Adaptive dendron: A bile acid oligomer behaving as both normal and inverse micellar mimic

Article abstract of DOI:10.1021/ol052631+

The normal and inverse micellar property of a bile-acid-based dendritic structure was established through dye solubilization studies in both polar and nonpolar media.

Full text of DOI:10.1021/ol052631+

ORGANIC
LETTERS
2006
Vol. 8, No. 3
399-402
Adaptive Dendron: A Bile Acid
Oligomer Behaving as Both Normal and
Inverse Micellar Mimic
Sanjib Ghosh and Uday Maitra*,†
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, India
maitra@orgchem.iisc.ernet.in
Received October 29, 2005
ABSTRACT
The normal and inverse micellar property of a bile-acid-based dendritic structure was established through dye solubilization studies in both
polar and nonpolar media.
During the past two decades, dendritic structures and
dendrimers have been utilized in a variety of applications
including host-guest chemistry, catalysis, metaloorganic
chemistry, light harvesting, and drug delivery.1 An important
structural feature of the dendritic architecture is their
resemblance to micellar structures and hence they are often
described as covalently linked micelles.2 Micellar structures,
which can solubilize guest molecules in their core,3 do so
only above the critical micellar concentration (CMC) of the
detergents, and this technique (dye solubilization) has
routinely been used to determine the CMC values. With
dendrimers, the “micellar structures” are maintained at all
concentration ranges and thus the guest solubilization
increases linearly with concentration. Newkome et al. have
described such structures as “unimolecular micelles”.4 De-
pending upon the nature of the interior, they have the ability
to either solubilize5 a polar guest molecule in a relatively
nonpolar solvent or vice versa. Regen et al. have described
a bile-acid-based “molecular umbrella”6 that can change its
conformation as a function of solvent polarity. Also, Kobuke
(4) (a) Newkome, G. R.; Moorefield, C. N.; Baker, G. R.; Saunders, M.
J.; Grossman, S. H. Angew. Chem., Int. Ed. Engl. 1991, 30, 1178. (b) Kim,
Y. H.; Webster, O. W. J. Am. Chem. Soc. 1990, 112, 4592. (c) Stevelmans,
S.; van Hest, J. C. M.; Jansen, J. F. G. A.; van Boxtel, D. A. F. J.; de
Brabander-van den Berg, E. M. M.; Meijer, E. W. J. Am. Chem. Soc. 1996,
118, 7398. (d) Piotti, M. E.; Rivera, F.. Jr.; Bond, R.; Hawker, C. J.; Fre´chet,
J. M. J. J. Am. Chem. Soc. 1999, 121, 9471. (e) Heise, A.; Hedrick, J. L.;
Frank, C. W.; Miller, R. D. J. Am. Chem. Soc. 1999, 121, 8647.
(5) (a) Cooper, A. I.; Londono, J. D.; Wignall, G.; McClain, J. B.;
Samulski, E. T.; Lin, J. S.; Dobrynin, A.; Rubinstein, M.; Burke, A. L. C.;
Fre´chet, J. M. J.; DeSimone, J. M. Nature 1997, 389, 368. (b) Baars, M.
W. P. L.; Froehling, P. E.; Meijer, E. W. Chem. Commun. 1997, 1959. (c)
Kramer, M.; Stumbe, J.-F.; Turk, H.; Krause, S.; Komp, A.; Delineau, L.;
Prokhorova, S.; Kautz, H.; Haag, R. Angew. Chem., Int. Ed. 2002, 41, 4252.
(d) Dykes, G. M.; Brierley, L. J.; Smith, D. K.; McGrail, P. T.; Seeley, G.
J. Chem. Eur. J. 2001, 7, 4730. (e) Sunder, A.; Kramer, M.; Hanselmann,
R.; Mulhaupt, R.; Frey, H. Angew. Chem., Int. Ed. 1999, 38, 3552.
(6) (a) Janout, V.; Lanier, M.; Regen, S. L. J. Am. Chem. Soc. 1996,
118, 1573. (b) Janout, V.; Lanier, M.; Regen, S. L. J. Am. Chem. Soc. 1997,
119, 640. (c) Janout, V.; Zhang, L.-H.; Staina, I. V.; Giorgio, C. D.; Regen,
S. L. J. Am. Chem. Soc. 2001, 123, 5401. (d) Janout, V.; Giorgio, C. D.;
Regen, S. L. J. Am. Chem. Soc. 2000, 122, 2671.
† Also at the Chemical Biology Unit, JNCASR, Bangalore 560012, India.
(1) (a) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A., III Angew. Chem.,
Int. Ed. Engl. 1990, 29, 138. (b) Bosman, A. W.; Janssen, H. M.; Meijer,
E. W. Chem. ReV. 1999, 99, 1665. (c) Archut, A.; Vo¨gtle, F. Chem. Soc.
ReV. 1998, 27, 233. (d) Zeng, F.; Zimmerman, S. C. Chem. ReV. 1997, 97,
1681. (e) Astruc, D.; Chardac, F. Chem. ReV. 2001, 101, 2991. (f) Grayson,
S. M.; Fre´chet, J. M. J. Chem. ReV. 2001, 101, 3819.
(2) Liu, M.; Fre´chet, J. M. J. Polym. Bull. 1999, 43, 379.
(3) (a) Schott, H. J. Phys. Chem. 1966, 70, 2966. (b) Venkatesan, P.;
Cheng, Y.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6955. (c) Vochten, R.;
Joos, P. J. Chim. Phys. Phys.-Chim. Biol. 1970, 67, 1372.
10.1021/ol052631+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/31/2005

Scheme 1
et al. have used an amphiphilic bile acid unit for the
damers”)11 in solvents of different polarities, through different
modes of intramolecular association of the peripheral bile
acid units depending upon the media, enabling them to act
as both intramolecular normal and inverse micelles (Figure
1).12,13 To synthesize the dendritic species, orthogonally
protected bile acid components 5, 6, and 1014 were synthe-
sized. Compound 10 was combined15 with 5 and 6 to get 11
construction of a supramolecular transmembrane ion chan-
nel.7 In this communication we report the synthesis of small
dendritic bile acid oligomer with a remarkable ability to act
as both normal and inverse micelles owing to the facially
amphiphilic nature of the bile acid backbone.
Bile acids are naturally occurring rigid, chiral molecules
with unique facial amphiphilicity.8 A few years ago we
initiated a long-term research program to design bile-acid-
based dendritic structures for a variety of applications. We9
and others10 have reported the synthesis of bile-acid-based
chiral dendritic species. Our earlier work resulted in dendrons
in which the hydroxy groups located on the peripheral bile
acid units were protected as acetates, in which the facial
amphiphilicity was lost. We reasoned that dendritic species
with bile acid fragments bearing free hydroxy groups on the
periphery are likely to adopt different conformations (“fol-
Figure 1. Cartoon representation of possible folding and guest
solubilization ability of an “adaptive dendron” serving as both
micellar and inverse micellar mimics.
(7) (a) Kobuke, Y.; Nagatani, T. J. Org. Chem. 2001, 66, 5094. (b)
Kobuke, Y.; Nagatani, T. Chem. Lett. 2000, 298. (c) Yoshino, N.; Satake,
A.; Kobuke, Y. Angew. Chem., Int. Ed. 2001, 40, 457.
(8) Mukhopadhyay, S.; Maitra, U. Curr. Sci. 2004, 87, 1666.
(9) (a) Balasubramanian, R.; Rao, P.; Maitra, U. Chem. Commun. 1999,
2353. (b) Balasubramanian, R.; Maitra, U. J. Org. Chem. 2001, 66, 3035.
(10) (a) Ropponen, J.; Tamminen, J.; Kolehmainen, E.; Rissanen, K.
Synthesis 2003, 14, 2226. (b) Ropponen, J.; Tamminen, J.; Lahtinen, M.;
Linnanto, J.; Rissanen, K.; Kolehmainen, E. Eur. J. Org. Chem. 2005, 73.
(11) Park, J.-S.; Lee, H.-S.; Lai, J. R.; Kim, B. M.; Gellman, S. H. J.
Am. Chem. Soc. 2003, 125, 8539.
and 12, respectively (Scheme 1). Finally, the protecting
groups were removed by hydrogenolysis, and the dendritic
structures (trimer 116 and tetramer 217) with free peripheral
hydroxyl and carboxyl groups were obtained.
400
Org. Lett., Vol. 8, No. 3, 2006

Figure 2. (A) Concentration dependence of Orange OT extraction from hexane to MeOH/H2O (1:1) after 12 h, r ) 0.996 for 2, 0.991 for
1, and 0.981 for 7. (B) Concentration dependence of solubilization of 14 in chloroform following solid-liquid extraction protocol after 48
h, r ) 0.992 for 2 and 0.874 for 8. (C) Time course study of the transportation of 14 through organic media and release in water, r ) 0.993.
(r indicates coefficient of linearity.)
Preliminary screening revealed that the sodium salts of
both 1 and 2 were able to solubilize Orange OT (13), a
nonpolar dye, in 50% MeOH/H2O. To study their dye
solubization abilities, partitioning of the dye between hex-
ane18 and 50% MeOH/H2O19 was carried out. It was observed
that the sodium salts of the dendritic species (1 and 2) were
able to extract 13 from hexane to 50% MeOH/H2O (Figure
3) and with increasing concentration of the dendritic
component in aqueous layer, the amount of dye extracted
from the organic layer increased linearly (Figure 2A). A
control experiment carried out with an excess of 7 showed
that only a small amount of dye was extracted in comparison
with 1 and 2. This clearly suggests that the amount of dye
extracted from the organic layer does not depend merely on
the number of steroid units present in the aqueous layer but
on the dendritic architecture, where a micellelike organization
develops once the facially amphiphilic units are appropriately
arranged with the polar hydroxyl groups pointing “out-
ward”.20 Thereby these amphiphilic dendrons create a
hydrophobic patch for the accommodation of a apolar dye
in the polar media.21 In the absence of any carrier in the
aqueous layer, no dye extraction was observed (Figure 3).
(12) Zhao et al. have attached cholate fragments on a tetraaminocalixarene
scaffold and have shown by NMR that the cholates can respond to
environmental (polarity) changes by rotation (Ryu, E.-H.; Zhao, Y. Org.
Lett. 2004, 6, 3187). This group has very recently shown phenyl â-D-
glucopyranoside binding with a calixarene tetracholamide derivative in a
CCl4/MeOH mixture and pyrene binding with a modified cholamide
calixarene derivative in water (Zhao, Y.; Ryu, E.-H. J. Org. Chem. 2005,
70, 7585).
Figure 3. Orange OT partitioning experiment in hexane equili-
brated with MeOH/H2O (1:1) after 12 h. Vial 1 has no additive,
vials 2 and 3 have NaDC 7 (48 mM) and tetramer 2 (12 mM),
respectively.
(13) Extensive study of hydrophilic dye solubilization by bile-acid-based
dendrons having glycolate spacer have been performed by our group. See:
J. Org. Chem. 2006, 71, posted ASAP (jo052173i).
(14) Burk, R. M.; Gac, T. S.; Roof, M. B. Tetrahedron Lett. 1994, 35,
8111.
These results prompted us to examine the solubilization
ability of a polar dye in a nonpolar media with dendrons 1
and 2. It was observed that only 2 was able to solubilize the
sodium salt of cresol red (14) in chloroform.22 With an
increase in the concentration of the dendron, the amount of
(15) Oppenauer, R. V. Monatsch 1966, 97, 62.
1
(16) Selected data for 1. H NMR (300 MHz, CDCl3, Me4Si): δH 5.12
(s, 1H, 12-â H), 4.70 (s, 1H, 3-â H), 4.15 (s, 2H, 12-â H’s), 3.62 (m, 1H,
3-â H), 3.47 (m, 1H, 3-â H), 2.61-0.67 (m). MALDI-TOF: calcd for
C72H116O10 1140.85, found 1163.1 (M + Na+ 1163.8). Anal. Calcd for
C72H116O10 0‚3H2O: C, 72.32; H, 10.28. Found: C, 72.08; H, 10.32. [R]25
(20) Maitra, U.; Mukhopadhyay, S.; Sarkar, A.; Rao, P.; Indi, S. S.
Angew. Chem., Int. Ed. 2001, 40, 2281.
(21) As a result of the solubilizing effect of MeOH, dendrons 1 and 2
are less likely to form aggregate in a MeOH/H2O (1:1) system at low
concentrations
(22) This dye solubilization was not due to an acid-base type of
interaction because 1, having a similar functional group, did not show dye
extraction. Possibly the tripodal geometry of 2 assisted dye encapsulation
better with additional functional groups. Compound 1, on the other hand,
has a tweezerlike geometry with fewer polar groups inside the cleft.
D
+69.0 (c 2.0, CHCl3).
1
(17) Selected data for 2. H NMR (300 MHz, CDCl3, Me4Si): δH 5.08
(s, 1H, 12-â H), 4.91 (s, 1H, 7-â H), 4.57 (m, 1H, 3-â H), 4.06 (s, 1H,
12-â H), 4.03 (s, 1H, 12-â H), 3.99 (s, 1H, 12-â H), 3.61 (m, 3H, 3-â H’s),
2.37-0.65 (m). MALDI-TOF: calcd for C96H154O14 1531.13, found 1555.7
(M + Na+ 1554.1). Anal. Calcd for C96H154O14 0‚6H2O: C, 70.29; H, 10.20;
Found: C, 70.19; H, 9.85. [R]25 +45.0 (c 2.0, CHCl3).
D
(18) Dendrons 1 and 2 were not soluble in hexane.
(19) Sodium salts of dendrons 1 and 2 were not soluble in pure water.
Org. Lett., Vol. 8, No. 3, 2006
401

dye solubilized was again found to increase linearly (Figure
2B). A control experiment carried out with an excess of 8
showed only a small amount of dye extraction.23 In a
nonpolar solvent such as chloroform, 2 must adopt a different
conformation where the polar hydroxyl groups point “in-
ward” to accommodate a polar guest inside. The unique
feature of 2 is that depending upon solvent polarity it can
adopt different conformations and is thus able to act as both
normal and inverse micelle mimics.24
experiment carried out with an excess of 8 showed a
negligible amount of transportation.
In conclusion, dendron 2 shows a remarkable ability of
solubilizing both a polar dye in a nonpolar medium and a
nonpolar dye in a predominantly aqueous medium, which is
very rare.25 Also this dendritic structure has an ability to
transport and release a dye. As these dendrons are constructed
exclusiVely from biocompatible bile acids, they are attractive
motifs for drug delivery/release studies.
To investigate the dye release in an aqueous system, a
transport experiment in a U-tube (18.6 ( 0.3 °C) was carried
out. Compound 14 dissolved in water (8.33 mM, pH 8.2)
was found to be transported from one arm of the U-tube to
another arm through a chloroform layer containing 2 (1.37
mM). A time course study (Figure 2C) revealed that with
time the amount of released dye increased linearly. A control
Acknowledgment. We thank DST, New Delhi for
financial support (grant no. SR/S1/OC-11/2004).
Supporting Information Available: Synthetic details and
experimental procedures for dye solubilization, extraction and
transport. This material is available free of charge via the
Internet at http://pubs.acs.org.
(23) This observation is very similar to what was observed in the case
of Orange OT extraction (Figure 2A). In a nonpolar solvent, a small portion
of methyl deoxycholate possibly aggregates to form an inverse micelle type
of structure.
OL052631+
(25) (a) Vutukuri, D. R.; Basu, S.; Thayumanavan, S. J. Am. Chem. Soc.
2004, 126, 15636. (b) Basu, S.; Vutukuri, D. R.; Thayumanavan, S. J. Am.
Chem. Soc. 2004, 126, 9890.
(24) 1H NMR spectra of 1 and 2 did not change with change in
concentration, suggesting that self-aggregation was negligible.
402
Org. Lett., Vol. 8, No. 3, 2006