ORGANIC
LETTERS
2003
Vol. 5, No. 18
3361-3364
Total Synthesis of (−)-Stemonine
David R. Williams,* Khalida Shamim, Jayachandra P. Reddy,
George S. Amato, and Stephen M. Shaw
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405-7102
Received July 22, 2003
ABSTRACT
An enantioselective total synthesis of (−)-stemonine (1) is reported via a convergent assembly of the acyclic precursor 2. Key transformations
include a Staudinger−aza-Wittig reaction to form the central perhydroazepine ring system and an iodine-induced tandem cyclization to construct
the pyrrolidino-butyrolactone framework.
Stemona alkaloids represent a class of approximately 50
structurally novel, polycyclic metabolites isolated from
monocotyledonous plants comprising the genera of Stemona,
Croomia, and Stichoneuron.1 Chinese and Japanese folk
medicine has recorded the extensive use of extracts and
herbal teas of Stemonaceae as remedies of respiratory
diseases, including tuberculosis, and as anthelmintics.2 Dried
plant materials are utilized as powerful insecticidal materials
for treatment of livestock throughout East Asia.3 Stemonine
(1), an important secondary metabolite of Stemona japonica,
was isolated and investigated as early as 1929.4,5 However,
the characterization of relative and absolute stereochemistry
remained unresolved until the report of the X-ray crystal-
lographic study of stemonine hydrobromide hemihydrate by
Koyama and Oda in 1970.6 Progress toward the synthesis
of Stemona alkaloids was elusive and uneventful until our
account of the total synthesis of (+)-croomine in 1989.7
Recent years have been marked by achievements of sev-
eral notable total syntheses of members of this family.8
Herein we disclose the first report of the total synthesis of
(-)-stemonine (1) nearly 75 years after its initial discovery.
We have applied a thematic strategy for the preparation
of Stemona alkaloids that has sought to assemble a fully
functionalized acyclic carbon chain as a prelude to sequential,
late-stage ring closure reactions. Since each alkaloid is
characterized by the presence of a unique 1-azabicyclo[5.3.0]-
decane as an integral part of the molecular architecture, the
facile and stereocontrolled formation of this moiety is a key
issue. In the case of (-)-stemonine (1), our retrosynthetic
plan suggested a convergent construction of the acyclic
precursor 2 from optically pure butyrolactone 3 and homoal-
lylic iodide 4 (Scheme 1).
The convenient preparation of iodide 4 is summarized in
Scheme 2, utilizing known aldehyde 6.9 The nonracemic
tosylate 5 is readily available via hydroxyl protection of (R)-
(-)-methyl-3-hydroxy-2-methyl propionate followed by hy-
(1) Dahlgren, R. M. T.; Clifford, H. T.; Yeo, P. F. The Families of the
Monocotyledons. Structure EVolution and Taxonomy; Springer-Verlag:
Berlin, 1985.
(2) (a) Sakata, K.; Aoki, K.; Chang, C.-F., Sakurai, A.; Tamura, S.;
Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457. (b) Shinozaki, H.; Ishida,
M. Brain. Res. 1985, 334, 33. (c) Ye, Y.; Qin, G.-W.; Xu, R.-S.
Phytochemistry 1994, 37, 1205.
(3) For recent reviews, see: (a) Pilli, R. A.; Ferriera de Oliviera, M.
Nat. Prod. Rep. 2000, 17, 117. (b) Ye, Y.; Qin, G.-W.; Xu, R.-S. J. Nat.
Prod. 1994, 57, 665.
(7) Williams, D. R.; Brown, D. L.; Benbow, J. M. J. Am. Chem. Soc.
1989, 111, 1923
(8) (a) Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001,
3, 2721. (b) Padwa, A.; Gin, J. D. Org. Lett. 2002, 4, 1515. (c) Kende, A.
S.; Hernando, J. I. M.; Milbank, J. B. J. Tetrahedron 2002, 58, 61. (d)
Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc. 2002, 124, 14848
(e) Kende, A. S.; Smalley, T. L.; Huang, H. J. Am. Chem. Soc. 1999, 121,
7431 and refs cited therein.
(4) Suzuki, K. J. Pharm. Soc. Jpn. 1929, 49, 457.
(5) Suzuki, K. J. Pharm. Soc. Jpn. 1931, 51, 419
(6) Koyama, H.; Oda, K. J. Chem. Soc. B. 1970, 1330.
(9) White, J. D.; Reddy, N. G.; Spessard, G. O. J. Am. Chem. Soc. 1988,
110, 1624.
10.1021/ol035368q CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/13/2003