450
J . Org. Chem. 2001, 66, 450-454
F u r th er Stu d ies of th e Da ph n iph yllu m Alk a loid P olycycliza tion
Ca sca d e
Grier A. Wallace and Clayton H. Heathcock*
Center for New Directions in Organic Synthesis,† Department of Chemistry, University of California,
Berkeley, California 94720
heathcock@cchem.berkeley.edu
Received J uly 28, 2000
The scope of the 2-azadiene intramolecular Diels-Alder cyclization, previously employed for
synthesis of the Daphniphyllum alkaloids, has been further investigated. Through a series of 1,5-
diol cyclization precursors the substitution pattern of both the dienophile and the 2-azadiene were
examined. From these studies it was shown that the cascade reaction is tolerant toward a variety
of alkyl-substituted dienophiles. However, it was also demonstrated that this reaction is very
sensitive to the substitution pattern of the 2-azadiene. Alterations made to the structure of the
2-azadiene cause either competing side reactions or complete failure of the reaction cascade.
Sch em e 1
The Daphniphyllum alkaloids are a group of polycyclic
natural products first isolated from the deciduous tree
Yuzuriha (Daphniphyllum macropodum) in 1909.1 Since
then, over 30 Daphniphyllum alkaloids have been iso-
lated and structurally characterized.2 Methyl homodaph-
niphyllate (1) and methyl homosecodaphniphyllate (2) are
representative members of this group of natural products
and illustrate two of the pentacyclic core structures that
are found.
During the 1980s, we developed the biomimetic ap-
proach to these alkaloids that is illustrated in Scheme
1.3,4 This one-pot procedure begins with the oxidation of
a 1,5-diol (3) to a dialdehyde (4). Treatment of the crude
oxidation mixture with ammonia, followed by acetic acid
and ammonium acetate, leads to the formation of an
azadiene (6), which undergoes an intramolecular Diels-
Alder cyclization to form imine 7. Heating the acetic acid
solution of imine 7 facilitates an intramolecular aza-Prins
cyclization to provide pentacyclic amine 8. This remark-
able process, which forms three carbon-carbon bonds
and two nitrogen-carbon bonds and establishes six
stereocenters, has been used as the key step in the
synthesis of five of the Daphniphyllum alkaloids.3,5,6
In this paper, we report further studies that explore
the scope and generality of the intramolecular 2-azadiene
Diels-Alder cyclization.7 By studying the cyclizations of
diols 9-16 we hoped to examine the effect of both the
† The Center for New Directions in Organic Synthesis is supported
by Bristol-Myers Squibb as Sponsoring Member.
(1) Yagim S. Kyoto Igaku Zasshi. 1909, 6, 208.
(2) For reviews on the Daphniphyllum alkaloids see: (a) Yamamura,
S.; Hirata, Y. In The Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, 1975; Vol. 15, p 41. (b) Yamamura, S.; Hirata, Y.
Int. Rev. Sci.: Org. Chem., Ser. Two 1976, 9, 161. (c) Yamamura, S.
In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1986;
Vol. 29, p 265.
(3) Heathcock, C. H.; Hansen, M. M.; Ruggeri, R. B.; Kath, J . C. J .
Org. Chem. 1992, 57, 2544.
(4) We have also reported a classical approach to these alkaloids:
Heathcock, C. H.; Davidsen, S. K.; Mills, S. G.; Sanner, M. A. J . Org.
Chem. 1992, 57, 2531.
(5) Heathcock, C. H.; Stafford, J . J . Org. Chem. 1992, 57, 2566.
(6) Heathcock, C. H.; Rugerri, R. B.; McClure, K. F. J . Org. Chem.
1992, 57, 2585.
(7) For references on 2-aza dienes, see: (a) Eddaif, A.; Mison, P.;
Laurent, A.; Pellissier, N.; Carrupt, P.-A.; Vogel, P. J . Org. Chem. 1987,
52, 5548. (b) Cheng, Y.-S.; Ho, E.; Mariano, P. S.; Ammon, H. L. J .
Org. Chem. 1985, 50, 5678. (c) Boger, D. L.; Weinreb, S. M. In Hetero
Diels-Alder Methodology in Organic Synthesis; Academic Press: San
Diego, CA, 1987; pp 255-260. (d) Boger, D. L. Tetrahedron 1983, 39,
2869.
10.1021/jo001145r CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/23/2000