A formal synthesis of (-)-swainsonine from a chiral aziridine

Article abstract of DOI:10.1016/j.tetlet.2010.04.069

A formal synthesis of enantiomerically pure (-)-swainsonine was successfully achieved using intramolecular cyclization of the amino alcohol 4 which was derived from a readily available 1-(R)-α-methylbenzylaziridine-2-carboxylic acid (-)-menthol ester 6.

Full text of DOI:10.1016/j.tetlet.2010.04.069

Tetrahedron Letters 51 (2010) 3284–3285
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A formal synthesis of (À)-swainsonine from a chiral aziridine
b
b,
*
Hwan Geun Choi a, Ji Hye Kwon a, Jong Chan Kim a, Won Koo Lee a, , Heesung Eum , Hyun-Joon Ha
*
a Department of Chemistry, Sogang University, Seoul 121-742, Republic of Korea
b Department of Chemistry, Hankuk University of Foreign Studies, Yonging, Kyunggi-Do 449-719, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 February 2010
Revised 9 April 2010
Accepted 16 April 2010
Available online 20 April 2010
A formal synthesis of enantiomerically pure (À)-swainsonine was successfully achieved using intramo-
lecular cyclization of the amino alcohol 4 which was derived from a readily available 1-(R)-
a-methylb-
enzylaziridine-2-carboxylic acid (À)-menthol ester 6.
Ó 2010 Elsevier Ltd. All rights reserved.
(À)-Swainsonine, first isolated from the fungus Rhizoctonia leg-
uminicola in 1973,1 is well known as an anti-cancer drug with po-
tential for treating glioma2 and gastric carcinoma.3 A number of
synthetic studies have been reported4 and efficient syntheses of
(À)-swainsonine still draw much attention from organic and
medicinal chemists due to its biological activities.5 Among many
available methods, the synthesis of (À)-swainsonine 1 via dihydr-
oxylation of the bicyclic intermediate 2 elaborated from RCM is
quite attractive. This intermediate was originally prepared from
sequential reactions including Borono-Mannich reaction of a chi-
ral hydroxyaldehyde as the key step. Recently, Dewey et al. elab-
orated the same intermediate 2 from piperidine compound 3
obtained from a gold(III)-catalyzed allene cyclization.6 We were
interested in developing an efficient synthetic method for (À)-
swainsonine via the synthetic intermediate 3 using recently
developed aziridine chemistry. In this Letter, we would like to
introduce the synthetic method for the desired substituted chiral
piperidine 3 starting from a readily available enantiomerically
95% yield. The Weinreb amide was reacted with magnesium and
commercially available (3-bromopropoxy)-tert-butyl-dimethylsi-
lane in THF to provide the corresponding ketone 5 in 67% yield.
The chelation-controlled reduction of the 2-acylaziridine8 5 by
NaBH4 in the presence of ZnCl2 was followed by protection of the
secondary alcohol moiety to provide 7 in 99% yield. The regioselec-
tive ring-opening reaction of the resulting protected diol 7 with
AcOH in CH2Cl2 at room temperature provided the ring-opening
product 8 in 88% yield. We previously reported that the nucleo-
phile, AcOÀ, attacks the aziridine ring at the less sterically hindered
C(3) position and the aziridine ring C(3)–N bond was regioselec-
tively cleaved.9 Then, deprotection of the primary silyl ether 8
was selectively achieved by reaction with AcOH/H2O/THF (3:1:1)
at room temperature, to give 4.10 The primary alcohol of 4 was acti-
vated, after which the mesylate was transformed into the substi-
tuted piperidine 9 in 61% yield via intramolecular cyclization
under the reaction conditions (Scheme 2).11
The a-methylbenzyl group of 9 was replaced by the Boc group
pure 1-(R)-
thol ester 6 (Scheme 1).
a
-methylbenzylaziridine-2-carboxylic acid (À)-men-
by applying a two-step reaction sequence: hydrogenation in the
presence of 30% Pd(OH)2 followed by reaction of the resulting
disubstituted piperidine with (Boc)2O in methanol.12 Then the
acetyl group was quantitatively hydrolyzed by KOH in methanol
at room temperature to provide 2-hydroxymethyl-N-Boc-piperi-
dine.13 The Swern oxidation14 of the primary alcohol provided
the piperidine-2-carbaldehyde which, by Wittig olefination with
methylenetriphenylphosphorane at 0 °C, provided the desired vi-
nyl piperidine 3 in 46% overall yield (from 9).15 We compared
the data of the 2-vinylpiperidines 3 with those reported previously
and confirmed that they were identical to the same intermediate
described by Dewey et al. upon occasion of the synthesis of (À)-
swainsonine (Scheme 3).
Two stereogenic centers in the compound 3 can be easily con-
structed via stereoselective reduction of the 2-acylaziridine 5 to
provide for the piperidine ring to have the relative erythro config-
uration. In addition to the stereoselective reduction of 5, homolo-
gation of the lateral chain is needed to isolate the target olefin.
Compound 5 is readily available by application of general synthetic
methods from the (2S)-aziridine carboxylic acid (À)-menthol ester
6, via the Weinreb amide.7 The reaction of N,O-dimethylhydroxyl-
amine hydrochloride and enantiomerically pure 6 in the presence
of i-PrMgCl in THF provides the corresponding Weinreb amide in
In summary, we have developed a new methodology for a for-
mal synthesis of (À)-swainsonine starting from a readily available
chiral aziridine-2-carboxylate 6 by making use of an intramolecu-
lar cyclization to access the key intermediate 9 in reasonably good
yields.
* Corresponding authors. Tel.: +82 2 705 8449; fax: +82 2 701 0967 (W.K.L.); tel.:
+82 31 330 4369; fax: +82 31 330 4566 (H.-J.H.).
E-mail addresses: wonkoo@sognag.ac.kr, wonkoo62@gmail.com (W.K. Lee),
hjha@hufs.ac.kr (H.-J. Ha).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.069

H. G. Choi et al. / Tetrahedron Letters 51 (2010) 3284–3285
3285
OTBS
OTBS
OH
OTBS
HO
OH
H
AcO
Ph
NH
Me
HO
N
N
N
Boc
Me
1
2
3
4
Ph
Ph
O
O
Me
N
N
OTBS
OMen
Men = (-)-Menthyl
H
H
5
6
Scheme 1. Retrosynthetic analysis.
Ph
Ph
Ph
O
OTBS
O
(a), (b)
(c), (d)
Me
Me
N
Me
OH
N
N
OTBS
OTBS
OMen
H
6
H
H
5
7
OTBS
OTBS
OTBS
OTBS
(e)
(f)
(g)
AcO
Ph
AcO
Ph
AcO
Ph
NH
Me
NH
Me
N
Me
8
4
9
Scheme 2. Reagents and conditions: (a) N,O-dimethylhydroxylamine hydrochloride, i-PrMgCl, THF, 0 °C, 95%; (b) Mg, (3-bromopropoxy)-tert-butyl-dimethylsilane, THF,
reflux, 67%; (c) NaBH4, ZnCl2, MeOH, À78 °C, 94% (>99:1); (d) TBSCl, DMAP, CH2Cl2, 0 °C to rt, 99%; (e) AcOH, CH2Cl2, rt, 88%; (f) AcOH/H2O/THF = 3:1:1, rt, 90%; (g) MsCl, NEt3,
CH2Cl2, 0 °C to rt, 61%.
References and notes
OTBS
OTBS
(a), (b)
(c), (d)
AcO
Ph
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2007, 14, 353.
N
N
Boc
Me
9
3
4. (a) Pyne, S. G. Curr. Org. Synth. 2005, 2, 39; (b) El Nemr, A. Tetrahedron 2000, 56,
8579.
Scheme 3. Reagents and conditions: (a) H2, Pd(OH)2, (Boc)2O, MeOH, rt; (b) KOH,
MeOH, rt; (c) (COCl)2, DMSO, NEt3, CH2Cl2, À78 °C; (d) MePPh3Br, LHMDS, THF, 0 °C,
46% (four steps yield).
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Acknowledgments
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The authors are grateful for the financial support from (KRF-
2008-C00481 and NRF-2009-0081956) for W.K.L. and KOSEF
(R01-2007-000-20037-0) for H.J.H.
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W. K.; Ha, H.-J.; Park, C.-S.; Igarashi, Y. Bioorg. Med. Chem. 2005, 13, 3475.
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Supplementary data
Supplementary data (detailed experimental procedures, opti-
cal rotations, 1H and 13C NMR spectra and high resolution mass
spectra of compounds 3, 4, 5, 7, 8 and 9) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.04.069.