Free-Radical Approaches to Stemoamide and
Analogues
Nicolas Bogliotti, Peter I. Dalko, and Janine Cossy*
Laboratoire de Chimie Organique, associe´ au CNRS, ESPCI,
10 rue Vauquelin, 75231, Paris Cedex 05, France
ReceiVed August 4, 2006
FIGURE 1. Stemoamide, 9a-epi-stemoamide and 9,10-bis-epi-ste-
moamide.
part of our continuing interest in the synthesis of Stemona
derivatives, we wish to report herein a short synthetic study,
which provides access to (()-stemoamide, as well as to (()-
9a-epi-stemoamide and to (()-9,10-bis-epi-stemoamide (Figure
1).
Formal Synthesis of (()-Stemoamide. The key step of the
synthesis is the construction of the lactone ring using a free
radical 5-exo-trig atom transfer cyclization of the halogeno-
ester D, which would produce compound of type C (Scheme
1). Although the relative C8/C9 stereochemistry of the cycliza-
tion could be anticipated to be trans by analogy with the
literature,11 the control of the C9a stereogenic center was
uncertain (Scheme 1).
The synthesis of stemoamide commenced with the preparation
of the monoprotected diol 3, which was synthesized from 2,3-
dihydrofuran (1), using a modified literature protocol (Scheme
2).12 The acid-catalyzed hydration of 2,3-dihydrofuran (1),
followed by the addition of vinylmagnesium bromide to the
resulting hemiacetal, afforded a mixture of diol 2 and protected
allylic alcohol 3 in 10% and 18% yield, respectively. Despite
the poor yield of protected allylic alcohol 3, the low cost of the
starting material and the reproducibility on large scale allowed
the preparation of multigram quantities of 3. Compound 3 was
then converted to the unsaturated bromoester 4 by addition of
bromoacetyl bromide in the presence of pyridine, and this latter
product was subjected to a cross-metathesis (CM) with ethyl
4-pentenoate13 (1.5 equiv) in the presence of the second
generation Grubbs’ catalyst G-II14 in refluxing CH2Cl2 to afford
Two approaches allowing access to the tricyclic stemona
backbone are presented. Both approaches rely on a free-
radical cyclization reaction as the key step. In the formal
synthesis of (()-stemoamide, the construction of the A ring
of the natural product was achieved via a 5-exo-trig radical
cyclization with atom transfer. The two diastereoisomers
issuing from this cyclization showed different reactivity while
forming the seven-membered ring of the final product. In
the second part of this study, a 7-exo-trig free radical
cyclization was realized allowing access to the (()-9,10-
bis-epi-stemoamide. This reaction was highly stereoselective
and allowed the control of three of the four contiguous
stereocenters present in the molecule.
The roots of Stemona tuberosa Lour. and related stemona
species have been used in traditional Asian folk medicine in
the treatment of respiratory diseases such as asthma, bronchitis,
petusis, and tuberculosis,1 and extracts have been utilized as
insecticides and antihelmintics.2 To date, more than 70 alkaloids
of the family of Stemonacea have been isolated, many of them
possessing an aza-azulene skeleton.3 The structurally simplest
member, (-)-stemoamide, which was isolated from Stemona
tuberosa, consists of a γ-butyrolactone fused to a pyrrolo[1,2a]-
azepine core and possesses four contiguous stereocenters (Figure
1).4 Although a considerable amount of work has been devoted
to the synthesis of both racemic5 and natural (-)-stemoamide,6
only little attention has been paid to the preparation of
analogues.7,8 Recently, Schultz et al.9 and our group10 have
reported two short syntheses of 9,10-bis-epi-stemoamide. As
(6) (a) Williams, D. R.; Reddy, J. P.; Amato, S. Tetrahedron Lett. 1994,
35, 6417- 6420. (b) Kinoshita, A.; Mori, M. J. Org. Chem 1996, 61, 8356-
8357. (c) Kinoshita, A.; Mori, M. Heterocyles 1997, 46, 287-299. (d)
Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295-4303. (e) Sibi,
M. P.; Subramanian, T. Synlett 2004, 7, 1211-1214. (f) Olivo, H. F.; Tovar-
Miranda, R.; Barraga´n, E. J. Org. Chem. 2006, 71, 3287-3290.
(7) Gurjar, M. K.; Reddy, D. S. Tetrahedron Lett. 2002, 43, 295-298.
(8) Recent synthetic studies: (a) Pyne, S. G.; Davis, A. S.; Gates, N. J.;
Hartley, J. P.; Lindsay, K. B.; Machan, T.; Tang, M. Synlett 2004, 15, 2670-
2680. (b) Alibe´s, R.; Blanco, P.; Casas, E.; Closa, M.; de March, P.;
Figueredo, M.; Font, J.; Sanfeliu, E.; Alvarez-Larena, A. J. Org. Chem.
2005, 70, 3157-3167.
(9) Khim, S.-K.; Schultz, A. G. J. Org. Chem. 2004, 69, 7734-7736.
(10) Bogliotti, N.; Dalko, P. I.; Cossy, J. Synlett 2005, 349-351.
(11) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2000, 122, 6496-6497.
(12) McClure, C. K.; Jung, K.-Y. J. Org. Chem. 1991, 56, 867-871.
(13) Winter, M.; Na¨f, F.; Furrer, A.; Pickenhagen, W.; Giersch, W.;
Meister, A.; Willhalm, B.; Thommen, W.; Ohloff, G. HelV. Chim. Acta
1979, 62, 135-139.
(1) Adams, M.; Pacher, T.; Greger, H.; Bauer, R. J. Nat. Prod. 2004,
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(2) Brem, B.; Seger, C.; Pacher, T.; Hofer, O.; Vajrodaya, S.; Greger,
H. J. Agric. Food. Chem. 2002, 50, 6383-6388.
(3) (a) Jiang, R.-W.; Hon, P.-M.; Zhou, Y.; Chan, Y.-M.; Xu, Y.-T.;
Xu, H.-X.; Greger, H.; Shaw, P.-C.; But, P. P.-H. J. Nat. Prod. 2006, 69,
749-754. (b) Lin, L.-G.; Zhong, Q.-X.; Cheng, T.-Y.; Tang, C.-P.; Ke,
C.-Q.; Lin, G.; Ye, Y. J. Nat. Prod. 2006, 69, 1051-1054.
(4) Isolation: Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571-
576.
(5) (a) Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69, 2063-
2070. (b) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119, 3409-3410.
10.1021/jo061628g CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/16/2006
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J. Org. Chem. 2006, 71, 9528-9531