Pyridine-containing chiral macrocycles for the enantioselective recognition of amino acid derivatives and their molecular dynamics simulations

Article abstract of DOI:10.1016/j.tetasy.2010.05.038

Two novel C₂-symmetric optically active pyridine-15-crown-5 type ligands containing lipophilic chains at the stereogenic centres, macrocycles 5 and 6, were prepared from (S)-1,2-propanediol and (S)-3-aryloxy-1,2-propanediol for the enantiomeric recognition of amino acid ester derivatives. These novel macrocycles have been shown to be strong complexing agents for primary organic ammonium salts (with K values of up to 1363.5 M^-1, ΔG ^o of up to 17.86 kJ mol^-1 and a selectivity ratio of 80:20) by ¹H NMR titration method. These macrocyclic host exhibited enantioselective binding towards the l-enantiomer of phenylalanine methyl ester hydrochloride with K_L/K_D up to 8.57 in CDCl₃ containing 0.25% CD₃OD. Experimental results have been detailed with molecular dynamic calculations at atomic level concerning the molecular recognition and discrimination properties of a chiral pyridino-15-crown-5. The binding free energies were calculated as ～-25 kJ mol^-1. The results indicated that the host binds and discriminates valine salts better than phenylalanine salts. The molecular dynamics, MM/PBSA calculations are consistent with the ¹H NMR results.

Full text of DOI:10.1016/j.tetasy.2010.05.038

Tetrahedron: Asymmetry 21 (2010) 990–996
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Pyridine-containing chiral macrocycles for the enantioselective recognition
of amino acid derivatives and their molecular dynamics simulations
*
Yilmaz Turgut , Safak Ozhan Kocakaya
University of Dicle, Faculty of Science, Department of Chemistry, TR-21280 Diyarbakir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Two novel C2-symmetric optically active pyridine-15-crown-5 type ligands containing lipophilic chains
at the stereogenic centres, macrocycles 5 and 6, were prepared from (S)-1,2-propanediol and (S)-3-aryl-
oxy-1,2-propanediol for the enantiomeric recognition of amino acid ester derivatives. These novel mac-
rocycles have been shown to be strong complexing agents for primary organic ammonium salts (with K
Received 28 April 2010
Accepted 21 May 2010
Available online 21 June 2010
values of up to 1363.5 Mꢀ1
,
DG
o of up to 17.86 kJ molꢀ1 and a selectivity ratio of 80:20) by 1H NMR titra-
-enantiomer of
tion method. These macrocyclic host exhibited enantioselective binding towards the
L
phenylalanine methyl ester hydrochloride with KL/KD up to 8.57 in CDCl3 containing 0.25% CD3OD. Exper-
imental results have been detailed with molecular dynamic calculations at atomic level concerning the
molecular recognition and discrimination properties of a chiral pyridino-15-crown-5. The binding free
energies were calculated as ꢁꢀ25 kJ molꢀ1. The results indicated that the host binds and discriminates
valine salts better than phenylalanine salts. The molecular dynamics, MM/PBSA calculations are consis-
tent with the 1H NMR results.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Chiral pyridine-containing macrocycles have been an attractive
area of research due to their chirality of chiral discrimination to-
The design, synthesis and use of macrocycles capable of selec-
tive recognition of other molecules are of great interest in a variety
of fields. Various types of natural and synthetic chiral compounds
have been used as chiral subunits for constructing optically active
crown ethers, while the continuing development of chiral building
blocks has resulted in the production of a wide variety of optically
active crown ethers exhibiting characteristic chiral recognition
behaviour.1 Modern chemistry utilizes these chemicals in various
respects, for instance as enzyme models2 in biochemistry, for
phase transfer catalysis3 in organic synthesis and analytical
chemistry.
A variety of chiral host compounds have recently been developed
for the discrimination of the molecular chirality of organic com-
pounds, such as chiral organic ammonium and amino acids ammo-
nium salts with good enantioselectivity in supramolecular
chemistry.4
wards chiral organic ammonium salts and amino acids deriva-
tives.21 The pyridine subunit of these macrocycles has been
reported to be important for the tripod hydrogen bonding forma-
tion with organic ammonium salts and the
p–p interaction with
the aromatic moiety of the ammonium guest and steric repulsion
between the bulky groups on the stereogenic centres of the ligand
and the substituents of the ammonium salt.10
The enantiomeric recognition of chiral amino acids by synthetic
and natural host compounds is one of the most challenging sub-
jects in modern host–guest chemistry. Host–guest chiral recogni-
tion plays an important role in biological process, resolution of
enantiomers and asymmetric catalysis reactions.22 A number of
synthetic model compounds have been designed and synthesized
as chiral host molecules that help chemists understand the basis
of the mechanism of host-guest complexations and their chiral rec-
ognitions. Hence, we herein report the synthesis of two types of
pyridine-containing macrocycles with methyl and aryloxy groups
on the stereogenic centre for the enantiomeric recognition of dif-
Since Cram and et al. prepared their important enantiomeric
recognition studies,5 many different chiral macrocyclic ligands
have been prepared for enantiomeric recognition studies. Some
of these ligands include those containing amino acid units,6 sugar
molecules,7,8 diaza crown units9 and chiral crown ethers which
contain the pyridine subcyclic unit.10–20
ferent
PheOMe,
a
-amino acid methyl ester hydrochlorides (
D-PheOMe, L-
D-ValOMe,
L
-ValOMe) by 1H NMR titration method in
CDCl3 with 0.25% CD3OD. Furthermore molecular modelling was
carried out in order to understand the recognition on a molecular
level; the results are in good agreement with the experimental
data. Both experimental and theoretical calculations have proven
to be powerful tools for studies on molecular recognition.
* Corresponding author. Tel.: +90 412 248 8550; fax: + 90 412 248 83 00.
E-mail address: yturgut@dicle.edu.tr (Y. Turgut).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.038

Y. Turgut, S. O. Kocakaya / Tetrahedron: Asymmetry 21 (2010) 990–996
991
at 298 K. The observed downfield shifts of pyridine triplet protons
at host were monitored, with addition of various quantities of the
guest. Before adding any guest, the proton of the pyridine host
showed one triplet peak around 7.79 ppm. For the host pyridine
triplet protons, the 1H NMR signal gradually shifted downfield
upon addition of the guest (Fig. 1). The Job’s plot based on the
chemical shift changes supported the 1:1 stoichiometry of host-
guest complexes (Fig. 2). A typical plot for the complexation of 6
2. Results and discussion
2.1. Synthesis
Compounds 1a,b, 2a,b, 3 and 4 were prepared according to our
previously described methods.23 Compounds 1a and 1b reacted
with excess (S)-a-phenyl ethylamine to obtain 2a and 2b in yields
of 65% and 63%, respectively (Scheme 1). The tetra-stereogenic C2-
symmetric chiral amino alcohols 3 and 4 were synthesized from
ditosylate with an excess of 2a and 2b in the presence of Na2CO3
in yields of 46% and 48%, respectively.
Chiral C2-symmetric pyridine-crowns 5, 6 were synthesized for
the enantiomeric recognition of a-amino acid methyl ester hydro-
chlorides. The syntheses of the designed chiral aza-crown ether 5
and 6 are summarized in Scheme 1. Cyclization of 2,6-pyridine-
dimethyl ditosylate with 3 and 4 using NaH as a base in dry THF
afforded 5 and 6.
with
D
-ValOMeꢂHCl salt (guest) is shown in Figure 3.
For amino acid methyl esters, association constants have pre-
sented the both steric and electronic effects, with the least bulky
ValOMe showing the largest association constant accordingly. For
ValOMe and PheOMe which have isopropyl and benzyl bulky
groups, the aromatic group in PheOMe gives it a more pronounced
electronic effect compared to ValOMe.
The association constants of
L-amino acid methyl ester hydro-
chlorides are higher than those of
D-amino acid methyl ester
hydrochlorides with chiral crown ether 5 and 6. The values of KL/
KD are presented in Table 1. These findings are supported theoret-
ically by the thermodynamical data calculated using MM/PBSA
method as shown in Table 2.
2.2. 1H NMR titration studies
NMR spectroscopy is one of the most common methods em-
ployed for the analysis of chiral compounds.24 Enantiomerically
pure derivatizing reagents can be used to prepare diastereomeric
compounds that have differences in their NMR spectra. Alterna-
tively, enantiomerically pure or enriched compounds can be used
as chiral solvating agents to form diastereomeric complexes that
associate through non-covalent interactions.
The association constants of the chiral crown ether 5 with the
and
-enantiomers of PheOMe were found to be 490.8 Mꢀ1and
662.9 Mꢀ1, respectively. The
-form is 1.35 times more stable than
the -form (selectivity ratio: 58/42) as shown in Table 1. This sta-
D-
L
L
D
bility is in accordance with thermodynamic values given in Table 2.
On the other hand, although host 5 has larger association constants
with
selectivity between
of the ValOMe salts (KL/KD: 1.35 and 1.17 with the selectivity ratio
58/42 and 56/54). This showed that -PheOMe and -PheOMe-con-
taining aromatic moieties make interactions with the pyridine
ring in the host in addition to the other non-covalent interactions.
However, since there is no interaction in the case of ValOMe
due to its smaller size it interacts with an enantiomer better and
showed more structure selectivity properties allowing it to interact
easier and link with the macrocyclic cavity.
D
- and
L
-ValOMe than
D
-PheOMe and
L-PheOMe salts, the
The NMR titration method has proven to be effective in deter-
mining the binding constant for chiral crown ether-chiral ammo-
nium cation interactions, especially for systems in which both
host and guest molecules contain aromatic groups. The advantages
of the 1H NMR method are that the experiment can be carried out
in a wide variety of solvents and that useful structural information
can often be obtained. The association constants of the supramo-
lecular systems formed was calculated according to the modified
Benesi–Hildebrand equation25 on the basis of the NMR spectrum
of complexes.
D-PheOMe and
L-PheOMe is lower than that
D
L
p–p
p–p
The association constants of the chiral crown ether 6 with the
and
-enantiomers of PheOMe were found to be 44.9 Mꢀ1and
385 Mꢀ1, respectively. The
-form is 8.57 times more stable than
the -form (selectivity ratio KL/KD = 89:11) as shown in Table 1.
D-
The enantiomeric recognition for the hydrogen chloride salts of
L
D
-, L-PheOMe, D-, L-ValOMe by the chiral crown ethers 5 and 6 has
been characterized by the 1H NMR titration method. The concen-
L
D
tration of host was fixed at 5.6 mM in CDCl3 with 0.25% CD3OD
Ph
N
Ph
N
R
R
TsO
Ph
N
i
Ph
N
+
ii
Ph
+
OTs
HO
HO
N
H
Ph
NH2
PhO
OPh
TsO
OH
HO
OH
HO
2a R:-CH3
1a R:-CH3
1b R:-CH2OPh
3
2b
R:-CH2OPh
4
Ph
Ph
Ph
N
N
Ph
N
iii
N
PhO
OPh
O
O
O
O
N
N
6
5
Scheme 1. Synthesis of chiral amino alcohols and chiral pyridine-containing macrocycles. Reagents and conditions: (i and ii) Na2CO3, 12 h, 110 °C, (iii) (1) NaH/THF, reflux,
(2) 2,6-pyridinedimethyl ditosylate/THF, 50 h.

992
Y. Turgut, S. O. Kocakaya / Tetrahedron: Asymmetry 21 (2010) 990–996
Figure 1. 1H NMR spectral changes of chiral crown ether 6 (5.6 mM) in the presence of phenyl alanine methyl ester hydrochloride (0–17.8 mM) in CDCl3 with 0.25% CD3OD.
0.9
y = 0,2004x - 0,1007
0.8
R2 = 0,9889
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
1/[G]o(mM-1)x10+2
Figure 2. Job plots for
D-ValOMeꢂHCl and host 6.
Figure 3. Typical plot of 1/Dd versus 1/[G]o for host guest complexion of host 6 and
D-ValOMeꢂHCl.
Table 1
Binding constants (Ka), the Gibbs free energy changes (ꢀ
D
Go) and enantioselectivites KL/KD for the complexation of L-/D-guests with the 5 and 6 in CDCl3 with 0.25% CD3OD
Entry
Guests
-PheOMeꢂHCl
-PheOMeꢂHCl
-ValOMeꢂHCl
-ValOMeꢂHCl
-PheOMeꢂHCl
-PheOMeꢂHCl
-ValOMeꢂHCl
-ValOMeꢂHCl
Ka (Mꢀ1
)
KL/KD
ꢀ
D
Goa (kJ molꢀ1
)
ꢀ
0.74
DDGob (kJ molꢀ1
)
5
490.8 0.021
662.9 0.018
1164.9 0.034
1363.5 0.028
1.35
15.35 0.023
16.09 0.057
17.49 0.032
17.86 0.033
D
L
1.17
0.37
D
L
6
44.9 0.016
385.0 0.021
502.4 0.031
593.9 0.018
8.57
1.18
9.43 0.014
14.75 0.016
15.41 0.033
15.83 0.014
5.32
0.42
D
L
D
L
a
D
G
o = ꢀ2.303RTLog Ka.
DDGo ¼ ꢀð
D
GLo
ꢀ
D
GoDÞ.
b

Y. Turgut, S. O. Kocakaya / Tetrahedron: Asymmetry 21 (2010) 990–996
993
Table 2
Calculated thermodynamic parameters for complexation of 5 and 6 with L-/D-guest by MM/PBSA method
Entry
Guests
-PheOMeꢂHCl
-PheOMeꢂHCl
-ValOMeꢂHCl
-ValOMeꢂHCl
-PheOMeꢂHCl
-PheOMeꢂHCl
-ValOMeꢂHCl
-ValOMeꢂHCl
D
Ha
T
D
Sb
ꢀ
D
Gc
D
GL/DGD
ꢀ
0.17
DDG
5
ꢀ78.25
ꢀ86.40
ꢀ84.06
ꢀ84.47
ꢀ53.25
ꢀ61.24
ꢀ59.36
ꢀ58.27
24.99
25.16
24.70
26.20
1.01
D
L
1.01
0.42
D
L
6
ꢀ67.26
ꢀ84.60
ꢀ85.61
ꢀ92.63
ꢀ58.27
ꢀ51.50
ꢀ52.12
ꢀ56.26
8.99
33.10
33.49
36.37
3.69
1.09
24.12
2.89
D
L
D
L
a
b
c
Enthalpy of binding calculated by MM/PBSA method in kJ molꢀ1
.
Entropy of binding calculated by MM/PBSA method multiplied by 300 K.
Theoretical binding free energy produced from G = S.
H ꢀ T
D
D
D
Figure 4. Molecular structures of lowest energy conformers observed in molecular dynamic simulation host 6
L
-PheOMe (left) and host 6 D-PheOMe (right).
This difference is also supported by the calculated thermodynamic
explained by steric hindrance of two aryloxy moieties on the stere-
ogenic centre of the host and interaction of bulky and non-bulky
groups in the amino acids. Furthermore, this can be explained by
the fact that the non-covalent interaction (e.g., ion pairing, hydro-
values (Table 2,
DGL/DGD = 3.69).
In the same way, crown 6 exhibited chiral recognition towards
the enantiomers of the ValOMe salt by forming a complex with the
L
-form of the guest, which was 1.18 times more stable than that
gen bonding, and cation–
interaction (molecular dynamics calculations also display this,
Figs. 4 and 5).
When host 5 and host 6 are compared, it can be seen that the
methyl substituent on 5 is replaced by an aryloxy group in 6. Nei-
ther host 5 nor host 6 exhibits high enantioselectivity for the ValO-
p interaction) is more important than the
formed with the
D
- and ꢀDDGo = 0.41 kJ molꢀ1. Although host 6
p–p
exhibits better complexation with ValOMe than PheOMe, the
enantioselectivity was substantially smaller between ValOMe
guests. In contrast, we determined high enantioselectivities for
the complexes of 6 with PheOMe. This result can probably be
Figure 5. Molecular structures of lowest energy conformers observed in molecular dynamic simulation host 6 L-ValOMe (left) and host 6 D-ValOMe (right).

994
Y. Turgut, S. O. Kocakaya / Tetrahedron: Asymmetry 21 (2010) 990–996
Me salts, while for the PheOMe salts especially host 6 exhibits high
enantioselectivity. Thus, it can be stated that host 6, which has
aryloxy group on two stereogenic centres, exhibits better rigidity
and molecular cavity and form sandwich-type complex, so it plays
an important role in molecular recognition.
The hydrogen bonding of the ammonium salt of the guest with
the oxygens and nitrogen of the macrocycle, and the steric effects
of the diaryloxy group of the macrocycle could play important
roles in enantiomeric recognition; this reason, the hydrogen bond-
ing between the host compound and the guest may lead the forma-
tion of the complex, while steric interaction contributes to
enantiomeric recognition.
(3 ꢃ 50 mL). The combined CHCl3 phase was washed with brine
and dried with Na2SO4. The organic phase was removed under re-
duced pressure and excess of (S)-a-phenyl ethylamine was dis-
tilled at 90–95 °C/1 mmHg and the product was distilled at 140–
141 °C/1 mmHg to give 2a as white oil (4.52 g, 65%).
½
a 3D4
ꢄ
¼ þ25:4 (c 1, CHCl3); IR:
m 3364, 2980, 2928, 1651, 1452,
1380, 1138, 1061 cmꢀ1 1H NMR (CDCl3): d (ppm) 1.10 (d, 3H,
;
J = 6.4 Hz), 1.40 (d, 3H, J = 6.8 Hz), 2.27 (q, 1H, J = 4.0 Hz), 2.52 (br
s, 2H), 2.63 (q, 1H, J = 8.8 Hz), 3.82 (q, 2H, J = 6.4 Hz), 7.25 (m,
5H). 13C NMR (CDCl3): d (ppm) 20.41, 24.46, 54.40, 57.68, 65.79,
126.54, 129.09, 128.56, 144.98. Anal. Calcd for C11H17NO: C,
73.74; H, 9.49; N, 7.82. Found: C, 74.00; H, 9.70; N, 7.80.
As deduced from the computational results of the complexes,
the phenyl groups adjacent to the recognition centre make
p
–p
4.2.2. (S)-1-[N-(S)-a-Phenyl ethyl]amino-3-phenoxypropanol-2-
interactions with the double bonds present in the ligand. In addi-
tion the affinity of the ligand towards the host is enhanced by H-
bonding interactions between aryloxy groups and the ammonium
protons of the ligand. The secondary function of the aryloxy groups
of the host is to facilitate cavity formation for ligand binding.
ol 2b
It was prepared and purified in the same way as described
above for 2a starting from (S)- -phenylethylamine (3.75 g,
31.05 mmol), (S)-1-(p-toluenesulfonate)-3-phenoxypropanol-2-ol
a
(2.00 g, 6.21 mmol) and Na2CO3 (0.65 g, 6.13 mmol) to give 2b as
yellow oil (1.00 g, 63%). ½a D34
ꢄ
¼ þ35:4 (c 1.68, CHCl3); IR:
m 3326,
3. Conclusions
3058, 3031, 2967, 2929, 2877, 1741, 1606, 1587, 1490, 1452,
1375, 1297, 1247, 1170, 1085, 1047 cmꢀ1 1H NMR (CDCl3): d
;
In summary, the novel C2-symmetric chiral amino alcohol and
crown macrocycles 5 and 6 possessing methyl and aryloxy groups
as chiral barriers were developed. Their enantiomeric recognition
(ppm) 1.44 (d, 3H, J = 6.8 Hz), 2.63 (br s, 2H, NH ve OH), 2.73 (m,
2H), 3.83 (q, 1H, J = 6.4 Hz), 3.97 (m, 3H), 6.95 (m, 3H), 7.39 (m,
10H). 13C NMR (CDCl3): d (ppm) 24.23, 50.12, 58.74, 68.95, 70.61,
115.65, 121.07, 126.69, 127.15, 128.61, 129.53, 145.15, 158.72.
Anal. Calcd for C17H21NO2: C, 75.27; H, 7.75; N, 5.16. Found: C,
75.25; H, 7.59; N, 5.18.
properties towards D- and L-amino acid methyl ester hydrochlo-
rides using NMR titration together with theoretical calculation
have been studied. Results obtained from the both methods were
found to be relatively comparable. The theoretical experiments re-
sults helped to understand details of binding mode of complexes.
Aza-crown macrocycle 6 exhibited the high enantioselectivity to-
4.2.3. (2S,9S)-4,7-[N-(S)-
(S)-1-[N-(S)- -Phenyl
a
-Phenylethyl]diaza-2,9-decanediol 3
a
ethyl] amino-2-propanol (9 g,
wards L-phenylalanine methyl ester hydrochloride with a good
selectivity ratio of 80:20.
50.28 mmol), ethylene glycol ditosylate (3.10 g, 8.38 mmol) and
Na2CO3 (1.5 g, 14.15 mmol) were stirred at 110 °C for 12 h under
argon. Then the mixture was cooled and 100 mL CHCl3 was added
to the mixture and refluxed for 2 h. The organic phase was sepa-
rated from the solid phase. The remaining solid was re-extracted
with CHCl3 (3 ꢃ 50 mL). The combined CHCl3 phase was washed
with brine and dried with Na2SO4. The organic phase was removed
4. Experimental
4.1. Reagents and general methods
All chemicals were reagent grade unless otherwise specified.
under reduced pressure and the excess (S)-1-[N-(S)-a-phenyl
(S)-
pany. The
a
-Phenyl ethylamine was purchased from Fluka chemical com-
ethyl] aminopropan-2-ol was distilled at 140–141 °C/1 mmHg.
The residue was purified by chromatography over silica gel using
EtOAc/Hexane/Et3N (10:30:2) to give 3 as yellow oil (1.50 g,
D
- and -amino acid methyl ester hydrochlorides were
L
obtained from Aldrich Chemical Co. Silica gel 60 (Merck, 0.040–
0.063 mm) and silica gel/TLC-cards (F254) were used for column
chromatography and TLC. All reaction was carried out under nitro-
gen or argon atmosphere with dry solvent under anhydrous condi-
tions, unless other noted. Tetrahydrofuran (THF) was distilled from
sodium/benzophenone ketyl immediately prior to use and methy-
lene chloride (CH2Cl2) was dried from calcium hydride. Melting
points were determined with a Gallenkamp Model apparatus with
open capillaries. Elemental analyses were performed with a Carlo-
Erba 1108 model apparatus. Optical rotations were taken on a Per-
kin Elmer 341 model polarimeter. 1H (400 MHz) and 13C (100 MHz)
NMR spectra were recorded on a Bruker DPX-400 High Perfor-
mance Digital FT-NMR Spectrometer. The chemical shifts (d) and
coupling constants (J) were expressed in parts per million and
hertz.
46.0%). ½a 2D5
ꢄ
¼ ꢀ72:9 (c 3.4, CHCl3). IR:
m 3428, 3070, 3031, 2979,
2831, 1740, 1458, 1375, 1075 cmꢀ1
;
1H NMR (CDCl3): d (ppm)
1.12 (d, 6H, J = 6.4 Hz), 1.48 (d, 6H, J = 7.2 Hz), 2.24 (t, 4H,
J = 12.0 Hz), 2.43 (q, 2H, J = 4.0 Hz), 2.71–2.76 (m, 2H), 3.76–3.90
(m, 4H), 4.86 (br s, 2H), 7.18–7.37 (m, 10H). 13C NMR (CDCl3): d
(ppm) 18.67, 20.25, 48.70, 58.56, 59.48, 63.57, 127.24, 128.18,
141.08. Anal. Calcd for C24H36O2N2: C, 75.00; H, 9.37; N, 7.29.
Found: C, 75.20; H, 9.45; N, 7.18.
4.2.4. (1S,8S)-3,6-[N-(S)-
methyl-1,8-decanediol 4
It was prepared and purified in the same way as described
above for 3 starting from (S)-1-[N-(S)- -phenyl ethyl]amino-3-
a-Phenylethyl]diaza-1,8-diphenoxy
a
phenoxypropan-2-ol 2b (5.60 g, 20.6 mmol), ethylene glycol
ditosylate (1.27 g, 3.43 mmol) and Na2CO3 (1.00 g, 9.40 mmol) to
give 4 as a yellow oil (1.90 g, 48.71%). ½a D34
¼ ꢀ40:5 (c 0.74, CHCl3);
ꢄ
4.2. Synthesis
IR:
m 3411, 3070, 3031, 2973, 2935, 2877, 1741, 1697, 1600, 1496,
1452, 1380, 1303, 1247, 1182, 1047, 912, 881, 823, 757 cmꢀ1 1H
;
4.2.1. (S)-1-[N-(S)-
a-Phenyl ethyl]aminopropanol-2-ol 2a
(S)- -Phenylethylamine (18.97 g, 156.52 mmol), (S)-(+)-2-
a
NMR (CDCl3): d (ppm) 1.40 (d, 6H, J = 6.9 Hz), 2.51–2.65 (m, 5H),
2.77–2.84 (m, 3H), 3.83–4.07 (m, 8H), 6.93–7.00 (m, 5H), 7.30–
7.33 (m, 15H). 13C NMR (CDCI3): d (ppm) 13.92, 49.76, 53.59,
59.43, 67.63, 70.10, 114.67, 120.92, 127.73, 128.20, 128.33,
129.50, 142.20, 158.88. Anal. Calcd for C36H44O4N2: C, 76.05; H,
7.75; N, 4.93. Found: C, 76.10; H, 7.85; N, 4.98.
hydroxypropyl p-toluenesulfonate (9 g, 39.13 mmol) and Na2CO3
(4.77 g, 45.00 mmol) were stirred at 110 °C for 12 h under argon.
The mixture was cooled and 100 mL CHCl3 was added to the mix-
ture and refluxed for 2 h. The organic phase was separated from
the solid phase. The remaining solid was re-extracted with CHCl3

Y. Turgut, S. O. Kocakaya / Tetrahedron: Asymmetry 21 (2010) 990–996
995
4.2.5. (4S,11S)-4,11-Dimethyl-6,9-bis(1-phenylethyl)-3,12-
dioxa-6,9,18-triaza bicyclo[12.3.1]octadeca-1(18),14,16-triene 5
To a well-stirred suspension of NaH (154 mg, 96%) in 50 mL dry
THF was added dropwise under argon at 0 °C to 3 (500 mg,
1.29 mmol) dissolved in 50 mL THF. The mixture was stirred at rt
for 1 h and at reflux temperature for 2 h. The reaction mixture
was cooled to 0 °C and 2,6-pyridinedimethyl ditosylate26
(576 mg, 1.29 mmol) dissolved in 100 mL THF was added drop-
wise. The resulting mixture was stirred at 0 °C for 30 min and then
refluxed for 50 h. After the reaction was completed, the solvent
was removed. The residue was taken up in the mixture of ice-water
(50 mL) and CH2Cl2 (3 ꢃ 100 mL). The resulting mixture was mixed
well and separated. The combined organic phase was dried over
MgSO4, filtered and the solvent evaporated. The crude product
was purified by chromatography on basic alumina (eluent: diethyl
ether then Hexane/EtOAc 4:1) to give 5 as a white oil (200 mg,
The SHAKE31 method was applied to constrain all the covalent
bonds involving hydrogen atoms.
To compare bound and unbound structures, additional MD sim-
ulations were performed for the host. Root-mean-square deviation
(RMSD) analysis fort the complex system was carried out of on the
trajectories by the ptraj module of AMBER (v9).
Structures are driven using by DSV, their three dimensional
structures displayed using by Chimera (UCSF) and VMD, RMSD
graphics are shown by XMGRACE package programme.
4.3.2. Molecular docking
In this study, dock calculations were performed to accommo-
date the guests within the pyridino-15-crown-5. The docking stud-
ies of the guests were carried out using the crown ether and guests
parameters obtained for the minimized structures of the com-
plexes between the host and guests. The initial coordinates of the
host molecule and guests for the docking studies were obtained
via MD studies for 2 ns for the host and minimized the guests.
Docking of the guests was carried out using program DOCK 6.0.32
Docking was performed with default settings to obtain a popula-
tion of possible conformations and orientations for the guests at
the binding site. Spheres around the centre of the binding pocket
were defined as binding pocket for the docking runs. All torsion an-
gles in each compound were allowed to rotate freely. Docking re-
sults suggested that several of these derivatives are active host
with a significant preference for binding modes.
32%). ½a 3D0
ꢄ
¼ ꢀ241 (c 0.067, CHCl3) 1H NMR (CDCl3): d (ppm) 0.96
(d, 6H, J = 5.6 Hz), 1.27 (d, 6H, J = 8 Hz), 2.29–2.53 (m, 6H), 2.65
(d, 2H, J = 8 Hz), 3.45 (d, 2H, J = 6 Hz), 3.66–3.80 (m, 2H, J = 8 Hz),
4.60 (d, 2H, J = 12 Hz), 4.73 (d, 2H, J = 12 Hz), 7.22–7.35 (m, 11H),
7.72–7.73 (t, 2H, J = 7.6 Hz); 13C NMR (CDCI3): d (ppm) 15.48,
18.25, 54.44, 56.97, 61.20, 71.13, 72.60, 122.68, 126.61, 127.85,
128.01, 137.48, 144.09, 157.88. Anal. Calcd for C31H41N3O2: C,
76.38; H, 8.42; N, 8.62. Found: C, 76.46; H, 8.05; N, 8.50.
4.2.6. (4S,11S)-4,11-Benzyloxy-6,9-bis(1-phenylethyl)-3,12-
dioxa-6,9,18-triaza bicyclo[12.3.1]octadeca-1(18),14,16-triene 6
Macrocycle 6 was prepared as described above for macrocycle 5
starting from 4 (500 mg, 0.88 mmol) and 2,6-pyridinedimethyldi-
tosylate (393 mg, 0.88 mmol). The crude product was purified by
chromatography on silica gel (eluent: petroleum ether/EtOAc/
4.3.3. MM/PBSA calculations
This study applies a second-generation form of the Mining Min-
ima33,34 algorithm, termed M2, to analyze the binding reactions of
host-guest complexes in an organic solvent. The MM-PB/SA mod-
ule of AMBER (v9) was applied to compute the binding free energy
Et3N 20:5:1) to give 6 as a yellow oil (200 mg, 36%). ½a D30
¼ ꢀ47
ꢄ
(c 1.00, CHCl3). 1H NMR (CDCI3): d (ppm) 1.25 (d, 6H, J = 6.8 Hz),
2.14 (t, 2H, J = 12 Hz), 2.34 (q, 2H, J = 3.6 Hz), 2.45 (q, 2H,
J = 7.2 Hz), 3.01 (q, 2H, J = 4 Hz), 3.32 (d, 2H, J = 7.2 Hz), 3.63 (q,
2H, J = 6.8 Hz), 3.89 (t, 2H, J = 4 Hz), 4.16 (q, 2H, J = 4.8 Hz), 4.81
(s, 4H), 6.99 (m, 6H), 7.11 (d, 2H, J = 6.8 Hz), 7.26–7.34 (m, 12H),
7.42 (d, 2H, J = 7.6 Hz), 7.69 (t, 1H, J = 6 Hz). 13C NMR (CDCI3): d
(ppm) 15.86, 52.07, 52.90, 61.20, 68.61, 72.22, 74.69, 114.71,
120.71, 123.18, 126.83, 127.88, 128.04, 129.41, 137.58, 142.60,
157.52, 159.01. Anal. Calcd for C43H49N3O4: C, 76.90; H, 7.30; N,
6.26. Found: C, 77.05; H, 7.40; N, 6.20.
(DGbind) of each complex using the MM/PBSA method. For each
complex, a total number of 200 snapshots were extracted from
the last 2 ns on the MD trajectory with an interval of 10 ps. of
the complex the simulation trajectories.
The vibrational entropy term (TS) was computed by using the
NMODE module in the AMBER program. The computation was based
on ten snapshots taken from the final 2 ns of the MD trajectory
with an even interval of 200 ps. Structural minimizations as well
as normal mode analyses were carried out with a distance-depen-
dent dielectric function (e = 4 Rij) to mimic the impact of solvent.
During conformational searching and the evaluation of configu-
ration integrals, Welec is computed with a simplified but fast gen-
eralized Born model.33 The electrostatic solvation energy of each
energy well is then corrected towards a more accurate but time-
consuming finite-difference solution of the Poisson equation. The
dielectric cavity radius of each atom is set to the mean of the sol-
vent probe radius 2.4 Å for chloroform29 and the atom’s van der
Waals radius, and the dielectric boundary between the molecule
and the solvent is the solvent-accessible molecular surface.35 The
a dielectric constant of 4.9 is used for chloroform.
4.3. Computational section
4.3.1. Molecular dynamics simulations
Molecular dynamics (MD) simulations were carried out in a Li-
nux-Cluster system to determine conformations for the each
crown ether complex studied. All simulations were conducted by
using AMBER (version 9.0)26 suit of programs. AM1-Bcc (Austian
model with Bond and charge correction)28 atomic partial charges
fort the host and guests were determined by antechamber module
of AMBER (v9) package. Charges for the ionizable residues were set at
The MM/PBSA method can be conceptually summarized as:
29
a neutral. The complex was solvated in a CHCl3 chloroform box
D
Gbind ¼ Gcomplex ꢀ ½Ghost þ Gligand
ꢄ
ð4:4:1Þ
ð4:4:2Þ
ð4:4:3Þ
ð4:4:4Þ
ð4:4:5Þ
ð4:4:6Þ
ð4:4:7Þ
with dimensions of 10 Å from the solute. 0.4 Å space was initially
generated at the boundary of the complex and the solvent mole-
cules during the solvation process. Clꢀ anions were added to neu-
tralized each complex system. The General AMBER Force Field
(GAFF)30 was adopted in simulation because it handles small or-
ganic molecules.
The entire system was minimized in two steps over a period of
100 ps. The system was then heated from 0 to 300 K in 200 ps and
allowed to equilibration at 300 K for another 1 ns of MD. Subse-
quently, MD computations were performed through 20 ns and
2 fs of time interval was used for each iteration in all MD studies.
G ¼ Egas þ Gsol ꢀ TS
Egas ¼ Ebond þ Eangle þ Etorsion þ Evdw þ Eele
Gsol ¼ GPB þ GSA
H ¼ Egas þ Gsol
Stot ¼ Svib þ Strans þ Srot
D
G ¼
D
H ꢀ T
DS
where Gcomplex, Ghost and Gligand are the absolute free energies of the
complex, host and the ligand species, respectively, as shown Eq.
4.4.1 Each of them is calculated by summing an internal energy in

996
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Further reading
27. Case, D. A.; Cheatham, T. E., III; Darden, T.; Gohlke, H.; Luo, R.; Merz, K. M.;
Onufriev, A., Jr.; Simmerling, C.; Wang, B.; Woods, R. J. Comput. Chem. 2005, 26,
1668–1688.