A Short Total Synthesis of

ORGANIC
LETTERS
A Short Total Synthesis of

()-Aspidospermidine
2006
Vol. 8, No. 5
831-834
Lisa A. Sharp and Samir Z. Zard*

Laboratoire de Synthe` se Organique associe au CNRS, E cole Polytechnique,
91128 Palaiseau, France
zard@poly.polytechnique.fr
Received November 14, 2005
ABSTRACT
A cascade radical cyclization starting from an amidyl radical has been used for the construction of ()-aspidospermidine. This approach has
also been developed for the preparation of a tricycle whose framework is contained in the stemona alkaloids.
The Aspidosperma family of indole alkaloids has inspired

many synthetic strategies for the construction of their
pentacyclic framework, in particular the parent compound
aspidospermidine 1.1 Our interest in the use of nitrogencentered radicals2 for the formation of various heterocycles
led us to investigate such an approach in the synthesis of
(1) (a) Stork, G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872. (b)
Camerman, A.; Camerman, N.; Kutney, J. P.; Piers, E.; Trotter, J.
Tetrahedron Lett. 1965, 637. (c) Harley-Mason, J.; Kaplan, M. J. Chem.
Soc., Chem. Commun. 1967, 915. (d) Laronze, J.-Y.; Laronze-Fontaine, J.;
Levy, J.; Le Men, J. Tetrahedron Lett. 1974, 491. (e) Ban, Y.; Yoshida,
K.; Goto, J.; Oishi, T. J. Am. Chem. Soc. 1981, 103, 6990. (f) Gallagher,
T.; Magnus, P.; Huffman, J. J. Am. Chem. Soc. 1982, 104, 1140. (g)
Wenkert, E.; Hudlicky, T. J. Org. Chem. 1988, 53, 1953. (h) Mandal, S.
B.; Giri, V. S.; Sabeena, M. S.; Pakrashi, S. C. J. Org. Chem. 1988, 53,
4236. (i) Meyers, A. I.; Berney, D. J. Org. Chem. 1989, 54, 4673. (j) Node,
M.; Nagasawa, H.; Fugi, K. J. Org. Chem. 1990, 55, 517. (k) Le Menez,
P.; Kunesch, N.; Lui, S.; Wenkert, E. J. Org. Chem. 1991, 56, 2915. (l)
Desmaele, D.; d'Angelo, J. J. Org. Chem. 1994, 59, 2292. (m) Wenkert,
E.; Lui, S. J. Org. Chem. 1994, 59, 7677. (n) Forns, P.; Diez, A.; Rubiralta,
M. J. Org. Chem. 1996, 61, 7882. (o) Schultz, A. G.; Pettus, L. J. Org.
Chem. 1997, 62, 6855. (p) Callaghan, O.; Lampard, C.; Kennedy, A. R.;
Murphy, J. A. J. Chem. Soc., Perkin Trans. 1 1999, 995. (q) Iyengar, R.;
Schildknegt, K.; Aube, J. Org. Lett. 2000, 2, 1625. (r) Toczko, M. A.;
Heathcock, C. H. J. Org. Chem. 2000, 65, 2642. (s) Patro, B.; Murphy, J.
A. Org. Lett. 2000, 2, 3599. (t) Kozmin, S. A.; Iwama, T.; Huang, Y.;
Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 4628. (u) Banwell, M. G.;
Smith, J. A. J. Chem. Soc., Perkin Trans. 1 2002, 2613. (v) Marino, J. P.;
Rubio, M. B.; Cao, G.; de Dios, A. J. Am. Chem. Soc. 2002, 124, 13398.
(w) Gnecco, D.; Vazquez, E.; Galindo, A.; Teran, J. L.; Berne`s, S.; Enrquez,
R. G. ArkiVoc 2003, xi, 185. (x) Tanino, H.; Fukuishi, T.; Ushiyama, M.;
Okada, K. Tetrahedron 2004, 60, 3273. (y) Banwell, M. G.; Lupton, D.
W. Org. Biomol. Chem. 2005, 3, 213.
(2) For reviews of cyclisation of nitrogen centred radicals, see: (a) Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. (b) Zard, S. Z. Synlett
1996, 1148.
10.1021/ol052749q CCC: $33.50
Published on Web 02/08/2006
2006 American Chemical Society
aspidospermidine. We have previously demonstrated the

potential of cyclizations of amidyl radicals in the synthesis
of (()-13-deoxyserratine.3
Our proposed synthesis of aspidospermidine hinges on the
5-exo/6-endo cascade of radical cyclizations from amidyl
radical 3 to provide the tricyclic system 2, which would later
be converted to aspidopermidine using the known Fischer
indole synthesis. The presence of the chlorine atom on the
alkene inhibits 5-exo closure in the second cyclization.4 The
required cyclohexadiene radical precursor could be prepared
starting from an aromatic precursor 4 (Scheme 1).
Scheme 1.
Approach to Aspidospermidine
Scheme 2.
Failed Ring Closure
The desired presursor for the amidyl radical cyclization

was synthesized as shown in Scheme 2. Birch reduction and
alkylation of the ester 4 with tert-butyl bromoacetate formed
cyclohexadiene 6. Numerous conditions for the cleavage of
the tert-butyl ester also resulted in cyclization onto the enol
ether. TMSOTf and 2,6-lutidine cleanly provided the required
acid 7, which was coupled to the hydroxylamine with EDC.
The starting material for the formation of the amidyl radical,
the benzoate ester 9, was formed on treatment with benzoyl
chloride. However, when 9 was treated with tributyltin
hydride and 1,1-azobis(cyclohexanecarbonitrile) (ACCN) in
refluxing R,R,R-trifluorotoluene, no amidyl radical cyclization took place; aromatization occurred instead to give
intermediate 4. Thus, in one clean sweep, the side chain we
had painstakingly attached was cut off and we were returned
to our starting point.
Presumably, this is the result of abstraction of a doubly
allylic hydrogen by a tributyltin radical or by radicals derived
from the initiation.5 To eliminate the possibility of this
occurring, the methyl enol ether was deprotected prior to
the radical step. By treating the crude Birch reduction product
with aqueous hydrochloric acid in THF, deprotection of both
Scheme 3.
Construction of the Key Tricyclic Intermediate
the tert-butyl ester and methyl enol ether groups gave the
desired acid, which existed in the lactolized form 10. This
was converted to the new benzoate ester radical precursor
11 (Scheme 3).
Pleasingly, the amidyl radical formed on treatment of 11
with tributyltin hydride and ACCN underwent 5-exo cyclization in useful yield. The major product of the reaction
was the tricycle 12, where desired 6-endo cyclization had
followed. The minor product (29%) was the monocyclized
Scheme 4.
Final Steps to Aspidospermidine
(3) (a) Cassayre, J.; Gagosz, F.; Zard, S. Z. Angew. Chem., Int. Ed. 2002,
41, 1783. (b) Cassayre, J.; Zard, S. Z. J. Am. Chem. Soc. 1999, 121, 6072.
(4) (a) Knapp, S.; Gibson, F. S.; Choe, Y. H. Tetrahedron Lett. 1990,
31, 5397. (b) Keusenkothen, P. F.; Smith, M. B. Tetrahedron 1992, 48,
2977.
(5) For precedence of this fragmentation, see inter alia: (a) Jackson, L.
V.; Walton, J. C. Chem. Commun. 2000, 3273. (b) Jackson, L. V.; Walton,
J. C. Tetrahedron Lett. 1999, 40, 7019. (c) Baguley, P. A.; Jackson, L. V.;
Walton, J. C. J. Chem. Soc., Perkin Trans. 1 2002, 304. (d) Studer, A.;
Amrein, S. Angew. Chem., Int. Ed 2000, 39, 3080. (d) Amrein, S.; Studer,
A. HelV. Chim. Acta 2002, 85, 3559.
832
Org. Lett., Vol. 8, No. 5, 2006
Scheme 5.
General Route to Pyrrolizidine, Indolizidine, and

Stemona Skeletons
derivative 13. It is interesting to note that in the absence of

the chlorine, the isomer with the pyrrolizidine structure was
obtained by two consecutive 5-exo ring closures in 46%
yield. The chlorine substituent was therefore necessary for
regiocontrol.
Tricycle 12 could be decarboxylated with lithium chloride
in DMSO to give 14, which has been previously converted
into aspidospermidine1a,q,w in a sequence requiring protection
of the ketone for reduction of the amide and then subsequent
Fischer indole synthesis (Scheme 4). However, the ester in
12 provides hindrance to the ketone, and thus selective
reduction of the lactam of 12 was envisaged.
Treatment with borane dimethyl sulfide complex gave only
the desired alcohol 15, the product of reduction of both
lactam and ketone functionalities. The bulkier 9-BBN
however provided selective reduction of the lactam.6 Decarboxylation of the -keto ester supplied the known tricycle
17, which was converted to aspidosperidine via a Fischer
indole synthesis with phenylhydrazine followed by sodium
borohydride reduction.
With the amidyl radical cyclizations we have access to
indolizidine and pyrrolizidine skeletons by a 5-exo cyclization
followed by either a 5-exo or 6-endo cyclization. This second
cyclization is directed 5-exo versus 6-endo by the presence
or absence of the chlorine on the alkene. An extension of
this work would be to investigate the analogous system
involving 5-exo followed by 7-endo cyclization, which would
(6) Collins, C. J.; Lanz, M.; Singaram, B. Tetrahedron Lett. 1999, 40,
3673.
Org. Lett., Vol. 8, No. 5, 2006
Scheme 6.
Approach to the Stemona Structure
generate the 5,7 system found in the Stemona alkaloids

(Scheme 5).7
The precursor 21 for the amidyl radical cyclization was
prepared in a similar way to the previous system 11 used in
the synthesis of aspidospermidine. Birch reduction and
alkylation of methyl p-ethylbenzoate followed by hydrolysis
of the tert-butyl ester gave an equal mixture of two
diastereomeric acids 19a/b. These could be separated by
crystallization of their benzylamine salts though the relative stereochemistry of each could not be determined by
NOE studies. Coupling of one of these diastereomers
with the hydroxylamine 20 and treatment with benzoyl
chloride provided the radical precursor 21a. Upon treatment of 21a with tributyltin hydride and ACCN the major
product 22 was obtained by 5-exo followed by 7-endo
cyclization. Thus, three of the four rings of stenine could be
assembled from methyl p-ethyl benzoate 18 in only four
steps. Only one isomer is obtained in the cyclization and is
very likely that indicated for 22a in Scheme 6, according to
molecular models, but this has not been totally ascertained
yet.
(7) For previous syntheses of Stemona alkaloids, see: (a) Zeng, Y.; Aube,
J. J. Am. Chem. Soc. 2005, 127, 15712. (b) Wipf, P.; Spencer, S. R. J. Am.
Chem. Soc. 2005, 127, 225. (c) Sibi, M. P.; Subramanian, T. Synlett 2004,
7, 1211. (d) Bruggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen,
M. D.; Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284. (e)
Williams, D. R.; Shamin, K.; Reddy, J. P. Org. Lett. 2003, 5, 3361. (f)
Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc. 2002, 124, 14848.
(g) Golden, J. E.; Aube, J. Angew. Chem., Int. Ed. 2002, 41, 4316. (h)
Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515. (i) Kende, A. S.; Hernando,
J. I. M.; Milbank, J. B. J. Tetrahedron 2002, 58, 61. (j) Morimoto, Y.;
Iwahashi, M.; Kinoshita, T. Nishida, K. Chem. Eur. J. 2001, 7, 4107. (k)
Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721.
(l) Kende, A. S.; Hernando, J. I. M.; Milbank, J. B. J. Org. Lett. 2001, 3,
2505. (m) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295. (n)
Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17, 117 and
references therein. (o) Kende, A. S.; Smalley, T. L.; Huang, H. J. Am. Chem.
Soc. 1999, 121, 7431.
833
In summary, by a simple choice of precursor, all the

possibilities indicated in Scheme 5 can be executed, thus
opening a simple yet highly efficient strategy for the
construction of numerous alkaloids possessing these ubiquitous skeletons.
834
Supporting Information Available: Experimental procedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL052749Q
Org. Lett., Vol. 8, No. 5, 2006

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ORGANIC

Lisa A. Sharp and Samir Z. Zard*

The Aspidosperma family of indole alkaloids has inspired

2006 American Chemical Society

aspidospermidine. We have previously demonstrated the

Failed Ring Closure

The desired presursor for the amidyl radical cyclization

Construction of the Key Tricyclic Intermediate

Final Steps to Aspidospermidine

Org. Lett., Vol. 8, No. 5, 2006

General Route to Pyrrolizidine, Indolizidine, and

derivative 13. It is interesting to note that in the absence of

Org. Lett., Vol. 8, No. 5, 2006

Approach to the Stemona Structure

generate the 5,7 system found in the Stemona alkaloids

In summary, by a simple choice of precursor, all the

Org. Lett., Vol. 8, No. 5, 2006

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