Nitrenium ion-mediated alkene bis-cyclofunctionalization: Total synthesis of (-)-swainsonine

Article abstract of DOI:10.1021/ol2006117

Chemical equations presented. The total synthesis of (-)-swainsonine from 2,3-O-isopropylidene-d-erythrose in 12 steps and an overall yield of 28% is reported. The pivotal transformation in our route to this indolizidine alkaloid is the formation of the pyrrolidine ring and C-8a/8 stereodiad through the diastereoselective, bis-cyclofunctionalization of an γ,ss-unsaturated O-alkyl hydroxamate. This transformation is believed to proceed via the intramolecular capture of an N-acyl-N-alkoxyaziridinium ion generated by the diastereoselective addition of a singlet acylnitrenium ion to the pendant alkene.

Full text of DOI:10.1021/ol2006117

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2376–2379
Nitrenium Ion-Mediated Alkene
Bis-Cyclofunctionalization: Total
Synthesis of (ꢀ)-Swainsonine
Duncan J. Wardrop* and Edward G. Bowen
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061, United States
wardropd@uic.edu
Received March 8, 2011
ABSTRACT
The total synthesis of (ꢀ)-swainsonine from 2,3-O-isopropylidene-D-erythrose in 12 steps and an overall yield of 28% is reported. The pivotal
transformation in our route to this indolizidine alkaloid is the formation of the pyrrolidine ring and C-8a/8 stereodiad through the
diastereoselective, bis-cyclofunctionalization of an γ,δ-unsaturated O-alkyl hydroxamate. This transformation is believed to proceed via the
intramolecular capture of an N-acyl-N-alkoxyaziridinium ion generated by the diastereoselective addition of a singlet acylnitrenium ion to the
pendant alkene.
(ꢀ)-Swainsonine (1), an alkaloid isolated first from the
fungal plant pathogen Rhizoctonia leguminicola1 and sub-
sequently from a range of other sources,2 has become one
of the most keenly studied of all naturally occurring
azasugars (Scheme 1). Interest in this indolizidine stems
principally from its role as an inhibitor of Golgi R-man-
nosidase II (GMII)3,4 and, to a lesser extent, lysosomal
R-mannosidase (LM).5 While the latter enzyme is involved in
the catabolism of N-linked oligosaccharides, GMII plays a
key role in the biosynthesis of glycoproteins, specifically in
the formation of their trimannose core.6 Since alterations
in the normal glycosylation patterns of such proteins are
often found onthe surface of tumorcellsand are associated
with metathesis and disease progression, inhibition of
GMII offers potential as a cancer treatment. In this
context, swainsonine is notable as being the first glycopro-
tein processing inhibitor selected for clinical evaluation.7
Most recently, 1 has also been found to be a strain-selective
inhibitor of infectious mammalian prions,8 which are
associated with a variety of neurodegenerative disorders
including CreutzfeldtꢀJakob disease and kuru.9 Although
the mechanism of action in this case awaits clarification,
swainsonine’s activity does not appear to be associated its
glycosidase inhibitory properties.
(1) (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, 39, 29.
(2) (a) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem.
1979, 32, 2257 (Swainsona canescens). (b) Molyneux, R. J.; James, L. F.
Science 1982, 216, 190 (Astragalus lentiginosus). (c) Hino, M.; Nakaya-
ma, O.; Tsurumi, Y.; Adachi, K.; Shibata, T.; Terano, H.; Kohsaka, M.;
Aoki, H.; Imanaka, H. J. Antibiot. 1985, 38, 926 (Metarhizium anisoplia).
(d) Molyneux, R. J.; McKenzie, R. A.; O’Sullivan, B. M.; Elbein, A. D.
J. Nat. Prod. 1995, 58, 878 (Ipomoea calobra). (e) Braun, K.; Romero, J.;
Liddell, C.; Creamer, R. Mycol. Res. 2003, 107, 980 (Undifilum
oxytropis).
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Acad. Sci. U.S.A. 1981, 78, 7393. (b) Tulsiani, D. R.; Harris, T. M.;
Touster, O. J. Biol. Chem. 1982, 257, 7936.
(4) For a comprehensive review of the enzyme inhibitory activity of
swainsonine, see ref 12c.
Since its isolation, swainsonine has proven a highly
popular target of both total10 and formal syntheses.11,12
Furthermore, the search for more potent glycosidase
(6) Hubbard, S. C.; Ivatt, R. J. Annu. Rev. Biochem. 1981, 50, 555.
(7) (a) Goss, P. E.; Baptista, J.; Fernandes, B.; Baker, M.; Dennis,
J. W. Cancer Res. 1994, 54, 1450. (b) Baptista, J. A.; Goss, P. E.; Nghiem,
M.; Krepinsky, J. J.; Baker, M.; Dennis, J. W. Clin. Chem. 1994, 40, 426.
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191, 649.
r
10.1021/ol2006117
Published on Web 04/12/2011
2011 American Chemical Society

inhibitors, which display improved GMII vs LM selectiv-
ity, has spurred the preparation of a large number of
analogues.13 That swainsonine has recently been the sub-
ject of a process research study further underscores the
continued relevance of this natural product as a synthetic
target.11n
bicyclic aziridinium ion in this key transformation by a
proximate carboxylate group offers a novel means of
alkene bis-cyclofunctionalization.
Scheme 1. Retrosynthetic Analysis of (ꢀ)-Swainsonine (1)
As part our ongoing study of the chemistry of nitrenium
ions,14 we recently reported a versatile method for the
preparation of R-hydroxyalkyl lactams involving the in-
tramolecular addition of acylnitrenium ions to alkenes.15
Having successfully utilized this methodology in the
stereocontrolled synthesis of the piperidine core of the
azasugar castanospermine,16 we were prompted to con-
sider whether this chemistry might also be brought to bear
on (ꢀ)-swainsonine. Herein we report the successful devel-
opment of an efficient route to this indolizidine alkaloid in
which the pyrrolidine ring and C-8a/8 threo stereodiad of
the target are simultaneously established in a substrate-
controlled nitrenium ion oxamidation reaction. Further-
more, we demonstrate that interception of the putative
(10) For selected total syntheses of (ꢀ)-swainsonine, see: (a) Bashyal,
B. P.; Fleet, G. W. J.; Gough, M. J.; Smith, P. W. Tetrahedron 1987, 43,
3083. (b) Bennett, R. B.; Choi, J. R.; Montgomery, W. D.; Cha, J. K. J.
Am. Chem. Soc. 1989, 111, 2580. (c) Pearson, W. H.; Hembre, E. J. J.
Org. Chem. 1996, 61, 7217. (d) Mukai, C.; Sugimoto, Yi, Y.; Miyazawa,
K.; Yamaguchi, S.; Hanaoka, M. J. Org. Chem. 1998, 63, 6281. (e)
Buschmann, N.; Ruckert, A.; Blechert, S. J. Org. Chem. 2002, 67, 4325.
(f) Lindsay, K.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774. (g) Martin, R.;
Murruzzu, C.; Pericas, M. A.; Riera, A. J. Org. Chem. 2005, 70, 2325. (h)
Guo, H.; O’Doherty, G. A. Org. Lett. 2006, 8, 1609. (i) Ceccon, J.;
Greene, A.; Poisson, J. Org. Lett. 2006, 8, 4739. (j) Au, C. W.; Pyne, S. G.
J. Org. Chem. 2006, 71, 7097. (k) Hakansson, A. E.; Van Ameijde, J.;
Horne, G.; Nash, R. J.; Wormald, M. R.; Kato, A.; Besra, G. S.; Gurcha,
S.; Fleet, G. W. J. Tetrahedron Lett. 2008, 49, 179. (l) Guo, H.;
O’Doherty, G. A. Tetrahedron 2008, 64, 304. (m) Ajish Kumar, K. S.;
Chaudhari, V. D.; Dhavale, D. D. Org. Biomol. Chem. 2008, 6, 703. (n)
Sharma, P. K.; Shah, R. N.; Carver, J. P. Org. Process Res. Dev. 2008, 12,
831. (o) Kwon, H.; Park, C.; Lee, S.; Youn, J.-H.; Kang, S. Chem.;Eur.
J. 2008, 14, 1023. (p) Alam, M. A.; Kumar, A.; Vankar, Y. D. Eur. J.
Org. Chem. 2008, 4972. (q) Shi, G. F.; Li, J. Q.; Jiang, X. P.; Cheng, Y.
Tetrahedron 2008, 64, 5005. (r) Tian, Y. S.; Joo, J. E.; Kong, B. S.; Pham,
V. T.; Lee, K. Y.; Ham, W. H. J. Org. Chem. 2009, 74, 3962. (s) Li, X.;
Zhu, Z.; Duan, K.; Chen, H.; Li, Z.; Li, Z.; Zhang, P. Tetrahedron 2009,
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V.; Pohmakotr, M. Org. Biomol. Chem. 2011, 9, 531.
From a retrosynthetic perspective, we initially envi-
sioned that the indolizidine skeleton of 1 could be gener-
ated from R-hydroxyalkyl lactam 2 through a sequence of
functional group reductions and N-alkylative ring closure
(Scheme 1). In turn, this compound would be accessed
through the intramolecular oxamidation of unsaturated
hydroxamate 6. On the basis of our previous studies,17 we
anticipated that this reaction would proceed via aziridi-
nium ion 3, which upon regioselective ion-pair collapse at
the external (R) position18 and hydrolysis of the resulting
trifluoroacetate ester adduct would provide δ-lactam 2,
thereby establishing the C-8/8a stereodiad of the natural
product. With regard to the diastereoselectivity of the
addition process, we anticipated that cyclization of the
singletnitrenium iongeneratedfrom6 wouldpreferentially
proceed via a transition state resembling pseudochair 4,
thereby avoiding the 1,3-allylic strain19 present in boat-like
conformer 5.20
(11) For recent formal syntheses of (ꢀ)-swainsonine, see: (a)
ꢀ
Dechamps, I.; Pardo, D. G.; Cossy, J. Tetrahedron 2007, 63, 9082. (b)
Our route to (ꢀ)-swainsonine (1) began from 2,3-O-
isopropylidene-D-erythronolactone (7), which is readily
available from the oxidative cleavage of sodium D-isoas-
corbate with hydrogen peroxide (Scheme 2).21 Following a
sequence of reactions developed by Pearson and Hembre
during their synthesis of 1,10c reduction of 7 with DIBAL-H
yielded the corresponding D-erythrose derivative,22
Kwon, H.; Park, C.; Lee, S.; Youn, J.-H.; Kang, S. Chem.;Eur. J. 2008,
14, 1023. (c) Bates, R. W.; Dewey, M. R. Org. Lett. 2009, 11, 3706. (d)
Choi, H. G.; Kwon, J. H.; Kim, J. C.; Lee, W. K.; Eum, H.; Ha, H.-J.
Tetrahedron Lett. 2010, 51, 3284. (e) Oxenford, S. J.; Moore, S. P.;
Carbone, G.; Barker, G.; O’Brien, P.; Shipton, M. R.; Gilday, J.;
Campos, K. R. Tetrahedron: Asymmetry 2010, 21, 1563.
(12) For reviews of recent total syntheses of (ꢀ)-swainsonine and
ꢀ
related glycosidase inhibitors, see: (a) Lopez, M.; Cobo, J.; Nogueras,
M. Curr. Org. Chem. 2008, 12, 718. (b) Pyne, S. Curr. Org. Synth. 2005, 2,
39. (c) El Nemr, A. Tetrahedron 2000, 56, 8579.
(13) For recent examples of swainsonine analogues, see: (a) Kuntz,
D. A.; Nakayama, S.; Shea, K.; Hori, H.; Uto, Y.; Nagasawa, H.; Rose,
D. R. ChemBioChem 2010, 11, 673. (b) Abrams, J. N.; Babu, R. S.; Guo,
H.; Le, D.; Le, J.; Osbourn, J. M.; O’Doherty, G. A. J. Org. Chem. 2008,
73, 1935. (c) Bi, J.; Aggarwal, V. K. Chem. Commun. 2008, 120. (d) Ajish
Kumar, K. S.; Chaudhari, V. D.; Dhavale, D. D. Org. Biomol. Chem.
2008, 6, 703. (e) Murray, A. J.; Parsons, P. J.; Hitchcock, P. Tetrahedron
2007, 63, 6485.
(17) (a) Reference 15. (b) Rudchenko, V. F.; Ignatov, S. M.;
Kostyanovsky, R. G. Chem. Commun. 1990, 261. (c) Vedejs, E.; Sano, H.
Tetrahedron Lett. 1992, 33, 3261. (d) Hoffman, R. V.; Christophe, N. B.
J. Org. Chem. 1988, 53, 4769.
(18) For regioselective ring opening of a 1-azabicyclo[4.1.0]heptane-
based aziridinium ion, see: D’hooghe, M. D.; Vanlangendonck, T.;
€
Tornroos, K. W.; De Kimpe, N. J. Org. Chem. 2006, 71, 4678.
(14) (a) Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3, 1053. (b)
Wardrop, D. J.; Zhang, W. M. Org. Lett. 2001, 3, 2353. (c) Wardrop,
D. J.; Zhang, W. M.; Landrie, C. L. Tetrahedron Lett. 2004, 45, 4229. (d)
Wardrop, D. J.; Burge, M. S. Chem. Commun. 2004, 1230. (e) Wardrop,
D. J.; Burge, M. S. J. Org. Chem. 2005, 70, 10271.
(15) Wardrop, D. J.; Bowen, E. G.; Forslund, R. E.; Sussman, A. D.;
Weerasekera, S. L. J. Am. Chem. Soc. 2010, 132, 1188.
(19) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(20) For a related conformational made in reference to an intramo-
lecular Huisgen dieneꢀazide cycloaddition, see: (a) Hudlicky, T.;
Seoane, G.; Lovelace, T. C. J. Org. Chem. 1988, 53, 2094. (b) Hudlicky,
T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem. 1990, 55, 4683.
(21) (a) Cohen, N.; Banner, B. L.; Laurenzano, A. J.; Carozza, L. In
Organic Syntheses; Wiley & Sons: New York, 1990; Vol. IV, pp 432ꢀ435.
(b) Dunigan, J.; Weigel, L. O. J. Org. Chem. 1991, 56, 6225.
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Org. Lett., Vol. 13, No. 9, 2011
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which through stereoselective addition of vinylmagnesium
bromide23 and selective O-silylation of the primary alco-
hol, was converted to allylic 8 alcohol is excellent overall
yield. Upon heating with trimethyl orthoacetate in the
presence of propionic acid, compound 8 underwent
JohnsonꢀClaisen rearrangement to provide β,γ-unsatu-
rated ester 9 as the E-isomer.24
than ion pair collapse.25 Fortuitously, separation of 12
from unwanted diastereomer 13 was readily accomplished
by flash chromatography on silica gel.
Scheme 3. Bis(cyclofunctionalization) of Substrate 6
Scheme 2. Preparation of Oxamidation Substrate 6
The relative stereochemistry at the C6 position of the
cyclization products was established by NOE analysis. In
the case of compound 12, the 2D NOESY spectrum
displayed a strong correlation between H-6 and H-3a,
which was conspicuously absent in the spectrum of 13
(Scheme 3). Further confirmation of the desired cis-cis
stereochemistry of the lactam ring in 12 was gleaned from
the vicinal coupling constant between H6 and H6a (6.4
Hz), which is diagnostic of the cis relationship between
these protons.26 At this point, assignment of the relative
C20 stereochemistry in 12 was made difficult by the con-
formational freedom of the C6ꢀC20 bond, although was
assumed to be R in view of the stereospecificity of the
oxamidation process with respect to alkene geometry.15
In order to progress toward swainsonine, we now sought
to globally reduce 12 to gain compound 14 (Scheme 4).
While treatment of12withexcessLiAlH4 in THF heated at
reflux led to lactam and lactone reduction, cleavage of the
NꢀO bond under these conditions proved to be rather
sluggish.27 Fortunately, reaction of 12 with LiAlH4 at
higher temperature, in 1,4-dioxane at reflux (bp 101 °C),
proved to be more fruitful and lead to the reduction of all
three functional groups and formation of 1-amino-2,5-diol
14 in excellent yield.
Removal of the TBS ether from 9 using TBAF provided
primary alcohol 10, which through a sequence of Dessꢀ
Martin and Pinnick oxidations was transformed to the
corresponding carboxylic acid. Conversion of this material
to methyl hydroxamate 6 was accomplished by treatment
with isobutyl chloroformate to generate the corresponding
mixed anhydride and coupling with methoxylamine.
Employing our previously reported oxamidation con-
ditions,15 cyclization of substrate 6 was now accomplished
by treatment with phenyliodine(III) bis(trifluoroacetate)
(PIFA, 1.2 equiv) and trifluoroacetic acid (1 equiv) in
methylene chloride at 0 °C (Scheme 3). After 9 h, the
reaction was simply concentrated to provide a 6:1 mixture
of bis-cyclization products 12 and 13. Notably, no pro-
ducts arising from alkene trifluoroacetoxyamidation were
observed in this mixture suggesting that interception of
aziridinium ion 11 (in the case of product 12) by the
proximate carboxylate group occurs significantly faster
Formation of the indolizidine ring system was now
accomplished through use of an Appel reaction.28 Thus,
selective bromination of the primary alcohol in 14 was
accompanied by spontaneous cyclization to generate 15.
Finally, removal of the acetonide group, using 6 M HCl,10c
provided (ꢀ)-swainsonine (1), after purification by ion-
exchange chromatography. The 1H and 13C NMR spectral
(22) Cohen, N.; Banner, B. L.; Lopresti, R. J.; Wong, F.; Rosenberger,
M.; Liu, Y. Y.; Thom, E.; Liebman, A. A. J. Am. Chem. Soc. 1983, 105,
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T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970,
92, 741.
(25) For the formation of a related bis-cyclic lactoneꢀlactam via
intramolecular capture of a 1-azabicyclo[4.1.0]heptane-based aziridi-
nium ion by a carboxylate group, see: Williams, D. R.; Fromhold, M. G.;
Earley, J. D. Org. Lett. 2001, 3, 2721.
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(27) For an example of the formation of a N-methoxylamine through
the incomplete reduction of an N-methoxy-γ-lactam, see ref 14a.
(28) Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801.
2378
Org. Lett., Vol. 13, No. 9, 2011

matched that of the natural product ([R]25D ꢀ87.2; c 2.1,
MeOH).1b
Scheme 4. Total Synthesis of (ꢀ)-Swainsonine (1)
In conclusion, we have developed a 12-step, azide-free
synthesis of (ꢀ)-swainsonine (1) in which the C-8/8a
stereodiad and pyrrolidine ring of the target are simulta-
neously established through the diastereoselective bis-cy-
clization of an unsaturated O-alkyl hydroxamate. Although
lost through reduction in our current synthesis, the bis-
cyclic lactoneꢀlactam framework accessible through this
nitrenium ion cyclization is present in a number of alka-
loids, most recognizably in the tuberostemospironine sub-
group of the Stemona alkaloid family,29 their biogenetic
relatives, the pandamarilactonines,30 and the Securinega
alkaloid (ꢀ)-norsecurinine.31 Extension of this type of
transformation to the preparation of these alkaloids is
now in progress.
data obtained from this material were identical to those
reported for the natural product.1b In addition, the optical
rotation of synthetic 1 ([R]24D ꢀ86.0; c 0.1, MeOH) closely
Acknowledgment. We thank the National Institutes of
Health (GM-67176) and the University of Illinois at
Chicago for financial support of this work.
(29) (a) Pilli, R.; Rosso, G.; De Oliveira, M. Nat. Prod. Rep 2010, 27,
1908. (b) Alibes, R.; Figueredo, M. Eur. J. Org. Chem. 2009, 2421.
(30) (a) Takayama, H.; Ichikawa, T.; Kuwajima, T.; Kitajima, M.;
Seki, H.; Aimi, N.; Nonato, M. G. J. Am. Chem. Soc. 2000, 122, 8635. (b)
Tan, M. A.; Kitajima, M.; Kogure, N.; Nonato, M. G.; Takayama, H.
Tetrahedron Lett. 2010, 51, 4143.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ
(31) (a) Weinreb, S. M. Nat. Prod. Rep 2009, 26, 758. (b) Alibes, R.;
Figueredo, M. Eur. J. Org. Chem. 2009, 2421.
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