ORGANIC
LETTERS
2012
Vol. 14, No. 14
3736–3739
Formal Synthesis of 7-Methoxymitosene
and Synthesis of its Analog via a Key
PtCl2-Catalyzed Cycloisomerization
Lianzhu Liu, Yanzhao Wang, and Liming Zhang*
Department of Chemistry and Biochemistry, University of California, Santa Barbara,
California 93106, United States
Received June 8, 2012
ABSTRACT
A formal synthesis of 7-methoxymitosene is achieved via a key platinum-catalyzed cycloisomerization. The precursor for the Pt catalysis, a fully
functionalized benzene intermediate, was prepared via a regioselective electrophilic bromination followed by a chemoselective Sonogashira
cross-coupling. It underwent the PtCl2-catalyzed cycloisomerization smoothly despite its hindered and highly electron-rich nature. Analogs of
7-methoxymitosene can be accessed in an expedient manner by following a similar synthetic sequence.
Mitomycins were isolated originally from Streptomyces
caespitosus in the 1950s1 and later from Streptomyces
verticillatus.2 They are members of a few aziridine-ring-
containing natural products3 and possess potent antibiotic
and antitumor activities (Figure 1). Mitomycin C is cur-
rently in clinical use and cross-links DNA upon in vivo
activation. The more stable aziridinomitosenes, different
from mitomycins by the formal loss of MeOH, possess
activities against tumor cells similar to mitomycin C.4
Among various analogs of these pharmacologically im-
portant mitosenes, 7-methoxymitosene, a compound lack-
ing the aziridine ring of 1, has shown to be effective against
Gram positive bacteria.5 Its total synthesis has been realized
by various creative approaches targeting the tricyclic pyrrolo-
[1,2-a]indole skeleton.6 In this manuscript, we describe a new
(1) (a) Hata, T.; Hoshi, T.; Kanamori, K.; Matsumae, A.; Sano, Y.;
Shima, T.; Sugawara, R. J. Antibiot. 1956, 9, 141–6. (b) Hata, T.;
Sugawara, R. J. Antibiot. 1956, 9, 147–51. (c) Wakaki, S.; Marumo,
H.; Tomioka, K.; Shimizu, G.; Kato, E.; Kamada, H.; Kudo, S.;
Fujimoto, Y. Antibiot. Chemother. 1958, 8, 228–40.
Figure 1. Mitomycins, aziridinomitosenes, and 7-metoxymitosene.
(2) Lefemine, D. V.; Dann, M.; Barbatschi, F.; Hausmann, W. K.;
Zbinovsky, V.; Monnikendam, P.; Adam, J.; Bohonos, N. J. Am. Chem.
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cycles 1995, 41, 255–8.
(4) (a) Orlemans, E. O. M.; Verboom, W.; Scheltinga, M. W.;
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Iyengar, B. S.; Remers, W. A.; Bradner, W. T. J. Med. Chem. 1986, 29,
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r
10.1021/ol301593w
Published on Web 07/05/2012
2012 American Chemical Society