restricted rotation. This allowed the ratio to be easily and
accurately measured by HPLC even in the absence of the
guest molecule. This screening method has two advantages.
First, it avoids the necessity of a multipoint titration
experiment for each host‚guest pairing. Second, the guest-
induced syn/anti ratios are stable even in the absence of guest
and therefore, can be measured with greater accuracy using
a wider range of methods and conditions.6
Atropisomeric receptor 1 was designed about a rigid
1,4,5,8-naphthalenediimide framework.7 Restricted rotation
about the two Caryl-Nimide bonds yields syn- and anti-
atropisomers in which the carboxylic acid groups are on the
same and opposite face of the naphthalenediimide surface,
respectively. Additional design features include pendant tert-
amyl groups and flexible OCH2 spacers for the carboxylic
acid to enhance the solubility of the rigid platform in organic
solvents.8
Finally, deprotection of di-tert-butyl ester 3 in trifluoroacetic
acid and methylene chloride at ambient temperature overnight
yielded the diacid 1. The atropisomers of diacid 1 were stable
at room temperature as evidenced by the ability to isolate
and separate the respective isomers by silica gel chroma-
tography (5% CH3CO2H/CH2Cl2). A rotational barrier of 26.1
kcal/mol was measured by following the equilibration of an
anti-enriched sample by 1H NMR at 65 °C in TCE-d2. Thus,
receptor 1 is conformationally stable at 23 °C with a half-
life of 12 days and is conformationally flexible on gentle
heating with a half-life of 32 min at 70 °C.
The syn- and anti-isomers were assigned on the basis of
the X-ray crystal structure of the more rapidly eluting anti-
isomer (Figure 1). Crystals were obtained of the more quickly
The synthesis of diacid 1 was carried out in three steps as
shown in Scheme 2. Condensation of 2-amino-4-tert-
Scheme 2. Synthesis of Diacid 1
Figure 1. Molecular structure of anti-1 with phenyl and naphtha-
lenediimide surfaces twisted out of plane with a dihedral angle of
79.9°.
amylphenol with 1,4,5,8-naphthalenetetracarboxylic dianhy-
dride gave diol 2 as a slowly equilibrating mixture of
isomers.4d Alkylation of diol 2 with tert-butyl bromoacetate
yielded tert-butyl ester 3 as a mixture of stable atropisomers.
eluting isomer from CH2Cl2/MeOH. The X-ray structure also
gave confirmation of the expected rigid structure. The phenyl
and naphthalenediimide surfaces are twisted out of plane with
a dihedral angle of 79.9°. The carboxylic acid moieties of
anti-1 are on opposite sides of the naphthalene diimide
surface and cannot hydrogen bond to the same guest
molecule. Molecular modeling of syn-1, based on the crystal
structure, positions the two carboxylic acids directed toward
each other with an O-O distance of 5.4 Å.
To test the ability of the guest-induced isomerization
strategy to identify high-affinity guests, a range of different
amine guests and control molecules was screened for their
ability to bind to receptor 1 (Figure 2). We were particularly
interested in whether the atropisomeric receptor 1 would
show selectivity for a specific nucleoside (4-9). Additional
monoamine (10, 11) and diamine (12-15) guests were tested.
The screening studies were carried out by heating a 1:1 ratio
of receptor 1 and guest (2 mM) in TCE-d2 for 3 h at 70 °C.
(3) (a) Borchardt, A.; Still, W. C. J. Am. Chem. Soc. 1994, 116, 373-
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