Synthesis of the Tetracyclic Core of Erythrina Alkaloids
0 °C. After the mixture was stirred at 0 °C for 1 h, a 0.33 g (1.4
mmol) sample of 4-(2-bromoethyl)-1,2-dimethoxybenzene was
added. The reaction mixture was stirred at room temperature
overnight and was then quenched with water. The aqueous layer
was extracted with EtOAc, and the combined organic layer was
washed with brine and dried over MgSO4. The solvent was removed
under reduced pressure, and the residue was purified by flash
column chromatography to give 0.25 g (80%) of 20 as a white
solid: mp 128-130 °C; IR (neat) 2983, 1736, 1677, 1027, and
organic layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
flash silica gel chromatography to give 0.06 g (61%) of 23 as a
white solid: mp 168-170 °C; IR (neat) 2981, 1727, 1643, 1211,
1050, and 729 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.49 (s, 3H),
1.57 (s, 3H), 1.96 (t, 1H, J ) 12.0 Hz), 2.59 (d, 1H, J ) 16.8 Hz),
2.60 (dd, 1H, J ) 12.0 and 4,8 Hz), 2.81 (d, 1H, J ) 16.8 Hz),
2.92 (dd, 1H, J ) 15.0 and 4.8 Hz), 3.02 (dd, 1H, J ) 15.0 and
10.2 Hz), 3.41-3.50 (m, 1H), 3.73 (s, 3H), 3.87 (s, 3H), 3.90 (s,
3H), 4.29 (brs, 1H), 4.36 (dt, 1H, J ) 12.0 and 4.8 Hz), 4.78 (d,
1H, J ) 4.8 Hz), 6.61 (s, 1H), and 7.66 (s, 1H); 13C NMR (CDCl3,
150 MHz) δ 26.6, 29.0, 33.7, 34.9, 41.8, 48.4, 51.1, 53.4, 55.8,
56.1, 71.9, 76.2, 108.9, 109.3, 111.5, 112.3, 128.0, 133.9, 141.0,
147.9, 172.0, and 173.3. Anal. Calcd for C23H27NO7: C, 64.32; H,
6.34; N, 3.26. Found: C, 64.06; H, 6.34; N, 3.10.
1
730 cm-1; H NMR (CDCl3, 400 MHz) δ 1.37 (s, 3H), 1.45 (s,
3H), 1.56 (dd, 1H, J ) 12.4 and 10.4 Hz), 2.42 (d, 1H, J ) 16.8
Hz), 2.64 (dd, 1H, J ) 12.4 and 6.0 Hz), 2.71-2.85 (m, 2H), 2.78
(d, 1H, J ) 16.8 Hz), 3.46 (ddd, 1H, J ) 14.0, 10.0, and 6.0 Hz),
3.63 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 4.50 (dt, 1H, J ) 10.4 and
6.0 Hz), 4.72 (dd, 1H, J ) 6.0 and 2.8 Hz), 5.17 (d, 1H, J ) 2.8
Hz), 6.72 (s, 1H), 6.75 (d, 1H, J ) 8.0 Hz), and 6.77 (d, 1H, J )
8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 25.2, 27.9, 32.2, 35.2,
40.9, 41.6, 47.5, 53.0, 55.9, 56.0, 71.2, 72.1, 97.2, 109.3, 111.4,
112.0, 120.8, 130.6, 143.6, 147.8, 149.0, 172.5, and 172.7. Anal.
Calcd for C23H29NO7: C, 64.02; H, 6.77; N, 3.25. Found: C, 63.83;
H, 6.83; N, 3.11.
Treatment of lactam 22 under similar radical conditions also
afforded 23 in 55% yield.
5-[2-(2-Bromo-4,5-dimethoxyphenyl)ethyl]-2,2-dimethyl-6-
oxo-3a,5,6,7,8,8a-hexahydro[1,3]dioxolo[4,5-f]indole-7a-carbox-
ylic Acid Methyl Ester (24). To a solution of 0.2 g (0.74 mmol)
of acetonide 11 in 3 mL of DMF was added 0.04 g (0.97 mmol)
60% NaH at 0 °C. After the mixture was stirred at 0 °C for 1 h,
0.43 g (1.33 mmol) of 1-bromo-2-(2-bromoethyl)-4,5-dimethoxy-
benzene was added. The reaction mixture was stirred from 0 °C to
room temperature overnight and then quenched with water. The
aqueous layer was extracted with EtOAc, and the combined organic
layer was washed with brine and dried over MgSO4. The solvent
was removed under reduced pressure, and the residue was purified
by flash column chromatography to afford 0.2 g (53%) of 24 as a
clear oil: 1H NMR (CDCl3, 600 MHz) δ 1.35 (s, 3H), 1.43 (s,
3H), 1.55 (dd, 1H, J ) 12.6 and 10.2 Hz), 2.43 (d, 1H, J ) 16.2
Hz), 2.63 (dd, 1H, J ) 12.6 and 6.6 Hz), 2.77 (d, 1H, J ) 16.2
Hz), 2.81 (ddd, 1H, J ) 13.8, 10.2, and 6.6 Hz), 2.96 (ddd, 1H, J
) 13.8, 10.2 and 6.6 Hz), 3.42-3.51 (m, 1H), 3.61 (s, 3H), 3.76-
3.84 (m, 1H), 3.78 (s, 3H), 3.80 (s, 3H), 4.48 (dt, 1H, J ) 10.2
and 6.6 Hz), 4.70 (dd, 1H, J ) 6.6 and 3.0 Hz), 5.29 (d, 1H, J )
3.0 Hz), 6.74 (s, 1H), and 6.96 (s, 1H); 13C NMR (CDCl3, 150
MHz) δ 25.2, 28.0, 33.0, 35.1, 40.0, 41.0, 47.5, 53.1, 56.2, 60.5,
71.2, 72.1, 97.6, 109.3, 113.6, 114.3, 115.6, 129.4, 143.5, 148.5,
148.6, 172.3, and 172.8.
(7aR,Z)-Methyl 1,2-(4,5-Dimethoxy)benzo-10,10-dimethyl-6-
oxo-3,4,51,6,7,7a,-8,8a,11a,11b-decahydroazepino[3,2,1-hi][1,3]-
dioxolo[4,5-f]indole-7a-carboxylate (25). To a solution of 0.1 g
(0.2 mmol) of bromo-lactam 24 in 20 mL of benzene was added
8.0 mg (0.05 mmol) of AIBN followed by 0.067 mL (0.25 mmol)
of Bu3SnH. The mixture was heated to reflux for 10 h, cooled to
room temperature, and poured into 10 mL of an aqueous KF
solution (1 M). The aqueous layer was extracted with EtOAc, and
the combined organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by flash silica gel chromatography to give 0.062 g (72%)
of 25 as a white solid: mp 138-140 °C; IR (neat) 1732, 1689,
1516, 1214, and 730 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.35 (s,
3H), 1.38 (s, 3H), 2.01 (dd, 1H, J ) 13.6 and 9.2 Hz), 2.44 (d, 1H,
J ) 17.6 Hz), 2.52-2.60 (m, 2H), 2.71 (d, 1H, J ) 17.6 Hz), 2.71-
2.74 (m, 1H), 2.88-2.96 (m, 2H), 3.75 (s, 3H), 3.75-3.81 (m,
1H), 3.84 (s, 3H), 3.88 (s, 3H), 4.42 (dt, 1H, J ) 9.6 and 7.2 Hz),
4.51 (ddd, 1H, J ) 13.6, 5.2 and 1.6 Hz), 4.57 (dd, 1H, J ) 11.6
and 7.2 Hz), 6.67 (s, 1H), and 7.00 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 25.2, 27.8, 34.2, 35.0, 42.1, 43.0, 44.5, 45.6, 53.2, 56.0,
56.3, 63.6, 71.2, 73.3, 109.2, 111.2, 112.7, 130.8, 133.9, 147.5,
147.6, 171.1, and 175.0. HRMS Calcd for C23H29NO7: 431.1944.
Found: 431.1943.
4-Bromo-5-[2-(3,4-dimethoxyphenyl)ethyl]-2,2-dimethyl-6-
oxo-3a,5,6,7,8,8a-hexahydro[1,3]dioxolo[4,5-f]indole-7a-carbox-
ylic Acid Methyl Ester (21). To a solution containing 0.16 g (0.37
mmol) of the above lactam 20 in 6 mL of CH3CN was added 0.07
g (0.37 mmol) of NBS. The reaction mixture was stirred at room
temperature for 1 h and was quenched with water. The aqueous
layer was extracted with EtOAc, and the combined extracts were
dried over MgSO4 and concentrated under reduced pressure.
Purification of the residue by flash silica gel chromatography
afforded 0.18 g (97%) of 21 as a colorless oil: IR (neat) 1732,
1
1664, 1515, 1213, and 731 cm-1; H NMR (CDCl3, 600 MHz) δ
1.39 (s, 3H), 1.49 (s, 3H), 1.71 (dd, 1H, J ) 12.6, 11.4 Hz), 2.50
(d, 1H, J ) 16.2 Hz), 2.59 (dd, 1H, J ) 12.6 and 6.0 Hz), 2.71 (td,
1H, J ) 12.0 and 6.0 Hz), 2.79 (d, 1H, J ) 16.2 Hz), 2.90 (td, 1H,
J ) 12.0 and 4.8 Hz), 3.65 (s, 3H), 3.83 (s, 3H), 3.85, (s, 3H),
4.14 (m, 2H), 4.45 (dt, 1H, J ) 11.4 and 6.0 Hz), 4.74 (d, 1H, J )
6.0 Hz), and 6.78 (m, 3H); 13C NMR (CDCl3, 150 MHz) δ 25.6,
28.1, 34.0, 35.0, 40.9, 72.9, 51.9, 53.3, 56.0, 72.4, 77.3, 94.5, 109.5,
111.4, 112.2, 120.9, 130.6, 140.3, 147.8, 149.0, 171.6, and 173.5.
4-Bromo-5-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-2,2-di-
methyl-6-oxo-3a,5,6,7,8,8a-hexahydro[1,3]dioxolo[4,5-f]indole-
7a-carboxylic Acid Methyl Ester (22). To a solution containing
0.047 g (0.09 mmol) of the above lactam 21 in 6 mL of CH3CN
was added 0.016 g (0.09 mmol) of NBS. The reaction mixture was
stirred at room temperature for 12 h and was quenched with water.
The aqueous layer was extracted with EtOAc, and the combined
extracts were dried over MgSO4 and concentrated under reduced
pressure. Purification of the residue by flash silica gel chromatog-
raphy afforded 0.05 g (93%) of 22 as a colorless oil: IR (neat)
1
2950, 1737, 1738, 1506, 912, and 729 cm-1; H NMR (CDCl3,
600 MHz) δ 1.40 (s, 3H), 1.50 (s, 3H), 1.71 (dd, 1H, J ) 12.6 and
11.4 Hz), 2.50 (d, 1H, J ) 16.8 Hz), 2.60 (dd, 1H, J ) 12.6 and
5.4 Hz), 2.80 (d, 1H, J ) 16.0.8 Hz), 2.89 (ddd, 1H, J ) 13.8,
10.2 and 6.6 Hz), 2.98 (ddd, 1H, J ) 13.8, 10.2 and 4.8 Hz), 3.66
(s, 3H), 3.82 (s, 3H), 3.83, (s, 3H), 4.16 (ddd, 1H, J ) 13.8, 10.2
and 4.8 Hz), 4.24 (ddd, 1H, J ) 13.8, 10.2 and 6.6 Hz), 4.45 (dt,
1H, J ) 11.4 and 5.4 Hz), 4.74 (d, 1H, J ) 5.4 Hz), 6.84 (s, 1H),
and 6.98 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ 25.7, 28.2, 34.3,
35.2, 41.1, 41.4, 52.1, 53.4, 56.3, 72.5, 94.9, 109.6, 113.4, 114.6,
115.7, 129.7, 140.4, 148.5, 148.6, 171.7, and 173.7.
(7aR,Z)-Methyl 1,2-(4,5-Dimethoxy)benzo-10,10-dimethyl-6-
oxo-3,4,6,7,7a,-8,8a,11a-octahydroazepino[3,2,1-hi][1,3]dioxolo-
[4,5-f]indole-7a-carboxylate (23). To a solution of 0.13 g (0.25
mmol) of lactam 21 in 25 mL of benzene was added 8.4 mg (0.05
mmol) of AIBN followed by 0.16 mL (0.61 mmol) of Bu3SnH.
The mixture was heated at reflux for 10 h, cooled to room
temperature, and poured into 10 mL of an aqueous KF solution (1
M). The aqueous layer was extracted with EtOAc, and the combined
1-[2-(3,4-Dimethoxyphenyl)ethyl]-2,5-dioxo-1,2,3,4,5,6-hexahy-
droindole-3a-carboxylic Acid Methyl Ester (27). To a solution
containing 0.38 g (0.88 mmol) of 20 in 5 mL of CH2Cl2 was added
1 mL of TFA. The reaction mixture was stirred at room temperature
for 30 min and was then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to give
J. Org. Chem, Vol. 71, No. 19, 2006 7399