Ring-closing metathesis towards functionalised pentacyclic steroids

Article abstract of DOI:10.1016/j.tetlet.2012.02.005

A new synthetic pathway towards pentacyclic steroids was described via a ring-closing metathesis reaction as the key step.

Full text of DOI:10.1016/j.tetlet.2012.02.005

Tetrahedron Letters 53 (2012) 1859–1862
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ring-closing metathesis towards functionalised pentacyclic steroids
Malika Ibrahim-Ouali , Hocine Bouleghlem a,b, Nour-Eddine Aouf b
a,
⇑
a
Institut des Sciences Moléculaires de Marseille, UMR 7313 CNRS and Université d’Aix Marseille, Faculté des Sciences et Techniques de Saint Jérôme, Avenue Escadrille
Normandie-Niemen, 13397 Marseille Cedex 20, France
b
Laboratoire de Chimie Organique Appliquée, Groupe de Chimie Bioorganique, Faculté des Sciences, Université d’Annaba, Annaba, Algeria
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic pathway towards pentacyclic steroids was described via a ring-closing metathesis reac-
Received 12 January 2012
Revised 30 January 2012
Accepted 1 February 2012
Available online 8 February 2012
tion as the key step.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Steroids
Macrocycles
Ring-closing metathesis (RCM)
Allylation
Due to their high profile biological activity, the steroids are
among the most important secondary metabolites. Pentacyclic ste-
roids constitute an important class of steroids. There are many
examples of pentacyclic steroidal derivatives of pharmacological
and biological importance.1 The incorporation of short carbon
bridges spanning characteristic positions of the steroid backbone
continues to be a popular stratagem in the search for new, biolog-
ically active steroid hormone analogues. Moreover, pentacyclic ste-
roids obtained by the fusion of a carbocyclic ring such as benzene
or cyclohexane or cyclopentane to the steroid nucleus or pentacy-
clic steroids derived by the fusion of a carbocyclic ring to a heteros-
teroid skeleton are known to exhibit interesting and diverse
and simple preparation of pentacyclic steroids possessing a macro-
cycle using a ring-closing metathesis reaction as the key step.
Firstly, we turned our attention to the synthesis of steroids con-
taining a new ring bridging rings C and D, and in particular 12,17-
annulated steroid pentacycles which were never described till
now. The key reactions leading to these new steroids are depicted
in Scheme 1. Cholic acid 1, a commercial bile acid both inexpensive
and readily available, was chosen as starting material. First, simple
esterification of cholic acid 1 led to methyl cholate, which was
methylated with methyl iodide-sodium hydride in THF affording
methyl 3a,7a-dimethoxy cholate 3 in a yield of 93%. Next, the C-
24 ester function of the lateral chain was reduced in excellent yield
with lithium aluminium hydride in diethyl ether to the tetraol
diprotected 4.
2
biological properties. We note that most of the partial and total
syntheses of pentacyclic steroids reported in the literature till
now, were concentrated on the synthesis of steroids containing a
In the next step, we had to prepare the key precursor of this syn-
thesis, possessing two terminal alkene functionalities suitable for
metathesis. This reaction constitutes a new and very interesting re-
sult. Indeed, hydroxyls at different positions on the nucleus have
different reactivities towards alkylating agents, generally in the or-
3
4
5
new ring fused to ring A, ring D or bridging rings A and B.
Olefin metathesis has become one of the most powerful and
attractive tools for the formation of carbon–carbon double bonds
widely used in organic synthesis. The spectacular improvements
in this reaction achieved over the last two decades are well known
to most chemists. An increasing number of papers devoted to the
applications of olefin metathesis in the synthesis of natural prod-
9
der C-3 > C-7 > C-12. It was not clear that it would be possible to
alkylate a hindered hydroxyl group such as the 12a-OH in a mole-
cule with several other functional groups. Indeed, attempts to ally-
6
ucts are observed. Although ring-closing metathesis (RCM) is
late diol 4 using classical methods [(a) allylbromide, sodium
7
10
known to be a powerful tool for the preparation of macrocycles,
hydride and tetrabutylammonium iodide in THF, (b) allylbromide
1
1
in the field of steroid chemistry, only few syntheses have been re-
and silver oxide in DMF, . . . ] all failed to give the desired product
ported based on metathesis reactions.8 Herein, we report a new
5. However, the method of Bundle and co-workers relative to the
12
benzyl protection of hydroxyl functions, employing in our case, O-
allyl 2,2,2-trichloroacetimidate and trifluoromethanesulphonic
acid, was more successful. The conversion was not entirely clean
due to the formation of byproducts, but careful optimisation
⇑
Corresponding author. Tel.: +33 0491288416; fax: +33 0491288234.
E-mail addresses: malika.ibrahim@univ-cezanne.fr, malika.ibrahim@univ-uma.fr
(
M. Ibrahim-Ouali).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.005

1
860
M. Ibrahim-Ouali et al. / Tetrahedron Letters 53 (2012) 1859–1862
O
HO
H
HO
OR'
OH
H
c
d
H
H
H
H
RO
OR
H CO
3
OCH3
H
H
1
2
3
R = R' = H
4
a
b
R = H, R' = CH3
R = R' = CH3
O
O
H
O
O
H
H
e
f
H
H
H
H CO
3
OCH3
H CO
3
OCH3
H
H
5
6
O
O
H
7
8
R = CH3
R = H
H
H
g
RO
OR
H
Scheme 1. Synthesis of a steroidal macrocycle 8 from cholic acid through seven steps sequence. Reaction conditions: (a) MeOH, PTSA,
4%; (c) LiAlH , Et O, 0 °C to rt, 12 h, 96%; (d) O-allyl 2,2,2-trichloroacetimidate, CSA cat, CH Cl , 24 h, 64%; (e) (PCy Cl Ru@CHPh = Grubbs catalyst, first generation, CH
, 12 h, 36%; (f) H /Pd-C/Na CO , EtOAc, 88%; (g) ISi(CH , CHCl , rt, 24 h, 92%.
D
, 2 h, 99%; (b) CH
3
I, NaH, THF, rt, 12 h,
9
D
4
2
2
2
)
3 2
2
2
Cl ,
2
2
2
3
)
3 3
3
(
10 mol % of CSA instead of CF
SO
3 3
H) resulted in a procedure giving
We decided to test the catalysts of Grubbs GI and GII (Table 1).
5
in a 64% yield. So, we disclosed in this Letter a method to allylate
In all cases, the Grubbs catalyst of second generation was more
efficient than this of first generation. We carried out the first exper-
iments under relatively mild conditions: 20 mol % of catalyst in dry
and degassed dichloromethane at room temperature. Using these
experimental conditions, fair yields were observed. The yields of
the cyclisation products of 11a, 11b and 11c were improved by
increasing the temperature (Table 1, entries 3, 6, 9 and 12). The
more reactive Grubbs catalyst of the second generation was nec-
essary to obtain the desired product starting with 11d (Table 1, en-
tries 10 and 11). Thus, cyclisation of 11d having a 5-pentenester
moiety could only be accomplished at reflux temperature in
dichloromethane. And its yield was improved with higher temper-
ature (refluxing toluene).
efficiently cholic acid derivatives at the C-12 position.
Cyclisation of 5 in the presence of first generation Grubbs cata-
lyst13 in CH
2 2
Cl led to the pentacyclic steroid 6 possessing a 13-
membered macrocycle within 12 h and in a 36% yield (mixture of
E/Z isomers). The remaining material was mainly the unreacted
starting diene 5. Hydrogenation of the double bond and subse-
quent cleavage of the protecting groups gave the saturated macro-
cycle 8. Despite extensive research on steroids, the synthesis of
such a compound has not been described before.
Encouraged by this result and to show that this ring enlarge-
ment is generally applicable, different types of olefins were
subjected to metathesis reaction (Scheme
1
5
1
4
2 and Table 1).
3
a
,7 -Dimethoxy cholate 3 was allylated as described above
a
Otherwise, the reaction was not stereoselective. All metathesis
products were obtained as mixtures of geometric E/Z-isomers with
the E isomer predominating. The structure of these new pentacy-
clic steroids 12 was completely characterised by NMR (400 MHz)
leading to 9 in 66% yield. The latter was reduced with lithium
aluminium hydride in diethyl ether providing the alcohol 10 in
good yield. Then, the dienes 11a–d were prepared in high yields
by the reaction of steroid 10 with alkenoic acids in the presence
of DCC and DMAP. All esters obtained were found to be stable and
were subjected to RCM reactions. According to the literature, syn-
thesis of unsaturated lactones through RCM has been accom-
plished using either Grubbs, first or second generation, or
Hoveyda catalyst.
1
6
and mass spectroscopic methods.
Finally, removal of methoxy groups of pentacyclic steroids 12
1
7
was carried out with trimethylsilyl iodide to afford the desired
compounds 13 in good yields. The problem of formation of isomers
can be, of course, overcome by hydrogenation of the newly formed
double bond.

M. Ibrahim-Ouali et al. / Tetrahedron Letters 53 (2012) 1859–1862
1861
O
O
HO
H
O
OCH3
OCH3
H
a
b
H
H
H
H
H CO
3
OCH3
H CO
3
OCH3
H
H
3
9
n
O
O
OH
O
O
H
H
H
c
H
H
H
H CO
3
OCH3
H CO
OCH3
3
H
H
11a-d
1
0
a - n = 0; 68%
b - n = 1; 75%
c - n = 2; 78%
d - n = 3; 72%
O
O
n
d
1
2 R = CH3
e
O
H
1
3 R = H
a - n = 0
b - n = 1
c - n = 2
d - n = 3
H
H
RO
OR
H
Scheme 2. Synthesis of steroidal macrocycles 13 from cholic acid through seven steps sequence. Reaction conditions: (a) O-allyl 2,2,2-trichloroacetimidate, CSA cat, CH
rt, 24 h, 66%; (b) LiAlH , Et O, 0 °C to rt, 12 h, 92%; (c) CH @CH(CH COOH, DCC, DMAP, n = 1, 2, 3 or CH @CHCOCl, NEt ; (d) catalyst conditions, see Table 1; (e) ISi(CH
CHCl , rt, 24 h.
2
Cl
2
,
,
4
2
2
)
2 n
2
3
3 3
)
3
Table 1
Metathesis reactions via Scheme 2
metathesis seems to be a method of choice for the synthesis of
pentacyclic steroids. These molecules can now be exploited for
the generation of diverse compound libraries.
Entry
Olefin
n
Cata
Condition
12: Yield (%)
1
2
3
4
5
6
7
8
9
11a
11a
11a
11b
11b
11b
11c
11c
11c
11d
11d
11d
0
0
0
1
1
1
2
2
2
3
3
3
A
B
B
A
B
B
A
B
B
A
B
B
DCM, rt, 24 h
DCM, rt, 24 h
26
34
48
20
46
63
28
32
56
—
Acknowledgments
MePh,
D, 4 h
DCM, rt, 24 h
DCM, rt, 24 h
This work has been financially supported by the CNRS and the
Ministère de l’Enseignement Supérieur et de la Recherche.
MePh,
D, 4 h
DCM, rt, 24 h
DCM, rt, 24 h
References and notes
MePh,
D, 4 h
10
11
12
DCM, rt, 24 h
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, 4 h
22
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A = RuCl
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3.
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4
1

1
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