Synthesis of (()-20-Deoxycamptothecin and (+)-Camptothecin
J ) 7.5 Hz, 3H), 2.00 (s, 3H), 2.02 (s, 3H), 2.17 (masked, 2H),
3.78 (s, 3H), 5.37 (s, 2H), 6.70 (d, J ) 7.5 Hz, 1H), 7.45 (d, J
) 7.5 Hz, 1H), 7.57 (t, J ) 8.1 Hz, 1H), 7.73 (t, J ) 8.4 Hz,
1H), 7.80 (d, J ) 7.5 Hz, 1H), 8.03 (d, J ) 8.7 Hz, 1H), 8.10 (s,
1H); 13C NMR δ 8.8 (CH3), 13.5 (CH3), 28.5 (CH2), 14.3 (CH3),
52.2 (CH2), 52.4 (CH3), 59.3 (C), 106.9 (CH), 127.0 (C), 127.3
(CH), 127.7 (CH), 128.1 (CH), 128.3 (C), 129.3 (C), 130.6 (CH),
133.0 (CH), 138.6 (CH), 142.4 (C), 146.2 (C), 147.7 (C), 162.9
(C), 171.4 (C). Anal. Calcd for C22H23BrN2O3S‚1/2H2O: C, 54.55;
H, 4.99; N, 5.78. Found: C, 54.37; H, 4.53; N, 6.02.
(C), 148.5 (C), 152.6 (C), 154.7 (C), 161.1 (C); HRMS calcd for
C20H20N2O3 336.1473, found 336.1474.
B: To a solution of tetracycle 25 (25 mg, 0.06 mmol) in THF
(0.5 mL) cooled at -78 °C was added DIBAL (1 M in THF,
0.18 mL, 0.18 mmol) under Ar, and the mixture was stirred
at -78 °C for 1.5 h. The reaction mixture was allowed to rise
to -40 °C and stirred for 10 min. NaBH4 (spatula) and H2O
(1 mL) were added and the mixture was stirred at room
temperature for 30 min. Workup and flash chromatography
as above gave diol 28: 16 mg (80%).
Met h yl r-E t h yl-3-(m et h oxyca r b on yl)-4-oxo-4,6-d ih y-
d r oin d olizin o[1,2-b]qu in olin e-2-a ceta te (25). AIBN (cata-
lytic) and TTMSS (0.03 mL, 0.09 mmol) were added to a heated
(reflux) solution of pyridone 23 (46 mg, 0.09 mmol) in dry
benzene (10 mL). After 2 h at reflux, AIBN (catalytic) and
TTMSS (0.03 mL, 0.09 mmol) were added, and the mixture
was stirred at the same temperature for 2 h. The reaction
mixture was poured into H2O and extracted with Et2O.
Concentration of the organic extracts and flash chromatogra-
phy (9:1 AcOEt-MeOH) of the crude product gave tetracycle
25: 25 mg (70%); 1H NMR δ 0.97 (t, J ) 7.2 Hz, 3H), 1.95 and
2.23 (2 m, 2H), 3.71 (s, 3H), 3.79 (t, J ) 7.5 Hz, 1H), 3.99 (s,
3H), 5.28 (s, 2H), 7.41 (s, 1H), 7.67 (t, J ) 7.2 Hz, 1H), 7.83 (t,
J ) 7 Hz, 1H), 7.94 (d, J ) 8.1 Hz, 1H), 8.23 (d, J ) 8.4 Hz, 1
H), 8.39 (s, 1H); 13C NMR (most significant signals) 12.0 (CH3),
25.6 (CH2), 49.4 (CH), 50.2 (CH2), 52.4 (CH3), 52.7 (CH3), 99.6
(CH), 128.1 (2CH), 129.7 (CH), 130.5 (CH), 131.0 (CH), 172.2
(C).
C: Operating as in the above method A, diol 28 was obtained
from tetracycle 27 (20 mg, 0.05 mmol), DIBAL (1 M in CH2Cl2
0.18 mL, 0.18 mmol), and NaBH4 (catalytic amount): 13 mg,
(75%).
Isop r op yl 1-[(2-Br om o-3-q u in olyl)m et h yl]-r-et h yl-3-
(m et h oxyca r b on yl)-r-(m et h ylsu lfa n yl)-2-oxo-1,2-d ih y-
d r op yr id in e-4-a ceta te (29). Isopropyl 2-(methylsulfanyl)-
buyrate (90 mg, 0.51 mmol) in THF (20 mL) was allowed to
react with LDA (0.5 mmol) at -78 °C for 30 min and then
with pyridinium triflate 21 (prepared from 0.43 mmol of
2-fluoropyridine 11a ) and DDQ as described for the prepara-
tion of pyridone 23. After flash chromatography (1:1 hexanes-
AcOEt) of the crude product pyridone 29 was obtained: 117
1
mg (50%); H NMR δ 0.91 (t, J ) 7.8 Hz, 3H), 1.27 and 1.31
(2d, J ) 6.3 Hz, 6H), 1.98 (s, 3H), 2.15 and 2.30 (2m, 2H), 3.84
(s, 3H), 5.06 (m, J ) 6.3 Hz, 1H), 5.38 (s, 2H), 6.56 (d, J ) 7.5
Hz, 1H), 7.58 (t, J ) 7 Hz, 1H), 7.60 (d, J ) 7.5 Hz, 1H), 7.74
(t, J ) 7 Hz, 1H), 7.81 (d, J ) 8.1 Hz, 1H), 8.01 (d, J ) 8.4 Hz,
1H), 8.22 (s, 1H); 13C NMR δ 9.5 (CH3), 13.9 (CH3), 21.2 (CH3),
21.6 (CH3), 29.7 (CH2), 51.9 (CH2), 52.3 (CH3), 60.2 (C), 69.4
(CH), 107.6 (CH), 125.4 (C), 127.0 (C), 127.4 (CH), 127.9 (CH),
128.0 (CH), 128.5 (C), 130.9 (CH), 136.5 (CH), 139.6 (CH),
142.3 (C), 147.8 (C), 149.3 (C), 160.2 (C), 166.4 (C), 168.4 (C);
HRMS calcd for C25H27BrN2O5S 546.0824, found 546.0793.
Anal. Calcd for C25H27BrN2O5S‚1.5H2O: C, 52.19; H, 5.27; N,
4.87. Found: C, 52.19; H, 5.21; N, 4.94.
Meth yl r-Eth yl-3-m eth yl-4-oxo-4,6-d ih yd r oin d olizin o-
[1,2-b]qu in olin e-2-a ceta te (26). Operating as above, tetra-
cycle 26 was obtained from pyridone 24 (42 mg, 0.09 mmol),
AIBN (catalytic), and TTMSS (2 × 0.03 mL, 0.18 mmol), after
flash chromatography (98:2 AcOEt-MeOH): 20 mg (65%); 1H
NMR δ 0.95 (t, J ) 7.5 Hz, 3H), 1.92 and 2.22 (2 m, 2H), 2.36
(s, 3H), 3.70 (s, 3H), 3.87 (t, J ) 7.6 Hz, 1H), 5.25 (s, 2H), 7.33
(s, 1H), 7.61 (t, J ) 8.1 Hz, 1H), 7.80 (t, J ) 8.4 Hz, 1H), 7.89
(d, J ) 8.1 Hz, 1H), 8.20 (d, J ) 8.4 Hz, 1H), 8.32 (s, 1H); 13
C
Isop r op yl r-Eth yl-3-(m eth oxyca r bon yl)-4-oxo-4,5-d i-
h yd r oin d olizin o[1,2-b]qu in olin e-2-a ceta te (30). Operating
as in the preparation of tetracycles 25 or 26, tetracycle 30 was
obtained from pyridone 29 (46 mg, 0.09 mmol) after flash
chromatography (9:1 AcOEt-MeOH): 25 mg (70%); 1H NMR
δ 0.98 (t, J ) 7.2 Hz, 3H), 1.18 and 1.26 (2d, J ) 6.3 Hz, 6H),
1.95 and 2.20 (2m, 2H), 3.72 (t, J ) 7.5 Hz, 1H), 3.99 (s, 3H),
5.03 (m, J ) 6.3 Hz, 1H), 5.28 (s, 2H), 7.45 (s, 1H), 7.66 (t, J
) 7 Hz, 1H), 7.83 (t, J ) 7 Hz, 1H), 7.93 (d, J ) 8 Hz, 1H),
8.22 (d, J ) 8.2 Hz, 1H), 8.38 (s, 1H); 13C NMR δ 12.0 (CH3),
21.6 (CH3), 21.8 (CH3), 25.6 (CH2), 50.1 (CH), 50.3 (CH2), 52.6
(CH3), 68.8 (CH), 99.7 (CH), 124.7 (C), 127.9 (CH), 128.0 (CH),
128.8 (2C), 129.8 (CH), 130.5 (CH), 130.9 (CH), 146.4 (C), 148.9
(C), 151.3 (C), 152.3 (C), 158.3 (C), 166.5 (C), 171.3 (C); HRMS
calcd for C24H24N2O5 420.1685, found 420.1688.
NMR δ 11.9 (CH3), 12.7 (CH3), 25.1 (CH2), 49.4 (CH), 49.9
(CH2), 52.2 (CH3), 100.1 (CH), 127.3 (CH), 127.9 (C), 127.8
(CH), 128.0 (C), 128.5 (C), 129.5 (CH), 130.1 (CH), 130.7 (CH),
142.4 (C), 147.4 (C), 148.7 (C), 153.2 (C), 161.4 (C), 172.9 (C);
HRMS calcd for C21H20N2O3 348.1473, found 348.1474. Anal.
Calcd for C21H20N2O3‚1.5H2O: C, 66.96; H, 6.19; N, 7.44.
Found: C, 66.68; H, 5.80; N, 7.70.
Dieth yl Ester (27). KF (70 mg, 1.2 mmol) was added to a
solution of tetracycle 25 (25 mg, 0.06 mmol) in dry EtOH (5
mL) and the mixture was heated (reflux) for 40 h. The solvent
was removed and the residue was partitioned between H2O
and AcOEt, then extracted with AcOEt. The organic extracts
were dried and concentrated, and the resulting residue was
chromatographed (99:1 AcOEt-MeOH) to give tetracycle 27:
21j
1
23 mg (90%); H NMR δ 0.97, 1.24, and 1.43 (3 t, J ) 7.2
Red u ction of Diester 30. A solution of diester 30 (15 mg,
0.03 mmol) in DME (2 mL) was added to a cooled (-70 °C)
solution of DIBAL (1 M in hexane, 0.1 mL, 0.1 mmol) in DME
(2 mL), and the resulting solution was stirred at -70 °C for
15 min. The reaction mixture was poured into H2O and
extracted with CH2Cl2. The organic extracts were concentrated
to give a residue, which was disolved in dry 2-propanol (1 mL).
NaBH4 (spatula) was added and the mixture was stirred at
room temperature for 30 min. After extractive workup (CH2-
Cl2) and flash chromatography (AcOEt-MeOH) of the crude
product the following compounds were isolated:
Hz, 9H), 1.95 (m, 1H), 2.22 (m, 2H), 3.75 (t, J ) 7.6 Hz, 1H),
4.16 (m, 2H), 4.48 (q, J ) 7.2 Hz, 2H), 5.30 (s, 2H, 5-H), 7.44
(s, 1H), 7.57 (t, J ) 7.6 Hz, 1H), 7.81 (t, J ) 7.8 Hz, 1H), 7.92
(d, J ) 8.2 Hz, 1H), 8.21 (d, J ) 8.4 Hz, 1H), 8.38 (s, 1H).
Diol 28. A: To a solution of tetracycle 25 (25 mg, 0.06 mmol)
in dry CH2Cl2 (0.5 mL) cooled at -78 °C was added DIBAL (1
M in CH2Cl2 0.18 mL, 0.18 mmol) under Ar, and the mixture
was stirred at -78 °C for 2 h. NaBH4 (spatula) and dry MeOH
(1 mL) were added, and the mixture was stirred at room
temperature for 30 min. The reaction mixture was poured into
H2O and extracted with CH2Cl2. Concentration of the organic
extracts and flash chromatography (98:2 CHCl3-MeOH) of the
(()-20-Deoxyca m p toth ecin (31):21a elution with 99:1 AcO-
Et-MeOH, 3.8 mg (32%); 1H NMR δ 1.09 (t, J ) 7.4 Hz, 3H),
2.09 (m, 2H), 3.62 (t, J ) 6.6 Hz, 1H), 5.29 (s, 2H), 5.39 (d, J
) 16.3 Hz, 1H), 5.57 (d, J ) 16.3 Hz, 1H), 7.19 (s, 1H), 7.66
(dt, J ) 7.5 and 1 Hz, 1H), 7.83 (dt, J ) 6.9 and 1.4 Hz, 1H),
7.93 (d, J ) 7 Hz, 1H), 8.21 (d, J ) 8.4 Hz, 1H), 8.39 (s, 1H).
1
crude product gave 28: 16 mg (80%); H NMR δ 0.89 (t, J )
7.5 Hz, 3H), 1.75 (m, 2H), 3.30 (m, 1H), 3.80 (dd, J ) 10.5 and
9.6 Hz, 1H), 3.98 (dd, J ) 10.5 and 4.8 Hz, 1H), 4.67 and 5.03
(2d, J ) 12.6 Hz, 2H), 5.17 (s, 2H), 7.28 (s, 1H), 7.57 (t, J )
7.8 Hz, 1H), 7.78 (m, 2H), 8.12 (d, J ) 8.4 Hz, 1H), 8.26 (s,
1H); 13C NMR δ 12.0 (CH3), 24.0 (CH2), 45.8 (CH), 49.9 (CH2),
56.5 (CH2), 66.0 (CH2), 99.5 (CH), 127.6 (CH), 127.8 (C), 128.0
(CH), 128.6 (C), 129.3 (CH), 130.3 (CH, C), 130.9 (CH), 144.4
La ctol 32:21m elution with 85:15 AcOEt-MeOH, 3.9 mg
1
(33%); H NMR δ 1.05 (t, J ) 7.4 Hz, 3H), 1.80 (m, 2H), 2.68
(t, J ) 6.6 Hz, 1H), 2.84 (s, 1H), 4.82 (s, 2H), 5.24 (s, 2H), 5.40
J . Org. Chem, Vol. 67, No. 21, 2002 7473