Cavity-extended inherently chiral resorcin[4]arenes: Synthesis and chiroptical properties of the cycloenantiomers

Article abstract of DOI:10.1002/ejoc.200700802

Inherently chiral resorcin[4]arenes 2 and 3 were prepared from enantiomerically pure C₄-symmetric rccc-2,8,14,20-tetraisobutyl-4,10, 16,22-tetra-O-methylresorcin[4]arene (1). The four 2-bromobenzyl ether residues in precursor 2 were introduced

Full text of DOI:10.1002/ejoc.200700802

FULL PAPER
DOI: 10.1002/ejoc.200700802
Cavity-Extended Inherently Chiral Resorcin[4]arenes: Synthesis and Chiroptical
Properties of the Cycloenantiomers
[a]
[a]
[b]
[b]
Marlene Paletta, Michael Klaes, Beate Neumann, Hans-Georg Stammler,
[
c]
[a]
Stefan Grimme, and Jochen Mattay*
Keywords: Atropisomerism / Calixarenes / Chirality / Circular dichroism / Cross-coupling
Inherently chiral resorcin[4]arenes 2 and 3 were prepared
from enantiomerically pure C -symmetric rccc-2,8,14,20-
ether compounds as well as (M,R)-(–)-3 and (P,S)-(+)-3 for the
cavity-extended resorcinarenes. The carbon scaffold of 3
contains four new stereogenic axes whose configurations
were assigned by single-crystal X-ray analysis. The simula-
tion of the CD spectra by time-dependent Pariser–Parr–Pople
calculations (TDPPP) based on the X-ray data gave very good
images of the experimental spectra.
4
tetraisobutyl-4,10,16,22-tetra-O-methylresorcin[4]arene (1).
The four 2-bromobenzyl ether residues in precursor 2 were
introduced as halide moieties to partake in an intramolecular
Pd-catalysed C–C cross-coupling reaction to give tetrabiaryl
ether compound 3. The absolute configurations could be de-
rived from the starting compounds and were assigned as
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
(
M,R)-(–)-2 and (P,S)-(+)-2 for the tetrakis(2Ј-bromobenzyl)
Introduction
of simple resorcinarenes by using Pd-catalysed intramolecu-
lar C–C cross-coupling reactions to obtain more stable
macrocycles of this type. The four phenolic hydroxy groups
of tetramethoxy resorcin[4]arene 1 provide the advantage of
introducing an aryl halide component as an ether or ester
Resorcinarenes are three-dimensional macrocycles that
are used in various aspects of supramolecular chemistry, for
[
1]
example, as building blocks and in molecular recognition
as well as in chiral assemblies.[ The chirality of inherently
chiral resorcinarenes originates from the topology of the
nonplanar structure. Host–guest complexation experiments
with chiral ammonium ions have shown some effect of chi-
2]
functionality for a subsequent intramolecular C–C cross-
[8,9]
coupling reaction.
The direct arylation leading to a bi-
aryl compound requires no further activation of the upper
rim aryl position of the resorcinarene, which is otherwise
necessary for intermolecular cross-coupling reactions. In-
tramolecular arylation reactions generating four carbon–
carbon bonds have not been reported in the literature so
far.
Herein, we report the synthesis and optical resolution of
inherently chiral resorcin[4]arenes with known absolute
configuration and an extended cavity following a synthetic
pathway for intramolecular biaryl formation. The circular
dichroism spectra of the enantiomers are compared to those
of time-dependent Pariser–Parr–Pople (TDPPP) calcula-
tions.
[
3]
ral discrimination. For the purpose of complex formation
with a larger variety of guest molecules, the synthetic ap-
proach to cavity-extended resorcinarenes is of interest.
Inherently chiral resorcinarenes can be obtained directly
as racemates from the Lewis acid catalysed reaction of 3-
alkoxyphenols with aldehydes[4] or from the cyclisation of
the corresponding benzylic alcohols.[ The C -symmetric
enantiomers of the starting material, rccc-2,8,14,20-tetraiso-
butyl-4,10,16,22-tetra-O-methylresorcin[4]arene, are already
5]
4
[
6]
characterised with regard to the absolute configuration.
A very convenient one-step procedure to synthesise cav-
ity-enlarged chiral 1,3-oxazine derivatives was reported by
us more than one decade ago.[ However, although enantio-
merically pure, these compounds were not stable under pro-
tic conditions. Therefore, we decided to enlarge the cavity
7]
Results and Discussion
Synthesis of Tetrakis(2Ј-bromobenzyl) Ether 2 and
Tetrabiaryl Ether 3
[
a] Organische Chemie I, Fakultät für Chemie, Universität Bielefeld,
Postfach 100131, 33501 Bielefeld, Germany
Fax: +-49-521-1066417
C -symmetric inherently chiral resorcin[4]arene rac-1 was
4
[
4]
synthesised according to literature procedures. The race-
mate was monofunctionalised with freshly prepared (S)-
(+)-10-camphorsulfonyl chloride in acetonitrile by using
K CO as the base to convert the enantiomers into dia-
E-mail: oc1jm@uni-bielefeld.de
[b] Anorganische Chemie III, Fakultät für Chemie, Universität
Bielefeld,
Postfach 100131, 33501 Bielefeld, Germany
c] Organisch-Chemisches Institut (Abt. Theoretische Chemie),
Westfälische Wilhelms-Universität,
2
3
[
[
7,10]
stereomers that were separable by silica gel HPLC.
resorcinarenes were characterised by NMR spectroscopy,
The
4
8149 Münster, Germany
Eur. J. Org. Chem. 2008, 555–562
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
555

M. Paletta, M. Klaes, B. Neumann, H.-G. Stammler, S. Grimme, J. Mattay
5
FULL PAPER
and the diastereomeric excess was determined to be 100%. –4.2 (c = 0.69, CHCl ) and [α]2 = +5.6 (c = 1.00, CHCl3),
3
D
The esters were hydrolysed under strong alkaline conditions respectively.
to afford (P,S)-(+)-1 and (M,R)-(–)-1 in overall moderate The synthetic challenge was to generate four new car-
yields. The [α]D values correspond to the optical properties bon–carbon bonds on the sterically demanding upper rim
of the resorcin[4]arenes with known absolute configura- of the resorcinarene. The biaryl scaffold was built up
[
5]
tions. The compounds subsequently synthesised from through an intramolecular coupling reaction following the
[
8a,8b,11–13]
(P,S)-(+)-1 and (M,R)-(–)-1 were therefore enantiomerically procedures for direct arylation of simple arenes.
pure. The reactions were carried out first with the racemates As the catalytic system, Pd(OAc) and PCy (2 equiv.) were
2
3
and then with the enantiomerically pure compounds chosen; an amount of 30 mol-% per functionality was nec-
Scheme 1). essary to complete the reaction and K CO (2 equiv. per
Tetrakis(2Ј-bromobenzyl) ether 2 was first prepared from functionality) was added as the base. The extent of conver-
(
2
3
rac-1 and 2-bromobenzyl bromide (1.4–1.8 equiv. per func- sion was followed by MALDI-ToF spectrometry. The grad-
tionality) in dry DMF in the presence of K CO (8 equiv.) ual formation of the product was observed as a mixture of
2
3
and were separated from the tris(bromobenzyl) ether by col- the mono, di, tri and tetrabiaryl compounds. After 20 h of
umn chromatography. To improve the procedure, racemate heating at 130 °C in DMA, the only indicated m/z signals
+
+
rac-1 was deprotonated with NaH (5 equiv. per function- were 1122 [M + H] and 1144 [M + Na] , which could be
ality) in dry DMF to yield the phenolate salt, which was ascribed to tetrabiaryl ether rac-3. Resorcinarene rac-3 was
then treated with 2-bromobenzyl bromide (1.07 equiv. per purified by column chromatography on silica gel to remove
hydroxy group) to give tetrakis(bromobenzyl) ether rac-2. inorganic salts and catalyst residues. After recrystallisation
Recrystallisation from chloroform and methanol yielded from chloroform and methanol the yield was 18%. The en-
84% of pure rac-2. The enantiomerically pure products antiomerically pure resorcinarenes were obtained in 12%
were obtained following the described protocol and purified [(M,R)-(–)-3] and 17% [(P,S)-(+)-3] yield starting from the
by column chromatography on silica gel to remove the ex- enantiomers of 2. The low yield of the arylation reaction
cess amount of 2-bromobenzyl bromide. Compounds cannot be justified yet. After workup and purification, there
(
M,R)-(–)-2 and (P,S)-(+)-2 were received in 92 and 72% was no difference in the yield due to the addition of the
25
yield, respectively, and show specific rotations of [α]
=
ligand as a free phosphane or as an HBF salt that could
D
4
Scheme 1. Synthesis of tetrakis(2Ј-bromobenzyl) ether 2 and cyclic tetrabiaryl ether 3. Reagents and conditions: (a) (i) NaH, DMF, (ii)
2 3 4 2 3
2-bromobenzyl bromide, 92%; (b) Pd(OAc) , PCy ·HBF , K CO , DMA, 130 °C, 20 h, 18%.
556
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Cavity-Extended Inherently Chiral Resorcin[4]arenes
have led to decomposition of the resorcinarene by a Lewis opposite axial chirality are located in the parallel arranged
acid catalysed reaction.
resorcinol residues. Each methoxy group points in the same
Recently, the absolute configuration of a C -symmetric direction as the methylene ether bridges of the dibenzopy-
4
tetramethyl resorcinarene (1) with pendant isobutyl groups ran units. Compound 3 containing four stereogenic bridg-
was determined by X-ray crystallographic analysis of the ing carbon atoms and four atropisomeric biaryl units was
separated diastereomers containing four (S)-(+)-10-cam- hence found to be of enantiomeric character.
phorsulfonyl esters as auxiliaries.[ The internal chirality
6]
reference revealed the configuration of the methine bridges.
After hydrolysis, the (–)-enantiomer of tetramethoxyresor-
cin[4]arene was shown to be of (M,R)-chirality and the (+)-
enantiomers of (P,S)-chirality. These results were confirmed
by analysis and alkaline hydrolysis of the tetra-(R)-(–)-10-
camphorsulfonyl ester diastereomers. Starting from com-
pounds (M,R)-(–)-1 and (P,S)-(+)-1, the absolute configura-
tions of the scaffolds of (+)-2 and (–)-2 had changed owing
to the introduction of the 2-bromobenzyl residues, which
have a higher priority according to the Cahn–Ingold–Prelog
rules. Thus, the configurations of (+)-2 and (–)-2 were de-
termined as (P,S) and (M,R), respectively, and in analogy,
those of (+)-3 and (–)-3 were determined as (P,S) and
(M,R).
Figure 1. Crystal structure of tetrakis(2Ј-bromobenzyl) ether resor-
cin[4]arene 2. Carbon atoms are shown as colourless circles, bro-
mine atoms as striped circles and the oxygen atoms as hatched
circles. Hydrogen atoms are omitted for clarity.
Crystal Structures and NMR Studies in Solution
Tetrakis(2Ј-bromobenzyl) ether resorcin[4]arene 2 was
The boat conformation should give rise to two sets of
1
recrystallised from chloroform and methanol to give trans- resonance signals for the aromatic protons in the H NMR
parent crystals suitable for single-crystal X-ray analysis. The spectrum; however, the cavity of 3 is not fixed in this con-
racemic crystal with a P2 /c space group shows a boat con- formation in solution. Instead, the C symmetry of 3 can
1
4
formation of the resorcinol scaffold. The 2Ј-bromobenzyl only be assumed on the basis of an averaged data set on
1
13
ether residues are not oriented regularly (Figure 1). The the NMR timescale (Figure 4). The H and C NMR reso-
crystal structure of 3 shows the extended resorcin[4]arene nance peaks were assigned by means of 1D and 2D NMR
in the boat conformation as well (Figure 2). The crystals of experiments (COSY, HMBC) (Figure 3). At room tempera-
¯
the racemic P1 space group comprise the two cycloenantio- ture, the peaks are slightly broadened and the multiplets are
mers. This differs from the enantiomerically pure com- not resolved properly. With increasing temperature up to
pounds precipitating each as an amorphous solid. The bi- 330 K, the resonances convert into definite singlets or mul-
aryl ether scaffold builds up four new atropisomeric units, tiplets, as can be seen for the methoxy groups at δ =
which leads to the potential diastereomeric nature of 3. In 3.26 ppm, the ether bridge protons at δ = 4.63 and
the solid state, the dibenzopyran units are twisted between 4.84 ppm, the aryl protons at δ = 6.73 ppm and 8.13 ppm
19.6 and 22.3° owing to the nonplanar ether bridges that and the diastereotopic protons of the methylene unit of the
have dihedral angles between 54.5° and 58.4°. On the basis alkyl chain at δ = 1.78 and 1.84 ppm (Figure 4). The ether
of the configuration of the methine bridges of 1, the relative bridges show two doublets for each proton at δ = 4.85 and
configuration can be derived as (M,M,M,P) for (M,R)-(–)- 4.64 ppm, respectively, which was already observed for the
3
and as (P,P,P,M) for (P,S)-(+)-3. The biaryl ethers with diastereotopic protons of 2 at δ = 5.03 and 4.82 ppm.
Figure 2. Crystal structure of tetrabiaryl ether resorcin[4]arene 3. View along the chiral axis of the inherently chiral scaffold. Carbon
atoms are shown as colourless circles and oxygen atoms as hatched circles. Hydrogen atoms are omitted for clarity.
Eur. J. Org. Chem. 2008, 555–562
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557

M. Paletta, M. Klaes, B. Neumann, H.-G. Stammler, S. Grimme, J. Mattay
FULL PAPER
Hence, for the observed doublets of 3, there are two pos-
sible effects on the benzylic protons resulting in that motif.
Either the anisotropic effect of the inherently chiral cavity
is very strong and helimerisation of the biaryl units is too
weak for monitoring by NMR spectroscopic techniques or
the ether bridge is configurationally stable and conse-
quently no interconversion occurs. The methoxy group is
sterically demanding and the high grade of substitution
prohibits free rotation around the C –O-bond. The sta-
Ar
bility of the chiral axes in cyclic ether atropisomers is
[
14]
known for several benzonaphthopyran compounds.
At
1
Figure 5. Partial H NMR spectrum (500 MHz) of biaryl ether res-
higher temperature, the doublets are resolved sharply, which orcinarene 3 at 213 K in CDCl
3
.
supports the assumption of a strong anisotropic effect. Fast
helimerisation should lead to a broadened signal for each
proton.
The interconversion of the two boat conformers becomes
slow and a coalescence point is observed at T = 263 K.
c
Below this temperature, peaks separate into two sets that
can be ascribed to the fixed boat conformation. The reso-
nance peaks were assigned by NOESY experiments at
2
03 K. The free enthalpy ∆Gc‡ for this interconversion was
calculated by Equation (1), where ∆ν is the resonance shift
[
15]
difference in Hz.
‡
∆
G = 19.1T
c
(9.97 + log T
c
– log ∆ν)
(1)
The complete freezing of the dynamics may not have
been reached, and therefore, the shift difference maxima of
the aromatic 3-H and 10-H protons and of the methoxy
Figure 3. The designation of the carbon and hydrogen atoms of 3
for NMR spectroscopic studies.
‡
groups were used. The energy barrier ∆G was calculated
c
–1
to be 48.4 kJmol . A very slow interconversion of the boat
conformations at low temperature minimises the anisotropy
for the coplanar arene units; however, the NMR spectro-
scopic experiments did not allow unambiguous interpret-
ation of the resonance peaks for the protons of the ether
bridge between 5.2 and 4.1 ppm and for those of the ortho
aryl position, which is referred to as diastereoisomerism of
the nonplanar pyran units. In conclusion the anisotropic
effect of the inherently chiral scaffold is adopted as the
main cause for the different resonance peaks, whereas a
stable configuration of the atropisomers cannot be ex-
cluded.
Chiroptical Properties
The UV and CD spectra of the enantiomeric pairs of 2
and 3 were measured in the nonpolar solvent cyclohexane
and show almost perfect mirror images (Figure 6 a and b).
The absolute configuration of the macrocyclic scaffold
can be deduced from the starting material, but the intro-
duced chiral axes may change their configuration in solu-
tion depending on the temperature. Only little is known
1
Figure 4. Partial H NMR spectra (500 MHz) of biaryl ether resor- about rotational barriers of cyclic biaryl ethers of the pyran
[
14]
cinarene 3 at (a) 300 K; (b) 310 K; (c) 320 K; and (d) 330 K in type.
CDCl
The racemisation of the atropisomers can take
3
.
place within hours at room temperature depending on the
ortho substituents, or it can be completely suppressed. The
Low-temperature NMR spectroscopic studies were car- configurations of the biaryl units in solution are not known
ried out in 1:1.5 mixtures of CDCl and CD Cl due to and the simulation of the CD spectra was performed on the
3
2
2
solubility of the sample. The NMR spectrum shown in Fig- basis of the X-ray data. The CD spectra of (M,R)-(–)-3 with
ure 5 was measured in deuterated chloroform. the (M,M,M,P)-configuration were generated by means of
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Cavity-Extended Inherently Chiral Resorcin[4]arenes
Figure 6. UV/Vis (top) and CD spectra (bottom) of (a) rac-2 and enantiomerically pure tetrakis(bromobenzyl) ether resorcin[4]arenes
(
(
M,R)-(–)-2 and (P,S)-(+)-2, respectively and of (b) rac-3 and enantiomerically pure tetrabiaryl ether resorcin[4]arenes (M,R)-(–)-3 and
P,S)-(+)-3, respectively. The measurements were carried out in cyclohexane at ambient temperature.
time-dependent Pariser–Parr–Pople (TDPPP) calcula- slightly shifted to shorter wavelengths. Analogous simula-
[
16]
tions,
which included only the π-electrons of the basic tions of the CD signal with different dibenzopyran and
biaryl ethers (Figure 7).
methoxy configurations resulted in significantly differing
spectra.
Conclusions
Cavity-extended inherently chiral resorcin[4]arenes
(
M,R)-(–)-3 and (P,S)-(+)-3 were prepared from enantio-
merically pure tetramethoxy resorcinarenes (P,S)-(+)-1 and
M,R)-(–)-1 with known absolute configurations by reac-
(
tion with 2-bromobenzyl bromide and a subsequent intra-
molecular Pd-catalysed C–C cross-coupling reaction. Race-
mic compounds 2 and 3 were characterised by X-ray data
analysis, and the relative configurations of the dibenzo-
pyran units of 3 in the solid state were determined as
(M,M,M,P) for (M,R)-(–)-3 and as (P,P,P,M) for (P,S)-(+)-
3. The conformational studies in solution show a magnetic
equivalence of all aromatic protons and of the benzylic pro-
tons at temperatures between 300 and 330 K. The intercon-
version process of the two boat conformations requires
Figure 7. CD spectrum of (M,M,M,P)-(M,R)-(–)-3 generated by
TDPPP calculations (dotted line) and the experimentally obtained
spectrum (solid line).
–1
48 kJmol .
TDPPP calculations gave very good reproduction of the
The CD spectra of (M,R)-(–)-3 and (P,S)-(+)-3 are mir-
experimental data. Compared to the experimental spec- ror images, which shows their enantiomeric nature. On the
trum, the theoretical excitation energies merely seem to be basis of the X-ray data, the spectra were simulated by
Eur. J. Org. Chem. 2008, 555–562
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559

M. Paletta, M. Klaes, B. Neumann, H.-G. Stammler, S. Grimme, J. Mattay
FULL PAPER
TDPPP calculations and reproduced the experimental data CO), 69.98 (OCH
CHAr), 25.94 [(CH
ppm. IR (KBr): ν˜ = 2951, 2864, 2831, 1610, 1582, 1498, 1464, 1444,
2
), 55.59 (OCH
3
), 43.81 (CHCH
2
CH), 33.46 (Ar-
3
)
2
CH], 22.89 [(CH
3
)
2
CH], 22.79 [(CH
3 2
)
CH]
in a very good manner. As compounds (M,R)-(–)-3 and
P,S)-(+)-3 are enantiomers in the crystal structure and
show mirror images in their CD spectra, they are denoted
as cycloenantiomers.
(
1
8
405, 1381, 1364, 1297, 1192, 1130, 1098, 1042, 1026, 944, 912,
13, 781, 750, 664, 613 cm . UV/Vis (cyclohexane):
mol dm cm ) = 224 (64000), 286 (17000) nm. HRMS (ESI):
–
1
λ (ε,
–
1
3
–1
+
+
calcd. for
C
76
H
88Br
4
NO
8
[M
+
NH
4
]
1458.3238; found
1
6
458.3246. C76
3.07, H 5.98.
H
84
O
8
4
Br (1445.1): calcd. C 63.17, H 5.86; found C
Experimental Section
rac-2: Crystal size 0.30ϫ0.30ϫ0.26 mm, monoclinic, P2
1
/c, a =
General Remarks: All solvents used were of an analytically pure
quality or purified by distillation. Melting points were determined
with a Büchi B-540 apparatus and are uncorrected. NMR spectra
1
1
9.1950(2) Å,
b
=
23.9900(3) Å,
c
=
15.98900(10) Å, β =
3
–3
11.2580(5)°, Z = 4, V = 6861.76(10) Å , ρcalcd. = 1.399 mgm ,
–
1
1
2Θmax = 54.96°, µ = 2.401 mm , F(000) = 2976, 817 parameters,
= 0.0500, wR = 0.1299 {for 12184 reflections [IϾ2σ(I)]}, R =
0.0682, wR(F ) = 0.1425 (for 15680 unique reflections), Rint
.057, S = 1.035, ∆ρ(min/max) = –1.59/2.81 eÅ .
were recorded with a Bruker DRX 500 ( H NMR: 500.13 MHz,
1
3
R
1
2
3 3
C NMR: 125.77 MHz) instrument in CDCl with CHCl as refer-
1
13
2
=
ence ( H: 7.24 ppm, C: 77.0 ppm). Single-crystal X-ray analyses
were carried out at 100(2) K with a Nonius KappaCCD dif-
–
3
0
fractometer by using Mo-K
α
radiation of the wavelength 0.71073 Å.
(M,R)-(–)-rccc-4,10,16,22-Tetrakis-O-(2Ј-bromobenzyl)-2,8,14,20-tet-
raisobutyl-6,12,18,24-tetra-O-methylresorcin[4]arene [(M,R)-(–)-2]:
NaH (60% in paraffin oil, 130 mg, 3.25 µmol) was washed twice
with cyclohexane and suspended in dry DMF (6 mL). A solution
of (P,S)-(+)-1 (143 mg, 186 µmol) in dry DMF (12 mL) was added
dropwise, and the suspension was stirred for 0.5 h at room tempera-
ture. 2-Bromobenzyl ether (398 mg, 1.59 mmol) was dissolved in
DMF (3 mL) and added dropwise. After the mixture was stirred
for 12 h, methanol (5 mL) was added to remove the excess amount
of NaH. The solvent was removed in vacuo, and the residue was
The structures were solved and refined with SHELXS-97 with re-
2
finements on F . The hydrogen atoms were normally calculated to
idealised temperature factors and refined as riding atoms. Disor-
dered solvent molecules and pendant alkyl chains were treated iso-
tropically. IR spectra were recorded with a Perkin–Elmer 841 infra-
red spectrophotometer. HRMS were recorded with a Bruker APEX
III with ESI in positive ion mode, and spectra were internally cal-
ibrated with HP TuneMix (m/z = 622/922/1522). Specific rotations
were recorded with a Perkin–Elmer 341 polarimeter. [a]
D
values
–1
2 –1
are given in units of 10 °cm g . CD spectra were recorded in
cyclohexane at room temperature with a JASCO J-810 spectropola-
rimeter.
dissolved in water and CHCl . The phases were separated, and the
3
aqueous phase was extracted with CHCl (3ϫ15 mL). The com-
3
bined organic phase was washed with brine, dried with anhydrous
MgSO
idue was purified by column chromatography (SiO
Ǟ cyclohexane/ethyl acetate, 9:1) to yield 247 mg of (M,R)-(–)-2
4
and evaporated under reduced pressure. The colourless res-
CCDC-644932 and -644933 contain the supplementary crystallo-
graphic 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.
2
; cyclohexane
2
5
(
92%). [α]
D
= –4.2 (c = 0.69, CHCl
3
). HRMS (ESI): calcd. for
+
+
C
76
H88Br
4
8 4
NO [M + NH ] 1458.3238; found 1458.3217.
(
؎)-rccc-4,10,16,22-Tetrakis-O-(2Ј-bromobenzyl)-2,8,14,20-tetraiso-
(
P,S)-(+)-rccc-6,12,18,24-Tetrakis-O-(2Ј-bromobenzyl)-2,8,14,20-tet-
butyl-6,12,18,24-tetra-O-methylresorcin[4]arene (rac-2): NaH (60%
in paraffin oil, 2.20 g, 55.0 mmol) was washed with cyclohexane
and suspended in dry DMF (50 mL). A solution of (Ϯ)-rccc-
raisobutyl-4,10,16,22-tetra-O-methylresorcin[4]arene [(P,S)-(+)-2]:
NaH (60% in paraffin oil, 30.0 mg, 750 µmol) was washed twice
with cyclohexane and suspended in dry DMF (6 mL). A solution
of (M,R)-(–)-1 (72.0 mg, 93.6 µmol) in dry DMF (5 mL) was added
dropwise, and the suspension was stirred for 0.5 h at room tempera-
ture. 2-Bromobenzyl ether (103 mg, 412 µmol) was dissolved in
DMF (8 mL) and added. After the mixture was stirred for 12 h,
methanol (5 mL) was added to remove the excess amount of NaH.
The solvent was removed in vacuo, and the residue was taken up
2
,8,14,20-tetraisobutyl-4,10,16,22-tetra-O-methylresorcin[4]arene
(rac-1; 2.00 g, 2.60 mmol) in dry DMF (30 mL) was added drop-
wise, and the suspension was stirred for 0.5 h at ambient tempera-
ture. 2-Bromobenzyl ether (2.78 g, 11.1 mmol, 4.3 equiv.) was dis-
solved in DMF (10 mL) and added dropwise. After the mixture
was stirred for 12 h, methanol (5 mL) was added to remove the
excess amount of NaH. The solvent was removed in vacuo, and the
with water (40 mL) and CHCl
rated, and the aqueous phase was extracted with CHCl
3
(30 mL). The phases were sepa-
residue was dissolved in water and CHCl
rated, and the aqueous phase was extracted with CHCl
3
. The layers were sepa-
3
3
(
3ϫ15 mL). The combined organic phase was washed with brine,
(2ϫ40 mL). The combined organic phase was washed with brine,
4
dried with anhydrous MgSO and evaporated under reduced pres-
sure and purified by column chromatography (cyclohexane/ethyl
acetate, 4:1) to yield the colourless solid of (P,S)-(+)-2 (98.0 mg,
7
dried with anhydrous MgSO
sure. The colourless solid was recrystallised from CHCl
give rac-2 as colourless crystals (3.15 g, 84%). M.p. 210–212 °C. H
NMR (500 MHz, CDCl , 25 °C): δ = 7.530 (dd, J = 8.2 Hz, J =
3
1
4
and evaporated under reduced pres-
/MeOH to
3
1
2
5
2%). [α]
D
= +5.6 (c = 1.00, CHCl
3
). HRMS (ESI): calcd. for
3
4
+
+
C H88Br NO [M + NH ] 1458.3238; found 1458.3244.
76 4 8 4
3
3
.3 Hz, 4 H, 3Ј-H), 7.305 (d, J = 7.6 Hz, 4 H, 6Ј-H), 7.159 (td, J
6.6 Hz, 4J = 1.3 Hz, 4 H, 5Ј-H), 7.118 (td, 3J = 7.5 Hz, J = Biaryl Ether rac-3: rac-2 (500 mg, 346 µmol), dried
), 6.384 (s, 4 (383 mg, 2.77 mmol) and DMA (10 mL) were placed and in a two-
), 5.030 (d, J = 12.6 Hz, 4 H, OCH ), 4.819 necked round-bottom flask. The suspension was degassed by three
), 4.715 (t, J = 7.6 Hz, 4 H, ArCHAr), freeze–pump–thaw cycles. Pd(OAc) (67.0 mg, 298 µmol) and
), 1.758 (m, 8 H, CHCH CH), 1.598 [m, 4 H, PCy ·HBF (206 mg, 559 µmol) were added under an argon atmo-
CH], 0.863 [d, J sphere. The yellow mixture was heated to 130 °C for 20 h. The sus-
4
=
1
2 3
K CO
.3 Hz, 4 H, 4Ј-H), 6.697 (s, 4 H, ArH meta ArOCH
3
2
H, ArH ortho ArOCH
3
2
2
3
(d, J = 13.2 Hz, 4 H, OCH
2
2
3
.424 (s, 12 H, OCH
3
2
3
4
3
3
(CH
3
)
2
CH], 0.897 [d, J = 6.3 Hz, 12 H, (CH
6.3 Hz, 12 H, (CH
CH] ppm. 13C NMR (125 MHz, CDCl
), 154.55 (ArOCH ), 136.97 (C-1Ј),
3 2
)
=
2
3
)
2
3
,
pension turned black and was filtered through silica gel. The sol-
vent was removed under reduced pressure, and the residue was
5 °C): δ = 155.64 (ArOCH
3
2
132.10 (C-3Ј), 129.25 (C-6Ј), 128.81 (C-4Ј), 127.36 (C-5Ј), 126.45 purified by column chromatography (SiO
2
; cyclohexane/ethyl ace-
(Ar
q
), 126.39 (Ar ), 125.97 (Ar ), 121.94 (ArBr), 97.51 (ArH ortho tate, 95:5). The colourless solid was recrystallised from CHCl /
q
q
3
560
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 555–562

Cavity-Extended Inherently Chiral Resorcin[4]arenes
MeOH to yield rac-3 (60.2 mg, 16%). M.p. 207 °C (decomp.). H
1
[2] M. O. Vysotsky, C. Schmidt, V. Böhmer, Advances in Supramo-
lecular Chemistry (Ed.: G. Gokel), JAI Press, Stamford, 2000,
vol. 7, pp. 139–233.
3
NMR (500 MHz, CDCl
3
, 57 °C): δ = 8.121 (d, J = 6.9 Hz, 4 H,
1
4
0-H), 7.029–7.160 (m, 12 H, 7-H, 8-H, 9-H), 6.728 (s, 4 H, 3-H),
2
3
[3] A. Medizadeh, M. C. Letzel, M. Klaes, C. Agena, J. Mattay, J.
.848 (d, J = 11.9 Hz, 4 H, OCH
2
), 4.759 (t, J = 7.5 Hz, 4 H,
), 3.285 (s, 12 H,
CH), 1.682 [m, 4 H, (CH CH],
CH], 1.010 [d, J = 6.9 Hz, 12
CH] ppm. 13C NMR (125 MHz, CDCl
, 25 °C): δ =
54.31 (C-1), 151.91 (C-4a), 131.97 (Ar ), 129.67 (Ar ), 128.21 (C-
or C-8 or C-9), 126.66 (C-7 or C-8 or C-9), 126.27 (C-3), 125.67
ArCHAr), 4.637 (d, 2J = 12.6 Hz, 4 H, OCH
Mass Spectrometry 2004, 10, 649–655.
4] M. J. McIldowie, M. Mocerino, B. W. Skeleton, H. A. White,
Org. Lett. 2000, 2, 3869–3871.
2
[
OCH
.027 [d, J = 6.9 Hz, 12 H, (CH
H, (CH
3
), 1.811 (m, 8 H, CHCH
2
3 2
)
3
3
1
3 2
)
[
5] J. Y. Boxhall, P. C. B. Page, M. R. J. Elsegood, Y. Chan, H.
Heaney, K. E. Holmes, M. J. McGrath, Synlett 2003, 1002–
3
)
2
3
1
7
q
q
1006.
[6]
B. R. Buckley, P. C. Bulman Page, Y. Chan, H. Heaney, M.
Klaes, M. J. McIldowie, V. McKee, J. Mattay, M. Mocerino, E.
Moreno, B. W. Skelton, A. H. White, Eur. J. Org. Chem. 2006,
5135–5151.
(
5
[
C-10), 124.11 (C-7 or C-8 or C-9), 115.52 (C-10b), 68.38 (C-6),
9.74 (OCH ), 44.05 (CHCH CH), 34.34 (ArCHAr), 25.97
(CH CH], 22.88 [(CH CH] ppm. UV/Vis (cyclohexane): λ (ε,
mol dm cm ) = 224 (68000), 278 (50000), 316 (16000) nm.
3
2
3
1
)
2
3 2
)
–
3
–1
[7] W. Iwanek, J. Mattay, Liebigs Ann. 1995, 1463–1466.
[8] a) L.-C. Campeau, M. Parisien, A. Jean, K. Fagnou, J. Am.
Chem. Soc. 2006, 128, 581–590; b) L.-C. Campeau, M. Par-
isien, M. Leblanc, K. Fagnou, J. Am. Chem. Soc. 2004, 126,
+
+
HRMS (ESI): calcd. for C76
H84NO
8
[M + NH
4
]
1138.6192;
found 1138.6200. C76 ·CHCl
H
80
O
8
3
(1240.8): calcd. C 74.53, H
6.58; found C 74.52, H 6.33.
9186–9187; c) L.-C. Campeau, K. Fagnou, Chem. Commun.
¯
rac-3·1.5CHCl
3
: Crystal size 0.30ϫ0.22ϫ0.08 mm, triclinic, P1,
2006, 1253–1264.
a = 12.4810(2) Å, b = 15.5000(3) Å, c = 18.5860(4) Å, α =
[9] a) G. Bringmann, M. Breuning, S. Tasler, Synthesis 1999, 4,
525–558; b) For a review, see: G. Bringmann, A. J. Price Morti-
mer, P. A. Keller, M. J. Gresser, J. Garner, M. Breuning, Angew.
Chem. 2005, 117, 5518–5563.
9
3
0
0
0
∆
8.1190(9)°, β = 108.1580(10)°, γ = 95.1430(10)°, Z = 2, V =
3
–3
347.95(11) Å , ρcalcd. = 1.290 mgm , 2Θmax = 54.96°, µ =
–1
.254 mm , F(000) = 1374, 841 parameters, R
1
= 0.0610, wR
2
=
[
10] M. Klaes, C. Agena, M. Köhler, M. Inoue, T. Wada, Y. Inoue,
J. Mattay, Eur. J. Org. Chem. 2003, 1404–1409.
11] For a review, see: D. Alberico, M. E. Scott, M. Lautens, Chem.
Rev. 2007, 107, 174.
.1585 {for 11846 reflections [IϾ2σ(I)]}, R = 0.0799, wR(F
2
) =
.1745 (for 15260 unique reflections), Rint = 0.042, S = 1.023,
[
–3
ρ(min/max) = –0.75/0.61 eÅ .
[
9]
(
1
M,R)-(–)-Biaryl Ether (M,R)-(–)-3: (M,R)-(–)-2 (200 mg,
38 µmol), dried K CO (174 mg, 1.26 mmol) and DMA (10 mL)
were placed and in a two-necked round-bottom flask. The suspen-
sion was degassed by two freeze–pump–thaw cycles. Pd(OAc)
50.1 mg, 223 µmol) and PCy ·HBF (162 mg, 440 µmol) were
[12] According to the Bringmann-lactone concept (see ref. ), tet-
rakis(2Ј-bromobenzoyl) ester resorcin[4]arene was synthesised
in 82% yield (see ref.[ ), and it was estimated to be trans-
formed into the tetralactone. Preliminary studies of the lactone
formation of 3-methoxyphenol-based esters were carried out
successfully. The lactone was formed in 78% overall yield as a
2
3
13]
2
(
3
4
added under an argon atmosphere. The yellow mixture was heated
to 130 °C for 20 h. The suspension turned black and was filtered
through silica gel. The solvent was removed under reduced pres-
sure, and the residue was purified by column chromatography
4
:1 mixture of isomers with the bond formed in the 6- and 2-
positions, respectively. Investigations on intramolecular coup-
ling reactions of the resorcin[4]arene to yield the lactone with
2 3 3 2 2
Pd(OAc) and 2 equiv. of PPh and Pd(PPh ) Cl with 2 equiv.
(
SiO
2
; cyclohexane/ethyl acetate, 95:5) to yield (M,R)-(–)-3 as a
per functionality of NaOAc in DMA at 120 °C led to decom-
position of the resorcinarene and to ester hydrolysis. Therefore,
we chose the ether functionality for further experiments, as it
is less sensitive to cleavage.
25
colourless solid (18.1 mg, 12%). [α]
HRMS (ESI): calcd. for C76
found 1138.6199.
D
= –7.1 (c = 1.00, CHCl
3
).
+
+
H
88NO
8
4
[M + NH ]
1138.6192;
[
13] (Ϯ)-rccc-4,10,16,22-Tetrakis-O-(2Ј-bromobenzoyl)-2,8,14,20-tet-
raisobutyl-6,12,18,24-tetra-O-methylresorcin[4]arene: 2-bromo-
benzoic acid (2.64 g, 13.1 mmol) was treated with thionyl
chloride (16.0 mL, 220 mmol) and heated to reflux for 10 min.
The excess amount of thionyl chloride was removed in vacuo.
The residue was dissolved in dry THF (15 mL). Pyridine
(
P,S)-(+)-Biaryl Ether (P,S)-(+)-3: (P,S)-(+)-2 (80.0 mg, 55.3 µmol),
dried K CO (86.1 mg, 623 mmol) and DMA (10 mL) were placed
and in a two-necked round-bottom flask. The suspension was de-
gassed by three freeze–pump–thaw cycles. Pd(OAc) (18.0 mg,
0.0 µmol) and PCy ·HBF (24.7 mg, 162 µmol) were added under
an argon atmosphere. The yellow mixture was heated to 130 °C for
0 h. The suspension turned black and was filtered through silica
gel. The solvent was removed under reduced pressure, and the resi-
due was purified by column chromatography (SiO ; cyclohexane/
ethyl acetate, 95:5) to yield (P,S)-(+)-3 as a colourless solid
2
3
2
8
3
4
(
3.0 mL, 36.6 mmol) was added under an argon atmosphere
and a colourless solid precipitated. A solution of (Ϯ)-rccc-
,8,14,20-tetraisobutyl-4,10,16,22-tetra-O-methylresorcin[4]-
2
2
arene (rac-1; 1.00 g, 1.30 mmol) in THF (6 mL) was added
slowly to the stirred suspension. After the mixture was stirred
for 17 h, the solvent was removed in vacuo. The residue was
dissolved in ethyl acetate (30 mL) and hydrochloric acid
(20 mL). The layers were separated, and the organic phase was
2
2
5
(
10.3 mg, 17%). [α]
D
= +7.2 (c = 1.00, CHCl
3
). HRMS (ESI):
+
+
calcd. for C76H88NO [M + NH ] 1138.6192; found 1138.6199.
8 4
washed with NaHCO
MgSO . The solvent was removed in vacuo and the colourless
solid was recrystallised from CHCl /EtOH (1:4) to give 1.59 g
3
solution (3ϫ25 mL) and dried with
4
Acknowledgments
3
1
(
82%) of the product. M.p. 256 °C (decomp.). H NMR
3
4
We gratefully acknowledge financial support of the Deutsche For-
schungsgemeinschaft and the Innovationsfonds der University of
Bielefeld. M. P. thanks the Gleichstellungskommission der Fakultät
für Chemie for a fellowship.
3
(500 MHz, CDCl , 25 °C): δ = 7.736 (dd, J = 7.6 Hz, J =
3
1
.3 Hz, 4 H, 6Ј-H), 7.701 (d, J = 8.2 Hz, 4 H, 3Ј-H), 7.496 (td,
3
4
3
4
J = 7.5 Hz, J = 1.3 Hz, 4 H, 5Ј-H), 7.358 (td, J = 8.2 Hz, J
1.9 Hz, 4 H, 4Ј-H), 6.751 (s, 4 H, ArH meta Ar-OCH ), 6.478
=
3
3
(
s, 4 H, ArH ortho Ar-OCH
CHAr), 3.358 (s, 12 H, OCH
CHCH CH), 1.615 [m, 4 H, (CH
12 H, (CH
3
), 4.484 (t, J = 7.6 Hz, 4 H, Ar-
), 1.762 (t, J = 6.9 Hz, 8 H,
3
3
3
[
1] a) C. D. Gutsche, Calixarenes Revisited, Royal Society of
Chemistry, Cambridge, 1998; b) B. Botta, M. Cassani, I. D’Ac-
quatica, D. Misiti, D. Subissati, G. Delle Monache, Curr. Org.
Chem. 2005, 9, 337–355.
2
3
)
2
CH], 0.879 [d, J = 6.3 Hz,
3
3
)
2
CH], 0.796 [d, J = 6.3 Hz, 12 H, (CH
C NMR (125 MHz, CDCl , 25 °C): δ = 163.76 (C=O), 155.20
(Ar-COH ), 147.23 (C-OC=O), 134.47 (C-3Ј), 132.94 (C-4Ј),
3 2
) CH] ppm.
1
3
3
3
Eur. J. Org. Chem. 2008, 555–562
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
561

M. Paletta, M. Klaes, B. Neumann, H.-G. Stammler, S. Grimme, J. Mattay
FULL PAPER
1
32.27 (C-6Ј), 131.16 (C-1Ј), 130.55 (Ar
q
ortho Ar-O), 128.10 [15] R. J. Abraham, J. Fisher, NMR Spectroscopy, Wiley, New York,
(Ar
q
ortho Ar-O), 127.39 (C-5Ј), 126.10 (ArH meta Ar-O),
22.28 (Ar-Br), 104.81 (ArH ortho Ar-O), 54.95 (OCH ), 43.74
CH), 33.97 (ArCHAr), 25.67 [(CH CH], 22.86
CH], 22.71 [(CH CH] ppm. HRMS (ESI): calcd. for
1988.
1
3
[
16] a) F. Vögtle, A. Hünten, E. Vogel, S. Bischbeck, O. Safarowsky,
J. Recker, A. Parham, M. Knott, W. Müller, U. Müller, Y. Oka-
moto, T. Kubota, W. Lindner, E. Francotte, S. Grimme, Angew.
Chem. Int. Ed. 2001, 40, 2468–2471; b) N. Harada in Circular
Dichroism: Principles and Applications (Eds.: N. Berova, K.
Nakanishi, R. W. Woody), VCH, New York, 2000, pp. 431–
(
CHCH
2
3 2
)
[(CH
3
H
)
2
3 2
)
+
+
C
C
76
80Br
4
NO12 [M + NH
4
]
1514.2409; found 1514.2425.
76
H
76
O12Br
4
(1500.2): calcd. C 60.81, H 5.10; found C 60.62,
H 5.08.
[
14] a) G. Bringmann, T. Hartung, L. Göbel, O. Schupp, C. L. J.
Ewers, B. Schöner, R. Zagst, K. Peters, H. G. von Schnering,
C. Burschka, Liebigs Ann. Chem. 1992, 225–232; b) G.
Bringmann, J. R. Jansen, Heterocycles 1989, 28, 137–142.
457.
Received: August 29, 2007
Published Online: November 12, 2007
562
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 555–562