Cycloalkane-1,2-diamine derivatives as chiral solvating agents. Study of the structural variables controlling the NMR enantiodiscrimination of chiral carboxylic acids

Article abstract of DOI:10.1016/j.tet.2008.06.031

A family of pincer-like receptors (2-5) has been synthesized and tested for the NMR enantiodiscrimination (CSA) of chiral carboxylic acids. Starting from a previous design (1), different structural variables have been mapped on the receptor frame. The spl

Full text of DOI:10.1016/j.tet.2008.06.031

Tetrahedron 64 (2008) 7709–7717
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Cycloalkane-1,2-diamine derivatives as chiral solvating agents. Study
of the structural variables controlling the NMR enantiodiscrimination
of chiral carboxylic acids
a
b
c
,
a,
a,
*
*
*
´
´
Carmen Pen˜a , Javier Gonzalez-Sabın , Ignacio Alfonso , Francisca Rebolledo , Vicente Gotor
a
´
´
´
´
Departamento de Qu´ımica Organica e Inorganica, Universidad de Oviedo, C/Julian Claverıa, s/n, Oviedo, Spain
b Entrechem, SL, Edificio Cient´ıfico Tecnolo´gico, Campus de El Cristo, E-33006 Oviedo, Spain
c
´
´
´
´
Departamento de Quımica Organica Biologica, Instituto de Investigaciones Quımicas y Ambientales de Barcelona,
´
Consejo Superior de Investigaciones Cientıficas (IIQAB-CSIC), C/Jordi Girona 18-26, E-08034 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 April 2008
Received in revised form 9 June 2008
Accepted 9 June 2008
Available online 12 June 2008
A family of pincer-like receptors (2–5) has been synthesized and tested for the NMR enantiodiscrimination
(CSA) of chiral carboxylic acids. Starting from a previous design (1), different structural variables have been
mapped on the receptor frame. The splitting of the signals of the acids upon the addition of the CSAs
largely depends on these structural variables. Thus, we concluded that the C2 symmetrical pyridine-2,6-
biscarboxamide moiety is a key structural feature for the efficiency of the CSA. Structural studies by NMR
and molecular modeling showed that this moiety promotes the U-shape-folded pincer-like conformation
by intramolecular H-bonds. On the other hand, we also observed that the cyclohexane-1,2-diamine de-
rivative 5 is a more versatile CSA than its cyclopentane analogue 1, as 5 shows a better performance for
more structurally different acids. However, the original cyclopentane derivative (1) remained the best for
the arylpropionic acids. Finally, combination of NMR and modeling studies allowed us to propose a rea-
sonable model for the interaction and, accordingly, for the observed NMR enantiodiscrimination.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Chiral solvating agent (CSA)
NMR
Anion recognition
Pincer
Enantiodiscrimination
1. Introduction
chiral materials, analyte and CSA, could be easily recovered after the
measurement. There are several CSAs described in the literature for
The development of more efficient methods for the easy and fast
measurement of the enantiomeric excess (ee) of a chiral organic
molecule1 is an area of increasing interest due to the importance
that chirality has in biological and pharmaceutical chemistry.
Among other spectroscopic and chromatographic techniques, NMR
spectroscopy has the advantages of easy performance and accessi-
bility,2 with no need for special equipment apart from the common
NMR spectrometers. However, this technique requires the modifi-
cation of the substrate with a chiral auxiliary, which would convert
the mixture of enantiomers into a mixture of diastereomeric mo-
lecular (covalent, chiral derivatizing agents, CDA) or supramolecular
(non-covalent, chiral solvating agents, CSA) complexes.3 Ideally,
these diastereomeric species will show chemical shift non-equiva-
lence of some of their NMR signals, allowing the determination of
the enantiomeric composition of the substrate by the direct in-
tegration of these bands.4 The advantage of using the non-covalent
chiral solvating agents relies on the possibility of carrying out the
experiment in situ, without purification steps.5 Besides, the starting
amines,6 amides,7 alcohols,8 ammonium salts,9 phosphorous-con-
taining molecules,10 and aromatic compounds.11 However, despite
the increasing number of papers describing CSAs for carboxylic
acids,12 useful receptors for the pharmacologically active arylpro-
pionic acids are very scarce.13
Within our current research project devoted to the preparation
of new receptors for the molecular recognition of chiral carboxylic
acids14 and taking advantage of our chemoenzymatic methodolo-
gies for the preparation of enantiopure forms of both trans-cyclo-
pentane-1,2-diamine15
and
trans-cyclohexane-1,2-diamine16
derivatives, we envisioned to implement these chiral moieties in
a family of new semi-rigid C2 symmetrical receptors, and to test
their abilities as CSAs for carboxylic acids. Additionally, we have
made an effort to understand the structural basis responsible for
the different behavior of all the receptors.
2. Results and discussion
2.1. Design and syntheses of the receptors 2–5
* Corresponding authors. Tel.: þ34 985103448.
E-mail addresses: iarqob@iiqab.csic.es (I. Alfonso), frv@fq.uniovi.es (F. Rebolledo),
vgs@fq.uniovi.es (V. Gotor).
Starting from the pincer-like receptor 1,17 and taking into ac-
count our previously reported results, we envisioned to carry out
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.031

7710
C. Pe˜na et al. / Tetrahedron 64 (2008) 7709–7717
O
O
O
X
N
N
NH
N
HN
N
NH
N
HN
N
NH
N
n
n
4
1 (X=N, n=1)
2 (X=CH, n=1)
5 (X=N, n=2)
3
Figure 1. Structures of the previous receptor (1) and those prepared and studied in this work (2–5).
successive structural changes (2–5) in order to check their effect on
the NMR chiral discrimination properties (Fig. 1).
U-shape conformation. This receptor was prepared by reductive
amination of the diamine (S,S)-6 with 2,6-pyridinedicarbox-
aldehyde (Scheme 2). However, in this process two compounds
with similar chromatographic retention factors were produced: the
polyamine 3 and an amino alcohol resulting from the mono-
amination of the dialdehyde and subsequent reduction of both
imino and carbonyl groups. In order to facilitate the isolation of 3,
the compound was derivatized with (Boc)2O and the resulting new
mixture formed by 8 and 9 easily separated by flash chromatog-
raphy. After the Boc groups of 8 were removed by acid treatment,
the desired C2 symmetric compound 3 was isolated in 55% overall
yield.
The first question to be answered is the importance of the pincer
conformation for the CSA ability. For this U-shape geometry,
a pyridine-2,6-biscarboxamide moiety is necessary,18 the pincer
conformation being fitted by two H-bonds formed between the NH
groups and the pyridine nitrogen. Thus, in order to check this as-
pect, we planned the synthesis of the receptor 2 incorporating
a benzene-1,3-biscarboxamide and receptor 4, which can be con-
sidered as ‘one half’ of the pincer structure. Both compounds 2 and
4 were prepared in high yields from the enantiopure diamine (R,R)-
6 which is indicated in Scheme 1.
Another important structural feature of the pincer is the chiral
moiety. In order to study the effect of this fragment, we also syn-
thesized the receptor 5, in which the size of the carbocycle of the
starting chiral diamine has been increased by one methylene group.
Therefore, we could also compare the performance of the cyclo-
hexane and cyclopentanediamine moieties. Thus, the rece-
ptor 5 was readily synthesized by coupling of the diamine (R,R)-716
with 0.5 equiv of 2,6-bis(chlorocarbonyl)pyridine in 90% yield
(Scheme 1).
On the other hand, compound 3 lacks the amide bond, retaining
the nitrogen atoms as secondary amino groups. In the presence of
the racemic acid, protonation could take place in these nitrogen
atoms thus favoring H-bonds with the pyridinic nitrogen and the
2.2. NMR enantiodiscrimination studies
We tested the abilities of receptors 2–5 as CSAs for several chiral
carboxylic acids (10–20 in Fig. 2) bearing different residues at-
tached to the stereogenic center. The experiments were carried out
by mixing equimolecular amounts of the corresponding receptor
and the racemic acid in CDCl3 (10 mM). Immediately after each
addition, 1H NMR spectrum was acquired in a 300 MHz spec-
trometer at room temperature. Table 1 shows the spectra of some
acids in the presence of receptor 2–5. In addition, Table 2 shows the
values for the induced chemical shifts (Dd) on the signals of all the
carboxylic acids after the addition of 2–5, as well as the splitting
ClOC
COCl
(R,R,R,R)-2
ClOC
COCl
N
NH2
N
NH2
N
(R,R,R,R)-5
(R,R)-4
ClOC
N
(R,R)-7
(R,R)-6
Scheme 1. Synthesis of receptors 2, 4, and 5.
N
N
NH2
N
i-iii
NBoc BocN
NBoc
OH
+
+
OHC
N
CHO
N
N
N
(S,S)-6
(S,S,S,S)-8
(S,S)-9
iv
(S,S,S,S)-3
Scheme 2. Reagents and conditions: (i) MgSO4, MeOH, 25 ꢀC; (ii) NaBH4, MeOH, 0 ꢀC; (iii) (Boc)2O, CH2Cl2; (iv) 3 N aq HCl, 25 ꢀC, 55% overall yield.

C. Pe˜na et al. / Tetrahedron 64 (2008) 7709–7717
7711
10 (R1=OH, R2=H)
11 (R1=OH, R2=Cl)
12 (R1=OH, R2=OMe)
13 (R1=OMe, R2=H)
14 (R1=Me, R2=H)
15 (R1=NHBoc, R2=H)
16 (R1=Me, R2=iPr)
compared. Thus, the derivative 2 was much less efficient for the
selected acids. On the other hand, the polyamine receptor 3 showed
a very good peak resolution for lactic acid 19 (Tables 1 and 2) al-
though, for the most of examples, it produced large line broadening
and smaller splitting. This observation suggested the involvement
of a mixture of different conformations as a consequence of the less
rigidity of the cavity of 3 (due to the change of carbonyl by meth-
ylenic units) as well as by the presence of two different basic ni-
trogens susceptible to be protonated. In contrast, the co-planarity
between the aromatic pyridine and both amide groups in 1 leads to
the more rigid pincer-like conformation, which is stabilized by
intramolecular H-bonds. This conformation would favor the NMR
enantiodiscrimination within the supramolecular receptor–sub-
strate complexes (see below). The elimination of one half of the
pincer biting cavity drastically reduced the splitting for most of the
acids (compare receptors 1 and 4), thus supporting the importance
of the mentioned cavity. Only for two substrates (12 and 15)
R1
R3
CO2H
CO2H
R2
19 (R3=OH)
20 (R3=OPh)
O
CO2H
CO2H
H3CO
17
18
Figure 2. Structures of the carboxylic acids studied.
between signals corresponding to each enantiomer of the acids
DDd). For the sake of an easier comparison, values previously
obtained with receptor 1 are also displayed in Table 2, and selected
representative splitting values for 1–5 are plotted in Figure 3. As
(
bearing an H-bonding donor at Ca, the receptor 4 behaves more
a general trend, the signals of the CaH protons of the acids move
upfield (Dd<0), implying a deprotonation of the carboxylic group,
which is more efficient for the stronger mandelic type acids such as
those indicated by the higher chemical shifts variations. Addition-
ally, other signals from the substrates also move upfield, suggesting
a shielding effect of the aromatic groups of the receptors over the
protons of the substrates. Only NH protons from N-Boc-phenyl-
glycine (15, entries 12 and 13 in Table 2) resonate at lower field
upon the addition of the receptors, which can be interpreted as the
establishment of a stronger intramolecular hydrogen bond with the
carboxylate anion than that with the carboxylic function.
efficiently than the original one 1.
On the other hand, we have found that substitution of the
cyclopentane moiety by a cyclohexane ring leads to a more versatile
CSA, with
DDdꢁ0.04 ppm for at least one of the signals of any of the sub-
strates. This CSA works with acids having either H-bonding or aro-
matic groups on C . However, the initial receptor 1 still remained
a broader applicability. Thus, receptor 5 showed
a
a
more suitable than 5 for the arylpropionic acids (14, 16–18). Thus,
we could get splitting of the signals of DDdꢁ0.05 ppm for all the
tested acids, by choosing the addition of either 1 or 5.
Regarding the NMR enantiodiscrimination, some important
differences must be pointed out. The pyridine-2,6-biscarboxamide
moiety led, in general, to the largest splitting values. This trend can
be easily checked if the splitting produced by receptors 1 and 2 are
We have also demonstrated the practical applicability of the
best of our receptors (5) for the measurement of the ee of carboxylic
acids, using 13 as a model compound. Samples containing different
proportions of both enantiomers of 13 were prepared and analyzed
Table 1
Partial 1H NMR spectraa of selected racemic acids in the presence of receptors 2–5
Receptor
Carboxylic acid
Spectrum
Receptor
Carboxylic acid
Spectrum
Me
Me
2
2
CO2H
CO2H
1.6
1.4
1.2
1.6
1.4
1.4
Me
1.2
CαH
OH
CO2H
OH
3
5
4
5
5
CO2H
Cl
Cl
1.2
1.0
5.2
4.8
OH
CO2H
OH
CO2H
NHBoc
CO2H
OMe
CO2H
5
a
Frequency: 300 MHz, 10 mM in CDCl3.

7712
C. Pe˜na et al. / Tetrahedron 64 (2008) 7709–7717
Table 2
Induced shift (Dd, ppm) and splitting (DDd, ppm) for the signals of the carboxylic acids 10–20 in the presence of receptors 1–5 (300 MHz, 10 mM in CDCl3)
Acid
Signal
Receptor
1a
2
3
4
5
Ddb
DDd
Ddb
DDd
Ddb
DDd
0.01
0.01
Ddb
DDd
Ddb
DDd
1
2
3
4
5
6
7
8
10
11
12
12
12
13
13
14
14
15
15
15
15
16
16
17
17
18
18
19
19
20
20
C
C
C
OMe
ArH
a
a
a
H
H
H
ꢂ0.54
ꢂ0.57
ꢂ0.40
ꢂ0.03
ꢂ0.06
ꢂ0.27
ꢂ0.18
ꢂ0.15
ꢂ0.14
ꢂ0.22
d
0.02
0.06
d
n.m.c
ꢂ0.71
n.m.c
n.m.c
n.m.c
ꢂ0.29
ꢂ0.25
ꢂ0.17
ꢂ0.14
n.m.c
n.m.c
n.m.c
n.m.c
ꢂ0.16
ꢂ0.07
ꢂ0.22
ꢂ0.18
n.m.c
n.m.c
n.m.c
n.m.c
n.m.c
n.m.c
n.m.c
0.01
n.m.c
n.m.c
n.m.c
0.01
<0.01
d
ꢂ0.55
ꢂ0.70
ꢂ0.50
ꢂ0.09
ꢂ0.13
d
ꢂ0.35
ꢂ0.51
ꢂ0.33
ꢂ0.01
d
0.04
0.06
0.05
d
ꢂ0.60
ꢂ0.58
ꢂ0.75
ꢂ0.05
ꢂ0.09
ꢂ0.27
ꢂ0.19
ꢂ0.10
ꢂ0.06
ꢂ0.36
ꢂ0.62
0.32
0.12
0.05
0.13
0.01
0.03
0.04
0.08
d
d
0.01
0.05
d
0.03
0.02
d
Ca
H
d
ꢂ0.08
ꢂ0.04
ꢂ0.05
ꢂ0.01
ꢂ0.07
ꢂ0.27
0.52
0.01
0.01
d
OMe
0.09
0.01
0.08
0.01
d
ꢂ0.21
ꢂ0.22
ꢂ0.12
ꢂ0.34
ꢂ0.50
0.47
0.02
d
Ca
H
9
Me
0.05
n.m.c
n.m.c
n.m.c
n.m.c
d
d
0.02
0.05
d
0.04
0.07
0.30
0.22
0.69
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
C
C
a
a
H1d
H2d
0.04
d
NH1d
NH2d
0.42
0.10
0.06
d
0.04
0.05
0.10
d
0.58
0.56
0.21
Ca
H
d
d
ꢂ0.24
ꢂ0.17
d
d
ꢂ0.04
ꢂ0.06
ꢂ0.11
ꢂ0.04
d
d
ꢂ0.02
ꢂ0.05
ꢂ0.06
ꢂ0.09
ꢂ0.30
ꢂ0.05
ꢂ0.68
ꢂ0.39
ꢂ0.23
ꢂ0.25
Me
ꢂ0.12
ꢂ0.20
ꢂ0.16
ꢂ0.31
ꢂ0.28
d
0.09
d
0.04
d
0.01
d
0.02
d
0.04
d
Ca
H
Me
0.09
d
0.04
n.m.c
n.m.c
n.m.c
n.m.c
n.m.c
n.m.c
ꢂ0.22
ꢂ0.28
d
d
d
0.04
d
Ca
H
d
d
Me
0.08
d
<0.01
d
ꢂ0.01
ꢂ0.35
ꢂ0.17
ꢂ0.06
ꢂ0.09
d
0.04
d
Ca
H
d
d
Me
CaH
Me
ꢂ0.35
ꢂ0.23
ꢂ0.20
0.02
d
ꢂ0.41
ꢂ0.43
ꢂ0.19
0.07
d
0.02
0.02
d
0.07
d
0.04
0.02
0.05
a
b
c
Taken from Ref. 17.
Averaged between signals from both enantiomers.
n.m.¼not measured.
d
The numbers 1 and 2 correspond to the presence of two rotamers in the carbamate bond.
with 5 as a CSA (Fig. 4), rendering an excellent linear response
correlation (R2¼0.9989). Moreover, samples containing 97.0, 98.0,
and 99.0% ee were carefully prepared and analyzed with receptor 5
at 500 MHz. They showed 96.5, 98.0, and 98.6% ee, respectively,
which rendered a w0.5% error in the determination of ees within
the most conflictive range. Therefore, both 1 and 5 have shown to
be useful CSAs for carboxylic acids, being the practical applicability
of either 1 or 5 dependent on the acid structure.
2.3. Structural studies in solution
Considering the obtained results, two main structural features
are especially important for this family of receptors: the pyridine-
2,6-biscarboxamide unit and the size of the cycloalkanediamine.
With the aim of proposing an explanation for these facts, we have
studied the solution structures of receptors 2 and 5 by NMR and
molecular modeling. Regarding compound 2, a full set of 1D NOESY
experiments (Fig. 5) showed that the receptor exists as a mixture of
cis/trans dispositions of the isophthalamide moiety. For instance,
0.25
0.20
0.15
ee = 50%
100
R2 = 0.9989
ee = 60%
80
60
0.10
0.05
0.00
ee = 80%
40
20
0
ee = 85%
20
19
18
17
16
0
20
40 60
ee prepared (%)
80
100
ee = 90%
5
15
4
14
Acid
3
13
12
2
3.4 3.3 3.2 3.1 3.0
Host
11
1
10
Figure 3. Plot of the splitting (DDd, ppm) observed by selected proton signals of 10–20
upon the addition of the receptors 1–5. The proton signals used in this plot were those
showing the largest splitting for every compound.
Figure 4. A selected region of the 300 MHz 1H NMR spectra of (R)-13 (20 mM) with
different enantiomeric purities in the presence of (R,R,R,R)-5 (20 mM) and correlation
between theoretical and observed % ee values.

C. Pe˜na et al. / Tetrahedron 64 (2008) 7709–7717
7713
Figure 5. Solution conformational analysis of compound 2: (A) 1H NMR spectrum (500 MHz, 10 mM in CDCl3) and selected 1D NOESY traces upon irradiation on proton signals of
(B) amide NH (red), (C) 4/6-positions (green) or (D) 2-position (blue) of the isophthalamide moiety. (E) Global minimum obtained by Monte Carlo MMFF calculations. (F) Second
lowest minimum.
irradiation of amide NH proton (Fig. 5B) produced NOE enhance-
ments on the aromatic protons at ortho positions to the carbonyl
groups (positions 2 and 4/6). This observation was further con-
firmed by the irradiation of either 4/6 (Fig. 5C) or 2 (Fig. 5D) proton
nuclei. Interestingly, Monte Carlo conformational searches ren-
dered the all trans conformation of the isophthalamide moiety as
the most stable one (Fig. 5E), with a small participation of the trans/
cis conformation (Fig. 5F). Thus, in this case, the U-shaped pincer
conformation is highly disfavored, in contraposition with the initial
receptor 1. This situation could account for the less efficient NMR
enantiodiscrimination observed here and highlight the structural
importance of the pyridine nitrogen.
rendered a folded geometry as the global minimum, which displays
bifurcated H-bonds between NH amide protons and both pyridine
and aliphatic amine nitrogen atoms. Moreover, the angles imposed
by the cyclohexane moieties produced steric repulsions between
the two equivalent methylamino groups, leading to a slight dis-
tortion from the ideal C2 symmetry in the global minimum (Fig. 6B).
The second lowest minimum is the C2 symmetrical one (Fig. 6C),
being only 0.1 kcal/mol higher in energy and supporting their co-
existence in solution at room temperature. The overall effect is
a slightly more flexible pincer conformation for 5 than for 1, which
could explain the more efficient capability of the receptor 5 to ac-
commodate to the carboxylic acids.
With respect to the solution conformation of receptor 5, the
analysis of their 2D NOESY spectra (Fig. 6A) showed cross-peaks
between the amide NH and the protons of the benzyl (CH2 and
Hortho) and methylgroups but not with the protons of the pyridine
moiety. This implies a U-shape-folded pincer-like conformation in
solution. In addition, Monte Carlo conformational searches also
We have also tried to get a deeper knowledge about the su-
pramolecular species formed in solution. With this aim, we focused
on the complexes formed between (R,R,R,R)-5 and 13. Job plots for
both enantiomers of the acid rendered a 1:2 CSA/acid stoichiometry
(Fig. 7). For this reason, to carry out the following 1H NMR exper-
iments, a sample 20 mM for the racemic acid 13 and 10 mM for the

7714
C. Pe˜na et al. / Tetrahedron 64 (2008) 7709–7717
Figure 6. (A) Selected regions of the 2D NOESY spectra (500 MHz, 10 mM in CDCl3) of 5 showing the cross-peaks implicating the amide NH proton (also shown in the structure by
double-headed arrows). (B) Global minimum obtained by Monte Carlo MMFF calculations. (C) Second lowest minimum. (D) Superposition of (B) and (C).
receptor was prepared. As it was expected, the addition of rac-13
over (R,R,R,R)-5 causes a deshielding of its proton signals close to
the amino group (0.17 and 0.89 ppm for NMe and chiral NCH, re-
spectively) as well as those close to the amide group (0.95 and
0.32 ppm for amide NH and CH, respectively). These data support
the proton transference from the acid to the receptor and the for-
mation of a strong carboxylate–amide hydrogen bond. Concomi-
tantly, protons 3 and 4 of the pyridine moiety moved upfield (0.18
and 0.08 ppm, respectively) suggesting a p–p interaction between
5 and 13. An additional proof for the formation of the supramo-
lecular complexes was obtained by 1D ROESY experiments (Fig. 8).
Irradiation of protons at positions 3/5 of the pyridine ring of 5
yielded small intermolecular ROEs on OMe and aromatic protons of
13, suggesting the co-existence of different orientations between
them (Fig. 8A).
Molecular modeling was also undertaken with all the possible
stereoisomeric combinations of two molecules of 13 and one of
(R,R,R,R)-5 (Fig. 8B–D). We obtained several energetically close local
minima, displaying different dispositions between receptor and
substrates, in a good agreement with NMR data. However, some
general trends can be extracted from the analysis of the obtained
structural ensembles. All the minima set the substrates on both
faces of the receptor with the carboxylate groups pointing to the
cavity of the pincer, thus forming strong H-bonds with both am-
monium and amide groups of 5. Additionally, the phenyl group of
the substrate tends to set parallel on top of the pyridine of the
pincer (inter-ring distance w3.7 Å). This disposition is favored for
(S)-13 (Fig. 8B), while for (R)-13 the steric hindrance with cyclo-
hexane moiety forces the acid to rotate w180ꢀ to the opposite
disposition (Fig. 8C). Both diastereomeric conformations would
locate the OMe group toward the benzyl sidearm of 5, but a bit
closer in the case of (R)-13. These facts agree with the observed
shielding of the OMe signals, being slightly larger for (R)-13.
Overall, the global picture for 5 is very similar to that found for 1,
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
0.0
0.1
0.2
0.3
0.4
0.5
acid (13)
0.6
0.7
0.8
0.9
1.0
X
Figure 7. Job plots for (R,R,R,R)-5 and either (S)-13 (magenta) or (R)-13 (blue).

C. Pe˜na et al. / Tetrahedron 64 (2008) 7709–7717
7715
moiety has been also studied comparing the cyclopentane (1) and
the cyclohexane (5) derivatives. The cyclohexane compound (5)
showed to be more versatile than 1, as it produced good splitting
(DDdꢁ0.04 ppm) for all the acids. Overall, the use of either 1 or 5
would cover quite structurally different chiral carboxylic acids,
and they can be considered complementary in that sense. Finally,
a deep NMR and modeling study of the supramolecular com-
plexes for one example allowed us to propose a model for the
interaction. These studies revealed a proton transference from the
acid to the receptor toward the formation of a 1:2 CSA/acid
complex. Besides, the key roles played by intermolecular H-
bonding (implicating both amide and ammonium NH) and
interactions were also highlighted.
p–p
4. Experimental section
4.1. Synthesis of receptor (R,R,R,R)-2
The enantiopure diamine (R,R)-6 (2.4 mmol) and isophthaloyl
dichloride (1.2 mmol) were dissolved in 18 mL of dry CH2Cl2 under
nitrogen atmosphere. The reaction mixture was stirred at room
temperature for 4 h after which the mixture was extracted with 3 N
aqueous NaOH. The organic layer was dried and evaporated, and
the product was purified by flash chromatography using ethyl ac-
20
etate/methanol mixtures. Yield: 90%; mp 30–32 ꢀC; [
a
]
D
þ78.7 (c
0.52, CHCl3) >99% ee; Rf (MeOH/AcOEt 1:6) 0.27; IR (cmꢂ1) 3244,
1636; 1H NMR (CDCl3, 300 MHz)
d (ppm): 1.33–1.50 (m, 2H), 1.50–
1.90 (m, 8H), 2.06–2.34 [mþs, (2ꢃCHþCH3), 8H], 2.90 (q, 3J¼7.8 Hz,
2H), AB quartet (dA¼3.51, dB¼3.60, JAB¼13.3 Hz, 4H), 4.31 (q,
3J¼7.7 Hz, 2H), 6.4 (d, 3J¼6.7 Hz, 2NH), 7.12–7.35 (m, 10H), 7.46 (t,
3J¼7.6 Hz, 1H), 7.86 (d, 3J¼7.8 Hz, 2H), 8.15 (s, 1H); 13C NMR (CDCl3,
75.5 MHz)
d (ppm): 21.2 (CH2), 23.5 (CH2), 31.5 (CH2), 37.9 (CH3),
52.5 (CH), 59.1 (CH2), 69.9 (CH), 125.2 (CH), 126.9 (CH), 128.2 (CH),
128.7 (CH), 129.7 (CH), 135.0 (C), 139.5 (C), 166.3 (C); ESI-MS (m/z):
539 [(Mþ1)þ, 15]. Anal. Calcd for: (C34H42N4O2) C, 75.80; H, 7.86; N,
10.40. Found C, 75.67; H, 8.06; N, 10.28.
Figure 8. (A) 1H NMR (lower trace) and 1D ROESY (upper trace) spectra upon irradi-
ation of the 3/5 pyridine protons in a sample containing a 1:2 mixture of (R,R,R,R)-5/
rac-13 with the schematic representation of the possible orientations between them,
with observed ROEs in red arrows. Optimized structures (global minima) of the cor-
responding supramolecular complexes with (B) two molecules of (S)-13, (C) two
molecules of (R)-13 and (D) (R)-13þ(S)-13. (E) Superposition of the energetically ac-
cessible local minima of (B).
4.2. Synthesis of (S,S,S,S)-3
Enantiopure diamine (S,S)-6 (1.8 mmol) was dissolved in 20 mL
of MeOH and MgSO4 (0.39 g) and pyridine-2,6-dicarboxaldehyde
(0.90 mmol) were added. The reaction mixture was stirred at room
temperature overnight. After filtration of the solid, the solution was
cooled to 0 ꢀC and NaBH4 (3.6 mmol) slowly added in portions.
After 12 h, the excess NaBH4 was destroyed by addition of 3 N
aqueous HCl and the solution evaporated to dryness. Aqueous
NaOH (3 N) was added (15 mL) and extracted with CH2Cl2
(3ꢃ15 mL). The combined organic layers were washed with brine
(10 mL), dried with Na2SO4, and evaporated under reduced pres-
sure. The resulting crude was dissolved in CH2Cl2 (10 mL) and
treated with di-tert-butyl dicarbonate (2.0 mmol). After 7 h of
stirring, the mixture was evaporated to dryness giving a mixture of
8 and 9. Then, further purification by flash chromatography (ethyl
although the analysis of the conformational ensemble suggests that
complexes with 5 are more flexible (a larger number of energeti-
cally accessible minima from a Boltzmann distribution, Fig. 8D), like
the receptor itself. This observation could explain the somehow
higher versatility of 5 versus 1, as the pincer cavity can be easier
adapted to the size and shape of the substrate.
3. Conclusions
In this paper, a family of pincer-like nitrogen-containing re-
ceptors (2–5) have been synthesized and tested as CSA for different
chiral carboxylic acids. Their structural variables have been mapped
in order to understand their effects on the NMR enantiodiscrimi-
nation. Thus, we have found that the pyridine-2,6-biscarboxamide
moiety is very important for the efficiency of these compounds as
CSA. This fact is closely related to the propensity of this sub-
structure to promote a U-shape-folded pincer-like conformation, as
demonstrated by NMR and molecular modeling studies of the re-
ceptors 2 and 5. Thus, compounds lacking either the pyridine ni-
trogen (2), or the amide functionality (3), or one chiral arm of the
pincer cavity (4) produced, in general, lower splitting than the
original CSA (1). On the other hand, the effect of the chiral diamine
acetate/hexane mixtures) allowed to isolate (S,S,S,S)-8 as the sole
20
product. Yield: 60%; yellow oil; [
a
]
þ33.0 (c 0.50, CHCl3) >99% ee;
D
Rf (Hex/AcOEt 1:1) 0.51; IR (cmꢂ1) 1681; 1H NMR (CDCl3, 300 MHz)
and 13C NMR (CDCl3, 75.5 MHz) spectra: a complex mixture of
rotamers was observed, the analyses of both spectra being very
difficult; ESI-MS (m/z): 712 [(Mþ1)þ, 70]. Anal. Calcd for
(C43H61N5O4): C, 72.54; H, 8.64; N, 9.84. Found C, 72.75; H, 8.46; N,
10.03.
(S,S,S,S)-8 (0.40 mmol) was hydrolyzed with 3 N aqueous HCl
(10 mL) at room temperature. Then, the solution was basified with
pellets of NaOH and extracted with CH2Cl2 (3ꢃ20 mL). The com-
bined organic layers were washed with brine (10 mL), dried with
Na2SO4, and evaporated under reduced pressure to yield (S,S,S,S)-3

7716
C. Pe˜na et al. / Tetrahedron 64 (2008) 7709–7717
20
in state of purity. Yield: 92%; yellow oil; [
a]
þ73.5 (c 0.60, CHCl3)
4.5. Molecular modeling
D
>99% ee; Rf (MeOH) 0.16; IR (cmꢂ1) 3385, 2952; 1H NMR (CDCl3,
300 MHz)
d
(ppm): 1.14–1.96 (m, 12H), 2.09 (s, 6H), AB quartet
To obtain the minima of energy by molecular modeling, the
conformer distribution calculation option available in Spartan 04 was
used.19 With this option, an exhaustive Monte Carlo search without
constraints was performed for every structure. The torsion angles
were randomly varied and the obtained structures fully optimized
using the MMFF force field. Thus, 100 minima of energy within an
energy gap of 10 kcal/mol were generated. These structures were
analyzed and ordered considering the relative energy, being the
repeated geometries eliminated. For the receptors alone, the two
lowest energy local minima are shown. For the supramolecular
complexes, this calculation was performed for every stereoisomeric
complex obtained by combination of one molecule of (R,R,R,R)-5
and either two of (R)-13, one (R) and one (S)-13 or two (S)-13.
(
dA¼3.45, dB¼3.53, JAB¼13.3 Hz, 4H), AB quartet (dA¼3.83, dB¼3.93,
JAB¼14.4 Hz, 4H), 7.00–7.36 (m, 12H), 7.50 (t, 3J¼7.4 Hz, 1H); 13C
NMR (CDCl3, 75.5 MHz) d (ppm): 21.5 (CH2), 22.8 (CH2), 30.7 (CH2),
37.9 (CH3), 53.7 (CH), 59.3 (CH2), 66.1 (CH), 71.3 (CH), 120.2 (CH),
126.7 (CH), 128.1 (CH), 128.6 (CH), 136.5 (CH), 139.7 (C), 159.2 (C);
ESI-MS (m/z): 512 [(Mþ1)þ, 100]. Anal. Calcd for (C33H45N5): C,
77.45; H, 8.86; N, 13.69. Found C, 77.32; H, 8.95; N, 13.57.
4.3. Synthesis of (R,R)-4
Receptor (R,R)-4 was prepared following the procedure de-
scribed for (R,R,R,R)-2, by mixing 0.5 mmol of the enantiopure di-
amine (R,R)-6 and 0.70 mL (0.70 mmol) of a 1 M solution of
picolinoyl chloride in CH2Cl2 (this acid chloride was previously
Acknowledgements
prepared by refluxing picolinic acid in thionyl chloride for 1 h).
20
Financial support from the Spanish M.E.C. (CTQ2007-61126) is
gratefully acknowledged.
Yield: 75%; yellow oil; [
a
]
ꢂ43.9 (c 0.50, CHCl3) >99% ee; Rf
D
(MeOH/AcOEt 4:1) 0.51; IR (cmꢂ1) 3380, 1666; 1H NMR (CDCl3,
300 MHz)
d
(ppm): 1.44–1.98 (m, 5H), 2.15–2.34 [mþs, (CH3þCH),
4H], 3.01 (q, 3J¼7.8 Hz, 1H), AB quartet
(
dA¼3.44, dB¼3.78,
References and notes
JAB¼13.3 Hz, 2H), 4.44 (q, 3J¼7.8 Hz, 1H), 7.16–7.42 (m, 5H), 7.41
(ddd, 3J¼7.7 Hz, 3J¼4.8 Hz and 4J¼1.3 Hz 1H), 7.83 (dt, 3J¼7.7 Hz and
4J¼1.6 Hz, 1H), 8.14 (d, 3J¼7.8 Hz, NH), 8.21 (d, 3J¼7.7 Hz, 1H), 8.55
(ddd, 3J¼4.8 Hz, 4J¼1.6 Hz, and 5J¼1.0 Hz 1H); 13C NMR (CDCl3,
1. (a) Vespalec, R.; Boceck, P. Chem. Rev. 2000, 100, 3715; (b) Schuric, V.; Nowotny,
A. P. Angew. Chem., Int. Ed. Engl. 1990, 29, 939; (c) Pirkle, W. H.; Bocek, P. Chem.
Rev. 1989, 89, 347.
2. (a) Wenzel, T. J. Discrimination of Chiral Compounds Using NMR Spectroscopy;
John Wiley and Sons: Hoboken, NJ, 2007; (b) Ucello-Barretta, G.; Baklzano, F.;
Salvadori, P. Curr. Pharm. Des. 2006, 12, 4023; (c) Seco, J. M.; Quin˜oa´, E.; Riguera,
R. Chem. Rev. 2004, 104, 17; (d) Wenzel, T. J.; Wilcox, J. D. Chirality 2003, 15, 256;
(e) Parker, D. Chem. Rev. 1991, 91, 1441.
3. (a) Uccello-Barretta, G.; Balzano, F.; Sicoli, G.; Scarselli, A.; Salvadori, P. Eur. J.
Org. Chem. 2005, 5349; (b) Uccello-Barretta, G.; Balzano, F.; Martinelli, J.; Berni,
M. G.; Villani, C.; Gasparrini, F. Tetrahedron: Asymmetry 2005, 16, 3746.
4. Ema, T.; Tanida, D.; Sakai, T. J. Am. Chem. Soc. 2007, 129, 10591.
5. For recent examples of in situ covalent CSRs, which do not require additional
75.5 MHz)
d (ppm): 21.6 (CH2), 25.3 (CH2), 32.0 (CH2), 38.0 (CH3),
57.7 (CH), 59.3 (CH2), 70.5 (CH), 122.0 (CH), 125.9 (CH), 126.7 (CH),
128.1 (CH), 128.7 (CH), 137.2 (CH), 139.5 (C), 147.9 (CH), 150.0 (C),
163.7 (C); ESI-MS (m/z): 310 [(Mþ1)þ, 100]. Anal. Calcd for:
(C19H23NO) C, 73.76; H, 7.49; N, 13.58. Found C, 73.56; H, 7.69; N,
13.48.
´
purification steps, see: (a) Perez-Fuertes, Y.; Kelly, A. M.; Johnson, A. L.; Arimori,
S.; Bull, S. D.; James, T. D. Org. Lett. 2006, 8, 609; (b) Chin, J.; Kim, D. C.; Kim,
H.-J.; Panosyan, F. B.; Kim, K. M. Org. Lett. 2004, 6, 2591.
4.4. Synthesis of (R,R,R,R)-5
6. (a) Lovely, A. E.; Wenzel, T. J. Tetrahedron: Asymmetry 2006, 17, 2642; (b) Ema,
T.; Ouchi, N.; Doi, T.; Korenaga, T.; Sakai, T. Org. Lett. 2005, 4, 3985; (c) Pazos, Y.;
It was prepared following the procedure described for (R,R,R,R)-
2, but employing the enantiopure diamine (R,R)-7 and 2,6-bis-
´
Leiro, V.; Seco, J. M.; Quin˜oa, E.; Riguera, R. Tetrahedron: Asymmetry 2004, 15,
1825; (d) Omata, K.; Aoyagi, S.; Kabuto, K. Tetrahedron: Asymmetry 2004, 15,
2351; (e) Menezes, P. H.; Gonçalves, S. M. C.; Hallwass, F.; Silva, R. O.; Bieber, L.
W.; Simas, A. M. Org. Lett. 2003, 5, 1601; (f) Hirose, T.; Naito, K.; Shitara, H.;
Nohira, H.; Baldwin, B. W. Tetrahedron: Asymmetry 2001, 12, 375.
7. (a) Ucello-Barreta, G.; Berni, M. G.; Balzano, F. Tetrahedron: Asymmetry 2007, 18,
2565; (b) Uccello-Barretta, G.; Nazzi, S.; Balzano, F.; Levkin, P. A.; Schurig, V.;
Salvadori, P. Eur. J. Org. Chem. 2007, 3219.
8. (a) Tanaka, K.; Fukuda, N.; Fujiwara, T. Tetrahedron: Asymmetry 2007, 18, 2657;
(b) Abid, M.; To¨ro¨k, B. Tetrahedron: Asymmetry 2005, 16, 1547; (c) Maly, A.;
Lejczak, B.; Kafarski, P. Tetrahedron: Asymmetry 2003, 14, 1019.
9. (a) Nakatsuji, Y.; Nakahara, Y.; Muramatsu, A.; Kida, T.; Akashi, M.
Tetrahedron Lett. 2005, 46, 4331; (b) Lacour, J.; Vial, L.; Herse, C. Org. Lett. 2002,
4, 1351.
10. (a) Ma, F.; Shen, X.; Ou-Yang, J.; Deng, Z.; Zhang, C. Tetrahedron: Asymmetry
2008, 19, 31; (b) Li, Y.; Raushel, F. M. Tetrahedron: Asymmetry 2007, 18, 1391.
11. (a) Bergman, S. D.; Frantz, R.; Gut, D.; Kol, M.; Lacour, J. Chem. Commun. 2006,
850; (b) Dignam, C. F.; Zopf, J. J.; Richards, C. J.; Wenzel, T. J. J. Org. Chem. 2005,
70, 8071; (c) Dignam, C. F.; Richards, C. J.; Zopf, J. J.; Wacker, L. S.; Wenzel, T. J.
Org. Lett. 2005, 7, 1773; (d) Hebbe, V.; Londez, A.; Goujon-Ginglinger, C.; Meyer,
F.; Uziel, J.; Juge´, S.; Lacour, J. Tetrahedron Lett. 2003, 44, 2467; (e) Planas, J. G.;
Prim, D.; Rose, E.; Rose-Munch, F.; Monchaud, D.; Lacour, J. Organometallics
2001, 20, 4107; (f) Lacour, J.; Ginglinger, C.; Favarger, F.; Torche-Haldimann, S.
Chem. Commun. 1997, 2285.
20
(chlorocarbonyl)pyridine. Yield: 86%; mp 57–58 ꢀC; [
a
]
ꢂ195.0 (c
D
0.50, CHCl3) >99% ee; Rf (MeOH/AcOEt 1:6) 0.20; IR (cmꢂ1) 3397,
1654; 1H NMR (CDCl3, 600 MHz)
d
(ppm): 1.04 (dq, 3JFax,Eeq¼3.0 Hz,
2JFax,Feq¼3JFax,Aax¼3JFax,Eax¼13.0 Hz, 2HFax),1.10 (tq, 3JDax,Cec¼3JDax,Eeq
¼
3.4 Hz, JDax,Eax¼3JDax,Cax¼2JDax,Deq¼13.0 Hz, 2HDax), 1.33 (dq,
3
3JCax,Deq¼3.4 Hz, JCax,Dax¼3JCax,Bax¼2JCax,Ceq¼12.2 Hz, 2HCax), 1.38
3
(tt, JEax,Deq¼3JEax,Feq¼3.6 Hz, JEax,Dax¼3JEax,Fax¼2JEax,Eeq¼13.2 Hz,
3
3
2
2
2HEax), 1.67 (d, JEeq,Eax¼13.7 Hz, 2HEeq), 1.83 (d, JDeq,Dax¼13.0 Hz,
2HDeq), 1.93 (d, 2JCeq,Cax¼12.2 Hz, 2HCeq), 2.22 (s, 6H), 2.33 (dt, 3JBax,
3
2
¼3.0 Hz, JBax,Cax¼12.2 Hz, 2HBax), 2.56 (d, JFeq,Fax¼12.2 Hz,
Ceq
2HFeq), AB system (dA¼3.40, dB¼3.81, JA,B¼14.3 Hz, 4HH), 3.83
(quintet, 3J¼5.4 Hz, 2HA), 7.16–7.44 (m, 10H), 8.04 (t, 3J¼6.4 Hz,1HI),
8.30 (d, 3J¼4.8 Hz, 2NH), 8.4 (d, 3J¼7.8 Hz, 2HIJ); 13C NMR (CDCl3,
151 MHz)
d (ppm): 23.0 (CH2), 24.7 (CH2), 25.3 (CH2), 32.5 (CH2),
37.0 (CH3), 51.1 (CH), 56.6 (CH2), 66.6 (CH), 124.7 (CH), 126.7 (CH),
128.1 (CH), 128.4 (CH), 138.8 (CH), 139.7 (C), 148.9 (C), 163.3 (C); ESI-
MS (m/z): 568 [(Mþ1)þ, 100]. Anal. Calcd for: (C36H45N5O2) C,
74.04; H, 7.99; N, 12.33. Found C, 73.94; H, 8.19; N, 12.13.
12. (a) Wang, W.; Ma, F.; Shen, X.; Zhang, C. Tetrahedron: Asymmetry 2007, 18, 832;
(b) Ma, F.; Shen, X.; Zhang, C. Org. Lett. 2007, 9, 125; (c) Ema, T.; Tanida, D.;
I
´
´
Sakai, T. Org. Lett. 2006, 8, 3773; (d) Gonzalez-Alvarez, A.; Alfonso, I.; Gotor, V.
Tetrahedron Lett. 2006, 47, 6397; (e) Cuevas, F.; Ballester, P.; Perica´s, M. A. Org.
Lett. 2005, 7, 5485; (f) Yang, D.; Li, X.; Fan, Y.-F.; Zhang, D.-W. J. Am. Chem. Soc.
2005, 127, 7996; (g) Zheng, Y. S.; Zhang, C. Org. Lett. 2004, 6, 1189; (h) Yang, X.;
Wu, X.; Fang, M.; Yuan, Q.; Fu, E. Tetrahedron: Asymmetry 2004, 15, 2491; (i)
Port, A.; Virgili, A.; Alvarez-Larena, A.; Piniella, J. F. Tetrahedron: Asymmetry
2000, 11, 3747; (j) Bilz, A.; Store, T.; Helmchen, G. Tetrahedron: Asymmetry 1997,
8, 3999.
J
J
L
O
O
N
K
F
N
P
A NH
HN
E
D
M
Ph:
Q
G
N
H
B
N
C
13. Yang, X.; Wang, G.; Zhong, Z.; Wu, X.; Fu, E. Tetrahedron: Asymmetry 2006, 17,
916.
Ph
(R,R,R,R)-5
Ph
´
´
´
´
˜
´
14. (a) Gonzalez-Alvarez, A.; Alfonso, I.; Dıaz, P.; Garcıa-Espana, E.; Gotor-Fernan-
´
dez, V.; Gotor, V. J. Org. Chem. 2008, 73, 374; (b) Gonza´lez-Alvarez, A.; Alfonso,

C. Pe˜na et al. / Tetrahedron 64 (2008) 7709–7717
7717
I.; Dı´az, P.; Garcı´a-Espan˜a, E.; Gotor, V. Chem. Commun. 2006, 1227; (c) Alfonso,
I.; Dietrich, B.; Rebolledo, F.; Gotor, V.; Lehn, J.-M. Helv. Chim. Acta 2001, 84, 280;
(d) Alfonso, I.; Rebolledo, F.; Gotor, V. Chem.dEur. J. 2000, 6, 3331.
17. Pen˜a, C.; Gonza´lez-Sabı´n, J.; Alfonso, I.; Rebolledo, F.; Gotor, V. Tetrahedron:
Asymmetry 2007, 18, 1981.
18. Gale, P. A.; Garric, J.; Light, M. E.; McNally, B. A.; Smith, B. D. Chem. Commun.
2007, 1736 and references cited therein.
19. Wavefunction, Inc. Irvine, CA. For MMFF force field calculations, see: Halgren,
T. A. J. Comput. Chem. 1996, 17, 490 and following papers in this issue.
´
´
15. (a) Gonzalez-Sabın, J.; Gotor, V.; Rebolledo, F. J. Org. Chem. 2007, 72, 1309; (b)
Luna, A.; Alfonso, I.; Gotor, V. Org. Lett. 2002, 4, 3627.
16. Gonza´lez-Sabı´n, J.; Rebolledo, F.; Gotor, V. Chem.dEur. J. 2004, 10, 5788.