Designed folding of pseudopeptides: The transformation of a configurationally driven preorganization into a stereoselective multicomponent macrocyclization reaction

Article abstract of DOI:10.1002/chem.200800726

The efficient synthesis of large-ring pseudopeptidic macrocycles through a multicomponent [2 + 2] reductive amination reaction is described. The reaction was entirely governed by the structural information contained in the corresponding open-chain pseudopeptidic bis(amidoamine) precursors, which have a rigid (R,R)-cyclohexane-1,2-diamine moiety. A remarkable match/mismatch relationship between the configurations of the chiral centers of the cyclic diamine and those of the peptidic frame was observed. The macrocyclic tetraimine intermediates have been studied in detail by NMR spectroscopy, circular dichroism (CD), and molecular modeling, and the results support the appropriate preorganization induced by the match combination of the chiral centers. We have also synthesized the corresponding open-chain bis(imine) model compounds. The structural studies (NMR spectroscopy, CD, modeling) of these systems showed an intrinsically lower reactivity of the mismatch combination, even when the product of the reaction was acyclic. In addition, a synergistic effect between the two chiral substructures for the correct folding of the molecules was observed. Finally, X-ray analysis of the HCl salt of one of the macrocycles showed an interesting pattern; the macrocyclic rings stack in columnar aggregates leaving large interstitial channels filled with water-solvated chloride anions.

Full text of DOI:10.1002/chem.200800726

FULL PAPER
DOI: 10.1002/chem.200800726
Designed Folding of Pseudopeptides: The Transformation of a
Configurationally Driven Preorganization into a Stereoselective
Multicomponent Macrocyclization Reaction
Ignacio Alfonso,*[a] Michael Bolte,[b] Miriam Bru,[c] M. Isabel Burguete,[c] and
Santiago V. Luis*[c]
Abstract: The efficient synthesis of
large-ring pseudopeptidic macrocycles
through a multicomponent [2+2] re-
ductive amination reaction is described.
The reaction was entirely governed by
the structural information contained in
the corresponding open-chain pseudo-
peptidic bis(amidoamine) precursors,
which have a rigid (R,R)-cyclohexane-
been studied in detail by NMR spec-
troscopy, circular dichroism (CD), and
molecular modeling, and the results
support the appropriate preorganiza-
tion induced by the match combination
of the chiral centers. We have also syn-
thesized the corresponding open-chain
bisACTHNUTRGNEUG(N imine) model compounds. The
structural studies (NMR spectroscopy,
CD, modeling) of these systems
showed an intrinsically lower reactivity
of the mismatch combination, even
when the product of the reaction was
acyclic. In addition, a synergistic effect
between the two chiral substructures
for the correct folding of the molecules
was observed. Finally, X-ray analysis of
the HCl salt of one of the macrocycles
showed an interesting pattern; the
macrocyclic rings stack in columnar ag-
gregates leaving large interstitial chan-
nels filled with water-solvated chloride
anions.
1,2-diamine moiety.
A
remarkable
match/mismatch relationship between
the configurations of the chiral centers
of the cyclic diamine and those of the
peptidic frame was observed. The mac-
rocyclic tetraimine intermediates have
Keywords: conformation analysis ·
foldamers · macrocycles · peptide-
like structures · preorganization
Introduction
Amino acid containing macrocycles[1] are important mole-
cules due to their interesting applications in molecular rec-
ognition,[2] biomedicine,[3] and materials science.[4] However,
in most cases, their synthesis is hampered by the macrocycli-
zation step, which usually requires high dilution techniques,
sophisticated protecting groups, or tedious purification
steps.[5] One possible way to improve that process is the con-
formational preorganization of the linear precursors.[6] How-
ever, for the de novo design of a conformation leading to
the intended macrocyclic ring, detailed knowledge of the
structural variables for the correct folding of the open-chain
precursors is mandatory. Therefore, the concept of program-
med folding arises as a key to the macrocyclization pro-
cess.[7] In nature, the structural information implemented
within a given sequence leads, under certain environmental
conditions, to a functional three-dimensional structure.[8]
This is often achieved by the homochirality of the mono-
mers that form the corresponding functional biopolymers.[9]
Thus, fundamental information is provided by the geometri-
[a] Dr. I. Alfonso
Departamento de Quꢀmica Orgꢁnica Biolꢂgica
Instituto de Investigaciones Quꢀmicas y Ambientales de Barcelona
Consejo Superior de Investigaciones Cientꢀficas (IIQAB-CSIC)
Jordi Girona, 18-26, E-08034, Barcelona (Spain)
Fax : (+34)932-045-904
E-mail: iarqob@iiqab.csic.es
[b] Dr. M. Bolte
Institut fꢃr Anorganische Chemie
J. W. Goethe-Universitꢄt Frankfurt
Max-von-Laue-Str. 7, 60438, Frankfurt/Main (Germany)
[c] M. Bru, Dr. M. I. Burguete, Prof. Dr. S. V. Luis
Departamento de Quꢀmica Inorgꢁnica y Orgꢁnica
UAMOA, Universidad Jaume I/CSIC, Campus del Riu Sec
Avenida Sos Baynat, s/n, E-12071, Castellꢂn (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.200800726.
Chem. Eur. J. 2008, 14, 8879 – 8891
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8879

cal parameters obtained by the correct combination of con-
figurations of the corresponding chiral centers, which is ex-
pressed when the chiral components are assembled into a
larger structure.[10] During the last decade, many chemists
have been fascinated by synthetic molecules that have been
designed with a preferred conformation in solution, com-
monly called foldamers.[11] Moreover, some research groups
have exploited the potential of structurally designed folding
for organic synthesis, especially in the macrocyclic field.[12]
For the efficient formation of large rings, the reactive cen-
ters must be in a well-defined spatial disposition, namely
preorganized in the corresponding cyclic conformation.
Therefore, the geometrical parameters of the linear precur-
sors must be carefully tuned for the correct folding, exactly
as in nature. To obtain that preorganization, very intelligent
approaches have been employed and include geometrical re-
strictions,[13] intramolecular hydrogen bonding,[14] solvopho-
bic interactions,[15] and p-stacking contacts.[16] However, re-
ports concerning the correlation between different combina-
tions of configurations of the chiral centers and designed
folding leading to an intended reactivity are scarce.[17]
ternatively be controlled by the appropriate redesign of
linear precursors. Herein we report a detailed structural
study of the configurationally driven preorganization of the
linear precursors for a highly efficient multicomponent mac-
rocyclization process that leads to new amino acid contain-
ing large macrocycles.
Results and Discussion
Design of the macrocyclization reaction: With the aim of
preparing large macrocyclic structures, we initially designed
a [2+2] reductive amination reaction (Scheme 1) between a
pseudopeptidic bis(amidoamine) (1a–i)[25] and a rigid planar
aromatic dialdehyde (2a,b). However, reactions performed
with the flexible derivatives (1a,b, entries 1 and 2 in
Table 1) led to a very complicated mixture of open-chain
oligomers with the corresponding [2+2] macrocycles detect-
ed by ESIMS only as minor products. These results indicat-
ed that the ethylenediamide moiety is too flexible in MeOH
to preorganize the system into a macrocycle-producing
folded conformation.
On the other hand, we have previously synthesized new
pseudopeptidic macrocycles by taking advantage of the U-
turn preorganization of this family of compounds in aprotic
polar solvents.[18] Some of these systems displayed interest-
ing properties as organogelators,[19] molecular receptors,[20]
chemosensors,[21] or molecular devices.[22] Within this re-
search 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. With this in mind, the reductive amination
reaction arose as an interesting alternative because imine
bonds are rigid and conformationally predictable scaffolds
that are very useful for the construction of macrocycles.[23]
With this aim, the preorganization of the linear precursor is
advisable to obtain acceptable final yields of the macrocycli-
zation product as well as to avoid oligomerization side-prod-
ucts. Accordingly, we recently reported the use of anion
templates to promote preorganization for the selective [2+
2] cyclization reaction.[24] This conformational trend can al-
After some preliminary molecular modeling, we decided
to prepare the corresponding derivatives with a cyclohex-
ane-1,2-diamine moiety, which was selected to favor a rigid
and well-defined spatial disposition of the bis(amidoamine)
fragment. Chiral cyclohexane-1,2-diamine has previously
been used as a scaffold for cyclization processes. Its chairlike
ꢀ
conformation, with the C N bonds forming angles of 608,
has served as an excellent scaffold for the construction of
large conformationally restricted macrocycles and pincers.
Thus, this diamine can undergo either [2+2] or [3+3] cyclo-
condensation reactions,[26] generate
a dynamic covalent
system,[27] or induce important constraints when forming
part of a longer open-chain molecule.[28] In our pseudopepti-
dic molecules, the cyclohexane frame induces a turn confor-
mation in the linear precursors, which favors the [2+2] cyc-
lization process. Satisfyingly, the macrocyclization reaction
proceeded smoothly with these redesigned systems. Thus, al-
dehyde–amine condensation between 1c and terephthalde-
Scheme 1.
8880
www.chemeurj.org
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8879 – 8891

Designed Folding of Pseudopeptides
FULL PAPER
Table 1. Results of the multicomponent reductive amination synthesis of pseudopeptidic macrocycles.
a cooperative relationship be-
tween the chiral centers of the
linear molecules, which plays a
fundamental role in the macro-
cyclization reaction. Thus, we
Substrate
Diamine
R (C-a conf.)
Dialdehyde
Product
Yield[a] [%]
[b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1c
1e
1 f
1g
1h
1i
en
en
A
iPr (S)
CH2Ph (S)
iPr (S)
CH2Ph (S)
iPr (S)
iBu (S)
2a
2a
2a
2a
2b
2a
2a
2a
2a
2a
3a
3b
3c
3d
m-3c
3e
3 f
3g
3h
3i
–
–
[b]
67
55
35
N
obtained
a positive (match)
R
combination with (R,R)-cyclo-
hexane and l-amino acids and,
E
58
E
sec-Bu (S)
41
E
A
17[c]
correspondingly,
a
negative
[b]
G
iPr (R)
CH2Ph (R)
–
–
(mismatch) combination with
d-amino acids. Therefore, the
macrocyclization reaction oc-
curred with a high diastereose-
lectivity. Because we found
these results quite intriguing,
we decided to perform an in-
[b]
10
A
[a] Isolated yield after chromatographic purification. [b] Yield not determined because a complicated mixture
of compounds was obtained, as shown by both ESIMS and TLC. [c] Non-optimized yield due to the insolubili-
ty of the final compound 3g.
hyde (2a; MeOH, RT, 20 h) led to the macrocyclic tetra-
imine, which was reduced in situ with sodium borohydride
depth study of the mechanism of the reaction by character-
izing the corresponding tetraimine intermediates.
ACHTUNGTRENNUNG
to the corresponding macrocyclic tetraamine 3c (R=iPr) in
a very good overall yield (entry 3, Table 1). To check the
generality of the procedure, we changed other fragments of
the cyclic structure in a modular way (Table 1). All the final
compounds were fully characterized by NMR spectroscopy
and mass spectrometry (see the Supporting Information).
Owing to the D2 averaged symmetry of the final macrocycle
and to the broadness of the signals in the NMR spectra for
most of the derivatives, the accurate ESI-TOF mass spectra
were especially illustrative, as unambiguous proof, of the
[2+2] macrocyclic structure. In addition, we were able to
obtain suitable crystals for X-ray diffraction analysis of one
derivative, 3d (R=Bn, see below). Comparison of the data
gathered in Table 1 shows that the reaction can be per-
formed with amino acid precursors with different aliphatic
or aromatic side-chains and give comparable final yields
(Table 1, entries 4, 6, and 7). The use of the meta-dialdehyde
(2b) instead of the para derivative decreased the isolated
yield, the rest of the material was recovered as the starting
compounds or as open-chain oligomers (Table 1, entry 5).
This result suggests that the geometrical disposition around
the flat and rigid aromatic spacer is also important, most
likely as a consequence of the higher symmetry of the para-
compared with the meta-substituted aromatic dialdehyde.
An example with hydrogen-bonding side-chains was also ob-
tained (derived from glutamine, entry 8 in Table 1), although
only in moderate (nonoptimized) yield. However, note that
the isolation of the final compound (3g) was greatly ham-
pered by its very low solubility in most organic solvents.
We also decided to study the effect of different combina-
tions of chiral centers of the linear pseudopeptidic bis(ami-
doamine) in this macrocyclization reaction. Thus, com-
pounds 1h,i with an R,R configuration in the cyclohexane
moiety, but a D configuration in the amino acid a-carbon
atom, were prepared and assayed. Very interestingly for this
combination of stereocenters, the reaction led to a mixture
Structural studies of the macrocyclic tetraimine intermedi-
ates: To obtain more precise information about the course
of the reaction, we followed (1H NMR, 500 MHz, CD3OD,
303 K) the formation of the tetraimine intermediate precur-
sor for 3c (see the Supporting Information). The reaction
started just a few minutes after mixing 1c and 2a. This was
indicated by the gradual disappearance of the aldehyde
CHO signals (d=9.99–10.11 ppm) and the growing of imino
methyne signals (d=8.07–8.34 ppm). In the first stage of the
reaction, a complicated group of signals was formed that
simplified after 24 h. At that point, a major compound (ca.
70% from integration of the signals) was obtained with a
1
highly symmetrical geometry, as shown by both its H and
13C NMR signals (see the Supporting Information for
1
gCOSY, TOCSY, and H–13C gHSQC spectra). This major
imine compound exhibited one singlet for the aromatic pro-
tons, which can be explained either by a fast rotation of the
aromatic ring with respect to the macrocyclic main plane or
by a D2 symmetrical conformation in solution. With regard
to the relative disposition between imine bonds, they must
all adopt the same S-trans configuration or again there must
be a fast equilibrium between the S-cis and S-trans configu-
rations in the NMR timescale to render the observed D2
symmetry. The presence of other minor imino signals (over-
all accounting for around an additional 25%) and the fact
that no other cyclic compounds were isolated after reduction
suggest that these minor nonsymmetrical imino groups arise
from the presence of different relative dispositions of the
C=N double bonds and support the assumption that the
major compound is an all-S-trans isomer. All of these imino
signals also showed strong NOE effects with the a-H pro-
tons of the peptidomimetic moiety (see the Supporting In-
formation for 2D NOESY spectra), which supports the con-
nectivity between the two substructures and a syn disposi-
tion of these protons in the major species, as depicted in
Scheme 2.
1
of compounds as detected by H NMR spectroscopy, TLC,
and ESIMS, the major ones corresponding to the starting
material (Table 1, entries 9 and 10). This means that there is
Despite this, the strong geometrical preference for the
system to form the D2 symmetrical cyclic structure is highly
Chem. Eur. J. 2008, 14, 8879 – 8891
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8881

I. Alfonso, S. V. Luis et al.
Figure 1)
with
a
minimum
at
296 nm
(De=
ꢀ110 cm2 mmolꢀ1) and
a
maximum at 269 nm (De=
132 cm2 mmolꢀ1). The CD bisigned signal passes through
zero at 280 nm, which is the lmax (e=59600mꢀ1 cmꢀ1) of the
UV absorbance (Figure 1). This UV band can be assigned to
p–p* transitions of the aromatic diimine.[30] The CD spec-
trum unambiguously implies a negative split-Cotton effect,
which allowed us to determine the disposition of the chro-
mophores in solution because the dipole moment associated
with the p–p* transition in this chromophore is known.[30]
The magnitude of the amplitude is in agreement with a
highly chiral and ordered structure with the corresponding
chromophores, namely the aromatic diimines, in close prox-
imity to one another. In addition, for an appropriate com-
parison, we prepared the corresponding (R,R)-cyclohexane-
1,2-bis(benzylimine) [(R,R)-4] and its CD spectrum was
measured under the same conditions (dotted line in
Figure 1). This compound showed a very similar split-Cotton
effect of negative sign (ꢀ,+), although at a shorter wave-
length due to less conjugation in the chromophores. All
these data imply that the chirality and the geometrical dis-
position of the (R,R)-cyclohexane-1,2-diamine have been ef-
ficiently transferred throughout the whole system of the
macrocyclic tetraimine formed by the reaction between 1c
and 2a. Even more interestingly, the corresponding experi-
ment with the mismatch combination of stereocenters (1h+
2a) gave a less intense CD spectrum (grey line in Figure 1)
with no sign of exciton-coupling. These results highlight the
importance of the configurationally driven preorganization
of precursors for the correct
Scheme 2. Observed NOEs for the macrocyclic tetraimine intermediate
obtained from the condensation reaction between 1c and 2a.
remarkable. The composition of this mixture does not
change over a long period of time (>8 weeks) or by heating
the sample up to 608C, which supports the suggestion that it
is an equilibrium mixture under thermodynamic control.
Note also that performing the same experiment with 1h (de-
rived from d-valine) instead of 1c (derived from l-valine)
1
led to a very complicated group of signals in the H NMR
spectrum and to the incomplete consumption of dialdehyde
2a even over very long reaction times (>3 d, see the Sup-
porting Information). This is also solid proof for the match/
mismatch effect of the configurations of the chiral centers.
The formation of the tetraimine intermediate was also
studied by electronic circular dichroism (CD).[29] The CD
spectrum of a mixture of 1c and 2a after 24 h of reaction
time clearly showed a bisigned (ꢀ,+) curve (black line in
folding of the system.
We also performed some mo-
lecular modeling studies to vis-
ualize these effects. Thus, Mon-
te Carlo conformational search-
es with MMFF minimizations
were performed for the pro-
posed macrocyclic tetraimines
derived from either 1c (match)
or 1h (mismatch) pseudopepti-
des (Figure 2). Interestingly, the
cyclic compound with the
match relationship rendered a
global minimum with a struc-
ture in very good agreement
with the experimental data
(Figure 2A). It shows an aver-
age D2 symmetry with intera-
tomic distances compatible with
the observed NOE contacts.
The cyclohexanes are in a per-
fect chair conformation with
the substituents in equatorial
positions. The structure pres-
ents an all-S-trans relative dis-
position of the imine bonds and
a flat conformation for the aro-
Figure 1. CD (top) and UV (bottom) spectra of the reactions between 1c+2a (black), 1h+2a (grey), and
(R,R)-4 (dotted).
8882
www.chemeurj.org
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8879 – 8891

Designed Folding of Pseudopeptides
FULL PAPER
from 1c. All these theoretical results also indicate that the
mismatch configurations do not favor the formation of the
macrocycle, as observed experimentally. In addition, as the
system is under thermodynamic control, these theoretical
calculations must reflect a reliable picture of the process.
Open-chain model systems: Taking into account the match/
mismatch effect observed for the macrocyclization reaction,
we wondered if that behavior is controlled by the structural
differences of the pseudopeptidic repeating units. In other
words, whether the different reactivity depends completely
on the formation of the macrocycle or whether it is inherent
to the pseudopeptidic moiety. Thus, we prepared four differ-
ent open-chain model compounds (5a–d) with similar pseu-
dopeptide–imine linkages. We synthesized both the match
(5a) and mismatch (5b) combinations of the cyclohexane
Figure 2. A) Minimized geometry of the macrocyclic tetraimine that
leads to 3c. B,C) Superposition of the energetically accessible (1% from
a
Boltzmann distribution) local minima (Monte Carlo searches with
MMFF minimizations) of the macrocyclic tetraimines obtained from 1c
(B, match) or 1h (C, mismatch). Hydrogen atoms have been omitted for
clarity in B and C.
derivatives, whereas for the flexible ethylene compounds,
we prepared two enantiomers (5c,d). The compounds were
synthesized by a simple condensation reaction between the
corresponding bis(amidoamine) and benzaldehyde in metha-
nol. Rather interestingly, the rate of formation of the imine
matic diimine groups, which maximizes the conjugation of
the system. The isopropyl side-chains are set in equatorial
positions, pointing away from the macrocyclic structure. In
addition, superposition of the energetically accessible local
minima (Figure 2B) showed a rigid averaged oval shape
with slight changes in the dispositions of the side-chains but
retaining the conformation of the macrocyclic backbone.
However, the same calculations performed with the hypo-
thetical macrocycle derived from 1h with mismatch configu-
rations rendered very different results. The macrocycle
1
bond (estimated by H NMR spectroscopy) was much lower
for the mismatch combination (5b) than for the match dia-
stereomer (5a). For instance, the reaction showed 98%
imine conversion for 5a after 23 h (10 mm, CD3OD, 303 K),
but a 78% conversion for 5b for the same reaction time.
This last derivative required 75 h to achieve 93% imine con-
version by NMR spectroscopy. Accordingly, there is a differ-
ence in the reactivity of the initial diastereomeric bis(amido-
amine) pseudopeptides 1c and 1h. Thus the difference in
the macrocyclization is not exclusively due to differences in
strain in the final cyclic structure, as can be observed even
in condensation reactions that lead to open-chain imines.
The different reactivities observed for 1c and 1h, which
lead to 5a and 5b, respectively, can be rationalized by con-
sidering the geometry of the possible conformations of the
showed an averaged distorted geometry with
a large
number of structurally different accessible minima (Fig-
ure 2C). Most of them showed the cyclohexane moiety in a
highly strained boat conformation and/or the iPr group in a
pseudoaxial position, which must be energetically demand-
ing. In fact, the global minimum of this system (1h) is much
less stable (6.58 kcalmolꢀ1) than the diastereomer derived
Chem. Eur. J. 2008, 14, 8879 – 8891
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8883

I. Alfonso, S. V. Luis et al.
two compounds 1c and 1h in solution (Scheme 3). By as-
suming diequatorial positioning of the amide groups on the
cyclohexane moiety and a trans disposition of the peptidic
served, which can be ascribed to these structural differences.
Monte Carlo studies of these systems showed that the type I
conformers would be the most favorable for both diastereo-
mers. This could be due to an
overestimation of the hydro-
gen-bonding stabilization within
the
force-field
calculations
(even by using polar solvents
such as water in the calcula-
tions). However, the corre-
sponding minimum for 1h is
more stable (2.16 kcalmolꢀ1)
than that of 1c, probably due to
the above-mentioned steric hin-
drance in 1c-I. These computa-
tional results are in line with
our initial hypothesis.
Once the model compounds
(5a–d) had been prepared, we
studied their conformations in
solution. First of all their
1H NMR spectra showed impor-
tant differences, especially in
Scheme 3. Proposed conformational equilibrium for A) 1c and B) 1h.
1
bonds, three different rotamers of the carbonyl–Ca bond
can be proposed (conformers I–III in Scheme 3). According
the imine-linkage region. The H chemical shifts of 5a are
very similar to those of the flexible ethylene derivatives 5c,d
(Figure 3, Table 2, entries 1 and 6). However, compound 5b
showed a more complex group of signals that indicated the
presence of at least four different imine groups. Integration
1
to the H and 13C NMR spectroscopy data, only C2 symmet-
rical conformations will be considered, although other non-
symmetrical geometries in dynamic equilibrium could also
be present in solution. The stability, and therefore, the popu-
lation of these species depend on the stabilizing/destabiliz-
ing interactions found in each case. For instance, conformer
1
of the different H NMR signals showed the species to be
present in a ratio of 80:14:3:2; some representative chemical
shifts are gathered in Table 2. The minor ones (overall ac-
counting for 19%) showed chemical shifts very similar to
those of 5a,c,d. However, for the major species (80%), the
ꢀ
I in compound 1c would allow amide–amine N H···N hy-
drogen-bonding interactions, thereby forming intramolecular
five-membered rings (Scheme 3a). These interactions have
previously been found for related systems both in solu-
tion[18,22] and in the solid state.[18] However, this conforma-
tion (I) would present a large steric hindrance between the
isopropyl groups. On the other hand, in conformer III of the
ꢀ
same compound the amide N H and iPr groups would be
eclipsed, which would result in a destabilizing interaction.
Therefore, in polar protic solvents, conformer II is expected
to be slightly favored for 1c as the steric hindrance between
the iPr groups would be diminished because they would be
in pseudoequatorial positions and far away from each other.
In the case of compound 1h (Scheme 3b), the scenario
would be much clearer because two of the rotamers (II and
III) show steric hindrance arising from the iPr groups,
whereas in conformer I the two iPr groups would be pseu-
doequatorial and would also exhibit the proposed amide–
amine hydrogen-bonding stabilizing interactions. Therefore,
conformer I should be the most populated for 1h. By com-
paring both structures (II for 1c versus I for 1h) one can
predict that the amino nitrogen atoms in 1h-I must be less
nucleophilic than those in 1c-II because their lone-pair elec-
trons are involved in intramolecular hydrogen bonds.[31] Al-
though MeOH would be able to break these hydrogen-
bonding interactions, a clear difference in reactivity was ob-
Figure 3. Selected region of the 1H NMR spectra of 5a (upper trace), 5b
(middle trace), and 5c,d (lower trace). Signals corresponding to the
minor species in 5b are shown with asterisks.
8884
www.chemeurj.org
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8879 – 8891

Designed Folding of Pseudopeptides
FULL PAPER
1
Table 2. Chemical shifts of selected H NMR signals of 5a–d.
group (namely, HC=N, a-H, and o-Ar-H) are above the ani-
sochronic shielding cone of the other aromatic ring
(Figure 4). This disposition explains the observed upfield
shifts for 5b. Although the computed geometries are not ac-
tually symmetrical, a dynamic equilibrium on the NMR
timescale would produce an averaged C2 symmetry, as ex-
perimentally observed.
Compound
Isomer [%]
HC=N
o-ArH
a-H
Amide NH
1
2
3
4
5
6
5a
n.a.
80
14
3
2
n.a.
8.14
7.56
8.08
8.15
8.24
8.07
7.81
7.65
7.79
7.84
7.96
7.77
3.57
3.15
3.54
3.60
3.57
3.58
6.99
6.82
6.96
7.19
7.19
7.11
5b
5b
5b
5b
5c,d
We also performed NOESY experiments on 5a,b (see the
Supporting Information). For the match diastereomeric
combination, strong NOE cross-peaks were observed, in
agreement with the presence of a conformation very similar
to that proposed for the cyclic tetraimine intermediate
(Scheme 4). However, a weaker NOE effect between the
protons surrounding the imine linkage shift upfield with re-
spect to the corresponding signals of 5a (Table 2, entries 1
and 2). This shielding can only be explained by the presence
of a conformation in which the aromatic ring of one benzyl-
imine group is above the proton nuclei (aromatic imine and
ꢀ
a-carbon atom) of the other equivalent arm in a C H···p
disposition.
With the aim of explaining these experimental differences,
we performed some molecular modeling calculations on
5a,b (Figure 4). Monte Carlo searches on these systems sup-
Scheme 4. Observed NOEs for compound 5a.
amide NH and the ortho proton of the aromatic ring sug-
gests the participation of other conformations with the ben-
zylimine group in a pseudoaxial position (Scheme 4). The
same experiment performed with 5b was inconclusive be-
cause the observed NOEs were of a much lower intensity
than those for 5a and indicated an imine linkage.
As a complementary technique, we also recorded the CD
spectra of the model compounds 5a–d in methanol. The
flexible derivative 5c (Figure 5, black trace) showed a
strong CD signal of the type (ꢀ,+,ꢀ) characterized as fol-
lows: lmin =277 nm, De=ꢀ7.5 cm2 mmolꢀ1
;
lmax =244 nm,
De=+20.8 cm2 mmolꢀ1
;
lmin =215 nm, De=
ꢀ16.0 cm2 mmolꢀ1. As expected, its enantiomer 5d (Figure 5,
grey line) displayed a perfect mirror image (+,ꢀ,+) CD
spectrum. The UV absorbance at lmax =250 nm (e=
40000mꢀ1 cmꢀ1) can be assigned to the p–p* transitions of
aromatic imine chromophores. The absence of a clear exci-
ton-coupling effect prevented the preferred conformation
being proposed, but the results obtained for the macrocycli-
zation reaction suggest that these systems are highly flexible
in methanol. Therefore, these spectra can be considered as a
random coil CD reference.
Figure 4. Superposition of the energetically accessible local minima for
A) 5a and B) 5b. The global minimum for 5b is also shown (C) in a dif-
ferent perspective to highlight the disposition between the aromatic
imines.
Some interesting trends were observed in the CD spectra
of the cyclohexane derivatives 5a,b. First, for 5b (Figure 6,
grey line), the CD signal shifted to more negative values
(lmax =275 nm, De=+3.7 cm2 mmolꢀ1; lmin =245 nm, De=
ported the data obtained by NMR spectroscopy. Thus, 5a
behaved slightly more flexible in solution, which accounts
for the chemical shifts being similar to those of 5c,d. How-
ever, 5b seemed to be more conformationally constrained;
in the accessible minima the protons of one aromatic imine
ꢀ26.9 cm2 mmolꢀ1
;
lmax =220 nm, De=+13.7 cm2 mmolꢀ1)
relative to the signals of the corresponding flexible refer-
ence compound 5d. Once again, no split-Cotton signal was
detected, which suggests that a preorganization suitable for
Chem. Eur. J. 2008, 14, 8879 – 8891
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8885

I. Alfonso, S. V. Luis et al.
(Figure 6, black line). A comparison of the CD data for 5a
with that for the flexible derivative 5c shows that the first
minimum decreases in intensity (lmin =265 nm, De=
ꢀ11.2 cm2 mmolꢀ1), the subsequent maximum increases in
intensity (lmax =241 nm, De=+22.7 cm2 mmolꢀ1), and the
second minimum also increases (lmin =215 nm, De=
ꢀ14.1 cm2 mmolꢀ1). A slight blueshift of the CD spectrum
was observed as a consequence of an incipient exciton-cou-
pling effect. In addition, as the UV absorbance shows a max-
imum at lmax =250 nm (e=34500mꢀ1 cmꢀ1) and the CD
passes through zero at lmax =254 nm, there must be a contri-
bution from bisigned exciton-coupling for the p–p* transi-
tion of the aromatic imines. In addition, this split-Cotton
effect clearly implies negative chirality.
The negative sign of the split-Cotton effect of the imines
in 5a reflects the effective preorganization induced by the
cyclohexane moiety, despite its open-chain nature. This pre-
organized conformation was observed in the macrocyclic tet-
raimine and must be the effective driving force for the [2+
2] multicomponent cyclization. Moreover, we aimed to de-
termine the contribution of each substructure (pseudopep-
tide and cyclohexane) in the overall preorganization.[32] To
do that, we attempted to deconvolute the CD spectrum of
5a into the corresponding two reference spectra for both
substructures. Accordingly, we utilized 5c as the reference
for the pseudopeptidic contribution and (R,R)-4 (Figure 1)
as the reference for the cyclohexane framework. Satisfying-
ly, we were able to reasonably reproduce the CD spectrum
of 5a (Figure 7) as a weighted combination of the two sub-
structures, rendering an approximate contribution of De5a
ꢁ0.86De5c +0.14De(R,R)-4. In addition, the amplitude of the
CD signal is inversely proportional to the square of the dis-
tance between the interacting chromophores, and that dis-
tance should be shorter for (R,R)-4 than for 5a. Thus, we
have used a model subsystem with a stronger CD signature
than that possible in 5a. Consequently, the actual conforma-
tional contribution of the cyclohexane moiety must be
Figure 5. CD (top) and UV (bottom) spectra of 5c (black) and 5d (grey).
Figure 6. CD (top) and UV (bottom) spectra of 5a (black) and 5b (grey).
Figure 7. Simulation of the CD spectra of 5a (black) obtained by the ad-
dition of weighted CD spectra of the corresponding substructures:
0.86De5c (dashed)+0.14De(R,R)-4 (dotted).
the macrocyclization process is not present in solution. For-
tunately, the CD data for 5a were much more informative
8886
www.chemeurj.org
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8879 – 8891

Designed Folding of Pseudopeptides
FULL PAPER
larger than that calculated by our approach (14%). Anyway,
this remarkable relationship can be understood as a semi-
quantitative expression of the match effect of the chiral cen-
ters on the conformational preorganization.
Overall, this in-depth structural study of open-chain
model compounds has allowed important conclusions to be
drawn regarding the match/mismatch effect of the chiral
centers. First, the amino nitrogen atoms in 1c are intrinsical-
ly more nucleophilic than those in 1h. On the other hand,
the NMR spectroscopy data suggest that 5a is slightly more
flexible than 5b because in the latter the close proximity of
the aromatic diimines leads to some conformational con-
strictions. However, despite the higher flexibility of 5a, its
chiral centers enable the compound to adopt a conformation
suitable for macrocyclization, as demonstrated by the NOEs
and CD results. More interestingly, for 5a, we have been
able to quantify the contribution of each substructure to the
averaged conformation in solution. Therefore, we have dem-
onstrated that the positive/negative preorganization for cyc-
lization involves a match/mismatch combination of the two
substructures (cyclohexane and peptidic) present in the mol-
ecules.
Crystal structure of 3d·4HCl: We were able to obtain crys-
tals of the tetrahydrochloride salt of 3d suitable for X-ray
diffraction analysis. The results are shown in Figures 8 and
9. The nanometer-sized (1.1ꢆ2.0 nm) macrocycle adopts a
conformation with almost D2 symmetry, as shown in Fig-
ure 8A. The cyclohexane moiety adopts a chair conforma-
tion with the amide substituents in equatorial positions. The
amide NH groups are trans with respect to the methynes of
the chiral centers of the cyclohexane rings and cis to the a-
hydrogen atoms of the peptidic fragments. The benzyl side-
chains are in pseudoequatorial positions and point away
from the macrocyclic ring. Interestingly, the aromatic rings
of the side-chains are folded towards the cyclohexane moiet-
ies, thereby forming a hydrophobic core that seems to play
an important role in the crystal packing (see below). The
amino nitrogen atoms are fully protonated and point out
from the macrocycle, thereby minimizing the mutual elec-
trostatic repulsions. The aromatic rings of the backbone
phenylene groups are perpendicular to the macrocyclic main
plane and very close to each other, which possibly allows p-
stacking interactions to be established (interplanar distance
ꢁ3.6–3.7 ꢇ). Overall, the conformation of the pseudopepti-
dic moiety is in good agreement with that proposed for the
precursor tetraimine intermediate. The crystal has four chlo-
ride anions per macrocycle. Two of them are above each
pseudopeptidic moiety and establish hydrogen-bonding in-
Figure 8. A) Top view of the macrocyclic tetracation alone and B) with
two hydrogen-bonded chloride anions. C) Side view of the columnar
stacked aggregation assisted by chloride anions (chloride ions are repre-
sented in the CPK model).
columns, which leads to tight packing of the columns
through aryl–aryl and hydrophobic contacts. The other two
faces leave large interstitial channels between the columns
(see Figure 9A for the top view of empty channels). These
channels have a rhomboid-shaped section with an estimated
area of 92.4 ꢇ2. They are filled with chloride anions and
water molecules as the ammonium groups point towards the
inner face of the interstitial holes, which makes them highly
hydrophilic (see Figure 9B for top view of the filled chan-
nels). A longitudinal section of the channel (Figure 9C)
shows an interesting pattern with solvated chloride anions
along the whole channel. Accordingly, the whole crystal
structure can alternatively be described as water-filled chlo-
ride channels embedded in a hydrophobic core.
ꢀ
ꢀ
teractions with the amide NH and N CH2 Ar hydrogen
atoms (Figure 8B). These interactions stabilize the stacking
of the macrocyclic rings within a columnar supramolecular
aggregate (Figure 8C). The other two chloride atoms are
outside the macrocyclic cavity.
Conclusion
The packing of the columnar aggregates is also notewor-
thy. The cores formed by the benzyl side-chains and the cy-
clohexane rings interpenetrate on two opposite faces of the
We have developed a multicomponent reductive amination
macrocyclization reaction for the synthesis of new amino
Chem. Eur. J. 2008, 14, 8879 – 8891
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8887

I. Alfonso, S. V. Luis et al.
sors. Moreover, the macrocyclization process is dominated
by a match/mismatch relationship of the relative configura-
tion of the chiral centers in both substructures: the cyclic di-
amine and peptidic moieties. The correct combination is
that with (R,R)-cylohexane-1,2-diamine and l-amino acids.
This effect has clearly been demonstrated by a study of the
macrocyclic tetraimine intermediates by different experi-
mental (CD and NMR spectroscopy, including NOEs) and
theoretical (Monte Carlo conformational searches) methods.
The match/mismatch effect on the reactivity has been fur-
ther studied by using the corresponding open-chain model
systems. From their detailed structural characterization
(NMR spectroscopy, CD, and modeling), some important
conclusions can be extracted. First, the mismatch combina-
tion of the chiral centers has an intrinsically lower reactivity,
even for a reaction leading to open-chain products. In addi-
tion, the slightly larger flexibility of the match diastereomer
allows it to adopt a folded conformation that leads to mac-
rocyclization. More importantly, the CD spectra of all the
model systems clearly indicate the synergistic effect between
the two (diamine and peptidic) substructures. For the match
combination, this cooperative folding is expressed by a
weighted participation of each conformation in the overall
folding.
Finally, the crystal structure of the tetrahydrochloride salt
of macrocycle 3d showed very interesting behavior. The
nanometric macrocycles stack in a columnar supramolecular
structure held together with the help of hydrogen-bonding
interactions with two chloride anions. These columnar enti-
ties are hydrophobically packed leaving interstitial channels
filled with chloride anions and water molecules. This supra-
molecular crystal packing can be described as an anion
channel inside a hydrophobic core. Anion channels are
highly important entities both in chemistry[33] and in biol-
ogy.[34] Our results show the potential of these simple macro-
cycles for preparing synthetic minimalistic chloride channels.
Experimental Section
General: Reagents were purchased from commercial suppliers (Aldrich,
Fluka, or Merck) and were used without further purification. Compounds
1a–i were prepared following slight variations of previously reported pro-
cedures for linear diamines.[18,24] Experimental and spectroscopic details
are given in the the Supporting Information.
The NMR experiments were carried out either on a Varian INOVA 500
(500 MHz for 1H and 125 MHz for 13C) or a Varian MERCURY 300
spectrometer (300 MHz for 1H and 75 MHz for 13C). Chemical shifts are
reported in ppm using residual nondeuteriated solvent peaks as internal
standards. Mass spectra were recorded on a hybrid QTOF I (quadrupole-
hexapole-TOF) mass spectrometer with an orthogonal Z-spray/electro-
spray interface (Micromass, Manchester, UK) or on a Micromass Quattro
LC spectrometer equipped with an electrospray ionization source and a
triple-quadrupole analyzer. Infrared spectra were recorded on a Perkin-
Elmer 2000 FT-IR spectrometer.
Figure 9. CPK representation of the crystal packing of 3d·4HCl. Upper
view of the interstitial channels A) without and B) with chloride anions
and solvent molecules. C) Longitudinal section of the chloride and water
filled channels. Hydrogen atoms have been omitted for clarity (carbon:
grey; nitrogen: blue; oxygen: red; chloride: green).
CD spectra were recorded with a JASCO J-810 spectropolarimeter at
RT. The normalized spectra were obtained by transforming the molar cir-
cular dichroic absorption data (De, cm2 mmolꢀ1) using the formula: De=
acid containing macrocycles. The efficiency of the reaction is
strongly dependent on the structural parameters of the
open-chain pseudopeptidic bis(amidoamine) linear precur-
q/ACTHNUTRGNEUGN(32980Cl), in which q is the measured ellipticity (in mdeg), C is the
8888
www.chemeurj.org
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8879 – 8891

Designed Folding of Pseudopeptides
FULL PAPER
concentration (in m), and l is the pathlength (in cm). No changes were
observed for normalized spectra at different overall concentrations.
53.7, 63.4, 128.8, 130.0, 130.8, 132.3, 133.5, 135.4, 168.5 ppm; IR (KBr):
n˜ =3402, 3048, 2935, 2856, 1668, 1557 cmꢀ1; MS (ESI-TOF): m/z (%):
409.4 (100) [M+2H]2+
.
Suitable crystals of 3d for X-ray diffraction were obtained as follows: A
small amount of pseudopeptidic macrocycle 3d (ꢁ3 mg) was dispersed
in HPLC-grade methanol (1 mL). Then a small excess of 10% aqueous
HCl was added dropwise until complete dissolution. Crystals of 3d·4HCl
were obtained by the very slow (several weeks) evaporation of the sol-
vents. C64H80N8O4·4Clꢀ·8H2O; formula weight 1311.29; orthorhombic;
space group P212121; a=13.0283(15) , b=13.0834(10), c=42.757(4) ꢇ;
V=7288.1(12) ꢇ3; Z=4; colorless block-shaped crystals; STOE-IPDS-II
two-circle diffractometer; T=173 K; MoKa radiation; 2q range=3.26–
Compound m-3c: This compound was obtained as described above start-
ing from 1c and isophthaldehyde, and was characterized as the corre-
sponding HCl salt. Yield: 35%; pale-yellow solid; m.p. 2308C (decomp);
[a]2D0 =+7.63 (c=0.375 in CH3OH); 1H NMR (CD3OD, 500 MHz): d=
1.04–1.16 (m, 24H), 1.37–1.43 (m, 8H), 1.78 (brs, 4H), 2.11 (d, J=
9.7 Hz, 4H), 2.29–2.36 (m, 4H), 3.57–3.82 (m, 4H), 3.91–4.30 (m, 12H),
7.40–7.61 ppm (m, 8H); 13C NMR (CD3OD, 125 MHz): d=18.3, 19.6,
25.4, 31.0, 33.6, 51.3, 54.1, 66.6, 131.0, 132.4, 132.9, 134.6, 168.0 ppm; IR
(KBr): n˜ =3387, 3215, 3055, 1959, 2936, 2856, 1670, 1554 cmꢀ1; MS (ESI):
51.36o; 26237 reflections collected; 12668 independent reflections (Rint
0.1586); empirical absorption correction[35] (MULABS); structure solu-
tion with SHELXD, refinement on F2 with SHELXL-97,[36]
1A[I>2s(I)]=
=
m/z (%): 415.1 (100) [M+2H]2+, 746.1 (30) [M+Na+K]2+
.
R CHTUNGTRENNUNG
Compound 3e: This compound was obtained as described above starting
from 1e and terephthaldehyde, and was characterized as the free amine.
Yield: 58%; white solid; m.p. 232–2378C; [a]2D0 =+11.76 (c=1.04 in
CHCl3/CH3OH 7:3); 1H NMR (CDCl3 with a few drops of CD3OD,
500 MHz): d=0.81–0.84 (brt, J=6.6 Hz, 24H), 1.22–1.33 (m, 12H), 1.50–
1.52 (m, 8H), 1.71 (brs, 4H), 1.97 (d, J=10.9 Hz, 2H), 2.08 (d, J=
11.8 Hz, 2H), 3.05–3.11 (m, 4H), 3.56 (ABq, dA =3.59, dB =3.52 ppm,
jJAB j=11.5 Hz, 8H), 3.63–3.68 (m, 4H), 7.11 (s, 6H), 7.22 ppm (s, 2H);
13C NMR (CDCl3 with drops of CD3OD, 75 MHz): d=22.5, 22.8, 24.8,
25.2, 32.7, 42.6, 52.6, 52.9, 61.0, 129.1, 137.8, 175.2 ppm; IR (KBr): n˜ =
3302, 3054, 2932, 2867, 1643, 1516 cmꢀ1; MS (ESI-TOF): m/z (%): 885.6
0.1215, GOF=0.858. The absolute configuration was determined: Flack x
parameter=ꢀ0.06(18). All non-hydrogen atoms were refined anisotropi-
cally. Hydrogen atoms were generated according to the stereochemistry
and refined by using a riding model. CCDC-682038 contains the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Molecular modeling: All the theoretical calculations were performed
using Spartan ꢈ06 program.[37] The optimized geometries for the corre-
sponding minima were obtained as follows: A stochastic conformational
search was applied (Monte Carlo search followed by MMFF force-field
minimization) without restrictions to each compound. More than 100
conformers were obtained in this way (with a cut off of ca. 10 kcalmolꢀ1).
The structures obtained were ordered by their energies and analyzed.
The Boltzmann distributions of the corresponding conformers were cal-
culated at 298.15 K and the superposition of the energetically accessible
local minima were carried out by using the same software package.
(100) [M+H]+, 908.7 (95) [M+Na]+, 454.3 (45) [M+H+Na]2+
.
Compound 3 f: This compound was obtained as described above starting
from 1 f and terephthaldehyde, and was characterized as the free amine.
Yield: 41%; white solid; m.p. 2908C (decomp); [a]2D0 =+17.68 (c=0.90 in
CHCl3/CH3OH 7:3); 1H NMR (CDCl3, CD3OD, 500 MHz): d=0.75 (t,
J=7.3 Hz, 12H), 0.78 (d, J=6.8 Hz, 12H), 0.91–1.01 (m, 4H), 1.13–1.27
(m, 8H), 1.34–1.42 (m, 4H), 1.60–1.66 (m, 8H), 2.02 (d, J=12.5 Hz, 4H),
2.84 (brs, 4H), 3.23–3.27 (m, 4H, overlapped with solvent signal), 3.37
(ABq, dA =3.44, dB =3.30 ppm, jJAB j=11.6 Hz, 8H), 3.60–3.62 (m, 4H),
6.95 ppm (s, 8H); 13C NMR (CDCl3, CD3OD, 75 MHz): d=11.5, 15.1,
24.4, 25.5, 32.5, 37.7, 52.4, 52.6, 66.7, 128.7, 137.2, 173.7 ppm; IR (KBr):
n˜ =3294, 3056, 3011, 2933, 2857, 1655, 1522 cmꢀ1; MS (ESI-TOF): m/z
General procedure for the macrocyclization reaction—synthesis of com-
pound 3c: Compound 1c (160 mg, 0.512 mmol) was dissolved in degassed
CH3OH (5 mL) and the solution was placed inside a flask under nitrogen.
Terephthaldehyde (70 mg, 0.512 mmol) was dissolved in degassed
CH3OH (3 mL) and this solution was added to the solution of 1c and
then, CH3OH (2.5 mL) was added to give a final volume of 10.5 mL (a
final concentration of 0.05m for each reagent). The mixture was stirred
overnight. After 20 h a large excess of NaBH4 (158 mg, 4.096 mmol) was
carefully added and the mixture was allowed to react for 24 h before
being hydrolyzed (concd HCl, to acidity) and evaporated to dryness. The
residue thus obtained was dissolved in water and basified with 1n
NaOH. The product was extracted with CHCl3. The combined organic
(%): 885.6 (100) [M+H]+, 907.6 (70) [M+Na]+, 443.3 (65) [M+2H]2+
454.8 (50) [M+H+Na]2+
,
.
Compound 3g: This compound was obtained as described above starting
from 1g and terephthaldehyde. To avoid deprotection of the side-chain
the reduction was hydrolyzed with a 1m aqueous solution of ammonium
acetate. Yield: 17%; white solid; m.p. 173–1788C; [a]2D0 =+4.06 (c=1.20
in CHCl3); 1H NMR (CD3OD, 500 MHz): d=1.23–1.38 (m, 12H), 1.66–
1.75 (m, 8H), 1.78–1.85 (m, 4H), 2.03 (d, J=11.5 Hz, 4H), 2.25–2.32 (m,
4H), 2.35–2.41 (m, 4H), 3.04 (t, J=6.6 Hz, 4H), 3.42 (ABq, dA =3.52,
dB =3.32 ppm, jJAB j=14.6 Hz, 8H), 3.65–3.67 (m, 4H), 7.02 (s, 8H),
7.17–7.24 ppm (m, 60H); 13C NMR (CD3OD, 125 MHz): d=24.6, 29.4,
32.4, 32.9, 52.0, 52.6, 61.5, 70.4, 126.6, 127.5, 128.5, 128.8, 138.3, 144.8,
layers were dried (MgSO4) and the solvents were evaporated in
a
vacuum. The product was purified by silica flash chromatography using
CH2Cl2 as the eluent while slowly increasing the polarity with MeOH;
several drops of NH3 were added to the mobile phase to improve the ex-
traction of the product. The product was characterized as the correspond-
ing HCl salt, prepared by addition of concd HCl to a methanolic solution
of the free amine. Yield: 67%; pale-yellow solid; m.p. >2308C
(decomp); [a]2D0 =+11.59 (c=0.92 in CH3OH); 1H NMR (CD3OD,
500 MHz): d=1.06 (d, J=6.8 Hz, 12H), 1.12 (d, J=6.7 Hz, 12H), 1.30–
1.41 (m, 8H), 1,77 (brs, 4H), 2.13 (d, J=11.4 Hz, 4H), 2.29–2.36 (m,
4H), 3.83 (d, J=4.9 Hz, 4H), 3.88 (brs, 4H), 4.14 (ABq, dA =4.10, dB =
4.18 ppm, jJAB j=13.3 Hz, 8H), 7.60 (s, 8H), 8.52 ppm (brs, 4H, ex-
changeable with solvent); 13C NMR (D2O, 75 MHz, 908C): d=18.1, 19.3,
25.5, 30.8, 33.9, 50.8, 53.8, 66.2, 132.4, 133.2, 167.7 ppm; IR (KBr): n˜ =
3399, 3210, 3055, 2967, 2937, 2856, 1665, 1551 cmꢀ1; MS (ESI-TOF): m/z
173.3, 175.2 ppm; IR (KBr): n˜ =3315, 3057, 2931, 2857, 1803, 1513 cmꢀ1
MS (ESI-TOF): m/z (%): 639.0 (100) [M+3H]3+, 957.9 (90) [M+2H]2+
;
.
Compound 5a: Bis(amidoamine) 1c (50.5 mg, 0.1616 mmol) was dis-
solved in degassed CH3OH (3 mL) and the solution was placed inside a
flask under nitrogen. Freshly distilled benzaldehyde (33 mL, 0.3232 mmol)
was dissolved in degassed CH3OH (200 mL) and this solution was added
to the solution of 1c (a final concentration of 1c of 0.05m). The mixture
was stirred overnight and the solvent evaporated in vacuum. The com-
pound obtained showed high purity by NMR and was used without fur-
(%): 415.5 (100) [M+2H]2+
.
ther purification. Yield: quantitative; white solid; m.p. 172–1768C; [a]D20
=
ꢀ25.57 (c=1.08 in CHCl3); 1H NMR (CDCl3): d=0.91 (d, J=6.8 Hz,
6H), 0.94 (d, J=6.8 Hz, 6H), 1.11–1.19 (m, 2H), 1.26–1.33 (m, 2H),
1.66–1.67 (m, 2H), 2.12 (brs, 1H), 2.15 (brs, 1H), 2.31–2.38 (m, 2H),
3.56 (d, J=5.0 Hz, 2H), 3.71–3.75 (m, 2H), 6.99 (brd, J=6.1 Hz, 2H),
7.43–7.47 (m, 6H), 7.81 (dd, J1 =7.2, J2 =2.3 Hz, 4H), 8.14 ppm (s, 2H);
13C NMR (CDCl3, 125 MHz): d=18.4, 20.0, 24.8, 32.6, 32.8, 53.2, 80.1,
128.8, 128.9, 131.3, 135.9, 162.3, 173.3 ppm; IR (KBr): n˜ =3280, 3062,
2959, 2931, 2856, 1643, 1533 cmꢀ1; MS (ESI-TOF): m/z (%): 489.3 (100)
[M+H]+, 511.3 (90) [M+Na]+.
Compound 3d: This compound was obtained as described above starting
from 1d and terephthaldehyde, and was characterized as the correspond-
ing HCl salt. Yield: 55%; pale-yellow solid; m.p. 2308C (decomp);
[a]2D0 =+26.79 (c=0.89 in CH3OH); 1H NMR (CD3OD, 500 MHz): d=
0.57 (brd, J=12.9 Hz, 2H), 0.68 (brs, 2H), 1.00–1.07 (m, 4H), 1.28–1.32
(m, 4H), 1.48 (brd, J=8.8 Hz, 4H) 3.02 (t, J=11.8 Hz, 4H), 3.45 (dd,
J1 =13.1, J2 =5.0 Hz, 4H), 4.03 (dd, J1 =10.5, J2 =5.1 Hz, 2H), 4.20 (ABq,
dA =4.15, dB =4.26 ppm, jJAB j=12.9 Hz, 8H), 7.25–7.35 (m, 20H),
7.69 ppm (s, 8H); 13C NMR (CD3OD, 125 MHz): d=25.2, 33.0, 36.8, 50.3,
Chem. Eur. J. 2008, 14, 8879 – 8891
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8889

I. Alfonso, S. V. Luis et al.
Compound 5b: This compound was obtained as described above starting
from 1h and benzaldehyde, but the mixture was stirred at RT for 3 d.
Yield: 93%; white solid; m.p. 149–1558C; [a]2D0 =ꢀ126.21 (c=0.93 in
CHCl3/MeOH 9:1); 1H NMR (CDCl3): d=0.77 (d, J=6.9 Hz, 6H), 0.83
(d, J=6.9 Hz, 6H), 1.27–1.42 (m, 4H), 1.74–1.76 (m, 2H), 2.09–2.14 (m,
2H), 2.17 (brs, 1H), 2.19 (brs, 1H), 3.14 (d, J=4.6 Hz, 2H), 3.70–3.75
(m, 2H), 6.81 (brd, J=5.7 Hz, 2H), 7.44–7.46 (m, 6H), 7.56 (s, 2H),
7.64–7.66 ppm (m, 4H); 13C NMR (CDCl3, 125 MHz): d=17.7, 19.5, 25.0,
32.8, 32.9, 52.9, 79.6, 128.8, 128.8, 131.3, 135.7, 161.8, 172.9 ppm; IR
(KBr): n˜ =3305, 3063, 2960, 2933, 2859, 1645, 1537 cmꢀ1; MS (ESI-TOF):
m/z (%): 489.23 (100) [M+H]+, 511.24 (50) [M+Na]+.
[5] a) K. Gloe Macrocyclic Chemistry: Current Trends and Future Per-
spectives, Springer, Dordrecht, 2005; b) D. Parker, Macrocycle Syn-
thesis: A Practical Approach, Oxford University Press, New York,
1996; c) B. Dietrich, P. Viout, J.-M. Lehn, Macrocyclic Chemistry,
VCH, Weinheim, 1993; d) F. Vçgtle, Cyclophane Chemistry, Wiley,
Chichester, 1993; e) N. Sokolenko, G. Abbenante, M. J. Scanlon, A.
Jones, L. R. Gahan, G. R. Hanson, D. P. Fairlie, J. Am. Chem. Soc.
1999, 121, 2603–2604.
[6] a) S. B. Y. Shin, B. Yoo, L. J. Todaro, K Kirshenbaum, J. Am. Chem.
Soc. 2007, 129, 3218–3225; b) D. G. Rivera, L. A. Wessjohann, J.
Am. Chem. Soc. 2006, 128, 7122–7123; c) H. Jiang, J.-M. Lꢉger, P.
Guionneau, I. Huc, Org. Lett. 2004, 6, 2985–2988; d) T. Velasco-Tor-
rijos, P. V. Murphy, Org. Lett. 2004, 6, 3961–3964; e) T. V. R. S.
Sastry, B. Banerji, S. K. Kumar, A. C. Kunwar, J. Das, J. P. Nandy, J.
Iqbal, Tetrahedron Lett. 2002, 43, 7621–7625.
[7] a) M. Amorꢀn, L. Castedo, J. R. Granja, Chem. Eur. J. 2008, 14,
2100–2111; b) M. Sastry, C. Brown, G. Wagner, T. D. Clark, J. Am.
Chem. Soc. 2006, 128, 10650–10651; c) Z.-T. Li, J.-L. Hou, C. Li, H.-
P. Yi, Chem. Asian J. 2006, 1, 766–778; d) R. P. Cheng, Curr. Opin.
Struct. Biol. 2004, 14, 512–520.
[8] a) N. Delsuc, J.-M. Lꢉger, S. Massip, I. Huc, Angew. Chem. 2007,
119, 218–221; Angew. Chem. Int. Ed. 2007, 46, 214–217; b) R. Gray,
J. O. Trent, Biochemistry 2005, 44, 2469–2477; c) M. Jourdan, M. S.
Searle, Biochemistry 2001, 40, 10317–10325.
Compound 5c: This compound was obtained as described above starting
from 1a and benzaldehyde. Yield: quantitative; white solid; m.p. 124–
1298C; [a]2D0 =+82.45 (c=1.05 in CHCl3); 1H NMR (CDCl3): d=0.89 (d,
J=6.8 Hz, 6H), 0.94 (d, J=6.8 Hz, 6H), 2.30–2.36 (m, 2H), 3.39–3.46 (m,
2H), 3.48–3.55 (m, 2H), 3.58 (d, J=3.9 Hz, 2H), 7.11 (brs, 2H), 7.42–
7.47 (m, 6H), 7.77 (d, J=6.6 Hz, 4H), 8.06 ppm (s, 2H); 13C NMR
(CDCl3, 125 MHz): d=17.6, 19.8, 33.1, 39.3,79.2, 128.7, 128.9, 131.4,
135.7, 162.5, 173.6 ppm; IR (KBr): n˜ =3378, 3341, 2963, 2930, 2867, 2846,
2819, 1651, 1519 cmꢀ1; MS (ESI-TOF): m/z (%): 457.22 (100) [M+Na]+,
435.28 (80) [M+H]+, 473.25 (50) [M+K]+.
Compound 5d: This compound was obtained as described above starting
from the d,d enantiomer of 1a and benzaldehyde. It showed spectroscop-
ic data identical to 5c, as expected for enantiomers. Yield: quantitative;
white solid; m.p. 132–1368C; [a]2D0 =ꢀ91.39 (c=0.99 in CHCl3).
[9] a) P. Cintas, Angew. Chem. 2002, 114, 1187–1193; Angew. Chem.
Int. Ed. 2002, 41, 1139–1145; b) J. L. Bada, Nature 1995, 374, 594–
595; c) W. A. Bonner, Origins Life Evol. Biosphere 1991, 21, 59–
111.
[10] a) W. C. Pomerantz, V. M. Yuwono, C. L. Pizzey, J. D. Hartgerink,
N. L. Abbot, S. H. Gellman, Angew. Chem. 2008, 120, 1261–1264;
Angew. Chem. Int. Ed. 2008, 47, 1241–1244; b) W. S. Horne, J. L.
Price, J. L. Keck, S. H. Gellman, J. Am. Chem. Soc. 2007, 129, 4178–
4180; c) T. A. Martinek, A. Hetꢉnyi, L. Fꢃlçp, I. M. Mꢁdity, G. K.
Tꢂth, I. Dꢉkꢁny, F. Fꢃlçp, Angew. Chem. 2006, 118, 2456–2460;
Angew. Chem. Int. Ed. 2006, 45, 2396–2400; d) C. Tomasini, G.
Luppi, M. Monari, J. Am. Chem. Soc. 2006, 128, 2410–2420; e) A. I.
Jimꢉnez, G. Ballano, C. Cativiela, Angew. Chem. 2005, 117, 400–
403; Angew. Chem. Int. Ed. 2005, 44, 396–399; f) C. Dolain, H.
Jiang, J.-M. Lꢉger, P. Guinneau, I. Huc, J. Am. Chem. Soc. 2005,
127, 12943–12951; g) D. Yang, J. Qu, W. Li, D.-P. Wang, Y. Ren, Y.-
D. Wu, J. Am. Chem. Soc. 2003, 125, 14452–14457; h) A. I. Jimꢉnez,
C. Cativiela, J. Gꢂmez-Catalꢁn, J. J. Pꢉrez, A. Aubry, M. Parꢀs, M.
Marraud, J. Am. Chem. Soc. 2000, 122, 5811–5821.
[11] For some reviews on foldamers, see: a) M. T. Stone, J. M. Heemstra,
J. S. Moore, Acc. Chem. Res. 2006, 39, 11–20; b) G. Licini, L. J.
Prins, P. Scrimin, Eur. J. Org. Chem. 2005, 969–977; c) I. Huc, Eur.
J. Org. Chem. 2004, 17–29; d) R. P. Cheng, S. H. Gellman, W. F. De-
Grado, Chem. Rev. 2001, 101, 3219–3232; e) D. J. Hill, M. J. Mio,
R. B. Prince, T. S. Hughes, J. S. Moore, Chem. Rev. 2001, 101, 3893–
4011; f) M. S. Cubberley, B. L. Iverson, Curr. Opin. Chem. Biol.
2001, 5, 650–653; g) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173–
180; h) D. Seebach, J. L. Matthews, Chem. Commun. 1997, 2015–
2022.
Acknowledgements
Dr. Cristian Vicent (SCIC-UJI) is gratefully acknowledged for his helpful
assistance with the ESI-TOF mass spectra. This work was supported by
the Spanish Ministerio de Educaciꢂn y Ciencia (CTQ2006-15672-C05-
02), CSIC-I3 (200780I001) and Bancaixa-UJI (P11B2004-38). M.B. also
thanks the MEC for personal financial support (Formaciꢂn de Profesora-
do Universitario, F.P.U.).
[1] For some recent examples, see: a) S. E. Gibson, C. Lecci, Angew.
Chem. 2006, 118, 1392–1405; Angew. Chem. Int. Ed. 2006, 45, 1364–
1377; b) L. A. Wessjohann, B. Voigt, D. G. Rivera, Angew. Chem.
2005, 117, 4863–4868; Angew. Chem. Int. Ed. 2005, 44, 4785–4790.
[2] For some examples of related systems, see: a) K. Choi, A. D. Hamil-
ton, Coord. Chem. Rev. 2003, 240, 101–110; b) K. Choi, A. D. Ham-
ilton, J. Am. Chem. Soc. 2003, 125, 10241–10249; c) K. Choi, A. D.
Hamilton, J. Am. Chem. Soc. 2001, 123, 2456–2457; d) L. Somogyi,
G. Haberhauer, J. Rebek, Jr., Tetrahedron 2001, 57, 1699–1708;
e) M. M. Conn, J. Rebek, Jr., Chem. Rev. 1997, 97, 1647–1668.
[3] a) L. Gentilucci, A. Tolomelli, F. Squassabia, Curr. Med. Chem.
2006, 13, 2449–2466; b) C. T. Walsh, Science 2004, 303, 1805–1810;
c) W. A. Loughlin, J. D. A. Tyndall, M. P. Glenn, D. P. Fairlie, Chem.
Rev. 2004, 104, 6085–6117; d) R. C. Reid, L. K. Pattenden, J. D. A.
Tyndall, J. L. Martin, T. Walsh, D. P. Fairlie, J. Med. Chem. 2004, 47,
1641–1651; e) R. C. Reid, G. Abbenante, S. M. Taylor, D. P. Fairlie,
J. Org. Chem. 2003, 68, 4464–4471; f) X. Hu, K. T. Nguyen,
C. L. M. J. Verlinde, W. G. J. Hol, D. Pei, J. Med. Chem. 2003, 46,
3771–3774; g) S. Fernꢁndez-Lꢂpez, H.-S. Kim, E. C. Choi, M. Del-
gado, J. R. Granja, A. Khasanov, K. Kraehenbuehl, G. Long, D. A.
Weinberger, K. M. Wilcoxen, M. R. Ghadiri, Nature 2001, 412, 452–
455; h) D. P. Fairlie, G. Abbenante, D. R. March, Curr. Med. Chem.
1995, 2, 654–686.
[12] For a recent review, see: J. Blankenstein, J. Zhu, Eur. J. Org. Chem.
2005, 1949–1964.
[13] a) J. M. Holub, H. J. Jang, K. Kirshenbaum, Org. Lett. 2007, 9, 3275–
3278; b) F. Campbell, J. Plante, C. Carruthers, M. J. Hardie, T. J.
Prior, A. J. Wilson, Chem. Commun. 2007, 2240–2242; c) X. Bu, X.
Wu, N. L. J. Ng, C. K. Mak, C. Qin, Z. Guo, J. Org. Chem. 2004, 69,
2681–2685; d) W. Jiang, J. Wanner, R. J. Lee, P. Y. Bounaud, D. L.
Boger, J. Am. Chem. Soc. 2003, 125, 1877–1887; e) X. Bu, X. Wu,
G. Xie, Z. Guo, Org. Lett. 2002, 4, 2893–2895; f) T. D. Clark, M. R.
Ghadiri, J. Am. Chem. Soc. 1995, 117, 12364–12365.
[14] a) W. T. Gong, K. Hiratani, T. Oba, S. Ito, Tetrahedron Lett. 2007,
48, 3073–3076; b) A. Zhang, Y. Han, K. Yamato, X. C. Zeng, B.
Gong, Org. Lett. 2006, 8, 803–806; c) C. Rotger, M. N. Pina, M.
Vega, P. Ballester, P. M. Deya, A. Costa, Angew. Chem. 2006, 118,
6998–7002; Angew. Chem. Int. Ed. 2006, 45, 6844–6848; d) L. Yuan,
W. Feng, K. Yamato, A. R. Sanford, D. Xu, H. Guo, B. Gong, J. Am.
[4] a) R. J. Brea, L. Castedo, J. R. Granja, Chem. Commun. 2007, 3267–
3269; b) N. Ashkenasy, S. W. Horn, M. R. Ghadiri, Small 2006, 2,
99–102; c) W. S. Horne, C. D. Stout, M. R. Ghadiri, J. Am. Chem.
Soc. 2003, 125, 9372–9376; d) D. T. Bong, T. D. Clark, J. R. Granja,
M. R. Ghadiri, Angew. Chem. 2001, 113, 1016–1041; Angew. Chem.
Int. Ed. 2001, 40, 988–1011; e) D. Ranganthan, Acc. Chem. Res.
2001, 34, 919–930.
8890
www.chemeurj.org
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8879 – 8891

Designed Folding of Pseudopeptides
FULL PAPER
Chem. Soc. 2004, 126, 11120–11121; e) M. C. Rotger, M. N. Pina, A.
Frontera, G. Martorell, P. Ballester, P. M. Deya, A. Costa, J. Org.
Chem. 2004, 69, 2302–2308; f) F. J. Carver, C. A. Hunter, R. J. Shan-
non, J. Chem. Soc., Chem. Commun. 1994, 1277–1280.
[26] a) J. GawroÇski, M. Kwit, J. Grajewski, J. Gajewy, A. Dlugokinska,
Tetrahedron: Asymmetry 2007, 18, 2632–2637; b) M. Kwit, A. Plu-
tecka, U. Rychlewska, J. GawroÇski, A. F. Khlebnikov, S. I. Koz-
hushkov, K. Rauch, A. De Meijere, Chem. Eur. J. 2007, 13, 8688–
8695; c) J. GawroÇski, K. Gawronska, J. Grajewski, M. Kwit, A. Plu-
tecka, U. Rychlewska, Chem. Eur. J. 2006, 12, 1807–1817; d) N.
Kuhnert, A. M. Lopez-Periago, G. M. Rossignolo, Org. Biomol.
Chem. 2005, 3, 524–537; e) N. Kuhnert, N. Burzlaff, C. Patel, A.
Lopez-Periago, Org. Biomol. Chem. 2005, 3, 1911–1921; f) J. Ga-
wroÇski, M. Brzostowska, M. Kwit, A. Plutecka, U. Rychlewska, J.
Org. Chem. 2005, 70, 10147–10150; g) N. Kuhnert, G. M. Rossigno-
lo, A. M. Lopez-Periago, Org. Biomol. Chem. 2003, 1, 1157–1170;
h) N. Kuhnert, C. Straßnig, A. M. Lopez-Periago, Tetrahedron:
Asymmetry 2002, 13, 123–128; i) M. Chadim, M. Budꢊ insky, J. Ho-
daꢋova, J. Zavada, P. C. Junk, Tetrahedron: Asymmetry 2001, 12,
127–133; j) J. GawroÇski, H. Kołbon, M. Kwit, A. Katrusiak, J. Org.
Chem. 2000, 65, 5768–5773.
[15] a) C. PeÇa, I. Alfonso, V. Gotor, Eur. J. Org. Chem. 2006, 3887–
3897; b) J. E. W. Scheuermann, K. F. Sibbons, D. M. Benoit, M. Mo-
tevalli, M. Watkinson, Org. Biomol. Chem. 2004, 2, 2664–2670;
c) G. Stones, G. Argouarch, A. R. Kennedy, D. C. Sherrington, C. L.
Gibson, Org. Biomol. Chem. 2003, 1, 2357–2363; d) B. Altava, M. I.
Burguete, B. Escuder, S. V. Luis, E. Garcꢀa-EspaÇa, M. C. MuÇoz,
Tetrahedron 1997, 53, 2629–2640; e) J. E. Richman, T. J. Atkins, J.
Am. Chem. Soc. 1974, 96, 2268–2270.
[16] a) D. Zhao, J. S. Moore, J. Org. Chem. 2002, 67, 3548–3554; b) R. A.
Abramovitch, X. Ye, W. T. Pennington, G. Schimek, D. Bogdal, J.
Org. Chem. 2000, 65, 343–351; c) R. A. Abramovitch, X. Ye, J. Org.
Chem. 1999, 64, 5904–5912.
[17] A. Saghatelian, Y. Yokobayashi, K. Soltani, M. R. Ghadiri, Nature
2001, 409, 797–801.
[27] a) A. Gonzꢁlez-ꢌlvaarez, I. Alfonso, V. Gotor, Chem. Commun.
2006, 224–226; b) A. Gonzꢁlez-ꢌlvarez, I. Alfonso, F. Lꢂpez-Ortiz,
A. Aguirre, S. Garcꢀa-Granda, V. Gotor, Eur. J. Org. Chem. 2004,
1117–1127.
[18] J. Becerril, M. Bolte, M. I. Burguete, F. Galindo, E. Garcꢀa-EspaÇa,
S. V. Luis, J. F. Miravet, J. Am. Chem. Soc. 2003, 125, 6677–6686.
[19] a) J. Becerril, B. Escuder, J. F. Miravet, R. Gavara, S. V. Luis, Eur. J.
Org. Chem. 2005, 481–485; b) J. Becerril, M. I. Burguete, B. Escud-
er, F. Galindo, R. Gavara, J. F. Miravet, S. V. Luis, G. Peris, Chem.
Eur. J. 2004, 10, 3879–3890; c) J. Becerril, M. I. Burguete, B. Escud-
er, S. V. Luis, J. F. Miravet, M. Querol, Chem. Commun. 2002, 738–
739.
[28] a) S. Hanessian, V. Vinci, K. Fettis, T. Maris, M. T. P. Viet, J. Org.
Chem. 2008, 73, 1181–1191; b) C. PeÇa, I. Alfonso, B. Tooth, N. H.
Voelcker, V. G. Gotor, J. Org. Chem. 2007, 72, 1924–1930.
[29] a) N. Berova, L. Di Bari, G. Pescitelli, Chem. Soc. Rev. 2007, 36,
914–931; b) N. Berova, K. Nakanishi, R. W. Woody, Circular Di-
chroism. Principles and Applications, Wiley-VCH, New York, 2000.
[30] M. Kaik, J. GawroÇski, Org. Lett. 2006, 8, 2921–2924.
[31] Experimental support for this hypothesis can be obtained from the
NMR spectroscopy data obtained for 1c and 1h in CDCl3 (see the
Supporting Information). The chemical shifts of the amide NH pro-
tons are d=7.25 and 7.36 ppm for 1c and 1h, respectively. This sug-
gests the proton in 1h has a greater hydrogen-bonded character. We
thank the suggestion of an anonymous referee who prompted us to
revise these data.
[32] a) N. J. Greenfield, Anal. Biochem. 1996, 235, 1–10; b) A. Percze1,
M. Hollꢂsi, B. M. Foxman, G. D. Fasman, J. Am. Chem. Soc. 1991,
113, 9772–9782.
[33] L. You, R. Ferdani, R. Li, J. P. Kramer, R. E. K. Winter, G. W.
Gokel, Chem. Eur. J. 2008, 14, 382–396; and references therein.
[34] E. Gouaux, R. MacKinnon, Science 2005, 310, 1461–1465.
[35] R. H. Blessing, Acta Crystallogr., Sect. A 1995, 51, 33–38.
[36] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
[37] Spartan ꢈ06. Wavefunction, Inc., Irvine, CA (USA).
[20] I. Alfonso, M. I. Burguete, S. V. Luis, J. F. Miravet, P. Seliger, E.
Tomal, Org. Biomol. Chem. 2006, 4, 853–859.
[21] a) M. I. Burguete, F. Galindo, M. A. Izquierdo, S. V. Luis, L. Vigara,
Tetrahedron 2007, 63, 9493–9501; b) M. I. Burguete, F. Galindo,
S. V. Luis, L. Vigara, Dalton Trans. 2007, 4027–4033; c) F. Galindo,
M. I. Burguete, L. Vigara, S. V. Luis, D. A. Russell, N. Kabir, J. Gav-
rilovic, Angew. Chem. 2005, 117, 6662–6666; Angew. Chem. Int. Ed.
2005, 44, 6504–6508; d) F. Galindo, J. Becerril, M. I. Burguete, S. V.
Luis, L. Vigara, Tetrahedron Lett. 2004, 45, 1659–1662.
[22] a) I. Alfonso, M. I. Burguete, F. Galindo, S. V. Luis, L. Vigara, J.
Org. Chem. 2007, 72, 7947–7956; b) I. Alfonso, M. I. Burguete, S. V.
Luis, J. Org. Chem. 2006, 71, 2242–2250.
[23] N. E. Borisova, M. D. Reshetova, Y. A. Ustynyuk, Chem. Rev. 2007,
107, 46–79.
[24] a) I. Alfonso, M. Bolte, M. Bru, M. I. Burguete, S. V. Luis, J. Rubio,
J. Am. Chem. Soc. 2008, 130, 6137–6144; b) M. Bru, I. Alfonso,
M. I. Burguete, S. V. Luis, Angew. Chem. 2006, 118, 6301–6305;
Angew. Chem. Int. Ed. 2006, 45, 6155–6159.
[25] M. Bru, I. Alfonso, M. I. Burguete, S. V. Luis, Tetrahedron Lett.
2005, 46, 7781–7785.
Received: April 15, 2008
Published online: August 7, 2008
Chem. Eur. J. 2008, 14, 8879 – 8891
ꢅ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8891