%, oil, 1H
NMR(CDCl3); δ 1.43-1.47 (2H, m, CH2 piperidine), 1.52-1.61
(4H, m, 2 CH2 piperidine), 2.31-2.46 (4H, m, 2 CH2 piperidine),
2.53-2.57 (2H, m, NCH2), 3.50-3.61 (2H, m, CH2Cl), 3.91 (1H,
qu, 3J ) 5.1 Hz, CHOH); 13C NMR(CDCl3) δ 24.0 (CH2
piperidine), 25.9 (2 CH2 piperidine), 47.2 (CH2Cl), 54.6 (2 CH2
piperidine), 61.5 (NCH2), 66.3 (CHOH); m/z; found (ES-MS+) [M
+ H]+ 178; found (HRMS FAB) [M + H]+ 178.09204 C8H16NOCl
requires 178.09214.
1-(Benzylamino)-3-[benzyl(methyl)amino]propan-2-ol (6a).
1
Yield 97%, oil, H NMR(CDCl3); δ 2.27 (3H, s, NCH3), 2.34-
2.77 (4H, m, 2 × NCH2CH), 3.52 (1H, d, 2J ) 13.5 Hz, ArCH2N),
3.66 (1H, d, 2J ) 13.5 Hz, ArCH2N), 3.84 (2H, s, ArCH2N), 3.88-
3.97 (1H, m, CHOH), 7.53 (10H, m, Har); 13C NMR(CDCl3) δ 42.7
(NCH3), 53.5 (NCH2CH), 54.4 (NCH2CH), 61.5 (ArCH2N), 63.0
(ArCH2N), 67.1 (CHOH), 127.4-129.5 (10 CHar), 138.9 (Car),
140.6 (Car); m/z; found (ES-MS+) [M + H]+ 285.
1-Chloro-3-morpholin-4-ylpropan-2-ol (4e). Yield 70%, oil;
1H NMR(CDCl3); δ 2.40-2.47 (4H, m, 2 NCH2 morpholine),
2.57-2.65 (2H, m, NCH2), 3.51-3.60 (2H, m, CH2Cl), 3.67-3.71
(4H, m, 2 OCH2 morpholine), 3.92 (1H, qu, 3J ) 5.1 Hz, CHOH);
13C NMR(CDCl3) δ 46.9 (CH2Cl), 53.6 (2 NCH2 morpholine), 61.3
(NCH2), 66.3 (CHOH), 66.7 (2 OCH2 morpholine); m/z; found (ES-
MS+) [M + H]+ 180; found (HRMS FAB) [M + H]+ 180.07932
C7H14NO2Cl requires 180.07913.
1,3-Bis[benzyl(methyl)amino]propan-2-ol (6b). Yield 99%, oil,
1H NMR(CDCl3); δ 2.28 (6H, s, 2 × NCH3), 2.42-2.52 (4H, m,
2 × NCH2CH), 3.54-3.66 (4H, m, 2 × ArCH2N), 3.90-3.99 (1H,
m, CHOH), 7.33 (10H, s, Har); 13C NMR(CDCl3) δ 43.0 (2 ×
NCH3), 62.0 (2 × NCH2CH), 63.1 (2 × ArCH2N), 65.7 (CHOH),
127.5-129.5 (10 CHar), 139.0 (2 × Car); m/z; found (ES-MS+) [M
+ H]+ 299.
1-Chloro-3-piperazin-1-ylpropan-2-ol (4f). Yield 61%, oil, 1H
NMR(CDCl3); δ 2.39-2.48 (4H, m, 2 CH2 piperazine), 2.55-2.62
(2H, m, NCH2), 2.86-2.92 (4H, m, 2 CH2 piperazine), 3.51-3.69
(2H, m, CH2Cl), 3.92 (1H, qu, 3J ) 5.1 Hz, CHOH); 13C
NMR(CDCl3) δ 45.5 (2 CH2 piperazine), 46.4 (CH2Cl), 47.0 (2
CH2 piperazine), 61.4 (NCH2), 66.5 (CHOH); m/z; found (ES-MS+)
[M + H]+ 179; found (HRMS FAB) [M + H]+ 179.08711
C7H15N2OCl requires 179.08705.
1-(Benzylamino)-3-[benzyl(ethyl)amino]propan-2-ol (6c). Yield
99%, oil, 1
H NMR(CDCl3); δ 1.07 (3H, t, 3J ) 7.2 Hz, CH3CH2),
2.26 (3H, s, NCH3), 2.44-2.67 (6H, m, 2 × NCH2CH and
CH3CH2), 3.58 (2H, s, ArCH2N), 3.60 (1H, d, 2J ) 13.5 Hz,
2
ArCH2N), 3.74 (1H, d, J ) 13.5 Hz, ArCH2N), 3.85-3.91 (1H,
1-Allylamino-3-chloropropan-2-ol (4g). Yield 55%, oil, 1H
NMR(CDCl3); δ 2.56 (1H, s, NH), 2.65-2.83 (2H, m, NCH2CH),
3.28 (2H, m, CH2dCHCH2), 3.50-3.62 (2H, m, CH2Cl), 3.90 (1H,
qu, 3J ) 5.1 Hz, CHOH), 5.10-5.23 (2H, m, CH2dCHCH2), 5.82-
5.95 (1H, m, CH2dCHCH2); 13C NMR(CDCl3) δ 47.3 (CH2Cl),
51.2 (NCH2CH), 52.0 (CH2dCHCH2), 69.3 (CHOH), 116.5 (CH2d
CH), 136.0 (CH2dCH); m/z; found (ES-MS+) [M + H]+ 150; found
(HRMS FAB) [M + H]+ 150.06865 C6H12NOCl requires 150.06857.
1-[Benzyl(methyl)amino]-3-chloropropan-2-ol (4h). Yield 76%,
m, CHOH), 7.27-7.33 (10H, m, Har); 13C NMR(CDCl3) δ 12.2
(CH3CH2), 43.1 (NCH3), 48.3 (CH2CH3), 58.3 (NCH2CH), 59.0
(NCH2CH), 62.1 (ArCH2N), 63.1 (ArCH2N), 65.9 (CHOH), 127.4-
129.5 (10 CHar), 139.2 (Car), 139.7 (Car); m/z; found (ES-MS+) [M
+ H]+ 313. HPLC 95% purity (A), 93% purity (B).
1-[Benzyl(methyl)amino]-3-(benzylthio)propan-2-ol (7). Yield
80%, oil, 1H NMR(CDCl3); δ 2.28 (3H, s, NCH3), 2.49-2.56 (4H,
m, NCH2CH and SCH2CH), 3.56 (1H, d, 2J ) 13.5 Hz, ArCH2N),
3.72 (1H, d, 2J ) 13.5 Hz, ArCH2N), 3.78 (2H, s, SCH2Ar), 3.83-
3.90 (1H, m, CHOH),7.33 (10H, s, Har); 13C NMR(CDCl3) δ 37.0
and 37.4 (ArCH2S and SCH2CH), 42.4 (NCH3), 62.3 and 62.7
(ArCH2N and NCH2CH), 67.1 (CHOH), 127.5-129.7 (10 CHar),
137.4 (Car), 138.8 (Car); m/z; found (ES-MS+) [M + H]+ 302.
General Procedure for the Synthesis of 8a,b and 9a,b. See
the general procedure for the synthesis of 1a-x. See 1p for chemical
data of 8a (enantiomeric excess >99% based on chiral HPLC) and
9a (enantiomeric excess >99% based on chiral HPLC). See 1t for
chemical data of 8b (enantiomeric excess >99% based on chiral
HPLC) and 9b (enantiomeric excess >99% based on chiral HPLC).
1
oil, H NMR(CDCl3); δ 2.21 (3H, s, NCH3), 2.43-2.57 (2H, m,
NCH2CH), 3.50-3.62 (2H, m, CH2Cl), 3.78 (2H, s, ArCH2N), 3.92
(1H, qu, 3J ) 5.1 Hz, CHOH), 7.19-7.33 (5H, m, Har); 13C
NMR(CDCl3) δ 42.1 (NCH3), 47.0 (CH2Cl), 58.2 (NCH2CH), 62.4
(ArCH2N), 67.1 (CHOH), 127.5 (CHar), 128.3 (2 CHar), 128.7 (2
CHar), 137.9 (Car); m/z; found (ES-MS+) [M + H]+ 214; found
(HRMS FAB) [M + H]+ 212.08390 C11H16NOCl requires 212.08422.
HPLC 98% purity (A), 86% purity (B).
Synthesis of N-benzyl-N-methyl-1-oxiran-2-ylmethanamine
(5).26 NaH (60% in mineral oil, 0.51 g, 12.9 mmol) was added to
a solution of N-methylbenzylamine (1.52 mL, 11.7 mmol) in THF

1-Aminopropan-2-ols with Anti Malaria ActiVities
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4249
(13) , Williams, D.; Bradley, G.; Lawton, M. Aluminium triflate:
a
Acknowledgment. We thank the European Union (project
number LSHP-CT-2004-012189, “malariaporin”) and the Royal
Society (to Sabine L. Flitsch) for support.
remarkable Lewis acid catalyst for the ring opening of epoxides by
alcohols. Org. Biomol. Chem. 2005, 3, 3269-3272.
(14) Chandrasekhar, S.; Ramachandar, T.; Jaya Prakash, S. TaCl5-
catalyzed cleavage of epoxides with aromatic amines. Synthesis 2000,
13, 1817-1818.
Supporting Information Available: Analytical data for 1d,e,
g,i,u,v,w, 2b-g, and 3b,c; HPLC data for selected compounds
1b,k,l,p,t, 4h, 6c, 8a,b, and 9a,b. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) Rajender, Reddy, L.; Arjun Reddy, M.; Bhanumathi, N.; Rama, Rao,
K. Cerium chloride-catalysed cleavage of epoxides with aromatic
amines. Synthesis 2001, 6, 831-832.
(16) Rajender, Reddy, L.; Arjun Reddy, M.; Bhanumathi, N.; Rama, Rao,
K. An efficient method for cleavage of epoxides with aromatic amines
catalyzed by â-cyclodextrin in water. Synlett 2000, 3, 339-340.
(17) Auge´, J.; Leroy, F. An unusual chemoselectivity in Cobalt (II)
chloride catalysed cleavage of oxiranes with aniline: a highly
regioselective synthesis of â-amino alcohols. Tetrahedron Lett. 1990,
37, 7715-7716.
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