trum Bunge.15 This plant has a history of use in Chinese
traditional medicine for the treatment of various conditions,
including rheumatism and inflammation. Luotonin A is active
in vitro against the murine leukemia P-388 cell line at a
concentration of 1.8 µg/mL13 and has been the subject of
several syntheses.7,16 Particularly noteworthy is an inter-
molecular Povarov route to the synthesis of luotonin A,
reported by Stevenson and co-workers.7
We envisaged an intramolecular Povarov reaction17,18 could
form the key ring-forming reaction in a general approach to
the syntheses of these alkaloids and their analogues (Figure
2). This disconnection would employ an intramolecular aza-
Figure 1. Pyrroloquinoline alkaloids.
core (Figure 1).5 We were interested in further showcasing
this useful reaction in other alkaloid syntheses and more
specifically in developing intramolecular variants. We now
report a concise intramolecular Povarov strategy for the
formation of pyrrolo[3,4-b]quinolines that has been applied
in a formal synthesis of camptothecin, as well as a total
synthesis of luotonin A (Figure 1).
Figure 2. Proposed retrosynthesis of the pyrrolo[3,4-b]quinoline
core 1 of Camptothecin and Luotonin A.
Pyrrolo[3,4-b]quinoline-based alkaloids have attracted
significant interest due to their intriguing structures and
biological activity. The most well-known example is camp-
tothecin, a novel alkaloid isolated from the stem wood of
the chinese tree, Camptotheca acuminata, which has potent
antitumor activity. Since its isolation in 1966 and its structure
elucidation by Wall and co-workers,8 the compound has been
the subject of numerous syntheses,9-14 in part, because of
its relationship to the antineoplastic chemotherapeutic drugs
irinotecan and topotecan, which are camptothecin analogues.
Luotonin A is a structurally related cytotoxic alkaloid first
isolated in 1997 from the aerial parts of Peganum nigellas-
Diels-Alder reaction of an imine derived from the aniline
2, heterocyclic aldehyde 3, and propargylic halide 4. The
resultant dihydroquinoline ring could then be oxidized to the
quinoline ring present in both camptothecin and luotonin A.
This modular approach should also provide a convenient
method for analogue synthesis.
Our initial goal was the synthesis of camptothecin, which
would require a pyridone precursor. Pyridone 5 was con-
structed in a one-pot protocol using commercially available
pyruvic acid dimethylacetal, dimethylacetamide dimethyl-
acetal, and cyanoacetamide.19,20 Despite various attempts to
optimize the reaction, the yield for this transformation
(8) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer. K. H.; MacPhail, A.
T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888-3890.
(9) For a recent review on Camptothecins, see: Du, W. Tetrahedron
2003, 59, 8649-8687.
(14) For Diels-Alder reaction approaches to B, C, and D ring formation,
see: (a) Fortunak, J. M. D.; Mastrocola, A. R.; Mellinger, M.; Sisti, N. J.;
Wood, J. L.; Zhuang, Z.-P. Tetrahedron Lett. 1996, 37, 5679-5682. (b)
Fortunak, J. M. D.; Kitteringham, J.; Mastrocola, A. R.; Mellinger, M.;
Sisti, N. J.; Wood, J. L.; Zhuang, Z.-P. Tetrahedron Lett. 1996, 37, 5683-
5686. (c) Blagg, B. S. J.; Boger, D. L. Tetrahedron 2002, 58, 6343-6349.
(d) Toyata, M.; Komori, C.; Ihara, M. J. Org. Chem. 2000, 65, 7110-
7113. (e) Rigby, J. H.; Danca, D. M. Tetrahedron Lett. 1997, 38, 4969-
4972.
(10) For approaches involving construction of the C ring via sp2-sp2
C-C bond formation followed by N-alkylation, see: (a) Comins, D. L.;
Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10971-10972.
(b) Comins, D. L.; Nolan, J. M. Org. Lett. 2001, 3, 4255-4257. (c)
Bennasar, M.-L.; Zulaica, E.; Juan, C.; Alonso, Y.; Bosch, J. J. Org. Chem.
2002, 67, 7465-7474.
(11) For approaches involving construction of the B and C rings using
a 4 + 1 radical annulation reaction, see: (a) Curran, D. P.; Liu, H. J. Am.
Chem. Soc. 1992, 114, 5863-5864. (b) Curran, D. P.; Liu, H.; Josien, H.;
Ko, S.-B. Tetrahedron 1996, 52, 11385-11404. (c) Curran, D. P.; Du, W.
Org. Lett. 2002, 4, 3215-3218. (d) Bowman, W. R.; Bridge, C. F.; Brookes,
P.; Cloonan, M. O.; Leach, D. C. J. Chem. Soc., Perkin Trans. 1 2002,
58-68.
(12) For Friedlander condensation approaches to form the B ring, see:
(a) Hutchinson, C. R. Tetrahedron 1981, 37, 1047-1065. (b) Ejima, A.;
Terasawa, H.; Sugimori, M.; Tagawa, H. Tetrahedron Lett. 1989, 30, 2639-
2640. (c) Jew, S.-S.; Ok, K.-D.; Kim, H.-J.; Kim, M. G.; Kim, J. M.; Cho,
Y.-S. Tetrahedron: Asymmetry 1995, 6, 1245-1248. (d) Shen, W.; Coburn,
C. A.; Bornmann, W. G.; Danishefsky, S. J. J. Org. Chem. 1997, 62, 6588-
6597.
(15) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Heterocycles 1997,
46, 541-546.
(16) For recent syntheses, see: (a) Azizian, J.; Mohammadi, A. A.;
Ardakani, F.; Karimi, A. R.; Mohammadizadeh, M. R. Heterocycles 2004,
63, 791-795. (b) Cagir, A.; Jones, S. H.; Eisenhauer, B. M.; Gao, R.; Hecht,
S. M. Bioorg. Med. Chem. Lett. 2004, 14, 2051-2054. (c) Mhaske, S. B.;
Argade, N. P. J. Org. Chem. 2004, 69, 4563-4566 and references therein.
(17) There have been few reports of intramolecular Povarov reactions;
see: (a) Laschat, S.; Lauterwein, J. J. Org. Chem. 1993, 58, 2856-2861.
(b) Wo¨lfling, J.; Frank, E.; Schneider, G.; Tietze, L. F. Eur. J. Org. Chem.
1999, 3013-3020. (c) Magomedov, N. A. Org. Lett. 2003, 5, 2509-2512.
(18) An intramolecular Diels-Alder reaction has been used to form the
B ring of topotecan, via activation of an N-aryl imidate with trimethyloxo-
nium fluoroborate; see: refs 14a and 14b.
(13) For inter- or intramolecular Michael addition approaches to D ring
construction, see: (a) Ciufolini, M. A.; Roschangar, F. Tetrahedron 1997,
53, 11049-11060. (b) Chavan, S. P.; Venkatraman, M. S. Tetrahedron Lett.
1998, 39, 6745-6748.
(19) Stockley, M.; Clegg, W.; Fontana, G.; Golding, B. T.; Martin, N.;
Rigoreau, L. J. M.; Smith, G. C. M.; Griffin, R. J. Bioorg. Med. Chem.
Lett. 2001, 11, 2837-2841.
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