Design and synthesis of novel chiral dendritic species derived from bile acids

Article abstract of DOI:10.1021/jo0013305

Bile acids have been used for the first time as the building block for the construction of dendritic units. Orthogonally functionalized 7-deoxycholic and cholic acid derivatives were synthesized. The construction of a bile acid heptamer, a nonamer, and a decamer using the convergent strategy are described in detail. Chromatographic, spectral, and optical properties of these molecules have been investigated. Molecular modeling suggests that these molecules have globular shapes with nanometric dimensions.

Full text of DOI:10.1021/jo0013305

J . Org. Chem. 2001, 66, 3035-3040
3035
Design a n d Syn th esis of Novel Ch ir a l Den d r itic Sp ecies Der ived
fr om Bile Acid s
R. Balasubramanian and Uday Maitra*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
maitra@orgchem.iisc.ernet.in
Received September 6, 2000
Bile acids have been used for the first time as the building block for the construction of dendritic
units. Orthogonally functionalized 7-deoxycholic and cholic acid derivatives were synthesized. The
construction of a bile acid heptamer, a nonamer, and a decamer using the convergent strategy are
described in detail. Chromatographic, spectral, and optical properties of these molecules have been
investigated. Molecular modeling suggests that these molecules have globular shapes with
nanometric dimensions.
Ba ck gr ou n d a n d Design
leading to applications in separation, catalysis, and
sensor technology. Additionally, studies on the optical
activity of chiral dendritic species have been of immense
interest because of a search toward chiral secondary
structures. As a dendrimer possesses three distinct
regions, viz. the core, the branching units, and the end
groups, the incorporation of chirality in these species can
in general be achieved by choosing a chiral core or chiral
branching units, by capping the end groups with a chiral
moiety or by a combination of the aforementioned pa-
rameters. The findings of Newkome (capping the en d
gr ou p s with amino acids),10 Seebach [using chiral tris-
(hydroxymethyl)methane derivatives as the cor e],11 Chow
(D- and L-tartaric acid derived br a n ch in g u n its),12
Meijer [amino acid terminated poly(propylene imine)
dendrimers],13 and McGrath (information that the con-
formation of the chiral dendrimers can be obtained using
small molecules as model compounds)14 led to a signifi-
cant understanding on this subject.
Ever since their first appearance in the literature,1 the
chemistry of dendrimers has grown enormously.2 In
recent years, there has been a shift in the direction of
research from the synthetic aspects of macromolecular
construction to functional dendritic species.3 Dendrimer
chemistry has been blended with several contemporary
themes such as host-guest chemistry,4 metalloorganic
chemistry,5 luminescent materials,6 catalysis,7 medicinal
chemistry,2d and polymers.8 Chiral dendritic species
appeared in the chemical literature shortly after the first
achiral version was reported.9 These molecules received
increased attention during the past decade due to their
potential applications in enantioselective clathration,
* To whom correspondence should be addressed. Telefax: +91-80-
360-1968/360-0529.
(1) Buhleier, E.; Wehner, W.; Vo¨gtle, F. Synthesis 1978, 155.
(2) (a) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A., III. Angew.
Chem., Int. Ed. Engl. 1990, 29, 138. (b) Tomalia, D. A.; Durst, H. D.
Top. Curr. Chem. 1993, 165, 193. (c) Newkome, G. R.; Moorefield, C.
N. Dendrimers. In Comprehensive Supramolecular Chemistry; Atwood,
J . L., Davies, J . E. D., MacNicol, D. D., Vo¨gtle, F., Lehn, J .-M., Eds.;
Pergamon: Tarrytown, NY, 1996; Vol. 10, p 771. (d) Bosman, A. W.;
J anssen, H. M.; Meijer, E. W. Chem. Rev. 1999, 99, 1665.
(3) (a) Issenberner, J .; Moors, R.; Vo¨gtle, F. Angew. Chem., Int. Ed.
Engl. 1994, 33, 2413. (b) Smith, D. K.; Diederich, F. Chem. Eur. J .
1998, 4, 1353. (c) Archut, A.; Vo¨gtle, F. Chem. Soc. Rev. 1998, 27, 233.
(d) Chow, H.-F.; Mong, T. K-K.; Nongrum, M. F.; Wan, C.-W.
Tetrahedron 1998, 54, 8543. (e) Fischer, M.; Vo¨gtle, F. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 884.
(4) (a) Zeng, F.; Zimmerman, S. C. Chem. Rev. 1997, 97, 1681. (b)
Narayanan, V. V.; Newkome, G. R. Top. Curr. Chem. 1998, 197, 20.
(c) Emrick, T.; Fre´chet, J . M. J . Curr. Opin. Colloid Interface Sci. 1999,
4, 15.
(5) Huck, W. T. S.; Prins, L. J .; Fokkens, R. H.; Nibbering, N. M.
M.; van Veggal, F. C. J . M.; Reinhoudt, D. N. J . Am. Chem. Soc. 1998,
120, 6240. For a review of metallodendrimers, see: Newkome, G. R.;
He, E.; Moorefield, C. N. Chem. Rev. 1999, 99, 1689.
(6) (a) Balzani, V.; Campagna, S.; Denti, G.; J uris, A.; Serroni, S.;
Venturi, M. Acc. Chem. Res. 1998, 31, 26. (b) Venturi, M.; Serroni, S.;
J uris, A.; Campagna, S.; Balzani, V. Top. Curr. Chem. 1998, 197, 193.
(7) Knapen, J . W. J .; van der Made, A. W.; de Wilde, J . C.; van
Leeuwen, P. W. N. M.; Wijkens, P.; Grove, D. M.; van Koten, G. Nature
1994, 372, 659.
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A. D.; Rabe, J . P. Angew. Chem., Int. Ed. Engl. 2000, 39, 864.
(9) (a) Peerlings, H. W. I.; Meijer, E. W. Chem. Eur. J . 1997, 3, 1563.
(b) Thomas, C. W.; Tor, Y. Chirality 1998, 10(1/2), 53. (c) Seebach, D.;
Rheiner, P. B.; Greiveldinger, G.; Butz, T.; Sellner, H. Top. Curr. Chem.
1998, 197, 125. (d) Chow, H.-F.; Mong, T. K-K.; Wan, C.-W.; Wang,
Z.-Y. Chiral Dendrimers. In Advances in Dendritic Macromolecules;
J AI Press, Inc: Greenwich, CT, 1999; Vol. 4, p 107.
Among the naturally available chiral species, amino
acids,15 nucleic acids,16 sugars,17 and tartaric acid12 have
already been exploited in dendritic chemistry. Bile acids
(1-3, Chart 1), forming another class of chiral molecules,
have been extensively used in many facets of chemistry18
(10) Newkome, G. R.; Lin, X.; Weis, C. D. Tetrahedron: Asymmetry
1991, 2, 957.
(11) (a) Seebach, D.; Lapierre, J .-M.; Skobridis, K.; Greiveldinger,
G. Angew. Chem., Int. Ed. Engl. 1994, 33, 440. (b) Murer, P.; Seebach,
D. Angew. Chem., Int. Ed. Engl. 1995, 34, 2116. (c) Murer, P.; Seebach,
D. Helv. Chim. Acta 1998, 81, 603.
(12) (a) Chow, H.-F.; Mak, C. C. Pure Appl. Chem. 1997, 69, 483.
(b) Chow, H.-F.; Mak, C. C. J . Chem. Soc., Perkin Trans. 1 1994, 2223.
(13) (a) den Bradander-van den Berg, E. M. M.; Meijer, E. W. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1308. (b) J ansen, J . F. G. A.; den
Brabander-van der Berg, E. M. M.; Meijer, E. W. Science 1994, 266,
1226. (c) J ansen, J . F. G. A.; Peerlings, H. W. I.; de Brabander-Van
den Berg, E. M. M.; Meijer, E. W. Angew. Chem., Int. Ed. Engl. 1995,
34, 1206.
(14) McElhanon, J . R.; McGrath, D.V. J . Am. Chem. Soc. 1998, 120,
1647.
(15) Denkewalter, R. G.; Kolc, J . F.; Lukasavage, W. J . U.S. Pat.
4,410,688, 1979.
(16) Hudson, R. H. E.; Damha, M. J . J . Am. Chem. Soc. 1993, 115,
2119.
(17) (a) For reviews, see: J ayaraman, N.; Nepogodiev, S. A.; Stod-
dart, J . F. Chem. Eur. J . 1997, 3, 1193. Roy, R. Curr. Opin. Struct.
Biol. 1996, 6, 692. (b) Llinares, M.; Roy, R. Chem. Commun. 1997,
2119. (c) Aoi, K.; Itoh, K.; Okada, M. Macromolecules 1995, 28, 5391.
(18) Maitra, U. Curr. Sci. 1996, 71, 617.
10.1021/jo0013305 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/05/2001

3036 J . Org. Chem., Vol. 66, No. 9, 2001
Balasubramanian and Maitra
Ch a r t 1
such as asymmetric synthesis,19 molecular recognition,20
drug delivery systems,21 and linear polymer chemistry,22
and as cationic facial amphiphiles.23 Several features of
bile acids make them attractive chiral building blocks.
The chemistry involved in constructing dendritic species
from these genuine AB2 (deoxycholic acid) and AB3 (cholic
acid) building blocks is straightforward, unlike with
many other building blocks24 in which functional group
modifications are needed. These naturally occurring
group of chiral amphifacial molecules are known to form
helical aggregates.25 Therefore, we felt that it would be
quite interesting to examine the possible existence of
helical conformations in bile acid derived dendritic
structures. The bio-compatible nature of these chiral
dendrons could also be exploited for other applications.26
We recently communicated the synthesis of a heptamer
and a nonamer derived from bile acid units.27 In this
paper, we disclose the full details of the work including
the synthesis of a bile acid based decamer (Figure 1) and
some properties of these molecules.
F igu r e 1. Bile acid decamer.
Ch a r t 2
Resu lts a n d Discu ssion
Syn th esis. Of the two general methods available for
the construction of dendrimers (the “divergent strategy”
developed independently by Tomalia and Newkome28 and
the “convergent strategy”29 of Fre´chet), we chose the
convergent method. Orthogonal protection of bile acids
(2 and 3) with acetate and 1-naphthylmethyl groups30
generated compounds 4-7 (Chart 2). All the esterification
reactions were carried out by the Oppenauer protocol.31
The carboxylic acid was converted to the corresponding
acid chloride and reacted with the polyol in the presence
of CaH2 and PhCH2Et3N+Cl- in refluxing toluene. Trimer
10 was obtained from 4 and 5 in 67% yield and was
deprotected by hydrogenolysis to yield trimer-COOH, 11.
Compound 11 on reaction with 5 generated heptamer 12
(2 × 3 + 1) in 74% yield, which was deprotected to afford
heptamer-COOH 13 (Scheme 1). The reaction between
11 and 7 also proceeded smoothly to generate the
decamer (3 × 3 + 1) 8 in 72% yield, which was subse-
quently converted to 9. In an analogous manner, 6 and
7 afforded tetramer 14 which was converted to tetramer-
COOH, 15. Nonamer 16 (2 × 4 + 1) was obtained upon
the reaction of 15 with 5, which subsequently afforded
nonamer-COOH 17 (Scheme 2). All the dendrons were
characterized by IR, 1H and 13C NMR, UV, MALDI-TOF
MS,32 and, wherever possible, HPLC and elemental
analysis.
(19) Bandyopadhyaya, A. K.; Sangeetha, N. M., Maitra, U. J . Org.
Chem. 2000, 65, 8239-8244.
(20) (a) Maitra, U.; D’Souza, L. J . J . Chem. Soc., Chem. Commun.
1994, 2793. (b) Potluri, V. K.; Maitra, U. J . Org. Chem. 2000, 65, 7764-
7769.
(21) Wess, G.; Kramer, W.; Schubert, G.; Enhsen, A.; Baringhaus,
K.-H.; Glomobik, H.; Mullner, S.; Bock, K.; Kleine, H.; J ohn, M.;
Neckermann, G.; Hoffmann, A. Tetrahedron Lett. 1993, 34, 819.
(22) Zhang, Y. H.; Akram, M.; Liu, H. Y.; Xhu, X. X. Macromol.
Chem. Phys. 1998, 199, 1399-1404.
(23) Walker, S.; Sofia, M. J .; Kakarla, R.; Kogan, N. A.; Wierichs,
L.; Longley, C. B.; Bruker, K.; Axelrod, H. R.; Midha, S.; Babu, S.;
Kahne, D. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 1585.
(24) For example, Sadalapure, K.; Lindhorst, T. K. Angew. Chem.,
Int. Ed. Engl. 2000, 39, 2010.
(25) (a) Rich, A.; Blow, D. M. Nature 1958, 182, 423. (b) Ra-
manathan, N.; Curie, A. L.; Colvin, J . R. Nature 1961, 190, 779.
(26) Choi, J . S.; J oo, D. K.; Kim, C. H.; Kim, K.; Park, J . S. J . Am.
Chem. Soc. 2000, 122, 474.
(27) Balasubramanian, R.; Rao, P.; Maitra, U. Chem. Commun.
1999, 2353.
(28) (a) Tomalia, D. A. Polymer J . 1985, 17, 117. (b) Newkome, G.
R.; Yao, Z.; Baker, G. R.; Gupta, V. K. J . Org. Chem. 1985, 50, 2003.
(29) Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1990, 112,
7638.
(30) The 1-naphthylmethyl group was employed for easier identi-
fication of the dendrons in the purification steps, and also in the HPLC,
UV, and NMR analysis.
HP LC, UV, a n d NMR An a lysis. The compounds
containing the naphthylmethyl group were examined by
reversed-phase HPLC, which provided information about
their purity. The order of elution (increasing retention
(32) MALDI-TOF MS measurements were carried out on a KRATOS
KOMPACT MALDI 4, with a pulsed nitrogen laser (337 nm, 3 ns pulse
width) and a continuous or pulsed extraction ion source control. All
spectra were obtained in positive ion mode with an accelerating voltage
of 20KV and linear geometry. The matrix composed of 3,5-dimethoxy-
4-hydroxycinnamic acid in 1: 1 acetone/H2O with 0.1% TFA.
(31) Oppenauer, R. V. Monatsch 1966, 97, 62.

Chiral Dendritic Species Derived from Bile Acids
J . Org. Chem., Vol. 66, No. 9, 2001 3037
Sch em e 1
F igu r e 2. Plot of molar rotation vs molecular weight of
dendrons.
suggested the absence of â hydrogens attached to unes-
terified OH groups.33
Ch ir op tica l P r op er ties. The molar specific rotation
values (in chloroform) showed a roughly linear relation-
ship with the number of bile acid units in each dendron
(or its molecular weight, Figure 2), thereby suggesting
the absence of any chiral conformation. This was also
supported by the lack of CD in THF solutions of most of
the dendrons, except decamers 8 and 9, which showed a
weak CD (data not shown). This suggests that higher
oligomers (beyond the decamer) might show well-defined
secondary structures.
Sch em e 2
Molecu la r Mod elin g. Insight II optimization (version
2.3.5, CVFF force field) of the dendrons was carried out
to get information about their dimensions. Modeling
shows that these molecules have dimensions of the order
of 2.6-5.2 nm. The structures obtained by Insight II
appear to be compact/globular. One of the possible
conformations of the decamer skeleton is shown in Figure
3.
Con clu sion
This work demonstrates the first utilization of large
bile acid units in dendrimer chemistry. Because of the
size of the building blocks, it is possible to achieve
significant differential gain in dendron dimensions with
additional repeating units. These molecules showed a
linear relationship between molar specific rotation of
dendrons and the number of bile acid units (or their
molecular weights), in line with observations made by
others. Compounds 9, 11, 13, 15 and 17 provide a free
carboxylic acid group which can easily be utilized for
further transformation into bigger macromolecules. The
design and synthesis of functional dendrimers from these
dendrons is in progress in our laboratory, and will be
reported in due course.
time) on a C-18 column was found to be 14 < 16 < 10<
12 < 8. Thin layer chromatographic analysis on silica
gel did not show a directly reversed order: the Rf values
increased in the order 16 < 14 < 8 < 12 < 10 (EtOAc/
hexanes, 2:3 v/v).
Exp er im en ta l Section
The naphthylmethyl group served as a UV marker, and
the quantitative UV spectral analysis of these dendrons
gave an independent measurement of their approximate
molecular weights, which were found to be in reasonable
agreement (typically within (10%) with the calculated
molecular weights.
Gen er a l Rem a r k s. Standard protocols were followed for
the purification of solvents and reagents. For other details,
see ref 19.
(33) Peaks arising out of the same type of â hydrogens generally
coalesced into a single peak. In many cases we observed two sets of 3â
and 12â hydrogens, in the ratio of 1:n for an (n + 1)-mer, whereas the
7â hydrogens were never split. The smaller peak (1 H) in the case of
12â was always shifted upfield, whereas for 3â hydrogens it shifted
both upfield and downfield with respect to the more intense peak. The
acetate signals also showed splitting. The ratio of 12 protons (from
OAc) from the trimer showed that the signals were split in the ratio
3;3;6. Even with higher oligomers splitting was observed. The char-
acteristic angular methyl region became too complex with higher
oligomers and little information could be obtained.
The methylene hydrogens of the naphthylmethyl group
1
also served as a label in H NMR of these compounds. In
all the spectra the integration for the methylene unit was
set to 2 and by comparison of other integrations informa-
tion about the number of bile acid units present was
obtained. The absence of signals in the 3-4 ppm region

3038 J . Org. Chem., Vol. 66, No. 9, 2001
Balasubramanian and Maitra
F igu r e 3. Representative structure of decamer 9.
3r,12r-Dia cetyloxy-5â-ch ola n ic a cid , 4. To an ice-cooled
suspension of 2 (4.15 g, 10.57 mmol) in Ac2O (23 mL, 243
mmol) were added Et3N (23 mL, 166 mmol) and DMAP (4-
(dimethylamino)pyridine, 0.080 g, 0.654 mmol) and the mix-
ture stirred at room temperature for a period of 23 h. The
reaction mixture was poured into water (100 mL) and ex-
tracted with EtOAc (2 × 80 mL). The organic layer was washed
with 1 M HCl (100 mL) and water (100 mL). The crude product
obtained after evaporating the solvent was chromatographed
on silica gel using 15-30% EtOAc/hexanes to yield 4.64 g (92%
yield) of a white solid.
71.59, 64.33, 48.07, 47.14, 46.35, 41.98, 36.30, 35.90, 35.17,
35.03, 34.02, 33.47, 31.31, 30.82, 30.30, 28.50, 27.36, 27.06,
26.04, 23.58, 23.05, 17.12, 12.56.
UV (THF, 263 µM), λ(log ꢀ)): 292.3 (3.71), 288.2 (3.70), 281.5
(3.88), 271.6 (3.80), 228.4 (4.01).
LRMS: 532 (<10%) (M+).
1-Na p h th ylm eth yl 3r,7r,12r-Tr ih yd r oxy-5â-ch ola n -24-
oa te, 7. In an analogous manner 3 (1.24 g, 3.03 mmol) yielded
1.23 g (77%) of a white solid.
IR (film, cm-1): 3360 (b), 2920, 2860, 1720, 1510, 1450, 1370,
1300, 1220, 1160, 1080, 1040, 980, 950, 910, 860, 790, 750,
660.
IR (film, cm-1): 2940, 2860, 1730, 1700, 1460, 1450, 1380,
1360, 1240, 1190, 1150, 1030, 970, 750.
1H NMR (CDCl3, 300 MHz) δ: 8.02 (d, 1 H, J ) 8.1 Hz),
7.90-7.84 (m, 2 H), 7.59-7.43 (m, 4 H), 5.58 (s, 2 H), 3.93 (s,
1 H), 3.84 (s, 1 H), 3.45 (m, 1 H), 2.42 (m, 1 H), 2.30 (m, 1 H),
1.99-1.00 (m), 0.94 (d, 3 H, J ) 6 Hz), 0.88 (s, 3 H), 0.61 (s, 3
H)
1H NMR (CDCl3, 300 MHz) δ: 5.09 (s, 1 H), 4.70 (s, 1 H),
2.36 (m, 1 H), 2.25 (m, 1 H), 2.11 (s, 3 H), 2.04 (s, 3 H), 1.84-
0.98 (m), 0.91 (s, 3 H), 0.82 (d, 3 H, J ) 6.3 Hz), 0.73 (s, 3 H).
3r,7r,12r-Tr ia cetyloxy-5â-ch ola n ic Acid , 6. In an analo-
gous manner, 3 (2.64 g, 6.48 mmol) yielded 1.68 g of the title
compound (48% yield).
13C NMR (CDCl3, 22.5 MHz) δ: 173.97, 133.56, 131.39,
129.01, 128.47, 127.17, 126.30, 125.65, 125.00, 123.37, 72.77,
71.58, 68.12, 64.11, 46.77, 46.12, 41.35, 39.19, 34.96, 34.53,
31.17, 27.27, 26.08, 22.18, 17.08, 12.21.
IR (film, cm-1): 2960, 2860, 1720, 1700, 1470, 1440, 1380,
1360, 1240, 1150, 1020, 950, 890, 750.
1H NMR (CDCl3, 300 MHz) δ: 5.09 (s, 1 H), 4.91 (s, 1 H),
4.58 (m, 1 H), 2.39 (m, 1 H), 2.27 (m, 1 H), 2.14 (s, 3 H), 2.09
(s, 3 H), 2.05 (s, 3 H), 2.00-0.96 (m), 0.92 (s, 3 H), 0.83 (d, 3
H, J ) 6.3 Hz), 0.74 (s, 3 H).
UV (THF, 104 µM), λ(log ꢀ)): 292.3 (3.73), 288.1 (3.73), 281.4
(3.90), 271.5 (3.82), 228.1 (4.26).
LRMS: 548 (<10%) (M+).
Tr im er (OAc, COOCH2Np ), 10. To a suspension/solution
of 4 (0.752 g, 1.57 mmol) in toluene (4 mL) was added oxalyl
chloride (0.7 mL), and the mixture was stirred in the presence
of 10 µL of DMF for 25 min. Volatiles were removed under
reduced pressure, and the residue was dried under vacuum
for 35 min. To 5 (0.259 g, 0.486 mmol) dissolved in toluene
(1.5 mL) were added CaH2 (0.430 g, 10.2 mmol) and BnNEt3-
Cl (0.030 g, 0.132 mmol). To this suspension was added the
acid chloride dissolved in toluene (4.5 mL), and the mixture
was refluxed for 2 days. The reaction mixture was filtered
through Celite, and volatiles were removed. To the residue
dissolved in EtOAc (10 mL) were added Et3N (0.3 mL) and
water (0.3 mL), and the mixture was stirred for 1.5 h. This
solution was diluted with EtOAc (60 mL) and washed with
water (3 × 40 mL). The evaporation of the organic layer yielded
the crude product which was chromatographed on silica gel
(28 × 1.1) with 15% EtOAc/hexanes to yield 0.475 g (67%) of
a white solid.
1-Naph th ylm eth yl 3r,12r-Dih ydr oxy-5â-ch olan -24-oate,
5. To a solution of 2 (2.58 g, 6.58 mmol) in DMF (3 mL) were
added DBU (1,8-diazabicyclo[5.4.0]undec-7-ene,1.2 mL, 8.03
mmol) and 1-naphthylmethyl chloride (1.0 mL, 6.80 mmol),
and the mixture was stirred at 55 °C for 24 h. The reaction
mixture was poured in water (100 mL) and extracted with
EtOAc (2 × 75 mL). The organic layer was washed with 150
mL each of water, 1 M HCl, water, and brine. The crude
material obtained after removal of the solvent was column
chromatographed on silica gel (18 × 1.6) using 40% EtOAc/
CHCl3 to yield 2.78 g (79%) of the title compound.
IR (film, cm-1): 3400(b), 2940, 2880, 1740, 1450, 1380, 1180,
1050, 800, 760.
1H NMR (CDCl3, 300 MHz) δ: 8.02 (d, 1 H, J ) 7.2 Hz),
7.90-7.84 (m, 2 H), 7.58-7.43 (m, 4 H), 5.58 (s, 2 H), 3.93 (s,
1 H), 3.61 (m, 1 H), 2.39 (m, 1 H), 2.27 (m, 1 H), 1.86-0.99
(m), 0.93 (d, 3 H, J ) 8.4 Hz), 0.90 (s, 3 H), 0.60 (s, 3 H).
13C NMR (CDCl3, 75 MHz) δ: 174.10, 133.65, 131.56, 131.51,
129.16, 128.63, 127.41,126.45, 125.85, 125.19, 123.51, 72.99,
IR (film, cm-1): 2920, 2860, 1720, 1440, 1370, 1240, 1150,
1080, 1020, 750.

Chiral Dendritic Species Derived from Bile Acids
J . Org. Chem., Vol. 66, No. 9, 2001 3039
1H NMR (CDCl3, 300 MHz) δ: 8.01 (d, 1 H, J ) 7.8 Hz),
7.91-7.84 (m, 2 H), 7.56-7.43 (m, 4 H), 5.58 (s, 2 H), 5.08,
5.04 (s, s, 3 H), 4.70 (m, 3 H), 2.30-2.18 (m), 2.10, 2.09, 2.04
(singlets, OAc protons), 1.84-0.98 (m), 0.92-0.65 (m, angular
methyl groups).
IR (film, cm-1): 3440(b), 2960, 2880, 1740, 1640, 1450, 1380,
1250, 1180, 1100, 1030, 760.
1H NMR (CDCl3, 300 MHz) δ: 5.08 (s, 7 H), 4.70 (m, 7 H),
2.28 (m), 2.114, 2.108, 2.03 (singlets, OAc protons), 1.80-0.94
(m), 0.91-0.73 (angular methyl groups).
13C NMR (CDCl3, 75 MHz) δ: 173.90, 173.54, 173.31, 170.53,
170.40, 170.32, 133.70, 131.52, 129.24, 128.69, 127.45, 126.50,
125.91, 125.25, 123.52, 75.86, 74.16, 64.40, 49.39, 47.83, 47.65,
45.01, 41.77, 35.64, 34.68, 34.36, 34.01, 32.23, 31.73, 31.52,
31.26, 30.89, 27.31, 26.87, 26.61, 25.86, 25.62, 23.41, 23.05,
21.44, 21.37, 17.49, 17.43, 12.49, 12.43. 12.31.
UV (THF, 81.4 µM), λ(log ꢀ)): 292.3 (3.74), 281.5 (3.92), 271.7
(3.84), 228.0 (4.36).
13C NMR (CDCl3, 75 MHz) δ: 173.56, 173.44, 173.32, 170.62,
170.55, 77.72, 77.69, 77.64, 77.21, 77.16, 76.85, 76.82, 75.96,
75.91, 75.87, 75.82, 75.66, 74.18, 73.93, 49.56, 49.51, 49.40,
47.85, 47.79, 47.74, 45.09, 45.02, 41.79, 41.72, 35.67, 34.86,
34.77, 34.70, 34.64, 34.61, 34.55, 34.44, 34.38, 34.18, 34.12,
34.02, 32.31, 32.24, 31.76, 31.62, 31.56, 31.53, 31.10, 31.07,
31.04, 30.98, 30.90, 30.86, 30.76, 27.50, 27.42, 27.37, 27.31,
26.86, 26.75, 26.61, 25.87, 25.78, 25.63, 23.46, 23.05, 21.43,
21.38, 17.59, 17.50, 17.47, 12.53, 12.44.
HPLC: tR ) 17.1 min (15% THF/MeOH, λ ) 280).
MALDI-TOF MS: 1474.2 (M + Na+, 1473.0), 1490.2 (M +
K+, 1489.1).
MALDI-TOF MS: 3000.7 (M + Na+ 2999.2), 3017.1 (M +
K+ 3015.3).
Anal. Calcd for C184H284O30: C, 74.26; H, 9.62. Found: C,
73.83; H, 9.67.
Anal. Calcd for C91H132O14: C, 75.37; H, 9.18. Found: C,
75.05; H, 9.38.
[R]25 (c 0.87, CHCl3): 96.6.
[R]25 (c 1.5, CHCl3): 86.6.
D
D
Deca m er (OAc, COOCH2Np ), 8. In an analogous manner,
11 (0.533 g, 0.406 mmol) and 7 (0.048 g, 0.088 mmol) yielded
280 mg (72%) of the title compound.
Tr im er (OAc, COOH), 11. To a solution of 10 (0.276 g,
0.190 mmol) in EtOAc (4 mL) under H2 atmosphere was added
10% Pd/C (0.077 g, 0.0729 mmol), and the mixture was stirred
under H2 atmosphere for 42 h. The reaction mixture was
filtered, and volatiles were removed under reduced pressure
to yield the crude product which was chromatographed on
silica gel (15 × 1.1) with 30-50% EtOAc/hexanes to yield 0.198
g (80%) of the title compound.
FT IR (film, cm-1): 3357, 2945, 2869, 1733, 1513, 1450,
1379, 1246, 1172, 1093, 1027, 972, 756, 666.
1H NMR (CDCl3, 300 MHz) δ: 7.98 (d, 1 H, J ) 7.5 Hz),
7.88-7.82 (m, 2 H), 7.56-7.43 (m, 4 H), 5.55 (s, 2 H), 5.07 (s,
10 H), 4.89 (s, 1 H), 4.68 and 4.53 (m, 10 H), 2.29 (m), 2.17
(m), 2.09, 2.08, 2.02 (singlets, OAc protons), 1.82-0.95 (m),
0.89-0.62 (angular methyl groups).
IR (film, cm-1): 2920, 2860, 1730, 1440, 1370, 1240, 1160,
1020, 750.
1H NMR (CDCl3, 400 MHz) δ: 5.09 (s, 3 H), 4.70 (s, 3 H),
2.34-2.18 (m, 3 H), 2.11, 2.10, 2.04 (singlets, OAc protons),
1.84-0.95 (m), 0.91-0.73 (m).
13C NMR (CDCl3, 75 MHz) δ: 173.73, 173.55, 173.44, 173.26,
170.53, 170.39, 170.29, 133.69, 131.56, 131.46, 129.26, 128.71,
127.46, 126.50, 125.92, 125.23, 123.45, 77.21, 75.85, 75.78,
75.53, 74.15, 73.89, 64.39, 49.38, 48.05, 47.84, 47.72, 45.10,
45.06, 45.00, 41.77, 35.65, 34.77, 34.68, 34.59, 34.35, 33.99,
32.22, 31.72, 31.53, 31.20, 30.99, 30.82, 27.36, 26.85, 26.59,
25.85, 25.60, 23.45, 23.04, 22.54, 21.43, 21.34, 17.49, 12.53,
12.42, 12.11.
13C NMR (CDCl3, 75 MHz) δ: 179.00, 173.59, 173.34, 170.59,
170.44, 75.87, 74.29, 49.49, 47.84, 45.09, 45.01, 41.78, 35.66,
34.68, 34.51, 34.38, 34.02, 32.23, 31.74, 30.85, 27.36, 26.86,
26.61, 25.87, 25.63, 23.46, 23.05, 21.44, 21.38, 17.49, 12.53,
12.43.
MALDI-TOF MS: 1333.8 (M + Na+ 1332.8), 1350.1 (M +
UV (THF, 22.8 µM), λ(log ꢀ)): 292.2 (3.65), 281.3 (3.81), 271.6
(3.74), 226.3 (4.68).
K+ 1348.9).
HPLC: tR ) 8.5 min (40% THF/MeOH, λ ) 280).
MALDI-TOF MS: 4447.6 (M + Na+ 4447.2) and 4463.2 (M
+ K+ 4463.4).
Anal. Calcd for C80H124O14: C, 73.36; H, 9.54. Found: C,
73.88; H, 9.94.
[R]25 (c 0.38, CHCl3): 94.7.
D
Anal. Calcd for C275H414O44: C, 74.66; H, 9.43. Found: C,
74.31; H, 9.53.
Hep ta m er (OAc, COOCH2Np ), 12. The procedure for the
synthesis of 10 was followed. From 11 (0.223 g, 0.170 mmol)
and 5 (0.033 g, 0.062 mmol) was obtained 0.142 g (74%) of the
title compound (white solid).
[R]25 (c 1.67, CHCl3): 103.6.
D
Deca m er (OAc, COOH), 9. Hydrogenolysis of 8 (258 mg,
0.058 mmol) yielded 124 mg (50%) of the title compound.
FT IR (film, cm-1): 3354, 2944, 2869, 1733, 1516, 1452,
1375, 1245, 1157, 1028, 755.
IR (film, cm-1): 3400 (b), 2940, 2880, 1730, 1450, 1370, 1240,
1170, 1090, 1020, 970, 750.
1H NMR (CDCl3, 300 MHz) δ: 8.01 (d, 1 H, J ) 7.8 Hz),
7.90-7.84 (m, 2 H), 7.58-7.43 (m, 4 H), 5.58 (s, 2 H), 5.08 (s,
7 H), 4.70 (m, 7 H), 2.28 (m), 2.19 (m), 2.11, 2.09, 2.04 (singlets,
OAc protons), 1.84-0.97 (m), 0.90-0.64 (angular methyl
groups).
1
1H NMR (CDCl3, 300 MHz) δ: 5.08 (s,10 H), 4.90 (s, 1 H),
4.68 and 4.54 (m, 10 H), 2.28 (m), 2.17 (m), 2.09, 2.08, 2.02
(singlets, OAc protons), 1.94-0.96 (m), 0.89-0.71 (angular
methyl groups).
13C NMR (CDCl3, 75 MHz) δ: 173.78, 173.50, 173.48, 173.38,
173.26, 173.17, 173.15, 170.46, 170.34, 170.25, 170.21, 133.65,
131.53, 131.46, 129.18, 128.64, 127.39, 126.43, 125.86, 125.18,
123.45, 77.20, 75.79, 75.75, 75.60, 75.54, 74.10, 74.07, 73.85,
64.33, 49.48, 49.33, 47.96, 47.90, 47.77, 47.70, 47.63, 45.06,
45.02, 44.98, 44.94, 41.72, 35.60, 34.70, 34.63, 34.56, 34.54,
34.46, 34.35, 34.31, 34.25, 33.95, 32.26, 32.18, 31.67, 31.48,
31.20, 30.99, 30.79, 27.31, 26.80, 26.55, 25.81, 25.55, 23.40,
23.00, 21.38, 21.31, 17.45, 17.40, 17.37, 12.47,12.44, 12.37,
12.26.
UV (THF, 74.1 µM), λ(log ꢀ)): 292.3 (3.72), 281.5 (3.89), 271.7
(3.82), 228.0 (4.34).
HPLC: tR ) 14.5 min (30% THF/MeOH, λ ) 280).
MALDI-TOF MS: 3143.0 (M + Na+ 3139.4), 3159.4 (M +
K+ 3155.5).
13C NMR (CDCl3, 75 MHz) δ: 173.54, 173.41, 173.33, 173.31,
173.29, 170.54, 170.47, 170.41, 170.39, 170.35, 170.28, 77.21,
77.12, 76.81, 76.44, 75.94, 75.84, 75.78, 75.58, 75.55, 74.14,
73.89, 73.83, 49.52, 49.45, 49.36, 47.83, 47.71, 45.09, 45.03,
44.98, 41.82, 41.75, 35.64, 34.85, 34.76, 34.66, 34.57, 34.34,
33.98, 32.31, 32.20, 32.11, 31.99, 31.72, 31.66, 31.57, 31.50,
31.03, 30.97, 30.93, 30.87, 30.81, 30.67, 27.43, 27.35, 27.27,
27.18, 26.94, 26.83, 26.57, 25.84, 25.60, 25.48, 23.43, 23.03,
21.42, 21.36, 21.34, 17.58, 17.47, 12.51, 12.40.
MALDI-TOF MS: 4321.6 (M + K+ 4323.3).
[R]25 (c 1.23, CHCl3): 98.4.
D
Tetr a m er (OAc, COOCH2Np ), 14. Starting with 6 (2.32
g, 4.339 mmol) and 7 (0.412 g, 0.75 mmol), 0.602 g (69%) of a
white solid was obtained.
IR (film, cm-1): 2960, 2880, 1730, 1470, 1440, 1380, 1360,
1250, 1180, 1030, 760.
Anal. Calcd for C195H292O30: C, 75.15; H, 9.44. Found: C,
75.33; H, 9.83.
1H NMR (CDCl3, 300 MHz) δ: 8.00 (d, 1 H, J ) 7.5 Hz),
7.90-7.84 (m, 2 H), 7.55-7.43 (m, 4 H), 5.57 (s, 2 H), 5.09,
5.04 (s, s, 4 H), 4.90 (s, 4 H), 4.58 (s, 4 H), 2.28 (m), 2.20 (m),
2.133, 2.088, 2.081, 2.052 (singlets, OAc protons), 1.93-1.07
(m), 0.91-0.63 (angular methyl groups).
[R]25 (c 1.4, CHCl3): 102.9.
D
Hep ta m er (OAc, COOH), 13. Heptamer 12 (0.270 g, 0.087
mmol) was hydrogenolyzed to yield 0.190 g (75%) of a white
solid.

3040 J . Org. Chem., Vol. 66, No. 9, 2001
Balasubramanian and Maitra
13C NMR (CDCl3, 75 MHz) δ: 173.71, 173.39, 173.31, 173.13,
170.45, 170.37, 170.33, 170.23, 133.62, 131.51, 131.41, 129.20,
128.63, 127.47, 126.46, 125.87, 125.19, 123.44, 75.27, 75.22,
78.98, 70.57, 64.36, 47.70, 47.63, 47.40, 45.00, 44.98, 43.28,
40.81, 37.62, 34.59, 34.49, 34.45, 34.23, 31.62, 31.34, 31.13,
30.74, 30.66, 30.51, 28.77, 27.09, 26.80, 25.48, 22.72, 22.46,
21.54, 21.41, 21.36, 17.45, 17.39, 17.32, 12.17, 12.04.
UV (THF, 64.3 µM), λ(log ꢀ)): 292.4 (3.69), 281.4 (3.86), 271.6
(3.78), 227.6 (4.44).
13C NMR (CDCl3, 75 MHz) δ: 173.79, 173.42,173.32, 173.11,
170.48, 170.45, 170.34, 170.25, 133.69, 131.58, 131.52, 129.21,
128.68, 127.44, 126.48, 125.91, 125.24, 123.51, 77.20, 75.32,
75.27, 74.02, 70.63, 64.38, 47.95, 47.79, 47.74, 47.44, 45.13,
45.07, 45.06,45.02, 43.34, 40.89, 37.72, 35.03, 34.66, 34.58,
34.35, 34.31, 34.03, 32.37, 31.92, 31.65, 31.43, 31.20, 30.82,
30.55, 28.84, 27.15, 26.86, 25.56, 23.08, 22.84, 22.52, 21.59,
21.44, 21.42, 21.39, 17.58, 17.53, 17.44, 17.35, 12.34.
UV (THF, 90.6 µM), λ(log ꢀ)): 292.2 (3.68), 281.4 (3.85), 271.5
(3.79), 229.1 (4.30).
HPLC: tR ) 13.8 min (MeOH, λ ) 280 nm).
MALDI-TOF MS: 2119.4 (M + Na+ 2121.8), 2135.9 (M +
HPLC: tR ) 12.9 min (15% THF/MeOH, λ ) 280).
K+ 2137.9).
MALDI-TOF MS: 4440.6 (M + Na+ 4436.9).
Anal. Calcd for C125H180O26: C, 71.54; H, 8.64. Found: C,
71.83; H, 9.01.
Anal. Calcd for C263H388O54: C, 71.57; H, 8.86. Found: C,
71.90; H, 9.26.
[R]25 (c 2.66, CHCl3): 80.8.
[R]25 (c 0.82, CHCl3): 84.2.
D
D
Tetr a m er (OAc, COOH), 15. Tetramer 14 was hydrogeno-
lyzed to yield 0.400 g (86%) of a white solid.
Non a m er (OAc, COOH), 17. Nonamer 16 (108 mg, 0.024
mmol) was hydrogenolyzed to give 49 mg (47%)of the title
compound.
IR (film, cm-1): 3400 (b), 2960, 2880, 1730, 1440, 1370, 1240,
1020, 750.
IR (film, cm-1): 3356, 2945, 1733, 1541, 1454, 1375, 1245,
1125, 1067, 1026, 755.
1H NMR (CDCl3, 300 MHz) δ: 5.10, 5.09 (s, s, 4 H), 4.91 (s,
4 H), 4.58 (m, 4 H), 2.32 (m, 4 H), 2.24 (m, 4 H), 2.15, 2.13,
2.093, 2.086, 2.05 (singlets, OAc protons), 2.00-1.07 (m), 0.92-
0.73 (angular methyl groups).
1H NMR (CDCl3, 300 MHz) δ: 5.08 (s, 9 H), 4.90 (s, 8 H),
4.57 (m, 9 H), 2.31-2.19 (m), 2.14, 2.13, 2.08, 2.04 (singlets,
OAc protons), 1.99-1.06 (m), 0.91-0.72 (angular methyl
groups).
13C NMR (CDCl3, 75 MHz) δ: 173.43, 173.31, 173.08, 170.52,
170.47, 170.39, 170.30, 77.20, 75.30, 75.18, 74.21, 74.03, 70.77,
70.63, 70.51, 47.81, 47.68, 47.54, 47.31, 45.06, 45.02, 43.31,
40.85, 37.68, 35.13, 34.96, 34.63, 34.55, 34.46, 34.33, 34.28,
31.96, 31.77, 31.49, 31.41, 31.18, 30.84, 30.78, 30.57, 28.82,
27.13, 27.07, 26.84, 25.54, 22.78, 22.50, 21.58, 21.44, 21.39,
17.55, 17.44, 17.39, 17.32, 12.22, 12.16.
13C NMR (CDCl3, 75 MHz) δ: 173.45, 173.39, 170.52, 170.40,
170.34, 170.30, 77.72, 77.63, 77.59, 77.20, 76.89, 76.81, 76.42,
75.64, 75.46, 75.33, 75.29, 75.20, 74.05, 73.93, 70.68, 70.59,
70.51, 47.85, 47.79, 47.71, 47.60, 47.57, 47.47, 47.45, 45.20,
45.07, 43.34, 40.89, 37.71, 34.99, 34.91, 34.87, 34.84, 34.66,
34.58, 34.35, 34.31, 31.56, 31.48, 31.43, 31.32, 31.21, 30.82,
30.77, 30.74, 30.65, 30.60, 30.55, 28.94, 28.84, 27.25, 27.16,
27.10, 27.00, 26.86, 25.56, 23.08, 22.81, 22.53, 21.59, 21.45,
21.41, 17.58, 17.53, 17.46, 17.40, 17.35, 12.35, 12.25.
MALDI-TOF MS: 4325.5 (M + K+ 4312.9).
MALDI-TOF MS: 1982.1 (M + Na+ 1981.6), 1999.6 (M +
K+ 1997.7).
Anal. Calcd for C114H172O26: C, 69.91; H, 8.85. Found: C,
69.69; H, 9.13.
[R]25 (c 1.55, CHCl3): 80.6.
[R]25 (c 0.81, CHCl3): 88.9.
D
D
Non a m er (OAc, COOCH2Np ), 16. From 15 (0.357 g, 0.182
mmol) and 5 (0.035 g, 0.065 mmol) was obtained 0.0998 g
(35%) of the title compound.
Ack n ow led gm en t. Financial support from Depart-
ment of Science & Technology, New Delhi (Grant No.
SP/S1/G-08/96) is gratefully acknowledged. We thank
P. Balaram, R. Sudha, and C. Das of the Molecular
Biophysics Unit of this Institute for the MALDI-TOF
MS.
IR (film, cm-1): 2950, 2900, 1740, 1250, 1040, 760.
1H NMR (CDCl3, 300 MHz) δ: 8.01 (d, 1 H, J ) 9.6 Hz),
7.91-7.85 (m, 2 H), 7.61-7.43 (m, 4 H), 5.57 (s, 2 H), 5.09,
5.04 (s, s, 9 H), 4.90 (s, 8 H), 4.57 (m, 9 H), 2.27 (m), 2.147.
2.141, 2.132, 2.127, 2.09, 2.08, 2.05 (singlets, OAc protons),
2.00-1.07 (m), 0.94-0.63 (angular methyl groups).
J O0013305