Synthesis and structural investigation of C4- and C 2-symmetric molecular scaffolds based on imidazole peptides

Article abstract of DOI:10.1002/ejoc.200600942

The syntheses of a C₄- and a C₂-symmetric scaffold are presented. The first is composed of four imidazole units, while the second contains two imidazole and two oxazole moieties. The synthesis of the key building block for both syste

Full text of DOI:10.1002/ejoc.200600942

FULL PAPER
DOI: 10.1002/ejoc.200600942
Synthesis and Structural Investigation of C4- and C2-Symmetric Molecular
Scaffolds Based on Imidazole Peptides
Gebhard Haberhauer,*[a] Áron Pintér,[a] Thomas Oeser,[b] and Frank Rominger[b]
Dedicated to Professor Rolf Gleiter on the occasion of his 70th birthday
Keywords: Amino acids / Cyclization / Imidazoles / Macrocycles / Molecular modelling
The syntheses of a C4- and a C2-symmetric scaffold are pre- square, whereas in the second case (type II), they form a par-
sented. The first is composed of four imidazole units, while
the second contains two imidazole and two oxazole moieties.
The synthesis of the key building block for both systems has
been fundamentally improved. Starting from these scaffolds,
various platforms possessing two or four arms can easily be
prepared. The structures of the scaffolds, together with that
of a C4-symmetric oxazole scaffold, were investigated in the
solid state and in the gas phase. We found that these 24-
membered cyclic peptides exist as two different structure
types. In one case (type I), the nitrogen atoms of the azole
units pointing into the interior of the macrocycle form a
allelogram. The type of molecular structure does not depend
on the symmetry of the system, but on the type of azole used.
Cyclic systems composed of four imidazole units are present
in the type I structure, whereas systems consisting of four ox-
azole units exhibit the type II nature. Structure type II is also
present in cycles composed of two oxazole units and two
imidazole units. The existence of the different structure types
can be explained in terms of the different orbital energies of
the imidazole and oxazole systems.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
generally synthesized stepwise from three subunits that al-
During the last few years, an emerging number of molec- ready carry their recognition sites,[3] so modification of the
ular platforms consisting of several arms fixed on a rigid recognition sites is only possible through transformation of
platform have been reported.[1] These arms can be used as, these functional groups, which is not always easy to achieve.
for example, recognition sites of a receptor.[2] For smaller
Recently, we were able to synthesize the C3-symmetric
systems – such as the benzene ring – a concept allowing the scaffold 2, on which we can attach a large variety of
synthesis of numerous receptors by making simple modifi- arms.[4,5] The scaffold consists of three imidazole units
cations has been developed. Larger platforms, though, are linked through trans amide bonds, making the macrocycle
Scheme 1. Synthesis of the C3-symmetric molecular scaffold 2.
[a] Institut für Organische Chemie, Fachbereich Chemie, Uni-
rigid. A variety of arms can be attached to the scaffold 2
by treatment of the secondary nitrogen atoms of the imid-
azole units with alkyl halides (Scheme 1). By this method
we were able to synthesize platform species 3, which act as
versität Duisburg-Essen,
Universitätsstraße 5, 45117 Essen, Germany
E-mail: gebhard.haberhauer@uni-due.de
[b] Organisch-Chemisches Institut, Universität Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
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FULL PAPER
Figure 1. Structures of C4- and C2-symmetric molecular scaffolds.
receptors for hydroxybenzenes[4] that can further be used from the imidazole building block 7a in at least 10%
for predetermining configurations at metal centres or nitro- yield,[8] however, the cyclization of 7b under the same reac-
gen atoms.[6]
tion conditions afforded only traces of the cycle 10, the pre-
Our intention was to apply this concept – a rigid scaffold dominant product being the trimer 1. The cyclization yields
to which various arms can be attached – not only to C3- in these systems thus strongly depend on the substituents R
symmetric systems, but to extend it to the synthesis of plat- used.
forms with four or as few as two arms.[7]
We therefore decided to apply a stepwise method. The
Here we describe the syntheses of the C4-symmetric scaf- starting material was the doubly protected benzyl-substi-
fold 4 and of the C2-symmetric scaffold 5 and show that tuted imidazole 12, obtainable from the imidazole 11 by
four and two arms, respectively, can be introduced by sim- alkylation with benzyl bromide in the presence of K2CO3
ple alkylation of the imidazole units (Figure 1). In addition, in acetonitrile (Scheme 3). Because of the presence of a tau-
we investigate the structural properties of these 24-mem- tomeric form of 11, not only the desired product 12 was
bered systems and compare them with the structure of the formed (32% yield), but also the undesired alkylation prod-
C4-symmetric oxazole platform 6, which was also synthe- uct 13 in a yield of 51%.[4] Since compound 12 is a building
sized.
block of utmost importance, we examined different meth-
ods for optimizing the ratio in favour of the desired isomer
12. Indeed, the yield of 12 could be enhanced from 32 to
72% by carrying out the alkylation in DMF at 0 °C in the
presence of NaH as base. The benzyl-substituted imidazole
12 can easily be deprotected to give two singly protected
Results and Discussion
Synthesis
The most efficient synthetic route to the molecular scaf- building blocks 14 and 15.
fold 2 is by synthesizing a platform with three benzylic arms
From these building blocks (14 and 15), we succeeded
and removing these arms by hydrogenolysis (Scheme 1).[4] in preparing the platform 10 (Scheme 4): The two building
This method not only provides the highest yields of 2 but blocks 14 and 15 were coupled with pentafluorophenyl di-
also affords the purest product. For this reason, we also set phenylphosphinate (FDPP)[9] to provide the dimer 16, and
out to apply this method to the preparation of the C4- and deprotection of the carboxyl residue by saponification af-
C2-symmetric systems. Thus, the simplest way to synthesize forded the acid 17. Subsequent removal of the Boc group
the C4-symmetric cyclic peptide 10 appeared to be a cyclo- provided the free amino acid 18, which was subjected to a
tetramerization of the corresponding imidazole building cyclodimerization with FDPP to give the tetramer 10 in
block 7b (Scheme 2). While the tetramer 9 had been formed yields as good as 65%. The removal of the benzyl groups
Scheme 2. i) FDPP, iPr2NEt, CH3CN, room temp.
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C4- and C2-Symmetric Molecular Scaffolds Based on Imidazole Peptides
FULL PAPER
Scheme 3. i) BnBr, K2CO3, CH3CN, ∆, 32% for 12, 51% for 13. ii) BnBr, NaH, DMF, 0 °C, 72% for 12, Ͻ 5% for 13. iii) 2  NaOH,
MeOH/dioxane, 95%. iv) TFA, DCM, quant.
Scheme 4. Synthesis of scaffold 4: i) FDPP, iPr2NEt, CH3CN, room temp., 78%. ii) 2  NaOH, MeOH/dioxane, 95%. iii) TFA, DCM,
quant. iv) FDPP, iPr2NEt, CH3CN, room temp., 65%. v) H2, Pd(OH)2, MeOH/DCM, 97%.
with palladium hydroxide yielded the desired C4-symmetric 19 afforded the dimer 20, which could be deprotected in
scaffold. Since this route requires only a few reaction steps two steps to give the free amino acid 22. The dimerization
and the yields are relatively high, the scaffold 4 is available of 22 gave the cyclic peptide 23, also in good yields, whilst
in quite large quantities.
in a final step the two benzyl arms were removed to yield
A similar concept was applied to the preparation of the the C2-symmetric scaffold 5.
scaffold 5, the successful synthesis of which is shown in
In the next step, different arms could be attached to the
Scheme 5. Coupling of the imidazole 14 with the oxazole successfully prepared scaffolds 4 and 5 through simple alky-
Scheme 5. Synthesis of scaffold 5: i) FDPP, iPr2NEt, CH3CN, room temp., 87%. ii) 2  NaOH, MeOH/dioxane, 98%. iii) TFA, DCM,
quant. iv) FDPP, iPr2NEt, CH3CN, room temp., 55%. v) H2, Pd(OH)2, MeOH/DCM, 95%.
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FULL PAPER
Scheme 6. i) RX, K2CO3, CH3CN, ∆. ii) RX, NaH, DMF, 0 °C Ǟ room temp. iii) TFA, DCM, quant. iv) DMC, aniline, Et3N, DCM,
0 °C Ǟ room temp., 44%.
Scheme 7. i) RX, K2CO3, CH3CN, ∆. ii) RX, NaH, DMF, 0 °C Ǟ room temp. iii) TFA, DCM, quant. iv) DMC, 3-aminopyridine, Et3N,
DCM, 0 °C Ǟ room temp., 87%.
lation reactions, and the platforms 9,[8a] 10 and 24 on the advantage that the arms can be modified further, such as
one hand and platforms 23, 27[8a] and 28 on the other were by conversion into the amides. Astonishingly, though, nu-
synthesized by this route (see Schemes 6 and 7). The best merous conventional coupling agents failed in the conver-
reaction mode proved to be the use of the alkyl halide to- sions of 25 to 26 and 29 to 30: the use of, for example,
gether with K2CO3 as base in acetonitrile under reflux. diphenylphosphoryl azide (DPPA),[10] FDPP, 1-[3-(di-
Lower yields were obtained when NaH was used at 0 °C in methylamino)propyl]-3-ethylcarbodiimide
hydrochloride
DMF. From the tetraester 24 and from the diester 28, the (EDCI)[11] or [(benzotriazol-1-yl)oxy]tripyrrolidinophos-
corresponding acids 25 and 29 could be obtained in quanti- phonium hexafluorophosphate (PyBOP)[12] afforded only
tative yields by treatment of the esters with trifluoroacetic traces of the desired compounds, with large amounts of
acid (TFA). The thus-formed acid functionalities have the nonisolable by-products being formed instead. The best
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C4- and C2-Symmetric Molecular Scaffolds Based on Imidazole Peptides
FULL PAPER
Scheme 8. Synthesis of cyclopeptide 6. i) FDPP, iPr2NEt, CH3CN, room temp., 74%. ii) 2  NaOH, MeOH/dioxane, 95%. iii) TFA,
DCM, quant. iv) FDPP, iPr2NEt, CH3CN, room temp., 72%.
coupling agent proved to be 2-chloro-1,3-dimethylimid-
The NMR spectra of the cyclic peptides 5, 23 and 28–30
azolinium chloride (DMC),[13] the use of which gave the are all consistent with C2-symmetrical structures in solu-
3
amides 26 and 30 in yields of 44% and 87%, respectively.
tion. The vicinal JHNCH values of 8.6 and 10.2 Hz for 23
The synthesis of the C4-symmetric cyclic peptide 6, which correspond to dihedral angles of 150° Ͻ |θ| Ͻ 180° in the
contains four oxazole units, is shown in Scheme 8. The two macrocycle.
building blocks 31 and 19 were coupled with pentafluo-
rophenyl diphenylphosphinate (FDPP) to give the dimer 32,
In the Solid State
We were able to obtain X-ray structures of the 24-mem-
bered cyclic peptides 6, 10 and 30. Figure 2 shows the mo-
lecular structures of 6 and 10, together with that of 27.[8a]
Comparison of the structural data for the four compounds
shows that two structural types are present: type I is repre-
sented by the C4-symmetric tetramer 10 and type II by the
C2-symmetric peptides 27 and 30. Surprisingly, the C4-sym-
metric tetramer 6 also exists as the structural type II. In
structural type I, the nitrogen atoms of the imidazole rings
pointing into the interior of the macrocycle form the cor-
and deprotection of the carboxyl residue by saponification
afforded the acid 33. Subsequent removal of the Boc group
provided the free amino acid 34, which was subjected to a
cyclodimerization with FDPP to give the tetramer 6 in
yields as good as 72%.
Structural Investigations
In Solution
The NMR spectra (1H, 13C) of the cyclic peptides 4, 6, ners of a square with edge lengths of approximately 5.3 Å
10 and 24–26 indicate that they are C4-symmetric in solu- (distance a in Table 1). The diagonal distance in this square
tion. The vicinal 3JHNCH values, of 9.7 and 9.4 Hz for 6 and amounts to 7.5 Å. The imidazole rings do not form a single
10, respectively, correspond to dihedral angles of 155° Ͻ |θ| plane but adopt a cone-like structure. Their deviation from
Ͻ 165° in both macrocycles.[14]
a coplanar structure, defined as the average angle between
Figure 2. Molecular structures of 10, 27 and 6: top view (upper row) and side view (lower row); all hydrogen atoms and all solvent
molecules have been omitted for clarity.
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G. Haberhauer, Á. Pintér, T. Oeser, F. Rominger
Distance a [Å]
FULL PAPER
Table 1. Measured (X-ray) dihedral angles and distances in 6, 10 and 27.[8a]
Structure
Dihedral angle [°]
χ [Namide–Cα–Cazole–Nimi
φ [H–Namide–Cα–Hα]
]
χ [Namide–Cα–Cazole–Ooxa
]
neighbouring Nazole–Nazole
10
27
6
type I
–152
–155
–162
–155
104.6
106.7
105.8
102.9
5.285
5.258
5.299
5.254
type IIa
type II
166
167
164
172
84.7
79.5
4.602
5.446
4.592
5.427
188.0
181.5
168
158
168
158
79.4
187.6
79.4
4.586
5.446
4.586
5.446
187.6
the imidazole ring planes and the plane of the macrocycle, on the azole rings forming the obtuse angle of the parallelo-
is 58°. All dihedral angles χ [Namide–Cα–Cazole–Nimi] are gram are in pseudoaxial orientations, whereas the -valine
approximately 100° (definition for the used abbreviations side chains on the azole rings forming the acute angle are
see Figure 3). The -valine side chains are in pseudoaxial arranged rather pseudoequatorially. The dihedral angles φ
orientation and are all directed from the same face of the [H–Namide–Cα–Hα], however, are quite similar in all azole
macrocycle.
systems. The most striking difference is the dihedral angle
χ: in the case of the azole rings forming the obtuse angle of
the parallelogram this angle amounts to 80°, whereas in
case of the azole rings forming the acute angle it is more
than 180°.
Gas-Phase Calculations
For determination of the structures of the 24-membered
oxazole- and imidazole-based cyclic peptides in the gas
phase, compounds 35–37 were investigated (Figure 4).
These advantageously have only methyl groups as side
chains, so rotation around the Cα–Cβ axis does not have to
be taken into consideration, the number of possible con-
Figure 3. Definition of the abbreviations used.
In the structure type II as present in the solid-phase formers thus being reduced. To determine the preferred
structures of 6, 27 and 30, in contrast, the nitrogen atoms conformations of the cycles 35–37, we performed full geom-
of the azoles pointing into the macrocycle form a parallelo- etry optimization by applying the HF and the DFT-B3LYP
gram with edge lengths of 4.6 and 5.4 Å (distance a in method.[15,16] As basis sets, we used the 3-21G* and the 6-
Table 1) and acute angles of approximately 78° in 27 and 31G* basis set for the HF and the 6-31G* and the 6-31G**
82° in 6. The distances between the nitrogen atoms of oppo- basis set for the DFT-B3LYP procedure.[17,18] Figure 5
site azoles differ markedly and amount to 6.3 and 7.8 Å for shows the lowest-energy structures of the conformers of 35–
27 and 6.6 and 7.6 Å for 6. In the macrocycles 27 and 30 37.
the oxazoles are positioned at the corners with acute angles
The calculations also afforded only two structural types;
and the imidazoles are positioned at the corners with ob- these two structure types are identical with those already
tuse angles of the parallelogram. The -valine side chains found in the solid state (for data see also Table 2). We fur-
Figure 4. Structures of the cyclic peptides investigated by gas-phase calculations.
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C4- and C2-Symmetric Molecular Scaffolds Based on Imidazole Peptides
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Figure 5. Molecular structures of the energetically preferred conformers of 35 (type I), 36 (type IIa) and 37 (type II) calculated with
B3LYP/6-31G**: top views (upper row) and side views (lower row); all hydrogen atoms have been omitted for clarity.
ther found that the energetically lowest conformation of the which is in perfect correlation with the fact that only struc-
imidazole tetramer is of type I, which correlates with the ture types IIa were found for compounds 27 and 30 in the
findings in the solid state. For the imidazole tetramer, solid phase. In the case of the tetrameric oxazole 37, only
type II is of much higher energy, independently of the structure type II was found as a minimum on the potential
method and the basis set used (see Table 3). In the case of energy hypersurface, which also correlates with the crystal
36, which is the cycle containing two oxazole and two imid- structure data for 6.
azole units, only two structures of type II were found, the
type I structure of 36 not being a minimum on the potential
Explanation
energy hypersurface. Of the two minimum structures of
In order to find an explanation for this behaviour, we
type II, structure type IIb, in which the oxazoles are posi- took a closer look at those structural parameters that pro-
tioned at the corners forming the obtuse angle of the paral- duce the most striking difference between the two structure
lelogram, is of much higher energy than structure type IIa, types: namely the dihedral angles χ. In structure type I,
Table 2. Calculated (B3LYP/6-31G**) dihedral angles and distances in 35, 36 and 37.
Structure
Dihedral angle [°]
χ [Namide–Cα–Cazole–Nimi
Distance a [Å]
neighbouring Nazole–Nazole
φ [H–Namide–Cα–Hα]
]
χ [Namide–Cα–Cazole–Ooxa
]
35
35
36
36
37
type I
–158.6
–158.6
–158.6
–158.6
101.9
101.9
101.9
101.9
5.290
5.290
5.290
5.290
type II
type IIa
type IIb
type II
–161.0
146.5
–161.0
146.5
93.1
164.3
93.1
4.590
5.510
4.600
5.510
164.3
–168.1
139.5
–168.1
139.5
89.4
89.4
4.560
5.460
4.560
5.460
178.8
178.8
90.0
–171.3
144.9
–171.3
144.9
4.560
5.480
4.560
5.480
166.9
166.9
90.0
179.5
142.1
179.5
142.2
86.3
182.3
86.3
4.570
5.460
4.570
5.460
182.3
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G. Haberhauer, Á. Pintér, T. Oeser, F. Rominger
Table 3. Calculated energy differences (∆E1), estimated strain energies (E2) and strain energy differences (∆E2).
FULL PAPER
[a]
[b]
[c]
Structure
∆E1 [kJmol–1]
E2 [kJmol–1]
∆E2 [kJmol–1]
HF
B3LYP
B3LYP
6-31G**
B3LYP
6-31G**
3-21G*
6-31G* 6-31G*
6-31G**
35
36
type I
type II
0.0
25.2
0.0
12.6
0.0
18.5
0.0
19.1
1.8
19.0
0.0
17.2
[d]
[d]
[d]
[d]
type I
type IIa
type IIb
–
–
–
–
11.5
0.2
30.0
11.3
0.0
29.8
0.0
46.6
0.0
23.0
0.0
27.1
0.0
28.0
[d]
[d]
[d]
[d]
37
type I
type II
–
–
–
–
21.2
10.2
11.0
0.0
0.0
0.0
0.0
0.0
[a] Relative energy relative to the lowest-energy conformer. [b] Estimated strain energy caused by the deviation from the optimum dihedral
angle with the following assumptions: type I: χ = 100°; type II: χ = 90 and 180°. [c] Relative strain energy relative to the lowest-energy
conformer. [d] No minimum found.
these angles are around 100° for all azole rings, whereas in systems 38 and 39:[15,19] in the imidazole system, the
structure type II they amount to approximately 90° in two π(Cazole–Nazole
) orbital is energetically much higher
of the azole rings and to 180° in the other two. We chose (–0.29908 au at χ = 90°) than in the corresponding oxazole
the two model systems 38 and 39 (Figure 6), in which we (–0.33246 au at χ = 90°). Accordingly, the interaction of
modified the dihedral angle χ stepwise and simultaneously this π-bond with the σ*(Cα–Namide) orbital is much stronger
optimized all the other structural parameters. The obtained than in the oxazole. The optimum interaction between these
energy profiles of the reference compounds 38 and 39 in two orbitals is at an angle of 90°, the σ*(Cα–Namide) orbital
relation to the dihedral angle χ are shown in Figure 7.
then being parallel to the π(Cazole–Nazole
)
orbital
(18.5 kJmol–1 for the imidazole vs. 16.4 kJmol–1 for the ox-
azole at χ = 90°). In contrast, the π*(Cazole–Nazole) orbital
in the oxazole is of lower energy (–0.00352 au at χ = 180°)
than in the imidazole (+0.00875 au at χ = 180°), so the in-
teractions with the higher-energy σ(Cα–Cβ) and σ(Cα–Hα)
orbitals are accordingly of more importance than in the
imidazole. The optimum interaction between these two or-
bitals with the π*(Cazole–Nazole) orbital takes place at an
angle of 180° (25.1 kJmol–1 for the imidazole vs.
30.3 kJmol–1 for the oxazole at χ = 180°).
Figure 6. Reference systems 38 and 39 for the determination of the
energy profiles in relation to the dihedral angles χ [Namide–Cα–
Cazole–Nimi] and χ [Namide–Cα–Cazole–Ooxa], respectively.
That this angle is indeed the decisive parameter for the
presence of the distinct structure types can be substantiated
as follows: an estimated strain energy (E2) is defined to be
the energy caused by the deviation from the optimum dihe-
dral angle in the cycle at each of the four azole units under
the assumption that in type I the angle is 100° for all of the
azoles, whilst in type II it amounts to 90° in two of the azole
units, but to 180° in the other two (see Table 3). In view,
then, of the relative strain energies in relation to the ener-
getically favoured conformer (∆E2 in Table 3), it can be seen
that this corresponds almost perfectly to the calculated en-
ergy differences (∆E1) at the same level of theory (B3LYP/
6-31G**) and thus explains very well why the specific struc-
ture types were found in the specific molecules.
Conclusions
Figure 7. Calculated energy profiles in relation to the dihedral
angles by use of B3LYP/6-31G**.
We have been able to show that C4- and C2-symmetric
scaffolds can both be obtained in good yields. The synthesis
Both reference systems show two minima in the region of the key building block required for their preparation has
of 20 to 200°, imidazole 38 having the lowest minimum at been significantly improved. Starting from these scaffolds,
90° and oxazole 39 at about 180°. The reason for this differ- various platforms with four or two arms can easily be pre-
ence can be explained by NBO analysis of the reference pared. Furthermore, we were able to show that 24-mem-
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General Procedure for the Cleavage of the Benzyl Group: The Bn-
protected compound (1 equiv.) was dissolved in MeOH (20 mL/
mmol starting material) at room temperature. Pd(OH)2 (50 mg/
mmol starting material) was added and the solution was stirred
under H2 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.
bered cycles composed of oxazoles and imidazoles are pres-
ent in the forms of two different structure types. The type
of molecular structure does not depend on the symmetry of
the system, but on the type of azole used, the reason for
this being the different energy profiles of oxazoles and imid-
azoles for the rotation around the dihedral angle χ. It can
be generalized that structure type I will predominate in sys-
tems containing four azole units with high-energy π-orbit-
als, whereas in systems having four azole units with low-
energy π*-orbitals, this will be the case for structure type II.
If a C2-symmetric system is composed both of azoles pos-
sessing high-energy π-orbitals and azoles possessing low-
energy π*-orbitals, structure type IIa will predominate, with
the azoles with high-energy π-orbitals being arranged at the
corners of the parallelogram with obtuse angles.
N-Boc-benzylimidazole Methyl Esters 12 and 13: NaH (60wt-%,
0.51 g, 12.9 mmol) and BnBr (1.70 mL, 13.9 mmol) were added at
0 °C to a solution of 11 (3.33 g, 10.7 mmol) in DMF (100 mL).
The mixture was stirred at that temperature for 2 h and at room
temperature overnight. The mixture was poured into water
(700 mL) and the precipitated white solid was washed several times
with water. The crude product was dissolved in DCM, extracted
with water and brine, dried with MgSO4 and concentrated in vacuo.
Purification was accomplished by chromatography on silica gel (pe-
troleum ether/ethyl acetate 3:1 to 1:1) to yield 13 (3.08 g, 72%) and
12 (0.22 g, 5%) as white solids.
In further studies we will investigate the use of these C4-
and a C2-symmetric platforms as receptors and for the pre-
determination of configurations at C4- and C2-symmetric
centres.
Aminoimidazole Methyl Ester (TFA Salt) 15: Compound 12 (2.01 g,
5.00 mmol) was converted into 15 as described above in the Gene-
ral Procedure for the cleavage of the Boc group. Yield: quantitative;
m.p. 48 °C. 1H NMR (300 MHz, CDCl3): δ = 10.40 (br. s, 3 H),
7.42–7.35 (m, 3 H), 7.13–7.04 (m, 2 H), 5.59–5.31 (m, 2 H), 4.53
(m, 1 H), 3.94 (s, 3 H), 2.63 (s, 3 H), 2.57–2.46 (m, 1 H), 1.06 (d,
Experimental Section
3
3JH,H = 5.26 Hz, 3 H), 0.33 (d, JH,H = 6.14 Hz, 3 H) ppm. 13C
General Remarks: Imidazole 11 and oxazoles 19 and 31 were pre-
pared according to reported procedures.[8] All chemicals were of
reagent grade and used as purchased. All moisture-sensitive reac-
tions were performed under argon in distilled dry solvents. Reac-
tions were monitored by TLC analysis with silica gel 60 F254 thin-
layer plates. Flash chromatography was carried out on silica gel 60
(230–400 mesh). Melting points were determined in capillary tubes
and are uncorrected. 1H and 13C NMR spectra were measured with
Bruker WH 300, Avance 300, and Avance 500 instruments. All
chemical shifts (δ) are given in ppm relative to TMS. The spectra
were referenced to deuteriated solvents indicated in brackets in the
analytical data. HRMS data were recorded with a JEOL JMS-700
instrument. IR spectra were measured with a Bruker Vector 22 FT-
IR spectrometer. Elemental microanalyses were performed in the
microanalytical laboratory of the University of Heidelberg.
NMR (75 MHz, CDCl3): δ = 159.65, 144.06, 137.81, 132.77,
129.56, 129.22, 126.38, 123.85, 52.63, 51.70, 48.67, 31.62, 18.81,
18.29, 9.95 ppm. IR (KBr): ν = 3587, 3567, 3419, 3400, 3035, 2969,
˜
2931, 1716, 1679, 1635, 1558, 1517, 1507, 1499, 1457, 1440, 1394,
1354, 1204, 722 cm–1. FAB-HRMS: calcd. for C17H24N3O2 [M +
H]+ 302.1856; found 302.1867.
N-Boc-imidazole–imidazole Methyl Ester 16: iPr2NEt (4.40 mL,
25.0 mmol) and FDPP (1.54 g, 4.00 mmol) were added at room
temperature to acid 14 (1.39 g, 3.60 mmol) and ammonium salt 15
(1.66 g, 4.00 mmol) in acetonitrile (80 mL) and the mixture was
stirred at room temperature for 2 d. The solvent was removed by
evaporation and the residue was dissolved in AcOEt and then ex-
tracted with water and brine, dried with MgSO4 and concentrated
in vacuo. Flash chromatography on silica gel (petroleum ether/ethyl
1
acetate, 1:1) gave 16 (1.88 g, 78%) as a white solid; m.p. 80 °C. H
Abbreviations: Bn: benzyl; Boc: tert-butoxycarbonyl; FDPP: penta-
fluorophenyl diphenylphosphinate; DCM: dichloromethane;
DMC: 2-chloro-1,3-dimethylimidazolinium chloride; DMF: N,N-
dimethylformamide; TFA: trifluoroacetic acid.
3
NMR (500 MHz, [D6]acetone): δ = 7.51 (d, JH,H = 9.83 Hz, 1 H),
3
3
7.38–7.02 (m, 10 H), 6.35 (d, JH,H = 9.40 Hz, 1 H), 5.55 (d, JH,H
3
= 17.10 Hz, 1 H), 5.37–5.28 (m, 3 H), 4.98 (t, JH,H = 9.40 Hz, 1
H), 4.51 (t, 3JH,H = 8.98 Hz, 1 H), 3.80 (s, 3 H), 2.47 (s, 3 H), 2.45–
2.40 (m, 1 H), 2.39 (s, 3 H), 2.29–2.22 (m, 1 H), 1.32 (s, 9 H), 0.97
General Procedure for the Cleavage of the Methyl Ester Group: The
protected compound (1 equiv.) was dissolved in methanol/dioxane
(10:7, 0.08 ), and this was followed by the slow addition of an
NaOH solution (2 , 10 equiv.) at 0 °C. Stirring was continued un-
til TLC showed the consumption of all starting material, after
which brine, HCl solution (1 ) and DCM were added. The aque-
ous phase was repeatedly extracted with DCM, and the organic
layers were combined, dried with MgSO4 and concentrated in
vacuo to give the acid compound, which was used in the next step
without further purification.
3
3
(d, JH,H = 6.84 Hz, 3 H), 0.95 (d, JH,H = 6.41 Hz, 3 H), 0.71 (d,
3JH,H = 6.84 Hz, 6 H) ppm. 13C NMR (125 MHz, [D6]acetone): δ
= 165.83, 164.59, 157.46, 150.35, 149.19, 138.73, 138.67, 137.94,
134.05, 131.28, 130.55, 130.51, 129.68, 129.33, 129.22, 128.27,
128.10, 80.04, 54.02, 51.99, 51.25, 48.22, 48.10, 33.78, 33.52, 29.49,
21.43, 21.25, 20.21, 19.87, 11.40, 10.93 ppm. IR (KBr): ν = 3400,
˜
2964, 2933, 2873, 1707, 1654, 1592, 1498, 1469, 1455, 1436, 1391,
1366, 1345, 1307, 1221, 1170, 1085, 730, 696, 582 cm–1. FAB-
HRMS: calcd. for C38H51N6O5 [M + H]+ 671.3921; found
671.3889. C38H50N6O5·MeOH (702.88): calcd. C 66.64, H 7.74, N
11.96; found C 66.77, H 7.66, N 11.83.
General Procedure for the Cleavage of the Boc Group: The Boc-
protected compound (1 equiv.) was dissolved in DCM (20 ml/mmol
starting material) and the solution was cooled to 0 °C. TFA
(1.5 mL/10 mL DCM) was added at that temperature. The ice bath
was removed after 30 min and stirring was continued at room tem-
perature for 3 h. The mixture was concentrated in vacuo to provide
a quantitative yield of the TFA salt, which was used in the next
step without further purification.
N-Boc-imidazole–imidazolecarboxylic Acid 17: Compound 16
(2.01 g, 3.00 mmol) was converted into 17 as described above in the
General Procedure for the cleavage of the methyl ester group. Yield:
1
1.87 g (95%); m.p. 114 °C. H NMR (300 MHz, [D6]DMSO): δ =
3
7.71 (d, JH,H = 7.89 Hz, 1 H), 7.39–7.18 (m, 6 H), 7.11–6.95 (m,
3
4 H), 5.42 (m, 2 H), 5.29 (m, 2 H), 4.94 (t, JH,H = 9.32 Hz, 1 H),
Eur. J. Org. Chem. 2007, 1779–1792
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1787

G. Haberhauer, Á. Pintér, T. Oeser, F. Rominger
FULL PAPER
4.38 (t, JH,H = 9.21 Hz, 1 H), 2.38 (s, 3 H), 2.35–2.16 (m, 2 H),
3
tracted with water and brine, dried with MgSO4 and concentrated
2.28 (s, 3 H), 1.27 (s, 9 H), 0.94–0.85 (m, 6 H), 0.66–0.59 (m, 6 H) in vacuo. Flash chromatography on silica gel (petroleum ether/ethyl
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 163.80, 162.24, 155.39,
147.90, 147.22, 136.42, 135.98, 135.73, 132.44, 128.64, 128.58,
acetate, 1:1) gave 20 (604 mg, 87%) as a white solid; m.p. 64 °C.
1H NMR (500 MHz, [D6]acetone): δ = 7.73 (br. s, 1 H), 7.38–7.25
128.17, 127.45, 127.37, 126.15, 77.97, 52.13, 49.14, 46.46, 46.05, (m, 3 H), 7.13–7.04 (m, 2 H), 6.35 (br. s, 1 H), 5.37 (m, 2 H), 5.10
31.40, 31.02, 28.01, 19.71, 19.50, 18.73, 9.97, 9.50 ppm. IR (KBr):
(m, 1 H), 4.55 (m, 1 H), 3.83 (s, 3 H), 2.60 (s, 3 H), 2.43 (s, 3 H),
2.35–2.26 (m, 1 H), 1.33 (s, 9 H), 1.01 (d, JH,H = 6.84 Hz, 3 H),
3
ν = 3437, 3415, 3399, 2969, 2931, 2873, 1706, 1655, 1591, 1500,
˜
1467, 1455, 1427, 1391, 1366, 1331, 1308, 1230, 1171, 731 cm–1.
FAB-HRMS: calcd. for C37H49N6O5 [M + H]+ 657.3764; found
657.3769.
0.98 (d, 3JH,H = 6.84 Hz, 3 H), 0.95 (d, 3JH,H = 6.41 Hz, 3 H), 0.76
(d, 3JH,H = 6.41 Hz, 3 H) ppm. 13C NMR (125 MHz, [D6]acetone):
δ = 164.73, 164.13, 163.77, 157.89, 157.47, 149.21, 138.67, 134.49,
131.29, 130.58, 129.34, 129.12, 128.20, 80.11, 54.05, 53.40, 52.75,
48.17, 34.09, 33.69, 29.47, 21.34, 20.34, 19.91, 19.65, 13.02,
Aminoimidazole–imidazolecarboxylic Acid (TFA Salt) 18: Com-
pound 17 (1.97 g, 3.00 mmol) was converted into 18 as described
above in the General Procedure for the cleavage of the Boc group.
Yield: quantitative; m.p. 148 °C. 1H NMR (300 MHz, [D4]meth-
anol): δ = 7.33–7.17 (m, 6 H), 7.09–6.94 (m, 4 H), 5.53–5.39 (m, 2
10.89 ppm. IR (film): ν = 3400, 2966, 2872, 1708, 1663, 1620, 1590,
˜
1498, 1444, 1389, 1365, 1351, 1307, 1246, 1173, 1098, 1014, 810,
785, 730 cm–1. FAB-HRMS: calcd. for C31H44N5O6 [M + H]+
582.3292; found 582.3264. C31H43N5O6·MeOH (613.74): C 62.62,
H 7.72, N 11.41; found C 62.66, H 7.40, N 11.45.
3
H), 5.28–5.17 (m, 2 H), 4.97 (d, JH,H = 9.70 Hz, 1 H), 4.25 (d,
3JH,H = 6.69 Hz, 1 H), 2.43 (s, 3 H), 2.38–2.31 (m, 1 H), 2.35 (s, 3
3
H), 2.19–2.10 (m, 1 H), 0.94 (d, JH,H = 6.61 Hz, 3 H), 0.91 (d,
N-Boc-imidazole–oxazolecarboxylic Acid 21: Compound 20
(582 mg, 1.00 mmol) was converted into 21 as described above in
the General Procedure for the cleavage of the methyl ester group.
Yield: 570 mg (98%); m.p. 201 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 7.77 (br. s, 1 H), 7.38–7.22 (m, 3 H), 7.06–6.95 (m, 2
3
3JH,H = 6.78 Hz, 3 H), 0.76 (d, JH,H = 6.86 Hz, 3 H), 0.55 (d,
3JH,H = 6.61 Hz, 3 H) ppm. 13C NMR (75 MHz, [D4]methanol): δ
= 165.06, 164.35, 164.11, 150.09, 144.18, 137.92, 136.98, 136.65,
136.55, 136.27, 130.99, 130.24, 130.18, 129.30, 129.23, 127.65,
127.31, 53.54, 51.78, 47.95, 33.30, 19.92, 19.52, 19.02, 17.82, 10.38,
3
H), 5.26 (m, 2 H), 4.94 (m, 1 H), 4.36 (t, JH,H = 9.21 Hz, 1 H),
10.09 ppm. IR (KBr): ν = 3446, 2970, 1674, 1593, 1509, 1500, 1203,
˜
2.49 (s, 3 H), 2.30 (s, 3 H), 2.27–2.11 (m, 2 H), 1.26 (s, 9 H), 0.93–
1138, 722 cm–1. FAB-HRMS: calcd. for C32H41N6O3 [M + H]+
557.3240; found 557.3217.
3
3
0.81 (m, 6 H), 0.74 (d, JH,H = 6.36 Hz, 3 H), 0.63 (d, JH,H
=
6.36 Hz, 3 H) ppm. 13C NMR (300 MHz, [D6]DMSO): δ = 165.12,
162.68, 160.09, 155.39, 147.04, 136.52, 132.38, 128.69, 128.58,
127.32, 126.10, 77.89, 52.13, 51.25, 45.92, 31.81, 31.76, 30.84,
Cyclic Peptide 10: iPr2NEt (2.40 mL, 13.5 mmol) and FDPP
(1.53 g, 3.98 mmol) were added at room temperature to a suspen-
sion of 18 (1.41 g, 2.10 mmol) in acetonitrile (200 mL) and the mix-
ture was stirred at room temperature for 2 d. The solvent was re-
moved by evaporation and the residue was dissolved in AcOEt and
then extracted with water and brine, dried with MgSO4 and con-
centrated in vacuo. Flash chromatography on silica gel (petroleum
ether/ethyl acetate, 1:2) gave 10 (735 mg, 65%) as a white solid;
27.99, 19.82, 18.80, 18.73, 18.30, 11.03, 9.43 ppm. IR (KBr): ν =
˜
3400, 2965, 2931, 2874, 1710, 1653, 1593, 1498, 1455, 1426, 1392,
1367, 1327, 1307, 1251, 1227, 1171, 1111, 729, 696, 582 cm–1. ESI-
HRMS: calcd. for C30H40N5O6 [M – H]– 566.2979; found 566.2980.
Aminoimidazole–oxazolecarboxylic Acid (TFA Salt) 22: Compound
21 (454 mg, 0.80 mmol) was converted into 22 as described above
in the General Procedure for the cleavage of the Boc group. Yield:
quantitative; m.p. 97 °C. 1H NMR (300 MHz, [D6]DMSO): δ =
1
3
m.p. Ͼ250 °C. H NMR (500 MHz, CDCl3): δ = 7.54 (d, JH,H
=
9.37 Hz, 4 H), 7.31–7.23 (m, 12 H), 7.11–7.08 (m, 8 H), 5.81 (d,
2
2JH,H = 16.73 Hz, 4 H), 5.11 (d, JH,H = 16.73 Hz, 4 H), 4.75 (t,
3
8.56 (s, 3 H), 7.80 (d, JH,H = 9.21 Hz, 1 H), 7.39–7.25 (m, 3 H),
3JH,H = 9.37 Hz, 4 H), 2.48 (m, 12 H), 2.42–2.35 (m, 4 H), 1.00 (d,
2
2
7.12–7.05 (m, 2 H), 5.39 (d, JH,H = 17.10 Hz, 1 H), 5.27 (d, JH,H
3
3JH,H = 6.69 Hz, 12 H), 0.47 (d, JH,H = 6.69 Hz, 12 H) ppm. 13C
3
= 17.10 Hz, 1 H), 4.97 (dd, JH,H = 7.02, 9.10 Hz, 1 H), 4.42 (br.
NMR (125 MHz, CDCl3): δ = 163.71, 147.76, 136.67, 131.89,
129.74, 128.70, 127.57, 126.50, 49.93, 46.57, 32.12, 19.74, 19.33,
s, 1 H), 2.55 (s, 3 H), 2.35 (s, 3 H), 2.29–2.08 (m, 2 H), 0.95 (d,
3
3JH,H = 6.91 Hz, 3 H), 0.91 (d, JH,H = 6.58 Hz, 3 H), 0.89 (d,
9.93 ppm. IR (KBr): ν = 3454, 3448, 3414, 2964, 2930, 1650, 1592,
3JH,H = 6.47 Hz, 3 H), 0.77 (d, 3 H, JH,H = 6.80 Hz) ppm. 13C
˜
3
1501, 1467, 1457, 1434, 1389, 1356, 1332, 1225, 730, 698, 581, 525,
NMR (75 MHz, [D6]DMSO): δ = 162.96, 162.21, 161.18, 155.51,
143.03, 136.03, 133.52, 129.34, 128.73, 127.64, 127.39, 126.35,
51.27, 50.89, 46.36, 31.74, 31.61, 18.86, 18.20, 18.16, 17.50, 11.75,
513 cm–1. FAB-HRMS: calcd. for C64H77N12O4 [M
1077.6191; found 1077.6189.
+
H]+
9.53 ppm. IR (KBr): ν = 3420, 3066, 2972, 2933, 2881, 1676, 1592,
˜
Scaffold 4: Cyclic peptide 10 (539 mg, 0.50 mmol) was converted
into 4 as described above in the General Procedure for the cleavage
of the benzyl group. Yield: 348 mg (97%); m.p. Ͼ 250 °C. 1H NMR
(300 MHz, [D4]methanol): δ = 4.88 (d, 3JH,H = 9.23 Hz, 4 H), 2.52–
1544, 1516, 1469, 1456, 1436, 1395, 1377, 1355, 1203, 1143, 800,
723, 698 cm–1. FAB-HRMS: calcd. for C25H34N5O4 [M + H]+
468.2611; found 468.2620.
3
2.38 (m, 4 H), 2.48 (s, 12 H), 1.10 (d, JH,H = 6.62 Hz, 12 H), 0.93
Cyclic Peptide 23: iPr2NEt (1.20 mL, 6.75 mmol) and FDPP
(765 mg, 1.99 mmol) were added at room temperature to a suspen-
sion of 22 (581 mg, 1.00 mmol) in acetonitrile (100 mL) and the
mixture was stirred at room temperature for 2 d. The solvent was
removed by evaporation and the residue was dissolved in AcOEt
and then extracted with water and brine, dried with MgSO4 and
concentrated in vacuo. Flash chromatography on silica gel (DCM/
3
(d, JH,H = 6.62 Hz, 12 H) ppm. 13C NMR (75 MHz, [D4]meth-
anol): δ = 162.77, 147.56, 134.81, 127.02, 53.93, 33.46, 19.76, 19.61,
10.79 ppm. IR (KBr): ν = 3400, 3048, 3038, 2965, 2932, 2875, 2763,
˜
2663, 1656, 1601, 1543, 1518, 1470, 1390, 1370, 1343, 1035,
577 cm–1. FAB-HRMS: calcd. for C36H53N12O4 [M
717.4313; found 717.4304.
+
H]+
N-Boc-imidazole–oxazole Methyl Ester 20: iPr2NEt (1.50 mL, AcOEt/MeOH, 75:25:0.5) gave 23 (247 mg, 55%) as a white solid;
1
3
8.50 mmol) and FDPP (692 mg, 1.80 mmol) were added at room
temperature to acid 14 (465 mg, 1.20 mmol) and ammonium salt
19 (587 mg, 1.80 mmol) in acetonitrile (45 mL) and the mixture was
stirred at room temperature for 2 d. The solvent was removed by
evaporation and the residue was dissolved in AcOEt and then ex-
m.p. 153 °C. H NMR (300 MHz, [D6]acetone): δ = 7.75 (d, JH,H
3
= 8.55 Hz, 2 H), 7.35 (d, JH,H = 10.19 Hz, 2 H), 7.27–7.17 (m, 6
3
H), 6.97–6.91 (m, 4 H), 5.43 (d, JH,H = 16.99 Hz, 2 H), 5.24 (d,
3JH,H = 17.10 Hz, 2 H), 5.04–4.93 (m, 4 H), 2.68–2.56 (m, 2 H),
3
2.53 (s, 6 H), 2.43 (s, 6 H), 2.28–2.17 (m, 2 H), 1.02 (d, JH,H
=
1788
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1779–1792

C4- and C2-Symmetric Molecular Scaffolds Based on Imidazole Peptides
FULL PAPER
3
3
6.80 Hz, 6 H), 1.01 (d, JH,H = 6.69 Hz, 6 H), 0.96 (d, JH,H
=
TFA (3.0 mL) was added at that temperature. The ice bath was
3
6.80 Hz, 6 H), 0.79 (d, JH,H = 6.58 Hz, 6 H) ppm. 13C NMR removed after 30 min and stirring was continued at room tempera-
(75 MHz, [D6]acetone): δ = 164.69, 164.06, 162.40, 154.37, 148.43,
ture for 1 d. The mixture was concentrated in vacuo to provide a
138.50, 135.01, 131.28, 130.49, 130.31, 129.19, 127.66, 53.66, 51.23, quantitative yield of the tetraacid 25, which was used in the next
47.91, 34.16, 32.71, 21.48, 20.38, 20.18, 19.68, 12.59, 10.73 ppm.
step without further purification; m.p. Ͼ 250 °C. 1H NMR
(500 MHz, [D4]methanol): δ = 5.21 (d, JH,H = 18.39 Hz, 4 H),
2
IR (KBr): ν = 3400, 2963, 2930, 2874, 1670, 1637, 1594, 1509, 1468,
˜
1454, 1390, 1371, 1353, 1220, 1189, 1148, 1126, 1113, 731, 696,
4.81–4.76 (m, 8 H), 2.44–2.36 (m, 4 H), 2.35 (s, 12 H), 1.05 (d,
3
583 cm–1. FAB-HRMS: calcd. for C50H63N10O6 [M
+
H]+
3JH,H = 6.51 Hz, 12 H), 0.83 (d, JH,H = 6.51 Hz, 12 H) ppm. 13C
899.4932; found 899.4943. C50H62N10O6·CH3OH·H2O (948.15):
NMR (125 MHz, [D4]methanol): δ = 170.30, 164.23, 149.03,
calcd. C 64.54, H 7.22, N 14.76; found C 64.68, H 6.92, N 14.71.
135.84, 128.75, 51.42, 46.07, 33.28, 20.13, 19.54, 9.71 ppm. IR
(KBr): ν = 3400, 2965, 2937, 1739, 1642, 1598, 1511, 1453, 1389,
˜
Scaffold 5: Cyclic peptide 23 (360 mg, 0.40 mmol) was converted
into 5 as described above in the General Procedure for the cleavage
of the benzyl group. Yield: 274 mg (95%); m.p. Ͼ 250 °C. 1H NMR
1376, 1348, 1221, 1206, 600, 572, 520, 470 cm–1. FAB-HRMS:
calcd. for C44H61N12O12 [M + H]+ 949.4532; found 949.4566.
3
(300 MHz, [D4]methanol): δ = 5.04 (d, JH,H = 7.78 Hz, 2 H), 4.99
Tetraamide 26: DMC (51 mg, 0.30 mmol) and NEt3 (0.20 mL,
1.40 mmol) were added at room temperature to a solution of 25
(48 mg, 0.05 mmol) and aniline (38 mg, 0.40 mmol) in DCM
(20 mL) and the mixture was stirred at room temperature for 1 d.
The solvent was removed by evaporation and the residue was dis-
solved in DCM and then extracted with water and brine, dried with
MgSO4 and concentrated in vacuo. Flash chromatography on silica
gel (DCM/AcOEt/MeOH, 75:25:9) gave 26 (28 mg, 44%) as a white
solid; m.p. Ͼ 250 °C. 1H NMR (300 MHz, [D4]methanol): δ =
7.51–7.45 (m, 8 H), 7.33–7.24 (m, 8 H), 7.12–7.05 (m, 4 H), 5.12
(d, 2JH,H = 17.42 Hz, 4 H), 4.89–4.85 (m, 8 H), 2.54–2.41 (m, 4 H),
3
(d, JH,H = 9.76 Hz, 2 H), 2.59–2.47 (m, 2 H), 2.54 (s, 6 H), 2.50
3
(s, 6 H), 2.40–2.27 (m, 2 H), 1.10 (d, JH,H = 6.69 Hz, 6 H), 1.04
(d, 3JH,H = 6.80 Hz, 6 H), 0.93 (m, 12 H) ppm. 13C NMR (75 MHz,
[D4]methanol): δ = 163.19, 162.37, 155.03, 147.41, 134.74, 129.61,
53.46, 53.33, 33.69, 33.08, 19.81, 19.78, 19.31, 19.18, 11.72,
10.85 ppm. IR (KBr): ν = 3411, 3041, 2965, 2932, 2875, 2735, 1660,
˜
1635, 1602, 1514, 1469, 1444, 1391, 1372, 1347, 1208, 1189, 1150,
1117, 579 cm–1. FAB-HRMS: calcd. for C36H51N10O6 [M + H]+
719.3993; found 719.4026. C36H50N10O6·CH2Cl2·CH3OH (835.82):
calcd. C 54.61, H 6.75, N 16.76; found C 54.58, H 6.87, N 17.02.
3
3
2.37 (s, 12 H), 1.12 (d, JH,H = 6.62 Hz, 12 H), 0.94 (d, JH,H
=
General Procedure for the Syntheses of Four-Armed Platforms 9, 10
and 24 and Two-Armed Platforms 23, 27 and 28: K2CO3 (207 mg,
1.50 mmol) and RX (1.00 mmol for 4 and 2.00 mmol for 5) were
added at room temperature to a solution of 4 or 5 (0.20 mmol) in
acetonitrile (40 mL) and the mixture was stirred at reflux for 8 h.
The solvent was removed by evaporation and the residue was dis-
solved in AcOEt, extracted with water and brine, dried with
MgSO4 and concentrated in vacuo. Purification was accomplished
by chromatography on silica gel (DCM/AcOEt/MeOH, 75:25:0.5)
to yield the four-armed platforms 9 (90%), 10 (85%) and 24 (91%)
and the two-armed platforms 23 (85%), 27 (92%) and 28 (73%),
respectively, as white solids.
6.62 Hz, 12 H) ppm. 13C NMR (300 MHz, [D4]methanol): δ =
166.73, 165.35, 149.03, 139.37, 135.54, 129.96, 129.92, 125.5,
121.26, 51.42, 47.58, 33.40, 20.33, 19.36, 9.92 ppm. IR (KBr): ν =
˜
3428, 3421, 3141, 3088, 2964, 2930, 1682, 1639, 1599, 1554, 1501,
1446, 1390, 1374, 1312, 1258, 1228, 758, 694, 612 cm–1. FAB-
HRMS: calcd. for C68H81N16O8 [M + H]+ 1249.6423; found
1249.6423.
Diacid 29: The di-tert-butyl ester 28 (66 mg, 0.07 mmol) was dis-
solved in DCM (5 mL) and the solution was cooled to 0 °C. TFA
(1.5 mL) was added at that temperature. The ice bath was removed
after 30 min and stirring was continued at room temperature for
1 d. The mixture was concentrated in vacuo to provide a quantita-
tive yield of the diacid 29, which was used in the next step without
1
Data for Receptor 24: M.p. 146 °C. H NMR (300 MHz, [D6]ace-
tone): δ = 7.61 (d, 3JH,H = 8.66 Hz, 4 H), 5.48 (d, 2JH,H = 18.31 Hz,
4 H), 4.70 (d, 2JH,H = 18.20 Hz, 4 H), 4.64 (m, 4 H), 2.57–2.45 (m,
1
further purification; m.p. 164 °C. H NMR (300 MHz, [D4]meth-
3
4 H), 2.43 (s, 12 H), 1.48 (s, 36 H), 1.14 (d, JH,H = 6.80 Hz, 12
anol): δ = 5.02–4.94 (m, 4 H), 4.87–4.77 (m, 4 H), 2.65–2.55 (m, 2
H), 0.87 (d, 3JH,H = 6.58 Hz, 12 H) ppm. 13C NMR (75 MHz, [D6]-
acetone): δ = 168.86, 164.81, 149.78, 134.03, 131.02, 83.96, 51.55,
3
H), 2.50 (s, 6 H), 2.31 (s, 6 H), 2.23–2.12 (m, 2 H), 1.01 (d, JH,H
3
3
= 6.58 Hz, 6 H), 0.89 (d, JH,H = 6.58 Hz, 6 H), 0.86 (d, JH,H
=
6.69 Hz, 6 H), 0.84 (d, JH,H = 6.58 Hz, 6 H) ppm. 13C NMR
(75 MHz, [D4]methanol): δ = 170.26, 164.52, 163.14, 162.91,
155.65, 148.11, 136.30, 129.44, 129.10, 53.34, 51.09, 45.97, 34.14,
3
47.13, 33.67, 29.10, 21.40, 20.75, 10.55 ppm. IR (KBr): ν = 3407,
˜
2965, 2936, 2874, 1746, 1654, 1597, 1503, 1456, 1394, 1371, 1286,
1237, 1223, 1157, 1107, 608, 579 cm–1. FAB-HRMS: calcd. for
C60H93N12O12 [M + H]+ 1173.7036; found 1173.6993.
31.84, 20.67, 19.68, 19.18, 18.38, 11.77, 9.67 ppm. IR (KBr): ν =
˜
1
3403, 3396, 3390, 3333, 3311, 2970, 2939, 2879, 1743, 1669, 1657,
1634, 1597, 1511, 1468, 1391, 1375, 1351, 1196, 1145 cm–1. FAB-
HRMS: calcd. for C40H55N10O10 [M + H]+ 835.4103; found
835.4121.
Data for Receptor 28: M.p. 147 °C. H NMR (500 MHz, [D6]ace-
tone): δ = 7.74 (br. s, 2 H), 7.47 (br. s, 2 H), 5.12–4.99 (m, 4 H),
4.89 (t, JH,H = 9.92 Hz, 2 H), 4.79 (d, JH,H = 18.24 Hz, 2 H),
2.71–2.63 (m, 2 H), 2.62 (s, 6 H), 2.40 (s, 6 H), 2.27–2.19 (m, 2 H),
3
2
3
3
1.42 (s, 18 H), 1.11 (d, JH,H = 6.66 Hz, 6 H), 1.01 (d, JH,H
=
=
Diamide 30: DMC (40 mg, 0.21 mmol) and NEt3 (0.15 mL,
1.00 mmol) were added at room temperature to a solution of 29
(58 mg, 0.07 mmol) and 3-aminopyridine (26 mg, 0.28 mmol) in
DCM (30 mL) and the mixture was stirred at room temperature
for 1 d. The solvent was removed by evaporation and the residue
was dissolved in DCM and then extracted with water and brine,
dried with MgSO4 and concentrated in vacuo. Flash chromatog-
raphy on silica gel (DCM/MeOH, 5:1) gave 30 (60 mg, 87%) as a
white solid; m.p. Ͼ 250 °C. 1H NMR (300 MHz, [D4]methanol/
CDCl3): δ = 10.30 (s, 2 H), 8.56 (m, 4 H), 8.24 (m, 4 H), 8.12 (m,
4 H), 7.85 (m, 2 H), 7.31 (m, 2 H), 5.18–4.97 (m, 4 H), 4.78–4.62
(m, 4 H), 2.69–2.56 (m, 2 H), 2.43 (s, 6 H), 2.42 (s, 6 H), 2.25–2.13
3
3
6.74 Hz, 6 H), 0.95 (d, JH,H = 6.51 Hz, 6 H), 0.94 (d, JH,H
6.74 Hz, 6 H) ppm. 13C NMR (125 MHz, [D6]acetone): δ = 168.53,
164.44, 164.13, 162.66, 154.53, 148.47, 135.03, 130.45, 84.13, 53.39,
51.17, 47.14, 34.41, 32.93, 29.03, 21.50, 20.54, 20.13, 19.56, 12.63,
10.46 ppm. IR (KBr): ν = 3411, 2965, 2933, 2875, 1746, 1671, 1637,
˜
1598, 1510, 1457, 1393, 1371, 1352, 1282, 1238, 1222, 1192, 1156,
1114, 582 cm–1. FAB-HRMS: calcd. for C48H71N10O10 [M + H]+
947.5355; found 947.5323. C48H70N10O10·H2O (965.15): calcd. C
59.73, H 7.52, N 14.51; found C 59.86, H 7.45, N 14.29.
Tetraacid 25: The tetra-tert-butyl ester 24 (153 mg, 0.13 mmol) was
dissolved in DCM (10 mL) and the solution was cooled to 0 °C.
Eur. J. Org. Chem. 2007, 1779–1792
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1789

G. Haberhauer, Á. Pintér, T. Oeser, F. Rominger
FULL PAPER
(m, 2 H), 1.04 (d, 3JH,H = 6.78 Hz, 6 H), 0.95–0.87 (m, 18 H) ppm.
13C NMR (75 MHz, [D4]methanol/CDCl3): δ = 165.11, 163.24,
161.73, 161.61, 153.50, 146.28, 143.53, 139.43, 135.47, 134.01,
H) ppm. 13C NMR (75 MHz, [D4]methanol): δ = 164.72, 162.92,
158.26, 157.83, 156.60, 130.14, 128.73, 55.32, 53.91, 33.29, 32.41,
19.41, 18.86, 18.75, 18.24, 12.03, 11.69 ppm. IR (KBr): ν = 3446,
˜
128.94, 127.92, 127.88, 124.23, 51.60, 49.95, 45.96, 32.65, 30.87, 3286, 3017, 2946, 2888, 1727, 1675, 1636, 1529, 1203, 1189,
19.96, 19.07, 18.51, 17.81, 11.38, 9.40 ppm. IR (KBr): ν = 3414,
1139 cm–1. FAB-HRMS: calcd. for C18H27N4O5 [M
379.1982; found 379.1962.
+
H]+
˜
2965, 2936, 1711, 1650, 1636, 1600, 1554, 1515, 1485, 1461, 1425,
1391, 1372, 1286, 1200, 708, 630 cm–1. FAB-HRMS: calcd. for
C50H63N14O8 [M + H]+ 987.4953; found 987.4942.
Cyclic Peptide 6: iPr2NEt (1.60 mL, 9.00 mmol) and FDPP (1.02 g,
2.65 mmol) were added at room temperature to a suspension of 34
(690 mg, 1.40 mmol) in acetonitrile (175 mL) and the mixture was
stirred at room temperature for 2 d. The solvent was removed by
evaporation and the residue was dissolved in AcOEt and then ex-
tracted with water and brine, dried with MgSO4 and concentrated
in vacuo. Flash chromatography on silica gel (DCM/AcOEt/
MeOH, 75:25:0.5) gave 6 (361 mg, 72%) as a white solid; m.p.
133 °C. 1H NMR (300 MHz, CDCl3): δ = 7.31 (d, 3JH,H = 9.65 Hz,
N-Boc-oxazole–oxazolecarboxylic Acid ((<=AUTHOR: Change
ok?)) Methyl Ester 32: iPr2NEt (4.40 mL, 25.0 mmol) and FDPP
(1.54 g, 4.00 mmol) were added at room temperature to acid 31
(1.07 g, 3.60 mmol) and ammonium salt 19 (1.31 g, 4.00 mmol) in
acetonitrile (80 mL) and the mixture was stirred at room tempera-
ture for 3 d. The solvent was removed by evaporation and the resi-
due was dissolved in AcOEt and then extracted with water and
brine, dried with MgSO4 and concentrated in vacuo. Flash
chromatography on silica gel (petroleum ether/ethyl acetate, 1:1)
gave 32 (1.32 g, 74%) as a white solid; m.p. 52 °C. 1H NMR
3
4 H), 5.14 (dd, JH,H = 7.67, 9.65 Hz, 4 H), 2.60 (s, 12 H), 2.41–
3
3
2.27 (m, 4 H), 1.06 (d, JH,H = 6.80 Hz, 12 H), 0.98 (d, JH,H
=
6.69 Hz, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.13,
3
(500 MHz, CDCl3): δ = 7.38 (d, JH,H = 9.54 Hz, 1 H), 5.13–5.05
160.89, 153.57, 128.49, 51.25, 32.40, 19.11, 18.50, 11.68 ppm. IR
(m, 2 H), 4.66 (m, 1 H), 3.85 (m, 3 H), 2.57 (s, 3 H), 2.55 (s, 3 H),
2.32–2.25 (m, 1 H), 2.15–2.07 (m, 1 H), 1.42 (s, 9 H), 0.99 (d, 3JH,H
= 6.69 Hz, 3 H), 0.92–0.87 (m, 9 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 162.60, 161.61, 161.44, 160.83, 156.22, 155.28, 153.37,
128.36, 127.37, 80.00, 54.03, 52.07, 51.90, 32.66, 32.58, 28.27,
(KBr): ν = 3448, 3417, 2965, 1679, 1634, 1578, 1512, 1470, 1391,
˜
1373, 1203, 1193, 1141, 1115 cm–1. ESI-HRMS: calcd. for
C36H49N8O8 [M + H]+ 743.3493; found 743.3509. C36H48N8O8·
1/2H2O·1/2MeOH (745.38): calcd. C 58.78, H, 6.89, N, 15.02;
found C 58.72, H 6.71, N 14.71.
19.05, 18.68, 18.54, 17.89, 11.97, 11.61 ppm. IR (film): ν = 3411,
˜
X-ray Crystal Structure Analysis
3328, 2967, 2933, 1718, 1672, 1633, 1581, 1511, 1469, 1457, 1442,
1391, 1367, 1351, 1293, 1246, 1204, 1174, 1099, 989, 735 cm–1.
FAB-HRMS: calcd. for C24H37N4O7 [M + H]+ 493.2662; found
493.2643. C24H36N4O7·1/2H2O (501.57): calcd. C 57.47, H 7.44, N
11.17; found C 57.25, H 7.23, N 10.94.
Data for 10: C64H76N12O4·3CHCl3 (crystallization from CHCl3);
M
= 1435.47, colourless crystal (polyhedron), dimensions
0.52ϫ0.45ϫ0.20 mm, crystal system orthorhombic, space group
P212121, Z = 4, a = 16.1337(3), b = 17.4146(3), c = 26.1804(2) Å,
α = β = γ = 90°, V = 7355.7(2) Å3, ρ = 1.296 gcm–3, T = 200(2) K,
θmax = 21.49°, radiation Mo-Kα, λ = 0.71073 Å, 0.3° ω-scans with
CCD area detector, covering a whole sphere in the reciprocal space,
45790 reflections measured, 8442 unique (Rint = 0.0431), 7047 ob-
served [IϾ2σ(I)], intensities were corrected for Lorentz and polar-
ization effects, an empirical absorption correction was applied by
use of SADABS[20] based on the Laue symmetry of the reciprocal
space, µ = 0.40 mm–1, Tmin = 0.82, Tmax = 0.92, structure solved
by direct methods and refined against F2 with a full-matrix, least-
squares algorithm with use of the SHELXTL-PLUS (5.10) soft-
ware package,[21] 991 parameters refined, hydrogen atoms were
treated by use of appropriate riding models, Flack absolute struc-
ture parameter 0.03(9), goodness of fit 1.09 for observed reflec-
tions, final residual values R1(F) = 0.050, wR(F2) = 0.125 for ob-
served reflections, residual electron density –0.26/0.53 e·Å–3.
N-Boc-Protected Amino Acid 33: Dimer 32 (850 mg, 1.73 mmol)
was dissolved in methanol/dioxane (35 mL/25 mL), and this was
followed by the slow addition of an NaOH solution (2 , 9.00 mL,
17.3 mmol) at 0 °C. Stirring was continued until TLC showed the
consumption of all starting material, after which brine, HCl solu-
tion (1 ) and DCM were added. The aqueous phase was repeat-
edly extracted with DCM and the organic layers were combined,
dried with MgSO4 and concentrated in vacuo to give the acid 33
as a white solid (790 mg, 95%), which was used in the next step
1
without further purification; m.p. 82 °C. H NMR (75 MHz, [D6]-
3
3
DMSO): δ = 8.08 (d, JH,H = 8.77 Hz, 1 H), 7.47 (d, JH,H
=
=
3
3
8.33 Hz, 1 H), 4.90 (t, JH,H = 8.33 Hz, 1 H), 4.42 (t, JH,H
8.33 Hz, 1 H), 2.54 (s, 3 H), 2.53 (s, 3 H), 2.39–2.27 (m, 1 H), 2.17–
3
2.05 (m, 1 H), 1.37 (s, 9 H), 0.97–0.89 (m, 6 H), 0.85 (d, JH,H
=
6.80 Hz, 3 H), 0.80 (d, JH,H = 6.91 Hz, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 162.89, 161.15, 160.80, 160.64, 155.49,
155.32, 152.59, 127.94, 127.26, 78.26, 54.37, 51.86, 31.09, 30.77,
3
Data for 30: C50H62N14O8·3.3CH3CN (crystallization from
CH3CN); M = 1122.61, colourless crystal (columns), dimensions
0.50ϫ0.14ϫ0.14 mm, crystal system orthorhombic, space group
P212121, Z = 4, a = 17.3820(3), b = 18.8274(3), c = 20.5823(3) Å,
α = β = γ = 90°, V = 6735.7(2) Å3, ρ = 1.107 gcm–3, T = 200(2) K,
θmax = 22.22°, radiation Mo-Kα, λ = 0.71073 Å, 0.3° ω-scans with
CCD area detector, covering a whole sphere in the reciprocal space,
44732 reflections measured, 8465 unique (Rint = 0.0507), 7302 ob-
served [IϾ2σ(I)], intensities were corrected for Lorentz and polar-
ization effects, an empirical absorption correction was applied by
use of SADABS[20] based on the Laue symmetry of the reciprocal
space, µ = 0.08 mm–1, Tmin = 0.96, Tmax = 0.99, structure solved
by direct methods and refined against F2 with a full-matrix, least-
squares algorithm with use of the SHELXTL (6.12) software pack-
age,[21] 821 parameters refined, hydrogen atoms were treated by use
28.07, 19.01, 18.95, 18.59, 11.71, 11.27 ppm. IR (KBr): ν = 3428,
˜
2952, 2920, 2867, 1702, 1664, 1631, 1508, 1241, 1159, 1095,
720 cm–1. FAB-HRMS: calcd. for C23H35N4O7 [M + H]+ 501.2325;
found 501.2314.
TFA Amino Acid 34: The Boc-protected amino acid 33 (766 mg,
1.60 mmol) was dissolved in DCM (35 mL) and the solution was
cooled to 0 °C. TFA (5.0 mL) was added at that temperature. The
ice bath was removed after 30 min and stirring was continued at
room temperature for 2 h. The mixture was concentrated in vacuo
to provide a quantitative yield of the amino acid 34 (787 mg), which
was used in the next step without further purification. 1H NMR
3
(300 MHz, [D4]methanol): δ = 4.91 (d, JH,H = 7.49 Hz, 1 H), 4.38
3
(d, JH,H = 6.62 Hz, 1 H), 2.58 (s, 3 H), 2.56 (s, 3 H), 2.39–2.24
3
3
(m, 2 H), 1.07 (d, JH,H = 6.79 Hz, 3 H), 0.98 (d, JH,H = 6.62 Hz, of appropriate riding models, Flack absolute structure parameter
3
3
3 H), 0.97 (d, JH,H = 6.97 Hz, 3 H), 0.90 (d, JH,H = 6.62 Hz, 3
–1.3(14), goodness of fit 1.09 for observed reflections, final residual
1790
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1779–1792

C4- and C2-Symmetric Molecular Scaffolds Based on Imidazole Peptides
FULL PAPER
values R1(F) = 0.056, wR(F2) = 0.145 for observed reflections, re-
[3]
For some recent examples, see: a) S. R. Waldvogel, R. Fröhlich,
C. A. Schalley, Angew. Chem. Int. Ed. 2000, 39, 2472; b) G.
Haberhauer, Synlett 2004, 1003.
sidual electron density –0.24/0.57 e·Å–3.
Data for 6: C36H48N8O8; M = 720.82, colourless crystal (polyhe-
dron), dimensions 0.38ϫ0.34ϫ0.12 mm, crystal system ortho-
rhombic, space group C222, Z = 4, a = 17.6317(7), b = 21.5974(9),
c = 12.2646(5) Å, α = β = γ = 90°, V = 4670.3(3) Å3, ρ =
1.025 gcm–3, T = 298(2) K, 2θmax = 21.99°, radiation Mo-Kα, λ =
0.71073 Å, 0.3° ω-scans with CCD area detector, covering a whole
sphere in reciprocal space, 10162 reflections measured, 2882 unique
(Rint = 0.0413), 2159 observed [IϾ2σ(I)], intensities were corrected
for Lorentz and polarization effects, an empirical absorption cor-
rection was applied by use of SADABS[20] based on the Laue sym-
[4]
[5]
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For other C3-symmetric cyclic pseudopeptides, see: a) T. K.
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Miller, J. Am. Chem. Soc. 1992, 114, 10975.
metry of the reciprocal space, µ = 0.17 mm–1, Tmin = 0.97, Tmax
=
0.99, structure solved by direct methods and refined against F2 with
a full-matrix, least-squares algorithm with use of the SHELXTL-
PLUS (5.10) software package,[21] 272 parameters refined, hydrogen
atoms were treated by use of appropriate riding models, Flack ab-
solute structure parameter –1(3), goodness of fit 1.03 for observed
reflections, final residual values R1(F) = 0.064, wR(F2) = 0.166 for
observed reflections, residual electron density –0.25/0.45 e·Å–3.
[6]
[7]
G. Haberhauer, T. Oeser, F. Rominger, Chem. Commun. 2005,
2799.
For other platforms with four azole building blocks in the cy-
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6335.
CCDC-625516, -625517 and -625790 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[8]
[9]
S. Chen, J. Xu, Tetrahedron Lett. 1991, 32, 6711.
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T. Shioiri, K. Ninomiya, S. Yamada, J. Am. Chem. Soc. 1972,
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Acknowledgments
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This work was generously supported by the Deutsche Forschungs-
gemeinschaft. The authors would like to express theirs special
thanks to Prof. Dr. Rolf Gleiter for helpful discussions. The authors
thank Dr. Andreea Schuster for assistance.
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[15]
[1] For some recent examples, see: a) F. Hettche, P. Rei, R. W.
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Eur. J. Org. Chem. 2007, 1779–1792
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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G. Haberhauer, Á. Pintér, T. Oeser, F. Rominger
FULL PAPER
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[20] Program SADABS V2.03 for absorption correction: G. M.
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[21] Software package SHELXTL V5.10 for structure solution and
refinement: G. M. Sheldrick, Bruker Analytical X-ray Division,
Madison, Wisconsin, 1997.
Received: October 29, 2006
Published Online: February 20, 2007
1792
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1779–1792