Chiral capsules. 1. Softballs with asymmetric surfaces bind camphor derivatives

Article abstract of DOI:10.1021/ja972885t

Self-assembling 'softballs' are hollow-pseudospherical dimers held together by hydrogen bonds in organic solvents, They encapsulate smaller molecules of suitable size and shape. Stereochemical aspects of these systems are explored through the encapsulatio

Full text of DOI:10.1021/ja972885t

66
J. Am. Chem. Soc. 1998, 120, 66-69
Chiral Capsules. 1. Softballs with Asymmetric Surfaces Bind
Camphor Derivatives
Yuji Tokunaga and Julius Rebek, Jr.*
Contribution from The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037
ReceiVed August 15, 1997
Abstract: Self-assembling “softballs” are hollow pseudospherical dimers held together by hydrogen bonds in
organic solvents. They encapsulate smaller molecules of suitable size and shape. Stereochemical aspects of
these systems are explored through the encapsulation of camphor derivatives. Both symmetrical softballs and
1
those rendered chiral by functional groups on the softball’s surface are examined by H NMR methods.
Introduction
Molecule-within-molecule complexes are proving ever more
useful in physical organic chemistry. They provide means of
stabilizing reactive intermediates,1 observing new forms of
stereoisomerism,2 and accelerating certain reactions.3 Although
a number of chiral cavitands and complexes have been made,4-8
and guests inside these have been expected to experience
intensified sensations of asymmetry as a result of cramped
quarters, the stereochemical features in these microenvironments
remain largely unexplored. The possibilities range from asym-
metric outer surfaces through asymmetric cavity linings to
asymmetric cavities. We now have them all in hand and
introduce here the initial molecules with asymmetric surfaces.
In the sequel, we will trace the gradual shift of research focus
from the outside to the inside of the self-assembling “softball”
1‚1.
Asymmetric Guests
The softball assembles through hydrogen bonds and exists
as a pseudospherical dimer (Figure 1) in organic solvents.
Solvent molecules and solute guests that fill, optimally, 55-
60% of the dimer’s interior volume are reversibly encapsulated
under ambient conditions.9,10 Guests the size of adamantane
or ferrocene fit well inside, and we have encapsulated, for the
first time, optically active guests such as the camphor derivatives
Figure 1. Structure of monomer unit (top) and assembled dimeric
softball (bottom).
1
2-5. Figure 2 compares the H NMR spectra of the softball
1b‚1b in CDCl3 alone and with excess camphanic acid (3). The
sharp signals, upfield shifts, and widely separated resonances
(1) (a) Cram, D. J.; Tanner, M. E.; Thomas, R. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1024-1027. (b) Warmuth, R. Angew. Chem., Int. Ed. Engl.
1997, 36, 1347-1350.
(2) Timmerman, P.; Verboom, W.; van Veggel, F. C. J. M.; van
Duynhoven, J. P. M.; Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl. 1994,
33, 2345-2348.
(3) Kang, J.; Rebek, J., Jr. Nature 1997, 385, 50-52.
(4) Canceill, J.; Lacombe, L.; Collet, A. J. Am. Chem. Soc. 1985, 107,
6993-6996.
(5) Costante-Crassous, J.; Marrone, T. J.; Briggs, J. M.; McCammon, J.
A.; Collet, A. J. Am. Chem. Soc. 1997, 119, 3818-3823.
(6) Judice, J. K.; Cram, D. J. J. Am. Chem. Soc. 1991, 113, 2790-2791.
(7) van Wageningen, A. M. A.; Timmerman, P.; van Duynhoven, J. P.
M.; Verboom, W.; van Veggel, F. C. J. M.; Reinhoudt, D. N. Chem. Eur.
J. 1997, 3, 639-654.
Figure 2. NMR spectrum (600 Mhz) of softball 1a‚1a in CDCl3 at
3.4 mM: (a) alone; (b) after addition of 12.4 mM camphanic acid.
Signals upfield of TMS represent encapsulated camphor, and the
doubling of signals of the softball (e.g., at ∼5, 6, and 8 ppm) indicate
loss of symmetry planes within the complex.
(8) Lee, S. B.; Hong, J.-I. Tetrahedron Lett. 1996, 37, 8501-8504.
(9) Meissner, R. S.; Rebek, J., Jr.; de Mendoza, J. Science 1995, 270,
1485-1488.
(10) Meissner, R. S.; Garcias, X.; Mecozzi, S.; Rebek, J., Jr. J. Am. Chem.
Soc. 1997, 119, 77-85.
S0002-7863(97)02885-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/14/1998

Chiral Capsules. 1
J. Am. Chem. Soc., Vol. 120, No. 1, 1998 67
Figure 3. Synthesis of the new monomer subunit 1c.
one camphor derivative was seen within each softball. Menthol
(6) was not encapsulated. Its more extended structure is too
long to fit comfortably, although a more compact conformation,
featuring an axial isopropyl group, differs little in size and shape
from the camphor derivatives. This level of selectivity of the
softball, or any other capsule held together by only weak
intermolecular forces, remains to be explored.
Asymmetric Hosts
The softballs with an asymmetric surface were next examined.
In their simplest embodiment they are available through the
dimerization of two subunits that feature different substituents
on each end of the tape-like monomer.11 When two such achiral
subunits associate, the result is a chiral capsule that maintains
a C2 axis but no longer has the planes of symmetry featured in
1a‚1a or 1b‚1b. Accordingly, the dimeric assembly is racemic
(Figure 4). The enantiomers can interconvert by dissociation
and recombination of the subunits, and the attendant dynamic
properties of these capsules are not without interest, even if the
cavity itself lacks asymmetry.
The synthesis was accomplished through the intermediates
shown (Figure 3) and followed precedents firmly established
in this research program. The centerpiece10,12 of the structuresthe
tetraester 7swas used first to acylate a hydrazine bearing a
glycoluril with isopentyl esters (8) and then with one bearing
p-(hexyloxy)phenyl esters (9). The intermediate 10 and un-
desired isomer of the initial coupling 11 were formed in roughly
for free and bound guest confirm that camphanic acid is
encapsulated within the softball under conditions of slow
exchange on the NMR time scale. The resonances of the
softball undergo doubling: with camphanic acid inside no planes
of symmetry exist and the two edges of the tape-like, monomeric
subunits are now in different magnetic environments. These
edges can exchange environments only through dissociation,
rotation, and subsequent recombination of the subunits, the
costly energetics of which are described elsewhere.11 Similar
spectra (not shown) were observed for the other camphor
derivatives; the stoichiometries of the complexes were such that
(12) Tokunaga, Y.; Rudkevich, D. M.; Rebek, J., Jr. Angew. Chem., Int.
Ed. Engl. in press.
(11) Szabo, T.; Hilmersson, G.; Rebek, J., Jr. Submitted for publication.

68 J. Am. Chem. Soc., Vol. 120, No. 1, 1998
Tokanaga and Rebek
Figure 4. Structure (top) and schematic (bottom) renderings of the racemic softball dimer 1c‚1c.
equal amounts but were readily separated. The yield of the
undesired S-shaped isomer 12 of the final coupling, featuring
the glycoluril substituents on opposite faces of the molecule,
varied depending on the solvent. This role of molecular
recognition in the synthesis of the softball is described else-
where12 and is consistent with the observations of Cram13 and
Sherman14 during the synthesis of covalently bound systems
surrounding guest templates.
Figure 5 shows the 1H NMR spectrum of the racemic
assembly 1b‚1b in benzene. Again, two sets of signals are
observed for protons along the edges of the tape-like structure.
Addition of camphor to this species in p-xylene-d10, itself a poor
guest for the softball, further complicates the spectrum. Dias-
teromeric complexes are formed as evidenced by the upfield
signals for encapsulated camphor which are doubled (Figure
5b,c). The equal intensity of these signals provides confirmation
that the asymmetry of this system is limited to the outer surface
of the assembly, rather than extending into the cavity: the
Figure 5. NMR spectrum (600 MHz) of racemic softball 1c‚1c and
its complex with camphor: (a) 1c‚1c at 3.8 mM in benzene-d6; (b)
1c‚1c at 3.8 mM in p-xylene-d10 after addition of 460 mM camphor;
(c) expanded upfield region of b showing the two diastereomeric
complexes.
asymmetry is not felt by the guest in a steric sense, but only in
a magnetic sense.
(13) (a) Bryant, J. A.; Blanda, M. T.; Vincenti, M.; Cram, D. J. J. Am.
Chem. Soc. 1991, 113, 2167-2172. (b) Sherman, J. C.; Knobler, C. B.;
Cram, D. J. J. Am. Chem. Soc. 1991, 113, 2194-2204.
(14) (a) Chapman, R. G.; Chopra, N.; Cochien, E. D.; Sherman, J. C. J.
Am. Chem. Soc. 1994, 116, 369-370. (b) Chapman, R. G.; Sherman, J. C.
J. Am. Chem. Soc. 1995, 117, 9081-9082. (c) Nakamura, K.; Sheu, C.;
Keating, A. E.; Houk, K. N.; Sherman, J. C.; Chapman, R. G.; Jorgensen,
W. L. J. Am. Chem. Soc. 1997, 119, 4321-4322.
Summary and Outlook
As the asymmetric elements are moved inward, a chiral cavity
will result and it is reasonable to expect that molecule-within-

Chiral Capsules. 1
J. Am. Chem. Soc., Vol. 120, No. 1, 1998 69
2.95 mg). After 1.5 h of stirring, dibromide 1410 (76.4 mg, 0.148 mmol)
in DMSO (20 ml) was added dropwise, and the mixture was heated
for 1.5 h. The reaction mixture was poured into 1% aqueous HCl.
The mixture was filtered, and the solid was washed with water and
then triturated with MeOH. Subsequent filtration recovered excess
glycolurea as a white solid. The filtrate was evaporated, and the residue
was chromatographed on silica gel with CH2Cl2/AcOEt (3:1) to give
compound 15 (64.1 mg, 51%) as a foam: 1H NMR (300 MHz, CDCl3)
δ 7.06 (d, 2H, J ) 8.4 Hz), 6.95 (d, 2H, J ) 8.4 Hz), 6.65 (d, 2H, J
) 8.4 Hz), 6.55 (d, 2H, J ) 8.4 Hz), 6.17-5.81 (m, 2H), 5.05-4.62
(m, 4H), 4.45-3.99 (m, 4H), 3.81 (t, 2H, J ) 6.7 Hz), 3.76 (t, 2H, J
) 6.7 Hz), 1.73-1.60 (m, 4H), 1.48-1.24 (m, 30H), 0.90-0.82 (m,
molecule complexes of this sort will prove useful for enanti-
oselective recognition; a better environment for such recognition
is hard to imagine. The experience with cyclodextrins does,
however, give cause for concern. The dozens of asymmetric
centers lining their cavities do not often translate into efficient
enantioselection.15 This may be a result of their open-ended
structures or their relatively smooth, rather than bumpy or
cratered interiors. Using calixarene-based capsules, it has
recently been possible to introduce handedness to the lining of
the cavity.16 The clockwise or anticlockwise arrangement of
the series of hydrogen-bonded ureas in these systems emerges
in heterodimers and affects guests accordingly. We will report
on these in due course.17
6H); IR (neat) 3256, 2931, 1708, 1610 1513, 1463, 1248, 1175 cm-1
;
HRMS (FAB, M + Cs+) calcd for C48H64N6O8Cs 985.3840, found
985.3880.
Deprotection. Through a solution of protected hydrazine 15 (713
mg, 0.724 mmol) in CHCl3 (35 ml) was bubbled HCl(g) through a
pipette for 3 min. After 8 h of stirring, the solution was purged with
N2. The solvent was removed in Vacuo, and the material was used in
the next step without further purification: 1H NMR (300 MHz, DMSO-
d6) δ 8.06 (s, 2H), 7.16 (s, 2H), 6.94 (d, 2H, J ) 8.8 Hz), 6.88 (d, 2H,
J ) 9.0 Hz), 6.74 (d, 2H, J ) 8.9 Hz), 6.62 (d, 2H, J ) 8.9 Hz), 4.60
(d, 2H, J ) 15.6 Hz), 4.24-4.00 (m, 4H), 4.03 (d, 2H, J ) 15.6 Hz),
3.86-3.74 (m, 4H), 1.63-1.54 (m, 4H), 1.38-1.19 (m, 12H), 0.86-
0.75 (m, 6H); IR (neat) 3399, 3231, 2931, 1691, 1611, 1511, 1468,
1250, 1178, 835 cm-1; HRMS (FAB, M + Cs+) calcd for C38H48N6O4-
Cs 653.3815, found 653.3845.
Experimental Section
Tetrakis(pentafluorophenyl)ester 7. To a solution of the corre-
sponding tetraacid chloride10 (110 mg, 0.30 mmol), pentafluorophenol
(220 mg, 1.20 mmol), and a catalytic amount of 4-(N,N-dimethylamino)-
pyridine (DMAP) in CH2Cl2 (3 mL) was added Et3N (273 mg, 270
mmol). The mixture was heated under reflux overnight, cooled, washed
with 10% aqueous HCl and water, and then dried over Na2SO4.
Purification of the residue by silica gel column chromatography with
CH2Cl2 as the eluent gave active ester 7 (170 mg, 60%) as a colorless
solid: 1H NMR (300 MHz, CDCl3) δ 4.94 (s, 2H), 2.01 (s, 4H); IR
(neat) 1762, 1652, 1520, 1274, 1208, 1036, 996 cm-1; LRMS (FAB,
M + H+) calcd for C36H7F20O8 947, found 946. The product was
further characterized as its tetra-p-methoxybenzylamide after reaction
with 4 equiv of p-methoxybenzylamine and Et3N in CH2Cl2: HRMS
(FAB, M + Cs+) calcd for C44H46N4O8Cs 891.2370, found 891.2334.
Diesters 10 and 11. To a mixture of the isoamyl hydrazine salt 810
(327 mg, 0.476 mmol) and Et3N (241 mg, 2.38 mmol) in THF (2.5
mL) was quickly added a solution of tetraester 7 (713 mg, 0.713 mmol)
in THF (2 mL). After 10 h of stirring, the solvent was removed.
Chromatography of the residue on silica gel with THF/CHCl3 (3:1)
gave 10 (187 mg, 31 %) and with THF/CHCl3 (1:1) gave the isomer
11 (155 mg, 26 %). Spectroscopic data for 10: 1H NMR (600 MHz,
DMSO-d6) δ 8.08 (s, 2H), 8.07 (s, 2H), 7.79 (s, 2H), 7.48 (s, 2H),
6.95 (d, 2H, J ) 8.8 Hz), 6.89 (d, 2H, J ) 8.8 Hz), 6.74 (d, 2H, J )
8.8 Hz), 6.61 (d, 2H, J ) 8.8 Hz), 5.36 (d, 2H, J ) 15.5 Hz), 5.16 (d,
2H, J ) 15.5 Hz), 4.99 (s, 2H), 4.65 (d, 2H, J ) 15.5 Hz), 4.06 (d,
2H, J ) 15.6 Hz), 3.82 (t, 2H, J ) 6.5 Hz), 3.79 (t, 2H, J ) 6.5 Hz),
1.80-1.74 (m, 2H), 1.65-1.55 (m, 6H), 1.47-1.23 (m, 12H), 0.85 (t,
6H, J ) 6.7 Hz); IR (neat) 3645, 3248, 2957, 2915, 1695, 1629, 1511,
1460, 1230, 1027, 860 cm-1; LRMS (FAB, M + Cs+) calcd 1389;
found 1389.
Softball 1c‚1c. To a suspension of the isoamyl diester 10 (19 mg,
0.017 mmol) and Et3N (8.8 mg, 0.087 mmol) in benzene (2 mL) was
added a solution of hydrazine hydrochloride 9 (12 mg, 0.017 mmol)
in benzene (1.5 mL). After 10 h of stirring, the solvent was removed.
The C-shaped compound (3.2 mg) was obtained by preparative TLC
(eluent CHCl3/AcOEt/MeOH ) 65:25:10). For 1c‚1c: 1H NMR (600
MHz, DMSO-d6) δ 8.45 (s, 2H), 8.04 (s, 2H), 7.44 (s, 2H), 7.42 (s,
2H), 6.93 (d, 2H, J ) 8.7 Hz), 6.88 (d, 2H, J ) 8.7 Hz), 6.73 (d, 2H,
J ) 8.8 Hz), 6.60 (d, 2H, J ) 8.8), 5.29 (d, 2H, J ) 15.7 Hz), 5.24 (d,
2H, J ) 15.7 Hz), 5.09 (d, 2H, J ) 15.7 Hz), 5.08 (d, 2H, J ) 15.7
Hz), 4.97 (s, 2H), 4.63 (d, 2H, J ) 15.7 Hz), 4.60 (d, 2H, J ) 15.7
Hz), 4.45 (d, 2H, J ) 15.7 Hz), 4.18 (t, 2H, J ) 6.8 Hz), 4.05 (t, 2H,
1
J ) 6.8 Hz), 3.82 (d, 2H, J ) 6.4 Hz), 3.79 (t, 2H, J ) 6.4 Hz); H
NMR (600 MHz, C6D6) δ 8.56 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 8.43
(s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.84-
7.80 (m, 2H), 7.08-7.02 (m, 2H), 6.78-6.71 (m, 2H), 6.68-6.62 (m,
2H), 6.59 (d, 1H, J ) 16 Hz), 6.56 (d, 1H, J ) 16 Hz), 6.34 (d, 1H,
J ) 16 Hz), 6.32 (d, 1H, J ) 16 Hz), 5.75 (d, 1H, J ) 16 Hz), 5.73
(d, 1H, J ) 16 Hz), 5.64 (d, 1H, J ) 16 Hz), 5.62 (d, 1H, J ) 16 Hz),
5.62 (s, 1H), 4.61 (s, 1H), 4.52 (d, 1H, J ) 16 Hz), 4.51 (d, 1H, J )
16 Hz), 4.08 (d, 1H, J ) 16 Hz), 4.07 (d, 1H, J ) 16 Hz), 3.85 (d, 1H,
J ) 16 Hz), 3.82 (d, 1H, J ) 16 Hz), 3.67 (d, 1H, J ) 16 Hz), 3.63
(d, 1H, J ) 16 Hz), 3.52-0.81 (4m, 48H); HRMS (FAB, M + Cs+)
calcd for C76H86N12O14Cs 1523.5441, found 1523.5525.
Hydrazine 9 via 15. To a solution of glycolurea 1310 (770 mg,
1.56 mmol) in DMSO (80 ml) at 70 °C was added KOtBu (0.331 mg,
(15) Easton, C. J.; Lincoln, S. F. Chem. Soc. ReV. 1996, 25, 163-170.
(16) Castellano, R. K.; Kim, B. H.; Rebek, J., Jr. Submitted for
publication.
(17) For other systems in which aggregation leads to new chirality, see:
(a) Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc. 1993, 115, 905-916.
(b) Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc. 1993, 115, 1330-
1340. (c) Simanek, E. E.; Wazeer, M. I. M.; Mathias, J. P.; Whitesides, G.
M. J. Org. Chem. 1994, 59, 4904-4909. (d) Simanek, E. E.; Qiao, S.; Choi,
I. S.; Whitesides, G. M. J. Org. Chem. 1997, 62, 2619-2621.
Acknowledgment. We are grateful to the National Institutes
of Health and The Skaggs Research Foundation for support of
this work and to Christopher Bayne for preliminary experiments.
JA972885T