220
J.F. Templeton et al. / Steroids 65 (2000) 219–223
2.2. Androst-4-ene-3,17-dion-19-oic acid (1a)
(150 mg, 30%) 2) the symmetrical dimer 3a, (67 mg, 6.5%),
m.p. 217–220°C (from CH2Cl2-EtOAc) (Found: C, 72.38;
H, 8.62. C40H54O8 requires C, 72.48; H, 8.22%);
Treatment of 19-hydroxyandrost-4-ene-3,17-dione (10 g,
33 mmol) in acetone (250 ml), cooled in an ice-bath, with
Jones reagent (30 ml, 80 mmol), added in portions over 40
min, gave the 19-acid (5.0 g, 48%), m.p. 146–148°C de-
comp. (from CH2Cl2-LP) (lit [10], m.p. 146°C), ␦H 0.91 (s,
13-Me), 5.95 (d, J ϭ 1.2 Hz, 4-H); ␦C 33.68 (1), 34.78 (2),
198.73 (3), 127.19 (4), 161.55 (5), 32.57 (6), 31.37 (7),
35.56 (8), 53.68 (9), 50.52 (10), 21.64 (11), 29.97 (12),
47.58 (13), 50.93 (14), 21.98 (15), 35.70 (16), 220.00 (17),
13.90 (18), 175.54 (19).
max(CH2Cl2) cmϪ1 3595, 3553 (3-OH), 1735 (17-C ϭ O
and 19-COOMe); ␦H 0.93 (s, 13-Me), 2.38 (m, 6-H), 2.45
(dd, 9.3, 19.3, 16-H), 3.69 (s, 19-OMe), 5.69 (s, 4-H); ␦C
29.71 (1), 28.62 (2), 73.60 (3), 124.63 (4), 143.06 (5), 33.94
(6), 31.56 (7), 36.19 (8), 52.74 (9), 50.22 (10), 21.71 (11),
31.70 (12), 47.83 (13), 51.54 (14), 21.71 (15), 35.72 (16),
221.00 (17), 13.84 (18), 174.32 (19), 51.42 (19-OMe);
EIMS m/z 644 (1%, Mϩ-H2O), 626 (25, Mϩ-2H2O), 567
(12), 508 (7), 338 (100), 272 (64), 270 (76), 253 (43);
FABMS m/z 685 [38%, (MϩNa)ϩ], 663 [10%, (MϩH)ϩ],
627 [78%, (M-H-H2O)ϩ], 331 [100%, (M2ϩ)].
2.3. Methyl androst-4-ene-3,17-dion-19-oate (1b)
The 19-acid 1a (2.26 g, 7.14 mmol) on treatment with
diazomethane in Et2O gave the methyl ester (2.1 g, 89%),
m.p. 142–145°C (from EtOAc-LP) (lit [11], m.p.
142–142.5°C from Et2O) ␦H 0.90 (s, 13-Me), 3.76 (s, 19-
OMe), 5.90 (d, J ϭ 1.5, 4-H): ␦C 33.82 (1), 34.91 (2),
198.57 (3), 126.76 (4), 161.96 (5), 32.56 (6), 31.35 (7),
35.59 (8), 53.75 (9), 50.85 (10), 21.64 (11), 30.06 (12),
47.52 (13), 50.88 (14), 21.92 (15), 35.69 (16), 219.97 (17),
13.77 (18), 171.63 (19), 50.85 (19-OMe).
2.5.2. Method 2
To a stirred solution of liquid NH3 (150 ml) and tetra-
hydrofuran (10 ml) containing dissolved Li metal (700 mg,
0.1 mol) was added a solution of the methyl ester 1b (709
mg, 2.15 mmol) in THF (20 ml) over 20 min. After stirring
for a further hour solid NH4Cl (6 g, 11 mmol) was added
followed by CH2Cl2 (150 ml). After evaporation of the NH3
the organic layer gave a residue that on FCC on elution with
LP/EtOAc (4:1) yielded the dimer 3a (170 mg, 12%), m.p.
217–220°C (from CH2Cl2-EtOAc-LP). H and 13C NMR
1
2.4. Methyl androst-4-ene-3,17-dion-19-oate (1b)
were in agreement with the product above.
To a solution of the dimer 3a (13.4 mg, 0.04 mmol) in
warm MeOH (3 ml) was added NaIO4 (150 mg, 0.07 mmol)
in hot water (1 ml) and the mixture refluxed for 4 h. On
cooling the mixture was diluted with water and extracted
with CH2Cl2 to give the methyl ester 1b (13 mg) that
2.6. Methyl 5␣- (2a) and 5-androst-3-en-17-on-19-oate
(2b) and 3␣,3␣Ј-bis(methyl 3-trimethylsilyloxyandrost-4-
en-17-on-19-oate-3-yl) (3b), and 3␣,3-bis(methyl 3-
trimethylsilyloxyandrost-4-en-17-on-19-oate-3-yl) (3c)
1
showed TLC and H and 13C NMR in agreement with the
The methyl ester 1b (2.22 g, 6.72 mmol) in acetic acid/
water (1:1) (40 ml) was stirred with zinc powder (40 g) for
2.5 h and the residue after work-up was treated with tri-
methylsilyl-imidazole reagent (2.24 ml, 15.3 mmol) in
CH2Cl2 (5 ml) for 1 h. FCC of the product gave fractions of
1) the methyl 5-androst-3-en-17-on-19-oate 2b (133 mg,
6.3%), m.p. 143–145.5°C (from Et2O-LP), 2) a mixture of
methyl 5␣- and 5-androst-3-en-17-on-19-oate 2a and 2b
(1.07 g, 52%), 3) the non-crystalline methyl 5␣-androst-3-
en-17-on-19-oate 2a (70 mg, 3.3%) ␦H 0.90 (13-Me), 2.45
(dd, J ϭ 9.5, 18.8, 16-H), 2.50 (d, J ϭ 12.7, 5␣-H over-
lapping with the 16-H), 3.66 (s, 19-OMe), 5.46 (dd, J ϭ
1.8, 9.8, 4-H), 5.55 (ddd, J ϭ 2.1, 6.5, 9.8, 3-H); ␦C 27.51
(1) 24.41 (2), 126.00 (3), 134.39 (4), 44.55 (5), 30.41 (6),
31.54 (7), 35.69 (8), 51.31 (9), 50.04 (10), 21.74 (11), 32.02
(12), 47.73 (13), 51.54 (14), 21.81 (15), 35.81 (16), 220.91
(17), 13.86 (18), 174.65 (19), 51.84 (19-OMe) and 4) the
silylated symmetrical dimer 3b (270 mg, 6%), m.p. 258–
260°C (from CH2Cl2-EtOAc) (Rf 0.17, 30% Et2O-LP)
(Found: C, 68.24; H, 9.00. C46H70O8Si2 requires C, 68.44;
H, 8.74%); max(CH2Cl2) cmϪ1 1735 (17-C ϭ O and 19-
COOMe); ␦H 0.04 (s, SiMe3), 0.90 (s, 13-Me), 2.46 (dd, J ϭ
8.8, 19.2, 16-H), 2.62, (td, J ϭ 3.3, 13.7, 6-H), 3.67 (s,
19-OMe), 5.63 (s, 4-H); ␦C 31.07 (1), 30.50 (2), 77.90 (3),
ester 1b obtained from the acid 1a above.
2.5. Methyl 5␣- (2a) and 5-androst-3-en-17-on-19-oate
(2b) and bis(methyl 3-hydroxyandrost-4-en-17-on-19-oate-
3␣-yl) (3a)
2.5.1. Method 1
The methyl ester 1b (526 mg, 1.6 mmol) was dissolved
in acetic acid/water (1:1) (20 ml) and zinc powder (10 g)
added in one portion. The mixture was stirred for 6 h at
room temperature, filtered, and the filtrate extracted with
CH2Cl2 to give a product that on FCC on silica gel on
elution with 3–25% acetone-LP yielded 1) the 5-isomer 2b
(75 mg, 15%), m.p. 143.5–145.5°C (from Et2O-LP) (Found:
C, 75.81; H, 9.15. C20H28O3 requires C, 75.91; H, 9.15%);
␦H 0.96 (s, 13-Me), 2.44 (dd, J ϭ 9.3, 19.1, 16-H), 2.74 (br
s, W1/2 11Hz, 5-H), 3.67 (s, 19-OMe), 5.38 (ddd, J ϭ 1.8,
3.6, 10.0, 4-H), 5.72 (m, 3-H); ␦C 28.52 (1), 21.45 (2),
126.80 (3), 130.99 (4), 39.18 (5), 28.77 (6), 25.97 (7), 35.86
(8), 40.27 (9), 47.30 (10), 21.62 (11), 32.03 (12), 48.08 (13),
51.56 (14), 21.68 (15), 35.99 (16), 221.51 (17), 14.01 (18),
176.81 (19), 51.42 (19-OMe) and a mixture of methyl 5␣-
and 5-androst-3-en-17-on-19-oates 2a and 2b (5␣:5; 1:4)