Concise total synthesis of (±)-maritidine

Article abstract of DOI:10.1021/ol0343358

(Matrix presented) Maritidine can be readily obtained from the corresponding protected β,γ-unsaturated ketone. The quaternary carbon of maritidine was created for the first time via an intramolecular Heck reaction.

Full text of DOI:10.1021/ol0343358

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1845-1846
Concise Total Synthesis of
(±)-Maritidine
Claire Bru, Claude Thal, and Catherine Guillou*
Institut de Chimie des Substances Naturelles,
CNRS AVenue de la Terrasse 91198 Gif-sur-YVette, France
guillou@icsn.cnrs-gif.fr
Received February 26, 2003
ABSTRACT
Maritidine can be readily obtained from the corresponding protected â,γ-unsaturated ketone. The quaternary carbon of maritidine was created
for the first time via an intramolecular Heck reaction.
Maritidine alkaloids1 have been found to possess cytotoxic
properties (Figure 1).2 These Amaryllidaceae alkaloids
previously created by different approaches involving long
multistep sequences.5 It should be noted that to date it is not
possible to oxidize (()-dihydromaritidine (3) to maritidine
(1) (Figure 1).
In our synthetic pathway, we planned to use for the first
time an intramolecular Heck reaction for the construction
of the quaternary center of the Amaryllidaceae maritidine-
(3) Maritidine: (a) Rao, R. V.; Rao, K.; Seshagiri, J. V. L. N. Curr. Sci.
1979, 48, 110. (b) Tani, S.; Kobayashi, N.; Fujiwara, H.; Shingu, T.; Kato,
A. Chem. Pharm. Bull. 1981, 29, 3381. (c) Hung, S.; Ma, G.; Sung, G.
Huaxue Xuebao 1981, 39, 529. (d) Ghosal, S.; Ashutosh, R.; Razdan, S.
Phytochemistry, 1985, 24, 635. (e) Ma, G.; Li, H. Y.; Lu, C.; Yang, X.;
Hong, S. Heterocycles 1986, 24, 2089. (f) Ghosal, S.; Singh, S.; Srivastava,
R. S. Phytochemistry 1986, 25, 1975. (g) Kihara, M.; Koike, T.; Imakura,
Y.; Kia, K.; Shingu, T.; Kobayashi, S. Chem. Pharm. Bull. 1987, 35, 1070.
(h) Bastida, J.; Llabres, J. M.; Viladomat, F.; Codina, C.; Rubiralta, M.;
Feliz, M. Planta Med. 1988, 54, 524. See also refs 2a,b. Oxomaritidine: (i)
Herrera, M. R.; Brun, R.; Villadoma, F.; Codina, C.; Bastida, J. Planta
Med. 2001, 67, 191.
(4) Maritidine: (a) Schwartz, M. A.; Holton, R. A. J. Am. Chem. Soc.
1970, 92, 1090. (b) Kametani, T.; Kohno, T.; Shibuya, S.; Fukumoto, K.
Chem. Commun. 1971, 14, 775. (c) Kametani, T.; Kohno, T.; Shibuya, S.;
Fukumoto, K. Tetrahedron 1971, 27, 5441. (d) Yamada, S.; Tomioka, K.;
Koga, K. Tetrahedron Lett. 1976, 1, 57. (e) Tomioka, K.; Shimizu, K.;
Yamada, S.; Koga, K. Heterocycles 1977, 6, 1752. (f) Tomioka, K.; Koga,
K.; Yamada, S. Chem. Pharm. Bull. 1977, 25, 2681. (g) Kita, Y.; Takada,
T.; Gyoten, M.; Tohma, H.; Zenk, M. H.; Eichhorn, J. J. Org. Chem. 1996,
61, 5857. Oxomaritidine: (h) Kotani, E.; Takeuchi, N.; Tobinaga, S. J. Chem.
Soc., Chem. Commun. 1973, 550. (i) Kotani, E.; Takeuchi, N.; Tobinaga,
S. Tetrahedron Lett. 1973, 29, 2735. (j) Ley, S. T.; Schucht, O.; Thomas,
A. W.; Murray, P. J. J. Chem. Soc., Perkin Trans. 1 1999, 1251. See also
ref 5a.
Figure 1.
display a spiro quaternary carbon. The incorporation of this
quaternary center is the critical element in the total synthesis
of maritidine-type alkaloids. Because of their limited avail-
ability from natural sources,3 several syntheses of these
compounds have been reported employing a biomimetic
intramolecular phenolic oxidative cyclization as the crucial
step in the formation of the tetracyclic framework.4 However,
the quaternary carbon of dihydromaritidine (3) has been
(1) For reviews, see: (a) Hoshino, O. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1998; Vol. 51, p 362. (b) Martin, S. F.
In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1987; Vol.
30, p 251.
(2) (a) Alarcon, M.; Cea, G.; Weigert, G. EnViron. Contam. Toxicol.
1986, 37, 508. (b) Pacheco, P.; Silva, M.; Steglich, W.; Watson, W. H.
ReV. Latinoam. Quim. 1978, 9, 28.
(5) (a) Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1978, 34,
2579. (b) Keck, G. E.; Webb, R. R. J. Org. Chem. 1982, 47, 1302. (c)
Michael, J. P.; Howard, A. S.; Katz, R. B.; Zwane, M. I. Tetrahedron Lett.
1992, 33, 6023.
10.1021/ol0343358 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/29/2003

type alkaloids. Our strategy was to form the key connection
bond between the C10a-C10b carbons of the target molecule
(1) by an intramolecular Heck reaction to access the spiro
tricyclic dienone (11), which could then be used as a valuable
precursor of (2) and (1). The intramolecular Heck reaction
leading to 7-exo trigonal cyclization has not often been
described.6 This process has rarely been used for the creation
of a spiro quaternary center.7
Enone (2) was stereoselectively reduced with the combined
reagent sodium borohydride-cerous chloride11 to give epi-
maritidine (12) (93%). Finally, the allylic alcohol of (12)
was converted to the corresponding mesylate and inverted
by displacement with cesium acetate. The resulting acetate
was saponified with potassium carbonate and methanol to
give (()-maritidine (1) (52%), which had spectral data in
accordance with published values (Scheme 2).4
The synthesis started with the known aryl iodide (4)8 and
amine (5).9 Reductive amination of these two components
followed by protection of the enol ether function gave amine
(7). Subsequent protection of the amine function with di-
tert-butyl dicarbonate furnished compound (8) (93%), the
precursor for the intramolecular Heck reaction (Scheme 1).
Scheme 2a
Scheme 1a
a Conditions: (a) [Pd2(dba)3], dppe, TlOAc, CH3CN, reflux, 3
days. (b) 1 N HCl, THF, rt. (c) SeO2, BuOH, AcOH, reflux. (d)
CF3CO2H, CH2Cl2, rt. (e) NaBH4, CeCl3, MeOH, rt. (f) (i) MsCl,
NEt3, CH2Cl2, rt; (ii) CsOAc, DMF, rt; (iii) K2CO3, MeOH, rt.
a Conditions: (a) NaBH4, MeOH, rt. (b) (CH2OH)2, BF3‚Et2O,
t
t
THF, rt. (c) Boc2O, BuOH/H2O 1/1, rt.
The key carbon bond-forming reaction was achieved in
59% yield by heating (8), catalytic amounts of 10%
[Pd2dba3], 20% dppe, and thallium acetate (1.2 equiv) in
acetonitrile.10 After removal of the dioxolane group of (9)
with hydrochloric acid to give (10) (83%), oxidation of the
R,â-unsaturated ketone function of the latter to the corre-
sponding dienone (11) was accomplished in 73% yield by
using selenium dioxide and acetic acid in tBuOH. Removal
of the N-Boc group of (11) with trifluoroacetic acid resulted
in spontaneous cyclization to afford oxomaritidine (2) (68%).
The total synthesis of (()-maritidine (1) disclosed herein
is the first such synthesis, which does not utilize an oxidative
phenol coupling to construct the quaternary center. An
intramolecular Heck reaction followed by a dehydrogenation
reaction provided the key intermediate spirocyclohexadi-
enone (11). The synthesis of compounds related to maritidine
and to other Amaryllidaceae alkaloids using this methodology
is in progress.
Acknowledgment. The authors thank the CNRS for
financial support. Professor J. Y. Lallemand is gratefully
acknowledged for his interest in our work. We would also
like to thank R. H. Dodd for carefully reading the manuscript
and for helpful comments.
(6) (a) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 2050. (b)
Tietze, L. F.; Schirok, H. . J. Am. Chem. Soc. 1999, 121, 10264.
(7) (a) Abelman, M. M.; Kado, N.; Overman, L. E.; Sarkar, A. Synlett
1997, 1469. (b) Ashimori, A.; Bachand, B.; Overmann, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1999, 120, 6477. (c) Guillou, C.; Beunard, J. L.; Gras,
E.; Thal, C. Angew. Chem., Int. Ed. 2001, 40, 4725.
(8) Ahmad-Junan, S. A.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1
1992, 675.
(9) (a) Catena, J.; Valls, N.; Bosch, J.; Bonjoch, J. Tetrahedron Lett.
1994, 35, 4433. (b) Guillou, C.; Millot, N.; Reboul, V.; Thal, C. Tetrahedron
Lett. 1996, 37, 4515.
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.
(10) Replacement of TlOAc by pentamethylpiperidine (PMP) or by a
PMP and Bu4NOAc mixture afforded the expected tricyclic compound 9
OL0343358
n
but in low yields of 15 and 20%, respectively. When the reaction was
performed in toluene, 9 was isolated in a lower yield (23%).
(11) Luche, J. L.; Rodriguez-Hahn, L., Crabbe, P. J. Chem. Soc., Chem.
Commun. 1978, 601.
1846
Org. Lett., Vol. 5, No. 11, 2003