3012 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16
Posner et al.
solution was added dropwise 1 mL (1.0 M solution in THF,
1.0 mmol) of TBAF. The reaction mixture was stirred over-
night at room temperature, quenched with water, and ex-
tracted with EtOAc. The combined organic portions were
washed with brine, dried, concentrated in vacuo, and purified
by column chromatography (20% EtOAc/hexanes) to give 78
dried, concentrated in vacuo, and then purified by chroma-
tography (EtOAc/hexanes/NEt3 ) 90/10/1) to afford 33 mg
(98%) of a mixture of two diastereomers as a white solid. The
diastereomers were separated by reverse phase HPLC (C-18
semipreparative column, 60% MeCN/H2O, 3 mL/min) to afford
12.5 mg (24%) of (-)-3a (1R,3â, tR 24.4 min) as a foaming solid
mg (99%) of the deprotected alcohol as a colorless oil: [R]25
and 13.6 mg (27%) of (+)-3b (1â,3R, tR 29.9 min) as a viscous
D
+8.7 (c 5.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.32 (t, J )
1.6 Hz, 1H), 4.16 (d, J ) 2.4 Hz, 1H), 2.21-2.30 (m, 1H), 2.01-
2.06 (m, 1H), 1.93-2.00 (m, 1H), 1.50-1.90 (m, 13H), 1.33-
1.43 (m, 2H), 1.02 (s, 3H), 1.00 (d, J ) 7.2 Hz, 3H), 0.86-0.93
(tt, J ) 7.6 Hz, 1.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
159.47, 126.59 (t, J ) 247.8 Hz), 120.47, 77.04, 69.39, 54.60,
46.50, 35.61, 34.10, 31.78, 30.44, 29.87 (t, J ) 25.3 Hz), 27.52,
25.58, 25.47, 22.65, 18.49, 18.00, 7.81; IR (neat, cm-1) 3604,
3430, 1460; MS m/z (70 eV, EI) 344 (M+); HRMS m/z (M+) calcd
344.2527 for C20H34F2O2, found 344.2533.
1
oil. (-)-3a (1R,3â): [R]25 -14.0 (c 0.4, EtOH); H NMR (400
D
MHz, CDCl3) δ 6.32 (d, J ) 11.2 Hz, 1H), 6.04 (d, J ) 11.2 Hz,
1H), 5.32 (t, J ) 1.2 Hz, 1H), 5.18 (d, J ) 1.6 Hz, 1H), 5.03 (d,
J ) 2.0 Hz, 1H), 3.93-4.00 (m, 1H), 3.52-3.59 (m, 2H), 2.78-
2.83 (m, 1H), 2.59-2.67 (m, 2H), 2.37 (dd, J ) 9.6, 6.4 Hz,
1H), 2.12-2.30 (m, 3H), 1.97-2.02 (m, 2H), 1.50-1.90 (m,
10H), 1.29 (s, 6H), 1.06 (d, J ) 6.8 Hz, 3H), 0.68 (s, 3H); 13C
NMR (100 MHz, CD3OD) δ 160.44, 147.54, 141.95, 136.22,
126.67 (t, J ) 245 Hz), 123.92, 121.89, 118.88, 114.14, 73.62
(t, J ) 27 Hz), 67.39, 64.68, 59.77, 51.13, 47.38, 46.55, 37.64,
36.52, 33.89, 30.41, 29.93 (t, J ) 25 Hz), 29.74, 28.65(t, J ) 3
Hz), 24.73, 23.88 (t, J ) 21 Hz), 22.27, 17.25; UV (MeOH) λmax
262 nm (ꢀ 21 400); IR (neat, cm-1) 3350, 2930, 1378, 1043; MS
m/z (70 eV, CI) 482 (M + NH4+); HRMS m/z (M+) calcd
464.3102 for C28H42F2O3, found 464.3102. (+)-3b (1â,3R):
To the solution of the deprotected C,D-ring alcohol (67 mg,
0.20 mmol) in 3.0 mL CH2Cl2 were added 3 Å molecular sieves
(0.6 g) and pyridinium chlorochromate (PCC, 320 mg, 1.50
mmol). The mixture turned dark red and was stirred over-
night. The reaction mixture was then passed through a short
silica gel pad, washed with ether, concentrated, and then
purified by column chromatography (20% EtOAc/hexanes) to
[R]25 +93.0 (c 0.5, EtOH); 1H NMR (400 MHz, CDCl3) δ 6.31
D
(d, J ) 11.2 Hz, 1H), 6.04 (d, J ) 11.2 Hz, 1H), 5.28 (t, J ) 1.2
Hz, 1H), 5.16 (dd, J ) 2.0, 0.8 Hz, 1H), 5.00 (d, J ) 2.0 Hz,
1H), 4.00 (septet, J ) 4.0 Hz, 1H), 3.57-3.65 (m, 2H), 2.79-
2.83 (m, 1H), 2.58-2.67 (m, 2H), 2.37 (dd, J ) 11.2, 6.4 Hz,
1H), 2.29 (dd, J ) 12.4, 6.4 Hz, 1H), 2.13-2.23 (m, 2H), 2.00
(dddd, J ) 14.8, 9.6, 6.4, 3.2 Hz, 1H), 1.50-1.88 (m, 11H), 1.28
(s, 6H), 1.06 (d, J ) 6.8 Hz, 3H), 0.66 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 158.90, 145.30, 142.41, 134.30, 125.38 (t, J )
245 Hz), 123.58, 120.72, 116.83, 113.77, 73.29 (t, J ) 27 Hz),
67.12, 64.34, 58.31, 59.96, 46.19, 44.32, 37.38, 35.23, 32.56,
29.33, 28.77, 28.74 (t, J ) 25 Hz), 27.28 (t, J ) 3 Hz), 23.58
(2C), 21.71, 16.72; UV (MeOH) λmax 262 nm (ꢀ 16 100); IR (neat,
cm-1) 3366, 2930, 2874, 1369, 1178, 1040; MS m/z (70 eV, CI)
482 (M + NH4+), 446 (M + NH4+); HRMS m/z (M+) calcd
464.3102 for C28H42F2O3, found 464.3107.
give 52 mg (79%) of the desired C,D-ring keto alcohol as a
1
colorless oil: [R]25 +19.8 (c 4.3, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 5.31 (t, J ) 1.2 Hz, 1H), 2.85 (dd, J ) 6.4 Hz, 10.4
Hz, 1H), 2.45 (ddt, J ) 16.0, 10.8, 1.6 Hz, 1H), 2.25-2.31 (m,
2H), 1.54-2.20 (m, 14H), 1.08 (d, J ) 6.8 Hz, 3H), 0.90 (t, J )
7.6 Hz, 6H), 0.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 210.90,
157.06, 126.25 (t, J ) 247.4 Hz), 120.75, 76.75 (t, J ) 23.6
Hz), 63.10, 53.75, 40.49, 34.33, 32.54, 29.34 (t, J ) 24.4 Hz),
27.23 (t, J ) 3.8 Hz), 27.09, 25.28 (t, J ) 1.9 Hz), 24.02, 21.17,
17.21, 7.57; IR (neat, cm-1) 3448, 2955, 1713, 1455; MS m/z
(70 eV, EI) 342 (M+); HRMS m/z (M+) calcd 342.2370 for
C20H32F2O2, found 342.2368.
To a solution of the C,D-ring keto alcohol (47.4 mg, 0.14
mmol) and 4.0 mL of CH2Cl2 was added 41 µL (0.28 mmol) of
TMS-imidazole at room temperature. After being stirred for
16 h at room temperature, the reaction mixture was concen-
trated and purified by column chromatography (17% EtOAc/
hexanes) to give 54 mg (94%) of the protected C,D-ring ketone
Syn th esis of 16-En e-24-d iflu or o Ca lcitr iol An a logu es
(-)-4a a n d (+)-4b. A solution of 69.4 mg (0.12 mmol) of
phosphine oxide (()-15 in 2.0 mL of anhydrous THF was cooled
to -78 °C and treated with 81 µL (0.12 mmol, 1.5 M solution
in THF) of phenyllithium under argon atmosphere. The
mixture turned reddish orange and was stirred for 30 min at
-78 °C. To the solution was added dropwise a solution of 47.9
mg (0.12 mmol) of the C,D-ring ketone (+)-14 in 1.0 mL of
anhydrous THF. The reaction kept going on until the reddish
orange color faded to yellow (about 6 h). The reaction was
quenched by adding 3.0 mL of a 1:1 mixture of 2 N sodium
potassium tartrate and 2 N K2CO3 solution. The reaction
mixture was extracted with EtOAc, washed with brine, dried,
concentrated in vacuo, and then purified by column chroma-
tography (97% hexanes/ether) to afford 68.0 mg (74%) of the
coupled product as a colorless oil. The silyl ethers were
dissolved in 3.0 mL of anhydrous THF, and to this solution
were added TBAF (0.52 mL, 0.52 mmol, 1.0 M solution in THF)
and 52 µL (0.39 mmol) of Et3N. The reaction was run in
darkness overnight, quenched with water, and extracted with
EtOAc. The combined organic portions were washed with
brine, dried, concentrated in vacuo, and then purified by
column chromatography (90% EtOAc/hexanes) to give 38.7 mg
(92%) of a mixture of two diastereomers as a white solid. The
diastereomers were separated by reverse phase HPLC (C-18
semipreparative column, 60% MeCN/H2O, 3.0 mL/min) to
afford 14.0 mg (24%) of (-)-4a (1R,3â, tR 48.5 min) as a
colorless oil and 15.5 mg (26%) of (+)-4b (1â,3R, tR 57.3 min)
as a foaming solid. (-)-4a : [R]25D -1.3 (c 1.4, EtOH); 1H NMR
(400 MHz, CDCl3) δ 6.32 (d, J ) 11.2 Hz, 1H), 6.04 (d, J )
11.2 Hz, 1H), 5.32 (t, J ) 1.6 Hz, 1H), 5.18 (d, J ) 1.6 Hz,
1H), 5.03 (d, J ) 2.0 Hz, 1H), 3.97 (septet, J ) 4.0 Hz, 1H),
3.50-3.60 (m, 2H), 2.77-2.85 (m, 1H), 2.57-2.69 (m, 2H),
2.10-2.40 (m, 4H), 1.44-2.02 (m, 16H), 1.06 (d, J ) 6.8 Hz,
3H), 0.91 (t, J ) 7.6 Hz, 6H), 0.68 (s, 3H); 13C NMR (100 MHz,
CD3OD) δ 160.37, 147.52, 141.91, 136.61, 127.57 (t, J ) 247.3
(+)-14 as a colorless oil: [R]25 +15.4 (c 4.9, CHCl3); 1H NMR
D
(400 MHz, CDCl3) δ 5.29 (t, J ) 1.6 Hz, 1H), 2.84 (dd, J ) 6.4
Hz, 10.4 Hz, 1H), 2.44 (ddt, J ) 16.0, 10.8, 1.6 Hz, 1H), 2.20-
2.32 (m, 2H), 1.48-2.34 (m, 14H), 1.06 (d, J ) 6.8 Hz, 3H),
0.84 (t, J ) 7.6 Hz, 6H), 0.78 (s, 3H), 0.08 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 210.91, 157.05, 126.40 (t, J ) 247.4 Hz),
120.65, 80.65 (t, J ) 25.4 Hz), 63.11, 53,76, 40.53, 34.34, 32.59,
29.57 (t, J ) 24.4 Hz), 27.23 (t, J ) 3.8 Hz), 27.08, 26.08, 25.93,
24.04, 21.93, 17.14, 8.17, 8.09, 2.40; IR (neat, cm-1) 2958, 1721;
MS m/z (70 eV, EI) 414; HRMS m/z (M+) calcd 414.2766 for
C23H40F2O2Si, found 414.2775.
Syn th esis of 16-En e-24-d iflu or o Ca lcitr iol An a logu es
(-)-3a a n d (+)-3b. A solution of 96 mg (0.16 mmol) of
phosphine oxide (()-15 in 1.5 mL of anhydrous THF was
treated dropwise with 100 µL (0.15 mmol) of a 1.5 M solution
of phenyllithium in THF under argon at -78 °C. The resulting
reddish orange solution was stirred for 30 min at -78 °C. To
the solution was added dropwise a solution of 43 mg (0.11
mmol) of C,D-ring ketone (+)-13 in 1 mL of anhydrous THF.
The reaction mixture was stirred until the reddish orange color
turned to pale yellow, and then it was quenched with 3 mL of
a 1:1 mixture of 2 N sodium potassium tartrate and 2 N K2CO3
solution, extracted with EtOAc (50 mL × 2), and washed with
brine. The combined organic portions were dried, concentrated
in vacuo, and then purified by chromatography (3% EtOAc/
hexanes) to afford 55 mg (66%) of the coupled product as a
colorless oil. The silyl ethers were dissolved in 3 mL of
anhydrous THF. To the solution were added 0.44 mL (0.44
mmol) of 1 M TBAF solution in THF and 43 µL (0.31 mmol) of
triethylamine. After 16 h at room temperature, the mixture
was quenched with water, extracted with EtOAc (2 × 50 mL),
and washed with brine. The combined organic portions were