pubs.acs.org/joc
Moracea plant families. To date, more than 60 structurally
Asymmetric Synthesis of (R)-Antofine
and (R)-Cryptopleurine via Proline-Catalyzed
Sequential r-Aminoxylation and
Horner-Wadsworth-Emmons
related phenanthroindolizidine and phenanthroquinolizidine
alkaloids together with their seco derivatives and N-oxides
have been isolated from various natural sources.1 Among
them, (R)-tylophorine (1), (R)-antofine (2), and (R)-crypto-
pleurine (3) are well-known representative members (Figure 1).
These alkaloids possess diverse biological properties, includ-
ing antitumor, antiviral, antiamoebic, antibacterial, antiinflam-
matory, and antifungal activities.1 Among these interesting
biological activities, the most intriguing property is the
profound cytotoxic activity against various cancer cell lines.2
In the early 1960s, tylocrebrine (4), a positional isomer of
tylophorine (1), was advanced to clinical trials but failed due
to central nervous system (CNS) toxicity, manifested by
ataxia and disorientation.3 This disappointing clinical result
discouraged further consideration of these alkaloids for drug
development. However, medicinal interest in these alkaloids
was revived in the 1990s. In the National Cancer Institute’s
60 tumor cell line assay, a number of these compounds showed
potent and uniform activity against 54 human tumor cell
lines with mean GI50 < 10-8 M.4 Moreover, their mode of
action appears to be different from that of other known
anticancer compounds.5
Olefination of Aldehyde
Mingbo Cui, Hongjian Song, Anzheng Feng, Ziwen Wang,
and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry,
Research Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China
wang98h@263.net; wangqm@nankai.edu.cn
Received August 6, 2010
Because of their remarkable bioactivities coupled with
extremely limited supply and interesting structures, these
alkaloids have attracted much attention from the synthetic
community. In the past decade, a number of impressive efforts
toward the synthesis of these alkaloids have appeared in the
literature.1,2d,i,6 Because the chiral centers of these alkaloids
are located r to the nitrogen atom, r-amino acids and their
derivatives such as proline, glutamic acid, aminoadipate,
pyroglutamate, and D-serine methyl ester hydrochloride have
been widely used as the sources of the chiral center in the
asymmetric synthesis of these alkaloids.2i,6c,i,7 Apart from
that, a few other strategies have been used in asymmetric syn-
thesis of these alkaloids, including a chiral auxiliary approach,8
a chiral allylic alcohol,6b enantioselective catalysis for intra-
molecular alkene carboamination,6c and enantioselective
Naturally occurring phenanthroindolizidine alkaloids (R)-
antofine and phenanthroquinolizidine alkaloids (R)-crypto-
pleurine have been synthesized in high optical purity via
proline-catalyzed sequential r-aminoxylation and Horner-
Wadsworth-Emmons olefination of aldehyde. Both enantio-
pure forms of proline are commercially available, and
thus, in principle, both isomers of antofine and cryptopleur-
ine can be accessed with the new method.
The phenanthroindolizidine and phenanthroquinolizidine
alkaloids are structurally related groups of pentacyclic nat-
ural products primarily found in the Asclepiadaceae and
(3) Suffness, M.; Douros, J. In Anticancer Agents Based on Natural
Product Models; Cassady, J. M., Douros, J. D., Eds.; Academic Press:
London, 1980; Med. Chem. Vol. 16, pp 465-487.
(4) The 60 cell line NCI test data, along with in vivo data, can be accessed
jsp.
(1) Reviews: (a) Li, Z.; Jin, Z.; Huang, R. Synthesis 2001, 2365–2378.
(b) Gellert, E. J. Nat. Prod. 1982, 45, 50–73. (c) Bick, I. R. C.; Sinchai, W. The
Alkaloids 1981, 19, 193–220. (d) Govindachari, T. R.; Viswanathan, N.
Heterocycles 1978, 11, 587–613. (d) Chemler, S. R. Curr. Bioact. Compd.
2009, 5, 2–19.
(5) Gao, W.; Lam, W.; Zhong, S.; Kaczmarek, C.; Baker, D. C.; Cheng,
Y. C. Cancer Res. 2004, 64, 678–688.
(6) For the most recent examples, see: (a) Kim, S.; Lee, J.; Lee, T.; Park,
H. G.; Kim, D. Org. Lett. 2003, 5, 2703–2706. (b) Kim, S.; Lee, T.; Lee, E.;
Lee, J.; Fan, G. J.; Lee, S. K.; Kim, D. J. Org. Chem. 2004, 69, 3144–3149.
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Chem. 2007, 72, 4886–4891. (e) Zeng, W.; Chemler, S. R. J. Org. Chem. 2008,
73, 6045–6047. (f) McIver, A.; Young, D. D.; Deiters, A. Chem. Commun.
2008, 39, 4750–4752. (g) Yamashita, S.; Kurono, N.; Senboku, H.; Tokuda,
M.; Orito, K. Eur. J. Org. Chem. 2009, 1173–1180. (h) Rossiter, L. M.; Slater,
M. L.; Giessert, R. E.; Sakwa, S. A.; Herr, R. J. J. Org. Chem. 2009, 74, 9554–
9557. (i) Stoye, A.; Opatz, T. Org. Lett. 2010, 12, 2140–2141. (j) Yang, X. M.;
Shi, Q.; Bastow, K. F.; Lee, K. H Org. Lett. 2010, 12, 1416–-1419.
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(2) (a) Strk, D.; Lykkeberg, A. K.; Christensen, J. B.; Budnik, A.; Abe, F.;
Jaroszewski, J. W. J. Nat. Prod. 2002, 65, 1299–1302. (b) Luo, Y.; Liu, Y.;
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Published on Web 09/16/2010
DOI: 10.1021/jo101510x
r
2010 American Chemical Society