Enantiopure substituted pyridines as promising antimalarial drug candidates

Article abstract of DOI:10.1016/j.tet.2020.131088

We describe the enantioselective synthesis and biological evaluation of 4-(2-amino-1-hydroxyethyl)pyridines (4 AHPs) as new antimalarial drug candidates. In particular, two routes to obtain the key-intermediate 4-vinyl-pyridine were studied. These routes are based on a Kr?hnke-type cyclization or on metal-catalyzed reactions. The Kr?hnke-type cyclization route is faster but only efficient at low scale since this pathway involves a Wittig reaction that requires severe temperature-control. Consequently, we designed a second route based on metal-catalyzed reactions. This way is longer but the 4-vinyl-pyridine can be obtained on a 5 g scale at least. Finally, a regioselective S_N2 ring-opening of enantiopure epoxides by alkyl primary amines allowed the synthesis of eight 4-AHPs with global yields up to 41%. These compounds show strong in vitro antimalarial activity against P. falciparum strains and are more active that chloroquine and mefloquine. These results demonstrate that 4-AHPs are promising antimalarial drug candidates.

Full text of DOI:10.1016/j.tet.2020.131088

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantiopure substituted pyridines as promising antimalarial drug
candidates
Guillaume Bentzinger a, Etienne Pair a, Jean Guillon b, Mathieu Marchivie c,
a
a
a, *
ꢀ a
Catherine Mullie , Patrice Agnamey , Alexandra Dassonville-Klimpt , Pascal Sonnet
a
ꢀ
ꢀ
ꢀ
Universite de Picardie-Jules-Verne, AGIR e Agents infectieux, resistance et chimiotherapie, UR 4294, UFR de pharmacie, 1, rue des Louvels, Amiens, F-
80037, cedex 1, France
b
ꢀ
ꢀ
Universite de Bordeaux, UFR des sciences pharmaceutiques, INSERM U1212/UMR CNRS 5320, Laboratoire ARNA, 146, rue Leo-Saignat, Bordeaux, F-33076
cedex, France
c
ꢀ
CNRS, Universite de Bordeaux, Bordeaux INP, ICMCB, UMR 5026, Pessac, F-33600, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the enantioselective synthesis and biological evaluation of 4-(2-amino-1-hydroxyethyl)
pyridines (4 AHPs) as new antimalarial drug candidates. In particular, two routes to obtain the key-
Received 21 January 2020
Received in revised form
25 February 2020
Accepted 28 February 2020
Available online xxx
€
intermediate 4-vinyl-pyridine were studied. These routes are based on a Krohnke-type cyclization or
€
on metal-catalyzed reactions. The Krohnke-type cyclization route is faster but only efficient at low scale
since this pathway involves a Wittig reaction that requires severe temperature-control. Consequently, we
designed a second route based on metal-catalyzed reactions. This way is longer but the 4-vinyl-pyridine
can be obtained on a 5 g scale at least. Finally, a regioselective SN2 ring-opening of enantiopure epoxides
by alkyl primary amines allowed the synthesis of eight 4-AHPs with global yields up to 41%. These
compounds show strong in vitro antimalarial activity against P. falciparum strains and are more active
that chloroquine and mefloquine. These results demonstrate that 4-AHPs are promising antimalarial
drug candidates.
Keywords:
Malaria
P. falciparum
Arylaminoalcohols
Enpiroline
Asymmetric synthesis
© 2020 Elsevier Ltd. All rights reserved.
1. Introduction
combination therapy (ACT), widely recommended by the WHO
since 2006 [2]. MQ-artesunate and lumefantrine-artemether are
Malaria is still today a major public health threat on a worldwide
scale. In 2018, 228 million cases of malaria were reported world-
wide and led to 405,000 deaths, 67% of them children aged under 5
years [1]. Since 2014, investments for malaria control and elimi-
nation were robust and resolute (2.7 billion dollars in 2018) but
falling far the 5 billion dollars funding target of the World Health
Organization (WHO) global strategy. Plasmodium falciparum is the
most prevalent malaria parasite in Africa and is responsible for
most malaria cases. It has shown great adaptive potential and the
apparition of resistances towards antiplasmodial molecules always
calls for new drug candidates. In the fight against malaria, the
family of arylaminoalcohol (AAA) drugs including quinine (QN),
mefloquine (MQ) and lumefantrine play an important role [1]. Not
only do they have good activities against P. falciparum but their
slow clearance makes them perfect partners for artemisinin-based
among the six ACT commercially available [1,3].
The first AAA used in antimalarial therapy was the enantio-
merically pure quinine, one of the four cinchona alkaloids. Quini-
dine (QD), the dextrorotatory diastereomer of quinine, was
discarded because it differs from QN in many pharmacological re-
spects. Although, QD is about three to four times more active as an
antimalarial drug[4], the QT (Q wave-T wave interval) prolongation
observed with it is about four times more than with QN [5].
Accordingly, QN was used as antimalarial drug while QD was for
years available as an anti-arrhythmic. For the MQ, another AAA,
several studies highlighted that the (R,S) enantiomer of MQ is the
least active (Fig. 1) and crosses more easily the blood-brain barrier
[6e10]. This latter ability making it, in part, responsible for the
important neurological side effects of MQ [11e13]. Despite impor-
tant disparities in activities, toxicities and pharmacokinetic profiles
of the AAA stereoisomers, current commercial drugs containing MQ
or lumefantrine are still used as racemates.
For those reasons, our group works on the enantioselective
synthesis of new AAA analogs. Previously, the synthesis of 4-(2-
* Corresponding author.
E-mail address: pascal.sonnet@u-picardie.fr (P. Sonnet).
https://doi.org/10.1016/j.tet.2020.131088
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: G. Bentzinger et al., Enantiopure substituted pyridines as promising antimalarial drug candidates, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131088

2
G. Bentzinger et al. / Tetrahedron xxx (xxxx) xxx
Fig. 1. Previous work: mefloquine and 4-AHQs 1a-d.
amino-1-hydroxyethyl)quinolines (4-AHQs) as enantiopure open
analogs of MQ was achieved (Fig. 1). Structure-activity-relationship
(SAR) studies on the aminoalcohol moiety allowed us to identify a
few molecules 1a-d with alkyl side chains, as active as MQ in vitro
and in vivo on the selected P. falciparum strains 3D7 and W2
[14e18]. These compounds 1a-d also showed a clearer (S)/(R)
selectivity in vitro than MQ with IC50 up to 15-fold higher for the
more active enantiomer.
The importance of the aminoalcohol stereochemistry for the
antimalarial activity was reinforced with our study on the pyrro-
loquinoxaline family [18]. Although their corresponding activity
was low (micromolar range), strong (S)/(R) disparities have been
observed (eudysmic ratio up to 15.5).
As a continuation of our SAR studies, we decided now to focus
our work on the aromatic ring role by restructuring the ring system.
Dissociation of the quinoline core by splitting the benzo compound
could lead to new antimalarial drugs such as 4-(2-amino-1-
hydroxyethyl)pyridines (4-AHPs) 2a-d. Furthermore, 4-AHPs
could also be considered as enpiroline (ENP) analogs (Fig. 2). ENP
is an AAA based on a pyridine core and was previously studied as a
drug candidate [19e22]. Surprisingly, this compound was never
fully exploited despite promising activities, good pharmacokinetic
parameters, and low toxicity. Also, ENP enantiomers have similar
activities with eudysmic ratios around 1.2 [6,23]. We thought that
4-AHPs 2a-d could display improved antimalarial activities and
enhanced eudysmic ratios compared to 4-AHQs 1a-d and lower
long-term toxicity than MQ [15]. Herein, we describe the enantio-
selective synthesis and biological evaluation of 4-AHPs 2a-d as new
antimalarial potential drugs.
Scheme 1. Retrosynthesis strategies for the 4-AHPs 2a-d.
and W2 strains. Thus, novel SAR were highlighted with regard to
their stereochemistry, alkyl substitution and in comparison with
the corresponding quinolines 4-AHQs 1.
2. Results and discussion
2.1. Chemistry
Two ways of making the 4-vinylpyridine 4 were explored either
via a Krohnke-type cyclization (7 steps, 46% overall yield)[24] or
metal-catalyzed reactions (9 steps, 37% overall yield).
€
€
2.1.1. Synthesis of 4 using a Krohnke-type cyclization
Having a Wittig reaction in mind for the synthesis of the enone
6, the commercial 2-bromo-4’-(trifluoromethyl)acetophenone 8
was treated with PPh3 (Scheme 2). The resulting phosphonium salt
9, obtained quantitatively, was then reacted with glyoxylic acid to
obtain 6 as the Wittig product in quantitative yield. The 1H NMR
analysis and the coupling constant between the ethylenic protons
(3JH1/H2 ¼ 15.6 Hz) confirmed the selective formation of the (E)-
isomer. In parallel, the commercially available 3-bromo-1,1,1-
trifluoroacetone 10 was reacted with pyridine in EtOH at 70 ꢀC.
In order to take advantage of the strategy we had optimized for
generating the library of enantiopure 4-AHQs 1 for making the
enantiopure 4-AHPs 2, we needed to access to the epoxides 3
through an indirect asymmetric epoxidation of the 4-vinyl-pyri-
dine 4 (Scheme 1) [14]. Two routes to obtain the key-intermediate
€
4-vinyl-pyridine 4 are studied based on a Krohnke-type cyclization
[24] or metal-catalyzed reactions. The respective advantages and
inconveniences of these ones are discussed below. Finally, the 4-
AHPs 2a-d were prepared in three steps from the vinyl pyridine 4
and their in vitro activities were measured against P. falciparum 3D7
€
Scheme 2. Preparation of the vinyl 4 by Krohnke-type cyclization. Reagents and
conditions: (a) PPh3, THF, 70 ꢀC. (b) Glyoxylic acid, NEt3, CHCl3/MeOH (1/1), 25 ꢀC. (c)
Pyridine, EtOH, 80 ꢀC. (d) NH4OAc, THF, 70 ꢀC. (e) BH3.DMS, THF, 25 ꢀC. (f) DMP, CH2Cl2,
Fig. 2. Present work: Enpiroline and 4-AHPs 2a-d.
0
ꢀC. (g) 1) BrPPh3CH3, n-BuLi, LiOH, THF, 0 ꢀC, 2) 13, ꢁ78 ꢀC, 1 h then ꢁ30 ꢀC, 6 h.
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G. Bentzinger et al. / Tetrahedron xxx (xxxx) xxx
3
one-pot oxidative cleavage of the boronate was performed with
Oxone® to afford 14 in an 82% yield [26]. An O-protecting reaction
was carried out with 4-methoxybenzyl chloride to give 15. A mono-
halogen exchange, using Grignard reagent in the presence of I2,
afforded the mono-iodinated compound 16 in 85% yield. After
optimization, the best conditions were found by using 1.6 equiva-
lents of both Turbo Grignard and I2 [27]. The mono-iodination
allowed to perform a selective Suzuki coupling with 4-(tri-
fluoromethyl)phenylboronic acid affording 17 in 95% yield [28]. At
that point, direct conversion of 17 into 19 using reaction conditions
described by Z. Gonda et al. [29] was unsuccessful. Consequently, a
copper-catalyzed aromatic Finkelstein reaction was used in order to
convert 17 into 18 in 88% yield [30,31]. The iodo derivative 18
proved to be more reactive and was converted into a eCF3 affording
19 in a satisfactory 89% yield [29]. After removal of the ePMB group,
the resulting alcohol 20 was reacted with POBr3 to isolate the
bromo compound 21 in 93% yield. This allowed a Suzuki coupling
with potassium (vinyl)trifluoroborate affording the key interme-
diate 4 in 98% yield. The global yield for this new synthetic pathway
is of 37% over 9 steps. The selected reactions proved to be very
robust whatever the scale (up to 5 g of vinyl 4 per sequence).
Scheme 3. Preparation of the vinyl 4 using metal-catalyzed reactions. Reagents and
conditions: (a) 1) [Ir(cod)Cl]2, pinacolborane, dtbpy, cyclohexane, 80 ꢀC, 2) Oxone, THF/
H2O (1/1), 25 ꢀC. (b) 4-methoxybenzyl chloride, K2CO3, DMF, 110 ꢀC. (c) iPrMgCl.LiCl, I2,
THF, 25 ꢀC. (d) 4-(trifluoromethyl)phenyl boronic acid, Na2CO3, Pd(PPh3)4, toluene/
H2O/EtOH (6/1/1), 110 ꢀC. (e) CuI, NaI, N,N0-dimethylethylenediamine, 1,4-dioxane,
110 ꢀC. (f) KF, CuI, TMSCF3, 1,10-phenantroline, B(OMe)3, DMSO, 60 ꢀC. (g) TFA, DCM,
25 ꢀC. (h) POBr3, DMF, 110 ꢀC. (i) Potassium (vinyl)trifluoroborate, Na2CO3, Pd(PPh3)4,
toluene/EtOH/H2O (6/1/1), 110 ꢀC.
2.1.3. Synthesis of 4-(2-amino-1-hydroxyethyl) pyridines 2 (4-
AHPs)
With intermediate 4 in hands, the diols (S)-22 and (R)-22 were
obtained enantioselectively using a Sharpless dihydroxylation in
The corresponding pyridinium salt 5 was afforded in 72% yield with
the ketone function completely hydrated due to its electro-
withdrawing environment [19,24,25]. This structure was
confirmed by 13C NMR (dC(C(OH)2): 148.2 ppm) and X-ray diffrac-
tion (Scheme 2, supplementary material). With the enone 6 and the
the presence of AD-mix-a or -b respectively in 99% yield and 99% ee.
A ring-closure was carried out in order to form the epoxides (S)-3
and (R)-3 by means of a slightly modified “one-pot” reaction,
previously described [14]. Those were obtained with complete
retention of configuration in 95% and 85% yield from (S)-22 and (R)-
22 respectively. X-ray diffraction of epoxide (S)-3 was performed
and the (S)-geometry was ascribed unambiguously (Scheme 4,
supplementary material).
The last step of the synthesis consisted in a regioselective SN2
ring-opening with diverse primary amines (Scheme 4, Table 1).
Using microwave irradiations allowed for reduced reaction times
compared to the classical heating that was used for making the
corresponding quinoline derivatives. Eight (S)- or (R)-4-AHPs 2a-
d were thus synthesized using four alkylamines of growing size in
good to excellent yields (60e96%) and with enantiomeric excesses
superior to 98%.
€
pyridinium salt 5 in hands, a Krohnke-type cyclization was per-
formed in order to form the isonicotinic acid 11 in 94% yield.
Thereafter, the acid function is converted into aldehyde in order to
introduce the vinyl group with a Wittig reaction. Different reducing
agents were tested to achieve the direct reduction of the acid
moiety to the aldehyde 13, but mixtures of the aldehyde 13 and the
alcohol 12 were afforded systematically. Thus, a two steps aldehyde
synthesis was performed: i) borane (BH3) was used as reducing
agent to obtain the primary alcohol 12 in 96% yield and ii) Dess-
Martin Periodinane as selective oxidant allowed to afford the
aldehyde 13 in 81% yield. For the Wittig reaction, the methyl-
triphenylphosphonium bromide was deprotonated in situ with n-
BuLi as the base at 0 ꢀC in THF to generate the corresponding ylide.
Due to the high reactivity of this ylide with aldehydes, the reaction
required serious optimization (temperature, additives, reaction
times). In our best conditions, the addition of aldehyde 13 was
carried out dropwise at ꢁ78 ꢀC. Then, the Wittig reaction itself was
performed at ꢁ30 ꢀC for 6 h. Thus, the vinyl derivative 4 was ob-
tained in 63% yield. When one gram or more of aldehyde were used,
yields dropped between 15% and 30%. This reaction being very
temperature sensitive, it proved to be hard to reproduce when
scaled-up, probably due to a lack of temperature-control. With this
synthetic pathway, the desired vinyl intermediate 4 is accessible in
a 46% yield in an overall 7 steps sequence. Because of the scalability
issues with the final Wittig step, we considered this method to be
unsuitable for making a library of compounds and devised a new
route to obtain the key derivative 4, based on robust and reliable
metal-catalyzed reactions (see Scheme 3).
2.1.2. Synthesis of 4 using metal-catalyzed reactions
The commercially available 2,6-dibromopyridine 7 was con-
verted into 4-hydroxypyridine 14 via the formation of a boronate
intermediate using the [Ir(cod)Cl]2 catalyst in the presence of
pinacolborane and 4,40-di-tert-butyl-2,20-dipyridyl (dtbpy). Then, a
Scheme 4. Synthesis of 4-AHPs 2a-d. Reagents and conditions: (a) AD-mix-
a or -b,
K2OsO2(OH)4, tBuOH/H2O (1/1), 0 ꢀCe25 ꢀC, 15 h. (b) i) trimethyl orthoacetate, pTsOH,
DCM, 25 ꢀC, 7 h, ii) TMSBr, DCM, 25 ꢀC, 15 h, iii) K2CO3, MeOH, 25 ꢀC, 4 h. (c) R1-NH2,
EtOH, 130 ꢀC (M W.), 30 min.
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G. Bentzinger et al. / Tetrahedron xxx (xxxx) xxx
Table 1
(S)- and (R)- enantiomers against Pf3D7 with a eudysmic ratio of
Yields and enantiomeric purities of the synthesized 4-AHPs 2a-d.
3.1. The newly synthesized 4-AHPs 2a-d are as much active as their
quinoline counterparts 4-AHQs 1, but clearly show less differences
between (S)- and (R)- enantiomers which had a eudysmic ratio
between 2.2 and 15.1 [15]. Nonetheless, disparities could appear
more clearly in pharmacokinetic properties like in the case of MQ.
These pharmacokinetic studies are currently under progress.
Entry
1
2
Compound
(S)-2a
(R)-2a
-NHR [1]
Yield
78%
96%
%eea
99
99
3
4
(S)-2b
(R)-2b
94%
85%
99
99
3. Conclusion
5
6
(S)-2c
(R)-2c
67%
65%
99
98
The synthesis of eight enantiopure AHPs 2a-d with varying alkyl
substituents was achieved from the 4-vinylpyridine 4. This key-
7
8
(S)-2d
(R)-2d
60%
85%
99
99
€
intermediate was obtained by two routes using either a Krohnke-
type cyclization or metal-catalyzed reactions. The cyclization route
led to 4 in a 46% yield in an overall 7 steps sequence. However, this
pathway was not suitable for making a library of compounds, as the
scaling-up was limited by the last step of the sequence. The metal-
catalyzed route proved to be more robust. However, 4 was obtained
in a lower yield of 37% yield over 9 steps. Nonetheless, this new
synthesis allowed us to obtain large quantities of the AHPs pre-
cursor 4 (up to 5 g per sequence). Consecutively, a regioselective
SN2-ring opening of enantiopure epoxides 3 with four alkyl primary
amines gave 4-AHPs 2a-d with good yields and excellent ee. These
pyridines 2a-d showed strong antimalarial activity with IC50
ranging from 3.5 to 10.0 nM against Pf3D7 and 17.7e56.7 nM
against PfW2. Compared with their quinoline counterparts AHQs 1,
the differences between (S)- and (R)- enantiomers IC50 are less
marked with eudysmic ratio between 1.1 and 3.1. These novel
promising antimalarial 4-AHPs 2a-d and derivatives were recently
patented [32]. Pharmacokinetic studies and in vivo experiments in a
mouse model are under progress to validate their potential as
antimalarial drug candidates.
a
Determined by chiral HPLC, see experimental part.
2.2. Biological evaluation
The activities of all 4-AHPs 2a-d were evaluated against P. fal-
ciparum 3D7 and W2 using the SYBR Green I method [32]. PfW2 is a
chloroquine (CQ) resistant strain and is MQ sensitive while Pf3D7 is
chloroquine sensitive and displays a decreased susceptibility to
MQ. The two antiplasmodial compounds CQ and MQ were used as
references. The half maximal inhibitory concentration (IC50
calculated are reported in Table 2.
)
Pleasingly, all IC50 are in the nanomolar range and all com-
pounds are more active than the references whatever the strain. As
previously observed for the AHQs 1a-d[15], the 4-AHPs 2a-d are
more active against PfW2 than Pf3D7, the CQ-resistant strain, with
IC50 ranging from 3.5 (entry 8) to 10.0 nM (entry 2). For the Pf3D7
strain, less sensitive to MQ, the IC50 are between 17.7 (entry 7) and
56.7 nM (entry 2). In general, it appears that a longer side chain
enhances the efficacy of the compound and the differences be-
tween (S)- and (R)- enantiomers. Interestingly, this trend correlates
with a higher calculated logP of the corresponding molecules.
Compound 2d, with a heptyl side chain, shows the best activities
against both Pf3D7 and PfW2 and has a clear difference between
4. Experimental
4.1. Chemistry
Reactions were monitored by thin-layer chromatography with
Table 2
In vitro antiplasmodial activities of the 4-AHPs 2a-d and references CQ and MQ against a chloroquine sensitive Plasmodium falciparum clone (3D7) and a chloroquine-resistant
Plasmodium falciparum clone (W2), eudysmic ratio and clogP values.
Entry
Compound code
-NHR [1]
IC50 SD (nM)a,b
eudysmic ratioc
clogPd
Pf3D7e
PfW2f
Pf3D7
PfW2
1
2
(S)-2a
(R)-2a
45.8 2.3
56.7 2.3
9.0 0.4
10.0 0.7
1.2
1.1
4.74
3
4
(S)-2b
(R)-2b
52.4 1.7
41.8 5.5
8.6 1.0
7.2 0.5
1.3
1.5
3.1
1.2
5.26
5.81
6.08
5
6
(S)-2c
(R)-2c
47.1 13.2
32.3 2.0
N.D.g
8.3 0.8
N.D.
1.6
7
8
(S)-2d
(R)-2d
17.7 4.7
54.4 3.2
5.6 0.3
3.5 0.5
9
10
Mefloquine (MQ)
Chloroquine (CQ)
75.9 3,0
79.7 8.5
198.8 27.0
31.8 1.0
e
e
e
e
3.91
4.40
a
in vitro measurements against P. falciparum using the SYBR Green I method, see experimental part.
Results expressed as mean standard deviation.
Ratio between the IC50 of the more active enantiomer and the less active.
Predicted octanol/water partition coefficient calculated with Maestro Material Sciences 2.9.011 software.
P. falciparum strain with decreased sensibility to MQ and sensitive to CQ.
P. falciparum strain resistant to CQ and sensitive to MQ.
b
c
d
e
f
g
Not determined.
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G. Bentzinger et al. / Tetrahedron xxx (xxxx) xxx
5
silica gel 60 F254 pre-coated aluminium plates (0.25 mm). Visuali-
zation was performed under UV light and PMA oxidation. Filtra-
tions were performed on Celite® 545. Chromatographic
purification of compounds was achieved with 60 silica gel
6.80 (d, J ¼ 15.6 Hz, 1H), 7.82 (d, J ¼ 8.1 Hz, 2H), 7.90 (d, J ¼ 15.6 Hz,
1H), 8.15 (d, J ¼ 8.1 Hz, 2H) ppm; NMR 13C (75 MHz, CD3OD): dC
129.4 (q, J ¼ 272.0 Hz), 127.0 (q, J ¼ 3.8 Hz), 130.5, 134.8, 135.7 (q,
J ¼ 32.5 Hz), 137.0, 140.9, 168.2, 190.3 ppm; IR nmax: 2982, 1691,
1665, 1504, 1170, 1134, 1111 cmꢁ1; HRMS calcd. for C11H7F3O3Na
[MþNa]þ 267.0245, found 267.0238.
(40e63 mm). Unless otherwise noted, all reagent-grade chemicals
and solvents were used as supplied (analytical or HPLC grade)
without prior purification. Melting points were measured on a
Stuart SMP3 apparatus with a precision of 1.5 ꢀC and are uncor-
rected. Infrared spectra (IR) were recorded on a FT/IR-4200 Jasco
with an ATR-Golden gate. Liquids and solids were applied on the
Single Reflection Attenuated Total Reflectance (ATR) Accessories.
Data are reported in cmꢁ1. Optical rotations were determined with
a Jasco P1010 polarimeter with a 10 cm cell. Specific rotations are
reported in 10ꢁ1 deg.cm [2].gꢁ1 and concentrations in g per 100 mL.
1H NMR Spectra (400 MHz) and 13C NMR spectra (100 MHz) were
recorded on a Bruker 400 MHz NMR. The field was locked by
external referencing to the relevant deuteron resonance. Data
appear in the following order: chemical shifts in ppm which were
referenced to the internal solvent signal, number of protons, mul-
tiplicity (s, singlet; d, doublet; t, triplet; dd, doublet of doublet, ddd,
doublet of doublet of doublet, ddt, doublet of doublet of triplet, m,
multiplet) and coupling constant J in Hertz. The abbreviation Ar is
used to denote aromatic, br. to denote broad and app. to denote
apparent. Coupling constants, J, are measured to the nearest 0.1 Hz
and are presented as observed. LC-HRMS analyses were performed
on an ACQUITY UPLC H-Class system (Waters-Micromass, Man-
chester, UK) coupled with a SYNAPT G2-Si Q-TOF hybrid quadru-
pole time-of-flight instrument (Waters-Micromass, Manchester,
UK), equipped with an electrospray (ESI) ionization source (Z-
spray) and an additional sprayer for the reference compound (Lock
Spray)., Torrance, CA, USA) heated at 50 ꢀC. High-resolution mass
spectra (HRMS) were obtained from a Micromass-Waters Q-TOF
Ultima spectrometer, in electrospray ionization (ESI) mode (posi-
tive or negative). Enantiomeric excesses were measured with
Schimadzu LC-20AD equipped with a Chiralpak column (IA, IB, IC,
ID or IG).
4.1.3. 1-(3,3,3-Trifluoro-2,2-dihydroxypropyl) pyridin-1-ium
bromide (5)
To a solution of 5.00 g (26.3 mmol, 1.3 eq.) of 3-bromo-1,1,1-
trifluoropropan-2-one 10 in 20 mL of EtOH were added 1.60 mL
(20.2 mmol, 1 eq.) of pyridine. The mixture was heated to reflux for
10 h, before to be cooled to 25 ꢀC. Et2O was then added until to
obtain a murky solution. The mixture was stirred at 25 ꢀC for 15 h.
The solid was then filtered to afford 5 (6.35 g, 72%) as a white solid.
m.p. 193 ꢀC; NMR 1H (300 MHz, D2O): dH 1.19 (t, J ¼ 7.0 Hz, 3H), 3.62
(q, J ¼ 7.0 Hz, 2H), 4.99 (s, 2H), 8.18 (t, J ¼ 6.9 Hz, 2H), 8.71 (t,
J ¼ 6.9 Hz, 1H), 8.91 (d, J ¼ 6.9 Hz, 2H) ppm; NMR 13C (75 MHz,
D2O): dC 18.4, 58.3, 63.8, 94.9 (q, J ¼ 32.0 Hz), 125.0 (q, J ¼ 291.1 Hz),
128.9, 148.2 ppm; IR nmax: 3157, 1300, 1239, 1152, 1087 cmꢁ1
.
4.1.4. 2-(Trifluoromethyl)-6-(4-(trifluoromethyl) phenyl)
isonicotinic acid (11)
In 300 mL of MeOH were added 2.92 g (9.24 mmol, 1 eq.) of 5,
3.38 g (13.9 mmol, 1.5 eq.) of 6 and 5.70 g (73.9 mmol, 8 eq.) of
NH4OAc. The reaction mixture was heated to reflux for 24 h before
to concentrate it in vacuo. The residue was directly purified by flash
chromatography (cyclohexane/AcOEt/AcOH 1/1/0.01) to afford 11
(2.92 g, 94%) as an orange solid. m.p. 205 ꢀC; NMR 1H (300 MHz,
CD3OD): dH 7.69 (d, J ¼ 8.2 Hz, 2H), 8.10 (s, 1H), 8.16 (d, J ¼ 8.2 Hz,
2H), 8.46 (s, 1H) ppm; NMR 13C (75 MHz, CD3OD): dC 120.0,122.4 (q,
J ¼ 273.6 Hz), 123.9, 125.6 (q, J ¼ 271.6 Hz), 126.8, 128.6, 132.9 (q,
J ¼ 32.4 Hz), 141.5, 143.1, 150.5 (q, J ¼ 35.2 Hz), 158.2, 166.3 ppm; IR
nmax: 2980, 1714, 1128 cmꢁ1; HRMS calcd. for C14H8F6NO2 [MþH]þ
336.0459, found 336.0466.
4.1.5. (2-(Trifluoromethyl)-6-(4-(trifluoromethyl) phenyl)pyridin-
4-yl)methanol (12)
4.1.1. (2-Oxo-2-(4-(trifluoromethyl)phenyl)ethyl) triphenyl
phosphonium bromide (9)
To a solution, at 0 ꢀC and under argon, of 78.0 mg (0.23 mmol, 1
eq.) of 11 in 2 mL of anhydrous THF were added 0.58 mL (1.15 mmol,
5 eq.) of BH3.DMS (2M in THF). The solution was stirred at 25 ꢀC for
8 h, cooled to 0 ꢀC and treated with an of excess MeOH. The reac-
tional mixture was stirred for 5 min at 0 ꢀC and 5 min at 25 ꢀC,
before concentrated in vacuo. The residue was extracted with Et2O.
The organic layers were combined, dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by flash chroma-
tography (cyclohexane/AcOEt 2/1) to afford 12 (71 mg, 96%) as a
light orange solid. m.p. 83 ꢀC; NMR 1H (400 MHz, CDCl3): dH 4.90 (s,
2H), 7.66 (s, 1H), 7.74 (d, J ¼ 8.2 Hz, 2H), 7.95 (s, 1H), 8.18 (d,
J ¼ 8.2 Hz, 2H) ppm; NMR 13C (100 MHz, CDCl3): dC 63.1, 116.8 (q,
J ¼ 2.7 Hz), 120.2, 121.5 (q, J ¼ 274.5 Hz), 124.0 (q, J ¼ 272.2 Hz),
125.6 (q, J ¼ 3.8 Hz), 127.5, 131.6 (q, J ¼ 32.6 Hz), 141.0, 148.6 (q,
J ¼ 34.7 Hz), 153.0, 156.4 ppm; IR nmax: 3249, 2918, 2850, 1323,
1116 cmꢁ1; HRMS calcd. for C14H9F6NONa [MþNa]þ 344.0486,
found 344.0496.
To a solution of 2-bromo-1-(4-(trifluoromethyl)phenyl)-etha-
none 8 (1.00 g, 3.70 mmol, 1 eq.) in THF (20 mL) were added tri-
phenylphosphine (1.08 g, 4.10 mmol, 1.1 eq.). The reactional
mixture was heated to reflux for 15 h and concentrated under
reduced pressure. The residue was washed with Et2O. The solid was
filtered, washed with toluene and then with Et2O to afford 9 (2.00 g,
quant.) as a white solid. m.p. 136 ꢀC; NMR 1H (400 MHz, CDCl3): dH
6.41 (d, J ¼ 12.1 Hz, 2H), 7.49e7.57 (m, 11H), 7.84e7.93 (m, 6H), 8.49
(d, J ¼ 7.5 Hz, 2H) ppm; NMR 13C (100 MHz, CDCl3): dC 38.7 (d,
J ¼ 61.3 Hz), 118.4 (d, J ¼ 89.3 Hz), 123.3 (q, J ¼ 272.9 Hz), 125.8 (q,
J ¼ 3.6 Hz), 130.1 (d, J ¼ 13.1 Hz), 130.4, 133.4 (d, J ¼ 10.7 Hz), 134.8
(d, J ¼ 2.9 Hz), 135.4 (q, J ¼ 32.7 Hz) 137.6 (d, J ¼ 5.6 Hz), 191.2 (d,
J ¼ 10.9 Hz) ppm; IR nmax: 3435, 3057, 2722, 1680, 1409, 1316,
1107 cmꢁ1; HRMS calcd. for C27H21F3OP [MþH]þ 449.1282, found
449.1285.
4.1.2. (E)-4-oxo-4-(4-(trifluoromethyl)phenyl)but-2-enoïc acid (6)
To a solution of 6.00 g (11.4 mmol, 1 eq.) of 9 in 30 mL of CHCl3
were added 2.00 mL (1.45 g, 17.0 mmol,1.5 eq.) of NEt3. The solution
was stirred at 25 ꢀC for 5 min, before to add 1.57 g (17.0 mmol, 1.5
eq.) of glyoxylic acid in 30 mL of MeOH. The reactional mixture was
stirred at 25 ꢀC for 15 h and then concentrated in vacuo. AcOEt
(30 mL) were added before to be treated with 4 ꢂ 30 mL sat. aq.
NaHCO3. The aqueous layers were combined and acidified (pH ~ 1)
with 1 M aq. HCl. The solid was filtered and dried to afford 6 (3.07 g,
quant.) as a white solid. m.p. 154 ꢀC; NMR 1H (300 MHz, CD3OD): dH
4.1.6. 2-(Trifluoromethyl)-6-(4-(trifluoromethyl) phenyl)
isonicotinaldehyde (13)
To a solution, at 0 ꢀC, of 90.0 mg (0.28 mmol, 1 eq.) of 12 in 2 mL
of CH2Cl2 were added 132 mg (0.31 mmol, 1.1 eq.) of Dess-Martin
Periodinane. The suspension was stirred at 0 ꢀC for 1.5 h before to
be treated with sat. aq. NaHCO3. The reaction mixture was stirred at
25 ꢀC for 5 min. The solid was then filtered and the filtrate extracted
with CH2Cl2. The organic layers were combined, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by
Please cite this article as: G. Bentzinger et al., Enantiopure substituted pyridines as promising antimalarial drug candidates, Tetrahedron,
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6
G. Bentzinger et al. / Tetrahedron xxx (xxxx) xxx
flash chromatography (cyclohexane/AcOEt 1/1) to afford 13
(72.0 mg, 81%) as a white solid. m.p. 69 ꢀC; NMR 1H (300 MHz,
CDCl3): dH 7.77 (d, J ¼ 8.2 Hz, 2H), 8.06 (s, 1H), 8.24 (d, J ¼ 8.2 Hz,
2H), 8.35 (s, 1H), 10.21 (s, 1H) ppm; NMR 13C (75 MHz, CDCl3): dC
118.0, 120.2 (q, J ¼ 272.0 Hz), 121.6, 123.9 (q, J ¼ 274.5 Hz), 126.0,
127.6,132.1 (q, J ¼ 32.7 Hz), 139.8,144.2,150.0 (q, J ¼ 35.9 Hz),158.0,
4.1.9. 2,6-Dibromo-4-((4-methoxybenzyl)oxy) pyridine (15)
To a solution of 14 (8.0 g, 31.6 mmol,1 eq.) in DMF (100 mL) were
added 4-methoxybenzyl chloride (4.3 mL, 31.6 mmol, 1 eq.) and
K2CO3 (5.7 g, 41.1 mmol, 1.3 eq.). The suspension was stirred at
110 ꢀC for 15 h, cooled back to 25 ꢀC, filtered over a Celite pad and
the filtrate was concentrated under reduced pressure. The residue
was placed in EtOAc and washed with 0.5 M NaOH. The aqueous
layer was extracted with EtOAc. The combined organic layers were
dried over Na2SO4, filtered and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica gel
(cyclohexane/EtOAc 9/1) affording 15 (11.7 g, 99%) as a white solid.
m.p. 69 ꢀC; 1H NMR (400 MHz, CDCl3): dH 3.83 (s, 3H), 5.00 (s, 2H),
6.94 (d, 3J ¼ 8.7 Hz, 2H), 7.04 (s, 2H), 7.31 (d, 3J ¼ 8.7 Hz, 2H) ppm;
13C NMR (100 MHz, CDCl3): dC 55.3, 70.8, 114.0, 114.2, 126.3, 129.5,
189.6 ppm; IR nmax: 1711, 1319, 1118 cmꢁ1
.
4.1.7. 2-(Trifluoromethyl)-6-(4-(trifluoromethyl) phenyl)-4-
vinylpyridine (4)
Method A: Wittig reaction: To a suspension, at 0 ꢀC and under
argon, of 729 mg (2.04 mmol, 1.3 eq.) of methyl-
triphenylphosphonium bromide, 75.0 mg (3.14 mmol, 2 eq.) of LiOH
in 30 mL of distilled THF were added 1.96 mL (3.14 mmol, 2 eq.) of
n-BuLi (1.6 M in hexane). The reaction mixture was stirred at 0 ꢀC
for 10 min, at 25 ꢀC for 10 min and cooled to ꢁ78 ꢀC. A solution of
500 mg (1.57 mmol,1 eq.) of 13 in 10 mL of distilled THF were added
dropwise. The solution was stirred for 20 min at ꢁ78 ꢀC before to be
heated to ꢁ30 ꢀC. The reaction mixture was stirred at ꢁ30 ꢀC for 6 h,
heated to 25 ꢀC in 5 h (0.2 ꢀC/min) and stirred at 25 ꢀC for 15 h. The
solution was treated with a MeOH excess before to be extracted
with AcOEt. The organic layers were combined, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by
141.1, 160.0, 166.7 ppm; IR nmax: 2925, 1572, 1514, 982, 826 cmꢁ1
;
79
HRMS calcd. for
395.9065.
C
H
Br2NO2Na [MþNa]þ 395.9054, found
13 11
4.1.10. 2-Bromo-6-iodo-4-((4-methoxybenzyl)oxy) pyridine (16)
To a solution of 15 (4.97 g, 13.1 mmol, 1 eq.) in anhydrous THF
(13 mL) were added iPrMgCl.LiCl (1.3 M in THF) (16.2 mL,
21.0 mmol, 1.6 eq.). The reaction mixture was stirred at 25 ꢀC for 2 h
and cooled to 0 ꢀC before adding portionwise I2 (5.33 g, 21.0 mmol,
1.6 eq.). The resulting mixture was stirred at 0 ꢀC for 5 min, at 25 ꢀC
for 15 h and quenched with 0.5 M Na2S2O3 aq. (3 ꢂ 40 mL). The
aqueous layer was extracted with EtOAc. The combined organic
layers were washed with brine, dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (cyclohexane/EtOAc 10/1)
affording 16 (4.68 g, 85%) as a white solid. m.p. 96 ꢀC; 1H NMR
(400 MHz, CDCl3): dH 3.83 (s, 3H), 4.99 (s, 2H), 6.93 (d, J ¼ 8.7 Hz,
2H), 7.04 (d, J ¼ 1.9 Hz, 1H), 7.26e7.34 (m, 3H) ppm; 13C NMR
(100 MHz, CDCl3): dC 55.3, 70.6, 114.3, 114.3, 115.5, 121.2, 126.4,
flash chromatography (cyclohexane/AcOEt 10/1) to afford
4
(270 mg, 63%) as an oil, solidifying over time into a light yellow
solid.
Method B: Suzuki coupling: An argon-purged mixture of 21 (6.0 g,
16.3 mmol, 1 eq.), potassium vinyltrifluoroborate (2.4 g, 17.9 mmol,
1.1 eq.), Na2CO3 (3.5 g, 32.6 mmol, 2 eq.) and Pd(PPh3)4 (0.94 g,
0.81 mmol, 0.05 eq.) in a mixture of toluene/EtOH/H2O (6/1/1,
280 mL) was stirred at 110 ꢀC for 16 h. The reaction mixture was
cooled to 25 ꢀC and extracted with AcOEt. The combined organic
layers were dried over Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by flash chromatog-
raphy on silica gel (cyclohexane/EtOAc 10/1) affording 4 (5.08 g,
98%) as a yellow oil, solidifying over time into light yellow solid.
m.p. 37 ꢀC; NMR 1H (400 MHz, CDCl3): dH 5.66 (d, J ¼ 10.9 Hz, 1H),
6.15 (d, J ¼ 17.6 Hz, 1H), 6.78 (dd, J ¼ 17.6 Hz, 10.9 Hz, 1H), 7.65 (s,
1H), 7.72 (d, J ¼ 8.2 Hz, 2H), 7.83 (s, 1H), 8.15 (d, J ¼ 8.2 Hz, 2H) ppm;
NMR 13C (100 MHz, CDCl3): dC 116.2 (q, J ¼ 2.7 Hz), 120.3, 120.7,
121.3 (q, J ¼ 272.2 Hz), 123.9 (q, J ¼ 272.2 Hz), 125.7 (q, J ¼ 3.4 Hz),
127.4, 131.5 (q, J ¼ 32.5 Hz), 133.7, 141.0, 147.7, 148.9 (q, J ¼ 34.5 Hz),
156.7 ppm; IR nmax: 1321, 1108 cmꢁ1; HRMS calcd. for C16H10F6N
[MþH]þ 318.0717, found 318.0725.
129.5, 141.0, 160.0, 165.6 ppm; IR nmax: 2928, 1563, 1516, 1251, 983,
79
826 cmꢁ1; HRMS calcd. for C13
419.9097.
H
BrINO2 [MþH]þ 419.9096, found
12
4.1.11. 2-Bromo-4-((4-methoxybenzyl)oxy)-6-(4-(trifluoromethyl)
phenyl)pyridine (17)
An argon-purged mixture of 16 (2.74 g, 6.52 mmol, 1 eq.), 4-
(trifluoromethyl)phenylboronic acid (1.11 g, 5.87 mmol, 0.9 eq.),
Na2CO3 (1.38 g, 13.0 mmol, 2 eq.) and Pd(PPh3)4 (377 mg,
0.33 mmol, 0.05 eq.) in a mixture of toluene/EtOH/H2O (6/1/1)
(109 mL) was stirred at 110 ꢀC for 15 h. The reaction mixture was
cooled to 25 ꢀC and concentrated under reduced pressure. The
residue was directly purified by flash chromatography on silica gel
(cyclohexane/EtOAc 8/1) affording 17 (2.73 g, 95%) as a yellow oil.
1H NMR (400 MHz, CDCl3): dH 3.83 (s, 3H), 5.08 (s, 2H), 6.95 (d,
J ¼ 8.6 Hz, 2H), 7.07 (d, J ¼ 2.0 Hz, 1H), 7.27 (d, J ¼ 2.0 Hz, 1H), 7.36
(d, J ¼ 8.6 Hz, 2H), 7.70 (d, J ¼ 8.2 Hz, 2H), 8.04 (d, J ¼ 8.2 Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3): dC 55.3, 70.5, 108.1, 112.7, 114.3,
124.0 (q, J ¼ 272.2 Hz), 125.6 (q, J ¼ 3.8 Hz), 126.8, 127.2, 129.5, 131.3
(q, J ¼ 32.6 Hz), 141.0, 143.1, 157.4, 160.0, 166.6 ppm; IR nmax: 2935,
1580, 1321 cmꢁ1; MS (ESIþ) m/z: 439 [MþH]þ.
4.1.8. 2,6-Dibromopyridin-4-ol (14)
An argon-purged mixture of 2,6-dibromopyridine 7 (2.0 g,
8.44 mmol, 1 eq.), pinacolborane (2.20 mL, 15.2 mmol, 1.8 eq.),
[Ir(cod)Cl]2 (56.7 mg, 0.08 mmol, 0.01 eq.) and 4,40-di-tert-butyl-
2,20-dipyridyl (45.3 mg, 0.017 mmol, 0.02 eq.) in cyclohexane
(15 mL) was stirred at 80 ꢀC for 18 h. The reaction mixture was
cooled back to 25 ꢀC and concentrated under reduced pressure. The
residue was dissolved in THF (20 mL) before adding dropwise a
solution of oxone monopersulfate (2.9 g, 9.3 mmol, 1.1 eq.) in H2O
(30 mL). The resulting mixture was stirred at 25 ꢀC for 30 min,
quenched with 1 M NaHCO3 aq. and extracted with EtOAc. The
combined organic layers were washed with water, brine, dried over
Na2SO4, filtered and concentrated under reduced pressure. The
resulting solid was purified by flash chromatography on silica gel
(cyclohexane/EtOAc 4/1) affording 14 (1.75 g, 82%) as a white solid.
m.p. 207 ꢀC; 1H NMR (400 MHz, CD3OD): dH 6.97 (s, 2H, H3, H5)
ppm; 13C NMR (100 MHz, CD3OD): dC 116.0 (C3, C5), 141.8 (C2, C6),
168.6 (C4) ppm; IR nmax: 2838, 1540, 1147, 769 cmꢁ1; HRMS calcd.
for C5H4NO79Br2 [MþH]þ 251.8660, found 251.8663.
4.1.12. 2-Iodo-4-((4-methoxybenzyl)oxy)-6-(4-(trifluoromethyl)
phenyl)pyridine (18)
To a solution of 17 (453 mg, 1.03 mmol, 1 eq.), CuI (10.0 mg,
0.05 mmol, 0.05 eq.) and NaI (309 mg, 2.06 mmol, 2 eq.) in anhy-
drous 1,4-dioxane (1.3 mL) were added N,N0-dimethylethylenedi-
amine (11.0
mL, 0.10 mmol, 0.1 eq.). The solution was stirred at
110 ꢀC for 28 h, cooled to 25 ꢀC, treated with NH4OH (28% in H2O)
(10 mL) and diluted with water. The mixture was extracted with
DCM. The organic layers were washed with brine, dried over
Please cite this article as: G. Bentzinger et al., Enantiopure substituted pyridines as promising antimalarial drug candidates, Tetrahedron,
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7
Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (cyclo-
hexane/EtOAc 8/1) affording 18 (442 mg, 88%) as a colorless oil. 1H
NMR (400 MHz, CDCl3): dH 3.74 (s, 3H), 4.96 (s, 2H), 6.86 (d,
J ¼ 8.6 Hz, 2H), 7.17 (d, J ¼ 2.0 Hz,1H), 7.21 (d, J ¼ 2.0 Hz,1H), 7.26 (d,
J ¼ 8.6 Hz, 2H), 7.59 (d, J ¼ 8.2 Hz, 2H), 7.93 (d, J ¼ 8.2 Hz, 2H) ppm;
13C NMR (100 MHz, CDCl3): dC 55.3, 70.3, 108.4, 114.2, 118.8, 119.7,
124.0 (q, J ¼ 272.3 Hz), 125.6 (q, J ¼ 3.7 Hz), 126.9, 127.2, 129.5, 131.2
(q, J ¼ 32.5 Hz), 141.0, 157.9, 160.0, 165.5 ppm; IR nmax: 2935, 1575,
1319,1110, 993, 827 cmꢁ1; HRMS calcd. for C20H16F3BrINO2 [MþH]þ
486.0178, found 486.0190.
126.0 (q, 3J ¼ 3.8 Hz), 126.4, 127.6, 132.2 (q, 2J ¼ 32.7 Hz), 134.9,
2
139.7, 149.3 (q, J ¼ 35.4 Hz), 157.5 ppm; IR nmax: 1573, 1320, 1119,
1057, 843 cm-1.
4.1.16. (S)-1-(2-(Trifluoromethyl)-6-(4-(trifluoro methyl)phenyl)
pyridin-4-yl)ethane-1,2-diol ((S)-22)
To a suspension of AD-mix
a (1.26 g) in a tBuOH/H2O mixture (1/
1) (22 mL) was added potassium osmate (3.00 mg, 0.09 mmol, 0.01
eq.). The mixture was cooled to 0 ꢀC and 4 (285.0 mg, 0.90 mmol, 1
eq.) was added. The reaction mixture was stirred at 0 ꢀC for 5 min
and at 25 ꢀC for 15 h. The reaction was cooled to 0 ꢀC and quenched
with Na2SO3 (980 mg). The suspension was stirred for 10 min at
4.1.13. 4-((4-Methoxybenzyl)oxy)-2-(trifluoro methyl)-6-(4-
(trifluoromethyl)phenyl)pyridine (19)
0
ꢀC, 10 min at 25 ꢀC and extracted with EtOAc. The combined
organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure. The residue was precipitated with cyclo-
hexane. The resulting solid was filtered affording (S)-22 (316 mg,
99%) as a white solid. m.p. 101 ꢀC; 1H NMR (400 MHz, CD3OD): dH
3.77 (m, 2H), 4.89 (m, 1H), 7.76 (d, J ¼ 8.3 Hz, 2H), 7.84 (s, 1H), 8.20
(s, 1H), 8.29 (d, J ¼ 8.3 Hz, 2H) ppm; 13C NMR (100 MHz, CD3OD): dC
67.8, 74.2,118.7 (q, J ¼ 2.8 Hz),122.5,123.2 (q, J ¼ 273.6 Hz),125.6 (q,
J ¼ 271.3 Hz), 126.8 (q, J ¼ 3.8 Hz), 128.7, 132.5 (q, J ¼ 32.3 Hz), 142.7,
149.2 (q, J ¼ 34.3 Hz), 157.0, 157.2 ppm; IR nmax: 3293, 1323,
1097 cmꢁ1; HRMS calcd. for C15H11F6NO2Na [MþNa]þ 374.0578,
found 374.0583;: þ29.1ꢀ (c 0.1; MeOH); Chiral HPLC 99% ee, Chir-
To a solution, under argon, of 18 (2.28 g, 4.70 mmol, 1 eq.), KF
(1.64 g, 28.2 mmol, 6 eq.), CuI (0.36 g, 1.88 mmol, 0.4 eq.) and 1,10-
phenantroline (0.34 g, 1.88 mmol, 0.4 eq.) in anhydrous DMSO
(68 mL) were added B(OMe)3 (3.14 mL, 28.2 mmol, 6 eq.) and
TMSCF3 (2 M in THF) (14.1 mL, 28.2 mmol, 6 eq.). The solution was
stirred at 60 ꢀC for 24 h. The reaction mixture was treated with
NH4OH (28% in H2O) (20 mL) and extracted with diethyl ether. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (cyclo-
hexane/EtOAc 4/1) affording 19 (1.78 g, 89%) as a yellow oil. 1H NMR
(400 MHz, CDCl3): dH 3.75 (s, 3H), 5.07 (s, 2H), 6.88 (d, J ¼ 8.7 Hz,
2H), 7.17 (d, J ¼ 2.0 Hz,1H), 7.30 (d, J ¼ 8.7 Hz, 2H), 7.35 (d, J ¼ 2.0 Hz,
1H), 7.63 (d, J ¼ 8.2 Hz, 2H), 8.02 (d, J ¼ 8.2 Hz, 2H) ppm; 13C NMR
(100 MHz, CDCl3): dC 55.3, 70.5, 106.6 (q, J ¼ 2.8 Hz), 109.7, 114.3,
121.4 (q, J ¼ 274.6 Hz), 124.0 (q, J ¼ 272.2 Hz), 125.7 (q, J ¼ 3.8 Hz),
126.7, 127.4, 129.5, 131.5 (q, J ¼ 32.6 Hz), 141.2, 150.0 (q, J ¼ 34.5 Hz),
157.9, 160.0, 166.7 ppm; IR nmax: 2935, 1604, 1324, 1126 cmꢁ1; MS
(ESIþ) m/z: 428 [MþH]þ.
alpak IB column, heptane/i-PrOH, 90/10, flow
tr(R) ¼ 10.6 min, tr(S) ¼ 11.6 min.
1 mL/min,
4.1.17. (R)-1-(2-(Trifluoromethyl)-6-(4-(trifluoro methyl)phenyl)
pyridin-4-yl)ethane-1,2-diol ((R)-22)
To a suspension of AD-mix b (8.85 g) in a tBuOH/H2O mixture (1/
1) (160 mL) was added potassium osmate (23.2 mg, 0.06 mmol, 0.01
eq.). The mixture was cooled to 0 ꢀC and 4 (2.00 g, 6.30 mmol, 1 eq.)
was added. The reaction mixture was stirred at 0 ꢀC for 5 min and at
25 ꢀC for 15 h. The reaction was cooled to 0 ꢀC and quenched with
Na2SO3 (7 g). The suspension was stirred for 10 min at 0 ꢀC,
10 min at 25 ꢀC and extracted with EtOAc. The combined organic
layers were dried over Na2SO4, filtered and concentrated under
reduced pressure. The residue was precipitated with cyclohexane.
The resulting solid was filtered affording (R)-22 (2.21 g, 99%) as a
white solid. m.p., 1H NMR, 13C NMR and IR spectra are the same that
those of (S)-22. HRMS calcd. for C15H11F6NO2Na [MþNa]þ 374.0578,
found 374.0583;: ꢁ29.3ꢀ (c 0.1; MeOH); Chiral HPLC >98,5% ee
(incomplete separation), Chiralpak IB column, heptane/i-PrOH, 90/
10, flow 1 mL/min, tr(R) ¼ 11.0 min, tr(S) ¼ 12.7 min.
4.1.14. 2-(Trifluoromethyl)-6-(4-trifluoromethyl) phenyl)pyridin-4-
ol (20)
To a solution of 19 (1.78 g, 4.17 mmol,1 eq.) in DCM (42 mL) were
added TFA (1 mL). The reaction mixture was stirred at 25 ꢀC for 7 h
and treated with 1 M NaOH aq. (3 ꢂ 20 mL). The aqueous layers
were acidified with 1 M HCl until pH~6 and concentrated under
reduced pressure. The residue was washed with MeOH and the
solid filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(cyclohexane/EtOAc 1/1) affording 20 (1.03 g, 80%) as a white solid.
m.p.: 170 ꢀC; 1H NMR (400 MHz, CD3OD): dH 7.14 (d, J ¼ 2.0 Hz, 1H),
7.48 (d, J ¼ 2.0 Hz, 1H), 7.77 (d, J ¼ 8.2 Hz, 2H), 8.20 (d, J ¼ 8.2 Hz,
2H) ppm; 13C NMR (100 MHz, CD3OD): dC 108.8 (q, J ¼ 2.8 Hz), 111.7,
123.0 (q, J ¼ 273.5 Hz), 125.7 (q, J ¼ 271.3 Hz), 126.7 (q, J ¼ 3.8 Hz),
128.7, 132.4 (q, J ¼ 32.2 Hz), 143.0, 150.8 (q, J ¼ 34.2 Hz), 159.2,
4.1.18. (S)-4-(Oxiran-2-yl)-2-(trifluoromethyl)-6-(4-
(trifluoromethyl)phenyl)pyridine (S)-3
To a solution, under argon, of (S)-22 (1.20 g, 3.42 mmol, 1 eq.) in
anhydrous DCM (35 mL) were added trimethylorthoacetate (1.3 mL,
10.25 mmol, 3 eq.) and pTsOH (32.5 mg, 0.17 mmol, 0.05 eq.). The
reaction mixture was stirred at 25 ꢀC for 30 min and then
concentrated under reduced pressure. The residue was placed un-
der argon, dissolved in anhydrous DCM (35 mL) and cooled to 0 ꢀC.
TMSBr (1.35 mL, 10.25 mmol, 3 eq.) was then added dropwise. The
solution was stirred at 0 ꢀC for 5 min, at 25 ꢀC for 30 min and
concentrated under reduced pressure. The residue was placed un-
der argon and dissolved in anhydrous MeOH (35 mL). K2CO3 (2.36 g,
17.08 mmol, 5 eq.) was then added. The suspension was stirred at
25 ꢀC for 1 h, quenched with sat. aq. NH4Cl and extracted with DCM.
The combined organic layers were dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (cyclohexane/EtOAc 6/1)
affording (S)-3 (1.08 g, 95%) as a white solid. m.p. 81 ꢀC; 1H NMR
(400 MHz, CDCl3): dH 2.84 (dd, J ¼ 5.6, 2.5, 1H), 3.29 (dd, J ¼ 5.6, 4.3,
1H), 4.02 (dd, J ¼ 4.3, 2.5 Hz,1H), 7.59 (m,1H), 7.75 d, J ¼ 8.3 Hz, 2H),
168.1 ppm; IR nmax: 3097, 1611, 1582, 1323, 1108, 1061, 849 cmꢁ1
HRMS calcd. for C13H8F6NO [MþH]þ 308.0510, found 308.0523.
;
4.1.15. 4-Bromo-2-(trifluoromethyl)-6-(4-(trifluoro methyl)phenyl)
pyridine (21)
To a solution, under argon, of 20 (6.5 g, 21.2 mmol, 1 eq.) in DMF
(130 mL) were added POBr3 (24.3 g, 84.6 mmol, 4 eq.). The sus-
pension was stirred at 110 ꢀC for 16 h and quenched with H2O. The
resulting mixture was extracted with EtOAc. The combined organic
layers were washed with brine, dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (cyclohexane/EtOAc 9/1)
affording 21 (6.02 g, 93%) as a white solid. m.p.: 59 ꢀC; 1H NMR
3
(400 MHz, CDCl3): dH 7.76 (d, J ¼ 8.2 Hz, 2H), 7.83 (s, 1H), 8.12 (s,
1H), 8.16 (d, 3J ¼ 8.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): dC
120.7 (q, 1J ¼ 275.1 Hz),122.9 (q, 3J ¼ 2.8 Hz),123.9 (q, 1J ¼ 272.4 Hz),
Please cite this article as: G. Bentzinger et al., Enantiopure substituted pyridines as promising antimalarial drug candidates, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131088

8
G. Bentzinger et al. / Tetrahedron xxx (xxxx) xxx
7.86 (m, 1H), 8.18 (d, J ¼ 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): dC
48.1 (q, J ¼ 4.1 Hz), 50.9, 121.9 (q, J ¼ 275.6 Hz), 123.1, 124.0 (q,
J ¼ 272.2 Hz), 125.9 (q, J ¼ 3.7 Hz), 127.3, 131.6 (q, J ¼ 32.5 Hz), 132.1,
135.5, 140.6, 145.6 (q, J ¼ 34.6 Hz), 154.3 ppm; IR nmax: 2928, 1319,
HPLC 99% ee, Chiralpak IB column, heptane/i-PrOH/EDA, 99/1/0.1,
flow 1 mL/min, tr(R) ¼ 17.7 min, tr(S) ¼ 21.2 min.
4.1.23. (S)-2-(Pentylamino)-1-(2-(trifluoromethyl)-6-(4-
(trifluoromethyl)phenyl)pyridin-4-yl)ethanol ((S)-2b)
1105, 1068 cmꢁ1
;
HRMS calcd. for C15H11F6NO2Na [MþH]þ
334.0667, found 334.0679.;: þ23.5ꢀ (c 0,1; MeOH).
Following the general method for the preparation of 4-AHPs and
starting from (S)-3 (200.0 mg, 0.60 mmol, 1 eq.) and n-pentylamine
(0.36 mL, 3.10 mmol, 5.15 eq.), the residue was purified by flash
chromatography on silica gel (DCM/MeOH 9/1) affording (S)-2b
(236.6 mg, 94%) as a white solid. m.p. 112 ꢀC; 1H NMR (400 MHz,
CDCl3): dH 0.89 (t, J ¼ 7.0 Hz, 3H), 1.20e1.42 (m, 4H), 1.52e1.62 (m,
2H), 2.60e2.81 (m, 3H), 3.09 (dd, J ¼ 12.2, 3.1 Hz, 1H), 3.87 (sbr, 2H),
4.94 (dd, J ¼ 9.2, 3.2 Hz,1H), 7.68 (s,1H), 7.73 (d, J ¼ 8.2 Hz, 2H), 8.00
(s, 1H), 8.18 (d, J ¼ 8.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): dC
13.9, 22.5, 29.3, 29.6, 49.3, 56.2, 69.7, 116.6 (q, J ¼ 2.5 Hz), 120.0,
124.0 (q, J ¼ 272.2 Hz), 124.2 (q, J ¼ 274.5 Hz), 125.7 (q, J ¼ 3.7 Hz),
127.5, 131.5 (q, J ¼ 32.5 Hz), 141.1, 148.5 (q, J ¼ 34.6 Hz), 155.0,
156.4 ppm; IR nmax: 2930, 1327, 1126 cmꢁ1; HRMS calcd. for
4.1.19. (R)-4-(Oxiran-2-yl)-2-(trifluoromethyl)-6-(4-
(trifluoromethyl)phenyl)pyridine ((R)-3)
To a solution, under argon, of (R)-22 (1.00 g, 2.85 mmol, 1 eq.) in
anhydrous DCM (30 mL) were added trimethylorthoacetate
(1.10 mL, 8.50 mmol, 3 eq.) and pTsOH (27.0 mg, 0.14 mmol, 0.05
eq.). The reaction mixture was stirred at 25 ꢀC for 30 min and then
concentrated under reduced pressure. The residue was placed un-
der argon, dissolved in anhydrous DCM (30 mL) and cooled to 0 ꢀC.
TMSBr (1.13 mL, 8.54 mmol, 3 eq.) was then added. The solution was
stirred at 0 ꢀC for 5 min, at 25 ꢀC for 30 min and concentrated under
reduced pressure. The residue was placed under argon and dis-
solved in anhydrous MeOH (30 mL). K2CO3 (1.97 g, 14.25 mmol, 5
eq.) was then added. The suspension was stirred at 25 ꢀC for 2 h,
quenched with sat. aq. NH4Cl and extracted with DCM. The com-
bined organic layers were dried over Na2SO4, filtered and concen-
trated under reduced pressure. The residue was purified by flash
chromatography on silica gel (cyclohexane/EtOAc 6/1) affording
(R)-22 (804 mg, 85%) as a white solid. m.p. 81 ꢀC; NMR and HRMS
C
20H22F6N2O [MþH]þ 421.1715, found 421.1720;: þ23.7ꢀ (c 0.1;
MeOH); Chiral HPLC 99% ee, Chiralpak IB column, heptane/i-PrOH/
EDA, 99/1/0.1, flow 1 mL/min, tr(R) ¼ 12.4 min, tr(S) ¼ 14.3 min.
4.1.24. (R)-2-(Pentylamino)-1-(2-(trifluoromethyl)-6-(4-
(trifluoromethyl)phenyl)pyridin-4-yl)ethanol ((R)-2b)
Following the general method for the preparation of 4-AHPs and
starting from (R)-3 (200.0 mg, 0.60 mmol, 1 eq.) and n-pentylamine
(0.36 mL, 3.10 mmol, 5.15 eq.), the residue was purified by flash
chromatography on silica gel (DCM/MeOH 9/1) affording (R)-2b
(214.0 mg, 85%) as a white solid. m.p., 1H NMR, 13C NMR and IR
spectra are the same that those of (S)-2b. HRMS calcd. for
data in accordance with (S)-22; IR nmax
: 2928, 1319, 1105,
1068 cmꢁ1; HRMS calcd. for C15H11F6NO2Na [MþH]þ 334.0667,
found 334.0679.: ꢁ20.8ꢀ (c 0,1; MeOH).
4.1.20. General procedure for the ring-opening reactions:
preparation of 4-AHPs (2)
C
20H22F6N2O [MþH]þ 421.1715, found 421.1720;: ꢁ27.9ꢀ (c 0.1;
To a solution of the epoxide 3 in ethanol (0.05 M) was added the
desired amine. The reaction mixture was stirred at 130 ꢀC using
microwaves for 30 min and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
affording the corresponding 4-AHP.
MeOH); Chiral HPLC 99% ee, Chiralpak IB column, heptane/i-PrOH/
EDA, 99/1/0.1, flow 1 mL/min, tr(R) ¼ 11.9 min, tr(S) ¼ 14.0 min.
4.1.25. (S)-2-(Hexylamino)-1-(2-(trifluoromethyl)-6-(4-
(trifluoromethyl)phenyl)pyridin-4-yl)ethanol ((S)-2c)
Following the general method for the preparation of 4-AHPs and
starting from (S)-3 (40.0 mg, 0.12 mmol, 1 eq.) and n-hexylamine
(0.05 mL, 0.36 mmol, 3 eq.), the residue was purified by flash
chromatography on silica gel (DCM/MeOH 9/1) affording (S)-2c
(35 mg, 67%) as a white solid. m.p. 84 ꢀC; 1H NMR (400 MHz, CDCl3):
dH 0.86 (t, J ¼ 6.6 Hz, 3H), 1.21e1.37 (m, 6H), 1.53e1.61 (m, 2H),
2.63e2.82 (m, 3H), 3.11 (dd, J ¼ 12.2, 3.4 Hz, 1H), 4.76 (sbr, 2H), 5.00
(dd, J ¼ 9.4, 3.0 Hz, 1H), 7.67 (s, 1H), 7.71 (d, J ¼ 8.3 Hz, 2H), 7.99 (s,
1H), 8.16 (d, J ¼ 8.1 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): dC 13.9,
22.5, 26.7, 29.4, 31.6, 49.3, 56.0, 69.5, 116.5 (q, J ¼ 2.6 Hz), 120.0,
124.0 (q, J ¼ 272.2 Hz), 124.2 (q, J ¼ 274.6 Hz), 125.7 (q, J ¼ 3.8 Hz),
127.5, 131.6 (q, J ¼ 32.6 Hz), 141.0, 148.5 (q, J ¼ 34.6 Hz), 154.7,
156.4 ppm; IR nmax: 2925, 1325, 1112 cmꢁ1; HRMS calcd. for
4.1.21. (S)-2-(Butylamino)-1-(2-(trifluoromethyl)-6-(4-
(trifluoromethyl)phenyl)pyridin-4-yl)ethanol ((S)-2a)
Following the general method for the preparation of 4-AHPs and
starting from (S)-3 (200.0 mg, 0.60 mmol, 1 eq.) and n-butylamine
(0.30 mL, 3.00 mmol, 5.0 eq.), the residue was purified by flash
chromatography on silica gel (DCM/MeOH 9/1) affording (S)-2a
(191.4 mg, 78%) as a white solid. m.p. 129 ꢀC; 1H NMR (400 MHz,
CDCl3): dH 0.93 (t, J ¼ 7.3 Hz, 3H), 1.31e1.44 (m, 2H), 1.45e1.56 (m,
2H), 2.61e2.79 (m, 3H), 3.06 (dd, J ¼ 12.3, 3.7 Hz, 1H), 3.07 (sbr, 2H),
4.84 (dd, J ¼ 9.2, 3.6 Hz,1H), 7.67 (s, 1H), 7.73 (d, J ¼ 8.2 Hz, 2H), 7.99
(s, 1H), 8.18 (d, J ¼ 8.1 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): dC
13.9, 20.2, 32.0, 49.0, 56.2, 69.7, 116.6 (q, J ¼ 2.6 Hz), 120.0, 124.0 (q,
J ¼ 272.3 Hz),124.2 (q, J ¼ 274.8 Hz),125.6 (q, J ¼ 3.8 Hz),127.5,131.5
(q, J ¼ 32.6 Hz), 141.1, 148.5 (q, J ¼ 34.6 Hz), 155.0, 156.4 ppm; IR
nmax: 2921, 1328, 1109 cmꢁ1; HRMS calcd. for C19H21F6N2O [MþH]þ
407.1558, found 407.1551;: þ31.1ꢀ (c 0.1; MeOH); Chiral HPLC 99%
ee, Chiralpak IB column, heptane/i-PrOH/EDA, 99/1/0.1, flow 1 mL/
min, tr(R) ¼ 17.8 min, tr(S) ¼ 20.8 min.
C
21H25F6N2O [MþH]þ 435.1871, found 435.1857;: þ30.8ꢀ (c 0.1;
MeOH); Chiral HPLC 99% ee, Chiralpak IB column, heptane/i-PrOH/
EDA, 99/1/0.1, flow 1 mL/min, tr(R) ¼ 9.7 min, tr(S) ¼ 10.8 min.
4.1.26. (R)-2-(Hexylamino)-1-(2-(trifluoromethyl)-6-(4-
(trifluoromethyl)phenyl)pyridin-4-yl)ethanol ((R)-2c)
4.1.22. (R)-2-(Butylamino)-1-(2-(trifluoromethyl)-6-(4-
(trifluoromethyl)phenyl)pyridin-4-yl)ethanol ((R)-2a)
Following the general method for the preparation of 4-AHPs and
starting from (R)-3 (50.0 mg, 0.15 mmol, 1 eq.) and n-hexylamine
(0.06 mL, 0.45 mmol, 3 eq.), the residue was purified by flash
chromatography on silica gel (DCM/MeOH 9/1) affording (R)-2c
(42 mg, 65%) as a white solid. m.p., 1H NMR, 13C NMR and IR spectra
are the same that those of (S)-2c. HRMS calcd. for C21H25F6N2O
[MþH]þ 435.1871, found 435.1857;: ꢁ28.6ꢀ (c 0.1; MeOH); Chiral
HPLC 98% ee, Chiralpak IB column, heptane/i-PrOH/EDA, 99/1/0.1,
flow 1 mL/min, tr(R) ¼ 9.6 min, tr(S) ¼ 10.7 min.
Following the general method for the preparation of 4-AHPs and
starting from (R)-3 (40.0 mg, 0.12 mmol, 1 eq.) and n-butylamine
(0.071 mL, 0.72 mmol, 6 eq.), the residue was purified by flash
chromatography on silica gel (DCM/MeOH 9/1) affording (R)-2a
(47 mg, 96%) as a white solid. m.p., 1H NMR, 13C NMR and IR spectra
are the same that those of (S)-2a. HRMS calcd. for C19H21F6N2O
[MþH]þ 407.1558, found 407.1551;: ꢁ31.0ꢀ (c 0.1; MeOH); Chiral
Please cite this article as: G. Bentzinger et al., Enantiopure substituted pyridines as promising antimalarial drug candidates, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131088

G. Bentzinger et al. / Tetrahedron xxx (xxxx) xxx
9
4.1.27. (S)-2-(Heptylamino)-1-(2-(trifluoromethyl)-6-(4-
(trifluoromethyl)phenyl)pyridin-4-yl)ethanol ((S)-2d)
inhibitory concentration or IC50 values) were then calculated from
the obtained experimental results using a regression program
available on line [36].
Following the general method for the preparation of 4-AHPs and
starting from (S)-3 (50.0 mg, 0.15 mmol, 1 eq.) and n-heptylamine
(0.13 mL, 0.90 mmol, 6 eq.), the residue was purified by flash
chromatography on silica gel (DCM/MeOH 9/1) affording (S)-2d
(40 mg, 60%) as a white solid. m.p. 76 ꢀC; 1H NMR (400 MHz, CDCl3):
dH 0.78e0.97 (m, 3H), 1.06e1.43 (m, 8H), 1.45e1.66 (m, 2H),
2.62e2.70 (m, 2H), 2.89 [AB(ABX), J ¼ 12.2, 8.6, 2.7 Hz, 2H],
3.25e3.80 (sbr, 2H), 4.86 [X(ABX), J ¼ 8.6, 2.7 Hz, 1H], 7.67 (s, 1H),
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
7.74 (d, J ¼ 7.8 Hz, 2H), 8.00 (s, 1H), 8.19 (d, J ¼ 7.8 Hz, 2H) ppm; 13
C
Acknowledgments
NMR (100 MHz, CDCl3): dC 14.0, 22.6, 27.1, 29.1, 29.8, 31.7, 49.3, 56.1,
69.6, 116.6 (q, J ¼ 2.6 Hz), 120.0, 124.0 (q, J ¼ 272.2 Hz), 124.2 (q,
J ¼ 274.6 Hz), 125.8 (q, J ¼ 3.8 Hz), 127.5, 131.2 (q, J ¼ 32.6 Hz), 141.1,
148.5 (q, J ¼ 34.7 Hz), 154.9, 156.4 ppm; IR nmax: 2928, 1324,
1114 cmꢁ1; HRMS calcd. for C22H27F6N2O [MþH]þ 449.2028, found
449.2040;: þ24.9ꢀ (c 0.1; MeOH); Chiral HPLC 99% ee, Chiralpak IB
ꢀ ꢀ
This project was financed in part from DGA (Direction Generale
ꢁ
ꢀ
de l’Armement, Ministere de la Defense, France), ANR Astrid
ꢀ
(project ANR-12-STR-003), region Picardie and the SATT Nord. G. B.
ꢀ
was the recipient of a grant from Region Picardie. The authors thank
ꢀ
Philippe Grellier (Museum National d’Histoire Naturelle) who
column, heptane/i-PrOH/EDA, 99/1/0.1, flow
tr(R) ¼ 11.7 min, tr(S) ¼ 13.5 min.
1
mL/min,
graciously provided P. falciparum strains. We thank Sophie Da
Nascimento for mass spectra recording.
4.1.28. (R)-2-(Heptylamino)-1-(2-(trifluoromethyl)-6-(4-
(trifluoromethyl)phenyl)pyridin-4-yl)ethanol ((R)-2d)
Appendix A. Supplementary data
Following the general method for the preparation of 4-AHPs and
starting from (R)-3 (31.0 mg, 0.09 mmol, 1 eq.) and n-heptylamine
(0.08 mL, 0.54 mmol, 6 eq.), the residue was purified by flash
chromatography on silica gel (DCM/MeOH 9/1) affording (R)-2d
(34 mg, 85%) as a white solid. m.p., 1H NMR, 13C NMR and IR spectra
are the same that those of (S)-2d. HRMS calcd. for C22H27F6N2O
[MþH]þ 449.2028, found 449.2040;: ꢁ27.4ꢀ (c 0.1; MeOH); Chiral
HPLC 99% ee, Chiralpak IB column, heptane/i-PrOH/EDA, 99/1/0.1,
flow 1 mL/min, tr(R) ¼ 11.6 min, tr(S) ¼ 13.5 min.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131088.
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Please cite this article as: G. Bentzinger et al., Enantiopure substituted pyridines as promising antimalarial drug candidates, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131088

10
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Please cite this article as: G. Bentzinger et al., Enantiopure substituted pyridines as promising antimalarial drug candidates, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131088