De novo asymmetric synthesis of D- and L-swainsonine

Article abstract of DOI:10.1021/ol0602811

The enantioselective syntheses of both enantiomers of the indolizidine natural product swainsonine have been achieved in 13 steps from furan. The indolizidine ring system is installed by a one-pot hydrogenolysis of both an azide and an O-Bn group along with an intramolecular reductive amination reaction. The asymmetry of swainsonine was introduced by Noyori reduction of an acylfuran. This route relies upon an Achmatowicz rearrangement, a diastereoselective palladium-catalyzed glycosylation, Luche reduction, and a dihydroxylation reaction.

Full text of DOI:10.1021/ol0602811

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1609-1612
De Novo Asymmetric Synthesis of
- and -Swainsonine
D
L
Haibing Guo and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
Received February 1, 2006
ABSTRACT
The enantioselective syntheses of both enantiomers of the indolizidine natural product swainsonine have been achieved in 13 steps from
furan. The indolizidine ring system is installed by a one-pot hydrogenolysis of both an azide and an O-Bn group along with an intramolecular
reductive amination reaction. The asymmetry of swainsonine was introduced by Noyori reduction of an acylfuran. This route relies upon an
Achmatowicz rearrangement, a diastereoselective palladium-catalyzed glycosylation, Luche reduction, and a dihydroxylation reaction.
Over the years, the indolizidine class of alkaloid natural
products has attracted a lot of attention from the synthetic
community because of their interesting structures and potent
biological activities.1 A unique subset of the indolizidine
natural products is noteworthy because of their ability to
serve as potent glycosidase inhibitors, and as such, they have
received attention from both the synthetic and carbohydrate
communities.2 The potent mannosidase inhibitor, swainsonine
1, has probably received most of this attention.3
of swainsonine. Most routes to swainsonine draw their
asymmetry from carbohydrate starting materials (e.g., Ri-
chardson and Fleet). Of the syntheses, the routes by Cha8
and Pearson3f,9 are the most practical. Cha’s route is
considered the shortest (eight steps from D-erythrose),
whereas the 15-step synthesis of swainsonine by Pearson
provided material on a multigram scale. Key to the success
of the Pearson synthesis is the use of highly diastereoselective
transformations.
In 1995, Hirama was the first to prepare the enantiomer
of swainsonine (ent)-1.10 Hirama synthesized L-swainsonine
in 20 steps from butyrolactone.10a A year later, Fleet
synthesized L-swainsonine for its evaluation as a glycosidase
inhibitor.10b Fleet’s study of L-swainsonine showed that it is
a potent inhibitor of naringinase, an L-rhamnosidase enzyme.
That is to say, a protonated L-swainsonine (ent)-2 functions
as a transition state mimic for the enzymatic hydrolysis of
both L-R-mannose (ent)-3 and L-rhamnose (ent)-4 (Figure
Since the first syntheses by Richardson,4 Fleet,5 Suami,6
and Sharpless7 in 1984, there have been over 30 syntheses
(1) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645-1680. (b) Michael, J. P. Nat.
Prod. Rep. 1997, 14, 619-636.
(2) For a review of iminosugars, see: (a) Sears, P.; Wong, C.-H. Angew.
Chem., Int. Ed. 1999, 38, 2300-2324. (b) Tyler, P. C.; Winchester, B. G.
Iminosugars as Glycosidase Inhibitors 1999, 125-156. (c) Burgess, K.;
Henderson, I. Tetrahedron 1992, 48, 4045-66. (d) Fellows, L. E.; Kite, G.
C.; Nash, R. J.; Simmonds, M. S. J.; Scofield, A. M. Rec. AdV. Phytochem.
1989, 23, 395-427.
(3) For a review of swainsonine syntheses, see: (a) Nemr, A. E.
Tetrahedron 2000, 56, 8579-8629. For more recent syntheses, see: (b)
Martin, R.; Murruzzu, C.; Pericas, M. A.; Riera, A. J. Org. Chem. 2005,
70, 2325-2328. (c) Heimgaertner, G.; Raatz, D.; Reiser, O. Tetrahedron
2005, 61, 643-655. (d) Song, L.; Duesler, E. N.; Mariano, P. S. J. Org.
Chem. 2004, 69, 7284-7293. (e) Lindsay, K. B.; Pyne, S. G. Aust. J. Chem.
2004, 57, 669-672. (f) Pearson, W. H.; Ren, Y.; Powers, J. D. Heterocycles
2002, 58, 421-430. (g) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002,
67, 7774-7780. (h) Buschmann, N.; Rueckert, A.; Blechert, S. J. Org.
Chem. 2002, 67, 4325-4329. (i) Zhao, H.; Hans, S.; Cheng, X.; Mootoo,
D. R. J. Org. Chem. 2001, 66, 1761-1767.
(5) Fleet, G. W. J.; Gough, M. J.; Smith, P. W. Tetrahedron Lett. 1984,
25, 1853-1856.
(6) Suami, T.; Tadano, K.; Iimura, Y. Chem. Lett. 1984, 513-516.
(7) Adams, C. E.; Walker, F. J.; Sharpless. K. B. J. Org. Chem. 1985,
50, 420-422.
(8) Bennett, R. B.; Choi, J. R.; Montgomery, W. D.; Cha, J. K. J. Am.
Chem. Soc. 1989, 111, 2580-2582.
(9) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 7217-7221.
(10) (a) Oishi, T.; Iwakuma, T.; Hirama, M.; Ito, S. Synlett 1995, 404-
406. (b) Davis, B.; Bell, A. A.; Nash, R. J.; Watson, A. A.; Griffiths, R.
C.; Jones, M. G.; Smith, C.; Fleet, G. W. J. Tetrahedron Lett. 1996 37,
8565-8568.
(4) Ali, M. H.; Hough, L.; Richardson, A. C. J. Chem. Soc., Chem.
Commun. 1984, 447-448.
10.1021/ol0602811 CCC: $33.50
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Published on Web 03/21/2006

1).10 Typically, the naturally occurring mannose exists in its
D-form, and the naturally occurring 6-deoxymannose, rham-
nose, exist in its L-form.
Scheme 1. Retrosynthetic Analysis of Swainsonine (1)
lective dihydroxylation reaction should install the manno-
stereochemistry in 6.
Figure 1. Swainsonine (1) and L-enantiomer (ent)-1.
Finally, we planned on a global hydrogenolysis/alkylation/
reductive amination sequence to convert azidosugar 6 into
swainsonine 1 via imine 5 (Scheme 2). This one-pot
As a continuation of our efforts aimed at the de novo
synthesis of oligosaccharides, we wanted to prepare swain-
sonine-containing manno-oligosaccharides. The goal of these
efforts is to develop a more selective glycosylation inhibitor,
with the hope that it will display better antitumor and antiviral
activity than swainsonine.11 Thus, we became interested in
a practical synthesis of swainsonine. In particular, we desired
a route that was shorter and as practical as the Pearson
approach. Since we wanted access to both the D- and
L-swainsonine, we planned to synthesize swainsonine by a
de novo route.
Scheme 2. Key Reductive Cyclization to Swainsonine (1)
Retrosynthetically, we envisioned that we could establish
the D/L stereochemistry by a Noyori reduction of acylfuran
10, which can be prepared in one step from furan and
γ-butyrolactone (Scheme 1). An Achmatowicz reaction
should convert the furyl alcohol 9 into a C-6-substituted
pyranone 8.12 A stereoselective protection of the anomeric
alcohol followed by ketone reduction and a palladium-
catalyzed allylic substitution should convert 8 into 7. With
the C-1,4,5 stereochemistry established in 7, a diastereose-
transformation would initially involve an azide reduction to
form the aminosugar 13, which after an intramolecular
alkylation would undergo hydrogenolysis to free up the
anomeric hydroxyl group to form 14. Finally, under the same
reaction conditions, 14 should undergo a reductive amination
reaction to form swainsonine.13 Herein, we describe our
successful efforts to implement this strategy for the de novo
synthesis of swainsonine.
(11) For the bioactivities of swainsonine, see: (a) Elbein, A. D. FASEB
J. 1991, 5, 3055-3063. (b) Goss, P. E.; Reid, C. L.; Bailey, D.; Dennis, J.
W. Clin. Cancer Res. 1997, 3, 11077-11086. (c) Galustian, C.; Foulds,
S.; Dye, J. F.; Guillou, P. J. Immunopharmacol. 1994, 27, 165-172. (d)
Grzegorzewski, K.; Newton, S. A.; Akiyama, S. K.; Sharrow, S.; Olden,
K.; White, S. L. Cancer Commun. 1989, 1, 373-279. (e) Elbein, A. D.
Annu. ReV. Biochem 1987, 56, 497-534. (f) Cenci Di Bello, I.; Fleet, G.;
Namgoong, S. K.; Tadano, K.; Winchester, B. Biochem. J. 1989, 259, 855-
861.(g) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199-210.
(h) Tulsiani, D. R. P.; Harris, T. M.; Touster, O. J. Biol. Chem. 1982, 257,
7936-7939. (i) Kino, T.; Inamura, N.; Nakahara, K.; Kiyoto, S.; Goto, T.;
Terano, H.; Kohsaka, M. J. Antibiot. 1985, 38, 936-940.
(12) An Achmatowicz reaction is the oxidative rearrangement of furyl
alcohols to 2-substituted 6-hydroxy-2H-pyran-3(6H)-ones; see: (a) Ach-
matowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165-176. For its recent
use in carbohydrate synthesis, see: (b) Guo, H.; O’Doherty, G. A. Org.
Lett. 2005, 7, 3921-3924 and references therein.
As outlined in Scheme 3, our approach to both D- and
L-swainsonine began with commercially available furan and
(13) In the Fleet synthesis of swainsonine a similar reductive amination
was employed; see ref 5.
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Org. Lett., Vol. 8, No. 8, 2006

With pyranone 18 suitably protected at the anomeric
position, we next investigated the stereoselective azide
incorporation at C-4 using palladium catalysis (Scheme 5).
Scheme 3. Enantioselective Synthesis of Pyranone (ent)-8
Scheme 5. Palladium-Catalyzed C-4 Azide Incorporation
γ-butyrolactone 12.14 Treatment of γ-butyrolactone 12 with
a THF solution of 2-lithiofuran 11 gave furyl ketone 16 in
good yield (74%). The primary alcohol of 16 was protected
as a TBS-ether using TBSCl/imidazole in DMF, providing
10 in an excellent yield (98%). The asymmetric reduction
of acylfuran 10 under modified Noyori conditions15 afforded
the desired furyl alcohol (ent)-9 in 89% yield with high
enantiomeric purity (>96% ee). Exposing furyl alcohol
(ent)-9 to the typical Achmatowicz conditions (NBS in THF/
H2O) gave the ring-expanded product pyranone (ent)-8 in
good yield (84%).
The C-4 ketone in 18 was diastereoselectively reduced with
NaBH4 (CH2Cl2/MeOH, -78 °C) forming the equatorial
allylic alcohol 19 in excellent yield (94%). To convert the
allylic alcohol of 19 into a better leaving group, it was
acylated with methyl chloroformate to form the mixed
carbonate 20 (72%). Exposing carbonate 20 to the conditions
developed by Sinou17 (TMSN3, (Pd(allyl)Cl)2/1,4-bis(diphen-
ylphosphino)butane) afforded a single regio- and stereoiso-
meric allylic azide (ent)-7 in a good yield (77%).18
Before the one-pot reductive cyclization could be at-
tempted, the TBS-protected primary alcohol needed to be
converted into a good leaving group and the C-2/C-3 diol
needed to be introduced (Scheme 6). Deprotection of TBS-
ether (ent)-7 with a THF solution of TBAF gave the primary
alcohol 21 in near-quantitative yield (99%). The primary
alcohol in 21 was converted to a mesylate (MeSO2Cl, Et3N,
0 °C), forming 22 in similarly excellent yield (99%). The
manno-stereochemistry in diol (ent)-6 was stereoselectively
installed by dihydroxylation of allylic azide 22 under Upjohn
conditions (OsO4/NMO, 93%).19 Finally, L-swainsonine
(ent)-1 was obtained by exhaustive hydrogenation of an
ethanol solution of diol (ent)-6 with Pd(OH)2/C in an
excellent yield of 88% (100 psi, 3 days).20
To diastereoselectively protect the anomeric position as
an O-benzyl ether, we employed a two-step acylation/Pd-
catalyzed glycosylation (Scheme 4). Diastereoselective acy-
Scheme 4. Palladium-Catalyzed C-1 Protection
Similarly, a protected form of L-Swainsonine 29 could also
be synthesized from (ent)-7 by incorporating an acetonide
(16) (a) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125,
12406-12407. (b) Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem.
Soc. 2004, 126, 3428-3429. (c) Babu, R. S.; O’Doherty, G. A. J.
Carbohydr. Chem. 2005, 24, 169-177.
lation of hemiacetal (ent)-8 with (Boc)2O provided the Boc-
protected pyranone 17 (8:1 R/â ratio) in excellent yield
(85%). Coupling of pyranone 17 with benzyl alcohol in the
presence of 2.5% palladium(0) and 5% triphenylphosphine
gave Bn-protected pyranone 18 as a single diastereomer in
excellent yield (88%).12b,16
(17) de Oliveira, R. N.; Cottier, L.; Sinou, D.; Srivastava, R. M.
Tetrahedron 2005, 61, 8271-8281.
(18) Presumably, because of the rigid nature of the 7 and the equatorial
nature of the allylic azide no [3,3] sigmatropic rearrangement was observed;
see: Feldman, A. K.; Colasson, B.; Sharpless, K. B.; Fokin, V. V. J. Am.
Chem. Soc. 2005, 127, 13444-13445.
(19) (a) Hudlicky, T.; Abboud, K. A.; Bolonick, J.; Maurya, R.; Stanton,
M. L.; Thorpe, A. J. Chem. Commun. 1996, 1717-1718. (b) Takao, K.-I.;
Hara, M.; Tsujita, T.; Yoshida, K.-I.; Tadano, K.-I. Tetrahedron Lett. 2001,
42, 4665-4668.
(20) By simply switching the (S,S)-Noyori reagent for the reduction of
10 to (ent)-9 to the (R,R)-Noyori reagent (10 to 9), D-swainsonine was
prepared from 9 in nearly identical overall yield.
(14) While we have prepared both D- and L-swainsonine, for simplicity
herein we only show the L-enantiomer.
(15) Previously, we have shown that a lower ratio of HCO2H/Et3N (1:1
instead of 2:1) was required for the Noyori reduction of compounds with
primary TBS groups; see: Li, M.; Scott, J. G.; O’Doherty, G. A.
Tetrahedron Lett. 2004, 45, 1005-1009.
Org. Lett., Vol. 8, No. 8, 2006
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Scheme 6. Diastereoselective C-2/3 Dihydroxylation and
Reductive Cyclization to L-Swainsonine (ent)-1
Scheme 7. Synthesis of Swainsonine (ent)-1 via a Protected
Swainsonine (29)
protection (Scheme 7). Once again, a stereoselective dihy-
droxylation of allylic azide (ent)-7 was performed (OsO4/
NMO), yielding diol 24 (92%). Protecting diol 24 with 2,2-
dimethoxypropane and acid catalyst p-TsOH afforded
acetonide 25 (97%), whose TBS group was deprotected
(TBAF) to provide primary alcohol 26. Mesylation of 26
(MeSO2Cl, Et3N, 0 °C) gave mesylate 28 in excellent yield
(99%). Once again, exhaustive hydrogenation/hydrogenolysis
of a THF/ethanol solution of azide 28 (100 psi, 4 days)
afforded the protected swainsonine 29, which was easily
deprotected (95%) to give L-swainsonine (ent)-1. This
alternative sequence gave L-swainsonine (ent)-1 in similarly
excellent overall yield (70% from allylic azide (ent)-7 in six
steps).20 Swainsonine prepared by either of these two
methods provided material with physical and spectral data
(melting point, 1H NMR, 13C NMR, IR, and optical rotation)
which matched that of the natural material.3-10
towicz reaction, and a palladium-catalyzed glycosylation for
natural product synthesis. This approach provided both
enantiomers of swainsonine in 17% overall yields from furan
11, respectively. It is also worth noting that this route
provided swainsonine in comparable efficiency to the previ-
ous carbohydrate-based approach;3-10 however, this de novo
approach started from achiral sources and required the use
of only two protecting groups. Further application of this
approach to the synthesis of swainsonine containing oli-
gosaccharides and biological testing is ongoing.
Acknowledgment. We are grateful to the NIH (GM63150)
and NSF (CHE-0415469) for support of our research
program and NSF-EPSCoR (0314742) for a 600 MHz NMR
at WVU.
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.
In conclusion, two short de novo asymmetric syntheses
of swainsonine (1) and its enantiomer (ent)-1 have been
developed. This highly enantio- and diastereocontrolled route
illustrates the utility of the Noyori reduction, the Achma-
OL0602811
1612
Org. Lett., Vol. 8, No. 8, 2006