InCl3-CH3CN-H2O: An efficient catalyst-solvent combination for the synthesis of Perlin aldehydes and related compounds. Application in the synthesis of unnatural l-azasugars

Article abstract of DOI:10.1016/j.tet.2010.11.050

InCl₃-CH₃CN-H₂O has been found to be an efficient catalyst-solvent combination for the synthesis of Perlin aldehydes and related compounds. While acetylated glycals afforded the Perlin aldehydes directly with InCl₃

Full text of DOI:10.1016/j.tet.2010.11.050

Tetrahedron 67 (2011) 769e776
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
InCl3eCH3CNeH2O: an efficient catalyst-solvent combination for the synthesis
of Perlin aldehydes and related compounds. Application in the synthesis
of unnatural -azasugars
L
y
*
Paramathevar Nagaraj, Muthupandian Ganesan , Namakkal G. Ramesh
Department of Chemistry, Indian Institute of TechnologydDelhi, Hauz Khas, New Delhi 110016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 October 2010
Received in revised form 11 November 2010
Accepted 11 November 2010
Available online 18 November 2010
InCl3eCH3CNeH2O has been found to be an efficient catalyst-solvent combination for the synthesis of
Perlin aldehydes and related compounds. While acetylated glycals afforded the Perlin aldehydes directly
with InCl3 and water, benzylated glycals on the other hand provided the hemiacetals under identical
condition. The methodology reports a non-mercurial approach to Perlin aldehydes. Noteworthy is that
this reaction is more facile as well as highly selective with glycals possessing a hydroxyl as a leaving
group than with a benzyloxy group. Extension of this reaction to 2-C-hydroxymethyl glycals resulted in
the formation of the corresponding hemiacetals, which were further transformed in to unsaturated
azasugars with an exo-methylene group at C-2 position. Glycosidase inhibition studies reveal that these
compounds display selectivity in inhibiting glucosidases rather than galactosidases.
Keywords:
Indium(III) chloride
Perlin aldehyde
Ferrier rearrangement
Azasugars
Ó 2010 Elsevier Ltd. All rights reserved.
Glycosidase inhibitors
Carbohydrates
1. Introduction
C-4 to C-5 carbon of 3 (Scheme 1). Similar reaction was observed
with tri-O-acetyl- -galactal 2 also.
D
Carbohydrate derived chiral intermediates have found enor-
mous applications in organic synthesis due to their inherent
functional group, stereochemical and structural diversities as well
as their ready availability.1 It has been well documented that the
R2
R2
R2
OAc
OH
HgSO4 (2 mol%)
H2SO4 (5 mM)
rt, dioxane
OAc
OAc
OAc
R1
R1
O
R1
+
AcO
O
presence of a pushepull
a,
b-unsaturated carbonyl group further
O
H
H
1 R1 = OAc, R2 = H
2 R1 = H, R2 = OAc
3 R1= OAc, R2 = H
5 R1= OH, R2 = H
6 R1 = H, R2 = OH
enhances the versatility of sugar nuclei as chiral templates in or-
ganic synthesis. Examples of such compounds include alkyl-hex-2-
4 R1 = H, R2 = OAc
eno-uloses,2 2-C-formyl glycals,3 2,3-dideoxy-
a
,
b
-unsaturated
sugar aldehydes4,5 and other carbohydrate based enones.6 Since
last three decades, 2,3-dideoxy- -unsaturated sugar aldehydes,
Scheme 1. Synthesis of Perlin aldehydes using HgSO4/H2SO4.
a,b
A couple of modified procedures developed later also rely on the
use of toxic Hg2þ salts.5,21 Further, a reinvestigation of the oxy-
mercurationedemercuration reaction of glycals by Shaw and co-
workers revealed that the reaction was highly solvent (THF vs
dioxane) dependent.21 The only non-mercurial method available as
of now for the synthesis of Perlin aldehydes is also due to Shaw and
co-workers.22 They had reported that exposure of diversely pro-
tected glycals to a mixed Lewis acid (HfCl4 and Znl2) catalyst at
room temperature to 140 ꢀC resulted in the facile formation of the
corresponding Perlin aldehydes 9 and 10 (Scheme 2). Notable
observation was that the reaction required both the Lewis acids and
was unsuccessful with either of them only. Moreover, in case of
benzyl and methyl protected glycals, the corresponding 2-deoxy-
hexoses 11 were obtained in considerable proportions.
popularly known as Perlin aldehydes, have been serving as at-
tractive precursors for the synthesis of a wide array of biologically
important natural and unnatural compounds.7e20 Conventionally,
Perlin aldehydes are prepared by oxymercurationedemercuration
reaction of suitably protected glycals in the presence of 5mM sul-
furic acid (Scheme 1).4 Perlin reported that tri-O-acetyl-
D
-glucal 1
on reaction with 2 mol % of HgSO4 in presence of 0.01e0.02 N H2SO4
afforded the corresponding -unsaturated aldehyde 3 along with
a,b
an inseparable side product 5, arising out of an acyl migration from
* Corresponding author. Tel.: þ91 11 26596584; fax: þ91 11 26581102; e-mail
address: ramesh@chemistry.iitd.ac.in (N.G. Ramesh).
y
Contributed in bio-assay studies.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.050

770
P. Nagaraj et al. / Tetrahedron 67 (2011) 769e776
In view of the growing importance of Perlin aldehydes as ver-
The reaction was also successful with tri-O-acetyl-
D-galactal 2
satile chiral substrates in organic synthesis, it was thought that
development of a new methodology, complementary to the exist-
ing ones, would be of significance. As a part of our ongoing research
on the use of InCl3 as a mild Lewis acid catalyst for various trans-
formations in carbohydrate chemistry,23,24 we explored its utility
towards the synthesis of Perlin aldehydes and related compounds.
Our results in this direction are reported here. We have also ex-
tended the reaction to 2-C-hydroxymethyl glycals 22 and 23, and
the resulting hemiacetals were further transformed to unnatural
azasugars.
and the -unsaturated aldehyde 4 was obtained in 5 h along with
a,b
compound 6 in a ratio of 70:30 with an overall yield of 74%. As
before, acetylation of the mixture afforded the triacetate 14 in 86%
yield (Scheme 4).
Scheme 4. InCl3 catalyzed synthesis of Perlin aldehyde from tri-O-acetyl-D-galactal 2.
R2
R2
R2
OR
O
OR
OH
OR
O
ZnI2 (8.8 mol%)
HfCl4 (22 mol%)
R1
R1
R1
The reaction of tri-O-benzyl- -glucal 15 with InCl3 in acetoni-
D
+
RO
CH3CN-H2O (7:3)
RO
trile and water required a slightly longer time (8 h) to go to com-
pletion, under identical condition. In this case, even with 20 mol %
of the catalyst, hemiacetal 19a was obtained as the major product
rt-140 oC, 6 min-2.5 h
O
OH
H
7 R1 = OAc, OBn,OMe;
9 R1 =OAc, OBn, OMe;
11 R1 =H; R2 = OBn,
OMe; R = Bn, Me
R
2 = H; R =Ac, Bn, Me
R
2 = H; R = Ac, Bn, Me
8 R1 =H; R2 = OAc, OBn,
10 R1 = H; R2 = OAc, OBn,
with only a trace amount (∼<10%) of the a,b-unsaturated aldehyde
20a, as could be seen from the 1H NMR spectrum of the crude re-
action mixture (Scheme 5, Table 1, entry 1). All our efforts to direct
the reaction exclusively towards the Perlin aldehyde 20a were in
vain. This observation indicates that in the reaction of acetyl pro-
tected glycals 1 and 2 with water (Schemes 3 and 4), the acetic acid,
that is, formed as the by-product plays a crucial role in catalyzing
the further transformation of the hemiacetal to Perlin aldehyde. On
OMe; R = Ac, Bn, Me
OMe; R = Ac, Bn, Me
Scheme 2. Synthesis of Perlin aldehydes using a mixed Lewis acid (HfCl4 and Znl2)
catalyst.
2. Results and discussion
Our initial studies began with the reaction of tri-O-acetyl-D-
the other hand, with tri-O-benzyl- -glucal 15 as the substrate, the
D
glucal 1 with water, in acetonitrile as a solvent, in presence of
5 mol % of InCl3 as a catalyst at room temperature. Though a new
product was formed (vide TLC), the reaction did not go to com-
pletion even after a long time. Complete consumption of the
starting material was noticed when the reaction was performed
for 7 h at 70 ꢀC with 5 mol % of InCl3 in acetonitrile and water
(9:1). However, it was observed that the isolated product was not
the expected Perlin aldehyde 3 as revealed by the absence of the
signal due to the aldehydic proton in its 1H NMR spectrum. De-
tailed analysis of the spectral data led to its identification as the
unsaturated hemiacetal 12 arising out of InCl3 catalyzed Ferrier
by-product benzyl alcohol is a neutral compound. It is likely that in
the absence of a strong acid, the reaction could not proceed further
towards Perlin aldehyde and InCl3 alone may not be enough to
catalyze the reaction completely resulting in its formation only in
a trace amount. While a couple of methods are available for the
direct synthesis of the Perlin aldehyde 20a from tri-O-benzyl-D-
glucal 15, to our knowledge, there is no practical method available
for the synthesis of the hemiacetal 19a as of today. It was obtained
only as a by-product in the enantioselective oxidation reaction of
olefins from the corresponding sugar peroxides.26 Hall and co-
workers have reported the synthesis of the hemiacetal 19a in only
rearrangement of tri-O-acetyl-D
-glucal with water (Scheme 3).25
20% from the reaction of ethyl 4,6-di-O-benzy1-2,3-dideoxy-a-D-
Prolonged reaction time did not lead to any appreciable con-
version of the cyclic hemiacetal 12 to the open-chain Perlin al-
dehyde 3. Subsequently, upon increasing the amount of the
catalyst from 5 to 20%, the expected Perlin aldehyde 3 could be
obtained along with another isomer 5 arising from the migration
of the acetyl group from C-4 carbon to C-5 carbon in a ratio of
60:40. In order to confirm that compounds 3 and 5 are positional
isomers, the inseparable mixture of 3 and 5 was acetylated with
acetic anhydride in the presence of Et3N and catalytic amount of
DMAP to get the single triacetate 13 in 74% yield whose spectral
data were identical with those of the literature reported values
(Scheme 3).4,21
erythro-hex-2-enopyranoside with chlorosulfonyl isocyanate.27 The
present methodology thus offers a convenient protocol for the
synthesis of the hemiacetal 19a.
The reaction of tri-O-benzyl- -galactal 16 with 20 mol % of InCl3
D
was sluggish and took 18 h for completion to give a mixture of the
hemiacetal 19b and the corresponding 2-deoxygalactose 21b in
almost equal proportion with an overall yield of 52% only (Scheme
5, Table 1, entry 2). This is not surprising, as it is well documented in
literature that during the Ferrier rearrangement of protected gal-
actals, the corresponding 2-deoxy products were invariably formed
in considerable amounts.22,28 Formation of 2-deoxygalactose 21b
even during the synthesis of Perlin aldehyde 20b from tri-O-ben-
zyl-
-galactal 16 was generally inevitable22 and the reaction was
D
InCl3 (5 mol%)
InCl3 (20 mol%)
solvent dependant as reported by Shaw and co-workers.21 En-
OAc
O
CH3CN/H2O (9/1)
CH3CN/H2O (9/1)
couraged by our recent finding24b on the efficient InCl3 catalyzed
AcO
1
3
5
+
70 0C, 4 h, 79 %
70 0C, 7 h, 88 %
Ferrier rearrangement of 4,6-di-O-benzyl- -galactal 17 with alco-
D
Et3N (1.5 equiv.)
Ac2O (1.2 equiv.)
hols and that too without the formation of the corresponding 2-
deoxygalactoside, we examined the behaviour of 1729 with water in
presence of InCl3 in CH3CN at 70 ꢀC. Quite surprisingly, the reaction
was found to be quite fast and complete consumption of starting
material was noticed in just 2 h (as compared to 18 h with tri-O-
OH
12
DMAP (0.1 equiv.)
CH2Cl2, 1 h, 74%
OAc
OAc
benzyl- -galactal 16). More so even, the reaction exclusively affor-
D
AcO
ded the hemiacetal 19b in 86% yield without the formation of
2-deoxygalactose 21b (Scheme 5, Table 1, entry 3). The reaction was
O
H
also found to be facile with 4,6-di-O-benzyl-
-glucal30 18 (Scheme
D
13
5, Table 1, entry 4). These reactions, typically involving a [1,3]-allylic
transposition of hydroxyl group, provide a ready access to sugar
Scheme 3. InCl3 catalyzed synthesis of Perlin aldehyde from tri-O-acetyl-D-glucal 1.

P. Nagaraj et al. / Tetrahedron 67 (2011) 769e776
771
R2
R2
R2
R2
OBn
O
OBn
O
OBn
OH
OBn
O
InCl3 (20 mol %)
R1
R1
R1
R1
+
+
CH3CN/H2O (9/1)
70 0C
RO
RO
O
2
OH
OH
1 2
21a R = OBn, R = H; R = Bn
H
20b R1 = H, R = OBn
1
2
1
15-18
19a R = OBn, R = H
20a R = OBn, R = H
2
19b R1 = H, R = OBn
2
2
21b R1 = H, R = OBn; R = Bn
Scheme 5. InCl3 catalyzed reaction of benzylated glycals 15e18 with water in acetonitrile solvent.
OH
OH
Table 1
OH
OH
InCl3 catalyzed reaction of benzylated glycals 15e18 with water in acetonitrile
solvent
OH
OH
HO
HO
HO
Entry Glycal R1
R2
R
Time (h) Ratio of Products
Yielda (%)
N
H
N
H
19
20
21
28
29
1
2
3
4
15
16
17
18
OBn
H
H
H
Bn
8
92
52
89
96
8
0
11
4
0
48
0
72
52
86
77
Nojirimycin
1-deoxynojirimycin
OBn Bn 18
OBn
H
H
H
2
3
OH
OH
OBn
0
OH
OH
OH
OH
HO
HO
a
overall isolated yield after column chromatography.
N
N
hemiacetals, for which a convenient method has remained elusive
so far especially with benzylated glycals. Moreover, these obser-
vations further strengthen our earlier findings that InCl3 has
a greater affinity to coordinate with a hydroxyl group over an alkyl
or acyl group.24
OH
31
30
glyset®
zavesca®
Extension of this reaction to 2-C-hydroxymethyl glycals 22 and
2331 afforded the corresponding 2-C-methylene hexoses 24 and 25
in 5 h and 4 h, respectively, in good yields (Scheme 6). In these
examples, the unsaturated hemiacetals 24 and 25 were found to be
Fig. 1. Representative examples of six-membered azasugars.
crude yield). Upon heating with benzylamine for 26 h at 90 ꢀC, the
dimesylate underwent a double nucleophilic substitution reaction
to afford the protected azasugar derivative 34 as a single di-
astereomer in 78% yield (Scheme 7).36 Gupta and Vankar recently
reported,37 through a facile and a novel in situ aza Claisen rear-
rangement of trichloroacetamidate derivative of 2-C-hydrox-
in equilibrium with their open-chain a,b-unsaturated aldehydes 26
and 27. Interesting observation is that while in case of glucal 22 the
equilibrium is in favour of the hemiacetal 24 (24/26¼89:11), it was
the other way in the galactal 23 with the a,b-unsaturated aldehyde
ymethyl-
D-galactal, the synthesis of azasugar 34 in seven steps from
27 being the predominant one (25/27¼1:2).
2-C-hydroxymethyl-D-galactal 23. While providing an alternative to
Vankar’s method, the present route is also versatile enough to in-
troduce diverse substituents on the ring nitrogen by way of utilizing
different amines during the cyclization step. Thus, the generality of
the cyclization reaction was demonstrated by heating the dimesy-
late 33 with a few other amines and the corresponding protected
azasugars 35e39 were obtained in good yields (Scheme 7).
R2
R2
InCl3 (20 mol%)
R2 OBn
OBn
OBn
OH
CH3CN/H2O (9/1)
R1
O
70 0C, 4-5 h, 77-86%
R1
R1
O
BnO
BnO
BnO
O
OH
H
OH
22 R1 = OBn, R2 = H
23 R1 = H, R2 = OBn
24 R1 = OBn, R2 = H
25 R1 = H, R2 = OBn
26 R1 = OBn, R2 = H
27 R1 = H, R2 = OBn
NaBH4 (1.5 equiv.)
OBn
OH
BnO
BnO
MeOH, rt,
Scheme 6. InCl3 catalyzed reaction of 2-C-hydroxymethyl glycals with water in ace-
30 min, 85 %
tonitrile solvent.
25+27
OH
Chemistry and biology of naturally occurring iminosugars
(azasugars) and their synthetic analogues continue to be in the
forefront of the inter-disciplinary research domain of glycobiology
for over four decades.32 Their significant and selective inhibition of
various glycosidases make them attractive lead molecules against
various carbohydrate-mediated disorders such viral, diabetes, HIV,
etc.33 The selective glycosidase inhibition property is attributed to
their structural resemblance as well as mimicry of glycosidase oxo-
carbenium-ion-like transition state.34 Azasugar based drugs such as
ZavescaÒ 30 and GlysetÒ 31 (Fig.1) are already in clinical use for the
treatment of diabetes, Gaucher’s disease, etc.33 In continuation of
our work on the synthesis of natural and novel unnatural azasu-
gars,35 it was envisaged that the hemiacetals 24 and 25 would be
ideal substrates for the synthesis of 2-C-methylene-azasugars
through cleavage of the O-C1 bonds of 24 and 25 followed by cy-
clization with amines.
32
MsCl (2.2 equiv.)
Et3N (2.5 equiv.)
CH2Cl2, 0 0
2 h, 85%
C
BnO
OBn
OBn
OMs
OMs
BnO
BnO
R-NH2
N
R
OBn
33
34 R = Bn, 26 h, 78%
35 R = n-Propyl, 28 h, 86%
36 R = n-Pentyl, 22 h, 82%
37 R = n-Hexyl, 18 h, 77%
38 R = n-Butyl, 17 h, 71%
39 R = n-Hydroxyethyl, 22 h, 54%
Reduction of an equilibrium mixture of 25 and 27 with 1.5 equiv
of NaBH4 at room temperature afforded the unsaturated diol 32 in
85% yield in 30 min. Mesylation of 32 with 2.2 equiv of mesyl chlo-
ride in presence Et3N at 0 ꢀC yielded the dimesylate 33 in 2 h (85%
Scheme 7. Synthesis of unsaturated azasugars 34e39 from 2-C-hydroxymethyl-D-
galactal 23.

772
P. Nagaraj et al. / Tetrahedron 67 (2011) 769e776
Extension of the synthetic sequence to 2-C-hydrxoymethyl-
D
-
3. Conclusions
glucal 22 resulted in the formation of the unsaturated azasugar 42,
(Scheme 8).
In conclusion, we have found that InCl3eCH3CNeH2O is an
efficient catalyst-solvent combination for the synthesis of Perlin
aldehyde and related compounds. With acylated glycals the a,b-
NaBH4 (1.5 equiv.)
OBn
unsaturated aldehydes (Perlin aldehydes) were obtained directly,
while benzylated glycals afforded the corresponding hemiacetals.
We have extended this reaction to 2-C-hydroxymethyl glycals to get
a new class of unsaturated carbohydrate derived hemiacetals.
Application of our methodology towards the synthesis of unsaturated
azasugars has been highlighted. The glycosidase inhibitions activ-
ities of these compounds show promising future for developing
new unsaturated azasugars with better inhibition properties.
Further functionalization of the exocyclic double bonds of com-
pounds 34e39 and 42 is in progress. Their synthesis and biological
activities will form part of our future work in this area.
MeOH, rt,
30 min, 84 %
OH
BnO
24+ 26
OH
BnO
40
MsCl (2.2 equiv.)
Et3N (2.5 equiv.)
CH2Cl2, 0 0
2 h, 88%
C
BnO
N
OBn
OMs
OMs
BnNH2
OBn
OBn
4. Experimental section
BnO
BnO
24 h, 74%
4.1. General considerations
Bn
42
All solvents were purified by standard procedures. Thin-layer
chromatography (TLC) was performed on Merck silica gel pre-
coated on aluminium plates. Flash column chromatography was
performed on 230e400 mesh silica gel. Optical rotations were
recorded on an Autopol V (Rudolph Research Flanders, New Jersey)
instrument. All the rotations were measured at 589 nm (sodium D
line). IR spectra were taken over the 4000e400 cmꢁ1 range as KBr
pellets on a Nicolet (Madison, USA) FTIR spectrophotometer (Model
41
Scheme 8. Synthesis of unsaturated azasugar 42 from 2-C-hydroxymethyl-D-glucal 22.
Deprotection of azasugars 34 and 38 was next carried out with
a view to studying the glycosidase inhibitory properties of these
classes of compounds. Selective O-debenzyaltion38 of compound 34
was achieved by exposing it to 6.0 equiv of BCl3 in CH2Cl2 at room
temperature to get the hitherto unreported azasugar analogue 43
in 82% yield. Both the N-benzyl as well the exo-methylene groups
remain unaffected during this deprotection step. Similar reaction
Protege 460). All the 1H and 13C NMR spectra were recorded on
ꢀ ꢀ
a 300 MHz Bruker Spectrospin DPX FT-NMR spectrometer. Chem-
ical shifts are reported as
ternal standard. Mass spectra were recorded with an Applied
Biosystems Q-Star instrument.
d values (ppm) relative to Me4Si as in-
with N-butyl derivative 38 afforded the corresponding new
sugar derivative 44 in 92% yield (Scheme 9).
L-aza-
4.2. 4,6-Di-O-acetyl-2,3-dideoxy-D-erythro-hex-2-
enopyranose 12
OBn
OH
OH
OH
BCl3 (6.0 equiv.)
CH2Cl2, rt, 24 h
OBn
Glycal 1 (0.272 g, 1 mmol) was dissolved in a 10 mL mixture of
acetonitrile and water (9:1). After 5 min, InCl3 (0.011 g, 0.05 mmol)
was added and the reaction mixture was stirred at 70 ꢀC for 7 h. It
was then quenched with water and extracted with chloroform
(3ꢂ50 mL). The organic layer was then dried over anhydrous so-
dium sulfate, filtered and concentrated. Purification by column
chromatography over silica gel using hexane/ethyl acetate (4:1)
afforded the hemiacetal 12 as a viscous colourless liquid in 88%
yield (0.202 g). The spectral data of compound 12 were found to be
identical with the literature reported values.25
N
N
R
R
OBn
34 R = Bn
43 R = Bn, 82%
38 R = Bu
44 R = Bu, 92%
Scheme 9. Deprotection of compounds 34 and 38.
Compounds 43 and 44 were tested for their inhibitory activi-
ties against four different commercially available enzymes (Table
2).35b They did not show any inhibition against
sidases. Compound 43 displayed inhibition against both
glucosidases with IC50 values of 4.5 mM and 8.2 mM, respectively.
a
- and
b
a
-galacto-
- and
4.3. General procedure for the synthesis of Perlin aldehydes
from acylated glycals 1 and 2
b-
On the other hand, compound 44 displayed selectivity by inhib-
Glycal 1 or 2 (1 mmol) was dissolved in a 10 mL mixture of
acetonitrile and water (9:1). After 5 min, InCl3 (0.20 mmol) was
added and the reaction mixture was stirred at 70 ꢀC for 4e5 h. It
was then quenched with water and extracted with chloroform
(3ꢂ50 mL). The organic layer was then dried over anhydrous so-
dium sulfate, filtered and concentrated. Purification by column
chromatography over silica gel using hexane/ethyl acetate (4:1)
afforded the corresponding Perlin aldehydes.
iting only
b-glucosidase with an IC50 value of 7.5 mM and not the
a
-glucosidase.
Table 2
Inhibition studies of compounds 43 and 44
Entry Enzyme Source
Condition
IC50, mM
43
44
1
2
3
4
a
b
a
b
-Glucosidase
-Glucosidase
-Galactosidase Green coffee beans
-Galactosidase E. coli
Baker’s yeast (type I) 37 ꢀC, pH¼6.8 4.5
8.2
NI
NI
NI
37 ꢀC, pH¼5
7.5
4.3.1. Synthesis of (2E)-4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-
Almond
25 ꢀC, pH¼6.5 NI
2-enose 3. Compound 3 was obtained along with 5 (0.335 g, 79%
yield) in 4 h as a colourless viscous liquid by the reaction of glycal 1
(0.500 g, 1.83 mmol) with InCl3 (0.081 g, 0.367 mmol). The spectral
37 ꢀC, pH¼7.3 NI
NI¼no inhibition was observed up to 10 mM inhibitor concentration.

P. Nagaraj et al. / Tetrahedron 67 (2011) 769e776
773
data of compounds 3 and 5 were found to be identical with the
5.79 (1H, d, J¼10.8 Hz, H-3), 5.41 (1H, br s, H-1), 4.61 (1H, d,
J¼12.0 Hz, eOCH2Ph), 4.60 (1H, d, J¼11.4 Hz, eOCH2Ph), 4.51 (1H,
d, J¼12.0 Hz, eOCH2Ph), 4.44 (1H, d, J¼11.4 Hz, eOCH2Ph), 4.10
literature reported values.4,25
4.3.2. Synthesis of (2E)-4,6-di-O-acetyl-2,3-dideoxy-
D
-threo-hex-2-
(2H, br s), 3.69 (2H, br s);dC (75 MHz, CDCl3) d 137.8, 130.2, 130.0,
enose 4. Compound 4 was obtained along with 6 (0.240 g, 74%
yield) in 5 h as a colourless viscous liquid by the reaction of glycal 2
(0.380 g, 1.40 mmol) with InCl3 (0.062 g, 0.28 mmol). The spectral
data of compounds 4 and 6 were found to be identical with the
literature reported values.4,25
128.5, 128.3, 127.9, 127.8, 127.7, 127.6, 127.4, 90.9, 88.8, 73.2, 70.9,
70.2, 68.8; HRMS (ESI): [MþNa]þ found 349.1399. C20H22O4Na
requires 349.1416.
4.6.2. 4,6-Di-O-benzyl-2,3-dideoxy-D-threo-hex-2-enopyranose
19b. Compound 19b (0.182 g, 56% yield) was obtained in 18 h as
a colourless viscous liquid from the reaction of 3,4,6-tri-O-benzyl-
4.4. Synthesis of (2E)-4,5,6-tri-O-acetyl-2,3-dideoxy-
D-
erythro-hex-2-enose 13
D-galactal 16 (0.420 g, 1.009 mmol) with InCl3 (0.044 g,
0.201 mmol). Alternatively, compound 19b (0.086 g, 86% yield) was
A mixture of compounds 3 and 5 (0.099 g, 0.430 mmol) was
dissolved in dry dichloromethane (10 mL). Triethylamine
(0.091 mL, 0.645 mmol) was added to the reaction mixture, fol-
lowed by DMAP (0.006 g, 0.0430 mmol) and acetic anhydride
(0.049 mL, 0.516 mmol) and the reaction mixture was stirred at
room temperature. After 1 h, when the reaction was found to be
completed, the reaction mixture was quenched with ammonium
chloride solution (100 mL) and extracted with chloroform
(3ꢂ50 mL). The organic layer was washed with aqueous saturated
bicarbonate solution and then dried over anhydrous sodium sul-
fate, filtered and concentrated. Purification by column chroma-
tography over silica gel using hexane/ethyl acetate (6:1) afforded
the triacetate 13 as a colourless viscous liquid in 74% yield (0.086 g).
The spectral data of compound 13 were found to be identical with
the literature reported values.4,25
also obtained in 2 h as a colourless viscous liquid from the reaction
of 4,6-di-O-benzyl- -galactal 17 (0.100 g, 0.306 mmol) with InCl3
D
(0.013 g, 0.061 mmol). Rf (30% EtOAc/hexane) 0.28. Specific rotation
reported here is for a mixture hemiacetal 19b and aldehyde 20b
28
present in a ratio of 89:11; [
a
]
D
ꢁ84.2 (c 0.38, CHCl3); nmax (KBr)
3426, 3087, 3063, 2926, 2880, 1741, 1687, 1496, 1453, 1399, 1260,
1201, 1095, 1058, 1026, 951, 907, 736, 696 cmꢁ1 1H and 13C NMR
;
values reported here correspond to the signals of only hemiacetal
19b taken from a mixture of hemiacetal 19b and aldehyde 20b; dH
(300 MHz, CDCl3) 7.37e7.33 (10H, m, aromatic), 6.14 (1H, dd,
J¼10.2, 5.4 Hz, H-2), 6.05 (1H, d, J¼10.2 Hz, H-3), 5.52 (1H, br s, H-
1), 4.68e4.42 (4H, m), 3.85e3.53 (4H, m).; dC (75 MHz, CDCl3) 138.2,
137.9, 130.4, 128.5, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 126.4, 88.4,
73.3, 70.8, 69.4, 69.2, 67.0; HRMS (ESI): [MþNa]þ found 349.1405.
C20H22O4Na requires 349.1416.
4.5. Synthesis of (2E)-4,5,6-tri-O-acetyl-2,3-dideoxy-
D
-threo-
4.6.3. 3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-D-arabino-hex-
hex-2-enose 14
opyranose 24. Compound 24 (0.210 g, 77% yield) was obtained in 5 h
as a colourless viscous liquid from the reaction of 3,4,6-tri-O-benzyl-
Compound 14 (0.243 g, 86% yield) was obtained (following the
same procedure as for 13) by the reaction of a mixture of 4 and 6
(0.240 g, 1.04 mmol), triethylamine (0.219 mL, 1.56 mmol), DMAP
(0.013 g, 0.104 mmol) and acetic anhydride (0.117 mL, 1.24 mmol).
The spectral data of compound 14 were found to be identical with
the literature reported values.4,25
2-C-hydroxymethyl-D-glucal 22 (0.272 g, 0.607 mmol) with InCl3
(0.027 g, 0.121 mmol). Rf (30% EtOAc/hexane) 0.35. Specific rotation
reported here is for a mixture hemiacetal 24 and aldehyde 26 present
in a ratio of 89:11; [
a
]
28 þ5.8 (c 1.00, CHCl3); nmax (KBr) 3411, 3031,
D
2919, 2866, 1609, 1499, 1455, 1359, 1208, 1103, 1019, 918, 740,
1
697 cmꢁ1; H and 13C NMR values reported here correspond to the
signals of only hemiacetal 24 taken from a mixture of hemiacetal 24
and aldehyde 26;dH (300 MHz, CDCl3) 7.35e7.15 (15H, m, aromatic),
5.54 (1H, s, ]CH2), 5.32 (1H, s, ]CH2), 5.13 (1H, s, H-1), 4.86 (1H, d,
J¼10.8 Hz, eOCH2Ph), 4.73 (1H, d, J¼11.1 Hz, eOCH2Ph), 4.67 (1H, d,
J¼11.1 Hz, eOCH2Ph), 4.60e4.53 (4H, m), 4.21 (1H, m), 3.86 (1H, br s),
3.64 (2H, m), 3.47 (1H, m); dC (75 MHz, CDCl3) 142.7,138.1,138.1,137.7,
128.5,128.3,128.2,127.9,127.8,127.7,127.6,110.4, 95.7, 80.6, 80.2, 74.7,
73.3, 73.2, 71.2, 69.1; HRMS (ESI): [MþNa]þ found 469.1995.
C28H30O5Na requires 469.1991.
4.6. General procedure for the synthesis of unsaturated
hemiacetals from benzylated glycals 15e18, 22, 23
Glycals 15e18 or 22 or 23 (1 mmol) was dissolved in a 10 mL
mixture of acetonitrile and water (9:1). After
5 min, InCl3
(0.020 mmol) was added and the reaction mixture was stirred at
70 ꢀC for appropriate time. It was then quenched with water and
extracted with chloroform (3ꢂ50 mL). The organic layer was then
dried over anhydrous sodium sulfate, filtered and concentrated.
Purification by column chromatography over silica gel using hex-
ane/ethyl acetate (4:1) afforded the corresponding hemiacetals.
4.6.4. 3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-D-lyxo-hexopyr-
anose 25. Compound 25 (0.860 g, 86% yield) was obtained in 4 h as
a colourless viscous liquid from the reaction of 3,4,6-tri-O-benzyl-
4.6.1. 4,6-Di-O-benzyl-2,3-dideoxy-
D
-erythro-hex-2-enopyranose
2-C-hydroxymethyl-D-galactal 23 (1.0 g, 2.24 mmol) with InCl3
19a. Compound 19a (0.175 g, 72% yield) was obtained in 8 h as
a colourless viscous liquid from the reaction of 3,4,6-tri-O-benzyl-
(0.099 g, 0.448 mmol). Rf (30% EtOAc/hexane) 0.36. Specific rota-
tion, 1H and 13C NMR reported here is for an equilibrium mixture of
D-glucal 15 (0.31 g, 0.745 mmol) with InCl3 (0.032 g, 0.143 mmol).
hemiacetal 25 and aldehyde 27 present in a ratio of 1:2. [
(c 1.05, CHCl3); nmax (KBr) 3421, 3031, 2920, 2865, 1741, 1688, 1612,
a
]
28 ꢁ7.14
D
Alternatively, compound 19a (0.093 g, 77% yield) was also
obtained in 3 h as a colourless viscous liquid from the reaction of
1491, 1455, 1361, 1308, 1217, 1099, 1017, 916, 741, 698 cmꢁ1
; dH
4,6-di-O-benzyl-
D
-glucal 18 (0.120 g, 0.368 mmol) with InCl3
(300 MHz, CDCl3) 9.58 (1H, s, CHO), 7.38e7.23 (23H, m, aromatic),
6.60 (1H, s, ]CH2 of 27), 6.24 (1H, s, ]CH2, of 27), 5.64 (0.5H, s, ]
CH2 of 25), 5.41 (0.5H, s, ]CH2 of 25), 5.27 (0.5H, s, H-1 of 25),
4.91e4.31 (12H, m), 3.94e3.91 (2H, m), 3.68 (1H, dd, J¼3.9, 1.8 Hz),
3.58 (1H, dd, J¼9.6, 6.9 Hz), 3.47 (1H, dd, J¼9.3, 5.7 Hz), 3.40e3.35
(1H, m), 3.10e3.08 (1H, m).; dC (75 MHz, CDCl3) 193.3, 146.8, 141.1,
138.3, 138.2, 137.8, 137.6, 137.2, 135.9, 128.4, 128.3, 128.3, 128.2,
128.2, 128.0, 127.8, 127.8, 127.7, 127.65, 127.60, 127.5, 127.4, 111.0,
96.0, 78.2, 77.5, 75.6, 75.4, 73.7, 73.2, 73.1, 73.0, 71.9, 71.5, 70.6, 70.4,
(0.016 g, 0.0736 mmol). Rf (30% EtOAc/hexane) 0.24. Specific ro-
tation reported here is for the mixture of hemiacetal 19a and al-
dehyde 20a present in a ratio of 96:4; [
nmax (KBr) 3394, 3033, 2911, 2862, 1686, 1452, 1388, 1307, 1247,
1204, 1072, 1026, 939, 740, 693, 611 cmꢁ1; 1H and 13C NMR values
reported here correspond to the signals of hemiacetal 19a taken
from a mixture of hemiacetal 19a and aldehyde 20a; dH (300 MHz,
CDCl3) 7.32e7.25 (10H, m, aromatic), 6.07 (1H, d, J¼10.8 Hz, H-2),
28
a
]
þ70.5 (c 0.38, CHCl3);
D

774
P. Nagaraj et al. / Tetrahedron 67 (2011) 769e776
69.7, 68.9; HRMS (ESI): [MþNa]þ found 469.1992. C28H30O5Na re-
chromatography using hexane/ethyl acetate mixture as an eluent to
obtain unsaturated azasugars.
quires 469.1991.
4.9.1. (2S,3S,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
5-C-methylene piperidine 34. Compound 34 (0.334 g, 78% yield)
was obtained in 26 h as a colourless low melting solid from the
4.7. Synthesis of (3R,4S,5R)-3,4,6-tris(benzyloxy)-5-hydroxy-
2-hydroxymethylhex-1-ene 32
reaction of dimesylate 33 (0.500 g, 0.827 mmol) with 15 mL of
An equilibrium mixture of compound 25 and 27 (0.210 g,
0.470 mmol) was dissolved in 10 mL of methanol. After 5 min, sodium
borohydride (0.027 g, 0.705 mmol) was added slowly to the reaction
mixture and the progress of the reaction was monitored by TLC. After
30 min when TLC indicated the completion of the reaction, the re-
action mixture was quenched with saturated ammonium chloride
solution (20 mL) and extracted with chloroform (3ꢂ50 mL). The or-
ganic layer was washed with aqueous saturated sodium bicarbonate
solution, dried over anhydrous sodium sulfate, filtered and concen-
trated. The crude product was purified by column chromatography
using hexane/ethyl acetate (4:1) as an eluent to get the diol 32
(0.179 g, 85% yield) as a colourless liquid; Rf (30% EtOAc/hexane) 0.21;
28
benzylamine at 90 ꢀC; Rf (10% EtOAc/hexane) 0.54; [
a]
ꢁ4.5
D
(c 1.10, CHCl3); nmax (KBr) 3030, 2965, 2867, 1653, 1597, 1491, 1452,
1360, 1315, 1236, 1109, 992, 911, 836, 739, 691 cmꢁ1
;
dH (300 MHz,
CDCl3) 7.31e7.20 (20H, m, aromatic), 4.98 (1H, s, ]CH2), 4.96 (1H, s,
]CH2), 4.59 (1H, d, J¼12.6 Hz, eOCH2Ph), 4.53e4.49 (3H, m), 4.36
(1H, d, J¼11.7 Hz, eOCH2Ph), 4.29 (1H, d, J¼12.6 Hz, eOCH2Ph), 4.09
(1H, d, J¼2.7 Hz), 3.95 (1H, d, J¼13.5 Hz, eNCH2Ph), 3.86 (1H, dd,
J¼10.5, 2.7 Hz, eCH2OBn), 3.80 (1H, dd, J¼10.5, 6.0 Hz, eCH2OBn),
3.68 (1H, dd, J¼9.3, 3.0 Hz, H-3), 3.57 (1H, J¼13.5 Hz, eNCH2Ph),
3.25e3.21 (1H, m), 3.09 (1H, d, J¼12.6 Hz, H-6), 2.99 (1H, d,
J¼12.6 Hz, H-6); dC (75 MHz, CDCl3) 140.4, 139.3, 138.4, 129.2,
128.35, 128.3, 128.2, 128.0, 127.99, 127.9, 127.6, 127.5, 126.8, 115.0,
76.6, 75.8, 73.3, 71.0, 68.9, 67.9, 60.1, 55.7, 52.7; HRMS (ESI):
[MþH]þ found 520.2845. C35H38NO3 requires 520.2852.
[a]
28 ꢁ11.6 (c 1.00, CHCl3); nmax (KBr) 3432, 3031, 2923, 2865, 1649,
D
1453, 1389, 1210, 1083, 742, 697, 608 cmꢁ1
;dH (300 MHz, CDCl3)
7.28e7.23 (15H, m, aromatic), 5.36 (1H, s, ]CH2), 5.25 (1H, s, ]CH2),
4.64e4.45 (5H, m), 4.29 (1H, d, J¼11.4 Hz, eOCH2Ph), 4.14e4.04 (4H,
m), 3.74e3.71 (1H, m), 3.52e3.47 (2H m), 2.88 (1H, brs, OH), 2.66 (1H,
br s, OH); dC (75 MHz, CDCl3) 145.7, 138.0, 137.8, 137.7, 128.7, 128.6,
128.5,128.42,128.45,128.0,127.9,127.86,127.83,116.1, 80.5, 79.7, 74.4,
73.4, 70.9, 70.8, 69.7, 63.6; HRMS (ESI): [MþNa]þ found 471.2161.
C28H32O5Na requires 471.2147.
4.9.2. (2S,3S,4R)-1-Propyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
5-C-methylene piperidine 35. Compound 35 (0.315 g, 86% yield) was
obtained in 28 h as a colourless liquid from the reaction of dime-
sylate 33 (0.470 g, 0.778 mmol) with 20 mL of propylamine at 60 ꢀC;
28
Rf (10% EtOAc/hexane) 0.38; [
a]
ꢁ2.9 (c 0.90, CHCl3); nmax (KBr)
D
3087, 3063, 3029, 2956, 2926, 2868, 1809, 1725, 1703, 1659, 1605,
1496, 1454, 1361, 1310, 1180, 1099, 1027, 912, 735, 697 cmꢁ1
;
dH
4.8. Synthesis of (3R,4R,5R)-3,4,6-tris(benzyloxy)-5-
(methylsulfonyloxy)-2-(methylsulfonyloxymethyl)-hex-1-ene 33
(300 MHz, CDCl3) 7.24e7.11 (15H, m, aromatic), 5.01 (1H, s, ]CH2),
4.88 (1H, s, ]CH2), 4.53 (1H, d, J¼12.3 Hz, eOCH2Ph), 4.47e4.36
(3H, m), 4.25e4.20 (2H, m), 3.99e3.95 (1H, m), 3.71e3.42 (3H, m),
3.15 (1H, d, J¼12.3 Hz, H-6), 3.06 (1H, d, J¼12.0 Hz, H-6), 2.94 (1H, d,
J¼9.6 Hz), 2.58e2. 35 (2H, m), 1.43e1.36 (2H, m), 0.746 (3H, t,
J¼7.5 Hz, eCH3); dC (75 MHz, CDCl3) 140.6, 138.3, 128.2, 128.15,
128.11, 128.0, 127.8, 127.5, 127.4, 115.0, 76.7, 75.5, 73.2, 70.9, 68.6,
66.1, 59.1, 53.8, 53.2, 18.3, 11.8; HRMS (ESI): [MþH]þ found
472.2859. C31H38NO3 requires 472.2852.
Diol 32 (0.500 g, 1.116 mmol) was dissolved in 10 mL of dry
ꢁ
dichloromethane and dried over 4 A molecular sieves in order to
remove any moisture if present. Triethylamine (0.388 mL, 2.79 mmol)
was then added and the reaction mixture was cooled to 0 ꢀC. After
5 min, mesyl chloride (0.189 mL, 2.45 mmol) was added and the re-
action mixture was stirred for 2 h at 0 ꢀC. The reaction mixture was
then quenched with saturated ammonium chloride solution (20 mL)
and extracted with chloroform (3ꢂ50 mL). The combined organic
layer was washed with saturated sodium bicarbonate solution and
then with water. The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated. The crude dimesylate 33 (0.570 g,
85% yield)wasobtained as ayellowliquid,which could notbepurified
by column chromatography due to its instability. Rf (40% EtOAc/hex-
ane) 0.23; nmax (KBr) 3062, 3030, 2870, 1647, 1495, 1454, 1355, 1209,
4.9.3. (2S,3S,4R)-1-Pentyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
5-C-methylene piperidine 36. Compound 36 (0.352 g, 82% yield) was
obtained in 22 h as a colourless liquid from the reaction of dimesy-
late 33 (0.520 g, 0.860 mmol) with 20 mL of pentylamine at 80 ꢀC; Rf
28
(10% EtOAc/hexane) 0.44; [
a
]
ꢁ20.0 (c 0.30, CHCl3); nmax (KBr)
D
3063, 3030, 2926, 2861, 1658, 1604, 1493, 1454, 1362, 1322, 1270,
1207,1098, 911, 737, 606 cmꢁ1
;
dH (300 MHz, CDCl3) 7.38e7.27 (15H,
1174, 1094, 1026, 967, 922, 830, 742, 700, 609 cmꢁ1
;dH (300 MHz,
m, aromatic), 5.15 (1H, s, ]CH2), 5.02 (1H, s, ]CH2), 4.67 (1H, d,
J¼12.3 Hz, eOCH2Ph), 4.61e4.50 (3H, m), 4.39e4.34 (2H, m), 4.12
(1H, br m), 3.78e3.59 (3H, m), 3.28 (1H, d, J¼12.0 Hz, H-6), 3.19 (1H,
d, J¼12.0 Hz, H-6), 3.07 (1H, d, J¼9.0 Hz), 2.73e2.56 (2H, m),1.50 (2H,
br m), 1.38e1.24 (4H, m), 0.93 (3H, t, J¼6.6 Hz, eCH3); dC (75 MHz,
CDCl3) 140.6, 138.2, 128.1, 128.0, 127.9, 127.7, 127.4, 127.3, 114.9, 76.5,
75.4, 73.2, 70.9, 68.6, 66.1, 59.0, 53.1, 51.8, 29.6, 24.6, 22.5,14.0; HRMS
(ESI): [MþH]þ found 500.3164. C33H42NO3 requires 500.3165.
CDCl3) 7.30e7.22 (15H, m, aromatic), 5.38 (1H, s, ]CH2), 5.26 (1H, s,
]CH2), 4.64 (1H, d, J¼11.4Hz, eOCH2Ph), 4.59e4.37 (5H, m), 4.31 (2H,
m), 4.15e4.04 (3H, m), 3.89 (3H, s, eOSO2CH3), 3.75 (1H, dd, J¼6.3,
3.0 Hz,), 3.50 (1H, d, J¼5.1 Hz), 2.29 (3H, s, eOSO2CH3); dC (75 MHz,
CDCl3)145.5,137.8,137.6,137.5,128.38,128.34,127.9,127.8,127.7,127.6,
116.2, 80.5, 79.6, 74.4, 73.3, 70.8, 70.7, 69.6, 63.6, 55.3, 36.5; HRMS
(ESI): [MþNa]þ found 627.1698. C30H36O9S2Na requires 627.1698.
4.9. General procedure for the synthesis of unsaturated
azasugars 34e39 and 42
4.9.4. (2S,3S,4R)-1-Hexyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
5-C-methylene piperidine 37. Compound 37 (0.367 g, 77% yield) was
obtained in 18 h as a colourless liquid from the reaction of dime-
sylate 33 (0.560 g, 0.927 mmol) with 20 mL of hexylamine at 90 ꢀC;
Dimesylate 33 was taken in a flame dried three-necked round
bottomed flask and amine (15e20 mL) was added to it. The reaction
mixture was stirred at appropriate bath temperature for the cor-
responding time. The reaction mixture was then quenched with
dilute hydrochloric acid and extracted with chloroform (3ꢂ50 mL).
The combined organic layer was washed with saturated sodium
bicarbonate solution, then with water and dried over anhydrous
sodium sulfate. The product was purified by column
Rf (10% EtOAc/hexane) 0.57; [
a
]
28 ꢁ22.40 (c 0.25, CHCl3); nmax (KBr)
D
3064, 3030, 2925, 2857, 1726, 1654, 1493, 1455, 1363, 1313, 1105,
911, 737, 698 cmꢁ1
; dH (300 MHz, CDCl3) 7.32e7.21 (15H, m, aro-
matic), 5.10 (1H, s, ]CH2), 4.96 (1H, s, ]CH2), 4.61 (1H, d,
J¼12.6 Hz, eOCH2Ph), 4.52e4.43 (3H, m), 4.30 (2H, d, J¼13.2 Hz,
eOCH2Ph), 4.06 (1H, br m), 3.73e3.60 (3H, m), 3.23 (1H, d,
J¼12.0 Hz, H-6), 3.15 (1H, d, J¼12.0 Hz, H-6), 3.09 (1H, d, J¼9.0 Hz),

P. Nagaraj et al. / Tetrahedron 67 (2011) 769e776
775
2.66e2.52 (2H, m), 1.45 (2H, m), 1.25 (6H, m), 0.877 (3H, t, J¼6.6 Hz,
4.11. Synthesis of (3R,4S,5R)-3,4,6-tris(benzyloxy)-5-
(methylsulfonyloxy)-2-(methylsulfonyloxymethyl)-
hex-1-ene 41
eCH3); dC (75 MHz, CDCl3) 140.4, 138.2, 128.1, 128.07, 128.01, 127.9,
127.7, 127.4, 127.3, 115.1, 76.5, 75.4, 73.1, 70.9, 68.6, 66.1, 59.0, 53.0,
51.8, 31.6, 27.1, 24.8, 22.5, 13.96; HRMS (ESI): [MþH]þ Found
514.3292. C34H44NO3 requires 514.3321.
Diol 40 (0.300 g, 0.669 mmol) was dissolved in 10 mL of dry
ꢁ
dichloromethane and dried over 4 A molecular sieves in order to
4.9.5. (2S,3S,4R)-1-Butyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-
C-methylene piperidine 38. Compound 38 (0.240 g, 71% yield) was
obtained in 17 h as a colourless liquid from the reaction of dime-
remove any moisture if present. Triethylamine (0.232 mL,
1.67 mmol) was then added and the reaction mixture was cooled to
0 ꢀC. After 5 min, mesyl chloride (0.114 mL, 1.47 mmol) was added
and the reaction mixture was stirred for 2 h at 0 ꢀC. The reaction
mixture was then quenched with ammonium chloride solution
(20 mL) and extracted with chloroform (3ꢂ50 mL). The combined
organic layer was washed with saturated solution of sodium bi-
carbonate solution, water and then dried over anhydrous sodium
sulfate, filtered and concentrated. The crude dimesylate 41 (0.356 g,
88% yield) was obtained as a yellow liquid, which could not be
purified by column chromatography due to its instability. Rf (40%
EtOAc/hexane) 0.25; nmax (KBr) 3028, 2930, 2870, 1457, 1353, 1173,
sylate 33 (0.420 g, 0.695 mmol) with 20 mL of butylamine at 75 ꢀC;
28
Rf (10% EtOAc/hexane) 0.43; [
a]
þ0.40 (c 1.50, CHCl3); nmax (KBr)
D
3064, 3030, 2925, 2863, 1657, 1597, 1491, 1455, 1361, 1266, 1207,
1106, 914, 740, 699 cmꢁ1
;
dH (300 MHz, CDCl3) 7.41e7.24 (15H, m,
aromatic), 5.15 (1H, s, ]CH2), 5.02 (1H, s, ]CH2), 4.67 (1H, d,
J¼12.6 Hz, eOCH2Ph), 4.58e4.49 (3H, m), 4.37 (2H, m), 4.12 (1H, d,
J¼2.7 Hz), 3.77 (1H, dd, J¼10.2, 3.0 Hz), 3.71 (1H, dd, J¼11.4, 2.1 Hz),
3.67 (1H, dd, J¼9.3, 3.0 Hz), 3.28 (1H, d, J¼12.0 Hz, H-6), 3.19 (1H, d,
J¼12.0 Hz, H-6), 3.06 (1H, d, J¼9.3 Hz), 2.79e2.64 (2H, m),1.52e1.47
(2H, m), 1.35e1.23 (2H, m), 0.94 (3H, t, J¼7.2 Hz, eCH3); dC (75 MHz,
CDCl3) 140.5, 138.25, 138.22, 138.1, 128.14, 128.12, 128.06, 128.03,
127.9, 127.7, 127.4, 127.34, 127.32, 114.9, 76.5, 75.4, 73.1, 70.8, 68.5,
66.0, 59.0, 53.1, 51.5, 27.1, 20.6, 13.9; HRMS (ESI): [MþH]þ found
486.3028. C32H40NO3 requires 486.3008.
1096, 924, 824, 745, 701, 526 cmꢁ1
; dH (300 MHz, CDCl3) 7.36e7.25
(15H, m, aromatic), 5.52 (1H, s, ]CH2), 5.34 (1H, s, ]CH2),
4.76e4.65 (4H, m), 4.54e4.49 (4H, m), 4.34 (1H, d, J¼11.4 Hz,
eOCH2Ph), 4.06 (1H, d, J¼6.0 Hz), 3.99e3.97 (1H, m), 3.86e3.78
(2H, m), 2.96 (3H, s, eOSO2CH3), 2.94 (3H, s, eOSO2CH3); dC
(75 MHz, CDCl3) 138.8, 137.5, 137.4, 137.3, 128.5, 128.47, 128.40,
128.3, 128.1, 127.9, 127.8, 119.7, 82.3, 81.2, 75.3, 73.3, 71.3, 68.6, 68.3,
38.3, 37.3; HRMS (ESI): [MþNa]þ found 627.1706. C30H36O9S2Na
requires 627.1698.
4.9.6. (2S,3S,4R)-1-(20-Hydroxyethyl)-3,4-bis(benzyloxy)-2-(benzyl-
oxymethyl)-5-C-methylene piperidine 39. Compound 39 (0.220 g,
54% yield) was obtained in 22 h as a colourless low melting solid
from the reaction of dimesylate 33 (0.520 g, 0.860 mmol) with
20 mL of 2-hydroxyethylamine at 90 ꢀC; Rf (20% EtOAc/hexane)
4.12. Synthesis of (2S,3R,4R)-1-benzyl-3,4-bis(benzyloxy)-2-
(benzyloxymethyl)-5-C-methylene piperidine 42
28
0.33; [
a
]
ꢁ150.8 (c 0.12, CHCl3); nmax (KBr) 3391, 3063, 3029,
D
2873,1653,1603,1493,1453,1394,1364,1331,1279,1243,1109, 986,
918, 737, 696, 611 cmꢁ1
;
dH (300 MHz, CDCl3) 7.33e7.19 (15H, m,
Compound 42 (0.127 g, 74% yield) was obtained in 24 h as
a colourless liquid from the reaction of dimesylate 41 (0. 200 g,
aromatic), 5.06 (1H, s, ]CH2), 5.02 (1H, s, ]CH2), 4.63 (1H, d,
J¼12.6 Hz, eOCH2Ph), 4.50e4.42 (3H, m), 4.33 (1H, d, J¼12.3 Hz,
eOCH2Ph), 4.30 (1H, J¼11.4 Hz, eOCH2Ph), 4.08 (1H, d, J¼2.1 Hz),
3.79e3.65 (2H, m), 3.53e3.47 (3H, m), 3.35e3.31 (2H, m), 3.14 (1H,
d, J¼12.9 Hz, H-6), 2.86e2.78 (1H, m), 2.66e2.59 (1H, m); dC
(75 MHz, CDCl3) 140.0, 138.10, 138.03, 137.7, 128.28, 128.24, 128.20,
128.0, 127.96, 127.7, 127.6, 127.5, 115.1, 76.3, 75.6, 73.2, 70.7, 68.9,
67.2, 59.3, 59.2, 53.1, 51.1; HRMS (ESI): [MþH]þ found 474.2644.
C30H36NO4 requires 474.2644.
0.331 mmol) with 20 mL of benzylamine at 90 ꢀC following the
28
general procedure. Rf (10% EtOAc/hexane) 0.45; [
a
]
D
ꢁ6.5 (c 1.10,
CHCl3); nmax (KBr) 3031, 2919, 2860, 1650, 1493, 1453, 1361, 1102,
911, 739, 698 cmꢁ1
;
dH (300 MHz, CDCl3) 7.40e7.28 (20H, m, aro-
matic), 5.25 (1H, s, ]CH2), 5.10 (1H, s, ]CH2), 4.75 (1H, d,
J¼12.0 Hz, eOCH2Ph), 4.68 (1H, d, J¼12.0 Hz, eOCH2Ph), 4.62e4.51
(4H, m), 4.16 (1H, d, J¼5.4 Hz), 3.97e3.77 (5H, m), 3.54e3.51 (1H,
m), 3.35e3.25 (2H, m); dC (75 MHz, CDCl3) 140.3, 139.5, 138.4,
138.36, 138.30, 128.8, 128.2, 128.19, 128.14, 128.03, 127.60, 127.5,
127.47, 127.41, 127.3, 126.6, 113.8, 79.6, 78.5, 73.0, 72.4, 70.7, 68.3,
59.2, 55.8, 52.3; HRMS (ESI): [MþH]þ found 520.2818. C35H38NO3
requires 520.2852.
4.10. Synthesis of (3R,4R,5R)-3,4,6-tris(benzyloxy)-5-hydroxy-
2-hydroxymethylhex-1-ene 40
An equilibrium mixture of compound 24 and 26 (0.250 g,
0.560 mmol) was dissolved in 10 mL of methanol. After 5 min,
sodium borohydride (0.032 g, 0.84 mmol) was added slowly to the
reaction mixture, and the progress of the reaction was monitored
by using TLC. After 30 min when TLC indicated the completion of
the reaction, the reaction mixture, was treated with saturated
ammonium chloride solution (20 mL) and extracted with chloro-
form (3ꢂ50 mL). The organic layer was washed with saturated bi-
carbonate solution, dried over anhydrous sodium sulfate and
concentrated. The crude product was purified by column chroma-
tography using hexane/ethyl acetate (4:1) as an eluent to get the
4.13. Synthesis of (2S,3S,4R)-1-benzyl-2-(hydroxymethyl)-5-C-
methylene piperidine-3,4-diol 43
Compound 34 (0.210 g, 0.404 mmol) was dissolved in 10 mL of
ꢁ
dry dichloromethane and dried over 4 A molecular sieves in order
to remove any moisture if present. BCl3 (2.5 mL, 6.0 equiv, 1.0 M
solution in heptane) was added to the reaction mixture at 0 ꢀC and
the reaction mixture was allowed to stir at room temperature. The
reaction was found to be completed in 24 h (monitored by TLC). The
reaction mixture was concentrated and the crude product was
purified by column chromatography using 10% ammonium hy-
diol 40 (0.210 g, 84% yield) as a colourless liquid; Rf (40% EtOAc/
28
hexane) 0.23; [
a
]
D
þ1.8 (c 0.50, CHCl3); nmax (KBr) 3431, 3030,
droxide in methanol as an eluent to obtain compound 43 (0.082 g,
28
2865, 2358, 1642, 1503, 1456, 1358, 1209, 1082, 916, 740, 697 cmꢁ1
;
82% yield) as a pale yellow liquid; Rf (10% MeOH/CHCl3) 0.22; [a]
D
dH (300 MHz, CDCl3) 7.34e7.22 (15H, m, aromatic), 5.36 (1H, s,
]CH2), 5.26 (1H, s, ]CH2), 4.66e4.50 (5H, m), 4.32 (1H, d, J¼11.4 Hz,
eOCH2Ph), 4.18e4.04 (3H, m), 3.98e3.93 (1H, m), 3.75e3.71 (1H,
m), 3.66e3.55 (2H, m), 2.82 (1H, br s, 1H, eOH), 2.34 (1H, br s, 1H,
eOH); dC (75 MHz, CDCl3) 145.5,137.7,137.6,137.4,128.2,127.8,127.7,
127.6, 115.9, 80.3, 79.5, 74.2, 73.2, 70.7, 70.6, 69.4, 63.4; HRMS (ESI):
[MþNa]þ found 471.2165. C28H32O5Na requires 471.2147.
ꢁ45.2 (c 0.80, MeOH); nmax (KBr) 3398, 3031, 2929, 2851, 1635,
1453, 1405, 1099, 1051, 943, 700, 518 cmꢁ1
dH (300 MHz, D2O)
;
7.339e7.331 (5H, m, aromatic), 5.25 (1H, s, ]CH2), 5.07 (1H, s,
]CH2), 4.12 (1H, d, J¼6.9 Hz), 3.93e3.84 (5H, m), 3.32e3.22 (3H,
m); dC (75 MHz, D2O) 139.1, 134.5, 130.3, 128.8, 128.5, 115.8, 71.9,
70.4, 61.5, 55.8, 50.7; HRMS (ESI): [MþH]þ found 250.1443.
C14H20NO3 requires 250.1443.

776
P. Nagaraj et al. / Tetrahedron 67 (2011) 769e776
4.14. Synthesis of (2S,3S,4R)-1-butyl-2-(hydroxymethyl)-5-C-
References and notes
methylene piperidine-3,4-diol 44
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Compound 38 (0.230 g, 0.474 mmol) was dissolved in 10 mL of
dry dichloromethane and dried over 4 A molecular sieves in order
ꢁ
to remove any moisture if present. BCl3 (2.85 mL, 6.0 equiv, 1.0 M
solution in heptane) was added to the reaction mixture at 0 ꢀC and
the reaction mixture was allowed to stir at room temperature. The
reaction was found to be completed in 24 h (monitored by TLC). The
reaction mixture was concentrated. The crude product was purified
by column chromatography using 10% ammonium hydroxide in
methanol as a eluent to obtain compound 44 (0.093 g, 92% yield) as
a pale yellow liquid; Rf (30% MeOH/CHCl3) 0.21; [
28
a]
þ1.2 (c
D
0.80, MeOH); nmax (KBr) 3414, 2961, 2927, 2855, 1635, 1459, 1405,
1079, 549 cmꢁ1
;
dH (300 MHz, D2O) 5.40 (1H, s, ]CH2), 5.31 (1H, s,
]CH2), 4.39 (1H, s), 4.05e3.73 (4H, m), 3.59e3.54 (2H, m),
3.17e3.11 (2H, m), 1.64e1.62 (2H, m), 1.32e1.23 (2H, m), 0.835 (3H,
t, J¼7.2 Hz, eCH3); dC (75 MHz, D2O)
d 135.5, 120.5, 70.3, 66.6, 61.67,
51.7, 25.0, 19.2, 12.8; HRMS (ESI): [MþH]þ found 216.1609.
C11H22NO3 requires 216.1600.
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4.15. General procedure for inhibition assay
The inhibitory effects of the azasugars were determined
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strates.
from green coffee beans,
and p-nitrophenyl- -galactopyranoside were purchased from
Sigma Chemicals Co., USA. -Glucosidase from almond, p-nitro-
phenyl- -glucopyranoside, p-nitrophenyl- -glucopyranoside
and p-nitrophenyl- -galactopyranoside were purchased from
SRL Chemicals Ltd., India.
Glycosidase was pre-incubated with various concentrations
(0.5e12 mM) of inhibitor for 30 min at its optimum pH and
a
-Glucosidase type I from Baker’s yeast,
a-galactosidase
b
-galactosidase from Escherichia coli
a-D
b
19. Kokatla, H. P.; Lahiri, R.; Kancharla, P. K.; Doddi, V. R.; Vankar, Y. D. J. Org. Chem.
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a
-
D
b-D
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b-D
temperature. 20
(p-NPG) in 0.1 M phosphate buffer was added to the reaction
mixture to initiate the reaction. In the case of -glucosidase ac-
mL of 25 mM p-nitrophenyl glycopyranoside
25. Baer, H. H.; Siemsen, L. Carbohydr. Res. 1984, 134, 49e61.
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b
etate buffer was used. The final volume of the reaction mixture
was adjusted to 1.1 mL with buffer. Control was also run in par-
allel without inhibitor. The reaction was then incubated at the
same pH and temperature for 10 min and quenched by adding
1 mL of 1 M Na2CO3 solution. The glycosidase activity was
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p-nitrophenyl glycopyranosides at 405 nm using Shimadzu
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€
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Acknowledgements
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Authors are grateful to the Department of Science and Tech-
nology, New Delhi, India for financial support. P.N. and M.G. thank
IIT-Delhi and DST, India respectively for senior research fellowships.
ꢀ
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Interplay of Chemical and Biological Sciences: Impact on Health and Environ-
ment, University of Delhi, Delhi, India 26th February to March 2009 and at the
5th J-NOST Conference, Indian Institute of Technology Kanpur, India, 4th to 7th
December 2009.
Supplementary data
Copies of 1H NMR and 13C NMR spectra of compounds 3, 4, 12,
13, 19a, 19b, 24, 25, 32e44 and 1H NMR of compound 14. Supple-
mentary data associated with this article can be found in online
version at doi:10.1016/j.tet.2010.11.050. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
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