A novel and enantioselective total synthesis of (20 S)-camptothecin via a Sharpless asymmetric dihydroxylation strategy

Article abstract of DOI:10.1055/s-0031-1289575

A novel and efficient asymmetric total synthesis of (20S)-camptothecin has been accomplished in an overall yield of 12% starting from the commercially available 2-methoxynicotinic acid. The key step in the sequence is the Sharpless asymmetric dihydroxylation of a 4-(but-1-en-2-yl)pyridine derivative to establish the stereocenter of (20S)-camptothecin. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289575

PAPER
4045
A Novel and Enantioselective Total Synthesis of (20S)-Camptothecin via a
Sharpless Asymmetric Dihydroxylation Strategy
A
Total
Synthes
e
is of (20
S
)
-
i
CamptothecinZhao,a,b Fang-Jun Xiong,a Wen-Xue Chen,a Fen-Er Chen*a,b
a
Fudan-DSM Joint Lab for Synthetic Method and Chiral Technology, Department of Chemistry, Fudan University, Shanghai, 200433,
P. R. of China
b
Institutes of Biomedical Sciences, Fudan University, Shanghai, 200031, P. R. of China
Fax +86(21)65643811; E-mail: rfchen@fudan.edu.cn
Received 6 September 2011; revised 4 October 2011
NMe2
Abstract: A novel and efficient asymmetric total synthesis of
(20S)-camptothecin has been accomplished in an overall yield of
12% starting from the commercially available 2-methoxynicotinic
acid. The key step in the sequence is the Sharpless asymmetric di-
hydroxylation of a 4-(but-1-en-2-yl)pyridine derivative to establish
the stereocenter of (20S)-camptothecin.
HO
O
O
N
N
N
N
O
O
Key words: total synthesis, stereoselectivity, asymmetric catalysis,
antitumor agents, Heck reaction
OH O
OH O
1
2
camptothecin
topotecan
N
H
O
N
Since its isolation from the Chinese plant Camptotheca
acuminata by Wall et al. in 1966,1 (20S)-camptothecin
(CPT, 1), a pentacyclic natural alkaloid, has re-emerged
as one of the most important lead compounds for the dis-
covery of new and selective anticancer drugs because of
the disclosure of its unique mechanism of action as a se-
lective inhibitor of DNA topoisomerase I, a process caus-
ing irreversible DNA damage and subsequent cell death.2
Three camptothecin derivatives with high antitumor ac-
tivity, topotecan (2),3 belotecan (3),4 and irinotecan (4)5
(Figure 1), have been launched as anticancer drugs in clin-
ical practice, and many other analogues are at various
stages of clinical development.
N
O
OH O
3
belotecan
N
N
O
O
N
O
N
O
OH O
4
irinotecan
Over the past decades, much effort has been spent on the
development of an efficient process for the total synthesis
of 1 and its analogues, and numerous approaches toward
this natural product and its analogues have been dis-
closed.6 The C-ring construction approach through join-
ing AB fragment and DE fragment (chiral a-hydroxy
lactone 6 as the key intermediate) provides a short and ef-
ficient approach for the total synthesis of 1 and its ana-
logues.7 Although several interesting approaches to the
preparation of 1 have been reported by employing differ-
ent chiral technologies to control the stereochemistry at
C20 in camptothecin, such as Comins’ chiral auxiliary7a–c
and Fang’s Sharpless asymmetric dihydroxylation proto-
cols,7e the chemical synthesis of 1 remains a challenge
since involvement of difficult operations and high costs
make most syntheses impractical in the commercial pro-
cess. Herein, we describe our achievements in developing
an efficient asymmetric total synthesis of 1 starting from
commercially available 2-methoxynicotinic acid (7).
Figure 1 Structure of (20S)-camptothecin (1) and its analogues
C-ring construction
O
OH
O
O
A
N
C
OTs
B
N
E
A
B
+
D
N
5
Cl
D
O
E
N
H
O
OH O
1
6
OH
OH
COOH
OMe
OTBS
OMe
OTBS
OMe
N
N
N
13
12
7
Scheme 1 Retrosynthesis of (20S)-camptothecin (1)
SYNTHESIS 2011, No. 24, pp 4045–4049
x
x.
x
x
.
2
0
1
1
Advanced online publication: 25.10.2011
DOI: 10.1055/s-0031-1289575; Art ID: F87011SS
© Georg Thieme Verlag Stuttgart · New York

4046
L. Zhao et al.
PAPER
diol 13 was oxidized to the corresponding carboxylic acid
14 with sodium hypochlorite and sodium chlorite in a
buffered solution (pH 6.7). Treatment of 14 with 3 M hy-
drochloric acid at reflux gave the DE fragment 6 in 88%
yield as a white solid: mp 223.3–225.6 °C (Lit.7c 222–225
OH
O
COOH
a
c
b
O
OH
OMe
N
OMe
OH
N
OMe
N
7
8
9
20
°C); [a]D +121.0 (c 0.2, CHCl3–MeOH, 4:1) [Lit.7c
O
[a]D23 +117 (c 0.2, CHCl3–MeOH, 4:1)].
e
d
f
OTBS
OMe
OTBS
OTBS
OH
a
OTs
N
N
OMe
N
OMe
N
Cl
N
Cl
10
11
12
O
15
5
OH
OH
OH
OH
O
O
COOH
N
g
h
Cl
N
b
OTBS
HO
OTBS
OMe
5
6
+
N
H
N
OMe
N
O
13
14
6
O
O
16
Scheme 2 Reagents and conditions: (a) BuLi, TMP, EtCHO, THF,
–65 °C, 1 h then r.t., 3 h, 75%; (b) KBH4, LiCl, THF, 35 °C, 12 h,
90%; (c) TBSCl, imidazole, CH2Cl2, r.t., 1 h, 85%; (d) PCC, CH2Cl2,
r.t., 12 h, 82%; (e) Zn, CH2Br2, TiCl4, CH2Cl2, r.t., 5 h, 80%; (f)
K2OsO2(OH)4 (cat.), (DHQD)2PHAL (cat.), K3Fe(CN)6, MsNH2,
K2CO3, t-BuOH–H2O (1:1), 0 °C, 40 h, 89%; (g) TEMPO (cat.),
NaClO2, NaClO, MeCN–H2O (2:1), r.t., 5 h, 83%; (h) 3 M HCl,
reflux, 10 h, 88%.
O
N
c
N
O
OH O
1
The retrosynthetic analysis of 1 is described as shown in
Scheme 1. It is assumed that the target compound 1 would
be accessed by the combination of AB- and DE-ring frag-
ments according to the Comins’ C-ring construction strat-
egy. The enantiopure DE-ring fragment 6 could be
derived from chiral diol 13, which should be constructed
from pyridine olefin 12 using a Sharpless asymmetric di-
hydroxylation. Compound 12 could in turn be prepared
from 7.
Scheme 3 Reagents and conditions: (a) TsCl, Et3N, THF, r.t., 12 h,
87%; (b) t-BuOK, DME, reflux, 12 h, 82%; (c) Pd(PPh3)2(OAc)2,
KOAc, MeCN, 100 °C, 12 h, 64%.
Treatment of the known (2-chloroquinolin-3-yl)methanol
(15)9 with tosyl chloride in the presence of triethylamine
in dichloromethane at room temperature afforded AB-
ring fragment 5 in 87% yield (Scheme 3). The two frag-
ments 5 and 6 were joined through N-alkylation utilizing
potassium tert-butoxide in 1,2-dimethoxyethane to give
compound 16 in 82% yield. The final C-ring construction
was realized via an intramolecular Heck reaction to pro-
vide (20S)-camptothecin in 64% yield after recrystalliza-
tion from 1,4-dioxane.7cAll aspects of the synthesized
(20S)-camptothecin are in good agreement with those of
reported literature values.10
Our synthesis is outlined in Scheme 2. The lithiation of 7
with lithium tetramethylpiperidide followed by treatment
with propanal, and subsequent cyclization under acidic
condition gave lactone 8 in 75% yield. Reduction of 8
with lithium borohydride, prepared in situ from potassium
borohydride and anhydrous lithium chloride, smoothly
proceeded in dry tetrahydrofuran at 35 °C to provide a
90% yield of alcohol 9. The selective protection of the pri-
mary hydroxy group in 9 with tert-butylchlorodimethylsi-
lane in the presence of imidazole in dichloromethane at
room temperature gave TBS ether 10 in 85% yield. Oxi-
dation of 10 was effected by treatment with pyridinium
chlorochromate in dichloromethane under mild reaction
conditions to form ketone 11 in 82% yield. Methylenation
of 10 with the Lombardo reagent8 (Zn, CH2Br2, TiCl4) in
dichloromethane at room temperature worked well to af-
ford olefin 12 in 80% yield. With olefin 12 in hand, our
endeavor continued toward the construction of the stereo-
center of (20S)-camptothecin. Thus, Sharpless asymmet-
ric dihydroxylation of 12 was performed in the presence
of a catalytic amount of chiral ligand (DHQD)2PHAL un-
der standard conditions to provide the desired diol 13 in
89% yield and 94% ee (determined by chiral HPLC). The
In summary, our synthetic efforts have provided an effi-
cient route for the preparation of (20S)-camptothecin. Fur-
ther application of this methodology to other
camptothecin analogues is underway in our laboratory.
Anhyd THF was distilled from Na/benzophenone prior to use. An-
hyd CH2Cl2 and toluene were distilled from CaH2. Other reagents
were obtained from commercial sources and used as received. All
melting points were uncorrected, and measured on a WRS-1B digi-
1
tal melting-point apparatus. H (400 MHz) and 13C (100 MHz)
NMR spectra were recorded on a Bruker Avance 400 spectrometer
in CDCl3, DMSO using TMS and CDCl3 (13C, d = 77.0 ppm) as in-
ternal standards. Mass spectra were recorded on a Waters Quattro
Micromass instrument using ESI techniques. IR spectra were re-
corded on a Jasco FT/IR-4200 spectrophotometer. Optical rotations
were obtained on a Jasco P1020 digital polarimeter.
Synthesis 2011, No. 24, 4045–4049 © Thieme Stuttgart · New York

PAPER
A Total Synthesis of (20S)-Camptothecin
4047
1-Ethyl-4-methoxyfuro[3,4-c]pyridin-3(1H)-one (8)
13C NMR (100 MHz, CDCl3): d = –5.3, 10.6, 18.3, 25.9, 29.4, 53.5,
To a stirred soln of tetramethylpiperidine (12.05 g, 0.085 mol) in
anhyd THF (200 mL) was added 2.5 M BuLi in n-hexane (58.5 mL)
at –65 °C under an argon atmosphere. To this soln was added 2-
methoxynicotinic acid (5 g, 0.033 mmol) dissolved in anhyd THF
(100 mL) and the mixture stirred at –65 °C for 1 h. A soln of propa-
nal (5.5 g, 0.095 mol) in anhyd THF (20 mL) was added. When the
addition was complete, the mixture was stirred at r.t. for 3 h. The re-
action was quenched with 2 M HCl soln (100 mL), the organic
phase was separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 150 mL). The combined organic phases were washed
with H2O and dried (NaSO4). The solvent was evaporated under re-
duced pressure, the residue was purified by column chromatogra-
phy (EtOAc–PE, 1:3) to yield 8 (4.72 g, 75%) as a yellow oil.
56.1, 71.4, 114.7, 119.9, 146.4, 154.9, 161.8.
MS (ESI): m/z = 312 [M + H]+.
Anal. Calcd for C16H29NO3Si: C, 61.69; H, 9.38; N, 4.50. Found: C,
61.57; H, 9.41; N, 4.49.
1-{3-[(tert-Butyldimethylsiloxy)methyl]-2-methoxypyridin-4-
yl}propan-1-one (11)
To a soln of 10 (3 g, 9.6 mmol) in CH2Cl2 (50 mL) was added PCC
(4.1 g, 19.2 mmol), and the suspension was stirred at r.t. for 12 h.
After quenched with MeOH (10 mL), the organic phase was filtered
and the filter was concentrated under reduced pressure. Purification
of the residue by column chromatography (silica gel, EtOAc–PE,
1:5) afforded 11 (2.44 g, 82%) as a yellow oil.
1H NMR (400 MHz, CDCl3): d = 0.08 (s, 6 H), 0.90 (s, 9 H), 1.18
(t, J = 7.2 Hz, 3 H), 2.81–2.86 (m, 2 H), 3.98 (s, 3 H), 4.79 (s, 2 H),
6.95 (d, J = 5.2 Hz, 1 H), 8.13 (d, J = 5.2 Hz, 1 H).
IR (KBr): 2966, 2917, 1763, 1611, 1407, 1323, 1044 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.00 (t, J = 7.6 Hz, 3 H), 1.76–1.86
(m, 1 H), 2.04–2.15 (m, 1 H), 4.14 (s, 3 H), 5.36 (dd, J1 = 7.0 Hz,
J2 = 4.6 Hz, 1 H), 6.97 (d, J = 5.2 Hz, 1 H), 8.39 (d, J = 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 8.7, 27.0, 54.3, 81.1, 108.8,
110.4, 152.5, 161.6, 162.8, 167.7.
MS (ESI): m/z = 310 [M + H]+.
4-(But-1-en-2-yl)-3-[(tert-butyldimethylsiloxy)methyl]-2-meth-
oxypyridine (12)
MS (ESI): m/z = 194 [M + H]+.
To a stirred suspension of Zn dust (5.75 g) in CH2Br2 (2.02 mL) and
THF (50 mL) was added TiCl4 (2.3 mL) dropwise at –40 °C over 10
min. The mixture was allowed to warm to 5 °C and stirred for 3 d to
give a thick grey slurry of an active species.
Anal. Calcd for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C,
62.11; H, 5.76; N, 7.23.
1-[3-(Hydroxymethyl)-2-methoxypyridin-4-yl]propan-1-ol (9)
KBH4 (4.2 g, 0.087 mol)was suspended in anhyd THF(30 mL), LiCl
(3.3 g, 0.087 mmol) was added in 1 portion, and then the mixture
was heated at reflux for 3 h. The mixture was cooled to r.t., and a
soln of 8 (5 g, 0.026 mol) in THF (20 mL) was added dropwise. The
mixture was stirred at 35 °C for 12 h, and then quenched with 2 M
HCl (20 mL), and extracted with EtOAc (3 × 25 mL). The com-
bined organic phases were dried (NaSO4); the solvent was evaporat-
ed under reduced pressure, and the residue was purified by column
chromatography (EtOAc–PE, 1:1) to yield 9 (4.63 g, 90%) as a col-
orless oil.
To a stirred soln of 11 (2.5 g, 8.1 mmol) in CH2Cl2 (25mL) was add-
ed the slurry (9.2 mL) prepared above at r.t. The mixture was stirred
at this temperature for 5 h, and then poured into sat. aq NaHCO3
soln (20 mL). The mixture was shaken and filtered, the organic
phase was separated, and the aqueous phase was extracted with
CH2Cl2 (2 × 20 mL). The combined organic phases were dried
(NaSO4) and concentrated under reduced pressure. Purification of
the residue by column chromatography (silica gel, EtOAc–PE,
1:10) afforded 12 (1.99 g, 80%) as a colorless oil.
IR (KBr): 2953, 2929, 2886, 2856, 1595, 1390, 1066 cm–1.
IR (KBr): 2966, 2917, 1763, 1611, 1407, 1323, 1044 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.11 (s, 6 H), 0.91 (s, 9 H), 1.06
(t, J = 7.2 Hz, 3 H), 2. 39–2.44 (m, 2 H), 3.97 (s, 3 H), 4.62 (s, 2 H),
5.06 (s, 1 H), 5.23 (s, 1 H), 6.68 (d, J = 5.2 Hz, 1 H), 8.03 (d, J = 5.2
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = –5.3, 12.3, 18.5, 26.0, 30.4, 53.3,
57.3, 114.0, 117.0, 119.9, 145.3, 148.3, 154.0, 163.0.
1H NMR (400 MHz, CDCl3): d = 0.99 (t, J = 7.2 Hz, 3 H), 1.77–1.82
(m, 2 H), 2.60* (s, 1 H,), 2.70* (s, 1 H), 4.00 (s, 3 H), 4.76 (dd,
J1 = 20 Hz, J2 = 12.4 Hz, 2 H), 4.91 (t, J = 7.2 Hz, 1 H), 7.02 (d,
J = 5.2 Hz, 1 H), 812 (d, J = 5.2 Hz, 1 H). * Exchangeable.
13C NMR (100 MHz, CDCl3): d = 10.2, 30.7, 53.8, 55.6, 71.3, 114.8,
119.5, 146.2, 154.0, 162.3.
MS (ESI): m/z = 308 [M + H]+.
MS (ESI): m/z = 198 [M + H]+.
Anal. Calcd for C17H29NO2Si: C, 66.40; H, 9.51; N, 4.55. Found: C,
66.27; H, 9.54; N, 4.54.
Anal. Calcd for C10H15NO3: C, 60.90; H, 7.67; N, 7.10. Found: C,
60.75; H, 7.69; N, 7.08.
(S)-2-{3-[(tert-Butyldimethylsiloxy)methyl]-2-methoxypyridin-
4-yl}butane-1,2-diol (13)
1-{3-[(tert-Butyldimethylsiloxy)methyl]-2-methoxypyridin-4-
yl}propan-1-ol (10)
(DHQD)2PHAL (0.1 g, 0.13 mmol, 2 mol%), K3Fe(CN)6 (6.4 g,
19.3 mmol), K2CO3 (2.7 g, 19.3 mmol), K2OsO2(OH)4 (10.3 mg,
0.028 mmol, 0.4 mol%), and MsNH2 (0.6 g, 6.5 mmol) were dis-
solved in H2O–t-BuOH (1:1, 40 mL). The mixture was stirred at r.t.
for 30 min and then cooled to 0 °C. Olefin 12 (2 g, 6.5 mmol) was
added to the mixture in 1 portion and it was stirred for 40 h at 0 °C.
The reaction was quenched at this temperature by addition of
Na2SO3 (11 g), and then warmed to r.t. and stirred for an additional
30 min. CH2Cl2 ( 50 mL) and H2O (10 mL) was added, and the
aqueous layer was further extracted with CH2Cl2 (3 × 15 mL). The
combined organic layers were dried (Na2SO4) and concentrated.
The residue was purified by flash column chromatography (silica
gel, EtOAc–PE, 1:2) to afford 13 (1.98 g, 89%) as a colorless oil;
94% ee (chiral HPLC: AD-H column, i-PrOH–hexanes, 1:50).
To a soln of 9 (3 g, 0.015 mol) in CH2Cl2 (30 mL) was added suc-
cessively TBSCl (2.5 g, 16.5 mmol) and imidazole (3.1 g, 0.046
mmol), and the mixture was stirred at r.t. for 1 h. The mixture was
added H2O (20 mL), the organic phase was separated, and the aque-
ous layer was extracted with CH2Cl2 (2 × 20 mL). The combined or-
ganic phases were dried (NaSO4) and concentrated under reduced
pressure. Purification of the residue by column chromatography
(silica gel, EtOAc–PE, 1:5) afforded 10 (4.02 g, 85%) as a colorless
oil.
IR (KBr): 3278, 2955, 2894, 1605, 1389, 1068, 1046, 836 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.10 (s, 3 H), 0.12 (s, 3 H), 0.90
(s, 9 H), 1.01 (t, J = 7.2 Hz, 3 H), 1.81–1.89 (m, 2 H), 3.35* (s, 1 H),
3.95 (s, 3 H), 4.80–4.90 (m, 3 H), 6.97 (d, J = 5.2 Hz, 1 H), 8.10 (d,
J = 5.2 Hz, 1 H). * Exchangeable.
[a]D23 +2.85 (c 1, CHCl3).
Synthesis 2011, No. 24, 4045–4049 © Thieme Stuttgart · New York

4048
L. Zhao et al.
PAPER
IR (CHCl3): 3414, 2952, 2931, 2857, 1594, 1556, 1381, 1059, 838
cm–1.
residue was purified by flash column chromatography (silica gel,
EtOAc–PE, 1:5) to afford 5 (1.56 g, 87%) as a white solid.
1H NMR (400 MHz, CDCl3): d = 0.13 (s, 6 H), 0.79 (t, J = 7.2 Hz,
3 H), 0.92 (s, 9 H), 1.80–1.93 (m, 2 H), 2.40–2.43 (m, 1 H), 3.70–
3.74 (m, 1 H), 3.82–3.86 (m, 1 H), 3.96 (s, 3 H), 4.50–5.09 (m, 2 H),
5.56 (s, 1 H), 6.79 (d, J = 5.2 Hz, 1 H), 8.07 (d, J = 5.2 Hz, 1 H).
* Exchangeable.
13C NMR (100 MHz, CDCl3): d = –5.3, 7.8, 18.2, 25.8, 31.9, 53.7,
56.8, 71.3, 80.0, 116.3, 120.4, 145.9, 154.4, 162.4.
IR (KBr): 1600, 1488, 1357, 1179, 1047, 950, 920, 847, 757, 661,
578, 546 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.44 (s, 3 H), 5.31 (s, 2 H), 7.33
(d, J = 8 Hz, 2 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.78 (t, J = 8 Hz, 1 H),
7.86 (t, J = 8 Hz, 3 H), 8.01 (d, J = 8.8 Hz, 1 H), 8.23 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.7, 68.1, 125.7, 126.8, 127.6,
127.8, 128.1, 128.3, 130.0, 131.2, 132.8, 138.4, 145.3, 147.5, 148.7.
MS (ESI): m/z = 342 [M + H]+.
MS (ESI): m/z = 348 [M + H]+.
Anal. Calcd for C17H31NO4Si: C, 59.79; H, 9.15; N, 4.10. Found: C,
59.63; H, 9.18; N, 4.11.
Anal. Calcd for C17H14ClNO3S: C, 58.70; H, 4.06; N, 4.03. Found:
C, 58.57; H, 4.07; N, 4.02.
(S)-2-{3-[(tert-Butyldimethylsiloxy)methyl]-2-methoxypyridin-
4-yl}-2-hydroxybutanoic Acid (14)
(S)-7-[(2-Chloroquinolin-3-yl)methyl]-4-ethyl-4-hydroxy-1H-
pyrano[3,4-c]pyridine-3,8(4H,7H)-dione (16)
To a mixture of 13 (1 g, 2.93 mmol), TEMPO (62.5 mg, 0.40 mmol,
0.14 equiv), and sodium phosphate buffer (20 mL, pH 6.7) in MeCN
(40 mL) were added, simultaneously, aq NaClO2 [1.7 g, 80% in
H2O (12 mL)] and bleach (5%, 0.8 mL) at r.t. The mixture was
stirred overnight, H2O (5 mL) was added at 0 °C and the pH was ad-
justed to 8.0 with 0.5 M NaOH. The reaction was quenched with aq
Na2SO3 [0.7 g in H2O (15 mL)] and the mixture was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(Na2SO4), concentrated in vacuo and the residue was purified by
column chromatography (silica gel, EtOAc–PE, 1:2) to afford 14
(0.86 g, 83%) as a colorless oil.
To a soln of 6 (100 mg, 0.48 mmol) in anhyd DME (40 mL) at r.t.
was added t-BuOK (69.6 mg, 0.62 mmol). The mixture was stirred
at this temperature for 30 min, and then 5 (233.0 mg, 0.67 mmol)
was added. The mixture was heated at reflux for 12 h. The cooled
mixture was concentrated, and the residue was purified by flash col-
umn chromatography (silica gel, MeOH–CH2Cl2, 1:5) to afford 16
(151 mg, 82%) as a foam.
[a]23D +76.7 (c 1, CHCl3) [Lit.7c [a]23D +79.9 (c 1.15, CHCl3)].
1H NMR (400 MHz, CDCl3): d = 0.99 (t, J = 7.4 Hz, 3 H), 1.76–1.87
(m, 2 H), 3.61 (s, 1 H), 5.21 (d, J = 15.6 Hz, 1 H), 5.35 (d, J = 15.6
Hz, 1 H), 5.46 (d, J = 15.2 Hz, 1 H), 5.63 (d, J = 16.4 Hz, 1 H), 6.61
(d, J = 7.2 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.64 (d, J = 7.2 Hz, 1
H), 7.77 (t, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 8.02 (d, J =
8.0 Hz, 1 H), 8.17 (s, 1 H).
[a]D20 +51.0 (c 1, CHCl3).
IR (KBr): 3457, 2958, 2852, 1743, 1380, 1259, 1101, 1060, 1037,
803 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.12 (s, 3 H), 0.16 (s, 3 H), 0.91
(s, 9 H), 1.03 (t, J = 7.2 Hz, 3 H), 2.16–2.29 (m, 2 H), 3.97 (s, 3 H),
4.82 (d, J = 12.4 Hz, 1 H), 5.13 (d, J = 12.4 Hz, 1 H), 6.91* (br, 1
H), 7.16 (d, J = 5.2 Hz, 1 H), 8.14 (d, J = 5.2 Hz, 1 H). * Exchange-
able.
13C NMR (100 MHz, CDCl3): d = –5.3, 8.0, 18.2, 25.7, 32.8, 54.0,
56.6, 80.0, 116.2, 119.5, 146.6, 151.4, 162.2, 175.5.
MS (ESI): m/z = 385 [M + H]+.
(20S)-Camptothecin (1)
To a mixture of 16 (100 mg, 0.260 mmol), KOAc (64.5 mg, 0.65
mmol), and Pd(PPh3)2(OAc)2 (29 mg, 0.039 mmol), anhyd MeCN
(10 mL) was added under an argon atmosphere. The mixture was
stirred at 100 °C for 12 h. To the cooled mixture was added 25%
NaOH (30 mL). The organic phase was separated and the aqueous
layer was extracted with a mixture MeOH–CHCl3 (1:10, 2 × 20
mL). To the aqueous layer was added 10% HCl portionwise until
pH 2, and it was extracted with MeOH–CHCl3 (1:10, 2 × 10 mL).
The combined organic layers were dried (MgSO4) and concentrat-
ed, the residue was triturated with hot Et2O (3 × 8 mL), and filtered
to afford crude 1 (76.9 mg, 85%) in 96% ee (chiral HPLC, OJ-H col-
umn, 100% MeOH + 0.1% AcOH + 0.1% Et3N). The crude product
was recrystallized (1,4-dioxane) to give 1 (58 mg, 64%) as a yellow
solid; mp 263–265 °C (Lit.1 264–267 °C); 99% ee (chiral HPLC,
OJ-H column, 100% MeOH + 0.1% AcOH + 0.1% Et3N).
20
MS (ESI): m/z = 356 [M + H]+.
Anal. Calcd for C17H29NO5Si: C, 57.43; H, 8.22; N, 3.94. Found: C,
57.30; H, 8.25; N, 3.93.
(S)-4-Ethyl-4-hydroxy-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-
dione (6)
The acid 14 (700 mg, 1.97 mmol) was suspended in 3 M HCl (5
mL). The mixture was heated at reflux for 10 h, then allowed to cool
to r.t., and concentrated in vacuo. Purification of the residue by col-
umn chromatography (silica gel, MeOH–CH2Cl2, 1:5) afforded 6
(362 mg, 88%) as a white solid; mp 223.3–225.6 °C (Lit.7c 222–225
°C); 95% ee (chiral HPLC, OD-H column, EtOH–hexanes, 1:9).
[a]D20 +121.0 (c 0.2, CHCl3–MeOH, 4:1) [Lit.7c [a]D23 +117 (c 0.2,
CHCl3–MeOH, 4:1)].
IR (KBr): 3241, 3193, 2978, 1752, 1644, 1618, 1157 cm–1.
[a]D +42.5 (c 0.2, CHCl3–MeOH, 4:1) [Lit.11 [a]20 +41.6 (c
D
0.201, CHCl3–MeOH, 4:1)].
IR (KBr): 3488, 3298, 2965, 1740, 1652, 1609, 1558, 1386, 1231,
1160, 872 cm–1.
1H NMR (400 MHz, DMSO): d = 0.88 (t, J = 7.2 Hz, 3 H), 1.83–
1.90 (m, 2 H), 5.28 (s, 2 H), 5.42 (s, 2 H), 7.34 (s, 1 H), 7.70 (t,
J = 7.6 Hz, 1 H), 7.86 (t, J = 7.2 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H),
8.15 (d, J = 8.4 Hz, 1 H), 8.68 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 8.3, 30.8, 50.7, 65.8, 72.9,
97.2, 119.6, 128.2, 128.4, 129.0, 129.5, 130.3, 130.9, 132.1, 146.0,
148.4, 150.5, 153.1, 157.3, 173.0.
1H NMR (400 MHz, DMSO-d6): d = 0.79 (t, J = 7.2 Hz, 3 H), 1.70–
1.77 (m, 2 H), 5.21 (s, 2 H), 6.23 (s, 1 H), 6.33 (d, J = 7.2 Hz, 1 H),
7.41 (d, J = 6.8 Hz, 1 H), 11.81 (s, 1 H).
MS (ESI): m/z = 210 [M + H]+.
(2-Chloroquinolin-3-yl)methyl 4-Methylbenzenesulfonate (5)
To a soln of (2-chloroquinolin-3-yl)methanol (1 g, 5.16 mmol) and
Et3N (2.6 g, 25.82 mmol) in THF (30 mL) was added TsCl (1.97 g,
10.32 mmol) at r.t. The mixture was stirred overnight and then it
was filtered, the filtrate was dried (Na2SO4) and concentrated. The
MS (ESI): m/z = 349 [M + H]+.
All these data are identical to reported literature values.10
Synthesis 2011, No. 24, 4045–4049 © Thieme Stuttgart · New York

PAPER
A Total Synthesis of (20S)-Camptothecin
4049
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Synthesis 2011, No. 24, 4045–4049 © Thieme Stuttgart · New York