An unexpected BF3·Et2O-catalyzed rearrangement of 23E-benzylidenespirostanes to spiro[furan-indenes]

Article abstract of DOI:10.1016/j.tetlet.2016.04.032

Treatment of 23E-benzylidenespirostanes with BF₃·Et₂O in 2/1 acetic acid/CH₂Cl₂ led to novel steroids bearing a spiro[furan-indene] moiety in the side chain. When steroid sapogenins were treated with benzaldehyde and BF₃·Et₂O in the same mixture of solvents, similar compounds were obtained. The structures of the novel spirocyclic steroids were confirmed by NMR and X-ray diffraction.

Full text of DOI:10.1016/j.tetlet.2016.04.032

Tetrahedron Letters 57 (2016) 2249–2252
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An unexpected BF3ꢀEt2O-catalyzed rearrangement of 23E-
benzylidenespirostanes to spiro[furan-indenes]
⇑
Manuel A. Ramos Enríquez, 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:
Treatment of 23E-benzylidenespirostanes with BF3ꢀEt2O in 2/1 acetic acid/CH2Cl2 led to novel steroids
bearing a spiro[furan-indene] moiety in the side chain. When steroid sapogenins were treated with ben-
zaldehyde and BF3ꢀEt2O in the same mixture of solvents, similar compounds were obtained. The struc-
tures of the novel spirocyclic steroids were confirmed by NMR and X-ray diffraction.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 8 March 2016
Revised 8 April 2016
Accepted 11 April 2016
Available online 13 April 2016
Keywords:
23E-Benzylidenespirostanes
BF3ꢀEt2O-catalyzed rearrangement
NMR
X-ray diffraction
Spiro[furan-indene] steroids
Introduction
Results and discussion
Steroid sapogenins have served as starting materials in the
synthesis of a wide variety of bioactive steroids that include
adrenocortical hormones,1 plant grow promoting substances,2
cephalostatins and ritterazines,3 and antioxidants,4 among many
others.5 Since the preparation of bioactive steroids starting from
this family of compounds implies the modification or cleavage of
the spiroketal side chain, considerable attention has been devoted
to the development of new methods for the transformation on this
fragment.6 In particular we have recently described that treatment
of acetylated steroid sapogenins with benzaldehyde and a large
excess of BF3ꢀEt2O in CH2Cl2 produced good yields of 23E-benzyli-
denspirostanes. (Scheme 1).6g
A study to produce a more environment friendly procedure led
us to change the conditions of the aldol condensation in a way that
the amount of BF3ꢀEt2O can be reduced. During the course of this
study, we found that the simple change of solvent from CH2Cl2 to
2/1 acetic acid/CH2Cl2 allowed the reduction in the amount of BF3-
ꢀEt2O necessary to produce the above mentioned aldol condensa-
tion and also promoted an unexpected rearrangement that
produces hereto unknown spirocyclic steroids bearing a spiro[fu-
ran-indene] moiety in the side chain.
When a solution of 1 mmol of tigogenin acetate (1a) in 2/1
acetic acid/CH2Cl2 mixture (9 mL) was treated with benzaldehyde
(2 mmol) and BF3ꢀEt2O (0.6 mL) the expected 23E-benzyliden-
spirostane 2a was produced in 41.5% yield after 4.5 h. Surprisingly
during the same treatment of 1b, the expected 23E-benzyliden-
spirostane 2b was slowly produced together with a more polar
compound that arose after 24 h (TLC). Consumption of the staring
material 1b was achieved only after 50 h and no trace of the
expected 23E-benzylidenspirostane 2b was observed in TLC after
that time. Chromatographic separation of the reaction mixture
afforded the unexpected compound 3b in 50.9% (Scheme 2 Eq. 1,
Table 1 entry 2). The same reaction with tigogenin acetate (1a)
afforded the corresponding compound 3a in only 19.7% after 63 h
(Scheme 2 Eq. 1, Table 1 entry 1). Additionally, when solutions of
our previously reported 23E-benzylidenespirostanes 2a and 2b6g
(1 mmol) in 2/1 acetic acid/CH2Cl2 mixture (9 mL) were treated
with BF3ꢀEt2O (0.6 mL), compounds 3a and 3b were produced in
almost similar yields as described above (Scheme
Table 1, entries 3 and 4).
2 Eq. 2;
The hereto unknown compounds 3a and 3b bear an indene moi-
ety fused to the furostane side chain through positions C-22 (spiro)
and C-23 (olefinic). Assignments of the NMR signals and elucidation
of the structures of the new spirocyclic compounds were carried
out employing a combination of 1D and 2D NMR techniques that
included 1H, 13C, HSQC, HMBC, NOESY, and COSY. The observed
H-60 M H-16 and H-60 M H-17 NOE effects indicate that the bond
⇑
Corresponding author. Tel./fax: +52 55 56223899x44417.
E-mail address: martin.iglesias@unam.mx (M.A. Iglesias-Arteaga).
http://dx.doi.org/10.1016/j.tetlet.2016.04.032
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

2250
M. A. Ramos Enríquez et al. / Tetrahedron Letters 57 (2016) 2249–2252
O
O
R
R
O
O
i
H3CCOO
H3CCOO
H
H
1a) R= H,H
1b) R= O
2a) R= H,H
2b) R= O
.
i) benzaldehyde, BF3 Et2O CH2Cl2
Scheme 1. Synthesis of 23E-benzylidenespirostanes.
OOCCH3
27
26
H
7´
25
24
25
21
21
8'
9'
O
26
23
R
R
R
27
H
18
18
20
17
6´
5´
20
17
23
22
22
24
12
11
12
11
1´
16
13
14
19
O
13
14
O
19
4´
H
1
4
1
4
16
9
9
2´
3´
2
H
H
15
15
8
10
8
10
3
5
3
5
7
7
i
NOE
eq. 1
H3CCOO
H3CCOO
6
6
H
H
(1a) R= H,H
(1b) R= O
(3a) R= H,H
(3b) R= O
25
21
O
26
23
R
27
18
20
17
22
24
23´
12
11
13
14
19
O
H
1
4
16
9
2
15
8
10
3
5
7
ii
eq. 2
H3CCOO
6
H
(2a) R= H,H
(2b) R= O
i) benzaldehyde, BF3•Et2O, AcOH/CH2Cl2 (2/1); ii) BF3•Et2O, AcOH/CH2Cl2 (2/1)
Scheme 2. Synthesis of the spiro[furan-indenes] 3a and 3b.
Table 1
C- 12, 41.6 C-13, 56.7 C-14, 32.5 C-15, 84.3 C-16, 63.2 C-17, 16.9
C-18, 12.3 C-19, 36.2 C-20, 15.3 C-21, 101.2 C-22, 148.5 C-23,
31.0 C-24, 31.4 C-25, 69.6 C-26, 17.1 C-27, 128.5 C-70, 142.8 C-10,
124.0 C-20, 127.9 C-30, 124.6 C-40, 120.6 C-50, 145.5 C-60, 21.5,
21.0 2 ꢁ CH3 acetyl, 170.7, 171.2 2 ꢁ C@O acetyl.
Synthesis of the spiro[furan-indenes] 3a and 3b
Entry
Starting material
Product
Time (h)
Yield (%)
1
2
3
4
1a
1b
2a
2b
3a
3b
3a
3b
63
50
48
48
19.7
50.9
13.2
40.4
(22R,25R)Indene[90,80:22,23]-3b,26-diacetoxy-5
a-furostan-12-
one (3b) Mp. 249.0–249.3 °C (from acetone/hexane). 1H NMR
(400 MHz, CDCl3) d 7.33 (d, J = 7.4 Hz, 1H, H-20), 7.18 (td, J = 7.4,
1.0 Hz, 1H, H-30), 7.13–7.09 (m, 1H, H-50), 7.07 (td, J = 7.4, 1.3 Hz,
1H, H-40), 6.38 (d, J = 1.5 Hz, 1H, H-70), 4.92 (td, J = 8.4, 7.3,
between C-22 and the phenyl ring is oriented to the
a-side of
the steroid nucleus, which results in the 22R configuration
(see Scheme 2). X-ray diffraction of compound 3b corroborated
the proposed structures (Fig. 1).7
4.2 Hz, 1H, H-16
H-26), 3.04 (dd, J = 9.4, 8.1 Hz, 1H, H-17
a
), 4.77–4.56 (m, 1H, H-3
a), 4.15–3.87 (m, 2H,
a), 2.44 (1H, m, H-24a),
2.39 (m, 1H, H-20b), 2.30 (m, 1H, H-25), 2.07 (s, 3H, CH3 acetyl),
2.03 (s, 3H, CH3 acetyl), 2.01 (m, 1H, H-24b), 1.26 (s, 3H, H-18),
0.98 (d, J = 6.7 Hz, 3H, H-27), 0.95 (s, 3H, H-19), 1.19 (m, 1H, H-
(22R,25R)Indene[90,80:22,23]-5
a-furostan-3b,26-diol diacetate
(3a) Mp. 194.5–196.7 °C (from CH2Cl2/MeOH). 1H NMR (400 MHz,
CDCl3) d 7.35–7.29 (m, 1H, H-20), 7.16 (td, J = 7.4, 1.1 Hz, 1H, H-
30), 7.12–7.09 (m, 1H, H-50), 7.05 (td, J = 7.4, 1.3 Hz, 1H, H-40),
9a
), 0.64 (d, J = 6.8 Hz, 3H, H-21). 13C NMR (100 MHz, CDCl3) d
ppm: 36.2 C-1, 27.2 C-2, 73.1 C-3, 33.8 C-4, 44.5 C-5, 28.1 C-6,
32.5 C-7, 34.2 C-8, 55.5 C-9, 36.1 C-10, 37.7 C-11, 213.0 C- 12,
55.8 C-13, 56.0 C-14, 32.0 C-15, 82.5 C-16, 53.9 C-17, 16.5 C-18,
11.9 C-19, 36.7 C-20, 14.0 C-21, 101.2 C-22, 147.9 C-23, 30.9 C-
24, 31.3 C-25, 69.5 C-26, 17.0 C-27, 128.8 C-70, 142.6 C-10, 124.0
C-20, 128.1 C-30, 124.7 C-40, 120.6 C-50, 145.1 C-60, 21.4, 21.0
2 ꢁ CH3 acetyl, 170.6, 171.1 2 ꢁ C@O acetyl.
6.36 (d, J = 1.5 Hz, 1H, H-70), 4.99 (dt, J = 9.2, 7.0 Hz, 1H, H-16
a
),
4.70 (tt, J = 11.3, 4.9 Hz, 1H, H-3a), 4.09–3.92 (m, 2H, H-26),
2.58–2.52 (m, 1H, H-20b), 2.49 (ddd, J = 15.3, 5.2, 1.8 Hz, 1H, H-
24a), 2.31 (ddt, J = 13.2, 6.5, 1.7 Hz, 1H, H-l25), 2.20 (dd, J = 9.3,
7.8 Hz, 1H, H-17a), 2.07 (s, 3H, CH3 acetyl), 2.05 (d, J = 1.6 Hz,
1H, H-24b), 2.02 (s, 3H, CH3 acetyl), 0.99 (s, 3H, H-18), 0.98 (d,
J = 6.5 Hz, 3H, H-27), 0.87 (s, 3H, H-19), 0.72 (td, J = 11.8, 10.4,
In a rational reaction pathway, activation of acetic acid by
BF3ꢀEt2O leads to acetylation of the hydroxyl group attached to
C-26, that results on the F-ring opening and concomitant generation
of the carbocation I. Resonance weakens the C-23–C-230 double
3.1, 1H, H-9a
), 0.55 (d, J = 6.9 Hz, 3H, H-21). 13C NMR (100 MHz,
CDCl3) d ppm: 36.7 C-1, 27.5 C-2, 73.7 C-3, 34.0 C-4, 44.7 C-5,
28.5 C-6, 32.2 C-7, 35.0 C-8, 54.2 C-9, 35.6 C-10, 21.1 C-11, 40.3

M. A. Ramos Enríquez et al. / Tetrahedron Letters 57 (2016) 2249–2252
2251
Figure 1. X-ray structure of compound 3b with the thermal ellipsoids drawn at 30% probability.
25
21
20
OOCCH3
O
26
OOCCH3
27
23
18
22
24
23´
O
23
16
23
23´
22
23´
22
BF3•Et2O
O
O
H3CCOO
CH3COOH
H
OOCCH3
2a
Ia
Ib
27
rotation arround
C-23-— C23´
OOCCH3
26
25
23
24
OOCCH3
21
OOCCH3
18
20
22
O
23
23
23
23´
16
23´
22
22
22
O
O
-H+
O
H
H3CCOO
H
3a
Id
Ic
II
Scheme 3. Plausible reaction mechanism.
bond and permits rotation, placing the phenyl ring near to the carbo-
cation at C-22 and allowing the internal SEAr that locks the indene
moiety through the spiro carbon at C-22 (Scheme 3).
hyde to produce 23E-benzylidenespirostanes6g followed by the
described rearrangement.
Production of the spiro[furan-indene] steroids 3a and 3b
directly from the corresponding steroid sapogenins 1a and 1b
can be rationalized in terms of a tandem process that includes
our previously reported aldol condensation of steroid sapogenins
with benzaldehyde to produce 23E-benzylidenespirostanes6g
followed by the described rearrangement.
Although experimental results clearly indicate that the pres-
ence of a carbonyl function at C-12 plays a determinant role in
the yield of the reaction, no explanation for this effect appears con-
vincing. Further studies are directed at clarifying the effect of the
C-12 carbonyl function on the reaction rate, improving overall
reaction yields, and extending the synthetic applications of this
new reaction to other spiroketalic compounds.
Acknowledgements
The authors acknowledge the financial support provided by
Dirección General de Asuntos del Personal Académico (Project
DGAPA-IN211714) and the Faculty of Chemistry (PAIP-5000-
9063). Thanks are due to CONACYT-México for the scholarship
granted to M.A.R-E. We want to express our gratitude to Minerva
Monroy-Barreto (USAI-UNAM) for recording NMR spectra. We
thank Dr. Carlos Cobas from MestrelabÒ for assistance with the
MestreNova NMR processing program.
References and notes
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Conclusions
Treatment of 23E-benzylidenespirostanes with BF3ꢀEt2O in 2/1
acetic acid/CH2Cl2 triggers a rearrangement that produces novel
steroids bearing a spiro[furan-indene] moiety in the side chain.
When steroid sapogenins were treated with benzaldehyde and
BF3ꢀEt2O in the same mixture of solvents, similar compounds were
obtained through a tandem process that includes our previously
reported aldol condensation of steroid sapogenins with benzalde-

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M. A. Ramos Enríquez et al. / Tetrahedron Letters 57 (2016) 2249–2252
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