Efficient synthesis of pseudopeptidic molecular cages

Article abstract of DOI:10.1002/chem.201104045

Pseudopeptidic cages have been efficiently prepared by combining a dynamic covalent procedure with the suitable preorganization of the building blocks by a conformational bias or an anion templation (see figure).

Full text of DOI:10.1002/chem.201104045

DOI: 10.1002/chem.201104045
Efficient Synthesis of Pseudopeptidic Molecular Cages
Alejandra Moure,[a] Santiago V. Luis,*[b] and Ignacio Alfonso*[a]
The construction of new molecular structures through the
lent procedure,[14,15] which is able to self-select the favored
structures by chemical exchange.[16] To this aim, we used two
approaches for inducing the needed preorganization: a con-
figurationally driven conformational bias[14] or an anion tem-
plation procedure.[15] In this regard, although anion templa-
tion is a well-known phenomenon,[17] most of the examples
found in the literature are based on inorganic anions,[17b–g]
while the use of more elaborated organic anionic templates
is scarce.[15,17a] These two methods (preorganization and
anion templation) allowed us to prepare a diverse family of
pseudopeptidic macrocycles in enough quantity for further
supramolecular chemistry studies.[18] Considering the success
of these methods in the macrocyclic field, we envisioned to
apply them to develop a versatile synthetic protocol for
pseudopeptidic molecular cages. The retrosynthetic analysis
considered a [3+2] reductive amination reaction between
three molecules of a C2 symmetrical pseudopeptidic bis(ami-
doamine) (1a–g) and two molecules of a flat and simple tri-
aldehyde (2) as depicted in Scheme 1. These [3+2] imine
programmed assembly of building blocks in a predictable
and selective way is a major challenge in modern chemis-
try.[1] To this aim, the understanding of the structural rules
governing the assembly allows the suitable design of increas-
ingly complicated scaffolds. Among the de novo designed
chemical entities recently prepared, molecular cages[2] are
fascinating architectures with important applications in mo-
lecular recognition,[3] catalysis,[4] and biomimetic chemistry.[5]
Their three dimensional hollow structures, leaving a well-de-
fined inner space, make them promising candidates for the
inclusion of interesting guests,[6] even for elusive[7] or unsta-
ble[8] species. In connection with the biochemical world, they
can mimic the solvent-excluded binding sites of natural re-
ceptors.[9] Moreover, they have been described as nanoreac-
tors, because the molecular confinement of the reactants
inside the macrobicyclic cavity can largely enhance kinetics
or dramatically change the final reaction outcome.[10] In-
spired by the seminal works in macrobicyclic peptides,[11] we
reasoned that the introduction of amino acid derived chemi-
cal moieties (peptide-like or pseudopeptides) would incre-
ment the functional variability and would be beneficial for
future biological applications. However, one of the main
drawbacks for the practical use of molecular cages is the
possibility of preparing them in an easy and modular way, in
reasonable yields and with enough structural diversity.[12]
Besides, the presence of different competing pathways in
the cyclization process and the use of multistep syntheses,
often lead to complex final mixtures, requiring to be sepa-
rated, which also limits the application of those proce-
dures.[13] Recently, we have shown that an efficient synthesis
of pseudopeptidic macrocycles can be carried out taking ad-
vantage of a designed preorganization and a dynamic cova-
[a] Dr. A. Moure, Dr. I. Alfonso
Departamento de Quꢀmica Biolꢁgica y Modelizaciꢁn Molecular
Instituto de Quꢀmica Avanzada de CataluÇa, IQAC-CSIC
Jordi Girona 18-26, 08034, Barcelona (Spain)
Fax : (+34)-932-045-904
E-mail: ignacio.alfonso@iqac.csic.es
[b] Prof. S. V. Luis
Departamento de Quꢀmica Inorgꢂnica y Orgꢂnica
Universitat Jaume I
Avenida Sos Baynat, s/n, 12071, Castellꢁn (Spain)
Fax : (+34)-964-728-214
E-mail: luiss@qio.uji.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201104045.
Scheme 1. Synthesis of pseudopeptidic cages: 1) equilibration at RT
either in the absence or in the presence of 5TBA. 2) BH3·py. 3) HCl.
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Chem. Eur. J. 2012, 18, 5496 – 5500

COMMUNICATION
À
condensations are highly challenging, since usually lead to
larger oligomers,[19] interlocked structures,[20] polymeric ma-
terials,[21] or dynamic mixtures.[22] Besides, in our case, the
overall process comprises the formation of six covalent
bonds in two steps each, which should be equivalent to
carry out twelve reactions in one pot. Accordingly, in order
to obtain a good selectivity towards the intended D3 sym-
metric cage, the starting material must be appropriately pre-
organized.
The key step for the success of the reaction is the forma-
tion of the hexaimine intermediate (3), through a dynamic
covalent process that is able to self-correct the wrong spe-
cies in the dynamic equilibrium. Initially, we used the bis-
the Ca H, as obtained by molecular modeling. Other addi-
tional nOes were consistent with a diequatorial chair confor-
mation of the cyclohexane moiety (Figure 1A).[23] To our de-
light, the in situ reduction of this intermediate led to the
pseudopeptidic hexamine cage 4a in very good overall iso-
lated yield from 1a (47%) considering the number of bonds
formed in a one-pot two-steps process, the necessary acidic
hydrolysis, the work-up and a reverse-phase chromatograph-
ic purification to obtain an analytically pure material.[24] Re-
markably, no other cyclic oligomers were isolated, support-
ing the excellent selectivity of the reaction. Further studies
showed that the reaction is also efficient with aromatic (4b,
R=Bn, 30% isolated yield) and polar (4c, R=CH2OH,
59% isolated yield) side chains on the pseudopeptidic
moiety.[23,24] The yield obtained with the Ser cage (4c) is
highly remarkable, especially considering that it includes the
ACHTUNGTRENNUNG(amidoamine) derived from the (R,R)-1,2-diaminocyclohex-
ane (chx) spacer and l-Valine (R=iPr) amino acid (1a).
Based on previous studies, this compound is preorganized in
a U-shaped conformation when the right combination of
chiral centers ((R,R)-diamine and (S)-amino acid) is imple-
mented in the molecule.[14] Thus, we monitored the reaction
À
step for the deprotection of the O tBu groups, performed
on the crude reaction before the final chromatographic pu-
rification.
1
between 1a and 2 by H NMR (500 MHz, RT, 10 mm of 1a
With the aim of generalizing our synthetic procedure, the
less rigid derivative with an ethylene (et) spacer and l-Val
(R=iPr) as the starting amino acid (1d) was also studied.
Despite the flexibility of 1d, the use of the suitable anion
template during the imine formation had largely improved
the process in the case of macrocycles.[15] Accordingly, we
also aimed to study the anion template effect in the synthe-
sis of the pseudopeptidic cages. Molecular modeling studies
showed that benzene-1,3,5-tricarboxylate (5) should be
a suitable template for the formation of the hexaimine cage
3d, perfectly filling the macrobicyclic cavity and forming up
to six hydrogen bonds between the carboxylate anions and
the amide groups of the pseudopeptidic moieties (Fig-
ure 1B). Taking into account these results, we monitored
in CD3OD).[23] We observed the decrease of the aldehyde
methyne signals (at 10.0–10.2 ppm) and the raise of the
imine-type protons (at ca. 8.3 ppm), until reaching an almost
complete conversion to a D3 symmetric imine compound.
1
The H and 13C NMR signals of this species were consistent
with the proposed hexaimine cage (3a), and also in full
agreement with the model structure (Figure 1A).[23] For in-
stance, the NOESY spectrum showed a cross peak between
À
the imine methyne and both the aromatic CH and the Ca
H of the pseudopeptide moiety (see double-headed arrows
in Figure 1A). These data imply the connectivity between
the fragments with an S-trans arrangement of the conjugated
À
imines, and a syn disposition between the imine C H and
1
the condensation between 1d and 2 by H NMR (500 MHz,
RT, 10 mm of 1d in CDCl3/CD3OH=9:1) in the absence
and in the presence of the trianion 5 as its tris(tetrabuthyl-
AHCTUNGTREGaNNNU mmonium) salt (5TBA). The evolution of the correspond-
ing spectra showed marked differences due to the presence
of the template (Figure 2A).[23]
Strikingly, in the presence of 5TBA, the system rapidly
evolved towards the formation (>80% as observed by
1H NMR)[23] of a highly symmetric imine compound in only
3 h of reaction. The chemical shifts and nOes (Figure 1B.)
are consistent with the presence of the D3 symmetric hexa-
AHCTUNGTRENNUNG
imine cage 3d.[23] Moreover, DOSY NMR spectra (Fig-
ure 2B) showed the same self-diffusion rate (D=6.49ꢄ
10À6 cm2 sÀ1) for the signals corresponding to the pseudopep-
tidic cage and those assigned to the template (both the aro-
matic tricarboxylate and the TBA cation) suggesting that
they are forming part of the same non-covalent species. Esti-
mation of the molecular volume of this supramolecular spe-
cies by DOSY[23] rendered a value of 2210 ꢅ3, in reasonably
good agreement with the one obtained for [3d+5+3TBA]
by modeling (2183 ꢅ3). A definitive proof for the formation
of this supramolecular complex was obtained by ESI-TOF
mass spectrometry (Figure 2C).[23] The mass spectrum of the
reaction mixture in the anion detection mode showed the
Figure 1. Optimized geometries for: A) the hexaimine cage 3a, B) the
supramolecular complex formed by 3d and 5 (in CPK representation).
Observed nOes are shown in curved double-headed arrows. C,D) Hypo-
thetical amino aldehyde intermediate previous to the macrobicycle for-
mation (for 3d) in the absence C) and in the presence D) of the template.
For simplicity, in C and D, nonpolar hydrogen atoms have been omitted.
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S. V. Luis, I. Alfonso et al.
ular modeling studies were performed with the hypothetical
amino aldehyde previous to the formation of the last imine
bond leading to the cage, in the absence (Figure 1C) and in
the presence (Figure 1D) of the template. The results clearly
showed the preorganization effect induced by the template,
which is able to fold the intermediate into the suitable con-
formation (with the pseudopeptide wrapping the template)
and with the right geometry for the reaction to take place
(compare the distances between the amino nitrogen and the
aldehyde carbon in Figure 1C and D). Besides, the anionic
template could act as a proton shuttle accelerating the reac-
tion by acid–base catalysis.
For the experimental support of this anion-induced preor-
ganization, circular dichroism (CD) has proved to be a very
valuable technique, since the CD signal reflects the spatial
organization of the UV chromophores in chiral molecules.[26]
Thus, we monitored the reaction between 1d and 2, with
and without template, by CD (Figure 3). The imine cage for-
Figure 3. CD spectra for the mixture of 1d and 2 in the absence (gray)
and in the presence (black) of template (5TBA) after 4 h of reaction.
Inset: time evolution of the CD signal at 255 nm with (black) or without
(gray) template.
Figure 2. A) Partial 1H NMR spectra of the crude reaction mixture of 1d
and 2 (500 MHz, RT, 10 mm of 1d in CDCl3/CD3OH=9:1 after 3 h of re-
action) in the absence (lower trace) and in the presence (upper trace) of
5TBA. B) DOSY NMR spectrum of the templated reaction (500 MHz,
mation was accompanied by the growth of an intense nega-
tive split Cotton effect in the CD spectrum, characterized by
a negative minimum at 278 nm and a positive maximum at
255 nm, in agreement with both the proposed model struc-
ture and our previous studies in macrocyclic related sys-
tems.[15] The formation of the cage is strongly favored by the
presence of the template as observed by the comparison of
the corresponding CD spectra at 4 h of reaction (Figure 3)
or by the plots of the time evolution of the CD signal at
255 nm (Figure 3, inset). The results suggested that the reac-
tion is approximately 4-fold faster in the presence of 5, im-
plying a remarkable kinetic template effect of the anion.
The in situ reduction of each reaction after 24 h of equili-
bration showed important differences, despite both of them
initially contained 3d as the main compound. The analytical
HPLC analysis of the crude of the templated reaction
298 K, in CDCl3/CD3OD=9:1 ) using SiACHTUNTGRNEUNG(SiMe3)4 as an internal standard
for the diffusion scale. C) Selected signals (calculated and experimental)
for the high resolution ESI-TOF mass spectrum of the [3d+5+TBA+H]À
complex (see also the Supporting Information).[23]
peaks for the corresponding supramolecular species:
[3d+5+H]2À (m/z=599.3, doubly charged), [3d+5+2H]À
(m/z=1199.6, monoanionic) and [3d+5+TBA+H]À (m/z=
1440.9, singly charged). On the other hand, the reaction per-
formed in the absence of the template required up to 27 h
to reach the imine conversion observed for the templated
reaction in 3 h. This difference suggested a remarkable ac-
celeration of the formation of the cage by the anion tem-
plate.[25] To visualize the source of this kinetic effect, molec-
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Chem. Eur. J. 2012, 18, 5496 – 5500

Synthesis of Pseudopeptidic Molecular Cages
COMMUNICATION
Acknowledgements
Financial support from the Spanish MICINN (CTQ2009-14366-C02 proj-
ect) is gratefully acknowledged. A. M. and I. A. also thank Prof. Angel
Messeguer for continuous support.
Keywords: anion templates
·
cage compounds
·
preorganization · pseudopeptides · supramolecular chemistry
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rivative prompted us to isolate it as the O-protected form (4 f, R=
CH2OtBu). Besides, during the chromatographic purification of 4 f,
some undesired partial O-deprotection was detected that lowered
the final (non-optimized) yield.
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Received: December 24, 2011
Revised: February 24, 2012
Published online: March 29, 2012
5500
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Chem. Eur. J. 2012, 18, 5496 – 5500