A. Marcos-Escribano et al. / Tetrahedron 65 (2009) 8493–8496
8495
was the key step in the synthesis of fluorometholone 7a, starting
from 17-hydroxy-4,9(11)-pregnadien-3,20-dione 13. The target
molecule was successfully achieved by application of a five-step
reaction sequence in 45% overall yield.
d
(ppm): 0.68 (s, 3H), 1.04 (d, J¼7.28 Hz, 3H), 1.21 (s, 3H), 2.26 (s,
3H), 0.5–2.8 (m, 19H), 5.42 (d, J¼6.0 Hz, 1H); 13C NMR (CDCl3)
(100 MHz)
d (ppm): 14.4, 15.3, 21.6, 25.0, 27.6, 32.0, 32.2, 32.7,
33.7, 38.2, 38.3, 39.4, 39.8, 43.2, 46.8, 46.9, 47.9, 89.7, 117.0, 145.8,
211.4, 212.3; HRMS-EI (MþNa) calcd for C22H32O3Na 367.2244,
found 367.2241.
4. Experimental
4.1. General experimental methods
4.4. 6a-Methyl-17a-hydroxy-pregna-4,9(11)-
diene-3,20-dione (17)
Melting points are uncorrected. 1H NMR spectra were measured
at either 200 or 400 MHz and 13C NMR were measured at 50 or
100 MHz in CDCl3 and referenced to TMS (1H) or solvent (13C),
except where indicated otherwise. IR spectra were recorded either
in CHCl3 solution or in NaCl plates, unless otherwise noted, on an
FTIR instrument. HRMS determinations (EI) were recorded at the
Mass Spectrometry Service of the University of Salamanca, Spain.
All reactions were conducted under a positive pressure of argon,
utilizing standard bench-top techniques for handling of air-sensi-
tive materials. Chemicals and solvents were obtained from com-
mercial sources and used as received with the exception of
tetrahydrofuran, benzene, toluene, and dioxane, which were dis-
tilled from sodium and benzophenone. The 10% palladium on ac-
tivated charcoal has been obtained from Fluka (Cat. No. 75993).
Unless specified otherwise, the yields reported are for chromato-
graphically pure isolated products.
The 6-methylene steroidal derivative 14 (18 g, 54 mmol) and
palladium (10%) over charcoal (50% wet, 0.1 g/g) were suspended
in dichloromethane (350 mL) and triethylamine (5 mL, 38 mmol)
was added via syringe; the reaction mixture was stirred under
a hydrogen atmosphere for 6 h. The reaction mixture was filtered
over Celite, and the solid washed five times with DCM. The organic
phase was evaporated off and the solid was redissolved in THF
(350 mL). HCl (37%, 11 mL, 135 mmol) was added and the reaction
mixture was stirred for an additional 12 h. Once the isomerization
process was completed, the reaction mixture was evaporated,
redissolved in methanol (30 mL), and poured very slowly into
water (200 mL). The suspended solid was filtered and dried,
20
yielding 17 (14.35 g, 61%) pure. Mp: 180–183 ꢀC; [
a
]
þ38.6 (c 1.1,
D
CHCl3); IR (CHCl3)
n
(cmꢁ1): 736, 918, 1242, 1359, 1664, 1709, 2968,
(ppm): 0.67 (s, 3H), 1.09 (d,
3448; 1H NMR (CDCl3) (400 MHz)
d
J¼12.6 Hz, 3H), 1.32 (s, 3H), 2.26 (s, 3H), 2.82 (s, 1H, OH), 0.5–2.6
4.2. 6-Methylen-17
diene-3,20-dione (14)
a-hydroxy-pregna-4,9(11)-
(m, 15H), 5.52 (d, J¼5.8 Hz, 1H), 5.77 (s, 1H); 13C NMR (CDCl3)
(100 MHz)
d (ppm): 15.3, 18.1, 24.6, 27.2, 27.5, 32.2, 33.7, 33.8, 34.0,
34.0, 37.2, 41.3, 46.6, 47.4, 89.5, 118.4, 121.2, 144.0, 172.8, 199.6,
211.2; HRMS-EI (MþNa) calcd for C22H30O3Na 365.2087, found
365.2098.
The steroidal diketone 13 (56 g, 170 mmol) and p-toluene-
sulfonic acid monohydrate (9 mmol) were dissolved in a mixture
of THF (385 mL) and ethanol (45 mL) at 37 ꢀC under argon. Triethyl
orthoformate (38 mL, 230 mmol) was added via syringe. After
2.5 h, N-methylaniline (19 mL, 176 mmol) and 40% formaldehyde
(16 mL) were consecutively added. After 3.5 h of additional stirring
at 40 ꢀC, 37% hydrochloric acid (100 mL) was added and the re-
action mixture was kept under stirring at 40 ꢀC for 3 h. The sus-
pension was cooled to room temperature, poured into water, and
cooled to 5 ꢀC while stirring. After 30 min, the steroid was filtered,
4.5. 6a-Methyl-17a-hydroxy-pregna-1,4,9(11)-
triene-3,20-dione (18)
To a solution of the steroidal diketone 17 (0.05 g, 0.14 mmol) in
DCM (0.5 mL), diisopropylethylamine (0.1 mL, 0.45 mmol) and
tert-butyldimethylsilyltrifluoromethanesulphonate
(TfOTBDMS,
0.08 mL, 0.35 mmol) were added successively via syringe. The re-
action mixture was stirred at 10 ꢀC for 3 h, after which water (1 mL)
was added and stirring was maintained for an additional 60 min.
The organic phase was extracted and pyridine (0.02 mL, 0.28 mL)
and chloranil (0.04 g, 0.15 mmol) were added. The mixture was
stirred at 15 ꢀC for 16 h, after which 5% NaHSO3 (1 mL) was added,
filtered over Celite, and extracted three times with DCM. The
combined organic phases were washed with water (3ꢂ15 mL),
brine (3ꢂ15 mL), dried (Na2SO4), and evaporated to afford a residue
that was fractionated by chromatography on silica gel. Elution with
suspended in water at 15 ꢀC, filtered again, and dried. Compound
20
14 was afforded (49 g, 84%) pure. Mp: 185–186 ꢀC; [
a
]
þ217.5 (c
D
1.3, CHCl3); IR (CHCl3)
n
(cmꢁ1): 730, 911, 1227, 1356, 1665, 2951,
(ppm): 0.67 (s, 3H), 1.25 (s, 3H),
3452; 1H NMR (CDCl3) (200 MHz)
d
0.5–3.0 (m, 15H), 2.27 (s, 3H), 5.01 (t, J¼2.0 Hz, 1H), 5.13 (t,
J¼2.0 Hz, 1H), 5.58 (d, J¼3.0 Hz, 1H), 5.91 (s, 1H); 13C NMR (CDCl3)
(50 MHz)
d (ppm): 15.2, 24.6, 26.2, 27.5, 32.2, 33.3, 33.7, 34.0, 37.8,
40.0, 41.4, 46.8, 48.0, 89.5, 114.0, 119.2, 121.7, 143.1, 145.5, 167.4,
199.5, 211.1; HRMS-EI (MþH) calcd for C22H29O3 341.2111, found
341.2112.
1:1 hexane/ethyl acetate gave 18 (0.035 g, 67%) pure. Mp: 197–
20
205 ꢀC; [
a]
þ45.7 (c 1.5, CHCl3); IR (CHCl3)
n
(cmꢁ1): 743, 924,
D
4.3. 6
a
-Methyl-17
a
-hydroxy-pregna-9(11)-
1015, 1177, 1385, 1469, 1625, 1664, 1697, 2936, 3474; 1H NMR
(CDCl3) (200 MHz)
ene-3,20-dione (15)
d
(ppm): 0.70 (s, 3H), 1.14 (d, J¼6.4 Hz, 3H), 1.40
(s, 3H), 2.26 (s, 3H), 0.5–3.0 (m, 12H), 5.52 (d, J¼5.4 Hz, 1H), 6.06 (s,
The 6-methylene steroidal derivative 14 (1.07 g, 3.16 mmol)
and palladium over charcoal 10% (50% wet, 0.1 g/g) were sus-
pended in ethanol (25 mL) keeping the reaction mixture under
hydrogen pressure (5 atm) and gently stirred for 7 h. The reaction
mixture was filtered over Celite, and the solid gently extracted
with ethanol. The organic phase was concentrated up to 25 mL
and 37% HCl (8.5 mL, 0.25 mL) was added, followed by 20 h of
stirring. Once the isomerization process was completed, a satu-
rated NaHCO3 solution (25 mL) was added and organic phase was
extracted with ethyl acetate, washed with brine (3ꢂ25 mL), dried
1H), 6.27 (d, J¼10.2 Hz,1H), 7.18 (d, J¼10.2 Hz,1H); 13C NMR (CDCl3)
(50 MHz)
d (ppm): 15.2, 17.6, 24.8, 27.1, 27.5, 32.3, 33.2, 33.7, 36.6,
43.6, 46.1, 46.9, 47.8, 89.4, 120.4, 121.1, 126.9, 142.7, 155.2, 169.7,
186.4, 211.0; HRMS-EI (MþNa) calcd for C22H28O3Na 363.1931,
found 363.1939.
4.6. 6
a-Methyl-9,11b-epoxy-17a-hydroxy-pregna-
1,4-diene-3,20-dione (19)
To a solution of the steroidal diketone 18 (2 g, 6 mmol) in
20 mL of mixture acetone/water 6:1 70% perchloric acid
(Na2SO4), and evaporated to obtain 15 (0.81 g, 57%) pure. Mp:
a
20
105 ꢀC; [
a
]
ꢁ7.6 (c 1.6, CHCl3); IR (Nujol)
n
(cmꢁ1): 723, 898,
(0.07 mL, 1.2 mmol) was added dropwise, and the temperature
fixed at 25 ꢀC. 1,3-Dibromo-5,5-dimethylhydantoin (DBH, 1.2 g,
D
1378, 1463, 1716, 2728, 2916, 3487; 1H NMR (CDCl3) (400 MHz)