New synthesis of pentacyclic steroids by stereoselective epoxide ring opening

Article abstract of DOI:10.1016/j.tetlet.2010.10.167

A stereoselective synthesis of pentacyclic steroids has been achieved. Starting from commercially available cholic acid 1, followed by asymmetric epoxidation and by stereoselective epoxide ring opening, employing nucleophilic species, the corresponding products were afforded in good yields. The compounds were being evaluated for their biological activity.

Full text of DOI:10.1016/j.tetlet.2010.10.167

Tetrahedron Letters 51 (2010) 6948–6950
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Tetrahedron Letters
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New synthesis of pentacyclic steroids by stereoselective epoxide ring opening
⇑
Malika Ibrahim-Ouali , Hamze Khalil
Institut des Sciences Moléculaires de Marseille, UMR 6263 CNRS and Université d’Aix Marseille III, Faculté des Sciences et Techniques de Saint Jérôme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of pentacyclic steroids has been achieved. Starting from commercially avail-
able cholic acid 1, followed by asymmetric epoxidation and by stereoselective epoxide ring opening,
employing nucleophilic species, the corresponding products were afforded in good yields. The com-
pounds were being evaluated for their biological activity.
Received 9 September 2010
Revised 26 October 2010
Accepted 29 October 2010
Available online 4 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pentacyclic steroids
Lactones
Epoxide
The classical approach to drug development from a known lead
structure remains the systematic variation of substitution pattern
and the alteration of stereochemical relationships. The efforts of
various groups reported after the discovery of the first progester-
one antagonist RU 486 (Mifepristone) can be viewed as a typical
example.1
The modifications made in a biologically active compound can
result in a very useful homologue eliciting a subtle biological dif-
ference from the patent substance. For example, the 11b-methyl
homologue of ethinodiol diacetate is 10–25 times more progesta-
tional.2 The direction of the change in the biological activities of
a homologue is unpredictable. It could result in a more potent ago-
nist, a more selective agonist or an antagonist.
of pentacyclic steroidal derivatives of pharmacological and biolog-
ical importance.4 The incorporation of short carbon bridges span-
ning characteristic positions of the steroid backbone continues to
be a popular stratagem in the search for new, biologically active
steroid hormone analogues.
So, it would be interesting to combine both by introducing a
new ring and a new function at the C-11 position of the steroidal
skeleton, in order to obtain a new class of steroids.
We report herein the stereoselective synthesis of pentacyclic
steroids 2 possessing an amino function at C-11, derived from
readily available cholic acid 1 (Scheme 1).
The synthesis of aminolactones 2 is described in Scheme 2.
Methyl 3,7-diacetoxycholate
3 was prepared according to a
The C-11 position of the steroid ring has a major effect on bio-
logical properties, such as corticoid activities. Recently, it was
reported that 11-amino-12-hydroxy/keto steroids are potential
inhibitors of HIV-1 protease.3 Otherwise, there are many examples
known procedure.5 Treatment of 3 with a slight excess of mesyl
chloride in the presence of pyridine gave a quantitative yield of
methyl 3,7-diacetyl-12-mesyl cholate 4. Dehydromesylation of 4
was done applying the conditions described by Chen.6 Mesylate
O
O
O
HO
OH
17
RHN
12
11
9
13
14
16
15
1
4
2
3
10
8
7
5
6
HO
OH
AcO
OAc
H
H
1
2
Scheme 1. Aminolactones 2.
⇑
Corresponding author. Tel.: +33 0491288416; fax: +33 0491288234.
E-mail address: malika.ibrahim@univ-cezanne.fr (M. Ibrahim-Ouali).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.167

M. Ibrahim-Ouali, H. Khalil / Tetrahedron Letters 51 (2010) 6948–6950
6949
O
O
HO
HO
OR
OMe
b
c
HO
OH
AcO
OAc
H
H
1 R = H
3
a
2 R = CH3
O
O
MsO
OMe
OMe
d
e
AcO
OAc
AcO
OAc
H
H
4
5
O
O
O
OMe
O
RHN
12
11
9
f
AcO
OAc
AcO
OAc
H
H
6
7
Scheme 2. Stereoselective synthesis of pentacyclic steroids from cholic acid. Reagents and conditions: (a) MeOH, PTSA,
D
; (b) Ac2O, pyridine, DMAP; (c) MsCl,pyridine, 0 °C to
rt, 24 h; (d) AcOK, HMPT, 100 °C, 48 h; (e) m-CPBA, CH2Cl2, rt, 24 h; (f) RNH2, EtOH/toluene (1/1),
D, 24 h.
4 was heated in hexamethylphosphoric triamide (HMPT) with an
Table 1
excess of potassium acetate at about 100 °C for two days. The de-
sired methyl 3,7-diacetylchol-11-enate 5 was isolated in good
Pentacyclic steroids 7a–j
O
yield (80%).
Next, an asymmetric epoxidation in the steroidal double bond
(C11@C12) was performed to introduce the desired epoxide func-
tional group in the steroidal nucleus, using m-CPBA as the oxidant
agent.7 Epoxidation of 5 with m-CPBA in CH2Cl2 resulted in the for-
O
RHN
7a-j
AcO
OAc
H
mation of the 11
ring was formed with high selectivity in the least hindered face
of steroid.8 The
configuration of the 11,12-epoxide was assigned
a,12a-epoxide 6 in excellent yield. The epoxide
Entry
1
Amines RNH2
NH2
Yield* of 7
a
due to the presence of the C-18 angular methyl group which blocks
the b-face of the C ring when the D11 double bond of 5 was epox-
idized. The observed 1H NMR spectrum showed characteristic dou-
blets (J = 4 Hz) for the CH-11 and CH-12 protons at dH 2.98 ppm
and 3.16 ppm, respectively.
7a: 81%
NH2
2
7b: 65%
H3CO
In the last step, we proceeded to a selective epoxide ring open-
ing with nucleophilic amines. Interestingly, we observed two reac-
tions during this step: a stereoselective epoxide ring opening and
3
4
5
6
7
7c: 88%
7d: 67%
7e: 64%
7f: 83%
7g: 72%
NH2
CH3
CH3O
F
NH2
NH2
an intramolecular lactonization. Thus, the 11a,12a-epoxide 6
was treated with different nucleophilic amines in EtOH/toluene
(1/1) at reflux during 24 h, affording steroidal lactones 7. The
assignment of structures 7 was supported by the NMR spectra
which showed a disappearance of the characteristic singlet (of
the lateral chain) at dH 3.6 ppm (s, C-23-OMe) and the coupling
constant between 11-H and 9-H is 3.9 Hz, which shows the 11-H
NH2
NH2
CF3
8
9
NH2
7h: 70%
7i: 75%
should be in
a position. Furthermore, the positions of the angular
NH2
NH2
methyl groups at dH ꢀ0.76 ppm (s, C-13-Me) and dH ꢀ 0.98 ppm
(s, C-10-Me) are consistent with a 11-amino-12-oxa structure.
The yields of the corresponding lactones 7 are depicted in Table
1.
10
7j: 66%
The stereo- and regioselectivity in the epoxide 6 ring opening
can be rationalized as shown in Scheme 3.
*
Yields are given for isolated products.

6950
M. Ibrahim-Ouali, H. Khalil / Tetrahedron Letters 51 (2010) 6948–6950
intramolecular
lactonization
not sterically favorable
O
O
anti-epoxide ring-
opening suitable to
a SN2 mechanism
HO
OMe
OMe
O
RHN
7
AcO
OAc
AcO
OAc
H
H
6
8
syn-epoxide ring-
opening not favorable
Scheme 3. Proposed mechanism of epoxide ring opening.
The nucleophilic attack in the epoxide ring opening would be
made exclusively on the least sterically hindered carbon of the
epoxide (C11) due to the SN2 mechanism employed in this method-
ology. In stereochemical terms, the classical and much stabilized
Acknowledgements
This work has been financially supported by the CNRS and the
Ministère de l’Enseignement Supérieur et de la Recherche.
anti approximation of nucleophiles species with the
a-epoxide
produces the respective trans-hydroxy amines 8, which are not iso-
lated (Scheme 3).
References and notes
By analysing Table 1, it is possible to verify that the epoxide ring
opening is not sensitive to electronic effects of the aromatic moiety
in the amines. For instance, for compound 7d (Table 1, entry 4),
made from a nucleophile with an activating R group, the yield
was 67%, while compound 7g (Table 1, entry 7), made with a deac-
tivating R group on the ring, had a quasi similar yield of 70%. The
reaction is also not sensitive to steric effects. Introducing a bulky
group as a naphthyl group at C-11 position is possible as shown
by the entry 10 (Table 1) which gave product 7j.
1. Neef, G.; Beier, S.; Elger, W.; Henderson, D.; Wiechert, R. Steroids 1984, 44,
349.
2. Baran, J. S.; Langford, D. D.; Laos, I.; Liang, C. D. Tetrahedron 1977, 33, 609.
3. Salunke, D. B.; Hazra, B. G.; Gonnade, R. G.; Bhadbhade, M. M.; Pore, V. S.
Tetrahedron 2005, 61, 3605.
4. Pinder, A. R. Steroidal alkaloids in Rodd’s chemistry of carbon compounds;
Elsevier: Amsterdam, 1998; (b) Ibrahim-Ouali, M. Steroids 2008, 73, 775.
5. Fieser, L. F.; Rajagopalan, S. J. Am. Chem. Soc. 1950, 72, 5530.
6. Chen, C. H. Synthesis 1976, 125.
7. Plesnicar, B. Oxidation in Organic Chemistry; Academic Press: New York, 1978.
pp 211–253.
In summary, we describe a new class of pentacyclic steroids9
from cholic acid, by a stereoselective intramolecular epoxide-
opening lactonization as the key step. It is also noteworthy to men-
tion that this synthesis is short, versatile, and moreover interesting
moieties can be introduced at the C-11 position of the steroidal
skeleton, which is a key position from a biological point of view.10
An application of this strategy to introduce a sulphur moiety at the
same position is in due course.
8. Marson, C. M.; Rioja, A. S.; Smith, K. E.; Behan, J. M. Synthesis 2003, 535.
9. Experimental data and results for the biological testing of 7 (which are under
progress) will be reported in due course as a full letter.
10. (a) Engel, C. R.; Rastogi, R. C.; Roy Chowdhury, M. N. Steroids 1972, 19, 1; (b)
Engel, C. R.; Salvi, S.; Roy Chowdhury, M. N. Ibid. 1975, 25, 781; (c) Gumulka,
M.; Ibrahim, I. H.; Bonczatomazewski, C. R. Can. J. Chem. 1985, 63, 766; (d)
Morand, P.; Lyall, J. Chem. Rev. 1968, 68, 85; (e) Huisman, H. O. Angew. Chem.,
Int. Ed. 1971, 10, 450.