S. Fort et al. / Tetrahedron Letters 42 (2001) 3443–3446
3445
OH
O
OTf
OBn
O
HO
OBn
O
OMe
d
a
HO
HO
R
OMe
OMe
BnO
BnO
N
OH
OBn
OBn
2
OH
3 R = CN
4 R = CH2NH2
1
HO
OH
O
HO
OH
O
OBn
OTBDMS
O
c
b
BnO
BnO
OH
BnO
OBn
BnO
O
OMe
6
7
5
Scheme 1. Synthesis of the imino-disaccharide 1. Conditions: (a) (i) Bu4NCN, toluene (43%), (ii) LiHBEt3 (15 equiv.), THF (43%);
(b) (i) Ac2O, H2SO4 (cat.) (ii) MeOH/MeONa (71% overall); (c) NaIO4, H2O/MeOH; (d) (i) NaBH3CN, AcOH, MeOH (62%),
(ii) H2, Pd/C, MeOH, HCl (51%).
competitive inhibitor (Ki 200 mM). In comparison, cel-
lobiose, the major reaction product of cellulose hydroly-
sis by Cel7B, inactivates Cel7B to a lesser extent (Ki
900 mM).25 The Ki observed for 1 is similar to the one
observed for a thio-trisaccharide substrate analogue.26
6. Sulzenbacher, G.; Driguez, H.; Henrissat, B.; Schu¨lein,
M.; Davies, G. J. Biochemistry 1996, 35, 15280–15287.
7. Tews, I.; Perrakis, A.; Oppenheim, A.; Dauter, Z.;
Wilson, K. S.; Vorgias, C. E. Nat. Struct. Biol. 1996, 3,
638.
8. Davies, G. J.; Mackenzie, L.; Varrot, A.; Dauter, M.;
Brzozowski, A. M.; Schu¨lein, M.; Withers, S. G. Bio-
chemistry 1998, 37, 11707–11713.
9. Zou, J.-y.; Kleywegt, G. J.; Stahlberg, J.; Driguez, H.;
Nerinckx, W.; Claeyssens, M.; Koivula, A.; Teeri, T. T.;
Jones, T. A. Structure 1999, 7, 1035–1045.
10. Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon Press: Oxford, UK, 1983.
11. Lorthiois, E.; Meyyappan, M.; Vasella, A. Chem. Com-
mun. 2000, 1829–1830.
In conclusion, we have reported the rational design and
the synthesis of the first C-linked imino-disaccharide
cellulase inhibitor 1. This inhibitor exhibits two features
expected to contribute to binding to cellulase active
sites at the time of formation of the Michaelis complex:
(1) a 1-N-imino linkage that when protonated should
interact with the nucleophile via an ion-pair, and (2) an
axial glycosidic-like bond to an ‘aglycon’ to mimic
substrate distortion. An extension of this methodology
to the synthesis of an iminocyclitol motif into higher
oligomers may be beneficial for glycoside hydrolase
inactivation by increasing the affinity of the ligand in
cellulases.
12. Dowd, M. K.; French, A. D.; Reilly, P. J. Carbohydr.
Res. 1992, 233, 15–34.
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1997, 27, 235–248.
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15. Allinger, N. L.; Rahman, M.; Lii, J. H. J. Am. Chem.
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Acknowledgements
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This work was supported by CNRS and the European
Union (Eurocell BIO4-CT97-2303). We are grateful to
Dr. J. K. Fairweather for useful discussions.
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24. Data for 1: [h]D −12.9 (c 0.49, H2O); 13C NMR (100
MHz, pyridine-d5; 348 K): l 105.54 (C-1), 78.45 (C-5),
76.65 (C-2), 76.22 (C-3), 72.20 (C-4%), 70.26 (C-3%), 64.50
(C-6), 63.07 (C-6%), 59.34 (C-7), 57.80 (C-2%), 53.62 (C-7%),
1
42.64 (C-4), 41.05 (C-5%); H NMR (400 MHz, pyridine-