Published on Web 03/14/2007
Total Syntheses of 2,2′-epi-Cytoskyrin A, Rugulosin, and the
Alleged Structure of Rugulin
K. C. Nicolaou,* Yee Hwee Lim, Jared L. Piper, and Charles D. Papageorgiou
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
the Department of Chemistry and Biochemistry, UniVersity of California, San Diego, 9500
Gilman DriVe, La Jolla, California 92093
Received November 29, 2006; E-mail: kcn@scripps.edu
Abstract: The total syntheses of 2,2′-epi-cytoskyrin A, rugulosin, and the alleged structure of rugulin are
described. These naturally occurring bisanthraquinones and their relatives are characterized by novel
molecular architectures at the core, at which lies a more or less complete, cage-like structural motif termed
“skyrane”. The strategies developed for their total synthesis feature a cascade sequence called the
“cytoskyrin cascade” and deliver these molecules in short order and in a stereoselective manner.
(5a),3 both of which were found in extracts of the endophytic
fungus Diaporthe sp. residing in a tea plant. Attracted by their
Introduction
The naturally occurring bisanthraquinones cytoskyrin A (1a),1
graciliformin (1b),2 2,2′-epi-cytoskyrin A (2a),3 rugulosin (2b),4
rugulin (3),5 deoxyrubroskyrin (4),4b 1,1′-bislunatin (5a),3 skyrin
(5b)4b,6 and flavoskyrin (6),4d all shown in Figure 1, represent
an impressive and growing class of compounds with varying
degrees of structural complexity. Isolated from a number of
fungi and lichens, these molecules exhibit a diverse array of
biological activities including cytotoxic (1a, 1b, 2b),7 antibacte-
rial (3),8 insecticidal (2b),9 anti-influenzal (2b),10 and anti-HIV
(2b)11 properties. The most recent members of the family are
cytoskyrin A (1a),1 isolated from small-scale cultures of the
endophytic fungus CR200 (Cytospora sp.) and possessing
potency down to 12.5 ng mL-1 in the biochemical induction
assay (BIA), and 2,2′-epi-cytoskyrin A (2a)3 and 1,1′-bislunatin
intriguing molecular architectures and diverse biological activi-
ties, we initiated a program directed toward the total syntheses
of these compounds, initially targeting cytoskyrin A (1a), the
newest member of the class at the time. Herein, we describe in
detail our investigations in this field12 that culminated in the
total syntheses of 2,2′-epi-cytoskyrin A (2a), rugulosin (2b),
and the alleged structure 3 of rugulin as well as a number of
analogues and model systems of these naturally occurring
substances. These investigations highlighted the importance of
cascade reactions in total synthesis, rendered readily available
a number of complex molecular architectures, and enabled us
to conclude that 3 does not represent the true structure of rugulin,
whose true molecular architecture remains elusive.
Results and Discussion
(1) (a) Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. Org. Lett. 2000, 2,
4047-4049. (b) Jadulco, R.; Brauers, G.; Edrada, R. A.; Ebel, R.; Wray,
V.; Sudarsono Proksch, P. J. Nat. Prod. 2002, 65, 730-733.
(2) (a) Ejiri, H.; Sankawa, U.; Shibata, S. Phytochemistry 1975, 14, 277-279.
(b) Shibata, S. Farumashia 2006, 42, 11-14.
The present study was inspired by the fascinating structures
of the bisanthraquinones and the possibility of sequentially
constructing them through cascade reactions starting from
monomeric anthraquinone precursors. This expectation was
fueled by the work of Shibata and co-workers, who demon-
strated the feasibility of such synthetic schemes decades ago.2b,4
These molecular assemblies are characterized by a central
structural motif, more or less complete, as we move from the
monomeric units to the more complex bisanthraquinones. The
structure of rugulin (3) in particular contains a closed cage-like
structural motif consisting of 12 carbon atoms arranged in such
a way as to form a short cylinder shaped by two six-membered
rings (top and bottom faces) and four five-membered rings. The
latter systems are uniformly twisted as they reach to form the
walls of the molecular cylinder which we termed, in our first
(3) Agusta, A.; Ohashi, K.; Shibuya, H. Chem. Pharm. Bull. 2006, 54, 579-
582.
(4) (a) Ogihara, Y.; Kobayashi, N.; Shibata, S. Tetrahedron Lett. 1968, 9,
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Kitagawa, I.; Shibata, S. Tetrahedron 1973, 29, 3703-3719. (c) Shibata,
S. Pure Appl. Chem. 1973, 33, 109-128. (d) Seo, S.; Sankawa, U.; Ogihara,
Y.; Iitaka, Y.; Shibata, S. Tetrahedron 1973, 29, 3721-3276. (e) Yang,
D.-M.; Sankawa, U.; Ebizuka, Y.; Shibata, S. Tetrahedron 1976, 32, 333-
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P.; Kittakoop, P.; Veeranondha, S.; Wanasith, S.; Thongwichian, R.;
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(8) Betina, V.; Nemec, P. Czech Patent CS187049, Jan 31, 1979.
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(11) Singh, S. B.; et al. J. Ind. Microbiol. Biotechnol. 2003, 30, 721-731.
(12) For preliminary communications, see: (a) Nicolaou, K. C.; Papageorgiou,
C. D.; Piper, J. L.; Chadha, R. K. Angew. Chem., Int. Ed. 2005, 44, 5846-
5851. (b) Nicolaou, K. C.; Lim, Y. H.; Papageorgiou, C. D.; Piper, J. L.
Angew. Chem., Int. Ed. 2005, 44, 7917-7921.
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10.1021/ja0685708 CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 4001-4013
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