Macrocyclic chiral receptors toward enantioselective recognition of naproxen

Article abstract of DOI:10.1021/ol061505i

(Chemical Equation Presented) A macrocyclic receptor based on a bischromenylurea and an α,α′-(o,o′-dialkyl)diphenyl-p- xylylenediamine spacer provides a C₂ chiral cavity to associate carboxylates by H-bonds. The extent of the selectivity obtain

Full text of DOI:10.1021/ol061505i

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4679-4682
Macrocyclic Chiral Receptors toward
Enantioselective Recognition of
Naproxen
Silvia Gonza´lez,† Rafael Pela´ez,‡ Francisca Sanz,§ Ma Bele´n Jime´nez,†
Joaqu´ın R. Mora´n,† and Ma Cruz Caballero*,†
Departamento de Qu´ımica Orga´nica, UniVersidad de Salamanca,
Plaza de los Ca´ıdos 1-5, 37008 Salamanca, Spain
ccsa@usal.es
Received June 20, 2006
ABSTRACT
A macrocyclic receptor based on a bischromenylurea and an
r,r′-(o,o′-dialkyl)diphenyl-p-xylylenediamine spacer provides a C2 chiral cavity
to associate carboxylates by H-bonds. The extent of the selectivity obtained for the racemic receptor 2 and enantiomerically pure (S)-naproxen
is 7.2:1. Steric repulsions close to the cavity are decisive for the chiral selectivity.
Within the field of molecular recognition, there is great
interest in the development of macrocyclic systems for the
chiral discrimination of biologically active molecules. The
recognition of enantiomers of naproxen [2-(6-methoxynaphth-
2-yl)propionic acid], a nonsteriodal antiinflammatory drug
(NSAID),1 remains a challenging task. The (S)-enantiomer
of this R-arylpropionic acid is more interesting because of
its greater pharmacological activity in comparison with the
(R)-isomer.2
the disposition of a small methyl group and a hydrogen atom
at the steric center. Therefore, the chirality associated with
the R position of the carboxylate could be exploited with
complementary shaped hosts with precise topology selecting
between the sizes of both methyl and hydrogen groups.
Several synthetic receptors have already been shown to
associate naproxen.3 Besides these, chiral receptors focused
on the resolution of this substrate have also been synthesized.
As far as we know, however, even though the formation of
the two diastereomeric complexes has been observed, enan-
tioselectivities lower than 1.3 in solution or 2.25 in chiral
stationary phases have been reported.
The chiral recognition of this kind of guest involves certain
special difficulties because both enantiomers differ only in
† Departamento de Qu´ımica Orga´nica.
‡ Departamento de Qu´ımica Farmaceu´tica.
A combination of geometrically well-defined cleft-type
hosts, to complex the carboxylate function by efficient
§ Servicio General de Difraccio´n de Rayos X.
(1) (a) Murray, M. D.; Brater, C. D. In Progress in Drug Research;
Jucker, E., Ed.; Basel: Switzerland, 1997. (b) Kurumbail, R. G.; Stevens,
A. M.; Gierse, J. K.; McDonald, J. J.; Stegeman, R. A.; Pak, J. Y.; Gildehaus,
D.; Miyashiro, J. M.; Penning, T. D.; Seibert, K.; Isakson, P. C.; Stallings,
W. C. Nature 1996, 384 (19), 644-648. (c) Loll, P. J.; Picot, D.; Ekabo,
O.; Garavito, R. M. Biochemistry 1996, 35, 7330-7340.
(2) (a) Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roszkowski,
A.; Tomolonis, A.; Fried, J. H. J. Med. Chem. 1970, 13, 203-205. (b)
Agranat, I.; Caner, H.; Caldwell, J. Nat. ReV. Drug DiscoVery 2002, 1, 753-
768.
10.1021/ol061505i CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/20/2006

hydrogen bonds, with appropriate alkyl substituents, to
introduce steric interaction near the guest’s stereogenic
center, could be useful in the resolution of the racemic
mixture.
and the guest could produce the selective binding of one of
the enantiomers of a racemic mixture.
Preparation of new receptors was carried out from dicar-
boxyethyl bischromenylurea4a,b 3 (Scheme 1) and the required
Receptors based on a bischromenylurea skeleton have
shown good results in the association of the carboxylate
group4 owing to four efficient hydrogen bonds for syn and
anti lone pairs of the oxoanion.
Scheme 1. Preparation of Diamines
Taking into account these observations, we searched for
suitable spacers able to close a macrocycle5 to restrict the
host conformation, by bridging the gap between the two-
chromenone binding arms with amide functions as H-bond
donors.
Initially, it was observed that a spacer of xylylenediamine
was appropriate to achieve the desired macrocycle. The para-
substituted isomer is a better spacer than the meta-substituted
one.6 Accordingly, the use as a spacer of a bulkier p-
xylylenediamine substituted by two R,R′-phenyl rings (Figure
1) should introduce steric hindrance close to the cavity.
diamines. p,p′-Bis-tert-butylphenyl-p-xylylenediamine (4)
was obtained by reductive amination of the dicarbonyl
compound formed by acylation of tert-butylbenzene with
terephthaloyl dichloride (Scheme 1). The tert-butyl groups,
not involved in the chiral cavity, were introduced to improve
solubility.
The synthesis of the designed macrocyclic receptors is
depicted in Scheme 2. Hydrolysis of ethoxycarbonyl amino
chromenone 34a gave a dicarboxylic acid, whose bistrieth-
ylammonium salt was derivatized with pivaloyl chloride. The
coupling with the diamine 4 in high-dilution conditions
afforded the desired macrocyclic receptor 1 in 29% yield.
1H NMR competitive experiments7 with receptor 1 were
undertaken to check the chiral recognition properties of the
racemic receptors (the meso form was separated by crystal-
lization in ethyl acetate/methanol, mp ) 294-296 °C;
racemate, mp ) 268-270 °C). The titrations were carried
Figure 1. Guest (S)-naproxen and C2 chiral cavity of hosts for
associate carboxylates by hydrogen bonds.
Each receptor enantiomer includes a C2 symmetry axis,
offering a chiral cavity for the association (Figure 1). The
steric effects between the peripheral phenyl rings of the host
(4) (a) Torre de la, M. F.; Campos, E. G.; Gonza´lez, S.; Moran, J. R.;
Caballero, M. C. Tetrahedron 2001, 57, 3945-3950. (b) Torre de la, M.
F.; Gonzalez, S.; Campos, E. G.; Mussons, M. L.; Moran, J. R.; Caballero,
M. C. Tetrahedron Lett. 1997, 38, 8591-8594. (c) Raposo, C.; Crego, M.;
Mussons, M. L.; Caballero, M. C.; Moran, J. R. Tetrahedron Lett. 1994,
35, 3409-3410.
(5) Choi, K.; Hamilton, A. D. Coord. Chem. ReV. 2003, 240, 101-110.
(6) Conventional NMR titrations of the p-xylylenediamine receptor 1
show Kass ) 6 × 105 and 2 × 104 M-1 (DMSO-d6) with the guests
tetraethylammonium acetate and benzoate, respectively. A similar macro-
cycle with a smaller cavity was made with m-xylylenediamine as a spacer;
(3) (a) Dharanipragada, R.; Diederich, F. Tetrahedron Lett. 1987, 28,
2443-2446. (b) Dharanipragada, R.; Ferguson, S. B.; Diederich, F. J. Am.
Chem. Soc. 1988, 110, 1679-1690. (c) Castro, P. P.; Georgiadis, T. M.;
Diederich, F. J. Org. Chem. 1989, 54, 5835-5838. (d) Echavarren A.; Gala´n,
A.; Lehn, J. M.; de Mendoza, J. J. Am. Chem. Soc. 1989, 111, 4994-4995.
(e) Diederich, F. J. Org. Chem. 1991, 56, 3362-3369. (f) Diederich, F.
Tetrahedron Lett. 1991, 32, 6277-6280. (g) Pirkle, H. W.; Welch, J. C.;
Lamm, B. J. Org. Chem. 1992, 57, 3854-3860. (h) Hamann, B. C.; Branda,
N. R.; Rebek, J., Jr. Tetrahedron Lett. 1993, 34, 6837-6840. (i) Davis, A.
P.; Dempsey, K. J. Tetrahedron: Asymmetry 1995, 6, 2829-2840. (j) Boyle,
P. H.; Davis, A. P.; Dempsey, K. J.; Hosken, G. D. J. Chem. Soc., Chem.
Commun. 1994, 1875-1876. (k) Kyne, G. M.; Light, M. E.; Hursthouse,
M. B.; Mendoza, J. de; Kilburn, J. D. J. Chem. Soc., Perkin Trans. 1 2001,
1258-1263. (l) Lawless, L. J.; Blackburn, A. G.; Ayling, A. J.; Perez-
Payan, M. N.; Davis, A. P. J. Chem. Soc., Perkin Trans. 1 2001, 1329-
1341.
the Kass’s in this case were reduced to 2 × 104 and 3.6 × 103 M-1
,
respectively. When naproxenate was used as a guest, the Kass value was
also one order higher with the former receptor (Kass ) 8.8 × 104 M-1
)
over the latter (Kass ) 6.6 × 103 M-1) because the larger cavity size of
receptor 1 is more appropriate for complexing a carboxylate function.
(7) (a) Fielding, L. Tetrahedron 2000, 56, 6151-6170. (b) Whitlock, B.
J.; Whitlock, H. W. J. Am. Chem. Soc. 1990, 112, 3910-3915.
4680
Org. Lett., Vol. 8, No. 21, 2006

2-meso and tetraethylammonium acetate establish a com-
plex with Kass ) 6.0 × 104 M-1 (DMSO-d6), whereas the
complex with the naproxenate salt has a Kass ) 4.2 × 103
M-1 (DMSO-d6).
Scheme 2. Synthesis of Receptors 1 and 2
The structure of the acetate complex was established
through X-ray diffraction studies9 (Figure 2). The carboxylate
Figure 2. X-ray crystal structure of the 2-meso and tetraethylam-
monium acetate complex. Four hydrogen bonds bind the carbox-
ylate.
out adding small amounts of the guest to the receptor
solution. Thus, small amounts of the tetraethylammonium
salt of enantiomerically pure S-naproxen were added to the
racemic receptor 1 in DMSO-d6. Because diastereomeric
ion is bound by four hydrogen bonds. The oxoanion lies
almost in the plane of the cavity. One of the oxygens of the
anion is almost symmetrically located (1.99 and 2.01 Å)
between the urea and amide H-bond donors, but the other
one is somewhat asymmetrically disposed (1.86 and 2.16
Å) due to the total lack of planarity of the structure.
Unfortunately, all our attempts to obtain single crystals
for X-ray analysis of any of the complexes with the
naproxenate salt failed.
The enantioselective complexation of (S)-naproxenate with
racemic mixture 2 led to two diastereomeric complexes. A
remarkable unfolding of the signal of the H-7 chromenone
(from 8.99 for the free receptor to 8.82 and 8.91 ppm in the
complexed forms) and the protons of chiral centers (from
6.65 for the free receptor to 6.35 and 6.43 ppm in the
complexed form) was observed. Also, a downfield shift and
broadening of the N-H signals and a low-field shift of the
H-3 of chromenone (0.20 ppm) occurred.
A good enantiomeric recognition of 7.2 was obtained with
racemic receptor 2 and (S)-naproxen salt in competitive
experiments.
According to molecular mechanics calculations, the (R,R)-
2-(S)-naproxenate (Figure 3) must be the most stable
complex [the calculated energy differences10 between the
(S,S)-2-(S)-naproxenate and the (S,S)-2-(R)-naproxenate
range from 0.5 kcal/mol (MM2) to 3 kcal/mol (MMFF), in
1
complexes show different H NMR chemical shifts, the
formation of the complexes with each enantiomer afforded
1
splitting of the H NMR host 1 signals. These are propor-
tional to the ratio between a receptor forming a complex
and a free receptor in solution. Plots of the chemical shifts
of the protons (H-7 and H-3, respectively) of chromenone
with respect to each other in the diastereomeric complexes
and treatment with a curve-fitting program provided a Kass
ratio between both enantiomeric receptors with only slight
chiral discrimination (ratio 1.2:1). However, this suggests
that the formation of an enantioselective receptor should be
possible by incorporating features that promote or block one
of the binding modes.
Analysis of CPK models revealed that the introduction of
alkyl substituents in ortho positions in the peripheral phenyl
rings restricts the rotation of the Caryl-Camide single bonds,
freezing the degrees of freedom of the macrocycle. Thus,
receptor 2 sets methyl groups at positions 2 and 6 of these
phenyl rings, which are located near the steric center of the
guest in the complex. The required diamine 5 was prepared
(Scheme 1). In this case, reductive amination was not
possible because the carbonyl functions were too sterically
hindered;8 therefore, the carbonyl groups were reduced to
hydroxyl functions, substituted by bromide, and transformed
into amine groups. The macrocyclization step yielded 26%
of receptor 2.
(9) Crystallographic data (excluding structure factors) have been depos-
ited at the Cambridge Crystallographic Data Centre as Supporting Informa-
tion no. CCDC-275962.
(10) Monte Carlo searches for both complexes (using MM2, MM3, and
MMFF as force fields) were run on Silicon Graphics workstations using
Macromodel. The resulting minimum-energy conformations were subjected
to 300 ps molecular dynamics at 600 K (temperature at which the complexes
did not break apart) and sampled the guest conformational and rotational
space. The sampled conformations were finally energy minimized.
The 2-meso form was isolated by crystallization in chloro-
form-methanol as a solid with a mp > 300 °C (decompose),
whereas the racemate has a mp ) 244-245 °C.
(8) (a) Lane, C. F. Synthesis 1975, 135-146. (b) Borch, R. F.; Bernstein,
M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897-2904.
Org. Lett., Vol. 8, No. 21, 2006
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The relatively large effect on chiral affinity observed by
us may be attributed to the framework of receptor 2, having
a rigid and hindered cavity where host-guest binding takes
place without disturbing the required complementary geom-
etry. Steric repulsion close to the cavity seems to be decisive
for the chiral selectivity.
Efforts to attain the resolution of racemic receptor 2 are
in progress. Also, binding studies with related guests such
as ibuprofen and ketoprofen are now under way in our
laboratory and will be reported in due course.
Acknowledgment. We thank Anna Lithgow for the 400
MHz NMR spectra and Ce´sar Raposo for the mass spectra
(Nuclear Magnetic Resonance and Mass Spectrometry
Services, Salamanca University). This work was financially
supported by “Ministerio de Ciencia y Tecnolog´ıa” (MCYT
Grant No. BQU-2002-00676) and JCyL (SA 053/03). We
also thank the M.E.C. for two fellowships (S.G. and M.B.J.;
Department of Organic Chemistry, Salamanca University).
Figure 3. Lowest-energy conformation proposed for the complex
between receptor (R,R)-2 and (S)-tetraethylammonium naproxenate.
It displays a geometry in which the interactions between the proton
and methyl group of the guest and the 2,6-dimethyl-tert-butylphenyl
peripheral groups are minimized.
Supporting Information Available: Experimental details
and characterization data of receptors 1 and 2 and intermedi-
ate compounds, details concerning the determination of the
relative binding constants, and a summary of the crystal-
lographic data of the complex between receptor 2-meso and
tetraethylammonium acetate. This material is available free
of charge via the Internet at http://pubs.acs.org.
good qualitative agreement with the experimentally measured
1.4 kcal/mol] with favorable interactions between the host
and guest methyl groups.
Using the reciprocity principle3g in chiral recognition, a
single enantiomer of receptor 2 would have the same
selectivity for enantiomers of naproxen. To the best of our
knowledge, this could be the highest chiral recognition
reported for naproxen.
OL061505I
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Org. Lett., Vol. 8, No. 21, 2006