Synthesis and antitumor activity of ring A- and F-modified hexacyclic camptothecin analogues

Article abstract of DOI:10.1021/jm970765q

Nineteen ring A- and F-modified hexacyclic analogues of camptothecin were synthesized by Friedlander condensation of appropriately substituted bicyclic amino ketones with tricyclic ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory

Full text of DOI:10.1021/jm970765q

2308
J . Med. Chem. 1998, 41, 2308-2318
Syn th esis a n d An titu m or Activity of Rin g A- a n d F -Mod ified Hexa cyclic
Ca m p toth ecin An a logu es1
Masamichi Sugimori,* Akio Ejima, Satoru Ohsuki, Kouichi Uoto, Ikuo Mitsui, Yasuyoshi Kawato,
Yasuhide Hirota, Keiki Sato, and Hirofumi Terasawa
Tokyo R&D Center, Daiichi Pharmaceutical Company, Ltd., 16-13, Kitakasai 1-Chome, Edogawa-ku, Tokyo 134, J apan
Received November 10, 1997
Nineteen ring A- and F-modified hexacyclic analogues of camptothecin were synthesized by
Friedla¨nder condensation of appropriately substituted bicyclic amino ketones with tricyclic
ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory activity. Seventeen
of the compounds showed cytotoxic effects comparable or superior to those of 7-ethyl-10-
hydroxycamptothecin (SN-38) against mouse leukemia P388 and human tumor cell lines HOC-
21 and QG-56. Introduction of a compact and inductively electron-withdrawing substituent
such as a hydroxy, methoxy, chloro, or fluoro group into position 5 of ring A of the hexacyclic
compound remarkably increased the antitumor activity. The potency of topoisomerase I
inhibition of these compounds showed good correlation with their cytotoxicity. Among them,
the 4-methyl-5-fluoro hexacyclic compound was the most potent of all and was 10 times as
active as SN-38 in in vitro antitumor activity.
Ch a r t 1
Camptothecin (1) (Chart 1), a pentacyclic alkaloid
isolated from Camptotheca acuminata, was first re-
ported by Wall and co-workers to have potent antitumor
activity in 1966.2 On the basis of its remarkable
antitumor activity in the preclinical study, campto-
thecin, which was formulated as a water-soluble camp-
tothecin sodium, was introduced into clinical trials.
Although objective antitumor responses were observed
among patients with gastric and colon cancer, severe
bone marrow suppression and nonhematological toxici-
ties were also observed, and thus further clinical
development of camptothecin was discontinued in the
early 1970s.3 In 1985, however, Liu and co-workers
reported that camptothecin traps the cleavable complex
between topoisomerase I and DNA, which induces
single-strand DNA breaks,4 and this discovery of the
unique mechanism of action of camptothecin revived
interest in the drug. Further modification of this potent
alkaloid was explored in order to find a more effective
compound with clinical value. As a result, irinotecan
(CPT-11) (2)5 and topotecan (3),6 both semisynthetic
water-soluble analogues of camptothecin, were launched
into the market in 1994 and 1996, respectively. Clinical
studies of 9-aminocamptothecin (9-AC) (4),7 orally ad-
ministered camptothecin, and GG-211 (6)8 are also
investigated.
In our previous paper, we reported the synthesis and
biological activity of hexacyclic analogues of campto-
thecin which exhibited antitumor activities superior to
that of the original pentacyclic ring system.1 To further
explore the potential of the hexacyclic compounds, we
synthesized hexacyclic analogues which have a six-
membered ring F and various substituents at positions
3, 4, and 5 and evaluated their antitumor activities.
optically active tricyclic ketone 7a 10 or 7b11 (Scheme 1).
Amino ketones were prepared as shown below. Amino
ketone 9 was obtained by regioselective N-acetylation
of 8.12 Catalytic hydrogenation of 11,12 followed by
conversion of an amino group to a hydroxy or a hydro
group via a diazonium compound, and hydrolysis af-
forded 12 and 15. Treatment of nitrobenzene deriva-
tives 17 and 21 with 3-chloro-1-propanol or ethyl
Ch em istr y
All of the hexacyclic compounds were prepared by
acid-catalyzed Friedla¨nder condensation9 between the
substituted bicyclic amino ketone and the racemic or
S0022-2623(97)00765-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/03/1998

Ring A- and F-Modified Camptothecin Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2309
Sch em e 1
3-bromopropionate was followed by oxidation or hy-
drolysis to afford 18 and 22. Bicyclic amino ketones 19
and 23 were prepared from 18 and 22 by hydrogenation
of the nitro group and Friedel-Crafts cyclization. Te-
tralone 2913 was converted into amino ketone 30 upon
nitration, displacement of the bromo atom to the cyano
group using CuCN,14 and hydrogenation of the nitro
group. Compound 3215 was oxidized with CrO3 in AcOH
at the peri-position of the acetamido group to give the
desired tetralone, which afforded 33 by deprotection and
hydrogenation.
Bicyclic amino ketones 38, 43, 49, 50, 56, 61, and 65
for 5-substituted hexacyclic compounds were prepared
from compounds 35,16 40,17 45,16 53,18 58,19 and 63,20
respectively, in several steps. (1) Phenylbutanoic acids
were prepared as mentioned below. Esterification of 35
followed by nitration, hydrogenation, and N-acetylation
afforded 36. Ester 40 was converted to 41 in the same

2310 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Sugimori et al.
Ta ble 1. In Vitro Antitumor Activities against Three Cell Line Cultures and Topoisomerase I Inhibitory Activities of Hexacyclic
Camptothecin Analogues
IC50 (ng/mL)a
cell line
ratio,b
compd no.
R1
R2
X
config
P388
HOC-21
QG-56
Topo I
10
13
14
16
20
24
25
28
31
34
39
44
51
52
57
62
66
67
69
70d
NH2
OMe
OH
H
NH2
OMe
OMe
OH
CN
NH2
H
H
F
F
Me
H
H
H
H
H
H
H
H
NH2
H
H
Cl
F
F
F
S
S
S
S
O
(R S)
(R S)
(R S)
(R S)
(R S)
(R S)
(R S)
(R S)
(R S)
(R S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R S)
(S)
1.08 (0.20)c
6.49 (1.49)
8.63 (1.71)
3.04 (0.59)
2.60 (0.78)
>62.5 (>14.4)
10.7 (2.28)
>62.5 (>16.4)
8.14 (1.70)
2.97 (0.51)
0.73 (0.24)
0.26 (0.18)
0.48 (0.20)
3.17 (1.28)
0.22 (0.08)
5.05 (1.91)
1.01 (0.39)
0.99 (0.39)
5.23 (1.23)
1.60 (0.22)
1.44-7.27 (1)
4.74 (2.44)
8.37 (0.17)
80.2 (1.88)
152.6 (1.54)
33.0 (0.80)
0.40 (0.25)
3.27 (2.02)
3.68 (1.91)
1.71 (1.06)
0.71 (0.59)
29.8 (18.4)
10.6 (2.72)
11.6 (12.9)
4.21 (2.07)
1.38 (0.84)
0.53 (0.35)
0.16 (0.11)
0.38 (0.27)
2.62 (1.42)
0.17 (0.07)
10.30 (2.61)
1.32 (0.75)
4.70 (1.25)
1.63 (1.66)
0.26 (0.10)
0.90-3.95 (1)
4.63 (1.80)
0.9
1.6
1.2
57.7 (0.51)
NAc
NH
>500 (>11.7)
106.5 (1.88)
>500 (>6.71)
73.45 (1.42)
35.89 (0.46)
14.00 (0.17)
3.39 (0.07)
10.90 (0.22)
68.90 (1.41)
2.06 (0.05)
101.00 (2.64)
17.40 (0.32)
20.60 (0.42)
92.9 (1.29)
CH2
CH2
CH2
CH2
CH2
CH2
CHOH
CH2
CH2
CH2
CH2
CH2
CH2
2.6
3.9
1.4
0.23
0.24
0.70
1.2
0.51
3.6
0.70
0.17
4.0
0.47
1
F
CH3
OMe
OH
H
H
H
H
OH
H
12.6 (0.22)
41.2-113.1 (1)
14.7 (1.09)
SN-38 (5)
camptothecin (1)
(S)
(S)
3.9
a
In vitro antitumor activities of the drugs against three cell lines (P388, mouse leukemia; HOC-21, human ovarian cancer; QG-56,
human lung squamous cell carcinoma) were measured by MTT assay after 3 days of incubation and expressed as the doses required to
b
inhibit the growth of 50% of the cells cultivated (IC50, ng/mL). Figures indicate the (IC50 of tested compounds)/(IC50 of SN-38). IC50 is
the concentration that inhibited the change in DNA from the supercoiled form to the relaxed form by 50% in the presence of topoisomerase
d
I. c Figures in parentheses indicate the (IC50 of tested compounds)/(IC50 of SN-38). Previously reported1 sample 70 is assembled to assist
the structure-activity relationship discussion.
manner, but in the case of 45 the acid group did not
need to be protected in conversion to 46 because the acid
group did not suffer from intramolecular cyclization at
position 2 in the nitration step. Treatment of tetralone
58 with hydroxylamine and tosyl chloride, followed by
transformation of an imine to an amine and a methyl
ester in a Neber rearrangement21 carried out by heating
in MeOH, afforded the methyl aminophenylpropionate
derivative, which was hydrolyzed and N-acetylated to
prepare 59. (2) Friedel-Crafts cyclization of phenylbu-
tanoic acids 36, 41, 46, 54, and 59 afforded the tetra-
lones. (3) The tetralones were reduced to tetralins with
Et3SiH22 or H2 gas at 5 atm in the presence of Pd/C or
in three steps involving reduction with NaBH4, dehy-
dration with TsOH, and hydrogenation. In the case of
the catalytic hydrogenation of difluorotetralone, tetralin
47 and acetoxytetralin 48 were obtained as a mixture.
Tetralin 64 was obtained through methyl ether forma-
tion, reduction, and N-acetylation of 63. (4) The tetra-
lins were oxidized to the tetralones using KMnO4. (5)
An acetamido group of the tetralones was hydrolyzed
to afford the bicyclic amino ketones. Amino ketones 9,
12, 15, 19, 23, 27, 30, 33, 38, 43, 49, 50, 56, 61, 65, and
6823 were condensed with 7a or 7b to prepare hexacyclic
compounds, and removal of the protecting group of 13,
24, and 66 afforded 14, 25, and 67, respectively.
we could not find a correlation between these calculative
energies and the reactivity. These energies may not
reflect the transition state or other factors such as
solubility, or the solvent effect may affect the reaction.
Resu lts a n d Discu ssion
Nineteen hexacyclic camptothecin analogues were
evaluated for cytotoxicity against murine and human
tumor cell lines (P388, HOC-21, and QG-56) and inhibi-
tory activity of topoisomerase I (Table 1). To obtain
more meaningful comparisons of relative potencies, SN-
38 (5),5 which is an active metabolite of CPT-11, was
tested at the same time.
In our previous paper, we reported that hexacyclic
camptothecin analogues which had an additional six-
membered heterocyclic ring or five- to seven-membered
carbocyclic ring exhibited stronger antitumor activity
than the original pentacyclic ring system of campto-
thecin.1 To further explore the potential of the hexacy-
clic compounds, we investigated modifications at posi-
tions 3, 4, and 5 upon the antitumor activity of hexacyclic
compounds with an additional six-membered ring F.
Seventeen of the hexacyclic compounds (Table 1)
showed comparable or superior cytotoxic activity to SN-
38 essentially, considering that racemic camptothecin
analogues have one-half the potency of the correspond-
ing (S)-analogues.
There were differences in the facility of the acid-
catalyzed Friedla¨nder condensation. For example, com-
pound 25 was not obtained directly by Friedla¨nder
reaction between tricyclic ketone 7a and 5-amino-2,3-
dihydro-8-methoxyquinolinone. The recation stopped at
an intermediate enamine. Though we calculated the
HOMO and LUMO energies of some amino ketones and
enamines using semiempirical molecular orbital calcu-
lation to find the cause of the difference in reactivity,
We have reported that changing the carbon atom at
position 3 into a heteroatom did not greatly affect
antitumor activity and topoisomerase I inhibition.1 The
behavior was again seen in the present study since
compounds having a different kind of atom at position
3 and the same substituent group such as amino or
methoxy group at position 4 (10, 20, and 34 or 13 and
25) showed almost equal cytotoxicity.

Ring A- and F-Modified Camptothecin Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2311
tained on a Hitachi 270-30 infrared spectrophotometer. Mass
spectra were recorded on a J EOL J MS-D300, a J MS-HX110,
or a J MS-AX505W spectrometer. 1H NMR spectra were
obtained on a J EOL J NM-FX90Q or a J NM-EX400 spectrom-
eter; all values are reported in ppm (δ) downfield from (CH3)4-
Si. Elemental analyses were obtained on a Heraeus CHN-
O-Rapid or a Perkin-Elmer 2400CHN analyzer. Column
chromatography was performed using silica gel 60 F254 (70-
230 mesh) (Merck).
8-Aceta m id o-5-a m in o-4-th ioch r om a n on e (9). To a solu-
tion of 5,8-diamino-4-thiochromanone (8) (2.88 g, 14.8 mmol)
and Et3N (2.07 mL, 14.9 mmol) in CH2Cl2 (100 mL) was added
AcCl (1.05 mL, 14.8 mmol) in CH2Cl2 (20 mL) over 1 h at -15
°C. After being stirred for 1 h, the solution was diluted with
CHCl3, washed with saturated NaCl, dried (Na2SO4), and
evaporated. The residue was purified by chromatography
(33% AcOEt-CHCl3) to afford 9 as a yellow-green solid (2.76
g, 59%).
Substitution with inductively electron-withdrawing
groups at position 5 of the hexacyclic analogue of
camptothecin showed a distinct tendency to increase in
vitro antitumor activity. Thus, 5-hydroxy, 5-methoxy,
5-chloro, or 5-fluoro hexacyclic compounds demonstrated
marked activity. Especially, compounds 44, 51, and 57
with a fluorine atom at position 5 were encouraging;
for example, 4-methyl-5-fluoro compound 51 was shown
to be 10 times as active as SN-38 in the assay of
cytotoxic activity. The studies of the structure-activity
relationship at position 11 of camptothecin, which
corresponds to position 5 in a hexacyclic ring system,
showed that substitution with a nitro or a trifluoro-
methyl group at this position reduces the antitumor
activity, while substitution with a hydroxy or a fluoro
group increases the activity.24 These results and our
data reveal that not only electronegativity of the sub-
stituent but also the steric factor of the substituent are
important for the activity at position 5 of the hexacyclic
analogues. Compact and inductively electron-withdraw-
ing substituents may be preferred at position 5. Among
the 4-substituted derivatives, the methoxy and cyano
compounds exhibited equal or inferior activity while
amino compounds showed activity superior to that of
the parent compounds.
Sixteen of the compounds were evaluated for topo-
isomerase I inhibitory activity. Good correlation was
observed between the cytotoxicity ratio against P388,
HOC-21, or QG-56 and topoisomerase I inhibitory
activity of the compounds25 (r ) 0.84, 0.83, and 0.81,
respectively). It is evident that cytotoxicity of the
hexacyclic analogues of camptothecin results from in-
hibition of topoisomerase I. It is interesting to note that
compound 28 had moderate topoisomerase I inhibitory
activity, while it was inactive in the antitumor assay.
It was recently reported that the number of potential
hydrogen-bonding sites or polar surface areas of the
compound was a principal determinant of permeability
through monolayers of Caco-2 cells or intestinal passive
absorption.26 It is likely that the hydroxy and amino
groups of 28 decrease membrane permeability, which
results in the difference between the cytotoxicity and
the topoisomerase I inhibitory activity of 28.
In conclusion, we have modified hexacyclic campto-
thecin analogues with a six-membered ring F at posi-
tions 3, 4, and 5 and found that compounds with a
compact and inductively electron-withdrawing substitu-
ent at position 5 demonstrated marked antitumor
potency and topoisomerase I inhibitory activity, and the
5-fluoro-4-methylhexacyclic compound 57 was the most
potent. The high potency of the hexacyclic compounds
enhanced by a combination of F-ring and the substitu-
ents at positions 4 and 5 will make future modification
easy for the purpose of acquiring water solubility needed
in drugs and allow low dose administration which may
mean the decrease of possible side effects, except for one
which is caused by the inhibition of topoisomerase I. The
structure-activity relationship information of the hexacy-
clic compounds reported in this paper should facilitate
the exploration of more effective camptothecin ana-
logues.
(RS)-4-Am in o-1,2-dih ydr o-9-eth yl-9-h ydr oxy-12H-th iin o-
[4,3,2-de]pyr an o[3′,4′:6,7]in dolizin o[1,2-b]qu in olin e-10,13-
(9H,15H)-d ion e (10). A solution of 9 (123 mg, 0.52 mmol)
and 7a (137 mg, 0.52 mmol) in AcOH (77 mL) was heated to
reflux under N2 for 20 h. The precipitate obtained after cooling
was collected and washed successively with AcOH, MeOH, and
AcOEt to give (RS)-4-acetamido-1,2-dihydro-9-ethyl-9-hydroxy-
12H-thiino[4,3,2-de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-
10,13(9H,15H)-dione as a yellow-green solid (62 mg, 26%): mp
>300 °C dec. This camptothecin analogue (352 mg, 0.76 mmol)
in 60% H2SO4 (4 mL) was heated at 100 °C for 2 h before the
mixture was poured into water. The pH of the mixture was
adjusted to 5 using 10% aqueous NaOH, and precipitated solid
was collected by filtration and washed successively with water,
EtOH, and CHCl3 to afford 10 as a yellow solid (257 mg,
80%): mp 260-262 °C dec; 1H NMR (DMSO-d6) δ 0.88 (t, 3H,
J ) 7 Hz), 1.87 (q, 2H, J ) 7 Hz), 3.0-3.6 (m, 4H), 5.18 (s,
2H), 5.40 (s, 2H), 5.65 (s, 2H), 6.43 (s, 1H), 7.20 (s, 1H), 7.31
(d, 1H, J ) 9 Hz), 7.70 (d, 1H, J ) 9 Hz). Anal. (C22H19N3O4S‚
1/4H2O) C, H, N.
5-Am in o-8-m eth oxy-4-th ioch r om a n on e (12). To a solu-
tion of 5-acetamido-8-nitro-4-thiochromanone (11) (23.2 g, 87.1
mmol) in AcOH (1 L) was added 10% Pd/C (5 g), and the
mixture was catalytically hydrogenated. After the catalyst
was removed by filtration, the solvent was evaporated and
hexane was added to the residue. The precipitate was filtered
to yield 5-acetamido-8-amino-4-thiochromanone (19.4 g, 94%).
To a solution of 5-acetamido-8-amino-4-thiochromanone (3 g,
12.7 mmol) in cooled (0 °C) 20% H2SO4 (23 mL) was added
NaNO2 (1.12 g, 16.2 mmol) in water (13 mL) dropwise. After
the mixture stirred for 30 min, a small amount of urea was
added, and then the mixture was poured into a vigorously
stirred solution of Cu(NO3)2‚3H2O (160 g, 662 mmol) in water
(500 mL). After Cu2O (1.69 g, 11.8 mmol) was added to the
mixture, the mixture was stirred for 15 min and extracted 10
times with CHCl3. The organic phase was concentrated and
chromatographed to afford 5-acetamido-8-hydroxy-4-thiochro-
manone (290 mg, 9.6%). A suspension of 5-acetamido-8-
hydroxy-4-thiochromanone (180 mg, 0.76 mmol), MeI (0.1 mL,
1.61 mmol), and K2CO3 (110 mg, 0.76 mmol) in acetone (20
mL) was heated to reflux for 3.5 h. The mixture was
concentrated and partitioned between AcOEt and water. The
organic phase was evaporated, and the resultant residue was
purified by chromatography (17% AcOEt-CHCl3) to give
5-acetamido-8-methoxy-4-thiochromanone as a yellow solid
(174 mg, 91%). After a solution of 5-acetamido-8-methoxy-4-
thiochromanone (172 mg, 0.68 mmol) in 35% H2SO4 (3 mL)
was warmed at 50-60 °C for 5 h, the mixture was neutralized
with NaHCO3 and extracted with CHCl3. The combined
organic phase was washed successively with water and
saturated NaCl, dried (Na2SO4), and evaporated. Column
chromatography (17% AcOEt-hexane) of the residue gave 12
as a red oil (123 mg, 86%).
Exp er im en ta l Section
(RS)-1,2-Dih yd r o-9-et h yl-9-h yd r oxy-4-m et h oxy-12H -
th iin o[4,3,2-de]pyr an o[3′,4′:6,7]in dolizin o[1,2-b]qu in olin e-
10,13(9H,15H)-d ion e (13). A mixture of 12 (120 mg, 0.57
Melting points were found using a Yanaco MP-S3 or MP-
500D apparatus and are uncorrected. IR spectra were ob-

2312 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Sugimori et al.
mmol) and 7a (150 mg, 0.57 mmol) in AcOH (5 mL) was heated
to reflux for 4 h. The precipitate obtained after cooling was
washed successively with AcOEt and CHCl3 to give 13 as a
yellow solid (170 mg, 70%): 1H NMR (DMSO-d6) δ 0.88 (t, 3H,
J ) 7 Hz), 1.88 (q, 2H, J ) 7 Hz), 3.15-3.45 (m, 4H), 4.02 (s,
3H), 5.25 (s, 2H), 5.43 (s, 2H), 6.49 (s, 1H), 7.30 (s, 1H), 7.84
(d, 1H, J ) 10 Hz), 8.08 (d, 1H, J ) 10 Hz). Anal.
(C23H20N2O5S‚1/2H2O) C, H, N.
for 15 min, the mixture was poured into water, and the
resultant precipitate was collected and dried to afford 18 as a
colorless solid (2.8 g, 74%).
8-Aceta m id o-5-a m in o-4-ch r om a n on e (19). A suspension
of 18 (2.6 g, 9.69 mmol) and PtO2 (300 mg) in EtOH (170 mL)
and water (40 mL) was stirred in an atmosphere of H2 (1 atm).
The catalyst was removed by filtration, and the solution was
concentrated to afford 3-(2-acetamido-5-aminophenoxy)-1-pro-
pionic acid as a colorless solid (2.3 g, 99%). A mixture of 3-(2-
acetamido-5-aminophenoxy)-1-propionic acid (7.0 g, 29.4 mmol)
in concentrated H2SO4 (30 mL) was warmed to 80 °C for 3 h
and poured into ice-water. The aqueous solution was basified
with Na2CO3 and extracted with AcOEt. The organic solution
was dried (Na2SO4), concentrated, and subjected to chroma-
tography (0.5% MeOH-CHCl3) to give 19 as a yellow solid (70
mg, 1%).
(RS)-1,2-Dih ydr o-4,9-dih ydr oxy-9-eth yl-12H-th iin o[4,3,2-
d e]p yr a n o[3′,4′:6,7]in d olizin o[1,2-b]q u in olin e -10,13-
(9H,15H)-d ion e (14). Compound 13 (102 mg, 0.23 mmol) in
47% aqueous HBr (5 mL) was heated to reflux for 7.5 h. The
mixture was poured into ice-water, basified with 10% NaOH,
and filtered. The filtrate was acidified with HCl, and the
resultant precipitate was collected by filtration and washed
successively with water, EtOH, and AcOEt to give 14 as a
yellow-green solid (95 mg, 96%): mp >250 °C dec; MS (FAB)
(RS)-4-Am in o-1,2-d ih yd r o-9-et h yl-9-h yd r oxy-12H -p y-
r a n o[4,3,2-d e]p yr a n o[3′,4′:6,7]in d olizin o[1,2-b]qu in olin e-
10,13(9H,15H)-d ion e (20). A solution of 19 (70 mg, 0.32
mmol) and 7a (92 mg, 0.35 mmol) in AcOH (3 mL) was heated
to reflux under N2 for 5 h. The precipitate obtained after
cooling was washed successively with AcOH, and acetone to
give (RS)-4-acetamido-1,2-dihydro-9-ethyl-9-hydroxy-12H-py-
rano[4,3,2-de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-
(9H,15H)-dione as a yellow solid (60 mg, 42%): mp 280-285
°C dec. This camptothecin analogue (50 mg, 0.112 mmol) in
6 N HCl (10 mL) was heated to reflux for 1 h and concentrated
to dryness. The residue was recrystallized (MeOH) twice to
give 20 as a yellow solid (40 mg, 82%): mp 240-245 °C dec;
IR (KBr) 3420, 3360, 1750, 1655, 1600 cm-1; MS (EI) m/z 405
1
423 (M + H); H NMR (DMSO-d6) δ 0.89 (t, 3H, J ) 7 Hz),
1.87 (q, 2H, J ) 7 Hz), 3.0-3.6 (m, 4H), 5.21 (s, 2H), 5.41 (s,
2H), 6.43 (s, 1H), 7.26 (s, 1H), 7.44 (d, 1H, J ) 9 Hz), 7.79 (d,
1H, J ) 9 Hz). Anal. (C22H18N2O5S‚5/4H2O) C, H, N.
5-Am in o-4-th ioch r om a n on e (15). A solution of NaNO2
(320 mg, 4.64 mmol) in water (10 mL) was added to a cooled
(0 °C) and stirred suspension of 5-acetamido-8-aminothiochro-
manone (1 g, 4.23 mmol) in 10% HCl (55 mL). After being
stirred for 30 min, the solution was added to cooled (10 °C)
50% H3PO2 (9 mL), and the mixture was allowed to warm to
room temperature and stirred for 2 days. The mixture was
extracted with CHCl3, and the organic phase was washed with
saturated NaCl, dried (Na2SO4), and evaporated. The residue
was purified by column chromatography to afford a mixture
of 15 and acetylated compound. The mixture in concentrated
HCl (5 mL) was heated at 80 °C for 2 h, basified with 10%
NaOH, and extracted (CHCl3). The organic phase was washed
successively with water and saturated NaCl, dried (Na2SO4),
and evaporated. The crude product was purified by chroma-
tography to give 15 as a yellow oil (280 mg, 37%).
(RS)-1,2-Dih yd r o-9-et h yl-9-h yd r oxy-12H -t h iin o[4,3,2-
d e]p yr a n o[3′,4′:6,7]in d olizin o[1,2-b]q u in olin e -10,13-
(9H,15H)-d ion e (16). A mixture of 15 (276 mg, 1.54 mmol),
7a (400 mg, 1.52 mmol), and TsOH‚H2O (170 mg, 0.894 mmol)
in toluene (30 mL) was heated to reflux for 5 h. The precipitate
obtained after cooling was washed successively with AcOEt,
CHCl3, aqueous MeOH, and MeOH to give 16 as a pale-yellow
solid (273 mg, 44%). An analytical sample was obtained by
recrystallization (AcOH): mp 298-300 °C dec; 1H NMR
(DMSO-d6) δ 0.89 (t, 3H, J ) 7 Hz), 1.92 (q, 2H, J ) 7 Hz),
3.1-3.7 (m, 4H), 5.24 (s, 2H), 5.43 (s, 2H), 6.50 (s, 1H), 7.33
(s, 1H), 7.50 (dd, 1H, J ) 8, 2 Hz), 7.68 (t, 1H, J ) 8 Hz), 7.90
(dd, 1H, J ) 8, 2 Hz). Anal. (C22H18N2O4S‚3/4CH3COOH) C,
H, N.
1
(M+), 361 (M - CO2); H NMR (DMSO-d6) δ 0.98 (t, 3H, J )
7 Hz),1.85-1.90 (m, 2H), 5.20 (s, 2H), 5.42 (s, 2H), 6.43 (s,
1H), 7.23 (s, 1H), 7.37 (d, 1H, J ) 9 Hz), 7.60 (d, 1H, J ) 9
Hz). Anal. (C22H19N3O6‚1/4H2O) C, H, N.
3-(2-Met h oxy-5-n it r oa n ilin o)p r op ion ic Acid (22).
2-Methoxy-5-nitroaniline (21) (100 g, 595 mmol) and NaHCO3
(50 g, 595 mmol) were heated at 125 °C and treated with ethyl
3-bromopropionate (100 mL, 780 mmol) over 2 h. After being
heated for an additional 2 h, the mixture was partitioned
between water and AcOEt, and the organic phase was dried
(Na2SO4) and concentrated. The residue was recrystallized
successively from AcOEt-Et2O and EtOH-hexane to afford
ethyl 3-(2-methoxy-5-nitroanilino)propionate as yellow needles
(75.7 g, 47%). Ethyl 3-(2-methoxy-5-nitroanilino)propionate
(10 g, 37.3 mmol) in a mixture of 1 N NaOH (40 mL) and EtOH
(100 mL) was heated until dissolved in the solvent. After being
stirred for 1 h, the solution was concentrated and neutralized
with aqueous HCl. The precipitate was collected by filtration
and purified by recrystallization (EtOH-water) to give 22 as
a yellow solid (8.60 g, 96%).
1-Acetyl-5-am in o-2,3-dih ydr o-8-m eth oxyqu in olin -4(1H)-
on e (23). To a solution of 22 (8.59 g, 35.76 mmol) in a mixture
of dioxane (130 mL), EtOH (130 mL), and concentrated HCl
(5 mL) was added PtO2 (500 mg) to effect catalytic hydrogena-
tion. The catalyst was removed by filtration, and the filtrate
was evaporated and washed with hexane to yield a crude
powder of 3-(5-amino-2-methoxyanilino)propionic acid. To
stirred and heated (120 °C) PPA (250 g) was added the above
crude acid over 20 min. Stirring was continued for 3 h before
the mixture was poured into water and neutralized with
NaHCO3. The mixture was extracted with AcOEt, and the
combined extracts were washed successively with water and
saturated NaCl, dried (Na2SO4), and concentrated to dryness.
The residue was subjected to chromatography (33% AcOEt-
hexane) to afford 5-amino-2,3-dihydro-8-methoxyquinolin-
4(1H)-one as a red oil (2.14 g, 31%). To a solution of 5-amino-
2,3-dihydro-8-methoxyquinolin-4(1H)-one (1.28 g, 6.68 mmol)
in a mixture of CH2Cl2 (20 mL) and pyridine (0.6 mL, 7.42
mmol) was added benzyl chloroformate (1.1 mL, 7.71 mmol)
in CH2Cl2 (5 mL). After being stirred for 1 h, the reaction
mixture was washed successively with water and saturated
NaCl, dried (Na2SO4), and evaporated. The residue was
purified by chromatography (20% AcOEt-hexane) and recrys-
tallization (AcOEt-hexane) to give 5-[(benzyloxycarbonyl)-
3-(2-Aceta m id o-5-n itr op h en oxy)p r op ion ic Acid (18).
2-Hydroxy-4-nitroaniline (17) (1.54 g, 10 mmol) and Ac2O (2.05
g, 20 mmol) in pyridine (10 mL) were stirred for 16 h before
the mixture was poured into ice-water. The precipitate
obtained by filtration was suspended in MeOH (20 mL), and
1 N NaOH (8.9 mL, 8.9 mmol) was added to the mixture. After
being stirred for 30 min, the mixture was acidified with 10%
HCl, and the resultant precipitate was collected and dried to
afford 2′-hydroxy-4′-nitroacetanilide (1.4 g, 71%). To a suspen-
sion of NaH (1.25 g, 52 mmol) in DMF (200 mL) was added
2′-hydroxy-4′-nitroacetanilide (10 g, 51 mmol). After the
mixture stirred for 20 min, 18-crown-6 (100 mg, 0.38 mmol)
followed by 3-chloro-1-propanol (7.2 g, 76.2 mmol) was added
to the mixture which was warmed to 80 °C for 2 days. The
mixture was poured into ice-water and extracted with AcOEt.
The organic phase was washed successively with 10% NaOH
and water, dried (Na2SO4), and concentrated. The residue was
recrystallized (CHCl3-hexane and EtOH) to give 3-(2-acet-
amido-5-nitrophenoxy)-1-propanol as a red solid (6.3 g, 49%).
To a cooled (0 °C) solution of 3-(2-acetamido-5-nitrophenoxy)-
1-propanol (3.6 g, 14.2 mmol) in acetone (150 mL) was added
dropwise a mixture of CrO3 (2.67 g, 26.7 mmol) and concen-
trated H2SO4 (2.3 mL) in water (4 mL). After being stirred

Ring A- and F-Modified Camptothecin Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2313
5-methoxy-8-nitro-1(2H)-naphthalenone (570 mg, 48%).
suspension of 6-acetamido-3,4-dihydro-5-methoxy-8-nitro-
1(2H)-naphthalenone (547 mg, 1.97 mmol) and 10% Pd/C (100
mg) in AcOH (10 mL) was hydrogenated at atmospheric
pressure. After catalyst was filtered, the solvent was evapo-
amino]-2,3-dihydro-8-methoxyquinolin-4(1H)-one as a yellow
solid (1.87 g, 86%). After a mixture of 5-[(benzyloxycarbonyl)-
amino]-2,3-dihydro-8-methoxyquinolin-4(1H)-one (510 mg, 1.56
mmol), Et3N (1.2 mL, 8.61 mmol), and AcCl (1.0 mL, 14.1
mmol) in CH2Cl2 (10 mL) was heated for 1 h, it was treated
with water and evaporated. The residue was dissolved in
AcOEt, and the organic solution was washed successively with
water and saturated NaCl, dried (Na2SO4), and evaporated.
The residue was purified by chromatography (50% AcOEt-
hexane) to give 1-acetyl-5-[(benzyloxycarbonyl)amino]-2,3-di-
hydro-8-methoxyquinolin-4(1H)-one as a pale-yellow solid (566
mg, 98%). 1-Acetyl-5-[(benzyloxycarbonyl)amino]-2,3-dihydro-
8-methoxyquinolin-4(1H)-one (566 mg, 1.54 mmol) and 10%
Pd/C (100 mg) in a mixture of EtOH (10 mL) and dioxane (10
mL) was stirred in an atmosphere of H2 for 0.5 h. The catalyst
was removed by filtration, and the filtrate was concentrated.
The residue was purified by chromatography (50% AcOEt-
hexane) to give 23 as a yellow solid (358 mg, 99%).
A
rated. The residue was recrystallized (CHCl3
27 as a pale-green solid (353 mg, 73%).
-Et2O) to afford
(RS)-5-Am in o-2,3-dih ydr o-4,9-dih ydr oxy-9-eth yl-1H,12H-
ben zo[de]pyr an o[3′,4′:6,7]in dolizin o[1,2-b]qu in olin e-10,13-
(9H,15H)-d ion e (28). A solution of 27 (100 mg, 0.40 mmol),
tricyclic ketone 7a (106 mg, 0.40 mmol), and a small amount
of p-TsOH‚H2O in AcOH (5 mL) was refluxed for 5 h before
the solvent was evaporated. The residue was purified by
chromatography (1% MeOH-CHCl3) and recrystallization
(CHCl3-Et2O) to give (RS)-5-acetamido-9-ethyl-2,3-dihydro-
9-hydroxy-4-methoxy-1H,12H-benzo[de]pyrano[3′,4′:6,7]indoliz-
ino[1,2-b]quinoline-10,13(9H,15H)-dione as a pale-yellow solid
(83 mg, 43%). A mixture of this camptothecin analogue (39
mg, 0.082 mmol) in 47% HBr (2 mL) was heated to reflux for
7 h, diluted with water (50 mL), and passed through HP20
column. After the column was washed with water, methanolic
eluent was condensed and purified with reverse-phase HPLC
to afford 28 (6 mg, 17%): mp >260 °C; MS (FAB) 420 (M +
(RS)-3-Acetyl-2,3-dih ydr o-9-eth yl-9-h ydr oxy-4-m eth oxy-
1H ,12H -p yr a n o[3′,4′:6,7]in d olizin o[1,2-c]b en zo[ij][2,7]-
n a p h th yr id in e-10,13(9H,15H)-d ion e (24). A solution of 23
(773 mg, 3.30 mmol) and 7a (780 mg, 2.96 mmol) in AcOH (20
mL) was heated to reflux under N2 for 5 h. The precipitate
obtained after concentration and dilution with acetone was
collected and washed successively with acetone, AcOEt, and
CHCl3 to give 24 as a pale-yellow solid (584 mg, 38%): mp
292-295 °C dec; MS (FAB) m/z 462 (M + H); 1H NMR (DMSO-
d6) δ 0.88 (t, 3H, J ) 7 Hz), 1.88 (q, 2H, J ) 7 Hz), 2.00 (s,
3H), 3.14-3.44 (m, 4H), 4.02 (s, 3H), 5.25 (brs, 2H), 5.43 (brs,
2H), 6.49 (s, 1H), 7.30 (s, 1H), 7.84 (d, 1H, J ) 9 Hz), 8.08 (d,
1H, J ) 9 Hz). Anal. (C25H23N3O6‚1/4H2O) C, H, N.
(RS)-2,3-Dih ydr o-9-eth yl-9-h ydr oxy-4-m eth oxy-1H,12H-
p y r a n o [ 3 ′,4 ′:6 ,7 ] i n d o l i z i n o [ 1 ,2 -c ] b e n z o [ i j ] [ 2 ,7 ] -
n a p h t h yr id in e-10,13(9H,15H)-d ion e (25). Compound 24
(114 mg, 0.24 mmol) in 47% aqueous HBr (5 mL) was heated
to reflux under N2 for 2 h. The mixture was poured into ice-
water, and the precipitate obtained was washed successively
with water, acetone, and EtOH to give 25 as a dark-green solid
1
H); H NMR (DMSO-d6) δ 0.88 (t, 3H, J ) 7 Hz), 1.9-2.6 (m,
4H), 2.9-3.8 (m, 4H), 5.10 (s, 2H), 5.40 (s, 2H), 7.00 (s, 1H),
7.17 (s, 1H). Anal. (C23H21N3O5‚2.2H2O) C, H, N.
8-Am in o-5-cyan o-3,4-dih ydr o-1(2H)-n aph th alen on e (30).
KNO3 (4.16 g, 41.1 mmol) in cooled (-10 °C) H2SO4 (30 mL)
was added dropwise to a solution of 29 (7.7 g, 34.3 mmol) in
H2SO4 (30 mL) over a period of 1.5 h. After being stirred for
0.5 h, the reaction mixture was poured into ice-water and
extracted with CHCl3. The combined organic phase was
washed successively with saturated Na2CO3, water, and
saturated NaCl, dried (Na2SO4), and evaporated. The residue
was chromatographed (CHCl3) and recrystallized (EtOH) to
give 5-bromo-3,4-dihydro-8-nitro-1(2H)-naphthalenone (4.68 g,
51%) as a pale-brown solid. A mixture of 5-bromo-8-nitro-3,4-
dihydro-1(2H)-naphthalenone (1.63 g, 6.05 mmol) and CuCN
(650 mg, 7.26 mmol) in DMF (7 mL) was heated to reflux for
2 h. The mixture was added to a mixture of FeCl3‚6H2O (2.5
g, 9.25 mmol) in 0.43 N HCl (16.6 mL), which was warmed to
60-70 °C for 30 min. After the mixture was filtered by Celite,
the filtrate was extracted with AcOEt, and the organic phase
was washed successively with water, saturated NaHCO3, and
NaCl, dried, and concentrated. The residue was purified with
chromatography (20% hexane-CHCl3) and recrystallization
(AcOEt-hexane) to give 5-cyano-3,4-dihydro-8-nitro-1(2H)-
naphthalenone as a colorless solid (540 mg, 41%). To a
suspension of 5-cyano-3,4-dihydro-8-nitro-1(2H)-naphtha-
lenone (100 mg, 0.46 mmol) in MeOH (0.5 mL) and concen-
trated HCl (3.5 mL) was added Fe powder (120 mg, 2.15 mmol)
in portions, and the mixture was warmed to 70 °C. The
mixture was partitioned between AcOEt and water, and the
organic phase was dried (Na2SO4), concentrated, and purified
with TLC (CHCl3) to give 30 as a colorless solid (50 mg, 58%).
1
(84 mg, 81%): mp >300 °C dec; MS (FAB) 420 (M + H); H
NMR (DMSO-d6) δ 0.88 (t, 3H, J ) 7 Hz), 1.86 (q, 2H, J ) 7
Hz), 3.1-3.8 (m, 4H), 3.94 (s, 3H), 5.20 (brs, 2H), 5.41 (brs,
2H), 7.27 (s, 1H), 7.38 (d, 1H, J ) 9 Hz), 7.59 (d, 1H, J ) 9
Hz). Anal. (C23H21N3O5‚2.1H2O) C, H, N.
6-Acet a m id o-8-a m in o-3,4-d ih yd r o-5-m et h oxy-1(2H )-
n a p h th a len on e (27). A mixture of 3,4-dihydro-5-hydroxy-
6-nitro-1(2H)-naphthalenone (26)27 (5.1 g, 24.6 mmol), MeI (2.3
mL, 36.9 mmol), and K2CO3 (3.55 g, 25.7 mmol) in acetone
(100 mL) was heated to reflux for 12 h. After concentration
of the mixture, the residue was dissolved in AcOEt and washed
successively with water, saturated NaHCO3, and saturated
NaCl. The organic phase was dried (Na2SO4) and evaporated
in vacuo. The residue was purified by chromatography (20%
AcOEt-hexane) to give 3,4-dihydro-5-methoxy-6-nitro-1(2H)-
naphthalenone (5.3 g, 97%). A suspension of 3,4-dihydro-5-
methoxy-6-nitro-1(2H)-naphthalenone (5.04 g, 22.3 mmol) and
10% Pd/C (1.28 g) in a mixture of dioxane (30 mL) and EtOH
(60 mL) was hydrogenated at atmospheric pressure for 2 h.
After catalyst was filtered, the solvent was evaporated. To a
solution of the residue and Et3N (4.8 mL, 34.4 mmol) in CH2-
Cl2 (10 mL) was added AcCl (3.2 mL, 45.0 mmol) in CH2Cl2
(10 mL). After being stirred for 1 h, the solution was washed
successively with saturated NaHCO3 and saturated NaCl,
dried (Na2SO4), and evaporated. The residue was purified by
chromatography (CHCl3) and recrystallization (CHCl3-Et2O-
hexane) to give 6-acetamido-3,4-dihydro-5-methoxy-1(2H)-
naphthalenone as a colorless solid (3.06 g, 58%). To a solution
of 6-acetamido-3,4-dihydro-5-methoxy-1(2H)-naphthalenone (1
g, 4.29 mmol) in H2SO4 (10 mL) was added KNO3 (480 mg,
4.75 mmol) in portions at 0 °C. After being stirred for 1 h,
the reaction mixture was poured into ice-water and extracted
with CHCl3. The combined organic phase was washed suc-
cessively with saturated NaHCO3, water, and saturated NaCl,
dried (Na2SO4), and evaporated. The residue was chromato-
graphed (10% AcOEt-CHCl3) to give 6-acetamido-3,4-dihydro-
(RS)-4-Cya n o-2,3-d ih yd r o-9-et h yl-9-h yd r oxy-1H ,12H -
ben zo[de]pyr an o[3′,4′:6,7]in dolizin o[1,2-b]qu in olin e-10,13-
(9H,15H)-d ion e (31). Compound 30 (46 mg, 0.25 mmol), 7a
(83 mg, 0.32 mmol), and a catalytic amount of p-TsOH‚H2O
in toluene (5 mL) was heated to reflux using a Dean-Stark
trap for 6 h. The precipitate obtained after cooling was washed
successively with AcOEt and MeOH and purified by chroma-
tography (3% MeOH-CHCl3) and recrystallization (CHCl3-
MeOH-acetone) to give 31 as a pale-yellow solid (61 mg,
60%): mp >300 °C dec; IR (KBr) 2950, 2224, 1752, 1662, 1611
1
cm-1; H NMR (DMSO-d6) δ 0.89 (t, 3H, J ) 7 Hz), 1.88 (q,
2H, J ) 7 Hz), 1.9-2.4 (m, 2H), 3.1-3.5 (m, 4H), 5.27 (s, 2H),
5.43 (s, 2H), 6.47 (s, 1H), 7.37 (s, 1H), 8.01 (s, 1H), 8.04 (s,
1H). Anal. (C24H19N3O4‚3/4H2O) C, H, N.
5,8-Dia m in o-3,4-d ih yd r o-1(2H )-n a p h t h a len on e‚2H Cl
(33). To a solution of CrO3 (24 g, 240 mmol) in water (100
mL) which was diluted with AcOH (350 mL) was added
8-acetamido-5-nitro-1,2,3,4-tetrahydronaphthalene (32) (14 g,
59.8 mmol) in AcOH (330 mL), and the mixture was stirred

2314 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Sugimori et al.
for 6 h at room temperature and for 3 h at 60 °C. The solvent
was concentrated, and the resultant residue was suspended
with dilute HCl. After the mixture was extracted with CHCl3,
the organic phase was washed successively with water,
saturated NaHCO3, and saturated NaCl and concentrated. The
residue was purified by chromatography (50% AcOEt-toluene)
to give 8-acetamido-3,4-dihydro-5-nitro-1(2H)-naphthalenone
(6.95 g, 47%): mp 159 °C. 8-Acetamido-3,4-dihydro-5-nitro-
1(2H)-naphthalenone (60 mg, 0.242 mmol) in 6 N HCl (2 mL)
was heated to reflux for 30 min before the mixture was
neutralized with NaHCO3 and extracted with CHCl3. The
combined organic phase was washed with saturated NaCl,
dried (Na2SO4), and evaporated to give 8-amino-3,4-dihydro-
5-nitro-1(2H)-naphthalenone as a yellow solid (40 mg, 80%).
A suspension of 8-amino-3,4-dihydro-5-nitro-1(2H)-naphtha-
lenone (40 mg, 0.194 mmol) and PtO2 (6 mg) in EtOH (2 mL)
and AcOEt (2 mL) was stirred under H2 gas. The mixture was
filtered, and the solvent was treated with concentrated HCl
and concentrated to give 33 as a solid (49 mg, q).
solid (1.2 g, 68%). To a solution of 5-acetamido-7-chloro-3,4-
dihydro-1(2H)-naphthalenone (1 g, 4.21 mmol) in trifluoroace-
tic acid (20 mL) was added dropwise Et3SiH (5 g, 9.3 mmol).
The stirring was continued at room temperature for 24 h. The
reaction mixture was poured into ice-water, neutralized with
NaHCO3, and extracted with CHCl3. The combined organic
phase was washed successively with water and saturated
NaCl, dried (Na2SO4), and evaporated. Column chromatog-
raphy (CHCl3) of the residue gave 37 (650 mg, 69%).
8-Am in o-6-ch lor o-3,4-d ih yd r o-1(2H )-n a p h t h a len on e
(38). To a solution of 37 (629 mg, 2.81 mmol) in a mixture of
acetone (40 mL) and 15% aqueous MgSO4 (2.6 mL) was added
KMnO4 (1.33 g, 8.4 mmol) in portions at 0 °C. The reaction
mixture was stirred for 2 h and diluted with water. The
mixture was extracted with CHCl3, and the organic phase was
washed with saturated NaCl, dried (Na2SO4), and evaporated.
Column chromatography (CHCl3) of the residue gave 8-acet-
amido-6-chloro-3,4-dihydro-1(2H)-naphthalenone (320 mg, 48%).
8-Acetamido-6-chloro-3,4-dihydro-1(2H)-naphthalenone (140
mg, 0.589 mmol) in 6 N HCl (7 mL) was heated at 90 °C for 3
h. The reaction mixture was cooled, neutralized with Na2CO3,
and extracted with AcOEt. The combined organic phase was
washed with saturated NaCl, dried (Na2SO4), and concentrated
to afford 38 as a colorless solid (110 mg, 95%).
(RS)-4-Am in o-2,3-d ih yd r o-9-et h yl-9-h yd r oxy-1H ,12H -
ben zo[de]pyr an o[3′,4′:6,7]in dolizin o[1,2-b]qu in olin e-10,13-
(9H,15H)-d ion e (34). Compound 33 (49 mg, 0.197 mmol), 7a
(91 mg, 0.346 mmol), and PPTS (5 mg, 0.02 mmol) in AcOH
(3 mL) were heated for 3 h. The mixture was concentrated,
and the residue was chromatographed (1% MeOH-CHCl3) and
washed with AcOEt and MeOH to afford 34 as a yellow solid
(14 mg, 18%): mp 240-245 °C dec; MS m/z (FAB) 404 (M +
(9S)-5-Ch lor o-2,3-d ih yd r o-9-et h yl-9-h yd r oxy-1H ,12H -
ben zo[de]pyr an o[3′,4′:6,7]in dolizin o[1,2-b]qu in olin e-10,13-
(9H,15H)-d ion e (39). A solution of 38 (50 mg, 0.26 mmol),
tricyclic ketone 7b (65 mg, 0.25 mmol), and PPTS (2 mg, 0.008
mmol) in toluene (20 mL) was refluxed using a Dean-Stark
trap for 3 h. p-TsOH‚H2O (2 mg, 0.01 mmol) was then added,
and refluxing was continued for an additional 24 h. The
reaction mixture was diluted with CHCl3, washed successively
with 10% HCl, water, and saturated NaCl, dried (Na2SO4), and
evaporated. The residue was washed with acetone and chro-
matographed (CHCl3) to give 39 as a colorless solid (30 mg,
28%): mp >270 °C dec; MS m/z 422 (M+), 423 (M + 1), 424
1
H), 369 (M - CO2); H NMR (DMSO-d6) δ 0.89 (t, 3H, J ) 8
Hz), 1.87 (q, 2H, J ) 8 Hz), 1.8-2.2 (m, 2H), 2.6-2.9 (m, 2H),
2.9-3.2 (m, 2H), 5.17 (s, 2H), 5.39 (s, 2H), 6.38 (s, 1H), 7.19
(s, 1H), 7.29 (d, 1H, J ) 9 Hz), 7.71 (d, 1H, J ) 9 Hz). Anal.
(C23H21N3O4‚2H2O) C, H, N.
4-(2-Aceta m id o-4-ch lor op h en yl)bu tyr ic Acid (36). 4-(4-
Chlorophenyl)butyric acid (35) (17 g, 85.6 mmol) and H2SO4
(0.5 mL) in MeOH (300 mL) were heated to reflux for 3 h. After
the mixture was concentrated, the residue was partitioned
between water and AcOEt; the organic phase was dried and
concentrated to yield methyl 4-(4-chlorophenyl)butyrate as a
colorless oil (18 g, 99%). KNO3 (9.4 g, 93.1 mmol) in H2SO4
(30 mL) was added dropwise to a solution of methyl 4-(4-
chlorophenyl)butyrate (18 g, 84.6 mmol) in H2SO4 (30 mL) at
0 °C over a period of 1 h. After being stirred for 2 h, the
reaction mixture was poured into ice-water and extracted
with AcOEt. The combined organic phase was washed suc-
cessively with water and saturated NaCl, dried (Na2SO4), and
evaporated to give a yellow oil, which was chromatographed
(50% CHCl3-hexane) to give methyl 4-(4-chloro-2-nitro-
phenyl)butyrate (3.5 g, 16%). A mixture of methyl 4-(4-chloro-
2-nitrophenyl)butyrate (3.5 g, 13.6 mmol) and PtO2 (200 mg)
in MeOH (50 mL) was stirred in an atomosphere of H2 for 2.5
h. The catalyst was removed by filtration, and the filtrate was
concentrated. To a solution of the residue in CH2Cl2 (50 mL)
was added Ac2O (5 mL, 53.0 mmol), and stirring was continued
for 2 h. The mixture was concentrated to afford methyl 4-(2-
acetamido-4-chlorophenyl)butyrate (3.6 g, 98%). A mixture of
methyl 4-(2-acetamido-4-chlorophenyl)butyrate (7.4 g, 27.4
mmol), 10% NaOH (20 mL), and MeOH (50 mL) was stirred
at room temperature for 1 h. The mixture was concentrated
and acidified with 10% HCl. The resulting precipitate was
collected, washed with water, and dried to afford 36 as a
colorless solid (4.9 g, 70%).
5-Acet a m id o-7-ch lor o-1,2,3,4-t et r a h yd r on a p h t h a len e
(37). Compound 36 (1.9 g, 7.43 mmol), Na2CO3 (0.8 g, 7.5
mmol), and SOCl2 (0.55 mL, 7.5 mmol) in CH2Cl2 (20 mL) were
heated at reflux for 40 min. The insoluble solid was removed
by filtration, and the filtrate was concentrated. The resulting
residue was added to AlCl3 (2 g, 15 mmol) in 1,2-dichloroethane
(20 mL), and the mixture was heated at 70 °C for 2 h. After
the reaction mixture was poured into ice-water, the aqueous
solution was extracted with CHCl3. The combined organic
phase was washed successively with water, saturated NaH-
CO3, and saturated NaCl, dried (Na2SO4), and evaporated. The
residue was recrystallized (AcOEt-n-hexane) to give 5-acet-
amido-7-chloro-3,4-dihydro-1(2H)-naphthalenone as a colorless
1
(M + 2); H NMR (DMSO-d6) δ 0.89 (t, 3H, J ) 7.8 Hz), 1.87
(m, 2H), 2.07 (m, 2H), 3.15 (m, 4H), 5.20 (s, 2H), 5.43 (s, 2H),
6.52 (s, 1H), 7.32 (s, 1H), 7.47 (d, 1H, J ) 1.8 Hz), 7.98 (d, 1H,
J ) 1.8 Hz). Anal. (C23H19ClN2O4‚1/4H2O) C, H, N.
4-(2-Acetam ido-4-flu or oph en yl)bu tyr ic Acid (41). KNO3
(53 g, 0.524 mmol) in H2SO4 (300 mL) was added dropwise to
a solution of methyl 4-(4-fluorophenyl)butyrate (40) (100 g,
0.510 mol) in H2SO4 (600 mL) at 0 °C over a period of 2 h.
After being stirred for 1.5 h, the reaction mixture was poured
into ice-water and extracted with CHCl3. The combined
organic phase was washed with saturated NaCl, dried (Na2-
SO4), and evaporated to give a crude product, which was
chromatographed (6% AcOEt-n-hexane) to give methyl 4-(4-
fluoro-2-nitrophenyl)butyrate (48.9 g, 44%). A mixture of
methyl 4-(4-fluoro-2-nitrophenyl)butyrate (41.8 g, 165 mmol)
and 10% Pd/C (4 g) in MeOH (250 mL) was stirred in an
atomosphere of H2 for 1.5 h. After the catalyst was removed
by filtration, the filtrate was concentrated. To a solution of
the residue in CH2Cl2 (150 mL) were added Et3N (46 mL, 330
mmol) and AcCl (17 mL, 248 mmol) at 0 °C, and stirring was
continued for 1 h. The mixture was acidified with 1 N HCl
(100 mL) and extracted with CHCl3. The combined organic
extract was washed successively with water and saturated
NaCl, dried (Na2SO4), and concentrated to afford methyl 4-(2-
acetamido-4-fluorophenyl)butyrate (41.8 g, 100%). A mixture
of methyl 4-(2-acetamido-4-fluorophenyl)butyrate (41.8 g, 165
mmol), 2 N NaOH (170 mL), and MeOH (100 mL) was heated
at 50 °C for 2 h. The mixture was cooled, acidified with
concentrated HCl, and extracted with AcOEt. The combined
organic extract was washed with saturated NaCl, dried (Na2-
SO4), and concentrated to afford 41 (33.4 g, 85%).
5-Acet a m id o-7-flu or o-1,2,3,4-t et r a h yd r on a p h t h a len e
(42). Compound 41 (33.4 g, 140 mmol), Na2CO3 (15.1 g, 142
mmol), and SOCl2 (10.7 mL,147 mmol) in CH2Cl2 (500 mL)
were heated at reflux for 2 h. The insoluble solid was removed
by filtration, and the filtrate was concentrated. The resulting
residue was combined with 1,2-dichloroethane (200 mL) and
AlCl3 (40 g, 300 mmol) and refluxed for 2 h. The reaction

Ring A- and F-Modified Camptothecin Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2315
mixture was cooled to 0 °C and acidified with 1 N HCl. The
aqueous solution was extracted with CHCl3, and the combined
organic phase was washed with saturated NaCl, dried (Na2-
SO4), and evaporated. Column chromatography (3% MeOH-
CHCl3) of the residue gave 5-acetamido-7-fluoro-3,4-dihydro-
1(2H)-naphthalenone (13.3 g, 36%). 5-Acetamido-7-fluoro-3,4-
dihydro-1(2H)-naphthalenone (9 g, 40.7 mmol) in a mixture
of HClO4 (5 mL) and AcOH (300 mL) was treated with 10%
Pd/C (5 g) and hydrogenated at 5 atm for 18 h. The catalyst
was removed, and the solvent was evaporated. The residue
was partitioned between water and CHCl3. The organic layer
was washed successively with saturated NaHCO3 and NaCl,
dried (Na2SO4), and concentrated to afford 42 (6.83 g, 81%).
was subjected to chromatography (3% MeOH-CHCl3) to give
a mixture of 47 and 48 (110 mg).
8-Am in o-5,6-d iflu or o-3,4-d ih yd r o-1(2H )-n a p h t h a le -
n on e (49) a n d 8-Am in o-5,6-d iflu or o-4-h yd r oxy-3,4-d ih y-
d r o-1(2H)-n a p h th a len on e (50). Starting from the above
mixture (105 mg) and KMnO4 (223 mg, 1.41 mmol), and
following the same procedure as described for 8-acetamido-6-
chloro-3,4-dihydro-1(2H)-naphthalenone, a mixture of 8-acet-
amido-5,6-difluoro-3,4-dihydro-1(2H)-naphthalenone and 8-acet-
amido-4-acetoxy-5,6-difluoro-3,4-dihydro-1(2H)-naphtha-
lenone (100 mg) was obtained as a pale-yellow solid. Starting
from the above mixture (95 mg) and 4 N HCl (4.5 mL), and
following the same procedure as described for 8-amino-6-
chloro-3,4-dihydro-1(2H)-naphthalenone, a mixture of 49 and
50 (67 mg) was obtained.
(9S)-4,5-Diflu or o-2,3-d ih yd r o-9-et h yl-9-h yd r oxy-1H ,-
12H-ben zo[d e]pyr a n o[3′,4′:6,7]in d olizin o[1,2-b]qu in olin e-
10,13(9H,15H)-d ion e (51) a n d (9S)-4,5-Diflu or o-2,3-d ih y-
d r o-3,9-d ih yd r oxy-9-eth yl-1H,12H-ben zo[d e]p yr a n o[3′,4′:
6,7]in d olizin o[1,2-b]qu in olin e-10,13(9H,15H)-d ion e (52).
A mixture of 49 and 50 (67 mg), 7b (90 mg, 0.342 mmol), and
PPTS (5 mg, 0.02 mmol) in toluene (10 mL) was heated to
reflux for 24 h. After the mixture was concentrated, the
residue in AcOH (4 mL) was heated at 100 °C for 2 h. The
mixture was evaporated and chromatographed (3% MeOH-
CHCl3) to give 51 (11 mg, 4% from 5-acetamido-7,8-difluoro-
3,4-dihydro-1(2H)-naphthalenone) and 52 (17 mg, 6% from
5-acetamido-7,8-difluoro-3,4-dihydro-1(2H)-naphthalenone).
(9S)-2,3-Dih yd r o-9-et h yl-5-flu or o-9-h yd r oxy-1H ,12H -
ben zo[de]pyr an o[3′,4′:6,7]in dolizin o[1,2-b]qu in olin e-10,13-
(9H,15H)-d ion e (44). To a solution of 42 (18 g, 87.3 mmol)
in a mixture of acetone (800 mL) and 15% aqueous MgSO4
was added KMnO4 (28.2 g, 178 mmol) in portions. The
reaction mixture was stirred at room temprature for 1 h and
diluted with water. The mixture was extracted with CHCl3,
and the organic phase was washed successively with water
and saturated NaCl, dried (Na2SO4), and evaporated to give
8-acetamido-3,4-dihydro-6-fluoro-1(2H)-naphthalenone (18.8 g,
97%). 8-Acetamido-3,4-dihydro-6-fluoro-1(2H)-naphthalenone
(92 mg, 0.416 mmol) in 4 N HCl (8 mL) was heated to reflux
for 1 h. The reaction mixture was cooled, diluted with water
(10 mL), and extracted with AcOEt. The combined organic
phase was washed successively with saturated NaHCO3 and
saturated NaCl, dried (Na2SO4), and concentrated to afford
crude 8-amino-3,4-dihydro-6-fluoro-1(2H)-naphthalenone (43)
as a brown solid. The residue, tricyclic ketone 7b (98 mg, 0.374
mmol), and a catalytic amount of PPTS in toluene (5 mL) was
refluxed using a Dean-Stark trap for 20 h. The reaction
mixture was concentrated, and the residue was purified
successively with preparative TLC (Whatman, PLK5F) and
recrystallization (EtOH) to give 44 as a colorless solid (32 mg,
19%): mp >220 °C dec; IR (KBr) 3424, 2944, 1754, 1660, 1614,
1250, 1162 cm-1; MS (FD) m/z 406 (M+); 1H NMR (DMSO-d6)
δ 0.89 (t, 3H, J ) 7 Hz), 1.87 (m, 2H), 2.08 (m, 2H), 3.16 (m,
4H), 5.20 (s, 2H), 5.42, 5.43 (ABq, 2H, J ) 16 Hz), 6.50 (s,
1H), 7.32 (s, 1H), 7.37 (d, 1H, J ) 9 Hz), 7.66 (d, 1H, J ) 10
Hz). Anal. (C23H19FN2O4‚4/5H2O) C, H, N.
4-(2-Aceta m id o-4,5-d iflu or op h en yl)bu tyr ic Acid (46).
Starting from 4-(3,4-difluorophenyl)butyric acid (45) (500 mg,
2.50 mmol) and KNO3 (371 mg, 3.67 mmol), and following the
same procedure as described for 6-acetamido-3,4-dihydro-5-
methoxy-8-nitro-1(2H)-naphthalenone, 4-(4,5-difluoro-2-nitro-
phenyl)butyric acid (480 mg, 78%) was obtained as a pale-
yellow solid. 4-(4,5-Difluoro-2-nitrophenyl)butyric acid (380
mg, 1.55 mmol) and 10% Pd/C (60 mg) in AcOH (5 mL) and
Ac2O (10 mL) were stirred in an atmosphere of H2. After the
catalyst was removed by filtration, the solution was concen-
trated and subjected to chromatography (9% MeOH-CHCl3)
to give 46 (90 mg, 23%).
5-Acet a m id o-7,8-d iflu or o-1,2,3,4-t et r a h yd r on a p h t h a -
len e (47) a n d 5-Aceta m id o-1-a cetoxy-7,8-d iflu or o-1,2,3,4-
tetr a h yd r on a p h th a len e (48). A solution of 46 (9.07 g, 35.3
mmol) in CH2Cl2 (450 mL) was treated with PCl5 (7.71 g, 37.0
mmol), stirred for 1 h, and concentrated. To a solution of the
residue in 1,2-dichloroethane (500 mL) was added AlCl3 (9.88
g, 74.1 mmol), and the mixture was heated to reflux for 15 h.
The mixture was poured into ice-water, and the aqueous
solution was extracted with AcOEt. The organic solution was
washed with saturated NaCl, dried (Na2SO4), and concen-
trated. The residue was subjected to chromatography (2%
MeOH-CHCl3) to give 5-acetamido-7,8-difluoro-3,4-dihydro-
1(2H)-naphthalenone (2.31 g, 27%). A mixture of 5-acetamido-
7,8-difluoro-3,4-dihydro-1(2H)-naphthalenone (180 mg, 0.752
mmol), 60% HClO4 (0.25 mL), and 10% Pd/C (30 mg) in AcOH
(7.5 mL) was stirred in an atmosphere of H2 (6.5 atm). After
the catalyst was removed by filtration, the solution was
concentrated. The residue was dissolved with CHCl3, and the
solution was washed successively with saturated NaHCO3 and
saturated NaCl, dried (Na2SO4), and evaported. The residue
51: mp 210-220 °C dec; IR (KBr) 1748, 1662, 1612, 1158 cm-1
;
MS m/z 424 (M+); 1H NMR (DMSO-d6) δ 0.86 (t, 3H, J ) 7
Hz), 1.7-1.9 (m, 2H), 1.9-2.1 (m, 2H), 2.9-3.4 (m, 4H), 5.27
(s, 2H), 5.43 (s, 2H), 6.51 (s, 1H), 7.30 (s, 1H), 8.00 (dd, 1H, J
) 8, 12 Hz). Anal. (C23H18F2N2O4‚1/4H2O) C, H, N. 52: mp
220-240 °C dec; IR (KBr) 1746, 1660, 1602, 1158 cm-1; MS
1
m/z 440 (M+); H NMR (DMSO-d6) δ 0.88 (t, 3H, J ) 7 Hz),
1.7-2.0 (m, 2H), 1.8-3.4 (m, 4H), 5.27, 5.36 (ABq, 2H, J ) 19
Hz), 5.44 (s, 2H), 5.3-5.8 (m, 2H), 6.52 (s, 1H), 7.32 (s, 1H),
8.13 (dd, 1H, J ) 8, 12 Hz); Anal. (C23H18F2N2O5‚3/4H2O) C,
H, N.
4-(4-F lu or o-5-m eth yl-2-n itr op h en yl)bu tyr ic Acid (54).
A solution of 4-(4-fluoro-3-methylphenyl)butyric acid (53) (25.4
g, 0.129 mol) and p-TsOH‚H2O (650 mg, 3.42 mmol) in MeOH
(300 mL) was heated to reflux for 3 h. After the solvent was
removed in vacuo, the residue was dissolved in AcOEt and
washed successively with water, saturated NaHCO3, and
saturated NaCl. The solution was dried (Na2SO4) and con-
centrated to give methyl 4-(4-fluoro-3-methylphenyl)butyrate
(17.9 g, 66%). KNO3 (5.77 g, 57.1 mmol) in H2SO4 (15 mL)
was added dropwise to a solution of methyl 4-(4-fluoro-3-
methylphenyl)butyrate (10.9 g, 51.8 mmol) in H2SO4 (6 mL)
at 0 °C. After being stirred for 20 min, the reaction mixture
was poured into ice-water and extracted with AcOEt. The
combined organic phase was washed successively with water,
saturated NaHCO3, and saturated NaCl, dried (Na2SO4), and
evaporated to give an oil, which was chromatographed (9%
AcOEt-n-hexane) to give methyl 4-(4-fluoro-5-methyl-2-nitro-
phenyl)butyrate (7.12 g, 54%). A mixture of methyl 4-(4-fluoro-
5-methyl-2-nitrophenyl)butyrate (7.10 g, 27.8 mmol), 15%
NaOH (10 mL), and MeOH (20 mL) was stirred at room
temperature for 3 h. The mixture was concentrated, diluted
with water, acidified with concentrated HCl, and extracted
with CHCl3. The combined organic phase was washed with
water and saturated NaCl, dried (Na2SO4), and concentrated
to afford 54 (6.35 g, 95%): mp 78-79 °C.
8-Acetam ido-6-flu or o-5-m eth yl-1,2,3,4-tetr ah ydr on aph -
th a len e (55). Compound 54 (3.0 g, 12.4 mmol) was added in
portions to stirred PPA (50 mL) at 110 °C. After stirring was
continued for 4.5 h, the mixture was poured into water and
extracted with AcOEt. The combined extracts were washed
successively with water and saturated NaCl, dried (Na2SO4),
and concentrated. The residue was chromatographed (50%
CHCl3-n-hexane) to give 7-fluoro-8-methyl-5-nitro-3,4-dihy-
dro-1(2H)-naphthalenone (1.75 g, 63%): mp 78-79 °C. To a
solution of 7-fluoro-8-methyl-5-nitro-3,4-dihydro-1(2H)-naph-

2316 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Sugimori et al.
thalenone (1.35 g, 6.05 mmol) in a mixture of THF (15 mL)
and EtOH (5 mL) was added NaBH4 (114 mg, 3.01 mmol), and
the mixture stirred for 20 min. After removal of the solvent,
the residue and p-TsOH‚H2O (840 mg, 4.42 mmol) in toluene
(25 mL) were heated to reflux for 30 min. The mixture was
diluted with AcOEt, washed successively with water and
saturated NaCl, dried (MgSO4), and concentrated to give crude
1,2-dihydro-6-fluoro-5-methyl-8-nitronaphthalene. A suspen-
sion of the residue and PtO2 (400 mg) in AcOEt (20 mL) was
hydrogenated at atmospheric pressure for 4 h. After catalyst
was filtered, the solvent was evaporated to give 8-amino-6-
fluoro-5-methyl-1,2,3,4-tetrahydronaphthalene as a yellow oil
(1.07 g, 99%). To a solution of 8-amino-6-fluoro-5-methyl-
1,2,3,4-tetrahydronaphthalene (1.07 g, 5.97 mmol) in CH2Cl2
were added Et3N (1.00 mL, 7.17 mmol) and Ac2O (0.68 mL,
7.21 mmol), and stirring was continued for 40 min. The
mixture was diluted with CHCl3, washed successively with
aqueous HCl, saturated NaHCO3, and saturated NaCl, dried
(MgSO4), and concentrated to give 55 (1.23 g, 93%).
water, dilute HCl, and saturated NaCl, dried, and concen-
trated. A mixture of the residue in MeOH (20 mL) and 1 N
NaOH (10 mL) was heated at 50-60 °C for 1.5 h before
concentration. After the residue was dissolved in water, the
solution was washed with Et2O, acidified with dilute HCl, and
extracted with AcOEt. The organic phase was washed with
saturated NaCl, dried (Na2SO4), and evaporated to afford 59
as a pale-red solid (903 mg, 93%).
(9S)-9-Eth yl-2,3-d ih yd r o-9-h yd r oxy-5-m eth yl-1H,12H-
ben zo[de]pyr an o[3′,4′:6,7]in dolizin o[1,2-b]qu in olin e-10,13-
(9H,15H)-d ion e (62). To a mixture of 59 (1.1 g, 4.68 mmol)
and Na2CO3 (500 mg, 4.72 mmol) in CH2Cl2 (20 mL) was added
SOCl2 (0.52 mL, 7.13 mmol), and the mixture was heated to
reflux for 1 h. The mixture was filtered, and the filtrate was
concentrated. The residue in CH2Cl2 (6 mL) was treated with
AlCl3 (1.8 g, 13.5 mmol) and heated to reflux for 6 h. The
mixture was poured into dilute HCl, and the aqueous solution
was extracted with CHCl3. The organic solution was washed
successively with 1 N NaOH and saturated NaCl, dried (Na2-
SO4), and concentrated. The residue was subjected to chro-
matography (20% AcOEt-CHCl3) to give 5-acetamido-7-methyl-
3,4-dihydro-1(2H)-naphthalenone (386 mg, 38%). A mixture
of 5-acetamido-3,4-dihydro-7-methyl-1(2H)-naphthalenone (375
mg, 1.73 mmol), HClO4 (1 mL), and 10% Pd/C (200 mg) in
AcOH (18 mL) was stirred in an atmosphere of H2 (5 atm).
After the catalyst was removed by filtration, the solution was
concentrated. The residue was dissolved with CHCl3, and the
solution was washed successively with saturated NaHCO3 and
saturated NaCl, dried (Na2SO4), and evaporated to afford crude
5-acetamido-7-methyl-1,2,3,4-tetrahydronaphthalene (60). To
a cooled mixture (0 °C) of the residue and 15% MgSO4 (2.5
mL) in acetone (25 mL) was added KMnO4 (0.82 g, 5.19 mmol)
in portions, and the mixture was stirred for 1 h at room
temperature. The mixture was partitioned between CHCl3
and water, and the organic phase was dried (Na2SO4) and
concentrated. The residue was subjected to chromatography
(25% AcOEt-hexane) to give 8-acetamido-3,4-dihydro-6-meth-
yl-1(2H)-naphthalenone (250 mg, 67%). A mixture of 8-acet-
amido-3,4-dihydro-6-methyl-1(2H)-naphthalenone (80 mg, 0.368
mmol) in 4 N HCl (4 mL) was heated to 100 °C for 1 h. The
solution was basified with NaHCO3 and extracted with AcOEt,
and the organic solution was dried (Na2SO4), concentrated, and
subjected to chromatography (0.5% MeOH-CHCl3) to give
8-amino-3,4-dihydro-6-methyl-1(2H)-naphthalenone (61) (61
mg). The residue, 7b (90 mg, 0.342 mmol) and catalytic
amount of PPTS in toluene (5 mL) were heated to reflux using
a Dean-Stark trap for 30 h. The mixture was concentrated
and chromatographed (3% MeOH-CHCl3) to give 62 (68 mg,
49%): mp >230 °C dec; IR (KBr) 3396, 2952, 2892, 1766, 1658,
1602, 1152 cm-1; MS (FD) 402 (M+); 1H NMR (DMSO-d6) δ
0.89 (t, 3H, J ) 7 Hz), 1.88 (m, 2H), 2.06 (m, 2H), 2.51 (s, 3H),
3.09 (m, 2H), 3.14 (m, 2H), 5.23 (s, 2H), 5.43 (s, 2H), 7.27 (s,
1H), 7.30 (s, 1H), 7.73 (s, 1H). Anal. (C24H22N2O4‚1/2H2O) C,
H, N.
8-Am in o-6-flu or o-5-m eth yl-3,4-d ih yd r o-1(2H)-n a p h th a -
len on e (56). To a solution of 55 (1.20 g, 5.42 mmol) in a
mixture of acetone (80 mL) and 15% aqueous MgSO4 (8 mL)
was added KMnO4 (2.63 g, 16.6 mmol) in portions at 0 °C. The
reaction mixture was stirred for 2 h at room temperature and
diluted with water. The mixture was extracted with CHCl3,
and the organic phase was washed successively with saturated
NaHCO3 and saturated NaCl, dried (Na2SO4), and evaporated.
Column chromatography (20% AcOEt-hexane) of the residue
gave 8-acetamido-6-fluoro-5-methyl-3,4-dihydro-1(2H)-naph-
thalenone (825 mg, 65%). 8-Acetamido-6-fluoro-5-methyl-3,4-
dihydro-1(2H)-naphthalenone (69 mg, 0.29 mmol) in 7 N HCl
(5 mL) was heated at 80 °C for 1 h and neutralized with
NaHCO3. The mixture was extracted with AcOEt, and com-
bined extracts were washed and dried to give 56 (58 mg, 100%).
(9S)-2,3-Dih yd r o-9-eth yl-5-flu or o-9-h yd r oxy-4-m eth yl-
1H,12H-ben zo[d e]p yr a n o[3′,4′:6,7]in d olizin o[1,2-b]qu in o-
lin e-10,13(9H,15H)-d ion e (57). A solution of 56 (58 mg, 0.30
mmol), tricyclic ketone 7b (79 mg, 0.30 mmol), and PPTS (50
mg, 0.20 mmol) in toluene (15 mL) was refluxed using a Dean-
Stark trap for 12 h before concentration. The residue was
chromatographed (1% MeOH-CHCl3) and recrystallized
(CHCl3-n-hexane) to give 57 (78 mg, 63%): mp 265 °C dec;
MS (FAB) m/z 421 (M + H); HRMS (EI) m/z 421.1565; 1H NMR
(CDCl3) δ 1.03 (t, 3H, J ) 7 Hz), 1.8-2.0 (m, 2H), 2.1-2.3 (m,
2H), 2.39 (d, 3H, J ) 1 Hz), 3.0-3.2 (m, 4H), 5.14, 5.18 (ABq,
2H, J ) 18 Hz), 5.28, 5.73 (ABq, 2H, J ) 16 Hz), 7.63 (d, 1H,
J ) 11 Hz), 7.64 (s, 1H).
4-(2-Aceta m id o-4-m eth ylp h en yl)bu tyr ic Acid (59). To
a solution of AcONa (1.73 g, 21.1 mmol) and HONH2‚HCl (1.10
g, 15.8 mmol) in water (7 mL) was added 7-methyl-3,4-dihydro-
1(2H)-naphthalenone (58) (1.7 g, 10.6 mmol) in EtOH (30 mL),
and the mixture was heated to reflux for 2.5 h. After the
mixture was concentrated, the residue was dissolved in Et2O,
and the solution was washed successively with water and
saturated NaCl, dried (Na2SO4), and evaporated to give crude
7-methyl-1,2,3,4-tetrahydro-1-(hydroxyimino)naphthalene. The
residue, KOH (726 mg, 12.9 mmol), and tosyl chloride (2.02 g,
10.6 mmol) in acetone (30 mL) were stirred at room temper-
ature for 1 h and warmed to reflux for an additional 1 h. The
precipitate obtained after being cooled (0 °C) and treated with
water (50 mL) was collected, washed with MeOH, and dried
to give 7-methyl-1,2,3,4-tetrahydro-1-[(p-tolylsulfonyloxy)imi-
no]naphthalene as a colorless solid (2.42 g, 69%): mp 109-
110 °C. A methanolic solution (75 mL) of 7-methyl-1,2,3,4-
tetrahydro-1-[(p-tolylsulfonyloxy)imino]naphthalene (2.4 g, 7.29
mmol) in a sealed tube was heated for 3 h at 120 °C. After
being concentrated, the residue was washed with AcOEt to
give 2-[3-(methoxycarbonyl)propyl]-5-methylphenylammonium
p-toluenesulfonate as a pale-red solid (2.0 g, 72%). To a cooled
solution (0 °C) of 2-[3-(methoxycarbonyl)propyl]-5-methyl-
phenylammonium p-toluenesulfonate (1.56 g, 4.11 mmol) and
Et3N (1.7 mL, 12.2 mmol) in CH2Cl2 (20 mL) was added AcCl
(0.59 mL, 8.30 mmol), and the solution was stirred for 1 h at
room temperature. The mixture was washed successively with
5-Acet a m id o-7-m et h oxy-1,2,3,4-t et r a h yd r on a p h t h a -
len e (64). To a solution of 7-hydroxy-5-nitro-1,2,3,4-tetrahy-
dronaphthalene (63) (640 mg, 3.3 mmol) in DMF (5 mL) was
added NaH (79 mg, 3.3 mmol) at 0 °C. After the mixture
stirred for 10 min, MeI (1.5 g, 10.6 mmol) was added, and
stirring was continued for an additional 30 min. The reaction
mixture was partitioned between water and AcOEt, and the
organic phase was dried (Na2SO4) and concentrated to give
7-methoxy-5-nitro-1,2,3,4-tetrahydronaphthalene (680 mg, 99%).
7-Methoxy-5-nitro-1,2,3,4-tetrahydronaphthalene (680 mg, 3.28
mmol) and PtO2 (100 mg) in EtOH (50 mL) were stirred in an
atomosphere of H2. After removal of the catalyst and the
solvent, the resultant residue and Ac2O (0.5 mL, 5.30 mmol)
in CH2Cl2 (10 mL) were stirred for 4 h. The mixture was
concentrated to give 64 (720 mg, 100%).
8-Am in o -3,4-d ih y d r o -6-m e t h o x y -1(2H )-n a p h t h a le -
n on e (65). To a solution of 64 (720 mg, 3.28 mmol) in a
mixture of acetone (50 mL) and 15% aqueous MgSO4 (3 mL)
was added KMnO4 (1.6 g, 9.8 mmol) in portions at 0 °C. The
reaction mixture was stirred for 1 h at 0 °C before being diluted

Ring A- and F-Modified Camptothecin Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2317
(5) Sawada, S.; Okajima, S.; Aiyama, R.; Nokata, K.; Furuta, T.;
Yokokura, T.; Sugino, E.; Yamaguchi, K.; Miyasaka, T. Synthesis
and Antitumor Activity of 20(S)-Camptothecin Derivatives:
Carbamate-Linked, Water-Soluble Derivatives of 7-Ethyl-10-
hydroxycamptothecin. Chem. Pharm. Bull. 1991, 39, 1446-1454.
(6) Kingsbury, W. D.; Boehm, J . C.; J akas, D. R.; Holden, K. G.;
Hecht, S. M.; Gallagher, G.; Caranfa, M. J .; McCabe, F. L.;
Faucette, L. F.; J ohnson, R. K.; Hertzberg, R. P. Synthesis of
Water-Soluble (Aminoalkyl)camptothecin Analogues: Inhibitor
of Topoisomerase I and Antitumor Activity. J . Med. Chem. 1991,
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(7) (a) Miyasaka, T.; Sawada, S.; Nokata, K.; Mutai, M. J apanese
Patent 59-51289; Chem. Abstr. 1984, 101, 91319d. (b) Wani, M.
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with water and extracted with CHCl3. The organic phase was
washed with saturated NaCl, dried (Na2SO4), and evaporated.
Column chromatography (CHCl3) of the residue gave 8-acet-
amido-3,4-dihydro-6-methoxy-1(2H)-naphthalenone (350 mg,
46%). 8-Acetamido-3,4-dihydro-6-methoxy-1(2H)-naphthale-
none (70 mg, 0.30 mmol) in 6 N HCl (7 mL) was heated at 90
°C for 1 h. The reaction mixture was concentrated, the residue
in water (10 mL) was neutralized with NaHCO3, and the
mixture was extracted with CHCl3. The combined organic
phase was washed with saturated NaCl, dried (Na2SO4), and
concentrated to afford 65 as an orange solid (54 mg, 94%).
(9S)-2,3-Dih ydr o-9-eth yl-9-h yd r oxy-5-m eth oxy-1H,12H-
ben zo[de]pyr an o[3′,4′:6,7]in dolizin o[1,2-b]qu in olin e-10,13-
(9H,15H)-d ion e (66). A mixture of 65 (47 mg, 0.25 mmol),
7b (64 mg, 0.25 mmol), and p-TsOH‚H2O (1 mg, 0.005 mmol)
in toluene (20 mL) was heated to reflux for 18 h using a Dean-
Stark trap. The solvent was removed in vacuo, and the residue
was chromatographed (CHCl3) to give 66 (35 mg, 33%): mp
265-267 °C dec; MS (EI) m/z 418; HRMS (EI) m/z 418.1539;
1H NMR (CDCl3) δ 1.02 (t, 3H, J ) 7.5 Hz), 1.8-2.0 (m, 2H),
2.1-2.3 (m, 2H), 3.1-3.2 (m, 4H), 3.98 (s, 3H), 5.15 (s, 2H),
5.31, 5.74 (ABq, 2H, J ) 16 Hz), 7.04 (d, 1H, J ) 2 Hz), 7.41
(d, 1H, J ) 2 Hz), 7.70 (bs, 1H).
(9S)-2,3-Dih yd r o-5,9-d ih yd r oxy-9-eth yl-1H,12H-ben zo-
[d e]p yr a n o[3′,4′:6,7]in d olizin o[1,2-b]q u in olin e -10,13-
(9H,15H)-d ion e (67). Compound 66 (19 mg, 0.045 mmol) in
47% HBr (0.5 mL) was brought to reflux for 3 h and was
diluted with water (0.5 mL). The precipitate obtained after
neutralizing with NaHCO3 was recrystallized (CHCl3-MeOH)
to give 67 as a yellow solid (11 mg, 60%): mp >250 °C dec;
MS (EI) m/z 404 (M+); HRMS (EI) m/z 404.1353; 1H NMR
(DMSO-d6) δ 0.89 (t, 3H, J ) 7 Hz), 1.89 (m, 2H), 2.03 (m,
2H), 3.32 (m, 4H), 5.16 (s, 2H), 5.42 (s, 2H), 6.48 (s, 1H), 6.99
(s, 1H), 7.18 (s, 1H), 10.24 (s, 1H).
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Antitumor Agents. 22. Isolation of 11-Hydroxycamptothecin from
Camptotheca acuminata Decne: Total Synthesis and Biological
Activity. J . Med. Chem. 1986, 29, 1553-1555.
(11) Tagawa, H.; Terasawa, H.; Ejima, A. J apanese Patent 85-233366;
Chem. Abstr. 1987, 107, 217320s.
(12) Cagnoli, N.; Martani, A.; Rossi, C. 5,8-Disubstituted Thiochro-
manones. Ann. Chim. (Rome) 1966, 56, 1075-1082; Chem. Abstr.
1967, 66, 55338j.
(13) Uyeo, S.; Mizutani, T.; Yoshitake, A.; Ito, A. 10-Isopropyl-1,7-
dimethyl-11H-naphtho-[2,1-a]fluorene. Yakugaku Zasshi 1964,
84, 458-462; Chem. Abstr. 1964, 61, 4286h.
(14) Lawton, E. A.; Mcritchie, D. D. Synthesis of Pyromellitonitrile
and Related Compounds. J . Org. Chem. 1959, 24, 26-28.
(15) Green, A. G.; Rowe, F. M. Tetrahydronaphthalene series. J .
Chem. Soc. 1919, 113, 955-973.
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of Some Gamma- and Beta-substituted Methyl Butyrates. J .
Chem. Soc. B 1969, 439-445.
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containing Aromatics as Potential Carcinostats. J . Org. Chem.
1957, 22, 193-197.
(9RS)-2,3-Dih yd r o-9-et h yl-9-h yd r oxy-1H ,12H -b en zo-
[d e]p yr a n o[3′,4′:6,7]in d olizin o[1,2-b]q u in olin e -10,13-
(9H,15H)-d ion e (69). 8-Amino-3,4-dihydro-1(2H)-naphtha-
lenone (68) (65 mg, 0.403 mmol), 7a (106 mg, 0.403 mmol),
and a catalytic amount of p-TsOH‚H2O in toluene (5 mL) were
heated to reflux using a Dean-Stark trap for 4 h. The
precipitate obtained after being cooled was washed with AcOEt
and acetone to give 69 (17 mg, 11%): mp >260 °C; IR (KBr)
3490, 2938, 1731, 1668, 1623, 1242, 1155 cm-1; MS (FAB) m/z
(19) Burnham, J . W.; Duncan, W. P.; Eisenbraun, E. J . Effects of
alkyl substituents in the chromic acid oxidation of tetralins. J .
Org. Chem. 1974, 39, 1416-1420.
(20) Schroeter, G.; Kindermann, E.; Dietrich, C.; Beyschlag, C.;
Fleischhauer, C.; Riebensahm, E.; Oesterlin, C. Nitro and Amino
Derivatives of Tetrahydronaphthalene. Ann. 1922, 426, 17-83;
Chem. Abstr. 1922, 16, 1763.
1
389 (M + H); H NMR (DMSO-d6) δ 0.90 (t, 3H, J ) 7 Hz),
1.93 (m, 2H), 2.0-2.2 (m, 2H), 3.0-3.4 (m, 4H), 5.26 (s, 2H),
5.43 (s, 2H), 7.10 (d, 1H, J ) 8 Hz), 7.35 (s, 1H), 7.40 (d, 1H,
J ) 8 Hz), 7.45 (t, 1H, J ) 8 Hz). Anal. (C23H20N2O4‚9/4H2O)
C, H, N.
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amino ketones (The Neber rearrangement). Chem. Rev. 1964,
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and Ketones by Trialkylsilanes in Trifluoroacetic Acid. A Selec-
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information is given on any current masthead page.
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