The enantiomeric recognition of chiral organic ammonium salts by chiral pyridino-macrocycles bearing aminoalcohol subunits

Article abstract of DOI:10.1016/j.tetasy.2009.06.010

Pyridine-based macrocycles were prepared by treating 2,6-bis[[2′6′-bis(bromomethyl)-4′-methylphenoxy]methyl]pyridine 3 with the appropriate chiral aminoalcohols. The enantiomeric recognition of these macrocycles bearing aminoalcohol subunits of the pyridinocrown type ligand was evaluated for chiral organic ammonium salts by UV titration. The important differences were observed in the K_a values of (R)-Am2 and (S)-Am2 for (S,S,S)-1, (S,S,S)-2 and (S,S,S)-3 hosts, K_S/K_R = 5.0, K_S/K_R = 2.4 and K_S/K_R = 5.0, respectively. There seems to be a general tendency for hosts to recognise (S)-enantiomers for both Am1 and Am2.

Full text of DOI:10.1016/j.tetasy.2009.06.010

Tetrahedron: Asymmetry 20 (2009) 1541–1546
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Tetrahedron: Asymmetry
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The enantiomeric recognition of chiral organic ammonium salts by chiral
pyridino-macrocycles bearing aminoalcohol subunits
Hayriye Ozer a, Sßafak Ozhan Kocakaya a, Abuzer Akgun b, Halil Hoßsgören a, Mahmut Togrul a,
*
a University of Dicle, Faculty of Science, Department of Chemistry, 21280 Diyarbakir, Turkey
b Adıyaman University, Faculty of Education Department of Science Education, 02030 Adıyaman, Turkey
a r t i c l e i n f o
a b s t r a c t
Pyridine-based macrocycles were prepared by treating 2,6-bis[[2060-bis(bromomethyl)-40-methylphen-
oxy]methyl]pyridine 3 with the appropriate chiral aminoalcohols. The enantiomeric recognition of these
macrocycles bearing aminoalcohol subunits of the pyridinocrown type ligand was evaluated for chiral
organic ammonium salts by UV titration. The important differences were observed in the Ka values of
(R)-Am2 and (S)-Am2 for (S,S,S)-1, (S,S,S)-2 and (S,S,S)-3 hosts, KS/KR = 5.0, KS/KR = 2.4 and KS/KR = 5.0,
respectively. There seems to be a general tendency for hosts to recognise (S)-enantiomers for both
Am1 and Am2.
Article history:
Received 12 May 2009
Accepted 10 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
ety of molecules presents various types of interaction modes.16
The development of new receptors capable of recognising amino
Molecular recognition, especially chiral recognition, is one of
the most significant processes for diverse physical, chemical and
biological phenomena. Therefore, the design, synthesis and use of
molecules capable of enantiomeric recognition of other molecules
are of great interest to workers in these fields.1,2 In particular, opti-
cally active macrocyclic receptors and their enantioselective recog-
nition of chiral compounds have been attracting much attention.3
Such model systems have found applications in the development
of pharmaceuticals,4–7 enantioselective catalysis,8 separation of
enantiomers,9 and the sensing,10 purification and analysis of enan-
tiomers.11–13 They can also contribute to a better understanding of
biological systems and their functions since chiral recognition is an
essential phenomena in living systems. Hence, the study of syn-
thetic modelling for chiral recognition is an area of ever increasing
research activity. Continuing efforts creating chiral artificial recep-
tors for enantioselective recognition have been made and the rec-
ognition mechanism has been gradually understood as the
combined efforts of several non-covalent interactions such as
hydrogen bonding, electrostatic interactions, hydrophobic interac-
acids and their derivatives has attracted more interest in the re-
cent past three decades. After the pioneering research of Cram
et al. on the use of chiral macrocyclic ligands in enantiomeric rec-
ognition17 a great number of chiral artificial receptors have been
synthesised and studied.16,18 Recently, a series of chiral artificial
receptors, such as the binaphthol dimmers,19 the chiral macrocy-
cles,20–22 the chiral crown ethers23,24 and cyclodextrin deriva-
tives25,26 have been synthesised for enantioselective recognition
of amino acid derivatives. It has been predicted that chiral macro-
cyclic compounds will play a major role in future enantiomeric
separations of amines and protonated amine compounds.16,27 In
particular, pyridine units containing crown ethers (pyridine-
crowns) are very useful for the recognition of amine and proton-
ated amine compounds since they form strong complexes with or-
ganic amine salts and also show appreciable enantiomeric
recognition in certain cases.1,28–30
Various methods have been used for determining the chiral rec-
ognition of chiral macrocyclic hosts. Examples are the methods of
titration UV–vis, extraction/NMR, extraction/polarimetry, titration
NMR, variable temperature NMR, NOE, induced circular dichro-
mism, liquid chromatography (LC), transport and capillary
electrophoresis.
Recently, our interest has concerned aza-macrocycles and their
molecular and enantiomeric recognitions towards amines and
protoned amine derivatives.22–24,31 Herein, we report the synthe-
sis of a series of pyridino-macrocycles bearing amino alcohol sub-
units and their enantiomeric recognition properties towards alkyl
ammonium salts which were investigated by UV–vis
spectroscopy.
tions, cation–
p interactions, p–p staking interactions and steric
complementarity14,15
The study of the enantiomeric recognition of amines and pro-
tonated amine compounds is of significance since these com-
pounds are the basic building blocks of biological molecules.
Amino acids are major components of proteins in natural living
systems and their versatile ability to form complexes with a vari-
* Corresponding author. Tel.: +90 412 2488550; fax: +90 412 2488039.
E-mail address: mtogrul@dicle.edu.tr (M. Togrul).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.06.010

1542
H. Ozer et al. / Tetrahedron: Asymmetry 20 (2009) 1541–1546
and infrared (IR), which are powerful tools used for examining
2. Results and discussion
2.1. Synthesis
the recognition ability of new chiral macrocycles.1,11,12 UV–vis
spectroscopic method is a convenient and a widely used method
for the study of binding phenomena, and there are now hundreds
of reports where UV-titration has been used to measure intermo-
lecular association.21 When the macrocycles absorb light at differ-
ent wavelengths in free and complexed states, the differences in
the UV–vis spectra may suffice for the estimation of molecular
and enantiomeric recognition thermodynamics. In UV spectro-
scopic titration experiments, the addition of varying concentra-
tions of guest molecules results in a gradual increase or decrease
of the characteristic absorption of the host molecules. The com-
plexation of ammonium cations [G] with chiral macrocycles [H]
is expressed by Eq. 1:
Tosylate 1 was prepared by the procedure given in the litera-
ture, as shown in Scheme 1.32 A tetra-bromide building block for
macrocycle synthesis from 4-methylphenol was prepared as
shown in Scheme 2. The conversion of 4-methylphenol to 2,5-dihy-
droxymethyl-4-methylphenol was carried out by our modified
previous method.33 The conversion of 2,5-dihydroxymethyl-4-
methylphenol to 2 and 3 was carried out according to the reported
procedure.29 Chiral macrocycles of (S,S,S)-1, (S,S,S)-2 and (S,S,S)-3
were obtained in 29%, 32% and 37% yields, respectively, as shown
in Scheme 3. The syntheses of macrocycles (S,S,S)-1, (S,S,S)-2 and
(S,S,S)-3 are of special interest. The reaction of tetrabromide 3 with
various amino alcohols was expected to afford (S,S,S,S)-1, (S,S,S,S)-2
and (S,S,S,S)-3, respectively. However, the main products obtained
were (S,S,S)-1, (S,S,S)-2 and (S,S,S)-3, respectively. By using either
excess or equivalent amount of amino alcohols, we obtained the
same products. As can be seen from Figure 1, the molecular
dynamics calculations for (S,S,S)-3 showed that when the first cyc-
lisation reaction occurs, the other two side arms of the molecules
become far from each other, and therefore, the second cyclisation
reaction cannot occur. These results show that the pyridine nitro-
gen has a template role for the cyclisation reaction.
K
H þ G ¡ H ꢀ G
ð1Þ
Under the conditions employed herein, chiral organic ammo-
nium hydrochloride salts were selected as the guest molecules
(Scheme 3). The binding constant (association constant) of the
supramolecular system formed can be calculated according to
modified Benesi–Hildebrand equation, (Eq. 2), where [H]o and
[G]o refer to the total concentration of the pyridine-macrocycles
and organic ammonium salts, respectively. Moreover,
ference between the molar extinction coefficient for the free and
complexed chiral macrocycle host; A denotes the change in
De is the dif-
D
absorption of the host on adding alkyl ammonium salts (guest).
The original Benesi–Hildebrand experiment concerned an optical
spectroscopy study of the association of iodine with aromatic
hydrocarbons.34 The key feature of this method is that by working
with a large excess of component H, the concentration of uncom-
plexed H can be set equal to the initial concentration, [H = Ho].
For all of the guests examined, plots of calculated [H]oꢀ[G]o/DA val-
ues as a function of [G]o values gave an excellent linear relationship
i
N
N
HO
OH
OTs
OTs
1
Scheme 1. Reagents and condition: (i) TsCl, KOH, ꢂ10 °C.
(R > 0.9992) with a slope 1/
ing the 1:1 complex formation.
D
e
and intercept 1/KaꢀD
e
thus support-
The structures proposed for these new chiral macrocycles are
consistent with the data obtained from 1H, 13C NMR, IR and ele-
mental analyses.
½Hꢁo ꢀ ½Gꢁo= A ¼ 1=Ka ꢀ þ ½Gꢁo=
D
D
e
D
e
ð2Þ
where = (eH
D
A ¼ ðAH ꢂ AobsÞ, and
D
e
ꢂ
eH.G).
2.2. Enantiomeric recognition studies using a UV-titration
method
It is well-known that crown ethers form very stable complexes
with ammonium salts by means of a hydrogen-bonding network,
thus making them useful in many applications;35 in particular,
those bearing stereogenic centres and a bulky substituent on their
ring core are of great interest in stereoselective applications.16 The
model compound, easily synthesised as compared to crown ethers,
might be considered to be a cyclic pyridine possessing crown
The main purpose of synthesising these receptors is to study
their enantiomeric recognition for guest molecules. The enantio-
meric recognition can be characterised by various spectroscopic
methods, such as NMR, ultraviolet visible (UV–vis), fluorescence
HO
OH
OH
N
i
ii
OH
OH
OH
O
O
2
HO
OH
iii
Br
Br
N
O
O
3
Br
Br
Scheme 2. Reagents and conditions: (i) HCHO, NaOH, 40 °C; (ii) 1, Cs2CO3, acetone; (iii) PBr3, THF.

H. Ozer et al. / Tetrahedron: Asymmetry 20 (2009) 1541–1546
1543
OH
OH
R
R
Br
Br
Br
HN
NH
N
R
N
X
O
O
+
O
H
O
H2N
OH
Br
R: isobuthyl; benzyl; phenyl
HN
NH
R
R
OH
OH
R: isobutyl (S,S,S,S)-1; benzyl (S,S,S,S)-2;
phenyl (S,S,S,S)-3.
HO
OH
OH
H
H2N
(S,S,S)-1
R
R
HN
NH
Br
Br
N
H
H2N
N
OH
O
O
(S,S,S)-2
O
O
N
Br
Br
H
H2N
R
OH
HO
R: isobutyl [(S,S,S)-1];benzyl [(S,S,S)-2];
phenyl [(S,S,S)-3]
(S,S,S)-3
Scheme 3. Reagents and conditions: Cs2CO3, CH3CN, reflux, 1 day.
ethers such as rings, and are predicted to behave in a similar way
to accommodate ammonium salts. In addition, because they pos-
sess pyridine units on their rings, they are expected to be superior
to crown ethers. The determination of K values for chiral host–
guest interactions provides information about the capability of
the chiral hosts to recognise enantiomers of the chiral guest under
given sets of conditions. The correlation of the degree of recogni-
tion with the structural features of the host guest complexes is
essential in understanding the origin of chiral recognition.
of the host was fixed to 3.33 ꢃ 10ꢂ5 M in CHCl3. The UV–vis spec-
trum at kmax 239 and 272 nm was monitored, with the addition of
various concentrations (1.33 ꢃ 10ꢂ5–6.67 ꢃ 10ꢂ4 M) of guests.
The typical UV spectral changes upon the addition of (R)-Am1
salt [(R)-
a
-(ꢂ) phenyl-ethylammonium hydrochloride] to (S,S,S)-2
are shown in Figure 2, while a typical plot is shown for the com-
plexation of compound (S,S,S)-2 with guest (R)-Am1 in Figure 3.
The Job’s plot based on the UV-spectroscopic changes which
supported the 1:1 stoichiometry of host–guest complexes is shown
in Figure 4.
We examined the binding properties of the novel pyridine-mac-
rocycles (S,S,S)-1, (S,S,S)-2 and (S,S,S)-3 towards the enantiomers of
Am1 and Am2 (Scheme 4) by using UV-titration. The concentration
The binding constant (Ka) of the inclusion complexes of pyri-
dine-macrocycles bearing amino alcohol subunits (S,S,S)-1,
(S,S,S)-2 and (S,S,S)-3, with organic ammonium salts was deter-
mined by the Benesi–Hildebrand equation on the basis of the
UV–vis spectrum of the complexes in CHCl3 collected at
25 1 °C. The binding constant (Ka) and the Gibbs free energy
changes (ꢂ
DGo) of these hosts with guest molecules obtained from
usual curve fitting analyses (R > 0.9992) of observed absorbance
changes are summarised in Table 1, along with enantioselectivity
KS/KR or DDGo calculated from ꢂ
DGo for the complexation of (R/
S)-organic ammonium salts by the given hosts.
Significant differences were observed in the Ka values of (R)-
Am2 and (S)-Am2 for (S,S,S)-1, (S,S,S)-2 and (S,S,S)-3 hosts, KS/
KR = 5.0, KS/KR = 2.4 and KS/KR = 5.0, DDGo = 3.99, 2.16 and
3.99 kJ molꢂ1, respectively, as shown in Table 1. On the other hand,
differences in the Ka values of (R)-Am1 and (S)-Am1 for (S,S,S)-1,
(S,S,S)-2, (S,S,S)-3 hosts, were moderate, KS/KR = 2.0, KS/KR = 0.9
and KS/KR = 2.1, DDGo = 1.63, ꢂ0.26 and 1.80 kJ molꢂ1, respectively.
Figure 1. Molecular dynamics calculations for (S,S,S)-3 by AMBER v9.

1544
H. Ozer et al. / Tetrahedron: Asymmetry 20 (2009) 1541–1546
NH3+Cl-
NH3+Cl-
H
H
H
NH3+Cl-
NH3+Cl-
H
(R)-Am1
(S)-Am2
(R)-Am2
(S)-Am1
Scheme 4. Ammonium hydrochloride salts used as a guest.
Table 1
Binding constant (Ka), the Gibbs free energy changes (ꢂ
DGo), enantioselectivities KS/
KR or DDGo for including the R/S guest with the chiral host macrocyles in CHCl3 at
25 °C
Guesta
Ka (Mꢂ1
)
KS/KR
ꢂ
D
Go
DDGo
b
Host
(kJ molꢂ1
)
(kJ molꢂ1
)
(S,S,S)-1
(R)-AM1
(S)-AM1
(R)-AM2
(S)-AM2
(2.0 0.23) ꢃ 104
(4.0 0.34) ꢃ 104
(1.0 0.42) ꢃ 104
(5.0 0.36) ꢃ 104
2.0
5.0
24.62
26.25
22.82
26.81
1.63
3.99
(S,S,S)-2
(S,S,S)-3
a
(R)-AM1
(S)-AM1
(R)-AM2
(S)-AM2
(2.0 0.31) ꢃ 105
(1.8 0.38) ꢃ 105
(1.67 0.19) ꢃ 104
(4.0 0.43) ꢃ 104
0.9
2.4
30.24
29.98
24.09
26.25
ꢂ0.26
2.16
Figure 2. UV–vis spectra of (S,S,S)-2 (3.33 ꢃ 10ꢂ5 mol dmꢂ3) in the presence of (R)-
AM1 (1.33 ꢃ 10ꢂ5–3.33 ꢃ 10ꢂ4) mol dmꢂ3).
(R)-AM1
(S)-AM1
(R)-AM2
(S)-AM2
(1.5 0.26) ꢃ 104
(3.1 0.18) ꢃ 104
(1.0 0.34) ꢃ 104
(5.0 0.46) ꢃ 104
2.1
5.0
23.82
25.62
22.82
26.81
1.80
3.99
Leucine-AM1( )
R
AM1:
a-phenylethylamine hydrochloride salts. AM2: cyclohexylethylamine
hydrochloride salts.
y = 0,1906x + 0,5507
2 = 0,9992
b
14
12
10
8
DDGo ¼ ꢂ
D
GoðRÞ
ꢂ DGoðSÞ.
R
6
This observation for the host bearing isobutyl groups was con-
firmed by an ERF (enantiomer recognition factor) of 2.0 and 5.0
(KS/KR), which corresponds to approximately 33% and 67% ees for
Am1 and Am2, respectively. For the host bearing a phenyl with
an ERF of 2.1 and 5.0 (KS/KR) it corresponds to approximately 36%
and 67% ees for Am1 and Am2, respectively. These findings clearly
indicate that the complex host bearing phenyl and isobutyl are
more stable with an (S)-configuration of the enantiomer of guests
of both Am1 and Am2; fits better than the one with an (R)-config-
uration because the phenyl and cyclohexyl groups in the former is
placed opposite to the isobutyl and phenyl side chains in the cavity
of the host, whereas in the latter, these groups are located in the
same face, causing unfavourable steric interactions. These chiral li-
gands exhibit enantiomeric recognition for the chiral forms of var-
ious organic ammonium salts. This is evident from the differences
in the Ka values as shown in Table 1. All hosts examined, formed
kinetically more stable complexes with an (S)-configuration enan-
tiomer than with (R)-configuration of both Am1 and Am2. There
seems to be a general tendency for hosts to recognise the (S)-enan-
tiomers for both Am1 and Am2. The host bearing benzyl (S,S,S)-2,
binds the guest of Am1 approximately 10 times strongly than that
of Am2. However, enantiomeric discrimination is lower than the
other hosts. The results show that the structures of host and guests,
4
2
0
0
20
40
60
80
[G]o/10-5 mol.dm-5
Figure 3. Typical plot of [H]oꢀ[G]o/DA versus [G]o for host–guest complexation of
(S,S,S)-2 and (R)-
a
-(ꢂ)phenyl-ethylammonium hydrochloride salt [(R)-AM1].
Job Plot
0.40
A
0.30
0.20
0.10
0.00
0.0
0.2
0.4
0.6
0.8
1.0
[G]o/([G]o+[H]o)
Figure 4. Job plot for pyridine-macrocycle (S,S,S)-2 (R)-AM1.
hydrogen bonding,
complementarity, may be responsible for the enantioselective
recognition.
p–p staking, p–charge interaction and steric
The result indicates that all hosts form very stable complexes with
Am1 and Am2 salts with relatively similar binding constants
(ꢄ104 Mꢂ1) except for host (S,S,S)-2 which has larger binding con-
stants (ꢄ105 Mꢂ1) for Am1 salts, The hosts exhibit a preference for
enantiomers with an absolute configuration of (S) for both amine
salts (guests Am1 and Am2). However, the hosts bearing phenyl
and bulky isobutyl process a better discrimination ability com-
pared to those bearing benzyl groups. The hosts bearing phenyl
and isobutyl groups form more stable complexes with the (S)-con-
figuration of the enantiomer of the guests of both Am1 and Am2.
3. Experimental
3.1. General information
Melting points were determined with a GALLENKAMP Model
apparatus with open capillaries and are uncorrected. Infrared

H. Ozer et al. / Tetrahedron: Asymmetry 20 (2009) 1541–1546
1545
spectra were recorded on a MIDAC-FTIR Model 1700 spectrometer.
3.5. 2,6-Bis[20,60-bis(bromomethyl)-40-
methylphenoxymethyl]pyridine 3
The elemental analyses were obtained with CARLO-ERBA Model
1108 apparatus. Optical rotations were taken on a Perkin–Emler
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 Perfor-
mance Digital FT-NMR spectrometer in the indicated solvents.
Chemical shifts are expressed in parts per million (d) using residual
solvent protons as internal standards.
All chemicals were of reagent grade and were purchased from
either Aldrich or Fluka, and used without further purification un-
less specified. All solvents were dried before use following stan-
dard procedures. All reactions were performed under an
atmosphere of dry nitrogen.
A 1.0 M solution of PBr3 in CH2Cl2 (35 mL) was added to a solu-
tion of 2 (3.80 g, 8.7 mmol) in dry THF (250 mL) under a nitrogen
atmosphere at 0 °C over a period of 30 min. Stirring was continued
at 0 °C for 3 h. The reaction mixture was evaporated under vacuum.
The residue was added to a mixture of ice-water (130 mL) and
CH2Cl2 (110 mL). The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (2 ꢃ 100 mL). The combined organic
layers were washed with saturated aqueous NaHCO3, dried
(MgSO4), filtered and evaporated under vacuum. The crude product
was recrystallised from ClCH2CH2Cl/MeOH to give 3 as a white so-
lid (3.89 g, 65%); mp 157–158 °C; IR (KBr, cmꢂ1) 3058, 3024, 2969,
1601, 1485, 1226, 1200, 983, 887, 717, 563 cmꢂ1; 1H NMR (DMSO-
d6) d: 2.35 (s, 6H), 4.63 (s, 8H), 5.31 (s, 4H) 7.24 (s, 4H), 7.72 (d, 2H,
J = 8.1 Hz), 7.93 (t, 1H, J = 8.1 Hz); 13C NMR (DMSO-d6) 20.68, 27.97,
77.01, 120.89, 131.79, 132.91, 135.10, 137.90, 153.05, 156.55 Anal.
Calcd for C25H25Br4NO2: C, 43.44; H, 3.64; N, 2.03. Found: C, 43.41;
H, 3.71; N, 1.98.
3.2. Synthesis of aminoalcohols
L
-Glycinol was purchased from Fluka, and used without further
purification. The synthesis of -leucinol and -phenylalanilol was
-phenylalanine
L
L
accomplished in one step from L-leucine and L
according to procedures described in the literature.36
3.6. Macrocyclic (S,S,S)-1
3.3. 2,6-[(Tosyloxy)methyl]pyridine 1
A 1 L four-necked, round-bottomed flask, fitted with a two-faced
condenser, was charged with 250 mL acetonitrile and Cs2CO3 (3.9 g,
12 mmol). The solution was refluxed vigorously while 2,6-bis[20,60-
This reaction was carried out according to the modified proce-
dure in the literature.32 A solution of 2,6-bis(hydroxymethyl)pyri-
dine (8.48 g, 61 mmol) in 200 mL CH2Cl2 was added to a 40%
aqueous solution of KOH (200 mL). The reaction mixture was
cooled at 0 °C and stirred for 30 min, after which a solution of p-
toluene sulphonyl chloride (23.25 g, 122 mmol) was added to it
in one portion. The reaction mixture was stirred for 1 h at 0 °C
and then at room temperature until silica gel TLC using 1/4 (v/v)
methanol/toluene as an eluent showed complete conversion of
the starting materials and only one main spot for the product (Rf
0.75). The mixture was washed in a separatory funnel with water
and CH2Cl2 (200 mL of each). The resulting mixture was shaken
well and separated. The aqueous phase was extracted with CH2Cl2
(3 ꢃ 200 mL), the combined organic phase was dried over anhy-
drous Na2SO4, filtered and solvent was removed under reduced
pressure. The residue was triturated with dry and pure methanol
to give 1 as a white crystal (25.18 g, 91%); mp 121–122 °C. IR
(KBr, cmꢂ1): 3070, 3031, 3001, 2962, 2893, 1601, 1361, 1196,
bis(bromomethyl)-40-methylphenoxymethyl] pyridine
3
(2.0 g,
2.9 mmol) in dry acetonitrile (50 mL) and
L-leucinol (1.40 g,
12 mmol) in dry acetonitrile (50 mL) were added dropwise at the
same rate under dry nitrogen atmosphere. After the addition was
complete, the reaction mixture was refluxed overnight. The solu-
tion was filtered hot. The volume of filtrate was reduced to
120 mL on a rotary evaporator. Cs2CO3 was precipitated on standing
at 4 °C. Then the mixture was filtered and the solvent was evapo-
rated. The crude product was washed with hot ether several times
to remove excess amino alcohols. The product was crystallised in
CHCl3/petroleum ether (2:1) to give (S,S,S)-1 as a white solid
(0.71 g, 33%); mp 124–126 °C; ½a D35
¼ þ6:8 (c 0.7, CH2Cl2). IR (KBr,
ꢁ
cmꢂ1): 3405, 3084, 2954, 2931, 2873, 1601, 1469, 1369, 1199,
1141, 1034, 983, 872; 1H NMR (400 MHz) in CDCl3 d, 0.76–0.94
(18H, m), 1.20–1.22 (4H, m), 1.24–1.26 (2H, m), 1.27–1.29 (1H,
m), 1.39–1.45 (2H, m), 2.30 (6H, s), 3.32–5.13 (21H, m), 6.99–7.09
(4H, m), 7.45–7.81 (2H, m); 13C NMR (100 MHz) in CDCl3 d, 20.91,
21.05, 22.03, 22.17, 22.90, 23.32, 23.64, 23.78, 23.95, 24.91, 25.42,
25.47, 25.56, 30.32, 34.45, 34.61, 47.09, 47.18, 49.12, 56.44, 57.80,
61.71, 63.45 65.84, 77.33, 78.30, 123.44, 129.41, 129.71, 130.88,
131.01, 132.06, 132.99, 133.04, 133.39, 137.50, 137.54, 155.26,
155.82, 156.61, 156.74, 156.99. Anal. Calcd for C43H66N4O5: C,
71.77; H, 9.25; N, 7.79. Found: C, 71.74; H, 9.25; N, 7.76.
1117, 964, 880, 607, 551 cmꢂ1 1H NMR (CDCl3): d 2.46 (s, 6H),
;
5.07 (s, 4H), 7.34–7.83 (m, 11H) ppm.
3.4. 2,6-Bis[20,60-bis(hydroxymethyl)-40-
methylphenoxymethyl]pyridine 2
A solution of 4-methyl-2,6-bis(hydroxymethyl)phenol (7.06 g,
42 mmol) and K2CO3 (6.21 g, 45 mmol) in 200 mL of acetone
was refluxed for 30 min. Next, 2,6-[(tosyloxy)methyl]pyridine
(10.10 g, 23 mmol) was added to the reaction mixture and
rinsed with 80 mL of acetone. The reaction mixture was heated
at reflux for 16 h. Then, H2O (100 mL) was added, and the reac-
tion mixture was filtered hot. The volume of the filtrate was re-
duced to 140 mL on a rotary evaporator. The analytically pure
product precipitated on standing at 4 °C to give 2 as a white
3.7. Macrocycle (S,S,S)-2
A 1 L four-necked, round-bottomed flask, fitted with a two-
faced condenser, was charged with 250 mL acetonitrile and Cs2CO3
(3.9 g, 12 mmol). The solution was refluxed vigorously while 2,6-
bis[20,60-bis(bromomethyl)-40-methylphenoxymethyl] pyridine 3
(2.0 g, 2.9 mmol) in dry acetonitrile (50 mL) and L-phenylalanilol
(1.81 g, 12 mmol) in dry acetonitrile (50 mL) were added dropwise
at the same rate under a dry nitrogen atmosphere. After the addi-
tion was complete, the reaction mixture was refluxed overnight
after which the solution was filtered hot. The volume of filtrate
was reduced to 120 mL on a rotary evaporator. Then, Cs2CO3 was
precipitated on standing at 4 °C. The mixture was filtered and the
solvent was evaporated. The crude product was washed with hot
ether several times to remove excess amino alcohols. The product
was crystallised from CHCl3/petroleum ether (2:1) to give (S,S,S)-2
crystal (8.73 g, 89%); mp 180–181 °C; IR (KBr, cmꢂ1
)
3411,
;
2960, 2914, 1601, 1486,1239,1158, 1024, 873, 619 cmꢂ1
1H
NMR (DMSO-d6) d: 2.51 (s, 6H), 4.58 (s, 8H), 4.97 (s, 4H) 5.29
(br s, 4H), 7.19 (s, 4H), 7.67 (d, 2H, J = 8.1 Hz), 8.00 (t, 1H,
J = 8.1 Hz); 13C NMR (DMSO-d6) 25.94, 63.34, 81.32, 125.87,
133.21, 137.98, 139.90, 143.24, 156.45, 161.98. Anal. Calcd for
C25H29NO6: C, 68.32; H, 7.47; N, 3.19. Found: C, 68.18; H,
7.49; N, 3.13.

1546
H. Ozer et al. / Tetrahedron: Asymmetry 20 (2009) 1541–1546
as a solid (0.74 g, 20%); mp 136–138 °C; ½a D35
¼ þ23:9 (c 0.7,
ꢁ
2. Izatt, R. M.; Wang, T.; Hathaway, J. K.; Zhang, X. X.; Curtis, J. C.; Bradshaw, J. S.;
Zhu, C. Y. J. Inclusion Phenom. Mol. Recognit. Chem. 1994, 17, 157–175.
3. Zhau, H. W.; Hua, W. T. J. Org. Chem. 2000, 65, 2933–2938.
4. Lehn, J. M. Supramolecular Chemistry: Concepts and Perspectives; VCH:
Weinheim, 1995.
5. Philp, D.; Stoddart, J. F. Angew. Chem., Int. Ed. 1996, 35, 1154–1196.
6. Murakami, Y.; Kikuchi, J.; Hisaeda, Y.; Hayashida, O. Chem. Rev. 1996, 96, 721–
758.
7. Izatt, R. M.; Pawlak, K.; Bradshaw, J. S. Chem. Rev. 1995, 95, 2529–2586.
8. Postnikova, B. J.; Anslyn, E. V. Tetrahedron Lett. 2004, 45, 501–504.
9. Gübitz, G.; Schmid, M. G. Biopharm. Drug Dispos. 2001, 22, 291–336.
10. Tanaka, H.; Matile, S. Chirality 2008, 20, 307–312.
CH2Cl2). IR (KBr, cmꢂ1): 3321, 3066, 3027, 2924, 2866, 1601,
1458, 1199, 1130, 1034, 732, 706; 1H NMR (400 MHz) in CDCl3 d,
2.18 (6H, s), 2.24–2.32 (6H, AB system), 2.65–4.95 (26H, m),
6.57–7.97 (22H, m);13C NMR (100 MHz) in CDCl3 d, 20.55, 20.81,
43.12, 43.73, 47.54, 47.91, 48.11, 49.94, 54.16, 57.83, 60.02,
61.13, 61.88, 62.94, 63.56, 68.12, 78.12, 120.67, 123.14, 125.91,
126.28, 127.25, 128.34, 128.98, 129.06, 129,48, 130.58, 131.95,
132.09, 132.85, 133.18, 133,89, 134.07, 136.11, 136.73, 137.59,
137.91, 138.12, 138.45, 140.53, 140.71, 142.70, 146.67, 155.48,
156.78, 157.12. Anal. Calcd for C52H60N4O5: C, 76.07; H, 7.37; N,
6.82. Found: C, 76.02; H, 7.41; N, 6.78.
11. Pu, L. Chem. Rev. 2004, 104, 1154–1196.
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13. Davis, A. P.; Wareham, R. S. Angew. Chem., Int. Ed. 1999, 38, 2978–2996.
14. Cram, D. J.; Trueblood, K. N. Concept, Structure, and Binding in Complexation.
In Host–Guest Complex Chemistry 1; Vögtle, F., Ed.; Springer: Berlin, 1981; pp
43–106. Chapter 2.
15. Chin, J. K.; Lee, K. J.; Park, S.; Kim, D. H. Nature 1999, 401, 254–257.
16. Zhang, X. X.; Bradshaw, J. S.; Izatt, R. M. Chem. Rev. 1997, 97, 3313–3361.
17. Kyba, E. P.; Koga, K.; Siegel, M. G.; Sousa, L. R.; Cram, D. J. J. Am. Chem. Soc. 1973,
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56, 3330–3336.
3.8. Macrocycle (S,S,S)-3
A 1 L four-necked, round-bottomed flask, fitted with a two-
faced condenser, was charged with 250 mL acetonitrile and Cs2CO3
(3.9 g, 12 mmol). The solution was refluxed vigorously while 2,6-
bis[20,60-bis(bromomethyl)-40-methylphenoxymethyl] pyridine 3
(2.0 g, 2.9 mmol) in dry acetonitrile (50 mL) and L-phenylglycinol
(1.64 g, 12 mmol) in dry acetonitrile (50 mL) were added dropwise
at the same rate under a dry nitrogen atmosphere. After the addi-
tion was complete, the reaction mixture was refluxed overnight
after which the solution was filtered hot. The volume of filtrate
was reduced to 120 mL on a rotary evaporator. Then, Cs2CO3 was
precipitated on standing at 4 °C. Then the mixture was filtered
and the solvent was evaporated. The crude product was washed
with hot ether several times to remove excess amino alcohols.
The product was crystallised from CHCl3/petroleum ether (2:1) to
give (S,S,S)-3 as
a
solid (0.78 g, 35%); mp 142–144 °C;
½
a 3D5
ꢁ
¼ ꢂ23:7 (c 0.7, CH2Cl2). IR (KBr, cmꢂ1): 3338, 3084, 3064,
29. Hellier, B. C.; Bradshaw, J. S.; Young, J. J.; Zhang, X. X.; Izatt, R. M. J. Org. Chem.
1996, 61, 7270–7275.
3030, 2922, 2856, 1601, 1459, 1355, 1201, 1028, 758, 708; 1H
NMR (400 MHz) in CDCl3 d, 2.23 (6H, s), 2.80–3.89 (22H, m),
4.65–4.85 (4H, AB system), 6.94–7.42 (22H, m); 13C NMR
(100 MHz) in CDCl3 d, 20.77, 20.98, 47.04, 47.61, 49.53, 57.38,
60.74, 63.46, 63.86, 64.37, 65.52, 66.86, 67.90, 78.37, 120.97,
123.37, 126.54, 127.46, 127.61, 128.14, 128.53, 128.59, 128.92,
129.11, 129.45, 129.95, 130.78, 131.93, 132.33, 132.93, 133.41,
133.99, 135.11, 136.05, 137.36, 138.09, 140.53, 140.78, 142.51,
153.77, 155.32, 156.48, 157.03. Anal. Calcd for C49H54N4O5: C,
75.55; H, 6.99; N, 7.19. Found: C, 75.52; H, 7.02; N, 7.17.
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31. Togrul, M.; Turgut, Y.; Hosgoren, H. Chirality 2004, 16, 351–355.
32. Horvath, G.; Rusa, C.; Kontos, Z.; Gerencser, J.; Huszthy, P. Synth. Commun.
1999, 29, 3719–3731.
33. Togrul, M.; Sunkur, M.; Kaynak, F. B.; Hosgoren, H.; Ozbay, S. J. Chem. Res.-S
2003, 10, 605.
34. Benesi, H.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703–2707.
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