Unambiguous syntheses of 3-o-benzyl-1,5-dideoxy-1,5-imino-d-glucitol and-l-iditol

Article abstract of DOI:10.1055/s-0029-1218850

Short and unambiguous syntheses of 3-O-benzyl-1,5-dideoxy-1,5-imino-d- glucitol and -l-iditol are described. The compound previously reported as 3-O-benzyl-1,5-dideoxy-1,5-imino-d-glucitol (Roy, A.; Achari, B.; Mandal, S. B. Synthesis 2006, 1035) is shown to be actually 3-O-benzyl-1,5-dideoxy-1,5-imino- l-iditol. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218850

2626
PAPER
Unambiguous Syntheses of 3-O-Benzyl-1,5-dideoxy-1,5-imino-D-glucitol and
-L-iditol
Zsuzsánna Csíki, Péter Fügedi*
Department of Carbohydrate Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri út 59-67, 1025 Budapest,
Hungary
Fax +36(1)4381145; E-mail: pfugedi@chemres.hu
Received 22 February 2010; revised 6 April 2010
Heparanase is a key enzyme in the cleavage of heparin
Abstract: Short and unambiguous syntheses of 3-O-benzyl-1,5-
and heparan sulfate chains. As part of a project to develop
dideoxy-1,5-imino-D-glucitol and -L-iditol are described. The com-
pound previously reported as 3-O-benzyl-1,5-dideoxy-1,5-imino-
D-glucitol (Roy, A.; Achari, B.; Mandal, S. B. Synthesis 2006,
selective inhibitors of this enzyme for potential use as an-
titumor compounds,3–5 we designed iminosugar-contain-
1035) is shown to be actually 3-O-benzyl-1,5-dideoxy-1,5-imino-L- ing heparin disaccharide analogues of types 1 and 2
(Scheme 1).6 A retrosynthetic analysis of these target
iditol.
structures revealed that they should be available from the
thioglycoside donor 3 and the azauronic acid glycosyl ac-
ceptors 4 and 5. The latter, in turn, should be accessible
from 3-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (6)
and -L-iditol (7), respectively (Scheme 1).
Key words: azasugars, glycosidases, inhibitors, deoxynojirimycin,
iminohexitols
Iminosugars are sugar analogues in which the ring oxygen
atom is replaced by nitrogen. Their importance as synthet-
ic targets has increased since they were shown to possess
potent glycosidase inhibitory activity and therefore to
have potential as therapeutic agents for several diseases,
including cancer, viral infections, inflammation, and dis-
orders related to carbohydrate metabolism.1,2 A common
problem associated with monosaccharidic iminosugars as
enzyme inhibitors is that they tend to have a fairly broad
spectrum of activity in inhibiting a variety of glycosi-
dases. One way to increase the selectivity of iminosugars
as inhibitors is to prepare larger molecules that are closer
mimetics of the natural substrates of the enzymes.
A compound to which the structure 6 was attributed has
been described recently.7 Its synthesis involved a config-
urational inversion with azide at the C-5 position of a D-
glucofuranose derivative, followed by cyclization of the
C-5 nitrogen with C-1. Despite the clear configurational
inversion at C-5 in the azide-replacement reaction, a D-
gluco configuration was attributed to the final product.
The b-orientation of the C-5 hydroxymethyl group was
deduced from mechanistic considerations. We now report
unambiguous syntheses of 3-O-benzyl-1,5-dideoxy-1,5-
imino-D-glucitol (6) and 3-O-benzyl-1,5-dideoxy-1,5-
imino-L-iditol (7), and we show that the compound that
OR3
OH
O
CO2R6
HO
HO
NH
HO
BnO
N
R7
HO
BnO
R2HN
CO2Na
NH
O
HO
OR5
OH
OR4
O
1
OR1
4
6
BnO
BnO
SPh
OR3
O
N3
NaO2C
R7
OH
H
BnO
OBn
N
H
HO
3
R6O2C
N
N
O
HO
R2HN
HO
R1O
OR5
HO
HO
OH
2
5
7
R1 = H or SO3Na; R2 = Ac or SO3Na; R3 = H or SO3Na
4 and R5 = temporary protecting groups
R6 and R7 = permanent protecting groups
R
Scheme 1 Retrosynthetic analysis of iminosugar-containing heparin disaccharides
SYNTHESIS 2010, No. 15, pp 2626–2630
x
x.
x
x
.
2
0
1
0
Advanced online publication: 29.06.2010
DOI: 10.1055/s-0029-1218850; Art ID: T04510SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
3-O-Benzyl-1,5-dideoxy-1,5-iminohexitols
2627
O
O
PivO
HO
O
OH
O
OBn
a
O
O
O
O
8
9
b
PivO
PivO
PivO
PivO
PivO
TfO
OH
O
OBn
N3
O
OBn
OTf
N3
O
OBn
O
OBn
i
O
OBn
c
e
d
O
O
O
O
O
O
O
O
O
O
16
13
11
10
12
j
f
HO
HO
N3
N3
O
OBn
O
OBn
O
O
O
O
17
14
g
k
OH
NH
OH
H
OH
N
H
OBn
N
HO
h
HO
BnO
NH
HO
l
HO
HO
OH
7
OH
OH
18
OH
OH
OH
6
15
Scheme 2 Synthesis of 3-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (6) and 3-O-benzyl-1,5-dideoxy-1,5-imino-L-iditol (7). Reagents and
conditions: (a) 1. BnBr, NaH, DMF, 0 °C, 3 h; 2. 60% AcOH, r.t., 36 h; 3. PivCl, CH2Cl2, py, 0 °C, 2 h, 75%; (b) Tf2O, CH2Cl2, py, –30 °C;
(c) NaNO2, DMF, r.t., 21 h, 80%; (d) Tf2O, CH2Cl2, py, –30 °C; (e) NaN3, DMF, r.t., 2 h, 75%; (f) NaOMe, MeOH, r.t., 5 d, 94%; (g) TFA,
H2O, r.t., 3 h, then H2, Raney Ni, MeOH, 77%; (h) H2, Pd/C, THF, H2O, r.t., 2 d, 98%; (i) NaN3, DMF, r.t., 3 h, 70%; (j) NaOMe, MeOH, r.t.,
4 d, 97%; (k) TFA, H2O, r.t., 1 h, then H2, Raney Ni, MeOH, 47%; (l) H2, Pd/C, THF, H2O, r.t., 2 d, 90%.
was claimed to have the D-gluco configuration (6) is actu- methanol. The physical constants of 6 differed from those
ally the L-ido derivative (7).
reported.7 Its structure, however, follows from the syn-
thetic route, and the C-5 configuration is clearly supported
by the 3JH-4,H-5 coupling constant, which was 9.4 Hz, cor-
responding to a trans diaxial arrangement. As further
proof of the structure of 6, it was subjected to catalytic hy-
drogenation with palladium-on-carbon catalyst in aque-
ous tetrahydrofuran to give the well-known 1-deoxy-
nojirimycin (15).10–12
We envisaged the synthesis of both 6 and 7 (Scheme 2)
from the partially protected D-glucofuranose derivative
9,8 which is easily obtained in three steps from commer-
cial diacetone-D-glucose (8) by benzylation, selective hy-
drolysis of the 5,6-O-isopropylidene acetal, and
pivaloylation. Compound 9, in which hydroxy group on
C-5 is unprotected, offers an easy route for the introduc-
tion of a nitrogen function with either inversion or overall For the synthesis of 3-O-benzyl-1,5-dideoxy-1,5-imino-
retention of configuration.
L-iditol (7), the common starting material 9 was converted
into the triflate 10 as previously described. Treatment of
10 with sodium azide in N,N-dimethylformamide gave the
5-azido-L-idofuranose derivative 16 in 70% yield. De-O-
pivaloylation with sodium methoxide in methanol then
gave the hydroxy azide derivative 17. Hydrolysis of the
isopropylidene acetal with trifluoroacetic acid, followed
by catalytic hydrogenation with Raney nickel in methanol
afforded 3-O-benzyl-1,5-dideoxy-1,5-imino-L-iditol (7).
The physical constants of 7 were close to those previously
reported for 6.7 The structure of 7 was confirmed by its
conversion into the known 1-deoxy-L-ido-nojirimycin
1813,14 by debenzylation through catalytic hydrogenation.
To synthesize 3-O-benzyl-1,5-dideoxy-1,5-imino-D-glu-
citol (6), the C-5 configuration was first inverted by pre-
paring the triflate (10) and treating this with sodium nitrite
to give the hydroxyl compound (11) with an inverted con-
figuration at C-5.9 Triflation of the L-ido derivative 11 fol-
lowed by a second inversion gave the D-gluco azide 13 in
75% yield. The pivaloyl group was removed under
Zemplén conditions to give the hydroxy azide 14. The
crystalline D-gluco-nojirimycin derivative 3-O-benzyl-
1,5-dideoxy-1,5-imino-D-glucitol (6) was readily pre-
pared from 14 by hydrolysis of the isopropylidene group
followed by catalytic hydrogenation with Raney nickel in
Synthesis 2010, No. 15, 2626–2630 © Thieme Stuttgart · New York

2628
Z. Csíki, P. Fügedi
PAPER
ESI-MS: m/z = 395.0 [M + H]+, 417.1 [M + Na]+, 433.0 [M + K]+.
In conclusion, we have developed a short and unambigu-
ous route to 3-O-benzyl-1,5-dideoxy-1,5-imino-D-gluci-
Anal. Calcd for C21H30O7: C, 63.94; H, 7.67. Found: C, 63.98; H,
tol and -L-iditol, which are useful as intermediates for the 7.64.
preparation of azasugar-containing oligosaccharides. We
3-O-Benzyl-1,2-O-isopropylidene-6-O-pivaloyl-b-L-idofura-
have also shown that the compound previously reported to
have the D-gluco configuration (6) is in fact the L-ido de-
rivative 7.
nose (11)
Tf2O (9.2 mL, 55.8 mmol) was added dropwise at –30 °C to a soln
of 9 (20 g, 50.7 mmol) in a mixture of anhyd CH2Cl2 (100 mL) and
anhyd pyridine (10 mL), and the mixture was stirred for 2 h at
–30 °C. It was then diluted with CH2Cl2 (300 mL) and washed se-
quentially with cold 2 M HCl, cold sat. aq NaHCO3, and cold H2O.
The organic layer was dried, and the solvent was removed under re-
duced pressure. The crude triflate 10 was dissolved in anhyd DMF
(100 mL), NaNO2 (14 g, 203 mmol) was added, and the mixture was
stirred for 21 h. The mixture was then diluted with CH2Cl2 (200 mL)
and washed with H2O (×4). The organic layer was dried and concen-
trated, and the residue was purified by column chromatography [tol-
uene–acetone (98:2 to 9:1)] to give the ido-derivative 11 as white
crystals; yield: 16.1 g (80%); mp 60–61 °C (Et2O–hexanes); [a]D
–47.7 (c 1.03, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.20 [s, 9 H, C(CH3)3], 1.33 and
1.47 [2s, 2 × 3 H, C(CH3)2], 3.04 (s, 1 H, OH), 4.01 (d, J3,4 = 3.0 Hz,
1 H, H-3), 4.13 (dd, J4,5 = 6.0 Hz, J5,6a ~ J5,6b = 5.7 Hz, 1 H, H-5),
4.17 (dd, J6a,6b = 12.9 Hz, 1 H, H-6b), 4.19 (d, 1 H, H-4), 4.20 (dd,
1 H, H-6a), 4.51 (d, J = 11.7 Hz, 1 H, PhCH2), 4.65 (d, J1,2 = 3.7 Hz,
1 H, H-2), 4.71 (d, J = 11.7 Hz, 1 H, PhCH2), 5.99 (d, 1 H, H-1),
7.22–7.41 (m, 5 H, aromatic).
Melting points were determined in capillary tubes on a Griffin melt-
ing point apparatus and are uncorrected. Optical rotations were
measured at r.t. with an Optical Activity P-2000 (Jasco) polarime-
ter. The IR spectra were recorded on a Thermo Nicolet Avatar 320
FT-IR spectrometer. The NMR spectra (1H: 300 MHz; 13C: 75
MHz) were recorded on Varian Unity Inova 3000 spectrometer at
r.t. and assigned by using 2D-methods (COSY, HSQC). The chem-
1
ical shifts were referenced to TMS (0.00 ppm for H); otherwise,
they were referenced to the central line of CDCl3 (77.0 ppm for 13C)
for solns in CDCl3, to the central line of the solvent (3.31 ppm for
1H, 49.00 ppm for 13C) for solns in CD3OD, or to the methyl signal
of acetone (2.22 ppm for 1H, 30.89 ppm for 13C) for solns in D2O.
Mass spectra were recorded on an Applied Biosystems 3200QTrap
hybrid mass spectrometer operated in the electrospray ionization
mode. Elemental analyses were performed by using an Elementar
Vario EL III instrument at the Analytical Department of the Chem-
ical Research Center of the Hungarian Academy of Sciences.
3-O-Benzyl-1,2-O-isopropylidene-6-O-pivaloyl-a-D-glucofura-
nose (9)
13C NMR (75 MHz, CDCl3): d = 26.3 and 26.7 [C(CH3)2], 27.1
[C(CH3)3], 38.7 [C(CH3)3], 64.9 (C-6), 68.6 (C-5), 71.9 (CH2Ph),
79.2 (C-4), 82.1 (C-2), 83.0 (C-3), 104.9 (C-1), 111.9 [C(CH3)2],
127.8, 128.2, 128.6, 136.6 (aromatic), 178.2 [COC(CH3)3].
A 60% suspension of NaH (13.7 g, 357 mmol) was added to a
stirred soln of diacetone-D-glucose (8; 62 g, 238 mmol) in anhyd
DMF (300 mL) at 0 °C. After 30 min, BnBr (33.9 mL, 285 mmol)
was added dropwise. Stirring was continued for 3 h and then MeOH
(30 mL) was added dropwise. After 30 min, the mixture was diluted
with CH2Cl2 (500 mL), washed with H2O (150 mL), dried, and con-
centrated. The crude syrupy product was dissolved in 60% aq
AcOH (300 mL) and stirred for 36 h at r.t. The mixture was neutral-
ized with aq K2CO3, and the aqueous layer was extracted with
CH2Cl2 (×3). The combined organic layer (500 mL) was washed
with H2O (100 mL), dried, and concentrated. The resulting crude 3-
O-benzyl-1,2-O-isopropylidene-a-D-glucofuranose (73 g, 238
mmol) was treated with PivCl (43.9 mL, 357 mmol) in a mixture of
anhyd pyridine (200 mL) and anhyd CH2Cl2 (100 mL) at 0 °C, and
the mixture was allowed to warm to r.t. over 2 h. It was then cooled
to 0 °C and the reaction was quenched with H2O. The mixture was
diluted with CH2Cl2 (500 mL) and washed sequentially with 2 M
HCl, sat. aq NaHCO3, and H2O. The organic layer was dried and
concentrated, and the residue was crystallized (EtOAc–hexanes) to
give the required product 9; yield: 70.6 g (75%); mp 99–101 °C
(EtOAc–hexanes) [Lit.8 100–101 °C (EtOAc–hexanes); Lit.15 oil];
[a]D –32 (c 1.00, CHCl3) [Lit.8 –32 (c 1.00, CHCl3); Lit.15 –49 (c
1.2, CHCl3)].
1H NMR (300 MHz, CDCl3): d = 1.21 [s, 9 H, C(CH3)3], 1.32 and
1.47 [2s, 2 × 3 H, C(CH3)2], 2.57 (d, J5,OH = 4.5 Hz, 1 H, OH), 4.05–
4.18 (m, 3 H, H-3, H-4, H-5), 4.19 (dd, J6a,6b = 13.5 Hz, J5,6b = 3.1
Hz, 1 H, H-6b), 4.36 (dd, J5,6a = 4.9 Hz, 1 H, H-6a), 4.59 (d, J = 11.7
Hz, 1 H, PhCH2), 4.61 (s, 1 H, H-2), 4.72 (d, J = 11.7 Hz, 1 H,
PhCH2), 5.93 (d, J1,2 = 3.6 Hz, 1 H, H-1), 7.34 (m, 5 H, aromatic).
13C NMR (75 MHz, CDCl3): d = 26.3 and 26.7 [C(CH3)2], 27.1
[C(CH3)3], 38.9 [C(CH3)3], 66.4 (C-6), 67.8 (C-5), 72.3 (CH2Ph),
79.2 and 81.7 (C-3 and C-4), 82.1 (C-2), 105.2 (C-1), 111.8
[C(CH3)2], 127.8, 128.1, 128.6, 137.2 (aromatic), 179.0
[COC(CH3)3].
ESI-MS: m/z = 395.0 [M + H]+, 417.1 [M + Na]+.
Anal. Calcd for C21H30O7: C, 63.94; H, 7.67. Found: C, 63.88; H,
7.70.
5-Azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-6-O-piv-
aloyl-a-D-glucofuranose (13)
Triflation of 11 (6.1 g, 15.5 mmol) was performed under the same
conditions as described for 9. The crude product (12) was dissolved
in anhyd DMF (50 mL) and NaN3 (1.8 g, 27.7 mmol) was added.
After 2 h, the soln was diluted with CH2Cl2 (200 mL) and washed
with H2O (×4). The organic layer was dried and concentrated, and
the residue was purified by column chromatography [hexanes–
EtOAc (98:2 to 9:1)] to give azide 13 as a syrup; yield: 4.8 g (75%);
[a]D –26.9 (c 1.00, CHCl3).
IR (KBr): 3567, 2348, 2098, 1481, 1374, 1281, 1217, 1163, 1074,
1027, 855 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 [s, 9 H, C(CH3)3], 1.32 and
1.47 [2s, 2 × 3 H, C(CH3)2], 4.04 (dd, J4,5 = 7.6 Hz, J5,6a ~ J5,6b = 6.9
Hz, 1 H, H-5), 4.05 (d, 1 H, H-4), 4.06 (s, 1 H, H-3), 4.18 (dd,
J6a,6b = 11.7 Hz, 1 H, H-6b), 4.50 (d, 1 H, H-6a), 4.60 (d, J = 11.6
Hz, 1 H, PhCH2), 4.62 (s, 1 H, H-2), 4.69 (d, J = 11.6 Hz, 1 H,
PhCH2), 5.89 (d, J1,2 = 3.4 Hz, 1 H, H-1), 7.20–7.42 (m, 5 H, aro-
matic).
13C NMR (75 MHz, CDCl3): d = 26.2 and 26.7 [C(CH3)2], 27.1
[C(CH3)3], 38.8 [C(CH3)3], 58.2 (C-5), 65.0 (C-6), 72.2 (CH2Ph),
78.2 (C-4), 81.3 (C-3), 81.6 (C-2), 105.3 (C-1), 112.0 [C(CH3)2],
127.9, 128.1, 128.5, 136.9 (aromatic), 177.9 [COC(CH3)3].
ESI-MS: m/z = 420.0 [M + H]+, 442.0 [M + Na]+.
Anal. Calcd for C21H29N3O6: C, 60.13; H, 6.97; N, 10.02. Found: C,
60.12; H, 7.02; N, 9.92.
Synthesis 2010, No. 15, 2626–2630 © Thieme Stuttgart · New York

PAPER
3-O-Benzyl-1,5-dideoxy-1,5-iminohexitols
2629
5-Azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-a-D-gluco-
furanose (14)
A catalytic amount of NaOMe was added to a soln of pivalate 13
(1.6 g, 3.7 mmol) in anhyd MeOH (10 mL). The mixture was stirred
for 5 d at r.t. then neutralized with Amberlite IR 120 (H+) resin, fil-
tered, and concentrated to give a syrup; yield: 1.2 g (94%); [a]D
–13.6 (c 1.03, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.31 and 1.48 [2s, 2 × 3 H,
C(CH3)2], 2.53 (s, 1 H, OH), 3.76 (dd, J6a,6b = 10.8 Hz, J5,6b = 5.2
Hz, 1 H, H-6b), 3.90 (ddd, J4,5 = 9.6 Hz, J5,6a = 3.8 Hz, 1 H, H-5),
3.95 (dd, 1 H, H-6a), 4.06 (dd, J3,4 = 2.9 Hz, 1 H, H-3), 4.12 (dd, 1
H, H-4), 4.59 (d, J = 11.6 Hz, 1 H, PhCH2), 4.63 (d, J1,2 = 3.6 Hz, 1
H, H-2), 4.68 (d, J = 11.6 Hz, 1 H, PhCH2), 5.90 (d, 1 H, H-1), 7.24–
7.42 (m, 5 H, aromatic).
1H NMR (300 MHz, D2O): d = 2.34 (dd, J1a,1b = 12.3 Hz,
J1b,2 = 10.9 Hz, 1 H, H-1b), 2.43 (ddd, J4,5 = 9.4 Hz, J5,6a = 3.0 Hz,
J5,6b = 6.2 Hz, 1 H, H-5), 3.00 (dd, J1a,2 = 5.2 Hz, 1 H, H-1a), 3.11
(t, J3,4 = 9.1 Hz, 1 H, H-4), 3.20 (t, J2,3 = 8.9 Hz, 1 H, H-3), 3.37
(ddd, 1 H, H-2), 3.51 (dd, J6a,6b = 11.7 Hz, 1 H, H-6b), 3.71 (dd, 1
H, H-6a).
13C NMR (75 MHz, D2O): d = 49.2 (C-1), 61.1 (C-5), 61.9 (C-6),
71.4 (C-2), 72.0 (C-4), 78.9 (C-3).
The 1H and 13C NMR data are in agreement with those reported in
the literature.10
ESI-MS: m/z = 164.3 [M + H]+.
Anal. Calcd for C6H13NO4: C, 44.16; H, 8.03; N, 8.58. Found: C,
44.15; H, 8.05; N, 8.60.
13C NMR (75 MHz, CDCl3): d = 26.2 and 26.7 [C(CH3)2], 60.5 (C-
5), 63.4 (C-6), 72.0 (CH2Ph), 79.1 (C-4), 81.5 (C-2), 81.6 (C-3),
105.2 (C-1), 112.0 [C(CH3)2], 127.9, 128.1, 128.5, 137.0 (aromat-
ic).
5-Azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-6-O-piv-
aloyl-b-L-idofuranose (16)
Tf2O (5 mL, 30.4 mmol) was added dropwise at –30 °C to a soln of
pivalate 9 (10 g, 25.4 mmol) in a mixture of anhyd CH2Cl2 (50 mL)
and anhyd pyridine (5 mL), and the mixture was stirred for 45 min
at –30 °C. The soln was then diluted with CH2Cl2 (200 mL) and
washed sequentially with cold 2 M HCl, cold sat. aq NaHCO3, and
cold H2O. The organic layer was dried and the solvent was removed
under reduced pressure. The residue was dissolved in anhyd DMF
(50 mL) and treated with NaN3 (1.8 g, 27.9 mmol). After 3 h, the
soln was diluted with CH2Cl2 (200 mL) and washed with H2O (×4).
The organic layer was dried and concentrated to give a crude prod-
uct that was purified by column chromatography [hexanes–EtOAc
(95:5 to 7:3)] to give a syrup; yield: 7.4 g (70%); [a]D –25.9 (c 1.10,
CHCl3).
ESI-MS: m/z = 335.9 [M + H]+, 352.9 [M + NH4]+, 357.9 [M +
Na]+.
Anal. Calcd for C16H21N3O5: C, 57.30; H, 6.31; N, 12.53. Found: C,
57.35; H, 6.28; N, 12.50.
3-O-Benzyl-1,5-dideoxy-1,5-imino-D-glucitol (6)
Azide 14 (1.0 g, 3.2 mmol) was dissolved in a 3:2 mixture of TFA
and H2O (10 mL), and the mixture was stirred for 3 h at r.t. The mix-
ture was concentrated under reduced pressure and co-evaporated
twice with toluene. The residue was purified by column chromatog-
raphy [CH2Cl2–MeOH (98:2 to 9:1)] to give 5-azido-3-O-benzyl-5-
deoxy-a,b-D-glucofuranose; yield: 0.9 g (95%).
IR (KBr): 2978, 2100, 1456, 1374, 1261, 1218, 1161, 1076, 1024,
858 cm–1.
A soln of this intermediate (0.8 g, 2.5 mmol) in anhyd MeOH (10
mL) was hydrogenated in the presence of Raney nickel catalyst at
atmospheric pressure and r.t. for 3 h. The resulting mixture was fil-
tered through a pad of Celite, and the filtrate was concentrated. The
residue was purified by column chromatography [CH2Cl2–MeOH
(4:1 to 7:3)] to give the imino product 6 as white crystals; yield: 0.5
g (77%); mp 128–129 °C (EtOAc–EtOH–hexanes); [a]D +27.9 (c
1.00, MeOH).
1H NMR (300 MHz, CDCl3): d = 1.22 [s, 9 H, C(CH3)3], 1.33 and
1.48 [2s, 2 × 3 H, C(CH3)2], 3.88 (d, J3,4 = 3.4 Hz, 1 H, H-3), 3.95
(ddd, J4,5 = 8.6 Hz, J5,6a = 3.3 Hz, J5,6b = 5.8 Hz, 1 H, H-5), 4.06
(dd, J6a,6b = 11.8 Hz, 1 H, H-6b), 4.09 (dd, 1 H, H-6a), 4.21 (dd, 1
H, H-4), 4.48 (d, J = 11.6 Hz, 1 H, PhCH2), 4.66 (d, J1,2 = 3.8 Hz, 1
H, H-2), 4.69 (d, J = 11.6 Hz, 1 H, PhCH2), 5.97 (d, 1 H, H-1), 7.25–
7.40 (m, 5 H, aromatic).
1H NMR (300 MHz, CD3OD): d = 2.42 (dd, J1a,1b = 12.1 Hz,
J1a,2 = 10.7 Hz, 1 H, H-1a), 2.44 (ddd, J4,5 = 9.4 Hz, J5,6a = 3.1 Hz,
J5,6b = 6.4 Hz, 1 H, H-5), 3.05 (dd, J1b,2 = 5.2 Hz, 1 H, H-1b), 3.15
(t, J2,3 ~ J3,4 = 8.8 Hz, 1 H, H-3), 3.26 (dd, 1 H, H-4), 3.51 (ddd, 1
H, H-2), 3.54 (dd, J6a,6b = 10.9 Hz, 1 H, H-6b), 3.79 (dd, 1 H, H-6a),
4.85 (d, J = 11.2 Hz, 1 H, PhCH2), 4.90 (d, J = 11.2 Hz, 1 H,
PhCH2), 7.20–7.30 (m, 5 H, aromatic).
13C NMR (75 MHz, CDCl3): d = 26.3 and 26.7 [C(CH3)2], 27.1
[C(CH3)3], 38.8 [C(CH3)3], 60.1 (C-5), 63.5 (C-6), 71.9 (CH2Ph),
79.2 (C-4), 81.5 (C-3), 81.8 (C-2), 104.8 (C-1), 112.0 [C(CH3)2],
127.9, 128.3, 128.6, 136.6 (aromatic), 177.9 [COC(CH3)3].
ESI-MS: m/z = 420.0 [M + H]+, 437.0 [M + NH4]+, 442.0 [M +
Na]+.
13C NMR (75 MHz, CD3OD): d = 51.4 (C-1), 63.0 (C-6), 63.2 (C-
5), 72.7 and 73.2 (C-2, C-4), 76.1 (CH2Ph), 89.0 (C-3), 128.4,
129.1, 129.2, 140.6 (aromatics).
Anal. Calcd for C21H29N3O6: C, 60.13; H, 6.97; N, 10.02. Found: C,
60.15; H, 6.94; N, 10.12.
5-Azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-b-L-idofura-
nose (17)
ESI-MS: m/z = 254.0 [M + H]+, 275.9 [M + Na]+.
Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C,
61.66; H, 7.55; N, 5.50.
A catalytic amount of NaOMe was added to a soln of pivalate 16
(6.9 g, 16.4 mmol) in anhyd MeOH (50 mL). The mixture was
stirred for 4 d at r.t., then neutralized with Amberlite IR 120 (H+)
resin, filtered, and concentrated to a syrup; yield: 5.4 g (97%); [a]D
–49.8 (c 0.96, CHCl3) (Lit.7 –41.6 (c 0.56, CHCl3)].
1,5-Dideoxy-1,5-imino-D-glucitol (15)
A soln of the benzyl derivative 6 (0.245 g, 0.96 mmol) in a 1:1 mix-
ture of THF and H2O (5 mL) was hydrogenated in the presence of
10% Pd/C catalyst for 2 d at atmospheric pressure and r.t. The mix-
ture was then filtered through a pad of Celite, and the filtrate was
concentrated. The residue was purified by column chromatography
[CH2Cl2–MeOH–H2O (4:3:1)] to give white crystals; yield: 0.153 g
(98%); mp 194–196 °C (aq MeOH) [Lit.10 199–201 °C (aq EtOH);
Lit.11 192–193 °C (aq EtOH); Lit.12 186–189 °C (aq EtOH)]; [a]D
+37.0 (c 1.03, H2O) [Lit.10 +42.1 (c 1.0, H2O); Lit.11 –46.5 (c 0.61,
H2O); Lit.12 +34.1 (c 0.15, H2O)].
IR (KBr): 3478, 2102, 1455, 1375, 1259, 1217, 1164, 1075, 1017,
858 cm–1. The IR data are in agreement with those reported in the
literature.7
1H NMR (300 MHz, CDCl3): d = 1.32 and 1.49 [2s, 2 × 3 H,
C(CH3)2], 2.15 (t, JOH,6 = 6.3 Hz, 1 H, OH), 3.40 (ddd, J6a,6b = 11.8
Hz, J5,6b = 6.1 Hz, 1 H, H-6b), 3.57 (dddd, J5,6a = 6.1 Hz, 1 H, H-6a),
3.88 (ddd, J4,5 = 9.0 Hz, 1 H, H-5), 3.92 (d, J3,4 = 3.2 Hz, 1 H, H-3),
4.25 (dd, 1 H, H-4), 4.44 (d, J = 11.6 Hz, 1 H, PhCH2), 4.66 (d,
Synthesis 2010, No. 15, 2626–2630 © Thieme Stuttgart · New York

2630
Z. Csíki, P. Fügedi
PAPER
J1,2 = 3.8 Hz, 1 H, H-2), 4.70 (d, J = 11.6 Hz, 1 H, PhCH2), 5.97 (d,
1 H, H-1), 7.25–7.41 (m, 5 H, aromatic).
1H NMR (300 MHz, D2O): d = 2.96 (dd, J1a,1b = 13.0 Hz, J1b,2 = 5.1
Hz, 1 H, H-1b), 3.10 (dd, J1a,2 = 3.0 Hz, 1 H, H-1a), 3.29 (ddd,
J4,5 = 7 Hz, J5,6a = 3.4 Hz, J5,6b = 7 Hz, 1 H, H-5), 3.66–3.82 (m, 5
H, H-2, H-3, H-4, H-6).
The 1H NMR data are in agreement with those reported in the liter-
ature.7
The 1H NMR data are in agreement with those reported in the liter-
13C NMR (75 MHz, CDCl3): d = 26.1 and 26.6 [C(CH3)2], 61.8 (C-
6), 62.9 (C-5), 71.6 (CH2Ph), 80.1 (C-4), 81.3 (C-3), 81.8 (C-2),
104.7 (C-1), 111.9 [C(CH3)2], 127.9, 128.2, 128.5, 136.6 (aromat-
ic).
ature.13
13C NMR (75 MHz, D2O): d = 44.7 (C-1), 56.6 (C-5), 58.4 (C-6),
68.1, 68.9 and 69.8 (C-2, C-3, C-4).
ESI-MS: m/z = 358.2 [M + Na]+, 374.1 [M + K]+.
ESI-MS: m/z = 164.3 [M + H]+, 186.2 [M + Na]+.
Anal. Calcd for C16H21N3O5: C, 57.30; H, 6.31; N, 12.53. Found: C,
57.21; H, 6.35; N, 12.62.
Anal. Calcd for C6H13NO4: C, 44.16; H, 8.03; N, 8.58. Found: C,
44.13; H, 8.00; N, 8.61.
3-O-Benzyl-1,5-dideoxy-1,5-imino-L-iditol (7)
Supporting Information for this article is available at
Azide 17 (5.1 g, 15.3 mmol) was dissolved in a 3:2 mixture of TFA
and H2O (50 mL) and the mixture was stirred for 1 h at r.t. The mix-
ture was concentrated under reduced pressure and the residue was
co-evaporated twice with toluene to give a crude product. The prod-
uct was dissolved in anhyd MeOH (50 mL) and hydrogenated in the
presence of Raney nickel catalyst at atmospheric pressure and r.t.
for 3 h. The resulting mixture was filtered through a pad of Celite
and the filtrate was concentrated. The residue was purified by col-
umn chromatography [CH2Cl2–MeOH (95:5 to 7:3)] to give a yel-
lowish syrup 7; yield: 1.8 g (47% for the two steps) [Lit.7 (for 6)
sticky gum]; [a]D –3.3 (c 1.03, MeOH) [Lit.7 (for 6) +2.6 (c 1.10,
MeOH)].
1H NMR (300 MHz, CD3OD): d = 3.19 (br s, 2 H, H-1a, H-1b), 3.27
(t, J = 6.5 Hz, 1 H, H-5), 3.69 (t, J2,3 ~ J3,4 = 3.3 Hz, 1 H, H-3), 3.76
(dd, J6a,6b = 12 Hz, 2 H, H-6), 3.99 (br s, 2 H, H-2, H-4), 4.60 (s, 2
H, PhCH2), 7.30 (m, 5 H, aromatic).
13C NMR (75 MHz, CD3OD): d = 46.9 (C-1), 57.3 (C-5), 60.6 (C-
6), 65.5 and 66.4 (C-2 and C-4), 72.1 (CH2Ph), 74.8 (C-3), 127.8,
128.3, 128.4, 138.1 (aromatics).
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We are grateful to Dr Pál Szabó and Dr Izabella Lois for their assi-
stance in recording the MS and the NMR spectra, respectively.
References
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The 1H and 13C NMR data are in agreement with those reported in
the literature7 for compound 6.
ESI-MS: m/z = 254.0 [M + H]+, 276.0 [M + Na]+.
Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C,
61.60; H, 7.60; N, 5.50.
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1,5-Dideoxy-1,5-imino-L-iditol (18)
A soln of 7 (0.376 g, 1.5 mmol) in a 1:1 mixture of THF and H2O
(5 mL) was hydrogenated in the presence of 10% Pd/C catalyst for
2 d at atmospheric pressure and r.t. The resulting mixture was fil-
tered through a pad of Celite, and the filtrate was concentrated. The
residue was purified by column chromatography [CH2Cl2–MeOH–
H2O (4:3:1)] to give crystals; yield: 0.218 g (90%); mp 124–126 °C
(aq MeOH) [Lit.13 125–127 °C (aq MeOH); Lit.14 139–141 °C (aq
MeOH)]; [a]D –14.9 (c 1.03, H2O) [Lit.13 –15.6 (c 1.1, H2O); Lit.14
–30.9 (c 1, MeOH)].
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Synthesis 2010, No. 15, 2626–2630 © Thieme Stuttgart · New York