Published on Web 08/22/2003
The First Total Synthesis of Discorhabdin A
Hirofumi Tohma, Yu Harayama, Miki Hashizume, Minako Iwata, Yorito Kiyono,
Masahiro Egi, and Yasuyuki Kita*
Contribution from the Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received June 6, 2003; E-mail: kita@phs.osaka-u.ac.jp
Abstract: The first stereoselective total synthesis of a potent antitumor alkaloid, discorhabdin A (1), which
is a unique sulfur-containing pyrroloiminoquinone alkaloid, is described. The key step in the stereocontrolled
total synthesis of 1 involves both a diastereoselective oxidative spirocyclization using a hypervalent iodine(III)
reagent and an efficient construction of the labile and highly strained N,S-acetal skeleton. These
methodologies provide a breakthrough in the total syntheses of these promising new antitumor agents,
discorhabdins and their analogues, which should serve as valuable probes for structure-activity studies.
Introduction
and highly strained N,S-acetal (sulfur cross-linked) core was
difficult. Furthermore, biosynthetically, the timing and insertion
point for the introduction of sulfur in discorhabdins have not
yet been clarified.4
Discorhabdins and prianosins were isolated from marine
sponges such as New Zealand sponges of the genus Latrunculia,
the Okinawan sponge Prianos melanos, the Fijian sponge Zyzzya
cf. Marsailis, and so on. Among the various discorhabdins (A-
R) isolated,1 discorhabdins A (1),1b,c B,1c D,1d Q,1m and R1n have
a unique sulfur-containing fused ring system incorporating the
azacarbocyclic spirocyclohexadienone and pyrroloiminoquinone
system (Chart 1) and show potent antitumor activity.2 Because
of their prominent biological activities and unusual ring
structures, the discorhabdins have attracted considerable atten-
tion, and several partial and total syntheses of discorhabdin C
have appeared in the past decade.3 However, in most cases,
synthetic efforts have been devoted only toward the diverse
preparation of the pyrroloiminoquinone unit. To the best of our
knowledge, the total syntheses of sulfur-containing discorhab-
dins have not yet been reported because construction of the labile
As part of our continued studies on the total syntheses of
discorhabdins and the related alkaloids, we have already reported
the total synthesis of discorhabdin C3f via spirodienone forma-
tion using a hypervalent iodine(III) reagent, phenyliodine bis-
(trifluoroacetate) (PIFA), and, recently, using several hypervalent
iodine(III)-induced reactions,5 we achieved the first total
synthesis of (()-makaluvamine F (2),6 which is assumed to be
the biosynthetic precursor of sulfur-containing discorhabdins
(Scheme 1).
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