COMMUNICATION
Ethyl 2-acetamido-4,6-di-O-benzyl-2,3-N,O-carbonyl-2-deoxy-1-thio-
b-D-glycopyranoside as a versatile GlcNAc donor{
Mike Boysen,ab Emiliano Gemma,ac Martina Lahmanna and Stefan Oscarson*c
Received (in Cambridge, UK) 11th March 2005, Accepted 18th April 2005
First published as an Advance Article on the web 6th May 2005
DOI: 10.1039/b503651h
isocyanates from amines (Scheme 1).6 This procedure yielded the
The title donor, ethyl 2-acetamido-4,6-di-O-benzyl-2,3-
cyclic carbamate in almost quantitative yield and in excellent
purity even without chromatography. Since our interest was in
b-linked GlcNAc-containing target structures, the nitrogen was
acetylated and the resulting N-acetyl-oxazolidinone thioglycoside
donor 1 tried in coupling reactions with various acceptors. As
desired, the donor showed complete b-selectivity using NIS and a
catalytic amount of AgOTf as promoter system at ambient
temperature. Both with a steroid alcohol and with primary and
secondary carbohydrate acceptors the isolated yields of glycosyla-
tion product were excellent (Table 1). A bit surprisingly and by
serendipity, similar high yields of a-coupling product could be
reproducibly obtained using a larger quantity (0.4 equiv.) of
AgOTf in the couplings, perhaps due to in situ anomerisation.
Recently Crich et al.,7 when attempting reductive benzylidene
openings of a b-thioglycoside, also noted a tendency of these 2,3-
oxazolidinone derivatives to rapidly anomerise to the a-anomer.
Thus, depending on the amount of promoter added either the a- or
the b-glycoside can be efficiently produced in the coupling
reactions. In our hands (i.e. using 4,6-di-O-benzyl-2,3-
N,O-carbonyl-2-deoxy-1-thio-b-D-glycopyranoside, is shown
to be an excellent glycosyl donor giving immediate and efficient
access to variant GlcNAc-containing oligosaccharides.
Glucosamine is a most common monosaccharide residue in
natural polysaccharides of animal, plant and microbial origin.
Almost always it is present as its 2-acetamido derivative. Hence,
from a synthetic point of view, a 2-acetamido type of donor is
desirable to minimise protecting group manipulations.
Unfortunately, donors of this type suffer from drawbacks mainly
due to competing oxazoline formation. Obviously, the participat-
ing properties of the N-acetate are also a problem if an a-linkage is
desired. To circumvent these problems, various protective groups
for the amino group have been developed and used in glycosyl
donors.1 However, although effective during coupling reactions, all
these groups have to be removed and substituted with an acetyl
group at some time during the synthesis; reactions which are not
always high-yielding. An alternative approach is to substitute the
hydrogen on the acetamide group with another protective group,
thus inhibiting oxazoline formation. The N,N-diacetate, where the
removal of the second acetate is trivial and high-yielding, was tried
by Schmidt.2 However, the coupling yields with N,N-diacetates as
donors are generally not too high, and so this methodology is not
frequently used. We reasoned that other protective groups might
be a better choice, and became especially interested in cyclic groups
linking the 2-N and the 3-O of the donor moiety. Several attempts
to introduce TIPDS-, isopropylidene-, BDA- or diacid groups
were made without success. The formation of the trans-fused cyclic
carbamate, on the other hand, worked nicely. This protection
mode was described as a non-participating group as early as 1969
by Gross et al.,3 and Kerns et al.4 have reported on 2-N,3-
O-carbamates as glycosyl donors. A high a-selectivity was
obtained, when a carbamate protected thiophenylglycoside was
used together with phenylsulfenyl triflate as promoter at low
temperature. Also, recently Crich et al.5 utilized the carbamate not
in glycosyl donors, but in efficient glycosyl acceptors. The standard
conditions employed for the introduction of the carbamate group
are the use of 4-nitrophenyl chloroformate, producing a mixture of
the desired compound and uncyclised material that is converted to
the fully protected material in an additional step. We were able to
improve this sequence by adapting a protocol with triphosgene as
reagent which was originally described for the formation of
N,O-carbonyl-2-deoxy-1-thio-b-D-glucopyranoside
as
donor
together with cholesterol as acceptor and the NIS/AgOTf (cat.)
promoter system at ambient temperature) also the non-acetylated
donor afforded the b-product in contrast to the earlier published
work.4 Although surprisingly there are precedents in the literature
of glucosamine donors without a 2-participating group giving
b-selectivity in glycosylations.8,9
Another attractive aspect of the N-acetylated compounds was
found when deprotection was attempted. Normally cyclic
carbonates are quite base stable; however, when the
N-acetyloxazolidinone was treated with sodium methoxide under
mild conditions, the carbonate was removed smoothly to produce
the desired N-acetamido compound.
In conclusion, a most effective glucosamine donor 1 has been
developed, which contains a number of attractive features. As
shown by others, similar derivatives are most efficient acceptors for
glycosylation in the 4-position,5 making a smooth entry into
LacNAc derivatives. The donor gives very high yields of
{ Electronic supplementary information (ESI) available: experimental
b503651h/
Scheme 1 Preparation of ethyl 2-acetamido-4,6-di-O-benzyl-2,3-
N,O-carbonyl-2-deoxy-1-thio-b-D-glucopyranoside 1.
*s.oscarson@organ.su.se
3044 | Chem. Commun., 2005, 3044–3046
This journal is ß The Royal Society of Chemistry 2005
Boysen, Mike
