New route to the 5-((arylthio- and heteroarylthio)methylene)-3-(2,2,2- trifluoroethyl)-furan-2(5H)-ones - Key intermediates in the synthesis of 4-aminoquinoline γ-lactams as potent antimalarial compounds

Article abstract of DOI:10.1016/j.bmcl.2013.08.108

In this Letter we report on a multi-step synthesis of 5-((arylthio- and heteroarylthio)-methylene)-3-(2,2,2-trifluoroethyl)furan-2(5H)-ones starting from γ-keto thiolester or γ-keto carboxylic acid. The key intermediate γ-lactones were then reacted with 4-aminoquinoline-derived amines via ring opening - ring closure (RORC) process affording the corresponding γ-hydroxy-γ-lactams in moderate to good yields. In vitro antimalarial activity of the resulting new 4-aminoquinoline γ-lactams were evaluated against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) and were found to be active in the range of 89-1600 nM with good resistance index and did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells (HUVEC) up to concentration of 50 μM.

Full text of DOI:10.1016/j.bmcl.2013.08.108

Bioorganic & Medicinal Chemistry Letters 23 (2013) 6167–6171
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New route to the 5-((arylthio- and heteroarylthio)methylene)-
3-(2,2,2-trifluoroethyl)-furan-2(5H)-ones—Key intermediates
in the synthesis of 4-aminoquinoline
antimalarial compounds
c-lactams as potent
Oleksandr S. Kanishchev a, Adeline Lavoignat b,c, Stéphane Picot b,c, Maurice Médebielle b,
,
⇑
Jean-Philippe Bouillon a,
⇑
a Equipe ‘‘Biomolécules Fluorées’’, Chimie Organique Bioorganique Réactivité et Analyses (COBRA), Institut de Recherche en Chimie Organique Fine de Rouen (IRCOF), UMR CNRS 6014,
Université et Institut National des Sciences Appliquées (INSA) de Rouen, F-76821 Mont Saint Aignan Cedex, France
b Equipe ‘‘Synthèse de Molécules d’Intérêt Thérapeutique (SMITH)’’, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), UMR CNRS-UCBL-INSA Lyon 5246,
Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Bâtiment Curien, 43 bd du 11 Novembre 1918, F-69622 Villeurbanne, France
c Malaria Research Unit (MRU), Faculté de Médecine, Université Claude Bernard Lyon 1, 8 Avenue Rockefeller, F-69373 Lyon Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter we report on a multi-step synthesis of 5-((arylthio- and heteroarylthio)-methylene)-3-
Received 17 July 2013
Revised 27 August 2013
Accepted 29 August 2013
Available online 7 September 2013
(2,2,2-trifluoroethyl)furan-2(5H)-ones starting from
intermediate -lactones were then reacted with 4-aminoquinoline-derived amines via ring opening—ring
closure (RORC) process affording the corresponding -hydroxy- -lactams in moderate to good yields. In
vitro antimalarial activity of the resulting new 4-aminoquinoline -lactams were evaluated against Plas-
c-keto thiolester or c-keto carboxylic acid. The key
c
c
c
c
modium falciparum clones of variable sensitivity (3D7 and W2) and were found to be active in the range of
89–1600 nM with good resistance index and did not show cytotoxicity in vitro when tested against
human umbilical vein endothelial cells (HUVEC) up to concentration of 50 lM.
Keywords:
Antimalarial
Fluorine
Ó 2013 Elsevier Ltd. All rights reserved.
Lactone
Lactam
Aminoquinoline
Half of the world population is currently at risk of malaria dis-
ease. Plasmodium falciparum parasite is responsible for almost one
million deaths each year affecting mainly children under 5 years
and pregnant women.1 Advances in malaria research have been re-
viewed,2–6 including a recent account of interest from a perspec-
tive in medicinal chemistry.7 The widespread resistance of many
P. falciparum parasites to the most available drugs, as well as the
lack of an efficient vaccine, cause an urgent need for new types
of antimalarial drugs. 7-Chloro-4-aminoquinoline derivatives,
especially chloroquine (CQ), amodiaquine (AQ) and also modified
CQ side-chain analogs,8–11 have been a representative class of such
antimalarial drugs. But the use of CQ and others first generation
antimalarial drugs is now very limited due to the widespread of
resistance. Therefore the current malaria treatment of choice in-
volves artemisinin-based combined therapies (ACTs),12 but never-
theless chemical exploration and structural modification of CQ is
still an attractive approach to propose new chemical entities that
are equally active against CQ-sensitive and CQ-resistant strains.
In the course of our medicinal chemistry project devoted to the
synthesis of new antimalarials, we have previously prepared a set
of compounds of general structure 1. All these compounds have
two major structural subunits, a 7-chloro-4-aminoquinoline core
and a 1H-pyrrole-2(5H)-one connected with a spacer. Based on
some difference in substitution patterns, they were divided in
0
two series
A
(R2 = CH2S(O)mAr, R4 = CF3, R4 = R5 = H) and
B
0
(R2 = Alk, Ar, R4 = CF3, R4 = H, R5 = SEt) (Fig. 1).13,14 Incorporation
of 1H-pyrrole-2(5H)-one unit into the side chain of quinoline and
synthetic antimalarials has been scarcely explored despite the fact
that natural products such as codinaepsin15 and ascosalipyrrolidi-
none A16 displayed promising antimalarial activity.
Compounds 1 in both series show high in vitro activity against
P. falciparum strains of variable sensitivity (3D7 and W2) and good
resistance index (in the range 1.0–2.5). Activity of the most potent
molecules was in the range of 40–50 nM (Fig. 2)13 and for most of
them correlated with high lipophilicity (c logP close to 4.5–6.6)
and c logD at pH 7.4 usually in the range of 1.2–2.8, except for
two molecules with values higher than 5.0. Moreover, they were
⇑
Corresponding authors. Tel.: +33 4 72431989 (M.M.); tel.: +33 2 35522422
(J.P.B.).
E-mail addresses: maurice.medebielle@univ-lyon1.fr (M. Médebielle), jean-
philippe.bouillon@univ-rouen.fr (J.-P. Bouillon).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.08.108

6168
O. S. Kanishchev et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6167–6171
spacer
Generally, compounds in series A were more active than those
O
R4
R4'
R5
obtained in series B. Further structure diversification of com-
pounds in series A was then explored in order to reduce the c logP
of the most active molecules and this may be achieved by judicious
choice of the aryl substitution or by changing aryl substituent (R6)
to heteroaryl one (Fig. 1). A series of new heterocyclic variants
were thus identified based on their compliance with the Lipinski’s
HN
N
Y
N
R1
New targeted molecules
R2
HO
R3
O
X
CF3
γ-hydroxy-γ-lactam
HN
N
N
n
4-aminoquinoline
1
‘rule of five’ criteria (Table 1);17,18 all the new targeted
c-lactams
HO
Previous molecules
SR6
have the following calculated values: (a) c logP lower than 5.0 in
contrast to most of the previous active molecules (Fig. 2)13, (b)
molecular weight in the range of 508–524 g/mol which is only
slightly higher than the accepted 500 g/mol, (c) clogD at pH 7.4
in the range of ꢀ1.10 to +0.45 and (d) are compliant with hydrogen
bonding properties.
Cl
Series A
2
R2 = -CH2S(O)mR6 (R6 = aryl); R3 = H
R
4 = CF3; R5 = R4' = H
n = 0, 1
R6 = substituted aryl or heteroaryl
Series B
R2 = alkyl, aryl; R3 = H
R
4 = CF3, C2F5; R4' = H
R4 = R4' = -C=C(RF)F, RF = CF3, CF2H
5 = SR6; R6= Et, CH2C6H5
During initial studies only three lactones 5a–c with Ar = –Ph,19
–C6H4–pCl,19 and –C6H4–pBr13 substituents were successfully
obtained and used to prepare target compounds. Our well estab-
lished synthetic methodology starts from commercially available
heptafluorobutyraldehyde and leads in five-steps to the key inter-
mediate lactones 5a–c as depicted on Scheme 1.
R
Figure 1. Structures of our previous 4-aminoquinoline-c-hydroxy-c
-lactams13 and
our new targeted molecules.
Unfortunately this methodology was totally fruitless when try-
ing to use heterocyclic thiols in the first thioacetalization step. Par-
ticularly, no reaction was observed with 2- or 4-pyridine thiols
both under Lewis acid (TiCl4) or protic (H2SO4) conditions, which
may be probably explained by pyridine complexation with Lewis
acid or its protonation. Moreover, thioacetalization also failed with
thiols bearing electron donating substituents such as p-methoxy
thiophenol.
Taking into account the lack of versatility (linear five-step se-
quence) and the above mentioned drawbacks of heteroaryl thiols,
a new improved synthesis of the lactone precursors from readily
available starting material and utilizing less number of steps was
urgently needed in order to support our antimalarial project.
Me
O
CF3
N
N
HN
N
HO
R
Cl
1a: R = CH2SPh: IC50(3D7) = 47nM, IC50(W2) = 55nM
1b: R = CH2SC6H4pCl: IC50(3D7) = 55nM, IC50(W2) = 57nM
1c: R = CH2SC6H4pBr: IC50(3D7) = 45nM, IC50(W2) = 42nM
Figure 2. Representative structures of our most active compounds.
found to have no cytotoxicity when tested against HUVEC cells in
concentrations up to 100
lM. These preliminary data demonstrate
c-Keto thiolester 6 is one of the easy accessible fluorinated
that structures in both series have some potential for generation of
new antimalarials, but one major concern is their relatively low
solubility due to high lipophilicity which is a potential issue when
progressing further potential hits. Our results presented herein are
directed to reduce the lipophilicity of the most active phenyl deriv-
atives keeping good potency against 3D7 and W2 strains with low
cytotoxicity in order to provide structures that will be more appro-
priate for in vivo oral assessment.
building blocks efficiently used in our previous syntheses of nitro-
gen containing heterocycles.20–22 It was prepared in large quanti-
ties and with good overall yield using cheap EtSH in the same
synthetic path as shown in Scheme 1 (steps a–d). When
c-keto
thiolester 6 was treated with SO2Cl2 in CH2Cl2,23–25 smooth quan-
titative conversion into corresponding acid chloride took place, and
the latter was immediately isomerized into its cyclic ‘pseudo acid
chloride’ 7 (Scheme 2). It is worth noting that compound 7 was
Table 1
Calculated physicochemical properties of the targeted c
-lactams 2 using MarvinSketch 5.11 from ChemAxon17
CF3
O
N
SR6
HN
N
HO
Cl
R6
MW (g/mol)
507.96
clogP/clogD (pH 7.4)
Polar surface area (PSA)
65.46
H-bond donors
2
H-bond acceptors
5
Violation parameters (MW)
>500
Ph
4.68/1.07
508.94
508.94
3.46/ꢀ0.15
78.35
78.35
2
2
6
6
>500
>500
N
N
4.05/0.45
O
N
524.94
2.80/ꢀ0.80
90.92
2
7
>500
N
N
509.93
512.94
3.43/ꢀ0.18
2.50/ꢀ1.10
91.24
96.17
2
2
7
8
>500
>500
N
N
N

O. S. Kanishchev et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6167–6171
6169
CF3CF2
O
CF3
CF3CF2
F
SAr
SAr
e
a,b
c,d
CF3(CF2)2CH(OH)2
SAr
SAr
O
O
O
3a-c
5a: Ar = Ph (51%)
4a: Ar = Ph (75%)
4b: Ar = p-Cl-C6H4 (62%)
4c: Ar = p-Br-C6H4 (51%)
5b: Ar = p-Cl-C6H4 (72%)
5c: Ar = p-Br-C6H4 (27%)
Scheme 1. Reagents and conditions: (a) ArSH, TiCl4, CH2Cl2, rt; (b) KOH, n-Bu4NBr, CH2Cl2/H2O, rt; (c) acetone, KH, THF, 0 °C; (d) TFA, H2O, reflux; (e) i-Pr2NH, Et2O, rt, 14 h.
CF3CF2
CF3CF2
O
O
Cl
a
SEt
O
O
6
7 (99%)
Scheme 2. Reagents and conditions: (a) SO2Cl2, CH2Cl2, 0 °C to rt, 1 h.
obtained as only one diastereomer (one set of signals was observed
in 19F NMR spectra); its stereochemistry was, however, not
determined.
Cyclic pseudo acid chlorides of this type are known to have dual
reactivity towards nucleophiles.26,27 Two major reaction sites for
nucleophilic attack are: (1) the carbon atom of carbonyl group,
resulting in a ring opening reaction, and (2) the chlorine atom at
the quaternary carbon center leading to SN1 type substitution.
Figure 3. X-ray diffraction analysis of compound 8b.
Additionally, in our case, the acidic cyclic proton in the a-position
to perfluoroalkyl substituent is prone to be easily abstracted under
basic conditions with further fluoride elimination.
First of all, we were interested in exploration of pseudo chloride
reactivity with thiolate anions, which in case of attack at the car-
bonyl carbon could lead to a formal transthioesterification product
of starting c-ketothiolester 6. However, reaction of chloride 7 with
aryl- or heteroaryl thiolates led nonselectively both to chlorine
SR
SR
CF3
CF3
OR1
SR
a
O
O
5
O
O
9a: R = Ph, R1 = H (67%)
9b: R = p-Tol, R1 = H (65%)
9c: R = Ph, R1 = Me (80%)
8a: R = Ph
8b: R = p-Tol
substitution and HF elimination/vinylic fluorine substitution,
Scheme 4. Reagents and conditions: (a) NIS (2 equiv), TfOH (1 equiv), H2O or R1OH
(9 equiv), MeCN, rt, 24 h.
affording new
a,b-unsaturated c-lactones 8 (Scheme 3). Conver-
sion was complete when using two equivalents of thiolate. This
reaction appeared to be general with aryl- and heteroaryl thiolates
and resulted in formation of lactones 8a–f as 50/50 mixtures of
diastereomers in good overall yields. Several base/solvent systems
were screened for this transformation (NaH/THF; NaH/DMSO;
K2CO3/NMP; Et3N/CH2Cl2; i-Pr2NH/CH2Cl2), and Cs2CO3/THF was
found to be the best combination for clean reaction and easy han-
dling. Crystal of single diastereomer of compound 8b was obtained
by slow evaporation of Et2O solution and its relative configuration
was determined by X-ray diffraction analysis (Fig. 3).28
CF3CF2
O
CF3CF2
a
Cl
OH
O
O
O
7
10 (95%)
Scheme 5. Reagents and conditions: (a) H2O, MeCN, reflux, 15 h.
It should be mentioned that –SAr substituent located at ‘ano-
meric’ position of the lactone ring in compounds 8 (Scheme 4: car-
bon 5) is activated for a selective nucleophilic substitution. For
example, it can be exchanged for hydroxy- or methoxy group in
reaction with water or MeOH using conditions described on
Scheme 4.
of
c
-keto thiolester 6 is not effective even under harsh reaction
conditions (for example, refluxing compound 6 in concd aq HCl/
dioxane mixture showed <5% conversion after 3 h when monitored
by 19F NMR), the two-step sequence 6 ? 7 ? 10 is a convenient
alternative route to perform such transformation.
Having carboxylic acid 10 in hand, we searched for the best
acid–thiol direct coupling conditions. Several acid activators ap-
peared either to be basic enough to induce fluoride elimination
(e.g., CDI) or to be completely ineffective (e.g., DMAP). Finally, we
have found that treating premixed solution of acid 10 and p-chlo-
rophenylthiol in MeCN with solid DCC gives known thiolester 4b,
which was earlier prepared in 4 steps utilizing route depicted on
Scheme 1. Corresponding p-methoxyphenyl thiolester 4d, which
was inaccessible by the previously reported sequence, was
obtained in 49% yield using DCC-mediated coupling procedure.
p-Fluorophenyl analogue 4e was also prepared by the same way
in 54% yield. Finally, pure isolated aryl thiolesters 4d and e were
reacted then with diisopropylamine (DIPA) in Et2O19 to give the
corresponding lactones 5d and e in moderate yields (Scheme 6).
Conversely to reaction with thiolates, simple solvolysis of chlo-
ride 7 with water in refluxing acetonitrile resulted in almost quan-
titative formation of
a-pentafluoroethyl substituted levulinic acid
(10) (Scheme 5).29 Taking into account that direct acid hydrolysis
SR
8a: R = Ph (90%)*
CF3CF2
CF3
8b: R = p-Tol (83%)*
Cl
8c: R = p-F-C6H4 (72%)*
8d: R = 2-Pyridyl (76%)*
8e: R = 4-Pyridyl(68%)*
8f: R = 2-Pyrimidyl(65%)*
*50/50 mixtures of diastereomers
a
SR
O
O
O
O
7
Scheme 3. Reagents and conditions: (a) RSH (2 equiv), Cs2CO3 (1.5 equiv), THF, rt,
4 h.

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O. S. Kanishchev et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6167–6171
CF3CF2
CF3CF2
All compounds 12a, d–j (Scheme 7) were evaluated against
O
O
CF3
CQ-sensitive (3D7) and CQ-resistant (W2) strains of P. falciparum
(Table 2).32 All experiments were carried out twice with wells in
triplicate. Data are reported as IC50 values. First of all, the spacer
shortening did not affect antimalarial activity as compound 12a
showed similar in vitro activity as previously tested analogue with
a –N(CH2)3N– spacer.13 All new derivatives are usually 3- to
17-fold less potent than CQ and 2- to 10-fold less potent than
the reference compound 12a, but most of them are more active
than chloroquine on W2 strain. Aryl derivatives 12a, d and e have
the highest logP in the tested series, and 12a and 12d are equally
good while the p-F-C6H4 derivative 12e was less active, especially
on W2 strain. Heteroaryl derivatives have usually lower logP and
logD (pH 7.4) and have similar or even better activity on 3D7 strain
compared to the aryl derivatives; the situation against W2 strain is
different since some of the less lipophilic structures (12g, 12h)
were less potent. Finally, almost all molecules have good resistance
index (better than CQ) close to 1.13–7.48. One of the more prom-
ising molecules is compound 12i since it has equal activity on both
strains and good calculated physicochemical properties. 2-Pyri-
midinyl derivative 12h is another promising molecule since a large
number of substituted 2-pyrimidine thiols can be prepared and can
deliver new analogues for a structure–activity relationship (SAR)
and hit to lead optimization. The 1,2,4-triazole derivative 12j was
the less active molecule against both 3D7 and W2 strains.
a
b
OH
O
SR
O
SR
O
O
10
4d:
R = p-MeO-C6H4 (49%)
4e: R = p-F-C6H4 (54%)
5d: R = p-MeO-C6H4 (16%)
5e:
R = p-F-C6H4 (30%)
5f: R = 2-Pyridyl (17%)
5g:
R = 4-Pyridyl (15%)
5h: R = 2-Pyrimidyl (18%)
5i:
R = 2-Pyridyl-N-oxide (18%)
5j: R = 3-(4-Methyl-4H-1,2,4-triazolyl) (13%)
Scheme 6. Reagents and conditions: (a) RSH (1 equiv), DCC (1 equiv), MeCN, rt,
17 h; (b) i-Pr2NH (2 equiv), Et2O, rt, 14-40 h.
CF3
O
NH2
HN
CF3
N
HN
N
SR
SR
HO
a
+
O
O
N
Cl
Cl
5a,d-j
11
12a: R = Ph (59%)
12d:
R = p-MeO-C6H4 (28%)
12e: R = p-F-C6H4 (29%)
12f:
R = 2-Pyridyl (32%)
12g:
R = 4-Pyridyl (56%)
12h: R = 2-Pyrimidyl (26%)
12i:
R = 2-Pyridyl-N-oxide (43%)
12j: R = 3-(4-Methyl-4H-1,2,4-triazolyl) (25%)
Selected representative compounds (12a, 12d–f, 12h, and 12i)
were evaluated against human umbilical vein endothelial cells
(HUVEC) using final concentrations ranging from 0.01 to
Scheme 7. Reagents and conditions: (a) THF/MeOH, rt.
50 l
mol/L.32 We did not detect significant cytotoxicity and no rel-
Heteroaryl thiols behaved slightly different under the same
coupling conditions. Although dicyclohexylurea (DCU) precipita-
tion was clearly observed confirming that activation step occurred,
19F NMR of the reaction mixtures showed many peaks, no one of
which could be definitely assigned to the corresponding heteroaryl
thiol ester. However, removing DCU by filtration, exchanging sol-
vent to Et2O and adding DIPA to that solution (i.e. applying stan-
dard conditions to form lactone from thiol ester) resulted in
heteroaryl lactone 5 formation. Thus, heterocyclic lactones 5f–j30
were obtained in moderate yields, from acid 10 using one-pot reac-
tion (Scheme 6).
evant IC50 could be obtained in the concentration range tested.
Based on these data, we extrapolate a minimum cytotoxicity value
over 10–50 lmol/L for all tested compounds, leading to an excel-
lent selectivity against parasites (both strains).
In conclusion, a series of new mixed aminoquinoline 5-((aryl-
thio- or heteroarylthio)methylene)-3-(2,2,2-trifluoroethyl)-
tams were prepared via ring opening—ring closure (RORC)
process from the corresponding -lactones. These precursors were
c-lac-
c
obtained from a two-step sequence involving DCC-mediated acid–
thiol coupling and lactonization reaction. Most 4-aminoquinoline
c
-lactams 12a, and d–j exhibited good in vitro antimalarial activity
5-((Arylthio- or heteroarylthio)methylene)-3-(2,2,2-trifluoro-
ethyl)furan-2(5H)-ones 5a, d–j prepared utilizing this newly devel-
oped methodology, were further used in RORC lactamization
reaction with aminoquinoline derivative 11 using our reported
methodology (Scheme 7).22 Shorter spacer –N(CH2)2N– was
preferred to keep lipophilicity not too high, in contrast with our al-
against P. falciparum clones of variable sensitivity (3D7 and W2)
with reasonable resistance index. The 1,2,4-triazole derivative
12j was the less active molecule especially against the W2 strain.
Compounds 12h and 12i from this series may serve as a good start-
ing hits for further optimization since they possess overall good
activity on both strains, good calculated physicochemical proper-
ties and chemical sites for possible SAR studies. We are also pursu-
ready reported 7-chloro-4-aminoquinoline
c-lactam derivatives
who had either a longer methylene spacer or a basic nitrogen.13
By this way, target molecules 12a, d–j31 were prepared for biolog-
ical testing.
ing efforts in preparing 4-aminoquinoline
derived from lactones 8a–f.
c-lactams that will
Table 2
In vitro data for compounds 12a, d–j against P. falciparum strains and resistance index
b
b
Compds
R
clogP/clogDa
IC50 (3D7, nM)
IC50 (W2, nM)
RIc
25
1.56
1.71
2.49
1.22
7.48
1.65
1.13
>3.20
CQ
/
Ph
3.69/0.88
4.68/1.07
4.52/0.91
4.82/1.21
4.05/0.45
3.46/ꢀ0.15
3.43/ꢀ0.18
2.80/ꢀ0.80
2.50/ꢀ1.10
30
107
101
305
179
89
278
242
499
750
167
173
759
218
666
458
274
>1600
12a
12d
12e
12f
12g
12h
12i
12j
p-MeO-C6H4
p-F-C6H4
2-Pyridyl
4-Pyridyl
2-Pyrimidyl
2-Pyridyl-N-oxide
3-(4-Methyl-4H-1,2,4-triazolyl)
a
b
c
All calculations were performed using MarvinSketch 5.11 from ChemAxon.17
Values are means determined from at least two experiments. Effective concentration for 50% inhibition.
Resistance index RI = IC50(W2)/IC50(3D7).

O. S. Kanishchev et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6167–6171
6171
27. Bhatt, M. V.; El Ashry, S. H.; Balakrishnan, M. Proc. Indian Acad. Sci. 1979, 88,
421.
Acknowledgments
28. Data for X-ray diffraction analysis of compound 8b have been deposited to the
Cambridge Crystallographic Data Centre (CCDC889153).
29. 4-Oxo-2-(perfluoroethyl)pentanoic acid (a-pentafluoroethyl levulinic acid) (10):
This work was supported by Agence Nationale de la Recherche
(ANR Emergence: ANR-11-EMMA-04-QUINOLAC), the Centre Na-
tional de la Recherche Scientifique (CNRS), and Universités de Rou-
en and Claude Bernard Lyon 1. K. Roussee, Dr. M. Sanselme and Dr.
D. Harakat are also thanked for their help for some syntheses, X-
ray diffraction analysis and HRMS, respectively.
To a solution of chloride 7 (3.0 g, 12 mmol) in MeCN (20 mL) was added water
(2 mL) and reaction mixture was refluxed for 15 h. Then it was filtered,
evaporated in vacuo, and residue dissolved in CH2Cl2 (40 mL) and dried over
MgSO4. After filtration and evaporation 2.65 g of product 10 was obtained as a
brown oil (yield: 95%). 1H NMR (CDCl3, d ppm): 2.24 (s, 3H), 2.88 (dd, 1H,
3
2
7
2JH,H = 18.4, JH,H = 2.9 Hz, CHAHB), 3.26 (dd, 1H, JH,H = 18.4, JH,H = 11.1 Hz,
CHAHB), 3.70 (m, 1H, CH), 9.04 (brs, 1H, COOH). 19F NMR (CDCl3, d ppm): ꢀ83.1
2
3
(m, 3F, CF3), ꢀ115.6 (dd, 1F, JF,F = 273.0, JF,H = 12.9 Hz, CFAFBCF3), ꢀ118.8 (dd,
1F, 2JF,F = 273.0, 3JF,H = 15.5 Hz, CFAFBCF3). 13C NMR (CDCl3, d ppm): 29.5 (s, Me),
References and notes
2
1
38.9 (s, CH2), 43.2 (t, JC,F = 21.9 Hz, CH), 113.7 (tq, JC,F = 258.8 Hz,
2JC,F = 38.5 Hz, CF2), 118.7 (qt, JC,F = 286.4, JC,F = 35.8 Hz, CF3), 171.4 (s,
1
2
1. Shetty, P. Nature 2012, 484, S14.
COOH), 204.9 (s, C@O).
30. Typical one-pot procedure for preparation of
2. Wu, T.; Nagle, A. S.; Chatterjee, A. Curr. Top. Med. Chem. 2011, 18, 853.
3. Chatterjee, A.; Yeung, B. K. S. Curr. Top. Med. Chem. 2012, 12, 473.
4. Dechy-Cabaret, O.; Benoit-Vical, F. J. Med. Chem. 2012, 55, 10328.
5. Gravitz, L. Nature 2012, 484, S26.
6. Staines, H. M.; Krishna, S. Treatment and Prevention of Malaria: Antimalarial Drug
Chemistry, Action and Use; Springer: Basel, 2012.
7. Biamonte, M. A.; Wanner, J.; Le Roch, K. G. Bioorg. Med. Chem. Lett. 2013, 23,
2829.
8. Schlitzer, M. Arch. Pharm. Chem. Life Sci. 2008, 341, 149.
9. Kaur, K.; Jain, M.; Reddy, R. P.; Jain, R. Eur. J. Med. Chem. 2010, 45, 3245.
10. Dive, D.; Biot, C. ChemMedChem 2008, 3, 383.
11. (a) Natarajan, J. K.; Alumasa, J. N.; Yearick, K.; Ekoue-Kovi, K. A.; Casabianca, L.
B.; de Rios, A. C.; Wolf, C.; Roepe, P. D. J. Med. Chem. 2008, 51, 3466; (b) Ekoue-
Kovi, K.; Yearick, K.; Iwaniuk, D. P.; Natarajan, J. K.; Alumasa, J.; de Dios, A. C.;
Roepe, P. D.; Wolf, C. Bioorg. Med. Chem. 2009, 17, 270; (c) Hwang, J. Y.;
Kawasuji, T.; Lowes, D. J.; Clark, J. A.; Connelly, M. C.; Zhu, F.; Guiguemde, W.
A.; Sigal, M. S.; Wilson, E. B.; DeRisi, J. L.; Guy, R. K. J. Med. Chem. 2011, 54, 7084;
(d) Manohar, S.; Rajesh, U. C.; Khan, S. I.; Tekwani, B. L.; Rawat, D. S. ACS Med.
Chem. Lett. 2012, 3, 355.
12. WHO Malaria Policy Advisory Committee and Secretariat, Malar. J. 2013, 12,
213.
13. Cornut, D.; Lemoine, H.; Kanishchev, O.; Okada, E.; Albrieux, F.; Beavogui, A. H.;
Bienvenu, A.-L.; Picot, S.; Bouillon, J.-P.; Médebielle, M. J. Med. Chem. 2013, 56,
73.
c-lactones 5f–j. 5-{[(Pyridin-4-
yl)sulfanyl]methylidene}-3-(2,2,2-trifluoroethyl)-2,5-dihydrofuran-2-one (5g): To
a solution of acid 10 (0.94 g, 4 mmol) in dry MeCN (10 mL) was added 4-
mercaptopyridine (0.45 g, 4 mmol) and after 5 min, DCC (0.83 g, 4 mmol) was
further added. Reaction mixture was stirred at a room temperature for 17 h.
After this time, 19F NMR of the reaction mixture showed full consumption of
acid. Solution was then filtered, the resulting precipitate was thoroughly
washed with MeCN (3 ꢁ 10 mL) and combined filtrates were evaporated to
dryness. Residue was dissolved in Et2O (30 mL) and i-Pr2NH (5 mL, 36 mmol)
was added to the resulting solution. Reaction mixture was stirred at room
temperature for 40 h. After this time 19F NMR of the reaction mixture showed
lactone as a sole product. Solvent was then evaporated in vacuo and residue
was purified by silica gel column chromatography (eluent: petroleum ether/
EtOAc, 1:1)) giving 0.17 g of lactone 5g (yield: 15%). Rf = 0.15 (PE–EtOAc, 1:1).
1H NMR (CDCl3, d ppm): 3.25 (q, 3JH,F = 10.3 Hz, 2H, CH2CF3), 6.33 (s, 1H, CH@S),
3
3
7.30 (d, JH,H = 6.2 Hz, 2H, H-3,5Py), 7.39 (s, 1H, C4H), 8.54 (d, JH,H = 6.2 Hz, 2H,
H-2,6Py). 19F NMR (CDCl3, d ppm): ꢀ65.6 (t, JF,H = 10.3 Hz, CF3). 13C NMR
3
2
(CDCl3,
d
ppm): 30.1 (q, JC,F = 32.3 Hz, CH2), 108.7 (s, CH=S), 122.2 (q,
3JC,F = 3.0 Hz, C3), 122.3 (s, C-3,5Py), 124.8 (q, JC,F = 276.9 Hz, CF3), 138.9 (s,
C4), 144.4 (s, C5), 147.6 (s, C-4Py), 150.2 (s, C-2,6Py), 168.1 (s, C@O). HRMS (ESI+):
calcd for C12H9F3NO2S m/z 288.0306, found 288.0305. .
1
31. Typical procedure for the synthesis of c-lactams 12a, d–j. 1-(2-((7-Chloroquinolin-
4-yl)amino)ethyl)-5-hydroxy-5-((pyridin-4-ylthio)methyl)-3-(2,2,2-
trifluoroethyl)-1H-pyrrol-2(5H)-one (12g): To a solution of lactone 5g (0.17 g,
0.59 mmol) in THF (5 mL) was added 4-aminoquinoline (11) (0.20 g, 0.9 mmol)
followed by MeOH (1 mL) until clear solution was obtained. Reaction mixture
was then stirred at room temperature for 4 days. After this time, 19F NMR of
the reaction mixture showed >95% conversion of starting lactone. Solvent was
then evaporated in vacuo and residue was purified by silica gel column
chromatography (eluent: EtOAc/MeOH, 9:1) giving 0.17 g of lactam (12g)
(yield: 56%). Rf = 0.4 (EtOAc-MeOH 9:1). 1H NMR (CD3OD, d ppm): 3.22 (q,
3JH,F = 10.8 Hz, 2H, CH2CF3), 3.47 (d, 2JH,H = 13.6 Hz, 1H, CHAHBS), 3.54–3.69 (m,
14. Médebielle, M.; Bouillon, J.-P.; Picot, S. PCT application, 2012, WO 2012104538,
Chem. Abstr. 2012, 157, 356567.
15. Kontnik, R.; Clardy, J. Org. Lett. 2008, 10, 4149.
16. Osterhage, C.; Kaminsky, R.; König, G. M.; Wright, A. D. J. Org. Chem. 2000, 65,
6412.
17. http://www.chemaxon.com.
18. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev.
2001, 46, 3.
19. Bouillon, J.-P.; Kikelj, V.; Tinant, B.; Harakat, D.; Portella, C. Synthesis 2006,
1050.
20. Bouillon, J.-P.; Hénin, B.; Huot, J.-F.; Portella, C. Eur. J. Org. Chem. 2002, 1556.
21. Bouillon, J.-P.; Tinant, B.; Nuzillard, J.-M.; Portella, C. Synthesis 2004, 711.
22. Bouillon, J.-P.; Shermolovich, Yu.; Mykhaylychenko, S.; Harakat, D.; Tinant, B. J.
Fluorine Chem. 2007, 128, 934.
23. Gilligan, W. H.; Stafford, S. L. Synthesis 1979, 600.
24. Folkmann, M.; Lund, F. J. Synthesis 1990, 1159.
2
3H, N(CH2)2N), 3.70 (d, JH,H = 13.6 Hz, 1H, CHAHBS), 3.77-3.88 (m, 1H,
3
N(CH2)2N), 6.60 (d, JH,H = 5.6 Hz, 1H, CHquin.), 7.03 (s, 1H, CHlactam), 7.20 (m,
3
4
2H, H-3,5Py), 7.38 (dd, JH,H = 9.0, JH,H = 2.1 Hz, 1H, CHquin), 7.77 (d,
3
4JH,H = 2.1 Hz, 1H, CHquin), 7.98 (d, JH,H = 9.0 Hz, 1H, CHquin), 8.24 (m, 2H, H-
3
2,6Py), 8.36 (d, JH,H = 5.6 Hz, 1H, CHquin). 19F NMR (CD3OD, d ppm): ꢀ64.7 (t,
3JF,H = 10.8 Hz, CF3). HRMS (ESI+): calcd for C23H21ClF3N4O2S m/z 509.1026,
found 509.1026
32. The in vitro drug sensitivity assay with cultured parasites, IC50 determination
by the SYBR Green I assay and cytotoxicity were determined as reported in our
25. Mulvihill, M. J.; Gallagher, J.; MacDougall, B. S.; Weaver, D. G.; Nguyen, D. V.;
Chung, K. H.; Mathis, W. Synthesis 2002, 365.
26. Bhatt, M. V.; Kamath, K. M.; Ravindranathan, M. J. Chem. Soc. 1971, 1772.
previous study, see Ref.13
.