Chapter 7
Dimethyl(methylthio)sulfonium Triflate as a Promoter for Creating Glycosidic Linkages in Oligosaccharide Synthesis 1
Fredrik Andersson, Winnie Birberg, Peter Fügedi , Per J. Garegg , Mina Nashed , and Åke Pilotti 2
3
Department of Organic Chemistry, Arrhenius Laboratory, University of Stockholm, S-106 91 Stockholm, Sweden Dimethyl(methylthio)sulfonium triflate has been evaluated as a promoter in glycoside synthesis employing thioglycosides as glycosyl donors. Those having a participating group in the 2-position produce 1,2 trans-glycosides with high stereoselec tivity. A nonparticipatmg group in the 2 position usually gives a preponderance of 1,2-cis-glycosides. The addition of tetraalkylammonium bromide to the latter reaction mixtures (nonparticipating benzyl group in the 2-position) transforms the reaction into a halide-assisted one with enhanced selectivity for 1,2-cis-glycosidation. These novel methods makes it possible to construct oligosaccharides with the 1-position protected as a stable alkylthio (arylthio) glycoside. When required, the thioglycoside is activated with the foregoing thiophilic reagent, and the oligosaccharide is joined to the desired acceptor. Oligosaccharides, substances
as
either
lipids
biological
interaction
biological
information.
of is
some that
reaction intact. paper of
at The
will
devising the
Their
a
covalently are in
which
one
problems
address
the
hydroxyl is
that
second
synthesis
has
they
have
one
act is to
strategy
group(s)
of
while
stereospecific of
been
these
to
in
synthesis
protective-group
desired
linked
involved
efficient
Two main
second
oligosaccharide
or
proteins
processes
importance. of
free
or
two
extensively
a as
such host
other of
carriers
therefore be that
dealt
of a
allows
leaving
the
reviewed
The
One
chemical others
glycosylation. topics.
matter
with.
This subject
(1-12).
Current address: Institute of Biochemistry, L. Kossuth University, P.O. Box 55, H-Debrecen, Hungary Address correspondence to this author. Current address: Faculty of Science, Chemistry Department, Alexandria University, Alexandria, Egypt
2
3
0097-6156/89/0386-0117$06.00/0 ° 1989 American Chemical Society
118
TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY In
order
hydroxyl
mandatory. glycoside
On
at
the
opposite
side
classical
at
a
use
time,
of is
a
small
those
is
than
that
(J_3).
glucan
to
our
original
the
problem
glycosyl raise
of
having
by
in
were and
use
in
?,:ν· molar
),
yield CHC.i^).
bromides and
smaller
,Fi- T e i . r a
1
557.
This
the route
w
not
e
r
n
i
into
In
n
t
o
a
permit
us
to
of
the
phytochemical
clearly
not
to
suitable
the
use
of
recently
following
key
participating
(b.)
by
large
a
quantities
taken
the
benzyhdene
α
use
methyl blocks.
methods:
benzoyl
regio-
triflate The
m.p. in
the
with
methyl
184- 1 8 5 ° , presence
and
(c)
in
synthesis
is
disaccharide
preferable
to
one
of
(27)
bromide
(1
4,6 -0- b e n z y l i d e n e -
QaJ
2 , ΓαΊ 0 involving
U.6,
(£
D
silver
(a)
groups
glycosylation
of (25i);
acetals
D-glucopyranosyl
condf>nsed
1,3--β-linked was
(J_3),
triflate-promoted
activated
0 benzoyl was
of
involving
dichloromethane of
the
megasperma.
(26).
O-giucopyranoside, m
of
defense
in
( 2 0 . 2 1 ).
carrying silver
illustrated
the
procedure
the
fragments;
cleavage
reactions
upon
in
the
was
therefore
laboratory
based
is
continued
glycosylation
this
was
the
equivalent)
1- t h i o - ( 3 t'MCI
in
Scheme
was
novel
the
are
to
Gram
synthesis
potential
encountered
This
did
in
and
they
tetrasaccharide 24"/..
for
original
Recourse a
a
above
required
thioglycosides
glycosylation outlined
step
our
reductive of
convert
this
donors
as
that
Phvtophthora
experimentation
2-position
making
selective the
that
glucosyl the
to
Extensive
synthesis
in
triggering
of
large
corresponds
heptasaccharide
Lonn
for
1
of
selectively
(14-20).
donors
this
developed
(24)
be
of
purpose.
of
may
the
performed
glycosyl
manipulations they
of
are
difficulties
-fact
synthesis
and
use
as
mould
thioglycosides
the
the
heptasaccharide for
most
reintroduced
in
monomer
disadvantage
severe
the
investigations,
The
use
to
by
yield
that
glycosyl
responsible
heptasaccharide
for
to
substi
large
conversion
infections
halide.
the
having
one
of
that
One
the
been
although
branched
fragment
soybean
Those
adding
synthesis
for
he
protecting-group
become
to The
is
block
lead
advantage
activated
this
a
recently
synthesis,
1.
for
halides
yields
oligosaccharide
Scheme
approach
C-2
synthesis
fragments.
may
have
than
the
requires
this
Their
normal
large
glycosyl
diminished
to
rather
in
normally
into
donors.
stable
is
preponderantly
participating
in
reason
on
it
Thioglycosides glycosyl
C- 2
ring.
hahdes.
lead
or
at
C-2 to
pyranose
glycosyl
a
strategy,
main
condensations; in
or
usually
having
manipulations
oligosaccharides
result
are
amino
1.2 - t r a n s -
a
nucleophile
furanose
advantageous
The
rather
further
the
of
participating
incoming
donors
block
highly
protecting-group on
efficient
an
substituent
synthesis
substituent
and
oligosaccharides.
approach
the
the
glycosyl
carrying
1,2- t r _ a n s - g l y c o s i d e s .
give The
an
of
C-2
glycoside
nonparticipatmg
hand,
directs
CIS-glycosides,
tuent
a
requires
nonparticipating
1.2
1,2-cis;
a
C- ? .
other
that
the The
a
make
usually
substituent from
to
function
triflate f6°
(c —
initial
1.1,
to
7. ANDERSSON ET AL.
Glycosidic Linkages in Oligosaccharide Synthesis
119
Η
η »
M
ι
Ο
ι
ο
a
S
en
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M
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7.
ANDERSSONETAL.
Glycosidic Linkages in Oligosaccharide Synthesis
121
122
TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY
protection glycosyl
by
position
2
m.p.
partial
acceptor. of
was
2
228-229°,
4
yield; [a J
1.2.3.4 L , a
and
+5°
1
-
converted
into
treatment
with
this
glycosyl
triflate
the
n
*~
*^'
The
also
The acceptor
of
group
activity
6 in
This to
a
give
e
3,
Π•• p o s i t i o n
m.p.
179
(28)
in
90"/.
glycosyl
then by
Condensation using
the
of
silver
m
5
837.
donor
for
181°,
and yield
acid.
compound
in
yield;
the
final
glycosyl
to
this
acceptor,
encountered,
namely,
derivatives of
expected
to
Attention
was
be
then
I.e.
more
of
it
reactions
with
turned
1.
had
and
phyto-
s y n t h e s i z e d (13.29).
the
utility
that,
the
quite
handling
leading
to
apart
of
methyl
may
be
2-hydroxy-
possibility
the
of
However.
disadvantages
of
glycosyl
unreactive
to
as
yield; l a
which
time
routine
in
the
" ^ hydrogenolysis
previously
other
and
with
by
found
the
group(s)
yield
oligosaccharides.
was
in
887.
937.
CHCI^).
with
triflate
demonstrates
synthesis
1.0,
in
5
in
retention
promoter,
severe
donor
material
byproducts,
therefore
7
methyl
heptasaccharide
involved
hydroxyl
give
using
promoter (c
treatment
deprotected
the
elimination
as
the
by to
(3- D - g l u c o as
-18°
heptasaccharide
laboratory
glycosylation
"a"*
glycosyl
again
clearly
block
hazard
yield;
the
benzoyl
triflate
removed
the
synthesis
0
methyl
837.
spectra,
the
in
health
methylation
h
acetonitrile
of
was
identical
for
work
as
t
was
protected
n.m.r.
foregoing
thioglycosides
glycal
in
dichloromethane,
in
elicitor
triflate
product
quantitative acetic
key
s
in
condensation
the
the
dichloromethane
in the
1,2,3,4- t e t r a -
7
rotation,
other
a
final
debenzoylation
from
the
in
the
botane —
dichloromethane
using
6
dithiocarbonate
optical
in
in
precursor
with
5
promoter, gave the ο 20 ( ç 1.2, CHCI^).
The
near
the w
the
tetrasaccharide
hydrazine
in
5
dichloromethane
chloroacetyl
and
l
in
in
follows:
in
afforded
3^
was
Condensation p y r a nose
in
4
h
(25)
group
bromide
T
with
D g l u c o p y r anose,
yielded
C H ( : : l
ot
).
group
group
chloroacetylated
bromide
with
2-hydroxyl
).
was
hydrogen
It
as
),
α
CHCI
chloride
benzoy!~(3
CHCI
promoter
condensation. obtained
7
· ·
}
the
hydroxyl
Treatment
1.1.
hydroxyl
CHO
1.2.
bromide
as 6
[)
free
Tetra- 0
( c n
(c
aluminum a
(c
of
free
benzoylated. f15°
having
d
remaining
[a]
trimethylamine afforded
benzoylation
The
competing
acceptor,
glycosyl
more-specifically
donors. thiophilic
reagents. Regiospecific use
of
a
"soft"
fluoroboronate it
has
was
many
indeed
yields most was
in
reacts
in
in
in
(37)
a
sulfur
rapidly
with (32,33).
activating
were
by
was
glycosylation
alkyl
moderate.
glycosylation replaced
(DMTST)
of
center
should
require
Dimethyl(methylthio)sulfonium
applications
glycosylation
therefore
promoter
(.30)
acid.
synthetic effective
useful
triflate
activation Lewis
reactions triflate.
thereby reactions.
dimethyl In
sulfide
pilot
(3J_)
Triflates
and
experiments,
1 -thioglycosides,
(2_2 -24,,
the
tetra
have
3j4-3jB)
but
been and
the
it the
found anion
Dimethyl (methyl thio)sul fonium found
to
be
a
most
efficient
7.
The
result
usefulness
of
reactions 2
Glycosidic Linkages in Oligosaccharide Synthesis
ANDERSSONETAL.
and
acceptors
(1.2
a
is
the
shown
Yields Scheme
participating
an
gives
of
product.
The
this
two
to
human
colonic
and
to
condensed the
containing from
bromine
to
give with
moderate
yields
foregoing
product
27
In
26
the
of
benzyl
illustrates of
this
the
mixture.
for
studies
34
as
ones
for
by
trisaccharide fucolipid the
in
other
fragment accumulating
thioglycoside
(Scheme
3). a
the workers
In
25
this
complicated
of
the
1,2-elimination
was
treated
which
a-bromide, of
silver
was
with
was
triflate.
obtained.
an
in
was
then
Only
However,
acceptable
yield
under
of
the
using
was
(1
in
the
means
the
(28)
of
DMTST
in
was
a
non-
was
attempted.
promoter the
with
glycosyl
generated
pentasaccharide
phosphate-specific
an
having
the
group
simultaneous
29)
2-position
triester
experiment promoter
the
added
at
donor
compatibility
thioglycosyl in
involving (compound
axial
example,
to
and
room of
raises for
a
with Thus
mixture
the in
the
donors
2-position.
equivalent)
sieves
glycosyl
the
6
4),
groups,
in
provides
situ
a
receptors
in
model
and
the
(40).
general
group
by
a
mannose
a
(j43)
separated
existing
25
(Scheme
deprotected
equivalents)
molecular
of
quantities
gave
particular The
mannosylation
equivalents)
and
use
experiment,
DMTST
phosphoric
fibroblasts
benzyl)
(1.2
a
of
by
-glycosides
(41 )
The
efficient
illustrated
produced
27
group
presence
as
a
glycosyl
glycosylation than
a
26
presence
involving
synthesis
The
a in
product
hydroxyl
the
DMTST
an
syntheses
of
unit
triflate
example
two
The
of
the
group.
further
acceptor
the
the
CHC.I^)
D-giucosylated
This
adenocarcinoma, the
in
other
participating
uptake
is
synthesis
conditions,
a- m a n n o s y l a t i o n
In
method
corresponding
of
m
findings,
(39).
glycosylation
donor.
high.
unpublished
another
the
( £a ]^
of
acetyl
in
room
glycosides.
methyl
In
at
affords
DMTST
thioglycoside
previous
advantageous
considerable
25.
condensed
a
liver
of
an
the
equivalent)
2-position
position
repeating
with
(1
sieves
with
in
glycosyl
the
compounds
does
more
of
In
the
the
experiments,
of
2 amino-2-deoxy-(3
the
the
use
product
the
of
pure
2
groups
these
acceptor
uniformly
1.2-trans
laboratory.
mixture
the
examples
In
mixture
molecular
than
in
hydroxyl
hexopyranoside
a
in
testing
1.2- t r a n s - g t y c o s y l a t i o n
accordance
group
potentially
corresponding
be
In
are
usefulness
instance,
4Â
protected
of
experiments
in
(.38).
glycosyl
yields
yields
is
following m
a
2 to
isolated,
2.
group
synthesis The
of
higher
synthesis
the
the
benzoyl
N-phthaloyl
procedure
Scheme added
and
model
suitable
containing
temperature. in
of
in
are
of
promoter
glycosylation of
was
equivalents)
dichloromethane
donor
a
6-positions
equivalents)
given
number as
involving
,3-,4
(4 — 5
of
DMTST
glycosyl
of
the
question
synthesis a
column
the
nonparticipating DMTST
the
thioglycoside
acceptors
Yields
chromatography
10
(4 — 5
(42),
containing of
isolated on
silica
use
1,2-cis-
the
dichloromethane
temperature.
of
of
(such
molar donor 16
31
(20).
4Â product, gel,
are
123
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ο
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ι
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