Ferric chloride: A mild and versatile reagent for the formation of 1,6-anhydro glucopyranoses

Article abstract of DOI:10.1016/S0040-4039(03)00821-9

A novel method for the preparation of 1,6-anhydro glucopyranoses (mono- and disaccharides) utilizing anhydrous FeCl₃ as Lewis acid is described. Treatment of methyl 6-O-benzyl and 6-O-p-methoxybenzyl-α/β D-glucopyranosides derivatives with FeCl₃ in CH₂Cl₂ at room temperature and 40°C afforded 1,6-anhydro glucopyranosides in moderate to good yields, through a debenzylation and intramolecular glycosidation in one step. A plausible reaction pathway is proposed.

Full text of DOI:10.1016/S0040-4039(03)00821-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3931–3934
Ferric chloride: a mild and versatile reagent for the formation of
1,6-anhydro glucopyranoses
Pedro O. Miranda, Ignacio Brouard, Juan I. Padro´n* and Jaime Bermejo*
Instituto Universitario de Bio-Orga´nica ‘Antonio Gonza´lez’, Instituto de Productos Naturales y Agrobiolog´ıa del C.S.I.C.,
Avenida Astrof´ısico Fco Sa´nchez 3, 38206 La Laguna, Tenerife, Canary Islands, Spain
Received 30 December 2002; accepted 7 March 2003
Dedicated to the memory of Professor Antonio G. Gonza´lez
Abstract—A novel method for the preparation of 1,6-anhydro glucopyranoses (mono- and disaccharides) utilizing anhydrous
FeCl3 as Lewis acid is described. Treatment of methyl 6-O-benzyl and 6-O-p-methoxybenzyl-a/b
D-glucopyranosides derivatives
with FeCl3 in CH2Cl2 at room temperature and 40°C afforded 1,6-anhydro glucopyranosides in moderate to good yields, through
a debenzylation and intramolecular glycosidation in one step. A plausible reaction pathway is proposed. © 2003 Published by
Elsevier Science Ltd.
1,6-Anhydropyranoses have proven to be valuable syn-
thons for the preparation of biologically important and
structurally diverse natural products (e.g. rifamycin S,
indanomycin, zaragozic acid, etc.)1 as well as for
modified sugars.
cosides. It was obtained later from starch and cellulose
by pyrolitic vacuum distillations.3 It can be also
obtained by alkaline treatment of phenyl b-D-glucopy-
ranoside,4 of 6-O-tosyl glucose,5 or of many other
glucose derivatives. In a general way, 1,6-anhydropy-
ranoses can be obtained under basic conditions,6 acid
conditions7 and through intramolecular anomeric O-
alkylation.8
1,6-Anhydro-b-D-glucopyranose (levoglucosan) was
prepared first by Tanret2 as a product of the alkaline
decomposition of several naturally occurring glu-
1,6-Anhydroglucopyranoses are usually prepared by
installing a leaving group at 6-O or 1-O and its further
displacement in an intramolecular reaction (intramolec-
ular glycosidation or otherwise). The reaction of 6-O-
leaving group glucopyranoses is not
a
true
intramolecular glycosylation because the glycosidic
bond is not formed; instead, the 1-O/6-C bond is
formed by intramolecular nucleophilic substitution
(intramolecular anomeric O-alkylation).
Different leaving groups can be used such as tosyl,
trityl, acetyl, etc. at the 6-O-position and phenyl, acetyl,
and methyl at the 1-O-position. In all cases it is neces-
sary to introduce the leaving group except with the
O-methyl group, which is incorporated in the starting
material. Several precedents are reported in the litera-
ture using the O-methyl group in the a or b anomeric
configuration as leaving group.7b,9
Scheme 1. Strategy for the preparation of 1,6-anhydro-b-D-
glucopyranoside.
We present herein a method to obtain 1,6-anhydro
glucopyranosides using methyl 6-O-benzyl and 6-O-p-
methoxybenzyl-a/b D-glucopyranosides derivatives hav-
* Corresponding authors. Tel.: (34) 922 250766; fax: (34) 922 318571;
e-mail: jbermejo@ull.es
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00821-9

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P. O. Miranda et al. / Tetrahedron Letters 44 (2003) 3931–3934
We obtained levoglucosan triacetate (2,3,4-tri-O-acetyl-
1,6-anhydro-b- -glucopyranoside) from methyl 2,3,4-
tri-O-acetyl-6-O-benzyl a/b -glucopyranoside in
higher yield from b methyl than from a according to
the higher reactivity of b anomer15 (Table 1, entry 1).
The same behaviour was observed using the p-
methoxybenzyl group (Table 1, entries 2–5). The 1H
and 13C NMR spectra of our levoglucosan triacetate
matched with those obtained from the acetylation of
commercially available levoglucosan.
ing the methoxyl as a leaving group and anhydrous
FeCl3 as Lewis acid through a debenzylation and
intramolecular glycosidation in one step.10 This method
is effective in mono- and disaccharides, for which fewer
precedents exist.11
D
D
The monosaccharide models were prepared from a and
b-D-glucopyranosides through formation of benzyli-
dene acetal,12 acylation (benzoylation or acetylation),
regioselective reductive ring opening of benzylidene and
final acylation (Scheme 1).
Due to a precedent to form 1,6-anhydrofuranoses from
A modified Koenigs–Knorr method13 was chosen for
the syntheses of disaccharide models. Such disaccha-
rides were synthesized from the 2,3,4,6-tetrakis-O-
methyl 2,3,5-tri-O-benzoyl-6-O-benzyl b-D-galactofura-
noside using SnCl4 as Lewis acid,16 and the fact that
this Lewis acid gave the best yields described in the
literature, we decided to use it for a comparison with
anhydrous ferric chloride. In all cases the SnCl4 pro-
duced 1,6-anhydropyranoses in lower yields (ca. 30%)
than anhydrous FeCl3.
(p-bromobenzoyl)-a-
D
-glucopyranosyl bromide14 with
the corresponding
methyl
b-D-glucopyranoside
derivatives in the presence of silver trifluoromethanesul-
fonate.
The results of this intramolecular glycosidation in vari-
ous substrates under our conditions are summarized in
Table 1.
It is noteworthy to mention that the role of the benzyl
or p-methoxybenzyl group is essential to achieving the
reported transformation, since when the 6-O position is
Table 1. Synthesis of 1,6-anhydroglucopyranoses (mono- and disaccharides)

P. O. Miranda et al. / Tetrahedron Letters 44 (2003) 3931–3934
3933
Acknowledgements
unprotected or is a benzylidene group the reaction
did not occur (entry 7) and the corresponding triol
was obtained. Precedents exist where these groups are
able to stabilize a positive charge at the benzylic posi-
tion.17 With these results in mind we decided to use
other stabilizing positive charge groups, such as
methoxymethyl (MOM),18 to verify this fact. With the
MOM group (entry 8) the 1,6-anhydro was produced
in 54% yield supporting the possible formation of a
positive charge at the position commented above. A
nucleophilic attack of a chlorine at benzylic position
following by an intramolecular glycosidation trapping
the oxocarbenium intermediate is the basis of our ten-
tative explanation (Scheme 2).19
This work was supported in part by FEDER Grant
No. 1FD 1997-1831 (J.B.B.). I.B. gratefully acknowl-
edges the Direccio´n General de Universidades
e
Investigacio´n del Gobierno de Canarias (Spain) for a
fellowship. We are indebted to Dr. Jesu´s Trujillo
Va´zquez for his generous help with the disaccharide
models.
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Scheme 2.

3934
P. O. Miranda et al. / Tetrahedron Letters 44 (2003) 3931–3934
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