murine leukemia P-388 cell line (IC50 1.8 µg/mL)8 and has
been shown to stabilize the human topoisomerase I-DNA
covalent binary complex in the same fashion as the antitumor
microwave-assisted domino reactions,21 as well as a novel
total synthesis of 5 via a three-component one-pot reaction
promoted by microwave irradiation.22 Further, the new
methods have a sufficiently broad chemistry scope, enabling
access to various derivatives of these natural products by
employing an economical, one-pot reaction process that
requires only one reagent, one protecting group, and one
solvent for complete syntheses from readily available an-
thranilic acids, Boc-amino acids, and benzaldehydes.
Retrosynthetic strategies are depicted in Figure 2. Within
9
alkaloid camptothecin and its analogues.
A number of methods have been reported for the synthesis
of deoxyvasicinone (1). These include carbonylation cata-
lyzed by palladium,10 transition-metal-catalyzed reductive
N-heterocyclization,11 coupling of O-methylbutyrolactim with
anthranilic acid,12 cycloaddition of anthranilic acid imi-
noketene to a methyl butyrolactam (via sulfonamide anhy-
dride),13 intramolecular aza-Wittig reactions using PPh3 and
PBu3,14 the cycloaddition of anthranilamide with succinic
anhydrides,15 and solvent-free microwave-assisted reactions
between isatoic anhydride and pyrrolidone.16 Some of these
methods are also applicable for the synthesis of mackina-
zolinone (2). In addition, isaindigotone (5) has been synthe-
sized in six steps from commercially available starting
materials.17
We recently reported a highly efficient, microwave-
assisted, three-component, one-pot reaction for the synthesis
of various 2,3-disubstituted quinazolin-4-ones from readily
available starting materials.18 On the basis of this methodol-
ogy, we successfully achieved a three-component one-pot
total synthesis of pyrazino[2,1-b]quinazoline-3,6-dione cores
and their natural product alkaloids.19 As a continuation of
our studies, the unique structures and biological activities
of the vasicinone family of natural products elicited our
interest in pyrrolo[2,1-b]quinazoline and related alkaloids as
targets for the total synthesis and natural product-templated
library synthesis. In addition, we envisioned that development
of efficient and concise methods for the total synthesis of
these chemotypes, which overcome the drawbacks of the
existing methods in terms of simplicity and versatility, would
provide a practical entry into natural product-templated
libraries suited for our broad-based phenotypic screens.20
Herein, we describe novel total syntheses of 1, 2, and 3 via
Figure 2. Retrosynthetic strategy of 1 and 5.
the context of the domino concept, 1 and 2 could be formed
via transannular cyclization of intermediate cyclic-diamide
10. The diamide 10 may be prepared via ring expansion of
the intermediate benzoxazinone 9b, which could be accessed
in situ from Boc-benzoxazinone 9a, which in turn should
be generated in situ from readily available anthranilic acid
(7a) and Boc-amino acids (8). In addition, we also envisioned
that isaindigotone (5) could be synthesized through a
condensation reaction of 1 with the aldehyde 11a via a three-
component one-pot reaction process. All of these transforma-
tions would be carried out under microwave conditions.
Empirical validation of our design started from the
synthesis of 1 by employing our “standard” microwave
conditions.18,19 Reaction of anthranilic acid (7a) (1.0 equiv)
with 4-(tert-butoxycarbonylamino)butyric acid (8a) (1.0
equiv) in the presence of P(OPh)3 (1.2 equiv) in pyridine
under microwave irradiation at 150 °C for 10 min generated
(7) (a) Johns, S. R.; Lamberton, J. A. Chem. Commun. 1965, 267. (b)
Fitagerald, J. S.; Johns, S. R.; Lamberton, J. A.; Redcliffe, A. H. Aust. J.
Chem. 1966, 19, 151.
(8) Ma, Z.; Hano, Y.; Nomura, T.; Chen, Y. Heterocycles 1997, 46, 541.
(9) (a) Cagir, A.; Jones, S. H.; Gao, R.; Eisenhauer, B. M.; Hecht, S. M.
J. Am. Chem. Soc. 2003, 125, 13628. (b) Cagir, A.; Jones, S. H.; Eisenhauer,
B. M.; Gao, R.; Hecht, S. M. Bioorg. Med. Chem. Lett. 2004, 14, 2051. (c)
Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Bioorg. Med. Chem. Lett.
2004, 14, 1193.
(10) Mori, M.; Kobayashi, H.; Kimura, M.; Ban, Y. Heterocycles 1985,
23, 2803.
(11) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1993, 58,
310.
(12) (a) Onaka, T. Tetrahedron Lett. 1971, 4387. (b) Morris, R. C.;
Hanford, W. E.; Roger, A. J. Am. Chem. Soc. 1935, 57, 951.
(13) Kametani, T.; Loc, C. V.; Higa, T.; Koizumi, M.; Ihara, M.;
Fukumoto, K. J. Am. Chem. Soc. 1977, 99, 2306.
(14) (a) Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y. J. Org. Chem.
1996, 61, 7316. (b) Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron
1989, 45, 6375.
(15) Mhaske, S. B.; Argade, N. P. J. Org. Chem. 2001, 66, 9038.
(16) Yadav, J. S.; Reddy, B. V. S. Tetrahedron Lett. 2002, 43, 1905.
(17) Molina, P.; Tarraga, A.; Gonzalez-Tejero, A. Synthesis 2000, 1523.
(18) Liu, J.-F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.;
McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241.
(19) Liu, J.-F.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes,
D.; Baldino, C. M. J. Org. Chem. 2005, in press (jo0508043).
(20) For examples of diversity-oriented synthesis and phenotypic screen-
ing, see: (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Tan, D. S. Comb.
Chem. High Throughput Screening 2004, 7, 631 and references therein.
(21) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Tietze, L. F.; Haunert,
F. In Stimulating Concepts in Chemistry; Shibasaki, M., Stoddart, J. F.,
Vo¨gtle, F., Eds.; Wiley-VCH: Weinheim, 2000; p 39.
(22) For multicomponent reactions, see: (a) Multicomponent Recations;
Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, 2005. (b) Do¨mling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (c) Hulme, C.; Gore, V.
Curr. Med. Chem. 2003, 10, 51. (d) Orru, R. V. A.; de Greef, M. Synthesis
2003, 1471. (e) Murakami, M. Angew. Chem., Int. Ed. 2003, 42, 718. (f)
Zhu, J. Eur. J. Org. Chem. 2003, 1133.
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