Chiral space in a unimolecular capsule [1]

Full text of DOI:10.1021/ja0016304

J. Am. Chem. Soc. 2000, 122, 7811-7812
7811
Communications to the Editor
Chiral Space in a Unimolecular Capsule
Jose´ M. Rivera and Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and
the Department of Chemistry
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
Figure 1. Structural depiction of the CLAM (14). Some hydrogens and
other solubilizing groups have been omitted for clarity.
ReceiVed May 12, 2000
Alder reactions with complementary dienophiles,7 and reaction
with maleimide 38 gave the adduct 4. Oxidation of the crude
product with bromine afforded the hydrated ketone 5 (Scheme
1).7 The formation of the expected endo product was confirmed
by NOE signals in the NMR spectrum. Condensation of 5 with
excess urea afforded glycoluril 6 in moderate yield and subsequent
silylation of the hydroxy group gave the desired glycoluril 7.
Self-assembled molecular hosts capable of completely sur-
rounding their guests are one of the most recent vehicles for
enantioselective recognition.1,2 Earlier, we reported the synthesis
and characterization of systems in which symmetrical molecules
assembled through hydrogen bonds to produce racemic capsules
with dissymmetric cavitiessthe chiral “softballs”.2a A chiral guest
dictates which enantiomeric capsule is preferentially formed: an
asymmetric cavity is imprinted on the capsule by the chiral guest.
Removal of the guest leaves a chiral, nonracemic host capsule
that “remembers” the guest template (rather than its mirror image)
for up to 20 h in organic solvents.3 Useful enantioselective
complexation and chiral catalysis requires even higher kinetic
stability and we report here our progress, using a combination of
noncovalent and covalent interactions.4,5
Scheme 1
The chiral softballs racemize by dissociation to their achiral
monomers followed by reassembly to either enantiomer. If the
monomers were covalently linked in such a way that permitted
only their return to the original enantiomer, this racemization
process could be abolished. This notion led us to the system
depicted in Figure 1, a covalently linked assembled molecule
(hereafter CLAM), featuring intramolecular self-assembly. The
glycoluril units at the ends of the monomers were the most likely
sites for covalent linkages to be introduced and this consideration
led us to the pentacyclic structure 7, in which a linking group
protrudes from only one edge of the glycoluril.
Condensation of 7 with dibromide 8 gave roughly equal
amounts of diastereomers 9 and 9′, in 67% combined yield, which
could be separated by normal phase chromatography. Both 9 and
9′ were desilylated using standard conditions and the resulting
diastereomers, 10 and 10′, were separately converted to the
appropriate monomers, 11 and 11′, using procedures developed
previously.9 Either diastereomer (11 or 11′) self-assembled in
noncompetitive solvents such as benzene-d6, to give capsules. The
covalent linkage of two molecules of 11 or 11′ with N-BOC-4-
aminobutyric acid followed by deprotection with trifluoroacetic
acid and coupling with 13 gave the desired CLAMs 14 and 14′
in good yields (Scheme 2).
There were compelling reasons for using a chiral, nonracemic
maleimide. First, model compounds analogous to 9 and 9′ without
a chiral auxiliary had been prepared, and all attempts to separate
the enantiomers by HPLC with a chiral stationary phase failed.
Second, molecular modeling studies10 suggested that only one of
the two diastereomeric CLAMs was likely to fold into a capsule
The synthesis of the modified glycoluril started with com-
mercially available 1,2-cyclohexanedione 1 which was sequen-
tially bis silylated to give 1,2-bis(trimethylsilyloxy)-1,3-cyclo-
hexadiene 2.6 This electron-rich diene pairs readily in Diels-
(1) For recent reviews on self-assembled capsules see: (a) Rebek, J., Jr.
Acc. Chem. Res. 1999, 32, 278-286. (b) Conn, M. M.; Rebek, J., Jr. Chem.
ReV. 1997, 97, 1647-1668.
(2) (a) Rivera, J. M.; Mart´ın, T.; Rebek, J., Jr. Science 1998, 279, 1021-
1023. For examples of other chiral nonracemic capsules, see: (b) Nuckolls,
C.; Hof, F.; Mart´ın, T.; Rebek, J., Jr. J. Am. Chem. Soc. 1999, 121, 10281-
10285. (c) Castellano, R. K.; Nuckolls, C.; Rebek, J., Jr. J. Am. Chem. Soc.
1999, 121, 11156-11163.
(3) Rivera, J. M.; Craig, S. L.; Mart´ın, T.; Rebek, J., Jr. Angew. Chem.,
Int. Ed. 2000, 39, 2130-3132.
(4) For examples of covalent-based chiral capsules see: (a) Park, B. S.;
Knobler, C. B.; Eid, C. N., Jr.; Warmuth, R.; Cram, D. J. Chem. Commun.
1998, 55-56. (b) Costante-Crassous, J.; Marrone, T. J.; Briggs, J. M.;
McCammon, J. A.; Collet, A. J. Am. Chem. Soc. 1997, 119, 3818-3823. (c)
Yoon, J.; Cram, D. J. J. Am. Chem. Soc. 1997, 119, 11796-11806. (d) Judice,
J. K.; Cram, D. J. J. Am. Chem. Soc. 1991, 113, 2790-2791. (e) Collet, A.
Tetrahedron 1987, 43, 5725-5759.
(7) Reetz, M. T.; Neumeier, G. Chem. Ber. 1979, 112, 2209-2219.
(8) Reddy, P. Y.; Kondo, S.; Toru, T.; Ueno, Y. J. Org. Chem. 1997, 62,
2652-2654.
(9) Tokunaga, Y.; Rudkevich, D. M.; Santamar´ıa, J.; Hilmersson, G.; Rebek,
J., Jr. Chem. Eur. J. 1998, 4, 1449-1457.
(5) For other examples of self-assembly with covalent modifications see:
Clark, T. D.; Kobayashi, K.; Ghadiri, M. R. Chem. Eur. J. 1999, 5, 782-792
and references therein.
(6) Emde, H.; Go¨tz, A.; Hofmann, K.; Simchen, G. Liebigs Ann. Chem.
1981, 1643-1657.
(10) Molecular modeling of capsules was carried out using MacroModel
6.5 and the Amber* force field: Mohamadi, F.; Richards, N. G.; Guida, W.
C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still,
W. C. J. Comput. Chem. 1990, 11, 440.
10.1021/ja0016304 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/29/2000

7812 J. Am. Chem. Soc., Vol. 122, No. 32, 2000
Communications to the Editor
Scheme 2
Figure 2. Cartoon representation of the CLAM in its closed and open
conformations.
(Figure 2); the other experiences severe steric clashes. Third, in
the absence of other structural information, we could not
determine the absolute stereochemistry of the chiral cavities. The
identity of the chiral capsule responsible for selecting an enan-
tiomer in a racemic mixture is the only way to understand the
details of the molecular recognition phenomena responsible for
the selectivity.
Figure 3. 1H NMR spectra (600 MHz) of (a) 14 and (b) 14′ in benzene-
d6.
We have previously shown that self-assembled capsules can
function as catalysts for encapsulated reagents.13 Covalent interac-
tions can complement noncovalent interactions and give unimo-
lecular capsules of increased kinetic stability.14 The results
presented here augur well for the use of the CLAM as a chiral
catalytic reaction chamber.
The 2,6-pyridyldicarboxamide linker lends some rigidity to the
system, and, combined with the chiral auxiliary, allows only one
of the two diastereomeric capsules to form. The two diastereo-
mers, 14 and 14′, exhibit very similar 1H NMR spectra in DMF-
d7, a solvent that disrupts the hydrogen bonds and favors the open
conformation. In contrast, with benzene-d6 the spectrum of 14
shows the characteristics of a closed capsular conformation
(Figure 3a), whereas 14′ exhibits a complex spectrum indicating
the presence of a mixture of higher order oligomers (Figure 3b).11
In the earlier softballs a guest was the template and the chiral
information flowed from the guest to the host. In the CLAM the
chiral information flows from the host to the guest. Encapsulation
studies with pinanediol and camphorsultam were performed in
order to assess the effect. Two solutions of 14 were independently
titrated with (+)- and (-)-pinanediol and their 1H NMR spectra
were recorded in 12% CD2Cl2/CCl4. After establishing the identity
of each individual diastereomeric complex each sample was
titrated with equal amounts of the enantiomer of the guest used
initially. After a few minutes (t1/2 ) 57 s for the guest exchange
process) both samples reached equilibrium at about 1.4:1 or 18%
DE. Analogous experiments with camphorsultam gave a 20% DE.
These experiments established that the aS-R capsule prefers the
(+)-pinanediol.12
Acknowledgment. We thank the Skaggs Research Foundation and
the National Institutes of Health for support. Administracio´n de Fomento
Econo´mico of Puerto Rico provided fellowship support to J.M.R.
Supporting Information Available: Procedures and spectral data for
all compounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA0016304
(12) The R in aS-R describes the configuration of the chiral auxiliary used
in the glycoluril. In the chiral softballs as well as in 14 the chirality of the
cavity is determined primarily by the spacers used in the monomers (i.e., the
phenyl ring and the ethylene spacers of 14). When the linker of the CLAM in
Figure 1 is disregarded, there is a vertical chiral axis running through the
middle of the capsule. A view down this chiral axis shows two “arms” pointing
up and two pointing down. We classify the chiral cavities in these systems
by using the length of the spacers to determine priorities. Near arms precede
far arms and the longer arm gets the highest priority (1 and 3 respectively).
If sense from 1 to 3 is clockwise, the configuration is aS (a for axial) or P.;
if counterclockwise, the configuration is aR or M. For more on nomenclature
of chiral compounds see: Eliel, E. L.; Wilen, S. H.; Mander, L. N.
Stereochemistry of Organic Compounds; John Wiley & Sons: New York,
1994; pp 1119-1122.
(13) (a) Kang, J.; Rebek, J., Jr. Nature 1997, 385, 50-52. (b) Kang, J.;
Santamar´ıa, J.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 120,
3650-3656.
(14) Brody, M. S.; Schalley, C. A.; Rudkevich, D. M.; Rebek, J., Jr. Angew.
Chem., Int. Ed. 1999, 38, 1640-1644.
(11) A compound similar to 14′, but with a flexible linker, showed the
predominant formation of the closed conformation, although small amounts
of other unidentified species were also present: Rivera, J. M. Ph.D. Thesis,
Massachusetts Institute of Technology, 2000.