ORGANIC
LETTERS
2012
Vol. 14, No. 3
852–854
Highly Enantioselective Total Synthesis of
(+)-Isonitramine
Yohan Park,† Young Ju Lee,‡ Suckchang Hong,‡ Myungmo Lee,‡ and
Hyeung-geun Park*,‡
College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749,
Korea, and Research Institute of Pharmaceutical Sciences and College of Pharmacy,
Seoul National Univerisity, Seoul 151-742, Korea
Received December 10, 2011
ABSTRACT
A new efficient enantioselective synthetic method of (þ)-isonitramine is reported. (þ)-Isonitramine was obtained in 12 steps (98% ee and 43%
overall yield) from δ-valerolactam via enantioselective phase-transfer catalytic alkylation, Dieckman condensation, and diastereoselective
reduction as key steps.
There are a number of biologically important natural
products1 containing optically active 2-azaspirocycle
structures, such as polyzonimine,1a nitropolyzona-
mine,1a horsfiline,1b and spirotryprostatin B.1c Among
these compounds, Nitraria alkaloids,2 (þ)-nitramine (1),
(þ)-isonitramine (2), and (ꢀ)-sibirine (3), have chiral
quaternary carbon centers on the 2-azaspiro[5,5]undecane-
7-ol skeletons. The structural similarity with the neurotoxic
(ꢀ)-histrionicotoxin has faciliated the development of effi-
cient synthetic routes of Nitraria alkaloids (Figure 1).
Recently, it was reported that the extracts of Nitraria plants
have antiproliferative effects on cancer cell lines through
the apoptosic pathway.3
† Inje University.
‡ Seoul National University.
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Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8, 2027. (c) Shanmugam,
P.; Viswambharan, B.; Madhavan, S. Org. Lett. 2007, 9, 4095.
(2) For a recent review on Nitraria alkaloid, see: Wanner, J. W.;
Koomen, G. J. In Studies in Natural Products Chemistry: Stereoselectivity
in Synthesis and Biosynthesis of Lupine and Nitraria Alkaloids; Atta-ur-
Rahman, Ed.; Elsevier: Amsterdam, 1994; p 731 and references therein.
(3) Boubaker, J.; Bhouri, W.; Ben Sghaier, M.; Bouhlel, I.; Skandrani,
I.; Ghedira, K.; Chekir-Ghedira, L. Cancer Cell International 2011, 11, 37.
(4) (a) McCloskey, P. J.; Schultz, A. G. Heterocycles 1987, 25, 437.
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Iwata, C. J. Chem. Soc., Chem. Commun. 1991, 1409. (e) Westermann,
B.; Scharmann, G.; Kortmann, J. Tetrahedron: Asymmetry 1993, 4,
2119. (f) Keppens, M.; De Kimpe, N. J. Org. Chem. 1995, 60, 3916. (g)
Kim, D.; Choi, W. J.; Hong, J. Y.; Park, I. Y.; Kim, Y. B. Tetrahedron
Lett. 1996, 37, 1433. (h) Yamane, T.; Ogasawara, K. Synlett 1996, 925.
(i) Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997,
119, 7879. (j) Francois, D.; Lallemand, M. C.; Selkti, M.; Tomas, A.;
Kunesch, N.; Husson, H. P. Angew. Chem., Int. Ed. 1998, 37, 104. (k)
Koreeda, M.; Wang, Y.; Zhang, L. Org. Lett. 2002, 4, 3329. (l) Alonso,
E. R.; Tehrani, K. A.; Boelens, M.; De Kimpe, N. Synlett 2005, 11, 1726.
Figure 1. Nitraria alkaloids.
Although numerous enantioselective synthetic methods
for Nitraria alkaloids have been reported thus far,4 most of
these approaches employed chiral auxiliaries,4a,d,j chiral
substrates,4b,g or enzymatic resolution,4e,f,h,l which cannot
be readily applied to large scale production. In addition,
r
10.1021/ol2033042
Published on Web 01/17/2012
2012 American Chemical Society