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Can C3-Symmetric Receptors Differentiate Enantiomers.

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DOI: 10.1002/anie.200601214
Threefold Symmetry (2)
Can C3-Symmetric Receptors Differentiate
Christina Moberg*
chiral recognition · enantioselectivity · host–guest
systems · molecular symmetry · receptors
Chiral recognition is a key issue in both
living and artificial systems. It is essential for biological function and has a
central role in asymmetric synthesis and
chiral separation. A combination of
attractive and repulsive interactions,
the former including hydrogen bonds,
ion–dipole and dipole–dipole interactions, p stacking, and hydrophobic interactions, is responsible for such chiral
Synthetic receptors that can differentiate enantiomers have been the subject of recent intensive studies. Symmetry properties of the receptor may play
an important role in the recognition
process. Artificial chiral receptors endowed with rotational axes have been
frequently employed as a result of their
ability to simplify the procedure for
their preparation and occasionally also
to improve the selectivity by reducing
the number of diastereomeric substrate–
receptor interactions.
The role of threefold rotational
symmetry in chiral recognition has been
a matter of some confusion. The ability
of C3- or D3-symmetric receptors to
differentiate the two enantiomers of a
chiral ammonium (or some other analogous) guest molecule was questioned
some time ago.[1] It was argued that the
steric requirements of the two host–
[*] Prof. C. Moberg
Department of Chemistry
KTH School of Chemical Science and
SE 100 44 Stockholm (Sweden)
Fax: (+ 46) 8-791-2333
[**] The European Community’s Human Potential Program under contract HPRN-CT2001-00187, [AC3S], is gratefully acknowledged.
Angew. Chem. Int. Ed. 2006, 45, 4721 – 4723
guest complexes obtained from the two
enantiomers of the guest and the chiral
receptor are the same and that chiral
recognition therefore must be absent or
at least poor. Although this statement
might have hampered the development
of receptors with threefold symmetry, a
number of C3-symmetic artificial receptors have recently been described.[2]
Over the last few years, Ahn and coworkers have presented a number of
tripodal oxazoline-based artificial receptors of general structure 1 by employing 1,3,5-R-2,4,6-R’-hexasubstituted arenes as a platform, thereby taking
advantage of the alternating ababab
geometric pattern that favors proper
organization.[3] Contrary to their expectations,[4] the receptors exhibited high
enantioselectivity in their complexation
to a-chiral primary ammonium ions.
That C3-symmetic receptors are capable
also of enantiofacial discrimination was
demonstrated upon complexation of
caffeine to 2 by Waldvogel and coworkers.[5]
A different strategy for the preparation of tripodal receptors was presented
by Haberhauer et al. Instead of using an
achiral platform for the construction of
the receptor, chiral arms were attached
by means of N-alkylation to a chiral
platform, 3 (in similar fashion to the
construction of the siderophore enterobactin).[6] Also, a chiral tren derivative
(tren = tris(2-aminoethyl)amine)
recently used as a platform for a calix[6]arene, thereby producing a pseudoC3-symmetric receptor.[7]
Successful examples of enantiodiscrimination by chiral receptors with
threefold symmetry prompted a reconsideration of the previous statements.[1]
The arguments for the predicted failure
of this type of receptors to differentiate
enantiomeric guests were as follows: If
we take a C3- or D3-symmetric receptor
H (Figure 1) and the two enantiomers of
a chiral guest molecule (GR and GS),
then these compounds form the two
diastereomeric complexes H-GR and HGS. In the analysis of the steric requirements of the two complexes, the environment of the small, medium, and large
groups of the guest were compared and
evidently found to be the same (Figure 2).
It is indeed obvious that the segments compared are isometric and even
identical. However, this simple analysis
does not take into account the chirality
of the guest molecule. One substituent
of a chiral compound is compared to the
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 1. C3-symmetric host (H), enantiomeric
guests (GR and GS), and diastereomeric host–
guest complexes. The green, dark blue, and
pale blue spheres represent large, medium,
and small substituents, respectively, in the
Figure 3. Non-identical segments of diastereomeric host–guest complexes.
the ligands. Conclusions regarding the
influence of symmetry alone are difficult
to make.
One advantage of C3-symmetric ligands is that their host–guest complexes
give rise to three identical situations,
that is, only one complex (Figure 5),
thereby frequently resulting in more
efficient discrimination of the enantiomeric guests.
Figure 4. A guest exhibits one favorable and
two unfavorable interactions with the host,
while its enantiomer exhibits two favorable
and one unfavorable interactions.
Figure 2. Isolated, isometric segments of diastereomeric host–guest complexes. L, M, and
S denote large, medium, and small, respectively.
same substituent in its enantiomer. This
situation is like comparing a methyl
group in l-alanine with the methyl
group in d-alanine; obviously they are
identical. Instead, the order in space—
the direction—of the three substituents
of the guest has to be taken into account.
The interactions of the large substituents in GR and GS and their clockwise
neighbors, as well as the interaction of
the large and small substituents in the
two complexes with the chiral host, are
shown in Figure 3. The latter segments
are obviously non-isometric (diastereomeric).
All the segments that should be
compared in the two complexes are
shown in Figure 4. It is clear that the
steric requirements in the two complexes are different and that the number
of favorable and unfavorable interactions is different. Some favorable interactions are more important than others,
and some unfavorable interactions are
more severe than others, with the interactions that involve the large and small
substituents probably being more important than those that involve other
pairs of substituents.
There is thus no principal reason
why C3- or D3-symmetric hosts would
not be able to recognize chiral ammonium ions. This argument was indeed
stressed by Ahn and co-workers upon
observing the high selectivity of the
trisoxazoline receptors 1.[4] It may certainly be the case that the energy difference between the host–guest complexes
of enantiomeric ammonium ions with a
host with lower symmetry (C1 or C2) is
larger, but there is no fundamental rule
governing these differences. To further
study the role of symmetry, Ahn and coworkers recently prepared a receptor, 4,
with reduced symmetry in which one of
the substituents was replaced by one
with opposite chirality.[8] This led to
lower selectivity but also to a different
type of binding (2:1 host–guest complex) owing to the different structures of
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 5. C3 symmetry reduces the number of
different complexes as compared to C1 and
C2 symmetry.
Symmetry is not in itself a property
that determines the ability of a receptor
to recognize a chiral guest. However,
symmetry reduces the number of different complexes obtained from a receptor
and a substrate. This factor may, but
does not necessarily have to, lead to
improved selectivity.[9] Rules based exclusively on the symmetry properties of
host compounds are therefore irrelevant.
Published online: June 23, 2006
[1] H.-G. L?hr, F. V?gtle, Acc. Chem. Res.
1985, 18, 65 – 72; See also: X. X. Zhang,
J. S. Bradshaw, R. M. Izatt, Chem. Rev.
1997, 97, 3313 – 3361.
[2] There are a few earlier examples, such as
the enantioselective binding of peptides
to C3-symmetric synthetic receptors:
D. Q. McDonald, W. C. Still, J. Am.
Chem. Soc. 1996, 118, 2073 – 2077.
[3] a) J. Kim, B. Raman, K. H. Ahn, J. Org.
Chem. 2006, 71, 38 – 45; b) J. Kim, D.
Ryu, Y. Sei, K. Yamaguchi, K. H. Ahn,
Chem. Commun. 2006, 1136 – 1138.
[4] S.-G. Kim, K.-H. Kim, J. Jung, S. K. Shin,
K. H. Ahn, J. Am. Chem. Soc. 2002, 124,
591 – 596.
Angew. Chem. Int. Ed. 2006, 45, 4721 – 4723
[5] M. C. Schopohl, C. Siering, O. Kataeva,
S. R. Waldvogel, Angew. Chem. 2003, 115,
2724 – 2727; Angew. Chem. Int. Ed. 2003,
42, 2620 – 2623; for the preparation of the
receptors, see: M. C. Schopohl, A. Faust,
D. Mirk, R. Fr?hlich, O. Kataeva, S. R.
Waldvogel, Eur. J. Org. Chem. 2005,
2987 – 2999.
Angew. Chem. Int. Ed. 2006, 45, 4721 – 4723
[6] a) G. Haberhauer, T. Oeser, F. Rominger,
Chem. Commun. 2005, 2799 – 2801; b) G.
Haberhauer, T. Oeser, F. Rominger,
Chem. Eur. J. 2005, 11, 6718 – 6726.
[7] E. Garrier, S. Le Gac, I. Jabin, Tetrahedron: Asymmetry 2005, 16, 3767 – 3771.
[8] J. Kim, S.-G. Kim, H. R. Seong, K. H.
Ahn, J. Org. Chem. 2005, 70, 7227 – 7231.
[9] For additional applications of C3-symmetric compounds, see: S. E. Gibson,
M. P. Castaldi, Angew. Chem. 2006, 118,
4834 – 4837; Angew. Chem. Int. Ed. 2006,
45, 4718 – 4720.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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enantiomers, can, differential, symmetries, receptors
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