Asymmetric [2 + 2] cycloaddition: Total synthesis of (-)-swainsonine and (+)-6-epicastanospermine

Article abstract of DOI:10.1021/ol0617751

(Chemical Equation Presented) An asymmetric total synthesis of (-)-swainsonine and (+)-6-epicastanospermine is described from a common intermediate, which is obtained through diastereoselective [2 + 2] cycloaddition of dichloroketene to a chiral enol ether.

Full text of DOI:10.1021/ol0617751

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4739-4742
Asymmetric [2
Total Synthesis of (
)-6-Epicastanospermine†
+
2] Cycloaddition:
−)-Swainsonine and
(+
Julien Ceccon, Andrew E. Greene, and Jean-Franc¸ois Poisson*
Chimie Recherche (LEDSS), UniVersite´ Joseph Fourier, 38041 Grenoble, France
jean-francois.poisson@ujf-grenoble.fr
Received July 19, 2006
ABSTRACT
An asymmetric total synthesis of (−)-swainsonine and (+)-6-epicastanospermine is described from a common intermediate, which is obtained
through diastereoselective [2 2] cycloaddition of dichloroketene to a chiral enol ether.
+
The [2 + 2] cycloaddition of dichloroketene (DCK) to chiral
enol ethers provides an efficient enantioselective approach
to substituted 4-hydroxypyrrolidinones.1 This methodology,
which has already been used successfully for the synthesis
of various relatively simple natural alkaloids,1b-h appeared
also to offer possible access to complex polyhydroxylated
indolizidines, such as (-)-swainsonine (1), (+)-6-epicastano-
spermine (2), and (+)-castanospermine (3) (Figure 1). These
naturally occurring azasugars, which are efficient glycosidase
inhibitors,2 have received considerable attention due to their
biological activities and the challenge inherent in their total
synthesis.3
Figure 1. Polyhydroxylated indolizidines.
Since a cis-trans aminodiol core is shared by many of
the polyhydroxylated indolizidines, (e.g., 1-3, highlighted
in red, Figure 1), it seemed a unified route to several of these
important compounds might be possible from a single
† Dedicated to the memory of an outstanding person, Dr. Pierre Potier
(deceased February 3, 2006).
(1) (a) Nebois, P.; Greene, A. E. J. Org. Chem. 1996, 61, 5210-5211.
(b) Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E. J. Org. Chem. 1998,
63, 4660-4663. (c) Delair, P.; Brot, E.; Kanazawa, A.; Greene, A. E. J.
Org. Chem. 1999, 64, 1383-1386. (d) Pourashraf, M.; Delair, P.; Rasmus-
sen, M. O.; Greene, A. E. J. Org. Chem. 2000, 65, 6966-6972. (e)
Rasmussen, M. O.; Delair, P.; Greene, A. E. J. Org. Chem. 2001, 66, 5438-
5443. (f) Roche, C.; Delair, P.; Greene, A. E. Org. Lett. 2003, 5, 1741-
1744. (g) Muniz, M. N.; Kanazawa, A.; Greene, A. E. Synlett 2005, 1328-
1330. (h) Ceccon, J.; Poisson, J. F.; Greene, A. E. Synlett 2005, 1413-
1416. (i) Roche, C.; Kadlecikova, K.; Veyron, A.; Delair, P.; Philouze, C.;
Greene, A. E.; Flot, D.; Burghammer, M. J. Org. Chem. 2005, 70, 8352-
8363.
(2) (a) Look, G. C.; Fotsch, C. H.; Wong, C. H. Acc. Chem. Res. 1993,
26, 182-190. (b) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed.
1999, 38, 750-770. (c) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed.
1999, 38, 2300-2324. (d) Watson, A. A.; Fleet, G. W. J.; Asano, N.;
Molyneux, R. J.; Nash, R. J. Phytochemistry 2001, 56, 265-295. (e)
Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. ReV. 2002, 102,
515-553. (f) Nash, R. Chem. World 2004, 1, 42-44.
(3) For reviews on the indolizidines, see: (a) El Nemr, A. Tetrahedron
2000, 56, 8579-8629. (b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet,
G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645-1680. (c) Michael, J.
P. Nat. Prod. Rep. 2005, 22, 603-626. (d) Pyne, S. G. Curr. Org. Synth.
2005, 2, 39-57 and references cited therein.
10.1021/ol0617751 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/13/2006

intermediate. We now describe the synthesis of (-)-swain-
sonine and (+)-6-epicastanospermine from a common in-
termediate.
(-)-Swainsonine was first isolated in 1973 from the fungus
Rhizoctonia leguminicolain.4 It has been identified as the
major toxin in the Australian legume Swainsona canescens5
and shown to be responsible for the “peastruck disease” in
sheep. It has also been found in Astragalus and Oxytropis
species (commonly called locoweed) and is currently ex-
tracted in gram quantities from the latter.6 Swainsonine is a
potent inhibitor of R-D-mannosidase and thus exhibits notable
biological properties, such as alteration of virus proliferation
and antimetastatic activity.7 It has been tested in many
countries as an adjunct to chemotherapy and is currently in
phase II clinical trials in the United States for the treatment
of cancer.8 Due to these exciting biological activities, as well
as its interesting structure, (-)-swainsonine has been a
particularly popular target for total synthesis.3,9 Most of the
approaches to date, however, parlay carbohydrate chirality.
(-)-Swainsonine, it seemed, would be obtainable by
dihydroxylation of dehydroindolizidine V,10 which could
arise through ring-closing metathesis (RCM) of IV (Figure
2). Despite the obviousness of forming the indolizidine
skeleton through the use of RCM to close the six-membered
ring, no total synthesis of (-)-swainsonine has so far been
reported using this strategy.11 The substrate for the metathesis
reaction, in turn, could originate from allylic alcohol III,
the envisioned pivotal intermediate for the preparation of
several of the polyhydroxylated indolizidines. This amino-
diol,12 secured by allylic oxidation of the Beckmann ring-
expanded product II, has recently been used in the synthesis
of the unusual amino acid (-)-detoxinine1h and in a prepara-
tion of (+)-retronecine.1i
Figure 2. Retrosynthetic approach to (-)-swainsonine.
1).13 The potassium alkoxide of this alcohol (4, R*OH)
reacted with trichloroethylene to give dichloroenol ether 5
in high yield. Treatment of the latter with 2 equiv of
n-butyllithium produced an ynol ether acetylide, which was
alkylated in situ with allyl iodide to yield ynol ether 6a. The
selective partial reduction of the triple bond in 6a with
diisobutylaluminum hydride in toluene14 at 50 °C then
afforded enol ether 6b, free of the allyl-reduced product
partially formed under catalytic hydrogenation conditions.15
Scheme 1. Synthesis of the Key Intermediate
Pyrrolidinone 9a was synthesized starting from the S
enantiomer of 1-(2,4,6-triisopropylphenyl)ethanol (Scheme
(4) (a) Guengerich, F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem.
Soc. 1973, 95, 2055. (b) Schneider, M. J.; Ungemach, F. S.; Broquist, H.
P.; Harris, T. M. Tetrahedron 1983, 29-32.
(5) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem. 1979,
32, 2257-2264.
(6) Gardner, D. R.; Lee, S. T.; Molyneux, R. J.; Edgar, J. A. Phytochem.
Anal. 2003, 14, 259-266.
(7) (a) Olden, K.; Breton, P.; Grzegorzewski, K.; Yasuda, Y.; Gause, B.
L.; Oredipe, O. A.; Newton, S. A.; White, S. L. Pharmacol. Ther. 1991,
50, 285-290. (b) Galustian, C.; Foulds, S.; Dye, J. F.; Guillou, P. J.
Immunopharmacology 1994, 27, 165-172.
(8) (a) Klein, J.-L. D.; Roberts, J. D.; George, M. D.; Kurtzberg, J.;
Breton, P.; Chermann, J.-C.; Olden, K. Br. J. Cancer 1999, 80, 87-95. (b)
Shaheen, P.; Stadler, W.; Elson, P.; Knox, J.; Winquist, E.; Bukowski, R.
InVest. New Drugs 2005, 23, 577-581.
The [2 + 2] cycloaddition of dichloroketene (DCK) to
enol ether 6b generated with excellent diastereoselectivity
(ca. 95%, H NMR) dichlorocylobutanone 7, which was
directly subjected to Beckmann ring expansion using Tamu-
ra’s reagent (MSH).16 Dechlorination of the uniquely formed
regioisomer with zinc-copper couple in acidic methanol then
afforded pyrrolidinone 8 in 34% overall yield for the 5 steps
(80%/step). It should be noted that this sequence was
routinely performed on a multigram scale with only a final
1
(9) For recent syntheses, see: (a) Mart´ın, R.; Murruzzu, C.; Perica`s, M.
A.; Riera, A. J. Org. Chem. 2005, 70, 2325-2328. (b) Guo, H.; O’Doherty,
G. A. Org. Lett. 2006, 8, 1609-1612 and references cited therein.
(10) (a) Mukai, C.; Sugimoto, Y.; Miyazawa, K.; Yamaguchi, S.;
Hanaoka, M. J. Org. Chem. 1998, 63, 6281-6287. (b) de Vicente, J.;
Arrayas, R. G.; Canada, J.; Carretero, J. C. Synlett 2000, 53-56. (c)
Buschmann, N.; Ruckert, A.; Blechert, S. J. Org. Chem. 2002, 67, 4325-
4329. (d) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774-7780.
(11) See, however, ref 9a. For the application of RCM to form the
6-membered ring in the preparation of other indolizidines, see: (a) Martin,
S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Pa¨tzel, M.; Ramser, M. N.;
Wagman, A. S. Tetrahedron 1996, 52, 7251-7264. (b) Park, S. H.; Kang,
H. J.; Ko, S.; Park, S.; Chang, S. Tetrahedron: Asymmetry 2001, 12, 2621-
2624. (c) El-Nezhawy, A. O. H.; El-Diwani, H. I.; Schmidt, R. R. Eur. J.
Org. Chem. 2002, 4137-4142. (d) Chandra, K. L.; Chandrasekhar, M.;
Singh, V. K. J. Org. Chem. 2002, 67, 4630-4633.
(13) This chiral alcohol was obtained by resolution of the racemic
material. See: Delair, P.; Kanazawa, A. M.; M. B. de Azevedo, M.; Greene,
A. E. Tetrahedron: Asymmetry 1996, 7, 2707-2710.
(14) Denmark, S. E.; Dixon, J. A. J. Org. Chem. 1998, 63, 6178-6195.
(15) There is usually ca. 10% reduction of the terminal double bond
under catalytic hydrogenation conditions.
(16) MSH ) O-mesitylenesulfonylhydroxylamine. See: Tamura, Y.;
Minamikawa, J.; Ikeda, M. Synthesis 1977, 1-17.
(12) With R* ) (S)-1-(2,4,6-triisopropylphenyl)ethyl.
4740
Org. Lett., Vol. 8, No. 21, 2006

purification. The assignment of the indicated stereochemistry
to the major diastereomer was initially based on considerable
precedent1 and was subsequently confirmed by the realization
of the synthesis of (-)-swainsonine. The minor lactam
diastereoisomer (ca. 5%), conveniently, filtered out over the
course of the synthesis.
Scheme 3. Synthesis of (-)-Swainsonine
Allylic oxidation of 8 under Sharpless conditions (SeO2,
t-BuOOH, ClCH2CH2Cl, reflux, 3.3 h) afforded the corre-
sponding allylic alcohols 9a,b in 56% yield as a difficult to
separate 1:1 mixture, together with 25% of recovered starting
material. These conditions were found to be optimal, as the
over-oxidized enone product was unstable under the reaction
conditions. Certain variations in the starting material, for
example, replacing the chiral auxiliary with a benzoyl group,
did afford the allylic alcohols in a better ratio, but at the
expense of the yield (2:1 ratio and 36% yield for benzoyl).
The allylic alcohols were therefore oxidized with the Dess-
Martin periodinane to the corresponding sensitive enone,
which was then directly reduced using LiAlH4 in THF at
-25 °C. The desired cis-anti isomer 9a was obtained as
the major product (92:8 diastereoisomeric ratio) in 82% yield
for the two steps. The assignment of the relative stereo-
chemistry in the major diastereoisomer was made through
1H NMR analysis of the oxazolidinone derivative 11 (LiAlH4;
carbonyldiimidazole, Scheme 2): a coupling constant of 8.2
elimination of the secondary hydroxyl group by using the
Martin sulfurane in ether then afforded the dehydroindolizi-
dine 16, which was used without purification.19 This
dehydration was particularly difficult, and numerous alterna-
tive conditions and procedures proved unsuccessful. The
sulfurane in dichloromethane or acetonitrile, instead of ether,
for example, failed to effect the elimination.
Dihydroxylation of 16 furnished the diol as a 20:1 mixture
of diastereoisomers, in favor of the desired endo isomer. The
observed selectivity in this reaction, which is concordant with
previously reported results with similar indolizidines, is
undoubtedly due to steric hindrance on the exo face by the
large silyloxy group and the pseudoaxial allylic protons.10
To facilate purification, the mixture was desilylated with
TBAF and the resulting triol peracetylated with acetic
anhydride in pyridine, which gave, after SiO2 chromatogra-
phy, pure triacetate 17 (41% over the last four steps, 80%/
step). This highly stereocontrolled total synthesis of (-)-
swainsonine was completed by treatment of 17 with the ion-
exchange resin IRA-402 (OH- form). (-)-Swainsonine
([R]20D -86.2 (c 1.0, MeOH), mp 143-144 °C) so obtained
was spectroscopically and chromatographically identical with
an authentic sample of the natural product ([R]20D -87.2 (c
2.1, MeOH), mp 144-145 °C).4b,20
Indolizidinone 14, the product of ring-closing metathesis,
also seemed to be an ideal intermediate for a straightforward
synthesis of (+)-6-epicastanospermine;21,22 however, the
absolute configuration required for this natural product is
opposite to that for (-)-swainsonine. The synthesis was thus
repeated starting now from the antipodal R enantiomer of
alcohol 4, which produced ent-14 in 10.4% overall yield.
Scheme 2. Assignment of Relative Stereochemistry
Hz was observed for the oxazolidinone protons, which
indicated a cis relationship17 and thus cis-anti stereochem-
istry in 9a.
With this central intermediate in hand, the synthesis of
(-)-swainsonine was pursued (Scheme 3). The allylic alcohol
was converted into its triisopropylsilyl ether 12 through
disilylation, followed by selective hydrolysis of the silyl
imidate with acetic acid (81%). N-Allylation of the lactam
was next achieved in 95% yield under phase-transfer
conditions (PTC).18 Ring-closing metathesis of 13 using the
Grubbs II catalyst could be efficiently achieved in refluxing
dichloromethane to provide bicyclic 14 in 84% yield.
Hydrogenation of the double bond over palladium on
charcoal was followed by selective cleavage of the chiral
auxiliary using TFA to furnish indolizidinone 15 (84% yield).
Reduction of the lactam with LiAlH4 and subsequent
(19) Compound 16 was contaminated with a byproduct from the Martin
sulfurane, but this impurity did not affect the outcome of the next step.
(20) The spectral data and chromatographic behavior were compared with
those of a sample of (-)-swainsonine purchased from Sigma.
(21) (+)-6-Epicastanospermine has been isolated from Castanospermum
australe and is a potent inhibitor of amyloglucosidase. See: (a) Molyneux,
R. J.; Roitman, J. N.; Dunnheim, G.; Szumilo, T.; Elbein, A. D. Arch.
Biochem. Biophys. 1986, 251, 450-457. (b) Nash, R. J.; Fellows, L. E.;
Girdhar, A.; Fleet, G. W. J.; Peach, J. M.; Watkin, D. J.; Hegarty, M. P.
Phytochemistry 1990, 29, 1356-1358.
(17) (a) Futagawa, S.; Inui, T.; Shiba, T. Bull. Chem. Soc. Jpn. 1973,
46, 3308-3310. (b) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Laboroi,
F.; Mazzanti, G.; Ricci, A.; Varchi, G. J. Org. Chem. 1999, 64, 8008-
8013. (c) Poisson, J. F.; Normant, J. F. J. Org. Chem. 2000, 65, 6553-
6560.
(18) At this stage, the minor diastereomer derived from 9b could be
completely removed chromatographically.
Org. Lett., Vol. 8, No. 21, 2006
4741

Dihydroxylation of the double bond with osmium tetrox-
ide23 led selectively (>20:1) to the corresponding diol, which
was directly converted into its acetonide derivative 18,
isolated as a single isomer in 80% yield (two steps, Scheme
4). In the most stable conformation of the olefin (AM1
Scheme 4. Synthesis of (+)-6-Epicastanospermine
Figure 3. Attack on the less hindered face of ent-14.
In summary, the total synthesis of two natural polyhy-
droxylated indolizidines has been achieved in a highly
stereoselective manner from a common intermediate, ob-
tained by asymmetric [2 + 2] cycloaddition. To underscore
the general nature of our approach, we are currently applying
a similar strategy from this same intermediate for the
synthesis of (+)-castanospermine.
calculations), the six-membered ring is quite flat and R-face-
protected by the bulky silyloxy group, which could explain
the observed face selectivity (Figure 3). The lactam was
reduced with LiAlH4 in THF to give amine 19, and then all
of the protecting groups were simultaneously removed with
acidic ethanol to afford (+)-6-epicastanospermine in excel-
lent yield. The spectroscopic data for 2 ([R]20D +2.3 (c 0.7,
MeOH)) were in complete agreement with the reported data
for the naturally derived product.24
Acknowledgment. We thank Professor P. Dumy (UJF)
for his interest in our work. Financial support from the CNRS
and the Universite´ Joseph Fourier (UMR 5616, FR 2607)
and a fellowship award (to J.C.) from the Research Ministry
(MENRT) are gratefully acknowledged.
(22) For a review on syntheses of 2 through 1992, see: (a) Burgess, K.;
Henderson, I. Tetrahedron 1992, 48, 4045-4066. For subsequent syntheses,
see: (b) Kang, S. H.; Kim, J. S. J. Chem. Soc., Chem. Commun. 1998,
1353-1354. (c) Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc.
1999, 121, 3046-3056. (d) Zhang, H.-X.; Xia, P.; Zhou, W.-S. Tetrahedron
2003, 59, 2015-2020. (e) Kim, J. H.; Seo, W. D.; Lee, J. H.; Lee, B. W.;
Park, K. H. Synthesis 2003, 2473-2478.
(23) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973-1976. (b) Chevallier, F.; Le Grognec, E.; Beaudet, I.;
Fliegel, F.; Evain, M.; Quintard, J.-P. Org. Biomol. Chem. 2004, 2, 3128-
3133.
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0617751
(24) Gerspacher, M.; Rapoport, H. J. Org. Chem. 1991, 56, 3700-3706.
4742
Org. Lett., Vol. 8, No. 21, 2006