Enantioselective cyclization of racemic supramolecular polymers

Article abstract of DOI:10.1021/ja034273g

Homochiral hydrogen-bonded cyclic assemblies are formed in dilute solutions of racemic supramolecular polymers based on the quadruple hydrogen bonding 2-ureido-4[1H]-pyrimidinone unit, as observed by 1H NMR and SEC experiments. Preorganization of the monomers and the combined binding strength of the eight hydrogen bonds result in a very high stability of the cyclic aggregates with pronounced selectivity between homochiral and heterochiral cyclic species, usually only observed in crystalline or liquid crystalline phases. Copyright

Full text of DOI:10.1021/ja034273g

Published on Web 05/14/2003
Enantioselective Cyclization of Racemic Supramolecular Polymers
A. Tessa ten Cate,† Patricia Y. W. Dankers,† Huub Kooijman,‡ Anthony L. Spek,‡
Rint P. Sijbesma,*,† and E. W. Meijer*,†
Laboratory of Macromolecular and Organic Chemistry, EindhoVen UniVersity of Technology, P.O. Box 513,
5600 MB EindhoVen, The Netherlands, and BijVoet Center for Biomolecular Research, Crystal and
Structural Chemistry, Utrecht UniVersity, Padualaan 8, 3584 CH Utrecht, The Netherlands
Received January 22, 2003; E-mail: r.p.sijbesma@tue.nl; e.w.meijer@tue.nl
Stereoselective association plays an important role in chemistry
and biology, for example, in recognition processes, asymmetric
catalysis, and chiral chromatographic separations.1 The phenomenon
is based on a difference in interaction energy between molecules
of equal and of opposite configuration, and the degree of selectivity
is dependent on the strength of the intermolecular interaction, which
may be different in different physical states. Since Pasteur’s
discovery of spontaneous resolution,2 discrimination in the solid
state has received much attention, and many examples of conglom-
erate crystallizations have been reported. Enantioselective self-
association in solution is a much less studied subject. Nonequiv-
alence between the 1H NMR spectra of pure enantiomers and
racemic mixtures has been reported for a number of associating
molecules.3 However, in most cases, the selectivity was limited,
probably due to the dynamic nature and low stability of the
aggregates. Much higher selectivities have been observed for
stronger interactions in metal-ligand complexes4 and assemblies
based on multiple hydrogen bonding.5 Homochiral supramolecular
polymerization of xylylene-bridged bis(cyclic peptide)s was de-
scribed recently.6 Furthermore, heterochiral dimerization by π-π
stacking was reported for octahedral eilatin complexes.7
Figure 1. Crystal structure of 1b, showing enantioselective dimerization.
Hydrogen atoms not involved in hydrogen bonds and not bonded to chiral
centra are omitted for clarity.13
of chiral bifunctional UPy derivatives 1 and 2 in solution selectively
produces homochiral assemblies.
Monomer 1a was synthesized as a diastereomeric mixture from
2,6-diisocyanatoheptane and 6-tridecylisocytosine. Racemic 1a was
separated from the meso stereoisomer by flash column chroma-
1
tography. In contrast to spectra of similar compounds, H NMR
spectra of 1a show a single peak for each proton attached to the
UPy unit, over a broad concentration range (5-300 mM), dem-
onstrating that 1a is present in solution as a single type of hydrogen-
1
bonded aggregate. On the basis of H NMR diffusion measure-
ments,11 this aggregrate was estimated to be dimeric in size.12 The
solution viscosity of 1a in chloroform was measured for concentra-
tions up to 94 mM and was found to be only slightly higher than
that of the solvent (specific viscosity below 0.5). Furthermore, the
specific viscosity increased linearly with concentration, character-
istic for aggregates of constant size. Together, these results
demonstrate that racemic 1a forms cyclic dimers in chloroform
solution and has a critical concentration above 300 mM. From 1H
NMR spectra, it was concluded that the dimer of 1a is fully
symmetrical. Molecular models show that this is only possible if
the dimers are homochiral, as heterochiral dimers have lower
By designing complexes that possess high stability, we are also
aiming at closing the gap between stereoselectivity in crystals and
in solution. On the basis of the knowledge gained from crystals,
we propose that C2-symmetrical units would preferably form
enantioselective “conglomerates”. Previously, we have shown that
dimerization of quadruply hydrogen bonding 2-ureido-4[1H]-
pyrimidinone (UPy)8 derivatives (Figure 1) is very strong and has
an association constant of 6 × 107 M-1 in CDCl3.8b Bifunctional
molecules based on the UPy moiety may form randomly coiled
supramolecular polymers as well as cyclic oligomers in solution,9
depending on the external conditions and on the geometry of the
monomer. Ring-chain equilibria are characterized by a critical
concentration,10 below which only cyclic species are present and
above which the concentration of cyclic oligomers is constant and
polymeric aggregates are formed. We report here that dimerization
1
symmetry, leading to doubling of the number of peaks in the H
NMR spectra. Enantioselective dimerization was confirmed by
single-crystal X-ray analysis of derivative 1b (Figure 1). Homochiral
dimers of different chirality alternated in racemic crystals (space
group P-1), obtained from dimethyl sulfoxide-acetic acid mixtures.
To study enantioselective dimerization in detail, (R,R)-2a and
(S,S)-2a were synthesized from enantiomerically pure cystine methyl
esters, and solutions of the enantiomers were compared to solutions
of the racemic mixture. In the 1H NMR spectra of the pure
substances at 30 mM, four peaks were observed for the pyrimidi-
none alkylidene proton between 5.7 and 6.1 ppm (Figure 2, bottom),
which were all assigned to cyclic assemblies. The 1H NMR
spectrum of the racemic mixture at 30 mM was indistinguishable
from that of the pure enantiomers, indicating again that only
homochiral cyclic species were formed in solution. Upon increasing
the concentration of the enantiomerically pure solutions, an
additional peak was observed (Figure 2, top), which was assigned
† Eindhoven University of Technology.
‡ Utrecht University.
9
6860
J. AM. CHEM. SOC. 2003, 125, 6860-6861
10.1021/ja034273g CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
homodimers (equilibrium fully to the left side), if cyclization indeed
occurs enantioselectively. SEC experiments confirmed the expected
behavior (Figure 3, bottom). While the chromatogram of (S,S)-2a
with (R,R)-2b contains only two peaks corresponding to the
homodimers, the chromatogram of (R,R)-2a with (R,R)-2b shows
one broad combined signal of homo- and heterodimers.
In conclusion, we have demonstrated the selective formation of
homochiral cyclic dimers of UPy derivatives 1 and 2 in chloroform
solution. The preorganization of the monomers and the combined
binding strength of the eight hydrogen bonds result in a very high
stability of the cyclic aggregates with pronounced selectivity
between homochiral and heterochiral cyclic species, usually only
found in the crystalline state.
Acknowledgment. We thank Xianwen Lou and Ralf Bovee for
SEC experiments and helpful discussions.
Figure 2. Alkylidene region of 1H NMR spectra of (R,R)-2a, (S,S)-2a,
and a racemic mixture in CDCl3; asterisks denote peaks assigned to
polymeric aggregates.
Supporting Information Available: Experimental details of syn-
thesis and characterization of 1 and 2a/b (PDF). Atomic displacement
ellipsoid plot and X-ray crystallographic file in CIF format for 1b. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Gu¨bitz, G.; Schmid, M. G. Biopharm. Drug Dispos. 2001, 22, 291.
(b) Schurig, V. J. Chromatogr., A 2001, 906, 275.
(2) Pasteur, L. C. R. Hebd. Seances Acad. Sci. 1853, 37, 162.
(3) (a) Dobashi, A.; Saito, N.; Motoyama, Y.; Hara, S. J. Am. Chem. Soc.
1986, 108, 307. (b) Luchinat, C.; Roelens, S. J. Am. Chem. Soc. 1986,
108, 4873. (c) Giordano, C.; Restelli, A.; Villa, M.; Annunziata, R. J.
Org. Chem. 1991, 56, 2270. (d) Jursic, B. S.; Goldberg, S. I. J. Org. Chem.
1992, 57, 7172. (e) Williams, T.; Pitcher, R. G.; Bommer, P.; Gutzwiller,
J.; Uskokovic, M. J. Am. Chem. Soc. 1969, 91, 1871.
(4) For example, see: (a) Masood, M. A.; Enemark, E. J.; Stack, T. D. P.
Angew. Chem., Int. Ed. 1998, 37, 928. (b) Enemark, E. J.; Stack, T. D. P.
Angew. Chem., Int. Ed. 1998, 37, 932. (c) Xu, J.; Parac, T. N.; Raymond,
K. N. Angew. Chem., Int. Ed. 1999, 38, 2878. (d) Vincent, J.-M.; Philouze,
C.; Pianet, I.; Verlhac, J.-B. Chem.-Eur. J. 2000, 6, 3595.
(5) For example, see: (a) Prins, L. J.; Huskens, J.; de Jong, F.; Timmerman,
P.; Reinhoudt, D. N. Nature 1999, 398, 498. (b) Shi, X.; Fettinger, J. C.;
Cai, M.; Davis, J. T. Angew. Chem., Int. Ed. 2000, 39, 3124. (c) Murguly,
E.; McDonald, R.; Branda, N. R. Org. Lett. 2000, 2, 3169. (d) Shi, X.;
Fettinger, J. C.; Davis, J. T. J. Am. Chem. Soc. 2001, 123, 6738.
(6) Ishida, Y.; Aida, T. J. Am. Chem. Soc. 2002, 124, 14017.
(7) Gut, D.; Rudi, A.; Kopilov, J.; Goldberg, I.; Kol, M. J. Am. Chem. Soc.
2002, 124, 5449.
(8) (a) Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer, E.
W. J. Am. Chem. Soc. 1998, 120, 6761. (b) So¨ntjens, S. H. M.; Sijbesma,
R. P.; van Genderen, M. H. P.; Meijer, E. W. J. Am. Chem. Soc. 2000,
122, 7487.
Figure 3. Schematic representation of the equilibrium between homo- and
heterodimers of 2a and 2b and corresponding molecular weights (top) and
results of SEC experiments with mixtures of 2a and 2b (bottom).
to a random coil polymeric aggregate with a low diffusion
coefficient14 as determined by 1H NMR spectroscopy. On the basis
(9) (a) Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.;
Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W.
Science 1997, 278, 1601. (b) Folmer, B. J. B.; Sijbesma, R. P.; Meijer, E.
W. J. Am. Chem. Soc. 2001, 123, 2093.
1
of H NMR spectra, the critical concentration for (R,R)-2a was
determined to be 270 ( 20 mM (294 K). Remarkably, for the
racemic mixture, a peak corresponding to a polymeric aggregate
was already observed at 150 mM, and the critical concentration
for racemic 2a was determined to be 120 ( 20 mM (294 K). The
large decrease in critical concentration is a very interesting
phenomenon and is in full agreement with enantioselective cy-
clization in combination with the presence of both enantiopure and
racemic dyads in linear hydrogen-bonded assemblies. If all dyads
would have the same cyclization constant, the critical concentration
would be the same as for the enantiomerically pure solutions.
However, if only homochiral dyads can form cyclic aggregates,
the critical concentration will be decreased.15
Size exclusion chromatography (SEC) has been demonstrated
to be an effective tool to study the size of supramolecular
aggregates.16 To use the molecular size of the cyclic dimers as a
probe for stereoselectivity, derivative 2b was synthesized, which
lacks the long alkyl tail on the pyrimidinone ring and has a lower
molecular weight than 2a. In dilute solutions containing mixtures
of (R,R)-2a and (R,R)-2b, homochiral homo- and heterodimers of
three different sizes17 are formed (Figure 3, top). Conversely,
solutions of (S,S)-2a and (R,R)-2b will contain only the two
(10) (a) Jacobson, H.; Stockmayer, W. H. J. Chem. Phys. 1950, 18, 1600. (b)
Ercolani, G.; Mandolini, L.; Mencarelli, P.; Roelens, S. J. Am. Chem.
Soc. 1993, 115, 3901. (c) So¨ntjens, S. H. M.; Sijbesma, R. P.; van
Genderen, M. H. P.; Meijer, E. W. Macromolecules 2001, 34, 3815.
(11) Diffusion measurements were performed using a bipolar pulse pair (BPP)
pulse sequence; for details, see: Wu, D.; Chen, A.; Johnson C. S., Jr. J.
Magn. Reson., Ser. A 1995, 115, 260.
(12) The diffusion coefficient of the aggregate of 1 was found to be similar to
that of the internal reference, heptakis(2,3,6-tri-O-methyl)-â-cyclodextrin
(M ) 1429 g/mol), denoting a dimeric size (M1‚1 ) 1817 g/mol).
(13) Crystal data of 1b: 2C19H28N8O4‚3C2H4O2, colorless, triclinic, space group
P-1 (No. 2), a ) 10.8659(10), b ) 14.784(2), c ) 16.870(3) Å, R )
82.746(12), â ) 82.149(10), γ ) 75.847(12)°, V ) 2590.9(6) A3, Z ) 2,
71 935 reflections measured, 11 813 unique, 150 K, Mo KR radiation,
θmax ) 27.5°, refined on F2, 331 parameters (including N- - -H coordi-
nates), wR2 ) 0.1333, R1 ) 0.0501 for 7020I > 2σ(I), S ) 1.038, -0.27,
and 0.42 e Å-3
.
(14) Diffusion coefficients relative to the internal reference12 for peaks assigned
to cyclic assemblies ranged between 0.67 and 0.91, while peaks assigned
to polymers displayed a relative diffusion coefficient of 0.32.
(15) For details, see Supporting Information.
(16) (a) Seto, C. T.; Mathias, J. P.; Whitesides, G. M. J. Am. Chem. Soc. 1993,
115, 1321. (b) Yang, J.; Fan, E.; Geib, S. J.; Hamilton, A. D. J. Am.
Chem. Soc. 1993, 115, 5314.
(17) 1H NMR experiments have shown that in solutions of 2a/b at concentra-
tions used for SEC (<2 mM) primarily dimeric aggregates are present.
Furthermore, heterodimerization was confirmed by 1H NMR spectroscopy
of mixtures of (R,R)-2a and (R,R)-2b.
JA034273G
9
J. AM. CHEM. SOC. VOL. 125, NO. 23, 2003 6861