Solvent-induced amphiphilic molecular baskets: Unimolecular reversed micelles with different size, shape, and flexibility

Article abstract of DOI:10.1021/jo0607663

Amphiphilic molecular baskets were obtained by attaching facially amphiphilic cholate groups to a covalent scaffold (calix[4]arene or 1,3,5-2,4,6-hexasubstituted benzene). In a solvent mixture consisting of mostly a nonpolar solvent (i.e., CCl₄

Full text of DOI:10.1021/jo0607663

Solvent-Induced Amphiphilic Molecular Baskets: Unimolecular
Reversed Micelles with Different Size, Shape, and Flexibility
Eui-Hyun Ryu, Jie Yan, Zhenqi Zhong, and Yan Zhao*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011-3111
zhaoy@iastate.edu
ReceiVed April 11, 2006
Amphiphilic molecular baskets were obtained by attaching facially amphiphilic cholate groups to a covalent
scaffold (calix[4]arene or 1,3,5-2,4,6-hexasubstituted benzene). In a solvent mixture consisting of mostly
a nonpolar solvent (i.e., CCl4) and a polar solvent (i.e., DMSO), the hydrophilic faces of cholates turned
inward to form a reversed-micelle-like conformer whose stability was strongly influenced by the number
of the cholates and the topology of the scaffold. Preferential solvation of the hydrophilic faces of cholates
within the molecule by the polar solvent was cooperative and gave the fundamental driving force to the
conformational change. The reversed-micelle-like conformer was most stable in structures that allowed
multiple cholates to form a microenvironment that could efficiently enrich the polar solvent molecules
from the bulk solvent mixture.
Introduction
new light on the folding and functions of biomolecules but also
enable chemists to prepare biomolecule-like, stimuli-responsive
materials from a bottom-up approach.
Conformational changes in biomolecules may be induced by
specific molecules such as an enzyme substrate or an allosteric
effector1 or by general changes in environmental conditions
including temperature, pH, and solvent polarity. Response to
solvent polarity is not a surprise, as hydrophobic interactions3
represent a major driving force for the folding of polypeptide
chains. An interesting class of biomolecules that display polarity-
Conformations represent different 3-D arrangements of atoms
in a molecule as a result of rotations around single bonds. As
a molecule adopts different conformations, its size, shape, and
distribution of functional groups change simultaneously. Since
these properties are intimately related to the physical and
chemical behavior of the molecule, conformational control could
serve as a rational way to design environmentally responsive
materials. This strategy is utilized elegantly by biomolecules
such as proteins, whose binding and catalytic functions are
frequently regulated through controlled conformational changes.1
In recent years, foldamers have attracted a great deal of attention
of chemists in different fields.2 As mimics of biomolecules with
specific, compact conformations, foldamers may not only shed
(2) For several recent reviews, see: (a) Gellman, S. H. Acc. Chem. Res.
1998, 31, 173-180. (b) Kirshenbaum, K.; Zuckermann, R. N.; Dill, K. A.
Curr. Opin. Struct. Biol. 1999, 9, 530-535. (c) Hill, D. J.; Mio, M. J.;
Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. ReV. 2001, 101, 3893-
4012. (d) Cubberley, M. S.; Iverson, B. L. Curr. Opin. Chem. Biol. 2001,
5, 650-653. (e) Sanford, A. R.; Gong, B. Curr. Org. Chem. 2003, 7, 1649-
1659. (f) Martinek, T. A.; Fulop, F. Eur. J. Biochem. 2003, 270, 3657-
3666. (g) Cheng, R. P. Curr. Opin. Struct. Biol. 2004, 14, 512-520. (h)
Huc, I. Eur. J. Org. Chem. 2004, 17-29. (i) Licini, G.; Prins, L. J.; Scrimin,
P. Eur. J. Org. Chem. 2005, 969-977.
(3) (a) Tanford, C. The Hydrophobic Effect: Formation of Micelles and
Biological Membranes, 2nd ed.; Wiley: New York, 1980. (b) Ben-Mailm,
A. Hydrophobic Interactions; Plenum Press: New York, 1980. (c) Dill, K.
A. Biochemistry 1990, 29, 7133-7155. (e) Blokzijl, W.; Engberts, J. B. F.
N. Angew. Chem., Int. Ed. Engl. 1993, 32, 1545-1579.
* To whom correspondence should be addressed. Phone: (515) 294-5845.
Fax: (515) 294-0105.
(1) (a) Koshland, D. E., Jr. Proc. Natl. Acad. Sci. U.S.A. 1958, 44, 98-
104. (b) Koshland, D. E., Jr. Nat. Med. 1998, 4, 1112-1114. (c) Perutz,
M. F. Mechanisms of CooperatiVity and Allosteric Regulation in Proteins;
Cambridge University Press: Cambridge, 1990. (e) Herve´, G., Ed. Allosteric
Enzymes; CRC Press: Boca Raton, FL, 1989. (e) Kvamme, E.; Pihl, A.,
Eds. Regulation of Enzyme ActiVity and Allosteric Interactions; Academic
Press: New York, 1968.
10.1021/jo0607663 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/19/2006
J. Org. Chem. 2006, 71, 7205-7213
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Ryu et al.
induced conformational changes is R-helical antimicrobial
peptides.4 These small peptides typically assume random
conformations in water but change to amphipathic R-helical
structures (which are surface active and can destabilize the
membrane) in contact with bacterial membranes, a much less
polar environment. In fact, polarity-induced conformational
change is important to many biological processes including the
translocation of proteins across membranes.5
several cholates are linked covalently, intramolecular aggrega-
tion should happen readily. The difference between inter- and
intramolecular aggregation is that cholates can freely approach
one another to minimize solvophobic exposure in the former
but are restricted by the covalent linkers and the topological
scaffold employed in the latter. Therefore, other than concentra-
tion independency, unimolecular micelles and reversed mi-
celles12 from intramolecular aggregation of cholates have the
additional advantage of being tuned systematically through
structural modification.
The previously reported compound 1a could encapsulate
hydrophobic guests in polar solvents and hydrophilic guests in
nonpolar solvents.9 We were interested in creating larger baskets
by insertion of a spacer between the cholates and the calixarene.
This is represented by compound 2 with a rigid p-aminobenzoyl
spacer and 3 with a flexible 4-aminobutyroyl spacer. Ring
inversion in calix[4]arene happens readily when the alkyl
substituents at the lower rim are smaller than propyl.13 Com-
pound 1b, therefore, has a less pre-organized scaffold and is
used to test whether solvophobic interactions among the cholates
are strong enough to fix the calixarene into one particular
conformation. Compounds 5-7 are control molecules used in
our studies. Most of these compounds were synthesized in a
straightforward fashion by amide coupling between the acids
and the corresponding amines. Compounds 2 and 3 were
We have been interested in using cholic acid6 as a building
block to construct both foldamers7 and nonfoldamers8,9 whose
conformations and properties can be reversibly switched. With
its large steroid backbone and oppositely facing hydrophilic and
hydrophobic groups,10 cholic acid is uniquely suited for solvo-
phobically driven conformational changes. Previously, we
synthesized an amphiphilic molecular basket by coupling
cholates to a cone-shaped, aminocalix[4]arene scaffold.8 The
molecule adopted micelle-like conformations in polar solvents
with the hydrophilic (R) faces turned outward and reversed-
micelle-like conformations in nonpolar solvents with the R faces
inward. In this paper, we extend the concept to prepare a series
of cholate baskets with different size, shape, and flexibility. We
were able to experimentally verify preferential solvation, which
had been speculated to drive the conformational changes in the
molecular basket. We also found an interesting correlation
between the stability of the reversed-micelle-like conformer and
the ability for the cholates to form a microenvironment to
concentrate polar solvents from a mostly nonpolar solvent
mixture such as 10% DMSO in CCl4.
(6) For some examples of supramolecular systems constructed from
cholic acid, see: (a) Davis, A. P.; Bonar-Law, R. P.; Sanders, J. K. M. In
ComprehensiVe Supramolecular Chemistry; Atwood, J. L., Davis, J. E. D.,
MacNicol, D. D., Vo¨gtle, F., Eds.; Pergamon: New York, 1996; Vol. 4,
Ch. 7, and references therein. (b) Li, Y.; Dias, J. R. Chem. ReV. 1997, 97,
283-304, and references therein. (c) Maitra, U. Curr. Sci. 1996, 71, 617-
624. (d) Smith, B. D.; Lambert, T. N. Chem. Commun. 2003, 2261-2268,
and references therein. (e) Davis, A. P.; Joos, J.-B. Coord. Chem. ReV. 2003,
240, 143-156, and references therein. (f) Burrows, C. J.; Sauter, R. A. J.
Inclusion Phenom. 1987, 5, 117-121. (g) Janout, V.; Lanier, M.; Regen,
S. L. J. Am. Chem. Soc. 1996, 118, 1573-1574. (h) Ariga, K.; Terasaka,
Y.; Sakai, D.; Tsuji, H.; Kikuchi, J.-I. J. Am. Chem. Soc. 2000, 122, 7835-
7836. (i) Werner, F.; Schneider, H.-J. J. Inclusion Phenom. Macrocyclic
Chem. 2001, 41, 37-40. (j) Yoshino, N.; Satake, A.; Kobuke, Y. Angew.
Chem., Int. Ed. 2001, 40, 457-459.
(7) (a) Zhao, Y.; Zhong, Z. J. Am. Chem. Soc. 2005, 127, 17894-17901.
(b) Zhao, Y.; Zhong, Z. J. Am. Chem. Soc. 2006, 128, 9988-9989.
(8) Ryu, E.-H.; Zhao, Y. Org. Lett. 2004, 6, 3187-3189.
(9) Zhao, Y.; Ryu, E.-H. J. Org. Chem. 2005, 70, 7585-7591.
(10) For other examples of facial amphiphiles, see: (a) Stein, T. M.;
Gellman, S. H. J. Am. Chem. Soc. 1992, 114, 3943-3950. (b) Cheng, Y.;
Ho, D. M.; Gottlieb, C. R.; Kahne, D.; Bruck, M. A. J. Am. Chem. Soc.
1992, 114, 7319-7320. (c) Venkatesan, P.; Cheng, Y.; Kahne, D. J. Am.
Chem. Soc. 1994, 116, 6955-6956. (d) McQuade, D. T.; Barrett, D. G.;
Desper, J. M.; Hayashi, R. K.; Gellman, S. H. J. Am. Chem. Soc. 1995,
117, 4862-4869. (e) Broderick, S.; Davis, A. P.; Williams, R. P.
Tetrahedron Lett. 1998, 39, 6083-6086. (f) Isaacs, L.; Witt, D.; Fettinger,
J. C. Chem. Commun. 1999, 2549-2550. (g) Taotafa, U.; McMullin, D.
B.; Lee, S. C.; Hansen, L. D.; Savage, P. B. Org. Lett. 2000, 2, 4117-
4120. (h) Arnt, L.; Tew, G. N. J. Am. Chem. Soc. 2002, 124, 7664-7665.
(i) Willemen, H. M.; Marcelis, A. T. M.; Sudho¨lter, E. J. R. Langmuir
2003, 19, 2588-2591. (j) Elemans, J. A. A. W.; Slangen, R. R. J.; Rowan,
A. E.; Nolte, R. J. M. J. Org. Chem. 2003, 68, 9040-9049. (k) Zhong, Z.;
Yan, J.; Zhao, Y. Langmuir 2005, 21, 6235-6239. (l) Menger, F. M.;
Sorrells, J. L. J. Am. Chem. Soc. 2006, 128, 4960-4961.
Results and Discussion
Design and Synthesis of Amphiphilic Molecular Baskets.
The geometry of an amphiphile dictates the possible aggregates
it can form. For a head/tail amphiphile, spherical micelles (or
reversed micelles) are the most common aggregates obtained
in water (or nonpolar solvents). With a contrafacial topology,
cholate amphiphiles tend to associate through the solvophobic
faces into oligomers that resemble micelles and reversed
micelles in polar and nonpolar environments, respectively.11 If
(11) Sterols and Bile Acids; Danielsson, H., Sjo¨vall J., Eds.; Elsevier:
Amsterdam, 1985.
(12) For some recent examples of interconvertable unimolecular micelles
and reversed micelles, see: (a) Basu, S.; Vutukuri, D. R.; Shyamroy, S.;
Sandanaraj, B. S.; Thayumanavan, S. J. Am. Chem. Soc. 2004, 126, 9890-
9891. (b) Vutukuri, D. R.; Basu, S.; Thayumanavan, S. J. Am. Chem. Soc.
2004, 126, 15636-15637. (c) Ghosh, S.; Maitra, U. Org. Lett. 2006, 8,
399-402.
(13) (a) Gutsche, C. D. In Calixarenes ReVisited, Monograph in
Supramolecular Chemistry; Stoddart, J. F., Ed.; Royal Society of Chem-
istry: Cambridge, 1998; Ch. 4. (b) Mandolini, L.; Ungaro, R., Eds.
Calixarenes in Action; Imperial College Press: London, 2000; Ch. 1.
(4) (a) Hwang, P. M.; Vogel, H. J. Biochem. Cell Biol. 1998, 76, 235-
246. (c) Hancock, R. E. W.; Chapple, D. S. Atimicrob. Agents Chemother.
1999, 43, 1317-1323. (d) Epand, R. M.; Vogel, H. J. Biochim. Biophys.
Acta 1999, 1462, 11-28. (e) Tossi, A.; Sandri, L.; Giangaspero, A.
Biopolymers 2000, 55, 4-30. (f) van’t Hof, W.; Veerman, E. C.;
Helmerhorst, E. J.; Amerongen, A. V. Biol. Chem. 2001, 382, 597-619.
(5) Cserhåti, T.; Szo¨gyi, M. Int. J. Biochem. 1994, 26, 1-18, and
references therein.
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SolVent-Induced Amphiphilic Molecular Baskets
SCHEME 1. Synthesis of Compound 8
prepared by coupling cholic acid to the spacer first and then
the resulting extended acid to calixarene amine 4a.
baskets with rigid (17), flexible (18), and â amino cholate (19)
spacers. A dendritic molecule (20) with six arms of cholates
was also prepared to increase the width of the basket. It was
prepared by coupling the acid derivative of the bis-armed 15 to
the triamine scaffold 14. It should be mentioned that a compound
similar to 15 was reported by Burrows and co-workers to form
a closed conformation in nonpolar solvents with the two cholates
hydrogen bonded to each other.6f In our paper, 15 mainly serves
as a control to study enrichment of polar solvents within the
basket.
Compound 8 uses cholate dimers as the wall material and
thus should contain a deeper capacity. The â-amino cholates
are chosen as linkers between the top cholates and the amino-
calixarene because the R,â dimer seems to be able to align
linearly according to CPK molecular models. (Cholate oligomers
consisting of all R linkages are known to fold into helical
structures due to the curved backbone.)7 The synthesis of 8 is
outlined in Scheme 1. The terminal hydroxyl group in methyl
cholate 9 is more reactive than the other two and was selectively
tosylated in pyridine in 85% yield. The tosylate was replaced
by azide through a SN2 reaction and reduced by triphenylphos-
phine in aqueous THF in 74 and 70% yield, respectively. The
amine ester 12 was coupled to cholic acid in the presence of
benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluo-
rophosphate (BOP) and diisopropylethylamine (DIPEA) in 75%
yield. The dimer ester 13 was hydrolyzed, converted to the
activated N-hydroxysuccinimide (HO-Su) ester, and reacted
with aminocalixarene 4a to afford the final product (8) in 86%
overall yield.
Conformational Changes in Calixarene-Based Molecular
Baskets. There were two main lines of evidence for the micelle-
and reversed-micelle-like conformations of 1a. It could bind
hydrophobic guests such as pyrene in polar solvent mixtures
(e.g., methanol/water ) 80:20) and hydrophilic guests such as
phenyl â-D-gluocopyranoside in nonpolar mixtures (e.g., meth-
anol/CCl4 ) 5:95).9 Pyrene caused upfield shifts of the methyl
protons on the â faces of cholates, consistent with the micelle-
like conformation with inwardly facing â faces. The other line
of evidence for the proposed conformations was from 1H NMR
data in the absence of guests. The aromatic protons ortho to
the amido group appear as a single peak in solvents with
intermediate polarity but as two peaks in either polar or nonpolar
solvents.8 The magnitude of splitting was found to correlate with
not only solvent polarity but also with the difference of the
solvophobicities of the R and â faces of cholates.8 Such a
Another scaffold commonly used in supramolecular chemistry
is 1,3,5-2,4,6-substituted benzene such as 14.14 Because of steric
crowdedness, the substituents on the phenyl prefer to alternate
up and down around the ring. Using this scaffold, we synthe-
sized a compact tripodal basket 16 as well as several extended
(14) Hennrich, G.; Anslyn, E. V. Chem.sEur. J. 2002, 8, 2218-2224,
and references therein.
J. Org. Chem, Vol. 71, No. 19, 2006 7207

Ryu et al.
end of the concentration range, typically about 1 mM. Aggrega-
tion should not be a problem.15 Additional evidence against
intermolecular aggregation is from the appearance of the proton
signals. The broadening of peaks typically associated with
intermolecular aggregation was essentially absent in all com-
pounds studied in this paper.
Splitting of the aromatic protons occurs in 1b at the polar
end (e.g., in 100% DMSO) as well, suggesting formation of
another ordered structure, most likely the micelle-like conformer.
The methylene bridge protons in this case, however, do not
appear as an AB quartet characteristic of the cone but are broad
and nearly invisible. The original basket 1a did not show such
a difference in the polar end because calix[4]arene was already
fixed as the cone by the long hexyl groups.8,9 It seems that
solvophobic interactions among the cholates are different for
the normal and reversed-micelle-like conformers. This is quite
likely because solvophobic interactions occur through direct
contact of the cholate â faces in polar solvents for the former
conformer but are probably mediated by polar solvent molecules
for the latter. In other words, in the reversed-micelle-like
conformer, DMSO is enriched in the interior of the molecule
from the mostly nonpolar environment and serves to bridge the
gap between the R faces of cholates. Direct contact of the R
faces to simultaneously satisfy all hydrogen bonds in four
cholates seems quite impossible, especially because the cholate
backbone is bent toward the R face. In fact, mediation by polar
solvents is also required in surfactant reversed micelles, which
typically need to be stabilized by a small amount of water.16
The cone conformation allows the R faces of all four cholates
to be simultaneously solvated by entrapped DMSO molecules
and thus should be the best for the reversed-micelle-like
conformer. On the other hand, direct contact of the â faces,
which is preferred by the normal-micelle-like conformer, may
not be best in the cone-shaped calixarene. Given that sodium
cholate frequently forms dimers in aqueous solutions,11 it is quite
possible that other conformations (such as 1,3-alternate) are
equally good for solvophobic interactions; thus, no particular
conformation of calixarene may be favored by the normal
micelle-like conformer.
FIGURE 1. Portions of 1H NMR (400 MHz) spectra of 1b in different
ratios of DMSO-d6/CCl4 at ambient temperature. The solvents are 100,
90, 80, 70, 60, 50, 40, 30, 20, and 10% DMSO from top to bottom.
See structure of cholic acid for OH labeling.
splitting is also observed for 1b (Figure 1, ArH), which is based
on a conformationally mobile scaffold. Splitting by itself does
not prove the two proposed conformers but does support a
transition between two ordered conformations as the solvents
go from mostly polar to mostly nonpolar. Given the binding
properties mentioned previously, it is reasonable to assume that
the conformer in polar solvents is micelle-like and that the one
in the nonpolar solvents is reversed-micelle-like.
Cholate substitution on the calixarene clearly had a dramatic
effect on the calixarene because the parent calixarene 4b
1
contained extremely broad peaks in the H NMR spectrum.
Since the distance between the two aromatic proton peaks
correlates with the stability of the ordered, micelle-like, or
reversed-micelle-like conformers based in 1a,8,9 we expected a
smaller splitting in the less pre-organized 1b, as part of the
solvophobic interactions among the cholates needs to compen-
sate for the loss of entropy during formation of an ordered
conformation. This is indeed the case. For example, the two
peaks are separated by 158 Hz for 1a but 140 Hz for 1b in
10% DMSO.
A change of conformation is also evident from the methylene
bridge protons (Ar-CH2-Ar), which are diagnostic of calix-
[4]arene conformations.13 The “axial” protons at ∼4.2 ppm
begin to appear as (part of) an AB quartet with DMSO ≈60%
and become more well-formed with lower DMSO, consistent
with a higher stability of the cone conformer. Conversion from
a conformationally random calixarene to the cone conformer
in 1b indicates the presence of intramolecular attractions among
the cholates, in agreement with the proposed reversed-micelle-
like conformations. Interestingly, the appearance of the AB
quartet concurs with the splitting of the aromatic peaks, implying
that both changes are of the same origin. This result confirms
our previous conclusion that splitting is caused by the adoption
of ordered conformations (i.e., micelle-like conformation in polar
solvents and the reversed-micelle-like conformation in nonpolar
solvents).
In aprotic solvents such as DMSO/CCl4, both the NH and
the OH protons are clearly visible. As shown in Figure 1, these
protons generally move to high field with a decrease in DMSO
percentage. Note that the doublets of the OH protons are clearly
visible in all solvent mixtures (as also in Figure 4). In nonpolar
solvents, aggregation would occur through hydrogen bonds and
undoubtedly would complicate the OH signals. Clear OH signals
thus once again provide evidence against intermolecular ag-
gregation. Interestingly, the upfield shift seems to slow below
50-60% DMSO and even reverses for the OH protons in <
20% DMSO. The trend is more obvious when changes in the
chemical shifts are plotted against DMSO percentages (Figure
2). Chemical shifts of NH and OH directly reflect the extent of
(15) One reviewer suggested dilution studies for other compounds,
preferably before and after a break point in the -∆δ-DMSO% curve. These
experiments represent more stringent tests for intermolecular aggregation.
In our experience, aggregation is much less of a problem with a higher
percentage of DMSO, as cholate derivatives are far more soluble in DMSO-
rich solvents than in CCl4-rich ones. Because the break points vary
depending on whether the curve is for NH or OH (and for different OH’s),
1
we instead recorded H NMR spectra of compounds 1a, 1b, 2, 3, 16, 17,
and 18 in DMSO/CCl4 (50:50) at ca. 0.1 mM or roughly 10 times diluted
from the original samples. Sharp peaks similar to those at higher concentra-
tions were found in all cases.
(16) Fendler, J. H. Membrane Mimetic Chemistry; Wiley: New York,
1982; Ch. 3.
The possibility of intermolecular aggregation of 1a was ruled
out previously because its 1H NMR spectrum was nearly
unchanged over a 0.2-15 mM concentration.9 All the NMR
experiments in the current study were performed at the lower
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SolVent-Induced Amphiphilic Molecular Baskets
periphery of the basket, shows less pronounced DMSO enrich-
ment (9 in Figure 2b) than OH12 ([ in Figure 2b), which is in
the interior. Such a trend is more or less maintained in all of
our cholate-derived compounds. This suggests that cooperativity
exists between the polar groups to enrich DMSO. Among a
cluster of polar groups, the ones in the center are more strongly
solvated by DMSO than the ones near the edge.
Conformational changes in our amphiphilic baskets were
previously hypothesized to occur as a result of preferential
solvation of the hydrophilic faces of cholates by the polar solvent
molecules.8 Similar conclusions were also inferred from their
guest-binding properties in response to polar solvents.9 The
-∆δ-DMSO% curves give an estimate of the average DMSO
concentration near the polar groups and provide further evidence
for the formation of the reversed-micelle-like conformers. Such
conformers by definition have inwardly facing polar groups and,
similar to surfactant reversed micelles, should enrich polar
solvents from a nonpolar environment to its interior. According
to Figure 2a,b, preferential solvation (shown by deviation from
control curves) seems to become important below 50-60%
DMSO and is most pronounced when the solvents contain
10-20% DMSO. This effect should be even stronger below
10% DMSO. However, solubility often becomes a problem in
such mixtures, precluding measurement.
1
FIGURE 2. Changes in H NMR chemical shifts of (a) NH and (b)
OH as a function of solvent composition in mixtures of DMSO-d6/
CCl4 for compounds 1a, 1b, 5, and 6. Data for OH7 sometimes cannot
be obtained because of overlapping with solvent signals (as shown by
Figure 1). Assignment of the OH groups is based on a 2-D COSY
spectrum (Figure 1S in the Supporting Information).
hydrogen-bonding interactions involved by these protons.17-22
In our mixed solvents, only DMSO can participate in hy-
drogen bonding; thus, the chemical shifts of the NH and OH
groups are good indicators of the local concentration of
DMSO near these groups. Figure 2a shows the relationship
between -∆δNH and DMSO percentage for several compounds.
The curves are nearly identical for monomer 5 and phenyl
acetamide 6, indicating similar solvation of amides in both
compounds. Apparently, a single cholate group does not have
any DMSO-enriching effect in comparison to a simple amide.
Under such conditions, -∆δNH-DMSO% simply reflects the
concentration of DMSO in the bulk mixture. When multiple
cholates are assembled on a calixarene, a completely different
situation is observed. The -∆δNH-DMSO% curves for 1a and
1b ([ and 0) initially trace those of control compounds 5 and
6 (4 and ×), suggesting that the NH groups are sensing the
DMSO concentration in the bulk in high DMSO solvents just
as 5 and 6. When DMSO in the bulk drops below 50-60%,
however, the curves bend downward substantially. In fact, the
NH protons of 1a and 1b experience the same degree of
hydrogen-bonding interactions (as indicated by the magni-
tude of -∆δ) in 10% as in 40-50% DMSO. In other words, it
seems as if 40-50% DMSO is still present near the amide
protons even when the bulk solvent only contains 10% of
DMSO.
For compounds 2 and 3, splitting of the aromatic protons is
hardly observable even under the most polar or nonpolar
conditions. Thus, a direct connection between cholate and
calixarene is needed for the splitting, and conformational insight
cannot be obtained in this way. The -∆δ-DMSO% curves for
NH/OH, however, show similar DMSO enrichment as in 1a
and 1b, suggesting the adoption of reversed-micelle-like con-
formations in low-polarity solvents (Figures 2S and 3S in the
Supporting Information). Apparently, insertion of short spacers
between cholates and calixarene does not affect the conforma-
tional changes significantly, at least for the reversed-micelle-
like conformer.
The double-decker basket 8 contains two layers of cholates.
With (the lower) cholates directly attached to calixarene, it
displays the typical splitting of aromatic protons in both polar
and nonpolar solvents (Figure 4S in the Supporting Information).
The splitting, however, is consistently smaller than that in 1a
or 1b (Figure 5S in the Supporting Information), indicating less
stable micelle- or reversed-micelle-like conformations. With two
layers of cholates, it is interesting to ask whether both layers
participate equally in the solvent enrichment discussed previ-
ously. Fortunately, the two layers of cholates are linked by
different types of amide bondssaromatic (Ar) amides for the
bottom layer and aliphatic (Alk) amides for the top, and the
The OH12 group on the cholate shows a similar downward
deviation from the control curve (Figure 2b). In fact, the DMSO-
enriching effect is so strong toward the low-polarity end that,
as far as this hydroxyl is concerned, the local DMSO concentra-
tion actually increases when the bulk DMSO is decreased from
20 to 10%. Most interestingly, the OH3 proton, located at the
1
(17) Pople, J. A. Schneider, W. G.; Bernstein, H. J. High-Resolution
Nuclear Magnetic Resonance; McGraw-Hill: New York, 1959; Ch. 15.
(18) Laszlo, P. Solvent Effects and Nuclear Magnetic Resonance
Spectroscopy. In Progress in Nuclear Magnetic Resonance Spectroscopy;
Emsley, J. W., Feeney, F., Sutcliffe, L. H., Eds.; Pergamon Press: Oxford,
1967; Vol. 3, Ch. 6.
(19) Ronayne, J.; Williams, D. H. Solvent Effects in Proton Magnetic
Resonance Spectroscopy. In Annual ReView of NMR Spectroscopy; Mooney,
E. F., Ed.; Academic Press: London, 1969; Vol. 2, p 83.
(20) Murthy, A. S. N.; Rao, C. N. R. Spectroscopic Studies of the
Hydrogen Bond. In Applied Spectroscopy ReView; Brame, E. G., Ed.;
Dekker: New York, 1969; Vol. 2, p 69.
(21) Davis, J. C.; Deb, K. K. Analysis of Hydrogen Bonding and Related
Association Equilibria by Nuclear Magnetic Resonance. In AdVances in
Magnetic Resonance; Waugh, J. S., Ed.; Academic Press: New York, 1970;
Vol. 4, p 201.
(22) Konrat, R.; Tollinger, M.; Kontaxis, G.; Kra¨utler, B. Monatsh. Chem.
1999, 130, 961-982.
corresponding amide protons are well-separated in H NMR.
Interestingly, downward deviation from the control curves is
still observed for the Ar amides ([ in Figure 3a) but is
completely absent for the Alk amides (0). This difference is
reproducible (Figure 6S). As discussed previously, the down-
ward deviation reflects stronger hydrogen-bonding interactions
experienced by the NH/OH protons of a basket compound than
those of the control and is a measure of the DMSO-enriching
ability of the reversed-micelle-like conformer. The deviation
has nothing to do with the nature of the amide itself because
the control compounds 5 (×) and 7 (+) give similar upward
curves even though they have different kinds (e.g., Ar and Alk)
of amides. Therefore, the lower amides experience higher-than-
usual or preferential solvation by DMSO in mostly nonpolar
J. Org. Chem, Vol. 71, No. 19, 2006 7209

Ryu et al.
over 150 Hz for 1a. This is the first indication that the
hexasubstituted benzene is a less ideal scaffold than calix[4]-
arene for these molecular baskets. The OH protons once again
appear as clear doublets (except in D2O/DMSO mixtures where
they are exchanged into deuterium), suggesting the absence of
intermolecular aggregation.
Splitting of benzylic protons disappears as soon as spacers
are introduced between cholates and scaffold (baskets 17 and
18). This is the same effect seen in the calixarene baskets.
Hence, we turn to the -∆δ-DMSO% curves to study the
(reversed-micelle-like) conformations. To our surprise, -∆δNH
of 16 gives a curve almost identical to that of control compound
7 (Figure 7S in the Supporting Information), seemingly sug-
gesting no DMSO enrichment from the environment by this
basket. DMSO enrichment does happen as judged by the
-∆δOH12 curves in all three tripodal baskets, as well as in the
bis-armed 15 (Figure 5a), although to a smaller extent in
comparison to the calixarene baskets (compare Figure 2b). This
is another piece of evidence that the hexasubstituted benzene
is not as good a scaffold as calix[4]arene for the molecular
basket, presumably because the calix[4]arene-based baskets can
better accommodate DMSO in the internal hydrophilic space
with four (instead of three) cholates. Basket 16 is soluble enough
in 5% DMSO. As shown in Figure 5a (+), enormous DMSO
enrichment occurs under this condition, causing the internal
DMSO concentration to reach nearly 50%. It seems that, for
the hexasubstituted benzene-derived baskets, a large scale
conformational change requires more extreme conditions due
1
FIGURE 3. Changes in H NMR chemical shifts of (a) NH and (b)
OH as a function of solvent composition in mixtures of DMSO-d6/
CCl4 for compounds 8, 5, 7, and 1a. Data point for 10% DMSO is
missing for 8 due to insolubility.
DMSO/CCl4 mixtures, but the top ones do not and are rather
disordered.
Because of this DMSO-enriching effect, -∆δNH(Ar) of 8 ([
in Figure 3a) displays a much smaller range of upfield shifts
(<0.15 ppm) during solvent titration than the those of 5 or 7
(>0.4 ppm). The range is even smaller for 1a and 1b in Figure
2a and similarly small for 2 and 3 in Figures 2S and 3S. It
should be noted that some of these -∆δ-DMSO% curves level
off but that others reverse their directions at low percentages
of DMSO. Reversed curves indicate that the local concentration
of DMSO increases as the overall DMSO percentage is
decreased. Such a reverse is most likely caused by the onset of
a conformer that is highly efficient at enriching DMSO from
the environment. This is quite possible because reversing
generally is absent in poorly organized baskets (also see the
results in the next sections). It is clear from these -∆δ-
DMSO% curves that many basket compounds begin to experi-
ence stronger (preferential) solvation by DMSO than the control
compounds early on during solvent titration. Preferential sol-
vation occurs even in moderately polar mixtures but becomes
more pronounced in mostly nonpolar mixtures such as 10%
DMSO. Unfortunately, 8 is not soluble in 10% DMSO, which
may be another reason that reversing is not observed for its Ar
amides in Figure 3a.
to less efficient solvophobic interactions. For example, -∆δOH12
-
DMSO% curves reverse directions with 20-30% DMSO in 1b
(Figure 2b) but only below 10% in 16.
The discrepancy between the -∆δNH and the -∆δOH12 curves
of 16 may come from the small size of the scaffoldsthe three
amide groups near the hexasubstituted benzene probably are
quite close in space. If DMSO molecules cannot approach the
amides from the inside of the basket, the -∆δNH curve will
only reflect DMSO concentrations in the bulk. The situation is
different for OH12 groups, located farther away from the
hexasubstituted benzene. With considerable flexibility between
the fused steroid backbone and the base, DMSO molecules
should have no difficulty entering the upper part of the basket,
making OH12 groups able to sense DMSO enrichment.
Only the cholates in the top layer have hydroxyls at the C3
positions; the bottom cholates are substituted with amides at
C3. A noticeable but much less significant deviation from the
control (× in Figure 3b) is observed for 8 ([) than for 1a (9).
This result suggests again that the top cholates of 8 are less
organized than those of 1a.
The chemical shifts of the amide protons in 17 are notewor-
thy. Its Ar amides and Alk amides are very different in their
response to DMSO percentage. Whereas the top Ar amides (4
in Figure 5b) deviate downward from that of the control 7 (+),
the bottom Alk amides (2) actually deviate upward. An upward
deviation means that the δNH(Alk) of 17 is more sensitive to bulk
DMSO% than that of 7. The exact reason for this high sensitivity
is unclear to us. What is clear is that the Alk amides do not
experience any DMSO-enriching effect. Also, within the same
molecule, the Ar amides near the cholates are less sensitive to
the environmental concentration of DMSO than the Alk amides
that are farther away.
Conformational Changes in 1,3,5-2,4,6-Substituted Benzene-
Based Molecular Baskets. In calixarene-based molecular
baskets, the splitting of aromatic protons coincides with the
formation of either the micelle- or reversed-micelle-like con-
formers. Splitting also happens in the tripodal basket 16 (Figure
4): the benzylic methylene protons at 4.2 ppm appear as an
AB quartet in nonpolar solvents but as a single peak in solvents
with intermediate polarity. (The peak pattern is a little compli-
cated in some cases because of an additional small coupling to
the amide proton.) As in the calixarene baskets (compare Figure
1), the reversed-micelle-like conformer seems to be better
formed than the micelle-like one, as shown by a larger splitting
of the benzylic protons in low DMSO mixtures than in high
DMSO ones. The micelle-like conformer, as expected, can be
stabilized by the addition of water, for the splitting is much
more visible in D2O/DMSO (20:80) than in pure DMSO.
Overall, the magnitude of splitting is smaller in the tripodal
basket than in the calixarene basketssup to 40 Hz for 16 versus
For 18, on the other hand, both the upper and the lower amide
protons (9 and 0 in Figure 5b) experience DMSO enrichment.
Note that the rigid and flexible linkers made no difference in
the calixarene baskets. But, for the hexasubstituted benzene-
derived ones, it seems as if the flexible 4-aminobutyroyl linker
not only allows more efficient aggregation of the cholates but
also opens up space above the lower amides so that the basket
can better accommodate DMSO. A possible explanation for the
7210 J. Org. Chem., Vol. 71, No. 19, 2006

SolVent-Induced Amphiphilic Molecular Baskets
1
FIGURE 4. Portions of H NMR (300 MHz) spectra of 16 in different solvents at ambient temperature. The broad singlets at 3.55-3.60 and
3.70-3.75 ppm are from protons on C12 and C3 adjacent to the hydroxyl groups.
1
1
FIGURE 5. Changes in H NMR chemical shifts of (a) OH12 for
FIGURE 6. Changes in H NMR chemical shifts of (a) NH and (b)
compounds 5, 15-18 and (b) NH for compounds 7, 17, and 18 as a
function of solvent composition in mixtures of DMSO-d6/CCl4.
OH for compounds 19 and 20 as a function of solvent composition in
mixtures of DMSO-d6/CCl4.
difference between 16/17 and 18 lies in the position of amides
relative to cholates. The solvophobic force in the baskets mostly
originates from the facially amphiphilic cholates. For a compact
basket (16) or one with rigid spacers (17), the solvophobic force
among the cholates will compress the structure and cause the
amide protons at the bottom to move closer. For a basket with
a flexible spacer (18), however, interactions among the cholates
may be insulated from the lower amides and do not change
their arrangements significantly. It is even possible that the
crowdedness near the lower amides in 16/17 may not come from
the size of the scaffold but actually from the solvophobic force
of the cholates.
Double-decker basket 19 represents the worst combinations
hexasubstituted benzene as a poor scaffold (in comparison to
calix[4]arene) and the cholate dimer as poor wall material (in
comparison to monomeric cholate). Not surprisingly, negligible
extent of DMSO enrichment is seen in either -∆δNH or -∆δOH
curves (Figure 8S in the Supporting Information). However,
when six cholates are arranged within one layer as in dendritic
basket 20 instead of in two layers in 19, a different result is
obtained. The top and bottom amide protons in 20 initially
overlap and respond to the DMSO percentage similarly as the
amide in the control 15 but very soon split to give two curves,
whereas the bottom amides (three protons by integration, 9 in
Figure 6a) follow the same track of amides in 15 (4), and the
top amides (six protons, 0) give a larger downward deviation.
Since 20 is essentially made of three units of 15, amides in the
latter and the top amides of the former should behave similarly
if only the cholates attached to the same phenyl ring can interact.
The fact that 20 can enrich DMSO much more efficiently than
part of its structure clearly indicates that DMSO enrichment by
cholates is a cooperative phenomenon and that all six cholates
work together to enrich DMSO instead of as three pairs. Also,
it appears that, as long as a sufficient number of cholates is
present to form an enclosed space, the reversed-micelle-like
conformer can be reasonably stable. Cooperativity is also
obvious from the -∆δOH curves (Figure 6b). On the basis of
both OH12 protons located in the center of the baskets and OH3
near the periphery, basket 20 (0 and 9) is better able to enrich
DMSO than control 15 (4 and 2). For the same basket, the
OH12 protons are less sensitive to changes in solvent composi-
tion than OH3. As mentioned previously, this is the same trend
observed for all the baskets synthesized in this paper and is
additional evidence for the cooperativity in DMSO enrichment.
Finally, this contrast between 20 and 15 also suggests that
the changes in the NH/OH chemical shifts are not caused by
J. Org. Chem, Vol. 71, No. 19, 2006 7211

Ryu et al.
30.9, 29.1, 27.8, 26.7, 23.3, 23.1, 17.6, 12.9. MALDI-TOFMS (m/
z): [M + Na]+ calcd for C128H187N4O20Na: 2125.9; found: 2128.6.
Compound 2. Acid 21 (450 mg, 0.854 mmol, see the Supporting
Information for its synthesis), 4a (159 mg, 0.194 mmol), and BOP
(378 mg, 0.854 mmol) were dissolved in anhydrous DMF (10 mL).
DIPEA (220 mg, 1.708 mmol) was added via a syringe. The
reaction mixture was stirred at 50 °C for 20 h and was precipitated
in acetone (100 mL). The precipitate was filtered, washed with
acetone (2 × 10 mL), and purified by preparative TLC (SiO2,
CHCl3/CH3OH ) 4:1) to give a white powder (250.4 mg, 45%
simple intramolecular hydrogen bonding with other NH/OH
protons-otherwise, 20 and 15 would behave the same. Another
piece of evidence against this intramolecular hydrogen-bonding
mechanism is the nearly identical -∆δNH-DMSO% curves of
19 and 5 (Figure 8S, part a). It is difficult to imagine that
intramolecular hydrogen bonds can have the exact same effect
on the δNH/OH of 19, a highly complex molecule, as DMSO in
the bulk has on that of 5, a monomeric cholate incapable of
intramolecular hydrogen bonds (at least for the NH proton).
1
yield). H NMR (DMSO-d6/CCl4 ) 1:1, 300 MHz, δ): 10.04 (s,
4H), 9.77 (s, 4H), 7.79 (d, 8H, J ) 9.0 Hz), 7.59 (d, 8H, J ) 8.4
Hz), 4.32 (s, 8H), 4.11 (s, 4H), 4.00 (d, 4H, J ) 2.1 Hz), 3.80 (m,
8H), 3.60 (m, 4H), 3.15 (m, 8H), 2.30-0.79 (m, 168H), 0.57 (s,
12H). 13C NMR (75 MHz, DMSO-d6/CCl4 ) 1:1, δ): 174.1, 166.6,
153.6, 141.9, 135.2, 132.2, 129.7, 128.4, 121.8, 119. 7, 77.8, 75.7,
73.2, 71.7, 68.3, 47.0, 46.5, 35.4, 34.9, 34.7, 34.2, 32.3, 32.0, 31.27,
31.25, 30.4, 30.1, 28.3, 27.74, 26.5, 26.2, 23.3, 23.0, 22.5, 17.3,
14.1, 12.5. MALDI-TOFMS (m/z): [M + Na]+ calcd for
Conclusion
Multiple cholates attached to a covalent scaffold can readily
aggregate intramolecularly to form unimolecular micelles and
reversed micelles. The micelle-like conformer prefers direct
contact of the hydrophobic â faces of cholates and seems to be
best formed in tight structures. The reversed-micelle-like
conformer is mediated by polar solvent molecules entrapped in
the interior of the molecule and can tolerate significant
modification of structures. Among the two scaffolds investi-
gated, calix[4]arene gives baskets that can better enrich polar
solvents than 1,3,5-2,4,6-hexasubstituted benzene from a mostly
nonpolar solvent mixture. The difference may simply be caused
by the number of arms (four vs three) in the two scaffolds. When
branched spacers are introduced into the latter scaffold to
increase the number of interacting cholates (e.g., basket 20),
an enclosed space for DMSO accommodation can be easily
formed, and the reversed-micelle-like conformer is quite stable.
C176H247N8O24Na: 2881.9; found: 2881.8.
Compound 3. Acid 22 (264.6 mg, 0.536 mmol, see the
Supporting Information for its synthesis), 4a (100.1 mg, 0.122
mmol), and BOP (237.4 mg, 0.536 mmol) were dissolved in
anhydrous DMF (10 mL) in N2. DIPEA (138 mg, 1.072 mmol)
was added via a syringe. The reaction mixture was stirred at 50 °C
for 20 h and was precipitated in acetone (50 mL). The precipitate
was filtered, washed with acetone (2 × 10 mL), and purified by
preparative TLC (SiO2, CHCl3/CH3OH ) 4:1) to give a white
1
powder (120.2 mg, 36% yield). H NMR (DMSO-d6/CCl4 ) 1:1,
300 MHz, δ): 9.45 (s, 4H), 7.76 (s, 4H), 6.89 (d, 8H, J ) 4.0 Hz),
4.32 (m, 8H), 4.09 (s, 4H), 4.00 (s, 4H), 3.75 (s, 8H), 3.57 (s, 4H),
3.14 (m, 8H), 2.99 (m, 12H), 2.24-0.77 (m, 168H), 0.54 (s, 12H).
13C NMR (75 MHz, DMSO-d6/CCl4 ) 1:1, δ): 173.2, 170.8, 152.4,
134.7, 133.8, 120.2, 75.6, 71.7, 71.1, 66.9, 46.8, 46.4, 42.2, 42.0,
38.8, 36.0, 35.9, 35.6, 35.1, 34.3, 33.4, 32.4, 32.4, 31.1, 30.4, 29.2,
28.0, 26.9, 26.2, 26.0, 23.5, 23.3, 23.1, 17.8, 14.6, 13.0. MALDI-
TOFMS (m/z): [M + H]+ calcd for C164H255N8O24: 2723.8;
found: 2725.9.
The calix[4]arene-derived baskets can also tolerate spacers
better than the 1,3,5-2,4,6-hexasubstituted benzene derivatives.
Both rigid 4-aminobenzoyl and flexible 4-aminobutyroyl spacers
afford stable reversed-micelle-like conformers in calix[4]arene-
based baskets. Baskets constructed from the hexasubstituted
benzene, on the other hand, prefer flexible spacers, which seem
to promote more efficient intramolecular aggregation of the
cholates. The R,â-cholate dimer (13) does not seem to be a good
wall material for the basket. Although the bottom cholates
directly attached to the scaffold can be organized by entrapped
polar solvents, the top cholates are quite disordered. This is
probably an entropic effectsas the cholates move farther away
from the scaffold, it is more difficult for solvophobic interactions
to constrain their movements.
Compound 5 and 10-12. See the Supporting Information.
Compound 13. Cholic acid (510 mg, 1.25 mmol), amine 12 (530
mg, 1.25 mmol), and BOP (663 mg, 1.5 mmol) were dissolved in
anhydrous DMF (8 mL). DIPEA (0.70 mL, 4.5 mmol) was added
with a syringe. The reaction mixture was stirred at room temperature
for 9 h. The mixture was concentrated to about 4 mL in vacuo.
The residue was triturated with ice water, filtered, washed with
water twice, and dried by air suction. The crude product was purified
by column chromatography over silica gel using CH2Cl2/MeOH
(20:1) as the eluents to obtain 755 mg of light yellow solid (75%
yield). 1H NMR (400 MHz, CDCl3/CD3OD ) 1:1, δ): 4.05-3.98
(m, 3H), 3.83 (br, 2H), 3.62 (s, CO2CH3, 3H), 3.42-3.85 (br, 1H),
2.58-0.85 (series of m, 60H), 0.65 (br, 6H). 13C NMR (100 MHz,
CD3OD/CDCl3 ) 1:1, δ): 175.3, 174.5, 72.7, 72.6, 71.2, 67.9, 67.8,
51.1, 46.6, 46.0, 45.4, 41.33, 41.26, 39.1, 38.9, 36.8, 35.2, 35.1,
35.0, 34.9, 34.5, 34.3, 33.9, 33.0, 32.9, 31.8, 30.73, 30.67, 29.5,
28.1, 27.8, 27.3, 27.2, 26.1, 25.6, 24.0, 22.9, 22.5, 22.0, 16.6, 12.0.
MALDI-TOFMS (m/z): [M + Na]+ calcd for C49H81NNaO8,
835.17; found, 834.09.
Compound 8. Compound 13 was hydrolyzed by aqueous LiOH
(1 M) in MeOH. The acid obtained (2.10 g, 2.63 mmol) and
N-hydroxysuccinimide (0.364 g, 3.16 mmol) were dissolved in
anhydrous THF (100 mL), and 1,3-dicyclohexylcarbodiimide (DCC,
0.652 g, 3.16 mmol) in anhydrous THF (5 mL) was added. After
24 h under N2, the white precipitate formed was removed by
filtration. The filtrate was concentrated to about 10 mL and
precipitated into CH3CN. A portion of the N-hydroxylsuccimide
ester derivative (158 mg, 0.176 mmol) and 4a (29.0 mg, 0.035
mmol) were dissolved in anhydrous DMF (2 mL). After 32 h at
120 °C under N2, the mixture was precipitated into CH3CN (50
mL). The solid was collected by suction filtration and purified by
Experimental Procedures
General Methods. See the Supporting Information.
Compounds 4a, 4b, and 1a. See the Supporting Information.
Compound 1b. Cholic acid (349.3 mg, 0.855 mmol), 4b (105.0
mg, 0.194 mmol), and benzotriazol-1-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate (BOP, 412.4 mg, 0.931 mmol)
were dissolved in anhydrous DMF (15 mL) in N2. Diisopropyl-
ethylamine (DIPEA, 238.0 mg, 1.707 mmol) was added via a
syringe. The reaction mixture was stirred at 50 °C for 18 h. The
solution was poured into brine (50 mL). The precipitate was filtered,
washed with water (2 × 10 mL) and CH3CN (5 mL), and purified
by preparative TLC (SiO2, CHCl3/CH3OH ) 8:1) to give a white
1
powder (301.9 mg, 0.144 mmol, 74% yield). H NMR (DMSO-
d6/CCl4 ) 1:1, 400 MHz, δ): 9.36 (s, 4H), 7.20 (s, 4H), 6.86 (s,
4H), 4.24 (d, 4H, J ) 11.6 Hz), 4.06 (d, 4H, J ) 4.4 Hz), 3.95 (d,
4H, J ) 4.0 Hz), 3.78 (m, 16H), 3.62 (s, 4H), 3.18 (s, 4H), 3.10
(d, 4H, J ) 12.4 Hz), 2.19-0.75 (m, 124H), 0.61 (s, 12H). 13C
NMR (75 MHz, CD3OD, δ): 171.6, 153.9, 134.2, 134.1, 119.9,
71.5, 70.9, 66.8, 46.7, 46.2, 42.0, 41.8, 35.8, 35.4, 34.9, 33.9, 32.0,
7212 J. Org. Chem., Vol. 71, No. 19, 2006

SolVent-Induced Amphiphilic Molecular Baskets
column chromatography over silica gel using CHCl3/MeOH/Et3N
(20:1:0.1) as the eluent to a light yellow solid (58 mg, 40% yield).
1H NMR (300 MHz, DMSO-d6, δ): 9.38 (br, 4H), 7.44 (br, 4H),
6.90 (br, 4H), 4.32 (m, 8H), 4.05-3.96 (m, 16H), 3.79-3.65(br,
12H), 3.56 (br, 8H), 2.42-0.76 (series of m, 240H), 0.56 (br, 24H).
13C NMR (75 MHz, CDCl3/CD3OD ) 1:1, δ): 174.4, 172.9, 152.7,
134.4, 131.9, 120.8, 75.0, 72.5, 71.1, 67.6, 46.4, 46.0, 45.9, 45.3,
41.2, 39.1, 38.7, 36.7, 35.1, 34.9, 34.7, 34.3, 34.2, 33.9, 32.7, 31.7,
30.5, 29.8, 29.5, 28.0, 27.8, 27.2, 26.0, 25.6, 23.9, 22.8, 22.4, 22.3,
21.9, 16.6, 16.5, 13.4, 11.8. MALDI-TOFMS (m/z): [M + H]+
calcd for C244H385N8O32, 3942.69; found, 3942.97. [M + Na]+ calcd
for C244H384N8NaO32, 3963.69; found, 3961.67.
Compound 15. Compound 24 (277 mg, 1.0 mmol, see the
Supporting Information for its synthesis), N-hydroxysuccinimide
ester of cholic acid (1.20 g, 2.4 mmol, see the Supporting
Information for its synthesis), and DIPEA (0.55 mL, 3.0 mmol)
were dissolved in anhydrous DMF (10 mL). After 12 h at 60 °C
under N2, the mixture was concentrated in vacuo and poured into
CH3CN (25 mL). The solid was collected by suction filtration and
purified by column chromatography over silica gel using CHCl3/
MeOH/H2O (5:1:0.1) as the eluents to give a white solid (0.52 g,
50% yield). 1H NMR (300 MHz, DMSO-d6, δ): 8.38 (t, 2H), 7.68
(s, 2H), 7.34 (s, 1H), 4.30 (d, 2H), 4.25 (s, 4H), 4.09 (d, 2H), 4.00
(d, 2H), 3.81 (s, 3H), 3.75 (s, 2H), 3.58(s, 2H), 3.22-3.09 (m,
2H), 2.30-1.85 (m, 12H), 1.84-1.51 (m, 14H), 1.49-0.70 (m,
34H), 0.53 (s, 6H). 13C NMR (75 MHz, CD3OD, δ): 175.54,
167.01, 140.09, 131.45, 130.69, 127.15, 72.82, 71.70, 67.85, 54.67,
51.57, 46.91, 46.32, 42.45, 42.02, 41.81, 39.94, 39.29, 35.67, 35.34,
35.34, 34.74, 32.97, 32.21, 30.03, 28.43, 27.55, 26.70, 25.13, 23.10,
22.06, 18.18, 16.61, 11.89. MALDI-TOFMS (m/z): [M + Na]+
calcd for C58H90N2NaO10, 998.33; found, 997.82; [M + K]+ calcd
for C58H90N2KO10, 1014.44; found, 1014.06.
Compound 16. Cholic acid triformate (396 mg, 0.804 mmol)
was dissolved in dry CH2Cl2 (20 mL). Oxalyl chloride (0.20 mL,
6.88 mmol) was added via a syringe, followed by two drops of dry
DMF. The mixture was stirred at room temperature under N2 flush
for 1.5 h. Solvents were removed in vacuo. Dry CH2Cl2 (2 × 5
mL) was added and evaporated again in vacuo. The residue was
dissolved in dry CH2Cl2 (30 mL) and was added to a stirred
suspension of amine 14 (61.4 mg, 0.246 mmol) and Et3N (0.2 mL,
1.4 mmol) in anhydrous THF (5 mL). After 1 h at room temperature,
solvents were evaporated in vacuo. The residue was combined with
K2CO3 (1.150 g, 8.3 mmol) and MeOH (30 mL). The mixture was
heated to reflux for 17 h. The solvent was evaporated, and the
residue was purified by column chromatography over silica gel
using CHCl3/MeOH (5:1) to give a white glass (238 mg, 68%). 1H
NMR (300 MHz, CD3OD/CCl4 ) 8:2, δ): 4.40 (s, 6H), 3.92 (br,
3H), 3.79 (br, 3H), 3.40-3.30 (m, 3H), 2.73 (q, 6 H, J ) 7.4 Hz),
2.28-0.88 (m, 99H), 0.70 (s, 9H). 13C NMR (75 MHz, CD3OD/
CCl4 ) 8:2, δ): 174.8, 144.0, 131.8, 72.9, 71.6, 67.9, 55.0, 46.7,
46.4, 41.9, 41.8, 39.8, 39.2, 38.0, 35.7, 35.6, 34.9, 34.8, 33.4, 32.5,
32.0, 30.0, 28.4, 27.7, 26.6, 23.3, 22.9, 22.6, 17.0, 16.0, 12.4.
MALDI-TOFMS (m/z): [M + Na]+ calcd for C87H141N3NaO12,
1444.05; found, 1438.90; [M + K]+ calcd for C87H141KN3O12,
1460.16; found, 1456.04.
DMSO, δ): 172.8, 166.2, 144.4, 142.6, 132.7, 129.1, 129.0, 118.6,
71.7, 71.1, 66.9, 46.8, 46.4, 42.2, 42.1, 36.0, 35.9, 35.6, 35.1, 34.2,
32.1, 31.1, 29.3, 28.0, 26.9, 23.5, 23.3, 17.9, 17.0, 13.1. MALDI-
TOFMS (m/z): [M + Na]+ calcd for C108H156N6NaO15, 1801.42;
found, 1794.39; [M + K]+ calcd for C108H156KN6O15, 1801.42;
found, 1817.52.
Compound 18. Acid 22 (614.1 mg, 1.244 mmol), amine 14 (70.5
mg, 0.283 mmol), and BOP (601.7 mg, 1.358 mmol) were dissolved
in anhydrous DMF (15 mL). DIPEA (323 mg, 2.321 mmol) was
added via a syringe. The reaction mixture was stirred at 50 °C for
20 h. The compound was precipitated in brine (50 mL), filtered,
and washed with water (2 × 10 mL). The residue was purified by
preparative TLC (SiO2, CH3Cl/CH3OH ) 4:1) to give a white
powder (312.3 mg, 0.187 mmol, 66% yield). 1H NMR (DMSO-d6,
400 MHz, δ):? 7.72 (m, 3H), 4.29 (d, 3H, J ) 4.0 Hz), 4.24 (s,
6H), 4.07 (d, 3H, J ) 2.4 Hz), 4.06 (s, 3H), 3.98 (d, 3H, J ) 2.8
Hz), 3.74 (s, 3H), 3.57 (s, 3H), 2.94 (q, 6H, J ) 6.0 Hz), 2.63 (m,
6H), 2.08-0.78 (m, 102H), 0.56 (s, 9H). 13C NMR (75 MHz,
DMSO-d6, δ): 175.55, 173.61, 143.88, 131.64, 72.66, 71.51, 67.66,
48.49, 46.66, 46.12, 41.83, 41.65, 39.66, 39.10, 38.45, 37.52, 35.57,
35.14, 34.55, 32.83, 32.03, 29.83, 28.25, 27.41, 26.51, 25.64, 22.91,
22.61, 21.86, 16.41, 15.29, 11.70. MALDI-TOFMS: calcd. for
C99H161N6O15Na [M + Na]+: 1698.4; found: 1693.0.
Compound 19. A portion of the N,N-hydroxysuccinimide ester
derivative of 13 (573 mg, 0.64 mmol, prepared as in the synthesis
of 8) and amine 14 (50.0 mg, 0.2 mmol) were dissolved in
anhydrous DMF (5 mL); the reaction mixture was stirred at 60 °C
under N2. After 26 h, the mixture was precipitated in CH3CN (50
mL). The solid was collected by suction filtration and purified by
column chromatography over silica gel using CHCl3/MeOH/Et3N
(20:1:0.1) as the eluents (467 mg, 65% yield). 1H NMR (300 MHz,
DMSO-d6, δ): 7.71 (br, 3H), 7.50 (br, 3H), 4.18-4.09 (m, 9H),
4.05-3.98 (m, 12H), 3.83-3.65 (br, 9H), 3.59 (br, 6H), 3.08 (br,
3H), 2.62 (br, 3H), 2.22-1.34 (series of m, 180H), 0.58 (br, 18H).
13C NMR (75 MHz, CD3OD/CDCl3 ) 1;1, δ): 174.40, 174.41,
143.44, 131.13, 72.46, 71.04, 67.53, 60.05, 51.57, 46.36, 45.80,
45.18, 41.13, 38.99, 38.63, 32.66, 32.54, 32.17, 31.67, 31.62, 30.33,
29.38, 27.93, 27.68, 27.09, 25.90, 25.41, 23.82, 22.64, 22.16, 21.76,
19.89, 16.34, 15.35, 13.18, 11.71. MALDI-TOFMS (m/z): [M +
Na]+ calcd for C159H258N6NaO21, 2612.78; found, 2612.03.
Compound 20. Ester 15 was hydrolyzed by aqueous LiOH (1
M) in MeOH. A portion of the solid (234 mg, 0.24 mmol) was
combined with amine 14 (20 mg, 0.08 mmol), BOP (143 mg, 0.314
mmol), and DIPEA (0.07 mL, 0.40 mmol) in DMF (5 mL). After
24 h at 60 °C under N2, the solvent was removed in vacuo, and the
residue was slowly added to CH3CN (15 mL). The solid was
purified by column chromatography over silica gel using CHCl3/
MeOH/Et3N (5:1:0.1) as the eluent to give a white solid (125 mg,
50% yield). 1H NMR (300 MHz, DMSO-d6, δ): 8.29 (t, 9H), 7.60
(s, 6H), 7.18 (s, 3H), 4.52 (s, 6H), 4.32 (d, 6H), 4.20 (s, 12H),
4.09 (d, 6H), 4.00 (d, 6H), 3.75 (s, 6H), 3.58(s, 6H), 3.22-3.09
(m, 6H), 2.30-1.85 (m, 36H), 1.84-1.51 (m, 42H), 1.49-0.70 (m,
102H), 0.54 (s, 18H). 13C NMR (75 MHz, CD3OD, δ): 175.5,
168.6, 144.7, 139.7, 134.7, 131.4, 130.3, 125.6, 124.2, 73.0, 71.7,
69.2, 46.9, 46.6, 46.5, 43.0, 41.8, 39.7, 39.3, 35.7, 34.9, 33.1, 32.0,
30.1, 28.4, 27.7, 26.6, 23.3, 22.5, 17.1, 16.2, 12.4, 8.8. MALDI-
TOFMS (m/z): [M + Na]+ calcd for C186H285N9NaO27, 3102.29;
found, 3102.35.
Compound 17. Acid 21 (204.9 mg, 0.388 mmol), amine 14 (32.2
mg, 0.129 mmol), tetramethyluronium hexafluorophosphate (HBTU,
176.6 mg, 0.466 mmol), and DIPEA (398.6 mg, 3.08 mmol) were
dissolved in dry DMF (4 mL). The mixture was heated at 90 °C
under N2 for 24 h. The mixture was precipitated into CH3CN (50
mL). The solid was collected by suction filtration and was purified
by column chromatography over silica gel using CHCl3/MeOH/
Acknowledgment. Acknowledgment is made to the donors
of Petroleum Research Fund, administered by the American
Chemical Society, and to Iowa State University for support of
this research.
1
H2O (5:1:0.1) to give an off powder (150.3 mg, 65%). H NMR
(400 MHz, d6-DMSO, δ): 10.05 (s, 3H), 8.16 (s, 3H), 7.80 (d,
6H, J ) 8.6 Hz), 7.59 (d, 6H, J ) 8.6 Hz), 4.52 (br, 6H), 4.32 (d,
3H, J ) 4.2 Hz), 4.12 (d, 3H, J ) 3.1 Hz), 4.02 (d, 3H, J ) 3.1
Hz), 3.77 (br, 3H), 3.59 (br, 3H), 3.16 (br, 3H), 2.88-2.71 (br,
6H), 2.41-0.74 (m, 99H), 0.56 (s, 9H). 13C NMR (100 MHz, d6-
Supporting Information Available: General method of the
experiments, synthetic procedures, and figures. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0607663
J. Org. Chem, Vol. 71, No. 19, 2006 7213