Bile acid-derived mono- and diketals-synthesis, structural characterization and self-assembling properties

Article abstract of DOI:10.1039/c003228j

Three oxo-derivatives of bile acid methyl esters have been used as starting compounds in the preparation of novel bile acid monoketals with 1,2-benzenediol (catechol) and 2,3-naphthalenediol, as well as mono- and diketals with pentaerythritol. Monoketals of pentaerythritol showed a tendency to form thermoreversible gels in many aromatic solvents and the methyl lithocholate derivative proved to be a supergelator able to form a gel with t-butylbenzene at a concentration as low as 0.5% w/v. Whereas the naphthalenediol ketals formed film-type materials in the studied solvents, the catechol ketals underwent rapid crystallization into X-ray quality single crystals. Single crystal X-ray structures of the catechol ketals have been determined. The monoketal obtained from methyl-3,7,12-trioxo-5β-cholan-24-oate (dehydrocholate) revealed to have an unusual packing pattern in its solid state compared to other bile acid derivatives reported in the literature. The synthesis of diketals from pentaerythritol furnished a mixture of two diastereomers which, in the case of the methyl lithocholate derivative, have been separated and the X-ray crystal structure of one isomer resolved.

Full text of DOI:10.1039/c003228j

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Bile acid-derived mono- and diketals—synthesis, structural characterization
and self-assembling properties†
Satu Ikonen,* Nonappa, Arto Valkonen, Raija Juvonen, Hannu Salo and Erkki Kolehmainen
Received 18th February 2010, Accepted 23rd March 2010
First published as an Advance Article on the web 15th April 2010
DOI: 10.1039/c003228j
Three oxo-derivatives of bile acid methyl esters have been used as starting compounds in the
preparation of novel bile acid monoketals with 1,2-benzenediol (catechol) and 2,3-naphthalenediol, as
well as mono- and diketals with pentaerythritol. Monoketals of pentaerythritol showed a tendency to
form thermoreversible gels in many aromatic solvents and the methyl lithocholate derivative proved to
be a supergelator able to form a gel with t-butylbenzene at a concentration as low as 0.5% w/v. Whereas
the naphthalenediol ketals formed film-type materials in the studied solvents, the catechol ketals
underwent rapid crystallization into X-ray quality single crystals. Single crystal X-ray structures of the
catechol ketals have been determined. The monoketal obtained from methyl-3,7,12-trioxo-
5b-cholan-24-oate (dehydrocholate) revealed to have an unusual packing pattern in its solid state
compared to other bile acid derivatives reported in the literature. The synthesis of diketals from
pentaerythritol furnished a mixture of two diastereomers which, in the case of the methyl lithocholate
derivative, have been separated and the X-ray crystal structure of one isomer resolved.
Introduction
Our interest in bile acid chemistry led us to undertake a program
towards novel conjugates of bile acids with ketal-functionality.
Bile acids are endogenous steroids which form as end products of
cholesterol metabolism in the liver. They are natural substrates of
enterohepatic circulation, and their main role is the digestion of
The spontaneous self-assembly of organic molecules into well-
defined molecular architectures has gained enormous interest in
the field of supramolecular chemistry in recent years. The cyclic
ketal unit serves as a rigid scaffold coordinating the side chains
in well-defined three-dimensional orientations. It is thus an at-
tractive building unit towards the construction of supramolecular
architectures, and in crystal engineering where the controllability
plays a significant role. As a ketal-forming alcohol, pentaerythritol
1
8
lipids and lipid-soluble vitamins. Bile acids, their salts and their
derivatives are found to have numerous applications in biology,
9
medicine and physiology, as well as in supramolecular chemistry
10
and nanoscience. Because of the unique facial amphiphilicity of
the bile acids, we anticipated that this may lead to molecules with
material properties like liquid crystals, organogels etc.
(
PE) can form both mono- and diketals (spirocyclic systems), and
rigid or flexible systems. Depending on the substituent, the ketals
derived from PE may contain one or two flexible dioxane rings or
they can be fully anancomeric. Grosu et al. have prepared different
types of PE ketals with flexible or anancomeric ring systems and
also studied the substituent effect on the magnetic properties of the
protons in the 1,3-dioxane ring system. Pentaerythritol ketals and
acetals have been widely used as building blocks aimed for use in
supramolecular chemistry, nanostructures and materials science.
Herein, we report the synthesis of several novel bile acid-
derived mono- and diketals and give detailed information of their
structures in solution and in solid state, and further describe
the preliminary studies of their self-assembling properties. Bile
acid ketals do not exist widely in the literature and only a few
2
11
reports were found. Here, we have chosen three different methyl-
3
-oxy-cholanoate derivatives (3a–c) as enantiopure ketones in the
preparation of the ketals. Three monoketals (5a–c) were prepared
with pentaerythritol forming a conformationally flexible dioxane
structure with two free hydroxymethyl extensions. Further, in order
to decrease the flexibility of the 1,3-dioxane ring, cathechol and
naphthol were introduced as the ketal-forming alcohols in 7a,c
and 8a,c. Finally, three diketals (10a–c) with pentaerythritol (PE)
were prepared and the influence of the bile acid substituent to the
flexibility of the dioxane rings and the conformational preferences
of these molecules in solution and in solid state were studied.
The monoketals 5a–c were studied for their organogelling
properties and 5a proved to form gels in many aromatic solvents at
0.5–2% w/v concentrations. Low molecular mass organogelators
3
4
5
These include dendrimers, macrocyclic structures, polymers
6
and molecular rods. Molecular rods are relatively rigid, linear
and long molecules and they have gained growing interest in
chemistry and biochemistry, as well as in materials science.
7
Wessig et al. have recently reported the synthesis of molecular
rods with oligospiroketal backbones with different solubility-
enhancing substituents and studied the use of these rods as
6
hydrophobic membrane anchors.
Department of Chemistry, P.O. Box 35, FIN-40014 University of Jyv a¨ skyl a¨ ,
Finland. E-mail: satu.ikonen@jyu.fi; Fax: +358 14 260 2501; Tel: +358 14
2
60 2654
(LMOGs) represent an active area of research not only for
†
Electronic supplementary information (ESI) available: Complete ex-
their organogelation properties but also for their numerous
perimental part, supplementary and clarifying figures. CCDC reference
numbers 766948–766950. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c003228j
12
applications as new organic soft materials. It is known that these
organogelators self-assemble through highly specific noncovalent
2
784 | Org. Biomol. Chem., 2010, 8, 2784–2794
This journal is © The Royal Society of Chemistry 2010

View Article Online
interactions, such as hydrogen bonding, resulting in the formation
of highly entangled fibrillar networks which encapsulate and
immobilize the solvent. However, the gelation phenomena by the
LMOGs still remain poorly understood. Bile acid derivatives,
13
including e.g. amino acid alkyl ester derivatives, bile acid
1
4
15
amidoalcohols, bile acid alkyl derivatives and cationic bile
16
salts have been widely studied as organo- or hydrogelators. Re-
cent reports from our laboratory have concentrated on unravelling
the interactions and self-assembling properties in the gel and their
comparison to those in the solid state. The gels and the xerogels
prepared here were further studied by electron microscopy and
NMR spectroscopy.
17
The synthetic procedure for the preparation of diketals with
PE produced a mixture of two isomers (I and II). In the case of
methyl lithocholate derivative 10a, the isomer I was isolated from
the mixture and crystallized, thus enabling more detailed study of
their structures. The molecular structure of 10aI in crystalline state
was determined by single crystal X-ray diffraction. Furthermore,
whereas the naphthalenediol-derived ketals 9a and 9c formed film-
type materials in the studied solvents, the catechol-derived ketals
7a and 7c were crystallized as single crystals, and their molecular
structure and crystal packing were studied.
Dimeric bile acid derivatives have found applications in the fields
18
of pharmaceutical and supramolecular chemistry. Furthermore,
the diketals prepared here might mimic the before mentioned
6
oligospiroketals and, in addition, introduce amphiphilicity and
chirality into the structure. Bile acids are substrates for transporter
proteins in the liver and the intestines, and they can thus be
19
exploited in drug delivery and targeting. On the other hand,
acetals are promising candidates for the development of acid-
20
sensitive linkages for hydroxyl groups. Thus, the preparation
of bile acid ketals may lead to novel prodrugs tailored for en-
hanced oral bioavailability or liver targeting of drugs; dihydroxy-
containing drugs can be conjugated directly to bile acids using
ketal linkage, or alternatively, pentaerythritol may be utilized as
a spacer linking a ketone-drug to bile acid. Many drugs (such
as catechins and catecholamines dopamine and epinephrine) are
derivatives of catechol, and thus the catechol ketals prepared here
are particularly interesting.
Results and discussion
Synthesis of bile acid-derived mono- and diketals of catechol,
◦
Scheme 1 (i) MeOH, AcCl, reflux, 18 h or MeOH, HCl, 0–55 C,
2
,3-naphthalenediol, and pentaerythritol
◦
4
Na
5
min; (ii) acetone, Jones reagent,
Cr O/H SO
0
C, 10 min or AcOH,
CO , DMF, rt, 24 h; (iv)
p-TSA, DMF–toluene (3 : 2), reflux, 44 h; (v) Montmorillonite, toluene,
2
2
O
7
·2H
2
2
4
, rt, 24 h; (iii) MeI, Cs
2
3
The synthetic route to the monoketals is presented in Scheme 1.
Preparation of the ketals started by synthesis of methyl esters of
the bile acids 1a and 1b using esterification methods described
reflux, 24 h.
21
in the literature, resulting in 2a and 2b. The next step was the
oxidation of the hydroxyl group/groups in the steroidal part, and
it was carried out by methods described in literature to give 3a
and 3b. In the case of 1c, esterification was carried out by its
v/v) with p-toluene sulfonic acid (p-TSA) as a catalyst and using
a Dean–Stark apparatus in order to remove the water from
the reaction mixture by azeotropic distillation with toluene. In
the reaction of 3a with pentaerythritol, 1 : 2 ratio was used. In
order to find out if only the keto-group at position 3 is reactive
towards the ketalization in these conditions, four- and six-fold
excess of pentaerythritol was used in the case of ketones 3b and
3c, respectively. It was discovered that the reaction took place
selectively at position 3 while the other keto-groups remained
intact. Yields of 3a–c varied between 48 and 81% after purification.
22
reaction with ca. six-fold excess of methyl iodide using Cs
2
CO as
3
a base at room temperature for 24 h. Pure product was gained by
precipitation from water.
At first, the monoketals of PE (4) and three different bile acid
methyl esters (3a–c) have been prepared. PE monoketals have a
flexible 1,3-dioxane ring with two free hydroxymethyl substituents.
The reactions were carried out in refluxing DMF–toluene (3 : 2
This journal is © The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2784–2794 | 2785

View Article Online
Next, the idea was to decrease the flexibility of the dioxane ring
and, therefore, vicinal aromatic diols were used (instead of PE)
in ketal formation. Clay-catalyst in the ketalization reaction was
selected since it has been used successfully in the preparation of
23
benzodioxoles before. Ketalization reactions between 3a,c and
aromatic diols, catechol (6) and 2,3-naphthalenediol (8), were
carried out by refluxing equimolar amounts of ketone with diol
using montmorrilonite as a catalyst in toluene with a Dean Stark–
trap for 24 h. Yields of 7a,c and 9a,c varied between 48 and 74%
after purification.
During the previous synthesis of PE-monoketals, the formation
of diketals as side products was already observed. In optimizing
the synthesis of diketals, it was found out that the use of ketone : PE
ratio 5 : 3 minimized the formation of side products, and the
main side product, namely monoketal, was easily removed by
column chromatography or by washing the product carefully with
EtOAc. Otherwise, reaction arrangements followed those for the
preparation of monoketals 5a–c. The synthesized diketals are
presented in Scheme 2. The synthetic procedure always produces
a mixture of two diastereomers, I and II, which cannot be
interconverted to each other without breaking a bond (i.e. by
conformational change in the 1,3-dioxane moieties). This was
13
Fig. 1 Partial C NMR spectra of 10a in CD
2
Cl
2
at 303 K showing the
differences between the isomers I and II.
Table 1 Gelation studies with 5a–c
Solvent
5a
5b
5c
Benzene
Toluene
p-Xylene
m-Xylene
o-Xylene
Mesitylene
Cumene
Ethylbenzene
t-Butylbenzene
Chlorobenzene
Anisole
s, G (2%)
s, G (2%)
s, G (1%)
s, G (1%)
s, G (2%)
s, G (1%)
s, G (2%), g (1%)
s, G (2%), g (1%)
s, G (0.5%)
s, p (2%)
s, p (2%)
s, pg (2%)
s, pg (2%)
s, pg (2%)
s, p (2%)
s, pg (2%)
s, pg (2%)
s, pg (2%)
s, pg (2%)
s, p (2%)
S
s, p (2%)
s, p (2%)
s, p (2%)
s, p (2%)
s, p (2%)
s, p (2%)
s, p (2%)
s, p (2%)
s, p (2%)
s, p (2%)
S
1
3
recognized by an appearance of two signals in the C spectra
for spiro-carbons C(3,3¢) and C(27) as well as in some carbons of
the steroidal skeleton. Yields of 10a (mixture of two isomers), 10b
(
6
mixture of two isomers) and 10c (mixture of two isomers) were
6, 29 and 48%, respectively. A small amount of isomer 10a(I) was
S, gf (2%)
isolated from the mixture of 10a(I) and 10a(II) based on its low
solubility in ethylacetate, where the isomer 10a(II) was soluble.
S = soluble at room temperature, s = soluble at boiling point,
G = transparent gel at rt, g = opaque gel at rt, gf = gel at refrigerator
temperature, pg = partly forms gel, p = precipitates, concentrations (%
w/v) are given in parenthesis.
NMR spectroscopy
Bile acid-derived monoketals of PE have a flexible 1,3-dioxane
ring to which two hydroxymethyl moieties are attached. H NMR
rings and, as a result, four possible conformational isomers. Two
of these conformers are C2-symmetric while the two others are
unsymmetric. As in the case of monoketals, the conformational
change is fast in the NMR time scale and only averaged chemical
shifts are seen for different conformers. As a result, the carbons
C(26) and C(26¢) give one resonance, as do the carbons C(28) and
C(28¢), and because of the chiral bile acid substituent, carbons
C(26) and C(28) as well as C(26¢) and C(28¢) remain magnetically
different. Consequently, the protons in the dioxane ring system
give two AB-quartets, which are overlapping in the spectrum
1
spectra of these compounds show different chemical shift values
for all the protons of the 1,3-dioxane ring resulting from their
diastereotopicity caused by the chiral bile acid backbone. Because
the change in conformation is fast in the NMR time scale, the
chemical shifts for different conformers are averaged. As a result,
1
in the H NMR spectrum of the monoketals 6a–c there should
be two AB-quartets in the subspectra of the 1,3-dioxane moiety
resulting from the axial and equatorial protons 26-CH
2
and 28-
CH , and two singlets for 26¢-CH and 28¢-CH . The spectral
2
2
2
measured in CDCl in the case of the isomer I, while in the
3
resolution of the AB-quartets and singlets was highly dependent
spectrum of isomer II they are well separated (see ESI† Fig. S2
on the solvent used. For example, when 6b was measured in
and S3 for the spectra).
CD OD (see the ESI† Fig. S1 for a copy of the spectrum), the
3
AB-quartets and singlets were nicely resolved, thus emphasizing
the significance of the solvent effects.
Self-assembly of bile acid ketals leading to organogelation
After successful synthesis and characterization, attempts were
made towards the crystallization of the ketals from a variety of
solvents. During the course of our investigation it was found that
PE monoketals 5a–c were able to immobilize a variety of aromatic
solvents, leading to organogelation. Table 1 presents the results
from the gelation tests.
Compound 5a was found to form a transparent gel at room
temperature with benzene, toluene, o-xylene, cumene, ethylben-
zene and chlorobenzene in concentrations of 2% w/v,‡ and with
In the case of diketals 10, unambiguous assignment of NMR
chemical shifts for protons and carbons in the dioxane ring system
2
is more complex. Grosu et al. have studied the stereoisomerism
of some trispiro-1,3-dioxanes obtained from substituted cyclo-
hexanones and pentaerythritol, and their results have been the
basis for the analysis of the diketal structures reported here. The
isolation of the pure isomer 10a(I) and the enrichment of the
other isomer (10a(II)) enabled differentiation of the resonance
lines originating from the different isomers. Based on the analysis
1
13
of the H and C NMR spectra (Fig. 1) of the two isomers, we
have concluded that both of the structures contain flexible dioxane
‡ All the concentrations given as % refer to % w/v (gelator/solvent).
2
786 | Org. Biomol. Chem., 2010, 8, 2784–2794
This journal is © The Royal Society of Chemistry 2010

View Article Online
Scheme 2 Prepared diketals.
p-xylene, m-xylene and mesitylene in concentrations of 1%. With
cumene and ethylbenzene it formed a gel also in concentration
of 1%, but the gel was already opaque indicating not so strong
ability to gel these solvents. In the case of t-butylbenzene, the
transparent gel was formed in 0.5% concentration. 5a is soluble
in anisole at room temperature; however, when the 2% solution
of 5a in anisole was cooled in a refrigerator, a transparent
gel was formed. In the case of compounds 5b and 5c, the
solubility to tested aromatic solvents was lower. 5b formed an
opaque gel-like material in concentrations of 2% with most
of the tested solvents, but soon after gel-formation, the com-
pound started to precipitate producing partly gelatinous and
partly solid material. Compound 5c was not able to form gels
with any of the tested solvents in the concentration of 2% or
below.
24
Maitra et al. have prepared an ester from deoxycholic acid
and PE, and studied its gelation ability; however, this ester did
not show any tendency to gel the investigated solvents. On the
other hand, the amide from deoxycholic acid and 2-amino-2-
hydroxymethyl-1,3-propanediol formed stable, transparent, ther-
moreversible hydrogels in the presence of varying amounts of
24
solvents such as MeOH, EtOH, DMSO, and DMF. It is often
deduced that the gel-formation by bile acid derivatives is due to the
14
25
amide-functionality in the side chain. However, a recent report,
together with the results presented here, show that stable gels may
also be formed by another type of derivative, and even when the
functionality is not in the side chain but conjugated to the steroidal
part.
Fig. 2 SEM images of xerogels obtained from the gels of 5a in toluene
(2% w/v) (above) and 5b in toluene (2% w/v) (below).
In order to have some insight into the morphology of the gels,
the xerogels obtained from the toluene, p-xylene or t-butylbenzene
gels of 5a and from the toluene gel of 5b were studied by scanning
electron microscopy (SEM). Repeatable spherical fine structures
were observed in the case of xerogels obtained from the gels derived
from 5a and 5b with different solvents (see Fig. 2 and 3, see
ESI† Fig. S4 for additional SEM images). Further, the spheres
are quite uniform and have somewhat fibrous substructures, as
may be seen in Fig. 3, representing the xerogel obtained from the
t-butylbenzene gel of 5a.
In order to study the formation and the thermoreversibility of
1
the gels, H NMR spectra were measured from the 3% toluene-d
gel of 5a at variable temperatures. Fig. 4 shows the H NMR
8
1
spectra of the gel when it is heated up (Fig. 4a) and when the
melted gel (sol) is cooled down (Fig. 4b). First, the gel was let to
settle down over night, after which the spectra were measured.
◦
At 30 C a significant line broadening of the proton signals
was observed to the extent that they almost disappeared. With
gradual increase in the temperature, recovery of the resonance
lines was observed, indicating disruption of the self-organization
This journal is © The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2784–2794 | 2787

View Article Online
due to thermal motion of the moieties. The resonance lines
◦
◦
started to become more visible at 40 C, and at 45 C there was a
considerable sharpening of all the resonance lines upon complete
gel melting. Following melting, the solution was again let to cool
down gradually, and before each measurement the temperature
1
was allowed to stabilize for 5 min and the H NMR spectra were
recorded. Upon cooling down the sample, there was a significant
change in the chemical shifts originating from the protons in
terminal hydroxyl groups of the PE-part of 5a (marked with an
asterisk in Fig. 4b). A small change in the chemical shift of the
protons originating from the CH
also be observed.
2
-protons in the the PE-part can
Interestingly, upon aging the sample (see Fig. 5) there are
again changes in the appearance of the spectra, but now they
are independent of the temperature and, thus, probably reflect
the changes in the structure when the gel starts to form. First
of all, the resonance peak of the hydroxyl protons gets broader
and becomes a bit more shielded. Another change is observed at
the resonances originating from the CH -protons of the PE-part.
2
While their peaks start to broaden, two forms appear (see Fig. 5
and ESI† Fig. S5) with different chemical shifts. The growing form
has its resonances more shielded. Finally, everything is in one form.
This is proposed to reflect the formation of hydrogen bonds which
eventually lead to gel formation, and finally to disappearance of
the resonances.
Fig. 3 SEM images of xerogel obtained from the gel of 5a and
t-butylbenzene (2% w/v).
1
Fig. 4 (A) Heating up the gel of 5a in toluene-d
8
, H NMR spectra at
(
a) 303 K, (b) 308 K, (c) 313 K, (d) 318 K, (e) 323 K and (B) cooling down
1
1
◦
the melted gel of 5a in toluene-d
8
, H NMR spectra at (a) 323 K, (b) 318 K,
Fig. 5 H NMR subspectra of 5a in toluene-d
8
at 30 C after aging for
(
c) 313 K after 10 min, (d) 308 K, and (e) 303 K.
0–60 min (sample measured every 3 min).
2
788 | Org. Biomol. Chem., 2010, 8, 2784–2794
This journal is © The Royal Society of Chemistry 2010

View Article Online
13
13
Fig. 6
C NMR spectrum of 5a in CDCl
3
(a) and C CP/MAS NMR spectra of 5a crystallized from acetonitrile (b), toluene (c), and benzene (d).
Studies in the solid state
kind of high order in the packing in the gel-state, more experiments
are needed.
Despite several attempts, we were not able to obtain single crystals
from 5a–c suitable for structure determination by single crystal
X-ray diffraction. In the case of 5a, the solids obtained by
crystallization from various solvents (benzene, toluene, p-xylene,
chlorobenzene, acetonitrile and acetone) were, however, highly
crystalline, thus enabling its study in the solid state by CP/MAS
NMR spectroscopy. In Fig. 6, the selected spectra are presented
with comparison to the spectrum measured in liquid state (see
ESI† Fig. S6 for more spectra). In the case of 5a crystallized from
toluene, p-xylene, and chlorobenzene, the spectra possess a doublet
resonance pattern for most of the carbons, indicating the crystal
structure of 5a to have two crystallographically independent
molecules per asymmetric unit.
In the case of solid crystallized from benzene, two different
forms were observed, from which the minor one seems to be
the same as the ones crystallized from other aromatic solvents
and the major form seems to be a benzene solvate. Interestingly,
when the same compound was crystallized from either acetonitrile
or acetone (in which it is freely soluble and thus does not form
gel), different spectra were obtained. In these spectra the doublet
resonance was only observed in some of the carbons and not,
for example, in the carbonyl carbon. Also, the signals originating
from the carbons in the pentaerythritol part were not resolved,
potentially resulting from severe disorder in that part of the
molecule. Interestingly, in all of the spectra of 5a crystallized
from gel-forming solvents, the region from 50 to 64 ppm includes
seven resonances (some of which are split to two) originating
from the carbons C(25), C(14), C(17) and the four carbons in
the pentaerythritol part. This reflects a highly ordered packing
system in the solids obtained from the gelling solvents. However,
in order to reveal whether this observation also reflects the same
Single crystals of catechol ketals 7a and 7c were obtained from
ethyl acetate–hexane.§ Compound 7a crystallizes in triclinic space
group P1 with two crystallographically independent molecules
in the asymmetric unit. The molecular structure of molecule A
in the crystals of 7a is illustrated in Fig. 7. The two molecules
differ by the conformation of their side chains. Conformation of
the bile acid side chain can be described using the value of the
C17-C20-C22-C23 dihedral angle, or more comprehensively by
examining all of the dihedral angles in the side chain using letters
t (trans), g (gauche) or i (intermediate) for the combination of
the four conformations, the first four in Table 2. Comparison of
the two molecules in the asymmetric unit of 7a reveals that they
differ slightly by their side chain conformations, indicated by the
◦
dihedral angles. C17-C20-C22-C23 in B is 11.7 smaller and C22-
◦
C23-C24-O25 in B is 13.6 larger than the respective angles in the
molecule A. Additionally, there are differences in the interactions
between the molecules A and between the molecules B.
§
Crystal data for 7a. C31
H
44
O
4
, M = 480.66, triclinic, a = 7.5708(2), b =
◦
1
1.1245(3), c = 16.1074(5) A˚ , a = 80.080(2), b = 85.635(2), g = 88.002(2) ,
T = 123 K, space group P1 (no. 1), Z = 2, Z¢ = 2, 10657 reflections
measured, 6565 unique (Rint = 0.055) which were used in all calculations.
The final R
7
1
1
and wR were 0.073 and 0.134, respectively. Crystal data for
2
c. C31
H
40
O
6
, M = 508.63, triclinic, a = 7.5916(1), b = 11.4074(2), c =
◦
6.0654(3) A˚ , a = 97.471(1), b = 102.069(1), g = 95.081(1) , T = 123 K,
space group P1 (no. 1), Z = 2, Z¢ = 2, 10685 reflections measured, 6588
unique (R = 0.024) which were used in all calculations. The final R and
int
1
wR
2
88 8
were 0.044 and 0.095, respectively. Crystal data for 10a(I). C55H O ,
M = 877.25, monoclinic, a = 29.4843(5), b = 6.4390(10), c = 12.7626(2) A˚ ,
◦
b = 97.7664(9) , T = 123 K, space group C2 (no. 5), Z = 2, 9619 reflections
measured, 3234 unique (Rint = 0.035) which were used in all calculations.
The final R and wR were 0.046 and 0.108, respectively.
1
2
This journal is © The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2784–2794 | 2789

View Article Online
◦
Table 2 Selected torsion angles ( ) in the molecules 7a, 7c, and 10a(I)
also by the orientation of the ketal-part. While in molecule B the
deviation of C3 from the plane of the aromatic ketal ring system
7
a(A)
7a (B)
7c(A)
7c (B)
10a(I)
˚
˚
is 0.274 A, in molecule A it is 0.037 A, making it almost flat while
the other one is slightly distorted.
C13-C17-C20-C22 176.8(4) 175.0(4) 173.4(2) -56.5(3)
-178.5(2)
C17-C20-C22-C23 -176.8(4) 165.1(4) -165.9(2) -160.5(2) -156.0(2)
C20-C22-C23-C24 174.8(4) 172.6(4) -170.5(2) -179.5(3)/ 74.9(3)
The packing in the crystals of 7c is illustrated in Fig. 8.
Interestingly, in its crystal, 7c forms chiral entities in which all
of the molecules are parallel oriented (see Fig. 6). The two
independent molecules A and B are inclined to each other by
-
157.5(6)
C22-C23-C24-O25 -146.6(4) -160.2(4) -165.8(2) 39.7(5)/
4.9(19)
C23-C24-O24-C25 -175.9(4) -176.5(5) -178.5(3) 178.7(3)/ 180(3)
176.9(11)
11.1(4)
2
◦
26.4 . This kind of packing, where all the bile acid backbones are
-
oriented in (almost) parallel fashion, and with their a- and b-faces
together, is very unusual for bile acid derivatives which usually
form bilayered structures where the hydrophobic parts unite and
hydrophilic parts are brought together. In fact, of the 532 bile
C1¢-O1¢-C3-O2¢
C2¢-O2¢-C3-O1¢
15.95
-16.47
16.50
-15.84
-3.02
3.72
-19.40
19.00
—
—
26
acid-derived structures in the CSD-database, only one structure
27
was found to pack in quite a similar way. It should be noted
that certain cyclocholates have been reported to display unusual
packing patterns (not bilayers) in their solid state, resulting from
28
the intrinsic structure of the molecules. Like in the case of
a, in the crystals of 7c the methyl carbon of the ester group
7
of one molecule B lies above the plane of the phenyl ring of
3
another molecule of B. The distance between the CH(sp )-proton
˚
and the centroid of the phenyl ring is 2.688 A, and the angle
◦
Fig. 7 Ortep drawing of 7a showing ellipsoids with 50% probability.
between the ring plane and the methyl carbon is 119.99 and, thus,
there may be weak CH–p hydrogen bonding interaction between
There is a weak non-conventional intermolecular hydrogen
bond between a proton attached to the aromatic ring of one
them. Centroid-to-centroid distance between the aromatic rings is
˚
4.510 A and the angle between the plane of the aromatic rings is
◦
molecule B and the carbonyl oxygen of another molecule B with
25.92 .
◦
˚
Attempts to crystallize the naphthalenediol ketals (9a and 9c)
3
.283 A donor-to-acceptor distance and 166.20 bond angle (See
ESI† Fig. S7 for the packing diagram of 7a). On the contrary,
molecules A do not form any intermolecular hydrogen bonds
between each other. The methyl-carbon from the ester group in
the side chain of molecule A lies above the plane of the phenyl ring
of molecule B and, thus, there are probably weak CH–p hydrogen
using different solvent systems resulted in thin film-type materials.
A thin film of compound 9a in CHCl
3
was placed over a glass slide
and observed under polarizing optical microscope. The compound
◦
◦
turned isotropic at 210 C. Upon cooling to 90 C, birefringent
textures were observed (for photographs see ESI† Fig. S9), but no
liquid crystalline phases were observed.
3
bonding interactions between the CH(sp ) and the phenyl ring.
The distance of the proton to the centroid of the phenyl ring is
Single crystals of 10a(I) were obtained from CH
2
Cl .§ Com-
2
◦
˚
pound 10a(I) crystallizes in monoclinic space group C2 and, as
pointed out earlier, this molecule has rotational symmetry over
the spirocarbon C27 and, thus, only half of the molecule is present
in an asymmetric unit of its crystal. The molecular structure of
10a(I) is illustrated in Fig. 9. Both of the 1,3-dioxane rings are in
chair conformation, as can be expected. The bile acid side chain is
in ttgg-conformation. The molecule is quite linear and its length
is approximately 3.3 nm, thus it resembles a molecular rod. The
linearity of this kind of steroidal molecular rod could be enhanced
by using, for example, allobile acid (with trans-fusion of the A and
B rings) or cholesterol as the steroidal part, since the ring junction
2
.795 A and the hydrogen bonding angle is 152.08 . No interaction
between the aromatic rings is observed.
Compound 7c crystallizes in triclinic space group P1 with two
crystallographically independent molecules in the asymmetric unit
as well (see ESI† Fig. S8 for the molecular structure of 7c). Again,
the differences between the two independent molecules are found
in the conformation of the side chain. Whereas the conformation
of the side chain of molecule A verges on perfect zigzag (all-trans,
tttt), the side chain in the molecule B is disordered between two
conformations where two of the angles are in gauche- and two are
in trans-conformation. The two molecules differ from each other
Fig. 8 Packing in the crystal of 7c. The disorder in the side chain and the hydrogen atoms are omitted for clarity.
790 | Org. Biomol. Chem., 2010, 8, 2784–2794
2
This journal is © The Royal Society of Chemistry 2010

View Article Online
Fig. 9 Ortep drawing of 10a(I) showing the ellipsoids with 50% probability. Only half of the molecule is found in an asymmetric unit.
1
3
between the A and B rings of these are cis instead of trans, as in bile
acids. The crystal packing of 10a(I) is driven by the close-packing
forces.
FT. The C CPMAS chemical shifts were referenced with those
of glycine standard measured before each sample.
X-Ray crystallography
Experimental
Single crystals of compounds 7a and 7c were grown from EtOAc–
hexane (10 : 90 v/v) and those of compound 10aI from CD
2
Cl ,
2
Typical experimental procedures and representative examples of
characterization of compounds are given below. Complete detailed
experimental part including full characterization data for all
compounds is in the ESI.†
respectively. Data were collected at 123(2) K on a Nonius
KappaCCD diffractometer with graphite monochromated Mo-
29
Ka radiation. COLLECT data collection software was utilized
30
and data was processed with DENZO-SMN. The reflections
were corrected for Lorenz polarization effects but absorption
correction was not used. The structures were solved by direct
General
31
32
methods (SIR2002 ) and refined anisotropically (SHELXL-97 )
Analytical grade reagents and solvents were used for the synthesis,
purification, crystallization and gelation studies. Bile acids were
2
by full matrix least squares on F values. Hydrogen atoms
were located from the expected geometry and were refined only
˚
purchased from Sigma Aldrich. Silica 0.043–0.060 A was used
33
1
13
isotropically. Figures were drawn with Ortep-3 for Windows and
in column chromatographic purifications. H and C NMR
experiments were run with a Bruker Avance DRX 500 NMR
spectrometer equipped with a 5 mm diameter broad band inverse
probehead working at 500.13 MHz for H and at 125.76 MHz for
C. The C{ H} NMR spectra were measured in standard way
using composite pulse, waltz16, decoupling. NMR spectra were
34
Mercury. CCDC 766948–766950 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
1
1
3
13
1
1
13
Gelation tests
measured in CDCl
were referenced to the solvent signals (d = 7.26 (CDCl
.09 (toluene-d
3
and toluene-d
8
. H and C chemical shifts
) and d =
) for H and d = 77.0 ppm for C from int. TMS).
3
For each experiment, a weighed amount of compound (5a–c) was
placed in a 5 mL test tube and the tested solvent was added. The
mixture was heated to reflux until it turned into a clear solution
1
13
2
8
Molecular masses of the compounds were confirmed either by
using a Micromass LCT ESI-TOF mass spectrometer in positive
ion mode or by VG AutoSpec 3500 HR-MS EI/CI high resolution
mass spectrometer. IR spectra were recorded on Bruker Tensor 27
FT-IR using Pike GladiATR attenuated total reflectance (ATR)
cell equipped with a diamond crystal plate. Elemental analyses
were carried out using Elementar Vario EL III-analyser.
(if soluble), after which the sample was sonicated for ca. 10–60 s.
Upon cooling down, the formation of transparent gel (G), opaque
gel (g), precipitate (P), or solution (S), or something between these
was detected. The state of the sample was defined as a gel when it
was stable to inversion. When the gel formation or precipitation
did not occur at room temperature, the sample was allowed to cool
◦
down to ~6 C in a refrigerator and its appearance was studied.
1
3
C CP/MAS NMR
SEM
For CP/MAS NMR spectroscopy, compound 5a was crystal-
1
3
1
lized from various solvents. The C{ H}CP/MAS spectra were
recorded on a Bruker AV 400 spectrometer equipped with a 4 mm
standard bore CP/MAS probehead whose X channel was tuned to
Scanning electron micrographs were taken with Bruker Quan-
tax400 EDS microscope equipped with a digital camera. Samples
of the xerogels were prepared by placing a hot, clear solution of
the gelator in toluene on carbon tape placed over a sample stub,
and after evaporation of the solvent, coated with gold in a JEOL
Fine Coat Ion Sputter JFC-1100.
1
3
1
00.62 MHz for C. The other channel was tuned to 400.13 MHz
1
for broad band H decoupling. Approximately 100 mg of dried
and finely powdered samples were packed in the ZrO rotor closed
2
1
3
1
with Kel-F cap and spun at 10 kHz. The C{ H}CP/MAS NMR
was carried out for all samples under Hartmann–Hahn conditions
with TPPM decoupling. The p/2 pulse for proton and carbons
were found to be 4.0 and 5 ms at power levels of -5.0 and -4.0 dB,
respectively. The experiments were conducted at contact time of
Synthesis and characterization
Methyl-3a-hydroxy-5b-cholan-24-oate (2a) and Methyl-3a,12a-
dihydroxy-5b-cholan-24-oate (2b) were prepared following the
2
1
2
ms. A total of 10 000 transients were recorded with 4 s recycle
known procedures.
Methyl 3,7,12-trioxo-5b-cholan-24-oate
35
delay for each sample. All FIDs were processed by exponential
apodization function with line broadening of 20–40 Hz prior to
(3c) was prepared from 1c by esterification reaction described
15b
in the literature for other bile acid esters.
Org. Biomol. Chem., 2010, 8, 2784–2794 | 2791
This journal is © The Royal Society of Chemistry 2010

View Article Online
22
Methyl-3-oxo-5b-cholan-24-oate (3a)
Cyclic benzene-1,2-diol ketal of methyl-3-oxo-5b-cholan-24-oate
(7a)
Method A. A solution of 2a (6.06 g, 15.51 mmol) in hot glacial
acetic acid (150 mL) was added dropwise over a period of 60 min
to a stirred solution of sodium dichromate dihydrate (7.12 g,
Method D. Montmorillonite (1.50 g) was added to a solution
of benzene-1,2-diol, 6, (1.50 g, 13.62 mmol) and 3a (1.77 g,
4.54 mmol) in 30 mL toluene. After stirring the reaction mixture
under reflux conditions for 24 h using Dean–Stark apparatus,
it was cooled and filtered. Removal of volatiles followed by
column purification using ethyl acetate–hexane (10 : 90-30 : 70 v/v)
resulted in a colorless solid which, upon recrystallization from
ethyl acetate–hexane (10 : 90 v/v), yielded 1.48 g (68%) of 7a as
2
3.89 mmol) in water (17 mL) containing conc. H
2
SO (1.8 mL)
4
and stirred at room temperature for 24 h. The precipitate obtained
after adding water (150 mL) was filtered and washed with water
(
(
3 ¥ 80 mL). The crude product was dissolved in dichloromethane
200 mL) and washed with water (3 ¥ 80 mL). The organic layer
was dried over anhydrous Na
2
SO , filtered and evaporated under
4
reduced pressure and column purified using 10–25% ethyl acetate
in hexane to yield 4.82 g (80%) of 3a as a colorless solid.
colorless X-ray quality crystals. d
(s, 3H, 18-CH
), 0.92 (3H, d, J = 6.5 Hz, 21-CH
9-CH ), 2.40-1.00 (m, 23-CH , steroidal -CH and -CH), 3.66
3H, s, 25-CH ), 6.77-6.71 (4H, m, 3¢-CH, 4¢-CH, 5¢-CH, 6¢-CH);
(125.7 MHz; CDCl ): 12.1 (C18), 18.3 (C21), 21.1 (C11), 23.0
H
(500.13 MHz; CDCl
3
): 0.67
3
3
), 1.01 (3H, s,
1
(
d
3
2
2
Method B. A solution of 2a (7.86 g, 20.0 mmol) in 200 mL
of acetone was cooled on an ice-bath, and to the cooled solution,
3
C
3
(C19), 24.2 (C15), 26.1 (C7), 26.4 (C6), 28.2 (C16), 30.3 (C2), 31.0
Jones reagent (prepared by dissolving 3 g of CrO
3
in conc. H
2
SO
4
(C23), 31.1 (C22), 33.3 (C1), 34.4 (C10), 35.4 (C20), 35.6 (C4),
(
3 mL) and water (9 mL) with powerful stirring) was added
3
5
1
2
1
5.6 (C8), 40.0 (C9), 40.2 (C12), 40.2 (C5), 42.8 (C13), 51.4 (C25),
dropwise with vigorous stirring. The oxidizing reagent was added
until the orange color was persistent in the mixture. Stirring of the
mixture was continued for another 10 min on ice, after which the
reaction was ceased by addition of a 6 mL portion of 2-propanol.
Acetone was removed by evaporation under reduced pressure and
the residue stirred vigorously with 250 mL of ethyl acetate. The
organic solution was washed three times with 10 mL of water
6.0 (C17), 56.5 (C14), 119.2 (C3), 108.3, 108.5 (C3¢, C6¢), 120.9,
-
1
20.9 (C4¢,C5¢), 147.3, 147.4 (C1¢, C2¢), 174.7 (C24); vmax/cm :
929, 2884, 2864, 1731, 1488, 1452, 1438, 1376, 1362, 1241, 1206,
+
169, 1072, 907, 733, 620, 532, 417; MS (ES ), found m/z: 503.25
+
(
[M+Na] ); Found: C 77.50, H 9.46; C31
H
44
4
O requires C 77.46,
H 9.23%.
and once with 20 mL of brine and dried over anhydrous Na
2
SO .
4
Volatiles were removed by evaporation under reduced pressure and
the resulting solid dried in vacuo to yield 7.05 g (91%) of 3a as a
colorless solid.
Cyclic naphthalene-2,3-diol ketal of 3,7,12-trioxo-5b-
cholan-24-oate (9c)
Prepared by method D from 8 (0.89 g, 5.56 mmol), 3c (1.45 g,
3
.48 mmol) and montmorillonite (1.52 g). Purification by column
chromatography using ethyl acetate–hexane (30 : 70–50 : 50 v/v)
yielded 0.89 g (47%) of 9c. d (500.13 MHz; CDCl ): 0.86 (3H, d,
J = 6.5 Hz, 21-CH ), 1.06 (3H, s, 18-CH ), 1.34 (3H, s, 19-CH ),
.96-1.20 (m, 23-CH , steroidal-CH and -CH), 7.01 (2H, br. t, 3¢-
CH, 6¢-CH), 7.30-7.27 (2H, m, 8¢-CH, 9¢-CH), 7.63-7.60 (2H, m,
Cyclic 3-ketal of methyl-3-oxo-5b-cholan-24-oate with
pentaerythritol (5a)
H
3
3
3
3
Method C. In a two-necked 250 mL flask fitted with a dropping
funnel and Dean–Stark trap pentaerythritol, 4, (2.45 g, 18.0 mmol)
and p-toluenesulfonic acid (0.18 g, 5% w/w of ketone) were added
to 60 mL DMF–toluene (3 : 2 v/v). The mixture was heated until
dissolution of all of the solids followed by dropwise addition of
2
2
2
7¢-CH, 10¢-CH); d
C
(125.7 MHz; CDCl ): 11.8 (C18), 18.6 (C21),
3
2
2.2 (C19), 25.2 (C15), 27.6 (C16), 29.9 (C2), 30.5 (C22), 31.3
(
(
(
(
C23), 32.2 (C1), 35.6 (C4), 35.7 (C10), 36.7 (C20), 38.6 (C11), 43.6
C5), 44.8 (C6), 45.3 (C9), 45.7 (C17), 49.0 (C8), 51.5 (C25), 51.8
C14), 56.9 (C13), 103.7, 103.9 (C3¢, C5¢), 117.6 (C3), 124.1, 124.1
3a (3.50 g, 9.0 mmol) dissolved in 40 mL of DMF–toluene (3 : 2
v/v). The reaction mixture was refluxed for 44 h. Precipitated
crude product obtained by addition of ice-water was filtered and
dissolved in 200 mL of ethyl acetate. The organic solution was
washed with 20 mL of water and with 20 mL of brine and
C8¢, C9¢), 126.8, 126.9 (C7¢, C10¢), 130.3, 130.4 (C4¢, C5¢), 147.2,
-1
1
47.4 (C1¢, C2¢), 174.5 (C24), 209.0 (C7), 212.1 (C12); vmax/cm :
2
964, 2871, 1737, 1706, 1471, 1250, 1166,1069, 857, 751, 621, 482;
dried over Na
chromatography with ethyl acetate as an eluent gave 3.00 g (66%)
of 5a as a colorless solid. d (500.13 MHz; CDCl ): 0.62 (3H, s, 18-
CH ), 0.88 (3H, d, 6.4 Hz, 21-CH ), 0.91 (3H, s, 19-CH ), 2.36-0.62
m, 23-CH , steroidal-CH and -CH), 2.97 (2H, br. s, 26¢-CH OH,
OH), 3.64 (3H,s, 25-CH ), 3.72-3.65 (8H, 4 ¥ s, 26-CH
, 26¢-CH , 28¢-CH ); d
2
SO
4
. Removal of volatiles followed by column
+
+
MS (ES ), found m/z: 581.20 ([M+Na] ); Found C 72.97, H 7.73;
·H O requires C 72.89, H 7.69%.
C
35
H
42
O
6
2
H
3
3
3
3
Cyclic diketal of methyl-3-oxo-5b-cholan-24-oate with
pentaerythritol (10a)
(
2
2
2
2
2
1
8¢-CH
2
3
2
,
8-CH
2
2
2
C
(125.7 MHz; CDCl
3
): 12.0 (C18),
Method E. Pentaerythritol, 4, (0.74 g, 5.4 mmol) and p-TSA
(0.18 g, 5% w/w ketone) were added to 60 mL of toluene–DMF
(2 : 3). The mixture was heated until dissolution of all of the solids,
followed by dropwise addition of 3a (3.50 g, 9.0 mmol) dissolved in
40 mL of DMF–toluene (3 : 2). The reaction mixture was refluxed
for 64 h. Precipitated crude product obtained by addition of ice-
water was filtered and dissolved in 50 mL of EtOAc–DCM (1 : 2).
8.2 (C21), 21.0 (C11), 23.1 (C19), 24.1 (C15), 26.2 (C7), 26.7
(
C2), 27.0 (C6), 28.1 (C16), 31.0 (C22, C23), 32.6 (C1), 33.5 (C4),
3
4
6
5.0 (C10), 35.3 (C20), 35.5 (C8), 39.1 (C27), 39.3 (C9), 39.8 (C5),
0.1 (C12), 42.7 (C13), 51.4 (C25), 55.9 (C17), 56.4 (C14), 61.9,
2.1 (C26, C28), 64.7, 64.7 (C26¢, C28¢), 99.6 (C3),174.8 (C24).
-
1
vmax/cm : 3336, 2927, 2864, 1738, 1446, 1366, 1250, 1167, 1143,
+
+
1
5
1
099, 1035, 870, 700; MS (ES ), found m/z: 529.3 ([M+Na] ),
45.3 ([M+K] ), 570.4 ([M+C
0.04; C30 requires C 71.11, H 9.95%.
The organic solution was washed with 20 mL of H
2
O and 20 mL
+
+
2
H
3
N+Na] ); Found: C 70.94, H
of brine and dried over anhydrous Na SO . Removal of volatiles
2
4
H
50
O
6
followed by column chromatography using EtOAc–DCM (1 : 2)
2
792 | Org. Biomol. Chem., 2010, 8, 2784–2794
This journal is © The Royal Society of Chemistry 2010

View Article Online
as an eluent gave 2.61 g (66%) of 7a as a white solid consisting of
isomers 10a(I) and 10a(II). 10a(I): d (500.13 MHz; CDCl ): 0.64
3H, s, 18-CH ), 0.92 (3H, s, 19-
), 0.90 (3H, d, J = 6.5 Hz, 21-CH
CH ), 2.38-1.00 (m, 23-CH , steroidal-CH and -CH), 3.66 (s, 6H,
5-CH ), 3.80-3.65 (m, 8H, 26-CH , 28-CH , 26¢-CH , 28¢-CH );
(125.7 MHz; CDCl ): 12.0 (C18), 18.3 (C21), 21.1 (C11), 23.2
structure of one isomer resolved. The bile acid substituent in the
dioxane ring seems to not disable the conformational changes in
the flexibility of the dioxane rings. In the future it will be interesting
to study whether the diketals could be crystallized also in the other
conformations and to compare the properties of these crystals.
Finally, the bile acid-derived acetals may serve as model structures
for preparation of novel prodrugs with the bile acid moiety aimed
for enhanced drug uptake or liver targeting.
H
3
(
3
3
3
2
2
2
d
3
2
2
2
2
C
3
(
C19), 24.2 (C15), 26.3 (C7), 26.8 (C6), 27.1 (C2), 28.2 (C16), 31.0,
3
1.1 (C22, C23), 32.6 (C1), 33.0 (C27), 33.3 (C4), 35.4 (C20), 35.7
(
C8), 39.4 (C9), 39.8 (C5), 35.0 (C10), 40.2 (C12), 42.8 (C13), 51.4
(
1
1
C25), 56.0 (C17), 56.5 (C14), 63.6, 63.3 (C26, C28, C26¢, C28¢),
-
1
00.1 (C3), 174.7 (C24); vmax/cm : 2923, 2850, 1734, 1439, 1365,
Acknowledgements
+
177, 1150, 1081, 1028, 998, 873, 732, 606, 423; MS (ES ), found
+
+
The authors wish to thank Spec. Lab. Tech. Reijo Kauppinen
for his help in running the NMR spectra, and Lab. Tech. Elina
Hautakangas for elemental analysis. Financial support from the
Finnish Ministry of Education, National Graduate School of
Organic Chemistry and Chemical Biology (S. Ikonen) and from the
Academy of Finland (project no. 121805, Nonappa) is gratefully
acknowledged.
m/z: 899.67 ([M+Na] ) and 915.61 ([M+K] ). Found: C 73.41, H
·H O requires C 73.79, H 10.13%.
9
.84; C55
H
88
O
8
2
1
0a(II).
d
H
(500.13 MHz; CDCl
), 0.92 (3H, s, 19-CH
and -CH), 3.66 (6H, s, 25-CH
, 28-CH , 26¢-CH , 28¢-CH , H
= 3.79 J = 13.7 Hz, H = 3.66, H
(125.7 MHz; CDCl ): 12.0 (C18), 18.3 (C21), 21.1 (C11), 23.1
3
): 0.64 (3H, s, 18-CH
3
), 0.90
(
2
3
H
d
(
(
(
3H, d, J = 6.5 Hz, 21-CH
3
3
), 2.38-1.00 (m,
3-CH
2
, steroidal -CH
2
3
), 3.82-
.62 (8H, 2 ¥ qAB, 26-CH
a
2
2
2
2
b
= 3.80
b
a
= 3.64 J = 11.6 Hz);
C
3
Notes and references
C19), 24.2 (C15), 26.2 (C7), 26.7 (C2, C6), 28.2 (C16), 31.1, 31.0
C23, C22), 32.6 (C1), 33.7 (C4), 35.0 (C10), 35.4 (C20), 35.7
C8), 39.4 (C9), 40.2 (C12), 40.2 (C5), 42.8 (C13), 51.4 (C25), 56.0
C17), 56.5 (C14), 63.6, 63.3 (C26, C28, C26¢, C28¢), 99.7 (C3),
74.7 (C24); vmax/cm : 2928, 2853, 1737, 1447, 1377, 1166, 1078,
022, 873, 608, 527, 423; Found: C 74.37, H 9.94; C30
1
(a) J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspectives,
VCH, Weinheim, Germany, 1995; (b) Molecular Self-Assembly, Struc-
ture and Bonding, ed. M. Fujita, Springer, Berlin, 2000, vol. 96; (c) The
Crystal as a Supramolecular Entity, Perspectives in Supramolecular
Chemistry, ed. G. R. Desiraju, Wiley, Chichester, U.K., 1995, vol. 2;
(
1
1
-
1
1
2
H
46
O
8
· H
2
O
(
d) M. D. Hollingsworth, Science, 2002, 295, 2410–2413.
2 (a) I. Grosu, S. Mager and G. Ple, J. Chem. Soc., Perkin Trans. 2,
995, 1351–1357; (b) I. Grosu, S. Mager, G. Ple, I. Turos, E. Mesaros
requires C 74.53, H 10.12%.
1
and I. Schirger, Monatsch. Chem., 1998, 129, 59–68; (c) A. Mihis, E.
Condamine, E. Bogdan, A. Terec, T. Kurtan and I. Grosu, Molecules,
Conclusions
2
008, 13, 2848–2858.
3
4
N. G. Lemcoff and B. Fuchs, Org. Lett., 2002, 4, 731–734.
Novel bile acid-derived monoketals with 1,2-benzenediol (cate-
chol) and 2,3-naphthalenediol as well as mono- and diketals with
pentaerythritol have been prepared and characterized. Monoke-
tals of pentaerythritol showed a tendency to form thermoreversible
gels in many aromatic solvents and the methyl lithocholate
derivative proved to be a supergelator able to form a gel in
t-butylbenzene at a concentration of 0.5% w/v. While most of
the bile acid-derived organogelators have the amide functionality
in their side chain, the type of organogelators presented here are
rare. It is thus interesting to further study the interactions and
the nucleation process required for the formation of the gel by
these and other similar LMOGs. Because of the biocompatibility
of the bile acid moiety, the gels derived from their derivatives
may find applications in the fields of supramolecular biochemistry
or biomedicinal chemistry. Furthermore, these monoketals may
serve as model compounds for a wide variety of similar bile
acid derivatives with organogelling fuctionality. Whereas the
naphthalenediol ketal 9a formed film-type materials in the studied
solvents, the catechol ketals underwent rapid crystallization to
X-ray quality single crystals and their crystal structures were
determined. Interestingly, very small changes in the steroidal part
induced completely different kinds of packing in the crystals
of 7a and 7c. The monoketal 7c, obtained from methyl-3,7,12-
trioxocholanoate (cholic acid derivative), revealed to have a
packing pattern which is very unusual for bile acid derivatives.
Formation of diketals of pentaerythritol always produced a
mixture of two diastereomers which, in the case of the methyl
lithocholate derivative, have been separated and the X-ray crystal
(a) I. Grosu, E. Bogdan, G. Ple, L. Toupet, Y. Ramondenc, E.
Condamine, V. Peulon-Agasse and M. Balog, Eur. J. Org. Chem., 2003,
3153–3161; (b) M. Balog, I. Grosu, G. Ple, Y. Ramondenc, L. Toupet,
E. Condamine, C. Lange, C. Loutelier-Bourhis, V. Peulon-Agasse and
E. Bogdan, Tetrahedron, 2004, 60, 4789–4799.
5
(a) H. A. Stanbury, and H. R. Guest, US Patent, US19570716, 1962.;
(b) D. B. Capps, US Patent, US2889290, 1959; (c) E. H. Pryde, R. A.
Awl, H. M. Teeter and J. C. Cowan, J. Org. Chem., 1960, 25, 2260–2261;
(
(
d) S. M. Cohen and E. Lavin, J. Appl. Polym. Sci., 1962, 6, 503–507;
e) M. S. Cohen, C. F. Hunt, R. E. Kass and A. H. Markhart, J. Appl.
Polym. Sci., 1962, 6, 508–517; (f) S. M. Cohen, and E. Lavin, US Patent,
US19570610, 1962.; (g) A. H. Markhart, C. F. Hunt, and E. Lavin, US
Patent, US19580811, 1962.; (h) W. J. Bailey and A. A. Volpe, J. Polym.
Sci., Part A-1, 1970, 8, 2109–2122; (i) F. V. Zalar, Macromolecules, 1972,
5
, 539–541; (j) S. Makhseed and N. B. McKeown, Chem. Commun.,
1999, 255–256.
6 (a) P. Wessig, K. M o¨ llnitz and C. Eiserbeck, Chem.–Eur. J., 2007, 13,
4
4
859–4872; (b) P. Wessig and K. M o¨ llnitz, J. Org. Chem., 2008, 73,
452–4457; (c) P. Mueller, J. Nikolaus, S. Schiller, A. Herrmann, K.
Moellnitz, S. Czapla and P. Wessig, Angew. Chem., Int. Ed., 2009, 48,
4433–4435.
7
8
9
(a) P. F. H. Schwab, J. R. Smith and J. Michl, Chem. Rev., 2005, 105,
1
1
197–1280; (b) P. F. H. Schwab, M. D. Levin and J. Michl, Chem. Rev.,
999, 99, 1863–1934.
H. Danielsson, in The Bile Acids: Chemistry, Physiology and
Metabolism, ed. P. P. Nair and D. Kritchevsky, Plenum Press, New
York, 1973, vol. 2, pp. 1-32.
(a) A. Enhsen, W. Kramer and G. Wess, Drug Discovery Today, 1998,
3
, 409–418; (b) S. Mukhopadhyay and U. Maitra, Curr. Sci., 2004, 87,
1666–1683; (c) A. F. Hofmann and L. R. Hagey, Cell. Mol. Life Sci.,
008, 65, 2461–2483.
2
1
0 (a) J. Tamminen and E. Kolehmainen, Molecules, 2001, 6, 21–46; (b) E.
Virtanen and E. Kolehmainen, Eur. J. Org. Chem., 2004, 3385–3399;
(
c) A. P. Davis, Molecules, 2007, 12, 2106–2122; (d) Nonappa and U.
Maitra, Org. Biomol. Chem., 2008, 6, 657–669.
This journal is © The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2784–2794 | 2793

View Article Online
1
1
1 (a) E. Bartoli, B. Palmieri, and A. Medici, European Patent,
EP2003095462, 2003.; (b) V. Bertolasi, V. Ferretti, G. Fantin and M.
Fogagnolo, Z. Kristallogr., 2008, 223, 515–523; (c) G. Fantin, M.
Fogagnolo, A. Medici, P. Pedrini and U. Cova, Steroids, 1993, 58,
20 E. R. Gillies, A. P. Goodwin and J. M. J. Fr e´ chet, Bioconjugate Chem.,
2004, 15, 1254–1263.
21 L. F. Fieser and S. Rajagopalan, J. Am. Chem. Soc., 1950, 72, 5530–
5536.
5
24–526.
22 G. P. Tochtrop, G. T. DeKoster, D. P. Cistola and D. F. Covey, J. Org.
Chem., 2002, 67, 6764–6771.
2 (a) P. Terech and R. G. Weiss, Chem. Rev., 1997, 97, 3133–3159;
(
(
(
b) N. M. Sangeetha and U. Maitra, Chem. Soc. Rev., 2005, 34, 821–836;
c) M. George and R. G. Weiss, Acc. Chem. Res., 2006, 39, 489–497;
d) S. Banerjee, R. K. Das and U. Maitra, J. Mater. Chem., 2009,
23 T. Li, L. Li, B. Lu and F. Yang, J. Chem. Soc., Perkin Trans. 1, 1998,
3561–3564.
24 N. M. Sangeetha, R. Balasubramanian, U. Maitra, S. Ghosh and A. R.
Raju, Langmuir, 2002, 18, 7154–7157.
25 P. Terech, N. M. Sangeetha and U. Maitra, J. Phys. Chem. B, 2006, 110,
15224–15233.
1
9, 6649–6687; (e) D. K. Smith, Chem. Soc. Rev., 2009, 38, 684–694;
(
f) A. R. Hirst, B. Escuder, J. F. Miravet and D. K. Smith, Angew.
Chem., Int. Ed., 2008, 47, 8002–8018.
1
1
1
3 H. M. Willemen, T. Vermonden, A. T. M. Marcelis and E. J. R.
Sudholter, Eur. J. Org. Chem., 2001, 2329–2335.
4 A. Valkonen, M. Lahtinen, E. Virtanen, S. Kaikkonen and E.
Kolehmainen, Biosens. Bioelectron., 2004, 20, 1233–1241.
5 (a) H. M. Willemen, T. Vermonden, A. T. M. Marcelis and E. J. R.
Sudhoelter, Langmuir, 2002, 18, 7102–7106; (b) Nonappa and U.
Maitra, Soft Matter, 2007, 3, 1428–1433.
26 Cambridge Structural Database (CSD) search was performed us-
ing the structure of cholic acid excluding the hydroxyl-groups and
gave 532 hits as a result including bile acids and their deriva-
tives.
27 U. Rychlewska, B. Warzajtis, R. Joachimiak and Z. Paryzek, Acta
Crystallogr., Sect. B: Struct. Sci., 2008, 64, 383–392.
28 J. R. Dias, R. A. Pascal, Jr., J. Morrill, A. J. Holder, H. Gao and C.
Barnes, J. Am. Chem. Soc., 2002, 124, 4647–4652.
29 COLLECT, Bruker AXS Inc., W. I. Madison, 2004.
30 C. W. Carter, Jr. and R. M. Sweet, in Methods in enzymology.
Macromolecular crystallography, Part A, Academic Press, New York,
1997, vol. 276.
1
1
1
6 (a) K. Nakano, Y. Hishikawa, K. Sada, M. Miyata and K. Hanabusa,
Chem. Lett., 2000, 1170–1171; (b) S. Bhat and U. Maitra, Tetrahedron,
2
007, 63, 7309–7320.
7 (a) V. Noponen, Nonappa, M. Lahtinen, H. Salo, and E. Siev a¨ nen,
Soft Matter, under revision; (b) Nonappa, M. Lahtinen, B. Behera, E.
Kolehmainen and U. Maitra, Soft Matter, 2010, 6, 1748–1757.
31 M. C. Burla, M. Camalli, B. Carrozzini, G. L. Cascarano, C. Gia-
covazzo, G. Polidori and R. Spagna, J. Appl. Crystallogr., 2003, 36,
1103.
8 For recent examples see: (a) L. Ma, M. Melegari, M. Colombini and
J. T. Davis, J. Am. Chem. Soc., 2008, 130, 2938–2939; (b) Y. Li, G.
Li, X. Wang, W. Li, Z. Su, Y. Zhang and Y. Ju, Chem.–Eur. J., 2009,
32 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008,
1
2
2
5, 6399–6407; (c) J. Koivukorpi and E. Kolehmainen, J. Mol. Struct.,
008, 875, 63–67; (d) N. G. Aher, V. S. Pore and S. P. Patil, Tetrahedron,
007, 63, 12927–12934.
64, 112–122.
33 L. J. Farrugia, J. Appl. Crystallogr., 1997, 30, 565.
34 C. F. Macrae, P. R. Edgington, P. McCabe, E. Pidcock, G. P. Shields,
R. Taylor, M. Towler and J. van de Streek, J. Appl. Crystallogr., 2006,
39, 453–457.
1
9 For reviews see: (a) E. Siev a¨ nen, Molecules, 2007, 12, 1859–1889; (b) A.
Balakrishnan and J. E. Polli, Mol. Pharmaceutics, 2006, 3, 223–230;
(
1
c) P. W. Swaan, F. C. Szoka, Jr. and Ø. Svein, Adv. Drug Delivery Rev.,
996, 20, 59–82.
35 A. J. Pearson, Y. S. Chen, G. R. Han, S. Y. Hsu and T. Ray, J. Chem.
Soc., Perkin Trans. 1, 1985, 267–273.
2
794 | Org. Biomol. Chem., 2010, 8, 2784–2794
This journal is © The Royal Society of Chemistry 2010