ORGANIC
LETTERS
2001
Vol. 3, No. 1
115-117
Facile Entry to the Tetracyclic 5-7-6-3
Tigliane Ring System
Timo V. Ovaska,* Sarah E. Reisman, and Meghan A. Flynn
Department of Chemistry, Connecticut College, 270 Mohegan AVenue,
New London, Connecticut 06320
Received November 3, 2000
ABSTRACT
A tandem anionic 5-exo-dig cyclization/Claisen rearrangement sequence was used to effect a facile, “one-pot” conversion of an appropriately
substituted 4-alkyn-1-ol to the tetracyclic carbon core structure of phorbol. The synthesis was conducted using readily available nonracemic
starting materials to provide the target structure as a single enantiomer in high chemical yield.
Among the most powerful methods of ring construction are
the various cascade reactions that allow several synthetic
transformations to take place in a single reaction vessel.
Applications of these sequential processes have resulted in
many elegant synthetic approaches to natural products,
including morphine,1 the prostaglandins,2 ∆9(12)capnellene,3
the scopadulcic acids,4 and dynemycin A,5 to mention a few
examples.
We have recently reported the use of a tandem anionic
cyclization/Claisen rearrangement sequence as a convenient
and highly stereoselective route to tricyclic ring systems.6
These reactions involve the use of appropriately substituted
4-alkyn-1-ols, which are easily converted to the target ring
structures in high yield simply on heating and in the presence
of catalytic amounts of a strong base.7 We have now explored
this strategy as an efficient route to the tetracyclic tigliane
core found in a number of biologically active compounds
such as phorbol, a potent tumor promoter.8
Synthetic approaches to the tigliane ring system have been
previously described by Wender,9 Paquette,10 Shibasaki,11
Dauben,12 and others.13 Wender reported the first synthesis
of the phorbol skeleton in 19879a and of phorbol itself a few
years later.9b His efforts culminated in the elegant asymmetric
total synthesis of phorbol in 1997.9e Key to this strategy is
the formation of the B/C ring fragment through an intramo-
lecular oxidopyrilium-alkene [5 + 2] cycloaddition reaction
(Scheme 1).9e
(8) Evans, F. J.; Taylor, S. E. Prog. Chem. Org. Nat. Prod. 1983, 44,
27.
(9) (a) Wender, P. A.; Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc.
1987, 109, 4390. (b) Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.; Williams,
P. D. J. Am. Chem. Soc. 1989, 111, 8954. (c) Wender, P. A.; Kogen, H.;
Lee, H. Y.; Munger, J. D., Jr.; Wilhelm, R. S.; Williams, P. D. J. Am.
Chem. Soc. 1989, 111, 8957. (d) Wender, P. A.; McDonald, F. E. J. Am.
Chem. Soc. 1990, 112, 4956. (e) Wender, P. A.; Rice, K. D.; Schnute, M.
E. J. Am. Chem. Soc. 1997, 119, 7897.
(1) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993,
115, 11028.
(2) (a) Larock, R. C.; Lee, N. H. J. Am. Chem. Soc. 1991, 113, 7815.
(b) Larock, R. C.; Lee, N. H. J. Org. Chem. 1991, 56, 6253.
(3) Curran, D. P.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991.
(4) (a) Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc.
1993, 115, 2042. (b) Kucera, D. J.; O’Connor, S. J.; Overman, L. E. J.
Org. Chem. 1993, 58, 5304.
(10) Paquette, L. A.; Sauer, D. R.; Edmondson, S. D.; Friedrich, D.
Tetrahedron 1994, 50, 4071.
(11) (a) Shigeno, K.; Ohne, K.; Yamaguchi, T.; Sasai, H., Shibasaki,
M. Heterocycles 1992, 33, 161. (b) Shigeno, K.; Sasai, H.; Shibasaki, M.;
Tetrahedron Lett. 1992, 33, 4937. (c) Sodeoka, M.; Sasai, H.; Shibasaki,
M. Tetrahedron Lett. 1995, 36, 1067.
(5) Porco, J. A., Jr.; Schoenen, F. J.; Stout, T. J.; Clardy, J.; Schreiber,
S. L. J. Am. Chem. Soc. 1990, 112, 7410.
(12) Dauben, W. G.; Dinges, J.; Smith, T. C. J. Org. Chem. 1993, 58,
7635.
(6) (a) Ovaska, T. V.; Roark, J. L.; Shoemaker, C. M. Tetrahedron Lett.
1998, 39, 5705. (b) Ovaska, T. V.; Roses, J. B. Org. Lett. 2000, 2, 2361.
(7) For an early report on this sequence, see: Marvell, E. N.; Titterington,
D. Tetrahedron Lett. 1980, 2123.
(13) (a) McMills, M. C.; Zhuang, L.; Wright, D. L.; Watt, W.
Tetrahedron Lett. 1994, 35, 8311. (b) Page, P. C. B.; Jennens, D. C.;
Mcfarland, H. Tetrahedron Lett. 1997, 38, 6913. (c) Rigby, J. H.; Niyaz,
N. M.; Short, K.; Heeg, M. J. J. Org. Chem. 1995, 60, 7720.
10.1021/ol006823a CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/15/2000