Planar chirality of imidazole-containing macrocycles-understanding and tuning atropisomerism

Article abstract of DOI:10.1002/ejoc.201100805

The synthesis and characterization of imidazole-containing macrocycles displaying planar chirality has been achieved. HLPC and NMR studies revealed the crucial role of the alicyclic chain length in determining the rate of stereoisomerisation: 15-and 16-me

Full text of DOI:10.1002/ejoc.201100805

FULL PAPER
DOI: 10.1002/ejoc.201100805
Planar Chirality of Imidazole-Containing Macrocycles – Understanding and
Tuning Atropisomerism
[a]
[a]
[a]
[a]
ˇ
ˇ
Emilie Van Den Berge, Jirí Pospísil, Tran Trieu-Van, Laurent Collard, and
Raphaël Robiette*[a]
Keywords: Nitrogen heterocycles / Macrocycles / Cyclophanes / Density functional calculations / Atropisomerism /
Chirality / Planar chirality
The synthesis and characterization of imidazole-containing
macrocycles displaying planar chirality has been achieved.
HLPC and NMR studies revealed the crucial role of the ali-
cyclic chain length in determining the rate of stereoisomeris-
ation: 15- and 16-membered cyclic compounds are chiral
whereas their larger-ringed analogues equilibrate rapidly at
room temperature. Computational calculations are in good
agreement with experimental observations and allow us to
understand the mechanism and the interactions involved in
the conformational equilibrium between the two atropiso-
mers. Separation of the two enantiomers of the 15-membered
macrocycle by semipreparative chiral HPLC allowed us to
investigate the influence of chirality on its biological activity.
Introduction
Imidazoles are key substructures in organic synthesis and
medicinal chemistry.[1] Due to their nucleophilic and basic
properties as well as their coordination ability, imidazole
derivatives have found various applications. Numerous
imidazole compounds are known to possess interesting bio-
logical activities,[2] be good organocatalysts[3] or act as li-
gands.[4]
In most of these applications, the presence and control
of the chiral properties of the imidazole compound are of
crucial importance (e.g. for chiral organocatalysis and bio-
logical activity). Accordingly, the design and synthesis of
new chiral structures containing an imidazole motif is of
continuous interest, with the main strategy to date con-
sisting of placing chiral substituents on the imidazole
core.[3,5]
In this context, we have recently designed and synthe-
sized a new family of compounds comprising a 5-aryl-1H-
imidazole motif included in a macrocycle (Scheme 1).[6]
Biological evaluation of these imidazole-containing macro-
cycles revealed that they display interesting binding activi-
ties towards biological targets, which are important factors
in the central nervous system: A3 adenosine (h) receptor,
dopamine D1 (h) receptor and chlorine channel (GABA-
gated).
Scheme 1. Structure of macrocycles 1 and their possible stereoiso-
mers.
We reasoned that macrocycles 1 can potentially be chiral.
Indeed, there are two structural motifs in these imidazole
derivatives that could restrict the rotational equilibrium be-
tween (M)-1 and (P)-1, and hence be a source of planar
chirality:[7–8] (1) steric effects could prevent rapid rotation
around the aryl imidazole C–C single bond (atropisomer-
ism as seen in biaryl compounds) and (2) the cyclophane-
type structure of the macrocycle may prevent the alicyclic
ring from flipping from one side of the plane of the imid-
azole ring to the other (rope skipping motion). Because of
the dearth of literature examples of imidazoles with planar
chirality[9] and the importance of chirality for the various
conceivable applications of these macrocycles, we decided
to investigate the barrier to stereoisomerisation for macro-
cycles 1 and the influence of their absolute configuration
on their biological activities.[10]
[a] Institute of Condensed Matter and Nanosciences, Université
catholique de Louvain,
Results and Discussion
Place Louis Pasteur 1, box L4.01.02, 1348 Louvain-la-Neuve,
Belgium
Synthesis
Fax: +32-10-474168
E-mail: raphael.robiette@uclouvain.be
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100805.
The synthesis of macrocycles 1a and 1c has already been
reported.[6] In order to investigate the influence of the size
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R. Robiette et al.
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of the macrocycle, we have synthesized imidazoles 1b and
1d using the same strategy (Scheme 2). The synthesis starts
from the trisubstituted imidazole 2, which was obtained by
a highly regioselective method previously developed in our
lab,[11] and is based on two key steps: a Suzuki coupling and
the formation of the macrocycle by ring closing metathesis.
Figure 1. Chiral HPLC chromatograms of macrocycles 1a–d (top
to bottom) performed on CHIRALPAK® IB (UV detection at
282 nm).
tween the two atropoisomers. Accordingly, we investigated
the kinetics of enantiomerisation by NMR spectroscopy.
Scheme 2. Synthesis of macrocycles 1a–d.
We therefore prepared four imidazole-containing macro-
cycles (1a–d), with the size of the macrocyclic ring ranging
from 15- to 18-membered (n = 1–4). The chiral properties
of these four imidazoles were first investigated by chroma-
tographic methods.
NMR Studies
1
Close analysis of the H NMR spectra of 1a–c reveals
the nonequivalence of the two geminal protons of both
methylene groups adjacent to the oxygen atoms (Figure 2).
Chiral HPLC
Imidazoles 1a–d were analysed by HPLC on a cellulose
carbamate chiral stationary phase at room temperature
(Figure 1). In the case of 1a and 1b (n = 1 and 2, respec-
tively), the observation of two peaks corresponding to the
two enantiomers[12] shows that there is no rapid equilibra-
tion between the two atropisomeric M and P forms on the
HPLC timescale.[13] For the larger 1c and 1d (n = 3 and 4,
respectively), every attempt to resolve the two enantiomers
failed (even at low temperature), which suggests a rapid en-
antiomerisation on the HPLC timescale.
In order to further investigate the influence of the macro-
cycle and the origin of the absence of rapid equilibration in
1a and 1b, we analyzed corresponding noncyclic 5a and 5b.
Whatever the column and the conditions, these chromato-
grams showed only one signal, which is characteristic of a
rapid stereoisomerisation. This suggests that the macro-
cyclic nature of 1a and 1b has an important role in de-
1
Figure 2. H NMR spectrum showing the diastereotopic nature of
termining the rate of the conformational equilibrium be- the two germinal OCH2 groups for 1c and their equivalence in 1d.
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Planar Chirality of Imidazole-Containing Macrocycles
This observation could be accounted for by the chiral na- of the N-methyl group and alicyclic chain (A) or occur in
ture of these molecules, which would render these methyl- the opposite direction with the alicyclic chain going
ene protons diastereotopic. No splitting of the OCH2 sig- through the imidazole plane on the C4–H side (B). We have
nals was observed for 1d.
obtained transition structures for both pathways from our
In order to further investigate the chirality of these imid- calculations, which indicate that the mechanism involving a
azoles, we carried out 1H NMR analysis of 1a–d in the pres- steric clash between the N-methyl group and the alicyclic
ence of different chiral shift reagents. We found that the chain (A) is less favoured (see Supporting Information).
addition of 1 equiv. of S-(+)-2,2,2-trifluoro-1-(9-anthryl)-
1
ethanol leads to the splitting of some H NMR signals of
1a–c, which indicates the formation of two diastereomeric
solvation complexes (Figure 3). This observation confirms
that, in these cases, isomerisation does not occur rapidly on
the NMR timescale at 25 °C. For imidazole 1d, no resolu-
tion of signals could be observed, which suggests rapid iso-
merisation.
Figure 4. Possible pathways for isomerisation.
The energy barriers obtained corroborate the chiral na-
ture of imidazoles 1a and 1b at room temperature (Table 1).
Indeed, the computed activation free energies (ΔG‡ = 40.9
and 26.2 kcalmol–1 for 1a and 1b, respectively) predict a
half life of racemisation (t1/2 enantio) at 25 °C of ca. 40 days
for 1b and several trillions of years for 1a. For 1c and 1d,
which have larger macrocycles, our calculations predict a
Figure 3. 1H NMR studies of 1a–d in the presence of a chiral deriv-
rapid isomerisation (t1/2 enantio Ͻ 3 min) as observed by chi-
1
atizing agent.
ral HPLC and H NMR spectroscopy.
1H NMR studies of the diastereomeric solvation com-
plexes of 1b and 1c at different temperatures were per-
formed to determine the coalescence temperature and the
exchange rate constant of isomerisation (Supporting Infor-
mation).[14] The activation energy of isomerisation calcu-
lated from these rate constants using the Arrhenius equa-
tion is 28.3 and 17.7 kcalmol–1 at 25 °C for 1b and 1c,
respectively.
Table 1. Computed energy barrier [kcalmol–1] for enantiomeris-
ation of 1a–d and 7 at the SCS-MP2/cc-pVTZ//B3LYP/6-31G*
level.
ΔE‡
ΔE‡(CHCl3)
ΔG‡(CHCl3)
1a
1b
1c
1d
7
37.8
24.8
17.1
14.5
5.2
38.5
25.7
17.9
15.4
5.0
40.9
26.2
20.2
16.3
6.8
We investigated the origin of chirality in 1a–d and the
factors that influence the enantiomerisation kinetics by
computational methods.
Our computational results are in good agreement with
our experimental observations and activation energies esti-
mated by NMR for imidazoles 1b and 1c. They also con-
firm the significant decrease of the energy barrier to iso-
merisation with the increasing size of the macrocycle, and
Computational Studies
We optimised macrocycles 1a–d and explored the confor- show that solvation and entropic effects only have a small
mational equilibrium responsible for their enantiomeri- influence.
sation [i.e. between (M)-1 and (P)-1].
The importance of the alicyclic ring was further con-
There are two conceivable pathways for isomerisation firmed by the low barrier to rotation computed for 7 (Fig-
(Figure 4): rope skipping motion can either involve crossing ure 5), which reveals the absence of atropisomerism in the
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nonmacrocyclic derivatives (Table 1), as suggested by the which are important actors in the central nervous system:
HPLC analysis of imidazoles 5. This result indicates that A3 adenosine (h) receptor, dopamine D1 (h) receptor and
the steric clash induced by rotation around the aryl imid- chlorine channel (GABA-gated). In order to investigate the
azole C–C single bond cannot account for the chiral nature importance of chirality on these biological activities, we
of imidazoles 1a and 1b at room temperature, and confirms submitted the two optically pure enantiomers of 1a as well
the decisive role of the alicyclic moiety on the rate of iso- as 1b–d to the same biological tests.
merisation of imidazoles 1a–d.
The results presented in Table 2 reveal that the size of the
ring has little influence on the inhibition activity. For the
three targets, an increase in the ring size seems to be benefi-
cial.
Table 2. Specific binding tests (concentration: 10 μm).
% Inhibition of control specific binding
Adenosine A3
Receptor
Dopamine
D1 Receptor
Cl–
Channel
Figure 5. Nonmacrocyclic 7.
(Ϯ)-1a
(+)-1a
(–)-1a
(Ϯ)-1b
1c
84
65
42
86
99
92
69
8
59
73
99
83
52
36
23
56
73
61
Analysis of the transition state (TS) structures indicates
that the barrier to atropisomerism is mainly due to the
steric interactions between the imidazole C4–H and the ali-
cyclic chain in the TS (Figure 6). The influence of the ring
size is explained as follows: the shorter the alicyclic chain,
the less possibility the chain has to decrease the steric clash
with C4–H in the TS.
1d
The influence of chirality was also examined. For adenos-
ine A3 receptor and chloride channel binding, the enantio-
mer (+)-1a is found to be slightly more active than (–)-1a.
For dopamine D1 receptor binding, the absolute configura-
tion of 1a has a significant impact on the inhibition activity:
(–)-1a is found to be active, whereas (+)-1a is inactive.
Conclusions
We have synthesized four 5-aryl-1H-imidazole-contain-
ing macrocycles (1a–d) with varying alicyclic chain length.
The synthesis relies on two key steps: Suzuki coupling and
the formation of the macrocycle by ring closing metathesis.
Figure 6. Optimised ground state (left) and isomerisation TS (right)
structures for 1a.
1
HPLC and H NMR studies of these imidazoles have
shown that 1a–b are planar chiral molecules whereas their
larger-ringed homologues 1c–d isomerise rapidly at room
temperature. It is thus possible to tune the rate of racemi-
sation (chirality) of these imidazoles simply by changing the
size of the alicyclic chain.
According to the computed free energy barrier, the two
enantiomers of 1a should be stable enough to be isolated
and stored separately. We thus undertook the resolution of
1a on a semipreparative scale.
The conformational equilibrium between the two atrop-
isomers has been investigated by computational means. The
energy barriers obtained are in good agreement with rate
Separation
Transposition of the analytical chiral HPLC conditions
to a semipreparative scale allowed us to obtain the two
enantiomers of 1a in milligram amounts with an enantio-
meric excess of Ͼ99% (Supporting Information).[15] As pre-
dicted by our calculations, these two isolated enantiomers
were found to be configurationally stable for months at
room temperature.[16]
We submitted the two optically pure enantiomers of 1a
for biological testing to investigate the influence of chirality
on their biological activities.
1
constants estimated by H NMR analysis at different tem-
peratures in the presence of a chiral shift reagent. Calcula-
tions also gave insights into the origin of the chirality, which
is that the cyclophane-type structure of 1a–b is responsible
for their chirality (and not their biaryl-type nature). More-
over, our computational results show that the mechanism
of isomerisation involves a rope skipping motion of the ali-
cyclic chain going through the imidazole plane on the C4–
H side and not on the N-Me side.
Transposition of the analytical chiral HPLC conditions
to a semipreparative scale allowed us to obtain the two
enantiomers of 1a in milligram amounts with an enantio-
meric excess of Ͼ99%. Biological evaluation of the two op-
Biological Evaluation
In a previous study,[6] we found that 1a and 1c display tically pure enantiomers of 1a enabled us to investigate the
potent binding activity towards three biological targets, influence of chirality on its biological activities.
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Planar Chirality of Imidazole-Containing Macrocycles
bined, washed with a saturated aqueous solution of NaCl (25 mL),
dried with MgSO4 and concentrated under reduced pressure. The
crude product was purified by flash chromatography using CH2Cl2/
2-propanol 97:3 as eluent.
Experimental Section
General Methods: Flash chromatography was performed on silica
gel (230–400 mesh). TLC was performed on aluminium backed sil-
ica plates, which were developed using standard visualizing agents:
UV fluorescence (254 and 366 nm), KMnO4. NMR spectra were
5-[2-(Hex-5-enyloxy)phenyl]-1-methyl-2-(pent-4-enyloxy)-1H-imid-
azole (5b): Orange oil; yield 81%. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.34–7.23 (m, 2 H), 7.00–6.92 (m, 2 H), 6.61 (s, 1 H),
5.89–5.72 (m, 2 H), 5.10–4.94 (m, 4 H), 4.40 (t, J = 6.5 Hz, 2 H),
3.96 (t, J = 6.5 Hz, 2 H), 3.25 (s, 3 H), 2.28–2.20 (m, 2 H), 2.10–
2.02 (m, 2 H), 1.97–1.87 (m, 2 H), 1.80–1.70 (m, 2 H), 1.52–1.42
(m, 2 H) ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 156.8, 153.4,
138.5, 137.8, 132.0, 129.6, 126.5, 121.6, 120.7, 119.9, 115.3, 114.9,
recorded at 300 or 500 MHz for H NMR and at 75 MHz for 13C
1
NMR spectroscopy. Chemical shifts (δ) are given in ppm downfield
from internal tetramethylsilane. Reactions with microwave heating
were conducted in a sealed tube using a MicroSYNTH instrument
(Milestone Srl). The temperature of the reaction mixture was moni-
tored by an infrared sensor. HPLC analyses were performed at a
flow rate of 1 mLmin–1 with a Daicel Chiralpak® IB 4 6ϫ250 mm
5 μm column with a mixture of 95% hexane and 5% ethanol
(v/v) as the mobile phase, using a UV detector. The synthesis and
characterization of 1, 2, 3, and 5 with n = 1 and 3 (denoted a and
c, respectively) have been previously reported.[6,11]
112.2, 68.8, 68.3, 33.4, 30.2, 29.5, 28.7, 28.5, 25.3 ppm. IR: ν =
˜
2974, 2941, 2872, 1537, 1497, 1448, 1377, 1244, 1144, 1009, 910,
752, 681 cm–1. MS (APCI): m/z = 341 [M + 1]+. HRMS: calcd. for
C21H29N2O2 [M + 1]+ 341.2229; found 341.2231.
2-(Hept-6-enyloxy)-5-[2-(hex-5-enyloxy)phenyl]-1-methyl-1H-imid-
azole (5d): Yellow oil; yield 84%. 1H NMR: (300 MHz, CDCl3,
25 °C): δ = 7.34–7.23 (m, 2 H), 7.00–6.92 (m, 2 H), 6.61 (s, 1 H),
5.86–5.73 (m, 2 H), 5.04–4.93 (m, 4 H), 4.38 (t, J = 6.6 Hz, 2 H),
3.96 (t, J = 6.6 Hz, 2 H), 3.25 (s, 3 H), 2.09–2.03 (m, 4 H), 1.85–
1.70 (m, 4 H), 1.52–1.42 (m, 6 H) ppm. 13C NMR (75 Hz, CDCl3,
25 °C): δ = 156.8, 153.5, 138.9, 138.5, 132.0, 129.6, 126.4, 121.6,
120.7, 120.0, 114.9, 114.5, 112.2, 69.4, 68.4, 33.7, 33.4, 29.4, 29.1,
General Procedure for SNAr (2 Ǟ 3): Pentenol (1.24 g, 14.36 mmol,
5 equiv.) was added to a solution of sodium hydride (528 mg of a
60 wt.-% suspension in mineral oil, 13.21 mmol, 4.6 equiv.) in dry
tetrahydrofuran (THF, 10 mL) under argon. The solution was
stirred until gas evolution was complete and then added to a solu-
tion of 1-methyl-5-iodo-2-phenylsulfonylimidazole (1 g, 2.87 mmol,
1 equiv.) in dry THF (50 mL). The reaction mixture was transferred
to a sealed tube and heated with a microwave for 6.5 h at 80 °C.
Ethyl acetate (100 mL) and saturated sodium chloride solution
(50 mL) were successively added. The organic phase was washed
twice with saturated sodium chloride solution (50 mL). The com-
bined aqueous phases were extracted with ethyl acetate (50 mL).
The combined organic phases were dried with MgSO4 and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography with silica using hexane/ethyl acetate, 80:20
as eluent.
2ϫ 28.7, 25.5, 25.3 ppm. IR: ν = 2928, 2856, 2380, 1535, 1497,
˜
1448, 1381, 1244, 1144, 995, 910, 752 cm–1. MS (APCI): m/z = 369
[M + 1]+. HRMS: calcd. for C23H33N2O2 [M + 1]+ 369.2542; found
369.2536.
General Procedure for Ring Closing Metathesis (5 Ǟ 6): Diene 5b
(95 mg, 0.279 mmol, 1 equiv.) and 1,2-dichloroethane (80 mL) were
heated to reflux and Grubbs catalyst (second generation) (13 mg,
0.015 mmol, 0.05 equiv.) was added. After 24 h, a second fraction
of Grubbs catalyst (6 mg, 0.008 mmol, 0.025 equiv.) was added. Af-
ter 24 h, the mixture was cooled to room temperature and potas-
sium isocyanoacetate[17] (17 mg) was added. After stirring for 1 h,
the solvent was evaporated. The crude product was filtered through
silica using CH2Cl2/2-propanol 97:3 as eluent. Compound 6b was
used directly in the next step.
5-Iodo-1-methyl-2-(pent-4-enyloxy)-1H-imidazole (3b): Yellow oil;
1
yield 88%. H NMR: (300 MHz, CDCl3, 25 °C): δ = 6.73 (s, 1 H),
5.88–5.79 (m, 1 H), 5.09–4.98 (m, 2 H), 4.34 (t, J = 6.5 Hz, 2 H),
3.34 (s, 3 H), 2.21–2.16 (m, 2 H), 1.90–1.85 (m, 2 H) ppm. 13C
NMR (75 Hz, CDCl3, 25 °C): δ = 153.6, 137.5, 130.1, 115.3, 69.1,
63.5, 31.1, 30.0, 28.2 ppm. IR: ν = 3076, 2974, 2947, 1541, 1497,
˜
1472, 1448, 1406, 1377, 1356, 1254, 1207, 1142, 1063, 1018, 912,
797, 708 cm–1. MS (APCI): m/z = 292 [M + 1]+. HRMS: calcd. for
C9H13IN2O [M + 1]+ 292.00671; found 292.00703.
General Procedure for Hydrogenation (6 Ǟ 1): Pd/C 10% catalyst
(≈ 0.05 equiv.) was added to a solution of imidazole 6b (1 equiv.)
in a 1:1 mixture of ethanol and ethyl acetate (10 mL). The resulting
suspension was degassed by a flow of argon for 30 min and then
stirred under a hydrogen atmosphere for 3 h at room temperature.
The suspension was filtered through a Celite pad, washed with
ethyl acetate and evaporated under reduced pressure. The crude
product was purified by flash chromatography using hexane/ethyl
acetate (70:30) as eluent.
2-(Hept-6-enyloxy)-5-iodo-1-methyl-1H-imidazole (3d): Yellow oil;
1
yield 80%. H NMR (300 MHz, CDCl3, 25 °C): δ = 6.73 (s, 1 H),
5.85–5.76 (m, 1 H), 5.03–4.93 (m, 2 H), 4.31 (t, J = 6.6 Hz, 2 H),
3.33 (s, 3 H), 2.08–2.05 (m, 2 H), 1.80–1.75 (m, 2 H), 1.46–1.43 (m,
4 H) ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 153.9, 138.8,
130.2, 114.6, 69.8, 63.4, 33.7, 31.2, 28.9, 28.6, 25.4 ppm. IR: ν =
˜
1b: Yellow oil; yield 41% over two steps. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 7.33–7.27 (m, 2 H), 7.00–6.90 (m, 2 H), 6.54 (s,
1 H), 4.90–4.82 (m, 1 H), 4.29–4.22 (m, 1 H), 4.17–4.11 (m, 1 H),
3.78–3.71 (m, 1 H), 3.25 (s, 3 H), 1.86–1.26 (m, 14 H) ppm. 13C
NMR (75 Hz, CDCl3, 25 °C): δ = 157.1, 153.3, 131.8, 129.9, 126.5,
121.2, 120.8, 120.2, 111.9, 69.4, 68.4, 30.0, 29.5, 28.1, 28.0, 27.7,
2930, 2856, 1541, 14475, 1379, 1254, 1142, 1063, 1018, 910, 708
cm–1. MS (APCI): m/z = 320 [M]+. HRMS: calcd. for C11H18IN2O
[M + 1]+ 321.04638; found 321.04619.
General Procedure for Suzuki Coupling (3 Ǟ 5): Tetrakis(triphenyl-
phosphanyl) palladium (6.5 mg, 0.006 mmol, 0.03 equiv.) and imid-
azole 3b (50 mg, 0.171 mmol, 1 equiv.) in dimethoxyethane (2 mL)
were put in a microwave tube. Boronic acid (41.5 mg, 0.188 mmol,
1.1 equiv.) in dimethoxyethane (2 mL), water (2 mL) and an aque-
ous solution of sodium carbonate (20%, 286 μL, 3 equiv.) were
added successively. The resulting mixture was degassed for 30 min
by a flow of argon and heated in a microwave oven at 105 °C and
200 W for 1 h. Ethyl acetate (50 mL) and water (25 mL) were
added. The phases were separated and the aqueous phases were
extracted with ethyl acetate (25 mL). The organic phases were com-
26.7, 24.7, 24.5 ppm. IR: ν = 2930, 2854, 1537, 1494, 1448, 1246,
˜
1053, 752 cm–1. MS (ESI): m/z = 315 [M + 1]+. HRMS: calcd. for
C19H27N2O2 [M + 1]+ 315.2073; found 315.2083.
1
1d: Colourless oil; yield 58% over two steps. H NMR (300 MHz,
CDCl3, 25 °C): δ = 7.33–7.25 (m, 2 H), 6.99–6.91 (m, 2 H), 6.55 (s,
1 H), 4.50–4.47 (m, 2 H), 3.97–3.94 (m, 2 H), 3.25 (s, 3 H), 1.82–
1.28 (m, 18 H) ppm. 13C NMR (75 Hz, CDCl3, 25 °C): δ = 157.1,
153.4, 132.3, 129.8, 126.8, 121.1, 120.7, 120.1, 111.9, 68.5, 68.4,
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29.7, 29.3, 28.7, 28.1, 27.9, 27.5, 26.8, 26.0, 25.7, 24.6 ppm. IR: ν
˜
Acknowledgments
= 2927, 2856, 1580, 1537, 1495, 1468, 1448, 1375, 1279, 1244, 1142,
1053, 1009, 752 cm–1. MS (ESI): m/z = 343 [M + 1]+. HRMS:
calcd. for C21H31N2O2 [M + 1]+ 343.2386; found 343.2393.
This work has been supported by the Fonds de la Recherche Sci-
entifique – FNRS (Fonds de la Recherche Fondamentale Collec-
tive, FRFC, project number 2.4502.05). We are grateful to Dr.
Cécile Le Duff for her technical assistance in NMR spectroscopy.
R. R. is a Chercheur Qualifié of the F.R.S.-FNRS.
Computational Details: All structures were obtained from geometry
optimizations in vacuo using the Jaguar 7.5 pseudospectral pro-
gram package.[18] These calculations used the well established
B3LYP hybrid functional,[19] as implemented in Jaguar 7.5, and the
standard 6-31G* basis set[20] on all atoms (default grid and geome-
try convergence criteria). For the large systems considered here,
there are several local minima or saddle points corresponding to
multiple conformations of substituents (in particular the alicyclic
chain). Each minimum was subjected to conformational searching
at the B3LYP/6-31G* level, using Spartan, to identify the lowest
energy conformer.
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level of theory with the cc-pVTZ basis[21] using the ORCA pack-
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the conductor-like screening model (COSMO) as implemented in
ORCA, using parameters appropriate for chloroform.
Vibrational frequencies were computed for all stationary points at
the B3LYP/6-31G* level of theory and used to include corrections
for zero-point energy as well as thermal and entropic corrections
to compute free energies. The correct nature of the stationary
points was checked: TS have only one imaginary frequency,
whereas minima have no imaginary frequency.
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Biological Assays: Assays were performed in duplicate (by CEREP,
France) on fumaric salts of synthesized macrocycles. The purity of
all tested compounds was determined by HPLC. The purity was
Ͼ98%, unless mentioned otherwise.
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[8] A referee of this article questioned the correctness of the term
“planar” for describing the chirality of macrocycles 1. In our
opinion both planar and axial terms are appropriate in this
case. However, as the origin of chirality of 1a–b is linked to
their cyclophane-type structure, and not their biaryl moiety, we
believe that “planar” chirality is more suitable.
[9] For the only reported example of a cyclophane-type imidazole
with a planar chirality, to the best of our knowledge, see: Y.
Ishida, E. Iwasa, Y. Matsuoka, H. Miyauchi, K. Saigo, Chem.
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[10] For an example illustrating the importance of atropoisomerism
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The specific ligand binding to the receptors is defined as the differ-
ence between the total binding and the nonspecific binding deter-
mined in the presence of an excess of unlabelled ligand. The results
are expressed as a percentage of control specific binding [(measured
specific binding/control specific binding) ϫ100] and as a percen-
tage inhibition of control specific binding [100 – {(measured spe-
cific binding/control specific binding)ϫ100}] obtained in the pres-
ence of the tested compound.
The IC50 values (concentration causing a half-maximal inhibition
of control specific binding) and Hill coefficients (nH) were deter-
mined by nonlinear regression analysis of the competition curves
generated with mean replicate values using Hill equation curve fit-
ting Y = D + [(A – D)/(1 + (C/C50)nH)], where Y = specific binding,
D = minimum specific binding, A = maximum specific binding, C
= compound concentration, C50 = IC50 and nH = slope factor. This
analysis was performed using software developed at CEREP (Hill
software) and validated by comparison with data generated by the
commercial software SigmaPlot® 4.0 for Windows® (© 1997 by
SPSS Inc.).
[12] The two separated compounds show identical UV spectra (see
Supporting Information).
[13] Careful analysis of the chromatogram for 1b reveals the occur-
rence of a plateau shape, which indicates enantiomer intercon-
version on the column at a rate similar to that of the separation
process. This plateau shape has been confirmed by performing
HPLC at different temperatures (see Supporting Information).
Determination of the kinetic constant for interconversion from
the height of this plateau gives an estimated activation free en-
ergy of 22.9 kcalmol–1 (see Supporting Information for full
details).
[14] a) E. S. Johnson, in: Advances in Magnetic Resonance (Ed.: J. S.
Waugh), Academic Press, New York, 1956, vol. 1, chapter 2,
pp. 64–68; b) H. Gunther, in: NMR spectroscopy, 2nd ed., New
York, Wiley, 1995, chapter 9.
The inhibition constants (Ki) were calculated using the Cheng Pru-
soff equation, Ki = IC50/[1 + (L/KD)], where L = concentration of
radioligand in the assay and KD = affinity of the radioligand for
the receptor.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra, HPLC chromatograms and UV
spectra of 1a–d and 5a–b; determination of activation energy for
1b–c; optimized Cartesian coordinates and corresponding energies
for all species discussed in the text.
[15] The identical UV spectra (see Supporting Information) and op-
posite optical activity ([α]2D0 = +92 and –93; CHCl3) of the two
isolated compounds confirm their enantiomeric relationship.
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Planar Chirality of Imidazole-Containing Macrocycles
[16] Investigation of the configurational stability at 37 °C in H2O/
dimethyl sulfoxide (95:5) did not show racemization.
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[22] F. Neese, ORCA, An Ab Initio, DFT, and Semiempirical Elec-
tronic Structure Package, version 2.7.0, University of Bonn,
Germany, 2010.
Received: June 6, 2011
Published Online: September 22, 2011
Eur. J. Org. Chem. 2011, 6649–6655
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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