M. E. El-Araby et al. / Bioorg. Med. Chem. 12 (2004) 2867–2879
2877
(t, 1H, J ¼ 7:0 Hz), 4.77 (s, 1H), 3.65 (d, 2H,
6.26. Compound 27
J ¼ 7:0 Hz), 3.62 (s, 3H), 2.55 (t, 2H, J ¼ 7:0 Hz), 2.42
(t, 2H, J ¼ 7:0 Hz), 2.37 (s, 3H), 1.83 (s, 3H); 13C NMR
(CDCl3, 125 MHz) d 174.40, 149.11, 136.40, 133.89,
131.35, 122.38, 121.00, 120.54, 117.78, 116.75, 109.51,
85.57, 51.63, 34.29, 31.50, 25.44, 16.80. 15.87; IR
This compound was synthesized using a procedure adopted
for preparation of 22. Purification by flash column chro-
matography (hexanes–CH2Cl2–EtOAc, 2:1:1) provided 27
(1.81 g, 87%) as yellowish crystals: Mp 68–69 ꢂC; 1H NMR
(CDCl3, 300 MHz) d 7.47 (s, 1H), 7.43 (s, 1H), 6.70 (s, 1H),
5.39 (t, 1H, J ¼ 6:6 Hz), 4.66 (d, 2H, J ¼ 6:6 Hz), 3.88 (s,
3H), 3.61 (s, 3H), 2.45 (m, complex, 4H), 2.31 (s, 3H), 1.84
(s, 3H); 13C NMR (CDCl3, 125 MHz) d 173.05, 155.97,
140.26, 134.52, 132.35, 123.02, 121.19, 120.50, 118.60,
116.37, 91.46, 84.67, 55.45, 51.59, 44.53, 34.17, 32.20, 16.68,
16.46; IR (KBr pellet) 2209, 1736 cmÀ1; HRMS (EI): Re-
quired Mþ for C19H22N2O3, 326.1630; Found, 326.1614.
Anal. Calcd for (C19H22N2O3): C, 69.92; H, 6.79; N, 8.58.
Found: C, 69.90; H, 6.73; N, 8.56.
(CHCl3) 3462, 3357, 2220, 1728 cmÀ1
.
6.24. Compound 24
A magnetically stirred solution of 3 (326 mg, 1 mmol) in
MeOH (10 mL) was treated with a solution of LiOH
(168 mg, 7 mmol in 10 mL H2O) by dropwise addition
with a dropping funnel. The turbid mixture was stirred
at ambient temperature until the mixture became
homogeneous (about 1.5 h). The mixture was trans-
ferred into a beaker and ice/H2O. HCl solution was
added cautiously until pHꢁ4 then the liberated product
was extracted with EtOAc (3 · 50 mL). The organic layer
was washed with water, dried, and evaporated in vacuo.
The crude product was purified using flash chromato-
graphy (1% formic acid in 5:1 CH2Cl2–EtOAc) to yield
220 mg (70%) of 24 as a sticky material that solidified
6.27. Compound 28
0.5 M KOH (50 mL) was added drop-wise at 0 ꢂC to a
solution of 27 (1.57 g, 4.81 mmol) in MeOH (40 mL). The
turbid mixture was stirred at room temperature for 2 h
until it became clear. The solution was cooled to 0 ꢂC and
0.5 M HCl was added dropwise until the pH became 3–4.
The product was extracted with EtOAc (500 mL then
2 · 100 mL). The combined organic extract was washed
with water, dried, and evaporated in vacuo. The crude
solid was purified with flash column chromatography
(1% formic acid in CH2Cl2–EtOAc, 2:1) to afford the acid
1
after several days of storage at 5 ꢂC: Mp 42–45 ꢂC; H
NMR (CDCl3, 500 MHz) d 9.22 (br, 1H), 7.64 (d, 1H,
J ¼ 3:0 Hz), 7.38 (s, 1H), 5.43 (t, 1H, J ¼ 6:0 Hz), 3.72
(s, 3H), 3.69 (d, 2H, J ¼ 6:0 Hz), 2.56 (t, 2H,
J ¼ 7:0 Hz), 2.41 (t, 2H, J ¼ 7:0 Hz), 2.39 (s, 3H), 1.85
(s, 3H); IR (neat) 3282, 2219, 1706 cmÀ1; Anal. Calcd for
(C18H20N2O3): C, 69.21; H, 6.45; N, 8.97. Found: C,
69.00; H, 6.69; N, 8.68.
1
28 (0.90 g, 59%) as white solid: Mp 127.5–128.5 ꢂC; H
NMR (CDCl3) d 7.44 (s, 1H), 7.40 (s, 1H), 6.71 (s, 1H),
5.18 (t, 1H, J ¼ 6:9 Hz), 4.65 (d, 2H, J ¼ 6:9 Hz), 3.88 (s,
3H), 2.55 (t, 2H, J ¼ 7:2 Hz), 2.44 (t, 2H, J ¼ 7:2 Hz),
2.32 (s, 3H), 1.86 (s, 3H); 13C NMR (CDCl3, 75 MHz) d
178.84, 156.04, 140.14, 134.61, 132.32, 123.06, 121.23,
120.45, 118.68, 116.40, 91.51, 84.57, 55.45, 44.40, 33.79,
32.05, 16.62, 16.38; IR (KBr pellet) 3200-2750, 2214,
1727 cmÀ1. HRMS (EI): Required Mþ for C18H20N2O3,
312.1473; Found: 312.1518; Anal. Calcd: C, 69.21; H,
6.45; N, 8.97. Found: C, 68.81; H, 6.46; N, 8.77.
6.25. Compound 25
A solution of 24 (155 mg, 0.5 mmol) in anhydrous
CH2Cl2 (6 mL) was cooled into )78 ꢂC under argon.
Dibal-H (3 mL of 1 M solution in CH2Cl2) was added
dropwise over 20 min and the mixture was stirred for
90 min. The reaction was quenched by pouring it into
20 mL of 10% solution of tartaric acid (containing four
drops of 2 N HCl) while stirring. The mixture was stir-
red for 30 min. The organic layer was separated, washed,
and dried. The aqueous layer was washed with EtOAc
(3 · 25 mL). The EtOAc extract was washed, dried, and
combined with the CH2Cl2 extract. The combined
extract was evaporated in vacuo to give the crude
aldehyde, which was purified by flash column
chromatography (0.75% formic acid in 3:1 mixture of
CH2Cl2 and EtOAc) to furnish 56 mg (36%) of the
6.28. Compound 29a
This compound was prepared using the procedure for
the preparation of 25. Purification using flash column
chromatography (0.75% formic acid in 3:1 mixture of
CH2Cl2–EtOAc) furnished 56 mg (36%) of the aldehyde
29a as a white powder: Mp 170–171.5 ꢂC; 1H NMR
(CDCl3, 300 MHz) d 10.27 (br, 1H), 9.86 (s, 1H), 8.01 (s,
1H), 7.57 (s, 1H), 6.69 (s, 1H), 5.48 (t, 1H, J ¼ 6:0 Hz),
4.67, (d, 2H, J ¼ 6:0), 3.88 (s, 3H), 2.53 (t, 2H,
J ¼ 7:2 Hz), 2.44 (t, 2H, J ¼ 7:2 Hz), 2.31 (s, 3H), 1.86
(s, 3H); 13C NMR (CDCl3, 75 MHz) d 184.88, 177.73,
156.05, 140.57, 136.84, 136.67, 123.60, 122.96, 118.71,
118.50, 117.76, 91.39, 55.45, 44.39, 33.97, 32.02, 16.60,
1
aldehyde 25 as a white powder: Mp 170–171.5 ꢂC; H
NMR (CDCl3, 400 MHz) d 10.27 (br, 1H), 9.70 (s, 1H),
7.93 (s, 1H), 7.84 (d, 1H, J ¼ 3:2 Hz), 5.56 (t, 1H,
J ¼ 6:0 Hz), 3.74, (d, 2H, J ¼ 6:0), 3.73 (s, 3H), 2.65 (t,
2H, J ¼ 7:2 Hz), 2.44 (t, 2H, J ¼ 7:2 Hz), 2.39 (s, 3H),
1.86 (s, 3H); 13C NMR (CDCl3, 125 MHz) d 186.24,
176.87, 153.82, 136.33, 136.02, 127.33, 123.16, 121.29,
121.07, 117.52, 117.04, 60.85, 34.51, 30.35, 24.88, 16.72,
15.473; IR (KBr pellet) 3308, 1703 cmÀ1; Anal. Calcd for
(C18H21NO4): C, 68.55; H, 6.71, N, 4.44. Found C,
68.56; H, 6.76, N, 4.49.
16.46; IR (KBr pellet) 3308, 1703 cmÀ1
.
6.29. Compound 30
This compound was prepared using the procedure for
the preparation of 2 starting from 133 mg (0.42 mmol) of