Synthesis and anion-binding properties of new disulfonamide-based receptors

Article abstract of DOI:10.1016/j.tet.2009.01.070

The synthesis of disulfonamide receptor scaffolds for anion binding is reported. Acyclic receptors are found to tightly bind acetate in MeCN-d₃ with dominant 1:1 stoichiometry, a smaller, sequential 1:2 (H+G) association is also found. Constrai

Full text of DOI:10.1016/j.tet.2009.01.070

Tetrahedron 65 (2009) 2184–2195
Contents lists available at ScienceDirect
Tetrahedron
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Synthesis and anion-binding properties of new disulfonamide-based receptors
*
Oscar Mammoliti, Sara Allasia, Sally Dixon, Jeremy D. Kilburn
School of Chemistry, Department of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of disulfonamide receptor scaffolds for anion binding is reported. Acyclic receptors are
found to tightly bind acetate in MeCN-d3 with dominant 1:1 stoichiometry, a smaller, sequential 1:2
(HþG) association is also found. Constraint of the disulfonamide receptor into macrocycles serves to
eliminate the 1:2 binding stoichiometry and X-ray crystal structures of several macrocyclic receptors
Received 24 October 2008
Accepted 15 January 2009
Available online 21 January 2009
allow rationalisation of their affinity for acetate binding. L-Valine derived macrocycles maintain tight 1:1
binding of acetate (K1a:1 >104
competitive MeCN-d3/2% H2O.
M
ꢀ1) in MeCN-d3 and display preference for oxyanion binding in more
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
intramolecularly folded structure and demonstrated relatively
weak association constants with peptide guests as a consequence of
the energetic penalty of unfolding this collapsed conformation. In
order to overcome the possibility that substantial reorganisation of
an intramolecularly folded receptor of type (b) (Fig. 1) will be re-
quired for anion binding, we have also considered constraining
such receptors in a macrocyclic framework. Herein we describe
studies in which we have sought firstly to prepare acyclic disul-
fonamides functionalised with additional amide hydrogen bonding
donors, and characterised their binding properties with simple
carboxylate guests. We have also prepared a series of macrocyclic
receptors (Fig. 1c and d), which may also incorporate chirality into
the receptor structure with the ultimate objective of preparing
receptors for the enantioselective recognition of amino acid-
s.4c,d,5a,12 Four hydrogen bonding interactions are possible for as-
sociation with a carboxylate guest molecule and each scaffold
possesses the benzene-1,3-disulfonamide moiety derivatised with
The development of synthetic receptors for anions is of con-
siderable interest because of their potential biomedical and envi-
ronmental applications.1 In particular, the role of carboxylate as
a functional group in many important biological systems has
prompted us, and others, to investigate various binding motifs,
incorporating multiple hydrogen bond donor sites, for binding
carboxylate functionality2 and there are many recent applications
of ureas,3 thioureas,4 guanidinium salts,5 amides,6 pyrroles7 and
polyamines,8,9 typically in development of receptors for amino acid
and peptide recognition. Several examples of acyclic receptors in-
corporating sulfonamides for hydrogen-bonded complexation of
anionic guests have also been reported.10 These include a simple
disulfonamide receptor, described by Crabtree et al.10g (Fig. 1a),
which accommodates halide and acetate guests with high associ-
ation constants in apolar solvents, as a result of the strong hydrogen
bond donating ability of sulfonamide NHs, and the receptor flexi-
bility, which allows optimal convergence of hydrogen bond donors
with the anion acceptor. We anticipated that tighter anion binding
could be achieved using this simple disulfonamide scaffold with
incorporation of additional hydrogen bonding (amide) functional-
ity. The simplest structures would incorporate such functionality in
an acyclic framework (Fig. 1b). However in earlier work we have
described the synthesis and binding properties of ‘tweezers’ bear-
ing sulfonamidopeptide side arms as receptors for N-protected
amino acids and peptides11 and the repeating backbone structure of
these receptors contained both strong sulfonamide hydrogen bond
donors and amide functionality, which collapsed into an
either diamines (Fig. 1c)13 or
a-amino acids (Fig. 1d).
Macrocyclisation is achieved with a bridging tether, which may
incorporate solublising substituents or be varied in structure and
length for optimisation of the cavity size or macrocycle flexibility.
2. Results and discussion
2.1. Synthesis and structure
Two synthetic approaches were adopted for preparation of re-
ceptors based upon the benzene-1,3-disulfonamide scaffold, via
condensation of benzene-1,3-disulfonyl chloride with either mono-
protected bis-amines or with L-valine. Both acyclic (3) and macro-
cyclic (6–9) bis-amine derived receptors were targeted in order that
comparative binding studies could be undertaken to ascertain the
effect of conformational constraints on the binding properties of the
* Corresponding author. Tel.: þ44 (0) 2380 593596; fax: þ44 (0) 2380 596805.
E-mail address: jdk1@soton.ac.uk (J.D. Kilburn).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.070

O. Mammoliti et al. / Tetrahedron 65 (2009) 2184–2195
2185
Figure 1. Schematic representation of acetate binding by (a) Crabtree’s benzene-1,3-disulfonamide, and proposed (b) acyclic and (c,d) macrocyclic benzene-1,3-disulfonamide
receptor scaffolds.
receptors. Furthermore, the size of the binding cavity was varied
with both achiral (6, 7) and chiral (8, 9) analogues (Scheme 1).
Ethylene diamine was mono-Boc protected14 to give 1, which
was coupled with benzene-1,3-disulfonyl chloride, furnishing 2.
Removal of the Boc protecting groups and coupling with 2 equiv of
valeryl chloride provided acyclic receptor 3 in a modest unopti-
mised yield. A [1þ1] direct macrocyclisation between diamine
2$2TFA salt and succinyl- or glutaryl- diacid chlorides, under high
dilution conditions, afforded achiral macrocycles 6 and 7, re-
spectively. Both 6 and 7 were obtained in modest yield, although
the former in somewhat lower yield presumably as a result of in-
creased conformational strain in the [1þ1] macrocyclisation which
may favour formation of the undesired [2þ2] cyclisation product.15
Chiral bis-amine derived receptors 8 and 9 were prepared in
analogous fashion. N-Boc-(S,S)-cyclohexane-1,2-diamine 4 was
prepared via mono-Boc protection of (1S,2S)-(ꢀ)-1,2-di
aminocyclohexane D-tartrate and coupled with benzene-1,3-sulfo-
nyl chloride, furnishing 5 in good yield. Once again, deprotection of
5 and subsequent [1þ1] coupling, with both succinyl- and glutaryl-
chloride, of the bis-amine liberated from 5$2TFA salt under basic,
high dilution conditions, afforded macrocyclic products 8 and 9,
respectively; the chiral analogues of 6 and 7. Macrocycles 6 and 7
were soluble only in hygroscopic dimethylsulfoxide (DMSO) and
we were unable to obtain diffraction grade single crystals. However,
(S,S)-cyclohexane-1,2-diamine-derived receptor
8 was crystalli
sed by vapour diffusion from MeOH. The crystal structure is
Scheme 1. Synthesis of bis-amine derived, benzene-1,3-disulfonamide receptors.

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O. Mammoliti et al. / Tetrahedron 65 (2009) 2184–2195
Table 1
Anion templating effect upon [1þ1] condensation between 11 and 1,5-
diaminopntanea
Entry
Templating anion
Yield [%] of 13b
1
2
3
4
5
None
Clꢀ
28c
79
65
0
Brꢀ
H2POꢀ4
AcOꢀ
21
a
Typically, 4 mL aliquots of each of a 0.07 M solution of 11 in CH2Cl2 containing
2 equiv TBA salt, and a 0.07 M solution of 1,5-diaminopentane in CH2Cl2 containing
3.4 equiv Et3N were added into CH2Cl2 (20 mL) over 1.75 h.
b
Yields refer to isolated, analytically pure material purified by column
chromatography.
c
[2þ2] Cyclisation product was also isolated in 26% yield.
Synthesis of
L
-valine derived receptors relied upon [1þ1] cycli-
sation of an activated bis-carboxylic ester 11 with a diamine cou-
pling partner as the key step.
Assembly of the cyclisation precursor 11 was made in three
steps; the bis-sulfonamide scaffold was constructed upon cou-
pling of benzene-1,3-disulfonyl chloride with 2 equiv of L-valine
benzyl ester, catalytic hydrogenolysis then furnished diacid 10 and
conversion to bis-pentafluorophenyl (Pfp) ester 11 was straight-
forward (Scheme 2). Preparation of an acyclic receptor 12 was
accomplished in reasonable yield, using a carbonyldiimidazole
(CDI) mediated coupling of diacid 10 and benzylamine. Attempted
CDI-mediated cyclisation of diacid 10, both with 1,5-dia-
minopentane and m-xylylenediamine, gave rise to unwanted
[2þ2] cyclisation products, and [1þ1] cyclisation products 13 and
14 were obtained in yields of only 23% and 6%, respectively.
Several reports of anion templated macrocyclisation have been
made recently16 and we also attempted anion templated synthesis
of macrocycles 13 and 14.
Figure 2. X-ray crystal structure of 8 illustrating antiparallel array of (S,S)-1,2-cyclo-
hexyl-linked amide and sulfonamide H-bond donors, solvent excluded, partial num-
bering for clarity.
characterised by intramolecular hydrogen bonding, importantly
between N1–H1/O5 [N1/O5 2.971(7) Å] and between N2–H2/
O6 [N2/O6 2.777(6) Å] (Fig. 2). The observed conformation results
in antiparallel positioning of sulfonamide and amide hydrogen
bond donors around the macrocycle and suggests that substantial
reorganisation would be required to align all four hydrogen bond
donors with an anionic guest. Unfortunately we did not succeed in
crystallising the homologous macrocycle 9.
Condensation of 11 with 1,5-diaminopentane was conducted in
the presence of tetra-n-butylammonium (TBA) salts of Clꢀ, Brꢀ,
H2POꢀ4 and AcOꢀ (Table 1). Templation by Clꢀ and Brꢀ is evidenced
by substantial improvement in the yield of [1þ1] product 13,
Scheme 2. Synthesis of L-valine derived benzene-1,3-disulfonamide receptors.

O. Mammoliti et al. / Tetrahedron 65 (2009) 2184–2195
2187
Finally, preparation of
L
-valine derived receptor 17, directly
analogous in structure with 14 but bearing solublising alkyl func-
tionality, was carried out, once again via macrocyclisation of acti-
vated bis-Pfp ester 11 with a bis-amine coupling partner 16
(Scheme 3). 5-Octyloxy-isophthalic acid (15) was obtained from
dimethyl-5-hydroxyisophthalate following alkylation and saponi-
fication.17 Amidation and reduction steps furnished 16 and TBACl
templated coupling of 16 with 11 gave the anticipated macrocyclic
product 17.
X-ray crystal structures of macrocycles 13 and 14 indicate that
the directionality of hydrogen bond donor groups alternates
around the receptor cavity in both cases (Fig. 3).
2.2. Binding studies
The binding properties of all of the disulfonamide derived re-
ceptors were investigated using the tetra-n-butylammonium salts
of various anions and in various solvents using standard NMR ti-
tration experiments.18 Initial studies were carried out with the
acyclic disulfonamides 2 and 3, which were not soluble in CDCl3
and titration experiments with n-Bu4NþAcOꢀ were therefore car-
ried out using MeCN-d3 as solvent. For both 2 and 3 the sulfon-
amide NH resonance broadened on addition of the acetate guest,
but a downfield shift of the amide resonance was observed (2:
Ddmax >1.20 ppm, 3: Ddmax >2.16 ppm) consistent with the for-
mation of hydrogen bonds. The titration curves did not reach sat-
uration (4.77 equiv and 6.25 equiv added guest to 2 and 3,
respectively) and the data could not be fitted to a simple 1:1 (host–
guest) binding isotherm but instead to a 1:2 (host–guest) binding
isotherm in which binding is dominated by a large 1:1 (HþG) as-
sociation (2: Ka1:1 3.6ꢁ104 Mꢀ1, 3: Ka1:1 1.1ꢁ104 Mꢀ1) with only a very
small contribution from sequential 1:2 (HGþG) binding (Table 2,
entries 1, 2). Dominant 1:1 stoichiometry for binding of acetate by
receptor 2 was confirmed by Job plot.19 The 1H NMR spectra of 2
and 3 also showed an initial downfield shift of the aromatic C2–H
proton upon addition of up to 1 equiv AcOꢀ followed by an upfield
shift with further equivalents of added guest (Fig. 4).
Scheme 3. Synthesis of L-valine derived benzene-1,3-disulfonamide receptor.
without formation of the [2þ2] product in the presence of either
anion (entries 1–3). No reaction occurred in the presence of
n-Bu4NþH2POꢀ4 (entry 4) and AcOꢀ failed to influence the macro-
cyclisation; in the presence of AcOꢀ, 13 was obtained in similar
yield to that observed under non-templated CDI-mediated cou-
pling conditions (entry 5). This suggests that the receptor motif
may demonstrate closer fit of the macrocyclic cavity and preferred
binding to Clꢀ and Brꢀ anion guests than to carboxylate in non-
polar organic solvents.
The TBACl templated macrocyclisation conditions were used for
the preparation of 14, in good yield (Scheme 2).
Figure 3. (a) X-ray crystal structures of (a) 13 and (b) 14, illustrating antiparallel arrays of (S,S)-1,2-cyclohexyl-linked amide and sulfonamide H-bond donors, solvent excluded,
partial numbering for clarity.

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O. Mammoliti et al. / Tetrahedron 65 (2009) 2184–2195
Table 2
1H NMR titration data for binding of disulfonamide receptors 2, 3, 6–9 and 12–14 with tetra-n-butylammonium acetate in various solvents at 298 K
Entry
1
Receptor
Solvent
Stoichiometry of binding
Ka (Mꢀ1) [%errora]
DG (kJ/mol)
2
MeCN-d3
1:1þ1:2
K1a:1¼36,000 [<5]
K1a:2¼26 [<5]
K1a:1¼11,000 [<5]
K1a:2¼4 [<5]
K1a:1¼3640 [<5]
K1a:2¼32 [<5]
K1a:1¼989 [11]
K1a:1¼1830 [6]
K1a:1¼>104
ꢀ26.0
ꢀ23.0
ꢀ20.3
2
3
3
MeCN-d3
MeCN-d3
1:1þ1:2
1:1þ1:2
12
4
5
6
7
8
9
8
9
13
14
6
MeCN-d3
MeCN-d3
MeCN-d3
MeCN-d3
DMSO-d6
DMSO-d6
1:1
1:1
1:1
1:1
1:1
1:1þ1:2
ꢀ17.1
ꢀ18.6
d
K1a:1¼>104
d
K1a:1¼236 [<5]
K1a:1¼710 [8]
K1a:2¼8 [8]
ꢀ13.5
ꢀ16.3
7
10
11
8
9
CDCl3
CDCl3
1:1þ1:2
db
d
1:1
K1a:1¼758 [9]
ꢀ16.4
a
When more than one proton could be monitored during the same titration the error was calculated on the basis of the average of all constants calculated. When only one
proton could be monitored the reported errors were calculated with EQNMR software,22 errors calculated below the 5% threshold in EQNMR are reported as <5%.
b
Data were not fitted reliably.
This can be attributed to tight binding of a first equivalent of
acetate by both sulfonamides simultaneously, followed by binding
of a second acetate by the two sulfonamides separately, as has
been proposed by Crabtree et al.10g for binding of acetate or
fluoride by simple acyclic disulfonamide receptors, and by oth-
ers10d (Scheme 4). Notably the C2–H proton is significantly af-
fected in the 1:1 binding mode, accounting for its pronounced
downfield shift on addition of the first equivalent of acetate, but is
relatively unaffected in the 1:2 binding mode, accounting for the
subsequent upfield shift back towards its unperturbed position as
more acetate is added. The acyclic disulfonamide 12 behaved very
similarly to the acyclic receptors 2 and 3 on addition of acetate
(Table 2, entry 3). Hence the amide NH resonance shifted down-
field in the titration experiment (Ddmax >2.30 ppm) and gave
a good fit to a sequential 1:2 binding isotherm, which is domi-
nated by 1:1 association (K1a:1 3.6ꢁ103 Mꢀ1) with a much smaller
1:2 association (K1a:2 32 Mꢀ1). Similarly an initial downfield shift of
the aromatic C2–H proton of 12 upon addition of up to 1 equiv
downfield shift of amide NH resonances (8: Ddmax¼1.42 ppm, 9:
Ddmax¼1.43 ppm), which could be fitted to 1:1 binding isotherm (8:
K1a:1 989 Mꢀ1, 9: Ka1:1 1830 Mꢀ1) (Fig. 5 and Table 2, entries 4, 5). No
evidence for 1:2 complexation was observed in either case. Hence,
the 1:2 complex formation observed in the acyclic series is sup-
pressed, but the constraint of the macrocyclic framework is coun-
terproductive. The more flexible macrocycle 9 binds acetate guest
in MeCN-d3 more tightly than does receptor 8 but binding in both
cases is significantly weaker than was observed for the acyclic an-
alogues 2 and 3. However, in contrast to receptors 8 and 9, con-
straining the L-valine derived disulfonamides into macrocycles 13
and 14 proved advantageous. Hence 13 and 14 demonstrated high
affinity for AcOꢀ in MeCN-d3. Titration curves obtained by moni-
toring the amide NH resonance gave in each case a linear increase
in dH with increasing [AcOꢀ] and a sharp plateau after addition of
1 equiv guest anion. The data implies very tight 1:1 binding (Table
2, entries 6, 7) but is beyond the upper limit (Ka >104 Mꢀ1) of as-
sociation constants that can be accurately determined by NMR
titration.20
For macrocycles 6 and 7 we were only able to carry out ti-
trations with n-Bu4NþAcOꢀ using DMSO-d6 as solvent (Table 2,
entries 8, 9) and unsurprisingly, association constants were found
to be lower in this solvent. Downfield shift of the amide NH
resonance of receptor 6 gave a straightforward titration curve,
which gave a good fit with a 1:1 binding isotherm, but a low
association constant (Ka1:1 239 Mꢀ1). Addition of acetate also led to
a downfield shift of the receptor 6 C2–H aromatic proton. For
homologous receptor 7, on the other hand, the titration curve for
the C2–H proton initially shifts downfield and then reverses up-
field following addition of more than 2 equiv of AcOꢀ (Fig. 6).
Close fit to a 1:1 binding isotherm could not be made for the ti-
tration curves. Titration of 7 with AcOꢀ also results in downfield
shift of the amide NH resonance, and fit of the data to a sequential
1:2 (HGþG) binding isotherm confirmed contribution of a partial
1:2 binding (K1a:2 8 Mꢀ1) association, although 1:1 stoichiometry
dominates (K1a:1 710 Mꢀ1).
AcOꢀ
(
Ddmax¼0.27 ppm) is observed, followed by an upfield shift
with addition of further guest.
We wished to compare the binding properties of macrocyclic
receptors with the analogous acyclic receptors, but unfortunately
both 6 and 7 were insoluble in MeCN-d3. However, titration of 8 and
9 with n-Bu4NþAcOꢀ in MeCN-d3 again led to broadening of sul-
fonamide protons in the 1H NMR spectrum, but also a defined
Receptors 8 and 9, on the other hand, also proved to be
soluble in CDCl3. Titration of 8 with n-Bu4NþAcOꢀ in CDCl3
(Table 2, entry 10) resulted in downfield shift of the amide NH
resonance, indicating involvement of the amide functionality in
hydrogen bonding, but a relatively small change in shift of the
sulfonamide NH resonance (Ddmax¼0.36 ppm) suggesting that
these protons are less accessible for binding. However, the ti-
tration curves could not be reliably fitted to a 1:1 or a 1:2
binding isotherm,21 which suggests that multiple receptor-
Figure 4. Binding titration curves of acyclic receptors (B) 2 and (C) 3 with tetra-n-
butylammonium acetate in MeCN-d3, showing the shift of the aromatic C2–H proton.

O. Mammoliti et al. / Tetrahedron 65 (2009) 2184–2195
2189
Scheme 4. Proposed formation of 1:1 (2/3)$AcOꢀ and 1:2 (2/3)$2AcOꢀ complexes.
anion equilibria are present in CDCl3. For macrocycle 9 the ti-
tration curve obtained, monitoring the amide NH resonance on
addition of AcOꢀ in CDCl3
Ddmax >2.10 ppm), gave a reasonable
(
fit using a 1:1 binding isotherm (Table 2, entry 11). However,
a low binding constant for this association (K1a:1 758 Mꢀ1) and
negligible change in shift of the aromatic C2–H proton follow-
ing addition of guest (Ddmax w0.05 ppm) indicates that the
guest anion is not accommodated within the macrocyclic cavity
by multiple hydrogen-bonded interactions but is most likely
bound externally.
The L-valine derived receptors 13 and 14 both proved to be
potent receptors for acetate in MeCN-d3 solvent, whereas 6–9
were relatively poor receptors, and indeed were weaker than
their acyclic analogues. Receptors 13 and 14 were therefore se-
lected for further binding studies with other anions. These
studies were carried out using a more competitive solvent mix-
ture, MeCN-d3/2% H2O as binding of acetate in neat MeCN-d3 had
proven to be beyond the limit of accurate determination by NMR
titration experiments. In MeCN-d3/2% H2O the titration of 13 and
14 with acetate, monitoring the chemical shift of the amide NH
proton, gave clean 1:1 binding (13: K1a:1 540 Mꢀ1, 14: K1a:1
351 Mꢀ1). Receptor 14 proved to be only sparingly soluble in this
solvent mixture however, whereas the analogous receptor 17 was
much more soluble, gave an essentially identical binding result
with acetate (17: K1a:1 372 Mꢀ1) and was therefore used in sub-
sequent studies. Titrations, using receptors 13 and 17, were car-
ried out using the tetra-n-butylammonium salts of acetate,
dihydrogen phosphate, chloride and bromide and all gave reli-
able data with good fit to a 1:1 binding isotherm (Table 3). Ti-
tration curves indicating the chemical shift of the amide NH
proton of each macrocycle with each of these anions are shown
in Figure 7.
Figure 6. Binding titration curves of macrocycles (C) 6 and (B) 7 with tetra-n-bu-
tylammonium acetate in DMSO-d6, showing the shift of the aromatic C2–H proton.
AcOꢀ>H2POꢀ4 >Clꢀ>Brꢀ, in reversal of the templating effect of
these anions in macrocycle synthesis under less polar conditions.
The more flexible receptor, 13 is a slightly stronger receptor than
17 for each anion. In a final series of titration experiments, the
binding of macrocycle 17 with the four anions was measured in
MeCN-d3/1% H2O (Table 3, entries 10–13), which unsurprisingly
gave higher association constants than in MeCN-d3/2% H2O, but
also showed greater selectivity between the four anions.
Table 3
Both receptors 13 and 17 demonstrate a preference for binding
1H NMR titration data for binding of
various anions at 298 K
L-valine derived disulfonamide receptors with
oxyanions
over
halides,
according
to
the
trend
Entry Receptor Aniona Solvent
K1a:1 (Mꢀ1) [%errorb]
DG (kJ/mol)
1
2
3
4
5
6
7
8
14
13
13
13
13
17
17
17
17
17
17
17
17
AcOꢀ
AcOꢀ
MeCN-d3/2% H2O 351 [<5%]
MeCN-d3/2% H2O 540 [<5%]
ꢀ14.5
ꢀ15.6
ꢀ14.0
ꢀ12.9
ꢀ11.7
ꢀ14.7
ꢀ13.1
ꢀ11.5
ꢀ9.9
H2POꢀ4 MeCN-d3/2% H2O 281 [<5%]
Clꢀ
MeCN-d3/2% H2O 183 [<5%]
MeCN-d3/2% H2O 111 [<5%]
MeCN-d3/2% H2O 372 [<5%]
Brꢀ
AcOꢀ
H2POꢀ4 MeCN-d3/2% H2O 201 [<5%]
Clꢀ
MeCN-d3/2% H2O 104 [c]
MeCN-d3/2% H2O 55 [c]
MeCN-d3/1% H2O 2690 [<5%]
9
Brꢀ
10
11
12
13
AcOꢀ
ꢀ19.6
ꢀ16.7
ꢀ14.3
ꢀ12.1
H2POꢀ4 MeCN-d3/1% H2O 866[<5%]
Clꢀ
Brꢀ
MeCN-d3/1% H2O 328 [11%]
MeCN-d3/1% H2O 134 [13%]
a
Anions were added as tetra-n-butylammonium salts.
When more than one proton could be monitored during the same titration the
b
error was calculated on the basis of the average of all constants calculated. When
only one proton could be monitored the reported errors were calculated with
EQNMR software,22 errors calculated below the 5% threshold in EQNMR are reported
as <5%.
c
Figure 5. Binding titration curves of macrocycles (B) 8 and (C) 9 with tetra-n-bu-
tylammonium acetate in MeCN-d3, showing the shift of the amide NH resonance.
Due to a low percentage saturation of the receptor, association constants should
be considered of approximate magnitude.

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O. Mammoliti et al. / Tetrahedron 65 (2009) 2184–2195
Figure 7. Binding titration curves of (a) macrocycle 13 and (b) macrocycle 17 with tetra-n-butylammonium salts of AcOꢀ (B), H2PO4 (C), Clꢀ (,) and Brꢀ (-) in MeCN-d3/2% H2O,
showing the shift of the amide NH resonance.
3. Conclusion
1H and 13C NMR spectra were recorded on Bruker AV300,
AM300 or DPX400 spectrometers. 1H chemical shifts are reported
as values in parts per million referenced to residual solvent. The
following abbreviations are used to denote multiplicity and may be
compounded: s¼singlet, d¼doublet, t¼triplet, q¼quartet, fs¼fine
splitting. Broadened resonances are abbreviated: br. Coupling
constants, J, are measured in hertz (Hz). 13C spectra were proton
decoupled and referenced to solvent. The number of adjacent
protons was determined by DEPT experiments.
We have prepared
a series of acyclic and macrocyclic
disulfonamide receptors. Synthesis of these compounds, from
benzene-1,3-disulfonyl chloride was straightforward. The syn-
thesis of the macrocyclic compounds benefited from a sub-
stantial templating effect using chloride and bromide ions, but
not using acetate or phosphate. The acyclic disulfonamides
proved to be potent receptors for carboxylates in MeCN-d3 al-
though, as has been observed previously with simpler disul-
fonamide receptors, binding involves both 1:1 and 1:2 binding
stoichiometries.
Macrocyclisation of the basic acyclic receptor structure served to
suppress the 1:2 binding mode such that the macrocyclic receptors
generally showed clean 1:1 binding. However, macrocycles 8 and 9
proved to be weaker binders of carboxylate than their acyclic an-
alogues whereas macrocycles 13 and 14 were significantly stronger.
The crystal structure of macrocycle 8 indicates a conformation,
stabilised by at least one intramolecular hydrogen bond, with al-
ternating NHs pointing in opposite directions as one moves around
the macrocyclic ring, rather than convergent on one face of the
macrocycle as would be preferred for strong anion recognition.
Crystal structures of macrocycles 13 and 14 on the other hand, also
indicate alternate NHs to be pointing in opposite directions; but
both of these macrocycles appear to be more flexible and lack
intramolecular hydrogen bond stabilisation of the conformation,
possibly explaining the much greater anion-binding affinity of 13
and 14, but rather limited selectivity between anions. Work to-
wards application of amino acid-derived disulfonamide receptor
macrocycles for enantioselective carboxylate recognition is in
progress.
Infra-red spectra were recorded on a BIORAD Golden Gate FTS
135. All samples were run either as neat solids or as oils. Absorp-
tions are given in wavenumbers (cmꢀ1) and the following abbre-
viations used to denote peak intensities: s¼strong, m¼medium,
w¼weak and/or br (broad).
Low resolution mass spectra were recorded on a Micromass
Platform II single quadrupole mass spectrometer in methanol or
acetonitrile. Accurate mass spectra were recorded on a VG analyt-
ical 70-250-SE double focussing mass spectrometer.
Melting points were determined in open capillary tubes using
a Gallenkamp Electrothermal melting point apparatus and are
uncorrected. Optical rotations were measured on a PolAr2001 po-
larimeter using the solvent stated, the concentration given is in
g/100 mL.
Microanalyses were performed by MEDAC Ltd., Surrey.
4.2. 1H NMR titration experiments18
1H NMR titration experiments were conducted on a Bru¨ker
AM300 spectrometer at 298 K. Deuterated solvents of commercial
grade were used. Inorganic guests, TBA acetate, dihydrogen phos-
phate, fluoride, chloride and bromide were of commercial grade.
The correct stoichiometry was verified performing NMR experi-
ments with long scan delays. A sample of host was dissolved in the
deuterated solvent or solvent mixture. A portion of this solution
was used as the host NMR sample and the remainder used to dis-
solve a sample of the guest, so that the concentration of the host
remained constant throughout the titration. Guest stock solutions
4. Experimental
4.1. General techniques
Unless otherwise stated, reagents and solvents were obtained
from commercial suppliers and if necessary dried and distilled
before use. THF was freshly distilled from sodium benzophenone
ketal under argon. Dichloromethane, acetonitrile and triethylamine
were freshly distilled from CaH2 as was petroleum ether where the
fraction boiling between 40 and 60 ꢂC was used. Reactions re-
quiring a dry atmosphere were conducted in oven dried glassware
under nitrogen. Column chromatography was performed on Sorbsil
C60, 40–60 mesh silica.
were typically prepared such that 10 mL of that solution contained
0.1 equiv of guest with respect to host, unless otherwise stated.
Successive aliquots of the guest solution were added to the host
NMR sample and 1H NMR sample recorded after each addition.
Changes in chemical shift of host proton signals, as a function of
guest concentration, were analysed using NMRTit HG and NMRTit
HGG software, assuming a 1:1 or 1:2 binding stoichiometry. When
more than one proton could be monitored during the same titration

O. Mammoliti et al. / Tetrahedron 65 (2009) 2184–2195
2191
the error was calculated on the basis of the average of all constants
calculated. When only one proton could be monitored the reported
errors were calculated with EQNMR software,22 errors calculated
below the 5% threshold in EQNMR are reported as <5%.
J¼6.0 Hz), 2.96 (4H, q, J¼6.0 Hz), 2.06 (4H, t, J¼7.5 Hz), 1.53–1.44
(4H, m), 1.28 (4H, sext, J¼7.0 Hz), 0.88 (6H, t); 13C NMR (100 MHz,
MeCN-d3):
d 175.0, 142.5, 131.6, 131.5, 126.1, 44.1, 39.6, 36.5, 28.5,
23.0, 14.1; ESMS: (m/z) 513 [MþNa]þ; HRMS (ES): calcd for
C20H35N4O6S2 ([MþH]þ) 491.1993, found 491.1988.
4.3. Synthetic procedures
4.3.4. Macrocycle 6
Preparation of 1-(tert-butyloxycarbonyl)ethyldiamine (1)
according to the method of Anslyn23 has been reported pre-
viously.14 N-Benzyloxycarbonyl-(S,S)-cyclohexane-1,2-diamine (4)
A solution of (2)$2TFA salt (201 mg, 0.365 mmol) and Et3N
(255
mL, 1.83 mmol) in MeCN (4 mL), and a solution of succinyl
dichloride (41
mL, 0.372 mmol) in MeCN (4 mL) were added si-
was prepared from (1S,2S)-(ꢀ)-1,2-diaminocyclohexane
D
-tartrate
multaneously, via syringe pump, into a flask equipped with con-
densor and CaCl2 drying tube containing MeCN (60 mL) at 60 ꢂC
over 4 h. The resultant mixture was stirred overnight at 60 ꢂC be-
fore cooling and concentration in vacuo. Purification by flash col-
umn chromatography (SiO2 eluted with CH2Cl2/94:6 CH2Cl2/
MeOH) and subsequent washing with MeOH gave the title com-
pound 6 as a white solid (21 mg, 14%). Mp >240 ꢂC (decomposes);
IR (neat): nmax 3301 (s), 3090 (w), 1650 (s), 1547 (s), 1434 (m), 1335
(s), 1177 (s), 1154 (s), 1106 (m), 1074 (m), 867 (m), 795 (m) cmꢀ1; 1H
and has been reported previously.24
4.3.1. {2-[3-(2-tert-Butoxycarbonylamino-ethylsulfamoyl)-
benzenesulfonylamino]-ethyl}-carbamic acid tert-butyl ester (2)
A solution of benzene-1,3-disulfonyl chloride (4.75 g,17.3 mmol)
in CH2Cl2 (30 mL) was added dropwise to a stirred solution of
1-(tert-butyloxycarbonyl)ethyldiamine 1 (6.08 g, 38.0 mmol) and
Et3N (2.5 mL,17.9 mmol) in CH2Cl2 (80 mL) at 0 ꢂC. The mixture was
warmed to room temperature and stirred overnight under N2 before
dilution with CH2Cl2 (100 mL), washing with KHSO4 (100 mL of
a 1 M aqueous solution), K2CO3 (100 mL of a 1 M aqueous solution)
and brine (100 mL), drying over MgSO4 and concentration in vacuo.
Purification by flash column chromatography (SiO2 eluted with 1:1
petroleum ether/EtOAc) gave the title compound 2 as a white solid
(4.42 g, 49%). Mp 64–66 ꢂC; IR (neat): nmax¼3273 (w), 2980 (w),
2935 (w), 1682 (s), 1516 (m), 1331 (s), 1153 (s), 1083 (s), 793
NMR (400 MHz, DMSO-d6):
d
8.11 (1H, t, J¼1.5 Hz), 8.04 (2H, dd,
J¼8.0, 1.5 Hz), 7.91 (1H, t, J¼8.0 Hz), 7.87 (2H, t, J¼6.0 Hz), 7.72 (2H,
br s), 3.06–2.97 (4H, m), 2.64 (4H, t, J¼7.5 Hz), 2.22 (4H, s); 13C NMR
(100 MHz, DMSO-d6):
d 171.6, 140.2, 131.4, 130.4, 125.1, 41.9, 38.0,
31.2; ESMS: (m/z) 405 [MþH]þ; HRMS (ES): calcd for C14H21N4O6S2
([MþH]þ) 405.0897, found 405.0902; calcd for C14H20N4NaO6S2
([MþNa]þ) 427.0716, found 427.0719.
(m) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
8.34 (1H, s), 8.06 (2H, dd,
4.3.5. Macrocycle 7
J¼8.0, 2.0 Hz), 7.67 (1H, t, J¼8.0 Hz), 5.61 (2H, br s), 4.91 (2H, br s),
A solution of (2)$2TFA salt (220 mg, 0.401 mmol) and Et3N
3.22 (4H, q, J¼5.5 Hz), 3.12 (4H, q, J¼5.5 Hz), 1.43 (18H, s); 13C NMR
(280
mL, 2.01 mmol) in MeCN (4 mL), and a solution of glutaryl
(100 MHz, CDCl3):
d
156.8, 141.8, 130.9, 130.2, 125.5, 80.2, 43.9, 40.4,
dichloride (52 mL, 0.407 mmol) in MeCN (4 mL) were added si-
28.5; ESMS: (m/z) 545 [MþNa]þ; HRMS (ES): calcd for C20H35N4O8S2
([MþH]þ) 523.1896, found 523.1892; calcd for C20H34N4NaO8S2
([MþNa]þ) 545.1710, found 545.1709.
multaneously, via syringe pump, into a flask equipped with con-
densor and CaCl2 drying tube containing MeCN (70 mL) at 60 ꢂC
over 4 h. The resultant mixture was stirred overnight at 60 ꢂC be-
fore cooling and concentration in vacuo. Purification by flash col-
umn chromatography (SiO2 eluted with CH2Cl2/92.5:7.5 CH2Cl2/
MeOH) and subsequent washing with MeOH, gave the title com-
pound 7 as a white solid (46 mg, 27%). Mp >240 ꢂC (decomposes);
IR (neat): nmax 3275 (s), 3087 (w), 2953 (w), 2874 (w), 1640 (s), 1543
4.3.2. (2)$2TFA salt
A solution of bis-sulfonamide 2 (1.95 g, 3.73 mmol) in 4:1
CH2Cl2/TFA (50 mL) was stirred for 5 h at room temperature. Tol-
uene was added and the solvent was removed under reduced
pressure. Trituration of the oily residue obtained with MeCN gave
the title compound as a white solid, collected by filtration (1.69 g,
82%). Mp 200–204 ꢂC; IR (neat): nmax 3161 (w), 1668 (s), 1595 (w),
(s), 1447 (m), 1331 (s), 1148 (s), 1086 (s) cmꢀ1
DMSO-d6):
;
1H NMR (400 MHz,
8.21 (1H, t, J¼2.0 Hz), 8.04 (2H, dd, J¼8.0, 2.0 Hz), 7.87
d
(1H, t, J¼8.0 Hz), 7.75 (2H, t, J¼6.0 Hz), 7.68 (2H, t, J¼6.0 Hz), 3.00
(4H, dt, J¼6.0, 7.0 Hz), 2.77 (4H, dt, J¼6.0, 7.0 Hz), 1.97 (4H, t,
J¼6.5 Hz), 1.67 (2H, quin, J¼6.5 Hz); 13C NMR (100 MHz, DMSO-d6):
1342 (m), 1191 (m), 1138 (s), 1079 (m), 798 (s) cmꢀ1
;
1H NMR
(300 MHz, DMSO-d6):
d
8.40–8.10 (2H, br s), 8.20 (1H, t, J¼2.0 Hz),
8.10 (2H, dd, J¼8.0, 2.0 Hz), 8.00 (6H, br s), 7.90 (1H, t, J¼8.0 Hz),
d 171.7, 140.9, 131.0, 130.3, 125.0, 42.2, 37.7, 34.0, 20.0; ESMS:
3.01 (4H, t, J¼6.0 Hz), 2.89 (4H, t, J¼6.0 Hz); 13C NMR (75 MHz,
(m/z)¼419 [MþH]þ; HRMS (ES): calcd for C15H22N4NaO6S2
DMSO-d6):
J¼300 Hz), 40.0, 38.6.
d
158.5 (q, J¼31 Hz), 140.9, 131.1, 130.6, 124.6, 117.1 (q,
([MþNa]þ) 441.0873, found 441.0866.
4.3.6. 1,3-Bis-((1S,2S)-2-tert-butoxycarbonylamino
4.3.3. Pentanoic acid {2-[3-(2-pentanoylamino-ethylsulfamoyl)-
cyclohexylsulfamoyl)-benzene (5)
benzenesulfonylamino]-ethyl}-amide (3)
A
solution of benzene-1,3-disulfonyl chloride (915 mg,
Valeryl chloride (80
a solution of (2)$2TFA salt (175 mg, 0.318 mmol) and Et3N (200
m
L, 0.675 mmol) was added dropwise to
L,
3.32 mmol) in CH2Cl2 (10 mL) was added dropwise to a stirred
solution of N-benzyloxycarbonyl-(S,S)-cyclohexane-1,2-diamine 4
m
1.43 mmol) in MeCN (10 mL) at 0 ꢂC. The mixture was warmed to
room temperature and stirred overnight under N2. Solvent was
then removed in vacuo and the residue obtained was dissolved in
CH2Cl2 (50 mL) and washed with KHSO4, (50 mL of a 1 M aqueous
solution), K2CO3 (50 mL of a 1 M aqueous solution) and brine
(500 mL) before drying over MgSO4 and concentration in vacuo.
Purification by flash column chromatography (SiO2 eluted with
CH2Cl2/96:4 CH2Cl2/MeOH) gave the title compound 3 as a white
solid (50 mg, 32%). Mp 64–66 ꢂC; IR (neat): nmax 3606 (w), 3254 (w),
2956 (w), 2931 (w), 2871 (w), 1630 (s), 1558 (s), 1431 (m), 1317 (s),
(1.44 g, 6.73 mmol) and Et3N (950 mL, 6.82 mmol) in CH2Cl2 (20 mL)
at 0 ꢂC. The mixture was warmed to room temperature and stirred
overnight under N2 before dilution with CH2Cl2 (90 mL), washing
with KHSO4 (80 mL of a 1 M aqueous solution), K2CO3 (80 mL of
a 1 M aqueous solution) and brine (80 mL), drying over MgSO4 and
concentration in vacuo. Purification by flash column chromatog-
raphy (SiO2 eluted with petroleum ether/70:30 petroleum ether/
EtOAc) gave the title compound 5 as a white solid (1.85 g, 88%). Mp
27
112–118 ꢂC; [
a
]
D
ꢀ76.9 (c 0.5, CHCl3); IR (neat): nmax 3270 (br),
2932 (m), 2859 (w), 1681 (s), 1515 (m), 1453 (m), 1320 (s), 1256 (m),
1156 (s), 1080 (m), 964 (w), 907 (m), 792 (m) cmꢀ1 1H NMR
(400 MHz, CDCl3):
8.35 (1H, t, J¼2.0 Hz), 8.01 (2H, dd, J¼8.0,
2.0 Hz), 7.60 (1H, t, J¼8.0 Hz), 5.98 (2H, d, J¼5.5 Hz), 4.48 (2H, d,
1147 (s), 1082 (s), 1073 (s), 796 (m) cmꢀ1
MeCN-d3):
8.21 (1H, t, J¼2.0 Hz), 8.03 (2H, dd, J¼8.0, 2.0 Hz), 7.76
(1H, t, J¼8.0 Hz), 6.57 (2H, br s), 6.26 (2H, br s), 3.15 (4H, q,
;
1H NMR (400 MHz,
;
d
d

2192
O. Mammoliti et al. / Tetrahedron 65 (2009) 2184–2195
J¼5.5 Hz), 3.39–3.26 (2H, m), 3.04–2.92 (2H, m), 2.05–1.89 (4H, m),
(2H, m), 3.22–3.09 (2H, m), 2.50–2.40 (2H, m), 1.92–1.83 (2H, m),
1.83–1.72 (8H, m), 1.66–1.39 (4H, m), 1.38–1.24 (6H, m); 13C NMR
1.75–1.60 (4H, m), 1.42 (18H, s), 1.32–1.10 (8H, m); 13C NMR
(100 MHz, CDCl3):
d
157.4, 143.2, 130.3, 130.1, 125.5, 80.5, 60.2, 53.6,
(75 MHz, CDCl3): d 174.5 (0), 143.5 (0), 130.6 (1), 130.4 (1), 124.9 (1),
34.1, 32.7, 28.5, 24.8, 24.5; ESMS: (m/z)¼631 [MþH]þ, 653
[MþNa]þ; HRMS (ES): calcd for C28H47N4O8S2 ([MþH]þ) 631.2830,
found 631.2827; calcd for C28H46N4NaO8S2 ([MþNa]þ) 653.2649,
found 653.2635.
61.4, 52.3, 35.8, 35.0, 32.4, 24.8, 24.5, 21.2; ESMS: (m/z) 527
[MþH]þ, 549 [MþNa]þ; HRMS (ES): calcd for C23H34N4NaO6S2
([MþNa]þ) 549.1812, found 549.1815.
4.3.10. (S)-2-[3-((S)-1-Carboxy-2-methyl-propylsulfamoyl)-
benzenesulfonylamino]-3-methyl-butyric acid (10)
4.3.7. (5)$2TFA salt
A solution of bis-sulfonamide 5 (898 mg, 1.42 mmol) in 4:1
CH2Cl2/TFA (20 mL) was stirred for 4 h at room temperature. Tol-
uene was added and the solvent was removed in vacuo. Trituration
of the oily residue obtained with CH2Cl2 gave the title compound as
A solution of benzene-1,3-disulfonyl chloride (3.55 g, 12.9 mmol)
in CH2Cl2 (10 mL) was added dropwise to a solution of H-L-Val-
OBn$TsOH (10.3 g, 27.1 mmol) and Et3N (5.6 mL, 40 mmol) in CH2Cl2
(50 mL) at 0 ꢂC. The mixture was warmed to room temperature and
stirred overnight under N2. The mixture was then diluted with CH2Cl2
(150 mL) and washed with HCl (250 mL of a 2 M aqueous solution),
K2CO3 (2ꢁ200 mL of a 1 M aqueous solution) and brine (200 mL)
before drying over MgSO4 and concentration in vacuo. Purification by
flash column chromatography (SiO2 eluted with 9:1/3:1 petroleum
ether/EtOAc) gave (S)-2-[3-((S)-1-benzyloxycarbonyl-2-methyl-pro-
an off-white solid, collected by filtration (917 mg, 98%). Mp 162–
27
165 ꢂC; [
a]
ꢀ64.1 (c 0.5, MeOH); IR (neat): nmax 3086 (br), 2937
D
(m), 2865 (m), 1666 (s), 1516 (w), 1331 (m), 1126 (s), 796 (m) cmꢀ1
;
1H NMR (400 MHz, MeOD-d4):
d
8.42 (1H, t, J¼2.0 Hz), 8.19 (2H, dd,
J¼8.0, 2.0 Hz), 7.86 (1H, t, J¼8.0 Hz), 3.18–3.07 (2H, m), 2.91 (2H, dt,
J¼4.0, 11.5 Hz), 2.14–2.04 (2H, m), 1.79–1.69 (2H, m), 1.63–1.54 (2H,
m), 1.44 (2H, dq, J¼3.5, 12.5 Hz), 1.35–1.03 (8H, m); 13C NMR
pylsulfamoyl)-benzenesulfonylamino]-3-methyl-butyric acid benzyl
27
(100 MHz, MeOD-d4):
d
144.3, 132.1, 132.0, 126.4, 56.6, 55.9, 32.3,
ester (10 R¼Bn) as a colourless oil (5.74 g, 72%). [
a
]
þ4.3 (c 0.75,
D
30.7, 25.4, 24.6; ESMS: (m/z)¼431 [MþH]þ, 453 [MþNa]þ.
CHCl3); IR (neat): nmax 3272 (w), 2963 (w),1729 (s),1453 (m),1334 (s),
1156 (s), 1135 (s), 913 (m), 681 (s) cmꢀ1; 1H NMR (400 MHz, CDCl3):
4.3.8. Macrocycle 8
d
8.25 (1H, t, J¼2.0 Hz), 7.88 (2H, dd, J¼8.0, 2.0 Hz), 7.38 (1H, t,
A solution of (5)$2TFA salt (216 mg, 0.328 mmol) and Et3N
J¼8.0 Hz), 7.29–7.24 (6H, m), 7.16–7.11 (4H, m), 5.27 (2H, d, J¼10.0 Hz),
4.88 (2H, d, J¼12.0 Hz), 4.84 (2H, d, J¼12.0 Hz), 3.80 (2H, dd, J¼10.0,
5.0 Hz), 2.10–1.96 (2H, m), 0.89 (6H, d, J¼7.0 Hz), 0.76 (6H, d,
(220
mL, 1.58 mmol) in MeCN (4 mL), and a solution of succinyl
dichloride (37
mL, 0.336 mmol) in dry MeCN (4 mL) were added
simultaneously, via syringe pump, into a flask equipped with con-
densor and CaCl2 drying tube containing MeCN (60 mL) at 60 ꢂC
over 4 h. The resultant mixture was stirred overnight at 60 ꢂC be-
fore cooling and concentration in vacuo. Purification by flash col-
umn chromatography (SiO2 eluted with CH2Cl2/96:4 CH2Cl2/
J¼7.0 Hz); 13C NMR (100 MHz, CDCl3):
d 171.0, 141.4, 134.9, 131.1, 130.1,
128.8,128.7,126.1, 67.7, 61.3, 31.8,19.1,17.3; ESMS: (m/z) 615 [MꢀH]ꢀ.
A
mixture of (S)-2-[3-((S)-1-benzyloxycarbonyl-2-methyl-pro-
pylsulfamoyl)-benzenesulfonylamino]-3-methyl-butyric acid benzyl
ester prepared above (5.48 g, 8.89 mmol) and Pd/C (10% wt, 976 mg,
0.917 mmol) in MeOH (60 mL) was stirred at room temperature un-
der H2 (w1 atm balloon) for 4 h. The mixture was then filtered
through a CeliteÔ pad and the filtrate concentrated in vacuo to give
MeOH) and recrystallisation (MeOH) gave the title compound 8 as
a crystalline powder (34 mg, 20%). Mp 185–190 ꢂC (MeOH); [
27
a]
D
þ31.5 (c 0.4, CHCl3); IR (neat): nmax 3251 (w), 3076 (w), 2930 (m),
2856 (w), 1633 (s), 1537 (s), 1434 (m), 1324 (s), 1172 (s), 1152 (s),
the title compound 10 as a white powder without further purification
(3.76 g, 97%). Mp 200–203 ꢂC; [
27
1072 (s), 906 (m) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
8.32 (1H, t,
a]
þ23.8 (c 0.5, MeOH); IR (neat):
D
J¼1.5 Hz), 8.06 (2H, dd, J¼8.0, 1.5 Hz), 7.68 (1H, t, J¼8.0 Hz), 7.18
(2H, d, J¼7.5 Hz), 6.10 (2H, d, J¼5.5 Hz), 3.62–3.51 (2H, m), 3.21 (2H,
sept, J¼5.5 Hz), 2.43–2.32 (2H, m), 1.96–1.84 (4H, m), 1.84–1.66 (6H,
m), 1.46 (2H, dq, J¼3.0, 12.5 Hz), 1.40–1.20 (6H, m); 13C NMR
nmax 3264 (m), 2969 (w), 1713 (s), 1668 (m), 1460 (w), 1413 (m), 1347
(s),1219(m),1142(s),1051(s), 897(m), 795(s),678(m) cmꢀ1;1HNMR
(400 MHz, DMSO-d6):
d
8.24 (2H, d, J¼8.5 Hz), 8.16 (1H, t, J¼2.0 Hz),
7.97 (2H, dd, J¼8.0, 2.0 Hz), 7.74 (1H, t, J¼8.0 Hz), 3.54(2H, t, J¼7.0 Hz),
(75 MHz, CDCl3):
d 174.2, 143.8, 130.0, 129.6, 124.9, 61.7, 51.9, 36.12,
1.95 (2H, oct, J¼7.0 Hz), 0.80 (6H, d, J¼7.0 Hz), 0.76 (6H, d, J¼7.0 Hz);
32.3, 31.4, 24.6, 24.2; ESMS: (m/z)¼513 [MþH]þ, 535 [MþNa]þ;
HRMS (ES): calcd for C22H33N4O6S2 ([MþH]þ) 513.1836, found
513.1837; calcd for C22H32N4NaO6S2 ([MþNa]þ) 535.1655, found
535.1681.
13C NMR (100 MHz, DMSO-d6):
d 172.1,142.0,130.0,130.0,124.5, 61.4,
30.3, 18.9, 17.8; ESMS: (m/z) 435 [MꢀH]ꢀ, 871 [2MꢀH]ꢀ. HRMS (ES):
calcd for C16H24N2O8S2Na ([MþNa]þ) 459.0866, found 459.0865.
4.3.11. N-Benzyl-(S)-2-[3-((S)-1-benzylcarbamoyl-2-
methyl-propylsulfamoyl)-benzenesulfonylamino]-3-
methyl-butyramide (12)
4.3.9. Macrocycle 9
A solution of (5)$2TFA salt (212 mg, 0.322 mmol) and Et3N
(225
mL, 1.61 mmol) in MeCN (4 mL), and a solution of glutaryl
A solution of (S)-2-[3-((S)-1-carboxy-2-methyl-propylsulfa-
dichloride (42
m
L, 0.329 mmol) in MeCN (4 mL) were added si-
moyl)-benzenesulfonylamino]-3-methyl-butyric acid 10 (97 mg,
0.22 mmol) and carbonyldiimidazole (73 mg, 0.45 mmol) in THF
(7 mL) was stirred at room temperature for 1 h. The mixture was
multaneously, via syringe pump, into a flask equipped with con-
densor and CaCl2 drying tube containing MeCN (60 mL) at 60 ꢂC
over 3.5 h. The resultant mixture was stirred overnight at 60 ꢂC
before cooling and concentration in vacuo. The residue was taken
into ethyl acetate (60 mL) and washed KHSO4 (40 mL of a 1 M
aqueous solution), K2CO3 (30 mL of a 1 M aqueous solution) and
brine (30 mL) before drying over MgSO4 and concentration in
vacuo. Purification by flash column chromatography (SiO2 eluted
then added to a solution of benzylamine (62
mL, 0.57 mmol) and
Et3N (50 L, 0.36 mmol) in THF (5 mL) and the resulting mixture
m
stirred overnight at room temperature, under N2 before concen-
tration in vacuo. Purification by flash column chromatography
(SiO2 eluted with 7:3/5.5:4.5 petroleum ether/EtOAc) gave the
title compound 12 as a white solid (87 mg, 64%). Mp 90–92 ꢂC;
25
with ethyl acetate, then 97:3/96:4 CH2Cl2/MeOH) gave the title
compound 9 as a white solid (48 mg, 28%). Mp 185–194 ꢂC; [
[a
]
þ33.2 (c 0.25, MeCN); IR (neat): nmax 3272 (w), 2966 (w),
D
22
a
]
1651 (s), 1539 (w), 1455 (w), 1434 (w), 1327 (s), 1156 (s), 1142 (s),
1080 (m), 1030 (w), 915 (w), 795 (m) cmꢀ1 1H NMR (400 MHz,
MeCN-d3):
(1H, t, J¼8.0 Hz), 7.32–7.21 (6H, m), 7.12–7.07 (4H, m), 6.92 (2H,
apparent t, J¼6.0 Hz), 6.11 (2H, br s), 4.14 (2H, dd, J¼15.0, 6.0 Hz),
4.04 (2H, dd, J¼15.0, 6.0 Hz), 3.57 (2H, d, J¼6.0 Hz), 1.97–1.88 (2H,
D
þ45.2 (c 0.3, CHCl3); IR (neat): nmax 3249 (w), 2933 (m), 2860 (w),
;
1642 (s), 1532 (s), 1450 (m), 1323 (s), 1171 (s), 1152 (s), 1077 (s), 957
d
8.26 (1H, t, J¼2.0 Hz), 7.99 (2H, dd, J¼8.0, 2.0 Hz), 7.61
(w), 899 (w), 795 (w), 681 (m) cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
8.27 (1H, t, J¼1.5 Hz), 8.02 (2H, dd, J¼8.0, 1.5 Hz), 7.63 (1H, t,
J¼8.0 Hz), 6.05 (2H, d, J¼8.0 Hz), 5.92 (2H, d, J¼6.5 Hz), 3.74–3.70

O. Mammoliti et al. / Tetrahedron 65 (2009) 2184–2195
2193
m), 0.83 (6H, d, J¼7.0 Hz), 0.82 (6H, d, J¼7.0 Hz); 13C NMR
2873 (w), 1688 (m), 1651 (s), 1548 (m), 1462 (m), 1454 (m), 1325 (s),
1269 (w), 1224 (w), 1178 (s), 1128 (m), 1089 (m), 1050 (m), 803 (m),
(100 MHz, MeCN-d3):
d 170.8, 142.4, 139.6, 131.8, 131.2, 129.4,
128.4, 128.1, 126.7, 63.1, 42.7, 32.5, 19.5, 17.9; ESMS: (m/z) 615
[MþH]þ, 637 [MþNa]þ; HRMS (ES): calcd for C30H39N4O6S2
([MþH]þ) 615.2306, found 615.2301; calcd for C30H38N4NaO6S2
([MþNa]þ) 637.2125, found 637.2176.
793 (m), 719 (w), 703 (w), 680 (m) cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6):
d
8.42 (2H, dd, J¼7.0, 4.0 Hz), 8.13 (2H, br s), 7.98 (1H, s),
7.62 (2H, dd, J¼8.0, 1.5 Hz), 7.33 (1H, t, J¼7.5 Hz), 7.21 (2H, d,
J¼7.5 Hz), 6.77 (1H, t, J¼8.0 Hz), 6.75 (1H, s), 4.34 (2H, dd, J¼14.0,
7.0 Hz), 3.75 (2H, dd, J¼14.0, 4.0 Hz), 3.62 (2H, br s), 1.92 (2H, oct,
J¼7.0 Hz), 0.95 (6H, d, J¼7.0 Hz), 0.94 (6H, d, J¼7.0 Hz); 13C NMR
4.3.12. 3-Methyl-(S)-2-[3-(2-methyl-(S)-1pentafluorophenyl
oxycarbonyl-propylsulfamoyl)benzenesulfonylamino]-butyric acid
pentafluorophenyl ester (11)
(100 MHz, DMSO-d6):
d 169.4, 142.5, 138.6, 128.9, 128.5, 128.3,
128.0, 127.6, 123.3, 61.9, 42.4, 31.3, 19.1, 18.3; ESMS: (m/z) 537
[MþH]þ, 559 [MþNa]þ; HRMS (ES): calcd for C24H32N4NaO6S2
([MþNa]þ) 559.1655, found 559.1666.
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (1.76 g, 9.19 mmol) in CH2Cl2 (35 mL) was added,
dropwise over 30 min, to a solution of (S)-2-[3-((S)-1-carboxy-2-
methyl-propylsulfamoyl)-benzenesulfonylamino]-3-methyl-butyric
acid (10) (1.95 g, 4.46 mmol) and pentafluorophenol (2.10 g,
11.4 mmol) in CH2Cl2 (50 mL) at 0 ꢂC. The mixture was then warmed
to room temperature and stirred overnight under N2 before washing
with NaHCO3 (2ꢁ150 mL of a 5% w/v aqueous solution), drying over
MgSO4 and concentration in vacuo. The residue obtained was taken
into EtOAc and filtered through a small silica pad before concentra-
tion of the filtrate in vacuo to give the title compound 11 as a white
4.3.15. 5-Octyloxy-isophthalic acid (15)
A
mixture of dimethyl-5-hydroxyisophthalate (6.20 g,
29.5 mmol), 1-iodooctane (5 mL, 27.5 mmol) and K2CO3 (13.9 g,
100.3 mmol) in acetone (140 mL) was heated to reflux overnight.
The mixture was then filtered and the filtrate concentrated in
vacuo. CH2Cl2 was added to the residue and insoluble material re-
moved by filtration before concentration of the filtrate in vacuo
once more. The crude material was then taken into 1,4-dioxane/
1.5 M aqueous LiOH (200 mL of a 1:1 mixture) and stirred over-
night. This mixture was washed with Et2O (2ꢁ200 mL) and acidi-
fied with 3 M aqueous KHSO4 solution. A white precipitate was
observed and was collected by filtration, washed consecutively
with CH2Cl2 and H2O and suspended in toluene. Concentration in
vacuo gave the title compound 15 as a white solid (5.81 g, 72%). Mp
225–227 ꢂC; IR (neat): nmax 2923 (m), 2855 (m), 2566 (w), 1705 (s),
1683 (s), 1595 (m), 1643 (m), 1413 (m), 1338 (m), 1309 (m), 1271 (s),
1125 (w), 1044 (m), 929 (m), 908 (m), 759 (s), 734 (s), 685
solid, which was used directly and not purified further (2.60 g, 76%).
27
Mp 55–61 ꢂC; [
a]
D
þ16.2 (c 0.5, CHCl3); IR (neat): nmax¼3285 (w),
2972 (w),1784 (m),1518 (s),1741 (w),1338 (m),1158(m),1085 (s), 992
(s), 921 (w), 893 (w), 799 (w), 682 (m) cmꢀ1 1H NMR (300 MHz,
CDCl3):
;
d
8.45 (1H, t, J¼2.0 Hz), 8.05 (2H, dd, J¼8.0, 2.0 Hz), 7.66 (1H, t,
J¼8.0 Hz), 5.77 (2H, d, J¼5.0 Hz), 4.25 (2H, dd, J¼10.0, 5.0 Hz), 2.43–
2.28 (2H, m), 1.10 (6H, d, J¼7.0 Hz), 0.97 (6H, d, J¼7.0 Hz).
4.3.13. Macrocycle 13
A solution of pentafluorophenol ester 11 (209 mg, 0.27 mmol)
and TBACl (149 mg, 0.534 mmol) in CH2Cl2 (4 mL), and a solution of
(m) cmꢀ1 1H NMR (300 MHz, DMSO-d6):
; d 13.20 (2H, br s), 8.06
(1H, t, J¼1.5 Hz), 7.62 (2H, d, J¼1.5 Hz), 4.06 (2H, t, J¼6.5 Hz), 1.78–
1,5-diaminopentane (32 mL, 0.27 mmol) and Et3N (114 mL,
1.66 (2H, m), 1.47–1.20 (10H, m), 0.85 (3H, t, J¼7.0 Hz); 13C NMR
0.82 mmol) in CH2Cl2 (4 mL) were added simultaneously, via sy-
ringe pump, into CH2Cl2 (20 mL) at room temperature over a period
of 1.75 h before stirring at room temperature overnight. The mix-
ture was then concentrated in vacuo. Purification by flash column
chromatography (SiO2 eluted with 1:1/3:1 EtOAc/petroleum
(75 MHz, DMSO-d6): d 166.4, 158.8, 132.6, 122.1, 119.0, 68.1, 31.2,
28.6, 28.6, 28.5, 25.4, 22.0, 13.9; ESMS: m/z¼293 [MꢀH]ꢀ, 587
[2 MꢀH]ꢀ. Anal. Calcd for C16H22O5: C, 65.29; H, 7.53. Found: C,
65.28; H, 7.52.
ether) gave the title compound 13 (108 mg, 79%). Mp 160–162 ꢂC;
4.3.16. 3-Aminomethyl-5-octyloxy-benzylamine (16)
26
[
a]
þ144 (c 0.5, MeCN); IR (neat): nmax 3409 (w), 3375 (w), 3271
A mixture of 5-octyloxy-isophthalic acid 15 (5.47 g, 18.6 mmol)
and PCl5 (10 g, 48 mmol) was stirred at 180 ꢂC until a homoge-
neous yellow solution was formed. The mixture was then cooled to
room temperature and carefully added into NH3 saturated CH2Cl2
(250 mL) at 0 ꢂC. A white precipitate was formed immediately,
which was collected by filtration, washed with H2O and suspended
in toluene. Concentration in vacuo gave 5-octyloxy-iso-
phthalamide as a white solid (4.53 g, 83%). Mp 200–203 ꢂC; IR
(neat): nmax 3400 (m), 3323 (w), 3418 (w), 3142 (w), 2951 (w),
2918 (m), 2871 (w), 2850 (w), 1692 (s), 1652 (s), 1625 (s), 1593 (s),
1470 (w), 1432 (s), 1394 (s), 1375 (s), 1255 (m), 1090 (w), 1048 (m),
D
(w), 2965 (w), 2936 (w), 1659 (s), 1538 (m), 1440 (w), 1414 (w), 1341
(s), 1329 (s), 1175 (s), 1130 (m), 1053 (m), 934 (w), 919 (w), 801 (m),
682 (m) cmꢀ1
; d 8.15 (1H, t,
1H NMR (400 MHz, DMSO-d6):
J¼2.0 Hz), 8.09 (2H, d, J¼9.0 Hz), 7.96 (2H, dd, J¼8.0, 2.0 Hz), 7.80
(2H, dd, J¼7.0, 4.5 Hz), 7.67 (1H, t, J¼8.0 Hz), 3.54 (2H, dd, J¼9.0,
7.0 Hz), 3.20–3.09 (2H, m), 2.67–2.57 (2H, m), 1.89 (2H, oct,
J¼7.0 Hz), 1.24–1.11 (2H, m), 1.11–1.00 (2H, m), 0.91 (6H, d,
J¼7.0 Hz), 0.88 (6H, d, J¼7.0 Hz), 0.69 (2H, quin, J¼7.0 Hz); 13C NMR
(100 MHz, DMSO-d6):
d 169.5, 142.7, 129.7, 129.2, 124.4, 61.7, 38.1,
31.1, 28.1, 23.3, 19.1, 18.2; ESMS: (m/z)¼503 [MþH]þ, 525 [MþNa]þ;
HRMS (ES): calcd for C21H35N4O6S2 ([MþH]þ) 503.1993, found
503.2014; calcd for C21H34N4NaO6S2 ([MþNa]þ) 525.1812, found
525.1815.
882 (m), 782 (m), 675 (m), 639 (m) cmꢀ1
DMSO-d6):
;
1H NMR (300 MHz,
7.99 (2H, br s), 7.96 (1H, t, J¼1.5 Hz), 7.53 (2H, d,
d
J¼1.5 Hz), 7.40 (2H, br s), 4.04 (2H, t, J¼6.5 Hz), 1.79–1.67 (2H, m),
1.48–1.22 (10H, m), 0.86 (3H, t, J¼7.0 Hz); 13C NMR (75 MHz,
4.3.14. Macrocycle 14
DMSO-d6): d 167.3, 158.5, 135.7, 119.0, 116.0, 67.9, 31.2, 28.7, 28.6,
A solution of pentafluorophenol ester 11 (677 mg, 0.881 mmol)
and TBACl (500 mg, 1.80 mmol) in CH2Cl2 (5 mL), and a solution of
m-xylylenediamine (120 mL, 0.909 mmol) and Et3N (500 mL,
3.59 mmol) in CH2Cl2 (5 mL) were added simultaneously, via sy-
ringe pump, into CH2Cl2 (100 mL) at room temperature over a pe-
riod of 5 h before stirring at room temperature overnight. The
mixture was then concentrated in vacuo. Purification by flash col-
umn chromatography (SiO2 eluted with 4:6/5.5:4.5 EtOAc/pe-
28.6, 25.4, 22.0, 13.9; ESMS: (m/z) 315 [MþNa]þ. HRMS (ES): calcd
for C16H25N2O3 ([MþH]þ) 293.1860, found 293.1861. A mixture of
5-octyloxy-isophthalamide prepared above (1.98 g, 6.77 mmol)
and LiAlH4 (1.12 g, 29.6 mmol) in THF (125 mL) was stirred under
N2 at room temperature for 30 min before warming to reflux for
2.5 h. The mixture was then cooled before addition of H2O
(100 mL) and concentration in vacuo. The residue was extracted
with CH2Cl2 (2ꢁ100 mL) and the combined organic layers dried
over MgSO4 before concentration in vacuo. The residue was taken
into HCl (50 mL of a 1 M aqueous solution) and washed with Et2O
(3ꢁ50 mL), basified with NaOH (60 mL of a 2 M aqueous solution)
troleum ether) gave the title compound 14 as a white solid (280 mg,
26
59%). Mp >240 ꢂC (MeOH) (decomposes); [
a
]
D
þ195 (c 0.5, DMSO);
IR (neat): nmax 3599 (w), 3488 (w), 3238 (m), 3090 (w), 2968 (w),

2194
O. Mammoliti et al. / Tetrahedron 65 (2009) 2184–2195
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4579–4581; (h) Schmuck, C.; Bickert, V.; Merschky, M.; Geiger, L.; Rupprecht, D.;
Dudaczek, J.; Wich, P.; Rehm, T.; Machon, U. Eur. J. Org. Chem. 2008, 324–329; (i)
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Geiger, L. Curr. Org. Chem. 2003, 7, 1485–1502; (k) Schmuck, C.; Geiger, L. J. Am.
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Lavigne, J. L.; Metzger, A.; Tobey, S. L.; Lynch, V.; Anslyn, E. V. Chem.dEur. J. 2004,
10, 3792–3804.
before re-extraction with CH2Cl2 (3ꢁ50 mL). The combined or-
ganic layers were dried over MgSO4 and concentrated in vacuo to
give the title compound 16 as a yellow oil, which was used in the
following reaction without further purification. (915 mg, 51%). IR
(neat): nmax 3358 (w), 2922 (s), 2854 (s), 1673 (w), 1593 (s), 1452
(s), 1378 (m), 1326 (m), 1287 (s), 1162 (s), 1053 (m), 976 (m), 836
(s), 702 (s) cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 6.84 (1H, s), 6.74
(2H, s), 3.96 (2H, t, J¼6.5 Hz), 3.82 (4H, s), 1.81–1.72 (2H, m), 1.49–
1.39 (2H, m), 1.39–1.21 (8H, m), 0.88 (3H, t, J¼7.0 Hz); 13C NMR
(75 MHz, CDCl3):
d 159.9, 145.3, 118.0, 111.7, 68.2, 46.7, 32.0, 29.5,
29.4, 29.4, 26.2, 22.8, 14.2; ESMS: (m/z) 265 [MþH]þ, 287
[MþNa]þ.
4.3.17. Macrocycle 17
A solution of pentafluorophenol ester 11 (682 mg, 0.888 mmol)
and TBACl (501 mg, 1.80 mmol) in CH2Cl2 (5 mL), and a solution of
3-aminomethyl-5-octyloxy-benzylamine 16 (239 mg, 0.904 mmol)
and Et3N (500 mL, 3.59 mmol) in CH2Cl2 (5 mL) were added simul-
taneously, via syringe pump, into CH2Cl2 (100 mL) at room tem-
perature over a period of 5 h. The mixture was then stirred
overnight before concentration in vacuo. Purification by flash col-
umn chromatography (SiO2 eluted with 8.5:1.5/6.5:3.5 petroleum
ether/EtOAc) and precipitation from EtOAc/petroleum ether gave
6. (a) Frontera, A.; Morey, J.; Oliver, A.; Pina, M. N.; Quinonero, D.; Costa, A.;
Ballester, P.; Deya, P. M.; Anslyn, E. V. J. Org. Chem. 2006, 71, 7185–7195; (b) Lin,
C.; Simov, V.; Drueckhammer, D. G. J. Org. Chem. 2007, 72, 1742–1746.
7. Miyaji, H.; Hong, S. J.; Jeong, S. D.; Yoon, D. W.; Na, H. K.; Hong, J.; Ham, S.;
Sessler, J. L.; Lee, C. H. Angew. Chem., Int. Ed. 2007, 46, 2508–2511.
8. (a) Carvalho, S.; Delgado, R.; Fonseca, N.; Felix, V. New J. Chem. 2006, 30, 247–
257; (b) Gonzalez-Alvarez, A.; Alfonso, I.; Diaz, P.; Garcia-Espana, E.; Gotor-
Fernandez, V.; Gotor, V. J. Org. Chem. 2008, 73, 374–382.
the title compound 17 as a white, flocculent solid (246 mg, 42%). Mp
26
130–132 ꢂC (EtOAC/petroleum ether); [
a
]
þ185 (c 0.25, MeCN); IR
D
(neat): nmax 3361 (w), 2929 (m), 1661 (s), 1598 (m), 1539 (m), 1456
(s), 1325 (s), 1297 (s), 1219 (w), 1174 (s), 1156 (s), 1125 (s), 1082 (s),
919 (m), 860 (m), 794 (s), 720 (m), 681 (m) cmꢀ1 1H NMR
;
(400 MHz, MeCN-d3):
d
8.11 (1H, t, J¼2.0 Hz), 7.64 (2H, dd, J¼8.0,
9. For a recent review of polyamine macrocyclic receptors and their metal com-
plexes see: Garcia-Espana, E.; Diaz, P.; Llinares, J. M.; Bianchi, A. Coord. Chem.
Rev. 2006, 250, 2952–2986.
2.0 Hz), 6.98–6.91 (2H, m), 6.95 (1H, t, J¼8.0 Hz), 6.75 (2H, d,
J¼1.5 Hz), 6.42 (1H, t, J¼1.5 Hz), 6.15 (2H, br s), 4.37 (2H, dd, J¼14.0,
8.0 Hz), 4.03 (2H, t, J¼6.5 Hz), 3.81 (2H, dd, J¼14.0, 4.5 Hz), 3.65
(2H, br s), 2.05–1.96 (2H, m), 1.85–1.76 (2H, m), 1.54–1.44 (2H, m),
1.43–1.24 (8H, m), 1.01 (6H, d, J¼7.0 Hz), 0.94 (6H, d, J¼7.0 Hz), 0.89
10. (a) Ayling, A. J.; Perez-Payan, M. N.; Davis, A. P. J. Am. Chem. Soc. 2001, 123,
12716–12717; (b) Caltagirone, C.; Bates, G. W.; Gale, P. A.; Light, M. E. Chem.
Commun. 2008, 61–63; (c) Chen, C. F.; Chen, Q. Y. Tetrahedron Lett. 2004, 45,
3957–3960; (d) Kondo, S.; Suzuki, T.; Toyama, T.; Yano, Y. Bull. Chem. Soc. Jpn.
2005, 78, 1348–1350; (e) Kondo, S.; Suzuki, T.; Yano, Y. Tetrahedron Lett. 2002,
43, 7059–7061; (f) Valiyayeettil, S.; Engbersen, J. F. J.; Verboom, W.; Reinhoudt,
D. N. Angew. Chem., Int. Ed. Engl. 1993, 32, 900–901; (g) Kavallieratos, K.; Bertao,
C. M.; Crabtree, R. H. J. Org. Chem. 1999, 64, 1675–1683.
11. (a) Botana, E.; Ongeri, S.; Arienzo, R.; Demarcus, M.; Frey, J. G.; Piarulli, U.;
Potenza, D.; Kilburn, J. D.; Gennari, C. Eur. J. Org. Chem. 2001, 4625–4634 See
also: (b) Gennari, C.; Gude, M.; Potenza, D.; Piarulli, U. Chem.dEur. J. 1998, 4,
1924–1931.
(3H, t, J¼7.0 Hz); 13C NMR (100 MHz, MeCN-d3):
d 170.6,160.1,143.1,
141.2,130.6,130.2,125.7,121.4,114.6, 68.9, 62.9, 43.9, 33.1, 32.6, 30.1,
30.0, 26.8, 23.4, 19.6, 17.9, 14.4; ESMS: (m/z)¼687 [MþNa]þ; HRMS
(ES): calcd for C32H48N4NaO7S2 ([MþNa]þ) 687.2857, found
687.2862.
Acknowledgements
12. Kyne, G. M.; Light, M. E.; Hursthouse, M. B.; de Mendoza, J.; Kilburn, J. D.
J. Chem. Soc., Perkin Trans. 1 2001, 1258–1263.
13. An (R,R)-cyclohexane-1,2-diamine motif has been exploited in: (a) synthesis of
macrocyclic peptide receptors: Gasparrini, F.; Misiti, D.; Still, W. C.; Villani, C.;
Wennemers, H. J. Org. Chem. 1997, 62, 8221–8224; Pan, Z. Y.; Still, W. C. Tetra-
hedron Lett. 1996, 37, 8699–8702; Still, W. C. Acc. Chem. Res. 1996, 29, 155–163;
Yoon, S. S.; Still, W. C. J. Am. Chem. Soc. 1993, 115, 823–824 and; (b) for anion
recognition: Amendola, V.; Boiocchi, M.; Esteban-Gomez, D.; Fabbrizzi, L.;
Monzani, E. Org. Biomol. Chem. 2005, 3, 2632–2639 and Ref. 8b.
We thank the European Commission (network grant IHP HPRN-
CT-2001-00182) for financial support and a post-graduate fellow-
ship (O.M.) and EPSRC for a studentship (S.A.).
Supplementary data
14. Jensen, K. B.; Braxmeier, T. M.; Demarcus, M.; Frey, J. G.; Kilburn, J. D. Chem.dEur.
J. 2002, 8, 1300–1309.
1H NMR titration data for receptors 6–9, 12–14 and 17, 1H
and 13C NMR spectra for all compounds reported in the man-
uscript. Crystallographic data for the structures in this manu-
script have been deposited with the Cambridge Crystallographic
Data Centre with deposition numbers CCDC 706271–706273.
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif. Supplementary data associated with
this article can be found in the online version, at doi:10.1016/
j.tet.2009.01.070.
15. Arnaud, N.; Picard, C.; Cazaux, L.; Tisnes, P. Tetrahedron 1997, 53, 13757–13768.
16. (a) Alfonso, I.; Bolte, M.; Bru, M.; Burguete, M. I.; Luis, S. V.; Rubio, J. J. Am. Chem.
Soc. 2008, 130, 6137–6144; (b) Katayev, E. A.; Boev, N. V.; Khrustalev, V. N.;
Ustynyuk, Y. A.; Tananaev, I. G.; Sessler, J. L. J. Org. Chem. 2007, 72, 2886–2896;
(c) Katayev, E. A.; Pantos, C. D.; Reshetova, M. D.; Khrustalev, V. N.; Lynch, V. M.;
Ustynyuk, Y. A.; Sessler, J. L. Angew. Chem., Int. Ed. 2005, 44, 7386–7390; (d)
Katayev, E. A.; Sessler, J. L.; Khrustalev, V. N.; Ustynyuk, Y. A. J. Org. Chem. 2007,
72, 7244–7252; (e) Ramos, S.; Alcalde, E.; Doddi, G.; Mencarelli, P.; Perez-
Garcia, L. J. Org. Chem. 2002, 67, 8463–8468; (f) Vilar, R. Angew. Chem., Int. Ed.
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17. Berl, V.; Krische, M. J.; Huc, I.; Lehn, J. M.; Schmutz, M. Chem.dEur. J. 2000, 6,
1938–1946.
18. NMR titration data were fitted to a 1:1 or 1:2 binding isotherm using NMRTit
HG or NMRTit HGG software kindly provided by Prof. C.A. Hunter, University of
Sheffield: Bisson, A. P.; Hunter, C. A.; Morales, J. C.; Young, K. Chem.dEur. J. 1998,
4, 845–851 All binding data from NMR titration experiments are provided in
the ESI.
19. Partial 1:2 stoichiometry of acetate binding by receptor 2 was not apparent
from the Job plot, which indicated 1:1 binding. For this reason, perfect fit of
NMR titration data to a 1:1 binding isotherm using NMRTit HG18 was judged
sufficient evidence of binding stoichiometry for those receptors, which did not
display the anomolous behaviour in Dd of the aromatic C2–H proton. Those
References and notes
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2195
recptors showing partial 1:2 binding stoichiometry, evidenced by the C2–H
titration curve are discussed in the text.
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