ORGANIC
LETTERS
2000
Vol. 2, No. 23
3611-3613
A Short Stereoselective Total Synthesis
of the Fusarium Toxin Equisetin
Lisa T. Burke, Darren J. Dixon,* Steven V. Ley, and Fe´lix Rodr´ıguez
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, U.K.
Received August 22, 2000
ABSTRACT
A short stereoselective synthesis of the fusarium toxin equisetin, an N-methylserine-derived acyl tetramic acid and potent inhibitor of HIV-1
integrase enzyme, is described using as the key step a stereoselective lithium perchlorate mediated intramolecular Diels−Alder reaction of a
fully conjugated E,E,E-triene with a trisubstituted γ,δ-unsaturated â-ketothioester.
The fusarium toxin equisetin 1, a fungal metabolite first
isolated in 1974 from the white mold Fusarium equiseti,1
exhibits an impressive range of biological properties,2-4
including antibiotic and HIV inhibitory activity, cytotoxicity,
and mammalian DNA binding. Equisetin falls into the acyl
tetramic acid5 class of natural products by virtue of its
N-methylserine-derived heterocycle which in turn is fused
to a quaternary stereogenic center of a trans octalin skeleton
additionally substituted with two methyl and one propenyl
groups. This exquisite three-dimensional structuring, com-
bined with the diverse biological profile and the potential to
exploit and develop methodology within our group, made
this natural product an ideal synthetic target.6 Here we
describe a short and stereoselective synthesis of equisetin,
1.
The synthetic plan relied on a late stage Lewis acid
mediated intramolecular Diels-Alder (IMDA) reaction of
2 in which all carbons barring those of the N-methylserine
component would be brought together to yield the ap-
propriately decorated octalin skeleton,7-8 suitably poised for
transformation to the target compound. More specifically, it
was believed that the fully conjugated all-E triene would
undergo a stereoselective cycloaddition9 with the attached
trisubstituted γ,δ-unsaturated â-ketothioester in which the
configurations of the four newly formed stereogenic centers
would be controlled by the methyl substituent adopting a
pseudoequatorial position during the transition state. It was
envisaged that this cycloaddition precursor would be readily
synthesized through sequential manipulation of the hydroxyl
(6) For proof of stereochemistry and the only total synthesis to date,
see: Turos, E.; Audia J. E.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
111, 8231.
(7) For related work, see: (a) Roush, W. R. ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: Oxford, New York, Seoul, Tokyo, 1991; Vol. 5, p 513 and references
therein. (b) Witter D. J.; Vederas, J. C. J. Org. Chem. 1996, 61, 2613. (c)
Shing, T. K. M.; Yang, J. J. Org. Chem. 1995, 60, 5785.
(8) For a recent review, see: Fallis, A. G. Acc. Chem. Res. 1999, 32,
464 and references therein.
(9) For work relating the lactone-enolate Claisen rearrangement of ref
6 to the cycloaddition approach adopted here for the preparation of trans-
fused carbocyclic systems, see: Burke, S. D.; Piscopio A. D.; Kort, M. E.;
Matulenko, M. A.; Parker M. H.; Armistead, D. M.; Shankaran, K, J. Org.
Chem. 1994, 59, 332.
(1) Burmeister, H. R.; Bennet, G. A.; Vesonder, R. F.; Hesseltine, C.
W. J. Antimicrob. Agents Chemother. 1974, 5, 634.
(2) Vesonder, R. F.; Tjarks, L. W.; Rohwedder, W. K.; Burmeister, H.
R.; Laugal, J. A. J. Antibiot. Agents Chemother. 1979, 32, 759.
(3) Phillips, N. J.; Goodwin, J. T.; Fraiman, A.; Cole R. J.; Lynn, D. G.
J. Am. Chem. Soc. 1989, 111, 8223.
(4) Singh, S. B.; Zink, D. L.; Goetz, M. A.; Dombrowski, A. W.;
Polishook, J. D.; Hazuda, D. J. Tetrahedron Lett. 1998, 39, 2243.
(5) For references to representative members of this class of natural
products, see: (a) Dixon, D. J.; Ley, S. V.; Gracza T.; Szolcsanyi, P. J.
Chem. Soc., Perkin Trans. 1 1999, 839. (b) Dixon, D. J.; Ley, S. V.;
Longbottom D. A. J. Chem. Soc., Perkin Trans. 1 1999, 2231 and references
therein.
10.1021/ol006493u CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000