Synthesis of rigid and C2-symmetric 18-crown-6 type macrocycles bearing diamidediester groups: Enantiomeric recognition for α-(1-naphthyl) ethylammonium perchlorate salts

Article abstract of DOI:10.1016/j.tetasy.2010.05.051

A series of rigid and chiral c₂-symmetric 18-crown-6 type macrocycles (S,S)-4, (S,S)-5, (S,S)-6 and (R,R)-2 bearing diamideester groups were synthesized. The binding properties of these macrocycles were examined for α-(1-naphthyl)ethylammonium perchlorates salts by an ¹H NMR titration method. Taking into account the host employed, important differences were observed in the K_a values of (R)- and (S)-enantiomers of guests for macrocycles (S,S)-4 and (S,S)-6, K_S/K_R = 3.6, and K_S/K_R = 0.1 (K_R/K_S = 10.3) δ δG = 3.19 and δ δG = -5.77 kJ mol^-1 respectively. The results indicated excellent enantioselectivity of macrocyclic (S,S)-6 towards the enantiomers of α-(1-naphthyl)ethylammonium perchlorate salts.

Full text of DOI:10.1016/j.tetasy.2010.05.051

Tetrahedron: Asymmetry 21 (2010) 1893–1899
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of rigid and C2-symmetric 18-crown-6 type macrocycles bearing
diamide–diester groups: enantiomeric recognition for
ethylammonium perchlorate salts
a-(1-naphthyl)
*
Deniz Barıßs, Sevil Sßeker, Halil Hoßsgören, Mahmut Tog˘rul
University of Dicle, Faculty of Science, Department of Chemistry, 21280 Diyarbakir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2010
Accepted 25 May 2010
A series of rigid and chiral C2-symmetric 18-crown-6 type macrocycles (S,S)-4, (S,S)-5, (S,S)-6 and (R,R)-2
bearing diamide–ester groups were synthesized. The binding properties of these macrocycles were exam-
ined for
a
-(1-naphthyl)ethylammonium perchlorates salts by an 1H NMR titration method. Taking into
account the host employed, important differences were observed in the Ka values of (R)- and (S)-enanti-
omers of guests for macrocycles (S,S)-4 and (S,S)-6, KS/KR = 3.6, and KS/KR = 0.1 (KR/KS = 10.3) DDG = 3.19
and DDG = ꢀ5.77 kJ molꢀ1, respectively. The results indicated excellent enantioselectivity of macrocyclic
(S,S)-6 towards the enantiomers of a-(1-naphthyl)ethylammonium perchlorate salts.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
have been synthesized and studied widely. Among these, chiral
macrocyclic compounds involving crown ethers25 and cyclodex-
trins26 are dominant structures. On the other hand, it is well
known, that rigid and C2-symmetric macrocycles are more selec-
tive for protonated amines than non rigid and C2-symmetric
molecules.24
Enantiomeric recognition is an essential process in living
organisms as well as in artificial systems and involves the dis-
crimination of one enantiomer of the guest from the other by
a chiral host. It is important from various viewpoints, such as
enzyme–substrate interactions,1 the resolution of enantiomers
in chemical processes, and asymmetric catalysis.2 Therefore, the
design, synthesis and use of molecules capable of enantiomeric
recognition of other molecules are of great interest to workers
in these fields.2,3 In particular optically active macrocyclic recep-
tors and their enantioselective recognition of chiral compounds
have attracted much attention.4 Such model systems have found
applications in the development of pharmaceuticals,5–8 enantio-
selective catalysis,9–11 separation of enantiomers,12–14 biology,15
sensing16,17 and purification and analysis of enantiomers.18,19
This is why the design, synthesis, and structural–activity rela-
tionships of enantioselective receptors are still vital areas of re-
search.20–23 The study of recognition of chiral amine and chiral
protoned amine compounds is of significance because these
compounds are basic building blocks of biological molecules
and therefore, these molecules are frequently used as guests in
chiral recognition.24 Macrocyclic structures have received much
attention in the search for artificial receptors, mainly because
of their higher degree of preorganization as compared to their
acyclic counterparts. A great number of artificial chiral receptors
It is also well known that the amide group has a high affinity
for cations with a high charge density. Many ionophores with
amide ligands are currently employed as chemical sensors that
can quantitatively and reversibly measure cationic analytes.27,28
Macrocyclic diamides and diesters are widely found in Nature
and constitute an extensive range of natural products with di-
verse biological activity.29,30 These natural compounds are com-
plex structures due to the presence of multi-functional groups
and their chirality. A number of macrocyclic compounds contain-
ing diamide–diester groups have been synthesized.30,31 However,
few examples have been reported, dealing with the synthesis and
chiral recognition studies of chiral macrocyclic containing dia-
mide–diester groups. The main aim of this study is to examine
the effect of a macrocyclic cavity on the enantiomeric recognition.
Herein, we report the synthesis of a series of 18-crown-6 type ri-
gid and C2-symmetric macrocycles with two amide and two ester
groups in a macrocyclic ring by high dilution techniques and eval-
uation of enantiomeric recognition properties of these macrocy-
cles toward primary organoammonium perchlorate salts
(Caution! The perchlorate salts must be handled with care as they
are potential explosives) by 1H NMR titration methods. The recog-
nition properties of these type (18-crown-6) macrocycles were
compared with our previous result of 15-crown-5 types that are
analogues of these macrocycles (Scheme 1).31
* Corresponding author. Tel.:+90 412 2488550; fax: +90 412 2488039.
E-mail address: mtogrul@dicle.edu.tr (M. Tog˘rul).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.051

1894
D. Barıßs et al. / Tetrahedron: Asymmetry 21 (2010) 1893–1899
2.2. Enantiomeric recognition studies using an NMR titration
method
2. Results and discussion
2.1. Synthesis
The main purpose of synthesizing these macrocycles was to
study their enantiomeric recognition for guest molecules. The
enantiomeric recognition can be characterized by various spectro-
scopic methods, such as NMR, ultraviolet–visible (UV–vis), fluores-
cence and Infrared (IR), which are powerful tools used for the
examination of the recognition ability of new chiral macrocycles.34
As NMR spectroscopy is one of most effective and it has become a
routine tool in studying host–guest supramolecular chemistry, and
there are now hundreds of reports of studies where NMR titration
was used to measure intermolecular association.31,35
Herein, chiral rigid and C2-symmetric macrocycles (S,S)-4, (S,S)-
5, (S,S)-6 and (R,R)-2, were synthesised from bis(aminoalcoholdi-
glycolediamides 1a–d respectively as shown in Schemes 2 and 3.
Previously, the macrocyclic (S,S)-4 was synthesised by Zingaro
et al.30 However, this macrocycle has not been used for enantio-
meric recognition of primary organoammonium salts. Chiral
bis(aminoalcohol)diglycoldiamides were synthesised from (R)-2-
amino-1-butanol, L-leucinol, L-phenylalaninol, and L-isoleucinol re-
acted with dimethyldiglycolate in toluene at reflux, respectively.
Bis(aminoalcoholdiglycolediamides 1a and 1c were synthesised
under vigorous conditions.32 On the other hand, our methodology
for the synthesis of these compounds is more straightforward. (R)-
(ꢀ)-2-Amino-1-butanol was purchased from Fluka, and used with-
In this study, we applied standard 1H NMR titration experi-
ments to investigate the stability of the complexes of the macrocy-
clic hosts receptors (S,S)-4, (S,S)-5, (S,S)-6 and (R,R)-2, with (R)- and
(S)-a-(1-napthyl)ethylamine perchlorate salts (guests). Upon the
addition of guest molecules to the hosts, some of the signals in
the 1H NMR spectra migrated upfield or downfield due to the
non-covalent interactions such as hydrogen-bond between host
and guest. The complexation of ammonium cations [G] with chiral
macrocycle [H] is expressed by Eq. 1:
out further purification. The synthesis of
and
-isoleucine and
L
-leucinol,
-phenylalanilol was accomplished in one step from
-phenylalanine according to procedures de-
L
-isoleucinol
L
L
-leucine,
L
L
scribed in the literature.33 Macrocycles were synthesised from
the corresponding chiral bis(aminoalcohol)diglycoldiamides by a
high dilution technique. These macrocycles are readily prepared
in moderate yields and short synthetic sequences and allow high
modularity by simple changing of the amino alcohol moiety. The
functionality of diamides and diesters is not only suitable for bind-
ing but also ensures high rigidity. The structures proposed for
these chiral bis(aminoalcohol)diglycoldiamides and macrocycles
are consistent with data obtained from 1H, 13C NMR, IR, and ele-
mental analysis. All 1H and 13C NMR signals were assigned on
the basis of DEPT and 1H–13C NMR correlation experiments.
K
H þ G ¢ H ꢁ G
ð1Þ
Under the conditions employed herein, chiral
a
-(1-naphthyl)
ethylamine perchlorate salts (R)- and (S)-NapEA were selected as
the guest molecules. The association constant of the supramolecu-
lar systems formed were calculated according to the modified
Benesi–Hildebrand equation (Eq. 2), where [H]o and [G]o refer to
the total concentration of macrocycles and organic ammonium
salts, respectively. The original Benesi–Hildebrand experiment
was an optical spectroscopy study of the association of iodine with
aromatic hydrocarbons.36 The 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]o. Relationships between known quantities (initial con-
centrations) and experimental observations can now be derived.
Mathur et. al.37 and Hannah and Ashbaugh38 have independently
derived the NMR version of the Benesi–Hildebrand equation. For
O
O
O
O
R
H
O
H
R
R
H
O
H
R
N
N
N
N
O
O
all the guests examined, plots of calculated 1/
Dd values as a func-
O
O
B
O
tion of 1/[G]o values showed a linear relationship with a slope 1/
O
O
O
KaꢁDdmax and intercept 1/
D
dmax, supporting the 1:1 complex
dmax
ð2Þ
A
formation.
A) R:benzyl (S,S)-1; isobutyl (S,S)-2; sec-butyl (S,S)-3, B) ethyl, (R,R)-1
Scheme 1. 15-Crown-5 type macrocycles.31
1=
D
d ¼ 1=ðKa ꢁ
D
dmax ꢁ ½GꢂoÞ þ 1=
D
Where
D
d = (dG ꢀ dobs), and
Ddmax = (dG ꢀ dHꢁG
)
O
O
H
H
R
N
O
N
R
OH
R
H
OMe
O
O
H2N
HO
OH
R: benzyl 1a; isobutyl 1b; sec-butyl 1c
Toluene, reflux
HO
O
N
O
N
OH
H2N
H
H
OMe
O
H
O
Toluene, reflux
OH
HO
1d
Scheme 2. The synthesis of diglycolediamides 1a–d.

D. Barıßs et al. / Tetrahedron: Asymmetry 21 (2010) 1893–1899
1895
O
H
O
O
H
R
R
N
O
N
O
1a-c
O
O
Cl
O
O
O
O
Benzene, DMF
R: benzyl (S,S)-4; isobuthyl (S,S)-5; sec-buthyl (S,S)-6
O
O
O
1d
H
H
Cl
N
O
N
O
Benzene, DMF
O
O
O
(R,R)-2
Scheme 3. The synthesis of 18-crown-6 type macrocycles.
It is well known fact that crown ethers form very stable com-
plexes with ammonium salts by means of a hydrogen bonding net-
work, thus making them useful in many applications;39–41 in
particular, those bearing stereogenic centres on their rings core
are of great interest in their usage in stereoselective applications.24
The model compounds, easily synthesized when compared to
crown ethers, might be considered to be cyclic esters possessing
crown ether like rings, and are predicted to behave in a similar
mode to accommodate ammonium salts. In addition, since they
hold carbonyl and amide functions on their rings, they are ex-
pected to be superior to crown ethers; because these functions
are thought to make the ring more rigid, which is a preferential
prerequisite for a host to include a guest more tightly.
Important differences were observed in the Ka values of (R)-Na-
pEA and (S)-NapEA for macrocyclic host receptors (S,S)-4 and (S,S)-
6, KS/KR = 3.63 and KR/KS = 10.29, DDGo = 3.19 and ꢀ5.77 kJ molꢀ1
,
respectively, as shown in Table 1. On the other hand, differences
in Ka values of (R)-NapEA and (S)-NapEA for macrocyclic host
receptors (R,R)-2 and (S,S)-5 were moderate, KS/KR = 1.63 and KS/
KR = 1.34, DDGo = 1.22 and 0.72 kJ molꢀ1, respectively.
When Ka binding constants (Table 1, entries 1–8) for the rigid
and C2-symmetric 18-crown-6 type macrocyclic host receptors
(S,S)-4, (S,S)-5, (S,S)-6 and (R,R)-2 were compared with those for
analogues of these macrocycles, 15-crown-5 type macrocyclic host
receptors (Table 1, entries 9–16), it can be seen that Ka binding
constants of 15-crown-5 type macrocyclic host receptors are gen-
erally higher. These results may be due to the more rigid 15-
crown-5 type macrocyclic host receptors and their proper
preorganizations.
In the cases of 18-crown-6 type macrocyclic host receptors with
benzyl side arms, (S,S)-4 recognizes the (R)-enantiomer of the Na-
pEA guest (entries 1 and 2) better, while its analogue 15-crown-5
type macrocyclic host receptor (S,S)-1 recognizes the (S)-enantio-
mer of the guest better (entries 11 and 12). Thus a reverse selectiv-
ity was obtained and this may be confirmed by ERF values. The ERF
with (S,S)-4 is 3.63 (which corresponds to approximately 56% ee)
and in favour of the (R)-enantiomer of the guest, whereas with
the analogue 15-crown-5 type (S,S)-1 is 5.55 (which corresponds
to approximately 70% ee) and in favour of the (S)-enantiomer.
These results show that (S,S)-1 complexes with the (S)-enantiomer;
the bulky naphthyl group in the guest is placed exactly opposite in
the cavity on the side of the benzyl moiety of the host molecule,
and it complexes with the (R)-enantiomer, both groups placed on
the same side of the macrocycle and this causes unfavourable ste-
ric interactions.31 Furthermore, the results indicate that placement
of the side arm groups guest and (S,S)-4 is the inverse of the (S,S)-1.
In the cases of 18-crown-6 type macrocyclic host receptors hav-
ing ethyl side arms, (R,R)-2 does not have a significant selectivity
between the (R)- and the (S)-enantiomers of NapEA guest (KS/
KR = 1.63, entries 3 and 4) whereas its analogue 15-Crown-5 type
macrocyclic host receptor (R,R)-1 shows good recognition in favour
of (R)-NapEA (KS/KR = 3.65, entries 9 and 10). This can be explained
by the fact due to the small cavity of the macrocycle (15-crown-5
type) ethyl moiety behaving as a bulky substituent that is capable
of making a discrimination between the (R)- and (S)-enantiomers
Initially, the binding properties (binding constant) of novel dia-
mide–diester macrocycles (S,S)-4, (S,S)-5, (S,S)-6 and (R,R)-2 with
(R)- and (S)-napthylethylamine [(R)-NapEA and (S)-NapEA] was
examined. These cations are well known used as a standard guest
for chiral recognition ions and most cases give the best re-
sults.18,31,42 The concentration of host was fixed at 1.33 ꢃ 10ꢀ3
M
in CD3CN for the measurements and the concentration of guests
were increased from 0.1 to 6 equiv. Significant shifts (downfield)
of the CH proton next to the nitrogen in the guest molecules were
observed during the titration. This finding indicated a strong
hydrogen-bonding interaction for this nitrogen (Fig. 1). The stan-
dard linear analysis of the chemical shift data (R = 0.9932) that
delivered the 1:1 binding constants Ka and Gibbs free energy
changes (ꢀ
and (R,R)-2 with guest molecules are summarised in Table 1 along
with enantioselectivity KS/KR or DDGo calculated from ꢀ Go for
complexation of (R/S)- -(1-naphthyl) ethylamine perchlorate salts
DGo) for the host macrocycles (S,S)-4, (S,S)-5, (S,S)-6
D
a
by these host macrocycles. To confirm the 1:1 stoichiometry, an
exampolar Job Plot of the complexation of the host macrocycle of
(S,S)-5 and perchlorate salts of (R)-
was constructed (Fig. 2). Typical plots for the complexation of
(S,S)-5 host with (R)- -(1-napthyl) ethylamine perchlorate salt
a-(1-naphthyl) ethylamine
a
(guest) are shown in Figure 3. In order to obtain an adequate com-
parison of binding constants, only the shifts of the CH proton in the
guest were used for the calculation of Ka. These chemical shifts
were the maximally shifted ones in all cases. In general, complex
formation led to a downfield shift of the observed proton, this
showed that the complexation occurs between the guest amine
proton and macrocycle host.

1896
D. Barıßs et al. / Tetrahedron: Asymmetry 21 (2010) 1893–1899
Figure 1. (A) Typical NMR spectrum of the complexation of (S,S)-5, with (R)-NapEA, changes upon the addition of constant concentration of Host molecule ((S,S)-5,
1.33 ꢃ 10ꢀ3 M) to the (R)-NapEA guest molecule at various concentrations (0–6 ꢃ 10ꢀ3 M) in CD3CN. (B) Extended chemical shifts of guest’s CH (methine) proton.
Table 1
Binding constant (Ka), the Gibbs free energy changes (
D
Go), and enantioselectivities KR/KS or DDGo for the inclusion of R/S guest with the chiral host macrocycles in CD3CN at 25 °C
b
Entry
Host
Guesta
Ka (Mꢀ1
)
KS/KR
ꢀ
D
Go (kJ molꢀ1
)
DDGo (kJ molꢀ1
)
ee
1
2
3
4
5
6
7
8
(S,S)-4
(S,S)-4
(R,R)-2
(R,R)-2
(S,S)-5
(S,S)-5
(S,S)-6
(S,S)-6
(R,R)-1
(R,R)-1
(S,S)-1
(S,S)-1
(S,S)-2
(S,S)-2
(S,S)-3
(S,S)-3
(R)-NapEA
(S)-NapEA
(R)-NapEA
(S)-NapEA
(R)-NapEA
(S)-NapEA
(R)-NapEA
(S)-NapEA
(R)-NapEA
(S)-NapEA
(R)-NapEA
(S)-NapEA
(R)-NapEA
(S)-NapEA
(R)-NapEA
(S)-NapEA
378.7 0.022
1375.1 0.016
735.0 0.023
1200.5 0.015
1171.5 0.034
1571.4 0.015
1252.1 0.032
121.7 0.042
7752.9 0.019
2122.9 0.028
1230.7 0.011
6835.7 0.021
2507.4 0.036
2669.4 0.026
1211.2 0.029
988.6 0.041
3.63
14.71
17.90
16.35
17.57
17.51
18.23
17.67
11.90
22.19
18.98
17.63
21.88
19.39
19.55
17.59
17.09
3.19
56 (S)
1.63
1.34
1.22
0.72
24 (S)
16 (R)
82 (R)
57 (R)
70 (S)
3 (S)
0.10 (KR/KS = 10.29)
0.53
3.65
ꢀ5.77
ꢀ3.21
+4.25
+0.16
ꢀ0.50
9c
10c
11c
12c
13c
14c
15c
16c
0.18 (KS/KR = 5.55)
0.94 (KS/KR = 1.07)
1.23
10 (R)
a
b
c
NapEA:
DDGo = ꢀ(
a
-(1-naphthyl)ethylammonium perchlorate salt.
Go(R) Go(S)).
Recognition properties of these macrocycles were published by our group.31
D
ꢀ
D
for (R,R)-1. On the other hand, in the case of (R,R)-2, because of the
cavity size of the macrocycle (18-crown-6 type), the ethyl group it
does not behave as a bulky group. Therefore, does not cause the
steric interactions that are capable of making a discrimination be-
tween (R)- and (S)- enantiomers of the guest.
host receptor (S,S)-2 do not display a significant recognition be-
tween (R)- and (S)-enantiomers of the guest (KS/KR = 1.34 and
1.07, respectively, entry 5, 6, 13 and 14).
The 18-crown-6 type macrocyclic host receptor having sec-bu-
tyl side arms, (S,S)-6 showed excellent recognition (KR/KS = 10.29,
which corresponds to approximately 82% ee) in favour of the (R)-
enantiomer of NapEA guest (entries 7 and 8), while its analogue
Both 18-crown-6 type macrocyclic host receptors having isobu-
tyl side arms, (S,S)-5 and its analogue 15-crown-5 type macrocyclic

D. Barıßs et al. / Tetrahedron: Asymmetry 21 (2010) 1893–1899
1897
45
40
35
30
25
20
15
10
5
and (R,R)-2, derived from dimethyldiglycolate and amino alcohols
by high dilution technique and evaluated enantiomeric
a
recognition properties of these macrocycles toward primary organ-
oammonium salts by 1H NMR titration. In addition enantiomeric
recognition properties of these macrocyclic host receptors were
compared with their analogues of 15-crown-5 type macrocyclic
host receptors, to determine whether sufficient stereoinduction
can be obtained.
These macrocycles can be readily prepared in short synthetic
sequences and allow high modularity by simply changing the ami-
no alcohol moiety. The functionality of amides and esters is not
only suitable for binding but also ensures high rigidity. The macro-
cycles have shown a considerable binding affinity and in turn
enantiomeric discrimination towards amine salts. The best enan-
tiomeric recognition was obtained for (S,S)-6.
0
0.0
0.2
0.4
0.6
0.8
1.0
1.2
[G]o/[G]o+[H]o
Figure 2. Job Plot titration for the complexation of macrocycle (S,S)-5, and
perchlorate salt of (R)-a-(1-naphthyl)ethyl amine ((R)-NapEA) in CD3CN.
4. Experimental
Macrocyclic- Naph
S
- )
3 (
0
-5
4.1. General information
y = -5.3844x - 8.4608
R2 = 0.9932
-10
-15
-20
-25
Melting points were determined with a GALLENKAMP Model
apparatus with open capillaries and uncorrected. Infrared spectra
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 indicated solvents. Chemical
shifts are expressed in part per million (d) using residual solvent
protons as internal standards.
0.0
0.5
1.0
G
1.5
]
(mM-1)
o
2.0
2.5
1/[
Figure 3. Typical plot of 1/
D
d
versus 1/[G]o for host–guest complexation of
a-(1-naphthyl)ethylamine perchlorate salt ((R)-
Macrocycle (S,S)-5 and (R)-(ꢀ)
NaptEA).
4.2. Synthesis of aminoalcohols
15-crown-5 type macrocyclic host receptor (S,S)-3 showed a low
recognition with the same guest (KS/KR = 1.23, entries 15 and 16).
This result indicates that its macrocyclic cavity and the substituent
bulkiness fit to each other in order to make the best discrimination
between the enantiomers of the guest in case of (S,S)-6. Further-
more this may be attributed to a second asymmetric centre (stere-
ogenic centre) on the sec-butyl side arm in 18-crown-6 type
macrocyclic host receptor (S,S)-6 being matching for the (R)-enan-
tiomer, while it is mismatching for the (S)-enantiomer.
To compare the newly synthesised macrocyclic host receptors
with each other, the best discrimination between the enantiomers
was obtained for the macrocyclic host receptor with sec-butyl side
arms, (S,S)-6, (KR/KS = 10.29, DDG = -5.77). These results indicate
that a sec-butyl group in side arm fits very well within the cavity
of the macrocycle. The fact that discrimination is quite good for
(R)-(ꢀ)-2-Amino-1-butanol was purchased from Fluka, and
used without further purification. The synthesis of L-leucinol, L-iso-
leucinol and L-phenylalanilol were accomplished in one step from
L
-leucine, L-isoleucine and L-phenylalanine according to procedures
described in the literature.33
4.3. Dimethyldiglycolate (DMG) 1
A solution of diglycolicaciddichloride 2 (17.1 g, 0.1 mol) in ben-
zene (150 mL) was added dropwise to a solution methanol (12.8 g,
0.4 mol) and pyridine (15.82 g, 0.2 mol) in 3 h under dry N2 atmo-
sphere. The reaction mixture was refluxed for 3 h. Then the mix-
ture was kept for one day at room temperature. The solution was
filtered, and the solvent evaporated in vacuum. The solid residue
was extracted with ice-cold ether (3 ꢃ 50 mL) and the white solid
obtained after evaporation. The product was recrystallized from
ether/petroleum ether (2:1) to give white solid (13 g, 80%); mp
36–37.5 °C; 1H NMR (400 MHz, CDCl3): d (ppm) 3.74 (s, 6H,
OCH3), 4.22 (s, 4H, OCH2C@O). Anal. Calcd for C6H10O5: C, 44.45;
H, 6.22. Found: C, 44.42; H, 6.23.
the macrocycle having benzyl side arm, (S,S)-4 implies that
p-p
interaction between the benzyl moiety in the host macrocycle
and the naphthyl moiety in the guest makes a significant contribu-
tion to this discrimination. The macrocyle with either ethyl or iso-
butyl side arms, (R,R)-2 and (S,S)-5 showed lower enantiomeric
recognition between (R)- and (S)-NapEA enantiomers.
These chiral, rigid and C2-symmetric macrocycles exhibit excel-
lent chiral recognition ability towards the enantiomers of (R)- and
(S)-NapEA. The macrocycles shape, cavity size, structural rigidity,
4.4. General procedure for the synthesis of diglycoldiamide
1a–d
steric effect, hydrogen bond and
matic groups may be responsible for the enantiomeric recognition
of protoned amine derivatives.
p–p stacking between the aro-
To a solution of desired aminoalcohols (2.5 mmol) in toluene
(25 mL) a solution of dimethyldiglycolate 1 (1.2 mmol) was added
dropwise at room temperature. After the addition is complete, the
reaction mixture was refluxed for a further 2 days. The crude prod-
uct was purified by column chromatography on silica gel (eluent:
ether/petroleum ether 2:1) or the analytically pure product precip-
itated as white crystals on standing at 4 °C and then filtered and
washed with small portion of petroleum ether.
3. Conclusion
In this study, we have synthesised a series of 18-crown-6 type
macrocycles with diamide–diester groups (S,S)-4, (S,S)-5, (S,S)-6

1898
D. Barıßs et al. / Tetrahedron: Asymmetry 21 (2010) 1893–1899
4.4.1. N,N0-Bis[(1S)-1-benzyl-2-hydroxyethyl]diglycoldiamide 1a
(400 MHz, DMSO-d6): d (ppm) 2.69–2.86 (m, 4H, CH2Ar), 3.75–
3.88 (m, 6H, CH2O ve CH–N), 4.25–4.57 (m, 8H, O–CH2–C@O),
7.18–7.26 (m, 10H, ArH), 8.52 (d, J = 8.8 Hz, 2H, NH); 13C NMR
(100 MHz, DMSO-d6): d 36.47 (t, CH2Ar), 49.41 (d, CH–N), 65.63
(t, CH–CH2O), 66.91 (t, OCH2C@O), 71.55 (t, OCH2C@O), 126.78,
128.72, 129.42 (d, aromatic CH), 138.42 (s, quaternary aromatic),
170.05 (s, C@O amide), 170.22 (s, C@O ester). Anal. Calcd for
Yield: 72%; mp 128–130 °C; ½a D34
¼ ꢀ39:2 (c 0.03, MeOH); IR
ꢂ
(KBr):
m 3413, 3316, 3243, 3070, 3031, 2931, 2873, 1643, 1546,
1110, 1045 cmꢀ1 1H NMR (400 MHz, CDCl3): d (ppm) 2.70 (2H,
;
dd, J = 16, J = 8.4 Hz), 2.90 (2H, dd, J = 8.4, J = 7.4 Hz), 3.39–3.46
(4H, m), 3.78–3.88 (4H, m), 3.92–4.05 (2H, m), 4.91 (2H, br s),
7.16–7.28 (10H, m) 7.90 (2H, d, J = 8.4); 13C NMR (100 MHz, CDCl3):
37.00, 52.71, 62.90, 70.85, 126.45, 128.61, 129.54, 139.49, 169.00.
Anal. Calcd for C22H28N2O5: C, 65.98; H, 7.05; N, 7.00. Found: C,
65.97; H, 7.09; N, 6.97.
C26H30N2O8: C, 62.64; H, 6.07; N, 5.62. Found: C, 62.61; H, 6.10;
N, 5.58.
4.6. (9,17R)-9,17-Diethyl-1,4,7,13-tetraoxa-10,16-diaza-
cyclooctadecane-2,6,11,15-tetraone (R,R)-2
4.4.2. N,N0-Bis[(1S)-2-hydroxyethyl-1-isobutyl]diglycoldiamide
1b
Yield: 66% as a yellow oil; ½a D39:5
ꢂ
¼ ꢀ40:3 (c 1, MeOH); IR:
m
The reaction was carried out by the high-dilution technique as
described above. Macrocyclic (R,R)-2; yield (0.8 g, 32%); mp 138–
3352, 3089, 2967, 2877, 1754, 1670, 1561, 1137, 1073 cmꢀ1
;
1H
NMR (400 MHz, CDCl3): d 0.90 (6H, d, J = 4.0 Hz), 0.92 (6H, d,
J = 4.0 Hz),1.29–1.36 (2H, m), 1.40–1.48 (2H, m), 1.59–1.66 (2H,
m), 2.45 (2H, br s), 3.49–3.53 (2H, m), 3.69–3.72 (2H, m), 4.04–
4.06 (2H, m), 4.08 (4H, s), 7.06 (2H, d, J = 8.8 Hz); 13C NMR
(100 MHz, CDCl3): 22.20, 23.02, 24.88, 40.09, 49.49, 64.91, 71.02,
169.71. Anal. Calcd for C16H32N2O5: C, 57.81; H, 9.70; N, 8.43.
Found: C, 57.85; H, 9.69; N, 8.39.
141 °C; IR (KBr): m 3300 (N–H), 1760 (C@O, ester), 1735 (C@O, es-
ter), 1665 (C@O, first amide band), 1554 (C@O, second amide
band), 1227(O@C–O–C), 1157 (C–O–C) cmꢀ1; ½a D34
¼ þ51 (c 0.01,
ꢂ
THF); 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.84 (t, J = 7.4 Hz,
6H, CH3), 1.39–1.58 (m, 4H, CHCH2CH3), 3.74–3.78 (m, 2H, CH–
N), 3.98–4.51 (m, 12H, CH2O ve O–CH2–C@O), 8.33 (d, J = 8.8 Hz,
2H, NH); 13C NMR (100 MHz, DMSO-d6): d 10.44 (q, CH3), 23.25
(t, CH2CH3), 48.84 (d, CH–N), 65.30 (t, CH–CH2–O), 66.46 (t, O–
CH2–C@O), 71.15 (t, O–CH2–C@O), 169.71 (s, amid C@O), 169.78
(s, ester C@O). Anal. Calcd for C16H26N2O8: C, 51.33; H, 7.00; N,
7.48. Found: C, 51.35; H, 7.02; N, 7.45.
4.4.3. N,N0-Bis[(1S)-2-hydroxyethyl-1-(S)-sec-
butyl]diglicoldiamide 1c
Yield: 75% as a yellow oil; ½a D41
ꢂ
¼ ꢀ21:3 (c 1, MeOH); IR:
m 3306,
3086, 2972, 2931, 2880, 1759, 1668, 1562, 1462, 1139, 1034 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d (ppm) 0.90 (6H, t, J = 4.2 Hz), 0.95 (6H,
d, J = 7.2 Hz), 1.15–1.20 (2H, m), 1.48–1.53 (2H, m), 1.64–1.66 (2H,
m), 3.14 (2H, br s), 3.64–3.68 (2H, m), 3.72–3.76 (2H, m), 3.87–3.89
(2H, m), 4.11 (4H, s), 7.08 (2H, d, J = 8.4 Hz); 13C NMR (100 MHz,
CDCl3): 11.31, 15.45, 25.63, 35.79, 55.47, 62.58, 71.15, 169.80.
Anal. Calcd for C16H32N2O5: C, 57.81; H, 9.70; N, 8.43. Found: C,
57.83, H, 9.72, N, 8.41.
4.7. (9,17S)-9,17-Diisobutyl-1,4,7,13-tetraoxa-10,16-diaza-
cyclooctadecane-2,6,11,15-tetraone (S,S)-5
The reaction was carried out by the high-dilution technique as
described above. Macrocyclic (S,S)-5; yield (0.48 g, 32%). Mp 187–
190 °C; IR (KBr):
m 3288 (N–H), 1760 (C@O, ester), 1747 (C@O, es-
ter), 1670 (C@O, first amide band), 1555 (C@O, second amide
band), 1235 (O@C–O–C), 1158 (C–O–C) cmꢀ1. ½a D31
¼ ꢀ32 (c 0.01,
ꢂ
4.4.4. N,N0-Bis[(1R)-1-ethyl-2-hydroxyethyl]diglycoldiamide 1d
THF); 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.86 (d, J = 8.8 Hz,
6H, CH3 (a)), 0.88 (d, J = 7.2 Hz, 6H, CH3 (b)), 1.16–1.21 (m, 2H,
CH(CH3)2), 1.22–1.56 (m, 4H,NCHCH2CH), 3.88–4.22 (m, 14H,
CHN, CHCH2O, N C@O–CH2–O ve O–CH2–C@O), 7.65 (d, J = 9.2 Hz,
2H, NH). 13C NMR (100 MHz, DMSO-d6): d 22.14 (q, CH3 (a)),
23.49 (q, CH3 (b)), 24.59 (d, CH(CH3)2), 38.94 (t, CH2CH(CH3)2),
45.67 (d, CH–N), 66.65 (t, CH–CH2–O), 67.77 (t, O–CH2–C@O),
69.98 (t, O–CH2–C@ON), 169.11 (s, amide C@O), 170.22 (s, ester
C@O). Anal. Calcd for C20H34N2O8: C, 55.80; H, 7.96; N, 6.51. Found:
C, 55.83; H, 7.99; N, 6.47.
Yield: 68% as a yellow oil; ½a D39
ꢂ
¼ ꢀ22:7 (c 1, MeOH); IR:
m 3333,
3089, 2967, 2935, 2877, 1766, 1657, 1542, 1464, 1131, 1047 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d (ppm) 0.93 (6H, t, J = 7.4 Hz), 1.47–
1.61 (4H, m), 3.52–3.69 (4H, m), 3.88–3.90 (2H, m), 4.11 (4H, s),
4.59 (2H, br s), 7,25 (2H, d, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3):
10.53, 24.14, 52.82, 63.89, 70.99, 169.73. Anal. Calcd for
C12H24N2O5: C, 52.16; H, 8.75; N, 10.14. Found: C, 52.15; H, 8.79;
N, 10.09.
4.5. (9,17S)-9,17-Dibenzyl-1,4,7,13-tetraoxa-10,16-diaza-
cyclooctadecane-2,6,11,15-tetraone (S,S)-4
4.8. (9,17S)-9,17-(S)-Disecbutyl-1,4,7,13-tetraoxa-10,16-diaza-
cyclooctadecane-2,6,11,15-tetraone (S,S)-6
This experiment was using a under high dilution technique. A 2-
L, 4-necked, round-bottomed flask, fitted with a mechanical stirrer
and two faced condenser is charged with 1 L of benzene (Caution!
Carcinogenic) and tritely amine equivalent to the produced HCl.
The solution was refluxed vigorously while 2 (1.6 g, 4.0 mmol) in
dry THF/DMF (w:w, 70/30 = 100 mL) and diglycolicacide dichloride
6 (0.83 g, 4.8 mmol) in dry benzene (100 mL) were added drop
wise at the same rate. After the addition was complete, the reac-
tion mixture was refluxed for a further 5 days. The solution was
cooled to room temperature, filtered and the solvent evaporated
under vacuum. The resulting white solid was crystallized from eth-
anol–acetonitrile mixture (2:1). Macrocyclic (S,S)-4; yield (0.9 g,
The reaction was carried out by the high-dilution technique as
described above. Macrocyclic (S,S)-6; yield (0.52 g, 26%). Mp 178–
180 °C; IR (KBr):
m 3281 (N–H), 1754 (C@O, ester), 1744 (C@O, es-
ter), 1670 (C@O, first amide band), 1555 (C@O, second amide
band), 1235 (O@C–O–C), 1158 (C–O–C) cmꢀ1; ½a D31
¼ ꢀ30 (c 0.01,
ꢂ
THF); 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.84 (t, J = 6.8 Hz,
6H, CH2CH3), 0.87 (d, J = 7.6 Hz, 6H, CHCH3), 1.06–1.13 (m, 2H,
CH2CH3 (a)), 1.39–1.42 (m, 2H, CH2CH3 (b)), 1.43–1.56 (m, 2H,
CHCH3), 3.88–4.24 (m, 14H, CH–N, NCHCH2O, OCH2C@ON ve
OCH2C@O), 7.69 (d, J = 9.2 Hz, 2H, NH); 13C NMR (100 MHz,
DMSO-d6): d 10.76 (q, CH2CH3), 15.27 (q, CHCH3), 25.03 (t,
CHCH2CH3), 35.33 (d, CHCH3), 50.95 (d, N–CH–), 64.34 (t, CH2O),
67.38 (t, OCH2C@O), 69.67 (t, OCH2C@ON), 168.67 (s, amide
C@O), 169.88 (s, ester C@O). Anal. Calcd for C20H34N2O8: C,
55.80; H, 7.96; N, 6.51. Found: C, 55.78; H, 7.99; N, 6.56.
45%); mp 230–232 °C; IR (KBr):
m 3268 (N–H), 3102 (Ar–H), 3063
(Ar–H), 3031 (Ar–H), 1754 (C@O, ester), 1728 (C@O, ester), 1670
(C@O, first amide band), 1561 (C@O, second amide band), 1151
(C–O–C, 1048 (C–O–C), cmꢀ1; ½a D31
ꢂ
¼ ꢀ109 (c 0.01, THF); 1H NMR

D. Barıßs et al. / Tetrahedron: Asymmetry 21 (2010) 1893–1899
1899
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E.; Huszthy, P.; Somogyi, L.; Hollosi, M. Tetrahedron: Asymmetry 1999, 10, 2775;
Ozbey, S.; Kaynak, F. B.; Togrul, M.; Demirel, N.; Hosgoren, H. J. Inclusion
Phenom. Macrcycl. Chem. 2003, 45, 123; Ozbey, S.; Kaynak, F. B.; Togrul, M.;
Demirel, N.; Hosgoren, H. Z. Kristallogr. 2003, 218, 381; Turgut, Y.; Sahin, E.;
Togrul, M.; Hosgoren, H. Tetrahedron: Asymmetry 2004, 15, 1583–1588; Togrul,
M.; Turgut, Y.; Hosgoren, H. Chirality 2004, 16, 351; Togrul, M.; Askin, M.;
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Akgun, A.; Hosgoren, H.; Togrul, M. Tetrahedron: Asymmetry 2009, 20, 1541;
Maczar, I.; Huszthy, P.; Mezei, A.; Kadar, M.; Nyitrai, J.; Toth, K. Tetrahedron
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Acknowledgements
This work was supported by The Scientific and Technical Re-
search Council of Turkey (TUBITAK), under project number:
106T395 and Dicle University Research Committee (DUBAP) under
project number 06-FF-39 and 06-FF-40. The authors thank the
TUBITAK and DUBAP for supporting this work.
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