Synthesis of new diaza-18-crown-6 ethers derived from trans-(R,R)-1,2- diaminocyclohexane and investigation of their enantiomeric discrimination ability with amino acid ester salts

Article abstract of DOI:10.1016/j.tet.2012.10.020

The synthesis of four diaza-18-crown-6 ethers with C₂-symmetry derived from trans-(R,R)-1,2-diaminocyclohexane bearing methyl, phenyl and phenoxymethyl moeities attached to a stereogenic centre on the crown ring were achieved. Enantiomeric discrimination of these macrocycles against amino acid methyl ester salts was examined by ¹H NMR titration method. They exhibit strong binding ability and some of them show a very high enantioselectivity towards amino acid esters, corresponding to 5.37 kJ/mol of binding energy difference in CDCl₃ at 25 °C. Computational modelling showed parallel results with experimental calculations, thus providing a detailed understanding of molecular recognition mode and binding sites between the hosts and the guests.

Full text of DOI:10.1016/j.tet.2012.10.020

Tetrahedron 69 (2013) 349e358
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new diaza-18-crown-6 ethers derived from
trans-(R,R)-1,2-diaminocyclohexane and investigation of their
enantiomeric discrimination ability with amino acid ester salts
€
*
€
Mehmet Karakaplan , Devran Ak, Mehmet C¸ olak, S¸ afak Ozhan Kocakaya, Halil Hos¸ goren,
*
ꢀ
Necmettin Pirinc¸ c¸ ioglu
Department of Chemistry, Faculty of Science, University of Dicle, 21280 Diyarbakır, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 July 2012
Received in revised form 17 September 2012
Accepted 5 October 2012
Available online 11 October 2012
The synthesis of four diaza-18-crown-6 ethers with C2-symmetry derived from trans-(R,R)-1,2-
diaminocyclohexane bearing methyl, phenyl and phenoxymethyl moeities attached to a stereogenic
centre on the crown ring were achieved. Enantiomeric discrimination of these macrocycles against
amino acid methyl ester salts was examined by 1H NMR titration method. They exhibit strong binding
ability and some of them show a very high enantioselectivity towards amino acid esters, corresponding
to 5.37 kJ/mol of binding energy difference in CDCl3 at 25 ꢀC. Computational modelling showed parallel
results with experimental calculations, thus providing a detailed understanding of molecular recognition
mode and binding sites between the hosts and the guests.
Keywords:
Chiral amino alcohols
Chiral diaza crown ethers
Enantiomeric recognition
Amino acid esters
Ó 2012 Elsevier Ltd. All rights reserved.
1H NMR titration
Computational modelling
1. Introduction
a trans-1,2-substitution also renders a C2-symmetry and a rigid
scaffold with a very precisely defined disposition of the two amino
Designing synthetic receptors that are capable of discriminating
between enantiomers have occupied a special place1 in gaining
a basic knowledge of molecular recognition, separation of enan-
tiomers for synthetic2 and analytical3 applications. The ability of
a molecule to discriminate between an enantiomer pair is based on
its capacity to form a molecular complex preferentially with one of
the enantiomers by non-covalent interactions, such as hydrogen
bonding, electrostatics and hydrophobics.4
Optically active polyazamacrocycles are important compounds in
organic,5 supramolecular,6 medicinal7 and bioorganic8 chemistry.
Additionally, these structures have shown extraordinary properties
for the molecular recognition of cationic9 and anionic species10 and
have been widely used as chiral solvating agents (CSAs) for the fast
andaccurate determination of enantiomeric excesses in combination
with NMR spectroscopy.11 Among the described non-racemic chiral
polyazamacrocycles, those bearing trans-1,2-diaminocyclohexane as
the chiral receptor are especially useful due to the structural pecu-
liarities of this moiety. The six-membered ring of the molecule with
groups.12 However, the syntheses of these systems are not trivial, due
to the low yields usually associated with the key macrocyclization
step.
Amino acids and their derivatives are chiral organic molecules
involved in a wide variety of biological processes. The study of the
enantiomeric recognition of these compounds is of particular sig-
nificance for understanding the interactions between biological
molecules and design of asymmetric catalytic systems, new phar-
maceutical agents,13 and separation materials.3a Chiral crown
ethers with C2-symmetry are characterized by their relatively
simple recognition mechanism and usually show higher enantio-
selectivity than those with C1- and D1-symmetry.1 In particular,
macrocycles with C2-symmetry have been extensively studied be-
cause of their structural architecture.14 It has been reported that
macrocycles synthesized from chiral 1,2-diaminocyclohexane have
been used as molecular receptors for peptides15 and in enantio-
meric recognition of amino acids.16 The fields of application of this
molecule range from the preparation of chiral catalysts for asym-
metric synthesis and the synthesis of supramolecular receptors or
the chiral stationary phases for separation science.17 Systematic
investigation on the synthesis of macromolecules from this versa-
tile amine should lead to fruitful results.
* Corresponding authors. Tel.: þ90 4122488550; fax: þ904122488039;
e-mail addresses: mkkaplan@dicle.edu.tr (M. Karakaplan), pirincn@dicle.edu.tr
ꢀ
(N. Pirinc¸ c¸ ioglu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.020

350
M. Karakaplan et al. / Tetrahedron 69 (2013) 349e358
We herein report on the results of the synthesis of C2-symmetric
benzaldehyde followed by NaBH4 reduction of the intermediate
imine.19 Chiral amino alcohols 2e4 were synthesized by the regio-
selective ring opening reaction of (S)-propylene oxide, (R)-styrene
oxide and (S)-glycidyl phenyl ether with chiral amine 1 in 99%, 75%
and 82.5% yields, respectively (Scheme 1). Amine 1 exhibited
a preference for nucleophilic attack at the terminal or achiral carbon
chiral diaza-18-crown-6 ether derivatives 5e8 and their molecular
recognition properties towards various salts of amino acid esters.
Therefore, C2-symmetric chiral amino alcohols 2e4 were synthe-
sized from chiral 1,2-diaminocyclohexane 1 and chiral terminal
epoxides by regioselective ring opening reaction in order to in-
corporate the additionally stereogenic centres to the macroring
(Scheme 1). This chirality built into the macrocycles offers addi-
tional interesting features enabling the macrocycle to be used as
a potential receptor for molecular recognition. Chiral diaza-18-
crown-6 derivative macrocycles 5e8 were synthesized by ring
closing reaction of chiral amino alcohols 2e4 and appropriate
ditosylates (Scheme 2). Their complexation ability and molecular
recognition properties towards enantiomers of alanine, phenylal-
anine and valine methyl ester hydrochlorides were investigated by
1H NMR titration method. Molecular dynamic calculations were
also performed for the complexes of the host 8 with enantiomers of
phenylalanine methyl ester salts to the detailed binding modes of
these complexes.
of epoxides with a SN2 reaction to give the corresponding chiral b-
amino alcohols 2e4 with retention of configuration at stereogenic
centre as reported previously.20,21 Therefore, this route provides an
easy and practical method for preparing chiral ligands incorporating
with different alkyl or aryl substituents. Diaza-18-crown-6 de-
rivatives 5e7 were synthesized under high dilution technique by
ring closing reaction of chiral amino alcohols 2e4 and triethylen-
glycol ditosylate in moderate yields (Scheme 2). Macrocyclic 8 was
also obtained by reacting chiral amino alcohols 3 with ditosylate
bearing a naphtho unit, which may create an additional binding
site, possibly providing
pep stacking interactions and enabling
specific recognition for amino acid derivatives with aromatic side
chains.22,23
HO
OH
+
HO2C
CO2H
NH2
H2N
(R,R)
1. CH3CO2H /H2O
2. KOH / H2O
NH2
H2N
(R,R)
1. PhCHO / CH3OH
2. NaBH4
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
N
O
O
N
H
Ph
Ph
N
Ph
H
HO
OH
HO
OH
1
2
3
OPh
OPh
O
N
Ph
Ph
N
PhO
HO
OH
4
Scheme 1. Synthesis of chiral amino alcohols 2e4.
2. Results
2.2. Determination of binding constant by 1H NMR titration
2.1. Synthesis
In order to determine the stoichiometry of the complexes, a Job
plot experiment was performed. A typical plot for the complex of 5
In the present study, four macrocycles involving chiral 1,2-
diaminocyclohexane unit and having stereogenic centres bearing
methyl, phenyl, phenoxymethyl moieties were synthesized. Chiral
1,2-diaminocyclohexane was chosen as a starting material because
of its ease of synthesis in sufficiently large quantities combined with
a unique molecular architecture, which allows further sophisticated
structures. Thus, (R,R)-trans-1,2-diaminocyclohexane, (S)-propylene
oxide, (R)-styrene oxide and (S)-glycidyl phenyl ether were used as
chiral sources. Chiral amine 1 was prepared by treating enantio-
merically pure trans-(R,R)-1,2-diaminocyclohexane obtained from
cis-/trans isomeric mixture by classical resolution technique,18 and
with L-alanine methyl ester salt is illustrated in Fig. 1. The con-
centration of the complex approaches maximum when the molar
fraction of [R]/[R]þ[L] is 0.5, suggesting that host 5 forms a 1:1
complex with L
-alanine methyl ester hydrochlorides. The 1H NMR
titrations were used to obtain binding constant between hosts and
guests. For each complex, a set of 9 samples containing constant
host concentration (0.833 mM) and increasing concentration of the
guest ranging from 0.417 to 4.54 mM was prepared and their 1H
NMR spectrum was recorded.
The chemical shifts in the
NMR spectrum versus increasing the guest concentration were
a
-hydrogen of each guest in the 1H

M. Karakaplan et al. / Tetrahedron 69 (2013) 349e358
351
Ph
Ph
R
Ph
Ph
Ph
Ph
N
O
N
O
N
N
1. NaH, THF
2. TEGDT
N
O
N
O
1. NaH, THF
2. TEGDT
R
R
R
O
O
HO
O
OH
O
2. R = -CH3
3. R = -Ph
6 R = -Ph
5
4. R = -CH2OPh
7 R = -CH2OPh
2.
1.NaH, THF
TsO
O
O
OTs
Ph
Ph
Ph
N
N
Ph
O
O
O
O
8
Scheme 2. Synthesis of chiral diaza-18-crown-6 ethers 5e8.
À
Á
d0
K
diss þ dmax½Guestꢂtot
À
Á
dobs
¼
(4)
Kdiss þ ½Guestꢂtot
where Kdiss is the dissociation constant between a host and a guest,
d0 is the chemical shift in specific hydrogen of a guest in the absence
of a host, dobs is the observed chemical shift in the same hydrogen in
the presence of a host and dmax is the maximum chemical shift
achieved in the presence of a host.
2.3. Computational modelling
Root Mean Square Displacement (RMSD) changes during the
molecular dynamic simulation performed for a period of 20 ns at
700 K for the host 8 are presented in Supplementary data. The
conformation with the largest population obtained from cluster
analyses for the host 8 is illustrated in Fig. 4. RMSD changes during
the molecular dynamic simulation performed for a period of 20 ns
Fig. 1. Job plots of macrocycle 5 with L-alanine methyl ester salt. [X¼molar fraction of
guest, Dd¼chemical shift change of -proton of guest].
a
at 300 K for the complexes of the host 8 with D- and L-phenylalanine
salts are displayed in Supplementary data. The conformation with
the largest population obtained from cluster analyses for the
determined. The changes in the chemical shifts of the
a-hydrogen of
D
- and -phenylalanine methyl ester salts upon complexation with
L
complexes of the hosts with
trated in Fig. 5.
D- and L-phenylalanine salts are illus-
the host 5 are demonstrated in Fig. 2. These changes were fitted to
Equation 3 derived from Equation 1 in order to calculate the disso-
ciation constant within 95% of confidence (see Table 1). A repre-
sentation of the data fitted to Equation 4 for the changes in the
3. Discussion
chemical shifts of the a-hydrogen of D- and L-alanine methyl ester
salts complexed with the host 5 are plotted in Fig. 3.
1H NMR spectra (400 MHz) of both chiral amino alcohols 2e4
and macrocycles 5e8 show considerable line broadening compared
to the compound 1 almost for all the peaks, probably indicating
a higher conformational flexibility and intermolecular mobility as
reported previously.14,24 It is known that the symmetry and rigidity
of cyclohexane ring display very characteristic 1H NMR spectra with
clear axial and equatorial positions for all the protons within the
ring.12 However, no significant change was observed in 1H NMR
spectrum at 233 K in CDCl3 as shown in Fig. 6 for chiral amino al-
cohol 3 which is in agreement with those reported previously.25,26
Systems having strong interactions or good chiral recognition
allow for further investigation of their structural properties. The
choice of the 18-membered macrocycles is generally based on the
k1
Host þ Guest # Host$Guest
(1)
k
ꢁ1
k
k1
½Hostꢂ½Guestꢂ
ꢁ1
Kdiss
¼
¼
(2)
(3)
½Host$Guestꢂ
½Guestꢂtot ¼ ½Guestꢂfree þ ½Guestꢂcomplex

352
M. Karakaplan et al. / Tetrahedron 69 (2013) 349e358
Fig. 2. Changes in 1H NMR chemical shifts in the
the macrocycle 5 (0.833 mM) in CDCl3 at 25 ꢀC.
a
-hydrogen of methyl ester salts of L-phenylalanine (left) and D-phenylalanine salt (right) on their concentration in the presence of
fact that they form more stable complexes with ammonium cations
in solution than other crown ethers with larger or smaller rings. The
insertion of 1,2-diaminocyclohexane subunit also provides
a favourable effect in their interaction with ammonium salts: first,
NþH/N hydrogen bond interaction are much more stable than
NþH/O bonds.27 Second, cyclic 1,2-diaminocyclohexane has
unique structural properties, which make it very useful for the
induction of a chiral environment (chiral ligands).12 To detail the
interactions in the complex formation is a very difficult task and
involves sophisticated use of various approaches. The use of NMR
spectroscopic methods to study such complexation phenomena is
one of the most useful techniques available to chemists. This
method includes the observation of changes in the chemical shift
occurred in one site of either the host or the guest. One of the dis-
advantages of this technique is the requirement for the higher
concentration of the species being followed, which may lead to self
aggregation and therefore misleading to changes in chemical shifts.
The data inTable 1 indicate that macrocycle 5 possessing a methyl
side arm attached to the stereogenic centre on the crown ring
Table 1
Binding constants (K), enantioselectivities KL/KD free-energy changes (ꢁ
D
Go), and
,
DDGo calculated from
DGo for complexation of guests with chiral hosts 5e8 in CDCl3
at 25 ꢀC
Hosta Guestb
K (Mꢁ1
)
KL/KD
ꢁ
D
Go
DDGo
(kJ molꢁ1
)
(kJ molꢁ1
)
prefers to bind
L enantiomers of all the guests. It is expected that
the side arms with small sizes like methyl would not have a signifi-
cant influence on the discrimination ability of a crown ring along
with its flexibility. However, the introduction of the trans-dia-
minocyclohexane unit into the crown ring may slow down the con-
formational changes in the ring as well as provide chiral binding sites
for the guests and hence this would be the main driving force for the
discrimination of the enantiomers as illustrated in Fig. 7. Thus, the
substituent on the crown ring will not be the primary contributors to
the enantiomeric recognition. In fact, the data in Table 1 for the
complexes of macrocycle 5 with amino acid salts pairs fit this as-
sumption since the host had a significant ability to discriminate be-
tween the enantiomers of phenylalanine methyl ester salts
comparedtothoseofalanineandvaline. Thismaybeattributedtothe
5
6
7
8
L
-AlaOMe$HCl
-AlaOMe$HCl
-PheOMe$HCl
-PheOMe$HCl
-ValOMe$HCl
-ValOMe$HCl
-AlaOMe$HCl
-AlaOMe$HCl
-PheOMe$HCl
-PheOMe$HCl
-ValOMe$HCl
-ValOMe$HCl
-AlaOMe$HCl
-AlaOMe$HCl
-PheOMe$HCl
-PheOMe$HCl 745,712ꢃ20,880
2060ꢃ47
1074ꢃ61
18,832ꢃ1224
2179ꢃ61
196ꢃ7
1.92
8.64
2.39
0.24
0.22
0.78
0.67
18.90ꢃ0.12 1.61
17.29ꢃ0.28
D
L
24.38ꢃ0.32 5.34
19.04ꢃ0.14
D
L
13.07ꢃ0.17 2.15
10.92ꢃ0.24
D
82ꢃ4
L
327ꢃ22
1355ꢃ58
378ꢃ24
1694ꢃ88
540ꢃ25
688ꢃ44
561ꢃ28
831ꢃ21
14.34ꢃ0.33 ꢁ3.53
17.87ꢃ0.21
D
L
14.70ꢃ0.32 ꢁ3.72
18.42ꢃ0.26
D
L
15.58ꢃ0.23 ꢁ0.60
16.19ꢃ0.36
D
L
15.68ꢃ0.25 ꢁ0.98
16.66ꢃ0.13
D
L
791,766ꢃ10,293 1.06
33.65ꢃ0.06 0.15
33.50ꢃ0.14
D
favourable pep interactions between the benzyl group of L guest and
L
-ValOMe$HCl
-ValOMe$HCl
-AlaOMe$HCl
-AlaOMe$HCl
-PheOMe$HCl
-PheOMe$HCl
-ValOMe$HCl
1858ꢃ19
3451ꢃ68
833ꢃ36
580ꢃ30
1302ꢃ73
194ꢃ12
1994ꢃ44
952ꢃ30
0.54
1.43
0.15
2.09
18.65ꢃ0.05 ꢁ1.53
20.18ꢃ0.10
the benzyl group of the host since it the anti (methyl¼[, benzyl¼Y),
anti (benzyl¼[, methyl¼Y) orientation of the methyl and the N-
benzyl groups on the crown ring is expected (Fig. 7). It is known that
this kind of stacking plays crucial roles in chemical and biological
recognition, which is detailed in an excellent review by Diederich
and co-workers.28 This assumption is based on the postulation that
D
L
16.67ꢃ0.21 0.91
15.76ꢃ0.26
D
L
17.77ꢃ0.35 4.75
13.02ꢃ0.30
D
L
18.82ꢃ0.28 1.83
16.99ꢃ0.16
D
-ValOMe$HCl
the a-hydrogen of the guests will have an average location facing
DDGo¼
D
Go(
L)ꢁD
Go( ).
D
a
Concentration of macrocycle 5e8¼8.33ꢄ10ꢁ4 mol dmꢁ3
.
opposite to the cyclohexane unit since this part of the crown ring is
thought to undergo major conformational changes and therefore it
will impose rather more steric sites to interact with the guests.
b
AlaOMe$HCl: alanine methyl ester hydrochloride, PheOMe$HCl: phenylalanine
methyl ester hydrochloride, ValOMe$HCl: valine methyl ester hydrochloride.

M. Karakaplan et al. / Tetrahedron 69 (2013) 349e358
353
Fig. 3. Chemicalshiftsinthe a
-hydrogenofmethyl estersalts ofD-alanine(left) and L-alanine(right)ontheirconcentration inthepresenceof themacrocycle 5 (0.833 mM)inCDCl3 at25ꢀC.
Fig. 4. A conformation of the macrocycle 8 with the largest population corresponding
to one of a lower energy conformer obtained from MD calculations.
Fig. 5. The superimposed structure of the complexes of the macrocycle 8 with D- and
L-phenylalanine methyl ester salts. Each complex corresponds to a conformation with
largest populations extracted from MD calculations.
In the case of macrocycle 6, the methyl group attached to the
stereogenic centre is replaced with the phenyl and the absolute
configuration is inverted. Therefore, one should expect that the
host 6 will have an opposite discrimination affect against the guests
compared to the host 5. In fact it was observed that the host 6
(benzyl¼Y, phenyl¼[) orientation is excepted (Figs. 8 and 9) and
therefore, the benzyl group in D-enantiomer will have a favourable
prefers to form more stable complexes with
discrimination factor is still significantly larger for the phenylala-
nine salts (Table 1). However, one may wonder why the enan-
tiomer of phenylalanine salt is not preferably bound to the host 6 if
the assumption of the attractive interactions between the
D
-enantiomers and the
p
e
p
interactions with the N-benzyl group of the host with syn
alignment as occurred between the enantiomer of phenylalanine
L
L
salt and the host 5. It was found that the host 6 shows a quite
similar discrimination factor against enantiomers of alanine methyl
ester salts. It is quite possible that a favourable interaction takes
pep
guest and the host is favoured. This may be attributed to the
changes in the orientation of the groups in the host 6, namely the
phenyl and benzyl. In this case, the anti (phenyl¼Y, benzyl¼[), anti
place between the methyl, the side group in
the benzyl in the host, which is regarded as CH/
also a common non-covalent interaction in chemical and biological
D
-alanine ester salt and
p
interactions. It is

354
M. Karakaplan et al. / Tetrahedron 69 (2013) 349e358
Fig. 6. 1H NMR spectra of amino alcohol 3 in CDCl3 at 298 and 233 K.
Fig. 7. A representative interaction of the macrocycle 5 with D- and L-phenylalanine ester salts.
Fig. 8. A representative interaction of the macrocycle 6 with D- and L-phenylalanine ester salts.

M. Karakaplan et al. / Tetrahedron 69 (2013) 349e358
355
Fig. 9. A representative interaction of the macrocycle 7 with D- and L-phenylalanine ester salts.
recognition, with particular interest in determining the tertiary
structure of proteins.29
Computational calculations indicated indeed that the host 8
forms more stable complex with enantiomer of phenylalanine
L
As to the host 7, a similar action was achieved in for the dis-
crimination between enantiomers of alanine and valine salts while
a reverse effect is found for that of phenylalanine salts compared to
the host 6. It is likely that eCH2OPh group will have more confor-
mational flexibility compared to the phenyl group in the host 6 and
probably larger pocket site. Sothe isopropyl group will be fitted to the
pocket and therefore it will be better differentiated by this pocket.
The introduction of the naphthyl unit into the crown ring
resulted in producing the host 8, which prefers to bind enantiomers’
salt. The superimposed conformers with the larger populations
obtained from cluster analysis showed that in fact the benzyl group
of L enantiomer has a location to interact with the naphthyl and the
phenyl groups in the host as postulated above (Fig. 10).
4. Conclusion
Four chiral diaza-18-crown-6 ether derivatives with C2-sym-
metry were prepared and their complexation and discrimination
ability against alanine, valine and phenylalanine methyl ester salts
were studied by 1H NMR titration method. They showed strong
affinity and different complementarities for various amino acid
ester salts, and exhibit excellent enantiodiscriminating abilities
towards some of these guests. It was observed that changes in
the substituents attached to chiral centre in the crown ring as
well as insertion of the naphthyl unit into the ring influence
both binding and enantiodiscrimination ability of macrocyclic
compounds against amino acid salts pairs. Thus the information
L
configuration, an opposite effect found by the host 6, although both
have the same absolute configuration at their stereogenic centres. It
is likely that the naphthyl group causes conformational changes in
the crown ring and hence in the alignment of the groups on the ring
and possibly forming a pseudo-chiral binding site with a hydro-
phobic nature. Thus, the site arms of all the amino acid ester salts
with L configuration will be sandwiched between the naphthyl unit
and the phenyl group (Fig. 10). The larger discrimination factor
found for the salts of phenylalanine methyl ester may be associated
Fig. 10. A representative interaction of the macrocycle 8 with D- and L-phenylalanine ester salts.
with the more pronounced interactions between the side arm of this
guest, namely the benzyl group, and the naphthyl and phenyl
groups in the host via pep stacking in a manner of sandwiching.
gained in this study provides significant results, which may be used
in the understanding of the molecular recognition in the biological
processes.

356
M. Karakaplan et al. / Tetrahedron 69 (2013) 349e358
5. Experimental
1.85e1.81 (2H, m),1.36e1.30 (2H, m),1.15e1.1 (2H, m); dC (100 MHz,
CDCl3) 141.0, 128.4, 128.2, 126.8, 60.9, 50.9, 31.6, 25.1.
5.1. General information
5.4.3. N,N0-Dibenzyl-N,N0-di[(S)-2-hydroxypropyl]-(1R,2R)-dia-
minocyclohexane (2). (S)-Propylene oxide (118 mg, 2.0 mmol) was
added to a solution of (R,R)-N,N0-dibenzyl-1,2-diaminocyclohexane
(1) (250 mg, 0.82 mmol) in methanol (3 mL) and stirred at 40 ꢀC for
24 h and 50 ꢀC for 24 h. Solvent evaporated to give pure of com-
pound 2 (340 mg, 99%) as a viscous colourless oil; [found: C, 76.16;
All chemicals were reagent grade unless otherwise specified.
(R)-styrene oxide, (S)-propylene oxide and (S)-glycidyl phenyl
ether were purchased from SigmaeAldrich. Silica Gel 60 (Merck,
0.040e0.063 mm) and silica gel/TLC-cards (F254) were used for
flash column chromatography and TLC. THF was dried (on sodium
benzophenone ketyl) and distilled prior to use. All reactions were
carried out under N2 atmosphere with a dry solvent of anhydrous
conditions, unless otherwise noted. Melting points were de-
termined with GALLENKAMP Model apparatus with open capil-
laries. Optical rotations were taken on a Perkin Elmer 341 model
polarimeter. IR spectra were recorded on Mattson 1000 ATI Unicam
FT-IR spectrometer. 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded on Bruker Avance-400 MHz high perfor-
mance digital FT-NMR spectrometer, with tetramethylsilane as the
internal standard solutions in deuteriochloroform. Elemental
analyses were obtained with CARLO-ERBA Model 1108 instrument.
H, 9.39; N, 6.76. C26H38N2O2 requires C, 76.06; H, 9.33; N, 6.82%];
20
[a
]
ꢁ38.3 (c 1, CHCl3); nmax (liquid film) 3384, 3031, 2923, 2858,
D
1953, 1600, 1452, 1296, 1388, 1336, 1253, 1132, 1060, 964, 746 cmꢁ1
;
dH (400 MHz, CDCl3) 7.36e7.15 (10H, m), 5.92 (2H, bs), 3.74 (2H, d, J
12.8 Hz), 3.49e3.40 (4H, m), 2.70e2.60 (4H, m), 2.40e2.34 (2H, m),
2.00e1.90 (2H, m), 1.80e1.60 (2H, m), 1.20e0.9 (10H, m); dC
(100 MHz, CDCl3) 139.8, 129.6, 128.2, 127.2, 65.9, 64.3, 59.8, 56.9,
26.0, 25.0, 21.78.
5.4.4. (1R,2R)-N,N0-Dibenzyl-bis[(R)-2-hydroxy(2-phenyl)ethyl]-1,2-
diaminocyclohexane (3). (R)-Styrene oxide (1.63 g, 13.6 mmol) was
added to a solution of (R,R)-N,N0-dibenzyl-1,2-diaminocyclohexane
(2 g, 6.8 mmol) in methanol (3 mL) and stirred at 40, 50 and 60 ꢀC,
24 h for each temperature. Solvent was evaporated and then
unreacted epoxide and amine was removed by kugelrohr distilla-
tion apparatus. Crude product was purified by crystallization from
n-hexane to give 3 (2.72 g, 75%) as a white powder, mp 202e203 ꢀC;
5.2. NMR hosteguest titration
The host compound was dissolved in an appropriate amount of
solvent (CDCl3) and the resulting solution evenly distributed
among eight NMR tubes. The guest compound was also dissolved in
the appropriate amount of solvent and added in increasing amount
to the NMR tubes, so that the solutions with the following relative
amounts (equiv) of guest versus host compound (concentration
was 8.33ꢄ10ꢁ4 M) were obtained 0.25, 0.50, 0.75, 1.0, 2.0, 3.0, 4.0,
[found: C, 80.25; H, 7.46; N, 5.30. C36H42N2O2 requires C, 80.89; H,
20
7.86; N, 5.24%]; [
a]
ꢁ147.6 (c 1, CHCl3); nmax (KBr) 3429, 3242,
D
3063, 3030, 2928, 2851, 1490, 1458, 1336, 1240, 1195, 1105, 1066,
1022, 758, 714 cmꢁ1
;
dH (400 MHz, CDCl3) 7.71e7.07 (20H, m), 5.78
5.0. The chemical shift change of
downfield by the increasing the ratio of guests as shown in Fig. 3.
The dissociation constants (K) between each host and guest were
a
-proton of guests shifted to the
(2H, bs, OH), 5.02 (1H, bs), 4.73 (1H, bs), 4.0e3.50 (4H, m),
3.19e2.55 (6H, m), 2.23e1.69 (4H, m), 1.28e1.23 (4H, m). dC
(100 MHz, CDCl3) 143.2, 138.4, 130.6, 130.1, 128.4, 127.3, 126.0, 72.3,
69.0, 58.4, 57.5, 25.7, 24.2.
calculated from the change in
d values against increasing guest
concentration in the presence of constant host concentration. by
non-linear least-squares fitting method30 using GraphPad Pris 4
pocket programme.
5.4.5. N,N0-Dibenzyl-N,N0-di[(S)-3-phenoxy-2-hydroxypropyl]-
(1R,2R)-1,2-diaminocyclo-hexane (4). (S)-Phenyl glycidyl ether
(1.53 g, 10.2 mmol) was added to a solution of (R,R)-N,N0-dibenzyl-
1,2-diaminocylohexane (1) (1.5 g, 5.1 mmol) in methanol (4 mL) at
60 ꢀC for 24 h. Solvent was evaporated then the crude product was
purified by crystallization from n-hexaneeethanol to give 4 (2.5 g,
5.3. Evaluation of the stoichiometry of the hosteguest
complex (Job plots)
The stoichiometry of hosteguest complexes were determined
according to Job’s method of continuous variations.31 Stock solu-
tions of hosts (5 mM) and guests (5 mM) were prepared in CDCl3.
These solutions were distributed among ten NMR tubes in such
a way that the molar fractions X of host and guest in the resulting
solutions increased (or decreased) from 0.1 to 1.0 (and vice versa).
The compellation-induced shifts (Dd) were multiplied by X and
plotted against X itself (Job plots). A representative example of
82.5%) as a white solid, mp 83e85 ꢀC; [
a
]
20 ꢁ53 (c 1, EtOH); [found:
D
C: 76.52, H: 7.52, N: 4.91. C38H46N2O4 requires C: 76.74, H: 7.80, N:
4.71%]; nmax (KBr) 3360, 3169, 3060, 3028, 2929, 2855, 1600, 1496,
1455, 1373, 1302, 1274, 1120, 1080, 1036, 935, 884, 813, 754,
693 cmꢁ1
; dH (400 MHz, CDCl3) 7.45e7.05 (10H, m), 5.6 (2H, bs, OH),
4.36e3.79 (4H, m), 3e2.68 (3H, m), 2.31e1.92 (3H, m), 1.26 (2H, bs);
dC (100 MHz, CDCl3) 158.8, 138.3, 129.9, 129.5, 128.9, 128.4, 120.9,
114.7, 70.5, 67.1, 58.7, 56.3, 52.2, 25.7, 24.3.
macrocycle 5 with L-alanine methyl ester hydrochloride can be seen
from Fig. 2.
5.4.6. N,N0-Dibenzyle(2R,9R)-dimethyl-(5S, 6S)-(5, 6)-cyclohexenyl-
4,7-diaza-1,10,13,16-tetraoxaoctadecane (5). To
a suspension of
5.4. Synthesis
325 mg (12.2 mmol, 90% in mineral oil) of NaH in 50 mL of the dry
THF at 0 ꢀC was added a solution of N,N0-dibenzyl-N,N0-di[(S)-2-
hydroxypropyl]-(1R,2R)-diaminocyclohexane (3) (1.0 g, 2.44 mmol)
in 50 mL of THF. The reaction mixture was refluxed for 2 h. After
cooling to 0 ꢀC a solution of tri(ethylene glycol)di(p-toluenesulfo-
nate) 1.12 g (2.44 mmol) in 75 mL of THF was slowly added. The
suspension was refluxed for 96 h. The solvent was evaporated after
adding50 mLof water totheresidue. Themixturewas extracted with
CH2Cl2 (3ꢄ25 mL) and the combined organic layers were washed
with water (30 mL), dried on MgSO4 and the solvent was evaporated
in vacuo to give the crude product, which was purified by column
chromatography on silica gel using (85:10:5 PE/EtOAc/TEA) as an
eluent to give compound 5 (0.67 g, 31.6%) as a viscous colourless oil;
[found: C: 54.20, H: 8.72, N: 5.31. C32H46N2O4 requires C: 54.40, H:
5.4.1. (R,R)-1,2-Diaminocyclohexane. (R,R)-1,2-Diaminocyclohexane
was isolated from isomeric cis- and trans-1,2-diaminocyclohexane
according to the method reported.18 (R,R)-1,2-Diaminocyclohexane
L-tartrate: yield: 39%; [
a]
D
20 þ11.6 (c 1, H2O) (lit.18 þ11.6 (c 1, H2O));
(R,R)-1,2-diaminocyclohexane: yield: 95%, [
a]
D
20 ꢁ19.8 (c 1, 1 M HCl),
[lit.18 ꢁ20 (c 1, 1 M HCl).
5.4.2. (R,R)-N,N0-Dibenzyl-1,2-diaminocyclohexane (1). This com-
pound was synthesized by a previous method.19 Yield: 2.60 g, 99%;
20
[
a]
ꢁ79.7 (c 2.5, CHCl3) (lit.19 ꢁ80 (c 2.5, CHCl3)); dH (400 MHz,
D
CDCl3) 7.50e7.20 (10H, m), 3.98 (2H, d, J 13.2 Hz), 3.75 (2H, d, J
13.2 Hz), 2.40e2.30 (2H, m), 2.24 (2H, d, J¼13.2 Hz), 2.15 (2H, bs),

M. Karakaplan et al. / Tetrahedron 69 (2013) 349e358
357
20
8.81, N: 5.36%]; Rf (85/10/5 PE/EtOAc/TEA, on silica gel TLC) 0.6; [
a
]
were determined by antechamber module of AMBER (v9) package
and the General AMBER Force Field (GAFF)36 was adopted in sim-
ulation because it handles small organic molecules. For guests pa-
rameters were adopted from ff99SB libary.37
D
ꢁ40.2 (c 1, CHCl3); nmax (liquid film) 3060, 3024, 2901, 2241, 1950,
1739,1704,1618,1493,1452,1371,1279,1107, 960, 828, 737, 700, 647,
470 cmꢁ1
; dH (400 MHz, CDCl3) 7.33e7.18 (5H, m), 3.77e3.43 (9H, m),
2.87 (1H, dd, J 8.4, 5.2 Hz), 2.77 (1H, m), 2.51 (1H, m), 2.04 (1H, d,
11.2 Hz), 1.71 (1H, d, 7.6 Hz), 1.29e1.06 (5H, m); dC (100 MHz, CDCl3)
141.5, 129.0, 127.9, 126.4, 76.1, 71.1, 71.0, 67.7, 27.3, 26.2, 18.7.
The host molecule was minimized with a total of 5000 steps,
2500 of steepest descent followed by 2500 of conjugate gradient
(maxcyc-ncyc), using a nonbonded cut off of 999 A and a general-
ꢁ
ized Born solvent model (igb¼0). The system was then heated from
0 K to 700 K at eight steps for a period of 200 ps and it was further
simulated at 700 K for a period of 20,000 ps (igb¼0). 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. A potassium ion was inserted into the crown
cavity of this conformer to achieve a preassociation conformation
in order to accommodate guests. Each ligand was manually placed
on the surface of the crown ring so that maximum contact points
between ammonium and crown donors are 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-
5.4.7. N,N0-Dibenzyl-(2R,9R)-2,9-diphenyl-(5R,6R)-5,6-cyclohexenyl-
4,7-diaza-1,10,13,16-tetraoxaoctadecane (6). This compound was
prepared as described above for compound 5 starting from NaH
(373 mg, 14 mmol, 90% in mineral oil), chiral amino alcohol 3 (1.5 g
2.8 mmol) and TEGDT (1.29 g, 2.8 mmol). The crude product was
purified by column chromatography on silica gel using 85:10:5 PE/
EtOAc/TEA as an eluent to give 6 (1.27 g, 45.5%) as a viscous col-
ourless oil; [found: C: 77.32, H: 7.89, N: 4.15. C42H52N2O4 requires C:
77.46, H: 8.02, N: 4.32%]; Rf (85:10:5 PE/EtOAc/TEA, on silica gel
TLC) 0.65; [
a
]
20 ꢁ39 (c 1, CHCl3); nmax (liquid film) 3082, 3025, 2930,
D
2859, 2363, 1738, 1616, 1493, 1451, 1372, 1243, 1109, 734, 700 cmꢁ1
;
ꢁ
dH (400 MHz, CDCl3) 7.36e7.24 (20H, m), 4.633 (2H, bs), 4.04e3.38
(18H, m), 2.75e2.66 (4H, m), 1.554 (4H, m), 0.94e0.92 (4H, m); dC
(100 MHz, CDCl3) 142.1, 141.6, 128.4, 128.2, 128.0, 127.5, 127.3, 126.1,
81.3, 72.2, 71.1, 70.9, 68.1, 60.7, 56.7, 28.3, 26.0.
bonded cut off of 999 A and a generalized Born solvent model
(igb¼0). The system was then heated from 0 K to 700 K at eight
steps for a period of 200 ps and it was further simulated at 700 K for
a period of 20,000 ps (igb¼0). A cluster analysis was performed
with 67 intervals out of 20,000 frames and the coordinates of the
structure with the largest population was recorded and this was
minimized followed by cooling from 700 K to 300 K at eight steps
for a period 200 ps and it was further computed at 300 K for a pe-
riod of 20,000 ps. Molecular dynamic coordinates were recorded
with 1.0 ps intervals. A cluster analysis was used to obtain the
conformer with the largest population for each complex.
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)38 and potential energy and
RMSD graphics are shown by GraphPad Pris 4 pocket programme.
5.4.8. N,N0-Dibenzyl-(2R,9R)-2,9-diphenoxymethyl-(5R,6R)-5,6-cyclo-
hexenyl-4,7-diaza-1,10,13,16-tetraoxaoctadecane (7). Macrocycle
7
was prepared as usual manner by using NaH (342.6 mg 12.85 mmol
90% in mineral oil), chiral amino alcohol 4 (1.5 g, 1.57 mmol) and
TEGDT (1.18 g, 1.57 mmol). Crude product was purified by column
chromatography on silica gel using 85:10:5 PE/EtOAc/TEA as an eluent
to give 7 (620 mg, 34%) as a viscous colourless oil; [found: C: 67.32, H:
7.89, N: 4.15. C44H56N2O4 requires C: 67.69, H: 7.90, N: 3.95%]; Rf
(85:10:5 PE/EtOAc/TEA, on silica gel TLC) 0.60; [
a
]
22 þ8.5 (c 1, CHCl3);
D
nmax (liquid film) 3060, 3009, 2927, 2858,1599,1494,1452,1350,1295,
1244, 1114, 1039, 970, 753, 694 cmꢁ1
. dH (400 MHz, CDCl3) 7.53e7.00
(m, 10H), 4.22e3.74 (m, 11H), 3.20 (bs, 1H), 2.86e2.78 (m, 2H),
1.94e1.71 (m, 2H), 1.37e1.29 (m, 2H). dC (100 MHz, CDCl3) 159.1,141.4,
129.5, 128.6, 128.2, 126.4, 120.8, 114.7, 71.5, 71.2, 70.1, 69.5, 61.4, 56.0,
51.2, 29.1, 26.2.
Acknowledgements
The authors are grateful to the Scientific and Technological Re-
search Council of Turkey (TUBITAK) (No. 110T468) for financial
support. We are also grateful to DA Case (University of California,
San Francisco) for providing a waiver of AMBER.
5.4.9. N,N0-Dibenzyl-(5R,6R)-5,6-cyclohexenyl-(2R,9R)-2,9-diphenyl-
14,15-naphtho-4,7-diaza-1,10,13,16-tetraoxaoctadecane
(8). In
a manner similar to that described for the preparation of 5 by using
NaH (150 mg, 5.6 mmol 90% in mineral oil), chiral amino alcohol 3
(0.6 g, 1.12 mmol) and 2,3-bis[2-(p-tolylsulphonyl)ethoxy]naph-
thalene (625 mg 1.12 mmol). Crude product was purified by column
chromatography on silica gel using 85:10:5 PE/EtOAc/TEA as an
eluent to give 8 (0.4 g, 32.65%) as a viscous yellow oil; [found: C:
Supplementary data
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.10.020.
80.05, H: 7.12, N: 3.60. C50H56N2O4 requires C: 80.21, H: 7.46, N:
20
References and notes
3.74%]; Rf (85:10:5 PE/EtOAc/TEA, on silica gel TLC) 0.63; [a]
D
ꢁ22.6 (c 1, CHCl3); nmax (liquid film) 3388, 3061, 3015, 2931, 2856,
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