A facile synthesis of Cerny epoxides and selectively blocked derivatives of 2-azido-2-deoxy-β-D-glucopyranose

Article abstract of DOI:10.1016/S0040-4039(01)01354-5

1,6:2,3-Dianhydro-β-D-glucopyranose and its 3-alkylated derivatives were prepared from D-glucal in one pot with overall isolated yields of 60-70%, and these Cerny epoxides were further conveniently converted to selectively blocked 2-azido-2-deoxy-β-D-glucopyranose derivatives by azido opening of the epoxide ring.

Full text of DOI:10.1016/S0040-4039(01)01354-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6487–6489
A facile synthesis of Cerny epoxides and selectively blocked
derivatives of 2-azido-2-deoxy-b- -glucopyranose
D
Jie Xue and Zhongwu Guo*
Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Received 18 June 2001; accepted 19 July 2001
Abstract—1,6:2,3-Dianhydro-b-
D-glucopyranose and its 3-alkylated derivatives were prepared from D-glucal in one pot with
overall isolated yields of 60–70%, and these Cerny epoxides were further conveniently converted to selectively blocked
2-azido-2-deoxy-b-D-glucopyranose derivatives by azido opening of the epoxide ring. © 2001 Elsevier Science Ltd. All rights
reserved.
1,6:2,3-Dianhydro-b-
D
-glucopyranose (1, one of the
-glucopyran-
synthesis also started from D-glucal (Scheme 1), and the
two-step transformation gave an overall yield of 68%.12
However, it involves time-consuming and costly separa-
tions, e.g. longtime continuous extractions, and our
study indicated that ordinary work-up procedures
could only produce very low yields (20–30%), though
the reactions were quite clean. In addition, the differen-
tiation of 3- and 4-hydroxyls in 2 requires multiple
protection and deprotection operations.12
Cerny epoxides) and 2-azido-2-deoxy-b-
D
ose (2) are useful precursors for complex oligosaccha-
ride synthesis.1–3 Consequently, the preparation of 1
and 2, as well as their derivatives, is a significant
research focus in carbohydrate chemistry. However, all
the reported synthetic methods4–24 for them are labori-
ous, multistep processes that result in unsatisfactory
yields. For example, the most efficient synthesis for
Cerny epoxides, which was illustrated in the prepara-
tion
of
4-O-benzyl-1,6:2,3-dianhydro-b-D-gluco-
We report herein a one-pot synthesis of 1 and its
pyranose (3) from
D
-glucal (4), involved five separate
steps that offered an overall yield of only 13.5%.13
Furthermore, the synthesis is incompatible with other
protecting groups, such as allyl. For 2, an efficient
derivatives from readily available
D
-glucal (4), as well
as a two-step, efficient route to selectively blocked
derivatives of 2 (Scheme 1).
,
Scheme 1. Reagents and conditions: (a) i. (Bu3Sn)2O, MS 3 A, MeCN, refl., 3 h; ii. I2, MeCN, rt, 1.5 h; (b) NaN3, DMF, 120°C,
overnight; (c) NaHCO3, DMF, 120°C, 4 h; (d) BnBr or AllBr, NaH, DMF, rt, 2 h.
* Corresponding author. Tel.: +1 216 368-3736; fax: +1 216 368-3006; e-mail: zxg5@po.cwru.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01354-5

6488
J. Xue, Z. Guo / Tetrahedron Letters 42 (2001) 6487–6489
Previous studies12,14 indicated that
D
-glucal (4) could
under vacuum, and the resulting residue was directly
treated with DMF and water (9:1) containing 1.2 M
sodium bicarbonate at 120°C for 4 h. After the reac-
tion mixture was again condensed under vacuum, the
residue was dissolved in anhydrous DMF, and the
solution was stirred with benzyl or allyl bromide and
sodium hydride at room temperature for 2 h. All
these steps were monitored with TLC. Finally, routine
workup, which include extraction with ethyl acetate,
washing of the extracts with acidic, basic aqueous
solutions and brine, drying over sodium sulfate and
condensation followed by silica gel column chro-
matography, afforded 7 and 8 in excellent overall
yield (65–70%).
be stereospecifically transformed to 2 following tin-
mediated 1,6-iodocyclization and azido substitution
(Scheme 1). The latter involved a double-inversion
process through an epoxide intermediate 6, which was
supported by the isolation of epoxide 1 under certain
strict conditions.12 Based on these results, we antici-
−
pate that if the nucleophile N3 is eliminated from the
reaction, the transformations may terminate at the
stage of intramolecular cyclization to afford Cerny
epoxide 1, which may be developed into a convenient
synthetic method for these useful compounds. For
this purpose, we studied the reactions of 5 under neu-
tral conditions. TLC showed that heating 5 in DMF
and water (9:1) at 120°C gave a new product, but the
reaction was very slow, and after 4 hours of treat-
ment, only less than 10% conversion was observed.
Nevertheless, the product was proved to be the
expected 1.25 To improve the reaction rate, we then
investigated the influence of mild bases on this reac-
tion. Thus, the solutions of 5 in DMF and water
(9:1) containing 10% pyridine, 1.2 M sodium acetate
or 1.2 M sodium bicarbonate were respectively heated
at 120°C. It was disclosed that pyridine had little
influence on the reaction rate, but sodium acetate and
sodium bicarbonate could significantly accelerate the
reaction, and under these conditions, the cyclization
could finish within 4 hours. After usual work-up and
column chromatography, 1 was obtained in 60%
yield. Thereafter, 1 was readily converted to its ben-
zyl and allyl derivatives 7 and 825 by conventional
alkylations in excellent yields.
We further examined the possibility to transform
D-
glucal (4) to 2 in one pot. Thus, after -glucal (4)
D
was sequentially treated with bis(tributylstannyl)oxide
and iodine, and then removal of the solvent under
vacuum, the resulting residue was heated at 120°C
with excess (5 equiv.) sodium azide in DMF and
water. To our surprise, however, no azido compound
2 was formed from this reaction. Instead, the product
turned out to be 1. The result suggests that the nucle-
ophilic attack of azide on the epoxide of 1 was some-
how prohibited in the one-pot procedure, even
though purified 1 could be readily converted to 2
under the same condition. Two possible mechanisms
are proposed to explain this experimental outcome.
One is that the azide was deactivated through com-
plexation with the stannyl compounds used and/or
formed in the 1,6-iodocyclization of
D
-glucal (4). A
more plausible explanation is that the stannyl com-
pounds could form a chelating structure (11) with the
epoxide 1 and its steric hindrance inhibited the
approach of azide to the epoxide ring. In either way,
the sodium azide was only acting as a weak base to
assist the formation of epoxide.
We further investigated the transformations of 7 and
8 to the selectively blocked derivatives of 2. The ring
opening of 7 and 8 by sodium azide was readily
achieved in DMF and water (9:1) at 120°C to give 3
and 925 in excellent isolated yields (80%). The reac-
tions were very clean, but slower than the azido sub-
stitution of 5 under the same conditions, which may
result from the steric hindrance in 7 and 8. Com-
pared to 2, these products could be much more con-
veniently isolated via ordinary extraction and column
chromatography. Finally, modification of the 3-posi-
tions of 3 and 9 by other protecting groups can be
easily achieved by conventional methods to afford
corresponding derivatives, e.g. 10, that have 3-, 4-
and 6-hydroxyls differentiated and can be used in the
preparation of various complex oligosaccharides.
In conclusion, this work presents a new, one-pot and
highly efficient synthetic method for 1 and its deriva-
tives, as well as a facile route to selectively blocked
derivatives of 2, from commercially available
(4). Thus, 2-azido-2-deoxy-b- -glucopyranose deriva-
tives with differentiated 3- and 4-positions, such as 3
and 9, can be prepared from -glucal (4) in two sepa-
D-glucal
D
D
rate steps and more than 50% yields. Compounds 3
and 9 can be directly used as glycosyl acceptors in
the synthesis of oligosaccharides containing 1,3-linked
glucosamine residues. They can also be very easily
After the reaction conditions for effective conversion
of 4 to 1 and its alkyl derivatives were established,
we further examined the possibility of achieving these
transformations in one pot. A one-pot procedure
should be very useful for the synthesis of Cerny epox-
ide, as the intermediates 5 and 1 are soluble in water,
and thus, their extractions are very difficult. There-
converted to other derivatives of 2-azido-2-deoxy-b-
D-
glucopyranose and -glucosamine which are of wide
D
applications in carbohydrate chemistry.
Acknowledgements
fore, after
D
-glucal 4 was refluxed with 0.8 equiv. of
bis(tributylstannyl)oxide in acetonitrile for 3 h, the
reaction mixture was treated with 1.2 equiv. of iodine
at room temperature. Then, acetonitrile was removed
We are grateful for the financial support from a
Research Innovation Award (RI 0663) of the
Research Corporation.

J. Xue, Z. Guo / Tetrahedron Letters 42 (2001) 6487–6489
6489
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