Synthesis of rigid and C2-symmetric pyridino-15-crown-5 type macrocycles bearing diamide-diester functions: Enantiomeric recognition for chiral primary organoammonium perchlorate salts

Article abstract of DOI:10.1016/j.tetasy.2014.01.009

Four novel C₂-symmetric macrocyclic compounds with a pyridine function and possessing amide and ester lingeages were prepared. The enantiomeric discrimination abilities of these macrocycles against α-phenylethylammonium and α-(1-naphthyl)ethylammonium perchlorate salts were measured by standard ¹H NMR titration techniques in DMSO-d₆. A binding constant ratio of 31 (Kbind(S)/Kbind(R)) for two enantiomers of α-(1-naphthyl)ethylammonium salt with the macrocyclic host (S,S)-4 bearing phenyl arms was observed, which corresponds to an enantiomeric discrimination of approximately 94%. Molecular dynamic calculations were performed for some of the supramolecular complexes to in order to gain insight into the mode of molecular recognition between the macrocyclic compounds and ammonium salts; these results were consistent with experimental observations, which may be relevant to those in biochemical processes occurring in organisms.

Full text of DOI:10.1016/j.tetasy.2014.01.009

Tetrahedron: Asymmetry 25 (2014) 411–417
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of rigid and C2-symmetric pyridino-15-crown-5 type
macrocycles bearing diamide–diester functions: enantiomeric
recognition for chiral primary organoammonium perchlorate salts
a,
Sevil Sßeker a, Deniz Barıßs b, Nevin Arslan a, Yılmaz Turgut a, Necmettin Pirinççiog˘lu a, , Mahmut Tog˘rul
⇑
⇑
a University of Dicle, Faculty of Science, Department of Chemistry, 21280 Diyarbakir, Turkey
b University of Batman, Faculty of Art and Science, Department of Chemistry, Batman, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Four novel C2-symmetric macrocyclic compounds with a pyridine function and possessing amide and
Received 14 October 2013
Revised 16 December 2013
Accepted 16 January 2014
ester lingeages were prepared. The enantiomeric discrimination abilities of these macrocycles against
a
-phenylethylammonium and
dard 1H NMR titration techniques in DMSO-d6. A binding constant ratio of 31 (Kbind(S)/Kbind(R)) for two
enantiomers of -(1-naphthyl)ethylammonium salt with the macrocyclic host (S,S)-4 bearing phenyl
a-(1-naphthyl)ethylammonium perchlorate salts were measured by stan-
a
arms was observed, which corresponds to an enantiomeric discrimination of approximately 94%. Molec-
ular dynamic calculations were performed for some of the supramolecular complexes to in order to gain
insight into the mode of molecular recognition between the macrocyclic compounds and ammonium
salts; these results were consistent with experimental observations, which may be relevant to those in
biochemical processes occurring in organisms.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
and their intermolecular interactions. Detailed investigations of
chiral recognition phenomena through the elucidation of non-
Enantiomeric recognition by model systems is essential in our
understanding the selectivity of very complex biochemical pro-
cesses occurring in living organisms, which involves the discrimi-
nation of one enantiomer of the guest from the other by a chiral
host. Therefore, the design and synthesis of new chiral systems
for the selective recognition of small molecules is one of the most
challenging topics, which finds broad application, such as enzyme-
substrate interactions,1 asymmetric catalysis,2 sensing,3 enantiose-
lective catalysis,4 separation science,5 development of pharmaceu-
ticals,6 biology7 and the purification and analysis of enantiomers.8
A number of synthetic models have been designed as chiral host
molecules to help chemists better understand the basis of the
mechanism of host–guest complexation and chiral recognition.
The complexation and chiral recognition mechanism are mainly
due to non-covalent interactions such as hydrogen bonds, ion-
covalent interactions are constantly required for the basis of new
approaches in the field of enzyme–substrate interactions, the res-
olution of enantiomers in chemical processes and asymmetric
catalysis. Therefore, the design, synthesis and use of molecules
capable of chiral recognition of other molecules are of great inter-
est in these fields.9
The study of the recognition of chiral amines and chiral proton-
ated amine compounds is of significance because these compounds
are the basic building blocks of biological molecules and therefore,
these molecules are frequently used as guests in chiral recogni-
tion.10 Macrocyclic structures have received much attention in
the search for artificial receptors, mainly because of their higher
degree of preorganization when compared to their acyclic counter-
parts. A great number of artificial chiral receptors have been syn-
thesized and studied widely.10 Among these, chiral macrocycles
containing pyridine units are dominant structures, due to their abil-
ity in chiral discrimination towards organoammonium salts and
amino acid derivatives. The pyridine subunits of these macrocycles
were reported to be important for tripodal hydrogen bond forma-
dipole, dipole–dipole interactions,
p-stacking, ion–p interactions
and hydrophobic interactions, which are also the main driving
forces in the maintenance of 3D structures of biological relevance
tion with primary organoammonium salts and p–p interaction with
⇑
Corresponding authors. Tel.: +90 412 2488550; fax: +90 412 2488300.
E-mail addresses: pirincn@dicle.edu.tr (N. Pirinççiog˘lu), mtogrul@dicle.edu.tr
the aromatic moiety of the organoammonium guests.10,11 It is also
well known that the amide group has a high affinity for cations with
(M. Tog˘rul).
http://dx.doi.org/10.1016/j.tetasy.2014.01.009
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

412
S. Sßeker et al. / Tetrahedron: Asymmetry 25 (2014) 411–417
O
O
a high charge density. Many ionophores with amide ligands are cur-
rently employed as chemical sensors, quantitatively and reversibly
measuring cationic analytes.12 Cyclic esters (lactones) can be con-
sidered as crown ether-like rings and hence are predicted to behave
in a similar manner to accommodate organoammonium salts. Pyr-
idine macrocyclic diamides and diesters are widely found in nature
and constitute an extensive range of natural products with diverse
biological activity.13 These natural compounds are complex struc-
tures due to the presence of multi-functional groups and their chi-
rality. A number of pyridine-macrocyclic compounds containing
diamide–diester groups have been synthesized.14,15 However, only
a few examples have been reported, that deal with the synthesis
and chiral recognition studies of chiral pyridine-macrocyclic con-
taining diamide–diester groups.15 Herein we report the synthesis
of a series of C2-symmetric, pyridine and diamide–diester groups
containing lactone type macrocycles with different side arms via
R
O
R
O
NH HN
O
O
2
N
O
O
Cl
Cl
benzene/DMF
N
5 (R = phenyl, benzyl, isobuthyl)
O
O
4
3
NH HN
benzene/DMF
O
O
N
O
O
a high dilution technique, for the recognition of
a-chiral primary
organoammonium perchlorate salts (Caution! The perchlorate salts
must be handled with care as they are potential explosives). The
enantiomeric recognition properties of these new macrocycles to-
wards primary organoammonium salts were estimated by standard
1H NMR titration techniques in DMSO-d6.
6
Scheme 2. Synthesis of pyridino-15-crown-5 type macrocycles.
2.2. Enantiomeric recognition studies: selective cation binding
2. Result and discussion
2.1. Synthesis
The enantiomeric recognition can be characterized by various
spectroscopic methods, such as NMR, ultraviolet–visible (UV–vis),
fluorescence and infrared (IR), which are powerful tools for the
examination of the recognition ability of new chiral macrocycles.17
Standard 1H NMR titration experiments were applied in order to
investigate the stability of the complexes of the pyridine-
15-crown-5 types macrocycles 5 and 6 with perchlorate salts of
enantiomers of Am1 and Am2, since it is one of the most effective
tools in studying host–guest supramolecular chemistry.18 These
cations are commonly used as standard guests for the chiral recog-
nition of primary organic ammonium ions and in most cases give
the best results. Upon the addition of guest molecules to the mac-
rocycles, the signals in the 1H NMR spectra shifted upfield or
downfield depending on the non-covalent interactions between
host and guest molecules. Increasing the concentration of organic
ammonium cations (guest), which were used as perchlorate salts
(Scheme 3) from 0.1 to 6 equiv in the presence of a constant host
concentration (1 ꢀ 10ꢁ3 M), was carried out for 1H NMR titration
measurements. The addition of increasing amounts of ammonium
salts to the diamide–diester pyridine-macrocycles caused consid-
The procedure for the synthesis of rigid C2-symmetric pyridino-
15-crown-5 type macrocycles (S,S)-4, (S,S)-5, and (R,R)-6 contain-
ing diamide–diester functions, derived from bis(aminoalcohol)
oxalamides (S,S)-2, and (R,R)-3 is outlined in Schemes 1 and 2. Chi-
ral bis(amino alcohol)oxalamides were synthesized according to
the procedures previously reported, by reacting
L-phenylglycinol,
L
-phenylalanilol, -leucinol and (R)-2-amino-1-buthanol with
L
dimethyloxalate in methanol at room temperature, with almost
quantitative yield.16 Pyridino-15-crown-5 type macrocycles were
synthesized from the corresponding chiral bis(amino alco-
hol)oxalamides. A high dilution technique was employed for the
cyclization step to afford the microcycles with high yields. The pro-
cedure involves short synthetic sequences and allows high modu-
larity by simply changing the amino alcohol moiety. The
functionality of the pyridine, amides and esters ensures a high
rigidity, which may play a crucial role in the binding and recogni-
tion of small chiral molecules. The structures proposed for these
new chiral bis(amino alcohol)oxalamides and macrocycles are con-
sistent with the data obtained from 1H, 13C NMR, IR spectroscopy
and elemental analysis. All of 1H and 13C NMR signals were as-
signed based on DEPT and 1H–13C correlation experiments.
erable and reproducible upfield or downfield shifts (Dd) in the pro-
tons of the NH (amide), the N–CH groups of the diamide–diester
pyridine-macrocycles, as well as in the CH and CH3 protons of
the ammonium salts. The NH (amide) protons of diamide–diester
pyridine-macrocycles and CH protons of the ammonium salts were
greatly affected and displayed significant upfield shifts. The associ-
ation constants of the complex formation between the host and the
guest were calculated according to a modified Benesi–Hildebrand
equation where [H]0 and [G]0 refer to the total concentration of
O
O
R
R
the macrocycles and organic ammonium salts, respectively.19
A
R
NH
HN
key feature of this method is that by working with a large excess
of component H the concentration of uncomplexed H, can be set
equal to the initial concentration, [H] = [H]0. Relationships between
H2N
OH
OH
HO
2 (R = phenyl, benzyl, isobutyl)
toluene
O
O
O
O
H2N
OH
O
O
1
ClO4
NH3
NH
HN
NH3 ClO4
ClO4
ClO4
NH3
H
NH3
H
toluene
H
H
OH
HO
Am1
Am1
Am2
Am2
3
(R)-
(S)-
(R)-
(S)-
Scheme 1. Synthesis of bis(aminoalcohol)oxalamides.
Scheme 3. Primary ammonium perchlorate salts used as guests.

S. Sßeker et al. / Tetrahedron: Asymmetry 25 (2014) 411–417
413
known quantities (initial concentration) and experimental obser-
vations can now be derived. Mathur et al. and Hannah and Ashb-
augh independently developed an NMR version of the Benesi–
Hildebrand equation.20,21 For all of the guests examined, the plots
downfield shift in the guest CH protons. In most cases, an approx-
imate 0.15 ppm shift in these protons was observed. The binding
constants were calculated with 95% confidence (Table 1). With
modern NMR instruments it is possible to obtain good quality
spectra with submillimolar concentrations (routinely as low as
10ꢁ4 M). This suggests that NMR is suitable for obtaining binding
constants in supramolecular systems up to and even above
of observed 1/
tionship with a slope 1/KaDdmax and 1/
D
d values as a function of 1/[G]0 give a linear rela-
dmax supporting the 1:1
D
complex formation. To confirm the 1:1 stoichiometry, Job Plots
for the complexed were studied. An example of Job plot for the
complex of diamide–diester pyridine-macrocycle 5a with (S)-
Am2 is illustrated in Figure 1. For a comparison of the binding con-
stants, the shifts in the NH (amide) protons of the diamide–diester
pyridine-macrocycles upon complexation were chosen for the cal-
culation of the binding constants Ka. In general, complex formation
led to an upfield shift in the observed NH (amide) protons and a
106 Mꢁ1
.
A general trend in the enantiomeric discrimination of the guests
by the hosts 5 was observed. It was found that 5 preferred to form
more stable complexes with the (S)-enantiomers of guests Am1
and Am2 although 5b preferred to form a more stable complex
with the (R)-enantiomer of Am2 (Table 1). A general model can
be proposed to explain the basis of the discrimination of these
ammonium salts by the hosts 5a, 5b and 5c. The representative
model for the complex of 5a with Am2 is illustrated in Figure 2.
It is likely that the bulkiest group, the naphthyl in Am2 (or phenyl
in the case of Am1) would lie over the pyridine ring, and thus leave
the methyl group to be discriminated between the phenyl rings on
5a or isobuthyl on 5c. A similar explanation could be proposed for
the discrimination of Am1 by 5b.
Replacing the phenyl group on the macrocyclic ring of 5a with a
benzyl group produced host 5b, and reverses the discrimination
between the enantiomers of Am2, from (S) to (R). In the case of
the complex with the (R)-enantiomer, it is likely that the naphthyl
group, instead of fully positioning over the pyridine ring, shifts to-
wards the benzyl ring in a sandwiched manner (Fig. 3) through
p–
p
interactions. In this model, the methyl group may also interact
Nph
Nph
O
O
O
O
N
N
H
H
H
H
O
O
O
O
Me
H
H
H
H
Me
HN
O
O
H
N
H
N
Ph
Ph
Ph
Ph
HN
O
O
Figure 2. An illustrative representation of the complexes of 5a with (R)-Am2 (right)
and (S)-Am2 (left).
Figure 1. Job plot for the complex of 5a with (S)-Am2.
Table 1
Binding constant (Ka), the Gibbs free energy changes (
DMSO-d6 at 25 °C
D
Go) and enantioselectivities KR/KS or DDGo for the inclusion of the (R)- or (S)-guest with the chiral host macrocycles in
Entry
Host
Guesta
Ka, Mꢁ1b
33.6 0.3
129.6 0.5
327.1 0.2
10,138 71
1852 17
2668 10
721.4 3.1
262.6 2.6
ꢁ
D
Go, kJmolꢁ1d
DDGo
EDf
e
KSa=KRa
c
1
2
3
4
5
6
7
8
(S,S)-5a
(S,S)-5a
(S,S)-5a
(S,S)-5a
(S,S)-5b
(S,S)-5b
(S,S)-5b
(S,S)-5b
(S,S)-5c
(S,S)-5c
(S,S)-5c
(S,S)-5c
(R,R)-6
(R,R)-6
(R,R)-6
(R,R)-6
(R)-Am1
(S)-Am1
(R)-Am2
(S)-Am2
(R)-Am1
(S)-Am1
(R)-Am2
(S)-Am2
(R)-Am1
(S)-Am1
(R)-Am2
(S)-Am2
(R)-Am1
(S)-Am1
(R)-Am2
(S)-Am2
3.86
8.71
12.05
14.35
22.85
18.64
19.55
16.31
13.80
19.44
19.56
17.41
18.14
21.30
3.34
59 (S)
31.0
1.44
0.36
1.05
1.34
8.50
0.91
94 (S)
18 (S)
47 (R)
2 (S)
ꢁ2.51
0.20
9
2559
2681
1126
1511
7
5
4
4
10
11
12
13
14
15
16
0.73
30 (S)
5412 17
ndg
4719
2833
9
7
0.60
20.96
19.69
ꢁ1.27
25 (R)
a
b
c
d
e
f
Am1: a-phenylethylammonium perchlorate salts; Am2: a-(1-naphthyl)ethylammonium perchlorate salts.
The binding constants between the hosts and the guests observed by 1H NMR titration.
The ratios of the binding constants for each enantiomer.
The binding free energy change for the complexes, calculated by
Go(R) Go(S)).
D
Go = ꢁRTlnKa.
DDGo = ꢁ(
D
ꢁ
D
Enantiomeric discrimination factor.
Not determined.
g

414
S. Sßeker et al. / Tetrahedron: Asymmetry 25 (2014) 411–417
of these hosts with the enantiomers of Am2 having the largest
Nph
O
O
populations obtained from MD calculations are shown in Figure 5.
In the case of complex of 5a, the naphthyl group is aligned over the
pyridine ring and thus in the complex of the host with the (R)-
enantiomer, the methyl group in the guest has unfavourable steric
interactions with the phenyl group, leading to a less stable
complex formation compared to that with the (S)-enantiomer.
With regard to the complex of the host 5b with the Am2 enantio-
mers, it seems that the (R)-enantiomer has more favourable inter-
actions with the host 5b compared to the (S)-enantiomer (Fig. 5).
This may be attributed to the fact that in the case of the complex
with an (R)-configuration, the naphthyl group slides towards the
benzyl group to gain more complimentary interactions with this
O
O
N
N
Nph
O
H
H
Me
H
H
O
O
O
H
H
Me
H
O
H
O
H
N
N
H
HN
HN
O
O
Figure 3. An illustrative representation of the complexes of 5b with (R)-Am2 (left)
and (S)-Am2 (right).
with another benzyl group via CH/p interactions, which are known
to be very significant in the molecular recognition that occurs in
biochemical processes and in maintaining 3D structures of biolog-
ical macromolecules.22 The complex of 5b with an (S)-configura-
tion lacks these two favourable interactions and therefore is less
stable compared to the (R)-enantiomer. Host 6 displayed a similar
trend to form complexes with the guests, but with inverted enan-
tiomeric discrimination, that is it forms a more stable complex
with the (R)-enantiomers (Table 1) since it has inverted stereogen-
ic centres compared to 5.
group as well as with the pyridine ring via
p–p interactions be-
cause the unsubstituted ring of the naphthalene in the (R)-enantio-
mer has a better spatial orientation for such interactions compared
with the (S)-enantiomer (Fig. 5). These observations are consistent
with the models proposed earlier (Figs. 3 and 4).
3. Conclusion
The preparation of four novel C2-symmetric macrocyclic com-
pounds was successfully achieved and their enantiomeric discrim-
ination abilities against various chiral primary ammonium salts
were estimated by standard 1H NMR titration techniques as mod-
els to better understand the non-covalent interactions and the
basis of molecular recognition in biological systems; these are per-
haps more relevant as chiral scaffolds in the separation of enanti-
omers, which is of great importance in the synthesis of new
pharmaceuticals.
Molecular dynamic calculations provide very significant results
to determine the nature of the complexes between the macrocylic
compounds and ammonium salts, and were consistent with exper-
imental results.
2.3. Computational modelling
It was previously reported that computational modelling pro-
duces valuable information regarding the mode of complexes of
crown-ethers possessing C2 symmetry with chiral ammonium
salts,30 and therefore a similar approach could be used to predict
the complexation mode of the current macrocyclics with the same
guests. Conformers of the hosts 5a and 5b with the largest popula-
tion obtained from molecular dynamic (MD) calculations are
shown in Figure 4. It can be seen that the ring has a rather flat
structure with the two phenyl and benzyl groups aligned on oppo-
site sides of the ring. The superimposed conformers of the complex
Figure 4. Conformers of the hosts 5a (left) and 5b (right) with the largest population obtained from molecular dynamic calculations. For the sake of simplicity, hydrogens are
omitted.
Figure 5. The superimposed conformers of the complex of the hosts 5a (left) and 5b (right) with the enantiomers of Am2 having the largest populations obtained from MD
calculations. Open brown represents the complex of the (R)-enantiomer while the open blue represents the complex of S enantiomer. For the sake of simplicity, hydrogens,
except those involved in hydrogen bond interactions, are omitted.

S. Sßeker et al. / Tetrahedron: Asymmetry 25 (2014) 411–417
415
62.7 (t, CH2OH), 126.4, 128.6, 129.4 (d, aromatic CH), 139.3 (qua-
ternary aromatic), 159.9 (s, C@O). Anal. Calcd for C20H24N2O4: C
67.40, H 6.79, N 7.86. Found: C 67.39, H 6.81, N 7.85.
4. Experimental
4.1. General
4.2.6. N,N0-[Bis(1S)-2-hydroxyethyl-1-isobutyl]ethanediamide
(S,S)-2c
Melting points were determined with a GALLENKAMP Model
apparatus with open capillaries and are uncorrected. Infrared spec-
tra were recorded on a MIDAC-FTIR Model 1700 spectrometer. The
Elemental analyses were obtained with CARLO-ERBA Model 1108
apparatus. Optical rotations were taken on a Perkin Elmer 341
Model polarimeter. 1H (400 MHz), 13C (100 MHz) 1H NMR titration
and two dimensional NMR (DEPT, COSY, HETCOR, HMQC, HMBC)
spectra were recorded on a BRUKER DPX-400 High Performance
Digital FT-NMR spectrometer in the solvents indicated. Chemical
shifts are expressed in part per million (d) using residual solvent
protons as the internal standards.
Yield: 99%; mp 175–176 °C; ½a D25
¼ ꢁ30:5 (c 1.0, DMSO); IR
ꢂ
(KBr)
m 3453 (O–H), 3288 (N–H), 1657 (C@O, first amide band),
1535 (C@O, second amide band), 1099 (C–O) cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6): d (ppm) 0.95 (d, J = 6.5 Hz, 6H, CH3, (a)),
0.96 (d, J = 6.4 Hz, 6H, CH3, (b)), 1.38 (m, 2H, CH(CH3)2), 1.40 (dd,
J = 8.6, J = 4.4 Hz, 2H, CH2–CH(CH3)2, (a)), 1.65 (dd, J = 8.6,
J = 4.4 Hz 2H, CH2–CH(CH3)2, (b)), 3.51 (m, 4H, CH2O), 3.80 (m,
2H, CH–N), 4.78 (br s, 2H, OH), 8.2 (d, J = 9.2 Hz, 2H, NH); 13C
NMR (100 MHz, DMSO-d6): d (ppm) 22.3 (q, CH(CH3)2, (A)), 23.6
(q, CH(CH3)2, (B)), 24.8 (d, CH(CH3)2), 40.0 (t, CH2–CH(CH3)2),
50.1 (d, CH–N), 63.8 (t, CH2OH), 160.2 (s, C@O). Anal. Calcd for
4.2. Synthesis
C14H28N2O4: C 58.30, H, 9.79, N, 9.71. Found: C 58.31, H 9.77; N
9.69.
4.2.1. Aminoalcohols
(R)-(ꢁ)-2-Amino-1-butanol and
chased from Fluka, and used without further purification. The syn-
thesis of -leucinol and -phenylalanilol was accomplished in one
-phenylalanine according to procedures
L-phenylglycinol were pur-
4.2.7. N,N0-[Bis(1R)-1-ethyl-2-hydroxyethyl]ethanediamide(R,R)-3
Yield: 99%; mp 212–213 °C; ½a D25
¼ þ30:3 (c 1.0, DMSO); IR
ꢂ
L
L
(KBr)
m 3365 (O–H), 3280 (N–H), 1665(C@O, first amide band),
step from L-leucine and L
1530 (C@O, second amide band), 1048 C–O) cmꢁ1
;
1H NMR
described in the literature.23
(400 MHz, DMSO-d6): d (ppm) 0.85 (t, J = 7.4 Hz, 6H, CH3), 1.42
(m, 2H, CH2CH3 (a)), 1.55 (m, 2H, CH2CH3 (b)), 3.30 (m, 4H, CH2OH),
3.71 (m, 2H, CH–N), 4.70 (br s, 2H, OH), 8.2 (d, J = 9.2 Hz, 2H, NH);
13C NMR (100 MHz, DMSO-d6): d (ppm) 11.4 (q, CH3), 24.4 (t,
CH2CH3), 54.2 (d, CH–N), 63.7 (t, CH2OH), 161.7 (s, C@O). Anal.
Calcd for C10H20N2O4: C 51.71, H 8.68, N 12.06. Found C 51.69, H
8.71, N 12.02.
4.2.2. Dimethyloxalate 1
A
solution of oxalylchloride (38.0 g, 0.3 mol) in benzene
(250 mL) was added dropwise to a solution of methanol (38.4 g,
1.2 mol) and pyridine (47.4 g, 0.6 mol) over 3 h under a dry N2
atmosphere. The reaction mixture was then refluxed for 3 h. Next,
the mixture was kept at room temperature for one day. The solu-
tion was then filtered, and the solvent evaporated in vacuo. The so-
lid residue was extracted with ice-cold ether (3 ꢀ 50 mL) and a
white solid was obtained after evaporation. The product was
recrystallized from ether–petroleum ether (2:1) (32.6 g, 92%); mp
54.0–54.5 °C; 1H NMR (400 MHz, CDCl3): d (ppm) 3.58 (s, 6H,
OCH3). Anal. Calcd for C4H6O4: C 40.69, H 5.12. Found: C 40.68; H
5.13.
4.2.8. (5S,10S)-5,10-Diphenyl-3,12-dioxa-6,9,18-triazabicyclo-
[12.3.1]octadeca-1(18),14,16-triene-2,7,8,13-tetraone [Macro-
cycle (S,S)-5a]
This experiment was conducted under high dilution. A two litre,
4-necked, round-bottomed flask, fitted with a mechanical stirrer
and two jacketed condenser was charged with 1 L of benzene
and triethylamine equivalent to the HCl produced. The solution
was refluxed vigorously while (S,S)-2a (1.5 g, 4.2 mmol) in dry
THF/DMF (w:w,70/30 = 100 mL) and 2,6-pyridinedicarbonyl
dichloride 4 (0.86 g, 5 mmol) in dry benzene (100 mL) were added
dropwise at the same rate. After the addition was complete, the
reaction mixture was refluxed for 5 days. The solution was cooled
to room temperature, filtered and the solvent evaporated under
vacuum. The white solid obtained was crystallized from an etha-
nol–acetonitrile mixture (2:1). Macrocycle (S,S)-5a; yield (1.26 g,
4.2.3. General procedure for the synthesis of diamidediols 2 and 3
To a solution of the desired aminoalcohol (32 mmol) in MeOH
(25 mL), a solution of dimethyloxalate 1 (16 mmol) was added
dropwise at room temperature. The reaction mixture was stirred
for a further 5 min after which the resulting white solid precipitate
was collected and washed with a small portion of diethyl ether to
give a white solid compound consisting of (S,S)-2 or (R,R)-3.
63%); mp 289–290 °C; IR (KBr):
(Ar-H), 3028 (Ar-H), 1759 (C@O, ester), 1731 (C@O, ester), 1659
m 3298 (N–H), 3086 (Ar-H), 3059
4.2.4. N,N’-[Bis(1S)-1-phenyl-2-hydroxyethyl]ethanediamide (S,S)-2a
Yield: 96%; mp 226–228 °C; ½a D25
¼ ꢁ35:2 (c 1.0, DMSO); IR (KBr)
ꢂ
(C@O, first amide band), 1516 (C@O, second amide band), 1130
m
3420 (O–H), 3296 (N–H), 3070 (Ar-H), 3043 (Ar-H), 1654 (C@O,
(C–O–C), 1053 (C–O–C), cmꢁ1; ½a D34
ꢂ
¼ ꢁ58 (c 0.04, CH3CN); 1H
first amide band), 1515 (C@O, second amide band), 1042 (C–O)
NMR (400 MHz, DMSO-d6): d (ppm) 2.75–2.87 (m, 4H, CH2Ar),
3.75–3.88 (m, 6H, CH2O and CH–N), 4.25–4.57 (m, 4H, O–CH2–
C@O), 7.17–7.26 (m, 10H, ArH), 8.60 (d, J = 10 Hz, 2H, NH); 13C
NMR (100 MHz, DMSO-d6): d (ppm) 35.04 (t, CH2Ar), 50.70 (d,
CH–N), 65.77 (t, CH–CH2O), 65.82 (t, OCH2C@O), 126.71, 128.69,
129.33 (d, aromatic CH), 138.42 (s, quaternary aromatic), 160.12
(s, C@O amide), 169.56 (s, C@O ester). Anal. Calcd for
cmꢁ1 1H NMR (DMSO-d6): d = 3.49–3.75 (6H, m), 4.85–4.90 (2H,
;
m), 7.21–7.42 (10H, m), 9.00 (2H, d, J = 8.8 Hz); 13C NMR (DMSO-
d6): d 56.21, 64.42, 127.48, 127.53, 128.64, 128.73, 160.22.
4.2.5. N,N0-[Bis(1S)-1-benzyl-2-hydroxyethyl]ethanediamide
(S,S)-2b
Yield: 99%; mp 252–253 °C; ½a D25
¼ ꢁ43:8 (c 0.03, MeOH); IR
ꢂ
C24H26N2O7: C 63.42, H 5.77, N, 6.16. Found: C 63.41, H 5.78; N
(KBr) m, 3416 (O–H), 3274 (N–H), 3063 (Ar-H), 3037 (Ar-H), 1658,
6.15.
(C@O, first amide band), 1523 (C@O, second amide band), 1047
(C–O)cmꢁ1 1H NMR (400 MHz, DMSO-d6): d = 2.77 (dd, J = 13.5,
;
4.2.9. (5S,10S)-5,10-Dibenzyl-3,12-dioxa-6,9,18-triazabicyclo-
[12.3.1]octadeca-1(18),14,16-triene-2,7,8,13-tetraone [Macro-
cycle (S,S)-5b]
The reaction was carried out by the high-dilution technique as
described before. Macrocycle (S,S)-5b; yield (0.98 g, 49%). mp
J = 5.4 Hz, 2H, CH2Ar (a)), 2.91 (dd, 13.5, 5.4 Hz, 2H, CH2Ar (b)),
3.43 (m, 4H, CH2O), 3.95 (m, 2H, CH–N), 4.93 (br s, 2H, OH), 7.3–
7.1 (m, 10 H, ArH), 8.4 (d, J = 9.2 Hz, 2H, NH); 13C NMR
(100 MHz, DMSO-d6): d (ppm) 36.6 (t, CH2Ar), 53.4 (d, CH–N),

416
S. Sßeker et al. / Tetrahedron: Asymmetry 25 (2014) 411–417
278–279 °C; IR (KBr):
m
3297 (N–H), 1751 (C@O, ester), 1728 (C@O,
ized Born solvent model (igb = 0). The system was then heated
from 0 to 700 K over 14 steps for a period of 350 ps and then
was simulated at 700 K for a period of 20,000 ps (igb = 0). A cluster
analysis was performed with 167 intervals out of 500,000 frames
to obtain a conformer with a larger population to represent the
lower energy conformer. Each ligand was manually placed on the
surface of the host ring so that the maximum contact points
between ammonium and the ring donors were achieved. The com-
plexes were minimized with a total of 5000 steps, 2500 of steepest
descent, followed by 2500 of conjugate gradient, using a non-
bonded cutoff of 999 Å and a generalized Born solvent model
(igb = 0). The system was then heated from 0 to 700 K over 14 steps
for a period of 350 ps and then was simulated at 700 K for a period
of 20,000 ps (igb = 0). A cluster analysis was performed with 50
intervals out of 20,000 frames and the coordinates of the structure
with the largest population were recorded and this was minimized
followed by cooling from 700 to 300 K over 8 steps for a period
200 ps and then was computed at 300 K for a period of 20,000 ps.
Molecular dynamic coordinates were recovered with 1.0 ps inter-
vals. A cluster analysis was used to obtain the conformer with
the largest population for each complex.
ester), 1659 (C@O, first amide band), 1520 (C@O, second amide
band), 1277 (O@C–O–C), 1130 (C–O–C) cmꢁ1. ½a D33
ꢂ
¼ ꢁ62:0 (c 0.1,
CH3CN); 1H NMR (400 MHz, DMSO-d6):
d (ppm) 0.84 (d,
J = 7.2 Hz, 6H, CH3 (a)), 0.86 (d, J = 7.2 Hz, 6H, CH3 (b)), 1.12–1.20
(m, 2H, CH(CH3)2), 1.49–1.60 (m, 4H,NCHCH2CH), 3.79–4.66 (m,
10H, CHN, CHN–CH2–C@O and O–CH2–C@O), 8.50 (d, J = 10 Hz,
2H, NH). 13C NMR (100 MHz, DMSO-d6): d (ppm) 21.91 (q, CH3
(a)), 23.54 (q, CH3 (b)), 24.76 (d, CH(CH3)2), 37.77 (t, CH2CH(CH3)2),
47.75 (d, CH–N), 65.81 (t, CH–CH2–O), 66.31 (t, O–CH2–C@O),
160.43 (s amide C@O), 169.52 (s, ester C@O). Anal. Calcd for
C18H30N2O7: C 55.95, H 7.83, N 7.25. Found: C 55.93, H 7.81, N 7.24.
4.2.10. (5S,10S)-5,10-Bis(2-methylpropyl)-3,12-dioxa-6,9,18-tri-
azabicyclo[12.3.1]octadeca-1(18),14,16-triene-2,7,8,13-tetraone
[Macrocycle (S,S)-5c]
The reaction was carried out by the high-dilution technique as
described before. Macrocycle (S,S)-5c; yield (0.88 g, 44%). mp
280–282 °C. IR (KBr):
(C@O, ester), 1659 (C@O, first amide band), 1524 (C@O, second
amide band), 1284 (O@C–O–C), 1149 (C–O–C) cmꢁ1
m 3282 (N–H), 1763 (C@O, ester), 1736
;
½
a 3D4
ꢂ
¼
þ153:0 (c 0.03, CH3CN); 1H NMR (400 MHz, DMSO-d6): d (ppm)
0.85 (t, J = 3.8 Hz, 6H, CH2CH3), 0.89 (d, J = 4.0 Hz, 6H, CHCH3),
1.04–1.11 (m, 2H, CH2CH3 (a)), 1.38–1.40 (m, 2H, CH2CH3 (b)),
1.68–1.70 (m, 2H, CHCH3), 3.81–3.93 (m, 2H, CH–N), 3.97–4.65
(m, 8H, NCHCH2O and OCH2C@O), 8.44 (d, J = 12 Hz, 2H, NH); 13C
NMR (100 MHz, DMSO-d6): d (ppm) 10.76 (q, CH2CH3), 15.84 (q,
CHCH3), 25.78 (t, CHCH2CH3), 34.66 (d, CHCH3), 53.42 (d, N–CH–
), 64.95 (t, CH2O), 66.22 (t, OCH2C@O), 160.72 (s, amide C@O),
169.61 (s, ester C@O). Anal. Calcd for C18H30N2O7: C 55.95, H
7.83, N 7.25. Found: C 55.94, H 7.84, N 7.23.
Energy changes and root-mean-square displacement (RMSD)
analysis for the hosts and complexes were carried out on the tra-
jectories by the ptraj module of AMBER (v9). 3D structures were
displayed using by Chimera (UCSF)29 and potential energy and
RMSD graphics are shown by GraphPad Pris 4 pocket programme.
Acknowledgements
We are grateful to the Scientific and Technical Research Council
of Turkey (TUBITAK) for supporting the project (106T395) and
Dicle University Research Council (DUBAP) for supporting the pro-
jects (10-FF-10 and 10-FF-11). We are also grateful to DA Case
(University of California, San Francisco) for providing a waiver of
AMBER.
4.2.11. (5R,10R)-5,10-Diethyl-3,12-dioxa-6,9,18-triazabicyclo-
[12.3.1]octadeca-1(18),14,16-triene-2,7,8,13-tetraone [Macro-
cycle (R,R)-6]
The reaction was carried out by the high-dilution technique as
described above. Macrocycle (R,R)-6; yield (1.14 g, 57%). mp
266.5–268 °C. IR (KBr):
(C@O, ester), 1659 (C@O, first amide band), 1520 (C@O, second
amide band), 1296 (O@C–O–C), 1149 (C–O–C) cmꢁ1
m 3282 (N–H), 1767 (C@O, ester), 1735
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;
½
a 3D4
ꢂ
¼
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