Synthesis of new camptothecin analogues with the E-lactone ring replaced by α,β-cyclohexenone

Article abstract of DOI:10.1002/ejoc.200600298

The total synthesis of racemic camptothecin analogues 12a and 12b, in which the E-lactone ring has been replaced by an α,β-cyclohexenone ring and the ethyl and hydroxy substituents have been retained, was achieved by first preparing the ABCD fragments 31a

Full text of DOI:10.1002/ejoc.200600298

FULL PAPER
DOI: 10.1002/ejoc.200600298
Synthesis of New Camptothecin Analogues with the E-Lactone Ring Replaced
by α,β-Cyclohexenone
Valeriy A. Bacherikov,[a] Tsong-Jen Tsai,[a] Jang-Yang Chang,[b] Ting-Chao Chou,[c]
Rong-Zau Lee,[a] and Tsann-Long Su*[a]
Keywords: Antitumor agents / Drug design / Alkaloids / Heterocycles / Aldol reactions / Dihydroxylation
The total synthesis of racemic camptothecin analogues 12a
and 12b, in which the E-lactone ring has been replaced by
an α,β-cyclohexenone ring and the ethyl and hydroxy substit-
uents have been retained, was achieved by first preparing
the ABCD fragments 31a and 31b, which were then con-
verted into the tetracyclic triol 36a and 36b by osmium-medi-
ized in one-pot reactions, followed by intramolecular aldol
condensation to furnish the desired pentacyclic 12a and 12b,
which retained topoisomerase I inhibitory activity and exhib-
ited cytotoxicity to tumor cell growth in culture.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ated dihydroxylation. Compounds 36a and 36b were oxid- Germany, 2006)
Studies on the mechanism of action of CPT showed that
Introduction
this agent rapidly blocks both DNA and RNA synthesis
in treated cells, and it has emerged as a potent anticancer
compound.[10–12] The sole intracellular target for CPT and
its derivatives is Topo I;[13,14] in vitro studies showed that
CPT and its analogues inhibited plasmid relaxation by hu-
man Topo I and increased the yield of covalent intermedi-
ates when the reaction was stopped with SDS.[7,11,14] A hy-
pothetical CPT binding model based on crystallographic in-
formation and SARs has been proposed by Redinbo
et al.,[15] demonstrating that a hydrogen-bonding network
could be established between the Asp533 and Arg364 side
chains and the (20S)-OH and lactone moieties of CPT. Mu-
tation of the Phe361 and Gly363 residues is likely to mediate
CPT resistance by disruption the conformation of the loop
that holds Arg364. The studies further confirmed that the
alteration of the CDE rings of CPT severely affects its abil-
ity to bind with Topo I and thus decreases its cytotoxicity.
In contrast, modifications in the AB ring, especially at C-
7, C-9, and C-10, are generally well tolerated and in many
cases enhance the potency of CPT analogues in both in
vitro and in vivo studies.[10] Furthermore, substantial evi-
dence indicates that CPT binds reversibly only after cleav-
age and covalent attachment for the enzyme to the DNA.[16]
In spite of the importance of the conformation of the E-
ring of CPT for enzyme inhibition and cytotoxicity, a CPT
analogue containing a seven-membered β-hydroxylactone,
homocamptothecin (hCPT, 10, Figure 1), was synthesized
by Lavergne et al.[17–19] Like CPT, hCPT contains an asym-
metric tertiary alcohol moiety and displays stereoselective
inhibition of Topo I, while being more potent than CPT.
hCPTs fluorinated in the A-ring were found to have potent
cytotoxicity against the A427 and PC3 tumor cell lines and
The natural antitumor alkaloid (20S)-camptothecin (1,
CPT, Figure 1), is a pentacyclic pyranoindolizino[1,2-b]-
quinoline derivative isolated from Camptotheca acuminata
(Nyssaceae) by Wall and co-workers in 1966.[1] The chemi-
cal and biological properties of CPT and its analogues have
been studied in great detail.[2–5] Phase I and II clinical trials
of this natural alkaloid were carried out with its water-solu-
ble sodium salt (CPT-Na salt), in which the E-lactone ring
had been cleaved by sodium hydroxide, but were abandoned
because of low efficacy and excess non-specific toxicity
(bone marrow and bladder).[6]
Numerous structure–activity studies (SARs) have iden-
tified several design principles for CPT analogues and have
also established a direct correlation between the ability of
CPT derivatives to stabilize the covalent topoisomerase I
(Topo I)-DNA intermediate and their ability to kill cancer
cells.[7,8] Several CPT derivatives with substituent(s) on the
AB ring system exhibit significant enzyme inhibitory ac-
tivity and antitumor efficacy. Among them, topotecan (2),
SN-38 (3), and irinotecan (4) have been clinically approved
for the treatment of cancers (Figure 1).[9]
[a] Laboratory of Bioorganic Chemistry, Institute of Biomedical
Sciences, Academia Sinica,
Taipei 115, Taiwan
Fax: +886-2-2782-9142
E-mail: tlsu@sinica.edu.tw
[b] Division of Cancer Research, National Health Research Insti-
tutes,
Taipei 115, Taiwan
[c] Molecular Pharmacology and Chemistry Program, Memorial
Sloan-Kettering Cancer Center,
New York, New York 10021, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Synthesis of New Camptothecin Analogues
FULL PAPER
Figure 1. Structures of camptothecin derivatives.
were more efficacious than CPT against HT-29 xenografts
in vivo. The homologation of the lactone E-ring reinforces
the stability of the lactone,[17] although the replacement of
the CPT lactone E-ring with a homologous seven-member
lactone ring was found to have changed the sequence speci-
ficity of the drug-induced DNA cleavage by Topo I,[20] sug-
gesting that the hCPT-Topo I binding site may differ from
that of the proposed model for CPT. The results showed
that the β-hydroxylactone ring in hCPT played an impor-
tant and positive role in the poisoning of Topo I.[21]
To elaborate the actual CPT-Topo I binding site, it is
worthwhile to synthesize CPT analogues with covalent
bond formation potential, so that a nucleophile generated
from enzyme or DNA can bind with CPT covalently. Dani-
shefsky et al.[22] synthesized the 18-noranhydrocampto-
thecin analogue 11 (Figure 1), bearing an exocyclic methyl-
ene group on the E-ring. Designed as an alkylating agent,
compound 11 exhibited CPT-like inhibition of Topo I, al-
though its cytotoxicity was significantly reduced in relation
to CPT. To design and synthesize CPT analogues with co-
valent bond formation capability, we replaced the E-ring of
CPT with an α,β-cyclohexenone moiety, so that the nucleo-
philic guanidine function of the Arg364 residue in the en-
zyme might attack the α,β-cyclohexenone moiety through
Michael addition to form the drug-Topo I adduct
(Scheme 1). The target compounds 12a and 12b may facili-
tate study of the drug-Topo I binding site, and their total
synthesis is described here.
Scheme 1. Covalent bond formation capability of 12a with topoiso-
merase I.
Results and Discussion
The novel structure and biological activity of (20S)-CPT
have sustained a high level of interest in the total synthesis
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FULL PAPER
of this agent.[23–25] Consideration of the synthesis of com-
pounds 12a and 12b indicates that one might be able to
construct this target compound either by applying the
shortest asymmetric synthesis of CPT suggested by Com-
ins,[26] involving the formation of the C-ring by connecting
the A,B and D,E fragments through an N-alkylation and a
key intramolecular Heck ring-closure (Scheme 2), or by first
synthesizing the ABCD fragment, followed by formation of
the E-ring.
Figure 2. Structures of olefins used for model studies and construc-
tion of the DE-ring of camptothecin.
Our model studies showed that (Z)-3-phenylpent-2-ene
(19a) or
a 4-((E/Z)-1-ethylpropenyl)-2-methoxypyridine
mixture (19b, 5:95) could be dihydroxylated by treatment
with AD-mix-α to give the desired diols 20a and 20b in
excellent yields (Scheme 3 and Table 1, Entries 1, 2) under
standard Sharpless AD reaction conditions.[30]
Scheme 2. Retrosynthesis of new CPT analogues.
Asymmetric dihydroxylation has been applied to prepare
optically active α-hydroxy lactones (E-ring) for use in CPT
synthesis: Curran et al.[27] synthesized three classes of ole-
fins – endocyclic ketene acetals (13, Figure 2), endocyclic
enol ethers (14), and exocyclic α,β-unsaturated lactones
(15) – that were used for a model study of E-ring construc-
tion. It was found that the dihydroxylation of 13 with com-
mercially available AD-mix-β by the standard procedure
was slow, but acceptable rates were obtained. A marked im-
Scheme 3. Model studies on dihydroxylation of olefins 19a and 19b.
Reagents and conditions: a) Ph3PEtBr KN(SiMe3)2, THF, –80 °C
to room temp., 2 h, 19a: 81 %; 19b: 95 %. b) AD-mix-α, Me-
SO2NH2, tBuOH, H2O, 0 °C, 20a: 10 h, 99%; 20b: 18 h, 94%.
The model studies encouraged us to prepare the 4-(1-
provement in enantioselectivity, together with a high yield, ethylpropenyl)pyridine derivative 22 from the known ketone
was obtained when the endocyclic enol ether 14 was treated 21[18] by a Wittig reaction with ethyltriphenylphosphonium
with AD-mix-β, whilst studies on the dihydroxylation of ylide (Scheme 4).
exocyclic olefins 15 showed disappointing results with the
The product 22 was obtained in good yield as an iso-
(E) isomer but dihydroxylation of the (Z) isomer to give the meric mixture with an (E/Z) ratio of 10:90, but attempts
desired (20S) configuration in 50% yield and with 99% ee to convert the olefin 22 into diol 23 by Sharpless catalytic
when the compounds were treated with AD-mix-α. Inde- asymmetric dihydroxylation with AD-mix-α or -β[30]
pendently, Fang et al.[28] reported that the DE ring frag- (Table 1, Entry 3) failed. We found that the dihydroxylation
ment could be obtained from the endocyclic enol ether (16) of 22 could be only achieved by treatment with 5 mol%
through dihydroxylation with AD-mix-α, whilst Henegar osmium tetraoxide in the presence of 3 equiv. of trimeth-
et al.[29] later developed a new synthetic strategy for prepar- ylamine N-oxide in tert-butyl alcohol at room temperature,
ing CPT analogues from the key intermediate 17, which was the desired diol 23 then being obtained only in a moderate
a good substrate for osmium-mediated dihydroxylation yield (Table 1, Entry 4) even after extension of the reaction
1
(OsO4/Me3NO·2H2O), a high yield of diol being obtained. time (5–10 d). H NMR spectral analysis showed that the
In view of the synthesis of the target compound by syn- (E) olefin 22 was converted into diol 23 more rapidly, since
thetic route 1, the key step for the successful synthesis of the recovered starting material was only (Z)-22. In an inves-
12a was the stereoselective formation of compound 23 tigation to optimize the content of (E)-22 in the isomeric
(Scheme 4).
mixture under various reaction conditions, we found that
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Synthesis of New Camptothecin Analogues
Table 1. Dihydroxylation of various olefins for E-ring construction. moved by catalytic hydrogenation (10% Pd/C, H2) to give
FULL PAPER
triol 24 in good yield (98%), and compound 24 was then
converted into 5H-isoquinoline-6-one 26 in good yield
(92%) by treatment with freshly prepared “active” MnO2
on carbon[31] in CH2Cl2 in the presence of acetic acid. Ap-
parently, the one-pot synthesis of 26 from triol 24 was
achieved through oxidation to give intermediate 25 and si-
multaneous intramolecular aldol-crotonic condensation un-
der the acid catalysis conditions. These results shed light on
the successes of the synthesis of 12a by the first synthetic
route. Unfortunately, though, in our attempts to convert 26
into the desired 1H,5H-isoquinoline-1,6-dione 27, to be
used for the condensation with the AB fragment, we found
that 26 was unstable under acidic conditions, treatment of
26 with acid (such as HCl or TMSI) for demethylation re-
sulting in the formation of a complex mixture of products.
The strategy for the synthesis of 12a was then switched
to the second synthetic route, involving the initial construc-
tion of the ABCD fragment, followed by the formation of
the E-ring as shown in Scheme 5.
Entry
Substrate
Reaction Method[b] Product Yield
time [d]
(E/Z ratio)[a]
[%][c]
1
2
3
4
5
6
7
8
9
19a (1:100)
19b (5:95)
22 (1:9)
1
1
1
A
A
A
B
20a
20b
n.r.[d]
23
99
94
22 (1:9)
5
68.5 (7.7)
31a (2:8)
31a (2:8)
34a (2:8)
34a (3:7)
34b (3:7)
1
5
1
1.5
4
A
C
A
D
D
n.r.
32a
n.r.
35a
35b
20.5 (71.8)
45.2 (36.7)
20.1 (17.5)
1
[a] Determined by H NMR spectroscopy. [b] Reagents and condi-
tions A: AD-mix-α or β, MeSO2NH2, tBuOH, H2O (1:1, v/v).[30]
Reagents and conditions B: OsO4 (0.05 equiv.), Me3NO·2 H2O
(3 equiv.), tBuOH. Reagents and conditions C: OsO4 (1 equiv.),
Me3NO·2H2O (3 equiv.), THF. Reagents and conditions D: OsO4
(0.3 equiv.), Me3NO·2H2O (2 equiv.), THF. [c] Numbers in paren-
theses are the percentage of recovered (Z)-olefin. [d] n.r.: no reac-
tion.
Compound 22 was treated with TMSCl/NaI in dry
CH3CN to afford pyridone 28 (Scheme 5), which was then
treated with dibromoquinoline 29a[26] to yield 30a. Subse-
quent ring-closure of 30a under Heck conditions afforded
the tetracyclic 31a. In our attempts to transform compound
31a into triol 36a by the same procedure as used for the
synthesis of triol 21, we found that the process was unsuit-
able, since the dihydroxylation of 31a took place only over
a long period of time (about 5 d), resulting in a low yield
of diol 32a (21%), together with unreacted 31a and side-
products (Table 1, Entry 6). In addition, the catalytic de-
benzylation of 32a yielded a complex mixture of products,
suggesting that the benzyl function in 31a was not a suitable
protecting group for preparing triol 36a, so we replaced the
benzyl group with THP as the protecting function and syn-
thesized compound 34a. The result was that all the (E)-
34a and some of the (Z)-34a were dihydroxylated (OsO4/
Me3NO·2H2O) to give diol 35a (45%), whilst unreacted
(Z)-34a (36.7%) was recovered from the reaction mixture
after column chromatography (Table 1, Entry 8). On re-
moval of the THP protecting group under acidic conditions,
compound 35a was converted into triol 36a (70%), which
was then smoothly transformed in a one-pot reaction to
give the desired racemic pentacyclic 12a in good yield by
treatment with MnO2 in acetic acid through oxidation and
ring-closure. By following the same synthetic route, we
also prepared (7RS)-7-ethyl-7-hydroxy-2-methoxy-7H,12H-
5,11a-diazadibenzo[b,h]fluorene-8,11-dione (12b).
Scheme 4. Preparation of isoquinolinone 26. Reagents and condi-
tions: a) Ph3PEtBr, KN(SiMe3)2, THF, –85 °C to room temp., 4 h,
96% or Ph3PEtBr, LiN(SiMe3)2, ether, –80 °C to room temp., 22 h,
35 %. b) OsO4, Me3NO·2 H2O, tBuOH, room temp., 5 d, 69 %.
c) H2, Pd/C (cat.), MeOH, room temp., 2 h, 98 %. d) MnO2/C,
CH3COOH, CH2Cl2, room temp., 4 h, 85 %. e) TMSCl, NaI,
MeCN, room temp.
This study showed that the dihydroxylation of olefins 22,
31a, 34a, and 34b proceeded in the presence of sufficient
amount OsO4 (0.05 to 1 equiv.) although they did not un-
dergo dihydroxylation with AD-mix-α (Table 1, Entries 3,
5, 7). The slow reaction rates and low yields of the dihy-
the amount of (E)-22 was increased to the ratio of E/Z = droxylations of these olefins can mainly be accounted for
3:7 when LiHMDS was employed as a base in ethereal solu- by the configurations of the olefins – low ratios of (E) iso-
tion, but that the total yield of the product was low mers in the mixtures – as we found that the (E) isomers
(34.5%), unreacted ketone 21 also being recovered (60%). were transformed into the corresponding diols, while the
The benzyl protecting group in diol 23 was carefully re- recovered starting materials were the unreacted (Z) forms.
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FULL PAPER
Scheme 5. Completion of the synthesis of 12a and 12b. Reagents and conditions: a) TMSCl, NaI, MeCN, room temp., 30 h, 84%. b) 29a[26]
or 29b,[32] tBuOK, DME, reflux, 30a: 5 h, 98%; 30b: 6 h, 90%. c) Pd(OAc)2, PPh3, KOAc, MeCN, reflux, 31a: 12 h, 99%; 31b: 30 h,
75%. d) BBr3, CH2Cl2, –80 °C, 3 h, 33a: 77%, 33b: 56%. e) THP, pTsA(cat), CH2Cl2, room temp., 5 h, 99%. f) OsO4, Me3NO·2H2O,
THF, room temp., 32a: 21%, 35a: 45%, 35b: 20%. g) pTsA(cat), CH3OH, room temp., 5 h, 36a: 70%, 36b: 71%. h) MnO2/C, CH3COOH
(cat), CH2Cl2, room temp., 12a: 85%, 12b: 17%.
230 mesh, ASTM; Merck). Thin-layer chromatography was per-
formed on silica gel G60 F254 (Merck) plates with short-wavelength
UV light for visualization. Elemental analyses were done on a
Heraeus CHN-O Rapid instrument.
Apparently, the benzyloxymethyl group at C-3 of the pyri-
dine affected the stereoselectivity in the formation of the
olefins, and consequently affected the dihydroxylation.
It is of great interest to note that compounds 12a and
12b exhibited potent CPT-like inhibitory effect against to-
poisomerase I and induced enzyme-mediated DNA cleav-
age. An antitumor study revealed that both compounds
were significantly less potent than CPT against human na-
sopharyngeal carcinoma and human lymphoblastic leuke-
mia cell growth in vitro, with IC50 values in a range of 1–
3 µ.
(Z)-3-Phenylpent-2-ene (19a): A solution of KN(SiMe3)2 in THF
(1 , 93 mL) was added to a suspension of ethyltriphenylphospho-
nium bromide (18.56 g, 100 mmol) in anhydrous THF (300 mL).
The mixture was stirred at room temperature for 0.5 h (red color
of mixture) and was then chilled to –80 °C, and propiophenone
(18a, 9.57 mL, 9.66 g, 72 mmol) was added dropwise. The mixture
was allowed to warm to room temperature and stirred for 1.5 h.
The reaction was quenched by dropwise addition of HCl (1 ,
100 mL), the layers were separated, the water layer was extracted
with diethyl ether (3×25 mL), and the organic layer and extracts
were combined, dried (MgSO4), and concentrated. The obtained
oil was chromatographed on a silica gel column (6×30 cm, hex-
ane), and the fractions containing the desired compound 19a were
combined and concentrated to dryness under reduced pressure to
Conclusions
In summary, we have modified the camptothecin E-ring
by replacing the lactone ring with an α,β-cyclohexenone
moiety, whilst retaining the ethyl and hydroxy functions. Al-
though compounds 12a and 12b exhibited CPT-like inhibi-
tory effect against topo I and induced enzyme-mediated
DNA cleavage, in vitro antitumor studies revealed both
compounds to be significantly less active then CPT.
1
give 19a (8.51 g, 80.8%) as a clear oil. H NMR (CDCl3): δ = 0.94
(dt, J = 2.0 and 7.6 Hz, 3 H, Me), 1.55 (d, J = 6.4 Hz, 3 H, Me),
2.34 (q, J = 7.7 Hz, 2 H, CH2), 5.52 (q, J = 6.4 Hz, 1 H, CH=),
7.13–7.33 (m, 5 H, PhH) ppm. A comparison of the 1H NMR spec-
trum of the product with the data in ref.[33] showed that only the
(Z) isomer of 19a had been isolated.
4-(1-Ethylpropenyl)-2-methoxypyridine (19b): Compound 19b was
obtained from 18b[18] (0.33 g, 2 mmol) by the same procedure as
used for the synthesis of 19a, with use of HMPA (5 equiv.) as co-
solvent, as a mixture of (E/Z) isomers (5:95, 1H NMR). Yield
0.34 g (94.8%), as a clear oil. 1H NMR (CDCl3) (E) isomer: δ =
0.95 (t, J = 7.4 Hz, 3 H, Me), 1.57 (d, J = 6.9 Hz, 3 H, Me), 2.30
(q, J = 7.4 Hz, 2 H, CH2), 3.95 (s, 3 H, MeO), 5.56 (q, J = 6.9 Hz,
1 H, CH=), 6.53 (s, 1 H, C3-H), 6.68 (dd, J = 1.1 and 5.2 Hz, 1
H, C5-H), 8.12 (d, J = 5.2 Hz, 1 H, C6-H) ppm; (Z) isomer: δ =
0.99 (t, J = 7.3 Hz, 3 H, Me), 1.81 (d, J = 7.0 Hz, 3 H, Me), 2.47
(q, J = 7.3 Hz, 2 H, CH2), 3.94 (s, 3 H, MeO), 5.94 (q, J = 6.9 Hz,
Experimental Section
General Methods: THF, ether, and DME were distilled from so-
dium–benzophenone, and acetonitrile and CH2Cl2 were distilled
from P2O5 immediately prior to use. The reactions were conducted
under argon. Melting points were determined on a Fargo melting
point apparatus and are uncorrected. 1H NMR and 13C NMR
spectra were determined on Bruker 400, 500, and 600 MHz spec-
trometers in CDCl3 or [D6]DMSO solution at 25 °C; chemical
shifts are expressed in ppm downfield from internal standard TMS.
Column chromatography was carried out over silica gel G60 (70–
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Synthesis of New Camptothecin Analogues
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1 H, CH=), 6.53 (s, 1 H, C3-H), 6.86 (dd, J = 1.5 and 5.3 Hz, 1 H,
δ = 0.85 (t, J = 7.8 Hz, 3 H, Me), 1.73 (d, J = 7.1 Hz, 3 H, Me),
C5-H), 8.06 (d, J = 5.2 Hz, 1 H, C6-H) ppm. C11H15NO·0.35H2O 2.37 (q, J = 7.6 Hz, 2 H, CH2), 3.96 (s, 3 H, OMe), 4.41 (m, 2 H,
(183.55): calcd. C 72.10, H 8.62, N 7.62; found C 72.40, H 8.68, N
7.35.
CH2Py), 4.59 (s, 2 H, CH2Ph), 5.48 (m, 1 H, CH=), 6.65 (d, J =
6.0 Hz, 1 H, C5-H), 7.21–7.43 (m, 5 H, ArH), 8.01 (d, J = 5.5 Hz,
1 H, C6-H) ppm; (Z) isomer: δ = 0.97 (t, J = 7.3 Hz, 3 H, Me),
1.36 (d, J = 7.6 Hz, 3 H, Me), 2.24 (m, 2 H, CH2), 3.99 (s, 3 H,
OMe), 4.41 (dd, J = 8.4 Hz, 2 H, CH2Py), 4.56 (s, 2 H, CH2Ph),
5.54 (m, 1 H, CH=), 6.57 (d, J = 5.1 Hz, 1 H, C5-H), 7.21–7.43
(m, 5 H, ArH), 8.07 (d, J = 5.5 Hz, 1 H, C6-H) ppm. C19H23NO2
(297.38): calcd. C 76.74, H 7.80, N 4.71; found C 76.42, H 7.48, N
4.55.
3-Phenylpentane-2,3-diol (20a): A mixture of 19a (0.73 g, 5 mmol),
AD-mix-α (7 g), and MeSO2NH2 (0.475 g, 5 mmol) in tBuOH/H2O
(1:1, 50 mL) was stirred for 10 h at 0 °C. The reaction was
quenched at 0 °C by addition of sodium sulfite (7.5 g) and the sys-
tem was then allowed to warm to room temperature and stirred for
0.5 h. The tBuOH and water layers were separated, the aqueous
layer was extracted with EtOAc (4×5 mL), and the tBuOH layer
and EtOAc extracts were combined, washed with KOH (2 ,
2×10 mL), dried (MgSO4), and concentrated. Compound 20a was
purified by silica gel column chromatography (3×25 cm), being
eluted (0.891 g, 99%) from EtOAc/hexane (1:2, v/v) as a clear oil.
Method 2: The procedure for the synthesis of 22 by Method 2 was
similar to that of Method 1: the reaction was carried out in anhy-
drous ether and lithium bis(trimethylsilyl)amide was used instead
of potassium bis(trimethylsilyl)amide. Compound 22 was prepared
1H NMR (CDCl3): δ = 0.74 (t, J = 6.9 Hz, 3 H, Me), 0.94 (d, J = from ketone 21 (14.27 g, 50.0 mmol). The reaction mixture was
6.9 Hz, 3 H, Me), 1.84 (d, J = 5.9 Hz, 1 H, exchangeable, OH),
worked up in the usual way and the residue was chromatographed
1.98 (m, 2 H, CH2), 2.35 (s, 1 H, exchangeable, OH), 3.94 (m, 1 H,
on a silica gel column. Compound 22 (5.18 g, 34.8%) was eluted
CHO), 7.22–7.38 (m, 5 H, PhH) ppm. C11H16O2 (180.24): calcd. C from EtOAc/hexane (3:97, v/v) as an oil (E/Z, 3:7, determined by
73.30, H 8.95; found C 73.28, H 8.99.
1H NMR) and the starting material 21 was eluted from EtOAc/
hexane (1:9, v/v), 8.89 g (59.8%).
3-(2-Methoxypyridin-4-yl)pentane-2,3-diol (20b): Compound 20b
was obtained from 19b (0.177 g, 1 mmol) by the same procedure as
used for the synthesis of 20a, with use of AD-mix-α for 18 h at
0 °C. Yield 0.198 g (93.8%), m.p. 60–63 °C as a mixture of dia-
stereomers (2:8, 1H NMR). 1H NMR ([D6]DMSO), major dia-
3-(3-Benzyloxymethyl-2-methoxypyridin-4-yl)pentane-2,3-diol (23):
A mixture of 22 (2.38 g, 8.0 mmol), OsO4 (0.102 g, 0.4 mmol), and
Me3NO·2H2O (2.67 g, 24 mmol) in tBuOH (16 mL) was stirred at
room temperature. The reaction was monitored by TLC (EtOAc/
stereomer: δ = 0.56 (t, J = 7.4 Hz, 3 H, Me), 0.78 (d, J = 6.3 Hz, hexane, 4:6, v/v). After the mixture had been stirred for 5 d the
3 H, Me), 1.73 and 1.94 (each: sext, J = 7.4 and 14.8 Hz, 1 H,
CH2), 3.71 (quint, J = 6.1 Hz, 1 H, CHO), 3.82 (s, 3 H, MeO),
4.48 (s, 1 H, exchangeable, OH), 4.64 (d, J = 5.9 Hz, 1 H, exchange-
able, OH), 6.78 (d, J = 0.8 Hz, 1 H, C3-H), 6.92 (dd, J = 1.4 and
5.4 Hz, 1 H, C5-H), 8.04 (dd, J = 0.4 and 5.4 Hz, 1 H, C6-H) ppm;
starting material 22 had not been consumed. The reaction mixture
was quenched by addition of aqueous NaHSO3 (39%, 16 mL) and
was then stirred at room temperature for 1 h and diluted with water
(30 mL), and the water layer was separated. The aqueous layer was
extracted with EtOAc (4×5 mL), and the tBuOH layer and EtOAc
minor diastereomer: δ = 0.63 (t, J = 7.3 Hz, 3 H, Me), 0.85 (d, J extracts were combined and stirred with Celite (2 g) for 1 h. After
= 6.3 Hz, 3 H, Me), 1.69 and 1.88 (each: m, J = 7.2 Hz, 1 H, CH2),
3.69 (m, 1 H, CHO), 3.82 (s, 3 H, MeO), 4.67 (s, 1 H, exchangeable,
OH), 4.68 (d, J = 5.2 Hz, 1 H, exchangeable, OH), 6.82 (dd, J =
2.4 and 2.6 Hz, 1 H, C3-H), 7.02 (dd, J = 1.4 and 5.5 Hz, 1 H,
C5-H), 8.02 (d, J = 5.5 Hz, 1 H, C6-H) ppm. C11H17NO3·0.4H2O
(218.46): calcd. C 60.48, H 8.21, N 6.41; found C 60.12, H 8.32,
N, 6.17.
filtration, the solid cake was washed with ethyl acetate (2×5 mL),
the combined filtrate and washings were evaporated in vacuo to
dryness, and the residue was dissolved in EtOAc (100 mL), dried
with MgSO4, and concentrated to dryness under reduced pressure.
The oil residue was chromatographed on a silica gel column, unre-
acted 22 being eluted in EtOAc/hexane (1:10, v/v), followed by
product 23 (1.35 g, 68.5%) as a clear oil and as a mixture of dia-
stereomers (3:7, 1H NMR). 1H NMR ([D6]DMSO) major dia-
stereomer: δ = 0.58 (t, J = 7.6 Hz, 3 H, Me), 0.77 (d, J = 6.1 Hz,
3 H, Me), 1.95 (m, 2 H, CH2), 3.85 (s, 3 H, OMe), 4.00 (m, 1 H,
CH), 4.37 (s, 1 H, exchangeable, OH), 4.53 and 4.56 (each: d, J =
12.2 Hz, 1 H, CH2-Ph), 4.67 and 4.71 (each: d, J = 9.9 Hz, 1 H,
CH2-Py), 4.75 (d, J = 5.6 Hz, 1 H, exchangeable, OH), 7.15 (brd,
J = 5.5 Hz, 1 H, C5-ArH), 7.25–7.38 (m, 5 H, ArH), 8.03 (d, J =
5.5 Hz, 1 H, C6-ArH) ppm; minor diastereomer: δ = 0.64 (t, J =
7.6 Hz, 3 H, Me), 0.97 (d, J = 6.3 Hz, 3 H, Me), 1.66 (m, 2 H,
CH2), 3.85 (s, 3 H, OMe), 3.89 (m, 1 H, CH), 4.37 (s, 1 H, ex-
changeable, OH), 4.52 (s, 2 H, CH2-Ph), 4.70 (s, 2 H, CH2-Py),
4.91 (d, J = 9.9 Hz, 1 H, OH), 7.10 (brd, J = 5.5 Hz, 1 H, C5-H),
7.25–7.38 (m, 5 H, ArH), 8.01 (d, J = 5.5 Hz, 1 H, C6-ArH) ppm.
C19H25NO4 (331.4): calcd. C 68.86, H 7.60, N 4.23; found C 68.56,
H 7.63, N 4.13.
3-Benzyloxymethyl-4-[(E/Z)-1-ethylpropenyl]-2-methoxypyridine
(22). Method 1: A mixture of ethyltriphenylphosphonium bromide
(16.27 g, 43.8 mmol) in dried THF (90 mL) containing anhydrous
HMPA (22 mL, 217.5 mmol) was cooled to 5 °C under argon. A
solution of potassium bis(trimethylsilyl)amide (8.50 g, 42.6 mmol)
in anhydrous THF (50 mL) was added dropwise to the above mix-
ture over 20 min and the system was then stirred at room tempera-
ture for 15 min. The resulting red mixture was cooled to –85 °C
and a solution of ketone 21[18] (6.95 g, 24.4 mmol) in anhydrous
THF (6 mL) was added dropwise with vigorous stirring, after
which the reaction mixture was allowed to warm to room tempera-
ture and continuously stirred for 2 h. The reaction mixture was
quenched by addition of saturated NH4Cl aqueous solution
(15 mL, 61 mmol), the resulting precipitate was filtered, and the
water layer was separated and extracted with diethyl ether
(3×10 mL). The combined organic extracts were washed success-
ively with brine and water and dried (Na2SO4), and the solvents
were evaporated in vacuo to dryness. The residue was chromato-
graphed on a silica gel column with EtOAc/hexanes (1:10, v/v) as
the eluent. Fractions containing the product 22 were combined and
concentrated to dryness under reduced pressure to give 22 (6.923 g,
95.6%) as an oil. The ratio of (E) and (Z) isomers (1:9) was deter-
mined by 1H NMR spectral analysis. 1H NMR (CDCl3) (E) isomer:
3-(3-Hydroxymethyl-2-methoxypyridin-4-yl)pentane-2,3-diol (24): A
mixture of diol 23 (2.891 g, 8.72 mmol) and Pd/C in methanol (5%,
50 mL) was hydrogenated at 1 atmosphere for 1.6 h. The mixture
was filtered through a pad of Celite, the solid cake was washed with
MeOH, and the combined filtrate and washings were concentrated
under reduced pressure to give an oil, which was recrystallized from
1
CHCl3/hexane to afford 24 (2.064 g, 98.1%), m.p. 101–104 °C. H
NMR ([D6]DMSO) major diastereomer: δ = 0.60 (t, J = 7.4 Hz, 3
Eur. J. Org. Chem. 2006, 4490–4499
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. A. Bacherikov, T.-J. Tsai, J.-Y. Chang, T.-C. Chou, R.-Z. Lee, T.-L. Su
FULL PAPER
H, Me), 0.80 (d, J = 6.4 Hz, 3 H, Me) 1.93 (m, 2 H, CH2), 3.85 (s, was then stirred under argon at room temperature for 1 h. Com-
3 H, OMe), 3.94 (m, 1 H, CH), 4.66 (brs, 1 H, CH2O), 4.72 (brt, pound 29a[26] (7.525 g, 25 mmol) was then added to the above mix-
J = 5.6 Hz, exchangeable, 1 H, OH), 4.77 (brd, J = 5.4 Hz, ex-
changeable, 1 H, OH), 4.91 (brs, 1 H, exchangeable, OH), 6.97 (d,
J = 5.4 Hz, 1 H, C5-ArH), 7.97 (d, J = 5.4 Hz, 1 H, C6-H) ppm;
ture in one portion. After having been heated at reflux for 5 h it
was allowed to cool to room temperature and the solvents were
evaporated in vacuo to dryness. The residue was mixed with a satu-
minor diastereomer: δ = 0.65 (t, J = 7.4 Hz, 3 H, Me), 0.97 (d, J rated solution of NH4Cl (50 mL) and then with diethyl ether
= 6.3 Hz, 3 H, Me) 1.93 (m, 2 H, CH2), 3.84 (s, 3 H, OMe), 4.02
(m, 1 H, CH), 4.66 (brs, 1 H, CH2O), 4.72 (brt, J = 5.6 Hz, ex-
changeable, 1 H, OH), 4.77 (brd, J = 5.4 Hz, exchangeable, 1 H,
OH), 4.91 (brs, 1 H, exchangeable, OH), 7.03 (d, J = 5.4 Hz, 1
H, C5-ArH), 7.88 (d, J = 5.4 Hz, 1 H, C6-ArH) ppm. C12H19NO4
(241.28): calcd. C 59.73, H 7.94, N 5.80; found C 59.95, H 7.86, N
5.71.
(100 mL), the ethereal layer was separated, and the water layer was
extracted with diethyl ether (3×20 mL). The combined ethereal ex-
tracts was washed with water (3×20 mL) and dried (Na2SO4), and
the solvents were evaporated in vacuo to dryness. The product 30a
was purified by column chromatography (EtOAc/hexane, 1:5, v/v).
Yield 10.42 g (86.2%) as a mixture of (E) and (Z) isomers (3:7),
m.p. 85–93 °C. 1H NMR (CDCl3) (E) isomer: δ = 0.90 (t, J =
7.4 Hz, 3 H, Me), 1.72 (d, J = 6.9 Hz, 3 H, Me), 2.35 (q, J =
7.4 Hz, 2 H, CH2), 4.43 (s, 2 H, CH2Py), 4.64 (s, 2 H, CH2Ph),
5.36 (s, 2 H, CH2N), 5.62 (q, J = 6.9 Hz, 1 H, CH=), 6.07 (d, J =
7.0 Hz, 1 H, C5-ArH), 7.40 (d, J = 7.0 Hz, 1 H, C6-ArH), 7.56
(ddd, J = 1.0 and 7.0 Hz, 1 H, C6Ј-ArH), 7.72 (ddd, J = 1.4, 6.8,
and 8.4 Hz, 1 H, C7Ј-ArH), 7.80 (d, J = 8.0 Hz, 1 H, C5Ј-ArH),
7.79 (d, J = 8.5 Hz, 1 H, C8Ј-ArH), 8.10 (s, 1 H, C4Ј-ArH); (Z)
isomer: δ = 1.00 (t, J = 7.4 Hz, 3 H, Me), 1.45 (dt, J = 1.6 and
6.9 Hz, 3 H, Me), 2.24 (qt, J = 1.6 and 7.4 Hz, 2 H, CH2), 4.35
and 4.44 (each: brd, J = 8.5 Hz, 1 H, CH2Py), 4.61 (brd, J =
6.5 Hz, 2 H, CH2Ph), 5.39 (s, 2 H, CH2N), 5.48 (qt, J = 1.6 and
6.9 Hz, 1 H, CH=), 5.97 (d, J = 7.0 Hz, 1 H, C5-ArH), 7.46 (d, J
= 7.0 Hz, 1 H, C6-ArH), 7.56 (ddd, J = 1.0 and 7.0 Hz, 1 H, C6Ј-
ArH), 7.72 (ddd, J = 1.4, 6.8, and 8.4 Hz, 1 H, C7Ј-ArH), 7.79 (dd,
J = 1.2 and 8.0 Hz, 1 H, C5Ј-ArH), 8.02 (d, J = 8.6 Hz, 1 H, C8Ј-
ArH), 8.13 (s, 1 H, C4Ј-ArH) ppm. C28H27BrN2O2 (503.42): calcd.
C 66.80, H 5.41, N 5.56; found C 66.82, H 5.49, N 5.60.
5-Ethyl-5-hydroxy-1-methoxy-5H-isoquinoline-6-one (26): Freshly
prepared active MnO2 (14.62 g) on carbon was added to a solution
of triol 24 (1.18 g, 4.87 mmol) in a mixture of CH2Cl2 (90 mL) and
acetic acid (4.5 mL).[31] The mixture was stirred at room tempera-
ture and the reaction was monitored by TLC (CH3OH/CHCl3,
1:10, v/v). After having been stirred for 2 h, the solid in the mixture
was filtered through a pad of Celite and the solid cake was washed
with CH2Cl2 (2×15 mL). The filtrate and washings were combined
and successively washed with water (2×15 mL), NaHCO3 (8 %,
2×10 mL), brine (10 mL), and water (10 mL), and dried (MgSO4),
and the solvents were evaporated in vacuo to dryness. The product
was purified by flash chromatography (CH3OH/CHCl3, 1:5, v/v) to
1
give 26 (0.983 g, 92.1%); m.p. 68–69 °C. H NMR ([D6]DMSO): δ
= 0.72 (t, J = 7.4 Hz, 3 H, Me), 1.92 (m, 2 H, CH2), 3.92 (s, 3 H,
OMe), 4.81 (d, J = 13.0 Hz, 1 H, CH), 4.95 (d, J = 13.0 Hz, 1 H,
CH), 6.52 (brs, 1 H, OH), 6.99 (d, J = 5.2 Hz, 1 H, C5-ArH), 8.14
(d, J = 5.2 Hz, 1 H, C6-ArH) ppm. C12H13NO3·0·13H2O (221.58):
calcd. C 61.82, H 6.44, N 6.32; found C 61.62, H 6.51, N 6.52.
3-Benzyloxymethyl-1-(2-bromo-6-methoxyquinolin-3-ylmethyl)-4-(1-
ethylpropenyl)-1H-pyridin-2-one (30b): Compound 30b (6.68 g,
89.6 %) was obtained from 28 (3.77 g, 13.3 mmol) and 29b[32]
(4.40 g, 14 mol) by the same procedure as used for the synthesis of
3-Benzyloxymethyl-4-(1-ethylpropenyl)-1H-pyridin-2-one (28): A
mixture of 22 (5.95 g, 20 mmol) and TMSI [freshly generated from
TMSCl (7.62 mL, 60 mmol) and NaI (9 g, 60 mmol)] in anhydrous
CH3CN (100 mL) was stirred at –10 °C for 10 min and was then
allowed to warm to room temperature. After having been stirred
for an additional 30 h, the reaction mixture was quenched with
aqueous NaHSO3 solution (39%, 30 mL) and stirred with EtOAc
(30 mL). The organic layer was separated, the water layer was ex-
tracted with ethyl acetate (4×15 mL), and the combined organic
extracts were successively washed with saturated NaHCO3 solution
(15 mL), Na2S2O3 (1 , 15 mL), and brine (5 mL), dried (MgSO4),
and concentrated under reduced pressure. The crude product was
purified by column chromatography (CH3OH/CH2Cl2, 2:98, v/v)
to give 28 (7.637 g, 84.4%) as syrup. Compound 28 was a mixture
of (E) and (Z) isomers (3:7) as determined by 1H NMR spectral
analysis. 1H NMR ([D6]DMSO) (E) isomer: δ = 0.88 (t, J = 7.5 Hz,
3 H, Me), 1.70 (d, J = 6.9 Hz, 3 H, Me), 2.33 (q, J = 7.5 Hz, 2 H,
CH2), 4.42 (s, 2 H, CH2Py), 4.63 (s, 2 H, CH2Ph), 5.57 (qt, J = 0.7
and 6.9 Hz, 1 H, CH=), 6.07 (d, J = 6.6 Hz, 1 H, C5-ArH), 7.23–
7.40 (m, 6 H, ArH), 13.00 (brs, 1 H, exchangeable, NH) ppm; (Z)
isomer: δ = 0.98 (t, J = 7.5 Hz, 3 H, Me), 1.42 (dt, J = 1.5 and
6.8 Hz, 3 H, Me), 2.22 (qt, J = 1.4 and 7.5 Hz, 2 H, CH2), 4.33
and 4.43 (each: d, J = 9.4 Hz, 1 H, CH2Py), 4.60 (dd, J = 11.3 Hz,
2 H, CH2Ph), 5.45 (qt, J = 1.5 and 6.8 Hz, 1 H, CH=), 5.98 (d, J
= 6.6 Hz, 1 H, C5-ArH), 7.23–7.40 (m, 6 H, ArH), 13.00 (brs, 1
H, exchangeable, NH) ppm. C18H21NO2·0.2H2O (286.96): calcd. C
75.34, H 7.52, N 4.88; found C 75.60, H 7.43, N 4.81.
1
30a, as a mixture of (E) and (Z) isomers (3:7), m.p. 81–90 °C. H
NMR (CDCl3) (E) isomer: δ = 0.90 (t, J = 7.8 Hz, 3 H, Me), 1.73
(d, J = 6.7 Hz, 3 H, Me), 2.36 (q, J = 7.4 Hz, 2 H, CH2), 3.89 (s,
3 H, OMe), 4.45 (s, 2 H, CH2Py), 4.65 (s, 2 H, CH2Ph), 5.35 (s, 2
H, CH2N), 5.63 (q, J = 7.0 Hz, 1 H, CH=), 6.06 (d, J = 7.0 Hz, 1
H, C5-ArH), 7.08 (d, J = 2.7, 1 H, C5Ј-ArH), 7.22–7.39 (m, 6 H,
C7Ј-ArH and Ph), 7.41 (d, J = 7.0 Hz, 1 H, C6-ArH), 7.90 (d, J =
9.0 Hz, 1 H, C8Ј-ArH), 8.04 (s, 1 H, C4Ј-ArH) ppm; (Z) isomer: δ
= 1.01 (t, J = 7.4 Hz, 3 H, Me), 1.45 (dt, J = 1.6 and 6.7 Hz, 3 H,
Me), 2.25 (qt, J = 1.6 and 7.4 Hz, 2 H, CH2), 3.88 (s, 3 H, OMe),
4.36 and 4.46 (each: brs, 1 H, CH2Py), 4.65 (brd, J = 5.7 Hz, 2 H,
CH2Ph), 5.37 (d, J = 10.0 Hz, 2 H, CH2N), 5.48 (qt, J = 1.6 and
6.7 Hz, 1 H, CH=), 5.96 (d, J = 7.0 Hz, 1 H, C5-ArH), 7.05 (d, J
= 2.7 Hz, 1 H, C5Ј-ArH), 7.22–7.39 (m, 6 H, Ph and C7Ј-ArH),
7.49 (d, J = 7.0 Hz, 1 H, C6-ArH), 7.91 (d, J = 9.0 Hz, 1 H, C8Ј-
ArH), 8.10 (s, 1 H, C4Ј-ArH) ppm. C29H29BrN2O2·0.9 H2O
(533.66): calcd. C 63.37, H 5.65, N 5.10; found C 63.58, H 5.66, N
4.97.
8-Benzyloxymethyl-7-(1-ethylpropenyl)-11H-indolizino[1,2-b]quino-
lin-9-one (31a): A mixture of 30a (2.517 g, 5 mmol), Pd(OAc)2
(0.112 g, 0.5 mmol), PPh3 (0.262 g, 1 mmol), and freshly dried po-
tassium acetate (1.472 g, 15 mmol) in anhydrous acetonitrile
(150 mL) was stirred under argon at room temperature for 2 h and
was then heated at reflux for 12 h. The reaction mixture was con-
centrated to dryness under reduced pressure, and the residue was
dissolved in CHCl3 (50 mL), filtered through a pad of Celite, and
washed with CHCl3 (3×15 mL). The combined filtrate and wash-
ing were evaporated to dryness in vacuo, and the product was puri-
fied by column chromatography (MeOH/EtOAc/hexanes 1:10:15,
3-Benzyloxymethyl-1-(2-bromoquinolin-3-ylmethyl)-4-(1-ethylpro-
penyl)-1H-pyridin-2-one (30a): Potassium tert-butoxide (3.37 g,
30 mmol) was added in one portion to a stirring solution of 28
(6.819 g, 24 mmol) in anhydrous DME (300 mL) and the mixture
4496
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4490–4499

Synthesis of New Camptothecin Analogues
FULL PAPER
v/v/v) to afford 31a (2.04 g, 96.3%), as a mixture of (E) and (Z)
isomers (3:7), and recrystallized from EtOAc, m.p. 215–217 °C. 1H
NMR (CDCl3) (E) isomer: δ = 0.88 (t, J = 7.2 Hz, 3 H, Me), 1.77
1 H, CH), 4.70 (m, 2 H, CH2Py), 5.16 and 5.21 (each: d, J =
10.3 Hz, 1 H, CH2Ph), 5.29 (d, J = 6.6 Hz, 1 H, CH2N), 7.12 (s, 1
H, C6-ArH), 7.26–7.42 (m, 5 H, Ph), 7.64 (m, 1 H, C2-ArH), 7.79
(d, J = 6.9 Hz, 3 H, Me), 2.49 (q, J = 7.4 Hz, 2 H, CH2), 4.55 (m, (m, 1 H, C3-ArH), 7.91 (d, J = 8.1 Hz, 1 H, C1-ArH), 8.21 (d, J
2 H, CH2Py), 4.70 (s, 2 H, CH2Ph), 5.67 (q, J = 6.9 Hz, 1 H, CH2), = 8.1 Hz, 1 H, C4-ArH), 8.35 (s, 1 H, C12-ArH) ppm.
7.16 (s, 1 H, C6-ArH), 7.26–7.40 (m, 5 H, Ph), 7.63 (m, 1 H, C2- C28H28N2O4·0.5 H2O (465.53): calcd. C 72.24, H 6.28, N 6.02;
ArH), 7.80 (m, 1 H, C3-ArH), 7.92 (m, 1 H, C4-ArH), 8.20 (m, 1
H, C1-ArH), 8.35 (s, 1 H, C12-ArH) ppm; (Z) isomer: δ = 1.06 (t,
J = 7.2 Hz, 3 H, Me), 1.48 (dt, J = 1.4 and 6.8 Hz, 3 H, Me), 2.35
(qt, J = 1.4 and 7.4 Hz, 2 H, CH2), 4.45 and 4.57 (each: d, J =
9.7 Hz, 1 H, CH2Py), 4.67 (each: d, J = 11.7 Hz, 1 H, CH2Ph),
5.57 (qt, J = 1.5 and 6.9 Hz, 1 H, CH2), 7.07 (s, 1 H, C6-ArH),
7.26–7.40 (m, 5 H, Ph), 7.63 (ddd, J = 1.2 and 6.9 Hz, 1 H, C2-
ArH), 7.80 (ddd, J = 1.4 and 6.9, 1 H, C3-ArH), 7.92 (dd, J = 1.4
and 6.9 Hz, 1 H, C4-ArH), 8.20 (dd, J = 1.2 and 6.9 Hz, 1 H, C1-
ArH), 8.37 (s, 1 H, C12-ArH) ppm. C28H26N2O2 (422.51): calcd. C
79.59, H 6.20, N 6.63; found C 79.68, H 6.26, N 6.62.
found C 71.98, H 6.32, N 5.94.
7-(1-Ethylpropenyl)-8-hydroxymethyl-11H-indolizino[1,2-b]quinolin-
9-one (33a): BBr3 (5.2 g, 20.7 mmol) was added at –80 °C to a stir-
ring solution of 31a (3.50 g, 8.28 mmol) in dried CH2Cl2 (110 mL)
and the reaction mixture was stirred at –80 °C for 1 h. The reaction
was quenched by dropwise addition of saturated aqueous NaHCO3
(60 mL) and the reaction mixture was then allowed to warm to –
10 °C and neutralized with aqueous Na2CO3 solution (10%). The
water layer was separated and extracted with CH2Cl2 (4×10 mL),
the combined organic layer and extracts were washed with brine
(10 mL) and dried (Na2SO4), and the solvents were evaporated to
dryness in vacuo. The residue was chromatographed on a silica gel
column (5.5 × 30 cm) with CHCl3 as the eluent. The product
(2.12 g, 77%) was eluted with CH3OH/CHCl3 (1:20, v/v) as a mix-
ture of (E) and (Z) isomers (3:7); m.p. 204–206 °C (dec.). 1H NMR
([D6]DMSO) (E) isomer: δ = 0.92 (t, J = 7.6 Hz, 3 H, Me), 1.80
(d, J = 7.0 Hz, 3 H, Me), 2.50 (q, J = 7.6 Hz, 2 H, CH2), 4.42 (m,
2 H, CH2O), 4.75 (s, exchangeable, 1 H, OH), 5.27 (s, 1 H, CH2N),
5.57 (q, J = 6.5 Hz, 1 H, CH2), 6.97 (s, 1 H, C6-ArH), 7.71 (m, 1
H, C2-ArH), 7.86 (m, 1 H, C3-ArH), 8.12 (m, 1 H, C4-ArH), 8.15
(m, 1 H, C1-ArH), 8.68 (s, 1 H, C12-ArH) ppm; (Z) isomer: δ =
1.01 (t, J = 7.3 Hz, 3 H, Me), 1.45 (dt, J = 1.5 and 6.8 Hz, 3 H,
Me), 2.36 (qt, J = 1.5 and 7.6 Hz, 2 H, CH2), 4.29 and 4.44 (each:
dd, J = 5.9 and 11.7 Hz, 1 H, CH2), 4.70 (t, J = 5.6 Hz, 1 H,
exchangeable, OH), 5.30 (s, 1 H, CH2N), 5.62 (qt, J = 1.2 and
7.0 Hz, 1 H, CH2N), 6.88 (s, C6–1 H, ArH), 7.63 (m, J = 1.2 and
6.8 Hz, 1 H, C2-ArH), 7.86 (m, J = 1.5 and 6.8 Hz, 1 H, C3-ArH),
8.13 (d, J = 9.4 Hz, 1 H, C4-ArH), 8.15 (d, J = 9.1 Hz, 1 H, C1-
ArH), 8.69 (s, 1 H, C12-ArH) ppm. C21H20N2O2 (332.39): calcd. C
75.88, H 6.06, N, 8.43; found C 75.77, H 6.12, N 8.26.
8-Benzyloxymethyl-7-(1-ethylpropenyl)-2-methoxy-11H-indolizino-
[1,2-b]quinolin-9-one (31b): Compound 31b was obtained from 30b
(5.89 g, 11 mmol) by the same procedure as used for the synthesis
of 31a. Yield 3.72 g (74.7%); m.p. 162–164 °C as a mixture of (E)
1
and (Z) isomers (3:7). H NMR (CDCl3) (E) isomer: δ = 0.94 (t, J
= 7.4 Hz, 3 H, Me), 1.77 (d, J = 7.0 Hz, 3 H, Me), 2.48 (q, J =
7.4 Hz, 2 H, CH2), 3.967 (s, 3 H, OMe), 4.54 (s, 2 H, CH2Py), 4.70
(s, 2 H, CH2Ph), 5.25 (d, J = 0.8 Hz, 2 H, CH2N), 5.66 (q, J =
6.7 Hz, 1 H, CH=), 7.09 (s, 1 H, C6-ArH), 7.15 (d, J = 3.1 Hz, 1
H, C1-ArH), 7.24–7.38 (m, 5 H, Ph), 7.42 (d, J = 9.0 Hz, 1 H, C3-
ArH), 8.08 (d, J = 9.0 Hz, 1 H, C4-ArH), 8.23 (s, 1 H, C12-
ArH) ppm; (Z) isomer: δ = 1.05 (t, J = 7.4 Hz, 3 H, Me), 1.48 (dt,
J = 1.2 and 7.0 Hz, 3 H, Me), 2.34 (qt, J = 1.2 and 7.4 Hz, 2 H,
CH2), 3.971 (s, 3 H, OMe), 4.44 and 4.54 (each: d, J = 9.8 Hz, 1
H, CH2Py), 4.67 (d, J = 3.5 Hz, 2 H, CH2Ph), 5.27 (s, 2 H, CH2N),
5.55 (qt, J = 1.6 and 7.0 Hz, 1 H, CH=), 7.00 (s, 1 H, C6-ArH),
7.17 (d, J = 3.0 Hz, 1 H, C1-ArH), 7.24–7.38 (m, 5 H, Ph), 7.42
(d, J = 9.0 Hz, 1 H, C3-ArH), 8.08 (d, J = 9.0 Hz, 1 H, C4-ArH),
8.25 (s, 1 H, C12-H) ppm. C29H28N2O3 (452.53): calcd. C 76.97, H
6.24, N 6.19; found C 77.15, H 6.38, N 6.36.
7-(1-Ethylpropenyl)-8-hydroxymethyl-2-methoxy-11H-indolizino-
[1,2-b]quinolin-9-one (33b): Compound 33b was obtained from 31b
(3.25 g, 7.17 mmol) by the same procedure as used for the synthesis
of 33a. Yield 1.46 g (56%) as a mixture of (E) and (Z) isomers
(3:7); m.p. 184–189 °C. 1H NMR ([D6]DMSO), (E) isomer: δ = 0.92
(t, J = 7.8 Hz, 3 H, Me), 1.80 (d, J = 6.4 Hz, 3 H, Me), 2.49 (q, J
= 7.8 Hz, 2 H, CH2), 3.94 (s, 3 H, OMe), 4.41 (d, J = 6.0 Hz, 2 H,
CH2O), 4.72 (t, J = 6.0 Hz, 1 H, exchangeable, OH), 5.22 (s, 1 H,
CH2N), 5.56 (q, J = 6.4 Hz, 1 H, CH2), 6.87 (s, 1 H, C6-ArH),
7.49 (dd, J = 3.1 and 9.3 Hz, 1 H, C3-ArH), 7.51 (d, J = 3.1 Hz, 1
H, C1-ArH), 8.01 (d, J = 7.8 Hz, 1 H, C4-ArH), 8.51 (s, 1 H, C12-
ArH) ppm; (Z) isomer: δ = 1.01 (t, J = 7.3 Hz, 3 H,Me), 1.45 (d,
J = 6.9 Hz, 3 H, Me), 2.35 (qt, J = 1.4 and 7.3 Hz, 2 H, CH2), 3.94
(s, 3 H, OMe), 4.29 and 4.43 (each: dd, J = 6.0 and 11.5 Hz, 1 H,
CH2O), 4.68 (t, J = 6.0 Hz, 1 H, exchangeable, OH), 5.26 (s, 1 H,
CH2N), 5.61 (qt, J = 1.4 and 6.9 Hz, 1 H, CH=), 6.79 (s, 1 H, C6-
ArH), 7.49 (dd, J = 3.1 and 9.3, 1 H, C3-ArH), 7.51 (d, J = 3.1 Hz,
1 H, C1-ArH), 8.03 (d, J = 9.2 Hz, 1 H, C4-H), 8.53 (s, 1 H, C12-
ArH) ppm. C22H22N2O3 (362.42): calcd. C 72.91, H 6.12, N 7.73;
found C 73.14, H 5.90, N 7.48.
8-Benzyloxymethyl-7-(1-ethyl-1,2-dihydroxypropyl)-11H-indolizino-
[1,2-b]quinolin-9-one (32a): A solution of OsO4 (0.508 g, 2 mmol)
in THF (3 mL) was added to a mixture of 31a (0.845 g, 2 mmol)
and (CH3)3NO·2H2O (0.67 g, 6 mmol) in THF (45 mL). The mix-
ture was stirred at room temperature for 5 d (31a was not con-
sumed completely) and was then quenched by addition of aq.
NaHSO3 (39%, 4 mL) and water (10 mL). The mixture was stirred
with Celite (2 g) for 1 h and then filtered, the solid cake was washed
with ethyl acetate (2×5 mL), the filtrate and washing were com-
bined and dried (Na2SO4), and the solvents were evaporated to
dryness. The residue was chromatographed on a silica gel column
(3×30 cm), the starting material 31a [0.453 g, 53.6%, only (Z) iso-
mer (1H NMR)] being eluted (CHCl3), followed by the product
(CH3OH/CHCl3 1:50). Yield 0.787 g (26.7 %), m.p. 179–192 °C
(recrystallized from CHCl3/hexane) as a mixture of diastereomers
1
1
(4:6, H NMR). H NMR (CDCl3) major diastereomer: δ = 0.80
(t, J = 7.3 Hz, 3 H, Me), 1.01 (d, J = 5.9 Hz, 3 H, Me), 2.00 and
2.26 (each: m, 1 H, CH2), 2.10 (brs, 1 H, exchangeable, OH), 4.13
(q, J = 5.9 Hz, 1 H, CH), 4.69 (dd, J = 11.0 Hz, 2 H, CH2Py), 5.10
and 5.19 (each: d, J = 10.3 Hz, 1 H, CH2Ph), 5.29 (s, 2 H, CH2N),
5.53 (brs, 1 H, exchangeable, OH), 7.12 (s, 1 H, C6-ArH), 7.26–
7-(1-Ethylpropenyl)-8-(tetrahydropyran-2-yloxymethyl)-11H-indo-
7.42 (m, 5 H, Ph), 7.65 (m, 1 H, C2-ArH), 7.82 (m, 1 H, C3-ArH), lizino[1,2-b]quinolin-9-one (34a): A mixture of 33a (1.308 g,
7.91 (d, J = 8.1 Hz, 1 H, C1-ArH), 8.23 (d, J = 8.1 Hz, 1 H, C4- 3.93 mmol), 3,4-dihydro-2H-pyran (1.65 g, 19.7 mmol), and p-tolu-
ArH), 8.38 (s, 1 H, C12-ArH) ppm; minor diastereomer: δ = 0.81 enesulfonic acid monohydrate (2 mg) in anhydrous CH2Cl2 (25 mL)
(t, J = 7.3 Hz, 3 H, Me), 1.30 (d, J = 5.9 Hz, 3 H, Me), 1.82 (m, 2 was stirred under argon atmosphere for 3 h. The reaction mixture
H, CH2), 2.10 (brs, 1 H, exchangeable, OH), 4.23 (q, J = 5.9 Hz,
was neutralized by addition of triethylamine (3 drops) and was then
Eur. J. Org. Chem. 2006, 4490–4499
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. A. Bacherikov, T.-J. Tsai, J.-Y. Chang, T.-C. Chou, R.-Z. Lee, T.-L. Su
FULL PAPER
evaporated to dryness in vacuo. The residue was chromatographed
on a silica gel column (4×29 cm) with CH3OH/CHCl3 (1:50, v/v)
and the product 34a was obtained as crystals (1.62 g, 99%) as a
mixture of diastereomers, m.p. 185–189 °C. 1H NMR (CDCl3): δ =
0.99–1.11 (m, 3 H, Me), 1.48–1.83 (m, 3 H, Me), 1.5–1.9 (m, 6 H,
THP), 2.34–2.55 (m, 1 H, CH2), 3.62 (m, 1 H, OCH, THP), 4.03
(m, 1 H, OCH, THP), 4.34–4.78 (m, 2 H, ArCH2O), 4.87–4.95 (m,
1 H, OCH, THP), 5.27–5.32 (m, 2 H, CH2N), 5.60–5.65 (m, 1 H,
CH=), 7.07–7.18 (m, 1 H, C6-ArH), 7.64 (m, 1 H, C2-ArH), 7.80
(m, 1 H, C3-ArH), 7.92 (d, J = 7.7 Hz, 1 H, C4-ArH), 8.20 (d, J
= 8.4 Hz, 1 H, C1-ArH), 8.37 (s, 1 H, C12-ArH) ppm.
C26H28N2O3·H2O (434.52): calcd. C 71.87, H 6.96, N 6.45; found
C 72.01, H 6.94, N 6.08.
(480.55): calcd. C 67.48, H 6.71, N 5.83; found C 67.68, H 6.85, N
5.69.
7-(1-Ethyl-1,2-dihydroxypropyl)-8-hydroxymethyl-11H-indolizino-
[1,2-b]quinolin-9-one (36a): p-Toluenesulfonic acid monohydrate
(2 mg) was added to a solution of 35a (0.481 g, 1.07 mmol) in
CH3OH (35 mL). The reaction mixture was stirred at ambient tem-
perature for 7 h and was then quenched by addition of NH4OH
(25%, 100 µL). The solvent was removed under reduced pressure
and the residue was chromatographed on a silica gel column
(2×30 cm) with CH3OH/CHCl3 (1:50, v/v) to afford 36a (0.272 g,
69.5%), m.p. 192–196 °C (recrystallized from CHCl3/hexane) as a
1
1
mixture of diastereomers (4:6, H NMR). H NMR ([D6]DMSO)
major diastereomer: δ = 0.74 (t, J = 7.6 Hz, 3 H, Me), 0.95 (d, J
= 6.3 Hz, 3 H, Me), 2.03 (m, 2 H, CH2), 4.06 (m, 1 H, CH), 4.70–
5.1 (m, 4 H, CH2O and 2×OH, exchangeable), 5.25 (s, 2 H, CH2N),
5.49 (brs, 1 H, exchangeable, OH), 7.36 (brs, 1 H, C6-ArH), 7.70
(m, 1 H, C2-ArH), 7.85 (m, 1 H, C3-ArH), 8.11 (d, J = 8.2 Hz, 1
H, C1-ArH), 8.17 (d, J = 8.6 Hz, 1 H, C4-ArH), 8.66 (s, 1 H, C12-
ArH) ppm; minor diastereomer: δ = 0.79 (t, J = 7.6 Hz, 3 H, Me),
1.09 (d, J = 6.3 Hz, 3 H, Me), 1.74 and 2.14 (each: m, 1 H, CH2),
3.93 (m, 1 H, CH), 5.24 (s, 2 H, CH2N), 7.44 (s, 1 H, C6-H) ppm;
signals from protons of CH2OH, OH and A,B rings of molecule
overlapped with signals from the protons of major diastereomer.
C21H22N2O4·H2O (384.42): calcd. C 65.61, H 6.29, N 7.29; found
C 65.69, H 6.03, N 7.20.
7-(1-Ethylpropenyl)-2-methoxy-8-(tetrahydropyran-2-yloxymethyl)-
11H-indolizino[1,2-b]quinolin-9-one (34b): Compound 34b (1.42 g,
3.92 mmol) was obtained from 33b by the same procedure as used
for the synthesis of 34a. Yield 1.75 g (99%) as a mixture of dia-
stereomers; m.p. 177–180 °C. 1H NMR (CDCl3): δ = 0.97–1.11 (m,
3 H, Me), 1.47–1.83 (m, 3 H, Me), 1.5–1.9 (m, 6 H, THP), 2.34–
2.54 (m, 1 H, CH2), 3.60 (m, 1 H, OCH, THP), 3.98 (s, 3 H, MeO),
4.00–4.13 (m, 1 H, OCH, THP), 4.33–4.76 (m, 2 H, ArCH2O),
4.88–4.94 (m, 1 H, OCH, THP), 5.25–5.28 (m, 2 H, CH2N), 5.60–
5.65 (m, 1 H, CH=), 7.01–7.17 (m, 1 H, C6-ArH), 7.44–7.50 (m, 2
H, C1-ArH, C3-H), 8.08 (d, J = 9.6 Hz, 1 H, C4-ArH), 8.24 (s, 1
H, C12-ArH) ppm. C27H30N2O4·0.5H2O (455.54): calcd. C 71.19,
H 6.86, N 6.15; found C 71.01, H 6.94, N 6.08.
7-(1-Ethyl-1,2-dihydroxypropyl)-8-hydroxymethyl-2-methoxy-11H-
indolizino[1,2-b]quinolin-9-one (36b): Compound 36b was obtained
from 35b (0.209 g, 0.43 mmol) by the same procedure as used for
synthesis of 36a. Yield 0.122 g (70.8 %), as a mixture of dia-
stereomers (1:1), m.p. 216–218 °C (recrystallized from CHCl3/hex-
7-(1-Ethyl-1,2-dihydroxypropyl)-8-(tetrahydropyran-2-yloxymethyl)-
11H-indolizino[1,2-b]quinolin-9-one (35a): A solution of OsO4
(0.64 g, 2.52 mmol) in THF (2 mL) was added to a mixture of 34a
(3.554 g, 8.4 mmol) and (CH3)3NO·2H2O (1.87 g, 16.8 mmol) in
THF (60 mL). The mixture was stirred at room temperature for
36 h (the olefin 34a was not consumed completely), the reaction
was quenched by addition of a solution of Na2SO3 (1.2 g) in water
(30 mL), the mixture was stirred with celite (2 g) for 1 h and then
filtered, and the solid cake was washed with ethyl acetate
(5×10 mL). The filtrate and washing were combined and dried
(Na2SO4), the solvents were evaporated to dryness, and the residue
was chromatographed on a silica gel column (6×30 cm). The start-
ing material 34a [0.505 g, 36.7%, only (Z) isomer (1H NMR)] was
eluted (CHCl3), followed by the product (CH3OH/CHCl3 1:50).
Yield 0.672 g (45.2 %), m.p. 175–188 °C, as a mixture of dia-
1
ane). H NMR ([D6]DMSO): δ = 0.73 and 0.78 ppm (each: t, J =
7.4 Hz, 3 H, Me), 0.93 and 1.07 (each: d, J = 6.3 Hz, 3 H, Me),
1.72 and 2.13 (each: m, 1 H, CH2), 2.01 (m, 2 H, CH2), 3.94 (s, 3
H, MeO), 4.04 (m, 1 H, CH), 4.68–5.1 (m, 4 H, CH2O and 2×OH,
exchangeable), 5.22 and 5.23 (each: s, 2 H, CH2N), 7.28 and 7.36
(each: brs, 1 H, exchangeable, OH), 7.51 (m, 4 H, C6-ArH and C3-
ArH), 8.06 (d, J = 9.4 Hz, 2 H, C4-ArH), 8.53 (s, 2 H, C12-ArH).
C
22H24N2O5 (396.43): calcd. C 66.65, H 6.10, N 7.07; found C
66.58, H 6.18, N 7.01.
(7RS)-7-Ethyl-7-hydroxy-7H,12H-5,11a-diazadibenzo[b,h]fluorene-
8,11-dione (12a): Active MnO2 on carbon, prepared by Caprino’s
method,[31] was added to a solution of 36a (0.22 g, 0.6 mmol) and
acetic acid (0.5 mL) in CH2Cl2 (170 mL). The reaction mixture was
heated at reflux under argon for 36 h and filtered while hot through
a pad of Celite, and the solid cake was washed with a hot CH3OH/
CHCl3 solution (10 mL). The filtrate and washings were combined
and the solvents were evaporated to dryness. The residue was chro-
matographed on silica gel column (1.5 × 30 cm) with CH3OH/
CHCl3 (1:25) to afford (7RS)-12a (0.161, g 85.2 %), m.p. 188–
190 °C (dec., recrystallized from CHCl3/hexane). 1H NMR ([D6]
DMSO): δ = 0.80 (t, J = 7.4 Hz, 3 H, Me), 2.01 (m, 2 H, CH2),
4.84 and 4.98 (each: d, J = 14.1 Hz, 1 H, CH=CH), 5.28 (s, 2 H,
CH2N), 6.72 (brs, 1 H, exchangeable, OH), 7.18 (s, 1 H, C6-ArH),
7.71 (ddd, J = 1.2 and 7.4 Hz, 1 H, C2-ArH), 7.86 (ddd, J = 1.6
and 7.0 Hz, 1 H, C3-ArH), 8.11 (d, J = 7.4 Hz, 1 H, C1-ArH),
8.15 (d, J = 8.6 Hz, 1 H, C4-ArH), 8.69 (s, 1 H, C14-ArH) ppm.
C21H16N2O3 (384.42): calcd. C 73.24, H 4.68, N 8.13; found C
73.27, H 4.76, N 7.97.
1
stereomers. H NMR (CDCl3): δ = 0.80–1.12 (m, 3 H, Me), 1.45–
1.63 (m, 7 H, Me, THP), 1.65–1.73 (m, 1 H, THP), 1.73–1.87 (m,
1 H, THP), 2.26–2.39 (m, 1 H, CH2), 3.47–3.61 (m, 1 H, OCH,
THP), 4.21–4.41, (m, 2 H, OCH), 4.50–4.70 (m, 2 H, OCH, THP),
4.72 (s, 1 H, exchangeable, OH), 4.76–4.86 (m, 1 H, THP), 4.91 (s,
2 H, CH2N), 5.56 (m, 1 H, THP), 6.76, (s, 1 H, C6-ArH), 7.56 (m,
1 H, C2-ArH), 7.71 (m, 1 H, C3-ArH), 7.83 (d, J = 8.2 Hz, 1 H,
C4-ArH), 8.05 (d, J = 8.2 Hz, 1 H, C1-ArH), 8.36 (m, 1 H, C12-
ArH) ppm. C18H21NO2·0.2H2O (286.96): calcd. C 75.34, H 7.52,
N 4.88; found C 75.46, H 7.43, N 4.91.
7-(1-Ethyl-1,2-dihydroxypropyl)-8-(tetrahydropyran-2-yloxymethyl)-
2-methoxy-11H-indolizino[1,2-b]quinolin-9-one (35b): Compound
35b was obtained from 34b (1.75 g, 3.92 mmol) by the same pro-
cedure as used for the synthesis of 35a. Yield 0.38 g (20.1%), m.p.
211–215 °C, as a mixture of diastereomers. 1H NMR ([D6]DMSO):
δ = 0.68–0.82 (m, 3 H, Me), 0.88–1.09 (m, 3 H, Me), 1.35–1.80 (m,
4 H, THP), 1.85–2.18 (m, 4 H, THP and CH2), 3.51 (m, 1 H, OCH,
THP), 3.94 (s, 3 H, MeO), 4.00 (m, 1 H, OCH), 4.71–4.91 (m, 1 (7RS)-7-Ethyl-7-hydroxy-2-methoxy-7H,12H-5,11a-diazadibenzo-
H, OCH, THP), 5.11–5.17 (m, 1 H, THP), 5.23 (s, 2 H, CH2N), [b,h]fluoren-8,11-dione (12b): Compound (7RS)-12b was obtained
7.35–7.55 (m, 3 H, C6-ArH, C3-ArH, and OH), 8.07 (d, J = 9.5 Hz, from 36b (0.117 g, 0.29 mmol) by the same procedure as used for
1 H, C4-ArH), 8.32–8.53 (m, 1 H, C12-ArH) ppm. C27H32N2O6 the synthesis of 12a. Yield 0.019 g (17.2%), m.p. 178–180 °C (dec.,
4498
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4490–4499

Synthesis of New Camptothecin Analogues
FULL PAPER
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recrystallized from CHCl3/hexane). H NMR ([D6]DMSO): δ =
0.79 (t, J = 7.4 Hz, 3 H, Me), 2.00 (m, 2 H, CH2), 3.95 (s, 3 H,
MeO), 4.82 and 5.27 (each: d, J = 13.7 Hz, 1 H, CH=CH), 5.27 (s,
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Acknowledgments
The research was supported by a grant from the National Science
Council of Taiwan (NSC 93-2320-B-001-010). The NMR spectra
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Received: April 6, 2006
Published Online: August 9, 2006
Eur. J. Org. Chem. 2006, 4490–4499
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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