1-C-(2′-Oxoalkyl) glycosides as latent α,β-unsaturated conjugates. Synthesis of aza-C-glycosides by an intramolecular hetero-Michael addition

Article abstract of DOI:10.1016/j.tet.2005.09.037

1-C-(2′-Oxoalkyl)-5-azido-5-deoxy-glycofuranosides were used as latent substrates for intramolecular hetero-Michael addition. Reduction of the azido groups by catalytic hydrogenation followed by base treatment produced 2′-ester and 2′-ketone aza-C-glycopy

Full text of DOI:10.1016/j.tet.2005.09.037

Tetrahedron 61 (2005) 11716–11722
1-C-(20-Oxoalkyl) glycosides as latent a,b-unsaturated conjugates.
Synthesis of aza-C-glycosides by an intramolecular
hetero-Michael addition
Tian Yi,a An-Tai Wu,b Shih-Hsiung Wub and Wei Zoua,
*
aInstitute for Biological Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, Ont., Canada K1A 0R6
bInstitute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, ROC
Received 28 July 2005; revised 6 September 2005; accepted 12 September 2005
Available online 29 September 2005
Abstract—1-C-(20-Oxoalkyl)-5-azido-5-deoxy-glycofuranosides were used as latent substrates for intramolecular hetero-Michael addition.
Reduction of the azido groups by catalytic hydrogenation followed by base treatment produced 20-ester and 20-ketone aza-C-
glycopyranosides. The conjugation addition was stereoselective in favor of aza-C-glycosides with equatorial substitutions at the pseudo
anomeric center.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
oxidation of 5,6-diol to aldehyde, and Wittig reaction. In
another example, Dhavale et al.12 prepared a conjugated
ester from 3-O-benzyl-1,2-O-isopropylidene-glucofuranose
through oxidation of 5,6-diol to 5-aldehyde, followed by a
Wittig reaction. An amino group was introduced at C5 by an
intermolecular Michael addition, and the azasugar was then
obtained following removal of 1,2-O-isopropylidene and
subsequent reductive amination. The major limitation
associated with these procedures, however, is the accessi-
bility of these intermediates, the formation of which is
highly dependent on the stereochemistry of the hydroxy
groups in the starting materials in order to achieve the regio-
selective protection. Therefore, easy access to molecules
with both amine and a,b-unsaturated ester (ketone)
functionalities is desired.
Azasugars (iminosugars)1 are powerful glyco-processing
enzyme inhibitors and potential therapeutics for the
treatment of diabetic, cancer, viral infection and other
diseases.2 For example, N-hydroxyethyl-1-deoxynojirimy-
cin (Miglitol)3 and N-butyl-1-deoxynojirimycin (Zavestca)4
have been approved, respectively, for the treatment of type 2
diabetes and type 1 Gaucher disease. Numerous synthetic
methods towards azasugars have been developed,2a,b,5
which include various reductive and double-reductive
amination between an azido/amino group and carbonyl
groups,6 and SN2 substitutions by nucleophilic amine to
epoxides,7 halides,8 and other leaving groups.9 Aza-C-
glycosides, azasugars with a C-linked aglycon, often
possess improved inhibition specificity and membrane
permeability. Besides the natural occurrences they have
been synthesized from azasugars via elimination, followed
by addition of organometallic reagent to C]N,10 and from
properly constructed substrates, by intramolecular and
intermolecular conjugation additions of nucleophilic
amines. For example, Compernolle et al.11 synthesized
aza-C-glycosides from 7-amino-2,3-unsaturated ketones
and esters, by an intramolecular Michael addition, which
were prepared from 1-amino-1-deoxy-D-glucitol by regio-
selective O-isopropylidenation, selective deprotection,
Previously, we had found that 1-C-(20-oxoalkyl)-glycosides,
following base-mediated b-elimination, formed acyclic a,b-
conjugates,13 which enabled an intramolecular addition by a
thiol group to form C-thioglycoside.14 Thus, 1-C-(20-
oxoalkyl)-glycosides can be considered as latent substrates
for Michael addition. We envisioned that 1-C-(20-oxoalkyl)-
glycosides with an amino group could undergo a similar
intramolecular Michael addition to produce aza-C-glyco-
sides. Additionally, the 20-oxoalkyl group, presented as a
C-aglycon, could be further condensed with various amines
for library constructions. The library approach has led to the
discovery of azasugars with improved inhibition activities
against fucosidase,15 N-acetyl-b-hexosaminidase,16 a-man-
nosidase,7e,17and b-glucosidase.18
Keywords: Aza-C-glycosides; Inhibitors; Michael addition; Synthesis.
*
Corresponding author. Tel.: C1 613 9910855; fax: C1 613 9529092;
e-mail: wei.zou@nrc-cnrc.gc.ca
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.037

T. Yi et al. / Tetrahedron 61 (2005) 11716–11722
11717
2. Results and discussion
D-arabinose),19 which can also be synthesized by Wittig
reaction to sugar lactols.20 Removal of the 5-O-acetyl group
in 2a–c followed by mesylation, afforded 3a–c (Scheme 1).
Displacement of 5-O-Ms by an azido group led to
20-Esters (2a–c) were prepared previously from three allyl
C-glycosides (1a–c) (L-arabinose, D-ribose, and
Scheme 1.
Scheme 2.
compounds 4a–c. Catalytic hydrogenation under balloon
pressure for 20 min selectively reduced the 5-azido groups
to 5-amines (5a–c) in 90% yield without affecting the
O-benzyl groups. Subsequent treatment of 5a–c with 4%
NaOMe overnight produced, via b-elimination and hetero-
Michael addition, aza-C-glycosides (6a–c) in 45–55% yield.
This conjugate addition was highly stereoselective to give
1-C-equatorial aza-C-glycosides, which were assigned
based on NMR anlysis. The stereochenmistry is in
agreement with the previous observation.11 No 1-C-axial
product was isolated. The moderate yields were the result of
competing side reactions such as amidation, as evidenced by
the isolatation of a cyclized amide dimer (ca. 10%) with m/z
707.3 (MHC).
In order to prepare 20-ketonyl aza-C-glycosides, 1-C-allyl
glycoside 1c was converted to 5-azido-C-glycoside 7 in
three steps similar to those descibed for 4a–c (Scheme 2).
Scheme 3.

11718
T. Yi et al. / Tetrahedron 61 (2005) 11716–11722
Scheme 4.
The 1-C-allyl group was in turn oxidized with
Hg(OAc)2 and Jones reagent21 to 1-C-acetylmethyl
glycoside 8. Reduction of the azido group by catalytic
hydrogenation to amine was followed by a base-
mediated Michael addition, to produce, as expected,
20-ketonyl aza-C-glycoside 9 in 75% yield. Similar to
the observation with 20-ester aza-C-glycosides (6a–c),
the 1-C-(20-ketone) group was equatorial at the pseudo
anomeric carbon.
3. Experimental
3.1. General methods
1H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively, with a Varian instrument at 293 K.
Chemical shifts were given in ppm downfield to the signal
of internal TMS, and were assigned on the basis of 2D
1
1H-COSY, TOCSY, and H–13C chemical-shift correlated
experiments. High-resolution fast-atom bombardment mass
spectrometry (HRFABMS) was carried out on a JEOL
JMS-AX505Hmass spectrometer using a 6 kV xenon beam
at an accelerating voltage of 3 kV. m-Nitrobenzyl alcohol
(m-NBA) was used as the matrix, and polyethylene glycol
(PEG) was the internal calibrant. All chemicals are
purchased from Aldrich Co. without further purification.
We attempted to extend this approach to the synthesis of
aza-C-glycofuranosides by introducing an azido group at
the 4-position of the pyranosides. However, sulfonation
(Tf2O) at the 4-OH of glucoside 10 followed by treatment of
NaN3 in DMF did not yield 4-azido-galactoside 11. Instead,
this azidolysis produced 5-azido galactofuranoside 12 in
excellent yield.22 The 5-azido substitution was unambi-
gously confirmed by various 2D NMR analysis including
HMBC, HSQC, and COSY. The transformation involves
participation of the ring-oxygen atom resulting in a
concurrent 4,5-migration of TfO-group and ring contraction
to intermediate 14 (Scheme 3) prior to the displacement of
its 5-OTf by an azido group. Although this type of
rearrangement has never been observed with C-glycosides,
it is known to occur in O-glycosides as a result of steric
hindrance in bimolecular displacement from axial
direction.23
3.1.1. Methyl 2-C-(2,3-di-O-benzyl-5-O-Ms-a/b-L-arabi-
nofuranosyl)acetate (3a). A solution of 2a (6.1 g,
14.3 mmol) in 0.1% MeONa–MeOH solution (50 mL) was
stirred for 1 h, and then neutralized by the addition of
Dowex 50WX2-100 (HC) resin. The filtrate was concen-
trated to a syrup (5.5 g), which was dissolved in 100 mL of
CH2Cl2 and triethyl amine (10 mL, 69 mmol). To the
solution was dropwise added MsCl (3.3 g, 28.8 mmol) at
0 8C, and the solution was stirred overnight at 0 8C to room
temperature. The reaction was quenched by the addition of
aq NaHCO3. Routine work-up and purification by chroma-
tography (Hexane/EtOAc 2:1) gave 3a (5.1 g, 70% in two
steps) as a mixture of two anomers (a/bZ3:1). For
a-anomer. 1H NMR (CDCl3): d 7.37–7.24 (m, 10H),
4.55–4.51 (m, 5H), 4.29–4.22 (m, 3H), 3.99 (m, 1H), 3.93
(m, 1H), 3.64 (s, 3H), 2.96 (s, 3H), 2.74–2.63 (m, 2H); 13C
NMR (CDCl3): d 171.0, 137.3, 137.2, 128.6, 128.5, 128.0,
127.9, 127.7, 85.7, 83.9, 80.9, 79.9, 72.1, 71.7, 69.0, 51.7,
37.7, 37.4; HRFABMS: Calcd for C23H29O8S (MHC), m/z
465.1583; Found: 465.1627.
The oxidation of 1-C-allyl glycoside 12 with Hg(OAc)2 and
Jones reagent21 afforded azide 15, which was reduced to
amine. Without purification, the crude product was
subsequently subjected to a base-mediated Michael
addition to produce a mixture of aza-C-galactosides, 16a
and 16b, in 84% yield in a 1:1 ratio. Pure forms of 16a
and 16b were obtained by chromatography, and their
stereochemistry was assigned based on the NOEs between
H1 and H5 (H3) in 16b and between H3 and H10 in 16a
(Scheme 4).
3.1.2. Methyl 2-C-(2,3-di-O-benzyl-5-O-Ms-a/b-D-xylo-
furanosyl)acetate (3b). Following the same procedures as
described above 3b was obtained from 2b as a mixture of
In summary, we have described a synthetic method toward
aza-C-glycosides from 1-C-(20-oxoalkyl)-5-amino-5-
deoxy-C-glycofuranosides via an intramolecular hetero-
Michael addition. This tandem b-elimination and conjugate
addition under basic conditions provides an easy access to
biologically important aza-C-glycosides. The core azasugar
structures are suitable for further development as potential
glycosidase inhibitors.
1
two anomers (a/bZ2:1) in 65% yield. For a-anomer. H
NMR (CDCl3): d 7.39–7.24 (m, 10H), 4.60–4.51 (m, 3H),
4.42–4.31 (m, 5H), 4.05 (d, 1H, JZ3.6 Hz), 4.03 (d, 1H, JZ
3.2 Hz), 3.66 (s, 3H), 2.99 (s, 3H), 2.74–2.59 (m, 2H); 13C
NMR (CDCl3): d 171.7, 137.5, 137.4, 128.6, 128.2, 128.0,
127.9, 127.8, 84.5, 82.4, 80.5, 77.6, 72.4, 71.7, 68.9, 51.8,

T. Yi et al. / Tetrahedron 61 (2005) 11716–11722
11719
1
38.8, 37.5. For b-anomer. H NMR (CDCl3): d 7.39–7.24
3.1.6. Methyl 2-C-(5-azido-2,3-di-O-benzyl-5-deoxy-a/b-
D-ribofuranosyl)acetate (4c). Obtained from 3c as a
mixture of two anomers (a/bZ4:1) in 78% yield. For
(m, 10H), 4.60–4.51 (m, 2H), 4.42–4.31 (m, 6H), 4.01 (dd,
1H, JZ4.0, 1.2 Hz), 3.90 (dd, 1H, JZ2.4, 1.2 Hz), 3.66 (s,
3H), 2.99 (s, 3H), 2.74–2.59 (m, 2H); 13C NMR (CDCl3): d
171.7, 137.5, 137.4, 128.6, 128.1, 128.0, 127.0, 127.8, 81.2,
78.8, 77.0, 72.4, 71.7, 68.7, 51.7, 34.0, 37.5; HRFABMS:
Calcd for C23H29O8S (MHC), m/z 465.1583; Found:
465.1547.
1
a-anomer. H NMR (CDCl3): d 7.33–7.32 (m, 10H), 4.79
(d, 1H, JZ11.6 Hz), 4.68 (d, 1H, JZ11.6 Hz), 4.54–4.52
(m, 3H), 4.18–4.15 (m, 2H), 4.02 (m, 1H), 3.63 (s, 3H), 3.53
(d, 1H, JZ13.2 Hz), 3.16 (d, 1H, JZ12.8 Hz), 2.84–2.75
(m, 2H); 13C NMR (CDCl3): d 171.7, 138.0, 137.4, 128.5,
128.3, 128.0, 127.7, 80.1, 78.9, 77.2, 76.7, 73.5, 72.9, 52.0,
51.6, 34.8; HRFABMS: Calcd for C22H25O5N3 (MHC), m/z
412.1872; Found 412.1907.
3.1.3. Methyl 2-C-(2,3-di-O-benzyl-5-O-Ms-a/b-D-ribo-
furanosyl)acetate (3c). Following the same procedures as
described above 3c was obtained from 2c as a mixture of
1
3.1.7. Methyl 2-C-(5-amino-2,3-di-O-benzyl-5-deoxy-a/
b-L-arabinofuranosyl)acetate (5a). A mixture of 4a (0.5 g,
1.2 mmol) and 10% Pd–C (50 mg) in methanol (20 mL) was
stirred under H2 atmosphere (balloon pressure) for 20 min
when the starting material was completely disappeared. The
reaction mixture was filtered and the filtrate was concen-
trated. Purification by chromatography (CH2Cl2/MeOH
10:1) gave 5a (0.4 g, 93%) as a mixture of two anomers
two anomers (a/bZ4:1) in 69% yield. For a-anomer. H
NMR (CDCl3): d 7.36–7.32 (m, 10H), 4.80 (d, 1H, JZ
11.6 Hz), 4.69 (d, 1H, JZ12.0 Hz), 4.56 (d, 1H, JZ
11.2 Hz), 4.53 (d, 1H, JZ11.2 Hz), 4.47–4.45 (m, 1H), 4.35
(d, 1H, JZ8.8 Hz), 4.24–4.20 (m, 1H), 4.12 (t, 1H, JZ
4.0 Hz), 4.05 (dd, 1H, JZ7.2, 4.4 Hz), 3.63 (s, 3H), 2.99 (s,
3H), 2.76 (d, 1H, JZ2.8 Hz), 2.74 (d, 1H, JZ3.2 Hz); 13C
NMR (CDCl3): d 171.6, 137.8, 137.2, 128.6, 128.5, 128.3,
128.1, 128.0, 127.9, 127.8, 79.3, 77.9, 77.0, 76.8, 73.6, 73.1,
69.1, 51.8, 37.4, 34.7; HRFABMS: Calcd for C23H29O8S
(MHC), m/z 465.1583; Found 465.3067.
1
(a/bZ3:1). For a-anomer. H NMR (CDCl3): d 7.39–7.21
(m, 10H), 4.59–4.50 (m, 4H), 4.41 (m, 1H), 3.99 (m, 1H),
3.90 (m, 1H), 3.86 (m, 1H), 3.66 (s, 3H), 2.83 (m, 2H), 2.65
(m, 2H); 13C NMR (CDCl3): d 171.4, 137.8, 137.7, 128.6,
128.0, 127.8, 127.7, 86.7, 85.7, 84.6, 79.0, 72.0, 71.8, 51.9,
44.3, 37.9; HRFABMS: Calcd for C22H28O5N (MHC), m/z
386.1967; Found: 386.1992.
3.1.4. Methyl 2-C-(5-azido-2,3-di-O-benzyl-5-deoxy-a/b-
L-arabinofuranosyl)acetate (4a). A mixture of 3a (5.1 g,
10.4 mmol) and NaN3 (2.1 g, 32 mmol) in DMF (80 mL)
was stirred overnight at 80 8C. Upon cooling to room
temperature the reaction mixture was diluted by the addition
of ethyl ether (200 mL) and the resulted solution was
washed with water and brine. Purification by chromato-
graphy (Hexane/EtOAc 4:1) gave 4a (4.1 g, 92%) as a
mixture of two anomers. For a-anomer. 1H NMR (CDCl3):
d 7.39–7.22 (m, 10H), 4.58 (m, 1H), 4.61–4.40 (m, 4H),
4.19 (m, 1H), 3.96 (m, 2H), 3.67 (s, 3H), 3.41–3.30 (m, 2H),
2.79 (m, 2H); 13C NMR (CDCl3): d 171.1, 137.6, 137.4,
128.6, 128.1, 128.0, 127.8, 127.7, 85.2, 82.2, 79.5, 77.8,
72.2, 71.9, 52.4, 51.8, 38.0; For b-anomer. 1H NMR
(CDCl3): d 7.39–7.22, 4.61–4.40 (m, 4H), 4.45 (m, 1H),
4.04 (m, 2H), 3.88 (m, 1H), 3.64 (s, 3H), 3.41–3.30 (m, 2H),
2.79 (m, 2H); 13C NMR (CDCl3): d 171.6, 137.6, 137.5,
128.6, 128.5, 128.1, 127.8, 86.2, 83.9, 82.7, 72.2, 71.9, 52.6,
51.7, 34.0; HRFABMS: Calcd for C22H26O5N3 (MHC), m/z
412.1872; Found: 412.1995.
3.1.8. Methyl 2-C-(5-amino-2,3-di-O-benzyl-5-deoxy-a/
b-D-xylofuranosyl)acetate (5b). Obtained from 4b
following the same procedures as described above as a
mixture of two anomers (a/bZ2:1) in 90% yield. For
a-anomer. 1H NMR (CDCl3): d 7.39–7.22 (m, 10H), 4.58–
4.41 (m, 4H), 4.33 (dt, 1H, JZ7.2, 2.8 Hz), 4.09 (m, 1H),
3.97 (d, 1H, JZ4.4 Hz), 3.87 (dd, 1H, JZ2.4, 1.2 Hz), 3.66
(s, 3H), 3.05 (m, 2H), 2.85 (br, 2H), 2.73 (dd, 1H, JZ15.6,
7.2 Hz), 2.64 (dd, 1H, JZ15.6, 6.8 Hz); 13C NMR (CDCl3):
d 171.5, 137.7, 137.5, 129.0, 128.7, 128.1, 127.9, 127.7,
85.4, 83.1, 81.8, 79.6, 71.9, 71.7, 51.8, 41.1, 38.9; For
1
b-anomer. H NMR (CDCl3): d 7.39–7.22 (m, 10H), 4.60
(m, 1H), 4.58–4.41 (m, 4H), 4.17 (dd, 1H, JZ10.4, 5.6 Hz),
4.09 (m, 1H), 3.99 (d, 1H, JZ4.4 Hz), 3.63 (s, 3H), 2.99 (m,
2H), 2.85 (br, 2H), 2.69 (m, 2H); 13C NMR (CDCl3): d
172.0, 137.7, 137.6, 128.7, 128.6, 128.0, 127.0, 127.7, 81.5,
80.0, 76.4, 72.3, 72.2, 51.7, 41.1, 34.2; HRFABMS: Calcd
for C22H28O5N (MHC), m/z 386.1967; Found: 386.2032.
3.1.5. Methyl 2-C-(5-azido-2,3-di-O-benzyl-5-deoxy-a/b-
D-xylofuranosyl)acetate (4b). Obtained from 3b as a
mixture of two anomers in 80% yield. For a-anomer. H
3.1.9. Methyl 2-C-(5-amino-2,3-di-O-benzyl-5-deoxy-a/
b-D-ribofuranosyl)acetate (5c). Obtained from 4c
following the same procedures as described above as a
mixture of two anomers (a/bZ4:1) in 92% yield. For
a-anomer. 1H NMR (CDCl3): d 7.36–7.27 (m, 10H), 4.64–
4.51 (m, 4H), 4.39 (dt, JZ6.0, 5.6 Hz, 1H), 4.07 (m, 1H),
3.84 (dd, JZ5.2, 5.2 Hz, 1H), 3.75 (dd, JZ5.2, 5.2 Hz, 1H),
3.65 (s, 3H), 2.94 (m, 1H), 2.71 (m, 1H), 2.61 (dd, JZ15.6,
5.2 Hz, 1H), 2.51 (dd, JZ16.6, 7.2 Hz, 1H), 2.35 (br, 2H);
13C NMR (CDCl3): d 173.1, 138.8, 137.7, 128.5, 128.4,
128.0, 127.8, 127.7, 82.6, 80.2, 77.5, 72.1, 51.9, 43.7, 38.4;
HRFABMS: Calcd for C22H28NO5 (MHC), m/z 386.1967;
Found 386.2029.
1
NMR (CDCl3): d 7.39–7.22 (m, 10H), 4.60–4.42 (m, 4H),
4.38 (dt, 1H, JZ6.8, 2.4 Hz), 4.26–4.17 (m, 1H), 3.96 (m,
1H), 3.91 (m, 1H), 3.66 (s, 3H), 3.55–3.38 (m, 2H), 2.73 (dd,
1H, JZ13.6, 6.8 Hz); 13C NMR (CDCl3): d 171.8, 137.6,
137.4, 128.6, 128.2, 128.1, 129.9, 127.8, 84.8, 82.6, 80.2,
1
79.8, 72.5, 71.7, 51.9, 50.2, 38.9; For b-anomer. H NMR
(CDCl3): d 7.39–7.22, 4.60–4.42 (m, 4H), 4.57 (m, 1H),
4.26–4.17 (m, 1H), 4.07 (d, 1H, JZ3.6 Hz), 3.96 (m, 1H),
3.66 (s, 3H), 3.55–3.38 (m, 2H), 2.73 (dd, 1H, JZ13.6,
6.8 Hz), 2.64 (dd, 1H, JZ13.6, 6.8 Hz); 13C NMR (CDCl3):
d 171.3, 137.6, 137.4, 128.6, 128.2, 128.0, 128.9, 127.8,
81.5, 81.3, 78.8, 76.8, 72.5, 71.7, 51.7, 50.2, 34.1;
HRFABMS: Calcd for C22H26O5N3 (MHC), m/z
412.1872; Found: 412.1826.
3.1.10. Methyl 2-C-(2,3-di-O-benzyl-5-imino-5-deoxy-a-
L-arabinopyranosyl)acetate (6a). A solution of 5a (83 mg,

11720
T. Yi et al. / Tetrahedron 61 (2005) 11716–11722
0.21 mmol) in 4% NaOMe/MeOH (10 mL) was stirred
overnight. NH4Cl (0.2 g) was added and the solvent was
evaporated under diminished pressure. The remaining
residue was dissolved in water, extracted with EtOAc. The
organic phase was dried and concentrated. Purification by
chromatography (EtOAc/MeOH 10:1) gave 6a (44 mg,
(m, 1H), 3.59 (dd, 1H, JZ12.8, 3.2 Hz), 3.16 (dd, 1H, JZ
13.2, 3.6 Hz), 2.49 (m, 2H); 13C NMR (CDCl3): d 138.4,
137.7, 134.7, 128.6, 128.4, 128.1, 127.9, 127.8, 117.1, 80.7,
80.4, 78.8, 77.5, 73.6, 73.0, 52.1, 34.3; HRFABMS: Calcd
for C22H25O3N3Na (MCNaC), m/z 402.1794; Found
402.1874.
1
55%) as a colorless syrup. [a]D C4.1 (c 1.15, CHCl3); H
NMR (CDCl3): d 7.37–7.24 (m, 10H), 4.64 (d, 1H, JZ
11.6 Hz), 4.57 (d, 1H, JZ11.6 Hz), 4.52 (d, 1H, JZ
11.6 Hz), 4.46 (d, 1H, JZ11.6 Hz), 3.85 (m, 1H), 3.75 (dd,
1H, JZ3.6 Hz), 3.62 (s, 3H), 3.60 (m, 1H), 3.41 (m, 1H),
2.94 (dd, 1H, JZ12.8, 4.4 Hz), 2.78 (dd, 1H, JZ13.2,
6.8 Hz), 2.43 (m, 2H), 1.93 (br s, 2H); 13C NMR (CDCl3): d
172.7, 137.9, 137.8, 128.7, 128.6, 128.3, 128.2, 128.0, 76.3,
75.3, 72.9, 66.6, 51.8, 51.2, 47.2, 35.6; HRFABMS: Calcd
for C22H28O5N (MHC), m/z 386.1967; Found: 386.1991.
3.1.14. 1-C-Acetylmethyl 5-azido-2,3-di-O-benzyl-5-
deoxy-a-D-ribofuranoside (8). To a solution of 7
(160 mg, 0.42 mmol), Hg(OAc)2 (96 mg, 0.3 mmol), and
water (1 mL) in acetone (4 mL) was added 2 mL of Jones
reagent (prepared by dissolving 2 mL of H2SO4 and 2 g of
Na2Cr2O7$2H2O in 6 mL of water). The reaction mixture
was stirred at room temperature for 4 h. The reaction
mixture was poured into water (10 mL) and extracted by
EtOAc, the organic phase was washed with water and brine.
Purification by column (Hexane/EtOAc 4:1) gave 8 as a
1
3.1.11. Methyl 2-C-(2,3-di-O-benzyl-5-imino-5-deoxy-b-
D-xylopyranosyl)acetate (6b). The same procedures as
described above were used for the preparation of 6b (45%).
[a]D C3.1 (c 0.23, CHCl3); 1H NMR (CDCl3): d 7.39–7.24
(m, 10H), 4.68–4.39 (m, 4H), 4.48 (br s, 2H), 3.79 (m, 2H),
3.62 (s, 3H), 3.62–3.58 (m, 2H), 3.23 (m, 1H), 3.12 (m, 1H),
2.69 (dd, 1H, JZ16.0, 6.8 Hz), 2.52 (dd, 1H, JZ16.0,
6.4 Hz); 13C NMR (CDCl3): d 172.2, 137.9, 136.6, 128.8,
128.7, 128.5, 128.2, 127.9, 75.2, 73.0, 72.4, 66.3, 51.9, 51.4,
47.2, 35.3; HRFABMS: Calcd for C22H28O5N (MHC), m/z
386.1967; Found: 386.1997.
syrup (133 mg, 80%). [a]D C83.3 (c 1, CHCl3); H NMR
(CDCl3): d 7.36–7.28 (m, 10H), 4.80 (d, 1H, JZ11.2 Hz),
4.69 (d, 1H, JZ12.0 Hz), 4.54 (d, 1H, JZ12.0 Hz), 4.48 (m,
1H), 4.46 (d, 1H, JZ11.2 Hz), 4.15 (m, 2H), 3.99 (dd, 1H,
JZ8.0, 3.6 Hz), 3.52 (dd, 1H, JZ12.8, 3.2 Hz), 3.18 (dd,
1H, JZ12.8, 3.6 Hz), 2.92 (dd, 1H, JZ17.6, 7.6 Hz), 2.82
(dd, 1H, JZ17.6, 6.0 Hz), 2.07 (s, 3H); 13C NMR (CDCl3):
d 207.2, 138.2, 137.6, 128.7, 128.5, 128.2, 128.0, 127.9,
80.5, 78.6, 77.5, 76.5, 73.9, 73.1, 52.2, 43.9, 30.6;
HRFABMS: Calcd for C22H25O4N3Na(MCNaC), m/z
418.1743; Found 418.1674.
3.1.12. Methyl 2-C-(2,3-di-O-benzyl-5-imino-5-deoxy-b-
D-ribopyranosyl)acetate (6c). The same procedures as
described above were used for the preparation of 6c (52%).
[a]D K10.2 (c 0.21, CHCl3); 1H NMR (CDCl3): d 7.35–7.34
(m, 10H), 5.00 (d, 1H, JZ11.6 Hz), 4.73 (d, 1H, JZ
11.6 Hz), 4.58 (d, 1H, JZ11.2 Hz), 4.52 (d, 1H, JZ
11.2 Hz), 4.06 (s, 1H), 3.64 (s, 3H), 3.60 (m, 1H), 3.39–3.35
(dt, 1H, JZ8.4, 2.6 Hz), 3.25 (d, 1H, JZ8.8 Hz), 2.88 (m,
1H), 2.82–2.75 (m, 2H), 2.33 (dd, 1H, JZ16.2, 8.4 Hz),
1.94 (br s, 2H); 13C NMR (CDCl3): d 172.8, 138.5, 137.5,
128.5, 128.4, 127.9, 127.8, 127.7, 80.8, 76.0, 74.0, 71.7,
69.0, 51.6, 51.2, 47.2, 36.0; HRFABMS: Calcd for
C22H28NO5 (MHC), m/z 386.1967; Found 386.2025.
3.1.15. 1-C-Acetylmethyl 2,3-di-O-benzyl-5-imino-5-
deoxy-b-D-ribopyranoside (9). A mixture of 8 (120 mg,
0.3 mmol) and 10% Pd–C (50 mg) in methanol (10 mL) was
stirred under H2 atmosphere (balloon pressure) for 20 min
when the starting material was disappeared. The reaction
mixture was filtered and the filtrate was concentrated to a
residue. The above residue was dissolved in 4% NaOMe/
MeOH (10 mL) and stirred overnight. NH4Cl (0.2 g) was
added and the mixture was evaporated. The remaining
residue was dissolved in water, extracted with EtOAc.
Purification by chromatography (EtOAc) produced 9 as a
1
syrup (83 mg, 75%). [a]D K38.8 (c 1.0, CHCl3); H NMR
(CDCl3): d 7.39–7.23 (m, 10H), 5.00 (d, 1H, JZ11.2 Hz),
4.74 (d, 1H, JZ11.6 Hz), 4.59 (d, 1H, JZ11.2 Hz), 4.50 (d,
1H, JZ11.6 Hz), 4.05 (s, 1H), 3.59 (m, 1H), 3.36 (dt, 1H,
JZ8.8, 3.2 Hz), 3.23 (d, 1H, JZ9.2 Hz), 2.88–2.76 (m,
3H), 2.39 (dd, 1H, JZ17.2, 8.8 Hz), 2.20 (br, 2H), 2.09 (s,
3H); 13C NMR (CDCl3): d 208.6, 138.7, 138.1, 137.7, 128.6,
128.1, 127.8, 127.7, 81.0, 76.2, 74.2, 71.8, 69.1, 50.7, 47.4,
45.4, 30.5; HRFABMS: Calcd for C22H28O4N (MHC), m/z
370.2019; Found: 370.2042.
3.1.13. 1-C-Allyl 5-azido-2,3-di-O-benzyl-5-deoxy-a-D-
ribofuranoside (7). A solution of 1c (300 mg, 0.76 mmol)
in 0.1% MeONa–MeOH (10 mL) was stirred for 1 h, and
then neutralized by the addition of Dowex 50WX2-100
(HC) resin. The filtrate was concentrated to a residue, which
was dissolved in CH2Cl2 (15 mL) and triethyl amine (1 mL,
6.9 mmol). To the solution was added MsCl (174 mg,
1.52 mmol) at 0 8C. The mixture was stirred overnight at
0 8C to room temperature, and then quenched by the
addition of aq NaHCO3. Routine work-up and chromato-
graphic purification (Hexane/EtOAc 4:1) afforded 5-OMs
product. A mixture of the above product and NaN3 (210 mg,
3.2 mmol) in DMF (10 mL) was stirred at 80 8C overnight.
Routine work-up and chromatographic purification
(Hexane/EtOAc 6:1) gave 7 as a syrup (170 mg, 59%).
[a]D C83.7 (c 1.0, CHCl3); 1H NMR (CDCl3): d 7.36–7.28
(m, 10H), 5.79 (m, 1H), 5.10 (m, 2H), 4.83 (d, 1H, JZ
11.6 Hz), 4.68 (d, 1H, JZ11.6 Hz), 4.61 (d, 1H, JZ11.6 Hz),
4.51 (d, 1H, JZ11.6 Hz), 4.21 (dt, 1H, JZ7.6, 3.6 Hz), 4.06
(dt, 1H, JZ3.2, 7.2 Hz), 4.02 (dd, 1H, JZ4.0 Hz), 3.98
3.1.16. 1-C-Allyl 5-azido-5-deoxy-2,3,6-tri-O-benzyl-a-D-
galactofuranoside (12). To a solution of 10 (450 mg,
0.95 mmol) and pyridine (210 mg, 2.65 mmol) in CH2Cl2
(10 mL) was added Tf2O (490 mg, 1.73 mmol) at 0 8C and
the solution was stirred at room temperature for 5 h. The
reaction was quenched by the addition of water, extracted
with CH2Cl2. The organic phase was washed with water,
dried, and concentrated to yellowish oil. A mixture of the
above oil and sodium azide (330 mg, 5.08 mmol) in DMF
(10 mL) was stirred overnight at room temperature. The
reaction mixture was diluted by ethyl ether (50 mL) and the
organic phase was washed with water and brine. Purification

T. Yi et al. / Tetrahedron 61 (2005) 11716–11722
11721
by chromatography (Hexane/EtOAc 8:1) gave 12 as a syrup
(410 mg, 86%). [a]D K63.0 (c 0.4, CHCl3); 1H NMR
(CDCl3): d 7.39–7.21 (m, 15H), 5.81 (m, 1H), 5.09 (m, 2H),
4.56–4.41 (m, 6H), 3.98 (m, 2H), 3.92 (dd, 1H, JZ4.8,
3.6 Hz), 3.81 (d, 1H, JZ3.6 Hz), 3.61 (m, 3H), 2.50 (m,
2H); 13C NMR (CDCl3): d 137.9, 137.7, 137.6, 134.7, 128.6,
128.5, 128.2, 128.0, 127.9, 127.8, 127.7, 117.1, 84.0, 83.6,
82.6, 81.3, 73.5, 71.8, 71.6, 70.0, 62.1, 33.2; HRFABMS:
Calcd for C30H34O4N (MHCKN2), m/z 472.2488; Found:
472.2407.
037. NMR spectra for compounds 5a–c, 6a–c, 7–9, 12, 15,
16a and 16b.
References and notes
1. (a) Yasuda, K.; Kizu, H.; Yamashita, T.; Kameda, Y.; Kato,
A.; Nash, R. J.; Fleet, G. W. J.; Asano, N. J. Nat. Prod. 2002,
65, 198–202. (b) Yamashita, T.; Yasuda, K.; Kizu, H.;
Kameda, Y.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.;
Asano, N. J. Nat. Prod. 2002, 65, 1875–1881. For early
reviews, see: (c) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet,
G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645–1680. (d)
Wagman, G. H.; Cooper, R. Natural Products Isolation;
Elsevier Science: New York, 1989; pp 530–559.
3.1.17. 1-C-Acetylmethyl 5-azido-5-deoxy-2,3,6-tri-O-
benzyl-a-D-galactofuranoside (15). The same procedures
as described for the preparation of 8 were used to obtain 15
in 81% yield. [a]D K40.6 (c 1.3, CHCl3); 1H NMR (CDCl3): d
7.38–7.21 (m, 15H), 4.51 (m, 4H), 4.44–4.34 (m, 3H), 4.03 (d,
1H, JZ4.0 Hz), 4.01 (dd, 1H, JZ4.0, 0.4 Hz), 3.90 (m, 1H),
3.58 (m, 3H), 2.88 (m, 2H), 2.12 (s, 3H); 13C NMR (CDCl3): d
207.0, 137.7, 137.5, 128.7, 128.6, 128.1, 128.0, 127.9, 127.8,
83.88, 83.81, 82.8, 77.5, 73.5, 72.0, 71.8, 69.9, 61.9, 42.9,
30.8; HRFABMS: Calcd for C30H33O5N3Na (MCNaC), m/
z 538.2318; Found: 538.2320.
2. For leading reviews, see: (a) Stu¨tz, A. E. Iminosugars as
Glycosidase Inhibitors: Nojirimycin and Beyound; Wiley-
VCH: New York, 1999. (b) Ganem, B. Acc. Chem. Res. 1996,
29, 340–347. (c) Lillelund, V. H.; Jensen, H. H.; Liang, X.;
Bols, M. Chem. Rev. 2002, 102, 515–553. (d) Sears, P.; Wong,
C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300–2322.
3.1.18. 1-C-Acetylmethyl 2,3,6-tri-O-benzyl-5-imino-5-
deoxy-a/b-D-galactopyranoside (16a/16b). The same
procedures as described for the preparation of 9 were used
for the transformation of 15 to a mixture of 16a and 16b,
with a 1:1 ratio, in 84% yield. For 16a: [a]D C9.3 (c 1.0,
3. Mitrakou, A.; Tountas, N.; Raptis, A. E.; Bauer, R. J.; Schulz,
H.; Raptis, S. A. Diabetic. Med. 1998, 15, 657–660.
4. (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Curr. Top. Med.
Chem. 2003, 3, 561–574. (b) Butters, T. D.; Dwek, R. A.; Platt,
F. M. Chem. Rev. 2000, 100, 4683–4696. (c) Cox, T.;
Lachmann, R.; Hollak, C.; Aerts, J.; vanWeely, S.; Hrebicek,
M.; Platt, F. M.; Butters, T. D.; Dwek, R. A.; Moyses, C.; Gow,
I.; Elstein, D.; Zimran, A. Lancet 2000, 355, 1481–1485.
5. For leading reviews, see (a) Cipolla, L.; Ferla, B. L.; Nicotra,
F. Curr. Top. Med. Chem. 2003, 3, 485–511. (b) Compain, P.;
Martin, O. R. Curr. Top. Med. Chem. 2003, 3, 541–560 and
Ref. 2a and b.
1
CHCl3); H NMR (CDCl3): d 7.38–7.21 (m, 15H), 4.69 (s,
2H), 4.64 (d, 1H, JZ11.6 Hz), 4.56 (d, 1H, JZ11.6 Hz),
4.48 (s, 2H), 3.99 (s, 1H), 3.84 (m, 2H), 3.62 (dd, 1H, JZ
9.2, 5.6 Hz), 3.52 (m, 1H), 3.45 (dd, 1H, JZ8.8, 2.8 Hz),
2.94 (dd, 1H, JZ5.6 Hz), 2.77 (dd, 1H, JZ17.2, 4.4 Hz),
2.59 (br s, 1H), 2.55 (dd, 1H, JZ16.8, 8.4 Hz), 2.08 (s, 3H);
13C NMR (CDCl3): d 207.9, 138.5, 138.4, 138.1, 128.5,
128.4, 128.2, 128.0, 127.9, 127.8, 79.1, 77.3, 73.6, 73.2,
72.4, 70.9, 68.0, 52.0, 50.6, 40.4, 30.9; HRFABMS: Calcd
for C30H36O5N (MHC), m/z 490.2593; Found: 490.2641.
6. (a) McDonnell, C.; Cronin, L.; O’Brien, J. L.; Murphy, P. V.
J. Org. Chem. 2004, 69, 3565–3568. (b) Tosin, M.; O’Brien,
J. L.; Murphy, P. V. Org. Lett. 2001, 3, 3353–3356. (c) Chery,
F.; Murphy, P. V. Tetrahedron Lett. 2004, 45, 2067–2069. (d)
Godin, G.; Compain, P.; Martin, O. R. Org. Lett. 2003, 5,
3269–3272. (e) Godin, G.; Compain, P.; Masson, G.; Martin,
O. R. J. Org. Chem. 2002, 67, 6960–6970. (f) Baxter, E. W.;
Reitz, A. B. J. Org. Chem. 1994, 59, 3175–3185. (l) Zou, W.;
Szarek, W. A. Carbohydr. Res. 1994, 254, 25–33. (h) Zou, W.;
Szarek, W. A. Carbohydr. Res. 1993, 242, 311–314. (i) Cheng,
X.; Kumaran, G.; Mootoo, D. R. Chem. Commun. 2001,
811–812. (j) Zhao, H.; Mootoo, D. R. J. Org. Chem. 1996, 61,
6762–6763. (k) Fleet, G. W. J.; Ramsden, N. G.; Witty, D. R.
Tetrahedron 1989, 45, 319–326. (l) Wong, C.-H.; Halcomb,
R. L.; Ichikawa, Y.; Kajimoto, T. Angew. Chem., Int. Ed. 1995,
37, 412–432 and references cited therein.
1
For 16b: [a]D K3.8 (c 0.4, CHCl3); H NMR (CDCl3): d
7.39–7.22 (m, 15H), 4.96 (d, 1H, JZ11.2 Hz), 4.75 (d, 1H,
JZ11.6 Hz), 4.65 (d, 1H, JZ10.4 Hz), 4.57–4.50 (m, 3H),
4.05 (s, 1H), 3.61 (dd, 1H, JZ9.2, 5.2 Hz), 3.53 (m,1H),
3.47 (m, 2H), 2.95 (dt, 1H, JZ8.8, 2.8 Hz), 2.90–2.83 (m,
2H), 2.50 (br, 1H), 2.43 (dd, 1H, JZ17.2, 8.8 Hz), 2.06 (s,
3H); 13C NMR (CDCl3): d 208.1, 138.5, 138.1, 128.6, 128.5,
128.2, 128.0, 127.9, 84.5, 79.3, 75.3, 73.6, 71.6, 70.8, 66.9,
57.4, 55.9, 46.1, 30.4; HRFABMS: Calcd for C30H36O5N
(MHC): m/z 490.2593; Found: 490.2611.
Acknowledgements
´ ´
7. (a) Pino-Gonzalez, M. S.; Assiego, C.; Lopez-Herrera, F. J.
Tetrahedron Lett. 2003, 44, 8353–8356. (b) Assiego, C.;
This is NRCC publication No. 42505. We are grateful to
Ms. Milan Bhasin for technical assistance and Ms. Lisa
Morrison for mass spectroscopic analysis. The authors also
thank Dr. Harry Jennings for helpful discussion.
´
´
Pino-Gonzalez, M. S.; Lopez-Herrera, F. J. Tetrahedron Lett.
2004, 45, 2611–2613. (c) Kim, N.-S.; Choi, J.-R.; Cha, J. K.
J. Org. Chem. 1993, 58, 7096–7099. (d) Saotome, C.; Kanie,
Y.; Osamu Kanie, O.; Wong, C.-H. Bioorg. Med. Chem. 2000,
8, 2249–2261. (e) Saotome, C.; Wong, C.-H.; Kanie, O. Chem.
Biol. 2001, 8, 1061–1070.
Supplementary data
8. Moreno-Vargas, A. J.; Robina, I.; Demange, R.; Vogel, P.
Helv. Chim. Acta 2003, 86, 1894–1913.
9. (a) Dondoni, A.; Perrone, D. Tetrahedron 2003, 59,
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.09.

11722
T. Yi et al. / Tetrahedron 61 (2005) 11716–11722
¨
4261–4273. (b) Pettersson, H.; Riesinger, S. W.; Backvall,
J.-E. J. Org. Chem. 1995, 60, 6091–6096.
17. Popwycz, F.; Gerber-Lemaire, S.; Rodriguez-Garcia, E.;
Schutz, C.; Vogel, P. Helv. Chim. Acta 2003, 86, 1914–1948.
18. Wrodnigg, T. M.; Withers, S. G.; Stu¨tz, A. E. Bioorg. Med.
Chem. Lett. 2001, 11, 1063–1064.
10. (a) Chapman, T. M.; Courtney, S.; Hay, P.; Davis, B. G. Chem.
Eur. J. 2003, 9, 3397–3414. (b) Maughan, M. A.; Davies, I. G.;
Claridge, T. D. W.; Courtney, S.; Hay, P.; Davis, B. G. Angew.
Chem., Int. Ed. 2003, 42, 3788–3792. (c) Wong, C.-H.;
Provencher, L.; Porco, J. A., Jr.,; Jung, S.-H.; Wang, Y.-F.;
Chen, L.; Wang, R.; Steensma, D. H. J. Org. Chem. 1995, 60,
1492–1501.
19. Yi, T.; Wu, S.-H.; Zou, W. Carbohydr. Res. 2005, 340,
235–244.
20. (a) Dawe, R. D.; Fraser-Reid, B. J. Org. Chem. 1984, 49,
522–528. (b) Dheilly, L.; Frechou, C.; Beaupere, D.; Uzan, R.;
Demailly, G. Carbohydr. Res. 1992, 224, 301–306. (c)
Pougny, J. R.; Nassr, M. A. M.; Sinay¨, P. J. Chem. Soc.,
Chem. Commun. 1981, 375–376. (d) Orhui, H.; Jones, G. H.;
Moffat, J. G.; Maddox, M. L.; Christensen, A. T.; Byram, S. K.
J. Am. Chem. Soc. 1975, 97, 4602–4613. (e) Hanessian, S.;
Ogawa, T.; Guindon, Y. Carbohydr. Res. 1974, 38, C12–C14.
21. (a) Rogers, H. R.; McDermott, J. X.; Whitesides, G. M. J. Org.
Chem. 1975, 40, 3577–3580. (b) Bowers, A.; Halsall, T. G.;
Jones, E. R. H.; Lemin, A. J. J. Chem. Soc. 1953, 2555–2560.
(c) Shao, H.; Ekthawatchai, S.; Chen, C.-C.; Wu, S.-H.; Zou,
W. J. Org. Chem. 2005, 70, 4726–4734.
11. (a) Compernolle, F.; Joly, G.; Peeters, K.; Toppet, S.;
Hoornaert, G.; Babady-Bila, A. K. Tetrahedron 1997, 53,
12739–12754. (b) Kilonda, A.; Compernolle, F.; Toppet, S.;
Hoornaert, G. J. Tetrahedron Lett. 1994, 35, 9047–9050.
12. (a) Chaudhari, V. D.; Kumar, K. S. A.; Dhavale, D. D.
Tetrahedron Lett. 2004, 45, 8363–8366. (b) Dhavale, D. D.;
Matin, M. M.; Sharma, T.; Sabharwal, S. G. Bioorg. Med.
Chem. 2003, 11, 3295–3305. (c) Patil, N. T.; Tilekar, J. N.;
Dhavale, D. D. J. Org. Chem. 2001, 66, 1065–1074.
13. (a) Wang, Z.; Shao, H.; Lacroix, E.; Wu, S.-H.; Jennings, H.;
Zou, W. J. Org. Chem. 2003, 68, 8097–8105. (b) Shao, H.;
Wang, Z.; Lacroix, E.; Wu, S.-H.; Jennings, H.; Zou, W. J. Am.
Chem. Soc. 2002, 124, 2130–2131.
22. Although 4-azido-C-glucopyranoside was obtained using this
method and converted to 1-acetylmethyl-4-azido-C-glucopyr-
anoside, the reduction of azido group led spontaneously to
intramolecular imination.
14. Zou, W.; Lacroix, E.; Wang, Z.; Wu, S.-H. Tetrahedron Lett.
2003, 44, 4431–4433.
23. (a) Horton, D.; Wander, J. D. In The Carbohydrates:
Chemistry and Biochemistry (IB); Pigman, W., Horton, D.,
Eds. 2nd ed.; Academic: New York, 1980; pp 643–760. (b)
Stevens, C. L.; Glinski, R. P.; Taylor, K. G.; Sirokman, F. J.
Org. Chem. 1970, 35, 592–596.
15. Wu, C.-Y.; Chang, C.-F.; Chen, J. S.-Y.; Wong, C.-H.; Lin, C.-
H. Angew. Chem., Int. Ed. 2003, 42, 4661–4664.
16. Liu, J.; Numa, M. M. D.; Liu, H.; Huang, S.-J.; Sears, P.;
Shikhman, A. R.; Wong, C.-H. J. Org. Chem. 2004, 69,
6273–6283.