Definitive evidence for inhibition of calix[6]arene ring inversion obtained from a 1,3-xylenyl-bridged chiral calix[6]arene

Article abstract of DOI:10.1021/ja953626b

To design calix[6]arene-based receptor molecules which show high affinity and high selectivity toward guest molecules, the construction of more rigid and conformationally-defined analogs has been long awaited (Gutsche; Alam Tetrahedron 1988, 44, 4689). It

Full text of DOI:10.1021/ja953626b

J. Am. Chem. Soc. 1996, 118, 4271-4275
4271
Definitive Evidence for Inhibition of Calix[6]arene Ring
Inversion Obtained from a 1,3-Xylenyl-Bridged Chiral
Calix[6]arene
Hideyuki Otsuka and Seiji Shinkai*
Contribution from the Department of Chemical Science & Technology, Faculty of Engineering,
Kyushu UniVersity, Fukuoka 812, Japan
ReceiVed October 30, 1995. ReVised Manuscript ReceiVed February 21, 1996X
Abstract: To design calix[6]arene-based receptor molecules which show high affinity and high selectivity toward
guest molecules, the construction of more rigid and conformationally-defined analogs has been long awaited (Gutsche;
Alam Tetrahedron 1988, 44, 4689). It has been predicted that in certain sterically-hindered calix[6]arenes the ring
inversion is suppressed. However, evidence presented so far (mainly from NMR spectroscopy) is indirect and is
valid only in the range of the NMR time scale. To find definitive evidence for the immobilization we synthesized
a calix[6]arene (4), the 1,3-phenyl units of which are bridged by an asymmetrical 4-methoxy-m-xylenyl unit, and
optically resolved it by an HPLC method using a chiral packed column. Since ring inversion is obligatorily
accompanied by racemization, one can easily discriminate between true immobilization and NMR time-scale
1
immobilization. The H NMR studies have established that 4 adopts a cone conformation, which is unaffected up
to 130 °C. Very importantly, it was shown that 4 does not racemize even at 100 °C. This provides unambiguous
evidence for the immobilization of the calix[6]arene ring in 4. This paper demonstrates that the racemization of
chiral calix[6]arenes is an effective (and probably sole at present) methodology to obtain the definitive evidence for
ring immobilization.
Introduction
isomers. On the other hand, the conformation of calix[4]arenes
can be immobilized by O-substituents bulkier than the ethyl
group: e.g., the O-propyl group in calix[4]arenes cannot engage
in the oxygen-through-the-annulus rotation because of the
bulkiness of the propyl group and the smallness of the calix-
[4]arene cavity.9a,b In contrast, conformational immobilization
of calix[6]arenes has been left ambiguous. In 1991 Casnati et
al.13 reported 1H NMR spectroscopic properties of 5,11,17,23,-
29,35-hexa-tert-butyl-37,39,41-trimethoxy-38,40,42-tris[(tert-
butoxycarbonyl)methoxy]calix[6]arene. Although the line-
broadening was scarcely induced over a wide temperature
range,13 it was later proven that the phenyl units in this
compound can still rotate, the rate being slower than the NMR
time scale.14-16 Then, how can we suppress the ring inversion
of calix[6]arenes? The importance of the ring immobilization
was previously pointed out by Gutsche et al.2c as “even the calix-
[6]arenes are rather flexible, and further insight into their mode
of action must await the construction of more rigid and
conformationally-defined analogs”.
Calix[n]arenes are a class of cavity-shaped macrocycles
composed of n molecules of phenol and n molecules of
formaldehyde.1-12 It is known that each phenol unit can enjoy
rotational freedom, which creates a number of conformational
X Abstract published in AdVance ACS Abstracts, April 15, 1996.
(1) For comprehensive reviews see: (a) Gutsche, C. D. In Calixarenes;
Royal Society of Chemistry: Cambridge, 1989. (b) Vicens, J.; Bo¨hmer,
V., Eds. In Calixarenes; Kluwer Academic Press: Dordrecht, The Neth-
erlands, 1991. (c) Shinkai, S. Bioorg. Chem. Front. 1990, 1, 161.
(2) (a) Gutsche, C. D.; Levine, J. A. J. Am. Chem. Soc. 1982, 104, 2652.
(b) Gutsche, C. D.; Lin, L.-G. Tetrahedron 1986, 42, 1633. (c) Gutsche, C.
D.; Alam, I. Tetrahedron 1988, 44, 4689.
(3) (a) Almi, M.; Arduini, A.; Casnati, A.; Pochini, A.; Ungaro, R.
Tetrahedron 1989, 45, 2177. (b) Arduini, A.; Manfredi, G.; Pochini, A.;
Sicuri, A. R.; Ungaro, R. J. Chem. Soc., Chem. Commun. 1991, 936.
(4) (a) Verboom, W.; Durie, A.; Egberink, R. J. M.; Asfari, Z.; Reinhoudt,
D. N. J. Org. Chem. 1992, 57, 1313. (b) van Loon, J.-D.; Arduini, A.;
Coppi, L.; Verboom, W.; Pochini, A.; Ungaro, R.; Harkema, S.; Reinhoudt,
D. N. J. Org. Chem. 1990, 55, 5639.
(5) (a) Shinkai, S.; Mori, S.; Koreishi, H.; Tsubaki, T.; Manabe, O. J.
Am. Chem. Soc. 1986, 108, 2409. (b) Shinkai, S.; Araki, K.; Tsubaki, T.;
Manabe, O. J. Chem. Soc., Perkin Trans. 1 1987, 2297. (c) Arimura, T.;
Nagasaki, T.; Shinkai, S.; Manabe, O. J. Org. Chem. 1989, 54, 3767. (d)
Komori, T.; Shinkai, S. Chem. Lett. 1992, 901.
In 1993, Biali et al.17 succeeded in the immobilization using
two dialkyl phosphates which can react with six phenol groups.
(6) (a) Gutsche, C. D.; Bauer, L. J. J. Am. Chem. Soc. 1985, 107, 6059.
(b) Gutsche, C. D.; Reddy, P. A. J. Org. Chem. 1991, 56, 4783. (c)
Kanamathareddy, S.; Gutsche, C. D. J. Org. Chem. 1992, 57, 3160.
(7) (a) Bocchi, V.; Foina, D.; Pochini, A.; Ungaro, R.; Andreetti, G. D.
Tetrahedron 1982, 38, 373. (b) Arduini, A.; Pochini, A.; Reverberi, S.;
Ungaro, R.; Andreetti, G. D.; Ugozzoli, F. Tetrahedron 1986, 42, 2089.
(c) (d) Auduini, A.; Casnati, A.; Fabbi, M.; Minari, P.; Pochini, A.; Sicuri,
A. R.; Ungaro, R. Supramol. Chem. 1993, 1, 235.
(8) (a) Groenen, L. C.; van Loon, J.-D.; Verboom, W.; Harkema, S.;
Casnati, A.; Ungaro, R.; Pochini, A.; Ugozzoli, F.; Reinhoudt, D. N. J.
Am. Chem. Soc. 1991, 113, 1285. (b) Verboom, W.; Datta, S.; Asfari, Z.;
Harkema, S.; Reinhoudt, D. N. J. Org. Chem. 1992, 57, 5394. (c) Groenen,
L. C.; Ruel, B. H. M.; Casnati, A.; Timmerman, P.; Verboom, W.; Harkema,
S.; Pochini, A.; Ungaro, R.; Reinhoudt, D. N. Tetrahedron Lett. 1991, 32,
2675.
(10) McKervey, M. A.; Seward, E. M.; Ferguson, G.; Ruhl, B.; Harris,
S. J. Chem. Soc., Chem. Commun. 1985, 388.
(11) Arnaud-Neu, F.; Collins, E. M.; Deasy, M.; Ferguson, G.; Harris,
S. J.; Kaitner, B.; Lough, A. J.; McKervey, M. A.; Marques, E.; Ruhl, B.
L.; Schwing Weill, M. J.; Seward, E. M. J. Am. Chem. Soc. 1989, 111,
8681.
(12) Arimura, T.; Kubota, M.; Matsuda, T.; Manabe, O.; Shinkai, S. Bull.
Chem. Soc. Jpn. 1989, 62, 1674.
(13) Casnati, A.; Minari, P.; Ungaro, R. J. Chem. Soc., Chem. Commun.
1991, 1413.
(14) Otsuka, H.; Araki, K.; Shinkai, S. Chem. Express 1993, 8, 479.
(15) Otsuka, H.; Araki, K.; Sakaki, T.; Nakashima, K.; Shinkai, S.
Tetrahedron Lett. 1993, 34, 7275.
(16) van Duynhoven, J. P. M.; Janssen, R. G.; Verboom, W.; Franken
S. M.; Casnati, A.; Pochini, A.; Ungaro, R.; de Mendoza, J.; Nieto, P. M.;
Prados, P.; Reinhoudt, D. N. J. Am. Chem. Soc. 1994, 116, 5814.
(17) Grynszpan, F.; Aleksiuk, O.; Biali, S. E. J. Chem. Soc., Chem.
Commun. 1993, 13.
(9) (a) Iwamoto, K.; Araki, K.; Shinkai, S. J. Org. Chem. 1991, 56, 4955.
(b) Iwamoto, K.; Araki, K.; Shinkai, S. Tetrahedron 1991, 47, 4325. (c)
Iwamoto, K.; Shinkai, S. J. Org. Chem. 1992, 57, 7066. (d) Shinkai, S.;
Fujimoto, K.; Otsuka, T.; Ammon, H. L. J. Org. Chem. 1992, 57, 1516.
S0002-7863(95)03626-2 CCC: $12.00 © 1996 American Chemical Society

4272 J. Am. Chem. Soc., Vol. 118, No. 18, 1996
Otsuka and Shinkai
We also synthesized triply-bridged calix[6]arenes at the upper
rim side18 or at the lower rim side.19-21 Judging from the CPK
molecular models it seems impossible for these capped calix-
[6]arenes to enjoy the ring inversion motion. Recently, Kan-
amathareddy and Gutsche22 synthesized compound 1 in which
the 1,4-phenyl units in calix[6]arene are bridged by a p-xylenyl
unit. It was shown that 1 is capable of undergoing a confor-
mational transformation in which the bridging moiety becomes
threaded through the annulus to produce a “self-anchored
rotaxane”. It was also noted by these authors,22 however, that
the calix[6]arene bridged 1,4 with an anthrylene moiety does
not form a self-anchored rotaxane but remaines conformationally
immobile. Meanwhile, we synthesized compound 2 (as a
reference compound for a triply-bridged calix[6]arene 3) in
which the 1,3-phenyl units are bridged by a m-xylenyl unit.20b
1
Surprisingly, the H NMR spectra (400 MHz) of 2 (as well as
3) were scarcely changed at 30-130 °C.20b The two-
dimensional (2D) EXSY measurements also indicated that the
ring inversion in 2 and 3 is apparently inhibited in terms of the
NMR time scale.20b Then, how can we obtain definitive
evidence for immobilization of the ring inversion motion? The
best and probably sole idea which comes to mind is the use of
chiral calix[6]arenes with molecular asymmetry in which ring
inversion is obligatorily accompanied by racemization. Mo-
lecular design of calix[4]arenes with molecular asymmetry has
been reported by several groups,23b but the successful examples
for optical resolution have still been very limited.23-26 Molec-
ular design of calix[6]arene with molecular asymmetry is more
difficult than that of calix[4]arenes, and to the best of our
knowledge no precedent exists for successful optical resolution
of chiral calix[6]arenes. We noted that when the 1,3-phenyl
units in calix[6]arene are bridged by a 4-methoxy-m-xylenyl
unit, the product 4 is chiral, providing a compound suitable for
testing the immobilization by measuring its enantiomeric
stability. Fortunately, racemic 4 could be optically resolved
by an HPLC method using a chiral packed column. We have
found that racemization of enantiomeric 4 does not take place
even at 100 °C. This is the first definitive evidence that the
calix[6]arene ring 4 is truly immobilized.
1
Figure 1. Temperature dependence of H NMR spectra for 4 (400
MHz, Cl2CDCDCl2).
Results and Discussion
Synthesis and Temperature-Dependent 1H NMR Spectra.
We previously reported that the reaction of 5,11,17,23,29,35-
(18) Takeshita, M.; Nishio, S.; Shinkai, S. J. Org. Chem. 1994, 59, 4032.
(19) Araki, K.; Akao, K.; Otsuka, H.; Nakashima, K.; Inokuchi, F.;
Shinkai, S. Chem. Lett. 1994, 1251.
(20) (a) Otsuka, H.; Araki, K.; Shinkai, S. J. Org. Chem. 1994, 59, 1542.
(b) Otsuka, H.; Araki, K.; Matsumoto, H.; Harada, T.; Shinkai, S. J. Org.
Chem. 1995, 60, 4862.
(21) Other examples for bridging or capping of calix[6]arenes (although
their purposes are not necessarily immobilization of the conformation): (a)
Janssen, R. G.; Verboom, W.; van Duynhoven, J. P. M.; van Velzen, E. J.
J.; Reinhoudt, D. N. Tetrahedron Lett. 1994, 35, 6555. (b) Kraft, K.;
Bo¨hmer, V.; Vogt, W.; Ferguson, G.; Gallagher, J. F. J. Chem. Soc., Perkin
Trans. 1 1994, 1221.
(22) Kanamathareddy, S.; Gutsche, C. D. J. Am. Chem. Soc. 1993, 115,
6572.
(23) (a) Pickard, S. T.; Pirkle, W. H.; Tabatabai, M.; Vogt, W.; Bo¨hmer,
V. Chirality 1993, 5, 310. (b) For a comprehensive review for inherently
chiral calixarenes see: Bo¨hmer, V.; Kraft, D.; Tabatabai, M. J. Inclusion
Phenom. 1994, 19, 17.
(24) (a) Shinkai, S.; Arimura, T.; Kawabata, H.; Murakami, H.; Araki,
K.; Iwamoto K.; Matsuda, T. J. Chem. Soc., Chem. Commun. 1990, 1734.
(b) Shinkai, S.; Arimura, T.; Kawabata, H.; Murakami, H.; Iwamoto K. J.
Chem. Soc., Perkin Trans. 1 1991, 2429.
(25) (a) Iwamoto, K.; Yanagi, A.; Arimura, T.; Matsuda, T.; Shinkai, S.
Chem. Lett. 1990, 1901. (b) Iwamoto, K.; Shimizu, H.; Araki, K.; Shinkai,
S. J. Am. Chem. Soc. 1193, 115, 3997 (Corrigendum Ibid. 1993, 115, 3997).
(26) (a) Pappalardo, S.; Caccamese, S.; Giunta, L. Tetrahedron Lett. 1991,
32, 7747. (b) Pappalardo, S.; Giunta, L.; Foti, M.; Ferguson, G.; Gallagher,
J. F.; Kaitner, B. J. Org. Chem. 1992, 57, 2611.
Figure 2. Proton assignment in the 1H NMR spectrum for 4 at
130 °C.
hexa-tert-butyl-37,38,39,41-tetramethoxycalix[6]arene-40,42-
diol (5) with R,R′-dibromo-m-xylene results in 2 in 93% yield.20b
Compound 4 was synthesized from 5 and 4-methoxy-R,R′-
dibromo-m-xylene in a similar manner used for the synthesis
of 5. The yield was 90%.
Figures 1 and 2 show temperature-dependent 1H NMR spectra
of 4 in Cl2CDCDCl2. All peaks are sharpened at 130 °C, which
are convenient for the peak assignments. Compound 2 without
the MeO group gave four singlet t-Bu peaks in a 1:1:2:2 integral
intensity ratio.20b On the other hand, 4 with the MeO group
gives six singlet t-Bu peaks, indicating that all t-Bu groups are
inequivalent. Similarly, compound 2 gave three singlet MeO
(calix[6]arene) peaks in a 1:1:2 integral intensity ratio.20b In 4,
on the other hand, four singlet MeO (calix[6]arene) peaks are
observable, indicating that they are all inequivalent. Obviously,

EVidence for Inhibition of Calix[6]arene Ring InVersion
J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4273
Chart 1
the inequivalence is induced by the 4-MeO group introduced
into the m-xylenyl cap. As also observed for 2,20b one MeO
group in 4 appears at a higher magnetic field (δH 2.38 ppm:
compare 2.32 ppm in 220b). This MeO group can be assigned
to that in the phenyl unit farthest from the bridgehead which is
considerably flattened, the MeO group undergoing the shielding
effect of the benzene ring in the cap. In the methylene proton
region we can find eight pairs of doublets, two of them being
assigned to the methylene groups in the m-xylenyl cap and six
of them being assigned to the ArCH2Ar protons in the calix-
[6]arene. Very importantly, the six pairs of doublets are firmly
maintained even at 130 °C. For compound 2 we were able to
assign four pairs of doublets to each ArCH2Ar methylene group
by 2D COSY 1H NMR spectroscopy and establish that it adopts
a (partially) flattened cone conformation.20b Although the
splitting pattern for the ArCH2Ar methylene protons in 4 is more
complicated and therefore difficult to assign to each ArCH2Ar
methylene group, the chemical shifts of each group are basically
similar to those of 2. One can consider, therefore, that 2 also
adopts a (partially) flattened cone conformation. The line-
broadening observed at 30 °C is attributable to the partial
fluctuation of the cap, the nonbridged phenyl units, etc.18-20
The foregoing 1H NMR spectral data indicate that the calix[6]-
arene ring does not undergo inversion at least on the NMR time
scale.
1
Figure 3. Partial H NMR spectra for the methylene protons in 4 (2
mM) at 30 °C in Cl2CDCDCl2: (A) 4; (B) 4 with Pirkle’s reagent (20
mM); (C) 4a with Pirkle’s reagent; (D) 4b with Pirkle’s reagent.
(Figure 3). The finding suggests that the Pirkle’s reagent
interacts via hydrogen bonding with the MeO groups.
The optical resolution of 4 was carried out with Daicel
Chiralpak AD (mobile phase: n-hexane/2-propanol, 98:2 v/v),
a representive chromatogram for which is shown in Figure 4.
Because of the favorable separation factor it was possible to
recover 4a (first fraction) in 50% yield and 100% ee and 4b
(second fraction) in 49% yield and 99% ee. As shown in Figure
5, the CD spectra of the two enantiomers are reciprocal to one
another.
Optical Resolution. To confirm that 4 consists of a pair of
enantiomers we measured its 1H NMR spectrum in the presence
of Pirkle’s chiral shift reagents ((S)-2,2,2-trifluoro-1-(9-anthryl)-
ethanol). We found that this reagent is effective24,25 to 4: the
peaks split into pairs with a 1:1 integral intensity ratio even at
30 °C. The cleanest split was observed for the methylene peaks
Thermal Racemization. Using optically-resolved 4, we can
now test whether the ring of 4 is immobilized or the rate of
ring inversion is simply slower than the NMR time scale. We
heated 4 in various solvents for 12 h and tested for racemization
by an HPLC method. To obtain a general conclusion for the
solvent effect on racemization we chose methanol, n-butanol,

4274 J. Am. Chem. Soc., Vol. 118, No. 18, 1996
Otsuka and Shinkai
Figure 4. Chromatogram for resolution of racemic 4. For separation
conditions, see the data given in the figure. Numbers recorded on the
peaks are the retention time (t/min).
Figure 6. Schematic representation of a stereo view for aromatic rings
in 3 and 4. p-tert-Butyl groups are omitted for clarity.
group or the t-Bu group inevitably hits the CAP ring. Hence,
this frame is firmly maintained and cannot undergo inversion.
1
As shown in Figure 1, the H NMR spectrum of 4 at 30 °C
consists of a mixture of sharp and broad peaks. Most of the
sharp peaks are assignable to protons in this firm frame,
indicating that the molecular motion is highly restricted. This
firm frame consists of 16 atoms, the number being the same as
that in calix[4]arenes. In calix[4]arenes the MeO-through-the-
annulus rotation is still allowed.1 Hence, the cavity size of this
firm frame should be smaller than that of calix[4]arenes. The
difference stems from the ortho linkages employed in the B
and B′ rings.
Conclusion. The ring inversion problem in calix[6]arenes
has been one of central interests in calixarene chemistry.13-20
1
It is rather easy to obtain evidence for ring inversion from H
NMR spectroscopy using, for example, temperature-dependent
1H NMR spectra and 2D EXSY measurements.14-17 In contrast,
it is very difficult to obtain unequivocal evidence for ring
immobilization. Although the 1H NMR spectra are unchanged
over a wide temperature range, one has to always take the NMR
time-scale problem into consideration. The present paper has
demonstrated, for the first time, a novel method to obtain
unequivocal evidence for ring immobilization in calix[6]arenes.
The basic idea is to use a chiral calix[6]arene with molecular
asymmetry: as ring inversion is obligatorily accompanied by
racemization, one can conveniently determine whether or not
the calix[6]arene ring is immobilized. We now consider that 4
is useful for testing several hypotheses in calix[6]arene chemistry
which have been ambiguous for lack of the absence of
appropriate calix[6]arenes: e.g., (i) the conformationally-defined
analogs should show better shape selectivity for guest molecules,2c
and (ii) guest inclusion into the invertible calix[n]arene cavities
suppresses the ring inversion and therefore accompanies the loss
of the conformational freedom: in this context, conformation-
ally-immobilized analogs should give larger association con-
stants,27 etc.
Figure 5. CD spectra of optically-resolved 4 at 25 °C in CD2Cl2.
n-octanol, n-octane, toluene, 1,1,2,2-tetrachloroethane, and DMF
which cover most categories of polar vs apolar, protic vs. aprotic,
halogenated, and aromatic solvents. When their boiling points
are higher than 100 °C, the racemization test was carried out at
100 °C because 4 slowly decomposed above this temperature.
When they are lower than 100 °C (e.g., methanol), we used the
reflux temperature. From the HPLC analysis of these solutions
we confirmed that the racemization does not take place in any
solvent. In addition, we left n-octane solution at room tem-
perature for 3 months. Again, the racemization was not
observed. The findings unequivocally establish that the ring
inVersion in 4 is inhibited. This is the first experimental
evidence that the calix[6]arene ring is truly immobilized on the
temporal time scale.
We now discuss why 1 can undergo ring inversion,22 whereas
4 cannot. The difference between 1 and 4 is only either the
p-xylenyl-bridging on the 1,4-phenyl units or the m-xylenyl-
bridging on the 1,3-phenyl units. It is known that 1 tends to
adopt a 1,2,3-alternate conformation with a “self-anchored
rotaxane” structure.22 This structure can be a symmetrical
intermediate in ring inversion, and the calix[6]arene annulus is
large enough to include the self-anchored p-xylenyl unit.
Furthermore, the 1,2,3-alternate conformation holds the 1,4-
phenyl units in the anti direction which makes the p-xylenyl-
bridging sterically advantageous. These stabilization effects act
synergistically and allow the ring inversion. In 4, on the other
hand, the bridging of 1,3-phenyl units with the m-xylenyl unit
creates a new small ring consisting of A-B-CAP-B′ phenyl
units (see Figure 6). Although the D ring retains considerable
conformational freedom (as shown by 1H NMR spectroscopy),
the rotation of the A ring is sterically impossible. The CAP
ring stands nearly perpendicularly to the calix[6]arene plane to
bridge the B and B′ rings to reduce the steric crowding with
the C and C′ rings. When the A ring rotates, either the MeO
Experimental Section
Materials. 2,4-Dimethylanisole was purchased from Janssen Chim-
ica. Preparation of 5,11,17,23,29,35-hexa-tert-butyl-37,38,39,41-
tetramethoxycalix[6]arene-40,42-diol has already been described.20a
4-Methoxy-r,r′-dibromo-m-xylene. A mixture of 2,4-dimethy-
lanisole (5 mL, 35.7 mmol), N-bromosuccinimide (12.7 g, 71.4 mmol),
benzoyl peroxide (100 mg), and tetrachloromethane (100 mL) was
heated at reflux temperature for 2 h under a N2 stream. The reaction
mixture was filtered to remove succinimide, washed with water, dried
over MgSO4, and filtered. The filtrate was evaporated to dryness and
the residue was triturated with cold MeOH. The white solid was
dissolved in CH2Cl2 and reprecipitated from cold MeOH to give the
pure product: mp 96.8-98.2 °C, yield 72%; 1H NMR (CDCl3, 60 MHz,
(27) Shinkai, S.; Araki, K.; Matsuda, T.; Manabe, O. Bull. Chem. Soc.
Jpn. 1989, 62, 3856.

EVidence for Inhibition of Calix[6]arene Ring InVersion
J. Am. Chem. Soc., Vol. 118, No. 18, 1996 4275
25 °C) δ 3.91 (3H, s), 4.47 (2H, s), 5.53 (2H , s), 6.7-7.4 (3H, m).
Anal. Calcd for C9H10OBr2: C, 36.77; H, 3.43. Found: C, 37.28; H,
3.46.
Chiralpak AD, and Sumitomo Sumichiral. We found that Daicel
Chiralpak AD shows satisfactory optical resolution ability for 4 (mobile
phase, n-hexane-2-propanol ) 98:2 (v/v)). We divided the eluent into
two fractions and recovered one optical isomer from the first fraction
and another optical isomer from the second fraction. Optically-resolved
4: 4a from the first fraction, mp >300 °C dec, recovery 50%, 100%
ee (from HPLC analysis); 4b from the second fraction, mp >300 °C
dec, recovery 49%, 99% ee (from HPLC analysis).
Chiral Calix[6]arene (4). 5,11,17,23,29,35-Hexa-tert-butyl-37,38,-
39,41-tetramethoxycalix[6]arene-40,42-diol (32 mg, 0.03 mmol) was
dispersed in acetone (30 mL) containing 4-methoxy-R,R′-dibromo-m-
xylene (9.2 mg, 0.03 mmol) and Cs2CO3 (203 mg, 0.60 mmol), and
the mixture was refluxed for 12 h under a N2 stream. After evaporation,
the solid residue was dispersed in aqueous 0.1 M HCl solution and
then extracted with CHCl3. The CHCl3 layer was separated, washed
with H2O, and dried over MgSO4. The solution was evaporated to
dryness, and the residue dissolved in CHCl3 was purified by repre-
cipitation from MeOH: mp >270 °C dec, yield 90%; IR(Nujol) no
Thermal Racemization. Enantiomer 4a in various solvents was
heated at 100 °C in an oil bath. The ee values were determined by an
HPLC method (Daicel Chiralpak AD, mobile phase, n-hexane-2-
propanol ) 98:2 (v/v)). Even after 12 h, no production of another
enantiomer 4b was detected. The same result was obtained from
thermal racemization of 4b.
ν
OH; 1H NMR ((CDCl2)2, 400 MHz, 130 °C) δ 0.70 (9H, s), 1.02 (9H,
s), 1.05 (9H, s), 1.24 (9H, s), 1.37 (9H, s), 1.38 (9H, s), 2.38 (3H, s),
3.28 (3H, s), 3.36 (3H, s), 3.46 (3H, s), 3.32 (1H, d), 3.38 (1H, d),
3.47 (1H, d), 3.48 (1H, d), 3.51 (1H, d), 3.63 (1H, d), 3.68 (1H, d),
3.80 (3H, s), 3.97 (1H, d), 3.98 (1H, d), 4.32 (1H, d), 4.33 (1H, d),
4.41 (1H, d), 4.43 (1H, d), 4.52 (1H, d), 4.78 (1H, d), 5.02 (1H, d),
6.20 (1H, s), 6.36 (1H, d), 6.39 (1H, d), 6.74 (1H, d), 6.81 (1H, d),
6.84 (1H, d), 6.86 (1H, d), 7.00 (1H, d), 7.04 (2H, s), 7.14 (1H, m),
7.17 (1H, d), 7.18 (1H, d), 7.22 (1H, d), 7.26 (1H, d). Anal. Calcd
for C79H100O7: C, 81.68; H, 8.68. Found: C, 81.97; H, 8.57.
Miscellaneous. 1H NMR, IR, and circular dichroism spectroscopic
measurements were carried out with a JEOL GSX-400 spectrometer, a
JASCO A-100 infrared spectrometer, and a JASCO spectropolarimeter
J-720, respectively. HPLC experiments were performed on a JASCO
PU-980 pump equipped with a JASCO UV-970 variable wavelength
detector at a flow rate of 0.5 mL min-1 at room temperature and
monitored at 254 nm.
Optical Resolution. In order to optically resolve racemates we
tested three chiral-packed HPLC columns: Daicel Chiralpak OP, Daicel
JA953626B