Asymmetric synthesis of new antimalarial aminoquinolines through Sharpless aminohydroxylation

Article abstract of DOI:10.1016/j.tetasy.2015.11.003

Recently, the asymmetric synthesis and biological activity of (R)- and (S)-4-aminoquinolinemethanols 1 as mefloquine analogues were reported. Several compounds showed very promising antimalarial activity, in the nanomolar range, against Plasmodium falciparum 3D7 and W2. Enantiomers with an (S)-absolute configuration were more active than their (R)-counterparts by a factor ranging from 2 to 15-fold, according to the compound and the plasmodial strain considered. In continuation of our work, three novel series of enantiopure aminoquinolines 2a, 2b, and 3 were synthesized via an asymmetric aminohydroxylation reaction. These compounds were obtained in 2 or 4 steps from a common amidoalcohol key-intermediate 4. They displayed IC₅₀ values close to the micromolar against the two P. falciparum strains 3D7 and W2. The study of the structure-activity relationships allows us to better understand the importance of the substitution and of the stereochemistry at C11 and C12 position of the quinoline and gives tracks for the design of new compounds more active against the plasmodial strains.

Full text of DOI:10.1016/j.tetasy.2015.11.003

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of new antimalarial aminoquinolines through
Sharpless aminohydroxylation
Guillaume Bentzinger , Wesley De Souza , Catherine Mullié , Patrice Agnamey a,c,
a
a,b
a
a
a,
⇑
Alexandra Dassonville-Klimpt , Pascal Sonnet
a
Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources, CNRS FRE 3517, UFR de Pharmacie, 1 rue des Louvels, Université de Picardie Jules Verne, F-80037
Amiens, France
Universidade Federal do Paraná, Departamento de Análises Clínicas, Avenida Prefeito Lothario Meissner, Jardim Botânico, 80210-170 Curitiba, PR, Brazil
b
c
Laboratoire de Parasitologie et Mycologie, Amiens University Hospital, Avenue Laënnec, 80054 Amiens, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Recently, the asymmetric synthesis and biological activity of (R)- and (S)-4-aminoquinolinemethanols 1
as mefloquine analogues were reported. Several compounds showed very promising antimalarial activity,
in the nanomolar range, against Plasmodium falciparum 3D7 and W2. Enantiomers with an (S)-absolute
configuration were more active than their (R)-counterparts by a factor ranging from 2 to 15-fold, accord-
ing to the compound and the plasmodial strain considered. In continuation of our work, three novel series
of enantiopure aminoquinolines 2a, 2b, and 3 were synthesized via an asymmetric aminohydroxylation
reaction. These compounds were obtained in 2 or 4 steps from a common amidoalcohol key-intermediate
Received 3 October 2015
Accepted 12 November 2015
Available online xxxx
4. They displayed IC50 values close to the micromolar against the two P. falciparum strains 3D7 and W2.
The study of the structure–activity relationships allows us to better understand the importance of the
substitution and of the stereochemistry at C11 and C12 position of the quinoline and gives tracks for
the design of new compounds more active against the plasmodial strains.
Ó 2015 Elsevier Ltd. All rights reserved.
1
. Introduction
Malaria is a neglected tropical disease that remains a leading
nomenon increased the urgency to discover and develop new
drugs against this disease.
3
Mefloquine (Fig. 1) was proposed, for a long time, as the drug of
choice for chloroquine-resistant malaria and artesunate–meflo-
quine combination was the most prescribed artemisinin-based
combination therapy in areas of highest parasite resistance. This
antimalarial drug possesses good pharmacokinetic properties such
as a longer half-life compared to other antimalarial drugs, which
permits weekly administration and facilitates a better observance
cause of morbidity and mortality among the world’s poorest pop-
ulations. More than 100 tropical and sub-tropical countries are
endemic for this infectious disease. Pregnant women and children
are the most sensitive to this infection and more than 750,000 peo-
ple die of malaria each year. Among the five species of Plasmodium
responsible for human malaria, P. falciparum is the parasite, which
causes the most serious form of the disease. Unfortunately this one
is difficult to eradicate because of its capacity to develop varying
degrees of resistance to many classes of antimalarial drugs. More
recent efforts have focused on the development of antimalarial
vaccines and since 2006,1 the World Health Organization
4
for prophylactic treatment. Mefloquine is relatively safe during
pregnancy and can be given to children of more than three years.5
However, the emergence of resistance to mefloquine and its asso-
ciated neuropsychiatric side effects limit its use.
Ò
Mefloquine is commercially available as a racemate (Lariam ),
2
recommends artemisinin-based combination therapies. However,
although both enantiomers have shown differences in biological
activities. On the one hand, the antimalarial activities of the two
artemisinin resistant strains of Plasmodium emerged in some
malaria endemic areas of South East Asia and efficacy of artemisi-
nin-based combination therapies might be lowered. This phe-
2
isomers are close but (+)-mefloquine is more active by a factor
6
,7
of 1.6–1.8 on D6, W2 and 3D7 strains. On the other hand, the
neuropsychiatric side effects correspond with a greater accumula-
tion of (ꢀ)-mefloquine compared to (+)-mefloquine in the central
nervous system due to a stereoselective cerebral transport of
⇑
Corresponding author. Tel.: +33 (0) 322827494; fax: +33 (0) 322827469.
E-mail address: pascal.sonnet@u-picardie.fr (P. Sonnet).
http://dx.doi.org/10.1016/j.tetasy.2015.11.003
957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
0
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2
G. Bentzinger et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
1
2
HO 11
HO
HO
HO
N
H
N
H
NHR
NHR
CF3
5
8
4
2
N
CF3
9
N
N
CF3
N
CF3
CF3
CF3
CF3
CF3
1
0
(+)-(11 S,12R)
(-)-(11 R,12S)
(S)-1a (R = pentyl)
(S)-1b (R = heptyl)
(R)-1a (R = pentyl)
(R)-1b (R = heptyl)
mefloquine
Figure 1. Mefloquine and aminoquinolinemethanol 1.
mefloquine.8–10 Moreover, (ꢀ)-mefloquine is 100 to 400-fold more
Further investigations were performed to highlight the mechanism
of action that could explain the difference in activity of the
enantiomers.
1
1
potent than (+)-mefloquine as an adenosine receptor agonist.
Among several approaches to lower the mefloquine neurotoxi-
city and to improve its resistance profiles,12 modulation of the
In continuation of our work concerning the research of new chi-
ral antimalarial drugs and to better understand the biological
mechanism of compounds 1, we were interested in the synthesis
of aminoquinolinethanols (R)- and (S)-2 and quinolinethanamines
(R)- and (S)-3 to establish new structure–activity relationships
(Fig. 2). Compared to the previous family of aminoquino-
linemethanol 1, we decided to study the importance of the amine
and the alcohol function positions grafted at the C11 and C12 posi-
tions of quinoline. Herein, we describe the synthesis and anti-
malarial activity of a new series of quinolines 2 and 3 with a
pentyl and/or heptyl chain (Fig. 2).
1
3
mefloquine core as a pure enantiomer is an attractive strategy.
Our team recently reported the asymmetric synthesis and the
biological activity of (R)- and (S)-4-aminoquinolinemethanols as
1
4,15
mefloquine analogues.
Several compounds, such as 1a and
1
b, showed a promising antimalarial activity, in the nanomolar
range, against P. falciparum W2 and 3D7 strains. Some structure–
activity relationships were highlighted: (i) the importance of the
absolute configuration of the stereogene centers (S) versus (R);
and (ii) the impact of the electron density around the amine
(
R = alkyl vs R = aryl). The most active molecule synthesized is
the aminoquinolinemethanol 1a with an (S)-configuration and a
pentylamino group at C12 position of the quinoline (Fig. 1, Table 1).
RHN
CF3
H2N
CF3
*
OH
*
OR
Table 1
The in vitro antimalarial activity of (S)- and (R)-1
a
Entry
Compounds
IC50 (nM)
N
CF3
N
CF3
Plasmodium falciparum
3
D7
W2
1
2
3
4
5
6
(S)-1a
(R)-1a
(S)-1b
(R)-1b
Chloroquine
Mefloquine
8.33 ± 0.44b
74.7 ± 4.71
33.0 ± 1.55
254 ± 26.9
25.7 ± 7.81
52.2 ± 4.18
6.98 ± 0.62
38.2 ± 3.63
NDc
ND
572 ± 112
26.5 ± 2.44
(R)-2a, (S)-2a (R = pentyl)
(R)-2b, (S)-2b (R = heptyl)
(R)-3, (S)-3 (R = pentyl)
Figure 2. Aminoquinolinethanols 2 and quinolinethanamines 3.
a
Isotope micromethod that measures inhibition of parasite uptake of tritiated
2
. Results and discussion
hypoxanthine in the presence of antimalarial agents.
b
The 50% inhibitory concentrations were calculated using Pk-Fit software.
Results expressed as mean ± standard deviation.
2.1. Chemistry
c
Not determined.
The retrosynthetic route chosen shows that the enantiopure
aminoquinolinethanols 2 and quinolinethanamines 3 can be pre-
pared from a common key intermediate 4 [for an example see
the (S)-enantiomers in Scheme 1] which could be obtained from
4-vinylquinoline 5. We have previously described a two step syn-
thesis of this vinylarene from 4-hydroxyquinoline 6 in 80% global
Compound (S)-1a was more active than chloroquine and meflo-
quine, whatever the strain and was 5 to 9-fold more active
(
(
IC50 = 6.98 nM (W2) and 8.33 nM (3D7)) than its (R)-enantiomer
R)-1a (IC50 = 38.2 nM (W2) and 74.7 nM (3D7)), depending on
16
14
the strain (entries 1 and 2, Table 1). These results confirmed
the importance of the stereochemistry in the design of mefloquine
analogues in malaria treatment. Interestingly, (S)-1a and its (S)-
heptyl analogue (S)-1b exhibited a steady activity against a panel
of P. falciparum strains with varying resistance profiles to chloro-
yield.
Our strategy is based on the aminohydroxylation reaction.18,19
This one permits the sequential or simultaneous addition of both
nitrogen and oxygen on an alkene compound. The sequential addi-
tion, developed by Davies et al., consists of the addition of a chiral
1
7
quine and mefloquine. Furthermore, we showed an additive or
synergic effect of in vitro (S)-1a/dihydroartemisinin and (S)-1b/
dihydroartemisinin combinations. Hemolysis tests pointed toward
a rather safe use compared to mefloquine. In order to elucidate the
mechanism of action of compounds 1, their effects on b-hematin
formation and on peroxidative-degradation of haemin were stud-
amide anion to an a,b-unsaturated ester. The resulting enolate is
trapped by an oxygen electrophile such as an oxaziridine, to lead
to the corresponding aminoalcohol in excellent diastereoselectiv-
1
8
ity.
The simultaneous addition is based on an asymmetric
Sharpless dihydroxylation reaction: the asymmetric Sharpless
1
9
aminohydroxylation. For this, Sharpless used a chiral amine
ligand such as phthalazine ligands (DHQ) PHAL or (DHQD) PHAL
1
6
ied. All derivatives tested were more efficient than mefloquine
at inhibiting b-hematin formation and haemin degradation
pathway. No significant difference in the inhibiting activity of the
2
2
to generate the asymmetric addition of an amide and a hydroxyl
group on the alkene double bond. Various nitrogen sources were
described in the aminohydroxylation reaction: sulfonamides,
(
R)- or (S)-enantiomer carrying the same side chain was observed.
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G. Bentzinger et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
RHN
CF3
OH
N
CF3
BnOOCHN
OH
OH
N
(
S)-2
lit. 14
H2N
OR
N
CF3
N
CF3
CF3
CF3
CF3
CF3
6
(
S)-4
5
N
CF3
CF3
(S)-3
Scheme 1. Retrosynthesis of (11S)-enantiopure aminoquinolinethanols 2 and quinolinethanamines 3.
carbamates, and amides. Optimal yields and enantioselectivities
All tests led to the desired compound 4 in poor yield ranging
from 26% to 48% (Table 2). These low chemical yields could be
explained by the formation of two principal by-products: the diol
were observed with
a,b-unsaturated esters and phosphonates as
substrates. For vinylarene substrates, the yield and the regioselec-
tivity are highly dependent on both the nature and the substitution
of the arene moiety, as well as the choice of ligand, solvent, and
ligand-solvent combination.20
0
and the regioisomer 4 . The quantification and separation of these
by-products were often difficult because they form a non-separa-
ble mixture with benzylcarbamate in excess. Hence, regioisomer
0
For the synthesis of the key intermediate 4, we decided to use
the Sharpless methodology using benzylcarbamate as the nitrogen
source since this is: (i) more appropriate in the case of terminal
4 was isolated only twice (entries 5 and 6).
The first assay was carried out in a mixture of 1:1 n-PrOH/H
2
O
with (DHQ)
2
PHAL as ligand and led to (ꢀ)-4 in 48% yield and with
2
0
alkenes; and (ii) easily cleavable under mild conditions.
80% ee (entry 1). In order to improve the carbamate-based amino-
hydroxylation, the addition of an excess of mercury salt was car-
ried out. In this reaction, the N-chlorosodiocarbamates react
in situ with the metallic salt to form more reactive N-chloro-N-
metallocarbamates. The beneficial effect of excess mercury salt
was previously reported by Sharpless. Unfortunately in our case,
this addition had a deleterious effect since no product was formed
(entry 2). Aminohydroxylation was also carried out by changing
The aminohydroxylation reaction assays of 4-vinylquinoline 5
to 4 are summarized in Table 2. In each case, the reactions were
achieved using 4 mol % of the osmium(VI) pre-catalyst, potassium
osmate(VI) dihydrate, 5 mol % of alkaloid ligand (1,4-bis(9-O-
2
1
dihydroquininyl)-phthalazine (DHQ)
droquinidinyl)-phthalazine (DHQD)
benzylcarbamate in an n-PrOH or acetonitrile/H
2
PHAL or 1,4-bis(9-O-dihy-
PHAL)), and 3.1 equiv of
O solvent mixture
2
2
at 25 °C. The benzylcarbamate was converted in situ into the
corresponding N-chlorosodiocarbamate salt in the presence of
sodium hydroxide and freshly prepared tert-butyl hypochlorite.
the solvent mixture to 2:1 n-PrOH/H
trile/H O (entry 4) hoping to limit the by-product formation.
In these two cases, the reaction proceeded with lower yield
2
O (entry 3) or 1:1 acetoni-
2
Table 2
Reagents and conditions used to prepare 4
BnOCONH2 (3.1 eq),
source of chlorine (3,05 eq)
ligand (5 mol %), NaOH
K2OsO2(OH)4 (4 mol %)
BnOOCHN
HO
OH
NHCOOBn
CF3
+
N
CF3
N
CF3
N
CF3
CF3
CF3
5
4
4'
Yielda (%)
eeb (%)
[a]
D
20c
Entry
Source of chlorine
Ligand
Solvent
3
Hg(NO )
2
(equiv)
0
0
4
4
4
4
t
t
t
t
NDd
ND
ND
ND
19
1
2
3
4
5
6
BuOCl
BuOCl
BuOCl
BuOCl
(DHQ)
(DHQ)
(DHQ)
(DHQ)
(DHQ)
2
PHAL
PHAL
PHAL
PHAL
PHAL
n-PrOH/H
2
2
2
O
O
O
48
0
80
/
ꢀ28.9
1
:1
n-PrOH/H
:1
n-PrOH/H
:1
MeCN/H
:1
n-PrOH/H
:1
n-PrOH/H
:1
2
2
2
2
3.05
/
1
36
31
26
33
74
60
76
70
2
2
O
/
1
1,3-Dichloro-5,5-dimethylhydantoin
2
O
O
+12.4
1
t
BuOCl
(DHQD)
2
PHAL
2
24
+9.5
ꢀ15.4
1
a
b
c
After chromatography purification.
Enantiomeric excesses of compounds 4 were determined by HPLC (Chiralpak IB column, heptane/i-PrOH 9:1; 1 mL/min, 278 nm) t
c 0.1, MeOH. Determined after chromatography purification.
R
R
(S) = 14.6 min; t (R) = 16.6 min.
d
Observed but not quantified.
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G. Bentzinger et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
(
31% and 36% vs 48%) and with the poorest enantioselectivity. In a
At this step, we decided to establish the absolute configuration
of (+)-8 and (ꢀ)-8, and indirectly those of (+)-4 and (ꢀ)-4. Thus, the
preparation of Mosher amides 9a and 9b from (+)-8 was achieved.
This amine was reacted with 1.5 equiv of Hünig’s base (DIPEA) and
(S)-methoxy(trifluoromethyl)phenylacetyl chloride (MTPA-Cl) as
well as (R)-MTPA-Cl (Scheme 2). The two diastereomers 9a and
9b were obtained in 79% and 69% yields, respectively. Their NMR
spectra were compared according to the Mosher method: the
interpretation of the significant chemical shift differences in the
individual diastereomeric MTPA amides 9a and 9b derived from
the (+)-8 clearly confirmed the supposed configuration S. Conse-
quently, (ꢀ)-8 should present the R-absolute configuration. These
results permit also to conclude that (ꢀ)-4 and (+)-4 can be assigned
as (S)-4 and (R)-4, respectively.
After confirmation of the configuration of the key intermediates
4 and 8, two steps were necessary to obtain final compounds 2 and
3. For compounds 2, the substitution of enantiomers 8 with alkyl
chains was followed by the deprotection of the alcohol moiety. In
order to optimize the alkylation step, several assays were achieved
using (S)-8 as the substrate and bromopentane as the halo-com-
pound reagent (entries 1–4, Table 4). All tests were performed in
acetonitrile as the solvent. Our first experiments (entries 1 and
2) were carried out in the presence of 1 or 2 equiv of triethylamine
or potassium carbonate in acetonitrile at reflux, but none of the
products were obtained. The addition of potassium iodide as a cat-
alyst slightly reduced the reaction time (15 h vs 20 h) and led to
the product (S)-10a in a poor yield of 19% (entry 3). Finally, to
accelerate the reaction and improve the yield, we used microwave
irradiation (entry 4). The reaction was optimized with respect to
the temperature (100–150 °C) and the total conversion of reactant
(S)-8 was observed after 3 h of reaction at 150 °C and (S)-10a was
obtained in 62% yield (entry 4).
last assay, the source of chlorine was changed and 1,3-dichloro-5,5-
dimethylhydantoin was used in place of tert-butyl hypochlorite
(
and the regioisomer 4 was isolated with 19% of yield. The best
results were obtained with a 1:1 ratio of n-PrOH/H
and tert-butyl hypochlorite as the source of chlorine (entry 1).
Thus, these same conditions were used to prepare the (+)-4 enan-
tiomer in 33% yield and with 70% ee (entry 6, Table 2).
As in the catalytic asymmetric dihydroxylation, the chiral
ligands favoured the addition to one face of the prochiral alkene
entry 5). In this case, compound 4 was obtained in 26% yield
0
2
4
2
O as the solvent
2
2
substrate. Thus, vinylquinoline 5 was converted into the corre-
2
0
sponding (S)-4 {[
was used as a ligand (entry 1, Table 2) and to (R)-4 {[
c 0.1, MeOH)} when (DHQD) PHAL was employed (entry 6,
a
]
D
= ꢀ28.9 (c 0.1, MeOH)} when (DHQ)
2
PHAL
a] = +9.5
D
2
0
(
2
Table 2). Concerning the regioselectivity of the aminohydroxyla-
tion, it was reported that the amination of the more substituted
carbon for monosubstituted alkenes, such as styrene, is
2
3
preferred.
Thus, provisionally, the majority of compound obtained (entries
and 6) was assigned as the (ꢀ)-(S)-4 when (DHQ) PHAL was
1
2
employed and (+)-(R)-4 when (DHQD)PHAL was used. In order to
achieve X-ray studies to prove the structure of 4, several assays
of crystallization were achieved but no solvent system used was
efficient. Thus, the stereoselectivity and the regioselectivity of
the aminohydroxylation reaction will be confirmed later by the
preparation of the Mosher amides 9 from amine (+)-8 (Scheme 2).
The obtained enantiomers 4 were used in reaction with tert-
butyldimethylsilyl chloride to give (ꢀ)-7 and (+)-7 (Table 3). After
removal of the benzylcarbamate group with hydrogen in the pres-
ence of palladium on charcoal, (ꢀ)-8 and (+)-8 were afforded in
good yields.
Ph
(R)
Ph
F3C
MeO
F3C
(
S)
O
O
MeO
HN
H2N
CF3
HN
OTBDMS
CF3
OTBDMS
CF3
OTBDMS
CF3
ii
i
N
N
N
CF3
CF3
9a
(+)-8
9b
Scheme 2. Reagents and solvents: (i) (S)-MTPA-Cl (1.2 equiv), DIPEA (1.5 equiv), CH
Cl
2 2
, 25 °C, 79%; (ii) (R)-MTPA-Cl (1.2 equiv), DIPEA (1.5 equiv), CH
2
2
Cl , 25 °C, 69%.
Table 3
Reagents and conditions used to prepare 8
BnOOCHN
*
BnOOCHN
H2N
OH
*
OTBDMS
CF3
*
OTBDMS
CF3
TBDMSCl, imidazole
CH2Cl2, 25°C
H2, Pd/C
MeOH, 25°C
step 1
step 2
N
CF3
N
N
CF3
CF3
CF3
8
4
7
Entry
Step 1
Yield (%)
Step 2
4
7
eea (%)
[
a
]
20c
7
8
Yield (%)
eeb (%)
[a]
D
20d
1
2
(ꢀ)-4
(+)-4
(ꢀ)-7
(+)-7
89
80
76
70
ꢀ7.8
(ꢀ)-7
(+)-7
(+)-8
(ꢀ)-8
81
81
74
70
+37.8
ꢀ36.9
+4.9
a
b
c
Enantiomeric excesses of compounds 7 were determined by HPLC (Chiralpak IB column, heptane/EtOH 95:5; 1 mL/min, 278 nm) t
Enantiomeric excesses of compounds 8 were determined by HPLC (Chiralpak IB column, heptane/EtOH 95:5; 1 mL/min, 278 nm) t
c 0.1, MeOH. Specific rotation of compounds 7.
R
(S) = 5.9 min; t
(S) = 6.6 min; t
R
(R) = 7.5 min.
(R) = 7.3 min.
R
R
d
c 0.1, MeOH. Specific rotation of compounds 8.
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G. Bentzinger et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
Table 4
Reagents and conditions used to the synthesis of 10
H2N
RHN
CF3
*
*
OTBDMS
CF3
OTBDMS
CF3
RBr, base
CH3CN
N
N
CF3
8
10
Entry
Reactant
R
Base (equiv)
Et N (1)
Catalyst (0.1 equiv)
Temperature (°C)
Time (h)
Product
Yieldb (%)
ee (%)
1
2
3
4
5
6
7
(S)-8
(S)-8
(S)-8
(S)-8
(S)-8
(R)-8
(R)-8
C
C
C
C
C
C
C
5
5
5
5
7
5
7
H
11
H
11
H
11
H
11
H
15
H
11
H
15
–
–
–
–
–
–
–
3
/
/
Reflux
Reflux
Reflux
20
20
15
3
3
3
—
—
0
0
—
—
—
78
74
K
K
K
K
K
K
2
CO
3
3
3
3
3
3
(2)
(2)
(2)
(2)
(2)
(2)
2
CO
2
CO
2
CO
2
CO
2
CO
KI
KI
KI
KI
KI
(S)-10a
(S)-10a
(S)-10b
(R)-10a
(R)-10b
19
62
67
60
64
a
c
150 °C (MW)
d
150 °C (MW)
150 °C (MW)
150 °C (MW)
c
62
d
3
70
a
b
c
Reaction was performed using microwave heating at 150 °C (200 W).
Yield of isolated product.
Enantiomeric excesses of compounds 10a were determined by HPLC (Chiralpak IB column, heptane/i-PrOH 99:1; 1 mL/min, 278 nm) t
Enantiomeric excesses of compounds 10b were determined by HPLC (Chiralpak IB column, heptane/i-PrOH 99:1; 1 mL/min, 278 nm) t
R
(S) = 3.8 min; t
R
(R) = 4.2 min.
d
R
(S) = 3.7 min; t
R
(R) = 4.0 min.
These microwave conditions were selected to prepare ana-
δH 3.66, 3.85
δc 66.7
δH 2.83, 2.99
δc 57.2
logues (R)-10a, (S)-10b, and (R)-10b, which were achieved in the
same range of yield (60–67%) and with an enantiomeric excess
between 62% and 78% (entries 5–7, Table 4).
Deprotection of the alcohol moiety was performed using tetra-
butylammonium fluoride in THF at 0 °C. After 1 h, the final com-
pounds 2 were obtained in good yields and with enantiomeric
excesses ranging from 56% to 86% (Table 5).
1
2
12
C5H11HN
HO
OH
11
NHC5H11
1
1
δH 4.77
δc 61.5
δH 5.68
δc 69.4
N
CF3
N
CF3
CF3
CF3
(S)-2a
(S)-1a
Table 5
Figure 3. (S)-2a and (S)-1a NMR data.
Reagents and conditions used to the synthesis of 2
RHN
*
RHN
CF3
conditions were attempted: (i) bromopentane with Et
3
N as the
OTBDMS
CF3
*
OH
base in acetonitrile at reflux; (ii) iodopentane in the presence of
a phase transfer catalyst (tetrabutylammonium sulfate) with
sodium hydroxide as the base in a biphasic solvent system (THF/
TBAF (3 equiv)
THF, 0°C
N
N
CF3
H
2
O); and (iii) iodopentane with silver oxide in dichloromethane.
Only the third assay allowed us to obtain the desired compounds
1 in yields ranging from 41% to 53%. Deprotection of amine moi-
CF3
1
0
2
1
2
0c
Entry
Reactant
R
Product Yield (%)
ee (%)
[
a
]
D
ety was carried out in a hydrogen atmosphere with palladium on
charcoal as the catalyst. Compounds 3 were obtained in 74% yield
and with moderate enantiomeric excesses up to 54%.
Thus, the key intermediates (R)-4 and (S)-4 were obtained in
one step from 4-vinylquinoline 5, through the aminohydroxylation
reaction in 33% (70% ee) and 48% (80% ee) yields, respectively. Six
novel compounds 2 and 3 were synthesized from 4 in 4 or 2 steps,
respectively, in moderate yield and with enantiomeric excesses
higher than 54%.
86a
74
70
56
1
2
3
4
(S)-10a
(S)-10b
(R)-10a
(R)-10b
C
5
C
7
C
5
C
7
H
11
H
15
H
11
H
15
–
–
–
–
(S)-2a
(S)-2b
(R)-2a
(R)-2b
83
73
100
85
+22.0
+25.6
ꢀ29.0
ꢀ28.9
b
a
b
a
Enantiomeric excesses of compounds 2a were determined by HPLC (Chiralpak
IB column, heptane/EtOH 99:1; 1 mL/min, 278 nm) (R) = 31.9 min; (S)
34.3 min.
Enantiomeric excesses of compounds 2b were determined by HPLC (Chiralpak
IB column, heptane/EtOH 99:1; 1 mL/min, 278 nm) (R) = 29.5 min; (S)
t
R
t
R
=
b
t
R
t
R
=
32.3 min.
c
c 0.1, MeOH. Specific rotation of compounds 2.
2.2. Biological evaluation
The in vitro antimalarial activity of the aminoquinolinethanols
(R)- and (S)-2, quinolinethanamine (R) and (S)-3 and some inter-
mediates during the synthesis were evaluated against P. falciparum
strains W2 and 3D7 (Table 7). W2 is a chloroquine resistant strain
and is mefloquine sensitive while 3D7 is chloroquine sensitive and
displays a decreased susceptibility to mefloquine. The biological
activity of the new products 2, 3, and intermediates (S)-8 and
(S)-10a was evaluated with a SYBR Green I fluorescence-based
In order to reinforce the regiochemistry established for the
aminohydroxylation reaction (Table 2), NMR data of the final pro-
duct (S)-2a and the lead compound (S)-1a were compared (Fig. 3).
Significant differences were raised between the chemical shift of
H11 [47.7 ppm for (S)-2a vs 5.68 ppm for (S)-1a] and H12 [3.66
and 3.85 ppm for (S)-2a vs 2.83 and 2.99 ppm for (S)-1a]. These dif-
ferences validate the structure of compounds 2, as regioisomers of
compounds 1.
2
5,26
method.
Chloroquine and mefloquine were routinely included
Finally, the O-alkylated compounds 3 were synthesized in two
steps from the aminohydroxylation products 4: alkylation, and car-
bamate cleavage (Table 6). Concerning the O-alkylation of 4, three
as positive controls as well as negative controls using the solvent.
The resulting IC50s were calculated using a regression program
available online and are reported in Table 7.
2
7
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6
G. Bentzinger et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 6
Reagents and conditions used to the synthesis of 3
BnOOCHN
BnOOCHN
H2N
CF3
*
OH
*
O
*
O
4
4
Ag2O, C5H11I
CH2Cl2, 25°C
H , Pd/C (10 mol%)
MeOH, 25°C
2
step 1
step 2
N
CF3
N
CF3
N
CF3
CF3
CF3
4
11
3
Entry
Step 1
Step 2
Eea (%)
11
3
Yield (%)
eeb (%)
[a]
D
20c
4
11
Yield (%)
1
2
(S)-4
(R)-4
(S)-11
(R)-11
41
53
64
68
(S)-11
(R)-11
(S)-3
(R)-3
74
74
58
66
+28.1
ꢀ43.3
a
b
c
Enantiomeric excesses of compounds 11 were determined by HPLC (heptane/i-PrOH, 90:10; flow 1 mL/min, 210 nm) t
R
R
(S) = 7.3 min, t (R) = 10.0 min.
Enantiomeric excesses of compounds 3 were determined by HPLC (heptane/i-PrOH, 95:5; flow 1 mL/min, 278 nm) t
c 0.1, MeOH. Specific rotation of compounds 3.
R R
(S) = 8.1 min, t (R) = 9.0 min.
–
OH group at C11. In the novel series, (S)-8 and (S)-3 carrying
Table 7
In vitro antimalarial activity of compounds (S)-8, (S)-10, and series 2–3
a –NH at the C11 position were more active than other (S)-enan-
2
a
tiomers with pentyl or heptylamino group at this position (Table 7).
For the (S)-enantiomers, the C11 position of the quinoline should
Entry
Compounds
IC50 (nM)
Plasmodium falciparum
be substituted preferably by an –OH group followed by –NH
finally by –NHR.
For (R)-compounds, this trend is less evident in the novel series.
Compounds of the series 1 (R)-1a and (R)-1b [IC50s = 74 and
254 nM (3D7)] are still much more active than (R)-2 (IC50 up to
5454 nM on 3D7) and (R)-3 [IC50 = 13605 nM (3D7)]. However,
2
and
3
D7
W2
1
2
3
4
5
6
7
8
9
(S)-8
(S)-10a
(S)-2a
(R)-2a
(S)-2b
(R)-2b
(S)-3
(R)-3
Chloroquine
Mefloquine
746 ± 58b
5042 ± 243
10,535 ± 721
5454 ± 322
26,541 ± 6972
15,532 ± 1754
4069 ± 289
13,605 ± 1329
75.9 ± 3
NDc
ND
2801 ± 255
2007 ± 299
>40,000
2446 ± 940
1730 ± 369
3175 ± 914
198.8 ± 27
31.8 ± 1
(R)-2a which is substituted at C11 by a pentylamino group, is more
active than (R)-3 with an –NH group at this position.
2
Evidently, the better substitution at the C11 position of the
quinoline is the –OH group, whatever the stereochemistry of the
1
0
79.7 ± 8
a
2
compounds. An –NH group or an –NHR in this position has a dele-
SYBR Green I in vitro test was used.
b
terious effect on the antimalarial activity. Thus, a hydrogen inter-
action seems to be essential for the antimalarial activity of this
type of quinoline. Furthermore, the more the heteroatom is elec-
tron withdrawing, the stronger this interaction is.
IC50s were calculated using WinNonlin software. Results expressed as
mean ± standard deviation.
c
Not determined.
The C11 substitution of the quinoline by a –OH group is essen-
tial for the antimalarial activity but not sufficient. Indeed, the weak
antimalarial activity of the racemic quinolines 12 and 13 (Fig. 4)
With mefloquine, all tested compounds were more active
against P. falciparum strains W2 than against P. falciparum strains
D7 (Table 7). Unfortunately, this novel series displayed lower
activities [IC50s = 746–26541 nM (3D7) and 1730–3175 nM (W2)]
than mefloquine and the lead compound 1a [IC50 = 8.33 nM (3D7)
and 6.98 nM (W2)] (Tables 1 and 7). Among these new tested com-
pounds, two quinolinethanamines with an (S)-configuration were
the most potent: the intermediate (S)-8 (IC50 = 746 nM) on the
3
2
carrying an –OH group at C11 and a polar group (–OH or –NH )
1
3c
at C12 was previously described by Milner et al.
The IC90s of
these two compounds is up to 1400 nM against W2 strains.
HO
HO
OH
NH2
3
1
D7 strain followed by the (S)-3 [IC50s = 4069 nM (3D7) and
730 nM (W2)] on the two strains.
As previously observed for compounds 1 (Table 1), the (R)- and
S)-enantiomers of compounds 2 and 3 showed different anti-
malarial activities. For compounds 3 as for compounds 1, (S)-
derivatives were more active than their (R)-counterparts (entries
and 8, Table 7). The IC50 ratio (R)/(S) ranged from 1.8 to 3
N
CF3
N
CF3
(
CF3
CF3
1
2
13
IC90 (W2) > 1538 nM (lit. 13c)
IC90 (W2) = 1459 nM (lit. 13c)
7
according to the strain considered, which is slightly less than the
ratio found for compounds 1a and 1b. In the case of the
aminoquinolinethanols 2, enantiomers with an (R)-absolute con-
figuration were more potent by a factor of 1.7 for 2b to 1.9 for
Figure 4. Antimalarial activity of 12 and 13.
Thus, a hydrophilic group such as –OH or –NH , at C12 seems
2
unfavorable to the antimalarial activity. The lead compounds 1
2
a on the 3D7 strain. Compounds 1 and 3 possess a polar group
possess an –NHR group (R = alkyl) at C12. For the (S)-enantiomers
of the new series, the silylated compound (S)-8 was the most
potent followed by (S)-10a and (S)-3 with an –OTBDMS and an
–OC H group at C12. Compounds 2 with a –OH group were lesser
active. Thus, we confirmed through the synthesis of this novel ser-
ies of quinoline that a hydrophobic group at C12 position of the
quinoline led to more potent compounds. The –NHR group, where
R is an alkyl, remains the most effective substituent (Fig. 5).
(
–OH or –NH ) at the C11 position of the quinoline and a substi-
2
tuted heteroatom (–OR or –NHR) at C12. For compounds 2, the
position of these groups is reversed. Thus, a polar group at C11
of the quinoline seems to support a better activity for the (S)-enan-
tiomers. This group should not be substituted, otherwise the anti-
malarial activity decreases [(S)-1 and (S)-3 vs (S)-2a or -2b, (S)-8 vs
5
11
(S)-10a]. Compounds (S)-1 were by far the most potent and carry a
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G. Bentzinger et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
polar group
hydrophobic group
OH >> NH2, NHR
NHR >> OH, OR
1
2
1
HO
R X
RHN
CF3
*
NHR
CF3
*
XR2
*
OR
1
1
N
N
CF3
N
CF3
CF3
CF3
1
2
, 3
(
S)-1 >> (S)-3 > (S)-2
(S)-1 > (R)-1
R = pentyl, heptyl
R = H, pentyl, heptyl
(
(
S)-3 > (R)-3
R)-2 > (S)-2
Figure 5. Structure–antimalarial activity relationships for 1–3.
3
. Conclusion
Three news series of enantiopure aminoquinolines 2a, 2b, and 3
4.1.1. Preparation of (ꢀ)-(S)-4 and (+)-(R)-4
.1.1.1. Preparation and titration of tert-butylhypochlo-
rite. To a solution of 500 mL of NaOCl (4.00–4.99% of available
4
were synthesized and evaluated for their antiplasmodial activity
toward two P. falciparum strains, W2 and 3D7. We obtained these
compounds 2 and 3 in 2 or 4 steps from the key intermediate 4,
which was successfully obtained via aminohydroxylation. All com-
pounds displayed IC50s close to the micromolar and were less
active than the previous series 1. This novel series of compounds
allowed us to establish new structure–activity relationships. The
best substitution at the C11 position of the quinoline is the –OH
group, whatever the stereochemistry of the compounds. The C12
position of the quinoline should be substituted by a hydrophobic
group, preferably an –NHR group. The lead compound (S)-1a
remains the most active one [IC50 = 6.98 nM (W2) and 8.33 nM
chlorine), cooled to 0 °C and placed in the dark, were added a solu-
tion of 20 mL of acetic acid and 31 mL of t-butyl alcohol in one sin-
gle portion. The solution was stirred for 10 min. The mixture was
then poured into a separatory funnel. The aqueous layer was dis-
carded and the organic layer washed, once, with 50 mL of an aque-
ous solution of NaHCO
organic layer was dried over CaCl
3
10% and then with 50 mL of water. The
and filtered. A yellow liquid
2
2
was obtained (32 g, 0.29 mol, 75%) and stored over CaCl , under
Ar atmosphere in a fridge.
t
Before each aminohydroxylation reaction, BuOCl was titrated: To
20.0 mL of a solution of potassium iodide (100 g/L) were added
t
15 drops of acetic acid, and 114.0
titrated with a solution of Na
l
L of BuOCl. The solution was
(
3D7)], whatever the strain. However, other structure–antimalarial
S
2 2
O
3
(0.1 M), after which 20.0 mL
activity relationships have been highlighted and give tracks for the
design of new compounds.
of sodium thiosulfate were added to give a pure product.
4
.1.1.2. (S)-Benzyl (1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-
To a solution of 804 mg
hydroxyethyl)carbamate (ꢀ)-(S)-4.
4
4
. Experimental
.1. Chemistry
(5.32 mmol, 3.1 equiv) of benzyl carbamate in propanol (7 mL)
was added a solution of 210 mg (5.24 mmol, 3.05 equiv) of NaOH
in water (13 mL). The solution was stirred for 5 min at 25 °C. Then
t
0
.62 mL (5.24 mmol, 3.05 equiv) of freshly prepared BuOCl and
Nuclear magnetic resonance (NMR) spectra were recorded
70.0 mg (0.09 mmol, 5 mol %) of (DHQ) PHAL in propanol (6 mL)
were added. The solution was placed into a water bath and stirred
for 10 min. To this solution were added 200 mg (1.72 mmol,
2
1
using Bruker 400 MHz NMR instrument ( H NMR at 400 MHz
1
3
and C NMR at 100 MHz) and Bruker 300 MHz NMR instrument
1
13
(
H NMR at 300 MHz and C NMR at 75 MHz). Chemical shifts
1 equiv) of vinyl 5 and 26.0 mg (0.07 mmol, 4 mol %) of K OsO2
2
are expressed in parts per million (d, ppm) downfield from
(OH) . The suspension was stirred in a water bath for 15 h. The
4
tetramethylsilane and are referenced to the deuterated solvent.
H NMR and C NMR data were reported in the order of chemical
mixture was then extracted with AcOEt (3 ꢁ 20 mL). The combined
1
13
organic layers were dried over Na SO , filtered, and concentrated
2
4
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. Melting points were determined on Electrothermal
Stuart SMP30 digital melting point apparatus and are uncorrected.
Infrared spectra were recorded with a Jasco FTIR-4200 and are
in vacuo. Flash chromatography on silica gel (cyclohexane/ethyl
acetate 2:1) afforded 378 mg (0.82 mmol) of (ꢀ)-(S)-4 as a white
solid. Yield 48%; ee 80%, HPLC analysis was performed with Chiral-
pak IB column (heptane/isopropanol, 90:10, flow 1 mL/min,
2
0
278 nm, t (S) = 14.6 min, t (R) = 16.6 min); [
R
R
a]
D
= ꢀ28.9 (c 0.1,
1
MeOH). R 0.23 (cyclohexane/ethyl acetate 2:1); mp 135 °C;
f
H
NMR (300 MHz, CD OD): d 3.89 [AB(ABX), J = 11.4, 6.4, 4.8 Hz,
3
2H], 5.08 (s, 2H), 5.62–5.80 [X(ABX), J = 6.4, 4.8 Hz, 1H], 7.14–
ꢀ1
reported using the frequency of absorption (cm ). High-resolution
mass spectra were obtained from a Micromass-Waters Q-TOF
Ultima spectrometer.
7.41 (m, 5H), 7.77 (t, J = 7.8 Hz, 1H), 8.02 (s, 1H), 8.19 (d,
1
3
J = 7.8 Hz, 1H), 8.57 (d, J = 7.8 Hz, 1H) ppm; C NMR (75 MHz,
CD OD): d 54.6, 65.1, 67.9, 116.3, 120.9 (q, J = 274.8 Hz), 123.1 (q,
3
Routine monitoring of reactions was performed using Merck
silica gel 60 F254 plates, thin layer chromatography (TLC) and visu-
alized under UV light (254 nm), with ethanolic phosphomolybdic
acid (PMA). Flash column chromatography was carried out on
J = 272.9 Hz), 126.8, 127.2, 127.3, 127.6, 128.4, 138.0, 144.9,
p
147.2 (q, J = 35.1 Hz), 151.9, 158.4 ppm; IR max: 3306, 1680,
ꢀ1
+
1545 cm ; HRMS calcd for C21H17F N O (M+H) 459.1132, found
6
2 3
459.1134.
Kielselgel 60 (40–63 lm) ASTM (Merck). All the moisture sensitive
reactions were performed using oven dried glassware and under an
inert gas atmosphere. In this case, solvents were dried with a
Serlabo PS-MD-5 drier.
4.1.1.3. (R)-Benzyl (1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-
hydroxyethyl)carbamate (+)-(R)-4. Compound (+)-(R)-4
was prepared from 5 according to the same procedure as that of
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8
G. Bentzinger et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
(
ꢀ)-(S)-4 with (DHQD)
analysis was performed with Chiralpak IB column (heptane/iso-
propanol, 90:10, flow 1 mL/min, 278 nm, t (S) = 14.6 min, t (R)
0.23 (cyclohexane/ethyl
acetate 2:1); mp 135 °C; H NMR (300 MHz, CD OD): d 3.89 [AB
ABX), J = 11.4, 6.4, 4.8 Hz, 2H], 5.08 (s, 2H), 5.62–5.80 [X(ABX),
J = 6.4, 4.8 Hz, 1H], 7.14–7.41 (m, 5H), 7.77 (t, J = 7.8 Hz, 1H), 8.02
2
PHAL as ligand. Yield 33%; ee 70%, HPLC
129.8 (q, J = 30.0 Hz), 35.9, 143.9, 148.0 (q, J = 35.5 Hz), 149.1,
p
ꢀ1
155.7 ppm. IR max: 3330, 2902, 1684, 1530 cm . HRMS calcd
+
R
R
30 6 2 3
for C27H F N O SiNa (M+Na) 595.1828, found 595.1851.
2
0
=
D f
16.6 min); [a] = +9.5 (c 0.1, MeOH); R
1
3
4.1.3. Preparation of (+)-(S)-8 and (ꢀ)-(R)-8
4.1.3.1. (S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-
butyldimethylsilyl)oxy)ethan-amine (+)-(S)-8. To 10 mL of
dried MeOH under an Ar atmosphere were added 63.0 mg (10%
w/w) of Pd/C. The suspension was placed under H atmosphere
(
1
3
(
s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.57 (d, J = 7.8 Hz, 1H) ppm;
C
NMR (75 MHz, CD
3
OD): d 54.6, 65.1, 67.9, 116.3, 120.9 (q,
2
J = 274.8 Hz), 123.1 (q, J = 272.9 Hz), 126.8, 127.2, 127.3, 127.6,
28.4, 138.0, 144.9, 147.2 (q, J = 35.1 Hz), 151.9, 158.4 ppm; IR
and stirred for 5 min. A solution of 630 mg (1.21 mmol, 1 equiv)
of (ꢀ)-(S)-7 in 10 mL of dried MeOH was added slowly to the sus-
pension and stirred for 8 h. The mixture then was filtered, and the
filtrate concentrated in vacuo. Flash chromatography on silica gel
(cyclohexane/ethyl acetate 2:1) afforded 430 mg of (+)-(S)-8 as a
colorless oil. Yield 81%; ee 74%, HPLC analysis was performed with
Chiralpak IB column (heptane/isopropanol, 95:5, flow 1 mL/min,
1
p
ꢀ1
17 6 2 3
max: 3306, 1680, 1545 cm ; HRMS calcd for C21H F N O (M
+
+
H) 459.1132, found 459.1136.
0
Regioisomer (R)-4 was isolated as a yellow oil. Yield: 24%;
2
0
1
[
[
(
a
]
D
= ꢀ15.4 (c 0.1, MeOH); H NMR (400 MHz, CD
3
OD): d 3.42
AB(ABX), J = 14.2, 7.8, 3.7 Hz, 2H], 4.97–5.07 (m, 2H), 5.68 [X
ABX), J = 7.8, 3.7 Hz, 1H], 7.19–7.32 (m, 5H), 7.76 (t, J = 7.9 Hz,
2
0
278 nm, (S) = 6.6 min,
t
R
R D
t (R) = 7.3 min); [a] = +37.8 (c 0.1,
1
H), 8.15 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.65 (d, J = 7.9 Hz, 1H)
MeOH). R
f
0.27 (cyclohexane/ethyl acetate 2:1); 1H NMR
1
3
ppm.
C
NMR (100 MHz, CD
3
OD):
d
67.6, 69.6, 115.7 (q,
(300 MHz, CDCl
3
): d ꢀ0.02 (s, 3H), 0.07 (s, 3H), 0.87 (s, 9H),
J = 1.9 Hz), 122.8 (q, J = 274.7 Hz), 125.1 (q, J = 272.9 Hz), 128.2,
28.7, 128.9, 129.0, 129.4, 129.7 (q, J = 30.0 Hz), 130.1
1.66–1.99 (m, 2H), 2.08–2.11 (s, 2H), 3.79 [AB(ABX), J = 9.8, 6.6,
3.9 Hz, 2H], 5.01 [X(ABX), J = 6.6, 3.9 Hz, 1H], 7.74 (t, J = 7.7 Hz,
1H), 8.04–8.25 (m, 2H), 8.39 (d, J = 8.9 Hz, 1H) ppm; 13C NMR
1
(
1
q, J = 5.2 Hz), 138.1, 144.7, 149.2 (q, J = 34.9 Hz), 154.0,
p
59.1 ppm. IR max: 3344, 1683, 1144, 1100 cm 1; HRMS calcd
ꢀ
3
(75 MHz, CDCl ): d 25.7, 29.7, 52.8, 67.9, 115.5, 121.1 (q,
+
for C21
H
16
F
N
6 2
O
3
Na (M+Na) 481.0963, found 481.0941.
J = 276.1 Hz), 123.5 (q, J = 273.2 Hz), 127.0, 127.1, 128.6, 143.8,
p
ꢀ1
1
48.4 (q, J = 33.7 Hz), 151.7 ppm. IR max: 2887, 1307 cm . HRMS
+
4
4
.1.2. Preparation of (ꢀ)-(S)-7 and (+)-(R)-7
.1.2.1. (S)-Benzyl(1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-
calcd for C19
25 6 2
H F N OSi (M+H) 439.1619, found 439.1613.
(
(tert-butyldimethylsilyl)oxy)-ethyl)carbamate (ꢀ)-(S)-7.
At first, (ꢀ)-(S)-4 (625 mg, 1.36 mmol, 1 equiv) was dissolved
under an argon atmosphere, in dry CH Cl (5 mL) and 102 mg
1.50 mmol, 1.1 equiv) of imidazole were added. The solution
was stirred at 25 °C for 5 min before the addition of 225 mg
1.50 mmol, 1.1 equiv) of TBDMSCl. The mixture was stirred for
5 h at 25 °C. The reaction was quenched with a saturated aqueous
solution of Na CO and extracted with CH Cl . The combined
organic layers were dried over Na SO , filtered, and concentrated
4.1.3.2.
(R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-
Compound
butyldimethylsilyl)oxy)ethan-amine (ꢀ)-(R)-8.
2
2
(ꢀ)-(R)-8 was prepared from (+)-(R)-7 according to the same pro-
cedure as that of (+)-(S)-8. Colorless oil; yield 81%; ee 70%, HPLC
analysis was performed with Chiralpak IB column (heptane/iso-
(
(
1
propanol, 95:5, flow 1 mL/min, 278 nm, t
= 7.3 min); [
acetate 2:1); H NMR (300 MHz, CDCl
R
(S) = 6.6 min, t
0.27 (cyclohexane/ethyl
): d ꢀ0.02 (s, 3H), 0.07 (s,
R
(R)
2
0
a
]
D
= ꢀ36.9 (c 0.1, MeOH); R
f
1
2
3
2
2
3
2
4
3H), 0.87 (s, 9H), 1.66–1.99 (m, 2H), 2.08–2.11 (s, 2H), 3.79 [AB
(ABX), J = 9.8, 6.6, 3.9 Hz, 2H], 5.01 [X(ABX), J = 6.6, 3.9 Hz, 1H],
7.74 (t, J = 7.7 Hz, 1H), 8.04–8.25 (m, 2H), 8.39 (d, J = 8.9 Hz, 1H)
in vacuo. Flash chromatography on silica gel (cyclohexane/ethyl
acetate 4:1) afforded 693 mg of (ꢀ)-(S)-7 as a colorless oil. Yield
1
3
8
9%; ee 76%, HPLC analysis was performed with Chiralpak IB col-
3
ppm; C NMR (75 MHz, CDCl ): d 25.7, 29.7, 52.8, 67.9, 115.5,
umn (heptane/isopropanol, 95:5, flow 1 mL/min, 278 nm, t
R
(S)
0.77
): d
121.1 (q, J = 276.1 Hz), 123.5 (q, J = 273.2 Hz), 127.0, 127.1, 128.6,
p
20
=
5.9 min, t
R
(R) = 7.5 min); [
a
]
D
= ꢀ7.8 (c 0.1, MeOH); R
f
143.8, 148.4 (q, J = 33.7 Hz), 151.7 ppm. IR
max
:
2887,
1
ꢀ1
+
(
cyclohexane/ethyl acetate 2:1); H NMR (300 MHz, CDCl
3
1307 cm ; HRMS calcd for C19
H
25
F
6
N
2
OSi (M+H) 439.1650, found
ꢀ
0.19 (s, 3H), ꢀ0.11 (s, 3H), 0.79 (s, 9H), 4.02 [AX(ABX), J = 10.3,
439.1640.
3
1
.8, 2.9 Hz, 2H], 5.13 (s, 2H), 5.54–5.77 [X(ABX), J = 3.8, 2.9 Hz,
H], 7.28–7.58 (m, 5H), 7.75 (t, J = 7.1 Hz, 1H), 7.87 (s, 1H), 8.19
4.1.4. Preparation of Mosher amides 9a and 9b
4.1.4.1. (R)-N-((S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-
((tert-butyldimethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2-methoxy-
(
d, J = 7.1 Hz, 1H), 8.35 (d, J = 7.1 Hz, 1H) ppm; 13C NMR (75 MHz,
CDCl
3
):
d
25.6, 29.7, 51.9, 64.7, 67.4, 115.6, 121.3 (q,
J = 271.6 Hz), 123.5 (q, J = 273.7 Hz), 126.8, 127.4, 128.4, 128.8,
2-phenylpropanamide 9a.
60.0 mg (0.14 mmol, 1 equiv) of amine (+)-(S)-8 in 2 mL of
anhydrous CH Cl were added 0.04 mL (0.21 mmol, 1.5 equiv)
of N,N-diisopropylethylamine and 0.03 mL (0.17 mmol, 1.2 equiv) of
S)-(+)- -methoxy- -(trifluoromethyl)phenylacetyl chloride. The
solution was stirred at 25 °C for 1 h and then concentrated under
reduced pressure. The resulting oil was taken up in 1 M NH Cl
and then extracted into methylene chloride. The combined organic
layers were dried over Na SO , filtered, and concentrated in vacuo.
To a solution, under argon, of
1
1
29.8 (q, J = 30.0 Hz), 35.9, 143.9, 148.0 (q, J = 35.5 Hz), 149.1,
p
ꢀ1
55.7 ppm. IR max: 3330, 2902, 1684, 1530 cm . HRMS calcd
2
2
+
31 6 2 3
for C27H F N O Si (M+H) 573.1995, found 573.2008.
(
a
a
4
.1.2.2. (R)-Benzyl(1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-
(
(tert-butyldimethylsilyl)oxy)-ethyl)carbamate (+)-(R)-7.
4
Compound (+)-(R)-7 was prepared from (+)-(R)-4 according to
the same procedure as that of (ꢀ)-(S)-7. Colorless oil; yield 80%;
ee 70%, HPLC analysis was performed with Chiralpak IB column
2
4
The residue was purified by flash chromatography (cyclohexane/
(
=
heptane/isopropanol, 95:5, flow 1 mL/min, 278 nm,
t
R
(S)
0.77
): d
ethyl acetate 5:1) to afford 73.0 mg of 9a as a colorless oil. Yield
20
20
5.9 min, t
R
(R) = 7.5 min); [
a]
D
= +4.9 (c 0.1, MeOH); R
f
D f
79%; [a] = +39.9 (c 0.1, MeOH); R 0.27 (cyclohexane/ethyl acetate
1
1
(
cyclohexane/ethyl acetate 2:1); H NMR (300 MHz, CDCl
3
5:1); H NMR (400 MHz, CDCl
3
): d ꢀ0.10 (s, 3H), 0.01 (s, 3H), 0.89
ꢀ
0.19 (s, 3H), ꢀ0.11 (s, 3H), 0.79 (s, 9H), 4.02 [AX(ABX), J = 10.3,
(s, 9H), 3.41 (s, 3H), 4.04 [AB(ABX), J = 10.4, 4.20, 3.4 Hz, 2H],
3
1
.8, 2.9 Hz, 2H], 5.13 (s, 2H), 5.54–5.77 [X(ABX), J = 3.8, 2.9 Hz,
H], 7.28–7.58 (m, 5H), 7.75 (t, J = 7.1 Hz, 1H), 7.87 (s, 1H), 8.19
5.84–5.91 (m, 1H), 7.41–7.50 (m, 3H), 7.52–7.57 (m, 2H), 7.73
(t, J = 8.0 Hz, 1H), 7.93 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.34
d, J = 7.1 Hz, 1H), 8.35 (d, J = 7.1 Hz, 1H) ppm; 13C NMR (75 MHz,
(d, J = 8.0 Hz, 1H) ppm; C NMR (100 MHz, CDCl
13
): d ꢀ5.93,
(
3
CDCl
3
):
d
25.6, 29.7, 51.9, 64.7, 67.4, 115.6, 121.3 (q,
ꢀ5.90, 18.0, 25.5, 50.1, 54.9, 64.0, 84.2 (q, J = 26.5 Hz), 115.6
(q, J = 1.6 Hz), 121.2 (q, J = 275.5 Hz), 123.5 (q, J = 273.7 Hz), 123.7
J = 271.6 Hz), 123.5 (q, J = 273.7 Hz), 126.8, 127.4, 128.4, 128.8,
Please cite this article in press as: Bentzinger, G.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.003

G. Bentzinger et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
9
(
q, J = 290.3 Hz), 126.8, 127.5, 127.7, 128.8, 128.9 (q, J = 5.4 Hz),
3
(300 MHz, CDCl ): d 0.02 (s, 6H), 0.86–0.90 (m, 12H), 1.19–1.40
1
1
29.6 (q, J = 30.2 Hz), 129.7, 131.6, 143.9, 148.0 (q, J = 35.4 Hz),
(m, 4H), 1.44–1.60 (m, 2H), 2.17 (sbr, 1H), 2.39–2.57 (m, 2H),
3.74 [AB(ABX), J = 10.1, 8.2, 4.1 Hz, 2H], 4.68 [X(ABX), J = 8.2,
4.1 Hz, 1H), 7.73 (t, J = 8.1 Hz), 8.11–8.19 (m, 2H), 8.52 (d,
p
ꢀ1
48.2, 166.2 ppm; IR max: 2932, 1700, 1142 cm ; HRMS calcd
+
32 9 2 3
for C29H F N O Si (M+H) 655.2039, found 655.2019.
1
3
3
J = 8.1 Hz, 2H) ppm; C NMR (75 MHz, CDCl ): d 14.0, 22.5, 25.7,
2
9.3, 29.8, 47.8, 60.8, 66.8, 116.2, 121.3 (q, J = 275.7 Hz), 123.5 (q,
4
.1.4.2. (S)-N-((S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-
J = 273.7 Hz), 126.8, 127.2, 128.5, 129.5 (q, J = 30.2 Hz), 144.0,
(
(tert-butyldimethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2-methoxy-
p
+
ꢀ
1
1
48.5 (q, J = 35.1 Hz), 150.5 ppm; IR max: 2929, 1308, 632 cm
;
2
-phenylpropanamide 9b.
0.0 mg (0.11 mmol, 1 equiv) of amine (+)-(S)-8 in 2 mL of
Cl were added 0.03 mL (0.17 mmol, 1.5 equiv)
of N,N-diisopropylethylamine and 0.02 mL (0.13 mmol, 1.2 equiv)
of (R)-(ꢀ)- -methoxy- -(trifluoromethyl)phenylacetyl chloride.
The solution was stirred at 25 °C for 1 h and then concentrated
under reduced pressure. The resulting oil was taken up in 1 M NH
Cl and then extracted into methylene chloride. The combined
organic layers were dried over Na SO , filtered, and concentrated
To a solution, under argon, of
35 6 2
HRMS calcd for C24H F N OSi (M+H) 509.2423, found 509.2418.
5
anhydrous CH
2
2
4
.1.5.3.
(tert-butyldimethylsilyl)oxy)ethyl)heptan-1-amine
0b. Yellow oil; yield 67%; ee 74%, HPLC analysis was
performed with Chiralpak IB column (heptane/isopropanol, 99:1,
flow 1 mL/min, 278 nm, (S) = 3.7 min, (R) = 4.0 min);
= +18.0 (c 0.1, MeOH); R 0.69 (cyclohexane/ethyl acetate
): d 0.01 (s, 6H), 0.84–0.91 (m,
2H), 1.19–1.40 (m, 4H), 1.44–1.58 (m, 2H), 1.92 (sbr, 1H),
(S)-N-(1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-
(
1
(ꢀ)-(S)-
a
a
4
-
t
R
t
R
2
0
[a
]
D
f
2
4
1
5
1
:1); H NMR (300 MHz, CDCl
3
in vacuo. The residue was purified by flash chromatography (cyclo-
hexane/ethyl acetate 5:1) to afford 50.0 mg of 9b as a colorless oil.
2
0
2.39–2.58 (m, 2H), 3.73 [AB(ABX), J = 10.1, 8.2, 4.1 Hz, 2H], 4.66
[X(ABX), J = 8.2, 4.1 Hz, 1H], 7.73 (t, J = 8.1 Hz), 8.11–8.20 (m, 2H),
8
Yield 69%; [
a
]
D
= ꢀ37.3 (c 0.1, MeOH); R
f
0.34 (cyclohexane/ethyl
): d ꢀ0.08 (s, 3H), 0.06 (s,
H), 0.89 (s, 9H), 3.49 (s, 3H), 4.05 [AB(ABX), J = 10.4, 4.2, 3.3 Hz,
1
acetate 5:1); H NMR (400 MHz, CDCl
3
1
3
.52 (d, J = 8.1 Hz, 1H) ppm; C NMR (75 MHz, CDCl
3
): d 14.1,
3
2
7
2
2.6, 25.8, 27.1, 29.1, 30.1, 31.8, 47.8, 60.8, 66.8, 116.2, 121.3
H], 5.86–5.95 (m, 1H), 7.29–7.45 (m, 5H), 7.69 (t, J = 8.0 Hz, 1H),
.75 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H) ppm;
(
q, J = 274.8 Hz), 123.5 (q, J = 273.8 Hz), 126.8, 127.2, 128.6, 129.5
p
1
3
(q, J = 29.8 Hz), 144.0, 148.5 (q, J = 35.6 Hz), 150.4 ppm; IR max:
3
C NMR (100 MHz, CDCl ): d ꢀ5.9, ꢀ5.8, 18.0, 25.5, 49.8, 55.0,
ꢀ1
OSiNa (M+Na)+
2
5
931, 1309, 632 cm ; HRMS calcd for C26
59.2555, found 559.2539.
H
38
F
6
N
2
6
4.0, 84.0 (q, J = 26.5 Hz), 115.5 (q, J = 1.9 Hz), 121.1 (q,
J = 275.6 Hz), 123.4 (q, J = 273.7 Hz), 123.7 (q, J = 290.1 Hz), 126.9,
1
1
27.2, 127.5, 128.8, 128.9 (q, J = 5.4 Hz), 129.3 (q, J = 30.1 Hz),
29.8, 131.8, 143.9, 147.8 (q, J = 35.3 Hz), 148.3, 166.2 ppm; IR
4
.1.5.4.
(R)-N-(1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-
(ꢀ)-(R)-
Yellow oil; yield 64%; ee 70%, HPLC analysis was per-
formed with Chiralpak IB column (heptane/isopropanol, 99:1, flow
p
ꢀ1
((tert-butyldimethylsilyl)oxy)ethyl)heptan-1-amine
10b.
32 9 2 3
max: 2932, 1700, 1142 cm ; HRMS calcd for C29H F N O Si (M
+
+H) 655.2039, found 655.2033.
20
1
0
mL/min, 278 nm, t
R
(S) = 3.7 min, t
0.69 (cyclohexane/ethyl acetate 5:1); H NMR
R
(R) = 4.0 min); [
a
]
D
= ꢀ30.1 (c
4
.1.5. General procedure for preparation of compounds 10
To a microwave vessel were added 210 mg (0.48 mmol, 1 equiv)
1
.1, MeOH); R
f
(
(
300 MHz, CDCl
3
): d 0.01 (s, 6H), 0.84–0.91 (m, 12H), 1.19–1.40
of (ꢀ)-(S)-8 or (+)-(R)-8, 6 mL of CH
3
CN, 133 mg (0.96 mmol,
, 8.00 mg (0.05 mmol, 0.1 equiv) of KI and
.06 mL (0.48 mmol, 1 equiv) of the appropriate bromoalkane.
m, 4H), 1.44–1.58 (m, 2H), 1.92 (sbr, 1H), 2.39–2.58 (m, 2H),
2
0
2 3
equiv) of K CO
3
4
.73 [AB(ABX), J = 10.1, 8.2, 4.1 Hz, 2H], 4.66 [X(ABX), J = 8.2,
.1 Hz, 1H], 7.73 (t, J = 8.1 Hz), 8.11–8.20 (m, 2H), 8.52 (d,
The solution was heated at 150 °C for 3 h with a power of 200 W.
The reaction was quenched with water and extracted with ethyl
acetate. The combined organic layers were dried over Na SO , fil-
2 4
tered, and concentrated in vacuo. The crude compound was puri-
fied by flash chromatography on silica gel (cyclohexane/ethyl
acetate 5:1).
1
3
J = 8.1 Hz, 1H) ppm; C NMR (75 MHz, CDCl
3
): d 14.1, 22.6, 25.8,
2
7.1, 29.1, 30.1, 31.8, 47.8, 60.8, 66.8, 116.2, 121.3 (q,
J = 274.8 Hz), 123.5 (q, J = 273.8 Hz), 126.8, 127.2, 128.6, 129.5 (q,
J = 29.8 Hz), 144.0, 148.5 (q, J = 35.6 Hz), 150.4 ppm; IR
p
max
:
ꢀ1
+
2
5
931, 1309, 632 cm ; HRMS calcd for C26
59.2555, found 559.2539.
38 6 2
H F N OSiNa (M+Na)
4
(
1
.1.5.1.
(tert-butyldimethylsilyl)oxy)ethyl)pentan-1-amine
0a. Yellow oil; yield 62%; ee 78%, HPLC analysis was per-
formed with Chiralpak IB column (heptane/isopropanol, 99:1, flow
(S)-N-(1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-
4
1
.1.6. General procedure for the preparation of compounds 2
To a solution of 114 mg (0.22 mmol, 1 equiv) of silylated alcohol
0a or 10b in dried THF (6 mL), under an Ar atmosphere and cooled
(+)-(S)-
to 0 °C, were added 0.67 mL (0.67 mmol, 3 equiv) of TBAF (1 M in
THF). The reaction was stirred at 0 °C for 1 h and then quenched
with water. The mixture was extracted with ethyl acetate. The
combined organic layers were dried over Na
centrated in vacuo. The crude compound was purified by flash
chromatography on silica gel (CH Cl /MeOH 99:1).
20
1
0
R R D
mL/min, 278 nm, t (S) = 3.8 min, t (R) = 4.2 min); [a] = +30.7 (c
1
.1, MeOH); R
f
0.62 (cyclohexane/ethyl acetate 5:1); H NMR
(
(
300 MHz, CDCl
3
): d 0.02 (s, 6H), 0.86–0.90 (m, 12H), 1.19–1.40
2 4
SO , filtered, and con-
m, 4H), 1.44–1.60 (m, 2H), 2.17 (sbr, 1H), 2.39–2.57 (m, 2H),
3
4
.74 [AB(ABX), J = 10.1, 8.2, 4.1 Hz, 2H], 4.68 [X(ABX), J = 8.2,
.1 Hz, 1H), 7.73 (t, J = 8.1 Hz), 8.11–8.19 (m, 2H), 8.52 (d,
2
2
1
3
J = 8.1 Hz, 2H) ppm; C NMR (75 MHz, CDCl
3
): d 14.0, 22.5, 25.7,
4
.1.6.1.
ylamino)ethanol (+)-(S)-2a.
HPLC analysis was performed with Chiralpak IB column (hep-
tane/ethanol, 99:1, flow 1 mL/min, 278 nm, t (R) = 31.9 min, t (S)
0.37 (CH Cl /MeOH
): d 0.82–0.95 (m, 3H),
(S)-2-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(pent-
2
9.3, 29.8, 47.8, 60.8, 66.8, 116.2, 121.3 (q, J = 275.7 Hz), 123.5 (q,
White solid; yield 83%; ee 86%,
J = 273.7 Hz), 126.8, 127.2, 128.5, 129.5 (q, J = 30.2 Hz), 144.0,
p
ꢀ1
1
48.5 (q, J = 35.1 Hz), 150.5 ppm; IR max: 2929, 1308, 632 cm
;
+
R
R
HRMS calcd for C24
H
35
F
6
N
2
OSi (M+H) 509.2423, found 509.2418.
20
=
9
34.3 min); [
a]
D
= +22.0 (c 0.1, MeOH); R
f
2
2
1
9:1); mp 50 °C; H NMR (400 MHz, CDCl
3
4
(
1
.1.5.2.
(tert-butyldimethylsilyl)oxy)-ethyl)pentan-1-amine
0a. Yellow oil; yield 60%; ee 62%, HPLC analysis was per-
formed with Chiralpak IB column (heptane/isopropanol, 99:1, flow
(R)-N-(1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-
1.20–1.40 (m, 4H), 1.46–1.60 (m, 2H), 2.16–2.39 (s , 2H),
2.45–2.63 (m, 2H), 3.78 [AB(ABX), J = 10.8, 7.9, 4.0 Hz, 2H], 4.75
br
(ꢀ)-(R)-
[X(ABX), J = 7.9, 4.0 Hz, 1H], 7.75 (t, J = 8.0 Hz), 8.04 (s, 1H), 8.18
13
(d, J = 8.0 Hz, 1H), 8.46 (d, J = 8.0 Hz, 1H) ppm;
C NMR
20
1
mL/min, 278 nm, t
R
(S) = 3.8 min, t
R
(R) = 4.2 min); [
a
]
D
= ꢀ15.4 (c
(100 MHz, CDCl ): d 13.9, 22.4, 29.3, 29.8, 47.7, 60.1, 65.7, 115.4,
3
1
0
.1, MeOH); R 0.62 (cyclohexane/ethyl acetate 5:1); H NMR
f
121.2 (q, J = 275.5 Hz), 123.7 (q, J = 273.7 Hz), 127.0, 127.2, 128.1,
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1
0
G. Bentzinger et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
2
0
1
3
28.8 (q, J = 5.4 Hz), 129.6 (q, J = 30.1 Hz), 144.0, 148.4 (q, J =
210 nm,
MeOH); R
NMR (400 MHz, CDCl
.44–1.57 (m, 2H), 3.24–3.52 (m, 2H), 3.64–3.97 (m, 2H), 5.12 (s,
t
R
(S) = 7.3 min,
0.67 (cyclohexane/ethyl acetate 2:1); mp 120 °C;
): d 0.84–0.89 (m, 3H), 1.13–1.31 (m, 4H),
t
R
(R) = 10.0 min); [
a
]
D
= ꢀ12.6 (c 0.1,
p
ꢀ1
1
5.2 Hz), 150.0 ppm; IR max: 2929, 1308, 1140, 629 cm ; HRMS
f
H
+
calcd for C18
H
21
N
OF
2 6
(M+H) 395.1558; found 395.1538.
3
1
4
.1.6.2. (R)-2-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(pent-
ylamino)ethanol (ꢀ)-(R)-2a. White solid; yield 100%; ee
0%, HPLC analysis was performed with Chiralpak IB column (hep-
tane/ethanol, 99:1, flow 1 mL/min, 278 nm, t (R) = 31.9 min, t (S)
0.37 (CH Cl /MeOH
): d 0.82–0.95 (m, 3H),
.20–1.40 (m, 4H), 1.46–1.60 (m, 2H), 2.16–2.39 (sbr 2H),
.45–2.63 (m, 2H), 3.78 [AB(ABX), J = 10.8, 7.9, 4.0 Hz, 2H], 4.75
1H), 5.76–5.84 (m, 1H), 5.92 (s, 1H), 7.26–7.45 (m, 5H), 7.75 (t,
J = 7.0 Hz, 1H), 7.91 (s, 1H), 8.18 (d, J = 7.0 Hz, 1H), 8.39 (d,
1
3
7
3
J = 7.0 Hz, 1H) ppm; C NMR (100 MHz, CDCl ): d 13.8, 22.4,
R
R
28.2, 29.0, 50.6, 67.4, 71.5, 71.8, 115.5, 120.9 (q, J = 275.6 Hz),
123.5 (q, J = 273.8 Hz), 126.8, 127.3, 127.6, 128.2, 128.4, 128.6,
2
0
=
9
1
2
34.3 min); [
a]
D
= ꢀ29.0 (c 0.1, MeOH); R
f
2
2
1
9:1); mp 50 °C; H NMR (400 MHz, CDCl
3
128.7 (q, J = 5.4 Hz), 129.6 (q, J = 30.2 Hz), 135.9, 143.9, 148.1 (q,
p
,
J = 35.3 Hz), 149.2, 155.8 ppm; IR
1104 cm ; HRMS calcd for C26
found 551.1761.
max: 2943, 1683, 1552,
ꢀ1
+
26 6 2 3
H F N O Na (M+Na) 551.1745,
[
(
(
1
1
X(ABX), J = 7.9, 4.0 Hz, 1H], 7.75 (t, J = 8.0 Hz), 8.04 (s, 1H), 8.18
13
d, J = 8.0 Hz, 1H), 8.46 (d, J = 8.0 Hz, 1H) ppm;
100 MHz, CDCl ): d 13.9, 22.4, 29.3, 29.8, 47.7, 60.1, 65.7, 115.4,
21.2 (q, J = 275.5 Hz), 123.7 (q, J = 273.7 Hz), 127.0, 127.2,
C NMR
3
4.1.7.2.
(R)-2-((1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-
(+)-(R)-11.
(pentyloxy)ethyl)imino)-1-phenylethanone
28.1, 128.8 (q, J = 5.4 Hz), 129.6 (q, J = 30.1 Hz), 144.0, 148.4
Compound (+)-(R)-11 was prepared from (R)-4 according to the
same procedure as that (ꢀ)-of (S)-11. White solid; yield 53%; ee
68%, HPLC analysis was performed with Chiralpak IB column (hep-
p
ꢀ1
(
q, J = 35.2 Hz), 150.0 ppm; IR max: 2929, 1308, 1140, 629 cm
;
+
21 2 6
HRMS calcd for C18H N OF (M+H) 395.1558; found 395.1540.
tane/isopropanol, 90:10, flow 1 mL/min, 210 nm, t
R
(S) = 7.3 min,
0.67 (cyclohexane/
ethyl acetate 2:1); mp 120 °C; H NMR (400 MHz, CDCl ): d 0.84–
2
0
4
.1.6.3.
ylamino)ethanol (+)-(S)-2b.
HPLC analysis was performed with Chiralpak IB column (hep-
tane/ethanol, 99:1, flow 1 mL/min, 278 nm, t (R) = 29.5 min, t (S)
0.17 (CH Cl /MeOH
): d 0.75–0.99 (m, 3H), 1.19–1.40
(S)-2-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(hept-
R D f
t (R) = 10.0 min); [a] = +3.2 (c 0.1, MeOH); R
1
Colorless oil; yield 73%; ee 74%,
3
0.89 (m, 3H), 1.13–1.31 (m, 4H), 1.44–1.57 (m, 2H), 3.24–3.52
(m, 2H), 3.64–3.97 (m, 2H), 5.12 (s, 1H), 5.76–5.84 (m, 1H), 5.92
(s, 1H), 7.26–7.45 (m, 5H), 7.75 (t, J = 7.0 Hz, 1H), 7.91 (s, 1H),
R
R
2
0
=
9
32.3 min); [
a]
D
= +25.6 (c 0.1, MeOH); R
f
2
2
1
13
9:1); H NMR (400 MHz, CDCl
3
8.18 (d, J = 7.0 Hz, 1H), 8.39 (d, J = 7.0 Hz, 1H,) ppm; C NMR
(
m, 8H), 1.44–1.61 (m, 2H), 2.46–2.63 (m, 2H), 2.72 (sbr, 2H),
3
(100 MHz, CDCl ): d 13.8, 22.4, 28.2, 29.0, 50.6, 67.4, 71.5,
3
3
1
1
.79 [AB(ABX), J = 10.9, 7.9, 3.9 Hz, 2H], 4.75 [X(ABX), J = 7.9,
71.8, 115.5, 120.9 (q, J = 275.6 Hz), 123.5 (q, J = 273.8 Hz), 126.8,
127.3, 127.6, 128.2, 128.4, 128.6, 128.7 (q, J = 5.4 Hz), 129.6
.9 Hz, 1H], 7.75 (t, J = 7.9 Hz), 8.06 (s, 1H), 8.18 (d, J = 7.9 Hz,
H), 8.46 (d, J = 7.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl
): d
4.0, 22.5, 27.1, 29.1, 30.0, 31.8, 47.7, 60.1, 65.7, 115.5, 121.2 (q,
(q, J = 30.2 Hz), 135.9, 143.9, 148.1 (q, J = 35.3 Hz), 149.2,
3
p
ꢀ
1
155.8 ppm; IR max: 2943, 1683, 1552, 1104 cm ; HRMS calcd
+
J = 275.5 Hz), 123.5 (q, J = 273.7 Hz), 126.9, 127.2, 128.1, 128.8 (q,
26 6 2 3
for C26H F N O Na (M+Na) 551.1745, found 551.1761.
J = 5.4 Hz), 129.7 (q, J = 30.4 Hz), 144.0, 148.3 (q, J = 35.4 Hz),
p
ꢀ1
1
C
49.6 ppm; IR max: 2928, 1308, 1142 cm ; HRMS calcd for
4.1.8. Preparation of (+)-(S)-3 and (ꢀ)-(R)-3
4.1.8.1. (S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(pent-
yloxy)ethanamine (+)-(S)-3. To solution of 115 mg
+
20
25 2 6
H N OF (M+H) 423.1871, found 423.1849.
a
4
.1.6.4. (R)-2-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(hept-
Colorless oil; yield 85%; ee
6%, HPLC analysis was performed with Chiralpak IB column (hep-
tane/ethanol, 99:1, flow 1 mL/min, 278 nm, t (R) = 29.5 min, t (S)
0.17 (CH Cl /MeOH
): d 0.75–0.99 (m, 3H), 1.19–1.40
(0.22 mmol, 1 equiv) of (S)-11 in 4 mL of EtOH, under argon, were
added 46.0 mg of Pd/C (40% w/w). The mixture was placed under
an H atmosphere and stirred at 25 °C for 8 h. The reaction mixture
2
ylamino)ethanol (ꢀ)-(R)-2b.
5
R
R
was filtered off through a Celite pad. The filtrate was concentrated
under reduced pressure. The residue was purified by flash chro-
matography on silica gel (cyclohexane/ethyl acetate 2:1). Orange
oil; yield 74%; ee 58%, HPLC analysis was performed with Chiralpak
IB column (heptane/isopropanol, 95:5, flow 1 mL/min, 278 nm,
2
0
=
9
32.3 min); [
a
]
D
= ꢀ28.9 (c 0.1, MeOH); R
f
2
2
1
9:1); H NMR (400 MHz, CDCl
3
(
m, 8H), 1.44–1.61 (m, 2H), 2.46–2.63 (m, 2H), 2.72 (sbr, 2H),
3
3
1
1
.79 [AB(ABX), J = 10.9, 7.9, 3.9 Hz, 2H], 4.75 [X(ABX), J = 7.9,
2
0
.9 Hz, 1H], 7.75 (t, J = 7.9 Hz), 8.06 (s, 1H), 8.18 (d, J = 7.9 Hz,
t
R
(S) = 8.1 min, t
R
(R) = 9.0 min); [
a]
D
= +28.1 (c 0.1, MeOH); R
f
H), 8.46 (d, J = 7.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl
): d
4.0, 22.5, 27.1, 29.1, 30.0, 31.8, 47.7, 60.1, 65.7, 115.5, 121.2 (q,
0.45 (cyclohexane/ethyl acetate 2:1); H NMR (400 MHz, CDCl
1
3
3
):
d 0.77–0.96 (m, 3H), 1.16–1.38 (m, 4H), 1.55–1.65 (m, 2H), 1.83–
2.09 (sbr, 2H), 3.37–3.56 (m, 3H), 3.72 (dd, J = 9.4, 3.6 Hz, 1H),
5.06–5.12 (m, 1H), 7.74 (t, J = 7.9 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H),
J = 275.5 Hz), 123.5 (q, J = 273.7 Hz), 126.9, 127.2, 128.1, 128.8 (q,
J = 5.4 Hz), 129.7 (q, J = 30.4 Hz), 144.0, 148.3 (q, J = 35.4 Hz),
p
ꢀ1
13
1
49.6 ppm; IR max: 2928, 1308, 1142 cm . HRMS calcd for
8.21 (s, 1H), 8.41 (d, J = 7.9 Hz, 1H) ppm; C NMR (100 MHz,
+
C
20
25
H N
2
OF
6
(M+H) 423.1871, found 423.1849.
3
CDCl ): d 14.0, 22.5, 28.3, 29.2, 51.1, 71.7, 75.3, 115.4, 121.3 (q,
J = 275.6 Hz), 123.5 (q, J = 273.7 Hz), 127.0, 127.1, 127.5, 128.6 (q,
4
4
.1.7. Preparation of (ꢀ)-(S)-11 and (+)-(R)-11
.1.7.1. (S)-2-((1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-
To
a solution of 100 mg (0.22 mmol, 1 equiv) of (S)-4 in 4 mL of
CH Cl , under argon and placed in the dark, were added 255 mg
1.10 mmol, 5 equiv) of silver oxide and 0.29 mL (2.20 mmol,
J = 5.5 Hz), 129.5 (q, J = 30.1 Hz), 143.8, 148.5 (q, J = 35.2 Hz),
p
ꢀ1
151.6 ppm; IR max: 2935, 2866, 1313, 1135, 1100 cm ; HRMS
+
(
pentyloxy)ethyl)imino)-1-phenylethanone (ꢀ)-(S)-11.
calcd for C18
20 6 2
H F N ONa (M+Na) 417.1378, found 417.1360.
2
2
4.1.8.2. (R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(pent-
(
yloxy)ethanamine (ꢀ)-(R)-3.
Compound (ꢀ)-(R)-3 was pre-
1
6
0 equiv) of iodopentane. The suspension was stirred at 25 °C for
3 h, filtered off through a Celite pad, and washed with CH Cl
pared from (R)-11 according to the same procedure as that of
(ꢀ)-(S)-11. Colorless oil; yield 74%; ee 66%, HPLC analysis was per-
formed with Chiralpak IB column (heptane/isopropanol, 95:5, flow
2
2
.
The filtrate was concentrated in vacuo. Flash chromatography on
silica gel (cyclohexane/ethyl acetate 4:1) afforded (ꢀ)-(S)-11 as a
white solid. Yield 41%; ee 64%, HPLC analysis was performed with
Chiralpak IB column (heptane/isopropanol, 90:10, flow 1 mL/min,
2
0
1 mL/min, 278 nm, t
0.1, MeOH); R 0.45 (cyclohexane/ethyl acetate 2:1); H NMR
(400 MHz, CDCl ): d 0.77–0.96 (m, 3H), 1.16–1.38 (m, 4H),
R
(S) = 8.1 min, t
R
(R) = 9.0 min); [
a]
D
= ꢀ43.3 (c
1
f
3
Please cite this article in press as: Bentzinger, G.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.003

G. Bentzinger et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
11
1
.55–1.65 (m, 2H), 1.83–2.09 (sbr, 2H), 3.37–3.56 (m, 3H), 3.72 (dd,
References
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Please cite this article in press as: Bentzinger, G.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.003