1H, J ) 7.0, 3.0 Hz), 3.19 (dd, 1H, J ) 7.0, 3.0 Hz), 1.04
(d, 3H, J ) 6.5 Hz), 0.59 (s, 3H), 0.85 (s, 9H), and 0.05 (s,
6H) ppm. Compound 21 was photolytically unstable and was
carried on directly to the next step.
layer was dried over anhydrous magnesium sulfate and
clarified, and the solvents were evaporated under reduced
pressure to afford a yellow oil (72 g). This oil was dissolved
in dry THF (1.3 L) and transferred to a dry, 3-L, three-neck,
round-bottom flask equipped with a mechanical stirrer,
thermocouple, nitrogen bubbler, and a rubber septum. The
reaction was cooled to -12 °C, and solid potassium
t-butoxide (70 g, 62.4 mmol) was added, producing an orange
reaction mixture. The reaction mixture was allowed to stir
at this temperature for 2.5 h at which point it was diluted
with ethyl acetate (1.4 L) and washed successively with 0.01
N aqueous hydrochloric acid solution (2 × 1 L), water (1
L), and saturated aqueous sodium chloride solution (1 L).
The organic extracts were dried over anhydrous magnesium
sulfate and clarified, and the solvent was evaporated under
reduced pressure, affording 58 g of crude compound 23 as
a yellow oil. This oil was used directly in the next step
without purification.
Preparation of trans-24(S)-Hydroxyvitamin D2 (24). To
a 3-L, three-neck, round-bottom flask equipped with a
mechanical stirrer, a rubber septum, and an addition funnel
was charged a solution of compound 23 (48 g, 74.0 mmol)
in dry THF (1 L). The stirrer was started, and the solution
was cooled to 0 °C at which point tetrabutylammonium
fluoride (1.0 M solution in THF, 500 mL, 500 mmol) was
slowly added. The resulting dark-colored solution stirred at
0 °C for 1 h and slowly warmed to ambient temperature
where it was stirred for 48 h. The reaction mixture was
diluted with water (1.5 L) and extracted with ethyl acetate
(2 × 1 L). The combined organic extracts were washed with
0.01 N aqueous hydrochloric acid solution (1 L) and saturated
aqueous sodium chloride solution (2 × 1.5 L), dried over
anhydrous magnesium sulfate, and clarified. The filtrate was
concentrated under reduced pressure to afford crude 24 as
an orange oil (58.5 g). Silica gel column chromatography
(20% ethyl acetate in hexanes) afforded 24 as a white foam
in an overall yield of 31% from 22 (9.5 g). By HPLC
analysis, this material consisted of 5.1% of the cis-isomer
and 85.8% of the trans-isomer (tR ) 19.4 and 21.4 min,
respectively) and 9.1% of related minor impurities. 1H NMR
(300 MHz, CDCl3) δ 6.55 (major, trans-isomer, d, 1H, J )
12.1 Hz), 6.23 (minor, cis-isomer, d, 1H, J ) 11.3 Hz), 6.03
(minor, cis-isomer, d, 1H, J ) 11.2 Hz), 5.87 (major, trans-
isomer, d, 1H, J ) 12.4 Hz), 5.45 (d, 1H, J ) 4.8 Hz), 5.44
(d, 1H, J ) 2.7 Hz), 5.04 (minor, cis-isomer, d, 1H, J )
2.0), 4.96 (major, trans-isomer, d, 1H, J ) 2.0 Hz), 4.81
(minor, cis-isomer, d, 1H, J ) 2.3), 4.69 (major, trans-
isomer, d, 1H, J ) 2.4 Hz), 3.90 (m, 1H), 2.88 (dd, 1H, J )
4.7, 12.7 Hz), 2.40-2.55 (m, 1H), 1.92-2.30 (m, 6H), 1.45-
1.80 (m, 8H), 1.22-1.44 (m, 6H), 1.21 (s, 3H), 1.03 (d, 3H,
J ) 6.7 Hz), 0.91 (d, 3H, J ) 4.0 Hz), and 0.60 ppm (s,
3H); CI MS m/z 412 [M]+.
Preparation of (3S)-tert-Butyldimethylsilyloxy-(20S)-
(diphenylphosphonium)-9,10-secopregna-5(Z),7(E),10(19)-
triene (22). To a 5-L, three-neck, round-bottom flask
equipped with a mechanical stirrer, thermocouple, nitrogen
bubbler, and two pressure-equalizing addition funnels was
charged diphenylphosphine (41 g, 0.22 mol) and dry THF
(570 mL). The stirrer was started, and the solution was cooled
to -78 °C. To one addition funnel was charged n-butyl-
lithium (2.5 M solution in hexanes, 90 mL, 0.23 mol), and
this was slowly added to the cooled solution, producing a
reddish-orange mixture that was stirred at -78 °C for 45
min. A solution of compound 21 (94 g, 0.17 mol) in dry
THF (570 mL) was transferred to the second addition funnel,
and this solution was added to the reaction mixture over 20
min. The resulting pale-yellow solution was stirred for 45
min at -78 °C and then gradually warmed to ambient
temperature where it was stirred for 3 h. The reaction mixture
was diluted with methyl tert-butyl ether (4 L) and washed
with saturated aqueous ammonium chloride solution (2 L).
The organic layer was gently washed with 10% hydrogen
peroxide solution (3 × 1 L). The organic layer was then
washed with saturated aqueous sodium chloride solution (2
× 1.5 L), dried over anhydrous magnesium sulfate, and
clarified. The yellow filtrate was evaporated under reduced
pressure to afford the crude product as a yellow oil (140 g).
Silica gel column chromatography (5% ethyl acetate in
hexanes) provided an 83% yield of compound 22 (88 g) as
a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.76 (m, 4H),
7.48 (m, 6H), 6.45 (d, 1H, J ) 12.5 Hz), 5.82 (d, 1H, J )
12.3 Hz), 4.92 (s, 1H), 4.64 (s, 1H), 3.84 (m, 1H), 2.84 (dd,
1H, J ) 4.1, 12.7 Hz), 2.63 (dd, 1H, J ) 3.7, 12.4 Hz), 2.43
(br m, 3H), 2.30-1.78 (b m, 9H), 1.75-1.40 (br m, 9H),
1.15-1.10 (m, 4H), 0.89 (s, 9H), 0.48 (s, 3H), and 0.15 (s,
6H) ppm; 13C NMR (75 MHz, CDCl3) δ 149.9, 136.5, 131.4,
130.9, 130.8, 130.6, 130.5, 128.6, 128.4, 121.2, 119.9, 118.1,
116.3, 112.0, 107.6, 70.5, 69.4, 58.2, 58.1, 56.5, 56.4, 46.8,
46.0, 40.4, 37.6, 36.4, 35.5, 35.2, 32.7, 32.1, 31.6, 31.2, 28.9,
27.9, 26.0, 25.9, 23.4, 22.6, 22.1, 21.3, 18.1, and 11.9 ppm.
Preparation of the Bis-silyl-protected trans-24(S)-
Hydroxyvitamin D2 (23). To a 3-L, three-neck, round-
bottom flask equipped with a mechanical stirrer, thermo-
couple, addition funnel, and nitrogen bubbler was charged a
solution of compound 22 (47.1 g, 74.9 mmol) in dry THF
(700 mL). The solution was cooled to -75 °C, and
n-butyllithium (2.5 M solution in hexanes, 60 mL, 150 mmol)
was added, producing a red solution that was stirred for 45
min. At this point, a solution of compound 17 (22.3 g, 96.8
mmol) in THF (100 mL) was added over 20 min. This
solution was stirred at -75 °C for 1 h, producing a yellow
solution. The solution was warmed to 0 °C over 1.5 h at
which point ethyl acetate (800 mL) was added. The reaction
solution was washed with saturated aqueous ammonium
chloride solution (800 mL), water (800 mL), and saturated
aqueous sodium chloride solution (800 mL). The organic
Preparation of 24(S)-Hydroxyvitamin D2 (1). To a 4-L,
water-jacketed, Pyrex photoreactor was charged a solution
of compound 24 (9.5 g, 23 mmol) and 9-acetylanthracene
(1.2 g, 6 mmol) in methanol (4 L). The stirrer was started,
and the resulting solution was cooled to 7 °C and purged
with nitrogen for 1.5 h. It was then irradiated using a 400
254
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Vol. 6, No. 3, 2002 / Organic Process Research & Development