Conversion of glycals into vicinal-1,2-diazides and 1,2-(or 2,1)-azidoacetates using hypervalent iodine reagents and Me3SiN3. Application in the synthesis of: N -glycopeptides, pseudo-trisaccharides and an iminosugar

Article abstract of DOI:10.1039/c7ra08637g

Glycals were found to react with a reagent system comprising of phenyliodine bis(trifluoroacetate) (PIFA) and Me₃SiN₃ in the presence of TMSOTf as a catalyst to form the corresponding vicinal 1,2-diazides. On the other hand, they rea

Full text of DOI:10.1039/c7ra08637g

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PAPER
Conversion of glycals into vicinal-1,2-diazides and
1,2-(or 2,1)-azidoacetates using hypervalent iodine
reagents and Me3SiN3. Application in the synthesis
of N-glycopeptides, pseudo-trisaccharides and an
iminosugar†
Cite this: RSC Adv., 2017, 7, 41755
*
Ande Chennaiah, Srijita Bhowmick‡ and Yashwant D. Vankar
Glycals were found to react with a reagent system comprising of phenyliodine bis(trifluoroacetate) (PIFA) and
Me3SiN3 in the presence of TMSOTf as a catalyst to form the corresponding vicinal 1,2-diazides. On the other
hand, they reacted with another reagent system phenyliodine diacetate (PIDA) and Me3SiN3, also in the
presence of TMSOTf as a catalyst, to lead to the corresponding vicinal 1,2-azidoacetates. These azido
Received 4th August 2017
Accepted 22nd August 2017
DOI: 10.1039/c7ra08637g
derivatives were converted into
a number of 2-azido-N-glycopeptides, pseudotrisaccharides, and
rsc.li/rsc-advances
a piperidine triol derivative, an iminosugar.
At the same time, there exist many oligosaccharides that
Introduction
contain N-glycopeptide units in which the sugar moiety carries
a C-2 amino functionality, and the glycopeptide part has an Asn-
linkage at the anomeric carbon.2b,7 Interest in the synthesis of
such molecules stems from the fact that protein N-glycosylation
occurs during post-translational modications in biological
systems. This has led to newer approaches towards function-
alization of glycals (or any other sugar derivative such as gly-
cosamines) to introduce 1,2-diamino (or equivalent)
functionalities that are useful in the synthesis of N-glycopep-
tides.8 Thus, improved or alternate approaches toward the
introduction of a nitrogen based functional group at C-1 and/or
C-2 of a sugar moiety are important. In view of our continued
interest2f,4a–c,8a,9 in functionalizing glycals en route to the
synthesis of iminosugars, aminosugars and glycopeptides, we
herein report an easy access to 1,2-diazido sugars from glycals
upon treatment with phenyliodine bis(triuoroacetate) (PIFA)
and Me3SiN3 reagent system. Also, we have developed condi-
tions that allow conversion of glycals into 1-azido-2-acetoxy
sugars or 2-azido-1-acetoxy sugars upon reaction with phenyl-
iodine diacetate (PIDA) and Me3SiN3. Further, we have
demonstrated the utility of these azido compounds in the
synthesis of 2-amino-N-glycopeptides, pseudotrisaccharides,
and an iminosugar.
The growing importance of aminosugars,1 N-glycopeptides2 and
sugar derived triazoles3 (obtained via click-chemistry) in bio-
logical systems is apparent from the recent literature. Synthesis
of such compounds has led to the development of a number of
synthetic methodologies involving functionalization of mono-
saccharides, in particular glycals. In this regard, methodologies
that allow attachment of an azido moiety4 at the anomeric
center are frequently used in the synthesis of N-glycopeptides,
although there are some other ways2e,5 of introducing
a ‘nitrogen’ unit. The azide group also allows click-chemistry, to
link with another sugar unit leading to pseudo di-, tri- or
oligosaccharides, to be carried out.3 Apart from this, introduc-
tion of an amino functionality (or an azido group) at the C-2
position of a sugar moiety, with an appropriate functional
group at the anomeric carbon for effecting glycosylation, is one
of the most important reactions known in carbohydrate chem-
istry.1a,6 This allows access to amino sugars with the amino
group at the C-2 position, a structural feature that is prevalent in
a number of oligosaccharides including aminoglycoside anti-
biotics. Toward this endeavor, conversion of glycals into sugar
derived 2-azido-1-nitrates using a combination of ceric ammo-
nium nitrate and NaN3 (and its improvements) in CH3CN,
a protocol developed by Lemieux et al.,6a is universally followed.
Results and discussion
Department of Chemistry, Indian Institute of Technology, Kanpur – 208016, India.
E-mail: vankar@iitk.ac.in
Hypervalent iodine reagents have gained enormous importance
in recent years due to their low toxicity, ease of handling and
ready availability.10 The use of hypervalent iodine reagents,
most notably PIDA, in conjunction with a halide ion source has
been reported on a few occasions in functionalizing olens,
† Electronic supplementary information (ESI) available: CCDC 1554251 and
1554252. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c7ra08637g
‡ M.Sc. research project participant (2016).
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formation of 1,2-diazides and there was always an incorporation
of the acetate moiety onto galactal 1 due to competition between
the azide and the acetate ions. Although, conversion of olens
into vicinal diazides is known with few reagents13a such as
13d
Mn(OAc)3–NaN3,13b azido iodine(III) reagent,13c NaIO4/NaN3
and Zhdankin reagent (a hypervalent iodine reagent) along with
a copper catalyst,13e formation of sugar derived 1,2-diazides
from glycals has been reported rarely.13b,14 Thus, for example,
2,4,6-tri-O-acetyl galactal has been reported to react with
Me3SiN3–PIDA–PhSeSePh14a to give cis-1,2-diazido galactal
with albeit in low yield and as a side product. On the other hand,
more recently Xu et al.14b demonstrated that the in situ prepared
Zhdankin reagent in presence of an iron catalyst converts
a broad range of olens, including one example of a glucal
Scheme
PIDA–Me3SiN3.
1 Exploratory reaction of galactal derivative 1
including glycals, to form vicinal halo alkoxides in an inter-
molecular fashion.11 Introduction of a nitrogen based func-
tional group at C-2 of a glucal derivative has also been realized
in an intramolecular fashion from glucal 3-carbamate upon its
reaction with PIDA along with Rh2(OAc)4.6c However, one of the
most interesting reactions to stereoselectively convert glycals
into sugar derived trans-1,2-diacetates involves their reaction
with PIDA in presence of BF3$Et2O as a catalyst as reported by
Gin et al.12 Further, the in situ formed trans-1,2-diacetates lead
to O-glycosylation when treated with an alcohol (ROH) and
TfOH (as a catalyst) in the same pot. The proposed mechanism
suggests that PIDA acts as an electrophile making a p-complex
with a glycal, followed by the attack of acetate ion at the
anomeric carbon as well as at C-2 leading to the observed trans-
1,2-diacetates. In view of this, and in view of the importance of
amino sugars and N-glycopeptides (vide supra) we surmised that
reaction of glycals with PIDA combined with Me3SiN3 may lead
to 1,2-diazido sugars. Our initial experiments involving reaction
of 3,4,6-tri-O-benzyl galactal 1 (Scheme 1) with both one equiv-
alent of PIDA and Me3SiN3 in the presence of BF3$Et2O or
TMSOTf (30 mol%) as a catalyst led to a mixture of four prod-
ucts. These were 1-azido-2-acetoxy sugar 2, 2-azido-1-acetoxy
sugar 3; 1,2-diacetoxy sugar 4 and 1,2-diazido sugar 5.
Increasing the amount of Me3SiN3 did not lead to increased
derivative, to the corresponding 1,2-diazides. In order to nd an
alternate route to convert glycals into sugar derived 1,2-dia-
zides, we explored their reactivity with PIFA–Me3SiN3 reagent
system15 in presence of an acid catalyst. Such a reagent system
has been used to introduce an azide group into aromatics and
some heterocycles akin to aromatic substitution,15a,b for
substitution of an azide moiety15c at benzylic positions, and
more recently to perform C–H activation.15d,e Apart from this, an
interesting intramolecular azidoarylation of alkenes using
PIFA–Me3SiN3 combination has been reported by Antonchick
et al.15f In these examples, PIFA–Me3SiN3 reagent system was
proposed to lead to the formation of PhI(N3)2 or PhIN3(OCOCF3)
as intermediate species which act as a source of azide radical to
effect the observed reactions. We expected that if PhI(N3)2 is
formed as an intermediate, in presence of an acid catalyst it may
convert glycals to sugar-derived 1,2-diazides in an analogous
manner as sugar derived 1,2-diacetates were obtained from
glycals upon reaction with PIDA as reported by Gin et al.12
Towards this endeavor, initial experiments involved treatment
of 3,4,6-tri-O-acetyl galactal 6a with PIFA (1.0 eq.) and 2 eq. of
ꢁ
Me3SiN3 in presence of BF3$Et2O (30 mol%) at ꢀ30 C which
gave only 38% of the expected 1,2-diazide 7a as a single isomer.
Further optimizations with respect to azide source and acid
catalyst (Table 1) led to the use of 3 eq. of TMSN3 and 30 mol%
Table 1 Optimization of reaction conditions to form 1,2-diazidesa
Entry
Catalyst
N3-Source
Equiv.
Solvent
Temp (ꢁC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
None
None
NaN3
2
2
2
3
3
3
3
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
0
24
24
No reaction
TMSN3
TMSN3
TMSN3
Bu4NN3
Bu4NN3
TMSN3
No reaction
BF3$OEt2
BF3$OEt2
BF3$OEt2
TMSOTf
TMSOTf
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
0.5
0.5
0.5
0.5
0.5
38b
44b
37b
33b
61
a
Reaction conditions: glycals (0.36 mmol), TMSN3, PhI(OCOCF3)2 (0.36 mmol), TMSOTf (0.10 mmol), CH2Cl2, ꢀ30 ꢁC, N2 atmosphere, isolated
yields aer purication by silica gel column chromatography. b Yield based on recovered starting material.
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ꢁ
of TMSOTf at ꢀ30 C as the best condition forming 7a in 61% irradiation of H-1 at d 5.43 in the homonuclear decoupling
yield (entry 7, Table 1). With this optimized condition we experiment led the doublet of doublet for H-2 to appear as
carried out the remaining studies. Thus, a variety of differently a doublet with J ¼ 10.6 Hz indicating that H-2 and H-3 are
protected glycal derivatives led to the corresponding 1,2-dia- diaxially oriented. Likewise, irradiation of H-4 at d 5.27 caused
zides in moderate yields (Scheme 2).
the doublet of doublet for H-3 at d 5.13 to appear as a doublet
It was generally found that while the galactal derivatives led with J ¼ 10.6 Hz. Further, in NOE experiments irradiation of H-3
exclusively to cis-1,2-diazides, the glucal derivatives gave did not lead to the enhancement of the signal for H-1, and also
a mixture of a- and b-anomers in varied ratios with the irradiation of H-2 did not show the enhancement of H-4. These
a-anomer being major in most of the cases. The structures and data conrm that H-2 and H-3 are diaxially oriented and that
the a/b ratios were established based on COSY, NOE, homo- 11a possesses 1C4 conformation. In a similar fashion, the
nuclear decoupling and DEPT experiments.16a Thus, for structure of 11b was established.
example, in the 1H NMR spectrum of compound 7a the
It is important to note that in the absence of an acid catalyst
anomeric proton (H-1) appeared as a doublet at d 5.48 with J ¼ no reaction was found to take place between a glycal derivative
4.12 Hz. The homonuclear decoupling of H-1 led the proton H-2 and PIFA–Me3SiN3 reagent combination indicating that the
to appear as a doublet, from a doublet of doublet, with J ¼ azido radical, if formed,15 does not add on to the electron rich
11.00 Hz indicating that H-2 and H-3 are trans-diaxial. Further, glycal double bond. Therefore we presume that in the present
in the NOE experiments no enhancement was observed for case, the reaction does not proceed via radical pathway,17a
protons H-3 and H-5 when H-1 was irradiated and vice versa instead it proceeds via ionic pathway similar to the ones
indicating that H-1 is equatorially oriented. In addition, the proposed by Moriarty,17b and Kirschning.17c Thus, in situ
structure of the galactal derivative 5 was proved by single crystal generated PhI(N3)2 upon p-interaction (complex A in Scheme 3)
X-ray analysis.16b Likewise, the spectral data of 1,2-diazide 9a, with the double bond from the a-side (in case of a galactal and
derived from glucal 8a, also showed that the azido moieties are a glucal derivative) leads to intermediate B and transfer of the
a-oriented.16a Thus, in NOE experiments, irradiation of proton azide moiety to C-2 occurs in an SNi fashion from the a-side
H-4 at d 5.00 led to the enhancement of signal for H-2 at d 3.61 only. Following this (or simultaneously) the second azide pref-
and vice versa indicating that H-2 is axially oriented. On the erentially attacks at the anomeric carbon of the galactal deriv-
other hand, no enhancement was observed for H-3 and H-5 ative from the a-side (path a) due to steric hindrance caused by
protons when H-1 was irradiated at d 5.44 suggesting that H-1 the substituents at C-3, C-4 and C-5. In case of glucal derivatives,
is equatorially oriented.
however, some product was also formed due to b-attack of the
Interestingly, the arabinal derivatives 10a and 10b gave the azide moiety via path b since the glucal derivatives show less
1
corresponding 1,2-diazides 11a and 11b having C4 conforma- steric bias from the b-side as compared to galactal derivatives.
tions which was conrmed by spectral studies.16a In case of 11a,
Further, in case of arabinal derivatives it appears that the
double bond preferentially forms p-complex from the less
hindered b-side (complex C), followed by azide ion attachments
at C-2 and C-1 from the opposite face to the two –OR groups, in
a similar manner as happens in galactal cases, eventually
Scheme 2 Percentage yield and a/b ratio of the 1,2-diazides.
Scheme 3 Proposed mechanism for the formation of 1,2-diazides.
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Scheme 4 Conversion of 1,2-diazides into bis-triazole 13 and pseu-
dotri-saccharide 15.
leading to the observed 1,2-diazides 11a and 11b (Scheme 3)
which assume 1C4 conformations. It is clear that the success of
the 1,2-diazide formation is mainly due to the low nucleophi-
licity of the triuoroacetate ion compared to the azide ion.
In order to demonstrate the utility of these 1,2-diazides, we
have utilized the click chemistry to prepare two bis-triazoles,
one from a non-sugar and the other from a sugar based
alkyne. Thus, 1,2-diazide 5 was reacted with 2 eq. of phenyl-
acetylene 12 to form the bis-triazole 13 (Scheme 4) in 80% yield
using standard conditions.3d Likewise, a sugar derived alkyne18
Scheme 5 Selective reduction of 1,2-diazides and synthesis of b-N-
glycopeptides.
b-glycopeptides via mutarotation. The azido moiety at C-2 of the
azido-glycopeptide 19 was readily reduced21 with Zn/AcOH/Ac2O
to form the 2-amino-N-glycopeptide 24 in 85% yield, and thus
the present method forms an alternate route to 2-amino-N-
glycopeptides.
Having explored the conversion of glycals to 1,2-diazides
using PIFA–Me3SiN3 reagent system, we studied their reactivity
with PIDA–Me3SiN3 under analogous conditions. As discussed
above, the galactal derivative 1 (Scheme 1) upon reaction with
PIDA and Me3SiN3 (both 1 eq.) gave a mixture of four products
2–5 and thus it was not a synthetically useful reaction. We
therefore examined the reaction conditions to incorporate both,
the acetate (more nucleophilic compared to triuoroacetate ion)
as well as the azide moieties onto glycals. Our aim was to
procure synthetically useful 1-azido-2-acetoxy sugars and/or
2-azido-1-acetoxy sugars, and to avoid the formation of 1,2-
diacetates and 1,2-diazides. Aer exploring various combina-
tions of the azide source and Lewis acids (Table 2), it became
clear that a combination of 3 eq. of Me3SiN3 and 1 eq. of PIDA
along with 30 mol% of TMSOTf at ꢀ30 ꢁC was optimum to form
vicinal azidoacetates. Thus, galactal derivative 1 led to the
formation of an inseparable mixture of two products, 1-azido-2-
acetoxy sugar 2 and 2-azido-1-acetoxy sugar 3 in 61% combined
yield (Scheme 6). The two compounds were formed in 1 : 2 ratio
which was ascertained aer selectively reducing the mixture of 2
and 3 with ammonium tetrathiomolybdate (vide supra) followed
by acetylation that gave chromatographically separable 25 and
unreacted 3.22a Further, 2-azido-1-acetoxy sugar 3 was found to
be a mixture of two anomers (a/b ¼ 63/37). The glucal derivative
8b, on the other hand, gave a chromatographically separable
mixture of 26 16a and 27 22a (a/b anomers ¼ 60/40) in 1 : 2 ratio.
Compound 26 was again reduced and acetylated to form 28 22b
14 led to the corresponding bis-triazole 15,
a pseudo-
trisaccharide,3 in 75% yield. The structures of these triazoles
were conrmed from their spectral data.16a
The importance of N-glycopeptides is apparent from the
introduction part (vide supra) and a number of synthetic
approaches have been reported to procure them, and newer
synthetic routes are still being developed. In view of this, we
demonstrate the utility of 1,2-diazides 7a and 9a to form the
corresponding 2-azido-N-glycopeptides 18–23 (Scheme 5). Thus,
selective reduction of the anomeric azide of 7a and 9a
was carried out with ammonium tetrathiomolybdate
2ꢀ
19
[(NH4)2MoS4
] to give the corresponding amino compounds
16 and 17 and, without isolating them, the crude amines were
coupled with a number of amino acids and small peptides,
mediated by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC)20a to lead to the corresponding 2-azido-N-glycopeptides
18–23. The stereochemistry of the 2-azido-N-glycopeptides was
conrmed to be 1,2-trans based on COSY, HETCOR and
homonuclear decoupling experiments16a of 18. Thus, selective
decoupling of C1NH at d 6.05 led the anomeric proton to appear
as a doublet with coupling constant J ¼ 9.96 Hz indicating that
both H-1 and H-2 are axial. The facile mutarotation of free
anomeric amines has been reported in many cases4b,20b,c and
their functionalization mainly leads to the b-anomers. It is
therefore not surprising that in the present case, reduction of
a-azides to the corresponding free amines exclusively lead to
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Table 2 Optimization of reaction conditions to form vicinal-azidoacetates from galactal derivative 1a
Yield (%)
Entry
Catalyst
N3-Source
Equiv.
Solvent
Temp (ꢁC)
Time (h)
(2 + 3)
4
5
1
2
3
4
5
6
BF3$OEt2
BF3$OEt2
BF3$OEt2
BF3$OEt2
TMSOTf
TMSOTf
TMSN3
TMSN3
TMSN3
Bu4NN3
Bu4NN3
TMSN3
1
2
3
3
3
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
1
1
0.5
0.5
0.5
0.5
30%
20%
52%
46%
38%
61%
30%
20%
—
—
—
21%
40%
12%
17%
30%
—
—
a
Reaction conditions: glycals (0.36 mmol), TMSN3 (1.10 mmol), PhI(OAc)2 (0.36 mmol), TMSOTf (0.10 mmol), CH2Cl2, ꢀ30 ꢁC, N2 atmosphere,
isolated yields aer purication by silica gel column chromatography.
which was spectroscopically characterized. Interestingly, the the intermediate B will undergo attack of the acetate ion either
arabinal derivative 10b (ref. 23) led to a single product 29 in 56% from a- or b-side (paths a and b) at the anomeric carbon
yield whose structure was established based on spectral data accompanied by an SNi type reaction with the azide ion at C-2 to
and also by single crystal X-ray analysis.16b
give compounds 3 and 27 with the loss of PhI. Likewise,
Based on these product distributions in the reactions with formation of 2 and 26 can be rationalized by invoking inter-
glycal derivatives 1 and 8b with PIDA–Me3SiN3 reagent system mediates C (a p-complex) and D in the reaction of glycals with
we propose a tentative mechanism as shown in Scheme 7. PIDA. The p-complex C will expel a molecule of TMSOAc only
Accordingly, we expect PIDA to react with excess of Me3SiN3 upon the formation of the intermediate D. Thus at any given
(3 eq.) resulting into species X and TMSOAc with the equilib- time, during this pathway, more amount of Me3SiN3 is available
rium being more favorable on the right side. Reaction of glycals to attack at intermediate D which leads to the observed prod-
1 and 8b with the species X in presence of TMSOTf should lead ucts 2 and 26.
to a p-complex A which should generate another molecule of
In case of arabinal derivative 10b, a complex similar to ‘C’
TMSOAc on the way to intermediate ‘B’. Thus, chances of should form from the b-face to avoid the steric repulsions from
TMSOAc acting as a preferred nucleophile to form products 3 the two –OBn groups. This should be followed by azide ion
and 27 appear to be high compared to TMSN3. Subsequently, attack in an intermolecular fashion from the axial orientation at
the anomeric carbon. Subsequent acetate ion attack at C-2
occurs, in an intramolecular fashion, again from the axial side
leading to the observed product 29. It is however not clear at this
moment why the product 29 prefers to have 4C1 conformation as
against compounds 11a and 11b which prefer 1C4
conformations.
We further checked the reactivity of 2,4,6-tri-O-acetylated
glycals 6a and 8a towards the PIDA–Me3SiN3 reagent system.
The reaction was extremely sluggish in presence of 30 mol% of
TMSOTf even at room temperature for prolonged reaction
Scheme 6 Reaction of glycal derivatives 1, 8b and 29 with PIDA– Scheme 7 Proposed mechanisms for the reaction of glycals with PIDA
Me3SiN3.
and Me3SiN3.
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Scheme 8 Reaction of glycal derivatives 6a and 8a with PIDA–
Me3SiN3.
times. Gradual increase in the amount of TMSOTf ultimately led
to the use of 1 eq. of it for complete consumption of the starting
ꢁ
material at ꢀ30 C. However, the galactal derivative 6a, inter-
estingly, led to 2-hydroxy-1-azido sugar 30 as a product in 68%
yield (Scheme 8) whose structure was established based on
spectral data including COSY, NOE, homonuclear decoupling
and DEPT experiments.16a Thus, in NOE experiments, irradia-
tion of H-3 at d 4.89, led to the enhancement of the signals for
protons H-1 and H-5 at d 4.19 and d 3.96 respectively. Also, when
H-1 at d 4.19 was irradiated, the signals for H-3 and H-5 were
enhanced suggesting that H-1 is axially oriented. In the homo-
nuclear decoupling experiment of 30 when H-4 at d 5.36 was
irradiated, the proton H-3 appeared as a doublet with J ¼
3.68 Hz suggesting that H-2 is equatorially oriented. These data
support the structure assigned to 30. Compound 30 was also
derivatized to 31 and 32 and their structures conrmed based
on spectral analysis. On the other hand, the glucal derivative 8a
led to the Ferrier reaction to form 33 24 in 76% yield as an
anomeric mixture (a : b ¼ 60 : 40).
Scheme 10 Synthesis of a pseudotrisaccharide 38.
In view of the importance of 2-amino-O-glycosides, 1-acetoxy-
2-azido galactose derivative 3 was hydrolyzed25 with benzyl
amine to form 2-azido-3,4,6-tri-O-benzyl-galactopyranose 34
(Scheme 10). The corresponding trichloroacetimidate 35,
a glyosyl donor, was readily prepared by following a literature
procedure26 and was reacted with 36,27 an orthogonal glycosyl
acceptor having a thioglycoside linkage, followed by the click
reaction with sugar derived alkyne 14 to form a pseudo-
trisaccharide 38.16a
Mechanistically, in case of 2,4,6-tri-O-acetyl galactal 6a, the
intermediate F (Scheme 9), resulting from the p-complex E,
should allow azide ion attack from the b-side leading to the
intermediate G. It is possible that intermediate G then
undergoes intramolecular participation by C4–OAc group to
form intermediate I which then hydrolytically decomposes to
give 30. Since the glucal derivative 8a does not give similar
reaction, instead undergoes the Ferrier reaction, intra-
molecular participation of C4–OAc group in 6a becomes
crucial.
Further, we also show the importance of 1-azido-2-acetoxy
sugar derivative 29 in the synthesis of a piperidine triol 44,
that belongs to a class of potential glycosidase inhibitors9h,i
(Scheme 11). Thus, the acetate moiety of azidoacetate 29 was
deprotected and converted to the MOM derivative 40 via 39
under standard reaction conditions. Subsequently, the
Scheme 9 Proposed mechanisms for the reaction of glycal 6 with Scheme 11 Synthesis of a piperidine derivative 44 from the azidoa-
PIDA and Me3SiN3.
cetate 29.
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¨
anomeric azide group was reduced with LiAlH4 followed by
protection of the resulting amine as N-nosyl group to give 41
which was cyclized to the piperidine derivative 42 under the
Mitsunobu conditions. Deprotections of the nosyl, benzyl and
the MOM groups led to the formation of the piperidine 44, an
iminosugar as a potential glycosidase inhibitor.28
I. Boos, J. Freund, C. Pohner, S. Schwarzinger and
C. Unverzagt, Angew. Chem., Int. Ed., 2012, 51, 11566–
11570; (h) C. M. Kaneshiro and K. Michael, Angew. Chem.,
Int. Ed., 2006, 45, 1007–1081; (i) R. Joseph, F. B. Dyer and
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Conclusions
In conclusion, we have shown that the reagent system PIFA–
Me3SiN3 in presence of TMSOTf as a catalyst conveniently
converts glycals into the corresponding 1,2-diazido derivatives.
These vicinal azido derivatives are converted to 2-azido-N-
glycopeptides, which are convenient precursors of 2-amino-N-
glycopeptides, and also into a pseudotrisaccharide 15. Likewise,
glycals are converted into a mixture of 1-azido-2-acetoxy sugars
and 2-azido-1-acetoxy sugars using the reagent system PIDA–
Me3SiN3 in the presence of TMSOTf as a catalyst. The –OAc
group of 2-azido-1-acetates can be hydrolyzed and converted
into a trichloroacetimidate group for effecting glycosylations.
One of the azidoacetates 3 was converted into a pseudo-
trisaccharide 38 aer glycosylation followed by click chemistry.
Further, 1-azido-2-acetoxy sugar derivative 29, derived from the
arabinal derivative 10b, was eventually converted into a piperi-
dine triol 44, a potential glycosidase inhibitor. Tentative
mechanisms have been proposed to account for the formation
of different azido sugars.
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There are no conicts to declare.
Acknowledgements
We thank the Department of Science and Technology, New
Delhi, India, for a J. C. Bose National Fellowship (No. SR/S2/JCB-
26/2010) to Y. D. V. A. C. thanks the Council of Scientic and
Industrial Research, New Delhi for
Fellowship.
a Senior Research
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