Expedient Syntheses of Antofine and Cryptopleurine via Intramolecular 1,3-Dipolar Cycloaddition Sanghee Kim,* Yun Mi Lee, Jaekwang Lee, Taeho Lee, Ye Fu, Yanling Song, Jihee Cho, and Deukjoon Kim College of Pharmacy, Seoul National UniVersity, San 56-1, Shilim, Kwanak, Seoul 151-742, Korea pennkim@snu.ac.kr ReceiVed April 2, 2007 The practical and expedient total syntheses of the representative phenanthroindolizidine and phenan- throquinolizidine alkaloids, antofine and cryptopleurine, are described. Construction of the pyrrolidine and piperidine ring of each alkaloid was achieved by using an intramolecular 1,3-dipolar cycloaddition of an azide onto an alkene and subsequent reduction of the resulting imine and aziridine. Introduction It is now over 70 years since the phenanthroindolizidine alkaloid, tylophorine (1, Figure 1), was first described in the literature. 1 Nowadays, numerous phenanthroindolizidine alka- loids and structurally related phenanthroquinolizidine alkaloids have been isolated from various natural sources. These penta- cyclic natural products exhibit a variety of biological effects including antitumor, antiamoebic, antibacterial, and antifungal activities. 2,3 Among these interesting biological activities, the most intriguing property is the profound cytotoxic activity against various cancer cell lines. For example, (-)-antofine ((-)-2, Figure 1) has IC 50 values in the low nanomolar range against drug-sensitive KB-3-1 and multidrug-resistant KB-V1 cancer cell lines, comparable to that of clinically employed cytotoxic drugs. 4 Because of the profound cytotoxic activity and interesting biochemical aspects, phenanthroindolizidine alkaloids together with phenanthroquinolizidine alkaloids have received significant attention as potential therapeutic leads. However, these classes of natural products have not yet been developed for clinical use. The major drawbacks to the potential therapeutic use of these compound classes are the serious central nervous side effects 5 and low water solubility. To overcome these pharmacologically unsuitable properties, more intense investiga- tions are deemed necessary from a medicinal chemical view- point. 6 * To whom correspondence should be addressed. Tel: 82-2-740-8913. Fax: 82-2-762-8322. (1) Ratnagiriswaran, A. N.; Venkatachalam, K. Indian J. Med. Res. 1935, 22, 433-441. (2) (a) Gellert, E. In Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Academic Press: New York, 1987; pp 55-132. (b) Suffness, M.; Cordell, G. A. In The Alkaloids, Chemistry and Pharmacology; Brossi, A., Ed.; Academic Press: New York, 1985; Vol. 25, pp 3-355. (3) For recent reviews, see: (a) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191-222. (b) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603-626. (c) Michael, J. P. Nat. Prod. Rep. 2004, 21, 625-649. (d) Michael, J. P. Nat. Prod. Rep. 2003, 20, 458-475. (e) Michael, J. P. Nat. Prod. Rep. 2002, 19, 719-741. (f) Michael, J. P. Nat. Prod. Rep. 2001, 18, 520-542. (g) Li, Z.; Jin, Z.; Huang, R. Synthesis 2001, 2365-2378. (4) (a) Stærk, D.; Lykkeberg, A. K.; Christensen, J.; Budnik, B. A.; Abe, F.; Jaroszewski, J. W. J. Nat. Prod. 2002, 65, 1299-1302. (b) Lee, S. K.; Nam, K.-A.; Heo, Y.-H. Planta Med. 2003, 69, 21-25. (5) Suffness, M.; Douros, J. In Anticancer Agents Based on Natural Product Models; Cassady, J. M., Douros, J. D., Eds.; Academic Press: London, 1980; pp 465-487. FIGURE 1. Chemical structures of compounds 1-3. 4886 J. Org. Chem. 2007, 72, 4886-4891 10.1021/jo070668x CCC: $37.00 © 2007 American Chemical Society Published on Web 05/25/2007