Synthesis and Characterization of Pyridine-Based Polyamido-Polyester Optically Active Macrocycles and Enantiomeric Recognition for D- and L-Amino Acid Methyl Ester Hydrochloride

Article abstract of DOI:10.1021/jo9913715

Five new chiral macrocycles, 3a-e, have been prepared by the acylation cyclization of chiral diamine dihydrobromide intermediates 2a-c with 2,6-pyridinedicarbonyl dichloride in highly diluted solution at room temperature. The chiral diesters 1a-c needed f

Full text of DOI:10.1021/jo9913715

J . Org. Chem. 2000, 65, 2933-2938
2933
Syn th esis a n d Ch a r a cter iza tion of P yr id in e-Ba sed
P olya m id o-P olyester Op tica lly Active Ma cr ocycles a n d
En a n tiom er ic Recogn ition for D- a n d L-Am in o Acid Meth yl Ester
Hyd r och lor id e
Hongwu Zhao and Wenting Hua*
Department of Chemistry, Peking University, Beijing 100871, PR China
Received August 30, 1999
Five new chiral macrocycles, 3a -e, have been prepared by the acylation cyclization of chiral diamine
dihydrobromide intermediates 2a -c with 2,6-pyridinedicarbonyl dichloride in highly diluted solution
at room temperature. The chiral diesters 1a -c needed for the preparation of the macrocycles were
obtained from condensation of corresponding N-(Z)-L-amino acids and 2,6-bishydroxymethyl pyridine
in the presence of DCC and DMAP. The enantiomeric recognition of chiral macrocycles 3a -e for
D- and L-amino acid methyl ester hydrochlorides has been characterized by fluorescence spectra,
which indicate that some of them exhibited significant chiral recognition for the enantiomers of D-
and L-amino acid methyl ester hydrochlorides. The stoichiometry and binding constants of 3a -L-
Am2 and 3c-L-Am2 complexes have been determined. An X-ray analysis of the chiral macrocycle
3b show that the chiral ligand is rather rigid and strained.
In tr od u ction
ques,13-15 transport of amides through liquid mem-
branes,16 and partial resolution of amino acids on silica
gel or polystyrene to which chiral host materials are
bonded.17 Lehn and co-workers have found that reactivity
of the thiolyzation reaction of certain p-nitrophenyl esters
increased dramatically after the addition of chiral host
molecules.18 In 1987, the Nobel Prize was awarded to
three pioneers in this field, Pedersen, Lehn, and Cram.
From then on, molecular recognition has attracted more
and more chemists. Our interest has focused on the
enantiomeric recognition of the synthetic chiral macro-
cycles for D- and L-amino acid methyl ester hydrochloride
(Am).
Molecular recognition exists in many biochemical
processes. Some examples are antibody-antigen interac-
tions, biocatalysis reactions, the DNA double helix, and
the use of single enantiomeric forms of amino acids and
sugars in metabolic pathways. The successful design,
synthesis, and use of chiral macrocyclic ligands capable
of the selective recognition of other species is of great
interest to workers in catalysis,1,2 separations,3,4 enzyme
mimics,5-7 and other areas involving chiral molecular
recognition. The study of the enantiomeric recognition
of amines and protonated amines by chiral macrocyclic
ligands8-12 is of significance because these compounds are
basic blocks of biological molecules with versatile abilities
to form complexes with a variety of molecules. Careful
characterization of such synthetic systems could lead to
better understanding of natural systems. Cram and co-
workers have reported enantiomeric recognition of or-
ganic ammonium salts by solvent extraction techni-
We here reported the synthesis of five new chiral
macrocyclic receptors, 3a -e, and their enantiomeric
recognition for different amino acid methyl ester hydro-
chlorides (Am1 ) alanine-OMe‚HCl; Am2 ) phenylala-
nine-OMe‚HCl; Am3 ) histidine-OMe‚2HCl). We also
report the X-ray crystal structure of 3b and the stoichi-
ometry and binding constant of 3a -L-Am2 and 3c-L-Am2
complexes.
(1) Groves, J . T.; Viski, P. J . Org. Chem. 1990, 55, 3628.
(2) O’Malley, S.; Kodadek, T. Organometallics 1992, 11, 2299.
(3) Helgson, R. C.; Koga, K.; Timko, J . M.; Cram, D. J . J . Am. Chem.
Soc. 1973, 95, 3021.
(4) Gasparrini, F.; Misiti, D.; Borchardt, A.; Burger, M. T.; Still, W.
C. J . Org. Chem. 1995, 60, 4314.
(5) Breslow, R.; Czanik, A. W.; Lauer, M.; Leppkes, R.; Winkler, J .;
Zimmerman, S. J . Am. Chem. Soc. 1986, 108, 1969.
(6) Talma, A. G.; J ouin, P.; De Vries, J . G.; Troostwijk, C. B.;
Werumeus Buning, G. H.; Waninge, J . K.; Visscher, J .; Kellogg, R. M.
J . Am. Chem. Soc. 1985, 107, 3981.
Resu lts a n d Discu ssion
Five new chiral macrocycles were prepared by acyla-
tion of chiral diamine dihydrobromide intermediates
2a -c with 2,6-pyridinedicarbonyl dichloride in highly
diluted solution at room temperature as shown in Schemes
1 and 2.
(7) Chao, Y.; Cram, D. J . J . Am. Chem. Soc. 1976, 98, 1015.
(8) Huszthy, P.; Bradshaw, J . S.; Zhu, C. Y.; Izatt, R. M.; Lifson, S.
J . Org. Chem. 1991, 56, 3330.
(9) Naemura, K.; Mizo-oku, T.; Kamada, K.; Hirose, K.; Tobe, Y.;
Sawada, M.; Takai, Y. Tetrahedron: Asymmetry 1994, 5, 1549.
(10) Echegoyen, L.; Martinez-Diaz, M. V.; de Mendoza, J .; Torres,
T.; Vicente-Arana, M. J . Tetrahedron 1992, 48, 9545.
(11) Naemura, K.; Ogasahara, K.; Hirose, K.; Tobe, Y. Tetrahe-
dron: Asymmetry 1997, 8, 19.
(13) Gokel, G. W.; Timko, J . M.; Cram, D. J . J . Chem. Soc., Chem.
Commun. 1975, 394.
(14) Lingenfelter, D. S.; Helgeson, R. C.; Cram, D. J . J . Org. Chem.
1981, 46, 393.
(15) Artz, S. P.; deGrandpre, M. P.; Cram, D. J . J . Org. Chem. 1985,
50, 1486.
(16) Newcomb, M.; Toner, J . L.; Helgeson, R. C.; Cram, D. J . J . Am.
Chem. Soc. 1979, 101, 4941.
(17) Sogah, G. D. Y.; Cram, D. J . J . Am. Chem. Soc. 1979, 101, 3035.
(18) Lehn, J . M.; Sirlin, C. J . Chem. Soc., Chem. Commun. 1978,
949.
(12) Yamamoto, K.; Fukushima, H.; Okamoto, Y.; Hatada, K.;
Nakazaki, M. J . Chem. Soc., Chem. Commun. 1984, 1111.
10.1021/jo9913715 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/19/2000

2934 J . Org. Chem., Vol. 65, No. 10, 2000
Sch em e 1. P r ep a r a tion of Ch ir a l Ma cr ocycles 3a -d
Zhao and Hua
Sch em e 2. P r ep a r a tion of Ch ir a l Ma cr ocycle 3e
1
The key intermediates 1a -c were prepared from
condensation of the corresponding N-(Z)-L-amino acids
and 2,6-bishydroxymethyl pyridine in the presence of
DCC and DMAP. The acylation of chiral diamine dihy-
drobromide 2a with 2,6-pyridinedicarbonyl dichloride
afforded [1 + 1] cyclization product 3a and [2 + 2]
cyclization product 3c simultaneously. Similarly, 2b gave
[1 + 1] product 3b and [2 + 2] product 3d . However, for
the reaction of 2c with 2,6-pyridinedicarbonyl dichloride
under the same conditions, only the [1 + 1] product 3e
was obtained, with no detectable [2 + 2] product. In
general, the yields of [1 + 1] products are higher than
those of the corresponding [2 + 2] products. Structures
of these macrocycles are identified by H NMR, MS, IR,
and elemental analysis.
The enantiomeric recognition for D- and L-amino acid
methyl ester hydrochlorides by these chiral macrocyclic
receptors has been characterized by fluorescence spectra.
It is evident from the differences in fluorescence intensity
and fluorescence maximum that these chiral ligands
exhibit significant chiral recognition for the enantiomers
of amino acid methyl ester hydrochlorides.
As shown in Table 1, the enantiomeric recognition for
D- and L-alanine methyl ester hydrochlorides (Am1) by
chiral macrocycles 3a -e differs, among which 3c and 3e
show chiral recognition better than that of the others.

Polyamido-Polyester Optically Active Macrocycles
J . Org. Chem., Vol. 65, No. 10, 2000 2935
Ta ble 1. Ch ir a l Recogn ition Da ta Deter m in ed by
F lu or escen ce Sp ectr a for th e In ter a ction s of
P yr id in e-Con ta in in g Ch ir a l Liga n d s w ith En a tiom er s of
Am in o Acid Meth yl Ester Hyd r och lor id es
ligand
cation
λ max (nm)
∆λ (nm)
I/I0 (rel intensity)
3a
350
342
350
350
400
350
350
392
362
374
360
350
362
400
348
400
348
352
400
352
351
392
354
366
380
366
350
364
350
400
450
350
400
348
340
D-Am1
L-Am1
D-Am2
L-Am2
D-Am3
L-Am3
8
50
0
0.68
0.68
0.84
1.25
0.67
0.66
3b
3c
3d
3e
D-Am1
L-Am1
D-Am2
L-Am2
D-Am3
L-Am3
12
10
38
1.08
0.84
1.32
1.21
0.91
0.98
D-Am1
L-Am1
D-Am2
L-Am2
D-Am3
L-Am3
52
48
1
0.37
0.85
0.69
1.50
0.72
0.77
F igu r e 1. The molecular structure of compound 3b with the
atom-labeling scheme. Displacement ellipsoids are shown at
the 50% probability level for non-H atoms; H atoms are shown
as spheres of arbitrary radii.
D-Am1
L-Am1
D-Am2
L-Am2
D-Am3
L-Am3
12
14
16
1.19
0.96
1.01
1.19
1.96
0.82
D-Am1
L-Am1
D-Am2
L-Am2
D-Am3
L-Am3
50
50
8
0.78
4.69
0.84
1.25
1.05
0.99
Shimadzu RF540 spectrofluorophotometer was used to recall
all Fluorescence specrta. Equimolar amounts of ligand and salt
was dissolved in the solvent (CH3OH/CH2Cl2)1:3, v/v). Am1
)
Alanine Methyl Ester Hydrochloride.Am2 ) Phenylalanine Methyl
Ester Hydrochloride. Am3 ) Histidine Methyl Ester Dihydrochlo-
ride.
Chiral ligands 3a , 3c, and 3e all show excellent chiral
recognition for enantiomers of phenylalanine methyl
ester hydrochloride (Am2), whereas 3b and 3d do not.
As for D- and L-histidine methyl ester dihydrochloride
(Am3), only 3b exhibits good recognition, and 3a , 3c, 3d ,
and 3e show little or no enantiomeric recognition.
The structure of chiral ligand 3b has been determined
by X-ray crystallography and is shown in Figure 1.
Although the structure of the ligand allows for symmetry
including a 2-fold axis, the conformation of the molecule
in the solid state does not contain any such symmetry.
The dihedral angle between the two aromatic pyridine
rings is 37.4°, which makes the chiral ligand rather rigid
and strained. The asymmetric steric structure of 3b will
contribute to chiral recognition.
CPK molecular model examination and molecular
structure of compound 3b show that the 3b-L-Am and
3b-D-Am complexes each have two possible conforma-
tions. In the two conformations of the 3b-L-Am complex,
there exists steric repulsion between the alkyl group on
the chiral carbon of amino acid methyl ester hydrochlo-
ride and the isopropyl on the chiral carbon of compound
3b. However, in one of the two possible conformations of
the 3b-D-Am complex, such steric repulsion is less severe.
The different degree of steric repulsion leads to the
F igu r e 2. The packing diagram of the unit cell along the C
axis of 3b with H-atoms omitted.
different stabilities of 3b-L-Am and 3b-D-Am complexes.
Therefore, we conclude that the different stability of the
two diasteromeric complexes can result in enantiomeric
recognition of compound 3b for D- and L-amino acid
methyl ester hydrochlorides. The facts have also dem-
onstrated that structural complementarity between host
and guest must be responsible for the enantiomeric
recognition.
The X-ray structure of 3b reveals that a water molecule
is bonded to the chiral macrocycle by hydrogen bonds,
as shown in Figure 2. It could be inferred that amino
methyl ester hydrochlorides are anchored to the chiral
macrocycles via tripod hydrogen bonding. It is likely that
two pyridine nitrogen atoms and an amide nitrogen of
compound 3b with three hydrogen atoms of the am-
monium cation are involved and that the interaction
imparts stability to the diastereomeric complexes 3b-D-
Am and 3b-L-Am. The fact that only 3c and 3e show
marked chiral recognition for D- and L-Am1 leads to the
conclusion that the steric repulsive interaction between
the alkyl groups on the chiral carbon of hosts and guests
is responsible. In addition, we also noticed that chiral

2936 J . Org. Chem., Vol. 65, No. 10, 2000
Zhao and Hua
F igu r e 3. Fluorescence emission spectra changes of 3a in the
absence and the presence of equimolar amounts of L-Am2: 3a
(- - -); 3a + L-Am2 (s). The excitation wavelength was 300 nm.
F igu r e 5. The J ob’s plot of fluorescence intensity (I) vs
[L-Am2]/[3a ]; total moles 5 × 10-4, the molar ratio of L-Am2 to
3a was varied: 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2.
F igu r e 4. Fluorescence emission spectra changes of 3c in the
absence and the presence of equimolar amounts of L-Am2: 3c
(- - -); 3c + L-Am2 (s). The excitation wavelength was 300 nm.
F igu r e 6. The J ob’s plot of fluorescence intensity (I) vs [L-Am]/
[3c]; total moles 5 × 10-4, the molar ratio of L-Am2/3c was
varied: 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2.
macrocycles 3a -e each show better chiral recognition for
Am2 than for Am1, and that suggests that not only steric
effects and hydrogen bond but also π-π stacking between
the aromatic groups of hosts and guests may play an
important role in chiral recognition. The reason that the
chiral macrocycles 3a , 3c, and 3e show little or no
enantiomeric recognition for D- and L-Am3 is not clear.
The fact mentioned above indicates that hydrogen bond-
ing and π-π stacking between hosts and guests lead to
the formation of the complex, while steric interaction
contributes to enantiomeric recognition.
As shown in the Figure 3, when L-Am2 is added to the
system of 3a , a new fluorescent emission peak for the
3a -L-Am2 complex can be observed at 400 nm. Similar
fluorescence emission spectra have also been observed
when L-Am2 is added to the system of 3c as shown in
Figure 4; the peak at 400 nm is ascribed to the 3c-L-Am2
complex.
To determine the binding constant, we first tried to
estimate the stoichiometry of the complex formed be-
tween chiral macrocycle and L-amino acid methyl ester
hydrochloride. Figure 5 shows that the fluorescence
emission intensity of the 3a -L-Am2 complex at 400 nm
increases with increasing concentration of L-Am2 until
the mole ratio of L-Am2 to the chiral macrocycle 3a is
near 0.92. However, as the mole ratio keeps on increas-
ing, the maximum fluorescence emission intensity of the
3a -L-Am2 complex decreases. A similar phenomenon was
also found for the interaction of 3c with L-Am2, as shown
in Figure 6. The maximum fluorescence emission inten-
sity corresponded to a mole ratio of 1:1.
From results mentioned above, it can be concluded that
the stoichiometry of 3a -L-Am2 and 3c-L-Am2 complexes
is approximately 1:1. The binding of L-Am2 to 3a and 3c
may be described in terms of the Scatchard equation.
Substituting for Nh and n in the Scatchard equation, Nh /
19
[C] ) n/Kd - Nh /Kd, yields F/[C] ) F∞/Kd - F/Kd, where
[C] is the free L-Am2 concentration and Kd is the dis-
sociation constant. F is the measured fluorescence in-
tensity, and F∞ is the fluorescence intensity in the
presence of infinite L-Am2 concentration. Kd may be found
from the slope of a linear plot of F/[C] versus F.
A series of assay mixtures were made up to contain a
constant concentration of 3a and 3c of 1 × 10-5 mol L-1
.
These mixtures varied in L-Am2 content from 1.65 × 10-4
mol L-1 to 8.00 × 10-4 mol L-1. The results are shown in
Figures 7 and 8. From the linear Scatchard plot, we can
obtain the binding constant for the interaction of 3a with
L-Am2 as 8.84 × 102 M-1 and that of 3c with L-Am2 as
9.52 × 102 M-1
.
(19) Scatchard, G. Ann. N.Y. Acad. Sci. 1949, 51, 660.

Polyamido-Polyester Optically Active Macrocycles
J . Org. Chem., Vol. 65, No. 10, 2000 2937
pyridinedimethanol and pyridine 2,6-bisdicarbonyl chloride
were prepared as reported.20,21
P r ep a r a tion of N-Ca r boben zyloxyl-L-a la n in e Diester
1a . In dry CH2Cl2 (75 mL) were dissolved 2,6-pyridinedimeth-
anol (500 mg, 3.6 mmol), N-carbobenzyloxyl-L-alanine (1.8 g,
8 mmol), 4-(dimethylamino)pyridine (200 mg, 1.62 mmol), and
1.3-dicyclohexylcarbodiimide (1.7 g, 8.16 mmol). After the
reaction was stirred overnight at room temperature, the
resulting white suspension was filtered. The filtrate was
evaporated. The residue was chromatographed on silica gel
using petroleum ether/ethyl acetate 1/1 as eluent to give a
colorless oil (yield 1.5 g, 75.8%). [R]25 ) -15.5 (c 1, CH2Cl2).
D
MS(FAB+): m/z 550 (M + H)+. 1H NMR: δ 7.8 (m, 3H), 7.3
(m, 10H), 5.2 (m, 4H), 5.0 (s, 4H), 4.2 (t, 2H), 1.3 (d, 6H). IR
(KBr): 3349, 1747, 1689, 1532, 1456, 1261, 1076 cm-1. Anal.
Calcd for C29H31N3O8 (549): C63.38, H5.69, N7.65, O23.28.
Found: C63.08, H5.89, N7.78, O23.25.
F igu r e 7. Scatchard plot of L-Am2 binding to 3a . Concentra-
tions in the systems: [3a ] 1.0 × 10-5 mol L-1, [L-Am2] ) 2.5 ×
10-4, 3.4 × 10-4, 4.0 × 10-4, 5.5 × 10-4, 6.8 × 10-4, 7.5 × 10-4
mol L-1, respectively.
P r ep a r a t ion of N-Ca r b ob en zyloxyl-L-va lin e Diest er
1b. Compound 1b was prepared as described above as a
colorless oil (yield 92%). [R]25 ) -12.6 (c 1, CH2Cl2). MS-
D
(FAB)+: m/z 606 (M + H). 1H NMR: δ 7.8 (m, 3H), 7.3 (m,
10H), 5.2 (m, 4H), 5.0 (m, 4H), 4.0 (m, 2H), 2.11 (m, 2H), 0.9
(d, 12H). IR (KBr): 3371, 2966, 1713, 1593, 1527, 1459, 1228,
1192, 1044 cm-1. Anal. Calcd for C33H39N3O8 (605): C65.44,
H6.49, N6.94, O21.13. Found: C65.29, H6.54, N6.90, O21.27.
P r ep a r a tion of N-Ca r boben zyloxyl-L-p r olin e Diester
1c. Compound 1c was prepared as described above as a
colorless oil (yield 92.4%). [R]25 ) -81.0 (c 1, CH2Cl2). MS-
D
(FAB+): m/z 602 (M + H)+. 1H NMR δ 7.26-7.56 (m, 13H),
5.27 (d, 2H), 5.11 (m, 6H), 4.51 (m, 2H), 3.64 (m, 4H), 2.26 (d,
2H), 2.11(brs, 2H), 1.95 (m, 4H). IR (KBr): 3328, 2944, 1751,
1706, 1417, 1353, 1169 cm-1. Anal. Calcd for C33H35N3O8
(601): C65.88, H5.86, N6.98, O21.28. Found: C66.18, H5.89,
N7.22, O20.98.
P r ep a r a tion of L-Ala n in e Diester Dia m in e Dih yd r o-
br om id e 2a . N-Carbobenzyloxyl-L-alanine diester (1 g, 1.8
mmol) was dissolved in 10 mL of 33% HBr-HOAc. The
mixture was stirred at room temperature for 2 h, and the
solution was the concentrated to dryness. After that, 10 mL
of anhydrous ethyl ether was added to the residue, and the
mixture was stirred for an additional 1 h and filtered to give
a light yellow powder (yield 0.80 g, ca. 100%). MS(FAB+): m/z
282 (M + H)+. 1H NMR: δ 8.43 (brs, 6H), 7.93 (t, 1H), 7.46 (d,
2H), 5.31 (m, 4H), 4.27 (t, 2H), 1.49 (d, 6H). IR (KBr): 3416,
F igu r e 8. Scatchard plot of L-Am2 binding to 3c. Concentra-
tions in the systems: [3c] 1.0 × 10-5 mol L-1, L-Am2 ) 2.5 ×
10-4, 3.4 × 10-4, 4.0 × 10-4, 5.5 × 10-4, 6.8 × 10-4, 7.5 × 10-4
mol L-1, respectively.
2931, 2560, 1764, 1628, 1512, 1235, 1186, 1117 cm-1
.
In summary, we can draw the following conclusions
from the above-mentioned facts: (1) The chiral macro-
cycles 3a -e show evident interaction with amino acid
methyl ester hydrochloride, and some of them recognize
D- and L- enantiomers of amino acid methyl ester
hydrochloride remarkably. (2) It is a simple method to
use fluorescent spectra to determine the degree of
interaction of enatiomeric recognition for D- and L-
enantiomers of amino acid methyl ester by these artificial
receptors.
P r ep a r a tion of L-Va lin e Diester Dia m in e Dih yd r obr o-
m id e 2b. Compound 2b was prepared as described above as
a light yellow powder (yield ca. 100%). MS(FAB+): m/z 338
(M + H)+. 1H NMR: δ 8.43 (brs, 6H), 7.93 (t, 1H), 7.52 (m,
2H), 5.36 (m, 4H), 4.06 (brs, 2H), 2.23 (m, 2H), 1.06 (m, 12H).
IR (KBr): 3426, 2969, 1749, 1629, 1510, 1465, 1289, 1216,
1162, 1041 cm-1
.
P r ep a r a tion of L-P r olin e Diester Dia m in e Dih yd r o-
br om id e 2c. Compound 2c was prepared as described above
as a light yellow powder (yield ca. 100%). MS(FAB+): m/z 334
1
(M + H)+. H NMR: δ 9.61 (brs, 2H), 8.99 (brs, 2H), 7.93 (t,
1H), 7.49 (d, 2H), 5.34 (m, 4H), 4.55 (m, 2H), 3.25 (m, 4H),
2.31 (m, 2H), 2.10 (m,2H), 1.96 (m, 4H). IR (KBr): 3416, 2925,
2548, 1890, 1753, 1649, 1626, 1569, 1391, 1242, 1197, 1064
Exp er im en ta l Section
cm-1
.
P r ep a r a tion of Ch ir a l Ma cr ocyclic Liga n d s 3a a n d 3c.
A solution of freshly prepared pyridine 2,6-bisdicarbonyl
chloride (200 mg, 0.97 mmol) in dry dichloromethane (10 mL)
was added dropwise to a well-stirred solution of diester
diamine dihydrobromide 2a (0.43 g, 0.97 mmol) and triethy-
lamine (0.66 mL, 4.12 mmol) in dry CH2Cl2 (120 mL) at 0 °C
over 30 min. The reaction mixture was stirred for an additional
12 h at room temperature. The resulting white suspension was
filtered, and the filtrate was evaporated. The residue was
chromatographed on silica gel using dichlormethane/ethyl
acetate/petroleum ether/methanol (2/1/0.1/0.1) as eluent to give
Infrared spectra were obtained on
a Bruker Vector22
instrument.1HNMR spectra were recorded on a Bruker ARX
400 spectrometer. Chemical shifts are indicated in δ values
(ppm) downfield from internal TMS. Multiplicities were re-
corded as s (singlet), d (double), t (triplet), and m (multiplet).
FAB-mass spectra were obtained on a VG-ZAB-HS mass
spectrometer. Elemental analyses were carried out on Carlo-
Erba-106 or Elementar Vario EL instruments. Melting points
were taken on an XT-4 melting point apparatus and are
uncorrected. Optical rotations were measured on a Perkin-
Elmer 241 MC. 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. The 2,6-
(20) Baker, W.; Buggle, K. M.; Mcomie, J . E. W.; Watkins, D. A. M.
J . Chem. Soc. 1958, 3594.
(21) Markees, D. G. J . Org. Chem. 1958, 23, 1030.

2938 J . Org. Chem., Vol. 65, No. 10, 2000
Zhao and Hua
1043 cm-1. Anal. Calcd for C24H28N4O6 (468): C61.53, H6.02,
Ta ble 2. Cr ysta l Da ta a n d Str u ctu r e Refin em en t for 3b
N11.96, O20.49. Found: C61.56, H6.31, N11.66, O20.47. 3d :
empirical formula
formula weight
temperature
wavelength
crystal system, space group
unit cell dimensions
C24H28N4O7
484.50
293(2) K
0.71073 A
yield 5.2%. [R]25 ) -60.7 (c 1, CH2Cl2). Mp 84-86 °C. MS-
D
(FAB+): m/z 937 (M + H)+. H NMR: δ 9.05 (d, 4H), 8.21 (t,
1
6H), 7.76 (t, 2H), 7.36 (d, 4H), 5.23 (m, 8H), 4.45 (m, 4H), 2.31
(m, 4H), 0.90 (m, 24H). IR (KBr): 3409, 2965, 2875, 1745, 1684,
1524, 1462, 1447, 1391, 1372, 1315, 1187 cm-1. Anal. Calcd
orthorhombic, P2(1) 2(1) 2(1)
a ) 11.816(2) Å, R ) 90°
b ) 20.541(4) Å, â ) 90°
c ) 10.066(2) Å, γ ) 90°
2443.1(8) Å3
for
C48H56N8O12 (936): C61.53, H6.02, N11.96, O20.49.
Found: C61.68, H6.10, N11.77, O20.45.
volume
Z, calcd density
absorption coefficient
F(000)
crystal size
P r ep a r a tion of Ch ir a l Ma cr ocycle Liga n d 3e. Com-
pound 3e was prepared as described above as a white solid.
4,1.317 mg/m3
0.098 mm-1
3e: yield 17.3%. [R]25 ) -213.36 (c 1, CH2Cl2). mp 258-260
D
°C. MS(FAB+): m/z 46 5(M + H)+. 1H NMR: δ 8.0 (m, 1H),
7.9 (t, 2H), 7.7 (t, 1H), 7.3 (d, 1H), 7.2 (d, 1H), 5.5 (m, 1H), 5.1
(m, 2H), 4.7 (s, 2H), 4.5 (d, 1H), 4.0 (s, 1H), 3.9 (s, 1H), 3.7 (s,
1H), 3.6 (s, 1H), 2.2 (s, 1H), 2.1 (d, 1H), 2.0 (m, 2H), 1.9 (m,
4H). IR (KBr): 3451, 2969, 2930, 1750, 1634, 1579, 1441, 1399,
1175, 1086 cm-1. Anal. Calcd for C24H24N4O6 (464): C62.06,
H5.21, N12.06, O20.67. Found: C62.21, H5.27, N11.85, O20.67.
X-r a y Str u ctu r a l Deter m in a tion of Com p ou n d 3b.
Computing data collection: MSC/AFC Diffractometer Control
Software (Molecular Structure Corporation, 1994). Cell refine-
ment: MSC/AFC Diffractometer Control Software. Data re-
duction: SHELXS 97 (Sheldrick, G. M., 1997). Structure
solution: SHELXS 97. Structure refinement: SHELXL 97.
Molecular graphics: Interactive Molecular Graphics XP, Ver-
sion 4.2 for MS DOS (1990). Crystal data and experimental
conditions are shown in Table 2.
10 024
0.45 mm × 0.35 mm × 0.15 mm
θ range for data collection
index ranges
2.25° to 24.99°
0 e h e 14, 0 e k e 24, 0 e l e 11
2429/2429 [R(int) ) 0.0000]
24.99 99.0%
reflections collected/unique
completeness to 2θ
absorption correction
max and min transmisson
refinement method
data/restraints/parameters
goodness-of-fit on F2
final R indices [I > 2σ(I)]
R indices (all data)
ψ scan
1.00000 and 0.5874
full-matrix least-squares on F2
4517/5/512
1.029
R1 ) 0.0598, WR2 ) 0.1514
R1 ) 0.0849, WR2 ) 0.1691
absolute structure parameter -1(2)
extinction coefficient
largest diff. peak and hole
0.009(3)
0.291 and -0.356 e/Å3
3a (60 mg, 14.9%) and 3c (20 mg, 2.48%) as white solids. 3a :
[R]25D ) -79.64 (c 1, CH2Cl2). Mp 186-188 °C. MS(FAB+): m/z
Ack n ow led gm en t. We thank Prof. Hongcheng Gao,
Department of Technical Physics, Peking University, for
his assistance in determining the stoichiometry and
binding constants of the complexes and Prof. Xianglin
J in, Department of Chemistry, Peking University, for
the X-ray crystal structure determination of compound
3b.
1
413 (M + H)+. H NMR: δ 9.19 (d, 2H), 8.14 (m,3H), 7.76 (t,-
1H), 7.40 (d, 2H), 5.21 (d, 2H), 5.08 (d, 2H), 4.70 (t, 2H), 1.52
(d, 6H). IR (KBr): 3397, 3295, 2993, 2939, 1741, 1679, 1652,
1528, 1452, 1239, 1136, 1113, 1059 cm-1. Anal. Calcd for
C
20H20N4O6 (412): C58.25, H4.89, N13.59, O23.28. Found:
C58.16, H4.98, N13.38, O23.48. 3c: [R]25 ) -26.8 (c 1, CH2-
D
Cl2). Mp 118-120 °C. MS(FAB+): m/z 825 (M + H)+. 1H
NMR: δ 9.54 (d, 4H), 8.23 (m,6H), 7.69 (m,2H), 7.26 (d, 4H),
5.21 (m, 8H), 4.63 (m, 4H), 1.54 (d, 12H). IR (KBr): 3448, 2938,
1746, 1671, 1532, 1453, 1176, 1135, 1059 cm-1. Anal. Calcd
Su p p or tin g In for m a tion Ava ila ble: Fluorescence spec-
tra data of enatiomeric recognition for D- and L-amino acid
methyl ester hydrochloride (2.0 × 10-3 M) by chiral macro-
cycles 3a -e (2.0 × 10-5 M) (25 °C, CH3OH/CH2Cl2 ) 1:3 v/v,
host/guest ) 1:1 mol/mol); atomic coordinates (× 104) and
equivalent istropic displacement coefficients (mtmex 105 nm3)
of chiral macrocyclic ligand 3b, Ueq defined as one-third of the
trace of the orthogonalized Uij tensor (Table 3); and ring torsion
angles (deg) of 3b with esd values (Table 4). This material is
available free of charge via the Internet at http://pubs.acs.org.
for
C40H40N8O12 (824): C58.25, H4.89, N13.59, O23.28.
Found: C58.02, H4.97, N13.37, O23.64.
P r ep a r a tion of Ch ir a l Ma cr ocyclic Liga n d s 3b a n d 3d .
Compounds 3b and 3d were prepared as described above as
white solids. 3b: yield 12.5%. [R]25 ) -211.15 (c 1, CH2Cl2).
D
Mp 156-158 °C. MS(FAB+): m/z 469 (M + H)+. H NMR: δ
1
8.5 (d, 2H), 8.20 (m, 3H), 7.83 (t, 1H), 7.44 (d, 2H), 5.49 (d,
2H), 5.05 (d, 2H), 4.66 (m, 2H), 2.32 (m, 2H), 0.85 (m, 2H). IR
(KBr): 3410, 2964, 1751, 1682, 1519, 1443, 1373, 1279, 1228,
J O9913715