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G. Akçay et al. / Tetrahedron Letters 56 (2015) 109–114
are particularly interested in characterizing trifluorobutyrylated
sLex–selectin binding in vitro. Accordingly, we focused our efforts
on the synthesis of C4F3-sLex.
improves stability of the
non-participating group at 2-OH to enable a 1,2-cis-
a
fucoside linkage while preserving a
-fucopyranosyl
L
glycosidic bond, (2) a 4,6-O-benzylidine acetal protection on the
glucosamine building block, that provides a 6-O-benzyl substituted
disaccharide acceptor that is sterically less demanding at the site of
the [2+2] glycosylation and (3) the presence of a flexible O-pentenyl
functionality at the anomeric oxygen that allows access to soluble
sLex constructs by simple removal of the O-pentenyl moiety through
aqueous N-bromosuccinimide (NBS) treatment or enables surface
conjugation of the compounds via thiol linkers. A thiol-terminated
linker can be introduced by addition of thiolacetic acid to the olefin
in the presence of azobisisobutyronitrile (AIBN).25 Other types of
linkers can also be presented via olefin metathesis reaction.26,27
For the construction of disaccharide acceptor III, we proposed
new building blocks 9 and 17 that can be prepared in a facile man-
ner, using both reported and new intermediate monosaccharides.
The preparation of fucosyl donor 9 started with the conversion of
The assembly of the tetrasaccharide sLex has been a nontrivial
task for synthetic chemists, as it requires selective formation of
glycosidic bonds with highly functionalized substrates. Persistent
challenges in synthesizing sLex include the spatial proximity of
the galactose and fucose at positions C-4 and C-3 of N-acetylgluco-
samine,14 resulting in low reactivity of C4-OH or C3-OH in glyco-
sylation reactions, pronounced acid lability of the
a-L-fucose
linkage15 and difficulties associated with chemical sialylation.2,16
Choosing a suitable set of orthogonal protecting groups to enable
anomeric control and high yielding glycosylations has been the
key to several successful sLex syntheses reported to date. Although
a variety of chemical and chemo-enzymatic methods are available
for the synthesis of naturally occurring sLex and sLex-containing
complex structures,17–21 only few methods have been reported to
make N-modified sialic acid containing oligosaccharides22–24 and
no efficient protocols exist for the preparation of N-modified sLex
analogues. We devised a versatile solution phase convergent
chemical strategy for the construction of N-substituted unnatural
sLex structures. Key features of our synthesis include simple and
efficient protecting group manipulation and orchestrated use of
glycosyl halide, phosphite and trifluoroimidate donors to ensure
sufficient reactivity and stereoselectivity. Furthermore, our syn-
thetic route offers the opportunity to install a wide range of C-5
modifications on the sialic acid that would allow construction of
N-modified sLex or more complex oligosaccharide libraries.
L-fucose tetraol to the peracetylated derivative 1. The reaction of
tetraacetate 1 with thiophenol (PhSH) in the presence of BF3ÁEt2O
afforded thioglycoside 228 in 85% yield. Next, global deprotection
of O-acetyl groups followed by 3,4-ortho ester formation using
2,2-dimethoxypropane with p-toluenesulfonic acid monohydrate
(pTsOHÁH2O) generated derivative 4.28 Benzylation of the 2-OH
and removal of the isopropylidene protection gave diol 619 in high
yields. Pivaloate esters were installed on the free hydroxyls by
treating 6 with pivaloyl chloride and DMAP. A final deprotection
step with NBS in aqueous medium furnished the reducing sugar
8
29 in 79% yield. Glycosyl fluoride donors in combination with pro-
moters, stannous chloride (SnCl2) and silver perchlorate (AgCl4) are
often used to achieve good
-stereoselectivity.30,31 Thus, we syn-
a
Results and discussion
thesized fucosyl fluoride 9 from the reaction of 8 with diethylami-
nosulfur trifluoride (DAST) at low temperatures (Scheme 2).
A carefully designed protection strategy enabled access to the
N-acetyl glucosamine acceptor 17 efficiently. Glycosylation of ace-
tate 10 with pentene-1-ol mediated by TMSOTf gave the known
compound 11.32 Zemplén deacetylation followed by addition of
the 4,6-O-benzylidine protection using benzaldehyde dimethyl
acetal and p-toluenesulfonic acid resulted in previously reported
intermediate 13.33 Next, the free alcohol was masked by treatment
with levulinic acid in the presence of an activating system com-
posed of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI)
and DMAP to yield 14. Regioselective opening of the benzylidene
acetal at 4-OH with triethylsilane and BF3ÁEt2O followed by ben-
zoyl protection of the free alcohol and finally the cleavage of the
levulinate ester via aqueous hydrazine afforded glycosyl acceptor
17 in 69% yield starting from 14 (Scheme 3).
For the synthesis of desired tetrasaccharide I, not only must the
strategy afford suitable quantities but it also must accommodate
structural variation to allow preparation of analogue structures.
We envisioned that sufficient quantities of such a complex target
could be obtained by employing a convergent approach that uses
orthogonally protected building blocks that can be assembled into
the target by using a minimal number of synthetic steps. In plan-
ning the synthetic route, target tetrasaccharide I was disconnected
into two blocks at the Galb(1–4)GlcNAc linkage, generating two
disaccharide precursors. Accordingly, the final tetrasaccharide
structure can be assembled through a [2+2] glycosylation of novel
building blocks, disaccharide donor II and disaccharide acceptor III
(Scheme 1).
Important features of the disaccharide acceptor III include, (1)
the protecting group pattern on the fucose building block, that
MeO
OAc
O
OBn
OAc
HN
OBn
O
OBn
O
AcO
O
O
O
F3C
O
O
OAc
AcO
NHAc
Me
O
O
OBn
OPiv
OPiv
I
OBn
O
HO
MeO
OAc
O
OBn
OAc
OBn
O
O
O
AcO
NHAc
Me
O
CF3
Ph
O
O
O
OBn
F3C
HN
OPiv
OAc
AcO
N
OPiv
O
III
II
Scheme 1. Target molecule and building blocks.