A convenient new route to protected and free 2,6-anhydro-d-glycero-d-gulo- heptoses (1-formyl-β-D-glucopyranosides)

Article abstract of DOI:10.1016/j.tetlet.2004.08.034

A new and efficient process has been developed for the synthesis of 1-formyl-β-glucopyranosides from D-glucose.

Full text of DOI:10.1016/j.tetlet.2004.08.034

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7761–7763
A convenient new route to protected and free 2,6-anhydro-D-
glycero-D-gulo-heptoses (1-formyl-b-D-glucopyranosides)
*
´ ´
Jennifer Zeitouni, Stephanie Norsikian and Andre Lubineau
´
Laboratoire de Chimie Organique Multifonctionnelle, UMR CNRS-UPS 8614‘Glycochimie Mole culaire’ Bat. 420,
´
Universite Paris Sud, 91405 Orsay Cedex, France
Received 30 June 2004;revised 5 August 2004;accepted 6 August 2004
Abstract—A new and efficient process has been developed for the synthesis of 1-formyl-b-D-glucopyranosides from D-glucose.
Ó 2004 Elsevier Ltd. All rights reserved.
C-Glycosides, in which the exo-anomeric oxygen atom is
replaced by a methylene group, have been the subject of
considerable interest in carbohydrate chemistry and bio-
chemistry. A wide variety of applications1 have been
developed from this class of compounds including their
use as synthetic intermediates for organic synthesis as
well as inhibitors of glycosidases and glycosyltrans-
ferases. In addition they are used as models in enzymatic
and metabolic studies, since it has been shown that the
conformational differences between the O- (or N-) and
C-linked analogues are minimal.2 A number of reliable
methods have been developed for the synthesis of
C-linked disaccharides.3 For example, the coupling
between 1-formyl-C-glycosides and another sugar moi-
ety or an aglycone residue was investigated for the for-
mation of C–C bonds at the anomeric position.4 Many
syntheses of these highly-coveted C-glycosylaldehydes
have been previously described5 but they often afford
an a/b anomeric mixture thus limiting their utilisation.
Moreover, in most cases, yields are modest and, for
the preparation of the most used aldehyde that is
formyl-2,3,4,6-tetra-O-benzyl-b-D-glucopyranoside,5e–g,k,l
they are calculated from 2,3,4,6-tetra-O-benzyl-D-gluco-
pyrolactone, which is commercially expensive and not
readily available.
charides under Barbier-type conditions in water,4d,6
we needed to synthesise formyl-2,3,4,6-tetraacetyl-b-D-
glucopyranoside and formyl-2,3,4,6-tetra-O-benzyl-b-
D-glucopyranoside. In this communication, we wish to
report a new and general method for the preparation
of these two compounds from D-glucose along with
the corresponding unprotected derivative.
Our approach towards the synthesis of sugar aldehydes
is described in Scheme 1. It is based on the utilisation of
b-C-glucosidic ketone 1, which was recently prepared by
our group7 in one-step from D-glucose (96% yield).
Indeed, to the best of our knowledge, this reaction con-
stitutes the most efficient way to selectively form a C–C
bond at the anomeric position of a pyranose. In our
strategy described herein towards various protected for-
myl glucopyranosides, we postulated that, after appro-
priate alcohol protection, enolisation of the resulting
ketone 2 using thermodynamic conditions then oxida-
tive cleavage of the more substituted double bond,
would furnish the desired aldehyde 6.
We started our study with the preparation of formyl-
2,3,4,6-tetraacetyl-b-D-glucopyranoside 6a.5c After acetyl-
ation of 1 (Ac2O, pyridine, 91% yield) to give 2a,8 enoli-
sation was performed under various conditions. We first
carried out the reaction using the conditions described by
Cazeau et al. with the Me3SiCl–NaI–NEt3 reagent.9 The
reaction proceeds very well at room temperature but the
major product obtained was the less substituted enoxysi-
lane 4a. However, when triethylamine was replaced by
pyridine, the reaction led only to the thermodynamic
compound 3a. With this base, the reaction was slower
and was performed at 52°C for 36h to achieve complete
In line with our recent interest in indium-mediated ster-
eoselective syntheses of C-linked glycosides and C-disac-
Keywords: 1-Formyl-b-D-glucopyranosides;C-Glycosides;Enoxysil-
anes;Oxidation;Aminal.
*
Corresponding author. Tel.: +33 (0)1 69 15 68 36;fax: +33 (0)1 69 15
47 15;e-mail: stephnorsikian@icmo.u-psud.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.034

7762
J. Zeitouni et al. / Tetrahedron Letters 45 (2004) 7761–7763
OR
O
RO
RO
3a R = Ac
3b R = Bn
OSiMe3
OR
OH
OR
O
O
RO
a
HO
HO
d
e
+
OH
OH
OR
RO
OR
1 R = H
OH
-glucose
O
O
4a R = Ac
4b R = Bn
RO
D
RO
b
OR
c
2a R = Ac
2b R = Bn
OSiMe3
Ph
OR
OR
OR
OR
O
O
O
O
O
N
RO
RO
f
g
O
i
RO
RO
RO
RO
RO
RO
O
H
H
OR
5 R = Ac
N
OR
6b R = Bn
OR
OR
6a R = Ac
Ph
7a R = Ac
7b R = Bn
h
Scheme 1. Reagents and conditions: (a) pentan-2,4-dione, NaHCO3, H2O (1, 96%);(b) Ac 2O, pyridine (2a, 91%);(c) Ag 2O, BnBr, DMF (2b, 30–
45%);(d) TMSCl, pyridine, NaI, CH 3CN/pentane (1.2/1);(e) i. dimethyldioxirane, K 2CO3, acetone;ii. HCl, H 2O/THF (5);(f) NaIO 4, THF/H2O (6a);
(g) N,N-dibenzylethylene diamine, toluene (7a, 68% from 2a);(h) i. NaOMe, MeOH;ii. NaH, BnBr, DMF ( 7b, 90%);(i) Dowex-H + resin, H2O/THF
(1/1) (6b, 94%).
conversion. The reaction carried out in the biphasic
acetonitrile–pentane medium allowed us to obtain rapid
(12h at 52°C) and more reproducible results.
with NaH in DMF and the cyclic ketal was deprotected
(TFA/H2O). Compound 2b was then submitted to the
enolisation conditions described above11 but the reac-
tion was not as regioselective as for 2a and led to the for-
mation of the thermodynamic product 3b and the
kinetic adduct 4b in a ratio of 90/10. For these reasons,
we decided not to pursue this way and formyl-2,3,4,6-
tetra-O-benzyl-b-D-glucopyranoside 6b was prepared in
a three-step procedure from aminal 7a. After deacetyla-
tion (NaOMe in MeOH) and benzylation with NaH in
DMF, 7b was obtained in 90% yield over two steps.
Deprotection of the aminal with Dowex-H+ resin
led to b-D-linked glucosyl aldehyde 6b, which was
isolated in 94% yield after purification by column
chromatography.
The resulting enoxysilane 3a was then directly engaged
(without purification) in an oxidation reaction with
ozone at À78°C in DCM. Under these conditions, mod-
est yields of the aldehyde were obtained (40–50%). These
results were improved by performing the oxidation in
two steps. The enoxysilane was first transformed into
a-hydroxyketone 5 by a freshly prepared solution of
dimethyldioxirane.10 Further treatment of 5 with sodium
metaperiodate in THF–water provided the desired b-D-
linked glucosyl aldehyde 6a. Due to its instability and to
achieve better purification by column chromatography,
the product was protected and stored as aminal 7a,
which was obtained in 68% overall yield from 2a.
Deprotection with Dowex-H+ resin led quantitatively
to 6a, which can be used directly without further
purification.
The synthesis of aminal 7a also allowed us to prepare
the free aldehyde 6c.5h This was achieved by simple ace-
tate deprotection (NaOMe in MeOH) to 7c, directly fol-
lowed by removal of the aminal function (Dowex-H+
resin). For proof of our obtaining aldehyde 6c, its
hydrated form was allowed to react in a mixture of
water and THF (1/1) in the presence of allyl bromide
and indium. After acetylation of the reaction mixture,
8 was obtained in 85% yield over four steps (Scheme 2).
The synthesis of formyl-2,3,4,6-tetra-O-benzyl-b-D-
glucopyranoside 6b was more challenging since obtain-
ing O-benzylated ketone 2b directly from 1 proved to
be non-trivial. Indeed, the classical benzylation method
(NaH, DMF, BnBr) led to complex mixtures whereas
under milder conditions no reaction was observed. Only
the utilisation of Ag2O in DMF allowed us to obtained
the desired compound 2b. This reaction required large
excess (8equiv) of the expensive Ag2O and gave 2b in
30–45% yield. Nevertheless, 2b could be obtained by
an alternative but longer four-step sequence in 83% yield
from 2a. Ketone 2a was protected with ethylene glycol
in toluene, deacetylated (NaOMe in MeOH), benzylated
In summary, we have reported an efficient strategy for
the preparation of synthetically useful 1-formyl-b-D-
glucopyranosides from D-glucose. Indeed, only five steps
from D-glucose were required to synthesise formyl-
2,3,4,6-tetraacetyl-b-D-glucopyranoside in 59% overall
yield. The use of this new protocol also allowed us to
prepare formyl-2,3,4,6-tetra-O-benzyl-b-D-glucopyrano-
side (nine steps, 50% overall yield from D-glucose)
Ph
OR
OH
OAc
N
b
O
OH
c
OAc
O
RO
O
HO
HO
AcO
AcO
RO
N
OH
OR
OH
OAc
7a R = Ac
6c
8
Ph
a
7c R = H
+
Scheme 2. Reagents and conditions: (a) NaOMe, MeOH (7c);(b) Dowex-H resin, H2O/THF (1/1) (6c);(c) i. allyl bromide, In, H 2O/THF (1/1);
ii. Ac2O, pyridine (8, 85% over four steps).

J. Zeitouni et al. / Tetrahedron Letters 45 (2004) 7761–7763
7763
3. Recent reviews: (a) Postema, H. D. Tetrahedron 1992,
48, 8545;(b) Levy, D. E.;Tang, C. The Chemistry
and 1-formyl-b-D-glucopyranoside (eight steps, 50%
overall yield from D-glucose). Further applications of
the above method for the synthesis of C-disaccharides
will be presented in due course.
of C-Glycosides;Pergamon: Oxford, 1995;(c) Du, Y.;
Lindhart, R. J.;Vlahov, I. R. Tetrahedron 1998, 54,
9913.
4. (a) Kobertz, W. R.;Bertozzi, C. R.;Bednarski, M. D. J.
Org. Chem. 1996, 61, 1844;(b) Dondoni, A.;Boscarato,
A.;Zuurmond, H. Tetrahedron Lett. 1996, 37, 7587;(c)
Dondoni, A.;Zuurmond, H. M.;Boscarato, A. J. Org.
Chem. 1997, 62, 8114;(d) Canac, Y.;Levoirier, E.;
Lubineau, A. J. Org. Chem. 2001, 66, 3206.
5. (a) Dettinger, H.-M.;Kurz, G.;Lehmann J. Carbohydr.
Res. 1979, 74, 301;(b) Reed, L. A.;Ito, Y.;Masamune, S.;
Sharpless, K. B. J. Am. Chem. Soc. 1982, 104, 6468;(c)
Martin, O. R.;Khamis, F. E.;Prahlada Rao, S. Tetrahe-
dron Lett. 1989, 30, 6143;(d) Kobertz, W. R.;Bertozzi, C.
R.;Bednarski, M. Tetrahedron Lett. 1992, 33, 737;(e)
Dondoni, A.;Scherrmann, M.-C. Tetrahedron Lett. 1993,
34, 7319;(f) Lasterra Sanchez, M. E.;Michelet, V.;
Acknowledgements
´
We thank the Universite Paris Sud, the CNRS for fund-
`
ing as well as the Ministere de lÕEducation Nationale et de
la Recherche for a Ph.D. grant (J.Z.).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.08.034. This contains a typical procedure for
the preparation of compounds 2a, 5, 7a, 7b, 8 and
ˆ
Besnier, I.;Gene t, J.-P. Synlett 1994, 705;(g) Dondoni, A.;
their H, 13C and elemental analysis data. H data for
1
1
Scherrmann, M.-C. J. Org. Chem. 1994, 59, 6404;(h)
Petrusova, M.;BeMiller, J. N.;Krihnova, A.;Petrus, L.
Carbohydr. Res. 1996, 295, 57;(i) Dent, B. R.;Furneaux,
R. H.;Gainsford, G. J.;Lynch, G. P. Tetrahedron 1999,
55, 6977;(j) Zhu, Y.-H.;Vogel, P. Synlett 2001, 79;(k)
3a, H and 13C data for 6a, 6c. Procedure for the prep-
aration of aldehydes 6a, 6b and 6c.
1
References and notes
´
`
Labeguere, F.;Lavergne, J.-P.;Martinez, J. Tetrahedron
Lett. 2002, 43, 7271;(l) Dondoni, A.;Marra, A. Tetra-
hedron Lett. 2003, 44, 13.
1. (a) Hanessian, S. Total Synthesis of Natural Products: The
Chiron Approach;Pergamon: New York, 1983;(b)
BeMiller, J. N.;Yadav, M. P.;Kalabokis, V. N.;Myers,
R. W. Carbohydr. Res. 1990, 200, 111;(c) Schmidt, R. R.;
Dietrich, H. Angew. Chem., Int. Ed. 1991, 30, 1328;(d)
Nicotra, F. Top. Curr. Chem. 1997, 187, 55;(e) Wang, J.;
Kovac, P.;Sinay, P.;Glaudemans, C. P. J. Carbohydr.
Res. 1998, 308, 191;(f) Marcaurelle, L. A.;Bertozzi, C. R.
Chem. Eur. J. 1999, 5, 1384.
6. Lubineau, A.;Canac, Y.;Le Goff, N. Adv. Synth. Catal.
2002, 344, 319.
7. Rodrigues, F.;Canac, Y.;Lubineau, A. Chem. Commun.
2000, 2049.
8. Riemann, I.;Papadopoulos, M. A.;Knorst, M.;Fessner,
W.-D. Aust. J. Chem. 2002, 55, 147.
9. Cazeau, P.;Buboudin, F.;Moulines, F.;Babot, O.;
Dunogues, J. Tetrahedron 1987, 43, 2089.
2. (a) Wu, T. C.;Goekjian, P. G.;Kishi, Y. J. Org. Chem.
1987, 52, 4819;(b) Wei, A.;Haudrechy, A.;Audin, C.;
Jun, H. S.;Haudrechy-Bretel, N.;Kishi, Y. J. Org. Chem.
1995, 60, 2160, and references cited therein.
10. Prepared according to: Adam, W.;Bialas, J.;Hadjiara-
poglou, L. Chem. Ber. 1991, 124, 2377.
11. The reaction was carried out at room temperature since
degradation was observed with heating at 52°C.