Facile syntheses of ABC ring skeleton of camptothecin and related alkaloids

Article abstract of DOI:10.1081/SCC-200028560

Facile synthetic approaches toward the preparation of ABC ring of camptothecin and related alkaloids starting from cheaper and readily available chemical reagents.

Full text of DOI:10.1081/SCC-200028560

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 17, pp. 3099–3110, 2004
Facile Syntheses of ABC Ring Skeleton of
Camptothecin and Related Alkaloids
*
Subhash P. Chavan, K. Pasupathy, R. Sivappa,
and M. S. Venkatraman
Organic Chemistry, Technology, National Chemical Laboratory,
Pune 411008, India
ABSTRACT
Facile synthetic approaches toward the preparation of ABC ring of camp-
tothecin and related alkaloids starting from cheaper and readily available
chemical reagents.
Key Words: Camptothecin; Alkaloids; ABC ring skeleton.
Wall and coworkers[1] isolated Camptothecin (1), a potential anticancer
chemotherapeutic agent, in the early 1960s from Camptotheca acuminata.
Spanning four decades it has been the compound of choice for both medicinal
as well as synthetic chemists. Nothapodytine B [Mappicine ketone (2b)]
*
Correspondence: Subhash P. Chavan, Organic Chemistry, Technology, National
Chemical Laboratory, Pune 411008, India; E-mail: spchavan@dalton.ncl.res.in.
3099
DOI: 10.1081/SCC-200028560
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Chavan et al.
isolated recently from Nothapodytes foetida[2] (an oxidized derivative of
Mappicine[3] and E-ring decarboxylated analogue of camptothecin) has
been identified as an antiviral lead with reported selectivity against HSV-1,
HSV-2, and HCMV.[4] Intense research on camptothecins has culminated in
launching
two successful compounds in clinical practice (irinotecan and topotecan) and
several other compounds in clinical development.[5] Given the current conti-
nued interest, many syntheses have been achieved, still there is an evident
need for the development of a new synthetic route amenable to camptothecin
and its analogues.
Several groups involved in the convergent synthesis of camptothecin and
mappicine ketone identified the tricylic amine 3 as a key synthon for the con-
struction of ABC ring system (Sch. 1).[6] Reports involving the preparation of
this key intermediate have utilized chemical reagents, which are either
expensive, unstable, low yielding, or pose handling problems.[6] These limit-
ations are certainly a drawback during large-scale preparation of this tricyclic
amine 3. This implies that there is an evident need for new methods to syn-
thesize this important intermediate. As a part of our research to explore new
synthetic approaches toward camptothecin[7a,7b] and mappicine ketone,[7c]
we decided to explore new synthetic sequences to provide the tricyclic
amine 3 using simple and commercially available starting materials.
Meth-Cohn’s quinoline aldheyde 4[8] with a formyl group at 3-position
and the handle at 2-position for the functionalization, i.e., C-C bond formation,
given the flexibility and simplicity for the analogues preparation,[9] appealed
to be the ideal starting material. This approach certainly circumvents the short-
Scheme 1.

Syntheses of ABC Ring Skeleton of Camptothecin
3101
comings of the earlier approaches such as usage of 2-aminobenzaldehyde,
regiochemistry problems encountered in Friedlander condensation, and the
usage of expensive starting materials like acridine, propargyl amine, and
dimethylacetylene dicarboxylate (DMAD).[6]
Thus, the formyl group of the iodoaldehyde 4 was protected as cyclic acetal
5 according to literature procedure (Sch. 2).[8] Quenching the lithio derivative
of 5 with dimethyl formamide (DMF) provided the 3-oxolyl-2-formyl-quinoline
(6) in 64% yield after column chromatography. Treatment of acetal 6 with 20%
HCl in ether furnished dialdehyde 7. Gratifyingly, the treatment of dialdehyde 7
with 0.6 equivalent of benzyl amine followed by the reduction (in the same pot)
with sodium borohydride at 08C and resulted in the formation of tricyclic amine
8 after usual work-up and column chromatography. The amine obtained was
converted to its carbamate 9[10] by refluxing with ethyl chloroformate whose
deprotection to tricyclic amine 3 can be obtained by established protocol.[6e]
A much closer look at the tricyclic amine revealed another synthetic route
starting from cheaper and readily available quinoline ester (Sch. 3).[11]
Reduction of the ester group in quinoline 10 with lithium aluminium
hydride furnished the corresponding hydroxyquinoline 11 in 55% yield.[11]
The oxidation of 11 with 13-chloroperbenzoic acid (MCPBA) at room
temperature resulted in the formation of corresponding quinoline N-oxide
12 in very high yields. The same transformation was also achieved with
peracetic acid as an oxidizing agent. Further treatment of quinoline N-oxide
12 with acetic anhydride followed by acetate hydrolysis furnished the diol
14 in good yields. The diol 14 obtained was converted to its dimesylate 15
as per Corey’s protocol whose conversion to tricyclic amine can be obtained
by literature reports.[6b,6c]
In conclusion, new and facile synthetic approaches toward the preparation
of ABC ring of camptothecin and related alkaloids were achieved starting
from cheaper and readily available chemical reagents.
EXPERIMENTAL SECTION
General Remarks
All melting points reported are uncorrected and the temperature is
expressed in degree scale. All solvents were distilled before use. Benzene,
tetrahydro furan (THF), and diethyl ether were dried over sodium. Dimethyl
formamide (DMF) was dried over calcium hydride. Petroleum ether refers
to the fraction boiling in the range of 608C–808C. When chromatographic
purification was done, SiO2 (60–120 mesh size) or activated neutral
alumina was used as stationary phase. The reaction progress was monitored

3102
Chavan et al.

Syntheses of ABC Ring Skeleton of Camptothecin
3103

3104
Chavan et al.
by the thin layer plates precoated with silica gel 60 F254 (Merck). Infrared (IR)
spectra were recorded on Perkin Elmer infrared spectrophotometer model
683B or 1605 FTIR, and IR absorbance is expressed in cm21. The proton
and carbon-13 NMR spectra were recorded on Bruker AC-200, MSL-300,
and DRX-500 and chemical shifts are reported on d scale. Mass spectra
were recorded at an ionization energy 70 eV on Finnigan MAT-1020, auto-
mated GC/MS instrument, and on API Q STARPULSAR using electron
spray ionization [(ESI), solvent medium-water, acetonitrile and ammonium
acetate] technique and mass values are expressed as m/z. Elemental analyses
(C, H, N) were obtained on a Carlo-Erber 1100 automatic analyzer.
3-[1,3] Dioxaolan-2-yl-2-iodo-quinoline [5]
A solution of 2-iodo-3-formyl quinoline (4) (28.3 g, 0.1 mol) in benzene
(300 mL) containing ethylene glycol (18.62 g, 0.3 mol) and catalytic amount
of PTSA was heated under reflux for 7 h with azeotropic removal of water.
The cooled solution was treated with sat. NaHCO3 solution (100 mL). The
organic layer was separated, dried over anhydrous sodium sulfate, filtered,
and evaporated under reduced pressure to give 5 as a white solid (34.1 g,
90%), which was pure enough for further use.
Melting point
1108C
1625, 1555, 1310, 1175
IR (Nujol): cm21
1H NMR (CDC13,
200 MHz): d
4.14 (m, 4H), 5.99 (s, 1H), 7.54 (m, 1H),
7.7–7.82 (m, 2H), 8.02 (m, 1H), 8.15 (s, 1H)
327 (Mþ, 5), 235 (80), 204 (10), 200 (30), 190
(50), 163 (100), 148 (75), 127 (50), 101 (30)
Mass: m/z (%)
3-[1,3] Dioxolan-2-yl-quinoline-2-carbaldehyde [6]
3-[1,3] Dioxolan-2y1-2-iodo-quinoline (5) (0.654 g, 2.88 mmol) in dry
ether at 2708C under N2 atmosphere was treated with n-BuLi (1.9 mL,
1.6 M sol in hexane, 3 mmol) with stirring, and after few minutes dry DMF
was added. After reaching ambient temperature the solution was quenched
with water and extracted with CHCl3 (3 ꢀ 20 mL). The combined organic
phase was dried over Na2SO4 and concentrated under reduced pressure to
give the crude aldehyde, which was purified by column chromatography
over silica gel using ethyl acetate-pet ether (3 : 7) as eluent to give pure 6 as
a pale yellow solid in 64% yield (0.278 g).
Melting point
IR (CHCl3): cm21
1038C
1685, 1617, 1560, 1145, 910

Syntheses of ABC Ring Skeleton of Camptothecin
3105
1H NMR (CDCl3,
200 MHz): d
4.18 (m, 4H), 6.73 (s, 1H), 7.57 (t, 1H),
7.61 (t, 1H), 7.81 (d, J ¼ 8.3 Hz, 1H), 8.25
(d, J ¼ 8.3 Hz, 1H), 8.6 (s, 1H), 10.37(s, 1H)
229 (Mþ, 1), 228 (5), 200 (92), 169(30),
157(100), 129(100)
Mass: m/z (%)
Quinoline-2, 3-dialdehyde [7]
The quinoline acetal 6 (0.460 g, 2 mmol) was suspended in a 1 : 2 mixture
of aq HCl solution (5 mL, 2 M) and ether (10 mL) for 1 h. Ether layer was
removed and the aqueous phase was rendered basic with saturated sodium
bicarbonate solution and extracted with CHCl3 (2 ꢀ 5 mL). The organic
layer was dried over sodium sulfate, filtered, and evaporated under reduced
pressure to give dialdehyde 7 as a yellow solid in 92% yeld (0.340 g).
Melting point
1738C–1758C
IR (CHCl3): cm21
1H NMR(CDCl3,
200 MHz): d
1705, 1680, 1620, 1575
7.8 (m, 1H), 7.98 (m, 1H), 8.06 (m, 1H),
8.31 (m, 1H), 8.86 (s, 1H), 10.38 (s, 1H),
11.02 (s, 1H)
Mass (ESI): m/z
184 (M21)þ
2-Benzyl-2,3-dihydro-lH-pyrrolo[3, 4-b]quinoline [8]
Quinoline dialdehyde 7 (1.85 g, 10 mmol) and benzylamine (0.645 g,
0.6 eq) were mixed in methanol (20 mL) at room temperature under nitrogen
atmosphere and the mixture was further stirred for 1 h, until the aldimine
formation was completed. The aldimine in methanol at 08C was carefully
treated with solid sodium borohydride (0.6 g, 1.6 mmol) and was stirred for
1 h. Methanol was reduced under reduced pressure, quenched with water,
and extracted with chloroform (2 ꢀ 30 mL). The combined organic extracts
were washed with saturated aq NaCl (10 mL) and dried over anhydrous
sodium sulfate. The solvent was evaporated and pure tricyclic amine 8
(80% yield, 2.10 g) was obtained by column chromatography over alumina
using 20% pet ether-ethyl acetate as a white solid.
Melting point
1168C–1188C, lit[6g] mp-1188C
3340, 1540, 260
IR (CHCl3): cm21
1H NMR (CDCl3,
200 MHz): d
4.00, (s, 2H), 4.05 (s, 2H), 4.13 (s, 2H), 7.5–7.23
(m, 6H), 7.76 (m, 1H), 7.73 (m, 1H), 7.86
(s, 1H), 8.05 (d, 1H)
260 (M)þ
Mass: m/z (%)

3106
Chavan et al.
N-Carbethoxy-2,3-dihydro-1H-(3, 4b)-quinoline [9]
To 0.35 g (1.23 mmol) of amine 8 was added (0.16 g, 1.53 mmol) of ethyl
chloroformate in 25 mL of dry benzene. The mixture was refluxed under a
nitrogen atmosphere for 2 h. After the completion of the reaction, benzene
was removed on a rotary evaporator and the crude urethane was purified by
column chromatography over silica gel using 25% pet ether-ethyl acetate as
eluent to furnish 0.242 g (74% yield) of urethane 9 as a yellow solid.
Melting point
1308C–1328C, lit[6e] mp-1348C
1710
IR (CHCl3): cm21
1H NMR (CDCl3,
500 MHz): d
1.36 (t, J ¼ 7.1 Hz, 3H), 4.25 (q, J ¼ 7.1 Hz,
2H), 4.80 (s, 2H), 4.90 (s, zH), 7.5
(t, J ¼ 8.00 Hz, 1H), 7.6 (t, J ¼ 8.00 Hz, 1H)
7.7 (s, 1H), 7.9–8.1(m, 2H)
241 (Mþ1)þ
Mass (ESI): m/z
2-Methyl-3-hydroxymethylquinoline [11]
To the ester 10 (5 g, 24.8 mmol) dry THF (50 mL) was added slowly at
08C to the suspension of LAH, (0.945 g, 24.8 mmol) in dry THF (20 mL).
The reaction mixture was stirred for 1 h at 08C, quenched with methanol,
and the precipitate was filtered. The precipitate was washed with ethyl
acetate (3 ꢀ 20 mL). The combined organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel
(eluting with pet ether-EtOAc ¼ 9 : 11) afforded the title compound 11 as
a pale yellow solid (2.37 g, 55%).
Melting point
IR (Nujol): cm21
1H NMR (CDCl3,
Above 2408C
3150, 2943, 2922, 1455
2.72 (s, 3H), 4.89 (s, 2H), 7.50 (m, 1H), 7.69
(m, 1H), 7.79 (d, J ¼ 8 Hz, 1H), 8.03 (d, 1H,
J ¼ 8.00 Hz), 8.12 (s, 1H)
¨
200 MHz): a
Mass: m/z
(100%)
173 (Mþ, 100), 155 (84), 144 (100), 131 (30), 115
(40), 103 (19), 89 (17), 77 (38), 63 (30)
2-Methyl-3-hydroxymethylquinoline 1-Oxide [12]
To the hydroxyquinoline 11 (2.5 g, 14.4 mmol) in acetonitrile (40 mL)
was added 55% MCPBA (5 g, 16 mmol) dissolved in acetonitrile (15 mL)
drop-wise. The reaction mixture was stirred overnight at room temperature.
The solid obtained was filtered; washed with saturated Na2SO3 solution

Syntheses of ABC Ring Skeleton of Camptothecin
3107
(10 mL), NaHCO3 solution (10 mL), and acetonitrile (10 mL); and dried under
reduced pressure as a white solid. The crude quinoline N-oxide 12 thus
obtained (2.45 g, 90% yield) was sufficiently pure for the subsequent reaction.
Melting point
IR (Nujol): cm21
1H NMR (CDCl3,
1918C–1938C
2924, 2855, 1601, 1564, 1461, 1377
4.29 (s, 3H), 6.36 (s, 2H), 8.95 (m, 3H), 9.36
(m, 1H), 10.23 (d, 1H), J ¼ 10.00 Hz)
148.59, 140.96, 136.29, 131.98, 129.54,
127.89, 119.7, 62.46, 14.33
189 (Mþ, 27), 172 (60), 155 (13), 144 (100),
128 (37), 115 (53), 102 (23), 89 (27), 77 (54)
C 69.84, H 5.82, N 7.40
¨
200 MHz): a
13C NMR (CD3OD,
¨
75 MHz): a
Mass: m/z (%)
Analysis expected
Observed
C 69.54, H 5.97, N 7.15
Acetic Acid 2-Acetoxymethyl-quinolin-3-ylmethyl ester [13]
To Ac2O (15 mL) preheated at 1108C, quinoline N-oxide 12 (2 g,
10.6 mmol) was added. After stirring at the same temperature for 5 min, the
reaction mixture was heated at 1308C for 90 min. Excess Ac2O was
removed under reduced pressure. The residue obtained was subjected to
column chromatography on silica gel (eluting with 30% pet ether-EtOAc)
afforded the title compound 13 as a colorless oil (2.17 g, 75%).
IR (CHCl3): cm21
1H NMR (CDCl3,
¨
200 MHz): a
1374, 1744
1.98 (s, 3H), 2.02 (s, 3H), 5.17 (s, 2H), 5.29
(s, 2H), 7.38 (m, 1H), 7.55 (m, 2H), 7.94
(m, 2H)
13C NMR(CDCl3,
¨
50 MHz): a
169.61, 153.91, 147.00, 136.82, 129.65,
129.14, 127.52, 127.26, 126.86, 65.51,
62.64, 20.48
273 (Mþ, 25), 230 (45), 170 (83), 143 (100),
130 (13), 115 (27)
Mass: m/z (%)
Analysis expected
Observed
C 65.93 H 5.53 N 5.13
C 65.45 H 5.44 N 5.10
2-Hydroxymethyl-quinolin-3-yl-methanol [14]
To the diacetate 13 (1 g, 5.29 mmol) dissolved in aq MeOH (10 mL) was
added K2CO3 (1.46 g, 10.58 mmol) at room temperature for 30 min. After the
methanol was removed under reduced pressure, the residue was extracted
with dichloromethane (3 ꢀ 20 mL). The organic layer was washed with

3108
Chavan et al.
water, brine, dried over Na2SO4, and concentrated under vacuum. Column
chromatography on silica gel (eluting with pet ether-EtOAc ¼ 32 : 1) furn-
ished the dihydroxy compound 14 as a pale yellow solid.
Melting point
IR (CHCl3): cm21
1H NMR (CDCl3,
1188C–1208C, lit[6b] 1158C–1188C
3202
1.77 (b, 1H), 4.83 (s, 2H), 4.93 (s, 2H), 7.56
(m, 1H), 7.73 (m, 1H), 7.84 (d, J ¼ 8.22 Hz,
1H), 8.08 (d, J ¼ 8.22 Hz, 2H), 8.18 (s, 1H)
189 (Mþ, 7), 171 (53), 160 (27), 143 (100),
130 (33), 115 (30), 103 (20)
¨
200 MHz): a
Mass: m/z (%)
Methanesulfonic Acid 2-Methanesulfonyloxymethyl-quinolin-
3-ylmethyl Ester [15]
To a mixture of 14 (0.500 g, 2.7 mmol) and triethylamine (1.06 g,
10.5 mmol) in dry benzene at 258C was added MsCl (0.909 g, 7.9 mmol)
drop-wise. The reaction mixture was stirred at the same temperature for 2 h.
The resulting mixture was washed with water (10 mL), saturated sodium
bicarbonate solution (10 mL), and brine (10 mL). The organic layer was
dried over Na2SO4, filtered, and concentrated under vacuum. The residue
obtained was subjected to column chromatography on silica gel (eluting
with 40% pet ether-EtOAc) afforded the title compound 15 as a colorless
oil (0.73 g, 80% yield).
IR (CHC13): cm21
1H NMR (CDCl3,
¨
200 MHz): a
3020, 1604, 1497, 1360, 1215, 1175
3.07 (s, 3H), 3.10 (s, 3H), 5.47 (s, 2H), 5.54
(s, 2H), 7.57 (s, 1H), 7.7–7.84 (m, 2H), 8.04
(d, J ¼ 8.30Hz, 1H), 8.24 (s, 1H)
ACKNOWLEDGMENTS
Authors K. P, R. S, and M. S thank CSIR New Delhi for fellowship and
funding from CSIR (New Delhi) under YSA (SPC) and DST scheme is grate-
fully acknowledged.
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3109
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Received in India May 18, 2004