New macrocycles with planar chirality - Synthesis and determination of absolute configurations

Article abstract of DOI:10.1002/chem.200501409

A versatile system for preparing macrocyclic compounds with planar chirality is presented. In this system chiral diazacoronands are synthesized readily from lariat-type diesters 13 and 14 and unsymmetrical diamines 7, 8,12,15, and 16 under non-high-diluti

Full text of DOI:10.1002/chem.200501409

FULL PAPER
DOI: 10.1002/chem.200501409
New Macrocycles with Planar Chirality—Synthesis and Determination of
Absolute Configurations
Jarosław Kalisiak,[a] Paweł Skowronek,[b] Jacek Gawron´ski,[b] and Janusz Jurczak*[a, c]
Abstract: A versatile system for preparing macrocyclic compounds with planar
chirality is presented. In this system chiral diazacoronands are synthesized readily
from lariat-type diesters 13 and 14 and unsymmetrical diamines 7, 8, 12, 15, and 16
under non-high-dilution conditions. The title compounds were subjected to struc-
tural analysis by X-ray crystallography and circular dichroism spectroscopy, and
absolute configurations for two representative examples (compounds 2 and 3)
were assigned by molecular modeling. The correctness of the theoretical approach
was verified by the crystallographic results obtained experimentally.
Keywords: chirality · circular di-
chroism · configuration determina-
tion · macrocycles · supramolecular
chemistry
Introduction
In our studies of the synthesis of macrocyclic compounds,
we have applied the double amidation reaction, in which di-
methyl a,w-dicarboxylates are treated with primary a,w-di-
Chiral recognition is one of the most important and fascinat-
ing areas in supramolecular chemistry.[1] Over the last few
decades, large numbers of chiral macrocyclic receptors have
been synthesized and subjected to host–guest investigations.
Most of these have a center[2] and/or an axis[3] as a chiral ele-
ment, but less attention has been paid to receptors possess-
ing planar chirality. This is probably because planar chiral
macrocyclic compounds are based mostly on small, rigid cy-
clophane backbones with smaller numbers of donor atoms[4]
and, although suitable for construction of ligands for asym-
metric synthesis,[5] they are completely inefficient in supra-
molecular applications. Among numerous examples of artifi-
cial receptors, only a few of those possessing planar chirality
possess a larger macroring structure with donor atoms.[6]
Therefore, the synthesis of efficient receptors with planar
chirality requires certain limitations to be overcome: 1) the
size of the macroring, and 2) the presence of the donor
groups and/or atoms in the macroring structure.
A
of the amide groups, which exhibit dual complexing charac-
ter (C=O and N or NH), thereby enabling amide-based mo-
lecular receptors to bind metal[7] and ammonium cations,[8]
neutral organic molecules,[9] and anionic species.[10] The de-
signed planar chiral system has two essential requirements:
1) the presence of the large intraannular group that cannot
go through the macroring plane easily, with the effect that
the top and bottom sides of the molecule are different, and
2) the presence of a group that breaks the symmetry of the
molecule (Scheme 1).
In accordance with these rules, we recently presented the
synthesis and chiro-optical properties of four representative
macrocyclic compounds.[11] Racemic compounds 1–4 were
resolved into enantiomers by conducting chiral HPLC, and
their high enantiomeric stability, sufficient for potential su-
pramolecular applications, was corroborated.
Here, we present further studies relating to the synthesis
of diazacoronands with planar chirality from different a,w-
[a] Dr. J. Kalisiak, Prof. J. Jurczak
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01–224 Warsaw (Poland)
Fax : (+48)22-632-66-81
E-mail: jurczak@icho.edu.pl
´
[b] Dr. P. Skowronek, Prof. J. Gawronski
Department of Chemistry, A. Mickiewicz University
´
Grunwaldzka 6, 61–780 Poznan (Poland)
[c] Prof. J. Jurczak
Department of Chemistry, University of Warsaw
Pasteura 1, 02–093 Warsaw (Poland)
Scheme 1. Representation of planar chirality in macrocyclic compounds.
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4397

complex (BMS) to give the cor-
responding a,w-diamines 7 and
8 in good yields (Scheme 2).
Another interesting and suit-
able precursor for the prepara-
tion of an appropriate a,w-dia-
mine seems to be 2,3-dihydrox-
ypyridine (9), because its tauto-
meric analogue 3-hydroxypyri-
dinone can bind trivalent
cations, such as indium and gal-
lium,[16] and its complexes are
used for medical purposes.[17] It
is known that direct alkylation
of hydroxypyridines may yield
either N-alkylpyridones or al-
koxypyridines, due to tautomer-
ic equilibrium.[18] In our case,
the main tautomeric form
was
3-hydroxy-1H-pyridin-2-
one (10), and its elongation
with chloroacetonitrile gave the
diamine building blocks. Structural features of the title com-
pounds were also investigated, including their absolute con-
figurations, by X-ray diffraction and circular dichroism (CD)
spectroscopy. In the latter case, the CD spectra for the mini-
mum-energy conformers of macrocycles 2 and 3 were calcu-
lated by using the semiempirical ZINDO/S method and the
absolute configurations were assigned by comparing the ex-
perimentally observed and the calculated CD spectra.
Scheme 2. Synthesis of unsymmetrical a,w-diamines 7 and 8.
Results and Discussion
a,w-dinitrile 11, which was subsequently reduced with BMS
to give the desired diamine 12 (Scheme 3).
Synthesis of macrocycles: For the preparation of diazacoro-
nands with planar chirality, the double amidation reaction
was applied. In this reaction, introduced by Tabushi[12] and
developed in our laboratories,[13] dimethyl a,w-dicarboxy-
lates are treated with primary a,w-diamines in the presence
The synthesis of chiral diazacoronands was carried out as
shown in Scheme 4, with the appropriate diesters 13[11a] and
14,[11b] and the unsymmetrical diamines 7 and 8, and also 15
and 16.[11b] These latter two possess a bromine atom and an
ester group, respectively, which are susceptible to further
modification.
of base [MeOÀ or 1,8-diazabicyclo
[5.4.0]undec-7-ene
A
(DBU)] under non-high-dilution conditions. The initial stage
in the synthesis of chiral diaza-
coronands was the preparation
of the appropriate unsymmetri-
cal building blocks. According
to our previous experience, we
decided to synthesize the un-
symmetrical a,w-diamines from
appropriate a,w-dinitrile pre-
cursors. Alkyl functions (Me
and tBu) were used as groups
to break symmetry, and the cor-
responding compounds 5[14] and
6[15] were reduced smoothly
with borane dimethylsulfide Scheme 3. Synthesis of unsymmetrical a,w-diamine 12.
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New Macrocycles with Planar Chirality
FULL PAPER
X-ray studies: The synthesized
diazacoronands
crystallized
readily under diffusive condi-
tions and single crystals suitable
for X-ray analysis were ob-
tained for compounds 1–3, 19
and 20, and 23.
The solid-state conformation
of rac-1 shows a U-shaped ar-
rangement of the macroring
with both aromatic rings almost
parallel. Two bromine atoms
were detected with a half occu-
pation (Figure 1). The intraan-
nular group in compound 1 is
turned away from the macro-
ring and participates in two in-
tramolecular hydrogen bonds
Scheme 4. Synthesis of diazacoronands possessing planar chirality.
In general, the cyclization step proceeded smoothly and
the macrocyclic products were isolated in moderate yields of
10–38%. The lowest yield was obtained for derivative 20,
containing the ester group, presumably due to autoconden-
sation of the diamine 16. Surprisingly, the yields observed
for the O-benzyl derivatives (17–20) were higher than those
for their N-benzoyl analogues (1 and 2, 21 and 22), probably
due to an additional contribution from the benzyloxy
oxygen atom, during the macrocyclization step, to the inter-
action between the substrates and a template molecule,
with the amide group protons.
To examine the influence on the diazacoronand structure
of substitution of the bromine atom (in derivative 1) by the
ester group, single crystals of compound 2 were obtained.
Unfortunately, these included solvent molecules (MeOH)
and underwent destruction immediately upon removal from
the crystallization vial. X-ray measurements performed at
low temperature allowed merely an estimation of the struc-
ture of compound 2 with a large parameter R1=0.18; never-
theless, the structures of both diazacoronands 1 and 2 show
significant similarity (Figure 2).
which could be methanol and/or
(Scheme 5).
a
sodium cation
Enantiomers of diazacoronand 3 were obtained in a suffi-
cient quantity and their crystallization, performed in a meth-
anol/pentane diffusive system, gave single crystals suitable
for X-ray investigation (Figure 3). Structural analysis of the
enantiomer (+)-(Rp)-3 reveals typical intramolecular hydro-
gen bonds, also observed in the N-benzoyl derivative 1. The
presence of the heavy bromine atom in the structure al-
lowed the absolute configuration to be determined with a
reliable Flack parameter of À0.016(7).[19]
The structure of diazacoronand 19, containing a bromine
atom, also shows intramolecular hydrogen bonds between
the oxygen atom of the benzyloxy function and the protons
of the amide groups (Figure 4). Additionally, a p–p-type in-
teraction between a side arm and the bromobenzene unit is
Scheme 5.
As discussed above, another
unsymmetrical building block
employed in the synthesis of
planar chiral receptors was the
pyridin-2-one derivative 12,
which was subjected to macro-
cyclization with diesters 13 and
14. In this case, the results ob-
tained with DBU as base were
better than those with MeONa
(Scheme 6).
Scheme 6. Synthesis of chiral diazacoronands containing the pyridin-2-one moiety.
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J. Jurczak et al.
Figure 1. X-ray structure analysis of the diazacoronand rac-1.
Figure 5. X-ray structure analysis of the diazacoronand rac-20.
The results obtained for compound 23, however, revealed
a completely different arrangement from the other O-benzyl
derivatives 3, and 19 and 20. The benzene ring is almost par-
allel to the pyridin-2-one moiety, and the intraannular group
is perpendicular to the macroring structure and does not
form hydrogen bonds with amide function, as in the cases of
3, and 19 and 20 (Figure 6).
Figure 2. X-ray structure analysis of the diazacoronand rac-2.
Figure 3. X-ray structure analysis of the diazacoronand (+)-(Rp)-3.
Figure 6. X-ray structure analysis of the diazacoronand rac-23.
Determination of absolute configurations: The assignment
of Rp and Sp configurations to the title compounds was per-
formed in the same way as for the cyclophane derivatives, as
shown in Scheme 7, and is initiated by choosing a plane that
contains as many atoms as possible. Thus, for the monosub-
stituted [2.2]paracyclophane depicted in Scheme 7 an appro-
priate chiral plane includes the bottom benzene ring. To de-
termine the descriptor of a chiral plane, the closest atom out
of the plane is chosen as a descriptor-determining atom. If
there are several candidates, the one of highest priority ac-
cording to CIP rules is chosen. Subsequently, three atoms
adjacent to the descriptor-determining atom and belonging
to the chiral plane are chosen and are labeled a, b, c, respec-
tively. If, upon viewing from the descriptor-determining
atom side of the chiral plane, these atoms are arranged
Figure 4. X-ray structure analysis of the diazacoronand rac-19.
observed, and is probably responsible for the relatively high
synthetic yield (38%) of compound 19.
In the case of diazacoronand 20, with an ester function,
structural investigation revealed only a few changes from
compound 19. Although the same type of hydrogen bonding
was observed, the benzyloxy group was directed outside the
macroring and no p–p-type interaction was detected
(Figure 5).
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New Macrocycles with Planar Chirality
FULL PAPER
Scheme 7. Principle of the assignment of absolute configuration to diazacoronands with planar chirality.
clockwise, the configuration is Rp, conversely, it is Sp. The
same procedure can be used for chiral [2.2]metacyclophane
and [2.2]metaorthocyclophane derivatives and—after minor
changes—for our macrocyclic system too.
The title compounds exhibit significantly higher confor-
mational flexibility than [2.2]cyclophane derivatives; there-
fore, chiral plane and descriptor have to be established inde-
pendently for each example of a chiral diazacoronand
(Scheme 7). In the case of compound (Rp)-3, the chiral
plane includes the 4-bromopyrogallol unit and the descriptor
is the carbon atom located below it.
A slightly different procedure was applied for assigning
the absolute configuration of compound 2 (Scheme 7). Ac-
cording to the X-ray structure analysis for racemic 2
(Figure 2), the chiral plane includes not only the 4-carboxy-
catechol unit, but also part of the macroring structure. The
closest atom out of the chiral plane is the nitrogen atom,
which is marked as the descriptor. The difference is that the
descriptor is located further from the benzene ring than in
the case of compound 3, so the ethylenoxy unit should be la-
beled (a, b, and c) according to the original rule. Unfortu-
nately, this unit is conformationally flexible and, because of
free rotation about the s bond, could give misleading stereo-
chemistry results. In our approach, we decided to disregard
the ethylenoxy unit and labeled only atoms in the aromatic
ring. According to this modified procedure, the absolute
configuration for compound 2 (Scheme 7) is defined as Rp.
This operation allowed the use of a procedure analogous to
that employed for compound 3, with the atoms labeled a, b,
and c adjacent to the descriptor. Only in the case of com-
pound 3 was the absolute configuration established by X-ray
studies.
Diazacoronands 1 and 2, and 4 were also resolved into
enantiomers, however, attempts to obtain single crystals
were unsuccessful. Therefore, a different approach to estab-
lish their absolute configurations had to be employed.
Among known methods, the most noteworthy and reliable
ones are those based on chirooptical techniques. The time-
dependent density functional theory (TD-DFT) method has
recently become an important tool for electronic circular-di-
chroism spectra calculation and provides more reliable re-
sults than Hartree–Fock (HF) or characteristic isochromat
spectroscopy (CIS) methods.[20,21] Unfortunately, the macro-
cycle 2 was too large to be subjected to the TD-DFT
method with required accuracy. For large macrocycles, the
semiempirical ZINDO/S method has been used successfully
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J. Jurczak et al.
for analysis of CD spectra.[22]
Unfortunately, computation of
the CD spectrum of compound
1 could not be performed, due
to the lack of parameters for
the bromine atom in the
ZINDO/S
method.
This
method was used instead for
the calculation of the CD spec-
tra of 2, which was structurally
very similar to bromine deriva-
tive 1.
To this end, conformational
analysis of 2 was carried out by
using the structures generated
by the Conflex/Cache[23] search
Figure 7. Left: calculated minimum-energy conformer of (Sp)-2. Right: comparison of the experimentally
measured (solid line) and calculated (broken line) CD spectra of 2. Bars represent calculated rotational
routine, together with those strengths of the component electronic transitions. Calculated CDs were blue-shifted by 13 nm.
generated from the X-ray data
for 2 and 1. These structures
were optimized further by
using semiempirical methods
with molecular mechanics cor-
rection (PM3MM),[24] and their
relative energies were calculat-
ed by using the DFT method
(B3LYP/6–31g*). An Sp abso-
lute configuration was arbitrari-
ly assigned to a thus-obtained
minimum-energy
conformer,
and the CD spectrum was cal-
culated by using the ZINDO/S
semiempirical
method
(Figure 7). The calculated rota-
tory strengths (shown as bars)
of the transitions at 230 nm
(negative) and 224 nm (posi-
tive) converge to a negative
Cotton effect at 238 nm and a
Figure 8. Left: calculated minimum-energy conformer of (Rp)-3. Right: comparison of the experimentally
measured (solid line) and calculated (broken line) CD spectra of 3. Bars represent calculated rotational
strengths of the component electronic transitions.
positive effect at 219 nm in the Gaussian CD curve. These
match satisfactorily the Cotton effects attributable to the
corresponding transitions in the experimentally measured
CD curve of (+)-2: a negative one at 225 nm and a positive
one at 207 nm. This allowed us to assign the Sp absolute con-
figuration to the (+)-enantiomer of 2. Note a red shift of
the calculated transitions caused by underestimation of the
electronic transition energies in the calculation and cancella-
tion of the Cotton effects of opposite sign.
Conclusion
We have developed a short and versatile route to diazacoro-
nands with planar chirality, based on a system with two es-
sential requirements. Our approach allowed us to obtain
stable chiral receptors with larger macroring structures and
including donor/acceptor functions. A range of macrocycles
were readily synthesized, and their structures were exam-
ined by X-ray crystallography. Absolute configurations were
established for two representative examples (2 and 3) from
molecular modeling and experimental circular dichroism re-
sults. An applied theoretical approach was verified by re-
sults of independent crystallographic experiments performed
for the diazacoronand (+)-(Rp)-3. The racemic compounds
obtained should serve, after enantiomeric resolution, as a
new type of chiral receptor for supramolecular purposes.
A similar analysis was performed for macrocycle 3. The
computed (TD-DFT B3LYP/6–31++g(d,p)) CD spectrum
A
of the enantiomer (Rp)-3 matched the experimentally meas-
ured CD spectrum of the (+) enantiomer of 3, and this con-
firmed the absolute configuration of 3 that was determined
by X-ray diffraction analysis (Figure 8).
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New Macrocycles with Planar Chirality
FULL PAPER
(28.0 g, 150 mmol) in anhydrous THF (700 mL), and the resulting mix-
ture was stirred under reflux for 3 h. After cooling, the reaction mixture
Experimental Section
was cautiously quenched with
(50 mL:50 mL), followed by HCl (5m, 200 mL), and stirred under reflux
for 20 min. The mixture was concentrated, made alkaline (NaOHsat
MeOH solution), and, after cooling, filtered to remove the inorganic salt.
The filtrate was concentrated and the residue was distilled under vacuum
a
mixture of water and THF
All precursors for the syntheses were used as received from Aldrich or
Fluka. THF was distilled from sodium/potassium alloy just before use.
Methanol was distilled from magnesium and stored over anhydrous mo-
lecular sieves (4 Š). Acetonitrile was freshly distilled from calcium hy-
dride. Thin-layer chromatography was performed by using Merck silica
gel glass plates (60 F254). Flash column chromatography was performed
by using Merck silica gel (60, particle size 0.040–0.063 mm). Melting
points were determined by using a Botius M HMK hot-stage apparatus
and are uncorrected. 1H and 13C NMR spectra were recorded by using
Varian Gemini 200BB or Bruker AM 500 spectrometers. Chemical shifts
are reported as d values relative to the TMS peak defined at d=0.00.
The mass-spectral analysis was performed by using the ESI-TOF techni-
que and a Mariner mass spectrometer from PerSeptive Biosystem, or by
using high-resolution liquid secondary-ion mass spectrometry (HR-
LSIMS) and an AMD-604 Intectra instrument.
/
to give
a yellow oil, 21.0 g (71%). B.p. 170–1748C (0.01 mmHg);
1H NMR (200 MHz, CDCl3, 258C, TMS): d=7.01 (d, 3J
A
1H), 6.68 (d, 3J
(H,H)=7.1 Hz, 1H), 6.10 (t, J
(H,H)=7.1 Hz, 1H), 4.06–
3
3.90 (m, 4H), 3.17–3.01 (m, 4H), 1.79 ppm (s, 4H); 13C NMR (50 MHz,
CDCl3, 258C, TMS): d=158.6 (CO), 149.6, 129.8, 114.6, 105.0, 71.4, 53.4,
41.7, 41.5 ppm; ESI-HRMS (MeOH): m/z calcd for C9H16N3O2 [M+H]+:
198.1237; found: 198.1246.
General procedure for the synthesis of compounds 17–24: The appropri-
ate diester 13 or 14 (10 mmol) was dissolved in dry MeOH (100 mL) and
added to the solution of the diamine (10 mmol). Subsequently, a solution
of MeONa (25 mmol in 100 mL MeOH) or DBU (3.8 g, 25 mmol, in the
cases of 23 and 24) was added. The mixture was left at ambient tempera-
ture over a period of 2–7 days (TLC monitoring). The solvent was then
evaporated and the residue was purified by column chromatography
(silica gel; AcOEt/MeOH 95:5 or 8:2 for 23 and 24, respectively) to give
the desired product.
Syntheses: Elemental analysis of the macrocycles under study gave unsat-
isfactory results, due to solvent molecules encapsulated in the crystals.
This phenomenon is well known and, even after prolonged heating in
high vacuum, the solvents can still be detected in the NMR spectra. The
isotope patterns seen in the ESI-MS spectra are, however, consistent with
those calculated on the basis of natural isotope abundances and, thus,
confirm the elemental composition.
Diazacoronand 17: Colorless solid, 16%. M.p. 72.7–75.18C; 1H NMR
(500 MHz, CDCl3, 258C, TMS): d=8.12–8.05 (m, 2H; CONH), 7.42–7.38
General method for the preparation of diamines 7 and 8: BMS (55 mL,
600 mmol, 4 equiv) was added to a solution of an appropriate dinitrile 5
or 6 (150 mmol) in anhydrous THF (700 mL), and the resulting mixture
was stirred under reflux for 4 h. After cooling, the reaction mixture was
cautiously quenched with a mixture of water and THF (50 mL:50 mL)
and concentrated. An HClconc/H2O solution (1:1, 150 mL) was added to
the residue, and the mixture was stirred under reflux for 20 min. The mix-
ture was then cooled, made alkaline with NaOH (20%), and extracted
with CH2Cl2 (3”). The organic layers were combined, washed with brine,
dried over MgSO4, and concentrated to give the crude product, which
was distilled under vacuum.
(m, 2H), 7.27–7.24 (m, 3H), 7.08 (t, 3J
ACHTREUNG
3J
ACHTREUNG
4.74–4.68 (m, 2H; CH2CO), 4.51–4.46 (m, 2H; CH2CO), 4.08–4.02 (m,
2H), 3.94–3.89 (m, 2H), 3.77–3.71 (m, 2H), 3.49–3.42 (m, 2H), 2.26 ppm
(s, 3H; CH3); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=168.8
(CONH), 168.7 (CONH), 153.2, 153.1, 147.7, 145.8, 130.6, 128.6, 128.5,
128.4, 128.2, 127.5, 125.6, 121.0, 113.5, 112.2, 111.4, 111.3, 76.5 (CH2Ph),
71.1, 71.0, 67.3, 67.2, 38.8, 38.8, 20.8 ppm; ESI-HRMS (MeOH): m/z
calcd for C28H30N2O7Na [M+Na]+: 529.1945; found: 529.1962.
Diazacoronand 18: Colorless solid, 22%. M.p. 65.1–67.78C; 1H NMR
(500 MHz, CDCl3, 258C, TMS): d=8.11 (m, 2H; CONH), 7.45–7.39 (m,
2-[2-(2-Aminoethoxy)-4-methylphenoxy]ethanamine (7): Colorless oily
wax, 83%. B.p. 106–1088C (0.05 mmHg); 1H NMR (200 MHz, CDCl3,
258C, TMS): d=6.85–6.65 (m, 3H), 4.02–3.94 (m, 4H), 3.11–2.99 (m,
4H), 2.27 (s, 3H; Me), 1.96 ppm (s, 4H); 13C NMR (50 MHz, CDCl3,
258C, TMS): d=148.7, 146.6, 131.3, 121.6, 115.6, 114.9, 71.9, 71.5, 41.6,
41.5, 20.8 ppm; ESI-HRMS (MeOH): m/z calcd for C11H19N2O2 [M+H]+:
211.1441; found: 211.1451.
3H), 7.28–7.24 (m, 3H), 7.08 (t, 3J
G
3
3
ACHTREUNG
3J1
6.70 (d, 3J
A
G
A
CH2CO), 4.52–4.47 (m, 2H; CH2CO), 4.14–4.03 (m, 2H), 3.97–3.90 (m,
2H), 3.82–3.72 (m, 2H), 3.46–3.38 (m, 2H), 1.28 ppm (s, 9H; tBu);
13C NMR (125 MHz, CDCl3, 258C, TMS): d=168.8 (CONH), 168.7
(CONH), 153.2, 153.1, 147.4, 145.7, 144.2, 139.3, 136.3, 128.5, 128.2, 127.9,
125.6, 117.3, 111.6, 111.4, 111.3, 110.0, 76.4 (CH2Ph), 71.1, 71.0, 67.3, 67.2,
38.8, 38.7, 34.3, 31.4 ppm; ESI-HRMS (MeOH): m/z calcd for
C31H36N2O7Na [M+Na]+: 571.2415; found: 571.2430.
2-[2-(2-Aminoethoxy)-4-tert-butylphenoxy]ethanamine (8): Yellowish
oily wax, 81%. B.p. 128–1308C (0.05 mmHg); 1H NMR (200 MHz,
CDCl3, 258C, TMS): d=7.01–6.84 (m, 3H), 4.20–3.93 (m, 8H), 3.12 (brs,
4H), 1.27 ppm (s, 9H; tBu); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=
148.7, 147.2, 145.8, 119.2, 115.2, 113.9, 71.5, 71.1, 41.7, 41.6, 34.9 (CCH3),
32.0 ppm (CH3); ESI-HRMS (MeOH): m/z calcd for C14H25N2O2
[M+H]+: 253.1911; found: 253.1922.
Diazacoronand 19: Crystallization in vapor diffusive system (MeOH/pen-
tane) gave colorless crystals, 38%. M.p. 175.6–177.18C; 1H NMR
(500 MHz, CDCl3, 258C, TMS): d=8.11–8.04 (m, 2H; CONH), 7.43–7.40
(m, 2H), 7.30–7.27 (m, 3H), 7.09 (t, 3J
G
3
3
ACHTREUNG
3J1
A
G
(3-Cyanomethoxy-2-oxo-2H-pyridin-1-yl)-acetonitrile (11): Anhydrous
K2CO3 (91 g, 660 mmol) and chloroacetonitrile (71 mL, 1.1 mol) were
added to a solution of 2,3-dihydroxypyridine (9, 25.0 g, 225 mmol) in an-
hydrous acetonitrile (500 mL). The resulting mixture was stirred under
reflux for 48 h. After filtration through Celite, the filtrate was concentrat-
ed and the residue was purified by column chromatography on silica gel
(CHCl3/MeOH 9:1). The brown solid was decolorized with active char-
coal to give a yellowish product (23.0 g, 54%). M.p. 121.9–123.48C;
6.73–6.69 (m, 2H), 6.60 (d, 3J
U
,
ACHTREUNG
AHCTREUNG
4.00 (m, 2H), 3.91–3.84 (m, 2H), 3.79–3.70 (m, 2H), 3.49–3.41 ppm (m,
2H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=169.0 (CONH), 168.9
(CONH), 153.2, 153.1, 148.6, 147.2, 139.4, 136.2, 129.0, 128.6, 128.5, 128.1,
125.7, 123.5, 115.5, 113.1, 112.8, 111.5, 111.3, 76.8 (CH2Ph), 71.0, 70.1,
67.6, 67.4, 38.7, 38.6 ppm; HR-LSIMS: m/z calcd for C27H28N2O779Br
[M+H]+: 571.1079; found: 571.1053.
1H NMR (200 MHz, [D6]DMSO, 258C, TMS): d=7.50 (dd, 3J1
6.9 Hz, 3J2(H,H)=1.6 Hz, 1H), 7.16 (dd, 3J1(H,H)=6.9 Hz, 3J2
1.6 Hz, 1H), 6.31 (t, 3J
(H,H)=6.9 Hz, 1H), 5.14 (s, 2H; CH2CN),
ACHTREUNG
A
N
ACHTREUNG
N
Diazacoronand 20: Crystallization in vapor diffusive system [MeOH/
CHCl3 (1:1)/Et2O] gave colorless crystals, 10%. M.p. 108.8–110.28C;
1H NMR (500 MHz, CDCl3, 258C, TMS): d=8.12–8.06 (m, 2H; CONH),
5.04 ppm (s, 2H; CH2CN); 13C NMR (50 MHz, [D6]DMSO, 258C, TMS):
d=156.0 (CO), 145.5, 131.6, 119.4, 115.9, 115.6, 104.7, 54.2 (CH2CN),
36.8 ppm (CH2CN); IR (KBr): n˜ =2993, 2971, 1662, 1605, 1229 cmÀ1
;
7.62 (dd, 3J1
C
ACHTREUNG
ESI-HRMS (MeOH): m/z calcd for C9H7N3O2Na [M+Na]+: 212.0430;
A
ACHTREUNG
found: 212.0433.
8.4 Hz, 1H), 6.71 (d, J
,
ACHTREUNG
3-(2-Amino-ethoxy)-1-(2-amino-ethyl)-1H-pyridin-2-one
(55.0 mL, 600 mmol, 4 equiv) was added to a solution of dinitrile 11
(12):
BMS
1H; CH2Ph), 5.04 (dAB
,
G
,
3J1(H,H)=15.5 Hz, 3J2
N
N
,
Chem. Eur. J. 2006, 12, 4397 –4406
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4403

J. Jurczak et al.
Table 1. Crystallographic data for the structures described.
Identification code
rac-1
rac-2
(Rp)-3
empirical formula
Mr
C28H25BrN3O8
611.42
C21H15N3O8.33
428.68
C21H23BrN2O6
479.32
T [K]
l [Š]
crystal system
space group
a [Š]
b [Š]
c [Š]
a [8]
293(2)
0.71073
monoclinic
P2(1)
8.4590(17)
14.840(3)
11.586(2)
90
120(2)
0.71073
150(2)
0.71073
monoclinic
P2(1)
10.567(2)
8.9840(18)
11.525(2)
90
triclinic
¯
P1
13.127(3)
15.887(3)
16.134(3)
90.00(3)
b [8]
106.35(3)
90
1395.6(5)
2
1.455
1.527
626
89.70(3)
77.90(3)
3289.9(11)
6
1.298
0.102
1330
103.34(3)
90
1064.6(4)
2
1.495
1.971
g [8]
V [Š3]
Z
1calcd [gcmÀ3
]
m [mmÀ1
(000)
]
F
A
492
crystal size [mm]
range of q [8]
0.37”0.39”0.26
3.50–20.00
0.43”0.21”0.07
2.58–28.91
0.3”0.2”0.1
3.63–23.00
index ranges
À8ꢀhꢀ7, À13ꢀkꢀ14, 0ꢀlꢀ11
À17ꢀhꢀ17, À21ꢀkꢀ21, À21ꢀlꢀ21
À11ꢀhꢀ11, À9ꢀkꢀ9, À12ꢀlꢀ12
rflns (collected/unique)
refinement method
data/restr./param.
GoF
2174/2174
57349/16024
13573/2926
full-matrix least-squares on F2
2174/1/371
0.987
full-matrix least-squares on F2
16024/36/879
0.935
full-matrix least-squares on F2
2926/1/293
0.999
R indices [I>2s(I)]
R indices (all data)
R1=0.0597, wR2=0.1408
R1=0.0860, wR2=0.1661
0.024(4)
0.250/À0.196
R1=0.1788, wR2=0.4116
R1=0.4251, wR2=0.5302
R1=0.0261, wR2=0.0540
R1=0.0286, wR2=0.0549
0.0047(10)
extinction coefficient
À3
D1max/1min [eŠ
]
0.573/À0.636
0.545/À0.159
Flack parameter
À0.016(7)
Identification code
rac-19
rac-20
rac-23
empirical formula
Mr
C27H27BrN2O7
571.42
C29H30N2O9
582.59
C27H31N3O8
525.55
T [K]
l [Š]
crystal system
space group
a [Š]
293(2)
0.71073
monoclinic
P2(1)/c
120(2)
293(2)
0.71073
monoclinic
P2(1)/c
0.71073
triclinic
¯
R3
10.106(2)
25.502(6)
7.6615(15)
b [Š]
c [Š]
17.225(3)
15.279(3)
25.502(6)
25.502(6)
19.539(4)
16.915(3)
a [8]
90
118.94(3)
90
b [8]
106.38(3)
118.94(3)
98.6
g [8]
90
118.94(3)
4425.2(19)
6
1.312
0.099
1848
90
V [Š3]
Z
2551.8(9)
4
1.487
1.661
2503.8(9)
4
1.394
0.104
1calcd [gcmÀ3
]
m [mmÀ1
(000)
]
F
A
1176
1112
crystal size [mm]
range of q [8]
0.18”0.44”0.53
3.65–22.00
0.2”0.1”0.1
3.21–22.49
0.15”0.15”0.15
2.65–28.76
index ranges
À10ꢀhꢀ10; 0ꢀkꢀ18; 0ꢀlꢀ16
À27ꢀhꢀ27, À27ꢀkꢀ27, À27ꢀlꢀ27
À10ꢀhꢀ9, À26ꢀkꢀ25, À22ꢀlꢀ22
rflns (collected/unique)
refinement method
data/restr./param.
GoF
3082/3082
51674/3844
22273/6098
full-matrix least-squares on F2
3082/0/347
0.974
full-matrix least-squares on F2
3844/0/418
1.169
full-matrix least-squares on F2
6098/0/468
0.697
R indices [I>2s(I)]
R indices (all data)
R1=0.0601, wR2=0.1616
R1=0.0802, wR2=0.1835
0.0
1.019/À0.413
R1=0.0799, wR2=0.1765
R1=0.0983, wR2=0.1881
0.0016(7)
1.086/À0.296
R1=0.0424, wR2=0.0552
R1=0.1696, wR2=0.0746
0.00085(15)
0.209/À0.192
extinction coefficient
À3
D1max/1min [eŠ
]
A
(H,H)=2.1 Hz, 2H; CH2CO), 4.15–4.10 (m, 2H),
71.1, 71.0, 67.6, 67.5, 51.9, 38.7, 38.6 ppm; ESI-HRMS (MeOH): m/z
calcd for C29H30N2O9Na [M+Na]+: 573.1844; found: 573.1872; elemental
analysis calcd (%) for C29H30N2O9: C 63.27, H 5.45, N 5.09; found: C
63.48, H 5.66, N 4.85.
4.00–3.94 (m, 2H), 3.88 (s, 3H; Me), 3.81–3.73 (m, 2H), 3.51–3.42 ppm
(m, 2H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=168.8 (CONH),
168.8 (CONH), 166.6 (COOMe), 153.2, 151.9, 147.6, 139.5, 136.3, 128.5,
128.4, 128.0, 125.6, 123.5, 122.7, 112.7, 111.4, 111.3, 111.0, 76.6 (CH2Ph),
4404
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4397 –4406

New Macrocycles with Planar Chirality
FULL PAPER
Diazacoronand 21: Crystallization in vapor diffusive system [MeOH/
CHCl3 (1:1)/pentane] gave colorless crystals, 13%. M.p. 244.8–245.88C;
1H NMR (500 MHz, CDCl3, 258C, TMS): d=8.22–8.15 (m, 2H; CONH),
7.98–7.95 (m, 2H), 7.83 (brs, 1H; NHCOPh), 7.64–7.59 (m, 1H), 7.54–
CCDC-288948 (rac-1), CCDC-288949 (rac-2), CCDC-288947 [(Rp)-3],
CCDC-288950 (rac-19), CCDC-288951 (rac-20), and CCDC-288952 (rac-
23) contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallograph-
ic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
3
7.50 (m, 2H), 6.66 (s, 2H), 6.64–6.60 (m, 2H), 6.32 (m, 2H), 4.66 (dAB, J-
A
,
3J
(H,H)=16.5 Hz, 2H;
A
Molecular modeling: Conformational analysis of 2 and 3 was performed
with structures generated by the Conflex/Cache[23] search routine as well
as with structures generated from the X-ray data. These structures were
further optimized by using PM3MM semiempirical methods with molecu-
lar mechanics correction,[24] and their relative energies were calculated
additionally by the DFT method (B3LYP/6–31g*). CD spectra were cal-
culated for the first 20 singlet transitions for each compound, by the
CH2CO), 4.30–4.23 (m, 2H), 3.94–3.87 (m, 2H), 3.75–3.69 (m, 2H), 3.38–
3.29 (m, 2H), 2.28 ppm (s, 3H; Me); 13C NMR (125 MHz, CDCl3, 258C,
TMS): d=168.4 (CONH), 168.3 (CONH), 168.1 (COPh), 152.9, 147.3,
145.5, 133.1, 132.6, 130.3, 128.8, 128.5, 127.8, 120.7, 113.4, 112.7, 111.4,
104.8, 104.7, 66.7, 66.4, 66.3, 39.0, 20.9 ppm; ESI-HRMS (MeOH): m/z
calcd for C28H29N3O7Na [M+Na]+: 542.1898; found: 542.1908.
ZINDO/S method for 2 and by TD-DFT (B3LYP/6–31++g(d,p)) for 3.
G
Diazacoronand 22: Crystallization in vapor diffusive system (MeOH/pe-
troleum ether) gave colorless crystals, 15%. M.p. 134.5–137.18C;
1H NMR (500 MHz, CDCl3, 258C, TMS): d=8.08 (m, 2H; CONH),
7,95–7.91 (m, 2H), 7.71 (s, 1H; NHCOPh), 7.62–7.58 (m, 1H), 7.52–7.48
(m, 2H), 6.86 (dd, 3J1
(H,H)=2.2 Hz, 1H), 6.72–6.65 (m, 2H), 6.37 (dd, 3J1
(H,H)=4.5 Hz, 2H), 4.65 (s, 4H; CH2CO), 4.28–4.20 (m, 2H), 3.95–3.85
A
N
Acknowledgements
A
ACHTREUNG
ACHTREUNG
Financial support from the State Committee for Scientific Research
(Project T09A 030 28) is gratefully acknowledged.
(m, 2H), 3.80–3.72 (m, 2H), 3.40–3.32 (m, 2H), 1.30 ppm (s, 9H; tBu);
13C NMR (125 MHz, CDCl3, 258C, TMS): d=168.4 (CONH), 167.9
(COPh), 152.9, 152.8, 147.2, 145.5, 143.9, 133.2, 132.5, 128.8, 128.5, 127.7,
117.0, 113.5, 111.0, 109.4, 104.8, 104.7, 66.8, 66.7, 66.4, 66.3, 39.1, 39.0,
34.3, 31.5 ppm; ESI-HRMS (MeOH): m/z calcd for C31H35N3O7Na
[M+Na]+: 584.2367; found: 584.2395.
[1] J. Steed, J. L. Atwood, Supramolecular Chemistry, Wiley, New York,
2000.
[2] B. D. White, J. Mallen, K. A. Arnold, F. R. Fronczek, R. D. Gan-
dour, L. M. B. Gehrig, G. W. Gokel, J. Org. Chem. 1989, 54, 937.
[3] a) L. R. Sousa, D. H. Hoffman, L. Kaplan, D. J. Cram, J. Am. Chem.
Soc. 1974, 96, 7100; b) K. Tsubaki, H. Tanaka, H. Morikawa, K.
Fuji, Tetrahedron 2003, 59, 3195.
Diazacoronand 23: Crystallization in vapor diffusive system [MeOH/
CHCl3 (1:1)/Et2O] gave colorless crystals: 28% (DBU), 8% (MeONa).
M.p. 104.5–107.28C; 1H NMR (500 MHz, CDCl3, 258C, TMS): d=7.85–
7.80 (m, 1H; CONH), 7.72 (m, 1H; CONH), 7.54–7.52 (m, 2H), 7.38–
3
3
ACHTREUNG
[4] For selected reviews, see: a) F. Vçgtle, P. Neumann, Top. Curr.
Chem. 1974, 48, 67; b) F. Vçgtle, G. Hohner, Top. Curr. Chem. 1978,
74, 1; c) V. Boekelheide, Acc. Chem. Res. 1980, 13, 65; d) A. Collet,
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106; Angew. Chem. Int. Ed. Engl. 1994, 33, 91; b) P. J. Pye, K.
Rossen, R. A. Reamer, N. N. Tsou, R. P. Volante, P. J. Reider, J. Am.
Chem. Soc. 1997, 119, 6207; c) S. Dahmen, S. Bräse, J. Am. Chem.
Soc. 2002, 124, 5940; d) S. E. Gibson, J. D. Knight, Org. Biomol.
Chem. 2003, 1, 1256; e) S. Bräse, S. Dahmen, S. Hçfener, F. Lauter-
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M. D. Smith, K. D. Shimizu, Org. Lett. 2002, 4, 723.
7.30 (m, 3H), 6.79 (dd, J1
3J
(H,H)=8.4 Hz, 1H), 6.47–6.44 (m, 1H), 6.37 (dd, J1
(H,H)=1.5 Hz, 1H), 6.25 (d, 3J(H,H)=8.4 Hz, 1H), 6.00 (t, 3J
7.1 Hz, 1H), 5.15 (s, 2H; CH2Ph), 4.68 (dA1B1 (H,H)=15.8 Hz, 1H;
3J
CH2CO), 4.57 (dA2B2 (H,H)=16.0 Hz, 1H; CH2CO), 4.47 (dA1B1
3J 3J-
(H,H)=15.8 Hz, 1H; CH2CO), 4.29 (dA2B2 (H,H)=16.0 Hz, 1H;
3J
CH2CO), 4.06–4.00 (m, 1H), 3.86–3.79 (m, 1H), 3.76–3.66 (m, 3H), 3.54–
3.46 (m, 2H), 3.20–3.14 ppm (m, 1H); 13C NMR (125 MHz, CDCl3, 258C,
TMS): d=169.5 (CONH), 168.9 (CONH), 158.7, 152.5, 151.8, 148.8,
137.6, 137.5, 128.6, 128.2, 128.1, 127.8, 123.9, 113.0, 107.4, 107.2, 105.4,
75.8 (CH2Ph), 68.8, 68.5, 67.0, 50.6, 46.9, 40.8, 38.2 ppm; ESI-HRMS
(MeOH): m/z calcd for C26H27N3O7Na [M+Na]+: 516.1741; found:
516.1762; elemental analysis calcd (%) for C26H27N3O7: C 63.28, H 5.47,
N 8.52; found: C 63.43, H 5.59, N 8.33.
A
3
ACHTREUNG
3
N
G
U
ACHTREUNG
,
ACHTREUNG
,
G
,
G
,
ACHTREUNG
Diazacoronand 24: Crystallization in vapor diffusive system (CHCl3/
THF) gave colorless crystals: 23% (DBU), 7% (MeONa). M.p. 119.2–
122.48C; 1H NMR (500 MHz, CDCl3, 258C, TMS): d=10.05 (brs, 1H;
NHCOPh), 8.66 (brs, 1H), 8.40 (brd, 2H), 8.09 (brd, 1H), 7.56–7.44 (m,
[7] a) P. Bakó, L. Fenichel, L. Tçke, Liebigs Ann. Chem. 1990, 1161;
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Rudiger, F. Eblinger, H.-J. Schneider, Eur. J. Org. Chem. 1998, 1379;
3H), 7.15 (t, 3J
1H), 6.65–6.61 (m, 1H), 6.53 (d, 3J
(H,H)=7.2 Hz, 1H), 4.75 (dA1B1 (H,H)=16.1 Hz, 1H; CH2CO), 4.64
3J
(dA1B1 (H,H)=16.1 Hz, 1H; CH2CO), 4.57 (dA2B2 (H,H)=15.7 Hz,
3J 3J
1H; CH2CO), 4.50 (dA2B2, J(H,H)=15.7 Hz, 1H; CH2CO), 4.26–4.18 (m,
ACHTREUNG
AHCTREUNG
A
,
ACHTREUNG
,
A
,
ACHTREUNG
´
´
d) D. T. Gryko, A. Pe¸cak, W. Kozminski, P. Pia¸tek, J. Jurczak, Supra-
3
AHCTREUNG
mol. Chem. 2000, 12, 229.
1H), 3.91 (brd, 1H), 3.81–3.73 (m, 2H), 3.59–3.46 (m, 3H), 3.21–
3.13 ppm (m, 1H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=169.0
(CONH), 168.7 (CONH), 167.1 (COPh), 159.6 (CO), 155.4, 153.2, 148.8,
133.6, 131.8, 129.9, 128.5, 128.3, 128.2, 128.1, 127.9, 116.8, 113.6, 108.7,
106.9, 105.0, 70.2, 67.4, 66.4, 49.2, 41.5, 37.6 ppm; ESI-HRMS (MeOH):
m/z calcd for C26H26N4O7Na [M+Na]+: 529.1694; found: 529.1996.
[8] a) P. Huszthy, J. S. Bradshaw, Y. C. Zhu, T. Wang, N. K. Dalley, J. C.
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X-ray crystallography: The X-ray measurements were undertaken in the
Crystallographic Unit of the Physical Chemistry Laboratory at the Chem-
istry Department of the University of Warsaw. Crystal data and details of
the crystal structure determinations are presented in Table 1. The intensi-
ty data were collected by using a Kuma KM4CCD diffractometer in the
omega scan mode. Data were corrected for decay, Lorentz, and polariza-
tion effects. The structure was solved by direct methods[25] and refined by
using SHELXL.[26] All non-hydrogen atoms were refined anisotropically.
All hydrogen atoms were identified from a difference density map and
refined without any constraints.
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Chem. Eur. J. 2006, 12, 4397 –4406
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4405

J. Jurczak et al.
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Received: November 12, 2005
Published online: March 24, 2006
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