Synthesis and functionalization of inherently chiral tetraoxacalix[2] arene[2]pyridines

Article abstract of DOI:10.1021/ol303019q

Inherently chiral tetraoxacalix[2]arene[2]pyridines containing C ₂ symmetry were synthesized efficiently from a macrocyclic condensation reaction of resorcinol derivatives with 2,6-dichloro-3- nitropyridine in a one-pot reaction manner, while tetraoxacalix[2]arene[2] pyridine with an ABCD-substitution pattern was prepared in a good yield by means of a stepwise fragment coupling approach. Postmacrocyclization chemical manipulations led to functionalized tetraoxacalix[2]arene[2]pyridines. A racemic sample was resolved into enantiopure (+)- and (-)-inherently chiral compounds.

Full text of DOI:10.1021/ol303019q

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6254–6257
Synthesis and Functionalization of
Inherently Chiral Tetraoxacalix[2]-
arene[2]pyridines
Shuai Pan,† De-Xian Wang,† Liang Zhao,‡ and Mei-Xiang Wang*,‡
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory for
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing, 100190, China, and Key Laboratory of Bioorganic Phosphorous
Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, China
wangmx@mail.tsinghua.edu.cn
Received November 2, 2012
ABSTRACT
Inherently chiral tetraoxacalix[2]arene[2]pyridines containing C2 symmetry were synthesized efficiently from a macrocyclic condensation
reaction of resorcinol derivatives with 2,6-dichloro-3-nitropyridine in a one-pot reaction manner, while tetraoxacalix[2]arene[2]pyridine with an
ABCD-substitution pattern was prepared in a good yield by means of a stepwise fragment coupling approach. Postmacrocyclization chemical
manipulations led to functionalized tetraoxacalix[2]arene[2]pyridines. A racemic sample was resolved into enantiopure (þ)- and (ꢀ)-inherently
chiral compounds.
Heteracalixaromatics are a new generation of macro-
cyclic host molecules in supramolecular chemistry.1 Being
different from the methylene linkages in conventional
calixarenes, heteroatoms such as nitrogen can adopt
different electronic configurations and, more remarkably,
form various conjugation systems with their adjacent
aromatic rings. As a consequence, bond lengths and
bond angles of bridging elements are varied, resulting
in a wide array of conformation and cavity self-tunable
macrocycles.2 The interplay between heteroatoms and
(hetero)aromatic rings also engenders synthetic macro-
cyclic receptors’ tunable electronic features that are essential
in molecular recognition toward electron-neutral or
charged guest species.3ꢀ8
(3) (a) Gong, H.-Y.; Zheng, Q.-Y.; Zhang, X.-H.; Wang, D.-X.;
Wang, M.-X. Org. Lett. 2006, 8, 4895. (b) Gong, H.-Y.; Wang, D.-X.;
Zheng, Q.-Y.; Wang, M.-X. Tetrahedron 2009, 65, 87. (c) Wu, J.-C.;
Zhao, L.; Wang, D.-X.; Wang, M.-X. Inorg. Chem. 2012, 51, 3860.
(4) (a) Gao, C.-Y.; Zhao, L.; Wang, M.-X. J. Am. Chem. Soc. 2011,
133, 8448. (b) Gao, C.-Y.; Zhao, L.; Wang, M.-X. J. Am. Chem. Soc.
2012, 134, 824.
(5) Gong, H.-Y.; Wang, D.-X.; Xiang, J.-F.; Zheng, Q.-Y.; Wang,
M.-X. Chem.;Eur. J. 2007, 13, 7791.
(6) (a) Wang, D.-X.; Zheng, Q.-Y.; Wang, Q.-Q.; Wang, M.-X.
Angew. Chem., Int. Ed. 2008, 47, 7485. (b) Wang, D.-X.; Wang, Q.-Q.;
Han, Y.; Wang, Y.; Huang, Z.-T.; Wang, M.-X. Chem.;Eur. J. 2010,
16, 13053. (c) Chen, Y.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X.
Chem. Commun. 2011, 47, 8112.
(7) (a) Ma, M.-L.; Li, X.-Y.; Wen, K. J. Am. Chem. Soc. 2009, 131,
8338. (b) Hu, S.-Z.; Chen, C.-F. Org. Biomol. Chem. 2011, 9, 5838.
(8) For interactions with fullerenes: (a) Wang, M.-X.; Zhang, X.-H.;
Zheng, Q.-Y. Angew. Chem., Int. Ed. 2004, 43, 838. (b) Liu, S.-Q.; Wang,
D.-X.; Zheng, Q.-Y.; Wang, M.-X. Chem. Commun. 2007, 3856. (c)
Zhang, E.-X.; Wang, D.-X.; Zheng, Q.-Y.; Wang, M.-X. Org. Lett.
2008, 10, 2565. (d) Wang, L.-X.; Zhao, L.; Wang, D.-X.; Wang, M.-X.
Chem. Commun. 2011, 47, 9690. (e) Hu, S.-Z.; Hu, C.-F. Chem. Commun.
2010, 46, 4199. (f) van Rossom, W.; Kundrat, O.; Ngo, T. H.; Lhotak, P.;
Dehaen, W.; Maes, W. Tetrahedron Lett. 2010, 51, 2423.
† Chinese Academy of Sciences.
‡ Tsinghua University.
(1) Recent reviews on heteracalixaromatics: (a) Wang, M.-X. Acc.
Chem. Res. 2012, 45, 182. (b) Wang, M.-X. Chem. Commun. 2008, 4541.
(c) Maes, W.; Dehaen, W. Chem. Soc. Rev. 2008, 37, 2393. (d) Tsue, H.;
Ishibashi, K.; Tamura, R. Top. Heterocycl. Chem. 2008, 17, 73. (e)
Morohashi, N.; Narumi, F.; Iki, N.; Hattori, T.; Miyano, S. Chem. Rev.
2006, 106, 5291.
(2) (a) Wang, M.-X.; Yang, H.-B. J. Am. Chem. Soc. 2004, 126,
15412. (b) Gong, H.-Y.; Zhang, X.-H.; Wang, D.-X.; Ma, H.-W.; Zheng,
Q.-Y.; Wang, M.-X. Chem.;Eur. J. 2006, 12, 9262.
r
10.1021/ol303019q
Published on Web 12/05/2012
2012 American Chemical Society

Inherently chiral calixarenes are chiral calixarenes not
based on a chiral subunit but on the absence of a plane
of symmetry or an inversion center in the molecule.9ꢀ11
A large number of racemic inherently chiral calixarenes
have been synthesized, and some of them have been
resolved into enantiomerically pure form.9ꢀ11 Applica-
tions of inherently chiral calixarene derivatives in mole-
cular recognition12 and asymmetric catalysis13 have
been demonstrated.
Owing to the intrinsic structural features,1 we envisioned
that heteracalixaromatics would provide a unique plat-
form for the construction of inherently chiral macrocycles.
The combination of different heteroatoms in the bridging
positions with various (hetero)aromatic rings can foresee-
ably lead to an unlimited amount of inherently chiral
heteracalixaromatics. Inherently chiral heteracalixaro-
matics can be roughly cataloged into three subtypes
based on their aromatic building units and bridging
elements. For example, differing only the aromatic rings
or the bridging heteroatoms would result in type-1 or
type-2 inherently chiral heteracalixaromatics, respec-
tively, while type-3 inherently chiral heteracalixaro-
matics are constructed by varying both aromatic rings
and heteroatom linkages.
We reported in 2004 the synthesis of azatrioxa- and
triazaoxacalix[2]arene[2]triazines, type-3 inherently chiral
macrocyclic compounds, based on the fragment coupling
protocol.1 A number of type-3 and type-1 inherently chiral
hetaracalixaromatics have been synthesized by us,14
Katz,15 and Siri16 since then using a similar stepwise
synthetic strategy with or without isolation of linear
“trimeric” intermediates. It is interesting to note that
whereas the reaction between 1,3-dihydroxybenzene
and 2,4-dichloroquinazoline gives a regioisomeric mix-
ture of tetraoxacalix[2]arene[2]quinazolines,17 the simple
one-pot condensation reaction between 3-aminophenols
or 4-substituted 1,3-phenylenediamine and 1,5-difluoro-
2,4-dinitrobenzene regioselectively affords type-3 inher-
ently chiral diazadioxa or tetraazacalix[4]arene products
in moderate to good yields.15 The type-1 inherently chiral
azacalix[2]arene[2]pyridines have also been obtained from
a desymmetrical m-bromination reaction of the pyridine
moiety of the parent symmetric macrocycle.18 Few type-2
inherently chiral heteracalixaromatics are known in litera-
ture,3c,19 and among them 1,3-alternate azacalix[4]pyridines
bearing two different substituents on the alternating nitro-
gen bridges are the representative examples.3c Our interest
in the supramolecular chemistry of heteracalixaromatics
has led us to undertake the current study. We report herein
the efficient synthesis of inherently chiral tetraoxacalix-
[2]arene[2]pyridines with C2 symmetry from the one-pot
reaction between 1,3-dihydroxybenzene derivatives and
2,6-dichloro-3-nitropyridine. Employing the fragment
coupling approach, we have also prepared an inherently
chiral tetraoxacalix[2]arene[2]pyridine with an ABCD-
substitution pattern. Facilepostmacrocyclization chemical
manipulations allowed us to conveniently construct the
functionalized inherently chiral macrocycles and calix-
crown molecule. Resolution of a racemic sample by means
of HPLC with a chiral stationary-phase-coated column
will also be presented.
We initiated our study with the examination of the
reaction between resorcinol 1a and 2,6-dichloro-3-nitro-
pyridine 2 in a 1:1 stoichiometry (Table 1). The reaction
proceeded effectively at 60 °C in DMSO in the presence
of 2 equiv of Cs2CO3 as an acid scavenger. Remarkably,
the inherently chiral tetraoxacalix[2]arene[2]pyridine 3a
was isolated as the sole product in 56% yield. The macro-
cyclic condensation reaction was then found to be very
efficient for the synthesis of functionalized inherently
chiralmacrocyclicproducts. Forexample, theemployment
of resorcinol analogs 1bꢀf that bear an alkoxy group at the
5-position, which were prepared readily from monoalk-
ylation of 1,3,5-trihydroxybenzene (see Supporting Infor-
mation (SI)), under identical conditions afforded the
corresponding inherently chiral compounds 3bꢀf in good
yields (entries 2ꢀ6, Table 1). A high yield of the upper-rim
bishydroxylated inherently chiral tetraoxacalix[2]arene-
[2]pyridine 3g was obtained from the reaction of 2 with
1,3,5-trihydroxybenzene 1g (entry 7, Table 1). In this
case, the free phenolic hydroxyl groups on the upper-rim
position remained intact. Inherently chiral tetraoxacalix-
[2]arene[2]pyridines functionalized on the lower-rim posi-
tion were also successfully synthesized by means of the
same one-pot reaction approach. This has been exempli-
fied by the preparation of the bisformyl-substituted tetra-
oxacalix[2]arene[2]pyridine 3h using 2,6-dihydroxybenzal-
dehyde 1hasa startingbisnucleophiliccomponent (entry 8,
Table 1). It was also noteworthy that the one-pot reac-
tion worked equally well with 2,5-disubstituted resorcinol
derivatives such as 5-tert-butybenzene-1,2,3-triol. The re-
action produced inherently chiral tetraozacalix[2]arene-
[2]pyridine 3i that contains substituents at both lower and
upper rims. It should be addressed that all reactions tested in
the study afforded inherently chiral tetraoxacalixaromatics
€
(9) Bohmer, V.; Kraft, D.; Tabatabai, M. J. Incl. Phenom. Mol.
Recog. Chem. 1994, 19, 17.
(10) (a) Zheng, Y.-S.; Luo, J. J. Incl. Phenom. Macrocycl. Chem.
2011, 71, 35. (b) Li, S.-Y.; Xu, Y.-W.; Liu, J.-M.; Su, C.-Y. Int. J. Mol.
Sci. 2011, 12, 429.
(11) Mclldowie, M. J.; Mocerino, M.; Ogden, M. I. Supramol. Chem.
2010, 22, 13.
(12) For selected examples: (a) Lou, J.; Zheng, Q.-Y.; Chen, C.-F.;
Huang, Z.-T. Tetrahedron 2005, 61, 8517. (b) Shirakawa, S.; Moriyama,
A.; Shimizu, S. Org. Lett. 2007, 9, 3117.
(13) For selected examples: (a) Shirakawa, S.; Moriyama, A.;
Shimizu, S. Eur. J. Org. Chem. 2008, 5957. (b) Miao, R.; Xu, Z.-X.;
Huang, Z.-T.; Chen, C.-F. Sci. China, Ser.
B 2009, 52, 505.
(c) Shirakawa, S.; Shimizu, S. New J. Chem. 2010, 12, 1916 and
references therein.
(14) Hou, B.-Y.; Zheng, Q.-Y.; Wang, D.-X.; Wang, M.-X. Tetra-
hedron 2007, 63, 10801.
(15) (a) Katz, J. L.; Tschaen, B. A. Org. Lett. 2010, 12, 4300. (b)
Bizier, N. P.; Vernamonti, J. P.; Katz, J. L. Eur. J. Org. Chem. 2012,
2303.
(16) Raimundo, J.-M.; Chen, Z.; Siri, O. Chem. Commun. 2011, 47,
10410.
(17) van Rossom, W.; Kishore, L.; Robeyns, K.; van Meervelt, L.;
Dehaen, W.; Maes, W. Eur. J. Org. Chem. 2010, 4122.
(18) Yao, B.; Wang, D.-X.; Gong, H.-Y.; Huang, Z.-T.; Wang,
M.-X. J. Org. Chem. 2009, 74, 5361.
(19) Ishibashi, K.; Tsue, H.; Takahashi, H.; Tamura, R. Tetrahedron:
Asymmetry 2009, 20, 375.
Org. Lett., Vol. 14, No. 24, 2012
6255

exclusively. In other words, two nitro groups are dis-
symmetrically positioned on the opposing benzene
rings, generating C2 symmetry within the macrocyclic
scaffold. No symmetric products were observed in the
reaction.
chiral tetraoxacalix[2]arene[2]pyridine proceeds through
dissymmetrical linear trimer intermediate 4, whereas the
direct one-pot condensation reaction between resorcinol
1a and 2,6-dichloro-3-nitropyridine 2 produces first di-
meric isomers 5a and 5b, which then undergo respectively
self rather than crossover condensation. The convergent
formation of either the final macrocyclic product 2 or the
linear trimer 4 implied the most likely thermodynamically
controlled nature of the reactions.
Table 1. Synthesis of 3 from One-Pot Reaction of 1 with 2a
Scheme 1. Reactions between 1a and 2
entry
1
R1
R2
3
yield (%)b
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
H
H
3a
3b
3c
3d
3e
3f
56
78
75
80
73
84
82
50
56
CH2=CHCH2O-
CH3CH2CH2O-
CH2=CHCH2CH2O-
CH3CH2CH2CH2O-
MeOCH2CH2OCH2O-
OH
H
H
H
H
H
1g
1h
1i
H
3g
3h
3i
H
CHO
OH
Taking advantage of the easy formation of a dissymmetric
linear trimer 4 and its reactivity toward 1,3-dihydroxyben-
zene, the synthesis of inherently chiral tetraoxacalixaromatics
with an ABCD-substitution pattern was attempted. Thus,
the reaction between 4 and 2,6-dihydroxybenzaldehyde 6 in
refluxing acetonitrile afforded the desired product 7 in 60%
yield (Scheme 2). Neither 3a nor 3h was formed, indicating
the stability of the diaryl ether bond which did not undergo a
scrambling reaction.
(CH3)3C
a A 1:1 stoichiometric ratio between two reactants was employed.
b Isolated yield.
The pronounced regioselectivity of the macrocyclic con-
densation reaction between resorcinol derivatives 1 and
2,6-dichloro-3-nitropyridine 2 was highly intriguing. To
shed light on the origin of the highly regioselective macro-
cyclization, the following experiments were conducted
(Scheme 1). The interaction of resorcinol 1a with 2 equiv
of 2 at rt in DMSO exclusively gave a linear trimeric
product4in10h. Acetonitrileassolventgaveananalogous
result while other nonpolar solvents had a detrimental
Scheme 2. Synthesis of 7 with a ABCD-Substitution Pattern
effect on the reaction. On the basis of H and 13C NMR
1
spectroscopic data, the resulting compound 4 is dissymme-
trically substituted. Further treatment of the trimer 4 with
an equimolar amount of 1a furnished the formation of the
inherently chiral macrocyclic product 3a in 62% yield. We
also tested the reaction of an equimolar mixture of 1aand 2
at rt in the presence of 1 equiv of Cs2CO3. After 6 h, an
isomeric mixture of products 5a and 5b, which was not
separable by chromatography, was observed. The ratio of
two isomers was roughly 1:1 based on integration of the
The resulting tetraoxacalixaromatics serve as versatile
platforms for the fabrication of sophisticated macrocyclic
host molecules because of the preinstallation of transform-
able functional groups such aldehyde, hydroxy, nitro, and
olefin. As illustrated in Scheme 3, for example, reduction
of aldehyde in compounds 3h and 7 using borane at 0 °C
gave hydroxymethylated inherently chiral molecules 8
and 9, respectively. These molecules and compounds 3g
and 3i that contain phenolic units may act as hydrogen
1
intensity of resonance signals in the H NMR spectrum.
Interestingly, two isomers in the mixture were converted
into a single inherently chiral tetraoxacalix[2]arene[2]-
pyridine product 3a after a prolonged period of time after
addition of another equivalent of base. Finally, treatment
of the mixture of the two isomers with another equivalent
of 2 gave rise to the formation of trimer 4. The outcomes
convincingly indicated that a stepwise approach to inherently
6256
Org. Lett., Vol. 14, No. 24, 2012

(CD) spectra of (þ)- and (ꢀ)-enantiomers, which were
depicted in Figure 1, showed perfect mirror images. The
absolute stereochemistry of enantiomers was assigned
based on DFT calculations of electronic circular dichroism
spectra (see SI).
Scheme 3. Preparation of 8 and 9
bond donors in molecular recognition and self-assembly.
O-Alkylation of 3i with allyl bromide with the aid of
Cs2CO3 led to product 10 in which the rotation of benzene
ringsaround the macrocyclicannulus isprohibitedbecause
of the steric hindrance of bulky substituents(Scheme 4). An
inherently chiral tetraoxacalix[2]arene[2]pyridine-crown
type molecule 11 was also readily prepared in high yield
from the ring closure metathesis of but-3-enyloxy-substi-
tuted oxacalixaromatics 3d catalyzed by the second gen-
eration Grubbs catalyst20 (Scheme 4).
Figure 1. CD of (þ)- and (ꢀ)-10.
In summary, we have developed an efficient one-pot
reaction protocol for the preparation of various inherently
chiral tetraoxacalix[2]arene[2]pyridine compounds that
contain C2 symmetry starting from readily available re-
sorcinol derivatives and 2,6-dichloro-3-nitropyridine. We
have also synthesized an inherently chiral tetraoxacalix-
[2]arene[2]pyridine with an ABCD-substitution pattern
using a stepwise fragment coupling approach. Postmacro-
cyclization chemical manipulations through the transfor-
mation of preinstalled functional groups have provided
useful methods for the construction of functionalized
macrocyclic products. Resolution of a racemic sample on
an HPLC column coated with a chiral stationary phase
gave, for the first time, enantiomerically pure (þ)- and
(ꢀ)-inherently chiral heteracalixaromatics.
Scheme 4. Synthesis of 10 and 11
Acknowledgment. We thank Dr. Rong-Xiu Zhu at
Shandong University for DFT calculations of CD spectra
of (þ)-10 and (ꢀ)-10. We also thank NNSFC (21132005,
21121004, 20972161), MoST (2011CB932501), and Tsinghua
University for financial support.
To resolve samples of prepared inherently chiral
tetraoxacalix[2]arene[2]pyridines, high efficiency liquid
chromatography (HPLC) was employed using columns
that are coated with chiral stationary phases. While most
of the racemic inherently chiral teraoxacalix[2]arene[2]-
pyridines were not resolved, separation of a pair of en-
antiomers of compound 10 was successfully achieved
on a DAICEL Chiralcel ADH column. Circular dichroism
Supporting Information Available. Experimental
1
details, H and 13C spectra of products. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(20) Zheng, H.; Ghanbari, S.; Nakamura, S.; Hall, D. G. Angew.
Chem., Int. Ed. 2012, 51, 6187.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
6257