Synthesis of iminoalditol analogues of galactofuranosides and their activities against glycosidases

Article abstract of DOI:10.1016/j.carres.2008.07.013

Iminoalditol analogues of galactofuranosides were synthesized from 1-C-(2′-oxo-propyl)-1,4-dideoxy-1,4-imino-d-galactosides and different amines by reductive amination, followed by removal of protecting groups. The activity of these compounds against galactosidases and other glycosidases was investigated. The best inhibitor against β-galactosidase (bovine liver) is a diastereomeric mixture of an iminoalditol (10h), which contains a hydrophobic hexadecyl aglycon (R = C₁₆H₃₃), whereas no significant inhibitory activity was observed with compounds having a hydrophilic aglycon. Surprisingly, activation of α-galactosidase (coffee bean) by 10h was also observed. Because these results were obtained from a mixture of iminoalditols, the inhibition and activation of glycosidases could result from different diastereomers. Crown Copyright

Full text of DOI:10.1016/j.carres.2008.07.013

Carbohydrate Research 343 (2008) 2878–2886
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of iminoalditol analogues of galactofuranosides and their
activities against glycosidases
Mahendra Sandbhor a, Milan Bhasin a, Dean T. Williams a, Margaret Hsieh a, Shih-Hsiung Wu b, Wei Zou a,
*
a Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada K1A 0R6
b Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Iminoalditol analogues of galactofuranosides were synthesized from 1-C-(20-oxo-propyl)-1,4-dideoxy-
1,4-imino- -galactosides and different amines by reductive amination, followed by removal of protecting
groups. The activity of these compounds against galactosidases and other glycosidases was investigated.
The best inhibitor against b-galactosidase (bovine liver) is a diastereomeric mixture of an iminoalditol
(10h), which contains a hydrophobic hexadecyl aglycon (R = C16H33), whereas no significant inhibitory
Article history:
Received 6 June 2008
Received in revised form 16 July 2008
Accepted 19 July 2008
Available online 26 July 2008
D
activity was observed with compounds having a hydrophilic aglycon. Surprisingly, activation of a-galac-
Dedicated to Professor Yongzheng Hui on
the occasion of his 70th birthday
tosidase (coffee bean) by 10h was also observed. Because these results were obtained from a mixture of
iminoalditols, the inhibition and activation of glycosidases could result from different diastereomers.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Keywords:
Iminoalditols
Synthesis
Glycosidase
Inhibition
Activation
1. Introduction
brosidase and a-galactosidase A deficiency. Other glycosidase
deficiency diseases, such as GM1-gangliosidosis and Morquio B
disease, have also been investigated in the animal model using
glycosidase inhibitors as chemical chaperons.7
Previously, we have synthesized various 2-keto-iminoalditols
with the aim of using them for diversity-oriented synthesis.8 For
example, by conjugation with various amines by reductive amina-
tion we will be able to obtain an array of diverse iminoalditols that
can be tested against glycosidases. In this report, we describe the
synthesis of various iminoalditol analogues of galactofuranosides
Iminosugars as potent glyco-processing enzyme inhibitors have
been clinically applied to the treatment of diabetes and glyco-
sidase-deficient diseases.1 For example, Miglitol (N-hydroxy-
ethyldeoxynojirimycin), a
a-glucosidase inhibitor, is used for
blood glucose control. Miglustat (N-butyldeoxynojirimycin), a gluco-
sylceramide synthase inhibitor, is one of the therapeutics for type
1 Gaucher disease. The therapeutic applications of iminosugars
could be expanded if better inhibition specificity against
a- or
b-glycosidases can be obtained. There have been examples sug-
and their activities against glycosidases, particularly, a- and
gesting that homoiminosugars and 1-C-alkyl iminosugars are more
selective inhibitors, particularly against
b-galactosidases.
a
-glycosidases.2 The
improved selectivity was attributed to the defined anomeric
configuration and additional interaction between the aglycon and
the lipophilic domain of glycosidases.3
In addition, iminosugars can also be utilized at subinhibitory
concentrations as chemical chaperons that resurrect misfolded en-
zymes in the ER/Golgi from degradation and facilitate the transpor-
tation to lysosome, where lower pH stabilizes the enzyme.4 This
chemical chaperon approach has been explored for the treatment
of both Gaucher5 and Fabry6 diseases with lysosomal b-glucocere-
2. Results and discussion
Five-membered iminosugar derivatives, containing a pyrrol-
idine core, demonstrated inhibitory potency against various glyc-
osidases because of their ability to mimic transition states.9 The
core structure of this study is an iminoalditol analogue of the
galactofuranoside ring, which was derivatized through the 2-keto
group via reductive amination with different amines. We first syn-
thesized 5 as a key intermediate following a procedure similar to
that used for the synthesis of similar iminosugar analogues of pyr-
anosides,8,10 which is illustrated in Scheme 1. Methyl 2,3,6-tri-O-
* Corresponding author. Tel.: +1 613 991 0855; fax: +1 613 952 9092.
E-mail address: wei.zou@nrc-cnrc.gc.ca (W. Zou).
benzyl-a-D
-glucopyranoside (1)11 was used as the starting material
0008-6215/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.07.013

M. Sandbhor et al. / Carbohydrate Research 343 (2008) 2878–2886
2879
1. Tf O/DCM/Py
2
2. NaN /DMF
3
OBn
O
Allyl-TMS/TMSOTf
70%
N
OBn
O
N
OBn
O
3
3
86%
HO
BnO
BnO
BnO
BnO
OMe
BnO
BnO
OMe
3
1
2
PdCl /CuCl /air/DMF-H O
2
2
2
86%
N
OBn
O
3
BnO
NH
O
BnO
BnO
BnO
1. H /Pd-C/MeOH
OH
OBn
2
O
2. LiOH/THF-H O, 70 ºC, 3d
2
4
5 α/β 1:3
72%
Scheme 1. Synthesis of 2-keto-iminoalditol 5.
and was converted to the 4-azido derivative 2 by a standard meth-
od, which was followed by 1-C-allylation to give compound 3. This
reaction sequence was necessary to avoid a ring contraction
reaction that occurred during azide substitution of the 4-OH of
allyl C-glycoside 6, leading to the formation of 5-azido-C-galacto-
furanoside 7 (Scheme 2).8a
Introduction of the ketone functionality was achieved by treat-
ment of 3 with either Hg(OAc)2–Jones reagent12 or PdCl2–CuCl2.13
A better chemical yield of 4 was obtained by the latter method.
The reduction of the 4-azido group by catalytic hydrogenation of
4 under balloon pressure afforded the 4-amino-derivative com-
pletely as indicated by TLC analysis. Without further purification,
the amine was treated with LiOH in THF–H2O at 70 °C for three
5. It should be noted that all those compounds obtained from
reductive amination are mixtures of four diastereomers as indi-
cated by 1H NMR.
The reductive amination between 5 and hexylamine to produce
9g was very sluggish and resulted in a poor yield of the target. An
alternative method to improve the chemical yield of the reductive
amination involved protection of both amino and 5-hydroxyl
groups of 5 (Scheme 4). Thus, compound 5 was treated with benzyl
bromide/K2CO3 (to 12), followed by acetic anhydride to furnish 13.
The reductive amination of 13 with hexylamine afforded imino-
alditol 14 in 66% yield, which, after catalytic removal of O-benzyl
groups, produced 10g.
With these compounds, we performed inhibition assays against
a range of glycosidases. None of these compounds showed signifi-
days to obtain keto-iminoalditol 5 as a mixture of anomers (a/b
1:3). Apparently, the tandem b-elimination and Michael addition
of the 2-keto-C-glycopyranosides such as 4 requires stronger con-
ditions than respective C-furanosides,8,10 which underwent the
same intramolecular rearrangement at room temperature using
1–4% NaOMe.
cant inhibitory activity against
dase (almond), -mannosidase (jack bean), b-mannosidase (snail),
and -fucosidase (bovine kidney) at 100 M concentrations. When
screened against galactosidases, only 10h and 11 were found to be
active. The diastereomeric mixture 10h was particularly potent
a-glucosidase, (B. yeast), b-glucosi-
a
a
l
Iminoalditol derivatives 10a–i were then prepared from 5 and
respective amines by reductive amination followed by catalytic
hydrogenation (Scheme 3). The reductive amination using sodium
cyanoborohydride led, in most cases, to amine 9; however, a signif-
icant amount of unreduced imine intermediate 8 was also obtained
when 1-(2-aminoethyl)-piperazine and 1-(2-aminoethyl)-morpho-
line were used (8a and 8b), as indicated by the presence of a singlet
of 30-Me resonance in the 1H NMR spectrum. Fortunately, the
catalytic hydrogenation in the next step converted both to desired
products (10a and 10b). In this study, we included heterocycles
against bovine liver b-galactosidase, with an IC50 = 2.74
at 100 M). On the other hand, compound 11 was shown to be a
moderate inhibitor of -galactosidase from coffee bean (58% at
100 M). The results provide another example that the hydro-
phobic aglycon is critical to the binding affinity to a particular
enzyme, which have been repeatedly observed previously, for
lM (81%
l
a
l
example, hydrophobicity of
a-1-C-alkyl-deoxynojirimycin deriva-
tives played a critical secondary binding to enzyme in the inhibi-
tion against isomaltase.3 However, one cannot exclude the
possibility that the hydrophobic binding could be the initial inter-
action prior to the more specific binding of iminosugar motif to the
enzyme, which may explain why 10h and 11 showed completely
different specificities. In addition, an inhibition kinetic study using
a Lineweaver–Burk plot showed that the inhibition was not
entirely competitive.
Because a diastereomeric mixture was used for the inhibition
assay, it is possible that not all the isomers contributed equally
to the activities observed. There have been examples indicating
that six-membered (piperidine) b-homoiminosugars are often
(10a and 10b),
a- and b- amino acids (10c, 10d, and 10f), alkyl-
amines (10g and 10h), and a uridine derivative (10i) as part of
the aglycon to evaluate their roles in the interaction with glycos-
idases. Under catalytic hydrogenation, the iminoalditol containing
the uridine group14 (9i) underwent not only de-O-benzylation but
also reduction of the double bond of nucleotide, which conse-
quently afforded 10i. Compound 11 with only the core structure
was obtained by direct catalytic removal of O-benzyl groups from
weaker inhibitors than
a-anomers as had been observed by Fleet
BnO
et al.15 in homonojirimycin and Martin et al. in homogalactono-
OBn
O
1. Tf O
2
O
jirimycin16 and
jirimycin and
a
a
-1-C-substituted fagomines.2c Both
-homogalactonojirimycin showed excellent
-glycosidases but not b-galactosidases.
a-homono-
2. NaN
HO
BnO
3
BnO
3
N
BnO
specificity toward
a
OBn
7
The non-activity of 10a–c, 10f, 10g, and 10i against galacto-
sidases was not a surprise as the serendipitous hydrophobic inter-
action, observed for 10h, is now absent or depleted with these
6
Scheme 2. Ring contraction of C-glycopyranoside.

2880
M. Sandbhor et al. / Carbohydrate Research 343 (2008) 2878–2886
BnO
NH
N R
BnO
8
OH
OBn
HO
1
NH
HO
1'
2'
H /Pd(OH)
2
2
NaCNBH
MeOH
NH R
3
+
BnO
+
H N R
2
5
AcOH-H O
2
(1:2)
NH
6
OH
3'
NH R
OH
10
BnO
OH
OBn
H /Pd(OH)
2
2
9
AcOH-H O
2
(1:2)
HO
R
NH
O
8/9
10
HO
OH
OH
4'
4'
4'
11
N
N
5'
a
b
5'
NH
O
NH
6'
6'
7'
7'
7'
4'
N
5'
N
5'
4'
O
6'
6'
7'
4'
CH CO H
9 only
2
2
c
d
e
f
CH CO H
2 2
4'
4'
CH CH CO Et
9 only
9 only
CH CH CO Et
2 2 2
2
2
2
4'
5'
CH CH CO Me
2
2
2
4'
CH CH CO H
2
2
2
9'
9'
4'
4'
CH (CH ) CH
CH (CH ) CH
2
2 4
3
2
2 4
3
g
h
i
19'
19'
4'
4'
9 only
9 only
CH (CH ) CH
CH (CH ) CH
2
2 14
3
2
2 14
3
O
O
7"
7"
NH
NH
5" 6"
5" 6"
N
N
O
O
O
O
1"
1"
OH OH
OBn OBn
Scheme 3. Reductive amination of 2-keto-iminoalditol 5.
hydrophilic aglycons. What surprised us was the observation of
activation of -galactosidase from coffee bean by 10h with
AC50 = 47 M (62% activation at 100 M). Because there are four
tosidase from coffee bean, the importance of this observation
should not be undermined, because it provides the possibility that
an activator for human glycosidases could be found and used for
the treatment of glycolipid storage diseases in conjunction with
enzyme replacement therapies.
In summary, we have synthesized an array of iminoalditol ana-
logues of galactofuranosides that contain entities of hydrophobic
and hydrophilic nature through reductive amination from 20-car-
bonyl iminosugar and different amines. The inhibition assay re-
vealed that a diastereomeric mixture of 10h specifically inhibited
a
l
l
diastereomers in 10h, we are not sure at this moment if the same
molecule played dual roles as inhibitor for one enzyme and activa-
tor for another, or the different activities were contributed individ-
ually from different molecules in the mixture. To the best of our
knowledge, this is the first example of activating a galactosidase
by a small molecule, but examples of enzyme activation by pro-
teins are well known.17 Although the enzyme activated is
a-galac-

M. Sandbhor et al. / Carbohydrate Research 343 (2008) 2878–2886
2881
Bn
N
Bn
N
BnO
BnBr/K CO /DMF
BnO
2
3
Ac O/Py
2
85%
75%
O
O
5
BnO
OH
OBn
OBn
13
OAc
OBn
12
NaCNBH
3
2
C H NH
6
13
66%
Bn
N
H /Pd(OH)
BnO
2
2
10g
NH
AcOH-H O
2
BnO
OH
OBn
(1:2)
60%
14
Scheme 4. Synthesis of 10g by an indirect route.
b-galactosidase from bovine liver and, unexpectedly, activated
-galactosidase from coffee bean. Currently, we are investigating
the function of each diastereomer of 10h, and the results will be
the optimum pH of each enzyme. The microtiter plate was incu-
bated at 37 °C for 10 min, and the reaction was terminated by addi-
tion of 0.5 M Na2CO3. The released nitrophenol was measured
spectrometrically at 400 nm using a microtiter plate reader. IC50
and AC50 were estimated from inhibition-concentration plot at
different inhibitor concentrations.
a
reported in due course.
3. Experimental
3.5. Methyl 4-azido-2,3,6-tri-O-benzyl-4-deoxy-a-D-
galactopyranoside (2)
3.1. General methods
1H and 13C NMR spectra were recorded at 400 MHz and
100 MHz, respectively, with a Varian instrument at 293 K. Chemi-
cal shifts were given in ppm downfield to the signal of internal
TMS, and were assigned on the basis of 2D 1H–1H COSY and
1H–13C chemical-shift-correlated experiments. For high resolution
mass spectroscopic analysis, samples in CH2Cl2–MeOH 1:1 were
mixed with Agilent ES tuning mix for internal mass calibration
and infused into an AB/MDS-Sciex (Concord, ON) QSTAR mass
To a solution of 1 (1.57 g, 3.38 mmol) in a mixture of anhydrous
pyridine (1.36 mL, 16.9 mmol) and CH2Cl2 (40 mL) was added tri-
fluoromethanesulfonic anhydride (0.76 mL, 4.52 mmol) over
5 min at 0 °C. Gradually, warming to room temperature over 3 h
led to near quantitative conversion. The reaction mixture was
diluted with CH2Cl2 (50 mL), and washed with equal amount of
ice-cold water, dried, filtered, and concentrated to a brown syrup.
Without further purification, the intermediate was dissolved in
DMF (15 mL) and sodium azide (0.439 g, 6.75 mmol) was added.
After stirring overnight, water (25 mL) was added and the aqueous
layer was extracted with diethyl ether. The combined organic layer
was further washed with satd NaCl (25 mL), dried, filtered, and
concentrated. Purification by column chromatography (20:1?3:1
spectrometer at a flow-rate of 4 lL/min. All glycosidases were pur-
chased from Sigma and all chemicals were purchased from Aldrich
Co. without further purification.
3.2. General method for reductive amination
hexane–EtOAc) gave 2 (1.42 g, 86%) as a syrup. [a] +4.0 (c 1.8,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.42–7.26 (m, 15H, 3 ꢀ Ph),
4.83 and 4.64 (2d, 2H, CH2Ph, J = 12.0 Hz), 4.81 and 4.74 (2d, 2H,
CH2Ph, J = 11.7 Hz), 4.58 (d, 1H, H-1, J1,2 = 3.5 Hz), 4.57 and 4.51
(2d, 2H, CH2Ph, J = 11.8 Hz), 4.02 (dd, 1H, H-3, J2,3 = 9.3 Hz,
J3,4 = 3.7 Hz), 3.99 (dd, 1H, H-4, J4,5 = 1.3 Hz), 3.93 (m, 1H, H-5),
3.83 (dd, 1H, H-2), 3.55 (m, 2H, H-6a, H-6b), 3.34 (s, 3H, OCH3);
13C NMR (100 MHz, CDCl3): d 138.7, 138.3, 137.9, 128.7, 128.6,
128.3, 128.1, 128.0, 128.0, 127.9, 98.9 (C-1), 77.9 (C-3), 76.3
(C-2), 74.0 (CH2Ph), 73.9 (CH2Ph), 73.4 (CH2Ph), 69.2 (C-6), 67.3
(C-5), 61.7 (C-4), 55.7 (Me); HRMS calcd for C28H32N3O5 [M+H]+
490.2342, found 490.2325.
To the solution of ketone 5 (1 mmol) in anhydrous MeOH
(20 mL) was added amine (2 mmol), followed by sodium cyano-
borohydride (1.5 mmol) at room temperature. The reaction mix-
ture was stirred for 2 days and concentrated. The residue was
dissolved in CH2Cl2 and washed with satd aq NaHCO3. The organic
layer was further washed with water followed by brine, dried over
sodium sulfate and concentrated to an oily residue, which was
purified by flash chromatography.
3.3. General method for debenzylation
The product from the reductive amination (0.13 mmol) was dis-
solved in acetic acid (3 mL) and water (4 mL). 20% Pd(OH)2 (0.05 g)
was added, and the reaction mixture was subjected to hydrogena-
tion at 45 psi for 12 to 24 h. The reaction mixture was filtered from
Pd(OH)2, rinsed with water, and lyophilized. The final products
were thus ammonium acetates.
3.6. 3-C-(4-Azido-2,3,6-tri-O-benzyl-1,4-dideoxy-a-D-
galactopyranosyl)-propene (3)
To a solution of 2 (5.28 g, 10.8 mmol) and allyl trimethylsilane
(8.56 mL, 53.9 mmol) in anhydrous acetonitrile (100 mL) was
added TMSOTf (2.92 mL, 16.2 mmol) over a period of 15 min at
0 °C under a nitrogen atmosphere. The solution was stirred for
20 h and diluted with CH2Cl2 (100 mL). Usual work-up and column
chromatography (20:1?3:1 hexane–EtOAc) gave 3 (3.78 g, 70%) as
3.4. Inhibition assay
The inhibition assay was performed following a procedure pre-
viously reported in the literature.18 Briefly, the enzyme and the
inhibitor were pre-incubated at room temperature for 5 min before
the addition of an appropriate nitrophenyl glycoside as substrate at
a white solid. [a]
D +41.8 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3): d
7.41–7.23 (m, 15H, 3 Ph), 5.75 (m, 1H, CH2–CH@CH2), 5.13–5.01
(m, 2H, CH2–CH@CH2), 4.79–4.70 (m, 3H, CH2Ph), 4.63–4.48 (m,

2882
M. Sandbhor et al. / Carbohydrate Research 343 (2008) 2878–2886
3H, CH2Ph), 4.11–4.02 (m, 2H, H-1, H-4), 3.96 (dd, 1H, H-2,
J1,2 = 5.9 Hz, J2,3 = 9.1 Hz), 3.84–3.76 (m, 2H, H-3, 5), 3.61–3.52
(m, 2H, H-6a, 6b), 2.49–2.30 (m, 2H, CH2–CH@CH2); 13C NMR
(100 MHz, CDCl3): d 138.5, 138.1, 138.0, 134.9, 128.7, 128.6,
128.6, 128.1, 128.0, 127.9, 117.2, 78.0 (C-3), 76.3 (C-2), 74.2
(C-1), 73.9 (CH2Ph), 73.8 (CH2Ph), 72.9 (CH2Ph), 68.9 (C-6), 68.8
(C-5), 61.1 (C-4), 30.2 (C-10); HRMS calcd for C30H34N3O4 [M+H]+
500.2549, found 500.2547.
71.7 (CH2Ph), 69.8 (C-5), 64.1 (C-4), 58.3 (C-1), 47.3 (C-10), 30.7
(C-30).
3.9. 1-C-(2,3,6-Tri-O-benzyl-1,4-dideoxy-1,4-imino-
galactosyl)-2-N-(1-piperazineethyl)-2-propylideneamine (8a)
and 1-C-(2,3,6-tri-O-benzyl-1,4-dideoxy-1,4-imino-
D-
D
-
galactosyl)-2-N-(1-piperazineethyl)-2-propylamine (9a)
Reductive amination of 5 (0.24 g, 0.50 mmol) with 1-(2-amino-
ethyl)-piperazine (0.13 g, 1.00 mmol) gave, after purification by
flash chromatography using a linear gradient from CH2Cl2 to 10%
NH4OH–MeOH (30%), a mixture of imine 8a and amine 9a
(0.15 g, 52%) as a syrup. Small amounts of the pure compounds
were collected for NMR analysis.
3.7. 1-C-(4-Azido-2,3,6-tri-O-benzyl-1,4-dideoxy-a-D-
galactopyranosyl)-acetone (4)
To
a mixture of 3 (3.78 g, 7.57 mmol), PdCl2 (0.635 g,
3.56 mmol), and CuCl2ꢁ2H2O (3.22 g, 18.93 mmol) in DMF–water
(10:1, 100 mL) was bubbled with air for 2 h. The reaction mixture
was then stirred for 5 days under constant pressure of air. The mix-
ture was diluted by the addition of water and extracted with Et2O.
Usual work-up and column chromatography (20:1?6:1 hexanes–
For 8a–
a:
1H NMR (CDCl3): d 7.40–7.20 (m, 15H, 3 ꢀ Ph), 4.73
(d, 1H, CH2Ph, J = 11.6 Hz), 4.58–4.46 (m, 5H, CH2Ph), 4.27 (dd,
1H, H-3, J = 6.0, 6.0 Hz), 3.94–3.82 (m, 3H, H-4, 1, 5), 3.72–3.61
(m, 2H, H-2, 6a), 3.56–3.50 (dd, 1H, H-6b, J = 12.4, 4.8 Hz), 2.85
(t, 4H, 2 ꢀ 70-CH2, J = 4.8 Hz), 2.59 (t, 2H, 40-CH2, J = 5.2 Hz), 2.44
(t, 2H, 50-CH2, J = 5.2 Hz), 2.40–2.26 (m, 3H, 2 ꢀ 60-CH2, H-10a),
1.82 (dd, 1H, H-10b, J = 13.2, 7.6 Hz), 1.30 (s, 3H, 30-Me); 13C NMR
(CDCl3): d 173.1 (C@N), 138.4, 138.2, 137.5, 128.7, 128.5, 128.4,
128.2, 127.9, 127.8, 127.7, 89.5 (C-2), 86.3 (C-3), 74.5 (C-5), 73.6
(CH2Ph), 72.7 (CH2Ph), 72.5 (C-6), 72.4 (CH2Ph), 64.2 (C-4), 62.3
(C-1), 57.8 (C-50), 54.3 (C-60), 46.4 (C-70), 43.0 (C-10) 39.7 (C-40),
24.6 (C-30).
EtOAc) afforded 4 (3.34 g, 86%) as a white solid. [a] +31.1 (c 0.5,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.40–7.24 (m, 15H, 3 ꢀ Ph),
4.75 and 4.71 (2d, 2H, CH2Ph, J = 11.7 Hz), 4.70 and 4.55 (2d, 2H,
0
CH2Ph, J = 11.1 Hz), 4.61 (ddd, 1H, H-1, J1,2 = 5.7 Hz, J1,1 a = 5.7 Hz,
0
J1,1 b = 8.4 Hz), 4.54 and 4.50 (2d, 2H, CH2Ph, J = 11.6 Hz), 4.04
(dd, 1H, H-4, J3,4 = 3.5 Hz, J4,5 = 2.1 Hz), 3.97 (dd, 1H, H-2,
J2,3 = 9.0 Hz), 3.78 (dd, 1H, H-5, J5,6 = 6.4 Hz), 3.71 (dd, 1H, H-3),
3.55 (d, 2H, H-6a, 6b), 2.77 (dd, 1H, H-10a, J1 a,1 b = 15.6 Hz), 2.60
(dd, 1H, H-10b), 2.07 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): d
206.1, 138.1, 137.9, 137.9, 128.7, 128.6, 128.2, 128.1, 128.0,
127.9, 77.8 (C-3), 75.7 (C-2), 74.2 (CH2Ph), 73.8 (CH2Ph), 72.8
(CH2Ph), 71.0 (C-1), 70.0 (C-5), 68.7 (C-6), 60.6 (C-4), 41.5 (C-10),
30.5 (C-30); HRMS calcd for C30H34N3O5 [M+H]+ 516.2498, found
516.2490.
0
0
For 8a–b: 1H NMR (CDCl3): d 7.80–7.40 (m, 15H, 3 ꢀ Ph), 4.70
(d, 1H, CH2Ph, J = 11.6 Hz), 4.58–4.46 (m, 5H, CH2Ph), 4.31 (dd,
1H, H-3, J = 5.6, 5.6 Hz), 4.04–3.96 (m, 1H, H-4), 3.96–3.88 (m,
1H, H-5), 3.86–3.78 (m, 1H, H-1), 3.76–3.68 (m, 2H, H-2, 6a),
3.62–3.54 (m, 1H, H-6b), 2.81 (t, 4H, 2 ꢀ 70-CH2, J = 4.8 Hz),
2.58–2.50 (m, 2H, 40-CH2), 2.46–2.28 (m, 6H, 50-CH2, 2 ꢀ 60-CH2),
2.02–1.94 (m, 2H, H-10a, 10b), 1.03 (s, 3H, 30-Me); 13C NMR
(CDCl3): d 173.4 (C@N), 138.5, 138.1, 137.5, 128.7, 128.5, 128.4,
128.2, 127.9, 127.8, 127.7, 127.6, 89.0 (C-2), 85.2 (C-3), 73.5
(CH2Ph), 72.6 (C-5), 72.4 (CH2Ph), 73.3 (C-6), 64.9 (C-4), 61.7
(C-1), 58.8 (C-50), 54.9 (C-60), 46.3 (C-70), 40.1 (C-10) 39.7 (C-40),
26.0 (C-30).
3.8. 1-C-(2,3,6-Tri-O-benzyl-1,4-dideoxy-1,4-imino-D-
galactosyl)-acetone (5)
A mixture of 4 (2.25 g, 4.36 mmol) and 10% palladium on char-
coal (0.67 g) in MeOH (40 mL) was stirred under H2 atmosphere
(balloon pressure) for 2 h. The reaction mixture was filtered and
the filtrate was concentrated to obtain 2.1 g of amine. To a solution
of above amine in THF–H2O (80 mL, 1:1) was added LiOH (2.16 g,
51.47 mmol), and the mixture was stirred at 70 °C for 3 days. The
reaction mixture was allowed to cool and separated into two
layers. The organic layer was separated and the aqueous layer
was extracted with EtOAc (100 mL). Usual work-up and purifica-
tion by chromatography using a linear gradient from hexane to
EtOAc (0–100% EtOAc) gave 5 (1.54 g, 72%), a mixture of two
For 9a: 1H NMR (CDCl3): d 7.40–7.20 (m, 15H, 3 ꢀ Ph), 4.62–
4.28 (m, 6H, 6 ꢀ CH2Ph), 3.94–3.88 (m, 1H, H-3), 3.87–3.64 (m,
2H, H-2, 5), 3.60–3.44 (m, 2H, H-6a, 6b), 3.42–3.14 (m, 2H, H-1,
4), 2.88–2.78 (m, 4H, 2 ꢀ 70-CH2), 2.64–2.50 (m, 3H, 50-CH2, H-20),
2.48–2.30 (m, 4H, 2 ꢀ 60-CH2), 1.78–1.48 (m, 2H, 10-CH2), 1.12–
1.02 (m, 3H, 30-Me); 13C NMR (CDCl3): d 138.4, 138.3, 138.2,
128.8, 128.6, 128.5, 127.9, 127.7, 90.8 (C-2), 90.2 (C-2), 86.4 (C-
3), 86.3 (C-3), 85.4 (C-3), 85.2 (C-3), 83.7 (C-2), 83.5 (C-2), 73.7
(CH2Ph), 73.6 (CH2Ph), 73.2 (CH2Ph), 73.1 (CH2Ph), 72.6 (CH2Ph),
72.5 (CH2Ph), 72.2 (CH2Ph), 72.1 (CH2Ph), 72.0 (CH2Ph), 71.5
(CH2Ph), 70.4 (C-5), 70.3 (C-5), 68.6 (C-5), 68.4 (C-5), 65.3 (C-4),
65.2 (C-4), 64.1 (C-4), 64.0 (C-4), 60.8 (C-1), 59.9 (C-1), 59.1 (C-
50), 58.9 (C-50), 58.7 (C-1), 54.8 (C-60), 54.7 (C-60), 52.4 (C-20), 52.3
(C-20), 51.4 (C-20), 51.2 (C-20), 46.4 (C-70), 46.3 (C-70), 43.8 (C-40),
41.9 (C-10), 41.2 (C-10), 37.1 (C-10), 36.7 (C-10), 21.3 (C-30), 21.1
(C-30), 20.9 (C-30), 20.7 (C-30); HRMS calcd for C36H51N4O4 [M+H]+
603.3910, found 603.3840.
anomers (a/b = 1:3), as a syrup.
For the b-anomer (pure compound): 1H NMR (CDCl3): d 7.40–
7.20 (m, 15H, 3 ꢀ Ph), 4.60–4.45 (m, 5H, CH2Ph), 4.32 (d, 1H,
CH2Ph, J = 11.2 Hz), 3.90 (dd, 1H, H-3, J = 3.6, 1.2 Hz), 3.82 (dd,
1H, H-2, J = 4.8, 1.2 Hz), 3.76 (m, 2H, H-1, H-5), 3.50–3.40 (m,
2H, H-6a, 6b), 3.30 (dd, 1H, H-4, J3,4 = 3.6 Hz, J4,5 = 3.6 Hz), 2.72
(d, 2H, H-10a, 10b, J = 6.8 Hz), 2.08 (s, 3H, 30-Me); 13C NMR
(CDCl3): d 208.0 (CO), 138.1, 137.9, 137.8, 128.5, 128.4, 127.8,
127.7, 127.6, 84.5 (C-3), 82.9 (C-2), 73.4 (CH2Ph), 72.8 (C-6),
71.8 (CH2Ph), 71.5 (CH2Ph), 69.7 (C-5), 64.5 (C-4), 56.0 (C-1),
44.2 (C-10), 30.5 (C-30); HRMS calcd for C30H36NO5 [M+H]+
490.2593, found 490.2579.
3.10. 1-C-(1,4-Dideoxy-1,4-imino-D-galactosyl)-2-N-
(1-piperazineethyl)-2-propylamine (10a)
For the
a
-anomer (data extracted from the spectrum of a mix-
Catalytic hydrogenation of 8a and 9a (0.04 g, 0.06 mmol) affor-
ded 10a (0.02 g, 80%) as pale yellow solid. Selected data: 1H NMR
(D2O): d 4.30–4.15 (m, 2H, H-1, 3), 4.10–3.60 (m, 5H, H-5, 2, 4,
6a, 6b), 3.40–3.10 (m, 5H, 2 ꢀ 70-CH2, H-20), 3.05–2.65 (m, 8H,
2 ꢀ 60-CH2, 40-CH2, 50-CH2), 2.65–2.35 (m, 1H, H-10a), 2.35–2.10
(m, 1H, H-10b), 1.70–1.25 (m, 3H, 30-Me); 13C NMR (D2O): d 80.2,
80.1, 79.1, 78.8, 72.3, 68.9, 68.4, 65.8, 64.8, 64.6, 64.5, 61.7, 56.9,
ture): 1H NMR (CDCl3): d 7.40–7.20 (m, 15H, 3 ꢀ Ph), 4.60–4.34
(m, 6H, 3 ꢀ CH2Ph), 3.90 (m, 1H, H-3), 3.76 (m, 1H, H-5), 3.70
(m, 1H, H-2), 3.64 (m, 1H, H-1), 3.54–3.50 (m, 2H, H-6a, 6b),
3.28 (dd, 1H, H-4, J3,4 = 3.5 Hz, J4,5 = 3.5 Hz), 2.71–2.66 (m, 2H,
H-10a, 10b), 2.10 (s, 3H, 30-Me); 13C NMR (CDCl3): d 207.0 (CO),
87.7 (C-2), 86.6 (C-3), 73.7 (CH2Ph), 73.0 (C-6), 72.0 (CH2Ph),

M. Sandbhor et al. / Carbohydrate Research 343 (2008) 2878–2886
2883
56.2, 52.8, 49.2, 49.1, 43.2, 42.7, 42.4, 40.5, 22.2; HRMS calcd for
C15H33N4O4 [M+H]+ 333.2501, found 333.2509.
25.2, 22.8, 18.2, 18.0; HRMS calcd for C32H41N2O6 [M+H]+
549.2964, found 549.2978.
3.11. 1-C-(2,3,6-Tri-O-benzyl-1,4-dideoxy-1,4-imino-
galactosyl)-2-N-(1-morpholineethyl)-2-propylideneamine (8b)
and 1-C-(2,3,6-tri-O-benzyl-1,4-dideoxy-1,4-imino-
D
-
3.14. 1-C-(1,4-Dideoxy-1,4-imino-D-galactosyl)-2-N-
carboxymethyl-2-propylamine (10c)
D
-
galactosyl)-2-N-(1-morpholineethyl)-2-propylamine (9b)
Catalytic hydrogenation of 9c (0.08 g, 0.15 mmol) gave, after
purification on a Biogel P2 column eluted by water, 10c (0.03 g,
80%) as a solid. Selected data: 1H NMR (D2O): d 4.20–4.06 (m,
2H, H-2, H-3), 4.02–3.92 (m, 1H, H-3), 3.92–3.78 (m, 3H, 2 ꢀ H-
5, 2), 3.78–3.50 (m, 9H, H-6, H-40, H-1), 3.50–3.40 (m, 2H,
2 ꢀ H-20), 3.30–3.20 (m, 2H, H-4, H-1), 3.14–3.06 (m, 1H, H-4),
2.04–1.93 (m, 4H, 2 ꢀ H-10), 1.39 and 1.35 (d and d, 6H each,
J = 6.4 Hz, 30-CH3); 13C NMR (D2O): d 171.9 (COOH), 81.1 (C-2),
77.3 (C-3), 77.2 (C-3), 76.9 (C-2), 70.9 (C-5), 70.1 (C-5), 65.4
(C-5), 63.3 (C-6), 63.2 (C-6), 61.9 (C-4), 58.7 (C-7), 57.8 (C-1),
53.5 (C-20), 53.2 (C-20), 46.6 (C-40), 35.4 (C-10), 16.1 (C-30), 15.9
(C-30); HRMS calcd for C11H23N2O6 [M+H]+ 279.1556, found
279.1565.
Reductive amination of 5 (0.17 g, 0.36 mmol) with 1-(2-amino-
ethyl)-morpholine (0.09 g, 0.72 mmol) afforded, after purification
by flash chromatography using a linear gradient with CH2Cl2 and
0.1% Et3N–MeOH (0–10%), a mixture of 8b and 9b (4:1, 0.14 g,
63%) as a syrup. Selected data: 1H NMR (CDCl3): d 7.39–7.20 (m,
30H, 6 ꢀ Ph), 4.72–4.38 (m, 12H, 6 ꢀ CH2Ph), 4.29 (dd, 1H, H-38b,
J = 5.4, 5.4 Hz), 3.96–3.80 (m, 4H, H-18b, 48b, 39b, 58b), 3.80–3.72
(m, 2H, H-59b, 29b), 3.71–3.60 (m, 11H, 4 ꢀ 70-CH2, H-69b, 68b
,
,
28b), 3.59–3.43 (m, 2H, H-69b, 68b), 3.42–3.14 (m, 3H, H-49b, 48b
19b), 2.78–2.50 (m, 5H, H-209b, 490 a-CH2, 40 -CH2), 2.50–2.26 (m,
8b
13H, 509b-CH2, 50 -CH2, 2 ꢀ 60 -CH2, 2 ꢀ 60 -CH2, H-180 b), 1.88–1.50
8b
9b
8b
(m, 3H, 109b-CH2; H-108b), 1.32 (s, 3H, 380 b-Me), 1.10–1.01 (m, 3H,
309b-Me); 13C NMR (CDCl3): d 172.9 (C@N), 138.4, 138.3, 138.2,
138.1, 137.5, 128.7, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9,
127.7, 90.8 (C-29b), 90.0 (C-28b), 89.4 (C-29b), 86.3 (C-38b), 86.2
(C-39b), 85.3 (C-39b), 85.2 (C-39b), 83.7 (C-29b), 83.5 (C-29b), 73.9
(C-58b), 73.6 73.5, 73.2, 73.1, 72.7, 72.5, 72.4, 72.2, 71.9, 71.4
(6 ꢀ CH2Ph and 2 ꢀ C-6), 70.3 (C-59b), 70.2 (C-59b), 68.5 (C-59b),
68.4 (C-59b), 67.2 (C-70), 67.1 (C-70), 65.5, 65.3, 65.2, 64.5, 64.2,
64.1, 62.7, 60.8, 59.9, 59.1, 58.6, 58.5, 58.2, 57.7 (C-1, C-4, and
C-50), 53.8 (C-60), 53.5 (C-60), 52.4 (C-20), 52.3 (C-20), 51.4 (C-20),
51.2 (C-20), 43.6 (C-40), 43.4 (C-40), 42.6 (C-180 b), 41.6, 40.8, 39.6,
37.1 (C-109b), 36.5, 24.8 (C-380 b), 21.2 (C-309b), 21.0 (C-390 b), 20.8
(C-309b), 20.7 (C-390 b); HRMS calcd for C36H50N3O5 [M+H]+
604.3750, found 604.3718.
3.15. 1-C-(2,3,6-Tri-O-benzyl-1,4-dideoxy-1,4-imino-D-
galactosyl)-2-N-ethoxycarbonylethyl-2-propylamine (9d)
To the solution of ketone 5 (0.26 g, 0.53 mmol) in anhydrous
MeOH (20 mL) was added b-alanine ethyl ester (0.16 g,
1.00 mmol), followed by sodium cyanoborohydride (0.66 g,
1.00 mmol) and anhydrous ZnCl2 (0.03 g, 0.27 mmol) at room tem-
perature. The reaction mixture was stirred for 2 days and concen-
trated. Usual work-up and purification by flash chromatography
using a linear gradient with CH2Cl2 and 0.1% Et3N–MeOH (0–
20%) gave 9d (0.16 g, 52%) as a syrup. Selected data: 1H NMR
(CDCl3): d 7.40–7.20 (m, 30H, Ph), 4.64–4.36 (m, 12H, CH2Ph),
4.18–4.06 (m, 4H, 2 ꢀ 60-CH2), 3.96–3.88 (m, 2H, 2 ꢀ H-3), 3.88–
3.80 (m, 1H, H-5), 3.80–3.72 (m, 2H, H-5, 2), 3.70–3.62 (m, 1H,
H-2), 3.60–3.44 (m, 4H, 2 ꢀ 6-CH2), 3.38–3.14 (m, 4H, 2 ꢀ H-4,
1), 2.88–2.84 (m, 2H, 2 ꢀ H-40), 2.80–2.60 (m, 4H, 2 ꢀ H-40, 20),
2.50–2.38 (m, 4H, 2 ꢀ 50-CH2), 1.74–1.48 (m, 4H, 2 ꢀ H-10), 1.30–
1.20 (m, 6H, 2 ꢀ 70-Me), 1.10–1.02 (m, 6H, 2 ꢀ 30-Me); 13C NMR
(CDCl3): d 173.0 (CO), 138.4, 138.3, 138.2, 138.1, 128.7, 128.6,
128.0, 127.9, 127.8, 90.7 (C-2), 90.0 (C-2), 86.4 (C-3), 86.2 (C-3),
85.3 (C-3), 85.2 (C-3), 83.6 (C-2), 83.5 (C-2), 73.6 (CH2Ph), 73.1
(CH2Ph), 73.0 (CH2Ph), 72.6 (CH2Ph), 72.5 (CH2Ph), 72.2 (CH2Ph),
72.1 (CH2Ph), 72.0 (CH2Ph), 71.9 (CH2Ph), 71.4 (CH2Ph), 70.3
(C-5), 70.2 (C-5), 68.7 (C-5), 68.6 (C-5), 65.2 (C-4), 64.9 (C-4),
64.1 (C-4), 64.0 (C-4), 61.1 (C-1), 60.6 (C-60), 60.5 (C-60), 59.8
(C-1), 59.3 (C-1), 57.9 (C-1), 52.4 (C-20), 52.1 (C-20), 51.0 (C-20),
50.9 (C-20), 42.5 (C-40), 41.6 (C-10), 40.8 (C-10), 37.1 (C-10), 36.6
(C-10), 35.2 (C-50), 35.1 (C-50), 21.1 (C-30), 20.9 (C-30), 20.8 (C-30),
20.7 (C-30), 14.4 (C-70); HRMS calcd for C35H47 N2O6 [M+H]+
591.3434, found 591.3434.
3.12. 1-C-(1,4-Dideoxy-1,4-imino-D-galactosyl)-2-N-
(1-morpholineethyl)-2-propylamine (10b)
Catalytic hydrogenation of 8b/9b (0.11 g, 0.19 mmol) afforded
solid 10b (0.07 g, 78%) as a mixture of diastereomers. Selected
data: 1H NMR (D2O): d 4.28–4.14 (m, 4H), 4.10–3.60 (m, 28H),
3.50–3.34 (m, 6H), 3.33–3.06 (m, 12H), 2.98–2.74 (m, 6H), 2.70–
2.60 (m, 8H), 2.55 (dd, 1H, J = 14.4, 7.6 Hz), 2.22 (dd, 1H, J = 14.4,
7.2 Hz), 2.16–1.98 (m, 4H), 1.56 (s, 3H), 1.44–1.25 (m, 12H); 13C
NMR (D2O): d 80.1, 79.7, 79.2, 77.4, 76.8, 76.5, 76.2, 74.7, 72.4,
70.2, 69.9, 69.3, 68.3, 67.5, 66.7, 66.1, 65.8, 64.6, 64.4, 63.2, 63.1,
63.0, 62.2, 61.8, 58.4, 58.3, 58.1, 56.5, 53.7, 53.6, 53.5, 52.7, 52.6,
52.3, 52.1, 51.6, 46.8, 40.1, 37.7, 34.9, 30.1, 29.1, 15.9; HRMS calcd
for C15H32N3O5 [M+H]+ 334.2341, found 334.2333.
3.13. 1-C-(2,3,6-Tri-O-benzyl-1,4-dideoxy-1,4-imino-
D-
galactosyl)-2-N-carboxymethyl-2-propylamine (9c)
3.16. 1-C-(1,4-Dideoxy-1,4-imino-D-galactosyl)-2-N-
Reductive amination of 5 (0.30 g, 0.61 mmol) with glycine gave,
after purification by flash chromatography using a linear gradient
with EtOAc and 0.1% Et3N–MeOH (0–30%), 9c (0.20 g, 72%) as a syr-
up. Selected data: 1H NMR (CDCl3): d 7.38–7.14 (m, 60H), 4.60–
4.24 (m, 28H), 4.22–3.72 (m, 12H), 3.68–2.99 (m, 28H), 2.81 (d,
1H, J = 14.4 Hz), 2.29 (dd, 2H, J = 13.6, 6.8 Hz), 1.94–1.66 (m, 4H),
1.58–1.42 (m, 4H), 1.19 (d, 6H, J = 6.8 Hz), 1.14 (d, 6H, J = 6.4 Hz);
13C NMR (CDCl3): d 177.0, 173.2, 171.5, 171.4, 170.9, 170.7,
138.7, 138.6, 138.5, 138.4, 138.3, 138.2, 138.1, 138.0, 137.7,
137.6, 137.3, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2,
128.0, 127.9, 127.8, 127.7, 127.6, 89.8, 88.5, 86.2, 86.1, 84.7, 83.2,
82.9, 73.5, 73.4, 73.2, 72.9, 72.6, 72.4, 72.3, 72.2, 72.1, 72.0, 71.8,
70.9, 70.8, 70.1, 69.7, 68.5, 66.2, 65.9, 65.1, 64.6, 64.1, 61.5, 58.1,
57.0, 55.3, 54.7, 54.2, 48.5, 48.1, 47.7, 47.4, 41.4, 35.1, 33.2, 32.8,
ethoxycarbonylethyl-2-propylamine (10d)
Catalytic hydrogenation of 9d afforded 10d (0.03 g, 91%) as a so-
1
lid. Selected data: H NMR (D2O): d 4.18 (q, 4H, 2 ꢀ 60-CH2,
J = 6.8 Hz), 4.16–3.78 (m, 6H, 2 ꢀ H-2, 3, 5), 3.78–3.52 (m, 5H,
2 ꢀ H-6, H-1), 3.52–3.08 (m, 9H, 2 ꢀ H-40, 20, 4, H-1), 2.90–2.70
(m, 4H, 2 ꢀ 50-CH2), 2.40–2.28 (m, 1H, H-10), 2.10–1.88 (m, 3H,
H-10, 10-CH2), 1.46–1.30 (m, 6H, 2 ꢀ 30-Me), 1.30–1.18 (t, 6H,
2 ꢀ 70-Me, J = 6.8 Hz); 13C NMR (D2O): d 172.6 (CO2Et), 80.1 (C-2
or C-3), 77.5 (C-2 or C-3), 76.9 (C-2 or C-3), 76.6 (C-2 or C-3),
74.8 (C-2 or C-3), 70.2 (C-5), 70.0 (C-5), 69.6 (C-5), 67.2 (C-4),
66.2 (C-4), 64.9 (C-4), 63.2 (C-6), 63.0 (C-6), 62.5 (C-60), 62.0 (C-
4), 58.1 (C-1), 57.5 (C-1), 57.3 (C-1), 53.3 (C-20), 52.1 (C-20), 52.0
(C-20), 40.3 (C-40), 40.2 (C-40), 35.1 (C-10), 34.9 (C-10), 30.7 (C-50),

2884
M. Sandbhor et al. / Carbohydrate Research 343 (2008) 2878–2886
30.6 (C-50), 29.1 (C-10), 15.8 (C-30), 15.7 (C-30), 13.3 (C-70); HRMS
calcd for C14H29N2O6 [M+H]+ 321.2025, found 321.2020.
(CH2Ph), 72.9, 72.4 (C-6), 72.3 (CH2Ph), 72.2 (CH2Ph), 72.1 (CH2Ph),
71.8 (CH2Ph), 68.8, 68.4, 68.2, 67.6, 65.0, 64.4, 43.3, 38.6, 32.0, 31.7,
28.6, 25.2, 24.6, 22.8, 22.7, 14.2; HRMS calcd for C36H51N2O4
[M+H]+ 575.3848, found 575.3820.
3.17. 1-C-(2,3,6-Tri-O-benzyl-1,4-dideoxy-1,4-imino-D-
galactosyl)-2-N-methoxycarbonylethyl-2-propylamine (9e)
3.20. 1-C-(2,3,6-Tri-O-benzyl-1,4-dideoxy-1,4-imino-
galactosyl)-2-N-hexadecyl-2-propylamine (9h)
D-
Reductive amination of 5 (0.15 g, 0.30 mmol) with b-alanine
ethyl ester (0.09 g, 0.60 mmol) in MeOH gave a mixture of methyl
and ethyl esters. Purification by flash chromatography using a lin-
ear gradient with CH2Cl2 and 0.1% Et3N–MeOH (0–20%) gave ethyl
ester 9d (0.03 g, 20%) and methyl ester 9e (0.09 g, 54%) as a syrup
and as a mixture of diastereomers. Selected data for 9e: 1H NMR
Reductive amination of 5 (0.17 g, 0.35 mmol) with hexadecyl
amine (0.17 g, 0.71 mmol) gave, after purification by flash chroma-
tography using a linear gradient with CH2Cl2 and 0.1% Et3N–MeOH
(0–10%), 9h (0.19 g, 78%) as a syrup. Selected data for two major
diastereomers (A and B): 1H NMR (CDCl3): d 7.38–7.18 (m, 30H,
6 ꢀ Ph), 4.78–4.35 (m, 12H, 6 ꢀ CH2Ph), 4.30–4.25 (m, 1H, H-3B),
3.95–3.88 (m, 2H, H-3A, H-1B), 3.88–3.70 (m, 3H, H-5A, H-5B,
H-4B), 3.70–3.59 (m, 4H, H-6A, H-6B, H-2A, H-2B), 3.58–3.43 (m,
(CDCl3):
d
7.40–7.18 (m, 30H, 6 ꢀ Ph), 4.60–4.34 (m, 12H,
6 ꢀ CH2Ph), 3.96–3.88 (m, 2H, H-3, 2), 3.88–3.70 (m, 2H, 2 ꢀ H-
5), 3.70–3.60 (m, 8H, 2 ꢀ 60-Me, H-3, 2), 3.60–3.44 (m, 4H, 2 ꢀ 6-
CH2), 3.44–3.04 (m, 4H, 2 ꢀ H-1, 4), 3.00–2.82 (m, 2H, 2 ꢀ H-40),
2.82–2.62 (m, 4H, 2 ꢀ H-40, 20), 2.54–2.40 (m, 4H, 2 ꢀ 50-CH2),
1.78–1.50 (m, 4H, 2 ꢀ 10-CH2), 1.10–1.02 (m, 6H, 2 ꢀ 30-Me); 13C
NMR (CDCl3): d 173.4 (CO), 173.3 (CO), 173.2 (CO), 138.4, 138.3,
138.2, 138.1, 138.0, 128.7, 128.6, 128.0, 127.9, 127.8, 90.5 (C-2 or
C-3), 89.5 (C-2 or C-3), 86.1 (C-2 or C-3), 84.7 (C-2 or C-3), 83.7
(C-2 or C-3), 83.6 (C-2 or C-3), 73.7 (CH2Ph), 73.6 (CH2Ph), 73.1
(C-6), 73.0 (C-6), 72.5 (C-6), 72.1 (CH2Ph), 72.0 (CH2Ph), 71.9
(CH2Ph), 71.6 (CH2Ph), 71.5 (CH2Ph), 70.2 (C-5), 70.1 (C-5), 68.8
(C-5), 68.5 (C-5), 65.2 (C-4), 65.0 (C-4), 64.2 (C-4), 64.1 (C-4),
61.4 (C-1), 59.8 (C-1), 59.2 (C-1), 57.8 (C-1), 52.9 (C-20), 52.7 (C-
20), 51.9 (C-60), 51.8 (C-60), 51.2 (C-20), 51.0 (C-20), 42.3 (C-40),
42.2 (C-40), 42.1 (C-40), 36.4 (C-10), 36.0 (C-10), 34.6 (C-50), 34.5
(C-50), 34.4 (C-50), 20.7 (C-30), 20.6 (C-30), 20.3 (C-30); HRMS calcd
for C34H45N2O6 [M+H]+ 577.3277, found 577.3267.
2H, H-60 , H-6B), 3.33–3.22 (m, 3H, H-1A, 2 ꢀ H-4A), 3.21–3.14 (m,
A
1H, H-1A), 2.76–2.67 (m, 1H, H-20 ), 2.66–2.52 (m, 2H, H-20 ,
A
H-4A0 ), 2.50–2.37 (m, 2H, H-4A0 , H-4B0 ), 2.30–2.24 (m, 1H, H-10BA),
1.82–1.74 (m, 1H, H-10B), 1.62–1.48 (m, 2H, H-10A), 1.48–1.32 (m,
2H, H-50A, H-50B), 1.32–1.14 (m, 58H, 3B0 -Me, 60–180 –CH2–), 1.04
(d, 3H, 30A-Me, J = 6.4 Hz), 0.80–0.90 (2d, 6H, 2 ꢀ 190-Me,
J = 6.8 Hz); 13C NMR (CDCl3): d 138.3, 138.2, 137.7, 128.8, 128.7,
128.6, 128.5, 128.2, 128.0, 127.9, 127.7, 90.6 (C-2A), 89.6 (C-2B),
86.3 (C-3A), 86.2 (C-3B), 83.8 (C-2A), 73.7 (CH2Ph), 73.6 (CH2Ph),
73.1 (C-6), 72.7 (CH2Ph), 72.6 (C-6), 72.5 (C-6), 72.1 (CH2Ph), 72.0
(CH2Ph), 71.5 (CH2Ph), 70.2 (C-5A), 68.6 (C-5A), 65.3 (C-4A), 65.2
(C-4B), 64.4 (C-4A), 63.9 (C-5B), 61.2 (C-1A), 59.3 (C-1A), 52.6
(C-2A0 ), 52.5 (C-20A, 47.5 (C-4A0 ), 43.9 (C-4B0 ), 42.5 (C-1B0 ), 41.5
(C-1A0 ), 32.1 (C-60–180), 30.8 (C-5A0 ), 35.6 (C-50A), 29.9 (C-60–180),
29.8 (C-60–180), 28.5 (C-60–180), 27.7 (C-60–180), 27.5 (C-60–180),
22.9 (C-60–180), 20.6 (C-30A), 14.3 (C-190); HRMS calcd for
C46H71N2O4 [M+H]+ 715.5414, found 715.3376.
3.18. 1-C-(1,4-Dideoxy-1,4-imino-D-galactosyl)-2-N-
carboxyethyl-2-propylamine (10f)
Hydrogenation of 9e (0.09 g, 0.16 mmol) in HOAc–H2O led to
the hydrolysis of methyl ester to carboxylic acid. Purification on
Biogel P2 column eluted with water gave a mixture of 10f
(0.04 g, 91%) as a white solid. Selected data for two sets of diaste-
reomers (A and B): 1H NMR (D2O): d 4.34–3.96 (m, 6H), 3.96–3.56
(m, 10H), 3.56–3.44 (m, 2H, 2 ꢀ H-20), 3.42–3.18 (m, 6H), 3.18–3.08
(m, 1H), 2.90–2.70 (m, 2H, 40 -CH2), 2.70–2.50 (m, 5H, 50 -CH2,
3.21. 1-C-(1,4-Dideoxy-1,4-imino-D-galactosyl)-2-N-hexadecyl-
2-propylamine (10h)
Hydrogenation of 9h (0.09 g, 0.13 mmol) and purification on a
Biogel P2 column eluted with water yielded 10h (0.05 g, 92%) as
a white solid. Selected data (NMR spectra were very complicated
due to presence of diastereomers): 1H NMR (CD3OD): d 4.30–4.22
(m, 1 H), 4.07–3.35 (m, 12H), 3.24–3.09 (m, 2H), 3.04–2.74 (m,
5H), 2.66–2.38 (m, 3H), 2.34–2.21 (m, 2H), 2.07–1.99 (m, 1H),
1.83–1.52 (m, 5H), 1.41–1.20 (m, 58H), 0.80–0.90 (2d, 6H, 190-
Me, J = 6.8 Hz); 13C NMR (CD3OD): d 179.3, 172.9, 172.2, 82.9,
81.4, 81.3, 80.6, 79.4, 79.2, 78.6, 78.3, 78.2, 77.9, 77.6, 77.3, 77.1,
71.6, 71.3, 70.7, 70.6, 70.2, 70.1, 68.9, 68.3, 66.8, 66.1, 65.6, 65.5,
64.5, 64.3, 64.2, 63.5, 63.1, 62.9, 62.0, 59.8, 57.9, 57.1, 54.8, 54.7,
53.1, 52.6, 45.2, 44.9, 43.6, 43.2, 38.0, 37.2, 35.7, 32.8, 32.4, 31.9,
29.7, 29.6, 29.4, 29.3, 29.2, 27.5, 27.3, 27.0, 26.9, 24.8, 23.4, 22.6,
16.9, 16.8, 13.6; HRMS calcd for C25H53N2O4 [M+H]+ 445.4005,
found 445.4048.
B
A
10 -CH2, H-10 ), 2.46–2.30 (m, 2H, 50 -CH2), 2.30–2.14 (m, 1H,
A
B
B
H-10B), 2.10–1.95 (m, 2H, 2 ꢀ H-1A0 ), 1.50–1.30 (m, 6H, 30-Me); 13C
NMR (D2O): d 180.5, 178.2, 80.9, 80.2, 79.0, 77.3, 77.1, 76.9, 76.8,
75.4, 72.5, 70.6, 70.4, 70.2, 68.4, 65.7, 64.7, 63.3, 63.2, 61.9, 61.8,
58.3, 57.7, 57.1, 53.2, 53.1, 51.9, 51.7, 41.8, 41.7, 41.6, 40.1, 37.7,
37.1, 35.5, 35.3, 32.8, 32.7, 32.5, 32.6, 16.0, 15.9, 15.8; HRMS calcd
for C12H25N2O6 [M+H]+ 293.1712, found 293.1700.
3.19. 1-C-(2,3,6-Tri-O-benzyl-1,4-dideoxy-1,4-imino-
D-
galactosyl)-2-N-hexyl-2-propylideneamine (8g) and 1-C-(2,3,6-
tri-O-benzyl-1,4-dideoxy-1,4-imino-D-galactosyl)-2-N-hexyl-2-
propylamine (9g)
3.22. 1-C-(2,3,6-Tri-O-benzyl-1,4-dideoxy-1,4-imino-D-
Reductive amination of 5 (0.09 g, 0.19 mmol) with hexylamine
(0.07 g, 0.76 mmol) gave, after flash chromatography using a linear
gradient with EtOAc and 0.1% Et3N–MeOH (0–30%), a mixture of 8g
and 9g (0.04 g, 22%) as a syrup. Selected data: 1H NMR (CDCl3): d
7.39–7.19 (m, Ph), 4.60–4.32 (m, CH2Ph, H-5, 3), 4.03–3.81 (m,
H-1, 4), 3.78–3.63 (m, H-2, 6), 3.60–3.51 (m, H-6), 3.40–-3.28
(m, H-1), 2.96–2.84 (m, H-40), 2.72–2.64 (m, H-40), 2.48–2.36 (m,
H-20, 40), 2.24–2.06 (m, H-40, H-10), 2.04–2.03 (m, H-10), 1.95 (s,
30-Me), 1.90–1.64 (m, H-10), 1.38 (m, 30-Me), 1.33–1.14 (m,
galactosyl)-2-N-(20,30-di-O-benzyl-50-deoxyuridine-50)-2-
propylamine (9i)
Reductive amination of 5 (0.15 g, 0.30 mmol) with 50-amino-
20,30-di-O-benzyl-50-deoxyuridine14 (0.15 g, 0.36 mmol) gave, after
flash chromatography using a linear gradient with EtOAc–10%
NH4OH–MeOH (0–30%), 9i (0.15 g, 55%) as a syrup. Selected data:
1H NMR (CDCl3): d 7.40–7.10 (m, 26H, Ph, H-600), 5.62 (d, 1H,
H-700, J = 8.0 Hz), 5.53 (d, 1H, H-100, J = 3.6 Hz), 4.70–4.35 (m, 11H,
5 ꢀ CH2Ph, H-400), 4.28–4.21 (m, 1H, H-200), 3.96–3.87 (m, 2H, H-3,
300), 3.87–3.74 (m, 2H, H-5, 1), 3.72–3.60 (m, 2H, H-2, 4), 3.60–
3.44 (m, 2H, H-6a,b), 3.26–3.04 (m, 3H, H-20, H-500a,b), 2.0–1.84
50,60,70,80-CH2–), 0.88 (m, 90-Me); 13C NMR (CDCl3):
d 172.1
(C@N), 138.3, 138.2, 138.0, 137.9, 137.6, 137.3, 128.7, 128.6,
128.5, 128.3, 128.0, 127.9, 127.8, 88.2, 87.7, 85.3, 84.0, 73.7

M. Sandbhor et al. / Carbohydrate Research 343 (2008) 2878–2886
2885
(m, 1H, H-10a), 1.42 (d, 1H, H-10b, J = 15.2 Hz), 1.17 (d, 3H, H-30,
J = 6.0 Hz); 13C NMR (CDCl3): d 163.8 (CO-Ur), 149.8 (CO-Ur),
142.8 (C-6B), 137.9, 137.4, 137.3, 137.1, 128.8, 128.7, 128.6,
128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 102.6 (C-700), 93.2 (C-100),
86.8 (C-2), 84.8 (C-300), 78.6 (C-400), 78.2 (C-200), 77.7 (C-3), 73.5
(CH2Ph), 72.8 (CH2Ph), 72.5 (CH2Ph), 72.0 (C-6), 71.7 (CH2Ph),
69.5 (C-5), 64.4 (C-4), 62.9 (C-1), 53.7 (C-20), 46.5 (C-500), 33.4 (C-
10), 18.8 (C-30); HRMS calcd for C53H61N4O9 [M+H]+ 897.4420,
found 897.4422.
6.8 Hz), 4.60–4.30 (m, 5H, CH2Ph), 4.25 (d, 1H, CH2Ph,
J = 11.6 Hz), 4.0 (d, 1H, H-2, J = 5.2 Hz), 3.95 (d, 1H, NCH2Ph,
J = 14.4 Hz), 3.88 (br s, 1H, H-3), 3.76 (d, 1H, NCH2Ph, J = 14.4 Hz),
3.70 (dd, 1H, H-6a, J = 11.2, 2.8 Hz), 3.52–3.59 (m, 1H, H-1), 3.44
(dd, 1H, H-6b, J = 11.2, 6.8 Hz), 3.22 (dd, 1H, H-4, J = 6.8, 2.4 Hz),
2.7 (dd, 1H, H-10a, J = 17.6, 9.2 Hz), 2.3 (dd, 1H, H-10b, J = 17.6,
4.8 Hz), 1.94 (s, 3H, OAc), 1.86 (s, 3H, 30-Me); 13C NMR (CDCl3): d
208.3 (CO), 170.6 (Ac), 139.9, 138.3, 138.0, 128.8, 128.6, 128.5,
128.0, 127.9, 127.8, 127.7, 127.2, 83.0 (C-2), 81.5 (C-3), 73.9 (C-
5), 74.0 (CH2Ph), 73.0 (CH2Ph), 72.3 (CH2Ph), 71.2 (CH2Ph), 70.8
(C-4), 69.6 (C-6), 63.2 (C-1), 60.5 (NCH2Ph), 44.1 (C0-1), 30.7
(C-30), 21.4 (Ac); HRMS calcd for C39H44NO6 [M+H]+ 622.3168,
found 622.3169.
3.23. 1-C-(1,4-Dideoxy-1,4-imino-D
-galactosyl)-2-N-(50-deoxy-
C5,C6-tetrahydro-uridine-50)-2-propylamine (10i)
Hydrogenation of 9i (0.11 g, 0.12 mmol) and purification on a
Biogel P2 eluted with water yielded 10i (0.07 g, 92%) as a syrup.
Selected data for two major diastereomers: 1H NMR (D2O): d
5.82–5.55 (m, 2H, 2 ꢀ H-100), 4.48–3.84 (m, 12H, 2 ꢀ H-200, 300, 400,
2, 3, 5), 3.82–3.02 (m, 18H, 2 ꢀ H-1, 4, 6-CH2, 20, 500, 600-CH2),
2.95–2.50 (m, 4H, 2 ꢀ 700-CH2), 2.22–1.58 (m, 4H, 2 ꢀ 10-CH2),
1.50–1.15 (m, 6H, 2 ꢀ 30-Me); 13C NMR (D2O): d 154.4 (CO-Ur),
154.3 (CO-Ur), 90.3 (C-1C), 89.8 (C-1C), 79.7, 78.6, 78.2, 77.9, 76.6,
76.5, 76.3, 71.4, 71.3, 71.1, 70.7, 70.6, 70.0, 69.1, 63.2 (C-6), 62.1,
58.4 (C-1), 58.3 (C-1), 52.9 (C-20), 47.0 (C-500), 46.8 (C-500), 41.6,
38.1 (C-600), 37.8 (C-600), 34.8 (C-10), 30.2, 16.1 (C-30), 15.7 (C-30);
HRMS calcd for C18H33N4O9 [M+H]+ 449.2247, found 449.2246.
3.27. 1-C-(N-Benzyl-2,3,6-tri-O-benzyl-1,4-dideoxy-1,4-imino-
D-galactosyl)-2-N-hexyl-2-propylamine (14)
Reductive amination of 13 (0.11 g, 0.18 mmol) with hexylamine
(0.05 g, 0.55 mmol) gave, after purification by flash chromato-
graphy using a linear gradient with CH2Cl2 and 0.1% Et3N–MeOH
(0–10%), 14 (0.08 g, 66%) as a syrup. Selected data: 1H NMR
(CDCl3): d 7.40–7.14 (m, 40H, 8 ꢀ Ph), 5.02–4.96 (m, 1H, H-5),
4.58–4.20 (m, 12H, 6 ꢀ CH2Ph), 3.99–3.65 (m, 10H), 3.46–3.14
(m, 9H), 2.54–2.18 (m, 6H), 1.82–1.73 (m, 2H), 1.60–1.15 (m,
16H, 8 ꢀ –CH2–), 0.93–0.78 (m, 12H, 2 ꢀ 90-Me, 30-Me); 13C NMR
(CDCl3): d 136.7, 135.9, 135.4, 127.0, 126.0, 125.9, 125.4, 125.3,
125.2, 124.9, 81.0, 80.3, 75.0, 74.7, 74.4, 70.9, 69.9, 69.5, 68.9,
67.5, 67.4, 60.8, 58.4, 48.6, 44.9, 33.7, 29.5, 28.2, 24.8, 20.3, 17.8,
11.7; HRMS calcd for C43H57N2O4 [M+H]+ 665.4318, found
665.4343.
3.24. 1-C-(1,4-Dideoxy-1,4-imino-D-galactosyl)-acetone (11)
Hydrogenation of 5 (0.12 g, 0.39 mmol) gave, after purification
on Biogel P2 column eluted with water, 11 (0.06 g, 70%), an
anomeric mixture as a syrup. 1H NMR (D2O): d 4.30–3.82 (m, 7H,
H-1, 2 ꢀ H-2, 5, 3), 3.82–3.58 (m, 5H, H-1, 2 ꢀ 6-CH2), 3.58–3.40
(m, 2H, 2 ꢀ H-4), 3.28–3.00 (m, 4H, 2 ꢀ H-10), 1.80 (s, 6H, 2 ꢀ 30-
Me); 13C NMR (D2O): d 210.9 (CO), 77.7 (C-2), 76.6 (C-3), 75.8
(C-3), 75.1 (C-2), 69.6 (C-5), 68.8 (C-5), 67.3 (C-4), 63.0 (C-6),
62.5 (C-4), 67.4 (C-1), 56.6 (C-1), 43.2 (C-10), 43.0 (C-10), 23.4 (C-30);
HRMS calcd for C9H18NO5 [M+H]+ 220.1184, found 220.1176.
3.28. 1-C-(1,4-Dideoxy-1,4-imino-D-galactosyl)-2-N-hexyl-2-
propylamine (10g)
Hydrogenation of 14 (0.07 g, 0.11 mmol) gave, after purification
on a Biogel P2 column eluted with water, 10g (0.02 g, 60%) as a so-
lid. Selected data: 1H NMR (D2O): d 4.23–4.16 (m, 4H, 2 ꢀ H-2, 3),
4.00–3.93 (m, 2H, 2 ꢀ H-5), 3.88–3.74 (m, 4H, 2 ꢀ H-1, 6a), 3.68
and 3.65 (2d, 1H each, 2 ꢀ H-6b, J = 4.91 Hz), 3.57–3.48 (m, 2H,
2 ꢀ H-4), 3.48–3.36 (m, 2H, 2 ꢀ H-20), 3.16–3.0 (m, 4H, 2 ꢀ 40-
CH2), 2.50–2.41 (m, 1H, H-10), 2.40–2.25 (m, 1H, H-10), 2.16–2.06
(m, 1H, H-10), 2.03–1.92 (m, 1H, H-10), 1.63–1.59 (m, 4H, 2 ꢀ 50-
CH2), 1.48–1.21 (m, 18H, 2 ꢀ 30-Me, 6 ꢀ –CH2–), 0.92–0.81 (m,
6H, 2 ꢀ 90-Me); 13C NMR (D2O): d 77.1 (C-2 or C-3), 76.6 (C-2 or
C-3), 76.2 (C-2 or C-3), 74.3 (C-2 or C-3), 69.9 (C-5) 69.8 (C-5),
68.0 (C-4), 67.8 (C-4), 62.8 (C-6), 58.7 (C-1), 58.6 (C-1), 51.8
(C-20), 51.2 (C-20), 45.1 (C-50), 45.0 (C-50), 30.5 1 (C-70), 29.2
(C-10), 28.6 (C-10), 25.8 (C-50) 25.7 (C-50), 25.5 (C-60), 21.8 (C-80),
15.7 (C-30), 15.6 (C-30), 13.3 (C-90); HRMS calcd for C15H33N2O4
[M+H]+ 305.2440, found 305.2433.
3.25. 1-C-(N-Benzyl-2,3,6-tri-O-benzyl-1,4-dideoxy-1,4-imino-
D
-galactosyl)-acetone (12)
To a suspension of iminosugar 5 (0.61 g, 1.24 mmol) in DMF
(10 mL) was added benzyl bromide (0.37 mL, 3.11 mmol) followed
by K2CO3 (0.38 g, 2.73 mmol). The mixture was stirred at 50 °C
overnight. Usual work-up and purification by chromatography (0–
50%, hexanes–EtOAc) gave 12 (0.93 mg, 75%) as a syrup. Selected
data for major anomer: 1H NMR (CDCl3): d 7.40–7.20 (m, 20H,
4 ꢀ Ph), 4.60–4.40 (m, 5H, CH2Ph), 4.30 (d, 1H, CH2Ph, J = 12.0 Hz),
4.10 (d, 1 H, H-2, J = 5.2 Hz), 4.00–3.90 (m, 2H, H-3, NCH2Ph),
3.80–3.60 (m, 3H, H-1, H-5, NCH2Ph), 3.45 (m, 2H, H-6a, 6b), 3.30
(d, 1H, H-4, J = 4.4 Hz), 2.70 (dd, 1H, H-10a, J = 17.2, 8.0 Hz), 2.20
(dd, 1H, H-10b, J = 5.2 Hz), 1.80 (s, 3H, CH3); 13C NMR (CDCl3): d
208.0 (CO), 139.4, 138.3, 138.2, 137.7, 129.3, 128.6, 128.5, 128.1,
128.0, 127.9, 127.8, 127.7, 127.5, 83.4 (C-3), 83.3 (C-2), 73.5
(CH2Ph), 72.6 (CH2Ph), 72.3 (C-6), 71.5 (CH2Ph), 71.1 (C-4), 69.8
(C-5), 63.5 (C-1), 62.2 (NCH2Ph), 44.4 (C-10), 30.4 (C-30); HRMS calcd
for C37H42NO5 [M+H]+ 580.3062, found 580.3057.
Acknowledgments
This is NRC-CNRC publication No. 42527. We thank Ken Chan
and Jacek Stupak for MS analysis and Nam Khieu for the assistance
in NMR analysis.
References
3.26. 1-C-(N-Benzyl-5-O-acetyl-2,3,6-tri-O-benzyl-1,4-dideoxy-
1,4-imino-D-galactosyl)-acetone (13)
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85%) as a syrup. Selected data for major anomer: 1H NMR (CDCl3):
d 7.40–7.20 (m, 20H, 4 ꢀ Ph), 5.05 (ddd, 1H, H-5, J = 2.8, 6.8,

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