resulted in a white glue (0.24 g, 94% yield). νmax (Nujol mull)/
cmϪ1 2923.1, 1456.6, 1376.9, 1123.1, 880.7; 1H NMR (300
MHz, CDCl3) δ 7.71–7.42 (4H, m, Ar), 5.42 (1H, s), 5.37 (1H, s,
12-H), 5.35 (1H, s), 4.52 (1H, m, 10-H), 2.62 (1H, m, 9-H), 2.28
(1H, dt, J = 13.9, 4.0 Hz), 2.06–1.20 (12H, m), 1.25 (3H, s, CH3
at C3), 0.98 (3H, d, J = 5.7 Hz, CH3), 0.96 (3H, d, J = 7.8 Hz,
CH3); 13C NMR (75 MHz, CDCl3) δ 145.02, 142.38, 129.74,
128.72, 123.99, 123.35, 116.03, 102.79 (C12), 89.72 (C10),
81.02, 71.42, 52.10, 44.11, 37.54, 36.64, 35.88, 34.44, 30.48,
25.67, 24.92, 24.79, 20.06, 12.59; MS m/z (EI) 163 (25.00%), 162
(53.19), 124 (23.01), 109 (20.74), 95 (28.46), 93 (23.54), 81
(27.79), 79 (21.68), 71 (20.61), 69 (31.38), 67 (24.20), 55 (59.04),
43 (100.00), 41 (36.17); Found 452.21724. C25H31O4F3 requires
452.21744.
(38.08), 55 (64.62), 43 (100.00), 41 (35.38); Found 452.21724.
C25H31F3O4 requires 452.21747.
10ꢁ-[2-(3-Fluorophenyl)allyl]deoxoartemisinin 11g
This was synthesised in accordance to general procedure 4
using 7b (0.28 g, 1.3 mmol). Purification of the product resulted
in a white glue (0.14 g, 90% yield). νmax (Nujol mull)/cmϪ1
2956.0, 1462.0, 1377.0, 1124.0, 872.0; 1H NMR (300 MHz,
CDCl3) δ 7.31–6.92 (4H, m, Ar), 5.38 (1H, d, J = 1.0 Hz), 5.34
(1H, s, 12-H), 5.31 (1H, d, J = 1.1 Hz), 4.52 (1H, m, 10-H), 2.62
(1H, m, 9-H), 2.27 (1H, dt, J = 13.7, 3.8 Hz), 2.02–1.18 (12H,
m), 1.27 (3H, s, CH3 at C3), 0.96 (3H, d, J = 7.6 Hz, CH3), 0.93
(3H, d, J = 7.7 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 162.95
(1C, d, JC–F = 244.1 Hz), 145.02, 143.97 (1C, d, JC–F = 7.1 Hz),
129.66 (1C, d, JC–F = 8.3 Hz), 122.10, 115.35, 114.07 (1C, d,
JC–F =21.3Hz), 113.45(1C, d, JC–F =21.8Hz), 102.80(C12), 89.75
(C10),81.03,71.42,52.11,44.13,37.54,36.68,35.88,34.45,30.48,
25.71, 24.93, 24.80, 20.06, 12.61; MS m/z (EI) 175 (20.98%), 165
(26.57), 163 (35.31), 162 (54.55), 161 (21.85), 147 (21.50), 138
(30.42), 135 (21.50), 133 (22.20), 124 (26.75), 123 (22.20), 109
(41.08),95(21.85),81(28.50),79(22.38),69(24.83),67(22.90),55
(60.14), 43 (100.00), 41 (37.41); Found 402.22040. C24H31O4F
requires 402.22064; found: C, 71.14; H, 7.71; requires C, 71.62;
H, 7.76%.
10ꢁ-[2-(4-Fluorophenyl)allyl]deoxoartemisinin 11d
This was synthesised in accordance to general procedure 4
using 10d (0.66 g, 3.2 mmol). Purification of the product
resulted in a clear glue (0.26 g, 86% yield). νmax (Nujol mull)/
cmϪ1 2922.7, 1455.9, 1375.8, 1125.9, 879.8; 1H NMR (300
MHz, CDCl3) δ 7.44–6.96 (4H, m, Ar), 5.34 (1H, s, 12-H),
5.30 (1H, s), 5.25 (1H, d, J = 1.2 Hz), 4.50 (1H, m, 10-H),
2.60 (1H, m, 9-H), 2.28 (1H, dt, J = 13.8, 3.7 Hz), 2.01–1.19
(12H, m), 1.26 (3H, s, CH3 at C3), 0.96 (3H, d, J = 6.1 Hz, CH3),
0.92 (3H, d, J = 7.6 Hz, CH3); 13C NMR (75 MHz, CDCl3)
δ 145.09, 137.56, 128.04 (1C, d, JC–F = 8.2 Hz), 115.18, 114.90,
114.40, 102.80 (C12), 89.72 (C10), 81.04, 71.50, 52.13, 44.16,
37.54, 36.67, 36.12, 34.46, 30.48, 25.74, 24.92, 24.79, 20.07,
12.65; MS m/z (CI, NH3) 373.2 (9%), 357.2 (100), 343.2 (19),
267.2 (8), 221.2 (9), 162.1 (7); Found 420.25622. C24H35NO4F
[M ϩ NH4]ϩ requires 420.25501.
FeCl2-mediated degradation of 10ꢁ-(2-phenylallyl)deoxo-
artemisinin (11a)
To a solution of 11a (0.14 g, 0.4 mmol) in CH3CN (13 mL) was
added FeCl2ؒ4H2O (0.1 g, 0.5 mmol) under nitrogen atmos-
phere. The reaction was left stirring at rt for 30 min before being
filtered through Celite and washed with CH3CN. Concentration
under reduced pressure and flash column chromatography
using ethyl acetate and hexane (1 : 10) as eluent yielded the
product 12 as yellow oil (0.86 g, 60% yield). νmax (Nujol mull)/
cmϪ1 3042.1, 2926.3, 1713.8, 1628.8; 1H NMR (300 MHz,
CDCl ) δ 7.99 (1H, s, HC᎐O), 7.43–7.21 (5H, m, Ar), 5.35 (1H,
10ꢁ-[2-(2-Fluorophenyl)allyl]deoxoartemisinin 11e
This was synthesised in accordance to general procedure 4
using 10e (0.46 g, 2.2 mmol). Purification of the product
resulted in a colourless glue (0.14 g, 70% yield). νmax (Nujol
mull)/cmϪ1 2923.4, 1448.2, 1375.4, 1092.9, 879.7; 1H NMR (300
MHz, CDCl3) δ 7.37–6.98 (4H, m, Ar), 5.40 (1H, s), 5.33 (1H, s,
12-H), 5.24 (1H, s), 4.40 (1H, m, 10-H), 2.61 (1H, m, 9-H), 2.29
(1H, dt, J = 12.8, 3.9 Hz), 2.01–1.17 (12H, m), 1.28 (3H, s, CH3
at C3), 0.96 (3H, d, J = 6.0 Hz, CH3), 0.88 (3H, d, J = 7.5 Hz,
CH3); 13C NMR (75 MHz, CDCl3) δ 158.31, 143.06, 130.83,
128.81 (1C, d, J = 8.2 Hz), 124.09, 117.61, 115.56 (1C, d,
J = 23.0 Hz), 102.88 (C12), 89.51 (C10), 81.06, 72.09, 52.23,
44.29, 37.53, 36.70, 34.49, 30.37, 25.81, 24.88, 24.79, 20.12,
12.68; MS m/z (EI) 312 (21.94%), 175 (38.27), 163 (42.18), 162
(44.22), 161 (39.29), 149 (23.30), 147 (20.75), 135 (39.63), 133
(29.08), 123 (40.65), 121 (35.37), 115 (22.62), 109 (78.23), 107
(28.06), 101 (21.09), 95 (43.54), 93 (31.12), 91 (20.58), 81
(39.46), 79 (27.89), 71 (27.72), 69 (40.48), 67 (33.33), 55 (67.35),
43 (100.00), 41 (37.93); Found 402.22001. C24H31FO4 requires
402.22064.
᎐
3
br s, C᎐CH), 5.14 (2H, m, C᎐CH & 10-H), 2.96–1.26 (12H, m),
᎐
᎐
2.11 (3H, s, CH3), 1.01 (3H, d, J = 6.3 Hz), 0.99 (3H, d, J =
6.9 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 213.31, 209.02,
160.66, 144.16, 140.12, 128.47, 127.79, 126.33, 115.85, 72.53,
57.52, 54.42, 41.38, 38.22, 34.60, 34.13, 31.02, 29.81, 20.40,
20.36, 12.26; MS m/z (CI, NH3) 355.3 (13%), 339.3 (100),
221.1 (6); Found 402.26497. C24H36NO4 [M ϩ NH4]ϩ requires
402.26443.
References
1 H. Jomaa, J. Wiesner, S. Sanderbrand, B. Altincicek, C. Weidemeyer,
M. Hintz, I. Tübachova, M. Eberl, J. Zeider, H. K. Liechtenthaler,
D. Soldati and E. Beck, Science, 1999, 285, 1573.
2 D. Klayman, Science, 1985, 228, 1049.
3 J. K. Baker, R. H. Yarber, C. D. Hufford, I.-S. Lee, H. N. Elsohly
and J. D. McChesney, Biomed. Environ. Mass Spectrom., 1988, 18,
337.
10ꢁ-[2-(4-Trifluoromethylphenyl)allyl]deoxoartemisinin 11f
4 A. J. Lin, M. Lee and D. L. Klayman, J. Med. Chem., 1989, 32, 1249.
5 J. L. Maggs, L. P. D. Bishop, G. Edwards, P. M. O’Neill, S. A. Ward,
P. A. Winstanley and B. K. Park, Drug Metab. Dispos., 2000, 28,
209.
6 J. M. Grace, A. J. Aguilar, K. M. Trotman and T. G. Brewer,
Drug Metab. Dispos., 1998, 26, 313.
This was synthesised in accordance to general procedure 4
using 7a (0.08 g, 0.3 mmol). Purification of the product resulted
in a white glue (0.04 g, 81% yield). νmax (Nujol mull)/cmϪ1
2923.5, 1456.5, 1376.1, 1127.4, 879.9; 1H NMR (300 MHz,
CDCl3) δ 7.59–7.50 (4H, m, Ar), 5.42 (1H, s), 5.37 (1H, s,
12-H), 5.33 (1H, s), 4.52 (1H, m, 10-H), 2.64 (1H, m, 9-H), 2.31
(1H, m), 2.09–1.05 (12H, m), 1.21 (3H, s, CH3 at C3), 0.96 (3H,
d, J = 6.3 Hz, CH3), 0.94 (3H, d, J = 7.8 Hz, CH3); 13C NMR
(75 MHz, CDCl3) δ 145.12, 135.12, 126.80, 125.26, 116.30,
102.73 (C12), 89.83 (C10), 81.01, 71.19, 52.05, 44.06, 37.54,
36.27, 35.96, 34.42, 30.49, 25.61, 24.91, 24.80, 20.03, 12.57; MS
m/z (EI) 225 (20.00%), 163 (37.31), 162 (66.92), 159 (27.12), 151
(27.31), 124 (23.46), 123 (25.77), 121 (21.92), 109 (27.69), 107
(25.58), 95 (24.62), 81 (37.88), 79 (26.15), 71 (24.62), 69
7 P. M. O’Neill, F. Scheinmann, A. V. Stachulski, J. L. Maggs and
B. K. Park, J. Med. Chem., 2001, 44, 1467.
8 M. Jung and S. Lee, Bioorg. Med. Chem. Lett., 1998, 8, 1003.
9 (a) M. Jung, D. A. Bustos, H. N. Elsohly and J. D. McChesney,
Synlett, 1990, 743; (b) M. Jung, D. Yu, D. A. Bustos, H. N.
Elsohly and J. D. McChesney, Bioorg. Med. Chem. Lett., 1991, 741;
(c) M. Jung and S. Lee, Heterocycles, 1997, 45, 1055.
10 Y. M. Pu and H. Ziffer, J. Med. Chem., 1995, 38, 613.
11 J. Ma, E. Katz, D. E. Kyle and H. Ziffer, J. Med. Chem., 2000, 43,
4228.
12 S. H. Woo, M. H. Parker, P. Ploypradith, J. Northrop and
G. H. Posner, Tetrahedron Lett., 1998, 39, 1533.
2688
J. Chem. Soc., Perkin Trans. 1, 2001, 2682–2689