Camptothecin Synthesis
67±83
J 7.3 Hz, 3H), 1.30 ± 1.70 (m, 6H), 1.90 (m, 2H), 3.36 (m, 1H), 3.40 ± 3.60
(m, 3H), 3.77 (m, 1H), 3.92 (brs, 1H), 4.16 (m, 1H), 4.47 (brt, 1H), 5.27 (d,
J 16.4 Hz, 1H), 5.31 (s, 2H), 5.72 (d, J 16.4 Hz, 1H), 7.62 (t, J 8.0 Hz,
1H), 7.65 (s, 1H), 7.76 (t, J 7.3 Hz, 1H), 8.10 (d, J 8.0 Hz, 1H), 8.21 (d,
J 8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 7.8, 19.3, 25.1, 30.3, 30.5,
31.5, 50.2, 62.1, 62.3, 66.3, 72.7, 97.9, 98.9, 118.4, 123.6, 127.4, 127.7, 130.0,
130.6, 147.0, 149.3, 150.1, 157.6, 162.5, 176.4; HRMS (EI): m/z calcd for
C27H28N2O6 (M ) 476.1947, found 476.1923; LRMS (EI): m/z 476 (M ,
44), 432 (22), 392 (26), 376 (33), 347 (82), 331 (47), 319 (50), 310 (39), 243
(46), 231 (100), 217 (44).
7.65 ± 7.75 (m, 4H), 8.08 (d, J 8.2 Hz, 1H), 8.66 (d, J 9.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3): d 7.8, 19.2, 26.4, 29.9, 31.6, 36.4, 50.2, 66.3, 70.4,
72.7, 98.1, 104.7, 118.5, 125.0, 125.5, 127.3, 127.7, 128.6, 128.8, 129.6, 130.0,
133.0, 133.5, 135.7, 142.6, 146.5, 147.9, 149.2, 150.1, 151.6, 157.7, 173.9;
HRMS (EI): m/z calcd for C37H38N2O3Si [M CO 2 ] 586.2652, found
586.2667; LRMS (EI): m/z 630 (M , 13), 586 (10), 573 (100), 555 (18), 529
(72), 495 (18), 357 (20), 329 (54).
ii) 1q (more polar, 34.9 mg, 28%), as an oil. [a] 2D0 27.6 (c 0.5,
1
CHCl3); H NMR (300 MHz, CDCl3): d 1.03 (t, J 7.4 Hz, 3H), 1.08 (s,
9H), 1.40 (d, J 6.3 Hz, 3H), 1.89 (m, 2H), 3.80 (brs, 1H), 5.06 (q, J
6.3 Hz, 1H), 5.28 (s, 2H), 5.29 (d, J 16.4 Hz, 1H), 5.73 (d, J 16.4 Hz,
1H), 7.10 (m, 1H), 7.21 (d, J 7.3 Hz, 2H), 7.30 (d, J 7.3 Hz, 1H), 7.35 ±
7.47 (m, 3H), 7.51 (d, J 7.7 Hz, 2H), 7.65 ± 7.70 (m, 2H), 7.73 (d, J 6.5 Hz,
2H), 7.84 (d, J 8.5 Hz, 1H), 8.05 (d, J 8.1 Hz, 1H), 8.33 (s, 1H); 13C
NMR (75 MHz, CDCl3): d 7.8, 19.3, 27.0, 29.7, 31.6, 37.8, 50.1, 66.3, 71.5,
72.8, 75.8, 98.1, 103.2, 118.5, 125.4, 126.3, 127.1, 127.7, 128.1, 129.7, 130.7,
133.3, 134.0, 135.8, 146.5, 149.0, 149.3, 150.1, 152.3, 157.6, 173.9; HRMS
8. (20S)-7-Azacamptothecin (1k): Use of the procedure described for the
synthesis of 1a with 25c (38.2 mg, 0.102 mmol) afforded a slightly yellow
solid (19.1 mg, 54%) after flash chromatography (CHCl3/acetone 9:1 to
7:3). M.p.: >2608C [(RS) isomer: ref. [5f] 280 ± 2858C decomp.]; [a] 2D0
29.0 (c 0.1, CHCl3/CH3OH 4:1); 1H NMR (300 MHz, CDCl3): d 1.02 (t,
J 7.3 Hz, 3H), 1.88 (m, 2H), 3.87 (brs, 1H), 5.29 (d, J 16.6 Hz, 1H), 5.30
(brs, 2H), 5.73 (d, J 16.6 Hz, 1H), 7.69 (s, 1H), 7.85 ± 7.95 (m, 2H), 8.18
(m, 1H), 8.23 (m, 1H); 13C NMR (75 MHz, CDCl3): d 7.7, 31.6, 50.5, 66.3,
72.5, 99.4, 129.4, 129.9, 131.0, 131.5, 149.7; HRMS (EI): m/z calcd for
(EI): m/z calcd for C34H29N2O5Si [M t-Bu ] 573.1846, found 573.1857;
LRMS (EI): m/z 630 (M , 2), 586 (9), 573 (92), 555 (13), 529 (100), 495
(18), 451 (18), 357 (15), 329 (47).
C19H15N3O4 (M ) 349.1063, found 349.1052; LRMS (EI): m/z 349 (M ,
100), 320 (29), 305 (33), 290 (22), 276 (24), 249 (33), 220 (21).
13. (20S)-9-Methyl-12-trimethylsilycamptothecin (1r): Use of the proce-
dure described for the synthesis of 1a with 23 (35.0 mg, 0.093 mmol) and 35
(54.0 mg, 0.28 mmol) gave a slightly yellow solid (20.3 mg, 50%) after flash
chromatography (CHCl3/MeOH 96:4; CHCl3/acetone 4:1). M.p.: 229 ±
2318C decomp.; [a] 2D0 30.0 (c 1, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.47 (s, 9H), 1.04 (t, J 7.4 Hz, 3H), 1.90 (m, 2H), 2.70 (s,
3H), 3.90 (brs, 1H), 5.26 (brs, 2H), 5.29 (d, J 16.3 Hz, 1H), 5.73 (d, J
16.3 Hz, 1H), 7.40 (d, J 7.1 Hz, 1H), 7.48 (s, 1H), 7.82 (d, J 7.1 Hz, 1H),
8.48 (s, 1H); 13C NMR (75 MHz, CDCl3): d 0.0, 7.7, 18.9, 31.4, 50.2, 66.2,
72.7, 97.2, 118.1, 127.2, 127.5, 128.0, 136.6, 140.2, 147.0, 150.4, 153.1, 157.6,
9. (20S)-10-Acetoxycamptothecin (1l): Use of the procedure described for
the synthesis of 1a with 23 (26.1 mg, 0.070 mmol) and 24b (29.0 mg,
0.18 mmol) gave
a slightly yellow solid (18.0 mg, 63%) after flash
chromatography (CHCl3/MeOH 96:4; CHCl3/acetone 4:1 to 2:1). M.p.:
257 ± 2598C decomp.; [a] D20 31.9 (c 0.2, CHCl3/MeOH 5:1); 1H NMR
(300 MHz, CDCl3/CD3OD 5:1): d 0.86 (t, J 7.4 Hz, 3H), 1.76 (m, 2H),
2.24 (s, 3H), 5.12 (s, 2H), 5.13 (d, J 16.4 Hz, 1H), 5.49 (d, J 16.4 Hz,
1H), 7.41 (dd, J 9.2, 2.6 Hz, 1H), 7.53 ± 7.56 (m, 2H), 8.02 (d, J 9.2 Hz,
1H), 8.26 (s, 1H); 13C NMR (75 MHz, CDCl3/CD3OD 5:1): d 7.8, 20.7,
31.1, 49.9, 65.6, 72.6, 98.6, 118.7, 118.8, 125.9, 128.4, 129.0, 130.4, 131.1, 149.4,
173.8; HRMS (EI): m/z calcd for C24H26N2O4Si (M ) 434.1662, found
434.1637; LRMS (EI): m/z 434 (M , 39), 419 (100), 390 (19), 375 (64).
150.9, 157.6, 169.4, 173.4; HRMS (EI): m/z calcd for C22H18N2O6 (M )
406.1165, found 406.1168; LRMS (EI): m/z 406 (M , 96), 364 (100), 335
14. (20S)-9-Methylcamptothecin (1s):
A solution of 1r (23.2 mg,
(18), 320 (43).
0.053 mmol) in 48% HBr (1.0 mL) was stirred for 3 h at 758C. The
reaction mixture was poured into saturated NaHCO3/brine 1:1 (60 mL),
extracted with AcOEt (5 Â 15 mL), and dried. After evaporation of the
solvent, the residue was purified by flash chromatography (CHCl3/acetone
4:1) to afford a slightly yellow solid (16.3 mg, 85%). M.p.: 270 ± 2728C
decomp. (ref. [5g] 278 ± 2808C); [a] 2D0 38.6 (c 0.15, CHCl3/MeOH
4:1); 1H NMR (300 MHz, CDCl3): d 1.04 (t, J 7.4 Hz, 3H), 1.88 (m, 2H),
2.73 (s, 3H), 3.92 (brs, 1H), 5.28 (brs, 2H), 5.28 (d, J 16.3 Hz, 1H), 5.72
(d, J 16.3 Hz, 1H), 7.44 (d, J 7.0 Hz, 1H), 7.66 (s, 1H), 7.66 (dd, J 8.5,
7.0 Hz, 1H), 8.05 (d, J 8.5 Hz, 1H), 8.51 (s, 1H); 13C NMR (75 MHz,
CDCl3/CD3OD 10:1): d 7.5, 18.7, 31.3, 50.2, 65.7, 72.7, 98.7, 118.8, 127.1,
127.6, 128.2, 128.6, 130.5, 135.0, 145.8, 148.7, 151.0, 151.4, 157.7; HRMS (EI):
10. (20S)-10-tert-Butyloxycarbonylaminocamptothecin (1m): Use of the
procedure described for the synthesis of 1a with 23 (35.0 mg, 0.094 mmol)
and 24c (61 mg, 0.28 mmol) provided a slightly yellow solid (25.3 mg, 58%)
after flash chromatography (CHCl3/MeOH 96:4; CHCl3/acetone 4:1).
[a] 2D0 32.7 (c 0.15, CHCl3/MeOH 5:1); 1H NMR (300 MHz, CDCl3/
CD3OD 4:1): d 0.86 (t, J 7.4 Hz, 3H), 1.41 (s, 9H), 1.75 (m, 2H), 5.07 (s,
2H), 5.12 (d, J 16.4 Hz, 1H), 5.48 (d, J 16.4 Hz, 1H), 7.49 (s, 1H), 7.51
(brd, J 9.0 Hz, 1H), 7.87 (d, J 9.0 Hz, 1H), 8.06 (s, 1H), 8.15 (s, 1H),
8.61 (brs, 1H); 13C NMR (75 MHz, CDCl3/CD3OD 4:1): d 7.3, 17.5, 29.4,
31.0, 51.0, 65.7, 72.6, 98.1, 113.2, 118.2, 124.1, 128.9, 129.1, 130.5, 138.7, 144.8,
146.0, 149.9, 151.1, 153.3, 157.7, 173.5; HRMS (EI): m/z calcd for
C25H25N3O6 (M ) 463.1743, found 463.1739; LRMS (EI): m/z 463 (M ,
m/z calcd for C21H18N2O4 (M ) 362.1267, found 362.1270; LRMS (EI): m/
14), 407 (46), 363 (100), 319 (51), 263 (30).
z 362 (M , 100), 333 (41), 318 (40), 303 (28), 289 (26), 262 (48), 233 (38).
11. (20S)-10-Aminocamptothecin (1n):
A solution of 1m (17.4 mg,
15. (20S)-11-Fluoro-12-trimethylsilycamptothecin (1t): Use of the proce-
dure described for the synthesis of 1a with 23 (37.3 mg, 0.10 mmol) and 39a
(77 mg, 0.40 mmol) gave a slightly yellow solid (28.1 mg, 64%) after flash
chromatography (CHCl3/acetone 6:1). [a] 2D0 26.1 (c 0.2, CHCl3); 1H
NMR (300 MHz, CDCl3): d 0.54 (d, J 1.8 Hz, 9H), 1.03 (t, J 7.4 Hz,
3H), 1.89 (m, 2H), 3.91 (brs, 1H), 5.25 (brs, 2H), 5.28 (d, J 16.4 Hz, 1H),
5.71 (d, J 16.4 Hz, 1H), 7.31 (t, J 8.8 Hz, 1H), 7.47 (s, 1H), 7.85 (dd, J
8.8, 6.1 Hz, 1H), 8.31 (s, 1H); 13C NMR (75 MHz, CDCl3): d 1.6, 7.7, 31.4,
50.0, 66.3, 72.7, 97.5, 118.7 (d, JCF 32 Hz), 123.3 (d, JCF 27 Hz), 125.0,
127.1, 131.2, 146.7, 150.3, 151.7, 154.1, 157.6, 167.8 (d, JCF 248 Hz), 173.8;
0.038 mmol) in CH2Cl2 (500 mL) and TFA (100 mL) was stirred for 3 h at
room temperature. The reaction mixture was poured into saturated
NaHCO3 (50 mL), extracted with AcOEt (10 Â 10 mL), and dried
(Na2SO4). The residue obtained after evaporation of the solvents was
purified by flash chromatography (CHCl3/MeOH 9:1) to give a yellow solid
(11.8 mg, 87%). M.p.: >2608C (ref. [5g] >2508C); [a] 2D0 29.9 (c 0.15,
1
CHCl3/MeOH 4:1); H NMR (300 MHz, CDCl3/CD3OD 4:1): d 0.86 (t,
J 7.4 Hz, 3H), 1.75 (m, 2H), 5.02 (s, 2H), 5.12 (d, J 16.4 Hz, 1H), 5.49
(d, J 16.4 Hz, 1H), 6.80 (d, J 2.5 Hz, 1H), 7.12 (dd, J 9.1, 2.5 Hz, 1H),
7.43 (s, 1H), 7.77 (d, J 9.1 Hz, 1H), 7.95 (s, 1H); HRMS (EI): m/z calcd for
HRMS (EI): m/z calcd for C23H23FN2O4Si (M ) 438.1411, found 438.1411;
C20H17N3O4 (M ) 363.1219, found 363.1216; LRMS (EI): m/z 363 (M ,
LRMS (EI): m/z 438 (M , 66), 423 (100), 394 (12), 379 (52), 293 (21).
100), 319 (96), 263 (55).
16. (20S)-10,11-Methylenedioxy-12-trimethylsilylcamptothecin (1u): Use
of the procedure described for the synthesis of 1a with 23 (37.3 mg,
0.10 mmol) and 39b (43.8 mg, 0.20 mmol) afforded a slightly yellow solid
(24.6 mg, 53%) after flash chromatography (CHCl3/acetone 6:1). M.p.:
225 ± 2288C decomp.; [a] D20 26.4 (c 0.2, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.51 (s, 9H), 1.02 (t, J 7.3 Hz, 3H), 1.89 (m, 2H), 3.85 (brs,
1H), 5.14 (brs, 2H), 5.27 (d, J 16.2 Hz, 1H), 5.70 (d, J 16.2 Hz, 1H),
6.10 (s, 2H), 7.03 (s, 1H), 7.37 (s, 1H), 8.04 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 1.1, 7.8, 31.4, 50.1, 66.3, 72.7, 96.4, 101.3, 103.5, 115.9, 117.2,
125.9, 126.6, 129.2, 136.1, 147.5, 148.1, 148.6, 150.3, 156.5, 157.6, 173.9;
12. (20S)-9-(1-tert-Butyldiphenylsilyloxyethyl)camptothecin (1p) and
(20S)-11-(1-tert-butyldiphenylsilyloxyethyl)camptothecin (1q): Use of the
procedure described for the synthesis of 1a with 23 (74.6 mg, 0.20 mmol)
and 28 (231 mg, 0.60 mmol) provided, after flash chromatography (CHCl3/
AcOEt 7:3):
i) 1p (less polar, 39.2 mg, 31%), as an oil. [a] 2D0 20.3 (c 0.5, CHCl3);
1H NMR (300 MHz, CDCl3): d 0.95 ± 1.10 (m, 12H), 1.59 (dd, J 7.3 Hz,
3H), 1.88 (m, 2H), 3.90 (brs, 1H), 5.17 (s, 2H), 5.29 (d, J 16.4 Hz, 1H),
5.42 (m, 1H), 5.73 (d, J 16.4 Hz, 1H), 7.10 (d, J 7.3 Hz, 2H), 7.21 (d, J
7.6 Hz, 1H), 7.30 ± 7.45 (m, 5H), 7.50 (s, 1H), 7.61 (t, J 7.6 Hz, 1H),
HRMS (EI): m/z calcd for C24H24N2O6Si (M ) 464.1404, found 464.1391;
Chem. Eur. J. 1998, 4, No. 1
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