SYNTHESIS OF 5α-HYDROXYECDYSTEROID ANALOGS
1459
substance. IR spectrum (film), ν, cm–1: 3440, 905.
1H NMR spectrum, δ, ppm: 0.84 s (3H, 18-Me), 1.02 s
(3H, 19-Me), 1.34 s (3H, 21-Me), 3.52 m (1H, 3-H),
4.96 d.d (1H, 23-H, J1 = 10.5, J2 = 1.5 Hz), 5.15 d.d
(1H, 23-H, J1 = 17, J2 = 1.5 Hz), 5.36 d (1H, 6-H, J =
4.5 Hz), 6.0 d.d (1H, 22-H, J1 = 10.5, J2 = 17 Hz).
for 30 min at –78°C, allowed to warm up to room
temperature, washed with water, dried over anhydrous
sodium sulfate, and evaporated, and the residue was
purified by recrystallization. Yield 2.46 g (82%),
mp 172–173°C (hexane–ethyl acetate). IR spectrum
1
(film), ν, cm–1: 3530, 1360. H NMR spectrum, δ,
ppm: 0.74 s (3H, 18-Me), 1.02 s (3H, 19-Me), 1.16 d
(9H, 21-Me, CHMe2, J = 7 Hz), 2.36 m (1H, 6-H),
2.42 s (3H, MeC6H4), 2.68 m (1H, CHMe2), 2.82 d
(2H, 4'-H, J = 10 Hz), 4.48 m (1H, 5'-H), 4.59 m (1H,
3-H), 7.34 d and 7.80 d (4H, C6H4, J = 7.5 Hz).
(5'R,20R)-20-(3-Isopropyl-4,5-dihydroisoxazol-5-
yl)pregn-5-ene-3,20-diol (III). N-Chlorosuccinimide,
10.5 g, was dispersed in 50 ml of dry chloroform
containing 0.1 ml of pyridine, 11 g of isobutyraldehyde
oxime was added, and the mixture was stirred for
15 min until it became homogeneous. A solution of 9 g
(25 mmol) of steroid II in 100 ml of chloroform was
added, and a solution of 9 ml of triethylamine in 40 ml
of chloroform was then added dropwise over a period
of 4 h. The mixture was stirred for 12 h, washed with
water, and dried over anhydrous sodium sulfate. The
solvent was distilled off, and the residue was subjected
to chromatography on silica gel using cyclohexane–
ethyl acetate (5:1). The major product was dihydroiso-
xazole derivative III; yield 10.93 g (75%), mp 200–
201°C (from methanol). IR spectrum, ν, cm–1: 3420,
(5'R,20R)-20-(3-Isopropyl-4,5-dihydroisoxazol-5-
yl)-3-(p-tolylsulfonyloxy)pregnane-5α,6β,20-triol
(VI). Epoxy derivative V, 0.9 g (1.5 mmol), was dis-
solved in a mixture of 80 ml of dioxane and 20 ml of
water, and 18 ml of 70% perchloric acid was added.
The mixture was stirred for 2 h at room temperature,
treated with a saturated solution of sodium carbonate
to neutralize excess perchloric acid, and extracted with
ethyl acetate. The extract was washed with water and
dried over anhydrous sodium sulfate, and the solvent
was distilled off to obtain 0.88 g (96%) of triol VI,
mp 213–214°C (from hexane–ethyl acetate). IR spec-
trum (film), ν, cm–1: 3520, 3470, 1610, 1360. 1H NMR
spectrum, δ, ppm: 0.82 s (3H, 18-Me), 1.12 s (6H,
19-Me, 21-Me), 1.16 d (6H, CHMe2, J = 7 Hz), 2.44 s
(3H, MeC6H4), 2.70 m (1H, CHMe2), 2.82 d (2H,
4'-H, J = 10 Hz), 3.48 m (1H, 6-H), 4.48 m (1H,
5'-H), 4.92 m (1H, 3-H), 7.34 d and 7.80 d (4H, C6H4,
J = 7.5 Hz).
1
1485, 1390. H NMR spectrum, δ, ppm: 0.84 s (3H,
18-Me), 1.02 s (3H, 19-Me), 1.16 d (9H, 21-Me,
CHMe2, J = 7 Hz), 2.70 m (1H, CHMe2), 2.84 d (2H,
4'-H, J = 10 Hz), 3.54 m (1H, 3-H), 4.50 m (1H, 5'-H),
5.36 d (1H, 6-H, J = 4.5 Hz).
(5'R,20R)-20-(3-Isopropyl-4,5-dihydroisoxazol-
5-yl)-3-(p-tolylsulfonyloxy)pregn-5-ene (IV). Com-
pound III, 2.7 g (8.54 mmol), was dissolved in 30 ml
of pyridine, 4.84 g (24.6 mmol) of p-toluenesulfonyl
chloride was added, and the mixture was kept for 24 h
at room temperature and poured into water. The pre-
cipitate was filtered off and dissolved in ethyl acetate,
and the solution was dried over sodium sulfate.
Removal of the solvent afforded 3.4 g (93%) of
3-(p-tolylsulfonyloxy) derivative IV, mp 158–159°C
(from hexane–ethyl acetate). IR spectrum, ν, cm–1:
(5'R,20R)-5α,20-Dihydroxy-20-(3-isopropyl-
4,5-dihydroisoxazol-5-yl)-3-(p-tolylsulfonyloxy)-
pregnan-6-one (VII). Triol VI, 0.9 g (1.46 mmol),
was dissolved in 30 ml of dry chloroform, and 0.49 g
(2.32 mmol) of pyridinium chlorochromate was added.
The mixture was stirred for 6 h at room temperature
and filtered through a layer of silica gel, the solvent
was distilled off from the filtrate, and the residue was
subjected to column chromatography on silica gel
using cyclohexane–ethyl acetate (1:1) as eluent. Yield
0.74 g (82%), mp 127–128°C (from hexane–ethyl
acetate). IR spectrum (film), ν, cm–1: 3510, 1390.
1H NMR spectrum, δ, ppm: 0.76 s (6H, 18-Me,
19-Me), 1.12 s (3H, 21-Me), 1.16 d (6H, CHMe2, J =
7 Hz), 2.46 s (3H, MeC6H4), 2.50 m (1H, CHMe2),
2.84 d (2H, 4'-H, J = 10 Hz), 4.48 m (1H, 5'-H),
4.82 m (1H, 3-H), 7.34 d and 7.80 d (4H, C6H4).
1
3550, 3450, 1610, 1350. H NMR spectrum, δ, ppm:
0.79 s (3H, 18-Me), 0.98 s (3H, 19-Me), 1.12 d (9H,
21-Me, CHMe2, J = 7 Hz), 2.44 s (3H, MeC6H4),
2.70 m (1H, CHMe2), 2.84 d (2H, 4'-H, J = 10 Hz),
4.32 m (1H, 3-H), 4.46 m (1H, 5'-H), 5.28 d (1H, 6-H,
J = 4.5 Hz), 7.34 d and 7.80 d (4H, C6H4, J = 7.5 Hz).
(5'R,20R)-5α,6α-Epoxy-20-(3-isopropyl-4,5-di-
hydroisoxazol-5-yl)-3-(p-tolylsulfonyloxy)pregnan-
20-ol (V). Compound IV, 2.6 g (5.07 mmol), was
dissolved in 30 ml of chloroform, the solution was
cooled to –78°C, and 1.55 g of m-chloroperoxybenzoic
acid was added under stirring. The mixture was stirred
(5'R,20R)-5α,20-Dihydroxy-20-(3-isopropyl-
4,5-dihydroisoxazol-5-yl)pregn-2-en-6-one (VIII).
Anhydrous lithium bromide, 0.944 g (10.85 mmol),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004