Crystal structure of 3β,12α-dihydroxy-5β-cholan-24-oic acid (iso- deoxycholic acid)

Article abstract of DOI:10.1016/S0022-2860(99)00410-X

Iso-deoxycholic acid (3β,12α-dihydroxy-5β-cholan-24-oic acid, iso- DCA), the 3β hydroxy epimer of deoxycholic acid (DCA), was synthesized from deoxycholic acid. The crystals, obtained by recrystallization from p-xylene, are orthorhombic, space group P2

Full text of DOI:10.1016/S0022-2860(99)00410-X

Journal of Molecular Structure 523 (2000) 299–307
www.elsevier.nl/locate/molstruc
Crystal structure of 3b,12a-dihydroxy-5b-cholan-24-oic acid
(iso-deoxycholic acid)
a
a
b
a,
c
*
A. Jover , F. Meijide , E. Rodr ´ı guez N u´ n˜ ez , J. V a´ zquez Tato , A. Casti n˜ eiras ,
d
d
A.F. Hofmann , H.-T. Ton-nu
a
Departamento de Qu ´ı mica F ´ı sica, Universidade de Santiago, Campus de Lugo, Facultade de Ciencias, 27002 Lugo, Spain
b
Departamento de F ´ı sica Aplicada, Universidade de Santiago, Campus de Lugo, Facultade de Ciencias, 27002 Lugo, Spain
c
Departamento de Qu ´ı mica Inorg a´ nica, Universidade de Santiago, Facultade de Farmacia, Santiago de Compostela, Spain
d
Department of Medicine, University of California, San Diego, CA 92093-0813, USA
Received 12 July 1999; received in revised form 25 October 1999; accepted 25 October 1999
Abstract
Iso-deoxycholic acid (3b,12a-dihydroxy-5b-cholan-24-oic acid, iso-DCA), the 3b hydroxy epimer of deoxycholic acid
(
DCA), was synthesized from deoxycholic acid. The crystals, obtained by recrystallization from p-xylene, are orthorhombic,
ꢀ
space group P2 2 2 , with a ˆ 7:3232ꢀ6†; b ˆ 10:5938ꢀ16† and c ˆ 28:2957ꢀ18† A: The crystals contained no inclusion
1
1 1
molecules, and thus differed from those of DCA when recrystallized from o-, m- and p-xylene. This absence of solvate
˚
molecules could explain the reduction of Ϸ3 A in the b-axis length in iso-DCA when compared with that of DCA with xylene
guests. ᭧ 2000 Elsevier Science B.V. All rights reserved.
Keywords: Crystal structure; Bile salts; Iso-deoxycholic acid
1
. Introduction
form aggregates above their critical micellization
concentration. The aggregates form mixed micelles
with insoluble, polar lipids. In bile, the mixed micelles
consist of bile salts, phospholipids and cholesterol. In
intestinal contents, the mixed micelles contain bile
salts, fatty acids and monoglycerides [2]. The self-
aggregation behavior of bile salts has been studied
by different techniques in different experimental
conditions [3–15], but there is not yet an agreement
about the mechanism of formation and structure of the
aggregates formed. Three main structures have been
proposed [1,16–18]. Those proposed by Giglio et al.
[17] for several bile salts in aqueous solution have
been constructed based on principles derived from
their crystal structures.
Bile salts are key biological surfactants in ver-
tebrates. A common bile acid is cholic acid
3a,7a,12a-trihydroxy-5b-cholan-24-oic acid, CA),
(
which is converted in vivo by bacterial enzymes to
deoxycholic acid (3a,12a-dihydroxy-5b-cholan-24-
oic acid, DCA). The perspective structural formula
of cholic and deoxycholic acids illustrate that their
hydroxy groups lie beneath the plane of the steroid
skeleton and its protruding methyl groups lie above it.
Bile salts thus contain an hydrophobic side, an hydro-
philic side and a short hydrophilic tail [1]. Therefore,
they possess a planar polarity and in aqueous solution
Solutions of sodium deoxycholate (NaDC) present
a particular behavior. At pH values close to neutrality
*
Corresponding author. Tel.: ϩ34-982-2233-25; fax: ϩ34-982-
2
249-04.
0
022-2860/00/$ - see front matter ᭧ 2000 Elsevier Science B.V. All rights reserved.
PII: S0022-2860(99)00410-X

3
00
A. Jover et al. / Journal of Molecular Structure 523 (2000) 299–307
it forms gels [19–24], a characteristic not described
for other bile salts with the exception of chenodeoxy-
cholic acid at high salt concentrations [25]. Hydro-
phobic interactions and hydrogen bonding between
hydroxyl groups play an important role in this aggre-
gation [26,27]. The 3b hydroxy epimer has an
hydroxy group directed to the apolar part of the mole-
cule, where the methyl groups are located; the global
polarity being considerably affected with respect to
the original compound. Therefore, it would be of
interest to study how this change in the configuration
of the 3-hydroxy groups affects the physicochem-
ical properties of the bile salt (aggregation proper-
ties, gel formation, crystal formation, etc.). It is
also of interest to test whether this change influ-
ences the formation of crystalline inclusion
compounds, as has been described for cholic [28–
37] and deoxycholic acids [38–45]. To this end, we
have synthesized iso-DCA and solved its crystal
structure.
COOH
OH
HO
H
CH
3
MeOH
OH
COOMe
OH
3
SO H
COOMe
pyridine
CH3
(
II)
TsO
(
I)
HO
H
+
-
H
SO3 Cl
N,N-dimethylformamide
COOMe
COOH
OH
OH
KOH/EtOH
(
III)
(
IV)
HCOO
HO
H
H
Fig. 1. Scheme of the synthesis of iso-DCA.

A. Jover et al. / Journal of Molecular Structure 523 (2000) 299–307
301
Table 1
Table 2
Ϫ4
Crystal data, data collection and refinement
Atomic coordinates ( × 10 ) and equivalent isotropic displacement
2 Ϫ3
parameters ꢀA × 10 † for iso-DCA. U(eq) is defined as one third of
Empirical formula
Formula weight
Temperature (K)
C
24
H
40
O
4
the trace of the orthogonalized U tensor
ij
392.56
291(2)
1.54184
x
y
z
U
(eq)
˚
Wavelength (A)
Crystal system, space group
Orthorhombic, P2
7.3232(6)
10.5938(16)
28.2957(18)
90Њ
90Њ
90Њ
2195.2(4)
4, 1.188
0.619
1
2
1
2
1
O(25)
O(26)
O(27)
O(28)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(18)
C(19)
C(20)
C(21)
C(22)
C(23)
C(24)
5260(3)
1185(3)
Ϫ608(4)
1230(2)
5368(2)
7472(3)
7199(2)
1818(3)
2753(3)
2301(3)
1941(3)
1048(2)
784(3)
1897(3)
2307(2)
2649(2)
1496(2)
3249(3)
4275(2)
3801(2)
3407(2)
3237(3)
4216(3)
4787(3)
2701(3)
399(3)
1753(1)
3415(1)
5938(1)
6114(1)
2335(1)
2085(1)
2073(1)
2562(1)
2829(1)
3326(1)
3661(1)
3686(1)
3184(1)
2846(1)
3189(1)
3561(1)
4056(1)
4022(1)
4536(1)
4812(1)
4466(1)
4200(1)
3003(1)
4708(1)
4366(1)
5131(1)
5465(1)
5868(1)
52(1)
47(1)
75(1)
66(1)
41(1)
45(1)
45(1)
42(1)
37(1)
43(1)
41(1)
33(1)
32(1)
35(1)
38(1)
35(1)
32(1)
33(1)
42(1)
45(1)
36(1)
42(1)
47(1)
43(1)
65(1)
51(1)
57(1)
47(1)
˚
A (A)
˚
B (A)
˚
Ϫ3536(4)
1988(4)
3213(4)
5177(4)
5840(4)
4584(4)
5347(4)
5089(4)
3090(4)
2403(3)
2563(4)
488(4)
C (A)
a
b
g
3
˚
Volume (A )
Ϫ3
Z, calculated density (g cm
Absorption coefficient (mm
F(000)
)
)
Ϫ1
864
Crystal size (mm)
u range for data collection (Њ)
Index ranges
0:40 × 0:20 × 0:20
3.12–74.18
Ϫ9 Ͻˆ h Ͻˆ 0; 0 Ͻˆ k Ͻˆ
1
3; 0 Ͻˆ l Ͻˆ 35
Reflections collected/unique
Absorption correction
Maximum and minimum
transmission
2576/2576 [R(int) ˆ 0.0000]
191(4)
757(3)
Psi-scan
2784(4)
3376(4)
2241(4)
824(4)
Ϫ479(4)
1332(4)
Ϫ995(4)
Ϫ2388(5)
Ϫ699(4)
Ϫ2304(5)
Ϫ2199(5)
0.977 and 0.953
2
Refinement method
Full-matrix least-squares on F
2576/0/255
1.088
R1 ˆ 0:0423; wR2 ˆ 0:1093
R1 ˆ 0:0590; wR2 ˆ 0:1188
0.0(4)
Data/restraints/parameters
2
Goodness of fit on F
Final R indices ‰I Ͼ sꢀI†Š
R indices (all data)
5141(3)
5714(4)
6032(3)
6077(3)
6976(3)
Absolute structure parameter
Extinction coefficient
Largest diff. Peak and hole
0.0041(4)
0.293 and Ϫ0.162 e.A
Ϫ3
2. Experimental
Methyl 3a-tosyloxy-12a-hydroxycholanate (II)
was prepared [47] by addition at room temperature
of p-toluenesulfonyl chloride (1.83 g) and dry pyri-
dine (20 ml) to the methyl ester (I) (3 g); yield is
nearly quantitative. The reaction was monitored by
TLC (CHCl /CH OH 9:1) and was completed in two
days. Work up of the reaction involves neutralization
of pyridine with HCl 1 M (260 ml) dripped in an ice
bath, then vacuum filtered and dissolved in ether. The
ethereal phase was washed three times with water
until pH 7, dried and evaporated.
The synthesis of the 3b,12a-dihydroxy-5b-cholan-
4-oic acid (iso-deoxycholic acid, iso-DCA) was
2
carried out following that reported in literature with
minor modifications. It begins (see Fig. 1) with the
preparation of the methyl ester of DCA (I) [46]. To a
solution of this bile acid (4 g) in 120 ml of absolute
methanol was added p-toluenesulfonic acid (520 mg).
After stirring for 12 h at room temperature, the reac-
tion was complete (followed by TLC CHCl /CH OH
3
3
3
3
9
:1). The reaction mixture was slowly dripped over
ice chips with stirring, forming a precipitate. This
precipitate was washed, vacuum filtered and then
dissolved in ether. The ether phase was washed with
dilute base (0.5 M NaOH), water, dried with sodium
sulfate, concentrated down to dry powder with the rota-
vapor, and then dried under vacuum for a few hours.
The obtained product was dissolved in N,N-
dimethylformamide (80 ml) at a constant temperature
of 77ЊC and the reaction, monitored by TLC (toluene/
acetone 7:3), showed complete disappearance of the
tosylate in 60 h [48]. The reaction content was slowly
dropped in ice and water, and the precipitate of methyl

3
02
A. Jover et al. / Journal of Molecular Structure 523 (2000) 299–307
Fig. 2. Perspective view of the molecule, showing 70% probability ellipsoids for the non hydrogen atoms and the numbering scheme of the
atoms in the molecule.
3
b-formate 12a-hydroxy cholanate (III) extracted
2.2. Structure solution and refinement
with ether and dried.
Compound III was hydrolyzed by the slow addition
of KOH 10% (w/w) (40 ml) and ethanol (95%)
The structure was solved by direct methods [51]
which revealed the position of all non-hydrogen
atoms, and refined on F by a full-matrix least-squares
2
(
(
40 ml) [42]. The reaction, monitored by TLC
CHCl /CH OH 9:1), was complete in 3–4 h. Ethanol
procedure using anisotropic displacement parameters
3
3
[52]. All hydrogen atoms were located in difference
was evaporated and the remaining solution acidified.
The precipitate of iso-DCA (IV) was filtered and
dissolved in ether. The ether phase was washed with
water until the water phase was neutral. The ether was
then dried, filtered and evaporated. Purification on a
silica gel 60 Merck column (particle size 0.040–
map and included as fixed contributions riding on
attached C atoms with isotropic thermal parameters
1
.2 or 1.5 times those of the respective C and O atoms.
The absolute structure for the compound was chosen
according to the Flack parameter [53]. Inspection of
F and F values indicated that a correction for
0.063 mm) with CHCl /CH OH 8.5–9.5:1.5–0.5 as
c
o
3
3
ء
c
secondary extinction was required ꢀF ˆ kF ‰1 ϩ
mobile phase. Crystals were obtained by re-crystal-
lization from p-xylene.
c
2
c
3
Ϫ1=4
0
:001 × F l =sinꢀ2u†Š
†; where k is the overall
scale factor, and x (extinction parameter) refined to
0
.0041(4) in the final run. Atomic scattering factors
were taken from International Tables for X-ray Crys-
tallography [54]. Molecular graphics are from
Platon [50] and Schakal [55]. A summary of the
crystal data, experimental details and refinement
results are listed in Table 1.
2
.1. X-ray data collection and reduction
Crystal data, data collection procedure and refine-
ment details are reported in Table 1, and fractional
atomic coordinates in Table 2. A colourless prismatic
crystal of iso-DCA was mounted on a glass fiber and
used for data collection. Cell constants and an orien-
tation matrix for data collection were obtained by
least-squares refinement of the diffraction data from
3. Results and discussion
2
5 reflections in the range of 22:794Њ Ͻ u Ͻ 42:642Њ
Fig. 2 represents a schematic view, showing a
crystal structure similar to that reported for other
bile acids with the same ring junctions in cis config-
uration. As can be seen in Fig. 3, the packing diagram
for iso-DCA shows an orthorhombic crystal system
with the space group P2 2 2 . This is the same crystal
on an ENRAF-NONIUS CAD4 automatic diffract-
ometer. Data were collected at 291 K using CuKa
ꢀ
radiation ꢀl ˆ 1:54184 A† and the omega-scans
mode and corrected for Lorentz and polarization
effects [49]. A semi-empirical absorption correction
1
1 1
(Psi-scans) was made [50].
system and space group as reported for cholic acid

A. Jover et al. / Journal of Molecular Structure 523 (2000) 299–307
303
Fig. 3. View of the crystal structure of the molecule. The origin of the unit cell is in the rear of the lower left corner, with a pointing toward the
reader, b from left to right and c upward.
crystals containing no guest molecules [56]. However,
the crystal structure of DCA has been solved only for
crystals containing different inclusion compounds and
not for the acid devoid of solvate molecules. There-
fore we cannot make a comparison with our data.
The crystallographic structure for DCA recrystal-
lized from xylenes was established by Gallese et al.
[57]. Table 3 summarizes the results from Gallese et
al. compared with those obtained in this work for iso-
DCA. The crystal systems for DCA are respectively
monoclinic for o- and p-xylene and orthorhombic for
m-xylene. This crystal system was also found for

3
04
A. Jover et al. / Journal of Molecular Structure 523 (2000) 299–307
Table 3
Comparison of some crystal data for deoxycholic and iso-deoxycholic acid recrystallized from xylenes
Crystal/solvent
Space group
DCA/o-xylene
P2
DCA/m-xylene
P2
7.20
13.69
25.75
90.00
2:1
DCA/p-xylene
P2
iso-DCA/p-xylene
P2
7.32
10.59
28.29
90.00
1
1
2
1
2
1
1
1 1 1
2 2
˚
a (A)
7.24
7.27
˚
b (A)
26.17(unique axis)
13.38(unique axis)
˚
c (A)
13.51
90.9
2:1
27.08
91.00
2:1
b (Њ)
Host/guest ratio
Fig. 4. View of a hydrogen-bonded molecular group. Some intermolecular hydrogen bonds are shown by dashed lines.

A. Jover et al. / Journal of Molecular Structure 523 (2000) 299–307
305
Table 4
Hydrogen bonds for iso-DCA
˚
˚
˚
D–H···A
d(D–H) (A)
d(H···A) (A)
d(D···A) (A)
Ͻ (DHA) (Њ)
a
O(26)–H(26)···O(28)
O(27)–H(27)···O(25)
O(25)–H(25)···O(26)
0.82
0.82
0.82
2.01
2.16
1.88
2.800(3)
2.908(3)
2.697(3)
161.3
152.3
171.5
b
c
a
Symmetry transformation used to generate equivalent atoms: Ϫx ϩ 1; y Ϫ 1=2; Ϫz ϩ 1=2:
x ϩ 1=2; Ϫy ϩ 3=2; Ϫz ϩ 1:
Ϫx ϩ 1=2; Ϫy ϩ 1; z ϩ 1=2:
b
c
iso-DCA in p-xylene. Moreover, both epimers belong
in the epimer of DCA. It may be caused by the
absence of solvent molecules in the crystal network
of iso-DCA. On the other hand, the length of c-
to the a group, because of the short length of one of
˚
their axes (Ϸ7.3 A). The main difference between
˚
˚
them is the length of b-axis, which is Ϸ3 A smaller
axis is Ϸ2.5 A higher in iso-DCA than in DCA.
Fig. 5. View showing the self-organization of the molecules along the b-axis.

3
06
A. Jover et al. / Journal of Molecular Structure 523 (2000) 299–307
This fact can be attributed to the different spatial
orientation of the hydroxyl group at C-3 in both
epimers.
Fig. 4 shows the hydrogen-bonded molecular
group. Three bile acid molecules are connected invol-
ving the carboxylic O and OH of the first, the OH at
[15] M.C. Carey, Sterols and bile acids, Elsevier (Biomedical Divi-
sion), Amsterdam, 1985.
[
[
16] D.M. Small, Adv. Chem. Ser. 84 (1968) 31.
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[18] H. Kawamura, M. Manabe, T. Narikiyo, H. Igimi, Y. Murata,
G. Sugihara, M. Tanaka, J. Solution Chem. 16 (1987) 433.
12a of the second and the OH at 3b of the third one
[
[
[
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with the oxygen atom of the carboxylic group of a new
one (H(26)–O(28)). Bond lengths and angles of
these interactions are summarized in Table 4,
and the self-organization of the molecules can be
seen in Fig. 5.
[22] G. Sugihara, M. Tanaka, Bull. Chem. Soc. Jpn 49 (1976) 3457.
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The authors from USC thank the Xunta de Galicia
for financial support (Project XUGA 26203B94). A.J.
thanks the Xunta de Galicia for a grant at UCSD.
Work at UCSD supported by NIH grant OK21506
and a grant in aid from the Falk Foundation e.V.,
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