Microwave-assisted saccharide coupling with n-pentenyl glycosyl donors

Article abstract of DOI:10.1016/j.tetlet.2003.09.206

n-Pentenyl glycosides, armed and disarmed, and n-pentenyl orthoesters couple with acceptors, hindered and unhindered, within 25 min under microwave activation. The reaction takes place in acetonitrile under neutral conditions with N-iodosuccinimide as pro

Full text of DOI:10.1016/j.tetlet.2003.09.206

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9051–9054
Microwave-assisted saccharide coupling with n-pentenyl glycosyl
ꢀ
donors
a
a
a,
b,
b
Felix Mathew, K. N. Jayaprakash, Bert Fraser-Reid, * Jessy Mathew * and Jan Scicinski
a
Natural Products and Glycotechnology Research Institute, Inc., 4118 Swarthmore Road, Durham, NC 27707, USA
b
Nuada Pharmaceuticals, Inc., 4324 South Alston Avenue, Durham, NC 27713, USA
Received 2 September 2003; revised 25 September 2003; accepted 25 September 2003
Abstract—n-Pentenyl glycosides, armed and disarmed, and n-pentenyl orthoesters couple with acceptors, hindered and unhin-
dered, within 25 min under microwave activation. The reaction takes place in acetonitrile under neutral conditions with
N-iodosuccinimide as promotor, which are therefore ideal for use with reactants bearing acid-labile protecting groups.
©
2003 Elsevier Ltd. All rights reserved.
1
a
1b
The pioneering 1986 report of Westaway, Majetich
tages are indisputable, having been demonstrated even
in enzymic reactions.
5
and their co-workers on the use of microwave activa-
tion for chemical reactions continues to inspire increas-
ing interest in this novel synthetic tool. The impressive
versatility of the technique may be judged by recent
reviews and monographs. Major attributes of the
method include faster reaction times and ‘cleaner’ reac-
tions, and although the science which underlies these
salutary effects remains debatable, the accruing advan-
6
2
Abramovitch and Loupy have postulated that reac-
tions in which ‘polarity is increased—from the ground
state towards the transition state’ are ideal candidates
for microwave assistance. This postulate, added to the
fact that microwave heating is less destructive of the
2
,3
4
7
substrate than thermal heating, holds promise for
Scheme 1.
Keywords: microwave; carbohydrate; saccharide coupling.
ꢀ
Supplementary data associated with this article can be found at doi:10.1016/j.tetlet.2003.09.206
Corresponding author. Tel.: +1-919-493-6113; fax: +1-919-493-6113; e-mail: dglucose@aol.com
*
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.206

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F. Mathew et al. / Tetrahedron Letters 44 (2003) 9051–9054
1
2
application to carbohydrates which are notoriously sen-
groups (LVGs) allow direct or remote activation lead-
ing to the crucial oxocarbenium ion 3. In the case of
n-pentenyl glycosides (NPGs) pioneered in this
sitive to heat. Apropos, experiments on installing/
8
removing protecting groups, nucleophilic displace-
9
10a
13
ments, enzyme-catalysed glycosidation
and, very
laboratory (Scheme 1b), the road to oxocarbenium
1
0b
recently, glycosylation of oxazolidine donors
have
ion 3 traverses increasingly polar intermediates, 5 and
6, that should present ideal opportunities for
microwave assistance in keeping with the Abramovitch/
been successful. In this communication we report the
first examples, to our knowledge, of non-enzymatic
saccharide coupling induced by microwave irradiation.
2,6
Loupy postulate.
The fundamental process for activation of the anomeric
center is depicted in Scheme 1a. Several leaving
Our initial work focused on the approach outlined in
Scheme 1b. Thus, coupling of the ‘armed’ NPG donor
1
1
Table 1. Microwave-promoted coupling of n-pentenyl donors and acceptors

F. Mathew et al. / Tetrahedron Letters 44 (2003) 9051–9054
9053
1
3 and 2 equiv. of the glucoside acceptor 10 in aceto-
cern. We therefore investigated the reaction using an
alternative activator. Independent experiments had
shown that donors 14 and 15 (a, b or c) were not
activated by molecular iodine either thermally or by
microwave radiation. The result in Scheme 2a in
which iodine was replaced by NIS under the experi-
nitrile solution containing 2.2 equiv. of N-iodosuccin-
14
imide (NIS) under microwave irradiation for 25 min
showed no evidence of a coupled product (Table 1,
entry i). By contrast, the ‘disarmed’ analogue 14,
under similar conditions, afforded disaccharide 17a,
albeit in poor (unoptimized) yield (Table 1, entry ii).
Nevertheless, it was encouraging that some coupling
had occurred. n-Pentenyl orthoesters (NPOEs), e.g. 7
14
mental conditions of entry (iii), show that 15a is not
activated by iodine under microwave conditions.
(
Scheme 1c) offer another avenue to the oxocarbe-
On the other hand, were the results in Table 1 merely
thermally induced? The experiment in entry (iii) was
again repeated, except under 24 h reflux (Scheme 2b).
Coupled product 17a was indeed obtained, but the
reaction was very messy, giving several side products.
15
nium ion 3 as shown in Scheme 1c. Notably, the
di/trioxolenium complex 9a/b, can also capture the
acceptor-OH at the anomeric center, and the fact
16
17
that the complex 9, is ꢀ30 kcal/mol lower in energy
than the disarmed oxocarbenium ion 3 (R=acyl)
makes 9 more accessible. Indeed manno NPOE 15a,
Performing the reactions in a focused microwave
instrument involves first setting a target temperature
for the reaction. Irradiation with microwave energy
results in the reaction reaching this temperature
rapidly. Subsequent maintenance of this target tem-
perature however only requires small bursts of
microwave energy. A feature of the CEM ‘Explorer’
focused microwave instrument is the ability to main-
tain the target temperature while subjecting the reac-
tion mixture to continuous irradiation with
microwaves by cooling the reaction vessel with a
stream of nitrogen.
1
4
reacted with acceptor 10 to give disaccharide 17a in
7% yield—in contrast to the 26% yield obtained with
7
NPG 14 (Table 1, entry ii versus iii). The reaction of
the gluco NPOE 16a with acceptor 10 (Table 1, entry
vii) also resulted in successful coupling to give disac-
charide 19a in 65% yield. It was of interest to see
how acceptors with hindered hydroxyl groups would
fare. The inositol (11) and mannoside (12) acceptors
had previously been coupled with manno (15a) and
gluco (16b) NPOEs under Lewis acid promoted condi-
tions furnishing yields of 18 and 19b in 80–90% and
18
8
4%, respectively. These couplings were therefore
repeated under our optimized microwave conditions.
Yields of 73 and 60% were obtained (Table 1, entries
vi and viii), somewhat lower than the Lewis acid con-
ditions; however the resulting reaction mixtures were
much cleaner, containing less side products.
To further test for thermal versus microwave effects,
we took advantage of this feature described above.
1
4
Thus, reaction of compounds 12 and 16a at 100°C
with 200 W of microwave energy with simultaneous
cooling gave product 20 in 41% yield (Table 1, entry
ix and Scheme 2d). When the same reaction carried
out without cooling, the microwave energy absorbed
was only 40–50 W and the product 20 was isolated in
only 21% (Scheme 2). This observation suggested that
the applied microwave energy rather than heat alone
had a substantial effect on the yields.
The successes listed in Table 1 (entries iv–vi) augured
well for use with substrates bearing acid labile pro-
tecting groups. In this context, a recent communica-
19
tion from our laboratory reported that ytterbium
III) triflate was specifically suited for use with NPOE
(
donors, especially those with acid labile protecting
groups such as present in 15b and 15c. Microwave-
induced coupling of the latter NPOEs with acceptor
In conclusion, the n-pentenyl family of glycosyl
donors, disarmed and orthoester, undergo ready cou-
pling with hindered or unhindered acceptors. When
the reactions are performed in a focused microwave
the yields range from excellent to modest, and the
reactions are always rapid and ‘clean’. The ability to
tolerate acid-labile protecting groups as well as short
reaction time are attractive advantages of this cou-
pling procedure.
1
0 provided modest yields (Table 1, entries iv and v).
However, it is notable that again the product mix-
tures were extremely ‘clean,’ allowing ready isolation
of the disaccharide products 17b and 17c, and recy-
cling of the starting material.
That the results in Table 1 were indeed attributable
solely to microwave irradiation was an obvious con-
Scheme 2.

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F. Mathew et al. / Tetrahedron Letters 44 (2003) 9051–9054
Chemistry and Their Roles in Natural Products; John
Acknowledgements
Wiley & Sons: New York, 1995; (b) Boons, G.-J. Carbo-
hydrate Chemistry; Blackie Academic & Professional:
Glasgow, 1998; Chapter 5.
B.F.R. is grateful to the National Science Foundation
for support.
12. Preparative Carbohydrate Chemistry; Hanessian, S., Ed.;
Marcel Dekker: New York, 1997; Chapter 16.
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