COMMUNICATION
Polyfunctionalized macrocycles demonstrate enantioselective and
ditopic binding properties{
Jiachang Gong and Bruce C. Gibb*
Received (in Columbia, MO, USA) 8th March 2005, Accepted 2nd May 2005
First published as an Advance Article on the web 27th May 2005
DOI: 10.1039/b501774b
gave macrocycle 2 and 9. Removal of the t-butyl group of 9 gave
macrocycle 3.
A pair of enantioselective, ditopic macrocycles is described; the
receptors bind chiral ammonium cations in a manner that
depends on the stereochemistry of the cation as well as the
nature of its counter anion.
Host 1 is not planar but dish-shaped. Furthermore, the
directionality of its peptidic moiety (anticlockwise N A C terminus
as shown) precludes the existence of any vertical mirror-plane in
this dish. Hence the molecule is chiral, with ring flipping
interconverting one enantiomer into the other. In addition to this
element of circular chirality,11 hosts 2 and 3 each possess a chiral
center. Thus, ring flipping amounts to diastereomer interconver-
sion. This flipping is facile; an examination of the NMR spectrum
of 2 down to 250 uC did not lead to signal decoalescence. It was
therefore not possible to identify which diastereomeric form of 2
and 3 predominates in solution. In addition to engendering a chiral
center, the side-chains in hosts 2 and 3 can contribute to the
ensemble of non-covalent interactions between host and guest. For
host 2, the benzyl group may take part in p–p stacking or cation–p
interactions. In the case of 3, its hydroxy group has the
opportunity to hydrogen bond to anions or acceptors on the
cation. It may also of course form intramolecular hydrogen bonds
with other functionalities in the macrocycle.
The design of enantioselective artificial receptors continues to be of
great interest in supramolecular chemistry.1 In addition to helping
understand enantioselective recognition processes in biological
systems, investigations of these artificial receptors raise the
opportunity of developing molecular devices for resolution,2 chiral
sensing,3 membrane transportation,4 and enzyme mimicking chiral
catalysis.5
We recently described rigid macrocyclic receptor 1 (Fig. 1),6 a
host that can simultaneously bind a mono-alkylammonium cation
and its counteranion.7 An important feature in the formation of 1
is the incorporation of an amino acid (glycine) residue in one of the
latter synthetic steps. This strategy allows a common precursor (4
in Scheme 1) to serve as a starting point for the formation of a
range of targets. In this paper we report the synthesis of chiral
macrocycles 2 and 3 (Fig. 1), and examine their enantioselective8–10
and ditopic recognition properties.
NMR was used to determine the enantioselective recognition
properties of receptors 2 and 3 (supplementary information{).
Titration experiments in 40% CD3CN–CDCl3 using nitrate salts,
gave a good balance between complexation strength and solubility,
and led to fast exchange (at 400 MHz) between the free host and
complex.6 As expected, binding fitted a 1 : 1 isotherm and induced
a downfield shift of the NMR signals.
The synthesis of receptors 2 and 3 is readily achieved by
coupling 46 with the respective N-Boc amino acids (Scheme 1 and
supplementary information{). Hydrolysis of the ester groups of 5
and 6 with 1 equivalent of NaOH afforded the corresponding
carboxyl acids. The Boc groups of these derivatives were then
removed with either aqueous HCl solution or HCl–ethyl acetate,
to yield respectively the cyclization precursors 7 and 8. Cyclization
under high dilute conditions, using DPPA as coupling reagent,
Macrocycles 2 and 3 exhibit mild to good enantioselectivity for
various a-amino acid methyl ester salts, with a preference for
S-isomers (Table 1). For both hosts, the smaller and/or the more
flexible guests bound more strongly. Thus the threonine and
alanine salts proved to be the best guests, with the former proving
the stronger binder presumably because it can form an additional
hydrogen bond with the host. All the guests examined were noted
to bind more strongly to host 2. This suggests that either the benzyl
group in 2 forms cation–p interactions with the guest, or that the
hydroxy group of 3 is involved in intramolecular hydrogen
bonding in such a manner as to inhibit guest binding. Two factors
are evidently important in enantioselective recognition (Table 1).
First, the larger and or more rigid the guest the better the
discrimination. Second, added functional groups, such as the
hydroxy group of the threonine salt, also led to better discrimina-
tion. It is interesting to note that for the series alanine, valine,
phenylalanine and phenylglycine, the decrease in the Ka of the
S-isomers (S-alanine : S-phenylglycine Ka ratio 5 5.4 : 1) is much
smaller than the decrease in the Ka for the R-isomers (e.g.,
R-alanine : R-phenylglycine Ka ratio 5 13.3 : 1). This suggests that
Fig. 1 The structures of macrocycle 1–3.
{ Electronic supplementary information (ESI) available: synthesis and
characterization, NMR spectra, binding isotherms and Job’s plots. See
*bgibb@uno.edu
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 3319–3321 | 3319
Gong, Jiachang
