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Artificial Receptors for Carbohydrate Derivatives.

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Artificial Receptors for Carbohydrate Derivatives **
By Richard P. Bonar-Law, Anthony P . Davis,*
and Brian A . Murray
There is widespread interest in the recognition and binding
of neutral, polar molecules in organic solvents. Particular
attention has been paid to derivatives of amino acids[’] and
nucleobases,[21but little has been published on the binding of
the third major class of natural building blocks, the carbohyd r a t e ~ . ‘ This
~ ’ is possibly because of the three-dimensional
complexity of carbohydrate structures. In order to take full
advantage of the potential binding sites on, for example, the
pyranose nucleus, it is necessary to design receptors which
can surround the nucleus on all sides with hydrogen-bond
donor and/or acceptor fun~tionality.~~’
We have recently
published syntheses of a series of “cholaphanes” 1 a-e.[’]
Noting that their common framework is able to enclose a
pyranose, and that l a in particular bears six functional
groups with hydrogen-bond donor/acceptor properties (four
hydroxyl and two secondary amide groups), we undertook
to investigate these macrocycles as receptors for carbohydrate derivatives. We now report evidence that 1a and 1 e
bind to the lipophilic glucoside 2 in CDCI, with stability
constants (K,) in the region of lo3 M-l.I6I
Fig. 1. Partial ’H NMR spectra in CDCI, of a) l a (1.1 mM). b) l a
(1 1. mM) + 2 (0.88 mM). c) l e (5.6 mM). d) l e (5.2 mM) + 2 (7.8 mM). Assignments: A = N H , B,C = CH,N; D,E = CH, of the OBn group ( l e only),
F = anomeric CH (see also formulas 1 and 2).
la: R,R’=H
I b R,R’ = AC
Ic: R = A c , R ’ = B n
I d R=Ac,R’=H
le: R = H , R ’ = B n
and there were substantial changes in the coupling constants
between the amide and benzylic protons (Fig. 1 b). The
changes were analyzed using an iterative least-squares curvefitting program with weighting of data points according to
the error analysis of D e r ~ n l e a u . ~They
~ ’ were found to be
consistent with the formation of a 1 :1 complex between 1 a
and 2 with K, = 1740(k200) M-’. The calculated binding
curve and chemical shifts for the amide resonance are shown
in Figure 2, and the limiting values for the chemical shifts are
given in Table 1.
When glucoside 2 was added incrementally to a ca. 1 mM
solution of the tetrahydroxycholaphane 1a in CDCI,, the
‘H NMR spectrum of the latter underwent a number of
changes. Initially, the region from 6 = 4.2 to 5.8 contained a
signal corresponding to the two amide NH protons (broad
triplet) and an AB quartet corresponding to the four benzylic
CH,-N protons, each of which is further coupled to the
amide protons (see Fig. 1 a and Table 1). As 2 was added, the
amide and the lower-field benzylic resonances moved downfield, the higher-field benzylic resonances moved upfield,
Dr. A. P. Davis, R. P. Bonar-Law, Dr. B. A. Murray
Department of Chemistry, Trinity College
IRL-Dublin 2 (Ireland)
[**] This work was supported by EOLAS (the Irish science and technology
agency), Loctite Corp. (provision of our molecular graphics facility) and
Diamalt AG (gifts of cholic acid and methyl cholate). B.A.M. is an employee of BioResearch Ireland. We thank Siobhan Stokes and Philippr
AImurgot for NMR and IR spectra.
AnReiv. Chem. Inr. Ed. Engl. 29 (1990) No. 12
6iA’I i
PI Lm1.
Fig. 2. Downfield shifts of the NH NMR signal of I a on incremental addition
of 2; experimental points and calculated binding curve.
Analysis of the carbohydrate resonances was less informative, because of overlap between the signals due to host and
guest. However, the anomeric CH proton of 2 does stand out
clearly as a sharp doublet F and can be seen to shift up field
by A6 > 0.1 on complex formation. To confirm that we
could discount self-association of host and guest, we recorded ‘H NMR spectra of each at various concentrations. As
anticipated, for both cases there was virtually no change
the concentration range important for the binding
Q VCH Verlagsgeselischaf< mbH, W-6940 Wetnheim, 1990
0S7#-0833/90/i2i2-i407S 3.SOi.ZSI0
Table 1. Selected 'H NMR data for hosts 1 a and 1e, and corresponding values
for complexes with 2 (by extrapolation; see text). A,B,C: see formula for 1.
6 (21-Me)
5 67
3 9(<3.3)
4.04 [a]
4.6 4.36
4.75 4.37
[a] Signal broadened: J too small to he discernible.
Similar experiments were used to investigate the interaction of 2 with 1 b-e in CDCI,. On addition of 2 the 'H NMR
spectra of 1b-d underwent no significant changes, but the
dibenzyl derivative 1 e showed evidence of binding in much
the same manner as 1 a (Fig. 1 c, 1 d and Table 1). New features were the movement of the signals due to the PhCH,-0
protons and the doublet corresponding to the methyl group
(21-Me) in the steroidal side chain (Table 1). Again, analysis
of the data indicated that a 1 : 1 complex had been formed,
with a binding constant of 700(+100) M - ' .
We believe that the glucoside is located inside the macrocycle in both the above complexes for the following reasons:
1) The changes in the HB,csignals on complex formation
clearly suggest a major alteration in the conformational
properties of the macrocycles, probably the "freezing out" of
one or a limited number of conformations (see below). This
is most easily accommodated by the inclusion of the carbohydrate molecule in the macrocyles. 2) In the case of le, the
changes in the PhCH,-0 resonances and the 21-Me provide
further support. They imply that conformational changes
are occurring in widely separated regions of the macrocycle,
and it is hard to see how such changes could be induced other
than by an inclusion process. 3) The binding constants are
sufficiently large to suggest that multiple hydrogen bonding
interactions are involved. As a comparison, in a recent study
by Rebek et al. involving the binding of adenine derivatives,
association constants in the range 100 to 400 M-' were measured for complexes in which two hydrogen bonds and one
n-stacking interaction were postulated.r2a1
The association between 1 e and 2 was also studied by IR
spectroscopy. Initially the IR spectrum of l e in CHC1,
(7.26 mM) showed a single band in the N-H stretching region
at 3446cm-', and bands at 1662cm-' (C=O) and
1513 cm-' (amide 11). On incremental addition of 2 the carbony1 stretching band was only marginally affected, broadening somewhat and shifting to a slightly lower frequency
(up to 10cm-I). In contrast the intensities of the N-H
stretching and amide I1 bands decreased steadily and in concert with each other. These results are significant in that,
when combined with the shift in the NH resonance, they
suggest strongly that the amide groups act as hydrogen bond
donors in complex formation.[81
We have attempted to interpret our results with the assistance of computer-based molecular modeling.tg1Calculations on l a suggest that the cholaphane framework does
have considerable flexibility; thus, 36 different conformations have been found within 4.5 kcal mol-' of the baseline
(which is as represented by I), and their structural variety is
such as to suggest that there are many more. However, although their shapes vary considerably (e.g. NH...HN distances from 11.I to 14.9 A), all have open conformations
with substantial cavities.
On addition of methyl P-D-glucopyranoside (a model for
2), it becomes clear that there are many possibilities for formation of multiple hydrogen bonds between host and guest.
VCH Verlagsgesellschaft mbH, W-6940 Weinheim. 1990
Fig. 3. A possible conformation for 1a and methyl P-D-glucopyranoside,minimized within the CHARMm force field. Dotted lines represent intermolecular
hydrogen bonds, ranging in length from 2.06 to 2.32 A.
One example which is consistent with the IR data is shown
in Figure 3. It is derived from a conformer of the macrocycle
which is 3.4 kcal mol-' above the baseline. Complex formation requires a further slight distortion of the macrocyclic
framework (3.2. kcal mol-I), but is promoted by the formation of six hydrogen bonds, as illustrated. Although this
specific structure may not be important, it does demonstrate
the ability of the glucoside to enter the cavity of 1 a and to
form multiple hydrogen bonds with its host without causing
undue distortion.
Similar studies on l e support the idea that complex formation would substantially reduce the conformational options of the 0-benzyl groups, accounting for the movement
of the CH,-0 NMR resonances. The shift of the 21-Me
resonance probably results from the same process, the effect
being transmitted via the diamagnetic anisotropy of the benzyl group.
Received: July 9, 1990 [Z 40591
German version: Angew. Chem. 102 (1990) 1497
CAS Registry numbers:
l a - 2, 130197-63-6; l e ' 2 , 130197-64-7
Recent examples: W. H.Pirkle, T. C. Pochopsky, J. Am. Chem. Sac. 109
(1987) 5975; P. E. Sanderson, J. D. Kilhurn, W. C. Still, ibid. lff (1989)
a) K. Williams, B. Askew, P. Ballester, C. Buhr, K. S. Jeong, S. Jones, J.
Rebek, Jr.. J Am. Chem. SOC.1 f f (1989) 1090; b) J. Rebek, Jr., Angew
Chem. f 0 2 (1990) 261; Angew. Chem. Inr. Ed. Engl. 29 (1990) 245, and
references cited therein.
For a notable exception, see: Y.Aoyama, Y. Tanaka, S . Sugahara, J. Am.
Chem. Soc. if1 (1989) 5391.
The system reported in 131 is unable to fulfill this condition and is thought
to hind its substrates by face-to-face interactions.
R. P. Bonar-Law, A. P. Davis, J Chem. Sac. Chem. Commun. 1989, 1050.
A preliminary indication of (unquantified) binding between a similar glucoside and a flexible, non-macrocyclic host containing two cholic acid units
has been reported by C . J. Burrows et al.: J. F. Kinneary, T. M. Roy. J. S.
Albert, H. Yoon, T. R. Wagler, L. Shen, C. J. Burrows, J. Inclusion Phenom.
and Mol. Recognit. Chem. 7 (1989) 155.
D. A. Deranleau, J. Am. Chem. Sac. 91 (1969) 4044.
D. Hadzi, S. Detoni, in S. Patai (Ed.): The Chemistry OfAcidDerivntives,
Part 1 , Wiley, New York 1979, p. 214.
Employing the QUANTA/CHARMm software package, implemented on
an IRIS 4D20C workstation.
0570-0833/90/1212-f408S 3.50+.255/0
Angew. Chem. Inr. Ed. Engl. 29 (1990) No. 12
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receptors, carbohydrate, derivatives, artificial
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