Efficient synthesis of the pyrido[2,3,4-kl]acridin-4-one system common to several cytotoxic marine alkaloids

Article abstract of DOI:10.1016/S0040-4039(03)01474-6

An efficient, four-step synthesis of the pyrido[2,3,4-kl]acridin-4-one system is described, using a Suzuki coupling of a 4-iodoquinoline and a oxidative demethylation of a dimethoxyquinoline containing an anilino unit with cobalt trifluoride as the key st

Full text of DOI:10.1016/S0040-4039(03)01474-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6003–6005
Efficient synthesis of the pyrido[2,3,4-kl]acridin-4-one system
common to several cytotoxic marine alkaloids
Eva Pascual-Alfonso, Carmen Avendan˜o and J. Carlos Mene´ndez*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 6 June 2003; revised 13 June 2003; accepted 14 June 2003
Abstract—An efficient, four-step synthesis of the pyrido[2,3,4-kl]acridin-4-one system is described, using a Suzuki coupling of a
4-iodoquinoline and a oxidative demethylation of a dimethoxyquinoline containing an anilino unit with cobalt trifluoride as the
key steps.
© 2003 Elsevier Ltd. All rights reserved.
Marine organisms are an increasingly important source
of bioactive natural products. Starting in 1983, a wide
range of polycyclic aromatic alkaloids have been iso-
lated from marine sources.1 Most of them can be
grouped into three categories, namely derivatives of the
pyrido[2,3,4-kl]acridine system with an additional ring
fused at the 5–6 bond, at the 4–5 bond or at both. As
a consequence, most of these compounds can be con-
sidered as derivatives of the structures 1 or 2. For
instance, amphimedine2 and meridine,3 among others,4
contain a common pyrido[2,3,4-kl]acridin-4-one sub-
structure 1, while ascididemin5 and eilatine,6 among
others,7 have a pyrido[2,3,4-kl]acridin-6-one moiety 2
or related substructures.
ridine in
a
four-step route involving two
palladium-catalyzed cross coupling reactions, but,
unfortunately, the final oxidation–cyclization step of
the synthesis proceeded in only 11% yield.11
Most of these ‘sea alkaloids’ show interesting biological
properties, including very potent antitumour activities,8
but their study is hampered by the difficulties found in
isolating sufficient material from their natural sources.
This fact, together with the need to obtain analogs in
order to establish structure–activity relationships, has
prompted extensive synthetic work in the field.9
Regarding the parent structures, compound 2 has been
recently prepared in eight steps from commercially
available starting materials, as an intermediate in the
synthesis of a regioisomer of ascididemin.10 On the
other hand, only one synthesis of the unsubstituted
parent system 1 has been published, to our knowledge.
It was based on the intramolecular condensation of a
suitable 4-acetyl-5-formyl-benzonaphthyrydine deriva-
tive, which was constructed from 2-chloro-3-iodopy-
* Corresponding author. Tel.: 34-91-3941840; fax: 91-3941822; e-mail:
josecm@farm.ucm.es
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01474-6

6004
E. Pascual-Alfonso et al. / Tetrahedron Letters 44 (2003) 6003–6005
One possible route to compound 1 could be based on
the creation of the 11aꢀ11b bond using a palladium-cat-
alyzed cross coupling reaction. Previous attempts at the
preparation of derivatives of 1 using a Stille coupling of
the 6-vinyl derivative of triflate 3 as the key step had to
be abandoned due to poor yields in the cross-coupling
step,9b and for this reason we decided to examine the
use of the less studied Suzuki reaction of 4-halogeno-
quinolines as an alternative.
and, after some experimentation with other reagents,
we found that cobalt trifluoride in dioxane15 was suit-
able for our purposes, since, gratifyingly, it led to the
transformation of compound 7 into the non-isolated
intermediate aminoquinone 8 which cyclized16 to the
target compound 117 in 95% combined yield.
In conclusion, we have achieved a simple and efficient
synthesis of pyrido[2,3,4-kl]acridin-4-one, the parent
system of a family of marine alkaloids with potent
cytotoxic activity, which proceeds in 52% overall yield
from a known 4-quinolyl triflate. This synthesis high-
lights the use of a Suzuki coupling of a 4-iodoquinoline
for the construction of the 11aꢀ11b bond of the pyri-
doacridine system and demonstrates the usefulness of
cobalt trifluoride in the oxidative demethylation of
substrates containing anilino subunits, a transformation
that has previously proved troublesome using alterna-
tive, better known methods.
As shown in Scheme 1, iodide 4 was prepared by
treatment of triflate 3, available in three steps and 67%
overall yield from commercially available starting mate-
rials,12 with potassium iodide under solvent-free condi-
tions, since all attempts to prepare 4 in solution from 3
or from the corresponding bromide were unsuccessful.
Compound 4 gave smoothly the desired Suzuki cou-
pling with boronic acid 513 in the presence of (Ph3P)4Pd
and potassium carbonate, and afforded compound 6 in
81% yield.14 Attempted oxidative demethylation of 6
with cerium ammonium nitrate in aqueous acetonitrile
gave an intractable mixture, a result that was attributed
to competing oxidation of the aniline ring. Instead of
replacing the pivaloyl group by the more electron-with-
drawing trifluoroacetyl unit, as proposed by other
authors in a related situation,12 we decided at this point
to attempt the search for a milder oxidant. Hydrolysis
of the pivaloyl group afforded amine 7 in 80% yield
Acknowledgements
We thank CICYT for financial support of this research
through grant PTR95-0623.OP.
References
´
1. For reviews, see: (a) Alvarez, M.; Joule, J. A. Heterocy-
cles 1992, 34, 2385–2405; (b) Molinski, T. F. Chem. Rev.
1993, 93, 1825–1838; (c) Ding, Q.; Chichak, K.; Lown, J.
W. Curr. Med. Chem. 1999, 6, 1–27; (d) Delfourne, E.;
Bastide, J. Med. Res. Rev. 2003, 23, 234–252.
2. Schmitz, F. J.; Agarwal, S. K.; Gunasekera, S. P.;
Schmidt, P. G.; Shoolery, J. N. J. Am. Chem. Soc. 1983,
105, 4835–4836.
3. Schmitz, F. J.; de Guzma´n, F. S.; Hossain, M. B.; van der
Helm, D. J. Org. Chem. 1991, 56, 804–808.
4. See, for instance: (a) Cystoditins: Kobayashi, J.; Cheng,
J.; Wa¨lchli, M. R.; Nakamura, H.; Hirata, Y.; Sasaki, T.;
Ohizumi, Y. J. Am. Chem. Soc. 1988, 53, 1800–1804; (b)
Lisoclines: Searle, P. A.; Molinski, T. F. J. Org. Chem.
1994, 59, 6600–6605; (c) Petrosamine: Molinski, T. F.;
Fahy, E.; Faulkner, D. I.; Van Duyne, G. D.; Clardy, J.
J. Org. Chem. 1988, 53, 1340–1341; (d) Eudistones: He,
H.; Faulkner, D. J. J. Org. Chem. 1991, 56, 5369–5371;
(e) Sebastianines: Torres, Y. R.; Bugni, T. S.; Berlinck, R.
G. S.; Ireland, C. M.; Magalhaes, A.; Ferraira, A. G.;
Mareira da Rocha, R. J. Org. Chem. 2002, 67, 5429–
5432.
5. Kobayashi, J.; Cheng, J.; Nakamura, H.; Ohizumi, Y.;
Hirata, Y.; Sasaki, T.; Ohta, T.; Nozoe, S. Tetrahedron
Lett. 1988, 29, 1177–1180.
6. Rudi, A.; Kashman, Y. J. Org. Chem. 1989, 54, 5331–
5337.
7. See, for instance: (a) Shermilamines: Carroll, A. R.;
Cooray, N. M.; Poiner, A.; Scheuer, P. J. J. Org. Chem.
1989, 54, 4231–4232; (b) Kuanoniamines: Scheuer, P. J.;
Carroll, A. R. J. Org. Chem. 1990, 55, 4426–4431; (c)
Dercitin: Gunawardana, G. P.; Koehn, F. E.; Lee, A. Y.;
Clardy, J.; He, H.-Y.; Faulkner, D. J. J. Org. Chem.
1992, 57, 1523–1526 and references cited therein.
Scheme 1. Reagents and conditions: (i) KI, 80°C, 2.5 days; (ii)
K2CO3, EtOH–H2O, (Ph3P)4Pd deoxygenated toluene, reflux,
24 h; (iii) 3 M HCl in 1:1 water–dioxane, reflux, 18 h; (iv)
CoF3, water, dioxane, rt, 1 h.

E. Pascual-Alfonso et al. / Tetrahedron Letters 44 (2003) 6003–6005
6005
8. See Ref. 1f and (a) Schmitz, F. J.; de Guzma´n, F. S.;
Choi, Y.-H.; Hossain, M. B.; Rizui, S. K.; van der Helm,
D. Pure Appl. Chem. 1990, 62, 1393–1396; (b) McDonald,
L. A.; Elerdge, G. S.; Barrows, L. R.; Ireland, C. M. J.
Med. Chem. 1994, 37, 3819–3827; (c) Lindsay, B. S.;
Barrows, L. R.; Copp, B. R. Bioorg. Med. Chem. Lett.
1995, 5, 739–742; (d) Lindsay, B. S.; Christiansen, H. C.;
Copp, B. R. Tetrahedron 2000, 56, 497–505; (e) De la
Fuente, J. A.; Mart´ın, M. J.; Blanco, M. M.; Pascual-
Alfonso, E.; Avendan˜o, C.; Mene´ndez, J. C. Bioorg. Med.
Chem. 2001, 9, 1807–1814 [the synthetic regioisomer of
meridine studied in this reference has been subsequently
isolated from a natural source. See: Akoi, S.; Wei, H.;
Matsui, K.; Rachmat, R.; Kobayashi, M. Bioorg. Med.
Chem. 2003, 11, 1969–1973]; (f) Delfourne, E.; Darro, F.;
Portefaix, P.; Galaup, C.; Bayssade, S.; Bouteille, A.; Le
Corre, L.; Bastide, J.; Collignon, F.; Lesur, B.; Frydman,
A.; Kiss, R. J. Med. Chem. 2002, 45, 3765–3771; (g)
Brahic, C.; Darro, F.; Belloir, M.; Bastide, J.; Kiss, R.;
Delfourne, E. Bioorg. Med. Chem. 2002, 10, 1845–1853.
0.017 mmol) was added, and the reacting mixture was
refluxed for 24 h. After cooling, the suspension was
filtered and the solid was washed with toluene (3×5 mL).
The combined toluene layers were evaporated and the
residue was chromatographed on silica gel, eluting with
2:1 petroleum ether–ethyl acetate, to give 150 mg (81%)
of compound 6. IR (NaCl): 3443 (NH), 1684 (CꢁO); 1262
1
(CꢀO) cm−1. H NMR (CDCl3, 250 MHz) l 8.95 (d, 1H,
J=4.3 Hz, H-2); 8.10 (d, 1H, J=8.1 Hz, H-3%); 7.35 (td,
1H, J=8.1 and 2.9 Hz, H-4%); 7.23 (d, 1H, J=4.3 Hz,
H-3); 7.17–7.10 (m, 2H, H-5%,6%); 6.99 (d, 1H, J=8.6 Hz,
H-7); 6.85 (br. s, 1H, NH); 6.74 (d, 1H, J=8.6 Hz, H-6);
4.04 (s, 3H, C8-OCH3); 3.39 (s, 3H, C5-OCH3); 0.72 (s,
9H, C(CH3)3) ppm. 13C NMR (63 MHz, CDCl3) l 176.1
(CꢁO); 150.1 (C-8); 149.6 (C-5); 149.5 (C-2); 143.3 (C-4);
141.2 (C-8a); 135.2 (C-2%); 133.7 (C-1%); 128.3 (C-4%); 127.9
(C-6%); 124.5 (C-5%); 123.7 (C-2%); 120.8 (C-3); 107.6 (C-7);
106.4 (C-6); 119.7 (C-4a); 56.2 and 56.1 (2 OCH3); 39.4
(C(CH3)3); 27.2 (C(CH3)3). Anal. calcd for C22H24N2O3,
M=364.3: C, 72.51; H, 6.64; N, 7.69. Found: C, 72.25,
H, 6.74; N, 7.44.
´
9. For some reviews, see Ref. 1 and: (a) Alvarez, M.; Salas,
15. Tomatsu, A.; Takemura, S.; Hashimoto, K.; Nakata, M.
Synlett 1999, 1474–1476.
M.; Joule, J. A. Heterocycles 1991, 32, 759–794; (b)
Echavarren, A. M. Advances in Nitrogen Heterocycles
1996, 2, 211–250; (c) Ozturk, T. The Alkaloids 1997, 49,
79–219; (d) Groundwater, P. M.; Munawar, M. A. Adv.
Heterocycl. Chem. 1998, 70, 89–161.
16. Amines related to 8, from acid hydrolysis of their tru-
ifluoroacetamido derivatives, are known to cyclize to the
corresponding pyridoacridine as soon as both the amine
and quinone groups are uncovered. For recent examples,
see: (a) Blanco, M. M.; Avendan˜o, C.; Mene´ndez, J. C.
Synlett 2000, 689–691; (b) Legentil, L.; Bastide, J.;
Delfourne, E. Tetrahedron Lett. 2003, 44, 2473–2475.
17. To a solution of compound 7 (40 mg, 0.18 mmol) in
dioxane (0.6 mL) was added cobalt trifluoride (83 mg,
0.71 mmol, 4 equiv.) and water (30 mL). The mixture was
vigorously stirred for 1 h at room temperature and
diluted with water (3 mL), which was extracted with ethyl
acetate (4×5 mL). The combined extracts were dried over
anhydrous sodium sulfate and evaporated. The residue
was washed with ethyl ether and chromatographed on
silica gel, eluting with ethyl acetate, to yield 40 mg (95%)
of compound 1, as yellow crystals. Mp 276°C (dec.),
´
10. Alvarez, M.; Feliu, L.; Ajana, W.; Joule, J. A.; Ferna´n-
dez-Puentes, J. L. Eur. J. Org. Chem. 2000, 849–855.
11. (a) Guillier, F.; Nivoliers, F.; Cochennec, C.; Godard, A.;
Marsais, F.; Que´guiner, G. Synth. Commun. 1996, 26,
4421–4436; (b) Guillier, F.; Nivoliers, F.; Godard, A.;
Marsais, F.; Que´guiner, G. J. Heterocycl. Chem. 1999,
36, 1157–1165; (c) Godard, A.; Rocca, P.; Duvey, G.;
Nivoliers, F.; Marsais, F.; Que´guiner, G. Can. J. Chem.
2001, 79, 1754–1761.
12. Preparation of 3: Echavarren, A. M.; Stille, J. K. J. Am.
Chem. Soc. 1988, 110, 4051–4053.
13. Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Tetra-
hedron 1993, 49, 49–64.
14. Iodide 4 (200 mg, 0.63 mmol) and boronic acid 513 (140
mg, 0.63 mmol) were dissolved in toluene (6 mL), previ-
ously degassed by means of an argon stream (15 min). A
solution of potassium carbonate (176 mg, 1.26 mmol) in
water (0.6 mL) and ethanol (0.6 mL) was added, and the
solution was stirred at room temperature for 30 min,
under an argon atmosphere. Solid (Ph3P)4Pd (22 mg,
1
lit.11a 278°C (dec.). IR and H NMR data were identical
to those described in Ref. 11a. 13C NMR (63 MHz,
CDCl3) l 183.5 (C-4); 161,2 (C-6a); 151.3 (C-4a); 150.7
(C-7a); 150.2 (C-2); 142.5 (C-6); 137.1 (C-12b); 134.1
(C-5); 131.8 (C-9); 131.6 (C-8); 129.7 (C-11); 121.7 (C-
11a); 122.9 (C-12); 119.5 (C-11); 117.9 (C-11c) ppm.