De novo asymmetric syntheses of d-, l- and 8-epi-d-swainsonine

Article abstract of DOI:10.1016/j.tet.2007.10.109

A highly enantioselective and stereocontrolled approach to d-, l- and 8-epi-d-swainsonine has been developed from achiral furan and γ-butyrolactone. A one-pot hydrogenolysis of both azide and benzyl ether followed by an intramolecular reductive amination has been employed as key step to establish the indolizidine ring system. The absolute stereochemistry was installed by the Noyori reduction and the relative stereochemistry by the use of several highly diastereoselective palladium-catalyzed glycosylation, Luche reduction, dihydroxylation, and palladium-catalyzed azide allylation reactions. This practical approach provide multigram quantities of indolizidine natural product d-swainsonine in 13 steps and 25% overall yield.

Full text of DOI:10.1016/j.tet.2007.10.109

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 304e313
www.elsevier.com/locate/tet
De novo asymmetric syntheses of D-, L- and 8-epi-D-swainsonine
*
Haibing Guo, George A. O’Doherty
Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA
Received 22 September 2007; received in revised form 27 October 2007; accepted 30 October 2007
Available online 4 November 2007
Abstract
A highly enantioselective and stereocontrolled approach to D-, L- and 8-epi-D-swainsonine has been developed from achiral furan and
g-butyrolactone. A one-pot hydrogenolysis of both azide and benzyl ether followed by an intramolecular reductive amination has been employed
as key step to establish the indolizidine ring system. The absolute stereochemistry was installed by the Noyori reduction and the relative
stereochemistry by the use of several highly diastereoselective palladium-catalyzed glycosylation, Luche reduction, dihydroxylation, and palla-
dium-catalyzed azide allylation reactions. This practical approach provide multigram quantities of indolizidine natural product D-swainsonine in
13 steps and 25% overall yield.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
syntheses. Thus, over 35 syntheses of both D- and L-swainso-
nine have been reported since the first syntheses by Richardson
and Fleet.10 Most of these syntheses reported to date utilize
carbohydrate starting materials to introduce asymmetry;
whereas, only eight syntheses used achiral starting materi-
als.10aed,h Herein we report the full account of a short and
efficient de novo syntheses of D- and L-swainsonine (1 and
2) from achiral commercially available starting material.11 In
addition to describing our optimized route (multigram scale)
to D- and L-swainsonine we disclose for first time the use of
this approach for the syntheses of 8-epi-D-swainsonine (3)
and 8-hydroxyindolizidine (4).
Over the past decade, polyhydroxylated indolizidine alka-
loids have received considerable attention because of their in-
teresting structures and their diverse biological activities (e.g.,
antiviral, antitumor, and immunomodulating activities).1 The
most well-known member D-swainsonine (1) (Fig. 1), a trihy-
droxyindolizidine alkaloid, was isolated from the fungus
Rhizoctonia leguminicola2 and Metarhizium anisopliae,3 as
well as found in the legume Swainsona canescens4 and the
spotted locoweed Astragalus lentiginosus.5 This natural prod-
uct has shown to be a potent inhibitor of both lysosomal
a-mannosidase6 and mannosidase II7 and has been applied
to clinical testing as anticancer drug8 to inhibit tumor growth
and metastasis.
Fleet has shown that the enantiomer of D-swainsonine (1),
L-swainsonine (2) selectively inhibited narginase (L-rhamnosi-
dase, Ki¼0.45 mM), whereas the D-swainsonine showed no
inhibitory activity toward this enzyme.9 Due to the biological
importance, of both D- and L-swainsonine, as well as several
epimers and analogues have become attractive targets for
Our strategy for the synthesis of D-swainsonine is outlined
in Scheme 1, which involves a key one-pot reductive
HO
HO
OH
OH
H
N
H
N
OH
OH
D-Swainsonine (1)
L-Swainsonine (2)
HO
H
HO
OH
H
OH
N
N
* Corresponding author. Tel.: þ1 304 293 3435x6444; fax: þ1 304 293
4909.
E-mail address: george.odoherty@mail.wvu.edu (G.A. O’Doherty).
8-epi-D-Swainsonine (3)
8-Hyroxyindolizidine (4)
Figure 1. Swainsonine and analogues.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.109

H. Guo, G.A. O’Doherty / Tetrahedron 64 (2008) 304e313
305
cyclization of azidosugar 6 into 1. Thus, we envisioned that
D-swainsonine could be obtained by hydrogenolytic deprotec-
tion and reductive amination of bicyclic amine intermediate 5,
which can be derived from azide-sugar 6 by reductive N-alkyl-
ation. The manno-stereochemistry of azide 6 could be readily
installed by diastereoselective dihydroxylation of 7. The al-
lylic azide 7 in turn could be prepared from palladium-cata-
lyzed azide allylation, Luche reduction, and stereoselective
palladium-catalyzed protection of pyranone 8a. A Noyori re-
duction and Achmatowicz oxidation should convert the fur-
furyl alcohol 9 into pyranone 8a. Eventually, the furfuryl
alcohol could be derived from commercially available furan
and g-butyrolactone 11. In addition to providing either swain-
sonine enantiomer (1 and 2), we envisioned with route being
able to provide the diastereomeric and deoxy-analogues 3
and 4.
9 to the Achmatowicz conditions14 (NBS in THF/H2O) pro-
vided the oxidative rearrangement product hemiacetal 14
(84%), which was converted ((Boc)2O at ꢀ78 ꢁC) to a mixture
of Boc-protected pyranones 8a and 8b in a good yield (85%)
and diastereoselectivity (8:1; a/b).15 The diastereoselectivity
of the Boc-acylation to form pyranones 8a and 8b was de-
creased (8a/8b in 1:1 ratio) when the reaction was performed
at elevated temperature (0 ꢁC to rt).
O
O
O
Li
+
O
OH
THF, -78 °C
74%
O
10
11
12
O
O
TBSCl/Imid.
DMF
Noyori (R,R)
HCO2Na/CTAB
98%
OTBS
13
OH
H
N
Reagents
Cat.
Yield
95%
HO
OH
H
N
HO
0.5%
5%
HCO2Na/CTAB
HCO2H/Et3N
OH
89%
BnO
O
D-swainsonine (1)
5
O
OH
NBS/H2O
0 °C
84%
OH
O
HO
N3
N3
HO
O
OTBS
OTBS
9
14
BnO
O
BnO
O
OTBS
OMs
O
(Boc)2O
DMAP
O
6
7
+
85%
BocO
O
BocO
O
O
OTBS
OTBS
8
8
BocO
O
Ts
N
OTBS
Temp.
– 78 °C
– 5 °C-rt
8
: 8
8
Ph
Ph
O
O
8:1
1:1
Ru
OH
N
H
O
Li
O
+
Noyori (R,R)
OTBS
9
10
11
Scheme 2. Enantioselective synthesis of pyranones.
Scheme 1. Retrosynthetic analysis of (ꢀ)-D-swainsonine (1).
2.2. Synthesis of D-swainsonine 1 via protected
swainsonine
2. Results and discussion
2.1. Approach to pyranones
With the successful synthesis of pyranone 8a, we next
installed manno-stereochemistry and C-1 benzyl ether
(Scheme 3). Exposure of the pyranone 8a and benzyl alcohol
to our palladium glycosylation conditions16 (2.5% Pd(0)/5%
PPh3) afforded OBn-protected pyranone 15 as a single diaste-
reomer and in an excellent yield (88%). Diastereoselective
reduction of the C-4 ketone in 15 under the Luche condition17
(NaBH4/CeCl3, ꢀ78 ꢁC) gave an equatorial allylic alcohol 16
in excellent yield (94%). Dihydroxylation of allylic alcohol 16
using the Upjohn conditions18 (OsO4/NMO) afforded triol 17
by in excellent yield (91%). The C-2/C-3 cis-diol 25 was
selectively protected as acetonide 18 by treatment with 2,2-
dimethoxypropane and catalytic amount of p-TsOH (96%).
In order to convert the C-4 equatorial hydroxyl group into
an equatorial azide, an oxidation/reduction/inversion sequence
was employed. Swern oxidation of alcohol 18, provided the
C-4 ketone 19, which was reduced with NaBH4 to provide
The syntheses of D- and L-swainsonine as well as 8-epi-
D-swainsonine began with commercially available achiral
g-butyrolactone 11 and furan (Scheme 2).12 Treatment of g-bu-
tyrolactone 11 with 2-lithiofuran 10 in THF solution afforded
furfuryl ketone 12 in 74% yield. Protection of primary alcohol
12 gave TBS-ether 13 (TBSCl/imid. in DMF) in excellent yield
(98%). The furfuryl alcohol 9 was obtained from furfuryl ke-
tone 12 by employing a phase transfer variant of the asymmetric
Noyori reduction in high enantiomeric excess (>96% ee) and
excellent yield (95%) using an aqueous solution of HCOONa/
cetyltrimethylammonium bromide (CTAB).13 Alternatively,
the Noyori reduction could be accomplished using a THF so-
lution of HCOOH/Et3N (1:1) in 89% yield, however, this re-
quired a 10-fold amount of Noyori catalyst and afforded
a slightly lower yield of product. Exposure of furfuryl alcohol

306
H. Guo, G.A. O’Doherty / Tetrahedron 64 (2008) 304e313
2.5% Pd(0)
5% PPh3
(2,2-dimethoxypropane/p-TsOH(cat)) to give acetonide 21 in
good yield (97%) and two fewer steps.
O
O
BnOH
88%
BocO
O
BnO
O
To complete the synthesis of D-swainsonine, a one-pot reduc-
tive cyclization was employed to furnish indolizidine ring
(Scheme 5). TBS-ether 21 was deprotected to yield primary
alcohol 24 by treatment with TBAF. Once again mesylation of
24 (MsCl/Et3N) produced mesylate 25 in excellent yield
(97%, two steps). The azidosugar 25 was converted into a pro-
tected swainsonine 31 via a cascade of transformations (global
hydrogenolysis, N-alkylation, and reductive amination). Mech-
anistically, this is believed to begin with an azide reduction to
produce aminosugar 26, which undergoes an intramolecular
N-alkylation to generate amine 27. Hydrogenolytic removal of
Bn-protecting group at the anomeric position should result in
hemiacetal 28, which exist in equilibrium with hydroxy alde-
hyde 29. A reductive amination of 29, via bicyclic iminium
ion intermediate 30, provided the protected swainsonine 31.
This one-pot reaction was performed with hydrogen (1 atm) in
aTHF/ethanol solutionand required 7 days for complete conver-
sion (85%). Finally, acidic hydrolysis of the acetonide 31 fol-
lowed by ion-exchange chromatography (basic OHꢀ form)
gave D-swainsonine (1) in excellent yield (95%).
OTBS
OTBS
OH
15
8
OH
OH
OsO4
HO
NaBH4/CeCl3
NMO
91%
– 78 °C
94%
BnO
O
O
BnO
O
OTBS
OTBS
17
16
O
O
Me2SO, (COCl)2
O
O
OH
O
O
Et3N, –78 °C
99%
p-TsOH
96%
BnO
O
BnO
O
19
O
OTBS
OTBS
OTBS
18
O
1) Tf2O/Pyr
NaBH4
O
O
N3
OH
0 °C
94%
1) NaN3/DMF
72%
OTBS
BnO
O
BnO
O
20
21
Scheme 3. Diastereoselective synthesis of azide 21.
the C-4 axial alcohol 20 in excellent yield for the two steps
(93%). Finally, treatment of alcohol 20 with triflic anhydride
gave a triflate, which without further purification underwent
an SN2 azide displacement (NaN3/DMF) to provide azide 21
in 72% yield from 20.
2.3. Alternative synthesis of swainsonine
Using the same strategy, we found D-swainsonine (1) could
also be efficiently synthesized without acetonide protection in
four steps from allylic azide 7 (Scheme 6). Deprotection of
TBS-ether 7 with a TBAF solution (99%) afforded the primary
alcohol 32, which after mesylation (MsCl/Et3N) gave mesylate
Alternatively, the acetonide 21 could also be prepared by
a short and efficient route that involved a palladium-catalyzed
azide installation (Scheme 4),19 this would eliminate the need
for the double inversion at C-4 (18 to 20 to 21). To perform the
palladium coupling reaction, a C-4 carbonate leaving group
was required. Thus, allylic alcohol 16 was treated with methyl
chloroformate and catalytic amount of DMAP to produce al-
lylic carbonate 22 in excellent yield (96%). The allylic azide
7 was formed by a regio- and stereoselective Pd-catalyzed al-
lylation of methyl carbonate 22 with TMSN3 in the presence
of (allylPdCl)2 and bis(diphenylphosphino)butane in excellent
yield (91%). Once again diastereoselective dihydroxylation of
allylic azide 7 generated diol 23 (92%), which was protected
O
O
O
O
N3
N3
TBAF/THF
98%
OH
BnO
O
BnO
O
21
OTBS
24
O
H2
P(OH)2/C
O
N3
MsCl, Et3N
99%
7 days
85%
BnO
O
OMs
25
O
O
O
O
O
H
N
OH
CH3OCOCl
DMAP/Pyr.
H
N
O
NH2
OCOCH3
O
BnO
O
96%
BnO
N3
O
BnO
O
BnO
O
HO
O
OTBS
OTBS
OMs
O
16
22
28
26
27
(Pd(ally)Cl)2/dppb
1:4
OsO4
H
N
O
O
NMO
92%
TMSN3
91%
BnO
O
HO
O
N
OTBS
O
O
HO
H
7
OH
N3
30
HO
29
O
O
HO
O
N3
OH
HO
H
O
O
H
p-TsOH
HCl
BnO
O
OH
97%
BnO
O
21
95%
N
OTBS
N
23
OTBS
31
D-swainsonine (1)
Scheme 4. Synthesis of azide 21 via palladium-catalyzed azide allylation and
dihydroxylation.
Scheme 5. Synthesis of D-swainsonine (1) via a one-pot reductive cyclization.

H. Guo, G.A. O’Doherty / Tetrahedron 64 (2008) 304e313
307
Pd(0)/PPh3
O
O
33 in near quantitative yield (99%). Upjohn dihydroxylation of
allylic azide 33 exclusively gave diol 6 (OsO4/NMO, 93%).
Finally, the natural product D-swainsonine 1 was obtained by
an analogous azide reduction/N-alkylation/reductive amina-
tion sequence under hydrogenation condition (100 psi H2,
Pd(OH)2/C).
DIBAL-H
89%
BnOH
88%
BocO
O
BnO
+
O
OTBS
OTBS
ent-8
34
β
OH
OH
OTBS
BnO
BnO
O
35
BnO
O
36
OTBS
N3
N3
K2CO3
MeOH
TBAF
OCOPh
DIAD, PPh3
THF
BnO
N3
O
BnO
O
PhCOOH
84%
99%
98%
O
OH
OTBS
32
7
OTBS
37
OsO4
MsCl, Et3N
99%
Reagents Ratio (35 : 36) yields
DIBAL-H
NaBH4
NMO
93%
BnO
O
1 : 2.5
1 : 1.3
89%
86%
OMs
33
OH
H2 (100 psi)
Pd(OH)2/C
HO
Scheme 7. Synthesis of allylic alcohol 36.
OH
HO
N3
H
N
OH
3 days
88%
BnO
O
a two-step Mitsunobu/ester hydrolysis sequence. Thus, expo-
sure of allylic alcohol 35 to typical Mitsunobu reaction condi-
tions (BzOH, DIAD and PPh3) yielded benzoate ester 37 with
inverted stereochemistry at C-4. Methanolysis of ester 37
(K2CO3/MeOH) provided allylic alcohol 35 in good yield
(82%, two steps).
OMs
D-swainsonine (1)
6
HO
H
H2 (100 psi)
Pd(OH)2/C
N3
3 days
68%
BnO
O
N
OMs
33
8-hyroxyindolizidine (4)
With a practical route to allylic alcohol 36 (the C-5 diaste-
reomer of 16) in hand, we explored the analogous application
of this approach for the synthesis of 8-epi-D-swainsonine (3)
(Scheme 8). Treatment of allylic alcohol 36 with methyl chloro-
formate formed carbonate 38 (Pyr/DMAP) in 94% yield. The
carbonate 38 was coupled with TMSN3 to give allylic azide
((allylPdCl)2/dppb) in excellent yield (92%). Stereoselective
dihydroxylation of allylic azide 38 under Upjohn conditions
Scheme 6. Synthesis of D-swainsonine (1) and 8-hydroxyindolizidine (4).
In addition, the known indolizidine analogue 8-hydroxyin-
dolizidine (4)20 was also prepared by the same one-pot hydro-
genation of allylic azide 33 (68%). It is worth noting this
sans-acetonide approach provided 8-hydroxyindolizidine (4)
as well as either enantiomer of swainsonine (1 and 2) while
using only two protecting groups (Bn and TBS). The route to
swainsonine can provide multigram quantities of both enantio-
mers (3 g of the D-isomer was prepared). The physical and spec-
tral data of our synthetic both D- and L-swainsonine by either
way is completely identical to those of the natural materials
(1H NMR, 13C NMR, optical rotation, and melting point).21
CH3OCOCl
DMAP
OH
OCOOCH3
OTBS
BnO
O
Pyr., 94 %
BnO
O
OTBS
38
36
N3
OsO4
(Pd(ally)Cl)2/dppb
2.4. Synthesis of 8-epi-D-swainsonine
NMO
96%
1:4
BnO
O
TMSN3, 92%
OTBS
O
39
Encouraged by these results, we next investigated the use of
this approach for the synthesis of 8-epi-D-swainsonine
(Scheme 7). We envisioned this approach starting with the
L-pyranone ent-8b. This enantiomeric b-anomer of 8a was
readily prepared in three steps from furfuryl ketone 13 by
switching to the use of the (S,S )-Noyori catalyst and perform-
ing the Boc-acylation at higher temperature (0 ꢁC to rt) to
ensure more b-pyranone ent-8b was produced (cf., Scheme 2).
Palladium-catalyzed glycosylation of pyranone ent-8b with
benzyl alcohol diastereoselectively afforded the C-1 BnO-pyr-
anone 34 in 88% yield (Scheme 7). Unfortunately, the Luche
reduction (NaBH4/CeCl3) of pyranone 34 provided a 1:1.3
mixture of allylic alcohols 35 and 36 in 86% yield. Improved
diastereoselectivity was obtained (35/36 in a 1:2.5 ratio) when
DIBAL-H was used as the reducing agent (89%). The easily
separated minor diastereomer, equatorial allylic alcohol 35,
could be easily converted into axial allylic alcohol 36 via
OH
O
O
O
HO
N3
N3
TBAF/THF
99%
P-TsOH
99%
BnO
O
BnO
O
OTBS
OTBS
41
40
O
O
O
O
MsCl, Et3N
98%
N3
N3
BnO
O
42
BnO
O
43
OH
OMs
HO
HO
H2
OH
O
H
H
Pd(OH)2/C
HCl
94%
OH
O
7 days
83%
N
N
44
8-epi-D-swainsonine (3)
Scheme 8. Synthesis of 8-epi-D-swainsonine (3).

308
H. Guo, G.A. O’Doherty / Tetrahedron 64 (2008) 304e313
(OsO4/NMO) afforded diol 40 as a single talo-diastereomer.
Diol 40 was protected as acetonide 41 in excellent yield
(95% two steps). Deprotection of TBS-ether 41 provided pri-
mary alcohol 42 (TBAF, 99% yield), which was followed by
mesylation to afford mesylate 43 in 98% yield. A one-pot
global hydrogenation/hydrogenolysis of azide 43 produced
protected 8-epi-D-swainsonine (3) in excellent yield (83%).
Eventually, 8-epi-D-swainsonine (3) was obtained by treatment
with HCl in 94% yield. The spectral and physical data of
8-epi-D-swainsonine (3) by our approach match those of refer-
ences reported (1H NMR, 13C NMR, optical rotation, and
melting point).22
4.2. (2S,3S,4S,5S,6R)-2-(Benzyloxy)-tetrahydro-6-
(3-tert-butyldimethylsilyloxypropyl)-2H-pyran-3,4,5-triol
(17)
To a tert-butanol/acetone (0.53 mL, 1:1, 1 M) solution of
allylic alcohol 16 (200 mg, 0.53 mmol) at 0 ꢁC was added a so-
lution of (50% w/v) of N-methyl morpholine N-oxide/water
(0.25 mL). Crystalline OsO4 (1.4 mg, 1 mol %) was added
and the reaction was stirred for 24 h. The reaction mixture
was concentrated with a small silica gel under reduced pres-
sure, purified using silica gel flash chromatography eluting
with 100% EtOAc to give triol 17 (199 mg, 0.48 mmol,
91%). Rf¼0.29 (70% EtOAc/hexane); [a]2D5 þ48 (c 3.11,
MeOH); IR (thin film, cmꢀ1) 3397, 2928, 2857, 1455, 1389,
3. Conclusions
1
1253, 1061, 833; H NMR (600 MHz, CD3OD) d 7.36e7.43
(m, 5H), 4.91 (s, 1H), 4.78 (d, J¼11.4 Hz, 1H), 4.57 (d,
J¼11.4 Hz, 1H), 3.97 (m, 1H), 3.83 (dd, J¼9.0, 3.0 Hz, 1H),
3.77 (m, 2H), 3.64 (dd, J¼9.0, 9.0 Hz, 1H), 3.59 (m, 1H), 2.00e
2.11 (m, 1H), 1.90e1.97 (m, 1H), 1.66e1.73 (m, 1H), 1.58e
1.64 (m, 1H), 1.01 (s, 9H), 0.16 (s, 6H); 13C NMR (150 MHz,
CD3OD) d 138.9, 129.5, 129.0, 128.8, 100.5, 73.6, 72.7,
72.4, 72.1, 64.5, 30.3, 29.0, 26.6, 19.2, ꢀ4.9; CIHRMS:
[C21H36O6SiNaþ]: calculated for 435.2176, found: 435.2179.
In conclusion, a de novo asymmetric approach to D-swain-
sonine (1), L-swainsonine (2), 8-epi-D-swainsonine (3) as well
as 8-hydroxylindolizidine (4) has been developed. Both D- and
L-swainsonine were achieved in 13 steps and 25% overall yield
from achiral furan 10. These practical syntheses are compara-
ble to the previous carbohydrate-based routes.10 Key to the
successful approach is the use of the Noyori reduction, palla-
dium-catalyzed glycosylation, diastereoselective dihydroxy-
lation, palladium-catalyzed azide allylation, and one-pot
reductive cyclization. The 8-epi-D-swainsonine (3) was also
synthesized in 10 steps in 34% overall yield from Boc-pyra-
none ent-8b (15 steps from furan 10 in 8% overall yield).
Further application of this approach to the synthesis of various
analogues is ongoing.
4.3. (3aS,4S,6R,7R,7aS)-4-(Benzyloxy)-tetrahydro-6-
(3-tert-butyldimethylsilyloxypropyl)-2,2-dimethyl-3aH-
[1,3]dioxolo[4,5-c]pyran-7-ol (18)
para-Toluenesulfonic acid monohydrate (19.4 mg,
5 mol %) was added to a stirred solution of diol 17 (840 mg,
2.08 mmol) and 2,2-dimethoxypropane (5.87 mL) in acetone
(31.2 mL) for 0.5 h at 0 ꢁC. The reaction mixture was
quenched with sodium bicarbonate solution (5 mL), removed
acetone in vacuo, extracted with Et2O (3ꢂ25 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified using silica gel flash chromatography
eluting with 15% EtOAc/hexane to give 904 mg (2.0 mmol,
96%) of colorless oil, acetonide 18. Rf (20% EtOAc/
hexane)¼0.40; [a]D25 þ36 (c 1.52, CH2Cl2); IR (thin film,
4. Experimental section23
4.1. General
1H and 13C NMR spectra were recorded on either a Jeol
270 MHz or a Varian 600 MHz spectrometer. Chemical shifts
were reported relative to internal tetramethylsilane (d
0.00 ppm) or CDCl3 (d 7.26 ppm) or CD3OD (d 4.89 ppm)
1
1
for H and CDCl3 (d 77.1 ppm) or CD3OD (d 49.15 ppm)
cmꢀ1) 3467, 2930, 2857, 1382, 1248, 1087, 835; H NMR
for 13C. Optical rotations were measured with a digital polar-
imeter in the solvent specified. Infrared (IR) spectra were ob-
tained on a FT-IR spectrometer. Flash column chromatography
was performed on ICN reagent 60 (60e200 mesh) silica gel.
Analytical thin-layer chromatography was performed with
(600 MHz, CDCl3) d 7.34 (m, 5H), 5.06 (s, 1H), 4.74 (d,
J¼11.4 Hz, 1H), 4.51 (d, J¼11.4 Hz, 1H), 4.18 (d, J¼6.0 Hz,
1H), 4.11 (dd, J¼6.0, 7.2 Hz, 1H), 3.67 (m, 2H), 3.56 (ddd,
J¼9.0, 9.0, 3.0 Hz, 1H), 3.48 (m, 1H), 2.15 (d, J¼3.0 Hz,
1H), 1.83e1.95 (m, 2H), 1.52e1.65 (m, 2H), 1.51 (s, 3H),
1.31 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR
(150 MHz, CDCl3) d 137.0, 128.6, 128.3, 128.1, 109.5, 96.2,
78.6, 75.9, 73.2, 69.8, 69.1, 63.3, 28.8, 28.1, 27.9, 26.3, 26.1,
18.5, ꢀ5.2; CIHRMS: calculated for [C24H40O6SiNaþ]:
475.2491, found: 475.2492.
˚
precoated glass-backed plates (K6F 60 A, F254) and visual-
ized by quenching of fluorescence and by charring after treat-
ment with p-anisaldehyde or phosphomolybdic acid or
potassium permanganate stain. Rf values were obtained by elu-
tion in the stated solvent ratios (v/v). Ether, THF, methylene
chloride, and triethylamine were dried by passing through ac-
tivated alumina (8ꢂ14 mesh) column with nitrogen gas pres-
sure. Commercial reagents were used without purification
unless otherwise noted. Air and/or moisture-sensitive reactions
were carried out under an atmosphere of argon/nitrogen using
oven/flame-dried glassware and standard syringe/septa
techniques.
4.4. (3aS,4S,6R,7aR)-4-(Benzyloxy)-dihydro-6-
(3-tert-butyldimethylsilyloxypropyl)-2,2-dimethyl-6H-
[1,3]dioxolo[4,5-c]pyran-7(7aH )-one (19)
To a solution of (COCl)2 (0.15 mL, 1.76 mmol) in CH2Cl2
(3.5 mL) was added DMSO (0.51 mL, 3.52 mmol) at ꢀ78 ꢁC,

H. Guo, G.A. O’Doherty / Tetrahedron 64 (2008) 304e313
309
and the mixture was stirred for 10 min. A solution of alcohol
18 (400 mg, 0.88 mmol) in 1.76 mL CH2Cl2 was added to the
resulting mixture, stirred for 0.5 h at ꢀ78 ꢁC. Then triethyl-
amine (0.50 mL, 3.52 mmol) was added at ꢀ78 ꢁC and the re-
action mixture was warmed to 0 ꢁC for 1 h. Water (50 mL)
was added to quench the mixture, and the aqueous mixture
was extracted (3ꢂ80 mL) with Et2O, dried (Na2SO4), and con-
centrated under reduced pressure. The crude product was pu-
rified using silica gel flash chromatography eluting with
15% EtOAc/hexane to give ketone 19 (392 mg, 0.87 mmol,
99%) as a colorless oil. Rf (20% EtOAc/hexane)¼0.61; [a]D25
þ74 (c 2.0, CH2Cl2); IR (thin film, cmꢀ1) 2954, 2929, 2857,
1741, 1472, 1253, 1077, 1023, 834; 1H NMR (600 MHz,
CDCl3) d 7.35 (m, 5H), 5.03 (d, J¼1.2 Hz, 1H), 4.76 (d,
J¼11.4 Hz, 1H), 4.57 (d, J¼11.4 Hz, 1H), 4.47 (dd, J¼6.6,
1.2 Hz, 1H), 4.46 (d, J¼6.6, 1H), 4.18 (dd, J¼4.8, 8.4 Hz,
1H), 3.65 (m, 2H), 1.90e1.96 (m, 1H), 1.72e1.84 (m, 2H),
1.58e1.65 (m, 1H), 1.48 (s, 3H), 1.35 (s, 3H) 0.90 (s, 9H),
0.05 (s, 6H); 13C NMR (67.5 MHz, CDCl3) d 196.5, 143.3,
137.1, 128.6, 128.2 (two carbon), 127.9, 92.1, 74.0, 70.6,
62.9, 28.5, 26.0, 18.4, ꢀ5.2; CIHRMS: calculated for
[C24H38O6SiþHþ]: 451.2514, found: 451.2516.
for 3 days at room temperature. The catalyst was filtered off
through a short pad of Celite, concentrated under reduced
pressure. The resulting crude was purified using silica gel flash
chromatography eluting with 30% MeOH/EtOAc to give pro-
tected swainsonine 31 (3.2 g, 15.0 mmol, 85%) as colorless
needles. Rf¼0.44 (10% MeOH/EtOAc); [a]2D5 ꢀ72 (c 1.0,
CH2Cl2); mp 102e104; IR (neat, cmꢀ1) 3194, 2942, 2793,
1
1466, 1371, 1260, 1209, 1113, 1068; H NMR (600 MHz,
CDCl3) d 4.67 (dd, J¼6.2, 4.8 Hz, 1H), d 4.24 (dd, J¼6.0,
4.2 Hz, 1H), 3.79 (ddd, J¼10.9, 8.9, 4.4 Hz, 1H), 3.11 (d,
J¼10.8 Hz, 1H), 2.96 (dt, J¼10.8, 3.0 Hz, 1H), 2.52 (br s, 1H),
2.09 (dd, J¼10.8, 4.8 Hz, 1H), 2.00e2.03 (m, 1H), 1.82 (ddd,
J¼10.8, 10.8, 3.6 Hz, 1H), 1.61e1.65 (m, 1H), 1.59 (dd,
J¼9.0, 4.8 Hz, 1H), 1.48 (s, 3H), 1.31 (s, 3H), 1.25 (m, 1H);
13C NMR (150 MHz, CDCl3) d 111.3, 79.2, 78.2, 73.8, 67.3,
60.0, 51.6, 33.0, 26.0, 24.9, 24.1.
4.7. (2S,6S)-6-(Benzyloxy)-2-(3-tert-
butyldimethylsilyloxypropyl)-2H-pyran-3(6H )-one (34)
To a solution of Boc-protected pyranone 8b (5.86 g,
15.8 mmol) and benzyl alcohol (3.28 g, 30.4 mmol) in dry
CH2Cl2 (8 mL), were added Pd2(DBA)3$CHCl3 (97.7 mg,
0.9 mol % Pd) and PPh3 (101.5 mg, 3.6 mol %) at 0 ꢁC under
argon atmosphere. After stirring for 2 h at 0 ꢁC to room tem-
perature, the reaction mixture was quenched with 200 mL of
saturated NaHCO3, extracted (3ꢂ200 mL) with Et2O, dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified using silica gel flash chromatography
eluting with 6% EtOAc/hexane to give benzyl ether 34
(5.02 g, 13.30 mmol, 88%) as a colorless oil. Rf (10%
EtOAc/hexane)¼0.75; [a]2D5 þ10 (c 1.4, CH2Cl2); IR (thin
film, cmꢀ1) 2954, 2929, 2856, 1695, 1471, 1254, 1092, 1024,
4.5. (3aS,4S,6R,7S,7aS)-4-(Benzyloxy)-tetrahydro-6-
(3-tert-butyldimethylsilyloxypropyl)-2,2-dimethyl-3aH-
[1,3]dioxolo[4,5-c]pyran-7-ol (20)
A CH2Cl2 (1 mL) solution of ketone 19 (370 mg,
0.82 mmol) and MeOH (1 mL, 1 M) was cooled to 0 ꢁC.
NaBH4 (37 mg, 0.98 mmol) was added and the reaction mix-
ture was stirred at 0 ꢁC for 20 min. The reaction mixture
was diluted with ether (20 mL) and quenched with 15 mL of
saturated NaHCO3, extracted (3ꢂ30 mL) with Et2O, dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified using silica gel flash chromatography
eluting with 15% EtOAc/hexane to give colorless oil,
323 mg (0.71 mmol, 87%) of alcohol 20. Rf (20% EtOAc/
hexane)¼0.41; [a]D25 þ16 (c 1.6, CH2Cl2); IR (thin film,
1
832; H NMR (600 MHz, CDCl3) d 7.36 (m, 5H), 6.89 (dd,
J¼10.2, 1.8 Hz, 1H), 6.10 (dd, J¼10.2, 1.2 Hz, 1H), 5.37 (d,
J¼1.2 Hz, 1H), 4.95 (d, J¼11.4 Hz, 1H), 4.71 (d, J¼
11.4 Hz, 1H), 4.09 (dd, J¼7.8, 3.6 Hz, 1H), 3.66 (m, 2H),
2.03e2.09 (m, 1H), 1.85e1.91 (m, 1H), 1.75e1.82 (m, 1H),
1.67e1.74 (m, 1H), 0.91 (s, 9H), 0.06 (s, 6H); 13C NMR
(150 MHz, CDCl3) d 200.0, 146.5, 137.0, 128.6, 128.15 (two
carbon), 128.1, 94.6, 78.9, 70.3, 62.9, 28.5, 28.0, 26.0, 18.4,
ꢀ5.2; CIHRMS: calculated for [C21H32O4SiNaþ]: 399.1962,
found: 399.1970.
1
cmꢀ1) 3568, 2928, 2857, 1381, 1251, 1070, 833; H NMR
(600 MHz, CDCl3) d 7.35 (m, 5H), 5.15 (s, 1H), 4.76 (d,
J¼11.4 Hz, 1H), 4.55 (d, J¼11.4 Hz, 1H), 4.22 (dd, J¼4.8,
6.0 Hz, 1H), 4.11 (d, J¼6.0 Hz, 1H), 3.76 (dd, J¼4.8, 9.0 Hz,
1H), 3.63e3.70 (m, 2H), 3.61 (d, J¼6.0, 6.0 Hz, 1H), 3.48 (m,
1H), 2.21 (d, J¼6.0 Hz, 1H), 1.84e1.90 (m, 1H), 1.73e1.80
(m, 1H), 1.65e1.71 (m, 1H), 1.59e1.64 (m, 1H), 1.58 (s,
3H), 1.38 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR
(150 MHz, CDCl3) d 137.1, 128.6, 128.3, 128.1, 109.3, 96.7,
73.6, 72.9, 69.4, 68.5, 66.1, 63.1, 29.4, 27.6, 26.1, 25.9,
25.4, 18.4, ꢀ5.2; CIHRMS: calculated for [C24H40O6SiNaþ]:
475.2491, found: 475.2490.
4.8. (2S,3S,6S)-6-(Benzyloxy)-3,6-dihydro-2-(3-tert-
butyldimethylsilyloxypropyl)-2H-pyran-3-ol (36)
To a solution of pyranone 34 (6.7 g, 17.7 mmol) in 130 mL
THF was added dropwise 1.0 M DIBAL-H in hexane
(17.8 mL, 17.8 mmol) at ꢀ78 ꢁC under nitrogen atmosphere.
The reaction mixture was kept stirring for 3 h at ꢀ78 ꢁC,
then treated with 1.0 M Na/K tartaric solution (50 mL) and
allowed to warm to room temperature. The resulting mixture
was extracted with diethyl ether (3ꢂ200 mL) and the com-
bined organic phases were dried (Na2SO4) and concentrated
under reduced pressure. The crude product was purified using
silica gel flash chromatography eluting with 20% EtOAc/
4.6. (3aR,9R,9aR,9bS)-Octahydro-2,2-dimethyl-
[1,3]dioxolo[4,5-a]indolizin-9-ol (31)
To a solution of acetonide 25 (7.79 g, 17.6 mmol) in dry
EtOH/THF (76 mL, v/v¼1:1) was added Pd(OH)2/C (1.9 g)
and the mixture was stirred under H2 at an 100 psi pressure

310
H. Guo, G.A. O’Doherty / Tetrahedron 64 (2008) 304e313
hexane to afford colorless oil, 6.0 g (15.8 mmol, 89%) of al-
lylic alcohol 35 and 36 in 1:2.5. Compound 36: Rf (20%
EtOAc/hexane)¼0.61; [a]2D5 þ52 (c 1.0, CH2Cl2); IR (thin
film, cmꢀ1) 3417, 2952, 2928, 2856, 1471, 1254, 1094,
1056, 834; 1H NMR (600 MHz, CDCl3) d 7.27e7.38 (m,
5H), 6.10 (dd, J¼9.6, 4.8 Hz, 1H), 5.86 (d, J¼9.6 Hz, 1H),
5.09 (d, J¼1.2 Hz, 1H), 4.92 (d, J¼11.4 Hz, 1H), 4.67 (d,
J¼11.4 Hz, 1H), 3.70 (m, 1H), 3.69 (m, 2H), 3.54 (ddd,
J¼7.2, 4.8, 2.4 Hz, 1H), 1.97 (d, J¼2.4 Hz, 1H), 1.78e1.84
(m, 1H), 1.69e1.77 (m, 2H), 1.62e1.67 (m, 1H), 0.91 (s,
9H), 0.07 (s, 6H); 13C NMR (150 MHz, CDCl3) d 137.6,
131.4, 130.9, 128.4, 128.1, 127.8, 97.2, 75.6, 70.0, 63.9,
63.2, 28.7, 27.3, 26.0, 18.4, ꢀ5.2; CIHRMS: calculated for
[C21H34O4SiNaþ]: 401.2118, found: 401.2132. Compound
35: Rf (20% EtOAc/hexane)¼0.58; [a]2D5 þ53 (c 1.0,
CH2Cl2); IR (thin film, cmꢀ1) 3426, 2932, 2928, 2856,
4.10. (2S,3S,6S)-6-(Benzyloxy)-3,6-dihydro-2-(3-tert-
butyldimethylsilyloxypropyl)-2H-pyran-3-yl-methyl
carbonate (38)
To a solution of allylic alcohol 36 (4.0 g, 10.6 mmol) and
pyridine (2.62 g, 31.6 mmol) in dry CH2Cl2 (53 mL) at 0 ꢁC,
was added DMAP (260 mg), and added dropwise methyl chloro-
formate (6.24 g, 63.6 mmol). After stirring 1 h at 0 ꢁC, a satu-
rated Cu2SO4 solution (500 mL) was added and then the
mixture was extracted with CH2Cl2 (3ꢂ300 mL), dried
(Na2SO4), concentrated under reduced pressure. The crude
product was purified using silica gel flash chromatography elut-
ing with 5% EtOAc/hexane to give 4.34 g (9.96 mmol, 94%) of
colorless oil, carbonate 38. Rf (20% EtOAc/hexane)¼0.62;
[a]2D5 þ110 (c 1.4, CH2Cl2); IR (thin film, cmꢀ1) 2955, 2929,
1
2886, 2857, 1745, 1442, 1264, 1098, 1059, 833; H NMR
1
1471, 1254, 1093, 1056, 834; H NMR (600 MHz, CDCl3)
(600 MHz, CDCl3) d 7.35 (m, 5H), 6.12 (ddd, J¼10.2, 4.8,
1.2 Hz, 1H), 6.03 (d, J¼10.2 Hz, 1H), 5.13 (d, J¼1.2 Hz, 1H),
4.88 (d, J¼11.4 Hz, 1H), 4.87 (dd, J¼4.8, 1.8 Hz, 1H), 4.68 (d,
J¼11.4 Hz, 1H), 3.78 (s, 3H), 3.62e3.73 (m, 3H), 1.73e1.84
(m, 2H), 1.64e1.70 (m, 1H), 1.57e1.63 (m, 1H), 0.90 (s, 9H),
0.06 (s, 6H); 13C NMR (150 MHz, CDCl3) d 155.8, 137.7,
133.7, 128.4, 128.1, 127.8, 126.5, 96.5, 73.6, 69.4, 69.2,
63.1, 55.0, 28.9, 27.1, 26.0, 18.4, ꢀ5.2; CIHRMS: calculated
for [C23H36O6SiNaþ]: 459.2173, found: 459.2179.
d 7.26e7.37 (m, 5H), 5.95 (ddd, J¼9.6, 3.0, 1.8 Hz, 1H),
5.81 (ddd, J¼9.6, 3.6, 1.2 Hz, 1H), 5.16 (dd, J¼3.6 1.8 Hz,
1H), 4.87 (d, J¼11.4 Hz, 1H), 4.64 (d, J¼11.4 Hz, 1H), 3.99
(ddd, J¼7.8, 7.2, 2.4 Hz, 1H), 3.68 (m, 2H), 3.47 (ddd,
J¼7.8, 7.2, 3.6 Hz, 1H), 2.29 (d, J¼7.2 Hz, 1H), 1.77e1.92
(m, 2H), 1.61e1.71 (m, 2H), 0.92 (s, 9H), 0.08 (s, 6H); 13C
NMR (150 MHz, CDCl3) d 137.7, 132.8, 128.8, 128.4,
128.0, 127.7, 96.0, 78.2, 69.5, 67.2, 63.2, 28.9, 28.8, 26.0,
18.4, ꢀ5.2; CIHRMS: calculated for [C21H34O4SiNaþ]:
401.2118, found: 401.2132.
4.11. (2S,3S,6S)-3-Azido-6-(benzyloxy)-3,6-dihydro-2-
(3-tert-butyldimethylsilyloxyprop-yl)-2H-pyran (39)
4.9. (2S,3S,6S)-6-(Benzyloxy)-3,6-dihydro-2-(3-tert-
butyldimethylsilyloxypropyl)-2H-pyran-3-yl benzoate (37)
To a mixture of carbonate 38 (2.2 g, 5.45 mmol), allylpalla-
dium chloride dimer (43.5 mg, 0.11 mmol) and 1,4-bis(diphe-
nylphosphino)butane (189 mg, 0.44 mmol) in dry THF
(1.2 mL) was added TMSN3 (684 mg, 5.95 mmol) under argon
atmosphere. The solution was stirred at room temperature for
0.5 h. Then the reaction mixture was passed through Celite
pad, concentrated under reduced pressure, and then purified
using silica gel flash chromatography eluting with 4%
EtOAc/hexane to give 2.0 g (4.96 mmol, 91%) allylic azide
39 as colorless oil. Rf (20% EtOAc/hexane)¼0.64; [a]D25
þ197 (c 1.9, CH2Cl2); IR (thin film, cmꢀ1) 2953, 2929,
2857, 2099, 1472, 1253, 1098, 835; 1H NMR (600 MHz,
CDCl3) d 7.36 (m, 5H), 6.10 (d, J¼10.2 Hz, 1H), 5.92 (ddd,
J¼10.2, 4.8, 1.2 Hz, 1H), 5.17 (d, J¼1.2 Hz, 1H), 4.90 (d, J¼
11.4 Hz, 1H), 4.68 (d, J¼11.4 Hz, 1H), 3.72 (ddd, J¼7.2, 4.8,
1.8 Hz, 1H), 3.68 (m, 2H), 3.63 (dd, J¼4.8, 3.0, 1.8 Hz, 1H),
1.81e1.89 (m, 1H), 1.69e1.75 (m, 2H), 1.59e1.64 (m, 1H),
0.91 (s, 9H), 0.07 (s, 6H); 13C NMR (150 MHz, CDCl3)
d 137.8, 133.3, 128.4, 128.1, 127.8, 126.1, 96.8, 75.5, 69.3,
63.1, 55.3, 28.7, 28.6, 26.0, 18.4, ꢀ5.2; CIHRMS: calculated
for [C21H33N3O6SiNaþ]: 426.2183, found: 426.2189.
Allylic alcohol 35 (1.1 g, 3.38 mmol) was dissolved in THF
(5 mL). The solution was cooled to 0 ꢁC and triphenylphos-
phine (1.77 g, 6.75 mmol), benzoic acid (0.82 g, 6.75 mmol),
and diisopropyl azodicarboxylate (1.33 mL, 6.75 mmol) were
added to the solution. The solution was stirred overnight,
quenched with saturated aqueous sodium bicarbonate
(50 mL), and extracted with ether (3ꢂ50 mL). The organic
fractions were combined, dried (Na2SO4), and concentrated
under reduced pressure. The crude product was purified using
silica gel flash chromatography eluting with 5% EtOAc/hex-
ane to afford colorless oil, 1.38 g (2.85 mmol, 84%) of allylic
ester 37. Rf (20% EtOAc/hexane)¼0.64; [a]2D5 þ122 (c 1.0,
CH2Cl2); IR (thin film, cmꢀ1) 2953, 2927, 2857, 1790,
1717, 1452, 1268, 1108, 1061, 835; 1H NMR (600 MHz,
CDCl3) d 8.09e8.10 (m, 2H), 7.52e7.57 (m, 2H), 7.28e
7.45 (m, 6H), 6.19 (ddd, J¼10.2, 4.8, 1.8 Hz, 1H), 6.05 (d,
J¼10.2 Hz, 1H), 5.28 (ddd, J¼7.2, 4.8, 2.4 Hz, 1H), 5.20
(d, J¼1.2 Hz, 1H), 4.94 (d, J¼11.4 Hz, 1H), 4.74 (d, J¼
11.6 Hz, 1H), 3.78 (ddd, J¼7.8, 4.8, 3.0 Hz, 1H), 3.60e3.68
(m, 2H), 1.84e1.90 (m, 1H), 1.75e1.82 (m, 1H), 1.67e1.73
(m, 1H), 1.58e1.65 (m, 1H), 0.08 (s, 9H), 0.02 (s, 3H), 0.01
(s, 3H); 13C NMR (150 MHz, CDCl3) d 166.3, 137.8, 134.6,
130.6, 129.9, 128.9, 128.5, 128.4, 128.1, 127.8, 127.1, 96.7,
74.0, 69.6, 66.0, 63.1, 28.9, 27.5, 26.0, 18.4, ꢀ5.3; CIHRMS:
calculated for [C28H38O5SiNaþ]: 505.2381, found: 505.2386.
4.12. (2S,3S,4S,5S,6S)-5-Azido-2-(benzyloxy)-
tetrahydro-6-(3-tert-butyldimethylsilyloxypropyl)-2H-
pyran-3, 4-diol (40)
To a tert-butanol/acetone (13.4 mL, 1:1, 1 M) solution of
allylic azide 39 (2.7 g, 6.7 mmol) at 0 ꢁC was added a solution

H. Guo, G.A. O’Doherty / Tetrahedron 64 (2008) 304e313
311
of (50% w/v) of N-methyl morpholine N-oxide/water (4 mL).
Crystalline OsO4 (17 mg, 1 mol %) was added and the reaction
mixture was stirred for 24 h. The reaction mixture was
quenched with 20 mL saturated Na2S2O3 solution, extracted
with ether (3ꢂ200), dried (Na2SO4), concentrated under re-
duced pressure, and then purified using silica gel flash chroma-
tography eluting with 30% EtOAc/hexane to give diol 40
(2.81 g, 6.43 mmol, 96%) as colorless oil. Rf¼0.47 (40%
EtOAc/hexane); [a]D25 þ41 (c 1.0, CH2Cl2); IR (thin film,
and concentrated under reduced pressure. The crude product
was purified using silica gel flash chromatography eluting
with 40% EtOAc/hexane to give alcohol 42 (401 mg,
1.11 mmol, 98%) as colorless oil. Rf¼0.45 (40% EtOAc/hex-
ane); [a]2D5 þ127 (c 0.8, CH2Cl2); IR (thin film, cmꢀ1) 3434,
1
2988, 2941, 2875, 2102, 1383, 1221, 1046, 854; H NMR
(600 MHz, CDCl3) d 7.26e7.38 (m, 5H), 4.90 (d, J¼
11.4 Hz, 1H), 4.66 (d, J¼11.4 Hz, 1H), 4.42 (dd, J¼5.4,
1.8 Hz, 1H), 4.41 (d, J¼7.8 Hz, 1H), 4.06 (dd, J¼7.8, 5.4 Hz,
1H), 3.73 (ddd, J¼8.4, 4.8, 1.8 Hz, 1H), 3.67 (m, 2H), 3.55
(dd, J¼1.8, 1.8 Hz, 1H), 1.88e1.95 (m, 1H), 1.73e1.81 (m,
1H), 1.65e1.71 (m, 2H), 1.37 (s, 3H), 1.32 (s, 3H); 13C NMR
(150 MHz, CDCl3) d 137.2, 128.4, 128.2, 127.8, 109.7, 101.1,
75.7, 74.3, 73.1, 70.2, 62.5, 60.3, 29.1, 27.8, 26.3; CIHRMS:
calculated for [C18H25N3O5Naþ]: 386.1686, found: 386.1680.
1
cmꢀ1) 3426, 2953, 2929, 2858, 2102, 1471, 1077, 835; H
NMR (600 MHz, CDCl3) d 7.34 (m, 5H), 4.93 (d, J¼
11.4 Hz, 1H), 4.63 (d, J¼7.8 Hz, 1H), 4.56 (d, J¼11.4 Hz,
1H), 4.23 (dd, J¼4.2, 2.4, 1.2 Hz, 1H), 3.95 (ddd, J¼7.8,
4.2, 1.2 Hz, 1H), 3.62e3.72 (m, 3H), 3.56 (dd, J¼3.0,
1.2 Hz, 1H), 2.73 (d, J¼1.2, 1H), 2.53 (d, J¼2.4 Hz, 1H),
1.80e1.87 (m, 1H), 1.71e1.77 (m, 1H), 1.57e1.68 (m, 2H),
0.91 (s, 9H), 0.07 (s, 6H); 13C NMR (150 MHz, CDCl3)
d 137.1, 128.6, 128.3, 128.2, 99.6, 72.5, 70.8, 70.1, 68.9,
63.6, 62.9, 29.3, 27.7, 26.1, 18.4, ꢀ5.2; CIHRMS: calculated
for [C21H35N3O5SiNaþ]: 460.2238, found: 460.2243.
4.15. 3-((3aS,4S,6S,7R,7aS)-7-Azido-4-(benzyloxy)-
tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]-
pyran-6-yl)propyl methanesulfonate (43)
To a stirred solution of alcohol 42 (1.8 g, 4.95 mmol) and
Et3N (1.5 g, 14.9 mmol) in dry CH2Cl2 (4.95 mL) was added
dropwise CH3SO2Cl (1.7 g, 1.49 mmol) at 0 ꢁC. The reaction
mixture was allowed to keep stirring for 0.5 h, and then water
30 mL was added, extracted with Et2O (3ꢂ200 mL), dried
(Na2SO4), and concentrated under reduced pressure. The re-
sulting crude product was purified using silica gel flash chro-
matography eluting with 45% EtOAc/hexane to give mesylate
43 (2.14 g, 4.85 mmol, 98%) as a colorless solid. Rf¼0.61
(50% EtOAc/hexane); mp: 85e87 ꢁC; [a]D25 þ110 (c 1.2,
CH2Cl2); IR (thin film, cmꢀ1) 2988, 2940, 2870, 2104, 1354,
4.13. (3-((3aS,4S,6S,7R,7aS)-7-Azido-4-(benzyloxy)-
tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]-
pyran-6-yl)propoxy)(tert-butyl)dimethylsilane (41)
para-Toluenesulfonic acid monohydrate (61.5 mg,
5 mol %) was added to a stirred solution of diol 40 (2.9 g,
6.6 mmol) and 2,2-dimethoxypropane (18.6 mL) in acetone
(99 mL) for 0.5 h at 0 ꢁC. The reaction mixture was quenched
with sodium bicarbonate solution (100 mL), removed acetone
in vacuo, extracted with Et2O (3ꢂ200 mL), dried (Na2SO4),
and concentrated under reduced pressure. The crude product
was purified using silica gel flash chromatography eluting
with 5% EtOAc/hexane to give 3.12 g (6.53 mmol, 99%) of
colorless oil, acetonide 41. Rf (20% EtOAc/hexane)¼0.67;
[a]2D5 þ96 (c 1.0, CH2Cl2); IR (thin film, cmꢀ1) 2952, 2930,
1
1173, 1051, 832; H NMR (600 MHz, CDCl3) d 7.26e7.37
(m, 5H), 4.90 (d, J¼11.4 Hz, 1H), 4.67 (d, J¼11.4 Hz, 1H),
4.43 (d, J¼7.8 Hz, 1H), 4.42 (dd, J¼5.4, 1.8 Hz, 1H), 4.30
(m, 1H), 4.25 (m, 1H), 4.06 (dd, J¼7.8, 5.4 Hz, 1H), 3.73
(ddd, J¼8.4, 4.8, 1.8 Hz, 1H), 3.53 (dd, J¼1.8, 1.8 Hz, 1H),
3.01 (s, 3H), 1.92e2.01 (m, 2H), 1.81e1.89 (m, 1H), 1.67e
1.72 (m, 1H), 1.37 (s, 3H), 1.33 (s, 3H); 13C NMR (150 MHz,
CDCl3) d 137.1, 128.4, 128.0, 127.8, 109.8, 101.2, 75.6, 74.3,
72.5, 70.4, 69.5, 60.1, 37.5, 27.7, 27.4, 26.3, 26.0; CIHRMS:
calculated for [C19H27N3O7SNaþ]: 464.1462, found: 464.1467.
1
2857, 2102, 1249, 1049, 835; H NMR (600 MHz, CDCl3)
d 7.27e7.37 (m, 5H), 4.91 (d, J¼11.4 Hz, 1H), 4.66 (d, J¼
11.4 Hz, 1H), 4.42 (dd, J¼5.4, 1.8 Hz, 1H), 4.41 (d, J¼7.8 Hz,
1H), 4.05 (dd, J¼7.2, 5.4 Hz, 1H), 3.72 (ddd, J¼8.4, 4.8,
1.8 Hz, 1H), 3.67 (m, 2H), 3.55 (dd, J¼1.8, 1.8 Hz, 1H),
1.84e1.90 (m, 1H), 1.65e1.78 (m, 2H), 1.57e1.64 (m, 1H),
1.37 (s, 3H), 1.31 (s, 3H), 0.91 (s, 9H), 0.06 (s, 6H); 13C
NMR (150 MHz, CDCl3) d 137.2, 128.4, 128.0, 127.8,
109.6, 101.0, 75.8, 74.4, 73.0, 70.1, 62.9, 60.2, 28.7, 29.1,
27.8, 26.3, 26.0, 18.3, ꢀ5.2; CIHRMS: calculated for
[C24H39N3O5SiNaþ]: 500.2551, found: 500.2556.
4.16. (3aR,9S,9aR,9bS)-Octahydro-2,2-dimethyl-
[1,3]dioxolo[4,5-a]indolizin-9-ol (44)
To a solution of acetonide 43 (410 mg, 0.928 mmol) in dry
EtOH/THF (4 mL, v/v¼1:1) was added Pd(OH)2/C (100 mg)
and the mixture was stirred under an atmosphere of H2 at
room temperature. After reacting for 1 day, the mixture was
concentrated, simply passed through a short pad of silica gel
to remove palladium toxicity byproduct and concentrated
again. The resulting residue was dissolved in EtOH/THF
(4 mL, v/v¼1:1) and Pd(OH)2/C (200 mg) was added. The
suspended mixture was stirred for another 6 days under an at-
mosphere of H2 at room temperature. Then the catalyst was fil-
tered off through a short pad of Celite, concentrated under
4.14. 3-((3aS,4S,6S,7R,7aS)-7-Azido-4-(benzyloxy)-
tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]-
pyran-6-yl)propan-1-ol (42)
To a solution of TBS-ether 41 (540 mg, 1.13 mmol) in dry
THF (1.1 mL), TBAF (1.3 mL, 1.3 mmol) was added at room
temperature under argon atmosphere. After 12 h, the reaction
mixture was quenched with sodium bicarbonate solution
(500 mL), extracted with Et2O (3ꢂ100 mL), dried (Na2SO4),

312
H. Guo, G.A. O’Doherty / Tetrahedron 64 (2008) 304e313
reduced pressure. The resulting crude product was purified us-
ing silica gel flash chromatography eluting with 30% MeOH/
EtOAc to give protected (ꢀ)-8-epi-D-swainsonine 44 (164 mg,
0.769 mmol, 83%) as colorless needles. Rf¼0.77 (50% MeOH/
EtOAc); [a]2D5 ꢀ33 (c 1.08, CH2Cl2); mp: 57.4e59.3 ꢁC; IR
(neat, cmꢀ1) 3513, 2982, 2937, 2786, 1464, 1373, 1262,
temperature. After reacting for 1 day, the mixture was concen-
trated, simply passed through a short Celite pad to remove by-
product and concentrated again. The resulting residue was
dissolved in EtOH/THF (0.5 mL, v/v¼1:1) and Pd(OH)2/C
(10 mg) was added. The suspended mixture was stirred under
H2 at 100 psi pressure for another 2 days at room temperature.
Then the catalyst was filtered off through a short pad of Celite,
concentrated under reduced pressure. The resulting crude
product was applied to ion-exchange chromatography (Dowex
1ꢂ8, 200 mesh, OHꢀ form) eluting with water. Removal of
0.078 mmol, 68%). Rf¼0.25 (MeOH); [a]2D5 ꢀ7.9 (c 0.4,
CH3OH); IR (thin film, cmꢀ1) 3365, 2936, 2805, 1639,
1328, 1069; 1H NMR (600 MHz, CD3OD) d 3.32 (ddd,
J¼10.2, 9.0, 4.8 Hz, 1H), 3.06 (ddd, J¼9.0, 9.0, 3.0 Hz, 1H),
2.99 (m, 1H), 2.21 (q, J¼9.0 Hz, 1H), 2.11 (dddd, J¼12.0,
10.2, 6.6, 3.6 Hz, 1H), 1.96e2.01 (m, 2H), 1.70e1.83 (m, 4H),
1.59e1.67 (m, 1H), 1.48e1.57 (m, 1H), 1.22 (dddd, J¼15.0,
12.6, 10.2, 4.2 Hz, 1H); 13C NMR (150 MHz, CD3OD)
d 73.4, 71.6, 55.1, 52.9, 34.5, 29.2, 25.1, 21.4; CIHRMS: cal-
culated for [C8H15NOHþ]: 142.1232, found: 142.1228.
1
1209, 1135, 1018; H NMR (600 MHz, CDCl3) d 4.67 (dd,
J¼6.0, 4.2 Hz, 1H), 4.56 (dd, J¼6.0, 4.2 Hz, 1H), 3.79 (ddd,
J¼10.9, 8.9, 4.4 Hz, 1H), 3.11 (d, J¼10.8 Hz, 1H), 2.96
(dt, J¼10.8, 3.0 Hz, 1H), 2.52 (br s, 1H), 2.09 (dd, J¼10.8,
4.8 Hz, 1H), 2.00e2.03 (m, 1H), 1.82 (ddd, J¼10.8, 10.8,
3.6 Hz, 1H), 1.61e1.65 (m, 1H), 1.59 (dd, J¼9.0, 4.8 Hz,
1H), 1.51 (s, 3H), 1.36e1.40 (m, 1H), 1.28 (s, 3H), 1.21e
1.32 (m, 1H); 13C NMR (150 MHz, CDCl3) d 111.5, 82.0,
78.1, 68.7, 65.8, 60.1, 53.3, 31.4, 25.8, 24.2, 19.7; CIHRMS:
calculated for [C11H19NO3Hþ]: 214.1443, found: 214.1438.
water in vacuo gave 8-hydroxyindolizidine
4 (11 mg,
4.17. (1S,2R,8R,8aR)-Octahydroindolizine-1,2,8-triol
(swainsonine 1)24
To a solution of diol 6 (4.0 g, 9.96 mmol) in dry EtOH
(40 mL) was added Pd(OH)2/C (1.5 g) and the mixture was
stirred under H2 at 100 psi pressure for 3 days at room temper-
ature. The catalyst was filtered off through a short pad of Cel-
ite, concentrated under reduced pressure. The resulting crude
product was applied to ion-exchange chromatography (Dowex
1C 8, 200 mesh, OHꢀ form) eluting with water. Removal of
water in vacuo gave colorless needles D-swainsonine 1
(1.48 g, 8.5 mmol, 86%). Rf¼(25% MeOH/CHCl3, 1%
NH4OH(aq))¼0.38; mp: 143e144 ꢁC; [a]D25 80 (c 1.1,
MeOH); [lit. [a]D23 74.0 (c 0.98, MeOH);24 [a]2D5 82.6 (c
1.03, MeOH);21b [a]D25 73.8 (c 0.21, EtOH);21c [a]2D5 75.7 (c
2.33, MeOH)];21d IR (thin film, cmꢀ1) 3287, 2953, 2722,
1639, 1405, 1338, 1141, 1076; 1H NMR (600 MHz,
CD3OD) 4.26 (ddd, J¼8.0, 6.0, 2.4 Hz, 1H), 4.24 (m, 1H),
3.83 (ddd, J¼4.5, 9.3, 10.8 Hz, 1H), 2.95e2.97 (m, 2H),
2.45 (dd, J¼7.2, 10.2 Hz, 1H), 2.08 (m, 1H), 1.92 (ddd,
J¼11.6, 11.4, 2.8 Hz, 1H), 1.75 (dd, J¼3.6, 9.6 Hz, 1H),
1.71e1.74 (m, 1H), 1.70 (m, 1H), 1.64 (qt, J¼13.2, 4.2 Hz,
1H), 1.25 (qd, J¼12.6, 4.8 Hz, 1H); 13C NMR (150 MHz,
CD3OD) d 75.4, 70.9, 70.0, 67.2, 63.3, 53.3, 34.3, 24.7.
To a solution of protected swainsonine (ent)-31 (100 mg,
0.47 mmol) in THF was added 6 N HCl (0.47 mL) at room
temperature over night. The resulting mixture was concen-
trated under reduced pressure and then eluted with water
through an ion exchange column (Dowex 1ꢂ8, 200 mesh,
OHꢀ, 1 g). Removal of water in vacuo gave colorless needles
swainsonine 2 (77.2 mg, 0.45 mmol, 95%). L-Swainsonine 2:
1H, 13C NMR and IR data are same as D-swainsonine 1, mp:
142e143 ꢁC; [a]D21 þ75 (c 0.92, MeOH); [lit. [a]2D1 þ84.3
(c 1.02, H2O); [a]2D5 þ83.3 (c 0.5, MeOH)].
4.19. (1S,2R,8S,8aR)-Octahydroindolizine-1,2,8-triol
((ꢀ)-8-epi-D-swainsonine) (3)22
To a solution of protected (ꢀ)-8-epi-D-swainsonine 44
(120 mg, 0.56 mmol) in THF (1.2 mL) was added 6 N HCl
(0.59 mL) at room temperature over night. The resulting mix-
ture was concentrated under reduced pressure and then eluted
with water through an ion exchange column (Dowex 1ꢂ8, 200
mesh, OHꢀ, 1 g). Removal of water in vacuo gave white pow-
der (ꢀ)-8-epi-D-swainsonine 3 (92 mg, 0.53 mmol, 94%).
Rf¼(50% MeOH/EtOAc)¼0.31; mp: 89e91 ꢁC [lit. mp: 92e
93 ꢁC];22a [a]2D5 25 (c 0.75, MeOH); [lit. [a]2D5 20 (c 0.3,
MeOH);22b [a]D25 24.8 (c 0.67, MeOH)];22c IR (thin film,
cmꢀ1) 3360, 2937, 2789, 1645, 1329, 1138, 1013; H NMR
1
(600 MHz, CD3OD) d 4.32 (m, 2H), 4.20 (ddd, J¼7.2, 6.6,
1.8 Hz, 1H), 3.11 (m, 1H), 2.99 (dd, J¼10.2, 1.8 Hz, 1H),
2.34 (dd, J¼10.2, 7.2 Hz, 1H), 1.98e2.10 (m, 3H), 1.85e
1.88 (m, 1H), 1.44e1.53 (m, 2H); 13C NMR (150 MHz,
CD3OD) d 74.3, 70.0, 69.5, 67.6, 63.1, 54.4, 32.2, 20.8;22c,d
CIHRMS: calculated for [C8H15NO3Hþ]: 174.1130, found:
174.1125.
Acknowledgements
We are grateful to NIH (GM63150) and NSF (CHE-
0415469) for the support of our research program and
NSF-EPSCoR (0314742) for a 600 MHz NMR at WVU.
4.18. (8R,8aS )-Octahydroindolizin-8-ol (4)
Supplementary data
To a solution of mesylate 33 (42 mg, 0.1148 mmol) in dry
EtOH/THF (0.5 mL, v/v¼1:1) was added Pd(OH)2/C (10 mg)
and the mixture was stirred under an atmosphere of H2 at room
Complete experimental procedures and spectral data for all
new compounds. This material is available free of charge via
the Internet. Supplementary data associated with this article

H. Guo, G.A. O’Doherty / Tetrahedron 64 (2008) 304e313
313
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11. Our initial effort toward the synthesis of swainsonine was previously
disclosed, see Ref. 10m.
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23. Presented in Section 4 are the experimental procedures and spectral data
for all new compounds. Complete experimental procedures and spectral
data for all compounds are presented in Supplementary data.
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