ORGANIC
LETTERS
2
005
Vol. 7, No. 4
85-588
Biomimetic Total Synthesis of
)-Himbacine
5
(+
Kirill Tchabanenko, Robert M. Adlington, Andrew R. Cowley, and
Jack E. Baldwin*
Chemistry Research Laboratory, UniVersity of Oxford, Mansfield Road,
Oxford OX1 3TA, United Kingdom
Received November 11, 2004
ABSTRACT
On treatment with trifluoroacetic acid butenolide 14 undergoes N-Boc deprotection and condensation followed by an iminium ion activated
intramolecular Diels
−
Alder cycloaddition to give the (
+
)-himbacine precursor 11 on reductive work up. Compound 11 was converted into
(
+
)-himbacine in four synthetic steps.
2
In 1956, Ritchie and Taylor reported isolation of the
Galbulimina family alkaloids from the bark of Himantandra
baccata.11 Overall 28 new alkaloids were isolated, which
were divided into 4 classes. Class 1 consisted of four
tetracyclic lactones.
effects. More recently though, himbacine has been shown
to be a selective muscarinic antagonist and thus a potential
3
new lead in the treatment of Alzheimer’s disease. Conse-
quently himbacine 1 has attracted much synthetic attention,4
and three successful total syntheses of this molecule have
been reported to date. Quite remarkably an intramolecular
Diels-Alder reaction was involved in the construction of
the tricyclic core unit of himbacine in all the synthetic efforts
published, however these approaches do not describe a
5-7
(
2) Collins, D. J.; Culvnor, C. C. J.; Lamberton, J. A.; Loder, J. W.;
Price, J. R. Plants for Medicines; C.S.I.R.O.: Melbourne, 1990.
3) Kozikowski, A. P.; Fauq, A. H.; Miller, J. H.; McKinney, M. Biol.
Med. Chem. Lett. 1992, 2, 797.
4) De Baecke, G.; De Clercq, P. J. Tetrahedron Lett. 1995, 36, 7515.
Hofman, S.; De Baecke, G.; Kenda, B.; De Clercq, P. J. Synthesis 1998,
79. Hofman, S.; Gao, L.-J.; Van Dingenen, H.; Hosten, N. G. C.; Van
Haver, D.; De Clercq, P. J.; Milanesio, M.; Viterbo, D. Eur. J. Org. Chem.
(
(
4
Within its class, himbacine (1) was the first and major
isolated representative. It was originally shown to exhibit
anti-spasmodic activity with low toxicity and few side
2
001, 2851. Wong, L. S.-M.; Sherburn, M. S. Org. Lett. 2003, 5, 3603.
(5) Hart, D. J.; Wu, W.-L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995,
17, 9369. Hart, D. J.; Li, J.; Wu, W.; Kozikowski, A. P. J. Org. Chem.
997, 62, 5023.
1
1
(
6) Chackalamannil, S.; Davies, R. J.; Asberom, T.; Doller, D.; Leone,
(
1) Brown, R. F. C.; Drummond, R.; Fogerty, A. C.; Hughes, G. K.;
D. J. Am. Chem. Soc. 1996, 118, 9812. Chakalamannil, S.; Davies, R. J.;
Wang, Y.; Asberom, T.; Doller, D.; Wong, J.; Leone, D. J. Org. Chem.
1999, 64, 1932.
(7) Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S. Tetrahedron Lett.
1999, 40, 3399. Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S.
Tetrahedron 2002, 58, 9903.
Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1956, 9, 284. Ritchie,
E.; Taylor, W. C. The Galibulimina Alkaloids. In The Alkaloids; Manske,
R. H. F., Ed.; Academic Press: New York, 1967; Vol. 9, p 529. Ritchie,
E.; Taylor, W. C. The Galibulimina Alkaloids. In The Alkaloids; Manske,
R. H. F., Ed.; Academic Press: New York, 1973; Vol. 13, p 227.
1
0.1021/ol047676+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/20/2005