ORGANIC
LETTERS
2009
Vol. 11, No. 22
5354-5356
Total Synthesis of (-)-Huperzine A
Takahiro Koshiba, Satoshi Yokoshima, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received September 28, 2009
ABSTRACT
The total synthesis of (-)-huperzine A was accomplished in 23 steps from a commercially available anhydride. Our synthetic route features
a facile construction of the bicyclo[3.3.1] skeleton equipped with proper functionalities to introduce the remaining substructures.
Huperzine A (1) was isolated from Huperzia serrata by Liu
and co-workers.1 It was found to exhibit a potent, selective,
and reversible inhibitory activity against acetylcholinesterase
(AchE). Because of this notable profile, huperzine A has
drawn considerable attention as a promising therapeutic agent
for Alzheimer’s disease and is currently undergoing extensive
clinical trials.2 It is also interesting to note that huperzine A
has recently been reported to show neuroprotective properties
against glutamate-induced cell death.3 From the synthetic
point of view, the structure of huperzine A is quite fascinating
in that it contains a bicyclo[3.3.1] skeleton fused with a
pyridone moiety as well as an ethylidene moiety. Thus,
considerable attention has been focused on the total synthesis
of this closely packed molecule. Kozikowski and co-workers
have established two synthetic routes, featuring either a
tandem Michael-aldol reaction or a palladium-catalyzed
annulation as the key step to build the bicyclo[3.3.1]
skeleton.4,5 Several research groups have applied these two
strategies to asymmetric synthesis using chiral catalysts or
reagents.6 More recent syntheses involving a manganese-
mediated cyclization and an intramolecular Heck reaction
have been developed to assemble the bicyclo[3.3.1] skel-
eton.7,8 Herein we report the total synthesis of (-)-huperzine
A, featuring a unique construction of the bicyclo[3.3.1]
skeleton.
Our retrosynthetic analysis of huperzine A (1) is shown
in Scheme 1. We envisaged that the ethylidene and the
(4) (a) Xia, Y.; Kozikowski, A. P. J. Am. Chem. Soc. 1989, 111, 4116.
(b) Kozikowski, A. P.; Campiani, G.; Aagaard, P.; McKinney, M. J. Chem.
Soc., Chem. Commun. 1993, 860
(5) Independently, Qian and Ji disclosed the synthesis of huperzine A,
which is almost the same as that reported by the Kozikowski group in 1989.
.
Qian, L.; Ji, R. Tetrahedron Lett. 1989, 30, 2089
.
(6) Asymmetric syntheses using the tandem Michel-aldol reaction: (a)
Yamada, F.; Kozikowski, A. P.; Reddy, E. R.; Pang, Y.-P.; Miller, J. H.;
McKinney, M. J. Am. Chem. Soc. 1991, 113, 4695. (b) Kaneko, S.; Yoshino,
T.; Katoh, T.; Terashima, S. Heterocycles 1997, 46, 27. (c) Kaneko, S.;
Yoshino, T.; Katoh, T.; Terashima, S. Tetrahedron 1998, 54, 5471. (d) Pan,
Q.-B.; Ma, D.-W. Chin. J. Chem. 2003, 21, 793. Asymmetric syntheses
using the palladium-catalyzed annulation: (e) Kaneko, S.; Yoshino, T.;
Katoh, T.; Terashima, S. Tetrahedron: Asymmetry 1997, 8, 829. (f)
Chassaing, C.; Haudrechy, A.; Langlois, Y. Tetrahedron Lett. 1999, 40,
8805. (g) Haudrechy, A.; Chassaing, C.; Riche, C.; Langlois, Y. Tetrahedron
2000, 56, 3181. (h) He, X.-C.; Wang, B.; Yu, G.; Bai, D. Tetrahedron:
Asymmetry 2001, 12, 3213.
(1) (a) Liu, J.-S.; Zhu, Y.-L.; Yu, C.-M.; Zhou, Y.-Z.; Han, Y.-Y.; Wu,
F.-W.; Qi, B.-F. Can. J. Chem. 1986, 64, 837. (b) Ayer, W. A.; Browne,
L. M.; Orszanska, H.; Valenta, Z.; Liu, J.-S. Can. J. Chem. 1989, 67, 1538.
(2) For reviews of huperzine A, see: (a) Kozikowski, A. P.; Tu¨ckmantel,
W. Acc. Chem. Res. 1999, 32, 641. (b) Bai, D. Pure Appl. Chem. 2007, 79,
469.
(3) (a) Peng, Y.; Jiang, L.; Lee, D.-Y. W.; Schachter, S.-C.; Ma, Z.;
Lemere, C. A. J. Neurosci. Res. 2006, 84, 903. (b) Wang, R.; Tang, X. C.
Neurosignals 2005, 14, 71. (c) Zhang, H. Y.; Yan, H.; Tang, X. C. Neurosci.
Lett. 2004, 360, 21. (d) Zhang, H. Y.; Liang, Y. Q.; Tang, X. C.; He, X. C.;
Bai, D. L. Neurosci. Lett. 2002, 317, 143. (e) Gordon, R. K.; Nigam, S. V.;
Weitz, J. A.; Dave, J. R.; Doctor, B. P.; Ved, H. S. J. Appl. Toxicol. 2001,
21, S47.
(7) (a) Lee, I. Y. C.; Jung, M. H.; Lee, H. W.; Yang, J. Y. Tetrahedron
Lett. 2002, 43, 2407. (b) Lucey, C.; Kelly, S. A.; Mann, J. Org. Biomol.
Chem. 2007, 5, 301
.
(8) A radical-mediated construction of the bicyclo[3.3.1] skeleton has
also been reported: (a) Ward, J.; Caprio, V. Tetrahedron Lett. 2006, 47,
553. (b) Ward, J.; Caprio, V. Heterocycles 2009, 79, 791
.
10.1021/ol9022408 CCC: $40.75
Published on Web 10/29/2009
2009 American Chemical Society