P. Chopra et al. / Tetrahedron Letters 54 (2013) 5558–5561
5559
cally-linked Neu5Ac derivatives. Towards this end, various meth-
ods to directly de-N-acetylate Neu5Ac-based compounds, under
the acetamido methyl protons (d 2.03 in Neu5Ac
observed.
a
2Me27) were
1
2–17
18
strongly basic
or acidic conditions have been reported. These
The concentration of alkali significantly influenced the rate of
reaction, with lower concentrations (0.2–0.6 M) resulting only in
saponification (Table 1, entries 1–3) while the highest alkali con-
centration (Table 1, entry 7) resulted in some decomposition of
the substrate and/or product (based on TLC analysis). However, a
significant yield of the desired de-N-acetylated product, Neua2Me
5, was obtained with 2.0 M NaOH (Table 1, entry 6) without any
observed decomposition.
Based on the above results (Table 1), 2.0 M NaOH was selected
as the optimum alkali concentration. We then proceeded to deter-
mine the optimum reaction time and temperature (Table 2). A pro-
gressive increase in the conversion into 5 was obtained with
increasing exposure to microwave irradiation at a fixed tempera-
ture of 120 °C (100 W max. power) for 5 (57% conversion into 5),
10 (72% conversion) or 15 (91% conversion) minutes. Irradiating
for more than 15 min, however, while maintaining excellent con-
version into 5 also resulted in some degradation of the carbohy-
drate substrate and/or product (Table 2, entries 5 and 6). In
evaluating the effect of the reaction temperature, while maintain-
ing the reaction time at 15 min, we observed that a temperature of
100 °C resulted in only saponification with little de-N-acetylation
(36% conversion into 5). Furthermore, employing a reaction tem-
perature above 120 °C (140 °C or 160 °C) led to increasing levels
of carbohydrate degradation. An optimal yield of 5 was therefore
obtained at a reaction temperature of 120 °C after exposure to
microwave irradiation for 15 min.
methods, however, generally require reaction at high temperature,
over long reaction times.
For numerous thermally-driven organic reactions, microwave
irradiation has been used as an alternative source of energy to
accelerate chemical transformations.19 Reduced reaction time, in-
creased purity and higher yields are some of the major advantages
2
0
often obtained when using microwave-assisted synthesis. The
scope of microwave irradiation in chemical manipulations of car-
2
1
22–24
bohydrates, and in particular sialic acids,
relatively poorly explored.
however, has been
Herein, we report the development of optimised microwave
irradiation based reaction conditions for the de-N-acetylation of
selected Neu5Ac compounds, and the further elaboration of the
resultant amines to the corresponding N-glycolylated derivatives.
Traditional thermal de-N-acetylation methods under acidic condi-
tions would readily hydrolyse an O-glycosidic linkage. We there-
fore selected basic reaction conditions to investigate the
microwave irradiation of the selected Neu5Ac substrates.
To begin this study, we selected the protected
a
-methyl glyco-
-linked sialoside to gauge
the stability of the glycosidic linkage, and of the sialoside substrate
2
5
side of Neu5Ac, 4, as a representative
a
2
6
in general, to basic conditions under microwave irradiation (Ta-
ble 1). In an initial screening, different concentrations of aq NaOH
(
0.2–4.0 M) were employed. We began with microwave conditions
24
that we have previously shown to be optimal for the synthesis of
the b-methyl glycoside of Neu5Ac: a reaction temperature of
To investigate the influence of reaction scale on the microwave-
based synthesis of 5, we increased the mass of substrate 4 by 20-
fold to 1.0 g. Reaction under the optimised microwave irradiation
conditions (15 min at 120 °C, at a maximum power of 100 W)
afforded the desired 5-amino derivative 5 in 80% yield (Table 3, en-
try 1). The general application of this method was demonstrated by
1
20 °C (at a microwave power of 100 W) for a period of 15 min.
The reaction progress was monitored by TLC using ninhydrin as
an amine-active stain. De-N-acetylation of the C-5 acetamido
1
group was confirmed by H NMR spectroscopy of the reaction mix-
ture (in NaOH/D
2
O) where a characteristic upfield shift of H-5 from
for the acetamido derivative Neu5Ac 2Me, to
2Me, as the sodium salt), and the lack of
2
7
d 3.80 ppm
.51 ppm in 5 (Neu
a
reaction of the alternative b-methyl glycoside, Neu5Ac1,b2Me
2
1
2
24
2
a
(6; , Table 3, entry 2), the peracetylated unsaturated derivative
2
8
Neu5Ac2en1Me (8; , Table 3, entry 3) and the
a-2,8-linked
Neu5Ac homopolymer (ꢀ100 residues, 10; Table 2, entry 4) under
2
9
Table 1
the optimised reaction conditions. To our delight, we found that
for each substrate we achieved excellent isolated yields of the de-
sired target 5-amino derivatives, in significantly shorter times than
Microwave-assisted de-N-acetylation of
4
at 120 °C: optimisation of alkali
concentrationa
1
2–14
reported
compared to, e.g., 16 h for reaction of 4 or 8 with Ba(OH)
and avoiding the extensive work-up typically required with re-
for reactions using conventional heating (15 min as
OAc
OH
12
13
AcO
OAc
CO
2
Me
HO
OH
CO –
OMe
2
Na+
2
),
aq NaOH
O
OMe
O
AcHN
H
2
N
12,13
2
agents such as Ba(OH) .
MW, 120˚C
OAc
OH
1
5 min
Finally, the target N-glycolyated derivatives were readily pre-
pared from the free amines by reaction with acetoxyacetyl chlo-
4
5
Table 2
Microwave-assisted de-N-acetylation of 4 in 2.0 M NaOH: optimisation of time and
temperature
Entry
(NaOH) (M)
Conversion into 5b (%)
a
1
2
3
4
5
6
7
0.2
0.4
0.6
0.8
1.0
2.0
4.0
0c
c
Entry
Reaction conditions
Conversion into 5 (%)
0
0
c
57b
72
90
91
1
2
3
4
5
6
7
8
9
5.0 min, 120 °C
10.0 min, 120 °C
12.5 min, 120 °C
15.0 min, 120 °C
17.5 min, 120 °C
20.0 min, 120 °C
15.0 min, 100 °C
15.0 min, 140 °C
15.0 min, 160 °C
b
10
16
91
d
c
90
95
c
94
a
Reaction was carried out on 4 (50 mg, 0.10 mmol) in NaOH solution (0.2–4.0 M
in D O, 1 mL) in a sealed reaction vessel, under MW irradiation (max. 100 W) at
b
36
2
c
99
1
20 °C for 15 min.
c
100
b
Conversion into 5 was determined from the 1H NMR (300 MHz, NaOH/D
2
O)
a
spectrum of the reaction mixture, based on comparison of the integration of H-5 of
at d 2.51, with that of the combined H-3 equiv for 4 and 5 at d 1.31–1.39 ppm. See
Reaction was carried out on 4 (50 mg, 0.10 mmol) in NaOH solution (2.0 M in
2
D O, 1 mL) in a sealed reaction vessel, under MW irradiation (max. 100 W) and the
5
Supplementary data.
specified conditions.
c
b
Partial to complete saponification was observed.
Partial to complete saponification was observed.
d
c
Decomposition of the carbohydrate was observed.
Decomposition of the carbohydrate was observed.
Chopra, Pradeep
