Synthesis and Characterization of Novel Steroidal Dendrons

Article abstract of DOI:10.1055/s-2003-41041

Some novel bile acid-derived dendritic aliphatic polyesters have been synthesized. These first and second generation dendrons have been prepared from 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) and lithocholic acid (3α-hydroxy-5β-cholan-24-oic acid, LCA) by a convergent method.

Full text of DOI:10.1055/s-2003-41041

2226
PAPER
Synthesis and Characterization of Novel Steroidal Dendrons
Synthesis
a
of
N
ovel St
r
eroidal
D
m
endrons o Ropponen, Jari Tamminen, Erkki Kolehmainen, Kari Rissanen*
Department of Chemistry, University of Jyväskylä, P. O. B. 35, 40014, Jyväskylä, Finland
Fax +358(14)2602501; E-mail: Kari.Rissanen@jyu.fi
Received 12 May 2003; revised 20 June 2003
droxy-5 -cholan-24-oic acid) and deoxycholic acid
(3 ,12 -dihydroxy-5 -cholan-24-oic acid) as starting
materials when prepayring a heptamer, a nonamer, and a
decamer using a convergent strategy.
Abstract: Some novel bile acid-derived dendritic aliphatic polyes-
ters have been synthesized. These first and second generation den-
drons have been prepared from 2,2-bis(hydroxymethyl)propionic
acid (bis-MPA) and lithocholic acid (3 -hydroxy-5 -cholan-24-oic
acid, LCA) by a convergent method.
Herein we present a convergent synthesis and character-
ization of novel bile acid-derived dendritic compounds
using 2,2-bis(hydroxymethyl)propionic acid (bis-MPA)
as dendritic moiety and lithocholic acid (3 -hydroxy-5 -
cholan-24-oic acid) as steroidal part of the synthesized
dendritic aliphatic polyesters. Lithocholic acid was select-
ed as steroidal moiety of these dendrons because of its
availability, low cost and owing only one hydroxyl group
in its structure. It is a very suitable model compound from
a synthetic point of view. Trifluoroacetoxy (TFA) was
chosen as a protecting group of steroidal hydroxyls since
TFA group can be inserted quantitatively to the bile acid
moiety, and it can be removed under mild conditions in
good yields. The entire synthetic route up to second gen-
eration is described in Schemes 1 and 2.
Key words: dendrimers, steroids, aliphatic esters, bile acids, drug
carriers
Dendrimers and dendrons are chemically discrete, highly
branched polymer-like macromolecules, which have a
well-defined structure. As the dendrimer generation in-
creases, these monodisperse macromolecules possess a
spherical three-dimensional structure.1 There are two dif-
ferent stepwise procedures in the synthesis of dendritic
structures, divergent1f,2 and convergent3 methods. Using
either of these methods, the shape, size and physical and
chemical properties of the molecule can be varied as de-
sired. Because of their unique properties dendrimers can
be used for applications in light harvesting systems,4 ca-
talysis,5 molecular encapsulation6 and biomedical appli-
cations.7
Lithocholic acid (3 -hydroxy-5 -cholan-24-oic acid, 1)
was first protected by treating it with trifluoroacetic acid
anhydride leading to 3 -trifluoroacetoxy-5 -cholan-24-
oic acid (2). The acid 2 was refluxed with thionyl chloride
to give 3 -trifluoroacetoxy-5 -cholan-24-oyl chloride
(3), quantitatively.17 The benzyl ester 4 of 2,2-bis(hy-
droxymethyl)propionic acid was synthesized by the nu-
cleophilic substitution of the bis-MPA potassium salt with
benzyl bromide.18 Detailed synthetic description and
spectroscopic characterization of compounds 2–4 have
been described earlier.17,18 The ester bond between 3 and
the AB2 monomer was formed by using small excess of
acid chloride 3 with the benzyl ester protected monomer
unit 4 in the presence of triethylamine and a catalytic
amount of DMAP (4-N,N-dimethylaminopyridine). The
crude product was purified by column chromatography
(silica gel, eluting with hexane gradually increasing to
10:1 hexane–ethyl acetate) and gave 50% of fully protect-
ed 5 (Scheme 1). Removal of the benzyl ester group by
catalytic hydrogenolysis gave trifluoroacetoxy protected
[G1]-acid 6 in 86% yield. Hydrolysis of 5 with aqueous
NaHCO3 in THF–methanol mixture gave 7 in 71% yield.
Hydrogenolysis of compound 7 in ethyl acetate afforded
entirely unprotected 8 in 55% yield. Dendron 6 was con-
verted into its acid chloride 9 with thionyl chloride in
quantitative yield. The fully protected second generation
dendron 10 was synthesized and purified in the same man-
ner as for compound 5 in 45% yield. Hydrogenolysis of
the compound 10 gave 90% of acid 11. Hydrolysis of 10
gave 81% of 12. Removal of the benzyl group from 12
Bile acids are polyhydroxylated steroidal acids obtained
from the digestive system of vertebrates.8 The physiolog-
ical function of bile acids is to participate in the digestion
and resorption of lipids and lipophilic vitamins. Bile acids
and their derivatives are important compounds from the
pharmaceutical point of view. 9–11
The large, rigid, and curved steroidal skeleton, chemically
different hydroxyl groups, enantiomeric purity, and
unique amphiphilicity together with their availability and
low cost make bile acids ideal building blocks for design-
ing novel molecular and supramolecular assemblies for
molecular recognition.12–14
Connecting the dendritic structure and steroidal moieties
to the same molecule could lead to very potential molecu-
lar assemblies with many interesting applications such as
organ-targeted drug carriers, artificial ion channels, and
molecular switches. Chen et al. have utilized a convergent
method to prepare estrone dendrimers with six estrones at-
tached to a benzene core by means of polyoxyethylene
chains to increase their polarity.15 Maitra et al. have re-
ported first bile acid-based chiral dendrons.16 They have
used acetoxy-functionalized cholic acid (3 ,7 ,12 -trihy-
Synthesis 2003, No. 14, Print: 02 10 2003. Web: 28 08 2003.
Art Id.1437-210X,E;2003,0,13,2226,2230,ftx,en;T04303SS.pdf.
DOI: 10.1055/s-2003-41041
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Novel Steroidal Dendrons
2227
Scheme 1
ternal TMS and to the signal of solvent (13CDCl3) = 77.00 from the
internal TMS, respectively.
gave a mixture of compounds 12 and 13, although hydro-
genolysis was repeated three times (Scheme 2). The rea-
son for this might be the steric hindrance.
Electrospray mass spectrometric measurements were obtained us-
ing the Micromass LCT time of flight (TOF) mass spectrometer
with electrospray ionization (ESI). All acid compounds (6, 8, 11 and
13) were measured using negative mode. Accurate mass measure-
ments were done for all compounds except 11 and the calibration of
the instrument was made with NaI. As reference ions substance P
was used for compounds 5–8 and renin for compounds 10, 12, and
13.
The compounds reported herein represent models for pos-
sible drug carriers. In our structure, the protective benzyl
group corresponds to a drug, which is surrounded by den-
dritic moieties like an umbrella.19 The solubility of this
kind of dendrons can be controlled by changing the bile
acid as well as modifying the external surface. Efforts
aimed extending this methodology to other bile acids as
cholic acid, deoxycholic acid and ursodeoxycholic acid
(3 ,7 -dihydroxy-5 -cholan-24-oic acid), which are not
gallstone forming compounds as lithocholic acid is, are
(C6H5CH2O-[G1]-TFA) (5)
3 -Trifluoroacetoxy-5 -cholan-24-oyl chloride 3 (6.99 g, 14.2
mmol), diluted with a small amount of CH2Cl2, was added to a so-
lution of benzyl-2,2-bis(methylol)propionate (4; 1.52 g, 6.78
currently in progress. We will change the trifluoroacetoxy mmol), DMAP (82.0 mg, 0.68 mmol), and Et3N (1.78 g, 17.6 mmol)
in CH2Cl2 (30 mL) at 0 °C under N2. After stirring at 0 °C for 1 h,
group to other protecting groups such as acetoxy groups,
the temperature was raised to r.t., and reaction was allowed to reach
because acetoxy derivatives are biochemically less harm-
completion over 2 d. The mixture was washed with H2O (2 × 50
mL), aq sat. NaHCO3 (2 × 50 L), and H2O (2 × 50 mL), dried
(MgSO4), and evaporated. The crude product was purified by gradi-
ful bile acids and so there is no need to remove it when
constructing potential drug carriers. Trifluoroacetoxy
groups cause also some problems in ESI-MS measure-
ments and on the synthetic pathway. For example, in the
hydrolysis of trifluoroacetoxy groups the treatment by sat-
urated sodium hydrogen carbonate had to be made twice
in order to complete the reaction.
ent column chromatography (silica gel, eluating with hexane grad-
ually increasing to 10:1 hexane–EtOAc) to give product as colorless
viscous oil; yield: 3.81 g (50%); Rf 0.26.
1H NMR (CDCl3, 500 MHz): = 7.33–7.26 (5 H, m, ArH), 5.14 (2
H, s, ArCH2), 4.90 (2 H, m, 3-CH ), 4.22 (4 H, m, [G-1]-CH2),
2.29–2.22, 2.17–2.10 (4 H, m, 23-CH2), 1.97–1.03 (52 H, m), 1.24
(3 H, s, [G-1]-CH3), 0.93 (6 H, s, 19-CH3), 0.87 (6 H, d, J = 6.3 Hz,
21-CH3), 0.63 (6 H, s, 18-CH3).
13C NMR (CDCl3, 126 MHz): = 173.4, 172.5, 156.8, 135.6, 128.4,
128.1, 127.9, 114.5, 79.2, 66.6, 65.2, 56.3, 55.9, 46.3, 42.6, 41.8,
40.4, 40.0, 35.7, 35.1, 34.6, 34.4, 31.5, 30.8, 30.7, 28.0, 26.8, 26.1,
26.0, 24.0, 23.1, 20.7, 18.1, 17.7, 11.9.
All chemicals were purchased from Aldrich, Acros or Fluka as
highest purity grade and used without any further purification. Col-
umn chromatography was performed with Merck silica gel 60 F254
,
particle size 0.040–0.063 mm, using hexane–EtOAc mixtures. All
1H and 13C NMR experiments were performed in 0.2–0.05 M CDCl3
solutions with a Bruker Avance DRX 500 NMR spectrometer work-
1
ing at 500.13 MHz for H, and 125.77 MHz for 13C experiments.
ESI-TOF-MS: m/z calcd for C64H90F6O10 [M + Na]+: 1155.6336;
The 1H and 13C NMR chemical shifts were referenced to the residual
signal of partly deuteriated solvent: (C1HCl3) = 7.26 from the in-
found: 1155.6327 [M + Na]+.
Synthesis 2003, No. 14, 2226–2230 © Thieme Stuttgart · New York

2228
J. Ropponen et al.
PAPER
Scheme 2
(HOOC-[G1]-TFA) (6)
1H NMR (CDCl3, 500 MHz): = 7.30–7.27 (5 H, m, ArH), 5.12 (2
H, s, ArCH2), 4.19 (4 H, m, [G-1]-CH2), 3.56 (2 H, m, 3-CH ),
2.25–2.20, 2.14–2.07 (4 H, m, 23-CH2), 1.92–0.92 (52 H, m), 1.22
(3 H, s, [G-1]-CH3), 0.87 (6 H, s, 19-CH3), 0.84 (6 H, d, J = 6.5 Hz,
21-CH3), 0.59 (6 H, s, 18-CH3).
13C NMR (CDCl3, 126 MHz): = 173.5, 172.4, 135.5, 128.4, 128.1,
127.8, 71.5, 66.5, 65.2, 56.3, 55.8, 46.2, 42.6, 42.0, 40.3, 40.0, 36.2,
35.7, 35.2, 35.1, 34.4, 30.8, 30.7, 30.3, 28.0, 27.1, 26.3, 24.0, 23.2,
20.7, 18.1, 17.6, 11.9.
Pd/C (10% wt, 0.22 g) was added to a solution of 5 (2.20 g, 1.94
mmol) in EtOAc (30 mL). The reaction vessel for catalytic hydro-
genolysis was evacuated and filled with H2. The mixture was stirred
16 h at r.t., the catalyst was then filtered off and carefully washed
with EtOAc. The filtrate was evaporated and dried in vacuo to give
white powder; yield: 1.73 g (86%).
1H NMR (CDCl3, 500 MHz): = 4.92 (2 H, m, 3-CH ), 4.23 (4 H,
m, [G-1]-CH2), 2.40–2.32, 2.26–2.19 (4 H, m, 23-CH2), 1.98–1.04
(52 H, m), 1.28 (3 H, s, [G-1]-CH3), 0.94 (6 H, s, 19-CH3), 0.90 (6
H, d, J = 6.5 Hz, 21-CH3), 0.64 (6 H, s, 18-CH3).
13C NMR (CDCl3, 126 MHz): = 178.0, 173.7, 157.0, 114.6, 79.4,
65.0, 56.4, 56.0, 46.1, 42.7, 41.9, 40.5, 40.1, 35.8, 35.3, 34.7, 34.5,
31.6, 31.0, 30.9, 28.1, 26.9, 26.2, 26.1, 24.1, 23.2, 20.8, 18.2, 17.8,
12.0.
ESI-TOF-MS: m/z calcd for C60H92O8 [M + Na]+: 963.6690; found:
963.6685 [M + Na]+.
(HOOC-[G1]-OH) (8)
Pd/C (10% wt, 20.0 mg) was added to a solution of 7 (0.17 g, 0.18
mmol) in EtOAc (30 mL). The reaction vessel for catalytic hydro-
genolysis was evacuated and filled with H2. The mixture was stirred
16 h at r.t., the catalyst was then filtered off and carefully washed
with EtOAc. The filtrate was evaporated and dried in vacuo to give
a white powder; yield: 83 mg (55%).
1H NMR (CDCl3, 500 MHz): = 5.42 (2 H, br, 3-COH), 4.21 (4 H,
m, [G-1]-CH2), 3.62 (2 H, m, 3-CH ), 2.36–2.30, 2.24–2.17 (4 H,
m, 23-CH2), 1.94–0.92 (52 H, m), 1.25 (3 H, s, [G-1]-CH3), 0.90 (6
H, s, 19-CH3), 0.89 (6 H, d, J = 6.5 Hz, 21-CH3), 0.62 (6 H, s, 18-
CH3).
ESI-TOF-MS: m/z calcd for C57H83F6O10 [M – H]–: 1041.5890;
found: 1041.5850 [M – H]–.
(C6H5CH2O-[G1]-OH) (7)
To a solution of 5 (0.39 g, 0.34 mmol) in THF–MeOH (1:1, 20 mL)
was added aq sat. NaHCO3 (5 mL) under stirring. After 1 h, an ad-
ditional portion of NaHCO3 solution (1 mL) was added and the mix-
ture was stirred for 2 h. Then the mixture was evaporated and
diluted with CHCl3 (30 mL). The CHCl3 layer was washed with
H2O (2 × 30 mL), dried (MgSO4) and evaporated to dryness. This
partially hydrolyzed product was hydrolyzed again in the same way
using aq sat. NaHCO3 (4 + 1 mL) to give a white powder; yield: 0.30
g (71%).
13C NMR (CDCl3, 126 MHz): = 176.9, 173.7, 71.9, 65.1, 56.4,
55.9, 46.0, 42.7, 42.1, 40.4, 40.1, 36.2, 35.8, 35.3, 35.3, 34.5, 31.1,
30.9, 30.3, 28.1, 27.1, 26.4, 24.2, 23.3, 20.8, 18.2, 17.8, 12.0.
ESI-TOF-MS: m/z calcd for C53H85O8 [M – H]–: 849.6244; found:
849.6202 [M – H]–.
Synthesis 2003, No. 14, 2226–2230 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Steroidal Dendrons
2229
(ClOC-[G1]-TFA) (9)
dried (Na2SO4), and evaporated under vacuum. This procedure was
repeated twice to afford a white powder; yield: 744 mg (81%).
A mixture of 6 (2.56 g, 2.45 mmol) and SOCl2 (30 mL) was refluxed
for 3 h and the excess of SOCl2 was evaporated under vacuo. The
crude product was dissolved in CCl4 (25 mL) and evaporated to dry-
ness under vacuum. This handling was repeated twice. The product
was kept in vacuo overnight to give a yellowish product quantita-
tively.
1H NMR (CDCl3, 500 MHz): = 4.93 (2H, m, 3-CH ), 4.28 (4 H,
m, [G-1]-CH2), 2.39–2.33, 2.27–2.20 (4 H, m, 23-CH2), 1.99–1.05
(52 H, m), 1.38 (3 H, s, [G-1]-CH3), 0.95 (6 H, s, 19-CH3), 0.91 (6
H, d, J = 6.5 Hz, 21-CH3), 0.65 (6 H, s, 18-CH3).
1H NMR (CDCl3, 500 MHz): = 7.35–7.34 (5 H, m, ArH), 5.16–
5.15 (2 H, m, ArCH2), 4.38–4.10 (12 H, m, [G-1]-CH2+[G-2]-CH2),
3.75–3.55 (4 H, m, 3-CH ), 2.39–2.12 (8 H, m, 23-CH2), 1.96–0.95
(104 H, m), 1.23 (3 H, s, [G-1]-CH3), 1.16 (6 H, s, [G-2]-CH3), 0.91
(12 H, s, 19-CH3), 0.89 (12 H, d, J = 6.5 Hz, 21-CH3), 0.63 (12 H,
s, 18-CH3).
13C NMR (CDCl3, 126 MHz): = 173.8, 173.7, 172.7, 135.6, 128.6,
128.3, 128.0, 71.8, 66.7, 65.2, 64.6, 56.5, 55.9, 46.5, 46.4, 42.7,
42.1, 40.4, 40.2, 36.4, 35.8, 35.3, 35.3, 34.6, 31.0, 30.9, 30.5, 28.1,
27.2, 26.4, 24.2, 23.3, 20.8, 18.2, 17.6, 17.5, 12.0.
13C NMR (CDCl3, 126 MHz): = 175.1, 173.3, 157.0, 114.6, 79.4,
64.9, 56.4, 56.0, 42.7, 41.9, 40.5, 40.1, 35.8, 35.3, 34.8, 34.5, 31.7,
31.0, 30.8, 28.1, 26.9, 26.2, 26.1, 24.1, 23.2, 20.9, 18.2, 17.9, 12.0.
ESI-TOF-MS: m/z calcd for C118H184O18 [M + Na]+: 1912.3380;
found: 1912.3357 [M + Na]+.
(C6H5CH2O-[G2]-TFA) (10)
(HOOC-[G2]-OH) (13)
Compound 9 (2.60 g, 2.45 mmol), diluted with a small amount of
CH2Cl2, was added to a solution of benzyl 2,2-bis(methylol)propi-
onate (0.25 g, 1.11 mmol), DMAP (14.0 mg, 0.11 mmol), and TEA
(0.29 g, 2.90 mmol) in CH2Cl2 (10 mL) at r.t. under N2, and reaction
mixture was refluxed 2 d under N2. The crude product was purified
by gradient column chromatography (silica gel, eluting with hex-
ane, gradually increasing to 10:1 hexane–EtOAc) to give the prod-
uct as a colorless viscous oil; yield: 1.14 g (45%); Rf 0.08.
Pd/C (10% wt, 70.0 mg) was added to a solution of 12 (0.70 g, 0.37
mmol) in EtOAc (30 mL). The reaction vessel for catalytic hydro-
genolysis was evacuated and filled with H2. The mixture was stirred
16 h at r.t., the catalyst was then filtered off and carefully washed
with EtOAc. The filtrate was evaporated and dried in vacuo to give
a white powder. This procedure was repeated three times, but the
benzyl protecting group could not be completely removed; yield:
0.35 g (30:70 mixture of compounds 12 and 13).
1H NMR (CDCl3, 500 MHz): = 7.37–7.31 (5 H, m, ArH), 5.15 (2
H, s, ArCH2), 4.93 (4 H, m, 3-CH ), 4.27 (4 H, m, [G-1]-CH2), 4.15
(8 H, m, [G-2]-CH2), 2.36–2.30, 2.24–2.15 (8 H, m, 23-CH2), 1.98–
1.02 (104 H, m), 1.26 (3 H, s, [G-1]-CH3), 1.16 (6 H, s, [G-2]-CH3),
0.95 (12 H, s, 19-CH3), 0.90 (12 H, d, J = 6.5 Hz, 21-CH3), 0.64 (12
H, s, 18-CH3).
13C NMR (CDCl3, 126 MHz): = 173.5, 172.0, 171.9, 157.0, 135.4,
128.6, 128.5, 128.3, 114.6, 79.4, 67.1, 65.7, 65.0, 56.4, 56.0, 46.7,
46.4, 42.7, 41.9, 40.4, 40.0, 35.8, 35.3, 34.7, 34.5, 31.6, 31.0, 30.8,
28.1, 26.9, 26.2, 26.1, 24.1, 23.2, 20.8, 18.2, 17.7, 17.6, 12.0.
ESI-TOF-MS: m/z calcd for C111H177O18 [M – H]–: 1798.2935;
found: 1798.3024 [M – H]–.
Acknowledgments
We are grateful to Spec. Lab. Tech Reijo Kauppinen for help in run-
ning NMR spectra and Spec. Lab. Tech Mirja Lahtiperä for running
the ESI-TOF-MS spectra. The National Technology Agency (TE-
KES, Project No. 40004/01) has financially supported this work.
ESI-TOF-MS: m/z calcd for C126H180F12O22 [M + Na]+: 2296.2672;
found: 2296.2607 [M + Na]+.
References
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(HOOC-[G2]-TFA) (11)
Pd/C (10% wt, 0.11 g) was added to a solution of 10 (1.10 g, 0.48
mmol) in EtOAc (30 mL). The reaction vessel for catalytic hydro-
genolysis was evacuated and filled with H2. The mixture was stirred
16 h at r.t., the catalyst was then filtered off and carefully washed
with EtOAc. The filtrate was evaporated and dried in vacuo to give
a white powder 0.94 g (90%).
1H NMR (CDCl3, 500 MHz): = 4.92 (4 H, m, 3-CH ), 4.27–4.16
(12 H, m, [G-1]-CH2, [G-2]-CH2), 2.37–2.30, 2.23–2.16 (8 H, m,
23-CH2), 1.98–1.05 (104 H, m), 1.26 (3 H, s, [G-1]-CH3), 1.16 (6 H,
s, [G-2]-CH3), 0.94 (12 H, s, 19-CH3), 0.90 (12 H, d, J = 6.7 Hz, 21-
CH3), 0.64 (12 H, s, 18-CH3).
13C NMR (CDCl3, 126 MHz): = 176.0, 173.7, 172.0, 157.0, 114.6,
79.4, 65.7, 65.1, 56.4, 56.0, 46.7, 46.4, 42.7, 41.9, 40.4, 40.0, 35.8,
35.3, 34.7, 34.5, 31.6, 31.0, 30.9, 28.1, 26.9, 26.2, 26.1, 24.1, 23.2,
20.8, 18.2, 17.7, 17.5, 12.0.
ESI-TOF-MS: m/z calcd C119H174F12O22: 2182.22 [M – H]–, found:
2182.83 [M – H]–.
(C6H5CH2O-[G2]-OH) (12)
To a solution of 10 (1.10 g, 0.48 mmol) in THF–MeOH (1:1, 20
mL) was added aq sat. NaHCO3 (5 mL) under stirring. After 1 h, an
additional portion of aq NaHCO3 solution was added and the mix-
ture was stirred overnight. The solvent was evaporated under vacu-
um and the crude product was extracted with Et2O/H2SO4 (40 mL/
20 mL, 0.6 M). The Et2O layer was washed with H2O (2 × 40 mL),
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J. Ropponen et al.
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