Bullington et al.
Anal. Calcd for C20H16F3NO3: C, 64.00; H, 4.30; N, 3.73. Found
C, 63.70; H, 4.01; N, 3.62.
EtOAc in hexane to give 10 (0.76 g, 92% yield) as a light yellow
solid. Recrystallization provided 10 as colorless crystals: mp
140-141 °C; 1H NMR (CDCl3, 400 MHz) δ 6.86 (d, J ) 8.9
Hz, 1H), 6.79-6.76 (m, 2H), 6.70 (d, J ) 8.2 Hz, 1H), 6.66 (s,
1H), 6.63-6.59 (m, 2H), 6.52-6.50 (m, 2H) 4.53 (br, 2H), 3.91
(s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.72 (s, 3H),
3.61 (s, 3H), 3.58 (s, 3H), 3.50 (s, 3H), 3.07 (t, J ) 7.2 Hz, 2H);
13C NMR (CDCl3, 400 MHz) δ 162.5, 151.9, 149.2, 149.0, 148.6,
148.0, 147.4, 143.0, 131.5, 128.2, 127.0, 126.3, 124.3, 121.2,
120.0, 119.8, 117.2, 116.3, 112.6, 111.7, 111.3, 111.3, 98.2, 56.8,
56.8, 56.4, 56.2, 56.1, 56.0, 55.7, 52.1, 51.1, 38.2; MS (M + Na,
614). Anal. Calcd for C33H37NO9: C, 66.99; H, 6.30; N, 2.37.
Found: C, 66.86; H, 6.20; N, 2.12.
1-(3,4-Dih yd r oxyp h en yl)-3-[2-(3,4-d ih yd r oxyp h en yl)-
eth yl]-7,8-d ih yd r oxy-3H-5-oxa -3-a za -cyclop en ta [a ]n a p h -
th a len -4-on e (11), Nin ga lin B. Compound 10 (60 mg, 0.1
mmol) was dissolved in CH2Cl2 (25 mL), and 1 N BBr3 (1.6
mL, 1 N BBr3 in CH2Cl2, 0.16 mmol) was added dropwise at
-78 °C. The solution was stirred overnight allowing the
temperature to slowly warm to 25 °C. The reaction was
quenched with H2O (5 mL) and the mixture concentrated in
vacuo. The mixture was extracted into EtOAc (3 × 15 mL),
and the organics were washed with brine (10 mL), dried (Na2-
SO4), and evaporated to a dark yellow solid (46 mg, 98%): 1H
NMR (20% MeOH-d4/DMSO-d6, 400 MHz) δ 7.23 (s, 1H), 7.12
(s, 1H), 6.85 (d, J ) 7.8 Hz, 1H), 6.82 (d, J ) 2.0 Hz, 1H), 6.8
(s, 1H), 6.67 (d, J ) 8.1 Hz, 1H), 6.48 (dd, J ) 2.0, 8.1 Hz,
1H), 6.64 (d, J ) 2.0 Hz, 1H), 6.48 (dd, J ) 2.0, 8.1 Hz, 1H),
4.54 (t, J ) 7.0 Hz, 2H), 2.92 (t, J ) 7.4 Hz, 2H); 13C NMR
(DMSO-d6, 400 MHz) δ 154.5, 146.0, 145.2, 145.1, 144.7, 144.7,
143.8, 142.1, 132.7, 128.9, 126.1, 125.0, 120.5, 119.4, 118.9,
116.9, 116.2, 115.8, 115.5, 113.7, 109.4, 108.5, 103.4, 49.7, 37.0;
MS (M + 1, 462), FAB-HRMS (M + 1, 462.1174, C25H20NO8,
requires 462.1189). Anal. Calcd for C25H19NO8‚1.75 H2O: C,
60.91; H, 4.60; N, 2.84. Found: C, 61.00; H, 4.33; N, 2.75.
3-(4-Meth oxyp h en yl)-4-p h en yl-1H-p yr r ole-2-ca r boxyl-
ic Acid Meth yl Ester (5). The general method was followed
to afford 5 (0.59 g, 51% yield) as a white solid: mp 166-168
1
°C; H NMR (CDCl3, 400 MHz) δ 9.2 (br, NH), 7.30 (m, 5H),
7.07 (d, J ) 3.0 Hz, 1H), 7.02 (d, J ) 8.8 Hz, 2H), 6.73 (d, J )
8.4 Hz, 2H), 3.78 (s, 3H), 3.73 (s, 3H); MS (M + 1, 330). Anal.
Calcd. for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C,
74.12; H, 5.44; N, 4.35.
3,4-Dip h en yl-1H-p yr r ole-2-ca r boxylic Acid Meth yl Es-
ter (6). The general method was followed to afford 6 (0.56 g,
54% yield) as a white solid: mp 130-131 °C (lit.23 125-126
1
°C); H NMR (CDCl3, 400 MHz) δ 9.288 (br, NH), 7.32-7.06
(m, 11H), 3.71 (s, 3H) MS (M + Na, 300). Anal. Calcd for
C
18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C, 77.97; H,
5.33; N, 4.89.
4-(3,4-Dim et h oxyp h en yl)-3-(2,4,5-t r im et h oxyp h en yl)-
1H-p yr r ole-2-ca r boxylic Acid Meth yl Ester (7). After the
addition was complete, the reaction was stirred for 1 h at 0
°C. No product was observed by TLC (10% MeOH in CH2Cl2),
so stirring was continued for 18 h allowing the reaction to
warm to 25 °C. Evaporation of the solvent, followed by
purification on SiO2 (35 g) eluting with a gradient of 1-5%
MeOH in CH2Cl2, gave compound 7 (910 mg, 57% yield): mp
155-156 °C; 1H NMR (CDCl3, 400 MHz) δ 9.24 (br, NH), 7.11
(d, J ) 3.2 Hz, 1H), 6.80-6.74 (m, 3H), 6.63 (d, J ) 1.6 Hz,
1H), 6.53 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.75 (s, 3H), 3.72
(s, 3H), 3.60 (s, 3H), 3.47 (s, 3H); MS (M + 1, 428). Anal. Calcd
for C23H25NO7: C, 64.63; H, 5.90; N, 3.28. Found: C, 64.41;
H, 5.82; N, 3.18. A second peak was isolated from the column,
and this compound was identified as 3-(2,4,5-tr im eth oxy-
p h en yl)-1H-p yr r ole-2,4-d ica r boxylic a cid d im eth yl ester
1
(9): mp 135-138 °C; H NMR (CDCl3, 400 MHz) δ 9.55 (br,
NH), 7.57 (d, J ) 3.2 Hz, 1H), 6.79 (s, 1H), 6.59 (s, 1H), 3.94
(s, 3H), 3.83 (s, 3H), 3.71 (s, 3H), 3.70 (s, 3H), 3.68 (s, 3H) MS
(M + 1, 350). Anal. Calcd for C17H19NO7: C, 58.45; H, 5.48;
N, 4.01. Found; C, 58.41; H, 5.53; N, 3.83.
Ack n ow led gm en t. We thank Ms. Danielle Soenen
and Professor Dale Boger for providing us with spec-
troscopic data and an authentic sample of ningalin B.
We thank Dr. Alexandra Shedlow for her assistance in
performing and interpreting the intricate NMR experi-
ments.
4-(3,4-Dim eth oxyp h en yl)-1-[2-(3,4-d im eth oxyp h en yl)-
et h yl]-3-(2,4,5-t r im et h oxyp h en yl)-1H-p yr r ole-2-ca r box-
ylic Acid Meth yl Ester (10). Compound 7 (600 mg, 1.4
mmol), 3,4-dimethoxyphenethyl bromide22 (1.0 g, 4.2 mmol),
and Cs2CO3 (1.4 g, 4.2 mmol) were heated to 60 °C in DMF
(15 mL). After 2.5 h, the reaction was cooled, diluted with
water (30 mL), and extracted into EtOAc (50 mL, 2 × 20 mL).
The combined organics were washed with water (4 × 10 mL)
and then brine (10 mL) and dried (Na2SO4). After evaporation
of the solvent, the oil was dissolved in toluene (5 mL) and
purified on SiO2 (35 g) eluting with a gradient of 50-70%
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 1-7 and 9-11. This material is available free of
J O026445I
9442 J . Org. Chem., Vol. 67, No. 26, 2002