Inherently chiral phosphonatocavitands as artificial chemo- and enantio-selective receptors of natural ammoniums

Article abstract of DOI:10.1039/c1ob05194f

Inherently chiral phosphonatocavitands with various bridging moieties at their wide rim were synthesized. Optical resolution by chiral HPLC was performed with cavitand 8 to afford enantiopure compounds (+)-8 and (-)-8. The molecular structures of hosts 8

Full text of DOI:10.1039/c1ob05194f

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PAPER
Inherently chiral phosphonatocavitands as artificial chemo- and
enantio-selective receptors of natural ammoniums†
Je´roˆme Vachon,a Steven Harthong,a Erwann Jeanneau,b Christophe Aronica,a Nicolas Vanthuyne,c
Christian Rousselc and Jean-Pierre Dutasta*a
Received 4th February 2011, Accepted 14th April 2011
DOI: 10.1039/c1ob05194f
Inherently chiral phosphonatocavitands with various bridging moieties at their wide rim were
synthesized. Optical resolution by chiral HPLC was performed with cavitand 8 to afford enantiopure
compounds (+)-8 and (-)-8. The molecular structures of hosts 8 and 12 were determined by X-ray
diffraction. The host properties were investigated by 1H and 31P NMR spectroscopy. The
phosphonatocavitands form inclusion complexes with chiral ammonium neurotransmitters, some
presenting enantioselectivity towards the right or left-handed host enantiomers.
is of importance to preserve this curvature leading to molecules
Introduction
belonging to the C1 group, and several examples of inherently
chiral cyclodextrins,8 and calixarenes9 were thus reported.
Previously, the groups of Cram, Rebek and Dalcanale success-
fully applied such a strategy to design inherently chiral cavitands.10
However, in all these cases, the lack of strong binding groups and
the rather achiral character of the inner cavity precluded their use
as efficient enantioselective receptors in solution.11 Interestingly,
cavitands based on the phosphorylated resorcin[4]arenes, such as
the tetraphosphonatocavitands,12 show remarkable binding prop-
erties towards alcohols,13 metal ions,14 and ammonium cations.15
Recently, our group described the synthesis of diphosphonate
cavitands of the ABii type, AB defining the vicinal positions of
the two phosphorus groups, and ii corresponding to the inward
orientations of the two P O groups (Fig. 1).16
Enantioselective recognition processes are part of various fasci-
nating but complexes biological mechanisms and hence play a
key role in living systems via hormones and neurotransmitters.
A better understanding of these phenomena can be obtained
from the study of artificial supramolecular systems as illustrated
by several examples reported in the literature during the last
two decades.1 Following this pioneering work, an increasing
interest in the design of various chiral systems with different
sizes and binding properties has emerged with, as its target,
potential applications as biosensors,2 therapeutic vectors and
also use in asymmetric synthesis and chiral separation.3 Among
these examples, calixarene type molecules have been shown to
be some of the most promising candidates due to the possibility
of functionalizing the narrow and/or the wide rim of this rigid
scaffold.4 These macrocycles being made from the repetition of
achiral units, a simple way to introduce dissymmetry can be
achieved by adding moieties bearing stereogenic centers usually
located remotely from the cavity.5 More recently, a growing interest
in the development of inherently chiral macrocycles has emerged.6
In this specific case, dissymmetry is the consequence of a difference
between the binding sites or the bridging units and the presence
of a curvature.7 Atropoisomerism between the aromatic moieties
a
´
Laboratoire de Chimie, CNRS, Ecole Normale Supe´rieure de Lyon, 46 Alle´e
Fig. 1 The resorcin[4]arene structure with its four possible bridging sites
A, B, C and D (left), and the ABii(PO) X-ray molecular structure with its
un-bridged C and D sites (right; R = C2H4Ph; from ref. 16a).
d’Italie, F-69364 Lyon, France. E-mail: jean-pierre.dutasta@ens-lyon.fr;
Fax: +33 4 7272 8860
bCentre de Diffractome´trie Henri Longchambon, Universite´ Claude Bernard
– Lyon 1, 43 Boulevad du 11 Novembre 1918, F-69622 Villeurbanne, France
cISM2, Chirosciences, Universite´ Paul Ce´zanne, Case A62, Avenue Escadrille
Normandie Niemen, F-13397 Marseille, France
The ABii structure possesses two P O bonds oriented towards
the cavity which favor the complexation of guest molecules. This
compound is an ideal precursor for inherently chiral cavitands
since bridging by at least one different group on a third site (C or
D sites, Fig. 1) leads directly to chiral species. Following this idea,
we recently reported the synthesis, the optical resolution and the
† Electronic supplementary information (ESI) available: Synthetic pro-
cedures and characterizations including 1H, 31P and 13C spectra, NMR
complexation experiments, CD spectra and HPLC chromatograms, X-
ray data. CCDC reference numbers 783436 and 783437. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05194f
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determination of the absolute configuration of the first inherently
chiral phosphonatocavitand (compound 1, Fig. 2).16b
ephedrine derivatives and to compare the new cavitands towards
the enantioselective complexation of such guest molecules. These
species are known to take part in biological processes such as
information transfers in the neuronal system.17
Starting from the precursor ABiiPS 2, we synthesized the four
new inherently chiral cavitands 5, 8, 11 and 12, which differ in
their extra bridging groups, which should afford different binding
properties (Scheme 1). Another chiral cavitand was prepared
from the tri-thiophosphonate cavitand 14,16b,18 incorporating a
binaphthyl bridge (compound 16) synthesized as a racemate and in
one enantiopure form (Scheme 2). In this case, the molecule is not
inherently chiral, with asymmetry resulting from the stereogenic
binaphthyl group.
Fig. 2 Enantiomers of the inherently chiral phosphonatocavitand 1:
(-)-cR-1 and (+)-cS-1.
Results and discussion
This compound showed interesting enantioselective bind-
ing properties towards L-adrenaline picrate, the complex L-
adrenaline@(+)-1 being favored in a 2 : 1 ratio compared to the
complex L-adrenaline@(-)-1. In order to better understand the
interactions involved in this type of cavitand, we wished to extend
this study to other chiral host molecules as well as other chiral
ammonium guests of biological interest such as nicotine and
Synthesis
We have considered four different bridges that were introduced
in the ABii type molecule bearing two inward oriented Ph–P
moieties: (i) one inward Me2N–P O (C site; compound 5), (ii)
one methylene bridge (C site; compound 8), (iii) one inward
O
Scheme 1 Synthesis of the inherently chiral cavitands 5, 8, 11 and 12 from the precursor ABiiPS 2 (R = C11H23).
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Fig. 3 Sticks and CPK views of the X-ray molecular structure of
CH3OH@( )-8.
Scheme 2 Synthesis of racemic cavitand ( )-16 and enantiopure (Ra)-16.
Ph–P S (C site; compound 11) and (iv) one inward Ph–P
S
bridge and one outward Ph–P S bridge (C and D sites; com-
pound 12).
the molecular cavity (mean distance to the phenyl centroids =
3.74 A), the OH group forming a strong H-bond with one
˚
˚
Concerning compound 5, a survey of the literature showed
that amidophosphite cavitands can be synthesized efficiently
using tris(dimethylamino)-phosphine as reactant,19 leading after
sulfurization to the inward orientation of the thiophosphoryl
moiety. The addition of one equivalent of tris(dimethylamino)-
phosphine to a toluene solution of compound ABiiPS 2 in the
presence of Hu¨nig’s base (N,N-diisopropylethylamine) followed
by the addition of sulfur, led to a mixture of compound ( )-
3 and tetra-bridged derivative 4 that both have the desired
inward orientation of the P S groups. These compounds were
separated by column chromatography in 43% and 14% yields
respectively (Scheme 1). The three P S moieties of compound
( )-3 were further transformed into P O groups by reaction with
m-chloroperoxybenzoic acid (m-CPBA) to give cavitand ( )-5, the
inward orientation of the three chelating groups being preserved.
Tetraresorcinarene type molecules bearing methylene bridges
are well described in the literature.10a,20 Following the reported
procedures, the addition of one equivalent of iodochloromethane
onto cavitand ABiiPS 2 in the presence of potassium carbonate,
in DMF at 90 ◦C, led to the desired chiral cavitand ( )-6 together
with the tetra-bridged parent molecule 7. Similarly to compounds
( )-3 and 4, compounds ( )-6 and 7 were separated by column
chromatography in 53% and 21% yield respectively (Scheme 1).
As described above, the thiophosphonate groups in ( )-6 and 7
were further transformed into phosphonate groups by reaction
with m-CPBA to give cavitands ( )-8 and 9, respectively, in high
yields. Compound 9 has been already reported and was obtained
in 33% yield by addition of iodochloromethane to compound
10,16a or by addition of phenyldichlorophosphine oxide to the bis-
methylene-bridged precursor (10% yield).21 Chiral compound 8
PO group (d(P O ◊ ◊ ◊ OH) = 2.763 A). A chloroform molecule
occupies interstitial positions in the lattice.
The mixed cavitand with P O and P S groups, was synthe-
sized from the ABiiPO derivative 10. Addition of one equivalent
of dichlorophenylphosphine, followed by in situ addition of sulfur,
led predominantly to the tri-bridged chiral compound ( )-11 with
the P S bond pointing inward, isolated in 29% yield. Interest-
ingly, when adding two equivalents of dichlorophenylphosphine
under the same reaction conditions, a 1 : 1 mixture of the chiral
ABii(PO)CDio(PS) ( )-12 and the achiral ABii(PO)CDii(PS) ( )-
13 was exclusively obtained. These compounds were separated
by column chromatography and both obtained with 25% yields.
It seems unlikely that the chiral compound 12 will possess any
binding affinity for a guest molecule as one of the P-phenyl groups
is shielding the accessibility to the cavity. This is shown by the
X-ray molecular structure depicted in Fig. 4.‡ Single crystals were
grown from hexane solution to give racemate ( )-12. The ii and
io orientation of the phosphonate and thiophosphonate groups,
respectively, are confirmed in the solid, and one phenyl group is
oriented towards the molecular cavity. The molecules are tightly
packed in the crystal with efficient Van der Waals interactions
between the long chain substituents of the narrow rim.
¯
crystallizes in the triclinic crystal system (P1) to give the racemate
( )-8.‡ The molecular structure depicted in Fig. 3 shows one
encapsulated CH3OH molecule with the CH3 group located inside
Fig. 4 Sticks and CPK views of the X-ray molecular structure of ( )-12
showing the occupancy of the molecular cavity by a P-phenyl group.
‡ Crystal data 8·CHCl3·CH3OH: C87H123Cl3O11P2, M = 1513.23, triclinic,
◦
¯
˚
P1, a = 11.9557(4), b = 15.3805(4), c = 22.8398(6) A, a = 95.810(2) , b =
◦
◦
3
-1
˚
95.876(2) , g = 90.902(2) , V = 4155.9(2) A , Z = 2, Dc = 1.209 g mL ,
m(Cu-Ka) = 1.816 mm-1, 2qmax = 124.3◦, T = 100 K, 60303 reflections
collected, 13020 unique reflections with I > 2s(I), Rint = 0.050 (928
parameters) and R1 = 0.092, wR2 = 0.200, GooF = 1.042, CCDC 783437.
12: C96H124O10P4S2, M = 1626.06, mo◦noclinic, P21/c,◦a = 14.338(1), b =
Finally, as a matter of comparison, chiral cavitand 16, bearing
a binaphthyl stereogenic group was synthesized in two steps
from the 3iPS cavitand 14 (Scheme 2).18 Combination of 14 and
2,2¢-bis(bromomethyl)-1,1¢-binaphthyl, which was prepared from
1,1¢-bi(2-naphthol) (BINOL) following a reported procedure,22
in the presence of Cs2CO3 in acetonitrile at reflux temperature
led to compound 15. The reaction of this latter compound with
m-CPBA gave cavitand 16 quantitatively. While starting from
◦
˚
34.567(3), c = 18.529(2) A, a = 90.00 , b = 106.02(1) , g = 90.00 , V =
3
-1
-1
˚
8827(1) A , Z = 4, Dc = 1.224 g mL , m(Cu-Ka) = 1.686 mm , 2qmax
=
134.7◦, T = 100 K, 64964 reflections collected, 15406 unique reflections
with I > 2s(I), Rint = 0.063 (1009 parameters) and R1 = 0.130, wR2 = 0.295,
GooF = 1.07, CCDC 783436.
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( )-BINOL, ( )-16 was obtained, whereas enantiopure (Ra)-
BINOL gave enantiopure (Ra)-16 (Scheme 2).
Chiroptical properties
The optical resolution of compound 8 was performed by
semi-preparative HPLC using a Chiralpack IA column and
a hexane/isopropanol/CHCl3 92/4/4 mixture as eluant. This
afforded up to 19 mg of each enantiopure (+)-8 (Rt = 9.03 min)
and (-)-8 (Rt = 12.39 min) with ee >99.5%. Interestingly, these
compounds display no optical rotation at wavelengths l = 589,
578, 546, 436 and 365 nm in CHCl3 or ethanol solution. Thus,
the dextrogyre and levogyre species were attributed from the sign
observed with the ECD detector of the HPLC at 295 nm. The ECD
spectra of (+)-8 and (-)-8 (c ~ 4 ¥ 10-5 M, CH2Cl2) showed identical
mirror-image signals confirming their enantiomeric relationship,
and were compared to the previously reported ECD spectra of
(+)-1 and (-)-1 (Fig. 5).16b A similar pattern was observed with
two consecutive strong positive Cotton effects (around 240 nm
and 280 nm) and a strong negative Cotton effect (around 295 nm)
for the levogyre compounds (same but opposite observation for
the dextrogyre compounds). Considering the high resemblance
between the structures of cavitands 1 and 8, it is likely that both
levogyre compounds are of cR configuration and the dextrogyre
compounds have the cS configuration. However, this hypothesis
needs to be confirmed without ambiguity by other means. All
attempts to perform the optical resolution, by semi-preparative
HPLC, of the other inherently chiral cavitands 4, 11 and 12, failed.
As mentioned above, compound 16 was obtained enantiopure
([a]2D5 = 158, c ~ 0.1, acetone) when using (Ra)-BINOL as the
starting material. The ECD spectra of (Ra)-16 (c ~ 10-5 M, CH2Cl2)
displayed a characteristic excitonic coupling around 230 nm
Fig. 6 ECD spectra of cavitand (Ra)-16 (c ~ 10-5 M, CH2Cl2).
1
the 31P signals) or by H NMR spectroscopy by following the
highfield shift of the NCH3 protons (for adrenaline, ephedrine and
pseudoephedrine), of the terminal CH3 protons (for norephedrine,
ephedrine and pseudoephedrine), or by the split of the CH
bridging protons of the cavitands (for nicotine) (Fig. 7).
1
1
corresponding to the Bb(1) et Bb(2) transitions from the two
naphthyl moieties: a positive followed by a negative Cotton effect
corresponding to the (Ra) configuration as depicted in Fig. 6.23
Fig. 7 Structures of the ammonium guests investigated.
The temperature was carefully controlled to run the experiment
under slow exchange conditions on the NMR time scale, so
that a good separation of the signals of the two diastereomeric
1
host–guest complexes could be observed in the H or 31P NMR
spectra. NMR experiments were performed at room temperature
for nicotine, but as a general trend, it appeared necessary for
the other ammonium guests to perform the experiments at lower
temperatures (253 K for adrenaline and 233 K for ephedrine and
its derivatives). In the cases where the cavitands were available in
their enantiopure form (i.e. for compounds 1 and 8) it has been
possible to assign each diastereomeric host–guest complex.
The results are gathered in Table 1. As expected, compound
12 with an inward oriented phenyl group displayed no com-
plexation towards ammonium salts. The other chiral cavitands
tested formed host–guest complexes. Among the inherently chiral
cavitands, only cavitands 1 and 8 showed noticeable diastere-
oselectivities except for nicotine (d.r. ~ 1 : 1). As mentioned
above, the complex L-adrenaline@(+)-1 was favored in a 2 : 1
ratio over complex L-adrenaline@(-)-1. A similar behavior was
observed with pseudoephedrine with a 2.2 : 1 ratio in favor of
pseudoephedrine@(+)-1. Interestingly, no diastereoselectivity was
observed with ephedrine and a reversed selectivity was obtained
with norephedrine (1 : 2.5 ratio in favor of norephedrine@(-)-
1) (Fig. 8). Concerning cavitand 8, a good selectivity was only
observed with pseudoephedrine (2.5 : 1 ratio in favor of cavitand
Fig. 5 ECD spectra of (-)-1 (red solid line), (+)-1 (blue solid line), (-)-8
(red dotted line) and (+)-8 (blue dotted line) (c ~ 4 ¥ 10-5 M, CH2Cl2).
Enantioselective complexation
The enantioselective complexation experiments consist in adding
a solution of the racemic cavitand (in CDCl3 or CD2Cl2) to a
solution of the enantiopure ammonium picrate salts in a 1 : 0.4
equiv host : guest ratio. This resulted in the formation of two
diastereomeric host–guest complexes. The complexation can be
observed either by 31P NMR spectroscopy (downfield shift of
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Table 1 Diastereomeric ratios d.r. (guest@(+)-host/guest@(-)-host) for the complexes of the racemic cavitands 1, 5, 8, 11, 12 and 16 with enantiopure
ammoniums (picrate salts; 1 : 0.4 host/guest ratio) measured by 1H and/or 31P NMR
Host
Guest
1
5
8
11
12
16
e
e
e
d
Nicotine
Adrenaline
Ephedrine
Pseudoephedrine
Norephedrine
~1 : 1a
—
~1 : 1a
—
—
No Complex.
No Complex.
—
~2 : 1b
~1 : 1a
~1 : 1c
~1 : 1b
e
e
e
~1 : 1c
—
—
—
~1 : 1.3c
~2.5 : 1c
~1 : 1a
—
—
—
e
e
e
~2.2 : 1c
~1 : 2.5c
—
—
~1 : 1.5b
e
d
e
e
d
—
—
—
1
a At 298 K in CDCl3. b At 253 K in CDCl3. c At 233 K in CD2Cl2. d No split visible by H and 31P NMR between the two diastereomeric host–guest
complexes. e Not done.
cavitand host, 3. equiv of ephedrine, 3 equiv. of pseudoephedrine,
and 3 equiv. of norephedrine). Interestingly, norephedrine is no
longer complexed by the cavitands (+)-1, (-)-1, (+)-8 and (-)-8.
Concerning the dextrogyre cavitands (+)-1 and (+)-8, a selectivity
towards pseudoephedrine compared to ephedrine was observed
with ~1.7 : 1 and 1.6 : 1 ratios, respectively (Fig. S69 and S71,
respectively, in the ESI†). Furthermore, the levogyre cavitands
(-)-1 and (-)-8 are selective for ephedrine, with a 1.8 : 1 ratio for
(-)-1 (Fig. S68 in the ESI†), and complete selectivity (>98 : 2) for
host (-)-8, ephedrine being the unique species complexed by this
cavitand as shown in Fig. 9.
Fig. 8 Diastereomeric ratios (d.r) obtained from 1H NMR spectra
(CD2Cl2) during complexation experiments with cavitands ( )-1, (-)-1 and
(+)-1 and with guests (G) pseudoephedrine, ephedrine and norephedrine
(host : guest ratios are in parentheses).
(+)-8), the other ammoniums leading to either poor (1 : 1.3
ratio with ephedrine) or no selectivity at all (with adrenaline).
Finally, compounds with 3i stereochemistry 5, 16 (three inward
orientated P O groups) and 11 (two inward P O and one
inward P S), display either low selectivity (1.5 : 1 ratio with
pseudoephedrine@( )-16 in favor of (-)-16) or no selectivity (1 : 1
ratio with adrenaline and ephedrine for 5 and 11, respectively).
The rather achiral character of the inner cavity is probably the
reason for such behavior.
Chemoselective complexation
Fig.
9
Chemoselective complexation experiments followed by 1H
Considering the high similarity between the three ephedrine
derivatives, we wondered if the chiral cavitands 1 and 8 could
discriminate one of the three ammoniums in a competitive
complexation experiment. To do so, we mixed the three CD2Cl2
solutions containing each host–guest complex in a 1 : 1 ratio,
the guests being ephedrine, pseudoephedrine and norephedrine
picrate salts. This led to a 1 : 1 host–guests ratio (i.e. 3 equiv.
of host and 1 equiv. of each of the three guests). Two sets of
experiments for each cavitand 1 and 8 were performed, one with
the dextrogyre cavitands and one with the levogyre cavitands.
In all cases, when lowering the temperature to 233 K, the three
complexed ammonium guests were easily distinguishable in the
1H and 31P NMR spectra. Due to the slight precipitation of
the ammonium salts in the NMR tube at this temperature, the
integration of the signals for each ammonium led to a small
deviation from the expected 1 : 1 : 1 stoichiometry. To this solution
was added 2 more equivalents of a 1 : 1 : 1 ratio of the three
ammoniums, resulting in a 1 : 3 host–guests ratio (i.e. 3 equiv. of
and 31P NMR in CD2Cl2 at 233 K: (a) ephedrine@(-)-8 (1 : 1);
(b) pseudoephedrine@(-)-8 (1 : 1); (c) norephedrine@(-)-8 (1 : 1);
(d) [ephedrine][pseudoephedrine][norephedrine]@(-)-8 (1 : 1 : 1 : 3); (e)
[ephedrine][pseudoephedrine][norephedrine]@(-)-8 (1 : 1 : 1 : 1).
Conclusions
In summary, we have developed an efficient synthesis of inherently
chiral cavitands following a strategy that can be extended to other
dissymmetrical cavitands. Semi-preparative chiral HPLC was
revealed to be an efficient means to optically resolve some of these
hosts andtheir chiropticalproperties have been investigated. Single
crystal X-ray analyses were performed for the two chiral hosts ( )-
8 and ( )-12 and confirmed the stereochemistry at the phosphorus
atoms, which adopt the inward orientation of the P O or
P
S bonds, an important feature for efficient complexation of
ammonium cations. The phosphonatocavitands are particularly
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efficient in the recognition of neurotransmitter guests. NMR
was used to study in solution the encapsulation process and
showed for some of them enantioselective recognition towards
adrenaline and ephedrine derivatives. Competition experiments
between ephedrine, norephedrine and pseudoephedrine in the
presence of cavitands 1 or 8 showed, in the case of (-)-8 a complete
chemoselectivity towards ephedrine.
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Acknowledgements
The authors are extremely grateful to Dr Be´atrice Dubessy for
her contribution in the early stage of this project. Sandrine
Denis-Quanquin and Dr Denis Bouchu are acknowledged for
NMR assistanceandmass spectrameasurements, respectively. The
Centre de Diffractome´trie Henri Longchambon (CDHL, Institute
of Chemistry, Lyon) is acknowledged for X-ray facilities access.
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