First enantioselective synthesis of 4-aminoalcohol quinoline derivatives through a regioselective SN2 epoxide opening mechanism

Article abstract of DOI:10.1016/j.tetasy.2011.01.003

Mefloquine derivatives, contrary to chloroquine derivatives have not been widely studied to date. Consequently, mefloquine and its derivatives still remain very attractive synthetic targets. Although mefloquine is usually used clinically as a racemic mixture, some studies have shown that its (+)-enantiomer is more potent than the (-)-enantiomer. Moreover, the (-)-enantiomer is responsible for side effects due to reaction with the central nervous system adenosine receptors, while the (+)-enantiomer does no bind at this binding site. Recently, different libraries of racemic 4-aminoalcohol quinolines showed interesting antimalarial activities. Herein, we describe an enantiopure synthetic and straightforward route to prepare pure enantiomer 4-aminoalcohol quinoline derivatives through a 4-oxirane key-intermediate. A regioselective S_N2 ring opening of this epoxide, by diverse amines, allows us to obtain the corresponding (R) or (S) 4-aminoquinolines with good yields and enantiomeric excesses generally superior to 92%. The reported methodology appears suitable for the synthesis of a large number of pure enantiomer 4-aminoalcohol quinoline derivatives.

Full text of DOI:10.1016/j.tetasy.2011.01.003

Tetrahedron: Asymmetry 22 (2011) 138–148
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
First enantioselective synthesis of 4-aminoalcohol quinoline derivatives
through a regioselective SN2 epoxide opening mechanism
Alexia Jonet a, Alexandra Dassonville-Klimpt a, Sophie Da Nascimento a, Jean-Michel Leger b, Jean Guillon b,
Pascal Sonnet a,
⇑
a UMR-CNRS 6219, Laboratoire des glucides, UFR de Pharmacie, Université de Picardie Jules Verne, 1 rue des Louvels, Amiens, France
b CNRS FRE 3396, Pharmacochimie, UFR des Sciences Pharmaceutiques, Université Bordeaux 2, Bordeaux, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Mefloquine derivatives, contrary to chloroquine derivatives have not been widely studied to date. Conse-
quently, mefloquine and its derivatives still remain very attractive synthetic targets. Although meflo-
quine is usually used clinically as a racemic mixture, some studies have shown that its (+)-enantiomer
is more potent than the (ꢀ)-enantiomer. Moreover, the (ꢀ)-enantiomer is responsible for side effects
due to reaction with the central nervous system adenosine receptors, while the (+)-enantiomer does
no bind at this binding site. Recently, different libraries of racemic 4-aminoalcohol quinolines showed
interesting antimalarial activities. Herein, we describe an enantiopure synthetic and straightforward
route to prepare pure enantiomer 4-aminoalcohol quinoline derivatives through a 4-oxirane key-inter-
mediate. A regioselective SN2 ring opening of this epoxide, by diverse amines, allows us to obtain the cor-
responding (R) or (S) 4-aminoquinolines with good yields and enantiomeric excesses generally superior
to 92%. The reported methodology appears suitable for the synthesis of a large number of pure enantio-
mer 4-aminoalcohol quinoline derivatives.
Received 8 November 2010
Accepted 23 December 2010
Available online 1 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
derivative presents two asymmetric carbon atoms (Fig. 1). Karle
et al. showed that the (+)-enantiomer of the mefloquine is more
Human malaria is one of the most important diseases in the
world, with a corresponding mortality of more than 1 million deaths
per year.1 Four species of Plasmodium are responsible for malaria in
human beings and among these, Plasmodium falciparum is the most
dangerous. Antifolates (pyrimethamine, trimethoprim, and sulph-
onamides) and quinoline-containing drugs (quinine, mefloquine,
halofantrine, chloroquine, and primaquine) are two principal clas-
ses of antimalarial drugs that have been developed during the past
50 years.2 Newer antimalarial agents such as antibiotics (doxycy-
cline), the hydroxynaphthoquinone derivatives (atovaquone, lume-
fantrine), and artemisinin (active principle of Artemesia annua) were
introduced during this period.3 Due to the efficiency decrease of
classical medication toward the rapid extension of P. falciparum
chloroquine-resistant strains, there is a need to develop new and
effective antimalarial drugs.4 Extensive work has been done to syn-
thesize chloroquine analogs but with much less in regard to meflo-
quine derivatives. Consequently, mefloquine and its derivatives still
remain very attractive synthetic targets. Mefloquine hydrochloride
(LariamÒ) is a highly active blood schizontocide against multi-drug
resistant falciparum malaria strains. This quinoline methanol
potent than the (ꢀ)-enantiomer by a factor of 1.69 (IC50 values
against Sierra Leone and Indochina P. falciparum strains).5 However,
mefloquine is commonly used clinically as a racemic mixture of
( )-(R⁄,S⁄)-
methanol which consists of individual enantiomers (+)-(11R,12S)-
-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol and
-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quino-
a-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinoline-
a
(ꢀ)-(11S,12R)-
a
linemethanol. Mefloquine remains the drug of choice for US
military deployments in such regions, primarily because its
longer half-life (compared to those of Malarone or doxycycline)6
HO
HO
N
N
H H
H H
N
CF3
N
CF3
CF3
CF3
(+)-enantiomer
(-)-enantiomer
(+)-(11R,12S)
(-)-(11S,12R)
⇑
Corresponding author.
E-mail address: pascal.sonnet@u-picardie.fr (P. Sonnet).
Figure 1. Mefloquine enantiomer structures.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.003

A. Jonet et al. / Tetrahedron: Asymmetry 22 (2011) 138–148
139
allows weekly administration, thereby making compliance less
2. Results and discussion
problematic.
However, undesirable side effects on the central nervous system
(CNS) have been associated with mefloquine use. These include dis-
turbed sleep, heightenedanxiety, panic attacks, depression, and psy-
chosis.7,8 It has been found that the (ꢀ)-enantiomer of mefloquine
binds to CNS adenosine receptors, while the (+)-enantiomer is with-
out significant activity at this binding site. Moreover, blocking of
central adenosine receptors by the (ꢀ)-enantiomer is believed to re-
sult in neuropsychiatric symptoms associated with mefloquine.9
Further evidence suggests that the neurotoxicity of mefloquine ap-
pears to be related to the piperidine ring.10 Previously, it was re-
ported that the opening of the piperidine ring at the 4-position of
the quinoline scaffold is associated with an improved potency and
a selectivity relative to mefloquine. Recently, Dow et al. described
the antimalarial potential together with the physicochemical prop-
erties, of several libraries describing racemic mixtures of mefloquine
non-piperidine analogs.11 According to these authors, mefloquine
neurological effects could be limited by a lower permeability of
the blood–brain barrier of new mefloquine analogs through physi-
cochemical property modifications. From their library, an active ser-
ies of diamines has been identified showing a similar metabolic
stability and a lower permeability than mefloquine. The main mod-
ification of the mefloquine derivatives concerns the 4-position of the
quinoline scaffold to synthesize 4-aminoalcohol quinoline.11,12
Racemic mixtures of mefloquine analogs were synthesized and eval-
uated for other biological properties such as treatment of tuberculo-
sis,13 bacterial infections, and treatment of movement disorders
(Parkinson’s or Alzheimer’s diseases) due to their binding affinity
to the adenosine A2 receptor.14
Several other approaches to reduce mefloquine neurotoxicity
have been proposed: (i) reformulation of mefloquine as a pure iso-
mer, and (ii) reengineering of mefloquine (based on physicochem-
ical property modifications) to obtain less neurotoxic derivatives
still showing an antimalarial activity. In the continuation of our
precedent work concerning the synthesis of new antimalarial
drugs,15 the asymmetric synthesis of enantiopure 4-aminoalcohol
quinoline mefloquine analogs has been considered as an interest-
ing goal. These compounds should present the physiochemical
properties required to achieve a balance between potency, reduced
blood–brain barrier penetration, and metabolic stability. To the
best of our knowledge, no enantioselective syntheses of meflo-
quine amino-analogs have been described. Consequently, our goal
is to propose a new enantioselective pathway to mefloquine ami-
no-analogs allowing access to new antimalarial compounds with
a strong antimalarial activity and few neurological side effects.
Mefloquine and its synthesis were first described by Ohnmacht
et al.16 in 1971. In 1974, a more detailed account of the synthesis
along with antimalarial activity of the mefloquine isomers is given
by Carroll and Blackwell.17 More recently, Xie et al. reported a new
and enantioselective synthesis of the (11R,12S)-mefloquine hydro-
chloride using a proline-catalyzed asymmetric direct aldol reaction
and a Beckmann rearrangement as the key steps. The experimental
analysis confirmed the absolute configuration of (+)-mefloquine as
(11R,12S).18
During the synthesis of (R)- and (S)-4aminoalcohol quinoline
mefloquine analogs 1, the envisaged strategy involved enantiopure
key-intermediate 2 (4-oxirane) synthesis (Scheme 1). This enantio-
selective epoxide can be easily diversified on position 4, through a
regioselective SN2 ring opening mechanism. The preparation of
4-oxirane 2 was carried out from 4-vinylquinoline 3 either in one
step by a Jacobsen epoxidation or in two steps via a Sharpless
asymmetric dihydroxylation (diol 4).
The 4-vinylquinoline 3 has been prepared either from the
corresponding 4-bromoquinoline or from 4-sulfoxyquinoline 6 (4-
tosyloxy- or 4-trifluorooxy-quinoline) (Scheme 2). The 4-bromo-
quinoline 6a is easily accessible by reaction of 4-hydroxyquinoline
5 with phosphorus oxybromide at 150 °C. Sulfonates 6b and 6c are
prepared from the same alcohol 5 by the action of triflic anhydride
X
OH
i) POBr3, 150 °C,
6h, 97%
or Tf2O, 0 °C,
3 3h, 50%
N
CF3
N
CF
CF3
or pTsCl, 0 °C,
96%
CF3
6a
(X=Br)
5
6b (X=OTf)
6c (X=OTs)
ii) Cross-coupling
reaction
N
CF3
CF3
3
Scheme 2. Synthesis of 2,8-trifluoromethyl-4-vinylquinoline 3.
O
N
CF3
HO
NRR1
CF3
HO
3
N
CF3
N
CF3
CF3
CF3
OH
1
2
N
CF3
CF3
4
Scheme 1. Retrosynthesis of (11R)-enantiopure 4-aminoalcohol quinoline 1.

140
A. Jonet et al. / Tetrahedron: Asymmetry 22 (2011) 138–148
(50% yield) and p-toluenesulfonic acid (96% yield), respectively.
These different precursors will be used as an electrophile in transi-
tion-metal-catalyzed cross couplings (Hiyama, Stille and Suzuki
reactions).
Other Pd complexes tested as catalysts were less effective than
Pd(PPh3)2Cl2 (entries 8 and 9). The addition of an inorganic base
such as K2CO3 increases the reaction yield (entries 10 vs 2). The
best yield with
a satisfactory purity was obtained using
Using reaction conditions reported in the literature,19 a Hiyama
coupling has been performed with vinyltrimethoxysilane and 2,8-
trifluoromethyl-4-bromoquinoline 6a on water using sodium
hydroxide as the activator at 120 °C. Normally, this process should
give good results in the presence of a low quantity of diacetate pal-
ladium (1 mol %). Unfortunately, in our case, 4-vinylquinoline 3 is
formed in only 14% yield after 16 h of reaction. In order to reduce
the reaction time and to increase the yield, two others tests have
been made: (i) under microwave and (ii) with 10 mol % of
palladium catalyst. However, we did not succeed in improving
the previous yield of 14%.
To overcome this, the Stille coupling reaction with vinyltribu-
tylstannane as a vinylating reagent has been investigated. In order
to determine the optimal cross-coupling reaction conditions (sol-
vents, catalysts, substrates and bases) a study has been carried
out. The results are shown in Table 1. A first assay was performed
by using the reaction conditions described by Comins et al. in 2005,
slightly modified.20 The 4-bromoquinoline 6a was reacted with
vinylstannane using the Pd(PPh3)2Cl2 as a catalyst and tetrabutyl-
ammonium bromide as an additive at reflux of degassed acetoni-
trile (Table 1, entry 1). The 4-vinyl product was obtained in 46%
yield with a purity of 98% determined by an HPLC. The starting
material was totally converted but the reaction suffered from an
instability of the catalyst, which was observable through the pre-
cipitation of black palladium over the course of the reaction. Thus,
when the same reaction was performed using oven dried glassware
and distilled acetonitrile: a yield increase of 20% was observed (en-
try 2). The comparison between three solvents (dimethylformam-
ide, toluene and acetonitrile) revealed that acetonitrile affords
the best yields (entries 2–5). Without adding tetrabutylammonium
bromide (TBAB), only a 43% yield (vs 65%) of the corresponding
cross-coupled product 3 was obtained (entry 5). Indeed, TBAB is
known to be able to stabilize colloidal palladium nanoparticules
that act as catalysts.
Pd(PPh3)2Cl2, TBAB, distilled acetonitrile and K2CO3 (75%, entry
10). When 4-tosyloxy- and 4-trifluorooxyquinoline were used in
the place of 4-bromoquinoline, in the optimal conditions previ-
ously described, the yields decreased in an important way by
60% and 42%, respectively. The vinylquinoline 3 was easily pre-
pared in good yield (82%) by a direct Suzuki–Miyaura cross-cou-
pling reaction of 4-bromoquinoline 6a with dibutyl vinylboronate
(Scheme 3). This step has been performed in the presence of
Pd(PPh3)4 as a catalyst and a 4 M aqueous solution of KOH solu-
tion.21 The Suzuki–Miyaura-type reaction was expanded with
potassium vinyltrifluoroborate and 4-bromoquinoline 6a as cou-
pling partners by using PdCl2(dppf)ꢁCH2Cl2 as the catalyst, Cs2CO3
as the base, and THF–H2O as the solvent system.22 Consequently,
this new palladium-catalyzed cross-coupling reaction led to the
expected 4-vinylquinoline 3 in 71% yield.
B(OBu)2
Pd(PPh3)4,
toluene/KOHaq
Br
reflux, 24h
82%
N
CF3
N
CF3
BF3K
or
CF3
CF3
PdCl2(dppf).CH2Cl2
Cs2CO3, THF/H2O
reflux, 24h
6a
3
71%
Scheme 3. Suzuki cross-coupling.
After optimization of the 4-vinylquinoline 3 preparation, a di-
rect asymmetric epoxidation using a chiral (salen)Mn catalyst
has been envisaged although several direct methods for olefin
Table 1
Stille coupling conditions to prepare alkene 3
Bu3SnCH=CH2,
Pd, Solvent, additive,
base, 90 °C, 4 h
Br
N
CF3
N
CF3
CF3
CF3
6a
3
Entrya
Pd catalyst (mol %)
TBAB (equiv)
Base (equiv)
Solventb
Yieldd (%)
Puritye (%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)2Cl2 (10)
Pd(PPh3)2Cl2 (10)
Pd(PPh3)2Cl2 (10)
Pd(PPh3)2Cl2 (10)
Pd(PPh3)2Cl2 (10)
Pd(PPh3)4 (10)
Pd(PPh3)2Cl2 (10) + PPh3 (20)
Pd2(dba)3 (10) + PPh3 (20)
Pd(OAc)2 (10)
1
1
1
1
—
1
1
1
1
1
1
1
—
—
—
—
—
2
—
—
—
2
MeCNc
MeCN
Toluene
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
46
65
7
13
43
9
16
84
60
75
88
48
98
nd
nd
nd
99
nd
96
72
83
100
68
96
10
11
12
Pd(PPh3)2Cl2 (10)
Pd2(dba)3 (10)
Pd(PPh3)2Cl2 (5)
2
2
a
b
c
All reactions were performed with 1 equiv of 6a and 2 equiv of Bu3SnCH@CH2.
Performed using dry solvents.
Performed using a degassed solvent.
Yield obtained after flash chromatography.
Determined by HPLC analysis.
d
e

A. Jonet et al. / Tetrahedron: Asymmetry 22 (2011) 138–148
141
epoxidation are known. In the case of ‘‘terminal’’ double bonds, the
corresponding epoxides are often obtained with low enantiomeric
excesses.23 However, in 1994, Jacobsen et al.24 reported the enan-
tioselective epoxidation of styrene, at low temperatures (ꢀ78 °C),
adding m-chloroperbenzoic acid (m-CPBA) and N-methylmorpho-
line-N-oxide (NMO) to the chiral (salen)Mn complexes. This effec-
tive anhydrous oxidant system was applied with success to a series
of various terminal aromatic olefins with a yield of around 80% and
an ee 80%.25 More recently, Prasad et al.26 developed a large-scale
Jacobsen asymmetric epoxidation methodology to obtain a chiral
dihydrobenzofuran epoxide (melatonin agonist precursor). Their
best result gives the terminal epoxide with 87% yield (72% ee). In
order to obtain the enantiopure 4-oxirane 2, we used various
experimental conditions for the Jacobsen epoxidation. Each assay
was run with NMO (5 equiv), m-CPBA (2 equiv), and chiral (sale-
n)Mn(III) complexes (10 mol %) at ꢀ78 °C. The experiments differ
by: (i) m-CPBA addition in solid form or in solution in absolute
EtOH, (ii) DCM or DCM/THF solvent mixtures, and (iii) work-up
at room temperature or at low temperature (ꢀ78 °C). Unfortu-
nately, each experiment led to a racemic mixture of oxirane with
80% yield average (Scheme 4).
A direct epoxide synthesis being impossible, an indirect way
thus appeared necessary. Our strategy consists of a two step pro-
cess synthesis based on asymmetric dihydroxylation chemistry fol-
lowed by a stereospecific cyclization. This cyclization can be
obtained according to different literature procedures: (i) a base-
mediated ring closure via selective hydroxyl activation, generally
via a mesylate or tosylate form,27 (ii) a formation of acetoxy halides
and epoxide via the Sharpless acetoxonium ion28 or (iii) a Mistun-
obu reaction.29 We chose the Sharpless asymmetric dihydroxyla-
O
cat I or II (10 mol %)
m-CPBA/NMO
-78 °C
tion method followed by
a cyclization via the Sharpless
80%, racemic
acetoxonium ion. We have developed the optimized conditions
for the Sharpless asymmetric dihydroxylation starting from the
2,8-bis(trifluoromethyl)-4-vinylquinoline. According to the final
enantiomeric alcohol expected 4a (R) or 4b (S) the vinylquinoline
N
CF3
N
CF3
CF3
3
CF3
2
Cat I
3 is reacted with commercially available AD-mix
a or AD-mix b,
in a solution of t-BuOH/H2O at 0 °C, with eventual addition of
K2OsO2(OH)4 and MeSO2NH2 (see Table 2).
H
H
N
O
N
The first assays of asymmetric dihydroxylation were carried out
Mn
Cl
with 1.4 g of AD-mix
a or b added to 1 equiv of methylsulfonamide
(entries 1 and 2) as described by Kolb et al.27 The corresponding
O
t-Bu
t-Bu
oxiranes 4a or 4b were obtained with 40% yield average. In order
t-Bu
t-Bu
to increase the yield, the quantities of AD-mix
a have been in-
creased: doubled (entry 3) or multiplied by four (entry 4), without
success. However, addition of 1 mol % of K2OsO2(OH)4 to 1.4 g of
AD-mix increased significantly the yield (78% vs 43% entries 5,
2). Furthermore, we have demonstrated that the presence of meth-
ylsulfonamide is not required for the advancement of the reaction
(entry 5 and 6). Finally, the treatment of vinylquinoline 3 with
Cat II
H
H
N
N
Mn
Cl
O
t-Bu
O
t-Bu
1.4 g of AD-mix
b in the presence of 1 mol % of oxidant
K2OsO2(OH)4 provided the corresponding (R)-diol {½a D20
¼ ꢀ52 (c
ꢂ
t-Bu
t-Bu
0.25, DCM)} in 68% yield and 97% enantiomeric excess (ee). The
(S)-diol {½a 2D0
ꢂ
¼ þ62 (c 0.25; DCM)} was prepared from 1.4 g of
Scheme 4. Direct oxirane synthesis using the chiral (salen)Mn(III) complexes.
Table 2
Reagents and conditions used to prepare enantiopure diol 4a and 4b
HO
HO
OH
OH
AD-mix α, K2OsO2(OH)4,
t-BuOH/H2O (1:1), 0 °C.
AD-mix β, K2OsO2(OH)4,
t-BuOH/H2O (1:1), 0 °C.
N
CF3
N
CF3
N
CF3
CF3
CF3
CF3
4a
3
4b
½ ꢂ
a 2D0
e
Entry
AD-mix (g)
K2OsO2(OH)4
MeSO2NH2
Time (h)
Yield (%)
% eec
Diol (absolute configuration)f
1
2
3
4
5
6
7
a
(1.4)a
b (1.4)b
—
—
—
—
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
—
26
30
28
47
24
19
18
37
43
36
26
78
68
78
ndd
nd
nd
96
98
97
96
—
—
—
+62
ꢀ52
ꢀ52
+62
—
—
—
4b (S)
4a (R)
4a (R)
4b (S)
a
a
(2.5)
(6.4)
b (1.4)
b (1.4)
1 mol %
1 mol %
1 mol %
a
(1.4)
—
a
b
c
d
e
f
1 g of AD-mix
a corresponds to 1.0 mol % of (DHQ)2-PHAL, 3 mmol of K3Fe(CN)6, 3 mmol of K2CO3, 0.4 mol % of K2OsO2(OH)4.
1 g of AD-mix b corresponds to 1.0 mol % of (DHQD)2-PHAL, 3 mmol of K3Fe(CN)6, 3 mmol of K2CO3, 0.4 mol % of K2OsO2(OH)4.
Enantiomeric excesses were determined by HPLC (Chiralpak IB column, heptane/i-PrOH 90:10; 1 mL/min, 210 nm) tR (R) = 26 min, tR (S) = 33 min.
Not determined.
c 0.25, DCM.
Configuration of the major enantiomer was determined by analyzing 1H NMR spectra of the Mosher monoesters and/or with crystallographic epoxide spectra.

142
A. Jonet et al. / Tetrahedron: Asymmetry 22 (2011) 138–148
high field shift
HO
HO
OH
OTBDMS
CF3
TBDMSCl,
imidazole,
DMF, RT,
OMe
R1
MeO
CF3
R1
R2
R2
O
O
39%.
CF3
N
N
CF3
syn
CF3
CF3
O
H
O
H
4a
7
syn
high field shift
syn
(R)-MTPA, EDCl,
DMAP, DCM, RT
49%.
syn
(S,X)-ester mosher (R,X)-ester mosher
MTPAO
Figure 2. Preferred conformations of MTPA esters.
OTBDMS
CF3
AD-mix
a
in the presence of 1 mol % of oxidant K2OsO2(OH)4 in 78%
yield and 96% ee.
N
The Mosher’s MTPA (methoxy(trifluoromethyl)phenylacetyl)
method is a well-known tool to determine the absolute configura-
tion of chiral alcohols and primary amines since this process does
not require the crystallization of compounds.30 In MTPA esters, the
aromatic substituent (phenyl group) generates a diamagnetic
anisotropy effect due to the ring current induced by the external
magnetic field. The proton NMR signals of the alcohol moiety fac-
ing the phenyl group on the preferred conformation are moved to a
higher magnetic field (high-field shift). In ester (S,X), the protons of
group R1 feel a diamagnetic anisotropy effect, and hence their 1H
NMR signals show high-field shifts whereas R2 does not (Fig. 2).
Conversely, in the ester (R,X), R2 is above the benzene plane of
the MTPA moiety, and hence the protons of group R2 show high-
CF3
Scheme 5. Preparation of Mosher’s monoesters 8a and 8b.
The 1H NMR analyses of the diastereomeric esters allowed us to
establish without ambiguity the absolute configuration of the diols
by combining the anisotropy effects discussed above with the def-
inition of the
Dd parameter. The MTPA moiety and the methine
proton of the secondary alcohol moiety are placed up in the front
side and in the rear side, respectively. The substituent R2 showing
positive
D
d values is placed at the right side, while the substituent
d values is at the left side. So, the absolute
R1 showing negative
D
field shifts. The parameter
as
d = d(S,X) ꢀ d(R,X).
In this work, the corresponding Mosher’s monoester 8 was
prepared, from the diol 4a (R), using (S)- -methoxy- -trifluoro-
methyl-phenylacetic acid or (R)- -methoxy- -trifluoromethyl-
phenylacetic acid. For this purpose, the alcohol 7 was obtained
with a 39% yield after selective primary alcohol protection of com-
pound 4a with t-butyldimethylsilylchloride in DMF, at room tem-
perature. Subsequently, the two diastereomeric esters 8a (R,R) and
8b (S,R) were synthesized by reaction of 7 with the corresponding
(R)- and (S)-Mosher’s MTPA in dichloromethane with a 49% yield
(Scheme 5).
D
d reflecting the anisotropy is defined
configuration (X = R) of our alcohol has been determined (Fig. 3).
Concerning the epoxide formation by ring closure via Sharpless
acetoxonium ion, we have chosen to use a ‘one-pot’ method, previ-
ously described by Sharpless for the stereospecific conversion of
each (R)- or (S)-1,2-diols into their corresponding epoxides.27 This
process involves three successive steps: (i) formation of the cyclic
orthoester by acid catalyzed transesterification; (ii) generation of
halohydrins ester via regioselective opening of an acetoxonium
ion by addition of tributyldimethylsilyl chloride, and (iii) cycliza-
tion to an epoxide by base mediated saponification in methanol.
This conversion of the diol 4a to the oxirane 2a was accomplished
with global retention of configuration because this process in-
D
a
a
a
a
OMTPA
H
R1
R2
Figure 3. 1H NMR analysis of the diastereomeric esters 8a and 8b.

A. Jonet et al. / Tetrahedron: Asymmetry 22 (2011) 138–148
143
OMe
O
O
HO
+
OH
O
MeC(OMe)3,
cat. PPTS
O
N
CF3
N
CF3
m/z : 350
CF3
4a
N
CF3
CF3
CF3
TBDMSCl
O
Cl
OAc
K2CO3, MeOH
N
CF3
N
CF3
CF3
CF3
2a
m/z : 385
Scheme 6. One-pot stereospecific conversion of the 1,2-diol 4a into epoxide 2a via a chlorhydrine ester.
volves two successive inversions at the same stereocenter: (i)
inversion at the halide receiving stereocenter at the time of halohy-
drin ester formation and (ii) second inversion at the halide center
during cyclization to the epoxide (Scheme 6).
All three operations have been carried out in one reaction vessel
without isolation of any intermediates but each step was followed
and validated by GCMS. Thus, the slightly modified Sharpless con-
ditions applied to the conversion of diols 4a and 4b give the corre-
sponding oxiranes 2a and 2b with retention of configuration
according to the specific rotation of each compound (Table 3).
In order to confirm the structure and the absolute configuration
of the synthesized quinoline epoxides 2, X-ray studies for the two
derivatives were performed. Unfortunately, suitable crystals were
only obtained for compound (ꢀ)-2a. Its molecular structure, de-
picted in Figure 4, confirms the structure in the solid state as antic-
ipated on the basis of IR and NMR data. Moreover, the
configuration of (ꢀ)-2a was determined by observing and calculat-
ing the F(+)/F(ꢀ) ratios of Bijvoet pairs using the mean F value of
each independent reflection.31 Based on these results, the absolute
configuration at C-11 in (ꢀ)-2a is determined to be (R). Conse-
quently, (ꢀ)-2a led us to consider that the (+)-enantiomer-2b
should present the (S)-absolute configuration. Furthermore, these
Figure 4. View of the crystal structure of (R)-2a with our numbering scheme;
displacement ellipsoids are drawn at the 30% probability level.
Table 3
Substrate scope of enantioselective epoxidation
results indirectly confirm the stereochemistry of each (R)- or (S)-
quinolin-4-yl-ethanediol precursors 4.
O
HO
1. MeC(OMe)3 (3 eq.),
cat. PTSA, dry DCM
2.TBDMSCl (3 eq.),
dry DCM
OH
Finally, the treatment of oxirane 2a or 2b with diverse amines,
in a regioselective SN2 nucleophilic ring opening mechanism, pro-
vided the corresponding enantiopure 4-aminoquinolines 1a–e (R)
or 1f–j (S) with good yield (35–96%) and ees that were generally
superior to 92% (Table 4). No epimerization at the stereogenic car-
bon was observed, as determined by chiral HPLC analysis, using the
opposite enantiomer as a standard.
N
CF3
3. K2CO3 (3 eq.),
MeOH
N
CF3
2a, 2b
CF3
4a, 4b
CF3
eea (%)
Absolute configurationc
½ ꢂ
a 2D0
b
4
2
Yield (%)
a
b
a
b
68
57
92
96
ꢀ52
(R)
(S)
+45
3. Conclusion
a
b
c
Enantiomeric excess was determined by GC.
c 0.25, MeOH.
Absolute configuration was determined with crystallographic epoxide spectra.
Previous work by Milner et al.12 described an exploratory 4-
alcohol quinoline library meant to provide early-lead racemate

144
A. Jonet et al. / Tetrahedron: Asymmetry 22 (2011) 138–148
Table 4
(11R) Pure 4-aminoquinolines derivatives synthesis by regioselective SN2 epoxyde opening
O
HO
NRR1
CF3
RR1NH (3 eq.), i-PrOH
N
N
N
O
CF3
CF3
HO
2a
2b
1a-e
CF3
NRR1
CF3
RR1NH (3 eq.), i-PrOH
CF3
N
CF3
1f-1j
CF3
c
½ ꢂ
a DT
Entry
Substrate: RR1NH
Product
Yield (%)
eea (%)
Absolute configurationb
tR (min)
1
2
1a
1f
66
89
95
98
ꢀ34.5d
(R)
(S)
16.8
18.9
+46.3d
CH2NH2
3
4
1b
1g
35
38
89
97
ꢀ70.7e
(R)
(S)
9.0
20.1
HN
N
+78.2e
(CH2)3COOEt
5
6
n-C5H11NH2
n-C6H13NH2
1c
1h
88
93
94
99
ꢀ50.3f
(R)
(S)
21.5
25.3
+49.8f
7
8
1d
1i
88
85
94
98
ꢀ47.5f
(R)
(S)
18.5
21.4
+54.0f
9
10
1e
1j
98
82
93
92
ꢀ49.6e
(R)
(S)
6.2
7.2
NH2
+50.6e
N
N
3
3
H2N
a
b
c
d
e
f
Enantiomeric excess was determined by Chiral HPLC.
Absolute configuration was determined with epoxide crystallographic spectra.
Retention time.
c 0.25, DMSO.
c 0.25, DCM.
c 0.25, MeOH.
compounds. In this article we proposed an enantiopure, synthetic,
and straightforward route to prepare 4-aminoquinolines deriva-
tives through enantiopure 4-oxirane 2 synthesis. The preparation
of 2 was carried out from 4-vinylquinoline 3 in two steps via a
Sharpless asymmetric dihydroxylation with retention of configura-
tion. The key-intermediate 2 has been easily diversified, on posi-
tion 4, through a regioselective SN2 ring opening mechanism
with various amines, to provide the corresponding enantiopure
4-aminoquinolines 1a (R) or 1b (S) with good yield (35–96%) and
ees generally superior to 92%. The antimalarial activity of these
compounds will be tested in vitro and in vivo.
were recorded using Bruker 600 MHz NMR instrument (1H NMR
at 600 MHz and 13C NMR at 150 MHz) and Bruker 300 MHz NMR
instrument (1H NMR at 300 MHz and 13C NMR at 75 MHz). Chem-
ical shifts are expressed in parts per million (d, ppm) downfield
from tetramethylsilane and are referenced to the deuterated sol-
vent. 1H NMR and 13C NMR data were reported in the order of
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, qt = quintuplet, m = multiplet), integration, coupling
constants in Hertz (Hz). High Performance Liquid Chromatography
(HPLC) was carried out on a Schimadzu LC-20AD equipped with a
Chiralpak IB column. Specific rotations were measured on a Jasco
P1010 polarimeter. High-resolution mass spectra were obtained
from a Micromass-Waters Q–TOF Ultima spectrometer. Infrared
spectra were recorded with a Jasco FTIR-4200 and are reported
using the frequency of absorption (cmꢀ1). Gas Chromatography–
Mass Spectrometry (GCMS) was carried out on a Schimadzu
GCMS-QP2010S equipped with a SLB-5 ms.
4. Experimental
4.1. General methods
All starting materials and reagents were obtained from com-
mercial suppliers and were used without further purification.
Reactions requiring anhydrous conditions were performed under
a blanket of argon. All solvents were purified via literature proce-
dures or used without further purification. Flash column chroma-
4.1.1. 4-Bromo-2,8-bis(trifluoromethyl)quinoline 6a
Phosphorous oxybromide (4 g, 14.2 mmol), under an argon
atmosphere, was heated to 90 °C until complete dissolution of
the solid. Compound 5 (4.08 g, 14.2 mmol) was added to this hot
solution and the bath temperature was increased to 150 °C. After
6 h, the resulting mixture was allowed to cool to room tempera-
ture. The reaction mixture was quenched by addition of ice-cold
water and the precipitate formed was filtered and washed with
tography was carried out on Kielselgel 60 (40–63 lm) ASTM
(Merck). Routine monitoring of reactions was performed using
Merck Silica Gel 60 F254 plates, thin layer chromatography (TLC)
and visualized under UV light (254 nm), with ethanolic phospho-
molybdic acid (PMA). Nuclear magnetic resonance (NMR) spectra

A. Jonet et al. / Tetrahedron: Asymmetry 22 (2011) 138–148
145
water to afford the expected compound 6a (4.70 g, 96%) as a white
solid. Rf 0.79 (cyclohexane/Et2O 5:1); mp: 60 °C; 1H NMR
(300 MHz, CDCl3) d 7.82 (t, J = 7.9 Hz, 1H), 8.11 (s, 1H), 8.22 (d,
J = 7.3 Hz, 1H), 8.46 (d, J = 8.6 Hz, 1H), NMR data were in agreement
with the lit.;13 13C NMR (125 MHz, CDCl3) d 120.9 (q, J = 276.0 Hz),
122.0 (q, J = 2.0 Hz), 123.6 (q, J = 273.8 Hz), 128.9, 129.4, 129.8 (q,
J = 30.8 Hz), 130.5 (q, J = 5.3 Hz), 131.5, 138.5, 144.5, 148.6 (q,
The reaction mixture was stirred at reflux for 24 h. The reaction
was allowed to cool to room temperature, transferred to a separat-
ing funnel, and then was washed with water (20 mL) and toluene
(2 ꢃ 20 mL), the washings being added to the separating funnel.
The organic layer was separated, washed with an aqueous 1 M
NaOH solution, then with a brine solution, dried over Na2SO4,
and evaporated to dryness. The residue was purified by column
chromatography (cyclohexane/ether 5:1) to afford 3 (82%) as a
white solid.
Method C: To a suspension of potassium vinyltrifluoroborate
(1.16 mmol), cesium carbonate (3.5 mmol), PdCl2(dppf)ꢁCH2Cl2
(0.116 mmol), and 6a (1.16 mmol) in THF (15 mL) was added water
(1.5 mL), under a nitrogen atmosphere. The reaction mixture was
stirred at reflux for 24 h. The reaction was allowed to cool to room
temperature, diluted with water (25 mL), and was extracted with
diethyl ether (3 ꢃ 25 mL). The combined organic extracts were
washed with brine and then dried over Na2SO4, filtered and con-
centrated in vacuo. The residue was purified by column chroma-
tography (cyclohexane/ether 5:1) to afford 3 (71%) as a white solid.
J = 36.1 Hz); IR
mmax = 1577, 1422, 1302, 1136, 1098, 1010, 876,
824 cmꢀ1
; GCMS (m/z): 343; HRMS calcd for C11H4BrF6NNa
(M+Na)+ 365.9329, found 365.9346.
4.1.2. 2,8-Bis(trifluoromethyl)quinolin-4-yl trifluoromethane-
sulfonate 6b
To a solution of 5 (1.5 g, 5.34 mmol) in toluene/aqueous solution
of LiOH (5%, w/v) (22 mL; 1:1, v/v) was added dropwise triflic anhy-
dride (1.1 mL, 6.41 mmol), at 0 °C. The resulting mixture was al-
lowed to warm to room temperature and was stirred for 3 h. The
reaction mixture was washed with water and the organic phase
was dried over anhydrous sodium sulfate, and was concentrated un-
der reduced pressure to afford 6b (1.12 g, 50%) as a colorless oil. 1H
NMR (300 MHz, CDCl3) d 7.86 (s, 1H), 7.95 (t, J = 8.0 Hz, 1H), 8.34
(d, J = 7.8 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
4.1.5. (R)-1-[2,8-Bis(trifluoromethyl)quinolin-4yl]ethane-1,2-
diol 4a
d
109.4 (q, J = 1.7 Hz), 118.9 (q, J = 320.5 Hz), 120.4 (q,
To a solution of AD-mix-b (4.8 g) and K2OsO2(OH)4 (12.7 mg,
1 mol %) in t-BuOH/H2O (34.4 mL; 1:1 v/v) was added 3 (1 g,
3.44 mmol) at 0 °C and stirred overnight. The reaction was
quenched at 0 °C by addition of Na2SO3 (5.16 g), then was warmed
to room temperature and stirred for 30 min. The reaction mixture
was extracted with EtOAc, dried with anhydrous Na2SO4, and evap-
orated under reduced pressure. The residue was precipitated in
cyclohexane, filtered on Buchner to afford 4a (945 mg, 84%, GCMS:
100%, and 98% ee) as a white solid. HPLC analysis (Chiralpak IB col-
umn, heptane/i-PrOH, 95:5; flow 1.0 mL/min, tR(R) = 26.8 min,
J = 275.5 Hz), 122.0 (q, J = 273.6 Hz), 125.1, 129.1(q, J = 27.3 Hz),
129.4, 130.8 (q, J = 5.0 Hz), 145.6, 149.4 (q, J = 36.8 Hz), 154.0.
4.1.3. 2,8-Bis(trifluoromethyl)quinolin-4-yl 4-methylben-
zenesulfonate 6c
To a solution of 5 (500 mg, 1.78 mmol) in acetone (4 mL) was
added an aqueous solution of NaOH 2 M until pH 11, and p-tolu-
enesulfonyl chloride (680 mg, 3.56 mmol) at 0 °C. The reaction
mixture was stirred overnight. After allowing warming to room
temperature, the solvent was reduced under pressure. The result-
ing residue was washed with water and filtered to afford com-
pound 6c (746 mg, 96%) as a white solid. Mp: 107 °C; 1H NMR
(300 MHz, CDCl3) d 7.86 (s, 1H), 7.95 (t, J = 7.9 Hz, 1H), 8.34 (d,
J = 7.8 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 21.7, 109.4, 120.6 (q, J = 275.6 Hz), 123.2 (q, J = 273.8 Hz),
123.6, 126.1, 127.9, 130.0 (q, J = 5.2 Hz), 130.4, 131.4 (q,
J = 3.9 Hz), 145.3, 147.0, 149.1 (q, J = 36.0 Hz), 154.6; HRMS calcd
for C18H11F6NO3SNa (M+Na)+ 458.0262, found 458.0270.
tR(S) = 32.9 min); ½a D20
ꢂ
¼ ꢀ52 (c 0.25, DCM); mp: 130–135 °C; 1H
NMR (300 MHz, CDCl3) d 3.77 (dd, J = 11.6, 4.2 Hz, 1H), 3.89 (dd,
J = 11.6, 5.2 Hz, 1H), 5.62 (dd, J = 5.9, 4.4 Hz, 1H), 7.83 (t,
J = 7.9 Hz, 1H), 8.15 (s, 1H), 8.23 (d, J = 7.2 Hz, 1H), 8.54 (d,
J = 8.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 67.9, 71.7, 116.3 (q,
J = 2.1 Hz), 122.9 (q, J = 274.8 Hz), 125.1 (q, J = 272.8 Hz), 128.4,
129.3, 130.0 (q, J = 5.6 Hz), 130.1 (q, J = 29.7 Hz), 144.8, 149.2 (q,
J = 34.9 Hz), 153.4; IR mmax = 3266, 2937, 1605, 1587, 1308, 1128,
1102, 838 cmꢀ1; GCMS (m/z): 325; HRMS calcd for C13H9F6NO2Na
(M+Na)+ 348.0435, found 348.0420.
4.1.4. 2,8-Bis(trifluoromethyl)-4-vinylquinoline 3
Method A: To a solution of 6a (100 mg, 0.29 mmol), TBAB
(93 mg, 0.29 mmol), K2CO3 (80 mg, 0.58 mmol), and Pd(PPh3)2Cl2
4.1.6. (S)-1-[2,8-Bis(trifluoromethyl)quinolin-4yl]ethane-1,2-
diol 4b
(20 mg, 10 mol %) in dry MeCN (580
l
L), was added tributylvinyl-
According to the same procedure for 4a, the product 4b was pre-
pared starting from 3 (640 mg) to obtain 4b (558 mg, 78%, 97% ee) as
a white solid. HPLC analysis (Chiralpak IB column, heptane/i-PrOH,
95:5; flow 1.0 mL/min, tR(R) = 26.8 min, tR(S) = 31.8 min); mp:
tin (102 L, 0.35 mmol), under an argon atmosphere. The tube
l
was sealed and the mixture was stirred at 90 °C. After 4 h, the reac-
tion was allowed to cool to room temperature then was filtered
through a pad of Celite and washed with MeCN. The filtrate was
evaporated under reduced pressure and the residue was purified
by column chromatography (cyclohexane/Et2O 5:1) to afford 3
(64 mg, 75%) as a white solid. Rf 0.34 (cyclohexane/Et2O 5:1);
mp: 76 °C; 1H NMR (300 MHz, CDCl3) d 5.83 (dd, J = 11.1, 0.7 Hz,
1H), 6.09 (dd, J = 17.3, 0.7 Hz, 1H), 7.43 (dd, J = 17.3, 11.1 Hz, 1H),
7.72 (t, J = 7.9 Hz, 1H), 7.86 (s, 1H), 8.15 (d, J = 6.9 Hz, 1H), 8.33
130–135 °C; ½a 2D0
ꢂ
¼ þ62 (c 0.25, DCM); 1H NMR (300 MHz, CDCl3)
d 3.77 (dd, J = 11.6, 4.2 Hz, 1H), 3.89 (dd, J = 11.6, 5.2 Hz, 1H), 5.62
(dd, J = 5.9, 4.4 Hz, 1H,), 7.83 (t, J = 7.9 Hz, 1H), 8.15 (s, 1H), 8.23 (d,
J = 7.2 Hz, 1H), 8.54 (d, J = 8.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) d
67.9, 71.7, 116.3 (q, J = 2.1 Hz), 122.9 (q, J = 274.8 Hz), 125.1 (q,
J = 272.8 Hz), 128.4, 129.3, 130.0 (q, 1H, J = 5.6 Hz), 130.1 (q,
J = 29.7 Hz), 144.8, 149.2 (q, J = 34.9 Hz), 153.4; IR
mmax = 3266,
(d, J = 8.6 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
114.1 (q,
2937, 1605, 1587, 1308, 1128, 1102, 838 cmꢀ1; GCMS (m/z): 325;
J = 2.1 Hz), 121.3 (q, J = 275.5 Hz), 123.2, 123.6 (q, J = 273.6 Hz),
127.0, 127.9, 127.8, 129.0 (q, J = 5.5 Hz), 129.2 (q, J = 30.5 Hz),
131.0, 144.0, 146.2, 148.4 (q, J = 35.6 Hz), NMR data were in agree-
HRMS calcd for C13H9F6NO2Na (M+Na)+ 348.0435, found 348.0440.
4.1.7. (R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-
butyldimethylsilyl)oxy)ethanol 7
ment with the lit.;12 IR
mmax = 1590, 1426, 1303, 1134, 1108, 888,
833 cmꢀ1
;
GCMS (m/z): 291; HRMS calcd for C13H7F6NNa
To a solution of 4a (140 mg, 0.43 mmol) in dry DMF (5 mL), un-
der an argon atmosphere, were added TDBMSCl (64.8 mg,
0.43 mmol) and imidazole (29.2 mg, 0.43 mmol). The mixture
was stirred at room temperature for 24 h. The solution was
concentrated under reduced pressure, and then the residue was
(M+Na)+ 314.0380, found 314.0390.
Method B: To a solution of 6a (1.16 mmol) in toluene/aqueous
solution of KOH (4 M) (9 mL; 8:1, v/v) was added dibutyl vinylbor-
onate (1.28 mmol) and Pd(PPh3)4 (0.035 mmol), under nitrogen.

146
A. Jonet et al. / Tetrahedron: Asymmetry 22 (2011) 138–148
dissolved in EtOAc and was washed with water, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by col-
umn chromatography (DCM/MeOH 99:1) to afford 7 (74 mg, 39%,
99% ee) as a colorless oil. HPLC analysis (Chiralpak IB column,
heptanes/i-PrOH 99:1; flow 1 mL/min, tR(R) = 13.9 min, tR(S) =
MeOH. The residue was redissolved in dry DCM (8.8 mL), under ar-
gon, and was cooled to 0 °C. Trimethylsilyl chloride (234 L,
l
1.85 mmol) was added dropwise. The reaction was warmed to room
temperature and stirred overnight. The volatiles were removed in
vacuo, and the residue was redissolved in MeOH (8.8 mL). Then
K2CO3 (254.8 mg, 1.85 mmol) was added, and the mixture was stir-
red for 5 h. The reaction was poured onto saturated aqueous solution
of NH4Cl, extracted with DCM. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The crude was purified by column chromatography (cyclohex-
ane/Et2O 1:1), to afford 2a (513 mg, 68%, 92% ee) as a yellow solid.
HPLC analysis (Chiralpak IB column, heptane/i-PrOH, 99:1; flow
16.6 min);
½
a 2D1
ꢂ
¼ ꢀ41:1 (c 0.25, DCM); Rf 0.88 (DCM/MeOH
99:1); 1H NMR (300 MHz, CDCl3) d 0.03 (s, 3H), 0.06 (s, 3H), 0.90
(s, 9H), 3.67 (dd, J = 10.3, 7.4 Hz, 1H), 4.03 (dd, J = 10.3, 3.7 Hz,
1H), 5.57 (dd, J = 7.2, 3.4 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 8.10 (s,
1H), 8.15 (d, J = 7.2 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3) 18.2, 25.8, 67.5, 70.3, 115.2 (q, J = 2.05 Hz),
121.3 (q, J = 275.1 Hz), 123.5 (q, J = 273.6 Hz), 126.8, 127.0, 127.2,
128.7 (q, J = 5.5 Hz), 129.2 (q, J = 32.7 Hz), 143.6, 148.5 (q,
1.0 mL/min, tR(S) = 15.1 min, tR(R) = 17.4 min); ½a D20
¼ ꢀ52 (c 0.25,
ꢂ
J = 36.8 Hz), 149.2; IR
m
max = 2956, 2932, 2861, 1604, 1586, 1431,
DCM); Rf 0.36 (cyclohexane/Et2O 1:1); mp: 84 °C; 1H NMR
(300 MHz, CDCl3) d 2.83 (dd, J = 5.7, 2.5 Hz, 1H), 3.42 (dd, J = 5.7,
4.2 Hz, 1H), 4.55 (dd, J = 3.6, 2.7 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H),
7.81 (s, 1H), 8.20 (d, J = 7.2 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H); 13C
NMR (150 MHz, CDCl3): 49.2, 50.8, 113.3 (q, J = 2.0 Hz), 121.1 (q,
J = 275.5 Hz), 123.4 (q, J = 273.6 Hz), 127.0, 127.4, 127.6, 129.1 (q,
J = 5.5 Hz), 129.4 (q, J = 30.5 Hz), 143.3, 146.8, 148.7 (q,
J = 35.5 Hz), 149.5, NMR data were in agreement with the lit.;12 IR
1308, 1144, 1108, 837, 807 cmꢀ1; HRMS calcd for C19H23F6NO2SiNa
(M+Na)+ 462.1300, found 462.1320.
4.1.8. (R)-(R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-
butyldimethylsilyl)oxy)ethyl-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate 8a
To a solution of 7 (43 mg, 0.098 mmol) in dry DCM (1 mL), un-
der an argon atmosphere, were added at 0 °C (R)(+)-MTPA (27 mg,
0.12 mmol), EDCI (37.5 mg, 0.2 mmol), and DMAP (3.6 mg,
0.029 mmol). The mixture was stirred at room temperature for
24 h. The solution was concentrated under reduced pressure. The
residue was purified by column chromatography (DCM/MeOH
99:1) to afford 8a (38 mg, 58%, 95% ee) as a yellow oil. The ee
m
max = 1606, 1587, 1431, 1308, 1276, 1213, 1102, 1069, 895, 982,
822 cmꢀ1; GCMS: 307; HRMS calcd for C13H7F6NONa (M+Na)+,
330.0330, found 330.0314.
4.1.11. (S)-4-(Oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline 2b
According to the same procedure that 2a, the product 2b was
prepared starting from 4b (800 mg) to obtain 2b (437 mg, 57%,
96% ee) as a yellow solid. HPLC analysis (Chiralpak IB column, hep-
tane/i-PrOH, 99:1; flow 1.0 mL/min, tR(S) = 14.9 min, tR(R) = 17.4
was determined by 1H NMR. ½a D24
¼ ꢀ19:2 (c 0.25, DCM); Rf 0.82
ꢂ
(DCM/MeOH 99:1); 1H NMR (600 MHz, CDCl3) d ꢀ0.044 (s, 3H),
ꢀ0.041 (s, 3H), 0.81 (s, 9H), 3.65 (d, J = 0.68 Hz, 3H), 3.99 (dd,
J = 11.4, 4.0 Hz, 1H), 4.05 (dd, J = 11.4, 6.8 Hz, 1H), 6.77 (dd,
J = 6.8, 4.0 Hz, 1H), 7.49–7.36 (m, 5H), 7.57 (s, 1H), 7.77 (t,
J = 7.9 Hz, 1H), 8.21 (d, J = 7.2 Hz), 8.32 (d, J = 8.4 Hz, 1H); 13C
NMR (150 MHz, CDCl3) d ꢀ5.6 (2C), 18.1, 25.6, 55.8, 65.1, 74.3,
115.4 (q, J = 1.8 Hz), 120.9 (q, J = 275.6 Hz), 123.2 (q, J = 288.7 Hz),
123.4 (q, J = 273.7 Hz), 126.4, 126.9 (3C), 127.7, 128.6, 129.1 (q,
J = 5.1 Hz), 129.7 (q, J = 30.4 Hz), 130.1, 131.7, 143.8, 145.0, 148.2
min); ½a 2D0
¼ þ45 (c 0.25, DCM); Rf 0.36 (cyclohexane/Et2O 1:1);
ꢂ
mp: 84 °C; 1H NMR (300 MHz, CDCl3) d 2.83 (dd, J = 5.7, 2.5 Hz,
1H), 3.42 (dd, J = 5.7, 4.2 Hz, 1H), 4.55 (dd, J = 3.6, 2.7 Hz, 1H),
7.79 (m, 2H), 8.20 (d, J = 7.2 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H); 13C
NMR (150 MHz, CDCl3): 49.2, 50.8, 113.3 (q, J = 2.0 Hz), 121.1 (q,
J = 275.5 Hz), 123.4 (q, J = 273.6 Hz), 127.0, 127.4, 127.6, 129.1 (q,
J = 5.5 Hz), 129.4 (q, J = 30.5 Hz), 143.3, 146.8, 148.7 (q,
J = 35.5 Hz), 149.5, NMR data were in agreement with the lit.;12
(q, J = 35.5 Hz), 165.9; IR
mmax = 2955, 2930, 2857, 1755, 1605,
1312, 1147, 1112, 1018, 837 cmꢀ1; HRMS calcd for C29H30F9NO4Si-
Na (M+Na)+ 678.1698, found 678.1688.
IR mmax = 1606, 1587, 1431, 1308, 1276, 1213, 1102, 1069, 895,
982, 822 cmꢀ1
; GCMS: 307; HRMS calcd for C13H7F6NONa
(M+Na)+, 330.0330, found 330.0314.
4.1.9. (S)-(R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-
butyldimethylsilyl)oxy)ethyl-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate 8b
4.2. General method for preparation of amino-alcohol 1
According to the same procedure for 8a, the product 8b was
prepared starting from 7 (41 mg) to obtain 8b (30 mg, 49%, 98%
To a solution of 2a or 2b (50 mg, 0.16 mmol) in i-PrOH (3.2 mL)
was added the appropriate amine (0.81 mmol). The mixture was
stirred for 24 h at 90 °C. The volatiles were removed in vacuo.
The crude was then purified by column chromatography.
ee) as
a
yellow oil. The ee was determined by 1H NMR.
½
a 2D4
ꢂ
¼ ꢀ36:7 (c 0.25, DCM); Rf 0.82 (DCM/MeOH 99:1); 1H NMR
(600 MHz, CDCl3) d ꢀ0.12 (s, 3H), ꢀ0.11(s, 3H), 0.74 (s, 9H), 3.49
(d, J = 1.2 Hz, 3H), 3.98 (dd, J = 11.2, 4.6 Hz, 1H), 4.02 (dd, J = 11.1,
5.9 Hz, 1H), 6.80 (t, J = 5.19 Hz, 1H), 7.57–7.32 (m, 5H), 7.81–7.78
(m, 2H), 8.22 (d, J = 7.2 Hz, 1H), 8.37 (d, J = 8.5 Hz, 1H); 13C NMR
(150 MHz, CDCl3) d ꢀ5.9, ꢀ5.8, 18.0, 25.5, 55.3, 65.0, 73.9, 115.8
(q, J = 1.9 Hz), 121.0 (q, J = 275.6 Hz), 123.3 (q, J = 289.0 Hz), 123.4
(q, J = 273.8 Hz), 126.5, 127.2, 127.4, 127.7, 128.6, 129.2 (q,
J = 5.6 Hz), 129.7 (q, J = 30.7 Hz), 129.9, 131.4, 143.8, 145.4, 148.1
4.2.1. (R)-2-(Benzylamino)-1-(2,8-bis(trifluoromethyl)
quinolin-4-yl)ethanol 1a
The crude was purified by column chromatography (EtOAc/
MeOH/NH4OH 90:5:5), to afford 1a (44 mg, 66%, 95% ee) as a white
solid. HPLC analysis (Chiralpak IB column, heptane/EtOH, 90:10;
flow 0.5 mL/min, tR(R) = 16.8 min, tR(S) = 18.9 min); ½a D27
¼ ꢀ34:5
ꢂ
(c 0.25, DMSO); Rf 0.78 (EtOAc/MeOH/NH4OH 80:10:10); mp:
163 °C; 1H NMR (300 MHz, CDCl3) d 2.78 (dd, J = 12.4, 6.9 Hz, 1H),
2.88 (dd, J = 12.5, 3.9 Hz, 1H), 3.72, (s, 2H), 5.61 (m, 1H), 7.20 (m,
5H), 7.85 (t, J = 8.0 Hz, 1H), 8.12 (s, 1H), 8.32 (d, J = 7.3 Hz, 1H),
8.55 (d, J = 8.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) d 52.3, 55.4,
68.1, 114.7, 121.5 (q, J = 275.4 Hz), 123.3 (q, J = 273.1 Hz), 126.4,
126.7, 126.9 (q, J = 28.5 Hz), 127.4, 127.7, 127.9, 129.1, 129.4 (q,
(q, J = 35.5 Hz), 165.9; IR
mmax = 2955, 2930, 2857, 1755, 1605,
1312, 1147, 1112, 1018, 837 cmꢀ1; HRMS calcd for C29H30F9NO4Si-
Na (M+Na)+ 678.1698, found 678.1688.
4.1.10. (R)-4-(Oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline 2a
To a solution of 4a (800 mg, 0.62 mmol) in dry DCM (8.8 mL), un-
der an argon atmosphere, were added trimethylorthoacetate
J = 5.5 Hz), 140.5, 142.5, 146.6 (q, J = 34.1 Hz), 155.0; IR mmax = 1603,
(236 lL, 1.85 mmol) and PTSA (5.3 mg, 0.031 mmol). The mixture
was stirred for 4 h at room temperature. The volatiles were removed
in vacuo, and the flask pumped on high vacuum to remove excess
1587, 1430, 1310, 1300, 1127, 1106, 903, 881, 835 cmꢀ1; HRMS calcd
for C20H17F6N2O (M+H)+ 415.1245, found 415.1265.

A. Jonet et al. / Tetrahedron: Asymmetry 22 (2011) 138–148
147
4.2.2. (S)-2-(Benzylamino)-1-(2,8-bis(trifluoromethyl)
quinolin-4-yl)ethanol 1f
2357, 1604, 1586, 1432, 1303, 1119, 1104, 889, 835 cmꢀ1; HRMS
calcd for C18H21F6N2O (M+H)+ 395.1558, found 395.1544.
The crude was purified by column chromatography (EtOAc/
MeOH/NH4OH 90:5:5), to afford 1f (59 mg, 89%, 98% ee) as a white
solid. HPLC analysis (Chiralpak IB column, heptane/EtOH, 90:10;
4.2.6. (S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-
(pentylamino)ethanol 1h
flow 0.5 mL/min, tR(R) = 16.8 min, tR(S) = 18.9 min); ½a D27
ꢂ
¼ þ46:3
The crude was purified by column chromatography (DCM/MeOH
90:10), to afford 1h (56 mg, 93%, 99% ee) as a white solid. HPLC anal-
ysis (Chiralpak IB column, heptane/i-PrOH/EDA, 99:1:0.1; flow
(c 0.25, DMSO); Rf 0.78 (EtOAc/MeOH/NH4OH 80:10:10); mp:
163 °C; 1H NMR (300 MHz, CDCl3) d 2.78 (dd, J = 12.4, 6.9 Hz, 1H),
2.88 (dd, J = 12.5, 3.9 Hz, 1H), 3.72, (s, 2H), 5.61 (m, 1H), 7.20 (m,
5H), 7.85 (t, J = 8.0 Hz, 1H), 8.12 (s, 1H), 8.32 (d, J = 7.3 Hz, 1H),
8.55 (d, J = 8.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) d 52.3, 55.4,
68.1, 114.7, 121.5 (q, J = 275.4 Hz), 123.3 (q, J = 273.1 Hz), 126.4,
126.7, 126.9 (q, J = 28.5 Hz), 127.4, 127.7, 127.9, 129.1, 129.4 (q,
1 mL/min, tR(R) = 22.2 min, tR(S) = 25.3 min); ½a D26
¼ þ49:8 (c 0.25,
ꢂ
MeOH); Rf 0.53 (DCM/MeOH 90:10); mp: 120 °C; 1H NMR
(300 MHz, MeOD) d 0.92 (t, J = 6.5 Hz, 3H), 1.36–1.21(m, 4H),
1.65–1.47 (m, 2H), 2.72–2.64 (m, 2H), 2.83 (dd, J = 12.30, 9.32 Hz,
1H), 2.99 (dd, J = 12.63, 2.20 Hz, 1H), 5.68 (dd, J = 9.0, 2.0 Hz, 1H),
7.87 (t, J = 7.9 Hz, 1 Hz), 8.15 (s, 1H), 8.26 (d, J = 7.0 Hz, 1H), 8.53
(d, J = 8.6 Hz, 1H); 13C NMR (150 MHz, MeOD) d 14.4, 23.6, 30.2,
30.6, 50.5, 57.2, 69.4, 115.7 (q, J = 1.96 Hz), 122.9 (q, J = 274.6 Hz),
125.1 (q, J = 272.6 Hz),128.0, 128.8, 129.1, 130.3 (q, J = 60.1 Hz),
130.3 (q, J = 5.7 Hz), 144.9, 149.4 (q, J = 34.8 Hz), 154.7; IR
J = 5.5 Hz), 140.5, 142.5, 146.6 (q, J = 34.1 Hz), 155.0; IR mmax = 1603,
1587, 1430, 1310, 1300, 1127, 1106, 903, 881, 835 cmꢀ1; HRMScalcd
for C20H17F6N2O (M+H)+ 415.1245, found 415.1265.
4.2.3. (R)-Ethyl-4-(4-(2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-
2-(hydroxyethyl)piperazin-1-yl)butanoate 1b
The crude was purified by column chromatography (DCM/MeOH
90:10), to afford 1b (29 mg, 35%, 89% ee) as a yellow oil. HPLC anal-
ysis (Chiralpak IB column, heptanes/i-PrOH/EDA 90:10:0.1; flow
m
max = 2934, 2841, 2357, 1604, 1586, 1432, 1303, 1119, 1104, 889,
835 cmꢀ1; HRMS calcd for C18H21F6N2O (M+H)+ 395.1558, found
395.1544.
1 mL/min, tR(R) = 9.0 min, tR(S) = 20.6 min); ½a D24
ꢂ
¼ ꢀ70:7 (c 0.25,
4.2.7. (R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-
(hexylamino)ethanol 1d
DCM); Rf 0.43 (DCM/MeOH 90:10); 1H NMR (300 MHz, CDCl3) d
1.26 (t, J = 7.1 Hz, 3H), 1.88–1.78 (m, 2H), 2.85–2.26 (m, 14H), 4.13
(q, J = 7.2 Hz, 2H), 5.54 (dd, J = 10.5, 3.2 Hz, 1H), 7.72 (t, J = 7.1 Hz,
1H), 8.12–8.14 (m, 2H); 13C NMR (150 MHz, CDCl3) d 14.2, 22.1,
32.2, 53.0, 57.5, 60.3, 64.5, 65.1, 114.5 (q, J = 1.8 Hz), 121.2 (q,
J = 275.6 Hz), 123.5 (q, J = 273.9), 126.6, 126.,7, 127.0, 128.7 (q,
J = 5.2 Hz), 129.6 (q, J = 29.8 Hz), 143.6, 148.7 (q, J = 34.9 Hz),
The crude was purified by column chromatography (DCM/MeOH,
90:10), to afford 1d (58 mg, 88%, 97% ee) as a white solide. HPLC
analysis (Chiralpak IB column, heptane/i-PrOH/EDA, 99:1:0.1; flow
1 mL/min, tR(R) = 18.5 min, tR(S) = 21.4 min); ½a D26
¼ ꢀ47:5 (c 0.25,
ꢂ
MeOH); Rf 0.58 (DCM/MeOH 90:10); mp: 108 °C; 1H NMR
(600 MHz, MeOD) d 0.91 (t, J = 6.9 Hz, 3H), 1.43–1.42 (m, 6H),
1.62–1.49 (m, 2H), 2.76–2.59 (m, 2H), 2.82 (dd, J = 12.6, 9.1 Hz,
1H), 2.99 (dd, J = 12.6, 2.9 Hz, 1H), 5.68 (dd, J = 9.0, 2.5 Hz, 1H),
7.88 (t, J = 7.2 Hz, 1H), 8.15 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.53 (d,
J = 8.6 Hz); 13C NMR (150 MHz, MeOD) d 14.4, 23.7, 28.1, 30.5,
32.9, 50.5, 57.3, 69.4, 115.7 (q, J = 2.3 Hz), 122.9 (q, J = 274.4 Hz),
125.2 (q, J = 272.8 Hz), 128.0, 128.8, 129.1, 130.3 (q, J = 5.4 Hz),
130.3 (q, J = 30.3 Hz), 144.9, 149.4 (q, J = 35.8 Hz), 154.8; IR
151.1, 173.5; IR mmax = 2941, 2818, 1731, 1604, 1585, 1430, 1308,
1140, 1108, 907 cmꢀ1; HRMS calcd for C23H28F6N3O3 (M+H)+
508.2035, found 508.2056.
4.2.4. (S)-Ethyl-4-(4-(2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-
2-(hydroxyethyl)piperazin-1-yl)butanoate 1g
The crude was purified by column chromatography (DCM/MeOH
90:10), to afford 1g (31 mg, 38%, 97% ee) as a yellow oil. HPLC anal-
ysis (Chiralpak IB column, heptanes/ i-PrOH/EDA 90:10:0.1; flow
m
max = 2928, 2858, 1603, 1586, 1432, 1304, 1119, 1103, 886,
837 cmꢀ1; HRMS calcd for C19H22F6N2O (M+H)+ 409.1726, found
409.1732.
1 mL/min, tR(R) = 9.1 min, tR(S) = 20.1 min); ½a D23
¼ þ78:2 (c 0.25,
ꢂ
DCM); Rf 0.43 (DCM/MeOH 90:10); 1H NMR (300 MHz, CDCl3) d
1.26 (t, J = 7.1 Hz, 3H), 1.88–1.78 (m, 2H), 2.85–2.26 (m, 14H), 4.13
(q, J = 7.2 Hz, 2H), 5.54 (dd, J = 10.5, 3.2 Hz, 1H), 7.72 (t, J = 7.1 Hz,
1H), 8.12–8.14 (m, 2H); 13C NMR (150 MHz, CDCl3) d 14.2, 22.1,
32.2, 53.0, 57.5, 60.3, 64.5, 65.1, 114.5 (q, J = 1.8 Hz), 121.2 (q,
J = 275.6 Hz), 123.5 (q, J = 273.9), 126.6, 126.,7, 127.0, 128.7 (q,
J = 5.2 Hz), 129.6 (q, J = 29.8 Hz), 143.6, 148.7 (q, J = 34.9 Hz),
4.2.8. (S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(hexyla-
mino)ethanol 1i
The crude was purified by column chromatography (DCM/MeOH,
90:10), to afford 1f (56 mg, 85%, 97% ee) as a white solide. HPLC anal-
ysis (Chiralpak IB column, heptane/i-PrOH/EDA, 99:1:0.1; flow 1 mL/
min, tR(R) = 19.1 min, tR(S) = 21.4 min);
½
a 2D7
ꢂ
¼ þ54:0 (c 0.25,
151.1, 173.5; IR
m
max = 2941, 2818, 1731, 1604, 1585, 1430, 1308,
MeOH); Rf 0.58 (DCM/MeOH 90:10); mp: 108 °C; 1H NMR
(600 MHz, MeOD) d 0.91 (t, J = 6.9 Hz, 3H), 1.43–1.42 (m, 6H),
1.62–1.49 (m, 2H), 2.76–2.59 (m, 2H), 2.82 (dd, J = 12.6, 9.1 Hz, 1H),
2.99 (dd, J = 12.6, 2.9 Hz, 1H), 5.68 (dd, J = 9.0, 2.5 Hz, 1H), 7.88 (t,
J = 7.2 Hz, 1H), 8.15 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.53 (d,
J = 8.6 Hz); 13C NMR (150 MHz, MeOD) d 14.4, 23.7, 28.1, 30.5, 32.9,
50.5, 57.3, 69.4, 115.7 (q, J = 2.3 Hz), 122.9 (q, J = 274.4 Hz), 125.2
(q, J = 272.8 Hz), 128.0, 128.8, 129.1, 130.3 (q, J = 5.4 Hz), 130.3 (q,
1140, 1108, 907 cmꢀ1; HRMS calcd for C23H28F6N3O3 (M+H)+
508.2035, found 508.2056.
4.2.5. (R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(pentyla-
mino)ethanol 1c
The crude was purified by column chromatography (DCM/MeOH
90:10), to afford 1c (56 mg, 88%, 94% ee) as a white solid. HPLC anal-
ysis (Chiralpak IB column, heptane/i-PrOH/EDA, 99:1:0.1; flow 1 mL/
J = 30.3 Hz), 144.9, 149.4 (q, J = 35.8 Hz), 154.8; IR
mmax = 2928,
min, tR(R) = 21.5 min, tR(S) = 25.3 min);
½
a 2D6
ꢂ
¼ ꢀ50:3 (c 0.25,
2858, 1603, 1586, 1432, 1304, 1119, 1103, 886, 837 cmꢀ1; HRMS
calcd for C19H22F6N2O (M+H)+ 409.1726, found 409.1732.
MeOH); Rf 0.53 (DCM/MeOH 90:10); mp: 120 °C; 1H NMR
(300 MHz, MeOD) d 0.92 (t, J = 6.5 Hz, 3H), 1.36–1.21(m, 4H), 1.65–
1.47 (m, 2H), 2.72–2.64 (m, 2H), 2.83 (dd, J = 12.30, 9.32 Hz, 1H),
2.99 (dd, J = 12.63, 2.20 Hz, 1H), 5.68 (dd, J = 9.0, 2.0 Hz, 1H), 7.87
(t, J = 7.9 Hz, 1 Hz), 8.15 (s, 1H), 8.26 (d, J = 7.0 Hz, 1H), 8.53 (d,
J = 8.6 Hz, 1H); 13C NMR (150 MHz, MeOD) d 14.4, 23.6, 30.2, 30.6,
50.5, 57.2, 69.4, 115.7 (q, J = 1.96 Hz), 122.9 (q, J = 274.6 Hz), 125.1
(q, J = 272.6 Hz), 128.0, 128.8, 129.1, 130.3 (q, J = 60.1 Hz), 130.3 (q,
4.2.9. (R)-tert-Butyl-(3-(4-(3((2-(2,8-bis(trifluoromethyl)
quinolin-4-yl)-2-(hydroxyethyl)amino)propyl)piperazin-1-
yl)propyl)carbamate 1e
The crude was purified by column chromatography (EtOAc/
MeOH/NH4OH, 80:10:10), to afford 1e (88 mg, 90%, 93% ee) as a col-
orless oil. HPLC analysis (Chiralpak IB column, MtBE/EDA 100:0.3;
J = 5.7 Hz), 144.9, 149.4 (q, J = 34.8 Hz), 154.7; IR
mmax = 2934, 2841,
flow 1 mL/min, tR(R) = 6.2 min, tR(S) = 7.2 min);
½
a 2D4
ꢂ
¼ ꢀ49:6

148
A. Jonet et al. / Tetrahedron: Asymmetry 22 (2011) 138–148
(c 0.25, DCM); Rf 0.29 (EtOAc/MeOH/NH4OH 80:10:10); 1H NMR
(300 MHz, MeOD) d 1.38 (s, 9H), 1.64–1.59 (m, 2H), 1.67 (dt,
J = 13.40, 6.76 Hz, 2H), 2.51–2.24 (m, 12H), 2.85–2.57 (m, 2H), 2.72
(dd, J = 12.41, 9.11 Hz, 1H), 3.05 (dd, J = 12.51, 2.77 Hz, 1H), 3.11
(m, 1H), 5.52 (dd, J = 8.4, 2.1 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 8.11–
8.09 (m, 2H), 8.23 (d, J = 8.5 Hz, 1H); 13C NMR (150 MHz, MeOD) d
26.2, 26.5, 28.3, 39.8, 48.0, 52.8, 53.2, 55.8, 56.5, 56.6, 67.7, 78.8,
114.5 (q, J = 1.6 Hz), 121.2 (q, J = 275.6 Hz), 123.4 (q, J = 273.8 Hz),
126.5, 126.9, 127.0, 128.6 (q, J = 5.6 Hz), 129.3 (q, J = 29.9 Hz),
10. Dow, G. S.; Heady, T. N.; Bhattarchargee, A. K.; Caridha, D.; Gerena, L.;
Gettayacamin, M.; Lanteri, C. A.; Obaldia, N., III; Roncal, N.; Shearer, T.; Smith,
P. L.; Tungtaeng, A.; Wolf, L.; Cabezas, M.; Yourick, D.; Smith, K. S. Antimicrob.
Agents Chemother. 2006, 50, 4132.
11. Milner, E.; McCalmont, W.; Bhonsle, J.; Caridha, D.; Cobar, J.; Gardner, S.;
Gerena, L.; Goodine, D.; Lanteri, C.; Melendez, V.; Roncal, N.; Sousa, J.; Wipf, P.;
Dow, G. S. Malar. J. 2010, 9, 51.
12. (a) Milner, E.; McCalmont, W.; Bhonsle, J.; Caridha, D.; Carroll, D.; Gardner, S.;
Gerena, L.; Gettayacamin, M.; Lanteri, C.; Luong, T.; Melendez, V.; Moon, J.;
Ronca, N.; Sousa, J.; Tungtaeng, A.; Wipf, P.; Dow, G. S. Bioorg. Med. Chem. Lett.
2010, 20, 1347; (b) Dow, G. S.; Koenig, M. L.; Wolf, L.; Gerena, L.; Lopez-
Sanchez, M.; Hudson, T. H.; Bhattacharjee, A. K. Antimicrob. Agents Chemother.
2006, 50, 4132.
13. (a) Jayaprakash, S.; Iso, Y.; Wan, B.; Franzblau, S. G.; Kozikowski, A. P. Chem.
Med. Chem. 2006, 1, 593; (b) Mao, J.; Wang, Y.; Wan, B.; Kozikowski, A. P.;
Franzblau, S. G. Chem. Med. Chem. 2007, 2, 1624; Mao, J.; Yuan, H.; Wang, Y.;
Wan, B.; Pak, D.; He, R.; Franzblau, S. G. Bioorg. Med. Chem. Lett. 2010, 20, 1263;
(c) Kunin, C. M.; Ellis, W. Y. Antimicrob. Agents Chemother. 2000, 44, 848; (d)
Vidal-Aroca, F.; Meng, A.; Minz, T.; Page, M. G. P.; Dreier, J. J. Microbiol. Methods
2009, 79, 232.
14. (a) Gillepsie, R. J.; Lerpiniere, J.; Giles, P. R.; Adams, D. R.; Stray Knutsen, L. J.;
Cliffe, I. A.; US 6,608,085 B1, 2003.; [b] Gillespie, R. J.; Adams, D. R.; Bebbington,
D.; Benwell, K.; Cliffe, I. A.; Dawson, C. E.; Dourish, C. T.; Fletcher, A.; Gaur, S.;
Giles, P. R.; Jordan, A. M.; Knight, A. R.; Knutsen, L. J. S.; Lawrence, A.;
Lerpiniere, J.; Misra, A.; Porter, R. H. P.; Pratt, R. M.; Shepherd, R.; Upton, R.;
Ward, S. E.; Weissa, S. M.; Williamson, D. S. Bioorg. Med. Chem. Lett. 2008, 18,
2916.
15. (a) Gnoatto, S. C. B.; Susplugas, S.; Vechia, L. D.; Ferreira, T. B.; Dassonville, A.;
Zimmer, K. R.; Demailly, C.; Da Nascimento, S.; Guillon, J.; Grellier, P.; Verli, H.;
Gosmann, G.; Sonnet, P. Bioorg. Med. Chem. 2008, 16, 771; [b] Mullié, C.; Jonet,
A.; Dassonville-Klimpt, A.; Gosmann, G.; Sonnet, P. Exp. Parasitol. 2010, 125, 202.
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17. Carroll, F. I.; Blackwell, J. T. J. Med. Chem. 1974, 17, 210.
143.5, 148.4 (q, J = 35.5 Hz), 152.0, 156.1; IR
mmax = 2940, 1433,
1307, 1132, 1104, 885, 838 cmꢀ1; HRMS calcd for C28H40F6N5O3
(M+H)+ 608.3035, found 608.3035.
4.2.10. (S)-tert-Butyl-(3-(4-(3((2-(2,8-bis(trifluoromethyl)
quinolin-4-yl)-2-(hydroxyethyl)amino)propyl)piperazin-1-yl)
propyl)carbamate 1j
The crude was purified by column chromatography (EtOAc/
MeOH/NH4OH, 80:10:10), to afford 1j (96 mg, 98%, 92% ee) as a col-
orless oil. HPLC analysis (Chiralpak IB column, MtBE/EDA 100:0.3;
flow 1 mL/min, tR(R) = 6.2 min, tR(S) = 7.2 min); ½a D24
¼ þ50:6 (c
ꢂ
0.25, DCM); Rf 0.29 (EtOAc/MeOH/NH4OH 80:10:10); 1H NMR
(300 MHz, MeOD) d 1.38 (s, 9H), 1.64–1.59 (m, 2H), 1.67 (dt,
J = 13.40, 6.76 Hz, 2H), 2.51–2.24 (m, 12H), 2.85–2.57 (m, 2H),
2.72 (dd, J = 12.41, 9.11 Hz, 1H), 3.05 (dd, J = 12.51, 2.77 Hz, 1H),
3.11 (m, 1H), 5.52 (dd, J = 8.4, 2.1 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H),
8.11–8.09 (m, 2H), 8.23 (d, J = 8.5 Hz, 1H); 13C NMR (150 MHz,
MeOD) d 26.2, 26.5, 28.3, 39.8, 48.0, 52.8, 53.2, 55.8, 56.5, 56.6,
67.7, 78.8, 114.5 (q, J = 1.6 Hz), 121.2 (q, J = 275.6 Hz), 123.4 (q,
J = 273.8 Hz), 126.5, 126.9, 127.0, 128.6 (q, J = 5.6 Hz), 129.3 (q,
J = 29.9 Hz), 143.5, 148.4 (q, J = 35.5 Hz), 152.0, 156.1; IR
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m
max = 2940, 1433, 1307, 1132, 1104, 885, 838 cmꢀ1; HRMS calcd
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Acknowledgments
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The authors are grateful to the CNRS, for the fellowship to A.
Jonet. We thank, J.F. Raimbert for his help and participation in
the purification of some intermediate compounds.
26. Prasad, J. S.; Vu, T.; Totleben, M. J.; Crispino, G. A.; Kacsur, D. J.; Swaminathan,
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31. Crystallographic data for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-780365. Copies of the data can be obtained free of charge
on application to CCDC, University Chemical Lab, 12 Union Road, Cambridge,
CB2 1EZ, UK (Fax: int. code +44 1223/336 033; E-mail: deposit@ccdc.
cam.ac.uk.
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