Neighboring group participation. Part 14. The preparation of the four stereoisomers of 16-hydroxymethyl-5α-androstane-3β,17-diol

Article abstract of DOI:10.1016/S0039-128X(00)00237-3

16α-Hydroxymethyl-5α-androstane-3β,17β-diol and 16β-hydroxymethyl-5α-androstane-3β,17β-diol, were obtained from reduction of 16-acetoxymethylene-5α-androstan-17-one. The corresponding 16α,17α- and 16β,17α-hydroxymethyl isomers were obtained by neighboring group participation of the 16- and 17-acetates, respectively. The reactions involving carbocation formation also led to ring D rearrangement products. Copyright

Full text of DOI:10.1016/S0039-128X(00)00237-3

Steroids 66 (2001) 623–635
Neighboring group participation. Part 14. The preparation of the four
stereoisomers of 16-hydroxymethyl-5␣-androstane-3␤,17-diol૾
Pa´l Tapolcsa´nyi, Ja´nos Wo¨lfling, Gyula Schneider*
Department of Organic Chemistry, University of Szeged, Do´m te´r 8, H-6720 Szeged, Hungary
Received 12 September 2000; received in revised form 13 November 2000; accepted 15 November 2000
Abstract
16␣-Hydroxymethyl-5␣-androstane-3␤,17␤-diol and 16␤-hydroxymethyl-5␣-androstane-3␤,17␤-diol, were obtained from reduction of
16-acetoxymethylene-5␣-androstan-17-one. The corresponding 16␣,17␣- and 16␤,17␣-hydroxymethyl isomers were obtained by neigh-
boring group participation of the 16- and 17-acetates, respectively. The reactions involving carbocation formation also led to ring D
rearrangement products. © 2001 Elsevier Science Inc. All rights reserved.
Keywords: 16-Hydroxymethyl-5␣-androstane-3␤,17-diol; Acetolysis; Neighboring group participation; Wagner-Meerwein rearrangement
1. Introduction
acetic acid yielded the fourth isomer of the series, 17␣-
acetoxy-16␣-acetoxymethyl-3-methoxyestra-1,3,5(10)-
triene [7]. The four isomers are suitable synthon reagents for
the synthesis of various heterocyclic steroid compounds
[8–10].
Our investigations in the present work had two aims. Re-
duction of 16-acetoxymethylene-3␤-acetoxy-5␣-androstan-17-
one (1b) yielded two epimeric diols, 3␤-acetoxy-16␤-hydroxy-
methyl-5␣-androstane-17␤-ol (3a) and 3␤-acetoxy-16␣-
hydroxymethyl-5␣-androstane-17␤-ol (4a). These were
converted into the 3␤,17␤-diacetoxy-16␤-toluene-p-sulfonyl-
oxymethyl-5␣-androstane (3e) and 3␤-acetoxy-16␣-ace-
toxymethyl-17␤-toluene-p-sulfonyloxy-5␣-androstane (4h).
Starting with 3e and 4h we wish to prepare by solvolysis in
acetic acid by neighboring group participation the isomers 5
and 6, with 17␣ configuration. Beside acetoxy participation,
we also wished to study benzoyloxy participation.
The presence of a 16-hydroxymethyl functional group in
the sterane skeleton greatly affects the chemical and bio-
logical properties [2]. Furthermore, it provides a possibility
for the preparation of 16-methyl-17-hydroxy steroids [3],
and construction of heterocycles condensed to the sterane
skeleton [4,5]. We reported earlier that the reduction of
16-hydroxymethylene-3-methoxyestra-1,3,5(10)-trien-17-one
with NaBH4 yields two isomers [6]. The acetolysis of 17␤-
acetoxy-16␤-toluene-p-sulfonyloxymethyl-3-methoxyestra-
1,3,5(10)-triene in the presence of potassium acetate led to
partial inversion at C-17, and gave a mixture of 17␣-
acetoxy-16␤-acetoxymethyl-3-methoxyestra-1,3,5(10)-
triene and 17␤-acetoxy-16␤-acetoxymethyl-3-
methoxyestra-1,3,5(10)-triene. The process involves
neighboring group participation characterized by the gen-
eral symbol (AcO-6). In the case of the epimer 17␤-
acetoxy-16␣-toluene-p-sulfonyloxymethyl-3-methoxyestra-
1,3,5(10)-triene, however, the acetolysis yielded exclusively
17␤-acetoxy-16␣-acetoxymethyl-3-methoxyestra-
1,3,5(10)-triene. Its formation can be explained by an SN2
exchange reaction of the primary toluene-p-sulfonyloxy
group. The acetolysis of 16␣-acetoxymethyl-3-
methoxyestra-1,3,5(10)-triene-17␤-p-tolylsulfonate in wet
2. Experimental
Melting points (mp) were determined on a Kofler block
and are uncorrected. Specific rotations were measured with
a POLAMAT-A (Zeiss-Jena) polarimeter for solutions in
chloroform, acetic acid or methanol (c 1) and are given in
units of 10Ϫ1 deg cm2 gϪ1. Elemental analysis data were
determined with a Perkin-Elmer CHN analyzer model 2400.
Thin-layer chromatography: silica gel 60, layer thickness
0.2 mm (Merck); solvent system (ss): (A) tert-butyl methyl
૾ For a preceding paper in this series, see Ref. [1].
* Corresponding author. Tel.: ϩ36-62-544276; fax: ϩ36-62-544200.
E-mail address: schneider@chem.u-szeged.hu (G. Schneider).
0039-128X/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved.
PII: S0039-128X(00)00237-3

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ether, (B) ethyl acetate/chloroform (10:90 v/v), (C) ethyl
acetate/chloroform (50:50 v/v), (D) chloroform; detection
by iodine or UV (365 nm) after spraying with 50% phos-
phoric acid and heating at 100–120°C for 10 min. Flash
chromatography: silica gel 60, 40–63 ␮m. Column chro-
matography: Al2O3 (standardized according to Brockmann)
with an activity of III-IV. The NMR spectra were recorded
with a Bruker AMX-400 instrument. Chemical shifts (␦) are
given in ppm and coupling constants (J) in Hz.
1H, 3-H), 5.27(s, 1H, 17-H) and 7.00(m, 1H, 16-CH); 13C-
NMR (100 MHz, CDCl3, Me4Si) ␦ ppm 12.8(2C, C-18 and
C-19), 21.4(C-11), 21.6, 21.7 and 22.1(3C, CH3CO), 27.9,
28.0, 29.0, 32.1, 34.6, 35.5(C-8), 36.2(C-10), 37.1, 37.3,
44.4(C-13), 45.2(C-5), 49.0(C-14), 54.7(C-9), 74.2(C-3),
82.3(C-17), 125.4(C-16), 131.6(C-16a), 168.4(16-CH3CO),
171.3 and 171.6(2C, 3- and 17-CH3CO).
2.3. 3␤-Acetoxy-16␤-hydroxymethyl-5␣-androstan-17␤-ol
(3b) and 3␤-acetoxy-16␣-hydroxymethyl-5␣-androstan-
17␤-ol (4b)
2.1. 3␤-Acetoxy-16-acetoxymethylene-5␣-androstan-17␤-
ol (2a)
Compound 2a (20.2 g, 0.05 mol) was suspended in
ethanol (500 ml), and KBH4 (5.4 g, 0.1 mol) was added in
small portions, during cooling in ice. The reduction mixture
was allowed to stand for 1 h, and was then acidified with
dilute hydrochloric acid. The resulting solution was poured
onto ice (1000 g) and the precipitate was filtered and dried
over P2O5. The dried isomeric mixture 3b and 4b was
suspended in a mixture of chloroform (500 ml) and acetone
(100 ml) in the presence of a catalytic amount of toluene-
p-sulfonic acid. The reaction mixture was kept at boiling
temperature for 1 h. It was neutralized with morpholine and
evaporated to dryness. The residue obtained was then dis-
solved in chloroform (50 ml) and chromatographed on alu-
mina. Chloroform/light petroleum (1:3) eluted the acetonid
3i (9.8 g; 48%), mp 157–159°C, Rf ϭ 0.80 (ss B); [␣]2D0 ϩ5
(c 1 in chloroform) (Found: C, 74.38; H, 9.76. C25H40O4
requires C, 74.22; H, 9.97%); 1H-NMR (400 MHz, CDCl3,
Me4Si) ␦ ppm 0.67(m, 1H), 0.82(s, 3H) and 0.84(s, 3H):
18-H and 19-H, 1.32(s, 3H) and 1.36(s, 3H): C(CH3)2,
2.02(s, 3H, CH3CO), 2.28(m, 1H), 3.50(m, 1H) and 3.63(m,
1H): 16-CH2, 3.66(d, 1H, J ϭ 9.2 Hz, 17-H) and 4.68(m,
1H, 3-H); 13C-NMR (100 MHz, CDCl3, Me4Si) ␦ ppm
12.9(C-19), 14.1(C-18), 21.5(C-11), 22.1(CH3CO),
25.7(2C, C(CH3)2) 28.6, 29.2, 32.8, 34.7, 35.2(C-8),
36.3(C-10), 37.5, 38.9, 39.0(C-16), 44.7(C-13), 45.4(C-5),
51.2(C-14), 55.0(C-9), 64.2(C-16a), 74.3(C-3), 79.9(C-17),
99.3(C(CH3)2) and 171.4(CH3CO). Continued elution with
chloroform yielded 4b (8.5 g; 46%), mp 240–242°C, Rf ϭ
0.30 (ss A); [␣]2D0 Ϫ14 (c 1 in chloroform) (Found: C, 72.35;
l6-Hydroxymethylene-5␣-androstan-3␤-ol-17-one 1a,
prepared according to the procedure of Ruzicka et al. [11]
(mp 223–225°C, [␣]D ϩ16 (c 1 in methanol)), was con-
verted into 3␤-acetoxy-16-acetoxymethylene-5␣-androstan-
17-one 1b with acetic anhydride in pyridine (mp 151–
153°C, [␣]2D0 Ϫ22 (c 1 in chloroform) [11]).
Compound 1b (20.1 g, 0.05 mol) was suspended in
ethanol (500 ml), cooled in an ice-bath and KBH4 (5.4 g, 0.1
mol) was added in small portions. The pH of the reaction
mixture was maintained between 6.5 and 7.5 by the addition
of acetic acid in the presence of bromothymol blue as
indicator. The mixture was allowed to stand for 6 h, and was
then acidified with dilute hydrochloric acid. The resulting
solution was poured onto ice (1000 g), and the precipitate
that separated was filtered and dried over P2O5. Crystalli-
zation from methanol/water gave 2a (18.5 g, 91%), mp
165–167°C, Rf ϭ 0.60 (ss B); [␣]2D0 Ϫ105 (c 1 in chloro-
form) (Found: C, 71.45; H, 8.78. C24H36O5 requires C,
1
71.26; H, 8.97%); H-NMR (400 MHz, CDCl3, Me4Si) ␦
ppm 0.68(s, 3H, 18-H), 0.74(m, 1H), 0.84(s, 3H, 19-H),
2.02(s, 3H, 3-CH3CO), 2.14(s, 3H, 16-CH3CO), 2.36(m,
1H), 4.06(d, 1H, J ϭ 8.7 Hz, 17-H), 4.68(m, 1H, 3-H) and
7.18(m, 1H, 16-CH); 13C-NMR (100 MHz, CDCl3, Me4Si)
␦ ppm 11.7(C-18), 12.9(C-19), 21.4 and 22.1(2C, CH3CO),
21.5, 27.7, 28.1, 29.0, 32.2, 34.6, 35.6(C-8), 36.3(C-10),
36.8, 37.4, 44.4(C-13), 45.3(C-5), 48.7(C-14), 55.0(C-9),
74.2(C-3), 83.0(C-17), 130.2(C-16), 131.8(C-16a),
168.6(16-CH3CO) and 171.4(3-CH3CO).
1
H, 9.87. C22H36O4 requires C, 72.49; H, 9.95%); H-NMR
2.2. 3␤-Acetoxymethylene-3␤,17␤-diacetoxy-5␣-
androstane (2b)
(400 MHz, CDCl3, Me4Si) ␦ ppm 0.67(m, 1H), 0.80(s, 3H)
and 0.82(s, 3H): 18-H and 19-H, 2.02(s, 3H, CH3CO),
2.03(m, 1H), 3.42(d, 1H, J ϭ 7.6 Hz, 17-H), 3.63(m, 1H)
and 3.76(m, 1H):16-CH2, 4.68(m, 1H, 3-H); 13C-NMR (100
MHz, CDCl3, Me4Si) ␦ ppm 12.7(2C, C-18 and C-19),
21.3(C-11), 22.3(CH3CO), 27.6, 28.1, 29.1, 32.1, 34.7,
35.9(C-8), 36.3(C-10), 37.3, 37.4, 41.0(C-13), 45.4, 46.3,
50.4(C-14), 55.1(C-9), 67.8(C-16a), 74.3(C-3), 86.8(C-17)
and 171.3(CH3CO). Compound 3i (8.0 g, 0.02 mol) was
dissolved in 96% ethanol (100 ml) in the presence of a
catalytic amount of toluene p-sulfonic acid. The reaction
mixture was allowed to stand at room temperature for 6 h,
and was then diluted with water. The crystalline substance
that separated out was recrystallized from methanol to ob-
Compound 2a (4.04 g, 10 mmol) was dissolved in a
mixture of pyridine (5 ml) and acetic anhydride (5 ml), and
the solution was allowed to stand at room temperature for
12 h. It was then diluted with water and the precipitate that
separated was filtered and recrystallized from acetone/water
gave 2b (4.3 g; 96%), mp 96–98°C, Rf ϭ 0.65 (ss B); [␣]D20
Ϫ78 (c 1 in chloroform) (Found: C, 70.05; H, 8.45.
C26H38O6 requires C, 69.93; H, 8.58%); 1H-NMR (400
MHz, CDCl3, Me4Si) ␦ ppm 0.73(s, 3H, 18-H), 0.74(m,
1H), 0.83(s, 3H, 19-H), 2.02(s, 3H, 3-CH3CO), 2.11(s, 3H)
and 2.14(s, 3H): 16- and 17-CH3CO, 2.39(m, 1H), 4.68(m,

P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
625
tain 3b (6.8 g; 93%), mp 194–196°C, Rf ϭ 0.60 (ss A);
[␣]2D0 Ϫ18 (c 1 in chloroform) (Found C, 72.54; H, 10.05.
C22H36O4 requires C, 72.49; H, 9.59%); 1H-NMR (400
MHz, CDCl3, Me4Si) ␦ ppm 0.64(m, 1H), 0.79(s, 3H) and
0.83(s, 3H): 18-H and 19-H, 2.02(s, 3H, CH3CO), 2.40(m,
1H), 3.61(m, 1H) and 3.80(m, 1H): 16-CH2, 3.86(d, 1H, J ϭ
9.9 Hz, 17-H) and 4.67(m, 1H, 3-H); 13C-NMR (100 MHz,
CDCl3, Me4Si) ␦ ppm 11.3 and 11.4(2C, C-18 and C-19),
19.8(C-11), 20.5(CH3CO), 26.5, 27.1, 27.4, 30.8, 33.0,
33.9(C-8), 34.6(C-10), 35.8, 36.7, 40.9(C-16), 43.1(C-13),
43.7(C-5), 49.0(C-14), 53.3(C-9), 63.8(C-16a), 72.7(C-3),
82.1(C-17) and 169.8(CH3CO).
2.7. 3␤-Acetoxy-17␤-benzoyloxymethyl-16␤-bromomethyl-
5␣-androstane (3g)
Compound 3j (2.26 g, 0.005 mol) was dissolved in car-
bon tetrachloride (50 ml) and the solution was refluxed with
1,3-dibromo-5,5-dimethylhydantoin (2.28 g, 8 mmol) for 15
min. The hydantoin that separated was filtered and the
filtrate was washed successively with solutions of KI and
Na2S2O3 and then evaporated to dryness. The residual yel-
low oil was subjected to chromatographic separation on
silica gel with a mixture of ethyl acetate/chloroform (2.5:
97.5) to obtain 3 g (2.3 g; 87%), mp 158–160°C, Rf ϭ 0.84
(ss B); [␣]2D0 ϩ19 (c 1 in chloroform) (Found C, 65.41; H,
1
7.35. C29H39BrO4 requires C, 65.53; H, 7.40%); H-NMR
2.4. 16␤-Hydroxymethyl-5␣-androstane-3␤,17␤-diol (3a)
(400 MHz, CDCl3, Me4Si) ␦ ppm 0.73(m, 1H), 0.84(s, 3H,
19-H), 0.94(s, 3H, 18-H), 2.02(s, 3H, CH3CO), 2.14(m,
1H), 2.86(m, 1H), 3.33(m, 1H) and 3.51(m, 1H): 16-CH2,
4.69(m, 1H, 3-H), 5.01(d, 1H, J ϭ 10.0 Hz, 17-H), 7.46(dd,
2H, J ϭ 7.5 Hz, 3Ј- and 5Ј-H), 7.58(t, 1H, J ϭ 7.5 Hz, 4Ј-H)
and 8.03(d, 2H, J ϭ 7.5 Hz, 2Ј- and 6Ј-H); 13C-NMR (100
MHz, CDCl3, Me4Si) ␦ ppm 12.6(2C, C-18 and C-19),
21.0(C-11), 22.0(CH3CO), 27.8, 28.8, 32.0, 33.3, 34.4(2C),
35.1(C-8), 36.0, 37.1, 38.0, 42.1(C-16), 44.6, 45.0(C-5),
49.5(C-14), 54.5(C-9), 74.0(C-3), 83.4(C-17), 128.9(2C,
C-3Ј and C-5Ј), 130.0(2C, C-2Ј and C-6Ј), 130.7(C-1Ј),
133.6(C-4Ј), 167.4(C6H5CO) and 171.0(CH3CO).
Compound 3b (182 mg, 0.5 mmol) was dissolved in
methanol (10 ml) containing NaOCH3 (5 mg, 0.092 mmol)
and the solution was allowed to stand for 24 h. It was then
diluted with water, and the hard crystals that separated were
filtered and recrystallized from a mixture of acetone/water;
3a (155 mg, 96%) mp 270–271°C, Rf ϭ 0.40 (ss A); [␣]D
-62 (c 1 in acetic acid) (Found C, 74.35; H, 10.72. C20H34O3
requires C, 74.49; H, 10.63%).
20
2.5. 16␣-Hydroxymethyl-5␣-androstane-3␤,17␤-diol (4a)
Compound 4b (182 mg, 0.5 mmol) was dissolved in
methanol (10 ml) containing NaOCH3 (5 mg, 0.092 mmol)
and the solution was allowed to stand for 24 h. It was then
diluted with water, and the white precipitate that separated
was filtered and recrystallized from a mixture of acetone/
water; 4a (150 mg, 93%) mp 261–263°C, Rf ϭ 0.20 (ss A);
[␣] Ϫ85 (c 1 in acetic acid) (Found C, 74.28; H, 10.81.
C20H34O3 requires C, 74.49; H, 10.63%.
2.8. 3␤-Acetoxy-16␤ toluene-p-sulfonyloxymethyl-5␣-
androstan-17␤-ol (3d) and 3␤-acetoxy-16␣-toluene-p-
sulfonyloxymethyl-5␣-androstan-17␤-ol (4d)
2.8.1. General procedure
Compound 3b or 4b (3.64 g, 0.01 mol) was dissolved in
anhydrous pyridine (30 ml) and a solution of toluene-p-
sulfonyl chloride (2.85 g, 0.015 mol) in anhydrous pyridine
(15 ml) was added dropwise during cooling with ice. The
reaction mixture was allowed to stand for 24 h and was then
poured onto a mixture of ice (500 g) and sulfuric acid (10
cm3. The precipitate that separated was filtered and recrys-
tallized from a mixture of benzene/light petroleum. 3d (4.85
g; 93%), mp 170–172°C, Rf ϭ 0.50 (ss B); [␣]2D0 Ϫ14 (c 1
in chloroform) (Found C, 67.05; H, 8.20. C29H42O6S re-
2.6. 3␤-Acetoxy-16␤-hydroxymethyl-5␣-androstan-17␤-ol
benzaldehyde acetal (3j)
Compound 3b (3.64 g, 0.01 mol) was dissolved in di-
chloromethane (50 ml) and the solution was refluxed with
an excess of benzaldehyde diethyl acetal (3.6 g, 0.02 mol) in
the presence of a catalytic amount of toluene-p-sulfonic acid
for 10 min. It was then neutralized with morpholine, evap-
orated to dryness and subjected to chromatographic separa-
tion on an alumina column. The excess of reagent was
eluted with light petroleum. Continued elution with a mix-
ture of light petroleum/chloroform (1:3) yields 3j (4.1 g;
90%), mp 144–145°C, Rf ϭ 0.65 (ss B); [␣]2D0 ϩ47 (c 1 in
chloroform) (Found: C, 76.88; H, 9.02. C29H40O4 requires
C, 76.95; H, 8.91%); 1H-NMR (400 MHz, CDCl3, Me4Si) ␦
ppm 0.70(m, 1H), 0.85(s, 3H, 19-H), 0.95(s, 3H, 18-H),
2.02(s, 3H, CH3CO), 2.51(m, 1H), 3.82(m, 1H) and 3.96(m,
1H): 16-CH2, 3.86(d, 1H, J ϭ 9.5 Hz, 17-H), 4.69(m, 1H,
3-H), 5.68(s, 1H, benzyl-H), 7.35(m, 3H, 3Ј-, 4Ј- and 5Ј-H)
and 7.48(d, 2H, J ϭ 7.4 Hz, 2Ј- and 6Ј-H).
1
quires C, 67.15; H, 8.16%); H-NMR (400 MHz, CDCl3,
Me4Si) ␦ ppm 0.66(m, 1H), 0.67(s, 3H, 18-H), 0.81(s, 3H,
19-H), 2.01(s, 3H, CH3CO), 2.45(s, 3H, Ts-CH3), 2.46(m,
1H), 3.73(d, 1H, J ϭ 10.0 Hz, 17-H), 4.02(m, 1H) and
4.24(m, 1H): 16-CH2, 4.67(m, 1H, 3-H), 7.34(d, 2H, J ϭ
8.1 Hz, 3Ј- and 5Ј-H) and 7.78(d, 2H, J ϭ 8.1 Hz, 2Ј- and
6Ј-H); 13C-NMR (100 MHz, CDCl3, Me4Si) ␦ ppm 12.4 and
12.6(2C, C-18 and C-19), 21.1(C-11), 21.8 and 22.0(2C,
CH3CO and Ts-CH3), 27.8, 28.7, 29.8, 32.1, 34.3, 35.1(C-
8), 35.9(C-10), 37.1, 37.8, 40.0(C-16), 44.2(C-13), 45.0(C-
5), 50.0(C-14), 54.6(C-9), 72.6(C-16a), 74.0(C-3), 81.8(C-
17), 128.3(2C, C-2Ј and C-6Ј), 130.2(2C, C-3Ј and C-5Ј),
133.6(C-1Ј), 145.1(C-4Ј) and 171.1(CH3CO). 4d (4.9 g;
94%); a non-crystallizing oil, Rf ϭ 0.50 (ss B); [␣]2D0 Ϫ10

626
P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
(c 1 in chloroform) (Found C, 67.42; H, 8.05. C29H42O6S
requires C, 67.15; H, 8.16%); 1H-NMR (400 MHz, CDCl3,
Me4Si) ␦ ppm 0.65(m, 1H), 0.74(s, 3H, 18-H), 0.81(s, 3H,
19-H), 2.01(s, 3H, CH3CO), 2.07(m, 1H), 2.44(s, 3H, Ts-
CH3), 3.30(d, 1H, J ϭ 7.4 Hz, 17-H), 4.07(m, 2H, 16-CH2),
4.67(m, 1H, 3-H), 7.34(d, 2H, J ϭ 8.4 Hz, 3Ј- and 5Ј-H) and
7.79(d, 2H, J ϭ 8.4 Hz, 2Ј- and 6Ј-H); 13C-NMR (100 MHz,
CDCl3, Me4Si) ␦ ppm 12.2 and 12.6(2C, C-18 and C-19),
21.0(C-11), 21.8 and 22.0(2C, CH3CO and Ts-CH3), 27.6,
27.8, 28.7, 31.8, 34.3, 35.5(C-8), 35.9(C-10), 36.9, 37.1,
43.6(C-16), 44.2(C-13), 45.1(C-5), 49.8(C-14), 54.6(C-9),
73.6(C-16a), 74.0(C-3), 84.0(C-17), 128.3(2C, C-2Ј and
C-6Ј), 130.3(2C, C-3Ј and C-5Ј), 134.9(C-1Ј), 145.2(C-4Ј)
and 171.3(CH3CO).
C-6Ј), 130.5(2C, C-3Ј and C-5Ј), 133.7(C-1Ј), 145.4(C-4Ј),
171.3 and 171.5 (2C, CH3CO).
2.10. 3␤-acetoxy-17␤-benzoyloxy-16␤-toluene-p-
sulfonyloxymethyl-5␣-androstane (3f) and 3␤-acetoxy-
17␤-benzoyloxy-16␣-toluene-p-sulfonyloxymethyl-5␣-
androstane (4f)
2.10.1. General procedure
Compound 3d or 4d (5.18 g, 0.01 mol) was dissolved in
pyridine (30 ml), and benzoyl chloride (2.8 g, 0.02 mol) was
added dropwise during cooling with ice. The reaction mix-
ture was stirred at 0°C for 6 h, and then diluted with water.
The oil which separated out was extracted with benzene
(3 ϫ 100 ml). The benzene solution was washed with
NaHCO3 solution and then with water, dried and evaporated
to dryness. The residual oil was chromatographed on silica
gel with a mixture of ethyl acetate/chloroform (1:99). The
product was crystallized from methanol. 3f (5.82 g; 93%),
mp 134–136°C, Rf ϭ 0.80 (ss B); [␣]2D0 ϩ3 (c 1 in chloro-
form) (Found C, 69.54; H, 7.35. C36H46O7S requires C, 69,
43; H, 7.44%); 1H-NMR (400 MHz, CDCl3, Me4Si) ␦ ppm
0.68(m, 1H), 0.83(s, 3H, 19-H), 0.89(s, 3H, 18-H), 2.01(s,
3H, CH3CO), 2.38(s, 3H, Ts-CH3), 2.70(m, 1H), 4.08(m,
2H, 16-CH2), 4.68(m, 1H, 3-H), 5.01(d, 1H, J ϭ 10.2 Hz,
17-H), 7.19(d, 2H, J ϭ 8.1 Hz, 3Ј- and 5Ј-H), 7.44(dd, 2H,
J ϭ 7.7 Hz, J ϭ 7.8 Hz, 3Љ- and 5Љ-H), 7.58(t, 1H, J ϭ 7.7
Hz, 4Љ-H), 7.63(d, 2H, J ϭ 8.1 Hz, 2Ј- and 6Ј-H) and 7.95(d,
2H, J ϭ 7.8 Hz, 2Љ- and 6Љ-H); 13C-NMR (100 MHz,
CDCl3, Me4Si) ␦ ppm 14.1 and 15.0(2C, C-18 and C-19),
22.5(C-11), 23.3 and 23.5(2C, CH3CO and Ts-CH3), 29.3,
30.2, 31.4, 33.5, 35.8, 36.5(C-8), 37.4(C-10), 38.6, 39.4,
40.1(C-16), 45.8(C-13), 46.5(C-5), 51.6(C-14), 55.9(C-9),
72.6(C-16a), 75.4(C-3), 84.0(C-17), 129.6(2C, C-2Ј and
C-6Ј), 130.3(2C, C-3Љ and C-5Љ), 131.4(2C, C-2Љ and C-6Љ),
131.5(2C, C-3Ј and C-5Ј), 131.8(C-1Љ), 134.7(C-1Ј), 134.9(C-
4Љ), 146.4(C-4Ј), 167.9(C6H5CO) and 172.5(CH3CO). 4f (5.75
g; 92%), mp 182–184°C, Rf ϭ 0.80 (ss B); [␣]2D0 Ϫ4 (c 1 in
chloroform) (Found C, 69.54; H, 7.30. C36H46O7S requires
C, 69.43; H, 7.44%); 1H-NMR (400 MHz, CDCl3, Me4Si) ␦
ppm 0.70(m, 1H), 0.82(s, 3H) and 0.89(s, 3ЈH): 18-H and
19-H, 2.02(s, 3H, CH3CO), 2.39(s, 3H, Ts-CH3), 2.45(m,
1H), 4.01(m, 1H) and 4.18(m, 1H): 16-CH2, 4.68(m, 1H,
3-H), 4.77(d, 1H, J ϭ 7.6 Hz, 17-H), 7.27(d, 2H, J ϭ 8.0
Hz, 3Ј- and 5Ј-H), 7.43(dd, 2H, J ϭ 7.6 Hz, J ϭ 7.8 Hz, 3Љ-
and 5Љ-H), 7.56(t, 1H, J ϭ 7.6 Hz, 4Љ-H), 7.75(d, 2H, J ϭ
8.0 Hz, 2Ј- and 6Ј-H) and 7.96(d, 2H, J ϭ 7.8 Hz, 2Љ- and
6Љ-H); 13C-NMR (100 MHz, CDCl3, Me4Si) ␦ ppm 12.9 and
13.5(2C, C-18 and C-19), 21.2(C-11), 22.1 and 22.3(2C,
CH3CO and Ts-CH3), 28.1, 28.5, 29.0, 32.0, 34.6, 35.7(C-
8), 36.2(C-10), 37.4, 37.5, 41.9(C-16), 45.0(C-13), 45.3(C-
5), 50.1(C-14), 54.6(C-9), 73.0(C-16a), 74.2(C-3), 84.1(C-
17), 128.6(2C, C-2Ј and C-6Ј), 129.0(2C, C-3Љ and C-5Љ),
130.2(2C, C-2Љ and C-6Љ), 130.5(2C, C-3Ј and C-5Ј), 131.1(C-
1Ј), 133.6(C-4Ј), 134.3(C-1Љ), 145.3(C-4Љ), 169.9(C6H5CO)
and 171.3(CH3CO).
2.9. 3␤,17␤-Diacetoxy-16␤-toluene-p-sulfonyloxymethyl-
5␣-androstane (3e) and 3␤,17␤-diacetoxy-16␣-toluene-p-
sulfonyloxymethyl-5␣-androstane (4e)
2.9.1. General procedure
Compound 3d or 4d (5.18 g, 0.01 mol) was dissolved in
a mixture of pyridine (10 ml) and acetic anhydride (10 ml)
and the solution was allowed to stand at room temperature
for 12 h. The mixture was then diluted with water and the
precipitate that separated was filtered and recrystallized
from methanol. 3e (5.45 g; 97%), mp 129–131°C, Rf ϭ
0.75 (ss B); [␣]2D0 ϩ2 (c 1 in chloroform) (Found C, 66.52;
H, 8.02. C31H44O7S requires C, 66.40; H, 7.91%); 1H-NMR
(400 MHz, CDCl3, Me4Si) ␦ ppm 0.63(m, 1H), 0.74(s, 3H,
18-H), 0.81(s, 3H, 19-H), 2.01(s, 6H, 3- and 17-CH3CO),
2.45(s, 3H, Ts-CH3), 2.54(m, 1H), 3.93(m, 1H) and 4.07(m,
1H): 16-CH2, 4.67(m, 1H, 3-H), 4.77(d, 1H, J ϭ 10.2 Hz,
17-H), 7.34(d, 2H, J ϭ 8.2 Hz, 3Ј- and 5Ј-H) and 7.77(d,
2H, J ϭ 8.2 Hz, 2Ј- and 6Ј-H); 13C-NMR (100 MHz,
CDCl3, Me4Si) ␦ ppm 12.6 and 13.3(2C, C-18 and C-19),
20.9(C-11), 21.2 and 21.8 and 22.0(3C, CH3CO and Ts-
CH3), 27.8, 28.7, 29.6, 31.9, 34.3, 35.0(C-8), 35.9(C-10),
37.0, 37.7, 38.1(C-16), 43.8(C-13), 45.0(C-5), 50.0(C-14),
54.4(C-9), 71.2(C-16a), 73.9(C-3), 81.7(C-17), 128.2(2C,
C-2Ј and C-6Ј), 130.2(2C, C-3Ј and C-5Ј), 134.1(C-1Ј),
145.1(C-4Ј), 170.0 and 171.2(2C, CH3CO). 4e (5.30 g;
94%), mp 161–163°C, Rf ϭ 0.75 (ss B); [␣]2D0 Ϫ25 (c 1 in
chloroform) (Found C, 66.33; H, 7.85. C31H44O7S requires
C, 66.40; H, 7.91%); 1H-NMR (400 MHz, CDCl3, Me4Si) ␦
ppm 0.65(m, 1H), 0.76(s, 3H) and 0.80(s, 3H): 18-H and
19-H, 2.00(s, 3H) and 2.01(s, 3H): 3- and 17-CH3CO,
2.30(m, 1H), 2.45(s, 3H, Ts-CH3), 3.93(m, 1H) and 4.07(m,
1H): 16-CH2, 4.48(d, 1H, J ϭ 7.7 Hz, 17-H), 4.67(m, 1H,
3-H), 7.34(d, 2H, J ϭ 8.2 Hz, 3Ј- and 5Ј-H) and 7.78(d, 2H,
J ϭ 8.2 Hz, 2Ј- and 6Ј-H); 13C-NMR (100 MHz, CDCl3,
Me4Si) ␦ ppm 12.8 and 13.3(2C, C-18 and C-19), 21.2(C-
11), 21.7, 22.1 and 22.3(3C, CH3CO and Ts-CH3), 28.1,
28.3, 29.0, 32.0, 34.6, 35.7(C-8), 36.2(C-10), 37.3, 37.4,
41.6(C-16), 44.6(C-13), 45.3(C-5), 50.0(C-14), 54.6(C-9),
73.1(C-16a), 74.2(C-3), 83.7(C-17), 128.6(2C, C-2Ј and

P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
627
2.11. 3␤-Acetoxy-16␣-acetoxymethyl-5␣-androstan-17␤-ol
(4g)
was stirred at 0°C for 12 h, and was then poured into ice
water. The precipitate was filtered off, dissolved in chloro-
form and chromatographed on silica gel with a mixture of
ethyl acetate/chloroform (5:95) to obtain 4i (3.85 g, 82%),
mp 133–135°C, Rf ϭ 0.35 (ss B); [␣]2D0 Ϫ19 (c 1 in chlo-
roform) (Found C, 74.52; H, 8.75. C29H40O5 requires C,
Compound 4b (3.64 g, 0.01 mol) was dissolved in pyridine
(40 ml), and acetic anhydride (1.2 g, 0.012 mol) dissolved in
pyridine (10 ml) was added dropwise during cooling in ice.
The reaction mixture was stirred at 0°C for 6 h, and was then
poured into ice water. The precipitate was filtered, dissolved in
ethyl acetate and chromatographed on silica gel with a mixture
of ethyl acetate/light petroleum (30:70) to obtain 4g (2.84 g,
69%), mp 137–140°C, Rf ϭ 0.25 (ss B); [␣]2D0 Ϫ23 (c 1 in
chloroform) (Found C, 70.78; H, 9.35. C24H38O5 requires C,
70.90; H, 9.42%); 1H-NMR (400 MHz, CDCl3, Me4Si) ␦ ppm
0.65(m, 1H), 0.76(s, 3H) and 0.80(s, 3H): 18-H and 19-H,
1.99(s, 3H) and 2.04(s, 3H): 3- and 16-CH3CO, 2.07(m, 1H),
3.33(d, 1H, J ϭ 7.9 Hz, 17-H), 4.08(m, 2H, 16-CH2), 4.68(m,
1H, 3-H); 13C-NMR (100 MHz, CDCl3, Me4Si) ␦ ppm 11.8
and 12.1(2C, C-18 and C-19), 20.5(C-11), 20.9 and 21.3(2C,
CH3CO), 27.3, 27.5, 28.2, 31.3, 33.8, 35.1(C-8), 35.4(C-10),
36.5, 36.6, 42.6(C-16), 43.7(C-13), 44.5(C-5), 49.4(C-14),
54.2(C-9), 67.5(C-16a), 73.5(C-3), 84.3(C-17), 170.6 and
171.2(2C, CH3CO).
1
74:33; H, 8.60%); H-NMR (400 MHz, CDCl3, Me4Si) ␦
0.69(m, 1H), 0.82(s, 3H) and 0.84(s, 3H): 18-H and 19-H,
2.01(s, 3H, CH3CO), 2.26(m, 1H), 3.47(dd, 1H, J ϭ 7.6 Hz,
J ϭ 5.5 Hz, 17-H), 4.37(m, 2H, 16-CH2), 4.68(m, 1H, 3-H),
7.44(dd, 2H, J ϭ 7.5 Hz, J ϭ 7.8 Hz, 3Ј- and 5Ј-H), 7.57(t,
1H, J ϭ 7.5 Hz, 4Ј-H) and 8.03(d, 2H, J ϭ 7.8 Hz, 2Ј- and
6Ј-H); 13C-NMR (100 MHz, CDCl3, Me4Si) ␦ ppm 12.6 and
12.9(2C, C-18 and C-19), 21.3(C-11), 22.2(CH3CO), 28.1,
28.3, 29.0, 32.0, 34.6, 35.9(C-8), 36.3(C-10), 37.4(2C),
43.7(C-16), 44.6(C-13), 45.4(C-5), 50.4(C-14), 55.0(C-9),
68.7(C-16a), 74.3(C-3), 85.4(C-17), 129.1(2C, C-3Ј and
C-5Ј), 130.2(2C, C-2Ј and C-6Ј), 131.0(C-1Ј), 133.7(C-4Ј),
167.4(C6H5CO) and 171.4(CH3CO).
2.14. 3␤-Acetoxy-16␣-benzoyloxymethyl-17␤-toluene-p-
sulfonyloxy-5␣-androstane (4j)
2.12. 3␤-Acetoxy-16␣-acetoxymethyl-17␤-toluene-p-
sulfonyloxy-5␣-androstane (4h)
Compound 4i (2.34 g, 0.005 mol) was dissolved in pyri-
dine (20 ml), and a solution of toluene-p-sulfonyl chloride
(1.05 g, 0.0055 mol) dissolved in pyridine (5 ml) was added
during cooling in ice. The reaction mixture was allowed to
stand at room temperature for 24 h, and was then saturated
with water. The precipitate was filtered, washed and dried.
The product was crystallized from methanol to obtain 4j
(2.8 g, 90%), mp 163–165°C, Rf ϭ 0.78 (ss B); [␣]2D0 Ϫ44
(c 1 in chloroform) (Found C, 69.55; H, 7.37. C36H46O7S
requires C, 69.43; H, 7.44%); 1H-NMR (400 MHz, CDCl3,
Me4Si) ␦ ppm 0.65(m, 1H), 0.81(s, 3H) and 0.88(s, 3H):
18-H and 19-H, 2.01(s, 3H, CH3CO), 2.37(s, 3H, Ts-CH3),
2.46(m, 1H), 3.86(m, 1H) and 4.20(m, 1H): 16-CH2, 4.32(d,
1H, J ϭ 7.6 Hz, 17-H), 4.66(m, 1H, 3-H), 7.22(d, 2H, J ϭ
8.0 Hz, 3Љ- and 5Љ-H), 7.47(dd, 2H, J ϭ 7.5 Hz, J ϭ 7.8 Hz,
3Ј- and 5Ј-H), 7.59(t, 1H, J ϭ 7.5 Hz, 4Ј-H), 7.75(d, 2H,
J ϭ 8.0 Hz, 2Љ- and 6Љ-H) and 7.97(d, 2H, J ϭ 7.8 Hz, 2Ј-
and 6Ј-H); 13C-NMR (100 MHz, CDCl3, Me4Si) ␦ ppm 12.9
and 13.2(2C, C-18 and C-19), 21.1(C-11), 22.1 and
22.3(2C, CH3CO and Ts-CH3), 28.1, 28.4, 28.9, 32.1, 34.6,
35.8(C-8), 36.2(C-10), 37.2, 37.4, 41.4(C-16), 44.7(C-13),
45.3(C-5), 50.3(C-14), 54.7(C-9), 66.1(C-16a), 74.2(C-3),
91.5(C-17), 128.5(2C, C-2Љ and C-6Љ), 129.1(2C, C-3Љ and
C-5Љ), 130.2(2C, C-2Ј and C-6Ј), 130.4(2C, C-3Ј and C-5Ј),
131.1(C-1Ј), 133.7(C-4Ј), 134.3(C-1Љ), 145.5(C-4Љ),
167.5(C6H5CO) and 171.3(CH3CO).
Compound 4g (4.06 g, 0.01 mol) was dissolved in pyri-
dine (30 ml), and a solution of toluene-p-sulfonyl chloride
(2.1 g, 0.011 mol) dissolved in pyridine (10 ml) was added
during cooling in ice. The reaction mixture was allowed to
stand at room temperature for 24 h, and was then saturated
with water. The precipitate was filtered, washed and dried.
The product was crystallized from methanol to obtain 4h
(5.25 g, 93%), mp 135–136°C, Rf ϭ 0.66 (ss B); [␣]2D0 Ϫ34
(c 1 in chloroform) (Found C, 66.58; H, 7.80. C31H44O7S
requires C, 66.40; H, 7.91%); 1H-NMR (400 MHz, CDCl3,
Me4Si) ␦ ppm 0.60(m, 1H), 0.77(s, 3H) and 0.79(s, 3H):
18-H and 19-H, 1.99(s, 3H) and 2.01(s, 3H): 3- and 16-
CH3CO, 2.33(m, 1H), 2.42(s, 3H, Ts-CH3), 3.71(m, 1H)
and 3.97(m, 1H): 16-CH2, 4.22(d, 1H, J ϭ 7.5 Hz, 17-H),
4.65(m, 1H, 3-H), 7.30(d, 2H, J ϭ 8.1 Hz, 3Ј- and 5Ј-H) and
7.76(d, 2H, J ϭ 8.1 Hz, 2Ј- and 6Ј-H); 13C-NMR (100 MHz,
CDCl3, Me4Si) ␦ ppm 12.2 and 12.5(2C, C-18 and C-19),
20.5(C-11), 20.9 and 21.4 and 21.6(3C, CH3CO and Ts-
CH3), 27.4, 27.6, 28.2, 31.3, 33.9, 35.1(C-8), 35.5, 36.3(C-
10), 36.7, 40.5(C-16), 44.0(C-13), 44.6(C-5), 49.2(C-14),
53.9(C-9), 65.3(C-16a), 73.5(C-3), 91.1(C-17), 127.4(2C,
C-2Ј and C-6Ј), 129.7(2C, C-3Ј and C-5Ј), 134.3(C-1Ј),
144.7(C-4Ј), 170.6 and 170.9(2C, CH3CO).
2.13. 3␤-Acetoxy-16␣-benzoyloxymethyl-5␣-androstan-
17␤-ol (4i)
2.15. Acetolysis of 3e, 3f, 3g, 4e or 4f in anhydrous
acetic acid
Compound 4b (3.64 g, 0.01 mol) was dissolved in pyri-
dine (50 ml), and benzoyl chloride (1.6 g, 0.011 mol) was
added dropwise during cooling in ice. The reaction mixture
2.15.1. General procedure
Anhydrous acetic acid (100 ml) was refluxed with acetic
anhydride (1 ml, 10 mmol) for 1 h. In the acetic acid

628
P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
prepared in this way, the starting materials 3e, 3f, 3g, 4e or
4f (10 mmol) was refluxed in the presence of AgOAc (1.92
g 12 mmol) for 18 h. The course of the reaction was
monitored by TLC (Kieselgel G, solvent: 30% tert-butyl
methyl ether/light petroleum 30:70). The reaction mixture
was poured onto ice (1000 g), the precipitate was filtered off
and washed until free from acid. The aqueous acetic acid
fraction was extracted with dichloromethane (4 ϫ 150 ml);
the dichloromethane fraction was then washed with water
and dilute NaHCO3 solution and combined with the precip-
itate. The substance obtained on drying and evaporation of
the solution to dryness was subjected to chromatographic
separation
36.2(C-10), 37.4, 45.1(C-13), 45.3(C-5), 46.2(C-16),
51.6(C-14), 54.4(C-9), 67.3(C-16a), 74.3(C-3), 84.2(C-17),
171.1, 171.4 and 171.8(3C, CH3CO). Continued elution
resulted in 3c (233 mg, 52%) mp 110–112°C, Rf ϭ 0.64 (ss
B); [␣]2D0 Ϫ6 (c 1 in chloroform) (Found: C, 69.48; H, 9.15.
C26H40O6 requires C, 69.61; H, 8.99%); 1H-NMR (400
MHz, CDCl3, Me4Si) ␦ ppm 0.68(m, 1H), 0.81(s, 3H) and
0.83(s, 3H): 18-H and 19-H, 2.01(s, 3H) and 2.02(s, 3H) and
2.05(s, 3H): 3-, 16- and 17-CH3CO, 2.61(m, 1H), 3.98(m,
1H) and 4.08(m, 1H): 16-CH2, 4.68(m, 1H, 3-H) and
4.79(d, 1H, J ϭ 10.1 Hz, 17-H); 13C-NMR (100 MHz,
CDCl3, Me4Si) ␦ ppm 12.9 and 13.6(2C, C-18 and C-19),
21.2(C-11), 21.6 and 22.1(3C, CH3CO), 28.1, 29.0, 30.2,
32.3, 34.6, 35.4(C-8), 36.2(C-10), 37.4, 38.1, 38.2(C-16),
44.0(C-13), 45.3(C-5), 50.3(C-14), 54.7(C-9), 66.0(C-16a),
74.2(C-3), 82.4(C-17), 171.3, 171.5 and 171.6(3C,
CH3CO).
2.16. Acetolysis of 3e in anhydrous acetic acid
Compound 3e (560 mg, 10 mmol) was subjected to
treatment in anhydrous acetic acid as described in the gen-
eral procedure. The resulting crude product was chromato-
graphed on silica gel with tert-butyl methyl ether/light pe-
troleum (10:90), yielding pure 10b (70 mg, 18%) as a white
solid, mp 102–105°C, Rf ϭ 0.80 (ss D); [␣]2D0 Ϫ66 (c 1 in
chloroform) (Found: C, 74.02; H, 9.45. C24H36O4 requires
C, 74.19; H, 9.34%); 1H-NMR (400 MHz, CDCl3, Me4Si) ␦
ppm 0.74(s, 3H, 19-H), 1.56(s, 3H, 17-CH3), 2.02(s, 3H)
and 2.05(s, 3H): 3- and 16-CH3CO, 2.22(m, 1H), 2.51(m,
1H), 2.77(m, 1H), 3.94(m, 1H) and 4.18(m, 1H): 16-CH2,
4.69(m, 1H, 3-H); 13C-NMR (100 MHz, CDCl3, Me4Si) ␦
ppm 12.2 and 12.6(2C, 17-CH3 and C-19), 21.4 and
21.9(2C, 3- and 16-CH3CO), 26.1, 26.2, 27.8, 28.7, 32.7,
33.2, 34.4, 36.0(C-10), 37.3, 44.7, 45.9, 48.0, 52.5, 52.7,
68.3(C-16a), 74.1(C-3), 127.2(C-17), 139.5(C-13), 171.1
and 171.7(2C, 3- and 16-CH3CO); Continued elution re-
sulted in 9b (30 mg, 8%), mp 139–141°C, Rf ϭ 0.75 (ss D);
[␣]2D0 Ϫ68 (c 1 in chloroform) (Found C, 74.30; H, 9.25.
C24H36O4 requires C, 74.19; H, 9.34%); 1H-NMR (100
MHz, CDCl3, Me4Si) ␦ ppm 0.73(s, 3H, 18-H), 0.74(m,
1H), 0.82(s, 3H, 19-H), 2.01(s, 3H, 3-CH3CO), 2.12(s, 3H,
17-CH3CO), 2.36(m, 1H), 4.68(m, 1H, 3-H), 4.89(s, 1H)
and 5.00(s, 1H): 16-CH2, 5.15(s, 1H, 17-H), 13C-NMR (100
MHz, CDCl3, Me4Si) ␦ ppm 12.5 and 12.6(2C, C-18 and
C-19), 21.1(C-11), 21.8(2C, CH3CO), 27.8, 28.8, 31.3,
31.9, 34.4, 35.2(C-8), 36.0(C-10), 36.9, 37.0, 43.4(C-13),
45.0(C-5), 48.6(C-14), 54.5(C-9), 74.0(C-3), 84.2(C-17),
108.9(C-16a), 148.4(C-16) and 171.4(2C, CH3CO). Contin-
ued elution with tert-butyl methyl ether/light petroleum
(30:70) yielded 5b (98 mg, 22%), mp 125–126°C, Rf ϭ
0.70 (ss B); [␣]2D0 ϩ7 (c 1 in chloroform) (Found: C, 69.50;
2.17. Acetolysis of 3f and 3g in anhydrous acetic acid
Compounds 3f (622 mg, 10 mmol) or 3g (531 mg, 10
mmol) was subjected to treatment in anhydrous acetic acid
as described in the general procedure. The resulting crude
product was chromatographed on silica gel with tert-butyl
methyl ether/light petroleum (10:90). The substance that
eluted first formed a critical isomer pair 9c, 10c (63 mg,
14%), which did not separate from one another. Continued
elution with tert-butyl methyl ether/light petroleum (30:70)
resulted in 5c (189 mg, 37%) mp 151–152°C, Rf ϭ 0.70 (ss
B); [␣]2D0 ϩ9 (c 1 in chloroform) (Found: C 72.77; H, 8.35.
C31H42O6 requires C, 72.91; H, 8.29%); 1H-NMR (400
MHz, CDCl3, Me4Si) ␦ ppm 0.70(m, 1H), 0.83(s, 3H) and
0.86(s, 3H): 18-H and 19-H, 2.02(s, 3H) and 2.05(s, 3H): 3-
and 17-CH3CO, 2.33(m, 1H), 4.42(m, 2H, 16-CH2),
4.68(m, 1H, 3-H), 4.77(d, 1H, J ϭ 2.2 Hz, 17-H), 7.44(dd,
2H, J ϭ 7.5 Hz, J ϭ 7.8 Hz, 3Ј- and 5Ј-H), 7.57(t, 1H, J ϭ
7.5 Hz, 4Ј-H) and 8.03(d, 2H, J ϭ 7.8 Hz, 2Ј- and 6Ј-H);
13C-NMR (100 MHz, CDCl3, Me4Si) ␦ ppm 12.9(C-19),
18.0(C-18), 21.1(C-11), 21.8 and 22.1(2C, CH3CO), 28.1,
29.1, 30.3, 32.8, 32.9, 34.6, 35.8(C-8), 36.2(C-10), 37.4,
45.1(C-13), 45.3(C-5), 46.4(C-16), 51.7(C-14), 54.5(C-9),
67.9(C-16a), 74.3(C-3), 84.3(C-17), 129.0(2C, C-3Ј and
C-5Ј), 130.3(2C, C-2Ј and C-6Ј), 130.9(C-1Ј), 133.6(C-4Ј),
167.4(C6H5CO), 171.1 and 171.4(CH3CO). Continued elu-
tion resulted in 3h (250 mg, 49%) mp 191–193°C, Rf ϭ
0.65 (ss B); [␣]2D0 ϩ28 (c 1 in chloroform) (Found: C, 72.85;
1
H, 8.20. C31H42O6 requires C, 72.91; H, 8.29%); H-NMR
(400 MHz, CDCl3, Me4Si) ␦ ppm 0.72(m, 1H), 0.82(s, 3H,
19-H), 0.96(s, 3H, 18-H), 1.72(s, 3H, 16-CH3CO), 2.02(s,
3H, 3-CH3CO), 2.74(m, 1H), 4.11(m, 2H, 16-CH2), 4.69(m,
1H, 3-H), 5.09(d, 1H, J ϭ 10.2 Hz, 17-H), 7.44(dd, 2H, J ϭ
7.5 Hz, 3Ј- and 5Ј-H), 7.56(t, 1H, J ϭ 7.5, 4Ј-H) and 8.03(d,
2H, J ϭ 7.5 Hz, 2Ј- and 6Ј-H); 13C-NMR (100 MHz,
CDCl3, Me4Si) ␦ ppm 12.2 and 13.2(2C, C-18 and C-19),
20.5(C-11), 20.6 and 21.4(2C, CH3CO), 27.4, 28.3, 29.4,
31.6, 33.9, 34.7(C-8), 35.6, 36.7, 37.5, 37.7(C-16), 43.7(C-
1
H, 9.05. C26H40O6 requires C, 69.61; H, 8.99%); H-NMR
(400 MHz, CDCl3, Me4Si) ␦ ppm 0.69(m, 1H), 0.81(s, 3H)
and 0.82(s, 3H): 18-H and 19-H, 2.02(s, 3H) and 2.04(s,
6H): 3-, 16- and 17-CH3CO, 2.19(m, 1H), 4.15(m, 2H,
16-CH2), 4.64(d, 1H, J ϭ 2.1 Hz, 17-H) and 4.68(m, 1H,
3-H); 13C-NMR (100 MHz, CDCl3, Me4Si) ␦ ppm 12.9(C-
19), 17.8(C-18), 21.1(C-11), 21.6 and 21.8 and 22.1(3C,
CH3CO), 28.1, 29.1, 30.2, 32.8(2C), 34.6, 35.8(C-8),

P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
629
13), 44.6(C-5), 49.6(C-14), 54.1(C-9), 65.4(C-16a), 73.5(C-
3), 81.9(C-17), 128.4(2C, C-3Ј and C-5Ј), 129.5(2C, C-2Ј
and C-6Ј), 130.3(C-1Ј), 133.0(C-4Ј), 166.2(C6H5CO), 170.6
and 171.0(2C, CH3CO).
pure 9a (28 mg, 92%) mp 179–181°C, Rf ϭ 0.50 (ss C);
[␣]2D0 Ϫ85 (c 1 in chloroform) (Found C, 78.73; H, 10.65.
C20H32O2 requires C, 78.90; H, 10.59%).
The white oily mixture of 9c and 10c (63 mg) obtained
in the chromatographic separation procedure was dissolved
in methanol (3 cm3). The reaction mixture was allowed to
stand overnight. Compound 9c separated out in the form of
fine crystals, while 10c remained in solution. 9c (36 mg,
8%) mp 190–192°C, Rf ϭ 0.55 (ss D); [␣]2D0 Ϫ66 (c 1 in
chloroform) (Found: C, 77.21; H, 8.42. C29H38O4 requires
C, 77.30; H, 8.50%); 1H-NMR (400 MHz, CDCl3, Me4Si) ␦
ppm 0.75(m, 1H), 0.84(s, 3H) and 0.86(s, 3H): 18-H and
19-H, 2.02(s, 3H, 3-CH3CO), 2.40(m, 1H), 4.69(m, 1H,
3-H), 4.98(s, 1H) and 5.04 (s, 1H): 16-CH2, 5.42(s, 1H,
17-H), 7.46(dd, 2H, J ϭ 7.5 Hz, 3Ј- and 5Ј-H), 7.56(t, 1H,
J ϭ 7.5 Hz, 4Ј-H) and 8.01(d, 2H, J ϭ 7.5 Hz, 2Ј- and
6Ј-H); 13C-NMR (100 MHz, CDCl3, Me4Si) ␦ ppm 12.2 and
12.3(2C, C-18 and C-19), 20.7(C-11), 21.4(CH3CO), 27.4,
28.4, 31.1, 31.5, 34.0, 34.9(C-8), 35.6(C-10), 36.6, 36.7,
43.4(C-13), 44.6(C-5), 48.3(C-14), 54.2(C-9), 73.6(C-3),
84.2(C-17), 108.9(C-16a), 128.4(2C, C-3Ј and C-5Ј),
129.7(2C, C-2Ј and C-6Ј), 130.4(C-1Ј), 132.9(C-4Ј),
147.9(C-16), 166.4(C6H5CO) and 170.6(CH3CO).
2.20. Acetolysis of 4e in anhydrous acetic acid
Compound 4e (560 mg, 10 mmol) was subjected to
treatment in anhydrous acetic acid as described in the gen-
eral procedure. The substance obtained was crystallized
from methanol; 4c (440 mg, 98%) mp 119–121°C, Rf ϭ
0.62 (ss B); [␣]2D0 Ϫ35 (c 1 in chloroform) (Found: C, 69.52;
1
H, 9.5. C26H40O6 requires C, 69.61; H, 8.99%); H-NMR
(400 MHz, CDCl3, Me4Si) ␦ ppm 0.68(m, 1H), 0.81(s, 3H)
and 0.83(s, 3H): 18-H and 19-H, 2.01(s, 3H) and 2.02(s, 3H)
and 2.05(s, 3H): 3-, 16- and 17-CH3CO, 2.61(m, 1H),
3.98(m, 1H) and 4.08(m, 1H): 16-CH2, 4.68(m, 1H, 3-H)
and 4.79(d, 1H, J ϭ 10.1 Hz, 17-H); 13C-NMR (100 MHz,
CDCl3, Me4Si) ␦ ppm 12.9 and 13.6(2C, C-18 and C-19),
21.2(C-11), 21.6 and 22.1(3C, CH3CO), 28.1, 29.0, 30.2,
32.3, 34.6, 35.4(C-8), 36.2(C-10), 37.4, 38.1, 38.2(C-16),
44.0(C-13), 45.3(C-5), 50.3(C-14), 54.7(C-9), 66.0(C-16a),
74.2(C-3), 82.4(C-17), 171.3 and 171.5 and 171.6(3C,
CH3CO).
To a methanol solution of 10c (27 mg, 6%) was added
methanol (1 ml) containing NaOCH3 (5 mg, 0.092
mmol). The reaction mixture was allowed to stand for
24 h, and was then diluted with water. The precipitate
was filtered, washed and dried; 10a (20 mg) mp 163–
165°C, Rf ϭ 0.50 (ss C); [␣]2D0 Ϫ92 (c 1 in chloroform)
(Found: C, 78.82; H, 10.67. C20H32O2 requires C, 78.90;
H, 10.59%). Compound 10a (20 mg, 0.033 mmol) was
dissolved in a mixture of pyridine (0.1 ml) and acetic
anhydride (1 ml), and the solution was allowed to stand
for 12 h, and was then diluted with water. The white solid
compound (16 mg) was identical with 10b that separated
out after the acetolysis of 3g.
2.21. Acetolysis of 4f in anhydrous acetic acid
Compound 4f (622 mg, 10 mmol) was subjected to
treatment in anhydrous acetic acid as described in the gen-
eral procedure. The resulting product was crystallized from
methanol, 4k (498 mg, 97%) mp 111–113°C, Rf ϭ 0.65 (ss
B); [␣]2D0 Ϫ9 (c 1 in chloroform) (Found: C, 73.02; H, 8.20.
C31H42O6 requires C, 72.91; H, 8.29%); 1H-NMR (400
MHz, CDCl3, Me4Si) ␦ ppm 0.70(m, 1H), 0.83(s, 3H, 19-
H), 0.93(s, 3H, 18-H), 1.91(s, 3H, 16-CH3CO), 2.02(s, 3H,
3-CH3CO), 2.51(m, 1H), 4.12(d, 2H, J ϭ 6.7 Hz, 16-CH2),
4.69(m, 1H, 3-H), 4.91(d, 1H, J ϭ 7.6 Hz, 17-H), 7.44(dd,
2H, J ϭ 7.5 Hz, J ϭ 7.8 Hz, 3Ј- and 5Ј-H), 7.56(t, 1H, J ϭ
7.5 Hz, 4Ј-H) and 8.04(d, 2H, J ϭ 7.8 Hz, 2Ј- and 6Ј-H);
13C-NMR (100 MHz, CDCl3, Me4Si) ␦ ppm 12.9 and
13.6(2C, C-18 and C-19), 21.2(C-11), 21.5 and 22.1(2C,
CH3CO), 28.1, 28.4, 29.0, 32.1, 34.6, 35.8(C-8), 36.2(C-
10), 37.4, 37.6, 41.0(C-16), 45.2(C-13), 45.3(C-5), 50.4(C-
14), 54.8(C-9), 67.6(C-16a), 74.3(C-3), 85.3(C-17),
129.0(2C, C-3Ј and C-5Ј), 130.2(2C, C-2Ј and C-6Ј),
131.1(C-1Ј), 133.6(C-4Ј), 166.9(C6H5CO), 171.3 and
171.8(2C, CH3CO).
2.18. 16␤-Hydroxymethyl-5␣-androstane-3␤,17␣-diol (5a)
Compound 5b (90 mg, 0.2 mmol) was dissolved in
methanol (10 ml) containing NaOCH3 (5 mg, 0.092 mmol)
and the solution was allowed to stand for 24 h. It was diluted
with water, and the white precipitate that separated was
filtered and recrystallized from a mixture of ethanol/water;
5a (58 mg, 90%) mp 299–301°C, Rf ϭ 0.15 (ss A); [␣]D20
Ϫ61 (c 1 in acetic acid) (Found C, 74.37; H, 10.55.
C20H34O3 requires C, 74.49; H, 10.63%).
2.22. Acetolysis of 4h and 4j in aqueous acetic acid
2.19. 16-Methylene-5␣-androstane-3␤,17␤-diol (9)
2.22.1. General procedure
AgOAc (1.92 g, 12 mmol) was dissolved in a mixture of
acetic acid (95 ml) and water (5 ml); 4h or 4j (10 mmol)
was added to the solution and the mixture was refluxed for
96 h. It was then poured onto ice (1000 g), and the precip-
itate was filtered and washed until free from acid. The
aqueous acetic acid fraction was extracted with dichlo-
Compound 9b (39 mg, 0.1 mmol) was dissolved in
methanol (5 ml) containing NaOCH3 (5 mg, 0.092 mmol)
and the solution was allowed to stand for 24 h. It was then
diluted with water. The fine precipitate was filtered and
recrystallized from chloroform/light petroleum to obtain

630
P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
romethane (4 ϫ 150 ml); the dichloromethane fraction was
then washed with water and dilute NaHCO3 solution and
combined with the precipitate. The substance obtained on
drying and evaporation of the solution to dryness was sub-
jected to chromatographic separation
anhydride (1 ml) and pyridine (1 ml). The reaction mixture
was allowed to stand overnight. After saturation with water,
the precipitate was filtered, washed with water, dried and
crystallized from methanol. The diacetate 15b (52 mg) mp
77–78°C, Rf ϭ 0.50 (ss D); [␣]2D0 Ϫ29 (c 1 in chloroform)
(Found C, 74.25; H, 9.22. C24H36O4 requires C, 74.19; H,
9.34%); 1H-NMR (400 MHz, CDCl3, Me4Si) ␦ ppm 0.80(s,
3H, 19-H), 1.00(d, 3H, J ϭ 6.9 Hz, 17-CH3), 2.03(s, 3H)
and 2.05(s, 3H): 3- and 16-CH3CO, 2.31(m, 2H), 4.04(m,
2H, 16-CH2) and 4.70(m, 1H, 3-H); 13C-NMR (100 MHz,
CDCl3, Me4Si) ␦ ppm 11.7(C-19), 18.9(17-CH3), 20.9 and
21.4(2C, 3- and 16-CH3CO), 22.6, 24.2, 27.3, 28.8, 31.1,
34.5, 35.2, 35.4(C-10), 36.3, 36.4, 44.5, 44.6, 44.9, 51.7(C-
9), 68.0(C-16a), 73.6(C-3), 136.0 and 136.8(2C, C-13 and
C-14), 170.5 and 171.2(2C, 3- and 16-CH3CO). The diac-
etate 16b (15 mg) mp 89–90°C, Rf ϭ 0.50 (ss D); [␣]D20
Ϫ20 (c 1 in chloroform) (Found C, 74.31; H, 9.38%).
C24H36O4 requires C, 74.19; H, 9.34%); 1H-NMR (400
MHz, CDCl3, Me4Si) ␦ ppm 0.74(s, 3H, 19-H), 1.60(s, 3H,
17-CH3), 2.02(s, 3H) and 2.04(s, 3H): 3- and 16-CH3CO,
2.51(m, 1H), 2.72(m, 1H), 3.88(m, 1H) and 4.03(m, 1H):
16-CH2, 4.70(m, 1H, 3-H); 13C-NMR (100 MHz, CDCl3,
Me4Si) ␦ ppm 12.1 and 12.2(2C, 17-CH3 and C-19), 21.0
and 21.4(2C, 3- and 16-CH3CO), 25.6, 25.7, 27.4, 28.3,
32.2, 33.2, 34.0, 35.6(C-10), 36.9, 44.2, 45.4, 48.3, 51.8,
52.1, 66.9(C-16a), 73.7(C-3), 126.9(C-17), 139.4(C-13),
170.6 and 171.3(2C, 3- and 16-CH3CO).
2.23. Acetolysis of 4h in aqueous acetic acid
Compound 4h (560 mg, 10 mmol) was subjected to
treatment in aqueous acetic acid as described in the general
procedure. The resulting crude product was chromato-
graphed on silica gel with tert-butyl methyl ether/light pe-
troleum (10:90), yielding a mixture of Wagner-Meerwein
rearrangement products 15b and 16b (78 mg, 20%). Con-
tinued elution yielded 11b (47 mg, 12%) mp 89–91°C, Rf ϭ
0.55 (ss D); [␣]2D0 Ϫ24 (c 1 in chloroform) (Found: C, 74.25;
1
H, 9.23. C24H36O4 requires C, 74.19; H, 9.34%); H-NMR
(400 MHz, CDCl3, Me4Si) ␦ ppm 0.76(m, 1H), 0.77(s, 3H)
and 0.85(s, 3H): 18-H and 19-H, 2.02(s, 3H) and 2.07(s,
3H): 3- and 16-CH3CO, 4.58(s, 2H, 16-CH2), 4.68(m, 1H,
3-H) and 5.75(s, 1H, 17-H); 13C-NMR (100 MHz, CDCl3,
Me4Si) ␦ ppm 12.9(C-19), 17.6(C-18), 21.6 and 22.1(2C,
CH3CO), 21.7(C-11), 28.1, 29.2, 32.6, 33.3, 34.7, 34.8(C-
8), 36.3, 36.4(C-10), 37.2, 45.6(C-5), 46.5(C-13), 55.6,
56.8, 64.5(C-16a), 74.3(C-3), 138.7(C-16), 141.4(C-17),
171.4 and 171.6(2C, CH3CO). Continued elution with tert-
butyl ether/light petroleum (30:70) resulted in 6b (305 mg,
68%) mp 108–110°C, Rf ϭ 0.72 (ss B); [␣]2D0 ϩ15 (c 1 in
chloroform) (Found C, 69.53; H, 9.10. C26H40O6 requires
C, 69.61, H, 8.99%); 1H-NMR (400 MHz, CDCl3, Me4Si) ␦
ppm 0.68(m, 1H), 0.81(s, 3H) and 0.82(s, 3H): 18-H and
19-H, 2.00(s, 3H), 2.02(s, 3H) and 2.05(s, 3H): 3-, 16- and
17-CH3CO, 2.72(m, 1H), 4.03(m, 2H, 16-CH2), 4.68(m,
1H, 3-H), 5.02(d, 1H, J ϭ 5.8 Hz, 17-H); 13C-NMR (100
MHz, CDCl3, Me4Si) ␦ ppm 12.9(C-19), 17.4(C-18),
21.0(C-11), 21.5 and 21.6 and 22.1(CH3CO), 28.1,
29.1(2C), 32.2, 32.8, 34.6, 36.2(C-10), 36.3(C-8), 37.4,
39.1(C-16), 45.3(C-5), 46.5(C-13), 49.6(C-14), 54.5(C-9),
64.8(C-16a), 74.3(C-3), 81.3(C-17), 171.0 and 171.4 and
171.7(3C, CH3CO). To separate the critical isomer pair, the
mixture of 15b and 16b (78 mg, 20%) was dissolved in
methanol (5 ml) containing NaOCH3 (5 mg, 0.092 mmol).
It was allowed to stand for 24 h, and was then diluted with
water. The precipitate was filtered, washed and dried. The
resulting mixture of crude products 15a and 16a (61 mg)
was chromatographed with chloroform/ethyl acetate (1:1)
on a silica gel column impregnated with silver nitrate; 15a
eluted first (44 mg, 14%), mp: 194–196°C, Rf ϭ 0.50 (ss
C); [␣]2D0 Ϫ76 (c 1 in chloroform) (Found: C, 78.82; H,
11.08. C20H32O2 requires C, 78.90; H, 10.59%). Further
elution gave 16a (17 mg, 6%), mp: 182–183°C, Rf ϭ 0.45
(ss C); [␣]2D0 Ϫ41 (c 1 in chloroform) (Found: C, 78.75 H,
10.65. C20H32O2 requires C, 78.90; H, 10.59%). 15a (44
mg) and 16a (17 mg) obtained from the chromatographic
separation procedure were dissolved in a mixture of acetic
2.24. 16␣-Hydroxymethyl-5␣-androstane-3␤,17␣-diol (6a)
Compound 6b (182 mg, 0.5 mmol) was dissolved in
methanol (10 ml) containing NaOCH3 (5 mg, 0.092 mmol)
and the solution was allowed to stand for 24 h. It was then
diluted with water and the hard crystals that separated were
filtered and recrystallized from a mixture of acetone/water;
6a (156 mg, 98%) mp 297–299°C, Rf ϭ 0.40 (ss A); [␣]D20
Ϫ58 (c 1 in acetic acid) (Found C, 74.50; H, 10.55.
C20H34O3 requires C, 74.49; H, 10.63%).
2.25. 16-Hydroxymethyl-5␣-androst-16-en-3␤-ol (11a)
Compound 11b (39 mg, 0.1 mmol) was dissolved in
methanol (5 ml) containing NaOCH3 (5 mg, 0.092 mmol)
and the solution was allowed to stand for 24 h. It was then
diluted with water, and the precipitate that formed was
filtered and recrystallized from acetone/water to obtain pure
11a (25 mg, 82%) mp 157–159°C, Rf ϭ 0.45 (ss C); [␣]D20
Ϫ2 (c 1 in chloroform) (Found C, 78.82; H, 10.67.
C20H32O2 requires C, 76.90; H, 10.59%).
2.26. Acetolysis of 4j in aqueous acetic acid
Compound 4j (622 mg, 10 mmol) was subjected to
treatment in aqueous acetic acid as described in the general
procedure. The resulting crude product was chromato-
graphed on silica gel with tert-butyl methyl ether/light pe-

P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
631
troleum (10:90), yielding the critical isomer pair 15c and
3. Results and discussion
16c (67 mg, 15%). Further elution yielded 11c (49 mg,
11%), light oil, Rf ϭ 0.60 (ss D); [␣]2D0 Ϫ19 (c 1 in
chloroform) (Found: C, 77.36; H, 8.32. C29H38O4 requires
C, 77.30; H, 8.50%); 1H-NMR (400 MHz, CDCl3, Me4Si) ␦
ppm 0.80(s, 3H) and 0.86(s, 3H):18-H and 19-H, 2.02(s,
3H, CH3CO), 2.15(m, 1H), 4.68(m, 1H, 3-H), 4.84(s, 2H,
16-CH2), 5.84(s, 1H, 17-H), 7.44(dd, 2H, J ϭ 7.5 Hz, J ϭ
7.8 Hz, 3Ј- and 5Ј-H), 7.55(t, 1H, J ϭ 7.5 Hz, 4Ј-H) and
8.06(d, 2H, J ϭ 7.8 Hz, 2Ј- and 6Ј-H); 13C-NMR (100 MHz,
CDCl3, Me4Si) ␦ ppm 12.2(C-19), 17.0(C-18), 21.1(C-11),
21.4(CH3CO), 27.5, 28.5, 31.9, 32.6, 34.0, 34.1(C-8), 35.7,
36.6, 36.8(C-10), 44.9(C-5), 45.9(C-13), 54.9, 56.1, 64.2(C-
16a), 73.6(C-3), 128.3(2C, C-3Ј and C-5Ј), 129.5 and 129.6:
(2C, C-2Ј and C-6Ј), 130.4(C-1Ј), 132.8(C-4Ј), 138.1(C-16),
140.6(C-17), 166.3(C6H5CO) and 170.6(CH3CO). Contin-
ued elution with tert-butyl methyl ether/light petroleum
(30:70) yielded 6c (378 mg, 74%), white oil, Rf ϭ 0.50 (ss
C); [␣]2D0 ϩ17 (c 1 in chloroform) (Found: C, 73.10; H,
Treatment of 3␤-acetoxy-5␣-androstan-17-one with
NaOMe and ethyl formate gave 1a in a yield of 96%. Its
acetyl derivative 1b, obtained quantitatively by the reaction
of 1a with acetic anhydride in pyridine, was reduced with
KBH4 in ethanol to give 3b and 4b in 92% yield. The
reduction initially led to 16-acetoxymethylene-3-acetoxy-
5␣-androstan-17␤-ol 2a. However, in the slightly alkaline
medium, the acetoxymethylene group was hydrolyzed and
the resulting carbonyl group partially epimerized and re-
duced to a mixture of 3b and 4b. In this two-step reduction
of the dicarbonyl system, the otherwise frequently occurring
fragmentation side-reaction [12] could be avoided (Scheme
1).
The simultaneous development of the two chiral centers
permits formation of the four isomers 3a, 4a, 5a and 6a.
However, isomers 3b and 4b were isolated in almost equal
amounts. The mixture of 3b and 4b was reacted with ace-
tone in dichloromethane in the presence of a catalytic
amount of toluene-p-sulfonic acid. 3b was converted into
the corresponding cyclic acetonide derivative 3i, whereas
4b could easily be separated by flash chromatography on
alumina. Since reduction of the 17-ketone function in ste-
roids normally yields a 17␤ group (with a few exceptions
[13]) isomers 3b and 4b are expected to have different
configurations at C-16. In the NMR spectrum of the triac-
etate 3c, the doublet at 4.79 ppm, due to coupling of the
protons on C-16 and C-17 with a coupling constant of 10.1
Hz, confirms the ␤,␤ arrangement of the substituents on
C-16 and C-17. The ␣,␤ arrangement of the C-16 and C-17
substituents in 4c is indicated by the lower coupling con-
stant (7.7 Hz) of the doublet appearing at 4.64 ppm; and
these values are in good agreement with earlier observations
[14].
1
8.20. C31H42O6 requires C, 72.91; H, 8.29%); H-NMR
(400 MHz, CDCl3, Me4Si) ␦ ppm 0.67(m, 1H), 0.82(s, 3H,
19-H), 0.88(s, 3H, 18-H), 1.89(s, 3H, 16-CH3CO), 2.01(s,
3H, 3-CH3CO), 2.84(m, 1H), 4.11(m, 2H, 16-CH2), 4.66(m,
1H, 3-H), 5.30(d, 1H, J ϭ 5.6 Hz, 17-H), 7.46(dd, 2H, J ϭ
7.5 Hz, J ϭ 7.8 Hz, 3Ј- and 5Ј-H), 7.57(t, 1H, J ϭ 7.5 Hz,
4Ј-H) and 8.01(d, 2H, J ϭ 7.8 Hz, 2Ј- and 6Ј-H); 13C-NMR
(100 MHz, CDCl3, Me4Si) ␦ ppm 12.6(C-19), 17.2(C-18),
20.7(C-11), 21.1 and 21.8(2C, CH3CO), 27.8, 28.8, 29.1,
32.1, 32.5, 34.4, 35.9(C-10), 36.0(C-8), 37.0, 39.1(C-16),
45.0(C-5), 46.7(C-13), 49.9(C-14), 54.2(C-9), 64.8(C-16a),
73.9(C-3), 81.7(C-17), 128.9(2C, C-3Ј and C-5Ј), 129.9(2C,
C-2Ј and C-6Ј), 130.6(C-1Ј), 133.4(C-4Ј), 166.2(C6H5CO),
171.0 and 171.4(2C, CH3CO).
The mixture of the critical isomer pair 15c and 16c (67
mg) was dissolved in methanol (5 ml) containing NaOCH3
(5 mg, 0.092 mmol). The reaction mixture was allowed to
stand for 24 h, and was then diluted with water. The pre-
cipitate was filtered, washed and dried. The resulting mix-
ture of crude products 15a and 16a (46 mg) was chromato-
graphed with chloroform/ethyl acetate (1:1) on a silica gel
column impregnated with silver nitrate. 15a eluted first (33
mg, 9%), mp: 194–196°C, Rf ϭ 0.50 (ss C); [␣]2D0 Ϫ76 (c
1 in chloroform) (Found: C, 78.82; H, 11.08. C20H32O2
requires C, 78.90; H, 10.59%). Further elution gave 16a (12
mg, 6%), mp: 182–183°C, Rf ϭ 0.45 (ss C); [␣]2D0 Ϫ41 (c
1 in chloroform) (Found: C, 78.75; H, 10.65. C20H32O2
requires C, 78.90; H, 10.59%). 15a (30 mg) or 16a (30 mg)
obtained from the deacetylation procedure was dissolved in
a mixture of acetic anhydride (1 cm3) and pyridine (1 cm3).
The reaction mixture was allowed to stand overnight. After
saturation with water, the precipitate was filtered, washed
with water and dried. The compounds 15b and 16b were
identical with the materials isolated from the acetolysis of
4h.
For confirmation of the configurations assumed for 3b
and 4b, transformations were carried out with the individual
isomers. Treatment of 3b and 4b with toluene-p-sulfonyl
chloride in pyridine and subsequent acylation afforded the
corresponding acyl derivatives 3e, 3f and 4e, 4f, respec-
tively. Furthermore, 3b was converted with benzaldehyde
diethylacetal to the corresponding cyclic benzylidene deriv-
ative 3e. When treated with 5,5-dimethyl-1,3-dibromohy-
dantoin, this was brominated on the primary carbon atom, in
a manner observed in sugar chemistry [15], and yielded
3␤-acetoxy-17␤-benzoyloxy-16␤-bromomethyl-5␣-andro-
stane 3g.
As 3e, 3f, 3g, 4e and 4f were all available, it seemed of
interest to study the neighboring group participation of
different types of acyl group in the ␥ position. These com-
pounds were subjected to acetolysis in the presence of silver
acetate in anhydrous acetic acid. 16␤-Toluene-p-sulfony-
loxymethyl-17␤-acetate 3e yielded a mixture of isomeric
triacetates, 3c and 5b, in 74% yield. 3c has the same con-
figuration as that of the starting compound 3e, but partial
isomerization occurred during the solvolysis, giving 5b in

632
P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
Scheme 1.
22%. During the acetolysis, 16-methylene-5␣-androstane-
3␤,17␤-diacetate 9b was also formed by a trans diaxial
elimination reaction involving 16␣-H of ambident cation
7a. The isomeric unsaturated compound 16␤-acetoxy-
methyl-17-methyl-18-nor-5␣-androst-13(17)-ene-3␤-acetate
10b, which was formed by Wagner-Meerwein rearrange-
ment, was also detected in the reaction mixture. The yield of
9b and 10b was 8% and 16%, respectively. 16␤-Toluene-
p-sulfonyloxymethyl-17␤-benzoate 3f and 16␤-bromom-
ethyl-17␤-benzoate 3g yielded a mixture of two isomeric
acetate-benzoates in 86% yield. 3h has the same configu-
ration as that of the starting compound 3f, and the yield of
the isomeric compound in this case was 37%. The yield of
the unsaturated mixed acetate-benzoates 9c and 10c was
14%. To separate 9c and 10c, we dissolved the chromato-
graphically separated oily residue in methanol. The bulk of
9c crystallized out as fine crystals, whereas 10c remained in
solution. After deacetylation by the Zemplen method, in
methanol in the presence of catalytic amount of sodium
methylate, we separated the white solid substance 10a. It
was acetylated and was identical with 10b, separated from
the acetolysis of 3e (Scheme 2).

P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
633
Scheme 2.
The formation of 3c and 3h can easily be explained by
the reaction of the primary toluene-p-sulfonyloxy or bro-
mine substituent with the solvent (KS) [16]. In order to
explain the formation of 5b and 5c, resulting from inversion
at C-17, the six-membered acyloxonium ions 7a and 7b
were assumed to be formed as intermediates. The acyloxo-
nium ions 7a and 7b formed in the K⌬ process are not
symmetrical and, in consequence of their ambident charac-
ter, they can be attacked at various positions. Attack on the
16-methylene is slightly hindered sterically and does not
affect any chiral center, and thus the result of the process is
identical with that of the KS conversion. Attack on the more
shielded C-17 is in turn accompanied by inversion, and this
can explain the formation of 5b and 5c. Since KS and K⌬
processes may occur simultaneously, and the product un-
dergoing inversion is formed in the K⌬ process, which is an
unfavored attack, it is evident that 5b and 5c are obtained in
lower amounts. Formation of 10b and 10c by the Wagner-
Meerwein rearrangement can also be explained by the K⌬
process. The sterically less favored acyloxonium cations 7a
and 7b, with delocalized systems, may be transformed by
isomerization into 8a and 8b, respectively. Since these have
a higher energy level they are stabilized by rearrangement
into 10b and 10c, respectively. The benzoxonium ion 7b is
more stable than the acetoxonium ion 7a, and the reaction
pathway therefore gives more of the acetate-benzoate iso-
mers 3h and 5c and less of the rearranged compound 10c
[17]. The other type of rearranged product with double bond

634
P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
Scheme 3.
between C13 and C14 was not detected in the reaction mix-
ture. The reason for this is that this compound would pos-
sess substituents in 16␤, 17␤ orientation which is sterically
unfavorable.
The processes of formation of 5b from 3e and of 5c from
3f and 3g are typical neighboring group participation’s
characterized by the general symbols (AcO-6) and (BzO-6),
respectively [18,19]. The phenomenon is in good agreement
with the observations on 2-toluene-p-sulfonyloxymethyl cy-
clohexyl acetate and benzoate [20].
yield. Their formation can be explained by an SN2 substi-
tution reaction of the primary toluene-p-sulfonyloxy group.
Since possession of the complete series of isomers would
permit a number of interesting comparative examinations,
we wished to prepare the unknown fourth isomer 6a, which
contains functional groups with the configuration 16␣,17␣.
The primary hydroxy group in 3␤-acetoxy-16␣-hydroxy-
methyl-5␣-androstan-17␤-ol 4b was acylated with acetic
acid and benzoic acid, and products 4g and 4i were esteri-
fied with toluene-p-sulfonic acid to obtain 3␤-acetoxy-16␣-
acetoxymethyl-5␣-androstane-17␤-toluene-p-sulfonate 4h
In the cases of 4e and 4f, however, which are the epimers
of 3e and 3f, respectively, acetolysis in the presence of
silver acetate yielded exclusively 4c and 4k in almost 100%
and
3␤-acetoxy-16␣-benzoyloxymethyl-5␣-androstane-
17␤-toluene-p-sulfonate 4j. Solvolysis of the mixed esters

P. Tapolcsa´nyi et al. / Steroids 66 (2001) 623–635
635
tion of steroid acetates on alumina. J Chem Soc Perkin 1998;1:
2873–5.
[2] Gao H, Katzenellenbogen JA, Garg R, Hansch C. Comparative
QSAR analysis of estrogen receptor ligands. Chem Rev 1999:99723–
44.
[3] Mesko´ E, Schneider G, Dombi G, Zeigan D. Configurational analysis
of 3-methoxy-16-methylestra-1,3,5(10)-trien-17-ol derivatives. Liebigs
Ann Chem 1990:419–21.
[4] Schneider G, Hackler L, Soha´r P. Ritter-reaction on steroids. Ring
expansion of steroid oxethans into dihydrooxazines. Tetrahedron
1985;41:3377–86.
4h and 4j was effected in the presence of silver acetate in
aqueous acetic acid. In the course of acetolysis in boiling
acetic acid containing 5% of water, the main products were
the triacyl derivatives 6b and 6c (68% and 74%). 3␤-
Acetoxy-16-acyloxymethyl-5␣-androst-16(17)-ene 11b and
11c (12% and 11%), 3␤-acetoxy-16␣-acyloxymethyl-17␤-
methyl-18-nor-5␣-androst-13(14)-ene 15b and 15c (14%
and 6%) and 3␤-acetoxy-16␣-acyloxymethyl-17-methyl-
18-nor-5␣-androst-13(17)-ene 16b and 16c (6% and 9%)
were also found in the reaction mixture (Scheme 3).
[5] Schneider G, Hackler L, Soha´r P. New synthesis of steroidal tetra-
hydrooxazin-2-ones. Tetrahedron 1987:433987–95.
In order to explain the partial inversion observed during
the solvolysis of 4h and 4j in aqueous acetic acid, it was
assumed that the 16␣-acyloxymethyl group with a favorable
steric position affects the substitution of the ␤-oriented
toluene-p-sulfonyloxy group. First, the six-membered acy-
loxoniumions 12a and 12b are formed by inversion, which
give unstable intermediates 14a and 14b on ionic associa-
tion with water. These decompose into 3␤-acetoxy-17␣-
acyloxy-16␣-hydroxymethyl-5␣-androstane, which under-
goes acetylation in the acetic acid medium to furnish 6b and
6c, respectively. The formation of a small quantity of alk-
enes 11b and 11c during the acetolysis can be explained by
deprotonation of 12a and 12b, respectively. The formation
of 15b, 15c, 16b and 16c can be interpreted by the opening
of the sterically favored acyloxonium ions 12a and 12b with
16␣, 17␣ configuration, to form ions 13a and 13b, respec-
tively, followed by stabilization of the latter by Wagner-
Meerwein rearrangement. The rearrangement products 15b,
16b and 15c, 16c were critical isomer pairs, which could not
be separated in the acetylated form. The products after
deacetylation by the Zemplen method, however, were sep-
arated on a silica gel column impregnated with silver nitrate.
Compounds 15a and 16a were then acetylated and charac-
terized as the diacetates 15b and 16b.
[6] Schneider G, Vass A, Vincze I, Soha´r P. Neighbouring group partic-
ipation in the 16-hydroxymethyl-3-methoxyestra-1,3,5(10)-trien-
17␤-ol series. Liebigs Ann Chem 1988:267–73.
[7] Schneider G, Hackler L, Soha´r P. Preparation of 16␣-hydroxymethyl-
3-methoxyestra-1,3,5(10)-trien-17␣-ol and solvolysis investigations.
Liebigs Ann Chem 1988:679–83.
[8] Tietze LF, Wo¨lfling J, Schneider G. Synthesis of D-homoestrone
derivatives by tandem knoevenagel hetero diels-alder reactions from
natural estrone. Chem Ber 1991;124:591–4.
[9] Tietze LF, Wo¨lfling J, Schneider G, Noltemeyer M. Synthesis of new
16-spirosteroids. Steroids 1994;59:305–9.
[10] Tietze LF, Schneider G, Wo¨lfling J, No¨bel T, Wulff C, Schubert I,
Ru¨beling A. Efficient synthesis of a novel estrone-talaromycin hybrid
natural product. Angew Chem Int Ed 1998;37:2469–70.
[11] Ruzicka L, Prelog V, Battegay J. Steroide und Sexualhormone. 153.
¨
Mitteilung. Uber einige Benzo-perhydro-cyclopenteno-phenantren
Derivate. Helv Chim Acta 1948;31:1296–301.
[12] Bondavalli F, Longobardi M, Schenone P. Reduction of 5-hydroxy-
methylene-cis-caran-4-one with complex hydrides. J Chem Soc Per-
kin 1976;1:678–80.
[13] Biggerstaff WR, Gallager TF. 3,16␤-Dihydroxy-⌬1,3,5-estratrien-17-
one and related compounds. J Org Chem. 1957;22:1220–2.
[14] Scho¨necker B, Tresselt D, Draffehn J, Ponsold K, Engelhardt G,
1
Zeigan D, Schneider G, Weisz-Vincze I, Dombi G. H-NMR-Unter-
suchungen. Konfigurationszuordnung von 16-substituierten 17-Hy-
droxy-Steroiden. J Prakt Chem 1977;319:419–31.
[15] Hanessian S, Plessas NR. The reaction of O-benzylidene sugars with
N-bromsuccinimide. IV. Neighboring-group effects and rearrange-
ments. J Org Chem 1969;34:1053–8.
[16] Streitwieser A. Solvolytic displacement reactions at saturated carbon
atoms. Chem Rev 1956;56:571–752.
Acknowledgments
Financial support by the National Research Foundation
(Grant OTKA T 032265) and by the Hungarian Board of
Education (FKFP 0110/2000) is gratefully acknowledged.
[17] Perst H. Stability of oxonium salts. In: Oxonium ions in organic
chemistry, Verlag Chemie, Weinheim 1971. pp. 11–21.
[18] Winstein S, Heck R. Role of neighboring groups in replacement
reactions. XIX. Polarimetric acetolysis rate of trans-2-acetoxycyclo-
hexyl p-toluene-sulfonate. J Am Chem Soc 1952;74:5584–6.
[19] Lwowski WL. Nachbargruppen-Effekte in der Organischen Chemie.
Angew Chem 1958;70:483–95.
References
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wave induced selective deacetylation and stereospecific acyl migra-