A ring-closing metathesis approach to secosteroidal macrocycles

Article abstract of DOI:10.1016/j.tetlet.2011.10.108

An efficient synthesis of secosteroidal macrocycles has been achieved via an oxidative ring-expansion/ring-opening sequence and a ring-closing metathesis reaction as the key steps.

Full text of DOI:10.1016/j.tetlet.2011.10.108

Tetrahedron Letters 52 (2011) 7128–7131
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A ring-closing metathesis approach to secosteroidal macrocycles
⇑
Malika Ibrahim-Ouali , Jamel Zoubir, Eugénie Romero
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:
An efficient synthesis of secosteroidal macrocycles has been achieved via an oxidative ring-expansion/
ring-opening sequence and a ring-closing metathesis reaction as the key steps.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 29 June 2011
Revised 18 October 2011
Accepted 19 October 2011
Available online 25 October 2011
Keywords:
Secocholane
Baeyer–Villiger oxidation
Macrocyclization
Ring-closing metathesis (RCM)
The majority of secosteroids has been isolated from sponges,
gorgonians, soft corals and from the ascidian Aplidium conicum.1
Secosteroids have been found to exhibit diverse biological activi-
ties, for example, antiproliferative, antifouling, anti-inflammatory,
antimicrobial, ichthyotoxic and antiviral. Most of the naturally
occuring secosteroids are 9,11-secosteroids that possess either
the usual trans A/B ring junction or, more rarely, the cis fusion of
the A and B rings.
The partial cleavage of the steroidal skeleton nucleus is a com-
mon approach in medicinal chemistry. Synthetic work on secoster-
oids has also traditionally rendered novel compounds displaying a
wide variety of biological activities, ranging from hormone antag-
onists2 to tyrosine phosphatase inhibitors.3
The Baeyer–Villiger reaction of ketocholanes was chosen for the
ring expansion, as the process incorporates an additional oxygen
atom and the resulting lactone ring can be submitted to a standard
ring-opening procedure. Moreover, the Baeyer–Villiger reaction
presents two advantages: a complete retention of configuration
and a well-known regioselectivity for ketosteroids.7
In the two envisaged syntheses (Schemes 1 and 2), we prepared
the RCM substrates from cholic acid, a commercial bile acid both
inexpensive and readily available. Firstly, we turned our attention
to the synthesis of 12,13-secosteroidal macrocycles matching a cis
A/B ring junction. The key reactions leading to these new secoster-
oids are depicted in Scheme 1. Simple esterification of cholic acid 1
led to methyl cholate,8 which was methylated with methyl iodide–
A quite attractive type of steroidal nucleus is the cholanic skel-
eton of bile acids. These readily available compounds have been
widely exploited for the construction of supramolecular receptors
featuring macrocyclic scaffolds.4,5
Herein we report a simple and versatile approach to produce
secocholanic steroids possessing a macrocycle in their structure.
Indeed, this combination of secocholanic skeleton with varied
types of macrocycles, produces high levels of skeletal diversity
and complexity.
Our approach relies on a sequential ring-expansion/ring-open-
ing and on a ring-closing metathesis (RCM) reaction that allows
the construction of macrocycles. Indeed, ring-closing metathesis
(RCM) has become a powerful tool for the construction of a variety
of cyclic structures that would be difficult to achieve using tradi-
tional methods.6
sodium hydride in THF affording methyl 3a,7a-dimethoxy cholate
3 in a yield of 93%. Simultaneous protection of the secondary hy-
droxyl groups at C-3 and C-7 was needed prior to the reductive
opening of the lactone ring. Microwave (MW)9 irradiation of 3 with
pyridinium chlorochromate furnished ketone 4 very quickly, in a
few minutes, and in a 70% yield. Baeyer–Villiger oxidation of keto-
cholane 4 led to lactone 5 as the single regioisomer, as a result of a
higher migration aptitude of the quaternary C-13 compared to the
secondary C-11. Next, the simultaneous reduction of both the lac-
tone moiety on ring C and the ester function at C-24 afforded the
diprotected pentahydroxysecocholane 6 in a 88% yield. Diallylation
of primary alcohols at C-24 and C-12 produced the corresponding
diallyl adduct 7 in moderate yield (58%). However, this reaction
permits in one step the installation of the two olefin units required
for RCM. Indeed, the key step of the synthesis is the construction of
the macrocycle using the RCM reaction.6 The RCM reaction of 7
was accomplished firstly by the treatment with a catalytic amount
of Grubbs-I catalyst (10 mol %) [(Cy3P)2Cl)2Ru@CHPh] in CH2Cl2 at
⇑
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 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.108

M. Ibrahim-Ouali et al. / Tetrahedron Letters 52 (2011) 7128–7131
7129
O
O
HO
H
HO
OR
OMe
H
b
c
H
H
H
H
HO
OH
MeO
OMe
H
H
1
2
R = H
R = CH3
3
a
O
O
O
O
OMe
O
OMe
H
H
d
e
H
H
H
H
MeO
OMe
MeO
OMe
H
H
4
5
O
OH
O
OH
HO
HO
f
g
H
H
H
H
MeO
OMe
MeO
OMe
H
H
6
7
O
O
HO
8 R = Me
9 R = H
h
H
H
RO
OR
H
Scheme 1. Synthesis of a 12,13-secosteroidal macrocycle 9 from cholic acid through eight steps sequence. Reagents and conditions: (a) MeOH, PTSA,
D
, 2 h, 99%; (b) CH3I,
NaH, THF, rt, 94%; (c) PCC, MW,5 min, 70%; (d) m-CPBA, PTSA, CH2Cl2, rt, 24 h, 98%; (e) LiAlH4, THF, 0 °C to rt, 12 h, 88%; (f) allyl bromide, KH, DMF, 0 °C to rt, 12 h, 58%; (g)
Grubbs-II catalyst (20 mol %), CH2Cl2, rt, 12 h, 65%; (h) ISi(CH3)3, CHCl3, rt, 24 h, 92%.
room temperature under argon atmosphere. The desired macrocy-
cle 8 was isolated as the sole product in a fair yield (18%). After sev-
eral trials, the reaction was improved with the use of Grubbs-II
catalyst (20 mol %) in toluene at 80 °C providing the secosteroid
8 in good yield (65%). However, reaction was not stereoselective,
a mixture of geometric isomers 8 was obtained with the E isomer
predominating (ratio E:Z = 8:2).
The structure of the macrocyle compound 8 was determined by
a series of 1D NMR, COSY and NOESY experiments (400 MHz), and
confirmed by the (+)-HRESI mass spectra of the speudomolecular
ion [M+H]+ at m/z 492.3818, corresponding to the molecular for-
mula C30H52O5. A 8:2 ratio of isomers was obtained with the trans
(J = 15.2 Hz) isomer prevailing over the cis (J = 10.6 Hz) isomer.
Finally, removal of methoxy groups of 8 was carried out with
trimethylsilyl iodide10 to afford the desired compound 9 in a 92%
yield.
the starting material. The regioselective oxidation of the hydroxyl
group at C-7 was performed with NBS.11 The resulting 7-keto
derivative 10 was then converted into cholate 11 in good yield
(95% yield over two steps).
As expected, the Baeyer–Villiger oxidation of ketocholane 11
furnished exclusively regioisomer 12, as a result of the favoured
migration of the tertiary C-8 compared to the secondary C-6. Con-
secutively, a reaction sequence consisted in TBDMS protection of
OH functionalities, followed by the reductive opening of the lac-
tone ring with simultaneous reduction of the ester function at C-
24 and finally regioselective diallylation reaction of primary alco-
hols at C-24 and C-7 led to the diallyl secocholane 15 in a 38% over-
all yield (over four steps). The RCM was promoted by the second
generation Grubbs’ catalyst and the reaction was very efficient. In-
deed, we were pleased to discover that treatment of diene 15 with
20 mol % of Grubbs’ 2nd generation catalyst in toluene at 80 °C
gave the macrocyclic product 16 in a 90% yield. Here too, this latter
16 was completely characterized by NMR and mass spectroscopic
Having achieved efficiently the first synthesis of 12,13-secoster-
oidal macrocycles using RCM as the key step,6 we turned our atten-
tion to the preparation of 7,8-secosteroidal macrocycles using an
analogous strategy. As reported in Scheme 2, cholic acid 1 was also
methods (HRMS calcd for
C40H76O5Si2 692.5231, found
692.5234). The E:Z 9:1 ratio observed in the 1H NMR spectrum of

7130
M. Ibrahim-Ouali et al. / Tetrahedron Letters 52 (2011) 7128–7131
O
O
HO
HO
H
OR
OH
H
a
c
H
O
H
H
H
HO
HO
OH
H
H
1
10 R = H
11 R = CH3
b
O
OMe
RO
TBSO
OH
H
H
H
H
e
f
H
O
OH
OH
RO
TBSO
H
O
12 R = H
13 R = TBS
14
d
RO
TBSO
H
H
H
H
O
g
O
OH
OH
RO
TBSO
O
O
15
16 R = TBS
17 R = H
h
Scheme 2. Synthesis of a 7,8-secosteroidal macrocycle 17 from cholic acid through eight steps sequence. Reagents and conditions: (a) NBS, H2O, NaHCO3, 12 h at rt then 2 h at
80–85 °C, 95%; (b) MeOH, PTSA, , 2 h, 100%; (c) m-CPBA, PTSA, CH2Cl2, rt, 24 h, 82%; (d) TBDMSCl, imidazole, DMF, rt, 12 h, 91%; (e) LiAlH4,THF, 0 °C to rt, 12 h, 90%; (f) allyl
bromide, KH, DMF, 0 °C to rt, 12 h, 56%; (g) Grubbs-II catalyst (20 mol %), CH2Cl2, rt, 12 h, 90%; (h) TBAF, THF, rt,12 h, 92%.
D
Sultan, C.; Rothwell, S.; Migeon, C. J. Steroids 1979, 33, 277; (d) Penning, T. M.;
the crude substance was strongly in favour of the E-isomer
(J = 15.6 Hz) with small amounts of sterically less favoured Z-dou-
ble bond (J = 10.4 Hz).
The 3- and 12-TBS ethers on the A and C rings of 16 were depro-
tected in a standard manner to afford the corresponding secoster-
oidal alcohol 17 in good yield.
The problem of formation of isomers can be, of course, over-
come by hydrogenation of the newly formed double bond.
In conclusion, the first short and efficient synthesis of 7,8- and
12,13-secosteroidal macrocycles has been accomplished in eight
steps, 20% and 30% overall yields, respectively, starting from com-
mercially available cholic acid. The synthesis features the selective
oxidations and protections, Baeyer–Villiger reaction, allylation and
RCM as the key steps.12 Further application of this strategy to the
synthesis of other secosteroids with a larger macrocycle is in pro-
gress in our laboratory.
Covey, D. F.; Talalay, P. J. Biol. Chem. 1981, 256, 6842; (e) Penning, T. M. Steroids
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Chem. Commun. 2005, 5263; (e) Averin, A. D.; Ranyuk, E. R.; Beletskaya, I. P.
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Acknowledgments
6. (a)For reviews on metathesis, see: Handbook of Metathesis; Grubbs, R. H., Ed.;
Wiley-VCH: Weinheim, Germany, 2003; pp 12–13; (b) Fürstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3012; (c) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed.
2003, 42, 1900; (d) Grubbs, R. H. Tetrahedron 2004, 60, 7117; For a review on
metathesis reactions in total synthesis, see: (e) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490.
7. (a) Takatsuto, S.; Ikekawa, N. Tetrahedron Lett. 1983, 24, 917; (b) Rivera, D. G.;
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This work has been financially supported by the CNRS and the
Ministère de l’Enseignement Supérieur et de la Recherche.
References and notes
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M. Ibrahim-Ouali et al. / Tetrahedron Letters 52 (2011) 7128–7131
7131
10. (a) Jung, M. E.; Lyster, M. A. J. Am. Chem. Soc. 1977, 99, 968; (b) Olah, G. A.;
Narang, S. C.; Gupta, B. G. B.; Malhotra, R. J. Org. Chem. 1979, 44, 1247.
11. Fieser, T. L.; Rajagopalan, S. J. Am. Chem. Soc. 1949, 71, 3935.
J = 6.2 Hz, J = 15.6 Hz, 1H, CH@); 13C NMR (100 MHz, CDCl3): d 18.8, 19.7, 23.3,
23.4, 24.2, 25.6, 29.5, 29.9, 31.5, 32.2, 33.1, 35.7, 36.4, 38.2, 41.4, 45.6, 50.8,
53.8, 59.0, 63.4, 67.2, 69.0, 70.6, 71.7, 72.2, 74.6, 119.4, 125.8. Compound 17
12. The typical procedure of the ring-closing metathesis reaction is as follows: To a
solution of Grubbs’ catalyst (0.002 mM, 20 mol %) in dry toluene (10 mL), a
solution of 7 or 15 (0.008 mM) in dry toluene (10 mL) was added dropwise
(over 30 min). The resulting mixture was stirred at 80 °C for 12 h under argon.
(major isomer): 1H NMR (400 MHz, CDCl3)
d 0.66 (s, 3H, H-18), 0.86 (d,
J = 6.4 Hz, 3H, H-21), 0.88 (s, 3H, H-19), 3.52 (m, 1H, H-8), 3.66 (m, 1H, H-3),
3.88 (m, 1H, H-12), 4.28 (m, 4H, OCH2–CH@), 4.82 (m, 4H, H-7 and H-24), 5.95
(td, J = 6.4 Hz, J = 15.4 Hz, 1H, CH@), 6.12 (td, J = 6.3 Hz, J = 15.4 Hz, 1H, CH@);
13C NMR (100 MHz, CDCl3): d 13.8, 18.0, 18.1, 23.7, 24.2, 24.6, 25.7, 29.5, 31.9,
35.4, 35.7, 36.0, 36.1, 37.3, 41.4, 47.5, 51.2, 53.8, 59.0, 63.4, 67.2, 68.0, 71.7,
71.9, 72.9, 74.0, 119.8, 126.4.
Selected spectral data of 9 and 17 are as follows: Compound 9 (major isomer): 1
H
NMR (400 MHz, CDCl3) d 0.88 (d, J = 6.4 Hz, 3H, H-21), 0.89 (s, 3H, H-19), 1.12
(s, 3H, H-18), 3.38 (m, 1H, H-12 and H-24), 3.66 (m, 1H, H-7), 3.88 (m, 1H, H-3),
4.16 (m, 4H, OCH2-CH@), 5.82 (td, J = 6.3 Hz, J = 15.6 Hz, 1H, CH@), 5.98 (td,