ORGANIC
LETTERS
2001
Vol. 3, No. 26
4323-4324
A Simple Biomimetic Synthesis of
Styelsamine B
David Skyler and Clayton H. Heathcock*
Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California, Berkeley, California 94720
Received November 7, 2001
ABSTRACT
An extremely rapid, low cost, and environmentally friendly entry into the pyridoacridine family of alkaloids has been devised, as demonstrated
here by the first total synthesis of styelsamine B (3) and its oxidation to the quinoneimine cystodytin J (4). The known reaction of cystodytin
J with methanethiol makes this a formal synthesis of diplamine.
For all natural products, there exists a synthesis from
ubiquitous biomolecules. The inherent interconnectivity of
natural products implies that a truly biomimetic total
synthesis represents a general solution not to the preparation
of a compound but to the preparation of all similarly derived
natural products (discovered and undiscovered). We herein
report our preliminary work toward a general solution to
pyridoacridine synthesis.
biological or synthetic studies on styelsamine B appear to
have been published as of yet.
It has previously been proposed that the pyridoacridine
alkaloids eilatin and ascidemnin arise biosynthetically by the
reaction of kynuramine/kynurenine with benzoquinone and
a quinolinequinone, respectively. The plausibility of this
proposal has been confirmed by the total synthesis of these
natural products using a protected form of kynuramine.4
Others have made the unsupported claim that the ethylamine
side chain bearing pyridoacridines such as those synthesized
here arise by oxidative merger of tyramine directly with the
biosynthetic precursor of kynuramine (1).3c
The pyridoacridines are representatives of a growing class
of polycyclic aromatic alkaloid zoochromes isolated from
marine invertebrates. Since the isolation and structural
elucidation of the first members of this class of compounds
in the 1980s, these redox active alkaloids have attracted a
great deal of synthetic attention due to their cytotoxicity and
the variety of biological activities they have been shown to
exhibit.1 In particular, cystodytin J (4) and diplamine are
potent cytotoxins that disrupt the action of topoisomerase II
by DNA intercalation.2 Total syntheses of these natural
products have previously been reported;3 however, no
These proposals claim the amine rather than the aniline
as the initial reactive partner, whereas our work in this area
implies that the Michael addition occurs in an environment
where the amine is protonated (acidic) and therefore the less
reactive nucleophilic center (Scheme 1). The rigidity of the
aromatic ring separating the aniline and ketone functionalities
appears to preorganize the system for the requisite cycliza-
tion, whereas no such bias exists in the cyclization of an
aliphatic â-amino ketone.
(1) Related reviews: (a) Molinski, T. Chem. ReV. 1993, 93, 1825. (b)
Bowden, B. Stud. Nat. Prod. Chem. 2000, 23, 233.
(2) Mcdonald, L.; Eldredge, G.; Barrows, L.; Ireland C. J. Med. Chem.
1994, 37, 3819.
(3) (a) Szczepankiewicz, B.; Heathcock, C. H. J. Org. Chem. 1994, 59,
3512. (b) Ciufolini, M.; Shen, Y. Tetrahedron Lett. 1995, 36, 4709. (c)
Ciufolini, M.; Shen, Y.; Bishop, M. J. Am. Chem. Soc. 1995, 117, 12460.
(4) (a) Gellerman, G.; Rudi, A.; Kashman, Y. Tetrahedron 1994, 50,
12959. (b) Gellerman, G.; Rudi, A.; Kashman, Y. Tetrahedron Lett. 1993,
34, 1823. (c) Gellerman, G.; Babad, M.; Kashman, Y. Tetrahedron Lett.
1993, 34, 1827. (d) Gellerman, G.; Rudi, A.; Kashman, Y. Synthesis 1994,
239.
10.1021/ol010262l CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/07/2001