Seo et al.
(1:1 EtOAc:hexanes) to give the amide 41 (1.16 g, 97%) as a white
solid (mp 126.5-127 °C): IR (film) 3368, 2859, 1661, 1509, 1226
14.8, 7.5 Hz, 1H), 7.07 (d, J ) 7.9 Hz, 1H), 6.87 (d, J ) 9.1 Hz,
2H), 6.82 (d, J ) 9.2 Hz, 2H), 6.65 (d, J ) 7.7 Hz, 1H), 4.93, 4.69
(ABq, J ) 11.6 Hz, 2H), 4.63 (s, 1H), 4.41, 4.29 (ABq, J ) 11.9
Hz, 2H), 3.89, 3.77 (ABq, J ) 11.1 Hz, 2H), 3.78 (s, 3H), 3.59 (s,
3H), 3.19 (m, 2H), 3.10 (s, 3H), 2.56 (dt, J ) 14.4, 7.2 Hz, 1H),
2.13 (dt, J ) 13.4, 4.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
178.2, 171.6, 154.5, 153.1, 145.4, 138.2, 136.5, 136.0, 133.4, 130.6,
129.7, 129.0, 128.8, 128.4, 128.3, 128.2, 128.1, 126.1, 123.5, 116.2,
115.1, 107.6, 73.4, 69.2, 68.9, 60.0, 56.1, 55.1, 52.5, 38.0, 26.9,
26.4, 26.2, 18.6, -5.3, -5.4; HRMS-ES [M + H]+ calcd for C42H52-
NO7Si, 710.3513; found, 710.3521.
1
cm-1; H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 8.11 (dd, J )
8.0, 1.5 Hz, 1H), 7.68 (s, 1H), 7.54 (m, 1H), 7.51-7.28 (m, 10H),
6.94-6.89 (m, 2H), 6.84-6.80 (m, 2H), 5.03 (s, 2H), 4.64 (s, 2H),
4.55 (s, 2H), 3.79 (t, J ) 5.8 Hz, 2H), 3.74 (s, 3H), 2.77 (t, J )
5.8 Hz, 2H), 2.70 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 168.9,
154.6, 153.1, 141.9, 138.64, 138.61, 138.3, 135.5, 135.3, 134.3,
129.9, 129.6, 129.3, 129.00, 128.95, 128.9, 128.3, 125.9, 122.5,
116.3, 115.2, 96.0, 77.1, 73.1, 69.7, 62.5, 56.2, 31.9; HRMS-ES
[M + H]+ calcd for C33H33INO5, 650.1404; found, 650.1404.
N-(3-Benzyloxymethyl-2-iodophenyl)-4-(tert-butyldimethylsi-
lanyloxy)-2-[2-(4-methoxyphenoxymethyl)benzylidene]butyr-
amide (42). To a solution of the amide 41 (568 mg, 0.87 mmol)
and imidazole (178 mg, 2.62 mmol) in DMF (8.7 mL) was added
TBSCl (316 mg, 2.09 mmol). The reaction mixture was stirred at
room temperature overnight and then diluted with EtOAc. The
solution was washed with water and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography (1:3 EtOAc:hexanes) to give the TBS ether 42 (641
mg, 96%) as a colorless oil: IR (film) 2950, 2848, 1678, 1509,
1226, 1090 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.2
(dd, J ) 8.0, 1.4 Hz, 1H), 7.74 (s, 1H), 7.56 (m, 1H), 7.44-7.29
(m, 9H), 6.94-6.91 (m, 2H), 6.85-6.82 (m, 2H), 5.03 (s, 2H),
4.65 (s, 2H), 4.59 (s, 2H), 3.9 (t, J ) 6.1 Hz, 2H), 3.76 (s, 3H),
2.84 (t, J ) 6.1 Hz, 2H), 0.87 (s, 9H), 0.03 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 167.7, 154.5, 153.3, 141.8, 139.0, 138.5, 138.3,
135.7, 135.2, 134.1, 129.9, 129.3, 129.2, 128.9, 128.8, 128.5,
128.23, 128.21, 125.6, 122.4, 116.4, 115.1, 95.9, 77.2, 73.1, 69.4,
62.5, 56.1, 31.8, 26.4, 18.8, -4.9; HRMS-ES [M + H]+ calcd for
C39H47INO5Si, 764.2268; found, 764.2271.
Synthesis of Spirolactone 45. To a stirred solution of methyl
ester 44 (172 mg, 0.24 mmol) in THF (10 mL) was added TBAF
(0.27 mL, 1.0 M in THF, 0.27 mmol) at 0 °C. The reaction mixture
was warmed to room temperature and stirred for 4 h. The mixture
was diluted with EtOAc and saturated aqueous NH4Cl. The organic
layer was dried over Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography (1:1 EtOAc:hexanes)
to give the lactone 45 (116 mg, 85%) as a separable mixture of
diastereomers (2:1). For analytical purposes, the diastereomers were
separated by preparative TLC (1:1 EtOAc:hexanes). More polar
major diastereomer of 45 (colorless oil): IR (film) 2927, 1752,
1712, 1605, 1509, 1226 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38-
7.01 (m, 11H), 6.83-6.74 (m, 4H), 6.54 (d, J ) 7.7 Hz, 1H), 5.03
(s, 1H), 4.83 (ddd, J ) 11.7, 6.7, 4.9 Hz, 1H), 4.67-4.43 (m, 6H),
4.30 (ddd, J ) 11.8, 7.2, 4.6 Hz, 1H), 3.77 (s, 3H), 2.96 (s, 3H),
2.61 (ddd, J ) 14.7, 6.8, 4.8 Hz, 1H), 2.27 (ddd, J ) 14.6, 7.4, 5.1
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 178.2, 171.1, 154.5, 153.0,
144.1, 137.3, 136.5, 134.4, 132.3, 130.8, 129.7, 129.2, 129.1,
128.79, 128.75, 128.7, 128.2, 127.8, 125.1, 116.3, 115.1, 108.6,
73.8, 70.0, 69.7, 64.8, 56.2, 52.6, 47.2, 30.3, 26.5; HRMS-ES [M
+ H]+ calcd for C35H34NO6, 564.2386; found, 564.2391. Less polar
minor diastereomer of 45 (colorless oil): IR (film) 2916, 1746,
1706, 1610, 1509, 1232 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.44-
7.30 (m, 5H), 7.27-7.23 (m, 3H), 7.09 (t, J ) 7.6 Hz, 1H), 6.93
(d, J ) 9.0 Hz, 2H), 6.88-6.84 (m, 3H), 6.63 (d, J ) 7.8 Hz, 1H),
6.54 (d, J ) 7.4 Hz, 1H), 5.32 (d, J ) 11.7 Hz, 1H), 4.98 (s, 1H),
4.80-4.55 (m, 6H), 4.38 (dd, J ) 11.7, 5.6 Hz, 1H), 3.79 (s, 3H),
2.91 (s, 3H), 2.73 (td, J ) 14.5, 5.8 Hz, 1H), 2.23 (d, J ) 14.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 179.4, 172.6, 154.6, 153.1,
144.2, 138.2, 136.7, 136.0, 131.5, 130.8, 129.8, 129.7, 129.0, 128.9,
128.6, 128.3, 128.2, 127.5, 125.4, 116.6, 115.1, 108.5, 73.6, 70.2,
69.2, 66.1, 56.1, 52.5, 47.1, 31.6, 26.8; HRMS-ES [M + Na]+ calcd
for C35H33NNaO6, 586.2206; found, 586.2210.
N-(3-Benzyloxymethyl-2-iodophenyl)-4-(tert-butyldimethylsi-
lanyloxy)-2-[2-(4-methoxyphenoxymethyl)benzylidene]-N-meth-
ylbutyramide (43). To a stirred suspension of NaH (40 mg, 60%
dispersion in mineral oil, 1.01 mmol) in THF (8 mL) was added a
solution of the amide 42 (641 mg, 0.84 mmol) in THF (3 mL) at
0 °C. The mixture was stirred at room temperature for 30 min and
recooled to 0 °C. To the solution was added MeI (0.08 mL, 1.29
mmol), and the reaction mixture was warmed to room temperature
and stirred for 12 h. The reaction mixture was diluted with saturated
aqueous NH4Cl and extracted with EtOAc. The organic layer was
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (1:3 EtOAc:hexanes) to
give the N-methyl amide 43 (630 mg, 96%) as a colorless oil: IR
1
(film) 2950, 2860, 1650, 1509, 1226, 1090 cm-1; H NMR (300
O-Allylation of Spirolactone 45. To a stirred suspension of
spirolactone 45 (20.6 mg, 0.037 mmol) and NaH (2.0 mg, 60%
dispersion in mineral oil, 0.050 mmol) in DMF (2 mL) was added
allyl iodide (0.010 mL, 0.109 mmol) at 0 °C. The mixture was
stirred for 1 h at room temperature. The reaction mixture was diluted
with saturated aqueous NH4Cl and extracted with EtOAc. The
organic layer was washed with water and brine, dried over Na2-
SO4, and concentrated in vacuo. The residue was purified by flash
column chromatography (1:2 EtOAc:hexanes) to give the O-allyl
ketene acetal 46 (12.7 mg, 57%, 71% based on recovered starting
material) as a colorless oil and unreacted spirolactone 45 (3.9
mg): IR (film) 3470, 2927, 1706, 1509, 1226 cm-1; 1H NMR (400
MHz, CDCl3, 2:1 atropisomeric mixture) δ 7.44-7.22 (m, 7H,
major and minor), 7.13 (t, J ) 7.7 Hz, 1H, minor), 7.08-7.01 (m,
1H, major and minor), 6.98-6.96 (m, 2H, major and minor), 6.91
(d, J ) 6.7 Hz, 1H, minor), 6.86-6.82 (m, 3H, major and minor),
6.77 (t, J ) 7.6 Hz, 1H, major), 6.58 (d, J ) 8.1 Hz, 1H, major
and minor), 6.35 (d, J ) 7.8 Hz, 1H, minor), 5.78 (m, 1H, major
and minor), 5.27 (d, J ) 13.3 Hz, 1H, major), 5.17-5.06 (m, 3H,
major, 2H, minor), 5.01-4.84 (m, 2H, major and minor), 4.77-
4.65 (m, 2H, major, 3H, minor), 4.44-4.24 (m, 4H, major and
minor), 3.78 (s, 3H, major and minor), 3.16 (s, 3H, minor), 2.95
(s, 3H, major), 2.58 (m, 1H, major and minor), 1.98 (d, J ) 14.6
Hz, 1H, major), 1.85 (d, J ) 14.3 Hz, 1H, minor); 13C NMR (300
MHz, CDCl3) δ 180.7, 179.4, 157.6, 156.3, 154.0, 153.9, 153.8,
MHz, toluene-d8, 90 °C) δ 7.38 (m, 1H), 7.28-7.01 (m, 12H), 6.78
(dt, J ) 12.8, 3.8 Hz, 2H), 6.72 (dt, J ) 12.8, 3.8 Hz, 2H), 4.59
(d, J ) 5.5 Hz, 2H), 4.42 (d, J ) 7.1 Hz, 2H), 4.38 (s, 2H), 3.94
(m, 2H), 3.45 (s, 3H), 3.22 (s, 3H), 2.75 (m, 1H), 2.57 (m, 1H),
0.95 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, toluene-d8, 90 °C)
δ 170.7, 155.1, 153.6, 148.3, 144.3, 137.5, 129.2, 136.3, 135.1,
131.9, 129.2, 129.1, 128.7, 128.5, 128.1, 127.84, 127.78, 127.7,
127.53, 127.48, 116.9, 115.3, 103.3, 77.1, 73.1, 69.1, 62.5, 55.4,
37.6, 34.0, 26.2, 18.5, -5.2; HRMS-ES [M + H]+ calcd for C40H49-
INO5Si, 778.2425; found, 778.2397.
{4-Benzyloxymethyl-3-[2-(tert-butyldimethylsilanyloxy)ethyl]-
1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl}-[2-(4-methoxyphen-
oxymethyl)phenyl]-acetic Acid Methyl Ester (44). To a solution
of N-methyl amide 43 (222 mg, 0.286 mmol) in DMA (3.0 mL)
and MeOH (1.5 mL) were added Pd(OAc)2 (6.4 mg, 0.029 mmol),
biphenyldicyclohexylphosphine (30.1 mg, 0.086 mmol), and NaOAc
(46.9 mg, 0.572 mmol). The mixture was stirred at 85 °C under a
CO atmosphere (1 atm) for 24 h. The catalyst was removed by
filtration and washed with EtOAc. The filtrate was washed with
water and brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by flash column chromatography (1:5
EtOAc:hexanes) to give the methyl ester 44 (145 mg, 71%) as a
colorless oil: IR (film) 2950, 2859, 1740, 1712, 1509, 1226 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.35-7.17 (m, 9H), 7.12 (dd, J )
8898 J. Org. Chem., Vol. 71, No. 23, 2006