Pyridine containing chiral macrocycles: Synthesis and their enantiomeric recognition for amino acid derivatives

Article abstract of DOI:10.1016/j.tet.2011.06.064

Four novel C₂-symmetric enantiomerically pure, chiral pyridine-18-crown-6 type macrocycles containing lipophilic chains at the stereogenic centers were prepared. The enantioselectivity of the new ligands toward the enantiomers of d-,l-amino acid methyl ester derivatives were also determined by ¹H NMR titration method. These novel macrocycles have been showed to be strong complexing agents for d- and l-amino acid methyl ester hydrochloride salts (with K_ass up to 13590 M^-1 and G ⁰ up to 23.3 kJ mol^-1 and selectivity ratio: 80:20) by ¹H NMR titration methods. These macrocyclic hosts exhibited enantioselective binding towards the d-enantiomer of valine methyl ester hydrochloride with K_d/K_l up to 5.08 in CDCl₃ with 0.25% CD₃OD.

Full text of DOI:10.1016/j.tet.2011.06.064

Tetrahedron 67 (2011) 6227e6232
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pyridine containing chiral macrocycles: synthesis and their enantiomeric
recognition for amino acid derivatives
*
Pınar Deniz, Yılmaz Turgut , Mahmut Togrul, Halil Hosgoren
University of Dicle, Faculty of Science, Department of Chemistry, TR 21280 Diyarbakir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Four novel C2-symmetric enantiomerically pure, chiral pyridine-18-crown-6 type macrocycles containing
Received 3 March 2011
Received in revised form 2 June 2011
Accepted 20 June 2011
lipophilic chains at the stereogenic centers were prepared. The enantioselectivity of the new ligands
toward the enantiomers of
titration method. These novel macrocycles have been showed to be strong complexing agents for
-amino acid methyl ester hydrochloride salts (with Kass up to 13590 Mꢀ1 and ΔG0 up to 23.3 kJ molꢀ1 and
selectivity ratio: 80:20) by 1H NMR titration methods. These macrocyclic hosts exhibited enantioselective
D-,L
-amino acid methyl ester derivatives were also determined by 1H NMR
D
- and
Available online 25 June 2011
L
binding towards the
with 0.25% CD3OD.
D
-enantiomer of valine methyl ester hydrochloride with KD/KL up to 5.08 in CDCl3
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Excellent reviews of chiral macrocycles and their interaction
with organic ammonium salts have been published.1d,22ꢀ24
A
Molecular recognition between molecules plays an important
role in biochemical systems. The careful characterization of such
synthetic systems could lead to a much improved understanding of
natural systems. One area of recent interest is the enantiomeric
recognition of organic ammonium cations by chiral macrocyclic
ligands. Hence, the design, synthesis, and use of macrocycles ca-
pable of selective recognition of other molecules is of great interest
in a variety of fields. Various types of natural and synthetic chiral
compounds have been used as chiral subunits for constructing
optically active crown ethers, and the continuing development of
chiral building blocks has resulted in the production of a wide va-
riety of optically active crown ethers exhibiting characteristic chiral
recognition behavior.1 Crown ethers, for example, have indicated
excellent enantiodiscrimination for the enantiomers of chiral or-
ganic ammonium guests.2
Since Cram and et al. prepared their important enantiomeric
recognition studies,3 many different chiral macrocyclic ligands
have been prepared for enantiomeric recognition. Some of these
ligands include amino acid units,4 sugar molecules,1a,5 diaza crown
units,6 and chiral crown ethers containing the pyridine subcyclic
unit.2,7e16 Macrocyclic pyridine-based systems are important in
metal chelation and extraction,17 hosteguest systems18 and en-
zyme mimics,19 antibiotics,20 and natural products, such as marine
alkaloids.21
number of synthetic model compounds have been designed and
synthesized as a chiral host molecule that help chemists un-
derstand the basis of the mechanisms of hosteguest complexation
and chiral recognitions.25
Chiral pyridine-containing macrocycles have been an attractive
research area due to their ability for chiral discrimination between
chiral organic ammonium salts and amino acid derivatives.26 The
pyridine subunit of these macrocycles were reported to be impor-
tant for the tripod hydrogen bonding formation with organic am-
monium salts, and the pep interactions with the aromatic moiety
of the ammonium guest, and steric repulsion between the bulky
groups on the stereogenic centers of the ligand and the substituents
of the ammonium salt.2 In addition, pyridine units as building
blocks are incorporated into the ring structure not only providing
proton acceptors at the pyridyl nitrogens, but also bringing rigidity
into the ring.27In many cases, macrocyclic pyridine-based systems
are chosen for study because they form thermodynamically stable
complexes with chiral primary ammonium cations in a number of
solvent mixtures, and they also exhibit appreciable enantiomeric
recognition.7,9e11
The present paper describes the synthesis of four novel C2-
symmetric chiral pyridine-containing 18-crown-6 macrocycles,
each containing pairs of the following substituents: ethyl (4), iso-
propyl (5), phenyl (6), and benzyl (7). The enantiomeric recognition
of chiral pyridine-containing 18-crown-6 ligands towards the en-
antiomers of different
-PheOMe, -PheOMe,
a
-amino acid methyl ester hydrochlorides
(D
L
D-ValOMe,
L
-ValOMe) by 1H NMR titrations
* Corresponding author. Tel.: þ90 412 2488550; fax: þ90 412 2488300; e-mail
in CDCl3 with 0.25% CD3OD were studied at 25 ꢁC. These
address: yturgut@dicle.edu.tr (Y. Turgut).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.064

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P. Deniz et al. / Tetrahedron 67 (2011) 6227e6232
macrocycles have a C2-symmetry axis and their chirality derives
from the -amino acid derivatives used in their synthesis.
prepared compounds were purified by appropriate methods and
characterized by spectroscopic methods (IR, 1H NMR, 13C NMR, MS
and when necessary 1He1H NMR, 1He13C NMR), and were then
employed in enantiomeric recognition. The cyclization is observed
with [1þ1] ratio according to MS spectra of 4, 5, 6, and 7.
D
2. Results and discussion
2.1. Synthesis
2.2. Enantiomeric recognition
In the present study, several macrocycles having different alkyl
moieties attached to the stereogenic center and containing dipyr-
idine units were synthesized, and effect of the alkyl moieties in the
stereogenic center on enantiomeric recognition was investigated.
In this study, since the chiral amino alcohols used as a chirality
source are expensive, they were not used directly, instead their
cheaper amino acid forms were purchased, which were reduced
with proper procedures28 to obtain the corresponding amino al-
Systems having strong interactions or good chiral recognition
allow for further investigation of their structural properties. The
chiral ligands studied in laboratories contain 18-membered mac-
rocycles and pyridine subunits. The choice of 18-membered mac-
rocycles is generally based on the fact that they form more stable
complexes with primary amines and ammonium cations in sol-
vents than other crown ethers with larger or smaller ring size.26,29
It is accepted that insertion of pyridine subunits into the mac-
rocycle has two positive effects: first, NþH/N hydrogen bond in-
teraction with the pyridine nitrogen are generally much more
stable than NþeH/O bonds.30 Second, if ammonium cation con-
tains an aromatic moiety, then the pyridine ring enables further
cohols in high yields (Scheme 1). As a source of chirality,
glycine, and -phenyl alanine were reduced with NaBH4-I2 and the
corresponding amino alcohols -gly-
-valinol 1b (91%, lit.28 94%),
cinol 1c (90%, lit.28 91%) and -phenylalaninol 1d (77%, lit.28 72%)
D-valine, D-
D
D
D
D
were obtained. (R)-(ꢀ)-2-Amino-1-butanol (98%) was purchased
and used without further purification.
interactions between the cation and the ligand due to
pep in-
Scheme 1. Synthesis of chiral amino alcohols and chiral macrocycles. Reagent and conditions: (i) NaBH4/I2/THF (ii) 1. benzaldehyde, 2. NaBH4, (iii) 2,6-bis(bromomethyl)pyridine,
110 ꢁC (iv) 1. NaH/THF, reflux, 2. 2,6-bis(bromomethyl)pyridine/THF, 58 h.
Compound 1a and reduced products 1bed were treated with
benzaldehyde in methanol under argon atmosphere at reflux
temperature to give their imines, which were then reduced with
NaBH4 in the same reaction medium to synthesize the corre-
sponding N-benzyl derivatives 2a (91%), 2b (94%), 2c (96%), and 2d
(93%) (Scheme 1).
Compound 2aed were the reacted with 2,6-bis(bromomethyl)
pyridine (using catalytic amount of KI) under Ar atmosphere in the
presence of Na2CO3 and refluxed at 100 ꢁC for 12 h to give 3aed
having C2-symmetric pyridine units and which will be used as
precursors for crown ethers in 73, 66, 68, and 69% yield, respectively.
The pyridino C2-symmetric 3aed having ethyl-, isopropyl-,
phenyl-, and benzyl-moieties in their side arms were converted
into the corresponding alcoholates with NaH in dried THF using
a quite dilute medium and then they were cyclised in a one to one
ratio with 2,6-bis(bromomethyl)pyridine. The chiral macrocycles
possessing dipyridine units obtained by column chromatography, 5
(43%), 6 (37%), 7 (38%) and 8 (46%) are shown in Scheme 1. All the
teractions. For enantiomeric recognition, binding constants (Kass),
Gibbs free energy change (ΔG0) and ratio of enantioselectivity (KD/
KL) for host macrocycles 4, 5, 6, and 7 with D-, L-Valine (ValOMe) and
phenyl alanine (PheOMe) methyl ester hydrochloride salts were
calculated using the 1H NMR titration technique (Table 1).
Amino acid ester salts are widely used in enantiomeric recog-
nition studies for three reasons: (i) ammonium salts make stronger
hydrogen bonds than the amines, which increases enantiose-
lectivity, (ii) ammonium salts containing an aromatic moiety enable
cationep interactions, (iii) the ester moiety in amino acid ester salts
contributes to the strength of hydrogen bonding due to its acceptor
property and if a proton exists in the macrocycle it also contributes
enantiomeric recognition by forming a hydrogen bond with it. To
compare the binding constants, the triplet signal of pyridine in the
macrocycle the chemical shift of which is d 7.725 ppm was chosen.
In the 1H NMR titrations, concentrations of the host macro-
cycle ligands were kept constant at 8.18 mM and increasing con-
centrations of (0e18.2 mM) guest were added. An illustrative

P. Deniz et al. / Tetrahedron 67 (2011) 6227e6232
6229
Table 1
Association constants (Kass), the Gibbs free energy changes (ꢀΔG0) and enantiose-
lectivites KD/KL for the complexation of D-/L- guest with the 4,5,6, and 7 in CDCl3 with
0.25% CD3OD
Entry Host Guests
Kass
(Mꢀ1
KD/KL
ꢀΔG0
ꢀΔΔG0
a
b
)
(kJ molꢀ1
)
(kJ molꢀ1
)
1
2
3
4
5
6
7
8
9
4
4
4
4
5
5
5
5
6
D
-PheOMe$HCI
-PheOMe$HCI
-ValOMe$HCI
-ValOMe$HCI
-PheOMe$HCI
-PheOMe$HCI
-ValOMe$HCI 13,590 5.08
2675
-PheOMe$HCI 395 0.77
1785 2.04
875
2325 2.63
885
2580 1.22
2105
18.3
16.5
18.9
16.6
19.2
18.7
23.3
19.3
14.6
1.80
2.30
0.5
L
D
L
D
L
D
4.00
0.60
L-ValOMe$HCI
D
Fig. 2. Job plot for L-PheOMe$HCI and host 5.
(KL/KD¼1.29)
10
11
6
6
L
-PheOMe$HCI
-ValOMe$HCI
510
15.2
8.5
D
32 0.33
2.80
(KL/KD¼3.00)
12
13
14
15
6
7
7
7
L
-ValOMe$HCI
-PheOMe$HCI
-PheOMe$HCI
-ValOMe$HCI
96
11.3
17.3
16.8
15.8
D
1190 1.21
983
660 0.72
0.50
0.8
L
D
(KL/KD¼1.38)
16
7
L-ValOMe$HCI
914
16.6
a
ΔG0¼ꢀ2.303 RTLog K.
b
DDG0 ¼ ꢀð
D
GD0
ꢀ
D
G0L Þ or DDG0 ¼ ꢀð
D
GL0
ꢀ
D
G0DÞ.
change in the chemical shift of the signal at
depending on increasing guest concentration for
d
7.725 ppm in the host
-ValOMe salts of
L
Fig. 3. Typical plot of 1/Dd versus 1/[G]o for hosteguest complexion of host 5 and
L-PheOMe$HCI.
macrocycle 5 is presented in Fig. 1. Furthermore, the stoichiometry
of the hosteguest complex was calculated in terms of chemical
shift of this signal. The stoichiometry was found to be 1:1 according
to Job plot method (Fig. 2). Typical plots are shown for the com-
Considering the values in Table 1, it can be noted that macrocycle
4 containing the ethyl moiety forms makes stronger complexes with
plexation of compound 5 with L-PheOMe$HCI in Fig. 3.
D
-forms of both phenyl alanine methyl ester hydrochloride and va-
line methyl ester hydrochloride, and that -ValOMe is better in
terms of the enantioselectivity of amino acid ester salts (enantio-
selectivity ratio for -, -, -ValOMe,
-PheOMe, KD/KL¼2.04; that for
-ValOMe are
D
D
L
D
L
KD/KL¼2.63). Binding constants for
D-PheOMe and D
1785 Mꢀ1 and 2325 Mꢀ1, respectively, showing that the steric effect
of the guests, which contain no aromatic moiety and in which there
exists no pep interaction is an important factor for good enantio-
selectivity. This is in agreement with the concept that repulsive in-
teractions of chiral macrocyclic receptors decreases complexation
stability of an enantiomer significantly and give the chance to form
a remarkably stable complex of the guest with the host, a basic
requisite for enantiomeric recognition.
In the case of macrocycle 5 possessing an isopropyl moiety of
the stereogenic center, binding constants with
D
-PheOMe and
L
-
-
PheOMe are 2580 Mꢀ1 and 2105 Mꢀ1, those with
D
-ValOMe and
L
ValOMe are 13590 Mꢀ1 and 2675 Mꢀ1, respectively. It is observed
that macrocycle 5 forms excellent complexes with both D- and L-
PheOMe but it does not show a high enantioselectivity between
these guests (KD/KL¼1.22). On the other hand, this macrocycle
shows five times higher enantioselectivity for D-ValOMe than the L-
form (KD/KL¼5.08), which implies that besides a steric repulsion
between the isopropyl moiety in the stereogenic center and that of
the guest molecule, the host makes a stronger interaction with
spatial orientation of
D-form of the amino acid. These results sug-
gest that the steric effect of ammonium guest is important for good
enantioselectivity when no aromatic group is available for
interactions.
pep
In considering the moieties in the stereocenters of macrocycles
4 and 5, which contain ethyl and isopropyl moieties, respectively,
the guests having no
pep interaction and containing no aromatic
moiety makes stronger complexes and show higher enantiose-
lectivity with the macrocycles (Table 1, entries: 3, 4, 7, and 8).
When macrocycle 6, containing a phenyl moiety of the stereo-
genic center is compared with 4 and 5, it can be easily seen that it
Fig. 1. 1H NMR spectral changes of chiral crown ether 5(8.18 mM) in the presence of
L-ValOMe (0e18.2 mM) in CDCl3 with 0.25% CD3OD at 25 ꢁC.

6230
P. Deniz et al. / Tetrahedron 67 (2011) 6227e6232
does not make strong complexes with phenyl alanine and valine
methyl ester salts, nor does it exhibit much enantioselectivity be-
tween the enantiomers. By comparing binding constants for mac-
rocycle 6 with guests, it can be shown that it has a greater binding
constant and a weak selectivity for PheOMe salts containing an
aromatic moiety compared with ValOMe salts containing aliphatic
moiety (KD/KL¼0.77 for PheOMe, KD/KL¼0.33 for ValOMe) (Table 1,
calcium hydride. Melting points were determined with a Gallen-
kamp Model apparatus with open capillaries. Elemental analyses
were performed with a Carlo-Erba 1108 model apparatus. Specific
rotations were taken on a PerkineElmer 341 model polarimeter.
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on
a Bruker DPXe400 High Performance Digital FT-NMR Spectrom-
eter. The chemical shifts (d) and coupling constants (J) were
expressed in parts per million and hertz.
entries: 9e12). This means that there may be a
pe
p
interaction
between the phenyl moiety present in the stereogenic centers of
the macrocycle and the amino acid ester salts containing aromatic
moiety.
Mass spectrometry analysis was performed on an autoflex III
MALDI-TOF/TOF-MS system (Bruker Daltonics, Bremen, Germany).
In the case of macrocycle 7 containing a benzyl moiety in the
stereogenic center, it was found that there was merely 1.21-fold
4.2. Synthesis
enantioselectivity between
D
-PheOMe and
L
-PheOMe, and that the
4.2.1. (2R)-2-{Benzyl[(6-{[benzyl(2R)-(1-hydroxybutan-2-yl)amino]
methyl]pyridin-2-yl)methyl]amino}-butane-1-ol (3a). (2R)-2-(Ben-
zylamino)butan-1-ol 2a (6.0 g, 33.5 mmol), 2,6-bis-(bromomethyl)
pyridine (4.5 g, 16.7 mmol), sodium carbonate (5.33 g, 50.0 mmol),
and KI (50 mg) in EtOH (50 mL) were stirred at 100 ꢁC for 12 h
under Argon. Then the mixture was cooled and CHCl3 (100 mL)
was added to the mixture and refluxed for 2 h. The solution was
filtered, EtOH was removed in vacuo and CHCl3 (50 mL) was added
to the residue. The solution was washed with water and brine
(50 mL) twice. The aqueous solution was extracted with CHCl3
(2ꢂ50 mL). The combined CHCl3 phases were dried over anhy-
drous Na2SO4. The solvent was concentrated and crude product
was purified by column chromatography over silica gel using tol-
uene/EtOAc/TEA (30/3/1) to afford 3a (5.65 g, 73%) as a yellow oil,
L-form exhibited a higher enantioselectivity than the
D-form (KD/
KL¼0.72, KL/KD¼1.37).
When 6 and 7, which have phenyl and benzyl moieties, re-
spectively, are compared with each other, it can be seen that 7
makes stronger complexes with both PheOMe and ValOMe salts,
but its enantioselectivity is not so different from 6. Macrocycles 4
and 5 displayed higher enantioselectivity for
nyl alanine methyl ester and valine methyl ester hydrochloride salts
than -forms. It was shown that 6 made stronger complexes with
forms of both amino acids, while 7 made stronger complexes with
-PheOMe and -ValOMe salts.
D-forms of both phe-
L
L-
D
L
3. Conclusions
TLC Rf¼0.25. ½a 2D7
ꢃ
ꢀ10.8 (c 1, EtOH); IR:
n 3288, 3072, 3031, 2978,
1. In view of binding constants and enantioselectivities,
exhibited the highest enantioselectivity as well as quite strong
complexation with - and -ValOMe guest. This supports the
5
2935, 1606, 1496, 1458, 1162, 1079, 912, 737 cmꢀ1. 1H NMR (CDCl3):
d
(ppm) 0.95 (t, 6H, J¼8.0 Hz), 1.28e1.35 (m, 2H), 1.74e1.81 (m,
D
L
2H), 2.80e2.86 (m, 2H), 3.53e3.74 (m, 8H), quartet of AB spin
system dA: 3.86ve dB: 3.97 (4H, J¼12.0 Hz), 5.07 (br s, 2H), 6.98 (d,
2H, J¼8.0 Hz) 7.16e7.32 (m, 10H), 7.46 (t, 1H, J¼8.0 Hz). 13C NMR
opinion that the nitrogen atom in the macrocycle makes better
three points hydrogen bonding with the eþNH3 moiety of
ammonium cations of the guest and increases binding
strength.31
2. When 4 and 5 are compared with 6 and 7, as shown in Table 1,
compound 4 and 5, which have ethyl and isopropyl moieties at
the stereogenic center, respectively, not only make stronger
complexes, but also exhibit higher selectivity (Table 1, entries:
1e8) Binding and enantioselectivity for 6 and 7, which possess
phenyl and benzyl moieties at the stereogenic center, re-
spectively, are low and medium level, which may be attributed
to prevention of the phenyl and benzyl moieties from
approaching the cation in the guest.
(CDCI3):
d (ppm) 11.85, 19.34, 54.48, 54.91, 61.64, 63.26, 121.21,
126.93, 128.20, 128.92, 136.89, 139.62, 159.61. Anal. Calcd
forC29H39N3O2: C, 75.48; H, 8.46; N, 9.11. Found: C, 75.60; H, 8.58;
N, 9.12.
4.2.2. (2R)-2-{Benzyl[(6-{[benzyl-(2R)-(1-hydroxy-3-methylbutan-
2-yl)amino] methyl]pyridin-2-yl)methyl]amino}-3-methylbutan-1-ol
(3b). This compound was prepared as described above for 3a
starting from 2b: (2R)-2-(benzylamino)-3-methylbutan-1-ol (5.0 g,
25.9 mmol), 2,6-bis-(bromomethyl)pyridine (3.43 g,12.95 mmol),
Na2CO3 (4.12 g, 38.85 mmol), and KI (50 mg). The crude product
was purified by column chromatography over silica gel using hex-
ane/EtOAc/TEA (60/20/5) to afford 3b (4.2 g, 66%) as a yellow oil TLC
3. It can be said that for 6 and 7, which have phenyl and benzyl
moieties at the stereogenic center, respectively, stronger com-
plexation especially with the amino acid methyl ester salts
having an aromatic moiety is due to the cavity of the host,
hydrogen bonding between the host and the guest combined
Rf¼0.42. ½a 3D1
ꢃ
þ3.5 (c 1,CHCl3); IR:
n
3391, 3069, 3030, 2928, 1592,
1458, 1369, 1267, 1157, 1113, 1074, 1016, 912, 797 cmꢀ1
.
1H NMR
(CDCl3):
d
(ppm) 0.95 (d, 6H, J¼8.0 Hz), 1.08 (d, 6H, J¼8.0 Hz),
with
pe
p
interactions.
1.91e1.99 (m, 2H), 2.62e2.67 (m, 2H), 3.68e4.08 (m, 12H), 5.72 (br
s, 2H), 6.91 (d, 2H, J¼8.0 Hz), 7.15e7.30 (m, 10H), 7.41 (t, 1H,
J¼8.0 Hz). 13C NMR (CDCI3):
d (ppm) 20.35, 21.96, 28.97, 55.51,
4. Experimental
55.62, 60.97, 68.45, 121.45, 126.83, 128.12, 129.04, 136.94, 140.06,
159.51. Anal. Calcd for C31H43 N3O2: C, 76.03; H, 8.85; N, 8.58.
Found: C, 76.10; H, 8.86; N, 8.58.
4.1. General information
All chemicals were reagent grade unless otherwise specified.
D
-
4.2.3. (2R)-2-{Benzyl[(6-{[benzyl-(2R)-(2-hydroxy-1-phenylethyl)
amino]methyl]pyridin-2-yl)methyl]amino}-2-phenylethan-1-ol
(3c). This compound was prepared as described above for 3a
starting from 2c: (2R)-2-(benzylamino)-2-phenylethan-1-ol (7.15 g,
31.5 mmol), 2,6-bis-(bromomethyl)pyridine (4.17 g,15.75 mmol),
Na2CO3 (5.0 gr, 47.2 mmol), and KI (50 mg). The crude product was
purified by column chromatography over silica gel using toluene/
Amino acids were purchased from SigmaeAldrich or Fluka
chemical company. The - and -amino acid methyl ester hydro-
D
L
chlorides were obtained from Aldrich Chemical Co. Silica gel 60
(Merck, 0.040e0.063 mm) and silica gel/TLC-cards (F254) were
used for column chromatography and TLC. All reactions were
carried out under Nitrogen or Argon atmosphere with dry solvent
under anhydrous conditions, unless other noted. Tetrahydrofuran
(THF) was distilled from sodium/benzophenone ketyl immediately
prior to use and methylene chloride (CH2Cl2) was dried from
EtOAc (5/3) to afford 3c (6.0 g, 68%) as a yellow oil TLC Rf¼0.21. ½a D31
ꢃ
ꢀ93.2 (c 4.1,CHCl3); IR:
n 3338, 3063, 3030, 2928, 2876, 2837, 1600,
1496, 1452, 1361, 1215, 1132, 1066, 1028,758 cmꢀ1. 1H NMR (CDCl3):

P. Deniz et al. / Tetrahedron 67 (2011) 6227e6232
6231
d
(ppm) 3.48e3.54 (m, 4H), 3.80e3.89 (m, 4H), 4.12 (q, 2H,
2H), 2.45e2.49 (m, 2H), 3.62e3.93 (m, 12H), quartet of AB spin
system dA: 4.76 and dB: 4.92 (4H, J¼12.0 Hz), 7.19e7.39 (m, 14H),
7.52 (t, 1H, J¼8.0 Hz) 7.72 (t, 1H, J¼8.0 Hz). 13C NMR (CDCI3):
J¼4.0 Hz), 4.23e4.33 (m, 4H), 5.62 (br s, 2H), 7.01 (d, 2H, J¼8.0 Hz),
7.20e7.45 (m, 20H), 7.50 (t, 1H, J¼8.0 Hz). 13C NMR (CDCI3):
d (ppm)
54.64, 55.63, 61.77, 65.43, 121.77, 127.04, 127.71, 128.29, 128.42,
128.49, 128.73, 128.99, 137.24, 139.12, 159.47. Anal. Calcd for
C39H43N3O2: C, 79.97; H, 7.40; N, 7.17. Found: C, 80.00; H, 7.45;
N, 7.17.
d (ppm) 20.38, 21.18, 28.69, 55.05, 56.83, 63.55, 68.43, 73.59, 120.92,
120.96, 126.61, 128.06, 128.94, 136.13, 136.83, 140.69, 158.19, 159.52.
Anal. Calcd for C38H48N4O2: C, 76.99; H, 8.16; N, 9.45. Found: C,
76.80; H, 8.20; N, 9.50.
4.2.4. (2R)-2-{Benzyl[(6-{[benzyl-(2R)-(1-hydroxy-3-phenylpropan-
2-yl)amino] methyl}pyridin-2-yl)methyl]amino}-3-phenylpropan-1-
ol (3d). This compound was prepared as described above for 3a
startingfrom2d:(2R)-2-(benzylamino)-3-phenylpropan-1-ol(7.41g,
30.7 mmol), 2,6-bis-(bromomethyl)pyridine (4.06 g,15.35 mmol),
Na2CO3 (4.87 g, 46.00 mmol), and KI (50 mg). The crude product was
recrystallized n-hexane/ethyl acetate (2:1) to afford 3d (6.2 g, 69%) as
4.2.7. (4R,14R)-(ꢀ)-4,14-Dibenzyl-5,15-diphenyl-3,17-dioxa-6-14-
23,24-tetraaza tricyclo[17.3.1.18,12}tetracosa-l(23),8,10,12(24),19,21-
hexaene (6). Macrocycle
6 was prepared as described above
for macrocycle 4 starting from 2-{benzyl[(6-{[benzyl(2-hydroxy-
1-phenylethyl)amino]methyl]pyridin-2-yl)methyl}amino}-2-
phenylethan-1-ol 3c (1.0 g, 1.79 mmol), NaH (0.151 g, 6.2 mmol), and
2,6-bis-(bromomethyl)pyridine (0.475 g, 1.79 mmol). The crude
product was purified by column chromatography over silica gel using
petroleum ether/EtOAc/TEA (85:10:5) as an eluent to give pure 6
a colorless solid mp: 126.5e128 ꢁC; ½a D31
ꢃ
ꢀ28.5 (c 1, CD3CN); IR:
n
3402, 3063, 3024, 2922, 2864,1587,1496,1452,1361,1132,1074,1016,
746, 700 cmꢀ1
.
1H NMR (CD3CN):
d
(ppm) 2.55e2.60 (m, 2H),
(0.450 g, 38%) as a clear oil TLC Rf¼0.26. ½a D27
ꢃ
ꢀ58.2 (c 6, CHCl3);
3057, 3024, 2934, 1587,
1H NMR (CDCl3):
(ppm)
2.99e3.08 (m, 4H), 3.34e3.36 (m, 2H), 3.62e3.85 (m, 8H), 4.03e4.07
(m, 2H), 4.75 (br s, 2H), 7.07 (d, 2H, J¼8.0 Hz), 7.18e7.29 (m, 20H), 7.51
MALDI-TOF-MS: m/z¼796.88 (MþAg)þ; IR:
n
1456, 1458, 1369, 1215, 1099, 752 cmꢀ1
.
d
(t,1H, J¼8.0 Hz).13C NMR (CD3CN):
d
(ppm) 32.63, 54.14, 54.78, 60.84,
3.50e3.54 (m, 2H) quartet of AB spin system dA: 3.64 and dB: 3.80 (4H,
J¼16.0 Hz), 3.91e3.98 (m, 8H), quartet of AB spin system dA: 4.51 and
63.51, 121.39, 125.86, 126.75, 128.03, 128.33, 128.88, 129.17, 137.02,
139.97,140.46,159.77. Anal. Calcd for C37H39N3O2: C, 79.68; H, 7.05; N,
7.53. Found: C, 79.70; H, 7.15; N, 7.53.
dB: 4.68 (4H, J¼12.0 Hz), 7.20e7.50 (m, 24H), 7.64 (t,1H, J¼8.0 Hz). 13
C
NMR (CDCI3): d (ppm) 55.75, 56.32, 63.77, 70.91, 73.72,120.12,120.93,
126.82, 127.19, 128.20, 128.73, 128.80, 136.25, 136.79, 139.92, 139.96,
157.98, 159.89. Anal. Calcd for C46H48N4O2: C, 80.20; H, 7.02; N, 8.13.
Found: C, 80.21; H, 7.02; N, 8.15.
4.2.5. (5R,15R)-6,14-Dibenzyl-5,15-diethyl-3,17-dioxa-6,14,23,24-
tetraaza tricyclo[17.3.1.18,12]tetracosa-1(23),8,10,12(24)19,21-hexaene
(4). To a stirred suspension of NaH (0.176 g, 7.35 mmol 96%) in dry
THF (10 mL) under Ar, at 0 ꢁC, was added dropwise to 3a (1.0 g,
2.1 mmol) dissolved in THF (75 mL). After addition, the mixture was
stirred at room temperature for 30 min then refluxed for 2.5 h. The
reaction mixture was cooled to 0 ꢁC, and 2,6-bis-(bromomethyl)
pyridine (0.556 g, 2.1 mmol) dissolved in 70 mL of THF was added
dropwise. After addition, the reaction mixture was stirred at rt for
1 h, and then refluxed for 58 h. After the reaction was completed,
the solvent was evaporated under reduced pressure. The residue
was thoroughly mixed with ice (10 g) and CHCl3 (100 mL) and the
phases were separated. The aqueous phase was washed twice with
100 mL portions of CHCl3. The combined organic phases were dried
(MgSO4), filtered, and the solvent was evaporated. The crude
product was purified by column chromatography over silica gel
using petroleum ether/EtOAc/TEA (85/10/5) to afford 4 (0.515 g,
4.2.8. (4R,14R)-(ꢀ)-5,6,14,15-Tetrabenzyl-3,17-dioxa-6-14-23,24-
tetraaza tricyclo[17.3.1.18,12}tetracosa-l(23),8,10,12(24),19,21-hexaene
(7). Macrocycle 7 was prepared as described above for macro-
cycle
4
starting from 2-{benzyl[(6-{[benzyl(1-hydroxy-3-
phenylpropan-2-yl)amino]methyl}pyridin-2-yl)methyl]amino}-3-
phenylpropan-1-ol 3d (1.0 g, 1.71 mmol), NaH (0.144 g, 6 mmol),
and 2,6-bis-(bromomethyl)pyridine (0.453 g, 1.79 mmol). The
crude product was purified by column chromatography over silica
gel using petroleum ether/EtOAc/TEA (85:10:5) as an eluent to give
pure 7 (0.540 g, 46%) as a clear oil TLC Rf¼0.29. ½a D26
ꢃ
þ48.3 (c
6.3,CHCl3); MALDI-TOF-MS: m/z¼768.76 (MþAg)þ; IR:
n
3057,
3024, 2928, 2857, 1600, 1496, 1452, 1220, 1113, 758 cmꢀ1. 1H NMR
(CD3CN): d (ppm) quartet of AB spin system (part of A: dA: 2.81 and
2.83, dd, 2H, J¼7.6 Hz), (part of B: dB: 2.92 and 2.95, dd, 2H,
J¼7.6 Hz), 3.28e3.35 (m, 2H), 3.64e3.96 (m, 12H) quartet of AB spin
system dA: 4.73 and dB: 4.80 (4H, J¼12.0 Hz), 6.90 (d, 2H, J¼8.0 Hz),
7.11 (t, 4H, J¼4.0 Hz), 7.21e7.30 (m, 20H), 7.71 (t,1H, J¼8.0). 13C NMR
43%) as a yellow oil TLC Rf¼0.58. ½a D30
ꢃ
þ34.7 (c 1.75,CHCl3); MALDI-
TOF-MS: m/z¼672.66 (MþAg)þ; IR:
n
3070, 3025, 2962, 2929, 2871,
1600, 1504, 1452, 1361, 1162, 1105, 914, 738 cmꢀ1. 1H NMR (CDCl3):
d
(ppm) 0.93 (t, 6H, J¼7.2 Hz), 1.51e1.57 (m, 4H), 2.84e2.86 (m, 2H),
(CDCl3): d (ppm) 35.10, 54.75, 55.82, 60.07, 69.77, 73.72, 120.67,
3.58e3.86 (m, 12H), 4.77 (s, 4H), 7.13 (d, 2H, J¼8.0 Hz), 7.19e7.46
120.90, 125.76, 126.61, 128.06, 128.10, 128.64, 129.44, 136.12, 136.86,
140.30, 140.38, 158.22, 159.37. Anal. Calcd for C44H44N4O2: C, 79.97;
H, 6.71; N, 8.48. Found: C, 80.01; H, 6.80; N, 8.50.
(m, 13H), 7.73 (t, 1H, J¼8.0 Hz). 13C NMR (CDCI3):
d (ppm) 11.69,
22.24, 54.75, 55.94, 59.97, 70.52, 73.78, 120.70, 120.95, 126.59,
128.06, 128.78, 136.05, 136.85, 140.82, 158.30, 159.69. Anal. Calcd
for C36H44N4O2: C, 76.56; H, 7.85; N, 9.92. Found: C, 76.65; H, 7.95;
N, 9.98.
Acknowledgements
We would like to thank to The Scientific and Technological
Research Council of Turkey (TUBITAK) for their financial support
(Project No: 110 T 004) and Partial support from Dicle University
(Project No: DUBAP-09-FF-72). The authors also would like to
thank to Izmir Institute of Technology (IYTE) Biolojical Mass
Spectrometry laboratory for taking the MS spectra. We are
grateful to Dr. Murat Kizil (Dicle University) for their invaluable
contribution.
4.2.6. (4R,14R)-(ꢀ)-4,14-Dibenzyl-5,15-bis(propan-2-yl)-3,17-dioxa-6-
14-23,24-tetra azatricyclo[17.3.1.18,12}tetracosa-l(23),8,10,12(24),19,21-
hexaene (5). Macrocycle 5 was prepared as described above for
macrocycle
4 starting from 2-{benzyl[(6-{[benzyl(1-hydroxy-3-
methylbutan-2-yl)amino]methyl]pyridin-2-yl)methyl]amino}-3-
methylbutan-1-ol 3b (1.0 g, 2.04 mmol), NaH (0.172 g, 7.14 mmol),
and 2,6-bis-(bromomethyl)pyridine (0.540 g, 2.04 mmol). The crude
product was purified by column chromatography over silica gel
using petroleum ether/EtOAc/TEA (85:10:5) as an eluent to give
pure 5 (0.450 g, 37%) as a clear oil TLC Rf¼0.53. ½a D26
ꢃ
þ36.8 (c 3.8,
Supplementary data
CHCl3); MALDI-TOF-MS: m/z¼700.75 (MþAg)þ; IR:
n
3063, 2961,
2876, 1600, 1458, 1355, 1259, 1151, 1099, 752 cmꢀ1. 1H NMR (CDCl3):
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.06.064.
d
(ppm) 0.91 (d, 6H, J¼8.0 Hz), 0.96 (d, 6H, J¼8.0 Hz), 1.86e1.92 (m,

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P. Deniz et al. / Tetrahedron 67 (2011) 6227e6232
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