ORGANIC
LETTERS
2013
Vol. 15, No. 1
132–135
Total Syntheses of (()-r-Lycorane and
(()-1-Deoxylycorine
Yong-Geun Jung, Sang-Choul Lee, Hyun-Kyu Cho, Nitin B. Darvatkar, Ji-Young Song,
and Cheon-Gyu Cho*
Department of Chemistry, Hanyang University, Seoul 133-791, Korea
Received November 15, 2012
ABSTRACT
New synthetic routes to (()-R-lycorane and (()-1-deoxylycorine were exploited. The endo-cycloadduct of 3,5-dibromo-2-pyrone with styrene-type
dienophile provided the pivotal intermediate for the syntheses of the titled natural products.
Lycorine (1) is a toxic crystalline alkaloid present in
a number of Amaryllidaceae plant species that include
Lycoris, Pancratium, Narcissus, Galanthus, Zephyranthes,
and Haemanthus.1 Bearing a pyrrolo[de]phenanthridine
common framework (Figure 1),2 lycorine and its conge-
neric natural compounds have many important biological
activities ranging from the inhibition of ascorbic acid bio-
synthesis to the prevention of cyanide-insensitive respiration
to the inhibition of growth and cell division in higher
plants.3 Because of their potentially useful bioactivities,
lycorine alkaloids have been the targets of interest, along
with other Amaryllidaceae small molecule constituents
such as trans-dihydronarciclasin and pancratistatin.4
(1) Cherkasov, O. A.; Tolkachev, O. N. In Narcissus and Daffodil;
Hanks, G., Ed.; CRC Press: Boca Raton, 2002; p 242.
(2) (a) Lewis, J. R. Nat. Prod. Rep. 1994, 11, 329. (b) Cook, J. W.;
Loudon, J. D. In The Alkaloids; Manske, R. H. F., Holmes, H. L., Eds.;
Academic Press: New York, 1952; Vol. 2, p 331.
(3) (a) Lamoral-Theys, D.; Decastecker, C.; Mathieu, V.; Dubois, J.;
Kornienko, A.; Kiss, R.; Evidente, A.; Pottier, L. Mini Rev. Med. Chem.
2010, 10, 41. (b) Liu, J.; Li, Y.; Tang, L.-J.; Zhang, G.-P.; Hu, W.-X.
Biomed. Pharmacother. 2007, 61, 229. (c) Liu, J.; Hua, W.-X.; He, L.-F.;
Ye, M.; Li, Y. FEBS Lett. 2004, 578, 245. (d) Ghosal, S.; Saini, K. S.;
Razdan, S. Phytochemistry 1985, 24, 2141.
(4) (a) Evidente, A.; Kornienko, A. Phytochem. Rev. 2009, 8, 449.
(b) Kornienko, A.;Evidente, A. Chem. Rev. 2008, 108, 1982. (c) Evidente,
A.; Kireev, A. S.; Jenkis, A. R.; Romero, A. E.; Steelant, W. F. A.; Van
Slambrouck, S.; Kornienko, A. Planta Med. 2009, 75, 501. (d) Lamoral-
Theys, D.; Andolfi, A.; Van Goietsenoven, G.; Cimmino, A.; Le Calve,
Figure 1. Selected pyrrolo[de]phenanthridine natural alkaloid.
ꢀ
ꢀ
B.; Wauthoz, N.; Megalizzi, V.; Gras, T.; Bruyere, C.; Dubois, J.;
Mathieu, V.; Kornienko, A.; Kiss, R.; Evidente, A. J. Med. Chem.
2009, 52, 6244.
Many synthetic studies were then followed,5 leading to
the development of various innovative synthetic strategies
(5) (a) Yamada, K.-i.; Yamashita, M.; Sumiyoshi, T.; Nishimura, K.;
Tomioka, K. Org. Lett. 2009, 11, 1631. (b) Schultz, A. G.; Holoboski,
M. A.; Smyth, M. S. J. Am. Chem. Soc. 1996, 118, 6210. (c) Hoshino, O.;
Ishizaki, M.; Kamei, K.; Taguchi, M.; Nagao, T.; Iwaoka, K.; Sawaki,
S.; Umezawa, B.; Iitaka, Y. J. Chem. Soc., Perkin Trans. 1 1995, 571.
(d) Boeckman, R. K., Jr.; Goldstein, S. W.; Walters, M. A. J. Am. Chem.
Soc. 1988, 110, 8250. (d) Martin, S. F.; Tu, C.-y. J. Org. Chem. 1981, 46,
3764. (e) Umezawa, B.; Hoshino, O.; Sawaki, S.; Sashida, H.; Mori, K.
Heterocycles 1979, 12, 1475. (f) Møller, O.; Steinberg, E.-M.; Torssell, K.
Acta Chem. Scand., Sect. B 1978, 32, 98. (g) Tsuda, Y.; Sano, T.; Taga, J.;
Isobe, K.; Toda, J.; Irie, H.; Tanaka, H.; Takagi, S.; Yamaki, M.;
Murata, M. J. Chem. Soc., Chem. Commun. 1975, 933.
(6) (a) Jung, Y.-K.; Kang, H.-U.; Cho, H.-K.; Cho, C.-G. Org. Lett.
2011, 13, 5890. (b) Chang, J. H.; Kang, H.-U.; Jung, I.-H.; Cho, C.-G.
Org. Lett. 2010, 12, 2016. (c) Tam, N. T.; Jung, E.-J.; Cho, C.-G. Org.
Lett. 2010, 12, 2012. (d) Tam, N. T.; Cho, C.-G. Org. Lett. 2008, 10, 601.
(e) Tam, N. T.; Chang, J.; Jung, E.-J.; Cho, C.-G. J. Org. Chem. 2008, 73,
6258. (f) Shin, I.-J.; Choi, E.-S.; Cho, C.-G. Angew. Chem., Int. Ed. 2007,
46, 2303. (g) Tam, N. T.; Cho, C.-G. Org. Lett. 2007, 9, 3319. (h) Kim,
H.-Y.; Cho, C.-G. Prog. Heterocycl. Chem. 2007, 18, 1. (i) Ryu, K.; Cho,
Y.-S.; Cho, C.-G. Org. Lett. 2006, 8, 3343.
r
10.1021/ol303157b
Published on Web 12/19/2012
2012 American Chemical Society