3312 J . Org. Chem., Vol. 62, No. 10, 1997
Posner et al.
Hz, 1H), 3.99-4.05 (m, 1H), 3.56-3.65 (m, 2H), 2.79-2.83 (m,
1H), 2.58-2.66 (m, 2H), 2.10-2.38 (m, 4H), 1.90-2.01 (m, 2H),
1.25-1.84 (m, 12H), 1.19 (s, 6H), 1.02 (d, J ) 6.4 Hz, 3H),
0.66 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 159.96, 145.33,
142.60, 133.24, 123.61, 120.07, 116.77, 113.75, 71.08, 67.12,
64.32, 58.34, 50.04, 46.21, 44.35, 44.08, 37.39, 36.92, 35.32,
32.65, 29.23, 29.26, 28.80, 23.61, 22.17, 21.54, 16.84; UV
(MeOH) λmax 261 nm (ꢀ 10 600); MS m/z (150 eV, CI) 429 (M
+ H+), 446 (M + NH4+); HRMS m/z (M+) calcd 428.3290 for
C28H44O3, found 428.3299; IR (neat, cm-1) 3342, 2929, 1367,
1040.
16-E n e 24-k et on e (+)-44. To a solution of diisopropyl-
amine (197 µL, 1.50 mmol, 1.3 equiv) in THF (5 mL) was added
a 1.6 M solution of n-BuLi in hexanes (1.0 mL, 1.3 equiv) at
-78 °C, and then it was stirred for an additional 30 min at
-78 °C and another 30 min at -35 °C. A solution of 2-[(tert-
butyldimethylsilyl)oxy]-2-methyl-3-butanone (42) (325 mg, 1.5
mmol, 1.3 equiv) in THF (3.0 mL) was added to the LDA
solution at -78 °C. After being stirred for 1 h, the enolate
solution was treated with a solution of the aldehyde (+)-43
(289 mg, 1.16 mmol, 1 equiv) in THF (5 mL) by dropwise
addition. The reaction mixture was stirred for 15 min at the
same temperature, quenched with the solution of phenyl
chlorothionocarbonate (0.3 mL, 2.0 equiv) in THF (5 mL), and
then warmed to rt. After being stirred for 30 min at rt, the
reaction mixture was extracted with ether (100 mL × 2),
washed with saturated NaHCO3 solution and brine, dried over
MgSO4, concentrated in vacuo, and then purified by chroma-
tography (10% Et2O/hexanes) to give 597 mg (88%) of the
desired phenylthiocarbonate as a diastereomeric mixture: 1H
NMR (400 MHz, CDCl3) δ 7.41 (bt, J ) 7.2, 2H), 7.28 (bd, J )
7.2, 1H), 7.07-7.08 (m, 2H), 5.84 (m, 1H), 5.50 (m, 1H), 5.20
(m, 1H), 3.17 (ddd, J ) 78.0, 18.8, 7.2 Hz, 1H), 2.67 (m, 1H),
2.06-2.17 (m, 2H), 2.05 (s, 3H), 1.78-1.89 (m, 4H), 1.57-1.64
(m, 2H), 1.38-1.44 (m, 1H), 1.35 (s, 3H),1.34 (s, 3H), 1.12 (d,
J ) 7.2 Hz, 3H), 1.08 (s, 3H), 0.91 (s, 9H), 0.15 (s, 3H), 0.14 (s,
3H). To the solution of the resultant phenylthiocarbonates
(622 mg, 1.06 mmol) in anhydrous benzene (40 mL) were added
AIBN (30 mg) and Bu3SnH (0.35 mL, 1.2 equiv) at rt. After
reflux for 3.5 h, the mixture was cooled to 0 °C and diluted
with ether (10 mL), and then it was quenched with 5 mL of
water. The reaction mixture was extracted with EtOAc (100
mL × 2), washed with brine, dried over MgSO4, concentrated
in vacuo, and then purified by chromatography (0-10% EtOAc/
hexanes) to give 445 mg (93 %) of (+)-44 as a colorless oil:
H om ologou s 16-E n e Ca lcit r iol An a logs (-)-11a a n d
(+)-11b. Ketone (+)-41b (39 mg, 0.10 mmol) was coupled with
phosphine oxide (()-20 (67 mg, 1.1 equiv) in THF (1 mL) as
described for preparation of 10. After the same workup
followed by deprotection with TBAF, 21.4 mg (46%) of a
mixture of two diastereomers and 20.4 mg (30.4 mg, 44%
recovery) of unreacted starting material (()-20 were obtained
as a white solid. The diastereomers were separated by
reversed-phase HPLC (C-18 semipreparative column, 65%
MeCN/H2O, 4 mL/min) to afford 7.9 mg (16%) of (-)-11a
(1R,3â, tR 41 min) and 7.2 mg (15%) of (+)-11b (1â,3R, tR 52
min) as a white solid. (-)-11a (1R,3â): [R]25 -48° (c 0.70,
D
1
EtOH); H NMR (400 MHz, CD3OD) δ 6.27 (d, J ) 10.8 Hz,
1H), 6.11 (d, J ) 10.8 Hz, 1H), 5.31 (br m, 1H), 5.13 (d, J )
2.0 Hz, 1H), 4.89 (overlapping with CD3OD, 1H), 3.84-3.90
(m, 1H), 3.40-3.51 (m, 2H), 2.82-2.86 (m, 1H), 2.53-2.61 (m,
2H), 2.34-2.40(m, 1H), 2.07-2.23 (m, 4H), 1.91-1.98 (m,
1H),1.25-1.80 (m, 12H), 1.42 (q, J ) 7.6 Hz, 4H), 1.03 (d, J
)6.8, 3H), 0.83 (t, J ) 7.6 Hz, 6H), 0.70 (s, 3H); 13C NMR (100
MHz, CD3OD) δ 161.23, 147.54, 142.07, 136.65, 123.94, 121.36,
118.84, 114.12, 75.47, 67.38, 64.68, 59.81, 51.17, 47.38, 46.52,
39.16, 38.39, 37.64, 36.64, 34.12, 31.77, 31.62, 30.37, 29.75,
24.74, 22.42, 22.19, 17.42, 8.12; UV (MeOH) λmax 262 nm (ꢀ
17 800); MS m/z (150 eV, CI) 429 (M + H+), 446 (M + NH4+);
HRMS m/z (M+) calcd 456.3603 for C30H48O3, found 456.3609;
[R]25 -3.0° (c 8.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.25
D
(m, 1H), 5.18 (m, 1H), 2.60-2.65 (m, 2H), 2.03 (s, 3H),1.95-
2.10 (m, 3H), 1.73-1.86 (m, 3H), 1.63-1.69 (m, 2H), 1.54-
1.58 (m, 2H), 1.36-1.45 (m, 1H), 1.29 (s, 6H), 0.99 (d, J ) 6.8
Hz, 3H), 0.95 (s, 3H), 0.88 (s, 9H),0.10 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 214.57, 170.71, 158.70, 126.29, 80.12, 70.73,
52.92, 46.61, 35.04, 34.53, 30.70, 30.52, 29.53, 27.28, 27.19,
25.75, 22.44, 21.32, 18.18, 18.04, 17.88, -2.27; MS m/z (150
eV, CI) 451 (M + H+); HRMS m/z (M + H+) calcd 451.3244 for
C26H46O4Si, found 451.3237; IR (neat, cm-1) 2932, 2856, 1738,
1717.
24-Keto 8,25-Diol (+)-45. A mixture of tertiary silyl ether
(+)-44 (445 mg, 1.0 mmol) and 1.0 g of 10 N NaOH (10 equiv)
in EtOH (4.0 mL) was stirred for 20 h at 30-35 °C. The
mixture was cooled to 0 °C, diluted with ether (10 mL), and
then neutralized with 10% HCl. It was extracted with EtOAc
(50 mL × 2), washed with aqueous saturated NaHCO3 solution
and brine, dried over MgSO4, and concentrated in vacuo. The
resultant oil was treated with TBAF in THF followed by
normal aqueous workup and then purified by chromatography
IR (neat, cm-1) 3341, 2930, 1367, 1043. (+)-11b (1â,3R): [R]25
D
+91° (c 0.65, CHCl3); 1H NMR (400 MHz, CD3OD) δ 6.30 (d, J
) 10.8 Hz, 1H), 6.12 (d, J ) 10.8 Hz, 1H), 5.31 (br m, 1H),
5.11 (d, J ) 2.0 Hz, 1H), 4.82 (d, J ) 2.4 Hz, 1H), 3.85-3.92
(m, 1H), 3.41-3.53 (m, 2H), 2.82-2.86 (m, 1H),2.53-2.61 (m,
2H), 2.34-2.48(m, 1H), 2.07-2.23 (m, 4H), 1.91-1.97 (m, 1H),
1.42 (q, J ) 7.6 Hz, 4H), 1.25-1.80 (m, 12H), 1.03 (d, J ) 6.8,
3H), 0.83 (t, J ) 7.6 Hz, 6H), 0.68 (s, 3H); 13C NMR (100 MHz,
CD3OD) δ 161.26, 147.65, 142.22, 136.66, 123.87, 121.35,
118.79, 113.78, 75.47, 67.43, 64.68, 59.76, 51.17, 47.37, 46.34,
39.16, 38.40, 37.61, 36.70, 34.11, 31.77, 31.63, 30.21, 29.77,
24.66, 22.43, 22.20, 17.41, 8.12; UV (MeOH) λmax 261 nm (ꢀ
18 100); MS m/z (150 eV, CI) 429 (M + H+); HRMS m/z (M+)
calcd 456.3606 for C30H48O3, found 456.3605; IR (neat, cm-1
3342, 2929, 1367, 1040.
)
16-En e Ald eh yd e (+)-43. To a suspension of NCS (513
mg, 3.84 mmol, 2.5 equiv) in 20 mL of anhydrous toluene was
added dimethyl sulfide (372 µL, 3.3 equiv) at 0 °C under argon.
After being stirred for 15 min at the same temperature, the
resulting white suspension was cooled to -30 °C. To this was
added dropwise a solution of the alcohol 37 (387 mg, 1.53
mmol) in 2 mL of anhydrous toluene at -30 °C. The reaction
mixture was stirred for an additional 2.5 h, and then the
reaction was quenched with a solution of triethylamine (0.75
mL, 3.5 equiv) in 1.5 mL of anhydrous toluene at -30 °C. The
reaction mixture was warmed to rt, stirred for 10 min, and
then extracted with ether. The combined organic extracts were
washed with 5% HCl and brine, dried over MgSO4, concen-
trated in vacuo, and then purified by chmatography (15%
(40% EtOAc/hexanes) to give 261 mg (90%) of diol (+)-45 as a
1
colorless oil: [R]25 +10.7° (c 4.6, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 5.29 (m, 1H), 4.16 (m, 1H), 3.83 (s, 1H), 2.40-2.58
(m, 2H), 2.26 (tm, J ) 13.2, Hz, 1H), 2.06-2.09 (m, 1H), 1.96
(ddd, J ) 14.4, 6.0, 2.8 Hz, 1H), 1.68-1.89 (m, 5H), 1.48-1.57
(m, 2H), 1.37-1.47 (m, 1H), 1.33 (s, 6H), 1.01 (s, 3H), 1.00 (d,
J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 214.70, 159.00,
120.28, 70.08, 68.95, 52.33, 46.24, 35.33, 33.87, 33.66, 31.20,
30.20, 29.84, 27.19, 26.59, 22.33, 18.41, 17.75; MS m/z (150
eV, CI) 312 (M + NH4+); HRMS m/z (M+) calcd 294.2195 for
C18H30O3, found 294. 2195; IR (neat, cm-1) 3456, 2929, 2808,
1738, 1706.
EtOAc/hexanes) to afford 320 mg (83%) of the desired aldehyde
16-En e 8,24-d ik eton e (+)-46. To a solution of C-8 alcohol
(+)-45 (94.6 mg, 0.32 mmol) in CH2Cl2 (10 mL) were added
0.36 g of oven-dried Celite and PDC (0.36 g, 3.0 equiv) at rt.
After being stirred at rt for 6 h, the mixture was passed
through 2 cm of flash silica gel pad and washed with EtOAc.
The filtrate was concentrated in vacuo and then chromato-
graphed with 30% EtOAc in hexanes to give 79.0 mg (84%) of
1
(+)-43 as a colorless oil: [R]25 +32° (c 5.6, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 9.39 (d, J ) 2.0 Hz, 1H), 5.41 (m, 1H),
5.17 (m, 1H), 2.96 (q, J ) 7.2 Hz, 1H), 2.06-2.16 (m, 2H), 2.09
(s, 3H), 1.72-1.85 (m, 3H), 1.47-1.61 (m, 2H), 1.32 (td, J )
12.0, 3.6 Hz, 1H), 1.13 (d, J ) 6.8 Hz, 3H), 0.97 (s, 3H; 13C
NMR (100 MHz, CDCl3) δ 200.57, 170.53, 151.21,126.12, 70.23,
52.46, 46.48, 45.23, 34.43, 30.90, 30.40, 21.22, 17.93, 17.65,
14.40; MS m/z (150 eV, CI) 268 (M + NH4+); HRMS m/z (M +
NH4+) calcd 268.1913 for C15H22O3, found 268.1916; IR (CHCl3,
cm-1) 2936, 2853, 1733.
the diketo alcohol as a colorless oil: [R]25 +24.3° (c 7.5,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.31 (m, 1H), 3.74 (s,
1H), 2.86 (dd, J ) 10.8, 6.8 Hz, 1H), 2.42-2.59 (m, 3H), 2.28-
2.33 (m, 2H), 1.97-2.20 (m, 4H), 1.67-1.94 (m, 4H), 1.36 (s,