1474
Vol. 59, No. 12
propanamide (7) A stirred solution of 6 (20 mg, 0.06 mmol), EDC (88.0 mg, 0.46 mmol) and DMAP (56.1 mg, 0.46 mmol) in DMF (2 ml) was
(35 mg, 0.18 mmol) and DMAP (7 mg, 0.06 mmol) in DMF (1 ml) was com-
bined with 3-aminoquinoline (8 mg, 0.06 mmol) at room temperature during
3 h. The reaction mixture was quenched with slow addition of saturated cit-
ric acid (2 ml), extracted with ethyl acetate (3ꢃ5 ml) and washed with
NaHCO3 (5 ml) and brine (5 ml). The organic layer was dried over MgSO4,
combined with olefinic daumone 10 (15.0 mg, 0.046 mmol) at room temper-
ature during 12 h. The reaction mixture was quenched with slow addition of
saturated citric acid (2 ml), extracted with ethyl acetate (3ꢃ5 ml) and
washed with NaHCO3 (5 ml) and brine (5 ml). The organic layer was dried
over MgSO4, filtered and concentrated in vacuo. The mixture was purified
filtered and concentrated in vacuo. The mixture was purified by flash column by flash column chromatography on silica gel with petroleum ether/ethyl
chromatography on silica gel with hexane/EtOAc (2 : 1, v/v) as eluant to give acetate (1 : 1 v/v) as eluant to give compound 14 (4.1 mg, 0.007 mmol,
7
(24 mg, 89%). Rfꢁ0.11 (n-hexane/EtOAcꢁ2 : 1 v/v); [a]D20 ꢄ18.0° 15.7% yield) and compound 15 (2.0 mg, 0.004 mmol, 7.7% yield), respec-
(cꢁ0.05, CHCl3); 1H-NMR (250 MHz, CDCl3) d: 8.89 (br s, 1H), 8.83— tively.
8.86 (m, 1H), 8.82 (s, 1H), 8.00 (d, Jꢁ7.90 Hz, 1H), 7.77 (d, Jꢁ8.21 Hz,
1
Compound 14: H-NMR (250 MHz, CDCl3) d: 0.87 (d, Jꢁ7.58 Hz, 3H),
1H), 7.55—7.62 (m, 1H), 7.49 (t, Jꢁ7.42 Hz, 1H), 5.36 (s, 1H), 4.14—4.25 0,96 (d, Jꢁ5.37, 3H), 1.07—1.24 (m, 4H), 1.12 (d, Jꢁ6.32 Hz, 3H), 1.21 (d,
(m, 1H), 1.33 (s, 3H), 0.93 (d, Jꢁ5.69 Hz, 3H), 0.89 (d, Jꢁ7.58 Hz, 3H); Jꢁ6.00 Hz, 3H), 1.40 (s, 3H), 1.48—2.23 (m, 17H), 2.24—2.56 (m, 2H),
13C-NMR (63 MHz, CDCl3) d: 172.5, 145.1, 144.5, 132.2, 129.0, 128.4,
128.1, 127.9, 127.1, 123.8, 103.6, 89.1, 81.3, 76.3, 52.4, 44.4, 37.5, 36.6,
36.2, 34.50, 30.4, 26.2, 25.2, 25.0, 24.7, 20.3, 13.1; IR (KBr, cmꢀ1) nmax
2965, 2855, 1684, 1559, 1490, 1375, 1188, 1125, 1093, 1052, 1012, 787,
756; MALDI-TOF MS: Found 467.1881 [MꢄH]ꢄ. HR-MS (FAB) Calcd for
C27H34N2O5 [MꢄH]ꢄ m/z 467.2546, Found 467.2542. Anal. Calcd for
C27H34N2O5: C, 69.52; H, 7.29; N, 6.00. Found: C, 69.48; H, 7.31; N, 6.10.
(3R,3ꢀR,5aS,5ꢀaS,6R,6ꢀR,8aS,8ꢀaS,9R,9ꢀR,10R,10ꢀR,12R,12ꢀR,12aR,
12ꢀaR)-N10,N10ꢀ-(1,4-Piperazinepropanediyl)-bis[decahydro-3,6,
9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-
propanamide (8) A stirred solution of 6 (25 mg, 0.074 mmol), HOBt
(30 mg, 0.22 mmol) and EDC (42 mg, 0.22 mmol) in dry CH2Cl2 (1 ml) was
combined with piperazine (3 mg, 0.037 mmol) at room temperature during
12 h. The reaction mixture was quenched with slow addition of saturated cit-
ric acid (2 ml), extracted with CH2Cl2 (3ꢃ10 ml) and washed with NaHCO3
(5 ml) and brine (5 ml). The organic layer was dried over MgSO4, filtered
and concentrated in vacuo. The mixture was purified by flash column chro-
2.60—2.84 (m, 2H), 3.72—3.85 (m, 2H), 3.89 (m, 1H), 4.67—4.82 (m, 1H),
4.71 (s, 1H), 4.83—4.92 (m, 1H), 4.95 (d, Jꢁ10.23 Hz, 1H), 5.00 (d,
Jꢁ16.94 Hz, 1H), 5.32 (s, 1H), 5.82 (tdd, Jꢁ16.94, 10.23, 6.79, 6.79 Hz,
1H). IR (KBr, cmꢀ1) nmax 3473, 2927, 2873, 2360, 2342, 1736, 1463, 1373,
1202, 1130, 1103, 1039. HR-MS (FAB) Calcd for C31H50NaO9 [MꢄNa]ꢄ
m/z 589.3353, Found 589.3377. Anal. Calcd for C31H50O9: C, 65.72; H, 8.83.
Found: C, 65.74; H, 8.91.
4-[(3R,5aS,6R,8aS,9R,10R,12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-
epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-acetate]-(1R)-1-methyl-
6-hepten-1-yl 3,6-Dideoxy-a-L-arabino-hexopyranoside (15) Com-
pound 15: 1H-NMR (250 MHz, CDCl3) d: 0.87 (d, Jꢁ7.58 Hz, 3H,) 0.97 (d,
Jꢁ5.69 Hz, 3H), 1.11 (d, Jꢁ6.00 Hz, 3H), 1.16—1.27 (m, 4H), 1.28 (d,
Jꢁ5.69 Hz, 3H), 1.41 (s, 3H), 1.49—2.23 (m, 17H), 2.25—2.49 (m, 2H),
2.61—2.83 (m, 1H), 3.58—3.85 (m, 3H), 3.63—3.71 (m, 1H), 4.70—4.82
(m, 1H), 4.73 (s, 1H), 4.91 (br s, 1H), 4.94 (d, Jꢁ10.19 Hz, 1H), 5.00 (d,
Jꢁ16.98 Hz, 1H), 5.34 (s, 1H), 5.70—5.93 (tdd, Jꢁ16.98, 10.19, 6.63,
6.63 Hz, 1H). IR (KBr, cmꢀ1) nmax 2924, 2851, 2369, 2337, 1734, 1456,
matography on silica gel with CH2Cl2/MeOH (15 : 1, v/v) as eluant to give 8 1368. HR-MS (FAB) Calcd for C31H49O9 [MꢄH]ꢄ m/z 567.9899, Found
(28 mg, 52%). Rfꢁ0.54 (CH2Cl2/MeOHꢁ15 : 1 v/v); [a]D24 ꢄ31.1° (cꢁ0.05,
567.9833. Anal. Calcd for C31H49O9: C, 65.84; H, 8.67. Found: C, 65.79; H,
1
CHCl3); H-NMR (250 MHz, CDCl3) d: 5.21 (s, 2H), 3.99—3.97 (m, 2H), 8.66.
3.71—3.69 (m, 1H), 3.65—3.57 (m, 4H), 3.56—3.43 (m, 4H), 2.70—2.68
(6R)-6-[(3,6-Dideoxy-a-L-arabino-hexopyranosyl)oxy]-heptanoic Acid
(m, 4H), 2.30—2.22 (m, 4H), 1.97—1.92 (m, 4H), 1.80—1.73 (m, 7H), 2-[(3R,5aS,6R,8aS,9R,10R,12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-
1.60—1.56 (m, 3H), 1.51—1.46 (m, 3H), 1.39—1.35 (m, 4H), 1.30 (s, 6H), epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl]ethyl Ester (16)
A
1.25—1.16 (m, 4H), 0.89 (d, Jꢁ6.00 Hz, 6H), 0.83 (d, Jꢁ7.63 Hz, 6H); 13C-
NMR (63 MHz, CDCl3) d: 171.8, 171.7 103.2, 88.6, 81.2, 74.2, 52.6, 45.5,
44.6, 41.7, 41.4, 37.4, 37.4, 34.5, 31.1, 31.0, 30.1, 26.2, 24.9, 24.5, 20.3,
13.4; IR (KBr, cmꢀ1) nmax 3403, 2941, 1725, 1712, 1605, 1511, 1451, 1384,
1263, 1174, 1118, 1025, 811, 767; MALDI-TOF MS: found 731.1315
[MꢄH]ꢄ. HR-MS (FAB) Calcd for C40H63N2O10 [MꢄH]ꢄ m/z 731.4483,
stirred solution of hydroxyethyldeoxoartemisinin (22.6 mg, 0.072 mmol),
EDC (139.0 mg, 0.72 mmol) and DMAP (88.0 mg, 0.72 mmol) in DMF
(2 ml) was combined with daumone 2 (20.0 mg, 0.072 mmol) at room tem-
perature during 12 h. The reaction mixture was quenched with slow addition
of satured citric acid (2 ml), extracted with ethyl acetate (3ꢃ5 ml) and
washed with NaHCO3 (5 ml) and brine (5 ml). The organic layer was dried
Found 731.4485. Anal. Calcd for C40H63N2O10: C, 65.75; H, 8.63; N, 3.84. over MgSO4, filtered and concentrated in vacuo. The mixture was purified
Found: C, 65.68; H, 8.62; N, 3.86. by flash column chromatography on silica gel with ethyl acetate as eluant to
(6R)-6-Hydroxyheptyl-2,4-O-benzoyl-3,6-dideoxy-L-rhamnoside (11) give compound 16 (24.4 mg, 0.043 mmol, 59.1% yield). 1H-NMR
To the solution of benzoyl-3,6-dideoxy-L-rhamnosepyranosyl)heptene 9
(200 mg, 0.42 mmol) in methylene chloride(20 ml), O3 was added through
bubbling at ꢀ78 °C for 3 min. After methylene chloride was removed in
vacuo, the reaction mixtures were dissolved in ethanol (30 ml) at 0 °C.
NaBH4 (195 mg, 5.14 mmol) was in several times added to the solution.
After 16 h stirring, the reaction was quenched by addition with distilled
water, extracted with EtOAc(150 mlꢃ3). Washing with sat. brine, drying
with anh. MgSO4, and concentration in vacuo afforded a solid. Purification
with flash column chromatography gave compound 11, a colorless solid
(126 mg, 66%).
(250 MHz, CDCl3) d: 0.87 (d, Jꢁ7.27 Hz, 3H), 0.96 (d, Jꢁ4.74 Hz, 3H),
1.12 (d, Jꢁ6.00 Hz, 3H), 1.28 (d, Jꢁ5.69 Hz, 3H), 1.41 (s, 3H), 1.53—2.15
(m, 19H), 2.24—2.42 (m, 3H), 2.58—2.79 (m, 1H), 3.49—3.92 (m, 4H),
4.06—4.38 (m, 3H), 4.70 (s, 1H), 5.30 (s, 1H). 13C-NMR (63 MHz, CDCl3)
d: 12.91, 17.70, 18.90, 20.16, 24.70, 24.77, 24.89, 25.19, 26.05, 29.69,
34.00, 34.26, 34.43, 35.21, 36.53, 36.76, 37.47, 44.26, 52.30, 62.46, 68.11,
69.34, 69.88, 70.97, 71.76, 81.06, 88.96, 95.82, 103.23, 173.78. IR (KBr,
cmꢀ1) nmax 3450, 2928, 2878, 2361, 2337, 1734, 1455, 1376, 1130, 1100,
1044. HR-MS (FAB) Calcd for C30H50O10 [M]ꢄ m/z 570.3302, Found
570.3382. Anal. Calcd for C30H50O10: C, 63.16; H, 8.77. Found: C, 63.21; H,
C27H34O7, Rfꢁ0.21 (n-hexane/EtOAc, 4 : 1, v/v), [a]D20 ꢀ6.1° (cꢁ0.5, 8.82.
CHCl3), 1H-NMR (250 MHz, CDCl3) d: 8.10 (d, Jꢁ7.1 Hz, 2H, aromatic H),
8.03 (d, Jꢁ7.1 Hz, 2H, aromatic H), 7.54—7.60 (m, 2H, aromatic H),
7.42—7.49 (m, 4H, aromatic H), 5.13—5.23 (m, 2H), 4.96 (s, 1H, H-1ꢅ),
In Vitro Antitumor Assay The in vitro cytotoxicity of artemisinin, dau-
mone and their synthesized hybrids to the human cancer cells was defined by
the microculture tetrazolium assay as described by Carmichel et al.48) Pacli-
4.07—4.15 (m, 1H, H-4ꢅ), 3.82—3.86 (m, 1H, H-6), 3.64 (t, Jꢁ6.5 Hz, 2H, taxel and cisplatin were used as the reference substances, exhibiting the ac-
H-2), 2.38—2.46 (m, 1H, H-3ꢅ eq), 2.16—2.27 (m, 1H, H-3ꢅ ax), 1.89 (s,
1H, alcohol), 1.53—1.67 (m, 3H), 1.42—1.53 (m, 5H), 1.27 (d, Jꢁ6.2 Hz,
3H, H-6ꢅ), 1.21 (s, 1H), 1.15 (d, Jꢁ7.4 Hz, 3H, H-7); 13C-NMR (63 MHz,
tivity with an IC50 (mM) as shown in Table 1 toward human cell lines.
Acknowledgments This study was supported by the Basic Science Re-
CDCl3) d: 165.9, 165.7, 133.3, 133.2, 130.1, 129.9, 129.7, 128.5, 93.9 (C- search Program through the National Research Foundation of Korea funded
1ꢅ, a), 72.7 (C-4ꢅ), 71.3 (C-2ꢅ), 70.7 (C-6), 67.0 (C-5ꢅ), 62.9 (C-1), 37.1 (C-
5), 32.8 (C-2), 29.8 (C-3), 25.8 (C-3ꢅ), 25.6 (C-4), 19.2 (C-7), 17.9 (C-6ꢅ) IR
by the Ministry of Education, Science and Technology (2010-0021716). J. R.
and M. K. received fellowships from the BK21 program of the Ministry of
nmax cmꢀ1 3519, 3431, 2971, 2933, 2859, 1722, 1601, 1451, 1376, 1316, Education and Human Resources Development, Republic of Korea.
1267, 1176, 1108, 1068, 1025, 943, 711. LC mass ESI probe 469.8 Da/e,
Scan ESꢄ4.41e. Anal. Calcd for C27H34O7: C, 68.94; H, 7.23. Found: C, References
68.89; H, 7.25.
1) Klayman D. L., Science, 228, 1049—1055 (1985).
2-[(3R,5aS,6R,8aS,9R,10R,12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-
epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-acetate]-(1R)-1-methyl-
6-hepten-1-yl 3,6-Dideoxy-a-L-arabino-hexopyranoside (14) A stirred
solution of carboxymethyldeoxoartemisinin (15.0 mg, 0.046 mmol), EDC
2) Warhurst D. C., Infection, 27, 55—58 (1999).
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