ORGANIC
LETTERS
2000
Vol. 2, No. 11
1625-1627
Regiocontrol in an Intramolecular
Schmidt Reaction: Total Synthesis of
(+)-Aspidospermidine
Rajesh Iyengar, Klaas Schildknegt, and Jeffrey Aube´*
Department of Medicinal Chemistry, The UniVersity of Kansas,
Lawrence, Kansas 66045-2506
Received April 7, 2000
ABSTRACT
A total synthesis of (+)-aspidospermidine (1) is described, featuring an intramolecular Schmidt reaction as the key step. The effects of
stereochemistry and protecting group status on the regio- and chemoselectivity of this reaction were examined.
The intramolecular Schmidt reaction is a versatile tool for
the synthesis of fused, nitrogen-containing heterocycles.1 As
part of a program to explore the use of this reaction in total
synthesis, we chose the pentacyclic alkaloid aspidospermi-
dine (1) as an initial entry into this interesting class of natural
products.2 The total synthesis of (()-aspidospermine by Stork
and Dolfini was an important achievement in alkaloid
chemistry.3 This work established that all of the stereocenters
in the final target were responsive to a single, nonepimer-
izable quaternary center in ketone 2 (C-22, Scheme 1). We
sought to utilize this finding in an asymmetric approach that
would focus on the enantioselective formation of this center.4
Further motivation was provided by the opportunity to
examine a challenging intramolecular Schmidt reaction, in
which selectivity for insertion into only one of two regioi-
someric ketones is required for the preparation of a key
tricyclic lactam 4. In this paper, we describe a route to (+)-
aspidospermidine (1) using these general strategies that
additionally uncovered some unexpected features of intramo-
lecular Schmidt chemistry.
(1) (a) Aube´, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965-
8966. (b) Pearson, W. H.; Schkeryantz, J. M. Tetrahedron Lett. 1992, 33,
5291-5294. (c) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.; Fang,
W.-k.; Blickensdorf, J. D. J. Am. Chem. Soc. 1993, 115, 10183-10194.
(d) Molina, P.; Alca´ntara, J.; Lo´pez-Leonardio, C. Synlett 1995, 363-364.
(e) Norris, P.; Horton, D.; Levine, B. R. Tetrahedron Lett. 1995, 36, 7811-
7814. (f) Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem. Soc.
1995, 117, 10449-10459. (g) Pearson, W. H.; Gallagher, B. M. Tetrahedron
1996, 52, 12039-12048.
(2) For a recent review, see: (a) Saxton, J. E. In The Alkaloids; Cordell,
G. A., Ed.; Academic: New York, 1998; Vol. 51, pp 1-197. References
to more recent work in this area include: (b) Callaghan, O.; Lampard, C.;
Kennedy, A. R.; Murphy, J. A. Tetrahedron Lett. 1999, 40, 161-164. (c)
Dupont, C.; Gue´nard, D.; Tchertanov, L.; Thoret, S.; Gue´ritte, F. Bioorg.
Med. Chem. 1999, 7, 2961-2969. (d) Kizil, M.; Patro, B.; Callaghan, O.;
Murphy, J. A.; Hursthouse, M. B.; Hibbs, D. J. Org. Chem. 1999, 64, 7856-
7862. (e) Quinn, J. F.; Bos, M. E.; Wulff, W. D. Org. Lett. 1999, 1, 161-
164. (f) Urrutia, A.; Rodriguez, G. Tetrahedron Lett. 1998, 39, 4143-4146.
(g) Urrutia, A.; Rodriguez, J. G. Tetrahedron 1999, 55, 11095-11108. (h)
Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1998, 120, 13523-13524.
(3) (a) Stork, G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872-
2873. Other racemic syntheses of aspidospermidine: (b) Laronze, J. Y.;
Laronze-Fontaine, J.; Levy, J.; Le Men, J. Tetrahedron Lett. 1974, 491-
494. (c) Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T. J. Am. Chem. Soc. 1981,
The key step for the preparation of enantiomerically
103, 6990-6992. (e) Gallagher, T.; Magnus, P.; Huffman, J. J. Am. Chem.
Soc. 1982, 104, 1140-1141. (e) Mandal, S. B.; Giri, V. S.; Sabeena, M.
S.; Pakrashi, S. C. J. Org. Chem. 1988, 53, 4236-4241. (f) Le Menez, P.;
Kunesch, N.; Liu, S.; Wenkert, E. J. Org. Chem. 1991, 56, 2915-2918.
(g) Wenkert, E.; Liu, S. J. Org. Chem. 1994, 59, 7677-82. (h) Forns, P.;
Diez, A.; Rubiralta, M. J. Org. Chem. 1996, 61, 7882-7888. (i) Callaghan,
O.; Lampard, C.; Kennedy, A. R.; Murphy, J. A. J. Chem. Soc., Perkin
Trans. 1 1999, 995-1002.
(4) Asymmetric total syntheses of aspidospermidine: (a) Node, M.;
Nagasawa, H.; Fuji, K. J. Org. Chem. 1990, 55, 517-521. (b) Desmae¨le,
D.; d'Angelo, J. J. Org. Chem. 1994, 59, 2292-2303. (c) Schultz, A. G.;
Pettus, L. J. Org. Chem. 1997, 62, 6855-6861. In addition, an asymmetric
approach to the Stork tricyclic intermediate 2 has been reported: (d) Meyers,
A. I.; Berney, D. J. Org. Chem. 1989, 54, 4673-4676.
(5) d'Angelo, J.; Desmae¨le, D.; Dumas, F.; Guingant, A. Tetrahedron:
Asymmetry 1992, 3, 459-505.
(6) Williams, D.; Cortez, G. S. Tetrahedron Lett. 1998, 39, 2675-2678.
10.1021/ol005913c CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/28/2000