Visible-Light-Induced Radical Cascade Cyclization: Synthesis of (20S)-Camptothecin, SN-38 and Irinotecan

Article abstract of DOI:10.1002/cjoc.201800358

(20S)-Camptothecin, irinotecan and SN-38 were successfully synthesized by a photocatalyzed radical cascade cyclization from an N-propargyl iodopyridinone and an arylisonitrile under visible light with a ruthenium catalyst. This synthetic method provided a useful entry into composing camptothecin family of antitumor agents in good yields under mild reaction conditions without the use of heavy metal reagents.

Full text of DOI:10.1002/cjoc.201800358

Visible-Light-Induced Radical Cascade Cyclization: Synthesis of
†
(20S)-Camptothecin, SN-38 and Irinotecan
a
a
a
a
,b
,a
Yao Yuan, Wuheng Dong, Xiaoshuang Gao, Xiaomin Xie, Dennis P. Curran,* and Zhaoguo Zhang*
ABSTRACT (20S)-Camptothecin, irinotecan and SN-38 were successfully synthesized by a photocatalyzed radical cascade cyclization from an N-propargyl
iodopyridinone and an arylisonitrile under visible light with a ruthenium catalyst. This synthetic method provided a useful entry into composing
camptothecin family of antitumor agents in good yields under mild reaction conditions without the use of heavy metal reagents.
KEYWORDS visible light, camptothecin, irinotecan, SN-38, arylisonitrile
Introduction
was constructed through a radical cascade cyclization process with
isocyanoarenes (A-ring) and N-propargylated
D/E-pyridone/lactone fragment (Figure 2, b) . Various functional
groups could be introduced into camptothecin by using various
substituted isocyanines to construct a library of bioactive
camptothecin derivatives. A different formation of the B- and
C-rings was reported by Yao using an intramolecular
a
9
(20S)-Camptothecin (CPT, Figure 1), a natural quinoline
1
alkaloid isolated from the Chinese plant Camptotheca acuminate ,
was one of the most important lead compounds in anticancer
drugs. It can bind to topoisomerase I and inhibit tumor growth,
which lead to DNA damage and subsequent cell death . However,
the clinical development of CPT was limited by its dose-limiting
2
aza-Diels-Alder reaction and an eliminative aromatization (Figure
3
toxicities and poor water solubility . Therefore, both academic
10
2
, c) . However, the use of multiple air-sensitive organometallic
community and pharmaceutical industry have devoted their
efforts to make various camptothecin derivatives that can be
applied to clinical treatment since CPT was discovered. One of the
most successful products is irinotecan (Figure 1), a first-line drug
for advanced colorectal cancer, which is also effective for lung
cancer, breast cancer and pancreatic cancer. SN-38 (Figure 1) is
the active metabolite of irinotecan and a topoisomerase I
inhibitor.
reagents in the substrate preparations limited the large-scale
synthesis and their potential applications in pharmaceutical
industry. Later, Yao reported
a further modification by
4
constructing the D/E-ring through intramolecular oxa-Diels-Alder
reaction and the A/B-ring through an amine-catalyzed cascade
5
11
reaction (Figure 2, d) . Alternatively, Chen and coworkers
employed
classical
Friedlander
reaction
between
2
-aminobenzaldehyde (A-ring) with the C/D/E-ring framework as
1
2
the key step for the total synthesis of camptothecin (Figure 2, e) .
Figure 1 Camptothecin, SN-38 and irinotecan.
Figure 2 Selected strategies for the synthesis of camptothecin.
However, extracting camptothecin from the medical plants is
unsustainable because it may cause a shortage of natural
resources and subsequent environmental problems. Therefore,
developing economic and efficient method for the synthesis of
CPT and its derivatives is of great importance. Since the first total
6
synthesis by Stork and Schultz in 1971 , chemists have made
remarkable progress in devising different synthetic strategies for
7
-12
camptothecin . Up to now, the shortest asymmetric synthesis of
Recently, our laboratory reported
constructing the ABCD ring backbone of camptothecin through a
visible-light-induced radical cascade cyclization process (Scheme 1,
II) . It was an improvement based on Curran’s first report of the
cascade cyclization between isocyanoarenes and
N-(alkyl-2-yn-1-yl)pyridin-2(1H)-ones (Scheme 1, I) . This photo
catalytic reaction proceeded under mild conditions without the
use of tin reagents and was compatible with versatile functional
a new strategy for
8
(
20S)-Camptothecin was reported by Comins and coworkers ,
involved
-chloro-3-(iodomethyl)quinoline
which
the
connection
between
the
1
3
2
(A/B-fragments)
and
(
S)-4-ethyl-4-hydroxy-1,7-dihydro-3H-pyrano[3,4-c]pyridine-3,8(4
1
4
H)-dione (D/E-fragments) via an N-alkylation and an
intramolecular Heck ring closure reaction (Figure 2, a). Curran
developed a strategy in which the B/C-pyrrolopyridine segment
a
b
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania,
Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800
Dongchuan Road, Shanghai 200240, China
E-mail: zhaoguo@sjtu.edu.cn
PA 15260 (USA)
E-mail: curran@pitt.edu
Dedicated to Professor Xiyan Lu on the occasion of his 90th birthday.
†
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.2001800358
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groups in good yields. Herein we report the synthesis of
camptothecin, irinotecan and SN-38 under our photocatalytic
conditions (Scheme 1, III).
Table 1 Model study for synthesis of SN-38, irinotecan and other
derivatives.
Scheme 1 Cascade cyclization of propargyl pyridone and isocyanoarene.
Results and Discussion
The most visual pathway for synthesis of SN-38 was a
photoreaction of 4-isocyanophenol (Table 1, 2c) and 1c. However,
we had not explored the reaction with 4-isocyanophenol as the
substrate in our previous work. In order to find a good condition
for
the
synthesis
of
SN-38,
we
used
6-iodo-1-(pent-2-yn-1-yl)pyridin-2(1H)-one (Table 1, 1b) as a
model substrate to test the reaction conditions for the synthesis
of SN-38. When 1b and 2c were subjected to the photoreaction
conditions,
1
3
the
2-ethyl-2-hydroxyindolizino[1,2-b]quinolin-9(11H)-one (Table 1,
c) was isolated in only 35% yield. This could presumably be
corresponding
product
attributed to the formation of insoluble potassium phenoxide
from 2c and K CO . Gratifyingly, the yield was improved to 54%
when K CO was replaced by NEt . As 2c was prepared from
2
3
2
3
3
tert-butyl(4-isocyanophenoxy)dimethylsilane (Table 1, 2d), we
wondered if we could first compose the TBSO-substituted product
and then remove the tert-butyldimethylsilyl group. To our
surprise, when 2d was subjected to the standard condition, 3c
was directly generated in 84% yield. Besides, we tried the
photoreaction with 1b and 2e under the standard conditions and
the corresponding product 3e was obtained in 68% yield, which
proved the feasibility of the direct synthesis of irinotecan by this
transformation. Furthermore, we explored other para-substituted
isocyanoarenes, such as methyl, halogen and cyano, which could
be well tolerated in this reaction to afford the corresponding
products in moderate to good yields (Table 1, 3f-3j).
Standard conditions: 1b (57.4 mg, 0.2 mmol), isonitriles (0.4 mmol), K
27.6 mg, 0.2 mmol), Ru(bpy) (PF (3.5 mg, 2 mol %), NEt (10.1 mg, 50
mol %), CH CN (3 mL), irradiation with a 7 W blue LED under nitrogen
atmosphere at rt for 24 h. a: standard conditions. b: Use 1.5 equiv. NEt
without K CO . c: R= 1,4'-bipiperidine
2 3
CO
To show the potential application of the current method, we
next embarked on the synthesis of biologically significant
anticancer drugs such as camptothecin, SN38, and irinotecan. The
challenge for the synthesis of CPT (Scheme 1, 3a) lays in the
(
3
6
)
2
3
3
3
2
3
construction
S)-4-ethyl-4-hydroxy-6-iodo-7-(prop-2-yn-1-yl)-1,7-dihydro-3H-py
rano[3,4-c]pyridine-3,8(4H)-diono (Scheme 1, 1a). We chose the
of
the
(
With 1a and isocyanobenzene in hand, we started to examine
the feasibility of the camptothecin synthesis by photoreaction. An
acetonitrile solution of 1a (37.3 mg, 0.1 mmol) and 2a (20.8 mg,
9
b
route reported by Curran , in which 2-bromo-6-methoxypyridine
was used as starting material to acquire 1a by 8 steps. Thankfully,
Curran’s
group
provided
us
with
the
0
.2 mmol), together with
Ru(bpy) (PF (1.7 mg, 0.002 mmol) and NEt
irradiated by a 7 W blue LED under nitrogen atmosphere at rt for
4 h. To our delight, 3a was isolated in 73% yield, a better result
than that of the previous radical cascade cyclization was
K
2
CO
3
(13.8 mg, 0.1 mmol),
(
3
S)-4-ethyl-4-hydroxy-6-iodo-1,7-dihydro-3H-pyrano[3,4-c]pyridin-
,8(4H)-dione (Scheme 2, 1)， which was then N-propargylated to
3
6
)
2
3
(5.1 mg, 0.05 mmol)
give 1a in 73% yield.
2
9
b
obtained .
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(
S)-4-Ethyl-4-hydroxy-9-methoxy-1,12-dihydro-14H-pyrano[3',4':6
Scheme 3 Synthesis of SN-38 and irinotecan.
,7]indolizino[1,2-b]quinolino-3,14(4H)-dione (Scheme 2, 3b) was
also obtained in 85% yield from the photoreaction, which could
be easily transformed into 10-hydroxycamptothecin.
Scheme 2 Synthesis of camptothecin and 10-methoxycamptothecin.
Encouraged by the successful assembly of camptothecin, we
switched our attention to the synthesis of SN-38 and irinotecan.
As expected from the results of the model reaction, SN-38 (3k)
was successfully obtained through the visible-light-induced radical
cascade cyclization by 1c and 2d in 63% yield (Scheme 3, I). From
1
3
the success of our previous work , a two-step synthesis of SN-38
with 1c and 2b is also feasible. Firstly, a photoreaction of 1c and
2
(
'
b
composed
S)-4,11-diethyl-4-hydroxy-9-methoxy-1,12-dihydro-14H-pyrano[3
,4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (3l) in 82% yield,
and then demethylation of 3l was completed with 40% HBr in a
o
sealed tube at 110 C to afford SN-38 in 86% yield (Scheme 3, II).
The overall efficiency of two steps was parallel to the pathway of
the direct photoreaction by 1c and 2d while 2b was more
convenient to be prepared.
The final work was the synthesis of irinotecan. When 1c and
e were subjected to the radical cascade cyclization to afford the
2
irinotecan (3m), however, only 29% yield was obtained (Scheme 3,
III). It is not clear whether the intrinsic instability of irinotecan in
solution under visible light impair the efficiency of the
photoreaction. Then we turned to the synthesis of it from SN-38.
To
our
delight,
SN-38
reacted
with
2 3
Standard conditions: 1c (40.1 mg, 0.1 mmol), isonitriles (0.2 mmol), K CO (13.8
4
-piperidinopiperidinecarbamyl chloride in pyridine and DCM to
mg, 0.1 mmol), Ru(bpy)
CH CN (1.5 mL), irradiation with a 7 W blue LED under nitrogen atmosphere at
3
3 6 2 3
(PF ) (1.8 mg, 2 mol %), NEt (5.1 mg, 50 mol %),
give irinotecan in 81% yield (Scheme 3, IV).
rt for 24 h.
Conclusions
In conclusion, we have successfully synthesized
20S)-camptothecin, irinotecan, and SN-38 through
(
a
visible-light-induced radical cascade cyclization with good yields
under mild reaction conditions. The omission of organometallic
reagents rendered a more efficient and sustainable method for
the preparation of CPT alkaloids.
Experimental
General Information: Unless otherwise noted, all reactions
were carried out under an atmosphere of nitrogen using standard
Schlenk techniques. Materials were purchased from commercial
suppliers and used without further purification. Anhydrous DMF
3
and CH CN were freshly distilled from calcium hydride. DME and
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1
13
13
THF were dried with sodium. H NMR and C NMR spectra were
recorded on a 400 MHz, 500 MHz or a 600 MHz spectrometers.
1H). C NMR (101 MHz, CDCl
3
) δ 159.5, 157.2, 128.1, 118.9,
116.4.
1
The chemical shifts for H NMR were recorded in ppm downfield
from tetramethylsilane (TMS) with the solvent resonance as the
internal standard. The chemical shifts for C NMR were recorded
in ppm downfield using the central peak of deuterochloroform
77.00 ppm) as the internal standard. Coupling constants (J) are
reported in Hz and refer to apparent peak multiplications. HRMS
were obtained on an ESI-TOF mass spectrometer. Flash column
chromatography was performed on silica gel (300-400 mesh).
A General procedure for the preparation of N-alkylation of
Tert-butyl(4-isocyanophenoxy)dimethylsilane (2d): The
15
procedure was adopted from the literature . Colorless liquid, 0.6
1
1
3
g, 48% yield. H NMR (400 MHz, CDCl
6.82 (d, J = 8.8 Hz, 2H), 0.99 (s, 9H), 0.22 (s, 6H). C NMR (101
MHz, CDCl ) δ 163.1, 156.3, 127.6, 120.7, 120.0, 25.5, 18.1, -4.6.
3
) δ 7.27 (d, J = 8.0 Hz, 2H),
13
(
3
+
HRMS-ESI (m/z): Calculated for C13
Found: 234.1304.
4-Isocyanophenyl [1,4'-bipiperidine]-1'-carboxylate (2e):
The procedure was adopted from the literature . White solid,
H20NOSi (M + H) : 234.1314,
9
b
o
1
substituted
2-pyridones;
355.0 mg, 58% yield. M.P.: 112.9-114.0 C. H NMR (400 MHz,
CDCl ) δ 7.39 – 7.34 (m, 2H), 7.16 – 7.12 (m, 2H), 4.29 (t, J = 13.6
Hz, 2H), 2.98 (t, J = 12.4 Hz, 1H), 2.84 (t, J = 12.0 Hz, 1H), 2.57 –
(
S)-4-Ethyl-4-hydroxy-6-iodo-7-(prop-2-yn-1-yl)-1,7-dihydro-3H-p
yrano[3,4-c]pyridino-3,8(4H)-dione
3
9b
(1a): To
a
solution of
1
3
(
S)-4-ethyl-4-hydroxy-6-iodo-1,7-dihydro-3H-pyrano[3,4-c]pyridin
o-3,8(4H)-dione (100.0 mg, 0.3 mmol) in DME (1.5 mL) and DMF
0.5 mL) was slowly added NaH (14.4 mg, 0.4 mmol, 60%) at 0 °C
under a nitrogen atmosphere and stirred for 10 min. Then LiBr
52.1 mg, 0.6 mmol) was added to the mixture and stirred for 15
min at room temperature. And then 3-bromoprop-1-yne (71.4 mg,
.6 mmol) was added to the mixture and the whole mixture was
2.42 (m, 5H), 1.89 (d, J = 12.8 Hz, 2H), 1.63 – 1.43 (m, 8H).
NMR (101 MHz, CDCl ) δ 164.2, 152.7, 151.8, 127.4, 123.5, 122.9,
62.3, 50.3, 44.4, 44.2, 28.3, 27.7, 26.5, 24.8.
1-Isocyano-4-methylbenzene (2f): The procedure was
adopted from the literature . Yellow liquid, 2.5 g (9.5 mm Hg, 69
C). 70% yield. H NMR (400 MHz, CDCl
7.19 (d, J = 8.4 Hz, 2H), 2.39 (s, 3H). C NMR (101 MHz, CDCl ) δ
3
C
3
(
1
3
(
o
1
3
) δ 7.27 (d, J = 8.0 Hz, 2H),
1
3
0
warmed to 65 °C for 2 h. The reaction was quenched with a
saturated aqueous solution of NaCl (10 mL) and extracted by
163.3, 139.5, 129.8, 125.9, 123.9, 123.8, 123.7, 21.1.
1-Chloro-4-isocyanobenzene (2g): The procedure was
1
3
1
AcOEt (3×10 mL). The organic phase was dried with Na
2
SO
4
and
adopted from the literature . White solid, 5.0 g, 72% yield. H
NMR (400 MHz, CDCl ) δ 7.40 – 7.35 (m, 2H), 7.32 (d, J = 8.8 Hz,
concentrated in vacuum. The residue was purified by silica gel
3
1
3
column chromatography (PE/EA = 20/1) to afford 1a (81.3 mg,
2H). C NMR (101 MHz, CDCl
3
) δ 165.7, 135.5, 129.8, 127.7, 125.3,
2
0
9b
20
7
+
CDCl
3
2
1
3
3%) as a white solid. [ɑ] = + 59.3 (c = 0.11, CHCl
3
). [ref. [ɑ]D
)]. M.P.: 140.2-141.3 C. H NMR (400 MHz,
) δ 7.18 (s, 1H), 5.49 (d, J = 16.8 Hz, 1H), 5.17 – 5.05 (m, 3H),
.78 (s, 1H), 2.37 (t, J = 2.4 Hz, 1H), 1.77 (ddt, J = 16.4, 14.8, 7.2 Hz, NMR (400 MHz, CDCl
=
125.1, 125.0.
D
o
1
59.1, (c = 1, CHCl
3
1-Bromo-4-isocyanobenzene (2h): The procedure was
13 1
3
adopted from the literature . White solid, 4.1 g, 85% yield. H
) δ 7.58 – 7.53 (m, 2H), 7.30 – 7.25 (m, 2H).
C NMR (101 MHz, CDCl ) δ 165.9, 132.8, 127.9, 125.6, 125.4,
123.5.
4-Isocyanobenzonitrile (2i): The procedure was adopted
3
1
3
13
H), 0.96 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl
58.1, 149.0, 118.4, 116.8, 100.1, 76.9, 73.7, 71. 9, 66.3, 44.2,
1.7, 7.8.
3
) δ 173.3,
3
1
3
1
6
-Iodo-1-(pent-2-yn-1-yl)pyridin-2(1H)-one
(1b):
The
from the literature . White solid, 0.5 g, 35% yield. H NMR (400
1
3
13
procedure was adopted from the literature . White solid, 1.1 g,
9% yield. M.P.: 146.0-147.2 C. H NMR (400 MHz, CDCl
3
MHz, CDCl ) δ 7.75 – 7.71 (m, 2H), 7.53 – 7.48 (m, 2H). C NMR
o
1
7
3
) δ 6.92
3
(101 MHz, CDCl ) δ 169.0, 133.6, 129.9, 129.7, 127.3, 117.3,
(
t, J = 7.2 Hz, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.48 (d, J = 9.2 Hz, 1H),
113.5.
5
.01 (s, 2H), 2.15 (dd, J = 14.4, 7.2 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H).
5-Isocyanobenzo[d][1,3]dioxole (2j): The procedure was
13 1
1
3
C NMR (101 MHz, CDCl
3
) δ 162.1, 140.0, 120.1, 120.0, 100.1,
adopted from the literature . White solid, 1.7 g, 83% yield. H
NMR (400 MHz, CDCl ) δ 6.90 (dd, J = 8.2, 1.6 Hz, 1H), 6.82 (d, J =
1.6 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.03 (s, 2H). C NMR (101
MHz, CDCl ) δ 162.7, 148.5, 148.1, 120.9, 120.4, 120.3, 120.1,
8
C
6.8, 73.0, 44.6, 13.6, 12.6. HRMS-ESI (m/z): Calculated for
3
+
13
10
H
11INO (M + H) : 287.9885, Found: 287.9891.
(
S)-4-Ethyl-4-hydroxy-6-iodo-7-(pent-2-yn-1-yl)-1,7-dihydro-
3
9
b
3
H-pyrano[3,4-c]pyridino-3,8(4H)-dione
(1c): Use of the
108.5, 107.3, 102.3.
procedure described for the synthesis of 1a with
S)-4-ethyl-4-hydroxy-6-iodo-1,7-dihydro-3H-pyrano[3,4-c]pyridin
o-3,8(4H)-dione (200.5 mg, 0.6 mmol) and 1-bromopent-2-yne
176.4 mg, 1.2 mmol) provided a yellow solid (178.0 mg, 78%)
A general procedure for the visible-light-induced radical
cascade cyclization; (20S)-camptothecin (3a): An oven dried
Schlenk tube equipped with a stirrer bar which was evacuated
9
b
(
(
and
backfilled
with
nitrogen
was
added
20
after flash chromatography (DCM/EA = 20/1). [ɑ] = + 51.8 (c =
(S)-4-ethyl-4-hydroxy-6-iodo-7-(prop-2-yn-1-yl)-1,7-dihydro-3H-py
rano[3,4-c]pyridino-3,8(4H)-dione (1a) (37.3 mg, 0.1 mmol),
D
o
1
0
.11, CHCl
3 3
). M.P.: 77.0-78.5 C. H NMR (400 MHz, CDCl ) δ 7.17
(
s, 1H), 5.51 (d, J = 16.4 Hz, 1H), 5.16 – 4.98 (m, 3H), 3.61 (s, 1H),
isocyanobenzene (26.8 mg, 0.2 mmol), K
NEt (5.1 mg, 0.05 mmol) and Ru(bpy) (PF
Then 1.5 mL of CH CN was added into the reaction tube via a
58.2, 148.7, 118.3, 116.6, 100.5, 87.5, 72.5, 71.9, 66.5, 44.7, 31.7, syringe. The reaction mixture was degassed by the
2
CO
3
(13.8 mg, 0.1 mmol),
2
3
1
1
.19 (qt, J = 7.6, 2.4 Hz, 2H), 1.86 – 1.69 (m, 2H), 1.13 (t, J = 7.6 Hz,
3
3
6 2
) (1.7 mg, 0.002 mmol).
1
3
H), 0.97 (t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl
3
) δ 173.4,
3
3.6, 12.6, 7.8.
Isocyanobenzene (2a): The procedure was adopted from the
freeze-pump-thaw method and then irradiated with a 7 W blue
LED (distance app. 5 cm) for 24 h. After the completion of the
reaction, the mixture was concentrated in vacuum and purified by
flash column chromatography on silica gel (DCM/MeOH = 100/1)
1
3
o
1
literature . Green liquid. 2.0 g (12 mm Hg, 56 C), 57% yield. H
1
3
NMR (400 MHz, CDCl
CDCl ) δ 164.1, 129.21, 129.16, 126.3, 126.1.
-Isocyano-4-methoxybenzene (2b): The procedure was
adopted from the literature . Green liquid, 15.6 g, 97% yield. H
NMR (400 MHz, CDCl ) δ 7.31 (d, J = 8.8 Hz, 2H), 6.89 – 6.84 (m,
2
1
3
) δ 7.41 – 7.32 (m, 5H). C NMR (101 MHz,
20
3
to give a white solid (25.4 mg, 73%). [ɑ] = + 39.2 (c = 0.10, CHCl
D
3
:
9b
20
1
MeOH = 4:1). [ref. [ɑ] = + 39.9, (c = 0.2, CHCl
3
/MeOH = 4/1)].
D
1
3
1
o
1
3 3
M.P.: 256.3-257.6 C. H NMR (600 MHz, CDCl : CD OD = 5: 1) δ
3
8.35 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.72 (t,
J = 7.2 Hz, 1H), 7.61 (s, 1H), 7.56 (t, J = 7.2 Hz, 1H), 5.54 (d, J = 16.2
Hz, 1H), 5.18 (t, J = 9.0 Hz, 3H), 1.81 (dp, J = 16.8, 7.2 Hz, 2H), 0.90
1
3
3
H), 3.82 (s, 3H). C NMR (101 MHz, CDCl ) δ 162.6, 159.9, 127.7,
19.6, 119.4, 119.3, 114.6, 55.6.
1
3
4
-Isocyanophenol (2c): The procedure was adopted from the
(t, J = 7.2 Hz, 3H). C NMR (151 MHz, CDCl
3
: CD
3
OD = 5: 1) δ 173.6,
1
5
1
literature . White solid, 150.0 mg, 98% yield. H NMR (400 MHz,
CDCl
157.8, 152.1, 151.1, 148.5, 145.9, 131.7, 130.8, 129.1, 128.6,
128.24, 128.21, 128.1, 118.9, 98.8, 72.8, 65.8, 50.1, 31.3, 7.6.
3
) δ 7.27 (d, J = 7.2 Hz, 2H), 6.83 (d, J = 7.6 Hz, 2H), 5.86 (s,
This article is protected by copyright. All rights reserved.

9
b
(
20S)-10-Methoxycamptothecin (3b): Use of the procedure
described for the synthesis of 3a with 1a (37.3 mg, 0.1 mmol) and
b (26.8 mg, 0.2 mmol) afforded a yellow solid (32.2 mg, 85%)
2-Bromo-12-ethylindolizino[1,2-b]quinolin-9(11H)-one (3h):
Use of the procedure described for the synthesis of 3a with 1b
(57.4 mg, 0.2 mmol) and 2h (72.8 mg, 0.4 mmol) afforded a
yellow solid (53.0 mg, 78%) after flash chromatography
2
20
after flash chromatography (DCM/MeOH = 100/1). [ɑ] = + 35.3
D
9
b
20
o
1
(
c = 0.12, CHCl
3
: MeOH = 4:1). [ref. [ɑ] = + 32.0, (c = 0.74,
(DCM/MeOH = 100/1). M.P.: 269.4-270.3 C. H NMR (400 MHz,
CDCl : CD OD = 5: 1) δ 8.08 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.70
D
o
1
CHCl
CDCl
3
/MeOH = 4/1)]. M.P.: 250.3-250.9 C. H NMR (600 MHz,
: CD OD = 5: 1) δ 8.17 (s, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.51 (s,
H), 7.33 (dd, J = 9.6, 3.0 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 5.51 (d, J
15.6 Hz, 1H), 5.15 (d, J = 16.2 Hz, 1H), 5.11 (s, 2H), 3.84 (s, 3H),
.79 (hept, J = 7.2 Hz, 2H), 0.89 (t, J = 7.8 Hz, 3H). C NMR (151
: CD OD = 5: 1) δ 173.7, 159.0, 157.8, 151.1, 149.6,
46.2, 144.6, 130.3, 129.9, 129.7, 129.1, 123.9, 118.2, 105.4, 98.1,
2.8, 65.8, 55.6, 50.1,31.3, 7.5.
2-Ethyl-2-hydroxyindolizino[1,2-b]quinolin-9(11H)-one (3c):
Use of the procedure described for the synthesis of 3a with 1b
57.4 mg, 0.2 mmol) and 2d (93.4 mg, 0.4 mmol) afforded a
yellow solid (46.9 mg, 84%) after flash chromatography
3
3
3
3
(dd, J = 8.8, 2.0 Hz, 1H), 7.61 (dd, J = 9.2, 7.2 Hz, 1H), 7.20 (d, J =
6.8 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.08 (s, 2H), 3.01 (q, J = 7.6 Hz,
1
=
1
1
3
3 3
2H), 1.27 (t, J = 7.6 Hz, 3H). C NMR (126 MHz, CDCl : CD OD = 5:
1
3
1) δ 161.9, 152.2, 147.5, 146.1, 145.1, 141.0, 133.5, 131.4, 127.9,
MHz, CDCl
3
3
127.5, 125.9, 121.9, 120.0, 102.0, 49.3, 22.8, 13.8. HRMS-ESI
+
1
7
(m/z): Calculated for C17
341.0293.
H14BrN
2
O (M + H) : 341.0290, Found:
1
12-Ethyl-9-oxo-9,11-dihydroindolizino[1,2-b]quinoline-2-car
bonitrile (3i): Use of the procedure described for the synthesis of
3a with 1b (57.4 mg, 0.2 mmol) and 2i (51.3 mg, 0.4 mmol)
afforded a yellow solid (22.0 mg, 39%) after flash chromatography
(
o
1
o
1
(
DCM/MeOH = 100/1). M.P.: > 300 C. H NMR (600 MHz, CDCl
CD OD = 5: 1) δ 7.90 (d, J = 9.0 Hz, 1H), 7.62 (dd, J = 9.0, 7.2 Hz,
3
:
(DCM/MeOH = 100/1). M.P.: 295.3-297.0 C. H NMR (400 MHz,
CDCl : CD OD = 5: 1) δ 8.44 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.84 (d,
3
3
3
1
1
1
1
1
H), 7.29 (dd, J = 9.0, 2.4 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J = 7.2 Hz,
H), 6.57 (d, J = 9.0 Hz, 1H), 5.07 (s, 2H), 2.98 (q, J = 7.8 Hz, 2H),
J = 8.4 Hz, 1H), 7.71 – 7.62 (m, 1H), 7.32 (d, J = 7.2 Hz, 1H), 6.69 (d,
J = 9.2 Hz, 1H), 5.20 (s, 2H), 3.15 (q, J = 8.0 Hz, 2H), 1.33 (t, J = 8.0
1
3
13
.25 (t, J = 7.2 Hz, 3H). C NMR (151 MHz, CDCl
3
: CD
3
OD = 5: 1) δ
Hz, 3H). C NMR (126 MHz, CDCl
3
: CD
3
OD = 5: 1) δ 161.9, 154.9,
62.2, 156.7, 148.9, 146.9, 144.1, 144.0, 141.4, 130.9, 128.6,
150.2, 146.9, 145.7, 141.1, 131.6, 130.6, 130.1, 128.4, 126.4,
26.8, 122.7, 118.8, 105.1, 101.4, 49.4, 22.9, 13.3. HRMS-ESI
121.0, 118.4, 110.9, 102.8, 49.3, 23.0, 14.1. HRMS-ESI (m/z):
+
+
(m/z): Calculated for C17
H
15
N
O
2 2
(M + H) : 279.1134, Found:
Calculated for C18
H
14
N
3
O (M + H) : 288.1137, Found: 288.1135.
2
79.1123.
2-Ethyl-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-2-yl
1,4'-bipiperidine]-1'-carboxylate (3e): Use of the procedure
described for the synthesis of 3a with 1b (57.4 mg, 0.2 mmol) and
e (125.4 mg, 0.4 mmol) afforded a white solid (64.5 mg, 68%)
after flash chromatography (DCM/MeOH 100/1). M.P.:
OD = 5: 1) δ 8.05 (d,
J = 9.0 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.63 (dd, J = 9.0, 6.6 Hz, 1H), (s, 2H), 2.98 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.8 Hz, 3H). C NMR
.46 (dd, J = 9.0, 2.4 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 6.6 (d, J = 7.2 (151 MHz, CDCl : CD OD = 5: 1) δ 162.2, 151.5, 149.6, 149.4,
Hz, 1H), 5.13 (s, 2H), 4.29 (dd, J = 83.4, 13.8 Hz, 2H), 3.05 (q, J =
.8 Hz, 2H), 2.95 (t, J = 13.2 Hz, 1H), 2.78 (t, J = 12.6 Hz, 1H), 2.57
s, 5H), 1.91 (t, J = 13.8 Hz, 2H), 1.62 – 1.48 (m, 6H), 1.39 (s, 2H),
12-Ethyl-[1,3]dioxolo[4,5-g]indolizino[1,2-b]quinolin-9(11H)
-one (3j): Use of the procedure described for the synthesis of 3a
with 1b (57.4 mg, 0.2 mmol) and 2j (58.9 mg, 0.4 mmol) afforded
a yellow solid (26.2 mg, 43%) after flash chromatography
1
[
o
1
2
(DCM/MeOH = 100/1). M.P.: > 300 C. H NMR (600 MHz, CDCl
CD OD = 5: 1) δ 7.62 (dd, J = 9.0, 7.2 Hz, 1H), 7.32 (s, 1H), 7.24 (s,
1H), 7.22 – 7.18 (m, 1H), 6.58 (d, J = 9.6 Hz, 1H), 6.07 (s, 2H), 5.06
3
:
=
3
o
1
2
3 3
16.0-217.8 C. H NMR (600 MHz, CDCl : CD
1
3
7
3
3
147.6, 146.9, 144.7, 141.3, 125.9, 124.4, 118.8, 105.6, 102.4,
7
(
1
1
1
4
101.3, 99.0, 49.4, 23.3, 13.6. HRMS-ESI (m/z): Calculated for
+
C
18
H
15
N
2
O
3
(M + H) : 307.1083, Found: 307.1086.
1
3
.27 (t, J = 7.8 Hz, 3H). C NMR (151 MHz, CDCl
62.1, 153.2, 151.7, 150.1, 146.7, 146.4, 145.8, 141.3, 130.9,
27.4, 127.1, 125.9, 119.7, 114.6, 102.0, 62.5, 50.0, 49.4, 44.1,
3
: CD
3
OD = 5: 1) δ
13-Ethyl-[1,3]dioxolo[4,5-f]indolizino[1,2-b]quinolin-10(12H
)-one (3j’): Use of the procedure described for the synthesis of 3a
with 1b (57.4 mg, 0.2 mmol) and 2j (58.9 mg, 0.4 mmol) afforded
3.7, 27.5, 26.8, 26.7, 25.1, 23.8, 23.0, 13.7. HRMS-ESI (m/z):
a
luminous yellow solid (14.2 mg, 23%) after flash
+
o 1
Calculated for C28
H
33
N
4
O
3
(M + H) : 473.2553, Found: 473.2541.
chromatography (DCM/MeOH = 100/1). M.P.: > 300 C. H NMR
(600 MHz, CDCl : CD OD = 5: 1) δ 7.84 (d, J = 8.4 Hz, 1H), 7.66 (t, J
1
2-Ethyl-2-methylindolizino[1,2-b]quinolin-9(11H)-one (3f):
Use of the procedure described for the synthesis of 3a with 1b
57.4 mg, 0.2 mmol) and 2f (46.9 mg, 0.4 mmol) afforded a white
solid (51.9 mg, 94%) after flash chromatography (DCM/MeOH =
3
3
= 7.8 Hz, 1H), 7.46 (d, J = 6.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.66
(d, J = 9.0 Hz, 1H), 6.17 (s, 2H), 5.16 (s, 2H), 3.18 (q, J = 7.8 Hz, 2H),
(
1
3
3 3
1.27 (t, J = 7.8 Hz, 3H). C NMR (151 MHz, CDCl : CD OD = 5: 1) δ
162.0, 149.4, 145.9, 145.7, 145.0, 143.3, 141.7, 141.3, 127.1,
o
1
100/1). M.P.: 268.6-269.8 C. H NMR (400 MHz, CDCl
3
) δ 8.05 (d,
J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.64 (dd, J = 8.8, 6.8 Hz, 1H), 7.58 (dd,
J = 8.8, 2.0 Hz, 1H), 7.21 (dd, J = 6.8, 1.2 Hz, 1H), 6.69 (dd, J = 9.2,
122.5, 120.4, 115.1, 114.8, 103.4, 102.4, 49.4, 25.3, 14.3.
+
HRMS-ESI (m/z): Calculated for C18
H
15
N
2
O
3
(M + H) : 307.1083,
1
.2 Hz, 1H), 5.15 (s, 2H), 3.10 (q, J = 8.0 Hz, 2H), 2.58 (s, 3H), 1.36
Found: 307.1085.
1
3
9b
(t, J = 7.6 Hz, 3H). C NMR (101 MHz, CDCl
3
) δ 161.8, 151.6, 148.0,
47.1, 144.6, 140.5, 137.7, 132.2, 130.2, 126.9, 122.4, 120.1,
00.7, 49.4, 23.0, 22.2, 14.1. HRMS-ESI (m/z): Calculated for
SN-38 (3k): Use of the procedure described for the
synthesis of 3a with 1c (40.1 mg, 0.1 mmol) and 2d (46.7 mg, 0.2
1
1
C
mmol) afforded a white solid (27.4 mg, 63%) after flash
+
20
18
H
17
N
2
O (M + H) : 277.1341, Found: 277.1342.
chromatography (DCM/MeOH = 50/1). [ɑ] = + 31.3 (c = 0.3,
D
9
b
20
D
2-Chloro-12-ethylindolizino[1,2-b]quinolin-9(11H)-one (3g):
CHCl
3
: MeOH = 4:1). [ref. [ɑ] = + 29.3, (c = 0.45, CHCl
4/1)]. M.P.: 226.7-228.1 C. H NMR (600 MHz, CDCl
3
/MeOH =
o
1
Use of the procedure described for the synthesis of 3a with 1b
57.4 mg, 0.2 mmol) and 2g (55.0 mg, 0.4 mmol) afforded a yellow
solid (42.9 mg, 72%) after flash chromatography (DCM/MeOH =
3
: CD OD = 5:
3
(
1) δ 7.91 (d, J = 9.0 Hz, 1H), 7.50 (s, 1H), 7.30 (dd, J = 9.0, 2.4 Hz,
1H), 7.25 (s, 1H), 5.54 (d, J = 16.2 Hz, 1H), 5.17 (d, J = 16.2 Hz, 1H),
o
1
1
1
7
00/1). M.P.: 269.0-270.5 C. H NMR (400 MHz, CDCl
3
: CD
3
OD = 5: 5.08 (s, 2H), 2.99 (q, J = 7.8 Hz, 2H), 1.79 (hept, J = 6.6 Hz, 2H),
1
3
) δ 7.97 (d, J = 9.2 Hz, 1H), 7.93 (s, 1H), 7.61 (q, J = 8.4 Hz, 2H),
.22 (d, J = 7.2 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 5.10 (s, 2H), 3.03 (q, CDCl
J = 8.0 Hz, 2H), 1.28 (t, J = 8.0 Hz, 3H). C NMR (126 MHz, CDCl
CD OD = 5: 1) δ 161.9, 152.2, 147.3, 146.1, 145.2, 141.11, 141.08,
33.7, 131.4, 131.0, 127.5, 122.6, 120.0, 102.0, 49.3, 22.9, 13.8.
HRMS-ESI (m/z): Calculated for C17
Found: 297.0797.
1.25 (t, J = 7.8 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H). C NMR (151 MHz,
: CD OD = 5: 1) δ 173.8, 157.9, 156.9, 151.2, 148.6, 147.0,
3
3
1
3
3
:
144.2, 144.0, 131.2, 128.7, 126.9, 122.8, 117.9, 105.0, 97.9, 72.9,
65.9, 49.4, 31.3, 23.0, 13.4, 7.6.
3
9
b
1
(20S)-7-Ethyl-10-methoxycamptothecin (3l): Use of the
procedure described for the synthesis of 3a with 1c (40.1 mg, 0.1
mmol) and 2b (26.8 mg, 0.2 mmol) afforded a white solid (33.2
+
2
H14ClN O (M + H) : 297.0795,
20
mg, 82%) after flash chromatography (DCM/MeOH = 100/1). [ɑ]D
This article is protected by copyright. All rights reserved.

9
b
20
=
0
+ 23.9 (c = 0.09, CHCl
.11, CHCl /MeOH = 4/1)]. M.P.: 260.6-261.3 C. H NMR (600
: CD OD = 5: 1) δ 7.96 (d, J = 9.0 Hz, 1H), 7.52 (s, 1H),
.35 (d, J = 9.0 Hz, 1H), 7.20 (s, 1H), 5.54 (d, J = 16.2 Hz, 1H), 5.17
d, J = 16.2 Hz, 1H), 5.11 (s, 2H), 3.88 (s, 3H), 3.05 (q, J = 7.8 Hz,
3
: MeOH = 4:1). [ref. [ɑ] = + 19.1, (c =
F.; Wani, M. C.; Wall, M. E. Proc. Natl. Acad. Sci. U. S. A. 1995, 92,
861.
D
o
1
3
8
MHz, CDCl
7
(
3
3
[
[
3] Moertel, C. G.; Schutt, A. J.; Reitemeier, R. J.; Hahn, R. G. Cancer
Chemother Rep. 1972, 56, 95.
4] (a) Kunimoto, T.; Nitta, K.; Tanaka, T.; Uehara, N.; Baba, H.; Takeuchi,
M.; Yokokura, T.; Sawada, S.; Miyasaka, T.; Mutai, M. Cancer Res.
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S.; Seeber, S.; Rustum, Y. M. J Clin Oncol. 2001, 19, 1501.
2
7
1
1
1
H), 1.79 (hept, J = 7.2 Hz, 2H), 1.28 (t, J = 7.8 Hz, 3H), 0.89 (t, J =
.2 Hz, 3H). C NMR (151 MHz, CDCl : CD OD = 5: 1) δ 173.7,
3 3
13
59.0, 157.8, 151.2, 149.2, 146.8, 145.0, 144.4, 131.3, 128.3,
27.3, 122.9, 118.1, 101.6, 98.1, 72.8, 65.8, 55.6, 49.5, 31.3, 23.0,
3.3, 7.6.
[
5] Kawato, Y.; Aonuma, M.; Hirota, Y.; Kuga, H.; Sato, K. Cancer Res.
16
Irinotecan (3m): To a solution of 3k (8.0 mg, 0.02 mmol) in
1991, 51, 4187.
0
.5 mL pyridine was added [1,4'-bipiperidine]-1'-carbonyl chloride
[
[
6] Stork, G.; Schultz, A. G. J. Am. Chem. Soc. 1971, 93, 4074.
7] (a) Peters, R.; Althaus, M.; Diolez, C.; Rolland, A.; Manginot, E.;
Veyrat, M. J. Org. Chem. 2006, 71, 7583. (b) Tang, C.; Babjak, M.;
Anderson, R. J.; Greene, A. E.; Kanazawa, A. Org. Biomol. Chem.
2006, 4, 3757. (c) Yu, S.; Huang, Q.; Luo, Y.; Lu, W. J. Org. Chem.
hydrochloride (27.2 mg, 0.10 mmol) and 4.5 mL DCM. After
stirring for 2 hours, the solution was quenched with a saturated
aqueous solution of NaHCO
mL). The organic phase was dried with Na
in vacuum. The residue was purified by silica gel column
3
(1.0 mL) and extracted by DCM (2×5
SO and concentrated
2
4
chromatography (DCM/MeOH = 20/1) to afford 3m (9.7 mg, 81%)
2
012, 77, 713. (d) Watanabe, T.; Odagi, M.; Furukori, K.; Nagasawa,
20
9b
20
as a yellow solid. [ɑ]D = + 61.9 (c = 0.18, CHCl ). [ref. [ɑ]D = +
3
K. Chem. Eur. J. 2013, 20, 591. (e) Li, K.; Ou, J.; Gao, S. Angew. Chem.
Int. Ed. 2016, 55, 14778; Li, K.; Ou, J.; Gao, S. Angew. Chem. 2016,
o
1
6
2.9, (c = 0.2, CHCl
CDCl ) δ 8.19 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.62 (s,
H), 7.55 (dd, J = 9.0, 2.4 Hz, 1H), 5.73 (d, J = 16.2 Hz, 1H), 5.29 (d,
J = 16.2 Hz, 1H), 5.24 (s, 2H), 4.51 (dd, J = 45.6, 13.8 Hz, 2H), 3.89
s, 1H), 3.24 – 2.80 (m, 9H), 2.43 (d, J = 7.2 Hz, 1H), 2.24 (d, J =
2.6 Hz, 1H), 1.89 (m, 10H), 1.40 (t, J = 7.8 Hz, 3H), 1.03 (t, J = 7.2
3
)]. M.P.: 212.7-214.0 C. H NMR (600 MHz,
3
128, 14998. (f) Chen, F.; Chen, L. Synlett 2017, 28, 1134-1150. (g)
1
Wang, L.; Xie, S.; Ma, L.; Chen, Y.; Lu, W. Eur. J. Med. Chem. 2016,
116, 84-89. (h) Jin, C.; Zhang, Q.; Lu, W. Eur. J. Med. Chem. 2017, 132,
135-141. (i) Zhu, Q.; Bao, B.; Zhang, Q.; Yu, J.; Lu, W. RSC Adv. 2018,
(
1
1
3
Hz, 3H). C NMR (151 MHz, CDCl
3
) δ 174.0, 157.8, 153.1, 151.8,
8
, 2818-2823.
8] (a) Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992,
14, 10971. (b) Comins, D. L.; Nolan, J. M. Org. Lett. 2001, 3, 4255.
1
1
3
50.3, 150.2, 147.4, 147.0, 145.4, 132.0, 127.6, 127.3, 125.7,
18.6, 114.7, 98.1, 72.9, 70.7, 66.5, 63.5, 50.2, 49.5, 43.7, 43.4,
1.7, 31.6, 27.1, 26.1, 23.6, 23.3, 23.1, 14.2, 8.0.
[
[
1
9] (a) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1991, 113, 2127 (b) Josien,
H.; Ko, S. B.; Bom, D.; Curran, D. P. Chem. Eur. J. 1998, 4, 67.
Supporting Information
[
10] Zhou, H.; Liu, G.; Yao, Z. Org. Lett. 2007, 9, 2003-2006.
The supporting information for this article is available on the [11] Liu, G.; Dong, Q.; Yao, Y.; Yao, Z. Org. Lett. 2008, 10, 5393-5396.
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
H and 13C NMR spectra.
[
[
12] (a) Zhao, L.; Xiong, F.; Chen, W.; Chen, F. Synthesis. 2011, 2011,
045. (b) Wang, X.; Xu, L.; Xiong, F.; Wu, Y.; Chen, F. Tetrahedron:
1
4
Asymmetry. 2017, 28, 843.
Acknowledgement (optional)
13] Yuan, Y.; Dong, W.; Gao, X.; Gao, H.; Xie, X.; Zhang, Z. J. Org. Chem.
2018, 83, 2840.
The authors acknowledge the financial support provided by
the National Natural Science Foundation of China (No. 21232003). [14] Curran, D. P.; Liu, H.; Josien, H.; Ko, S.-B. Tetrahedron. 1996, 52,
DPC thanks the US National Institutes of Health RAID program for
1
1385.
preparation
of
[
[
15] Kim, M.; Euler, W. B.; Rosen, W. J. Org. Chem. 1997, 62, 3766-3769.
16] Henegar, K. E.; Ashford, S. W.; Baughman, T. A.; Sih, J. C.; Gu, R. J.
Org. Chem. 1997, 62, 6588.
(
3
S)-4-ethyl-4-hydroxy-6-iodo-1,7-dihydro-3H-pyrano[3,4-c]pyridin-
,8(4H)-dione. We also express gratitude for the support of the
Instrumental Analysis Center of Shanghai Jiao Tong University.
(
The following will be filled in by the editorial staff)
References
Manuscript received: XXXX, 2017
Revised manuscript received: XXXX, 2017
Accepted manuscript online: XXXX, 2017
Version of record online: XXXX, 2017
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This article is protected by copyright. All rights reserved.