ORGANIC
LETTERS
2
003
Vol. 5, No. 19
499-3502
Bridgehead Arylation: A Direct Route to
Advanced Intermediates for the
3
Synthesis of C-20 Diterpene Alkaloids
,†
‡
Craig M. Williams* and Lewis N. Mander
Chemistry Department, School of Molecular and Microbial Sciences, UniVersity of
Queensland, St. Lucia, 4072, Queensland, Australia, and Research School of
Chemistry, Australian National UniVersity, Canberra, ACT, Australia
Received July 16, 2003
ABSTRACT
Rapid access to the ABCE ring system of the C20 diterpene alkaloids was achieved by silver(I)-promoted intramolecular Friedel−Crafts arylation
of a functional group-specific 5-bromo-3-azabicyclo[3.3.1]nonane derivative.
Diterpene alkaloids are distributed widely throughout the
plant world and have been isolated from a variety of genera
extraordinary series of biogenetically modeled total syntheses
of the more complex C19 derivatives as well as a number of
related C20 analogues. Equally creative endeavors leading
7
(
Aconitum, Delphinium, Consolida, Thalictrum, and Spi-
1,2
raea). Although these alkaloids display a range of biologi-
cal activity, it is their structurally congested skeletons that
to the simpler C20 alkaloids have been described by Masam-
3
8
9
10
une, Fukumoto, and Nagata. The highly bridged structure
1
1
12
13
have attracted and continue to command considerable interest
of the kobusine (1)-hetisine (2) family of alkaloids
(Figure 1) also poses an alluring target for synthetic chemists,
prompting the development of ingenious strategies and new
4,5
6
from natural product and synthetic chemists. Over a period
of two to three decades, the Wiesner group reported an
1
4-16
methodology.
These recent reports prompted us to
†
University of Queensland.
Australian National University.
‡
(
1) Pelletier, S. W.; Page, S. W. Nat. Prod. Rep. 1986, 3, 451-475. (b)
(6) Barker, D.; McLeod, M. D.; Brimble, M. A.; Savage, G. P.
Tetrahedron Lett. 2002, 43, 6019-6022. (b) Barker, D.; Brimble, M. A.;
McLeod, M. D.; Savage, G. P.; Wong, D. J. J. Chem. Soc., Perkin Trans.
1 2002, 924-931. (c) Baillie, L. C.; Bearder, J. R.; Whiting, D. A. J. Chem.
Soc., Chem. Commun. 1994, 2487-2488. (d) Kraus, G. A.; Dneprovskaia,
E. Tetrahedron Lett. 1998, 39, 2451-2454.
Yunusov, M. S. Nat. Prod. Rep. 1993, 10, 471-486. (c) Atta-ur-Rahman;
Choudhary, M. I. Nat. Prod. Rep. 1999, 16, 619-635.
(2) Pelletier, S. W.; Mody, N. V. In The Alkaloids; Manske, R. H. F.,
Rodrigo, R. G. A., Eds.; Academic Press: New York, 1981; Vol. 18, pp
9-216. (b) Wang, F.-P.; Liang, X.-T. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1992; Vol. 42, pp 151-247.
3) Jacyno, J. M. In Chemistry and Toxicology of DiVerse Classes of
Alkaloids; Blum, M., Ed.; Alaken, Inc.: Ft. Collins, CO, 1996; p 301.
4) Selection of recent reports: Mericli, A. H.; Mericli, F.; Seyhan, G.
V.; Bahar, M.; Desai, H. K.; Ozcelik, H.; Ulubelen, A. Pharmazie 2002,
9
(7) Wiesner, K. Tetrahedron 1985, 41, 485-497.
(
(8) Masamune, S. J. J. Am. Chem. Soc. 1964, 86, 291.
(9) (a) Ihara, M.; Suzuki, M.; Fukumoto, K.; Kametani, T.; Kabuto, C.
J. Am. Chem. Soc. 1988, 110, 1963-1964. (b) Ihara, M.; Suzuki, M.;
Fukumoto, K.; Kabuto, C. J. Am. Chem. Soc. 1990, 112, 1164-1171.
(10) Nagata, W.; Narisada, M.; Wakabayashi, T.; Sugasawa, T. J. Am.
Chem. Soc. 1967, 89, 1499-1504 and references therein.
(11) Okamoto, T.; Natsume, M.; Zenda, H.; Kamata, S. Chem. Pharm.
Bull. 1962, 10, 883.
(12) Varughese, K. I.; Pelletier, S. W. J. Nat. Prod. 1984, 47, 470-473.
(13) Bessonova, I. A.; Saidkhodzhaeva, Sh. A. Chem. Nat. Compd. 2000,
36, 419-477.
(14) Kwak, Y.-S.; Winkler, J. D. J. Am. Chem. Soc. 2001, 123, 7429-
7430.
(
5
5
7, 761-762. (b) Wang, F.-P.; Peng, C.-S.; Yu, K.-B. Tetrahedron 2000,
6, 7443-7446. (c) He, H.-P.; Shen, Y.-M.; Zhang, J.-X.; Zuo, G.-Y.; Hao,
X.-J. J. Nat. Prod. 2001, 64, 379-380. (d) Grandez, M.; Madinaveitia, A.;
Gav ´ı n, J. A.; Alva, A.; de la Fuente, G. J. Nat. Prod. 2002, 65, 513-516.
(
e) Saidkhodzhaeva, Sh. A.; Bessonova, I. A.; Abdullaev, N. D. Chem. Nat.
Compd. 2001, 37, 466-469.
(5) Selection of recent reports: (a) Xu, L.; Chen, Q.-H.; Wang, F.-P.
Tetrahedron 2002, 58, 4267-4271. (b) Chen, Q.-H.; Xu, L.; Wang, F.-P.
Tetrahedron 2002, 58, 9431-9444. (c) Wang, F.-P. Chen, Q.-H.; Li, Z.-
B.; Li, B.-G. Chem. Pharm. Bull. 2001, 49, 689-694.
(15) Muratake, H.; Natsume, M. Tetrahedron Lett. 2002, 43, 2913-2917.
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0.1021/ol0353060 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/28/2003