Supramolecular control for the modular synthesis of pseudopeptidic macrocycles through an anion-templated reaction

Article abstract of DOI:10.1021/ja710132c

The anion-templated synthesis of different pseudopeptidic macrocycles has been studied in detail by using a multidisciplinary approach. The reaction between an open-chain pseudopeptidic diamine and the appropriate dialdehyde is highly affected by the presence of the best fitting anionic template. The formation of the corresponding macrocyclic tetraimino-template supramolecular complex is demonstrated by NMR (ROESY and PGSE) and mass spectrometry (ESI-TOF). These supramolecular complexes can be easily reduced to the corresponding more stable tetraamine macrocycles. Accordingly, we have used this reaction to efficiently synthesize a family of new pseudopeptidic macrocycles in a one-pot two-steps anion-templated reductive amination reaction, which comprises a multicomponent macrocyclization through the selective formation of four chemical bonds to yield a unique macrocyclic structure. Different variables like the aliphatic spacer between amino acidic moieties, geometry of the dialdehyde, and structure of the amino acid side chains were thoroughly studied, and their effect in the formation and stability of the supramolecular complexes discussed. The conformational preorganization induced by the template has been monitored by circular dichroism, reflecting the differences observed in the isolated yields, as well as by NMR spectroscopy. This effect has been also supported by molecular modeling. All the experimental and theoretical techniques were strongly consistent and reflected the same trends by comparing the different structural variables introduced in the system.

Full text of DOI:10.1021/ja710132c

Published on Web 04/11/2008
Supramolecular Control for the Modular Synthesis of
Pseudopeptidic Macrocycles through an Anion-Templated
Reaction
Ignacio Alfonso,*,† Michael Bolte,‡ Miriam Bru,§ M. Isabel Burguete,§
Santiago V. Luis,*,§ and Jenifer Rubio§
Departamento de Química Orgánica Biológica, Instituto de InVestigaciones Químicas y
Ambientales de Barcelona, Consejo Superior de InVestigaciones Científicas (IIQAB-CSIC), Jordi
Girona, 18-26, E-08034, Barcelona, Spain, Institut für Anorganische Chemie, J. W.
Goethe-UniVersität Frankfurt, Max-Von-Laue-Strasse 7, 60438, Frankfurt am Main, Germany,
Departamento de Química Inorgánica y Orgánica, UAMOA, UniVersidad Jaume I/CSIC,
Campus del Riu Sec, AVenida Sos Baynat, s/n, E-12071, Castellón, Spain
Received November 8, 2007; E-mail: iarqob@iiqab.csic.es; luiss@qio.uji.es
Abstract: The anion-templated synthesis of different pseudopeptidic macrocycles has been studied in detail
by using a multidisciplinary approach. The reaction between an open-chain pseudopeptidic diamine and
the appropriate dialdehyde is highly affected by the presence of the best fitting anionic template. The
formation of the corresponding macrocyclic tetraimino-template supramolecular complex is demonstrated
by NMR (ROESY and PGSE) and mass spectrometry (ESI-TOF). These supramolecular complexes can
be easily reduced to the corresponding more stable tetraamine macrocycles. Accordingly, we have used
this reaction to efficiently synthesize a family of new pseudopeptidic macrocycles in a one-pot two-steps
anion-templated reductive amination reaction, which comprises a multicomponent macrocyclization through
the selective formation of four chemical bonds to yield a unique macrocyclic structure. Different variables
like the aliphatic spacer between amino acidic moieties, geometry of the dialdehyde, and structure of the
amino acid side chains were thoroughly studied, and their effect in the formation and stability of the
supramolecular complexes discussed. The conformational preorganization induced by the template has
been monitored by circular dichroism, reflecting the differences observed in the isolated yields, as well as
by NMR spectroscopy. This effect has been also supported by molecular modeling. All the experimental
and theoretical techniques were strongly consistent and reflected the same trends by comparing the different
structural variables introduced in the system.
non-natural tertiary structures.7 Thus, they are excellent candi-
dates as scaffolds for the design of relatively complex structures
Introduction
Amino acid derived macrocyclic compounds have recently
drawn much attention in very different fields like synthetic,1
bioorganic,2 medicinal,3 and supramolecular chemistry.4 Their
large ring structure restricts the conformational freedom and
usually confers them a geometrical organization of the amino
acid residues in a preferred disposition,5 allowing them to host
small molecules and ions,6 with interesting potentials in mol-
ecular recognition. Besides, they are attractive scaffolds for the
assembly of functional groups in a well defined three-
dimensional geometry, for the mimicry of biological natural and
aiming the interaction with biological functions.8 Another
interesting property of peptide-like macrocycles is their ability
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Chem. ReV. 2004, 104, 6085–6117. (b) Reid, R. C.; Pattenden, L. K.;
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† Consejo Superior de Investigaciones Científicas (IIQAB-CSIC).
‡ Goethe-Universität Frankfurt.
§ Universidad Jaume I/CSIC.
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Int. Ed. 2005, 44, 2215–2220. (d) Cristau, P.; Martin, M.-T.; Tran Hu
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2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 6137–6144 6137

A R T I C L E S
Alfonso et al.
to self-assemble into superior structures.9 Accordingly, they can
form supramolecular nanotubes10 and gels11 with very interest-
ing biological properties as antibacterial or anti-HIV drugs,12
delivery systems,13 and nanomaterials.14 The peptidic frame
usually makes them highly biocompatible and also allows a
broad range of molecular diversity through side-chain replace-
ments. However, the key step for the chemical synthesis of this
family of compounds is the macrocyclization reaction.15 Apart
from those systems showing a conformational preorganization
for the cyclic structure,16 this step usually requires high dilution
techniques or the use of protecting groups which lead to low
yields, mixtures of oligomers of different sizes, and tedious
purification steps.17 Several approaches to overcome this
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supramolecular techniques like templated synthesis seemed
especially attractive within this context.19 Although templation
based on cationic species is a well-known process,20 anion
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to inorganic spherical species.21 As far as we know, only some
remarkable examples dealing with tetrahedral22 and octahedral23
anions have been reported. The reason for the gap between the
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chemistry studies a bit tougher. During the last couple of years,
anion templation has been successfully used for the synthesis
of rotaxanes,25 pseudorotaxanes,26 catenanes,27 (metalla)mac-
rocycles,28 and molecular cages,29 but the use of this approach
for peptide-like macrocycles is almost nonexistent.
On the other hand, we have recently synthesized and studied
new pseudopeptidic macrocycles30 with interesting properties
as organogelators,31 molecular receptors,32 chemosensors,33 or
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Synthesis of Pseudopeptidic Macrocycles
A R T I C L E S
Scheme 1
molecular devices.34 Within this research project, we envisioned
the preparation of larger structures to expand the possibilities
for the generation of a family of compounds by increasing the
size and complexity of the substrates. To achieve this goal
reductive amination between the corresponding bis(amidoamine)
1a and dialdehyde 2a seemed to be a reasonable option (Scheme
1). Unfortunately, we found that a well-defined conformational
preorganization is mandatory for the formation of the desired
[2 + 2] tetraimino intermediate.35 In the absence of such
preorganization, the reaction always led to a complex mixture
of oligomers. Here we report on the use of anionic dicarboxy-
lates to template36 this process for the most flexible examples,
bearing a linear aliphatic spacer between aminoacidic moieties.
Different structural variables have been mapped on the mac-
rocyclic framework and their effect on the templation procedure
has been studied by different experimental and theoretical
approaches.
Results and discussion
Design of the Anion Templation Approach. After the pre-
liminary study of the configurationally driven preorganization
necessary for the proposed [2 + 2] macrocyclization reaction,
we decided to use a different method to promote such a
conformational folding. According to the well-established
binding modes between anions and NH amide groups,37 we
screened, by molecular modeling, several anions as templates
for the desired process.38 Starting from the modeled structure
of the [2 + 2] tetraimino intermediate, we studied the possible
noncovalent complexes between the proposed macrocycle and
different anions. Monte Carlo analyses rendered terephthalate
3a as the best candidate, showing an excellent structural
complementarity with the macrocycle (Figure 1). According to
the computer generated structure, this dianion would present
four hydrogen bonds between its carboxylate groups and the
amide hydrogen atoms of the bisamide moieties and also a
possible π-stacking interaction with the aromatic rings of the
macrocycle.39 Besides, CPK inspection of this structure showed
that the template perfectly fills the macrocyclic cavity, maximiz-
ing the entropic contribution due to the desolvation of the inner
cavity of the cycle.
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To check this proposal, we followed the reaction between
the bis(aminoamide) 1a and dialdehyde 2a by different tech-
1
niques. The H NMR spectrum of the crude of the reaction
between 1a and 2a (methanol-d4, room temp, 3 h) showed a
complicated group of signals (Figure 2a), indicative of a mixture
of species in solution. The observation of aldehyde (9.9–10.2
ppm) and R-methoxyamine (at ca. 5.6 ppm) protons clearly
demonstrates the existence of open-chain derivatives. The
presence of other anions (as tetrabutylammonium -TBA- salts)
had minor effects on the 1H NMR spectra (Figure 2b-d).
However, when terephthalate dianion 3a was used, the spectrum
after 3 h showed an almost quantitative conversion to a major
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Escuder, B. F.; Galindo, R.; Gavara, J. F.; Miravet, S. V.; Luis, G.
Chem. Eur. J. 2004, 10, 3879–3890.
(32) Alfonso, I.; Burguete, M. I.; Luis, S. V.; Miravet, J. F.; Seliger, P.;
Tomal, E. Org. Biomol. Chem. 2006, 4, 853–859.
(37) (a) Kang, S. O.; Begum, R. A.; Bowman-James, K. Angew. Chem.,
Int. Ed. 2006, 45, 7882–7894. (b) Kang, S. O.; Hossain, M. A.;
Bowman-James, K. Coord. Chem. ReV. 2006, 250, 3038–3052. (c)
Chimielewski, M. J.; Jurczak, J. Chem. Eur. J. 2005, 11, 6080–6090.
(d) Kang, S. O.; VenderVelde, D.; Powell, D.; Bowman-James, K.
J. Am. Chem. Soc. 2004, 126, 12272–12273. (e) Bondy, C. R.; Loeb,
S. J. Coord. Chem. ReV. 2003, 240, 77–99. (f) Beer, P. D.; Hayes,
E. J. Coord. Chem. ReV. 2003, 240, 167–189.
(33) (a) Burguete, M. I.; Galindo, F.; Izquierdo, M. I.; Luis, S. V.; Vigara,
L. Tetrahedron 2007, 63, 9493–9501. (b) Galindo, F.; Burguete, M. I.;
Vigara, L.; Luis, S. V.; Russell, D. A.; Kabir, N.; Gavrilovic, J. Angew.
Chem., Int. Ed. 2005, 44, 6504–6508. (c) Galindo, F.; Becerril, J.;
Burguete, M. I.; Luis, S. V.; Vigara, L. Tetrahedron Lett. 2004, 45,
1659–1662.
(34) (a) Alfonso, I.; Burguete, M. I.; Galindo, F.; Luis, S. V.; Vigara, L. J.
Org. Chem. 2007, 72, 7947–7956. (b) Alfonso, I.; Burguete, M. I.;
Luis, S. V. J. Org. Chem. 2006, 71, 2242–2250.
(38) Monte Carlo conformational searches with MMFF force field mini-
mizations and estimation of molecular volumes were performed with
the Spartan 04 package.
(39) Recent studies suggested that such π-stacking interactions can be
discarded or have a minor importance: Dell’Anna, G.; Benaglia, M.;
Raimondi, L.; Cozzi, F Org. Biomol. Chem. 2007, 5, 2205–2206.
(35) Bru, M.; Alfonso, I.; Burguete, M. I.; Luis, S. V. Tetrahedron Lett.
2005, 46, 7781–7785.
(36) Bru, M.; Alfonso, I.; Burguete, M. I.; Luis, S. V. Angew. Chem., Int.
Ed. 2006, 45, 6155–6159.
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A R T I C L E S
Alfonso et al.
in the computed structure). Moreover, PGSE NMR42 experi-
ments showed that signals from the macrocyclic imine and from
the anion diffuse at the same rate, supporting that they form
part of the same supramolecular entity. Quantitative analysis
rendered a self-diffusion coefficient D ) 5.9 ( 0.1 × 10-10
m2 ·s-1, much smaller than that of the free solvated template
(6.4 ( 0.1 × 10-10 m2 ·s-1). Accordingly, the diffusion volume
of the supramolecular complex was estimated to be 950 Å3,
while the computed volume of the minimized structure was 907
Å3. This represents a very good agreement considering the
number of approximations assumed.43
Definitive proofs for the existence of the proposed supramo-
lecular structure were obtained by mass spectrometry. Thus, ESI-
TOF mass spectra of the crude reaction mixture, at the negative
detection mode, showed two major peaks at m/z ) 438.2 and
877.5 corresponding to the dianionic and sodiated monoanionic
complexes, respectively. Full isotopic analyses also confirmed
these assignments (Figure S4) showing a perfect agreement
between simulated and experimental mass spectra, and sup-
porting the large stability of the proposed supramolecular
complex, which resists the conditions of the mass spectrometry
measurement. We also performed the ESI-TOF MS with the
other assayed templates (chloride, acetate and benzoate).
Interestingly, the supramolecular complexes formed by the
macrocyclic tetraimine and the anions were detected as minor
peaks. However, they were accompanied by major species where
the imine bond has not been formed, namely of the type [1a +
2a + A]- and [1a + (2a)2 + A]- with A as the corresponding
anion. This observation suggests a less specific association with
a lower propensity to undergo condensation toward the corre-
sponding macrocycles.
Thus, combination of NMR and ESI-TOF MS techniques
unambiguously showed the anion templation effect on this
system and also served to characterize the corresponding
supramolecular species formed in solution. At that point, we
wondered if this methodology would allow us to synthetically
prepare the corresponding tetraamino derivative, by the in situ
reduction of the four imine bonds on the intermediate. Satisfy-
ingly, borohydride reduction of the supramolecular complex led
to the expected compound in very good overall yield (60%)
after chromatographic purification. The final compound was
fully characterized by spectroscopic techniques and single crystal
X-ray diffraction analysis of the corresponding tetrahydrochlo-
ride salt (see Supporting Information). We envisioned to extend
this methodology to the preparation of a family of compounds
by mapping different variables of the macrocyclic structure
(Scheme 2, Table 1) such as the aliphatic spacer (n ) 0–2),
amino acid side chain (aliphatic, aromatic, branched, H-
bonding), and dialdehyde geometry (para/meta). In all the cases,
the corresponding macrocycles were obtained in good overall
yields (Table 1), considering the difficulty of macrocyclization
Figure 1. (A) Up and (B) side views of the optimized geometry for the
proposed supramolecular complex between the tetraimino macrocycle (stick)
and terephthalate dianion (space filling).
(>90%) imino compound with a remarkable D2 symmetry
(Figure 2e). The supramolecular species thus formed was
completely characterized by a full set of NMR experiments
(Supporting Information, Figures S1-S3), showing a good
agreement with the proposed structure.40 The macrocycle shows
only one imine methyne signal and one single aromatic peak.
Besides, the 13C NMR chemical shift for the inimo CdN atom
(162.7 ppm) suggests a conjugated aromatic diimine moiety.
The high symmetry of the spectra implies an S-trans configu-
ration of the diimino moieties. The imino proton signal (at 8.24
ppm) showed a strong ROE effect with the CRH (at 3.59 ppm)
of the pseudopeptidic moiety (Supporting Information, Figure
S3), supporting the connectivity between both substructures, and
a syn disposition between these hydrogens in the major species
(Figure 2, inset on the upper left), in good agreement with the
computed geometry (Figure 1). By following the gradual
increase of the imine signal (Figure 2, inset on the upper right),
we observed that the formation of the imine bond in the presence
of 3a·2TBA was ca. 6-fold faster than in the absence of the
template. These data suggest that the template also catalyzes
the imine condensation.41 The proposed inclusion of the anion
within the macrocyclic polyimine was also demonstrated
independently by additional techniques. For instance, intermo-
lecular 1D ROESY enhancement was observed between ortho
protons of the aromatic imine and the ortho protons from the
template (see Figure 2f, and Figure S3 for the 2D ROESY),
supporting a close proximity between both nuclei (3.6–3.8 Å
(42) (a) For recent reviews, see: Pregosin, P. S. Prog. Nucl. Magn. Reson.
Spectrosc. 2006, 49, 261–288. (b) Pregosin, P. S.; Kumar, P. G. A.;
Fernández, I. Chem. ReV. 2005, 105, 2977–2998. (c) Cohen, Y.;
Avram, L.; Frish, L. Angew. Chem., Int. Ed. 2005, 44, 520–554.
(43) The exprimental molecular volume was calculate by approximating
the shape of the molecul to a sphere (V ) 4/3πr3) of a radius equal
to the hydrodynamic radius (rH), which was estimated using the
Stokes-Einstein equation: D ) kBT/6πhrH where kB is the Boltzmann
constant and h is the viscosity of pure solvent. All these approximations
could render a quantitative difference between the theoretical and
experimental value of molecular volume. Additionally, counterions
and salvation shell were not considered for the molecular modeling
structure. These facts also would increase the experimentally obtained
volume as compared with the theoretical one.
(40) After the complete characterization of the [2 + 2] tetraimine
1
macrocycle and the assignation of its H NMR signals, we observed
that this species was also present in the reactions templated by acetate
and benzoate anions (see Figure 2). Acquisition of the corresponding
NMR spectra of these samples after longer reaction times showed an
increase of the signals of the intended macrocycle, but always mixed
with other open-chain derivatives.
(41) Ramos, S.; Alcalde, E.; Doddi, G.; Mencarelli, P.; Pérez-García, L. J.
Org. Chem. 2002, 67, 8463–8568.
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Synthesis of Pseudopeptidic Macrocycles
A R T I C L E S
Figure 2. Partial 1H NMR spectra (500 MHz, 303 K, after 3 h of reaction in CD3OD) of a mixture of 1a and 2a (a) alone and in the presence of the
corresponding TBA salts of (b) chloride, (c) acetate, (d) benzoate, or (e) 3a; (f) 1D ROESY trace upon irradiation of the template 3a signal. Other key ROE
effects are shown with double-headed arrows in the structure on the upper left (see Figure S3 in the Supporting Information). The increment of overall imine
conversion versus time is also plotted for spectra a, b, and e on the upper right corner.
Scheme 2. Synthesis of Pseudopeptidic Macrocycles through Anion-Templated Reductive Amination
processes, and the decrease in yields associated to a careful
chromatographic purification. Besides, for the accurate evalu-
ation of the yield, we have to take into account that four
independent bonds in two-step processes have to be formed.
Accordingly, for an overall 26% yield, we can estimate an 85%
average theoretical yield for every step. However, some remark-
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A R T I C L E S
Alfonso et al.
Table 1. Obtained Yields for the Synthesis of Pseudopeptidic Macrocycles through Anion-Templated Reductive Amination
entry
sust.
n
R
Aaa
dialdehyde
template
product
Yield (%)a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1a
1b
1g
1h
1i
0
0
1
1
2
2
0
0
0
0
0
0
1
0
iPr
CH2Ph
iPr
CH2Ph
iPr
CH2Ph
iPr
CH2Ph
(CH2)4NHBoc
iBu
sec-Bu
sec-Bu
Val
Phe
Val
Phe
Val
Phe
Val
Phe
Boc-Lys
Leu
Ile
Ile
Ile
2a
2a
2a
2a
2a
2a
2b
2b
2a
2a
2a
2b
2a
2a
3a
3a
3a
3a
3a
3a
3b
3b
3a
3a
3a
3b
3a
3a
4a
4b
4c
4d
4e
4f
m-4a
m-4b
4g
4 h
4i
60
65
30
36
26
33
36
30 [17]b
40
50
35
26
27
9
10
11
12
13
14
1i
1j
1k
m-4i
4j
4k
sec-Bu
(CH2)2CONHTr
GlnTr
31
a Isolated overall yields after condensation, reduction, hydrolysis, workup, and chromatographic purification, calculated from the starting pseudopeptidic
bis(amidoamine) 1a-k. b The value between brackets shows the isolated yield of the corresponding [3 + 3] macrocyclic byproduct.
able differences in Table 1 must be pointed out.44 For instance,
the enlargement of the spacer by one methylene group led to
an important decrease of the yield (compare entries 1 and 3 or
2 and 4), as expected considering the larger flexibility of the
propylene moiety. Surprisingly, the decrease in the efficiency
was not so large with an additional methylene group in the
spacer (see entries 5 and 6). Regarding the dialdehyde geometry,
we have found that para substitution is more efficient than meta,
probably due to its higher symmetry and lower number of
possible conformations of the open-chain intermediates. How-
ever, meta-derivatives were obtained in acceptable to good yields
(entries 7, 8, and 12) by using the best fitting isophthalate 3b
template, which again highlights the important role played by
the template. Interestingly, in the case of phenylalanine deriva-
tive 1b, the reaction with the isophthaldehyde 2b and the
template 3b produced the expected [2 + 2] macrocycle in 30%
yield in addition to an important amount of the [3 + 3]
macrocycle in 17% yield (entry 8 in Table 1). This surprising
and remarkable result suggests that it is possible to obtain larger
macrocycles by optimizing the size and topology of the template.
Studies in that direction are currently under development and
will be published in due course.
Regarding the effect of the side chain, the reaction works
with aliphatic and aromatic residues, aromatic side chain being
slightly better (entries 2, 4, and 6). In this regard, the benzyl
side chain can prevent amide solvation in polar environments,
favoring its interaction with the anionic template.34 Among the
aliphatic derivatives (deriving from amino acids Val, Leu, and
Ile), some surprising differences were obtained since the
observed trend (Val > Leu > Ile) is not trivial to rationalize
(see below in text). Interestingly, two examples bearing H-
bonding donor groups (amide and carbamate) were successfully
assayed (entries 9 and 14), suggesting that the templated process
is highly selective toward the backbone amide group.
selected examples. To understand the differences due to the
aliphatic spacer (n), we studied the templated reaction with 1c
(n ) 1) and 1e (n ) 2) (see Supporting Information for details).
Both the NMR and ESI-TOF MS data support the formation of
the corresponding tetraimine-dianion supramolecular com-
plexes, although with a slightly lower efficiency. The effect of
the aldehyde geometry was also studied in a similar way,
following the templated and nontemplated reactions between
1a and 2b. Although the supramolecular species was completely
characterized also in this case (Figures S7-S9), its formation
is slower and some other uncharacterized species remained
detectable even after long reaction times. Finally, an example
bearing a hydrogen-bonding side chain (1g) was also studied.
Also in this case, the experimental data (Figures S10-S12)
strongly support the formation of the intended supramolecular
macrocycle-anion complex, despite the competing presence of
H-bond donor groups in the side chain. However, NMR spectra
showed broad signals implying a conformationally more flexible
structure in solution (see Supporting Information). This fact
would disfavor the templation effect, explaining the somehow
lower final yield.
Anion Template Induced Preorganization: Circular Dichro-
ism and Molecular Modeling Studies. The presence of the
template must preorganize the system leading to the supramo-
lecular tetraimino-dianion intermediate. Thus, the spatial
disposition of aromatic bis(imine) chromophores must be well
defined and highly determined by the template. This effect can
be accurately measured by electronic circular dichroism (CD)
spectroscopy.45 Accordingly, CD spectra were acquired for the
crude condensation reaction (40 mM in methanol, after 3 h at
room temp) between 1a and 2a in the absence and in the
presence of 3a·2TBA. A more pronounced Cotton effect was
found with the template (Figure 3), implying a more organized
system due to the presence of the dicarboxylate. Besides, the
observed negative sign of the Cotton effect clearly reflects the
relative disposition of the chromophores in the computed
geometry, as seen in Figure 1.
Intrigued by some of these observations, we have character-
ized the tetraimine-dianion supramolecular complexes for some
(44) The estimated loss of material due to chromatographic purification
was around 5–10%. No important differences due to the structure of
to the final compound were observed. The rest of the mass of the
crude corresponded to a trace amount of open-chain oligomers (not
fully characterized) and to the starting bis(amidoamine) 1a-k. On
the other hand, as the imine groups of the corresponding intermediates
are electronically and sterically very similar, the observed differences
in the yields are not expected to be due to the reduction step.
Accordingly, there must be a direct correlation between the observed
final yields and the formation and stability of the supramolecular
tetraimino-dianion intermediate.
At that stage, we wondered if we could use this technique
for the comparison of the differences observed with the side-
chain nature or the aliphatic spacer. To do that, we selected
some representative examples and performed the CD spectra
of the crude of the condensation in the absence and in the
(45) (a) Berova, N.; Di Bari, L.; Pescitelli, G. Chem. Soc. ReV. 2007, 36,
914–931. (b) Berova, N.; Nakanishi, K.; Woody, R. W. Circular
Dichroism. Principles and Applications, Wiley-VCH: New York, 2000.
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Synthesis of Pseudopeptidic Macrocycles
A R T I C L E S
proportional to the induced increase of the signal intensity.
Accordingly, the larger is the induced preorganization (CD),
the more efficient (higher yield) is the templated reaction.
We have also performed molecular modeling calculations to
better understand the process, by studying the effect of the
template in the hypothetical aminoaldehyde intermediates previ-
ous to the formation of the last CdN bond, which would
complete the macrocyclization (Figure 5). At that point, the
anion must induce a structural organization of the linear
precursor to adapt it to the molecular shape and charge density
of the template. Monte Carlo simulations of the corresponding
open chain tris(imino)aminoaldehyde were carried out, in the
absence (Figure 5A) and in the presence (Figure 5B) of the
corresponding templates. The binding with the template dra-
matically increased the rigidity of the intermediate leading to a
lower number of accessible local minima. In the absence of the
template, the system behaved as a mixture of quite structurally
different conformations, while the presence of the template
clearly rigidified its conformational freedom.
A close inspection of the global minima of the open-chain
intermediates gave additional clues about the templation process.
The proposed stabilizing H-bonding interactions between the
template and the macrocycle (Figure 1) are already present in
the previous open-chain derivative (Figure 5B). Even more
interestingly, the presence of the template approximates both
ends of the linear molecule, with the correct geometry for the
nucleophilic attack of the amine to the aldehyde carbonyl (see
distances depicted in Figure 5). Moreover, the H-bonding pattern
involving terephthalate also suggests that 3a could act as a
proton shuttle, explaining the observed acceleration of the
templated cyclization process by general acid–base catalysis.
Thus, an H-bond can be proposed between the nucleophilic
amino NH and the COO of the template (1.71 Å). On the other
hand, the aldehyde carbonyl is H-bonded to the amide NH (1.81
Å). This arrangement would facilitate the proton transfer from
the amine NH to the aldehyde CO, through the participation of
the carboxylate of the template (distance CHO · · ·OOC ) 3.28
Å). Therefore, the effect of the template could be double:
thermodynamic and kinetic. On one hand, it favors the formation
of the correct macrocycle by stabilizing its structure through
noncovalent interactions. Additionally, it could accelerate the
imine bond formation by acid–base catalysis and by setting the
reacting groups at the correct geometry to undergo condensation.
To break down thermodynamic and kinetic contributions seems
Figure 3. Normalized CD spectra (MeOH, 3 h of reaction at room temp)
of a 1:1 mixture of 1a and 2a in the absence (blue trace) and in the presence
(red trace) of 0.5 equiv of 3a·2TBA.
presence of the template. To avoid problems comparing chro-
mophores with different electronic transitions, we used the
p-dialdehyde 2a in all the cases. We also avoided interfering
aromatic groups in the side chains. For the study of the effect
of the aliphatic spacer (n), experiments with increasing lengths
(1a, 1c, 1e) were carried out. To study the intriguing effect of
the aliphatic side chain, the leucine derivative 1h was also
measured. For the right isolation of the effect of the template
on the CD signal, we obtained the corresponding difference CD
spectra (templated minus nontemplated) for every example. The
results are shown in Figure 4A. Interestingly, the intensity of
the template-induced Cotton effect increases in the order 1e <1c
< 1h < 1a, exactly with the same trend as for the isolated yields
of the templated reaction. More remarkably, if we plot the
intensities of the template-induced CD signal, either at the
maximum or at the minimum wavelength, versus the isolated
yield, we obtain a linear correlation with a similar slope
(∼0.6–0.7), obviously differing by the sign (Figure 4B). Our
interpretation of these results is that the template effect causes
a preorganization of the system, readily measurable by CD and
Figure 4. (A) CD difference spectra between the templated (∆εT) and nontemplated (∆εo) reaction of 2a with 1a (red), 1h (blue), 1c (green), and 1e (black);
(B) plot of the template-induced CD signal intensity (∆εT - ∆εo) either at the maximum (red) or at the minimum (blue) wavelength versus the final yield
of anion-templated reaction.
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A R T I C L E S
Alfonso et al.
presence of the template increased the negative Cotton effect,
in agreement with the rearrangement of the aromatic bis(imine)
chromophores in a more defined conformational disposition.
Thus, we have used CD spectroscopy for comparing different
derivatives. The anion-induced CD signal increase clearly
correlates with the template effect and, ultimately, with the
reaction yields. This trend was found for examples bearing
different side chains and different aliphatic spacers. This anion-
templated preorganization effect has been further supported by
molecular modeling calculations.
In summary, a simple and highly efficient anion-templated
synthesis of new pseudopeptidic macrocycles has been achieved.
A wide structural diversity can be implemented in the reaction
leading, in all the cases, to the desired compound. The
differences observed in the isolated yields have been explained
in terms of the flexibility and stability of the key supramolecular
intermediate complexes. This new synthetic procedure demon-
strates the success of applying concepts from the supramolecular
chemistry field to face and solve synthetic challenges.
Experimental Details
General Procedure for the Anion-Templated Macrocycliza-
tion Reaction (Shown for 4a). Pseudopeptidic bis(amidoamine)
1a (100 mg, 0.282 mmol) was dissolved in 2 mL of degassed
CH3OH, inside a flask under nitrogen. Terephthalate dianion 3a
(bis-TBA salt, 91.5 mg, 0.141 mmol) was dissolved in 1 mL of
degassed CH3OH and added over the solution of 1a. Terephthal-
dehyde 2a (37.8 mg, 0.282 mol) was dissolved in 1 mL of degassed
CH3OH, added over the solution mixture of 1a + 3a, and then 1.5
mL of CH3OH was added until a final volume of 5.5 mL. The
mixture was stirred overnight, then a large excess of NaBH4 (87
mg, 2.257 mmol) was carefully added at 0 °C, and the mixture
was allowed to react for 24 h before being hydrolyzed (conc. HCl,
to acidity) and evaporated to dryness. The residue obtained was
dissolved in water, basified with 1N NaOH, and extracted with
CHCl3. The combined organic layers were dried (MgSO4) and the
solvents were evaporated in vacuum. The product was purified by
flash chromatography on silica gel using CH2Cl2 as eluent while
slowly increasing the polarity with MeOH containing a few drops
of aqueous ammonia.
Figure 5. Global minima for the hypothetical aminoaldehyde intermediate
of [1a + 2a] (A) in the absence and (B) in the presence of the template 3a.
Hydrogen bonds are shown as gray dotted lines and computed distances
between reacting aldehyde and amino groups are also displayed.
to be difficult in this case, as the macrocycle is formed at the
expense of the template and both effects (thermodynamic and
kinetic) would be acting at the same time.
Conclusions
In this paper, we have deeply studied the anion-templated
synthesis of pseudopeptidic macrocycles, obtained upon mul-
ticomponent46 reductive amination reaction between an open
chain pseudopeptidic bis(amidoamine) and an aromatic dialde-
hyde in the presence of the corresponding aromatic dicarboxy-
late. Different structural variables on the macrocyclic framework
have been mapped, such as the aliphatic spacer between amino
acid moieties, geometry of the dialdehyde, or nature of the side
chain. The effect of the dicarboxylate anion template has been
clearly demonstrated by NMR (including intermolecular ROEs
and self-diffusion rates) and ESI-TOF mass spectrometry.
The structural preorganization necessarily induced by the
template has been studied by electronic CD spectroscopy. The
Acknowledgment. Dr. Cristian Vicent (SCIC-UJI) is grate-
fully acknowledged for his helpful assistance with the ESI-TOF
mass spectra. This work was supported by the Spanish Minis-
terio de Educación y Ciencia (CTQ2006-15672-C05-02), CSIC-
I3 (200780I001) and Bancaixa-UJI (P11B2004-38). M.B. and
J.R. also thank M.E.C. for personal financial support (F.P.U.).
Supporting Information Available: Detailed experimental
procedures, full spectroscopic data, selected 1D and 2D NMR
spectra, copies of 1H and 13C NMR spectra of the final
compounds and X-Ray crystallographic CIF file for 4a·4HCl.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(46) (a) Rivera, D. G.; Wessjohann, L. A. J. Am. Chem. Soc. 2006, 128,
7122–7123. (b) Wessjohann, L. A.; Voigt, B.; Rivera, D. G. Angew.
Chem., Int. Ed. 2005, 44, 4785–4790.
JA710132C
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6144 J. AM. CHEM. SOC. VOL. 130, NO. 19, 2008