Stereoselective formal total synthesis of (-)-swainsonine from Garner's aldehyde

Article abstract of DOI:10.1055/s-0030-1258418

A simple and facile stereoselective formal total synthesis of (-)-swainsonine has been reported starting from Garner's l-serine derived oxazolidine aldehyde. Our synthetic strategy involves stereoselective allylation and Still olefination as key intermedi

Full text of DOI:10.1055/s-0030-1258418

PAPER
755
Stereoselective Formal Total Synthesis of (–)-Swainsonine from Garner’s
Aldehyde
Stereoselectiv
a
e
F
ormal To
b
tal Synthesi
b
s
of (–)-Sw
a
a
Organic Chemistry Divison-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax +91(40)27160512; E-mail: dryvdnageswar@gmail.com
Received 2 December 2010; revised 16 December 2010
plant species, such as Asclepiadaceae, Convolvulaceae,
Moraceae, and Orchidaceae.4 These alkaloids are broadly
classified into two classes based on the family of species
from which they have been isolated. These alkaloids are
widely found in nature with the 1-azabicyc-
lo[4.3.0]nonane structural skeleton possessing a broad
range of structural and stereochemical features. To date
numerous total syntheses have been reported. Mooto et
al.5 reported the total synthesis of (–)-swainsonine from
triple reductive amination of a keto-dialdehyde. Trost et
al.6 used tris(dibenzylideneacetone)dipalladium and
Trost’s chiral ligand, N,N¢-(1R,2R)-cyclohexane-1,2-diyl-
bis[2-(diphenylphosphino)benzamide], in a palladium-
catalyzed desymmetrization reaction. Katsuki et al.7 have
concisely synthesized (–)-swainsonine from a meso-pyr-
rolidine derivative using a (salen)manganese-catalyzed
oxidative-desymmetrization. Pearson et al. used D-
isoascorbic acid8 and inexpensive D-ribose9 to afford (–)-
swainsonine. Carretero et al.10 developed the total synthe-
sis of (–)-swainsonine involving kinetic resolution of a ra-
cemic alcohol followed by intramolecular Michael
addition as the key step. Pyne et al.11 utilized the Sharpless
asymmetric epoxidation and the nucleophilic ring open-
ing of a chiral vinyl epoxide with an amine. In a novel ap-
proach by Blechert et al.,12 a ruthenium-catalyzed
metathesis rearrangement reaction was used. Even though
a wide range of synthetic strategies have been reported for
the synthesis of (–)-swainsonine, these potent molecules
and their analogues are still challenging targets for syn-
thetic organic chemists in the development of practical,
relatively short, and efficient synthetic protocols that in-
volve simple reactions. In this regard, we report herein an
alternative practical synthesis of (–)-swainsonine via an
L-serine-derived oxazolidine aldehyde.
Abstract: A simple and facile stereoselective formal total synthesis
of (–)-swainsonine has been reported starting from Garner’s L-
serine derived oxazolidine aldehyde. Our synthetic strategy in-
volves stereoselective allylation and Still olefination as key inter-
mediary reaction steps.
Key words: swainsonine, indium, allylation, Garner’s aldehyde,
Still olefination, indolizidine alkaloid
Due to their significant glycosidase inhibition activity nu-
merous azasugars have been isolated from plant sources
as well as microorganisms in the development of thera-
peutically potent glycosidase inhibitors.1 Over the years,
several synthetic drugs have been developed with a poly-
hydroxylated piperidine skeleton which have a wide spec-
trum of biological activity. These include miglitol and
miglustat, imino sugars and synthetic analogues of D-glu-
cose that acts as drugs against diabetes mellitus type-2 and
Gaucher’s type-1 disease, respectively (Figure 1).2
OH
OH
N
OH
OH
N
HO
HO
HO
HO
OH
miglitol
miglustat
OH
H
OH
OH
OH
H
HO
OH
N
N
HO
castanospermine
2-epi-swainsonine
Our retrosynthetic analysis of (–)-swainsonine is shown in
Scheme 1. The key steps involved are indium-mediated
stereoselective allylation of 5 and the Still reaction with
intermediate 3. The intermediate 3 can be obtained from
L-serine-derived oxazolidine aldehyde after a series of
functional group manipulations (Scheme 1).
Figure 1 Some of glycosidase inhibitors with a polyhydroxylated
piperidine skeleton
Naturally occurring (–)-swainsonine, and its counterpart
(+)-swainsonine, with a polyhydroxylated piperidine
skeleton belongs to a class of indolizidine alkaloids that The synthesis of (–)-swainsonine (1, Scheme 2) started
has diverse biological activity.3 The indolizidine ring sys- with the preparation of Garner’s aldehyde 5 from readily
available L-serine.13 Garner’s aldehyde 5 was subjected to
tem is found in many alkaloids isolated from different
allylation by the literature procedure14 with allyl bromide
to afford a diastereomeric mixture of the homoallylic al-
SYNTHESIS 2011, No. 5, pp 0755–0758
x
x
.
x
x
.2
0
1
1
cohol 6 (anti/syn 3:1) that could not be separated by col-
umn chromatography. After silylation of homoallylic
Advanced online publication: 21.01.2011
DOI: 10.1055/s-0030-1258418; Art ID: Z30510SS
© Georg Thieme Verlag Stuttgart · New York

756
S. N. Murthy, Y. V. D. Nageswar
PAPER
OH
OBn
The absolute stereochemistry of the major diastereomeric
homoallylic alcohol was further supported by 1D NOE 1H
NMR studies and compared with the literature data.15
Strong NOE was observed between the bridgehead proton
and the adjacent proton attached to the quaternary carbon
in the five-membered cyclic carbamate due to the cis-sub-
stitution pattern.
OBn
H
OH
H
O
OH
COOMe
N
N
NHBoc
Boc
1
2
3
O
OBn
H
NBoc
OMs
HO
After establishing the absolute stereochemistry of the ho-
moallylic alcohol 7, it was benzylated to afford 9 in 85%
yield, which on hydroboration using borane–dimethyl sul-
fide produced the corresponding alcohol 10 in 89% yield.
Then alcohol 10 was transformed into oxazolidine mesy-
late 11 in excellent yield (90%) on treatment with mesyl
chloride in the presence of triethylamine. Then the ace-
tonide in 11 was deprotected to obtain 12 in 88% yield us-
ing cerium(III) chloride heptahydrate and oxalic acid, and
the resulting alcohol 12 was silylated using tert-butyldi-
methylsilyl chloride and imidazole and cyclized using so-
dium hydride. The intermediates 11, 12, and 4 were found
to be unstable and were isolated and the crude products
were subsequently transformed. The silylated alcohol 13
O
NHBoc
4
5
Scheme 1 Retrosynthetic analysis of (–)-swainsonine
alcohol in 6 with tert-butyldimethylsilyl chloride, the two
diastereomers 7 and 8 can be readily separated by column
chromatography. In order to assign the absolute stereo-
chemistry at the newly generated stereocenter in the major
diastereomer, the diastereomer was desilylated to yield
diastereomerically pure alcohol 7¢, which on treatment
with triflic anhydride in the presence of pyridine as base
produced the cyclic carbamate 15 (Scheme 3).
O
OTBS
OTBS
HO
H
NBoc
a
b
O
O
+
O
O
NBoc
NBoc
NBoc
5
6
7
8
OTBS
BnO
OBn
OH
d
O
e
c
O
O
NBoc
NBoc
NBoc
7
9
10
BnO
OMs
OBn
OBn
g
f
OMs
OMs
HO
TBSO
O
NBoc
NHBoc
NHBoc
11
12
4
OBn
N
OBn
H
OBn
OBn
h
k
j
O
i
OTBS
OH
Boc
COOMe
N
N
N
Boc
Boc
Boc
13
14
3
2
OH
OH
H
OH
N
1
Scheme 2 Reagents and conditions: (a) allyl bromide, indium metal, THF, sat. NH4Cl soln (cat.), 3 h, 85%; (b) TBDMSCl, CH2Cl2, imida-
zole, 24 h, 95%; (c) (i) TBAF, THF, 1.5 h, 92%; (ii) BnBr, NaH, TBAI, THF, r.t., 24 h, 85%; (d) BH3–DMS, THF, 0 °C, 2 h, 89%; (e) MsCl,
Et3N, CH2Cl2, 0 °C, 2 h, 90%; (f) CeCl3·7 H2O, (CO2H)2, MeCN, r.t., 2 h, 88%; (g) TBDMSCl, CH2Cl2, imidazole, 2 h, 84%; (h) NaH, THF,
0 °C, 24 h, 87%; (i) TBAF, THF, 3 h, 81%; (j) Dess–Martin periodinane, CH2Cl2, 3 h, 80%; (k) (CF3CH2O)2POCH2CO2Me, 18-crown-6,
KHMDS, THF, –78 °C, 82%.
Synthesis 2011, No. 5, 755–758 © Thieme Stuttgart · New York

PAPER
Stereoselective Formal Total Synthesis of (–)-Swainsonine
757
1H NMR (300 MHz, CDCl3): d = 5.88 (m, 1 H), 5.11 (m, 2 H), 4.02–
3.76 (m, 4 H), 3.32 (br s, 1 H), 2.20–2.11 (m, 2 H), 1.56 (s, 3 H),
1.47 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 156.3, 138.7, 114.2, 92.9, 79.4,
70.8, 63.9, 62.5, 33.5, 28.5, 28.1, 25.1.
HRMS: m/z [M + Na]+ calcd for C14H25NNaO4: 294.1681; found:
294.1669.
on reaction with tetrabutylammonium fluoride yielded
hydroxymethylpiperidine derivative 14 in 81% yield, ox-
idation of which by Dess–Martin periodinane16 afforded 3
in 80% yield. This Boc-protected 2-formylpiperidine de-
rivative 3 on reaction with bis(2,2,2-trifluoroethyl) phos-
phonate under Still reaction conditions17 gave Z-isomer 2
as the major product. The spectral and analytical data of 2
were compared with that reported in the literature. Syn-
thesis of 1 from 2 has already been reported.18
tert-Butyl (2S,3R)-3-(Benzyloxy)-2-[(tert-butyldimethylsil-
oxy)methyl]piperidine-1-carboxylate (13)
To a suspension of NaH (60%, 3.9 mmol) in anhyd THF (2 mL) at
0 °C was added 4 (1.0 mmol) in THF (2 mL). The mixture was
stirred at r.t. for 24 h and then the reaction was quenched by addition
of H2O and extracted with Et2O. The combined ether layers were
washed with brine, dried (anhyd Na2SO4), and evaporated. The re-
sultant crude product was subjected to column chromatography (sil-
ica gel) to give 13 as a colorless oil in 87% yield; Rf = 0. 5 (5%
EtOAc–hexane).
HO
HO
O
O
O
N
O
N
O
O
7′
8′
[a]D25 +31. 5 (c 1.0, CHCl3).
a
a
1H NMR (300 MHz, CDCl3): d = 7.44 (m, 5 H), 4.79(d, J = 12.0 Hz,
1 H), 4.61 (d, J = 12.0 Hz, 2 H), 3.81 (m, 4 H), 2.92 (m, 1 H), 2.01
(m, 2 H), 1.83 (m, 2 H), 1.60 (s, 9 H), 1.01 (s, 9 H), 0.18 (s, 6 H).
O
O
O
O
13C NMR (75 MHz, CDCl3): d = 155.4, 138.7, 128.1, 127.2, 79.3,
N
N
H
H
71.0, 69.8, 61.1, 55.2, 39.3, 28.3, 25.7, 19.3, 18.0, –5.5.
H
H
O
O
HRMS: m/z [M + Na]+ calcd for C24H41NNaO4Si: 458.2702; found:
458.2692.
strong NOE
weak NOE
15
16
tert-Butyl (2S,3R)-3-(Benzyloxy)-2-(hydroxymethyl)piperidine-
1-carboxylate (14)
Scheme 3 Reagents and conditions: (a) Tf2O, CH2Cl2, pyridine.
To a soln of 13 (1.0 mmol) in anhyd THF (2 mL), a soln of TBAF
(3.0 mmol) in THF was added and the stirring was continued at r.t.
for 3.0 h. When the reaction was complete (TLC), the mixture was
partitioned between H2O and Et2O. The organic layer was washed
with sat. aq NaHCO3 soln and brine and dried (anhyd Na2SO4). The
resultant crude oil was purified by column chromatography to yield
14 as a colorless oil in 81% yield; Rf = 0.22 (30% EtOAc–hexane).
In conclusion, formal total synthesis of (–)-swainsonine
has been achieved in an efficient manner from readily
available L-serine.
Solvents were dried and purified by conventional methods prior to
use. The progress of all the reactions were monitored by TLC using
glass plates precoated with silica gel-60 F254 to a thickness of 0.5
mm (Merck). Column chromatography was performed on silica gel
(60–120 mesh) using EtOAc and hexane as the eluents. Optical ro-
tation values were recorded on a Horiba high sensitive polarimeter
and IR spectra were recorded with a Perkin-Elmer FT-IR spectro-
photometer. 1H NMR spectra were recorded at 200, 300, 400, and
500 MHz and 13C NMR spectra were recorded at 75 MHz using
TMS as an internal standard in CDCl3. Mass spectra were obtained
on Finnigan MAT1020B or micromass VG 70e70H spectrometer
operating at 70 eV using a direct inlet system. All HRMS were re-
corded on QSTAR XL hybrid MS/MS system equipped with an ESI
source (IICT, Hyderabad). Literature procedures were followed for
the preparation of 514 and other intermediates18,19 not given below.
[a]D25 –40.3 (c 0.9, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.31 (m, 5 H), 4.63 (d, J = 12.0
Hz, 1 H), 4.51 (m, 2 H), 3.99 (m, 1 H), 3.72 (dd, J = 10.2, 8.8 Hz, 1
H), 3.65 (m, 2 H), 2.80 (m, 1 H), 2.40 (br s, 1 H), 1.86 (m, 2 H), 1.58
(m, 1 H), 1.45 (s, 9 H), 1.39 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 156.2, 138.5, 128.1, 127.3, 79.7,
71.3, 69.9, 60.3, 55.3, 39.5, 28.2, 24.9, 19.4.
MS (ESI): m/z = 344 [M + Na]+.
tert-Butyl (2S,3R,Z)-3-(Benzyloxy)-2-(3-methoxy-3-oxoprop-1-
enyl)piperidine-1-carboxylate (2)
To a soln of 18-crown-6 (5.0 mmol) and methyl bis(2,2,2-trifluoro-
ethoxy)phosphonoacetate (1.12 mmol) in anhyd THF at –78 °C was
added KHMDS (1.12 mmol). The mixture was stirred for 1.5 h at
this temperature and a soln of aldehyde 3 (1.0 mmol) in THF (2 mL)
was added slowly. The resulting mixture was stirred at –78 °C until
the reaction was complete (TLC). The reaction was quenched by the
addition of aq NH4Cl soln and extracted with Et2O. The combined
ether layers were washed with brine and dried (anhyd Na2SO4). The
crude product was purified by column chromatography to give 2 as
a colorless oil in 82% yield; Rf = 0.30 (20% EtOAc–hexane).
1H NMR (300 MHz, CDCl3): d = 7.21 (m, 5 H), 6.38 (dd, J = 11.6,
8.4 Hz, 1 H), 6.16 (m, 1 H), 5.89 (dd, J = 11.6, 1.6 Hz, 1 H), 4.89
(d, J = 12 Hz, 2 H), 4.10 (m, 1 H), 3.70 (s, 3 H), 3.63 (m, 1 H), 2.92
(m, 1 H), 1.96 (m, 2 H), 1.86 (m, 2 H), 1.41 (s, 9 H).
tert-Butyl (R)-4-[(R)-1-Hydroxybut-3-enyl)-2,2-dimethyloxazo-
lidine-3-carboxylate (7¢)
To a magnetically stirred soln of 7 (1.0 mmol) in anhyd THF (2
mL), a soln of TBAF (3.0 mmol) in THF was added and stirring was
continued at r.t. for 1.5 h. When the reaction was complete (TLC),
the mixture was partitioned between H2O and Et2O. The organic
layer was washed with sat. aq NaHCO3 soln and brine and dried (an-
hyd Na2SO4). The resultant crude oil was purified by column chro-
matography to yield 7¢ as a colorless oil in 92% yield; Rf = 0.25
(30% EtOAc–hexane).
[a]D25 +25. 2 (c 1.1, CHCl3).
IR (KBr): 3401, 2978, 2936, 1690, 1514, 1374, 1249, 1170, 1053,
858, 770 cm–1.
Synthesis 2011, No. 5, 755–758 © Thieme Stuttgart · New York

758
S. N. Murthy, Y. V. D. Nageswar
PAPER
13C NMR (75 MHz, CDCl3): d = 165.2, 154.9, 144.6, 139.3, 128.2,
127.5, 126.3, 120.2, 79.9, 74.1, 70.6, 51.1, 39.5, 29.9, 28.1, 25.8,
19.0.
P. R.; Huxtable, C. R. Aust. J. Chem. 1979, 32, 2257. From
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of the synthesis and biological activity of swainsonine and
other glycosidase inhibitors, see: Nishimura, Y. Studies in
Natural Products Chemistry, Vol. 10; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1992, 495–583.
MS (ESI): m/z = 376 [M + 1]+.
Acknowledgment
We are thankful to Council of Scientific and Industrial Research
(CSIR), New Delhi for providing a fellowship to S.N.M.
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Synthesis 2011, No. 5, 755–758 © Thieme Stuttgart · New York