Bismuth(III) salts mediated regioselective ring opening of epoxides: an easy route to halohydrins and β-hydroxy nitrates

Article abstract of DOI:10.1016/j.tet.2007.06.054

The ring opening of various epoxides was achieved under mild conditions using bismuth(III) salts. Halohydrins and β-hydroxy nitrates were efficiently obtained from the corresponding 5α,6α-, 2α,3α-, and 5β,6β-epoxysteroid using BiCl₃, BiBr₃

Full text of DOI:10.1016/j.tet.2007.06.054

Tetrahedron 63 (2007) 9221–9228
Bismuth(III) salts mediated regioselective ring opening of
epoxides: an easy route to halohydrins and b-hydroxy nitrates
b
Rui M. A. Pinto,a Jorge A. R. Salvadora, and Christophe Le Roux
*
aLaboratoꢀrio de Quꢀımica Farmace^utica, Faculdade de Farmaꢀcia, Universidade de Coimbra, 3000-295 Coimbra, Portugal
b
´ ´
´
´
Laboratoire Heterochimie Fondamentale et Appliquee, Universite Paul Sabatier 118,
route de Narbonne, 31062 Toulouse Cedex 9, France
Received 5 June 2007; accepted 14 June 2007
Available online 22 June 2007
Abstract—The ring opening of various epoxides was achieved under mild conditions using bismuth(III) salts. Halohydrins and b-hydroxy
nitrates were efficiently obtained from the corresponding 5a,6a-, 2a,3a-, and 5b,6b-epoxysteroid using BiCl3, BiBr3 or Bi(NO3)3$5H2O.
Considerations about the probable reaction mechanism are provided. 2D homo- and heteronuclear correlation NMR spectroscopic techniques
were used to unequivocally demonstrate the trans-diaxial nature of the epoxide ring opening.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
species9 and withanolides such as jaborosalactone C and
jaborosalactone E isolated from Jaborosa integrifolia,10
and physalolactone,11a 4-deoxyphysalolactone11b and
physalolactone C11c from Physalis peruviana. 6a-Chloro-
5b-hydroxywithaferin A12 and 6a-chloro-5b-hydroxywitha-
nolide D13 have also been isolated from Withania frutescens
and Withania somnifera, respectively.
Epoxides are versatile synthetic intermediates in organic
chemistry. For instance, epoxide ring opening with nucleo-
philic agents is an easy step for the preparation of several
1,2-disubstituted products,1 such as vicinal halohydrins
and b-hydroxy nitrates.
Chlorohydrins and other halohydrins are an important class
of organic compounds and are useful intermediates for the
synthesis of a vast range of biologically active natural and
synthetic products.2,3 In biological systems, hypochlorous
acid, generated from H2O2 and chlorine by myeloperoxi-
dase, is known to form chlorohydrin addition products
with unsaturated fatty acids and cholesterol.4 The formation
of cholesterol chlorohydrins has been a subject of intense
research5 and three different chlorohydrin compounds
have been identified from the reaction of cholesterol with
HOCl.6 The role of these compounds is not yet fully under-
stood, but in addition to cytotoxicity and a possible action
on the physiopathology of atherosclerosis,5d they have
been proposed as biomarkers of myeloperoxidase-derived
HOCl.7 The vicinal chlorohydrin group has been identified
in some steroid natural compounds, such as blattellastano-
side B, an aggregation pheromone of German cockroach
Blattella germanica,8 marine steroids isolated from coral
The conventional reagents for the formation of halohydrins
from epoxide ring opening reaction are hydrogen halides
and hypohalite–water.14 However, the disadvantages associ-
ated with these processes such as intolerance of acid sensi-
tive groups and by-product formation, led to intense
research in this field. The use of pyridinium chloride,15
ammonium halides in the presence of metal salts16 or
BF3$OEt2, haloborane compounds,18 direct halogenation
17
of epoxides19 and ring opening with halides of a variety of
elements20,21 have been reported for this reaction. Some
ionic liquid based systems were also developed for the prep-
aration of halohydrins from epoxides.22 For steroid sub-
strates, the synthesis of halohydrins from epoxides is
mainly performed using hydrogen halides.23 Alternative
methods for this transformation involve the use of phos-
phine–halogen reagents,24 palladium–halogen complexes,25
and Dowex-50/sodium halides as an in situ generator of
hydrogen halides.26
Organic nitrates have useful applications in organic synthe-
sis27 including as effective protecting groups for hydroxy
groups.28 The intense research related to nitric oxide (NO)
and its biological effects led to the design of new drugs
capable to act as NO-donors29 and to the hybridization of
Keywords: Bismuth(III) salts; Epoxysteroids; Halohydrins; b-Hydroxy
nitrates.
* Corresponding author. Tel.: +351 239859950; fax: +351 239827126;
e-mail: salvador@ci.uc.pt
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.054

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R. M. A. Pinto et al. / Tetrahedron 63 (2007) 9221–9228
NO-donating moieties (e.g., nitrate esters) with well-known
drugs, some of them containing the steroid nucleus.30
with nitriles (Ritter reaction).43 The reaction with 5a,6a-
epoxycholestan-3b-yl acetate 1 was performed in acetonitrile
under catalytic (10 mol % of BiBr3, 48 h, 93% yield) or stoi-
chiometric conditions (1.5 equiv of BiBr3, 4.5 h, 91% yield)
to afford the 6b-acetamido-5a-hydroxy derivative 13.43
Traditionally, the synthesis of b-hydroxy nitrates has been
performed through the reaction of epoxides in concentrated
nitric acid31 and nitration of halohydrins with silver
nitrate.32 Non-attractive features of these methods are the
highly acidic conditions used on the first one and the use
of an expensive silver salt for the second one. The immobi-
lization of nitrate ions on Amberlite IRA-400 allowed the
preparation of b-hydroxy nitrates in a non-catalyzed reac-
tion.33 Iranpoor et al. used ceric ammonium nitrate (CAN)
When catalytic amounts of BiCl3 (10–20 mol %) were used
forthesameconversionnosignificantreactionoccurred. How-
ever, the use of 1.5 equiv of BiCl3 led to the formation of the
6b-acetamido-5a-hydroxy compound 13 and 6b-chloro-
5a-hydroxycholestan-3b-yl acetate 7 (Scheme 1, Table 1,
entry 1). McCluskey et al. reported that ring opening of
cyclohexene oxide with BiCl3/acetonitrile, in the presence
of an amine or H2O afforded the corresponding trans-chloro-
hydrin.44 The only by-products identified were the trans-diol
or b-amino alcohol derivatives in some of the experiments.
Under our reaction conditions, where the amine was absent,
we verified that there was competition between the Ritter re-
action and the formation of a chlorohydrin derivative, a situ-
ation not described by those authors. In light of such
discrepancy, we decided to study the influence of a base ei-
ther inorganic (NaN3) or organic (4-dimethylaminopyridine,
DMAP), in the BiCl3 mediated ring opening of epoxysteroids
in acetonitrile (Scheme 1, Table 1, entries 2–8). We observed
that using 1.5 equiv of NaN3 (Table 1, entries 2, 7, and 8) or
10–30 mol % of DMAP (Table 1, entries 3–5) the 6b-chloro-
5a-hydroxy products were preferentially obtained. On the
other hand 50 mol % of DMAP dramatically decreases the
reaction rate and only traces of products were observed after
8 h (Table 1, entry 6). These results suggest that the presence
of a base stabilizes the reaction medium, making chlorohy-
drin the major reaction product.
in stoichiometric amounts to perform the same reaction.34
CAN,34 FeCl3$6H2O supported on SiO2
and Ce(OTf)4
16b
in micellar media35 have been used catalytically for the
ring opening of several epoxides by the nitrate ion derived
from NH4NO3, Bu4NNO3 or NaNO3. Recently, the use
of nitric oxide36 and zirconyl nitrate37 emerged as new
methods that afford b-hydroxy nitrates. Epoxysteroids
were converted into the corresponding b-hydroxy nitrates
by treatment with stoichiometric amounts of thallium(III)
nitrate,38 a highly toxic heavy metal derivative. Hanson
and co-workers applied CAN to the opening of steroidal
epoxides and the corresponding b-hydroxy nitrates were
obtained.39
The methods previously described for the preparation of halo-
hydrins and b-hydroxy nitrates suffer from one or more dis-
advantages such as acidity, handling of toxic, sensitive and/
or expensive reagents, in situ preparation of the reagents,
relative long reaction time, unwanted by-products, and low
regioselectivities. Therefore, new methods that use environ-
mental friendly, cheap, and easily available reactants to effi-
ciently perform these reactions would be of considerable
interest.
In order to avoid any traces of Ritter reaction products we ex-
plored the reactivity of BiCl3 towards the epoxysteroids 1–6
in a different solvent, 1,4-dioxane, and the corresponding
chlorohydrins 7–12 were obtained in high yields (Scheme
1, Table 2). The reaction occurred at room temperature
(Table 2, entry 1) but it was faster when performed at
80 ꢀC (Table 2, entry 2). Under similar conditions the
5a,6a-epoxysteroids 2 and 3 and 2a,3a-epoxy-5a-choles-
tane 4 were efficiently converted to the chlorohydrins 8, 9,
and 10, respectively, with yields ranging from 92 to 94%
(Table 2, entries 3–5). The trans-diaxial ring opening of
5b,6b-epoxysteroids 5 and 6 at room temperature gave the
corresponding 5a-chloro-6b-hydroxy products 11 and 12
(Table 2, entries 6 and 8). In the case of substrate 5 the selec-
tivity was lower and the yield after flash column chromato-
graphy was 76% (Table 2, entry 6). Increasing the reaction
temperature decreased the yield of 5a-chloro-6b-hydroxy
derivative 11 (Table 2, entry 7).
Over the last decade the increasing concern about the envi-
ronment has put focus on bismuth and its compounds,40
mainly due to their relatively non-toxic character41 that
makes them suitable ‘ecofriendly’ reagents for a large vari-
ety of processes. We have recently reported the use of bis-
muth(III) salts as efficient catalysts for selective allylic
oxidation reactions42 and for the one-step conversion of
epoxides into vic-acylamino hydroxy compounds.43
In this work we report the use of bismuth(III) salts for the re-
gioselective ring opening of epoxides. These new processes
proved to be easy, economical, and efficient for the prepara-
tion of halohydrins and b-hydroxy nitrates from epoxides in
high yields and under mild conditions.
2. Results and discussion
Using BiBr3 in 1,4-dioxane, the 6b-bromo-5a-hydroxy
product 16 was also prepared from the 5a,6a-epoxysteroid
1 at room temperature in 90% yield (Scheme 2).
2.1. BiCl3 and BiBr3 mediated ring opening of epoxides:
synthesis of halohydrins
To check if the observed reactivity is due to the in situ forma-
tion of HCl from BiCl3, we performed the reaction in the
presence of 2,6-di-tert-butylpyridine, a known proton scav-
enger, which only binds to protons and is unable to coordi-
nate to metal ions due to the bulky tert-butyl groups.45
Using substrate 1 in the conditions of the general procedure,
the 6b-chloro-5a-hydroxy product 7 was isolated in 90%
Although in most reactions bismuth(III) compounds act as
Lewis acid catalysts, some processes have been reported
where they are used in stoichiometric amounts.40c
In a previous communication, we reported the synthetic ap-
plication of bismuth(III) salts in the ring opening of epoxides

R. M. A. Pinto et al. / Tetrahedron 63 (2007) 9221–9228
R1 R1
9223
R1
R2
R2
R2
BiCl3
+
Solvent
AcO
AcO
AcO
O
HO
HO
Cl
NHCOCH3
1....................R1=C8H17;R2=H....................7............................................13
2..........................R1;R2=O..........................8............................................14
3...................R1=COCH3;R2=H...................9............................................15
C8H17
C8H17
BiCl3
Cl
O
Solvent
HO
10
4
R1
R2
R1
R2
BiCl3
Solvent
AcO
AcO
O
Cl
OH
5....................R1=C8H17;R2=H....................11
6...................R1=COCH3;R2=H..................12
Scheme 1.
yield after 3.5 h.46 This result suggests that the ring opening
is mediated by the Lewis acidity of bismuth towards the ep-
oxide, alike the Bi–O interaction proposed by Keramane and
co-workers for the chlorination of alcohols with BiCl3.47
attached to the geminal pair at 1.36 and 2.02 ppm, giving
cross peaks with the proton at 4.09 ppm in the COSY spec-
trum, showed no coupling to 19-CH3, so it can be assigned
as C-4. Thus, the product is a 2-chloro-3-hydroxy derivative.
Strong correlations of 19-CH3 with 1b-H (1.99 ppm) and 4b-
H (2.02 ppm) and a weak interaction with 3-H were detected
in the NOESY spectrum, but none with 2-H. These observa-
tions are in accordance with a 2b-chloro-3a-hydroxy struc-
ture where the A-ring is in a chair conformation and both
2-H and 3-H are in equatorial positions. The steroselectivity
for this reaction is consistent with the classical trans-diaxial
opening of 2a,3a-epoxysteroids.48
The stereochemistry for compounds 10 and 11 was deter-
mined using COSY, HMQC, HMBC and NOESY experi-
ments to unequivocally confirm the trans-diaxial ring
opening of 2a,3a-epoxysteroid 4 and 5b,6b-epoxysteroid 5.
For compound 10, the two protons with high chemical shifts
(4.16 and 4.09 ppm) correspond to 2-H and 3-H, respectively.
2-H was distinguished by the coupling with a geminal pair at
1.82 and 1.99 ppm attached to a carbon with a chemical shift
of 40.0 ppm, which showed a cross peak with 19-CH3 (at
1.06 ppm) in the HMBC spectrum, being thus assigned as
C-1. On the other hand, the carbon atom (31.0 ppm) that is
For compound 11, the observed multiplicity for the proton
at 5.38 ppm (triplet of triplets, J1¼10.9 Hz and J2¼
5.5 Hz), attributed to 3-H, was indicative of a trans-fused
(5a,10b)-steroid structure with the hydrogen in an axial
Table 1. Ring opening of 5a,6a-epoxysteroids with BiCl3 in MeCNa
Entry
Substrate (mmol)
Solvent (mL)
BiCl3 (mmol)
Base (mmol)
Time (h)
Productb
Yieldc (%)
Ratiod
1
2
3
4
5
6
7
8
1/0.125
1/0.125
1/0.25
1/0.25
1/0.25
1/0.25
2/0.25
3/0.25
MeCN (3)
MeCN (3)
MeCN (6)
MeCN (6)
MeCN (6)
MeCN (6)
MeCN (6)
MeCN (6)
0.19
0.19
0.25
0.25
0.25
0.25
0.37
0.37
—
0.5
0.5
2
1
0.5
8
7+13
7+13
7+13
7+13
7+13
—
8+14
9+15
94
93
91
91
94
—
93
93
45:55
87:13
71:29
63:33
63:33
—
NaN3 (0.19)
DMAP (0.08)
DMAP (0.05)
DMAP (0.03)
DMAP (0.13)
NaN3 (0.37)
NaN3 (0.37)
e
0.5
1
83:17
87:13
a
Reactions performed at 80 ꢀC.
Analytical data for the Ritter reaction products 13–15 were in accordance with literature.43
Yield of the reaction crude based on chlorohydrin.
b
c
d
e
Calculated by 1H NMR integration of 6a-H in the crude product.
Only traces of products were observed in TLC plate after 8 h.

9224
R. M. A. Pinto et al. / Tetrahedron 63 (2007) 9221–9228
Table 2. BiCl3 mediated ring opening of epoxysteroids: synthesis of chlorohydrins
Entry
Substrate (mmol)
Solvent (mL)
BiCl3 (mmol)
Temp (ꢀC)
Time (h)
Product
Isolated Yield (%)
1
2
3
4
5
6
7
8
1/0.10
1/0.10
2/0.25
3/0.25
4/0.10
5/0.50
5/0.125
6/0.10
1,4-Dioxane (3)
1,4-Dioxane (3)
1,4-Dioxane (6)
1,4-Dioxane (6)
1,4-Dioxane (3)
1,4-Dioxane (15)
1,4-Dioxane (3)
1,4-Dioxane (3)
0.10
0.15
0.37
0.37
0.10
0.50
0.19
0.10
rt
9
1
1
1.5
4.5
9
0.5
19
7
7
8
94
94
94
92
92
76a
61a
89
80
80
80
rt
rt
80
rt
9
10
11
11
12
a
Purified by flash column chromatography on silica gel (toluene/diethyl ether 7:3).
C8H17
C8H17
R1
R2
R1
R2
BiBr3
(1 equiv.)
Bi(NO3)3·5H2O
1,4-dioxane
1,4-dioxane, r.t.
24 h, 90% yield
AcO
AcO
AcO
AcO
O
HO
O
HO
Br
ONO2
1
16
1....................R1=C8H17;R2=H....................18
2..........................R1;R2=O..........................19
3...................R1=COCH3;R2=H...................20
Scheme 2.
a-conformation. The signal at 3.96 ppm was assigned to 6-H
and showed in COSY spectrum a correlation with the protons
at 1.61 and 2.03 ppm. These protons were correlated with
a carbon located at 34.1 ppm, which showed a cross peak
with C-6 (75.6 ppm) in HMBC. This experiment provided
further information about the carbon nucleus located in
the vicinity of C-6. Cross peaks with carbons assigned
as C-4 (37.6 ppm), C-5 (83.3 ppm), C-10 (39.7 ppm), C-7
(34.1 ppm), and C-8 (30.4 ppm) were found in HMBC spec-
trum and were in accordancewith the one previously reported
for 5a-chloro-3b,6b-dihydroxycholestane.6 The NOESYex-
periment did not show any correlations between 6-H and
19-CH3, which in addition to the nature of the 6-H signal
(doubletof doublets, J1¼5.3 Hzand J2¼2.3 Hz), is indicative
of equatorial conformation and supports the proposed struc-
ture for 5a-chloro-6b-hydroxycholestan-3b-yl acetate 11.
C8H17
C8H17
Bi(NO3)3·5H2O O2NO
O
1,4-dioxane
HO
4
21
O
O
O
O
Bi(NO3)3·5H2O
1,4-dioxane
AcO
AcO
O
17
HO
ONO2
22
Scheme 3.
2.2. Bi(NO3)3$5H2O mediated ring opening of epoxides:
synthesis of b-hydroxy nitrates
selective for the 5a,6a-epoxide group and a new steroid
compound 22 was obtained in 91% yield (Scheme 3, Table
3, entry 7). The 16a,17a-epoxide group remains intact al-
lowing further important funtionalizations. Thus the reaction
performed on substrate 17 is chemo-, regio- and stereoselec-
tive, which shows the synthetic applicability of the reported
process.
The use of bismuth salts for the selective ring opening of ep-
oxides was extended to Bi(NO3)3$5H2O and under these
specific reaction conditions, the b-hydroxy nitrate products
18–22 were obtained from epoxysteroids 1–4 and 17 in
very high yields (Scheme 3, Table 3). The reaction can be
performed at room temperature or at 80 ꢀC with 1 equiv
per mole of Bi(NO3)3$5H2O (Table 3, entries 1 and 2), but
faster reactions were obtained using 1.5 equiv of Bi
(NO3)3$5H2O at 80 ꢀC (Table 3, entries 3–7).
To enlarge the scope of this process, the ring opening of the
non-steroidal substrates cyclohexene oxide 23 and styrene
oxide 24 was performed with Bi(NO3)3$5H2O in 1,4-diox-
ane at room temperature (Scheme 5). For substrate 23, the
corresponding trans-b-hydroxy nitrate product 25 was ob-
tained in 83% yield after 1 h of reaction. The expected
ring opening at the benzylic position was observed for sub-
strate 24 and thus product 26 was isolated in 90% yield.
Interestingly, using acetonitrile as solvent49 the reaction of
5a,6a-epoxysteroid 1 with Bi(NO3)3$5H2O gave mainly
the Ritter reaction product 13 and only small amounts of
5a-hydroxy-6b-nitrate derivative 18 were observed (Scheme
4, Table 3, entry 8). The addition of 1.5 equiv of NaN3 to this
reaction increased the yield of 5a-hydroxy-6b-nitrate prod-
uct 18 to 61% (Table 3, entry 9).
The ring opening of 5a,6a-epoxysteroid 1 with Bi
(NO3)3$5H2O in 1,4-dioxane was also investigated in the
presence of 2,6-di-tert-butylpyridine. After 1.5 h the reac-
tion was complete, which indicates that the nucleophilic at-
tack of the nitrate on the epoxide ring is not due to the in situ
formation of HNO3.50 This suggests that Bi(NO3)3$5H2O
It is noteworthy that the ring opening of the 5a,6a;16a,17a-
diepoxysteroid 17 with Bi(NO3)3$5H2O proved to be highly

R. M. A. Pinto et al. / Tetrahedron 63 (2007) 9221–9228
9225
Table 3. Bi(NO3)3$5H2O mediated ring opening of epoxysteroids: synthesis of b-hydroxy nitrates
Entry
Substrate (mmol)
Solvent (mL)
Bi(NO3)3$5H2O (mmol)
Temp (ꢀC)
Time (h)
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
9
1/0.10
1/0.10
1/0.10
2/0.10
3/0.10
4/0.10
17/0.10
1/0.10
1/0.10
1,4-Dioxane (3)
1,4-Dioxane (3)
1,4-Dioxane (3)
1,4-Dioxane (3)
1,4-Dioxane (3)
1,4-Dioxane (3)
1,4-Dioxane (3)
MeCN (3)
0.10
0.10
0.15
0.15
0.15
0.15
0.15
0.15
0.15
rt
24
4
2
2.5
3
2.5
4.5
0.5
1.5
18
18
18
19
20
21
22
13+18
13+18
90
90
93
93
88
85
91
95a
90c
80
80
80
80
80
80
80
80
MeCN (3)b
Yield of the reaction based on 5a-hydroxy-6b-acetamide derivative 13; by 1H NMR integration of 6a-H in the crude product it was found a ratio of 88:12
between the products 13 and 18.
Reaction performed in the presence of 1.5 equiv of NaN3.
a
b
c
Yield of the reaction based on 5a-hydroxy-6b-nitrate derivative 18; by 1H NMR integration of 6a-H in the crude product it was found a ratio of 39:61 between
the products 13 and 18.
C8H17
C8H17
C8H17
Bi(NO3)3·5H2O
MeCN, 80 ºC
+
AcO
AcO
AcO
O
HO
HO
ONO2
NHCOCH3
1
13
18
88%
12%
Scheme 4.
Bi(NO3)3·5H2O
(1.5 equiv.)
detected, but none were seen between 6-H and 19-CH3.
These observations allowed us to assign the 5a-hydroxy
6b-nitrate configuration to compound 19.
ONO2
O
1,4-dioxane, r.t.
1 h, 83% yield
OH
25
23
ONO2
OH
3. Conclusions
O
Bi(NO3)3·5H2O
(1.5 equiv.)
In summary, we developed new processes for the selective
trans-diaxial ring opening of epoxides using economical,
non-toxic, and easily available bismuth salts. These methods
allowed the effective synthesis of halohydrins and b-
hydroxy nitrates under mild conditions. A remarkable
solvent effect in the reactivity of bismuth salts towards epoxy-
steroids was demonstrated and a probable reaction mecha-
nism was discussed. These procedures were found to be
very simple, economic, and ecofriendly leading to high
yields and therefore should find a large application in chem-
ical synthesis.
1,4-dioxane, r.t.
1 h, 90% yield
24
26
Scheme 5.
coordinates with the epoxide, increasing the polarity of the
C–O bond and making the adjacent carbons more suscepti-
ble to nucleophilic attack.
The trans-diaxial nature of 5a,6a-epoxysteroid ring opening
with Bi(NO3)3$5H2O was determined using 2D NMR tech-
niques to unequivocally attribute the 6b-substitution that re-
sults from the nucleophilic attack on C-6 by the b-face of the
steroid nucleus. For compound 19, the protons with chemi-
cal shifts at 5.14 and 4.92 ppm were assigned as 3-H and
6-H, respectively. The multiplicity of the 3-H (a triplet of
triplets with J1¼11.1 Hz and J2¼5.5 Hz) was indicative of
a trans-fused (5a,10b)-steroid structure. The coupling pat-
tern observed for 6-H (doublet of doublets, J1¼5.4 Hz and
J2¼2.1 Hz) was indicative of equatorial–equatorial and
equatorial–axial couplings, consistent with 6b-substitution.
The resonance due to 6-H at 4.92 ppm gave strong correla-
tions with a geminal pair at 1.88 ppm and 1.90 ppm in the
1H–1H COSY spectrum, which were correlated with a carbon
at 29.1 ppm. The HMBC experiment provided useful corre-
lations for 6-H, showing cross peaks with carbon nucleus,
which were assigned as C-5 (74.8 ppm), C-10 (38.7 ppm),
C-7 (29.1 ppm), and C-9 (30.4 ppm). In the NOESY experi-
ment interactions of 6-H with the geminal pair at C-7 were
4. Experimental
4.1. General
5a,6a-Epoxysteroids (1–3 and 17) and 2a,3a-epoxy-5a-
cholestane (4) were prepared from the corresponding D5-
steroids and from 5a-cholest-2-ene, respectively, by
epoxidation with m-CPBA.51 5b,6b-Epoxysteroids (5 and
6) were obtained by b-selective epoxidation of D5-steroids
using a method developed by our group.52 The starting
materials, bismuth salts and solvents were purchased from
Sigma-Aldrich Co. Solvents were distilled before use
according to standard procedures. Kieselgel 60HF245
/
Kieselgel 60G was used for TLC plates. Melting points
were determined on a Buchi Melting point B-540 and are un-
corrected. IR spectra were performed in a Jasco FT/IR 420

9226
R. M. A. Pinto et al. / Tetrahedron 63 (2007) 9221–9228
1
spectrophotometer. 1H, 13C NMR, 2D homonuclear correla-
tion (COSY), Nuclear Overhauser Enhancement Spectros-
copy (NOESY), 2D heteronuclear multiple quantum
correlation (HMQC) and 2D heteronuclear multiple bond
correlation (HMBC) were recorded in a Bruker AMX
300 MHz and in a Bruker Avance 300 MHz equipped with
a BBO-ATMA 5 mm probe. The NMR samples were pre-
pared in CDCl3 solution with Me4Si as internal standard.
Mass spectral analyses were made on a Thermo Quest
TSQ 7000; the samples were dissolved in dichloromethane
and the spectra were obtained by direct chemical ionization
(DCI) using NH3 as the reactant gas.
1009 cmꢁ1; H NMR (CDCl3, 300 MHz) d 0.67 (s, 3H,
18-CH3), 0.87, 0.89 (2d, J¼1.3 Hz, each 3H, 26-CH3 and
27-CH3), 0.92 (d, J¼6.5 Hz, 21-CH3), 1.06 (s, 3H, 19-
CH3), 4.09 (m, 1H, 3b-H), 4.16 (m, 1H, 2a-H); 13C NMR
(CDCl3, 75 MHz) d 12.1 (C-18), 14.8 (C-19), 31.0 (C-4),
40.0 (C-1), 59.9 (C-2), 71.2 (C-3); MS [m/z (%)] 440 (3)
[M+NH4]+, 421 (30), 404 (100), 402(14), 318 (3), 304 (8),
117 (3), 100 (7).
4.2.4. Compound 11. Mp 194–196 ꢀC (CHCl3); lit.,24 195–
197 ꢀC; IR (ATR) 3434, 2936, 1737, 1704, 1379, 1268,
1089, 1034, 891 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d 0.69 (s, 3H, 18-CH3), 0.87, 0.89 (2d, J¼1.3 Hz, each 3H,
26-CH3 and 27-CH3), 0.92 (d, J¼6.5 Hz, 21-CH3), 1.30 (s,
3H, 19-CH3), 2.04 (s, 3H, CH3COO), 3.96 (dd, J1¼5.3 Hz
and J2¼2.3 Hz, 1H, 6a-H), 5.38 (tt, J1¼10.9 Hz and
J2¼5.5 Hz, 1H, 3a-H); 13C NMR (CDCl3, 75 MHz) d 12.2
(C-18), 18.0 (C-19), 21.4 (CH3COO), 30.4 (C-8), 34.1 (C-
7), 37.6 (C-4), 39.7 (C-10), 71.0 (C-3), 75.6 (C-6), 83.3
(C-5), 170.5 (CH3COO); MS [m/z (%)] 516 (5)
[M+N2H7]+, 499 (100) [M+NH4]+, 462 (21), 404 (4), 354
(6), 180 (6), 145 (5), 115 (5).
4.2. General procedure for BiX3 mediated ring opening
of epoxides
To a solution of 5a,6a-epoxycholestan-3b-yl acetate 1
(44.4 mg, 0.10 mmol) in 1,4-dioxane (3 mL), BiCl3
(31.5 mg, 0.1 mmol) was added. After 9 h under magnetic
stirring at room temperature the reaction was complete as
verified by TLC control. The reaction mixture was filtered
through a Celite pad, the filtrate was concentrated under
vacuum and the resulting residue dissolved in ethyl acetate
(60 mL). The organic phase was washed with HCl (10%
aq), Na2SO3 (10% aq), water, dried with anhydrous
Na2SO4, and evaporated to dryness to give 6b-chloro-5a-
hydroxycholestan-3b-yl acetate 7 (45.0 mg, 94% yield). Slow
crystallization from ethyl acetate afforded 82% of pure prod-
uct. Mp 178–181 ꢀC; lit.,24 180–182 ꢀC; IR (ATR) 3401,
2933, 1735, 1699, 1364, 1273, 1246, 1033 cmꢁ1; 1H NMR
(CDCl3, 300 MHz) d 0.71 (s, 3H, 18-CH3), 0.87, 0.89 (2d,
J¼1.3 Hz, each 3H, 26-CH3 and 27-CH3), 0.92 (d,
J¼6.5 Hz, 3H, 21-CH3), 1.29 (s, 3H, 19-CH3), 2.05 (s, 3H,
CH3COO), 3.85 (m, 1H, 6a-H), 5.12 (tt, J1¼11.6 Hz and
J2¼5.9 Hz, 1H, 3a-H); 13C NMR (CDCl3, 75 MHz) d 12.1
(C-18), 18.2 (C-19), 18.6 (C-21), 21.4 (CH3COO), 64.0 (C-
6), 71.1 (C-3), 76.5 (C-5), 171.0 (CH3COO); MS [m/z (%)]
516 (1) [M+N2H7]+, 499 (100) [M+NH4]+, 480 (18), 462
(37), 354 (9), 180 (9), 173 (2), 115 (8).
4.2.5. Compound 12. Mp 203–205 ꢀC (MeOH); lit.,54 206–
207 ꢀC; IR (ATR) 3402, 2942, 1734, 1700, 1235, 1090,
1
894 cmꢁ1; H NMR (CDCl3, 300 MHz) d 0.65 (s, 3H, 18-
H3), 1.31 (s, 3H, 19-H3), 2.05 (s, 3H, CH3COO), 2.13 (s,
3H, 21-CH3), 3.98 (m, 1H, 6a-H), 5.38 (tt, J1¼11.0 Hz
and J2¼5.6 Hz, 1H, 3a-H); 13C NMR (CDCl3, 75 MHz)
d 70.9 (C-3), 75.4 (C-5), 83.2 (C-6), 170.5 (CH3COO),
209.5 (C-20); MS [m/z (%)] 445 (10) [M+N2H7]+, 428
(75) [M+NH4]+, 392 (100), 378 (9), 351 (18), 334 (20),
332 (15), 304 (10).
4.2.6. Compound 16. Mp 140–142 ꢀC (MeOH); lit.,24 140–
142 ꢀC; IR (ATR) 3410, 2941, 1734, 1705, 1365, 1246,
1
1036 cmꢁ1; H NMR (CDCl3, 300 MHz) d 0.73 (s, 3H,
18-CH3), 0.87, 0.89 (2d, J¼1.3 Hz, each 3H, 26-CH3 and
27-CH3), 0.93 (d, J¼6.4 Hz, 21-CH3), 1.37 (s, 3H, 19-
CH3), 2.05 (s, 3H, CH3COO), 3.99 (m, 1H, 6a-H), 5.10
(m, 1H, 3a-H); 13C NMR (CDCl3, 75 MHz) d 12.1 (C-18),
19.1 (C-19), 18.6 (C-21), 21.4 (CH3COO), 56.2 (C-6),
71.2 (C-3), 76.2 (C-5), 170.9 (CH3COO); MS [m/z (%)]
542 (100) [M+NH4]+, 498 (6), 480 (36), 462 (64), 404 (4),
354 (8), 180 (7), 140 (10).
4.2.1. Compound 8. Mp 199–201 ꢀC (MeOH); lit.,53 204–
205 ꢀC; IR (ATR) 3569, 2947, 1737, 1726, 1372, 1243,
1
1027 cmꢁ1; H NMR (CDCl3, 300 MHz) d 0.91 (s, 3H,
18-CH3), 1.29 (s, 3H, 19-CH3), 2.05 (s, 3H, CH3COO),
3.89 (m, 1H, 6a-H), 5.09 (tt, J1¼10.6 Hz and J2¼5.1 Hz,
1H, 3a-H); 13C NMR (CDCl3, 75 MHz) d 13.9 (C-18),
18.2 (C-19), 21.6 (CH3COO), 63.6 (C-6), 71.1 (C-3), 76.2
(C-5), 171.3 (CH3COO), 221.3 (C-17); MS [m/z (%)] 417
(2) [M+NH4]+, 400 (29), 381 (5), 364 (100), 336(4), 304
(6), 234 (6), 216(3), 153 (1).
4.3. General procedure for Bi(NO3)3$5H2O mediated
ring opening of epoxides
To a solution of 5a,6a-epoxycholestan-3b-yl acetate
(44.4 mg, 0.10 mmol) in 1,4-dioxane (3 mL),
1
4.2.2. Compound 9. Mp 232–234 ꢀC (MeOH); lit.,53 237–
Bi(NO3)3$5H2O (72.7 mg, 0.15 mmol) was added. After
2 h under magnetic stirring at 80 ꢀC the reaction was com-
plete as verified by TLC control. The reaction mixture was
filtered through a Celite pad, the filtrate was concentrated
under vacuum and the resulting residue dissolved in ethyl
acetate (60 mL). The organic phase was washed with HCl
(10% aq), Na2SO3 (10% aq), water, dried with anhydrous
Na2SO4, and evaporated to dryness to give 5a-hydroxy-
6b-nitratecholestan-3b-yl acetate 1838 (46.7 mg, 93%
yield). Crystallization from acetone afforded 82% of pure
product. Mp 138–139 ꢀC; IR (ATR) 3432, 2940, 1734,
238 ꢀC; IR (ATR) 3342, 2945, 1731, 1688, 1363, 1248,
1
1029 cmꢁ1; H NMR (CDCl3, 300 MHz) d 0.65 (s, 3H,
18-CH3), 1.28 (s, 3H, 19-CH3), 2.04 (s, 3H, CH3COO),
2.13 (s, 3H, 21-CH3), 3.85 (m, 1H, 6a-H), 5.11 (m,
1H, 3a-H); 13C NMR (CDCl3, 75 MHz) d 63.7 (C-6),
70.9 (C-3), 76.3 (C-5), 171.0 (CH3COO), 209.6 (C-20);
MS [m/z (%)] 445 (2) [M+N2H7]+, 428 (72) [M+NH4]+,
409 (3), 392 (100), 350 (9), 334 (6), 304 (6), 129 (3).
4.2.3. Compound 10. Mp 124–125 ꢀC (MeOH); lit.,24 122–
124 ꢀC; IR (ATR) 3335, 2931, 1467, 1442, 1376,
1714, 1632, 1279, 1244, 1032, 849 cmꢁ1 1H NMR
;

R. M. A. Pinto et al. / Tetrahedron 63 (2007) 9221–9228
9227
(CDCl3, 300 MHz) d 0.69 (s, 3H, 18-CH3), 0.87, 0.89 (2d,
J¼1.3 Hz, each 3H, 26-CH3 and 27-CH3), 0.92 (d,
J¼6.5 Hz, 21-CH3), 1.14 (s, 3H, 19-CH3), 2.05 (s, 3H,
CH3COO), 4.88 (m, 1H, 6a-H), 5.14 (tt, J1¼10.9 Hz and
J2¼5.3 Hz, 1H, 3a-H); 13C NMR (CDCl3, 75 MHz) d 12.1
(C-18), 16.0 (C-19), 18.8 (C-21), 21.4 (CH3COO), 70.3
(C-3), 75.0 (C-5), 85.4 (C-6), 171.0 (CH3COO); MS [m/z
(%)] 542 (6) [M+N2H7]+, 525 (100) [M+NH4]+, 480 (9),
478 (17), 462 (22), 418 (3), 408 (2), 354 (2).
(CDCl3, 300 MHz) d 3.78, 3.90 (2 m, 2H, 1-H2), 5.86 (m,
1H, 2-H), 7.25–7.40 (m, 5H, Ar); 13C NMR (CDCl3,
75 MHz) d 67.3 (C-1), 85.5 (C-2).
Acknowledgements
~
^
R.M.A.P. thanks Fundac¸ao para a Ciencia e Tecnologia for
a grant (SFRH/BD/18013/2004). J.A.R.S. thanks Universi-
dade de Coimbra for financial support. We are grateful to
ꢀ
Dr. Yannick Chollet (Service Commun de RMN, Universite
4.3.1. Compound 19. Mp 187–188 ꢀC (MeOH); lit.,39 189–
191 ꢀC; IR (ATR) 3559, 2943, 1735, 1727, 1633, 1613, 1284,
1242. 1031, 864 cmꢁ1; 1H NMR (CDCl3, 300 MHz) d 0.89 (s,
3H, 18-CH3), 1.16 (s, 3H, 19-CH3), 2.04 (s, 3H, CH3COO),
4.92 (dd, J1¼5.4 Hz and J2¼2.1 Hz, 1H, 6a-H), 5.14 (tt,
J1¼11.1 Hz and J2¼5.5 Hz, 1H, 3a-H); 13C NMR (CDCl3,
75 MHz) d 13.9 (C-18), 16.0 (C-19), 21.4 (CH3COO), 29.1
(C-7), 30.4 (C-9), 38.7 (C-10), 70.2 (C-3), 74.8 (C-5), 85.0
(C-6), 171.1 (CH3COO), 220.5 (C-17); MS [m/z (%)] 444
(7) [M+N2H7]+, 427 (62) [M+NH4]+, 380 (83), 364 (100),
320 (22), 304 (39), 242 (13), 180 (18).
Paul Sabatier, Toulouse, France) for his help in the acquisi-
tion and data treatment of 2D NMR spectra and to Prof. Rui
A. Carvalho (Center of NMR Spectroscopy, University of
Coimbra, Portugal) for the helpful discussions with which
he kindly privileged us.
References and notes
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196 ꢀC; IR (ATR) 3326, 2949, 1729, 1686, 1635, 1281,
1
1245, 846 cmꢁ1; H NMR (CDCl3, 300 MHz) d 0.64 (s,
3H, 18-CH3), 1.14 (s, 3H, 19-CH3), 2.05 (s, 3H, CH3COO),
2.13 (s, 3H, 21-CH3), 4.88 (m, 1H, 6a-H), 5.14 (tt,
J1¼11.1 Hz and J2¼5.6 Hz, 1H, 3a-H); 13C NMR (CDCl3,
75 MHz) d 70.2 (C-3), 74.9 (C-5), 85.1 (C-6), 171.0
(CH3COO), 209.4 (C-20); MS [m/z (%)] 472 (7)
[M+N2H7]+, 455 (100) [M+NH4]+, 424 (20), 408 (61), 392
(72), 348 (14), 180 (26), 163 (17).
4.3.3. Compound 21. Mp 88–91 ꢀC (MeOH); lit.,56 90–
91 ꢀC; IR (ATR) 3382, 2929, 1632, 1467, 1279, 1019,
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865 cmꢁ1; H NMR (CDCl3, 300 MHz) d 0.66 (s, 3H, 18-
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CH3); 0.91 (d, J¼6.5 Hz, 21-CH3), 0.91 (s, 3H, 19-CH3),
4.02 (m, 1H, 3b-H), 5.01 (m, 1H, 2a-H); 13C NMR
(CDCl3, 75 MHz) d 66.1 (C-3); 82.0 (C-2); MS [m/z (%)]
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18-CH3), 1.13 (s, 3H, 19-CH3), 2.03 (s, 6H, CH3COO and
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171.0 (CH3COO); 204.8 (C-20); MS [m/z (%)] 486
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2867, 1627, 1454, 1277, 1076, 995, 873 cmꢁ1; H NMR
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1
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