Intramolecular Host-Guest Complexes Of D- And L-Mono-6-Phenylalanyl-Amino-6-Deoxy Cyclomalto-Heptaoses.

Article abstract of DOI:10.1016/0957-4166(90)90035-9

Coupling of L- and D-phenylalanine to mono 6-amino-β-cyclodextrin leads to the formation of diastereoisomeric intramolecular inclusion compounds.The proton NMR spectra of the two products show clear chiral discrimination between the two molecules with regard to the interaction of the aromatic moieties with the cyclodextrin cavity.

Full text of DOI:10.1016/0957-4166(90)90035-9

Asymmetry Vol.
Printed in Great Britain
1990
Intramolecular Host-Guest Complexes Of D- And L-Mono-6
Phenylalanyl-Amino-6-Deoxy Cyclomalto-Heptaoses.
Parrot-Lopez
Florence Djedaini
Galons Anthony W. Coleman
Nelly Keller and Bruno Perly
a-
de Chimie Organiqtte 3,
CNRS
de Paris V, 75006 Paris (France)
de Paris XI. 922% Chatenay (France)
de 91191 Gif sur Yvette (France)
b-
c- Service de Chimie
Centre
(Received 14 May 1990)
Abstract Coupling of L- and D-phenylalanine to mono
leads to the
formation of diastereoisomeric intramolecular inclusion compounds. The proton NMR spectra of
the two products show clear chiral discrimination between the two molecules with regard to the
interaction of the aromatic moieties with the cyclodextrin cavity.
Chiral differentiation in host-guest systems has received extensive study in recent years in view of its
importance in bio-organic chemistry and its applications in enantio-selective separation&b. The cyclomalto-
oligosaccharides (cyclodextrins or
represent a particularly am-active class of readily available natural host
and in separation
molecules exhibiting chiral discrimination properties in inclusion
The enantio-selective properties are dependent on differences in interactions between the host cavity and the
substrate isomers. It is hence expected that chemical modification of the cyclodextrin will strongly affect this
selectivity owing to possible variations in both the interactions and the conformation of the host
D- and L- and L-Phe-NH-P-CD, Figure 1) are
diastereoisomers resulting from the grafting of L- or D-phenylalanine on mono cyclomalto-
heptaose They were synthesized as models of host molecules possessing both an hydrophobic
cavity and a chiral aromatic moiety. The present NMR study of the title compounds in aqueous solutions
reveals the formation of intramolecular inclusion complexes with differentiation between the two
The
diastereoisomers in terms of the conformational adaptation required to optimize the interaction of the aromatic
moiety with the hydrophobic cyclodextrin cavity.
D- and L-Phe-NH-P-CD were prepared by the following synthetic route. Mono-6-azido-cyclomalto-
0.86 mmol.) was reduced smoothly by treatment with triphenylphosphine (3.45 mmol) in
anhydrous dimethylformamide (15
for 1 h at room temperature followed by addition of
ammonium
hydroxide After 12 h at room temperature, the solvent was removed in
2
and the solid
residue taken up in water. Removal of the insoluble triphenylphosphine and triphenylphosphine oxide by
filtration and recrystallization in water afforded the mono-6-amino-cyclomalto-heptaose in 99% yield. The
latter compound was coupled to the pertinent N-Boc protected isomer of phenylalanine by the
procedure8 in dimethylformamide at 0’ and the protecting
group was cleaved in neat trifluoroacetic acid.
1 and 2 were obtained in 75% yields. Purification was achieved
by recrystallization at
8-9 since both compounds are sparingly soluble in water as free
367

3 6 8
For NMR experiments, they were converted into the corresponding hydrochlorides. It is noteworthy that the
ionic state does not affect the major results presented in paper. The chemical integrity and purity of the title and
intermediate compounds were checked by proton NMR and by thin-layer chromatography.
1: L-Phe-NH-P-CD
S configuration at
2 D-Phe-NH-P-CD
R configuration at
Figure 1 Molecular structures of the title compounds
1
and 2.
The 600 MHz
NMR spectra of
1
and 2 in deuterium oxide are displayed in Figure 2. All experiments were
performed using 10
solutions of the corresponding hydrochlorides
= 4.0) in deuterium oxide at 298 K.
The most striking effect of the reduction of symmetry to Cl is provided by the anomeric protons in the 4.95
5.20 ppm range. The seven expected individual signals are indeed observed for 2. The corresponding spectral
region of
Cl symmetry in which every proton becomes theoretically inequivalent. This inequivalence has been observed
for other but such a striking modification of the NMR spectra is not commonly encountered. A
more classical situation was found for the intermediate compounds used in this The high field
region containing all non-anomeric protons of the cyclomalto-heptaose and the aliphatic protons of the
acid moiety is strongly different for the two A general feature is however the considerable
1 shows slightly weaker inequivalence of the anomeric protons. Mono-substitution indeed leads to a
spectral dispersion as compared to unmodified cyclodexttin for which the corresponding protons appear in the
3.6 4.0 ppm range. Besides the expected effect of substitution by the amino group, a large number of signals
are shifted
and the observed spectral complexity implies that all protons are affected by the reduction of
molecular symmetry.

369
Host-guest complexes
Anomeric protons
Aromatic protons
7.4
7.2
5.1
5 . 0
5 .1
5 . 0
7.4
7.2
ppm 4.2
3.8
3.6
Figure
2
NMR spectra of 10
solutions of
1
and 2 in
oxide at 298 K.
Signals indicated by
arise from a small (ca. 4
amount of residual unmodified

3 7 0
H.
The large shielding effects can be rationalized by considering inclusion of the aromatic ring into the
internal cavity. This phenomenon is indeed expected to induce shielding ring currents and to enhance the
inequivalence due to substitution. This assumption is further supported by the chemical shifts of protons
the phenyl ring of the amino-acid. The corresponding signals are indeed deshielded relative to free
phenylalanine as encountered for the inclusion of the free amino-acid in
This deshielding
effect is due to a strong modification of the polarity experienced by the phenyl ring upon inclusion in the
relatively hydrophobic cavity of the cyclodexttin.
At this point, one must make a clear distinction between inter- and intramolecular complexes. NMR
provides evidences for the reality of the latter situation leading to a model where the modified
heptaose includes its own aromatic ring in the hydrophobic cavity. This is indeed supported by the fact that the
NMR spectra of both compounds in deuterium oxide are not affected by concentration in the l-20
range.
In the case of intermolecular inclusion complexes, a large concentration dependence is expected owing to the
generally weak association constants involved in these processes In the present case, additional interactions
have to be considered (i.e. intramolecular hydrogen bonds) to account for the unexpected stability of these
inclusion complexes. New ultra-high resolution bidimensional NMR experiments dedicated to an accurate
sequential determination of chemical shifts and coupling constants for all protons are currently being
undertaken and will be described elsewhere. Preliminary data has already shown that several torsional angles
derived from the coupling constants are unusual and fully support the presence of intramolecular complexes.
These molecules are hence of considerable interest as they provide pure inclusion complexes in solution. A
complete NMR analysis and the subsequent modelling of ring current effects and coupling constants is
expected to provide, in conjunction with molecular graphics analysis, the first example of three-dimensional
determination in these series and a better understanding of molecular adaptation phenomena involved
in inclusion processes.
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