Published on Web 06/14/2006
Enantioselective Total Synthesis of Avrainvillamide and the
Stephacidins
Phil S. Baran,* Benjamin D. Hafensteiner, Narendra B. Ambhaikar,
Carlos A. Guerrero, and John D. Gallagher
Contribution from the Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
Received March 9, 2006; E-mail: pbaran@scripps.edu
Abstract: In this article, full details regarding our total synthesis of avrainvillamide and the stephacidins
are presented. After an introduction and summary of prior synthetic studies in this family of structurally
complex anticancer natural products, the evolution of a final synthetic approach is described. Thus, a
thorough description of three separate model studies is provided for construction of the characteristic bicyclo-
[2.2.2]diazaoctane ring system common to these alkaloids. The first and second approaches sought to
build the core using formal Diels-Alder and vinyl radical pathways, respectively. Although these strategies
failed in their primary objective, they fostered the development of a new and mechanistically intriguing
method for the synthesis of indolic enamides such as those found in numerous bioactive natural products.
The scope and generality of this simple method for the direct dehydrogenation of tryptophan derivatives is
described. Finally, details of a third and successful route to the core of these alkaloids are described which
features oxidative C-C bond formation. Specifically, the first heterocoupling of two different types of carbonyl
species (ester and amide) is accomplished in good yield, on a preparative scale, and with complete
stereocontrol. The information gained in these model studies enabled an enantioselective total synthesis
of stephacidin A. The absolute configuration of these alkaloids was firmly established in collaboration with
Professor William Fenical. A full account of our successful efforts to convert stephacidin A into stephacidin
B via avrainvillamide is presented. Finally, the first analogues of these natural products have been prepared
and evaluated for anticancer activity.
by a Pfizer group in Japan and named CJ-17,665.6 The signature
bicyclo[2.2.2]diazaoctane ring system common to these alkaloids
has inspired numerous synthetic approaches.
Birch,7 Sammes,8 and Williams9 have proposed that this ring
system is derived biosynthetically from a Diels-Alder reaction.
This hypothesis has influenced several creative synthetic strate-
Introduction
In 2002, scientists from Bristol Myers Squibb added a new
entry to the list of structurally intriguing and bioactive indole
alkaloids with the discovery of stephacidins A and B (1 and 2
in Figure 1, respectively).1 Isolated from a fungal species found
in an Indian clay sample, they show obvious structural similari-
ties to the brevianamides,2 paraherquamides,3 and asperpara-
lines.4 In 2000, the Fenical group at the Scripps Institution of
Oceanography disclosed the structure of avrainvillamide (3) in
a patent.5 This compound was independently described in 2001
(5) Fenical, W.; Jensen, P. R.; Cheng, X. C. Avrainvillamide, a Cytotoxic
Marine Natural Product, and Derivatives thereof. U.S. Patent 6,066,635,
2000.
(6) Sugie, Y.; Hirai, H.; Inagaki, T.; Ishiguro, M.; Kim, Y.-S.; Kojima, Y.;
Sakakibara, T.; Sakemi, S.; Sugiura, A.; Suzuki, Y.; Brennan, L.; Duignan,
J.; Huang, L. H.; Sutcliffe, J.; Kojima, N. J. Antibiot. 2001, 54, 911-916.
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52.
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10.1021/ja061660s CCC: $33.50 © 2006 American Chemical Society