Synthesis and application of amino alcohol imides as NMR solvating agents for chiral discrimination of carboxylic acids

Article abstract of DOI:10.1016/j.tetasy.2016.05.009

A series of amino alcohol imides 2–8 have been synthesized from commercially available starting materials by regioselective ring opening reaction of epoxides with chiral amines. Compounds 2–8 were tested as chiral solvating agents (CSAs) for enantiomeric discrimination of biological important carboxylic acids. C₂-Symmetric (S,R,R,S)-3 was found to be a satisfactory CSA for mandelic acid with ΔΔδ of 24.8?Hz. CSA (S,S)-5 exhibited the best enantiomeric discrimination for α-phenyl-α-methoxyacetic acid with ΔΔδ of 32?Hz. Enantiomeric differentiated values found for mandelic acid, o-chloro mandelic acid, ibuprofen and naproxen are 7.2, 4.4, 2 and 3?Hz respectively.

Full text of DOI:10.1016/j.tetasy.2016.05.009

Tetrahedron: Asymmetry 27 (2016) 597–602
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and application of amino alcohol imides as NMR solvating
agents for chiral discrimination of carboxylic acids
⇑
Mehmet Karakaplan , Basam Jameel
Department of Chemistry, Faculty of Science, University of Dicle, 21280 Diyarbakır, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of amino alcohol imides 2–8 have been synthesized from commercially available starting mate-
rials by regioselective ring opening reaction of epoxides with chiral amines. Compounds 2–8 were tested
as chiral solvating agents (CSAs) for enantiomeric discrimination of biological important carboxylic acids.
C2-Symmetric (S,R,R,S)-3 was found to be a satisfactory CSA for mandelic acid with DDd of 24.8 Hz. CSA (S,
Received 15 March 2016
Accepted 27 May 2016
Available online 25 June 2016
S)-5 exhibited the best enantiomeric discrimination for
a-phenyl-a-methoxyacetic acid with DDd of
32 Hz. Enantiomeric differentiated values found for mandelic acid, o-chloro mandelic acid, ibuprofen
and naproxen are 7.2, 4.4, 2 and 3 Hz respectively.
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
for the commercialization of drug substances with chiral
properties.11 Therefore, the development of new CSAs continues to
Chiral recognition has received considerable attention due to
the significant importance of chirality in biology. It is very impor-
tant to check or ascertain the enantiomeric composition and abso-
lute configuration of chiral molecules. Ever growing requirement
for enantiopure molecules in the pharmaceutical industries and
the consequent demand for asymmetric synthesis impose the
necessity for exploring simple, easy to use, cost effective and reli-
able techniques for testing of enantiopurity.1 Among the various
methods, NMR spectroscopy has the advantages of easy perfor-
mance and accessibility with no need for special equipment apart
from the common NMR spectrometers.2
be an active area research and several types of CSAs have been pro-
posed, from very simple chiral organic molecules to supramolecular
or multiselector systems.12 In the present study we report the syn-
thesis of chiral amino alcohol imides and their applications as CSAs
for enantio discrimination of carboxylic acids by NMR spectroscopy.
For this purpose, amino alcohol imides 3–8 were synthesized by
regioselective ring opening reaction of (R)-N-(2,3-epoxypropyl)
phthalimide with appropriate chiral amines (Schemes 1 and 2).
2. Results and discussions
Chiral carboxylic acids are basic building blocks of natural prod-
ucts and drug molecules as well as versatile functional synthons.3
Due to their importance in biological systems and usefulness as a
source of chirality in organic synthesis, the chiral recognition of car-
boxylic acids by artificial receptors is of critical importance in the
preparation, separation, and analysis of enantiomers. Dioxocyclens,4
macrocyclic dioxopolyamines,5 proline derivatives,6 amines,7 amine
and amide functionalized macrocycles,8 aminonaphthols or amino
alcohols,9 calixarene10 have been designed and used for enantiodis-
crimination of chiral carboxylic acids.
The basic unit amino alcohol imide functionality was created by
the regioselective ring opening reaction of (R)-N-(2,3-epoxypropyl)
phthalimide with various chiral amines. We chose this system due
to the simplicity of its preparation from readily available sub-
stances and connected with three functional groups of hydroxyl,
secondary or tertiary amine and imide groups which are closely
to the stereocenters. Herein we planned to make different deriva-
tives of enantiomerically pure N,N0-dibenzyl-1,2-diamnocyclohex-
ane 1 which is used as many asymmetric reactions as a catalyst.13
Therefore, C2-symmetric compound (R,R,R,R)-2 with secondary
amine alcohol functionality was prepared by reaction of (R,R)-1
with (R)-styrene oxide to give a tertiary amino alcohol which was
then debenzylated to give (R,R,R,R)-2 in 71.7% yield. C2-symmetric
(S,R,R,S)-3 with tertiary amine functionality was easily prepared
by regioselective ring opening of (R)-N-(2,3-epoxypropyl)phthalim-
ide with chiral amine (R,R)-1 in high yield (70%).
Nowadays, world regulatory authorities such as U.S. Food
and Drug Administration (FDA) and European Medicines Agency
(EMA) impose that the control of enantiomeric purities is crucial
⇑
Corresponding author. Tel.: +90 4122488550; fax: +90 4122488300.
E-mail address: mkkaplan@dicle.edu.tr (M. Karakaplan).
http://dx.doi.org/10.1016/j.tetasy.2016.05.009
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.

598
M. Karakaplan, B. Jameel / Tetrahedron: Asymmetry 27 (2016) 597–602
Amino alcohol and amino alcohol imide functionalized 2–8
molecules were used as potential CSAs for enantio discrimination
of mandelic acid (A), o-chloromandelic acid (B), -phenyl-
a
a-
H2N
NH2
methoxyacetic acid (C), ibuprofen (D) and naproxen (E) as analytes
in 1H NMR spectroscopy (Fig. 1). The results obtained by this work
are as follows:
1. PhCHO, MeOH
2. NaBH4, HO-
O
Ph
Ph
Ph
1.
, MeOH
OH
Ph
Ph
Ph
Ph
O
OH
N
N
OH
OH
OH
OH
O
OH
NH
NH
1
HO
OH
O
O
O
O
O
1b
OMe
Cl
N
Pd(OH)2/C,
[H], MeOH
i-PrOH
O
i-Bu
MeO
C
D
A
B
E
O
O
Ph
Ph
Ph
Ph
N
Figure 1. Structure of analytes used herein.
N
N
N
NH
NH
HO
OH
HO
OH
O
O
2
3
Amino alcohol (R,R,R,R)-2 with secondary alcohol and amine
functionality shifted the signal C- -H of analytes to the high mag-
Scheme 1. Synthesis of amino alcohol (R,R,R,R)-2 and amino alcohol imid (S,R,R,S)-
3.
a
netic field (0.02–0.3 ppm) and exhibited low enantiomeric dis-
criminations. The best differentiated value was obtained in the
case of mandelic acid with DDd of 10 Hz (Table 1). C2-Symmetric
amino alcohol imide (S,R,R,S)-3 was found to be the best reagent
for enantio discrimination of mandelic acid with DDd of 24.8 Hz.
O
N
,
O
O
The values for
a-phenyl-a-methoxyacetic acid and o-chloroman-
O
delic acid were found to be 16.6 and 8 Hz respectively (Table 1).
Therefore, we have shown the practically applicable of the (S,R,R,
S)-3 as a good CSA for the measurement of mandelic acid as a
model analyte (Fig. 2).
We have also tried to get a deeper knowledge about inclusion
complexes formed in solution. Therefore, we focused on the spe-
cies formed between (S,R,R,S)-3 and analyte A. Job plots for both
mandelic acid’s enantiomers indicate 1:1 CSA/A stoichiometry
(Fig. 3).
N
H
N
NH2
N-(2,3-epoxypropyl)
phthalimide, i-PrOH
OH
O
4
O
N-(2,3-epoxypropyl)
phthalimide
N
N
NH2
H
i-PrOH
OH
O
1. PhCHO, MeOH
2. NaBH4, HO-
5
Amino alcohol amide (R,S)-4 which derived from (R)-
hexylethylamine was showed a good enantiomeric discrimination
towards mandelic acid, o-chloro mandelic acid and -phenyl-
-methoxyacetic acid with DDd of 8.8, 6.4 and 3.6 Hz respectively.
Amino alcohol amide (S,S)-5 which derived from (S)- -cyclo-
a-cyclo-
O
N-(2,3-epoxypropyl)
Ph
a
phthalimide
N
N
N
H
Ph
a
i-PrOH
OH
a
O
hexylethylamine was also exhibit a good enantiomeric discrimina-
tion towards all of the analtytes. The best enantio differentiated
6
value was found to be for
a-phenyl-a-methoxyacetic acid with
O
N-(2,3-epoxypropyl)
DDd of 32 Hz. Enantiomeric differentiated values found for man-
delic acid, o-chloro mandelic, ibuprofen and naproxen are 7.2,
4.4, 2.0 and 3.0 Hz respectively. It is indicate that the S configura-
tion of amine has a broad enantio discrimination ability than the
(R,S)-4 by creation of better pocket sides to binding with one of
enantiomer of chiral acids. Additionally, it can be stated that polar
group of stereogenic center causes strong hydrogen bonding,
dipol–dipol interaction to enantio discrimination of mandelic acid
or its derivatives when compared with ibuprofen and naproxen.
Reasonable CSA activity of (S,S)-5 lead us to prepare samples of
phthalimide
R
N
H
N
R
NH2
i-PrOH
OH
O
7
8
: R = phenyl,
: R = 1-naphthyl
Scheme 2. Synthesis of amino alcohol imides 4–8.
Chiral compound (R,S)-4 and (S,S)-5 were prepared by the ring
opening reaction of (R)-N-(2,3-epoxypropyl)phthalimide with
(R)- and (S)-cyclohexylethylamine in 68% and 73% yield respec-
tively. We next tried to block the N–H functionality of (S,S)-5 in order
to see the effect of tertiary amine and/or hydroxyl and imide groups
different enantiomeric purity (0–100%) of
acetic acid and it showed a satisfactory experimentally enan-
tiomeric discrimination (Fig. 4).
a-phenyl-a-methoxy-
Amino alcohol imide (S,S)-6 as a N-benzyl derivative of (S,S)-5
exhibit low enantio differentiated values. It showed discrimination
ability towards only mandelic acid, o-chloro mandelic acid with
DDd of 2.4 and 3 Hz respectively (Table 2). This is indicate that sec-
ondary amine functionality of (S,R)-5 play an important rule on
enantiomeric recognition via hydrogen bonding. The better CSA
ability of (S,R,R,S)-3 with tertiary amine functionality can be
attributed to its symmetry and less flexibility properties when com-
pared with (S,R)-6. Surprisingly, it was found that amino alcohol
imide (S,R)-7 and (S,R)-8 which are bearing phenyl and naphthyl
on chiral solvating process. With this aim (S)-a-cyclohexylethy-
lamine was condensed with benzaldehyde to the imine intermedi-
ate and then reduced to form benzylated product which was then
converted to the (S,S)-6 by using (R)-N-(2,3-epoxypropyl)phthalim-
ide with excellent conversion (Scheme 2). Extended studies
were focused on the introducing aromatic substituents to this
system. Therefore, (S)-a-phenylethylamine and (S)-1-(1-naphthyl)
ethylamine were treated with (R)-N-(2,3-epoxypropyl)phthalimide
to give (S,S)-7 and (S,S)-8 in high yields (Scheme 2).

M. Karakaplan, B. Jameel / Tetrahedron: Asymmetry 27 (2016) 597–602
599
Table 1
Induced shifts (
D
d, ppm) and splitting (DDd, ppm) for the signal of the carboxylic acids A–E in the presence of CSA 2–5 (400 MHz, 20 mM in CDCl3 at 25 °C)
Acid
Signal
CSA
2
3
4
5
D
da
DDdb
D
da
DDdb
D
da
DDdb
D
da
DDdb
1
2
3
4
5
A
B
C
D
E
Ca
Ca
Ca
Ca
Ca
H
H
H
H
H
ꢀ0.300
ꢀ0.247
ꢀ0.002
0.015
10
ꢀ0.513
ꢀ0.514
ꢀ0.164
ꢀ0.020
ꢀ0.045
24.8
8.0
16.8
0.0
0.489
8.8
5.6
3.6
1.2
3.2
ꢀ0.474
ꢀ0.452
ꢀ1.117
ꢀ0.147
ꢀ0.110
7.2
4.4
32.0
2.0
4.4
0.0
0.8
0.0
ꢀ0.456
ꢀ0.242
ꢀ0.384
ꢀ0.236
ꢀ0.013
0.0
2.4
a
Averaged between signals (ppm) from both enantiomers.
DDd: Hz.
b
% ee
100
80
60
40
20
0
Figure 2. 1H NMR spectra of ( )-mandelic acid (A) of various ratios of optical purity (0–100% ee) in the presence of (S,R,R,S)-3 [1:2 equiv of (S,R,R,S)-3/A].
nating abilities for carboxylic acids have been investigated by 1H
NMR spectroscopy. Chiral amino alcohol imids (S,R,R,S)-3 and (S,
S)-5 were discovered to exhibit good enantio discrimination
towards mandelic and
a-phenyl-a-methoxyacetic acids respec-
tively, indicating the possible use of these compounds as potential
CSAs. The results indicate that not only class of chiral amine but also
both polarity and chiral environment of reagent and analyte are
effective in the chiral discrimination in 1H NMR analysis.
4. Materials and methods
Figure 3. Job plots for (S)- and (R)-A with CSA (S,R,R,S)-3.
4.1. Apparatus and chemicals
Melting points were determined with GALLENKAMP Model
apparatus with open capillaries. Infrared spectra were recorded
on a MIDAC-FTIR Model 1700 spectrophotometer. The Elemental
substituents exhibit any significant enantiomeric discriminations
with all of the analytes. This is may be due to the lower polarity
and planar shape of side arm of (S,S)-7 and (S,S)-8 is not sufficient
driving force to form relative stable inclusion complexes.
_
analyses were obtained with CARLO-ERBA Model 1108 apparatus.
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded
on BRUKER DPX-400 high performance digital FT-NMR spectrome-
ter, with tetramethylsilane as the internal standard solutions in
deuteriochloroform. Optical rotations were recorded using PERKIN
ELMER Model 341 polarimeter. All chemicals were purchased from
Sigma Aldrich and Merck and reagent grade unless otherwise
specified.
3. Conclusion
In conclusion, we have synthesized novel an amino alcohol and
six amino alcohol imide functionalized compounds (3–8) by regios-
elective ring opening of terminal epoxides. Their enantiodiscrimi-

600
M. Karakaplan, B. Jameel / Tetrahedron: Asymmetry 27 (2016) 597–602
% ee
100
80
60
40
20
0
Figure 4. 1H NMR spectra of ( )-
a
-phenyl-
a
-methoxyacetic acid (C) of various ratios of optical purity (0–100% ee) in the presence of (S,S)-5. [1:1 equiv of (S,S)-5/C].
4.2.2. General procedure for the synthesis of compounds 3–7
Table 2
Compounds 3–7 have been synthesized using a procedure orig-
Induced shifts (Dd, ppm) and splitting (DDd, ppm) for the signal of the carboxylic
acids A–E in the presence of CSA 6–8 (400 MHz, 20 mM in CDCl3 at 25 °C)
inally reported by Roehrig et al.16 Chiral amine or amino alcohol
(0.6 mmol, 1.2 equiv) in 10 mL isopropanol was added to the solu-
tion of (R)-N-(2,3-epoxypropyl)phthalimide (102 mg, 0.50 mmol)
in 10 mL of isopropanol at in an ice bath and stirred for 1 h. then
refluxed for 12 h. The reaction monitored by TLC. Solvent was
removed by rotary evaporator under reduced pressure after com-
pletion of the reaction.
Acid
Signal
CSA
6
7
8
D
da
DDdb
D
da
DDdb
D
da
DDdb
6
7
8
9
A
B
C
D
E
Ca
Ca
Ca
Ca
Ca
H
H
H
H
H
ꢀ0.153
ꢀ0.167
ꢀ0.007
ꢀ0.067
ꢀ0.007
2.4
3.0
0.0
0.0
0.0
ꢀ0.136
ꢀ0.173
ꢀ0.059
ꢀ0.093
ꢀ0.166
7.6
0.0
0.0
0.0
2.2
ꢀ0.006
0.015
0.002
0.0
0.0
0.0
0.0
0.0
ꢀ0.002
4.2.3. N,N0-Dibenzyl-N,N0-bis[(S)-2-hydroxy-3-phtalimido]-
(1R,2R)-1,2-diaminocyclo-hexane 3
10
0.013
a
Averaged between signals from both enantiomers.
DDd: Hz.
Compound (S,R,R,S)-3 was synthesized by reacting (R)-N-(2,3-
epoxypropyl)phthalimide (2.04 g, 5 mmol) and 1 (0.73 g, 5 mmol)
as the method described above. Solvent was removed under
reduced pressure by completion of the reaction and the crude pro-
duct was purified by crystallization with MeOH to give 2.45 g 70%
b
as a white crystals. Mp: 164–165 °C, [
(KBr): 3434.6, 3384.5, 3332.4, 3053.75, 2931.3, 2859.9, 1771.3,
a
]
20 = ꢀ14.2° (c = 1, CHCl3). IR
D
4.2. Synthesis
1709.6, 1612.2, 1434.97, 1393.3, 1147.4, 1083.8, 1011.5, 842.7,
626.0, 619.0 cmꢀ1 1H NMR (400 MHz, CDCl3, ppm) d: 7.84 (d,
.
4.2.1. (1R,2R)-Bis[(R)-2-hydroxy(2-phenyl)ethyl]-1,2-
diaminocyclohexane 2
J = 2.4 Hz, 2H); 7.713 (d, J = 2.8 Hz, 2H); 7.468–7335 (m, 10H);
4.34–3.27 (m, 10H); 2.86–2.14 (m, 6H); 1.69–1.67 (m, 6H); 1.05
(m, 4H). 13C NMR (100 MHz CDCl3, ppm) d: 168.33, 138.08,
133.80, 132.17, 128.33, 127.35, 123.24, 66.58, 58.86, 56.28, 53.08,
42.21, 25.40, 23.76. Anal. Calcd for C42H44N4O6: C, 72.0; H, 6.28;
N, 8.0. Found: C, 71.58; H, 6.12; N, 7.78.
Compounds 1 and 1b were synthesized starting from chiral 1,2-
diaminocyclohexane as described in previously report.14 Pd(OH)2/C
(20%, 75 mg) was added in one portion to a solution of the appro-
priate compound 1b (400 mg, 0.75 mmol) in methanol (2 mL) as
described previously report.15 The mixture was stirred under
hydrogen and the reaction was monitored by TLC. Sodium carbon-
ate (80 mg, 0.75 mmol) was added and stirred for 1 h by the com-
pletion of the reaction. The solution was filtrated and washed with
methanol, then concentrated in vacuum. The crude product was
purified by flash chromatography on silica gel H:EtOAc:EtOH:TEA
(4:1:1:0.5 as eluent) to give 190 mg 71.7% of compound 2 as a vis-
4.2.4. 2-[(2S)-2-Hydroxy-3-[[(1R)-a-cyclohexylethyl]amino]
propyl]isoindoline-1,3-dione 4
Compound 4 was synthesized by reacting (R)-N-(2,3-epoxypro-
pyl)phthalimide (767 mg, 3.77 mmol) and (R)- -cyclohexylethy-
a
lamine (0.4 g, 3.15 mmol) as usual manner. Solvent was removed
under reduced pressure by completion of the reaction and the
crude product was purified by flash chromatography on silica gel
with n-hexane:EtOAc (1:4 as eluent) to give 0.707 mg 68% yield
cous oil. [
a
]
20 = ꢀ52.2° (c = 1, CHCl3). IR (KBr): 3346, 3250, 3057,
D
3030, 2926, 2860, 1493, 1453, 1348, 1310, 1195, 1139, 1056,
924, 893, 854, 791, 756, 701 cmꢀ1 1H NMR (400 MHz, CDCl3,
.
20 = 14° (c = 1, CHCl3).
ppm) d: 7.41–7.27 (m, 10H), 4.55 (dd, J = 4, J = 8.12 Hz, 2H), 2.90–
2.71(m, 8H), 2.32–2.27 (m, 2H), 2.12–1.99 (m, 2H), 1.38–1.37 (m,
2H); 1.28–1.05 (m, 4H). 13C NMR (100 MHz, CDCl3, ppm) d:
142.55, 128.39, 127.48, 125.90, 72.00, 60.32, 53.84, 31.87, 25.01.
Anal. Calcd for C22H30N2O2: C, 74.57; H, 8.47; N, 7.90. Found: C,
74.89; H, 8.36; N, 7.82.
as white powder crystals. Mp 136–138 °C, [a]
D
IR (KBr): 3460.7, 3453.6, 3319.8, 3262.9, 3032.5, 2911.0, 2848.3,
2760.6, 2697.9, 1769.3, 1709.6, 1439.6, 1393.3, 1318.1, 1163.8,
1112.74, 1094.42, 1024.0, 898.9, 836.9, 789.7, 717.7 cmꢀ1 1H
.
NMR (400 MHz, CDCl3, ppm) d: 1H NMR (CDCl3): 7.88–7.86 (m,
2H); 7.75–7.73 (m, 2H); 4.04–4.01 (m, 1H); AB system; A part:

M. Karakaplan, B. Jameel / Tetrahedron: Asymmetry 27 (2016) 597–602
601
3.808 (dd, J = 24.8 Hz, J = 13.6 Hz, –CH2–, 1H); B part: 3.793 (dd,
J = 23.2 Hz, J = 14 Hz, –CH2–, 1H); 2.83 (dd, J = 9.2 Hz, J = 3.2 Hz,
1H); 2.69 (dd, 12.4 Hz, 7.2 Hz, 1H); 2.572–2.542 (m, 1H): 1.77–
1.69 (m, 5H); 1.26–1.01 (m, 9H). 13C NMR (100 MHz CDCl3, ppm)
d: 168.64, 134.07, 132.03, 123.41, 66.99, 58.19, 49.38, 42.24,
41.60, 29.61, 28.20, 26.54, 26.40, 26.29, 16.29. Anal. Calcd for
by flash chromatography on silica gel with n-hexane:EtOAc:TEA
(1:0.5:0.1 as eluent) to afford pure compound 6 (612 mg, 76.69%)
as a viscous oil. [
a]
20 = 10.7° (c = 1, CHCl3). IR (KBr): 3264, 2921,
D
2851, 1773, 1714, 1566, 1463, 1395, 1085, 1023, 918, 627 cmꢀ1
.
1H NMR (400 MHz, CDCl3, ppm) d: 7.84–7.81 (m, 2H); 7.72–7.69
(m, 2H); 7.31–7.22 (m, 5H); 3.912–3.87 (m, 1H); 3.807–3.689 (m,
3H); 2.71 (br s, 1H); 2.62–2.56 (m, 2H); 1.39–1.26 (m, 5H). 13C
NMR (100 MHz CDCl3, ppm) d: 168.70, 145.14, 134.05, 131.98,
128.53, 127.08, 126.57, 123.37, 68.47, 58.52, 50.50, 42.00, 24.14.
Anal. Calcd for C19H20N2O3: C, 70.37; H, 6.17; N, 8.64. Found: C,
70.56; H: 6.10; N, 8.54.
C19H26N2O3: C: 69.09, H: 7.87; N: 8.48. Found: C, 68.87; H, 7.69;
N, 7.79.
4.2.5. 2-[(2S)-2-Hydroxy-3-[[(1S)-a-cyclohexylethyl]amino]
propyl]isoindoline-1,3-dione 5
Compound 5 was synthesized by reacting (R)-N-(2,3-epoxypro-
pyl)phthalimide (767 mg 3.77 mmol) and (S)- -cyclo-
a
4.2.8. 2-[(2S)-2-Hydroxy-3-[[(1S)-1-naphthylethyl]amino]
propyl]isoindoline-1,3-dione 8
hexylethylamine (0.4 g, 3.15 mmol) as usual manner. Solvent was
removed under reduced pressure by completion of the reaction
and the crude product was purified by flash chromatography on sil-
ica gel with n-hexane:EtOAc (3:2 as eluent) to give 0.76 mg 73.07%
Compound 8 was synthesized by reacting (R)-N-(2,3-epoxypro-
pyl)phthalimide (528 mg 2.6 mmol) and (S)-1-(1-naphthyl)ethy-
lamine (442.45 mg, 2.6 mmol) as usual manner. Solvent was
removed under reduced pressure by completion of the reaction
and the crude product was purified by flash chromatography on sil-
ica gel with n-hexane:EtOH (4:1 as eluent) to give pure compound 6
of 5 as viscous oil. [a]
20 = +7.2° (c = 1, CHCl3). IR (KBr): 3386.5,
D
3380.5, 3378, 3156.29, 3142.3, 3130.4, 3125.5, 2918.75, 2850.3,
1710.65, 1614.14, 1429.0, 1394.29, 1329.69, 1189.8, 1127.2,
1087.67, 1029.8, 982.5, 917.0, 722.2 cmꢀ1
.
1H NMR (400 MHz,
(698 mg, 72%) as a white solid. Mp 249–250 °C, [a]
20 = +16.9°
D
CDCl3, ppm) d: 7.86–7.71 (m, 4H); 3.96–3.93 (m, 1H); AB system;
A part: 3.78 (dd, J = 22.8 Hz, 17.6 Hz, –CH2–, 1H); B part: 3.76 (dd,
J = 21.2 Hz, J = 14 Hz, –CH2–, 1H); 3.103 (m, 2H): 2.86 (dd,
J = 12.4 Hz, J = 4 Hz. 1H); 2.536–2.449 (m, 1H); 1.75–1.65 (m, 5H);
1.22–0.98 (m, 10H). 13C NMR (100 MHz CDCl3, ppm) d: 168.64,
134.01, 132.02, 123.35, 67.98, 58.45, 50.20, 42.69, 41.89, 29.75,
27.95, 26.66, 26.54, 26.40, 16.93. Anal. Calcd for C19H26N2O3: C,
69.09; H, 7.87; N, 8.48. Found: C, 68.72; H, 7.62; N, 7.92.
(c = 0.5, DMSO). IR (KBr): 3492, 3468, 3421, 3352, 3290.9, 3051.8,
2952.5, 2843.5, 2796.3, 2689.2, 2622.7, 2526.3, 1773.2, 1711.5,
1588.1, 1433.8, 1395.2, 1345.1, 1296.9, 1092.5, 1008.6, 964.2,
801.3, 779.1, 723.2 cmꢀ1 1H NMR (400 MHz, CDCl3, ppm) d: 9.78
.
(br s, 1H); 9.08 (br s, 1H): 8.20–8.18 (m, 1H); 8.00–7.56 (m, 8H);
5.86 (s, 1H); 5.36 (s, 1H); 4.20 (s, 1H); 3.57–3.12 (m, 3H); 2.67 (s,
1H): 2.47 (s, 1H); 1.68–1.67 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz
CDCl3, ppm) d: 168.28, 134.81, 134.10, 133.80, 132.12, 130.83,
129.37, 127.41, 126.60, 126.60, 124.74, 123.50, 122.96, 64.36,
52.76, 49.40, 41.97, 20.55. Anal. Calcd for C23H22N2O3: C, 73.80; H,
5.88; N, 7.49. Found: C, 73.36; H: 6.10; N, 7.84.
4.2.6. 2-[(2S)-2-Hydroxy-3-[N-benzyl-[(1S)-a-cyclohexylethyl]
amino]propyl]isoindol-ine-1,3-dione 6
(S)-N-Benzyl-
sor of compound 6. Therefore, (S)-
6.82 mmol) was benzylated to give 1.42 g 96% of (S)-N-benzyl-
a
-cyclohexylethylamine was prepared as a precur-
a-cyclohexylethylamine (1 mL,
4.2.9. Evaluation of the stoichiometric ratio of the (S,R,R,S)-3
and mandelic acid complexes (Job plots)
a
-
cyclohexylethylamine according to the literature method.15 IR
(KBr): 3321.8, 3161.7, 3067.2, 2940.12, 1643.9, 1582.3, 1483.0,
1431.9, 1378.8, 1332.8, 1224.5, 1189.8, 1068.3, 981.6, 838.8
(cmꢀ1). 1H NMR (400 MHz, CDCl3, ppm) d: 7.38–7.29 (m, 5H), 3.89
(d, 1H, J = 13.2 Hz), 3.75 (d, J = 13.2 Hz, 1H), 2.58–2.51 (m, 1H),
1.82–1.71 (m, 6H), 1.44–1.14 (m, 4H), 1.09–1.01 (m, 5H). 13C NMR
(100 MHz CDCl3, ppm) d: 141.16, 128.34, 128.12, 126.75, 57.12,
51.62, 43.02, 29.89, 28.13, 26.84, 26.72, 26.59, 16.79). Compound
The stoichiometry of the complexes between (S,R,R,S)-3 and
enantiomers of mandelic acid were clarified by Job plot.17 There-
fore, equimolar amounts of CSA and analytes were dissolved in
CDCl3. The solution distributed among nine NMR tubes that molar
reaction of that solutions was kept from 0.1 to 0.9. Chemical shifts
differences (Dd) C-a-H of mandelic acid was determined. Mol frac-
tion (X) of these nine tubes plotted against X. (Dd) itself.
6
was prepared by using (R)-N-(2,3-epoxypropyl)phthalimide
Acknowledgement
(0.655 mg, 3.77 mmol) and (S)-N-benzyl- -cyclohexylethylamine
a
(0.7 g, 3.22 mmol) as usual manner. Solvent was removed under
reduced pressure by completion of the reaction and the crude pro-
duct was purified by flash chromatography on silica gel with n-hex-
ane:EtOAc (2:1 as eluent) to give compound 6 as viscous oil (1.05 g,
This research was supported by the Research Project Council of
Dicle University (DÜBAP). (Project No.: FEN-15-006).
References
77.66%). [
3434, 3086, 2913, 2859, 1772, 1712, 1611, 1429, 1393, 1327,
1262, 1151, 1086, 1027, 960, 722 cmꢀ1 1H NMR (400 MHz, CDCl3,
a]
20 = +9.8° (c = 1, CHCl3). IR (KBr): 3564, 3514, 3476,
D
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