An alternative reduction course of the spiroketal side chain of steroid sapogenins induced by the presence of a 23E-benzylidene moiety

Article abstract of DOI:10.1016/j.tetlet.2013.06.011

Treatment of 25R and 25S-23E-benzylidenespirostanes with NaBH₃CN in acetic acid produced the hydride addition at either C-23 (normal course) or C-23′ (abnormal course) leading to 23E-benzylidenefurostanes and 23R-benzylspirostanes. In the case of the 25S-23E-benzylidenespirostane a minor amount of a 23R-benzylfurostane produced by the over-reduction of the side chain was isolated.

Full text of DOI:10.1016/j.tetlet.2013.06.011

Tetrahedron Letters 54 (2013) 4401–4405
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An alternative reduction course of the spiroketal side chain of steroid
sapogenins induced by the presence of a 23E-benzylidene moiety
⇑
Manuel A. Ramos-Enríquez, Margarita Romero-Ávila, Marcos Flores-Álamo, Martín A. Iglesias-Arteaga
Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México, D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 May 2013
Revised 28 May 2013
Accepted 3 June 2013
Available online 10 June 2013
Dedicated to the Memory of Dr. Fernando
Albertús Areces an Excellent Professor and
Friend
Treatment of 25R and 25S-23E-benzylidenespirostanes with NaBH3CN in acetic acid produced the
hydride addition at either C-23 (normal course) or C-230 (abnormal course) leading to 23E-benzylidenefu-
rostanes and 23R-benzylspirostanes. In the case of the 25S-23E-benzylidenespirostane a minor amount of
a 23R-benzylfurostane produced by the over-reduction of the side chain was isolated.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
23E-Benzylidenespirostanes reduction
23E-Benzylidenefurostanes
23R-Benzylspirostanes
23R-Benzylfurostanes
Introduction
Results and discussion
Steroid sapogenins (SE) occupy a paramount place as starting
materials for the synthesis of a wide variety of bioactive steroids
that include sexual and adrenocortical hormones,1 plant growth
promoting substances,2 and the potent antitumor agents rittera-
zines and chephalostatines,3 among many others. For nearly
70 years the synthesis of such bioactive compounds has prompted
an intensive search for new ways for the modification or degrada-
tion of the side chain of SE.4 In particular, the reductive opening of
the spiroketal side chain to produce dihydrosapogenins has been
achieved by treatment with different reducing reagents under
both, Bronsted or Lewis catalysis (Scheme 1).5
Additionally, the functionalization at C-23 has recently focused
increased attention because the presence of a substituent at this
position produces changes in the reactivity profile of the spiroketal
moiety and also triggers interesting rearrangements that are not
observed in the non-fuctionalized SE.6
We have recently described that treatment of different SE with
benzaldehyde and BF3ꢀEt2O produces moderate to good yields of
the corresponding 23E-benzylidenespirostanes.7 This has prompted
us to study the influence of the 23E-benzylidene moiety in the
course of the reduction of the spiroketal moiety. Herein we report
on the reduction 23E-benzylidenespirostanes with NaBH3CN in
acetic acid.
Treatment of 23E-benzylidene tigogenin acetate (1a) with
NaBH3CN in acetic acid/CH2Cl2 afforded a 2/1 mixture of the 23E-
benzylidenfurostane 2a and the 23R-benzylspirostane 3a. Almost
similar results were obtained when 23E-benzylidene sarsasapoge-
nin acetate (1b) was submitted to the same procedure. Meanwhile
reduction of 1b also afforded a minor amount of the over-reduced
derivative 4b, all attempts at production and isolation of the over-
reduced derivative 4a were unsuccessful (Scheme 2 and Table 1).
The reductive opening of the F ring can be corroborated by up-
field shift of the signal of C-22 and the presence of a new 1H signal
corresponding to H-22 (See Supplementary data file for compara-
tive NMR tables). The configuration at C-22 in the (22S, 23E)-ben-
zylidenfurostanes 2a and 2b was verified by the observation of the
effect that indicates their spatial proximity and,
as a consequence, the S configuration at C-22 (Fig. 1). The addi-
tional NOE and HMBC correlations indicate the integrity of the tet-
rahydrofuran ring and the benzylidene moiety (Fig. 1).
In the 23S-benzylspirostanes 3a and 3b, the reduction of the
double bond between C-23 and C-230 can be corroborated by the
upfield shifts of the NMR signals associated to C-23, C-230, and
H-23 (See Supplementary information file for comparative NMR ta-
bles). The additional NOE and HMBC correlations indicate the
integrity of the spiroketal moiety and the phenyl group. The S con-
figuration at C-23 in compounds 3a and 3b can be determined by
observation of the
orientation of H-23. In addition, the strong
effect that indicates the axial
⇑
Corresponding author. Tel./fax: +52 55 56223899X 44417.
E-mail address: martin.iglesias@unam.mx (M.A. Iglesias-Arteaga).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.011

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M. A. Ramos-Enríquez et al. / Tetrahedron Letters 54 (2013) 4401–4405
R1 R2
R1 R2
R1 R2
R1
OX
OH
OX
O
R2
22R
H
O
O
O
O
i, ii , iii or iv
25R: R1= H; R2= CH3
25S: R1=CH3; R2= H
.
X, H, or AlCl3 or BF3 Et2O
i) H2 PtO2/HClO4/ AcOH; ii) NaBH3CN / AcOH; iii) LiAlH4 / AlCl3 Et2O; iv: Et3SiH / BF3·Et2O / CH2Cl2
Scheme 1. Reductive F ring opening in SE.
R2
R1
OH
R2
R1
R1
OH
O
R2
H
O
O
2
O
H
R1
O
+
4
O
R2
NaBH3CN
AcOH
AcO
1
H
a) 5α, 25R; R1= H, R2 = CH3
b) 5β, 25S; R1= CH3, R2 = H
3
Scheme 2. Reduction of 1a and 1b.
27
27
CH3
CH3
25
25
OH
OH
21
H3C
21
H3C
24
23
24
H
H
26
26
H
H
18
18
CH3
CH3
para
para
ipso
23´
23
ipso
20
20
S
S
22
22
23´
17
ortho
17
ortho
13
13
O
H
O
H
meta
meta
16
16
H
H
14
14
15
15
2a
2b
Figure 1. Selected
y
correlations in the side chains of the (22S,23E)-benzylidenfurostanes 2a and 2b.
CH327
21
H3C
21
H3C
H
H
H
H
O
O
25
25
CH3
26
26
23
23
27
18
18
20
20
CH3
CH3
22
22
24
24
H2C 23´
H2C 23´
ipso
ipso
17
17
O
O
16
16
para
para
14
14
15
15
ortho
ortho
H
H
meta
meta
3a
Figure 2. Selected
3b
y
correlations in the side chains of the 23R-benzylspirostanes 3a and 3b.
27
CH3
25
OH
21
H3C
24
H
26
H
23
18
CH3
par
23´
C
ipso
20
22
R
H2
Table 1
17
13
O
ortho
meta
Products and yields of the reduction of 1a and 1b
16
H
4b
correlations in the side chain of the (22R,23S)-
14
Starting material
Products (Yield%)
15
(1a) 5
a
, 25R; R1= H, R2 = CH3
2a (64)
2b (52)
3a (32)
3b (18)
-
(1b) 5b, 25S; R1= CH3, R2 = H
4b (4)
Figure 3. Selected
benzylfurostane 4b.
y

M. A. Ramos-Enríquez et al. / Tetrahedron Letters 54 (2013) 4401–4405
4403
effect observed in compound 3b provides further evidence on the S
configuration at C-23 (Fig. 2).
In compound 4b, the reductive opening of the F ring can be cor-
roborated by the upfield shift of the signal of C-22 and the presence
of a new 1H signal corresponding to H-22. The upfield shifts of the
NMR signals associated to C-23, C-230, and H-23 indicate the
reduction of the double bond between C-23–C-230 (See Supple-
mentary data file for comparative NMR tables). The observed
effect indicates the alpha orientation of H-22
and consequently the R configuration at C-22. The NMR spectra
do not provide conclusive evidence on the configuration at C-23,
but it can be inferred by mechanistic considerations (vide infra).
2a
3a
3b
Figure 4. Crystal structures of compound 2a, 3a and 3b with the thermal ellipsoids drawn at 50% of probability.

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M. A. Ramos-Enríquez et al. / Tetrahedron Letters 54 (2013) 4401–4405
H
O
O
23
23
+H+
22
22
23´
23´
O
O
-H+
I
1b
OH
OH
OH
H
23
23
23
23´
22
22
23´
22
23´
O
O
H
O
H
IIb
IIa
IIc
OH
OH
H
23
23´
23
22
23´
22
H
H
O
O
2b
III
H
OH
H
O
O
23
23
23´
23
23´
23´
22
22
22
+H+
-H+
H
H
H
H
O
O
O
H
H
IV
3b
OH
OH
H
23
23
23´
23´
22
22
H
H
H
H
O
O
4b
Scheme 3. Possible reaction mechanism.
The integrity of the tetrahydrofuran ring can be verified by the
additional NOE and HMBC correlations (Fig. 3).
X-ray studies carried out in monocrystals of compounds 2a, 3a,
and 3b confirmed the proposed structures (Fig. 4), (See supplemen-
tary data file for X-ray refinement data).8
reactivity shown by 3b may be explained considering that the F
ring opening in the 23S,25S-23-benzyl side chain of 3b, produces
the release of tensions associated with the presence of the axial
methyl group at C-25, favoring the F ring opening.
Conclusions
Possible reaction mechanism
We have found that 23E-benzylidenespirostanes undergo hy-
dride addition at either C-23 (normal course) or C-230 (abnormal
course). This finding indicates that the presence of the benzylidene
moiety at C-23 produces a deviation of the normal course of the
reductive F ring opening followed by the non-functionalized SE.
The hereto unknown compounds may constitute useful synthetic
intermediates in the preparation of potentially bioactive steroids.
Further experiments directed to study the reactivity of the 23E-
benzylidenespirostane side chain are on development.
The occurrence of the isolated compounds can be rationalized
by a pathway that initiates with the acid catalyzed F ring opening
to produce the intermediate II. At this point addition of the hydride
at C-22 leads to the observed 23E-benzylidenespirostane 2a and
2b. The occurrence of the 23-benzylspirostanes 3a and 3b evi-
dences the addition of the hydride to C-230 and suggests the signif-
icant contribution of the allylic-benzylic carbocation IIc to the
actual structure of the intermediate (Scheme 3).
The occurrence of the over-reduced compound 4b can be ex-
plained by acid catalyzed F ring opening of 3b leading to the inter-
mediate IV that undergoes hydride addition to C-22. Considering a
fast hydride addition to C-22 in the intermediate IV, it can be as-
sumed that compound 4b retains the S-configuration of 3b at C-23.
Attempts at production and isolation of the over-reduced com-
pound 4a derived from reduction of 3a included scaling up the
reaction or increase of the amount of NaBH3CN added, and were
all unsuccessful. This indicates the resistance of the 23S,25R-23-
benzyl side chain of 3a to the F ring opening. The slightly increased
Acknowledgements
The authors thank Dirección General de Asuntos del Personal
Académico (DGAPA-UNAM) for financial support via project
IN221911-3. Thanks are due to Rosa I. del Villar Morales, Geor-
gina Duarte Lisci (USAI-UNAM) for recording NMR and MS spec-
tra. We want to express our gratitude to Dr. Carlos Cobas from
MestrelabÒ for assistance with the MestreNova NMR processing
program.

M. A. Ramos-Enríquez et al. / Tetrahedron Letters 54 (2013) 4401–4405
4405
8029–8031; Iglesias-Arteaga, M. A.; Arcos-Ramos, R. O. Tetrahedron Lett. 2007,
48, 7485–7488; Jastrze˛bska, I. Curr. Org. Chem. 2012, 16, 353–372.
Supplementary data
5. (a) Pettit, G. R.; Bowyer, W. J. J. Org. Chem. 1960, 25(1), 84–86; (b) Faul, W. H.;
Failli, A. J. Org. Chem. 1970, 35(8), 2571–2585; (c) Bäsler, S.; Brunck, A.; Jautelat,
R.; Winterfeldt, E. Helv. Chim. Acta 2000, 83, 1854–1880; (d) Lee, S.; LaCour, T. G.;
Lantrip, D.; Fuchs, P. L. Org. Lett. 2002, 4(3), 313–316; (e) Chaosuancharoen, N.;
Kongkathip, N.; Kongkathip, B. Synth. Commun. 2004, 34, 961–983.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
06.011.
6. (a) Hernández, R.; Marrero-Tellado, J. J.; Prout, K.; Suárez, E. J. Chem. Soc., Chem.
Commun. 1992, 275–277; (b) Betancor, C.; Dorta, R. L.; Freire, R.; Martín, A.;
Prangé, T.; Suárez, E. J. Org. Chem. 1998, 63, 6355–6362; (c) Morzycki, J. W.;
Jastrze˛bska, I. Tetrahedron Lett. 2001, 42, 5989–5991; (d) Anulewicz-Ostrowska,
R.; Morzycki, J. W.; Jastrze˛bska, I.; Wojcik, J. J. Org. Chem. 2002, 67, 6916–6924;
(e) Cyranski, M. K.; Frelek, J.; Jastrze˛bska, I.; Morzycki, J. W. Steroids 2004, 69,
395–400; (f) Iglesias-Arteaga, M. A.; Velázquez-Huerta, G. A.; Méndez-Stivalet, J.
M.; Galano, A.; Alvarez-Idaboy, J. R. ARKIVOC VI 2005, 109–126; (g) Iglesias-
Arteaga, M. A.; Sandoval-Ramírez, J.; Mata-Esma, M. Y.; Viñas-Bravo, O.; Bernès,
S. Tetrahedron Lett. 2004, 45, 4921–4926; (h) Iglesias-Arteaga, M. A.; Alvarado-
Nuño, A. A. Tetrahedron Lett. 2006, 47, 5351–5353; (i) Iglesias-Arteaga, M. A.;
Velázquez-Huerta, G. A. Tetrahedron Lett. 2005, 46, 6897–6899.
References and notes
1. Lednicer, D. Strategies for organic drug synthesis, second ed.; John Wiley & Sons,
Inc.: Hoboken, New Jersey, 2009 (Chapters 4 and 5, and references therein).
2. (a) Iglesias-Arteaga, M. A.; Pérez, R.; Pérez, C. S.; Coll, F. J. Chem. Soc. Perkin Trans.
1 2001, 261–266; (b) Iglesias-Arteaga, M. A.; Pérez, R.; Pérez, C. S.; Coll, F.
Steroids 2002, 67, 159–163; (c) Romero-Ávila, M.; de Dios-Bravo, G.; Mendez-
Stivalet, J. M.; Rodríguez-Sotres, R.; Iglesias-Arteaga, M. A. Steroids 2005, 72,
955–959; (d) Rosado-Abón, A.; de Dios-Bravo, G.; Rodríguez-Sotres, R.; Iglesias-
Arteaga, M. A. J. Steroid Biochem. Mol. Biol. 2013, 134, 45–50.
3. (a) Moser, B. R. J. Nat. Prod. 2008, 71, 487–491; (b) Iglesias-Arteaga, M. A.;
Morzycki, J. W.; Cephalostatins; Ritterazines In The Alkaloids: Chemistry and
Biology; Knölker, H. J., Ed.; Elsevier: Amsterdan, 2013; pp 153–279.
4. (a) LaCour, T. G.; Tong, Z.; Fuchs, P. L. Org. Lett. 1999, 1, 1815–1818; (b)
Sandoval-Ramírez, J.; Meza-Reyes, S.; del Río, R. E.; Hernandez-Linares, G.;
Suárez-Rojas, A.; Rincón, S.; Farfán, N.; Santillán, R. L. Steroids 2003, 68, 199–
204; (c) Jastrze˛bska, I.; Morzycki, J. W.; Trochimowicz, U. Tetrahedron Lett. 2004,
45, 1929–1932; (d) Jastrze˛bska, I.; Morzycki, J. W. Pol. J. Chem. 2005, 79, 1245–
1248; (e) Iglesias-Arteaga, M. A.; Arcos-Ramos, R. O. Tetrahedron Lett. 2006, 47,
7. Ruíz-Pérez, K. M.; Romero-Ávila, M.; Tinajero-Delgado, V.; Flores-Álamo, M.;
Iglesias-Arteaga, M. A. Steroids 2012, 77, 819–828.
8. Crystallographic data have been deposited with the Cambridge Crystallographic
Data Center as Supplementary material numbers CCDC 939827 (2a), 939828
(3a) and 939829 (3b). Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. E-
mail:deposit@ccdc.cam.ac.uk.