Combined directed ortho metalation/cross-coupling strategies: Synthesis of the tetracyclic A/B/C/D ring core of the antitumor agent camptothecin

Article abstract of DOI:10.1021/jo049890h

A convergent synthesis of the A/B/C/D ring fragment 5 of camptothecin using a combination of directed ortho metalation and Negishi cross-coupling is described. The key features of the synthetic sequence are an anionic ortho-Fries rearrangement (10 → 12), a Negishi cross-coupling (7 → 6), and a terminal modified von Braun reaction (16 → 5) that leads to tetracyclic derivative 5 in 7 steps and 11% overall yield.

Full text of DOI:10.1021/jo049890h

Combined Directed Ortho Metalation/Cross-Coupling Strategies:
Synthesis of the Tetracyclic A/B/C/D Ring Core of the Antitumor
Agent Camptothecin
Tam Nguyen, Markus A. Wicki,‡ and Victor Snieckus*,†
The Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry,
University of Waterloo, Waterloo, ON, Canada N2L 3G1
snieckus@chem.queensu.ca
Received January 19, 2004
A convergent synthesis of the A/B/C/D ring fragment 5 of camptothecin using a combination of
directed ortho metalation and Negishi cross-coupling is described. The key features of the synthetic
sequence are an anionic ortho-Fries rearrangement (10 f 12), a Negishi cross-coupling (7 f 6),
and a terminal modified von Braun reaction (16 f 5) that leads to tetracyclic derivative 5 in 7
steps and 11% overall yield.
Introduction
for the treatment of ovarian cancer and small-cell lung
cancer10 and refractory colorectal cancer, respectively.11
(20S)-Camptothecin (1a), one of the most potent anti-
tumor natural products, was first isolated in 1966 from
Camptotheca acuminata Nyssaceae by Wall et al.1,2 Its
unusual structure and intriguing speculative biosynthetic
pathway3 stimulated immediate and intense synthetic
activity worldwide,4,5 which subsequently precipitously
declined due to the finding of discouraging biological
activity data of 1a5 showing serious toxic side effects. In
the past 15 years, renewed synthetic interest in 1a and
analogues6 evolved due to findings that substituted
derivatives of 1a such as 9-aminocamptothecin (1b),7
9-((dimethylamino)methyl)-10-hydroxycamptothecin (To-
potecan, 1c),8 and Irinotecan (1d)9 show low overall
toxicity, higher solubility, and still impressive in vivo
activity against certain solid tumors. In fact, Topotecan
1c and Irinotecan 1d were recently approved by the FDA
Alkaloids structurally related to camptothecin (1a)
such as homocamptothecin (2),12g,13 mappicine (3),14,15 and
mappicine ketone (4)15 are also of clinical relevance.
Homocamptothecin (2) and its derivatives show similar
therapeutic activities to the camptothecins (1). The E-ring
lactone in 1a easily hydrolyzes at physiological pH
leading to the biologically inactive carboxylate, an inher-
ent deficiency of the parent compound 1a.16 In the E-ring
lactone of 2 the tertiary alcohol and the lactone carbonyl
are separated by a methylene spacer. It was found in
bioassays that the longevity of activity of 2 was increased
compared to that of 1a.17 Mappicine ketone (4) has been
identified as an antiviral lead compound with selective
† Present address: Department of Chemistry, Queen’s University,
Kingston, ON, Canada K7L 3N6.
‡ Present address: Corporate Research & Development Laboratory,
3M Canada Company, P.O. Box 5757, London, ON, Canada N6A 4T1.
(1) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail,
A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888.
(2) For other natural sources of camptothecin and its derivatives,
see: Das, B.; Madhusudhan, P.; Reddy, P. V.; Anitha, Y. Indian J.
Chem. 2001, 40B, 453.
(10) Herzog, T. J. Oncologist 2002, 7 (Suppl. 5), 3.
(11) Henegar, K. E.; Ashford, S. W.; Baughman, T. A.; Sih, J. C.;
Gu, R.-L. J. Org. Chem. 1997, 62, 6588.
(12) (a) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863.
(b) Curran, D. P.; Ko, S.-B.; Josien, H. Angew. Chem., Int. Ed. Engl.
1995, 34, 2683. (c) Curran, D. P.; Liu, H.; Josien, H.; Ko, S.-B.
Tetrahedron 1996, 52, 11385. (d) Josien, H.; Ko, S.-B.; Bom, D.; Curran,
D. P. Chem. Eur. J. 1998, 4, 67. (e) Yabu, K.; Masumoto, S.; Yamasaki,
S.; Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M.
J. Am. Chem. Soc. 2001, 123, 9908. (f) Yabu, K.; Masumoto, S.; Kanai,
M.; Curran, D. P.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 2923. (g)
Curran, D. P.; Du, W. Org. Lett. 2002, 4, 3215. (h) Du, W.; Curran, D.
P. Synlett 2003, 1299.
(3) Brown, R. T.; Liu, J.; Santos, C. A. M. Tetrahedron Lett. 2000,
41, 859.
(4) Winterfeldt, E. Recent Dev. Chem. Nat. Carbon Compds. 1975,
6, 11-34.
(5) Nicholas, A. W.; Wani, M. C.; Manikumar, G.; Wall, M. E.; Kohn,
K. W.; Pommier, Y. J. Med. Chem. 1990, 33, 972.
(6) Du, W. Tetrahedron 2003, 59, 8649.
(7) Giovanella, B. C.; Stehlin, J. S.; Wall, M. E.; Wani, M. C.;
Nicholas, A. W.; Liu, L. F.; Silber, R.; Potmesil, M. Science 1989, 246,
1046.
(13) Gabarda, A. E.; Du, W.; Isarno, T.; Tangirala, R. S.; Curran,
D. P. Tetrahedron 2002, 58, 6329.
(8) Kingsbury, W. D.; Boehm, J. C.; Jakas, D. R.; Holden, K. G.;
Hecht, S. M.; Gallagher, G.; Caranfa, M. J.; McCabe, F. L.; Faucette,
L. F.; Johnson, R. K.; Hertzburg, R. P. J. Med. Chem. 1991, 34, 98.
(9) Sawada, S.; Okajima, S.; Aiyama, R.; Nokata, K.; Furuta, T.;
Yokokura, T.; Sugino, E.; Yamaguchi, K.; Miyasaka, T. Chem. Pharm.
Bull. 1991, 39, 1446.
(14) Boger, D. L.; Hong, J. J. Am. Chem. Soc. 1998, 120, 1218.
(15) Comins, D. L.; Saha, J. K. J. Org. Chem. 1996, 61, 9623.
(16) Turner, K. Org. Process Res. Dev. 2004, 8, 553.
(17) Blagg, B. S. J.; Boger, D. L. Tetrahedron 2002, 58, 6343 and
references therein.
10.1021/jo049890h CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/21/2004
7816
J. Org. Chem. 2004, 69, 7816-7821

Synthesis of the Antitumor Agent Camptothecin
FIGURE 1. Selected strategies for the synthesis of camptothecin.
activities against herpes viruses HSV-1 and HSV-2 and
human cytomegalovirus.18
Camptothecin and its analogues have provided a rich
playing field for development of convergent total synthe-
sis strategies. To date, the shortest asymmetric synthesis
of 1a by Comins involves the formation of the C-ring by
connecting the A/B- and D/E-fragments via an N-alky-
lation and a key intramolecular Heck ring closure reac-
tion (Figure 1, A).22 Curran devised an imaginative
strategy in which the appropriately functionalized A- and
D/E-fragments (Figure 1, B) participate in a free-radical
cascade leading to the formation of the B- and C-rings of
1a.12 A different concomitant formation of the B- and
C-rings was reported by Fortunak using an efficient
intramolecular Diels-Alder reaction (Figure 1, C) that
is now used on an industrial scale.23 Boger devised an
approach in which a D-ring forming intermolecular
Diels-Alder process precedes a C-ring cyclization (Figure
1, D).17 The key features of an inventive strategy24 by
Bosch consisted of an intramolecular radical cyclization
to form the C-ring followed by asymmetric construction
of the E-ring using enolate chemistry (Figure 1, E).
The antitumor activity of the camptothecins is now
accepted to be associated with the inhibition of DNA
relaxation by specific interference of the function of DNA
topoisomerase I.19,20 Interestingly, it has been shown that
the tetracyclic A/B/C/D ring core of 1a functions as the
key binding site to DNA.21
(18) (a) Pendrak, I.; Barney, S.; Wittrock, R.; Lambert, D. M.;
Kingsbury, W. D. J. Org. Chem. 1994, 59, 2623. (b) Pendrak, I.;
Wittrock, R.; Kingsbury, W. D. J. Org. Chem. 1995, 60, 2912.
(19) Berry, D. E.; MacKenzie, L.; Shultis, E. A.; Chan, J. A. J. Org.
Chem. 1992, 57, 420.
(20) Fang, S.-D.; Wang, L.-K.; Hecht, S. M. J. Org. Chem. 1993, 58,
5025.
(21) Perzyna, A.; Marty, C.; Facompre´, M.; Goossens, J.-F.; Pom-
mery, N.; Colson, P.; Houssier, C.; Houssin, R.; He´nichart, J.-P.; Bailly,
C. J. Med. Chem. 2002, 45, 5809.
(22) Comins, D. L.; Nolan, J. M. Org. Lett. 2001, 3, 4255 and
references therein.
(23) Fortunak, J. M. D.; Mastrocola, A. R.; Mellinger, M.; Sisti, N.
J.; Wood, J. L.; Zhuang, Z.-P. Tetrahedron Lett. 1996, 37, 5679.
(24) Bennasar, M.-L.; Zulaica, E.; Juan, C.; Alonso, Y.; Bosch, J. J.
Org. Chem. 2002, 67, 7465.
J. Org. Chem, Vol. 69, No. 23, 2004 7817

Nguyen et al.
SCHEME 1
SCHEME 2
Intermolecular25 (Figure 1, F) and intramolecular26 (Fig-
ure 1, G) Michael addition reactions by Ciufolini and
Chavan, respectively, were utilized for the D-ring con-
struction of 1a. Finally, in a route that has been widely
traveled from the beginning of camptothecin synthetic
work, a classical Friedlander reaction of 2-aminobenzal-
dehyde (A-ring) with the assembled C/D/E-ring frame-
work (Figure 1, H) was used by Henegar for B-ring
annelation of 1a.11
Herein, we report a new synthesis of the A/B/C/D-ring
core 527 of 1a using a combined directed ortho metalation
(DoM)-transition metal catalyzed cross-coupling tactic.28
Thus, the construction of 5 is based on the initial coupling
of 7, prepared by anionic Fries rearrangement,29 with the
organozinc species 8 to afford 6, which, by simple
functional group manipulation-cyclization leads to C-
ring formation (Scheme 1).
Results and Discussion
As an appropriate precursor of coupling partner 7,
2-quinolone (9) (Scheme 2), prepared in sizable quantities
following Henze’s procedure,30 was converted into the
O-carbamate 10 by treatment with sodium hydride and
diethyl carbamoyl chloride in refluxing THF31 followed
by purification by flash chromatography on SiO2. In an
alternative purification of carbamate 10 via short path
distillation, a clean thermal 1,3-carbamoyl rearrange-
ment was observed to form urea 11.32 As reported by
Queguiner,31 treatment of carbamate 10 with LDA
resulted in, even at -75 °C, C-3 metalation-anionic Fries
rearrangement to give the 3-amidoquinolone 12. How-
ever, in contrast to the observations of Queguiner, apart
from 12 (61%), the self-condensation product 13 was also
isolated in 13% yield. When the reaction was carried out
at -42 °C, compound 13 was not formed and the yield of
the desired rearrangement product 12 increased to 71%.
The increased selectivity favoring the intramolecular
rearrangement at higher temperature may be rational-
ized by the difference in temperature dependence of a
(25) Ciufolini, M. A.; Roschangar, F. Angew. Chem., Int. Ed. Engl.
1990, 35, 1692. Ciufolini, M. A.; Roschangar, F. Tetrahedron 1997, 32,
11049. Ciufolini, M. A.; Roschangar, F. Targets Heterocycl. Syst. 2000,
4, 25.
(26) Chavan, S. P.; Venkatraman, M. S. Tetrahedron Lett. 1998, 39,
6745.
(30) Henze, M. Chem. Ber. 1936, 69, 1566.
(31) Jacquelin, J. M.; Robin, Y.; Godard, A.; Queguiner, G. Can. J.
Chem. 1988, 66, 1135.
(32) (a) For an analoguous thermal carbonate-carbamate rear-
rangement, see: Nagata, T.; Koide, Y.; Nara, K.; Itoh, E.; Arisawa, M.
Chem. Pharm. Bull. 1996, 44, 451. (b) For the equilibrium of N-acetyl-
2-pyridone and 2-acetoxypyridine, see: McKillop, A.; Zelesko, M. J.;
Taylor, E. C. Tetrahedron Lett. 1968, 48, 4945. Fleming, I.; Philippides,
D. J. Chem. Soc. C 1970, 2426. (c) Miah. M. A. J. Ph.D. Thesis,
University of Waterloo, 1985.
(27) Compound 5 has been previously prepared, see: (a) Kametani,
T.; Nemoto, H.; Takeda, H.; Takano, S. Tetrahedron 1970, 26, 5753.
(b) See ref 12a. (c) Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan,
M. O.; Leach, D. C. J. Chem. Soc., Perkin Trans. 1 2002, 58.
(28) For a recent review, see: (a) Anctil, E.; Snieckus, V. J.
Organomet. Chem. 2002, 653, 150. (b) Anctil, E.; Snieckus, V. In Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; Diederich, F., de Meijere,
A., Eds., 2004, in press.
(29) Sibi, M.; Snieckus, V. J. Org. Chem. 1983, 48, 1935.
7818 J. Org. Chem., Vol. 69, No. 23, 2004

Synthesis of the Antitumor Agent Camptothecin
SCHEME 3
uni- vs. bimolecular reaction. To complete the synthesis
of the A/B-fragment, the quinolone 12 was transformed
into the triflate 7 with use of standard conditions.
As a model reaction, the cross-coupling reaction be-
tween triflate 7 and 2-bromopyridine,33 representing the
D-ring fragment, was undertaken (Scheme 3) with use
of the Negishi protocol34 with Pd(PPh3)4 as catalyst and
provided the biaryl 14 in satisfactory yield (57%). With
this procedure, 2-bromo-6-methoxypyridine, prepared
from 2,6-dibromopyridine (86% yield),35 was sequentially
treated with 2 equiv of t-BuLi at -78 °C and anhydrous
ZnBr2. The resulting organozinc species 8 was subjected
to the Pd0-catalyzed cross-coupling procedure with triflate
7 to afford the biaryl 6 in 59% yield.
To avoid complications of reduction of π-deficient
heterocyclic rings, the biaryl 6 was subjected to the mild
reduction protocol of Raucher.36 Thus, 6 was converted
with use of Lawesson’s reagent into the corresponding
thioamide 15, which, upon sequential ethylation with
ethyl-Meerwein salt and reduction with NaBH4, was
transformed into the tertiary amine 16 in 83% yield. The
final cyclization of 16 to the tetracycle 527 was achieved
in 62% yield via a modified von Braun reaction with ethyl
chloroformate and potassium carbonate.37 Compound 5
was found to be identical by comparison of physical and
spectroscopic properties with those reported (see the
Experimental Section).
chemistry, and the potential further modification of ring
D in 5, taken in sum, offer consideration of additional
avenues for synthetic excursions in the camptothecin
field.
Experimental Section
N,N-Diethyl O-(Quinolyl-2) Carbamate (10). To a sus-
pension of NaH (959 mg, 60% in mineral oil, 24.0 mmol) in
anhydrous THF (45 mL) was added 930 (2.88 g, 19.8 mmol)
portionwise at room temperature under N2 atmosphere. The
greenish suspension was stirred at room temperature for 30
min and then ClCONEt2 (3.75 g, 27.6 mmol) was added via
syringe. The reaction mixture was refluxed for 2 h. Since TLC
showed only about 50% conversion, more ClCONEt2 (3.75 g,
27.6 mmol) was added and the mixture was stirred for an
additional hour. The reaction mixture was cooled in ice and
carefully treated with saturated aq NH4Cl (20 mL). The
aqueous layer was separated and extracted with Et2O (2 × 20
mL). The combined organic phase was washed with H2O (50
mL) and brine (50 mL) and dried (Na2SO4). Removal of the
solvent gave the crude product as a brown oil, which was
purified by flash chromatography on SiO2 (Et2O/hexane (1:1))
to yield 10 as a yellowish oil (4.26 g, 88%): IR (film) 3062,
2977, 2935, 1721, 1598, 1505, 1417, 1216, 1150, 1045, 978, 779,
1
752 cm-1; H NMR (250 MHz, CDCl3) δ 1.23 (t, J ) 7.1 Hz,
3H), 1.30 (t, J ) 7.1 Hz, 3H), 3.43 (q, J ) 7.1 Hz, 2H), 3.53 (q,
J ) 7.1 Hz, 2H), 7.24 (d, J ) 8.7 Hz, 1H), 7.51 (td, J ) 7.5, 1.1
Hz, 1H), 7.69 (td, J ) 7.7, 1.5 Hz, 1H), 7.81 (d, J ) 8.1 Hz,
1H), 8.01 (d, J ) 8.4 Hz, 1H), 8.19 (d, J ) 8.7 Hz, 1H); MS
(EI, 70 eV) m/z 244 (18, M+), 227 (17), 145 (27), 128 (30), 116
(36), 100 (100), 72 (80).
Thus, the tetracyclic A/B/C/D-ring system 5 of camp-
tothecin (1a) has been synthesized from quinolone 9 in
7 steps and 11% overall yield, which represents a
valuable alternative to previously achieved syntheses (7
steps, 6%;27a 2 steps, 27%;27b and 5 steps, 17%27c). The
simplicity of the steps, the ready availability of starting
materials of both A/B- and D-ring fragments by DoM
N-(N,N-Diethylaminocarbonyl)-2-quinolone (11). Short
path distillation (173-175 °C/0.5 Torr) of 4.26 g of 10 yielded
a mixture of 10 and a new product. Flash chromatography on
SiO2 (Et2O) gave recovered 10 (2.39 g) and a colorless crystal-
line material (1.81 g), which upon recrystallization from CHCl3/
Et2O (1:3) yielded pure 11 (1.07 g, 25%): mp 108.5-110 °C;
IR (KBr) 2988, 2943, 2880, 1695, 1659, 1591, 1430, 829 cm-1
;
1H NMR (200 MHz, CDCl3) δ 1.06 (t, J ) 7.2 Hz, 3H), 1.41 (t,
J ) 7.2 Hz, 3H), 3.04-3.31 (m, 2H), 3.52-3.86 (m, 2H), 6.64
(d, J ) 9.6 Hz, 1H), 7.13 (d, J ) 8.5 Hz, 1H), 7.25 (td, J ) 7.6,
1.0 Hz, 1H), 7.47-7.60 (m, 2H), 7.74 (d, J ) 9.6 Hz, 1H); 13C
NMR (50.3 MHz, CDCl3) δ 12.6, 13.7, 41.8, 43.4, 114.4, 119.9,
121.6, 123.1, 128.6, 131.0, 137.3, 140.7, 152.0, 160.2; MS (EI,
(33) Bunlaksananusorn, T.; Polborn, K.; Knochel, P. Angew. Chem.,
Int. Ed. 2003, 42, 3941.
(34) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42,
182.
(35) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1990, 55, 69.
(36) Raucher, S.; Klein, P. Tetrahedron Lett. 1980, 21, 4061.
(37) Mornet, R.; Gouin, L. Synthesis 1977, 786.
J. Org. Chem, Vol. 69, No. 23, 2004 7819

Nguyen et al.
70 eV) m/z 244 (18, M+), 227 (9), 145 (12), 100 (100), 72 (67).
Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47.
Found: C, 68.75; H, 6.70; N, 11.48.
washed with H2O and dried (Na2SO4). Evaporation to dryness
in vacuo gave the crude product as a brownish oil (208 mg),
which was purified by flash chromatography on SiO2 (CHCl3)
to yield 14 as a yellowish oil (85 mg, 57%): IR (CDCl3) 3064,
N,N-Diethyl
1,2-Dihydro-2-oxo-3-quinolinecarbox-
2981, 2837, 2875, 1723, 1618, 1559, 1480, 1279, 1097 cm-1
;
amide (12). To a stirred LDA solution (diisopropylamine (592
mg, 5.9 mmol) and n-BuLi (3.9 mL (1.6 M in hexane), 6.2
mmol)) in THF (30 mL), a solution of 10 (1.10 g, 4.5 mmol) in
THF (8 mL) (precooled to -78 °C) was added via cannula at
-78 °C under N2 atmosphere. After the solution was stirred
for 1 h, anhydrous MeOH (562 mg, 17.5 mmol) was added and
the reaction mixture was stirred for an additional hour at -78
°C. After quenching with saturated aq NH4Cl (15 mL), the
aqueous phase was extracted with CHCl3 (3 × 30 mL). The
combined organic phase was washed with H2O and dried (Na2-
SO4). Removal of the solvent gave the crude product as yellow
crystals (1.11 g). Flash chromatography on SiO2 (EtOAc/MeOH
(95:5)) yielded 12 as pale yellow crystals (666 mg, 61%): mp
166-167 °C (toluene) (lit.31 mp 167 °C); IR (KBr) 3063, 2968,
1H NMR (200 MHz, CDCl3) δ 1.00 (t, J ) 7.1 Hz, 3H), 1.30 (t,
J ) 7.1 Hz, 3H), 3.21 (s br, 2H), 3.93 (s br, 2H), 7.28-7.34 (m,
1H), 7.58 (t, J ) 7.2 Hz, 1H), 7.72-7.87 (m, 3H), 8.14 (s, 1H),
8.19 (d, J ) 8.5 Hz, 1H), 8.42 (d, J ) 7.9 Hz, 1H), 8.59 (s br,
1H); 13C NMR (50 MHz, CDCl3) δ 11.7, 13.3, 38.7, 42.7, 123.1,
123.8, 127.0, 127.4, 127.5, 129.6, 130.1, 130.7, 134.8, 136.6,
147.3, 148.2, 153.4, 156.2, 170.3; MS (EI, 70 eV) m/z (305 (<1,
M+), 233 (100), 205 (19); HRMS calcd for C19H19N3O 305.1528,
found 305.1500.
2-Bromo-6-methoxypyridine. A solution of NaOMe in
MeOH (Na (1.33 g, 58 mmol) in anhydrous MeOH (14 mL))
was added to a suspension of 2,6-dibromopyridine (8.0 g, 34
mmol) in anhydrous MeOH (22 mL) and the resulting mixture
was refluxed for 25 h. The reaction mixture was allowed to
cool to room temperature, cold 5% aq NaHCO3 (25 mL) was
added, and the mixture was extracted with Et2O (1 × 30 mL,
2 × 20 mL). The combined organic phase was concentrated,
the resulting residue was taken up in Et2O (30 mL), and the
Et2O solution was washed with brine (20 mL) and dried (K2-
CO3). Removal of the solvent gave a yellowish liquid (5.72 g).
Kugelrohr distillation yielded 2-bromo-6-methoxypyridine as
a colorless liquid (5.48 g, 86%): bp 87-91 °C/15 Torr (lit.35 bp
85-95°/15 Torr); IR (film) 2985, 2952, 2850, 1594, 1581, 1556,
1467, 1408, 1296, 1020, 854 cm-1; 1H NMR (200 MHz, CDCl3)
δ 3.93 (s, 3H), 6.68 (d, J ) 7.7 Hz, 1H), 7.05 (d, J ) 7.4 Hz,
1H), 7.40 (t, J ) 7.8 Hz, 1H).
1
2897, 1662, 1617, 1569, 1433, 1221, 946, 749 cm-1; H NMR
(200 MHz, CDCl3) δ 1.17 (t, J ) 6.6 Hz, 3H), 1.32 (t, J ) 6.6
Hz, 3H), 3.34 (q, J ) 6.8 Hz, 2H), 3.63 (q, J ) 6.7 Hz, 2H),
7.24 (td, J ) 7.5, 1.3 Hz, 1H), 7.41 (d, J ) 7.9 Hz, 1H), 7.49-
7.60 (m, 2H), 7.87 (s, 1H), 12.36 (s br, 1H, exchangeable with
D2O).
A second fraction was obtained and recrystallized from
EtOAc/MeOH (2:1) to yield 13 as colorless crystals (122 mg,
13%): mp >180 °C dec; IR (KBr) 3063, 2974, 2938, 2892, 2853,
1718, 1658, 1619, 1591, 1564, 1399, 1275, 1196, 1080, 754
1
cm-1; H NMR (200 MHz, CDCl3/DMSO-d6 (2:1)) δ 0.87 (t, J
) 7.0 Hz, 3H), 0.94 (t, J ) 7.0 Hz, 3H), 2.98-3.06 (m, 4H),
7.22 (t, J ) 7.7 Hz, 1H), 7.39 (d, J ) 8.2 Hz, 1H), 7.54-7.67
(m, 2H), 7.77-7.87 (m, 2H), 7.96 (d, J ) 8.2 Hz, 1H), 8.12 (d,
J ) 7.9 Hz, 1H), 8.35 (s, 1H), 8.70 (s, 1H), 12.10 (s, 1H); 13C
NMR (50 MHz, CDCl3/DMSO-d6 (2:1)) δ 11.1, 11.8, 39.3, 39.7,
113.7, 116.7, 120.7, 124.8, 125.1, 125.9, 126.7, 127.2, 127.8,
129.0, 130.0, 130.9, 138.7, 138.8, 141.2, 145.0, 150.7, 151.8,
158.5, 188.7.
N,N-Diethyl 2-(2-Methoxypyridin-6-yl)-3-quinolinecar-
boxamide (6). To a solution of 2-bromo-6-methoxypyridine
(301 mg, 1.6 mmol) in THF (6 mL) at -78 °C was added
dropwise t-BuLi (1.7 M in pentane, 1.9 mL, 3.2 mmol) under
N2 atmosphere. The resulting pale yellow solution was stirred
for 15 min at -78 °C. A solution of anhydrous ZnBr2 (409 mg,
1.8 mmol) in THF (4 mL) was added via cannula and the
mixture was stirred for 70 min at -78 °C. The reaction mixture
was allowed to warm to room temperature and was added via
cannula to a solution of 7 (399 mg, 1.1 mmol) and Pd(PPh3)4
(62 mg, 54 µmol) in THF (4 mL), which had been stirred for
20 min at room temperature. The resulting solution was
refluxed for 45 h and the solvent was removed in vacuo. The
residue was dissolved in CHCl3/MeOH (9:1) (15 mL) and
washed with Na2EDTA‚2H2O (1.35 g in 15 mL of H2O). The
aqueous phase was extracted with CHCl3/MeOH (9:1) (5 × 12
mL) and the combined organic phase was dried (Na2SO4).
Removal of the solvent gave a yellow gum (569 mg) that was
purified by flash chromatography on SiO2 (EtOAc/hexane (2:
1)) to give 6 as a pale yellow oil (211 mg, 59%): IR (film) 3060,
2979, 2934, 2874, 1634, 1574, 1556, 1267, 1047, 921, 888, 792
N,N-Diethyl 2-Trifluoromethanesulfonyloxy-3-quino-
linecarboxamide (7). To a solution of 12 (441 mg, 2.0 mmol)
in CH2Cl2 (18 mL) at 0 °C was added NEt3 (365 mg, 3.6 mmol)
and Tf2O (560 mg, 2.0 mmol) dropwise under N2 atmosphere.
The solution was stirred at 0 °C for 1 h and quenched with
saturated aq NaHCO3 (20 mL). The aqueous phase was
extracted with CH2Cl2 (2 × 10 mL) and the combined organic
phase was washed H2O and dried (Na2SO4). Removal of the
solvent gave the crude product as yellow crystals (887 mg).
Flash chromatography on SiO2 (Et2O) afforded 7 as pale yellow
crystals (478 mg, 70%): mp 89.5-91 °C (CHCl3/hexane (4:1));
IR (film) 3059, 2981, 2939, 1635, 1573, 1424, 1217, 1140, 1052,
918, 884, 847, 801, 759 cm-1 1H NMR (200 MHz, CDCl3) δ
;
1.12 (t, J ) 7.1 Hz, 3H), 1.31 (t, J ) 7.1 Hz, 3H), 3.25 (q, J )
7.1 Hz, 2H), 3.61 (s br, 2H), 7.67 (td, J ) 7.5, 1.2 Hz, 1H),
7.84 (td, J ) 8.4, 1.5 Hz, 1H), 7.90 (d, J ) 8.4 Hz, 1H), 8.06 (d,
J ) 8.5 Hz, 1H), 8.28 (s, 1H); 13C NMR (62.9 MHz, CDCl3) δ
12.4, 13.9, 39.5, 43.1, 118.5 (q, 321), 122.6, 127.1, 127.8, 128.3,
128.6, 131.7, 139.0, 145.4, 149.6, 163.8; MS (EI, 70 eV) m/z
376 (36, M+), 304 (100), 227 (49), 172 (82), 143 (66); HRMS
calcd for C15H15F3N2O4S 376.0705, found 376.0693.
1
cm-1; H NMR (200 MHz, CDCl3) δ 0.84 (t, J ) 7.1 Hz, 3H),
1.22 (t, J ) 7.1 Hz, 3H), 2.90-2.99 (m, 1H), 3.16-3.36 (m, 2H),
3.79-3.87 (m, 1H), 3.97 (s, 3H), 6.79 (d, J ) 8.2 Hz, 1H), 7.56
(t, J ) 7.9 Hz, 1H), 7.69-7.77 (m, 2H), 7.84 (d, J ) 8.1 Hz,
1H), 7.97 (d, J ) 7.4 Hz, 1H), 8.17 (s, 1H), 8.18 (d, J ) 5.8 Hz,
1H); 13C NMR (50 MHz, CDCl3) δ 12.8, 13.4, 38.9, 43.2, 53.7,
111.3, 116.3, 126.9, 127.4, 127.5, 129.5, 130.1, 130.3, 135.9,
139.2, 147.3, 153.4, 154.0, 163.4, 169.8; MS (EI, 70 eV) m/z
335 (7, M+), 263 (100), 235 (23); HRMS calcd for C20H21N3O2
335.1634, found 335.1602.
N,N-Diethyl 2-(2-Pyridyl)-3-quinolinecarboxamide (14).
A solution of 2-bromopyridine (117 mg, 741 µmol) in THF
(3 mL) was treated at -78 °C with t-BuLi (1.7 M in pentane,
867 µL, 1.5 mmol) under N2 atmosphere. After the dark red
solution was stirred for 15 min at -78 °C, a solution of
anhydrous ZnBr2 (183 mg, 813 µmol) in THF (2 mL) was added
via cannula. The resulting orange solution was stirred at -78
°C for 1 h and then allowed to warm to room temperature. A
solution of 7 (185 mg, 492 µmol) and Pd(PPh3)4 (28 mg, 24
µmol) in THF (3 mL), which had been stirred for 15 min at
room temperature, was added via cannula. The reaction
mixture was refluxed (60 h) and quenched with saturated aq
NH4Cl (2 mL). The aqueous phase was extracted with CH2Cl2
(1 × 20 mL, 2 × 10 mL) and the combined organic phase was
N,N-Diethyl 2-(2-Methoxypyridin-6-yl)-3-quinoline-
thiocarboxamide (15). A solution of 6 (120 mg, 358 µmol)
and Lawesson’s reagent (241 mg, 596 µmol) in anhydrous
benzene (3 mL) was refluxed for 8 h under N2 atmosphere.
The reaction mixture was passed through a cotton plug and
the filtrate was concentrated. The resulting orange oil was
purified by flash chromatography on SiO2 (CH2Cl2/Et2O (9:1))
to yield 15 as a yellow viscous liquid (105 mg, 83%): IR (film)
3064, 2982, 2941, 2876, 2221, 1592, 1575, 1498, 1266, 816
1
cm-1; H NMR (250 MHz, CDCl3) δ 1.03 (t, J ) 7.2 Hz, 3H),
7820 J. Org. Chem., Vol. 69, No. 23, 2004

Synthesis of the Antitumor Agent Camptothecin
1.27 (t, J ) 7.1 Hz, 3H), 3.25 (dq, J ) 14.3, 7.1 Hz, 1H), 3.66
(dq, J ) 14.3, 7.2 Hz, 1H), 3.95 (s, 3H), 4.03-4.19 (m, 2H),
6.78 (dd, J ) 8.0, 0.6 Hz, 1H), 7.56 (td, J ) 8.0, 1.0 Hz, 1H),
7.68-7.76 (m, 2H), 7.82 (dd, J ) 8.1, 0.7 Hz, 2H), 8.09 (s, 1H),
8.17 (d, J ) 8.5 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 11.1,
13.3, 45.9, 48.7, 53.9, 110.9, 117.3, 126.8, 127.4, 127.5, 129.2,
130.1, 134.3, 135.8, 139.1, 146.7, 152.2, 154.2, 163.2, 197.6;
MS (EI, 70 eV) m/z 351 (25, M+), 280 (47), 265 (100), 243 (12).
3-N,N-Diethylaminomethyl-2-(2-methoxypyridin-6-yl)-
quinoline (16). To a solution of 15 (105 mg, 299 µmol) in
anhydrous CH2Cl2 (1.5 mL) at 0 °C was added Et3O+BF4- (0.5
M in CH2Cl2, 0.62 mL, 310 µmol) under N2 atmosphere. The
resulting mixture was stirred for 5 min at 0 °C and then for
90 min at room temperature. The solvent was removed in
vacuo and the solid residue was dissolved in anhydrous MeOH
(2.5 mL). NaBH4 (29 mg, 767 µmol) was added at 0 °C and
the mixture was stirred for 5 min at 0 °C and then for 3 h at
room temperature. HCl (5%, 2 mL) was added and the mixture
was stirred for 5 min. After addition of aq NaOH solution to
pH >10, the reaction mixture was extracted with Et2O (1 ×
20 mL, 2 × 15 mL). The combined organic phase was washed
with H2O (20 mL) and dried (Na2SO4). Removal of the solvent
gave a yellow oil (101 mg) that was purified by flash chroma-
tography on SiO2 (EtOAc) to yield 16 as a yellow gum (80 mg,
83%): IR (CDCl3) 3064, 2971, 2935, 2874, 2809, 1722, 1576,
261 µmol) in anhydrous THF (1 mL) was added a solution of
16 (67 mg, 208 µmol) in anhydrous THF (1 mL) via cannula
under N2 atmosphere. The mixture was stirred at room
temperature for 2.5 h. TLC showed a new spot with intense
blue fluorescence under UV light. The reaction mixture was
heated at reflux for 3 h. To the resulting orange suspension
was added ClCOOEt (10 µL, 105 µmol) and the mixture was
heated at reflux for 1 h. After the solution was cooled to room
temperature, H2O (10 mL) was added and the whole was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
phase was washed with brine (10 mL) and dried (Na2SO4).
Removal of the solvent gave a yellow solid (48 mg) that was
purified by flash chromatography on SiO2 (EtOAc/NEt3 (99:
1)) to yield 5 as pale yellow crystals (30 mg, 62%) (lit.27a mp
265 °C; lit.27c mp 253-254 °C): IR (CDCl3) 3056, 1663, 1594,
1159 cm-1; 1H NMR (250 MHz, CDCl3) δ 5.25 (s, 2H), 6.73 (dd,
J ) 9.0, 0.7 Hz, 1H), 7.30 (dd, J ) 6.1, 0.8 Hz, 1H), 7.60-7.70
(m, 2H), 7.80 (ddd, J ) 8.4, 7.0, 1.4 Hz, 1H), 7.89 (d, J ) 8.1
Hz, 1H), 8.20 (d, J ) 8.5 Hz, 1H), 8.34 (s, 1H). The spectro-
scopic properties are identical with those reported for 5
prepared previously.27
Acknowledgment. This paper is dedicated with
respect and in friendship to Professor Yuichi Kanaoka,
a heterocyclic chemist par excellence. This work was
supported by an NSERC Strategic Grant in collabora-
tion with SmithKline Beecham. We thank Dr. J. For-
tunak (now at Abbott Laboratories) for passionate
interest and many stimulating discussions.
1
1464, 1411, 1261 cm-1; H NMR (250 MHz, CDCl3) δ 0.98 (t,
J ) 7.1 Hz, 6H), 2.54 (q, J ) 7.1 Hz, 4H), 3.96 (s, 3H), 4.09 (s,
2H), 6.80 (dd, J ) 8.4, 0.6 Hz, 1H), 7.49-7.55 (m, 2H), 7.64-
7.77 (m, 2H), 7.86 (d, J ) 8.1 Hz, 1H), 8.14 (d, J ) 8.5 Hz,
1H), 8.53 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 11.8, 47.2, 53.4,
54.9, 110.2, 117.3, 126.6, 127.4, 127.9, 129.0, 129.2, 132.3,
136.7, 139.3, 156.8, 157.2, 162.7; MS (EI, 70 eV) m/z 321 (35,
M+), 292 (100), 249 (86), 235 (50), 205 (40), 185 (53); HRMS
calcd for C20H23N3O 321.1841, found 321.1820.
Supporting Information Available: Spectroscopic infor-
mation and reagent purification and availability. This material
is available free of charge via the Internet at http://pubs.acs.org.
11H-Indolizino[1,2-b]quinolin-9-one (5). To a suspension
of anhydrous K2CO3 (23 mg, 166 µmol) and ClCOOEt (25 µL,
JO049890H
J. Org. Chem, Vol. 69, No. 23, 2004 7821