Molecular scaffold for the construction of three-armed and cage-like receptors

Article abstract of DOI:10.1002/chem.200500224

An efficient procedure was developed for the synthesis of the C ₃symmetric molecular scaffold 2. The latter can easily he converted by a single step into either the three-armed receptors 11-16 or the cage-like receptor 17. X-ray structures were

Full text of DOI:10.1002/chem.200500224

DOI: 10.1002/chem.200500224
Molecular Scaffold for the Construction of Three-Armed and Cage-Like
Receptors
Gebhard Haberhauer,* Thomas Oeser, and Frank Rominger[a]
Dedicated to Professor Günther Helmchen on the occasion of his 65th birthday
Abstract: An efficient procedure was
developed for the synthesis of the C3-
symmetric molecular scaffold 2. The
latter can easily be converted by a
single step into either the three-armed
receptors 11–16 or the cage-like recep-
tor 17. X-ray structures were obtained
for 2, 11, and 16, which are discussed in
regard to their aptitude as receptor
platforms. The interaction of the three-
armed receptors 12–16 and the cage-
like receptor 17 with phloroglucinol
was investigated. In accordance with
the conclusions obtained from molecu-
lar modeling and X-ray crystallograph-
ic studies on the host–guest complexes,
the three-armed bipyridine receptor 16
exhibits, due to its induced fit, a larger
association constant toward phloroglu-
cinol than the cage 17. This newrecep-
tor system shows all of the positive fea-
tures characteristic of 2,4,6-trialkylben-
zene receptor systems, such as confor-
mational control by steric gearing,
ready availability, and versatility in de-
rivatization. These attributes, combined
with the advantageous size of the com-
ponents, allows this system to be readi-
ly tailored to provide receptors for
larger, biologically important mole-
cules.
Keywords: C3 symmetry · chirality ·
molecular recognition · receptors ·
supramolecular chemistry
Introduction
geometric pattern.[4] It is this conformational control that
renders supplementary complex syntheses superfluous, thus
making the benzene platform so attractive.[3] In the case of
larger platforms, the above two properties—easy modifica-
tion and preorganization of the receptor arms by steric gear-
ing—have not been combined, yet. In general, larger plat-
forms are synthesized stepwise from three subunits that al-
ready carry the recognition sites (Scheme 1, route A). The
conformational rigidity, which guarantees the orientation of
the receptor arms, is achieved by the incorporation of sup-
Recently, an increasing number of molecular receptors con-
sisting of three receptor arms fixed on a rigid platform have
been reported.[1,2] Among these, the benzene ring has
proved to be a particularly effective scaffold, as it combines
two properties that are essential for a useful platform: a
good synthetic availability and the preorganization of the re-
ceptor arms.[2] By making simple modifications, numerous
receptors with different functionalities can be synthesized,
thus allowing rapid optimization with respect to a certain
substrate. In the case of the benzene platform, the preorga-
nization of the arms is due to the so-called steric gearing.[3]
This is based on the fact that certain subunits within the re-
ceptor obtain and retain a preorganized geometry by adop-
tion of a thermodynamically favored conformation, in which
steric interactions are minimized.
For instance, the preferred conformation of 1,3,5-R-2,4,6-
R’-substituted benzene moieties is an alternating ababab
[a] Dr. G. Haberhauer, Dr. T. Oeser, Dr. F. Rominger
Organisch-Chemisches Institut, Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-544-205
E-mail: gebhard.haberhauer@urz.uni-heidelberg.de
Scheme 1.
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FULL PAPER
plementary cycles or polycycles.[5] A modification of the rec-
ognition sites is only possible by transformation of the func-
tional groups. A representative example of such a system is
the platform 1.[6] The three bicyclic imidazole units linked
by trans amide bonds form the rigid scaffold, and the preor-
ganization of the three hydroxyl groups is based on the
identical configuration of the carbon atoms that carry them.
A variation in the recognition sites, that is, the hydroxy
groups, is not easy to realize.
Here, we report on the efficient synthesis of a system that
combines the properties of good versatility in derivatization
and preorganization of the receptor arms by steric gearing.
In contrast to platform 1, the first requirement is the step-
wise construction of scaffold 2 (Scheme 1, route B). Only
then are the three arms attached to the scaffold by simple
alkylation reactions. This permits the synthesis of numerous
receptor systems possessing different recognition sites. As in
the benzene systems, the preorganization of the receptor
arms is based exclusively upon steric gearing. Some of the
results of this work have already been communicated in pre-
liminary form.[7] Here, we report details of the extended
study.
Scheme 2. Synthesis of scaffold 2: a) ClCOOiBu, NMM, THF, À258C,
80%; b) see Table 1; c) Boc2O, H2, Pd(OH)2, THF, 95%; d) BnBr,
K2CO3, CH3CN, D, 32% for 8, 51% for 9; e) 2m NaOH, MeOH/dioxane,
95%; f) H2, Pd(OH)2, MeOH; g) TFA, DCM, 90% (two steps); h) FDPP,
iPr2NEt, CH3CN, RT, 35%.
Table 1. Yields and enantiomeric purities for 6, obtained under various
reaction conditions for cyclization.
Reagents
Solvent
T [8C]
t
Yield [%] ee [%]
CH3COONH4
CH3COONH4
AcOH, NH3
CF3COONH4
CF3COONH4
CF3COONH4
AcOH
xylenes
xylenes
xylenes
115
145
145
145
145
150
145
5 d
6 h
7 h
6 h
5 h
50
30
15
37
25
30
72
38
90
92
94
94
xylenes, DMSO
Results and Discussion
10 min
8 h
90
>96
CF3COOH, NH3 xylenes
Synthesis: The first variant in the synthesis of scaffold 2 is
shown in Scheme 2. In the first step, the amido ketone 5 is
synthesized from readily available 3 and 4[8] by the mixed
anhydride method. Condensation of 5 with ammonia to the
desired imidazole 6 needed to be optimized. Application of
the conditions reported to be useful for the synthesis of imi-
dazoles, that is, the use of ammonium acetate in acetic
acid,[9] gave only moderate yields of 6, and partial racemiza-
tion at the a-carbon atom of the l-valine-based moiety was
observed (Table 1).
water. Hydrolysis of the methyl ester of imidazole 6 without
racemization at the a-carbon atom of the l-valine-based
moiety failed. To overcome this problem, we replaced the
benzyloxycarbonyl (Cbz) group by the tert-butyloxycarbonyl
(Boc) group and protected the NH group of the imidazole
ring with a benzyl group. The methyl esters of the resulting
benzyl imidazoles 8 and 9 can be simply hydrolyzed by
using aqueous NaOH, thus providing the corresponding car-
bocyclic acids in 95% yield. Subsequent removal of the
benzyl group at the imidazole ring by hydrogenolysis fol-
lowed by amine deprotection with trifluoroacetic acid gave
The best results, 72% yield and essentially no racemiza-
tion, were obtained by using ammonium trifluoroacetate,
formed in situ from methanolic ammonia and trifluoroacetic
acid, in the refluxing of xylenes with azeotropic removal of
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G. Haberhauer et al.
the amino acid 10. The most advantageous route for a one-
pot trimerization of the imidazole 10 proved to be the acti-
vation of the acid group with pentafluorophenyl diphenyl-
phosphinate (FDPP) in the presence of excess Hünigꢁs base
in acetonitrile under high dilution conditions at room tem-
perature. This method provided scaffold 2 in a moderate
yield (35%).
A significantly better yield of scaffold 2 was achieved by
the second synthetic variant (Scheme 3). In this case, the
Scheme 4. Syntheses of the three-armed receptors 11–16: a) RCH2Br,
K2CO3, CH3CN, D, 65–77%; b) H2, Pd(OH)2, MeOH, 60–90%.
Scheme 3. Improved synthesis of scaffold 2: a) 2m NaOH, MeOH/diox-
ane, 95%; b) TFA, DCM; c) FDPP, iPr2NEt, CH3CN, RT, 60%; d) H2,
Pd(OH)2, MeOH, 90%.
imidazole building block 8 is deprotected at the C terminus
and then at the N terminus, thus yielding the free amino
acid, which is cyclotrimerized as described above by using
FDPP and Hünigꢁs base in acetonitrile. The platform
formed can be isolated in 60% yield. The removal of the
benzyl groups with palladium hydroxide yields the desired
scaffold. By this synthetic route, scaffold 2 is available on a
gram scale.
Starting from scaffold 2, the corresponding receptors can
nowbe obtained by simple fixation of the arms (Scheme 4).
The three-armed receptors were formed in good yields (65–
77%) if the alkylation was carried out in the presence of
K2CO3 in acetonitrile. A further advantage of these systems
is that benzylic arms can be removed by hydrogenolysis,
thus making the scaffold recyclable. The cage-like receptor
17 can also be synthesized in good yields by using the above
alkylation protocol (Scheme 5).
Scheme 5. Syntheses of the cage-like receptor 17: a) BrCH2RCH2Br,
K2CO3, CH3CN, D, 46%.
11–16 is the three-down conformation, that is, all three arms
should be oriented opposite to the isopropyl groups of the
adjacent a-carbon atoms. To determine the preferred stereo-
chemical orientation of the arms of platform 11 in the gas
phase, we applied the Austin Model 1 (AM1) semiempirical
quantum chemical method[10,11] to calculate several confor-
mations with different orientations of the benzyl and isopro-
pyl groups. As expected, the low-energy conformation of 11
is the three-down conformation. However, the lowest-energy
two-down-one-up conformation was calculated to be only
1.1 kJmolÀ1 higher in energy, and the lowest-energy three-up
conformation was 4.7 kJmolÀ1 higher in energy. The lowest
activation energy required for the changing from down to
up was determined to be 15.2 kJmolÀ1. In summary, the cal-
culations predict a slight preference of the three-down con-
formation.
Structural investigations: We hypothesized that the steric
gearing in the receptors 11–16 is due to repulsive interac-
tions between the isopropyl groups and the receptor arms.
Therefore, we expected that the preferred conformation of
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Three-Armed and Cage-Like Receptors
FULL PAPER
the three-down conformation is
formed irrespective of the sol-
vent from which the crystals
were isolated. A superposition
of the structures of 11 (Fig-
ure 1b–d) shows that, although
different solvent molecules are
incorporated, there are scarce-
ly any conformational differen-
ces. In addition, the distance
between and orientation of the
bipyridyl arms in 16 are essen-
tially the same as for the
benzyl arms in 11. The shortest
distance between two phenyl
arms or two bipyridyl arms is
about 8 Š, which means that
these receptors should definite-
ly be able to include larger
molecules. As in similar imida-
zole platforms, the azole moi-
eties of the macrocycles do not
form a single plane, but have a
cone-like structure.[12] This de-
Figure 1. Crystal structures of scaffold 2 (a) and the three-armed receptor 11 crystallized from methylene chlo-
ride (b),[7] acetone (c), and methanol (d). All hydrogen atoms, and in (a) some solvent molecules, have been
omitted for clarity.
For further stereochemical investigations, we examined
the solid-state structures of scaffold 2 and the receptors 11
and 16 (Figure 1a–d and Figure 2a). As can be seen, the
solid structures obtained supported the assumption that, in
the case of the receptors 11–16, the three-down conforma-
tion is preferred. This conformation also leads to the forma-
tion of a cavity under the platform, which is filled out by
(disordered) solvent molecules. For 11, we could show that
viation from planarity results in the three arms of 11 and 16
being largely equidistant and without divergence from each
other, which should make them more suitable for the inclu-
sion of substrates.
Indirect evidence for preorganization of the arms in solu-
tion is, in our opinion, the successful synthesis of the cage
molecule 17. Generally, the yields of such five-component
cyclizations are very poor. The known difficulties in the syn-
Figure 2. Crystal structures of the free receptor 16 with acetonitrile guest (a),[7] the complex of receptor 16 with phloroglucinol and dichloromethane
(b),[7] and the cage-like receptor 17 with chloroform guests (c). All hydrogen atoms have been omitted for clarity. In (a), a second independent molecule
with some disorder has been omitted, as well as some acetonitrile of solvation. In (c), all solvent molecules outside the cage and the phloroglucinol mole-
cules outside the cage have been omitted.
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G. Haberhauer et al.
theses of such cage-like compounds can be overcome only
by arranging the reactive centers in a way that forces the
closure of the desired ring system.[13] For example, if 1,3,5-
R-2,4,6-R’-substituted benzene moieties are used as building
blocks, the corresponding cage molecules are obtained in a
single-step reaction under mild conditions in 40% yield.[14]
Because 17 can be obtained in a single-step reaction and in
a similar yield, we conclude that the arms in this case, too,
are well preorganized in solution.
expected. Interestingly, the platform 15, which possesses
only one pyridine ring per arm, has a value significantly
lower (50Æ10mÀ1) than 16. Very surprisingly, the cage-like
compound 17, which, like 16, has three bipyridine groups as
recognition sites and which, due to its cage-like structure, is
much better preorganized, shows an association constant
four times lower than that of 16.
Binding studies: To test the concept described, the behavior
of the receptors 12–17 toward phloroglucinol was investigat-
ed.[15] These receptors possess three recognition sites that
should be able to accept hydrogen bridges. Because phloro-
glucinol is not soluble in pure CDCl3, the association con-
stants of the complexes were determined by performing
NMR titrations in CDCl3 containing 10% acetonitrile. The
results are summarized in Table 2. Receptor 16, which has
three bipyridine arms, shows the highest association constant
by far (680Æ85mÀ1). Comparison with the known receptors
18[15b] and 19[15c] is difficult, as their association constants
were determined by using pure CDCl3 and, therefore, have
higher values. However, Nolte et al. showed that the binding
constants drop by a factor of twenty upon progression from
pure CDCl3 to a mixture of CDCl3/CD3CN (10%) (entries 3
and 4 in Table 2).[15b] If this factor is considered, the associa-
tion constant of 16 is of the same order as those of 18 and
19.
The receptors 12–14, with an ester, amide, or ether as hy-
drogen-acceptor groups, exhibit lower stability constants, as
To obtain insights into the binding mode, we tried to
obtain single crystals of both of the latter receptor–phloro-
glucinol complexes. In case of the platform 16, we were able
to growsingle crystals of this complex from CD 2Cl2 (Fig-
ure 2b).[7] The three bipyridyl arms take hold of the phloro-
glucinol molecule by forming three hydrogen bridges. These
hydrogen bridges are formed exclusively by the nitrogen
atoms of the pyridyl rings remote from the scaffold. From
the X-ray structure, it is unclear whether the nitrogen atoms
of the pyridine rings neighboring the scaffold face into the
interior or towards the exterior of the receptor. The cavity
between the phloroglucinol and the platform is filled with
disordered solvent molecules (CD2Cl2).
In the case of the cage-like compound 17, we were able to
growsingle crystals of a mixture of 17 and phloroglucinol
from CDCl3 and acetonitrile. Interestingly, in the solid struc-
ture, phloroglucinol is not incorporated into the cage, but re-
mains outside, together with further solvent molecules.
Inside the cage, there are three places for chloroform mole-
cules, and two of the vacancies are completely occupied
(Figure 2c). The reason why phloroglucinol is not included
in the cage in the solid state and why 16 is a better receptor
than 17 by a factor of four can be recognized by taking the
distances between the bipyridine arms into consideration: In
the free receptor 16, the distance between the centers of the
lower pyridine units is 9.46 Š, whereas in the corresponding
receptor–substrate complex with phloroglucinol, it is
10.05 Š. This means that, for optimal binding, the distance
between the arms must increase. This is easily feasible for
Table 2. Association constants of complexes formed between receptors
12–19 and polyhydroxybenzene moieties.
Receptor Substrate
Solvent
Ka [mÀ1
]
19
18
18
18
1,3,5-trihydroxybenzene CDCl3
1,3,5-trihydroxybenzene CDCl3
11000Æ2000[15c]
3500Æ400[15b]
2000Æ300[15b]
109Æ15[15b]
1,3-dihydroxybenzene
1,3-dihydroxybenzene
CDCl3
CDCl3/CD3CN
(10%)
12
13
14
15
16
16
16
16
16
16
17
1,3,5-trihydroxybenzene CDCl3/CD3CN
15Æ5
130Æ15
65Æ10
50Æ10
680Æ85
120Æ15
85Æ10
40Æ8
(10%)
1,3,5-trihydroxybenzene CDCl3/CD3CN
(10%)
1,3,5-trihydroxybenzene CDCl3/CD3CN
(10%)
1,3,5-trihydroxybenzene CDCl3/CD3CN
(10%)
1,3,5-trihydroxybenzene CDCl3/CD3CN
(10%)
trihydroxyacetophenone CDCl3/CD3CN
(10%)
1,2,3-trihydroxybenzene CDCl3/CD3CN
(10%)
1,2-dihydroxybenzene
1,3-dihydroxybenzene
1,4-dihydroxybenzene
CDCl3/CD3CN
(10%)
CDCl3/CD3CN
(10%)
CDCl3/CD3CN
(10%)
50Æ10
30Æ5
1,3,5-trihydroxybenzene CDCl3/CD3CN
(10%)
150Æ15
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Three-Armed and Cage-Like Receptors
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and Avance 500 instruments. All chemical shifts (d) are given in ppm rel-
ative to TMS. The spectra were referenced to deuterated solvents, indi-
cated in brackets in the analytical data. HRMS spectra were recorded by
using a JEOL JMS-700 instrument. IR spectra were measured by using a
Bruker Vector 22 FTIR spectrometer. Elemental microanalyses were per-
formed at the microanalytical laboratory of the University of Heidelberg.
16, as receptor 16 permits an induced fit. In the case of the
cage-like compound 17, the distances between the pyridine
ring centers are 9.31 Š and 9.36 Š, which are too low to
permit optimal binding. Because of its rigid structure, an ad-
justment is not possible.
This hypothesis was proved by the results of AM1 calcula-
tions in the gas phase: The complex of 16 and phlorogluci-
nol demonstrated an energetic stabilization of DH=
18.6 kJmolÀ1, whereas the value calculated for the complex
of 17 and phloroglucinol was only DH=6.2 kJmolÀ1. In the
latter case, the phloroglucinol molecule is not bound per-
pendicularly to the bipyridine arms, because the distance be-
tween the arms is too short. Rather, it is placed diagonally
inside the cage.
To investigate the selectivity of 16 toward phloroglucinol,
comparative experiments using di- and triphenol derivatives
were conducted (Table 2). As expected, the association con-
stants were drastically reduced once the symmetry of the
substrates no longer corresponded to C3 symmetry and/or
the number of binding sites of the substrates decreased.
Thus, the data obtained are in good agreement with expect-
ations based on host–guest complementarity.
General procedure for the cleavage of the methyl ester group: The pro-
tected compound (1 equiv) was dissolved in methanol/dioxane (10:7,
0.08m), then 2m NaOH (10 equiv) was added slowly at 08C. Stirring was
continued until TLC analysis revealed the consumption of all starting
material, then brine, 1m HCl, and dichloromethane (DCM) were added.
The aqueous phase was extracted repeatedly with DCM; the organic
layers were combined, dried over MgSO4, and concentrated in vacuo to
give the acid compound, which was used in the next step without further
purification.
General procedure for the cleavage of the Boc group: The Boc-protected
compound (1 equiv) was dissolved in DCM (20 mLmmolÀ1 starting mate-
rial) and the solution was cooled to 08C. TFA (1.5 mL/10 mL DCM) was
added at this temperature. The ice bath was removed after 30 min and
stirring was continued at room temperature for 3 h. The mixture was con-
centrated in vacuo to yield quantitatively the TFA salt, which was used
in the next step without further purification.
General procedure for the cleavage of the benzyl group: The benzyl
(Bn)-protected compound (1 equiv) was dissolved in MeOH
(20 mLmmolÀ1 starting material) at room temperature. Pd(OH)2
(50 mgmmolÀ1 starting material) was added and the solution was stirred
under an H2 atmosphere at room temperature for 1 d. The solution was
filtered and the solvent was removed in vacuo to give the free imidazole,
which was used in the next step without further purification.
Conclusion
Amidoketone 5: Compound (S)-Z-Val-OH (3; 16.33 g, 65.0 mmol, Z=
benzyloxycarbonyl) was dissolved in tetrahydrofuran (THF) (400 mL),
N-methylmorpholine (NMM) (6.574 g, 65.0 mmol) was added, and the so-
lution was cooled to À258C. Isobutyl chloroformate (8.877 g, 65.0 mmol)
was added, during which the reaction mixture was maintained at À258C.
After 35 min, aminoketone 4 (10.89 g, 65.0 mmol), followed by a second
equivalent of NMM (6.574 g, 65.0 mmol), were added at À258C. Stirring
was continued for 20 h as the mixture was allowed to warm to room tem-
perature. The solvent was evaporated and the residue was dissolved in
AcOEt, and then washed with water and brine. The organic layer was
dried over MgSO4 and concentrated in vacuo. Purification was achieved
by performing chromatography with silica gel (petroleum ether/ethyl ace-
tate: 1:1) to yield 3 (19.00 g, 52.33 mmol, 80%) as a white solid. M.p.
We have developed an efficient procedure for the synthesis
of a C3-symmetric molecular scaffold that can easily be con-
verted by a single step into either three-armed receptors or
cage-like receptors. Because of the versatility in derivatiza-
tion of this scaffold, optimization with respect to different
substrates is feasible. The preorganization by steric gearing
in the three-armed receptors is good and conforms to the
desired receptor properties; however, improving the preor-
ganization by the formation of cage-like structures can even
be counterproductive, as the possibility of an induced fit is
abolished.
The newreceptor system described exhibits all of the pos-
itive features characteristic of 2,4,6-trialkylbenzene receptor
systems, such as conformational control by steric gearing,
ready availability, and versatility in derivatization. These at-
tributes, combined with the advantageous size of the compo-
nents, allows this system to be readily tailored to provide re-
ceptors for larger, biologically important molecules.
1
1328C; H NMR (300 MHz, CDCl3): d=7.38–7.27 (m, 10H; CArH), 7.13–
7.03 (m, 2H; CONH), 5.42–5.31 (m, 2H; NHCO2), 5.23 (m, 2H;
CHCO2Me), 5.12 (m, 4H; CArCH2), 4.22–4.12 (m, 2H; CHCONH), 3.80
(s, 6H; CO2Me), 2.38 (s, 3H; COMe), 2.37 (s, 3H; COMe), 2.26–2.10 (m,
2H; CHMe2), 1.02–0.90 ppm (m, 12H; CHMe2); 13C NMR (75 MHz,
CDCl3): d=197.9, 197.8, 171.1, 166.21, 166.18, 156.3, 136.2, 128.52,
128.51, 128.2, 128.1, 128.04, 128.03, 67.2, 67.1, 63.0, 62.8, 59.9, 53.32,
53.27, 31.2, 31.0, 28.0, 27.9, 19.1, 19.0, 17.5, 17.4 ppm; IR (KBr): n˜ =3415,
3297, 3064, 3036, 2962, 2874, 1754, 1725, 1689, 1651, 1536, 1454, 1438,
1366, 1289, 1249, 1160, 1042, 700 cmÀ1; HRMS (FAB+): m/z calcd for
C18H25N2O6 [M+H]+: 365.1713; found: 365.1739; elemental analysis calcd
(%) for C18H24N2O6: C 59.33, H 6.64, N 7.69; found: C 59.10, H 6.66, N
7.72.
N-Z-imidazole methyl ester
6 (Z=benzyloxycarbonyl): Both TFA
Experimental Section
(3.88 g, 34.0 mmol) and NH3 in MeOH (7m, 4.86 mL, 34.0 mmol) were
added to a solution of 5 (6.19 g, 17.0 mmol) in xylenes (200 mL) at room
temperature. The solution was stirred at 1508C with azeotropic removal
of water for 8 h and then cooled to room temperature. The solvent was
concentrated, and the residue was dissolved in AcOEt, and then washed
with saturated NaHCO3 solution and brine. The organic layer was dried
over MgSO4 and concentrated in vacuo. Purification was achieved by per-
forming chromatography with silica gel (petroleum ether/ethyl acetate:
2:3) to provide 4.24 g of 6 (12.3 mmol, 72%) as a white solid. M.p. 133–
General remarks: Aminoketone 4,[8] 4-(2-pyridyl)benzylbromide,[16] 5-
(bromomethyl)-5’-methyl-2,2’-bipyridyl,[17] and 5,5’-bis(bromomethyl)-
2,2’-bipyridyl[17] were prepared according to reported procedures. All
chemicals were of reagent grade and were used as purchased. All mois-
ture-sensitive reactions were performed under an inert atmosphere of
argon using distilled dry solvents. Reactions were monitored by perform-
ing TLC analysis with silica gel 60 F254 thin-layer plates. Flash chromatog-
raphy was performed by using silica gel 60 (230–400 mesh). Melting
points were determined in capillary tubes and are uncorrected. 1H and
13C NMR spectra were measured by using Bruker WH 300, Avance 300,
1
1348C; H NMR (500 MHz, [D4]methanol): d=7.42–7.27 (m, 5H; CArH),
5.18–5.04 (m, 2H; CArCH2), 4.51 (d, J=7.6 Hz, 2H; CHCImi), 3.88 (s, 3H;
COOMe), 2.49 (s, 3H; CImiMe), 2.21–2.10 (m, 1H; CHMe2), 1.00 (d, J=
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G. Haberhauer et al.
6.5 Hz, 3H; CHMe2), 0.87 ppm (d, J=6.6 Hz, 3H; CHMe2); 13C NMR
(125 MHz, [D4]methanol): d=158.4, 138.2, 129.5, 129.0, 128.9, 67.8, 56.8,
51.7, 33.9, 19.6, 19.1 ppm; IR (KBr): n˜ =3205, 3065, 3033, 2963, 2875,
1715, 1581, 1532, 1443, 1405, 1341, 1284, 1242, 1210, 1111, 1026, 735,
697 cmÀ1; HRMS (FAB+): m/z calcd for C18H24N3O4 [M+H]+: 346.1767;
found: 346.1813; elemental analysis calcd (%) for C18H23N3O4: C 62.59,
H 6.71, N 12.17; found: C 62.34, H 6.66, N 11.99.
C21H30N3O4 [M+H]+: 388.2236; found: 388.2234; elemental analysis calcd
(%) for C21H29N3O4·0.5H2O: C 63.62, H 7.63, N 10.60; found: C 63.34, H
7.43, N 10.48.
The free acid (1.84 g, 4.75 mmol) was converted into the N-benzyl-depro-
tected free acid as described above in the general procedure for the
cleavage of the benzyl group. Yield 1.27 g (4.27 mmol, 90%). M.p. 92–
948C; 1H NMR (300 MHz, [D4]methanol): d=4.41 (d, J=7.4 Hz, 1H;
CHCImi), 2.45 (s, 3H; CImiMe), 2.12–1.97 (m, 1H; CHMe2), 1.30 (s, 9H;
CMe3), 0.92 (d, J=6.7 Hz, 3H; CHMe2), 0.77 ppm (d, J=6.8 Hz, 3H;
CHMe2); 13C NMR (75 MHz, [D4]methanol): d=161.6, 157.7, 150.0,
137.3, 122.6, 81.5, 55.8, 33.1, 28.6, 19.3, 19.1, 10.9 ppm; IR (KBr): n˜ =
3387, 2973, 2935, 2879, 1718, 1645, 1517, 1475, 1391, 1370, 1348, 1285,
N-Boc-imidazole methyl ester 7: Di-tert-butyldicarbonate (Boc2O)
(5.76 g, 26.0 mmol) and Pd(OH)2 (0.80 g) were added to a solution of 6
(8.12 g, 23.5 mmol) in THF (200 mL) at room temperature. The solution
was stirred under an H2 atmosphere at room temperature for 1 d, then
filtered, and the solvent was removed in vacuo. Flash chromatography
with silica gel (petroleum ether/ethyl acetate: 2:3) gave 6.96 g of 7
1252, 1164, 1132, 1013, 874 cmÀ1
; HRMS (FAB+): m/z calcd for
1
(22.4 mmol, 95%) as a white solid. M.p. 161–1628C; H NMR (300 MHz,
C14H24N3O4 [M+H]+: 298.1767; found: 298.1743.
[D4]methanol): d=4.36 (d, J=7.6 Hz, 1H; CHCImi), 3.79 (s, 3H;
COOMe), 2.40 (s, 3H; CImiMe), 2.07–1.92 (m, 1H; CHMe2), 1.37 (s, 9H;
CCMe3), 0.89 (d, J=6.6 Hz, 3H; CHMe2), 0.76 ppm (d, J=6.8 Hz, 3H;
CHMe2); 13C NMR (75 MHz, [D4]methanol): d=157.7, 80.6, 56.1, 51.7,
34.2, 28.7, 19.6, 19.0 ppm; IR (KBr): n˜ =3335, 3071, 2971, 2934, 2875,
1715, 1594, 1525, 1441, 1394, 1368, 1324, 1285, 1247, 1206, 1172, 1113,
1040, 1013 cmÀ1; HRMS (FAB+): m/z calcd for C15H26N3O4 [M+H]+:
312.1923; found: 312.1944; elemental analysis calcd (%) for C15H25N3O4:
C 57.86, H 8.09, N 13.49; found: C 57.72, H 7.99, N 13.32.
The N-benzyl-deprotected free acid was subjected to Boc deprotection to
give the free amino acid 10. M.p. 50–528C; 1H NMR (300 MHz,
[D6]DMSO): d=9.75–8.09 (brs, 5H; NH3, COOH, NImiH), 4.07 (d, J=
6.7 Hz, 1H; CHCImi), 2.41 (s, 3H; CImiMe), 2.26–2.14 (m, 1H; CHMe2),
0.93 (d, J=6.8 Hz, 3H; CHMe2), 0.82 ppm (d, J=6.8 Hz, 3H; CHMe2);
13C NMR (75 MHz, [D6]DMSO): d=162.9, 159.0, 158.6, 158.1, 157.6,
143.5, 139.5, 123.5, 122.0, 118.1, 114.2, 110.3, 53.1, 31.1, 18.3, 17.9,
12.4 ppm; IR (KBr): n˜ =3433, 2977, 2943, 1672, 1558, 1504, 1558, 1504,
1439, 1397, 1385, 1318, 1260, 1202, 1142, 839, 799, 723 cmÀ1; HRMS
(FAB+): m/z calcd for C11H17F3N3O4 [M+H]+: 198.1243; found:
198.1241.
N-Boc-benzyl-imidazole methyl esters 8 and 9: Both K2CO3 (9.54 g,
69.0 mmol) and BnBr (5.99 g, 35.0 mmol) were added to a solution of 7
(7.16 g, 23.0 mmol) in acetonitrile (400 mL) at room temperature and the
mixture was stirred at reflux for 4 h. The solvent was evaporated and the
residue was dissolved in AcOEt, extracted with water and brine, dried
over MgSO4, and concentrated in vacuo. Purification was achieved by
performing chromatography with silica gel (petroleum ether/ethyl ace-
tate: 3:1 to 1:1) to yield 9 (4.73 g, 11.8 mmol, 51%) and 8 (2.98 g,
7.42 mmol, 32%) as white solids.
Data for 8: M.p. 148–1498C; 1H NMR (300 MHz, CDCl3): d=7.36–6.94
(m, 5H; CArH), 5.33 (d, J=16.9 Hz, 1H; CArCH2), 5.20–5.09 (m, 2H;
CArCH2, NHCO2), 4.45 (m, 1H; CHCImi), 3.89 (s, 3H; COOMe), 2.48 (s,
3H; CImiMe), 2.31–2.17 (m, 1H; CHMe2), 1.35 (s, 9H; CMe3), 0.93 (d,
J=6.7 Hz, 3H; CHMe2), 0.58 ppm (d, J=6.6 Hz, 3H; CHMe2); 13C NMR
(75 MHz, CDCl3): d=164.3, 155.4, 148.9, 136.1, 135.6, 128.9, 128.1, 127.9,
126.1, 79.4, 52.1, 51.5, 46.8, 32.5, 28.2, 19.9, 18.5, 10.3 ppm; IR (KBr): n˜ =
3353, 2968, 2931, 1699, 1574, 1520, 1454, 1441, 1390, 1364, 1335, 1307,
1246, 1221, 1171, 1084, 1015, 730 cmÀ1; HRMS (FAB+): m/z calcd for
C22H32N3O4 [M+H]+: 402.2393; found: 402.2394; elemental analysis calcd
(%) for C22H31N3O4: C 65.81, H 7.78, N 10.47; found: C 65.68, H 7.81, N
10.41.
Scaffold 2: Both iPr2NEt (1.24 g, 9.60 mmol) and FDPP (1.61 g,
4.20 mmol) were added to a solution of 10 (1.00 g, 3.20 mmol) in acetoni-
trile (70 mL) at room temperature, and the mixture was stirred at this
temperature for five days. The solvent was evaporated and the residue
was dissolved in AcOEt, then extracted with water and brine, dried over
MgSO4, and concentrated in vacuo. Flash chromatography with silica gel
(DCM/AcOEt/MeOH: 75/25/10) gave 200 mg of 2 (0.37 mmol, 35%) as a
white solid. M.p.>2508C; 1H NMR (300 MHz, [D4]methanol): d=4.87
(d, J=5.5 Hz, 3H; CHCImi), 2.49 (s, 9H; CImiMe), 2.21–2.07 (m, 3H;
CHMe2), 0.98 (d, J=6.8 Hz, 9H; CHMe2), 0.95 ppm (d, J=6.8 Hz, 9H;
CHMe2); 13C NMR (75 MHz, [D4]methanol): d=165.3, 146.6, 133.1,
130.2, 53.4, 35.8, 19.0, 18.8, 10.7 ppm; IR (KBr): n˜ =3378, 3225, 2965,
2931, 2875, 1646, 1603, 1546, 1516, 1466, 1439, 1405, 1389, 1370, 1336,
1286, 1224, 1155, 1038, 1023, 909, 880, 806, 783, 775, 643 cmÀ1; HRMS
(FAB+): m/z calcd for C27H40N9O3 [M+H]+: 538.3254; found: 538.3243;
elemental analysis calcd (%) for C27H39N9O3·1= CH2Cl2·1= CH3OH:
C
3
3
57.63, H 7.17, N 21.86; found: C 57.39, H 7.45, N 21.89.
Receptor 11: Imidazole 8 (2.01 g, 5.00 mmol) was subjected to methyl
and Boc deprotection successively to give the corresponding free amino
acid. Yield 1.91 g (4.76 mmol, 95%). M.p. 728C; 1H NMR (300 MHz,
[D6]DMSO): d=8.48 (s, 3H; NH3), 7.43–7.04 (m, 5H; CArH), 5.45–5.24
(m, 2H; CArCH2), 4.35 (s, 1H; CHCImi), 2.36 (s, 3H; CImiMe), 2.20–2.06
(m, 1H; CHMe2), 0.91 (d, J=6.7 Hz, 3H; CHMe2), 0.72 ppm (d, J=
6.8 Hz, 3H; CHMe2); 13C NMR (75 MHz, [D6]DMSO): d=164.3, 158.7,
158.3, 157.9, 157.4, 143.9, 136.4, 136.0, 128.7, 128.5, 127.6, 126.2, 122.3,
118.4, 114.4, 110.5, 51.0, 46.4, 31.8, 18.4, 17.6, 10.1 ppm; IR (KBr): n˜ =
3433, 3035, 2973, 2940, 1679, 1547, 1514, 1506, 1435, 1354, 1328, 1202,
1
Data for 9: M.p. 91–938C; H NMR (300 MHz, CDCl3): d=7.32–7.02 (m,
5H; CArH), 5.81 (d, J=16.1 Hz, 1H; CArCH2), 5.52 (d, J=16.1 Hz, 1H;
CArCH2), 5.08 (d, J=9.6 Hz, 1H; NHCO2), 4.53 (m, 1H; CHCImi), 3.79 (s,
3H; COOMe), 2.49 (s, 3H; CImiMe), 2.15–2.00 (m, 1H; CHMe2), 1.39 (s,
9H; CMe3), 0.92 (d, J=6.7 Hz, 3H; CHMe2), 0.53 ppm (d, J=6.6 Hz,
3H; CHMe2); 13C NMR (75 MHz, CDCl3): d=161.6, 155.4, 152.4, 147.5,
137.4, 128.6, 127.4, 126.5, 118.3, 79.5, 51.8, 51.2, 48.1, 32.9, 28.3, 19.4, 18.4,
16.0ppm; IR (KBr): n˜ =3430, 3361, 2971, 2933, 1709, 1517, 1472, 1451,
1392, 1368, 1314, 1282, 1247, 1170, 1134, 1011, 733 cmÀ1; HRMS (FAB+):
m/z calcd for C22H32N3O4 [M+H]+: 402.2393; found: 402.2374; elemental
analysis calcd (%) for C22H31N3O4: C 65.81, H 7.78, N 10.47; found: C
65.59, H 7.79, N 10.31.
1141, 800, 725 cmÀ1
; HRMS (FAB+): m/z calcd for C18H23F3N3O4
[M+H]+: 288.1712; found: 288.1717; elemental analysis calcd (%) for
C18H22F3N3O4·0.5CF3COOH: C 49.78, H 4.95, N 9.17; found: C 49.71, H
5.12, N 9.15.
TFAaminoimidazole carboxylic acid 10 : Imidazole 8 (2.01 g, 5.00 mmol)
was converted into the free acid as described above in the general proce-
dure for the cleavage of the methyl ester group. Yield 1.84 g (4.75 mmol,
95%). M.p. 86–888C; H NMR (300 MHz, CDCl3): d=7.64–7.43 (m, 1H;
NHCO2), 7.39–7.05 (m, 5H; CArH), 5.23 (d, J=16.9 Hz, 1H; CArCH2),
5.14 (d, J=16.9 Hz, 1H; CArCH2), 4.44 (m, 1H; CHCImi), 2.54 (s, 3H;
Both iPr2NEt (1.24 g, 9.60 mmol) and FDPP (1.61 g, 4.20 mmol) were
added to a solution of the free amino acid (1.28 g, 3.20 mmol) in acetoni-
trile (70 mL) at room temperature, and the mixture was stirred at room
temperature for 5 d. The solvent was evaporated and the residue was dis-
solved in AcOEt, then extracted with water and brine, dried over
MgSO4, and concentrated in vacuo. Purification was achieved by per-
forming chromatography with silica gel (petroleum ether/ethyl acetate:
1:2) to yield 520 mg (0.64 mmol, 60%) of 11 as a white solid. M.p.
1
C
ImiMe), 2.53–2.39 (m, 1H; CHMe2), 1.39 (s, 9H; CMe3), 0.97 (d, J=
6.6 Hz, 3H; CHMe2), 0.46 ppm (d, J=6.6 Hz, 3H; CHMe2); 13C NMR
(75 MHz, CDCl3): d=165.6, 156.2, 149.2, 135.9, 135.6, 134.1, 128.9, 127.9,
126.4, 78.8, 52.3, 47.0, 32.1, 28.3, 20.0, 19.2, 10.0 ppm; IR (KBr): n˜ =3409,
3258, 2972, 2932, 2876, 1709, 1631, 1503, 1455, 1390, 1368, 1281, 1252,
1
2468C; H NMR (500 MHz, CDCl3): d=8.51 (d, J=9.1 Hz, 3H; CONH),
7.31–6.96 (m, 15H; CArH), 5.22–5.15 (m, 6H; CArCH2, CHCImi), 5.08 (d,
J=16.9 Hz, 3H; CArCH2), 2.41 (s, 9H; CImiMe), 2.00–1.92 (m, 3H;
CHMe2), 0.99 (d, J=6.7 Hz, 9H; CHMe2), 0.96 ppm (d, J=6.9 Hz, 9H;
1169, 1119, 1013, 873, 731 cmÀ1
; HRMS (FAB+): m/z calcd for
6724
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6718 – 6726

Three-Armed and Cage-Like Receptors
FULL PAPER
CHMe2); 13C NMR (125 MHz, CDCl3): d=163.2, 147.2, 135.3, 132.3,
130.1, 129.0, 127.9, 126.0, 49.6, 46.9, 34.5, 19.8, 17.2, 9.9 ppm; IR (KBr):
n˜ =3387, 3064, 3032, 2963, 2930, 2873, 1662, 1595, 1508, 1456, 1427, 1388,
1369, 1355, 1261, 1223, 1141, 1092, 1029, 933, 877, 810, 783, 770, 730, 696,
632, 510 cmÀ1; HRMS (FAB+): m/z calcd for C48H58N9O3 [M+H]+:
808.4663; found: 808.4661; elemental analysis calcd (%) for
0.98 ppm (d, J=6.7 Hz, 9H; CHMe2); 13C NMR (75 MHz, CDCl3): d=
163.1, 156.3, 152.9, 149.7, 147.3, 147.2, 137.4, 134.7, 133.7, 132.0, 130.6,
130.5, 121.0, 120.7, 49.6, 44.7, 34.6, 19.9, 18.4, 17.5, 9.9 ppm; IR (KBr):
n˜ =3388, 2962, 2927, 2873, 1662, 1596, 1556, 1508, 1468, 1426, 1403, 1387,
1373, 1337, 1221, 1132, 1109, 1058, 1029, 934, 829, 784, 759, 739, 650,
634 cmÀ1
;
HRMS (FAB+): m/z calcd for C63H70N15O3 [M+H]+:
C48H57N9O3·2= CH2Cl2: C 67.60, H 6.80, N 14.58; found: C 67.55, H 6.88,
1084.5786; found: 1084.5774.
3
N 14.53.
Cage-like receptor 17: Both K2CO3 (166 mg, 1.20 mmol) and BrCH2-
(C5H3N)2CH2Br (103 mg, 0.30 mmol) were added to a solution of 2
(108 mg, 0.20 mmol) in acetonitrile (200 mL) at room temperature and
the mixture was stirred at reflux for 8 h. The solvent was evaporated and
the residue was dissolved in AcOEt, extracted with water and brine,
dried over MgSO4, and concentrated in vacuo. Purification was achieved
by performing chromatography with silica gel (DCM/AcOEt/MeOH:
75:25:7) to yield 74 mg of 17 (0.046 mmol, 46%) as a white solid. M.p.
>2508C; 1H NMR (300 MHz, CDCl3): d=8.70 (d, J=8.6 Hz, 6H;
General procedure for the syntheses of three-armed platforms 12–16:
Both K2CO3 (207 mg, 1.50 mmol) and RCH2Br (0.75 mmol) were added
to a solution of 2 (108 mg, 0.20 mmol) in acetonitrile (30 mL) at room
temperature and the mixture was stirred at reflux for 8 h. The solvent
was evaporated and the residue was dissolved in AcOEt, extracted with
water and brine, dried over MgSO4, and concentrated in vacuo. Purifica-
tion was achieved by performing chromatography with silica gel (DCM/
AcOEt/MeOH: 75:25:5) to yield the three-armed platforms 12–16 (65–
77%) as white solids.
CArH), 8.24 (d, J=8.3 Hz, 6H; NHCO), 8.11 (m, 6H; CArH), 7.21–7.15
Data for receptor 12: Yield 70%. M.p. 1838C; 1H NMR (300 MHz,
CDCl3): d=8.49 (d, J=9.2 Hz, 3H; NHCO), 7.98 (d, J=8.4 Hz, 6H;
(m, 6H; CArH), 5.39 (d, J=17.6 Hz, 6H; CArCH2), 5.15 (m, 6H; CHCImi),
5.05 (d, J=17.6 Hz, 6H; CArCH2), 2.33 (s, 18H; CImiMe), 2.22–2.09 (m,
6H; CHMe2), 1.11 (d, J=6.8 Hz, 18H; CHMe2), 1.06 ppm (d, J=6.7 Hz,
18H; CHMe2); 13C NMR (75 MHz, CDCl3): d=162.6, 155.3, 146.7, 146.2,
134.2, 132.1, 130.9, 130.7, 121.2, 49.6, 44.6, 35.7, 19.6, 17.8, 9.6 ppm; IR
(KBr): n˜ =3389, 2962, 2931, 2872, 1660, 1596, 1555, 1508, 1469, 1428,
1388, 1372, 1329, 1223, 913, 824, 781, 763, 733, 638 cmÀ1; HRMS (FAB+
): m/z calcd for C90H103N24O6 [M+H]+: 1615.8492; found: 1615.8499.
CArH), 7.05 (d, J=8.4 Hz, 6H; CArH), 5.29–5.09 (m, 9H; CArCH2,
CHCImi), 3.90 (s, 9H; COOMe), 2.39 (s, 9H; CImiMe), 2.05–1.91 (m, 3H;
CHMe2), 1.00 (d, J=6.8 Hz, 9H; CHMe2), 0.97 ppm (d, J=6.8 Hz, 9H;
CHMe2); 13C NMR (75 MHz, CDCl3): d=166.4, 163.0, 147.3, 140.3, 132.2,
130.4, 130.0, 126.0, 52.2, 49.6, 46.7, 34.6, 19.8, 17.3, 9.8 ppm; IR (KBr):
n˜ =3388, 2961, 2874, 1725, 1664, 1614, 1595, 1558, 1509, 1460, 1434, 1417,
1388, 1372, 1314, 1283, 1224, 1192, 1111, 1019, 964, 930, 839, 771, 751,
627 cmÀ1; HRMS (FAB+): m/z calcd for C54H64N9O9 [M+H]+: 982.4827;
found: 982.4878.
Data for receptor 13: Yield 65%. M.p. 1918C; 1H NMR (300 MHz,
CDCl3): d=8.51 (d, J=9.1 Hz, 3H; CONH), 7.67 (d, J=8.3 Hz, 6H;
CArH), 6.98 (d, J=8.3 Hz, 6H; CArH), 6.33 (t, J=5.7 Hz, 3H;
CONHCH2), 5.24–5.05 (m, 9H; CArCH2, CHCImi), 3.47–3.35 (m, 6H;
CONHCH2), 2.35 (s, 9H; CImiMe), 2.07–1.93 (m, 3H; CHMe2), 1.62–1.49
(m, 6H; CH2), 1.44–1.31 (m, 6H; CH2), 1.03–0.89 ppm (m, 27H;
CH2CH3, CHMe2); 13C NMR (75 MHz, CDCl3): d=166.8, 163.0, 147.2,
138.5, 134.7, 132.2, 130.3, 127.7, 126.0, 49.6, 46.6, 39.8, 34.7, 31.7, 20.1,
19.8, 17.3, 13.8, 9.8 ppm; IR (KBr): n˜ =3382, 3068, 2960, 2930, 2872, 1649,
1595, 1573, 1508, 1463, 1432, 1388, 1372, 1350, 1310, 1225, 1192, 1146,
1111, 1019, 963, 929, 839, 814, 783, 771, 747, 636, 539 cmÀ1; HRMS
(FAB+): m/z calcd for C63H85N12O6 [M+H]+: 1105.6715; found:
1105.6704.
Data for receptor 14: Yield 70%. M.p. 1598C; 1H NMR (300 MHz,
CDCl3): d=8.48 (d, J=9.1 Hz, 3H; NHCO), 6.91 (d, J=8.7 Hz, 6H;
CArH), 6.79 (d, J=8.8 Hz, 6H; CArH), 5.21–4.93 (m, 9H; CArCH2,
CHCImi), 3.75 (s, 9H; CArOMe), 2.40 (m, 9H; CImiMe), 2.02–1.88 (m, 3H;
CHMe2), 1.01–0.92 ppm (m, 18H; CHMe2); 13C NMR (75 MHz, CDCl3):
d=163.2, 159.2, 147.1, 132.2, 130.1, 127.4, 114.3, 55.3, 49.5, 46.5, 34.5,
19.9, 17.2, 9.9 ppm; IR (KBr): n˜ =3386, 2962, 2932, 2873, 2836, 1662,
1613, 1594, 1515, 1463, 1420, 1388, 1370, 1354, 1331, 1294, 1251, 1177,
1142, 1111, 1090, 1033, 916, 878, 821, 783, 730, 635, 554, 515 cmÀ1; HRMS
(FAB+): m/z calcd for C51H64N9O6 [M+H]+: 898.4980; found: 898.4958.
Host–guest titrations: Stock solutions of the guest (1 mmol/100 mL) in
CD3CN and the receptor (1 mmol/100 mL) in CDCl3 were prepared. In
total, 10 NMR tubes were set up by adding increasing amounts of the
host solution (0–500 mL) to 100 mL of the guest solution. All samples
were made up to a volume of 1 mL with CDCl3 and the respective
1H NMR spectra were recorded. The chemical shifts of prominent guest
protons were plotted against the host concentration. From the resulting
saturation curves, Ka and dmax were calculated by using the SIGMA
Plot 8.0 software package.
X-ray crystal structure analysis: For C27H39N9O3·2CH3OH (2); Mr =
601.76, colorless crystal (irregular), dimensions 0.27”0.23”0.11 mm3,
crystal system orthorhombic, space group P212121, Z=4, a=9.1365(6),
b=9.3066(6), c=40.850(3) Š, V=3473.5(4) Š3, 1calcd =1.151 gcmÀ3, T=
100(2) K, qmax =24.758, radiation MoKa, l=0.71073 Š, 0.38 omega scans
with CCD area detector, covering a whole sphere in reciprocal space,
27209 reflections measured, 5906 unique (R(int)=0.0392), 5496 observed
[I>2s(I)], intensities were corrected for Lorentz and polarization effects,
an empirical absorption correction was applied by using SADABS[18]
based on the Laue symmetry of the reciprocal space, m=0.08 mmÀ1, min/
max transmission=0.98/0.99, structure was solved by using direct meth-
ods and refined against F2 with a full-matrix least-squares algorithm by
using the SHELXTL (6.12) software package,[19] 578 parameters refined,
hydrogen atoms were treated by using appropriate riding models, except
for 31, which were refined isotropically, Flack absolute structure parame-
ter À0.3(13), goodness of fit 1.13 for observed reflections, final residual
values R1(F)=0.049, wR(F2)=0.115 for observed reflections, residual
À3
Data for receptor 15: Yield 77%. M.p. 1988C; 1H NMR (500 MHz,
CDCl3): d=8.66 (d, J=4.5 Hz, 3H; CArH), 8.54 (d, J=9.2 Hz, 3H;
NHCO), 7.93 (d, J=8.3 Hz, 6H; CArH), 7.75–7.66 (m, 6H; CArH), 7.21
electron density À0.19 to 0.35 eŠ
.
For C48H57N9O3·C3H6O·H2O (11) (crystallization from acetone); Mr =
882.10, colorless crystal (polyhedron), dimensions 0.25”0.22”0.14 mm3,
crystal system hexagonal, space group P63, Z=2, a=13.4888(4), b=
13.4888(4), c=14.9241(9) Š, V=2351.61(17) Š3, 1calcd =1.246 gcmÀ3, T=
100(2) K, 2qmax =28.398, radiation MoKa, l=0.71073 Š, 0.38 omega scans
with CCD area detector, covering a whole sphere in reciprocal space,
25065 reflections measured, 3917 unique (R(int)=0.0447), 3861 observed
[I>2s(I)], intensities were corrected for Lorentz and polarization effects,
an empirical absorption correction was applied by using SADABS[18]
based on the Laue symmetry of the reciprocal space, m=0.08 mmÀ1, min/
max transmission=0.98/0.99, structure was solved by direct methods and
refined against F2 with a full-matrix least-squares algorithm by using the
SHELXTL-PLUS (5.10) software package,[19] 227 parameters refined, hy-
drogen atoms were treated by using appropriate riding models, except
for H9 at N9, which was refined isotropically, Flack absolute structure
parameter À1(2), goodness of fit 1.26 for observed reflections, final resid-
(m, 3H;
CArH), 7.10 (d, J=8.2 Hz, 6H; CArH), 5.27–5.13 (m, 9H;
CArCH2, CHCImi), 2.43 (s, 9H; CImiMe), 2.05–1.97 (m, 3H; CHMe2), 1.02
(d, J=6.7 Hz, 9H; CHMe2), 0.99 ppm (d, J=6.8 Hz, 9H; CHMe2);
13C NMR (75 MHz, CDCl3): d=163.2, 156.6, 149.5, 147.3, 138.9, 136.9,
136.2, 132.3, 130.3, 127.6, 126.4, 122.3, 120.6, 49.6, 46.8, 34.6, 19.9, 17.3,
9.9 ppm; IR (KBr): n˜ =3387, 3051, 2962, 2928, 2872, 1661, 1593, 1563,
1508, 1467, 1436, 1410, 1388, 1371, 1348, 1294, 1224, 1195, 1153, 1110,
1094, 1060, 1015, 989, 926, 828, 776, 738, 623, 551 cmÀ1; HRMS (FAB+):
m/z calcd for C63H67N12O3 [M+H]+: 1039.5459; found: 1039.5436.
Data for receptor 16: Yield 65%. M.p. 1788C; 1H NMR (300 MHz,
CDCl3): d=8.45 (m, 9H; NHCO, CArH), 8.30 (d, J=8.3 Hz, 3H; CArH),
8.24 (d, J=8.1 Hz, 3H; CArH), 7.59 (m, 3H; CArH), 7.38 (m, 3H; CArH),
5.30–5.13 (m, 9H; CArCH2, CHCImi), 2.44 (s, 9H; CImiMe), 2.37 (s, 9H;
CArMe), 2.11–1.95 (m, 3H; CHMe2), 1.04 (d, J=6.7 Hz, 9H; CHMe2),
Chem. Eur. J. 2005, 11, 6718 – 6726
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6725

G. Haberhauer et al.
ual values R1(F)=0.068, wR(F2)=0.151 for observed reflections, residual
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2002, 124, 591; e) S.-G. Kim, K. H. Ahn, Chem. Eur. J. 2000, 6, 3399;
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1974, 13, 814.
À3
electron density À0.31 to 0.62 eŠ
.
For C48H57N9O3·disordered solvent (11) (crystallization from methanol);
Mr =808.03, colorless crystal (polyhedron), dimensions 0.22”0.06”
0.05 mm3, crystal system hexagonal, space group P63, Z=2, a=13.535(2),
b=13.535(2), c=14.845(4) Š, V=2355.3(8) Š3, 1calcd =1.139 gcmÀ3, T=
100(2) K, qmax =24.148, radiation MoKa, l=0.71073 Š, 0.38 omega scans
with CCD area detector, covering a whole sphere in reciprocal space,
17654 reflections measured, 2517 unique (R(int)=0.1251), 2210 observed
[I>2s(I)], intensities were corrected for Lorentz and polarization effects,
an empirical absorption correction was applied by using SADABS[18]
based on the Laue symmetry of the reciprocal space, m=0.07 mmÀ1, min/
max transmission=0.98/1.00, structure was solved by direct methods and
refined against F2 with a full-matrix least-squares algorithm by using the
SHELXTL-PLUS (5.10) software package,[19] 214 parameters refined, hy-
drogen atoms were treated by using appropriate riding models, except
for the amide hydrogen atom H9 at N9, which was refined isotropically,
Flack absolute structure parameter À1(4), goodness of fit 1.18 for ob-
[3] a) G. Hennrich, E. V. Anslyn, Chem. Eur. J. 2002, 8, 2218; b) for a
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[6] G. Haberhauer, Synlett 2004, 1003.
served reflections, final residual values R1(F)=0.087, wR(F2)=0.206 for
À3
observed reflections, residual electron density À0.49 to 0.46 eŠ
.
[7] G. Haberhauer, T. Oeser, F. Rominger, Chem. Commun. 2004, 2044.
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Lett. 1993, 34, 211.
For C90H102N24O6·2C6H6O3·disordered solvent (17); Mr =2832.09, color-
less crystal (polyhedron), dimensions 0.40”0.30”0.28 mm3, crystal
system hexagonal, space group P63, Z=2, a=15.119(2), b=15.119(2), c=
[9] a) J. R. Davies, P. D. Kane, C. J. Moody, Tetrahedron 2004, 60, 3967;
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[11] All computations were performed by using the Gaussian 03 pro-
gram-package: Gaussian 03, Revision C.02, M. J. Frisch, G. W.
Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman,
J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M.
Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi,
G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gom-
perts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Po-
melli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Sal-
vador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Dan-
iels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Ragha-
vachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford,
J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Ko-
maromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y.
Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson,
W. Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc.,
Wallingford, CT, 2004.
34.458(5) Š, V=6821.7(17) Š3, 1calcd =1.379 gcmÀ3, T=100(2) K, qmax
=
21.968, radiation MoKa, l=0.71073 Š, 0.38 omega scans with CCD area
detector, covering a whole sphere in reciprocal space, 40674 reflections
measured, 5530 unique (R(int)=0.0456), 5179 observed [I>2s(I)], inten-
sities were corrected for Lorentz and polarization effects, an empirical
absorption correction was applied by using SADABS[18] based on the
Laue symmetry of the reciprocal space, m=0.54 mmÀ1, min/max transmis-
sion=0.81/0.86, structure was solved by direct methods and refined
against F2 with
a full-matrix least-squares algorithm by using the
SHELXTL (6.12) software package,[19] 565 parameters refined, hydrogen
atoms were treated by using appropriate riding models, Flack absolute
structure parameter 0.27(14), goodness of fit 1.30 for observed reflec-
tions, final residual values R1(F)=0.100, wR(F2)=0.264 for observed re-
flections, residual electron density À0.45 to 0.93 eŠ
À3
.
CCDC 264694–264697 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Acknowledgements
This work was generously supported by the Deutsche Forschungsgemein-
schaft. The authors thank Dr. Andreea Schuster for helpful discussions.
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Received: February 27, 2005
Published online: August 30, 2005
6726
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6718 – 6726