Anion recognition by neutral macrocyclic azole amides

Article abstract of DOI:10.1002/ejoc.200800811

A straightforward synthesis of C₂-symmetric azole-containing macrocyclic peptides is presented. This type of macrocycle possesses four amide groups directed into the interior of the scaffold that act as hydrogen-bond donors and two nitrogen ato

Full text of DOI:10.1002/ejoc.200800811

FULL PAPER
DOI: 10.1002/ejoc.200800811
Anion Recognition by Neutral Macrocyclic Azole Amides
Markus Schnopp,[a] Silvia Ernst,[a] and Gebhard Haberhauer*[a]
Keywords: Anions / Host–guest systems / Hydrogen bonds / Macrocyclic ligands / Receptors
for Y-shaped anions like AcO– and H2PO4 with a selectivity
for dihydrogen phosphate versus acetate, as was shown with
1H NMR titration techniques in [D6]DMSO/5% CDCl3.
–
A straightforward synthesis of C2-symmetric azole-contain-
ing macrocyclic peptides is presented. This type of macro-
cycle possesses four amide groups directed into the interior
of the scaffold that act as hydrogen-bond donors and two ni-
trogen atoms from the azole unit that act as hydrogen-bond
acceptors. This arrangement makes them sensitive receptors
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
other and to reduce the possible number of conformers of
the macrocyclic rings. The valine–azole subunits in these
macrocycles show, similarly to 2,6-pyridinediamides, strong
preference for a syn–syn conformation of both amide NH
groups.[13,14] This syn–syn preference results from hydrogen
bonding with the azole nitrogen atom (Figure 1). The alter-
native conformations (syn–anti and anti–anti) are disfav-
oured due to lone pair repulsion. As a result, the azole sub-
unit is rigid and shows two hydrogen-bond donation groups
in a common direction, and therefore, it should be able to
strongly bind anions.
Introduction
The design and synthesis of new systems for selective
anion recognition is an emerging field in supramolecular
chemistry,[1–3] as noncovalent anion interaction plays an im-
portant role in many essential biological, chemical and envi-
ronmental processes.[4] A key problem herein is the design
of synthetic receptors with convergent binding groups that
are arranged to match the functionality of the guest mole-
cule. Such receptors are not only to show high affinity, but
also high selectivity, as this is important for sensing applica-
tions. Many anions like acetate, phosphate or sulfate anions
have different geometric structures, which open up possible
routes to the development of shape-selective anion recep-
tors. Examples of natural receptors binding strongly and
effectively phosphate or sulfate anions in water indicate that
there is a potential for further improvements.[5] In these re-
ceptors, amide groups with their intrinsic ability to form
hydrogen bonds play an important role. Therefore, the
study of amide-based recognition systems appears particu-
larly interesting. The directional character and the relatively
small strength of individual hydrogen bonds requires the
active cooperation of multiple, precisely positioned hydro-
gen-bond donor groups in the host structure in order to
achieve strong and selective complexation with anionic
guests.[6,7]
Figure 1. Conformations of the valine–azole subunits.
Our intention was to develop efficient receptors for Y-
shaped anions such as acetate and phosphate in polar sol-
vents. Therefore, we decided to study C2-symmetric recep-
Recently, we developed novel macrocyclic azole-contain-
ing ligands based on the structural motif of Lissoclinum cy-
clopeptide alkaloids as receptors for neutral guest mole-
cules,[8] for the control of axial and planar chirality[9,10] and
for chirality transfer in C3-symmetric compounds.[11,12] In
these systems, the amide groups of the macrocyclic ligands
are primarily used to connect the azole units with each
[a] Institut für Organische Chemie, Fachbereich Chemie, Uni-
versität Duisburg-Essen,
Figure 2. Structures of the azole-containing C2-symmetric macro-
cyclic receptors.
Universitätsstraße 7, 45117 Essen, Germany
E-mail: gebhard.haberhauer@uni-due.de
Eur. J. Org. Chem. 2009, 213–222
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
213

M. Schnopp, S. Ernst, G. Haberhauer
FULL PAPER
tors consisting of two valine–azole subunits linked with val- aminobenzoate (10) to afford building block 11. This coup-
ine units and meta-aminobenzoic acid moieties (Figure 2). ling required uncommonly long reaction times (1 week at
Herein we report the synthesis of the azole-containing C2- room temperature) to obtain acceptable yields of the prod-
symmetric receptors 2–4 and the anion binding properties ucts (41% for 11), which is the result of the lower nucleo-
1
of 1–4 by using H NMR titration techniques.
philicity of aniline 10 relative to that of amine 7. Deprotec-
tion of the carboxyl residue by saponification afforded acid
12. Subsequent removal of the Boc group provided free
amino acid 13, which was submitted to a cyclodimerization
with FDPP to give receptor 4 in a good yield of 52%.
Results and Discussion
Synthesis of the Receptors
The synthesis of receptors 2 and 3 was conducted in
analogy to the straightforward synthesis of macrocycle 1[9]
(Scheme 1). The starting materials for all receptors are the
corresponding azoles 5. Saponification of methyl esters 5
with NaOH in a mixture of MeOH/dioxane afforded azole
acids 6 in almost quantitative yield. Without further purifi-
cation, azole carboxylic acids 6 were coupled by using
pentafluorophenyl diphenylphosphinate (FDPP) and N-
ethyldiisopropylamine in absolute CH3CN at room tem-
perature with readily available ()-valine tert-butyl ester hy-
drochloride (7) in very high yields (89 to 98%). The so-
received valine–azole building blocks 8 can be deprotected
on both sides by stirring in a solution of HCl in ethyl ace-
tate or by using a large excess of trifluoroacetic acid (TFA)
in dichloromethane. In a final step, free amino acids 9 were
dimerized under high-dilution conditions. The best yields
(up to 48%) were obtained by using FDPP as the coupling
reagent in the presence of N-ethyldiisopropylamine.
Scheme 2. Synthesis of receptor 4. Reagents and conditions: (i)
FDPP, iPr2NEt, CH3CN, r.t., 41%; (ii) 2  NaOH, MeOH/dioxane,
0 °C Ǟ r.t., quant.; (iii) TFA, DCM, 0 °C Ǟ r.t., quant.; (iv) FDPP,
iPr2NEt, CH3CN, r.t., 52%.
Structural Investigations
The NMR spectra of cyclic peptides 1–4 are consistent
with a C2-symmetric structure in solution. The vicinal
3JHN,CH values of 7.2–10.3 Hz for 1–4 correspond to dihe-
dral angles of 145° Ͻ |θ| Ͻ 180° in the macrocycle.[15]
The structures of azole-based cyclic amides 1–4 in the
gas phase were investigated by molecular modelling studies
by using the Gaussian software program.[16] To determine
the preferred conformation of the cycles, we performed full
Scheme 1. Synthesis of receptor 1–3. Reagents and conditions: (i)
2  NaOH, MeOH/dioxane, 0 °C Ǟ r.t., 99%; (ii) FDPP, iPr2NEt, geometry optimization by applying the DFT-B3LYP
CH3CN, r.t., 89% for 8a, 94% for 8b and 98% for 8c; (iii) HCl,
method and by using the 6-31G* basis set. A comparison
EtOAc, quant.; (iv) FDPP, iPr2NEt, CH3CN, r.t., 45% for 1, 48%
of the calculated structure data of azole amides 1–3 shows
for 2 and 19% for 3.
that they exhibit essentially the same structure. This is in
Larger receptor 4 was prepared in an analogues manner contrast to the known C2-symmetric azole macrocycles
(Scheme 2). Imidazole carboxylic acid 6a was coupled by where the structural type depends on the type of the azole
using FDPP in CH3CN to commercially available methyl 3- unit.[17] The valine–azole subunits in macrocycles 1–4 have
214
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Anion Recognition by Neutral Macrocyclic Azole Amides
Figure 3. Molecular structures of the energetically preferred conformers of 3 and 4 calculated by using B3LYP/6-31G*; all hydrogen
atoms except those pointing into the interior of the macrocycles are omitted for clarity.
syn–syn conformations for both amide NH groups, and the drawn as to which individual protons are involved in the
()-valine side chains are all directed from the same face of interaction, as well as to the extent to which they partici-
the macrocycle. The four hydrogen atoms of the amides and pate.[18,19] As solvent, we decided to use DMSO, which with
the electron pairs of the azole nitrogen point into the inte- its strong hydrogen-acceptor properties of the oxygen is able
rior of the macrocycle (Figure 3). All dihedral angles χ to act as a strong competitor for hydrogen-bond donor sites
[Namide–Cα–Cazole–Xazole] of macrocycles 1–3 are approxi- in a receptor. In the case of very good anion receptors, the
mately 100°, and the distance between the tertiary nitrogen use of apolar solvents like CDCl3 would result in binding
atoms of the azole rings is between 4.5 and 4.7 Å.
constants higher than 105 –1, which goes beyond the limit
The interior of macrocycle 4 is larger; here, the distance of the NMR technique. A further reason to perform NMR
between the tertiary nitrogen atoms of the azole rings is titrations in DMSO is the fact that this method is com-
calculated to be 7.1 Å. Here again, the four hydrogen atoms monly used in the literature and comparisons to other
of the amides point into the interior of the macrocycle. anion receptors can readily be made. Nevertheless we added
Therefore, the NH groups are perfectly arranged in a corpo- 5% of CDCl3, because the solubility of the receptors in
rate direction, which should result in a strong binding of pure DMSO was too low.
anions through hydrogen bonding.
For the measurements we used a constant host concen-
tration (1ϫ10–3 ) and increased the concentration of the
anions (0.2–10 equiv.). We could observe significant down-
field shifts of the amide signals, which indicate the hydro-
Anion Binding
For investigating the stability of the complexes of recep- gen-bonding interactions. Furthermore, the spectra show a
tors 1–4 and anions we applied standard 1H NMR titration fast equilibrium between free and complexed forms of the
experiments, as NMR spectroscopy is one of the most effec- ligands. Standard nonlinear analysis of the chemical shift
tive tools to study host–guest supramolecular chemistry. By data delivered the 1:1 binding constants for receptors 1–4,
1
adding guest molecules to the ligands, the signals in the H which are summarized in Table 1. To confirm the 1:1 stoi-
NMR spectra migrate upfield or downfield as a result of chiometry, Job plots for complexation of receptor 3 and the
the interactions between the hydrogen-bond donor and ac- TBA salts of dihydrogen phosphate and acetate as examples
ceptor. From the extent of these shifts, conclusions can be were performed (Figure 4). For an adequate comparison of
Table 1. Binding constants Ka (–1) for the formation of 1:1 complexes of 1–4 with various anions in [D6]DMSO/5% CDCl3 at 298 K.[a]
Anion
1
2
3
4
pKa of HX in
Gas phase basicity Anion volume
DMSO (H2O)
(kJmol–1)[c]
(Å3)[d]
[b]
–
H2PO4
AcO–
F–
2640Ϯ610
270Ϯ11
140Ϯ15
14Ϯ10
Ͻ5Ϯ4
13Ϯ8
24700Ϯ1070
7120Ϯ1660
820Ϯ170
15Ϯ4
30000Ϯ9500[e]
23400Ϯ5500[e]
6990Ϯ1080
130Ϯ37
140Ϯ15
150Ϯ34
4010Ϯ480
200Ϯ56
460Ϯ31
980Ϯ42
380Ϯ9
35Ϯ12
18Ϯ4
14Ϯ8
25Ϯ7
– (2.1)
12.6 (4.8)
15.0 (3.2)
– (–3.0)
– (–)
1.6 (–2.6)
1.8 (–8.0)
– (–1.3)
0.9 (–9.0)
– (–)
1351
1427
1529
1251
–
1318
1373
1357
1332
–
33.5
17.8
10.0
28.7
–
–
HSO4
–
TolSO3–
MeSO3
Cl–
92Ϯ7
140Ϯ6
88Ϯ26
–
15Ϯ4
42Ϯ2
24.8
24.0
31.5
38.8
57.9
–
NO3
22Ϯ13
20Ϯ7
Ͻ5Ϯ10
16Ϯ15
29Ϯ11
27Ϯ3
Br–
I–
–
–
220Ϯ51
–
[f]
[f]
[f]
–
[f]
[f]
[f]
[f]
ClO4
–
–
–
–
– (–10.0)
1180
1
[a] The association constants Ka [–1] were measured by using H NMR spectroscopic titrations. The R2 values for the curve fits used to
determine the affinity constants range between 0.974 and 0.999. The anions were used as their tetrabutylammonium salts. [b] Taken from
refs.[3e,20] [c] Standard free enthalpy of protonation in the gas phase, taken from refs.[3e,21] [d] Taken from refs.[1i,3f] [e] A host concentration
of 2.5ϫ10–4  was used for titration studies, because of the high binding constants.[22] [f] The value of ∆δmax was too low for reasonable
calculations of Ka.
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215

M. Schnopp, S. Ernst, G. Haberhauer
FULL PAPER
the binding constants, only the shifts of the amide proton
of the azole amide group were used for the calculation of
Ka. The maximum shifts ∆δmax of these protons after add-
ing 10 equiv. of the guests to the hosts are listed in Table 2.
In almost all cases these chemical shifts were the maximum
shifted ones. Typical titration curves of 1–4 with selected
anions are shown in Figures 5, 6, 7 and 8.
1
Figure 6. H NMR titration curves for the complexation of 2 with
tetrabutylammonium salts of acetate, hydrogen sulfate and methyl
sulfonate in [D6]DMSO/5% CDCl3.
Figure 4. Job plots for complexation of receptor 3 with tetrabu-
tylammonium salts of acetate and dihydrogen phosphate in [D6]
DMSO/5% CDCl3.
Table 2. Values for ∆δmax observed by repeated titrations between
the anionic guests and receptors 1–4 for the amide proton of the
azole amide group.
Anion
1
2
3
4
–
H2PO4
AcO–
F–
0.905
1.094
0.803
0.031
0.043
0.050
0.067
0.023
0.027
0.016
0.006
2.075
1.798
1.422
0.209
0.390
0.564
0.131
0.058
0.041
0.026
0.022
1.446
1.295
1.389
0.189
0.222
0.222
1.759
0.255
0.996
0.174
0.040
0.583
0.458
0.231
0.044
0.052
0.067
0.093
0.044
0.080
0.010
1
Figure 7. H NMR titration curves for the complexation of 3 with
–
HSO4
tetrabutylammonium salts of acetate, chloride, fluoride and dihy-
drogen phosphate in [D6]DMSO/5% CDCl3.
–
TolSO3–
MeSO3
Cl–
–
NO3
Br–
I–
–
[a]
ClO4
–
[a] No shift was observed.
1
Figure 8. H NMR titration curves for the complexation of 4 with
tetrabutylammonium salts of acetate, chloride, and dihydrogen
phosphate in [D6]DMSO/5% CDCl3.
Initially, the spherical halides were evaluated. The ad-
dition of I– to receptors 1, 2 and 4 resulted in only minimal
and inconstant downfield shifts of 0.01–0.026 ppm, so that
no binding constant could be calculated. By adding
1
Figure 5. H NMR titration curves for the complexation of 1 with
tetrabutylammonium salts of acetate, dihydrogen phosphate and
hydrogen sulfate in [D6]DMSO/5% CDCl3.
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Anion Recognition by Neutral Macrocyclic Azole Amides
10 equiv. of iodide to 3, the amide proton shifted about
0.174 ppm and Ka was estimated to be 220 –1. Comparable
results were obtained for the interaction of Br– and Cl– with
1, 2 and 4. The values for ∆δmax are rather small (0.027–
0.131 ppm), and the binding constants are in a range 15–
88 –1. A different behaviour is observed for thiazole recep-
tor 3. Here, shifts of the amide proton of 0.996 and
1.759 ppm for Br– and Cl–, respectively, occurred. The bind-
ing constant Ka was calculated to be 460 –1 for bromide
and 4010 –1 for chloride. The progression of the titration
curves shows that after adding approximately 2 equiv. of the
guests, the curves fade into a plateau and saturation of the
host begins to arise (Figure 7).
The addition of F– caused in all cases reasonable shifts
between 0.231 and 1.422 ppm. Here again, the highest bind-
ing constant (7000 –1) was observed for the interaction
with receptor 3; the titration curve shows that after
1.5 equiv. of fluoride, saturation of the host begins to arise.
If the binding constants of the different receptors are
compared with each other a general tendency is seen. Both
imidazole receptors 1 and 4 deliver the lowest values for Ka,
followed by oxazole receptor 2. Thiazole receptor 3 shows
the highest binding constants for all halides. The compara-
tively low Ka values for the imidazole receptors can be easily
explained. The imidazole is the most basic azole unit and,
consequently, when approaching the binding sites, the
Figure 9. Molecular structures of 3·F–, 3·H2PO4– (above) and 4·Cl–
(below) calculated by using B3LYP/6-31G*; all hydrogen atoms ex-
cept those pointing into the interior of the macrocycles are omitted
for clarity.
anions are exposed a much higher repulsion by the lone to-medium values for the binding constants (Ͻ5–200 –1)
–
–
–
–
pairs of the imidazole nitrogen atoms than in the case of were observed for HSO4 , TolSO3 , MeSO3 and NO3 . In
the thiazole and the oxazole rings. The fact that the oxazole the case of ClO4 , the chemical shifts were too low to get
–
receptor with the lowest basicity nevertheless has lower reasonable values for Ka. All titration curves show a similar
binding constants than the thiazole receptor cannot be ex- progression. Saturation of the host after adding 10 equiv. of
plained by the basic character of the azole units.
guest was not achieved for any of the guests (Figures 5 and
A comparison of the binding constant of complexes 6).
1–3·X– reveals the relationship between the binding con-
A completely different behaviour was observed for the
–
stant and the volume of the halide anions (Table 1). The bonding of AcO– and H2PO4 . By adding acetate, the amide
small fluoride ion binds better than the bigger chloride ion protons reach a maximum shift around 0.458–1.789 ppm.
and this in turn interacts stronger than the bromide, After adding 1.5 equiv. of guest, the titration curves show
whereas for the bulky iodide ion, very weak binding, if at for 2 and 3 a crossover into a plateau and consequently a
all, can be observed. The reason for this trend is obvious: saturation of the host (Figures 5–8). The binding constants
The small fluoride fits best into the interior of receptors 1– vary between 270 and 23400 –1 for 1 and 3, respectively.
3 (Figure 9: molecular structure of 3·F– calculated by using In the case of the titration with dihydrogen phosphate, the
B3LYP/6-31G*). An enlargement of the interior of the cy- ∆δmax value for the NH groups is between 0.583 and
clic peptide leads to a revision of this selectivity. In the case 2.075 ppm and the binding constants achieve a maximum
of receptor 4 the hollow space is increased relative to that value of 30000 –1 for interaction with receptor 3. Adding
of receptors 1–3, and therefore, the chloride fits better than one equiv. guest to scaffolds 2 and 3 the curve progression
the fluoride anion (Table 1 and Figure 9: molecular struc- shows saturation (Figure 7). In case of the curves for 1 and
ture of 4·Cl– calculated by using B3LYP/6-31G*). Worth 4 the transition is not as straight as that for 2 and 3, which
mentioning is that by adding anions to receptor 4 strong is due to the smaller binding constants.
Har interactions were observed. This can be seen from the
A comparison of receptors 1–4 shows the same trend
values of ∆δmax of the aromatic protons extending into the that was already found for the halides. The best receptor for
interior of the scaffold, which are in the same range as the all anions is again thiazole receptor 3, followed by oxazole
ones of the amide protons, which indicates direct contacts receptor 2 and imidazole macrocycle 1. The smallest Ka val-
of these protons to the guests.[23,24] The other aromatic pro- ues are found generally for receptor 4. Because of the ben-
tons shift only slightly upfield.
zene ring, the interior of this receptor is too large to ade-
After the spherical halides, the trigonal planar and tetra- quately bind the used anions. The complex stability of the
–
–
–
–
hedral anions (H2PO4 , HSO4 , AcO–, TolSO3 , MeSO3 , individual anions is partially caused by their basicity. The
–
–
–
–
–
NO3 and ClO4 ) were analyzed. Small-to-medium maxi- least basic anions like NO3 , ClO4 and HSO4 show the
mum shifts (0.023–0.564 ppm) in combination with small- smallest binding constants, whereas acetate and dihydrogen
Eur. J. Org. Chem. 2009, 213–222
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217

M. Schnopp, S. Ernst, G. Haberhauer
FULL PAPER
tions were monitored by TLC analysis by using silica gel 60 F254
thin-layer plates. Flash chromatography was carried out on silica
gel 60 (230–400 mesh). 1H and 13C NMR spectra were measured
with a Bruker Avance DMX 300 and Avance DRX 500 spectrome-
ters. All chemical shifts (δ) are given in ppm relative to TMS. The
spectra were referenced to deuterated solvents indicated in brackets
in the analytical data. HRMS spectra were recorded with a Bruker
BioTOF III Instrument. IR spectra were measured with a Varian
3100 FTIR Excalibur Series spectrometer. UV/Vis absorption spec-
tra were obtained with a Varian Cary 300 Bio.
phosphate, which are more basic than the others, show very
high values for Ka.
A general comparison shows that the affinity of the re-
ceptors to the anions does not directly depend on the vol-
–
ume of the anions. For example, HSO4 and Cl– adopt dif-
ferent volumes but their binding constants are very similar.
In contrast, Br– and H2PO4– have similar volumes but their
values for Ka differ enormously. Even more striking is the
comparison of acetate and dihydrogen phosphate: although
dihydrogen phosphate is almost twice as large as the acetate
ion, their binding constants are quite similar for the interac-
tion with 3. That means that in addition to their volume,
the basicity of the different anions is essential for the
strength of their binding. As already mentioned, the bind-
ing constants for the weakly basic anions are rather low and
with rising basicity their values increase. Because of this,
the most basic acetate anion should form the most stable
complexes, which however is not the case. Here a further
Abbreviations: Bn: benzyl; Boc: tert-butyloxycarbonyl; FDPP:
pentafluorophenyl diphenylphosphinate; DCM: dichloromethane;
DMF: N,N-dimethylformamide; THF: tetrahydrofuran; TFA: tri-
fluoroacetic acid; Val: valine.
Boc-Oxazole Carboxylic Acid 6b: Oxazole 5b (750 mg, 2.40 mmol)
was dissolved in a mixture of methanol (36 mL) and dioxane
(24 mL) followed by slow addition of 2  NaOH solution (12 mL,
24.00 mmol) at 0 °C. The ice bath was removed and stirring was
continued overnight. After TLC showed consumption of all start-
ing material, the solution was poured into a mixture of ice (100 g)
and DCM (100 mL) and acidified with 2  HCl to pH = 1. The
layers were separated, and the aqueous layer was then repeatedly
extracted with DCM (3ϫ100 mL). The organic layers were com-
bined, dried with MgSO4 and concentrated in vacuo to give 707 mg
(98.8%) of free acid 6b, which was used without further purifica-
–
criterion comes into play. The protons of the H2PO4 ion
are able to form additional hydrogen bonds with the azole
nitrogen atom, and so the binding constants are enhanced
–
(Figure 9: molecular structure of 3·H2PO4 calculated by
using B3LYP/6-31G*). The higher the basicity of the azole
nitrogen atom, the higher the selectivity for the H2PO4– ion:
The less basic thiazole receptor 3 forms strong complexes
1
tion for the next step. H NMR (500 MHz, CD3OD): δ = 4.52 [d,
3JH,H = 7.4 Hz, 1 H, Val α-CH], 2.60 (s, 3 H, oxazole-CH3), 2.19–
3
–
with H2PO4 (Ka = 30000 –1) and AcO– (Ka = 23400 –1)
2.12 (m, 1 H, Val β-CH), 1.44 (s, 9 H, Boc CH3), 0.97 (d, JH,H
=
3
6.7 Hz, 3 H, Val CH3), 0.88 (d, JH,H = 6.8 Hz, 3 H, Val CH3)
ppm. 13C NMR (125 MHz, CD3OD): δ = 164.9 (q, CO2H), 163.8
(q, oxazole C-5), 157.9 (q, Boc CONH), 157.5, (q, oxazole C-2),
128.5 (q, oxazole C-3), 80.7 (q, Boc C), 56.4 (t, Val α-CH), 33.3 (t,
Val β-CH), 28.7 (p, Boc CH3), 19.5 (p, Val CH3), 18.9 (p, Val CH3),
and, thus, no selectivity can be observed. In contrast, the
more basic imidazole receptor 1, although yielding dis-
tinctly smaller overall Ka values for both (2640 –1 for
–
–
H2PO4 and 270 –1 for AcO–), it binds H2PO4 with a 10-
fold selectivity vis-a-vis acetate. Consequently, by changing
12.0 (p, oxazole -CH ) ppm. IR (KBr): ν = 3318, 2975, 2934, 1724,
˜
3
–
the azole unit the selectivity and the affinity for H2PO4
1628, 1530, 1368, 1248, 1168, 1096, 1043, 1015, 877, 753 cm–1. UV/
Vis (MeOH, c = 4.00ϫ10–5 mmolmL–1): λ (log ε) = 215 (3.98) nm.
HRMS (ESI): calcd. for C14H22N2O5 [M + Na]+ 321.1421; found
321.1404.
complexation can be controlled.
Conclusions
Boc-Thiazole Carboxylic Acid 6c: Thiazole 5c (1.42 g, 4.30 mmol)
was dissolved in a mixture of methanol (65 mL) and dioxane
(44 mL) followed by slow addition of 2  NaOH solution (22 mL,
24.00 mmol) at 0 °C. The ice bath was removed and stirring was
continued overnight. After TLC showed consumption of all start-
ing material, the solution was poured onto a mixture of ice (100 g)
We were able to synthesize new azole-based C2-symmet-
ric macrocyclic peptides and evaluated the binding ability
towards anions by using H NMR titration techniques in
[D6]DMSO/5% CDCl3. On the one hand, we could show
1
that both the basicity of the anions and the basicity of the and DCM (100 mL) and acidified with 2  HCl to pH = 1. The
layers were separated, and the aqueous layer was then repeatedly
extracted with DCM (3ϫ100 mL). The organic layers were com-
bined, dried with MgSO4 and concentrated in vacuo to give 1.34 g
(99.0%) of the free acid 6c, which was used without further purifi-
receptors play an important role in the formation of strong
hydrogen bonds in a host–guest complex. On the other
hand, the dimension of the interior of the scaffold is essen-
tial for selectivity, especially for the spherical halides. With
the synthesis of thiazole receptor 3 we were able to design
1
cation for the next step. H NMR (500 MHz, CDCl3): δ = 5.17 (d,
3
3
3JH,H = 8.1 Hz, 1 H, Boc-NH), 4.78 (dd, JH,H = 5.9 Hz, JH,H
=
–
an excellent receptor for H2PO4 und AcO– ions. However,
7.0 Hz, 1 H, Val α-CH), 2.77 (s, 3 H, thiazole-CH3), 2.37–2.25 (m,
imidazole receptor 1 shows overall smaller binding con-
3
1 H, Val β-CH), 1.45 (s, 9 H, Boc CH3), 0.98 (d, JH,H = 6.8 Hz,
–
3
3 H, Val CH3), 0.93 (d, JH,H = 6.8 Hz, 3 H, Val CH3) ppm. 13C
stants; thus, its selectivity for H2PO4 is the highest. Varia-
tion of the azole units enables us to design receptors that
are either selective or have an affinity for specific anions.
NMR (125 MHz, CDCl3): δ = 168.4 (q, thiazole C-5), 162.7 (q,
CO2H), 155.4 (q, Boc CONH), 145.1, (q, thiazole C-3), 140.2 (q,
thiazole C-2), 80.3 (q, Boc C), 57.7 (t, Val α-CH), 33.0 (t, Val β-
CH), 28.3 (p, Boc CH3), 19.3 (p, Val CH3), 17.4 (p, Val CH3), 12.9
(p, thiazole-CH ) ppm. IR (KBr): ν = 3338, 2976, 2933, 2871, 1686,
˜
3
Experimental Section
1519, 1368, 1314, 1279, 1249, 1167, 1016, 941, 741 cm–1. UV/Vis
(MeOH, c = 2.00ϫ10–5 mmolmL–1): λ (log ε) = 242 (4.21), 305
(3.95), 324 (sh., 3.84) nm. HRMS (ESI): calcd. for C14H22N2O4S
[M + Na]+ 337.1209; found 337.1192.
General Remarks: All chemicals were reagent grade and used as
purchased. All moisture-sensitive reactions were performed under
an inert atmosphere of argon by using distilled dry solvents. Reac-
218
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 213–222

Anion Recognition by Neutral Macrocyclic Azole Amides
Boc-Oxazole tert-Butyl Ester 8b: To a solution of acid 6b (716 mg,
2.40 mmol) and ()-valine tert-butyl ester hydrochloride (682 mg,
3.25 mmol) dissolved in absolute CH3CN (80 mL) was added N-
ethyldiisopropylamine (0.70 g, 5.40 mmol, 0.92 mL, 2.25 equiv.) at
room temperature. Then, FDPP (1.25 g, 3.25 mmol) and an ad-
ditional amount of N-ethyldiisopropylamine (0.70 g, 5.40 mmol,
0.92 mL, 2.25 equiv.) was added. The solution was stirred overnight
at room temperature, the solvent was evaporated and the residue
was resolved in EtOAc (100 mL). The organic layer was washed
with water (3ϫ30 mL) and brine (1ϫ30 mL), dried with MgSO4
and concentrated, and the residue was subjected to column
chromatography on silica gel (n-hexane/EtOAc, 2:1) to obtain
1.03 g (94.2%) of 8b as a white solid. TLC: Rf = 0.52 (n-hexane/
EtOAc, 3:1; silica). 1H NMR (500 MHz, CDCl3): δ = 7.38 (d, 3JH,H
= 9.2 Hz, 1 H, oxazole-CO-NH), 5.11 (d, 3JH,H = 8.9 Hz, 1 H, Boc-
19.0 (p, Val CH3), 17.8 (p, Val CH3), 17.4 (p, Val CH3), 12.6 (p,
thiazole-CH ) ppm. IR (KBr): ν = 3573, 3408, 3286, 2969, 2933,
˜
3
2876, 1728, 1694, 1655, 1519, 1465, 1393, 1369, 1296, 1243, 1166,
1146, 997 cm–1. UV/Vis (MeOH, c = 2.00ϫ10–5 mmolmL–1): λ (log
ε) = 226 (4.25), 244 (sh., 4.20), 306 (3.77), 326 (sh., 3.63) nm.
HRMS (ESI): calcd. for C23H39N3O5S [M + H]+ 470.2683; found
470.2712. HRMS (ESI): calcd. for C23H39N3O5S [M + Na]+
492.2530; found 492.2520.
Oxazole Trifluoroacetate 9b: Ester 8b (500 mg, 1.10 mmol) was dis-
solved in absolute DCM (10 mL) and cooled to 0 °C. TFA (2.50 g,
22.00 mmol, 1.63 mL) was added slowly, and the reaction mixture
was warmed up to room temperature and stirred for another 24 h.
Then, the solvent was evaporated, and the residue was stripped
several times to remove the remaining TFA to provide 453 mg
(100.0%) of trifluoroacetate 9b as a dark-brown sticky solid. 1H
3
3
NH), 4.69 (dd, JH,H = 6.5 Hz, JH,H = 8.7 Hz, 1 H, Boc-Val α-
3
NMR (500 MHz, CD3OD): δ = 4.52, (d, JH,H = 5.0 Hz, 1 H, ox-
3
3
CH), 4.54 (dd, JH,H = 4.7 Hz, JH,H = 9.2 Hz, 1 H, oxazole-Val
α-CH), 2.59 (s, 3 H, oxazole-CH3), 2.27–2.19 (m, 1 H, Boc-Val β-
CH), 2.19–2.10 (m, 1 H, oxazole-Val β-CH), 1.48 (s, 9 H, Boc
3
azole-Val α-CH), 4.44 (d, JH,H = 6.5 Hz, Val-oxazole α-CH), 2.65
(s, 1 H, oxazole-CH3), 2.44–2.34 (m, 1 H, Val-oxazole β-CH), 2.33–
2.25 (m, 1 H, oxazole-Val β-CH), 1.13 (d, 3JH,H = 6.9 Hz, 3 H, Val
CH3), 1.04–0.98 (m, 9 H, Val CH3) ppm. 13C NMR (125 MHz,
CD3OD): δ = 174.4 (q, Val -COOH), 162.9 (q, oxazole C-5), 158.3
(q, oxazole-CONH), 156.3 (q, oxazole C-2), 130.3 (q, oxazole C-
3), 58.9 (t, oxazole-Val α-CH), 58.3 (t, Val-oxazole α-CH), 32.5 (t,
Val-oxazole β-CH), 32.4 (t, oxazole-Val β-CH), 19.5 (p, Val CH3),
18.7 (p, Val CH3), 18.2 (p, Val CH3), 18.1 (p, Val CH3), 11.7 (p,
3
CH3), 1.46 (s, 1 H, tert-butyl CH3), 0.99 (d, JH,H = 6.6 Hz, 3 H,
3
3
Val CH3), 0.97 (d, JH,H = 6.5 Hz, 3 H, Val CH3), 0.94 (d, JH,H
=
3
6.5 Hz, 3 H, Val CH3), 0.92 (d, JH,H = 6.9 Hz, 3 H, Val CH3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 170.9 (q, tert-butyl COO),
161.8 (q, oxazole C-5), 160.7 (q, oxazole-CONH), 155.4 (q, Boc
CONH), 153.1 (q, oxazole C-2), 128.7 (q, oxazole C-3), 82.0 (q,
tert-butyl C), 80.1 (q, Boc C), 57.1 (t, Boc-Val α-CH), 54.1 (t, ox-
azole-Val α-CH), 32.7 (t, Boc- Val β-CH), 31.7 (t, oxazole-Val β-
CH), 28.3 (p, Boc CH3), 28.0 (p, tert-butyl CH3), 19.0 (p, Val CH3),
19.7 (p, Val CH3), 17.9 (p, Val CH3), 17.8 (p, Val CH3), 11.6 (p,
oxazole-CH ) ppm. IR (KBr): ν = 3403, 2970, 2937, 1733, 1661,
˜
3
1531, 1519, 1372, 1195, 1150, 1015, 996, 980 cm–1. UV/Vis (MeOH,
c = 4.00ϫ10–5 mmolmL–1): λ (log ε) = 222 (4.15) nm. HRMS
(ESI): calcd. for C14H23N3O4 [M + H]+ 298.1761; found 298.1764.
HRMS (ESI): calcd. for C14H23N3O3S [M + Na]+ 320.1581; found
320.1574.
oxazole-CH ) ppm. IR (KBr): ν = 3369, 3313, 2972, 2937, 2875,
˜
3
1719, 1690, 1666, 1636, 1519, 1394, 1370, 1144, 1043, 976,
875 cm–1. UV/Vis (MeOH, c = 2.00ϫ10–5 mmolmL–1): λ (log ε) =
222 (4.18) nm. HRMS (FAB): calcd. for C23H39N3O6 [M + Na]+
454.2912; found 454.2929. HRMS (FAB): calcd. for C23H39N3O6
[M – C4H8+] 398.2286; found 398.2257.
Thiazole Hydrochloride Salt 9c: Ester 8c (860 mg, 1.83 mmol) was
dissolved in EtOAc (50 mL), cooled down to 0 °C and a saturated
solution of HCl in EtOAc (150 mL) was added slowly. After
30 min, the ice bath was removed and stirring was continued at
room temperature for an additional 24 h. To remove HCl, argon
was bubbled through the solution for 30 min, and then the solvent
was evaporated. The residue was stripped several times with EtOAc
to provide 637 mg (99.4%) of hydrochloride salt 9c as a yellow-
brown, slightly sticky solid, which was used without further purifi-
cation for the next step. 1H NMR (500 MHz, CD3OD): δ = 4.60 (d,
3JH,H = 6.3 Hz, 1 H, Val-thiazole α-CH), 4.53 (d, 3JH,H = 5.0 Hz, 1
H, thiazole-Val α-CH), 2.81 (s, 3 H, thiazole-CH3), 2.41–2.32 (m,
1 H, Val-thiazole β-CH), 2.34–2.26 (m, 1 H, thiazole-Val β-CH),
Boc-Thiazole tert-Butyl Ester 8c: To a solution of acid 6c (690 mg,
2.20 mmol) and ()-valine tert-butyl ester hydrochloride (620 mg,
2.98 mmol) dissolved in absolute CH3CN (90 mL) was added N-
ethyldiisopropylamine (0.64 g, 4.95 mmol, 0.84 mL, 2.25 equiv.) at
room temperature. Then, FDPP (1.25 g, 3.25 mmol) and an ad-
ditional amount of N-ethyldiisopropylamine (0.64 g, 4.95 mmol,
0.84 mL, 2.25 equiv.) was added. The solution was stirred overnight
at room temperature, the solvent was evaporated and the residue
was resolved in EtOAc (100 mL). The organic layer was washed
with water (3ϫ30 mL) and brine (1ϫ30 mL), dried with MgSO4
and concentrated, and the residue was subjected to column
chromatography on silica gel (n-hexane/EtOAc, 3:1) to obtain
1.02 g (98.2%) of 8c as a slightly brown solid. TLC: Rf = 0.46 (n-
3
1.12 (d, JH,H = 6.9 Hz, 3 H, Val CH3), 1.06–1.02 (m, 9 H, Val
CH3) ppm. 13C NMR (125 MHz, CD3OD): δ = 174.6 (q, Val
-COOH), 163.6 (q, thiazole C-5), 161.3 (q, thiazole-CONH), 144.5
(q, thiazole C-3), 143.3 (q, thiazole C-2), 58.4 (t, Val α-CH), 58.3
(t, thiazole-Val α-CH), 33.6 (t, Val β-CH), 32.1 (t, thiazole-Val β-
CH), 19.4 (p, Val CH3), 18.4 (p, Val CH3), 18.3 (p, Val CH3), 18.1
1
hexane/EtOAc, 3:1; silica). H NMR (500 MHz, CDCl3): δ = 7.86
(d, 3JH,H = 9.2 Hz, 1 H, thiazole-CO-NH), 5.11 (d, 3JH,H = 8.6 Hz,
1 H, Boc-NH), 4.76 (dd, 3JH,H = 5.6 Hz, 3JH,H = 8.7 Hz, 1 H, Boc-
Val α-CH), 4.54 (dd, 3JH,H = 4.7 Hz, 3JH,H = 9.2 Hz, 1 H, thiazole-
Val α-CH), 2.76 (s, 3 H, thiazole-CH3), 2.37–2.28 (m, 1 H, Boc-Val
β-CH), 2.29–2.20 (m, 1 H, thiazole-Val β-CH), 1.48 (s, 9 H, Boc
(p, Val CH ), 12.5 (p, thiazole-CH ) ppm. IR (KBr): ν = 3376,
˜
3
3
2967, 2936, 1715, 1647, 1533, 1515, 1394, 1231, 1114, 995,
979 cm–1. UV/Vis (MeOH, c = 2.00ϫ10–5 mmolmL–1): λ (log ε) =
203 (4.10), 228 (3.90), 352 (sh., 3.82) nm. HRMS (ESI): calcd. for
C14H23N3O3S [M + H]+ 314.1533; found 314.1559. HRMS (ESI):
calcd. for C14H23N3O3S [M + Na]+ 336.1352; found 336.1377.
3
CH3), 1.46 (s, 9 H, tert-butyl CH3), 0.99 (d, JH,H = 7.0 Hz, 3 H,
3
3
Val CH3), 0.99 (d, JH,H = 6.7 Hz, 3 H, Val CH3), 0.98 (d, JH,H
=
3
7.0 Hz, 3 H, Val CH3), 0.93 (d, JH,H = 6.8 Hz, 3 H, Val CH3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 170.9 (q, tert-butyl COO), Oxazole Receptor 2: To a solution of trifluoroacetate 9b (453 mg,
167.1 (q, thiazole C-5), 162.5 (q, thiazole-CONH), 155.5 (q, Boc 1.10 mmol) in anhydrous CH3CN (50 mL) was added iPr2NEt
CONH), 142.4 (q, thiazole C-3), 140.7 (q, thiazole C-2), 81.9 (q, (569 mg, 4.40 mmol, 750 µL) at 0 °C followed by the addition of
tert-butyl C), 80.2 (q, Boc C), 57.6 (t, Boc-Val α-CH), 57.3 (t, thi- FDPP (634 mg, 1.65 mmol). The solution was warmed up to room
azole-Val α-CH), 33.0 (t, Boc-Val β-CH), 31.7 (t, thiazole-Val β- temperature and stirred for another 5 d. The solvent was evapo-
CH), 28.3 (p, Boc CH3), 28.1 (p, tert-butyl CH3), 19.3 (p, Val CH3), rated, the residue was taken up in EtOAc (150 mL) and then
Eur. J. Org. Chem. 2009, 213–222
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
219

M. Schnopp, S. Ernst, G. Haberhauer
FULL PAPER
washed with H2O (3ϫ50 mL) and brine (1ϫ50 mL). The organic
layer was dried with MgSO4 and concentrated. The residue was
subjected to column chromatography on silica gel (DCM/EtOAc/
MeOH, 75:25:1 Ǟ 75:25:2) to obtain 148 mg (47.3%) of receptor
2 as a slightly yellow solid. TLC: Rf = 0.14 (DCM/EtOAc/MeOH,
raphy on silica gel (n-hexane/EtOAc, 2:1) to obtain 533 mg (40.8%)
11 as a white solid. TLC: Rf = 0.30 (n-hexane/EtOAc, 2:1; silica).
1H NMR (500 MHz, CDCl3): δ = 9.16 (s, 1 H, imidazole -CO-
NH), 8.18 (m, 1 H, Har), 8.12–8.11 (m, 1 H, Har), 7.78–7.76 (m, 1
H, Har), 7.44–7.41 (m, 1 H, Har), 7.33–7.27 (m, 3 H, Har), 7.02–
1
3
2
75:25:2; silica). H NMR (500 MHz, CDCl3): δ = 7.00 (d, JH,H
=
7.00 (m, 2 H, Har), 5.30 (d, JH,H = 16.8 Hz, 1 H, CH2), 5.17 (d,
3
3
10.3 Hz, 2 H, oxazole-Val NH), 6.71 (d, JH,H = 7.2 Hz, 2 H, Val- 2JH,H = 16.8 Hz, 1 H, CH2), 4.98 (d, JH,H = 9.7 Hz, 1 H, Boc-
3
3
oxazole NH), 4.91 (dd, JH,H = 6.3 Hz, JH,H = 6.9 Hz, 2 H, Val-
NH), 4.54–4.50 (m, 1 H, Boc-Val α-CH), 3.93 (s, 3 H, CO2CH3),
2.56 (s, 3 H, imidazole-CH3), 2.23–2.16 (m, 1 H, Boc-Val β-CH),
3
3
oxazole α-CH), 4.61 (dd, JH,H = 7.3 Hz, JH,H = 10.3 Hz, 2 H,
oxazole-Val α-CH), 2.58 (s, 6 H, oxazole-CH3), 2.42–2.32 (m, 2 H,
3
1.39 (s, 9 H, Boc CH3), 0.98 (d, JH,H = 6.6 Hz, 3 H, Val CH3),
Val-oxazole β-CH), 2.32–2.23 (m, 2 H, oxazole-Val β-CH), 1.10 (d, 0.71 (d, 3JH,H = 6.6 Hz, 3 H, Val CH3) ppm. 13C NMR (125 MHz,
3JH,H = 6.7 Hz, 6 H, Val CH3), 1.06 (d, JH,H = 6.7 Hz, 6 H, Val CDCl3): δ = 166.95 (q, methyl COO), 162.00 (q, imidazole-CONH),
3
3
3
CH3), 1.02 (d, JH,H = 6.9 Hz, 6 H, Val CH3), 0.93 (d, JH,H
=
155.37 (q, Boc CONH), 147.35 (q, imidazole C-5), 138.64 (q, Car),
135.68 (q, imidazole C-3), 133.60 (q, Car), 130.80 (q, Car), 129.93
6.8 Hz, 6 H, Val CH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
170.4 (q, CO-NH-Val), 161.3 (q, oxazole C-5), 161.0 (q, oxazole- (q, imidazole C-2), 129.09 (t, Car), 128.96 (t, Car), 127.89 (t, Car),
CONH), 154.0 (q, oxazole C-2), 128.5 (q, oxazole C-3), 59.1 (t,
oxazole-Val α-CH), 53.3 (t, Val-oxazole α-CH), 32.3 (t, Val-oxazole
126.05 (t, Car), 124.54 (t, Car), 123.86 (t, Car), 120.24 (t, Car), 79.74
(q, Boc C), 52.18 (p, CO2CH3), 51.99 (t, Boc-Val α-CH), 46.71 (s,
β-CH), 31.2 (t, oxazole-Val β-CH), 19.4 (p, Val CH3), 18.8 (p, Val CH2), 32.63 (t, Boc-Val β-CH), 28.29 (p, Boc CH3), 19.81 (p, Val
CH3), 18.3 (p, Val CH3), 17.8 (p, Val CH3), 11.6 (p, oxazole-CH3) CH3), 18.32 (p, Val CH3), 10.00 (p, imidazole-CH3) ppm. IR (KBr):
3348, 3000, 1724, 1644 cm–1. UV/Vis (MeOH,
3.22ϫ10–5 mmolmL–1): λ (log ε) = 271 (4.36) nm. HRMS (ESI):
ppm. IR (KBr): ν = 3382, 3322, 2964, 2925, 1655, 1522, 1468,
ν
=
c =
˜
˜
1189 cm–1. UV/Vis (CH2Cl2, c = 2.00ϫ10–5 mmolmL–1): λ (log ε)
= 217 (4.31) nm. HRMS (ESI): calcd. for C28H42N6O6 [M + H]+ calcd. for C28H37N4O5 [M + H]+ 521.2758; found 521.2763. HRMS
559.3239; found 559.3264. HRMS (ESI): calcd. for C23H39N3O5S
(ESI): calcd. for C28H37N4O5 [M + Na]+ 543.2578; found 543.2583.
HRMS (ESI): calcd. for C28H37N4O5 [2M + H]+ 1041.5444; found
1041.5464. HRMS (ESI): calcd. for C28H37N4O5 [2M + Na]+
1063.5264; found 1063.5285.
[M + Na]+ 581.3058; found 581.3046.
Thiazole Receptor 3: To a solution of hydrochloride 9c (658 mg,
1.88 mmol) in anhydrous CH3CN (95 mL) was added iPr2NEt
(970 mg, 7.52 mmol, 1.28 mL) at 0 °C followed by FDPP (1.08 g, Boc-Aminobenzoic Acid 12: Ester 11 (130 mg, 0.25 mmol) was dis-
2.82 mmol). The solution was warmed up to room temperature and
stirred for another 5 d. The solvent was evaporated, and the residue
was taken up in EtOAc (150 mL) and then washed with H2O
(3ϫ50 mL) and brine (1ϫ50 mL). The organic layer was dried
with MgSO4 and concentrated. The residue was subjected to col-
umn chromatography on silica gel (n-hexane/EtOAc, 1:3) to obtain
106 mg (19.1%) of scaffold 3 as a white solid. TLC: Rf = 0.14 (n-
hexane/EtOAc, 1:3; silica). 1H NMR (500 MHz, CD3OD): δ = 4.80
solved in a mixture of methanol (6.0 mL) and dioxane (6.0 mL)
followed by the slow addition of 2  NaOH solution (1.25 mL,
2.50 mmol) at 0 °C. The ice bath was removed and stirring was
continued overnight. After TLC showed consumption of all start-
ing material, the solution was poured into a mixture of ice (20 g)
and DCM (20 mL) and acidified with 2  HCl to pH = 1. The
layers were separated, and the aqueous layer was then repeatedly
extracted with DCM (3ϫ100 mL). The organic layers were com-
bined, dried with MgSO4 and concentrated in vacuo to give 126 mg
3
3
(d, JH,H = 8.5 Hz, 2 H, Val-thiazole α-CH), 4.30 (d, JH,H
=
9.5 Hz, 2 H, thiazole-Val α-CH), 2.62 (s, 6 H, thiazole-CH3), 2.46–
(100.0%) of free acid 12, which was used without further purifica-
1
2.34 (m, 2 H, Val-thiazole β-CH), 2.22–2.11 (m, 2 H, thiazole-Val tion for the next step. H NMR (500 MHz, CDCl3): δ = 8.95 (s, 1
3
3
β-CH), 1.10 (d, JH,H = 6.7 Hz, 12 H, Val CH3), 1.05 (d, JH,H
=
H, imidazole -CO-NH), 8.62 (m, 1 H, Har), 8.04 (m, 1 H, Har),
3
6.7 Hz, 6 H, Val CH3), 0.91 (d, JH,H = 6.7 Hz, 6 H, Val CH3)
7.92–7.90 (m, 1 H, Har), 7.49–7.46 (m, 1 H, Har), 7.37–7.30 (m, 3
ppm. 13C NMR (125 MHz, CD3OD): δ = 173.3 (q, CO-NH-Val), H, Har), 7.10–7.09 (m, 2 H, Har), 5.58 (d, JH,H = 16.8 Hz, 1 H,
2
165.7 (q, thiazole C-5), 163.8 (q, thiazole-CONH), 143.4 (q, thi-
azole C-3), 142.9 (q, thiazole C-2), 62.1 (t, Val-thiazole α-CH), 57.8
(t, thiazole-Val α-CH), 34.7 (t, Val-thiazole β-CH), 32.2 (t, thiazole-
CH2), 5.24 (d, 2JH,H = 16.8 Hz, 1 H, CH2), 4.60–4.56 (m, 1 H, Boc-
Val α-CH), 2.66 (s, 3 H, imidazole-CH3), 2.40–2.30 (m, 1 H, Boc-
3
Val β-CH), 1.45 (s, 9 H, Boc CH3), 0.99 (d, JH,H = 6.5 Hz, 3 H,
Val β-CH), 20.0 (p, Val CH3), 19.9 (p, Val CH3), 19.9 (p, Val CH3), Val CH3), 0.54 (d, JH,H = 6.5 Hz, 3 H, Val CH3) ppm. 13C NMR
3
19.9 (p, Val CH ), 12.6 (p, thiazole-CH ) ppm. IR (KBr): ν = 3467,
(125 MHz, CDCl3): δ = 168.77 (q, methyl COOH), 160.84 (q, imid-
azole-CONH), 156.04 (q, Boc CONH), 148.94 (q, imidazole C-5),
138.50 (q, Car), 135.22 (q, imidazole C-3), 135.00 (q, Car), 130.66
˜
3
3
3414, 2966, 2933, 2874, 1655, 1545, 1499, 1467, 1167, 1104,
1075 cm–1. UV/Vis (CH2Cl2, c = 2.00ϫ10–5 mmolmL–1): λ (log ε)
= 229 (sh., 4.14), 244 (4.20) nm. HRMS (ESI): calcd. for (q, Car), 129.37 (q, imidazole C-2), 129.08 (t, Car), 128.15 (t, Car),
C28H42N6O4S2 [M + Na]+ 613.2601; found 613.2657. HRMS (ESI):
calcd. for C28H42N6O4S2 [2M + Na]+ 1203.5310; found 1203.5442.
126.30 (t, Car), 125.82 (t, Car), 124.64 (t, Car), 124.63 (t, Car), 120.21
(t, Car), 79.64 (q, Boc C), 52.23 (t, Boc-Val α-CH), 47.05 (s, CH2),
HRMS (ESI): calcd. for C28H42N6O4S2 [3M + Na]+ 1794.8047; 32.08 (t, Boc-Val β-CH), 28.36 (p, Boc CH3), 19.90 (p, Val CH3),
found 1794.8248.
19.23 (p, Val CH ), 10.26 (p, imidazole-CH ) ppm. IR (KBr): ν =
˜
3 3
3356, 3000, 1685, 1679 cm–1. UV/Vis (MeOH,
c
=
Boc-Aminobenzoate 11: To a solution of 6a (980 mg, 2.50 mmol)
and methyl 3-aminobenzoate (1.14 g, 7.50 mmol) dissolved in abso-
lute CH3CN (75 mL) was added N-ethyldiisopropylamine (0.98 g,
7.50 mmol, 1.30 mL) at room temperature within 10 min. Then, a
1.66ϫ10–5 mmolmL–1): λ (log ε) = 272 (4.34) nm. HRMS (ESI):
calcd. for C28H34N4O5 [M + H]+ 507.2602; found 507.2632. HRMS
(ESI): calcd. for C28H34N4O5 [M + Na]+ 529.2421; found 529.2451.
suspension of FDPP (1.44 g, 3.75 mmol) in absolute CH3CN Trifluoroacetate 13: Boc protected amino acid 12 (115 mg,
(10 mL) was added slowly. The solution was stirred for 7 d at room
temperature, and the solvent was then evaporated. The residue was
dissolved in EtOAc (100 mL). The organic layer was washed with
water (2ϫ30 mL) and brine (1ϫ30 mL), dried with MgSO4 and
concentrated. The residue was subjected to column chromatog-
0.23 mmol) was dissolved in absolute DCM (5 mL) and cooled to
0 °C. TFA (360 µL) was added slowly, and the reaction mixture was
warmed up to room temperature and stirring was continued for
another 3 h. Then, the solvent was evaporated, and the residue was
stripped several times to remove the remaining TFA and to provide
220
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Eur. J. Org. Chem. 2009, 213–222

Anion Recognition by Neutral Macrocyclic Azole Amides
119 mg (100.0%) of trifluoroacetate 13 as a white sticky solid,
sured. The shifts of the proton signals were monitored and 10 data
1
which was used without further purification for the next step. H points were recorded. The association constants were calculated
NMR (500 MHz, [D6]DMSO): δ = 9.77 (s, 1 H, imidazole -CO- from changes in chemical shifts from the amide protons of the li-
NH), 8.60–8.50 (m, 3 H, NH3+), 8.33–8.32 (m, 1 H, Har), 8.03–8.01 gands. Nonlinear curve fit for a simple 1:1 binding model was car-
(m, 1 H, Har), 7.67–7.65 (m, 1 H, Har), 7.49–7.46 (m, 1 H, Har),
7.40–7.37 (m, 2 H, Har), 7.33–7.30 (m, 1 H, Har), 7.12–7.10 (m, 2
ried out with the SigmaPlot 9.0 program.
For the Job plot titrations, stock solutions of the host molecule
and the respective guest molecules were made up in [D6]DMSO/
5% CDCl3 with a final concentration of 4ϫ10–3 mmolmL–1. From
the host solution, 100–1000 µL were put into an NMR tube and
filled with the guest solution up to 1 mL, so that the sum of the
host and guest concentration was constant in each sample. The
samples were measured and afterwards analyzed by plotting the
molar fraction of guest (XG) as a function of [H0]ϫ∆δ.[25] The
plots themselves were generated by using SigmaPlot 9.0.
2
2
H, Har), 5.42 (d, JH,H = 17.1 Hz, 1 H, CH2), 5.33 (d, JH,H
=
17.1 Hz, 1 H, CH2), 4.51–4.45 (m, 1 H, Val α-CH), 2.41 (s, 3 H,
3
imidazole-CH3), 2.23–2.16 (m, 1 H, Val β-CH), 0.93 (d, JH,H
=
3
6.8 Hz, 3 H, Val CH3), 0.82 (d, JH,H = 6.8 Hz, 3 H, Val CH3)
ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 167.05 (q, COOH),
161.15 (q, imidazole-CONH), 142.88 (q, imidazole C-5), 138.74 (q,
Car), 135.92 (q, imidazole C-3), 134.24 (q, Car), 131.34 (q, Car),
129.62 (q, imidazole C-2), 129.02 (t, Car), 128.72 (t, Car), 127.63 (t,
Car), 126.28 (t, Car), 123.98 (t, Car), 123.22 (t, Car), 119.88 (t, Car),
51.17 (t, Val α-CH), 46.41 (s, CH2), 31.48 (t, Val β-CH), 18.28 (p,
Val CH3), 17.37 (p, Val CH3), 9.60 (p, imidazole-CH3) ppm. IR
Acknowledgments
(KBr): ν = 3375, 3000, 1680, 1679 cm–1. UV/Vis (MeOH, c =
˜
1.96ϫ10–5 mmolmL–1): λ (log ε) = 268 (4.32) nm. HRMS (ESI):
calcd. for C23H26N4O3 [M + H]+ 407.2078; found 407.2108. HRMS
(ESI): calcd. for C23H26N4O3 [M + Na]+ 429.1897; found 429.1920.
This work was generously supported by the Deutsche Forschungs-
gemeinschaft. The authors thank Dr. Andreea Schuster for helpful
discussions.
Receptor 4: To
0.99 mmol) in anhydrous CH3CN (34 mL) was added iPr2NEt
(384 mg, 2.97 mmol, 508 µL) at 0 °C followed by FDPP (571 mg, [1] For selected reviews, see: a) P. A. Gale, S. E. Garcia-Garrido,
a solution of trifluoroacetate 13 (515 mg,
J. Garric, Chem. Soc. Rev. 2008, 37, 151–190; b) J. L. Sessler,
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Anions, Wiley-VCH, Weinheim, 1997.
1.49 mmol). The solution was warmed up to room temperature and
stirred for another 7 d. The solvent was evaporated, and the residue
was taken up in EtOAc (150 mL) and then washed with H2O
(3ϫ50 mL) and brine (1ϫ50 mL). The organic layer was dried
with MgSO4, filtered and concentrated, and the residue was sub-
jected to column chromatography on silica gel (DCM/EtOAc/
MeOH, 75:25:1 Ǟ 75:25:5) to obtain 200 mg (52.5%) of receptor
4 as a white solid. TLC: Rf = 0.30 (DCM/EtOAc/MeOH, 75:25:2;
silica). 1H NMR (500 MHz, CDCl3): δ = 9.18 (s, 2 H, imidazole
-CO-NH), 8.71–8.70 (m, 2 H, Har), 7.80–7.78 (m, 2 H, Har), 7.53–
3
7.50 (m, 2 H, Har), 7.35–7.30 (m, 8 H, Har), 7.15–7.13 (d, JH,H
=
[2] For some recent examples, see: a) A. J. Lowe, G. A. Dyson,
F. M. Pfeffer, Eur. J. Org. Chem. 2008, 1559–1567; b) Y. Li,
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Johnson, J. Am. Chem. Soc. 2008, 130, 10895–10897; d) C.
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45, 2890–2893; j) K. Navakhun, P. A. Gale, M. B. Hursthouse,
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[3] For some recent examples of cyclopeptide-based anion recep-
tors, see: a) D. Meshcheryakov, F. Arnaud-Neu, V. Böhmer, M.
Bolte, V. Hubscher-Bruder, E. Jobin, I. Thondorf, S. Werner,
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Garcia-Garrido, M. E. Light, P. A. Cole, P. A. Gale, Chem.
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bik, New J. Chem. 2007, 31, 2095–2101; d) S.-W. Kang, C. M.
Gothard, S. Maitra, A.-T. Wahab, J. S. Nowick, J. Am. Chem.
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Y. A. Ustinyuk, Org. Lett. 2005, 7, 5277–5280; g) K. Choi,
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h) R. Herges, A. Dikmans, U. Jana, F. Köhler, P. Jones, I. Dix,
T. Fricke, B. König, Eur. J. Org. Chem. 2002, 3004–3014; i) D.
Ranganathan, Acc. Chem. Res. 2001, 34, 919–930; j) H. Ishida,
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5374–5375.
8.2 Hz, 2 H, NH- Val), 7.04–7.03 (m, 4 H, Har), 5.44–5.40 (m, 6 H,
CH2, Val α-CH), 2.55 (s, 6 H, imidazole-CH3), 2.10–2.04 (m, 2 H,
3
3
Val β-CH), 1.00 (d, JH,H = 6.6 Hz, 6 H, Val CH3), 0.82 (d, JH,H
= 6.6 Hz, 6 H, Val CH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
165.51 (q, PhCOONH), 161.56 (q, imidazole-CONH), 147.34 (q,
imidazole C-5), 138.38 (q, Car), 134.96 (q, imidazole C-3), 134.00
(q, Car), 133.73 (q, Car), 130.26 (q, imidazole C-2), 130.09 (t, Car),
129.18 (t, Car), 128.24 (t, Car), 126.04 (t, Car), 123.86 (t, Car), 122.76
(t, Car), 115.22 (t, Car), 50.81 (t, Val α-CH), 47.24 (s, CH2), 34.41
(t, Val β-CH), 19.40 (p, Val CH3), 18.05 (p, Val CH3), 10.06 (p,
imidazole-CH ) ppm. IR (KBr): ν = 3430, 3378, 3000, 1673,
˜
3
1679 cm–1. UV/Vis (MeOH, c = 2.78ϫ10–5 mmolmL–1): λ (log ε)
= 270 (4.42) nm. HRMS (ESI): calcd. for C46H48N8O4 [M + H]+
777.3871; found 777.3876. HRMS (ESI): calcd. for C46H48N8O4
[M + Na]+ 799.3691; found 799.3696.
1H NMR Titrations: All salts and ligands were predried under high
vacuum and then kept under an atmosphere of argon. [D6]DMSO
of 99.9% isotopic purity and CDCl3 of 99.8% isotopic purity, pur-
chased from Sigma–Aldrich, were used as received. For the ti-
tration experiments a Bruker Avance DMX 300 (1H: 300 MHz) was
used.
For determination of the binding constants, stock solutions of the
host molecule being studied were made up in [D6]DMSO/5%
CDCl3 with a final concentration of 1.00ϫ10–3 mmolmL–1. Stock
solutions of the anions were prepared by dissolving around
20 equiv. of the TBA salts in 2 mL of the host stock solution.
From this, 10 to 500 µL portions were again diluted with the host
stock solution up to 1 mL to receive the samples that were mea-
Eur. J. Org. Chem. 2009, 213–222
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221

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Published Online: November 27, 2008
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Eur. J. Org. Chem. 2009, 213–222