Due to its low reactivity as a donor, harsh reaction condi-
tions2,11 using strong Lewis acids (such as TMSOTf) or
strong Brønsted acids (such as p-TsOH) as well as elevated
temperature are required for glycosylations. Although some
improvements were achieved using 1,2-dichloroethane as a
use of a furanose oxazoline (6) as a key intermediate (Scheme
2). Compound 6 can be conveniently prepared on a large
scale in good yield (77%) from N-acetylglucosamine with
dry acetone using anhydrous FeCl3 as a catalyst.21 The crude
furanose oxazoline 6 is pure enough for use in the next step
without the need for chromatography. The literature reports
that the furanose oxazoline 6 can be converted to the methyl
â-furanoside 7 when reacted with dry methanol (as a solvent)
for 3 h at pH 3∼4 using p-TsOH as a catalyst.22 However,
our experience indicates that under the reported conditions,
the furanoside 7 forms initially and then slowly converts to
a new spot on TLC identified as the pure methyl 2-aceta-
mido-2-deoxy-â-D-glucopyranoside (8). The rate for conver-
sion of 7 into 8 accelerates if the amount of p-TsOH is
increased. For example, if 0.5 equiv of p-TsOH is used,
compound 6 can be converted to compound 8 within 1 h.
The 5,6-O-isopropylidene group is apparently transacetalized
in-situ with methanol. To stop the transformation at the stage
of furanoside 7, the acidity of the reaction has to be carefully
controlled.
16
solvent13 and FeCl3,14 CuCl2,15 or Yb(OTf)3 as catalysts,
elevated temperature is still required. Recently, Boysen et
al.17 designed a bicyclic thioglycoside as a versatile GlcNAc
donor, and Mohan et al.18 employed microwave as an
efficient way of heating to convert a pyranose oxazoline
derivative to some N-acetyllactosamine glycosides.
Scheme 1. Conventional Routes to GlcNAc â-Glycosides 4
Scheme 2. New Route for Synthesis of â-Glycosides 8
The chloride (2) is prepared by reacting N-acetylglu-
cosamine (1) with neat acetyl chloride19 (Scheme 1).
Although this reaction works reasonably well, it is not a clean
reaction.20 Together with the desired chloride (2), frequently
pentaacetate (3) remains, and recrystallization does not
remove this side-product. Consequently, the impurity (3) has
to be removed by chromatography; alternatively, the crude
chloride (2) is used for glycosylation, and the impurity (3)
has to be removed at the next step. However, chromatography
of polar acetamido intermediates is troublesome, because they
have poor solubility in common organic solvents and streak
badly. Consequently, the preparation of â-glucopyranosides
of GlcNAc with simple aglycones by conventional routes
that start from N-acetylglucosamine is not a straightforward
task. In this study, we report a simple and general method
for the preparation of 2-acetamido-2-deoxy-D-glucopyrano-
sides from a furanose oxazoline derivative.
The direct transformation of the furanose 6 to pyranoside
8 proceeds equally well on a small or large scale. When
performed on a 20 gram scale, compound 8 was obtained in
quantitative yield by simply evaporating the reaction mixture
after neutralization with Et3N, followed by multiple washing
of the residue with CH2Cl2 in order to remove p-TsOH salts.
Furthermore, compound 6 could be prepared from 1 on a
large scale without the need for chromatography. This now
provides a viable two-step procedure to prepare compound
8 that is otherwise troublesome to make using conventional
approaches. A literature search revealed that there are no
other instances of the direct conversion of a furanosyl
oxazoline to 2-acetamido-2-deoxy-â-D-glucopyranosides.
However, Gigg’s group have reported a similar transforma-
tion using a furanose phenyloxazoline derivative to prepare,
in a one-pot reaction, the 4,6-O-benylidene acetal of two
â-glycosides of GlcNBz.23
When planning the synthesis of a bioactive phytosphin-
gosine and glycosylceramide derivatives, we envisioned the
(13) Warren, C. D.; Jeanloz, R. W. Carbohydr. Res. 1977, 53, 67-84.
(14) (a) Kiso, M.; Anderson, L. Carbohydr. Res. 1979, 72, C12-C14.
(b) Kiso, M.; Anderson, L. Carbohydr. Res. 1979, 72, C15-C17.
(15) Wittmann, V.; Lennartz, D. Eur. J. Org. Chem. 2002, 1363-1367.
(16) Crasto, C. F.; Jones, G. B. Tetrahedron Lett. 2004, 45, 4891-4894.
(17) Boysen, M.; Gemma, E.; Lahmann, M.; Oscarson, S. Chem.
Commun. 2005, 3044.
(18) Mohan, H.; Gemma, E.; Ruda, K.; Oscarson, S. Synlett 2003, 1255-
1256.
(19) Horton, D. Methods Carbohydr. Chem. 1972, 6, 282-285.
(20) (a) Heidlas, J. E.; Lees, W. J.; Pale, P.; Whitesides, G. M. J. Org.
Chem. 1992, 57, 146-151. (b) Macmillan, D.; Daines, A. M.; Bayrhuber,
M.; Flitsch, S. Org. Lett. 2002, 4, 1467-1470. (c) Bamford, M. J.; Pichel,
J. C.; Husman, W.; Patel, B.; Storer, R.; Weir, N. G.; J. Chem. Soc., Perkin
Trans. 1 1995, 1181-1187.
(21) Mack, H.; Basabe, J. V.; Brossmer, R. Carbohydr. Res. 1988, 175,
311-316.
(22) Furneaux, R. H.; Gainsford, G. J.; Lynch, G. P.; Yorke, S. C.;
Tetrahedron 1993, 42, 9605-9612.
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Org. Lett., Vol. 7, No. 18, 2005