Synthesis of (+)-1-epi-castanospermine from l-sorbose

Article abstract of DOI:10.1016/j.tet.2008.06.021

Diastereoselective synthesis of 1-epi-castanospermine (2) from l-sorbose is described. The successful approach involved the use of 8-azido-2,8-dideoxy-α-l-gulo-oct-4-ulo-4,7-furanosononitrile intermediate (17). This compound was easily made in five steps

Full text of DOI:10.1016/j.tet.2008.06.021

Tetrahedron 64 (2008) 7910–7913
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of (þ)-1-epi-castanospermine from
Isidoro Izquierdo , Juan A. Tamayo , Miguel Rodrıguez, Francisco Franco, Daniele Lo Re
L
-sorbose
*
*
´
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 May 2008
Received in revised form 4 June 2008
Accepted 6 June 2008
Available online 10 June 2008
Diastereoselective synthesis of 1-epi-castanospermine (2) from L-sorbose is described. The successful
approach involved the use of 8-azido-2,8-dideoxy-
(17). This compound was easily made in five steps from 3-O-benzoyl-2-deoxy-4,5:6,8-di-O-iso-
propylidene- -gulo-oct-4-ulo-4,7-furanosononitrile (7) previously synthesized from -sorbose. Cata-
a-L-gulo-oct-4-ulo-4,7-furanosononitrile intermediate
a
-L
L
lytic hydrogenation of the azido intermediate 17 with Pd–C afforded with total stereocontrol one of the
two possible piperidine diastereomers. Acid-catalyzed internal reductive deamination of the nitrile de-
rivative completed the total synthesis of (1R,6S,7R,8R,8aR)-1,6,7,8-tetrahydroxyindolizidine [(þ)-1-epi-
castanospermine, 2].
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
castanospermine by means of the key intermediate 5, readily
obtained from commercially and cheap L-sorbose.
Polyhydroxyindolizidines are a widespread variety of alkaloids
well known for their glycosidase inhibitory activity.1 One of the
most representative examples is castanospermine (1), first iso-
lated2 from the seeds of the Australian legume Castanospermum
australe. This and other closely related compounds (Fig. 1), as is the
case of 1-epi-castanospermine (2), have been extensively studied as
potential therapeutic agents against diabetes,3 cancer4 and viral
infections such as HIV.5
2. Results and discussion
The previously described9 3-O-benzoyl-4-octulosononitrile 7,
obtained from -sorbose in four steps, was initially deacetonated
L
with 50% aqueous AcOH to afford diol 8, a candidate of choice for
the introduction at C-8 of the masked amino group. With this aim,
regioselective tosylation of the primary alcohol gave 9 in good yield
(see Scheme 2). Regrettably, attempt to introduce the azido moiety
with LiN3 was unsuccessful, leading only to substrate
decomposition.
For these reasons, many synthetic methodologies6 have been
explored in order to set up chemical libraries of these and related
isomers for biological and structure–activity studies.
Particularly, in the case of 1-epi-castanospermine (2), several
syntheses7 have been published to date, many of them based on
sugar chemistry. As part of our previous work, we reported8 on the
synthesis of several polyhydroxyindolizidines based on 4-octulose
intermediates readily available from commercial sugars. Retro-
synthetic analysis of 1-epi-castanospermine (2) (see Scheme 1)
shows that this molecule can be synthesized by appropriate chain
extension and functional group modification of a partially pro-
Based on this negative result a different approach was tried. Diol
8 was transformed into mono-iodo derivative 10 under Garegg’s
conditions (13C NMR evidence); unfortunately, nucleophilic dis-
placement on 10 using LiN3 yielded an inseparable mixture of the
substitution (11) and elimination (12) products (see Scheme 3).
OH
OH
OH
OH
H
H
tected aldehyde 6, obtained in two steps from L-sorbose.
HO
HO
HO
HO
1
According to the synthetic strategy, the presence of a masked
amino group at C-8 in intermediate 5 makes this compound a good
substrate for a one-step double cyclization synthesis of 2, after
removal of the suitable protecting groups. Hence, in this work we
want to communicate the stereoselective synthesis of (þ)-1-epi-
N
N
1
2
OH
OH
OH
OH
H
H
HO
HO
HO
HO
N
N
3
4
* Corresponding authors. Tel.: þ34 958 249583; fax: þ34 958 243845 (I.I.); tel.:
þ34 958 243846 (J.A.T.).
Figure 1. Structure of natural (þ)-castanospermine (1) and some of its isomers: 1-epi-
castanospermine (2), 6-epi-castanospermine (3) and 6,7-di-epi-castanospermine (4).
E-mail addresses: isidoro@ugr.es (I. Izquierdo), jtamayo@ugr.es (J.A. Tamayo).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.021

I. Izquierdo et al. / Tetrahedron 64 (2008) 7910–7913
7911
HO
O
CMe2
CN
OH
a
c
O
OP
OP
O
9
H
HO
N
O
CN
R
8
OH
N3
OH
OP
15 R = OTs
13 R = N3
HO
OH
b
2
5
O
CMe2
CHO
O
O
OH OH
N
OH
OH
L-Sorbose
d
HO
HO
CN
O
O
Me2C
O
CN
6
N3
OH
17
OH
Scheme 1. Retrosynthetic analysis of 1-epi-castanospermine (2).
A
d
O
CMe2
CN
OBz
O
O
OH
OH OH
H
O
OH
NH
4 steps
(ref. 9)
a
H
L-Sorbose
HO
HO
HO
HO
CN
e
O
O
N
NH
Me2C
7
B
18
O
e
CMe2
CN
CMe2
O
O
O
O
b
c
decom-
position
CN
(+)-2
HO
TsO
OH
OH
OBz
OBz
Scheme 4. Synthesis of (þ)-1-epi-castanospermine (2). Reagents and conditions: (a)
MeONa–MeOH, 0 ꢀC, 60%; (b) LiN3–anhyd DMF, 90 ꢀC, quantitative; (c) 50% aqueous
TFA, rt, 75%; (d) H2, 10% Pd–C, MeOH, 70 psi, rt; (e) H2, 10% Pd–C, AcOH–AcONa–H2O
(pH¼3.9), 70 psi, rt (two steps 25%).
8
9
Scheme 2. Synthesis of tosylate 9 from nitrile 7. Reagents and conditions: (a) 50%
aqueous AcOH, 50 ꢀC, 92%; (b) TsCl–TEA–DMAP (cat.)–CH2Cl2, rt, 91%; (c) LiN3–anhyd
DMF, 60 ꢀC.
cyano group in 18 eventually led to the indolizidine ring of 2 by
reductive deamination of intermediate B.
O
CMe2
CN
OBz
O
a
b
The configuration at the new C-8a stereogenic centre in the
indolizidine ring may be rationalized on the basis of a preferential
attack of hydrogen from the less hindered face of the planar imine
intermediate A (see Fig. 2). As expected, only the R epimer was
isolated after catalytic hydrogenation of 17, in agreement with
previous results reported by us8a,b and other authors.10
O
8
I
OH
10
O
O
O
CMe2
CMe2
CN
OH
O
O
O
From the coupling constants of H-6,7,8 and 8a
(J6,7¼J7,8¼J8,8a¼9.0 Hz) in the 1H NMR spectrum of 2, it can be de-
duced that the six-membered ring adopts a chair-like conformation
(8C5). The hydroxyl groups at C-6,7 and 8 are displayed in equatorial
positions and the piperidinic ring is trans-fused with the five-
membered ring (see Fig. 3). This result is in agreement with those
reported by Mulzer et al.7f for the tetrabenzylated derivative of 2.
O
O
CN
N3
N3
OH
OH
13
OBz
11
c
+
+
O
CMe2
CMe2
O
O
O
CN
CN
N3
N3
OH
14
OH
OMe
12
3. Conclusions
Scheme 3. Unsuccessful route to azide 13. Reagents and conditions: (a) I2–Ph3P–im-
In conclusion, 4-octulosononitrile derivative 8 was shown to be
a good precursor for the stereoselective synthesis of (þ)-1-epi-
castanospermine (2), which was achieved in 11 synthetic steps
idazole, PhCH3, 100 ꢀC, 85%; (b) LiN3–anhyd DMF, 60 ꢀC; (c) MeONa–MeOH, rt.
Subsequent Zemplen’s debenzoylation of this mixture afforded the
desired 13 together with compound 14, resulting from the Michael
from
L-sorbose. The key reaction in this sequence was the catalytic
addition of MeOH to the a,b-unsaturated nitrile 12. Compounds 13
and 14 could be finally separated by column chromatography and
13 was fully characterized.
OH
HO
OH
HO
Due to the low yield obtained in the synthesis of 13, an alter-
native route was sought where OH at C-3 is unprotected (see
Scheme 4). Thus, tosylate 9 was debenzoylated under Zemplen
conditions to afford diol 15 without production of elimination by-
products. Satisfactorily, reaction of LiN3 with 15 afforded 13 in
quantitative yield. Deacetonation of 13 with 50% aqueous TFA
N
H
CN
H
re
si
H
afforded the totally deprotected 8-azido-2,8-dideoxy-a-L-gulo-oct-
4-ulo-4,7-furanosononitrile (17).
H
OH
R
N
H
HO
HO
Compound 17 was subjected to catalytic hydrogenation (H2–Pd–
C–MeOH) to afford, after 18 h, a single compound that showed
lower Rf by TLC, presumably the piperidine intermediate 18. Sub-
sequent acid-catalyzed (AcOH–AcONa–H2O, pH¼3.9) internal nu-
cleophilic addition of the piperidine nitrogen to the protonated
H
H
R = -CHOHCH2CN
Figure 2. Proposed si-face hydrogen approach for the reduction of intermediate A.

7912
I. Izquierdo et al. / Tetrahedron 64 (2008) 7910–7913
H8
7.61 (t, 1Hpara, Bz), 7.46 (t, 2Hortho, Bz), 7.38 (d, 2Hmeta, Bz), 5.60
J
6,7 = J7,8 = J8,8a = 9.0 Hz
H
6N
0
(dd, 1H, J2,3¼5.6 Hz, J2 ,3¼6.4 Hz, H-3), 4.51 (dt, 1H, J6,7¼2.8 Hz,
HO
HO
J
5α,6 = 10.6 Hz
5β,6 = 5.3 Hz
H5β
H5α
0
J7,8¼J7,8 ¼6.4 Hz, H-7), 4.38 (s, 1H, H-5), 4.30 (dd, 1H, H-8), 4.33 (d,
OH
H8a
J
H7
0
1H, H-6), 4.15 (dd, 1H, J8,8 ¼10.4 Hz, H-8), 2.95 (d, 1H, H-2), 2.94 (d,
1H, H-20), 2.47 (s, 3H, Me Ts), 1.35 and 1.49 (2s, 6H, CMe2). 13C NMR:
Figure 3. Chair-like spatial disposition of the piperidinic ring of (þ)-1-epi-castano-
spermine (2).
d
165.7 (PhCO), 145.6, 134.8, 134.2, 132.7, 130.2, 128.8, 28.5, 128.4,
128.3 (PhCO and Ts), 116.7 (C-1), 113.9 and 113.3 (C-4, CMe2), 85.0
and 74.2 (C-5,6), 79.9 (C-7), 68.9 (C-3), 66.8 (C-8), 27.7 and 26.8
(CMe2), 21.9 (Me Ts) and 18.8 (C-2). HRMS (LSIMS): m/z 540.1304
[MþþNa]. For C25H27O9NSNa 540.1299 (deviation ꢁ0.9 ppm).
reductive amination of azide 17 to afford diastereoselectively
a single piperidine intermediate 18. We come to show here the
versatility of such octulosononitrile derivatives in the stereo-
selective synthesis of polyhydroxyindolizidine alkaloids.
4.1.3. 3-O-Benzoyl-2,8-dideoxy-8-iodo-4,5-O-isopropylidene-a-L-
gulo-oct-4-ulo-4,7-furanosononitrile (10)
4. Experimental
4.1. General
To a solution of I2 (1.22 g, 4.8 mmol), PPh3 (1.26 g, 4.8 mmol) and
imidazole (0.60 g, 8.8 mmol) in toluene (15 mL) was added a solu-
tion of 8 (1.45 g, 4 mmol) in toluene (10 mL). The reaction mixture
was stirred at 100 ꢀC for 2 h. TLC (ether) revealed the absence of the
starting material and the presence of a new product of higher Rf.
The mixture was concentrated, the residue dissolved in CH2Cl2
(15 mL) and washed with 10% aqueous Na2S2O3 and water. The
solvent was evaporated and the residue chromatographed (ether–
Solutions were dried over MgSO4 before concentration under
reduced pressure. The 1H and 13C NMR spectra were recorded with
Bruker AMX-300, AM-300, ARX-400 and AMX-500 spectrometers
for solutions in CDCl3 (internal Me4Si). Splitting patterns are des-
ignated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet; m, multiplet and br, broad. IR spectra were recorded with
a Perkin–Elmer FT-IR Spectrum One instrument and mass spectra
were recorded with a Hewlett–Packard HP-5988-A and Fisons mod.
Platform II and VG Autospec-Q mass spectrometers. Optical rota-
tions were measured, unless otherwise stated, for solutions in
CHCl3 (1-dm tube) with a Jasco DIP-370 polarimeter. TLC was per-
formed on precoated silica gel 60 F254 aluminium sheets and
detected by employing a mixture of 10% ammonium molybdate (w/
v) in 10% aqueous sulfuric acid containing 0.8% cerium sulfate (w/v)
and heating. Column chromatography was performed on silica gel
(Merck, 7734). The non-crystalline compounds were shown to be
homogeneous by chromatographic methods and characterized by
NMR and HRMS (LSIMS).
hexane, 1:1) to give 10 (1.6 g, 85%) as a colourless syrup. Rf¼0.33
28
(ether–hexane, 3:2). [
a
]
D
þ31 (c 0.34). IR: nmax/cmꢁ1 3425 (OH),
2257 (CN) and 1729 (C]O). 1H NMR (400 MHz):
d 8.08 (d, 2Hortho,
Bz), 7.60 (t, 1Hpara, Bz), 7.50 (t, 2Hmeta, Bz), 5.58 (dd, 1H,
0
J2,3¼4.8 Hz, J2 ,3¼7.2 Hz, H-3), 4.57 (m, 1H, H-7), 4.44 (s, 1H, H-5),
4.24 (s, 1H, H-6), 3.34–3.26 (m, 2H, H-8,80), 3.07 (dd, 1H,
0
0
J2,2 ¼17.2 Hz, H-2), 3.01 (dd, 1H, H-2 ), 1.53 and 1.36 (2s, 6H, CMe2).
13C NMR:
d
165.8 (PhCO), 134.2, 130.3, 128.9 and 128.8 (PhCO), 116.9
(C-1), 113.8 and 113.8 (C-4, CMe2), 85.2 and 74.6 (C-5,6), 83.0 (C-7),
69.1 (C-3), 27.8 and 26.9 (CMe2), 19.0 (C-2) and 1.0 (C-8). HRMS
(LSIMS): m/z 458.0107 [MþꢁMe]. For C17H17O6NI 458.0101 (de-
viation ꢁ1.3 ppm).
4.1.4. Reaction of 10 with LiN3
To a solution of 10 (300 mg, 0.63 mmol) in anhydrous DMF
(3 mL) was added LiN3 (62 mg, 1.26 mmol) and the reaction mix-
ture stirred for 3 h at 50 ꢀC. TLC (ether–hexane, 2:3) revealed the
presence of a new product of slightly lower Rf. The mixture was
concentrated to a residue that was chromatographed in ether
yielding an inseparable mixture of 11 and 12 (88 mg).
This mixture was dissolved in anhydrous MeOH (5 mL) and 2 M
MeONa (0.2 mL) was added. After stirring at rt for 18 h, TLC (ether–
hexane, 3:1) revealed the presence of two new compounds of lower
Rf. This mixture was neutralized by addition of AcOH and evapo-
rated to a residue that was chromatographed (ether–hexane, 2:3/
3:1) to yield two compounds.
4.1.1. 3-O-Benzoyl-2-deoxy-4,5-O-isopropylidene-a-L-gulo-oct-4-
ulo-4,7-furanosononitrile (8)
A stirred solution of compound 79 (3.5 g, 8.6 mmol) in 50%
aqueous acetic acid (25 mL) was heated to 50 ꢀC for 4 h. TLC (ether)
revealed the absence of 7 and the presence of a lower Rf compound.
The mixture was concentrated and repeatedly codistilled with
water and toluene. Column chromatography of the residue (ether–
hexane, 3:2/ether) gave 8 (2.87 g, 92%) as a white foam. Rf¼0.52
24
(ether). [
a
]
þ13 (c 1.5). IR: nmax/cmꢁ1 3453 (OH), 3066 (aromatic),
D
2257 (CN) and 1728 (C]O). 1H NMR (400 MHz):
d 8.10 (d, 2Hortho,
Bz), 7.61 (t, 1Hpara, Bz), 7.47 (t, 2Hmeta, Bz), 5.64 (t, 1H,
0
J2,3¼J2 ,3¼5.2 Hz, H-3), 4.40 (m, 2H, H-5,6), 4.33 (br s, 1H, H-7), 4.13
Firstly was eluted compound 13 (33 mg). Rf¼0.38 (ether–hex-
27
þ27 (c 1.3, MeOH). IR: nmax/cmꢁ1 3492 and 3420
0
(br dd, 1H, J7,80 ¼2.8 Hz, J8,8 ¼12.8 Hz, H-8), 4.04 (br dd, 1H,
ane, 3:1). [
a
]
D
J7,8 ¼2.8 Hz, H-8 ), 3.12 (dd, 1H, J2,2 ¼17.2 Hz, H-2), 3.03 (dd, 1H, H-
(OH), 2261 (CN) and 2101 (N3). 1H NMR (400 MHz, MeOH-d4):
0
0
20), 1.39 and 1.51 (2s, 6H, CMe2). 13C NMR:
d
165.56 (PhCO), 134.3,
d
4.84 (s, 1H, H-5), 4.35 (m, 1H, H-7), 4.11 (d, 1H, J6,7¼2.5 Hz, H-6),
0
130.3, 130.2 and 128.9 (PhCO), 117.7 (C-1), 113.5 and 113.3 (C-4,
CMe2), 85.9 and 77.0 (C-5,6), 80.9 (C-7), 69.9 (C-3), 61.2 (C-8), 26.9
and 27.8 (CMe2) and 19.2 (C-2). HRMS (LSIMS): m/z 386.1219
[MþþNa]. For C18H21O7NNa 386.1215 (deviation ꢁ0.9 ppm).
3.99 (dd, 1H, J2,3¼3.1 Hz, J2 ,3¼9.4 Hz, H-3), 3.51 (dd, 1H,
0
0
0
J8,8 ¼12.9 Hz, J7,8¼7.4 Hz, H-8), 3.42 (dd, 1H,0J7,8 ¼5.1 Hz, H-8 ), 2.87
0
(dd, 1H, J2,2 ¼17.2 Hz, H-2), 2.65 (dd, 1H, H-2 ), 1.38 and 1.47 (2s, 6H,
CMe2). 13C NMR:
d 118.6 (C-1), 114.9 and 112.9 (C-4, CMe2), 85.5 and
74.2 (C-5,6), 81.1 (C-7), 68.3 (C-3), 49.7 (C-8), 26.8 and 25.8 (CMe2)
4.1.2. 3-O-Benzoyl-2-deoxy-4,5-O-isopropylidene-8-O-p-
toluenesulfonyl-
and 20.1 (C-2). HRMS (LSIMS): m/z 269.0886 [MþꢁMe]. For
a-L
-gulo-oct-4-ulo-4,7-furanosononitrile (9)
C
10H13O5N4 269.0886 (deviation 0.0 ppm).
25
To a stirred solution of 8 (2.1 g, 5.75 mmol) in anhydrous CH2Cl2
(20 mL) were added Et3N (2 mL, 14.4 mmol), DMAP (50 mg) and
TsCl (1.32 g, 6.9 mmol). The reaction mixture was stirred at rt for
1.5 h. TLC (ether) showed the presence of a faster moving com-
pound. The mixture was concentrated and chromatographed
Secondly was eluted compound 14 (20 mg). [
a]
þ19 (c 2). IR:
D
nmax/cmꢁ1 3451 (OH), 2252 (CN) and 2105 (N3). 1H NMR (400 MHz):
d
4.42 (s, 1H, H-5), 4.34–4.30 (m, 1H, H-7), 4.08 (br d, 1H,
J6,OH¼9.4 Hz, H-6), 3.68 (s, 3H, OMe), 3.68 (dd, 1H, H-3), 3.51 (d0d,
0
0
1H, J8,8 ¼18.9 Hz, J7,8¼7.1 Hz, H-8), 3.46 (dd, 1H, J7,8 ¼5.9 Hz, H-8 ),
0
(ether–hexane, 1:1) to give 9 (2.7 g, 91%) as a white foam. Rf¼0.89
3.29 (d, 1H, OH), 2.86 (dd, 1H, J2,2 ¼17.4 Hz, J2,3¼3.5 Hz, H-2), 2.75
23
þ7 (c 1). IR: nmax/cmꢁ1 3502 (OH), 2257 (CN) and 1730
(dd, 1H, J2 ,3¼8.0 Hz, H-20), 1.51 and 1.38 (2s, 6H, CMe2). 13C NMR:
0
(ether). [
a
]
D
(C]O). 1H NMR (400 MHz):
d
7.81 and 8.08 (2d, 4H, J¼8.6 Hz, Ts),
d 118.1 (C-1), 113.4 and 113.2 (C-4, CMe2), 86.7 (C-5), 81.2 (C-7), 80.1

I. Izquierdo et al. / Tetrahedron 64 (2008) 7910–7913
7913
0
(C-3), 74.7 (C-6), 60.4 (C-8), 49.6 (OMe), 27.4 and 26.4 (CMe2), 18.4
(C-2). HRMS (LSIMS): m/z 283.1042 [MþꢁMe]. For C11H15O5N4
283.1049 (deviation þ2.4 ppm).
J1,2 ¼8.6 Hz, H-1), 3.45 (ddd, 1H, J5 ¼5.3 Hz, J5 ¼10.6 Hz,
b
,6
a,6
J6,7¼9.0 Hz, H-6), 3.22 (t,1H, J7,8¼J8,8a¼9.0 Hz, H-8), 3.17 (t,1H, H-7),
0
2.98 (dd, 1H, J5 ¼10.9 Hz, H-5
b
0
), 2.78 (dt, 1H, J2 ,3¼1.5 Hz,
a,5b
0
0
0
0
J2,3¼9 Hz, H-3), 2.40 (q, 1H, J3,3 ¼J2,3 ¼J2 ,3 ¼9.1 Hz, H-3 ), 2.14 (dq,
0
4.1.5. 2-Deoxy-4,5-O-isopropylidene-8-O-p-toluenesulfonyl-
a-L
-
1H, J2,2 ¼14.1 Hz, H-2), 2.07 (t, 1H, H-5
a), 1.95 (dd, 1H, H-8a) and
gulo-oct-4-ulo-4,7-furanosononitrile (15)
1.52 (dddd, 1H, H-20). 13C NMR:
d 83.9 (C-7), 78.9 (C-1), 78.5 (C-8),
To a solution of 9 (1.14 g, 2.20 mmol) in anhydrous MeOH
(15 mL) was added 2 M MeONa in MeOH (0.5 mL) and the reaction
mixture was stirred for 3 h at 0 ꢀC. TLC (ether) revealed the pres-
ence of a new product of lower Rf. The reaction mixture was
evaporated and the residue chromatographed (ether–hexane,
78.0 (C-8a), 75.1 (C-6), 60.0 (C-5), 56.0 (C-3) and 37.6 (C-2). HRMS
(LSIMS): m/z 190.1080 [MþþH]. For C8H16O4N 190.1079 (deviation
ꢁ0.5 ppm).
Acknowledgements
2:1/ether–MeOH, 10:1) to give 15 (1.3 g, 60%) as a white foam.
24
Rf¼0.30 (ether–hexane, 2:1). [
a]
þ42 (c 0.2). IR: nmax/cmꢁ1 3490
D
Major support for this project was provided by Ministerio de
(OH) and 2252 (CN). 1H NMR (400 MHz, MeOH-d4):
d 7.80 and 7.45
´
Educacion y Ciencia of Spain (Project Ref. No. CTQ2006-14043).
(2d, 4H, J¼8.3 Hz, Ts), 4.41 (s, 1H, H-5), 4.34 (dt, 1H, J6,7¼J7,8¼3.3 Hz,
Additional support was provided by Junta de Andalucı´a (Group CVI-
250) and University of Granada (Spain) for a grant (D.L.R.).
0
0
J7,8 ¼7.5 Hz, H-7), 4.28 (dd, 1H, J8,8 ¼11.1 Hz, H-8), 4.10 (dd, 1H, H-
80), 4.09 (d, 1H, H-6), 3.82 (dd, 1H, J2,3¼3.0 Hz, J2 ,3¼9.7 Hz, H-3),
0
0
0
2.66 (dd, 1H, J2,2 ¼17.1 Hz, H-2), 2.53 (dd, 1H, H-2 ), 2.47 (s, 3H, Me
References and notes
Ts), 1.40 and 1.34 (2s, 6H, CMe2). 13C NMR:
d 143.7, 134.3, 131.1, 129.2
(Ts), 119.7 (C-1), 114.2 and 116.3 (C-4, CMe2), 86.4 and 75.2 (C-5,6),
80.9 (C-7), 70.3 (C-8), 69.4 (C-3), 27.9 and 26.9 (CMe2), 21.6 (Me Ts)
and 21.2 (C-2). HRMS (LSIMS): m/z 436.4315 [MþþNa]. For
1. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645–1680; (b) Elbein, A. D.; Molyneux, R. J. In Alkaloid Glycosidase
Inhibitors; Barton, D., Nakanishi, K., Meth-Cohn, O., Eds.; Comprehensive Nat-
ural Products Chemistry; Elsevier: Oxford, 1999; Vol. 3, p 129; (c) Sears, P.;
Wong, C.-H. Chem. Commun. 1998, 1161–1170; (d) Ganem, B. Acc. Chem. Res. 1996,
29, 340–347; (e) Dwek, R. A. Chem. Rev. 1996, 96, 683–720; (f) Kaushal, G. P.;
Elbein, A. D. Methods Enzymol. 1994, 230, 316–329; (g) Look, G. C.; Fotsch, C. H.;
Wong, C.-H. Acc. Chem. Res. 1993, 26, 182–190; (h) Legler, G. Adv. Carbohydr. Chem.
Biochem. 1990, 48, 319–384; (i) Sinnot, M. L. Chem. Rev. 1990, 90, 1171–1202.
2. Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.; Pryce, R. J.; Arnold,
E.; Clardy, J. Phytochemistry 1981, 20, 811–814.
3. (a) Platt, F. M.; Neises, G. R.; Reinkensmeier, G.; Townsend, M. J.; Perry, V. H.;
Proia, R. L.; Winchester, B.; Dwek, R. A.; Butters, T. D. Science 1997, 276, 428–
431; (b) Rhinehart, B. L.; Robinson, K. M.; Payne, A. J.; Wheatley, M. E.; Fisher,
J. L.; Liu, P. S.; Cheng, W. Life Sci. 1987, 41, 2325–2331.
4. For a review, see: Gross, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer
Res. 1995, 1, 935–944; (a) Yee, C. S.; Schwab, E. D.; Lehr, J. E.; Quigley, M.; Pienta,
K. J. Anticancer Res. 1997, 17, 3659–3663; (b) Pili, R.; Chang, J.; Partis, R. A.;
Mueller, R. A.; Chrest, F. J.; Passaniti, A. Cancer Res. 1995, 55, 2920–2926; (c)
Ostrander, G. K.; Scribner, N. K.; Rohrschneider, L. R. Cancer Res. 1988, 48, 1091–
1094; (d) Dennis, J. W.; Laferte, S.; Wahome, C.; Breitman, M. L.; Kerbel, R. S.
Science 1987, 236, 582–585.
5. (a) Tyms, A. S. PCT Int. Appl. WO 2330336017, 2003; Chem. Abstr. 2003, 138,
117633; (b) Ouzounov, S.; Mehta, A.; Dwek, R. A.; Block, T. M.; Jordan, R. Anti-
viral Res. 2002, 55, 425–435; (c) Furneaux, R. H.; Gainsford, G. J.; Mason, J. M.;
Tyler, P. C. Tetrahedron 1997, 53, 245–268; (d) Ratner, L.; Heyden, N. V.; Dedera,
D. Virology 1991, 181, 180–192; (e) Sunkara, P. S.; Taylor, D. L.; Kang, M. S.;
Bowlin, T. L.; Liu, P. S.; Tyms, A. S.; Sjoerdsma, A. Lancet 1989, 333, 1206; (f)
Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms, A. S.; Petursson, S.;
Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.; Son, J. C.; Wilson, F.; Witty,
D. R.; Jacob, G. S.; Rademacher, T. W. FEBS Lett. 1988, 237, 128–132; (g)
Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.; Namgoog, S. K.;
Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W. Proc. Natl. Acad. Sci. U.S.A.
1988, 85, 9229–9233 and references therein.
6. For selected syntheses of 1 and derivatives, see: (a) Machan, T.; Davis, A. S.;
Liawruangrath, B.; Pyne, S. G. Tetrahedron 2008, 64, 2725–2732; (b) Michael, J. P.
Nat. Prod. Rep. 2004, 21, 625–649; (c) Somfai, P.; Marchand, P.; Torsell, S.;
Lindstrom, U. M. Tetrahedron 2003, 59, 1293–1299; (d) Kim, J. H.; Woo, D.; Lee,
J. H.; Lee, B. W.; Park, K. H. Synthesis 2003, 2473–2478; (e) Tyler, P. C.; Win-
chester, B. G. In Iminosugars as Glycosidase Inhibitors; Stuetz, A., Ed.; Wiley-VCH
Verlag GmbH: Weinheim, Germany, 1999; pp 125–156; (f) Zhao, H.; Mootoo,
D. R. J. Org. Chem. 1996, 61, 6762–6763; (g) Grassberger, V.; Berger, A.; Dax, K.;
Fechter, M.; Gradnig, G.; Stuetz, A. E. Liebigs Ann. Chem. 1993, 379–390.
7. (a) Wu, T.-J.; Huang, P.-Q. Tetrahedron Lett. 2008, 49, 383–386 and references
herein; (b) Karanjule, N. S.; Markad, S. D.; Shinde, V. S.; Dhavale, D. D. J. Org.
Chem. 2006, 71, 4667–4670; (c) Cronin, L.; Murphy, P. V. Org. Lett. 2005, 7, 2691–
2693; (d) Denmark, S. E.; Herbert, B. J. Org. Chem. 2000, 65, 2887–2896; (e) Ina,
H.; Kibayashi, C. J. Org. Chem. 1993, 58, 52–61; (f) Mulzer, J.; Dehmlow, H.;
Buschmann, J.; Luger, P. J. Org. Chem. 1992, 57, 3194–3202; (g) Anzeveno, P. B.;
Angell, P. T.; Creemer, L. J.; Whalon, M. R. Tetrahedron Lett. 1990, 31, 4321–4324;
(h) Setoi, H.; Takeno, H.; Hashimoto, M. Tetrahedron Lett. 1985, 26, 4617–4620;
(i) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1984, 25, 165–168.
C
18H23O8NSNa 436.4319 (deviation þ0.9 ppm).
4.1.6. 8-Azido-2,8-dideoxy-4,5-O-isopropylidene-a-L-gulo-oct-4-
ulo-4,7-furanosononitrile (13)
To a stirred solution of 15 (800 mg, 1.93 mmol) in anhydrous
DMF (12 mL) was added LiN3 (170 mg, 3.4 mmol) and the mixture
was heated to 90 ꢀC for 5 h. TLC (ether) revealed the presence of
a new product of slightly higher Rf. The reaction mixture was
evaporated and the residue chromatographed (ether) to give 13
(550 mg, quantitative) as a white foam.
4.1.7. 8-Azido-2,8-dideoxy-a-L-gulo-oct-4-ulo-4,7-
furanosononitrile (17)
A solution of 13 (200 mg, 0.67 mmol) in 50% aqueous TFA (10 mL)
was stirred at rt for 17 h. The mixture was evaporated and codistilled
with water and toluene several times. The final residue was chro-
matographed (ether) to give 17 (124 mg, 75%) as a colourless syrup.
27
Rf¼0.36 (ether–methanol, 10:1). [
a
]
þ4 (c 2.5, MeOH). IR: nmax
/
D
cmꢁ1 3401 (OH), 2257 (CN) and 2107 (N3). 1H NMR (400 MHz,
0
MeOH-d4):
d
4.24 (dt, 1H, J7,8¼J6,7¼4.6 Hz, J7,8 ¼6.6 Hz, H-7), 4.11 (m,
0
2H, H-5,6), 3.91 (dd, 1H, J2,3¼3.1 Hz, J2 ,3¼9.3 Hz, H-3), 3.46–3.30 (m,
2H, H-8,80), 2.83 (dd, 1H, J2,2 ¼17.1 Hz, H-2) and 2.66 (dd, 1H, H-2 ).
0
0
13C NMR:
d
118.9 (C-1), 103.5 (C-4), 78.2, 76.8 and 76.9 (C-5,6,7), 70.7
(C-3), 50.5 (C-8) and 20.0 (C-2). HRMS (LSIMS): m/z 267.1948
[MþþNa]. For C8H12O5N4Na 267.1944 (deviation ꢁ1.5 ppm).
4.1.8. (1R,6S,7R,8R,8aR)-1,6,7,8-Tetrahydroxyindolizidine
[(þ)-1-epi-castanospermine, 2]
A solution of compound 17 (72 mg, 0.3 mmol) in MeOH (12 mL)
was hydrogenated at 70 psi over 10% Pd–C (20 mg) for 24 h. TLC
(ether–MeOH, 10:1) showed the presence of a single compound of
lower mobility. The catalyst was filtered off, washed with MeOH
and the filtrate evaporated to a residue that was dissolved in 1%
AcOH (12 mL). Then NaOAc (24 mg) and 10% Pd–C (12 mg) were
added. The mixture was hydrogenated at 70 psi for 24 h. TLC
(CH2Cl2–MeOH, 1:1) revealed the presence of a single compound.
The catalyst was filtered off, washed with water and MeOH and
evaporated. The residue was chromatographed (CH2Cl2–MeOH,
2:1) and the product obtained was transferred to a DowexÒ 50Wx8
(200–400 mesh) column that was eluted with MeOH (15 mL), H2O
8. (a) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Mota, A. J. Eur. J. Org. Chem. 2000, 2071–
2078; (b) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Rodrı´guez, C.; Ramı´rez, A.; Mota,
A. J. Eur. J. Org. Chem. 1999, 1269–1274; (c) Izquierdo, I.; Plaza, M.-T.; Robles, R.;
Mota, A. J. Tetrahedron: Asymmetry 1998, 9, 1015–1027; (d) Izquierdo, I.; Plaza,
M.-T.; Robles, R.; Mota, A. Tetrahedron: Asymmetry 1997, 8, 2597–2606.
9. Izquierdo, I.; Plaza, M.-T.; Tamayo, J. A.; Mota, A. J. Synthesis 2004, 1083–1087.
10. (a) von der Osten, C.-H.; Sinskey, A. J.; Barbas, A. F.; Pederson, R. L., III; Wang,
Y.-F.; Wong, C.-H. J. Am. Chem. Soc. 1989, 111, 3924–3927; (b) Kajimoto, T.; Chen,
L.; Liu, K. K.-C.; Wong, C.-H. J. Am. Chem. Soc. 1991, 113, 6678–6680.
(10 mL) and 5% NH4OH (40 mL) consecutively to afford 2 (14 mg,
27
25%) as a white solid. Rf¼0.36 (CH2Cl2–MeOH, 1:1). [
a
]
þ10 (c
D
0.25, MeOH, pH 6) [lit.:7a
(400 MHz, D2O):
[
a
]
þ3.8 (c 0.54, MeOH)]. 1H NMR
22
D
d
4.07 (ddd, 1H, J1,8a¼6.5 Hz, J1,2¼3.7 Hz,