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.
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Org. Lett., Vol. 8, No. 21, 2006