2032 J . Org. Chem., Vol. 66, No. 6, 2001
Faul and Krumrich
4H), 3.48 (s, 3H), 2.42 (s, 1H), 2.12-2.01 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 137.6, 135.8, 128.6, 128.4, 127.8, 127.7,
121.4, 120.9, 119.2, 109.2, 101.1, 76.1, 73.4, 71.9, 71.3, 62.2,
42.4, 32.5. IR (CHCl3) v 3009, 2931, 2868, 1464, 1455, 1317,
1089, 1049 cm-1. Anal. Calcd for C21H25NO3 C, 74.31, H, 7.42,
N, 4.13. Found C, 74.50, H, 7.59, N, 4.14.
125.2, 121.8, 121.6, 121.4, 120.9, 119.6, 119.4, 111.8, 110.1,
105.5, 105.2, 75.3, 72.4, 72.0, 69.2, 42.4, 33.0, 32.0. IR (CHCl3)
v 3469, 1758, 1716, 1533, 1457, 1178, 1134, 1117, 1101 cm-1
.
Anal. Calcd for C33H30N3O4Br C, 64.10, H, 4.94, N, 6.86, Br,
13.05. Found C, 63.92, H, 5.17, N, 6.48, Br, 13.24.
6,7,10,11-Tetr a h yd r o-9-[(p h en ylm eth oxy)m eth yl]-9H,-
18H,-5,21:12,17-dim eth en odiben zo[e,k]-pyr r olo[3,4-h ][1,4,-
13]oxa d ia za cycloh exa d ecin e-18, 20(19H)-d ion e (8b) fr om
Str a tegy B. To a slurry of Cs2CO3 (0.13 g, 408 µmol) in DMF
(30 mL) at 100 °C was added a solution of 40 (0.25 g, 408 µmol)
in DMF (20 mL) by syringe pump over 6 h. The heat was
removed and the reaction mixture allowed to cool to room
temperature, diluted with EtOAc, and quenched with satu-
rated aqueous NH4Cl. The organic layer was washed with
water and saturated aqueous NaCl and dried (MgSO4). The
solvent was removed in vacuo to give a red residue that was
purified by column chromatography (1:1 hexanes:EtOAc) to
afford 68 mg 8b (32%), 52 mg 43 (24%), and 37 mg 42 (17%)
as dark red solids. 8b: 1H NMR (300 MHz, DMSO-d6) δ 10.9
(s, 1H), 7.82 (t, 2H, J ) 8.7 Hz), 7.53-7.42 (m, 4H), 7.35-7.09
(m, 9H), 4.39 (s, 2H), 4.34-4.21 (m, 2H), 4.16 (bs, 2H), 3.88-
3.83 (m, 1H), 3.64-3.56 (m, 1H), 3.49-3.37 (m, 3H), 2.18-
1.95 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 172.3, 138.1,
135.6, 132.1, 131.6, 131.4, 131.3, 128.2, 127.5, 127.4, 126.6,
121.6, 121.5, 121.4, 120.1, 110.1, 110.0, 103.2, 103.1, 75.5, 72.3,
70.4, 66.4, 45.8, 42.5, 31.7. IR (CHCl3) v 1767, 1721, 1535, 1470,
1390, 1337 cm-1. HRMS (FAB+) calcd for C33H29N3O4 532.2236,
found m/z (M + 1) 532.2245 (100%). 42: 1H NMR (300 MHz,
DMSO-d6) δ 11.70 (s, 1H), 10.85 (s, 1H), 7.91 (m, 4H), 7.78-
7.75 (m, 2H), 7.68 (s, 2H), 7.55-7.17 (m, 12H), 7.08 (t, 2H, J
) 7.4 Hz), 6.91 (t, 4H, J ) 7.8 Hz), 6.68 (t, 2H, J ) 7.3 Hz),
6.50-6.40 (m, 2H), 4.50 (s, 2H), 4.40 (s, 2H), 4.35 (bm, 2H),
4.25-4.03 (bm, 4H), 3.94-3.78 (bm, 4H), 3.60-3.33 (m, 6H),
2.16-1.92 (bm, 2H). IR (CHCl3) v 3468, 3439, 3010, 2942, 2867,
1759, 1714, 1698, 1533, 1470, 1393, 1338, 1104 cm-1. HRMS
(FAB+) calcd for C66H59BrN6O8 1063.4394. Found m/ z (M +
1) 1063.4378 (100%).
Meth yl 2-(1-{3-[2-(Meth ylsu lfon yloxy)eth oxy]-4-(p h en -
ylm eth oxy)bu tyl}in d ol-3-yl)-2-oxoa ceta te (46). To a solu-
tion of 37 (1.00 g, 2.95 mmol) in CH2Cl2 (20 mL) at 0 °C was
added pyridine (953 µL, 11.8 mmol) and methanesulfonic
anhydride (1.05 g, 5.89 mmol), and the mixture was allowed
to warm to room temperature for 15 min. The reaction mixture
was cooled to 0 °C and quenched with saturated aqueous NH4-
Cl. The organic layer was washed with 1 N HCl and saturated
aqueous NaCl and dried (MgSO4). The solvent was removed
in vacuo to give a yellow oil that was purified by column
chromatography (2:1 hexanes:EtOAc) to afford 1.17 g (95%)
of mesylate as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ
7.62 (d, 1H, J ) 7.9 Hz), 7.40-7.25 (m, 7H), 7.20 (t, 1H, J )
7.6 Hz), 7.10 (t, 1H, J ) 7.3 Hz), 6.50 (d, 1H, J ) 3.0 Hz), 4.47
(s, 2H), 4.36-4.31 (m, 2H), 4.31-4.23 (m, 2H), 3.96-3.86 (dt,
1H), 3.70-3.60 (dt, 1H), 3.48-3.36 (m, 3H), 3.00 (s, 3H), 2.10-
1.97 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 137.7, 135.8,
128.5, 128.4, 127.7, 127.6, 121.4, 120.9, 119.2, 109.2, 101.2,
76.2, 73.3, 72.1, 69.2, 69.0, 67.6, 42.3, 37.5, 32.2; IR (CHCl3) v
3009, 1464, 1454, 1358, 1318, 1175, 1020, 971, 923 cm-1. Anal.
Calcd for C22H27NO5S C, 63.28, H, 6.52, N, 3.35, found C, 62.89,
H, 6.53, N, 3.26.
Meth yl 2-{1-[3-(2-Hyd r oxyeth oxy)-4-(p h en ylm eth oxy)-
bu tyl]in d ol-3-yl}-2-oxoa ceta te (38). To a solution of 37 (2.00
g, 5.89 mmol) in Et2O (40 mL) at 0 °C was added oxalyl
chloride (1.03 mL, 11.8 mmol), and the mixture was allowed
to stir at 0 °C for 30 min and then cooled to -60 °C, and a 25
wt % solution of NaOMe in MeOH (5.22 mL, 24.2 mmol) was
added. The reaction mixture was stirred at -60 °C for 30 min,
allowed to warm to room temperature, quenched with water,
and diluted with EtOAc. The organic layer was washed with
saturated aqueous NaCl and dried (MgSO4) and the solvent
removed in vacuo to give a yellow oil that was purified by
column chromatography (1:1 hexanes:EtOAc) to afford 2.27 g
1
of 38 (91%) as a pale yellow solid. H NMR (300 MHz, CDCl3)
δ 8.46-8.39 (m, 2H), 7.42-7.24 (m, 8H), 4.50 (s, 2H), 4.39-
4.30 (m, 2H), 3.94 (s, 3H), 3.84-3.70 (m, 3H), 3.63-3.54 (m,
1H), 3.50-3.38 (m, 3H), 2.30 (s, 1H), 2.17-2.06 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 176.8, 163.4, 139.8, 137.4, 136.4,
128.4, 127.8, 127.7, 127.2, 124.0, 123.5, 122.9, 112.8, 110.0,
75.5, 73.4, 71.4, 71.3, 62.2, 52.6, 43.5, 31.9; IR (CHCl3) v 3012,
1727, 1644, 1521, 1401, 1282, 1176, 1141, 1089, 1060 cm-1
.
Anal. Calcd for C24H27NO6 C, 67.75, H, 6.40, N, 3.29. Found
C, 68.07, H, 6.33, N, 3.69.
3-{1-[3-(2-Hyd r oxyeth oxy)-4-(p h en ylm eth oxy)bu tyl]in -
d ol-3-yl}-4-in d ol-3-yl-3-p yr r olin e-2,5-d ion e (39). To a solu-
tion of 38 (2.00 g, 4.70 mmol) and indole-3-acetamide 12 (0.98
g, 5.64 mmol) in THF (60 mL) at 0 °C was added dropwise a
1.0 M solution of tert-BuOK in THF (23.5 mL, 23.5 mmol) and
the mixture allowed to warm to room temperature and stir
for 6 h. After the reaction mixture was cooled to 0 °C,
concentrated HCl (3.90 mL, 47.0 mmol) was added and the
slurry stirred overnight at room temperature. The reaction
mixture was quenched with water and diluted with EtOAc.
The organic layer was washed with saturated aqueous NaCl,
dried (MgSO4), and filtered. The solvent was removed in vacuo
to give a red residue that was purified by column chromatog-
raphy (EtOAc) to afford 1.91 g 39 (74%) as a red solid. 1H NMR
(300 MHz, DMSO-d6) δ 11.69 (d, 1H, J ) 2.5 Hz), 10.92 (s,
1H), 7.80 (d, 1H, J ) 2.8 Hz), 7.75 (s, 1H), 7.46 (d, 1H, J ) 8.3
Hz), 7.40-7.21 (m, 6H), 7.05 (t, 1H, J ) 7.3 Hz), 7.00-6.86
(m, 2H), 6.78-6.63 (m, 2H), 6.57 (t, 1H, J ) 7.2 Hz), 4.77-
4.57 (bs, 1H), 4.48 (s, 2H), 4.35 (t, 2H, J ) 6.2 Hz), 3.64-3.25
(m, 7H), 2.05-1.79 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ
173.0, 172.9, 138.4, 136.0, 135.7, 132.2, 131.9, 129.3, 128.3,
128.1, 127.5, 127.4, 127.1, 126.2, 125.2, 121.7, 121.6, 121.2,
120.9, 119.6, 119.3, 111.8, 110.2, 105.6, 105.1, 75.2, 72.4, 71.8,
71.2, 60.6, 42.3, 32.1. IR (CHCl3) v 3468, 1715, 1533, 1457,
1338, 1101 cm-1. Anal. Calcd for C33H31N3O5 C, 72.12, H, 5.69,
N, 7.65, found C, 71.89, H, 5.72, N, 7.57.
3-{1-[3-(2-Br om oeth oxy)-4-(ph en ylm eth oxy)bu tyl]in dol-
3-yl}-4-in d ol-3-yl-3-p yr r olin e-2,5-d ion e (40). To a solution
of bromine (253 µL, 4.91 mmol) in CH2Cl2 (20 mL) at -30 °C
was added triphenyl phosphite (1.29 mL, 4.91 mmol) by
syringe, and the dark red solution becomes colorless. Pyridine
(792 µL, 9.81 mmol) was added to the reaction followed by a
solution of 39 (1.80 g, 3.27 mmol) in CH2Cl2 (20 mL) and the
mixture allowed to warm to room temperature. The reaction
mixture was quenched with 1 N HCl and diluted with EtOAc.
The organic layer was washed with saturated aqueous NaCl
and dried (MgSO4) and the solvent removed in vacuo to give
a red residue that was purified by column chromatography
(1:1 hexanes:EtOAc) to afford 1.80 g 40 (90%) as a red solid.
1H NMR (300 MHz, DMSO-d6) δ 11.69 (d, 1H, J ) 2.5 Hz),
10.92 (s, 1H), 7.80 (d, 1H, J ) 2.8 Hz), 7.72 (s, 1H), 7.47 (d,
1H, J ) 8.3 Hz), 7.42-7.21 (m, 6H), 7.05 (t, 1H, J ) 7.5 Hz),
7.00-6.89 (m, 2H), 6.72 (m, 2H, J ) 7.6 Hz), 6.57 (t, 1H, J )
7.6 Hz), 4.48 (s, 2H), 4.33 (t, 2H, J ) 6.7 Hz), 3.92-3.80 (m,
1H), 3.66-3.52 (m, 3H), 3.46 (d, 2H), 3.41-3.30 (m, 1H), 2.06-
1.81 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 172.9, 138.3,
136.1, 135.6, 131.8, 129.3, 128.3, 128.1, 127.5, 127.1, 126.2,
To a solution of the mesylate (1.75 g, 4.19 mmol), prepared
above, in Et2O (40 mL) at 0 °C was added oxalyl chloride (731
µL, 8.38 mmol) and the mixture allowed to stir at 0 °C for 30
min and then cooled to -60 °C. A 25 wt % solution of NaOMe
in MeOH (3.80 mL, 17.6 mmol) was added and the reaction
mixture stirred at -60 °C for 30 min and then allowed to come
to room temperature. The reaction mixture was quenched with
water and diluted with EtOAc. The organic layer was washed
with saturated aqueous NaCl and dried (MgSO4) and the
solvent removed in vacuo to afford 1.90 g 46 (90%) as a yellow
1
oil. H NMR (300 MHz, CDCl3) δ 8.47-8.40 (m, 1H), 8.38 (s,
1H), 7.43-7.24 (m, 8H), 4.47 (s, 2H), 4.41-4.30 (m, 4H), 4.02-
3.87 (m, 1H), 3.87 (s, 3H), 3.72-3.63 (m, 1H), 3.50-3.39 (m,
3H), 3.03 (s, 3H), 2.16-2.05 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 176.9, 163.3, 139.6, 137.5, 136.4, 128.4, 127.8, 127.6,
127.1, 124.1, 123.5, 122.8, 112.8, 110.1, 75.8, 73.4, 71.8, 69.1,