A mild one-pot method for conversion of various steroidal secondary alcohols into the corresponding olefins

Article abstract of DOI:10.1055/s-0030-1260803

The addition of Tf₂O to some hydroxy steroids in the presence of excess base directly leads to steroidal olefins. This methodology is useful for the one-pot synthesis of Δ²- or Δ³-steroids under mild conditions from the corresponding alcohols. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260803

LETTER
1709
A Mild One-Pot Method for Conversion of Various Steroidal Secondary
Alcohols into the Corresponding Olefins
C
R
onversion of
V
a
a
rious Stero
j
idal Se
u
condary Alcohols
i
R
nto the Correspo
a
nding Olefi
n
ns jith Kumar, Shrutisagar Dattatraya Haveli, Henri B. Kagan*
Laboratoire de Catalyse Moléculaire, Institut de Chimie Moléculaire et des Matériaux d’Orsay (UMR CNRS 8182),
Bâtiment 420, Université Paris-Sud, 91405 Orsay, France
Fax +33(1)69154680; E-mail: henri.kagan@u-psud.fr
Received 7 April 2011
Dedicated to Professor Carmen Nájera on her 60 birthday
th
dehydrating agents, but these methods require harsh con-
ditions or a special reagent.
Abstract: The addition of Tf O to some hydroxy steroids in the
2
presence of excess base directly leads to steroidal olefins. This
2
3
methodology is useful for the one-pot synthesis of D - or D -steroids Herein we report the use of Tf O (triflic anhydride)/
2
under mild conditions from the corresponding alcohols.
DMAP (dimethylaminopyridine) or Tf O/pyridine as an
2
Key words: alcohols, biliary acid, elimination, steroids, triflic an- efficient system for the direct synthesis of various steroid
hydride
olefins from the corresponding secondary alcohols.
In our ongoing research on steroid systems we treated 5a-
cholestan-3b-ol 1 with 1 equivalent of Tf O and 3 equiv-
2
Steroids are important compounds in biological systems
due to their vital role in hormonal cycles. Among them
alents of DMAP in dichloromethane (CH Cl ) at 0 °C. In-
2
2
1
stead of the expected triflate, the corresponding olefin 2
was isolated in excellent yield (Scheme 1).
steroid epoxides belong to the class of oxysterols (deriva-
tives of cholesterol) that regulate cell proliferation and
2
a
Since the scope of this reaction has not been explored, we
cholesterol homeostasis in organism. They are also ver-
satile intermediates for organic synthesis as they can be
1
0
decided to apply it to various steroids. Thus, compounds
2
b–d
3a and 3b under Tf O/DMAP conditions were trans-
2
transformed to various steroidal derivatives.
The pre-
1
1
12
formed to the corresponding olefins 4a and 4b in good
yields (Table 1). 5a-cholestan-3a-ol (3c) also gave D -
cholestene (2) under similar reaction conditions, but long-
cursors for such epoxides may be the corresponding ole-
fins. There are various direct and indirect established
methods for the synthesis of such olefins. Usual proce-
dures involve transformation of keto-steroids to a-halo
2
er reaction time was needed.
ketones subsequently converted into the corresponding Homoallylic alcohols, such as cholesterol 3d and preg-
hydrazone followed by a Kishner reduction to obtain the nenolone 3e, were transformed to the corresponding i-ste-
3
a
13
14
olefins or reduction of a-haloketones to halohydrins fol- roid olefins 4d (46%) and 4e (58%). Testosterone (3f)
lowed by Zn-mediated reductive elimination.3b,c An alter- provided a mixture of unsaturated olefins 4f in 70%
native approach is the conversion of steroidal secondary yield. In this case the dehydration was accompanied by a
15
4
5
alcohols into the corresponding tosylates, halides, or methyl migration as is often observed in the case of a car-
6
10
propargyl xanthates followed by the base-mediated elim- bocation generated at C17.
ination.
The DMAP/Tf O methodology was also applied to sever-
2
There are few reports of direct conversion of steroid al biliary acid derivatives (Table 2). Methyl cholate (3g)
2
3
secondary alcohols into the corresponding olefins. For gave a mixture of olefins 4g in 76% yield (D /D = 1:4).
7
example, TsOH on silica gel or methyl(carboxysulfa- Methyl deoxycholate (3h) gave the corresponding olefin
8
16
moyl)triethylammonium hydroxide inner salt can act as 4h (74%); whereas methyl lithocholate (3i) led to an in-
2
3
17
separable mixture of D /D -olefins 4i (78%).
Tf2O/DMAP (3 equiv)
CH2Cl2, 0 °C, 1.5 h
HO
H
H
1
2 90%
2
Scheme 1 Synthesis of D -cholestene
SYNLETT 2011, No. 12, pp 1709–1712
x
x
.x
x
.2
0
1
1
Advanced online publication: 21.06.2011
DOI: 10.1055/s-0030-1260803; Art ID: D10411ST
©
Georg Thieme Verlag Stuttgart · New York

1
710
R. R. Kumar et al.
LETTER
Table 1 Synthesis of Steroidal Olefins Using Tf O/DMAP System
2
Alcohol
Product
Yield (%)a,b
OBz
OBz
9
7
7
4
5
7
2
HO
H
H
H
H
H
H
3a
4a
4b
O
O
0c
0d
6
HO
3b
C8H17
C8H17
HO
3c
2
HO
3d
4d
O
O
8
HO
4
e
f
3e
OH
0
O
O
4
3f
17 13 12
D /D /D = 1.2:1.1:0.4
a
Reaction conditions: steroid (1 mmol), Tf O (1 equiv), DMAP (3 equiv), CH Cl (5 mL), 0 °C, 2 h. Isolated yield after flash chromatography
2
2
2
on silica gel.
b
1
Structure established by comparison of H NMR spectra with reported compounds.
Reaction was quenched over cold solution of sat. NaHCO solution to destroy some enol triflate at C17.
c
3
d
Reaction was quenched after 5 h.
The influence of the base on the elimination reaction was scaled up to 10 g scale with 75% yield after crystalliza-
checked with cholestanol 1 (Table 3). DMAP, pyridine, tion.
and DIPEA (diisopropylethylamine) gave excellent yields
while triethylamine provided moderate yields.
In conclusion, we have developed conditions where the
use of Tf O in the presence of excess base leads directly
2
In order to make the procedure synthetically useful we to steroidal olefins. This methodology is particularly use-
2
3
developed an approach for the multigram-scale synthesis ful for the one-pot synthesis of certain D - or D -steroids
2
of D -cholestene (2) from commercially available from the corresponding alcohols. We have also developed
2
cholestanol (1) using pyridine as a base. The reaction was a multigram-scale approach for the synthesis of D -cho-
Synlett 2011, No. 12, 1709–1712 © Thieme Stuttgart · New York

LETTER
Conversion of Various Steroidal Secondary Alcohols into the Corresponding Olefins
1711
Table 2 Treatment of Various Biliary Acid Derivatives with Tf O/
hyd Na SO . After evaporation of solvent, the crude solid was puri-
2
4
2
DMAP System
fied by flash chromatography on silica gel to furnish the
corresponding alkene.
Alcohol
Product
Yield
a,b
2
(
%)
Multigram Scale Synthesis of D -Cholestene (2)
Triflic anhydride (6.52 mL, 38 mmol) was slowly added to a solu-
tion of cholestanol 1 (10 g, 25 mmol) and pyridine (6 mL, 150
mmol) in CH Cl (60 mL) at 0 °C. After completion of addition, the
OH
R
OH
R
2
2
reaction was stirred for 2 h. The reaction was quenched in ice-cold
H O and extracted with CH Cl (3 × 20 mL). The organic layer was
2
2
2
7
7
7
6
4
8
separated and dried over anhyd Na SO . After evaporation of sol-
2
4
vent, the crude solid was purified by crystallization using CH Cl –
2
2
HO
OH
OH
2
H
H
MeOH to obtain D -cholestene 2 (7.28 g, 75%).
3
g
4g
2
9
2
3
D -Cholestene
Mp 68 °C; [a] +63.5 (c 1, CHCl ). H NMR (250 MHz, CDCl ):
R = CH CH COOMe
D /D = 1:4
2
2
1
D
3
3
OH
R
OH
R
d = 0.70 (s, 3 H), 0.79 (s, 3 H), 0.88 (d, J = 6.8 Hz, 6 H), 0.91 (d,
13
J = 7.8 Hz, 3 H), 1.01–2.00 (m, 29 H), 5.61–5.63 (m, 2 H).
C
NMR (62.5 MHz, CDCl ): d = 125.9, 128.8, 54.1, 56.5, 56.3, 42.5,
3
41.4, 40.0, 39.8, 39.5, 36.2, 35.8, 35.6, 34.6, 31.8, 30.3, 28.8, 28.3,
2
8.0, 24.2, 23.9, 22.8, 22.6, 22.9, 18.7, 12.0, 11.7.
HO
H
H
3
h
4
h
Acknowledgment
R = CH CH COOMe
2
2
RRK and SDH thank CNRS for a post-doctoral fellowship. We
acknowledge University of Paris–Sud and CNRS for financial assis-
tance.
R
R
References and Notes
HO
H
H
(
(
1) Baulieu, E. E. Biol. Cell. 1991, 71, 3.
3i
4i
2) (a) Kandutsch, A. A.; Chen, H. W.; Heiniger, H. J. Science
1978, 201, 498. (b) Smith, J. G. Synthesis 1984, 629.
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Tkachev, Y. V.; Timofeev, V. P. Bioorg. Med. Chem. 2008,
2
3
R = CH CH COOMe
D /D = 3:7
2
2
a
Reaction conditions: steroid (1 mmol), Tf O (1 equiv), DMAP (3
2
equiv), CH Cl (5 mL), 0 °C, 2 h. Isolated yield after flash chromatog-
2
2
1
6, 1460.
(3) (a) Wharton, P. S.; Dunny, S.; Krebs, L. S. J. Org. Chem.
964, 29, 958. (b) Fieser, L. F.; Dominguez, X. A. J. Am.
raphy on silica gel.
b
Structure established by comparison of proton NMR spectra with
1
reported compounds.
Chem. Soc. 1953, 75, 1704. (c) Roy, J.; DeRoy, P.; Poirier,
D. J. Comb. Chem. 2007, 9, 347.
Table 3 Effect of Base on Elimination Reaction with Cholestanol
(
(
(
4) Santos, G. A. G.; Murray, A. P.; Pujol, C. A.; Damonte, E.
B.; Maier, M. S. Steroids 2003, 68, 125.
5) Henningsen, M. C.; Jeropoulos, S.; Smith, E. H. J.Org.
Chem. 1989, 54, 3015.
(
1)
Base
Yield of olefin 2 (%)a,b
6) Freaure-Tromeur, M.; Zard, S. Z. Tetrahedron Lett. 1999,
DMAP
pyridine
DIPEA
90
85
89
72
40, 1305.
(
(
7) D’Onofrio, F.; Scettri, A. Synthesis 1985, 1159.
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2005, 61, 3065.
Et N
3
(10) Shimizu et al. have studied the leaving group ability of some
steroidal sulfonates in substitution reactions. During the
triflation reaction of several secondary alcohols they noticed
formation of an alkene instead of the expected triflate. See:
Shimizu, T.; Ohzeki, T.; Hiramoto, K.; Nakatha, T.
Synthesis 1999, 1373.
a
Isolated yield after chromatography on silica gel.
Reaction conditions: cholestanol (1, 1 mmol), Tf O (1 equiv),
b
2
DMAP (3 equiv), CH Cl (5 mL), 0 °C, 2 h.
2
2
lestene. Details on the scope and the mechanism of the
reaction are under investigation.
(
11) Edwards, J. A.; Holton, P. G.; Orr, J. C.; Ibanez, L. C.;
Necoechea, E.; de la Roz, A.; Segovia, E.; Urquiza, R.;
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1
8
(
12) Neti, S.; Vijayavitthal, T. M.; Vurimindi, H.; Jaydeepkumar,
L. Asian. J. Chem. 2009, 21, 4399.
General Procedure
Triflic anhydride (1.5 mmol) was slowly added to a solution of al-
cohol (1 mmol) and DMAP (3 mmol) in CH Cl (5 mL) at 0 °C. Af-
ter completion of addition the reaction was stirred for 2 h. The
reaction was quenched in ice-cold H O and extracted with CH Cl
(13) Xiong, Q.; Wilson, W. K.; Pang, J. Lipids 2007, 42, 87.
(14) Romeo, A.; Villotti, R. Ann. Chim. (Rome) 1957, 47, 684.
(15) Miura, T.; Takagi, H.; Harita, K.; Kimura, M. Chem. Pharm.
Bull. 1979, 27, 452.
2
2
2
2
2
(
3 × 20 mL). The organic layers were separated and dried over an-
Synlett 2011, No. 12, 1709–1712 © Thieme Stuttgart · New York

1
712
R. R. Kumar et al.
LETTER
(
(
(
16) Iida, T.; Momose, T.; Chang, F. C.; Goto, J.; Nambara, T.
Chem. Pharm. Bull. 1989, 37, 3323.
17) Hodosan, F.; Jude, I.; Serban, N. Bull. Soc. Chim. Fr. 1964,
were transformed into the corresponding triflates devoid of
elimination products. Triflates were also produced from
some secondary alcohols in carbohydrate family (as
bisacetonide of galactopyranose). Terpenoid secondary
alcohols provided elimination products.
10, 2691.
18) The Tf O/DMAP protocol was applied to primary alcohols
2
(aliphatic alcohols, bisacetonide of glucopyranose), which
Synlett 2011, No. 12, 1709–1712 © Thieme Stuttgart · New York

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