First bile acid-derived chiral dendritic species with nanometric dimensions

Full text of DOI:10.1039/a907297g

First bile acid-derived chiral dendritic species with nanometric dimensions
R. Balasubramanian, Photon Rao and U. Maitra*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India.
E-mail: maitra@orchem.iisc.ernet.in
Received (in Cambridge, UK) 9th September 1999, Accepted 12th October 1999
This paper describes the first synthesis of branched bile acid
oligomers.
The chemistry of dendrimers has been a dominating theme in
chemical sciences in recent years. Chiral dendritic species1 also
appeared in the chemical literature shortly after the first achiral
version was reported.2 Apart from their potential applications in
asymmetric catalysis and chiral recognition,3 chiral dendritic
species have been of considerable interest because of a search
towards macromolecular asymmetry.4 A dendrimer possesses
three distinct regions, viz. the core, the branching units and the
end groups, and the incorporation of chirality in the dendrimer
can in general be achieved by choosing one or more such
components to be chiral.1b Molecules from the natural chiral
pool, e.g. amino acids,1a nucleic acids,5 sugars6 and tartaric
acid,4e,f have been employed to design chiral dendrimers. Bile
acids, forming another class of the naturally occurring group of
chiral molecules, have been extensively used in supramolecular
chemistry including the synthesis of cyclic and linear poly-
mers.7 Bile acids (e.g. 1–3) offer a carboxy group and multiple
hydroxy groups (up to three) and are versatile AB2 or AB3
building blocks for dendritic construction. We report here the
synthesis of the first bile acid-based chiral dendrons 8 and 9, a
heptamer and a nonamer, respectively. These relatively small
The mobility of these compounds on reversed-phase HPLC
oligomers of large chiral building blocks are of nanometric
shows an interesting pattern (Table 1). With the increase in the
dimensions.
oligomeric size, both the polarity (increased number of ester
groups) and the lipophilicity (increased number of bile acid
We adopted Fre´chet’s convergent strategy8 to accomplish the
synthesis of 8 and 9. Orthogonal protection of deoxycholic acid
2 with acetate and 1-naphthylmethyl groups9 generated steroids
4 (Ac2O, Et3N, DMAP, 92%) and 5 (1-naphthylmethyl
chloride/DBU/DMF, 79%), respectively. In an analogous
manner cholic acid 3 was converted to 6 (45%) and 7 (77%).
Steroid 4 was converted to the acid chloride, and reacted with
5, (CaH2, BnEt3N+Cl2, toluene, reflux, 2 d) to generate trimer
1
10 (70%) which was characterized by IR, H and 13C NMR,
UV, HPLC, elemental analysis and MALDI-TOF MS (Scheme
1). The deprotection of 10 to 11 (Pd/C, H2), conversion to the
acid chloride and subsequent reaction with 5 provided heptamer
8 in 75% yield.10
The use of cholic acid-based starting materials 6 and 7 led to
an increase in the number of branching units, which allowed us
to construct tetramer 12 in 69% yield. The deprotection of 12 to
13, followed by its coupling with 5 generated nonamer 13
(35%).10 One of the (many possible) conformations of 9 is
shown in Fig. 1.
Scheme 1
Chem. Commun., 1999, 2353–2354
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of larger functionalized dendrimers using analogous repeating
units is in progress in our laboratory.
Financial support from the Department of Science &
Technology, New Delhi (grant # 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, and S. Ghosh for his involvement in the synthesis and
purification of 12.
Notes and references
1 (a) The first report of a chiral dendrimer: R.G. Denkewalter, J. F. Kolc
and W. J. Lukasavage, U.S. Pat. 4,410,688, 1979; (b) Review on chiral
dendrimers: H. W. I. Peerlings and E. W. Meijer, Chem. Eur. J., 1997,
3, 1563; C. W. Thomas and Y. Tor, Chirality, 1998, 10, 53; D. Seebach,
P. B. Rheiner, G. Greiveldinger, T. Butz and H. Sellner, Top. Curr.
Chem., 1998, 197, 125.
2 E. Buhleier, W. Wehner and F. Vögtle, Synthesis, 1978, 155.
3 D. A. Tomalia, A. M. Naylor and W. A. Goddard III, Angew. Chem., Int.
Ed. Engl., 1990, 29, 138; D. A. Tomalia and H. D. Durst, Top. Curr.
Chem., 1993, 165, 193; J. Issenberner, R. Moors and F. Vögtle, Angew.
Chem., Int. Ed. Engl., 1994, 33, 2413; G. R. Newkome and C. N.
Moorefield, Dendrimers, in Comprehensive Supramolecular Chem-
istry, ed. J. L. Atwood, J. E. D. Davies, D. D. MacNicol, F. Vögtle, J.-M.
Lehn, Pergamon, Tarrytown, NY, 1996, vol. 10, p. 777; F. Zeng and
S. C. Zimmerman, Chem. Rev., 1997, 97, 1681; D. K. Smith and F.
Diederich, Chem. Eur. J., 1998, 4, 1353; M. Fischer and F. Vögtle,
Angew. Chem., Int. Ed., 1999, 38, 884.
Fig. 1 Representation of one of the many possible conformations of 9. The
‘length’ and the ‘width’ are indicated in Å.
Table 1 HPLC data on bile acid oligomers (25 cm C-18 column, 4.6 mm
4 (a) G. R. Newkome, X. Lin and C. D. Weis, Tetrahedron: Asymmetry,
1991, 2, 957; (b) D. Seebach, J.-M. Lapierre, K. Skobridis and G.
Greiveldinger, Angew. Chem., Int. Ed. Engl., 1994, 33, 440; (c) P. Murer
and D. Seebach, Angew. Chem., Int. Ed. Engl., 1995, 34, 2116; (d)
J. F. G. A. Jansen, H. W. I. Peerlings and E. M. M. de Brabander2van
den Berg, E. W. Meijer, Angew. Chem., Int. Ed. Engl., 1995, 34, 1206;
(e) H.-F. Chow and C. C. Mak, J. Chem., Soc., Perkin Trans. 1, 1994,
2223; (f) H.-F. Chow and C. C. Mak, Pure Appl. Chem., 1997, 69, 483;
(g) H.-T Chang, C.-T Chen, T. Kondo, G. Siuzdak and K. B. Sharpless,
Angew. Chem., Int. Ed. Engl., 1996, 35, 182; (h) J. R. McElhanon and
D. V. McGrath, J. Am. Chem. Soc., 1998, 120, 1647.
id)
Steroidal oligomers Solvent system
Retention time/min
8 (7a, 15b)
9 (9, 27)
30% THF–MeOH
15% THF–MeOH
15% THF–MeOH
MeOH
14.5
12.9
17.1
13.8
10 (3, 7)
12 (4, 13)
a Number of bile acid moieties present. b Number of ester linkages.
5 R. H. E. Hudson and M. J. Damha, J. Am. Chem. Soc, 1993, 115,
2119.
units) increase. Experimentally, the order of elution (increasing
retention time) on a C-18 column is: 12 < 9 < 10 < 8. On silica
gel TLC a different order is observed; the Rf values increase in
the order: 9 < 12 < 8 < 10 (EtOAc–hexanes, 2+3 v/v).
The optical rotations of these dendrons are given in Table 2.
The molar rotation values show a roughly linear relationship
with the number of bile acid units in each dendron (or its
molecular weight). This suggests the absence of chiral con-
formations and local micropolarity which might affect the
optical rotation.
6 K. Aoi, K. Itoh and M. Okada, Macromolecules, 1995, 28, 5391.
7 U. Maitra and L. J. D’Souza, J. Chem. Soc., Chem. Commun., 1994,
2793; U. Maitra, S. Balasubramanian, J. Chem. Soc., Perkin Trans. 1,
1995, 83; A. P. Davis, R. P. Bonar-law and J. K. M. Sanders, Receptors
Based on Cholic Acid, in Comprehensive Supramolecular Chemistry,
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Lehn, Pergamon, Tarrytown, NY, 1996, vol. 4, p. 257; P. A. Brady, R. P.
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Commun., 1996, 319; Y. Li and J.R. Dias, Chem. Rev., 1997, 97, 283;
Y. H. Zhang, M. Akram, H. Y. Liu and X. X. Xhu, Macromol. Chem.
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These bile acid-based dendrons are of considerable interest
because of their shape and nanometric dimensions. The design
8 C. J. Hawker and J. M. J. Fréchet, J. Am. Chem. Soc., 1990, 112,
7638.
9 The 1-naphthylmethyl group was employed for easier identification of
the dendrons in the purification steps, and also in the analysis of the
sample by UV and HPLC measurements.
10 The MALDI-TOF MS spectrum showed a peak for 8 at m/z 3143.0
[expected for (M+Na)+ 3139.4] (Calc. for C195H292O30: C, 75.15; H,
9.44%. Found: C, 75.33; H, 9.83%). For 9, MALDI-TOF MS spectrum
showed a peak for at m/z 4440.6 [expected for (M+Na)+ = 4436.9]
(Calc. for C263H388O54: C, 71.57; H, 8.86. Found: C, 71.89; H,
9.26%).
Table 2 Molar and specific rotation values of dendrons in CHCl3
Compound (MW)
Specific rotation
Molar rotation
8 (3116.4)
9 (4413.9)
10 (1450.0)
11 (1309.9)
12 (2098.8)
13 (1958.6)
102.9
84.2
86.6
94.7
80.8
80.6
3207
3717
1256
1240
1696
1579
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Chem. Commun., 1999, 2353–2354