Copper(I) iodide-promoted hydroxylation onto the lithium or potassium enolate of lactones and lactams

Article abstract of DOI:10.3987/com-01-9330

After enolization of lactones (1a,b) and lactams (2a,b) with lithium or potassium hexamethyldisilazide in THF, each resultant enolate was treated with a solution prepared by mixing copper(I) iodide, pyridine, and tert-butyl hydroperoxide or N-methylmorpho

Full text of DOI:10.3987/com-01-9330

HETEROCYCLES, Vol. 55, No. 11, 2001, pp. 2157 - 2170, Received, 27th August, 2001
COPPER(I) IODIDE-PROMOTED HYDROXYLATION ONTO
THE LITHIUM OR POTASSIUM ENOLATE OF LACTONES
AND LACTAMS
a
b
a
a
Norio Nakazawa, Keiko Tagami, Hitoshi Iimori, Shigeki Sano,
c
a,
Tsutomu Ishikawa, and Yoshimitsu Nagao *
a
Faculty of Pharmaceutical Sciences, The University of Tokushima,
Sho-machi, Tokushima 770-8505, Japan
b
Faculty of Pharmaceutical Sciences, Mukogawa Women's University,
1
1-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179, Japan
Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi,
c
Inage, Chiba 263-8522, Japan
Abstract-After enolization of lactones (1a,b) and lactams (2a,b) with
lithium or potassium hexamethyldisilazide in THF, each resultant enolate
was treated with a solution prepared by mixing copper(I) iodide,
pyridine, and tert-butyl hydroperoxide or N-methylmorpholine N-oxide in
THF to give α-hydroxy lactones (3a,b) and α-hydroxy lactams (4a,b) in
satisfied yields. This hydroxylation method was successfully applied to
conversion of dl-desoxycamptothecin (dl-7) to dl-camptothecin (dl-5).
In the hydroxylation reactions at the α-methylene and α-methyne positions of various carbonyl

compounds, a large number of oxidations of the silyl enolates were performed by employing
many oxidizing reagents such as osmium tetroxide together with 4-methylmorpholine
1
a
1b
2
3
N-oxide,
chiral AD-mix-α and -β,
chromyl chloride, m-chloroperbenzoic acid,
4
5
6
dimethyldioxirane, fructose-derived dioxirane, chiral (salen)manganese(III) complexes,
7
8
9
singlet oxygen, iodosobenzene-BF ·OEt , and N-sulfonyloxaziridines. Similar oxidation
3
2
reactions of the alkaline metal enolates of carbonyl compounds in order to obtain the
1
0
α-hydroxy derivatives were also achieved by employing MoO ·Py·HMPA (MoOPH), achiral
5
1
1
4,12
13
and chiral N-sulfonyloxaziridines, dimethyldioxirane,
and benzeneseleninic anhydride,
respectively. There have been some reports of oxidative hydroxylation at the α-position of
1
4
15
lactams and lactones using CuCl -O , cobalt(II) Schiff's base complexes-O , LDA or lithium
2
2
2
1
6
hexamethyldisilazide (LHMDS)-MoOPH, and LHMDS or potassium hexamethyldisilazide
1
1a
(
KHMDS)-N-sulfonyloxaziridines. However, most of above hydroxylations of the lactams and
lactones were exploited only for the one-step reaction in the total synthesis of natural products
1
1a,15
except for a few cases.
We now report direct hydroxylation reactions onto the lithium and/or potassium enolates of
lactones (1a,b), lactams (2a,b), and dl-desoxycamptothecin (dl-7) by employing copper(I)
iodide (CuI) and an oxidizing reagent, tert-butyl hydroperoxide (t-BuOOH) or
N-methylmorpholine N-oxide (NMO). The compounds (1a,b and 2a,b), precursors of
hydroxylation, were prepared by treatment of commercially available isochroman-3-one and
1
-methylindolin-2-one with n-BuLi or LHMDS and then methyl iodide or benzyl bromide in
THF-HMPA (5 : 1), as shown in Scheme 1.
Scheme 1
R
1) n-BuLi
O
THF-HMPA (5 :1)
O
-78 °C
O
O
2
) MeI or PhCH Br
2
-78 °C
1
1
a 90%
b 50%

1
) LHMDS
THF-HMPA (5 :1)
R
O
-78 °C
N
O
2) MeI or PhCH Br
N
2
-78 °C
Me
Me
2
2
a 42%
b 53%
a : R = Me, b : R = PhCH2
First of all, hydroxylation of 4-methyl-2-benzopyran-3-one (1a) was attempted as follows. To a
mixture of CuI, pyridine, and t-BuOOH in THF was added a THF solution of the lithium enolate
generated by treatment of 1a with LHMDS in THF utilizing a cannula system. The whole
mixture was stirred at -78 °C for 36 h to give desired 4-hydroxy-4-methyl-2-bezopyran-3-one
(
3a) in 77% yield, as shown in Scheme 2 and Table 1 (Entry 1). Because the similar treatment
of other compounds (1b and 2a,b) resulted in 20-30% yields of the corresponding α-hydroxy
lactone (3b) and α-hydroxy lactams (4a,b), their reactions were tentatively carried out by
employing two times amounts of t-BuOOH and pyridine (except for Entry 2) in comparison with
the case of 1. The yields of 3b and 4a,b were improved to be 38-80%, as shown in Table 1
(
Entries 2-4).
Scheme 2
R
HO
R
O
O
1) LHMDS, THF, -78 °C, 1h
O
O
2) CuI, t-BuOOH, pyridine,
THF, -78 °C, time
1a, b
3a 77%
3b 80%
OH
R
O
"
"
R
O
N
N
Me
Me
2a, b
4a 38%
4b 56%
a : R = Me, b : R = PhCH2

Table 1. CuI-Promoted Hydroxylation onto Lactones (1a,b) and Lactams
(2a,b) after Enolization with LHMDS.
Time
(h)
36
t-BuOOH Pyridine
Entry
Compd.
1a
Product
3a
Yield (%)
(mol eq.) (mol eq.)
1
2
3
4
77
80
38
56
1
.1
.2
4.4
4.2
1b
40
3b
2
2a
60
4a
8
.8
"
"
2b
20
4b
"
Subsequently, α-hydroxylation of 1a,b and 2a,b was attempted by using KHMDS and NMO, as
shown in Scheme 3. Namely, after enolization of 1a,b and 2a,b with KHMDS in THF at -78 °C
for 1 h, each resultant potassium enolate in THF was allowed to react with a mixture of CuI,
NMO, and pyridine in THF at each indicated temperature. The desired oxidative hydroxylation
proceeded to furnish the corresponding α-hydroxy lactones (3a,b) and α-hydroxy lactams
(
4a,b) in 47-70% yields, respectively, as shown in Table 2. The similar hydroxylation onto the
potassium enolate of 1a without use of CuI turned out to be 68% recovery of 1a with 3a in 9%
yield. Thus, CuI seems to be essential for this hydroxylation in the presence of NMO and
pyridine. This CuI-promoted α-hydroxylation onto the lactones and lactams using more than
2
.2 mol eq. of t-BuOOH and NMO resulted in very low yields of their α-hydroxy products
together with miscellaneous products.
Scheme 3
R
HO
R
O
1
) KHMDS (1.1 mol eq.),
THF, -78 °C, 1 h
O
O
O
2
) CuI (1.1 mol eq.), NMO,
pyridine (4.4 mol eq.),
THF, temp, time
1
a, b
3a 60%
3b 70%
OH
R
O
"
"
R
O
N
N
Me
Me
2a, b
4a 47%
4b 63%
a : R = Me, b : R = PhCH2

Table 2. CuI-Promoted Hydroxylation onto Lactones (1a,b) and Lactams
2a,b) after Enolization with KHMDS.
(
NMO
(mol eq.)
Temp
( °C)
Time
(h)
Entry
1
Compd.
Yield (%)
60
Product
1a
1.1
2.2
rt
15
3a
-
78
rt
78
rt
6
12
6
30
2
3
4
1b
2a
2b
3b
4a
4b
70
47
63
and then
and then
-
"
"
"
"
Finally, we applied this CuI-promoted α-hydroxylation to the conversion of
1
4,17
14,17,18
dl-desoxycamptothecin (dl-7)
to dl-camptothecin (dl-5),
as shown in Scheme 4. The
compound (dl-7) was prepared by treatment of 20(S)-camptothecin acetate [(S)-6], obtained
1
9
20
by acetylation of 20(S)-camptothecin [(S)-5], with SmI in THF-MeOH (1:1) at -78°C. After
2
enolization of dl-7 with KHMDS in THF at -78 °C, the resultant lithium enolate was treated with
Scheme 4
O
O
Ac O
pyridine, rt
N
2
N
N
N
O
O
94%
Et
Et
OH O
0(S)-camptothecin [(S)-5]
OAc O
(
S)-6
2
SmI2
THF-MeOH (1 : 1)
78 °C
-
38%
O
N
1) LHMDS
THF, -78 °C, 1 h
N
dl-camptothecin (dl-5)
O
O
2
) CuI, t-BuOOH,
pyridine, THF,
43%
-78 °C, 60 h
Et
dl-7
a mixture of CuI, t-BuOOH, and pyridine in THF at -78 °C under argon atmosphere to afford

dl-camptothecin (dl-5) in 43% yield. Recently, we have accomplished an asymmetric total
synthesis of 20(S)-camptothecin [(S)-5], in which dl-desoxycamptothecin (dl-7) was
2
1
successfully synthesized from a pyrrolidinone derivative. Thus, the conversion of dl-7 to dl-5
exploiting the CuI-promoted hydroxylation method is regarded as a total synthesis of
dl-camptothecin (dl-5).
EXPERIMENTAL
All melting points were measured on a Yanagimoto apparatus and are uncorrected. IR spectra
1
were recorded on a JASCO FT/IR-420 infrared Fourier transform spectrophotometer. H-NMR
(
300 MHz) spectra were taken on a JEOL JNM-AL 300 spectrometer with tetramethylsilane as
an internal standard, and chemical shifts are recorded in δ values (ppm). HR-MS spectra were
measured on a JEOL JMS SX-102A mass spectrometer using a direct inlet system.
Elementary combustion analyses were performed by a Yanagimoto CHN Corder. All reactions
were monitored by thin-layer chromatography employing 0.25 mm E. Merck silica gel plates
(
60F-254). Preparative thin-layer chromatography was performed on 0.5 mm E. Merck silica
gel (60F-254). Column chromatography was carried out on Kanto silica gel 60N (spherical
neutral, 63-210 µ m). THF was employed after treating with ketyl radical, distillation, and
passing argon for 1 h.
4
-Methyl-2-benzopyran-3-one (1a)
To a solution of isochroman-3-one (500 mg, 3.4 mmol) in THF (30 mL) and HMPA (5 mL) was
added dropwise n-BuLi (1.61 M hexane solution, 2096 µL, 3.4 mmol) at -78 °C under argon,
and the mixture was stirred at -78 °C for 1 h. Then, MeI (1350 µL, 16.9 mmol) was added
dropwise with stirring, and the whole mixture was stirred at -78 °C for 1 h. The reaction mixture
was treated with 5% HCl, extracted with CHCl , and then the CHCl extract was washed with
3
3

brine. The organic layer was dried over MgSO and filtered, and the filtrate was concentrated
4
in vacuo. The oily residue was purified by column chromatography on silica gel with
1
1
1
hexane-AcOEt (2 : 1) to give known compound (1a) (491.9 mg, 90%) as a colorless oil. H
NMR (CDCl )δ 1.65 (3H, d, J = 7.0 Hz), 3.65 (1H, q, J = 7.0 Hz), 5.28 (1H, d, J = 13.8 Hz), 5.35
3
-
1
(
1H, d, J = 13.8 Hz), 7.23-7.42 (4H, m); IR (neat) 1745 cm ; HR-MS Calcd for C H O :
10 10 2
+
1
4
62.0681, Found m/z: 162.0691 (M ).
-Benzyl-2-benzopyran-3-one (1b)
A solution of n-BuLi (1.61 M hexane solution, 1383 µL, 2.2 mmol) was added dropwise to a
solution of isochroman-3-one (300 mg, 2.0 mmol) in THF (30 mL) and HMPA (6 mL) at -78 °C
under argon. The mixture was stirred at -78 °C for 1 h, and then benzyl bromide (241 µL, 2.0
mmol) was added dropwise with stirring. After being stirred at -78 °C for 1 h, the reaction
mixture was treated with 5% HCl, extracted with CHCl , and then the CHCl extract was
3
3
washed with brine. The organic layer was dried over MgSO , filtered, and the filtrate was
4
evaporated in vacuo. The oily residue was purified by column chromatography on silica gel
1
with hexane-AcOEt (2 : 1) to give compound (1b) (242.0 mg, 50%) as a colorless oil. H NMR
(
CDCl ) δ 3.29 (2H, d, J = 6.4 Hz), 4.00 (1H, t, J = 6.4 Hz), 4.74 (1H, d, J = 14.3 Hz), 5.08 (1H, d,
3
-
1
J = 14.3 Hz), 6.94-7.28 (9H, m); IR (neat) 1740 cm ; HR-MS Calcd for C H O : 238.0994,
1
6
14
2
+
Found m/z: 238.0987 (M ); Anal. Calcd for C H O : C, 80.65; H, 5.92. Found: C, 80.41; H,
1
6
14
2
6
.07.
1
,3-Dimethylindolin-2-one (2a)
To a solution of 1-methylindolin-2-one (400 mg, 2.7 mmol) in THF (30 mL) and HMPA (6 mL)
was added dropwise a solution of lithium bis(trimethylsilyl)amide (1.08 M hexane solution,
2
516 µL, 2.7 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 1 h, and then
MeI (2531 µL, 4.1 mmol) was added dropwise with stirring. After being stirred at -78 °C for 1 h,
the reaction mixture was submitted to the usual work-up to give an oily residue.

Chromatographic purification of the residue on a silica gel column with hexane-AcOEt (2 : 1)
1
afforded compound (2 a) (184 mg, 42%) as a colorless oil. H NMR (CDCl ) δ 1.48 (3H, d, J =
3
7
7
.7 Hz), 3.21 (3H, s), 3.43 (1H, q, J = 7.7 Hz), 6.82 (1H, d, J = 7.7 Hz), 7.06 (1H, dd, J = 7.7 and
-
1
.3 Hz), 7.22-7.30 (2H, m); IR (neat) 1710 cm ; HR-MS Calcd for C H NO: 160.0762, Found
1
0
11
+
m/z: 160.0751 (M ).
3
-Benzyl-1-methylindolin-2-one (2b)
To a solution of 1-methylindolin-2-one (500 mg, 3.4 mmol) in THF (30 mL) and HMPA (6 mL)
was added dropwise a solution of lithium bis(trimethylsilyl)amide (1.08 M hexane solution,
3
146 µL, 3.4 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 1 h, and then
benzyl bromide (606 µL, 5.1 mmol) was added dropwise with stirring. After being stirred at -78
C for 1 h, the reaction mixture was submitted to the usual work-up to give a purple residue.
°
The residue was purified by chromatography on a silica gel column with hexane-AcOEt (2 : 1)
1
to afford compound (2b) (456.3 mg, 53%) as a purple solid. mp 61-62 °C; H NMR (CDCl ) δ
3
2
.87 (1H, dd, J = 13.6 and 9.4 Hz), 3.16 (3H, s), 3.50 (1H, dd, J = 13.6 and 4.4 Hz), 3.71 (1H,
dd, J = 9.4 and 4.4 Hz), 6.72-6.76 (2H, m), 6.91 (1H, dd, J = 7.9 and 7.2 Hz), 7.15-7.28 (6H, m);
-
1
+
IR (KBr) 1698 cm ; HR-MS Calcd for C H NO: 237.1154, Found m/z: 237.1171 (M ).
1
6
15
General Procedure for Copper(I) Iodide-Promoted Hydroxylation Using t-BuOOH
and Pyridine
4
-Hydroxy-4-methyl-2-benzopyran-3-one (3a)
4
-Methyl-2-benzopyran-3-one (1a) (50 mg, 0.31 mmol) was dissolved in THF (10 mL)
degassed with argon, and then a solution of lithium hexamethyldisilazide (1.08 M hexane
solution, 315 µL, 0.34 mmol) was added dropwise at -78 °C under argon atmosphere. After
being stirred at -78 °C for 1 h, the resultant solution was employed as the lithium enolate of 1a.
Pyridine (109 µL, 1.36 mmol) and tert-butyl hydroperoxide (37 µL, 0.34 mmol) were added to a

suspension of copper(I) iodide (64.6 mg, 0.34 mmol) in THF (10 mL) degassed with argon in
another vessel, and the mixture was stirred at -78 °C for 1 h under argon atmosphere. To the
resultant suspension was added a solution of the lithium enolate of 1a by using a cannula
system, and then the whole mixture was stirred at -78 °C for 36 h under argon. The reaction
mixture was treated with 5% HCl, 20% Na SO , and extracted with CHCl . The CHCl extract
2
3
3
3
was submitted to the usual work-up to give an oily residue. The residue was chromatographed
on a silica gel plate with hexane-AcOEt (2 : 1) to give compound (3a) (42.5 mg, 77%) as a
1
white solid. mp 68-70 °C; H NMR (CDCl ) δ 1.61 (3H, s), 3.68 (1H, s), 5.34 (1H, d, J = 14.5
3
Hz), 5.53 (1H, d, J = 14.5 Hz), 7.18 (1H, d, J = 7.5 Hz), 7.35 (1H, dd, J = 7.5 and 7.5 Hz), 7.45
-
1
(
1H, dd, J = 7.5 and 7.5 Hz), 7.70 (1H, d, J = 7.5 Hz); IR (KBr) 3490, 1735 cm ; HR-MS Calcd
+
for C H O : 178.0630, Found m/z: 178.0642 (M ); Anal. Calcd for C H O : C, 67.41; H, 5.66.
1
0
10
3
10 10
3
Found: C, 67.22; H, 5.67.
-Benzyl-4-hydroxy-2-benzopyran-3-one (3b)
4
The reaction was carried out by employing 1b (30 mg, 0.13 mmol), lithium
hexamethyldisilazide (1.08 M hexane solution, 128.2 µL, 0.14 mmol), pyridine (44.8 mL, 0.55
mmol), tert-butyl hydroperoxide (34.7 µL, 0.28 mmol), and copper(I) iodide (26.4 mg, 0.14
mmol) to give compound (3b) (25.5 mg, 80%) as colorless needles from benzene. mp
1
1
30-131 °C; H NMR (CDCl ) δ 3.12 (2H, s), 3.70 (1H, s), 5.00 (1H, d, J = 14.7 Hz), 5.22 (1H, d,
3
J = 14.7 Hz), 6.95-6.97 (2H, m), 7.10 (1H, d, J = 7.2 Hz), 7.18-7.31 (3H, m), 7.31-7.41 (2H, m),
-
1
7
.53 (1H, d, J = 5.5 Hz); IR (KBr) 3447, 1725 cm ; HR-MS Calcd for C H O : 254.0943, Found
16 14 3
+
m/z: 254.0935 (M ); Anal. Calcd for C H O : C, 75.57; H, 5.55. Found: C, 75.39; H, 5.59.
1
6
14
3
1
,3-Dimethyl-3-hydroxyindolin-2-one (4a)
The reaction was carried out by employing 2 a (14 mg, 0.087 mmol), lithium
hexamethyldisilazide (1.08 M hexane solution, 88.5 µL, 0.096 mmol), pyridine (61.8 µL, 0.764
mmol), tert-butyl hydroperoxide (23.9 µL, 0.19 mmol), and copper(I) iodide (18.2 mg, 0.096

mmol) to give compound (4 a) (5.9 mg, 38%) as colorless prisms from benzene. mp 146-147
1
°
C; H NMR (CDCl ) δ 1.61 (3H, s), 3.16 (1H, br s), 3.20 (3H, s), 6.85 (1H, d, J = 7.9 Hz), 7.11
3
(1H, dd, J = 7.7 and 7.3 Hz), 7.33 (1H, dd, J = 7.9 and 7.7 Hz), 7.41 (1H, d, J = 7.3 Hz); IR (KBr)
-
1
+
3
306, 1698 cm ; HR-MS Calcd for C H NO : 177.0790, Found m/z: 177.0797 (M ); Anal.
10 11 2
Calcd for C H NO : C, 67.78; H, 6.26; N, 7.90. Found: C, 67.81; H, 6.29; N, 7.79.
1
0
11
2
3
-Benzyl-3-hydroxy-1-methyl-indolin-2-one (4b)
The reaction was carried out by employing 2b (30 mg, 0.126 mmol), lithium
hexamethyldisilazide (1.08 M hexane solution, 128.8 µL, 0.139 mmol), pyridine (90 µL, 1.113
mmol), tert-butyl hydroperoxide (34.8 µL, 0.278 mmol), and copper(I) iodide (26.5 mg, 0.139
mmol) to give compound (4b) (18 mg, 56%) as pale yellow prisms from benzene. mp 161-162
1
°
C; H NMR (CDCl ) d 2.77 (1H, s), 3.01 (3H, s), 3.12 (1H, d, J = 12.9 Hz), 3.30 (1H, d, J = 12.9
3
-
1
Hz), 6.65 (1H, d, J = 7.9 Hz), 6.94-7.28 (8H, m); IR (KBr) 3382, 1700 cm ; HR-MS Calcd for
+
C H NO : 253.1103, Found m/z: 253.1095 (M ); Anal. Calcd for C H NO : C, 75.85; H, 5.97;
1
6
15
2
16 15
2
N, 5.53. Found: C, 75.51; H, 5.97; N, 5.53.
General Procedure for Copper(I)
Iodide-Promoted
Hydroxylation
Using
N-Methylmorpholine N-Oxide and Pyridine
-Hydroxy-4-methyl-2-benzopyran-3-one (3a)
4
To a solution of 4-methyl-2-benzopyran-3-one (1a) (50 mg, 0.31 mmol) in THF (10 mL)
degassed with argon was added dropwise potassium hexamethyldisilazide (1.08 M toluene
solution, 564 µL, 0.34 mmol) at -78 °C under argon atmosphere. After being stirred at -78 °C
for 1 h, the resultant solution was employed as the potassium enolate of 1a. Pyridine (109 µL,
1
.36 mmol) and N-methylmorpholine N-oxide (40.9 mg, 0.34 mmol) were added to a
suspension of copper(I) iodide (64.6 mg, 0.34 mmol) in THF (10 mL) degassed with argon in
another vessel, and the mixture was stirred at -78 °C for 1 h under argon atmosphere. To the
resultant suspension was added a solution of the potassium enolate of 1a by using a cannula

system at -78 °C, and then the whole mixture was stirred at room temperature for 15 h. The
reaction mixture was treated as usual to give compound (3a) (33.2 mg, 60%).
Other compounds (1b, 2a, and 2b) were also submitted to the similar treatment described
above to furnish the corresponding hydroxy products [3b (70% yield), 4a (47% yield), and 4b
(
63% yield)], respectively (See Table 2).
2
0(S )-Camptothecin Acetate [(S )-6]
To a suspension of 20(S)-camptothecin [(S)-5] (500 mg, 1.44 mmol) in pyridine (40 mL) was
added acetic anhydride (2031 µL, 21.54 mmol) at 0 °C. After being stirred at rt for 3 days, the
reaction mixture was evaporated in vacuo to give an oily residue, which was dissolved in
CHCl . The CHCl solution was washed with brine, dried over MgSO , and filtered. After
3
3
4
evaporation of the filtrate in vacuo, the residue was crystallized in CHCl -MeOH to afford
3
2
0(S)-camptothecin acetate [(S)-6] (528.5 mg, 94%) as colorless needles. mp 287-290 °C
1
9
1
decomp (lit., 271-274 °C decomp); H NMR (CDCl ) δ 0.98 (3H, t, J = 7.5 Hz), 2.09-2.33 (2H,
3
m), 2.22 (3H, s), 5.29 (2H, s), 5.42 (1H, d, J = 17.3 Hz), 5.68 (1H, d, J = 17.3 Hz), 7.23 (1H, s),
7
8
.68 (1H, dd, J = 8.5 and 7.2 Hz), 7.85 (1H, dd, J = 8.3 and 7.2 Hz), 7.95 (1H, d, J = 8.3 Hz),
-
1
.23 (1H, d, J = 8.5 Hz), 8.40 (1H, s); IR (KBr) 1747, 1670, 1619 cm ; HR-MS Calcd for
+
C H N O : 390.1216, Found m/z: 390.1203 (M ).
2
2
18
2
5
dl-Desoxycamptothecin (dl-7)
To a suspension of 20(S)-camptothecin acetate [(S)-6] (500 mg, 1.3 mmol) in a degassed
solution of MeOH (10 mL) and THF (10 mL) was added dropwise a 0.1M THF solution of SmI2
(
51 mL, 5.1 mmol) with stirring at -78 °C under argon atmosphere. After being stirred at -78 °C
for 4 h, the reaction mixture was treated with sat. K CO aqueous solution and then acidified
2
3
with 5% HCl. The acidic solution was extracted with CHCl , and the CHCl extract was dried
3
3
over MgSO . After filtration, the filtrate was evaporated in vacuo to give a residue. The residue
4

was purified on a silica gel column with CHCl -MeOH (50 : 1) to afford dl-desoxycamptothecin
3
1
7a
(
dl-7) (163 mg, 38%) as a pale yellow solid from CHCl -AcOEt. mp 258-260 °C decomp (lit.,
3
1
mp 258-260 °C decomp); H NMR (CDCl ) δ 1.10 (3H, t, J = 7.3 Hz), 2.06-2.16 (2H, m), 3.64
3
(3H, t, J = 6.4 Hz), 5.31 (2H, s), 5.40 (1H, d, J = 16.3 Hz), 5.58 (1H, d, J = 16.3 Hz), 7.20 (1H, s),
7
8
.68 (1H, dd, J = 8.4 and 7.0 Hz), 7.84 (1H, dd, J = 7.9 and 7.0 Hz), 7.95 (1H, d, J = 7.9 Hz),
-
1
.23 (1H, d, J = 8.4 Hz), 8.40 (1H, s); IR (KBr) 1738, 1663, 1603 cm ; HR-MS Calcd for
+
C H N O : 332.1161, Found m/z: 332.1176(M ).
2
2
16
2
3
dl-Camptothecin (dl-5)
The reaction was carried out by employing dl-7 (20 mg, 0.060 mmol), lithium
hexamethyldisilazide (1.08 M hexane solution, 61.3 µL, 0.066 mmol), pyridine (42.2 µL, 0.530
mmol), tert-butyl hydroperoxide (16.6 µL, 0.132 mmol), and copper(I) iodide (12.6 mg, 0.066
mmol) to give dl-camptothecin (dl-5) (9 mg, 43%) as pale a yellow solid from MeCN-MeOH.
1
8
1
mp 287-288 °C decomp. (lit., 287-288 °C decomp); H NMR [CDCl -MeOH (4 : 1)] δ 1.05 (3H,
3
t, J = 7.3 Hz), 1.90-1.98 (2H, m), 5.32 (2H, s), 5.33 (1H, d, J = 16.5 Hz), 5.71 (1H, d, J = 16.5
Hz), 7.69 (1H, dd, J = 8.5 and 7.5 Hz), 7.75 (1H, s), 7.82 (1H, dd, J = 8.1 and 7.5 Hz), 7.97 (1H,
-
1
d, J = 8.1 Hz), 8.23 (1H, d, J = 8.5 Hz), 8.47 (1H, s); IR (KBr) 1652, 1602, 1581 cm ; HR-MS
+
Calcd for C H N O : 348.1110, Found m/z: 348.1090(M ).
2
2
16
2
4
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