Selective Synthesis of r-C-(Alkynyl)-galactosides by an Efficient
Tandem Reaction
Ste´phane Guillarme, Karen Ple´,† and Arnaud Haudrechy*
Laboratoire de Glycosynthe`se, UMR 6519, UFR Sciences Exactes et Naturelles, Baˆt. 18, BP 1039,
51687 Reims Cedex 2, France, and CNRS FRE 2715 Isolement, Structure, Transformations et Synthe`se de
Substances Naturelles, IFR 53, UFR Pharmacie, Baˆt. 18, BP 1039, 51687 Reims Cedex 2, France
arnaud.haudrechy@uniV-reims.fr
ReceiVed September 21, 2005
Several R-C-(alkynyl)-galactosides were synthesized using a tandem reaction involving the addition of
a metal alkynylide to a chiral acyclic epoxyaldehyde, followed by an in situ closure of the generated
alkoxide on the epoxide function.
Introduction
C-glycoside analogue, that of KRN 7000, has been recently
described to show a biological activity better than that of the
corresponding O-glycoside.4
Carbohydrates are important constituents of glycoproteins and
glycolipids that are involved in numerous biological processes.1
Unfortunately, the use of carbohydrate-based molecules as
therapeutics is limited because of the hydrolytic lability of the
glycoside bond. Replacing the anomeric oxygen atom with a
methylene group leads to more stable C-glycoside analogues
with higher chemical and enzymatic stability. These compounds
can be used as tools to study the role of the carbohydrate moiety
in biological processes and to design potential drugs. As a result,
it is not surprising that C-glycoside analogues have gained
considerable attention in the past 2 decades, and to date
numerous methods have been described for their synthesis.2 In
the literature, biological activity of C-glycoside analogues is
generally described to be similar or lower than the parent
O-glycoside. For example, Kishi et al. reported that the
replacement of the anomeric oxygen atom with a methylene
group did not significantly diminish the biological activity of
the H-type II blood group trisaccharide, as a result of the similar
solution conformation of the C-trisaccharide compared to the
O-one.3 To the best of our knowledge, only one example of a
The development of effective C-glycoside syntheses depends
on the selective formation of only one anomer as the major
reaction product in good to excellent yield. As part of an ongoing
program aimed at developing the synthesis of R-C-glycoside
analogues of complex bioactive glycosides, we report herein
an efficient method to selectively access R-C-(alkynyl)-ga-
lactosides from an acyclic carbohydrate. Syntheses of R-C-
(alkynyl)-galactosides have increased in the past decade because
they are attractive building blocks for the synthesis of galac-
tosides analogues.5 To the best of our knowledge, no synthesis
of R-C-(alkynyl)-galactosides from an acyclic carbohydrate has
been previously reported.
Results and Discussion
Our strategy is based on a one-pot, two-step sequence
involving the addition of a metal alkynylide to the open chain
epoxyaldehyde 1, followed by intramolecular epoxide opening
(3) Wei, A.; Boy, K. M.; Kishi, Y. J. Am. Chem. Soc. 1995, 117, 9432-
9436.
(4) Yang, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Angew. Chem., Int.
Ed. 2004, 43, 3818-3822.
(5) (a) Leteux, C.; Veyrie`res, A. J. Chem. Soc., Perkin Trans. 1 1994,
2647-2655. (b) De´sire´, J.; Veyrie`res, A. Carbohydr. Res. 1995, 268, 177-
186. (c) Leeuwenburgh, M. A.; Timmers, C. M.; van der Marel, G. A.; van
Boom, J. H.; Mallet, J. M.; Sinay¨, P. G. Tetrahedron Lett. 1997, 38, 6251-
6254. (d) Dondoni, A.; Mariotti, G.; Marra, A. J. Org. Chem. 2002, 67,
4475-4486. (e) Chen, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Org. Lett.
2004, 6, 4077-4080. (f) Toba, T.; Murata, K.; Yamamura, T.; Miyake, S.;
Annoura, H. Tetrahedron Lett. 2005, 46, 5043-5047.
* To whom correspondence should be addressed. Tel: 33(0)326913236.
Fax: 33(0)326913166.
† CNRS FRE 2715.
(1) Dwek, R. A. Chem. ReV. 1996, 96, 683-720.
(2) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599. (b)
Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca Raton, 1995.
(c) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon:
Tarrytown, NY, 1995. (d) Togo, H.; He, W.; Waki, Y.; Yokoyama, M.
Synlett 1998, 700-717. Smoliakova, I. P. Curr. Org. Chem. 2000, 4, 589-
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10.1021/jo0519817 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/05/2006
J. Org. Chem. 2006, 71, 1015-1017
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