Simple Total Syntheses of (+)-Castanospermine and (+)-6-Epicastanospermine Using Indium-Mediated Allylation

Article abstract of DOI:10.1055/s-2003-42423

The indium-mediated allylation of α-aminoaldehyde 3 from D-glucono-δ-lactone provided the syn-aminoalcohol with excellent diastereoselectivity. syn-Aminoalcohol was easily applied to the total syntheses of the potent glycosidase inhibitors; (+)-castanospe

Full text of DOI:10.1055/s-2003-42423

PAPER
2473
Simple Total Syntheses of (+)-Castanospermine and (+)-6-Epicastanospermine
Using Indium-Mediated Allylation
Total
S
ynt
i
heses
o
n
f
(+)-Castanosper
m
H
ine and
(
+)-6-Epi
y
castanosperm
o
ine Kim, Woo Duck Seo, Jin Hwan Lee, Byong Won Lee, Ki Hun Park*
Division of Applied Life Science, BK21 Programs, Department of Agricultural Chemistry, Gyeongsang National University, Jinju 660-701,
Korea
Fax +82(55)7570178; E-mail: khpark@gshp.gsnu.ac.kr
Received 7 July 2003; revised 4 August 2003
OH
8
OH
OH
OH
Abstract: The indium-mediated allylation of -aminoaldehyde 3
from D-glucono- -lactone provided the syn-aminoalcohol with ex-
cellent diastereoselectivity. syn-Aminoalcohol was easily applied to
the total syntheses of the potent glycosidase inhibitors; (+)-castano-
spermine and (+)-6-epicastanospermine.
H
H
N
HO
HO
HO
HO
1
7
6
8a
N
1
2
Keywords: (+)-castanospermine, (+)-6-epicastanospermine, indi-
um-mediated allylation, (+)-cinchonine, glycosidase inhibitor
Figure 1 Target compounds 1 and 2
ence of (+)-cinchonine with anticipation of a high
selectivity and stereointegrity.
(+)-Castanospermine (1) and (+)-6-epicastanospermine
(2) (Figure 1) are natural indolizidine alkaloids isolated
from Castanospermum australe1 and Alexa leiopetala.2
These indolizidine alkaloids are a potent glycosidase
inhibitor3 with broad biological activities such as diabe-
tes,4 cancer,5 and viral replication.6 Thus, many synthetic
strategies to target molecules (1 and 2) have been devel-
oped,7 and the most practical route is starting from carbo-
hydrate because of minimizing the need to create the
requisite stereocenters. The efficiency of this approach to
indolizidine alkaloids like castanospermine from carbo-
hydrate would largely rely on how chiral induction of C-1
is carried out. Efficient, asymmetric methodology for ma-
nipulation of simple aminoaldehyde from carbohydrate
into aminoalcohol is, therefore, of considerable merit.
This key step has been accomplished through reduction of
keto group,8 Michael type reaction,9 or aldol type
reaction10 because direct nucleophilic addition to ami-
noaldehyde does not give a high level of stereocontrol.11
Although the above mentioned approaches have been
proven as useful methods, they suffer from the disadvan-
tage of either including non-stereoselective steps or have
1
HO
5
O
O
OH
O
OH
4
O
O
2
HO
3
O
NHPf
OH
2
4
Scheme 1 Retrosynthesis of target compounds 1 and 2
In our retrosynthesis (Scheme 1), D-glucono- -lactone
was chosen as the starting material with C2, C3, C4, and
C5 being transferred into the C6, C7, C8, and C8a, respec-
tively, in target molecules 1 and 2. -Aminoaldehyde 3 al-
lows the introduction of C2 unit for target compounds via
an organometallic reagent (Scheme 2). We also anticipat-
ed the indium-mediated allylation in the presence of (+)-
cinchonine to give the chiral syn-aminoalcohol 4 as the
key intermediate of compounds 1 and 2.
(+)-Castanospermine (1)
low overall yields owing to their tedious number of steps. Our synthesis commenced with the synthesis of -ami-
Herein, we describe a highly diastereoselective synthesis noaldehyde 3, which was easily accessible via known
of syn-aminoalcohol 4 via indium-mediated allylation in procedures8 from D-glucono- -lactone. We chose the 9-
the presence of (+)-cinchonine as a chiral promoter.12 syn- phenylfluoren-9-yl (Pf) group for protection of amine
Aminoalcohol 4 was easily converted enantiomerically to since this protecting group has been shown to inhibit
pure (+)-castanospermine (1) and (+)-6-epicastanosper- deprotonation at the α-position of α-aminoaldehyde.8 α-
mine (2).
Aminoaldehydes having the Pf group are stable to Grig-
nard reaction condition.9 α-Aminoaldehyde 3 was treated
with allylbromide and indium in the presence of (+)-cin-
chonine as a chiral promoter at –40 °C for 10 minutes to
give syn-aminoalcohol 4 in a 50:1 ratio in 87% yield via a
diastereoselective addition. As shown in Table 1, the op-
timum reaction conditions involved the use of (+)-cincho-
Our approach to syntheses of 1 and 2 envisaged the use of
syn-aminoalcohol 4, which can be obtained from -ami-
noaldehyde 3 via indium-mediated allylation in the pres-
nine as
a
chiral promoter in THF. The syn
SYNTHESIS 2003, No. 16, pp 2473–2478
Advanced online publication: 07.10.2003
DOI: 10.1055/s-2003-42423; Art ID: F05803SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
3
diastereoselectivity of allylation could be explained by the
chelation control model,13 which concisely accommo-

2474
J. H. Kim et al.
PAPER
dates favored formation of the syn-aminoalcohol
(Figure 2). Fortunately, each diastereomeric allylic alco-
hol obtained by the allylation could be isolated in pure
form by column chromatography. The stereochemistry of
product 4 was deduced from NOE experiment of final
product 2.
L
H
H
L
In
O
L
L
OH
In
NHPf
O
H
PfHN
R
R
NHPf
H
R
H
Figure 2
HO
O
O
O
5
O
The secondary hydroxy group of 4 was easily protected
with TBDMSCl, to give silylate 5 in 98% yield. The ter-
minal olefin group in 5 should be cleaved for the forma-
tion of five-membered ring in castanospermine. The
compound 5 was ozonized with anticipation of the alde-
hyde product, but this reaction kept running directly to in-
tramolecular amination to give corresponding hemiaminal
15, which was used in the next step without a further pur-
ification (Figure 3).
O
a
OH
4
O
H
2
HO
3
O
NHPf
OH
3
b
O
OR
O
O
OTBDMS
O
c
O
O
d
O
NHPf
4: R = H
5: R = TBDMS
O
N
R
6: R = H
e
7: R = Cbz
O
OTBDMS
OH
O
f
O
6
5
OH
O
OTBDMS
O
N
Pf :
Pf
HO
15
O
N
Cbz
8
Figure 3
Scheme 2 a) Ref.7; b) AllylBr, In, (+)-cinchonine, THF, –78 °C; c)
TBDMSCl, Imidazole, DMF, r.t.; d) O3, CH2Cl2, –78 °C, 10%
Pd(OH)2, H2, EtOH, r.t.; e) CbzCl, K2CO3, CH2Cl2, 0 °C; f) Dowex
50W-X8, 90% MeOH, r.t.
Catalytic hydrogenolysis of hemiaminal 15 over palladi-
um hydroxide in EtOH cleaved Pf group, and subsequent-
ly produced pyrrole 6 in 63% yield from 5. The observed
one-pot cyclization probably curtailed two steps in our
scheme. The pyrrole 6 was protected with benzyl chloro-
formate (CbzCl) in quantitative yield. For regioselective
hydrolysis of the terminal O-isopropylidene group in di-
isopropylidene 7 under acidic condition, Dowex 50W-X8
was treated with 7 in 90% MeOH to give diol 8 in 93%
yield.
Table 1 Stereoselective Allylation of Aminoaldehyde with Allyl-
bromidea
OH
OH
AllylBr
Indium
3
NH
Pf
syn
NH
Pf
anti
Entry Chiral promoter
Conditionb
Ratioc
(syn/anti) (%)d
Yield
OH
O
OTBDMS
TBDMSO
g
8
1
2
3
4
None
THF
2:1
3:1
70
75
87
75
80
O
N
Cbz
9
None
THF–H2O (3:1)
THF
h
(+)-cinchonine
(+)-cinchonine
50:1
1:1
O
OH
MsO
O
OTBDMS
O
THF–hexane (3:1)
TBDMSO
i
5
(–)-cinchonidine THF
1:2
O
N
O
N
Cbz
Cbz
10
11
a
All experiments were performed at least in duplicate.
b The solution of allylbromide was heated to reflux with indium prior
j
to reaction. The mixture was cooled prior to introduction of the alde-
O
OH
OH
OH
hyde.
O
k
HO
c The ratio was determined by 1H NMR analysis of the reaction mix-
tures.
N
N
d Isolated yield.
HO
HO
12
1
Scheme 3 g) TBDMSCl, Imidazole, CH2Cl2, r.t.; h) MsCl, Et3N,
CH2Cl2, 0 °C; i) TBAF, K2CO3, THF, r.t.; j) H2, 10% Pd/C, NaOAc,
MeOH, 60 °C; k) Dowex 50W-X8, THF–H2O (3:1), reflux
Synthesis 2003, No. 16, 2473–2478 © Thieme Stuttgart · New York

PAPER
Total Syntheses of (+)-Castanospermine and (+)-6-Epicastanospermine
2475
The primary hydroxy group of 8 was highly selectively pound 1, and between H1–H8a and H6–H7 in compound
protected with TBDMSCl to give 9, and the secondary hy- 2.
droxy group of 9 was mesylated to give compound 10 in
We have prepared (+)-castanospermine (1) and (+)-6-epi-
92% yield. To prepare (+)-castanospermine (1) from the
castanospermine (2) through highly diastereoselective in-
well-designed intermediate 10, all that was required was
dium-mediated allylation. The developed synthetic route
should be valuable for the total synthesis of indolizidine
alkaloids as like swainsonine and lentiginosine.
the inversion of the C3 hydroxy group. The inversion of
stereochemistry at C3 in 11 was accomplished by epoxi-
dation. The TBDMS group of 10 was deprotected with tet-
rabutylammonium fluoride (TBAF) in THF at room
All non-aqueous reactions were carried out under an inert N2 atmos-
temperature and then treated with K2CO3 in MeOH to give
phere. THF was distilled from Na/benzophenone whereas Et3N,
2,2-dimethoxypropane, DMF, and CH2Cl2 were distilled from
CaH2. All reactions were monitored by TLC with commercially
epoxide 11 in 90% yield. Hydrogenolysis of epoxide 11 in
the presence of 10% Pd/C and NaOAc removed the Cbz
group and led to highly selective 6-membered intramolec-
ular cyclization to give indolizidine 12 in 65% yield. (+)-
Castanospermine (1) was easily obtained by treatment of
12 with Dowex 50W-X8 in THF–H2O (3:1) in nearly
quantitative yield without the necessity of additional ion-
exchange chromatography. The spectral and physical
properties of (+)-castanospermine (1) matched those re-
ported in the literature {[ ]D20 +79.8 (c 0.90, H2O); lit.,14
[ ]D20 +79.7 (c 1.06, H2O)} (Scheme 3).
available glass-backed plates. Column chromatography was carried
out using 230–400 mesh silica gel. Final solution before the remov-
al of solvent was washed with brine and dried over anhyd Na2SO4.
Melting points are uncorrected. 1H and 13C NMR spectra were mea-
sured downfield relative to TMS on a Brucker AW-500 spectrome-
ter in CDCl3 unless otherwise noted ( in ppm). HREIMS were
obtained on a JEOLJMS-700 mass spectrometer. Optical rotations
were measured on a Perkin-Elmer polarimeter 343 and [ ]D values
are given in units of 10–1 deg cm2 g–1.
2-[(9-Phenylfluoren-9-yl)-amino]-2-deoxy-3,4;5,6-di-O-isopro-
pylidene-D-mannose (3)
OH
O
OTBDMS
This compound was prepared as described in literature;8 [ ]D
20
MsO
l
+16.9 (c 0.49, CHCl3).
8
O
N
IR (neat): 1720, 3305 cm–1.
Cbz
13
1H NMR (500 MHz, CDCl3): = 1.09, 1.18, 1.25, 1.27 (4 s, 12 H),
2.83 (m, 1 H), 3.45 (br s, 1 H), 3.72–3.83 (m, 3 H), 3.93 (dd, J = 7.0,
5.0 Hz, 1 H), 4.02 (m, 1 H), 7.19–7.63 (m, 13 H), 9.27 (d, 1 H).
13C NMR (125 MHz, CDCl3): = 24.1, 25.2, 25.6, 25.7, 62.1, 66.5,
71.7, 77.3, 80.5, 108.7, 108.9, 118.9, 119.1, 124.1, 124.6, 125.2,
126.3, 126.8, 126.9, 127.2, 127.5, 127.8, 139.6, 139.7, 143.1, 147.8,
147.9, 200.1.
m
OH
O
OTBDMS
OH
O
HO
HO
n
N
N
HO
2
14
Anal. Calcd for C31H33NO5: C, 74.5; H, 6.6; N, 2.8. Found: C, 74.4;
H, 6.7; N, 2.7.
Scheme 4 l) MsCl, Et3N, CH2Cl2, –40 °C; m) 10% Pd/C, H2, Me-
OH, NaOAc, r.t.; n) Dowex 50W-X8, THF–H2O (3:1), reflux.
(1S)-1-Allyl-2-[(9-phenylfluoren-9-yl)-amino]-2-deoxy-3,4;5,6-
di-O-isopropylidene-D-mannitol (4)
(+)-6-Epicastanospermine (2)
Allylbromide (0.98 g, 7.61 mmol) was added to an In suspended so-
lution (0.26 g, 2.28 mmol) in THF (20 mL) and then the reaction
mixture was stirred vigorously till it became clear at reflux to which
then was added (+)-cinchonine (0.88 g, 3.04 mmol) at r.t. To the re-
action mixture was added compound 3 (0.76 g, 1.52 mmol) at –78
°C and then stirred for 2 h. The reaction mixture was filtered and
evaporated. The residue was chromatographed on silica gel (hex-
ane–EtOAc, 15:1) to give compound 4 (0.72 g, 87%) as a solid; mp
115–116 °C, [ ]D20 +182.8 (c 2.00, CHCl3).
Diol 8 was treated with mesylchloride under CH2Cl2 at
–40 °C for 5 minutes to give monomesylate 13 selectively
in 86% yield (based on 68% conversion). The longer reac-
tion time results in a diminution of selectivity. Monome-
sylate 13 was hydrogenated in the presence of 10% Pd/C
and NaOAc to remove Cbz group, and led to direct in-
tramolecular cyclization to give indolizidine 14 in 85%
yield. Indolizidine 14 was protected with acid-sensitive
groups and was refluxed with Dowex 50W-X8 in 90%
MeOH for 5 hours and filtered. The filterate was washed
with MeOH, and then eluted with 3 N NH3 solution to af-
ford enantiomerically pure (+)-6-epicastanospermine (2)
in 90% yield (Scheme 4). The physical properties and the
1H and 13C spectral data of (+)-6-epicastanospermine (2)
matched with those reported in the literature {[ ]D20 +2.8
(c 1.00, H2O); lit.,8 [ ]D20+2.2 (c 0.70, MeOH)}. The rel-
ative stereochemistry of the target molecules 1 and 2 were
determined from 2D NOESY experiment. Strong NOE
cross peaks were observed only between H1–H8a in com-
IR (neat): 1636, 2997, 3078, 3509 cm–1.
1H NMR (500 MHz, CDCl3): = 0.95 (s, 3 H), 1.05 (s, 3 H), 1.16
(s, 3 H), 2.25 (m, 1 H), 2.40 (m, 1 H), 2.56 (s, 1 H), 3.19 (m, 1 H),
3.33 (t, J = 8.0 Hz, 1 H,), 3.42 (dd, J = 8.5, 2.0 Hz, 1 H), 3.66 (dd,
J = 8.5, 5.0 Hz, 1 H), 3.73 (t, J = 6.5 Hz, 1 H), 3.81 (dd, J = 8.5, 6.5
Hz, 1 H), 4.96 (m, 1 H), 5.03 (dd, J = 17.0, 1.5 Hz, 1 H), 5.63 (m, 1
H), 7.19–7.70 (m, 13 H).
13C NMR (125 MHz, CDCl3): = 25.3, 26.6, 27.5, 38.9, 54.9, 67.5,
71.3, 72.5, 77.7, 78.1, 83.3, 109.4, 109.6, 117.1, 120.4, 120.5,
125.6, 126.3, 126.6, 127.5, 128.1, 128.2, 128.6, 128.7, 136.1, 140.6,
141.3, 145.9, 149.3, 152.1.
Anal. Calcd for C34H39NO5: C, 75.4; H, 7.3; N, 2.6. Found: C, 75.3;
H, 7.2; N, 2.5.
Synthesis 2003, No. 16, 2473–2478 © Thieme Stuttgart · New York

2476
J. H. Kim et al.
PAPER
(1S)-1-Allyl-1-O-t-butyldimethylsilyl-2-[(9-phenylfluoren-9-yl)-
amino]-2-deoxy-3,4;5,6-di-O-isopro-pylidene-D-mannitol (5)
To a solution of 4 (2.20 g, 4.06 mmol) in anhyd DMF (20 mL) were
added imidazole (0.69 g, 10.15 mmol) and TBDMSCl (0.91 g, 6.09
mmol) at r.t. After stirring for 6 h, sat. NaHCO3 (60 mL) was added
and the mixture was extracted with EtOAc (5 × 20 mL). The com-
bined extract was evaporated, and the residue was chromatographed
on silica gel (hexane–EtOAc, 10:1) to give compound 5 (2.61 g,
98%) as a solid; mp 73–74 °C, [ ]D20 +70.3 (c 2.0, CHCl3).
13C NMR (125 MHz, CDCl3): = –5.1, –5.0, –4.8, 18.2, 25.4, 25.8,
26.4, 27.0, 27.2, 31.2, 31.9, 43.2, 43.3, 59.0, 60.3, 66.9, 67.0, 67.8,
72.2, 72.9, 76.8, 79.5, 80.5, 109.4, 127.9, 128.0, 128.3, 128.5,
136.7, 155.7.
Anal. Calcd for C28H45NO7Si: C, 62.8; H, 8.5; N, 2.6. Found: C,
62.7; H, 8.4; N, 2.6.
(1 R,2 S,3 R,3S)-2-(1 ,2 -O-Isopropylidene-1 ,2 ,3,4-tetrahy-
droxy butyl)-3-O-t-butyl-dimethylsilyl-3-hydroxy-N-(benzyl-
oxycarbonyl)-pyrrolidine (8)
IR (neat): 1648, 2590, 2935, 3070 cm–1.
To a solution of compound 7 (1.21 g, 2.26 mmol) in 90% MeOH
was added Dowex 50W-X8 resin (400 mg). The reaction mixture
was stirred for 18 h at r.t., then filtered and the solvent was evapo-
rated. The crude residue was chromatographed on silica gel (hex-
ane–EtOAc, 2:1) to give compound 8 (1.04 g, 93%) as an oil; [ ]D
+20.6 (c 2.0, CHCl3).
1H NMR (500 MHz, CDCl3): = 0.00 (s, 3 H), 0.21 (s, 3 H), 0.95
(s, 9 H), 1.40 (d, J = 4.5 Hz, 6 H), 1.44 (d, J = 10 Hz, 6 H), 2.17 (m,
1 H), 2.45 (s, 1 H), 3.12 (m, 1 H), 3.32 (dd, J = 8.5, 5.0 Hz, 1 H),
3.73 (m, 2 H), 3.78 (t, J = 8.0 Hz, 1 H), 3.92 (m, 1 H), 4.44 (m, 1
H), 5.06 (m, 2 H), 5.73 (m, 1 H), 7.35–7.89 (m, 13 H).
13C NMR (125 MHz, CDCl3): = 18.0, 25.4, 25.9, 26.2, 26.7, 27.5,
38.8, 55.8, 65.3, 72.8, 75.7, 76.4, 80.9, 108.4, 108.8, 116.4, 120.0,
125.7, 126.2, 127.0, 127.8, 128.0, 128.2, 128.3, 128.4, 136.7, 140.1,
141.0, 145.6, 150.0 and 150.8.
20
IR (neat): 1686, 2942, 3442 cm–1.
1H NMR (500 MHz, CDCl3): = 0.01 (s, 6 H), 0.81 (s, 9 H), 1.24–
1.31 (m, 6 H), 1.87 (m, 1 H), 2.08 (m, 1 H), 3.37 (m, 2 H), 3.53–3.61
(m, 3 H), 4.01 (m, 1 H), 4.18–4.34 (m, 4 H), 4.98–5.07 (m, 2 H),
7.16–7.28 (m, 5 H).
13C NMR (125 MHz, CDCl3): = –5.1, –4.9, 18.2, 25.8, 27.0, 27.2,
32.2, 43.9, 64.1, 67.2, 72.6, 73.5, 76.8, 78.1, 79.3, 109.3, 128.2,
128.5, 136.5.
Anal. Calcd for C40H53NO5Si: C, 73.2; H, 8.1; N, 2.1. Found: C,
73.2; H, 8.1; N, 2.2
(1 R,2 S,3 R,3S)-2-(1 ,2 ,3 ,4 -O-Di-isopropylidene-1 ,2 ,3 ,4 -tet-
rahydroxy butyl)-3-O-t-butyldimethylsilyl-3-hydroxypyrroli-
dine (6)
Anal Calcd for C25H41NO7Si: C, 60.6; H, 8.3; N, 2.8. Found: C,
60.5; H, 8.4; N, 2.8.
A solution of 5 (2.61 g, 3.98 mmol) in MeOH (30 mL) was ozonized
at –78 °C until the solution turned blue, then the residual ozone was
removed with N2 gas. Then dimethylsulfide (0.87 mL, 11.94 mmol)
was added, and the reaction mixture was allowed to warm to r.t. (12
h). The solvent was evaporated to give corresponding hemiaminal
12, the remaining residue was directly hydrogenated with 10%
Pd(OH)2/C (0.03 g) in EtOH (30 mL) for 10 h, and the mixture was
filtered and the solvent was evaporated. The residue was chromato-
graphed on silica gel (CH2Cl2–acetone, 10:1) to give the compound
6 (1.01 g, 63%) as an oil; [ ]D20+37.9 (c 2.0, CHCl3).
(1 R,2 S,3 R,3S)-2-(1 , 2 -O-Isopropylidene-4 -O-t-butyldimeth-
ylsilyl-1 ,2 ,3 ,4 -tetrahydroxy-butyl)-3-O-t-butyldimethylsilyl-
3-hydroxy-N-(benzyloxycarbonyl)-pyrrolidine (9)
To a solution of diol 8 (1.04 g, 2.10 mmol) in CH2Cl2 (10 mL) were
added imidazole (0.37 g, 5.45 mmol) and TBDMSCl (0.54 g, 3.36
mmol) at r.t. After stirring the mixture for 1 h, sat. NaHCO3 (30 mL)
was added and the mixture was extracted with CH2Cl2 (3 × 15 mL).
The organic layer was concentrated and the residue was chromato-
graphed on silica gel (hexane–EtOAc, 10:1) to give compound 9
(1.27 g, 99%) as an oil; [ ]D20 +10.7 (c 1.0, CHCl3).
IR (neat): 2983, 3354 cm–1.
1H NMR (500 MHz, CDCl3): = 0.00 (s, 6 H), 0.81 (s, 9 H), 1.27
(m, 9 H), 1.36 (s, 3 H), 1.69 (m, 1 H), 1.82 (m, 1 H), 2.84 (m, 2 H),
3.10 (m, 1 H), 3.90 (m, 3 H), 4.04 (m, 2 H), 4.24 (m, 1 H).
13C NMR (125 MHz, CDCl3): = –5.0, –4.7, 18.2, 25.4, 25.8, 26.4,
27.1, 27.4, 35.7, 44.6, 67.1, 67.3, 72.8, 77.3, 77.8, 80.8, 109.1,
109.7.
IR (KBr): 1704, 2950, 3489 cm–1.
1H NMR (500 MHz, CDCl3): = 0.01 (s, 12 H), 0.83 (s, 18 H),
1.18–1.37 (m, 6 H), 1.90 (br s, 1 H), 2.12 (m, 1 H), 3.31 (m, 1 H),
3.39 (m, 2 H), 3.50 (m, 1 H), 3.73 (m, 1 H), 4.09 (m, 1 H), 4.23–4.33
(m, 3 H), 5.10 (d, J = 12.4 Hz, 1 H), 5.11 (d, J = 12.2 Hz, 1 H), 4.32
(m, 1 H), 7.31 (m, 5 H).
13C NMR(125 MHz, CDCl3): = –5.3, –5.0, 18.2, 18.3, 25.8, 25.9,
27.0, 43.4, 64.9, 74.3, 77.3, 109.3, 127.9, 128.4, 136.9, 155.7.
Anal. Calcd for C20H39NO5Si: C, 59.8; H, 9.8; N, 3.5. Found: C,
59.9; H, 9.7; N, 3.4.
(1 R,2 S,3 R,3S)-2-(1 ,2 ,3 ,4 -O-Di-isopropylidene-1 ,2 ,3 ,4 -tet-
rahydroxy butyl)-3-(O-t-butyl dimethylsilyl)-3-hydroxy-N-
(benzyloxycarbonyl)-pyrrolidine (7)
Anal. Calcd for C31H55NO7Si2: C, 61.0; H, 9.1; N, 2.3. Found; C,
61.0; H, 9.1; N, 2.3.
To a solution of pyrrolidine 6 (1.01 g, 2.51 mmol) in CH2Cl2 (10
mL) was added aq K2CO3 (1.05g, 7.68 mmol) and the mixture was
cooled in an ice-bath. To this stirred mixed-phase solution was add-
ed dropwise a solution of benzylchloroformate (0.73 mL, 5.12
mmol) in CH2Cl2 (5 mL), and the mixture was stirred at r.t. for 30
min. The organic phase was washed with brine, and evaporated. The
residue was chromatographed on silica gel (hexane–EtOAc, 6:1) to
give compound 7 (1.21 g, 90%) as an oil; [ ]D +15.1 (c 2.0,
CHCl3).
IR (neat): 1698, 2942 cm–1.
1H NMR (500 MHz, CDCl3): = 0.00 (s, 6 H), 0.94 (s, 9 H), 1.16–
1.37 (m, 12 H), 1.92 (m, 1 H), 2.05 (m, 1 H), 3.28–3.35 (m, 2 H),
3.77 (m, 2 H), 3.97 (m, 2 H), 4.15 (m, 1 H), 4.29 (m, 2 H), 5.00 (m,
1 H), 5.11 (m, 1 H), 7.17–7.30 (m, 5 H).
(1 R,2 S,3 R,3S)-2-(1 , 2 -O-Isopropylidene-3 -O-methanesulfo-
nyl-4 -O-t-butyldimethylsilyl-1 ,2 ,3 ,4 -tetrahydroxybutyl)-3-
O-t-butyldimethylsilyl-3-hydroxy-N-(benzyloxycarbonyl)-pyr-
rolidine (10)
To a solution of compound 9 (1.27 g, 2.08 mmol) in THF (8 mL)
were added Et3N (0.63 mL, 4.58 mmol) and methanesulfonyl chlo-
ride (0.19 mL, 2.50 mmol) at 0 °C. The reaction mixture was stirred
for 20 min at r.t., and was then quenched with sat. NaHCO3 (30
mL). The reaction mixture was extracted with EtOAc (3 × 15 mL).
The organic layer was concentrated and the residue was chromato-
graphed on silica gel (hexane–EtOAc, 10:1) to give compound 10
(1.32 g, 92%) as an oil; [ ]D20 +28.3 (c 1.0, CHCl3).
20
IR (KBr): 1697, 2960 cm–1.
1H NMR (500 MHz, CDCl3): = 0.00 (s, 12 H), 0.82 (s, 18 H), 1.29
(s, 3 H), 1.37 (s, 3 H), 1.85–1.94 (m, 2 H), 3.03 (s, 3 H), 3.39 (m, 3
Synthesis 2003, No. 16, 2473–2478 © Thieme Stuttgart · New York

PAPER
Total Syntheses of (+)-Castanospermine and (+)-6-Epicastanospermine
2477
H), 3.72 (m, 1 H), 3.95 (m, 1 H), 4.24–4.32 (m, 2 H), 4.60 (m, 2 H),
5.05 (m, 2 H), 7.27 (m, 5 H).
Anal. Calcd for C8H15NO4: C, 50.8; H, 8.0; N, 7.4. Found: C, 50.7;
H, 7.9; N, 7.4.
13C NMR (125 MHz, CDCl3): = –5.4, –5.1, 18.4, 25.8, 26.0, 27.1,
32.5, 38.9, 44.0, 61.9, 62.5, 67.2, 72.1, 77.3, 83.8, 109.9, 128.0,
128.5, 128.7, 136.7, 156.6.
(1 R,2 S,3 R,3S)-2-(1 , 2 -O-Isopropylidene-4 -O-methansulfo-
nyl-1 ,2 ,3 ,4 -tetrahydroxybutyl)-3-O-t-butyldimethylsilyl-3-
hydroxy-N-(benzyloxycarbonyl)-pyrrolidine (13)
Anal. Calcd for C32H57NO9SSi2: C, 55.9; H, 8.4; N, 2.0. Found; C,
55.8; H, 8.4; N, 2.0.
To a solution of 8 (1.03 g, 2.09 mmol) in CH2Cl2 (10 mL) were add-
ed diluted Et3N (0.32 mL, 2.30 mmol) in CH2Cl2 (5 mL) and diluted
MsCl (0.18 mL, 2.3 mmol) in CH2Cl2 (5 mL) at –40 °C. The reac-
tion mixture was stirred for 5 min at same temperature, and then sat.
NaHCO3 (50 mL) was added and extracted with CH2Cl2 (5 × 25
mL). The combined extract was evaporated, and the residue was
chromatographed on silica gel (hexane–EtOAc, 3:1) to give com-
pound 13 (1.03 g, 86%, based on 68% conversion) as an oil and
starting material 8 (0.33 g); [ ]D20 +34.3 (c 1.5, CHCl3).
(1 R,2 S,3 S,3S)-2-(3 ,4 -Anhydro-1 ,2 -O-isopropylidene-1 ,2 -
dihydroxybutyl)-3-hydroxy-N-(benzyloxycarbonyl)-pyrroli-
dine (11)
To a solution of 10 (1.32 g, 1.91 mmol) in THF (8 mL) was added
TBAF in 1 M THF (4.20 mL) and stirred for 2 h at r.t. The reaction
mixture was quenched with water (30 mL) and extracted with
EtOAc (3 × 15 mL). The organic layer was concentrated and added
to K2CO3 (0.5 g) in MeOH (8 mL). The mixture was stirred for 30
min at r.t., and was quenched with sat. NaHCO3 (30 mL) and ex-
tracted with EtOAc (3 × 15 mL). The organic phase was evaporated
and chromatographed on silica gel (hexane–EtOAc, 10:1) to give
compound 11 (0.62 g, 90%) as an oil; [ ]D20 +51.4 (c 2.0, CHCl3).
IR (KBr): 1687, 2943, 3433 cm–1.
1H NMR (500 MHz, CDCl3): = 0.00 (s, 6 H), 0.81 (s, 9 H), 1.22
(s, 3 H), 1.30 (s, 3 H), 1.87 (br s, 1 H), 2.06 (m, 1 H), 2.93 (s, 3 H),
3.38 (m, 2 H), 3.68 (br s, 1 H), 4.00 (m, 1 H), 4.11–4.22 (m, 3 H),
4.33 (m, 2 H), 5.00–5.08 (m, 2 H) and 7.16–7.28 (m, 5 H).
IR (KBr): 1648, 2937, 3465 cm–1.
13C NMR (125 MHz, CDCl3): = – 5.1, –4.9, 18.2, 25.8, 27.0, 27.1,
37.5, 67.3, 71.8, 72.4, 72.7, 109.8, 128.2, 128.6 and 136.5.
1H NMR (500 MHz, CDCl3): = 1.38 (s, 3 H), 1.44 (s, 3 H), 2.03
(m, 2 H), 2.71 (m, 2 H), 2.90 (s, 1 H), 3.36 (m, 1 H), 3.48–3.63 (m,
2 H), 4.07 (m, 1 H), 4.28 (t, J = 12.5 Hz, 1 H,), 4.44–4.49 (m, 2 H),
5.11 (s, 2 H), 7.32 (m, 5 H).
Anal. Calcd for C26H43NO9SSi: C, 54.4; H, 7.6; N, 2.4. Found: C,
54.4; H, 7.5; N, 2.5.
1-O-t-Butyldimethylsilyl-7,8-O-isopropylidene-(+)-6-epi-
castanspermine (14)
13C NMR (125 MHz, CDCl3): = 26.4, 27.1, 32.5, 44.5, 44.7, 51.3,
61.3, 67.2, 72.6, 77.5, 77.9, 78.2, 109.7, 127.9, 128.2, 128.6, 136.4,
156.0.
A mixture of 13 (1.00 g, 1.74 mmol), NaOAc (0.89 g, 10.8 mmol)
and 10% Pd/C (50 mg) in MeOH (10 mL) was hydrogenated at at-
mospheric pressure for 10 h. The catalyst was filtered, the filtrate
was refluxed for 2 h, and the reaction mixture was filtered, and
evaporated. The residue was chromatographed on silica gel
(CH2Cl2–acetone, 10:1) to give compound 14 (0.51 g, 85%) as an
oil; [ ]D20 +4.8 (c 1.5, CHCl3).
Anal. Calcd for C19H25NO6: C, 62.8; H, 6.9; N, 3.9. Found; C, 62.8;
H, 6.9; N, 3.8.
7,8-O-Isopropylidene-(+)-castanospermine (12)
A mixture of epoxide 11 (0.62 g, 1.71 mmol), NaOAc (0.45 g) and
10% Pd/C (0.03 g) in MeOH (8 mL) was hydrogenated at 60 °C for
6 h. After the reaction mixture was filtered with Celite, the filtrate
was concentrated. The remaining residue was chromatographed on
silica gel (CH2Cl2–acetone, 3:1) to give compound 12 (0.25 g, 65%)
as an oil; [ ]D20 +40.1 (c 0.4, CHCl3).
IR (KBr): 1648, 2937, 3455 cm–1.
1H NMR (500 MHz, CDCl3): = 0.01 (s, 6 H), 0.81 (s, 9 H), 1.36
(s, 6 H), 1.75 (s, 1 H), 2.03 (m, 1 H), 2.13 (m, 2 H), 2.21 (d, J = 12
Hz, 3 H), 2.34 (br s, 1 H), 3.06 (m, 1 H), 3.13 (dd, J = 12, 2.5 Hz, 1
H), 3.28 (dd, J = 9.5, 2.5 Hz, 1 H), 3.90 (t, J = 9.3 Hz, 1 H), 4.16 (s,
1 H), 4.32 (m, 1 H).
13C NMR (125 MHz, CDCl3): = –5.0, –4.9, 18.4, 25.9, 26.6, 27.0,
35.1, 51.8, 55.7, 65.8, 70.3, 71.3, 71.4, 82.1, 110.2.
IR (KBr): 1678, 2956, 3455, cm–1.
1H NMR (500 MHz, CD3OD): = 1.42 (s, 3 H), 1.43 (s, 3 H), 1.91
(m, 1 H), 2.00 (m, 1 H), 3.12–3.15 (m, 2 H), 3.21–3.31 (m, 1 H),
3.80 (dd, J = 12.9, 5.4 Hz, 1 H), 3.97 (dd, J = 12.9, 3.2 Hz, 1 H),
4.26 (t, J = 5.8 Hz, 1 H), 4.50 (m, 2 H), 4.80 (m, 1 H).
13C NMR (125 MHz, CD3OD): = 26.7, 27.9, 28.0, 39.3, 45.8, 62.4,
68.9, 74.5, 76.7, 80.8, 84.7, 111.6.
Anal. Calcd for C17H33NO4Si: C, 59.4; H, 9.7; N, 4.1. Found: C,
59.5; H, 9.6; N, 4.0.
(+)-6-Epicastanospermine (2)
Anal. Calcd for C11H19NO4: C, 57.6; H, 8.4; N, 6.1. Found: C, 57.6;
H, 8.3; N, 6.1.
To a solution of 14 (0.51 g, 1.48 mmol) in THF–H2O (3:1) was add-
ed Dowex 50W-X8 (200 mg) and refluxed overnight. The mixture
was filtered, and washed with MeOH. The remaining residue was
eluted with 2 N NH3 solution. The NH3 solution was evaporated to
give compound 2 (0.25 g, 90%) as a solid, mp 203–206 °C (de-
comp.); [ ]D20 +2.8 (c 1.0, H2O).
(+)-Castanospermine (1)
To a solution of 12 (0.25 g, 1.09 mmol) in THF–H2O (3:1) was add-
ed Dowex 50W-X8 (200 mg) and the solution was refluxed over-
night. The reaction mixture was filtered, and washed with MeOH.
The remaining residue was eluted with 2 N NH3 solution. The NH3
solution was evaporated to give compound 1 (0.19 g, 92%) as a sol-
id; mp 203–205 °C (decomp.), [ ]D20 +79.8 (c 0.9, H2O).
IR (KBr): 1648, 2940, 3394 cm–1.
1H NMR (500 MHz, D2O): = 1.67 (m, 1 H), 1.95 (m, 1 H), 2.18
(m, 1 H), 2.26 (m, 2 H), 3.07 (m, 2 H), 3.47 (dd, J = 9.5, 3.0 Hz, 1
H,), 3.82 (m, 1 H), 3.94 (m, 1 H), 4.33 (m, 1 H).
13C NMR(125 MHz, D2O): = 33.0, 52.1, 55.6, 67.4, 69.1, 70.3,
72.1, 75.6.
IR (KBr): 1658, 2980, 3484 cm–1.
1H NMR (500 MHz, D2O): = 1.69 (m, 1 H), 2.15–2.17 (m, 2 H),
2.26–2.33 (m, 2 H), 3.14 (m, 1 H), 3.20 (dd, J = 11, 5.0 Hz, 1 H),
3.29 (t, J = 9.1 Hz, 1 H), 3.54–3.60 (m, 2 H), 4.38 (m, 1 H).
MS: m/z = 189 (M+).
13C NMR (125 MHz, D2O): = 32.9, 51.9, 55.2, 68.8, 69.6, 70.0,
71.7, 78.9.
HRMS–FAB: m/z [M] calcd for C8H15NO4, 189.1001; found,
189.1003.
MS (FAB): m/z = 211.92 (M + Na).
Synthesis 2003, No. 16, 2473–2478 © Thieme Stuttgart · New York

2478
J. H. Kim et al.
PAPER
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Acknowledgment
This work was supported by Korea Research Foundation Grant.
(KRF-2001-041-F00294)
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Synthesis 2003, No. 16, 2473–2478 © Thieme Stuttgart · New York