Flexible approach to stemona alkaloids: Total syntheses of (-)-stemospironine and three new diastereoisomeric analogs

Article abstract of DOI:10.1021/ol302185j

Total syntheses of (-)-stemospironine and three new diastereoisomeric analogs have been completed through a flexible strategy devised for Stemona alkaloids. The azabicycle 7 is the pivotal intermediate, from which the sequence splits according to each particular target. The most remarkable differential feature for stemospironine is the installation of the spiranic γ-lactone through an intramolecular Horner-Wadsworth-Emmons olefination. The configuration of the stereogenic center at C-11 was controlled by fine-tuning of the synthetic sequence.

Full text of DOI:10.1021/ol302185j

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4854–4857
Flexible Approach to Stemona Alkaloids:
Total Syntheses of (ꢀ)-Stemospironine
and Three New Diastereoisomeric Analogs
ꢀ
Nuria Bardajı, Francisco Sanchez-Izquierdo, Ramon Alibes, Josep Font,
Felix Busque,* and Marta Figueredo*
ꢀ
ꢀ
´
ꢀ
ꢀ
ꢁ
´
Universitat Autonoma de Barcelona, Departament de Quımica, 08193 Bellaterra, Spain
marta.figueredo@uab.es; felix.busque@uab.es
Received August 6, 2012
ABSTRACT
Total syntheses of (ꢀ)-stemospironine and three new diastereoisomeric analogs have been completed through a flexible strategy devised for
Stemona alkaloids. The azabicycle 7 is the pivotal intermediate, from which the sequence splits according to each particular target. The most
remarkable differential feature for stemospironine is the installation of the spiranic γ-lactone through an intramolecular HornerꢀWadsworthꢀ
Emmons olefination. The configuration of the stereogenic center at C-11 was controlled by fine-tuning of the synthetic sequence.
The extracts of several plants of the Stemonaceae family
have long been used in East Asian countries for the
treatment of respiratory disorders, as antihelmintics, and
also as domestic insecticides. Significant constituents of
these extracts are a series of structurally related alkaloids
that may be responsible for their medicinal and antipar-
asitic properties, although studies on the specific activity of
individual members of this alkaloid family are scarce.1
All the Stemona alkaloids are polycyclic and most of
them enclose a pyrrolo[1,2-a]azepine core and one or more
R-methyl-γ-butyrolactone units as the most characteristic
structural features (Figure 1). Their intricate architectures
have motivated the development of imaginative strategies
for the construction of their skeletons.2 Nevertheless,
among the roughly 140 natural Stemona alkaloids cur-
rently known,1a the reported total syntheses target fewer
than 20 members of the family, and in most of them, the
azabicyclic skeleton is generated from a quite advanced
intermediate, usually with several stereogenic centers, and,
therefore, specifically assembled for one particular target.
Considering the high and continuously increasing number
of Stemona alkaloids isolated from natural sources, and
the subtle structural differences between some of them, we
thought that a flexible synthetic design with some common
intermediates was very desirable. Therefore, we devised a
strategy in which the azabicyclic core was generated at an
early stage of the sequence and the γ-butyrolactone moieties
and other specific fragments were incorporated later
(Scheme 1).3 We planned the formation of the azabicycle
via 1,3-dipolar cycloaddition of a pyrroline N-oxide to a
suitable olefin, followed by reductive cleavage of the NꢀO
bond and then 7-exo-trig cyclization. Previous studies re-
garding the cycloadditions of nitrones such as 4, to electron-
deficient olefins of type 3, had indicated the relative trans
configuration of the stereogenic centers at C-3 and C-9a
would be attained as required for the target alkaloids.3b,4
With respect to their connectivity pattern1b and biogen-
etic relations,1c the Stemona alkaloids have been classified
into several groups. The tuberostemospironine group is
characterized by the presence of a spiro-γ-butyrolactone
(3) (a) Cid, P.; Closa, M.; de March, P.; Figueredo, M.; Font, J.;
ꢀ
(1) For comprehensive reviews, see: (a) Pilli, R. A.; Rosso, G. B.; de
Oliveira, M. C. F. Nat. Prod. Rep. 2010, 27, 1908. (b) Pilli, R. A.; Rosso,
G. B.; de Oliveira, M. C. F. In The Alkaloids; Cordell, G. A., Ed.; Elsevier:
New York, 2005; Vol. 62, p 77. (c) Greger, H. Planta Med. 2006, 72, 99.
(2) For a recent review on synthetic strategies to Stemona alkaloids,
Sanfeliu, E.; Soria, A. Eur. J. Org. Chem. 2004, 4215. (b) Alibes, R.;
Blanco, P.; Casas, E.; Closa, M.; de March, P.; Figueredo, M.; Font, J.;
ꢀ
Sanfeliu, E.; Alvarez-Larena, A. J. Org. Chem. 2005, 70, 3157.
(4) (a) Closa, M.; de March, P.; Figueredo, M.; Font, J. Tetrahedron:
ꢀ
Asymmetry 1997, 8, 1031. (b) Busque, F.; de March, P.; Figueredo, M.;
ꢀ
ꢀ
Font, J.; Gallagher, T.; Milan, S. Tetrahedron: Asymmetry 2002, 13, 437.
see: Alibes, R.; Figueredo, M. Eur. J. Org. Chem. 2009, 2421.
r
10.1021/ol302185j
Published on Web 08/31/2012
2012 American Chemical Society

diol 8, an intermediate en route to stemonidine, we have
now completed the synthesis of stemospironine and three
additional analogs, thus demonstrating the flexibility of
our synthetic design.
Scheme 2. Preparation of Diol 8
Stemospironine possesses a methoxy group at C-8 with the
same stereochemical orientation as that of the putative ste-
monidine, but requires the formation of the spiranic lactone
with the opposite configuration. We envisaged the installa-
tion of this lactone through an intramolecular Hornerꢀ
WadsworthꢀEmmons olefination of a derivative of the
common intermediate 8, which was prepared from the
R,β-unsaturated diester 5 and the enantiomerically pure
nitrone 6,9 derived from L-(þ)-prolinol, as previously reported
(Scheme 2).8 It is remarkable that, after the initial formation
of the azabicycle 7, the inversion of configuration at C8
and the diastereofacial oxidation at C9 was efficiently ac-
complished in a cooperative manner through dehydration
and subsequent dihydroxylation. The “eastern” lactone, ap-
pended to the pyrrolidine ring, features identically in both
alkaloids.
Figure 1. Some representative examples of Stemona alkaloids.
Scheme 1. Retrosynthetic analysis for some Stemona alkaloids
Progression of our synthesis of stemospironine was
attempted as shown in Scheme 3. The oxidation of alcohol
8 with N-chlorosuccinimide in the presence of TEMPO
and tetrabutylammonium chloride in basic medium and a
biphasic system10 provided aldehyde 9 in 91% yield. Spiro-
lactonization was accomplished by esterification of the
tertiary alcohol by reaction with 2-(diethoxyphosphoryl)-
propanoic acid and cyclohexylcarbodiimide,11 followed
by a basic treatment of the intermediate phosphonate, in
71% yield. Next, the silyl protection was removed and the
primary alcohol was oxidized to the corresponding alde-
hyde 12, which treated with ethyl bromomethylacrylate
and zinc12 furnished a roughly 1:1 mixture of bislactones 13
and 14 in 74% overall yield. The relative erythro/threo
configuration of 13 and 14 was tentatively assigned by NMR
in comparison with literature data7,13 and unambigously
established in a more advanced intermediate (vide infra).
attached to C-9 and includes 12 members. Within this
group, only four successful total syntheses have been
described to date. The first one (which was also the first
described synthesis of any Stemona alkaloid) was that of
(þ)-croomine reported by Williams and co-workers in
1989,5 through an impressive 24-step linear sequence,
involving the preliminary construction of a branched car-
bon chain, followed by consecutive ring closures to gen-
erate each heterocycle. Some years later, the same group
completed, by an analogous pathway, the synthesis of
(ꢀ)-stemospironine.6 A second synthesis of (þ)-croomine,
starting from L-pyroglutamic acid, was described by
Martin and Barr.7 We recently described the synthesis of
the proposed stemonidine8 and, in so-doing, demonstrated
that the hypothetical stemonidine was in fact stemospir-
onine, as had been previously suggested.6 Starting from
ꢀ
ꢀ
(5) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc.
1989, 111, 1923.
(6) Williams, D. R.; Fromhold, M. G.; Early, J. D. Org. Lett. 2001, 3,
2721.
(9) Gella, C.; Ferrer, E.; Alibes, R.; Busque, F.; de March, P.;
Figueredo, M.; Font, J. J. Org. Chem. 2009, 74, 6365.
(10) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org.
Chem. 1996, 61, 7452.
(7) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299.
(11) Nahmany, M.; Melman, A. Org. Lett. 2001, 3, 3733.
(12) Rauter, A. P.; Figueiredo, J.; Ismael, M.; Canda, T.; Font, J.;
Figueredo, M. Tetrahedron: Asymmetry 2001, 12, 1131.
ꢀ
ꢀ
ꢀ
(8) Sanchez-Izquierdo, F.; Blanco, P.; Busque, F.; Alibes, R.; de
March, P.; Figueredo, M.; Font, J.; Parella, T. Org. Lett. 2007, 9, 1769.
Org. Lett., Vol. 14, No. 18, 2012
4855

Scheme 3. Preparation of Bislactones 13 and 14
Scheme 4. Synthesis of 11-epi-Stemospironine, 17, and 11-epi-
14-epi-16-epi-Stemospironine, 20
From the threo isomer 13, the remaining transforma-
tions to conclude the synthesis of stemospironine were,
theoretically, the hydrogenation of the endo- and exocyclic
CꢀC double bonds and the deoxygenation of the lactam.
These transformations were undertaken from both epi-
meric bislactones, 13 and 14, separately (Scheme 4).
Despite the fact that the hydrogenation reaction gener-
ates two new stereogenic centers at C11 and C16, lactams 15
and 18 were exclusively isolated from 13 and 14, respec-
tively, in good yields. The configuration at C16 was con-
sistent with the approach of the hydrogen by the less
hindered face of the “eastern” lactone, as expected,8 while
a rational explanation of the configuration at C11, which is
the opposite in stemospironine, may be found by observa-
tion of a simple tridimensional molecular model of com-
pound 13 (Figure 2) that shows how the pyrrolidine ring
obstructs one of the faces of the “western” lactone. Although
other reduction protocols were tried, the C11 epimers of 15
or 18 were never detected. The deoxygenation of lactams 15
and 18, accomplished by treatment with Lawesson’s reagent
and then RaꢀNi, gave 11-epi-stemospironine, 17, and
11-epi-14-epi-16-epi-stemospironine, 20, respectively. The
structural assignment of all the intermediates was confirmed
by X-ray analysis of thiolactam 19 (Figure 3).
Figure 2. Molecular model of bislactone 13 (ChemBio3D Ultra
12.0).
In view of the high diastereoselectivity accomplished
in the reduction of the C10ꢀC11 double bond, we reasoned
that the methylation of an enolate formed by deprotona-
tion of C11 should occur with the same facial selectivity,
leading to the correct stemospironine-like configuration.
Figure 3. Crystal structure of thiolactam 19.
Org. Lett., Vol. 14, No. 18, 2012
ꢀ
(13) Blanco, P.; Busque, F.; de March, P.; Figueredo, M.; Font, J.;
Sanfeliu, E. Eur. J. Org. Chem. 2004, 48.
4856

Scheme 5. Preparation of Bislactones 27 and 28
Scheme 6. Synthesis of Stemospironine and 14-epi-16-epi-Ste-
mospironine, 33
established protocols, namely, catalytic hydrogenation of
the precursor bislactones 27 and 28, followed by deoxy-
genation via the corresponding thiolactams 30 and 32,
respectively. The analytical data of our synthetic stemo-
20
spironine including optical rotation, [R]D ꢀ8.6 (c 0.23,
CHCl3), are in total agreement with those described for the
natural alkaloid, [R]D ꢀ8.2 (c 0.92, CHCl3).14
27
In summary, we have accomplished the syntheses of
stemospironine and the three additional diastereoisomers
11-epi-stemospironine, 17, 11-epi-14-epi-16-epi-stemospir-
onine, 20, and 14-epi-16-epi-stemospironine, 33, through a
flexible strategy, which allows the preparation of different
Stemona alkaloids by splitting the sequence in the appro-
priate late-stage step. The configuration of the stereogenic
center at C11 has been totally controlled by a fine-tunning
of the synthetic pathway.
To test this hypothesis, we decided to investigate the spiro-
lactonization of aldehyde 9 with diethoxyphosphorylacetic
acid (Scheme 5). This reaction delivered the expected lactone
21, along with the undesired Knoevenagel product 22, and
despite many attempts including changing the base, solvent,
and other experimental conditions, this competitive pattern
could not be completely inhibited. Fortunately, compound
22 could be recycled to 21 by treatment of the former with
MeONa in MeOH to afford the latter in a reasonable 53%
yield. Catalytic hydrogenation furnished the saturated lac-
tone 23, which was R-methylated without problems and
with the previously predicted stereoselectivity to furnish 24
in good yield. Installation of the second lactone was made,
as before, by desilylation of 24, followed by oxidation to the
aldehyde 25 and then reaction with ethyl bromomethyla-
crylate and zinc. As expected, this last reaction furnished a
mixture of the threo, 27, and erythro, 28, epimers in a
roughly 1:1 ratio and excellent overall yield. The stereoche-
mical assignment of these bislactones was confirmed by their
conversion to the target alkaloids (Scheme 6).
Acknowledgment. We acknowledge financial support
from DGI (Project CTQ2010-15380) and grants from
MECD (F.S.) and MCI (N.B.). We are grateful to Dr. Inhar
Imaz, Catalan Institute of Nanotechnology, for performing
the X-ray analysis of 19 and to Dr. Tamsyn Montagnon,
University of Crete, for her critical reading of the manuscript.
Supporting Information Available. Experimental de-
tails, spectral data and copies of NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) Sakata, K.; Aoki, K.; Chang, C.-F.; Sakurai, A.; Tamura, S.;
Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457.
The syntheses of stemospironine and 14-epi-16-epi-ste-
mospironine, 33, were completed using the previously
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4857