The fragmentation reaction of 16R-bromopregnane-3S,20S-diol

Article abstract of DOI:10.1016/j.tetlet.2007.05.126

16R-Bromopregnane-3S,20S-diol reacted with potassium t-butoxide to afford androst-16-en-3S-ol in a moderate yield via fragmentation reaction. The latter is a key intermediate for the synthesis of 5α-androst-16-en-3-one, as boar sex pheromone, and other steroidal drugs. In addition, 16R,20S-epoxypregnane-3S-ol was also obtained as a major product by changing the reaction solvent.

Full text of DOI:10.1016/j.tetlet.2007.05.126

Tetrahedron Letters 48 (2007) 4987–4989
The fragmentation reaction of 16R-bromopregnane-3S,20S-diol
a
a
b
a
a,b,
*
Jing-Rong Lin, Nan-Yan Zhou, Qi-Hai Xu, Shi-Feng Jian and Wei-Sheng Tian
a
Department of Chemistry, College of Life Sciences and Environment, Shanghai Normal University, Shanghai 200234, China
b
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 22 January 2007; revised 22 May 2007; accepted 22 May 2007
Available online 25 May 2007
Abstract—16R-Bromopregnane-3S,20S-diol reacted with potassium t-butoxide to afford androst-16-en-3S-ol in a moderate yield via
fragmentation reaction. The latter is a key intermediate for the synthesis of 5a-androst-16-en-3-one, as boar sex pheromone, and
other steroidal drugs. In addition, 16R,20S-epoxypregnane-3S-ol was also obtained as a major product by changing the reaction
solvent.
Ó 2007 Elsevier Ltd. All rights reserved.
Tigogenin 1 (Fig. 1) is a by-product in the hemp-making
industry using sisal, and is also an environmental
pollutant. Currently, about 500 tons of tigogenin are
produced from industrial waste in making hemp annu-
ally in China. In connection with our project of organic
synthetic chemistry based on the rational utilization of
natural resource compounds (i.e., resource chemis-
application of pregnane-3,16,20-triol in the synthesis
of medicines, pesticides and organic molecules with
bioactivity, we also explored its reaction with a variety
of chemicals and found that compound 2 can be easily
transformed into 16R-bromopregnane-3S,20S-diol di-
acetate 3 in a good yield through regioselective acetyl-
7
ation–bromination. In connection with this study, we
1
–4
try),
we have finished the direct degradation of
continued to explore the reaction of 16R-bromopregn-
ane-3S,20S-diol 4, a hydrolysis product derived from 3
tigogenin into (3S,16S,20S)-pregnane-3,16,20-triol 2
t
and 4R-methyl-d-valerolactone using 30% aqueous
(Scheme 1), with KOBu . As expected, compound 4
5
,6
hydrogen peroxide on a scale of 10 kg. For the further
was converted into 5a-androst-16-en-3S-ol (5) directly
via a fragmentation reaction. It is obvious that this frag-
mentation reaction provided a new and concise method
for the synthesis of 5a-androst-16-en-3-ol and its ana-
logues from steroidal sapogenins such as tigogenin.
The results about this fragmentation reaction will be
reported in this Letter.
O
OH
O
OH
HO
HO
Tigogenin(1)
Pregnanetriol(2)
Compound 4 was easily prepared in the manner de-
picted in Scheme 1. (3S,16S,20S)-Pregnane-3,16,20-triol
Figure 1.
OH
OAc
OH
Br
OH
Br
a
b
HO
AcO
HO
2
3
4
Scheme 1. Preparation of 16R-bromopregnane-3S,20S-diol (4). Reagents and conditions: (a) 30% HBr/HOAc, 40–45 °C, 1.5 h; (b) K
0–45 °C, 2 h, 78% in two steps from 2.
2 3
CO /MeOH,
4
Keywords: Tigogenin; Pregnanetriol; 16R-Bromopregnane-3S,20S-diol; Fragmentation.
*
Corresponding author. Tel./fax: +86 21 54925176; e-mail: wstian@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.126

4988
J.-R. Lin et al. / Tetrahedron Letters 48 (2007) 4987–4989
OH
Br
O
t
-BuOK
-BuOH
+
t
HO
HO
HO
4
5
6
Scheme 2. Fragmentation of 16R-bromopregnane-3S,20S-diol (4).
(
2) reacted with a 30% solution of hydrogen bromide in
acetic acid at 45–50 °C to afford 16R-bromopregnane-
S,20S-diol diacetate 3. Without purification, com-
O-
O-
O
3
Br
Br
pound 3 was hydrolyzed to the corresponding 16R-
bromopregnane-3S,20S-diol 4 in 78% overall yield from
5
6
2
in two steps of the reaction. No signal peak for acet-
1
Scheme 4. The possible mechanism for the formation of 5 and 6.
oxy group appeared in the H NMR and IR spectra of
; this implied that two acetoxy groups of 3 had been
hydrolyzed. The structure of 4 was further confirmed
4
A plausible mechanism for the formation of 5 and 6 is
proposed (Scheme 4). The 16a derivative 4 has anti-
clinal bond, and the concerted reaction proceeds to give
the fragmentation product 5. Oxetane ring formation
may proceed by the intermediate formation of the anion
of hydroxyl group, which attacks the backside of C-16
by the displacement of bromine.
1
1
by the mass spectrum and elemental analysis.
On treatment of 16R-bromopregnane-3S,20S-diol 4
with 10 equiv of potassium t-butoxide in t-butyl alcohol
under reflux temperature, a fragmentation product
androst-16-en-3S-ol (5) was produced in 52% yield as
1
2
a major product, and the 16S,20S-epoxypregnane-
S-ol 6 was isolated simultaneously in 46% yield
3
The fragmentation reaction was related to the reac-
tion temperature and the results are summarized in
Table 1. As Table 1 shows, the reaction time will be
shortened and the ratio of 5 and 6 will be also improved
along with the raise of reaction temperature. These facts
elucidate that a lower temperature is advantageous to
the formation of the oxetane product, and a higher tem-
perature is beneficial to the formation of the fragmenta-
tion product.
1
3
(
Scheme 2). The fragmentation product 5 was charac-
terized by NMR and mass spectra even though it is a
known compound. The oxetane derivative 6 was also
8
identified by NMR and mass spectra and elemental
analysis. Evidence for the oxetane ring formation was
derived from the doublet at d 1.47 (J = 6.4 Hz) for the
C-21 methyl protons and the multiplet at d 4.51 for
the C-16 methine proton. A similar fragmentation reac-
8
b
tion has been reported by Matsyui and Fukushima
with pregnane-3S,20S-diol 16S-mesylate (7), in which
the fragmentation product 5 was only obtained in poor
yield. In addition to the preparation of pregnane-
The amount of potassium t-butoxide also influenced
the fragmentation reaction, but it was not so obvious
(Table 2). The increment of the amount of potassium
t-butoxide caused the yield of 5 to improve slightly,
and that of 6 to decline (entries 1–3). But there was no
effect on the selectivity of products by using more than
3
S,20S-diol 16S-mesylate is not convenient by compar-
ison with 16R-bromopregnane-3S,20S-diol 4 (Scheme
).
3
a
Table 1. The effect of temperature on the reaction
O
OH
OH
OH
Br
Entry
Temperature (°C)
Time (h)
Yields (%)
O
5
6
1
2
3
60
70
82
18
16
5
30
39
52
65
57
46
HO
HO
HO
Tigogenin(1)
Pregnanetriol(2)
4
b
AcO
O
a
Reactions were carried out with 10 equiv of t-BuOK.
Under reflux.
O
b
HO
AcO
AcO
AcO
t
a
Table 2. The effect of the amount of KOBu on the reaction
t
Entry
KOBu (equiv)
Time (h)
Yields (%)
O
O
OH
OMs
5
6
OH
OMs
1
2
3
4
3
5
10
15
6
5
5
4.5
44
47
52
52
52
48
46
44
AcO
AcO
7
Scheme 3. The comparison of the preparation of 16R-pregnane-
S,20S-diol with pregnane-3,16,20-triol 16-mesylate.
a
3
Reactions were carried out under reflux condition.

J.-R. Lin et al. / Tetrahedron Letters 48 (2007) 4987–4989
4989
OH
Br
t-BuOK
HO
DMSO
HO
HO
4
8
Scheme 5. The elimination of 16R-bromopregnane-3S,20S-diol (4).
1
0 equiv of potassium t-butoxide (entry 4). Then, we
3. Tian, W. S.; Guan, H. P.; Pan, X. F. Chin. J. Chem. 2003,
1, 793.
. Yang, Q. X.; Tian, W.-S.; Pan, S. Acta Chim. Sinica 2004,
2, 2171 (in Chinese).
. Marker, R. E.; Turner, D. L.; Wagner, R. B.; Ulshafer,
P. R.; Crooks, H. M., Jr.; Wittle, E. L. J. Am. Chem. Soc.
2
prolonged the reaction time, and found that no change
in the ratio of product 5/6 was observed. This implied
that the reaction time had no effect on the fragmentation
reaction.
4
5
6
1
941, 63, 77.
. Tian, W.-S. CN Patent 96-116304, 1997; Chem. Abstr.
998, 128, 167599.
The influence of the solvent was also observed. Besides
t-butoxy alcohol, dimethyl sulfoxide and dimethyl form-
amide were explored, respectively. In DMF, the oxetane
product 6 was superior, but in DMSO, the predominant
product is pregnan-14,16-dien-3S-ol (8), an elimination-
rearrangement product of 4 (Scheme 5). Moreover, the
effect of a base such as sodium hydride, lithium alumin-
ium hydride and lithium diisopropylamide was exam-
ined. But no satisfactory results were obtained as
expected.
6
1
7. Lin, J. R.; Wang, J.; Chen, L. J.; Wang, Y. C.; Tang, X.
M.; Xu, Q. H.; Zhu, Z.; Tian, W. S. Acta Chim. Sinica
2006, 64, 1265 (in Chinese).
. (a) Pospisek, J.; Vesely, Z.; Trojanek, J. Collect. Czech.
Chem. Commun. 1968, 33, 76; (b) Matsui, M.; Fukushima,
D. K. J. Org. Chem. 1970, 35, 561; (c) Bose, A. K.;
Steinberg, N. G. Synthesis 1970, 11, 595.
8
9
. (a) Cox, P. J.; Tunrner, A. B. Tetrahedron 1984, 40, 3153;
(
1
b) Han, G. D.; Han, G. T.; Zhu, L. Y. Acta Pharm. Sinica
982, 17, 696 (in Chinese); (c) Zhao, M.; Xiang, M. W.;
In conclusion, the reaction of 16R-bromopregnane-
Liao, Q. J. Nanjing Yaoxueyuan Xuebao 1986, 17, 241 (in
Chinese).
3
S,20S-diol with potassium t-butoxide has been investi-
gated in detail. According to the reaction condition
used, fragmentation, intramolecular etherification and
elimination-rearrangement of 16R-bromopregnane-
10. Buckett, W. R.; Hewett, C. L.; Savage, D. S. J. Med.
Chem. 1973, 16, 1116.
1
1. The spectral data of 16R-bromopregnane-3S,20S-diol (4):
25
1
Mp 165–167 °C, ½aꢀ +9.19 (c 0.77, CHCl3); H NMR
3
S,20S-diol with potassium t-butoxide occurred, respec-
D
(
3
400 MHz, CDCl ): d 4.51–4.42 (m, 1H, 16-H), 3.89–3.82
tively. The desired fragmentation reaction provided a
new and concise method for the synthesis of 5a-and-
rost-16-en-3-ol and its analogues from steroidal sapoge-
nins such as tigogenin. The fragmentation product 5 is a
(
m, 1H, 20-H), 3.65–3.57 (m, 1H, 3-H), 0.80 (s, 3H, 18-
Me), 0.65 (s, 3H, 19-Me); IR (KBr): 3415, 2921, 2847,
ꢁ1
1
(
442, 1372, 1041 cm ; MS (EI) m/z (intensity): 381
+
+
+
M ꢁ18), 365 (M ꢁ34), 301 (M ꢁ98). Anal. Calcd for
Br: C, 63.15; H, 8.83. Found: C, 63.36; H, 8.47.
12. The spectral data of androst-16-en-3S-ol (5): Mp 125–
key intermediate for the synthesis of 5a-androst-16-en-
21 35 2
C H O
9
3
-one, as boar sex pheromone. The application of this
1
0
25
D
1
fragmentation reaction for the synthesis of Pavaulon,
127 °C, ½aꢀ +13.29 (c 1.30, CHCl ); H NMR (400 MHz,
3
a steroidal muscle relaxant, is currently in progress in
this laboratory.
CDCl
3
): d 5.84–5.83 (m, 1H, 16-H), 5.69 (d, J = 1.6 Hz,
1
0
1
3
1
1
2
H, 17-H), 3.63–3.56 (m, 1H, 3-H), 0.85 (s, 3H, 18-Me),
1
3
.74 (s, 3H, 19-Me); C NMR (400 MHz, CDCl ): d
3
44.19, 129.51, 71.52, 56.33, 55.42, 45.80, 45.31, 38.44,
7.08, 36.17, 36.00, 34.34, 32.36, 32.24, 31.74, 28.93, 21.45,
7.31, 12.57; IR (KBr): 3346, 3040, 2938, 1611, 1450, 1368,
Acknowledgements
ꢁ
1
+
041, 706 cm ; MS (EI) m/z (intensity): 292 (M +18),
+
57 (M ꢁ17).
We are grateful for financial support of this work by the
National Science Foundation (Nos. 29372077,
1
3. The spectral data of 16S,20S-epoxypregnane-3S-ol (6): Mp
25
1
1
94–196 °C, ½aꢀD +19.56 (c 1.39, CHCl3); H NMR
2
0472052), Shanghai Municipal Education Commission
(
(
400 MHz, CDCl ): d 5.16–5.10 (m, 1H, 20-H), 4.54–4.49
m, 1H, 16-H), 3.63–3.56 (m, 1H, 3-H), 1.47 (d,
3
(
No. 05DZ18).
J = 6.4 Hz, 3H, 21-Me), 1.18 (s, 3H, 18-Me), 0.83 (s,
1
3
3
H, 19-Me); C NMR (400 MHz, CDCl ): d 83.85, 76.50,
3
7
1.28, 57.06, 56.28, 54.58, 45.05, 40.68, 40.09, 38.35, 37.22,
References and notes
35.80, 35.13, 34.83, 32.75, 31.67, 28.84, 23.33, 21.59, 16.13,
2.56; IR (KBr): 3444, 2925, 2848, 1446, 1377, 1054,
1
ꢁ
706 cm ; MS (EI) m/z (intensity): 319 (M +1), 302
+ +
1
+
1
2
. Tian, W. S. Acta Chim. Sinica 1992, 50, 72 (in Chinese).
. Tian, W. S.; Guan, H. P.; Pan, X. F. Chin. Chem. Lett.
994, 5, 1013.
(M ꢁ16), 301 (M ꢁ17). Anal. Calcd for C21
34 2
H O : C,
1
79.19; H, 10.76. Found: C, 78.79; H, 10.36.