Direct C-glycosylation by indium-mediated alkynylation on sugar anomeric position

Article abstract of DOI:10.1021/ol7029257

Indium-mediated alkynylation reaction was studied for the direct preparation of C-glycosides. Easily available starting sugar derivatives with an acetyl group at the anomeric position were tested as electrophiles toward alkynylindium reagents under Barbier conditions. Good yields and stereoselectivities were observed during the reaction. The alkynylation was applied to the synthesis of an α-(1-6)-C-disaccharide analogue of isomaltoside.

Full text of DOI:10.1021/ol7029257

ORGANIC
LETTERS
2008
Vol. 10, No. 5
725-728
Direct C-Glycosylation by
Indium-Mediated Alkynylation on Sugar
Anomeric Position
Nade`ge Lubin-Germain,*,† Jean-Pierre Baltaze,‡ Alexis Coste,† Agne`s Hallonet,†
Hugo Laure´ano,† Gre´gory Legrave,† Jacques Uziel,*,† and Jacques Auge´†
Laboratoire de Synthe`se Organique Se´lectiVe et Chimie Organome´tallique, Unite´
CNRS-UCP-ESCOM 8123, 5 mail Gay-Lussac, NeuVille-sur-Oise,
95031 Cergy-Pontoise, France, and ICMMO-UMR 8182 Baˆtiment 420, UniVersite´
Paris-Sud XI, 15 rue Georges Cle´menceau, 91405 Orsay Cedex, France
nadege.lubin-germain@u-cergy.fr
Received December 4, 2007
ABSTRACT
Indium-mediated alkynylation reaction was studied for the direct preparation of C-glycosides. Easily available starting sugar derivatives with
an acetyl group at the anomeric position were tested as electrophiles toward alkynylindium reagents under Barbier conditions. Good yields
and stereoselectivities were observed during the reaction. The alkynylation was applied to the synthesis of an
of isomaltoside.
r-(1f6)-C-disaccharide analogue
Over the last couple of years, indium has been receiving an
increasing interest,1 due to its smooth reactivity and its ease
of use. Even though indium is particularly used in allylation
reactions in polar solvents, we looked into its potential to
catalyze alkynylation reactions of carbonyl compounds under
Barbier conditions2 and investigated new methods3 to prepare
C-glycosides. These nonhydrolyzable carbohydrate isosteres
have become of great interest since they were found to have
potent biological properties and to be useful building blocks.
Thus, we successfully applied this reaction to C-glycosides
synthesis,4 using formylglucoses as electrophiles. We also
demonstrated the possibility of accessing various function-
alized C-glycosides after transformation of the resulting
propargylic alcohols. The creation of the C-C bond by direct
alkynylation, starting from more simple carbohydrate deriva-
tives, represents a significant achievement. Such an alkyny-
lation was previously carried out by the addition of ethy-
nylmagnesium bromide and ethynylaluminium derivatives
on D-glucopyranosyl bromide, which led to byproducts.5
Organotin acetylides which are softer nucleophiles, were also
used with sugar bromides,6 but the application was limited
by the toxicity of tin reagents which need to be prepared
first. As a matter of fact, the most frequently used method
is the addition of an organometallic reagent onto a sugar
lactone.7 The diastereoselectivity is controlled during the
subsequent reduction of the lactol, leading to â isomers. An
alternative to this approach is the addition of organometallic
reagents to glycal epoxides. The control of the anomeric
stereoselectivity is then dependent on the metal.8 As sug-
gested by our previous results on the indium-mediated Ferrier
† University of Cergy-Pontoise.
(5) (a) Zelinski, R.; Meyer, R. J. Org. Chem. 1957, 23, 810. (b) Tolstikov,
G. A.; Prokhorova, N. A.; Spivak, A.; Khalilov, L. M.; Sultamuratova, V.
R. J. Org. Chem. USSR (Engl. Transl.) EN 27, 1991, 10, 1858.
(6) Zhai, D.; Zhai, W.; Williams, R. M. J. Am. Chem. Soc. 1988, 110,
2501.
(7) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976. (b) Lancelin, J.-M.; Amvam Zollo, P. H.; Sinay¨, P. Tetrahedron Lett.
1983, 24, 4833. (c) Dondoni, A.; Mariotti, G.; Marra, A.; Massi, A. Synthesis
2001, 2129. (d) Gomez, A. M.; Uriel, C.; Valverde, S.; Jarosz, S.; Cristobal
Lopez, J. Tetrahedron Lett. 2002, 43, 8935.
‡ University of Paris-Sud.
(1) (a) Nair, V.; Ros, S.; Jayan, C. N.; Pillai, B. S. Tetrahedron 2004,
60, 1959. (b) Auge´, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007, 1739.
(2) Auge´, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett. 2003,
44, 819.
(3) Ousmer, M.; Boucard, V.; Lubin-Germain, N.; Uziel, J.; Auge´, J.
Eur. J. Org. Chem. 2006, 1216.
(4) Picard, J.; Lubin-Germain, N.; Uziel, J.; Auge´, J. Synthesis 2006,
979.
10.1021/ol7029257 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/06/2008

Table 1. Alkynylation of Pyranosyl Carbohydrates
rearrangement,9 we anticipated interesting reactivities of
indium reagents for the anomeric center of peracetylated
sugars.
We first studied this reaction with the â-D-glucopyranose
pentaacetate 1, the most accessible protected carbohydrate.
The conditions determined in our previous works were
followed with an excess of 2.4 equiv of metallic indium.
The substrate disappeared as determined by tlc, leading to a
well-defined spot. After isolation (86% yield) and charac-
terization, the single compound was found to be the cyclic
acetal 2a and not the expected C-glycoside.
quaternary stereogenic center. This compound results from
the addition of the indium acetylenide species to the
acetoxonium intermediate, formed by the participation of the
acetate group in position 2. This participation is well-known
and is generally used for 1,2-trans glycosylation. In fact, it
was already reported by Wyatt10 that, as opposed to the
glycosylation, allenylstannanes in the presence of a Lewis
acid add to the carbenium and not to the anomeric carbon.
Compound 2 presents an H-1 chemical shift of 5.73 ppm
inconsistent with a C-glycoside, but the R configuration was
assigned by analogy with the NMR spectrum described by
Wyatt. The same reactivity was observed with the galactose
pentaacetate 3. In this case, 4 was obtained with good yield
as a mixture of R diastereomers in an 89:11 ratio (Table 1,
entry 2).
Compound 2a was identified as a mixture of two R
diastereomers in a 98:2 ratio resulting from the newly created
(8) (a) Leeuwenburgh, M. A.; Timmers, C. M.; Van der Marel, G. A.;
Van Boom, J. H.; Mallet, J.-M.; Sinay¨, P. Tetrahedron Lett. 1997, 38, 6251.
(b) Leeuwenburgh, M. A.; Overkleeft, H. S.; Van der Marel, G.A.; Van
Boom, J. H. Synlett 1997, 1263. (c) Xue, S.; Han, K.-Z.; He, L.; Guo, Q.-
X. Synlett 2003, 870.
In a second step, we chose to work on 2-deoxycarbohy-
drates to bypass this reactivity. The reaction was conducted
(9) Lubin-Germain, N.; Hallonet, A. Huguenot, F.; Palmier, S.; Uziel,
J.; Auge´, J. Org. Lett. 2007, 9, 3679.
(10) Chan, K. L.; Coumbarides, G. G.; Islam, S.; Wyatt, P. B.
Tetrahedron Lett. 2005, 46, 61.
726
Org. Lett., Vol. 10, No. 5, 2008

Table 2. Alkynylation of Furanosyl Carbohydrates
with tetra-O-acetyl-2-deoxyglucopyranose 5. Starting from
different mixtures of R/â anomers, we showed that the
reaction rate is correlated to the anomeric mixture, i.e., to
the ability to form the oxonium intermediate. The diaste-
reoselectivity is then independent of the composition of the
starting acetate. Therefore, we always observed the single
R-C-glycoside 6 as the major product (Table 1, entry 3). The
same diastereoselectivity was reported with organotin re-
agents.11
fluorinated glucoside 11 was tested as a starting material.
Even if the rate of the reaction increased, the yield
significantly decreased (entry 6). Furthermore, as we dem-
onstrated previously in the indium-mediated Ferrier rear-
rangement,9 a significantly lower yield was observed when
InBr was used instead of indium, due to the formation of
compound 12 (Figure 1). We believe that this compound
could result from a Friedel-Crafts-type reaction, that could
Using an acetonide as the nonparticipating protecting
group, we carried out the alkynylation reaction with com-
pound 7. The C-glycoside 8 was isolated with a moderate
yield but an excellent diastereoselectivity (Table 2, entry 4).
Interestingly, benzyl protected carbohydrates can also be
used in this alkynylation reaction. Despite the decreased
reactivity of these compounds toward organoindium species,
the C-glycoside 10 was obtained with a moderate yield
(60%). With the objective to enhance the reactivity, the
Figure 1. Friedel-Crafts reaction.
be mediated by the Lewis acid character of InBr, leading to
an early oxonium transition state.
(11) Nishikawa, T.; Ishikawa, M.; Isobe, M. Synlett 1999, 123.
Org. Lett., Vol. 10, No. 5, 2008
727

Similar results were obtained with furanosyl compounds
(Table 2). We also observed the participation of the C-2
acetate group with compound 13, whereas the expected
C-glycosylated compounds were obtained with the 2-deoxy-
carbohydrate 1512 or with the acetonides 1713 and 19, both
bearing nonparticipating groups. Compounds 1814 and 2015
were isolated with moderate yields, and the stereochemistry
of the C-glycosides depends on both the C-3 configuration16
and the nature of the protecting group.17 With compound
21, a lack of selectivity was observed, resulting from
equilibrium of the conformations leading to both attacks of
the nucleophile.
disaccharide 25. The stereochemistry of this compound was
confirmed by reference to published data (Figure 2).8a,19
Even if the alkynylation led to â-C-furanosylriboside
(Table 2, entries 2, 3, 5), the reverse anomer could be
obtained with the manno configuration (Table 2, entry 4).
The configuration of the anomeric position of the compounds
1818 and 20 was determined by 2D-NMR spectroscopic
analysis.
Figure 2. Methyl-2-deoxy-R-(1f6)-C-isomaltoside 25 synthesis.
Ultimately, alkynylation conditions were applied to the
synthesis of an R-(1f6)-C-disaccharide analogue of methyl
isomaltoside. In the presence of the benzylated iodoglucopy-
ranoside 23,9 the 2-deoxyglucopyranose 5 led to coupling
product 24 with 53% yield. The single diastereomer obtained
was transformed by treatment under hydrogen in the presence
of Pd/C followed by acetylation leading to the R-(1f6)-C-
In conclusion, we report herein a new access to C-
glycosides from 2-deoxy acetylated carbohydrates using a
new reaction in indium chemistry. For the carbohydrates
bearing an oxygen atom on position 2, nonparticipating
groups such as acetonide or benzyl groups, however, are
required in this new indium-mediated C-glycosylation.
Acknowledgment. This research was supported by the
French Ministry of Research and the CNRS.
(12) Gold, A.; Sangaiah, R. Nucleosides, Nucleotides Nucleic Acids 1990,
9, 907.
(13) Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett 1994,
485.
(14) Fu¨rstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C.
W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061.
(15) Hamamishi, N.; Miyasaka, T.; Arakawa, K. Chem. Pharm. Bull.
1978, 26, 898.
(16) Larsen, C.; Ridgway, B.; Shaw, J.; Smith, D.; Woerpel, K. A. J.
Am. Chem. Soc. 2005, 127, 10879.
Supporting Information Available: General experimen-
tal procedures for reactions; NMR (1H and 13C) characteriza-
tion data for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL7029257
(17) Isobe, M.; Saeng, R.; Nishizawa, R.; Konobe, M.; Nishikawa, T.
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E. T. J. Am. Chem. Soc. 1996, 118, 7671.
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