Acid-promoted rearrangement of carbonate functionality anchored to the lower rim of a calix[4]arene skeleton: A new class of chiral calix[4]arene and its chiroptical properties

Article abstract of DOI:10.1021/ol005984b

(equation presented) A unique calix[4]arene lower-rim intramolecular rearrangement, resulting in molecular asymmetry arising from the upper- and lower-rim substitution pattern, produces a new class of inherently chiral calix[4]arenes in a partial cone con

Full text of DOI:10.1021/ol005984b

ORGANIC
LETTERS
2
000
Vol. 2, No. 15
237-2240
Acid-Promoted Rearrangement of
Carbonate Functionality Anchored to the
Lower Rim of a Calix[4]arene Skeleton:
A New Class of Chiral Calix[4]arene and
Its Chiroptical Properties
2
,
†
,†
‡
§
Dusan Hesek,* Yoshihisa Inoue,* Michael G. B. Drew, Paul D. Beer,
†
†
†
Guy A. Hembury, Hitoshi Ishida, and Fumiko Aoki
Inoue Photochirogenesis Project, ERATO, JST, 4-6-3 Kamishinden, Osaka 565-0085,
Japan, Department of Chemistry, The UniVersity of Reading, Whiteknights, Reading,
RG6 6AD, U.K., and Department of Chemistry, Oxford UniVersity, South Parks Road,
Oxford OX1 3QR, U.K.
inoue@chem.eng.osaka-u.ac.jp
Received April 25, 2000
ABSTRACT
A unique calix[4]arene lower-rim intramolecular rearrangement, resulting in molecular asymmetry arising from the upper- and lower-rim substitution
pattern, produces a new class of inherently chiral calix[4]arenes in a partial cone conformation. This was aided by molecular rigidification
arising from π−π and C−H‚‚‚π interactions between bulky lower-rim substituents, with the corresponding circular dichroism spectra exhibiting
the most intense bisignate Cotton effects yet observed for calix[4]arenes not bearing a chiral center.
2
As a part of our ongoing work on calix[4]arene derived
compounds, we are developing hosts that are able to carry
out chiral recognition processes during complexation and
which allow energy/electron transfer and we are further
conformation. Modification of the upper rim can simplify
this situation; then only two different substituents are required
on the lower rim, although a controlled preparation of the
required asymmetrically derivatized lower rim is still not a
simple task to achieve. However, the preparation can be
facilitated by rigidifying the calixarene conformation, which
is accomplished here by restricting the rotation of the phenyl
units in the calix[4]arene core, by the introduction of selected
bulky substituents at the top and/or bottom of the rim.
1
investigating the effects of weak intramolecular interactions
on the conformation of calix[4]arenes. To achieve the
synthesis of chiral calix[4]arenes without attaching asym-
metric groups to the calixarene moiety, the lower rim must
be derivatized with at least three different substituents
(
including the OH group) if the molecule adopts a cone
A particularly straightforward, but elegant, example of
such an idea was achieved here when the diametrically
†
Inoue Photochirogenesis Project.
University of Reading.
Oxford University.
‡
§
(2) Iwamoto, K.; Shimizu, H.; Araki, K.; Shinkai, S. J. Am. Chem. Soc.
1993, 115, 3997-4006.
(1) Desiraju, R. G. Acc. Chem. Res. 1996, 29, 441-449.
1
0.1021/ol005984b CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/08/2000

3
substituted calix[4]arene 1 (synthesis described below) was
initially nitrated using an AcONO /CH Cl solution (gener-
ated in situ from HCl, NaNO and a catalytic amount of Ac
in CH Cl ). Under the reaction conditions employed, the
2
2
2
Scheme 1a
3
2
O
2
2
nitration leads to two products, one major and one minor, 4.
The benzyloxycarbonyl protecting group anchored to the
calix[4]arene moiety at the bottom of the rim was chosen
specifically for its resistance to oxidation in the presence of
nitric acid and its stability in acidic media.
Under optimized reaction conditions, the combined yield
of these two products could be obtained in a moderate 77%.
Subsequent tosylation in order to allow full characterization
4
afforded 2 and 3 in a ratio of 15:85 (Scheme 1), although
(
3) Experimental Procedure for 1: A mixture of calix[4]arene (4.2 g,
1
0 mmol) and NaH (80% in oil, 0.7 g, 23 mmol) in anhydrous THF (100
mL) was stirred at room temperature for 1 h. Chlorobenzyl carbonate (3.2
mL) was then added, and the mixture was stirred for 6 h. The progress of
the reaction was followed by monitoring the disappearance of calix[4]arene
on TLC (SiO2, toluene/hexane/acetonitrile, 80:18:2). When complete
conversion was observed, the THF was removed under reduced pressure,
and the remaining residue was partitioned between water and CH2Cl2.
Separation of the organic layer and evaporation of the solvent in vacuo
yielded 6.6 g (96%) of crude product, which was purified by recrystallization
from toluene/hexane to give white crystals. A sample for the next reaction
step was further purified by column chromatography on silica gel, by eluting
1
a
the product 1 with toluene/hexane/acetonitrile, 7:2:1 v/v. H NMR (400
Reagents: (i) HCl, NaNO
THF.
3 2 2 2
, Ac O, CH Cl ; (ii) TsCl, NaH,
MHz, CDCl3) δ (ppm) 7.55-7.35 (m, 10H, ArH), 7.08 (d, J ) 7.3 Hz, 4H,
ArH), 6.90-6.7 (m, 8H, ArH), 5.30 (s, 4H, OCH2Ar), 4.00 and 3.51 (ABq,
1
3
8
H, J ) 14.3 Hz, ArCH2Ar). C NMR (CDCl3) δ 188.3 (s, CdO), 155.0
and 152.7 (s, Ar 25, 26, 27, 28-C), 145.8 (s, Ar-C), 135.0 (s, Ar-C),
1
1
7
32.2 (s, Ar-C), 129.0 (d, Ar-C), 128.7 (d, Ar-C), 128.6 (d, Ar-C),
28.5 (d, Ar-C), 127.9 (d, Ar-C), 126.8 (d, Ar-C), 119.9 (d, Ar-C),
0.7 (t, OCH2Ar), 32.2 (t, ArCH2Ar). MS m/z 692 (M + 1, 100). Anal.
optimization of the reaction conditions to maximize the yield
of 2 was not performed.
Calcd for C44H36O8 (692.77): C, 76.29; H, 5.24. Found: C, 76.20; H, 5.18.
This approach led to the synthesis of a new class of
inherently chiral calix[4]arene 2, whose asymmetry derives
from the substitution pattern of the upper and lower rims.
The formation of precursor 4 is likely to occur via a
proton-assisted intramolecular rearrangement of the BnO-
(
4) Experimental Procedure for 2 and 3: To a solution of 1 (0.69 g,
mmol) dissolved in a CH2Cl2 (10 mL)-diethyl ether (17 mL) solvent
mixture were added NaNO3 (0.45 g, 5 mmol), concentrated HCl (1.5 mL,
8 mmol), and a catalytic amount of acetic anhydride. The mixture was
1
1
allowed to stir at room temperature for 1 h. The organic solvents were
removed under diminished pressure. Water (10 mL) was added to the yellow
residue, and the solid material formed was filtered off. The product was
dissolved in CH2Cl2 and washed with water, and the solvent was evaporated
to dryness. The material formed was solidified by addition of methanol
and filtered off. The crude product was recrystallized from toluene in the
presence of charcoal to give a 0.6 g (77%) yield containing two products,
one major and one minor (85:15). The mixture was introduced into the
next reaction step without further purification. The mixture of major and
minor products (0.78 g, 1 mmol) and NaH (80% in oil, 0.12 g, 4 mmol) in
THF (20 mL) was stirred at room temperature for 10 min. Toluene-4-
sulfonyl chloride (0.5 g, 2.6 mmol) was added, and the reaction mixture
was allowed to stir for 12 h. The progress of the reaction was followed by
monitoring the disappearance of the major product on thin-layer chroma-
tography (SiO2, benzene/CH2Cl2, 75:25 v/v). The reaction was quenched
with water (20 mL), and the sample was reduced to dryness. The excess
toluene-4-sulfonyl chloride was removed by heating the residue with
n-hexane, producing a yellow solid which was purified by recrystallization
from toluene/hexane to give 0.75 g (68%) yield. Analytical samples of 2
and 3 were further purified by column chromatography on silica gel, eluting
(
CO) group. The intramolecular nature of this rearrangement
is supported by the absence of the mono- and tris- benzoyl-
oxycarbonyl substituted products that would occur from an
intermolecular rearrangement process. The distance found
from the crystal structure of 1 between the unprotected
hydroxyl group and the carbonyl of the carbonate group is
5
4
.53 Å (Figure 1), which could be reduced by molecular
δ (ppm) 7.82 (d, J ) 7.3 Hz, 4H, ArH), 7.54 (d, 4H, ArH), 7.56 (s, 4H,
ArH, ortho to NO2), 7.50 (m, 10H, ArH), 7.32 (d, J ) 7.6 Hz, 4H, ArH),
7.16 (dd, 2H, ArH), 5.62 (s, 4H, OCH2Ar), 4.02 and 3.00 (ABq, J ) 13.9
Hz, 8H, ArCH2Ar), 2.43 (s, 6H, CH3). 13C NMR (CDCl3) δ (ppm) 188.0
(s, CdO), 154.4 (s, Ar-C), 148.1 (s, Ar-C), 145.2 (s, Ar-C), 136.7 (s,
Ar-C), 134.1 (s, Ar-C), 131.7 (s, Ar-C), 130.0 (d, Ar-C), 129.2 (d,
Ar-C), 128.8 (d, Ar-C), 128.7 (d, Ar-C), 128.6 (d, Ar-C), 128.3 (d,
Ar-C), 127.2 (d, Ar-C), 124.0 (d, Ar-C), 71.1 (t, OCH2Ar), 31.1 (t,
ArCH2Ar), 21.7 (q, CH3). MS m/z 1091 (M + 1, 100). Anal. Calcd for
C58H46N2O16S2 (1091.31): C, 63.84; H, 4.25; N, 2.57. Found: C, 63.72;
H, 4.20; N, 2.55.
1
with benzene/CH2Cl2, 7:3 v/v. 2: H NMR (400 NMR, CD2Cl2) δ (ppm)
.41 (d, J ) 2.7 Hz, 1H), 8.22 (d, J ) 2.8 Hz, 1H), 7.96 (d, J ) 8.4 Hz,
H, ArH-Tos), 7.87 (d, J ) 2.7 Hz, 1H), 7.45 (m, 22H), 6.51 (m, 3H),
.40 (d, J ) 11.8 Hz, 1H, OCH2), 5.26 (d, J ) 11.8 Hz, 1H, OCH2), 4.93
14.5 Hz, 2H, CH2), 3.78 (d, J ) 13.5 Hz, 1H, CH2), 3.61 (d, J ) 14.0
(5) (a) Crystal data for 1: C44H35O8; FW ) 691.72, monoclinic, space
group P21/a, Z ) 4, a ) 12.302(12), b ) 20.42(3), and c ) 14.135(17) Å,
3
â ) 105.90(1)° , V ) 3414 Å, Dcalc ) 1.346 g/cm . Crystal data for 2:
1
3
C58H46N2O16S2; FW ) 1091.09, orthorhombic, space group Fdd2, Z ) 16,
3
a ) 37.289(5), b ) 54.376(13), and c ) 10.517(6) Å, V ) 21325 Å , Dcalc
3
1
1
1
1
7
35.9 (s), 135.8 (s), 134.6 (s), 134.4 (s), 133.7 (s), 133.4 (s), 132.6 (s),
32.4 (s), 130.8 (d), 130.6 (d), 129.9 (d), 129.8 (d), 129.7 (d), 129.3 (d),
29.1 (d), 129.0 (d), 128.9 (d), 128.6 (d), 128.5 (d), 128.4 (d), 128.2 (d),
27.1 (d), 126.8 (d), 126.7 (d), 125.1 (d), 125.0 (d), 124.6 (d), 71.0 (t),
0.9 (t), 35.9 (t), 35.6 (t), 30.7 (t), 30.4 (t), 21.9 (q), 21.6 (q). MS m/z 1091
) 1.359 g/cm . Both sets of data were taken using Mo KR radiation at 293
K. For 1 6081 independent reflections were measured on a Marresearch
Image Plate system and for 2 3994 reflections were measured on a Rigaku
AFC7R circle diffractometer using the ω-scan technique. Both structures
were determined by direct methods using Shelx86.3b All non-hydrogen atoms
were refined anisotropically; hydrogen atoms were included in calculated
(
M + 1, 100). Anal. Calcd for C58H46O16S2N2 (1091.31): C, 63.84; H, 4.25;
1
2
3c
N, 2.57. Found: C, 63.52; H, 4.25; N 2.63. 3: H NMR (400 MHz, CDCl3)
238
positions. Both structures were refined on F to convergence using Shelxl.
2
Org. Lett., Vol. 2, No. 15, 2000

7
rim substitution and not from chiral centers, the CD spectra
of the enantiomers of 2 show multiple bisignate Cotton
effects which are particularly intense in the region between
2
50 and 200 nm, a feature which has not been reported
previously in calixarene chemistry. These interactions ob-
served by the CD spectroscopy are attributed to exciton
coupling between the aromatic chromophores, which are in
8
a partial cone conformation.
The assignments of the 1D proton resonances were made
on the basis of DIFNOE and 2D NMR (COSY, ROESY)
experiments, revealing typical splitting patterns of AB
quartets (ca. J ) 13 Hz) arising from the Ar-CH
linking groups, possessing C2V symmetry in 1 and 3. A
complicated splitting pattern of Ar-CH -Ar resonances and
2
-Ar
2
a set of through-space interactions arising from the neighbor-
ing aromatic rings in 2 indicated that these moieties possess
1
C
1
symmetry (Figure 3). H NMR spectra shows a large
Figure 1. X-ray structure of 1 (50% probability).
motions in solution, showing that this order of distance may
be suitable for the intramolecular rearrangement to occur.
This is the first time that such a chirogenic rearrangement
process between the lower-rim phenoxy groups (and after-
sylation) has been observed, although nonchiral rearrange-
ments between lower-rim phenoxy substituents and the
6
methylene position have been reported. The conformational
stability of these highly preorganized macrocycles allows us
to separate racemic 2 into its pure enantiomers by chiral
stationary phase HPLC on a CHIRALCEL OJ-R column
eluting with a (7:3) acetonitrile/water solvent and thus
investigate the chiroptical properties of these newly synthe-
sized calix[4]arene derivatives (see Figure 2).
1
Figure 3. 1D and 2D COSY H NMR spectra of 2 in CDCl
3
.
difference in the resonance frequencies of the AB quartets
of the two methylene groups in ArCH OCO, indicating that
2
the magnetic environments experienced by these two groups
are not identical.
The conformation of the derivatives synthesized in this
1
work were further analyzed by means of VT H NMR
measurements of 2, which when carried out in the temper-
ature range of -100 to 25 °C in acetone-d
in the signal positions, while between 25 and 100 °C in
DMSO-d shifts were observed (Figure 4), but they are small
6
revealed no shifts
6
3
Figure 2. CD and UV/vis spectra of 2 in CH CN.
in comparison to those expected for major conformational
9
rearrangements, i.e., the increase in temperature does not
Although circular dichroism (CD) spectra have been
reported for calixarenes in which the chirality arises from
significantly affect the conformation, implying that the
structure of the molecule is particularly rigid.
Final R1 and wR2 values for observed data (> 2σ(I)) were 0.0804, 0.1710
and 0.0396, 0.0714, respectively. Crystallographic details have been
deposited at the Cambridge Crystallographic Data Centre. (b) Sheldrick,
G. M. (Shelx86), Acta Crystallogr. 1990, A46, 467. (c) Sheldrick, G. M.
Shelxl program for structure refinement, University of G o¨ ttingen, Germany,
(6) Middel, O.; Greff, Z.; Taylor, N. J.; Verboom, W.; Reinhoudt. D.;
Snieckus, V. J. Org. Chem. 2000, 65, 667-675.
(7) (a) Iwamoto, K.; Yanagi, A.; Arimura, T.; Matsuda, T.; Shinkai. S.
Chem. Lett. 1990, 1901-1904. (b) Iwamoto, K.; Shimizu. H.; Araki K.;
Shinkai. S. J. Am. Chem. Soc. 1993, 115, 3997-4006.
1
993.
(8) Ikeda, A.; Shinkai, S. Chem. ReV. 1997, 97, 1713-1734.
Org. Lett., Vol. 2, No. 15, 2000
2239

Figure 4. 1H VT NMR spectra of 2 in DMSO-d
.
6
X-ray crystallographic studies were subsequently carried
out in order to examine the structural characteristics of 2
and to understand the reasons for this structural rigidity. The
5
structure of 2 (Figure 5) shows the four aromatic rings on
the substituents augmenting the four aromatic rings of the
calixarene in the partial cone conformation to form a rigid,
crowded, cylindrically shaped molecule.
Figure 5. X-ray structure of 2 (50% probability).
There are several close π-π and C-H‚‚‚π contacts
between the substituents which contribute to the stability of
the partial cone conformation, with distances in the range
of 2.42-2.67 Å, although no interactions are found between
atoms significantly less than the sum of van der Waals radii.
Preliminary molecular dynamics calculations confirm the
rigidity of this molecular conformation. The detailed elucida-
tion of the reaction mechanism and intramolecular rear-
rangement are currently under investigation.
1
1
Supporting Information Available: Additional H and
C NMR spectra for 1, 2, 3 and the major intermediate.
1
3
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Harada, T.; Ohseto, F.; Shinkai, S. Tetrahedron 1994, 50 (47),
1
3377-13394.
OL005984B
2240
Org. Lett., Vol. 2, No. 15, 2000