Kurek-Tyrlik et al.
(
20 mL) was added dropwise to a stirred at -78 °C solution of
LDA [prepared from n-BuLi (2.5 M, 1.4 mL, 3.5 mmol) and
i-Pr) NH (0.485 mL, 3.5 mmol)] in THF (20 mL). After 30 min,
25.0, 22.8, 22.6, 22.4, 21.5, 20.7, 19.3, 17.0, 13.1. HRMS: calcd
52 3
for C33H O , 496.39165; found, 496.39121.
(
2
1
7r-Cholest-5-en-3â,25-diol (5a). Palladium-on-carbon
MeI (0.22 mL, 3.5 mmol) and HMPA (0.615 mL, 3.5 mmol)
were consecutively added. The mixture was stirred at -50 °C
for 16 h and then diluted with hexanes (100 mL) and washed
with water (2 × 50 mL). The solvent was evaporated, and the
residue was chromatographed on silica gel (20 g, hexanes-
(5%, 30 mg) and NaHCO (50 mg) were added to a solution of
3
18 (1.006 g, 2.03 mmol) in EtOAc (30 mL). The suspension
was vigorously stirred under hydrogen for 72 h and then
filtered through a pad of Cellite. The Cellite was washed with
EtOAc. The combined filtrates were vaporated to give O-
(tetrahydropyran-2ê-yl)-25-hydroxy-6â-methoxy-3R,5-cyclo-
2
5
EtOAc, 95:5) to give 14 (1.078 g, 98%): [R]
D
) +49.7 (c )
1
1
1
2
0
3
8
5
2
.04, CHCl
3
); H NMR (200 MHz) 3.65 (s, 3H), 3.31 (s, 3H),
5R,17R-cholestane (1.011 g, 100%): H NMR (200 MHz), 4.73-
.76 (t, 1H, J ) 2.8 Hz), 2.28 (dq, 1H, J ) 10.5, 6.8 Hz), 2.10-
.70 (m, 19H) overlapping 1.09 (d, 3H, J ) 6.8 Hz), 1.00 (s,
H), 0.84 (s, 3H), 0.63 (t, 1H, J ) 4.9 Hz), 0.42 (dd, 1H, J )
4.67 (m, 1H), 4.00-3.87 (m, 1H), 3.48-3.35 (m, 1H), 3.31 (s,
3H), 2.75 (t, 1H, J ) 2.5 Hz), 1.98-0.68 (m, 32H) overlapping
1.18 (s, 3H), 1.17 (s, 3H), 1.01 (s, 3H), 0.81 (d, 3H, J ) 6.6 Hz)
and 0.79 (s, 3H), 0.62 (t, 1H, J ) 4.8 Hz), 0.41 (dd, 1H, J )
1
3
.1, 5.1 Hz); C NMR (50 MHz) 178.6, 82.9, 57.2, 52.6, 52.0,
1.1, 48.4, 44.3, 44.0, 42.1, 36.3, 35.9, 34.8, 34.0, 31.3, 26.5,
6.4, 25.6, 23.5, 22.1, 19.9, 17.9, 13.8. HRMS: calcd for
1
3
8.1, 5.1 Hz); C NMR (50 MHz), 93.9, 82.4, 63.4, 56.5, 52.7,
52.6, 52.4, 48.1, 43.9, 43.5, 42.1, 38.4, 35.7, 35.3, 34.1, 33.4,
32.9, 32.9, 32.6, 30.9, 26.8, 26.2, 26.1, 25.5, 24.9, 22.8, 22.6,
C
24
H
38
O
3
, 374.28210; found, 374.28173.
â-Methoxy-3r,5-cyclo-23,24-bisnor-5r,17r-cholan-22-
ol (17a). LiAlH (150 mg, 3.59 mmol) was added in four
2
2.4, 21.9, 21.5, 20.9, 19.3, 17.0, 17.0, 13.1. HRMS: calcd for
, 500.42295; found, 500.42554.
Water (20 mL) and TsOH (250 mg) were added to a solution
6
33 56 3
C H O
4
portions to a solution of 14 (888 mg, 2.38 mmol) in THF (30
mL). The mixture was stirred at room temperature for 30 min,
and the reagent excess was destroyed with saturated aqueous
of this product (2.46 g, 4.9 mmol) in dioxane (80 mL). The
mixture was stirred at 65 °C for 3 h, cooled, and the bulk
solvent was evaporated. The residue was diluted with water
Na
with hexanes (100 mL) and filtered. The filtrate was evapo-
2 4
SO . The mixture was diluted with ether (30 mL) and then
(
ca. 80 mL). The precipitate was collected and washed with
2
5
water (2 × 25 mL) and then with hexanes (3 × 10 mL). Diol
rated to give 17a (821 mg, 100% yield): [R]
D
) +12.8 (c )
); H NMR (200 MHz) 3.46-3.18 (m, 2H) over-
lapping 3.30 (s, 3H), 2.74 (t, 1H, J ) 2.7 Hz), 1.98-0.67 (m,
1
5a (1.83 g, 92% yield, 48% yield from 7) was obtained: mp
1
.19, CHCl
3
2
6
1
81-183 °C (from EtOAc); [R]
D
3
) -71.3 (c ) 0.31, CHCl );
1
H NMR (200 MHz) 5.34 (d, 1H, J ) 5.3 Hz), 3.61-3.43 (m,
H), 2.28-0.70 (m, 29H) overlapping 1.21 (s, 6H), 1.01 (s, 3H),
2
0
0H) overlapping 1.00 (s, 3H) and 0.86 (d, 3H, J ) 6.6 Hz),
.81 (s, 3H), 0.62 (t, 1H, J ) 4.8 Hz), 0.41 (dd, J ) 8.1, 5.1
1
13
1
3
0.81 (d, 3H, J ) 6.4 Hz), 0.76 (s, 3H); C NMR (50 MHz) 140.7,
Hz); C NMR (50 MHz) 82.4, 68.3, 56.5, 52.5, 48.3, 48.1, 44.0,
1
3
2
21.7, 71.8, 71.1, 52.9, 52.6, 50.2, 44.2, 43.5, 42.3, 38.3, 37.3,
6.6, 33.6, 33.0, 32.5, 32.4, 31.7, 29.3, 26.3, 22.4, 22.3, 22.1,
4
2
3
3.4, 35.9, 35.6, 35.2, 34.1, 33.3, 30.9, 26.1, 24.9, 22.7, 22.3,
2.1, 21.4, 19.3, 14.0, 13.1. HRMS: calcd for C23
46.28718; found, 346.28651.
38 2
H O ,
46 2
1.1, 19.4, 16.9. Anal. Calcd for C27H O (402.65): C, 80.54;
H, 11.51. Found: C, 80.33; H, 11.61.
â,25-Dihydroxy-17r-cholest-5-ene 3-acetate (5b). Al-
O-(Tetrahydropyran-2ê-yl)-25-hydroxy-6â-methoxy-
r,5-cyclo-5r,17r-cho lest-23-yn (18). To a stirred solution
3
3
cohol 5a (0.33 g) was dissolved in a mixture of pyridine (6.4
mL) and acetic anhydride (2.8 mL) with slight warming. The
solution was set aside for 20 h at room temperature, and then
water (50 mL) was added. After 4 h, the precipitate was
collected and air dried. This product (0.34 g) was chromato-
graphed on silica gel (12 g, hexanes-acetone, 97:3) to give 5b
of 17a (815 mg, 2.36 mmol) in DCM (20 mL) were added
consecutively Et
mmol), and DMAP (5 mg). The mixture was stirred for 16 h,
and then saturated aqueous NaHCO (10 mL) was added. The
3
N (2.0 mL, 14.5 mmol), TsCl (1320 mg, 6.95
3
mixture was stirred for 1 h and poured into water. The product
was extracted with hexanes (100 mL). The organic extract was
washed with water and evaporated. The residue was chro-
matographed on silica gel (30 g, hexanes-EtOAc, 95:5 con-
2
5
(
D
0.31 g, 86% yield): mp 98-100 °C (from hexanes); [R] )
1
-
72.0 (c ) 1, CHCl
m, 1H), 4.64-4.56 (m, 1H), 2.36-2.27 (m, 2H), 2.03 (s, 3H),
.90-1.80 (m, 2H), 1.80-1.10 (m, ca. 24H) overlapping 1.21
s, 6H) and 1.02 (s, 3H), 0.82 (d, J ) 6.5 Hz, 3H), 0.77 (s, 3H);
3 3
); H NMR (500 MHz, CDCl ) 5.39-5.36
(
3
taining a few drops of Et N). Tosylate 17b was obtained (1.257
1
1
g): H NMR (200 MHz) 7.77 (d, 2H, J ) 8.2 Hz), 7.33 (d, 2H,
J ) 8.2 Hz), 3.82 (dd, 1H, J ) 9.3, 6.1 Hz), 3.66 (dd, 1H, J )
(
13
C NMR (125 MHz) 170.5, 139.6, 122.6, 74.0, 71.0, 52.9, 52.7,
0.1, 44.3, 43.5, 38.4, 38.1, 33.0, 32.5, 32.3, 29.27, 29.26, 27.8,
48 3
6.3, 22.3, 22.1, 21.4, 21.1, 19.3, 17.0. Anal. Calcd for C29H O
444.67): C, 78.32; H, 10.88, Found: C, 78.37; H, 10.74.
â,25-Dihydroxy-17r-cholesta-5,7-diene-3-acetate (19a).
A mixture of 5b (1.09 g, 2.45 mmol), powdered NaHCO (1.05
9
.3, 7.3 Hz), 3.30 (s, 3H), 2.74 (t, 1H, J ) 2.6 Hz), 2.45 (s, 3H),
.10-0.63 (m, 20H) overlapping 1.00 (s, 3H), 0.84 (d, 3H, J )
.7 Hz), 0.75 (s, 3H) and 0.63 (t, 1H, J ) 4.9 Hz), 0.42 (dd, J
5
2
(
2
6
1
3
)
8.1, 5.1 Hz); C NMR (50 MHz) 144.5, 133.2, 129.7, 127.8,
3
8
3
1
2.2, 75.4, 56.5, 52.4, 47.9, 44.0, 43.4, 35.6, 35.2, 34.0, 33.3,
2.9, 30.9, 25.9, 24.9, 22.6, 22.3, 22.1, 21.6, 21.4, 19.2, 14.1,
4.0, 13.1.
3
g, 12.5 mmol), 1,3-dibromo-5,5-dimethylhydantoin (0.51 g, 1.77
mmol), and hexanes (35 mL) was stirred at reflux temperature
for 30 min. After cooling, the solid was filtered off under argon
and washed with hot hexanes. The combined filtrates were
evaporated. To the residue xylene (35 mL) and collidine (3.5
mL) were added, and the mixture was heated under reflux
for 1.5 h. After cooling, the mixture was poured into water
and the product was extracted with ether (3 × 60 mL).
Combined extracts were washed consecutively with cold 5%
n-BuLi (2.5 M in hexanes, 5.7 mL, 14.2 mmol) was added
dropwise to a stirred at 5 °C solution of 3-methyl-3-(terahydro-
pyran-2-yl)oxy-but-1-yne (2.40 g, 14.2 mmol) in dioxane (30
mL). After 30 min, the solution was added to a solution of 17b
(
1.246 g) in dioxane (10 mL). The mixture was heated at the
reflux temperature for 72 h, cooled, and partitioned between
hexanes (100 mL) and water (100 mL). The organic layer was
washed with water and evaporated. The residue was chro-
matographed on silica gel (100 g, hexanes-EtOAc, 98:2 and
HCl (2 × 30 mL), water, saturated aqueous NaHCO
3
, and
brine. The solvent was evaporated on a rotary evaporator and
then in high vacuum (xylene). The residue was dissolved in
dioxane (35 mL), and TsOH (35 mg) was added. The solution
was stirred at 55 °C for 4 h, whereupon it was poured into
water and the product was extracted with ether. The crude
product (1.28 g) was chromatographed on silica gel (45 g,
acetone-hexanes, 97:3). Fractions containing 5,7-diene were
collected to give 19a (0.44 g, 40%): UV (EtOH) λmax 271 nm (ꢀ
9
1
6
3
2
0
5:5) to give 18 (1.025 g, 88% yield from 17a) and unchanged
1
7b (61 mg, 5%). 18: H NMR (200 MHz) 5.04 (dd, 1H, J )
.0, 3.3 Hz), 3.99-3.88 (m, 1H), 3.54-3.42 (m, 1H), 3.31 (s,
H), 2.75 (t, 1H, J ) 2.7 Hz), 2.30-0.70 (m, 26H) overlapping
.05 (t, 2H, J ) 6.4 Hz), 1.49 (s, 3H), 1.45 (s, 3H), 1.02 (s, 3H),
.93 (d, 3H, J ) 6.4 Hz) and 0.82 (s, 3H), 0.64 (t, 1H, J ) 4.8
1
3
Hz), 0.42 (dd, 1H, J ) 8.1, 5.2 Hz); C NMR (50 MHz) 96.2,
1
8
3
4.0, 83.4, 82.4, 71.4, 63.5, 56.5, 52.4, 51.8, 48.1, 44.0, 43.5,
5.7, 35.3, 34.3, 33.4, 32.1, 31.1, 30.9, 30.2, 27.0, 26.1, 25.4,
8817), 281 nm (ꢀ 9225), 292 nm (ꢀ 5452); H NMR (200 MHz)
5.61-5.50 (m, 1H), 5.47-5.35 (m, 1H), 4.80-4.60 (m, 1H), 2.04
8520 J. Org. Chem., Vol. 70, No. 21, 2005