A tetraguanidinium macrocycle for the recognition and cavity expansion of calix[4]arene tetraoxoanions

Article abstract of DOI:10.1080/10610278.2013.835814

Molecular containers have raised an increased interest over the last decade. These supramolecular architectures have found applications in catalysis, molecular sensing or as insulators for key intermediates, among others. In this study, we describe the synthesis and binding properties of a tetraguanidinium macrocycle which forms robust complexes with diverse calix[4]arene tetraoxoanions through hydrogen bonding and electrostatic interactions. The binding behaviour and affinity strength of these constructs have been measured by NMR and isothermal titration calorimetry. Besides, VT NMR experiments show that this novel cyclic tetracation is able to stabilise the cone conformation of these calix[4]arenes. Preliminary NMR-binding experiments between a tetraguanidinium calix[4]arenate and quinolinium or isoquinolinium salts suggest an effective increase in the cavity volume of these supramolecular constructs. 2013

Full text of DOI:10.1080/10610278.2013.835814

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A tetraguanidinium macrocycle for the recognition and
cavity expansion of calix[4]arene tetraoxoanions
Julián Valeroa & Javier de Mendozaa
a Institute of Chemical Research of Catalonia (ICIQ), Avgda. Països Catalans 16, 43007
Tarragona, Spain
Published online: 06 Sep 2013.
To cite this article: Julián Valero & Javier de Mendoza (2013) A tetraguanidinium macrocycle for the recognition and cavity
expansion of calix[4]arene tetraoxoanions, Supramolecular Chemistry, 25:9-11, 728-740, DOI: 10.1080/10610278.2013.835814
To link to this article: http://dx.doi.org/10.1080/10610278.2013.835814
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Supramolecular Chemistry, 2013
Vol. 25, Nos. 9–11, 728–740, http://dx.doi.org/10.1080/10610278.2013.835814
A tetraguanidinium macrocycle for the recognition and cavity expansion of calix[4]arene
tetraoxoanions
1
Julian Valero and Javier de Mendoza*
´
¨
Institute of Chemical Research of Catalonia (ICIQ), Avgda. Paısos Catalans 16, 43007 Tarragona, Spain
(Received 5 June 2013; accepted 12 August 2013)
Molecular containers have raised an increased interest over the last decade. These supramolecular architectures have found
applications in catalysis, molecular sensing or as insulators for key intermediates, among others. In this study, we describe the
synthesis and binding properties of a tetraguanidinium macrocycle which forms robust complexes with diverse calix[4]arene
tetraoxoanions through hydrogen bonding and electrostatic interactions. The binding behaviour and affinity strength of these
constructs have been measured by NMR and isothermal titration calorimetry. Besides, VT NMR experiments show that this
novel cyclic tetracation is able to stabilise the cone conformation of these calix[4]arenes. Preliminary NMR-binding
experiments between a tetraguanidinium calix[4]arenate and quinolinium or isoquinolinium salts suggest an effective increase
in the cavity volume of these supramolecular constructs.
Keywords: bicyclic tetraguanidinium; macrocycle; calix[4]arenes; molecular recognition; host–guest interactions
Introduction
accessible space to reversibly encapsulate different guests
inside without the dependence on the dynamic assembly of
diverse components, due to the fact that encapsulation
occurs with closed capsular-like structures.
Nature uses clefts, well-defined pockets and solvent-
hindered structures to direct and allow efficient molecular
recognition. By size and shape discrimination, in addition
to other essential interactions, biological systems are able to
selectively bind target molecules. This enables membrane
transport, delivery to a different organelle or diverse
synthetic transformations, such as in enzymatic active sites,
allosteric pockets or transmembrane pore channel proteins.
Inspired by these complex systems, synthetic molecu-
lar containers are based on the same fundamental
principles that govern host–guest recognition at the
biological level. Different pre-organised concave scaffolds
such as resorcinarenes, calixarenes or cyclotriveratrylenes
have been used as supramolecular baskets and capsules for
binding, isolation and sensing of small molecules and ions
(1), catalysis (2) or trapping of unstable intermediates (3).
Another significant group of molecular containers is
based on the expansion of hollow cavitands to afford open
void-like molecular architectures. Rebek and others
explored this approach by deepening resorcinarenes-
based self-assembled cavities (4). Recently, our group
detailed different examples of calix[4]arene deep cavi-
tands, in which the confined space was locked by either
hydrogen bonding (5) or metal bridges (6) between their
aromatic extended walls. These interactions prevented the
molecules from adopting partially collapsed pinched
conformations. These molecular vessels offer a solvent
Herein, we describe the construction of stable and
robust open molecular containers based on the binding
between different oxoanionic calix[4]arenes and the
cationic macrocyclic tetraguanidinium ligand 1 in its two
possible diastereomeric forms (Figure 1). Namely, ligand 1
stabilises the cone conformation of these calix[4]arenes by
means of hydrogen bonding and ion pairing and expands
the inner volume of the cavity allowing association with a
guest that would otherwise not fit inside. To the best of our
knowledge, this is the first example of a cavity expansion
promoted by non-covalent reversible bonds to generate an
open-shell construct.
Results and discussion
Design and synthesis
Macrocyclic tetraguanidinium hexafluorophosphate salt 1
was prepared after five synthetic steps starting from
functionalised monoguanidines 2 and 3 (Scheme 1). R,R-
thioacetyl monoguanidine 3 was coupled by nucleophilic
attack of its thiolate to S,S-guanidine mesylate 2, giving
rise to R,R-S,S-diguanidinium 4. Cleavage of the silyl
groups and activation of the diol with methanesulphonic
anhydride afforded dimesylate diguanidinium 6 in good
*Corresponding author. Email: jmendoza@iciq.es
q 2013 Taylor & Francis

Supramolecular Chemistry
729
Figure 1. Tetraguanidinium macrocyclic ligand 1 (left, diastereoisomer R,R-S,S-R,R-S,S; right, diastereoisomer R,R-S,S-S,S-R,R), and
calix[4]arene tetracarboxylic and sulphonic acids a–e.
Scheme 1. Synthesis of tetraguanidinium macrocycle 1. Conditions: (i) 2.7 equiv. Cs2CO3, MeOH/ACN, N2; (ii) MsOH, THF/H2O; (iii)
Ms2O, NMM in CH2Cl2; (iv) KSCOCH3, ACN, reflux; (v) 1 equiv. 6, 2.7 equiv. Cs2CO3, (nBu)2PhP polystyrene, in MeOH/ACN (high
dilution conditions), 2 days, N2.
yields. Thioacetylation of 6 resulted in dithiolate precursor
7. Finally, coupling of diguanidinium dimesylate 6 with
dithioacetylated diguanidinium salt 7 afforded tetraguani-
dine 1 (mixture of two diastereoisomers R,R-S,S-R,R-S,S
and R,R-S,S-S,S-R,R) in a 21% overall yield.
formation of undesirable linear oligomeric or polymeric
products. In this respect, it is worth mentioning that the
configuration of each stereogenic centre in the molecule is
relevant. Indeed, R,R-S,S-diguanidines (meso), despite their
inherent flexibility, should provide the correct orientation of
their reactive side arms pointing towards the same face of the
molecule to allow formation of the macrocycle.
The cyclisation step deserves several considerations.
First, high dilution conditions were required to avoid

730
J. Valero and J. de Mendoza
Separation of the two possible diastereoisomers was
Molecular modelling indicates that only the CH2S and
CHa protons of macrocycle 1 should be within the optimal
distance to display nOe contacts with the aromatic protons
of the calix[4]arene. However, the b and g methylene
protons also showed nOe contacts, revealing that the
inherent flexibility of macrocycle 1 could allow for the
dynamic bending and twisting of some of the bicyclic
guanidines of the ring, resulting in a closer proximity of
these protons to the aromatic protons of the calixarene in
the NMR timescale.
unsuccessful by HPLC. However, the thioether linkages
between the different bicyclic guanidinium moieties
should provide enough flexibility to accommodate well
and orient the ion-pair interactions of both diastereomers
with the corresponding calixarenate. Indeed, we expect a
similar interaction and strength of binding due to the high
preorganisation of these cyclic tetraguanidinium species.
Thus, we decided to use this diastereomeric mixture to
conduct the characterisation and subsequent binding
experiments described here, although for clarity we used
only the R,R-S,S-R,R-S,S isomer for the molecular models.
On the other hand, calix[4]arenes (a, c–e) were
synthesised according to the literature precedents, whereas
compound b was commercially available (see further
details in the ‘Experimental section’) (Figure 1). For-
mylation of the corresponding O-alkyl calix[4]arenes,
followed by oxidation with sulphamic acid and sodium
chlorite, afforded tetracarboxylic compounds a, c and d in
moderate to good yields. Subsequent O-debenzylation of
compound a gave rise to calix[4]arene e.
In addition, 1@a and 1@b were also characterised by
mass spectrometry analysis (7) ([M–H]2 ¼ 1555.8 and
1531.5 m/z, respectively; see Supplementary Material,
available online). The masses of the individual species
were also found in the gas phase, as a result of complex
fragmentation.
To further investigate the structural features of these
complexes in solution, NMR DOSY experiments were
conducted (8, 9). DOSY spectra of complexes 1@a and
1@c in a D2O:CD3CN (1:3) showed sharp DOSY peaks,
respectively, pointing to a single complexed species in
solution without scrambling between the free species in
the NMR timescale (Figure 4).
NMR characterisation of the complexes
Hydrodynamic radii of different complexes and free
species in solution were determined both experimentally
and theoretically. These data provide qualitative infor-
mation about the complexation and validate the postulated
model for the association. As illustrated in Table 1,
theoretical hydrodynamic radii of the calix[4]arene
carboxylate salts and macrocycle 1 are similar, and
therefore, it was expected to observe similar values of the
hydrodynamic radii as well as of the complexes. Indeed, the
experimental hydrodynamic radii obtained for the com-
plexes are in good fit with the calculated hydrodynamic
radii. Two theoretical radii were considered depending on
The 1H NMR spectra of 1:1 mixtures of macrocyclic
tetraguanidine 1 and the sodium salts of calix[4]arenes
a–c revealed no significant chemical shifts with respect to
the original calix[4]arene signals in a CD3CN/D2O (2:1)
mixture. However, the broadening of the original proton
signals of the independent species indicated that molecular
assembly was likely taking place.
Molecular models of macrocyclic tetraguanidinium
calix[4]arenate complexes pointed out that molecule 1
should sit on the anionic edge of the calix[4]arenes,
compensating the four positive charges of 1 (Figure 2).
Hence, it was expected to find nuclear Overhauser effect
(nOe) contacts between the upper rim proton signals of the
calix[4]arene and tetraguanidinium molecule 1. Thus,
NMR ROESY experiments were conducted. Indeed, after
selective irradiation of the aromatic signals of calix[4]
arene c, 1D ROESY showed nOe contacts with almost all
signals of macrocyclic tetraguanidinium 1 (Figure 3).
˚
the conformation of the calix[4]arene a: 5.9 A for the cone
˚
conformation and 6.5 A for the pinched cone, which is the
preferred conformation for this compound. Indeed, the
˚
experimental hydrodynamic radius (6.7A) is in good
agreement with that extracted from the pinched cone model.
This preferred conformation was also confirmed by
preliminary X-ray crystallography data (not shown).
Figure 2. (Colour online) Side view (left) and top view (right) of the molecular model (MM3) of complex 1@e.

Supramolecular Chemistry
731
Figure 3. 1D ROESY experiment showing contacts between the aromatic part of calixarene c and 1.
Figure 4. (Colour online) DOSY spectra of 1@a (left) and 1@c (right) measured in D2O:CD3CN (1:3) with the corresponding
molecular models used to calculate their theoretical Rh.
Table 1. Theoretical and experimental hydrodynamic radius
extracted from the molecular models and DOSY experiments,
respectively.
Conformational study of the tetraguanidinium
calix[4]arenate complexes in solution
Calixarenes can adopt different conformations due to the
˚
Rcalc (A)
˚
Rexp (A)
inherent flexibility of the phenol rings around the methylene
bridges (10). In particular, calix[4]arenes with bulky
substituents such as a and c (i.e. benzyl or propyl chains at
the lower rim) show a restricted conformation, whereas the
aryl moieties of calix[4]arenes b and e, with hydroxyl groups
at the lower rim, can unrestrictedly rotate. These hydroxyl
Tetraguanidinium 1
Calix (OBn) a
Calix (OPr) c
Complex 1@a
Complex 1@c
5.6
5.1
6.7
–
8.9
7.8
5.9/6.5
5.6
8.1
7.5

732
J. Valero and J. de Mendoza
accounting for a rapid interconversion between different
conformers in solution. Upon cooling, the cone confor-
mation was stabilised, and thus, the proton signal became a
doublet at 278 K. Conversely, at room temperature in the
presence of tetraguanidinium ligand 1, the calix[4]arene b
adopted a more stable cone conformation which should
facilitate the complexation with this polycationic mol-
ecule. Consequently, the doublet signal was observed up to
318 K (the upper temperature limit for this solvent
system). A similar trend was observed for calix[4]arene e.
Gutsche et al. (Gutsche and Bauer 11 and van Hoorn
et al. 12) described a method to assess conformational
mobilities in calix[n ]arenes by means of dynamic
1H NMR spectroscopy (see Supplementary Material,
Figure S1, available online). Applying this methodology,
conformational barriers of calix[4]arene inversions with
and without ligand 1 were deduced from the coalescence
temperatures extracted from the variable temperature
1H NMR data.
Figure 5. Example of a variable temperature 1H NMR
experiment monitoring the protons in the methylene bridge of
calix[4]arene b with 1 (right) and without 1 (left).
groups provide an intramolecular hydrogen-bonding array
that predominantly stabilises the cone conformation.
However, in the presence of polar solvents, hydrogen
bondingisdisruptedandconsequently, the1H NMRsignalof
the methylene protons appears as a broad singlet indicating a
statistical distribution of the different conformations due to a
rapid exchange between the conformers.
The macrocyclic tetraguanidinium compound 1 should
stabilise the cone conformation of otherwise flexible calix
[4]arenes, providing a strong and robust complex which
should prevent or slow down the conformational exchange.
Each bicyclic guanidinium may face a negatively charged
group of the calix[4]arene, hereby influencing its
orientation through electrostatic and hydrogen-bonding
interactions. Therefore, the association should increase the
inversion energy barriers which can be measured by the
determination of coalescence temperatures using variable
Table 2 summarises the data obtained from these
experiments. In general, tetrabutylammonium calix[4]arene
salts display lower coalescence temperatures (Tc) than the
corresponding tetraguanidinum calix[4]arenate complexes.
The numbers (together with those shown in Table 3) were
calculated assuming an accuracy of ^58C for the value of
Tc; ^15Hz for the value of Dn and ^1 Hz for the value
of JAB. It is also estimated that DG – values are accurate
to ^0.4 kcalmol21
.
1
However, Tc values are higher than 328 K for the
tetraguanidinium calix[4]arenate complexes, and there-
fore, free energy interconversion barriers cannot be
accurately determined as the solvent mixture employed
(CD3CN/CD3OD) does not allow to reach this temperature
(see the corresponding NMR spectra in Supplementary
Material, Figures S2 and S3, available online).
temperature H NMR experiments.
To conduct these experiments, tetrabutylammonium
salts of the anionic calix[4]arenes b and e were formed to
enhance their solubility in organic solvents. Hence,
mixtures of CD3CN:CD3OD (6:4) which tolerate a wide
range of temperatures (from 245 to 558C) were used in
the variable temperature NMR experiments.
In DMSO, the upper limit of the temperature range
increases, but extrapolation from previous experiments
As shown in Figure 5, the methylene protons of calix
[4]arene b appeared as a broad signal at room temperature,
Table 2. Calculated values for the coalescent constant (Kc) and DG – in the system depicted.
In CD3CN/CD3OD
Tc (K)
Dn
JAB
Kc (s21
)
DG – (^0.4 kcal mol21
)
Calix b (Z ¼ SO23 )
Calix e (Z ¼ CO22 )
Complex 1@b
308–318
308–318
.328
280
255
271
273
12.5
12.9
12.9
12.5
626.4
570.5
609.0
608.7
14.36
14.42
–
Complex 1@e
.328
–

Supramolecular Chemistry
733
Table 3. Calculated values for the coalescent constant (Kc) and DG – in DMSO.
In DMSO
Tc (K)
Dn (Hz)
JAB (Hz)
Kc (s21
)
DG – (^0.4 kcal mol21
)
Calix b (Z ¼ SO23 )
Calix b þ 4 equiv. 8
Calix b þ 2 equiv. 4
Complex 1@b
Calix e (Z ¼ CO22 )
Calix e þ 4 equiv. 8
Calix e þ 2 equiv. 4
Complex 1@e
298–308
298–308
298–308
.408
318–328
318–328
368–378
388–398
280
280
280
12.5a
626.4
626.4
626.4
520.6
438.6
438.6
438.6
471.4
13.9
13.9
13.9
.19.1
15.3
15.3
17.4
18.4
12.5a
12.5a
232.5b
200
200
12.45b
12.95a
12.95a
12.95a
12.8
200
210
a Extrapolated from the experiment conducted in CD3CN/MeOD (6/4).
b These numbers correspond to the last complex observed.
made in CD3CN/CD3OD mixture was necessary for
parameters such as JAB and Dn, as the lower temperature
limit of DMSO does not allow their direct measurement
(see the corresponding NMR spectra in Supplementary
Material, Figures S4–S9, available online).
Isothermal titration calorimetry studies
Isothermal titration calorimetry (ITC) was used to assess
quantitatively and qualitatively the thermodynamic factors
of the binding between macrocyclic tetraguanidinium
ligand 1 and tetraoxoanionic calix[4]arenes. The exper-
iments were carried out in a tetrahydrofuran (THF)/H2O
(3:1) mixture to allow solubilisation of the more
hydrophilic sodium calix[4]arenate salts a–d.
High binding constants (within the range of 104–
106 M21, see Table 4) were determined even in the
presence of polar solvents such as water, accounting for a
robust and cooperative enthalpically driven interaction.
Hence, the binding is dominated by hydrogen bonding and
ion-pair formation. Conversely, the entropic factor, which
mainly depends on disorder in the molecular assembly
process, solvation effects and solvent-shell reorganisation
upon complexation, has only a minor contribution in these
systems.
Control tests with mono- and diguanidinium calix[4]
arene salts were conducted to evaluate their effect in the
conformational stability of the complexes. Addition of
stoichiometric amounts (4 equiv.) of a bicyclic guanidi-
nium monomer 8 (see formula in Supplementary Material,
Figure S2, available online) did not influence the
interconversion rate (Table 3), the calix[4]arene carbox-
ylate salts showing similar coalescence temperatures as the
tetrabutylammonium salts. Interestingly, diguanidine 4
had an effect on the conformational barrier of calix[4]
arene tetracarboxylate e but not on tetrasulphonate b. This
accounts for slower kinetic off-rates for guanidinium
cations with carboxylates than with sulphates, in
agreement with thermodynamic data reported for similar
complexes (13). This trend is also observed with
macrocyclic tetraguanidinium ligand 1 [complex 1@e
showed higher coalescence temperatures (up to 408 K)
than the 1@b adduct (ca. 393 K)].
As previously discussed, molecular modelling and VT
1H NMR experiments suggested that the preferred calix[4]
arene conformation to maximise the interaction with
macrocyclic tetraguanidinium ligand 1 is the cone
conformation.
In conclusion, binding of tetraguanidinium multivalent
ligand 1, and to a lesser extent diguanidine 4, stabilises the
conformation of oxoanionic calix[4]arenes by hindering the
mobility of their aryl moieties. This effect is not attributable
to the intrinsic interaction of four ‘monovalent’ guanidine
ligands with anionic calix[4]arenes as demonstrated by
controlexperiments. Thehigherconformationalstabilisation
of the calix[4]arene carboxylates over the corresponding
sulphonates indicates that a stronger interaction results in a
structurally more stable complex. Indeed, as the number of
guanidinium moieties increases, the strength of the
interaction should also increase, both by effective molarity
and by the cooperativity effect.
In fact, the highly preorganised calix[4]arene d showed
an association constant with ligand 1 up to two orders of
magnitude higher than the more flexible calix[4]arenes a
and c. This molecule, bearing bridges between vicinal
phenols at the lower rim, displays a restricted cone
conformation (14) which facilitates the interaction with 1.
Tetrasulphonatocalix[4]arene b should also show a
preferred cone conformation due to the intramolecular
hydrogen-bonding array between the phenolic groups of the
lower rim. However, in polar media, this array is less stable.
Indeed, the binding constant drops by one order of
magnitude due to the weaker sulphonate–guanidinium
interaction and also due to the fact that this molecule is
conformationally less robust than calix[4]arene d. Indeed,
compounds a and c preferentially display a pinched
conformation which results in weaker binding to the
tetraguanidinium ligand 1 (Ka ¼ 2.5 £ 104 and 8.3
£ 104 M21, respectively). This pinched disposition of the
aryl moieties prevents interaction with the macrocyclic
This structural behaviour in solution is essential to
allow molecular recognition at these interfaces, because
stabilisation of the cone conformations allows for the
formation of robust and well-defined void-like structures
which are able to bind other guest molecules even at high
temperatures.

734
J. Valero and J. de Mendoza
Table 4. ITC profiles and thermodynamic data obtained by ITC measurements.
Complex 1@a
Complex 1@b
Complex 1@c
Complex 1@d
Ka (M21
DH (kcal mol21
DS (cal mol21 K21
DG (kcal mol21
)
2.46 £ 104
2.03 £ 105
8.25 £ 105
2.45 £ 106
)
210.4
214.7
26.0
29.9
210.8
26.7
211.7
214.8
27.3
212.6
212.9
28.8
)
)
Notes: Stoichiometry of the complexes (1:1). Errors # 10%.
tetraguanidine, and thus, lack of a correct preorganisation in
a conical shape translates into a lower association constant.
Finally, titrations with bicyclic guanidinium monomer 8
and dimer 5, respectively, didnot produce anysignificantheat
exchange in the presence of tetracarboxylic calix[4]arene
a (see Supplementary Material, Figure S10, available online).
This highlights the requirement of having multivalent
systems such as ligand 1 to allow complexation even in
highly competitive polar solvents.
tetraguanidinium calix[4]arenate complex (1@d) in terms
of binding and structural stability.
Host–guest interactions between calixarenes and
ammonium salts have been extensively reported (15).
Their inclusion is mainly driven by cation–p, CH–p and
p–p contacts, although hydrophobic effects should also
be taken into account in polar solvents (Figure 7).
Guest complexation in calix[4]arene-tetraguanidinium
expanded cavities
Asshowninpreviousmolecularmodels, complexationofthe
tetraguanidinium ligand 1 with oxoanionic calix[4]arenes
may result in the increase in the inner volume of these
molecular containers.
To demonstrate the ability of calixarene-guanidinium
expanded cavities to effectively include and bind guest
molecules, titration experiments of 1@d with two different
quinolinium iodide salts (9 and 10) (Figure 6) were carried
out. For this purpose, we selected the most robust
Figure 6. 2-Methylisoquinolinium
methylquinolinium iodide salts 9 and 10.
and
1-ethyl-2-
Figure 7. Molecular model (MM3) of guest encapsulation
complex 9@[1@e].

Supramolecular Chemistry
735
Figure 8. 1H NMR titration (in 3:1 THF-d8/D2O mixture) of the selected guest 9 with oxoanionic calix[4]arene d.
In terms of size, it is likely that 2-methylisoquinoli-
nium guest 9 should not allow an effective complexation
with a simple calix[4]arene. Indeed, no binding was
observed by 1H NMR titration experiments between calix
[4]arenate d and quinolinium 9 (Figure 8) in the absence of
tetraguanidinium. Also, no appreciable changes in the
spectra were observed upon adding guest 10 to a solution
containing macrocyclic tetraguanidine 1.
As illustrated in Figure 11, the addition of an excess of
ammonium guest resulted in the appearance of new broad
signals, which corresponds in chemical shift with the free
2-methylisoquinolinium guest in solution. The data
strongly support slow exchange equilibrium between the
free and the bound guest (16). The broadness of the signals
did not allow an accurate integration for the association
constant determination.
1H NMR titration experiments with guest 9 in
the presence of the supramolecular tetraguanidinium
calix[4]arenate host 1@d (Figure 9) in a (3:1) THF-d8/
D2O mixture revealed upfield shifting of the guest proton
signals, accounting for a molecular encapsulation process.
As shown in Figure 10, nOe cross peaks between these
two bound and free species confirmed the existence of a
chemical exchange due to guest inclusion.
1H NMR titrations in a (3:1) THF-d8/D2O mixture with
1-ethyl-2-methylquinolinium iodide guest 10 were also
Figure 9. 1H NMR titration (in 3:1 THF-d8/D2O mixture) of guest 9 with complex 1@d.

736
J. Valero and J. de Mendoza
Figure 10. NOESY spectrum showing exchange cross peaks between free and bound guest (9) signals.
performed to explore the possibility of this bulkier
molecule to be included into 1@d complex. Indeed, the
spectra showed well-defined upfield shifted signals
accounting for the complexation of 10 (Figure 11).
When an excess guest was added, a new set of signals
corresponding to the free species appeared, clearly
indicating a slow exchange process on the NMR timescale.
The chemical exchange observed in the NOESY
spectrum (Figure 12) confirmed this two-state (free and
bound) behaviour for guest 10.
Conclusions
We have shown that the cavity of a calix[4]arene
containing anionic functions at the upper rim (such as
carboxylates or sulphates) can be expanded by complexa-
tion with a macrocycle that is complementary in size
and binding sites. For this purpose, we employed a
tetraguanidinium macrocycle that can provide well-
oriented hydrogen bonds and strong electrostatic inter-
actions in apolar solvents. The resulting expanded cavity is
able to complex large guests such as quinolinium salts that
Figure 11. 1H NMR titration (in 3:1 THF-d8/D2O mixture) of guest 10 with complex 1@d.

Supramolecular Chemistry
737
Figure 12. NOESY spectrum showing exchange cross peaks between free and bound guest (10) signals.
could not be accommodated in simple calixarene
scaffolds. This constitutes a new strategy based on the
self-assembly to build up large containers for host–guest
interactions.
solvents were provided by Scharlau and Carlo Erba
(HPLC gradient grade).
Analysis
NMR spectra were recorded on a Bruker Advance 400 (1H:
400 MHz; 13C: 100 MHz) equipped with a z-gradient 5-mm
broadband observe probe with ATM Ultrashield spec-
trometer. Deuterated solvents used are indicated in each
case. Chemicals shifts (d) are expressed in ppm, and are
referred to the residual peak of the solvent. Mass spectra
were recorded in a Waters LCT Premier (electrospray
ionisation or atmospheric pressure chemical ionisation
mode), Waters GCT (electronic impact and chemical
ionisation modes) or Bruker MALDI-TOF spectrometers.
Calorimetric measurements were made in an isothermal
titration microcalorimeter Microcal VP-ITC. The operating
temperature range varies from 28C up to 808C with a noise
level of 1 nanocal s21 (4 nanowatts).
Experimental section
Materials and methods
Synthesis
All commercially available reagents (Aldrich, Fluka,
Acros, NovaBiochem, Panreac) were used without further
purification. Anhydrous solvents were obtained from a
solvent purification system. All reactions were carried out
under nitrogen atmosphere unless specified.
Chromatography
Thin layer chromatography (TLC) was performed on pre-
coated TLC plates SIL G-25 UV254 (Macherey-Nagel,
Du¨ren, Germany) glass supported with UV detection at
254 nm and/or bromocresol green stain (in EtOH and 1 N
NaOH mixture). Column chromatography was done using
silica gel (Chromagel SDS 40–60 mm) following the
procedure described by W.C. Still. HPLC chromatograms
were recorded on Agilent Technologies 1100 (UV
detector) analytical HPLC C18 Symmetry300 and SunFire
C18 columns (4.6 £ 150 mm, 5 mm). For semi-preparative
HPLC, an LC 18 column Symmetry (10 £ 150 mm, 5 mm)
was used. The mobile phase consisted of CH3CN/H2O
mixture containing 0.05 or 0.1% trifluoroacetic acid. The
Synthesis
Calix[4]arenes a, c, d and e were synthesised according to
described procedures (17). Calix[4]arene tetrasulphonic
acid b was commercially available.
(2S,8S)-2-(tert-butyldiphenylsilanyloxymethyl)-8-
methanesulphonyloxymethyl-3,4,6,7,8,9,-hexahydro-2H-
pyrimido[1,2-a ]pyrimidin-1-ium hexafluorophosphate (2)
To a solution of mono-deprotected guanidine (PF26 )
(1.23 g, 2.11 mmol) in dry CH2Cl2 (25 ml) were added

738
J. Valero and J. de Mendoza
Ms2O (1.84 g, 10.55 mmol) and N-methylmorpholine
(NMM) (1.87 ml, 16.87 mmol), and the mixture was stirred
for 4 h at room temperature. After evaporation of the
solvent, the resulting solid was dissolved in CH2Cl2
(100 ml) and washed with a 0.1 N NH4PF6 solution (2
£ 50 ml). The organic layer was filtered over cotton and
concentrated at reduced pressure. Purification by silica gel
column chromatography (CH2Cl2/MeOH, 98:2) afforded
the corresponding mesylate 2 (1.23 g, 88%) as a white solid.
M.p. 60–618C. ½aꢀD þ 78 (c ¼ 0.8, CHCl3). H NMR
(400 MHz, CDCl3) d 7.68–7.63 (m, 4H, CHAr), 7.50–741
(m, 6H, CHAr), 6.28 (s, 1H, NH), 6.12 (s, 1H, NH), 4.33 (dd,
J ¼ 4.5 and 10.3 Hz, 1H, CH2OMs), 4.19 (dd, J ¼ 6.5 and
10.3 Hz, 1H, CH2OMs), 3.86–3.79 (m, 1H, CHa), 3.72–
366 (m, 2H, CH2OSi), 3.63–3.56 (m, 1H, CHa), 3.43–3.27
(m, 4H, CH2g), 3.11 (s, 3H, CH3MsO), 2.15–1.87 (m, 4H,
CH2b), 1.08 (s, 9H, CH3t-Bu). 13C NMR (100 MHz, CDCl3)
d 150.7 (Cguan), 135.6, 135.5, 132.6, 132.5, 130.1, 130.1,
128.0 (CHAr, CAr), 69.5 (CH2OMs), 65.4 (CH2OSi), 50.2,
47.8 (CHa), 45.4, 45.0 (CH2g), 37.2 (CH3MsO), 26.8 (CH3t-
Bu), 22.5, 22.0 (CH2b), 19.2 (Ct-Bu). HR-MS calcd for
[C26H38N3O4SSi]þ 516.2352; found 516.2354.
(2S,8S)-2-Hydroxymethyl-8-[(2R,8R)-8-hydroxymethyl-3,
4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a ]pyrimidin-2-
ylmethylsulphanylmethyl-1-ium hexafluorophosphate]-3,
4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a ]pyrimidin-1-ium
mesylate (5)
A solution of 4 (1.20 g, 1.03 mmol) and MsOH (1.46 mL,
22.53 mmol) in a mixture of THF/H2O (3:1, 40 ml) was
heated overnight at 768C. The solvent was evaporated, and
the acid mixture was diluted in water and washed with
CH2Cl2 (2 £ 50 ml). The aqueous phase was partially
evaporated under reduced pressure. Afterwards, KHCO3
was added until a neutral pH was reached. The water was
evaporated, and the crude was dissolved in a mixture of
CH2Cl2/MeOH (1:20, 50 ml). The resulting precipitate
was filtered off. The polarity of the solvent mixture was
gradually reduced until pure CH2Cl2. The solvent was then
evaporated to afford compound 5 (573 mg, 93%) as a pale
1
25
1
yellow powder. H NMR (400 MHz, MeOD) d 3.78 (dd,
J ¼ 4.0 and 11.7 Hz, 2H, CH2O), 3.68–3.48 (m, 6H,
CH2O, CHa, CH2g), 3.60–3.40 (m, 10H, CHa, CH2g), 3.01
(dd, J ¼ 3.9 and 13.8 Hz, 2H, CH2S), 2.75 (dd, J ¼ 8.0 and
13.8 Hz, 2H, CH2S), 2.19–2.08 (m, 2H, CH2b), 2.07–1.84
(m, 6H, CH2b).13C NMR (100 MHz, MeOD) d 152.1
(Cguan), 65.0 (CH2O), 51.7 (CHa), 46.4 (CH2g), 36.6
(CH2S), 26.7, 23.5 (CH2b). ESI-MS m/z 397.3
(M 2 HCl 2 Cl2)þ, 199.1 (M 2 2Cl2)2þ. HR-MS calcd
for [C18H33N6O2S]þ397.2386; found 397.2381.
(2S,8S)-2-(tert-Butyldiphenylsilanyloxymethyl)-8-[(2R,
8R)-8-(tert-butyldiphenylsilanyloxymethyl)-3,4,6,7,8,9-
hexahydro-2H-pyrimido[1,2-a ]pyrimidin-2-
ylmethylsulphanylmethyl-1-ium hexafluorophosphate]-3,
4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a ]pyrimidin-1-ium
hexafluorophosphate (4)
(2S,8S)-2-Methanesulphonyloxymethyl-8-[(2R,8R)-8-
methanesulphonyloxymethyl-3,4,6,7,8,9-hexahydro-2H-
pyrimido[1,2-a ]pyrimidin-2-ylmethylsulphanylmethyl-1-
ium hexafluorophosphate]-3,4,6,7,8,9-hexahydro-2H-
pyrimido[1,2-a ]pyrimidin-1-ium hexafluorophosphate (6)
A mixture of compound R,R-3 (751 mg, 1.17 mmol),
mesylate S,S-2 (774 mg, 1.17 mmol) and Cs2CO3 (761 mg,
2.34 mmol) was dissolved in 20 mL of degassed (3:1)
CH3CN/MeOH at 08C under N2, and the solution was
stirred for 4 h. The solvent was evaporated under vacuum
at room temperature. The crude was dissolved in CH2Cl2
(20 ml) and washed with aqueous 1 N NH4PF6 (2 £ 15 ml).
The organic phase was filtered over cotton and
concentrated to dryness to give a crude residue which
was purified by silica gel (with KPF6) column chroma-
tography (CH2Cl2/MeOH, 96:4), affording symmetric
diguanidinium 4 (1.20 g, 88%) as a white solid. M.p. 84–
Compound 5 (610 mg, 1.04 mmol) and NMM (1.84 ml,
16.59 mmol) were mixed in dry CH2Cl2 (25 ml) under N2
at 08C, and the mixture was stirred for 5–10 min. Then,
Ms2O (1.81 g, 10.37 mmol) was added, and stirring was
continued for 24 h. The solution was directly washed with
a 0.1 N NH4PF6 solution (2 £ 15 ml). The organic layer
was filtered over cotton and left slowly to evaporate. A
white precipitate was filtered off affording 6 (771 mg,
1
1
25
868C. ½aꢀD þ 3 (c ¼ 1.0, CHCl3). H NMR (400 MHz,
CDCl3) d 8.24 (s, 2H, NH), 8.05 (s, 2H, NH), 7.71–7.55
(m, 8H, CHAr), 7.50–7.33 (m, 12H, CHAr), 3.73 (dd,
J ¼ 4.7 and 9.8 Hz, 2H, CH2O), 3.67–3.50 (m, 5H, CH2O,
CHa), 3.48–3.10 (m, 9H, CHa,CH2g), 3.00 (dd, J ¼ 2.7
and 13.5 Hz, 2H, CH2S), 2.59 (dd, J ¼ 10.8, 13.5 Hz, 2H,
CH2S), 2.18–1.69 (m, 8H, CH2b), 1.06 (s, 18H, CH3t-Bu).
13C NMR (100 MHz, CDCl3) d 151.2 (Cguan), 135.6,
135.6, 132.8, 132.7, 129.9, 127.9, 127.9 (CHAr, CAr), 65.2
(CH2O), 49.7, 48.3 (CHa), 45.1, 44.7 (CH2g), 38.5 (CH2S),
26.9 (CH3t-Bu), 26.2, 22.6 (CH2b), 19.2 (Ct-Bu). HR-MS
calcd for [C50H69N6O2SSi2]þ873.4741; found 873.4754.
88%) as a yellowish oil. H NMR (400 MHz, CD3CN) d
6.60 (s, 2H, NH), 6.50 (s, 2H, NH), 4.32 (dd, J ¼ 4.1 and
10.5 Hz, 2H, CH2O), 4.15 (dd, J ¼ 7.1 and 10.5 Hz, 2H,
CH2O), 3.87–3.77 (m, 2H, CHa), 3.61–3.51 (m, 2H,
CHa), 3.44–3.29 (m, 8H, CH2g), 3.12 (s, 6H, CH3MsO),
2.83 (dd, J ¼ 5.4 and 14.0 Hz, 2H, CH2S), 2.64 (dd,
J ¼ 8.4 and 13.9 Hz, 2H, CH2S), 2.17–2.05 (m, 4H,
CH2b), 1.94–1.80 (m, 4H, CH2b).13C NMR (100 MHz,
CD3CN) d 150.4 (Cguan), 70.4 (CH2O), 47.5, 47.4 (CHa),
44.8, 44.4 (CH2g), 36.4 (CH3MsO) 35.3 (CH2S), 24.6, 21.3
(CH2b). HR-MS calcd for [C20H38N6O6S3PF6]þ699.1657;
found 699.1630.

Supramolecular Chemistry
739
(2S,8S)-2-(Acetylthiomethyl)-8-[(2R,8R)-8-
(acetylthiomethyl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,
2-a ]pyrimidin-9-ium-2-yl)methylthio)methyl)-2,3,4,6,7,8-
hexahydro-1H-pyrimido[1,2-a ]pyrimidin-9-ium
hexafluorophosphate (7)
at room temperature for 2 days. The solvent was removed,
and the resulting crude was dissolved in H2O (50 mL) and
washed with CH2Cl2 (4 £ 50 ml). The aqueous phase was
evaporated under reduced pressure affording 8 (1.16 mg,
25
97%) as a white solid. M.p. 178–1808C. ½aꢀD –64
(c ¼ 0.5, H2O). 1H NMR (400 MHz, D2O) d 3.46 (m,
A mixture of 6 (250 mg, 0.296 mmol) and potassium
thioacetate (203 mg, 1.776 mmol) in CH3CN (20 ml) was
stirred and refluxed overnight. Then, the solution was
evaporated under vacuum, dissolved in CH2Cl2 and washed
with a 0.1 N NH4PF6 solution (2 £ 20 ml). The organic
layer was filtered over cotton and evaporated giving a crude
residuewhich was purified by silica gel (with KPF6) column
chromatography (CH2Cl2/MeOH, 98:2 ( 96:4), affording
2H, CH2O), 3.35 (m, 2H, CH2O), 3.32 (m, 2H, CHa),
C
3.26–3.13 (m, 4H, CH2g), 1.86–1.66 (m, 4H, CH2b). 13
NMR (100 MHz, D2O) d 151.2 (Cguan), 64.3 (CH2OSi),
48.8 (CHa), 45.0 (CH2g), 22.7 (CH2b). ESI m/z 200.13
[(M 2 Cl2)þ, 100%].
1H NMR complexation host–guest studies
1
7 (171 mg, 72%) as a brownish oil. H NMR (400 MHz,
These experiments were conducted by mixing equimolar
amounts of the host and the guest in the solvents specified
earlier. All trials were made at the millimolar range
concentration.
CD3CN d 6.15 (bs, 4H, NH), 3.63–3.49 (m, 4H, CHa),
3.44–3.28 (m, 8H, CH2g), 3.14–3.03 (m, 4H, CH2SCO),
2.78 (dd, J ¼ 5.8 and 13.7 Hz, 2H, CH2S), 2.62 (dd, J ¼ 7.9
and 13.7 Hz, 2H, CH2S), 2.40 (s, 6H, CH3COS), 2.15–2.03
(m, 4H, CH2b), 1.90–1.78 (m, 4H, CH2b). 13C NMR
(100 MHz, CD3CN) d 195.1 (SCO), 150.2 (Cguan), 47.6,
47.4 (CHa), 44.8, 44.5 (CH2g), 37.5 (C H2SCO), 35.3
(CH2S), 30.8 (C H3COS), 24.6, 21.5 (CH2bþ). ESI m/z 659.4
(M 2 PF26 )þ, 513.6 (M 2 PF62 2 HPF26 ) .
1
Variable temperature H NMR experiments
These experiments required the formation of the tetra-
butylammonium salt of the corresponding calix[4]arene for
solubility. After adding 4 equivalents of 1 M tetrabutylam-
monium hydroxide solution to 1 equiv. of calix[4]arene
tetracarboxylate, the mixture was evaporated until dryness.
Then, another equiv. of tetraguanidinium salt was added,
and the resulting powder was dissolved in the methanol/
acetonitrile mixture as previously described.
Compound 1
A solution of compound 7 (95 mg, 0.118 mmol), caesium
carbonate (173 mg, 0.531 mmol) and (nBu)2PhP poly-
styrene resin (323 mg, 0.260 mmol) in dry MeOH (40 mL)
was stirred under inert atmosphere for 20 min. Then, a
solution of compound 6 in MeCN (100 ml) was added
dropwise, and the final mixture was stirred for 2 days. The
phosphine resin was filtered off, and the solvent was
evaporated under vacuum, dissolved in CH2Cl2 and
washed with a 0.1 N NH4PF6 solution (3 £ 30 ml). The
organic phase was filtered over cotton and concentrated to
dryness to give a crude residue which was purified by silica
gel (with KPF6) column chromatography (CH2Cl2/MeOH,
100:0 ( 94:6), affording cyclic tetraguanidinium 1 (60 mg,
41%) as a pale yellow solid. 1H NMR [400 MHz, CD3CN:
D2O (3:1)] d 3.58–3.45 (m, 8H, CHa), 3.41–3.25 (m,
16H, CH2g), 2.91–2.77 (m, 8H, CH2S), 2.68–2.52 (m, 8H,
CH2S), 2.15–2.02 (m, 8H, CH2b), 1.87–1.67 (m, 8H,
CH2b). 13C NMR (100 MHz, CD3CN) d 151.2, 151.1
(Cguan), 48.4, 48.2, 47.5 (CHa), 45.0, 44.9, 44.8 (CH2g),
37.8, 37.5, 36.3 (CH2S), 25.7, 25.4, 25.3, 22.5 (CH2b).
MALDI m/z 789.6 (M 2 PF26 2 3HPF26 )þ. HR-MS calcd
for [C36H61N12S4]þ789.4019; found 789.4458.
ITC studies
The general conditions for the performance of these
experiments consist of previously dissolving all the
species in THF/H2O (8:2), and adding a 4-mM solution
of oxoanionic calix[4]arene (syringe) over a 0.5-mM
solution of the cyclic tetraguanidine at 258C.
Host–guest encapsulation experiments
These experiments were conducted in (3:1) THF-d8/D2O
in the millimolar range (between 2 and 10 mM),
successively adding different amounts of quinolinium or
isoquinolinium guests (9 and 10) to tetraguanidinium
calixarenate (1@d) complex.
Acknowledgements
The Ministry of Economy and Competitivity (MINECO, Spain)
(Projects CTQ2008-00183 and CTQ2011-28677), the ICIQ
Foundation and Consolider Ingenio (Grant 2010 CSD 2006-
0003) are kindly acknowledged. The authors also thank the group
(2S,8S)-2,8-Bis-(hydroxymethyl)-3,4,6,7,8,9-hexahydro-
2H-pyrimido-[1,2-a ]-pyrimidin-1-ium chloride (8)
´
members Dr A. Durana, Dr E. da Silva, Elena Galan and Dr
A solution of silyl-protected bicyclic guanidinium chloride
(3 g, 5.1 mmol) in 3 N HCl/CH3CN (1:2, 75 ml) was stirred
V. Martos for providing some of the calix[4]arenes and their
corresponding precursors described in this study.

740
J. Valero and J. de Mendoza
(9) (a) Timmerman, P.; Weidmann, J.-L.; Jollife, K.A.; Prins,
Note
L.J.; Reinhoudt, D.N.; Shinkai, S.; Frish L.; Cohen, Y.
Perkin Trans. 2000, 2, 2077–2089; (b) Giuseppone, N.;
Schmitt, J.-L.; Allouche, L.; Lehn, J.-M. Angew. Chem. Int.
1. Current address: LIMES Institute, Chemical Biology and
´
Medicinal Chemistry Unit, c/o Kekule Institute of Organic
Chemistry and Biochemistry, Gerhard-Domagk-Strasse 1,
53121 Bonn, Germany.
´
Ed. 2008, 120, 2267–2271; (c) Oliva, A.I.; Gomez, K.;
Gonzalez, G.; Ballester, P. New J. Chem. 2008, 32, 2159–
´
2163; (d) Metselaar, G.A.; Sanders, J.K.M.; de Mendoza, J.
Dalton Trans. 2008, 588–590.
(10) (a) Jaime, C.; de Mendoza, J.; Prados, P.; Nieto, P.M.;
References
´
Sanchez, C. J. Org. Chem. 1991, 56, 3372–3376; (b)
(1) (a) Rebek, J. Jr. Chem. Commun. 2000, 637–643; (b) Biros,
S.M.; Rebek, J. Jr. Chem. Soc. Rev. 2007, 36, 93–104; (c)
Schmuck, C. Angew. Chem. Int. Ed. 2007, 46, 5830–5833;
(d) Ballester, P. Chem. Soc. Rev. 2010, 39, 3810–3830.
Iwamoto, K.; Araki, K.; Shinkai, S. J. Org. Chem. 1991, 56,
4955–4962.
(11) (a) Gutsche, C.D.; Bauer, L.J. J. Am. Chem. Soc. 1985, 107,
6052–6059; (b) Kanamathareddy, S.; Gutsche, C.D. J. Org.
Chem. 1994, 59, 3871–3879; (c) Stewart, D.R.; Gutsche,
C.D. J. Am. Chem. Soc. 1999, 121, 4136–4146.
(12) van Hoorn, W.P.; Briels, W.J.; van Duynhoven, J.P.M.; van
Veggel, F.C.J.M.; Reinhoudt, D.N. J. Org. Chem. 1998, 63,
1299–1308.
(13) Jadhav, V.D.; Herdtweck, E.; Schmidtchen, F.P. Chem. Eur.
J. 2008, 14, 6098–6107.
(14) Arduini, A.; Fabbi, M.; Mantovani, M.; Mirone, L.; Pochini,
A.; Secchi, A.; Ungaro, R. J. Org. Chem. 1995, 60,
1454–1457.
`
(2) (a) Vriezema, D.M.; Comellas Aragones, M.; Elemans, J.A.
A.W.; Cornelissen, J.J.L.M.; Rowan, A.E.; Nolte, R.J.M.
Chem. Rev. 2005, 105, 1445–1489; (b) Lu¨tzen, A. Angew.
Chem. Int. Ed. 2005, 44, 1000–1002; (c) Koblenz, T.S.;
Wassenaar, J.; Reek, J.N.H. Chem. Soc. Rev. 2008, 37, 247–
262; (d) Lu¨tzen, A. ChemCatChem 2010, 2, 1212–1214.
(3) Mal, P.; Breiner, B.; Rissanen, K.; Nitschke, J.R. Science
2009, 324, 1697–1699.
(4) (a) Tucci, F.C.; Renslo, A.R.; Rudkevich, D.M.; Rebek,
J. Jr. Angew. Chem. Int. Ed. 2000, 39, 1076–1079; (b)
Menozzi, E.; Onagi, H.; Rheingold, A.L.; Rebek, J. Jr. Eur.
J. Org. Chem. 2005, 3633–3636; (c) Ajami, D.; Rebek, J. Jr.
Proc. Natl. Acad. Sci. USA 2007, 104, 16000–16003; (d)
(15) (a) Abraham, W. J. Incl. Phen. Macrocycl. Chem. 2002, 43,
159–174; (b) Mutihac, L.; Lee, J.H.; Kim, J.S.; Vicens, J.
Chem. Soc. Rev. 2011, 40, 2777–2796.
´
Lledo, A.; Rebek, J. Jr. Chem. Commun. 2010, 46, 8630–
8632.
(16) (a) Saito, S.; Nuckolls, C.; Rebek, J. Jr. J. Am. Chem. Soc.
2000, 122, 9628–9630; (b) Trembleau, L.; Rebek, J. Jr.
Science 2003, 301, 1219–1220.
¨
(5) Botana, E.; Nattinen, K.; Prados, P.; Rissanen, K.; de
Mendoza, J. Org. Lett. 2004, 6, 1091–1094.
(6) (a) Botana, E.; Da Silva, E.; Benet-Buchholz, J.; Ballester,
P.; de Mendoza, J. Angew. Chem. Int. Ed. 2007, 46, 198–
201; (b) Botana, E.; Lubinu, M.C.; Da Silva, E.; Espinet, P.;
de Mendoza, J. Chem. Commun. 2010, 46, 4752–4754.
(7) Zadmard, R.; Kraft, A.; Schrader, T.; Linne, U. Chem. Eur.
J. 2004, 10, 4233–4239.
(17) (a) Sansone, F.; Barboso, S.; Casnati, A.; Fabbi, M.;
Pochini, A.; Ugozzoli, F.; Ungaro, R. Eur. J. Org. Chem.
1998, 897–905; (b) Sansone, F.; Barboso, S.; Casnati, A.;
Sciotto, D.; Ungaro, R. Tetrahedron Lett. 1999, 40, 4741–
4744; (c) Zhou, H.; Wang, D.; Baldini, L.; Ennis, E.; Jain,
R.; Carie, A.; Sebti, S.M.; Hamilton, A.D. Org. Biomol.
Chem. 2006, 4, 2376–2386; (d) Martos, V.; Bell, S.C.;
Santos, E.; Isacoff, E.Y.; Trauner, D.; de Mendoza, J. Proc.
Natl. Acad. Sci. USA 2009, 106, 10482–10486.
(8) Cohen, Y.; Avram, L.; Frish, L. Angew. Chem. Int. Ed.
2005, 44, 520–554.