ORGANIC
LETTERS
1999
Vol. 1, No. 4
663-665
A Concise Total Synthesis of
(±)-Bakkenolide A by Means of an
Intramolecular Diels−Alder Reaction
,†
Thomas G. Back* and Joseph E. Payne
Department of Chemistry, UniVersity of Calgary, Calgary, Alberta, Canada T2N 1N4
Received June 18, 1999
ABSTRACT
(±)-Bakkenolide A was prepared in five steps from ethyl 4-benzyloxyacetoacetate by sequential alkylations with tiglyl bromide and cis-5-
bromo-1,3-pentadiene, followed by an intramolecular Diels−Alder reaction as the key step. The known 7-epibakkenolide A and novel 10-epi-
and 7,10-diepibakkenolide A stereoisomers were obtained as minor byproducts.
Bakkenolide A (1) is a sesquiterpene â-methylene spiro
lactone that is structurally related to the eremophilanes.1 It
was first isolated from the wild butterbur Petasites japonicus
by Kitahara et al.,2 and independently by Naya et al.3
means of a radical cyclization/high-pressure intermolecular
Diels-Alder approach.7 Unfortunately, this resulted in poor
stereoselectivity and afforded the corresponding 6-keto
analogue that could not be reduced to the desired product.
We now report a concise new synthesis of (()-1 based on
an intramolecular Diels-Alder reaction.
The known â-keto ester 28 was sequentially alkylated with
tiglyl bromide (3)9 and cis-5-bromo-1,3-pentadiene (5)10,11
in yields of 85% and 92%, respectively, as shown in Scheme
1. The resulting pre-Diels-Alder triene 6 was then heated
in toluene at 190 °C for 24 h in a sealed reaction vessel to
effect the cycloaddition. Significantly improved yields were
Subsequent studies showed that 1 is cytotoxic toward several
carcinoma cell lines4 and that it acts as an effective insect
antifeedant.5 The reported biological activity and unusual
structure of bakkenolide A have prompted several previous
syntheses.6 We recently attempted the preparation of 1 by
(5) (a) Harmatha, J.; Nawrot, J. Biochem. Syst. Ecol. 1984, 12, 95. (b)
Nawrot, J.; Harmatha, J.; Novotny´, L. Biochem. Syst. Ecol. 1984, 12, 99.
(c) Nawrot, J.; Bloszyk, E.; Harmatha, J.; Novotny´, L.; Drozdz, B. Acta
Entomol. BohemosloV. 1986, 83, 327. (d) Isman, M. B.; Brard, N. L.;
Nawrot, J.; Harmatha, J. J. Appl. Entomol. 1989, 107, 524. (e) Nawrot, J.;
Koul, O.; Isman, M. B.; Harmatha, J. J. Appl. Entomol. 1991, 112, 194.
(6) (a) Hayashi, K.; Nakamura, H.; Matsuhashi, H. Chem. Pharm. Bull.
1973, 21, 2806. (b) Evans, D. A.; Sims, C. L.; Andrews, G. C. J. Am. Chem.
Soc. 1977, 99, 5453. (c) Greene, A. E.; Depre´s, J.-P.; Coelho, F.; Brocksom,
T. J. J. Org. Chem. 1985, 50, 3943. (d) Greene, A. E.; Coelho, F.; Depre´s,
J.-P.; Brocksom, T. J. Tetrahedron Lett. 1988, 29, 5661. (e) Srikrishna, A.;
Reddy, T. J.; Nagaraju, S.; Sattigeri, J. A.; Tetrahedron Lett. 1994, 35,
7841.
† Phone: (403) 220-6256. Fax: (403) 289-9488.
(1) For a review of bakkenolide A and other sesquiterpene lactones,
see: Fischer, N. H.; Olivier, E. J.; Fischer, H. D. In Progress in the
Chemistry of Organic Natural Products; Herz, W., Grisebach, H., Kirby,
G. W., Eds.; Springer-Verlag: New York, 1979; Vol. 38, Chapter 2.
(2) Abe, N.; Onoda, R.; Shirahata, K.; Kato, T.; Woods, M. C.; Kitahara,
Y. Tetrahedron Lett. 1968, 369.
(3) Naya, K.; Takagi, I.; Hayashi, M.; Nakamura, S.; Kobayashi, M.;
Katsumura, S. Chem. Ind. (London) 1968, 318.
(4) (a) Jamieson, G. R.; Reid, E. H.; Turner, B. P.; Jamieson, A. T.
Phytochem. 1976, 15, 1713. (b) Kano, K.; Hayashi, K.; Mitsuhashi, H.
Chem. Pharm. Bull. 1982, 30, 1198.
(7) Back, T. G.; Gladstone, P. L.; Parvez, M. J. Org. Chem. 1996, 61,
3806.
(8) Meul, T.; Miller, R.; Tenud, L. Chimia 1987, 41, 73.
(9) Katzenellenbogen, J. A.; Crumrine, A. L. J. Am. Chem. Soc. 1976,
98, 4925.
10.1021/ol990747y CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/17/1999