An effective enantioselective approach to the securinega alkaloids: Total synthesis of (-)-norsecurinine

Article abstract of DOI:10.1021/ol0522079

(Chemical Equation Presented) A highly versatile approach to the enantioselective synthesis of securinega alkaloids is presented. Crucial steps are a palladium-catalyzed enantioselective imide alkylation, a vinylogous Mannich reaction, and a ring-closing

Full text of DOI:10.1021/ol0522079

ORGANIC
LETTERS
2005
Vol. 7, No. 22
5107-5109
An Effective Enantioselective Approach
to the Securinega Alkaloids: Total
Synthesis of (−)-Norsecurinine
Ramo´n Alibe´s, Pau Bayo´n, Pedro de March, Marta Figueredo,* Josep Font,
Elena Garc´ıa-Garc´ıa, and David Gonza´lez-Ga´lvez
UniVersitat Auto`noma de Barcelona, Departament de Qu´ımica,
08193 Bellaterra, Spain
marta.figueredo@uab.es
Received September 13, 2005
ABSTRACT
A highly versatile approach to the enantioselective synthesis of securinega alkaloids is presented. Crucial steps are a palladium-catalyzed
enantioselective imide alkylation, a vinylogous Mannich reaction, and a ring-closing metathesis process. Through this strategy, the synthesis
of (−)-norsecurinine has been accomplished in nine steps and 11% overall yield.
The securinega alkaloids comprise a group of more than 20
tetracyclic compounds produced by some plants of the
Securinega, Phyllanthus, Margaritaria, and Brenia species,
belonging to the Euphorbiaceae family,1 which have been
used for years in traditional folk medicine in China and the
Amazonia.2 Typically, the skeleton of securinega alkaloids
(Figure 1) encloses a 6-azabicyclo[3.2.1]octane system (rings
B and C) fused to a 2-furanone (ring D) and either a
piperidine or pyrrolidine (ring A), with the size of this last
ring characterizing the securinine- and norsecurinine-type
subgroups, respectively. Securinine (1) was the first isolated
and is the major securinega alkaloid.3 Its enantiomer,
virosecurinine, and their epimers at C2, allosecurinine (2)
and viroallosecurinine, have also been isolated from natural
sources. (-)-Norsecurinine (3), the first isolated and most
representative member of its subgroup, and its antipode are
also both naturally occurring.4 Herein, we describe an
enantioselective synthesis of (-)-3, through a highly efficient
route, that enables the preparation of either enantiomer of
(1) For a review, see: Snieckus, V. In The Alkaloids; Manske, R. H. F.,
Ed.; Academic Press: New York, 1973; Vol. 14, pp 425-503.
(2) (a) van der Woerd, L. A. Genneskd. Tijdschr. Ned.-Indie 1941, 81,
1963-1980. (b) Serra, R. M. An. UniV. Santo Domingo 1944, 8, 295-297.
Figure 1. Representative examples of securinega alkaloids.
10.1021/ol0522079 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/01/2005

the alkaloid and can be extended to the securinine-type
subgroup.
Scheme 1
The securinega alkaloids have been associated with a
number of biological activities, some of which are well
documented. Securinine (1) is a stimulant of the central
nervous system5 and has shown antimalarial and antibacterial
activities.6 Several securinega alkaloids act also as antitumor
agents.7 Despite their attractive potential as pharmacological
agents, published synthetic investigations related to these
alkaloids are quite limited. Racemic securinine was synthe-
sized by Horii et al. a few years after its isolation,8a and
much more recently, two additional total syntheses8b,c and
one formal synthesis8d were reported. Very recently, two
rather similar stereoselective syntheses of 1 have been
described by the Honda group and by our group.9 Both
sequences start from (R)-pipecolinic acid, which determines
the configuration of C2 in 1. When we performed an
analogous sequence starting from (S)-proline, we ended up
with (-)-allonorsecurinine (4), a previously unknown epimer
at C2 of (-)-norsecurinine (3). The same starting material
was used by Heathcock et al. in the first reported successful
synthesis of (()-310 and by Jacobi and co-workers in the
first preparation of (-)-3.11 The groups of Magnus and
Weinreb have described alternative successful approaches
to (()-3 and to (-)-3, respectively.6a,12
metathesis (RCM) reaction, which would furnish the seven-
membered cycle embracing rings B and C. The stereogenic
center of 7 should afford the configuration at C7 in the
alkaloid, while the diastereoselectivity of its addition to 8
would determine the relative configuration at C2. Therefore,
the main concerns of our investigations were as follows:
preparing a suitable precursor of 7 in enantiopure form and
getting good steric control in the vinylogous Mannich
reaction.
Recently, Trost et al. described the conversion of racemic
butadiene monoepoxide (10) into a single enantiomeric
product through a palladium-catalyzed asymmetric allylic
alkylation of phthalimide in the presence of some chiral
phosphine ligands.13 Inspired by this work, we investigated
the reaction between succinimide (9) and epoxide 10 under
similar conditions (Scheme 2), and after extensive experi-
mentation, we isolated the alkylated product 11 in 91% yield
and 87% ee. We tentatively assigned the R configuration to
the major enantiomer, by analogy to the phthalimide analogue
obtained in the presence of the same ligand. Alcohol 11 was
converted into the corresponding tert-butyldiphenylsilyl
(TBDPS) ether 12, which upon crystallization in 2-propanol
afforded a highly enantiomerically enriched material (>98%
ee) in 81% yield from 9. Reduction of 12 with lithium
triethylborohydride furnished a mixture of the epimeric
aminals 13 in 87% yield. Triisopropylsilyloxyfuran 8 was
prepared in 97% yield from 4-vinyl-2(5H)-furanone.14 Then,
the crucial vinylogous Mannich reaction15 was investigated,
and we found that the reaction was best accomplished with
1.2 equiv of 8, in ether at 0 °C, in the presence of BF3‚
Et2O. Under these conditions, 1H NMR analysis of the crude
reaction material evidenced the full conversion of 13 and
the formation of a clean mixture of diastereomeric products
14. All attempts to separate these isomers by chromatography
led to complex mixtures of decomposition products, but on
standing at room temperature overnight, the major isomer
14a crystallized and could be separated from the mixture
by filtration in 51% yield.
During the past few years, we have been trying to develop
new, general strategies for the synthesis of both types of
securinega alkaloids. Scheme 1 shows the retrosynthetic
analysis for one of the investigated approaches, where key
steps are a vinylogous Mannich reaction between an iminium
cation 7 and a silyloxyfuran 8, which would, respectively,
provide rings A and D of the alkaloid and a ring-closing
(3) Isolation: (a) Murev’eva, V. I.; Ban’kovskii, A. I.; Dokl. Akad. Nauk
SSSR 1956, 110, 998-1000. Structural assignment: (b) Satoda, I.; Mu-
rayama, M.; Tsuji, Y.; Yoshii, E. Tetrahedron Lett. 1962, 1199-1206. (c)
Saito, S.; Kotera, K.; Shigematsu, N.; Ide, A.; Sugimoto, N.; Horii, Z.;
Hanaoka, M.; Yamawaki, Y.; Tamura, Y. Tetrahedron 1963, 19, 2085-
2099. (d) Horii, Z.; Ikeda, M.; Yamawaki, Y.; Tamura, Y.; Saito, S.; Kodera,
K. Tetrahedron 1963, 19, 2101-2110. Absolute configuration: (e) Imado,
S.; Shiro, M.; Horii, Z.; Chem. Ind. (London) 1964, 1691.
(4) Isolation and structural assignment of (-)-norsecurinine: (a) Iketu-
bosin, G. O.; Mathieson, D. W. J. Pharm. Pharmacol. 1963, 15, 810-815.
Absolute configuration: (b) Saito, S.; Tanaka, T.; Kotera, K.; Nakai, H.;
Sugimoto, N.; Horii, Z.; Ikeda, M.; Tamura, Y. Chem. Pharm. Bull. 1965,
13, 786-796. Isolation of (+)-norsecurinine: (c) Rouffiac, R.; Parello, J.
Plant. Med. Phytother. 1969, 3, 220-223.
(5) Beutler, J. A.; Karbon, E. W.; Brubaker, A. N.; Malik, R.; Curtis, D.
R.; Enna, S. J. Brain Res. 1985, 330, 135-140.
(6) See references in: (a) Han, G.; LaPorte, M. C.; Folmer, J. J.; Werner,
K. M.; Weinreb, S. M. J. Org. Chem. 2000, 65, 6293-6306. (b) Kammler,
R.; Polborn, K.; Wanner, K. Th. Tetrahedron 2003, 59, 3359-3368.
(7) Tatematsu, H.; Mori, M.; Yang, T.-H.; Chang, J.-J.; T. Lee, T.-Y.;
Lee, K.-H. J. Pharm. Sci. 1991, 80, 325-327.
(8) (a) Horii, Z.; Hanaoka, M.; Yamawaki, Y.; Tamura, Y.; Saito, S.;
Shigematsu, N.; Kotera, K.; Yoshikawa, H.; Sato, Y.; Nakai, H.; Sugimoto,
N. Tetrahedron 1967, 23, 1165-1174. (b) Xi, F. D.; Liang, X. T. Acta
Pharm. Sin. 1992, 27, 349-352. (c) Liras, S.; Davoren, J. E.; Bordner, J.
Org. Lett. 2001, 3, 703-706. (d) Honda, T.; Namiki, H.; Kudoh, M.; Nagase,
H.; Mizutani, H. Heterocycles 2003, 59, 169-187.
(9) (a) Honda, T.; Namiki, H.; Kaneda, K.; Mizutani, H. Org. Lett. 2004,
6, 87-89. (b) Alibe´s, R.; Ballbe´, M.; Busque´, F.; de March, P.; Elias, L.;
Figueredo, M.; Font, J. Org. Lett. 2004, 6, 1813-1816.
The relative configuration of 14a-d could be established
by performing a RCM16 experiment with the crude reaction
material containing the mixture of all the isomers. The olefins
(12) Magnus, P.; Rodr´ıguez-Lo´pez, J.; Mulholland, K.; Matthews, I.
Tetrahedron 1993, 49, 8059-8072.
(13) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am.
Chem. Soc. 2000, 122, 5968-5976.
(14) Lattmann, E.; Hoffmann, H. M. R. Synthesis 1996, 155-163.
(15) (a) Morimoto, Y.; Nishida, K.; Hayashi, Y.; Shirahama, H.
Tetrahedron Lett. 1993, 34, 5773-5776. For a recent review, see: (b)
Martin, S. F. Acc. Chem. Res. 2002, 35, 895-904.
(10) Heathcock, C. H.; von Geldern, T. W. Heterocycles 1987, 25, 75-
78. This synthesis rendered racemic 2 due to racemization of an intermediate.
(11) Jacobi, P. A.; Blum, C. A.; DeSimone, R. W.; Udodong, U. E. S.
J. Am. Chem. Soc. 1991, 113, 5384-5392. This paper describes the
independent preparation of (+)- and (-)-3, starting from L- and D-proline,
respectively.
5108
Org. Lett., Vol. 7, No. 22, 2005

delighted to discover that the major diastereomer 15a
presented the same relative configuration at C2 and C7 as
norsecurinine. When the RCM reaction was applied to the
crystallized isomer 14a, the expected diene 15a was isolated
in nearly quantitative yield. The two transformations required
to conclude the synthesis of (-)-norsecurinine were reducing
the lactam to amine and connecting the stereogenic centers
C7 and C9 through the one-carbon bridge to complete the
tetracyclic skeleton. Conversion of 15a into the correspond-
ing thiolactam, followed by treatment with Raney nickel or
other reducing agents, ended up with decomposition products,
but direct reduction of the lactam with freshly prepared
aluminum hydride17 allowed the isolation of 16 in 57% yield.
Other standard desilylation protocols applied to 16 failed,
but the free alcohol 17 was obtained in good yield by reaction
of 16 with an excess of Et3N‚3HF in THF at room
temperature.
Scheme 2. Enantioselective Synthesis of (-)-Norsecurinine
((-)-3)
Alcohol 17 is the penultimate intermediate in the synthesis
of (-)-norsecurinine published by Jacobi et al., who con-
verted it into the alkaloid by mesylation and subsequent
treatment with potassium bis(trimethylsilyl)amide in 60%
overall yield,11 but an optical rotation value for 17 was not
given. Therefore, to assess the absolute configuration of our
synthetic material we completed the synthesis of the alkaloid
according to Jacobi’s protocol. The yields were satisfactorily
reproduced and we obtained the levorotatory enantiomer of
norsecurinine, [R] ) -270 (c 0.20, EtOH) [lit.4b [R] ) -270
(c 6.9, EtOH)].
In summary, we have completed a new synthesis of (-)-
norsecurinine in nine steps and 11% total yield. The three
crucial steps of this synthesis (enantioselective allylic alky-
lation of succinimide, vinylogous Mannich reaction, and
RCM) have been performed in a synthetically useful scale
(more than 500 mg). Since the enantioselectivity was
originated by the phosphine ligand (S,S)-19, the antipode of
which is equally available, the same route gives access to
(+)-norsecurinine. For the preparation of securinine, a
parallel sequence starting from glutarimide is currently under
study.
Acknowledgment. We acknowledge financial support
from DGES (BQU2001-2600) and CIRIT (2001SGR00178)
and grants from DGR (to E.G.-G.), MEC (to D.G.-G), and
AUR (to P.B.).
Supporting Information Available: Experimental pro-
1
cedures, listing of spectral data, and HNMR spectra of
compounds 12, 14a, 15a, 16, 17, and (-)-3. This material
is available free of charge via the Internet at http://pubs.acs.org.
15a-d could be chromatographically separated in three
fractions (15a, 15b + 15c, and 15d) and their configuration
determined with the help of nOe experiments. We were
OL0522079
(16) For recent reviews, see: (a) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012-3043. (b) Grubbs, R. H. Tetrahedron 2004, 60, 7117-
7140.
(17) (a) Brown, H. C.; Yoon, N. M. J. Am. Chem. Soc. 1966, 88, 1464-
1472. (b) Giraud, L.; Huber, V.; Jenny, T. Tetrahedron 1998, 54, 11899-
11906.
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