A practical large-scale access to 1,6-anhydro-β-D-hexopyranoses by a solid-supported solvent-free microwave-assisted procedure

Article abstract of DOI:10.1055/s-2003-39168

Microwave irradiation of 6-O-tosyl or 2,6-di-O-tosyl peracetylated hexopyranoses absorbed on basic alumina in a dry medium afforded the corresponding 1,6-anhydro-β-D-hexopyranoses. A direct access to 1,6:3,4-dianhydro-β-D-altropyranose (16) from D-glucose is also described.

Full text of DOI:10.1055/s-2003-39168

SHORT PAPER
1015
A Practical Large-Scale Access to 1,6-Anhydro- -D-hexopyranoses by a Solid-
Supported Solvent-Free Microwave-Assisted Procedure
Large-Scale
A
cces
i
s
to 1,6
n
-Anhydro-
β
c
-
D
-
hexopyr
e
s
nt Bailliez, Renata M. de Figueiredo, Alain Olesker, Jeannine Cleophax*
Institut de Chimie des Substances Naturelles du C.N.R.S, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Fax +33(1)69077247; E-mail: Jeannine.Cleophax@icsn.cnrs-gif.fr
Received 28 January 2003; revised 28 February 2003
starting materials. In spite of improvements accomplished
Abstract: Microwave irradiation of 6-O-tosyl or 2,6-di-O-tosyl
peracetylated hexopyranoses absorbed on basic alumina in a dry
medium afforded the corresponding 1,6-anhydro-β-D-hexopyra-
noses. A direct access to 1,6:3,4-dianhydro-β-D-altropyranose (16)
from D-glucose is also described.
in recent years by the work of Fraser-Reid,8e Nagarajan,10d
and Descotes,8d a ready access to these 1,6-anhydrosugars
is still of considerable interest.
In this paper, a mild, rapid, and solvent-free procedure for
the preparation of 1,6-anhydro-β-D-hexopyranoses from
mono- and ditosylates of D-pyranoses, absorbed on basic
alumina, is described by classical thermal reaction (heat-
ing in an oil-bath) or irradiation under microwave.
Key words: anhydrosugars, solid support synthesis, solvent-free
reactions, microwave activation, ring closure
Among the carbohydrate derivatives, 1,6-anhydro-β-D-
glycopyranoses are valuable intermediates in the synthe-
sis of a large variety of biologically important natural
products and their analogues.1 They have been known
since a long time,2 especially the 1,6-anhydro-β-D-glu-
copyranose (levoglucosan), and used as synthons in the
preparation of rare sugars,3 diverse non-carbohydrate
products,4 and complex oligosaccharides.5 Their bicyclic
framework involves a 1C4 locked conformation of the py-
ranose ring, where the 2,3,4-stereocentres are in opposite
orientation with respect to the corresponding classical
pyranosides. The reactivity (stereo- and regioselectivity)
of the different sites of the sugar is therefore modified and
this has been widely exploited, in particular by Cerny et
al.6 These derivatives have been obtained by two main
pathways: 1) pyrolysis under vacuum or recently, using
microwave irradiation of polysaccharides as starches and
celluloses;2b,7 and 2) by intramolecular cyclization of gly-
copyranoses with a good leaving group at either the
primary8 or the anomeric9 position, or by treatment of pro-
tected glucopyranoses with various Lewis acids.10
In the literature, hydrolysis of various aliphatic and aro-
matic esters absorbed on neutral alumina, under micro-
wave irradiation, has already been described.11 The
tertiary esters are, in general, more easily hydrolyzed than
the secondary or primary esters, whereas for methyl
2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranoside, only the 6
position was deprotected and no reaction was observed
under classical heating. In the cases of peracetylated alkyl
glycopyranosides absorbed on alumina, deacetylation did
not occur, even by microwave irradiation.11c
We anticipated that on the acetyl 6-O-tosyl-2,3,4-tri-O-
acetyl-α/β-D-glucopyranose (2), the most labile anomeric
acetate could be probably more easily removed, followed
by a ready 1,6-oxirane formation. And when 2, readily
prepared by selective tosylation at C-6 of D-glucose (1)
followed by peracetylation,12 was absorbed on various
alumina and heated, in dry media by microwave irradia-
tion, 1,6-anhydro-2,3,4-tri-O-acetyl-β-D-glucose (3)8d,9c
was formed with a small amount of partially random
deacetylated levoglucosan. Our hypothesis was con-
firmed since, in spite of some non-selective partial deacyl-
ation, no 3,6-anhydroglucopyranose derivatives were
In the synthesis of 1,6-anhydrosugars from monosaccha-
rides, 6-O-sulfonylated pyranoses were used most often as
OH
OTs
O
O
TsCl, pyridine
Alumina, M.W.
Ac2O, AcOK
OAc
O
O
OH
1
HO
HO
AcO
AcO
OH
Ac2O, Pyridine
OAc
OAc
OAc OAc
2
3 : 80 %
OH
OH
OH
O
HO
HO
OH
O
O
HO
HO
HO
HO
OH
OH
OH
OH
4
5
6
Scheme 1
Synthesis 2003, No. 7, Print: 20 05 2003.
Art Id.1437-210X,E;2003,0,07,1015,1017,ftx,en;Z01503SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1016
V. Bailliez et al.
SHORT PAPER
detected. The crude mixture was then eluted and reacetyl- 1,6:2,3-dianhydro-β-D-mannopyranose and the more sta-
ated giving the 2,3,4-tri-O-acetyl-1,6-anhydro-β-D-glu- ble 1,6:3,4-dianhydro-β-D-altropyranose (16) could be
copyranose (3) (Scheme 1).
formed selectively. These two derivatives have been
largely used in the synthesis of aminodeoxy sugars.5d,18
With basic alumina (ICN, Brockmann Act. II–III), a good
conversion (94%) was obtained by irradiation of 2 (ab- With the objective of the selective preparation of the altro-
sorbed on alumina, 1.5 g/1 g of 2) under microwaves with epoxide 16, we have modified the workup after irradia-
a low power (300 W) at 110 °C over 7 minutes. After elu- tion. The crude eluted mixture was treated with NaOMe in
tion of the crude material and peracetylation of the mix- MeOH–CH2Cl2 solution, giving exclusively 16 (52%
ture, the 2,3,4-tri-O-acetyllevoglucosan (3) was isolated from 13) (Scheme 2) in 4 steps from D-glucose (1).
by crystallization (70% for 1 to 3 g of starting material,
Alumina, M.W.
O
80% for 6 g). On a 1 to 6 g scale, the same process (same
temperature, same time) using oil-bath heating gave near-
ly the same results (80% for 1 g, 85% for 6 g). As has been
already observed, under microwave irradiation,13 the
method has been successfully extended up to a 38 g scale,
always in 7 minutes, without loss of efficiency (85%
yield).
OTs
O
O
AcO
AcO
OH
OAc
OTs
O
MeONa, MeOH
16 : 52%
13
Scheme 2
In conclusion, we have developed an easy solvent-free
procedure, under microwave irradiation, for the prepara-
tion of important 1,6-anhydroglycopyranose synthons in
three or four steps from hexopyranoses. This method us-
ing a tosylate absorbed on alumina is simple, rapid, and
inexpensive and can be extended to a large-scale.
Our method has been applied to other hexoses as well: 2-
deoxy-D-glucose (4), D-mannose (5), and D-galactose (6).
The acetyl 2-deoxy-3,4-di-O-acetyl-6-O-tosyl-α/β-D-glu-
copyranose (7),14 the acetyl 2,3,4-tri-O-acetyl-6-O-tosyl-
α/β-D-mannopyranose (8)8b and the galactose derivative
98d,15 were readily prepared in few steps by known proce-
dures. They were converted to the corresponding 1,6-an-
hydro-β-D-derivatives 10,16 11,8d and 128d under the same
conditions (Table 1). The relatively low yield of the 2-
deoxy derivative 10 may be explained by the instability of
that series.
1,6-Anhydrosugars 3, 10–12; General Procedure
To the corresponding tosylate 2, 7, 8, or 9 dissolved in CH2Cl2 (10
mL for 10 mmol), was added basic alumina (ICN, Brockmann Act.
II–III, 15 g for 1 g of tosylate). After evaporation under vacuum, the
resulting powder was dried under 0.1 mm Hg and transferred to the
reactor. This powder was irradiated under microwave (P 300 W, t =
7 min, T = max 110 °C), and the reaction mixture was eluted
through a pad of Celite with a mixture of EtOAc–EtOH (9:1). The
residue, after evaporation, was peracetylated with Ac2O (10 equiv)
and KOAc (1.1 equiv) for 15–20 min at 100 °C. The mixture was
diluted with ice-water and extracted with CH2Cl2. The organic
phase was dried (MgSO4) and concentrated to dryness. The residue
was recrystallized to furnish the corresponding per-O-acetyl-1,6-
anhydro-β-D-glycopyranoses 3, 10, 11 or 12, respectively. 1H NMR
spectra recorded were identical with those described in precedent
syntheses. 13C NMR spectra have been reported by Perlin and col-
laborators,19 except for 10.
Table 1 1,6-Anhydrosugars Prepared
Starting Material
Product
Yield (%)
45
64
86
2,3,4-Tri-O-acetyl-1,6-anhydro- -D-glucopyranose (3)
Mp 107–109 °C (EtOH); [α]D –60.0 (c = 1, CHCl3) {Lit.8d mp 108–
109 °C (EtOH); [α]D –62.0 (c = 1, CHCl3)}.
60
3,4-Di-O-acetyl-1,6-anhydro-2-deoxy- -D-arabinohexopyra-
nose (10)
[α]D –109.0 (c = 1, CHCl3) {Lit.16 [α]D –122.0 (c = 1.26, CHCl3)}.
13C NMR (CDCl3): δ = 170.2 (2 CH3CO), 99.7 (C-1), 73.3 (C-5),
70.8 (C-4), 67.2 (C-3), 64.8 (C-6), 33.1 (C-2), 21.1–20.9 (2
CH3CO).
In the same way, irradiation of the acetyl 3,4-di-O-acetyl-
2,6-di-O-tosyl-α/β-D-glucopyranose (13),12b absorbed on
alumina with microwaves followed by reacetylation af-
forded the 3,4-di-O-acetyl-1,6-anhydro-2-O-tosyl-β-D-
glucopyranose (14) in 60% yield with a low (about 5%)
proportion of the 1,6:2,3-dianhydro-4-O-acetyl-β-D-man-
nopyranose (15). Cerny and co-workers9b,17 have shown
that from 14, according to experimental conditions, the
2,3,4-Tri-O-acetyl-1,6-anhydro- -D-mannopyranose (11)
Mp 88–90 °C (EtOH); [α]D –123.0 (c = 1.2, CHCl3) {Lit.8d mp 89–
90 °C (EtOH); [α]D –123.5 (c = 1, CHCl3)}.
2,3,4-Tri-O-acetyl-1,6-anhydro- -D-galactopyranose (12)
Mp 77–79 °C (EtOH–Et2O); [α]D –5.0 (c = 1, CHCl3) {Lit.8d mp
77–78 °C (EtOH–Et2O); [α]D –4.3 (c = 1, CHCl3)}.
Synthesis 2003, No. 7, 1015–1017 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Large-Scale Access to 1,6-Anhydro-β-D-hexopyranoses
Goto, T. Tetrahedron Lett. 1987, 28, 6485.
1017
1,6:2,3- or 1,6:3,4-Dianhydrosugars 15 and 16; General Proce-
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Isolation of 3,4-Di-O-acetyl-1,6-anhydro-2-O-tosyl-β-D-glycopyr-
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(15):
To the ditosylate 13 dissolved in CH2Cl2 (10 mL for 10 mmol) was
added basic alumina (ICN, Brockmann Act. II–III, 15 g for 1 g of
13). After evaporation and drying under high vacuum (1 mm Hg),
the powder was transferred to the reactor and irradiatedfor 6 min un-
der microwaves (P 300 W, T = max 110 °C). The mixture was elut-
ed through a pad of Celite with a mixture of EtOAc–EtOH (9:1) and
concentrated to dryness. The residue was peracetylated with Ac2O
(10 equiv) and KOAc (1.1 equiv) for 15–20 min at 100 °C. After ex-
traction and separation of the reaction product on silica gel, the de-
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1
rivatives 14 and 15 were identified by comparison of their H and
13C NMR spectra20 (except the 13C NMR spectrum of 14, which is
given below).
14
Mp 115–116 °C (EtOH); [α]D –43.0 (c = 1, CHCl3) {Lit.17b mp
116–117 °C (EtOH); [α]D –44.0 (c = 1.5, CHCl3)}.
13C NMR (CDCl3): δ = 170.1–168.6 (2 CH3CO), 133.2–128.0 (4-
CH3C6H4SO2), 99.6 (C-1), 74.7, 73.9 (C-2, C-5), 70.4 (C-4), 69.3
(C-3), 65.8 (C-6), 21.7 (4-CH3C6H4SO2), 20.9–20.7 (2 CH3CO).
1,6:3,4-Dianhydro-β-D-altropyranose (16)
The residue from the above reaction workup was dissolved in
CH2Cl2 (8 mL). To this solution was gradually added a solution of
NaOMe (80 mg) in absolute MeOH (8 mL). After stirring for 12 h,
the solution was diluted with CH2Cl2 (80 mL), filtered through a pad
of silica gel and eluted with CH2Cl2–MeOH (9:1). The filtrate was
concentrated under vacuum and the derivative 16 was isolated by
crystallization (yield: 62% from 13) and identified by its 1H and 13
C
NMR spectra.20 By the same procedure, but with classical heating,
the yield was 55%.
16
Mp 160–162 °C (EtOH); [α]D –118.0 (c = 1.1, CHCl3) {Lit.17b mp
160–162 °C; [α]D –120.0 (c = 0.6, MeOH).
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Synthesis 2003, No. 7, 1015–1017 ISSN 0039-7881 © Thieme Stuttgart · New York