B. Zhang et al. / Steroids 76 (2011) 56–59
57
Scheme 1. Synthetic route for the ether (4) from 11␣-hydroxy canrenone (1).
161.20, 137.06, 129.09, 125.53, 94.30, 77.80, 53.40, 46.43, 46.41,
40.84, 40.20, 37.60, 36.67, 35.40, 34.78, 34.23, 30.87, 29.05, 22.58,
17.19, 15.53. EI-MS (70 eV, m/z): 434 (M+, 2%), 338 ([M−MeSO3H]+,
100%), 323 ([M−MeSO3H−Me]+, 62%).
then at room temperature (r.t.) for 10 h, quenched with a saturated
Na2SO3 solution (10 ml) over 30 min, and filtered. The filtrate and
washes were combined and concentrated. The residue was diluted
with EtOAc, washed with saturated brine, dried over magnesium
sulphate, filtered and concentrated. The crude product was puri-
fied by column chromatography (petroleum ether:acetone, 4:1) to
give compound 4 (6.3 g, 71%): m.p. 200–202 ◦C; [␣]17d: −22◦ (c 0.1,
CH2Cl2); 1H NMR (300 MHz, CDCl3) ı (ppm) 5.57–5.48 (m, 1H), 3.70
(dd, J = 8.0, 4.2 Hz, 1H), 3.60 (d, J = 8.0 Hz, 1H), 2.81 (d, J = 15.0 Hz, 1H),
1.27 (s, 3H), 0.93 (s, 3H); 13C NMR (100 MHz, CDCl3) ı (ppm) 209.69
(q), 176.54 (q), 142.82 (q), 120.25 (t), 95.26 (q), 87.90 (q), 69.09 (d),
47.96 (d), 44.10 (q), 43.12 (q), 43.04 (t), 42.39 (t), 40.36 (d), 38.29
(t), 37.55 (d), 35.37 (d), 32.99 (d), 32.94 (d), 31.49 (d), 29.20 (d),
23.96 (s), 23.27 (d), 14.40 (s); EI-MS (70 eV, m/z): 370 (M+, 38%),
355 ([M−Me]+, 7%), 271 (64%), 124 (100%), 137 (85%).
1.2. ꢀ9(11)-Canrenone (3)
A mixture of formic acid (125 ml), potassium acetate (58 g,
591 mmol) and acetic anhydride (40 ml) was heated at 80 ◦C. After
18 h, compound 2 (10 g, 23 mmol) was added. The resulting solution
was heated at 100 ◦C for 4 h and concentrated under reduced pres-
sure. Ice water was added to the residue with stirring. After 20 min,
the mixture was extracted with ethyl acetate (50 ml). The organic
extracts were washed with cold water (50 ml), sodium bicarbonate
(50 × 3 ml), water (50 ml), saturated sodium chloride (50 ml) and
dried with anhydrous sodium sulphate. The solvent was removed
in vacuo to furnish the crude product. This crude product was
purified by column chromatography (petroleum ether:acetone,
4:1) to give compound 3 as a white powder (7 g, 90%): 1H NMR
(300 MHz, CDCl3) ı (ppm) 6.16 (C7–H, dd, J = 9.7, 2.19 Hz, 1H),
6.09 (C6–H, dd, J = 9.7, 1.3 Hz, 1H), 5.69 (C4–H, s, 1H), 5.55–5.48
(C11–H, m, 1H), 2.93 (d, J = 11.19 Hz, 1H), 1.30 (C19–H, s, 3H), 0.99
(C18–H, s, 3H); 13C NMR (75 MHz, CDCl3) ı (ppm) 199.07, 176.36,
161.83, 140.33, 137.85, 127.26, 123.90, 118.501, 94.79, 44.28, 43.96,
38.84, 38.54, 35.21, 34.02, 32.88, 32.02, 31.17, 29.08, 24.35, 22.88,
14.32. EI-MS (70 eV, m/z): 338 (M+, 100%), 323 ([M−Me]+, 57%),
305([M−Me−H2O]+, 12%).
1.4. 17ˇ-Hydroxy-7˛-(1ꢀ-hydroxy)methylene-5˛-oxo-pregna-
4,9(11)-dien-3-one-21-carboxylic acid, ꢁ-lactone (5)
Methyltrifluoromethyldioxirane [14] was bubbled into the solu-
tion of compound 4 (120 mg, 0.32 mmol) in CH2Cl2 (50 ml) at
−25 ◦C for 2 h. The solvent was removed in vacuo to furnish the
crude product. This crude product was purified by column chro-
matography (petroleum ether:EtOAc, 1:1) and recrystallised from
acetone/CH2Cl2 to give colourless, transparent crystalline com-
pound 5 (111 mg, 90%): m.p. 260–262 ◦C; 1H NMR (300 MHz, CDCl3)
ı (ppm) 5.55–5.45 (C11–H, m, 1H), 5.01 (C5–OCH–, s, 1H), 3.04
(C5–OCHOH–, brs, 1H), 2.84 (C4–H, d, J = 15.18 Hz, 1H), 1.28 (C19–H,
s, 3H), 0.91 (C18–H, s, 3H); 13C NMR (100 MHz,CDCl3) ı (ppm)
209.64 (q), 176.58 (q), 142.65 (q), 120.38 (t), 95.20 (q), 90.25 (q),
98.31 (t), 48.44 (d), 44.20 (q), 42.80 (q), 44.54 (t), 42.09 (t), 37.48
(d), 41.18 (t), 37.13 (d), 35.32 (d), 33.08 (d), 32.93 (d), 31.43 (d),
29.18 (d), 23.38 (s), 23.38 (d), 14.17 (s); EI-MS (70 eV, m/z): 386
(M+, 7%), 368 ([M−H2O]+, 44%), 353 (28%), 371 (12%), 124 (100%).
1.3. 17ˇ-Hydroxy-7˛-methylene-5˛-oxo-pregna-4,9(11)-dien-
3-one-21-carboxylic acid, ꢁ-lactone (4)
To
a
solution of CuI·2LiCl (100 ml, 100 mmol) in THF, i-
PrOMe2SiCH2MgCl (100 ml, 100 mmol) in THF was added dropwise
at −68 ◦C with vigorous stirring. After 10 min, BF3·OEt2 (12.6 ml,
100 mmol) was added dropwise. After 1 h, a solution of compound
3 (8.45 g, 25 mmol) in 25 ml THF was added dropwise to the black
brown reaction mixture. After 10 h, the reaction mixture was cooled
to 0 ◦C, and was quenched with HCl aqueous solution (5%, w/w)
and extracted with CH2Cl2 (3 × 50 ml). The combined organic layers
were filtered, washed with water (3 × 100 ml) and saturated brine,
dried over anhydrous sodium sulphate, filtrated and concentrated.
The above residue was diluted with THF/MeOH (100 ml/100 ml),
and then KHCO3 (10 g, 100 mmol) and KF (11.6 g, 200 mmol) were
added. To the stirred mixture, H2O2 (30%, w/w) (160 ml) was added
in one portion. The reaction mixture was stirred at 40–50 ◦C for 4 h,
1.5. 5˛,17ˇ-Dihydroxy-3-oxo-pregn-9(11)-ene-7˛,
21-dicarboxylic acid, bis-ꢁ-lactone (6)
To a suspension of the lactol 5 (31 mg, 0.08 mmol) and molec-
ular sieves 4A (120 mg) in anhydrous CH2Cl2 (0.5 ml) pyridinium
dichromate (60 mg, 0.16 mmol) was added. The mixture was stirred
overnight at room temperature, diluted with n-hexane/ethyl
acetate (4/1, v/v), and filtered through a pad of silica gel. The fil-
trate was concentrated under reduced pressure and recrystallised
from acetone to give crystalline 63 (28 mg, 98%): m.p. 256–258 ◦C;