Table 1 Classification of C-linked disaccharide mimetics
Parent a-linked
disaccharide(s)
Parent b-linked
disaccharide(s)
Compound
4
6
7
9
D
D
D
D
D
D
D
D
D
-Alt-a(1?6)-
D
-Man
-Gul
L
L
L
L
L
L
L
L
L
-Gal-b(1?6)-
D
-Man
-Gal-a(1?6)-
D
-Alt-b(1?6)-
-Tal-b(1?6)-
D-Gul
-Tal
-Tal or
-Gul
-Man or
-Gul
-Man or
-Tal
-All-a(1?6)-
D
-Tal
D
Fig. 1
-Gal-a(1?6)-
D
-Tal or
-Alt-b(1?6)-
D
-All-a(1?6)-
D
-Gul
D
-Tal-b(1?6)-
D
1
2
3
-Gal-a(1?6)-
-Man or
-Alt-b(1?6)-
D
-Alt-a(1?6)-
-All-a(1?6)-
-Alt-a(1?6)-
D
-Gul
-Man or
-Tal
-Gal-b(1?6)-
D
1
D
-Tal-b(1?6)-
D
D
-Gal-b(1?6)-
D
disaccharides are likely to predominantly populate the con-
formation 15 which resembles a b-linked disaccharide formed
from a
D
and an
L
sugar (see Table 1), higher energy
conformations can often be stabilised by complexation with a
carbohydrate receptor.4b The conformations 14 mimic a(1?6)-
linked disaccharides formed from two natural sugars (see Table
1
).
We believe that our work is the first synthesis of C-linked
disaccharides entirely from non-carbohydrate based precursors,
though Vogel has reported the use of a non-carbohydrate based
template to introduce one of the sugar rings.11 Most other
1
2–15
syntheses rely on the coupling of sugar derivatives.
A
particular merit of our approach, which makes it amenable to the
synthesis of libraries of stereoisomeric carbohydrate mimetics,
is that several diastereomeric C-linked disaccharides may be
prepared by minor variation of a general reaction sequence.
There are 136 possible stereoisomeric carbohydrate mimetics
1
4 (ignoring anomers); we have reported the stereoselective
synthesis of five of these mimetics, and their enantiomers could
have been synthesised by using the enantiomeric reagent in the
enantioselective step.
We thank the Leverhulme Trust for a grant to the University
of Leeds, the Royal Society for funds for chiral HPLC
equipment, AstraZeneca and Pfizer for strategic research
funding and Robert Hodgson for helpful discussions.
Notes and references
1
R. Liang, L. Yan, J. Loebach, M. Ge, Y. Uozumi, K. Sekanina, N.
Horan, J. Gildersleeve, C. Thompson, A. Smith, K. Biswas, W. C. Still
and D. Kahne, Science, 1996, 274, 1520.
Scheme 2
2
3
Y. Du, R. J. Linhardt and I. R. Vlahov, Tetrahedron, 1998, 54, 9913.
J. Wang, P. Kovác, P. Sinäy and P. J. Glaudemans, Carbohydr. Res.,
1
998, 308, 191.
4
See: (a) Y. Wang, P. G. Goekjian, D. M. Ryckman, W. H. Miller, S. A.
Babirad and Y. Kishi, J. Org. Chem., 1992, 57, 482; (b) J. F. Espinosa,
E. Montero, A. Vian, J. L. García, H. Dietrich, R. R. Schmidt, M.
Martín-Lomas, A. Imberty, F. J. Canada and J. Jiménez-Barbero, J. Am.
Chem. Soc., 1998, 120, 1309.
Fig. 2
5
(a) R. W. Armstrong and D. P. Sutherlin, Tetrahedron Lett., 1994, 35,
7
743; (b) D. P. Sutherlin and R. W. Armstrong, J. Org. Chem., 1997, 62,
etics. For example, benzoylation of one of the homotopic
alcohols of 3, inversion of the remaining alcohol and hydrolysis,
gave 11 in which the dihydropyran rings had been stereochem-
ically differentiated (Scheme 2). Dihydroxylation of 11, anti to
both of the hydroxy groups8 (Fig. 1) gave the protected
carbohydrate mimetic 12.
5267.
6
7
Y. Kobayashi, M. Kusakabe, Y. Kitano and F. Sato, J. Org. Chem.,
1
988, 53, 1586.
D. J. Aldous, W. M. Dutton and P. G. Steel, Tetrahedron: Asymmetry,
000, 11, 2455.
2
8
9
J. K. Cha, W. J. Christ and Y. Kishi, Tetrahedron, 1984, 40, 2247.
C. Poss and S. L. Schreiber, Acc. Chem. Res., 1994, 27, 9.
More remarkably, the diol 11 could be elaborated in a two-
directional fashion such that the stereochemical outcome of
dihydroxylation was different in each of the rings. The diol 11
has both an axial and an equatorial hydroxy group; the
dihydroxylation of 11 under Donohoe’s conditions (TMEDA,
1
0 T. J. Donohoe, P. R. Moore, M. J. Waring and N. J. Newcombe,
Tetrahedron Lett., 1997, 38, 5027.
11 (a) R. Ferritto and P. Vogel, Tetrahedron: Asymmetry, 1994, 5, 2077;
(b) R. M. Bimwala and P. Vogel, J. Org. Chem., 1992, 57, 2076.
1
2 F. K. Griffin, D. E. Paterson and R. J. K. Taylor, Angew. Chem., Int. Ed.,
1999, 38, 2939.
10
4 2 2
OsO , CH Cl , 278 °C) was directed by the axial alcohol but
1
3 (a) A. Dondoni, H. M. Zuurmond and A. Boscarato, J. Org. Chem.,
occurred anti to the equatorial alcohol (Fig. 1) to give, after
acetylation, the protected disaccharide mimetic 13 in 83%
yield.
1
997, 62, 8114; (b) O. R. Martin and W. Lai, J. Org. Chem., 1993, 58,
1
76.
1
4 W. R. Kobertz, C. R. Bertozzi and M. D. Bednarski, J. Org. Chem.,
996, 61, 1894.
The stereoisomeric compounds 4, 6, 7, 9, 12 and 13 can be
considered to be protected versions of either C-a(1?6)- or C-
b(1?6)-linked disaccharides (see Fig. 2). Although the free C-
1
15 M. H. D. Postema and D. Calimente, Tetrahedron Lett., 1999, 40,
4755.
696
Chem. Commun., 2001, 695–696