SYNTHESES OF POWERFUL ENDOGLYCOSIDASE
INHIBITORS FROM REDUCING DISACCHARIDES
Andreas J. Steiner , Friedrich K. (Fitz) Sprenger, Josef Spreitz,
Tanja M. Wrodnigg and Arnold E. Stütz
Glycogroup, Institute of Organic Chemistry, Technische Universität Graz, Stremayrgasse 16, A-8010 Graz, Austria
INTRODUCTION
Several O-glycosylated derivatives of iminoalditols and
related alkaloids have been found to be powerful glycosidase inhibitors.[1] Syntheses of such compounds have
been based on enzymatic or classical organic-chemical
means of glycoside formation.[2] Examples not relying
on glycoside synthesis have rarely been reported.[3]
Our approach leads to 4-O-0-D-glucopyranosyl-1deoxynojirimycin (2) and 4-O-3-D-glucopyranosyl-1deoxynojirimycin (4) from the corresponding disaccharides D-maltose (1) and D-cellobiose (3) avoiding a glycosylation step (Scheme 1).
OH
OH
H
N
O
RO
RO
HO
OH
OH
HO
OH
2 R = -D-glucopyranosyl
4 R = -D-glucopyranosyl
1 R = -D-glucopyranosyl
3 R = -D-glucopyranosyl
Scheme 1
SYNTHESIS
Starting from D-maltose (1) acid-catalyzed treatment
with methanol furnished the anomeric mixture of both
methylglycosides. After the regioselective introduction of
a benzylidene protecting group at C-4’ and C-6’ the 6deoxy-6-iodo-compound was created.[4] Acetylation of
the four remaining hydroxyl-functions and subsequent
elimination lead to the corresponding 5-enopyranoside.
Ph
OH
O
O
RO
O
HO
R =
Ph
HO
- D -glucopyranosyl
O
HO
HO
O
O
HO
OH
O
O
O
I
HO
OH
OH
1
O
Ph
O
O
HO
O
OH
A cO
A cO
O
O
A cO
O
O
OA c
OH
OH
O
HO
OH
HO
H
N
HO
O
O Me
HO
OH
2
O Me
The 5-ulosugar was created by epoxidation of the double bond followed by Zemplén saponification and acidcatalyzed hydrolysis of the epoxide.[5] Finally intramolecular reductive amination and simultaneous
cleavage of the protecting group [H2O/NH3 (1:1),
Pearlman-catalyst, H2 (1bar)] furnished the desired
product 2 (Scheme 2).[6]
4-O-3-D-Glucopyranosyl-1-deoxynojirimycin (4) was
prepared in the same way starting from methyl-3-Dcellobioside which was obtained from D-cellobiose (3) in
three steps.
CONCLUSION
Our new synthesis allows access to 4-O-0-Dglucopyranosyl-1-deoxynojirimycin (2) and 4-O-3-Dglucopyranosyl-1-deoxynojirimycin (4) from D-maltose
(1) and D-cellobiose (3), respectively in 9 and 11 steps
with fair overall yields of 8 to 10 percent. The described
synthesis can also be applied to other disaccharides
(e.g. D-lactose).
ACKNOWLEDGEMENT
Synthetic studies were kindly supported by the Austrian Fonds
zur Förderung der wissenschaftlichen Forschung (FWF), Project P 15726-N03.
REFERENCES
[1] A. E. Stütz (Ed.), Iminosugars as Glycosidase Inhibitors,
1999, Wiley-VCH: Weinheim.
[2] see for example: Y. Ezure, S. Maruo, N. Ojima, K. Konno,
H. Yamashita, K. Miyazaki, T. Seto, N. Yamada, M. Sugiyama, Agric. Biol. Chem., 1989, 53 , 61-68; N. Asano, K.
Oseki, E. Kaneko, K. Matsui, Carbohydr. Res., 1994, 258,
255-266; M. Kiso, H. Furui, A. Hasegawa, J. Carbohydr.
Chem., 1992, 11, 627-644.
[3] F. D’Andrea, G. Catelani, M. Mariani, B. Vecchi,
Tetrahedron Lett., 2001, 42, 1139-1142.
[4] P. J. Garegg, B. Samuelsson, J. Chem. Soc., Perkin
Trans.1, 1980, 2866-2868.
[5] P. M. Enright, M. Tosin, M. Nieuwenhuyzen, L. Cronin, P.
V. Murphy, J. Org. Chem., 2002, 67, 3733-3741.
[6] R. H. Furneaux, G. J. Gainsford, G. P. Lynch, S. C. Yorke,
Tetrahedron, 1993, 49, 9605-9612; E. W. Baxter, A. B.
Reitz, Bioorg. Med. Chem. Lett., 1992, 2, 1419-1422.
Scheme 2
E-Mail: [email protected]
www.orgc.tugraz.at/orgc/glycogroup