Synthesis of castanospermine

Article abstract of DOI:10.1016/j.tet.2008.01.073

The diastereoselective synthesis of castanospermine is described in 11 synthetic steps from l-xylose. The borono-Mannich reaction between l-xylose, allylamine, and (E)-styrene boronic acid gives a tetrahydroxy amine with the desired configurations for C-6

Full text of DOI:10.1016/j.tet.2008.01.073

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2725e2732
www.elsevier.com/locate/tet
Synthesis of castanospermine
Theeraphan Machan a,b, Andrew S. Davis a, Boonsom Liawruangrath b, Stephen G. Pyne a,
*
a School of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia
b Department of Pharmaceutical Science, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
Received 16 October 2007; received in revised form 3 January 2008; accepted 17 January 2008
Available online 25 January 2008
This paper is dedicated to E.J. Corey in the year of his 80th birthday
Abstract
The diastereoselective synthesis of castanospermine is described in 11 synthetic steps from L-xylose. The borono-Mannich reaction between
L-xylose, allylamine, and (E)-styrene boronic acid gives a tetrahydroxy amine with the desired configurations for C-6, C-7, C-8, and C-8a in the
target molecule. A novel pyrrolo[1,2-c]oxazol-3-one precursor was employed to allow for the control of p-facial diastereoselectivity in an
osmium(VIII)-catalyzed syn-dihydroxylation (DH) reaction. A regioselective ring-opening of the cyclic sulfate derivative of the resulting
diol then secured the C-1 hydroxyl group of castanospermine with the correct configuration. A Mitsunobu cyclization then provided di-O-benzyl
castanospermine and ultimately the final target alkaloid.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The indolizidine alkaloid castanospermine 1 (Fig. 1) was
first isolated from the seeds of Castanospermum australe1 and
then later from the dry pods of Alexa leiopetala.2 Castanosper-
mine is a potent inhibitor of several glucosidases3 and has
potential for the treatment of viral infections,4 cancers,5 and
diabetes.6 In addition it shows anti-inflammatory7 and immuno-
suppressant8 properties. Recent in vitro studies have demon-
strated that 1 was able to prevent mortality in mice infected
with dengue virus.9 Because of its unique structure and bio-
logical activities many syntheses of castanospermine have
been reported.10 As part of our program concerned with the
synthesis of polyhydroxylated indolizidine and pyrrolizidine
alkaloids11e19 we report here a 11-step synthesis of castano-
spermine from L-xylose. This synthesis demonstrates the versa-
tility and flexibility of our earlier synthetic strategy for
preparing polyhydroxyindolizidines.17
The known amino-tetraol 2,17 obtained from the borono-
Mannich reaction of L-xylose, allylamine, and (E)-styrene bo-
ronic acid, was converted to oxazolidin-2-one 3 upon treatment
with triphosgene under basic conditions (Scheme 1).13,14 The
triol 4 was readily converted to its O-trityl derivative 4 in 87%
yield under standard conditions.17 Under basic O-benzylation
reaction conditions17 compound 4 gave a mixture of the corre-
sponding di-O-benzyl-oxazolidin-2-one 5 and oxazin-2-one 6
(Scheme 1). These could be separated by column chromatogra-
phy to provide pure samples of 5 and 6 in yields of 56% and
22%, respectively, however, this separation was difficult. Treat-
ment of 5 with Grubbs’ second generation ruthenium catalyst19
gave the pyrrolo[1,2-c]oxazol-3-one 7 in 88% yield. Alterna-
tively, 7 could be more readily obtained by treating a mixture
HO
OH
H
HO
N
HO
1
* Corresponding author.
E-mail address: spyne@uow.edu.au (S.G. Pyne).
Figure 1. Structure of castanospermine (1).
0040-4020/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.073

2726
T. Machan et al. / Tetrahedron 64 (2008) 2725e2732
.
of 5 and 6 with Grubbs’ second generation ruthenium catalyst
followed by a relatively easier separation of 7 (68%) from the
pyrrolo[1,2-c]oxazin-1-one 8 (20%) (Scheme 1).
K2OsO4 2H2O, NMO
TrO
BnO
OBn
acetone/H2O
rt, 48 h
H
OH
H
7
dr = 83 : 17
(84%)
O
OH
N
HO
O
B(OH)2
H
Ph
L-xylose
HO
HO
Ph
9 (60%)
OBn
(Cl3CO)2CO
TrO
BnO
HN
Et3N, THF
rt, 10 h
53%
(i) SOCl2, Et3N
CH2Cl2
(ii) RuCl3, NaIO4
H
NH2
O
H
SO2
HO
2
O
O
64%
HO
N
OH
O
NaH, BnBr, Bu4NI
THF, 50 °C, 4d
RO
Ph
10
O
N
(i) NaBH4
DMA,
HO
BnO
OBn
H
O
OH
OH
H
rt,6 h
TrCl, pyridine
rt, 20 h
3; R = H
4; R = Tr
(ii) H2SO4,
H2O, THF,
rt, 20 h
O
N
87%
O
63%
11
TrO
BnO
OBn
OBn
H
OBn
H
HO
NaOH, H2O,
MeOH
H
H
H
BnO
TrO
Ph
Ph
MW
110 °C, 2 h
O
+
HN
HO
12 (80%)
+
O
N
O
N
BnO
O
6 (22%)
5 (56%)
Grubbs' II cat.
CH2Cl2,
reflux 48 h
88%
BnO
OBn
OH
H
O
TrO
HN
OBn
H
H
13 (16%)
BnO
O
Scheme 2.
N
O
7
which the O-trityl group had also been cleaved (Scheme 2).
Base catalyzed hydrolysis of the oxazolidinone ring of 11 under
microwave irradiation conditions gave the pyrrolidine 12 in
80% yield, which was readily separated from the unexpected
cyclized product, the furan derivative 13 (16% yield). We
have not unequivocally proved the structure of 13. However,
this compound is also produced as a byproduct from the Mitsu-
nobu reaction of 12 as shown in Scheme 3. The most likely
mechanism for the formation of 13 as shown in Scheme 3 is
OBn
H
Grubbs' II cat.
CH2Cl2,
reflux 48 h
OBn
H
TrO
5 + 6
+
7 (68%)
O
N
O
8 (20%)
Scheme 1.
Based on our previous work,13,14,19 and that of Parsons,20,21
we expected that the syn-dihydroxylation (DH) of 7 would fur-
nish the corresponding diol with the desired stereochemistry for
the synthesis of the target alkaloid. In the event, osmium(VIII)-
catalyzed syn-DH of 7 furnished the desired diol 9 accompanied
by 17% of its diastereomeric diol in 84% yield after purification
of the crude reaction mixture by column chromatography
(Scheme 2). Separation of this mixture by further column chro-
matography gave diastereomerically pure 9 in 60% yield and
6,7-di-epi-9 in 16% yield. The diol 9 was then converted to
the cyclic sulfate 10 in 64% overall yield by first treatment
with thionyl chloride under basic conditions to give the corre-
sponding cyclic sulfite followed by oxidation at sulfur with
catalytic ruthenium tetraoxide (RuCl3, NaIO4).13,22 Regioselec-
tive reductive ring-opening of 10 with sodium borohydride10f in
dimethylacetamide (DMA) at rt for 6 h followed by acid hydro-
lysis of the resulting adduct gave the diol 11 in 63% yield in
HO
OH
H
DIAD, Ph3P, THF
BnO
0-5 °C, 48 h
12
N
BnO
14 (25%)
BnO
BnO
5
OBn
H
BnO
OH
O
+
+
H
5'
2'
8
O
HO
3
H
1
HN
HN
13 (22%)
15 (11%)
1. PdCl2, H2
MeOH, rt, 1 h
1
14
2. ion-exchange
95%
Scheme 3.

T. Machan et al. / Tetrahedron 64 (2008) 2725e2732
2727
via initial activation of the primary hydroxyl. We therefore
speculate that 13 arises from 11 (Scheme 2) via cyclization of
the incipient alkoxide ion that is generated from collapse of
the initial tetrahedral intermediate formed from addition of hy-
droxide ion to the carbonyl group of the oxazolidinone moiety
of 11. This incipient alkoxide intermediate then attacks the car-
bon of the terminal methylene of the side chain to displace hy-
droxide ion and give the furan ring.23
(DEPT) spectra at 125 MHz in CDCl3 solution, unless other-
wise noted. NMR assignments are based on COSY, DEPT,
and HSQC NMR experiments and sometimes HMBC and
NOESYexperiments. IR spectra were determined as neat samples.
Petrol refers to petroleum spirit, bp 40e60 ꢀC.
4.1.1. (4R,5R)-3-Allyl-5-((1R,2S)-1,2,3-trihydroxypropyl)-4-
((E)-2-phenyl-vinyl)-1,3-oxazolidin-2-one (3) and its 1,3-
dioxolan-2-onyl derivative, (4R,5R)-3-allyl-5-(((4S)-1,3-
dioxolan-2-onyl)-hydroxymethyl)-4-((Z)-2-phenylvinyl)-1,3-
oxazolidin-2-one
Attempts to cyclize the amino-triol 12 under Appel cyclization
reaction conditions (Ph3P/CBr4/Et3N)24 were unsuccessful and
a complex mixture of products resulted. Treatment of 12 under
Mitsunobu reaction conditions25 produced the desired indolizi-
dine product 14 in 25% yield along with the furan 13 (22% yield)
and the oxepino[3,2-b]pyrrole 15 (11% yield) (Scheme 3). These
three isomeric compounds were readily distinguished by 13C and
HMBC NMR experiments. The structure of the indolizidine 14
was clear from the relatively upfield 13C NMR methylene reso-
nances at d 54.2 (C-5) and d 52.0 (C-2) for the methylenes directly
attached to nitrogen. While the downfield methylene resonances
at d 72.0 (C-50) and d 72.2 (C-5) in 13 and 15, respectively,
were consistent with methylenes directly attached to oxygen in
a ring system. HMBC NMR experiments on 13 demonstrated
a 3-bond correlation between C-20 and H-50, such a correlation
between the analogous carbon (C-8) and proton(H-5) in 15would
not be expected as this would represent a 4-bond correlation.
Debenzylation of 14 under hydrogenolysis conditions using
To a solution of the amino alcohol 217 (4.560 g, 15.56 mmol)
in dry THF (400 mL) was added triethylamine (4.3 mL,
31.13 mmol) and then triphosgene (1.390 g, 4.68 mmol). The
mixture was stirred at rt for 10 h, followed by the evaporation
of all volatiles in vacuo. The residue was suspended in water
(100 mL) and extracted with ethyl acetate (3ꢁ100 mL). The
combined organic extracts were dried (MgSO4) and filtered
then concentrated in vacuo to give a yellow solid. Chromatog-
raphy of the crude product and eluting with 90e100% EtOAc/
petrol and then 2% MeOH/EtOAc gave compound 3 as a white
crystalline solid (2.65 g, 53%, Rf¼0.20, 2% MeOH/EtOAc).
[a]2D7 ꢂ10 (c 4.5, MeOH). Mp 141 ꢀC. IR nmax/cmꢂ1 3550,
2950, 2914, 1737, 1447, 1094, 1041. MS (ESIþ) m/z 320
1
(MþHþ, 100%). H NMR (CD3OD) d 3.57 (1H, dd, J¼11.3,
6.3 Hz, H30), 3.60 (1H, app. ddt, J¼15.7, 6.7, 1.3 Hz, H1000),
3.65 (1H, dd, J¼11.3, 5.3 Hz, H30), 3.73 (1H, m, H20), 3.83
(1H, app. t, J¼4.3 Hz, H10), 4.01 (1H, app. ddt, J¼15.7, 4.7,
1.7 Hz, H1000), 4.61 (1H, app. t, J¼9.0 Hz, H4), 4.83 (1H, dd,
J¼8.5, 4.0 Hz, H5), 5.20 (1H, dd, J¼10.0, 1.5 Hz, H3000), 5.22
(1H, dd, J¼17.5, 1.0 Hz, H3000), 5.79 (1H, m, H2000), 6.38 (1H,
dd, J¼16.0, 9.5 Hz, H100), 6.70 (1H, d, J¼16.0 Hz, H200), 7.36
(5H, m, AreH). 13C NMR (CD3OD) d 45.5 (CH2), 62.6
(CH), 64.1 (CH2), 70.9 (CH), 73.3 (CH), 78.9 (CH), 118.3
(CH), 124.2 (CH), 127.9 (2ꢁAreCH), 129.4 (AreCH), 129.7
(2ꢁAreCH), 133.4 (CH), 137.2 (C), 138.5 (CH), 159.8 (CO).
26
PdCl2/H2 gave castanospermine 1 in 95% yield after ion-
1
exchange chromatography (Scheme 3). The H and 13C NMR
spectral data of this compound matched very closely to that re-
ported in the literature.1 The optical rotation of this compound
[a]2D7 þ82 (c 1.2, H2O) also agreed with that reported (lit.1 [a]2D4
þ79.7 (c 0.93, H2O)). This sample was also identical to an
authentic sample by TLC analysis.27
3. Conclusions
In conclusion we have successfully developed a diastereo-
selective synthesis of castanospermine in 11 synthetic steps from
L-xylose using the borono-Mannich reaction to give a tetrahy-
droxy amine with the desired configurations for C-6, C-7, C-8,
and C-8a in the target molecule. A novel pyrrolo[1,2-c]oxazol-
3-one precursor was employed to allow for the control of p-facial
diastereoselectivity in an osmium(VIII)-catalyzed syn-dihydrox-
ylation (DH) reaction. A regioselective ring-opening of the cyclic
sulfate derivative of the resulting diol then secured the C-1 hy-
droxyl group of castanospermine with the correct configuration.
A Mitsunobu cyclization then provided di-O-benzyl castanosper-
mine and ultimately the final target alkaloid. This synthesis
further demonstrates the versatility and flexibility of our earlier
synthetic strategy for preparing polyhydroxyindolizidines.17
4.1.2. (4R,5R)-3-Allyl-5-((1R,2S)-1,2-dihydroxy-3-(triphenyl-
methyloxy)-propyl)-4-((E)-2-phenylvinyl)-1,3-oxazolidin-2-
one (4)
To a solution of oxazolidinone 3 (2.42 g, 7.59 mmol) in an-
hydrous pyridine (40 mL) was added trityl chloride (3.17 g,
11.38 mmol). The mixture was stirred for 20 h at rt. The reac-
tion was quenched with water (60 mL) then extracted with
diethyl ether (3ꢁ80 mL). The combined organic phases were
washed with saturated CuSO4 (3ꢁ90 mL) and brine (90 mL),
dried (MgSO4), and evaporated to give a yellow oil that was
purified by column chromatography (30e50% EtOAc/petrol)
to give compound 4 as a white foamy solid (3.68 g, 87%,
Rf¼0.20, 30% EtOAc/petrol). [a]2D7 ꢂ18 (c 4.4, CHCl3). IR
nmax/cmꢂ1 3401, 3053, 3027, 2914, 1731, 1448, 1070. MS
(ESIþ) m/z 579 (MþNHþ4 , 100%); HRMS (ESIþ) calcd for
C36H35NO5Na (MþNaþ) 584.2413, found 584.2419. 1H
NMR d 2.57 (1H, br d, J¼5.0 Hz, OH10), 2.82 (1H, br d,
J¼5.5 Hz, OH20), 3.18 (1H, dd, J¼10.0, 5.5 Hz, H30), 3.31
(1H, dd, J¼9.5, 5.0 Hz, H30), 3.54 (1H, dd, J¼15.5, 7.5 Hz,
H1000), 3.90 (1H, br t, J¼4.0 Hz, H20), 3.96 (1H, br d,
4. Experimental
4.1. General
1
General methods were as described previously.12,13 All H
NMR spectra were performed at 500 MHz and all 13C NMR

2728
T. Machan et al. / Tetrahedron 64 (2008) 2725e2732
J¼3.5 Hz, H10), 4.11 (1H, dd, J¼15.8, 6.5 Hz, H1000), 4.46 (1H,
app. t, J¼9.3 Hz, H4), 4.55 (1H, dd, J¼8.8, 3.8 Hz, H5), 5.18
(1H, dd, J¼17.3, 1.0 Hz, H3000), 5.21 (1H, dd, J¼10.3, <1 Hz,
H3000), 5.74 (1H, m, H2000), 6.32 (1H, dd, J¼16.0, 9.5 Hz,
H100), 6.61 (1H, d, J¼15.5 Hz, H200), 7.39e7.19 (20H, m, Ar).
13C NMR d 44.8 (CH2), 61.1 (CH), 64.4 (CH2), 69.9 (CH),
71.0 (CH), 77.3 (CH), 87.2 (C), 118.7 (CH), 123.0 (CH),
127.1e129.0 (20ꢁAreCH), 132.1 (CH), 135.6 (AreC),
137.6 (CH), 143.7 (AreC), 157.2 (CO).
1.8 Hz, H20), 3.90 (1H, app dt, J¼7.8, 1.8 Hz, H10), 4.08 (1H,
app. dt, J¼6.3, 1.7 Hz, H4), 4.24 (1H, d, J¼11.1 Hz, CH2Ph),
4.60e4.52 (1H, m, H1000), 4.70 (1H, d, J¼11.4 Hz, CH2Ph),
4.84 (1H, d, J¼11.4 Hz, CH2Ph), 4.93 (1H, dd, J¼7.8,
1.5 Hz, H6), 5.12 (1H, dd, J¼10.2, 1.5 Hz, H3000), 5.16 (1H,
dd, J¼17.4, 1.5 Hz, H3000), 5.77 (1H, m, H2000), 5.93 (1H, dd,
J¼15.9, 6.3 Hz, H100), 6.54 (1H, dd, J¼15.9, 1.5 Hz, H200),
7.57e7.06 (30H, m, Ar). 13C NMR d 50.0 (CH2), 57.9 (CH),
62.2 (CH), 71.6 (CH2), 73.2 (CH), 73.9 (CH2), 77.6 (CH),
79.3 (CH), 86.5 (C), 118.0 (CH2), 125.2 (CH), 127.2e129.1
(30ꢁAreCH), 132.9 (CH), 134.1 (CH), 135.7 (AreC), 137.2
(AreC), 138.8 (AreC), 143.6 (3ꢁAreC), 153.2 (CO).
4.1.3. (4R,5R)-3-Allyl-5-((1S,2S)-1,2-bis(benzyloxy)-3-(trip-
henylmethoxy)-propyl)-4-((E)-2-phenylvinyl)-1,3-
oxazolidin-2-one (5) and (4R,5R,6S)-3-allyl-5-(benzyloxy)-
6-((S)-1-(benzyloxy)-2-(triphenylmethoxy)-ethyl)-4-((E)-2-
phenylvinyl)-1,3-oxazinan-2-one (6)
4.1.4. (1R,7aR)-1-((1S,2S)-1,2-Bis(benzyloxy)-3-(triphenyl-
methoxy)propyl)-1,7a-dihydropyrrolo[1,2-c]oxazol-3(5H)-
one (7) and (3S,4R,4aR)-4-(benzyloxy)-3-((S)-1-(benzyloxy)
-2-(triphenylmethoxy)-ethyl)-4,4a-dihydro-3H-pyrrolo[1,2-c]-
[1,3]oxazin-1(7H)-one (8)
To a solution of 4 (4.403 g, 7.85 mmol) in dry THF (50 mL)
was added 40% NaH in mineral oil (1.20 g, 19.62 mmol).
After H2 evolution had ceased (15 min), benzyl bromide
(7.5 mL, 62.79 mmol) and tetrabutylammonium iodide
(444 mg, 1.18 mmol) were added. The mixture was stirred for
24 h at rt, then treated with methanol (10 mL) and triethylamine
(6 mL) and stirred for 15 min. All volatiles were removed in va-
cuo and the residue was dissolved in CH2Cl2, filtered through
a pad of Celite, followed by further washings of the solids
with CH2Cl2. The filtrate was washed with water and brine
and then dried (MgSO4) and concentrated to give a yellow oil.
The residue was purified by column chromatography (20e
40% EtOAc/petrol) to yield two compounds, 5 as a yellow oil
(3.258 g, 56%) and 6 as a yellow oil (1.299 g, 22%). Because
of the similar polarity of the products (Rf of 5¼0.60 and Rf of
6¼0.55 in 40% EtOAc/petrol), they were used in the subsequent
RCM reaction step without separation.
4.1.4.1. Method 1: synthesis of 7 from pure 6. Grubbs’ II cata-
lyst (105.2 mg, 0.124 mmol) was added to a solution of oxazol-
idinone 6 (918.8 mg, 1.240 mmol) in dry CH2Cl2 (150 mL) under
nitrogen. The mixture was heated at reflux for 48 h, followed by
cooling to rt and then removal of the solvent in vacuo to give
a brown oil. The residue was purified by column chromatography
(20e50% EtOAc/petrol) to give compound 7 (695.1 mg, 88%,
Rf¼0.26, 30% EtOAc/petrol) as a white foamy solid.
4.1.4.2. Method 2: synthesis of 7 and 8 from a mixture of 6 and
7. Grubbs’ II catalyst (199 mg, 0.234 mmol) was added to a so-
lution of the mixture of 6 and 7 (2.383 g, 3.22 mmol), obtained
above from 4, in dry CH2Cl2 (350 mL) under nitrogen. The
mixture was heated at reflux for 48 h, followed by cooling to
rt and then removal of the solvent in vacuo to give a brown
oil. The residue was purified by column chromatography
(20e50% EtOAc/petrol) to give compound 7 (1.403 g, 68%,
Rf¼0.26, 30% EtOAc/petroleum ether) as a white foamy solid,
and 8 (412.4 mg, 20%, Rf¼0.07, 30% EtOAc/petrol) as a white
foamy solid.
Compound 5: [a]D26 þ52 (c 3.2, CHCl3). IR nmax/cmꢂ1 3058,
3027, 2945, 2873, 1752, 1450, 1070. MS (ESIþ) m/z 764
(MþNaþ, 85%); HRMS (ESIþ) calcd for C50H47NO5Na
1
(MþNaþ) 764.3351, found 764.3378. H NMR (300 MHz)
d 3.32 (1H, dd, J¼16.0, 7.5 Hz, H1000), 3.39 (1H, dd, J¼9.5,
5.0 Hz, H30), 3.44 (1H, dd, J¼10.0, 5.0 Hz, H30), 3.58 (1H,
app. t, J¼8.0 Hz, H4), 3.75 (1H, m, H20), 4.01 (1H, dd,
J¼7.5, 3.3 Hz, H10), 4.08 (1H, app. dd, J¼16.0, 4.5 Hz, H1000),
4.13 (1H, d, J¼12.0 Hz, CH2Ph), 4.60 (1H, d, J¼11.4 Hz,
CH2Ph), 4.65 (1H, d, J¼12.0 Hz, CH2Ph), 4.79 (1H, app. t,
J¼7.4 Hz, H5), 4.85 (1H, d, J¼11.1 Hz, CH2Ph), 5.06 (1H, d,
J¼17.0 Hz, H3000), 5.15 (1H, d, J¼10.0 Hz, H3000), 5.63 (1H,
m, H2000), 5.93 (1H, d, J¼15.5 Hz, H200), 5.99 (1H, dd,
J¼16.0, 9.0 Hz, H100), 7.35e7.09 (30H, m, Ar). 13C NMR
d 43.8 (CH2), 59.4 (CH), 60.6 (CH2), 70.7 (CH2), 74.3 (CH2),
74.4 (CH), 76.6 (CH), 77.2 (CH), 77.4 (CH), 86.6 (C), 117.7
(CH2), 121.0 (CH), 126.1e128.7 (30ꢁAreCH), 131.9 (CH),
134.5 (AreC), 136.8 (CH), 137.4 (AreC), 137.7 (AreC),
143.2 (3ꢁAreC), 156.8 (CO).
Compound 7: [a]D25 þ13 (c 4.5, CHCl3). IR nmax/cmꢂ1 3063,
3027, 2945, 2868, 1696, 1125, 1070, 1029. MS (ESIþ) m/z 660
(MþNaþ, 43%); HRMS (ESIþ) calcd for C42H39NO5Na
1
(MþNaþ) 660.2726, found 660.2712. H NMR d 3.43 (1H,
dd, J¼10.0, 4.8 Hz, H30), 3.52 (1H, dd, J¼10.0, 5.0 Hz, H30),
3.66e3.61 (1H, m, H5), 3.69e3.70 (2H, m, H10, H20), 4.04e
4.08 (1H, m, H7a), 4.22e4.27 (1H, m, H5), 4.35 (1H, d,
J¼11.5 Hz, CH2Ph), 4.58 (1H, d, J¼11.0 Hz, CH2Ph), 4.64
(1H, d, J¼11.5 Hz, CH2Ph), 4.71 (1H, d, J¼11.5 Hz, CH2Ph),
4.77 (1H, dd, J¼8.0, 6.0 Hz, H1), 5.65 (1H, app. dd, J¼6.0,
1.0 Hz, H6), 5.84 (1H, app. dd, J¼6.0, 1.5 Hz, H7), 7.43e
7.12 (25H, m, Ar). 13C NMR d 54.7 (CH2), 62.5 (CH2), 67.0
(CH), 72.6 (CH2), 74.6 (CH), 77.1 (CH), 78.3 (CH), 79.0
(CH), 87.4 (C), 126.2 (CH), 127.4e128.8 (25ꢁAreCH),
131.7 (CH), 138.1 (AreC), 138.2 (AreC), 144.0 (3ꢁAreC),
162.2 (CO).
Compound 6: [a]2D6 þ37 (c 1.2, CHCl3). MS (ESIþ) m/z 764
(MþNaþ, 100%); HRMS (ESIþ) calcd for C50H47NO5Na
1
(MþNaþ) 764.3352, found 764.3364. H NMR (300 MHz)
d 2.92 (1H, dd, J¼10.7, 2.9 Hz, H20), 3.34 (1H, app. ddt,
J¼15.5, 7.7, 1.1 Hz, H1000), 3.45 (1H, app. t, J¼1.8 Hz, H5),
3.57 (1H, d, J¼10.8 Hz, CH2Ph), 3.70 (1H, dd, J¼10.5,
Compound 8: [a]2D7 þ67 (c 5.15, CHCl3). IR nmax/cmꢂ1
3052, 3027, 2924, 2863, 1685, 1105, 1096. MS (ESIþ) m/z

T. Machan et al. / Tetrahedron 64 (2008) 2725e2732
2729
660 (MþNaþ, 42%); HRMS (ESIþ) calcd for C42H39NO5
5.5 Hz, H30), 3.53 (1H, dd, J¼10.0, 5.0 Hz, H30), 3.81 (1H,
dd, J¼13.0, 5.5 Hz, H5), 3.83 (1H, m, H7), 3.96 (1H, dd,
J¼8.0, 3.5 Hz, H10), 4.08e4.09 (2H, m, H20, H6), 4.41 (1H,
d, J¼12.0 Hz, CH2Ph), 4.53 (1H, d, J¼11.0 Hz, CH2Ph),
4.70 (1H, d, J¼11.5 Hz, CH2Ph), 4.71 (1H, d, J¼11.5 Hz,
CH2Ph), 4.83 (1H, app. t, J¼7.5 Hz, H1), 7.44e7.14 (m, 25H,
Ar). 13C NMR d 52.7 (CH2), 62.2 (CH2), 63.5 (CH), 70.0
(CH), 71.4 (CH), 72.5 (CH2), 74.7 (CH), 76.2 (CH), 76.8
(CH), 77.2 (CH), 87.7 (C), 127.5e129.1 (25ꢁAreCH),
137.2 (AreC), 137.8 (AreC), 143.7 (3ꢁAreC), 161.0 (CO).
1
(Mþ) 637.2828, found 637.2811. H NMR d 3.51 (1H, dd,
J¼10.0, 7.0 Hz, H20), 3.54 (1H, dd, J¼10.0, 6.0 Hz, H20),
3.60 (1H, dd, J¼10.0, 6.0 Hz, H4), 3.86 (1H, ddd, J¼7.2,
6.0, 1.5 Hz, H10), 4.03 (1H, ddt, J¼16.0, 4.5, 1.5 Hz, H7),
4.40 (1H, ddt, J¼16.0, 4.5, 1.5 Hz, H7), 4.45 (1H, d,
J¼11.5 Hz, CH2Ph), 4.52 (1H, dd, J¼9.8, 1.5 Hz, H4a), 4.57
(1H, d, J¼11.5 Hz, CH2Ph), 4.59 (1H, d, J¼11.5 Hz,
CH2Ph), 4.60 (1H, d, J¼11.5 Hz, CH2Ph), 4.61 (1H, dd,
J¼6.0, 1.0 Hz, H3), 5.84 (2H, br m, H5, H6), 7.43e7.20
(25H, m, Ar). 13C NMR d 55.4 (CH2), 63.0 (CH), 63.1
(CH2), 72.5 (CH2), 73.1 (CH2), 74.3 (CH), 75.4 (CH), 75.6
(CH), 87.7 (C), 127.3e128.9 (25ꢁAreCH), 127.9
(HC]CH), 137.3 (AreC), 138.4 (AreC), 144.2 (3ꢁAreC),
152.1 (CO).
4.1.6. (3aR,3bS,4R,8aS)-Tetrahydro-4-((1S,2S)-1,2-bis(benzyl-
oxy)-3-triphenylmethoxy)-propyl)-2,2-dioxide,5H,4H-
1,3,2-dioxathiolo[3,4]pyrrolo[1,2-c]oxazol-6-one (10)
To a solution of 9 (1.207 g, 1.80 mmol) in dry CH2Cl2
(40 mL) was added triethylamine (4 mL, 28.78 mmol) and
thionyl chloride (0.2 mL, 2.70 mmol). The mixture was stirred
for 48 h at rt, and then water (50 mL) was added to the mixture.
The aqueous layer was extracted with CH2Cl2 (3ꢁ100 mL). The
combined extracts were washed with brine and dried (MgSO4)
then evaporated under reduced pressure to give a brown foamy
solid. The crude cyclic sulfite was used for the next step without
further purification. The crude obtained above was dissolved
in 50 mL of a solution of CCl4/CH3CN/H2O (2:3:2, v/v/v)
then NaIO4 (1.539 g, 7.12 mmol) and RuCl3$3H2O (23.5 mg,
0.09 mmol) were added. The mixture was stirred for 3 h at rt
and then diluted with diethyl ether (80 mL). The organic layer
was filtered through a pad of Celite. The filtrate was washed
with brine and dried (MgSO4). The solvent was removed in va-
cuo then purified by column chromatography (30e70% EtOAc/
petrol) to give compound 10 (849 mg, 64%, Rf¼0.49, 50%
EtOAc/petrol) as a white foamy solid. [a]2D7 þ30.6 (c 7.5,
CHCl3). IR nmax/cmꢂ1 3050, 3020, 2935, 2850, 1761, 1349,
1173, 1075. MS (ESIꢂ) m/z 732 (MꢂHþ, 100%); HRMS
(ESIþ) calcd for C42H39NO9SNa (MþNaþ) 756.2243, found
756.2297. 1H NMR d 3.15 (1H, dd, J¼15.0, 5.5 Hz, H8), 3.30
(1H, dd, J¼7.0, 3.5 Hz, H3b), 3.50e3.55 (2H, m, 2ꢁH30),
3.56e3.60 (1H, m, H20), 4.13 (1H, dd, J¼14.5, 1.0 Hz, H8),
4.26 (1H, dd, J¼9.5, 4.0 Hz, H10), 4.29 (1H, d, J¼11.5 Hz,
CH2Ph), 4.54 (1H, d, J¼11.5 Hz, CH2Ph), 4.58 (1H, d,
J¼11.5 Hz, CH2Ph), 4.80 (1H, dd, J¼5.5, 3.5 Hz, H3a), 4.84
(1H, d, J¼11.5 Hz, CH2Ph), 5.03e5.05 (2H, m, H4, H8a),
7.31 (25H, m, AreH). 13C NMR d 50.2 (CH2), 61.5 (CH2),
63.5 (CH), 72.3 (CH2), 74.3 (CH2), 74.9 (CH), 77.0 (CH),
77.8 (CH), 83.6 (CH), 84.3 (CH), 87.8 (C), 127.3e129.0
(25ꢁAreCH), 137.0 (AreC), 137.5 (AreC), 143.5 (3ꢁAre
C), 159.0 (CO).
4.1.5. (1R,6S,7R,7aR)-1-((1S,2S)-1,2-Bis(benzyloxy)-3-(tri-
phenylmethoxy)propyl)-tetrahydro-6,7-dihydroxypyrrolo-
[1,2-c]oxazol-3(1H)-one (9) and (1R,6R,7S,7aR)-1-((1S,2S)-
1,2-bis(benzyloxy)-3-(triphenylmethoxy)-propyl)-tetra-
hydro-6,7-dihydroxypyrrolo[1,2-c]oxazol-3(1H)-one
(6,7-di-epi-9)
To a solution of 7 (1.403 g, 2.203 mmol) in acetone
(13.2 mL) and water (8.8 mL) was added potassium osmate
dihydrate (57 mg, 0.15 mmol) and 4-morpholine N-oxide
(516 mg, 4.41 mmol). The mixture was stirred at rt for 48 h fol-
lowed by evaporation of all the volatiles to give a black oil. Pu-
rification by column chromatography (70e90% EtOAc/petrol)
gave a mixture of diastereoisomeric dihydroxy products, 9 and
6,7-di-epi-9, as a white foamy solid (1.242 g, 84%, dr¼83:17).
The isomers were separated using 2% MeOH/CH2Cl2 as an el-
uent on a silica gel column (1 cm diameterꢁ30 cm long) to give
the pure compound 9 (894 mg, 60%) and 6,7-di-epi-9 (248 mg,
16%) (Rf of 9¼0.33 and Rf of 6,7-di-epi-9¼0.27, 2% MeOH/
CH2Cl2).
Compound 9: [a]2D7 þ43 (c 3.5, CHCl3). IR nmax/cmꢂ1
3411, 3058, 3027, 2914, 2848, 1734, 1445, 1093, 1055. MS
(ESIþ) m/z 694 (MþNaþ, 100%); HRMS (ESIþ) calcd for
C42H42NO7 (MþHþ) 672.2961, found 672.3005. 1H NMR
d 2.57 (br, OH), 2.94 (1H, dd, J¼8.0, 2.0 Hz, H7a), 3.40
(1H, dd, J¼10.5, 4.8 Hz, H30), 3.36 (1H, dd, J¼11.5, 8.0 Hz,
H5), 3.29 (1H, dd, J¼11.5, 7.5 Hz, H5), 3.54e3.55 (2H, m,
H30, H7), 3.76 (dd, J¼9.5, 5.0 Hz, H20), 4.14 (1H, m, H6),
4.32 (1H, dd, J¼6.0, 4.5 Hz, H10), 4.41 (1H, d, J¼12.0 Hz,
CH2Ph), 4.64 (1H, dd, J¼7.5, 6.0 Hz, H1), 4.71 (1H, d,
J¼11.0 Hz, CH2Ph), 4.73 (1H, d, J¼12.0 Hz, CH2Ph), 4.76
(1H, d, J¼11.0 Hz, CH2Ph), 7.44e7.18 (25H, m, Ar). 13C
NMR d 50.6 (CH2), 62.6 (CH2), 64.6 (CH), 70.8 (CH), 72.3
(CH2), 74.1 (CH), 75.0 (CH2), 76.6 (CH), 76.6 (CH), 77.4
(CH), 87.4 (C), 127.5e129.0 (25ꢁAreCH), 137.2 (AreC),
138.0 (AreC), 144.0 (3ꢁAreC), 162.1 (CO).
4.1.7. (7S,7aR)-1-((1S,2S)-1,2-Bis(benzyloxy)-3-hydroxy-
propyl)-tetrahydro-7-hydroxypyrrolo[1,2-c]oxazol-3(1H)-
one (11)
To a solution of 10 (689 mg, 0.940 mmol) in anhydrous
N,N-dimethylacetamide (2.5 mL) was added NaBH4 (62 mg,
1.410 mmol). The reaction was stirred under nitrogen at rt
for 6 h, then the N,N-dimethylacetamide was removed under re-
duced pressure and the residue was suspended in THF (30 mL).
Water (1 mL) followed by concentrated H2SO4 (0.5 mL) was
Compound 6,7-di-epi-9: [a]2D4 þ24 (c 1.2, CHCl3). IR
nmax/cmꢂ1 3412, 3058, 3027, 2930, 1731, 1447, 1095, 1053. MS
(ESIþ) m/z 694 (MþNaþ, 100%); HRMS (ESIþ) calcd for
C42H42NO7 (MþHþ) 672.2961, found 672.3020. 1H NMR
d 2.49 (1H, br, OH), 3.08 (1H, dd, J¼12.8, 1.8 Hz, H5),
3.34 (1H, dd, J¼9.0, 7.0 Hz, H7a), 3.44 (1H, dd, J¼10.0,

2730
T. Machan et al. / Tetrahedron 64 (2008) 2725e2732
added, and the suspension became a clear solution. The solution
was stirred for 48 h at rt followed by the addition of water
(20 mL). The mixture was extracted with EtOAc (3ꢁ30 mL)
and the combined extracts were washed with brine, dried
(MgSO4), and concentrated. The residue was purified by
column chromatography (5e10% MeOH/EtOAc) to give
compound 11 (248 mg, 63%, Rf¼0.40, 8% MeOH/EtOAc)
as a white foamy solid. [a]2D8 þ19 (c 16.6, CHCl3). IR
nmax/cmꢂ1 3426, 3050, 2950, 2840, 1732, 1075, 1052. MS
(ESIþ) m/z 414 (MþHþ, 100%); HRMS (ESIþ) calcd for
C23H28NO6 (MþHþ) 414.1917, found 414.1926. 1H NMR
d 1.74 (1H, dddd, J¼13.5, 10.0, 10.0, 3.5 Hz, H6), 1.93 (1H,
ddd, J¼13.5, 8.0, 2.0 Hz, H6), 3.11 (1H, br d, J¼9.5 Hz,
H7a), 3.14 (1H, dd, J¼7.5, 2.0 Hz, H5), 3.68 (1H, m, H5),
3.78e3.81 (2H, m, H20, H30), 3.89 (1H, dd, J¼11.0, 3.5 Hz,
H30), 3.93 (1H, app. br s, H7), 4.20 (1H, app. t, J¼4.5 Hz,
H10), 4.54 (1H, d, J¼12.0 Hz, CH2Ph), 4.72 (1H, d,
J¼11.5 Hz, CH2Ph), 4.75 (1H, d, J¼11.0 Hz, CH2Ph), 4.79
(1H, d, J¼11.0 Hz, CH2Ph), 4.94 (1H, dd, J¼7.0, 5.0 Hz,
H1), 7.33 (10H, m, AreH). 13C NMR d 34.5 (CH2), 43.8
(CH2), 61.1 (CH2), 67.2 (CH), 70.1 (CH), 72.3 (CH2), 74.5
(CH2), 76.4 (CH), 76.7 (CH), 77.7 (CH), 128.4e129.0
(10ꢁAreCH), 137.0 (AreC), 137.8 (AreC), 162.9 (CO).
Compound 13: [a]2D8 þ21 (c 9.4, CHCl3). IR nmax/cmꢂ1
3450, 3057, 3027, 2930, 2868, 1614, 1454, 1096, 1073. MS
(ESIþ) m/z 370 (MþHþ, 100%); HRMS (ESIþ) calcd for
C22H28NO4 (MþHþ) 370.2018, found 370.2010. 1H NMR
d 1.81 (1H, m, H4), 1.97 (1H, m, H4), 2.87 (1H, m, H5),
3.05 (1H, app. t, J¼5.0 Hz, H2), 3.21 (1H, m, H5), 3.90
(1H, dd, J¼10.5, 4.5 Hz, H50), 4.08e4.01 (3H, m, H20, H40,
H50), 4.15 (1H, br d, J¼5.0 Hz, H30), 4.23 (1H, m, H3), 4.50
(1H, d, J¼12.5 Hz, CH2Ph), 4.54 (1H, d, J¼12.0 Hz,
CH2Ph), 4.57 (1H, J¼12.0 Hz, CH2Ph), 4.61 (1H, d,
J¼11.5 Hz, CH2Ph), 7.39 (10H, m, AreH). 13C NMR
(CDCl3) d 35.4 (CH2, C4), 44.7 (CH2, C5), 65.5 (CH, C2),
71.6 (C40eOCH2Ph), 72.0 (CH2, C50), 72.5 (C30eOCH2Ph),
73.4 (CH, C3), 83.0 (CH, C40), 83.3 (CH, C20), 86.1 (CH,
C30), 137.4 (AreC), 137.6 (AreC).
4.1.9. (1S,6S,7S,8R,8aS)-6,7-Bis(benzyloxy)-octahydroindo-
lizine-1,8-diol (14) and (3aS,6S,7S,8R,8aS)-6,7-bis(benzyl-
oxy)-octahydro-1H-oxepino-[3,2-b]pyrrol-8-ol (15)
To a solution of 12 (49.2 mg, 0.13 mmol) in dry THF (2 mL)
was added triphenylphosphine (47 mg, 0.18 mmol) and diiso-
propyl azodicarboxylate (36 mg, 0.18 mmol) at 0 ꢀC. The
mixture was stirred at 0e5 ꢀC for 12 h, then the volatiles
were removed in vacuo to give an oil. The pure products were
obtained by column chromatography (100% EtOAc and
8.4:1.4:0.2 EtOAc/MeOH/NH4OH), which gave the major
compound 14 (11.5 mg, 25%, Rf¼0.47, 8.4:1:4.0.2 EtOAc/
MeOH/NH4OH) as a clear oil and compound 13 (10 mg, 22%
Rf¼0.15, 8.4:1:4.0.2 EtOAc/MeOH/NH4OH or Rf¼0.44,
10:1:0.5 EtOAc/MeOH/NH4OH), as a white solid, as well as
compound 15 (5.0 mg, 11%, Rf¼0.27, 8.4:1:4.0.2 EtOAc/
MeOH/NH4OH) as a white solid.
4.1.8. (2S,3S)-2-((1R,2S,3S)-2,3-Bis(benzyloxy)-1,4-dihydr-
oxybutyl)-pyrrolidin-3-ol (12) and (2R,3S)-2-((2R,3S,4S)-
3,4-bis(benzyloxy)-tetrahydrofuran-2-yl)pyrrolidin-3-ol (13)
Compound 11 (65.4 mg, 0.16 mmol) was dissolved in
MeOH (20 mL) and then a solution of NaOH (63.2 mg,
1.58 mmol) in water (5 mL) was added. The mixture was placed
in a Teflon tube with a 100 bar pressure cap, then heated in
a CEM Discover microwave reactor with constant temperature
heating at 110 ꢀC for 2 h. After cooling the mixture was poured
into water (50 mL), then extracted with EtOAc (4ꢁ30 mL). The
combined organic extracts were dried (MgSO4), filtered, and
evaporated in vacuo to give a semisolid. The pure products
were obtained by column chromatography (10:1:0.5 EtOAc/
MeOH/NH4OH), which gave the desired compound 12
(49 mg, 80%, Rf¼0.33, 10:1:0.5 EtOAc/MeOH/NH4OH), as
a clear oil, and product 13 (10 mg, 16%, Rf¼0.44, 10:1:0.5
EtOAc:MeOH:NH4OH) as a white solid.
Compound 12: [a]2D7 þ32 (c 7.5, CHCl3). MS (ESIþ) m/z
388 (MþHþ, 100%); HRMS (ESIþ) calcd for C22H30NO5
(MþHþ) 388.2128, found 388.2128. 1H NMR (CD3OD)
d 1.69 (1H, m, H4), 1.84 (1H, dd, J¼13.5, 8.0 Hz, H4), 2.71
(1H, dd, J¼7.5, 2.5 Hz, H2), 3.06 (1H, app. dt, J¼10.5,
2.0 Hz, H5), 3.54 (1H, ddd, J¼10.5, 9.5, 8.0 Hz, H5), 3.94
(1H, app. t, J¼2.5 Hz, H3), 4.00 (1H, app. dt, J¼6.0,
2.5 Hz, H30), 4.21 (1H, dd, J¼10.5, 6.0 Hz, H40), 4.35 (1H,
dd, J¼11.0, 5.5 Hz, H40), 4.52 (1H, dd, J¼9.0, 2.5 Hz, H20),
4.56 (1H, d, J¼12.0 Hz, CH2Ph), 4.63 (1H, d, J¼11.0 Hz,
CH2Ph), 4.77 (1H, d, J¼11.5 Hz, CH2Ph), 4.81 (1H, dd,
J¼9.0, 7.5 Hz, H10), 4.83 (1H, d, J¼10.5 Hz, CH2Ph), 7.37
(10H, m, AreH). 13C NMR (CD3OD) d 34.8 (CH2), 43.2
(CH2), 65.4 (CH), 66.3 (CH2), 69.4 (CH), 71.5 (CH2), 74.6
(CH), 74.9 (CH2), 76.8 (CH), 78.9 (CH), 127.8e128.5
(10ꢁAreCH), 138.0 (AreC), 138.4 (AreC).
Compound 14: [a]2D7 þ71 (c 2.5, CHCl3). IR nmax/cmꢂ1
3360, 3000, 2940, 2868, 1662, 1091, 1075. MS (ESIþ) m/z
370 (MþHþ, 100%); HRMS (ESIþ) calcd for C22H28NO4
1
(MþHþ) 370.1135, found 370.1130. H NMR d 1.74 (1H,
m, H2), 1.85 (1H, dd, J¼10.0, 4.5 Hz, H8a), 1.94 (1H, app.
t, J¼9.8 Hz, H5), 2.12 (1H, app. q, J¼9.0 Hz, H3), 2.33
(1H, m, H2), 3.08 (1H, app. dt, J¼9.0, 2.5 Hz, H3), 3.29
(1H, dd, J¼9.0, 5.5 Hz, H7), 3.34 (1H, app. t, J¼9.8 Hz,
H5), 3.62 (1H, m, H6), 3.76 (1H, app. t, J¼9.5 Hz, H8),
4.30 (1H, m, H1), 4.62 (1H, d, J¼11.5 Hz, CH2Ph), 4.66
(1H, d, J¼11.5 Hz, CH2Ph), 4.87 (2H, br s, CH2Ph), 7.30
(10H, m, AreH). 13C NMR d 33.4 (CH2, C2), 52.0 (CH2,
C3), 54.2 (CH2, C5), 69.4 (CH, C8), 69.8 (CH, C1), 72.5
(C7eOCH2Ph), 72.8 (CH, C8a), 75.1 (C6eOCH2Ph), 78.8
(CH, C8), 87.3 (CH, C7), 127.2e128.1 (10ꢁAreCH), 138.4
(AreC), 138.8 (AreC).
Compound 15: [a]2D7 þ45 (c 2.3, CHCl3). IR nmax/cmꢂ1
3288, 2904, 2842, 1665, 1091, 1075. MS (ESIþ) m/z 370
1
(MþHþ, 100%). H NMR d 1.89 (1H, m, overlapped with
OH and NH, H3), 1.95 (1H, m, overlapped with OH and
NH, H3), 2.93 (1H, m, H2), 3.15 (1H, m, H2), 3.35 (1H, dd,
J¼8.8, 3.8 Hz, H8a), 3.83 (1H, dd, J¼9.8, 1.8 Hz, H5),
4.09e4.20 (4H, m, H5, H6, H7, H8), 4.47 (1H, m, H3a),
4.48 (1H, d, J¼12.0 Hz, CH2Ph), 4.53 (1H, d, J¼12.0 Hz,
CH2Ph), 4.55 (1H, d, J¼11.5 Hz, CH2Ph), 4.63 (1H, d,

T. Machan et al. / Tetrahedron 64 (2008) 2725e2732
2731
J¼11.5 Hz, CH2Ph), 7.30 (10H, m, AreH). 13C NMR d 34.9
(CH2, C3), 44.9 (CH2N, C2), 61.5 (CHN, C8), 71.7
(CH2Ph), 72.2 (CH2, C5), 72.3 (CH2Ph), 73.2 (CH, C3a),
80.3 (CH, C8), 81.9 (CH, C7), 82.5 (CH, C6), 127.9e128.8
(10ꢁAreCH), 137.9 (AreC), 138.0 (AreC).
J. Chem. Ecol. 1985, 11, 1045e1051; (d) Nash, R. J.; Evans, S. V.;
Fellows, L. E.; Bell, E. A. Plant Toxicology; Seawright, A. A., Hegarty,
M. P., James, L. F., Keeler, R. F., Eds.; Queensland Poisonous Plants Com-
mittee: Yeerongpilly, Australia, 1985; p 309; (e) Trugnan, G.; Rousset, M.;
Zweibaum, A. FEBS Lett. 1986, 795, 28e32; (f) Fellows, L. E. Pestic. Sci.
1986, 17, 602e606; (g) Campbell, B. C.; Molyneux, R. J.; Jones, K. C.
J. Chem. Ecol. 1987, 13, 1759e1770; (h) Cenci di Bello, I.; Mann, D.;
Nash, R. J.; Winchester, B. G. Lipid Storage Disorders: Biological and
Medical Aspects; Salvayre, R., Douste-Blazy, L., Gatt, S., Eds.; Plenum:
New York, NY, 1988; p 635; (i) Fellows, L. E.; Fleet, G. W. J. Natural
Products Isolation; Wagman, G. H., Cooper, R., Eds.; Elsevier: New
York, NY, 1989; p 539; (j) Fellows, L. E.; Kite, G.; Nash, R.; Simmonds,
M.; Scofield, A. Plant Nitrogen Metabolism; Poulton, J. E., Romeo, J. T.,
Conn, E. E., Eds.; Plenum: New York, NY, 1989; p 395; (k) Scofield,
A. M.; Rossiter, J. T.; Witham, P.; Kite, G. C.; Nash, R. J.; Fellows,
L. E. Phytochemistry 1990, 29, 107e109; (l) Yamamoto, I.; Muto, N.;
Murakami, K.; Akiyama, J. J. Nutr. 1992, 722, 871e877; (m) Hempel,
A.; Camerman, N.; Mastropaolo, D.; Camerman, A. J. Med. Chem.
1993, 36, 4082e4086; (n) Valaitis, A. P.; Bowers, D. F. Insect Biochem.
Mol. Biol. 1993, 23, 599e606; (o) Walter, S.; Fassbender, K.; Gulbins,
E.; Liu, Y.; Rieschel, M.; Herten, M.; Bertsch, T.; Engelhardt, B. J. Neuro-
immunol. 2002, 132, 1e10.
4.1.10. (1S,6S,7R,8R,8aS)-Octahydroindolizine-1,6,7,8-
tetraol (castanospermine) (1)
The indolizidine 14 (6.4 mg, 0.173 mmol) was dissolved in
methanol (1 mL), then PdCl2 (2.4 mg, 0.013 mmol) was added.
The mixture was stirred under an atmosphere of H2 (balloon) for
1 h at rt, before the mixture was filtered through a plug of cotton
wool. The filtrates were evaporated in vacuo, then the residue
was dissolved in water (1 mL) and applied to a column of
DOWEX-1-basic ion-exchange resin. Elution with water
(30 mL) followed by evaporation of the eluent in vacuo gave
the title product castanospermine, 1 (3.1 mg, 95%) as a colorless
solid. Mp 206e208 ꢀC (lit.1 212e215 ꢀC). [a]2D7 þ82 (c 1.2,
H2O) (lit.1 [a]D24 þ79.7 (c 0.93, H2O)). Rf 0.18 (96:4 EtOH/aque-
ous NH3). MS (ESIþ) m/z 190 (MþHþ, 100%). 1H NMR (D2O,
HOD ref. at 4.79 ppm) d 1.72 (1H, dddd, J2b,2a¼14 Hz,
J2b,3a¼8.5 Hz, J2b,3b¼8.5 Hz, J2b,1¼1.8 Hz, H2b), 2.03 (1H,
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dd, J8a,8¼10 Hz, J8a,1¼4.5 Hz, H8a), 2.07 (1H, t, J5b,5a
¼
¼
J5b,6¼10.5 Hz, H5b), 2.23 (1H, q, J3b,2b¼J3b,3a¼J3b,2a
9.5 Hz, H3b), 2.35 (1H, dddd, J2b,2a¼14 Hz, J2a,3b¼9.5 Hz,
J2a,1¼7.5 Hz, J2a,3a¼2.5 Hz, H2a), 3.09 (1H, ddd, J3a,3b
J3a,2b¼9 Hz, J3a,2a¼2.5 Hz, H3a), 3.19 (1H, dd, J5a,5b
¼
¼
10.5 Hz, J5a,6¼5 Hz, H5a), 3.34 (1H, t, J7,8¼J6,7¼9.5 Hz,
H7), 3.61 (1H, t, J8,8a¼J8,7¼9.5 Hz, H8), 3.63 (1H, ddd,
J6,5b¼10.5 Hz, J6,7¼9.5 Hz, J6,5a¼5 Hz, H6), 4.42 (1H,
ddd, J1,2a¼7 Hz, J1,8a¼4.5 Hz, J1,2b¼1.8 Hz, H1). 13C NMR
(D2O, internal reference, acetone at 30.89 ppm) d 79.3 (CH,
C7), 71.7 (CH, C8a), 70.4 (CH, C8), 69.9 (CH, C1), 69.2 (CH,
C6), 55.7 (CH2, C5), 51.8 (CH2, C3), 33.0 (CH2, C2).
Acknowledgements
We thank the Australian Research Council for financial sup-
port. T.M. would like to thank the Royal Golden Jubilee Ph.D.
program (RGJ) from the Thailand Research Fund (TRF) and the
Lecturer/Student Exchange Program from the Commission on
Higher Education, Ministry of Education, Thailand, and the
University of Wollongong as well as the Graduate School,
Chiang Mai University for financial support. We thank Dr.
Reg Smith, Phytex, Sydney for an authentic sample of castano-
spermine and a referee for comments on the mechanism of the
formation of 13.
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13. The fact that the same compound 13 is produced in both Schemes 2
and 3 suggests that this alternative mechanism does not occur since the
primary hydroxyl in 12 would be expected to be selectively activated
under Mitsunobu cyclization conditions. We thank a referee for bringing
this to our attention.
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27. Kindly supplied by Dr. Reg Smith Phytex, Sydney.