ORGANIC
LETTERS
2002
Vol. 4, No. 10
1779-1781
Total Synthesis of (−)-Lasubine II by the
Conjugate Addition and Intramolecular
Acylation of an Amino Ester with an
Acetylenic Sulfone
Thomas G. Back* and Michael D. Hamilton
Department of Chemistry, UniVersity of Calgary, Calgary, Alberta, Canada T2N 1N4
Received March 9, 2002
ABSTRACT
The conjugate addition of methyl (S)-(2-piperidyl)acetate (3) to 2-(3,4-dimethoxyphenyl)-1-(p-toluenesulfonyl)ethyne (4), followed by LDA-promoted
intramolecular acylation, stereoselective reduction, and desulfonylation, afforded (−)-lasubine II.
Unsaturated sulfones have proven to be versatile synthetic
reagents.1 For example, the activating effects of the sulfone
moiety enable these compounds to undergo conjugate ad-
ditions, cycloadditions, and deprotonation and alkylation of
the corresponding R-anions. Moreover, the sulfone group can
be removed at the end of a synthetic sequence by a variety
of reductive, alkylative, or oxidative methods.2 We recently
reported the synthesis of various types of nitrogen hetero-
cycles by conjugate additions of cyclic or acyclic secondary
amines bearing â- or γ-chloro substituents to acetylenic
sulfones, followed by intramolecular alkylation3 (Scheme 1).
This methodology has been successfully applied to the
enantioselective total synthesis of several dendrobatid alka-
loids, including indolizidines (-)-167B, (-)-209D, (-)-
209B, and (-)-207A.3b The decahydroquinoline (-)-
pumiliotoxin C was obtained by a similar cyclization
employing an exocyclic primary amine as the nucleophile,
followed by intramolecular acylation of the resulting enamine
(Scheme 1).4 We now report a new variation of this protocol
that provides a concise synthesis of the quinolizidine alkaloid
(-)-lasubine II (1). Both 1 and several other quinolizidine
alkaloids,5 including (-)-lasubine I (the 10-epi derivative
of 1), and their respective 3,4-dimethoxycinnamate esters
(+)-subcosine II and I have been isolated from plants of the
Lythraceae family.6 Whereas numerous racemic syntheses
* To whom correspondence should be addressed. Tel.: (403) 220-6256.
Fax: (403) 289-9488.
(1) For a general review of sulfones, see: (a) Simpkins, N. S. Sulphones
in Organic Synthesis; Pergamon Press: Oxford, 1993. (b) For acetylenic
and allenic sulfones, see: Back, T. G. Tetrahedron 2001, 57, 5263. (c) For
vinyl sulfones, see: Simpkins, N. S. Tetrahedron 1990, 46, 6951. (d) For
dienyl sulfones, see: Ba¨ckvall, J.-E.; Chinchilla, R.; Na´jera, C.; Yus, M.
Chem. ReV. 1998, 98, 2291.
(4) Back, T. G.; Nakajima, K. J. Org. Chem. 1998, 63, 6566.
(5) For selected reviews of quinolizidine alkaloids, see: (a) Howard, A.
S.; Michael, J. P. In The Alkaloids; Brossi, A., Ed.; Academic Press:
Orlando, 1986; Vol. 28, Chapter 3. (b) Herbert, R. B. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1987;
Vol. 3, Chapter 6. (c) Kinghorn, A. D.; Balandrin, M. F. In Alkaloids:
Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New
York, 1987; Vol. 2, Chapter 3. (d) Michael, J. P. Nat. Prod. Rep. 2001, 18,
520. See also earlier reviews by this author in this series, as cited therein.
(2) For a review of desulfonylation, see: Na´jera, C.; Yus, M. Tetrahedron
1999, 55, 10547.
(3) (a) Back, T. G.; Nakajima, K. Org. Lett. 1999, 1, 261. (b) Back, T.
G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543.
10.1021/ol0258482 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/23/2002