Stereoselective synthesis of β-N-glycosides through 2-deoxy-2-nitroglycal

Article abstract of DOI:10.1016/j.carres.2011.01.032

An efficient, base-free protocol has been developed for the β-stereoselective synthesis of N-glycosides from 2-nitroglycal and secondary amines. Simple protection and deprotection manipulations on the N-glycosides pave a way for the synthesis of biologica

Full text of DOI:10.1016/j.carres.2011.01.032

Carbohydrate Research 346 (2011) 2957–2959
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Carbohydrate Research
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Note
Stereoselective synthesis of b-N-glycosides through 2-deoxy-2-nitroglycal
⇑
Shaohua Xiang, Jimei Ma, Bala Kishan Gorityala, Xue-Wei Liu
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, base-free protocol has been developed for the b-stereoselective synthesis of N-glycosides
from 2-nitroglycal and secondary amines. Simple protection and deprotection manipulations on the N-
glycosides pave a way for the synthesis of biologically significant1,2-diaminosugars and glycopeptides.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 23 December 2010
Received in revised form 17 January 2011
Accepted 20 January 2011
Available online 4 February 2011
Keywords:
Glycosylation
N-Glycosides
2-Nitroglycal
Michael addition
1,2-Diaminosugar
Glycopeptides
Synthesis of glycosides and glycoconjugates has always posed
new challenges and inspired glycochemists for their inextricable
association with legions of biological functions.1–3 Besides O- and
C-glycosides,4–21 synthesis of N-glycosides22–26 has never been
thoroughly explored, since the stereoselective induction of nitro-
gen scaffolds at the anomeric position remains a particularly diffi-
cult task.27,28 Increasing interest in the synthesis of N-glycosides is
ascribed to the fact that they are integral constituents of proteogly-
cans, glycoproteins, peptidoglycans and glycolipids in biological
systems. Moreover, N-glycosyl amines were found to be potential
therapeutic candidates for the treatment of inflammation and
infection.27,29–31 Owing to the biological significance and existing
restricted synthetic methodologies, there is an exigent need for a
facile and efficient protocol to synthesize N-glycosides. Herein,
we report a versatile, operationally simple and catalyst free N-gly-
cosylation protocol to synthesize b-N-glycosides of 2-deoxy-2-ni-
tro-glycals. 2-Nitroglycals are powerful glycosyl donors which
have been included in the synthesis of many biologically signifi-
cant compounds since the nitro group can be readily reduced to
an amino group.32 In our present work, the Michael-type addition
synthesize biologically potent molecules.32 Earlier Schmidt and
co-workers reported the synthesis of N-glycosides, but the protocol
requires the use of base in the reaction and is confined to the for-
mation of nucleoside containing N-glycosides.26 Our continuous ef-
forts in exploring new glycosylation strategies36–39 prompted us to
develop a base-free methodology to synthesize aliphatic N-glyco-
sides to elaborate the substrates which can readily be converted
to N-glycopeptides. The present form of N-glycoside synthesis
complements the previous work done by Schmidt and Kunz et
al.8,22–26
At the beginning, the reaction between 0.1 mmol of 2-nitroglu-
cal 1 with 0.11 mmol of benzyl amine in 1 mL THF was conducted
at room temperature for 1 h. Unfortunately, the reaction afforded
an inseparable mixture. In a bid to improve the reaction conditions,
we proceeded with the optimization by employing various sol-
vents such as CH2Cl2, CH3CN and DMF. In addition, attempts were
made to vary the glycosyl acceptor (aniline) and the reaction tem-
peratures (0, ꢀ40, ꢀ78 °C). However, there was no improvement in
the experimental results. We presumed that the primary amine
was not an appropriate glycosyl acceptor to carry out this transfor-
mation, thus the acceptor was replaced with a secondary dibenzyl
amine. The reaction between 2-nitroglucal 1 and dibenzyl amine
3a in THF proceeded smoothly and afforded the desired N-glyco-
side product 4a as a single diastereomer in 85% yield (Table 1, en-
try 1). Other solvents such as CH2Cl2, DCE, DMF, DMSO, toluene,
CH3CN, [BMIm]BF4 and H2O were then screened. The results
indicated that CH2Cl2 was superior to other solvents in terms of
reaction time and yield (Table 1).
of secondary amine to 3,4,6-tri-O-benzyl-2-nitro-
the formation of exclusive b-N-glycoside in high yield. Conse-
quently, 1,2-trans-N-acetyl- -glycosylamine, the key structure in
D-glycal leads to
D
most of the 2-amino-2-deoxy-glycosides, can be readily pre-
pared.33–35
Schmidt and Vankar pioneered in utilizing 2-nitroglycals and
demonstrated a wide variety of glycochemical transformations to
Based on the optimization results, the best condition was
2-nitroglucal 1 (1 equiv) with dibenzyl amine 3a (1.1 equiv) in
⇑
Corresponding author. Tel.: +65 63168901; fax: +65 67911961.
E-mail address: xuewei@ntu.edu.sg (X.-W. Liu).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.01.032

2958
S. Xiang et al. / Carbohydrate Research 346 (2011) 2957–2959
Table 1
Table 2
Optimization of the conditions for N-glycosylation
N-Glycosylation of different amine to 2-nitro-D-glucal
R1
N
O
Bn
N
R1 CH2Cl2, rt
BnO
BnO
O
R2
O
BnO
BnO
HN
R2
BnO
O
Bn
solvent, rt
BnO
BnO
Bn
NO2
HN
Bn
NO2
BnO
NO2
OBn
NO2
OBn
4
OBn
OBn
4a
3
1
1
3a
Entry
1
Amine (3)
Producta
Time (h)
36
Yieldb (%)
93
Entry
Solvent
Time (h)
Yielda (%)
Bn
HN
1
2
3
4
5
6
7
8
9
THF
CH2Cl2
DCE
48
36
48
48
48
48
96
96
96
84
93
84
82
68
72
45
86
—
4a
Bn
Bn
DMF
HN
Me
2
4b
4c
4d
4e
4f
24
24
36
36
24
92
90
85
89
90
DMSO
Toluene
CH3CN
[BMIm]BF4
H2O
Me
HN
Me
3
Et
a
Isolated yields.
HN
Et
4
CH2Cl2 at room temperature for 36 h, delivering the desired N-gly-
coside in 93% yield (Table 1, entry 2). Encouraged by this result, the
scope of the N-glycosylation between 2-nitroglucal 1 and a wide
variety of secondary amines 3 was subsequently examined. The re-
sults were summarized in Table 2. As evident from Table 2, all the
reactions proceeded smoothly with good to excellent yields (Table
2, entries 1–13). It is noteworthy that the reaction is compatible
with amine substituents bearing long chains (Table 2, entry 5).
The scope of the reaction was further extended to cyclic amines
to produce the desired compounds in excellent yields (Table 2, en-
tries 7–11). However, neither hindered amines such as diisopropyl
amine nor aromatic secondary amine such as N-methyl aniline
could produce good results. It is worthy of note that the reaction re-
sulted in the characteristic formation of N-glycosides rather than O-
glycosides when it was conducted with O- and N-containing glyco-
syl acceptors without any base. This clearly demonstrates the high
chemoselectivity and synthetic utility of this methodology (Table
2, entries 12–13). We endeavored to achieve the N-glycosylation be-
tween 2-nitroglucal and N-glycosyl acceptors to synthesize glyco-
peptides. Gratifyingly, the desired N-glycopeptide was formed in
excellent yield with exclusive b-selectivity (Table 2, entry 14).
The stereochemistry of the N-glycosides was deduced from
their spectroscopic properties. 1H NMR spectrum of 4b revealed
that the anomeric hydrogen signal appeared as a doublet with
J1,2 = 9.5 Hz. Similarly, H-2 signal appeared as a doublet of doublet
with J1,2 = 9.5, J2,3 = 9.8 Hz. This clearly indicated trans relationship
between H-1 and H-2, H-2 and H-3, which coincided with the re-
ported result.21,26,40 The stereochemistry of compounds 4i (Fig. 1)
and 4k was further confirmed by X-ray diffraction crystallographic
analysis.41
C8H17
HN
C8H17
Me
5
NH HCl
OMe
6c
7
4g
4h
4i
24
24
24
24
24
87
92
94
92
93
HN
HN
HN
HN
8
9
O
S
10
11
4j
4k
HN
HN
N
Me
CH2CH2OH
12
4l
36
72
CH2CH2OH
Me
NH HCl
OH
13c,d
14
4m
4n
24
72
80
90
H
N
COOMe
Bn
Only b-isomer was detected in the 1H NMR spectrum.
Isolated yields.
1 equiv of Et3N was added.
a
b
c
d
The product 4m is unstable.
We next set out to explore the Michael-type addition with
2-nitrogalactal. Under the same reaction conditions, the reaction
between 3,4,6-tri-O-benzyl-2-nitro-D-galactal 2 with different
amines 3 also afforded pure b-isomers in good to excellent yields.
The results were summarized in Table 3. Similarly, the structure of
the products could be determined by the characteristic vicinal cou-
pling constants between the protons H-1 and H-2, H-2 and H-3.
In conclusion, an efficient, straightforward N-glycosylation pro-
tocol has been developed based on the Michael-type addition of
exclusive b-selectivity (e) simple operation; precludes the use of
stringent inert conditions and no aqueous work-up (f) ready access
to glycopeptides; deprotection of nitrogen at the anomeric position
would afford N-glycosylamine, which are versatile building blocks
for the synthesis of glycopeptides.
1. Experimental
secondary amine to 3,4,6-tri-O-benzyl-2-nitro-D-glycal. Some of
1.1. General procedure for the synthesis of N-glycosides of 2-
deoxy-2-nitroglycal from 3,4,6-tri-O-benzyl-2-nitro-D-glycal
the salient features of this methodology include (a) catalyst and
base-free reaction (b) applicability to aliphatic and long chain sec-
ondary amines; simple reduction of nitro group to amine would
furnish 1,2-diamino sugars (c) high chemoselectivity; nitrogen
competes with oxygen to provide exclusive N-glycosides (d)
To a solution of 3,4,6-tri-O-benzyl-2-nitro-D-glycal (1 mmol) in
CH2Cl2 was added secondary amine (1.1 mmol). The mixture was

S. Xiang et al. / Carbohydrate Research 346 (2011) 2957–2959
2959
128.4, 128.4, 137.2, 137.6, 138.1 ppm; MS (ESI): 562 m/z (M+H+);
HRMS (ESI) calcd for
562.2918.
C
32H40N3O6 [M+H]+: 562.2917; found:
Acknowledgments
The authors thank Dr. Yong-Xin Li for X-ray analyses and grate-
fully acknowledge Nanyang Technological University (RG50/08)
and Ministry of Education (MOE 2009-T2-1-030), Singapore for
funding this research.
Supplementary data
Supplementary data (experimental details, product character-
izations for compound 4a–n, 5a–d, X-ray crystallography structure
and parameters for compound 4i and 4k) associated with this arti-
cle can be found, in the online version, at doi:10.1016/j.carres.
2011.01.032.
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Table 3
N-Glycosylation of different amine to 2-nitro-D-galactal
R1
N
O
BnO
O
R1 CH2Cl2, rt
BnO
BnO
R2
HN
BnO
NO2
R2
NO2
OBn
OBn
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2
3
Entry
Amine (3)
Producta
Time (h)
48
Yieldb (%)
88
C8H17
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C8H17
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3
4
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5c
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93
90
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stirred at room temperature until the reaction was completed. The
solvent was evaporated under vacuum. The resulting residue was
purified by flash chromatography on silica gel to provide the N-gly-
coside product. For example, compound N’-methyl-N-3,4,6-tri-O-
benzyl-2-deoxy-2-nitro-b-D-glucopyranosylpiperaz-ine (4k) was
afforded as a white solid. mp 100–101 °C; ½a D21
ꢁ
ꢀ1.4 (c 1.0 CHCl3);
IR (neat)
m
;
: 3063, 3032, 2934, 2851, 1557, 1454, 1373, 1099, 737,
698 cmꢀ1
1H NMR (CDCl3, 400 MHz): d 2.2 (br s, 3H), 2.21–2.38
(m, 4H), 2.58–2.64 (m, 2H), 2.88–2.96 (m, 2H), 3.37–3.42 (m,
1H), 3.55–3.64 (m, 2H), 3.67 (dd, J = 11.4, 3.6 Hz, 1H), 4.21 (dd,
J = 9.7, 9.2 Hz, 1H), 4.27 (d, J = 9.5, 1H), 4.42–4.58 (m, 4H), 4.65–
4.73 (m, 3H), 7.10–7.28 (m, 15H) ppm; 13C NMR (CDCl3,
100 MHz): d 45.9, 47.3, 54.9, 68.3, 73.7, 75.1, 75.4, 77.2, 77.9,
82.2, 86.2, 92.1, 127.5, 127.6, 127.8, 127.9, 127.9, 128.0, 128.3,
39. Lorpitthaya, R.; Xie, Z. Z.; Kuo, J. L.; Liu, X.-W. Chem. Eur. J. 2008, 14, 1561–1570.
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41. The X-ray structure of 4k and the X-ray data of compounds 4i and 4k are in the
Supplementary data.