W.Du et al./ Bioorg.Med.Chem.11 (2003) 451–458
455
prepared from camptothecin (22 mg, 0.06 mmol) in
0% yield as yellow solid. The reaction also gave 12-
triethylsilylcamptothecin 3c (3.1 mg, 11%) and recov-
gave 12-cyclohexyldimethylsilyl camptothecin 3g (19.4
mg, 19%) and recovered camptothecin (50%).
3
2
0
[a] =+27.9 (c 0.48, CH Cl ); IR 3313 (br), 2919, 2845,
D
1749, 1658, 1596, 1556, 1446, 1256, 1225, 1157, 1047,
2
2
2
0
ered camptothecin (12.5 mg, 57%). [a] =+38.1 (c
D
1
1
0
.26, CH Cl ); H NMR (CDCl , 300 MHz) d 0.99 (t,
910, 728; H NMR (500 MHz, CDCl ) d 0.64 (s, 6H),
2
2
3
3
J=7.9 Hz, 9H), 1.05 (t, J=7.3 Hz, 3H), 1.13 (q, J=7.9
Hz, 6H), 1.93 (m, 2H), 3.76 (s, 1H), 5.32 (d, J=16.2 Hz,
1.05 (t, J=7.4 Hz, 3H), 1.21 (m, 6H), 1.66 (m, 5H), 1.88
(m, 2H), 3.79 (s, 2H), 5.31 (s, 2H), 5.31 (d, J=16.3 Hz,
1H), 5.76 (d, J=16.3, 1H), 7.64 (td, J=7.3, 0.9 Hz, 1H),
7.67 (s, 1H), 7.79 (t, J=7.2, 1H), 8.21 (d, J=8.0 Hz,
1H), 5.33 (s, 2H), 5.77 (d, J=16.2, 1H), 7.65 (td, J=7.5,
1.2 Hz, 1H), 7.68 (s, 1H), 7.80 (td, J=7.4, 0.8 Hz, 1H),
8.24 (d, J=6.6 Hz, 1H), 8.26 (d, J=7.2 Hz, 1H); HRMS
1
3
1H), 8.23 (d, J=7.4 Hz, 1H); C NMR (CDCl3,
125 MHz) d À1.4, 7.9, 26.6, 26.7, 27.5, 27.8, 31.7, 52.2,
m/z calcd for C H N O Si 462.1975, found 462.1985.
6
2
30
2
4
66.5, 72.9, 97.8, 118.3, 127.3, 128.5, 129.8, 131.1, 132.4,
135.6, 143.6, 146.6, 148.0, 150.2, 150.8, 157.6, 174.1;
(
20S)-7-Isopropyldimethylsilyl camptothecin (2d). Using
the general procedure A, 22 mg of the title compound
was prepared in 31% yield as yellow solid from camp-
tothecin (50 mg, 0.14 mmol). The reaction also gave 12-
isopropyldimethylsilyl camptothecin 3d (6 mg, 8%) and
HRMS m/z calcd for C H N O Si 488.2131, found
4
488.2155.
2
8
32
2
(20S)-7-Diethylmethylsilyl camptothecin (2h). Using the
general procedure A, 13.1 mg of the title compound was
prepared in 20% yield from camptothecin (50 mg, 0.14
mmol) as yellow solid. The reaction also gave 12-di-
ethylmethylsilyl camptothecin 3h (5.2 mg, 8%) and
2
0
recovered camptothecin (33.2 mg, 57%). [a] =+42.1
D
1
(
c 1.01, CH Cl ); H NMR (CDCl , 300 MHz) d 0.65 (s,
2
2
3
6H), 1.00 (d, J=7.4 Hz, 3H), 1.02 (d, J=7.4 Hz, 3H),
1.05 (t, J=7.3, Hz, 3H), 1.49 (hep, 7.4 Hz, 1H), 1.91 (m,
2H), 5.32 (d, J=16.2 Hz, 1H), 5.33 (s, 2H), 5.76 (d,
2
0
recovered camptothecin (67%). [a] =+50.0 (c 0.23,
D
CH Cl ); IR 3319 (br), 2959, 2876, 1748, 1658, 1595,
J=16.2, 1H), 7.65 (ddd, J=8.4, 6.7, 1.1 Hz, 1H), 7.74
s, 1H), 7.81 (ddd, J=8.4, 7.1, 1.1 Hz, 1H), 8.23 (d,
J=8.4 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H); HRMS m/z
2
2
1
(
1557, 1225, 1157, 1047, 727; H NMR (500 MHz,
CDCl ) d 0.67 (s, 3H), 0.95–1.19 (m, 13H), 1.90 (m, 2H),
3.77 (s, 1H), 5.31 (d, J=16.2 Hz, 1H), 5.33 (s, 2H), 5.76
3
calcd for C H N O Si 448.1818, found 448.1815.
2
2
5
28
4
(d, J=16.2, 1H), 7.64 (td, J=8.2, 1.0 Hz, 1H), 7.68 (s,
1H), 7.79 (td, J=8.2, 0.9 Hz, 1H), 8.23 (d, J=8.7 Hz,
(
20S)-7-Tripropylsilyl camptothecin (2e). Using the gen-
1
3
eral procedure A, 16.6 mg of the title compound was
prepared in 22% yield from camptothecin (50 mg, 0.14
mmol) as yellow solid. The reaction also gave 12-tri-
propylsilyl camptothecin 3e (11.2 mg, 15%) recovered
camptothecin (63%). [a] =+39.4 (c 0.49, CH Cl ); IR
3
2H). C NMR (CDCl , 125 MHz) d À2.7, 7.5, 7.7, 7.9,
3
31.7, 52.1, 66.5, 72.9, 97.8, 118.3, 127.4, 128.1, 129.8,
131.1, 132.4, 135.7, 143.0, 146.6, 148.0, 150.2, 150.9,
157.6, 174.1. HRMS m/z calcd for C H N O Si
2
5
28
2
4
2
0
448.1818, found 448.1815.
D
325 (br), 2956, 2927, 2869, 1750, 1659, 1596,1556,
2
2
1
1
224, 1157, 1056, 762, 728; H NMR (CDCl , 500 MHz)
3
General procedure B: synthesis of 12-silyl camptothecins
ꢀ
d 0.98 (t, J=7.2 Hz, 9H), 1.03 (t, J=7.4, Hz, 3H), 1.15
at 160 C. To a suspension of camptothecin 1a (20 mg,
(
(
m, 6H), 1.35 (m, 6H), 1.91 (m, 2H), 3.75 (s, 1H), 5.32
d, J=16.3 Hz, 1H), 5.33 (s, 2H), 5.77 (d, J=16.3, 1H),
.65 (td, J=8.2, 1.3 Hz, 1H), 7.68 (s, 1H), 7.80 (td,
0.057 mmol) in dioxane (2 mL) in a pressure tube was
added the corresponding silane (0.5 mL) followed by 20
mL of tert-butylperoxide (20 mL, 0.09 mmol) and triiso-
propylsilanethiol or t-BuSH (0.11 mmol). The pressure
7
J=8.0, 0.9 Hz, 1H), 8.24 (d, J=6.7 Hz, 1H), 8.27 (d,
J=7.4 Hz, 1H); C NMR (CDCl , 125 MHz) d 7.9,
1
3
ꢀ
tube was then sealed and heated to 160 C for 16 h.
3
1
1
1
6.7, 17.8, 18.4, 31.7, 52.0, 66.5, 72.9, 97.8, 18.2, 27.4,
28.0, 129.8, 131.2, 132.6, 135.7, 143.4, 146.6, 147.9,
50.2, 150.9, 157.6, 174.1; HRMS m/z calcd for
After evaporation of the volatile components, the resi-
due was purified by flash chromatography (5% acetone
in dichloromethane) on silica gel column to give the 12-
silyl camptothecin 3 and recovered camptothecin.
C H N O Si 504.2444, found 504.2467.
2
9
36
2
4
(
20S)-7-Phenyldimethylsilyl camptothecin (2f). Using the
(20S)-12-t-Butyldimethylsilyl camptothecin (3b). Using
the general procedure B, 5.8 mg of the title compound
was prepared from camptothecin (20 mg, 0.057 mmol)
in 22% yield as pale yellow solid, in addition to recov-
general procedure A, 16 mg of the title compound was
prepared in 23% yield from camptothecin (50 mg, 0.14
mmol) as yellow solid. The reaction also gave 12-phe-
nyldimethylsilyl camptothecin 3f (4.6 mg, 7%) and
recovered camptothecin (65%). [a] =+44.9 (c 0.74,
CH Cl ); H NMR (300 MHz, CDCl ) d 0.90 (s, 6H),
2
0
ered camptothecin (20%). [a] =+75.0 (c 0.04
D
CH Cl ); IR 3380 (br), 2927, 2854, 1747, 1658, 1602,
2
0
D
2
2
1
1557, 1487, 1401, 1247, 1223, 1157, 1046, 840, 769, 732;
1
2
2
3
1
.03 (t, J=7.5, Hz, 3H), 1.88 (m, 2H), 4.95 (s, 2H), 5.27
H NMR (500 MHz, CDCl ) d 0.56 (s, 6H), 0.98 (s, 9H),
3
(
(
d, J=16.4 Hz, 1H), 5.71 (d, J=16.4, 1H), 7.37–7.59
m, 6H), 7.74 (s, 1H), 7.77 (t, J=7.2, 1H), 8.14 (d,
J=8.5 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H); HRMS m/z
1.06 (t, J=7.4 Hz, 3H), 1.94 (m, 2H), 3.76 (s, 1H), 5.31
(s, 2H), 5.32 (d, J=16.1 Hz, 1H). 5.77 (d, J=16.1 Hz,
1H), 7.54 (s, 1H), 7.64 (t, J=7.4 Hz, 1H), 7.93 (d,
J=7.4 Hz, 1H), 8.00 (d, J=7.4 Hz, 1H), 8.37 (s, 1H);
calcd for C H N O Si 482.1662, found 482.1663.
2
8
26
2
4
1
3
C NMR (125 MHz, CDCl ) d À3.3, 7.8, 17.7, 27.7,
3
(
20S)-7-Cyclohexyldimethylsilyl
camptothecin
(2g).
31.5, 50.3, 66.5, 72.8, 97.7, 118.3, 127.4, 127.9, 129.3,
131.3, 138.6, 141.1, 147.1, 150.3, 151.1, 153.3, 157.8,
174.1; HRMS m/z calcd for C H N O Si 462.1975,
Using the general procedure A, 16.3 mg of title com-
pound was prepared in 22% yield from camptothecin
2
6
30
2
4
(
50 mg, 0.14 mmol) as yellow solid. The reaction also
found 462.1972.