Formal total syntheses of aspidosperma alkaloids via a novel and general synthetic pathway based on an intramolecular Heck cyclization

Article abstract of DOI:10.1021/ol0712576

Cyclizations of bicyclic amides via an intramolecular Heck reaction followed by an oxidation reaction generate tricyclic spirocyclohexadienones. From these compounds, tetracyclic ketones can be synthesized to provide useful intermediates for the synthesis

Full text of DOI:10.1021/ol0712576

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3101-3103
Formal Total Syntheses of
Aspidosperma Alkaloids via a Novel and
General Synthetic Pathway Based on an
Intramolecular Heck Cyclization
Jennifer Pereira, Mireille Barlier, and Catherine Guillou*
Institut de Chimie des Substances Naturelles, Bt 27, CNRS AVenue de la Terrasse,
91198 Gif-sur-YVette, France
guillou@icsn.cnrs-gif.fr
Received May 29, 2007
ABSTRACT
Cyclizations of bicyclic amides via an intramolecular Heck reaction followed by an oxidation reaction generate tricyclic spirocyclohexadienones.
From these compounds, tetracyclic ketones can be synthesized to provide useful intermediates for the synthesis of indole alkaloids.
Indole alkaloids are an important class of natural products
especially as many members of this family display a wide
range of biological activities. These properties include
antitumor,1 adrenergic blocking,2 and glycine antagonist3
activities. Such alkaloids are exemplified by strychnine 1,4
tubifoline 2, aspidospermine 3a,5 vindoline 4 and the
clinically used anticancer drug agents vinblastine 5 and
vincristine 6, which are produced in extremely small quanti-
ties in the plant Vinca rosea (Figure 1).6
to synthesize this skeleton based on the chemistry of free
radicals, of tandem radical cyclization,7 of palladium-
catalyzed asymmetric allylic substitution,8 of skeletal re-
arrangement of a 3-chloroindolenine,4 of an intramolecular
The [6.5.6.5] ABCE ring system 7 is the common scaffold
of indole alkaloids. Several approaches have been developed
(1) (a) Kama, T.; Chooa, Y. Bisindole Alkaloids. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 2006; Vol. 63, p 181. (b)
Saxton, J. E. Synthesis of the Aspidosperma Alkaloids. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol. 50, p 343.
(2) Deutsch, H. F.; Evenson, M. A.; Drescher, P.; Sparwasser, C.;
Madsen, P. O. J. Pharm. Biomed. Anal. 1994, 12, 1283.
(3) Aprison, M. H. In Glycine Neurotransmission; Otterson, O. P., Storm-
Mathisen, J., Eds.; Wiley: New York, 1990; p 1.
(4) For reviews, see (a) Bonjoch, J.; Sole´, D. Chem. ReV. 2000, 100,
3455. (b) Bosch, J.; Bonjoch, J.; Amat, M. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, 1996; Vol. 48, p 75.
(5) For reviews, see (a) Hajicek, J. Coll. Czech. Chem. Commun. 2004,
69, 1681. (b) Saxton, J. E. Alkaloids in the Aspidospermine Group. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol.
51, p 2.
Figure 1. Aspidosperma alkaloids.
10.1021/ol0712576 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/13/2007

Diels-Alder reaction,9 of catalyzed polycyclization,10 or of
tandem Mannich condensation followed by a [3,3]-sigma-
tropic rearrangement.11
Table 1. Heck Cyclizations of 10
The indole alkaloids display a spiro quaternary carbon.
The incorporation of this quaternary center is the critical
element in the total synthesis of indole-type alkaloids. We
previously reported the use of an intramolecular Heck
reaction as an alternative for creating the spiro quaternary
center of the Amaryllidaceae galanthamine-type12 and mar-
itidine-type13 alkaloids.
In our synthetic pathway, we planned to use an intramo-
lecular Heck reaction to access spirotricyclic dienones 9,
which can provide the tetracyclic ketones 8 as key intermedi-
ates in the synthesis of indole alkaloids and their analogues
(Scheme 1). The intramolecular Heck reaction has rarely been
Heck yielda Heck free
precursor R1
R2
R3 products
(%)
yielda (%)
10a
10b
10c
10d
10e
H
OMe
H
H
H
H
H
H
13a
13b
13c
13d
13e
52
88
94
96
80
92
87
86
ndb
ndb
H
H
OMe
OMe Boc
OMe Me
Scheme 1. Retrosynthesis of Ketones 8
a Isolated yield after column chromatography. b Not determined.
1). Under “ligand-free” conditions the yield of 13a was
greatly increased (92%) while the yield of 13b remained
unchanged and the yield of 13c decreased (Table 1).
After hydrolysis of the dioxolane group of 13 with
hydrochloric acid and protection of the amide function with
Boc2O, oxidation of the R,â-unsaturated ketone function of
the resulting product 14 to the corresponding dienones 15
was accomplished by using selenium dioxide and acetic acid
applied to anilides to access spirodihydroquinolones.14 The
diastereoselective construction of the common [6.5.6.5]
ABCE scaffold 8 started with acid 1115 and anilines 12,16
which were coupled to furnish the corresponding anilides
10 in satisfactory yields (Scheme 2).
t
in BuOH. The amine function was then reprotected with
Boc group to give compounds 9a-c (Table 2).
Table 2. Synthesis of the Spirodienones 9
Scheme 2. Synthesis of the Anilides 10
precursor
product
overall yield (%)
13a: R1 ) R2 ) H
13b: R1 ) OMe; R2 ) H
13c: R1 ) H; R2 ) OMe
9a
9b
9c
62
58
68
Heck cyclizations of 10 were accomplished in the presence
or absence of phosphine ligands in dimethylacetamide (Table
(6) (a) For reviews, see: Pearce, H. L. The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1990; Vol. 37, p 145. (b) Saxton, J. E.
Nat. Prod. Rep. 1995, 385.
With a ready access to the three key spirodienone
precursors, we next turned our attention to the crucial lactam
(7) (a) Zhou, S.; Bommezijn, S.; Murphy, J. A. Org. Lett. 2002, 4, 443.
(b) Kizil, M.; Murphy, J. A. J. Chem. Soc., Chem. Commun. 1995, 1405.
(8) (a) Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem.
Soc. 2005, 127, 10186. (b) For asymmetric versions, see: Mori, M.;
Nakanishi, M.; Kajiishima, D.; Sato, Y. J. Am. Chem. Soc. 2003, 125, 9801.
Nakanishi, M.; Mori, M. Angew. Chem., Int. Ed. 2002, 41, 1934. Mori,
M.; Nakanishi, M.; Kajiishima, D.; Sato, Y. Org. Lett. 2001, 3, 1913.
(9) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685.
(11) (a) Kuehne, M. E.; Xu, F. J. Org. Chem. 1998, 63, 9427. (b) Kuehne,
M. E.; Xu, F. J. Org. Chem. 1993, 58, 7490.
(12) Guillou, C.; Beunard, J. L.; Gras, E.; Thal, C. Angew. Chem., Int.
Ed. 2001, 40, 4745.
(13) (a) Bru, C.; Thal, C.; Guillou, C. Org. Lett. 2003, 5, 1845. (b) Bru,
C.; Guillou, C. Tetrahedron 2006, 62, 9043.
(14) Thal, C.; Guillou, C.; Beunard, J. L.; Gras, E.; Potier, P. European
Patent 2,826,005-A1; Chem. Abstr. 2003, 138, 39446.
(15) For preparation of acid 11, see ref 13.
(10) (a) Heureux, N.; Wouters, J.; Marko, I. E. Org. Lett. 2005, 7, 5245.
(b) Ando, M.; Buechi, G.; Ohnuma, T. J. Am. Chem. Soc. 1975, 97, 6880.
3102
Org. Lett., Vol. 9, No. 16, 2007

opening. Previous attempts at such conversions have been
unsuccessful.17 However, in our hands reaction of anilides
9 with different primary amines provided the corresponding
mixtures of tricyclic compounds 16-19 by a Michael
addition and tetracyclic compounds 20-23 by a double
Michael addition. These mixtures were subjected to basic
cyclization in the presence of sodium hydride or sodium
hydroxide to yield only the tetracyclic products 20-23 (Table
3). Compounds 20-23 are interesting scaffolds for the
alkaloid families was the reduction of the pentacyclic amide
function. This reduction can be accomplished after depro-
tection of the aniline function of 23 and protection of the
ketone by a dioxolane group to yield 24. The deprotection
of the aniline was realized before the protection of the ketone
function to optimize the yield (Scheme 3).
Scheme 3
Table 3. Preparation of Tetracyclic Compounds 20-23
Finally, the amide functions of 24a-c were reduced with
lithium aluminum hydride to afford the corresponding amines
25, which were subsequently subjected to N-debenzylation
and deprotection of the ketone. Compounds 8a-c were thus
obtained in satisfactory yields.
In summary, we have developed an efficient and diaste-
reoselective methodology that enables the construction of a
large series of tetracyclic indolino derivatives 20-23, 25,
and 8, which correspond to the cores of the Aspidosperma
and Strychnos alkaloids as well as their analogues. The
approach is based on two key steps: an intramolecular Heck
cyclization applied to anilides and a lactam opening-Michael
addition reaction. Current efforts are now directed toward
developing an enantioselective version and application to the
synthesis of natural indole alkaloids.
precursor
products
yield (%)
9a: R1 ) R2 ) H
20a, R4 ) Me
21a, R4 ) Et
22a, R4 ) Bu
23a, R4 ) Bn
20b, R4 ) Me
21b, R4 ) Et
22b, R4 ) Bu
23b, R4 ) Bn
20c, R4 ) Me
21c, R4 ) Et
22c, R4 ) Bu
23c, R4 ) Bn
68
35
48
79
66
27
30
73
74
63
64
70
9b: R1 ) OMe; R2 ) H
9c: R1 ) H; R2 ) OMe
Acknowledgment. We thank the CNRS for financial
support and Dr. R. H. Dodd, ICSN-CNRS, Gif-sur-Yvette,
France, for carefully reading the manuscript and for helpful
comments.
synthesis of N-substituted and A-modified ring analogues
of indole alkaloids.
At this stage, all that remained to complete the synthesis
of the tetracyclic core of the Aspidosperma and Strychnos
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Aniline 12a is commercially available. (b) For preparation of
12b, see: Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62,
6507. For preparation of 12c, see: Lizos, D. E.; Murphy, J. A. Org. Biomol.
Chem. 2003, 1, 117.
(17) Moisan, L.; Wagner, M.; Comesse, S.; Doris, E. Tetrahedron Lett.
2006, 47, 9093.
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