Oxidation of unsaturated steroid ketones with hydrogen peroxide catalyzed by Fe(bpmen)(OTf)2. New methodology to access biologically active steroids by chemo-, and stereoselective processes

Article abstract of DOI:10.1016/j.tet.2012.08.079

In this paper we describe a new environmentally friendly method to promote the oxidation of steroids. The chemo- and stereoselective aspects of the oxidation of conjugated enones, dienones, further unsaturated enones, estrone, and cholestane acetates were under study. The great facial stereoselectivity of the method has been shown on substrates 12, 14, and 18 improving some of the updated reported procedures in the literature. Reaction with substrate 16 displays the competition between the C4-C5 and the C9-C11 double bonds. The steric hindrance around C ring activates the C-H hydroxylation at the allylic position on C-12 by formation of the allylic alcohol 17c. The C-H activation at C-5 was proven to succeed on the oxidation reaction of androstane 26 by formation of the tertiary alcohol 27.

Full text of DOI:10.1016/j.tet.2012.08.079

Tetrahedron 68 (2012) 9249e9255
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Oxidation of unsaturated steroid ketones with hydrogen peroxide catalyzed
by Fe(bpmen)(OTf)2. New methodology to access biologically active
steroids by chemo-, and stereoselective processes
*
ꢀ
David Clemente-Tejeda, Alejandro Lopez-Moreno, Francisco A. Bermejo
ꢀ
Departamento de Química Organica, Universidad de Salamanca, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2012
Received in revised form 22 August 2012
Accepted 27 August 2012
Available online 1 September 2012
In this paper we describe a new environmentally friendly method to promote the oxidation of steroids.
The chemo- and stereoselective aspects of the oxidation of conjugated enones, dienones, further un-
saturated enones, estrone, and cholestane acetates were under study.
The great facial stereoselectivity of the method has been shown on substrates 12, 14, and 18 improving
some of the updated reported procedures in the literature. Reaction with substrate 16 displays the
competition between the C4eC5 and the C9eC11 double bonds. The steric hindrance around C ring
activates the CeH hydroxylation at the allylic position on C-12 by formation of the allylic alcohol 17c.
The CeH activation at C-5 was proven to succeed on the oxidation reaction of androstane 26 by for-
mation of the tertiary alcohol 27.
Keywords:
Steroids
Iron(II)complexes
Oxidation
Exemestane
Nestorone
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
tosyliminophenyliodinane,6 2,6-dichloropyridine N-oxide,7 and
cumene hydroperoxide,8 in oxidative processes catalyzed by metal
Nature’s capacity to catalyze the oxidation of unactivated CeH
bonds, the epoxidation and dihydroxylation of carbonecarbon
double bonds in steroids employing enzymatic systems has been
known for a long time.1 However, attempts to mimic natural
methods by replacing a hydrogen atom bonded to an unactivated
carbon of a steroid with a hydroxyl group while maintaining the
integrity of the carbon atom, and by regio- and stereoselective
epoxidation and dihydroxylation of unsaturated steroids, constitute
a huge challenge. In nature, most of the significant enzymatic
transformations involve oxidation by metalloporphyrins through
catalytic processes.2 In the aim to propose an artificial cytochrome
P450 enzyme, the use of attached templates to promote remote
functionalization of steroids was introduced by Breslow in 1980,3
the direct transformation of steroids with high predictability and
specificity has yet to be accomplished and constitutes an area of
increasing interest.
porphyrins, where manganese Mn(III), ruthenium Ru(II), and iron
Fe (III), play relevant activating roles.
Furthermore, Salvador and col. have reviewed the contributions
on catalytic epoxidation, syn-dihydroxylation, allylic oxidation, al-
cohol oxidation, and remote functionalization reactions in steroid
chemistry.9 However, even when focus has been given to catalytic
processes, most of the transformations promoted by metal com-
plexes are porphyrin-type derivatives of Ru (II),10 Ru (IV),11 Ru(VI),12
Mn(III),13,16 Fe(III).14 Special attention has been paid to catalytic
remote functionalization promoted by Fe(III),8 Mn(III),5,6,13,15 and
Ru(II),10a porphyrin derivatives.
Cavaleiro and col. reported in 2004 on the oxidation reactions of
D
4- and 5-steroids with hydrogen peroxide catalyzed by porphy-
D
rin complexes of Mn(II) and Fe(III).16 These metalloporphyrins ef-
ficiently catalyze the epoxidation reactions of 17 -acetoxy-4-
androstene 1,4-cholestene 2, and 3 -acetoxy-5-cholestene 3 in
b
b
Recently, Pellissier and Santelli have summarized the most
outstanding contributions to the chemical and biochemical hy-
droxylation of steroids.4 Among others, they pointed directly to
hydroxylations achieved by oxidants like iodosobenzene,5 N-
the presence of H2O2 as oxygen donor (Scheme 1). Porphyrins with
bulky, electron-withdrawing groups in the ortho positions of the
meso phenyls and with MnIII as the central metal ion, such as
[Mn(tdcpp)Cl], gave preferentially the
steroids (4b, 5b, and 6b). However, [Fe(tpfpp)Cl] catalyzes prefer-
entially the -epoxidation of
4-steroids (4a and 5a), and increases
the -stereoselectivity in the epoxidation of
5-steroids (6a). Based
b-epoxide of D -
4- and D5
a
D
* Corresponding author. E-mail address: fcobmjo@usal.es (F.A. Bermejo).
a
D
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.079

9250
D. Clemente-Tejeda et al. / Tetrahedron 68 (2012) 9249e9255
Scheme 1.
on the experimental data, the authors make a mechanistic proposal
involving an oxo species for the -approach and a peroxy species
for the
-approach.17
In 2011 Reetz and col. reported their results on the regio- and
stereoselectivity of the P450-catalyzed hydroxylation of steroids
based on directed evolution of Cytochrome P450 enzymes. Using
P450 BM3(F87A) as the starting enzyme and testosterone (7) as the
The acetates 20, 22, and 24 were obtained from the pre-
cursor alcohols by treatment with acetic anhydride under
perchloric acid catalysis in the case of 20, or under pyridine
catalysis in the case of 24. The isolation of acetate 22 was
possible by treatment of estrone with isopropenyl acetate in the
presence of iodine at 90 ꢀC.28 The oxidation reactions were
carried out at room temperature with progressive addition of
H2O2, in the open air (see Experimental part). The reactions
were followed by TLC and were stopped after 10 min (method
A), and after 30 min (method B). The product mixtures resulting
from substrates oxidation reactions were fractionated by col-
umn chromatography and identified by comparing their 1H
NMR and 13C NMR spectra with literature data. Table 1 sum-
marizes our results.
The catalytic oxidation of 4-androsten-3,17-dione (10) with
hydrogen peroxide in the presence of Fe(bpmen)(OTf)2 afforded the
same mixture of epoxides 11a/11b¼65:35 independently of the
catalyst charge (method A: 5%; method B: 15%) (Table 1, entries 1
and 2). However, only in the second case (method B) the reaction
went to completion after 30 min. The oxidative process under
method A occurred with only 70% conversion. This oxidative
transformation allowed us to isolate the two epoxides by flash
chromatography and unambiguously assign the structure of both
products. According to the literature, the 13C NMR chemical shift
corresponding to the C-19 in 4,5-epoxiandrostanes appear upfield
b
a
substrate, they obtained a 1:1 mixture of the 2b- and 15b-alcohols
(8 and 9, respectively). However, they obtained mutants of the
enzyme that were 96e97% selective for either of the two
regioisomers.18
During the last two decades great efforts have been devoted to
the preparation of bio-inspired non-heme iron complexes capable
of not only oxidizing hydrocarbons to alcohols, but also epoxida-
tion and cis-dihydroxylation of olefins by using H2O2. Among them,
the Fe(II) complexes, Fe(bpmen)(OTf)2 (III), Fe(6-Me2-bpme-
n)(OTf)2 (IV) [bpmen: N,N0-dimethyl-N,N0-bis(2pyridylmethyl)-1,2-
diaminoethane], [Fe(tpa) (CH3CN)2](OTf)2 (V), and [Fe(6-Me3-
tpa)(CH3CN)2](OTf)2 (VI), [tpa¼tris(2-pyridylmethyl)amine], were
reported to allow stereospecific alkane hydroxylation,19 epoxida-
tion,20 and dihydroxylation of C]C double bonds.21
2. Results and discussion
The chemical modification of the steroid backbone can lead to
significant biological effects.22 Compounds like exemestane (6-
methyleneandrosta-1,4-diene-3,17-dione),23 and formestane (4-
hydroxyandrostene-3,17-dione),24 have been found to be effective
as aromatase inhibitors by blocking the estrogen biosynthesis and
thereby used as anti-breast cancer medication for postmenopausal
women.25 Furthermore, the capacity of progesterone and nestor-
in
a
epoxides
(
d
¼17.4 ppm) compared to
b-epoxides
(d
¼19.2 ppm);16 However, the 1H NMR chemical shift of the H-4
proton appears downfield (
d¼2.93 ppm) in
a-epoxides compared to
b
-epoxides (
found for 11a (
and
¼2.94) are shown in Table 1 as indicated.
d¼2.90 ppm); therefore, the structural assignments
d
¼16.6 ppm and ¼3.00 ppm) and 11b ( ¼19.1 ppm
d
d
d
one (16-methylene-17
a-acetoxy-19-norpregn-4-ene-3,20-dione)
We were interested to study the regioselectivity of the ep-
oxidation reaction in androstanes with two double bonds
[cross-conjugated (14, 18), linear-conjugated (12), and not-
conjugated (16, 20)] with the carbonyl group. With the
double-conjugated dienones 1,4-androstadien-3,17-dione 14,
for myelin repair, a major therapeutic challenge in demyelinating
diseases, such as multiple sclerosis, has been recently discovered.26
Stereoselective strategies for the modification of the steroid back-
bone aimed to improve the activity of these compounds are chal-
lenging goals.27
To the best of our knowledge no report has been given on the
catalytic oxidation of steroids by using non-heme iron complexes of
type III in the presence of H2O2 as oxygen donor. In this paper we
describe a new environmentally friendly method to promote the
oxidation of steroids. The chemo- and stereoselective aspects of the
oxidation of conjugated enones, dienones, further unsaturated
enones, estrone derivatives, and cholestane acetate were under
study.
and
dien-21-propionate 18, the oxidation reactions proceeded ster-
eoselective to the 4,5- -epoxides 15 and 19, with 100% and 70%
17a-acetoxy-21-hydroxy-16a-methyl-3,11,20-trioxo-1,4-
a
yields, respectively (Table 1, entries 5 and 9). In the first case
with 60% conversion independently of the catalyst charge
(methods A & B), and in the second case, with 50% conversion
for a 15% catalyst charge.
The structural assignments of epoxides 15 and 19 have been
made based on the proton and carbon displacements found for H-4

D. Clemente-Tejeda et al. / Tetrahedron 68 (2012) 9249e9255
9251
Table 1
Oxidation of unsaturated steroids with hydrogen peroxide in the presence of Fe(bpmen)(OTf)2
Entry Substrate Conversion (%)
Protocola
Oxidation products (% yield)b
1
A
70
2
3
B
100
100
A
4
B
100
5
6
7
A
B
A
60
60
40
8
B
100
9
B
50
(continued on next page)

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D. Clemente-Tejeda et al. / Tetrahedron 68 (2012) 9249e9255
Table 1 (continued)
Entry
Substrate
Protocola
Conversion (%)
Products (%yield)b
10
A
15
11
B
30
12
B
16
13
A
90
14
B
100
15
B
30
a
Protocol A: 5% mol of catalyst, 1 equiv of H2O2, 0.5 equiv of AcOH, reaction time:10 min. Protocol B: 15% mol of catalyst, 3 equiv of H2O2, 1.5 equiv of AcOH, reaction time:
30 min.
b
Yields were calculated based on recovered starting material.
and C-19 in the 1H NMR and 13C NMR spectra for both products
according to the literature data.16
The oxidation of 6-methylen-4-androsten-3,17-dione 12 with
H2O2 in the presence of Fe(bpmen)(OTf)2, provided the external
epoxide 13a with quantitative yields by applying method A (Table 1,
entry 3); however, increasing the catalyst charge (method B) pro-
vided the mixture of the monoepoxide 13a (50%) and the diepoxide
13b (30%) (Table 1, entry 4). Again, the proton and carbon

D. Clemente-Tejeda et al. / Tetrahedron 68 (2012) 9249e9255
9253
displacements found for H-4 and C-19 in the 1H NMR and 13C NMR
spectra for both products resulted to be crucial for structural as-
signments based on literature precedents of similar trans-
formations.23 The first result (method A) may be highlighted as
a regio- and stereoselective transformation since it is known that
the m-CPBA (m-chloroperbenzoic acid) oxidation of exemestane
by Fe(bpmen)(OTf)2. The mild open-air conditions, short reaction
times and, in some cases the high yields obtained, are promising
enough to apply this method to other types of compounds.
The Fe(bpmen)(OTf)2 complex has been shown like an efficient
catalyst in the presence of H2O2 for epoxidation reactions. The great
facial stereoselectivity has been shown on substrates like 12, 14,
and 18 improving some of the updated reported procedures in the
literature. Furthermore, it is worth to mention the chemoselectivity
developed by the catalyst against certain dienic systems like 14 and
18, where only the more electronic-rich double bond reacts with
the oxidant.
Other issue, which is been discussed in the paper is the possi-
bility of activating CeH bonds by the same complex Fe(bpme-
n)(OTf)2. The reaction with substrate 16 displays the competition
between the C4eC5 and the C9eC11 double bonds. In this case, the
great steric hindrance for the complex to approach C-ring of the
steroid is driving the activation to the allylic position C-12; there-
fore, making the CeH activation to compete with the epoxidation
reaction.
led to an epimeric mixture of 6
a- and 6b-spirooxiranandrosta-1,4-
diene-3,17-diones.23b
The 4,9(11)-androstadien-3,17-dione 16 afforded complex mix-
tures following both procedures A and B (Table 1, entries 7 and 8).
With 5% of catalyst charge the reaction proceeded with a modest
conversion (40%) and afforded an equimolecular mixture of the
monoepoxides 17a (25%), 17b (25%) and the product of the allylic
hydroxylation 17c (25%). The assignment of the resonances in the
1H and 13C NMR spectra of compounds 17a, 17b, and 17c was ach-
ieved by using dimensional techniques, namely COSY (1H/1H),
HMQC (1H/13C) and HMBC (1H/13C-long range) experiments, as well
as by DEPT techniques (see Supplementary data). With 15% of
catalyst charge, the oxidative transformation went to completion
and afforded a complex reaction mixture in which, the diepoxide
17d was the major product (50%); in addition, the epoxy ketone 17e
(25%) and a mixture of the monoepoxides 17a and 17b (10%) were
also isolated. We assume by mechanistic reasons that the formation
of 17e should be preceeded by the formation of 17c through a three-
step sequence: allylic CeH activation of 16, alcohol oxidation to the
enone, and epoxidation of the enone.
Having into account the competition between epoxidation and
CeH activation, clearly driven to the epoxidation with this complex,
we tried this methodology on substrate 26, an androstane diketone
lacking of all types of CeC unsaturation. This reaction showed the
great synthetic CeH activation potential of complex Fe(bpme-
n)(OTf)2 by giving rise to the exclusive formation of the 5a-hydroxy
derivative 27.
By applying method A (Table 1, entry 10), the oxidation of nes-
torone 20 led to the monoepoxide 21a with quantitative yields but
low conversions (15%). However, by increasing the catalyst charge
(method B, entry 11) the oxidation led to a mixture of diepoxides
21b (36%), 21c (28%), and 21d (36%) with double degree of con-
version (30%). Again, the structural assignments were based on
spectral data of related oxidation products.16
4. Experimental section
4.1. General experimental methods
1H NMR spectra were measured at either 200 or 400 MHz and
13C NMR were measured at 50 or 100 MHz in CDCl3 and referenced
to TMS (1H) or solvent (13C), except where indicated otherwise.
HRMS determinations were recorded at the Mass Spectrometry
Service of the University of Salamanca, Spain, in an Applied Bio-
systems QSTAR XL with ESI ionization. HPLCeMS analysis of 11a
The oxidation of 3b-acetoxy-5-cholestene afforded the a-epox-
ide 25a with 95% yield and 90% conversion by applying method A
(Table 1 entry 13). Increasing the catalyst charge to 15% (method B,
entry 14) the oxidation reaction afforded the mixture of epoxides
25a (59%) and 25b (13%) together with an irresolvable mixture of
epoxides, which also showed oxidation at the lateral chain (28%).
The structural assignments were possible by comparison with the
spectral data given for 25a and 25b in the literature.16
The oxidation of estrone acetate 22 by method B (Table 1, entry
12) afforded the mixture of 1,2-dihydroxy acetate 23a (63%) and
1,4-dihydroxy acetate 23b (37%) with low conversions (16%).
The iron-promoted CeH activation on saturated androstane
derivatives would open new approaches to interesting starting
materials. Aimed to this target we decided to try the CeH activation
on saturated androstanes. The oxidation reaction of 3,17-
androstanedione 26 (trans/cis¼80:20), by method A led to the 5-
hydroxy derivative 27 with 67% yield and 30% of conversion. This
derivative corresponds to the CeH activation product at the C-5
center in the androstane backbone. The assignment of the config-
and 11b was performed using a Waters XBridge C18, 3.5 mm,
2.1ꢁ100 mm column. Chemicals and solvents were obtained from
commercial sources and used as received with the exception of
tetrahydrofuran, which was distilled from sodium and benzophe-
none. Yields reported are for chromatographic pure isolated prod-
ucts unless mentioned otherwise. Preparation of the catalyst
Fe(bpmen)(OTf)2 (III) was achieved according to the literature.19g
4.2. Method A (5 mol % of catalyst)
A 10 mL round bottom flask was charged with: 0.75 mL of
a 0.33 M AcOH solution in CH3CN, Fe(bpmen)(OTf)2 (15.6 mg,
0.025 mmol, 5 mol %), and substrate (0.5 mmol, 1.0 equiv). The so-
lution was stirred vigorously at room temperature. A solution of
H2O2 (30 wt %, 68 mL, 0.6 mmol, 1.2 equiv) in CH3CN (4 mL, 0.13 M)
uration
data obtained for 27 [13C NMR
(C-5)] and the ones described in the literature for 5
drostane-3,17-dione29 13C NMR
: 13.8 (C-18), 16.2 (C-19), and 78.4
(C-5)] and for 5 : 13.8
-hydroxyandrostane-3,17-dione30 13C NMR
(C-18), 15.7 (C-19), and 77.4 (C-5)]. Treatment of 27 with chlor-
osulfonic acid in dichloromethane at 0 ꢀC led to 10 in quantitative
yields.
a
at C-5 of 27 was possible by comparison of the spectral
: 13.10 (C-18), 15.4 (C-19), and 77.7
-hydroxyan-
was added dropwise via syringe. After addition was completed, the
reaction mixture was stirred for additional 10 min. Then NaHCO3
saturated aqueous solution was added and the mixture was
extracted with ethyl acetate. The combined organic layers were
dried over anhydrous Na2SO4, evaporated under reduced pressure,
and purified by flash chromatography.
d
b
[
d
a
[
d
4.3. Method B (15 mol % of catalyst)
3. Conclusions
A 50 mL round bottom flask was charged with: 0.75 mL of
a 0.33 M AcOH solution in CH3CN, Fe(bpmen)(OTf)2 (15.6 mg,
0.025 mmol, 5 mol %), and substrate (0.5 mmol, 1.0 equiv). The so-
lution was stirred vigorously at room temperature. A solution of
In this paper a new environmentally friendly methodology for
oxidation of biologically active steroids is under study. The oxida-
tion of different steroid enones with hydrogen peroxide is catalyzed
H2O2 (30 wt %, 68 mL, 0.6 mmol, 1.2 equiv) in CH3CN (4 mL, 0.13 M)

9254
D. Clemente-Tejeda et al. / Tetrahedron 68 (2012) 9249e9255
was added dropwise via syringe. After stirring for 10 min, 0.5 mL of
a 0.5 M AcOH solution in CH3CN and Fe(bpmen)(OTf)2 (15.6 mg,
0.025 mmol, 5 mol %) were added. This was followed by the
4.9. 4,5a a,11-Diepoxy-androstan-3,17-dione 17d
-9
1H NMR (CDCl3):
d
¼0.90 (s, 3H), 1.31 (s, 3H), 1.85 (d, J¼3.0 Hz,
dropwise addition of H2O2 (30 wt %, 68
mL, 0.6 mmol, 1.2 equiv) in
2H), 3.02 (s, 1H), 3.15 (dd, J1¼3.0 Hz, J2¼3.0 Hz, 1H) ppm. 13C NMR
CH3CN (4 mL, 0.13 M). A third addition was performed for a total of
15 mol % Fe(bpmen)(OTf)2, 1.5 equiv of AcOH, and 3.6 equiv of H2O2.
After the last 10 min of stirring NaHCO3 saturated aqueous solution
was added and the mixture was extracted with ethyl acetate. The
combined organic layers were dried over anhydrous Na2SO4,
evaporated under reduced pressure, and purified by flash
chromatography.
(CDCl3):
d¼16.6 (q), 19.9 (q), 22.1 (t), 22.2 (t), 25.1 (t), 30.2 (t), 31.7
(t), 32.5 (t), 35.1 (d), 36.5 (t), 38.4 (s), 41.3 (d), 45.5 (s), 52.7 (d), 61.2
(d), 66.8 (s), 68.6 (s), 206.3 (s), 220.6 (s) ppm. ESIeHRMS (MþþNa):
calculated for C19H24O4Na: 339.1566, experimental: 339.1561.
4.10. 9a,11-Epoxy-androst-4-ene-3,12,17-trione 17e
1H NMR (CDCl3):
d
¼1.13 (s, 3H), 1.33 (s, 3H), 3.15 (s, 1H), 5.86 (d,
J¼2.2 Hz, 1H) ppm. 13C NMR (CDCl3):
¼14.5 (q), 21.2 (t), 24.3 (q),
d
4.4. 4,5
a-Epoxy-androstan-3,17-dione and 4,5b-epoxy-
27.0 (t), 27.9 (t), 28.9 (t), 32.9 (t), 37.0 (t), 37.3 (d), 40.5 (s), 47.9 (d),
53.7 (s), 62.6 (d), 68.9 (s), 123.6 (d), 167.2 (s), 196.3 (s), 204.9 (s),
211.3 (s) ppm. ESIeHRMS (MþþNa): calculated for C19H22O4Na:
337.1410, experimental: 337.1402.
androstan-3,17-dione 11a and 11b
Compound 11a: Retention time: 12.56 min. 1H NMR (CDCl3):
d
¼3.00 (s, 1H) ppm. 13C NMR (CDCl3):
¼13.9 (q), 16.6 (q), 20.8 (t),
d
21.9 (t), 27.9 (t), 29.2 (t), 29.6 (t), 33.2 (t), 31.5 (t), 35.1 (d), 35.9 (t),
37.0 (s), 51.0 (d), 47.9 (s), 51.0 (d), 63.0 (d), 70.1 (s), 206.8 (s), 220.7
(s) ppm. ESIMS: m/z 303.2 [Mþ]. Compound 11b: Retention time:
4.11. 17
a-Acetoxy-4,5a-epoxy-21-hydroxy-16a-methyl-3,11,20-
trioxo-1-pregnene propionate 19
12.88 min. 1H NMR (17CDCl3):
(CDCl3):
d
¼2.94 (s, 1H) ppm. 13C NMR
1H NMR (CDCl3):
d
¼0.76 (s, 3H), 0.96 (d, J¼4.8 Hz, 3H), 1.14 (t,
d
¼13.9 (q), 19.1 (q), 21.0 (t), 21.9 (t), 26.3 (t), 29.3 (t), 29.7
J1¼7.6 Hz, J2¼6 Hz, 3H), 1.45 (s, 3H), 2.11 (s, 3H), 3.17 (d, J¼2 Hz, 1H),
(t), 31.2 (t), 32.6 (t), 34.8 (d), 35.9 (t), 37.5 (s), 46.8 (d), 47.8 (s), 50.8
(d), 62.7 (d), 70.0 (s), 206.5 (s), 220.0 (s) ppm. ESIMS: m/z
303.2 [Mþ].
4.72 (ddd, J1¼16 Hz, J2¼11.6 Hz, J3¼2 Hz, 2H), 5.79 (dd, J1¼10.6 Hz,
J2¼2 Hz, 1H), 7.08 (d, J¼10.6 Hz, 1H) ppm. 13C NMR (CDCl3):
¼9.2
d
(q), 15.5 (q), 16.2 (q), 17.3 (q), 20.6 (q), 27.3 (t), 29.7 (t), 30.5 (t), 33.3
(t), 35.8 (d), 36.2 (d), 41.4 (s), 48.1 (d), 49.6 (t), 51.7 (s), 62.3 (d), 64.3
(d), 66.2 (s), 67.0 (t), 94.0 (s), 123.1 (d), 155.0 (d), 170.7 (s), 174.0 (s),
195.9 (s), 197.8 (s), 207.3 (s) ppm. ESIeHRMS (MþþNa): calculated
for C27H34O8Na: 509.2145, experimental: 509.2150.
4.5. 6a-Spiroxirandrost-4-ene-3,17-dione 13a
1H NMR (CDCl3):
d
¼0.90 (s, 3H), 1.20 (s, 3H), 2.52 (d, J¼6 Hz, 1H),
2.87 (d, J¼6 Hz, 1H), 5.97 (s, 1H) ppm. 13C NMR (CDCl3):
¼13.9 (q),
d
17.9 (q), 20.3 (t), 21.9 (t), 31.3 (t), 34.0 (t), 34.2 (d), 35.8 (t), 36.0 (t),
37.8 (t), 39.8 (s), 47.7 (s), 51.0 (d), 52.8 (d), 56.9 (s), 58.7 (s), 119.9 (d),
167.2 (s), 199.0 (s), 219.9 (s) ppm. ESIeHRMS (MꢂHþ): calculated
for C20H27O3: 315.1954, experimental: 315.1956.
4.12. 17
a-Hydroxy-4,5a-epoxy-16-methylene-3,20-dioxo-
pregnane acetate 21a
1H NMR (CDCl3):
1H), 5.43 (s, 1H), 5.57 (s, 1H) ppm. 13C NMR (CDCl3):
d
¼0.72 (s, 3H), 2.13 (s, 3H), 2.14 (s, 3H), 3.06 (s,
d
¼14.6 (q), 17.0
(t), 21.5 (q), 26.0 (t), 27.8 (q), 30.3 (t), 30.6 (t), 31.9 (t), 32.8 (t), 33.4
(t), 40.2 (d), 40.7 (d), 43.5 (d), 47.3 (d), 47.9 (s), 62.0 (d), 67.7 (s), 94.2
(t), 144.7 (s), 170.4 (s), 202.8 (s), 207.0 (s) ppm. ESIMS: m/z 387.3
[MþH], 409.3 [MþNa].
4.6. 4,5
a
-Epoxy-6a-spiroxirandrostan-3,17-dione 13b
1H NMR (CDCl3):
d
¼0.91 (s, 3H), 1.09 (s, 3H), 2.65 (d, J¼4.8 Hz,
1H), 2.82 (d, J¼4.8 Hz, 1H), 3.26 (s, 1H) ppm. 13C NMR (CDCl3):
d
¼13.9 (q), 16.0 (q), 20.7 (t), 21.9 (t), 29.1 (t), 31.3 (t), 33.0 (t), 34.7
4.13. 17
a-Hydroxy-4,5a-epoxy-3,20-dioxo-16b-spiroxiran-
(d), 35.5 (t), 35.8 (t), 38.7 (s), 47.8 (s), 50.3 (d), 50.8 (d), 54.1 (s),
54.6 (t), 57.2 (d), 71.5 (s), 205.8 (s), 219.9 (s) ppm. ESIeHRMS
(MþþNa): calculated for C20H26O4Na: 353.1723, experimental:
353.1721.
pregnane acetate 21b
1H NMR (CDCl3):
d
¼1.06 (s, 3H), 2.07 (s, 3H), 2.28 (s, 3H), 3.06 (s,
1H), 3.06 (dd, J1¼5.6 Hz, J2¼107 Hz, 2H) ppm. 13C NMR (CDCl3):
d
¼14.5 (q), 16.9 (d), 21.2 (q), 25.6 (d), 29.9 (d), 30.0 (d), 30.3 (d), 31.6
4.7. 4,5-Epoxy-androst-1-ene-3,17-dione 15
(q), 31.9 (d), 33.4 (d), 34.4 (d), 40.1 (t), 40.8 (t), 43.7 (t), 45.7 (t), 49.6
(s), 50.8 (d), 62.0 (t), 64.7 (s), 67.6 (s), 91.8 (s), 170.5 (s), 202.7 (s),
207.0 (s) ppm. ESIMS: m/z 403.3 [MþH], 425.3 [MþNa].
1H NMR (CDCl3):
1H), 5.87 (dd, J1¼1.8 Hz, J2¼10.6 Hz, 1H), 6.47 (d, J¼10.6 Hz, 1H)
ppm. 13C NMR (CDCl3):
d
¼0.90 (s, 3H), 1.32 (s, 3H), 3.21 (d, J¼1.8 Hz,
d
¼13.9 (q), 16.4 (q), 21.7 (t), 21.9 (t), 28.9 (t),
4.14. 17
a-Hydroxy-4,5a-epoxy-3,20-dioxo-16a-spiroxiran-
30.0 (t), 31.2 (t), 34.9 (d), 35.7 (t), 42.5 (s), 47.6 (s), 50.5 (d), 54.2 (d),
62.5 (d), 67.1 (s), 123.6 (d), 155.1 (d), 195.8 (s), 220.0 (s) ppm.
ESIeHRMS (MþþNa): calculated for C19H24O3Na: 323.1617, experi-
mental: 323.1608.
pregnane acetate 21c
1H NMR (CDCl3):
d
¼1.06 (s, 3H), 1.42 (s, 3H), 1.72 (s, 3H), 3.03 (s,
1H), 4.05 (dd, J1¼10.2 Hz, J2¼42 Hz, 2H) ppm. 13C NMR (CDCl3):
d
¼14.8 (q), 17.1 (t), 23.0 (q), 26.0 (t), 29.9 (t), 30.3 (t), 32.3 (q), 33.1
4.8. 12
a-Hydroxy-androst-4,9(11)-diene-3,17-dione 17c
(t), 33.5 (t), 33.5 (t), 36.1 (d), 40.5 (d), 40.8 (s), 42.8 (d), 43.2 (d), 48.4
(t), 61.3 (s), 62.1 (d), 65.8 (s), 94.0 (s), 170.0 (s), 202.8 (s), 207.1 (s)
ppm. ESIMS: m/z 403.3 [MþH], 425.3 [MþNa].
1H NMR (CDCl3):
d
¼0.83 (s, 3H), 1.25 (s, 3H), 4.19 (d, J¼5.6 Hz,
1H), 5.69 (dd, J1¼1.8 Hz, J2¼5.6 Hz, 1H), 5.77 (d, J¼1.8 Hz, 1H) ppm.
13C NMR (CDCl3):
d
¼12.7 (q), 21.9 (t), 26.5 (q), 30.2 (t), 32.3 (t), 33.5
4.15. 17
b-Hydroxy-4,5b-epoxy-3,20-dioxo-16b-spiroxiran-
(t), 34.0 (t), 36.8 (t), 37.1 (d), 41.1 (d), 51.6 (s), 68.9 (d), 119.0 (d),
124.6 (d), 151.0 (s), 167.8 (s), 179.7 (s), 198.6 (s), 220.3 (s) ppm.
ESIeHRMS (MþþNa): calculated for C19H24O3Na: 323.1601, exper-
imental: 323.1609.
pregnane acetate 21d
1H NMR (CDCl3):
d
¼0.80 (s, 3H), 1.97 (s, 3H), 2.16 (s, 3H), 3.02 (s,
1H), 3.04 (dd, J1¼5 Hz, J2¼52 Hz, 2H) ppm. 13C NMR (CDCl3):
¼15.1
d

D. Clemente-Tejeda et al. / Tetrahedron 68 (2012) 9249e9255
9255
3. Breslow, R. Acc. Chem. Res. 1980, 13, 170e177.
4. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2001, 33, 1e58.
(q), 20.6 (t), 20.8 (t), 26.0 (t), 27.4 (q), 28.6 (t), 29.9 (t), 33.1 (t), 35.7
(t), 36.5 (t), 39.9 (d), 40.6 (d), 45.6 (d), 47.4 (s), 48.3 (d), 54.1 (t), 61.8
(d), 64.6 (s), 65.1 (s), 93.5 (s), 171.4 (s), 202.5 (s), 205.8 (s) ppm.
ESIMS: m/z 403.3 [MþH], 425.3 [MþNa].
5. (a) Breslow, R.; Zhang, X.; Huang, Y. J. Am. Chem. Soc. 1997, 119, 4535e4536; (b)
Breslow, R.; Gabriele, B.; Yang, J. Tetrahedron Lett. 1998, 39, 2887e2890.
6. Yang, J.; Weinberg, R.; Breslow, R. Chem. Commun. 2000, 531e532.
7. Shingaki, T.; Miura, K.; Higuchi, T.; Hirobe, M.; Nagano, T. Chem. Commun. 1997,
861e862.
8. Vijayarahavan, B.; Chauan, S. M. S. Tetrahedron Lett. 1990, 31, 6223e6226.
9. (a) Salvador, J. A. R.; Silvestre, S. M.; Moreira, V. M. Curr. Org. Chem. 2006, 10,
2227e2257; (b) Salvador, J. A. R.; Silvestre, S. M.; Moreira, V. M. Curr. Org. Chem.
2008, 12, 492e522.
10. (a) Iida, T.; Ogawa, S.; Miyata, S.; Goto, T.; Mano, N.; Goto, J.; Nambara, T. Lipids
2004, 39, 873e880; (b) Kesavan, V.; Chandrasekaran, S. J. Chem. Soc., Perkin
Trans. 1 1997, 3115e3116; (c) Kesavan, V.; Chandrasekaran, S. J. Org. Chem. 1998,
63, 6999e7001; (d) Zhang, J.-L.; Zhou, H.-B.; Huang, J.-S.; Che, C.-M. Chem.dEur.
J. 2002, 8, 1554e1562; (e) Che, C.-M.; Huang, S.; Zhang, J.-L. C. R. Chim. 2003, 6,
1105e1115.
4.16. 1,2,3-Trihydroxy-estra-17-oxo-1,3,5(10)-triene-3-acetate 23a
1H NMR (CDCl3):
d
¼0.92 (s, 3H), 2.33 (s, 3H), 6.43 (s, 1H) ppm.
ESIeHRMS [MþNa]: calculated for C20H24NaO5: 367.1521, experi-
mental: 367.1509.
4.17. 1,3,4-Trihydroxy-estra-17-oxo-1,3,5(10)-triene-3-acetate 23b
1H NMR (CDCl3):
d
¼0.93 (s, 3H), 2.28 (s, 3H), 6.04 (d, J¼1.8 Hz,
11. Zhang, J.-L.; Che, C.-M. Chem.dEur. J. 2005, 11, 3899e3914.
12. (a) Marchon, J.-C.; Ramaseul, R. J. Chem. Soc., Chem. Commun. 1988, 298e299;
(b) Marchon, J.-C.; Ramaseul, R. Synthesis 1989, 389e391; (c) Marchon, J.-C.;
1H) ppm. ESIeHRMS [MþNa]: calculated for C20H24NaO5: 367.1521,
experimental: 367.1519.
ꢀ
Ramaseul, R. J. Mol. Catal. 1989, 51, 29e33; (d) Tavares, M.; Ramasseul, R.;
Marchon, J.-C.; Bachet, B.; Brassy, C.; Mornon, J.-P. J. Chem. Soc., Perkin Trans. 2
1992, 1321e1329.
4.18. 3-Hydroxy-5
a,6-epoxy-cholestane acetate 25a
13. Groves, J. T.; Neumann, R. J. Org. Chem. 1988, 53, 3891e3893.
14. (a) Chauan, S. M. S.; Ray, P. C.; Mohibb, M.; Azam, E.; Parkash, S.; Sharma, T. K. J.
Indian Chem. Soc. 1997, 74, 199e201; (b) Prandi, J.; Kagan, H. B.; Mimoun, H.
Tetrahedron Lett. 1986, 27, 2617e2620.
15. (a) Breslow, R.; Yang, J.; Yan, J. Tetrahedron 2002, 58, 653e659; (b) Yan, J.;
Breslow, R. Angew. Chem., Int. Ed. 2000, 39, 2692e2694; (c) Yang, J.; Gabriele, B.;
1H NMR (CDCl3):
d
¼0.58 (s, 3H), 0.82 (s, 3H), 0.85 (s, 3H), 0.88 (s,
3H), 1.00 (s, 3H), 2.01 (s, 3H), 2.17 (t, J¼6 Hz, 1H), 2.89 (d, J¼4.4 Hz,
1H), 4.92 (m, 1H) ppm. 13C NMR (CDCl3):
d
¼12.0 (q), 16.0 (q), 18.8
(q), 20.8 (t), 21.5 (q), 22.7 (t), 23.0 (t), 24.0 (t), 24.2 (t), 27.4 (t), 28.2
(d), 28.2 (t), 28.9 (t), 30.0 (d), 32.3 (t), 35.0 (s), 35.9 (d), 36.3 (t), 36.3
(d), 39.5 (t), 42.5 (d), 42.6 (s), 56.0 (d), 56.9 (d), 59.3 (d), 65.3 (s),
71.6 (d), 170.4 (s) ppm. ESIMS: m/z 467.5 [MþNa].
Belvedere, S.; Huang, Y.; Breslow, R. J. Org. Chem. 2002, 67, 5057e5067; (d)
Breslow, R.; Yang, J.; Belvedere, S. Tetrahedron Lett. 2002, 43, 363e365; (e) Yang,
Z.; Breslow, R. Tetrahedron Lett. 1997, 38, 6171e6172; (f) Breslow, R.; Fang, Z.
Tetrahedron Lett. 2002, 43, 5197e5200; (g) Belvedere, S.; Breslow, R. Bioorg.
Chem. 2001, 29, 321e331.
16. Rebelo, S. L. H.; Simoes, M. M. Q.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro,
J. A. S.; Peixoto, A. F.; Pereira, M. M.; Solva, M. R.; Paixao, J. A.; Beja, A. M. Eur. J.
Org. Chem. 2004, 4778e4787.
4.19. 3-Hydroxy-5b,6-epoxy-cholestane acetate 25b
17. Rebelo, S. L. H.; Pereira, M. M.; Simoes, M. M. Q.; Neves, M. G. P. M. S.; Cavaleiro,
J. A. S. J. Catal. 2005, 234, 76e87.
1H NMR (CDCl3):
d
¼0.63 (s, 3H), 0.80 (s, 3H), 0.84 (s, 3H), 0.87 (s,
¼12.2 (q), 14.1 (q), 20.2
18. Kille, S.; Zilly, F. E.; Acevedo, J. P.; Reetz, M. T. Nature Chem. 2011, 738e743.
19. (a) Costas, M.; Que, L. Angew. Chem., Int. Ed. 2002, 41, 2179e2181; (b) Chen, K.;
Que, L. Chem. Commun. 1999, 1375e1376; (c) Nakanishi, M.; Bolm, C. Adv. Synth.
3H), 0.91 (s, 3H), 2.00 (s, 3H), 2.75 (t, J1¼12 Hz, J2¼6 Hz, 1H), 2.91 (s,
1H), 5.00 (m, 1H) ppm. 13C NMR (CDCl3):
d
€
€
€
Catal. 2007, 349, 861e864; (d) Moller, K.; Wienhoffer, G.; Schroder, K.; Join, B.;
Junge, K.; Beller, M. Chem.dEur. J. 2010, 16, 10300e10303; (e) Kim, C.; Chen, K.;
Kim, J.; Que, L., Jr. J. Am. Chem. Soc. 1997, 119, 5964e5965; (f) Chen, K.; Que, L., Jr.
J. Am. Chem. Soc. 2001, 123, 6327e6337; (g) Britovsek, G. J. P.; England, J.; White,
A. J. P. Inorg. Chem. 2005, 44, 8125e8134; (h) England, J.; Davies, C. R.; Banaru,
M. ,; White, A. J. P.; Britovsek, G. J. P. Adv. Synth. Catal. 2008, 350, 883e897; (i)
(t), 20.8 (q), 21.6 (q), 22.8 (q), 23.0 (q), 24.1 (t), 26.5 (t), 28.2 (d), 28.2
(d), 28.3 (t), 29.1 (t), 31.3 (t), 35.9 (d), 36.2 (t), 37.5 (t), 39.7 (t), 39.7
(t), 41.9 (t), 42.7 (s), 44.5 (s), 45.2 (d), 55.8 (d), 56.4 (d), 56.4 (d), 70.9
(d), 80.5 (s), 170.4 (s) ppm. ESIMS: m/z 367.5 [MꢂOAc], 385.5
[MꢂAc], 467.5 [MþNa].
ꢀ
England, J.; Gondhia, R.; Bigorra-Lopez, L.; Petersen, A. R.; White, A. J. P.;
Britovsek, G. J. P. J. Chem. Soc., Dalton Trans. 2009, 5319e5334; (j) Lyakin, O. Y.;
Bryliakov, K. P.; Britovsek, G. J. P.; Talsi, E. P. J. Am. Chem. Soc. 2009, 131,
10798e10799; (k) Chen, M. S.; White, M. C. Science 2007, 318, 783e787; (l)
Vermeulen, N. A.; Chen, M. S.; White, M. C. Tetrahedron 2009, 65, 3078e3084;
(m) Chen, M. S.; White, M. C. Science 2010, 327, 566e571.
4.20. 5
a-Hydroxy-androstan-3,17-dione 27
1H NMR (CDCl3):
d
¼0.87 (s, 3H), 1.01 (s, 3H), 2.98 (d, J¼13 Hz,
2H) ppm. 13C NMR (CDCl3):
d¼13.1 (q), 15.4 (q), 20.2 (t), 21.0 (t), 27.1
20. White, M. C.; Doyle, A. G.; Jacobsen, E. J. Am. Chem. Soc. 2001, 123, 7194e7195.
21. Chen, K.; Que, L. Angew. Chem. 1999, 111, 2365e2368; Angew. Chem., Int. Ed.
1999, 38, 2227e2229.
22. (a) Fried, J.; Edwards, J. A. Organic Reactions in Steroid Chemistry; van Nostrand
Reinhold: New York, NY, 1972; (b) Djerassi, C. Steroid Reactions; Holden Day,: S.
Francisco, 1963; Vols. I & II; (c) Dewick, P. M. Medicinal Natural Products,
a Biosynthetic Approach; John Wiley: Chichester, UK, 1997.
(t), 30.4 (t), 30.7 (t), 33.7 (d), 35.1 (t), 35.2 (t), 36.5 (t), 39.6 (s), 43.3
(d), 47.0 (s), 48.6 (t), 50.7 (d), 77.6 (s), 210.3 (s), 219.7 (s) ppm.
Acknowledgements
23. (a) Marcos-Escribano, A.; Bermejo, F. A.; Llorente Bonde-Larsen, A.; Iglesias
ꢀ
We are grateful to Crystal Pharma (Parque Tecnologico de Boe-
ꢀ
Retuerto, J.; Herraiz Sierra, I. Tetrahedron 2009, 65, 7587e7590 and references
therein; (b) Buzzetti, F.; Di Salle, E.; longo, A.; Briatio, G. Steroids 1993, 58,
527e532.
cillo, Valladolid, Spain) for a generous gift of steroids. D.C.-T. wish to
ꢀ
thank the F.S.E and the Consejería de la Junta de Castilla y Leon for
€
24. Kohler, M.; Parr, M. K.; Opfermann, G.; Thevis, M.; Schlorer, N.; Marner, F. J.;
a predoctoral grant.
€
Schanzer, W. Steroids 2007, 72, 278e286.
ꢀ
ꢀ
25. (a) Perez Carrion, R.; Alberola, C. V.; Calabresi, F.; Michel, R. T.; Santos, R.;
Delozier, T.; Goss, P.; Mauriac, L.; Feuilhade, F.; Freue, M. Ann. Oncol. 1994, 5,
S19eS24; (b) Brodie, A. M. H.; Njar, V. C. O. Steroids 2000, 65, 171e179.
26. Hussain, R.; El-Etr, M.; Gaci, O.; Rakotomamonjy, J.; Macklin, W. B.; Kumar, N.;
Sitruk-Ware, R.; Scgumacher, M.; Ghoumari, A. M. Endocrinology 2011, 152,
3820e3831.
Supplementary data
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.08.079.
ꢀ
27. Freixa, Z.; Pereira, M. M.; Bayon, J. C.; Silva, A. M. S.; Salvador, J. A. R.; Beja, A. M.;
Paixao, J. A.; Ramos, M. Tetrahedron: Asymmetry 2001, 12, 1083e1087.
28. Naseem, A.; van Lier, J. E. Tetrahedron Lett. 2006, 47, 5345e5349.
29. Tavares da Silva, E. J.; Roleira, F. M. F.; Sa e Melo, M. L.; Campos Neves, A. S.;
References and notes
ꢀ
Paixao, J. A.; Almeida, M. J.; Silva, M. R.; Andrade, L. C. R. Steroids 2002, 311e319.
30. Holland, H. L.; Thomas, E. M. Can. J. Chem. 1979, 57, 3069e3072.
1. Hall, P. F. Steroids 1986, 48, 131e196.
2. Akhtar, M.; Wright, J. N. Nat. Prod. Rep. 1991, 527e551.