Synthesis of spiroannulated oligopyrrole macrocycles derived from lithocholic acid

Article abstract of DOI:10.1016/j.steroids.2009.04.004

Two new steroidal spiroannulated calix[4]pyrroles 5 and 10, derived from bile acids (lithocholate), were prepared by the acid catalyzed condensation of methyl-3,3-bis(pyrrol-2-yl)-5β-cholan-24-oate 3 with carbonyl compounds and with 2,2′-propane-2,2-diylbis(1H-pyrrole), respectively. The new compounds were fully characterized by physicochemical methods.

Full text of DOI:10.1016/j.steroids.2009.04.004

Steroids 74 (2009) 715–720
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Steroids
journal homepage: www.elsevier.com/locate/steroids
Rapid communication
Synthesis of spiroannulated oligopyrrole macrocycles derived from
lithocholic acid
Nguyen Thi Thu Huonga, Petra Klímkováa, Alessandro Sorrentib, Giovanna Mancinib, Pavel Drasˇarc,∗
a
ˇ
Department of Chemistry, J.E. Purkyneˇ University, Ceské mládezˇe 8, 400 96 Ústí nad Labem, Czech Republic
b CNR IMC-Sezione Meccanismi di Reazione, c/o Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185, Italy
c Department of Chemistry of Natural Compounds, Institute of Chemical Technology, Technická 5, 166 28 Praha 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new steroidal spiroannulated calix[4]pyrroles 5 and 10, derived from bile acids (lithocholate), were
prepared by the acid catalyzed condensation of methyl-3,3-bis(pyrrol-2-yl)-5␤-cholan-24-oate 3 with
carbonyl compounds and with 2,2ꢀ-propane-2,2-diylbis(1H-pyrrole), respectively. The new compounds
were fully characterized by physicochemical methods.
Received 13 August 2008
Received in revised form 5 March 2009
Accepted 8 April 2009
Available online 18 April 2009
© 2009 Elsevier Inc. All rights reserved.
Keywords:
Steroidal heterocycle
Chiral receptor
Pyrrole macrocycle
Microwave synthesis
Calix[4]pyrrole
Supramolecular synthon
1. Introduction
calix[4]pyrroles [6], where similar structural features are exploited
in enantioselective recognition. The estradiol porphyrin conjugate
In the last years, steroidal constructs have been attracting the
interest of many research groups in many branches of science
and technology, such as the medical and pharmacological fields,
supramolecular chemistry and nanotechnology [1–4]. In fact, the
inclusion of steroid residues in the molecular structure of certain
molecular species could ascribe them with new physicochemi-
cal and biological features, as well as new morphological features
related to their self-assembly. Upon the inclusion of spiroanu-
lated steroidal substituents in tetrapyrrole macrocycles we can
expect new and interesting properties in their association capabil-
ity with different compounds, new selective molecular interactions,
changes in fluorescence spectra and electrochemical properties,
as well as different and chiral sensitive changes in excited triplet
states. Moreover, this new class of compounds may also bear inter-
esting stereochemical features, which would definitely serve as a
new tool in molecular recognition, ion channel building-up, mem-
brane penetration and even photodynamic therapy (PDT). A very
important feature is the solvent assisted amplification of chiral-
ity studied in similar compounds (cf. [5] and papers cited therein).
A nice example of similar interesting compounds is the steroidal
was synthesized as a targeted photodynamic drug [7]. Despite the
fact that the structural type of compounds described is new their
properties could be compared with “steroidal dimers”, which may
be rather simple [8] or more complex, as described in recent reviews
[9,10].
In a recent study we provided data on the synthesis of a new type
of steroidal oligopyrrole macrocycles and their synthons [11–15].
We focused our interest also towards the improvement of some
already used chemical reactions, by means of microwave chemistry,
as used in contemporary literature [16]; for example, part of the
experimental descriptions on this communication has appeared in
the patented literature, in a foreign language [11–13].
2. Experimental
2.1. Materials and methods
TLC was performed on either HF254 plates (Merck) with detec-
tion by UV light or on plates made from MP Biomedicals SilicaGel G
with detection by spraying with a solution of 5 g of Ce(SO4)2(H2O)4
in 500 ml 10% H2SO4 and subsequent heating. Flash column chro-
matography was performed on silica gel (Merck, 100–160 ␮m)
with solvents distilled prior to use. 1H and 13C NMR spectra were
taken on a Bruker AVANCE 500/300 (500.1/300.13 MHz for 1H and
∗
Corresponding author. Tel.: +420 220 443 698.
E-mail address: Pavel.Drasar@vscht.cz (P. Drasˇar).
0039-128X/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2009.04.004

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N.T.T. Huong et al. / Steroids 74 (2009) 715–720
125.8/75 MHz for 13C), Varian Gemini 300 HC (300 MHz for 1H and
75 MHz for 13C) NMR spectrometer at 300 K if not stated otherwise.
The internal signal of tetramethylsilane (ı 0.0) for 1H and the central
line of solvent (ı 77.0) for 13C spectra were used as standards. Chem-
ical shifts are presented in ppm (ı), coupling constants in Hz (J). UV
spectra were taken on a Carey-300 UV-VIS spectrophotometer, CD
spectra were taken on a Jasco spectropolarimeter J-715 using quartz
cuvettes (path length l = 0.5 cm). Mass spectra were taken on a Q
TOF (Micromass) spectrometer with direct inlet (ESI), on a ZAB-EQ
(VG Analytical) instrument (FAB) with Xe ionization, or Autospec
Ultima (Micromass) by EI technique. As the source of microwave
(MW) irradiation a microwave microprocessor controlled chemical
reactor Plasmatronika M REOS with electromagnetic stirring, MW
generator of 2.45 GHz and temperature regulation was used.
31.25, 6; 28.45, 16; 27.45, 7; 24.43, 15; 24.11, 19; 21.12, 11; 18.52, 21;
12.29, 18.
2.2.2.2. Condensation with pyrrole with TFA. Trifluoroacetic acid
(8 ␮l) was added to the mixture of methyl ester of 3-oxo-5-␤-
cholan-24-oic acid (194 mg, 0.5 mmol) and pyrrole (2 ml, 3.01 g,
44 mmol) under argon and the mixture was stirred for 3 h at
room temperature. Then, the mixture was evaporated and co-
evaporated with toluene (3 × 1 ml). The residue was dissolved in
dichloromethane (20 ml), filtered through silica gel (10 g), and
washed with dichloromethane (50 ml). The filtrate was evaporated
and the residue chromatographed on a column of silica gel (27 g)
by cyclohexane: ether 9:1, yielding 3 (185 mg; 73%), as above.
2.2.3. Condensation of
methyl-3,3-bis(pyrrol-2-yl)-5ˇ-cholan-24-oate 3 with carbonyl
compounds
2.2. Chemical synthesis
2.2.3.1. General procedure. All reactions were performed under
inert atmosphere of argon using the vacuum line. Trifluoroacetic
acid was added under stirring to a mixture of methyl-3,3-bis(pyrrol-
2-yl)-5␤-cholan-24-oate 3 (0.5 mmol) and 10 equivalents of the
respective carbonyl compound in a suitable solvent were also
added. The reaction mixture was monitored by TLC and was stirred
until acceptable conversion. Then, dry Na2CO3 was added and, after
filtration, the filtrate was evaporated to dryness. The rough product
was purified by column chromatography on silica gel.
2.2.1. Esterification and subsequent oxidation of lithocholic acid 1
under microwave irradiation
A mixture of lithocholic acid (1, 1.27 g, 3.4 mmol) and p-toluene
sulphonyl acid monohydrate (281 mg, 1.5 mmol) in methanol
(80 ml) was irradiated by MW for 6 min at 50% of maximum inten-
sity (i.e. at 375 W). After the evaporation of methanol, water was
added (30 ml) and the crude product was filtered and washed with
water. Recrystallization from ether yielded 1.27 g (97%) of methyl
lithocholate, identical to the product described in the literature,
however, with m.p. 71–73 ◦C where literature mostly gives different
melting points [17] between 115 and 157 ◦C.
Fresh distilled pyridine (5.6 ml, 69 mmol) was added to
the mixture of dry chromium (VI) oxide (2.3 g, 23 mmol) and
dichloromethane (10 ml) at 0 ◦C, and the mixture was stirred until a
suspension was formed. Then methylester of lithocholic acid (1.5 g,
3.85 mmol) dissolved in dichloromethane (40 ml) was added. The
mixture was irradiated by MW for 6 min at 50% of maximum inten-
sity (i.e. at 375 W). Dichloromethane was distilled and the residue
was diluted by diethyl ether (20 ml), filtered through a layer of alu-
mina (30 g) and the filtrate was evaporated and co-evaporated with
toluene (3 × 10 ml). The product was recrystallized from diethyl
ether providing 1.45 g (97%) of methyl 5␤H-3-oxocholan-24-oate
2 with similar properties to those reported in the literature [18,19].
2.2.3.2. Condensation with pentafluorobenzaldehyde. The reaction
was set using 913 mg (5 mmol) of pentafluorobenzalde-
hyde, 253 mg (0.5 mmol) steroidal dipyrrylmethane 3 in dry
dichloromethane (5 ml) and 154 ␮l TFA. After 3 h, DDQ (116 mg) in
dry dichloromethane (5 ml) was added and the mixture was kept
at room temperature overnight. For purification, 120 g of silica gel
were used in cyclohexane: diethyl ether (24:1 mixture). It yielded
6.1 mg (2%) of product 5 as a brown colored amorphous powder. 1
H
NMR (CDCl3; 400 MHz): 0.64–2.46 m, steroid skeleton; 3.67 s, 3 H,
(24-COOCH3); 5.40–5.60 m (pyrrole); 5.95–6.20 m, (pyrrole); 7.55
m, 1 H (NH-pyrrole); 7.70 m, 1 H (NH-pyrrole). For C80H90F10N4O4
(1361.579) monoisotopic mass 1360.680; found MS: m/z: 1360
(M+.), 1359 (M+−H), 167 (–C6F5).
2.2.3.3. Condensation with acetone. Steroidal dipyrromethane 3
(252 mg, 0.5 mmol) was mixed with 50 ml of dry acetone and 8 ␮l
TFA for 1 h. Chromatography with C6H12:CH2Cl2 1:1 yielded 11 mg
(3%) of 10, as in Section 2.2.3.4.
2.2.2. Methyl-3,3-bis(pyrrol-2-yl)-5ˇ-cholan-24-oate 3
2.2.2.1. Condensation with pyrrole and BF3·OEt2. BF3·OEt2 (0.61 ml,
6.6 mmol) was slowly added to the mixture of methyl 5␤H-3-
oxocholan-24-oate (3, 1.3 g, 3.4 mmol) and pyrrole (5 ml) under Ar
and stirring. Stirring was continued for 3.5 h at room temperature
[20]. The mixture was evaporated and co-evaporated with toluene
(4 ml). The residue was dissolved in dichloromethane (20 ml) and
filtered through a small column of silica (10 g). The column was then
washed with dichloromethane (120 ml). Collected filtrates were
evaporated and then chromatographed on a column of silica in
cyclohexane:diethyl ether 9:1. It yielded 462 mg (27%) of product
3 and 123 mg (7%) of its isomer 4 as an amorphous powder. Prod-
uct 3 was identical to the compound described in the literature
[20].
2.2.3.4. MacDonald [2 + 2] condensation with 2,2ꢀ-propane-2,2-
diylbis(1H-pyrrole) and acetone. Steroidal dipyrromethane
3
(249 mg, 0.5 mmol) and 2,2ꢀ-propane-2,2-diylbis(1H-pyrrole) [21]
(176.5 mg, 1.0 mmol) in 50 ml of dry acetone and 8 ␮l TFA were
stirred for 1.5 h. Chromatography on 100 g silica gel in cyclo-
hexane: dichloromethane 2:1 yielded 183 mg of 10 (24%) as a
brownish amorphous powder. 1H NMR (299.97 MHz; pyridine-d5,
see Fig. 1 for atom numbering): 0.88 s, 3 H (18-CH3); 1.08 s, 3
2
H (19-CH3); 1.21 d, JH-H = 6.0, 3 H (21-CH3); 1.98 bs, 18 H (6
CH3-calix[4]pyrrole); 1.05–2.9 m steroid skeleton; 3.96 s, 3 H
(24-COOCH3); 6.14–6.36 m, 8 H); 8.67 bs, NH, 8.84 bs, NH, 9.79
pseudo-d (2 NH). 1H NMR (300 MHz; MeOD): 0.66 s 3 H (18-CH3);
0.90–0.96 bs, 3 H (19-CH3); 0.96–0.98 m, 3 H (21-CH3); 2.11–2.29
m, 2 H (6 CH3-calix[4]pyrrole); 1.0–2.4 m (steroid skeleton); 3.63 s,
5 H (24-COOCH3); 5.49–6.22 m, 8 H (calix[4]pyrrole); 7.21 (dt,
J = 8.50, 2.56 Hz, 1 H) 7.66 (ddd, J = 32.31, 5.64, 3.59 Hz, 1 H); 7.84 (d,
J = 51.29 Hz, 1 H); 8.46 (d, J = 16.41 Hz, 1 H). 13C NMR (75.48 MHz,
MeOD): 12.53, 18; 18.79, 21; 22.03, 11; 25.31, 19; 27.68, 2; –, 15; –,
16; 29.27, 7; 30.27, 23ꢀ; 30.93, 22ꢀ; 31.35, 21ꢀ; 31.77, 20ꢀ; 30.08, 24ꢀ;
29.99, 25ꢀ; 31.88, 22; 31.88, 23; 32.26, 6; 34.08, 1; 36.73, 10; 35.96,
Product 4 was characterized by 1H NMR (CDCl3; 400 MHz):
2
0.64 s, 3 H, (18-CH3); 0.84 s, 3 H, (19-CH3); 0.93 d, JH-H = 4.0, 3
H, (21-CH3); 1.05–2.46 m, steroidal skeleton; 3.67 s, 3 H, (1ꢀꢀ; 24-
COOCH3); 6.02 m 1 H (18ꢀ; pyrrole); 6.13 m, 2 H (2ꢀ + 17ꢀ; pyrrole);
6.50 m, 1 H (16ꢀ; pyrrole); 6.68 m, 1 H (3ꢀ; pyrrole); 6.78 m, 1 H (4ꢀ;
pyrrole); 7.68 bs, 1 H (N1H; pyrrole); 8.13 bs, 1 H (N4H; pyrrole). 13
C
NMR (75.44 MHz, CDCl3): 175.12, 24; 137.64, 19ꢀ; 129.42, 1ꢀ; 118.40,
16ꢀ; 115.89, 4ꢀ; 115.31, 3ꢀ; 108.15, 17ꢀ; 107.82, 18ꢀ; 56.74, 14; 56.15,
17; 51.75, 1ꢀꢀ; 50.39, 9; 42.99, 5; 40.65, 13; 40.65, 3; 40.43, 12; 39.42,
4; 36.04, 20; 35.62, 8; 35.24, 10; 34.32, 1; 32.45, 2; 31.30, 22 + 23;

N.T.T. Huong et al. / Steroids 74 (2009) 715–720
717
Fig. 1. (a) Atom numbering in 10 for description of 13 C NMR spectrum; (b) atom numbering in 4 for description of 13 C NMR spectrum.
20; 36.45, 8; 36.73, 5ꢀ; 36.73, 15ꢀ; 37.27, 10ꢀ; 32.26, 12; 38.36, 4;
40.62, 13; 41.36, 5; 41.81, 3; 43.96, 9; 52.05, 1ꢀꢀ; 57.34, 17; 57.92, 14;
101.59, 18ꢀ; 101.59, 2ꢀ; 103.81, 12ꢀ; 104.07, 13ꢀ; 103.28, 8ꢀ; 102.78,
7ꢀ; 106.21, 3ꢀ; 106.21, 17ꢀ; 129.90, 1ꢀ; 132.39, 19ꢀ; 139.17, 16ꢀ; 136.35,
4ꢀ; 140.04, 9ꢀ; 142.34, 11ꢀ; 139.89, 6ꢀ; 139.93, 14ꢀ; 176.51, 24. For
C50H70N4O2 (759.116) monoisotopic mass 758.549; found 758
(M+).
reaction times to 2 and 6 min with good yields—97% (see Scheme 1).
Both intermediates, i.e. the methyl ester of the lithocholic acid and
the subsequent methyl-3-oxo-5␤-cholan-24-oate 2 were obtained
very pure. In both cases, the intermediates crystallized immediately
after the work-up of the reaction mixture.
The reaction of methyl-3-oxo-5␤-cholan-24-oate 2 with 20
equivalents of pyrrole, under the catalysis of BF3.OEt2 without any
solvent, was performed in an inert atmosphere of argon at room
temperature [12,13]. In addition to the expected product, the methyl
3,3-bis(1H-pyrrol-2-yl)-5␤-cholan-24-oate 3 (27%), a mixture of
the isomers of methyl 3␰-(1H-pyrrol-2-yl)-3␰-(1H-pyrrol-3-yl)-5␤-
cholan-24-oates 4 (7%) was also isolated. From the two broad N–H
signals at 7.68 and 8.13 we assume that there are two kinds of
pyrrole moieties in the molecule. This assumption is further sup-
ported by 5 different proton signals of pyrrole C–H at 6.03, 6.13 (2H),
3. Results and discussion
The synthesis of the title compounds originated from lithocholic
acid 1, which was transformed into the carbonyl compound 2 in
two steps: esterification, protecting the carboxylic acid, followed
by the oxidation of a 3␣-hydroxygroup. Both steps were performed
in a microwave environment [11], allowing the shortening of the
Scheme 1. .

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N.T.T. Huong et al. / Steroids 74 (2009) 715–720
Scheme 2. Two diastereoisomers of 5.
Scheme 3. .

N.T.T. Huong et al. / Steroids 74 (2009) 715–720
719
Fig. 2. UV spectrum of 10 in CH3OH, conc. = 4.6 × 10−5 M.
Fig. 3. CD spectrum of 10 in CH3OH, conc. = 4.6 × 10−5 M.
6.50, 6.67, and 6.78, together with 6 protons. Similarly, the bis-2ꢀ-
substituted pyrrole only has 3 proton signals here [20]. Both the
2ꢀ-pyrrolyl-3-alfa/3ꢀ-pyrrolyl-3-beta and the 2ꢀ-pyrrolyl-3-beta/3ꢀ-
pyrrolyl-3-alfa are present in the mixture. This structure is further
supported by all 13C NMR lines obtained. We assume, based on
stereochemical considerations, that the 2-substituted pyrrole and
the 3-substituted pyrrole are present 1:1 in a mixture that we are
not able to separate. Under catalysis of the trifluoracetic acid only
product 3 was isolated in a good yield (73%) and there were even no
traces of 4. Isolation of 4 is the main focus of this report (Scheme 1).
The condensation products of methyl-3,3-bis(pyrrol-2-yl)-5␤-
cholan-24-oate 3 with carbonyl compounds are formed with
difficulty for several reasons. Steroidal dipyrromethane 3 is rather
unstable in the reaction media used, being readily decomposed
back to free pyrrole, which reacts with other components of the
reaction mixture to give complex mixtures. Thus, the reaction with
pentafluorobenzaldehyde, catalyzed by trifluoroacetic acid (TFA) in
dry dichloromethane under Ar and at room temperature, with the
subsequent oxidation by DDQ (dichlordicyanoquinone, 4,5-dichlor-
3,6-dioxocyklohexa-1,4-dien-1,2-dicarbonitrile, gave the expected
product 5, with only a 2% yield (Scheme 2). The product is expected
to be a mixture of two diastereoisomers, having two steroid units
connected to the calix[4]pyrrole, with the same or the opposite
absolute stereochemistry on the spiro-carbon. This interesting fea-
ture, which is supported by the broad lines of the 1H NMR spectrum
and t hexperience from the previous synthetic work [22], is being
further investigated. Although we were able to isolate and charac-
terize the compound, due to a very low yield we did not have the
possibility to do any separation or stereochemical study so far.
The reaction of 3 with benzaldehyde under the catalysis
of BF3·Et2O or TFA, as well as the condensation of steroid
dipyrromethane 3 with trimethylorthoformate and the conden-
sation with 5,5ꢀ-propane-2,2-diylbis(1H-pyrrole-2-carbaldehyde)
[5,5-dimethyldipyrromethan-1,9-dicarbaldehyde in some publica-
tions] with TFA did not give even a trace of the expected product(s).
This could be due to the insufficient electrophilicity of the carbonyl
carbon. Hence, we tried stronger Lewis acids, such as BF3.Et2O and
SnCl4, but also in this case we did not isolate any traces of product 8.
Condensation of 3 with acetone did not give the expected product
9 but the spiro-calixpyrrole 10 (3%). On the other hand, MacDonald
[2 + 2] condensation of methyl 3,3-bis(pyrrol-2-yl)-5␤-cholan-24-
oate 3 with 2,2ꢀ-propane-2,2-diylbis(1H-pyrrole) and acetone gave
desired product 10 in 49% yield (Scheme 2).
Fig. 4. Spatial representation of one diastereoisomer of 5 after molecular mechanics
geometry optimization (Cambridge Software, Chem Office, ver. 2008).
2,2ꢀ-propane-2,2-diylbis(1H-pyrrole) have been studied to search
for suitable preparation of new types of spiro-calix[4]pyrroles with
bile acid (Scheme 3). Results of this study will serve to broaden the
synthetic capacity of synthetic receptors containing highly orga-
nized chiral natural compounds. A systematic effort to improve the
low yields of the target compounds has been undertaken. However,
as it is well recognized, the cyclization of oligopyrrole macrocycles
could give a 10% yield considered “very high for this reaction”.
Spiro steroidal calix[4]pyrrole 10 was characterized by spec-
trometric measurements that, under the conditions used in the
experiments, did not show any superassembly observed in rela-
tive steroidal derivatives [23]. Relatively simple UV spectrum in
methanol (see Fig. 2) did not show any interesting changes with
time (3 h, 1 d) or with concentration changes. Similarly, the CD spec-
trum in methanol (see Fig. 3) showed only a weak chiral effect,
again, with no interesting changes with time (3 h, 1 d) or concen-
tration. The reason could be, as discussed above, that it is a mixture
of stereoisomers, which we were not able to separate so far (Fig. 4).
Acknowledgements
This
work
was
supported
by
the
NATO
grant
CBP.EAP.CLG.982972, and the Ministry of Education, Youth
and Sports of the Czech Republic projects No. 203/06/0006,
MSM6046137305, OC08043 (NPFM-II), 2B06024 (SUPRAFYT).
Acid catalyzed condensations of methyl 3,3-bis(pyrrol-2-
yl)-5␤-cholan-24-oate
3 with carbonyl compounds and with

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[14] Drasˇar P, Klímková P, Huong NTT. Syntéza spiroanelovany´ch oligopyrrolovy´ch
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