1728 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8
Posner et al.
ethanol/hexanes, buffered with 0.5% Et3N) to give 4 mg (7%,
2% overall) of the natural A-ring isomer 4b.
min. HMPA (500 µL) was then added via syringe, and the
reaction mixture was allowed to stir for an additional 15 min.
A solution of iodide (-)-5 (100 mg, 0.22 mmol) in 3 mL of THF
was cooled to -78 °C and added to the reaction mixture via
cannula. The reaction mixture was stirred at -78 °C for 1 h,
and then, it was allowed to warm to room temperature over
the course of 2 h and to stir for an additional 6 h. The resulting
yellow solution was quenched with 4 mL of water, extracted
with ethyl acetate (3 × 35 mL), dried over MgSO4, concen-
trated, and purified using silica gel column chromatography
(0-20% ethyl acetate/petroleum ether) to give a colorless oil
(92 mg, 85%). 1H NMR (400 MHz, CDCl3): δ 7.36-7.23 (m,
5H), 5.16 (t, J ) 1.4 Hz, 1H), 4.10 (d, J ) 2.0 Hz, 1H), 2.27-
1.55 (m, 16H), 1.13 (s, 9H), 1.47 (s, 9H), 0.98-0.94 (t, J ) 8
Hz, 9H), 0.92 (s, 3H), 0.90-0.88 (d, J ) 6.8 Hz, 3H), 0.59-
0.53 (q, J ) 7.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 194.7,
160.0, 148.3, 128.6, 126.7, 126.0, 119.6, 69.0, 55.0, 52.2, 46.6,
37.6, 35.9, 35.7, 34.9, 31.5, 30.7, 25.2, 25.1, 22.4, 22.2, 18.7,
18.0, 6.9, 4.9. IR (neat): 2955, 1742, 1710, 1457, 1372, 1240,
1081, 1030, 734 cm-1. [R]25D ) +20.0° (c ) 0.60, CHCl3). HRMS
calcd for C31H50O2SiNa [M + Na], 505.3472; found, 505.3494.
Alter n a te Syn th esis of 4a a n d 4b. Anhydrous phosphine
oxide (()-9 (89 mg, 0.15 mmol, 2 equiv) was dissolved in 2.5
mL of distilled THF and cooled to -78 °C. Phenyllithium (93
µL of a 1.8 M solution in cyclohexane-ether, 0.17 mmol, 2.2
equiv) was added dropwise via syringe resulting in a deep red
color. This solution was left to stir for 20 min. Anhydrous CD-
ring ketone (+)-10 (23 mg, 0.08 mmol) was dissolved in 1.5
mL of distilled THF and cooled to -78 °C. This solution was
then added to the reaction mixture via cannula, and the red
color persisted. This solution was stirred at -78 °C in the dark
for 7 h at which point it was quenched with saturated
potassium carbonate (1 mL) and potassium sodium tartrate
(2 mL of a 2 M solution). The product was extracted with ethyl
acetate (4 × 60 mL), dried using MgSO4, filtered, concentrated,
and purified using silica gel column chromatography (3-10%
ethyl acetate/hexanes buffered with 1% Et3N) to give a
colorless oil. A 5 mL round-bottom flask was charged with a
portion of this material (12 mg, 0.02 mmol) dissolved in 1.5
mL of anhydrous pyridine. Methoxylamine hydrochloride (27
mg, 0.33 mmol, 20 equiv) was added, and the reaction was
allowed to stir in the dark at room temperature. Additional
portions of methoxylamine were added (60 equiv total), and
the reaction was stirred for a total of 36 h. The starting
material and the product were very similar in polarity, and
TLC analysis was not particularly useful for following the
reaction. This material was purified directly using silica gel
column chromatography (3% ethyl acetate/hexanes buffered
with 1% Et3N) to give a colorless oil. A 5 mL round-bottom
flask was charged with this oil dissolved in 2 mL of THF, TBAF
hydrate (59 mg, 0.22 mmol, 14 equiv), 4 Å molecular sieves
(60 mg), and 1 drop of Et3N sequentially. This solution was
left to stir in the dark at room temperature for 24 h. The
reaction mixture was purified directly using silica gel column
chromatography (99% ethyl acetate buffered with 1% Et3N)
to give 4a and 4b (6 mg, 59%) as a mixture of diastereomers
(1:3.5), which were separated using reverse phase HPLC
chromatography (15% H2O/acetonitrile) to give 1.4 mg (19%,
6% overall) of 4a and 2.8 mg (37%, 12% overall) of 4b. 4a (1â,
3R): 1H NMR (400 MHz, CDCl3): δ 6.41-6.38 (d, J ) 11.2
Hz, 1H), 6.11-6.08 (m, J ) 11.6 Hz, 1H), 5.32 (m, 1H), 5.29
(t, J ) 1.2 Hz, 1H), 5.02 (m, 1H), 4.46-4.44 (m, 1H), 4.24-
4.20 (m, 1H), 3.78 (s, 3H), 2.84-2.80 (dm, J ) 11.8 Hz, 1H),
2.65-2.60 (dd, J ) 13.0 Hz, 3.8 Hz, 1H), 2.38-1.35 (m, 18H),
1.09 (s, 9H), 1.03-1.01 (d, J ) 6.8 Hz, 3H), 0.69 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 166.8, 159.7, 147.1, 142.7, 132.7,
125.0, 120.3, 116.8, 112.5, 71.4, 66.9, 60.9, 58.3, 50.0, 45.2, 42.8,
37.1, 35.3, 32.6, 29.4, 28.8, 27.8, 26.5, 24.6, 23.6, 21.3, 17.0.
[R]25D ) 2.4° (c ) 0.14. CHCl3). HRMS calcd for C30H48NO3 [M
+ H], 470.3634; found, 470.3623. 4b (1R, 3â): 1H NMR (400
MHz, CDCl3): δ 6.39-6.37 (d, J ) 11.2 Hz, 1H), 6.12-6.09
(m, J ) 11.2 Hz, 1H), 5.34-5.33 (t, J ) 1.6 Hz, 1H), 5.29 (t, J
) 1.2 Hz, 1H), 5.02 (m, 1H), 4.46-4.43 (m, 1H), 4.26-4.23 (m,
1H), 3.78 (s, 3H), 2.84-2.80 (dm, J ) 11.8 Hz, 1H), 2.63-2.58
(dd, J ) 13.6 Hz, 3.6 Hz, 1H), 2.38-1.35 (m, 18H), 1.09 (s,
9H), 1.03-1.01 (d, J ) 7.2 Hz, 3H), 0.69 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 166.8, 159.7, 147.6, 142.6, 132.9, 124.9, 120.3,
116.8, 111.7, 70.7, 66.8, 60.9, 58.4, 50.0, 45.2, 42.8, 37.1, 35.3,
32.6, 29.7, 29.4, 28.8, 27.8, 26.5, 24.6, 23.6, 21.3, 16.9. IR
Syn th esis of CD-Rin g Keton e (+)-10′. A 10 mL round-
bottom flask was charged with tert-butyl ketone 6′ (46 mg, 0.10
mmol) dissolved in 3 mL of distilled THF. Tetrabutylammo-
nium fluoride (286 µL of a 1.0 M solution, 3 equiv) was added
to the reaction flask, and this solution was left to stir at room
temperature for 8 h. The reaction mixture was directly purified
using silica gel column chromatography (50% ethyl acetate/
petroleum ether). The resulting material was dissolved in 5
mL of distilled dichloromethane (CH2Cl2). To this solution was
added 4 Å molecular sieves (20 mg), NMO (15 mg, 0.13 mmol,
2 equiv), and a catalytic amount of TPAP. After the solution
was stirred for 1 h, TLC showed complete consumption of
starting material. The reaction solution was filtered through
a plug of silica gel using ethyl acetate as the eluent to remove
TPAP and molecular sieves. This solution was concentrated
and purified using silica gel column chromatography (20%
ethyl acetate/petroleum ether) to give a colorless oil (14 mg,
47%). 1H NMR (400 MHz, CDCl3): δ 7.36-7.23 (m, 5H), 5.18-
5.17 (t, J ) 1.2 Hz, 1H), 2.82-2.78 (dd, J ) 10.8, 6.4 Hz, 1H),
2.43-2.36 (ddm, J ) 15.8, 10.6 Hz, 1H), 2.29-2.25 (m, 2H),
2.19-2.15 (t, J ) 7.0 Hz, 2H), 2.12-1.68 (m, 10H), 1.47 (s,
6H), 0.97-0.95 (d, J ) 6.8 Hz, 3H), 0.72 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 213.0, 211.1, 157.6, 144.0, 128.6, 126.8, 126.0,
120.2, 63.1, 53.7, 52.2, 40.5, 37.4, 35.7, 34.3, 32.6, 27.0, 25.1,
25.1, 24.0, 22.3, 21.6, 17.2. IR (neat): 2965, 1712, 1496, 1448,
1373, 1242, 1047 cm-1. [R]25 +20.1° (c ) 0.1.60, CHCl3).
D
HRMS calcd for C25H34O2Na [M + Na], 389.2451; found,
389.2465.
Syn th esis of 4a ′ a n d 4b′. Anhydrous phosphine oxide (()-9
(53 mg, 0.09 mmol, 1.9 equiv) was dissolved in 1.5 mL of
distilled THF and cooled to -78 °C. Phenyllithium (45 µL of a
2.0 M solution in cyclohexane-ether, 0.09 mmol, 1.9 equiv)
was added dropwise via syringe resulting in a deep red color.
This solution was left to stir for 20 min. Anhydrous CD-ring
ketone (+)-10′ (18 mg, 0.05 mmol) was dissolved in 1.0 mL of
distilled THF and cooled to -78 °C. This solution was then
added to the reaction mixture via cannula, and the red color
persisted. This solution was stirred at -78 °C in the dark for
4 h at which point it was quenched with saturated potassium
carbonate (1 mL) and potassium sodium tartrate (2 mL of a 2
M solution). The product was extracted with ethyl acetate (4
× 30 mL), dried using MgSO4, filtered, concentrated, and
purified using silica gel column chromatography (3-10% ethyl
acetate/petroleum ether buffered with 1% Et3N) to give a
colorless oil. A 5 mL round-bottom flask was charged with a
portion of this material (12 mg, 0.02 mmol) dissolved in 1.5
mL of anhydrous pyridine. Methoxylamine hydrochloride (27
mg, 0.33 mmol, 20 equiv) was added, and the reaction was
allowed to stir in the dark at room temperature. Additional
portions of methoxylamine were added (100 equiv total), and
the reaction was stirred for a total of 36 h. The starting
material and the product were very similar in polarity and
TLC analysis was not particularly useful for following the
(neat): 3331, 2955, 2919, 2849, 1461, 1361, 1049, 885 cm-1
.
UV (MeOH) λmax 264 nm (ꢀ 6923). [R]25 ) +6.0° (c ) 0.28,
D
CHCl3). HRMS calcd for C30H48NO3 [M + H], 470.3634; found,
470.3636.
Syn th esis of Dim eth yl P h en yl Keton e (+)-6′. A 50 mL
round-bottom flask was charged with diisopropylamine (167
mg, 1.65 mmol, 7.4 equivsdistilled over calcium hydride prior
to use) and 10 mL of distilled THF. This solution was cooled
to -78 °C, and n-butyllithium (1 mL of 1.6 M solution, 1.60
mmol, 7.2 equiv) was added via syringe. 3-Methyl-3-phenyl-
2-butanone (253 mg, 1.56 mmol, 7.0 equivsprepared according
to literature procedure41) was dissolved in 5 mL of distilled
THF and cooled to -78 °C at which point it was added to the
reaction flask via cannula. The reaction was left to stir for 30