Synthesis of C1- and C8a-epimers of (+)-castanospermine from d-glucose derived γ,δ-epoxyazide: Intramolecular 5-endo epoxide opening approach

Article abstract of DOI:10.1016/j.tet.2011.02.030

A concise synthesis of two diastereomers of (+)-castanospermine namely 1- and 8a-epi-castanospermine 1b and 1c, respectively, is reported from d-glucose. The methodology involves stereoselective cross metathesis of d-glucose derived alkene 2 with 4-bromo-

Full text of DOI:10.1016/j.tet.2011.02.030

Tetrahedron 67 (2011) 2773e2778
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journal homepage: www.elsevier.com/locate/tet
Synthesis of C1- and C8a-epimers of (þ)-castanospermine from
D
-glucose derived
g,d-epoxyazide: intramolecular 5-endo epoxide opening approach
,
Navnath B. Kalamkar a, Vedavati G. Puranik b, Dilip D. Dhavale a
*
a Department of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
b Centre for Material Characterization, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise synthesis of two diastereomers of (þ)-castanospermine namely 1- and 8a-epi-castanospermine
1b and 1c, respectively, is reported from -glucose. The methodology involves stereoselective cross
metathesis of -glucose derived alkene 2 with 4-bromo-1-butene followed by azide displacement and
m-CPBA oxidation to afford diastereomeric -epoxyazides 5a/5b. The Staudinger reaction of epoxyazide
5a followed by reaction with benzylchloroformate (CbzCl) unexpectedly furnished 1,3-oxazinan-2-one
derivative 7 whose stereochemistry was establish by single crystal X-ray. This helps to assign the ste-
reochemistry in the epoxidation reaction. The reduction of 5a/5b was then carried out by transfer hy-
Received 14 December 2010
Received in revised form 10 February 2011
Accepted 12 February 2011
Available online 18 February 2011
D
D
g,d
Keywords:
Alkaloids
Polyhydroxy indolizidines
Cross metathesis
Epoxide
drogenation to provide
g,d-epoxyamine that concomitantly undergoes intramolecular 5-endo-tet
cyclization to afford hydroxypyrrolidine ring skeleton with sugar framework-a precursor to castano-
spermine analogues 1b/1c.
Ó 2011 Elsevier Ltd. All rights reserved.
D
-glucose
Oxazinanone
OH
HO
1. Introduction
H
H
OH
R
α
C-δ attack
ω
HO
R
H2N
N
H
Common occurrence of hydroxypyrrolidine motif in biologically
active natural products1 and its applications in petidomimetics2
along with its use as chiral auxiliary3,4 in asymmetric synthesis
led to the development of a number of inter- and intra-molecular
pathways for its synthesis.5,6 Among intramolecular cyclization
strategies,6 one of the widely used reaction is either 5-endo-tet
N
δ
5-exo
O
HO
opening
Polyhydroxy
R = sugar
Perhydroaza-azulenes
OH
δ
C-δ attack
H2N
Castanospermine
analogues
R
γ
O
α
R
5-endo
N
H
cyclization7 of
amines to get hydroxypyrrolidine ring system.8
In this direction, we have recently reported an intramolecular
5-exo-tet opening of -glucose derived -epoxyamine (generated
g,d-epoxyamine or 5-exo-tet opening of d,u-epoxy-
H
opening
Scheme 1. Intramolecular cyclization to pyrrolidine-ring system.
D
d,u
HO
HO
OH
OH
in situ) to afford sugar appended pyrrolidine ring that was explored
in the synthesis of polyhydroxy perhydroaza-azulenes8a (Scheme 1).
As a part of our interest in the synthesis of iminosugars,9 we
are now reporting regioselective intramolecular 5-endo-tet cycli-
H
O5
H
8
HO
HO
HO
HO
1
6
4
8a
3
7
N
2
1
6
3
zation of sugar derived
g,d-epoxyamine (generated in situ from
OH
D-glucose
epoxyazide) to provide 3-hydroxypyrrolidine ring7 with sugar
framework-a key synthon to castanospermine analogues.
1a α C8a−H, β C1−OH (+)−Castanospermine
1b α C8a−H, α C1−OH 1-epi-castanospermine
1c β C8a−H, β C1−OH 8a-epi-castanospermine
Castanospermine 1a (Fig.1), isolated from the Australian legume
Castanospermum australae and Alexa leopetala,10 is of interest
amongst synthetic organic chemist and biologists due to its
Fig. 1. (þ)-Castanospermine/analogues.
potential utility in the treatment of cancer,11 diabetes,12 malaria13
and AIDS.14 It is predicted that castanospermine and its analogues
may play a role in transplant surgery as they can inhibit the
rejection of transplanted tissues.15 In the search for
* Corresponding author. Tel.: þ912025691727; fax: þ912025691728; e-mail
address: ddd@chem.unipune.ac.in (D.D. Dhavale).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.030

2774
N.B. Kalamkar et al. / Tetrahedron 67 (2011) 2773e2778
structureeactivity relationship, a number of natural and unnatural
analogues of 1a; with variation in the number, position and ste-
reochemistry of the hydroxyl groups on the indolizidine skeleton,
have been synthesized and studied for their biological activity.16
Amongst these analogues, the 1-epi-castanospermine 1b was
found to be a potential anti-AIDS therapeutic.17f A number of chiron
and asymmetric approaches for 1aec are known in the literature.17
Due to the sugar like (highly oxygenated) framework in 1, com-
monly occurring sugars are appropriate starting material for their
D-Glucose
a
X
O
H
O
O
b
O
H
O
BnO
O
BnO
3 X = Br
4 X = N3
2
c
synthesis. In fact, the -glucose type of hidden symmetry in 1 could
D
be easily recognized in the trihydroxylated architect of the piperi-
dine ring wherein; the C6, C7 and C8 of 1 match with that of C2, C3
and C4 of D-glucose as far as the position and stereochemical as-
pects are concerned. However, building of the hydroxypyrrolidine
core, with stereochemically well-defined carbon centres at C1 and
at ring-junction (C8a) of 1, requires an asymmetric pathway. While
working in the area of synthetic carbohydrate chemistry, we have
d
N3
N3
O
H
δ
H
O
O
O
O
γ
O
BnO
O
O
BnO
5a (major)
5b (minor)
investigated intramolecular 5-endo-tet cyclization of
D-glucose
derived -epoxyamine. The reaction follows 5-endo-tet cycliza-
g,d
e
e
H
H
OH
OH
H
tion path to give of 3-hydroxypyrrolidine ring, which was elabo-
rated towards synthesis of C1- and C8a-epi-castanospermine
analogues 1b and 1c, respectively. Our results are described herein.
H
5
O
1
O
O
N
Cbz
O
N
Cbz
4
H
HO
H
HO
O
O
2. Result and discussion
6b
6a
The required 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-
a-
f
f
D
-ribo-hexofuran-5-ene 2 was prepared from -glucose in four
D
steps as reported earlier by us and others.18 As shown in Scheme 2,
the cross metathesis reaction of 2 with 4-bromo-1-butene using
the Grubb’s second-generation catalyst afforded an alkenyl bro-
mide 3 in 71% yield with exclusively E-selectivity (JH5, H6¼16 Hz).19
The bromo compound 3 was subjected for the nucleophilic azide
displacement with sodium azide in refluxing acetone to furnish
1b
1c
aReagents and conditions : (a) Ref−18 (b) 4-bromo-1-
butene, Grubbs catalyst II gen (10 mol%), CH2Cl2, rt, 24h,
71%; (c) NaN3, acetone, reflux, 8h, 88%; (d) m-CPBA,
CH2Cl2, 0 οC to 25 C, 24h; (e) (i) HCOONH4, 10% Pd-C,
ο
g,d-alkenylazide 4 in 88% yield. Azide 4 on epoxidation with
EtOH, reflux, 26h; (ii) ClCOOBn, aq NaHCO3, EtOH, 12h; (f)
(i) TFA/H2O (3:2), 0 οC to rt, 5h; (ii) H2, Pd(OH)2, aq MeOH,
90 psi, 15h.
m-CPBA gave a diastereomeric mixture of epoxides in the ratio 3:1
(as evident from the 1H NMR of crude product) that was separated
by column chromatography to afford g,d-epoxyazide 5a and 5b in
Scheme 2. Synthesis of 1b and 1c. Reagents and conditions.
good yields. At this stage, we tried reduction of azide using the
Staudinger conditions.20 Thus, the major isomer 5a was treated
with triphenylphospine in THF/H2O and after the complete disap-
pearance of 5a (as monitored by TLC) the reaction mixture was
directly treated with benzylchloroformate in aq NaHCO3 that
afforded unexpected oxazinanone 7, and not the expected N-Cbz
protected pyrrolidine compound A (Scheme 3). Fortunately, com-
pound 7 was obtained as a colourless solid and the single crystal
X-ray analysis (Fig. 2) established the absolute configurations at
newly generated stereocenters in 7 as 5S and 6R.21 The plausible
mechanism for the formation of 7 could be explained as follows
(Scheme 3).
We believe that the Staudinger reduction of epoxyazide 5a
results initially in the formation of epoxyamine X, which on re-
action with CbzCl gives N-Cbz protected epoxyamine Y.22 Sub-
sequently, the Ph3P]O (generated in situ during the Staudinger
reaction) activated oxirane ring undergoes epoxide opening via
6-exo-tet mode to give 1,3-oxazinium intermediate Z that on
hydrolysis gives sugar substituted oxazinanone derivative 7. The
formation of 7 guided us to assign the absolute stereochemistry in
the epoxidation reaction. Thus, as 7 is derived from the major
epoxide 5a, the absolute configurations at newly generated ster-
eocenters in 5a were assigned as 5R,6S and thus the minor epoxide
5b was given the absolute configurations as 5S,6R.23
H
N
H
H
O
OH
H
8
7
i. Ph3P
O
O
N
THF/H2O
O
R
H
H
5a
S
Cbz
O
1
O
HO
ii.ClCOOBn,
aq NaHCO3
rt, 70%
O
4
BnO
H
3
O
BnO
A (expected)
7 (isolated)
5
6
R
O
Ph3P
HN
O
R
R
O
O
1
BnO
Y
THF/H2O
BnOCOCl
N3
NH2
5a
X
6-exo-tet
OH
OH
H
O
O
O
S
H2O
R
R
R
R =
HN
O
HN
O
-BnOH
As an alternative pathway to target molecules, we thought of
reduction of azide under transfer hydrogenation conditions.24 Thus,
reaction of 5a using ammonium formate and 10% Pd/C in refluxing
ethanol followed by treatment with benzylchloroformate in sodium
bicarbonate afforded N-Cbz protected 3-hydroxypyrrolidine
BnO
OBn
O
7
Z
Scheme 3. Formation and plausible mechanism for oxazinanone 7.

N.B. Kalamkar et al. / Tetrahedron 67 (2011) 2773e2778
2775
Fig. 2. ORTEP diagram of 7. Ellipsoids are drawn at 40% probability.
compound 6a. This reaction probably involves first reduction of
azide to -epoxyamine, which attacks the oxirane ring via 5-endo-
4. Experimental
g,d
tet epoxide opening at 80 ꢀC to give pyrrolidine ring25 that was
protected as N-Cbz derivative. Finally, hydrolysis of 1,2-acetonide
functionality in 6a using TFA/water (3:2) furnished C1 anomeric
mixture of hemiacetal, which on intramolecular reductive amino-
cyclization26 under hydrogenation conditions (H2, 10% Pd(OH)2/C,
80 psi) afforded 8a-epi-castanospermine 1c as a thick liquid. The
spectroscopic and analytical data of 1c were found to be in agree-
4.1. General methods
Melting points were recorded with Thomas Hoover Capillary
melting point apparatus and are uncorrected. IR spectra were
recorded with Shimadzu FTIR-8400 as a thin film or in Nujol mull or
using KBr pellets and are expressed in cmꢁ1. 1H (300 MHz) and 13
C
(75 or 100 MHz) NMR spectra were recorded with Varian Mercury
instrument using CDCl3 as solvent and Me4Si (
¼0.0 ppm) is used
an internal standard. When D2O was used as NMR solvent internal
standard for D2O 1H (
¼4.82 ppm) is used. Bruker SMART APEX CCD
mentwith those reported;[
a
]
25 þ27 (c0.5, MeOH), [lit17r
[
a]
20 þ28 (c
d
D
D
0.3, MeOH), lit17p for the antipode [
a]
25 ꢁ33 (c 0.31, MeOH)].
D
While targeting the synthesis of 1-epi-castanospermine 1b, the
epoxyazide 5b was subjected to transfer hydrogenation using
HCOONH4 and 10% Pd/C in ethanol under reflux condition for 26 h
followed by reaction with benzylchloroformate in aq NaHCO3 to
afford N-Cbz protected pyrrolidine 6b in 55% yield. The 1,2 aceto-
nide opening of 6b using TFA/H2O (6:4) and intramolecular re-
ductive aminocyclization using H2 and 10% Pd(OH)2 in aq methanol
afforded 1-epi isomer 1b in overall 23% yield from epoxyazide 5b.
The spectral and analytical data of 1b were found to be in conso-
d
diffractometer was used for X-ray crystallographic analysis. Ele-
mental analyses were carried out with Thermo-Electron Corpora-
tion CHNS analyzer Flash-EA-1112 at Department of Chemistry,
University of Pune, Pune. Optical rotations were measured using
Jasco P-1020 digital polarimeter at 25 ꢀC. Thin layer chromatogra-
phy was performed on pre-coated plates (0.25 mm, silica gel 60-
F254). Visualization was made by absorption of UV light or by
thermal development after spraying with 3.5% solution of 2,4-
dinitrophenylhydrazine in ethanol/H2SO4 and with basic aq po-
tassium permanganate solution. Column chromatography was
carried out with silica gel (100e200 mesh). The reactions were
carried out in oven-dried glasswares under dry N2 atmosphere.
Acetone, dichloromethane, chloroform, ethanol and methanol were
purified and dried before use. Distilled n-hexane, ethyl acetate,
CH2Cl2 and methanol were used for column chromatography. After
decomposition of the reaction with water, the workup involves
washing of combined organic layer with water, brine, drying over
anhydrous sodium sulfate and evaporation of solvent at reduced
pressure using rotary evaporator.
25
22
nance with that reported; [
þ3.8 (c 0.54, MeOH)].
a]
þ8.4 (c 0.21, MeOH), [lit17o
[a]
D
D
3. Conclusion
A short and convenient synthesis of two epimers of (þ)-casta-
nospermine 1b and 1c is reported using intramolecular 5-endo-tet
cyclization approach with D-glucose derived g,d-epoxyazide. Dur-
ing the course of the synthesis we noticed an interesting formation
of 1,3-oxazinan-2-one derivative 7, in the Staudinger reduction and
N-Cbz protection of g,d-epoxyazide 5a. The structure of 7 was de-
4.1.1. 8-Bromo-3-O-benzyl-1,2-O-isopropylidene-5,6,7,8-tetradeoxy-
termined by X-ray crystallographic analysis that assisted us to de-
cide absolute configuration at C5 and C6 in the epoxides 5a and 5b.
Intramolecular 5-endo-tet epoxide opening to the pyrrolidine ring
formation was however achieved under thermodynamically con-
trolled condition in the presence of ammonium formate and Pd
catalyst, which was further elaborated to the castanospermine
stereoisomers 1b and 1c.
a-D
-xylo-oct-5-en-1,4-furanose (3). To a stirred solution of com-
(0.5 g, 0.47 mmol) and 4-bromo-1-butene (0.16 mL,
pound
2
0.95 mmol) in dry DCM (60 mL) at 30 ꢀC was added the second-
generation Grubb’s catalyst (0.04 g, 0.047 mmol). The reaction
mixture was stirred for 24 h at room temperature (27e30 ꢀC). The
solvent was evaporated and the crude product was purified by

2776
N.B. Kalamkar et al. / Tetrahedron 67 (2011) 2773e2778
column chromatography using n-hexane/ethyl acetate (95:5) as an
eluent to give 3 (0.49 g, 71%) as viscous oil; Rf 0.50 (n-hexane/ethyl
1.60e1.95 (2H, m, H-7), 2.86e2.93 (1H, m, H-6), 3.09 (1H, dd, J¼5.7
and 2.2 Hz, H-5), 3.37 (2H, t, J¼6.8 Hz, H-8), 3.88 (1H, dd, J¼5.7 and
3.6 Hz, H-4), 3.98 (1H, d, J¼3.5 Hz, H-3), 4.49 (1H, d, J¼12.0 Hz, O-
CH2Ph), 4.62 (1H, d, J¼3.8 Hz, H-2), 4.72 (1H, d, J¼12.0 Hz, O-
CH2Ph), 5.96 (1H, d, J¼3.8 Hz, H-1), 7.25e7.41 (5H, m, Ar-H); 13C
NMR (CDCl3) 26.4 (CH3), 26.9 (CH3), 31.2, (C7), 48.1 (C8), 52.0, 56.0
(C5 and C6), 71.8 (O-CH2Ph), 81.0, 82.1, 82.8 (C2, C3 and C4), 105.3
(C1), 111.9 (isopropylidene), 127.6 (strong), 128.0, 128.4 (strong),
137.0 (Ar). Anal. Calcd for C18H23N3O5: C, 59.82; H, 6.41; N, 11.63.
Found: C, 59.92; H, 6.51; N, 11.70.
acetate, 75:25); [
a
]
ꢁ26.44 (c 0.41, CH2Cl2); IR (neat): 1649, 1447,
1295, 1078 cmꢁ1
;
1DH NMR (CDCl3)
d 1.28 (3H, s, CH3), 1.47 (3H, s,
CH3), 2.55e2.78 (2H, m, H-7), 3.35e3.45 (2H, m, H-8), 3.85 (1H, d,
J¼3.3 Hz, H-3), 4.54 (1H, d, J¼12.3 Hz, O-CH2Ph), 4.56e4.72 (3H, m,
O-CH2Ph, H-2 and H-4), 5.75 (1H, dd, J¼16.0 and 6.4 Hz, H-5),
5.82e5.90 (1H, m, H-6), 5.95 (1H, d, J¼3.8 Hz, H-1), 7.20e7.42 (5H,
m, AreH); 13C NMR (CDCl3)
d 26.1 (CH3), 26.7 (CH3), 31.7(C7), 35.7
(C8), 72.1 (O-CH2Ph), 80.9 (C2), 82.9 (C3), 83.3 (C4), 104.7 (C1), 111.5
(isopropylidene), 126.9, 127.5, 127.8, 128.4, 132.1, 137.5 (C5, C6 and
Ar). Anal. Calcd for C18H23BrO4: C, 56.41; H, 6.05. Found: C, 56.62; H,
5.95. The same experiment was repeated twice on 1.0 g of scale to
get combined 1.96 g of product that was utilized for the subsequent
step.
4.1.4. 1,2-O-Isopropylidene-5,7,8-trideoxy-5,8-imino
(N-benzylox-
ycarbonyl)-6-(S)-hydroxy- -glycero- -ido-octafuranose (6a). A so-
b
-L
L
lution of azido epoxide 5a (0.61 g, 2.67 mmol), ammonium formate
(0.63 g, 10.13 mmol) and 10% Pd/C (120 mg) in ethanol (20 mL) was
vigorously refluxed for 26 h. The reaction mixture was filtered
through Celite and the filtrate evaporated to give viscous oil. A
solution of the above product (0.3 g, 1.22 mmol) in ethanol (10 mL)
was added aq NaHCO3 (0.51 g, 6.11 mmol in 3 mL water) followed
by addition of 50% solution of benzylchloroformate in toluene
(0.43 mL 3.06 mmol) and the reaction mixture was stirred at room
temperature for 12 h. Ethanol was evaporated under reduced
pressure and the residue was extracted with chloroform (3ꢂ10 mL).
The combined organic layer was dried over Na2SO4 and evaporated.
Purification by column chromatography using n-hexane/ethyl ac-
etate (7:3) gave 6a (0.38 g, 59% overall two steps) as a white solid;
4.1.2. 8-Azido-3-O-benzyl-1,2-O-isopropylidene-5,6,7,8-tetradeoxy-
a-D-xylo-oct-5-en-1,4-furanose (4). To a stirred solution of 3 (1.9 g,
4.97 mmol) in acetone (35 mL) was added sodium azide (1.29 g,
19.9 mmol) and the reaction mixture was refluxed. After 8 h the
solution was cooled to 25 ꢀC, acetone was removed on rotary
evaporator and the reaction mass was poured into EtOAc/H2O
(70 mL, 1:1). The organic layer was separated and aqueous phase
was extracted with ethyl acetate (3ꢂ20 mL). Usual workup and
column purification (n-hexane/ethyl acetate, 9:1) afforded 4 (1.51 g,
88%) as a thick liquid; Rf 0.54 (n-hexane/ethyl acetate, 8:2); [a]
D
ꢁ62.4 (c 1.0, CHCl3); IR (neat) 2096, 1648, 1456, 1377 cmꢁ1; 1H NMR
mp 151e153 ꢀC; Rf 0.40 (n-hexane/ethyl acetate, 2:8); [
a
]
D ꢁ67.0 (c
(CDCl3)
d
1.21 (3H, s, CH3), 1.41 (3H, s, CH3), 2.26e2.38 (2H, m, H-7),
0.4, CHCl3); IR (KBr) 3545e3140, 1692 cmꢁ1; 1H NMR (CDCl3þD2O)
3.23 (2H, t, J¼6.8 Hz, H-8), 3.58 (1H, d, J¼12.0 Hz, O-CH2Ph), 3.76
(1H, d, J¼3.0 Hz, H-3), 4.44 (1H, d, J¼12.0 Hz, O-CH2Ph), 4.50 (1H,
dd, J¼3.5 and 3.0 Hz, H-4), 4.54 (1H, d, J¼3.8 Hz, H-2), 5.66 (1H, dd,
J¼16.0 and 3.4 Hz, H-5), 5.70e5.82 (1H, m, H-6), 5.85 (1H, d,
d 1.30 (3H, s, CH3), 1.47 (3H, s, CH3), 1.78e1.98 (1H, m, H-7a),
2.16e2.38 (1H, m, H-7b), 3.51 (1H, t, J¼9.6 Hz, H-8a), 3.74 (1H, q,
J¼10.2 Hz, H-8b), 3.90e4.12 (1H, m, H-4), 4.15 (1H, d, J¼2.7 Hz, H-
3), 4.21 (1H, d, J¼5.0 Hz, H-5), 4.25e4.34 (1H, m, H-6), 4.49 (1H, d,
J¼3.6 Hz, H-2), 5.12 (2H, ABq, J¼12.4 Hz, NCO2CH2Ph), 5.88 (1H, d,
J¼3.8 Hz, H-1), 7.50e7.18 (5H, m, Ar-H); 13C NMR (CDCl3)
d 26.2
(CH3), 26.8 (CH3), 32.0 (C7), 50.5 (C8), 72.0 (O-CH2Ph), 80.9, 82.8,
83.3 (C2, C3, C4), 104.6 (C1), 111.4 (isopropylidine), 126.8, 127.4,
127.7, 128.3, 131.1, 137.4 (C5, C6 and Ar). Anal. Calcd for C18H23N3O4:
C, 62.49; H, 6.90; N, 12.29. Found: C, 62.59; H, 6.71; N, 12.17.
J¼3.6 Hz, H-1), 7.18e7.42 (5H, m, AreH); 13C NMR (CDCl3)
d 26.1
(CH3), 26.8 (CH3), 32.0 (C7), 45.4 (C8), 64.7 (C5), 67.6 (O-CH2Ph),
75.2, 75.5, 80.6, 85.0 (C2, C3, C4 and C6), 104.5 (C1), 111.3 (iso-
propylidene), 127.7 (strong), 128.0, 128.4 (strong), 136.0 (Ar), 157.5
(NC]O). Anal. Calcd for C19H25NO7: C, 60.15; H, 6.64; N, 3.69.
Found: C, 60.30; H, 6.85; N, 3.83.
4.1.3. 3-O-Benzyl-1,2-O-isopropylidene-7,8-dideoxy-8-azido-5,6-ox-
irano-b-
L
-glycero-D-gluco-oct-1,4-furanose (5a) and 3-O-benzyl-1,2-
O-isopropylidene-7,8-dideoxy-8-azido-5,6-oxirano-
a
-
D
-glycero-
L
-
4.1.5. (1S,6S,7R,8R,8aS)-1,6,7,8-Tetrahydroxy-indolizidine [(þ)-8a-
epi-castanospermine] (1c). A solution of 6a (0.12 g, 0. 31 mmol) in
TFA/H2O (8 mL, 3:2) was stirred at 0 ꢀC for 30 min and at 25 ꢀC for
5 h. TFA was co-evaporated with toluene to give viscous oil. A so-
lution of the above product and 10% Pd(OH)2/C (0.05 g) in aq
methanol (12 mL, 9:1) was hydrogenated at 90 psi for 15 h at 25 ꢀC.
The catalyst was filtered through Celite and solvent was evaporated
to afford thick liquid. Purification by column chromatography
(CH2Cl2/MeOH/25%NH4OH, 7:2:1) yielded 1c (42 mg, 76%) as
ido-oct-1,4-furanose (5b). To a solution of 4 (1.5 g, 4.34 mmol) in
dichloromethane (40 mL) was added m-chloroperbenzoic acid
(1.49 g, 8.69 mmol) at 0 ꢀC. The resulting reaction mixture was
stirred at 25 ꢀC for 24 h. To the reaction mixture H2O (30 mL) was
added and the aqueous phase was extracted with dichloromethane
(3ꢂ15 mL). The combined organic phase was washed with 2 N
NaOH (2ꢂ10 mL) and worked up to afford a diastereomeric mixture
of epoxides 5a/5b. Purification by column chromatography and
elution with n-hexane/ethyl acetate (97:3) afforded 5a (0.86 g, 55%)
a thick liquid; Rf 0.40 (MeOH/CH2Cl2/NH4OH, 5:3:2); [
a
]
þ27 (c
D
20
as a thick liquid; Rf 0.53 (n-hexane/ethyl acetate, 8:2); [
1.0, CH2Cl2); IR (neat): 2100, 1549, 1455, 1374 and 1077 cmꢁ1
NMR (300 MHz, CDCl3) 1.39 (3H, s, CH3), 1.49 (3H, s, CH3),
a
]
D ꢁ53.1 (c
0.4, MeOH), [lit17r
[a
]
þ28 (c 0.3, MeOH); [lit17p for the antipode
D
25
;
1H
[a
]
ꢁ33 (c 0.31, MeOH)]; IR (neat) 3600e3200 cmꢁ1
;
1H NMR
D
d
(D2O) d 1.62e1.78 (1H, m, H-2a), 2.22e2.40 (1H, m, H-2b), 2.53 (1H,
1.60e1.90 (1H, m, H-7a),1.93e2.20 (1H, m, H-7b), 3.10e3.30 (2H, m,
H-5 and H-6), 3.50 (2H, t, J¼6.8 Hz, H-8), 3.90 (1H, dd, J¼6.5 and
3.3 Hz, H-4), 4.12 (1H, d, J¼3.3 Hz, H-3), 4.68 (1H, d, J¼3.5 Hz, H-2),
4.74 (2H, ABq, J¼11.8 Hz, O-CH2Ph), 5.98 (1H, d, J¼3.5 Hz, H-1),
dd, J¼7.8 and 1.9 Hz, H-8a), 2.59e2.78 (2H, m, H-3a and H-5a),
2.92e3.12 (2H, m, H-3b and H-5b), 3.82e3.92 (1H, m, H-6), 3.98
(1H, t, J¼7.4 and 3.8 Hz, H-7), 3.99e4.08 (1H, m, H-8), 4.42 (1H, dt,
J¼8.0 and 4.1 Hz, H-1); 13C NMR (D2O)
d 32.5 (C2), 54.3 (C3), 56.0
7.25e7.56 (5H, m, AreH); 13C NMR (CDCl3)
d
26.3 (CH3), 26.8 (CH3),
(C5), 70.3, 70.6, 71.1, 71.3, 71.5 (C1, C6, C7, C8 and C8a). The spectral
data were found to be matching with that reported.17p Anal. Calcd
for C8H15NO4 C, 50.78; H, 7.99; N, 7.40. Found: C, 50.81; H, 8.11.
N, 7.51.
31.3 (C7), 48.2 (C8), 54.3, 55.7 (C5 and C6), 72.3 (O-CH2Ph), 80.9,
82.0, 82.5 (C2, C3 and C4), 105.3 (C1), 111.9 (isopropylidene), 127.5
(strong), 127.9, 128.4 (strong), 137.2 (Ar). Anal. Calcd for
C18H23N3O5: C, 59.82; H, 6.41; N, 11.63. Found: C, 60.01; H, 6.38; N,
11.78. Further elution with n-hexane/ethyl acetate (96:4) afforded
4.1.6. 1,2-O-Isopropylidene-5,7,8-trideoxy-5,8-imino-(N-benzylox-
5b (0.31 g, 20%) as a thick liquid; Rf 0.50 (n-hexane/ethyl acetate,
ycarbonyl)-6-(R)-hydroxy-a-D-glycero-D-gluco-octafuranose
(6b). The reaction of epoxide 5b (0.21 g, 0.58 mmol) with ammo-
nium formate (0.22 g, 3.5 mmol) and 10% Pd/C (0.05 g) in ethanol at
25
8:2); [
a
]
D
ꢁ45.1 (c 0.9, CH2Cl2); IR (neat): 2099, 1550, 1455, 1374
and 1078 cmꢁ1; 1H NMR (CDCl3)
d
1.36 (3H, s, CH3),1.43 (3H, s, CH3),

N.B. Kalamkar et al. / Tetrahedron 67 (2011) 2773e2778
2777
reflux temperature (3 mL) and further reaction of resulted crude
amino alcohol (0.082 g, 0.33 mmol) with aq sodium bicarbonate
(0.14 g, 1.67 mmol in 2 mL water) and 50% solution of benzyl-
chloroformate in toluene (0.12 mL, 0.83 mmol), was performed
under similar reaction conditions as described for 6a, and purifi-
cation by column chromatography (n-hexane/ethyl acetate, 3:2)
afforded 6b (0.12 g, 55%, overall two steps) as a viscous oil; Rf 0.50
confirmed by COSY and HETCOR experiments (spectra are given
Supplementary data). Anal. Calcd for C19H25NO7: C, 60.15; H, 6.64;
N, 3.69. Found C, 59.95; H, 6.67; N, 3.75.
4.2. Crystal data for 7
Single crystals of the compound 7 were grown by slow evapo-
ration of the solution mixture of methanol: water (9:1). Needles of
approximate 0.46ꢂ0.18ꢂ0.09 mm3, was used for data collection on
(n-hexane/ethyl acetate, 2:8); [
a
]
ꢁ42.2 (c 0.5, CHCl3); IR (neat)
D
3552e3135, 1688 cmꢁ1
;
1H NMR (CDCl3þD2O)
d 1.31 (3H, s, CH3),
1.46 (3H, s, CH3), 1.90e2.20 (2H, m, H-7), 3.48 (1H, dt, J¼8.8 and
2.2 Hz, H-8a), 3.65 (1H, dd, J¼10.45 and 1.92 Hz, H-4), 3.68 (1H, m,
H-8b), 3.98 (1H, d, J¼10.45 Hz, H-5), 4.15 (1H, d, J¼1.92 Hz, H-3),
4.48 (1H, d, J¼3.6 Hz, H-2), 4.61 (1H, d, J¼2.7 Hz, H-6), 5.13 (2H, q,
J¼12.4 Hz, NCO2CH2Ph), 5.92 (1H, d, J¼3.6 Hz, H-1), 7.21e7.41 (5H,
Bruker SMART APEX CCD diffractometer using Mo Ka radiation with
fine focus tube with 50 kV and 30 mA. Crystal to detector distances
6.05 cm, 512ꢂ512 pixels/frame, hemisphere data acquisition. Total
scansh3, total framesh1271, oscillation/frame ꢁ0.3ꢀ, exposure/
frameh7.0 s/frame, maximum detector swing anglehꢁ30.0ꢀ,
beam centerh(260.2, 252.5), in plane spot widthh1.24, SAINT in-
m, AreH); 13C NMR (CDCl3)
d 26.0 (CH3), 26.9 (CH3), 31.1 (C7), 45.3
tegration, q q
rangeh1.58e24.99ꢀ, completeness to of 25.0ꢀ is 100%.
(C8), 64.2 (C5), 67.8 (NCO2CH2Ph), 73.1, 73.8, 81.0, 84.5 (C2, C3, C4
and C6), 104.7 (C1), 111.4 (isopropylidene), 127.8 (strong), 128.1,
128.4 (strong), 135.8 (Ar), 157.1 (NC]O). Anal. Calcd for
C19H25NO7: C, 60.15; H, 6.64; N, 3.69. Found: C, 60.22; H, 6.78;
N, 3.74.
SADABS correction applied, C19H25NO7, Mh379.40. Crystals be-
ꢀ
longs to Orthorhombic, space group P212121, ah12.3002(6) A,
3
ꢀ
ꢀ
ꢀ
bh12.6031(7) A, ch25.807(1) A, Vh4000.7(4) A , Zh8,
Dch1.260 g/cc,
(Mo Ka)h0.096 mmꢁ1, Th296(2) K, 20,322 re-
flections measured, 6997 unique [I>2 (I)], value 0.0493,
m
s
R
4.1.7. (1R,6S,7R,8R,8aR)-1,6,7,8-Tetrahydroxyindolizidine [(þ)-1-epi-
castanospermine] (1b). Reaction of 6b (0.95 g, 0.25 mmol) with
TFA/H2O (3:2, 4 mL) followed by hydrogenation with 10% Pd(OH)2/
C (50 mg) in aq methanol (10 mL, 9:1) as described for 1c and
column chromatography purification using CH2Cl2/MeOH/25%
wR2h0.0957. All the data were corrected for Lorentzian, polariza-
tion and absorption effects. SHELX-97 (ShelxTL)27 was used for
structure solution and full matrix least squares refinement on F2.
There were two molecules in the asymmetric unit. Hydrogen atoms
were included in the refinement as per the riding model. Data
collection and refinement parameters are listed in Table 1 (see,
Supplementary data). X-ray analysis revealed the conformation of
the molecule and shows that C1, C2, C3, C4, C5 and C6 have R, R, S, R,
S and R configurations, respectively.
NH4OH (4:1:0.2) afforded 1b (35 mg, 74% overall) as a thick liquid;
22
Rf 0.50 (methanol/CH2Cl2, 8:2); [
a
]
D þ8.4 (c 0.21, MeOH), [lit17o
[a]
D
þ3.8 (c 0.54, MeOH)]; IR (neat) 3600e3210 cmꢁ1
;
1H NMR (D2O)
d
1.72e1.88 (1H, m, H-2a), 2.37 (1H, ddd, J¼14.0, 9.0 and 3.5 Hz, H-
2b), 2.42e2.58 (2H, m, H-3a and H-5a), 2.87 (1H, q, J¼18.5 and
9.0 Hz, H-8a), 3.09 (1H, ddd, J¼10.0 and 2.5 Hz, H-3b), 3.28 (1H, dd,
J¼11.5 and 5.2 Hz, H-5b), 3.33e3.50 (2H, m, J¼15.4 and 9.0 Hz, H-8
and H-7), 3.62e3.78 (1H, m, H-6), 4.34 (1H, ddd, J¼8.5, 5.5 and
Acknowledgements
We are grateful to Prof. M.S. Wadia for helpful discussions. We
are thankful to the Council of Scientific and Industrial Research,
New Delhi for financial support (CSIR-01(2343)/09/EMR-II) and for
Senior Research Fellowship (SRF) to N.B.K.
3.3 Hz, H-1); 13C NMR (D2O)
d 32.1 (C2), 51.0 (C3), 53.8 (C5), 69.0
(C8a), 72.1, 72.5, 73.2, 78.0 (C1, C6, C7 and C8). The spectral data was
found to be matching with that reported.17m Anal. Calcd for
C8H15NO4 C, 50.78; H, 7.99; N, 7.40. Found: C, 50.87; H, 8.19. N, 7.55.
Supplementary data
4.1.8. 3-O-Benzyl-(8-N,6-O-carbonyl)-7,8-dideoxy-1,2-O-iso-
Copies of 1H and 13C NMR spectra of compounds 3, 4, 5a,b, 6a,b,
7, 1b,c and copies of 2D NMR (COSY, HMBC and HSQC) spectra
and X-ray crystal data of 7. Supplementary data associated with
this article can be found in online version at doi:10.1016/
j.tet.2011.02.030. These data include MOL files and InChIKeys of the
most important compounds described in this article.
propylidene-a-D-glycero-D-gluco-octafuranose (7). To a solution of
5a (0.12 g, 0.33 mmol) in THF/water (9:1, 8 mL) was added tri-
phenyl phosphine (0.13 g, 0.5 mmol) and reaction mixture was
stirred at room temperature for 15 h. To an ice cold solution of
above product was added aq sodium bicarbonate solution (0.14 g,
1.66 mmol in 3 mL water) followed by 50% solution of benzyl-
chloroformate in toluene (0.11 mL, 3.92 mmol) and the resulting
reaction mixture was stirred at 30 ꢀC for 15 h. Solvent was removed
under reduced pressure and the residue was extracted with ethyl
acetate (3ꢂ10 mL). Usual workup and column purification using n-
hexane/ethyl acetate (1:1) as an eluent gave 7 (0.087 g, 70%) as
References and notes
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a white solid; mp 178e181 ꢀC; Rf 0.40 (ethyl acetate); [
1.3, CHCl3); IR (Nujol): 2922, 1687, 1462 and 1376 cmꢁ1
1.30 (3H, s, CH3), 1.46 (3H, s, CH3), 1.85e2.20 (2H, m,
a
]
D ꢁ54.0 (c
;
1H NMR
(CDCl3þD2O)
d
H-7), 3.22e3.47 (2H, m, H-8), 4.07e4.18 (2H, m, H-3 and H-5), 4.30
(1H, dd, J¼8.0 and 3.6 Hz, H-4), 4.33e4.42 (1H, m, H-6), 4.58 (1H, d,
J¼12.0 Hz, O-CH2Ph), 4.61 (1H, d, J¼3.6 Hz, H-2), 4.70 (1H, d,
J¼12.0 Hz, O-CH2Ph), 5.92 (1H, d, J¼3.6 Hz, H-1), 7.21e7.43 (5H, m,
AreH); 13C NMR (100 MHz, CDCl3)
d 19.6 (C7), 26.3 (CH3), 27.0
(CH3), 38.6 (C8), 67.9 (C5), 72.6 (O-CH2Ph), 78.94, 78.97 (C4 and C6),
81.7 (C3), 82.2 (C2), 105.3 (C1), 111.9 (isopropylidene), 127.9
(strong), 128.1, 128.6 (strong), 137.4 (Ar), 155.1 (NC]O). Previously
when 13C NMR of 7 was recorded on 75 MHz machine frequency,
only one signal at
d
¼78.8 was observed, however when it was
recorded on 100 MHz machine frequency showed two signals (very
close) at
d
¼78.94 and 78.97. Assignment of 1H and 13C signals was

2778
N.B. Kalamkar et al. / Tetrahedron 67 (2011) 2773e2778
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d
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19. Use of the Grubb’s first-generation catalyst in this reaction afforded compound
3 in 57e60% yield with >98% E-selectivity (as evident from the 1H NMR of
a crude product). The results were found in accord with our earlier studies on
the cross metathesis reaction on analogous substrate, see: Chaudhari, V. D.;
Ajish Kumar, K. S.; Dhavale, D. D. Org. Lett. 2005, 7, 5805.
20. For reduction of epoxyazide to -amine and intramolecular cyclization via endo-
tet mode under Staudinger conditions followed by N-protection see, Ref. 8c,e.
21. Crystallographic data for compound 7 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC-804510.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK. Fax: þ44 1223 336033. E-mail: deposit@
ccdc.cam.ac.uk. The formation of 7 was further supported by 2D NMR (COSY
and HETCOR) techniques.
22. The column purification of epoxyamine X led to the mixture of products and
hence it was directly reacted further with benzylchloroformate.
23. The diastereoselectivity in the epoxidation reaction to get 5a as the major
product could be explained by the preferred hydrogen bonding of m-CPBA with
the
the
b
a
-oriented C3eOBn oxygen; while the hydrogen bonding of m-CPBA with
-oriented furanose-ring oxygen, which is sterically compressed due to
-epoxide 5b as a minor product.
13. Tyler, P. C.; Winchester, B. G. Synthesis and Biological Activity of Castano-
spermine and Close Analogs In Iminosugars as Glycosidase Inhibitors; Stutz, A. E.,
Ed.; Wiley-VCH: Weinheim, 1999; pp 125e156.
14. (a) Taylor, D. L.; Sunkara, P. S.; Liu, P. S.; Kang, M. S.; Bowlin, T. L.; Tyms, A. S.
AIDS 1991, 5, 693; (b) Willenborg, D. O.; Parish, C. R.; Cowden, W. B. Immunol.
Cell Biol. 1992, 70, 369.
C3eOBn group, affords
a
24. The hydrogenation of epoxyazide 5a with 10% Pd/C or Pd(OH)2 under variety of
pressure and temperature conditions afforded complex mixture of products.
25. For exclusive 5-endo-tet cyclization at high temperature conditions, see: (a)
Medjahdi, M.; Gonzalez-Gomez, J. C.; Foubelo, F.; Yus, M. J. Org. Chem. 2009,
74, 7859; (b) Kang, B.; Chang, S.; Decker, S.; Britton, R. Org. Lett. 2010, 12,
15. Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phyto-
chemistry 2001, 56, 265.
1716 For
a theoretical investigation on the 5-endo-tet cyclization, see:
16. For reviews on the synthesis and biological investigations of natural/unnatural
analogues of castanospermine see, (a) Furneaux, R. H.; Gainsford, G. J.; Mason,
J. M.; Tyler, P. C. Tetrahedron 1995, 51, 12611; (b) Furneaux, R. H.; Gainsford, G. J.;
Mason, J. M.; Tyler, P. C. Tetrahedron 1997, 53, 245; (c) Michael, J. P. Nat. Prod.
Rep. 2005, 22, 603; (d) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139; (e) Pandey, G.;
Dumbre, S. G.; Pal, S.; Khan, M. I.; Shabab, M. Tetrahedron 2007, 63, 4756.
(f) Coxon, J. M.; Morokuma, K.; Thorpe, A. J.; Whalen, D. J. Org. Chem. 1998,
63, 3875.
26. For 1,2 acetonide hydrolysis and reductive cyclization, see our recent reports;
Ref. 9
27. Sheldrick, G. M. SHELX-97 Program for Crystal Structure Solution and Refinement;
University of Gottingen: Germany, 1997.