Z. Rao et al. / European Journal of Medicinal Chemistry 46 (2011) 3934e3941
3939
(m, 3H), 1.02e0.77 (m, 6H); 13C NMR (75 MHz, CDCl3):
170.3, 155.0, 152.1, 132.0, 131.1, 124.1, 123.0, 121.2, 73.7, 72.4, 44.2,
41.3, 28.0, 25.7, 24.9, 19.7, 13.8; HRMS calcd for C23H28O7: 416.1835,
found: 416.1827.
d
184.2,
14 (2 mmol) in ethanol (5 ml) was added 5 drops of concentrated
hydrochloricacid. The mixturewasstirredat rtfor 5 min. The reaction
mixture was poured into saturated aqueous NaHCO3 (25 ml). The
mixture was extracted with ethyl acetate (25 ml ꢁ 2). The combined
organic extracts were dried over anhydrous MgSO4 and filtered. The
filtrate was concentrated under vacuum to afford the crude material
which was purified by flash column chromatography to give 15.
5.4.8. 2-[1-(3-Hydroxy-3-methylheptanoxy)-4-methyl-3-pentenyl]
naphthazarin (7i)
Yield 77.6%, red oil; 1H NMR (300 MHz, CDCl3):
d 12.62 (s, 1H),
12.43 (s, 1H), 7.19 (s, 2H), 7.05 (s, 1H), 6.16e6.05 (m, 1H), 5.20e5.07
(m, 1H), 2.72e2.33 (m, 4H), 1.76e1.16 (m, 15H), 0.99e0.78 (m, 3H);
5.5.1. 2-[1-(3-Furoyl)-4-methyl-3-pentenyl]naphthazarin (15a)
Yield 52.5%, red oil; 1H NMR (300 MHz, CDCl3, d ppm):
d 12.63 (s,
13C NMR (75 MHz, CDCl3):
d
184.6, 170.3, 155.1, 152.0, 132.0, 131.1,
1H),12.43 (s,1H), 8.11 (s,1H), 7.49 (s,1H), 7.20(s, 2H), 7.04(s,1H), 6.79
123.9, 123.0, 121.2, 74.0, 64.7, 47.9, 43.6, 28.2, 27.0, 25.4, 23.6, 19.7,
13.8; HRMS calcd for C24H30O7: 430.1992, found: 430.1989.
(s,1H), 6.29e6.14 (m,1H), 5.26e5.12 (m,1H), 2.87e2.41 (m, 2H),1.69
(s, 3H), 1.62 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 184.5, 162.1, 154.3,
150.6, 147.2, 144.1, 134.1, 126.7, 123.7, 122.1, 120.1, 111.2, 74.1, 29.2,
26.2, 18.9; HRMS calcd for C21H18O7: 382.1053, found: 382.1049.
5.4.9. 2-[1-(3-Hydroxy-3-methylnonanoxy)-4-methyl-3-pentenyl]
naphthazarin (7j)
Yield 72.1%, red oil; 1H NMR (300 MHz, CDCl3)
12.42 (s, 1H), 7.19 (s, 2H), 7.04 (s, 1H), 6.16e6.06 (m, 1H), 5.20e5.09
(m, 1H), 3.24 (s, 1H). 2.74e2.29 (m, 4H), 1.70 (s, 3H), 1.60 (s, 3H),
1.42e1.18 (m, 13H), 0.97e0.79 (m, 3H); 13C NMR (75 MHz, CDCl3):
d
: 12.61 (s, 1H),
5.5.2. 2-[1-(2-Furoyl)-4-methyl-3-pentenyl]naphthazarin (15b)
Yield 66.1%, red oil; 1H NMR (300 MHz, CDCl3, d ppm):
d 12.61 (s,
1H),12.42 (s, 1H), 7.63 (s, 1H), 7.19 (s, 2H), 7.08 (s, 1H), 6.61e6.52 (m,
1H), 6.29e6.18 (m,1H), 5.28e5.11 (m,1H), 2.84e2.47 (m, 2H),1.68 (s,
d
184.7, 170.7, 155.1, 152.3, 132.2, 131.1, 124.3, 123.2, 121.3, 74.2, 64.7,
3H), 1.60 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 184.5, 157.0, 153.4,
46.9, 42.7, 33.5, 31.1, 27.9, 26.8, 25.5, 21.5, 19.5, 16.2; HRMS calcd for
C26H34O7: 458.2305, found: 458.2301.
152.0, 146.8, 145.1, 133.7, 127.3, 123.4, 121.5, 117.3, 111.4, 72.9, 27. 5,
24.3, 18.7; HRMS calcd for C21H18O7: 382.1053, found: 382.1050.
5.4.10. 2-[1-(3-Hydroxy-3-phenyl-butanoxy)-4-methyl-3-pentenyl]
5.5.3. 2-[1-(3-Tetrahydrofuroyl)-4-methyl-3-pentenyl]
naphthazarin (7k)
naphthazarin (15c)
Yield 64.4%, red oil; 1H NMR (300 MHz, CDCl3):
d
12.52 (s, 1H),
Yield 74.1%, red oil; 1H NMR (300 MHz, CDCl3, d ppm):
d 12.60 (s,
12.41 (s, 1H), 7.69e7.12 (m, 7H), 6.70 (s, 1H), 5.98e5.89 (m, 1H),
5.10e4.99 (m, 1H), 4.15 (s, 1H), 3.20e2.78 (m, 2H), 2.60e2.28 (m,
2H), 1.72e1.63 (m, 3H), 1.61e1.50 (m, 6H); 13C NMR (75 MHz,
1H), 12.43 (s, 1H), 7.19 (s, 2H), 7.01 (s, 1H), 6.13e6.03 (m, 1H),
5.17e5.07 (m, 1H), 4.09e3.77 (m, 1H), 3.25e3.10 (m, 1H), 2.71e2.42
(m, 2H), 2.27e2.08 (m, 2H), 1.71 (s, 3H), 1.60 (s, 3H); 13C NMR
CDCl3):
d
184.3, 170.2, 155.1, 152.1, 132.0, 131.1, 124.1, 123.0, 121.2,
(75 MHz, CDCl3): d 184.5, 174.2, 156.3, 151.2, 133.4, 126.5, 122.6,
73.7, 70.2, 48.9, 29.1, 27.9, 26.4, 19.7; HRMS calcd for C26H26O7:
450.1679, found: 450.1671.
121.7, 75.2, 68.2, 64.7, 42.3, 28.1, 26.2, 25.1, 20.2; HRMS calcd for
C21H22O7: 386.1366, found: 386.1361.
5.4.11. 2-[1-(3-Acetoxyhexanoxy)-4-methyl-3-pentenyl]naphthaz-
5.5.4. 2-[1-(2-Tetrahyrofuroyl)-4-methyl-3-pentenyl]naphthazarin
arin (7m)
(15d)
Yield75.6%, redoil;1HNMR(300MHz, CDCl3):
d
12.58 (s,1H),12.43
Yield 62.0%, red oil; 1H NMR (300 MHz, CDCl3, d ppm):
d 12.59 (s,
(s, 1H), 7.17 (s, 2H), 7.02 (s, 1H), 6.09e5.98 (m, 1H), 5.31e5.18 (m, 1H),
5.17e5.04 (m, 1H). 2.76e2.38 (m, 4H), 2.08e1.96 (m, 3H), 1.71e1.27
1H),12.43(s,1H), 7.19(s, 2H), 7.03(s,1H), 6.18e6.05(m,1H),5.18e5.08
(m,1H), 4.63e4.49 (m,1H), 4.10e3.88 (m, 2H), 2.74e1.85 (m, 6H),1.70
(m,10H), 0.99e0.78 (m, 3H); 13C NMR (75 MHz, CDCl3):
d
184.7,170.4,
(s, 3H), 1.60 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 184.5, 171.5, 154.2,
155.1, 152.1, 132.0, 131.1, 124.1, 123.0, 121.2, 74.3, 61.7, 33.2, 26.9, 25.9,
19.7, 18.0; HRMS calcd for C24H28O8: 444.1784, found: 444.1779.
151.2, 140.3, 132.7, 126.5, 124.2, 122.7, 84.0, 75.1, 66.2, 27.9, 26.3, 25.5,
23.9, 19.0; HRMS calcd for C21H22O7: 386.1366, found: 386.1362.
5.4.12. 2-[1-(3-Acetoxyheptanoxy)-4-methyl-3-pentenyl]naphtha-
5.5.5. 2-[1-(3-Tetrahydropyroyl)-4-methyl-3-pentenyl]
zarin (7n)
naphthazarin (15e)
Yield 65.2%, red oil; 1H NMR (300 MHz, CDCl3):
d
12.60 (s, 1H),
Yield 70.1%, red oil; 1H NMR (300 MHz, CDCl3, d ppm):
d 12.60 (s,
12.45 (s, 1H), 7.20 (s, 2H), 7.00 (s, 1H), 6.08e6.00 (m, 1H), 5.30e5.19
(m, 1H), 5.17e5.08 (m, 1H). 2.72e2.27 (m, 4H), 2.11e2.00 (m, 3H),
1.70 (s, 3H), 1.59 (s, 3H), 1.41e1.29 (m, 6H), 1.01e0.81 (m, 3H); 13C
1H), 12.44 (s, 1H), 7.19 (s, 2H), 7.00 (s, 1H), 6.11e5.99 (m, 1H),
5.19e5.04 (m, 1H), 4.12e3.33 (m, 4H), 2.74e2.34 (m, 3H), 2.14e1.43
(m, 10H); 13C NMR (75 MHz, CDCl3):
d 184.5, 174.2, 155.0, 150.8,
NMR (75 MHz, CDCl3):
123.0, 121.5, 74.2, 70.7, 39.4, 32.5, 28.4, 26.9, 25.1, 23.2, 19.4, 17.4,
15.2; HRMS calcd for C25H30O8: 458.1941, found: 458.1937.
d
184.5, 170.3, 155.1, 152.1, 132.0, 131.1, 124.3,
151.3, 133.7, 126.3, 123.5, 121.2, 74.8, 69.7, 40.7, 28.7, 25.2, 19.0;
HRMS calcd for C22H24O7: 400.1522, found: 400.1517.
5.5.6. 2-[1-(3-Tetrahydropyroyl)-4-methyl-3-pentenyl]
5.5. General methods for the synthesis of 15ae15f
naphthazarin (15f)
Yield 65.7%, red oil; 1H NMR (300 MHz, CDCl3, d ppm):
d 12.58 (s,
K2CO3 (15 mmol) and methyl chloromethyl ether (10 mmol) was
added to a solution of shikonin (5 mmol) in acetone (10 ml). The
mixture was stirred at rt for 3 h. The resulting mixture was filtered.
The organic phase was concentrated under vacuum and the residue
was purified by flash column chromatography to give 13. Yield 84.5%,
yellow oil. To a solution of heterocycle-bearing acid (4 mmol) and 13
(2 mmol) in CH2Cl2 (10 ml) were added DCC (5 mmol) and DMAP
(0.3 mmol). The mixture was stirred at rt for 1 h. After filtration, the
solvent of the filtrate was removed to give the residue which was
purified by flash column chromatography to give 14. To a solution of
1H), 12.41 (s, 1H), 7.18 (s, 2H), 7.00 (s, 1H), 6.16e6.06 (m, 1H),
5.15e5.04 (m, 1H), 4.16e4.00 (m, 2H), 3.59e3.42 (m, 1H), 2.72e2.35
(m, 2H), 2.04e1.47 (m,12H); 13C NMR (75 MHz, CDCl3):
d 184.5,172.1,
154.3,152.2,140.1,133.4,126.7,123.5,121.9, 81.5, 75.2, 66.2, 27.8, 25.2,
21.0, 18.7; HRMS calcd for C22H24O7: 400.1522, found: 400.1520.
5.6. General methods for the synthesis of 20ae20i
A
mixture of shikonin (1 mmol), KI (2 mmol), K2CO3
(15 mmol) and CH2Br2 (20 mmol) in DMF (10 ml) was stirred at