3
3
H), 1.25-1.5 (m, 6H), 1.55-1.75 (m, 4H), 3.02 (s, 1H),
.15-3.55 (m, 3H), 3.7 (s, 3H) 4.5 (m, 1H).
mmol, 60% of a dispersion in paraffine) in 100 mL of THF
at 0 °C were added slowly 42 g (133 mmol) of 28 dissolved
in 250 mL of THF. The solution was stirred for 1 h at rt,
and then 65.9 g (115 mmol) of (5E,7E)-(1S,3R)-1,3-bis(tert-
butyldimethylsilyloxy)-9,10-secopregna-5,7,10(19)-triene-20-
carbaldehyde (4) dissolved in 400 mL of THF were added.
The solution was stirred 1 h at 20 °C and 19 h at 50 °C. The
reaction was monitored by thin layer chromatography (TLC)
1-(2-Oxo-hexylcarbamoyl)cyclopropanecarboxylic Acid
Methyl Ester (26): A solution of 35.8 mL (0.5 mol) of
DMSO in 100 mL of dichloromethane was cooled to -40
°
C, and 19.8 mL (0.23 mol) of oxalyl chloride in 198 mL of
dichloromethane (precooled to -40 °C) were slowly added.
After 10 min of stirring, a solution of 51.6 g (0.18 mol) 1-(2-
hydroxy-hexylcarbamoyl)cyclopropanecarboxylic acid meth-
yl ester 25 (crude, content 83%, dissolved in 198 mL of
dichloromethane) was slowly added over a period of 40 min.
The reaction was stirred for 30 min at -40 °C. Then 69.8
mL (0.5 mol) of triethylamine were added followed by 300
mL of water. Extraction with dichloromethane and evapora-
tion of the solvent yielded 44.72 g (100% yield) of crude 26
as an oil.
on SiO
2
plates (eluent ethyl acetate/hexane 1:9 v/v), R
f
)
0
.15 (product 29), R
f
) 0.53 (educt 4). 6 g (100 mmol) of
acetic acid in 50 mL of THF were added for workup followed
by 1 L of water, with citric acid used to adjust pH to 7. The
product was extracted twice with 500 mL of methyl tert-
butylether and evaporated to dryness. The crude material was
purified by chromatography on silica gel by elution with
hexanes and an increasing gradient of ethyl acetate (0-15%).
The evaporation of the fractions gave 79.5 g of 29 in 90%
yield.
2
6: C12
H
19NO
4
, mw 241.29 MS (CI-NH
3
, 70 eV): m/z
+
1
)
3
3
242 [M - H ]; H NMR (CDCl
3
, 400 MHz): δ ) 0.9 (t,
H), 1.25-1.43 (m, 2H), 1.55-1.74 (m, 6H), 2.45 (m, 2H),
.7 (s, 3H), 4.15-4.2 (m, 2H), 9,3 (s, 1H).
2
9: C46
H
75NO
4
Si
2
, mw 762,29; MS (CI-NH
3
, 70 eV):
+
+
1
m/z ) 762 [M - H ], 730 [(M-TBDMSOH)-H ]; H
1-(5-Butyl-oxazol-2-yl)cyclopropylcarboxylic Acid Meth-
NMR (CDCl
0
1
3
, 400 MHz): δ ) 0.04 (s, 6H), 0.05 (s, 6H),
.5 (s, 3H, H-19), 0.9 (s, 9H), 0.95 (s, 9H), 1.05 (d, 3H),
.1-2.1 (m), 2.55 (m, 1H), 2.65 (m, 2H), 2.85 (m, 1H), 4.2
yl Ester (27): 44 g (0.18 mol) of compound 26 in 100 mL
of dichloromethane were slowly added to 132 mL of concd
sulfuric acid at 20-30 °C. The reaction was stirred for 14 h
at 40 °C. For workup the solution was poured onto 200 mL
of ice-water and 200 mL of dichloromethane. Phase
separation and evaporation of the solvent yielded 45 g of
crude product, which gave after distillation at 78 °C/1 mbar
(
1
m, 1H, H-3), 4.5 (m, 1H, H-1), 4.95 (d, 2H, H-19), 5.8 (d,
H, H-7), 6.1 (d, 1H, H22), 6.47 (d, 1H, H-6), 6.65 (s, 1H,
H-4′), 6.75 (m, 1 H, H-23).
5Z,7E,22E)-(1S,3R,24R)-1,3-Bis(tert-butyl-dimethyl-
silyloxy)-24-hydroxy-25-(5-butyloxazol-2-yl)-26,27-cyclo-
,10-secocholesta-5,7,10(19),22-tetraene (8b). 48.4 g (63.5
mmol) of compound 29 were dissolved in 240 mL of THF
and 200 mL of methanol. 3.29 g (8.8 mmol) of CeCl
heptahydrate were added and stirred for 15 min. 3.68 g (97
mmol) of NaBH were dissolved in 22 mL of water and
dropped at 5 °C to the solution of the enone. The reaction
was monitored by TLC (SiO plates, hexane/ethyl acetate
:1 v/v, R ) 0.55 (for educt 29, 0.35 for 8a (24R) and 0.31
(
2
8.77 g of compound 27 (72% yield) in a GC purity of 98%.
, mw 223.17, MS (CI-NH , 70 eV): m/z
, 400 MHz): δ ) 0.95 (t,
9
2
7: C12
H
17NO
3
1
3
+
)
224 [M-H ]; H NMR (CDCl
3
3
-
3
(
H), 1.3-1.7 (m, 8H), 2.58-2.67 (m, 2H), 3.7 (s, 3H), 6.64
s, 1H)
2-[1-(5-Butyl-oxazol-2-yl)cyclopropyl]-2-oxoethyl}-
4
{
phosphonic Acid Dimethylester (28): Under an inert
atmosphere of nitrogen, to 41.9 mL (198 mmol) of dry
hexamethyldisilazane (HMDS) dissolved in 155 mL of
tetrahydrofuran was added 124 mL (0.198 mol) of butyl-
lithium (1.6 M in hexanes) at -50 °C and stirred for 15
min. Then 12.33 g (99 mmol) of dimethyl methylphospho-
nate in 4 mL of tetrahydrofuran was added at -50 °C to the
solution. After 30 min 22.2 g of 1-(5-butyl-oxazol-2-yl)-
cyclopropylcarboxylic acid methyl ester 27 (99 mmol)
dissolved in 30 mL of THF were added, and the reaction
was stirred for over 2 h. The temperature came up to 0 °C.
Then 20 mL of acetic acid were added followed by 80 mL
of water. The product 28 was extracted with ethyl acetate
and purified by chromatography on silica gel with ethyl
acetate-hexanes as eluent. Evaporation of the product
fractions gave 28.05 g (90% yield) of phosphonate 28 as a
colourless oil.
2
3
f
for 8b (24S))). For quenching and workup 4 mL of acetone
were added followed by 145 mL of water. After adjusting
pH to 7 using acetic acid, the product was extracted with
methyl tert-butylether. After phase separation and evapora-
tion to dryness the diastereomeric alcohols were separated
by chromatography on Merck silicagel with hexanes-ethyl
acetate as eluent, starting with 10% ethyl acetate/90% hexane
as a gradient up to 20% ethyl acetate. The first fraction was
the 24S-alcohol 8a, the second fraction was the desired 25R-
alcohol 8b. The evaporation of the fractions gave 26 g of
8
b as a white solid. The 24S isomer 8a (22 g) was oxidized
by MnO (10 equiv) in DCM to ketone 29 which was reduced
2
by the previously described method giving after purification
by chromatography an additional 8.5 g of compound 8b in
71% yield.
2
8: C14
H
22NO
5
P, mw 315.3, MS (CI-NH
3
, 70 eV): m/z
+
1
)
316 [M - H ]; H NMR (CDCl
3
, 400 MHz): δ ) 0.93
8b: C46
H
77NO
4
Si
2
, mw 7642,289; MS (CI-NH
3
, 70
+
+
(
t, 3H), 1.33-1.75 (m, 8 H), 2.65 (m, 2H), 3.54 (d, 2H, J )
5 Hz), 3.75 (d, 6H, J ) 15 Hz), 6.69 (s, 1H).
5E,7E,22E)-(1S,3R)-1,3-Bis(tert-butyldimethylsilyloxy)-
4-oxo-25-(5-butyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-
,7,10(19),22-tetraen (29). To 4.84 g of sodium hydride (121
eV): m/z ) 764 [M - H ]; 732 [(M-TBDMSOH)-H ];
H NMR (CDCl , 400 MHz): δ ) 0.04 (s, 6H), 0.045 (s,
3
1
2
(
6H), 0.53 (s, 3H, H-19), 087 (s, 9H), 0.91 (s, 9H), 1.03 (d,
3H), 1.1-1.6 (m), 1.85-2.1 (m), 2.3 (m, 1H), 2.57 (m, 2H),
2.87 (m, 1H), 4.1 (m, 1H, H-24), 4.2 (m, 1H, H-3), 4.5 (m,
2
5
204
•
Vol. 11, No. 2, 2007 / Organic Process Research & Development