9412 J . Org. Chem., Vol. 64, No. 26, 1999
Sasaki et al.
Ben zyl Eth er 45. A solution of the spiroketal 44 (4.22 g,
6.77 mmol) in THF (60 mL) and DMF (20 mL) was cooled to
0 °C and treated with sodium hydride (60% dispersion in
mineral oil, 541 mg, 13.5 mmol), and the mixture was stirred
at room temperature for 30 min. The mixture was recooled to
0 °C and treated with benzyl bromide (1.2 mL, 10.1 mmol),
and the resulting mixture was stirred at 0 °C for 1 h, at room
temperature for 14 h, and then at 50 °C for 3 h. The reaction
was quenched with saturated aqueous NH4Cl, and the solution
was diluted with EtOAc (400 mL), washed with brine, dried
(MgSO4), filtered, and concentrated. Flash chromatography on
silica gel (5-10% EtOAc-hexane) afforded benzyl ether 45 as
and the resulting mixture was heated at 70 °C for 5.5 h. The
mixture was cooled to room temperature, poured into saturated
aqueous NH4Cl (100 mL), and extracted with EtOAc (300 mL).
The organic layer was washed with water and brine, dried
(MgSO4), filtered, and concentrated. Flash chromatography on
silica gel (30-50% EtOAc-hexane) afforded nitrile 48 as a pale
yellow oil (1.86 g, 89%): [R]28 ) -38.8° (c 0.393, CHCl3); IR
D
(film) 3501, 2927, 2253, 1456, 940, 737, 699 cm-1
;
1H NMR
(CDCl3, 500 MHz) δ 7.30-7.20 (10H, m), 4.86 (1H, d, J ) 11.7
Hz), 4.57 (1H, d, J ) 11.7 Hz), 4.47 (1H, d, J ) 12.0 Hz), 4.45
(1H, d, J ) 12.0 Hz), 4.26 (1H, m), 3.96 (1H, dd, J ) 9.7, 2.0
Hz), 3.86 (2H, m), 3.79 (2H, m), 3.34 (1H, t, J ) 10.0 Hz), 2.73
(1H, m), 2.72 (1H, dd, J ) 16.7, 3.0 Hz), 2.49 (1H, dd, J )
16.7, 8.8 Hz), 2.42 (1H, m), 2.13 (2H, m), 1.67 (1H, m), 1.54
(1H, m), 1.15 (3H, d, J ) 6.3 Hz), 1.03 (3H, d, J ) 7.6 Hz),
1.01 (3H, d, J ) 6.6 Hz); HRMS (FAB) calcd for C31H39O6NNa
[(M + Na)+] 544.2675, found 544.2695.
r,â-Un sa tu r a ted Ester 49. A solution of nitrile 48 (1.76
g, 3.37 mmol) in CH2Cl2 (40 mL) was cooled to -78 °C and
treated with DIBALH (1.02 M solution in toluene, 8.2 mL, 8.36
mmol). After being stirred at -78 °C for 1 h, the reaction was
quenched with 1 N aqueous HCl (15 mL), and the cooling bath
was removed. The mixture was vigorously stirred at room
temperature for 15 min and diluted with EtOAc (300 mL). The
organic layer was washed with 1 N aqueous HCl, saturated
aqueous NaHCO3, and brine, dried (MgSO4), filtered, and
concentrated. Purification by florisil column chromatography
(30% EtOAc-hexane) afforded a mixture of hemiacetal as a
colorless oil (1.721 g), which was used in the next reaction
without further purification.
a colorless oil (4.01 g, 83%): [R]27 ) -25.9° (c 0.87, CHCl3);
D
IR (film) 2538, 1653, 1358, 1506, 940, 883, 732 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 7.42-7.15 (10H, m), 4.73 (1H, d, J ) 12.4
Hz), 4.70 (1H, d, J ) 12.4 Hz), 4.64 (1H, d, J ) 6.5 Hz), 4.62
(1H, d, J ) 6.5 Hz), 4.47 (1H, d, J ) 11.9 Hz), 4.44 (1H, d, J
) 11.9 Hz), 4.25 (1H, m), 4.07 (1H, m), 3.92 (1H, dd, J ) 9.8,
1.7 Hz), 3.83 (1H, dd, J ) 9.8, 5.1 Hz), 3.82 (1H, dd, J ) 10.4,
2.0 Hz), 3.72 (1H, dd, J ) 10.0, 1.5 Hz), 3.70 (1H, d, J ) 9.5
Hz), 3.60 (1H, dd, J ) 5.9, 1.5 Hz), 3.48 (1H, dd, J ) 10.4, 6.8
Hz), 3.34 (3H, s), 3.31 (1H, dd, J ) 10.0, 10.0 Hz), 2.52 (1H,
m), 2.13 (1H, dd, J ) 13.7, 7.0 Hz), 2.06 (1H, dd, J ) 13.7, 3.6
Hz), 1.61 (1H, m), 1.50 (1H, m), 1.07 (3H, d, J ) 6.3 Hz), 1.06-
1.03 (21H), 1.04 (3H, m), 0.98 (3H, d, J ) 6.6 Hz); 13C NMR
(CDCl3, 125 MHz) δ 139.7, 138.2, 128.4, 127.9, 127.59, 127.56,
127.0, 126.8, 109.3, 106.4, 103.6, 100.1, 96.8, 84.1, 83.5, 81.6,
81.3, 78.5, 76.4, 72.1, 71.52, 71.46, 71.4, 71.0, 70.2, 63.2, 60.4,
55.8, 55.1, 54.5, 42.6, 42.1, 41.0, 39.1, 35.1, 19.1, 18.4, 18.3,
15.3, 13.4, 13.1, 12.9, 10.3, 4.9; HRMS (FAB) calcd for
C
41H64O8SiNa [(M + Na)+] 735.4268, found 735.4268.
Diol 46. A solution of benzyl ether 45 (4.01 g, 5.62 mmol)
A solution of the above hemiacetal (1.721 g) in dry benzene
(40 mL) was treated with Ph3PdCHCOOMe (5.50 g, 16.5
mmol), and the resulting mixture was heated at 80 °C for 1 h.
The solvent was evaporated, and the residue was directly
subjected to flash chromatography on silica gel (30% EtOAc-
hexane) to give R,â-unsaturated ester 49 as a colorless oil
and dimethyl sulfide (10 mL) in CH2Cl2 (80 mL) was cooled to
0 °C and treated with boron trifluoride etherate (3.5 mL, 28.4
mmol). After being stirred at 0 °C for 20 min, the reaction was
quenched with saturated aqueous NaHCO3 (20 mL). The
solution was diluted with EtOAc (400 mL), washed with
saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered,
and concentrated. Flash chromatography on silica gel (40%
EtOAc-hexane) afforded diol 46 as a colorless oil (2.22, 77%):
(1.574 g, 80% for the two steps): [R]28 ) -21.0° (c 0.54,
D
CHCl3); IR (film) 3525, 1724 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 7.33-7.24 (10H, m), 7.03 (1H, ddd, J ) 15.6, 7.9, 6.5 Hz),
5.88 (1H, br d, J ) 15.6 Hz), 4.85 (1H, d, J ) 11.7 Hz), 4.58
(1H, d, J ) 11.7 Hz), 4.47 (1H, d, J ) 12.0 Hz), 4.44 (1H, d, J
) 12.0 Hz), 4.26 (1H, m), 3.95 (1H, dd, J ) 9.7, 2.0 Hz), 3.85
(1H, dd, J ) 9.7, 5.2 Hz), 3.80 (1H, dd, J ) 6.4, 1.8 Hz), 3.77
(1H, dd, J ) 9.9, 1.8 Hz), 3.70 (3H, s), 3.63 (1H, ddd, J ) 8.6,
8.6, 3.6 Hz), 3.29 (1H, br d, J ) 8.6 Hz), 3.23 (1H, dd, J ) 9.9,
9.9 Hz), 2.93 (1H, br d, J ) 8.6 Hz), 2.61 (1H, m), 2.45 (1H,
m), 2.39 (1H, m), 2.12 (2H, m), 1.62 (1H, m), 1.51 (1H, m),
1.02 (3H, d, J ) 6.3 Hz), 1.00 (3H, d, J ) 7.5 Hz), 0.99 (3H, d,
J ) 6.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 166.9, 146.8, 138.7,
138.1, 128.5, 128.4, 127.7, 127.6, 127.6, 127.6, 122.9, 109.2,
87.0, 84.3, 82.6, 79.3, 78.3, 74.3, 72.1, 71.6, 71.0, 51.3, 42.8,
42.1, 41.9, 39.3, 38.9, 17.3, 15.6, 13.4; HRMS (FAB) calcd for
[R]25 ) -36.2° (c 0.83, CHCl3); IR (film) 3460 cm-1; 1H NMR
D
(C6D6, 500 MHz) δ 7.50-7.00 (10H, m), 4.77 (1H, d, J ) 11.8
Hz), 4.58 (1H, d, J ) 11.8 Hz), 4.18 (2H, s), 4.01 (1H, m), 3.95
(1H, dd, J ) 9.6, 1.5 Hz), 3.92 (1H, dd, J ) 9.8, 1.5 Hz), 3.86
(2H, m), 3.73-3.65 (3H, m), 3.49 (1H, m), 3.42 (1H, t, J ) 10.0
Hz), 3.06 (1H, br d, J ) 9.8 Hz), 2.43 (1H, m), 2.06 (2H, m),
1.85 (1H, m), 1.36 (1H, m), 1.03 (3H, d, J ) 6.4 Hz), 1.02 (3H,
d, J ) 6.6 Hz), 0.91 (3H, d, J ) 7.6 Hz); 13C NMR (C6D6, 125
MHz) δ 139.4, 138.8, 128.7, 128.6, 128.3, 127.9, 127.8, 127.7,
109.4, 87.3, 84.8, 81.7, 78.8, 76.5, 74.0, 72.6, 71.7, 71.1, 65.8,
43.2, 42.3, 42.2, 39.5, 17.6, 15.8, 13.7; HRMS (FAB) calcd for
C
30H40O7Na [(M + Na)+] 535.2672, found 535.2662.
Tosyla te 47. A solution of diol 46 (2.20 g, 4.33 mmol),
C
34H44O8Na [(M + Na)+] 603.2934, found 603.2944.
Silyl Eth er 50. A solution of R,â-unsaturated ester 49
DMAP (1.00 g, 8.19 mmol), and triethylamine (6.0 mL, 43.0
mol) in CH2Cl2 (50 mL) was cooled to 0 °C and treated with
p-toluenesulfonyl chloride (0.99 g, 5.20 mmol), and the result-
ing mixture was stirred at 0 °C for 2 h. The solution was
diluted with EtOAc (300 mL), washed with 1 N aqueous HCl,
saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered,
and concentrated. Purification by chromatography on silica gel
(20-30% EtOAc-hexane) afforded monotosylate 47 as a
(1.574 g, 2.71 mmol) and 2,6-lutidine (1.0 mL, 8.59 mmol) in
CH2Cl2 (40 mL) was cooled to 0 °C and treated with TBDM-
SOTf (1.0 mL, 4.35 mmol), and the resulting solution was
stirred at 0 °C for 40 min. The reaction mixture was parti-
tioned between EtOAc (250 mL) and saturated aqueous
NaHCO3 (70 mL), and the organic layer was washed with
brine, dried (MgSO4), filtered, and concentrated. Purification
by chromatography on silica gel (15% Et2O-hexane) afforded
silyl ether 50 as a colorless oil (1.823 g, 97%): [R]28D ) -17.5°
colorless oil (2.68 g, 93%): [R]28 ) -31.8° (c 0.413, CHCl3);
D
IR (film) 3535, 2972, 2924, 2881, 1363, 1176, 737, 698, 555
1
cm-1; H NMR (CDCl3, 500 MHz) δ 7.76 (2H, d, J ) 8.3 Hz),
(c 0.487, CHCl3); IR (film) 1726 cm-1 1H NMR (CDCl3, 500
;
7.34-7.24 (12H, m), 4.83 (1H, d, J ) 11.7 Hz), 4.55 (1H, d, J
) 11.7 Hz), 4.47 (1H, d, J ) 12.0 Hz), 4.44 (1H, d, J ) 12.0
Hz), 4.25 (1H, m), 4.14 (1H, dd, J ) 10.2, 2.3 Hz), 3.98 (1H,
dd, J ) 10.2, 7.9 Hz), 3.94 (1H, dd, J ) 9.7, 1.9 Hz), 3.84 (1H,
dd, J ) 9.8, 5.1 Hz), 3.79 (1H, br d, J ) 6.7 Hz), 3.76 (1H, m),
3.73 (1H, dd, J ) 9.9, 1.6 Hz), 3.20 (1H, t, J ) 10.0 Hz), 3.18
(1H, m), 2.87 (1H, br d, J ) 10.2 Hz), 2.42 (1H, m), 2.41 (3H,
s), 2.10 (2H, m), 1.56 (1H, m), 1.49 (1H, m), 1.00 (3H, d, J )
6.3 Hz), 0.99 (3H, d, J ) 6.5 Hz), 0.94 (3H, d, J ) 7.6 Hz).
Nitr ile 48. A solution of tosylate 47 (2.68 g, 4.02 mmol) in
DMSO (40 mL) was treated with NaCN (591 g, 12.0 mmol),
MHz) δ 7.40-7.20 (10H, m), 7.05 (1H, ddd, J ) 15.6, 8.2, 6.2
Hz), 5.87 (1H, d, J ) 15.6 Hz), 4.76 (1H, d, J ) 12.6 Hz), 4.63
(1H, d, J ) 12.6 Hz), 4.47 (1H, d, J ) 11.9 Hz), 4.44 (1H, d, J
) 11.9 Hz), 4.24 (1H, m), 4.07 (1H, ddd, J ) 9.3, 9.3, 2.4 Hz),
3.92 (1H, br d, J ) 9.7 Hz), 3.81 (1H, dd, J ) 9.7, 5.1 Hz), 3.70
(3H, s), 3.68 (1H, dd, J ) 8.9, 1.6 Hz), 3.53 (1H, dd, J ) 5.5,
1.6 Hz), 3.36 (1H, br d, J ) 9.3 Hz), 3.27 (1H, dd, J ) 9.8, 8.9
Hz), 2.62 (1H, m), 2.41 (1H, m), 2.20 (1H, m), 2.15 (1H, dd, J
) 13.7, 7.0 Hz), 2.07 (1H, dd, J ) 13.7, 3.6 Hz), 1.58 (1H, m),
1.52 (1H, m), 1.02 (3H, d, J ) 7.8 Hz), 1.00 (3H, d, J ) 6.2
Hz), 0.97 (3H, d, J ) 6.5 Hz), 0.88 (9H, s), 0.10 (3H, s), 0.04