A concise formal stereoselective total synthesis of (-)-swainsonine

Article abstract of DOI:10.1016/j.cclet.2013.12.003

A short formal stereoselective synthesis of (-)-swainsonine (1) is described. Our synthesis started with the versatile building block (R)-3-benzyloxyglutarimide 5. Through controlled regioselective reduction, Ley's-sulfone chemistry (N-α-sulfonylation and ZnCl₂-catalyzed N-α-amidovinylation), an RCM reaction, and an amide reduction, the synthesis of unsaturated indolizidine (8R,8aS)-3 has been achieved in five steps. The indolizidine (8R,8aS)-3 is an advanced intermediate toward the synthesis of (-)-swainsonine (1).

Full text of DOI:10.1016/j.cclet.2013.12.003

Chinese Chemical Letters 25 (2014) 193–196
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Chinese Chemical Letters
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Original article
A concise formal stereoselective total synthesis of (ꢀ)-swainsonine
Xiao-Gang Wang a, Ai-E Wang a,b, Pei-Qiang Huang a,b,
*
a Department of Chemistry, College of Chemistry and Chemical Engineering, and Fujian Provincial Key Laboratory of Chemical Biology, Xiamen University,
Xiamen 361005, China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A short formal stereoselective synthesis of (ꢀ)-swainsonine (1) is described. Our synthesis started with
the versatile building block (R)-3-benzyloxyglutarimide 5. Through controlled regioselective reduction,
Received 28 August 2013
Received in revised form 31 October 2013
Accepted 8 November 2013
Available online 7 December 2013
Ley’s-sulfone chemistry (N-a-sulfonylation and ZnCl2-catalyzed N-a-amidovinylation), an RCM
reaction, and an amide reduction, the synthesis of unsaturated indolizidine (8R,8aS)-3 has been
achieved in five steps. The indolizidine (8R,8aS)-3 is an advanced intermediate toward the synthesis of
(ꢀ)-swainsonine (1).
Keywords:
Indolizidines
Alkaloids
ß 2013 Pei-Qiang Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
a-Amidoalkylation
Building blocks
Stereoselective synthesis
1. Introduction
A survey of literature revealed that among the many
approaches to swainsonine [4–7], the unsaturated indolizidine
derivatives 2 [5], 3 [6a], and 4 [6b] proved to be reliable advanced
intermediates for the synthesis of swainsonine (Scheme 1). Since
indolizidine 2 is a silica gel sensitive compound [5d], we chose the
unsaturated indolizidine 3 as our target in view of developing a
short formal stereoselective synthesis of (ꢀ)-swainsonine.
(ꢀ)-Swainsonine (Fig. 1) is an indolizidine alkaloid that is also
classified as an azasugar (imino sugar) [1] due to the presence of
three hydroxyl groups in the molecule. After its first isolation in
1973 from the fungus Rhizoctomia leguminicola [2a], it has also
been extracted from diverse fungi and numerous species of
flowering plants [2b,1a]. As an azasugar, (ꢀ)-swainsonine exhibits
lysosomal
a-mannosidase and mannosidase II inhibitory proper-
2. Experimental
ties. Although the pharmacological properties of this product have
not been fully investigated, it has been tested as a treatment for
cancer [3], HIV, and immunological disorders [1,4a]. The important
biological properties of swainsonine have attracted the interest of
many synthetic and medicinal chemists. Numerous methods have
been developed for the stereoselective synthesis of swainsonine
and its diastereomers [4–7]. In connection with a general program
on the development of efficient and general methodologies for the
synthesis of N-containing bioactive compounds and alkaloids [8],
we became interested in the stereoselective synthesis of (ꢀ)-
swainsonine, and have recently reported the synthesis of two
diastereomers of (ꢀ)-swainsonine [9]. We now report a short
formal stereoselective synthesis of (ꢀ)-swainsonine.
2.1. (5R,6R/S)-1-Allyl-5-(benzyloxy)-6-vinylpiperidin-2-one (7)
To a solution of anhydrous zinc chloride (1.0 mol/L in diethyl
ether, 3.6 mL. 3.6 mmol) in dichloromethane (0.5 mL) was added
dropwise an Et2O solution of vinylmagnesium bromide (1.0 mol/L
in diethyl ether, 6.0 mL, 6.0 mmol). The mixture was stirred at
room temperature under nitrogen for 30 min. A solution of a
diastereomeric mixture of sulfone
8 (1.16 g, 3.01 mmol) in
anhydrous dichloromethane (8 mL) was added and the mixture
was stirred at room temperature for 14–16 h. The reaction was
quenched with a saturated aqueous NH4Cl and the resulting
mixture was extracted with dichloromethane (3ꢁ 25 mL). The
combined organic extracts were dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (eluent: EtOAc/
PE = 1/4) to give an inseparable diastereomeric mixture of trans-7
and cis-7 as a colorless oil (612 mg, combined yield: 75%, trans/
*
Corresponding author at: Department of Chemistry, College of Chemistry and
Chemical Engineering, and Fujian Provincial Key Laboratory of Chemical Biology,
Xiamen University, Xiamen 361005, China.
cis = 6/1). IR (film, cmꢀ1):
1266, 1076, 922, 730, 698; 1H NMR (400 MHz, CDCl3):
n
max 2925, 1723, 1652, 1457, 1403, 1358,
E-mail address: pqhuang@xmu.edu.cn (P.-Q. Huang).
d
(data of the
1001-8417/$ – see front matter ß 2013 Pei-Qiang Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.12.003

194
X.-G. Wang et al. / Chinese Chemical Letters 25 (2014) 193–196
OH
4 h. The reaction was quenched with a saturated aqueous NaHCO3
OH
H
N
at 0 8C. The resulting slurry was filtered through a celite pad and
washed with EtOAc (5 mL). The filtrate was extracted with EtOAc
(3ꢁ 5 mL), and the combined organic extracts were dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (EtOAc/PE = 1/1) to give compound 3 (22 mg, yield: 89%)
OH
Fig. 1. The structure of (ꢀ)-swainsonine (1).
as a colorless oil: ½a D20
ꢂ
ꢀ115 (c 1.0, CHCl3) {½a D20
ꢀ115 (c 3.85,
ꢂ
major diastereomer read from the spectrum of the diastereomeric
mixture) 1.96 (dt, 2H, J = 8.8, 4.4 Hz), 2.35 (dt, 1H, J = 18.0, 4.4 Hz),
2.65 (dt, 1H, J = 18.0, 9.6 Hz), 3.18 (dd, 1H, J = 15.6, 7.2 Hz), 3.65
(dd, 1H, J = 5.6, 2.8 Hz), 4.11 (d, 1H, J = 5.6 Hz), 4.56 (d, 1H,
J = 12.8 Hz), 4.60 (d, 1H, J = 12.8 Hz), 4.77 (dt, 1H, J = 15.6, 2.0 Hz),
5.11–5.29 (m, 4H), 5.61–5.79 (m, 1H), 7.26–7.35 (m, 5H); 13C NMR
d 21.4, 27.1, 47.1, 62.2, 70.3, 73.9, 116.9, 118.2,
127.4 (2C), 127.7, 128.4 (2C), 132.9, 135.8, 138.0, 169.6; HRESIMS
calcd. for [C17H21NNaO2]+ (M+Na+): 294.1465; found: 294.1470.
CHCl3) [6a]}; IR (film, cmꢀ1): nmax 3058, 3029, 2925, 2851, 2772,
2751, 1635, 1494, 1449, 1192, 1088, 889, 731, 694; 1H NMR
(400 MHz, CDCl3):
d 1.14–1.32 (m, 1H), 1.52–1.74 (m, 2H), 2.20
(ddd, 1H, J = 11.7, 7.1, 3.9 Hz), 2.43 (dt, 1H, J = 11.4, 3.2 Hz), 2.94
(dd, 1H, J = 11.4, 3.6 Hz), 2.97–3.04 (m, 1H), 3.23–3.32 (m, 2H), 3.63
(d, 1H, J = 13.2 Hz), 4.54 (d, 1H, J = 12.0 Hz), 4.66 (d, 1H, J = 12.0 Hz),
5.89 (ddd, 1H, J = 6.0, 4.0, 2.0 Hz), 6.14 (dd, 1H, J = 6.0, 0.8 Hz),
7.20–7.36 (m, 5H); 13C NMR (100 MHz, CDCl3):
d 24.2, 30.4, 48.9,
57.7, 71.0, 72.1, 78.5, 127.5, 127.6 (2C), 128.4 (2C), 128.8, 131.4,
138.9; HRESIMS calcd. for [C15H20NO]+ (M+H+): 230.1539; found:
230.1540.
(100 MHz, CDCl3):
2.2. (8R,8aS/R)-8-Benzyloxy-6,7,8,8a-tetrahydroindolizin-5(3H)-one
(6)
3. Results and discussion
A solution of a diastereomeric mixture of 6-vinylpiperidin-2-
one 7 (116.7 mg, 0.43 mmol) in degassed CH2Cl2 (8 mL) containing
Grubbs second generation catalyst 10 (36 mg, 0.043 mmol) was
stirred for 12 h at refluxing. The solution was concentrated and the
resulting residue was purified by flash chromatography on silica
gel (eluent: EtOAc/PE = 1/3) to give trans-6 (83 mg, yield: 80%) and
cis-6 (14 mg, yield: 13%).
Our retrosynthetic analysis of indolizidine 3 is outlined in
Scheme 2. The essential of this analysis resides on the use of (R)-
benzyloxyglutarimide (5), a versatile chiral building block devel-
oped from our laboratory as a source of chirality for (ꢀ)-
swainsonine [10]. Indolizidine 3 can be derived from indolizidi-
none 6. The pyrroline moiety in indolizidinone 6 is accessible by
the RCM reaction from diene 7 [11], and one vinyl group in 7 can be
introduced by the Ley’s sulfone-based chemistry [12].
trans-6: colorless oil. ½a D20
ꢀ110.1 (c 0.33, CHCl3); IR (film,
ꢂ
cmꢀ1):
nmax 2925, 2847, 1648, 1611, 1441, 1407, 1096, 1063, 740,
698; 1H NMR (400 MHz, CDCl3):
d
1.78–1.88 (m, 1H), 2.17–2.23 (m,
The synthesis commenced with the regio- and diastereoselec-
tive reduction [10a] of the known chiral building block (R)-
benzyloxyglutarimide 5 [10b] (NaBH4, THF, ꢀ30 8C, 10 min), which
1H), 2.40 (dt, 1H, J = 17.6, 8.0 Hz), 2.62 (ddd, 1H, 17.6, 8.0, 4.8 Hz),
3.41 (ddd, 1H, J = 14.4, 9.2, 5.6 Hz), 4.04 (d, 1H, J = 16.0 Hz), 4.27–
4.28 (m, 1H), 4.44 (dt, 1H, J = 16.0, 2.2 Hz), 4.52 (d, 1H, J = 11.6 Hz),
4.68 (d, 1H, J = 11.6 Hz), 5.88–5.93 (m, 1 H), 6.01–6.05 (m, 1H),
produced the hemiaminal
9 as a diastereomeric mixture
(dr = 11:1) in a combined yield of 82% (Scheme 3). The major
diastereomer was tentatively assigned as cis in light of our previous
7.28–7.38 (m, 5H); 13C NMR (100 MHz, CDCl3):
d
26.4, 29.7, 52.9,
67.4, 71.3, 77.1, 126.9, 127.7 (2C), 127.9, 128.3, 128.5 (2C), 137.9,
168.7; HRESIMS calcd. for [C15H17NNaO2]+ (M+Na+): 266.11515;
found: 266.11514.
results on a similar system [10a]. Without separation, the
diastereomeric mixture [13,14] of 9 was treated with phenylsul-
finic acid and CaCl2 [12a] in CH2Cl2 at r.t. for 2 h to give the sulfone
8 in a yield of 86%. Although sulfone 8 was obtained as an
inseparable diastereomeric mixture, the diastereomeric mixture
can be used in the next step without separation. The subsequent
reaction is considered to pass through an N-acyliminium
intermediate [10,13], either diastereomer could give the same
N-acyliminium ion. On standing at ꢀ20 8C for two weeks, the
minor diastereomer in the diastereomeric mixture was epimerized
gradually and completely to give the trans-diastereomer. This is in
accordance with the phenomenon we observed previously on the
corresponding 5-phenylsulfonyl-pyrrolidin-2-one homologue
[12b]. Reaction of the diastereomeric mixture of 6-phenylsulfo-
nyllactam 8 with organozinc reagent, generated in situ from
vinylmagnesium bromide and a 1.0 mol/L solution of anhydrous
ZnCl2 in diethyl ether [12a], at r.t. for 14–16 h yielded 6-
vinyllactam 7 in 75% yield as an inseparable 6:1 diastereomeric
mixture (determined by 1H NMR). The stereochemistry of the
major diastereomer was tentatively deduced as trans based on our
previous results with the pyrrolidinone homologous [12b,12d],
which was confirmed by converting the diastereomeric mixture 7
into the known compounds cis-6 [14] and 3 [6a], respectively.
We next investigated the RCM reaction [8b,11]. Treatment of
the diastereomeric mixture of diene 7 with Grubbs second
generation catalyst [15] 10 in CH2Cl2 at reflux produced the
desired unsaturated indolizidinones trans-6 and cis-6 (ratio = 6:1)
in a combined yield of 93%. The physical and spectral data of cis-6
cis-6: colorless oil. ½a D20
ꢂ
ꢀ8.5 (c 0.8, CHCl3) {½a D20
ꢀ8.4 (c 1.31,
ꢂ
CHCl3) [14]}; 1H NMR (400 MHz, CDCl3):
d 1.77–1.98 (m, 1H), 2.09–
2.26 (m, 1H), 2.44–2.57 (m, 2H), 3.93–3.98 (m, 1H), 4.05 (d, 1H,
J = 16.0 Hz), 4.39–4.45 (m, 1H), 4.49 (d, 1H, J = 12.4 Hz), 4.59 (dt,
1H, J = 16.0, 2.4 Hz), 4.60 (d, 1H, J = 12.4 Hz), 5.76–5.81 (m, 1H),
5.93–5.98 (m, 1H), 7.25–7.36 (m, 5H); 13C NMR (100 MHz, CDCl3):
d
24.8, 27.0, 53.0, 68.0, 70.5, 70.7, 127.0, 127.3, 127.4 (2C), 127.7,
128.4 (2C), 138.3, 169.1; HRESIMS calcd. for [C15H17NNaO2]+
(M+Na+): 266.11515; found: 266.11515.
2.3. (8R,8aS)-8-Benzyloxy-3,5,6,7,8,8a-hexahydroindolizine (3)
To an ice-cooled, stirred solution of indolizidinone trans-6
(25.9 mg, 0.11 mmol) in THF (2 mL) was added LiAlH4 (20.0 mg,
0.53 mmol), and the mixture was stirred at room temperature for
OH
H
OP
H
OTBS
ref. [6a]
ref. [6b]
H
ref. [5]
OH
N
N
N
OH
(−)-swainsonine (1)
3 (P = Bn)
4 (P = Bz)
2
match those reported {½a D20
ꢂ
ꢀ8.5 (c 0.8, CHCl3); ½a D20
ꢀ8.4 (c 1.31,
ꢂ
Scheme 1. Typical synthetic approaches to (ꢀ)-swainsonine based on the
unsaturated indolizidines 2–4.
CHCl3) [15]}. Reduction of indolizidinone trans-6 with LiAlH4 in

X.-G. Wang et al. / Chinese Chemical Letters 25 (2014) 193–196
195
OBn
OBn
OBn
OBn
H
OBn
O
H
O
N
O
N
SO2Ph
N
O
N
O
N
3
8
6
7
5
Scheme 2. Retrosynthetic analysis of indolizidine 3.
OBn
OBn
OBn
OBn
OH
NaBH4 , THF
CH2=CHMgBr, ZnCl2
PhSO2H, CaCl2
-30 oC, 15 min
82%
O
N
O
O
O
N
SO2Ph
O
N
N
CH2Cl2, r.t., 2 h
86%
CH2Cl2, r.t., 14-16 h
75%
5
8
7
9
(dr = 6: 1)
(cis/ trans = 11: 1)
OH
CH2Cl2 , reflux, 12 h
OBn
OBn
OBn
ref. [6a]
LiAlH4 , THF
H
H
H
H
OH
N
0 oC ~ r.t., 4 h
89%
(from trans-6)
O
N
MesN
NMes
Ph
N
O
N
(6: 1)
10
(5% mol)
Cl
Cl
OH
(-)-swainsonine (1)
Ru
cis-6
13%
3
trans-6
80%
PCy3
Scheme 3. Formal stereoselective synthesis of (ꢀ)-swainsonine (1).
[2] (a) F.P. Guengerich, S.J. DiMari, H.P. Broquist, Isolation and characterization of a l-
pyrindine fungal alkaloid, J. Am. Chem. Soc. 95 (1973) 2055–2056;
(b) S.M. Colegate, P.R. Dorling, C.R. Huxtable, A spectroscopic investigation of
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Aust. J. Chem. 32 (1979) 2257–2264.
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295;
THF provided the known unsaturated (8R,8aS)-indolizidine (3) in
an 89% yield. The physical and spectral (1H NMR and 13C NMR) data
of the synthetic indolizidine 3 are in agreement with those
reported {½a 2D0
ꢂ
ꢀ115 (c 1.0, CHCl3); ½a D20
ꢀ115 (c 3.85, CHCl3)} [6a].
ꢂ
Thus, the stereochemistry assigned for trans-6 and cis-6 was
further confirmed. Since the unsaturated indolizidine (8R,8aS)-3
has been converted by Pyne and co-workers in four steps into (ꢀ)-
swainsonine (1) [6a], our synthesis thus constitutes a short formal
stereoselective synthesis of this alkaloid.
(b) P.E. Shaheen, W. Stadler, P. Elson, et al., Phase II study of the efficacy and safety
of oral GD0039 in patients with locally advanced or metastatic renal cell carci-
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In summary, we have developed a five-step synthesis of the
unsaturated indolizidine (8R,8aS)-3, and thus accomplished a short
formal stereoselective synthesis of (ꢀ)-swainsonine (1). Through
this work, we have demonstrated that a combination of the
versatile building block (R)-5 with the Ley’s-sulfone chemistry and
the RCM reaction constitutes a powerful method for a rapid access
to the highly functionalized 8-oxygenated indolizidin-5-one 6,
which may be used as a versatile intermediate for the stereo-
selective synthesis of other hydroxylated indolizidine alkaloids.
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(b) H.G. Choi, J.H. Kwon, J.C. Kim, et al., A formal synthesis of (ꢀ)-swainsonine
from a chiral aziridine, Tetrahedron Lett. 51 (2010) 3284–3285;
(c) R.W. Bates, M.R. Dewey, A formal synthesis of swainsonine by gold-catalyzed
allene cyclization, Org. Lett. 11 (2009) 3706–3708;
(d) H.Y. Kwon, C.M. Park, S.B. Lee, J.H. Youn, S.H. Kang, Asymmetric iodocycliza-
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Acknowledgments
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The authors are grateful for financial support from the National
Basic Research Program (973 Program) of China (No.
2010CB833200), the NSF of China (Nos. 21332007, 21072160),
and the Program for Changjiang Scholars and Innovative Research
Team in University (PCSIRT) of Ministry of Education, China for
financial support.
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