Production of 16β-(acetoxy)acetoxy derivatives by reaction of 17-keto steroid enol acetates with lead (IV) acetate

Article abstract of DOI:10.1016/S0039-128X(01)00103-9

Treatment of enol acetates of 3β-acetoxyandrost-5-en-17-one and its 5α-reduced analog, 5α-androstan-17-one, and estrone acetate, 1-4, with Pb(OCOCH₃)₄ in acetic acid and acetic anhydride gave the previously unreported products, 16β-(acetoxy)acetoxy-17-ketones 8-10 and 12, in 9-15% yields along with the known major products, 16β-acetoxy-17-ketones 5-7 and 11. Similar treatment of the 16β-acetoxy-17-ketones with the lead reagent did not yield the corresponding (acetoxy)acetates. Reaction of the enol acetate 3 with Pb(OCOCD₃)₄ in CD₃COOD yielded principally the labeled (acetoxy)acetate 10-d₃, which had a CD₃COOCH₂COO moiety at C-16β. In contrast, when the deuterated enol acetate 3-d₃, which was obtained by treatment of the 17-ketone 14 with (CD₃CO)₂O in the presence of LDA and which had a CD₃COO moiety at C-17, was reacted with Pb(OCOCH₃)₄, the resulting product was the labeled compound 10-d₂. This product had a CH₃COOCD₂COO function at C-16β. Based on these results, along with further isotope-labeling experiments, it seems likely that the (acetoxy)acetate is produced through a lead (IV) acetate-catalyzed migration of the 17-acetyl function of the enol acetate to the C-16β-position followed by attack of an acetoxy anion of the lead reagent. Copyright

Full text of DOI:10.1016/S0039-128X(01)00103-9

Steroids 66 (2001) 743–748
Production of 16␤-(acetoxy)acetoxy derivatives by reaction of 17-keto
steroid enol acetates with lead (IV) acetate
Mitsuteru Numazawaa,*, Momoko Shelangouskia, Masamichi Nakakoshib
aTohoku Pharmaceutical University1, 4-4-1, Komatsushima, Aobaku, Sendai 981-8558, Japan
bResearch Institute of Life Science, Snow Brand Milke Products Co. Ltd., Ishibashimachi, Tochigi, Japan
Received 18 September 2000; received in revised form 6 December 2000; accepted 15 December 2000
Abstract
Treatment of enol acetates of 3␤-acetoxyandrost-5-en-17-one and its 5␣-reduced analog, 5␣-androstan-17-one, and estrone acetate, 1–4,
with Pb(OCOCH3)4 in acetic acid and acetic anhydride gave the previously unreported products, 16␤-(acetoxy)acetoxy-17-ketones 8–10
and 12, in 9–15% yields along with the known major products, 16␤-acetoxy-17-ketones 5–7 and 11. Similar treatment of the 16␤-acetoxy-
17-ketones with the lead reagent did not yield the corresponding (acetoxy)acetates. Reaction of the enol acetate 3 with Pb(OCOCD3)4 in
CD3COOD yielded principally the labeled (acetoxy)acetate 10-d3, which had a CD3COOCH2COO moiety at C-16␤. In contrast, when the
deuterated enol acetate 3-d3, which was obtained by treatment of the 17-ketone 14 with (CD3CO)2O in the presence of LDA and which
had a CD3COO moiety at C-17, was reacted with Pb(OCOCH3)4, the resulting product was the labeled compound 10-d2. This product had
a CH3COOCD2COO function at C-16␤. Based on these results, along with further isotope-labeling experiments, it seems likely that the
(acetoxy)acetate is produced through a lead (IV) acetate-catalyzed migration of the 17-acetyl function of the enol acetate to the
C-16␤-position followed by attack of an acetoxy anion of the lead reagent. © 2001 Elsevier Science Inc. All rights reserved.
Keywords: 17-Enol acetoxy steroid; Lead (IV) acetate; 16␤-(Acetoxy)acetoxylation; 16␤-Acetoxylation; Reaction mechanism; Isotope-labeling
1. Introduction
anism by which these 16␤-(acetoxy)acetoxyketones are pro-
duced was then studied using deuterium-labeling experi-
ments.
Reaction of 17-keto steroid enol acetates with lead (IV)
acetate has been used for stereospecific introduction of an
acetoxy group at the 16␤-position [1–3]. This reaction is
thought to be ionic as it occurs at room temperature [4]. The
products are 16␤-acetoxy-17-ketones in contrast to the 16␣-
configuration [5–9] of bromination products obtained from
the same enol acetates. A recent study using deuterium-
labeling experiments has unambiguously established that
the 16␤-acetoxy derivative is not an isomerized product of
the 16␣-isomer initially formed by ␣-attack of the reagent,
but a product of direct ␤-attack [3,10].
2. Experimental
Melting points were measured on a Yanagimoto melting
point apparatus (Kyoto, Japan) and are uncorrected. Infrared
(IR) spectra were recorded in KBr pellets on a Perkin Elmer
FT-IR 1725X spectrophotometer (Norwalk, CT, USA). Pro-
ton and 13C nuclear magnetic resonance (1H NMR and 13
C
NMR) spectra in CDCl3 were obtained with a JEOL EX 270
(270 MHz for 1H and 67.5 MHz for 13C) spectrometer
(Tokyo, Japan) using tetramethylsilane (␦ ϭ 0.00) as an
internal standard, and mass (MS) spectra were determined
with a JEOL JMS-DX 303 spectrometer. Thin-layer chro-
matography (TLC) was performed on E. Merck precoated
TLC plates, silica gel 60–254, layer thickness 0.25 mm
(Darmstadt, Germany). Silica gel column chromatography
was conducted with E. Merck Kieselgel 60 (70–230 mesh).
CD3COOD and (CD3CO)2O were obtained from Acros Or-
In connection with our study of 16␤-hydroxy steroids,
we treated the 17-ketone enol acetates 1–4 with lead (IV)
acetate and found, for the first time, the production of the
16␤-(acetoxy)acetoxy-17-ketones 8–10 and 12. The mech-
* Corresponding author. Tel.: ϩ81-22-234-4181; fax: ϩ81-22-275-
2013.
E-mail address: numazawa@tohoku-pharm.ac.jp (M. Numazawa).
1 Formerly Tohoku College of Pharmacy.
0039-128X/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved.
PII: S0039-128X(01)00103-9

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M. Numazawa et al. / Steroids 66 (2001) 743–748
ganics (New Jersey, USA), and CD3COOH was obtained by
treatment of (CD3CO)2O with H2O.
4.63–4.75 (m, 1H), 4.98 (t, J ϭ 8.6 Hz, 1H); FT-IR 1730,
1750 cmϪ1 (C¢O).
Androsta-5,16-diene-3␤,17-yl diacetate (1) [2], 3␤,17-
diacetoxy-5␣-androsta-16-ene (2) [1], and 3,17-diace-
toxyestra-1,3,5(10),16-tetraene (4) [11] were synthesized
according to the methods previously reported. Pb(O-
COCD3)4 was prepared from Pb3O4 according to the known
method [12] using CD3COOD and (CD3CO)2O.
2.5. 16␤-Acetoxy-5␣-androstan-17-one (7)
The crude product was recrystallized from MeOH to give
compound 7 (450 mg, 54%) as colorless needles; mp 149–
152°C (lit. 154–155°C [13]). 1H NMR ␦ 0.81 (s, 3H), 0.95
(s, 3H), 2.11 (s, 3H), 4.98 (t, J ϭ 8.6 Hz, 1H); FT-IR 1730,
1741 cmϪ1 (C¢O).
2.1. 5␣-Androstan-16-en-17-yl acetate (3)
Catalytic solution [0.4 ml of H2SO4:isopropenyl acetate
(0.05:1, v/v)] was added to a solution of 5␣-androstan-17-
one (1 g, 3.6 mmol) in 15 ml of isopropenyl acetate, and the
resulting mixture was distilled over a period of 5 h. The
solution was then cooled and diluted with ether (100 ml).
The ether solution was washed sequentially with 5%
NaHCO3 solution and water and then dried with Na2SO4.
Evaporation of the solvent yielded a brown solid that was
dissolved in 50 ml of a mixture of hexane and ethyl acetate
(4:1, v/v) and passed through a column packed with 30 g of
silica gel. Evaporation of the solvent from the eluate gave
the crude product, which was recrystallized from acetone to
give compound 3 as colorless needles; mp 73–75°C (lit.
76–80°C [13]). 1H NMR ␦ 0.82 (s, 3H), 0.88 (s, 3H), 2.13
(s, 3H), 5.45 (m, 1H); FT-IR 1620 cmϪ1 (C¢O).
2.6. 3␤-Acetoxy-16␤-(acetoxy)acetoxyandrost-5-en-17-one
(8)
1
Yield: 10% (96 mg). mp 195–197°C (from acetone); H
NMR ␦ 0.98 (s, 3H), 1.06 (s, 3H), 2.04 (s, 3H), 2.16 (s, 3H),
4.60 (m, 1H), 4.63 and 4.70 (d, J ϭ 8.3 Hz, 2H), 5.03 (t,
J ϭ 8.6 Hz, 1H), 5.41 (d, J ϭ 4.9 Hz, 1H); 13C NMR ␦
14.20, 19.28, 20.02, 20.36, 21.33, 27.62, 29.22, 30.64,
30.78, 31.52, 36.77, 36.82, 37.99, 46.07, 46.78, 50.19,
60.50, 73.57, 75.20, 121.53, 139.93, 167.21, 170.14,
170.19, 213.31. FT-IR 1752 (C¢O) cmϪ1. Analysis calcu-
lated for C25H34O7: C, 67.24; H, 7.67. Found: C, 66.98; H,
7.69.
2.7. 3␤-Acetoxy-16␤-(acetoxy)acetoxy-5␣-androstan-17-
one (9)
2.2. Reaction of the enol acetates 1–4 with lead (IV)
acetate
1
Yield: 9% (88 mg). mp 112–114°C (from acetone); H
NMR ␦ 0.85 (s, 3H), 0.95 (s, 3H), 2.02 (s, 3H), 2.16 (s, 3H),
4.69 (m, 1H), 4.65 and 4.67 (d, J ϭ 10.1 Hz, 2H), 5.01 (t,
J ϭ 8.6 Hz, 1H). FT-IR 1728, 1749 cmϪ1 (C¢O). Analysis
calculated for C25H36O7: C, 66.94; H, 8.09. Found: C,
66.67; H, 8.12.
A solution of 800 mg (2.1–2.5 mmol) of each enol
acetate in 15 ml of acetic acid and 5 ml of acetic anhydride
was treated with a 1.1 mol equivalent of lead (IV) acetate at
room temperature for 10 or 20 h with stirring in the dark.
After this time, the reaction mixture was diluted with ethyl
acetate (300 ml), washed sequentially with 5% NHCO3
solution and water, and dried with Na2SO4. Evaporation of
the solvent gave a brown oil, which was purified by silica
gel column chromatography (hexane/ethyl acetate, 25:1,
v/v, for isolation of 7 and 10, 10:1, v/v, for isolation of 5 and
8 or 6 and 9, and 4:1, v/v, for isolation of 11 and 12), and
recrystallization afforded the 16␤-acetoxy steroids 5–7 and
11 (47–70% yield) and the 16␤-acetoxyacetates 8–10 and
12 (9–15% yield), respectively.
2.8. 16␤-(Acetoxy)acetoxy-5␣-androstan-17-one (10)
1
Yield: 14% (133 mg). mp 89–91°C (from MeOH); H
NMR ␦ 0.81 (s, 3H), 0.95 (s, 3H), 2.17 (s, 3H), 4.62 and
4.70 (d, J ϭ 16.0 Hz, 2H), 5.01 (t, J ϭ 8.6 Hz, 1H). FT-IR
1759 cmϪ1 (C¢O). Analysis calculated for C23H34O5: C,
70.73; H, 8.70. Found: C, 70.76; H, 8.96.
2.9. 3,16␤-Diacetoxyestra-1,3,5(10)-trien-17-one (11)
1
2.3. 3␤,16␤-Diacetoxyandrost-5-en-17-one (5)
Yield: 47%. mp 143–145°C (lit. 148–149°C [11]); H
NMR ␦ 1.00 (s, 3H), 2.13 (s, 3H), 2.28 (s, 3H), 2.91 (m,
2H), 5.05 (t, J ϭ 8.4 Hz, 1H), 6.82 (d, J ϭ 2.5 Hz, 1H),
6.86 (dd, J ϭ 2.6 and 8.4 Hz, 1H), 7.28 (d, J ϭ 6.6 Hz,
1H).
1
Yield: 62%. mp 167–170°C (lit. 168–170°C [14]). H
NMR ␦ 0.98 (s, 3H), 1.06 (s, 3H), 2.02 (s, 3H), 4.61 (m,
1H), 5.00 (t, J ϭ 8.7 Hz, 1H), 5.41 (d, J ϭ 5.1 Hz, 1H),
FT-IR 1726, 1752 cmϪ1 (C¢O).
2.10. 3-Acetoxy-16␤-(acetoxy)acetoxyestra-1,3,5(10)-trien-
17-one (12)
2.4. 3␤,16␤-Diacetoxyandrostan-17-one (6)
1
Yield: 60%. mp 159–160°C (lit. 156–158°C [1]). H
Yield: 15% (152 mg). mp 161–163°C (from MeOH); 1H
NMR ␦ 0.86 (s, 3H), 0.95 (s, 3H), 2.02 (s, 3H), 2.11 (s, 3H),
NMR ␦ 1.00 (s, 3H), 2.17 (s, 3H), 2.29 (s, 3H), 2.91 (m,

M. Numazawa et al. / Steroids 66 (2001) 743–748
745
2H), 4.64 and 4.71 (d, J ϭ 16.1 Hz, 2H), 5.08 (t, J ϭ 8.3
Hz, 1H), 6.82 (d, J ϭ 2.5 Hz, 1H), 6.86 (dd, J ϭ 2.5 and
8.4 Hz, 1H), 7.28 (d, J ϭ 7.1 Hz, 1H). FT-IR 1765 cmϪ1
(C¢O). Analysis calculated for C24H28O7: C, 67.27; H, 6.59.
Found: C, 67.33; H, 6.60.
2.11. Treatment of the 16␤-acetates 5 and 11 with lead
(IV) acetate
(A) Compounds 5 and 11 were separately treated with
lead (IV) acetate under the conditions described for the
reaction of the enol acetate: compounds 5 and 11, 0.13
mmol; acetic acid, 1 ml; acetic anhydride, 0.3 ml; reaction
time 20 h.
(B) A mixture of compounds 5 and 11 (50 mg each, ca.
0.13 mmol) and the lead reagent (66 mg, 0.15 mmol) in
acetic anhydride (3 ml) or benzene (3 ml) was stirred at
room temperature for 20 h. After the same work-up as
described above, TLC analysis of the product showed that
the substrate was quantitatively recovered, and there was no
production of the acetoxy acetate derivative.
2.12. Treatment of the 16␤-(acetoxy)acetate 8 with NaOH
Compound 8 (50 mg, 0.11 mmol) was dissolved in
MeOH (5 ml). 1% NaOH solution in MeOH was added to
this solution and the mixture was stirred for 2 h at room
temperature. The mixture was subsequently diluted with
EtOAc (50 ml), washed sequentially with 5% HCl, 5%
NaHCO3 solution, and H2O, and dried with Na2SO4. Evap-
oration of the solvent gave a crude product, which was
recrystallized from acetone to give 3␤,17␤-dihydroxyan-
drost-5-en-16-one (13) (20 mg, 55%). mp 201–204°C (lit.
202–205°C [2]). 1H NMR ␦ 0.75 (3H, s, 18-Me), 1.05 (3H,
s, 19-Me), 3.58 (1H, m, 3␣-H), 3.76 (1H, s, 17␣-H), 5.36
(1H, d, J ϭ 4.9 Hz, 6-H). This was identical with the
authentic sample.
Scheme 1. Reaction of 17-enol acetates with lead (IV) acetate.
sp2 carbons (four carbonyls and two C¢C carbons) in the
low field region. Treatment of compound 8 with NaOH in
aqueous MeOH gave the 17␤-hydroxy-16-keto derivative
13, the most thermodynamically stable ketol among the four
possible 16,17-ketols [4,16,17]. This derivative was pro-
duced through isomerization of its 16␤-hydroxy-17-keto
isomer, which was the most unstable ketol initially pro-
duced (Scheme 2). These NMR and alkaline hydrolysis
results along with IR (␯max: 1752 cmϪ1) and mass (Mϩ:m/z
388) spectral data supported the assigned structure. The
final proof for the structure of compound 8 was obtained
from two dimensional sequences (COSY and NEOSY) in
NMR spectroscopy.
3. Results and discussion
The other enol acetates 2–4 (5␣-reduced, 3-deoxy, and
A-ring aromatic steroids, respectively) were also subjected
to reaction with the lead reagent under similar conditions
and gave the corresponding 16␤-(acetoxy)acetoxy com-
pounds 9, 10, and 12, respectively, in addition to the cor-
responding 16␤-acetates 6, 7, and 11, respectively (Scheme
1).
Reaction of the enol acetate of 3␤-acetoxyandrost-5-en-
17-one, compound 1, with lead (IV) acetate in acetic acid
containing acetic anhydride was initially carried out at room
temperature according to a previously reported method [1].
Column chromatography followed by recrystallization gave
16␤-acetoxy-17-ketone 5 [2] as the major product along
with 3␤-acetoxy-16␤-(acetoxy)acetoxyandrost-5-en-17-one
(8) as the minor product (Scheme 1). The structural assign-
ment for compound 8 was confirmed by its spectral data and
elemental analysis, along with a chemical aspect of this
compound. The 1H NMR spectrum showed a singlet signal
for acetyl protons (␦: 2.04), two doublet signals for meth-
ylene protons (␦: 4.63 and 4.70, J ϭ 8.3 Hz), and a triplet
1
signal (␦: 5.41) for the 16␣-proton. The H decoupled 13C
NMR spectrum for compound 8 disclosed the presence of 6
Scheme 2. Alkaline hydrolysis of 16␤-(acetoxy)acetate 8.

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M. Numazawa et al. / Steroids 66 (2001) 743–748
and/or substrate
3 under various conditions. When
CD3COOD was employed as a solvent in the (acetoxy)ace-
toxylation reaction of non-labeled substrate 3 with either
non-labeled Pb(OCOCH3)4 or labeled reagent Pb(O-
COCD3)4, deuterium atoms were incorporated efficiently
into the 16␤-(acetoxy)acetoxy moiety of compound 10,
producing d3-species with a CD3COOCH2COO function as
well as d4-species with a CD3COOCH(D)COO function in
a ratio of d3 to d4 of 73:19, 60:18, or 61:25 (Scheme 3;
Table 1, entry a, c, or d). In contrast, (acetoxy)acetoxylation
reaction with deuterated Pb(IV) reagent in the non-labeled
solvent (entry b) did not give rise to significant incorpora-
tion of deuterium in the (acetoxy)acetate 10. These results
show that the acetoxy group in product 10 came from the
acetic acid solvent. Moreover, it is likely that this occurred
via exchange of an acetoxy anion of the reagent for the
solvent acetic acid, although there is no direct evidence for
this.
Scheme 3. Deuterium-labeling of 16␤-(acetoxy)acetate 10 under various
conditions.
Treatment of the non-labeled (acetoxy)acetate 10 with
Pb(OCOCH3)4 in CD3COOD and (CD3CO)2O under the
same conditions as those described for the treatment of enol
acetate 3 failed to label the 16␤-substituent with deuterium
(entry g). Moreover, when the deuterium-labeled product 10
(d3, 73 atom%; d4, 19 atom%) was similarly treated under
the above conditions using non-labeled reagent and sol-
vents, there was no significant difference in a deuterium
content before and after the treatment. These results reveal
that all of the deuterium atoms labeled in the methyl and
methylene groups of the 16␤-(acetoxy)acetoxy substituent
were incorporated not through enolization of carbonyl func-
tions of the 16␤-substituent of the (acetoxy)acetate initially
produced, but through the lead (IV) acetate-assisted reaction
sequence.
Treatment of the 16␤-acetates 5, 6, 7, and 11 with lead
(IV) acetate under the same conditions as those employed
for the reaction of the enol acetate did not produce the
corresponding 16␤-(acetoxy)acetates 9, 10, 11, and 12, re-
spectively, indicating that the (acetoxy)acetates were not
produced through acetoxylation of the 16␤-acetates initially
formed.
When acetic anhydride or benzene was used as a solvent
instead of acetic acid for the reaction of the enol acetate 3
with lead (IV) acetate, neither the 16␤-acetate 7 nor the
16␤-(acetoxy)acetate 10 was produced, suggesting that ace-
tic acid is essential as the reaction solvent for the production
of both steroids 7 and 10.
Then, to confirm the origin of the methylene moiety, we
synthesized the deuterated enol acetate 3 with a 17-
OCOCD3 moiety (d3, 83 atom%) by treatment of 5␣-an-
To further explore the mechanism for the production of
the 16␤-(acetoxy)acetate, the (acetoxy)acetoxylation reac-
tion was carried out using deuterated solvents, reagent,
Table 1
Deuterium-labeling of the 16␤-(acetoxy)acetate 10 and the 16␤-acetate 7 under various conditions
Conditions
Deuterium content, atom%a)
Deuterium labeling
of a 16␤-substituent
of compound 10,
b)
%
Entry Substrate
Reagent
Solvent
16␤-(Acetoxy)acetate 10
16␤-Acetate 7
d1 d2 d3
82 Ͼ98
Methyl Methylene
d0
d1 d2 d3 d4 d5 d0
a
b
c
d
e
f
Non-labeled 3
Pb(OCOCD3)4 CD3COOD and (CD3CO)2O
Pb(OCOCD3)4 CH3COOH and (CH3CO)2O
Pb(OCOCH3)4 CD3COOD and (CH3CO)2O
Pb(OCOCH3)4 CD3COOD and (CD3CO)2O
Pb(OCOCH3)4 CD3COOH and (CD3CO)2O
Pb(OCOCH3)4 CH3COOH and (CH3CO)2O
0
2
2
5
3
4
3
0
2
4
9
73 19
3
0
2
5
0
0
0
—
12
97
4
2
20
0
Non-labeled 3
Non-labeled 3
Non-labeled 3
Non-labeled 3
95
13
2
6
6
3
0
0
3
4
4
2
0
2
0
9
5
3
69
79
76
22
—
0
0
67
95
95
0
60 18
61 25
26
10
12
71
—
100
20
30
30
83
0
79
2
2
0
Labeled-d3
3
24 68
g
h
Non-labeled 10 Pb(OCOCH3)4 CD3COOD and (CD3CO)2O
Non-labeled 7 Pb(OCOCH3)4 CD3COOD and (CD3CO)2O
100
—
0
—
0
—
0
—
0
—
—
0
—
0
0
aDeuterium content was obtained by mass spectrometry.
bDeuterium labeling data was obtained by 1H NMR spectrometry.

M. Numazawa et al. / Steroids 66 (2001) 743–748
747
Scheme 5. Proposed mechanism for 16␤-acetoxylation of a 17-enol
acetate.
terminal methylene of a cyclic intermediate 18 completes
the first oxidation, producing an enol 17-(acetoxy)acetate
(19) (alternate oxidation, Scheme 6). The second oxidation
is electrophilically driven like the first, since an enol ester
19 was regenerated. Isomerization of a cyclic carbocation
20, produced by reaction of the intermediate 19 with the
lead reagent, to a 17␣-lead adduct 21 followed by attack of
an acetoxy anion yields an acetal 22 (path a), which is
transformed into carbonyl compound 24 by attack of a
nucleophile. In contrast, deprotonation of a methylene func-
tion of the adduct 21 produces an olefin 23 to which addi-
tion of acetic acid also gives the intermediate 22 (path b).
This deprotonation-addition process causes the partial loss
of the methylene deuteriums (Table 1, entry f) or the partial
labeling of the methylene hydrogens with a deuterium (en-
tries a, c, and d). There was no significant production of the
d4-species of compound 10 in the reaction using CD3COOH
instead of CD3COOD (d3, 79 atom%, d4, 2 atom%, entry
e), which is consistent with the involvement of this process
in the reaction sequence.
Scheme 4. Synthesis and reaction of deuterium-labeled 17-enol acetate 3.
drost-17-one (14) with (CD3CO)2O in the presence of LDA
at Ϫ78°C (Scheme 4) [17]. Reaction of compound 3-d3
with Pb(OCOCH3)4 in acetic acid containing acetic anhy-
dride produced the deuterated (acetoxy)acetate 10, which
had a CH3COOD2COO function at C-16␤ (d1, 24 atom%;
d2, 68 atom%) (Table 1, entry f). The length of the reaction
period (10 or 20 h) did not affect the deuterium content of
product 10. Since the methylene hydrogens did not ex-
change with a hydrogen of the solvent during the reaction
and isolation procedures described above, it seems likely
that the formation of the d1-species occurred in the reaction
sequence. The relative amounts of the d1- to d2-species
corresponded well to those of the d3- to d4- plus d5-species
(d3, 60–73 atm%; d4 ϩ d5, 20–30 atom%) obtained by
reaction of the non-labeled substrate 3 with CD3COOD as
solvent under various conditions (Table 1, entries a, c, and
d). On the basis of these results, it is concluded that a
methylene carbon of the 16␤-(acetoxy)acetoxy group was
derived from a methyl carbon of a 17-acetoxy function of
the enol acetate.
The deuterium content of the 16␤-acetate 7, obtained as
Taken together, the acetoxylation and (acetoxy)acetoxy-
lation sequences are thought to proceed as follows
(Schemes 5 and 6). The first oxidation proceeds via an
electrophilic attack of Pb(IV) acetate on an olefin produces
a cyclic carbocation 15. This reacts with an acetoxy anion to
complete the first oxidation, giving a 16␤-acetate 17
through a 16␤-acetoxy-17␣-Pb(OCOCH3)3 intermediate 16
(normal oxidation, Scheme 5). On the other hand, migration
of a 17-acetyl group of the carbocation 15 to the 16␤-
position followed by attack of an acetoxy anion on the
Scheme 6. Proposed mechanisms for the production of
16␤-(acetoxy)acetate.

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M. Numazawa et al. / Steroids 66 (2001) 743–748
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hydroxy-16-ones with acid and base. Chem Pharm Bull 1987;35:
4763–8.
the major product of the reaction of the enol acetate 3 under
various conditions was also analyzed (Table 1). The reac-
tion with either Pb(OCOCH3)4 or Pb(OCOCD3)4 in deuter-
ated acetic acid (CD3COOD or CD3COOH) gave essen-
tially the deuterated compound 7, which had a 16␤-
OCOCD3 group (d0, 10–26 atom%; d3, 69–82 atom%,
respectively; entries a, c, d, and e). On the other hand,
treatment of the deuterated enol acetate 3-d3 with the non-
labeled reagent and solvents produced principally non-la-
beled 16␤-acetate 7 (d0, 71 atom%; d3, 22 atom%, entry f).
On the basis of these labeling results, it seems likely that the
16␤-acetoxy moiety of compound 7 principally came from
the lead reagent through an ionic attack sequence, as pre-
viously reported [4].
In conclusion, reaction of a steroidal 17-enol acetate with
Pb(IV) acetate in acetic acid gave a 16␤-(acetoxy)acetoxy-
17-ketone as the minor product along with a 16␤-acetoxy-
17-ketone as the major product. The production of the
(acetoxy)acetate occurred first through Pb(IV) acetate-cata-
lyzed migration of a 17-acetyl group to the 16␤-position and
the acetoxy moiety directly attached to the steroid nucleus
originated from a 17-acetyl function of the substrate. A
terminal acetoxy moiety of the 16␤-(acetoxy)acetoxy func-
tion of the (acetoxy)acetate as well as the 16␤-acetoxy
group of the acetate could arise from either the lead reagent
or the acetic acid solvent since, presumably, there is some
exchange and/or equilibration between them.
[4] Kirk DN, Hartshorm MP. Steroid Reaction Mechanisms, New York,
Elsevier Publishing Company, 1968. pp. 176–7.
[5] Fajkos J. Steroids. XV. Configuration of 16-bromo derivatives of
androstane. Collection Czechoslov Chem Communs 1955;20:312–4.
[6] Ellis B, Patel D, Petrow V. Modified steroid hormones. VIII. Some
16-bromo- and 16-chloro derivatives of testosterone. J Chem Soc
1958:800–4.
[7] Shoppee CW, Jenkins RH, Summers GHR. Steroids and Walden
inversion part XL. The configurations of the bromination products of
androsta-17-one. J Chem Soc 1958:3048–58.
[8] Glazier ER. Bromination with cupric bromide. II. Bromination in the
presence of an olefinic bond. J Org Chem 1962;27:4397–9.
[9] Numazawa M, Osawa Y. Improved synthesis of 16␣-hydroxylated
androgens: intermediates of estriol formation in pregnancy. Steroids
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[10] Numazawa M, Nagaoka M. Intramolecular 1,2-hydride shift in the
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[11] Biggerstaff WR, Gallagher TF. 3,16␤-Dihydroxy-1,3,5-estratrien-17-
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[12] Fieser LF, Fieser M. Reagents for Organic Synthesis, Vol. 1, New
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