Synthesis and characterization of an inherently chiral calix[6]arene in the 1,4-alternate conformation

Article abstract of DOI:10.1016/j.tetlet.2006.07.087

An inherently chiral calix[6]arene possessing a C₂-symmetric A-B-H substitution pattern was synthesized via a two step process starting from the parent hexa-t-butylcalix[6]arene. The racemic, inherently chiral compound exists as a single isomer with the 1,4-alternate conformation. The inherent chirality was confirmed by treatment of the racemic compound with Pirkle's reagent to form diastereomeric complexes in solution.

Full text of DOI:10.1016/j.tetlet.2006.07.087

Tetrahedron Letters 47 (2006) 7081–7084
Synthesis and characterization of an inherently chiral
calix[6]arene in the 1,4-alternate conformation
Michael T. Blanda,* Lauren Edwards, Ralph Salazar and Mikki Boswell
Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
Received 19 June 2006; revised 18 July 2006; accepted 19 July 2006
Available online 14 August 2006
Abstract—An inherently chiral calix[6]arene possessing a C2-symmetric A–B–H substitution pattern was synthesized via a two step
process starting from the parent hexa-t-butylcalix[6]arene. The racemic, inherently chiral compound exists as a single isomer with the
1,4-alternate conformation. The inherent chirality was confirmed by treatment of the racemic compound with Pirkle’s reagent to
form diastereomeric complexes in solution.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
considering calixarene-based receptors. Of the various
immobilized calix[6]arenes reported most are cone or
1,2,3-alternate conformers, but many intriguing host
architectures can be envisioned based on the other
shapes, especially the 1,4-alternate. Recently, Chen
and co-workers have reported the crystal structure of
an achiral 1,4-2,5-biscrown-4 calix[6]arene in the 1,4-
alternate conformation.10 Herein, we wish to report
the synthesis, structural determination and NMR reso-
lution of an inherently chiral calix[6]arene in the rare
1,4-alternate conformation.
Calixarenes continue to be one of the most frequently
used macrocyclic systems for constructing host mole-
cules with tailored recognition properties.1 However,
chiral recognition by calixarenes represents a relatively
unexplored area. Two general strategies have been
employed to impart chirality to calixarene structures:
appending chiral auxiliaries onto the achiral molecular
framework or appending achiral moieties in an asym-
metric substitution pattern onto the aromatic residues
thereby creating inherently chiral calixarenes.2 Pure
optical isomers of inherently chiral calix[4]-3 and
calix[5]arene,4 have been reported. In contrast, the earli-
est reports of inherently chiral calix[6]arenes did not
attempt chiral recognition studies or resolution of the
racemates.5–7 However, Shinkai and co-worker were
successful at resolving an inherently chiral calix[6]arene
and demonstrated that Pirkle’s reagent was effective in
creating diastereomeric complexes with the racemic
host.8 Compared with the recent advances in chiral
recognition by calix[6]arenes with chiral appendages,9
chiral discrimination using inherently chiral calix[6]-
arenes is undeveloped and warrants more attention.
2. Synthesis
Our strategy was based on the Gutsche method which
provides a C2-symmetric A–B–H substitution pattern
of the aromatic rings.5 Instead of the all-carbon chains
with ester linkages, we chose to employ the more iono-
phoric ethyleneoxy ether tethers. In addition, we used
p-cyanobenzyloxy groups rather than tolyl groups for
further elaboration of the cyano groups (see Fig. 1).
The first step involved 1,4- regioselective ether forma-
tion using potassium trimethylsilanolate as the base
and a-bromotolunitrile as the alkylating agent to pro-
duce the 1,4-diether 2 in 90–95% yield.11 When 2 was
deprotonated with NaH and reacted with triethylenegly-
col di-p-tosylate in acetone, the mono-bridged calix[6]-
arene 3 was formed in approximately 30% isolated
yield.12 The racemic mixture was effectively separated
using a CHIRALPAK AD-H chiral HPLC column with
hexanes/2-propanol (9:1) as the eluent and the separa-
tion factor was calculated to be 1.1.
Besides the inherent chirality of the calixarene frame-
work, conformational isomerism is important when
Keywords: Inherently chiral; 1,4-Alternate conformation; Calix[6]-
arene; NMR resolution.
*
Corresponding author. Tel.: +1 512 245 3121; fax: +1 512 245
2374; e-mail: mb29@txstate.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.087

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M. T. Blanda et al. / Tetrahedron Letters 47 (2006) 7081–7084
tBu
tBu
tBu
tBu
O
tBu
OH
OR
OH
OH
OR
HO
i
ii
tBu
RO
tBu
tBu
X
RO
tBu
HO
O
HO
OH
6
tBu
tBu
tBu
tBu
3
1
2
CH2
CN
CN
CH2
R =
X =
R =
CH2CH2OCH2CH2OCH2CH2
α
i) (CH3)3SiOK/p-cyano- -bromotoluene/THF/DMF/D/90-95%
ii) NaH/triethyleneglycol-di-p-tosylate/ acetone/30-35%
Figure 1. Synthetic route to inherently chiral compound 3.
3. Solid state structure of 3
Table 1. Conformational parameters u and v in compound 3
Ring
U (degrees)
v (degrees)
Orientation
The solid state structure of 3 was determined by X-ray
diffraction and is shown in Figure 2.13 For purposes of
this discussion, we define the A and D rings as the
bridged pair, the B and E rings as the p-cyanobenzyl-
oxy-substituted rings and the C and F rings as the
unsubstituted phenolic rings. Visual inspection of the
structure readily suggested that 3 adopted the 1,4-alter-
nate conformation with the four t-butyl groups on the
A, C, D, and F rings oriented downwards and the two
t-butyl groups on the Band E rings pointed upwards
relative to a line that passes through the oxygen atoms
of the C/F rings. In addition to the conformation, the
inherent chirality of the structure due to the C2-sym-
metric A–B–H substitution pattern of the aromatic
rings was also confirmed. A more rigorous classifica-
tion of calixarene conformations was made by measur-
ing the values and signs of the dihedral angles phi and
chi between pairs of adjacent aromatic rings.14 The
values and signs for the six dihedral angles of 3
are listed in Table 1 and unambiguously describe the
1,4-alternate conformation wherein there are four
pairs of anti-oriented rings and two pairs syn-oriented
rings.
A/B
B/C
C/D
D/E
E/F
F/A
146.9
2.0
98.7
150.8
2.1
133.8
85.9
À80.6
122.2
93.8
anti
anti
syn
anti
anti
syn
99.3
À76.3
4. Conformation of 3 in solution
1
In the H spectrum (CDCl3) at room temperature, the
C2-axis was evident by noting the three singlet reso-
nances for the t-butyl groups and six doublets for the
aromatic hydrogens of the calix framework. The C2-
symmetry was also consistent with the three resonances
observed in the 13C spectrum for the carbons of the
ethylenoxy bridging unit and one resonance each for
the benzylic and nitrile carbons of the p-cyanobenzyloxy
groups.
Besides the molecular symmetry, H and 13C signals for
1
the ArCH2Ar methylene bridges provided insight into
the conformation of 3 in solution. Three signals were
observed at 29.52, 31.75, and 38.72 ppm in the 13C spec-
trum while an AX, AM, and AB quartet were observed
for the diastereotopic methylene bridge hydrogens in the
1H spectrum. The Dds between the doublets were found
to be 1.32, 0.63, and 0.12, which are commensurate with
one syn-orientation, one intermediate syn/anti-orienta-
tion and one anti-orientation between the three contigu-
ous rings.11
5. NMR resolution of 3
Titration experiments wherein successive amounts of
(S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol
(Pirkle’s
reagent) were added to racemic 3 in CDCl3 clearly
demonstrated the formation of two diastereomeric
1
complexes at room temperature. The H NMR regions
for the aromatic (Ar–H, d 6.3–4.7) and benzylic (ArCH2-
Ar and CH2ArCN, d 4.7–3.2) are shown in Figure 3 with
Figure 2. X-ray crystal structure of compound 3. Hydrogens have been
omitted for clarity.

M. T. Blanda et al. / Tetrahedron Letters 47 (2006) 7081–7084
7083
Figure 3. (a) Compound 3 with no Pirkle’s reagent added. (b) Compound 3 with 1 equiv of Pirkle’s reagent added. (c) Compound 3 with 2 equiv of
Pirkle’s reagent added.
5. Kanamathareddy, S.; Gutsche, C. D. J. Am. Chem. Soc.
1993, 115, 6572–6579.
6. Neri, P.; Rocco, C.; Consoli, G. M. L.; Piattelli, M. J. Org.
Chem. 1993, 58, 6535–6537.
7. Janssen, R. G.; Verboom, W.; Harkema, S.; van Hummel,
G. J.; Reinhoudt, D. N.; Pochini, A.; Ungaro, R.; Prados,
P.; de Mendoza, J. J. Chem. Soc. Chem. Comm. 1993, 6,
506–508.
8. Otsuka, H.; Shinkai, S. J. Am. Chem. Soc. 1996, 118,
4271–4275.
9. Erdemir, S.; Tabakci, M.; Yilmaz, M. Tetrahedron:
Asymmetry 2006, 17, 1258–1263.
10. Guan, B.; Gong, S.; Wu, X.; Chen, Y. Tetrahedron Lett.
2005, 46, 6041–6044.
11. Kanamathareddy, S.; Gutsche, C. D. J. Org. Chem. 1992,
57, 3160–3166.
coupled signals designated by matching symbols. Upon
addition of 1 equiv of the Pirkle’s reagent, the signals for
the CH2–Ar–CN protons were doubled and shifted
slightly while aromatic resonances associated with the
calixarene framework were only broadened. The
ArCH2Ar signals were all affected significantly as well.
At 2 equiv of Pirkle’s reagent, additional changes to the
spectrum were observed. Of the three pairs of doublets
for the Ar–H protons of the calixarene rings, two
(square and diamond) showed doubling of only one sig-
nal within a coupled pair and the third (circles) showed
no doubling at all and not much broadening. Based on
the doubling behavior of certain signals, it is tempting
to conclude that Pirkle’s reagent interacts preferentially
with one side of the molecule.
12. Into a round bottom flask was placed 3.34 g (2.78 mmol)
of 2 along with 500 mL of acetone. To this was added
0.95 g (40 mmol) of sodium hydride (Caution!: flammable).
Tri(ethyleneglycol)di-p-tosylate (1.82 g, 3.97 mmol) was
dissolved in 100 mL of acetone and added over 45 min.
The reaction was heated to reflux for 48 h and then the
solvent was removed. The residue was re-dissolved in
CHCl3 and the solution was washed with 2 N HCl. The
organic layer was dried over MgSO4, filtered, and
concentrated to a minimal volume then poured into
CH3OH to precipitate the product. Isolated yields of 26–
33% of 3 as a pure white powder were routinely obtained.
The product was recrystallized from n-octane to obtain
crystals suitable for X-ray diffraction. 1H NMR
(400 MHz, CDCl3) d = 7.54 (s, 2H), 7.34, 7.03 (AXq,
J = 2.4 Hz), 7.14, 6.80 (AXq, J = 2.0 Hz, 4H), 7.00, 6.48
(AXq, J = 2.0 Hz, 4H), 6.70, 6.38 (AXq, J = 8.0 Hz, 8H),
4.65, 4.49 (ABq, J = 13.6 Hz, 4H), 4.59, 3.26 (AXq,
J = 17.2 Hz, 4H), 4.19, 3.56 (AMq, J = 17.6 Hz, 4H),
4.16, 4.03 (ABq, J = 16.8 Hz, 4H), 3.87 (t, J = 10 Hz, 2H),
3.51 (t, J = 10 Hz, 2H), 3.33–3.35, (m, 3H), 3.23–3.21 (m,
3H), 2.10 (t, J = 10 Hz, 2H), 1.42 (s, 18H), 1.17 (s, 18H),
0.89 (s, 18H). 13C {1H} NMR (100 MHz, CDCl3)
d = 152.92, 151.38, 150.02, 147.48, 145.84, 143.27,
141.78, 135.53, 133.20, 131.17, 131.08, 129.85, 127.51,
126.44, 125.31, 125.26, 125.16, 124.84, 124.07, 118.89,
Acknowledgements
We would like to thank the Robert A. Welch Founda-
tion for financial support and Professor Carl Carrano
at San Diego State University for providing the X-ray
structure. The NSF-MRI program Grant CHE-
0320848 is acknowledged for support of the X-ray
diffraction facilities at SDSU.
References and notes
1. Calixarenes 2001; Asfari, Z., Bohmer, V., Harrowfield,
J., Vicens, J., Eds.; Kluwer Academic: Dordrecht,
2001.
2. Bohmer, V.; Kraft, D.; Tabatabai, M. J. Incl. Phenom.
1994, 19, 17–39.
3. Luo, J.; Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T. Chem.
Eur. J. 2005, 11, 5917–5928.
4. Li, S.-Y.; Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T.
Tetrahedron: Asymmetry 2005, 16, 641–645.

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M. T. Blanda et al. / Tetrahedron Letters 47 (2006) 7081–7084
71.42, 69.81, 69.57, 68.70, 38.72, 34.22, 33.98, 33.79, 31.79,
31.75, 31.46, 30.91, 29.53. Mp 260 °C (dec) C88H104N2O8
calcd: C, 80.24, H, 7.90. Found: C, 79.91, H, 7.88.
tary publication (CCDC 602359). Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0)1223
336033 or e-mail: deposit at CCDC.cam.ac.uk).
13. Crystallographic data, excluding structure factors, for the
structure in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
14. Ugozzoli, F.; Andretti, G. D. J. Incl. Phenom. Mol.
Recognit. Chem. 1992, 13, 337–348.