Protecting group directed diversity during Mitsunobu cyclization of a carbohydrate derived diamino triol. Synthesis of novel bridged bicyclic and six-membered iminocyclitols

Article abstract of DOI:10.1039/c2ob27000e

A novel protecting group directed diversity leading to the synthesis of bridged bicyclic and six-membered iminocyclitols from a common carbohydrate derived diamino triol under Mitsunobu conditions is reported. When the intramolecular cyclization of benzoyl derivative 16 was carried out under Mitsunobu conditions, an unprecedented one-pot domino intramolecular cyclization-N → O benzoyl migration-cyclization reaction sequence occurred resulting in the formation of a chiral 2,6-diazabicyclo[3.2.1] octane-4,8-diol 21 in high yield. The structure of this novel bridged bicyclic compound was established through detailed NMR studies and single crystal X-ray analysis. On the other hand, the tert-butyldimethylsilyl derivative of the same substrate afforded protected 6-amino-1,6-dideoxy-l-gulonojirimycin 32 as the sole product under identical conditions. An attempt has been made to explain this difference in their reactivity through conformational analysis. The glycosidase inhibition studies of new compounds reported in this manuscript revealed that these molecules display moderate but selective inhibition against β-N-acetylhexosaminidase.

Full text of DOI:10.1039/c2ob27000e

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Organic & Biomolecular Chemistry
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Protecting Group Directed Diversity During Mitsunobu Cyclization
of a Carbohydrate Derived Diamino Triol. Synthesis of Novel
Bridged Bicyclic and Six-membered Iminocyclitols.†
Authors: Muthupandian Ganesan, Rahul Vilas Salunke, Nem Singh and Namakkal G. Ramesh*
Department of Chemistry, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi-110016,
India.
*Corresponding author. E-mail: ramesh@chemistry.iitd.ac.in, Tel.: +91-11-26596584; fax: +91-
11-26581102.
Graphical contents entry:
A novel and an unprecedented protecting group directed diversity leading to the synthesis of
bridged bicyclic and six-membered iminocyclitols from a common carbohydrate derived diamino
triol under Mitsunobu condition is reported.
Under Mitsunobu condition
OH
OH
R1 = TBS;
OH
BzO
TBSO
domino one-pot
three step
OR1
R2 = H
NTs
NR2Ts
NHTs
HO
HO
BzO
exclusive
R1 = R2 = Bz
N
TsN
Ts
NHTs
Summary:
A novel protecting group directed diversity leading to the synthesis of bridged bicyclic
and six-membered iminocyclitols from a common carbohydrate derived diamino triol under
Mitsunobu condition is reported. When the intramolecular cyclization of benzoyl derivative 16
was carried out under Mitsunobu condition, an unprecedented one-pot domino intramolecular
“cyclization – N→O benzoyl migration – cyclization” reaction sequence occurred resulting in the
formation of a chiral 2,6-diazabicylo[3.2.1]octane-4,8-diol 21 in high yield. The structure of this
novel bridged bicyclic compound was established through detailed NMR studies and single
crystal X-ray analysis as well. On the other hand, the tert-butyldimethylsilyl derivative of the

Organic & Biomolecular Chemistry
Page 2 of 29
same substrate afforded protected 6-amino-1,6-didieoxy-L-gulonojirimycin 32 as the sole
View Online
product under identical condition. An attempt has been made to explain this difference in their
reactivity through conformational analysis. The glycosidase inhibition studies of new compounds
reported in this manuscript revealed that these molecules display moderate but selective
inhibition against β-N-acetylhexosaminidase.
Introduction:
Iminocyclitols (azasugars) represent a unique class of molecules having structural and
stereochemical resemblance to natural carbohydrates but with properties that are quite distinct
from them. Due to their ability to inhibit various glycosidases through mimicry of the
glycosidase oxo-carbenium-ion transition state, they have been found to be of medicinal value in
the treatment of diseases due to viral infections and metabolic disorders including HIV and
diabetes.1,2 Their low-molecular weight, high water solubility, stability and ability to access
selective targets make them attractive drug candidates especially against carbohydrate-mediated
disorders.3 Since the successful development of drugs, such as Zavesca® 1 and Glyset® 2 (Fig.
1),4 through synthetic modifications of natural azasugars, research focus in this area has been
greatly devoted toward such functional group modifications with a view to identifying better and
specific glycosidase inhibitors. In this context, amino derivatives of naturally occurring five-
membered iminocyclitol DMDP 4, such as 5 and its stereo-analogues have received extensive
attention in recent years5–13 and some of these compounds have been identified as novel
structures for antivirals and osteoarthritis.14 On the other hand, literature reports on the synthesis
of amino derivatives of six-membered azasugar 1-deoxynojirimycin 3, such as 6-amino-1,6-
dideoxynojirimycin 6 and its other stereo analogues, although available, are scattered, despite the
fact that these compounds not only display improved inhibition against glycosidases but also
serve as convenient precursors for the synthesis of other azasugars.10,15–18 Though the amino-
modified five-membered and six-membered azasugars (5 and 6) are structural isomers, the
available methodologies are limited toward the synthesis of either one of them only. Synthetic
approaches toward both of them from a common intermediate are still at large, the lone
exception being due to McCort et al.10 Even in this case, compounds 2-epi-5 and 2-epi-6 were
obtained as a mixture, during a Lewis-acid catalyzed ring opening of sugar derived bis-aziridine
with allyl alcohol, amongst which the latter was the major product (55%). To the best of our
knowledge, methodology that leads to exclusive formation of amino-modified five-membered

Page 3 of 29
Organic & Biomolecular Chemistry
azasugar and its six-membered analogue, from a common intermediate, through a diverVgieewntOnline
approach, has not been reported so far.
OH
OH
OH
HO
OH
HO
OH
HO
OH
N
N
N
H
OH
HO
OH
OH
1
2
3
Zavesca
Glyset
1-deoxynojrimycin
(DNJ)
HO
OH
HO
OH
OH
HO
OH
N
N
H
H
N
H
HO
OH
RHN
OH
NHR
4
6
5
DMDP
amino-DMDP
6-amino-DNJ
Figure 1 Representative example of natural and synthetic iminocyclitols.
Recently, we had reported a very short synthesis of a new stereo analogue of amino-
DMDP and its derivatives 10 starting from diamino alcohol 9, which in turn was synthesized in
two steps from tri-O-benzyl-D-glucal 7 through a direct diamination followed by reduction
(Scheme 1).19,20 While further exploring the versatility of 9 towards the synthesis of amino-
modified 1-deoxynojirimycin analogue 13, serendipitous formation of a novel bridged bicyclic
diaza derivative 21, through a domino process, under Mitsunobu condition, was observed. Quite
interestingly, a change in the protecting group of the same substrate exclusively afforded 6-
amino-1,6-dideoxy-L-gulonojrimycin derivative 32 without any domino reaction. The new
OBn
O
OBn
O
one-pot
BnO
BnO
BnO
BnO
NHTs
Ref. 20
NHTs
7
8
LiAlH4
HO
OH
OBn
2 - 4 steps
Ref. 19
OH
BnO
BnO
NHTs
N
H
NHTs
RHN
OH
10 R = H, Me, Et, Ts, Ac
9
Scheme 1 Synthesis of amino-modified five-membered iminocyclitols 10 from tri-O-benzyl-D-
glucal 7.

Organic & Biomolecular Chemistry
Page 4 of 29
compounds synthesized, after final deprotection, displayed moderate but selective inhibition
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against β-N-acetylhexosaminidase.
Results and Discussion:
The retrosynthetic pathway of our proposed synthesis of 6-amino-1,6-dideoxy-L-
gulonojirimycin 13 is depicted in Scheme 2. Protection of the hydroxyl group of 919 followed by
debenzylation would lead to the formation of triol 11. Intramolecular cyclization of 11 was
expected to preferably afford the polyhydroxylated piperidine 12. Subsequent deprotection of all
the protecting groups would then deliver the hitherto unreported 6-amino-1,6-dideoxy-L-
gulonojirimycin 13.
OH
OH
HO
OH
RO
OH
N
H
N
Ts
NH2
NHTs
12
13
OH
OR
HO
HO
9
NHTs
NHTs
11
Scheme 2 Retrosynthetic route for the formation of 6-amino-1,6-didoxy-L-gulonojirimycin 13
Synthesis of 2,6-diazabicyclo[3.2.1]octan-4,8-diol through a domino process.
Our efforts towards the synthesis of 6-amino-1,6-dideoxy-L-gulonojirimycin 13 started
with benzoylation of the hydroxyl group of 9. An intriguing observation was that the expected
esterification reaction, while did not go to completion with 1.2 equiv. of BzCl in presence of
triethyl amine and 20 mol% of DMAP, afforded a mixture of two compounds. Separation of
them by column chromatography and through careful analysis of their spectral data, they were
identified as compounds 14 and 15, the latter arising out of an initial O-benzoylation followed by
a selective N-benzoylation at C-1 nitrogen atom. On the other hand, use of 2.5 equiv. of BzCl in
presence of 2.6 equiv. of Et3N and 20 mol% of DMAP led to complete conversion of 9 resulting
only in the formation of 15 in 83% yield (Scheme 3).

Page 5 of 29
Organic & Biomolecular Chemistry
BzCl (2.5 equiv.)
Et3N (2.6 equiv.)
DMAP (0.2 equiv.)
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9
83%
BzCl (1.2 equiv.)
Et3N (1.3 equiv.)
DMAP (0.2 equiv.)
OBn
OBn
OBz
OBz
+
BnO
BnO
BnO
BnO
NHTs
NBzTs
NHTs
NHTs
14 (55%)
15 (6%)
Scheme 3 Benzoylation reaction of diamino alcohol 9.
The chemoselective N-benzoylation at C-1 nitrogen and not at C-2 nitrogen was
confirmed from the 1H and 13C-NMR spectral data of 15. In its 1H-NMR spectrum, signals of the
two diastereotopic protons at C-1 appeared more deshielded and resonated at δ 3.92 and 3.77 as
compared to the protons at C-1 of compound 9 that resonated at δ 2.88 and 2.79 respectively.
Further, in the 13C-NMR spectrum, there was an appreciable downfield shift in the signal of C-1
carbon from δ 44.4 in the hydroxyl compound 9 to δ 47.0 in the product 15.
The dibenzoylation reaction observed above, though not expected, was indeed
advantageous, as it ensured the participation of only C-2 nitrogen atom (and not C-1 nitrogen
atom) of 15 in our planned intramolecular cyclization reaction, eventually leading to the
formation of our required 6-amino-1,6-dideoxy-L-gulonojirimycin derivative 17 (Scheme 4). In
order to proceed in this direction, the benzyl groups of 15 were cleaved through catalytic
hydrogenation in presence of 10% Pd/C to get the triol 16 in 85% yield.
When intramolecular cyclization of compound 16 was investigated under Mitsunobu
condition, the reaction was not as straight-forward as anticipated. The product formation was
found to be dependent on the stoichiometry of the reagents. With 1.1 equiv. of Ph3P and DEAD,
the reaction while remained incomplete, afforded two products, a major and a minor one.
Separation of them by column chromatography over silica gel followed by careful analysis of
their NMR spectral data revealed that none of these two products correspond to the expected
compound 17.
From the HRMS data of the major product, its molecular composition was deduced to be
C34H34N2O9S2 suggesting that an intramolecular cyclization indeed had taken place with the loss
1
of one molecule of water. Interestingly, its H-NMR spectrum displayed a signal at δ 5.57
resonating as a triplet (J = 5.1 Hz, exchangeable with D2O), indicating the presence of an acidic

Organic & Biomolecular Chemistry
Page 6 of 29
proton that has two neighbouring protons to couple with. Subsequently, through a detailed
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analysis of the spectral data, the structure of the major compound was identified as 18 (Scheme
4). The formation of compound 18 was thus a result of a facile N→O 1,3-benzoyl migration of
the initially formed piperidine derivative 17 under the reaction condition. Fortunately, compound
18 could be crystallized and the structural assignment was established through single crystal X-
ray analysis as well (Fig. 2).21 The possibility of benzoyl migration during the debenzylation of
13
15 to 16 was ruled out from the CNMR spectral analysis. There was hardly any shift in the
signals of the C-1 carbons of 15 and 16, confirming the retention of the benzoyl group at the C-1
nitrogen of 16 during debenzylation.
15
H2, Pd/C
MeOH
85%
OH
OH
6
BzO
OH
4
4
5
OBz
1
3
2
5
6
HO
NBzTs
HO
1
2
3
N
Ts
NHTs
NBzTs
16
17
expected
Ph3P (1.1 equiv.)
DEAD (1.1 equiv.)
THF, rt, 3 h
OBz
OH
4
HO
OBz
BzO
OBz
5
6
3
+
2
N
1
N
Ts
Ts
NHTs
NHTs
18
major (23%)
19
minor (12%)
Scheme 4 Synthesis and Mitsunobu cyclization of compound 16
The molecular composition of the minor compound was also found to be the same as that
of 18 and its 1H-NMR spectrum also displayed a signal due to a proton that resonated at δ 5.64 as
a triplet (J = 5.4 Hz) that was exchangeable with D2O. After thorough analysis of its 1H and 13C-
NMR spectral data, its structure was deduced as 19. The structural assignment of 19 was
subsequently substantiated through a chemical transformation. Since both compounds 18 and 19
differ only in the position of one of their benzoyl groups, upon hydrolysis with Na in MeOH,
both of them afforded the same product 20 (Scheme 5) thereby clearly establishing the structure
of compound 19.

Page 7 of 29
Organic & Biomolecular Chemistry
View Online
Figure 2 Single crystal X-ray structure of compound 18. Solvent (THF) and hydrogens other
than those on the piperidine ring are omitted for clarity.
OH
Na, MeOH
rt, 30 min.
Na, MeOH
rt, 30 min.
HO
OH
18
19
91%
80%
N
Ts
NHTs
20
Scheme 5 Basic hydrolysis of compounds 18 and 19 to give the triol 20
Deeper investigations on the Mitsunobu reaction of triol 16 with varying proportions of
Ph3P and DEAD further led to some unusual and surprising results. When the reaction was
performed with 2.2 equiv. of Ph3P and DEAD, the reaction was still incomplete. Rather,
appearance of a new non-polar spot was noticed in TLC. Interestingly, with 3.1 equiv. of Ph3P
and DEAD, not only did the reaction go to completion, but also was very clean resulting in the
formation of the new non-polar compound exclusively. Under this condition, formation of
compounds 18 and 19 were not at all noticed. The HRMS data of the compound revealed the
molecular composition to be C34H32N2O8S2, indicating the loss of two molecules of water.
1
Moreover there were no exchangeable protons in the molecule as revealed from its H-NMR
spectra. Through detailed analyses of various 2D-NMR spectra (supporting information), the
structure of the product was identified as the bridged bicyclic compound 21 (Scheme 6). Its
structure was subsequently confirmed through single crystal X-ray analysis22 of its di

Organic & Biomolecular Chemistry
Page 8 of 29
debenzoylated derivative 22 (Fig. 3), which was obtained by exposing it to Na in MeOH
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(Scheme 7).
BzO
NTs
Ph3P (3.1 equiv.)
DEAD (3.1 equiv.)
THF, rt, 3 h, 73%
BzO
16
N
one-pot
three step
Ts
21
second
intramolecular
cyclization
intramolecular
cyclization
OH
OH
N
O
BzO
OH
benzoyl
migration
BzO
OBz
N
N
Ts
Ts
NBzTs
NHTs
17
18
Scheme 6 Synthesis of bridged bicyclic compound 21 through a domino process
Figure 3 Single crystal X-ray structure of compound 22
HO
NTs
Na, MeOH
HO
21
rt, 30 min.,
77%
N
Ts
22
-78 0C, 3 h
84%
Na/liq. NH3
HO
NH
HO
N
H
23
Scheme 7 Synthesis of 2,6-diazabicyclo[3.2.1]octan-4,8-diol 23
The formation of the protected 2,6-diaza bicyclo [3.2.1]octane-4,8,diol 21 directly from
16 can be visualized as an one-pot three-step domino intramolecular “cyclization-benzoyl
migration-cyclization” process (Scheme 6).

Page 9 of 29
Organic & Biomolecular Chemistry
A plausible mechanism for the direct formation of the bicyclic derivative 21 from 16 is
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depicted in Scheme 8. First intramolcular cyclization of compound 16 in presence of Ph3P and
DEAD would give rise to the piperidine derivative 17 in which the C-3 hydroxyl group and C-1
amino functionality (numbering based on parent carbohydrate), being in cis geometry to each
other, are properly positioned for a possible migration of the benzoyl group. Abstraction of
proton from the C-3 hydroxyl group of 17 by the anion adduct 24 generated from the second
equivalent of Ph3P and DEAD would give rise to the alkoxy anion 25. Intramolecular
nucleophilic addition of the alkoxy anion 25 to the carbonyl carbon of the benzoyl group at C-1
nitrogen atom would result in the formation of a six-membered cyclic intermediate 27, which on
ring opening, with the departure of the benzoyl group to C-3 position, would then lead to the
resonance stabilized anion 28. In the adduct 28, the nucleophilic nitrogen being trans to C-4
OH
6
3
PPh3
4
OBz
1
HO
HO
2
O
5
NBzTs
PPh3
N
NHTs
N
N
OEt
EtO
OEt
EtO
N
16
O
O
O
24
PPh3, DEAD
H
OH
OH
OH
PPh3
N
PPh3
DEAD
BzO
O
O
BzO
O
BzO
OH
H
N
O
EtO
OEt
4
3
2
5
6
+
Ph
Ph
N
N
O
O
1
N
N
O
N
O
S
S
Ts
Ts
26
Ts
O
NBzTs
O
17
25
17
O
O
OH
OH
OH
O
Ph
Ph
BzO
O
BzO
O
BzO
O
Ph
O
O
O
S
N
N
N
N
N
N
S
S
Ts
Ts
Ts
O
O
O
28
27
O
26
H
EtO
N
N
OEt
H
O
O
N
PPh3
O
Ph3PO
O
BzO
NTs
Ph
BzO
BzO
O
TsN
N
S
21
Ts
O
29
Scheme 8 Proposed mechanism for domino one-pot formation of bicyclic derivative 18.

Organic & Biomolecular Chemistry
Page 10 of 29
hydroxyl group is suitably oriented for a second cyclization. Nucleophilic attack of theVCiew-4Online
hydroxyl group on the phosphonium salt 26 to give the alkoxy phosphonium salt 29, which when
displaced by the anionic nitrogen atom, in an intramolecular fashion, would deliver the novel
bridged bicyclic compound 21. In order to provide an additional support for the proposed
mechanism, compound 18 was independently subjected to a second Mitsunobu cyclization with
1.2 equiv. of PPh3 and 1.4 equiv. of DEAD. The reaction proceeded smoothly to afford the
bicyclic derivative 21 80% yield in just 30 min thereby confirming that 18 is indeed an
intermediate in the formation of 20.
Even though two equivalents of Mitsunobu reagents are sufficient for the formation of
the bridged bicyclic compound 21, experimentally, it was obtained only in about 50% yield even
with 2.2 equivalents. This is probably due to the competing formation of compound 17 in a
reasonable amount. However, with the use of 3.1 equivalents, the reaction was quite rapid
affording the bicyclic compound 21, as the only isolable product, in 69% yield in just 30 min. A
slight, but not an appreciable, increase in the yield (73%) was noticed when the reaction time
was increased to 3 h.
Migration of functional groups during Mitsunobu reactions though reported,23 to our
knowledge, only a lone example is available on the migration of a benzoyl group and too in an
intermolecular fashion.24 The result observed in this paper is quite unique as the benzoyl group
migration was not only very facile, but it also provided the opportunity for a successive second
intramolecular cyclization to take place in situ affording the bicyclic compound in a single step.
Bridged bicyclic iminosugars, calystegines and related compounds such as teloidine,
baogongton, erycibelline have attracted the attention of organic chemists owing to their
biological significance as glycosidase inhibitors.1,25 There are also examples of endo-endo type
bridged bicyclic conformationally restricted diamines (CRDA).26 However, there are no reports
on the synthesis of bridged bicyclic diazasugar possessing a [3.2.1] skeleton and the present
work perhaps represents the first of its kind.
In order to investigate the glycosidase inhibition activities, deprotection of the tosyl
groups of 22 was perfomed with Na/liq. NH3 to get the final compound, 2,6-diaza-
bicyclo[3.2.1]octan-4,8-diol, 23 in 84% yield (Scheme 7).
Synthesis of 6-amino-1,6-dideoxy-L-gulonoijirimycin 13
In light of the unexpected results observed with the benzoyl protected triol 16, we were
interested in protecting the hydroxyl group of 9 as its silyl ether and study its effect on the

Page 11 of 29
Organic & Biomolecular Chemistry
outcome of the Mitsunobu cyclization. Thus, silylation of 9 was accomplished smoothly with
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TBS chloride and imidazole to get the TBS ether 30 in 85% yield. Catalytic hydrogenation of 30
in presence of 10% Pd/C afforded the triol 31 (91%). Intramolecular Mitsunobu reaction of triol
31 with 1.3 equiv. Ph3P and 1.5 equiv. of DEAD proceeded in a regioselective manner to give
exclusively the protected 6-amino-1,6-didexoy-L-gulonojirimycin 32 (Scheme 9). However, as
the separation of compound 32 from diethyl hydrazodicarboxylate, the reduction product of
DEAD, was found to be difficult during purification by column chromatography, the crude
product was carried over for subsequent desilylation step. Exposure of crude 32 to camphor
sulfonic acid (CSA) conveniently cleaved its TBS group to provide the triol 19 in 86% yield (for
two steps). Detosylation of triol 19 with Na/liq. NH3 delivered the hitherto unreported 6-amino-
1,6-dideoxy-L-gulonojirimycin 13 (93%) which on chemoselective acetylation at the side chain
nitrogen atom with acetic anhydride under solvent free sonication condition afforded the acetyl
derivative 33 in 88% yield (Scheme 9).
OR
OTBS
NHTs
TBSCl
RO
RO
9
imidazole
85%
NHTs
30 R = Bn
H2, Pd/C
MeOH
91%
31 R = H
Ph3P (1.3 equiv.)
DEAD (1.4 equiv.)
OH
TBSO
OH
CSA
MeOH
20
86%
(for two steps)
N
Ts
NHTs
OH
32
Na/liq. NH3
93%
OH
HO
13
Ac2O, )))
88%
N
H
NHAc
33 R = Ac
Scheme 9 Synthesis of 6-amino-1,6-dideoxy-L-gulonojirimycin 13 and its acetyl derivative 33
Conformational analysis of compounds 18 and 32
An interesting and noteworthy observation is that, unlike the previous case, formation of
the corresponding bicyclic compound 34 from 32, through a second intramolecular cyclization,
was not at all observed, even with an excess (3.1 equiv.) of the reagents and longer reaction

Organic & Biomolecular Chemistry
Page 12 of 29
View Online
OH
OTBS
HO
HO
32
NHTs
excess
Ph3P
DEAD
NHTs
31
HO
NTs
TBSO
N
Ts
34
Scheme 10 Attempted Mitsunobu reaction of compound 31 with excess of the reagents
times (Scheme 10). Given the nature and bulkiness of the protecting groups, it is quite likely that
compounds 18 and 32 prefer to exist in different conformations. Their feasibility toward second
intramolecular cyclization, through a SN2 reaction, may thus depend upon the attainability of
requisite orientation by the nucleophile and the leaving group, in their respective conformations.
Thus, in order to get an insight in to the observed difference in the reactivity of compounds 18
and 32 towards second intramolecular cyclization, conformational analysis of these compounds
were carried out. In literature, unprotected as well as protected six-membered azasugars have
been shown to exist in 1C4 or 4C1 conformation.27 Based on these literature precedence, one may
consider that the protected azasugar molecules 18 and 32 also adopt one of the two stable chair
conformations i.e. 1C4 or 4C1 (Figures 4 and 5). In order for these molecules to participate in the
second intramolecular cyclization, proper orientation of the nucleophile for back side attack at
the reaction site (C-3 carbon, Fig. 4) is an essential requisite. Such an orientation demands that,
in both the molecules, the side chain CH2NHTs bearing the nucleophilic nitrogen atom should
occupy the axial position. This type of arrangement is possible only when the compounds adopt
4C1 conformation. Construction of a molecular model of compound 18 revealed its preferred
conformation to be 4C1 and not 1C4. In this conformation, despite the C-2 benzoyl and CH2NHTs
groups occupying the axial positions (Fig. 4), there is least steric hindrance between various
4
protecting groups. The existence of compound 18 in its C1 conformation was also evidenced
1
from the coupling constants of various protons in its H-NMR spectrum, which displayed the
appearance of the signal of H-4 at δ 5.26 ppm as a double doublet with coupling constants of 9.6
Hz (J4a,3a) and 6.0 Hz (J4a,5e) confirming that H-4 is in the axial position. The signal of H-3
appeared at δ 4.02 ppm as a double doublet with coupling constants of 9.6 Hz (J3a,4a) and 2.7 Hz
(J3a,2e). There was hardly any coupling between H-2 and both H-1axial as well as H-1equatorial

Page 13 of 29
Organic & Biomolecular Chemistry
1
indicating that H-2 is in equatorial position. H-NMR spectral data thus provided convinVciienwgOnline
4
evidence for the existence of compound 18 in its C1 conformation. Structure deduced from
single crystal X-ray analysis was also supportive of this observation (Fig. 2). On the other hand,
1
in C4 conformation, the molecular model displayed greater steric hindrance between the axial
C-4 benzoyl group and the tosyl group attached to the ring nitrogen. This would make 1C4 a less
preferred conformation. In order to verify this, conformational search was done using
HyperChem.28 Keeping the absolute configurations of all chiral centres fixed, conformational
search was initially carried out for compound 18 using molecular mechanics, with an acceptance
energy criterion of a maximum of 10 kcal/mol between various possible conformations. The
optimization cycle was kept at 1000. A total of 13 structures, possessing different conformations
and orientations of the substituents, were obtained during the initial geometry optimization using
molecular mechanics calculations. Then, geometry optimization was done for each of these 13
structures, independently, using AM1 calculations to obtain the binding energy and heat of
formation. The results from these calculations confirmed that the most stable conformation of
compound 18 is 4C1 (Fig. 6). The calculated binding energy and heat of formation of compound
18 are −8715.17 kcal/mol and −238.03 kcal/mol respectively. The 4C1 conformation was found to
1
be more stable than its C4 conformation by 4.8 kcal/mol. In this conformation, the side chain
CH2NHTs group is suitably positioned for SN2 attack at C-3 and hence compound 18 could
undergo the intramolecular cyclization readily to give the bicyclic compound 21.
O
H
4
H
O
O
S
H
OH
H
O
O
1
N
6
4
5
N
O
S
5
N
2
3
2
HO
O
H
O
O
O
1
H
3
6
H
O
O
S
H
O
O
NH
O
H
O
S
4C1
1C4
Figure 4 4C1 and 1C4 conformations of compound 18 (numbering as per parent DNJ 3)
In case of compound 32, it was expected that the bulkiness of the TBS group might play a
4
greater role in dictating its preferred conformation. In its C1 conformation (Fig. 5), as revealed
by the molecular model, the two bulky groups, TBS and CH2NHTs, would occupy the axial
1
positions making the molecule in this conformation less stable. On the other hand, in C4

Organic & Biomolecular Chemistry
Page 14 of 29
conformation, the less bulky hydroxyl groups are axially positioned leaving the bulkier TBSVaienwdOnline
CH2NHTs in the equatorial positions, a conformation that was supposed to be energetically more
1
preferred. The conformation of compound 32 could not be deduced from its H-NMR H-
NMRspectral data due to the difficulty in its separation from diethyl hydrazodicarboxylate
during column chromatography. Hence, in order to identify the preferred conformation of
compound 32, AM1 calculations were performed as before. In this case, a total of 20 structures,
with different conformations and orientations of the substituents, were obtained during the initial
geometry optimization using molecular mechanics calculations. Subsequently, when geometry
optimization was carried out for each of these 20 structures, independently, using AM1
calculations, the calculations revealed a skew conformation (1S5) (Fig. 6) as the preferred one for
compound 32 with a binding energy and heat of formation of −7709.07 kcal/mol and −297.75
4
1
kcal/mol respectively. It was found to be more stable than its energetically nearest C1 and C4
1
conformations by 2.5 and 4.6 kcal/mol respectively. In its S5 conformation, the CH2NHTs
bearing the nucleophilic nitrogen atom is probably in an orientation not suitable for a SN2 attack
at C-3 (Fig. 6) indicating a possible higher energy transition state for the cyclization. Thus,
preliminary conformational analysis based on AM1 calculations suggests the existence of
compounds 18 and 32 in different preferred conformations thereby providing support for the
observed difference in their reactivity towards second intramolecular cyclization reaction.
Further detailed studies in this direction are expected to throw more light on this interesting
aspect.
H3C
H3C
CH3
CH3
Si
H3C
H
O
OH
H
N
1
O
H
4
HO
HO
6
S
5
O
N
H
CH3
CH3
5
6
CH3
N
2
4
O
H
S
3
O
2
O
O
H
OH
S
O
CH3
3
H
H 1
NH
H3C
H
O
S
O
4C1
1C4
Figure 5 4C1 and 1C4 conformations of compound 32 (numbering as per parent DNJ 3)

Page 15 of 29
Organic & Biomolecular Chemistry
View Online
Figure 6 Different conformations and their calculated binding energies (in parenthesis) of
compounds 18 and 32 based on AM1 calculations. Hydrogen atoms are omitted for clarity. I 4C1
conformation of 18; II 1C4 conformation of 18; III 4C1 conformation of 32; IV 1C4 conformation
of 32; V 1S5 conformation of 32.
Glycosidase Inhibition Studies:
Compounds 13, 23 and 33 were screened for their glycosidase inhibition activities against
five commercially available enzymes.19,29 These compounds did not inhibit any of the common
glycosidases such as α− and β−glucosidases, and α− and β−galactosidases. However, all of them
showed moderate inhibition against β−N−acetylhexosaminidase from jack bean (Table 1), with
compound 33, among them being a better inhibitor with an IC50 value of 385 μm.

Organic & Biomolecular Chemistry
Page 16 of 29
Table 1 Glycosidase inhibition studies and IC50 values of compounds 13, 23 and 33
View Online
IC50, mM
Enzyme
Entry
1.
(source, conditions)
13
NI
NI
NI
NI
3.6
23
NI
NI
NI
NI
9.6
33
NI
α–glucosidase type I
(bakers yeast, 37 oC & 6.8 pH
β−glucosidase
2.
NI
(almond, 37 oC & 5 pH)
α–galactosidase
3.
NI
(green coffee beans, 25 oC & 6.5 pH)
β−galactosidase
4.
NI
(Escherichia coli, 37 oC & 7.3 pH)
β−N−acetylhexosaminidase
(jack bean, 37 oC & 5 pH)
5.
0.385
NI no inhibition was observed up to 10 mM inhibitor concentration
Conclusions:
In conclusion, we have disclosed the synthesis of skeletally distinct bridged bicyclic
diazasugar 23 and 6-amino-1,6-dideoxy-L-gulonojirimycin 13 from a single starting material,
through protecting group dictated diversity. The novel benzoyl migration and cascade reaction
observed under Mitsunobu condition is quite unique and is likely to draw the attention of
synthetic organic chemists. Conformational studies provide support for the observed diversity.
Selective glycosidase inhibition activities of compounds 13, 23 and 23, though moderate, against
β-N-acetylhexosaminidase may provide vital information regarding the structure-activity
relationship of such classes of compounds. Further, we expect that compound 23 being a chiral
conformationally restricted diamine (CRDA)26 would find wide applications in the area of
asymmetric catalysis, chiral base, coordination and supramolecular chemistry. Our research
focus in this direction is currently underway.
Experimental Section:
All solvents were purified using standard procedures. Thin-layer chromatography (TLC)
was performed on Merck silica gel pre-coated on aluminium plates. Flash column
chromatography was performed on 230-400 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). Melting points of the compounds are uncorrected. IR

Page 17 of 29
Organic & Biomolecular Chemistry
spectra were taken within the range 4000-400 cm-1 as KBr pellets on a Nicolet (Madison, USA)
View Online
1
13
FT-IR spectrophotometer (Model Protege 460). All the H and C NMR spectra were recorded
on a 300 or 500 MHz Bruker Spectrospin DPX FT-NMR. Chemical shifts are reported as δ
values (ppm) relative to internal standard Me4Si. Mass spectra were recorded using Bruker
MicroTOF-QII instrument.
5-O-Benzoyl-3,4,6-tri-O-benzyl-1,2-dideoxy-1,2-(di-p-toluenesulfonamido)-D-glucitol (14)
and 5-O-Benzoyl-3,4,6-tri-O-benzyl-1,2-dideoxy-1-N-benzoyl-1,2-(di-p-toluenesulfonamido)-
D-glucitol (15). In a 50 mL round bottomed flask, compound 919 (0.400 g, 0.527 mmol) was
taken and dissolved with CH2Cl2 (10 mL). The solution was cooled in an ice bath. Et3N (0.095
mL, 0.685 mmol) was then added to the reaction mixture followed by DMAP (0.013 g, 0.105
mmol). The reaction mixture was stirred at the same temperature for 10 min under N2
atmosphere. BzCl (0.071 mL, 0.632 mmol) was then added, after which the ice bath was
removed and the reaction mixture was stirred at 35 °C. The progress of the reaction was
monitored by TLC which displayed two new spots in addition to the spot corresponding to the
starting material. However, there was no significant change in the intensities of the different
spots in TLC from 30 min. to 3 h. The reaction mixture was then diluted with water and
extracted with CH2Cl2 (3 x 15 mL). The combined organic layer was washed with aqueous
NaHCO3 solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure. Purification of the products by flash column
chromatography over 230-400 mesh silica gel using 15% ethyl acetate in hexane as an eluent
afforded compounds 14 (0.250 g, 55%) and 15 (0.030g, 6%) as colorless liquids along with
unreacted starting material (0.060g, 15%).
Compound 14: Rf: 0.4 (hexane : ethyl acetate = 2 : 1); [α]29 +19.1 (c 0.722, CHCl3);
D
ν
max(KBr)/cm-1 3283, 3031, 2921, 2866, 1719, 1597, 1452, 1334, 1160, 704, 549; δΗ (300 MHz,
CDCl3, Me4Si) 7.96 (2H, d, J = 7.5 Hz); 7.63 (2H, d, J = 8.1 Hz); 7.60−7.53 (2H, m); 7. 43 (2H,
t, J = 7.5 Hz); 7.32−7.22 (16H, m); 7.14−7.12 (2H, m), 7.07 (2H, d, J = 8.1 Hz), 5.24-5.23 (2H,
m, including one exchangeable proton); 4.65 (1H, d, J = 10.5 Hz); 4.59−4.40 (6H, m); 3.94 (1H,
d, J = 7.2 Hz); 3.87 (1H, dd, J = 10.5, 5.4 Hz); 3.67−3.63 (2H, m); 3.45 (1H, m); 2.92−2.79 (2H,
s); 2.40 (3H, s), 2.11 (3H, s); δC (75 MHz, CDCl3, Me4Si): 165.4, 143.5, 143.4, 138.0, 137.7,
137.4, 137.1, 136.5, 133.2, 129.8, 129.7, 128.5, 128.4, 128.1, 127.9, 127.8, 127.7, 127.1, 78.8,

Organic & Biomolecular Chemistry
Page 18 of 29
76.6, 75.0, 74.5, 73.3, 72.5, 67.6, 53.5, 44.8, 21.5, 21.2; HRMS (ESI): [M+Na]+ FoVuinewd:Online
885.2849, C48H50N2O9S2Na requires 885.2850.
Compound 15: Rf: 0.5 (hexane : ethyl acetate = 2 : 1); [α]29
−1.8 (c 0.99, CHCl3);
D
νmax(KBr)/cm-1 3293, 3061, 3031, 2922, 2856, 1718, 1685, 1597, 1451, 1360, 1270, 1164, 1093,
704, 663; δΗ (300 MHz, CDCl3, Me4Si): 8.00 (2H, d, J = 7.5 Hz); 7.31 (2H, d, J = 7.5 Hz); 7.56
(2H, t, J = 7.2 Hz); 7. 42 (3H, t, J = 7.2 Hz); 7.27−7.09 (24H, m); 5.61 (1H, br s, exchangeable
with D2O); 5.39 (1H, s); 4.67 (2H, s), 4.60−4.48 (4H, m); 4.27−4.24 (1H, m); 4.09 (1H, s);
3.99−3.88 (4H, m); 3.78−3.73 (1H, m); 2.38 (3H, s); 2.24 (3H, s); δΗ (300 MHz, CDCl3+DMSO-
d6, Me4Si): 7.87 (2H, d, J = 7.2 Hz); 7.61 (2H, d, J = 8.1 Hz); 7.46 (2H, t, J = 7.2 Hz); 7. 32 (5H,
t, J = 7.2 Hz); 7.21−7.05 (19H, m); 7.02 (3H, t, J = 8.4 Hz), 6.14 (1H, d, J = 7.2 Hz,
exchangeable with D2O); 5.41 (1H, q, J = 4.5 Hz); 4.61-4.34 (6H, m); 4.08 (1H, dd, J = 10.8, 4.2
Hz); 3.9−3.80 (5H, m); 3.62 (1H, dd, J = 10.8, 4.2 Hz); 2.27 (3H, s); 2.13 (3H, s); δC (75 MHz,
CDCl3, Me4Si): 171.8, 165.5, 144.9, 143.4, 138.1, 137.9, 137.4, 137.3, 135.2, 135.1, 133.0,
131.3, 130.5, 129.8, 129.76, 129.72, 128.7, 128.47, 128.40, 128.34, 127.85, 127.81, 127.5, 127.3,
78.1, 77.5, 74.1, 73.9, 73.2, 73.1, 67.8, 53.5, 47.0, 21.6, 21.4; δC (75 MHz, CDCl3 + DMSO--d6,
Me4Si): 171.3, 165.0, 144.5, 142.8, 137.7, 137.5, 137.4, 137.0, 134.8, 134.7, 132.7, 131.0, 129.6,
129.38, 129.31, 128.25, 128.22, 128.0, 127.97, 127.91, 127.8, 127.4, 127.3, 127.29, 127.21,
127.18, 126.7, 77.0, 73.51, 73.0, 72.6, 67.5, 52.9, 46.5, 21.2, 21.0; HRMS (ESI): [M+Na]+
Found: 989.3151, C55H54N2O10S2Na requires 989.3112.
5-O-Benzoyl-3,4,6-tri-O-benzyl-1,2-dideoxy-1-N-benzoyl-1,2-(di-p-toluenesulfonamido)-D-
glucitol (15). In a 50 mL round bottomed flask, compound 9 (1.0 g, 1.31 mmol) was taken and
dissolved with CH2Cl2 (15 mL). The solution was cooled in an ice bath. Et3N (0.474 mL, 3.40
mmol) was then added to the reaction mixture followed by DMAP (0.032g, 0.26 mmol). The
reaction mixture was stirred at the same temperature for 10 min under N2 atmosphere. BzCl
(0.382 mL, 3.29 mmol) was then added, after which the ice bath was removed and the reaction
mixture was stirred at 35 °C for 3 h. The reaction mixture was then diluted with water and
extracted with CH2Cl2 (3 x 30 mL). The combined organic layer was washed with aqueous
NaHCO3 solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure. Purification of the product by flash column
chromatography over 230-400 mesh silica gel using 15% ethyl acetate in hexane as an eluent
afforded compound 15 (1.08 g, 83%) as a colorless liquid, the spectral data of which matched
precisely with the product obtained in the previous experiment.

Page 19 of 29
Organic & Biomolecular Chemistry
1-N-Benzoyl-5-O-benzoyl-1,2-dideoxy-1,2-(di-p-toluenesulfonamido)-D-glucitol (16). 10% Pd
View Online
on charcoal (0.520 g, 100% w/w) was taken in a 50 mL three necked round bottomed flask.
Compound 15 (0.520 g, 0.538 mmol) dissolved in methanol (3 mL) was added to it and the
reaction mixture was stirred at 42 oC. Hydrogen gas was then bubbled continuously into reaction
mixture. Progress of the reaction was monitored by TLC and after completion (3 h), the reaction
mixture was filtered through a celite pad and washed with methanol. The filtrate was then
concentrated to get the product 16 (0.320 g) in 85% yield as a viscous liquid. Rf: 0.1 (hexane :
ethyl acetate = 2 : 1); [α]29 +1.4 (c 0.1, MeOH); νmax(KBr)/cm-1 3415, 1708, 1274, 1163, 812,
D
709, 665; δΗ (300 MHz, CDCl3, Me4Si): 8.09 (2H, d, J = 6.3 Hz); 7.8 (2H, d, J = 6.9 Hz); 7.58-
7.44 (6H, m); 7.20−7.18 (8H, m); 6.58 (1H, br s, exchangeable with D2O); 4.94 (1H, br s); 4.38
(1H, br d, exchangeable with D2O); 4.11 (3H, m, with two exchangeable protons); 3.88−3.79
(6H, m); 2.41 (3H, s); 2.33 (3H, s); δC (75 MHz, CDCl3 + DMSO--d6, Me4Si): 171.6, 165.8,
144.8, 143.0, 137.1, 134.8, 134.6, 132.9, 131.2, 129.7, 129.5, 129.4, 129.3, 128.2, 128.1, 127.7,
127.4, 127.0, 74.5, 70.0, 66.9, 60.6, 56.9, 47.1, 21.3, 21.2; HRMS (ESI): [M+Na]+ Found:
719.1711, C34H36N2O10S2Na requires 719.1704.
(2S,3R,4R,5R)-3,5-Di-benzoyloxy-4-hydroxy-2-(N-p-toluenesulfonyl)aminomethyl-1-N-(p-
toluenesulfonyl)-piperidine (18) and (2S,3R,4R,5R)-3,4-Di-benzoyloxy-5-hydroxy-2-(N-p-
toluenesulfonyl)aminomethyl-1-N-(p-toluenesulfonyl)-piperidine (19). A 50 mL three necked
round bottomed flask was flame dried and cooled under argon atmosphere. Compound 16 (0.300
g, 0.430 mmol) was taken in it and dissolved with dry THF. PPh3 (0.124 g, 0.47 mmol) was then
added and the reaction mixture was cooled to 0 °C. DEAD (0.074 mL, 0.47 mmol) was slowly
injected into the reaction mixture drop wise. The reaction mixture was then brought to room
temperature (30 °C) and stirred for 3 h under argon atmosphere, after which the reaction was
stopped and the solvent was evaporated. Flash chromatography of the crude residue was
performed over silica gel (230-400 mesh) using a mixture of hexane and ethyl acetate (7 : 2) as
an eluent to get compound 18 (0.066 g, 23%) and compound 19 (0.038 g, 12%) along with
unreacted starting material 16 (0.101 g, 33%).
o
Compound 18. Rf: 0.4 (hexane : ethyl acetate = 3 : 2); M.p.: 94 C; [α]29 +10.4 (c 0.440,
D
THF); νmax(KBr)/cm-1 3328, 1723, 1269, 1157, 967, 886, 811, 711; δΗ (300 MHz, CDCl3 +
DMSO-d6, Me4Si): 8.00 (2H, d, J = 8.1Hz); 7.72 (2H, d, J = 8.1Hz); 7.65 (2H, d, J = 8.1Hz);
7.59−7.50 (4H, m); 7.44 (2H, t, J = 7.5 Hz); 7.33 (2H, t, J = 7.5 Hz); 7.16 (2H, d, J = 8.1 Hz);
6.89 (2H, d, J = 7.8 Hz); 5.57 (1H, t, J = 5.1 Hz, exchangeable with D2O); 5.26 (1H, dd, J = 9.6,

Organic & Biomolecular Chemistry
Page 20 of 29
6.0 Hz); 5.14 (1H, br m); 4.47 (1H, m); 4.14 (1H, d, J = 15.9 Hz); 4.02 (2H, dd, J = 9.6, 2.7 Hz
View Online
with one exchangeable proton); 3.32−3.19 (2H, m); 3.12 (1H, d, J = 15.9 Hz); 2.30 (3H, s); 2.13
(3H, s); δC (75 MHz, CDCl3 + DMSO--d6, Me4Si): 165.8, 165.7, 143.49, 143.41, 136.7, 136.2,
133.5, 133.0, 129.77, 129.71, 129.5, 129.2, 128.9, 128.4, 128.1, 127.0, 126.6, 71.1, 70.1, 66.4,
54.4, 42.6, 37.9, 21.4, 21.3; HRMS (ESI): [M+Na]+ Found: 701.1599, C34H34N2O9S2Na requires
701.1598.
o
Compound 19: Rf: 0.6 (hexane : ethyl acetate = 3 : 2); M.p.: 197 C; [α]29 −89.7 (c 0.274,
D
THF); νmax(KBr)/cm-1 3549, 3351, 1717, 1597, 815, 712; δΗ (300 MHz, CDCl3 + DMSO-d6,
Me4Si): 7.82 (6H, dd, J = 15.3, 8.1 Hz); 7.65 (2H, d, J = 6.9 Hz); 7.55−7.41 (2H, m); 7.35−7.26
(6H, m); 7.15 (2H, d, J =7.5 Hz); 5.64 (1H, t, J = 5.4 Hz, exchangeable with D2O); 5.28 (1H, dd,
J = 11.1, 6.0 Hz); 5.17 (1H, dd, J = 11.1, 2.7 Hz); 4.29 (1H, q, J = 5.4 Hz); 4.13 (1H, br s); 4.02
(1H, d, J = 15.6 Hz); 3.55 (1H, d, J = 3.3 Hz, exchangeable with D2O); 3.27 (2H, m); 3.05 (1H,
d, J = 15.6 Hz); 2.41 (3H, s); 2.36 (3H, s); δC (75 MHz, CDCl3 + DMSO--d6, Me4Si): 165.6,
164.8, 143.6, 143.1, 136.3, 136.2, 133.3, 133.1, 129.58, 129.53, 129.4, 129.3, 129.0, 128.5,
128.3, 128.1, 127.8, 127.0, 70.6, 66.6, 66.0, 54.2, 44.8, 37.5, 21.4, 21.3; HRMS (ESI): [M+Na]+
Found: 701.1590, C34H34N2O9S2Na requires 701.1598.
(2S,3R,4R,5R)-2-(N-p-Toluenesulfonyl)aminomethyl-3,4,5-trihydroxy-1-N-(p-
toluenesulfonyl)-piperidine (20)
From compound 18. Compound 18 (0.032 g, 0.040 mmol) was taken in a 50 mL round
o
bottomed flask and dissolved with MeOH (3 mL). The reaction mixture was cooled to 0 C.
Sodium metal (0.020 g, 0.869 mmol) was added in portions. The reaction mixture was then
brought to room temperature (30 °C) and stirred for 30 min., after which the reaction was
stopped and solvent was evaporated. Water was added to the resulting residue and the reaction
mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium
sulphate, filtered and concentrated to get compound 20 as a white solid in 91% (0.020 g) yield.
From compound 19. Compound 19 (0.070 g, 0.103 mmol) was taken in a 50 mL round
o
bottomed flask and dissolved with MeOH (5 mL). The reaction mixture was cooled to 0 C.
Sodium metal (0.045 g, 1.96 mmol) was added in portions. The reaction mixture was then
brought to room temperature (30 °C) and stirred for 30 min., after which the reaction was
stopped and solvent was evaporated. Water was added to the resulting residue and the reaction
mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium
sulphate, filtered and concentrated to get compound 20 as a white solid in 80% (0.039 g) yield.

Page 21 of 29
Organic & Biomolecular Chemistry
Rf: 0.1 (100% ethyl acetate); M.p.: 125 oC; [α]29 +12.1 (c 0.387, THF); νmax(KBr)/cm-1 3507,
D
View Online
2920, 2593, 1314, 1154, 1039, 667, 555; δΗ (300 MHz, CDCl3 + DMSO-d6, Me4Si): 7.56−7.51
(4H, m); 7.10 (2H, m); 7.03 (2H, d, J = 7.5 Hz); 5.55 (1H, br s, exchangeable with D2O),
3.77−3.73 (2H, m); 3.61 (1H, s), 3.33−3.31 (1H, m); 3.21−3.11 (3H, m, including one
exchangeable proton); 2.69−2.64 (2H, m); 2.22 (3H, s); 2.19 (3H, s); δC (75 MHz, CDCl3 +
DMSO--d6, Me4Si): 142.7, 142.6, 136.4, 136.3, 129.1, 128.7, 127.3, 126.5, 69.7, 67.2, 66.6,
55.5, 44.2, 37.4, 21.0; HRMS (ESI): [M+Na]+ Found: 493.1093, C20H26N2O7S2Na requires
493.1074.
(1S,4R,5S,8R)-4,8-Di-O-benzoyl-2,6-(di-N-p-toluenesulphonyl)-2,6-diazabicyclo-
[3.2.1]octane-4,8-diol (21). A 50 mL three necked round bottomed flask was flame dried and
cooled under argon atmosphere. Compound 16 (0.300 g, 0.430 mmol) was taken in it and
dissolved with dry THF. PPh3 (0.349 g, 1.33 mmol) was then added and the reaction mixture was
cooled to 0 °C. DEAD (0.209 mL, 1.33 mmol) was slowly injected into the reaction mixture
drop wise. The reaction mixture was then brought to room temperature (30 °C) and stirred for 3 h
under argon atmosphere, after which the reaction was stopped and the solvent was evaporated.
Flash chromatography of the crude residue was performed over silica gel (230-400 mesh) using a
mixture of benzene and ethyl acetate (30 : 1) as an eluent to get compound 21 (0.207 g, 73%) as
a colorless liquid. Rf: 0.8 (hexane : ethyl acetate = 3 : 2); [α]29 −16.3 (c 0.927, THF);
D
ν
max(KBr)/cm-1 1725, 1350, 1262, 1162, 1097, 711, 668; δΗ (300 MHz, CDCl3 + DMSO-d6, Me4-
Si): 7.95 (2H, d, J = 7.8 Hz); 7.68−7.43 (10H, m); 7.34−7.29 (2H, m); 7.20 (2H, d, J = 8.1 Hz);
6.97 (2H, d, J = 8.1 Hz); 5.37 (1H, m); 5.32 (1H, br m); 4.85 (1H, br m); 4.55 (1H, br m); 3.98
(1H, d, J = 14.4 Hz); 3.58−3.48 (2H, m); 3.32 (1H, d, J = 10.8 Hz); 2.32 (3H, s); 2.03 (3H, s);
δC (75 MHz, CDCl3 + DMSO--d6, Me4Si): 171.8, 165.5, 144.9, 143.4, 138.1, 137.9, 135.1,
133.0, 131.3, 130.0, 129.8, 129.7, 128.7, 128.4, 128.3, 127.8, 127.5, 127.3, 74.1, 73.2, 73.1, 67.8,
53.5, 47.0, 21.6, 21.1; HRMS (ESI): [M+Na]+ Found: 683.1476, C34H32N2O8S2Na requires
683.1492.
(1S,4R,5S,8R)-2,6-(Di-N-p-toluenesulphonyl)-2,6-diazabicyclo[3.2.1]octane-4,8-diol
(22).
Compound 21 (0.1 g, 0.151 mmol) was taken in a 50 mL round bottomed flask and dissolved
o
with MeOH (3 mL). The reaction mixture was cooled to 0 C. Sodium metal (0.080 g, 3.48
mmol) was added in portions. The reaction mixture was then brought to room temperature (30
°C) and stirred for 3 h, after which the reaction was stopped and solvent was evaporated. Water
was added to the resulting residue and the reaction mixture was extracted with ethyl acetate. The

Organic & Biomolecular Chemistry
Page 22 of 29
organic layer was dried over anhydrous sodium sulphate, filtered and concentrated toVigewetOnline
compound 22 as a white solid in 77% (0.053 g) yield. Rf: 0.1 (hexane : ethyl acetate = 2 : 1);
o
M.p.: 164 C; [α]28 −54.8 (c 0.268, THF); νmax(KBr)/cm-1 3449, 1340, 1280, 1162, 1098, 966,
D
668; δΗ (300 MHz, CDCl3 + DMSO-d6, Me4Si): 7.52−7.48 (4H, m); 7.25 (2H, d, J = 8.1 Hz);
7.12 (2H, d, J = 8.1 Hz); 4.19 (2H, br m); 4.00 (1H, br m); 3.87 (1H, d, J = 4.8 Hz); 3.45 (1H, d,
J = 12.6 Hz); 3.08 (1H, dd, J = 10.2, 3.9 Hz); 2.82 (1H, dd, J = 12.6, 2.1 Hz); 2.58 (1H, d, J =
10.2 Hz); 2.34 (3H, s); 2.27 (3H, s); δC (75 MHz, CDCl3 + DMSO--d6, Me4Si): 143.5, 142.9,
135.0, 134.6, 129.6, 128.9, 127.1, 126.7, 69.7, 68.2, 65.4, 59.7, 46.4, 45.6, 21.2, 21.1; HRMS
(ESI): [M+Na]+ Found: 475.0968, C20H24N2O6S2Na requires 475.0968.
(1S,4R,5S,8R)-2,6-diaza-bicyclo[3.2.1]octane-4,8-diol (23). Liquid ammonia (25 mL) was
collected in a 100 mL three necked round bottomed flask at −78 °C. Sodium metal (0.088 g, 3.83
mmol) was added to it. Deep blue colour appeared. Compound 22 (0.800 g, 1.768 mmol)
dissolved in THF was added to the reaction mixture and stirred at −78 °C for 3 h. Then the
reaction was quenched by the addition of benzene until the blue colour disappeared followed by
water. The reaction mixture was allowed to slowly warm to room temperature. The organic layer
was separated and the crude aqueous reaction mixture was dried in a lyophilizer. Column
chromatography of the residue over deactivated silica gel using a mixture of CH3CN and aq.
NH4OH (8 : 2) as an eluent yielded compound 23 as a low melting solid in 84% (0.215 g) yield.
Rf: 0.3 (CHCl3 : MeOH : NH4OH = 1 : 3 : 1); [α]20 −11 (c 0.7, H2O); νmax(KBr)/cm-1 3288,
D
1612, 1402, 1133, 617; δΗ (300 MHz, CDCl3 + DMSO-d6, Me4Si): 4.46 (1H, br m); 4.10 (1H, br
m); 3.79−3.73 (2H, m); 3.48−3.41(1H, m); 3.33−3.28 (1H, m); 2.90 (2H, m); δC (75 MHz,
CDCl3 + DMSO--d6, Me4Si): 69.0, 65.1, 62.5, 57.1, 44.2, 41.9; HRMS (ESI): [M+H]+ Found:
145.0971, C6H13N2O2 requires 145.0972.
5-O-(tert-Butyldimethylsilyl)-3,4,6-tri-O-benzyl-1,2-dideoxy-1,2-(di-p-toluenesulfonamido)-
D-glucitol (30). In a 50 mL round bottomed flask, compound 9 (4.60 g, 6.06 mmol) was taken
o
and dissolved with dry dichloromethane (25 mL). The reaction mixture was cooled to 0 C.
Imidazole (0.91 g, 13.33 mmol) was added to the reaction mixture followed by TBSCl (1.00 g,
6.67 mmol). The reaction mixture was allowed to warm to room temperature. When the reaction
was over (vide TLC) (3 h), it was quenched with iced water and the reaction mixture was
extracted with dichloromethane (3 x 80 mL). The combined organic layer was then washed
thoroughly with saturated brine solution, dried over anhydrous sodium sulphate and filtered. The
reaction mixture was then concentrated. Flash chromatography of crude reaction mixture was

Page 23 of 29
Organic & Biomolecular Chemistry
performed over silica gel using a mixture of hexane and ethyl acetate (11 : 2) as an eluent to get
View Online
compound 30 in 85% (4.50 g) yield as a low melting colorless solid. Rf: 0.5 (hexane :
ethylacetate = 2 : 1); [α]29 + 8.1 (c 0.718, MeOH); νmax(KBr)/cm-1 3361, 3256, 2927, 1598,
D
1212, 1162, 1088, 1049, 757, 668; δΗ (300 MHz, CDCl3 + DMSO-d6, Me4Si): 7.63 (2H, d, J =
7.8 Hz); 7.41−7.15 (21H, m); 5.08 (1H, d, J = 8.7 Hz, exchangeable with D2O); 4.73−4.66 (2H,
m); 4.59−4.50 (3H, m); 4.35 (1H, J = 11.1Hz); 4.24−4.17 (2H, m, including one exchangeable
proton); 3.79−3.67 (3H, m); 3.57 (1H, m); 3.36 (1H, dd, J = 9.6, 4.8 Hz); 2.76−2.71 (1H, m);
2.57−2.50 (1H, m); 2.39 (6H, s); 0.86 (9H, s); 0.09 (6H, s); δC (75 MHz, CDCl3 + DMSO--d6,
Me4Si): 143.4, 143.2, 138.7, 137.98, 137.91, 136.5, 129.7, 129.5, 128.4, 128.3, 128.2, 128.0,
127.9, 127.7, 127.4, 127.05, 127.02, 82.2, 77.3, 74.82, 74.76, 73.3, 72.2, 71.3, 54.0, 44.3, 25.9,
21.53, 21.50, 18.0, −4.5, −4.8; HRMS (ESI): [M+H]+ Found: 873.3666, C47H61N2O8S2Si requires
873.3633.
5-O-(tert-Butyldimethylsilyl)-1,2-dideoxy-1,2-(di-p-toluenesulfonamido)-D-glucitol
(31).
10% Pd on charcoal (3.43 g, 100% w/w) was taken in a 50 mL three necked round bottomed
flask. Compound 30 (3.43 g, 3.928 mmol) dissolved in methanol (15 mL) was added to it and the
o
reaction mixture was stirred at 42 C. Hydrogen gas was then bubbled slowly into reaction
mixture. Progress of the reaction was monitored by TLC and after completion (30 min), the
reaction mixture was filtered through a celite pad and washed with methanol. The filtrate was
then concentrated to get the product 31 (2.16 g) in 91% yield as a colorless viscous liquid. Rf: 0.1
(hexane : ethylacetate = 2 : 1); [α]29 +30.8 (c 0.816, MeOH); νmax(KBr)/cm-1 3491, 3285, 2932,
D
1599, 1330, 1159, 1093, 665, 552; δΗ (300 MHz, CDCl3 + DMSO-d6, Me4Si): 7.75 (2H, d, J =
8.1Hz); 7.62 (2H, d, J = 8.1Hz); 7.28 (4H, t, J = 8.1 Hz); 5.76 (1H, br s, exchangeable with
D2O); 5.53 (1H, br s, exchangeable with D2O); 3.98 (1H, d, J = 3.9 Hz); 3.81−3.79 (1H, m);
3.66−3.60 (3H, m); 3.32 (3H, br m, including two exchangeable protons); 2.96 (2H, m); 2.42
(6H, s); 0.86 (9H, s); 0.09 (3H, s); 0.078 (3H, s); δC (75 MHz, CDCl3 + DMSO--d6, Me4Si):
143.5, 143.3, 136.6, 136.15, 129.66, 129.63, 127.2, 126.9, 72.7, 71.6, 68.2, 63.1, 55.5, 43.4, 25.6,
21.45, 21.4, 17.8, −4.7,−5.0; HRMS (ESI): [M+Na]+ Found: 625.2047, C26H42N2O8S2SiNa
requires 625.2044.
(2S,3R,4R,5R)-2-(N-p-Toluenesulfonyl)aminomethyl-3,4,5-trihydroxy-1-N-(p
toluenesulfonyl)-piperidine (20). A 50 mL three necked round bottomed flask was flame dried
and cooled under argon atmosphere. Compound 31 (2.7 g, 4.479 mmol) was taken in it and
dissolved with dry THF. PPh3 (1.52 g, 5.823 mmol) was then added and the reaction mixture was

Organic & Biomolecular Chemistry
Page 24 of 29
cooled to 0 °C. DEAD (1.045 mL, 6.721 mmol) was slowly injected into the reaction mixture
View Online
drop wise. The reaction mixture was then brought to room temperature (30 °C) and stirred for 30
min under argon atmosphere, after which the reaction was stopped and the solvent was
evaporated The crude reaction mixture was then dissolved in MeOH (30 mL) and camphor
sulfoinic acid (3.618 g, 14.4 mmol) was added to it. The reaction mixture was stirred at room
temperature and the progress of the reaction was monitored by TLC. After 6 h, when TLC
indicated the disappearance of the starting material, the reaction was quenched with water and
the reaction mixture was extracted with ethyl acetate (3x50 mL). The combined organic layer
was then washed with saturated NaHCO3 solution and dried over anhydrous sodium sulfate and
filtered. Flash chromatography of the residue over silica gel using a mixture of hexane and ethyl
acetate (1:1) as an eluent afforded 1.82 g (86%, for two steps) of compound 20 as a white solid.
1
The specific rotation and spectral data (IR, H-NMR, 13C-NMR, HRMS) were found to be
identical with those of compound 20 prepared earlier from compounds 18 and 19.
(2S,3R,4R,5R)-2-Aminomethyl-3,4,5-trihydroxy-piperidine (13) [6-Amino-1,6-dideoxy-L-
gulonojirimycin]. Liquid ammonia (25 mL) was collected in a 100 mL three necked round
bottomed flask at −78 °C. Sodium metal (0.08 g, 3.48 mmol) was added to it. Deep blue colour
appeared. Compound 20 (0.600 g, 1.27 mmol) dissolved in THF was added to the reaction
mixture and stirred at −78 °C for 3 h. Then the reaction was quenched by the addition of benzene
until the blue colour disappeared followed by water. The reaction mixture was allowed to slowly
warm to room temperature. The organic layer was separated and the crude aqueous reaction
mixture was dried in a lyophilizer. Purification of the product was performed by flash column
chromatography over silica gel using a mixture of CH3CN and NH4OH (8 : 2) as an eluent to get
compound 13 (0.192 g, 93 % yield) as a low melting solid. Rf: 0.3 (CHCl3 : MeOH : NH4OH =
1:3:1); [α]20 +7.3 (c 1.56, H2O); νmax(KBr)/cm-1 3126, 1619, 1401, 1105, 619; δΗ (300 MHz,
D
CDCl3 + DMSO-d6, Me4Si): 3.75−3.65 (3H, m); 3.14 (1H, m); 2.98−2.93 (1H, m); 2.88−2.81
(1H, m); 2.77−2.71 (1H, m); 2.61−2.54 (1H, m); δC (75 MHz, CDCl3 + DMSO--d6, Me4Si): 68.9,
68.3, 63.7, 57.1, 43.2, 38.7; HRMS (ESI): [M+Na]+ Found: 185.0888, C6H14N2O3Na requires
185.0897.
(2S,3R,4R,5R)-2-Acetamidomethyl-3,4,5-trihydroxy-piperidine (33) [6-Acetamido-1,6-
dideoxy-L-gulonojirimycin]. In a 50 mL round bottomed flask, compound 13 (0.05 g, 0.308
mmol) was taken and cooled to 0 oC. Acetic anhydride (0.032 mL, 0.339 mmol) was added to it.
The reaction mixture was then brought to room temperature and sonicated under solvent free

Page 25 of 29
Organic & Biomolecular Chemistry
condition for 30 min, after which the reaction was quenched with water (1 mL). Triethyl amine
View Online
(approx. 2 mL) was then added to the reaction mixture until the pH of the solution rose to 9. The
added triethylamine was washed out by extracting the solution with CHCl3 (4x20 mL).
Purification of the product from the aqueous layer by column chromatography over silica gel
using a mixture of CH2Cl2 and MeOH (5 : 1) as an eluent afforded compound 33 in 88% (0.056
g) yield as a low melting colourless solid. Rf: 0.4 (CHCl3 : MeOH : NH4OH = 1 : 3 : 1); [α]20
D
+8.6 (c 0.81, H2O); νmax(KBr)/cm-1 3126, 1640, 1401, 1242, 1117; δΗ (300 MHz, CDCl3 +
DMSO-d6, Me4Si): 4.08–4.04 (1H, m); 3.89 (2H, s); 3.48–3.27 (3H, m); 3.12–3.06 (1H, m);
2.892.85 (1H, m); 1.86 (3H, s); δC (75 MHz, CDCl3 + DMSO--d6, Me4Si): 175.1, 68.2, 67.3,
62.1, 53.2, 42.3, 37.8, 21.8; HRMS (ESI): [M+H]+ Found: 205.1184, C8H17N2O4 requires
205.1183.
Procedure for glycosidase inhibition studies.
Glycosidase inhibition studies were carried out, spectrophotometrically, following the
standard procedure,19,29 by measuring the enzyme velocity at constant substrate concentration
with varying concentrations of an inhibitor (iminosugar), utilizing the corresponding p–
nitrophenyl glycosides as the substrates. α–Glucosidase type I from Baker’s yeast, α–
galactosidase from green coffee beans, β–galactosidase from Escherichia coli, β-N-
acetylhexosaminidase from Jack bean, 4-nitrophenyl-N-acetyl-β-D-glucosmainide and 4-
nitrophenyl-α-D-galactopyranoside were purchased from Sigma Chemicals Co. USA. β–
glucosidase
from
almond,
4-nitrophenyl-α-D-glucopyranoside,
4-nitrophenyl-β-D-
glucopyranoside and 4-nitrophenyl-β-D-galactopyranoside were purchased from SRL Chemicals
Ltd., India.
Glycosidase was pre-incubated with various concentrations (0.5-12 mM) of inhibitor for
30 min. at its optimum pH and temperature (see Table 1). 20μL of 25mM p-nitrophenyl
glycopyranoside (p-NPG) in 0.1M phosphate buffer was added to the reaction mixture to initiate
the reaction. In the case of β–glucosidase acetate buffer was used. The final volume of the
reaction mixture was adjusted to 1.1 mL with buffer. Control was also run in parallel without
inhibitor. The reaction was then incubated at the same pH and temperature for 10 min. and
quenched by adding 1 mL of 1M Na2CO3 solution. The glycosidase activity was determined by
measuring the p-nitrophenol released from p-nitrophenyl glycopyranosides at 405 nm using a
UV-visible Microplate Reader (M/s. Biotek Instrumets Inc. USA, Model Synergy 2 SAD).

Organic & Biomolecular Chemistry
Page 26 of 29
Experimental data were plotted as Vi/V0 (fractional activity) versus the inhibitor concentratioVnie[wI]Online
at a constant concentration of substrate, where Vi and V0 represent the enzyme velocity (activity)
in the presence and absence of inhibitor respectively. IC50 values were obtained from the
inhibitor concentration [I] corresponding to fractional activity of 0.5. IC50 value was defined as
the concentration of the inhibitor to inhibit 50% of enzyme activity under the assay conditions.
Each experiment was repeated thrice to get a range of IC50 values and the mean IC50
values were reported in the manuscript.
Acknowledgements:
We thank the Department of Science and Technology, New Delhi, India for financial
support, Prof. Nalin Pant and Mr. Amit Singh for their help in AM1 calculations and the single
crystal X-ray analysis respectively. MG and RVS thank IIT Delhi and CSIR, New Delhi for
research fellowships. We acknowledge DST-FIST and IIT Delhi for funding of the single crystal
X-ray diffractometer and ESI-HRMS facility at IIT Delhi. DST and SAIF-IIT Madras are
acknowledged for recording of 2D NMR spectra.
1
13
† Electronic supplementary information (ESI) available: Copies of H and C NMR spectra
of all new compounds are provided.
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