Total Synthesis of Ningalin B
J . Org. Chem., Vol. 65, No. 8, 2000 2483
J ) 1.8 Hz, 1H), 6.35 (s, 1H), 4.89 (m, 2H), 4.76 (m, 2H), 3.89
(s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.63 (s, 3H),
3.60 (s, 3H), 3.59 (s, 3H), 3.56 (s, 3H), 3.27 (s, 3H), 3.09 (t, J
) 7.3 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 162.24, 162.19,
149.6, 148.9, 148.6, 147.83, 147.79, 147.65, 143.6, 131.2, 130.9,
127.3, 126.5, 125.1, 123.9, 122.7, 121.2, 117.0, 114.8, 113.8,
112.4, 111.3, 110.2, 101.5, 96.8, 56.2, 56.15, 56.02, 55.91, 55.85,
55.82, 55.7, 51.51, 51.48, 48.7, 38.0; IR (film) νmax 2949, 2834,
1718, 1610 cm-1; FABHRMS (NBA/NaI) m/z 702.2553 (M +
Na+, C36H41NO12 requires 702.2526).
1H), 6.79 (d, J ) 8.2 Hz, 1H), 6.74 (s, 1H), 6.71 (dd, J ) 1.8,
7.9 Hz, 1H), 6.58 (d, J ) 1.5 Hz, 1H), 4.65 (t, J ) 7.0 Hz, 2H),
3.93 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.77 (s,
3H), 3.57 (s, 3H), 3.11 (t, J ) 7.0 Hz, 2H); 13C NMR (CDCl3,
125 MHz) δ 155.7, 149.2, 149.1, 149.0, 148.7, 148.0, 146.4,
145.8, 132.1, 130.7, 127.4, 126.9, 122.3, 121.1, 119.3, 115.1,
113.2, 112.3, 111.4, 111.2, 110.6, 104.9, 100.8, 56.3, 56.2, 56.1
(3C), 56.0, 51.3, 38.0; IR (film) νmax 2931, 2835, 1709, 1591,
1551, 1515 cm-1; MALDIHRMS (DHB) m/z 546.2111 (M + H+,
C
31H31NO8 requires 546.2128).
Nin ga lin B (1). A solution of 13 (5.9 mg, 11 µmol, 1.0 equiv)
Meth yl 7,8-Dim eth oxy-3-(2-(3,4-d im eth oxyp h en yl)eth -
yl)-1-(3,4-d im eth oxyp h en yl)-[1]-ben zop yr a n o[3,4-b]p yr -
r ol-4(3H)-on e-2-ca r boxyla te (11). A sample of 10 (272 mg,
400 µmol, 1.0 equiv) was treated with 3 M HCl-EtOAc (16
mL) and stirred under Ar at 25 °C for 2 h. Chromatography
of the concentrated mixture (SiO2, 4.5 × 5 cm, 15% EtOAc/
CH2Cl2) afforded pure 11 (229 mg, 95%) as a light yellow
in CH2Cl2 (1.1 mL) under Ar at -78 °C was treated with BBr3
(1 M in hexanes, 160 µL, 160 µmol, 15 equiv), and the mixture
was allowed to warm to 25 °C over 24 h. Following dilution
with MeOH (0.50 mL), the solvent was removed by a stream
of N2 to afford synthetic 1 (5.2 mg, 98%) identical in all respects
(1H NMR, 13C NMR, IR, MS) when compared to spectra of
naturally derived ningalin B: 1H NMR (17% CD3OD/DMSO-
d6, 400 MHz) δ 7.17 (s, 1H), 7.07 (s, 1H), 6.80 (d, J ) 8.2 Hz,
1H), 6.77 (d, J ) 2.0 Hz, 1H), 6.75 (s, 1H), 6.63 (m, 2H), 6.59
(d, J ) 1.8 Hz, 1H), 6.43 (dd, J ) 2.1, 7.9 Hz, 1H), 4.49 (t, J )
7.0 Hz, 2H), 2.87 (t, J ) 7.4 Hz, 2H); 13C NMR (17% CD3OD/
DMSO-d6, 100 MHz) δ 155.0, 146.2, 145.4, 145.3, 145.2, 144.9,
144.0, 142.3, 133.0, 129.4, 126.6, 125.6, 121.0, 119.9, 119.4,
117.2, 116.4, 116.0, 115.8, 114.2, 109.9, 108.8, 103.7, 50.2, 37.4;
IR (film) νmax 3333, 2923, 1673 cm-1; MALDIHRMS (DHB) m/z
484.1009 (M + Na+, C25H19NO8 requires 484.1008).
1
solid: mp 192-193 °C; H NMR (CDCl3, 500 MHz) δ 6.97 (d,
J ) 8.2 Hz, 1H), 6.90 (dd, J ) 2.0, 8.1 Hz, 1H), 6.87 (s, 1H),
6.85 (d, J ) 1.9 Hz, 1H), 6.79 (m, 3H), 6.51 (s, 1H), 5.10 (t, J
) 7.6 Hz, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85 (s,
3H), 3.84 (s, 3H), 3.57 (s, 3H), 3.42 (s, 3H), 3.10 (t, J ) 7.7 Hz,
2H); 13C NMR (CDCl3, 125 MHz) δ 161.4, 155.2, 149.3, 148.95,
148.89, 148.7, 147.9, 146.1, 145.8, 130.6, 129.6, 127.0, 126.9,
124.3, 122.8, 121.3, 117.6, 113.5, 112.4, 111.3, 111.0, 109.6,
104.6, 100.4, 56.2, 56.1 (2C), 56.0, 55.9, 55.6, 51.9, 48.8, 38.0;
IR (film) νmax 3001, 2952, 2835, 1732, 1699 cm-1; FABHRMS
(NBA/NaI) m/z 626.2017 (M + Na+, C33H33NO10 requires
626.2002).
9,10-Dih yd r o-12,13-d im eth oxy-1-(3′,4′-d im eth oxyp h en -
yl)-3,4-d im eth oxy- [4,3-d ]-[1]-ben zop yr a n o-15H-ben za ze-
p in o[3,2-a ]-[3]-p yr r ol-7,15(18H)-d ion e (14). A sample of 12
(3.3 mg, 5.6 µmol) was treated with Eaton’s Acid19 (200 µL,
7.5% P2O5-MeSO3H) and stirred under Ar at 25 °C. After 18
h, the reaction was diluted with H2O, extracted with CH2Cl2,
washed with saturated aqueous NaHCO3 and saturated aque-
ous NaCl, dried (Na2SO4), and concentrated under reduced
pressure. Chromatography (SiO2, 1.5 × 5 cm, 10% EtOAc/CH2-
Cl2) afforded 14 (2.1 mg, 66% yield) as a yellow solid: mp 225-
226 °C; 1H NMR (CDCl3, 500 MHz) δ 7.71 (s, 1H), 7.03 (d, J )
8.1 Hz, 1H), 6.99 (dd, J ) 1.8, 8.1 Hz, 1H), 6.94 (d, J ) 1.8 Hz,
1H), 6.89 (s, 1H), 6.70 (s, 1H), 6.51 (s, 1H), 5.26 (m, 2H), 3.98
(s, 3H), 3.94 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H),
3.44 (m, 5H); 13C NMR (20% CD3OD/CDCl3, 100 MHz) δ 181.9,
156.2, 153.3, 149.2, 149.0, 148.5, 148.1, 145.9, 145.7, 138.6,
136.0, 128.7, 127.5, 127.3, 126.0, 122.4, 115.1, 113.3, 113.1,
112.3, 111.3, 109.6, 104.7, 100.3, 56.1, 56.0 (2C), 55.9 (2C), 55.4,
46.2, 36.0; IR (film) νmax 2995, 2944, 2831, 1711, 1692, 1590
7,8-Dim eth oxy-3-(2-(3,4-d im eth oxyp h en yl)eth yl)-1-(3,4-
d im et h oxyp h en yl)-[1]-b en zop yr a n o[3,4-b]p yr r ol-4(3H)-
on e-2-ca r boxylic Acid (12). A stirred mixture of 11 (120 mg,
0.20 mmol, 1.0 equiv) and LiI (80 mg, 0.60 mmol, 3.0 equiv)
in DMF (13 mL) under Ar was warmed at reflux. After 24 and
48 h, the reaction was treated with additional LiI (80 mg, 2 ×
3 equiv). The mixture was warmed for a total of 3.5 d before
the reaction was diluted with H2O, acidified with 10% aqueous
HCl, extracted with CH2Cl2, and dried (Na2SO4). Chromatog-
raphy (SiO2, 2.0 × 15 cm, 5% MeOH/CHCl3) afforded 12 (94
1
mg, 80% yield) as a yellow solid: mp 219-220 °C; H NMR
(10% CD3OD/CDCl3, 400 MHz) δ 6.94-6.73 (m, 7H), 6.44 (s,
1H), 5.05 (t, J ) 7.9 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.81 (s,
3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.36 (s, 3H), 3.06 (t, J ) 7.9 Hz,
2H); 13C NMR (10% CD3OD/CDCl3, 100 MHz) δ 162.5, 155.5,
149.1, 148.82, 148.77, 148.5, 147.6, 145.9, 145.6, 130.8 (2C),
127.4, 127.2, 124.5, 122.8, 121.2, 117.4, 113.6, 112.3, 111.3,
111.0, 109.6, 104.5, 100.3, 56.1, 56.0, 55.93, 55.87, 55.7, 55.4,
cm-1; MALDIHRMS (DHB) m/z 572.1940 (M + H+, C32H29
NO9 requires 572.1921).
-
37.9, 29.7; IR (film) νmax 3273, 2925, 2851, 1726, 1515 cm-1
;
MALDIHRMS (DHB) m/z 589.1940 (M+, C32H31NO10 requires
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institute of Health (CA
42056), the Skaggs Institute for Chemical Biology, and
the award of an Achievement Rewards for College
Scientists scholarship (D.R.S.).
589.1948).
Hexa m eth yl Nin ga lin B (13). A solution of 12 (9.3 mg,
16 µmol, 1.0 equiv) and cuprous oxide18 (2.3 mg, 16 µmol, 1.0
equiv) in degassed quinoline (450 µL) was warmed at 220 °C
under Ar for 5 min. The mixture was cooled to 25 °C, and the
solvent was removed by a stream of N2. Chromatography (SiO2,
0.5 × 10 cm, 10% EtOAc/CH2Cl2) provided 13 (6.0 mg, 70%
yield) as a white solid: mp 186-187 °C; 1H NMR (CDCl3, 400
MHz) δ 7.09 (s, 1H), 6.95-6.92 (m, 3H), 6.88 (d, J ) 1.2 Hz,
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
5-14 and 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O9916535
(18) Cohen, T.; Schambach, R. A. J . Am. Chem. Soc. 1970, 92, 3189.
Trost, B. M.; Kinson, P. L. J . Org. Chem. 1972, 37, 1273.
(19) Eaton, P. E.; Carlson, G. R.; Lee, J . T. J . Org. Chem. 1973, 38,
4071.