Synthesis of (-)-swainsonine and (-)-8epi-swainsonine by the addition of allenylmetals to chiral α,β-alkoxy sulfinylimines

Article abstract of DOI:10.1021/ol202747p

The asymmetric synthesis of (-)-swainsonine and (-)-8epi-swainsonine is reported through the addition of either the allenylzinc or the allenyl lithio cyanocuprate reagents derived from [3-(methoxymethoxy)prop-1-ynyl] trimethylsilane to enantiopure α,β-dialkoxy N-tert- butanesulfinylimines derived from Derythronolactone.

Full text of DOI:10.1021/ol202747p

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6452–6455
Synthesis of (À)-Swainsonine and
(À)-8-epi-Swainsonine by the Addition of
Allenylmetals to Chiral R,β-Alkoxy
Sulfinylimines
Julien Louvel,† Fabrice Chemla,*,† Emmanuel Demont,‡ Franck Ferreira,*,† and
,†
ꢀ
Alejandro Perez-Luna*
ꢀ
UPMCÀUniv Paris 6, UMR CNRS 7201, Institut Parisien de Chimie Moleculaire,
ꢀ
Institut de Chimie Moleculaire (FR 2769), case 183, 4 Place Jussieu, 75005 Paris,
France, and Immuno-Inflammation CEDD Medicinal Chemistry, GlaxoSmithKline
R&D, Medicines Research Centre Stevenage, SG1 2NY Hertfordshire, U.K.
fabrice.chemla@upmc.fr; franck.ferreira@upmc.fr; alejandro.perez_luna@upmc.fr
Received October 13, 2011
ABSTRACT
The asymmetric synthesis of (À)-swainsonine and (À)-8-epi-swainsonine is reported through the addition of either the allenylzinc or the allenyl
lithio cyanocuprate reagents derived from [3-(methoxymethoxy)prop-1-ynyl]trimethylsilane to enantiopure R,β-dialkoxy N-tert-butanesulfinylimines
derived from D-erythronolactone.
(À)-Swainsonine (Figure 1) is a naturally occurring
trihydroxylated indolizidine alkaloid found in nature in
several species of flowering plants and some fungi. It
was first isolated in 1973 by Broquist1 from the fungus
Rhizoctonia leguminicola. Since then, it has also been
extracted from diverse fungi such as Embellisia2a and
Metharhizium anisopliae F-36222b and from other plants
of the Swainsona2c (flowering plants of western Australia),
Astragalus, and Oxytropis species2d (herbs and small
shrubs of southwestern USA). Because they cause chronic
intoxication with a variety of neurological disorders in
livestock, these plants are collectively known as locoweeds.
Diverse effects of intoxication including reduced appetite
and consequent reduced growth in young animals and loss
of weight in adults, loss of fertility, and abortion have been
extensively reported.3 All of these severe adverse effects on
livestock, analogous to those of human R-mannosidosis, have
been attributed to the remarkable lysosomal R-mannosidase
inhibitory activities of (À)-swainsonine.4 Furthermore, this
molecule exhibits interesting activity against some mamma-
lian tumor cell lines5 and possesses immunomodulatory2b,6
(3) Panter, K. E.; James, L. F.; Stegelmeier, B. L.; Ralphs, M. H.;
Pfister, J. A. J. Nat. Toxins 1999, 8, 53.
(4) (a) Tulsiani, D. R. P.; Harris, T. M.; Touster, O. J. Biol. Chem.
1982, 257, 7936. (b) Kang, M. S.; Elbein, A. D. Plant Physiol. 1983,
71, 551.
(5) (a) Sun, J. Y.; Yang, H.; Miao, S.; Li, J. P.; Wang, S. W.; Zhu,
M. Z.; Xie, Y. H.; Wang, J. B.; Liu, Z.; Yang, Q. Phytomedicine 2009, 16,
1070. (b) Kajimoto, T.; Node, M. Curr. Top. Med. Chem. 2009, 9, 13.
(6) (a) Kino, T.; Inamura, N.; Nakahara, K.; Kiyoto, S.; Goto, T.;
Terno, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1985, 38,
936. (b) Humphries, M. J.; Matsumoto, K.; White, S. L.; Molyneux,
R. J.; Olden, K. Cancer Res. 1988, 48, 1410.
† UPMCÀUniv Paris 6.
‡ GlaxoSmithKline R&D.
(1) Schneider, M. J.; Ungermach, F. S.; Broquist, H. P.; Harris, T. M.
Tetrahedron 1983, 39, 29.
(7) Elbein, A. D.; Dorling, P. R.; Vosbeck, K.; Horisberger, M.
J. Biol. Chem. 1982, 257, 1573.
(8) (a) Oredipe, O. A.; Furbert-Harris, P. M.; Laniyan, I.; Green,
W. R.; White, S. L.; Olden, K.; Parish-Gause, D.; Vaughn, T.; Shrihar,
R. Int. Immunopharmacol. 2003, 3, 445. (b) Oredipe, O. A.; Furbert-
Harris, P. M.; Laniyan, I.; Griffin, W. M.; Sridhar, R. Int. Immuno-
pharmacol. 2003, 3, 1537.
(2) (a) McLain-Romero, J.; Creamer, R.; Zepeda, H.; Strickland, J.;
Bell, G. J. Anim. Sci. 2004, 82, 2169. (b) Hino, M.; Nakayama, O.;
Tsurumi, Y.; Adachi, K.; Shibata, T.; Kohsaka, M.; Aoki, H.; Imanaka,
H. J. Antibiot. 1985, 38, 926. (c) Colegate, S. M.; Dorling, P. R.;
Huxtable, C. R. Aust. J. Chem. 1979, 32, 2257. (d) Molyneux, R. J.;
James, L. F. Science 1982, 216, 190.
r
10.1021/ol202747p
Published on Web 11/14/2011
2011 American Chemical Society

and antiviral7 activities. (À)-Swainsonine also has poten-
tial uses as an adjuvant for anticancer drugs and other
therapies in use.8
in the literature.9À12 In this paper, we disclose our recent
efforts in this field.
Scheme 1. Synthesis of Imines 4 and 5
Figure 1. (À)-Swainsonine and (À)-8-epi-swainsonine.
Due to their interesting biological properties, (À)-swain-
sonine and a number of its epimers, including (À)-8-epi-
swainsonine (Figure 1), have been the subject of frequent
publications. To date, several reports on the synthesis of
(À)-swainsonine and (À)-8-epi-swainsonine can be found
As part of our ongoing research on the preparation and
use of 3-heterosubstituted allenylmetal species,13 we have
shown that the reaction of N-tert-butanesulfinylimines
with allenylmetals derived from [3-(methoxymethoxy)-
prop-1-ynyl]trimethylsilane can afford either anti14a or
syn14b acetylenic 1,2-amino ethers with high selectivities
depending on the metal salt used. More recently, a stereo-
selective access to O,N,O-stereotriads by addition of 3-
(methoxymethoxy)allenylzinc bromide to N-tert-butane-
sulfinylimines possessing an R-alkoxy stereocenter has
been developed.14c The overall utility of the methodology
is reflected in applications to the synthesis of several
biologically active compounds.13,14b
To broaden further the synthetic scope of our technol-
ogy, we envisioned preparing (À)-swainsonine and (À)-8-
epi-swainsonine starting from imines 4 and 5 having
both an R- and a β-alkoxy stereocenter. These imines
were readily prepared as single isomers in five steps
and good yields (38% and 43%, respectively) from
commercially available D-erythronolactone (1). The
synthetic sequence involved condensation of (SS)- or
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Org. Lett., Vol. 13, No. 24, 2011
6453

(RS)-N-tert-butanesulfinamide with the aldehyde derived
from 3 prepared following a described procedure15
(Scheme 1).
synthesis of O,N,O-stereotriads14c (Scheme 4). In M1, the
imine adopts its less energetic conformation17 and the
lithium cation is chelated by both the oxygen atoms of the
methoxymethyl ether and the sulfinyl group. The addition
occurs from the face opposite to the bulky tert-butyl group.
The high level of stereoselectivity is consistent with a
cooperative effect between the sulfinyl group and the R-
benzyloxy stereocenter by FelkinÀAnh control. Corre-
spondingly, we explain the selectivity observed with 5 with
model M2. In this case an anti-Felkin approach with respect
to the R-benzyloxy stereocenter is involved. Hence the lower
selectivity observed is consistent with a noncooperative
effect between the two stereodirecting groups of the imine.
Scheme 2. Reaction of 4 and 5 with 6
Scheme 4. Stereoselectivity Models with 6
Having imines 4 and 5 in hand, we examined their
reaction with allenylzinc 6 prepared by lithiation of
[3-(methoxymethoxy)prop-1-ynyl]trimethylsilane followed
by transmetalation with ZnBr2 (Scheme 2). Under our
reported condions,14a,c i.e. 4 equiv of 6 at À80 °C in
Et2O, the reaction of 4 led exclusively to adduct 7 in 66%
yield.16 Conversely, the reaction of 5 afforded a mixture of
two isomeric adducts in an 80:20 ratio. Major and minor
isomers were isolated in 75% and 17% yields respectively
bysilicagel columnchromatography. Theconfigurationof
8 was established by completion of the synthesis of (À)-
swainsonine (vide infra). The configuration of the two
newly created stereogenic centers of 7 and 9 was proven
to be identical and opposite respectively to 8 following
their transformation into oxazolidinone 10 (Scheme 3).
We next envisaged securing adducts with a syn relation-
ship between the two newly created stereocenters by
carrying out an addition of allenyl(cyano)cuprate 11 pre-
pared by lithiation of [3-(methoxymethoxy)prop-1-ynyl]-
trimethylsilane followed by transmetalation with CuCN•
2LiCl (Scheme 5).
Scheme 5. Reaction of 4 and 5 with 11
Scheme 3. Stereochemical Assignment of 7 and 9
We explain the high stereoselectivity observed with 4
using model M1 analogous to that postulated for the
Much to our surprise, under our reported conditions14b
at À80 °C in THFÀHMPA, the reaction with 4 afforded
(15) Marshall, J. A.; Seletsky, B. M.; Luke, G. P. J. Org. Chem. 1994,
59, 3413.
(16) Noteworthy is that the excess of allenylmetal used gave
[3-(methoxymethoxy)prop-1-ynyl]trimethylsilane upon hydrolysis.
(17) Ferreira,F.;Audouin,M.;Chemla,F.Chem.;Eur. J. 2005,11, 5269.
6454
Org. Lett., Vol. 13, No. 24, 2011

an inseparable mixture of major 7 and minor 12 stereo-
isomers in 90% overall yield and a 12:7 ratio of 30:70.16
The syn stereochemistry of the two newly created stereo-
centers of 12 was assigned by conversion to the corre-
sponding trans oxazolidinone (isomeric of 10).18
Scheme 7. Synthesis of (À)-Swainsonine and (À)-8-epi-Swain-
sonine
Conversely, under the same conditions, 5 afforded a
mixture of two isomers in a ratio of 92:08. In this case, the
major adduct 13 could be isolated by silica gel column
chromatography in 82% yield. As before, its absolute
stereochemistry was established by completion of the
synthesis of (À)-8-epi-swainsonine (vide infra). Noteworthy
is that the minor isomer was found to be compound 8.
While we cannot put forward a satisfying model to
account for the selectivity observed with 4, the one ob-
servedwith5 can be explainedby modelM3, similar tothat
postulated in previous works14b (Scheme 6). This model, in
which no chelation of the lithium cation occurs, affords 13
(anti-Felkin adduct) as the major isomer.
Scheme 6. Stereoselectivity Model for 13
Having an efficient entry to O,O,N,O-stereotetrads, we
undertook the preparation of (À)-swainsonine and (À)-8-
epi-swainsonine from 8 and 13, respectively.
In conclusion we have developed a stereoselective access
to O,O,N,O-stereotetrads through the coupling of N-tert-
butanesulfinylimines derived from D-erythronolactone with
allenylmetals obtained from [3-(methoxymethoxy)prop-1-
ynyl]trimethylsilane by a lithiation/transmetalation se-
quence. The anti or syn relationship between the two newly
created stereocenters can be selected by simply choosing the
appropriate solvent and metal salt for the transmetalation
step. The synthetic usefulness and flexibility of the method
have been demonstrated by the development of a new access
to (À)-swainsonine and (À)-8-epi-swainsonine in 15 steps
and 11% and 8% overall yield, respectively.
First, product 8 was converted into intermediate 16
through desilylation of the acetylenic position followed
by semi-reduction of the carbonÀcarbon triple bond with
Schwartz’s reagent and desilylation of the tert-butyldi-
methylsilyl ether moiety (Scheme 7).14b The pyrrolizidine
ring of (À)-swainsonine was constructed by mesylation of
the primary hydroxyl group and subsequent treatment of
the resulting mesylate with NaH. Selective acidic removal
of the sulfinyl auxiliary, by treatment with methanolic HCl
at 0 °C, followed by allylation of the nitrogen atom led to
divinylic product18. Upon treatment with2 Â 10mol % of
second generation Grubbs’ catalyst in toluene at 100 °C,
the latter gave bicyclic intermediate 19. Finally, (À)-
swainsonine was obtained by acidic hydrolysis of the
methoxymethyl ether and concomitant hydrogenolysis of
the two benzyl ethers and reduction of the internal alkene.
The productobtainedwasspectroscopicallyand physically
in good agreement with the literature data reported1,2c for
(À)-swainsonine.
Acknowledgment. The authors cordially thank UPMC
and CNRS for financial support and GlaxoSmithKline for
a Ph.D. grant to J.L.
Supporting Information Available. General informa-
tion; experimental procedures; 1H and 13C spectra for all
new compounds, (À)-swainsonine, and (À)-8-epi-swain-
sonine. This material is available free of charge via the
Internet at http://pubs.acs.org.
The same synthetic sequence was successfully applied to
13 to prepare (À)-8-epi-swainsonine in similar yields. The
product obtained exhibits spectroscopical and physical
data in good agreement with those reported (Scheme 7).9m
Note Added after ASAP Publication. This manuscript
was published ASAP on November 14, 2011. In Scheme
5, structures 4 and 5 have been switched and Compound 8
has been updated. The corrected version was reposted on
November 21, 2011.
(18) Further removal of the sulfinyl auxiliary of 12 gave a product
which was found to be isomeric to that obtained from 13. This allowed
unambiguous assignment of the absolute stereochemistry of 12.
Org. Lett., Vol. 13, No. 24, 2011
6455