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Fig. 1. Structures of acylshikonins, Cpd5, F-Cpd5, and 5-FU.
C18H16F2O6 ([M-H]-), 365.09 found 365.42. Anal. Calcd. for C18H16F2O6: C,
59.02; H, 4.40; O, 26.21. Found: C, 58.94; H, 4.65; O, 26.14.
2-[1-(2-fluoropropionyl)-4-methyl-3-pentenyl] naphthazarin
(S2). Red powder, 53% yield. Mp: 109.3-110.8°C. 1H NMR (500 MHz,
CDCl3) δ: 12.59 (s, 1H); 12.41 (s, 1H); 7.19 (s, 2H); 7.04 (s, 1H); 6.16
(dd, J1 = 4.5 Hz, J2 = 7.5Hz, 1H); 5.16-5.01 (m, 2H); 2.71-2.66 (m, 1H);
2.58-2.51 (m, 1H), 1.71 (s, 3H); 1.61 (dt, J1 = 6 Hz, J2 = 24 Hz, 6H). 19F
NMR (500 MHz, CDCl3) δ: -184.41 (s, 1F). ESI-MS: calcd. for
C19H19FO6 ([M-H]-), 361.12 found 361.33. Anal. Calcd. for C19H19FO6:
C, 62.98; H, 5.29; O, 26.41. Found: C, 62.78; H, 5.35; O, 26.29.
Fig. 2. Structure of fulvestrant.
1H NMR spectra were recorded on a Bruker DRX 500 spectrometer in
CDCl3. All the 19F NMR spectra were recorded on a Bruker Avance III
500 spectrometer in CDCl3. Chemical shifts (δ) for 1H NMR and 19F
NMR spectra are reported in ppm (δ). Melting points (uncorrected) were
measured on an XT4 MP Apparatus (Taike, Beijing, China). The
electrospray ionization, mass spectrometry {ESI-MS} spectra were
recorded on a Mariner System 5304 mass spectrometer. Thin-layer
chromatography (TLC) was carried out on the glass-backed silica gel
sheets (silica gel 60 Å GF254) and visualized in UV light (254 nm).
Elemental analyses were performed on a CHN–O–Rapid instrument and
were within 0.4% of the theoretical values.
2-[1-(2, 2-difluoropropionyl)-4-methyl-3-pentenyl] naphthazarin
(S3). Red powder, 66% yield. Mp: 67.2-69.0°C. 1H NMR (500MHz,
CDCl3) δ: 12.58 (s, 1H); 12.40 (s, 1H); 7.19 (s, 2H); 7.07 (s, 1H); 6.18
(dd, J1 = 4.5 Hz, J2 = 7.5 Hz 1H); 5.13 (t, J = 7.5 Hz, 1H); 2.74-2.69 (m,
1H); 2.61-2.55 (m, 1H); 1.85 (t, J = 18.5 Hz, 3H); 1.71 (s, 3H); 1.61 (s,
3H). 19F NMR (500MHz, CDCl3) δ: -98.91 (s, 2F). ESI-MS: calcd. for
C
19H18F2O6 ([M-H]-), 379.11 found 379.50. Anal. Calcd. for C19H18F2O6:
C, 60.00; H, 4.77; O, 25.24. Found: C, 59.91; H, 4.93; O, 25.19.
2-[1-(3, 3, 3-trifluoropropionyl)-4-methyl-3-pentenyl] naphthazarin
(S4). Red powder, 57% yield. Mp: 96.6-99.1°C. 1H NMR (500 MHz,
CDCl3) δ: 12.58 (s, 1H); 12.40 (s, 1H); 7.19 (s, 2H); 7.02 (s, 1H); 6.16 (dd,
J1 = 5 Hz, J2 = 7 Hz 1H); 5.12 (t, J = 7 Hz, 1H); 3.27 (q, J = 10 Hz, 2H), 2.70-
2.65 (m, 1H); 2.56-2.50 (m, 1H); 1.71 (s, 3H); 1.60 (s, 3H). 19F NMR (500
MHz, CDCl3) δ: -63.15 (s, 3F). ESI-MS: calcd. for C19H17F3O6 ([M-H]-)
397.10, found 397.42. Anal. Calcd. for C19H17F3O6: C, 57.29; H, 4.30; O,
24.10. Found: C, 57.20; H, 4.49; O, 24.01.
General Procedure for Preparation of Compounds
Shikonin 0.288 g (1 mmol) was dissolved in 10 mL of anhydrous
dichloromethane, and 0.416 g (2.02 mmol) of dicyclohexylcarbodiimide
(DCC) was added to the reaction system. The reaction mixture was
stirred under nitrogen atmosphere in an ice bath for 20 min. 0.049 g
(0.4 mmol) of 4-(dimethylamino) pyridine (DMAP) was added and
stirring in the ice bath for a further 10 min. Then 1 mmol of carboxylic
acid was added to the reaction mixture and stirred in the ice bath for
40 min. While stirring, the product was checked with TLC continually.
After 40 min stirring, the reaction was stopped. After removal of solvent
by evaporation, the product of the reaction was dissolved by normal
hexane. Then the impurity was filtered and the solvent was collected.
After the removal of solvent again, the residue was purified by column
chromatography on silica gel with EtOAc – petroleum ether (1:8) to afford
the target compounds. After the target compound was purified by column
chromatograph, the compounds were dissolved by normal hexane and
filtered three times, aiming at better removal of dicyclohexylurea
(DCU) and obtaining higher purity compounds.
2-[1-(2, 2, 3, 3-tetrafluoropropionyl)-4-methyl-3pentenyl]
naphthazarin (S5). Red powder, 39% yield. Mp: 76.4-77.5°C. 1H NMR
(500 MHz, CDCl3) δ: 12.59 (s, 1H); 12.40 (s, 1H); 7.20 (s, 2H); 7.10
(s, 1H); 6.29 (dd, J1 = 3.5 Hz, J2 = 5.5 Hz, 1H); 5.99 (t, J = 53 Hz, 1H);
5.13 (t, J = 5 Hz, 1H); 2.78-2.72 (m, 1H); 2.65-2.59 (m, 1H); 1.73 (s, 3H);
1.63 (s, 3H). 19F NMR (500MHz, CDCl3) δ: -120.35 (s, 2F); -139.23
+
(s, 2F) ESI-MS: calcd. for C19H16F4O6 ([M+H] ), 417.09, found 417.48.
Anal. Calcd. for C19H16F4O6: C, 54.81; H, 3.87; O, 23.06. Found: C,
54.68; H, 3.98; O, 22.96.
2-[1-(2, 2, 3, 3, 4, 4, 4-heptafluorobutyryl)-4-methyl-3-pentenyl]
1
naphthazarin (S6). Red powder, 42% yield. Mp: 67.1-68.4°C. H NMR
(500MHz, CDCl3) δ: 12.60 (s, 1H); 12.40 (s, 1H); 7.20 (s, 2H); 7.10
(s, 1H); 6.32 (dd, J1 = 4.5Hz, J2 = 7.5 Hz, 1H); 5.12 (t, J = 7 Hz, 1H);
2.77-2.72 (m, 1H); 2.66-2.60 (m, 1H); 1.72 (s, 3H); 1.62 (s, 3H). 19F
NMR (500 MHz, CDCl3) δ: -79.95 (s, 3F); -113.09 (s, 2F); -124.80
(s, 2F). ESI-MS: calcd. for C20H15F7O6 ([M-H]-) 483.08, found 483.25.
Anal. Calcd. for C20H15F7O6: C, 49.60; H, 3.12; O, 19.82. Found: C,
49.51; H, 3.23; O, 19.78.
2-[1-(2, 2-difluoroacetyl)-4-methyl-3-pentenyl] naphthazarin
(S1). Red powder, 73% yield. Mp: 65.4-66.6°C. 1H NMR (500 MHz,
CDCl3) δ: 12.58 (s, 1H); 12.39 (s, 1H); 7.19 (s, 2H); 7.08 (s, 1H); 6.23
(dd, J1 = 4.5 Hz, J2 = 6.5 Hz, 1H); 5.99 (t, J = 53.5 Hz, 1H); 5.13 (t, J = 7.5
Hz, 1H); 2.75-2.70 (m, 1H); 2.62-2.57 (m, 1H); 1.72 (s, 3H); 1.61 (s, 3H).
19F NMR (500MHz, CDCl3) δ: -126.45 (s, 2F). ESI-MS: calcd. for
Chirality DOI 10.1002/chir