Novel chiral hexaazamacrocycles for the enantiodiscrimination of carboxylic acids

Article abstract of DOI:10.1016/j.tet.2012.09.093

New enantiopure amines (R,R)-1 and (S,S)-1 were obtained from (R)- or (S)-2,2′-diamino-1,1′-binaphthyl and 2,6-diformylpyridine in a synthesis templated by lead(II) or lanthanide(III) ions, reduction with NaBH₄ and subsequent demetallation. Similarly new amines (R,R,R,R)-2 and (S,S,S,S)-2 were obtained from (1R, 2R)- or (1S, 2S)-1,2- diphenylethylenediamine. The X-ray crystal structure of the Pb(II) complex with macrocyclic Schiff base precursor of (R,R)-1 indicates helical twisted conformation of this macrocycle, while the ROESY spectrum of R,R-1 suggests less twisted conformation. (R,R)-1 and (R,R,R,R)-2 were tested as chiral shift reagents (chiral solvating agents) for various α-substituted carboxylic acids, including non steroidal anti-inflammatory drugs. Enantiodiscrimination of carboxylate ¹H NMR signals was observed with ΔΔδ values up to 0.1 ppm.

Full text of DOI:10.1016/j.tet.2012.09.093

Tetrahedron 68 (2012) 9930e9935
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel chiral hexaazamacrocycles for the enantiodiscrimination of carboxylic acids
a
b
a
a,
*
ꢀ
Krzysztof Gospodarowicz , Ma1gorzata Ho1ynska , Marta Paluch , Jerzy Lisowski
a Department of Chemistry, University of Wrocław, 14 F. Joliot-Curie, 50-383 Wrocław, Poland
Fachbereich Chemie and Wissenschaftliches Zentrum fur Materialwissenschaften, Universitat Marburg, Hans-Meerwein-Straße, D-35032 Marburg, Germany
b
€
€
a r t i c l e i n f o
a b s t r a c t
New enantiopure amines (R,R)-1 and (S,S)-1 were obtained from (R)- or (S)-2,20-diamino-1,10-binaphthyl
and 2,6-diformylpyridine in a synthesis templated by lead(II) or lanthanide(III) ions, reduction with
NaBH4 and subsequent demetallation. Similarly new amines (R,R,R,R)-2 and (S,S,S,S)-2 were obtained
from (1R, 2R)- or (1S, 2S)-1,2-diphenylethylenediamine. The X-ray crystal structure of the Pb(II) complex
with macrocyclic Schiff base precursor of (R,R)-1 indicates helical twisted conformation of this macro-
cycle, while the ROESY spectrum of R,R-1 suggests less twisted conformation. (R,R)-1 and (R,R,R,R)-2 were
Article history:
Received 5 April 2012
Received in revised form 27 August 2012
Accepted 21 September 2012
Available online 26 September 2012
Keywords:
tested as chiral shift reagents (chiral solvating agents) for various
a-substituted carboxylic acids, in-
Macrocycles
Chiral recognition
Carboxylic acids
Amines
cluding non steroidal anti-inflammatory drugs. Enantiodiscrimination of carboxylate 1H NMR signals was
observed with DDd values up to 0.1 ppm.
Ó 2012 Published by Elsevier Ltd.
Solvating agents
1. Introduction
The incorporation of chiral building blocks, such as chiral di-
amines to macrocylic systems can lead to the formation of enan-
tiopure polyazamacrocycles, which attract continuing attention in
organic, coordination and biological chemistry.1 For instance, the
chiral 2þ2 or 3þ3 macrocycles derived form (1R,2R)- or (1S,2S)-1,2-
diaminocyclohexane and diformylpyridine or other aromatic dia-
ldehydes are interesting hosts, which can bind both metal ions or
organic molecules.2e7 In particular, macrocycles, such as 3 and 5
(Scheme 1) and related compounds have been shown to interact
with chiral carboxylic acids. Compound 3 has been used as chiral
solvating agent for the determination of the enantiomeric excess of
various carboxylic acids.2 This macrocycle has also been shown to
be a stereoselective receptor for biologically important dicarbox-
ylate anions.3 Since NMR is a common spectroscopic technique, the
application of chiral shift reagents (chiral solvating agents) is
complementary to chromatographic methods in the determination
of enantiomeric excess and enantiomeric purity. For this reason
new chiral derivatives, which can form NMR-distinguishable di-
astereomeric supramolecular assemblies with the two enantiomers
of a given analyte, attract continuing attention.2e5,8
Scheme 1. Structures of macrocyclic compounds 1e5 and the labelling of (R,R)-1.
In this contribution we present the synthesis of new chiral pol-
yazamacrocylic hosts 1 and 2. In comparison with the related mac-
rocycle 3, these macrocycles possess additional aromatic
substituents, which in principle can enhance enantiodiscrimination
of bound guest molecules by exerting additional chemical shifts,
arising from the ring current effects. In addition, these substituents
may give rise to different steric interaction with the enantiomers of
chiral guest molecules. Interestingly, 1 is an all-aza analogue of the
Cram’s crown ether 4, which is an effective host9 for chiral
* Corresponding author. Tel.: þ48 71 3757 252; fax: þ48 71 3282 348; e-mail
addresses: jerzy.lisowski@chem.uni.wroc.pl, jurekl@wchuwr.pl (J. Lisowski).
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2012.09.093

K. Gospodarowicz et al. / Tetrahedron 68 (2012) 9930e9935
9931
recognition of protonated amines. We have previously reported
lanthanide(III) complexes of Schiff base precursors of 1 and 2, that is
1b and 2b.10e12 Here we use an analogous metal templation with
lead(II) and subsequent reduction for the synthesis of amine mac-
rocycles. We also report the enantiodiscrimination of chiral car-
boxylic acids, including important chiral anti-inflammatory drugs 2-
(p-isobutylphenyl)propanoic acid (ibuprofen), 2-(2-fluorobiphenyl-
4-yl)propanoic acid (fluoribuprofen) and 2-(3-benzoylphenyl)
propanoic acid (ketoprofen).
2. Results and discussion
2.1. Macrocycle synthesis and characterization
The macrocycles 1 and 2 were obtained through the NaBH4 re-
duction of the precursor 2þ2 macrocyclic Schiff bases 1b and 2b,
respectively. These 2þ2 Schiff base macrocycles can be obtained in
good yields as complexes with lanthanide(III) or Pb(II) ions, such as
complex 1c. On the other hand, the direct condensation of (1R,2R)-
1,2-diphenylethylenediamine and 2,6-diformylpyridine leads to
a mixture of products corresponding to a dynamic library7f,13 of
Schiff bases. This library includes the 2þ2, 3þ3 and 4þ4 macro-
cycles (Scheme 2), as indicated by ESI mass spectra of the crude
reaction products. In contrast, the same condensation performed in
the presence of a metal template, such as Pb(II), results in a selec-
tion of the 2þ2 product 2c from the dynamic library (Scheme 2).
Analogous metal template effect has been observed previously for
the Schiff base precursor of 3.7f Similarly, the direct condensation of
(R)- or (S)-2,20-diamino-1,10-binaphthyl and 2,6-diformylpyridine
did not lead to selective formation of the 2þ2 Schiff base macro-
cycle, while this product can be easily obtained in the form of Pb(II)
complex 1c.
Fig. 1. The NOESY spectrum of CD3OD/CDCl3 solution of (R,R)-1.
considerably different, for instance this macrocycle can adopt
a more squeezed conformation analogous to that observed11 in the
crystal structure of azacrown 3.
As expected, the enantiomeric nature of (S,S)-1, (R,R)-1, (S,S,S,S)-
2 and (R,R,R,R)-2 is reflected in their mirror image CD spectra
(Fig. 2), dominated by exciton-coupled transitions.
Fig. 2. CD spectras of enantiomers of 1 and 2.
2.2. Crystal structure of (R,R)-1c
Scheme 2.
The identity of 1 and 2 is confirmed by their ESI-MS and NMR
spectra. The signals of 2 can be assigned on the basis of integration
and chemical shift values. The 1H NMR signals of 1 were assigned
on the basis of COSY, NOESY and HMQC spectra (Fig. 1,
Supplementary Figs. S1eS3). While the NOE crosspeaks between
the methylene protons c,c0 and b, as well as between c,c0 and d were
observed (Fig. 1, see Scheme 1 for labelling), there is no cross-peak
corresponding to the NOE between protons c,c0 and i. This indicates
a different conformation of this macrocycle in comparison with the
conformation of the parent Schiff base macrocycle 1b observed in
its Eu(III) complex,10 or Pb(II) complex described below. For the
complexed 1b a highly twisted conformation corresponds to close
distance between the azomethine proton c and aromatic proton i,
which is reflected in the observation of the relevant cross-peak in
the NOESY spectrum.11 It follows that the conformation of (R,R)-1 is
The successful formation of the 2þ2 macrocylic system of (R,R)-1
is confirmed by the X-ray crystal structure of its precursor (R,R)-1c.
In this structure two symmetry-independent complex molecules
were found: one lying in general position (with Pb1 atom, Fig. 3) and
one lying on a crystallographic two-fold axis (with Pb2 atom, Fig. 3).
The molecule in general position contains one Pb2þ ion with one
macrocyclic ligand L (coordinated through six N atoms) and two
bidentate nitrate ligands in its coordination sphere. The ligand L
adopts a twisted conformation (Fig. S4), similar to that observed in
the analogous Eu(III) complex.10 The site on a two-fold symmetry
axis is randomly occupied by two different species: a neutral mol-
ecule analogous in composition to the molecule with Pb1 (A) and
a cation with one nitrate ligand substituted with two water ligands
(B). Within the macrocyclic ligand the dihedral angle between the
pyridine rings is 43.1(4)ꢀ for the molecule with Pb1 atom and

9932
K. Gospodarowicz et al. / Tetrahedron 68 (2012) 9930e9935
63.9(3)ꢀ for the molecule with Pb2 atom. The CeNeNeC pseudo-
torsion angles defining the ‘helical twist’ of the macrocyclic ligand
are ꢁ44(1)ꢀ (C5eN1eN4eC28) and ꢁ53.0(8)ꢀ (C59eN9eN9ieC55i,
where [i] 1ꢁx, y, 2ꢁz) for the molecule with Pb1/Pb2 atom, re-
spectively (these values are comparable to the reported ones, e.g.,
ꢁ48 to ꢁ59ꢀ range reported for three symmetry-independent
complex molecules in a europium(III)10 complex). In all complex
species, the Pb2þ ion is 10-coordinate with coordination sphere of
irregular geometry (see Supplementary data for the more details).
Fig. 4. Chiral carboxylic acid used in enantiodiscrimination studies. Compounds 6e8
are non-steroidal anti-inflammatory drugs.
Fig. 5. Partial 1H NMR spectra of 6 in the absence (upper) and presence (lower) of
(R,R,R,R)-2 (500 MHz, 2.05 mM in CDCl3). Molar ratio 1:0.25 2:6. The simplified
structures are for the illustration purpose only.
Fig. 3. Top: The neutral complex molecule lying in general position with atom label-
ling scheme. H atoms are omitted for clarity. Thermal ellipsoids are shown at 30%
probability level. Bottom: The neutral complex molecule occupying a special position
on
a two-fold symmetry axis with atom labelling scheme (for the symmetry-
independent part, the unlabelled part is generated by a symmetry operation 1ꢁx, y,
2ꢁz). H atoms are omitted for clarity. Thermal ellipsoids are shown at 30% probability
level. The disordered site is represented by transparent spheres of arbitrary radii and
with bonds shown as dashed lines.
2.3. 1H NMR enantiodiscrimination of chiral carboxylic acids
Addition of racemic chiral carboxylic acids (Fig. 4) to the
6.45ꢂ10ꢁ3 mmol solutions of single enantiomers of (R,R)-1 or
(R,R,R,R)-2 in CDCl3 or benzene-d6 results in splitting of the 1H NMR
signals of the two enantiomers, indicating that both macrocycles are
effective chiral solvating agents (Figs. 5e8, Table 1, Supplementary
data S9/S21). The macrocycles were also effective as chiral shift re-
agents for a protected aminoacid Boc-Ser(OBzl)-OH (Fig. 6). The
enantiodiscrimination of the NMR signals of the guest carboxylic
acid can arise from two mechanisms: (i) chiral recognition, i.e., dif-
ferent binding constants for the R and S enantiomers of the acid, (ii)
the magnetic nonequivalence of the two diastereomers corre-
sponding to association of the R and S enantiomers of the chiral acid
with a given enantiomer of the macrocycle. The observed NMR
signals of the guest are associated with the regime of fast chemical
exchange, so it is difficult to distinguish between these two
Fig. 6. Partial 1H NMR spectra of 11 in the absence (a) and presence of different molar
ratio (b,c) of (R,R)-1 (500 MHz, 2.05 mM in CDCl3), (b) molar ratio 1:0.25 1:11 (c) molar
ratio 1:1 1:11. The simplified structures are for the illustration purpose only.
mechanisms. For the first mechanism different chemical shifts of the
two enantiomers would correspond to different molar fractions of
the free and bound acid, event in the case of identical chemical shifts
of the diastereomeric associates. For the second mechanism

K. Gospodarowicz et al. / Tetrahedron 68 (2012) 9930e9935
9933
Table 1
Induced chemical shifts (a) and splitting (b) of selected probe signals of 1H NMR
spectra for mixture of (R,R)-1 or (R,R,R,R)-2 (separately) macrocycles and carboxylic
acids (500 MHz, 2.05 mM). A is acid, M is (R)-macrocycle
A
6
M
Solvent Probe signal Molar ratio M:A Dda (ppm) DDdb (ppm)
1
2
1
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
2
1
1
1
1
2
2
1
2
1
2
1
1
1
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
C6D6
C6D6
CDCl3
C6D6
C6D6
CDCl3
CDCl3
CDCl3
C6D6
C6D6
C6D6
CDCl3
C6D6
C6D6
C6D6
C6D6
C6D6
C6D6
CDCl3
C6D6
C6D6
C6D6
CDCl3
CDCl3
C6D6
CDCl3
C6D6
C6D6
C6D6
C6D6
CDCl3
CDCl3
CH3C
CH3C
a
a
1:1
1:4
1:1
1:4
ꢁ0.010
ꢁ0.050
ꢁ0.010
ꢁ0.045
ꢁ0.005
0.170
0.005
0.004
0.008
0.004
0.006
0.009
0.007
0.003
0.006
0.004
0.010
0.006
0.007
0.005
0.008
0.010
0.005
0.014
0.030
0.020
0.005
0.007
0.013
0.005
0.008
0.014
0.013
0.070
0.020
0.010
0.020
0.010
0.040
0.115
0.020
0.020
0.030
H C
H C
a
a
H 2-benzene 1:4
H 2-benzene 1:4
H 3-benzene 1:4
CH3(isobutyl)
CH3(isobutyl)
CH2(isobutyl)
CH2(isobutyl)
CH2(isobutyl)
0.030
1:1
1:4
ꢁ0.018
ꢁ0.200
0.040
ꢁ0.020
ꢁ0.020
ꢁ0.060
0.014
0.030
0.050
0.003
0.016
1:0.25
1:0.25
1:1
1:0.25
1:1
1:0.5
1:0.25
1:0.25
1:1
1:0.5
1:0.25
1:1
1:0.5
1:0.25
1:0.25
1:1
1:0.5
1:0.25
1:4
1:1
1:4
1:4
1:4
1:0.25
1:8
1:0.25
1:1
7
CH3C
CH3C
CH3C
CH3C
a
a
a
a
Fig. 7. Partial 1H NMR spectra of 10 in the absence (upper) and presence (lower) of
(R,R,R,R)-2 (500 MHz, 2.05 mM in C6D6). Molar ratio 1:4 2:10. The simplified structures
are for the illustration purpose only.
H C
H C
H C
H C
a
a
a
a
0.040
0.060
0.003
0.007
8
9
CH3C
CH3C
CH3C
CH3C
a
a
a
a
0.020
ꢁ0.050
H C
H C
H C
H C
H C
H C
a
a
a
a
a
a
0.001
0.003
0.019
ꢁ0.088
ꢁ0.140
0.360
OMe
OMe
OMe
OMe
OMe
0.030
0.260
ꢁ0.027
10
11
0.190
0.046
0.010
0.010
H C
H C
a
a
1:0.25
monoprotonated macrocycle, two carboxylates/diprotonated mac-
rocycle or four carboxylates/tetraprotonated macrocycle. Additional
forms, such as diprotonated macrocycle associated with a single
carboxylate or heterochiral associates cannot be excluded. Because
of this complexity, it is very difficult to quantitatively assign the
corresponding equilibrium constants and determine the contribu-
tion of particular species to the chiral spectroscopic discrimination
(the simplified structures of monoadducts in Figs. 5e8 are for the
illustration purpose only). The observed separation of enantiomeric
signals is dependenton the acid tomacrocycle ratio. Generallybetter
separations (higher DDd values) were obtained with higher ratios
(Table 1). This trendalso corresponds tohigher Dd values and reflects
the protonation of the macrocyclic amines by the carboxylic acid and
the subsequent association of cationic macrocycle and carboxylate
anion (Job’s plot, Supplementary Fig. S23). Thus 4:1 and 2:1 asso-
ciates seem to be responsible for the enantiodiscrimination, as it was
observed for other macrocylic hosts.2,4,5,8,14 On the other hand, as
mentioned above, the excess of acid may just serve to increase
protonation of the macrocycle.
Despite the fact that aromatic substituents introduced to these
macrocycles potentially give rise to additional steric effects and ring
current effects,8a the enantiodiscrimination was not improved in
comparison with the macrocycle 3 derived from the chiral aliphatic
diamine. The likely explanation for this is the reduced basicity of 1
and 2. As the aromatic substituents make the formation of pro-
tonated cationic forms of these macrocycles less favourable, the
extent of associate formation with deprotonated carboxylic acids is
small, and so are the chemical shift changes.
Fig. 8. Partial 1H NMR spectra of 6 in the absence (upper) and presence (lower) of
(R,R,R,R)-2 (500 MHz, 2.05 mM in C6D6). Molar ratio 1:4 2:6. The simplified structures
are for the illustration purpose only.
different chemical shifts of the two enantiomers would reflect dif-
ferent averaged spatial orientation of the guest within the frame of
the host, in particular different orientation of the substituents in
respect to the position of the aromatic rings of the macrocycle. The
situation is further complicated by the fact that association between
the acid and macrocycle 1 or 2 is most likely dominated by the ionic
interaction between the deprotonated acid and protonated macro-
cycle, strengthened by hydrogen bonding, as it was observed2,4,5,8,14
for other macrocyclic amine hosts. Thus instead of a simple
hosteguest binding equilibrium, there are three corresponding
equilibria: deprotonation of the acid, protonation of the macrocycle
and the binding of the resulted ions. Since the macrocycle can exist
in various protonation stages, and it can theoretically bind one, two,
three or four carboxylic acids, a variety of hosteguest associated
forms can exist in solution (Supplementary Fig. S22), all these forms,
together with unbound acids can contribute to the chemical shifts of
the averaged signals. It should be noted that 1:1, 2:1 or 4:1 acid/
macrocycle stoichiometries do not have to correspond to the (most
probable) dominant associates, such as one carboxylate/

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K. Gospodarowicz et al. / Tetrahedron 68 (2012) 9930e9935
3. Conclusions
(S,S)-1 was obtained in the same way as (R,R)-1 in method A,
starting form (S)-2,20-diamino-1,10-binaphthyl.
Two new chiral macrocycles 1 and 2, based on binaphthyldi-
amine or diphenylethylenediamine moieties, respectively, have
been successfully synthesized in enantiopure forms. The applica-
tion of the Pb(II) or Ln(III) templates was crucial for the formation of
the 2þ2 system of the precursor macrocyclic Schiff bases. The
crystal structure of the Pb(II) complex of the Schiff base precursor of
1 indicates a highly twisted macrocycle, while the NOESY spectrum
of the amine macrocycle 1 suggests a different type of conforma-
tion. Both macrocycles are effective chiral solvating agents for the
carboxylic acids; enantiodiscrimination of carboxylate 1H NMR
signals was observed with DDd values reaching 0.1 ppm and in
many cases baseline resolution of signals was observed, which is
a prerequisite for practical applications.
Pb(II) complex (R,R,R,R)-2b. (1R, 2R)-1,2-diphenylethylene-
diamine (330.2 mg, 1.56 mmol) and lead(II) nitrate (258.3 mg,
0.78 mmol) were stirred for 10 min in ethanol (100 ml) at 40 ꢀC.
Then 2,6-diformylpyridine (210.8 mg, 1.56 mmol) was added and
the mixture was refluxed for 12 h. After cooling the volume was
reduced to ca. 10 ml and the resulting yellow precipitate was fil-
tered, washed with methanol and dried. Yield 583.3 mg
(0.611 mmol, 78%). EA C42H34N8O6Pb$H2O: calcd: C, 51.90; N, 11.53;
H, 3.73; found: C, 51.60; N, 11.46; H, 3.59, ESI-MS 865.2 [MþCl]þ 1H
NMR (500 MHz, CD3OD, ppm):
d
8.74 (s, 2H) 8.33 (t, JHH¼7.6 Hz, 1H)
7.97 (d, JHH¼7.6 Hz, 2H) 7.46 (d, JHH¼7.6 Hz, 4H) 7.40, (t, JHH¼7.3 Hz,
4H) 7.32 (t, JHH¼7.6 Hz, 2H), 5.57 (s, 2H); 13C NMR (500 MHz,
CD3OD, ppm):
d 164.84; 154.35; 142.83; 139.56; 131.30; 130.35;
130.14; 129.65; 78.04.
4. Experimental section
4.1. Synthesis
4.1.2. Macrocycle (R,R,R,R)-2. Method A. NaBH4 63.4 mg (1.67 mmol)
was added gradually over 15 min to a stirred solution of Pb(II)
complex (R,R,R,R)-2b (200 mg, 0.21 mmol) in methanol (60 ml)
cooled in an ice-bath. The stirring was continued for 2 h at room
temperature, and concentrated H2SO4 was added carefully until
pH¼2 to precipitate PbSO4. The mixture was refluxed for 72 h,
cooled down, neutralized with 10 M NaOH, filtered and extracted
with chloroform/water system. The organic fractions were dried
over Na2SO4 and evaporated to dryness, then MeOH (2 ml) and
water (10 ml) were added and the precipitated product was filtered
off and then recrystallized from methanol/water mixture. Yield
[La(R,R-1b)(NO3)2]NO3$4H2O and [Ce(R,R-2b)Cl3] have been
synthesized as described previously.11
Pb(II) complex (R,R)-1c. (R)-2,20-diamino-1,10-binaphthyl
(545.6 mg,1.9 mmol) and lead(II) nitrate (635.5 mg,1.9 mmol) were
stirred for 10 min in 250 ml ethanol at 40 ꢀC. Then 2,6-
diformylpyridine (259.2 mg, 1.9 mmol) was added and the mix-
ture was refluxed for 12 h. After cooling, the resulting yellow pre-
cipitate was filtered off, washed with ethanol and methanol and
dried. Yield 973 mg (0.886 mmol, 93%). ½a D25
ꢃ
ꢁ724 (c 0.29 mM,
76.8 mg (0.122 mmol)d58%; ½a D25
ꢃ
ꢁ1.21 (c 1.83ꢂ10ꢁ2 mM, MeOH);
CHCl3); EA. C54H34N8O6Pb$4H2O: calcd C, 55.43; H, 3.62; N, 9.58;
found: C, 55.84; H, 3.43; N, 9.51; ESI-MS 1009.3 [MþCl]þ (m/z), 1H
EA C42H42N6$MeOH: calcd C, 77.91; N, 12.68; H, 6.91; found C, 77.92;
N, 11.46; H, 6.32; ESI-MS 631.2 [MþH]þ, 316.5 [Mþ2H]2þ
;
1H NMR
7.42 (t, JHH¼7.6 Hz, 2H), 7.12e7.08
NMR (500 MHz, CDCl3, ppm):
d
6.86 (d, JHH¼8.0 Hz, 2H), 7.13 (t,
(500 MHz, CDCl3, ppm):
d
JHH¼7.1 Hz, 2H), 7.22 (d, JHH¼8.4 Hz, 2H), 7.27 (d, JHH¼7 Hz, 2H), 7.36
(t, JHH¼7 Hz, 2H), 7.72 (t, JHH¼7.6 Hz, 1H), 7.84 (d, JHH¼8.4 Hz, 2H),
7.98 (d, JHH¼8.8 Hz, 2H), 8.61 (s, 2H), 13C NMR (500 MHz, CDCl3,
(m, 12H), 7.01e6.99 (m, 8H), 6.80 (d, JHH¼7.6 Hz, 4H), 3.77 (s, 4H),
3.70 (AB system, JHH¼13.2 Hz, 8H), 13C NMR (500 MHz, CDCl3, ppm):
d
159.24; 141.07; 136.44; 128.33; 127.81; 126.82; 121.81; 69.13;
ppm):
d
161.31; 153.13; 145.70; 139.12; 133.46; 132.44; 130.06;
52.48.
Method B. [Ce(R,R,R,R-2b)Cl3] complex was reduced with NaBH4
similarly as [La(R,R-1b)(NO3)2]NO3$4H2O.
(S,S,S,S)-2 and (S,S,S,S)-2b were obtained in the same way as
(R,R,R,R)-2 and (R,R,R,R)-2b with method A, starting from (1S,2S)-
1,2-diphenylethylenediamine.
128.78; 128.57; 126.87; 125.43; 125.31; 124.67; 120.22.
Single crystals of (R,R)-1c were grown by slow evaporation of
a solution in 2 ml of CHCl3 and 1 ml of MeOH.
4.1.1. Macrocycle (R,R)-1. Method A. NaBH4 (27.56 mg, 0.73 mmol)
was added gradually for 15 min to a stirred suspension of Pb(II)
complex (710 mg, 0.646 mmol) (R,R)-1c in methanol (30 ml) cooled
in an ice-bath. The stirring was continued for 2 h at room tem-
perature, and the resulting suspension was filtered and evaporated
to dryness. The residue was extracted in chloroform/water system,
organic fractions were dried over Na2SO4. The chloroform solution
was concentrated to 2 ml, methanol (10 ml) was added and the
precipitated product, filtered and then recrystallized from metha-
nol/benzene mixture. Yield 42.5 mg (0.055 mmol)d61%; EA
C54H42N6$MeOH$H2O: calcd C, 80.07; N, 10.19; H, 5.45; found: C,
80.02; N, 10.05; H, 4.97; ESI-MS 775 [MþH]þ.
4.2. Methods
The NMR spectra were taken on Bruker Avance 500 spectrom-
eter. The TOCSY, COSY, NOESY and HMQC spectra were acquired
using 512ꢂ1 K data points and zero filled to 1ꢂ1 K matrix. Mixing
time equal to 400 ms was used in NOESY experiments. The CD
spectra were measured on a Jasco J-715 Spectropolarimeter. The
positive-mode electrospray mass spectra of methanol or chloro-
form solutions of the complexes were obtained using Bruker
microOTOF-Q instrument. The elemental analyses were carried out
on a PerkineElmer 2400 CHN elemental analyzer.
Method B. Solid NaBH4 (20 mg, 0.53 mmol) was gradually added
to
a
suspension of [La(R,R-1b)(NO3)2]NO3$4H2O (60.8 mg,
0.053 mmol) in methanol (50 ml). The mixture was stirred addi-
tionally for 1 h at room temperature and evaporated to dryness. The
product was suspended in water, extracted with chloroform, dried
over Na2SO4, filtered and evaporated to dryness. Yield 39 mg
4.3. X-ray crystal structure determination
A selected monocrystal of (R,R)-1c was mounted on an Xcalibur
diffractometer equipped with an Onyx area detector and graphite-
monochromatized MoKa radiation. In Table S1 the basic X-ray data
are summarized. (R,R)-1c was solved by direct methods in SHELXS
and refined in SHELXL.15 C-bonded H atoms positions were calcu-
lated and a riding model was applied with Ueq¼1.2 Ueq (parent
atom).
Absolute configuration was determined based on the known
configuration of the enantiomeric substrate used for the synthesis
of (R,R)-1c (no isomerization expected).
(0.05 mmol)d94%.
½
a 2D5
ꢃ
þ475 (c 4.09ꢂ10ꢁ3 mM, CHCl3); EA
C54H42N6O: calcd C, 81.90; H, 5.47; N, 10.61%; found: C, 81.73; H,
5.34; N, 10.37; ESI-MS 775 m/z [MþH]þ 1H NMR (500 MHz, CDCl3,
ppm):
d
7.88 (d, JHH¼8.8 Hz, 4H), 7.80 (d, JHH¼7.6 Hz, 4H), 7.23e7.17
(m, 12H), 7.05 (d, JHH¼8.0 Hz, 4H), 6.89 (t, JHH¼7.6 Hz, 2H), 6.73 (d,
JHH¼7.6 Hz, 4H), 4.40 (t, JHH¼6.1 Hz, 4H), 4.23 (t, JHH¼6.1 Hz, 8H). 13
C
NMR (500 MHz, CDCl3, ppm):
d 158.19; 143.90; 136.78; 129.69;
128.07; 127.90; 126.8; 124.08; 122.15; 119.25; 114.47; 112.97; 49.39.

K. Gospodarowicz et al. / Tetrahedron 68 (2012) 9930e9935
9935
Two complex molecules were found, one lying in general posi-
tion and one in special position on a two-fold axis (see Article). The
complex molecule lying in special position is disordered. Two dif-
ferent complexes seem to occupy this site statistically. First kind of
complex molecule (A) is of [PbL(NO3)2] formula, the second kind (B)
is a cationic complex of [PbL(NO3)(H2O)2]þ formula. A and B differ
in one coordination place at the Pb2þ central ion, which in case of A
is occupied by a bidentate nitrate ligand, whereas in case of B two
water ligands are involved. The refined occupancies of A and B
(adding to a fully-occupied site) are 0.79(2) and 0.21(2), re-
spectively. Charge balance requires additional nitrate anion in the
presence of B (monopositive species, in contrast to neutral A). The
relevant anion position was determined and refined as co-
operatively disordered. This cooperatively disordered anion lies in
special position on a two-fold axis. Additional restraints had to be
introduced for this anion (DFIX restraint setting NeO bond lengths
publication nos. CCDC 874480. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-mail: depos-
it@ccdc.cam.ac.Uk). Supplementary data related to this article can
be found at http://dx.doi.org/10.1016/j.tet.2012.09.093.
References and notes
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3
ꢁ
On the final difference Fourier map the highest peak of 1.69 e/A
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Supplementary data
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1H and 13C NMR spectra, crystal data for (R,R)-1c: geometric
parameters, additional data for structure description (Tables S1eS2,
Figs. S1eS24). Crystallographic data (excluding structure factors)
for the structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary