Bis(amino amides) derived from natural amino acids as chiral receptors for N-protected dicarboxylic amino acids

Article abstract of DOI:10.1016/j.tetlet.2012.10.099

A family of bis(amino amides) derived from natural amino acids has been synthesized and tested for the NMR enantiodiscrimination, as chiral receptors, of some N-protected dicarboxylic amino acids. The influence of the amino acid side chain is an important parameter to obtain good enantiodiscrimination. The binding between bis(amino amides) and N-protected dicarboxylic amino acids has been thoroughly studied by ESI-MS and NMR spectroscopic methods as well as by molecular modeling.

Full text of DOI:10.1016/j.tetlet.2012.10.099

Tetrahedron Letters 54 (2013) 72–79
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bis(amino amides) derived from natural amino acids as chiral receptors for
N-protected dicarboxylic amino acids
Belén Altava a, , M. Isabel Burguete a, Noèlia Carbó a, Santiago V. Luis a, , Vicente Martí-Centelles a,
⇑
⇑
Cristian Vicent b
a Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, Avda. Sos Baynat, s/n, 12071 Castellón, Spain
b Servei Centrals d0Instrumentaciò Cinetífica, Universitat Jaume I, Avda. Sos Baynat, s/n, 12071 Castellón, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A family of bis(amino amides) derived from natural amino acids has been synthesized and tested for the
NMR enantiodiscrimination, as chiral receptors, of some N-protected dicarboxylic amino acids. The influ-
ence of the amino acid side chain is an important parameter to obtain good enantiodiscrimination. The
binding between bis(amino amides) and N-protected dicarboxylic amino acids has been thoroughly stud-
ied by ESI-MS and NMR spectroscopic methods as well as by molecular modeling.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 September 2012
Revised 19 October 2012
Accepted 23 October 2012
Available online 1 November 2012
Keywords:
Bis(amino amides)
CSA
Chiral receptors
Dicarboxylic amino acids
Enantiodiscrimination
Introduction
Taking this into account, we considered the synthesis of new
bis(amino amides) derived from natural amino acids, with the gen-
Selective receptors for chiral molecules have many technologi-
cal, industrial, biomedical, and environmental applications.1 Thus,
artificial chiral receptors for carboxylic acids are important as
many relevant biomolecules contain this functionality. Dicarboxyl-
ates, implicated in different biomolecular processes, are particu-
larly important targets in this regard.2
eral structure 4 as effective chiral solvating agents for N-protected
dicarboxylic amino acids. An aliphatic spacer with five methylene
groups was selected for our study after some molecular modeling
in order to develop the appropriate ditopic receptor, and several
starting amino acids were considered.
Some polyamine receptors are able to interact with dicarboxylic
acids in both organic solvents and aqueous media.3 Although most
dicarboxylic acids present in biological systems are chiral, only a
few enantioselective receptors for chiral dicarboxylic acids have
been described.4 Peptidomimetic structures have been designed
for multiple purposes, including their use as chiral receptors, and
we have been recently involved in the preparation and study of
pseudopeptides with the general structure 4.5 In this context, some
of those compounds have shown to be efficient chiral shift agents
(CSAs) for the enantiodifferentiation of mandelic acid and some re-
lated guests, including relevant aryl propionic acids.6 Futhermore,
in the literature several host compounds with bisamide functional-
ities have been developed and studied as CSAs,7 for amines,7a,7b
derivatized amino acids,7c,7d and carboxylic acids.7e,7f,4q
Results and discussion
Open-chain pseudopeptides 4 derived from
L-phenylalanine,
L
-tryptophan, and -proline, were prepared from the corresponding
L
N-Cbz protected amino acid through the initial formation of their
activated N-hydroxysuccinimide esters (2), coupling with 1,5-pen-
tanediamine, and final N-deprotection, following reported proce-
dures (Scheme 1).8 Overall yields, after the final deprotection
step, were in the range of 80%. These chiral bis(amino amides)
were fully characterized by 1H NMR, 13C NMR, IR, ESI-MS, and EA.
Chiral Shift Agents (CSAs)
In preliminary experiments, 1H NMR spectroscopy was used to
investigate their chiral recognition ability using the racemic man-
delic acid 5.6 Table 1 shows the chemical shift non-equivalences
(
DDd) for the enantiomers of mandelic acid in the presence of
⇑
Corresponding authors. Tel.: +34 6472 8237; fax: +34 6472 8214 (B.A.); tel.: +34
6472 8239; fax: +34 6472 8214 (S.V.L.).
2 equiv of the different hosts in CDCl3/CD3OD (5%) at 30 °C. Higher
chemical shift non-equivalences were obtained with the bis(amino
E-mail addresses: altava@uji.es (B. Altava), luiss@uji.es (S.V. Luis).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.099

B. Altava et al. / Tetrahedron Letters 54 (2013) 72–79
73
O
(a)
O
O
H
N
H
N
i)
ii)
CαH
N
Cbz
O
OH
O
O
Cbz
R
O
O
R
2
1
NH
O
H
N
H
N
iii), iv)
H2N
NH2
N
N
N
N
H
Cbz
Cbz
3
H
H
3
H
R
R
R
R
(b)
3a Phe
3b Trp
3c Pro
4a Phe
4b Trp
4c Pro
CαH
NH
Scheme 1. Synthesis of chiral bis(amino amide) ligands. Reagents and conditions:
(i) DCC, N-hydroxysuccinimide, THF, rt, 24 h; (ii) H2NCH2(CH2)3CH2NH2, DME, rt
24 h; (iii) HBr/AcOH, rt 6 h; (iv) NaOHaq, rt.
6.5
6.3
6.1
5.9
5.7
5.5
5.3
5.1
4.9
4.7
4.5
4.3
4.1
3.9
δ (ppm)
Table 1
1H chemical non-equivalences
(DDd, 500 MHz) for
Figure 1. Partial 1H NMR spectra (CDCl3/CD3OD (1.5%), 500 MHz) of racemic CBz-
aspartic acid (a) before and (b) after the addition of 2 equiv of 4a (10 mM), showing
the splitting of signals corresponding to the carbamide NH and C H protons.
racemic mandelic acid in the presence of 4a–c in
CDCl3/CD3OD (5%) at 30 °C
a
Entrya
CSA
DDd (ppm)b
1
2
3
4
4a
4a
4b
4c
0.081c
0.033
0.045
0.021
Table 2
1H chemical non-equivalences (DDd, 500 MHz) of racemic dicarboxylic acids in the
presence of 4a–c in CDCl3/CD3OD (1–10%) at 30 °C
Entrya
CSA
Dicarboxylic acid
DDd (ppm)b
DDd (ppm)c
a
All samples were prepared by mixing 1 equiv of
racemic carboxylic acid (0.01 M) and 2 equiv of chiral
1
2
3
4
5
6
7
8
4a
4a
4b
4c
4a
4a
4b
4c
Cbz-Asp
Cbz-Asp
Cbz-Asp
Cbz-Asp
Cbz-Glu
Cbz-Glu
Cbz-Glu
Cbz-Glu
0.068d
0e
0.140d
0.150e
0.180e
0.050e
0.090d
0.075e
—
host (0.01 M) in NMR tubes.
0e
1H chemical shift non-equivalences of
a-H of
b
0e
mandelic acid.
0.010d
0e
c
CDCl3/CD3OD (1.5%).
0f
0e
0.170e
amides) containing aromatic side chains 4a and 4b (entries 1–3).
This suggests the location of the aromatic ring of the mandelic acid
close to the aromatic side chain of the hosts and the presence of
a
All samples were prepared by mixing 1 equiv of racemic dicarboxylic acid and
2 equiv of chiral host (0.01 M in CDCl3/CD3OD (1–10%) in NMR tubes.
intermolecular p–p
interactions.6
b
1H chemical shift non-equivalences of the
a
-H of dicarboxylic acids.
1H chemical shift non-equivalences of the carbamide NH proton of dicarboxylic
acids.
c
The enantiomeric discriminating ability of these bis(amino
amides) for the natural dicarboxylic amino acid derivatives Cbz-
aspartic acid 6 and Cbz-glutamic acid 7 (Chart 1) was then ex-
d
NMR measurements in CDCl3/CD3OD (1.5%).
NMR measurements in CDCl3/CD3OD (5%).
NMR measurements in CDCl3/CD3OD (10%).
e
f
plored. When the bis(amino amide) derived from L-phenylalanine
4a was used as CSA, upon addition of 0.5 equiv of Cbz-aspartic acid
in CDCl3/CD3OD (1.5%), the chemical shift values of the methine
CaH and carbamide NH proton signals of (L)-and (D)-Cbz-aspartic
in the presence of 2 equiv of the different bis(amino amides) 4a–c.
acid exhibited large upfield and downfield shifts respectively, lead-
As a general trend, the CaH from the guests moves upfield (Fig. 1)
ing to significant 1H chemical shift non-equivalences (DDd). This is
suggesting a deprotonation of the carboxylic groups.6 Concomi-
tantly, the amine NH proton signals of the receptors moves upfield
(see Fig. 4), indicating its protonation, leading to the formation of
the diastereomeric salts.
illustrated in Figure 1. In this case,
Dd values for CaH were 0.789
and 0.720 ppm for ( )- and ( )-enantiomers respectively, and
L
D
ꢀ0.507 and ꢀ0.386 ppm for carbamide NH protons.
Table 2 shows the chemical shift non-equivalences (DDd) ob-
served for the enantiomers of Cbz-aspartic and Cbz-glutamic acids
As shown in Table 2, all assayed bis(amino amides) produce
chemical shift non-equivalences for the carbamide NH proton
H
(a)
(b)
O
N
HO
CO2H
CO2H
CO2H
O
O
6
4 3
O
2
H2N
NH2
N
N
H
H
5
R
R
4a Phe
4b Trp
4c Pro
6
5
H
O
N
CO2H
O
CO2H
7
Chart 1. (a) Labeling of atoms for the general structure of the bis(amino amides). (b) Guests studied in this work: mandelic acid 5, Cbz-aspartic acid (Cbz-AspOH) 6, and Cbz-
glutamic acid (Cbz-GluOH) 7.

74
B. Altava et al. / Tetrahedron Letters 54 (2013) 72–79
interactions and dissociation of the ion pairs. In this regard, DD
d
(a)100
values were 0 or very small for the C -H protons when 4a–c were
a
used as CSAs in CDCl3/CD3OD containing >5% of CD3OD (entries 3,
4). For 4b, a higher amount of CD3OD was needed, in general, to ob-
tain clear solutions, explaining the lower DDd values observed in
some cases (i.e. entry 7 in Table 2).
As observed for mandelic acid, for Cbz-aspartic acid there were
always higher DDd values for the carbamide NH when receptors 4a
and 4b were used (DDd = 0.150 and 0.180 ppm), suggesting an
important role of intermolecular interactions involving the aro-
matic ring from the amino acid side chains and the aromatic at
the N-protecting group from the guest. The situation is, however,
different for Cbz-glutamic acid, for which the best DDd values
were obtained with the most basic receptor 4c (DDd = 0.170 ppm
for the carbamide NH).
90
80
70
60
50
40
30
20
10
0
y = 0,9808x + 0,3516
R² = 0,9982
0
20
40
60
80
100
ee % (prepared)
The practical applicability of receptor 4a to determine the enan-
tiomeric excess of different enantiomeric Cbz-AspOH mixtures by
integration of the corresponding NMR signals in the presence of
2 equiv of 4a was also demonstrated. The results, based on the car-
(b)100
90
80
70
60
50
40
30
20
10
0
bamide NH (Fig. 2a) and CaH (Fig. 2b) proton signals, are within
3% of the actual enantiopurity of the samples, rendering an excel-
lent linear response (R2 = 0.9982 and R2 = 0.9955 for the C
for the carbamide NH protons, respectively).
aH and
Binding studies
y = 0,9776x - 0,234
R² = 0,9955
The stoichiometries of the complexes were analyzed by Job’s
plot method. The determination of the stoichiometry of the species
formed is important to analyze in more detail the structure of the
complexes.9 As can be observed in Figure 3 for 4a, 1:1 recep-
tor:guest stoichiometries were obtained for the complexes formed
0
20
40
60
80
100
ee % (prepared)
Figure 2. Correlation between prepared and observed ee values obtained by
with both (L) and (D)-Cbz-aspartic acid. XG and XH are the molar
fractions of the guest Cbz-AspOH and the host 4a, respectively.
Similar results were obtained for other related systems.
Complexation studies of N-protected dicarboxylic amino acids
were also performed using 1H NMR titrations1,10 in CDCl3/CD3OD
(5%) at a constant concentration of the receptor, by the addition
of increasing amounts of the guest until saturation. Some interest-
500 MHz 1H NMR titrations of enantiomerically enriched mixtures of Cbz-AspOH
using 4a as CSA in CDCl3/CD3OD (1.5%) at 303 K. (a) For CaH proton signals. (b) For
carbamide NH proton signals.
0.25
Δδ XH
ing features can be pointed out. For 4a and Cbz-(D)-aspartic acid,
the C2-H and the amine NH protons (Chart 1) for 4a moved signif-
icantly downfield (Fig. 4). As mentioned previously, this supports a
proton transfer from the carboxylic group of the substrate to the
amino group of the receptor and hence, the formation of an ionic
pair. H4 and H5 protons in 4a also move upfield suggesting a
hydrogen bond interaction of the amide group from 4a and Cbz-
0.2
0.15
0.1
(D)-aspartic acid. Finally, changes observed for the phenyl moieties
of 4a (Fig. 4) point out to the participation of the aromatic rings in
the complex formation.
0.05
0
One important change upon diastereomeric complex formation
is the different multiplicity pattern obtained for the Cbz methylene
protons (see Fig. 5). This suggest that an important interaction for
the enantiopreference is close to these positions, reducing the con-
formational freedom and making the two methylene protons of the
Cbz group chemically non-equivalent (see Fig. 5a for the com-
0
0.2
0.4
0.6
0.8
1
XG
Figure 3. Job plots of 4a with
L
-Cbz-aspartic acid (stars) and with
D
-Cbz-aspartic
acid (squares). The d stands for the chemical shift change of the CaH proton of
D
Cbz-AspOH in the presence of host 4a. Total concentration is 10 mM, CDCl3/CD3OD
(1.5%).
plexes formed between 4a and (D) and (L)-Cbz-AspOH. Similar re-
sults were observed when 4b was used as receptor in the
titration experiments by the addition of increasing amounts of
signals of the Cbz-aspartic and glutamic acids (0.050–0.180 ppm).
The observed enantiodifferentiation was more efficient for both
dicarboxylic acids than for the monocarboxylic acid 5, according
to the design of the receptors. Compounds 4a and 4b were the best
CSAs for the enantiodiscrimination of Cbz-aspartic acid, while
receptor 4c exhibits best enantiodiscrimination for Cbz-glutamic
acid (entry 8). The use of polar protic solvents decreases the chem-
ical shift non-equivalences (DDd (compare entries 1–2 and 5–6),
which can be associated to favoring a decrease in intermolecular
(D) and (L)-Cbz-aspartic acid (Fig. 5b), while no differences in the
1H NMR between both enantiomers of Cbz-aspartic acid were ob-
served in the titration experiments when 4c was used as receptor
(Fig. 5c).
This behavior of the methylene protons from (D) and (L)-Cbz-
aspartic acid 6 was not observed for the two enantiomers of Cbz-
glutamic acid 7 when receptors 4a and 4c were used (see Fig. S1).
Taking into account the former results from NMR experiments,
we performed molecular modeling calculations to better

B. Altava et al. / Tetrahedron Letters 54 (2013) 72–79
75
NH
H5
H2
H4
H4
NH
H2
H5
NH
H5
H2
H4
NH
H5
H2
H4
7.35 7.30
7.25 7.20 7.15 7.10
4.2 3.9
3.5
3.1
2.7
2.3
1.9
1.5
1.1
δ (ppm)
δ (ppm)
Figure 4. Partial 1H NMR spectra (CDCl3, 300 MHz) of 4a in the presence of different amounts of (
D)-Cbz-AspOH (from bottom to top 1:0, 3:1, 2:1, 1:1 receptor:guest ratios).
(a)
(b)
(c)
Figure 5. Partial 1H NMR spectra (CDCl3/CD3OD (5%), 300 MHz) for
(c) 4c. All the signals correspond to the Cbz-methylene protons.
L-Cbz-aspartic acid (top) and D-Cbz-aspartic acid (bottom) in the presence of 1 equiv of (a) 4a (b) 4b and
understand the nature of the complexes formed between 4a–4c
and ( ) and ( )-Cbz-AspOH. The calculations were carried out with
after proton transfer from the aspartic acid to the amino group of
the receptor) are shown in Fig. 6. The relative energies for the com-
D
L
the program Spartan’08,11 using the Monte Carlo conformational
searches performed at the Merck molecular force field (MMFF).
The most stable conformers obtained in the conformational search
were then optimized with the semiempirical PM6 method using
the GAUSSIAN 09 program12 in CHCl3 using the SCRF methodology.
The stationary points have been characterized as true minima by
the calculation of the normal vibration modes, being all the values
positive. The conformers with the minimum energy obtained for
plexes of receptors 4a–c with both
also computed. For all the cases, the
form more stable complexes than the
Moreover, several interactions are present in the optimized
structures for the complexes of 4a–c with ( ) and ( )-Cbz-AspOH
(1:1 ratio). The first one is the electrostatic interactions due to
ion-pair formation. An intermolecular hydrogen bond between
one of the carboxylate groups and the two amide NH groups of
the receptor is also present.
D
and
-enantiomer was found to
-enantiomer (Table 3).
L guest enantiomers were
D
L
L
D
the complexes between 4a–c and (L) and (D)-Cbz-AspOH (1:1 ratio,

76
B. Altava et al. / Tetrahedron Letters 54 (2013) 72–79
Finally, the binding constants (Ka) were calculated by means of
a nonlinear curve fitting method for the downfield shift of the C2-H
proton signal observed upon addition of the guest (see Supplemen-
tary data for complexation curves).13 Association constants (Ka)
and free energy changes (ꢀ
constants could not be obtained for 4b because some precipitation
occurs in NMR tubes during titration experiments. In general, ( )-
Cbz-AspOH and ( )-Cbz-GluOH acids have association constants
slightly higher than their ( )-enantiomers and data presented in
DGo) are shown in Table 4. Binding
D
D
L
Table 4 reveal that the enantiorecognition process is weak for the
1:1 equilibrium. It is interesting to note that 4a shows a small
selective recognition of Cbz-aspartic acid over Cbz-glutamic acid
(selectivity constant ꢁ2), while no selectivity at all is observed
for 4c. In addition, the stronger association constants are observed
for the most basic receptor 4c,5l which confirms that protonation of
the receptor and the consequent ion pair formation is a critical
event and determines the strength of such association process.
As very low enantioselectivities were displayed by 4a and 4c in
terms of association constants, the enantiodifferentiation process
must be associated to the presence of clearly different structures
for the two diastereomeric complexes.
Finally, we also studied the supramolecular complex formed be-
tween 4a–4c with the (D)-Cbz-aspartic acid by ESI-MS experi-
ments. The use of mass spectrometry in supramolecular
chemistry has tremendously grown, as soft ionization techniques
(such as ESI) usually render a good preservation of weak intermo-
lecular interactions, allowing the detection of the corresponding
receptor–substrate complexes.14 To study the binding difference
between receptors 4a, 4b, and 4c a series of competition experi-
ments were undertaken.15 Typically, to a equimolar mixture of
4a–4c in CH2Cl2:CH3OH (9:1) a deficit of (D)-Cbz-aspartic acid
was added and the resulting mixture was directly electrosprayed
using soft ionization conditions, with low cone voltages
Uc = 15 V. As seen in Figure 7, peaks corresponding to the supramo-
lecular [4a–4c + A + 2H]2+ species are clearly inferred.
Figure 6. Minimum energy structures for the complexes formed between receptors
The corresponding doubly-charged [4a–4c + A + 2H]2+ supra-
4a–c and (
L
) or (D)-Cbz-AspOH. (a) 4a:
D-Cbz-AspOH (b) 4a:
L
-Cbz-AspOH (c) 4b:
-Cbz-AspOH.
D-Cbz-AspOH (d) 4b:
L-Cbz-AspOH (e) 4c:
D
-Cbz-AspOH (f) 4c: L
molecular species (where A corresponds to (D)-Cbz-AspOH) were
detected in the positive ESI scan mode, and clear differences in
terms of signal abundances were observed. These can be used to
extract relative binding affinities.14b,c The experimental ESI compe-
tition results suggest relative binding affinities following the
4c > 4b > 4a trend. This correlates well with the trends from solu-
tion binding constants.
We also investigated the intrinsic gas-phase stability of these
[4a–4c + A + 2H]2+ adducts by collision induced dissociation (CID)
experiments (Figs. S3-S5). A number of dissociation channels were
observed for the [4a–4c + A + 2H]2+ dications that are summarized
in Eqs. (1) and (2).
Table 3
Relative energies for the supramolecular complexes
calculated at PM6 level of theory in CHCl3
Complex
DGD–L (kcal/mol)
4aꢂZ-Asp
4bꢂZ-Asp
4cꢂZ-Asp
ꢀ1.54
ꢀ0.71
ꢀ0.54
However, the most important differences between the diaste-
reomeric complexes are associated to intermolecular interactions
involving the Cbz moiety. One of them is a H-bond between one
ammonium group of the receptors 4a and 4b and the carbamide
Table 4
CO group; this interaction is only present in the
plexes (Fig. 6a and c). At the same time, intermolecular
actions can be detected involving the aromatic rings of the
receptors 4a and 4b and the aromatic ring of the Cbz-AspOH
D
-AspOH com-
inter-
Asociation constants (Ka), Gibbs free energy changes (ꢀ
Ka(D)/Ka(L) (or DDGo calculated from ꢀ Go) for the complexation of 4a and 4c with
(D)- or (L)-dicarboxylic acids in CDCl3/CD3OD (5%) at 30 °C
DGo), and enantioselectivity
D
p–p
Entry
Host
Guest
Ka (Mꢀ1
)
ꢀ
D
Go
DDGo
(kcal/mol)
(kcal/mol)
(i.e:
4a:
p
–
p
distances 2.849 and 2.817 Å for 4a:
D-Cbz-AspOH and
1
2
3
4
5
6
7
8
4aa
4aa
4ab
4ab
4cb
4cb
4cb
4cb
(
(
(
(
(
(
(
(
D
)-CbzAspOH
)-CbzAspOH
)-CbzGluOH
)-CbzGluOH
)-CbzAspOH
)-CbzAspOH
)-CbzGluOH
)-CbzGluOH
411 37
378 35
218 19
227 20
650 51
572 55
844 50
750 35
3.3
3.2
3.1
3.1
3.5
3.4
3.6
3.6
0.1
0
L
-Cbz-AspOH respectively). These intermolecular interactions
L
are not present in the diastereomeric complexes formed with 4c
and this can explain the differences observed in 1H NMR experi-
ments when the aromatic receptors 4a–4b and the non aromatic
receptor 4c are used as CSA for the Cbz-AspOH. Moreover, the
different environment observed in Fig. 6 for the protons of the
NH carbamide group in diastereromeric complexes are in good
agreement with the observed differences in chemical shifts
(Table 2, entries 2–4).
D
L
D
0.1
0
L
D
L
a
Concentration of host 0.016 M.
Concentration of host 0.009 M.
b

B. Altava et al. / Tetrahedron Letters 54 (2013) 72–79
77
[4b+A+2H]2+
371.7
100
[4a+A+2H]2+
332.7
339.3
[4c+2H]2+
354.1
363.1
368.1
149.1
100
[4a+2H]2+
346.1
199.2
0
m/z
330 335 340 345 350 355 360 365 370 375
[4b+2H]2+
[4c+A+2H]2+
238.2
[4a+H]+
[4c+H]+
397.3
297.3
[4b+H]+
475.3
309.3
283.2
0
m/z
150
200
250
300
350
400
450
500
Figure 7. Positive ESI mass spectrum of an equimolar mixture of 4a–4c and 0.5 equiv of (D)-Cbz-AspOH recorded in CH2Cl2:CH3OH (9:1) and at Uc = 15 V. The circled area
shows an inset of the m/z 330–380 region.
2þ
½4 þ A þ 2Hꢃ ! ½4 þ 2Hꢃ2þ þ A
ð1Þ
ð2Þ
basicity, according to previously reported data for similar com-
pounds,5l which could indicate the key importance of proton trans-
2þ
½4 þ A þ 2Hꢃ ! ½4 þ Hꢃþ þ ½A þ Hꢃþ
fer. In the case of receptors containing aromatic side-chains,
p–p
interactions seem to be involved in complex formation. A good
agreement was observed between NMR results and those obtained
by ESI-MS and calculations.
For [4a–4b + A + 2H]2+ dications, both dissociation channels de-
picted in Eqs. (1) and (2) are operative where the supramolecular
[4a + A + 2H]2+ adduct is more prone to be dismantled at identical
collision energies, thus suggesting an inherently lower gas-
Experimental section
phase stability than that of [4b + A + 2H]2+
. CID spectra of
[4c + A + 2H]2+ revealed the exclusive release of neutral A accord-
ing to Eq. (1) while dissociation channel depicted in Eq. (2) was
not operative. Higher collision energies to those observed for
[4a–4b + A + 2H]2+ were required to promote dissociation of the
[4c + A + 2H]2+ dication. Noticeably, dissociation of two neutral
NH3 molecules from [4c + A + 2H]2+ was observed (most likely
associated to the two amino groups of the 4c host) simultaneously
with the liberation of the guest A. Dissociation of host:guest supra-
molecular adducts via covalent bond cleavages is less common
than those of liberation of the guest. It has been observed for
example in cucurbituril host:guest chemistry16 and it is indicative
of a remarkable gas-phase stability.
Materials and reagents
All reagents were used as purchased from commercial suppliers
without further purification. Chiral a-amino amides were synthe-
sized as previously described7 while all the N-protected amino
acids were commercially available. The NMR spectroscopic exper-
iments were carried out on a 500 or 300 MHz for 1H and 13C NMR,
respectively. The chemical shifts are reported in ppm using tri-
methylsilane (TMS) as a reference. FTIR spectra were acquired with
a MIRacle single-reflection ATR diamond/ZnSe accessory.
General procedure for the preparation of N-hydroxysuccinimide
esters of amino acids7
Conclusions
N-Cbz-L-aa (1 mmol) and N-hidroxysuccinimide (1 mmol) were
dissolved in dry THF at 0 °C. Once a clear solution had been ob-
tained, DCC (1 mmol) in anhydrous THF (40 mL) was added in sev-
eral aliquots and the resulting solution was stirred at 0–5 °C for
3 h. The dicyclohexylurea formed was filtered off and the filtrate
was concentrated to dryness. The crude product was recrystallized
from 2-propanol to furnish the pure product.
In conclusion, we have synthesized a new family of CSAs based
on bis(amino amide) ligands derived from natural amino acids and
demonstrated that they are good receptors for N-protected dicar-
boxylic amino acids. The formation of diastereomeric complexes
is fast and quantitative, being possible the analysis in situ using
NMR spectrometry. A multidisciplinary study using mass spec-
trometry, NMR, and molecular modeling, has allowed us to identify
the structural factors responsible for the interactions. In solution,
the substrate-induced chemical shifts of the NMR signals of recep-
tors 4a–4c showed the formation of an ionic pair upon proton
transfer from the carboxylic groups to the amino nitrogen of bis(a-
mino amides). Different intermolecular interactions between the
Cbz moiety of the guest and the receptors are observed, which
could explain the strong chemical shift non-equivalence for the
NH carbamide signal. In some instances, chemical shift non-
General procedure for the synthesis of Cbz-N-protected
bis(amino amide) ligands7
The N-hydroxysuccinimide ester of N-Cbz-L-aa (1 mmol) was
dissolved in anhydrous DME (30 mL) cooled in an ice bath. Penthy-
lenediamine (0.5 mmol) dissolved in dry DME was added several
times. The reaction mixture was stirred at room temp for 18 h
and then was warmed for 6 h at 40–50 °C. The white solid was fil-
tered off and washed with cold water and cold methanol. The ob-
tained compounds showed high purity by NMR and were used in
the next step without further purification steps.
equivalences are observed for the Ca-H of the guest, but only for
the receptor 4a derived from Phe. It seems that the stronger
complexes (Ka >500) are formed with receptor showing a higher

78
B. Altava et al. / Tetrahedron Letters 54 (2013) 72–79
General procedure for the deprotection of N-protected
bis(amino amide) ligands7
NMR chiral shift experiments
The chiral shift experiments were performed at 30 °C. Samples
for analysis were prepared by mixing CSA 4a–c with different car-
boxylic acids.
N,N0-bis(N-Cbz-
L-aa)-1,5-diaminopentane (1 mmol) was added
to HBr/AcOH (33%) (20 mL) and the mixture was stirred at room
temp. until CO2 evolution ceased. At this point, diethyl ether
(50 mL) was added to the clear solution, which led to the deposi-
tion of a white precipitate. This was filtered off, washed with addi-
tional ether, and dissolved in distilled water, the resulting solution
was extracted with chloroform (3 ꢄ 10 mL). Solid NaOH was then
added up to a pH value of 12 and the resulting solution was satu-
rated with NaCl and extracted with chloroform (3 ꢄ 10 mL). The
organic phase was dried over MgSO4 and evaporated under vac-
uum to obtain a white solid.
NMR host–guest titration
1H NMR titrations were performed by adding incremental
amounts of (R)- or (S)-CBz-dicarboxylic amino acid to a NMR tube
containing a solution of host 4a or 4c (10 mM, CDCl3/CD3OD (5%))
so that the total concentration of host was kept constant.
Determination of stoichiometry of the host–guest complex (Job
plots)
Synthesis of N,N0-bis(N-
This compound was obtained as described above starting
L-phenylalanine)-1,5-diaminopentane
The CSA 4a and Cbz-AspOH were distributed among 10 NMR
tubes, with various amounts of CSA and Cbz-AspOH, so that the to-
tal concentration of CSA and acid was 10 mM, and the molar ratio
of the CSA to the acid in the 10 tubes was increased from 0.1 to 1.
The 1H NMR spectrum of each sample was recorded on a 500 MHz
spectrometer.
from N,N0-bis(N-Cbz-
L-phenylalanine)-1,5-diaminopentane and
HBr–AcOH solution. Yield = 82% (1.1 g); mp = 132–134 °C; ½a D20
ꢃ
=
ꢀ82.4° (c = 0.01, CHCl3); ESI-MS m/z = 397.1 (100, M+H+), 419.1
(30, M+Na+); IR max = 3365, 3289, 1650, 1628, 1547, 1525 cmꢀ1
m ;
1H NMR (500 MHz, CDCl3/CD3OD (1.5%), 30 °C) d = 1.2–1.30 (m,
2H, (CH2)2CH2(CH2)2), 1.44–1.53 (m, 4H, CH2CH2CH2CH2CH2),
2.68 (dd, 2H, J = 13.52, 5.5 Hz, CH2Ph), 3.17–3.27 (m, 6H, CH2Ph,
CH2CH2CH2CH2CH2), 3.56 (dd, 2H, J = 9.2, 4.2 Hz, CH⁄), 7.17–7.34
(m, 10H, Ar-H); 13C NMR (125 MHz, CDCl3, 30 °C) d = 26.3, 29.4,
38.8, 41.0, 56.4, 126.6, 128.5, 129.1, 137.8, 173.9; Elemental anal-
ysis calcd (%) for C23H32N4O2: C, 69.67; H, 8.13; N, 14.13. Found:
C, 69.85; H, 8.21; N, 14.18
Acknowledgments
Financial support from Ministerio de Ciencia y Tecnología
(CTQ2011-28903-C02-01), Fundación Caixa Castelló-Bancaixa
(P1-1B-2009-58), and Generalitat Valenciana PROMETEO 2012/
020 is acknowledged. N.C. thanks Bancaixa for a fellowship. The
authors are grateful to the Serveis Centrals d’Instrumentació
Científica (SCIC) of the Universitat Jaume I for the spectroscopic
facilities.
Synthesis of N,N0-bis(N-
This compound was obtained as described above starting from
N,N0-bis(N-Cbz-
-triptophan)-1,5-diaminopentane and HBr–AcOH
solution. Yield: 93% (1.8 gr). Mp = 110–115 °C; = +19.9°
(c = 0.01, MeOH); ESI-MS m/z = 475.3 (100, M+H+); IR
max = 3288,
3112, 2929, 2861, 1643, 1534, 1456, 1439, 1023, 1004, 740 cmꢀ1
L-triptophan)-1,5-diaminopentane
L
Supplementary data
½ ꢃ
a 2D0
m
Supplementary data (partial 1H NMR for
-Cbz-GluOH in the presence of 4a, 4c. Complexation curves for
L-Cbz-GluOH and
;
D
1H NMR (500 MHz, CDCl3/CD3OD (5%), 30 °C) d = 0.95–0.86 (m,
2H, (CH2)2CH2(CH2)2), 1.21–1.28 (m, 4H, CH2CH2CH2CH2CH2),
3.02–3.12 (m, 6H, CH2Ind, CH2CH2CH2CH2CH2), 3.20 (dd, 2H,
J = 14.4, 5.6 Hz, CH2Ind), 3.60–3.68 (m, 2H, CH⁄), 7.01 (s, 2H, Ar-
H), 7.06 (t, 2H, J = 7.5 Hz, Ar-H), 7.14 (t, 2H, J = 7.5 Hz, Ar-H),
7.36 (d, 2H, J = 8.1 Hz, Ar-H), 7.61 (d, 2H, J = 7.9 Hz, Ar-H); 13C
NMR (125 MHz, CDCl3, 30 °C): 23.7, 29.3, 30.7, 38.8, 55.8, 110.8,
111.4, 111.6, 118.6, 118.7, 119.3, 119.5, 121.8, 122.0, 123.4,
123.6, 127.9, 136.4; Elemental analysis calcd (%) for C27H34N6O2.
H2O: C, 65.85; H, 7.32; N, 17.07. Found: C, 65.33; H, 6.87; N,
16.61.
4a and 4c with (L) and (D)-Cbz-AspOH and (L) and (D)-Cbz-GluOH.
CID spectra for mass selected [4a + A + 2H]2+. CID spectra for mass
selected [4b + A + 2H]2+. CID spectra for mass selected [4c + A +
2H]2+. Cartesian coordinates for the minimized structures) associ-
ated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.10.099.
References and notes
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Synthesis of N,N0-bis(N-
This compound was obtained as described above starting from
N,N0-bis(N-Cbz-
-proline)-1,5-diaminopentane and HBr–AcOH
solution Yield = 80% (0.8 gr); mp = 95–100 °C;
(c = 0.01, MeOH); ESI-MS m/z = 297.0 (100, M+H+); IR
2931, 2864, 1646, 1522 cmꢀ1
L-proline)-1,5-diaminopentane
L
½
a 2D0
ꢃ
= ꢀ73.7°
m
max = 3297,
;
1H NMR (500 MHz, CDCl3, 30 °C)
d = 1.23–1.32 (m, 2H, (CH2)2CH2(CH2)2)), 1.40–1.50 (m, 4H,
CH2CH2CH2CH2CH2), 1.58–1.68 (m, 4H, CH2), 1.77–1.89 (m, 2H,
CH2), 2.00–2.10 (m, 2H, CH2), 2.78–2.85 (m, 2H, CH2), 2.89–2.97
(m, 2H, CH2), 3.15 (dd, 4H, J = 13.5, 6.8 Hz, CH2CH2CH2CH2CH2),
3.64 (dd, 2H, J = 9.1, 5.3 Hz, CH⁄), 7.53 (br, 2H, NH); 13C NMR
(125 MHz, CDCl3, 30 °C) d = 24.2, 26.1, 29.3, 30.7, 38.6, 47.2,
60.6, 174.8; Elemental analysis calcd (%) for C15H28N4O2. H2O: C,
57.32; H, 9.55; N, 17.83 Found: 57.02; H, 10.01; N, 17.3

B. Altava et al. / Tetrahedron Letters 54 (2013) 72–79
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