Synthesis of novel chiral polyamide macrocycles containing pyridyl side-arms and their molecular recognition properties

Article abstract of DOI:10.1016/S0957-4166(03)00173-3

Seven novel C₂-symmetrical macrocycles containing pyridyl units have been prepared by the cyclic condensation of homochiral diamide intermediates with 2,6-pyridinedicarbonyl dichloride under high dilution at room temperature. The molecular reco

Full text of DOI:10.1016/S0957-4166(03)00173-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 999–1007
Synthesis of novel chiral polyamide macrocycles containing
pyridyl side-arms and their molecular recognition properties
Xiao Chen, Da-Ming Du and Wen-Ting Hua*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
Received 31 October 2002; revised 14 February 2003; accepted 17 February 2003
Abstract—Seven novel C2-symmetrical macrocycles containing pyridyl units have been prepared by the cyclic condensation of
homochiral diamide intermediates with 2,6-pyridinedicarbonyl dichloride under high dilution at room temperature. The molecular
recognition of these homochiral macrocycles for amino acid derivatives has been characterized by various spectroscopic methods
such as IR, FAB-MS, fluorescence and UV–vis. The macrocycle 11 exhibited significant chiral recognition towards the
enantiomers of
D- and L-alanine methyl ester hydrochlorides for which association constants have been determined. Molecular
modeling was also used to simulate the interaction mode between the hosts and the guests. © 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
acceptors at the pyridyl nitrogens, but also bringing
rigidity into the ring.6 All the structural characteristics
of the macrocycles make them form a certain confor-
mation via weak forces such as hydrogen bonds and
Molecular recognition has been the focus of
supramolecular chemistry as one of fundamental pro-
cesses in biochemical systems.1 Recent successes in imi-
tating the natural phenomena using synthetic artificial
receptors have shown that biological behavior can be
engineered into relatively simple molecules.2 Therefore,
the design and synthesis of different kinds of synthetic
macrocycles and studies on their molecular recognition
abilities have been one of the focuses in the fields of life
science and material science. In particular, optical
active macrocyclic receptors and their enantioselective
recognition of chiral compounds have been attracting
much attention.3
p-stacking interactions, thus offering
environment.
a
chiral
2. Results and discussion
2.1. Synthesis
In this paper, seven new chiral macrocycles are pre-
pared. The synthesis of macrocycles 6, 7 and 8 as an
example is shown in Scheme 1. The tosylamine 1 was
transformed into its sodium salt, and then reacted with
2,6-bis(bromomethyl)pyridine to give compound 2.
Detosylation of compound 2 in concentrated H2SO4
gave 2,6-bis(N-picolylaminomethyl)-pyridine 3. How-
ever, if the compound 3 was prepared by reacting
2-aminomethylpyridine with 2,6-bis(bromomethyl)-
pyridine, the products were so complicated that
the desired product was hard to separate and purify.
Next, the diamine 3 was condensed with Z-protected
valine in the presence of DCC to give compound 4. It
should be noticed that Z-protected valine must be
mixed with DCC for 0.5 h to form the symmetric
anhydride before the addition of compound 3 to the
mixture, otherwise, the yield of acylated product is very
low. Subsequently, compound 4 was deprotected with
We report here the synthesis of seven novel chiral
polyamide macrocycles and a study of their enan-
tiomeric recognition for amino acid derivatives by spec-
troscopic
methods.
These
macrocycles
have
C2-symmetry axis and their chirality derives from
L-
amino acid derivatives.4 Because they have amide
groups similar to cyclopeptides, they can be classified as
cyclophanes or cyclopseudopeptides.5 In addition, pyri-
dine units as building blocks are incorporated into the
ring structure and side-arm, not only providing proton
* Corresponding author. Tel.: 86-10-62756568; fax: 86-10-62751708;
e-mail: huawt@pku.edu.cn
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00173-3

1000
X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 999–1007
Scheme 1. Preparation of macrocycles 6–8.
33% HBr–HOAc to afford compound 5. Then three
new chiral macrocycles 6, 7 and 8 were prepared by
acylation of chiral diamine dihydrobromide intermedi-
ate 5 with 2,6-pyridinedicarbonyl dichloride at high
dilution (10−2 M) at room temperature. The macrocy-
cles 6, 7 and 8 are the products of [1+1], [2+2] and [3+3]
cyclization and the corresponding yields are 15.6%,
5.1% and 3.7%, respectively. To our knowledge,
product 8, a 54-membered macrocycle, has seldom
reported previously. With the increase of ring size, the
yield reduced, which may be ascribed to the collision
ratio of two terminal units decreasing with the increase
in chain length in the intramolecular cyclization. The
structures of the new chiral macrocycles were confirmed
Similarly, the macrocycles 11, 15, 16 and 19 can be
synthesized according to the above-mentioned method,
as shown in Schemes 2–4. It should be noticed that the
intermediate 12 was prepared by 2,6-bis(bromo-
methyl)pyridine with a great excess of benzylamine.7
2.2. Molecular recognition
The main purpose of synthesizing these artificial recep-
tors is to study their molecular recognition for guest
molecules. Molecular recognition can be characterized
by various spectroscopic methods, such as ultraviolet-
visible (UV–vis), fluorescence and infrared (IR) spec-
troscopy, which are powerful tools used for the
examination of the recognition ability of new chiral
macrocycles. Different methods work together to show
1
by H NMR, IR, MALDI-TOF-MS spectra and ele-
mental analyses.

X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 999–1007
1001
Scheme 2. Preparation of macrocycle 11.
Scheme 3. Preparation of macrocycles 15 and 16.
the main role in molecular recognition based on our
previous research.3
that homochiral macrocycles can possess chiral molecu-
lar recognition ability for organic molecules. Amino
acids and derivatives, as the fundamental building
blocks of biological systems, are the most attractive
objectives. Herein, amino acid methyl ester hydrochlo-
rides and dipeptides were selected as the guest
molecules. We only use [1+1] macrocycles as the hosts,
because the functional groups of macrocycles as build-
ing blocks instead of the size of the macrocycle plays
2.3. IR spectroscopy
Infrared spectroscopy is a convenient and widely used
method for the study of molecular recognition.8 For the
polyamide macrocycles, the CꢀO double bond has an
obvious characteristic peak at 1650 cm−1. Hydrogen

1002
X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 999–1007
Scheme 4. Preparation of macrocycle 19.
Table 1. IR Data of macrocycles with the guest molecules
(w/cm−1
bond formation makes the peak position shift to lower
frequency, which can indicate an interaction between
the host and the guest.
)
Host+Guest
wCꢀO
DwCꢀO
wNꢁH
DwNꢁH
From the IR data in Table 1, it can be seen that when
the macrocycles and the guests were mixed, the stretch-
ing vibrations of CꢀO and NꢁH all shift to lower
frequency, which shows that there are hydrogen bonds
formed between the hosts and the guests. Among the
items, the macrocycle 6 has an significant recognition
6
1669
1658
1651
1659
1650
1655
1659
1657
1648
1644
1642
3426
3422
3420
3420
3390
3420
3392
3443
–
6+
6+
6+
6+
6+
6+BPHME
6+CPH
19
L
-Ala-OMe·HCl
-Ala-OMe·HCl
-Phe-OMe·HCl
-Phe-OMe·HCl
-Val-Obz·HCl
11
18
10
19
14
10
12
4
6
6
D
L
D
36
6
34
−17
L
for
19, macrocycle 6 demonstrates better chiral recognition
for - or -phenylalanine methyl ester hydrochloride.
Generally, the shift value of -amino acid methyl ester
hydrochloride is greater than that of -isomer, demon-
strating that the macrocycle has the enantiomeric dis-
crimination ability between - and -isomers of amino
D-phe-OMe·HCl. Compared with the macrocycle
D
L
19+
19+
L
-Phe-OMe·HCl
-Phe-OMe·HCl
4
6
–
–
–
–
D
D
L
*Measured in 1:1 mole ratio of the host–guest mixture in the solid
state. Ala-OMe: alanine methyl ester; Phe-OMe: phenylalanine
methyl ester; Val-OBz: valine benzyl ester; BPHME: linear dipeptide
Z-Phe-His-OMe. CPH: cyclodipeptide Phe-His.
D
L
acid methyl ester hydrochlorides.
2.4. FAB-MS
Table 2. FAB-MS data of the macrocycles with amino
acid derivativesa
Fast atom bombardment mass spectrometry (FAB-MS)
as a soft ionization technique is effective for a variety of
supramolecular complexes.9 FAB mass spectra in Table
2 demonstrate that the host-guest 1+1 molecular ion
peaks appear in some host–guest systems. We can see
that both macrocycle 6 and macrocycle 19 can bind
amino acid methyl ester hydrochlorides. The
hydrochlorides containing a benzene ring bind well with
the macrocycles. Because the benzene ring in the guest
can have p–p stacking with the pyridine in the macrocy-
cle, the size of benzene ring also matches very well to
the cavity size of macrocycle. There is no molecular ion
peak when the guest is alanine methyl ester hydrochlo-
ride. There is also no molecular ion peak of complexes
between macrocycle 6 and CPH, possibly because of its
bulky size compared to the macrocycle. Furthermore,
there is no evidence that one macrocycle binds two
guests, so the binding stoichiometry can be inferred as
1:1.
Host+Guest
M+1 Peak
Relative intensityb
6+
6+
6+
6+
6+
L
-Ala-OMe·HCl
-Ala-OMe·HCl
-Phe-OMe·HCl
-Phe-OMe·HCl
-Val-OBz·HCl
649 (H)
649 (H)
S
S
D
L
828 (H+G)
828 (H+G)
856 (H+G)
1099 (H+G)
649 (H)
W
W
W
W
S
D
L
6+BPHME
6+CPH
19+
19+
L
-Phe-OMe·HCl
-Phe-OMe·HCl
822 (H+G)
822 (H+G)
W
W
D
a Measured in a 1:1 mole ratio of the host-guest mixture.
b S=Strong; W=Weak.
2.5. Fluorescence spectroscopy
Fluorescence spectroscopy is known to have high sensi-
tivity compared to other spectroscopic methods.10

X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 999–1007
1003
Therefore, the enantiomeric recognition for
-amino acid derivatives by these homochiral macro-
D
- and
5[G]o[H]o/DA=1/KDm+[G]o
L
[H]o: the concentration of macrocycle; [G]o: the concen-
tration of the guest; DA: the change of UV–vis intensity
of the macrocycle upon addition of amino acid methyl
ester hydrochloride; K: association constant; Dm: the
molar extinction coefficient.
Fig. 1 shows the absorption maximum of the macrocy-
cle 11 gradually increases upon the addition of
nine methyl ester hydrochloride with varying
concentrations. The plots of calculated [G]o[H]o/DA
values as a function of [G]o give good straight lines, the
result is shown in Fig. 2. From the linear plot, we can
obtain the association constant for the interaction of
cycle receptors has been characterized by fluorescence
spectra. It is evident from the differences in these
fluorescence intensity and fluorescence maxima that
these chiral ligands exhibit chiral recognition. As shown
in Table 3, both fluorescence intensity and fluorescence
maximum exhibit some differences. The intensities of
fluorescence increase (or decrease) according to the
environment of fluorescence molecules. When mixed
with the guests, the fluorescence intensities of the
macrocycles 6 and 11 increase, while the fluorescence
intensities of the macrocycles 15 and 19 decrease. The
reason for this phenomenon may be that the nitrogen in
the pyridine ring as a binding site interacts with proton
by static force, but there is no such effect for a benzene
ring.
D-ala-
the macrocycle 11 with
D
-Ala-OMe·HCl as KD=8.12×
102 M−1 (r=0.992) and that of the macrocycle 11 with
L
-Ala-OMe·HCl as KL=2.03×103 M−1 (r=0.982).
Therefore, the selectivity ratio is 2.5.
2.6. UV–vis
UV–vis spectroscopy is a convenient and widely used
method for the study of binding phenomena.11 When
the receptor (or substrate) absorbs light at different
wavelengths in the free and complexed states, the differ-
ences in ultraviolet spectrophotometry may suffice for
estimation of molecular recognition.
We use a UV spectral titration method to obtain the
association constant. When the concentration of the
macrocycle is much smaller than that of the guest
([H]oꢀ[G]o), the modified Hilderbrand–Benesi equation
can be employed under these conditions.12
Table 3. Fluorescence data of the macrocycles with enan-
tiomers of amino acid methyl ester hydrochlorides
Figure 1. UV–vis spectra of 11 (1×10−5 mol dm−3) in the
Hosta+Guesta
umax(nm)b
Du (nm)
I/Io (relative
intensity)
presence of
D
-Ala-OMe·HCl. a: 0; b: 6×10−4; c: 8×10−4; d:
10×10−4; e: 14×10−4; f: 16×10−4 mol dm−3
.
6
361.2
362.5
362.0
361.6
363.0
382.1
374.0
6+
6+
6+
6+
11
L
-Ala-OMe·HCl
-Ala-OMe·HCl
-Phe-OMe·HCl
-Phe-OMe·HCl
1.3
0.8
0.4
1.8
1.07
1.24
1.12
1.23
D
L
D
11+
11+
11+
11+
15
L
-Ala-OMe·HCl
-Ala-OMe·HCl 380.1
-Phe-OMe·HCl 368.4
-Phe-OMe·HCl 372.9
−8.1
−2.0
−13.7
−9.2
1.18
1.26
1.89
1.52
D
L
D
371.1
15+
15+
15+
15+
19
L
-Ala-OMe·HCl
-Ala-OMe·HCl 378.7
-Phe-OMe·HCl 362.4
-Phe-OMe·HCl 372.0
376.4
5.3
7.6
−8.7
0.9
0.56
1.11
0.77
0.71
D
L
D
377.4
19+
19+
19+
19+
L
-Ala-OMe·HCl
-Ala-OMe·HCl 380.4
-Phe-OMe·HCl 381.2
-Phe-OMe·HCl 378.2
379.8
2.4
3.0
3.8
0.8
0.49
0.49
0.65
0.52
D
L
D
a Equimolar amounts of the macrocycles and salts were dissolved in
the solvent (CH3OH/CH3CN=1:30) with the concentration of 2×
Figure 2. Typical plot of [G]o[H]o/DA versus [G]o for the
inclusion complexation of 11 with
solvent (CH3OH:CH3CN=1:30).
10−5 M.
D-Ala-OMe·HCl in the
b uex=300 nm.

1004
X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 999–1007
2.7. Molecular modeling
In order to study further the structure and interaction
mode between the host and the guest, we also use
computer modeling to simulate the binding. Just from
the IR data, we can see that the hosts and the guests
interact with each other by hydrogen bonding between
amide groups and protons. Based on our previous
research,3 we think there are tripod hydrogen bonds
formed between the macrocycles and the guests. Here,
the macrocycles 6 and 11 were chosen as candidates for
the conformational search using Sybyl6.4 performed on
Silicon Graphics O2 (R5000) workstations. Fig. 3 rep-
resents the predicted conformation of the macrocycle 6
combining with
chloride and Fig. 4 represents the macrocycle 11 with
-alanine methyl ester hydrochloride. From the energy
L-phenylalanine methyl ester hydro-
D
data in Table 4, we can see that when the macrocycles
combine with the guests, the total energy values are
lower. It can also be inferred that both of the macrocy-
cles 6 and 11 have a better enantiomeric discrimination
Figure 4. Complex conformation formed by the macrocycle
11 with -Ala-OMe·HCl.
D
Table 4. Energy data of optimized conformation of
macrocycles with enantiomers of amino acid methyl ester
hydrochlorides (kcal/mol)
towards the
energy of the complex of the
is lower than that of -isomer. The molecular modeling
D
-isomer than to
L-isomer, because the
D
-isomer with macrocycle
L
Host+Guest
Energy
DE
is in agreement with the experimental conclusions.
6
38.535
10.785
3.279
18.130
−6.305
−14.070
6+
6+
11
11+
11+
L
-Phe-OMe·HCl
-Phe-OMe·HCl
−27.750
−34.256
D
L
-Ala-OMe·HCl
-Ala-OMe·HCl
−24.435
−32.200
D
hydrochlorides significantly; (2) It is effective to use
various spectroscopic methods together to determine
Firstly, the initial structures of the molecules were input. These
structures were then successively refined using minimization options
of Sybyl with Tripos force field. The entire complex was then
minimized using 5000 steps of steepest descent, followed by conjugate
the enantiomeric recognition ability for
D- and L-enan-
tiomers of amino acid methyl ester by these artificial
receptors.
gradient algorithm leading to a maximum derivative of less than a
2
,
0.010 kcal/(mol A ) (root-mean-square (rms) energy gradient).
Gasterger–Huckel charges were employed throughout.
3. Experimental
3.1. General comments
Infrared spectra were measured on a Bruker Vector 22
spectrometer. 1H NMR spectra were recorded on a
Bruker ARX 400 spectrometer. Chemical shifts are
indicated in l values (ppm) downfield from internal
TMS. FAB-mass spectra were measured on VG-ZAB-
HS mass spectrometer. Elemental analyses were carried
out on Elementar Vario EL instrument. Melting points
were taken on an XT-4 melting point apparatus and
were uncorrected. Optical rotations were measured on a
Perkin–Elmer 241 MC spectrometer. Commercial grade
solvents were used without further purification unless
specified. CH2Cl2 was distilled from calcium hydride.
Starting materials were purchased from the Acros
chemical company unless otherwise noted. Compound
1 was prepared according to the literature.13 as was
compound 12.7
Figure 3. Complex conformation formed by the macrocycle 6
with L-Phe-OMe·HCl.

X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 999–1007
1005
3.2. Spectra measurement
neutralized with 1N NaOH and then extracted with
ethyl acetate (2×50 mL). The organic layer was dried
over anhydrous Na2SO4 and evaporated. Flash chro-
matography on silica gel using ethyl acetate afforded
colorless oil (0.91 g, 85% yield). [h]2D0=−18.7 (c 1.80,
CHCl3); MS (EI): m/z 785 (M+); IR (KBr): w 3439, 1645,
The fluorescence spectra were measured at 25°C with
970-CRT fluorescence spectrometer. The excitation
wavelength of the fluorescence spectra was 300 nm and
the excitation and emission slits were 10 nm. A solution
of nitrile–methanol (30:1 v/v) was used as the solvent.
The UV–vis spectra were measured at 25°C with TU-
1901 UV spectrometer. The maximum wavelength is 262
nm. A solution of nitrile-methanol (30:1 v/v) was used
as the solvent. The concentration of the host is 1×10−5
M with the increasing concentration of the added guest.
1
1539, 1456, 1237, 1164, 1024 cm−1; H NMR (CDCl3):
l 8.50 (m, 2H), 7.57 (m, 3H), 7.32–7.06 (m, 14H), 5.87
(m, 1H), 5.75 (m, 1H), 5.10–4.37 (m, 14H), 2.08 (m, 2H),
0.91 (m, 12H). Anal. calcd for C45H51N7O6: C, 68.74%;
H, 6.54%; N, 12.48%. Found: C, 68.63%; H, 6.59%; N,
12.38%.
3.3. 2,6-Bis(N-tosyl-picolylaminomethyl)pyridine 2
3.6. 2,6-Bis(N-picolyl-valinylaminomethyl)pyridine
hydrobromide 5
To a stirred suspension of the sulfonamide 1 (2.62 g, 10
mmol) in absolute EtOH (30 mL), NaOEt prepared by
dissolving sodium (0.247 g, 10.7 mmol) in EtOH (10
mL) was added dropwise at rt. The reaction mixture was
refluxed for 5 h and then cooled. After removing etha-
nol, the precipitate was collected by rapid filtration and
dried to give white solid (2.16 g, 76.5%).
Compound 4 (0.8 g, 1 mmol) was dissolved in 33%
HBr–HOAc (10 mL). The mixture was stirred at rt for
2 h and the solution was concentrated to dryness.
Anhydrous diethyl ether (10 mL) was added to the
residue, and the mixture was stirred for additional 1 h
and then filtered to give a light yellow powder (ca. 100%
yield). Mp 232–233°C, MS (FAB): m/z 518 (M+H)+; IR
1
A mixture of 2,6-bis(bromomethyl)pyridine (1.31g, 4.95
mmol) and tosylate sodium salt (2.8 g, 9.9 mmol) was
stirred in absolute ethanol (40 mL) at ambient tempera-
ture for 8 h. After removing EtOH, the residue was
purified by column chromatography on silica gel using
ethyl acetate–petroleum ether (1:1) as eluent to give
sticky liquids, which was recrystallized from hexane to
give white solid (1.66 g, 53.5% yield). Mp 72–74°C, MS
(FAB): m/z 626 (M+H)+; IR (KBr): w 3455, 2361, 1646,
1595, 1435, 1336, 1153 cm−1; 1H NMR (CDCl3): l
8.35–8.33 (t, 1H), 7.67–7.06 (m, 18H), 4.48 (s, 4H), 4.36
(s, 4H), 2.39 (s, 6H). Anal. calcd for C33H33N5O4S2: C,
63.14%; H, 5.30%; N, 11.16%. Found: C, 63.03%; H,
5.36%; N, 11.13%.
(KBr): w 3437, 2363, 1664, 1464, 1165, 1049 cm−1; H
NMR (CD3OD): l 8.53 (m, 1H), 8.44 (m, 1H), 7.80–
7.66 (m, 3H), 7.36–7.16 (m, 6H), 5.00–4.89 (m, 4H), 4.75
(m, 1H), 4.67 (m, 2H), 4.40 (m, 1H), 3,75 (m, 2H), 1.98
(m, 2H), 0.93 (m, 12H).
3.7. Pyridine-valine macrocycles 6, 7 and 8
A solution of freshly prepared 2,6-pyridinedicarbonyl
dichloride (0.26 g, 1.27 mmol) in dry dichloromethane
(20 mL) was added dropwise to well-stirred solution of
diester diamine dihydrobromide 5 (0.79 g, 1.17 mmol)
and triethylamine (0.98 mL, 7 mmol) in dry CH2Cl2
(120 mL) at 0°C over 0.5 h. The reaction mixture was
stirred for additional 12 h at rt. The resulting solution
was concentrated to 60 mL and was washed with water
and 5% NaHCO3, dried over anhydrous Na2SO4. The
solvent was evaporated and the residue was purified by
column chromatography on silica gel using chloroform–
methanol (30:1) as eluent to give white solid 6 (95 mg,
15.6% yield), 7 (46 mg, 5.1% yield) and 8 (27 mg, 3.7%
yield).
3.4. 2,6-Bis(N-picolylaminomethyl)pyridine 314
2,6-Bis(N-tosyl-picolylaminomethyl)pyridine (1.66 g,
2.6 mmol) was dissolved in concentrated H2SO4 (10 mL)
and then stirred at 110°C under nitrogen for 2 h. After
cooling, the solution was diluted with water and then
neutralized by aqueous 4N NaOH with cooling in an ice
bath. The free amine was extracted with CHCl3, dried
over anhydrous Na2SO4 and then concentrated to dry-
ness to give 3 as yellow liquid (0.736 g, 87.1% yield). MS
(EI): m/z 319.
6: mp 150–151°C, [h]D20=−104.3 (c 1.11, CHCl3); MS
(FAB): m/z=649 (M+H)+; IR (KBr) w 3452, 2926, 1669,
1
1593, 1437, 1323, 1220 cm−1; H NMR (CDCl3): l 8.16
(d, 2H, J=4.4 Hz), 8.05 (d, 2H, J=7.6 Hz), 7.90 (t, 1H,
J=7.6 Hz), 7.67 (t, 2H, J=7.6 Hz), 7.36 (m, 2H), 7.19
(m, 2H), 6.56 (m, 3H), 5.71 (d, 2H, J=15.2 Hz),
4.92–4.09 (m, 8H), 2.57 (m, 2H), 0.98 (d, 12H, J=6.8
Hz). Anal. calcd: C36H40N8O4 C, 66.65%; H, 6.21%; N,
17.27%. Found: C, 66.47%; H, 6.23%; N, 17.13%.
3.5. 2,6-Bis(N-picolyl-Z-valinylaminomethyl)pyridine 4
N-Carbobenzyloxyalanine (14.1 g, 5.71 mmol) and
DCC (1.18 g, 5.71 mmol) were dissolved in dry CH2Cl2
(10 mL). After stirring for 0.5 h at 0°C, 2,6-bis(N-
picolylaminomethyl)pyridine 3 (0.434 g, 1.36 mmol) in
CH2Cl2 (10 mL) was added dropwise to the mixture at
the same temperature. After stirring at rt for additional
2 h, the resulting white suspension was filtered. The
filtrate was washed with 5% aqueous NaHCO3 (2×25
mL) and then concentrated to dryness. The residue was
dissolved in ethyl acetate (40 mL) and washed with 1N
HCl (2×30 mL). The separated aqueous phase was
7: mp 136–138°C, [h]D20=+7.9 (c 2.77, CHCl3), FABMS:
m/z 1297 (M+H)+; IR (KBr): w 3455, 2966, 2352, 1645,
1523, 1434, 1330, 1173 cm−1; 1H NMR (CDCl3): l
8.53–7.00 (m, 28H), 5.29–4.03 (m, 20H), 2.37 (m, 4H),
1.01 (m, 24H). Anal. calcd: C72H80N16O8·H2O C,
65.73%; H, 6.28%; N, 17.04%. Found: C, 65.59%; H,
6.31%; N, 17.02%.

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X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 999–1007
8: mp 134–136°C, [h]2D0=+23.9 (c 1.12, CHCl3), MS
(MALDI-TOF): m/z 1945 (M+H)+; IR (KBr): w 3470,
2966, 1641, 1525, 1432, 1330, 1212, 1170 cm−1; 1H
NMR (CDCl3): l 8.52–7.09 (m, 42H), 5.13–4.10 (m,
30H), 2.27 (m, 6H), 0.95 (m, 36H). Anal. calcd:
C72H80N16O8·H2O C, 65.74%; H, 6.28%; N, 17.04%.
Found: C, 65.67%; H, 6.26%; N, 16.98%.
yield). Mp 141–143°C; [h]2D0=−134.6 (c 1.7, CHCl3);
MS (FAB): m/z 648 (M+H)+; IR (KBr): w 3447, 2966,
1
2361, 1646, 1438, 1338, 1211 cm−1; H NMR (CDCl3):
l 8.61–6.51 (m, 14H), 5.64–3.44 (m, 14H), 2.31–1.67
(m, 8H). Anal. calcd for C36H36N8O4·H2O: C, 65.24%;
H, 5.78%; N, 16.91%. Found: C, 65.19%; H, 5.81%; N,
16.87%.
3.8. 2,6-Bis(N-picolyl-Z-prolinylaminomethyl)pyridine 9
3.11. 2,6-Bis(N-benzyl-Z-valinylaminomethyl)pyridine 13
N-Carbobenzyloxyalanine (0.47 g, 1.87 mmol) and
DCC (0.39 g, 1.87 mmol) were dissolved in dry CH2Cl2
(5 mL). After stirring for 0.5 h at 0°C, 2,6-bis(N-picolyl-
aminomethyl)-pyridine 3 (0.27 g, 0.85 mmol) in CH2Cl2
(5 mL) was added dropwise to the mixture at the same
temperature. After stirring at rt for additional 2 h, the
resulting white suspension was filtered. The filtrate was
washed with 5% aqueous NaHCO3 (2×25 mL) and then
concentrated to dryness. The residue was dissolved in
ethyl acetate (30 mL) and washed with 1N HCl (2×20
mL). The separated aqueous phase was neutralized with
1N NaOH and then extracted with ethyl acetate (2×40
mL). The organic layer was dried over Na2SO4 and
then evaporated. Flash chromatography on silica gel
using ethyl acetate–petroleum ether (1:1) as eluent
afforded colorless oil (0.58 g, 87.2% yield). [h]2D0=−2.0
(c 3.0, CHCl3); MS (FAB): m/z 782 (M+H)+; IR (KBr):
w 3391, 2954, 2362, 1655, 1591, 1416, 1352, 1202, 1121
The mixture of carbobenzyloxyvaline (1.25 g, 4.96
mmol) and DCC (1.02 g, 4.96 mmol) in CH2Cl2 (10
mL) was stirred with cooling in an ice bath for 0.5 h. A
solution of compound 17 (0.78 g, 2.48 mmol) in CH2Cl2
was added dropwise to the reaction mixture at the same
temperature. After stirring for additional 2 h at ambi-
ent temperature, the reaction mixture was filtered. The
filtrate was concentrated to dryness and the residue was
purified by column chromatography on silica gel using
ethyl acetate–petroleum ether (1:2) as eluent to afford
viscous oil (1.45 g, 74.8% yield). [h]2D0=−17.0 (c 0.50,
CHCl3); IR (KBr): w 3439, 3030, 1715, 1642, 1525,
1448, 1317, 1225 cm−1; MS (FAB): m/z 784 (M+H)+;
1H NMR (CDCl3): l 7.56 (m, 1H), 7.36–7.11 (m, 20H),
5.70–5.52 (m, 2H), 5.13–4.58 (m, 11H), 4.51–4.40 (m,
2H), 4.24–4.09 (m, 1H), 2.05 (m, 2H), 0.91 (m, 12H).
Anal. calcd for C47H53N5O6: C, 72.01%; H, 6.81%; N,
8.93%. Found: C, 71.97%; H, 6.76%; N, 8.89%.
1
cm−1; H NMR (CDCl3): l 8.52–8.42 (m, 2H), 7.70–
6.74 (m, 19H), 5.15–4.45 (m, 14H), 3.67 (m, 2H), 3.52
(m, 2H), 2.06–1.80 (m, 8H). Anal. calcd for
C45H47N7O6: C, 69.12%; H, 6.06%; N, 12.54%. Found:
C, 69.07%; H, 6.10%; N, 12.49%.
3.12. 2,6-Bis(N-benzyl-valinylaminomethyl)pyridine
hydrobromide 14
Compound 13 (1.28 g, 1.6 mmol) was dissolved in 33%
HBr–HOAc (12 mL). The mixture was stirred at rt for
2 h and then was concentrated to dryness. Anhydrous
ethyl ether (25 mL) was added to the residue, and the
mixture was stirred for additional 1 h. The mixture was
then filtered to give a light yellow powder (1.05 g, 95%
yield). Mp 231–233°C; MS (FAB): m/z 516 (M+H)+; IR
(KBr): w 3415, 2934, 2360, 1655, 1452, 1363, 1228, 1172
3.9. 2,6-Bis(N-picolyl-prolinylaminomethyl)pyridine
hydrobromide 10
Compound 9 (0.6 g, 0.77 mmol) was dissolved in 33%
HBr–HOAc (10 mL). The mixture was stirred at rt for
2 h, and then the solution was concentrated to dryness.
Anhydrous ethyl ether (25 mL) was added to the
residue, and the mixture was stirred for additional 1 h.
The mixture was filtered to afford light yellow powder
(0.648 g, 92% yield). Mp 193–195°C; MS (FAB): m/z
514 (M+H)+; IR (Kr): w 3418, 2941, 1668, 1541, 1462,
1
cm−1; H NMR (DMSO): l 8.25–8.18 (m, 4H), 7.83–
7.74 (m, 1H), 7.40–7.14 (m, 10H), 4.96–3.87 (m, 10H),
2.15–2.07 (m, 2H), 0.96–0.82 (m, 12H).
3.13. Pyridine–valine macrocycles 15 and 16
1
1368, 1239, 1168 cm−1; H NMR (DMSO): l 8.73–7.18
(m, 11H), 4.95–4.66 (m, 10H), 3.22 (m, 4H), 2.50 (m,
2H), 1.89 (m, 8H).
A solution of freshly prepared 2,6-pyridinedicarbonyl
dichloride (0.27 g, 1.3 mmol) in dry dichloromethane
(20 mL) was added dropwise to well-stirred solution of
compound 14 (0.87 g, 1.3 mmol) and triethylamine
(0.91 mL, 6.5 mmol) in dry CH2Cl2 (120 mL) at 0°C
over 0.5 h. The reaction mixture was stirred for addi-
tional 12 h at rt. The resulting solution was concen-
trated to 60 mL and was washed with water and 5%
NaHCO3, dried over anhydrous Na2SO4. The solvent
was evaporated and the residue was purified by column
chromatography on silica gel using chloroform–
methanol (100:1) as eluent to give white solid 15 (63
mg, 7.5% yield) and 16 (37 mg, 2.2% yield).
3.10. Pyridine–proline macrocycle 11
A solution of freshly prepared 2,6-pyridinedicarbonyl
chloride (0.14 g, 0.71 mmol) in dry dichloromethane (20
mL) was added dropwise to well-stirred solution of
compound 10 (0.65 g, 0.71 mmol) and triethylamine
(0.7 mL, 5 mmol) in dry CH2Cl2 (100 mL) at 0°C over
0.5 h. The reaction mixture was stirred for additional
12 h at rt. The resulting solution was concentrated to 60
mL and was washed with water and 5% NaHCO3,
dried over anhydrous Na2SO4. The solvent was evapo-
rated and the residue was purified by column chro-
matography on silica gel using chloroform–methanol
(20:1) as eluent to give white solids (47 mg, 10.3%
15: mp 134–136°C [h]2D0=−50.2 (c 2.97, CHCl3); MS
(FAB): m/z 647 (M+H)+; IR (KBr): w 3482, 2961, 2366,
1661, 1524, 1426, 1317, 1223, 1172 cm−1; 1H NMR

X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 999–1007
1007
(CDCl3): l 8.16 (d, 2H, J=7.6 Hz), 7.90 (t, 1H, J=7.6
Hz), 7.35–7.21 (m, 10H), 6.55 (m, 3H), 5.81 (d, 2H,
J=13.6 Hz), 5.17–4.26 (m, 8H), 2.84 (s, 1H), 2.05 (m,
1H), 1.13–0.97 (m, 12H). Anal. calcd for
C38H42N6O4·0.5H2O: C, 69.59%; H, 6.61%; N, 12.82%.
Found: C, 69.63%; H, 6.64%; N, 12.79%.
h. The reaction mixture was stirred for additional 12 h
at rt. The resulting solution was concentrated to 60 mL
and was washed with water and 5% NaHCO3, dried
over anhydrous Na2SO4. The solvent was evaporated
and the residue was purified by column chromatogra-
phy on silica gel using chloroform–methanol (100:1) as
eluent to give white solid 19 (85 mg, 6.6% yield). Mp
132–134°C; [h]2D0=−172.4 (c 0.35, CHCl3); MS (FAB):
m/z 643 (M+H)+; IR (KBr): w 3485, 2924, 1648, 1453,
16: mp 140–142°C; [h]2D0=−20.4 (c 0.26, CHCl3); MS
(FAB): m/z 1293(M+H)+; IR (KBr): w 3414, 2964, 2359,
1643, 1522, 1440, 1368, 1215, 1167 cm−1; 1H NMR
(CDCl3): l 9.10–6.86 (m, 32H), 5.34–4.02 (m, 20H),
2.31–2.25 (m, 4H), 1.03–0.96 (m, 24H). Anal. calcd for
C76H84N12O8.H2O: C, 69.60%; H, 6.61%; N, 12.81%.
Found: C, 69.57%; H, 6.62%; N, 12.79%.
1
1349, 1213, 1165 cm−1; H NMR (CDCl3): l 8.04–6.77
(m, 16H), 6.27–3.78 (m, 14H), 2.34–1.65 (m, 8H). Anal.
calcd for C38H38N6O4: C, 71.01%; H, 5.96%; N, 13.07%.
Found: C, 70.98%; H, 5.99%; N, 13.01%.
Acknowledgements
3.14. 2,6-Bis(N-benzyl-Z-prolinylaminomethyl)-pyridine
17
Project supported by the National Natural Science
Foundation of China (Grant No. 29872023, 20172001).
We thank Dr. Ying Gao for the help with molecular
modeling.
The mixture of carbobenzyloxyproline (3.36 g, 13.48
mmol) and DCC (2.78 g, 13.48 mmol) in CH2Cl2 (10
mL) was stirred with cooling in an ice bath for 0.5 h. At
the same temperature, a solution of 12 (2.14 g, 6.74
mmol) in CH2Cl2 was added dropwise to the reaction
mixture. After stirring for additional 2 h at ambient
temperature, the reaction mixture was filtered. The
filtrate was concentrated to dryness and the residue was
purified by column chromatography on silica gel using
ethyl acetate–petroleum ether (3:1) as eluent to afford
viscous oil (2.83 g, 65.4% yield). [h]2D0=−3.2 (c 2.37,
CHCl3); MS (FAB): m/z 780 (M+H)+; IR (KBr): w
3381, 3030, 1660, 1593, 1537, 1416, 1355, 1206, 1120
References
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1
cm−1; H NMR (CDCl3): l 7.38–7.22 (m, 21H), 5.18–
5.08 (m, 4H), 4.88–4.28 (m, 10H), 3.72–3.51 (m, 4H),
2.08–1.94 (m, 8H). Anal. calcd for C47H49N5O6: C,
72.38%; H, 6.33%; N, 8.98%. Found: C, 72.41%; H,
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3.15. 2,6-Bis(N-benzyl-Z-prolinylaminomethyl)pyridine
hydrobromide 18
Compound 17 (2 g, 2.56 mmol) was dissolved in 33%
HBr–HOAc (12 mL). The mixture was stirred at rt for
2 h and then was concentrated to dryness. Anhydrous
ethyl ether (25 mL) was added to the residue, and the
mixture was stirred for additional 1 h. The mixture was
then filtered to give a light yellow powder (1.71 g, ca.
100% yield). Mp 166–168°C; MS (FAB): m/z 512 (M+
H)+; IR (KBr): w 3415, 2928, 1653, 1451, 1366, 1233,
1169 cm−1; 1H NMR (DMSO): l 9.45 (m, 1H), 8.64 (m,
1H), 7.80 (m, 1H), 7.38–7.16 (m, 12H), 4.71–4.40 (m,
10H), 3.29–3.20 (m, 4H), 2.34 (m, 2H), 1.92–1.82 (m,
6H).
3.16. Pyridine–proline macrocycle 19
A solution of freshly prepared 2,6-pyridinedicarbonyl
dichloride (0.42 g, 2 mmol) in dry dichloromethane (20
mL) was added dropwise to well-stirred solution of
compound 18 (1.34 g, 2 mmol) and triethylamine (1.41
mL, 10 mmol) in dry CH2Cl2 (150 mL) at 0°C over 0.5