Communication
lose disaccharide bearing a methyl group at one of the termini.
Moreover, the methyl group bearing a d-glucopyranoside unit
should also be equipped with a temporary protecting group at
the O3’ position so that it can be selectively removed prior to
attachment with the l-rhamnose end of the oligosaccharide.
There are a few methods reported in the literature for con-
constructed by a [4+5] glycosylation between the tetrasac-
charide thioglycoside donor 2 and the pentasaccharide accept-
or 3. The pentasaccharide could be synthesized by a [3+2] gly-
cosylation between the trisaccharide thioglycoside donor 4
and the 6’-OMe trehalose acceptor 5, which in turn could be
synthesized from d-glucose-derived building blocks 6 and 7
employing the IAD reaction. The trisaccharide donor 4 could
be obtained by glycosylation of monosaccharide building
blocks 8 and 9. The terminal tetrasaccharide donor 2 could be
assembled starting from the monosaccharide building blocks
10, 11, 12, and 13 through sequential couplings.
[14–16]
structing the 1,1’-a,a-glycosidic bond.
However, most of
the methods are limited by poor anomeric selectivity of the
glycosylation step, as not one but two anomeric linkages are
formed simultaneously and four products are possible in the
case of unsymmetrical derivatives. To tackle this problem, Ber-
tozzi and co-workers reported for the first time a methodology
for the synthesis of 1,1’-a,a-trehalose derivatives, using Ito’s
Our synthesis began with the construction of the unique
1,1’-a,a-trehalose acceptor
5
through the IAD route
[
17]
[16]
variant
of intramolecular aglycon delivery (IAD).
In this
(Scheme 2). For this purpose, the known 3-O-allyl diacetone
[
19]
method, the glucosyl donor and acceptor molecules are oxida-
tively tethered and oriented prior to activation in such a way
that only the desired 1,1’-a,a-stereoisomer can be formed. This
elegant method is so far the best among all the existing meth-
ods for the formation of unsymmetrically substituted 1,1’-a,a-
trehalose derivatives. Alternatively, one can use commercially
available trehalose. However, regioselective differentiation of
glucose 14, obtained by allylation of diacetone glucose, was
converted into its pyranose form thioglycoside 15 in three
steps (55% overall) through acid hydrolysis of the acetonides,
per-O-acetylation, and concomitant nucleophilic displacement
of the anomeric acetate by ethanethiol. Removal of acetates in
15 using NaOMe in MeOH and benzylidene protection of the
4,6-diol furnished the suitably protected 2-OH derivative 6 in
chemically similar, six secondary hydroxyl groups, in the C
88% yield over two steps. The key IAD reaction of 6 and easily
2
18]
[
[16a]
symmetrical, non-reducing disaccharide is again a challenge.
Owing to its convergent nature and exclusive stereoselectivity,
accessible a-linked dimethoxybenzyl (DMB) glycoside 7
was
conducted next. Compound 6 was first linked with 7 by oxida-
tion of the DMB ether using 2,3-dichloro-5,6-dicyano-1,4-ben-
zoquinone (DDQ) to form the mixed acetal 16, which upon
aqueous work up was subsequently activated using methyl tri-
[
16]
the IAD method seemed more appropriate for our purpose.
Our retrosynthetic strategy entailed a convergent assembly
of the nonasaccharide, as shown in Scheme 1. It was envisaged
that the target molecule 1 could be obtained upon global de-
protection from its fully protected precursor, which could be
[
16b]
fluoromethanesulfonate
to afford the unsymmetrically sub-
stituted 1,1’-a,a-trehalose derivative 17 exclusively in 58%
yield over two steps. The stereo-
chemistry of the newly installed
glycosidic linkage in 17 was as-
1
13
signed through H, C, and 2D
1
NMR. The H NMR spectrum of
1
7
showed two overlapping
doublets for 1H each at d=5.19
J=2.8 Hz) and 5.18 ppm (J=
(
3
1
.1 Hz) corresponding to the H-
13
and H-1’ of trehalose. C NMR
spectrum of 17 showed two sep-
arate peaks for the 1,1’-linked
glucosides at d=95.3 and
1
9
3.8 ppm with characteristic J
CH
coupling constants of 170 and
69 Hz, respectively, confirming
the a,a-linkage (see the Sup-
1
[
20]
porting Information). The free
hydroxyl group in 17 was pro-
tected as benzyl ether to afford
the fully protected trehalose
building block 18 (benzyl bro-
mide, NaH, 82%). A regioselec-
tive reductive ring opening of
the 4,6-O-benzylidene acetal in
[
13b,21]
18 using DIBAL-H
in tolu-
ene furnished the primary alco-
Scheme 1. Retrosynthetic analysis of OSE-1 1.
hol 19 (68%), as a major isomer
Chem. Eur. J. 2015, 21, 13544 – 13548
13545
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