Stereoselective synthesis of selenosteroids

Article abstract of DOI:10.1016/j.tetlet.2010.02.090

A stereoselective synthesis of selenosteroids 4 and 5 has been achieved. Starting from commercial available cholesterol 1, followed by asymmetric epoxidation, and subsequently, by stereoselective epoxide ring opening, employing a selenium nucleophilic spe

Full text of DOI:10.1016/j.tetlet.2010.02.090

Tetrahedron Letters 51 (2010) 2237–2240
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of selenosteroids
a
a
a
a
Oscar E. D. Rodrigues a, , Diego de Souza , Letiére C. Soares , Luciano Dornelles , Robert A. Burrow ,
*
Helmoz R. Appelt b, Camila F. Alves b, Diego Alves b, , Antonio L. Braga
c
*
a Universidade Federal de Santa Maria—Departamento de Química, CEP 97105-900, Camobi, Santa Maria, RS, Brazil
b Centro Universitário Franciscano—UNIFRA—Rua dos Andradas, 1614 Centro, CEP 97010-032, Santa Maria, RS, Brazil
c Universidade Federal de Santa Catarina—UFSC—Departamento de Química, CEP 88040-900, Florianópolis, SC, Brazil
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 selenosteroids 4 and 5 has been achieved. Starting from commercial avail-
able cholesterol 1, followed by asymmetric epoxidation, and subsequently, by stereoselective epoxide
ring opening, employing a selenium nucleophilic species, the correspondent products were afforded in
high yields. The compounds were being evaluated for their biological activity and as a chiral pool for
asymmetric transformations.
Received 29 September 2009
Revised 12 February 2010
Accepted 16 February 2010
Available online 21 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Selenosteroids
Oxysterols
Selenolates
1. Introduction
droxyl protection in C3 position in cholesterol 1 was introduced
using sodium hydride and methyl iodide to afford the respective
Oxygenated derivatives of cholesterol, known as oxysterols,
represent a group of biomolecules receiving much attention in re-
cent years due to their relevant bioactivities.1 Oxysterols have been
detected in appreciable quantities in human tissues and fluids and
have been implicated in a number of important biological pro-
cesses such as regulation of cholesterol homeostasis, atherosclero-
sis, cytotoxicity2, and have found use as antitumoral and
antileukemic compounds for inducing apoptosis.3 Likewise, com-
pounds containing selenium can possess biological properties
and have been used as antiviral, antihypertensive, antibacterial,
or chemopreventive anticancer agents.4 There are several reports
in the literature describing the antitumoral activity of selenium
compounds via apoptosis in cancer cells induced by the generation
of ROS in a pro-oxidant fashion.5 The combination of oxysterols
and selenium is quite rare and only a few examples are described
in the literature with a very limited selenium moiety.6 The de-
signed synthesis of new pro-oxidant biomolecules combining oxy-
sterol and selenium-containing compounds has a great potential
for the creation of a new library of molecules important for biolog-
ical applications.
methyl-ether 2. Next, an asymmetric epoxidation in the cholesterol
double bond (C5@C6) was performed to introduce the desired
epoxide functional group in the steroidal nucleus, using the proto-
col employed by Marson and co-workers with MCPBA as the oxi-
dant agent to give the epoxide ring with high selectivity in the
least hindered face of steroid.7 The introduction of selenium in
the steroid moiety was performed using a selective epoxide ring
opening with nucleophilic selenolates. For compounds 4a–i, the
anionic species were generated from the respective diselenides.
To optimize the selenium insertion, a standard condition was em-
ployed and the epoxide 3 was treated with diphenyl diselenide
using two methodologies. In the first protocol, the selenolates were
generated from the appropriate diselenide, followed by the reduc-
tive cleavage of dichalcogenide bond using sodium borohydride in
EtOH/THF (Method A). In the second methodology, the selenolate
species were obtained by reductive cleavage of the Se–Se bond of
diselenide using Zn and HCl (Method B), as depicted in Scheme
1. Since we found that Method B gave better yields than Method
A (90% vs 63% for the compound 4a, respectively), Method B was
used as the standard protocol for the synthesis of selenides 4. For
the diselenide 5, the nucleophilic species was formed using ele-
mental selenium and lithium triethylborohydride to give Li2Se2,
as shown in Scheme 1 (for detailed procedures, see Section 2).
The yields of the respective seleno-oxysterols 4 and 5 are depicted
in Table 1.
This field has been explored by our research group and in this
context, we report herein the stereoselective synthesis of selenos-
teroids 4 and 5 derived from cholesterol 1 (Fig. 1). Firstly, the hy-
* Corresponding authors. Tel.: +55 55 3220 8761; fax: +55 55 3220 8998
(O.E.D.R.).
E-mail addresses: oscar.rodrigues@pq.cnpq.br, rodriguesoed@smail.ufsm.br
(O.E.D. Rodrigues).
The stereo- and regioselectivity in the epoxide 3 ring opening
can be rationalized as shown in Figure 2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.090

2238
O. E. D. Rodrigues et al. / Tetrahedron Letters 51 (2010) 2237–2240
Figure 1. Selenosteroids 4 and 5.
H
H
i
1
2
HO
O
ii
H
3
iii or iv
O
v
O
H
H
4
5
O
O
OH
OH
Se
)
2
SeR
Scheme 1. Synthesis of steroids containing selenium. Reagents and conditions: (i) (a) THF, NaH; (b) CH3I, rt; (ii) CHCl3, MCPBA, rt; (iii) (a) EtOH/THF, (RSe)2, NaBH4; (b)
epoxide 3, reflux; (iv) (a) THF, ZnO, HCl, (RSe)2, ultrasound; (b) epoxide 3, ultrasound; (v) (a) THF, SeO, lithium triethylborohydride; (b) epoxide 3, reflux.
The nucleophilic attack in the epoxide ring opening would be
made exclusively on the least sterically hindered carbon of the
epoxide (C6), due to the SN2 mechanism employed in this method-
ology. In stereochemical terms, the classical and much stabilized
5. To prove the regio- and stereochemistry we attempted the single
crystal X-ray analysis of the selenosteroids. Unfortunately none of
the compounds was suitable for this analysis. As proof of the ste-
reochemistry, the single crystal X-ray structure of the chloride 6
(Fig. 3), synthesized by epoxide ring opening via a SN2 mechanism,
was performed.
anti approximation of selenium nucleophiles species with the
a-
epoxide8 produces the respective trans-hydroxy selenides 4 and
H
O
OH
Cl
Figure 2. Proposed mechanism of epoxide ring opening.
Figure 3. 6b-Chloro-5a-hydroxy-3b-methoxycholestane, 6.

O. E. D. Rodrigues et al. / Tetrahedron Letters 51 (2010) 2237–2240
2239
Table 1
Selenosteroids compounds 4a–i and 5
H
O
OH
SeR
Entry
1
R
Yielda (%)
Figure 4. Molecule structure and numbering scheme for 6.
90
92
membered ring systems, all in the chair configuration to which a
five-membered ring system is fused. The three substitutions have
an effect only on the molecular packing. In 6, the individual mole-
cules are joined into chains along the crystallographic a axis by
hydrogen-bonded interactions between the hydrogen atom of O1
and O2 [d(O1Á Á ÁO2a) = 2.8266(13) Å; d(H1Á Á ÁO2a) = 1.99 Å; \O1–
H1Á Á ÁO2a = 170.5°;a: x + 1/2, Ày + 3/2, Àz].
2
3
95
The respective steroid 6 obtained via a similar reactional path-
way as the selenosteroids 4 and 5, allowed the confirmation of
the regio- and stereochemistry of the respective compounds, as
depicted in Figure 2.
The yields of the respective selenosteroids are depicted in
Table 1.
By analyzing Table 1, it is possible to verify that the epoxide ring
opening is not sensitive to electronic effects of the aromatic moiety
in the selenium nucleophiles. For instance, for compound 4g (Table
1, entry 7), made from a selenium nucleophile with an activating R
group, the yield was 88%, while compound 4e (Table 1, entry 5),
made with a deactivating R group on the selenium nucleophile,
had a similar yield of 87%. Also, these reactions are not sensitive
to steric effects as shown by the diselenides containing mesityl
and naphthyl groups which gave the corresponding products 4c
and 4h in excellent yields (Table 1, entries 3 and 8).
4
5
91
87
6
7
87
88
As noted earlier, both oxysterol and selenium-containing com-
pounds show very interesting biological applications related to
the pro-oxidant activity inducing apoptosis. The selenosteroid 5
should show this behavior. Indeed, 5 shows a pro-oxidant effect
leading to the formation of reactive oxygen species.12
In summary, we describe a versatile stereoselective synthesis of
a new class of selenosteroids. Organoselenium compounds have
been documented as promising pharmacological agents against a
number of diseases. Tests to check the biological activity of sele-
nosteroids were performed and the compound 5 showed a pro-oxi-
dant activity. Tests to check the biological activity of the steroids 4,
antitumoral activity of compound 5, and the asymmetric applica-
tion of the related compounds in chiral transformations are being
conducted by our group.
8
9
94
85
10
82
a
Yields are given for isolated products.
2. Experimental
Experimental data of the steroids 4–6 and general procedures to
the synthesis of the respective compounds are detailed in Supple-
mentary data.
The structure9 of 6, 6b-chloro-5
a
-hydroxy-3b-methoxycholes-
tane (C28H49ClO2), determined in the noncentrosymmetric space
group P212121, is that of a single stereoisomer with the stereocen-
ters C3 = R, C5 = R, C6 = R, C8 = S, C9 = S, C10 = R, C13 = R, C14 = S,
C17 = R and C20 = R (using the standard chlorestane numbering
scheme)10 resolved absolutely by the anomalous dispersion effects
of the chlorine atom (Fig. 4). The molecule has the same conforma-
tion as the core of the cholestane parent compound11 (see Supple-
mentary data for an overlay diagram) possessing three fused six-
Acknowledgments
The authors would like to thank FAPERGS (PROADE 3 project),
CNPq (Ed. Universal/2007, Ed. Jovem pesquisador em nanotecnolo-
gia/2008, INCT-Catálise and INCT-NANOBIOSIMES) and CAPES for
the financial support.

2240
O. E. D. Rodrigues et al. / Tetrahedron Letters 51 (2010) 2237–2240
6. (a) Wolf, G. C.; Sadek, S. A.; Shaw, S. M.; Kessler, W. V. J. Org. Chem. 1981, 46,
Supplementary data
3259; (b) Caspi, E.; Arunachalam, T.; MacKoul, P. J.; Green, N. M. J. Org. Chem.
1981, 46, 2966; (c) Mornon, J.-P.; Surcouf, E.; Lepicard, G.; Ojasoo, T.; Raynaud,
J.-P. J. Med. Chem. 1983, 26, 1320; (d) Djerassi, C.; Konopelski, J. P. J. Med. Chem.
1980, 23, 722.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.090.
7. Marson, C. M.; Rioja, A. S.; Smith, K. E.; Behan, J. M. Synthesis 2003, 535.
8. (a) Back, T. G. Organoselenium Chemistry: A Pratical Approach; Oxford University
Press: Oxford, UK, 1999; (b) Paulmier, C. Selenium Reagents and Intermediates in
Organic Synthesis; Pergamon: Oxford, 1986; (c) Liotta, D. Organoselenium
Chemistry; Wiley: New York, 1987; (d) Wirth, T. Organoselenium Chemistry –
Modern Developments in Organic Synthesis; Springer: Heidelberg, Germany,
2000.
References and notes
1. (a) Ferderbar, S.; Pereira, E. C.; Apolinário, E.; Bertolami, M. C.; Faludi, A.;
Monte, O.; Calliari, L. E.; Sales, J. E.; Gagliardi, A. R.; Xavier, H. T.; Abdalla, D. S. P.
Diabetes Metab. Res. Rev. 2007, 23, 35; (b) Glass, C. K.; Saijo, K. Nature 2008, 455,
40; (c) van Reyk, D. M.; Brown, A. J.; Hult’en, L. M.; Dean, R. T.; Jessup, W. Redox
Rep. 2006, 11, 255; (d) Olkkonen, V. M. Lipids Insights 2008, 2, 1.
2. (a) Brown, A. J.; Jessup, W. Atherosclerosis 1999, 142, 1; (b) Gill, S.; Chow, R.;
Brown, A. J. Prog. Lipid Res. 2008, 47, 391; (c) Vejux, A.; Malvitte, L.; Lizard, G.
Braz. J. Med. Biol. Res. 2008, 41, 545; (d) Murphy, R. C.; Johnson, K. M. J. Biol.
Chem. 2008, 283, 15521.
3. (a) Ayala-Torres, S.; Moller, P. C.; Johnson, B. H.; Thompson, E. B. Exp. Cell Res.
1997, 235, 35; (b) Ayala-Torres, S.; Zhou, F.; Thompson, E. B. Exp. Cell Res. 1999,
246, 193.
4. (a) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004, 104, 6255; (b)
Mugesh, G.; du Mont, W. W.; Sies, H. Chem. Ver. 2001, 101, 2125.
5. (a) Spallholz, J. E. Free Radical Biol. Med. 1994, 17, 45; (b) Davis, R. L.; Spallholz, J.
E. Biochem. Pharmacol. 1996, 51, 1015; (c) Sarafian, T. A.; Bredeson, D. E. Free
Radical Res. 1994, 21, 1; (d) Stewart, M. S.; Davis, R. L.; Walsh, L. P.; Pence, B. P.
Cancer Lett. 1997, 117, 35; (e) Shen, H.-M.; Yang, C.-F.; Liu, J.; Ong, C.-N. Free
Radical Biol. Med. 2000, 28, 1115.
9. Crystal data for 6: Colorless block, 0.19 Â 0.28 Â 0.40 mm3, C28H49ClO2,
M = 453.12, orthorhombic, space group P212121 (No. 19), a = 7.5811(2) Å,
b = 15.1268(5) Å, c = 22.4198(8) Å, V = 2571.05(17) Å3, T = 100(2) K, Z = 4,
Dcalcd = 1.171 g/cmÀ3
,
l
= 0.170 mmÀ1
,
2.69° < h < 30.64°, F(0 0 0) = 1000;
53,592 reflections measured, 7910 unique (Rint = 5.55%, Rsig = 4.08%). The final
wR2 = 10.03% (all data), R1 [I > r(I)] = 3.78%, 288 parameters, GoF = 1.064,
q
max = 0.608 eÀ/Å3,
q
min = À0.366 eÀ/Å3. CCDC No. 759891. Crystallographic
data (excluding structure factors) for the structure in this Letter have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
10. Moss, G. P. Pure Appl. Chem. 1989, 61, 1783.
11. Coles, S. J.; Frampton, C. S.; Hursthouse, M. B. Acta Crystallogr., Sect. E 2002, 58,
o445.
12. Kade, I. J.; Paixão, M. W.; Rodrigues, O. E. D.; Ibukun, E. O.; Braga, A. L.; Zeni, G.;
Nogueira, C. W.; Rocha, J. B. T. Toxicology In Vitro 2009, 23, 14–20.