Improved synthesis of 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-α-D- mannopyranose

Article abstract of DOI:10.1016/j.carres.2005.09.008

By improved (anhydrous) work-up conditions of a triflate displacement reaction, the yield in the preparation of the versatile synthetic intermediate 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-α-D-mannopyranose has been significantly enhanced. This important precursor is now available in three efficient steps from D-glucose.

Full text of DOI:10.1016/j.carres.2005.09.008

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 2675–2676
Note
Improved synthesis of 1,3,4,6-tetra-O-acetyl-
2-azido-2-deoxy-a-D-mannopyranose
*
˚
´
Peter Teodorovic, Rikard Slattegard and Stefan Oscarson
¨
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
Received 2 June 2005; received in revised form 23 August 2005; accepted 7 September 2005
Available online 23 September 2005
Abstract—By improved (anhydrous) work-up conditions of a triflate displacement reaction, the yield in the preparation of the ver-
satile synthetic intermediate 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-a-D-mannopyranose has been significantly enhanced. This
important precursor is now available in three efficient steps from D-glucose.
Ó 2005 Elsevier Ltd. All rights reserved.
Keywords: 2-Azido-2-deoxy-mannose; Triflate displacement; Anhydrous work-up; Pre-dried silica gel
Mannosamine, that is, 2-amino-2-deoxy-mannose, is a
motif in bacterial polysaccharides, that is usually found
as the acetamido derivative.1,2 This is a precursor in the
biosynthesis of N-acetyl-neuraminic acid3 and has been
recognized as a strong ligand for the natural killer cell
activating protein NKR-P1.4 Thus, mannosamine or
analogues thereof are important synthetic precursors
for various biologically relevant oligosaccharides.
However, there is no native glycan built from ManNAc
residues and hence no cheap commercial source of man-
nosamine. As a synthetic intermediate, the correspond-
ing azido derivative has been used extensively. This is
most often synthesized either by an azidonitration reac-
tion on glucal derivatives5 or by displacement reactions
at C-2 on glucose derivatives,6 but so far there has been
no optimal pathway for the simple formation of 2-azido-
2-deoxy-mannose in large scale, the azidonitration reac-
tion being limited by the low mannose/glucose ratio
obtained. An obvious way would be displacement by
azide ion of the 2-O-triflate derivative of 1,3,4,6-tetra-
O-acetyl-a-D-glucopyranose, a crystalline compound
easily obtained on a large scale in a one-pot reaction
from D-glucose,7 but so far this reaction has given very
low yield, with a recently published one of 7%.8 We now
show that with a careful work-up procedure following
the displacement reaction, the yield can be raised to an
acceptable 56% (over two steps).
Forming the 2-O-triflate of 1 using standard condi-
tions7,9 was no problem and the intermediate 2 was
formed in an almost quantitative amount (Scheme 1).
When attempting the displacement reaction using so-
dium azide in DMF at elevated temperature, the desired
product was also formed in very high yield according
to TLC. No other major spots were detected, but
the product decomposed considerably during work-up.
However, once purified, the 2-azido compound 3 was
reasonably stable. No major side product could be iso-
lated, making it difficult to speculate on the reasons
for the instability and the breakdown mechanism. How-
ever, the same reaction starting from the mannose deriv-
ative 1,3,4,6-tetra-O-acetyl-b-D-mannopyranose, to give
the corresponding 2-azido glucose compound, is not
beset by similar decomposition during work-up, but
the product could be isolated in a high 84% yield.9 Many
(TfO)2O
OAc
O
NaN3
DMF
pyridine
CH2Cl2
OAc
O
N3
O
AcO
AcO
AcO
AcO
AcO
AcO
AcO
58%
97%
HO
OAc
OAc
TfO
OAc
1
2
3
*
Corresponding author. Tel.: +46 8 16 24 80; fax: +46 8 15 49 08;
e-mail: s.oscarson@organ.su.se
Scheme 1.
0008-6215/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.09.008

2676
P. Teodorovic´ et al. / Carbohydrate Research 340 (2005) 2675–2676
various work-up methodologies were tried without
much improvement, but slightly better yields were ob-
tained when non-aqueous conditions were employed.
Thus, efforts were made to perform the work-up exclud-
ing water to as high degree as possible. Dried solvents
were used and, perhaps most importantly, the silica gel
used for chromatography was dried extensively before
use. When these precautions and conditions were ap-
plied to the work-up procedure, much less decomposi-
tion was observed, and the product 3 could be isolated
in about 60% yield. Even when performing the reaction
on a larger scale, a 60% yield was reproducibly obtained.
Although there might be room for further improvements
in the work-up procedure (as indicated by TLC),
perhaps based on investigations of the decomposition
mechanism, still, with these simple work-up alterations
and precautions discussed, the yield in the reaction is
now quite acceptable and the important synthetic build-
ing block 3 is easily available in large amounts from
D-glucose in an efficient three-step synthesis including
only one chromatographic purification step.
30 min at ꢀ20 °C, then diluted with CH2Cl2 and washed
with water, saturated NaHCO3 and water. Filtration
through a silica plug followed by concentration gave 2,
which can be used in the subsequent reaction without
further purification. To obtain a yield, the residue
was put on to a short silica gel column and eluted
(toluene–EtOAc 10:1!1:1) to yield 2 (1.33 g, 2.77 mmol,
97%). [a]D +101 (c 1.0, CHCl3), lit.8: +99.6. NMR data
were in agreement with those reported earlier.8
1.3. 1,3,4,6-Tetra-O-acetyl-2-azido-2-deoxy-a-D-manno-
pyranose (3)
A mixture of compound 2 (1.578 g, 3.29 mmol) and
NaN3 (408 mg, 6.28 mmol) in dry DMF (20 mL) was
stirred under argon at 60 °C for 30 min. Most of the
DMF was then removed under reduced pressure and
the residue transferred to a dried glass column contain-
ing a slurry of pre-heated silica in dry toluene. The
remaining DMF was eluted with dry toluene and then
a gradient of toluene and dry EtOAc was used to elute
product 3 (707 mg, 1.90 mmol, 58%). NMR data were
in agreement with those reported earlier.6
1. Experimental
1.1. General
Acknowledgements
TLC was carried out on Merck precoated 60 F254 plates
using 8% H2SO4 for visualization. Column chromatog-
raphy was performed on silica gel (0.040–0.063 mm,
Amicon), which was first poured into a glass vessel
and heated over an open flame until all water had been
boiled away (approx. 15 min for 220 g silica gel) and
then put in an oven at 150 °C overnight. The silica gel
was then allowed to cool under an argon atmosphere be-
fore being used. NMR spectra were recorded in CDCl3
(internal Me4Si, d = 0.00) at 25 °C on a Varian
300 MHz or 400 MHz instrument. Organic solutions
were concentrated at 40 °C under reduced pressure.
We are grateful for financial support from the Swedish
Research Council.
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